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TNM分期对于远期预后的影响是毋庸置疑的，但术后短期内出现的预后不良事件在发生机制上似乎与远期预后不良有些差异。它多为术前业已存在常规检查却无法发现的微转移，或是由于肺癌高凝状态引起的血栓事件，而病理分期对于上述机制几乎无法评估。如果术前常规检查判断适合手术，则提示根据TNM分期与预后的关系，术后短期内不该出现预后不良事件，起码概率很低。但事实上临床上的确存在这样的小概率事件，并且还往往是医疗纠纷的根源。对此，经典的TNM分期体系几乎无能为力。而根据我们的结果，DD可以判断手术后短期预后不佳。它独立于TNM分期体系，是其有益的补充。本组肺癌Ⅱ期患者中18%（4/22）和Ⅲ期患者中38%（7/18）术后1年内出现预后不良事件，无法从手术中获益。如果使用术前DD来判断，可以预测全体NSCLC患者中79%的不良预后事件。结合特异性、阳性预测值和阴性预测值，对于早期（Ⅰ期、Ⅱ期）腺癌，DD的预判效果最佳，而中晚期（Ⅲ期）腺癌预判效果最差，鳞癌介于两者之间。目前最大一项评估DD在肺癌中意义的研究结果提示在早期肺癌和腺癌患者中DD预测效率更高。而本研究中DD在中晚期腺癌中的预测效率却很低，两研究结果有明显差异。分析原因，首先本研究病例数太少，结果需要更大样本量证实，其次东方人和高加索人在肺腺癌基因突变的差异也应该被考虑。
ATPA (1 µm) application robustly increased sIPSC frequency in neonatal (5.415 ± 0.983 times, p < 0.0001; paired t-test) and juvenile (3.368 ± 0.598, p = 0.008) control mice (Fig. 2Ai, ii, B), confirming previous results [22, 23]. Notably, ATPA effect was gradually diminishing with age in accordance with the declining expression of GluK1 towards the adulthood. In adult animals, ATPA increased sIPSC frequency, yet this effect did not reach statistical significance (2.589 ± 0.521 times, p = 0.081, paired t-test; Fig. 2Aiii, B). In Gad-Grik1−/− mice, ATPA had no effect on sIPSC frequency neither in neonates nor in the juvenile animals, but surprisingly, caused a slight increase in sIPSC frequency in adults (1.572 ± 0.258 times, p = 0.029, paired t-test; Fig. 2 Ai-iii, B). These observations confirm that GluK1 activation in the hippocampal interneurons efficiently recruit GABAergic drive, particularly at earlier developmental stages.Fig. 2Pharmacological characterization of spontaneous synaptic activity in Gad-Grik1−/− mice. A Example traces of recordings from neonatal (i and iv), juvenile (ii) and adult (iii) control (left columns) and Gad-Grik1−/− (right columns) slices, before (baseline) and during ATPA (i, ii, iii) or ACET (iv) application. B Pooled data illustrating the effect of ATPA (1 µM) on sIPSC frequency in CA3 pyramidal cells from acute control and Gad-Grik1−/− slices at different stages of development (neonatal: n = 14 (10) and 10 (10); juvenile: n = 10 (10) and 8 (7); adult: n = 5 (5) and 6 (6), for control and Gad-Grik1−/−, respectively). C Effect of ATPA on sEPSC frequency, for the same cells as in B. D Effect of ACET (200 nM) on the frequency of sEPSCs and sIPSCs in neonatal control and Gad-Grik1−/− slices (n = 13 (N = 10) and 7 (6), for control and Gad-Grik1−/−, respectively). Bars represent mean ± SEM. Frequency of events is normalized to the baseline (dashed line). Activity during ATPA / ACET application is compared to the baseline by paired t-test or Wilcoxon paired test. **p < 0.0001; p < 0.001; p < 0.01; p < 0.05
Frequency score distribution (A) E_score (only values higher than 0 are shown; N = 2546); (B) P_score (only values higher than 0 are shown; N = 21667); (C) correlation between P_score and E_score. The solid red line represents the best linear fit to the data with R2 = 0.67 (p < 0.001).
Regarding the 9 patients without cholesteatoma, reader 1 negatively diagnosed all 9 patients with tseDWI and topupDWI, leading to specificities of 100% (95% CI: 66–100%). In addition, 8/9 patients were correctly classified as negative by rsDWI, yielding a specificity of 89% (95% CI: 52–100%). On the other hand, reader 2 correctly classified all 9 patients without cholesteatoma with rsDWI, topupDWI, and tseDWI, leading to specificities of 100% for all three modalities (95% CI: 66–100%). Therefore, due to the high number of correctly diagnosed patients without cholesteatoma in all three modalities for both readers, McNemar’s test is not reasonably applicable in this situation.
PCA was performed on spectra obtained from five different multidonor batches of ASCs. A total of 15 spectra were acquired from each ASC batch at each time point for a total of 75 spectra at each time point, data was then averaged using one spectrum from each ASC batch per time point which were then used for PCA. Figure 2 is a two‐dimensional (2D) scatter plot of PC1 and PC2 scores accounting for 99.3% and 0.3% of the variation in the data set, respectively. There was a clustering of all the spectra from ASCs in basal culture and the majority of the spectra at days 0 and 3 from the adipo‐induced ASCs (boxed in the figure). However, spectra from adipo‐induced ASCs at days 7, 10, and 14 clearly cluster away from this and from one another. This resulted in two trends, firstly in PC1 from Day 0 to 14, secondly in PC2 from Day 0 to 7 and then Day 7 to 14.
Cette classification dite classification de Clavien-Dindo divise les CPO de grade I à grade V, selon le besoin de traitement: Grade I: tout écart par rapport à une évolution postopératoire normale, sans aucun besoin de traitement chirurgical, endoscopique, radiologique ou médical, débridement d'abcès de paroi au lit du malade traitement autorisés: antiémétiques, antipyrétiques, analgésiques, diurétiques, électrolytes et kinésithérapie; Grade II: nécessité de traitements pharmacologiques autres que ceux autorisés ci-dessus; Indication de transfusion ou de nutrition parentérale totale. Grade III: Complication nécessitant un traitement chirurgical, endoscopique ou radiologique: gradeIIIa: sous anesthésie locale, gradeIIIb: sous anesthésie générale; Grade IV: complications menaçantes, y compris neurologiques centrales; indication d'USI (unité de soins intensif): gradeIVa: défaillance d'un organe (y compris dialyse), gradeIVb: défaillance multi-viscérale; Grade V: Décès. L'applicabilité, la simplicité et la variabilité inter-observatrice de ce système de classification révisé a été validée concomitamment dans une grande étude de cohortes . La classification Clavien-Dindo est maintenant largement adoptée et utilisé dans la littérature sur la chirurgie lourde [3, 12]. C'est donc afin d'obtenir des résultats objectifs sur l'activité de notre service de chirurgie générale durant sept mois, que nous avons mené ce travail. Le but de cette étude est d'évaluer le bilan global de notre pratique hospitalière par l'étude de la fréquence des aspects cliniques des complications post opératoires survenues dans le service de chirurgie générale du centre hospitalier de Nouakchott (CHN) pendant une période de sept mois (1er janvier 2017-au 31 juillet 2017) . Dans cette étude nous rapportons l'applicabilité de la Classification de Clavien-Dindo dans la pratique chirurgicale en Mauritanie.
Within a feminist disability framework, understandings such as these control differentiation and highlight hiddennorms of which bodies of people with disability arenot part of (Garland-Thomson 2002). Furthermore, these understandings perpetuate the characterisation of the people with disabilities as inadequate, redundant or restrained (Garland-Thomson 2002).
La investigación en salud es reconocida como una herramienta para mejorar la salud y la equidad en las poblaciones, así como un catalizador del desarrollo socioeconómico (1–4). Las necesidades de investigación en salud en un contexto específico y los potenciales beneficios de ésta son amplios y variados; no obstante, los recursos disponibles para su ejecución son limitados en cualquier escenario, particularmente en países de bajos y medianos ingresos (5).
There is evidence that some countries such as the US and the Netherlands have ongoing initiatives aimed at tackling health determinants in their populations. It is yet to be seen how successful these programs would be if specific attention is not given to re-engineering public health systems. Increasing healthcare coverage is yet another important way of improving population health and its distribution. This is particularly important for the US where coverage is still a big problem.
The mean annual effective doses resulting from the radon gas in different floors of dwellings in Shabestar County are shown in Table 4. The results comparison with data obtained from other parts of the country (See Table 1) suggests that the average mean value for Shabestar County is less than the calculated mean effective dose rates for other parts of Iran (2.6 ± 2.4 mSv.y−1).Table 4Indoor radon concentration and their respective doses at different floor.Table 4Rn concentration (Bq/m3)DT)mSv/y(1 st floorBedroom60.411.52Living room52.141.32Average60.891.542nd and upper floorsBedroom56.651.43Living room51.581.3Average41.151.04
A farmacoterapia de pacientes com insuficiência cardíaca é complexa e abrange medicamentos de várias classes terapêuticas. Além disso, as múltiplas comorbidades que os idosos apresentam aumentam ainda mais a complexidade do regime medicamentoso. Regimes medicamentosos complexos estão associados com má adesão ao tratamento,21 , 22 polifarmácia21 , 23 e hospitalização por eventos adversos.24 A descompensação aguda da insuficiência cardíaca é um importante determinante da busca por departamentos de emergência.25 , 26 A não adesão devido à complexidade da farmacoterapia ou o uso incorreto de medicamentos podem contribuir para a descompensação aguda da insuficiência cardíaca.27 Escores elevados do MRCI na alta hospitalar fornecem avaliação mais global do risco associado com o regime medicamentoso complexo. Pacientes com valores mais elevados de MRCI apresentam maior probabilidade de adoecer e apresentar mais resultados negativos.21 , 24 Esses fatores podem explicar a associação positiva entre visita a departamentos de emergência, insuficiência cardíaca e complexidade da farmacoterapia elevada.
CPP screening and selection process. (a) Selection begins with a T7 phage library displaying a fusion of a cargo (in this example, an EGFR receptor binding domain, EBD), an Avitag and Phylomer peptides; (b) Avitagged-Phylomer sequences with potential for CPP activity are internalized into cells; this uptake can also be facilitated by binding to specific cell types via a cell surface receptor (CSR) and uptake into endosomes by receptor-mediated endocytosis; (c) peptides with capacity for cytosolic delivery allow the phage to enter the cytoplasm; (d) selection is performed in mammalian cells expressing the bacterial biotin ligase BirA in the cytoplasm, which ligates free biotin to the lysine residue of the phage-displayed Avitag sequence; this step produces selectively labeled T7 phage that have internalized into the cytoplasm by virtue of the CPP; (e) sodium pyrophosphate (PPi), a specific inhibitor of BirA, is added to the cells to terminate the biotinylation reaction; (f) cells are lysed and streptavidin-coated magnetic beads (SAV) are added to the lysate to selectively capture and concentrate biotinylated T7 phage. Enriched phage are then amplified in E. coli and subjected to further rounds of selection. Identification of specific CPPs is achieved by deep sequencing of early selection rounds or by Sanger-sequencing of individual phage clones after 3–4 rounds of selection.
Накопление каротинов в зерне, особенно β-каротина, обуславливает изменение интенсивности окраски семоли- ны от желто-оранжевого до красноватого оттенка. Ксан- тофиллы обеспечивают желто-оранжевую окраску крупки и макарон. Схема биосинтеза каротиноидов показана на рисунке. Исходным веществом для биохимического син- теза каротинов служит 5-углеродный (С-5) изопреноид – изопентилпирофосфат. Конденсация этого изопреноида представляет собой основу для образования геранил- геранилпирофосфата (С-20). В результате соединения двух молекул геранилгеранилпирофосфата при участии фермента фитоенсинтетазы образуется фитоен (С-40) – первое промежуточное вещество в биосинтезе каротинов. Этот этап является ключевым – скорость биосинтеза и на- копления фитоена влияет на весь пул каротиноидов (Cazzonelli, Pogson, 2010; Ke et al., 2019). Фитоен в результате десатурации под действием ферментов фитоендесатуразы (PDS), z-каротиндесатуразы (ZDS), каротинизомеразы (CRTISO) и последовательного удаления четырех атомов водорода превращается в ликопин. Ликопин – каротиноид, определяющий красную и оранжевую окраску плодов, – исходное вещество для синтеза α-каротина/лютеина (класс ксантофиллов) – главного каротиноида зерна твердой пшеницы и β-каротина/зеаксантина (класс ксантофил- лов) – главного компонента каротиноидных пигментов в зерне кукурузы (Zhang, Dubcovsky, 2008). Дальнейшее гидроксилирование α-каротина приводит к образованию желтого зейоксантина и лютеина. Трансформация β-каротина продуцирует образование β-криптоксантина, зеа- ксантина, антраксантина, виолаксантина и неоксантина. Эти реакции катализируются двумя негемовыми β-каротингидроксилазами (ВСН1 и ВСН2) и двумя гемгидроксилазами (CYP97A и CYP97C) соответственно (Sun et al., 2018). Последняя фаза биосинтеза каротиноидов, катализируемая неоксантиноксидазой (NXS), заключается в превращении виолаксантина в неоксантин. Окисление виолаксантина и неоксантина приводит к образованию ксантоксина, превращаемого в растительный гормон – абсцизовую кислоту (ABA), которая способствует регу- лярному и сбалансированному накоплению пигментов в растениях и формированию устойчивости к абиотическим стрессам (Al-Babilli, Bowmeester, 2015; Nisar et al., 2015). Еще одна ветвь трансформации β-каротина представляет превращение его под действием ферментов диоксигеназ- ной группы (CCD7, CCD8, CYP711A1) в стриголактоны – ингредиенты гормональной природы, регулирующие развитие и ростовые процессы растений (Colasuonno et al., 2019).
where W(t) and L(t) are win and loss functions, respectively. The PVL model builds on the EV model, and it uses the prospect-utility function, which is a non-linear utility function from Prospect theory proposed by Tversky and Kahneman (1992). Unlike the EV model, the expectancies of unchosen options are also discounted in the PVL model. The PVL model has four free parameters: shape parameter α, loss aversion parameter (λ), recency parameter (A), and consistency parameter (c). The α parameter determines the shape of the utility function. The λ parameter determines the attention weight toward losses or rewards. The A parameter indicates the effect of recency of outcomes. The c parameter determines the amount of exploration vs. exploitation in decision making.
肺癌另一常见的基因突变则为ALK融合。ALK融合患者可通过PI3K-AKT及MEK-ERK通路减少新抗原的产生，增加免疫抑制细胞的数量，导致免疫单药治疗效果不佳[12, 13]。KRAS基因同样是肺癌发生的驱动基因，KRAS基因突变在白种人中的发病率较高，约为30%。KRAS突变可通过调节PD-L1 mRNA 3’UTR区的稳定性，上调PD-L1表达促进免疫逃逸。但是对于免疫检查点抑制剂，KRAS却表现出了良好的反应性。在一项单中心回顾性研究中，纳入了25例KRAS突变和47例野生型，予以Nivolumab±抗CTLA-4抗体，两组的中位总生存时间（overall survival, OS）分别为18.1个月 vs 8.1个月（HR=0.48, P=0.04）。究其原因，可能是由于KRAS突变上调新抗原的表达并改变了细胞周期调控、DNA复制及DNA修复等一系列基因，但是没有明显的活化免疫抑制细胞作用。
The wind data were obtained from the ERA-interim reanalysis provided by the European Center for Medium-range Weather Forecast (ECMWF) for the North-East Atlantic (29 °N–51 °N, 20 °W–10 °W) (freely available at http://apps.ecmwf.int/datasets/, data downloaded on 12 June, 2013)
The surgeon viewed the robot using video from a monocular camera located at the remote site. This image was transmitted over the internet and displayed on a large overhead monitor at the local site (Fig. 2c). The camera used was a SONY NX5R, producing a 1080i50 10bit 4:2:2 uncompressed video feed through a 3 G SDI output. This was captured by a video grabber card (Blackmagic DeckLink DUO 2 mini) on a local workstation and was compressed to 1080p25 using the H264 codec, with a variable bitrate of 1.5–2 Mbps. This was performed using hardware encoding with the NVIDIA Encoder (NVENC) on a QUADRO P620 graphics card. The feed was then streamed over the internet to the surgeon’s site using a commercial video streaming service (Zoom). The required bandwidth was 2Mbps. The average latency to the Zoom server was 25 ms. Overall end-to-end latency, from the patient side to the surgeon side, was 250 ms on average.
To test this idea and help relate the mechanism of the two helicases, the single turnover ATPase measurement for PcrA was repeated with a fluorescent ATP analog whose diphosphate has much tighter binding to the protein and so would remain bound under the experimental conditions. In this case (Fig. 10B), a second fluorescence phase was observed with PcrA, equivalent to that with RecD2. In other words, this shows that PcrA may have a similar mechanism at this stage of the cycle. The importance of this pre-cleavage conformation change is highlighted by the fact that it is this step that is rate-limiting and, therefore, controls progression of the whole cycle. This suggests that, despite the different polarities of movement, RecD2 and PcrA have similar ATPase mechanisms.
Schematic preparation of the (a) fluoroPOS@silica nanoparticles and b POA/fluoroPOS@silica coatings. “d” in (b) is the mean distance between protrusions. c, d Surface and (e) cross-sectional scanning electron microscopic (SEM) images of the coating. f Fourier transform infrared (FTIR) spectrum of POA/fluoroPOS@silica. g X-ray photoelectron spectrum (XPS) and (h) high-resolution C 1s spectrum of the POA/fluoroPOS@silica coating.
HFNC therapy presents certain advantages over NIV. It is probably easier to apply, it needs less equipment, and it generates lower workloads. Importantly, it is more comfortable for the patient and is better tolerated and does not seem to be inferior in terms of clinical outcomes in patients with hypoxemic respiratory failure. However, HFNC therapy may not be indicated in all patients with ARF . Currently, NIV should still be considered as a first-line treatment in a variety of clinical situations, such as hypercapnic respiratory failure during COPD exacerbations or ACPE . In fact, as HFNC therapy generates only slight increases in airway pressure at end expiration, it is unlikely to reduce the work of breathing as effectively as NIV. Therefore, NIV appears to be more effective in patients who are more severely affected. Finally, at centers with substantial experience treating hypoxemic ARF with NIV, decisions on the strategy to use should be individualized.
Positive changes were strongly linked with feeling supported by other women in the group process. A feeling of connection with other women was cited as extremely important. For many women in the group, this was a new experience. They felt less alone in their addiction and in their feelings. The group offered a supportive environment to both learn new gambling related information and coping strategies and also provide a safe space to discuss other pertinent issues connected to gambling. The group social support and sharing was crucial to enhancing a sense of wellness.“I haven’t felt isolated or alone for quite a while. Listening to other participant’s stories and struggles reminds me I am not alone. I don’t have to die of shame off in a corner. During the group, I was comfortable to say what was true for me and hopefully I can stay connected with the group members” (Participant #709).
微管蛋白分为α、β2个亚型，为细胞骨架的重要组成部分，它担任着维持细胞形态、进行物质交换、传递信息以及参与有丝分裂等重要功能。紫杉醇可以促进微管蛋白装配成微管，但抑制微管的解聚，从而导致微管束的排列异常，形成星状体，使纺锤体失去正常功能，导致细胞死亡。最近的一项多中心随机研究显示采用吉西他滨/cDDP、长春瑞滨/cDDP和紫杉醇/卡铂治疗NSCLC患者在疾病进展时间（time to progression, TTP）方面无差别。这些药物主要的耐药机制是特定微管蛋白的基因多态性或同型过度表达，特别是氨基酸残基1-31和217-233，它们在紫杉醇与微管蛋白的结合过程中发挥着重要作用，而在结合位点附近的突变，如β-微管蛋白的Thr274Ile和Arg282Gln，可能与耐药产生有关。因此，微管蛋白序列变异分析和同型抗原表达测定对评估紫杉烷类疗效非常重要。β-微管蛋白CLASS1突变已经在NSCLC患者中被发现：49例NSCLC患者中有33%被检测到该突变，对紫杉醇治疗均无反应。β-Ⅲ微管蛋白同种型表达上调是耐药产生的另一重要原因，β-Ⅲ微管蛋白浓度增高与紫杉醇类药物的敏感性降低相关。在紫杉醇/卡铂组的患者中β-Ⅲ微管蛋白低水平可以获得更好的疗效，并且β-Ⅲ微管蛋白表达水平和TTP也有相互关联的趋势。
The present study was associated with several limitations. First, this study was a monocentric study based on a retrospective analysis. Second, the sample size was relatively small. Third, higher surgical difficulty may potentially affect the quality of TME or pathological CRM and thus impairs the oncological outcome and survival . Since the present study aimed to identify predictors of surgical difficulty of LaTME in male patients after NCRT, we did not evaluate oncological factors, which could be a limitation of our study. Fourth, our predictive nomogram required further validation in other independent patient cohorts. Despite these limitations, the present study might add to the understanding of the predictive value of MRI-based pelvimetry when estimating the surgical difficulty of LaTME in male LARC patients after NCRT.
In the epicardial layer, over 70 % of the patients had a moderate to pronounced amount of adipose tissue (Fig. 1f and i). There was no significant difference between the two groups. No adipose tissue was observed in the myocardium or the endocardium (Table 5). There was no relationship between the amount of epicardial adipose tissue and epicardial ICIs, body mass index, and inflammatory markers in serum (CRP, pentraxin 3, and ESR). Nor was there a relationship between the amount of epicardial adipose tissue and the amount of collagen in the myocardium.Table 5The amount of adipose tissue in the cardiac layers, per sectionIRD (n = 48)Non-IRD (n = 40) p ValueEpicardium None3 (12)1 (4)0.55 Little3 (12)6 (25) Moderate16 (64)2 (63) Pronounced3 (12)2 (8)Myocardium None42 (98)40 (100)1.00 Little1 (2)0 (0) Moderate and pronounced0 (0)0 (0)Endocardium None26 (74)25 (83)0.38 Little9 (26)5 (17) Moderate and pronounced0 (0)0 (0) IRD Inflammatory rheumatic diseaseValues are the number (percentage) of patients. Owing to missing data for some variables, numbers may not add up to the expected total
肺癌是常见的恶性肿瘤之一，近年来发病率上升速度高居各种肿瘤之首。据卫生部2008年统计数据显示，我国每年肺癌的发病人数约为70万，2/3的患者发现时已失去手术根治机会。其中，占肺癌80%-90%的非小细胞肺癌（non-small cell lung cancer, NSCLC）患者5年生存率仅为8%-15%，但Ⅰ期肺癌术后10年生存率可达到92%。由此可见早诊断早治疗是降低肺癌死亡率的关键所在。传统的医学诊断主要通过影像学检查，尽管低剂量螺旋CT的应用相比胸部X线片提高了肺癌早诊率，死亡率下降了20%，然而，早期肺癌患者体内潜在癌变的细胞克隆远远小于现今影像学测量技术可达的最小阈值，因此有必要寻找更早于影像学诊断的灵敏性和特异性更高的方法以提高肺癌的早期确诊率。肿瘤蛋白质组学从蛋白、肽段等更微观的角度研究肿瘤，寻找肿瘤标志蛋白，进而阐明其表达水平的变化与肿瘤发生、发展的相互关系，在肿瘤早期诊断中极具潜力。其核心技术质谱分析近年已逐渐应用于乳腺癌、胃癌、大肠癌等恶性肿瘤早期诊断的探索性研究。本研究旨在应用基质辅助激光解析电离飞行时间质谱（matrix assisted laser desorption ionization-time of flight-mass spectrometry, MALDI-TOF-MS）与纳米磁珠提取血清多肽方法相结合--ClinProtTM系统，探索性分析NSCLC患者与健康人群的血清，从中筛选差异性多肽，通过统计学方法建立诊断NSCLC的分类模型并进行验证，以期为建立NSCLC血清学诊断方法奠定基础。
In addition to gastrectomy, ER is the main treatment method to treat EGC and is appropriate for EGC with a low LNM rate, including endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR). According to the Japanese Gastric Cancer Treatment Guidelines 2018 (5th edition) (6), the absolute indications for ESD and EMR are a differentiated-type EGC with an infiltration level limited to the mucosa, a tumor size of ≤2 cm, and no presence of ulcers. Absolute indications of ESD also include a differentiated-type mucosal EGC without the prevalence of ulcers with a tumor size of >2 cm, and a differentiated-type mucosal EGC with a prevalence of ulcers and a tumor size of ≤2 cm. Compared with gastrectomy, EMR and ESD are more minimally invasive, significantly improving EGC patients’ quality of life (20, 21). EMR and ESD have been widely used in recent years with the gradual indication expansion. However, the use of ER in patients with expanded indications is controversial, due to the lack of long-term evidence of its safety (20–23). In the present study, 512 patients met the absolute indications and 15 (2.9%) had LNM, whose possibility was higher than the 1% possibility required for absolute indications (6). Compared with Japan, the diagnostic rate of EGC in China is relatively low, resulting in a relatively low sample size. In addition, different from the trials in Japan using ER (24), all patients in this study underwent radical gastrectomy, and the differences in the corresponding inclusion criteria may also lead to differences between the results.
We also demonstrated that besides the genetic alteration, the deregulation of miRNAs expression was triggered by the cfDNA treatments. The upregulation of miR-125b-5p in the treatment with T3/T4 cfDNA was associated with the malignant transformation in this cell, since miR-125b-5p is abnormally expressed in multiple cancers and is closely related to invasion and metastasis. In PCa, previous studies have shown an upregulation of miR-125b in malignant prostate cancer cell lines as well as clinical tissues of prostate cancer31,32. In other tumors the overexpression of the same miRNA promoted an increase in cellular migration, a significant decrease in expression of E-cadherin, and an increase in the expression of genes, such as MMP9 in PC-1 cells, characterizing the EMT in those cells33. These results corroborate our findings about the treatment with T3/T4 cfDNA, it also suggests that the miR-125b can be a biomarker for the detection of PCa.
The main outcome measure was the difference in UM-specific survival between the two groups according to YAP activity. The other clinicopathological features included patient age, sex, American Joint Committee on Cancer (AJCC; 8th edition) stage, dominant cell type, pigmentation, mitotic count, largest tumor basal diameter, tumor thickness, presence or absence of metastasis, and metastatic sites.
Bias assessment for individual studies was evaluated using the Newcastle-Ottawa Quality Assessment Scale for Cohort studies, which evaluates studies based on selection (maximum of 4), comparability (maximum of 2), and outcome (maximum of 3) (20, 21). Factors included in the “comparability” category included control for KPS and extent of resection, as each of these factors has consistently been shown in multiple studies to be highly associated with prognosis (22–24).
Meta-analysis of effect sizes: population characterization, original values (t-scores and Z-scores), contrasts, type of analysis, p-values and corrections taken from the studies feasible for meta-analysis for the contrast "Untrustworthy > Trustworthy" or correlation with facial trustworthiness scores in the (right) amygdala.
Structural differences between ventricular and atrial myocytes may also explain why atrial SERCA2a overexpression would not alter atrial Ca-ALT thresholds. Small mammal and pathophysiologic atrial myocytes (i.e. heart failure, dilated atrium in large mammals) differ from ventricular myocytes in that they lack t-tubules.[17–19] This produces a fundamental change in the mechanism of electromechanical coupling. In contrast to ventricular myocytes, junctional SR-calcium propagates as a wave toward nonjunctional-SR, stimulating calcium release toward the central part of an atrial cell. Therefore, calcium waves are predicted to be strongly dependent upon junctional-SR content in the atrium. Overexpressing SERCA2a would serve to overload the SR, as shown with our data, but would not inhibit a calcium wave toward the central region of cell. This would allow for a cell to have minimal beat-to-beat variability in calcium cycling with increasing heart rates without the development of Ca-ALT.
In funcție de mecanismele de producere, accidentele vasculare cerebrale pot fi clasificate în accidente vasculare ischemice (85%) sau hemoragice (15%). Factorii de risc sunt reprezentați de vârstă (riscul de producere a unui accident vascular cerebral crește odată cu vârstă), sexul (bărbații sunt mai frecvent afectați, însă după vârsta de 75 de ani femeile devin cele la care se întâlnește mai frecvent accidentul vascular), hipertensiunea arterială, diabetul zaharat, diverse afecțiuni ale inimii (afecțiuni ale valvelor cardiace, cardiomiopatiile, endocarditele, fibrilația atrială), existent unui accident vascular cerebral în antecedente sau în familie, obezitatea, fumatul, diverse medicamente (anticoncepționale orale, anticoagulante, corticosteroizi), consumul excesiv de alcool, consumul de droguri.
Central neck lymph node dissection refers to the dissection of all lymph adipose tissue and prelaryngeal lymph node in the front and side of the trachea and laryngeal recurrent nerve areas. The specific dissection range included all of the lymph adipose tissue in the region under the thyroid cartilage and over the sternal notch and medial area of the common carotid artery. The relevant data were collected, including demographic features (sex, age), clinical features (calcium and PTH levels, tumor size), and pathological features (multifocality, T stage, extrathyroid invasion). Clinicopathological classification was performed according to the TNM classification criteria (seventh edition, 2010) by the American Joint Committee (AJCC) on Cancer . All of the operations were conducted by the same team of doctors, and histological specimens were independently reviewed by two pathologists in a blinded manner. In this study, all of the patients and their families fully understood the treatment process, written informed consent was obtained from all of the participants, and the study was approved by Ethics Committee of the Second Affiliated Hospital at Harbin Medical University.
The limited level of reporting method detail by many included studies hampered the full assessment of their risk of bias (see Table 2). Only one trial provided details of random sequence generation and two trials reported the method of allocation concealment. Although four studies employed a 'SCS ON' vs. 'SCS OFF' cross over design blinding is likely to have been prevented by patient's perception of paraesthesia. One study achieved double blinding by employing a very low stimulus control group (0.1 v 24 hours per day) . One study reported blinded ECG outcome assessment . There was little evidence of attrition bias, all studies reporting follow up on 90% or more of patients randomised. The median Jadad score was 2 (range, 2 to 4, out of a maximum score of 5) indicating overall, a moderate level of risk of bias.
Um dos métodos usados para a avaliação clinica da habilidade aeróbica é o teste de caminhada de 6 minutos (TC6M), que é um teste simples utilizado para verificar o nível de limitação funcional e a estratificação prognóstica em adultos e crianças.7 , 8 O teste foi usado para avaliar desfechos em diferentes estágios do tratamento de várias doenças, e demonstrou uma forte associação com a dessaturação da oxihemoglobina na cardiopatia crônica.
The Poloxamer hydrogel core also increased the encapsulation efficiency of a small, hydrophilic, cationic, and acid-stable peptide. The core–shell PLGA microspheres encapsulated in Goserelin was synthesized by double-emulsion–solvent evaporation method. Poloxamer hydrogel has a disperse phase that enables regulating the release pattern by manipulating pH. The microspheres showed a Di-Depot structure which means that Goserelin acetate (GOS) was scattered throughout PLGA (PLGA depot) and also encapsulated inside the hydrogel core (hydrogel depot). The Di-Depot structure allowed high encapsulation efficiency of 94.16%, and resulted in the release pattern of two peaks, where GOS in PLGA depots diffused first followed by the diffusion of GOS in Poloxamer hydrogel depots. The delay between two release stages could be minimized by decreasing the inner phase pH, since acetic acid provoked the heterogeneous degradation . Another aqueous core–PLGA microcapsule also illustrated a 2.5-fold increase in encapsulation efficiency (31.6%) in comparison to the PLGA microspheres (12.7%). The microcapsules were synthesized by a new method—acetone–water in oil emulsion followed by internal phase separation. The resulting aqueous core–PLGA microcapsules were spherical, poly-nuclear, and their average size was 1.1 ± 0.39 μm. They were able to encapsulate risedronate sodium, a water-soluble model drug, and the microcapsules exhibited a sustained release behavior that followed the diffusion-controlled Higuchi model . Similarly, one more hydrophilic model drug, fluorescein sodium, was encapsulated in the aqueous core of PLGA and PLA microshell. The internal phase separation technique was used and the internal phase polymer to water ratio for maximizing the encapsulation efficiency was 1 to 3. The synthesized PLGA and PLA microvehicles exhibited sustained release over 7 and 49 d, respectively . However, the hydrophobic nature of PLGA often requires using harmful organic solvents to make aqueous core microcapsules. Therefore, Nomura et al. attempted to solve this problem by utilizing a plant oil for the continuous phase in a single emulsion method. It achieved the encapsulation efficiency of Rhodamine B up to 95.8% .
2009年5月-2012年5月前瞻性随机选取我科收治的已确诊的肺癌患者58例。纳入标准：①首次病理确诊的原发性支气管肺癌并未进行过化疗的患者；②根据2009年NCCN肺癌国际分期标准为Ⅲ期-Ⅳ期；③体力评分KPS评分≥70分；④预期生存期 > 3个月；⑤愿意接受问卷调查。排除标准：①既往精神病史；②文盲者或者小学以下文化程度者；③经解释后仍不能理解问卷条目者；④既往接受抗焦虑治疗；⑤既往酒精或药物依赖史。化疗方案：非小细胞肺癌一线化疗予含铂两药方案（铂类+吉西他滨或长春瑞滨、紫杉醇、培美曲塞等），小细胞肺癌一线化疗予依托泊甙或替尼泊苷+顺铂方案，疾病进展给予二线化疗方案（多西紫杉醇、培美曲塞等），其余均继续原方案化疗，化疗每2周期后进行病情评估。
腺癌是本研究中最常见的组织学亚型，占所有患者的74.4%。在相当一段时间内，组织学亚型（包括小细胞肺癌、鳞癌和非鳞肺癌）已足以指导肺癌患者的治疗。但近年来，随着肿瘤分子生物学研究的深入，出现了针对驱动基因的靶向治疗方案，使得生物标志物检测愈加重要。本研究中，291例（58.2%）患者进行了生物标志物检测，提示在真实世界的临床实践中，针对驱动基因的分子生物学检测已成为肺癌的诊疗常规。本研究中仅观察到EGFR突变（n=178）和ALK融合（n=12）两种驱动基因。EGFR突变发生率（61.2%）与既往报告的亚洲患者EGFR突变率基本一致。PIONEER研究分析了亚洲1482例患者的肿瘤，EGFR突变发生率为22%-62%。与既往研究报道相符，21 L858R和19 Del是本研究中EGFR突变的主要亚型，18、20位点突变和双突变仅占4.8%。ALK融合在非小细胞肺癌中相对罕见，在未选择群体中其突变率为1.5%-6.7%，而在非吸烟患者中，ALK阳性率可高达22%。本研究中，4.1%的患者出现ALK重排，阳性率与既往研究一致。
Our findings that MYO1E loss slows down tumor progression in a mouse model of breast cancer were further extended by performing meta-analysis of the relationship between MYO1E expression and breast cancer patient survival (Figure 5A, 5B), and supported by an earlier study on gene signature predicting patient outcome in breast cancer . High MYO1E expression level in basal breast cancer and grade 1 breast cancer was associated with decreased patient survival, indicating that MYO1E could serve as a biomarker predicting cancer progression and overall patient outcome. Patient meta-analysis data align well with our observations that the morphology of MYO1E KO PyMT tumors is consistent with primarily non-invasive and confined papillary tumors that pose minimal risk to patients.
Depletion of diverse populations of CD32-expressing CD4 T cells by negative bead selection due to the expression of non-T cell markers. (A) The frequency of CD32+CD3+CD4+ T cells when measured in peripheral blood mononuclear cells (PBMCs), or in CD4 T cells purified by negative bead selection, with and without Fc block prior. (B) Representative gating of data shown in panel (A). (C) Gating of three CD32-expressing populations based on differing levels of expression and CD14: CD32low, CD32+CD14+, and CD32high. (D) Heat-map showing the percentage expression of markers used in CD4 negative bead isolation kits on subsets of CD3+CD4+ T cells [defined in panel (C)]. Expression was measured by flow cytometry, and values are shown as the mean of three individual donors. (E) Percentage expression of CD11b, CD19, CD36, and CD20 on CD3+CD4+ subpopulations as shown in panel (D). Bar is shown at the mean.
Le lymphangiome kystique peut être asymptomatique apparaissant sous forme d'une tuméfaction molle, rénitente, régulière et bien limitée ou se manifestant à la suite de complications en rapport avec la compression et le refoulement des structures de voisinage: des signes respiratoires, dysphagie, troubles neurologiques périphériques, surinfection avec fistulisation à la peau ou hémorragies intrakystique . La nature kystique de la tumeur est suspectée sur l'examen clinique, doit être confirmée par les données de l’imagerie . L'échographie est l'examen de première intension permet de montrer la tumeur kystique sous forme d'une masse hypo-échogène bien limitée; elle est utile pour le diagnostic prénatal des lymphangiomes kystiques. La tomodensitométrie montre une masse de contenu hypodense, bien circonscrite sans invasion des structures anatomiques environnantes. L’IRM est complémentaire au scanner permet d'étudier les rapports du lymphangiome avec les structures de voisinage. L'imagerie permet également de faire le diagnostic différentiel avec d'autres lésions cervico-faciales de nature kystique, tel que: le kyste bronchial, le kyste thymique, le kyste du tractus thyreoglosse, l'abcès collecté, l'hématome, les tumeurs nécrosées, le tératome kystisé . Le traitement des lymphangiomes kystiques de la cavité buccale devient parfois obligatoire voir urgent devant la présence de complications; Il fait essentiellement appel à la chirurgie qui consiste en une exérèse complète du kyste afin d'éviter les récidives [4, 9]. Les autres alternatives thérapeutiques devant un lymphangiome kystique simple sont: Le drainage-aspiration, les stéroïdes, la sclerothérapie, l'exérèse au laser, l'ablation et la cautérisation à la radiofréquence, la radiothérapie utilisée il y a longtemps est actuellement abandonnée [3, 4].
The Model-based Analysis of ChIP-Seq (MACS) was used to analyze all ER ChIP-seq data in breast cancer prior to July 2014 (Additional file 1: Table S1). MACS models the length of ChIP-seq reads to improve the resolution of predicted binding sites. A p value cutoff of 1e-5 was used and genome size which matches UCSC human hg18 assembly was used. In datasets which had sequenced untreated genomic DNA as a control, we used this sequence as input (untreated) control. MACS automatically calculates the tag size based on the reads length in the treatment file. Peak calling was performed in each ChIP-seq dataset first and binding sites from the same cell line were pooled.
Immunogenicity is one of the key features of the therapeutic vaccines as it represents the potential of the vaccine to induce virus-specific T cell response, in particular HPV E6 and E7 specific CD8+ T cell immune response. IFN-γ response was measured by means of ex vivo ELISpot assay with cryopreserved and thawed peripheral blood mononuclear cells (PBMCs) at pre- and post-treatment stages. The vaccine response is considered positive when the increase in T-cell frequency was at least three times greater compared to the study entry measurement. GX-188E both in phase I and phase II studies showed a significant increase in IFN-γ response, which was correlated with the histopathologic regression and viral clearance. Moreover, an E6 specific response was more pronounced than E7 specific . VGX-3100 induced 9.5 times greater IFN-γ response in the treatment group compared to the placebo, which lasted as long as 24 weeks post-vaccination . On the contrary, MEDI0457 induced a greater response to E7, particularly in newly diagnosed cohort 1 that persisted up to 48 weeks . In cohort 1, 4 of 7 patients exhibited IFNγ-producing spots exceeding 100 SFU/106 PBMC, whereas no patients produced similar responses in cohort 2 . pNGVL4a-CRT/E7(detox) and pNGVL4a Sig/E7(detox)/HSP70 showed minimal dose-dependent immune response, which was remarkable from the unvaccinated group .
A post hoc repeated measures analysis for students’ self-evaluation of their work performance, as measured by the Performance Capacity Card, indicated that all students evaluated themselves with a score of 10 (the highest score) in all three measures. There was therefore no difference between students’ self-rated scores across the three assessment times—the first (T1), middle (T2), and last (T3) days of the five-day work experience period. However, analysis of Performance Capacity Card data collected from their supervisors revealed significant differences between the three assessment times (Figure 2). As assessed by the supervisors, the students’ work performance improved significantly from T1 to T2 to T3 as measured in four work-performance areas: security (p < 0.001), performance, initiative, and independence (p < 0.001). Overall, the results partially confirm H5, only as related to supervisors’ assessment of the students’ participation at work.
Le déficit congénital en facteur V est une anomalie rare de la coagulation, initialement décrite par Owren en 1947 et connue sous le nom de para hémophilie. Elle est transmise selon un mode autosomique récessif. En générale elle est symptomatique à l'état homozygote . Le facteur V est un cofacteur essentiel dans la conversion de la prothrombine en thrombine par le facteur X activé. En l'absence du facteur V, la génération de thrombine est ralentie et la formation de fibrine est retardée. Il en résulte une tendance aux saignements . Le déficit en facteur V est une coagulopathie congénitale rare, sa prévalence est estimée à une personne pour un million d'habitants [3, 4], se manifestant à tout âge par un syndrome hémorragique de sévérité variable, dont le diagnostic repose sur le bilan d'hémostase avec dosage du facteur V et dont le traitement se base sur la perfusion de PFC .
4. 多因素分析：将单因素分析P值<0.3的纳入多因素分析，通过Cox多因素回归分析发现：0 d融合基因高定量及初诊时骨髓流式细胞术原始细胞比例≥60％是移植后复发的独立危险因素。初诊时骨髓流式细胞术原始细胞比例≥60％，达到完全缓解所需的疗程数≥2是OS的独立危险因素（表4）。根据造成移植后血液学复发的危险因素（初诊时骨髓流式细胞术原始细胞比例≥60％、0 d融合基因高定量）分为高危组（具备2个危险因素，7例）、中危组（具备1个危险因素，24例）和低危组（不具备危险因素，42例），移植后3年CIR分别为57.1％、14.8％、3.0％（P<0.001）（图4）。根据影响OS的危险因素分为高危组（具备2个危险因素，5例）、中危组（具备1个危险因素，28例）和低危组（不具备危险因素，40例），移植后3年OS率分别为0％、52.5％、86.1％（P<0.001）。
A specific comparison of both availability of TDM and respondent involvement in TDM (in any capacity), by drug/drug class, between UK and non-UK respondents is shown in Figs. 1 and 2. Availability was broadly similar between UK and non-UK respondents, although there appeared greater nominal TDM availability for antiviral drugs, antifungal drugs, conventional chemotherapy drugs, tricyclic antidepressants, SSRIs, and other antidepressants in the non-UK group. On the other hand, UK respondents reported more involvement in the monitoring of paracetamol, lithium, anticonvulsants and oral anticoagulants.
Real-time PCR was performed with twelve genes, which were randomly selected from the list of DEGs, to confirm the significance of RNA-seq results. The primers and descriptions for each gene are presented in the Supplementary file, Table S2. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH; AJ289783) was used as a reference gene . A reaction mixture of 20 μL included 10 μL of 2X SYBR Green PCR Master Mix (PE Applied Biosystems, Waltham, MA, USA), 0.8 μL of 10 pmol/μL of primers, 0.5 μL of cDNA, and 8.7 μL of distilled water. Real-time PCR was conducted using a 7900HT Sequence Detection System (PE Applied Biosystems, Waltham, MA, USA) with triplicates of each reaction. The PCR conditions consisted of a 5 min. denaturation step at 95 °C, followed by 40 cycles of 95 °C for 30 seconds, 55 °C for 30 s, and 72 °C for 30 s, and a final extension at 72 °C for 5 min. Relative expression of transcripts was calculated using the 2–∆∆Ct method through quantification cycle (Cq) values . The significance of differences was analyzed with a pairwise t-test (p < 0.05) using the PASW Statistics 18 program (SPSS Inc., Chicago, IL, USA).
TM是机体对癌细胞反应过程中合成和释放的一类物质。据报道，CSF中TM水平的高低与CSF中癌细胞数量呈正比。在我们的研究中，与经CSF细胞学确诊人群相比，经MRI确诊人群CSF中TM检出阳性率更低，分析可能与细胞学阳性人群CSF中癌细胞数量更多相关。因此，临床实践中，针对MRI阳性但CSF细胞学阴性人群，可尝试其他癌症筛查手段或组合多种TM进一步辅助诊断。当然，CSF中不同TM诊断的敏感性不同[14, 18, 19]，本研究CSF中CYFRA21-1敏感性最高，达到88.2%，CEA特异性最高，达到92.3%，尤其是TM的联合检测能进一步提高LM诊断的敏感性和特异性，改善由于当前诊断方法如CSF细胞学或MRI手段不灵敏引起的治疗延迟。值得注意的是，临床上CSF中TM的升高常常早于MRI异常，故对NSCLC患者，如出现可疑的LM症状者，任一项TM的异常都具有重要的提示作用，利用CSF中TM的指标，有助于诊断和治疗LM，对该亚群患者预后的改善具有非常重要的临床意义。总之，与CSF细胞学和MRI相比，寻找具有高敏感性CSF中TM对LM诊断可能更加有效。
Durante o acompanhamento pós-operatório com 1, 3 e 12 meses, apresentou evolução favorável e sem sinais de síndrome de hipertensão portal (SHP) nos exames clínicos, laboratoriais e de imagem. Foram feitos exames para trombofilia, após a suspensão da anticoagulação, com resultados normais. Após 2 anos de acompanhamento, a paciente retornou em consulta ambulatorial grávida de 14 semanas, sem sinais de descompensação clínica ou laboratorial, sendo introduzida anticoagulação com heparina fracionada pela gastroenterologia e hematologia. A gestação veio a termo com 38 semanas, e, no puerpério, a paciente manteve evolução favorável, sendo mantida a anticoagulação. Após o puerpério, realizou nova TC que demonstrou uma diminuição do diâmetro da via de saída (7 mm) comparada ao exame prévio (12 mm), com o aparecimento de ascite detectada pela TC, porém sem evidências clínicas (Figura 1B). Optado, em conjunto com a gastro-hepatologia, por nova angioplastia da veia supra-hepática.
A total of 58 samples of Corni Fructus were from the primary places of origin and medicinal material markets distributed in Henan, Zhejiang, Shanxi, and Shaanxi provinces of China. All samples were identified by Prof. Suiqing CHEN at Henan University of CM as the pulp of the ripe fruit of Cornus officinalis Sieb. et Zucc. (Cornaceae). Furthermore, in accordance with the “Chinese Pharmacopoeia I” (edition 2015), the components Monoside (C17H26O11) and Loganin (C17H26O10) were identified in the water-soluble extracts of all individual samples examined.
By comparing the data with all the reported up-regulated microRNAs, hsa-miR-125a-3p showed the highest change of log2 fold expression in the untreated control vs. 40 μM EGCG treatment (7.12 log2 fold change) and untreated control vs. 100 μM EGCG treatment (7.47 log2 fold change). Furthermore, hsa-miR-548o-3p was down-regulated by -9.12 and -8.12 log2 fold change in the untreated control vs. 40 μM EGCG and the untreated control vs. 100 μM EGCG treatments, respectively. We observed 21 up- and 24 down-regulated microRNAs in the untreated control vs. 40 and the untreated control vs 100 µM EGCG treatments (Figure 7).
The ability of CPPs to penetrate almost all biological membranes makes the targeted delivery of proteins a very important issue in order to minimize undesirable effects. One should take in consideration the special characteristics of the targeted organ microenvironment. Torchillin’s group developed “smart” delivery platforms for organ-tissue specific targeting, after administration of the desired cargo (e.g. the PT of interest) in the circulation: CPP - cargo is shielded with a protective molecule, like PEG (polyethylene glycol polymer), thus enhancing solubility, decreasing accessibility for the circulating proteolytic enzymes and increasing the half time of the PT by reducing kidney filtration due to its increased size. PEG chains can carry target-specific antibodies, attached to the surface via bonds sensitive to cell environmental (e.g. pH, temperature, matrix metalloproteinases) or external (magnetic field, ultrasound) stimulus conditions. After accumulation of the “smart” nanocarrier in the targeted organ and release of the PEG-antibody conjugates, the exposed CPP permits the transduction of the cargo intracellularly. Such an approach seems reasonable for the design of tumor-specific drugs/prodrugs/biodrugs, although the observed cell heterogeneity in tumors raises a number of limitations.
In this regard, we hypothesise that Vγ7Vδ6.3+ IEL may have been selected on Btnl1 + 4 even in wt mice, with their CD122 expression likewise maintained by Btnl1 + 4; hence, they were essentially insensitive to acute Btnl6 depletion, phenocopying Vγ7Vδ6.3+ IEL and some Vγ7Vδ4+ IEL in constitutive Btnl6−/− mice. Evidence in support of this hypothesis was provided by further analysis of Vδ usage by Vγ7+ IEL, which was essentially unaffected at 3 days following Btnl6 depletion, but which was significantly skewed toward Vδ6.3+ cells by day 56 (Fig. 5e, f). This would be consistent with natural IEL turnover favouring newly-maturing Vγ7 Vδ6.3+ IEL versus Vγ7Vδ4+ IEL, since following Btnl6 deletion, the former could more efficiently engage Btnl1 + 4.
To verify the function of TEM8 in regulating tumor cell VM, stable TEM8-overexpressing and TEM8-knockdown TNBC cell lines were established (Supplementary Fig. 2b, c). TEM8 overexpression promoted breast tumor growth and metastasis (Supplementary Fig. 3f–h), whereas TEM8 knockdown had the opposite effects (Supplementary Fig. 3i–k), as previously reported20. Consistently, the results of in vitro tube formation assays showed that capillary-like structures were significantly increased in TEM8-overexpressing cells (Fig. 1i). Significant positive correlations were observed between TEM8 and VM markers such as EphA2 and VE-cadherin in both TNBC patient samples and cell lines (Supplementary Fig. 1g, h). Xenograft experiments supported the effect of TEM8 overexpression on increasing EphA2 expression, dextran leakage, pericyte density, and tumor vessel density (Fig. 1j, k), whereas TEM8 knockdown decreased tumor vessel density (Fig. 1l). Taken together, the results suggested that TEM8 promoted VM in breast tumor cells.
To test the functions of sPH20-IgG2-expressing CAR-T cells in vivo, we utilized cell line-derived xenograft mouse model. Firstly, NSI mice were subcutaneously inoculated with 1×106 BGC823 human gastric cancer cells. After 10 days, when tumors were palpable, 5×106 Mock-T cells, anti-MSLN CAR-T cells or anti-MSLN-sP CAR-T cells were injected via the tail vein. Tumor growth was monitored with a caliper. After 30 days, the mice were sacrificed, and the tumor tissues were weighed and dissected for IHC analysis ( Figure 4A ). The results showed that the conventional anti-MSLN CAR-T cells could significantly inhibit tumor growth compared with the Mock-T cells in these mice; However, the anti-MSLN-sP CAR-T cells showed a significantly stronger capacity to regress tumors, as depicted by combined tumor growth curves and tumor weight measurements ( Figures 4B, C ), as well as individual tumor growth curves ( Figure 4D ). Immunohistochemical staining for CD3 suggested that T cell infiltration in the anti-MSLN-sP CAR-T cell group was significantly higher than that in the conventional anti-MSLN CAR-T cell group ( Figures 4E, F ).
The persistence of transcriptional modulation over generations was further confirmed by measuring the physiological capability of the fourth-generation plants to re-induce the ability to take up nitrate at a higher rate. Indeed, TTCT plants reached the highest uptake rate of nitrate in comparison to the other treatments (which followed the series TTCT > CTCT > TCCT = CCCT; Figure 7). This evidence suggests that the transcriptional modulation induced by N-limiting conditions during previous generations promotes a more reactive adaptation of plants to environmental changes, as N availability in the soil solution and effect is enhanced if the plants were treated twice in N-limiting conditions and disappears after two generations under N-sufficient conditions.
The protein expression levels of MMP14 and PKM2 in pancreatic cancer tissues were also varied significantly. We identified 18 pancreatic cancer tissues were with high MMP14 expression and 40 pancreatic cancer tissues were with low MMP14 expression (Figure 9A). Also, we found that 35 PKM2 highly expressed and 22 PKM2 lowly expressed pancreatic cancer tissues (Figure 9A). Consistent with the bad prognosis of MMP14 and PKM2, pancreatic cancer patients with higher expression of MMP14 or PKM2 had more unfavorable clinical overall survival (Figure 9B).
[Ovviamente la DAD mi ha colto ‘impreparato’. Per mio carattere e per le caratteristiche dei miei alunni, il mio insegnamento si basa moltissimo sul rapporto, sull’empatia, sull’emozione e non da ultimo sulla fisicità, molto spesso anche teatrale, in classe.]
A 70-year-old man previously being treated for stable alcoholic liver disease presented with gradually progressive diffuse abdominal pain associated with vomiting and constipation for 7 days. Physical examination revealed gaseous abdominal distention without tenderness or mass. He had a history of 2 laparotomies in the past both for small bowel obstruction secondary to enterolith impaction that had failed to resolve with conservative measures.
Since expectation is a linear operator and these two events are independent, the above expression can be decomposed as: (13)\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document} $${} \begin{aligned} p_{\text{out}}(\lambda,T,\alpha,S,\gamma) &= 1 - \underbrace{\mathbb{E}_{r}\left[ \mathbb{P}\left[\text{ln}(1 + \text{SINR}) > T \mid r \right] \right]}_{(i)}\\ &\qquad\quad\underbrace{\mathbb{E}_{r}\left[ \mathbb{P}\left[f_{o} \in \Delta_{b_{o}} \mid r\right] \right]}_{(ii)}. \end{aligned} $$ \end{document}pout(λ,T,α,S,γ)=1−𝔼rℙln(1+SINR)>T∣r⏟(i)𝔼rℙfo∈Δbo∣r⏟(ii).
目前关于老年肺癌患者治疗的相关研究内容有限，在借鉴《老年肺部手术围手术期加速康复护理专家共识》的同时，仍需关注接受放化疗及免疫靶向治疗的老年肺癌患者的护理。为此，中国老年保健协会肺癌专业委员会组织全国部分胸科医护专家，依据当前国内外最新研究进展及最佳的临床证据，牵头编写了《老年肺癌护理中国专家共识（2022版）》。通过检索国内外相关文献并结合我国临床实际情况，以循证医学为基础，以问题为导向，对于老年肺癌患者不同的治疗手段，进一步规范评估工具的应用、指导落实临床症状观察及护理措施、关注老年患者各种高危风险因素的预防，以多学科合作为模式，整体化护理为内涵，制定本共识，以期使老年肺癌患者治疗和护理实践更为规范、更具针对性，从而降低并发症的发生，也为未来临床研究提供了参考依据和指导意见。
L’examen cardio-vasculaire, en dehors d’une tachycardie sinusale, a été sans particularité. Le reste de l’examen somatique a été normal. L’électrocardiogramme n’a pas montré de troubles de rythme ou de repolarisation. Un traitement par alpha-methyldopa à la dose de 750 mg/jour a été débuté. Devant la persistance des pics tensionnels sous traitement, avec des céphalées et des épisodes de sueurs, le diagnostic de phéochromocytome a été évoqué et la patiente a été mise sous prazosine à dose progressivement croissante: débuté à 0,5 mg 3 fois par jour augmenté par palier de 0,5 mg par prise tous les 3 jours avec une dose efficace à 10 mg sans épisodes d’hypotension artérielle. L’adrénaline plasmatique a été indétectable et la noradrénaline très élevée à 820 nmol/l (Normale < 580 nmol/l).
In total, 18,555 DEGs were identified using DESeq (version 1.18.0), including 1182 DEGs in the roots and 7373 DEGs in the leaves, and 1612 DEGs in common between the roots and leaves. Among the DEGs, 9460 were upregulated in seedlings grown on NAC compared to N6 medium, and 7483 were downregulated (Fig. 7). To identify the functional pathways the DEGs are involved in, we used KEGG pathway analysis, including 254 KEGG functional pathways. In total, 226 KEGG pathways were commonly differentially regulated by AC in the roots as well as leaves. Among these, “metabolic pathways” (105, 39.10%) represented the largest group, followed by “organismal systems” (58, 25.66%), “environmental information processing” (24, 10.62%), “genetic information processing” (21, 9.29%), and “cellular processes” (18, 7.96%). P < 0.05 was considered as a threshold for screening. Further, 37 KEGG pathways were enriched for AC-regulated genes in the roots, and 30 KEGG pathways in the leaves (Fig. 8). In the roots, the three most gene-enriched pathways were “phenylpropanoid biosynthesis”, “starch and sucrose metabolism”, and “biosynthesis of amino acids”. In the leaves, the three most enriched pathways were “plant hormone signal transduction”, “phenylpropanoid biosynthesis”, and “glyoxylate and dicarboxylate metabolism”. By comparison, we found that “phenylpropanoid biosynthesis”, “plant hormone signal transduction”, “starch and sucrose metabolism”, “biosynthesis of amino acids”, and other metabolic pathways were the main gene-enriched pathways in wheat seedlings (Fig. 9). We analyzed three major metabolic pathways, i.e., “phenylpropanoid biosynthesis”, “plant hormone signal transduction”, and “starch and sucrose metabolism” in more detail. In these pathways, there were 29 DEGs between the NAC and N6 groups. Twenty-one of these genes were upregulated, including genes related to cell differentiation, seedling growth, and enhanced stress and disease resistance (e.g., PLA, HCT, ZIM, and JAC), and eight of them were downregulated, and were mainly related to the inhibition of plant growth (e.g., BKI1, ARR-B, DELLA, and ABF) (Table 1). Fig. 7DEGs in wheat roots and leaves from seedlings grown on NAC or N6 (control condition)Fig. 8Major pathways differentially regulated by AC in roots and leaves as revealed by KEGG enrichment analysis. KEGG pathways are shown in the ordinate. Dot size indicates how many DEGs are annotated to the pathway. The 20 most significant pathways identified in roots and leaves are shownFig. 9Major pathways differentially regulated by AC in wheat seedings as indicated by KEGG enrichment analysisTable 1Three pathways and major related genes differentially expressed in wheat seedlings grown on medium containing CA, as indicated by KEGG enrichment analysisPathwayGene IDFold change (NAC/N6)Expression in NACDescriptionPhenylpropanoid biosynthesisTRIAE_CS42_1BS_TGACv1_049914_AA016415047.15up(PAL) phenylalanine ammonia-lyaseTRIAE_CS42_1DS_TGACv1_080107_AA023932012.22up(PAL) phenylalanine ammonia-lyaseTRIAE_CS42_1BS_TGACv1_049965_AA016487010.79up(PAL) phenylalanine ammonia-lyaseTRIAE_CS42_2AL_TGACv1_096113_AA031723010.21up(PAL) phenylalanine ammonia-lyaseTRIAE_CS42_6DL_TGACv1_527273_AA17016308.24up(PAL) phenylalanine ammonia-lyaseTRIAE_CS42_1AS_TGACv1_019041_AA00587107.14up(PAL) phenylalanine ammonia-lyaseTRIAE_CS42_3AL_TGACv1_194598_AA06365209.78up(CYP73A) trans-cinnamate 4-monooxygenaseTRIAE_CS42_3B_TGACv1_220699_AA07158506.61up(CYP73A) trans-cinnamate 4-monooxygenaseTRIAE_CS42_2BS_TGACv1_148390_AA04925906.15up(CYP73A) trans-cinnamate 4-monooxygenaseTRIAE_CS42_5AL_TGACv1_378388_AA12530805.77up(CYP73A) trans-cinnamate 4-monooxygenaseTRIAE_CS42_3DS_TGACv1_271628_AA09042305.50up(CYP73A) trans-cinnamate 4-monooxygenaseTRIAE_CS42_6DS_TGACv1_543204_AA17370204.28up(COMT) caffeic acid 3-O-methyltransferaseTRIAE_CS42_6BS_TGACv1_514476_AA16603402.19up(COMT) caffeic acid 3-O-methyltransferaseTRIAE_CS42_2BL_TGACv1_132718_AA04393607.96up(CYP84A, F5H) ferulate-5-hydroxylaseTRIAE_CS42_2AS_TGACv1_113803_AA03608406.15up(4CL) 4-coumarate—CoA ligaseTRIAE_CS42_6BL_TGACv1_502904_AA16266205.14up(4CL) 4-coumarate—CoA ligaseTRIAE_CS42_7BS_TGACv1_591841_AA19232608.26up(HCT) shikimate O-hydroxycinnamoyltransferaseTRIAE_CS42_2DS_TGACv1_178855_AA06018305.80up(HCT) shikimate O-hydroxycinnamoyltransferaseTRIAE_CS42_7AS_TGACv1_569782_AA18240705.73up(HCT) shikimate O-hydroxycinnamoyltransferaseTRIAE_CS42_3AL_TGACv1_194329_AA06311502.42up(CYP98A, C3’H) 5-O-(4-coumaroyl)-D-quinate 3′-monooxygenaseTRIAE_CS42_7BS_TGACv1_592306_AA19353903.59upcaffeoyl-CoA O-methyltransferaseTRIAE_CS42_7DS_TGACv1_621454_AA20162104.05upcaffeoyl-CoA O-methyltransferaseTRIAE_CS42_5DL_TGACv1_436308_AA14599006.25up(CCR) cinnamoyl-CoA reductaseTRIAE_CS42_5BL_TGACv1_406204_AA13421805.56up(CCR) cinnamoyl-CoA reductaseTRIAE_CS42_5AL_TGACv1_375041_AA12145805.15up(CCR) cinnamoyl-CoA reductasePlant hormone signal transductionTRIAE_CS42_4BL_TGACv1_321177_AA10566602.09up(ARR-A) two-component response regulator ARR-A familyTRIAE_CS42_3B_TGACv1_221378_AA073875020.04up(PYL) abscisic acid receptor PYR/PYL familyTRIAE_CS42_7DL_TGACv1_602538_AA19597902.44up(EBF1_2) EIN6-binding F-box proteinTRIAE_CS42_6BS_TGACv1_514535_AA16611502.40up(EBF1_2) EIN3-binding F-box proteinTRIAE_CS42_3DL_TGACv1_251912_AA08858903.87up(EIN3) ethylene-insensitive protein 3TRIAE_CS42_2DS_TGACv1_178626_AA05984802.61up(BZR1_2) brassinosteroid resistant ½TRIAE_CS42_1BL_TGACv1_030488_AA00922205.34up(JAR1_4_6) jasmonic acid-amino synthetaseTRIAE_CS42_4BL_TGACv1_320580_AA10437106.24up(JAZ) jasmonate ZIM domain-containing proteinTRIAE_CS42_5BL_TGACv1_405157_AA132131024.45up(PR1) pathogenesis-related protein 1TRIAE_CS42_7DS_TGACv1_625472_AA20652808.73up(PR1) pathogenesis-related protein 1TRIAE_CS42_3B_TGACv1_221831_AA07508700.32down(AHP) histidine-containing phosphotransfer proteinTRIAE_CS42_7AS_TGACv1_569714_AA18224000.31down(ARR-B) two-component response regulator ARR-B familyTRIAE_CS42_7AS_TGACv1_569714_AA18224000.31down(DELLA) DELLA proteinTRIAE_CS42_3AL_TGACv1_197036_AA06644800.19down(ABF) ABA responsive element binding factorTRIAE_CS42_5BL_TGACv1_404247_AA12921000.22down(BKI1) BRI1 kinase inhibitor 1TRIAE_CS42_3DL_TGACv1_250531_AA08698100.48down(NPR1) regulatory protein NPR1Starch and sucrose metabolismTRIAE_CS42_2AS_TGACv1_114089_AA036394010.52up(otsB) trehalose 7-phosphate phosphataseTRIAE_CS42_2DS_TGACv1_178535_AA05972404.84up(otsB) trehalose 8-phosphate phosphataseTRIAE_CS42_1AL_TGACv1_003899_AA00518902.29up(TREH, treA, treF) alpha, alpha-trehalaseTRIAE_CS42_1DL_TGACv1_061138_AA01866102.03up(TREH, treA, treF) alpha, alpha-trehalaseTRIAE_CS42_3DL_TGACv1_249164_AA08400302.79up(scrK) fructokinaseTRIAE_CS42_7DS_TGACv1_624145_AA2059200Infup(glgA) starch synthaseTRIAE_CS42_4DS_TGACv1_361541_AA11698600.31downsucrose-phosphate synthaseTRIAE_CS42_6DL_TGACv1_526359_AA16803900.08down(AMY, amyA, malS) alpha-amylaseTRIAE_CS42_2DL_TGACv1_158310_AA05153300.43down(GBE1, glgB) 1,5-alpha-glucan branching enzyme
The resting motor threshold (rMT) was defined as the minimum stimulus intensity at which five of the 10 consecutive single stimuli at the hot spot elicited an MEP amplitude of at least 50 μV in the relaxed muscle (Rossini et al., 2015). The single pulse of the TMS intensity to elicit MEP during the entire stimulation paradigm was set at 120% rMT of the FDI. In the single iTBS group, the MEPs were measured “before” (10 min before iTBS, referred to as iTBSpre) and “after” (30 min after iTBS, referred to as iTBSpost–5 min, iTBSpost–15 min, and iTBSpost–30 min). In the iTBS-acupuncture group, the MEP was measured “before” (10 min before iTBS, referred to iTBS’pre) and “after” (10 min after iTBS, referred to iTBS’post–5 and iTBS’post–10), as well as “in” (30 min with the needle in situ, referred to as acupuncturein–5 min, acupuncturein–15 min, and acupuncturein–30 min) and “off” (30 min after needle removal, referred to as acupuncturepost–5 min, acupuncturepost–15 min, and acupuncturepost–30 min) (Figure 1A). The mean MEP amplitude was calculated as the average of the MEPs at each time point and then normalized to the 15-min pre-iTBS baseline.
A total of 248 RT-qPCR positive samples for DENV1 (n = 62) and DENV2 (n = 186) were screened. Of the samples tested, 227 (DENV1 = 57, DENV2 = 170) contained sufficient DNA ( ≥ 2 ng/µL) to proceed to library preparation. For those positive samples, PCR cycle threshold (Ct) values were on average 22 (range: 15 to 35) for DENV1 and 23 (range: 16 to 35) for DENV2. Epidemiological details of the samples processed are provided in Supplementary Table 2. We used a portable nanopore sequencing approach23 to generate the complete genome sequences from the 227 viral samples. The resulting average coverage was 89% for DENV1 and 88% for DENV2. Sequencing statistics are detailed in Supplementary Table 3.
A SQN requer um alto índice de suspeição para seu diagnóstico. O tratamento passa por uma ampla gama de possibilidades, dependendo do quadro clínico e das características anatômicas de cada caso. Neste estudo, a técnica endovascular se mostrou segura e eficaz. A embolização da VGE não foi realizada, já que essa conduta ainda não é consenso na literatura16. Costa et al.17 relataram o caso de uma paciente de 24 anos, portadora de SQN, tratada por técnica endovascular sem embolização de VGE que teve como desfecho o desaparecimento das varizes anexiais e a remissão completa dos sintomas. Contudo, publicação recente do Jornal Vascular Brasileiro10 fortalece a indicação de embolização da veia gonadal de rotina associada ao implante de stent na VRE. Diante disso, novos estudos podem auxiliar a investigar sobre a necessidade de embolização para todos os casos de SQN, considerando a possibilidade de retorno das veias anexiais ao seu calibre original após correção do refluxo e da hipertensão da VRE.
(B) Distribution of GREs relative to target gene transcription start site is shown. The chart presents percentage of GREs at various positions upstream and downstream of target genes. Note that only 64 of the 73 GREs detected in A549 cells were included in these analyses; the remaining nine GREs did not associate with a dex-responsive gene in these cells. The GREs were assigned to the nearest gene regulated by GR in A549 cells from the final list of genes that were included or impinged upon by the ChIP-chip arrays. Coordinates of TSSs were obtained from UCSC Genome Browser based on RefSeq. Similar results were obtained when we used TSS coordinates that were experimentally determined (DataBase of Transcriptional Start Sites) through 5′ end cloning (unpublished data) . The TSS of the longest transcript was used for genes that have multiple alternative TSSs. Similar results were obtained if the GREs were assigned the closest TSS of the associated dex-responsive gene: 38% of GREs were located downstream from TSS; 58% of GREs were positioned farther than 10 kb from the assigned TSSs.
在世界范围内，肺癌已经成为严重威胁人类生存健康的恶性肿瘤之一，其发病率和死亡率位列肿瘤首位。中国国家卫生部公布的资料显示，肺癌已替代肝癌成为我国首位恶性肿瘤死亡原因，占全部恶性肿瘤死亡的22.7%。肿瘤相关蛋白标志物是重要的辅助诊断、判断预后和指导治疗的生物学指标。目前，临床常规使用的肺癌相关血清学蛋白标志物主要包括癌胚抗原（carcinoembryonic antigen, CEA）、糖蛋白抗原125（carbohydrate antigen 125, CA125）、鳞状细胞癌相关抗原（squamous cell carcinoma antigen, SCC Ag）、细胞角蛋白19血清片段21-1（cytokeratin fragment antigen 21-1, CYFRA21-1）和神经元特异性烯醇化酶（neuron specific enolase, NSE），但其敏感性和特异性不高。
Entre as terapias não farmacológicas, o exercício físico se destaca na prevenção e tratamento das DCV. A pesquisa básica e translacional tem focado nos mecanismos envolvidos nos efeitos benéficos do exercício.9-11 Vários estudos mostraram que o exercício melhora a remodelação cardíaca induzida por infarto do miocárdio extenso.12 Souza et al.,10 observaram que, também em situação de agressão cardíaca menos grave como no infarto do miocárdio pequeno, o exercício aeróbio em esteira, por 12 semanas, melhora a capacidade funcional e preserva a geometria ventricular esquerda. Da mesma maneira, o exercício resultou em efeitos benéficos em ratos com hipertensão renovascular.11 Exercício resistido por 12 semanas aumentou a atividade de enzimas antioxidantes e reduziu o dano oxidativo cardíaco e renal, caracterizado por diminuição da concentração de peróxido de hidrogênio e preservação da concentração de grupos sulfidrílicos.11
Although we addressed the problem of excluding personal dilemmas in VR research , we acknowledge the limitation of including a single virtual reconstruction of the footbridge dilemma in the present research; as such, the generalizability of our results is limited in the broader moral decision-making literature. However, given that previous virtual paradigms have considered only impersonal moral dilemmas, this research has offered initial insights into the immediate emotional responses prompted by a novel simulation of a personal moral dilemma. Future research might consider constructing multiple personal moral dilemmas in VR in order to investigate further personal factors such as physical contact and spatial proximity in this action framework.
Im Jahr 1922 berichtete Jean Lhermitte , dass Patienten mit pedunkulären Hirnstammläsionen insbesondere vaskulärer Natur über geformte, farbige und sehr lebhafte VH klagten, die sie häufig auch wahnhaft verarbeiteten. Diese Patienten wiesen deutliche Störungen des Schlaf-wach-Rhythmus auf. Lhermitte charakterisierte den prototypischen Patienten mit pedunkulären Halluzinationen als einen „wachen oder nur unvollständig schlafenden Träumer“. Erst viel später wurde die Schlüsselfunktion des dorsolateralen Nucleus geniculatus erkannt . Üblicherweise unterliegt diese Struktur dem hemmenden Einfluss der Raphé-Kerne und des Nucleus pedunculopontinus (NPP). Beim Fehlen dieser Hemmung kommt es zur ungebremsten Erregung verschiedener Thalamuskerne und des Kortex. Im Falle der PK könnte ein solcher Mechanismus tatsächlich aktiv werden, da bereits in vivo eine Atrophie des NPP nachweisbar ist und die Autopsie einen zusätzlichen LK-Befall dieses Kerns anzeigt [31, 57]. Einschränkend ist jedoch festzustellen, dass PK-Patienten zumeist keine Unterschiede zwischen Tag- und Nachtzeit in Bezug auf Erscheinungsformen der VH aufweisen. Mittels Polysomnographie konnte aber ein Auftreten der VH unmittelbar im Anschluss an eine REM-Schlaf-Phase beobachtet werden . Auch legen Korrelationsstudien einen Zusammenhang zwischen VH und REM-Schlaf-Verhaltensstörung nahe . Es bestehen also Gemeinsamkeiten von einerseits dem Lhermitte-Syndrom und andererseits den VH bei der PK. So ist in beiden Fällen eine Intrusion von REM-Schlaf-Fragmenten in den Wachzustand zu postulieren; die Neuropathologie deutet in beiden Fällen auf Läsionen der „Traumfabrik“ und der Schlafregulierungszentren hin . Doch auch diese Hypothese kann nicht sämtliche VH erklären. So weisen z. B. die VH des PK-Patienten nicht die bizarren Charakteristika des REM-Schlafs auf. Zudem erleben PK-Patienten VH auch bei vollem Bewusstsein.
Moreover, recent work with Carboxydothermus hydrogenoformans describes the regulation of both hydrogenase-linked CODH and CODH/ACS operons for efficient consumption of CO across a wide range of concentrations (Techtmann et al., 2011). Those authors presented that under high pCO the bacteria were able to catabolize more CO into energy by overexpression of the hydrogenase, while at low CO concentrations the CO is mainly used toward carbon fixation. It seems that methanogens needed a longer adaptation time to achieve methane production at high CO concentrations.
«Je fais tout ce qu´un médecin peut faire, de la consultation aux actes chirurgicaux. […] Je suis conscient que ce n´est pas du PMA, mais je pense aussi que ce PMA n´était pas conçu pour nous médecins. Faut-il vraiment référer un patient à l´hôpital général pour un acte qu´on peut poser ici tout simplement parce que ce n´est pas dans le PMA? Soyons réalistes!» (MED-04).
Most epithelial tumor cells overexpress the Lewis(y) antigen, and this may result in Lewis(y)-induced modification of receptor structures on the cell surface. Basu et al. reported that epithelial growth factor receptor (EGFR) in Lewis(y) overexpressing tumor cells exhibit surface-exposed Lewis(y) moieties . We detected that Lewis(y) structures were present not only on EGFR but also on CD44 . Insulin-like growth factor receptor-1 is initially synthesized as a single-chain proreceptor polypeptide and is processed by glycosylation, proteolytic cleavage, and covalent bonding to assemble into a mature heterotetramer . Despite overexpression and invasion promoting ability of Lewis(y), and IGF-1R being separately reported in various types of human cancer, a direct association between Lewis(y) and IGF-1R has never been described. In this study, we demonstrate that IGF-1R mRNA and protein are elevated in RMG-I-H cells, which was substantially increased with Lewis(y). Exposure to anti-Lewis(y) antibodies could downregulate IGF-1R expression in a time-dependent manner. Lewis(y) was shown to be present in the oligosaccharides of IGF-1R. Notably, the relative content of Lewis(y) structures expressed on IGF-1R was not significantly different between RMG-I and RMG-I-H cells. Our previous results support that Lewis(y) affects cellular biological behaviors (e.g., cell proliferation, apoptosis inhibition) by influencing the activation of signal transduction pathways . We speculate that Lewis(y) activated downstream signaling transduction pathways and growth signals are delivered to the nucleus, leading to accelerated gene transcription of IGF-1R in nucleus, and finally promoting the expression of IGF-1R. Then the amplification of IGF-1R gene and overexpression of its protein product closely relate to the poor prognosis in cancer patients.
Sexual partners can also base an argument for disclosure on autonomy and bodily integrity, it being claimed that disclosure is necessary to enable an informed, autonomous choice about the risks they are willing to take.132 This view may be challenged on a number of grounds, two will be highlighted here. First, a failure to disclose does not necessarily preclude an autonomous choice.133 A sexual partner can have knowledge regarding HIV transmission risk even in the absence of direct disclosure by the infected individual and make their choice about whether to engage in sexual activity accordingly.134 Some would contend that knowledge of infected status places greater responsibility on the HIV+ individual.135 Yet, it is arguable that this responsibility to sexual partners can be met either through disclosure or by ensuring sexual activity only takes place in the context of low or negligible risk of transmission.136 Secondly, and more to the point for our present purposes, in the context of low viral load and condom use, the level of risk may be deemed so low as to not engage a disclosure requirement for the purposes of considering recklessness or consent to risk; the risk could be judged to be legally insignificant.137 To allow condom use or low viral load to negate a charge of reckless transmission or exposure, even without disclosure, arguably strikes the appropriate balance between the privacy and autonomy interests of the HIV+ individual and the autonomy and bodily integrity interests of their sexual partner.
In principle, 3D-CMF allows for a selective treatment of the 3D printed structures. We verified the superior characteristics of this method by selectively performing 3D-CMF on 3D printed structures with a complex shape and compared it with other treatments. Figure 2(b) shows 3D printed structure samples simulating a dog. The two samples undergoing surface treatment showed improvements compared to the untreated sample; however, one can realize that the eye lines vanish when focusing around the eyes of the dog that was treated with acetone vapor. In contrast, 3D-CMF improved the surface roughness while maintaining the eyes by performing a selective treatment. Therefore, it was verified that 3D-CMF can selectively treat complex-shaped 3D printed structures. Figure 2(c) shows how 3D-CMF is conducted to hole shape. It can be confirmed that the layer grooves inside the hole is being removed by adapting the shape of the pen tip to the hole. Figure 2(d) shows that by changing the pen tip, it is able to correspond to the wave structure shape. (d-1) shows how the pen tip is not suited for the structure and cannot correspond with the structure. (d-2) shows that by changing the pen tip, it has corresponded with the structure. The pressing force of the 3D-CMF performed on the complex 3D printed structure, shown in Fig. 2, needs to be set at a proper range in order to enable all area 3D-CMF. The force of 3D-CMF was applied in a range between the determined maximum and minimum force. (see Supplementary Fig. S1).
Hatchling mass and test temperatures for each species and location are reported in Tables 1 and 2, respectively. Hatchling MRs (Table 3) varied significantly with behavioural stage, activity and species (Table 4). Hatchling ID nested within location and species, and test temperature explained 76% and 24% respectively of the variation in metabolic rate. The interactions between activity and species, activity and behavioural stage, and among all three fixed effects were significant. Thus, we also evaluated differences among and within species, activity and behavioural stage separately. We report the results of mass-specific metabolic rate comparisons below. Table 1Hatchling mass and the number of hatchlings tested (mean ± SD, N) for each species, location, age and respirometry technique in this studySpeciesOlive ridley (Lepidochelys olivacea)Flatback (Natator depressus)Leatherback (Dermochelys coriacea)Loggerhead (Caretta caretta)Green (Chelonia mydas)Population/sAustraliaAustraliaUSAUSAaUSAbMalaysiaFrenzyClosed: 16.5 ± 0.2 g, 74Closed: 40.4 ± 0.3 g, 80Open: 44.9 ± 0.7 g, 27Open: 18.4 ± 0.4 g, 21Closed: 24.6 ± 0.2 g, 6aOpen: 24.7 ± 0.4 g, 24aOpen: 21.4 ± 0.2 g, 95b6 dClosed: 16.8 ± 0.2 g, 57 dOpen: 45.2 ± 1.11 g, 10Open: 20.9 ± 0.7 g, 10Open: 26.8 ± 0.6 g, 8a12 dOpen: 20.4 ± 0.9 g, 1520 dClosed: 68.0 ± 5.5 g, 422 dOpen: 28.9 g, 1a23 dClosed: 61.6 ± 3.3 g, 6Open: 31.2 ± 0.6 g, 6a25 dOpen: 37.3 ± 1.5 g, 7a26 dOpen: 35.3 g, 1a28 dClosed: 19.4 ± 0.3 g, 70Closed: 63.3 ± 0.5 g, 7931 dOpen: 35.4 ± 2.5 g, 343 dClosed: 60.7 ± 7.95 g, 244 dClosed: 99.2 g, 145 dOpen: 70.2 ± 1.96 g, 1950 dOpen: 94.0 g, 151 dClosed: 89.9 g, 252 dClosed: 53.7 g, 1Only green turtles were tested from two different locations, denoted with superscript lettersTable 2The air temperature (RMR & CMR) or water temperature (AMR & MMR) that hatchling oxygen consumption was measured at for each species, location and activity levelOlive ridleyFlatbackLeatherbackLoggerheadGreenAustraliaAustraliaUSAUSAaUSAbMalaysiaRMRClosed: 25 °CClosed: 25 °COpen: 23.5 ± 0.6 °COpen: 24 ± 0.8 °CClosed: 27.5 ± 1.2°CbOpen: 23.9 ± 0.5°CaCMROpen: 23.5 ± 0.6 °COpen: 24 ± 0.8 °COpen: 23.9 ± 0.5°CaAMRClosed: 22.5 ± 0.2 °COpen: 22.5 ± 2.7 °CClosed: 28.8 ± 0.6 °COpen: 23.6 ± 1.5 °CClosed: 28.4 ± 0.9°CaOpen: 24.6 ± 0.7°CaMMRClosed: 26.3 ± 0.4 °CClosed: 26.3 ± 0.4 °CClosed: 26.6 ± 1°CbOnly green turtles were tested from two different locations, denoted with superscript lettersTable 3Olive ridley, flatback, leatherback, loggerhead and green sea turtle hatchlings resting metabolic rate (RMR), crawling metabolic rate (CMR), metabolic rate during routine swimming (AMR) and maximal metabolic rate (MMR) during the frenzy and post-frenzyWhole animalMass-specificOlive ridley (μL O2 min−1)Flatback (μL O2 min−1)Green (μL O2 min−1)Leatherback (μL O2 min−1)Loggerhead (μL O2 min−1)Olive ridley (μL O2 g−0.67 min−1)Flatback (μL O2 g−0.67 min−1)Green (μL O2 g−0.67 min−1)Leatherback (μL O2 g−0.67 min−1)Loggerhead (μL O2 g−0.67 min−1)FrenzyRMR30 ± 2.06, n = 74122.54 ± 4.5, 8079.2 ± 3.4, 103313.55 ± 35.93, 863.73 ± 6.45, 34.59 ± 0.3110.3 ± 0.3810.17 ± 0.4523.76 ± 2.469.45 ± 1.06CMR228.1 ± 95.85, 8377.09 ± 47.14, 6201.47 ± 32.28, 726.62 ± 11.0928.82 ± 3.3328.19 ± 4.6AMR445.17 ± 26.43, 14385.92 ± 36.87, 13253.19 ± 15.2, 1152.57 ± 3.3430.84 ± 2.8636.33 ± 2.24MMR121.3 ± 6.88, 71280.93 ± 18.83, 79518.44 ± 14.46, 9018.42 ± 0.9923.6 ± 1.5666.68 ± 1.9Mass (g)16.46 ± 0.4440.39 ± 0.4322.17 ± 0.5244.91 ± 0.5218.39 ± 0.4Post-frenzyRMR26.89 ± 1.55, 7075.01 ± 1.82, 79156.09 ± 23.06, 11238.3 ± 28.95, 6131.32 ± 53.94, 153.7 ± 0.224.67 ± 0.1213.09 ± 1.9413.94 ± 1.4218.91 ± 8.61AMR392.89 ± 68.98, 23235.21 ± 12.84, 32197.79 ± 29.82, 2437.24 ± 6.6915.18 ± 0.9719.65 ± 2.26MMR78.98 ± 4.53, 70373.35 ± 18.52, 7910.83 ± 0.6223.02 ± 1.08Mass (g)19.39 ± 0.5363.32 ± 0.5837.04 ± 1.9563.45 ± 1.8929.33 ± 3.81Values are given as μL O2 min−1 (whole animal) and μL O2 g−0.67 min−1 (mass-specific) ± standard errorTable 4Results from linear mixed effects model evaluating the effect of activity, behavioural stage, species and their interactions on oxygen consumptionF-valueDfp-valueActivity265.163 < 0.001Behavioural stage36.434 < 0.001Species166.934 < 0.001Activity: behavioural stage10.974 < 0.001Activity: species22.436 < 0.001Behavioural stage: species7.556 < 0.001Activity: behavioural stage: species10.861 < 0.001Significant relationships are highlighted in bold
Our analyses showed that when instructed to detect an increment of contrast at a specific orientation, humans were better with oblique as compared to cardinal orientations, with an additional horizontal suppression. This cardinal\horizontal suppression appeared unspecific to the face category (i.e. upright vs inverted). These results resemble the cardinal\horizontal suppression observed previously with other categories of broadband stimuli (20,23; see S1 File of Fig 1A). It has been suggested that primary tuning away from horizontal orientations serves to counteract natural anisotropies in the visual environment (i.e. whitening), an explanation which could apply to faces as well, as they are also dominated by horizontal information . Hansen and Essock further showed that the horizontal effect is especially strong for horizontally sparse images. Face images are horizontally sparse: most of their energy is concentrated at the level of the horizontally-structured brows, eyes, and mouth cues . Whitening is therefore a plausible explanation for the horizontal effect occurring for face images.
Tomodensitométrie: La TDM a été pratiquée chez 7 patient afin d’évaluer le capital osseux acétabulaire et fémorale. Elle a été couplée à une angiographie dans 2 cas de protrusion cupulaire importante. Dans les deux cas, il n’y avait pas de contact avec les vaisseaux iliaques.
Este estudo dá subsídios para a discussão de duas possíveis estratégias no tratamento ao RN com gastrosquise. A primeira seria a centralização do cuidado aos RN com gastrosquise em unidades terciárias, possibilitando que o cuidado à malformação seja analisado de forma mais minuciosa e padronizada. A segunda, e talvez mais factível, seria a elaboração de diretrizes clínicas que padronizem o cuidado imediato aos RN com gastrosquise nascidos fora de centros terciários, bem como a padronização do transporte do RN até a chegada no centro terciário, minimizando possíveis complicações favorecidas pelo manejo inadequado após o nascimento.
By creating a KPDI Index weighted according to the average association of each pair with mortality, we accounted for this variation and optimised the ability of the KPDI Index to explain the association between non-ART medication count and adverse outcomes. When we summed pairwise interactions and their unadjusted component associations with survival into a severity index, we observed J-shaped associations with overall non-ART medication count and mortality rates. Although both people ageing with and without HIV infection in the lowest KPDI Index quintile were on more non-ART medications than those with no KPDI, they had lower mortality.
Se han realizado varios estudios de seroprevalencia de chikungunya en todo el mundo. Estos estudios describen seroprevalencias de 10% en el noreste de Italia (12), 37% en Mayotte (13), 38% en Reunión (14), 56% en Bagan Panchor, Malasia (15), 63% en las Comoras (16), 68% en Kerala, India (17), y 75% en la isla de Lamu, Kenia (18). Sin embargo, resulta difícil comparar los resultados obtenidos en Nicaragua con otros estudios, ya que estos se realizaron en situaciones geográficas diferentes, algunos en contexto de brotes (12–14, 16) y otros en zonas endémicas (15, 17, 18). Además, algunos de estos estudios corresponden a genotipos virales diferentes (12–17) del genotipo asiático que ha estado circulando en la región (11, 19). Finalmente, otros factores como el nivel de inmunidad poblacional, factores genéticos, los vectores causales y las medidas de control vectorial también podrían tener un impacto sobre la seroprevalencia.
Numbers of CD3-positive lymphocytes in gastric mucosa of A4gnt KO and wildtype mice. (A) Wildtype mouse administered saline. (B) A4gnt KO mouse administered saline. (C) A4gnt KO mouse administered 50 mg/day of Euglena. (D) A4gnt KO mouse administered 50 mg/day of paramylon. CD3-positive cells were stained brown by diaminobenzidine tetrahydrochloride. (E) Mean ± SD of numbers of CD3-positive cells in pyloric mucosa. Arrowheads indicate CD3-positive cells. The mean number of CD3-positive cells in gastric mucosa of A4gnt KO mice was significantly more than that of wildtype mice. Administration of Euglena and paramylon significantly reduced the number of CD3-positive cells of A4gnt KO mice compared with those in control group administered with saline.
The endothelium plays an important role in clinical ischaemia/reperfusion (I/R) injury. It is the first organ to be affected by I/R and to respond to it, and dysfunctional endothelium can contribute to local and systemic sequelae14. I/R compromises the local barrier function of endothelium, resulting in leakage and tissue edema, which can elicit an inflammatory response.
The assessment of the minimum duration and the length of the radius of the protection and surveillance zones (ToR 3) will be done independently. The setting of these two zones (protection and surveillance zones) surrounding an affected establishment and the control measures implemented in each one of the zones are based on the general principle that the probability of disease spread is larger the closer the establishment is to an affected establishment. The validity of this statement will not be assessed in this opinion; nonetheless, the limitations that this assumption may have in the control of certain diseases will, where relevant, be discussed.
В данном пилотном исследовании проведена сравнитель- ная оценка биоразнообразия и таксономической струк- туры 16S-профилей кишечного микробиома пациентов с СРК, ЯК и БА и здоровых добровольцев. Подтверждены различия между кишечными сообществами бактерий у пациентов с воспалительными заболеваниями кишечника и таковыми у здоровых людей. В ряде случаев полученные нами данные согласуются с результатами аналогичных зарубежных исследований: уменьшение индекса Шен- нона, соотношения и обилия представителей Firmicutes/ Bacteroidetes и увеличение доли последовательностей Proteobacteria в микробиоме пациентов с воспалитель- ными заболеваниями кишечника в отличие от здоровых. Вместе с тем по некоторым показателям наши результаты отличаются от опубликованных ранее. Так, у пациентов с СРК и ЯК не уменьшилась доля последовательностей Erysipelotrichaceae, а даже несколько увеличилась (пред- ставители этого семейства продуцируют короткоцепочеч- ные жирные кислоты); не отмечено и уменьшение встреча- емости лакто- и бифидобактерий (отвечают за продукцию полиненасыщенных жирных кислот). Также нетипично увеличение доли последовательностей Bacteroidetes, в частности Bacteroides spp., у больных ЯК и СРК вместо зарегистрированного ранее уменьшения (Machiels et al., 2014; Dubinsky, Braun, 2015); не обнаружен рост доли последовательностей Veillonella spp. при СРК. Подоб- ные отличия могут быть объяснены как многократными попытками лечения пациентов, кишечные сообщества которых изучали, так и региональными характеристиками популяции и особенностями питания.
A presença de anticorpos contra SARS-CoV-2 foi avaliada pelo resultado do teste rápido: quando o resultado era positivo, considerou-se que o indivíduo apresentava anticorpos contra o vírus. O uso de máscara foi avaliado pela pergunta “Você usa máscara quando sai de casa?” (“sim”, “não” ou “não sai de casa”). A adesão ao distanciamento social foi avaliada pelas seguintes questões:
Yoon Ming Chin and Rie Hayashi were reported as employees of Cancer Precision Medicine Inc, Japan. Kazuma Kiyotani and Siew‐Kee Low reported consulting or advisory roles with Cancer Precision Medicine Inc, Japan. Yusuke Nakamura reported consulting and advisory roles with OncoTherapy Science, Inc, Japan.
(a) Soil samples were immersed in PBS, then pre-enriched in overnight cultures in 0.1X Nutrient Broth. Post-enrichment cultures were mixed to form the final inoculum. The final inoculum was also frozen for follow-up experiments. (b) Timeline for the DDR64 Experiment. Cultures were sampled daily for plating and sequencing to determine composition. Cultures completed ~20–90 generations over 6 days. The 0.1 h−1 cultures were carried out for an additional 6 days in order to complete an additional 20 generations, for a total of 40. (c) Timeline and sampling schedule for DDR Washout Experiment. This experiment was started from a frozen sample of the inoculum used in the DDR64 experiment.
Zespół Bardeta i Biedla należy do tzw. grupy ciliopatii i charakteryzuje się heterogennością genetyczną – jest uwarunkowany zmianami w co najmniej 20 różnych genach: BBS1, BBS2, ARL6 (BBS3), BBS4, BBS5, MKKS (BBS6), BBS7, TTC8 (BBS8), BBS9, BBS10, TRIM 32 (BBS11), BBS12, MKS1 (BBS13), CEP290 (BBS14), WDPCP (BBS15), SDCCAG8 (BBS16), LZTFL1 (BBS17), BBIP1 (BBS18). Najczęściej mutacje stwierdza się w genach: BBS1 – 23,1%, BBS10 – 20%, BBS2 – 8,1%, BBS9 – 6% oraz MKKS (BBS6) – 5,8%. W około 20% przypadków nie identyfikuje się mutacji w żadnym z wymienionych genów . Zazwyczaj BBS dziedziczy się jako cecha autosomalna recesywna, ale w kilkunastu rodzinach (19 z typem 2 BBS oraz 9 z typem 6 BBS) stwierdzano tzw. dziedziczenie trójalleliczne. Sugerowano na tej podstawie, że BBS jest chorobą o kompleksowym wielogenowym uwarunkowaniu, a do pełnej ekspresji cech klinicznych konieczna jest obecność dodatkowej trzeciej mutacji w innym locus.
Reproduction is a fundamental process for all life. Reproductive periodicities are often intrinsic rhythms entrained by external cues that aid synchronicity in reproduction, as well as timing the arrival of vulnerable early life-stages with favourable conditions1,2. To understand environmental influences on reproductive processes, innate reproductive periodicities must be detangled from environmental fluctuations, both for regular seasonal variation and isolated events.
Starting from N-carbamimidoylindoline-1-carboximidamide hydrochloride (0.384 g, 1.60 mmol). The title compound was obtained after extraction of the impurities with boiling ethanol (1:45), a second fraction of the solid crystallized from filtrate. Yield 0.120 g (25%); m.p. 267–269 °C; IR (KBr): 3420, 3324, 3186 (N-H), 2960, 2922, 2857 (C-H), 1515, 1481 (C=N, C=CAr), 1385, 1133 (SO2) cm−1; 1H NMR (500 MHz, DMSO-d6) δ: 2.30 (s, 3H, CH3), 3.06–3.09 (t, J=8.6 Hz, 2H, 3H-indolinyl), 3.95–3.99 (m, 2H, S-CH2), 4.03–4.07 (t, 2H, J=8.6 Hz, 2H, 2H-indolinyl), 6.79–7.79 (m, 7H, 7 HAr and 2H, NH2, 1H, H-3), 7.97 (m, 1H, H-6), 11.80 (m, 2H, NH, 5-fluorobenzimidazolidine) ppm; Anal. calcd. for C26H22ClFN8O2S2 (597.09); C, 52.30; H, 3.71; N, 18.77. Found: C, 52.26; H, 3.70; N, 18.53. HRMS (ESI-TOF) (596.0980) calcd for C26H22ClFN8O2S2 [M + H]+ (597.1058) found 597.1050.
A two-factor dosage and duration experiment was set up with eight and ten levels, respectively. HL60 cells were subjected to the following dosages (μM): 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001, and 0.0005 in conjunction with the following durations (Days of Treatment): 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13. For example, one of the eighty treatment combinations is 1 μM/4 Days, in which, we treated the HL60 cells with 1 μM of ATRA for 4 Days and measured the CD11b expression of these treated cells by flow cytometry. Each of the 80 dosage/duration combinations and CD11b measurements were performed in triplicate.
Por todo ello, prevalece en nuestro equipo la confianza de que nos esperan muchos más años en este camino de apoyo a la divulgación y la cooperación científica. La publicación ininterrumpida de la revista en estos 40 años refleja el incansable interés y el compromiso de los editores y los revisores expertos, de tantos autores influyentes y, por supuesto, del equipo editorial. Agradecemos profundamente el aporte de todos ellos, así como el del Instituto Nacional de Salud por garantizar la autonomía y la independencia de la revista y por la gestión y promoción que le han permitido mantenerse durante estas cuatro décadas.
虽然靶向治疗在表皮生长因子受体（epidermal growth factor receptor, EGFR）基因突变的晚期NSCLC患者的一线治疗中取得了明确的疗效，但对于大多数晚期NSCLC患者取得组织学标本进行基因突变检测仍然受限。TORCH研究的结论指出，对于EGFR基因突变状态未知的NSCLC患者，一线接受化疗患者的生存优于一线接受靶向治疗患者。而吉西他滨联合铂类是晚期NSCLC一线治疗最常用的化疗方案。吉西他滨与铂类的作用机制不同，在疗效上有协同作用[7, 8]，而主要毒性作用无明显叠加，两者联合治疗晚期NSCLC疗效已被国外30多项Ⅲ期临床试验所评估。ECOG 1594研究比较了4个常用的标准一线化疗方案的疗效，在生存期和有效率方面4个方案相似，而吉西他滨联合顺铂在疾病进展时间（time to progression, TTP）和1年生存率方面占有优势。
Тест-версию PHPQoL проверяли в фокусной популяции пациентов с ПГПТ в процессе индивидуального интервьюирования. В зарубежных рекомендациях этот этап называют когнитивным дебрифингом . Данный этап состоит в тестировании опросника в рамках создания его русской версии на основании мнения пациентов. Цель тестирования (когнитивного дебрифинга) русской версии PHPQoL — максимально приблизить концепцию инструмента к культурным и языковым традициям и особенностям популяции больных ПГПТ в России. Интервьюирование (тестирование) больных проводили на базе отделения эндокринной хирургии Клиники высоких медицинских технологий им. Н.И. Пирогова СПбГУ после подписания пациентами информированного согласия. Ключевыми аспектами при тестировании PHPQoL в процессе интервьюирования пациентов по каждому пункту опросника являлись:
Chloroviruses are ubiquitous in freshwater environments, and virus concentrations can fluctuate weekly, with titers occasionally reaching thousands of PFU/mL of water (11–13). An ongoing question has been: how do the chloroviruses replicate in their natural environments? This question is relevant because zoochlorellae are protected from chlorovirus infection while they are in their symbiotic phase due to the physical barrier of the paramecium cell membrane, which prevents chlorovirus–zoochlorellae interactions. There is no evidence for an alternative chlorovirus host and, although zoochlorellae can grow in culture in the laboratory, the zoochlorellae grow poorly, if at all, in native waters free of viruses (Quispe et al., unpublished results). It is known, however, that chloroviruses can attach to the external surface of paramecia without infecting them . Consequently, the viruses are positioned to attack the zoochlorellae if the paramecia are disrupted.
Exosomes mediate cell-to-cell communication through the transfer of their cargoes of proteins, mRNAs, miRs, and lncRNAs that participate in the genetic exchange among cells . To provide valuable insight into the underlying molecular mechanism of exosomes, we detected the expression of some miRs and lncRNAs present in the HCC microenvironment. Administration of CSCs-exosomes increased the expression of HCC exosomal miR21 and decreased the expression of liver miR122 and HCC miRs (miR148a, miR16, and miR125b) than that of HCC liver injected by PBS. This expression profile for miRs was reversed in the MSC-Ex group. Among these miRs, miR122 is a liver-specific miR constituting 70% of the liver miRs and its downregulation associated with HCC progression in humans and rodents [55, 56]. However, miR21, as a liver-specific antiproliferative miR, is overexpressed in HCC cells and promotes their proliferation and metastasis . Consequently, miR21 inhibition induces apoptosis in CSCs . In addition, miR122-loaded MSC exosomes increased the chemosensitivity of HCC cells both in vitro and in vivo , indicating a potential role for MSCs-exosome, through their antitumor miRs, in HCC treatment. In consistence, we also found increased expression of miR122 along with increased apoptosis in HCC liver following injection of MSCs-exosomes. The anti-HCC effect of miR122 is prevented by IGF1 produced by HCC cells to ensure their own proliferation . Thus, in the present study, CSCs may induce HCC progression through downregulation of miR122 in the tumor microenvironment, but this needs experiments using mimic122 and anti-miR122 to confirm this hypothesis. Similarly, anti-HCC miR148a and miR125b exert inhibitory effects on epithelial mesenchymal transition (EMT) and CSC-like phenotypes by targeting TGFβ1, which is a potent stimulator for EMT in the tumor microenvironment and induces the transformation of liver stem cells into CSCs in HCC . In agreement, animals injected by CSCs-exosomes exhibited a decreased level of these two miRs (miR148a and miR125b) and an increased serum level of TGFβ1 and hepatic expression of TGFβ1 mRNA and protein. miR148a is also a proapoptotic miRNA which represses Bcl2 . This may explain decreased apoptosis in HCC cells of the CSCs-Ex group which had lowest miR148a and highest Bcl2 mRNA levels. In contrast, MSCs-exosomes' repressive role on HCC may be mediated by high miR148a and low Bcl2 mRNA and TGFβ1 mRNA and protein levels. Furthermore, MSCs-exosomes are highly enriched in antiangiogenic miR16 that suppresses VEGF expression thereby favoring the inhibition of angiogenesis in recipient breast cancer cells (reviewed by ). In a similar way, we found upregulation of miR16 and VEGF gene in livers of HCC rats receiving BM-MSCs.
One of the limitations of this study was the decision to only consider systematic reviews of interventional studies. This decision was made because systematic reviews of diagnostic and observational studies use different RoB assessment tools compared to interventional studies. This also helped us to better organize the findings and provide the results for most interventional reviews published by the Cochrane Oral Health group.

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