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The truncated chromosome 22 that results from the reciprocal translocation t(9;22)(q34;q11) is known as the Philadelphia chromosome (Ph) and is a hallmark of chronic myeloid leukemia (CML). In leukemia cells, Ph not only impairs the physiological signaling pathways but also disrupts genomic stability. This aberrant fusion gene encodes the breakpoint cluster region‐proto‐oncogene tyrosine‐protein kinase (BCR‐ABL1) oncogenic protein with persistently enhanced tyrosine kinase activity. The kinase activity is responsible for maintaining proliferation, inhibiting differentiation, and conferring resistance to cell death. During the progression of CML from the chronic phase to the accelerated phase and then to the blast phase, the expression patterns of different BCR‐ABL1 transcripts vary. Each BCR‐ABL1 transcript is present in a distinct leukemia phenotype, which predicts both response to therapy and clinical outcome. Besides CML, the Ph is found in acute lymphoblastic leukemia, acute myeloid leukemia, and mixed‐phenotype acute leukemia. Here, we provide an overview of the clinical presentation and cellular biology of different phenotypes of Ph‐positive leukemia and highlight key findings regarding leukemogenesis.

Despite the progress of treatment in gastric cancer (GC), the overall outcomes remain poor in patients with advanced diseases, underscoring the urgency to develop more effective treatment strategies. BH3-mimetic drugs, which inhibit the pro-survival BCL2 family proteins, have demonstrated great therapeutic potential in cancer therapy. Although previous studies have implicated a role of targeting the cell survival pathway in GC, the contribution of different pro-survival BCL2 family proteins in promoting survival and mediating resistance to current standard therapies in GC remains unclear. A systematic study to elucidate the hierarchy of these proteins using clinically more relevant GC models is essential to identify the most effective therapeutic target(s) and rational combination strategies for improving GC therapy. Here, we provide evidence from both in vitro and in vivo studies using a broad panel of GC cell lines, tumoroids, and xenograft models to demonstrate that BCLXL and MCL1, but not other pro-survival BCL2 family proteins, are crucial for GC cells survival. While small molecular inhibitors of BCLXL or MCL1 exhibited some single-agent activity, their combination sufficed to cause maximum killing. However, due to the unsolved cardiotoxicity associated with direct MCL1 inhibitors, finding combinations of agents that indirectly target MCL1 and enable the reduction of doses of BCLXL inhibitors while maintaining their anti-neoplastic effects is potentially a feasible approach for the further development of these compounds. Importantly, inhibiting BCLXL synergized significantly with anti-mitotic and HER2-targeting drugs, leading to enhanced anti-tumour activity with tolerable toxicity in preclinical GC models. Mechanistically, anti-mitotic chemotherapies induced MCL1 degradation via the ubiquitin-proteasome pathway mainly through FBXW7, whereas HER2-targeting drugs suppressed MCL1 transcription via the STAT3/SRF axis. Moreover, co-targeting STAT3 and BCLXL also exhibited synergistic killing, extending beyond HER2-amplified GC. Collectively, our results provide mechanistic rationale and pre-clinical evidence for co-targeting BCLXL and MCL1 (both directly and indirectly) in GC. ( i ) Gastric cancer cells rely on BCLXL and, to a lesser degree, on MCL1 for survival. The dual inhibition of BCLXL and MCL1 with small molecular inhibitors acts synergistically to kill GC cells, regardless of their TCGA molecular subtypes or the presence of poor prognostic markers. While the effect of S63845 is mediated by both BAX and BAK in most cases, BAX, rather than BAK, acts as the primary mediator of BCLXLi in GC cells. ( ii ) Inhibiting BCLXL significantly synergizes with anti-mitotic and HER2-targeting drugs, leading to enhanced anti-tumour activity with tolerable toxicity in preclinical GC models. Mechanistically, anti-mitotic chemotherapies induce MCL1 degradation via the ubiquitin-proteasome pathway mainly through FBXW7, whereas HER2-targeting drugs suppress MCL1 transcription via the STAT3/SRF axis. The combination of the STAT3 inhibitor and BCLXL inhibitor also exhibits synergistic killing, extending beyond HER2-amplified GC.

Sr-doped SnO2 thick film gas sensors were prepared for domestic liquefied petroleum gas (LPG) determination down to several ppm levels using the screen-printing technique. Characterization of Sr-doped SnO2 thick film was investigated by XRD, XPS and DTA-TGA analyses. The sensitivity, selectivity, sintering temperature, and static and dynamic measurement were investigated. The results showed that the Sr-doped SnO2 thick film sensor is suitable for several ppm levels LPG determination because of the high sensitivity (S = 12.7 to 10 ppm LPG). The dynamic measurements showed that the sensor exhibited high sensitivity and selectivity to domestic LPG at 210–300 °C.

R373.1; 严重急性呼吸综合征冠状病毒2(SARS-CoV-2)导致的新型冠状病毒肺炎(COVID-19)自暴发以来迅速在全球蔓延,造成数以千万人感染及数十万患者死亡.基于研究证据的临床实践指南是诊治COVID-19的有力武器.在疫情早期阶段,该团队制定并发布了《新型冠状病毒(2019-nCoV)感染的肺炎诊疗快速建议指南(标准版)》.疫情暴发后大量相关临床研究陆续开展并发表,新的证据可能会改变以前的推荐意见,更新指南的时机已经成熟.因此,该团队成立了由临床专家和方法学家组成的工作组,通过咨询一线临床专家提出并确定了与COVID-19管理相关的29个临床问题.通过系统检索有关COVID-19预防及诊疗的直接证据,使用GRADE方法评估证据质量并制订推荐意见,最终形成34条建议,其中6条强推荐,14条弱推荐,3条弱不推荐,11条为基于共识的建议;共涵盖4个方面,分别为药物预防,诊断(包括临床表现、RT-PCR检测、呼吸道标本、IgM和IgG抗体检测、CT检查、胸部X线片及无症状感染的CT特征),治疗方法[包括洛匹那韦-利托那韦、阿比朵尔、法匹拉韦、干扰素、瑞德西韦、抗病毒药的组合、羟氯喹/氯喹、白介素-6抑制剂、白介素-1抑制剂、糖皮质激素、清肺排毒汤、连花清瘟胶囊/颗粒、康复者血浆、肺移植、有创或无创通气、体外膜肺氧合支持(ECMO)]以及出院管理(包括复阳患者管理及出院标准).此外,还制订了针对推荐意见的指南实施工具流程图,以期有力支持医护人员对COVID-19患者的照护.