Gastric cancer (GC) is an aggressive and heterogeneous disease with poor survival outcomes. The progression of GC involves complex, multi-step processes. Endothelial cells (ECs) play a crucial role in tumor angiogenesis, proliferation, invasion, and metastasis, particularly through the process of endothelial-to-mesenchymal transition (EndoMT). However, the specific role and mechanisms of EndoMT in gastric cancer remain unclear. Based on 6 GC single-cell RNA-sequencing (scRNA-seq) cohorts (samples = 97), we established an EndoMT-related gene signature, termed EdMTS. Leveraging this gene signature, ssGSEA was applied to calculate sample scores across multiple bulk RNA-seq datasets, which include information on immunotherapy, metastasis, GC progression, and survival. Moreover, we applied the Monocle2 method to calculate cell pseudotime and used CellChat to analyze interactions between malignant and EC cells. We verified the molecular mechanism by multiple immunofluorescence and cell function experiments. Findings In this study, we established a single-cell atlas of ECs in GC and identified a subpopulation of COL1A1+ ECs that play a critical role in tumor progression and metastasis. These COL1A1+ ECs were significantly associated with worse clinical outcomes in GC patients. Further analysis revealed that COL1A1+ ECs originated from lymphatic ECs and underwent EndoMT through the upregulation of CEBPB, driving tumor invasiveness. Moreover, COL1A1+ ECs interacted with malignant cells via ANGPTL4-SDC4 axis, enhancing invasion and migration. These findings provide a deeper understanding of the role of COL1A1+ ECs in GC progression and highlight potential therapeutic targets for disrupting the EndoMT process in these cells to provide a benefit for GC patients.

Angioimmunoblastic T-cell lymphoma (AITL) is a kind of aggressive T-cell lymphoma with significant enrichment of non-malignant tumor microenvironment (TME) cells. However, the complexity of TME in AITL progression is poorly understood. We performed single-cell RNA-Seq (scRNA-seq) and imaging mass cytometry (IMC) analysis to compare the cellular composition and spatial architecture between relapsed/refractory AITL (RR-AITL) and newly diagnosed AITL (ND-AITL). Our results showed that the malignant T follicular helper (Tfh) cells showed significantly increased proliferation driven by transcriptional activation of YY1 in RR-AITL, which is markedly associated with the poor prognosis of AITL patients. The CD8+ T cell proportion and cytotoxicity decreased in RR-AITL TME, resulting from elevated expression of the inhibitory checkpoints such as PD-1, TIGIT, and CTLA4. Notably, the transcriptional pattern of B cells in RR-AITL showed an intermediate state of malignant transformation to B-cell-lymphoma, and contributed to immune evasion by highly expressing CD47 and PD-L1. Besides, compared to ND-AITL samples, myeloid-cells-centered spatial communities were more prevalent but showed reduced phagocytic activity and impaired antigen processing and presentation in RR-AITL TME. Furthermore, specific inhibitory ligand-receptor interactions, such as CLEC2D-KLRB1, CTLA4-CD86, and MIF-CD74, were exclusively identified in the RR-AITL TME. Our study provides a high-resolution characterization of the immunosuppression ecosystem and reveals the potential therapeutic targets for RR-AITL patients.

"自然辩证法"是恩格斯自然观的表现形式,其内容过去一般表述为逻辑形态的"三大规律",而比较忽视其历史形态,或将历史形态归结为逻辑形态.恩格斯自然辩证法或包括恩格斯思想在内的马克思主义的自然观具有两种形态——逻辑形态和历史形态,两种形态的辩证法既有联系亦有区别,不应完全加以混淆,否则在凸显了(自然)辩证法的逻辑形态的同时可能会遮蔽其历史形态的另一面,而后者是马克思主义自然观和辩证法更为重要的一面.可以说,历史性或历史主义是恩格斯自然观(当然也是马克思自然观)最为本质的属性和品格.

马克思的辩证法可以称之为历史辩证法.相比于恩格斯,马克思更多地关注社会历史领域,他的辩证法主要表现为一种历史形态,呈现为一种看待事物和问题的历史性或历史主义原则.当然,马克思的历史辩证法不仅涵盖了社会历史领域,而且也关涉到自然界,因此,它是统摄一切的世界观而不仅仅是一种历史观.恩格斯的辩证法给人印象更为突出和深刻的似乎是一种以自然辩证法为代表的逻辑形态的辩证法,表现为哲学教科书那般以范畴和规律为内容的理论体系.然而实际上,恩格斯也有与马克思相一致的丰富的历史辩证法思想.马克思的历史辩证法或曰辩证法的历史形态与恩格斯的自然辩证法或曰辩证法的逻辑形态在本质上是完全一致的.历史形态的辩证法更为根本,它是因,逻辑形态的辩证法则是果.两者的根本一致性就在于,辩证法的本质就是历史性或历史主义,辩证的就是历史的.

Introduction Orelabrutinib (ICP-022) is a novel and highly selective irreversible Bruton's tyrosine kinase (BTK) inhibitor which showed high bioavailability with ~100% BTK occupancy at 24 h at 150 mg daily dosing regimen and demonstrated excellent safety and efficacy profiles in a Phase I/II trial of refractory/relapsed (r/r) chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL). However, the resistant mechanisms of orelabrutinib have not been reported yet. Methods Deep targeted-gene next generation sequencing (NGS) covering BTK (exon 1-19), PLCG2 (exon 1-33) and high sensitivity droplet digital PCR (ddPCR) detecting BTK Cys481 mutation were assessed in available serial samples in orelabrutinib progression patients in NCT03493217. Results We identified 6 patients of our cohort who progressed on orelabrutinib treatment in clinical trial, the median time from orelabrutinib initiation to resistance was 31 months. 3 patients progressed due to lymph nodes enlargement while other 3 patients due to increasing CLL counts in peripheral blood (Figure A). Deep targeted-gene NGS showed that BTK mutations were detected in 5 of 6 patients (5/6, 83.3%, Figure B). Remarkably, BTK kinase domain mutation, BTK Thr474Ile (NM_000061.2: exon15: c.1421C>T: p.T474I) was detected in 2 patients progressed on orelabrutinib. BTK Cys481 mutation was found in other 3 patients progressed on orelabrutinib, among them one patient harboring both BTK Cys481Arg (NM_000061.2: exon15: c.1441T>C: p.C481R) and BTK Leu528Trp (NM_000061.2: exon16: c.1583T>G: p.L528W). In the patient who harbored both BTK C481R and BTK L528W, the variant allele frequency (VAF) of BTK L528W were significantly than BTK L528W (median BTK L528W 9.16% vs. BTK C481S 3.45%). Assessment of the BTK Cys481 mutation with ddPCR confirmed the above results. Longitudinal NGS analysis of the six patients before orelabrutinib initiation and after orelabrutinib resistances was conducted and the mutational landscape was shown in Figure C. TP53 mutation detected in 2 patients (one of them harbored TP53 Deletion) before orelabrutinib initiation remained existence after orelabrutinib resistance while 1 patient with TP53 deletion before orelabrutinib initiation evolved novel TP53 mutation clone. Conclusion: We firstly described the BTK mutations occurring in patients with CLL progressing on Orelabrutinib. BTK T474I and BTK L528W were found enriched, suggesting its different mechanisms from the first-generation BTK inhibitor, ibrutinib. Moreover, BTK T474I and L528W were reported to result in resistance to LOXO-305 while ibrutinib could partly overcome the resistance cause by BTK T474I and L528W, indicating different treatment options after orelabrutinib resistance. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

马克思主义具有极其强烈的历史意识.马克思主义哲学不应被理解为唯物主义与辩证法的结合,而应是唯物主义与历史的结合,它包括"唯物主义的历史化"和"历史的唯物主义化"两个方面.这种结合使马克思主义的历史概念具有两层内涵:一是历史的"唯物"性.其理论表现形态是"唯物史观",属于一种狭义的历史观.它是对历史的唯物主义定位,即将历史视为人的实践活动特别是生产活动的领域;二是历史的流变性.其理论表现形态是"历史(的)唯物主义".它不是前者那种狭义的历史观,而是对事物的一种历史主义的理解和把握,是一种哲学的新形态——历史哲学.将这种"唯物主义与历史的结合"的观点运用到对科学的理解上,产生了马克思独具特色的"一门科学"思想.

Background Males and females differ in their immunological responses to foreign pathogens. However, most of the current COVID-19 clinical practices and trials do not take the sex factor into consideration. Methods We performed a sex-based comparative analysis for the clinical outcomes, peripheral immune cells, and severe acute respiratory syndrome coronavirus (SARS-CoV-2) specific antibody levels of 1558 males and 1499 females COVID-19 patients from a single center. The lymphocyte subgroups were measured by Flow cytometry. The total antibody, Spike protein (S)-, receptor binding domain (RBD)-, and nucleoprotein (N)- specific IgM and IgG levels were measured by chemiluminescence. Results We found that male patients had approximately two-fold rates of ICU admission (4.7% vs. 2.7% in males and females, respectively, P = 0.005) and mortality (3% vs. 1.4%, in males and females, respectively, P = 0.004) than female patients. Survival analysis revealed that the male sex is an independent risk factor for death from COVID-19 (adjusted hazard ratio [HR] = 2.22, 95% confidence interval [CI]: 1.3–3.6, P = 0.003). The level of inflammatory cytokines in peripheral blood was higher in males during hospitalization. The renal (102/1588 [6.5%] vs. 63/1499 [4.2%], in males and females, respectively, P = 0.002) and hepatic abnormality (650/1588 [40.9%] vs. 475/1499 [31.7%], P = 0.003) were more common in male patients than in female patients. By analyzing dynamic changes of lymphocyte subsets after symptom onset, we found that the percentage of CD19+ B cells and CD4+ T cells was generally higher in female patients during the disease course of COVID-19. Notably, the protective RBD-specific IgG against SARS-CoV-2 sharply increased and reached a peak in the fourth week after symptom onset in female patients, while gradually increased and reached a peak in the seventh week after symptom onset in male patients. Conclusions Males had an unfavorable prognosis, higher inflammation, a lower percentage of lymphocytes, and indolent antibody responses during SARS-CoV-2 infection and recovery. Early medical intervention and close monitoring are important, especially for male COVID-19 patients.

Background COVID-19 has resulted in high mortality worldwide. Information regarding cardiac markers for precise risk-stratification is limited. We aim to discover sensitive and reliable early-warning biomarkers for optimizing management and improving the prognosis of COVID-19 patients. Methods A total of 2954 consecutive COVID-19 patients who were receiving treatment from the Wuhan Huoshenshan Hospital in China from February 4 to April 10 were included in this retrospective cohort. Serum levels of cardiac markers were collected after admission. Coronary artery disease diagnosis and survival status were recorded. Single-cell RNA-sequencing and bulk RNA-sequencing from different cohorts of non-COVID-19 were performed to analyze SARS-CoV-2 receptor expression. Results Among 2954 COVID-19 patients in the analysis, the median age was 60 years (50–68 years), 1461 (49.5%) were female, and 1515 (51.3%) were severe/critical. Compared to mild/moderate (1439, 48.7%) patients, severe/critical patients showed significantly higher levels of cardiac markers within the first week after admission. In severe/critical COVID-19 patients, those with abnormal serum levels of BNP (42 [24.6%] vs 7 [1.1%]), hs-TNI (38 [48.1%] vs 6 [1.0%]), α- HBDH (55 [10.4%] vs 2 [0.2%]), CK-MB (45 [36.3%] vs 12 [0.9%]), and LDH (56 [12.5%] vs 1 [0.1%]) had a significantly higher mortality rate compared to patients with normal levels. The same trend was observed in the ICU admission rate. Severe/critical COVID-19 patients with pre-existing coronary artery disease (165/1,155 [10.9%]) had more cases of BNP (52 [46.5%] vs 119 [16.5%]), hs-TNI (24 [26.7%] vs 9.6 [%], α- HBDH (86 [55.5%] vs 443 [34.4%]), CK-MB (27 [17.4%] vs 97 [7.5%]), and LDH (65 [41.9%] vs 382 [29.7%]), when compared with those without coronary artery disease. There was enhanced SARS-CoV-2 receptor expression in coronary artery disease compared with healthy controls. From regression analysis, patients with five elevated cardiac markers were at a higher risk of death (hazards ratio 3.4 [95% CI 2.4–4.8]). Conclusions COVID-19 patients with pre-existing coronary artery disease represented a higher abnormal percentage of cardiac markers, accompanied by high mortality and ICU admission rate. BNP together with hs-TNI, α- HBDH, CK-MB and LDH act as a prognostic biomarker in COVID-19 patients with or without pre-existing coronary artery disease.

马克思主义理解的“科学”主要有两重含义:首先是对客观事物规律的揭示.以此观之,马克思主义可以被视为人类社会发展规律的科学.但马克思主义对科学的理解还有另外一个极为重要但不太为所人注意的侧面,那就是它强调一切科学的“历史性”,认为科学不是纯粹理性的产物,而是与人的感性活动即生活和实践密切相关,因而是历史地演变着的.在这个意义上,自然科学与人文社会科学都是“历史科学”.这一点是马克思主义的科学概念区别于同时期其他科学概念的主要之处.

马克思主义传入中国后,围绕着马克思主义爆发了一场著名的争论——"问题与主义"论战.它对于迅速扩大马克思主义在中国的影响意义重大.但它并不仅仅局限于具体的解决社会问题的策略和方案的争执,而是反映了现代中国人对两种理性即"进化理性"和"建构理性"的取舍和偏好.早期马克思主义者的注意力主要集中在与中国革命关系更为直接的唯物史观和阶级斗争学说上,力图为现实的革命斗争服务;就马克思主义哲学而言,早期传播的重点在唯物史观,对辩证法则相对比较忽视.

Increasing evidence indicates that tumor-initiating cells (TICs) are responsible for the occurrence, development, recurrence, and development of the drug resistance of cancer. MicroRNA (miRNA) plays a significant functional role by directly regulating targets of TIC-triggered non-small-cell lung cancer (NSCLC), but little is known about the function of the miR-30 family in TICs. In this study, we found the miR-30 family to be downregulated during the spheroid formation of NSCLC cells, and patients with lower miR-30a/c expression had shorter overall survival (OS) and progression-free survival (PFS). Moreover, transmembrane 4 super family member 1 (TM4SF1) was confirmed to be a direct target of miR-30a/c. Concomitant low expression of miR-30a/c and high expression of TM4SF1 correlated with a shorter median OS and PFS in NSCLC patients. miR-30a/c significantly inhibited stem-like characteristics in vitro and in vivo via suppression of its target gene TM4SF1, and then it inhibited the activity of the mTOR/AKT-signaling pathway. Thus, our data provide the first evidence that TM4SF1 is a direct target of miR-30a/c and miR-30a/c inhibits the stemness and proliferation of NSCLC cells by targeting TM4SF1, suggesting that miR-30a/c and TM4SF1 may be useful as tumor biomarkers for the diagnosis and treatment of NSCLC patients.

MicroRNAs (miRNAs) are a class of evolutionarily conserved small noncoding RNAs, ~22 nt in length, and found in diverse organisms and play important roles in the regulation of mRNA translation and degradation. It was shown that miRNAs were involved in many key biological processes through regulating the expression of targets. Genetic polymorphisms in miRNA target sites may alter miRNA regulation and therefore result in the alterations of the drug targets. Recent studies have demonstrated that SNPs in miRNA target sites can affect drug efficiency. However, there are still a large number of specific genetic variants related to drug efficiency that are yet to be discovered. We integrated large scale of genetic variations, drug targets, gene interaction networks, biological pathways, and seeds region of miRNA to identify miRNA polymorphisms affecting drug response. In addition, harnessing the abundant high quality biological network/pathways, we evaluated the cascade distribution of tarSNP impacts. We showed that the predictions can uncover most of the known experimentally supported cases as well as provide informative candidates complementary to existing methods/tools. Although there are several existing databases predicting the gain or loss of targeting function of miRNA mediated by SNPs, such as PolymiRTS, miRNASNP, MicroSNiPer, and MirSNP, none of them evaluated the influences of tarSNPs on drug response alterations. We developed a user-friendly online database of this approach named Mir2Drug.

马克思固然不是一个古典意义上的自由主义者或人道主义者，但今天越来越多的人已经认识到，马克思主义的出发点、目的和归宿是人道主义，马克思主义是西方人道主义传统的继承者和捍卫者，并且把传统人道主义发展到了一个全新的阶段。围绕着马克思的自由观，文章主要讨论了以下问题：马克思主义如何理解和看待自由？这种理解与自由主义对自由的理解是什么关系？人的自由如何才能得到实现？文章将马克思主义的自由概念界定为：以人的独立性为前提，以人的自主性选择为基础，通过对客观世界（包括自然界和社会）的认识和改造即对象化的活动而实现的一种解放与自我发展。对自由的这种界定与自由主义对自由的理解存在以下差别：（1）人类解放与政治解放的差别。（2）自觉性与自发性的差别。（3）社会性自由与个人主义式自由的差别。关于自由的实现条件，马克思的观点是：首先，生产力水平的高度发展和物质产品的极大丰富是实现人的自由的基本前提。其次，公有制是实现人的自由的基本保障。再次，人的自由的真正实现不仅需要经济条件，也同样必须具备政治条件，即推翻国家，建立消除阶级和阶级对立的“自由人联合体”。

In the modern China nothing can be more acceptable than the western science,that is,firstly, scientific instruments,secondly,scientific knowledge and disciplines,and lastly scientific way of thinking and spirit.Among the western cultural factors,Marxism is also an influencing one in China.Why is Marx-ism accepted widely in China?According to cultural logic,it can be said that in China scientific socialism is regarded as a science and Marxism an ideology of science.

十月革命前夕,普列汉诺夫与列宁曾经就资本主义落后的俄国能否立即推翻资产阶级临时政府、实行社会主义革命展开过激烈的争论.普列汉诺夫秉持历史决定论的立场,主张俄国革命必须严格遵循由资产阶级民主革命循序渐进地演变到社会主义革命的规律,认为俄国当前的任务是建立资本主义民主制度,大力发展生产力,而不是立刻实施社会主义.而列宁则主张在资产阶级革命成功后不失时机地将革命引向社会主义,由布尔什维克夺取政权.在这场争论中,就成功地夺取政权、建立人类历史上第一个社会主义国家而言,列宁无疑是胜利者.而从后来社会主义实践的进程来说,普列汉诺夫的一些观点对我们今天的社会主义建设事业也不无启示意义.

在黑格尔那里,异化是指绝对观念的自我异化,即对象化、外化、物化,此后又经扬弃回到自身.异化是否定之否定运动的一个必然环节,绝对观念经自我丧失又自我复归.马克思肯定黑格尔抓住了劳动的本质,把人的自我产生看作一个过程,即人通过自我的对象化、外化劳动这种异化的形式,才能作为现实存在物得到实现,即作为他自己劳动的结果而复归了.[1]因此,在黑格尔那里,异化并不是一种价值判断,而是一种“事实判断”,异化不作为价值判断,故不含褒贬之意.而马克思则将异化概念价值化了,他将对象化与异化作了重要区分,认为对象化、外化、物化是事实判断,而异化则是对事实的价值判断,异化是应予消除的.他认为劳动是人的本质,因此劳动“应该”成为人的目的价值,而“不应该”当作有损于人的手段价值.“应该”就是价值判断,当劳动“不应该”成为损人的手段时,马克思就认为雇佣劳动被异化了.

马克思的人学思想主要包括以下几个方面的内容:人的全面发展思想;把劳动作为人的第一需要的思想;关于人的本质的思想.人的全面发展和视劳动为生存第一需要的思想是对资本主义社会异化劳动和分工的强烈控诉和反拨,因而具有极强的审美和道德意味.然而,这些在当今社会越来越发达的分工和越来越令人窒息的生存压力的现状下被许多人视为难以实现的“劳动乌托邦”.而对人的本质的两种理解也再一次表现了马克思思想中所固有的决定论与意志自由论的张力.

科学对中国现代思想的形成和演变具有极为重要的影响,而科学又是理性的产物,因此中国现代思想表现出一种明显的唯理主义品格。理性(科学)是中国现代思想衡量一种学说和理论能否被接受的最基本的标准之一。现代中国人对社会主义和共产主义理想的信奉和追求,对人的自觉能动性的推崇,对计划经济的偏爱,无不与理性息息相关。然而,理性虽然对中国社会极端重要,但其在社会政治领域中的不恰当运用却可能造成以下后果:一、激进的或极端的反传统主义。二、政治理想主义。三、政治思维取向上的"未来主义"。造成这种状况的理论原因在于:一是对理性的纯粹化、理想化的理解,从而把理性与实践对立起来,不了解实践理性也是理性的一种形式。二是由于未能正确把握理性与实践、纯粹理性与实践理性的关系,因而只把技术性知识当作知识,而忽视实践性知识的重要性。

进步的观念是近代以来最为流行的观念之一,是所谓"现代性"的核心价值与理念。进步观念在近代的降临与科学有关,人们之所以敢于以前所未有的自信肯定社会的进步,预测社会的未来,皆因科学这种征服自然和改造自然的能力与所创造的物质财富的数量和质量是可以精确衡量的。近代以来,奠基于科学基础之上的进化思潮对国人产生了深远的影响,它极大地支配了我们对革命、创新、民主等观念的诠释与理解。