Comparison of the safety and prognosis of sequential regorafenib after sorafenib and lenvatinib treatment failure in patients with unresectable hepatocellular carcinoma: a retrospective cohort study

BackgroundThere is lack of studies on sequential regorafenib after sorafenib and lenvatinib treatment failure in patients with unresectable hepatocellular carcinoma (HCC). This study was to explore the safety and prognosis of sequential regorafenib after sorafenib and lenvatinib failure in HCC patients.MethodsThis study was a retrospective, real-world study that included 50 HCC patients who received sequential regrafinib after sorafenib and lenvatinib failure. The safety and prognosis of two groups were compared.ResultsThe incidence of all grade and III/IV adverse events were 68% and 24%. According to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 and modified (m) RECIST standards, the objective response rates (ORRs) after receiving regorafenib were 14.0% and 22.0%, respectively. The disease control rates (DCRs) were 62.0% and 60.0%, respectively. Based on different first-line targeted drugs, 50 patients were divided into sorafenib (n=22) and lenvatinib group (n=28). There was no differences between two groups except age and bilirubin. And there was no differences in other treatments before or after regorafenib. The baseline between two groups was basically same and had good comparability. There was no difference in incidence of all grade and III/IV adverse events, ORR and DCR between two groups (P>0.05). On long-term prognosis, total overall survival (TOS) in sorafenib and lenvatinib group were 23.0 (95% CI: 15.1–30.9) vs. 29.7 (95% CI: 21.4–38.1) months. The difference was statistically significant (P=0.041). Besides, regorafenib overall survival (ROS) in sorafenib and lenvatinib group were 11.7 (95% CI: 7.1–16.3) vs. 15.9 (95% CI: 8.3–23.5) months. The difference was statistically significant ( P=0.045). The regorafenib progression-free survival (RPFS) was 5.6 (95% CI: 1.9–9.2) vs. 8.0 (95% CI: 5.1–10.9) months in sorafenib and lenvatinib group, respectively, and difference was not statistically significant (P=0.380).ConclusionsRegorafenib is an effective drug for second-line treatment of HCC, with fewer severe adverse events, ORR and DCR was 14–22% and 62–60%, respectively. Both TOS and ROS in lenvatinib group were better than those in sorafenib group. For HCC patients whose first-line targeted drug is lenvatinib, it is safe and effective to accept regorafenib after disease progresses.     

视野半侧缺损的原发性开角型青光眼视网膜微循环改变的研究

目的:研究视野半侧缺损的原发性开角型青光眼（POAG）视盘旁和黄斑区血管密度的改变及其与视网膜神经纤维层（RNFL）厚度及视野指标的关系。方法:横断面研究。收集2015年10月至2018年10月于复旦大学附属眼耳鼻喉科医院眼科应用Humphery视野计30-2程序检测为视野半侧缺损的POAG患者（POAG组）28例（2...     

LINC00941 promoted in vitro progression and glycolysis of laryngocarcinoma by upregulating PKM via activating the PI3K/AKT/mTOR signaling pathway

BackgroundLINC00941 has been proved to be related to various tumors, but its relationship with laryngocarcinoma remains vague.MethodsLINC00941 expression in laryngocarcinoma tumor and laryngocarcinoma cells was determined by real time‐quantitative polymerase chain reaction (RT‐qPCR). Besides, the five‐year survival of laryngocarcinoma patients with different LINC00941 expression was analyzed with Kaplan–Meier survival analysis, and the clinical characteristics of laryngocarcinoma patients were also recorded. After transfection, cell viability, cell proliferation, apoptosis, cell cycle, migration, and invasion were detected by cell counting kit‐8 (CCK‐8), colony formation, flow cytometry, cell scratch, and Transwell assays, respectively. Glycolysis was assessed by the colorimetric method. Expressions of proliferation‐associated proteins, migration‐associated proteins, glycolysis‐associated proteins, and phosphatidylinositol 3‐kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signal pathway‐associated proteins were detected by Western blot.ResultsIn laryngocarcinoma tumor tissues and cells, LINC00941 was highly expressed. High expression of LINC00941 decreased the 5‐year survival of laryngocarcinoma patients, and it was positively related to lymph node metastasis and clinical stages. LINC00941 overexpression decreased apoptosis but promoted cell viability, proliferation, cell‐cycle progression, migration, and invasion, and glucose consumption and lactate production in laryngocarcinoma cells. Moreover, LINC00941 overexpression elevated expressions of Ki‐67, PCNA, MMP2, N‐Cadherin, HK2, PFKFB4, and PKM, activated the PI3K/AKT/mTOR signal pathway but reduced E‐Cadherin expression, while LINC00941 silencing had the opposite effects. PKM overexpression reversed the effects of LINC00941 silencing on cellular and glycolytic phenotypes.ConclusionLINC00941 promoted in vitro progression and glycolysis of laryngocarcinoma cells by upregulating PKM via activating the PI3K/AKT/mTOR signaling pathway.     

CHM基因变异女性携带者表型和基因型特点

目的 总结分析中国CHM基因变异女性携带者表型、基因型特点.设计 回顾性病例系列.研究对象 北京同仁医院眼科就诊并已确定携带CHM基因变异的5个无脉络膜症(choroideremia,CHM)家系中的6例女性携带者.方法 先证者及家系成员均进行详细的眼科检查.用sanger测序、目标区域捕获测序(target exon...     

New possible silver lining for pancreatic cancer therapy: Hydrogen sulfide and its donors

As one of the most lethal diseases, pancreatic cancer shows a dismal overall prognosis and high resistance to most treatment modalities. Furthermore, pancreatic cancer escapes early detection during the curable period because early symptoms rarely emerge and specific markers for this disease have not been found. Although combinations of new drugs, multimodal therapies, and adjuvants prolong survival, most patients still relapse after surgery and eventually die. Consequently, the search for more effective treatments for pancreatic cancer is highly relevant and justified. As a newly re-discovered mediator of gasotransmission, hydrogen sulfide (H₂S) undertakes essential functions, encompassing various signaling complexes that occupy key processes in human biology. Accumulating evidence indicates that H₂S exhibits bimodal modulation of cancer development. Thus, endogenous or low levels of exogenous H₂S are thought to promote cancer, whereas high doses of exogenous H₂S suppress tumor proliferation. Similarly, inhibition of endogenous H₂S production also suppresses tumor proliferation. Accordingly, H₂S biosynthesis inhibitors and H₂S supplementation (H₂S donors) are two distinct strategies for the treatment of cancer. Unfortunately, modulation of endogenous H₂S on pancreatic cancer has not been studied so far. However, H₂S donors and their derivatives have been extensively studied as potential therapeutic agents for pancreatic cancer therapy by inhibiting cell proliferation, inducing apoptosis, arresting cell cycle, and suppressing invasion and migration through exploiting multiple signaling pathways. As far as we know, there is no review of the effects of H₂S donors on pancreatic cancer. Based on these concerns, the therapeutic effects of some H₂S donors and NO–H₂S dual donors on pancreatic cancer were summarized in this paper. Exogenous H₂S donors may be promising compounds for pancreatic cancer treatment.KEY WORDS: Pancreatic cancer, Hydrogen sulfide donor, Sulfur-containing compound, Cell proliferation, Antitumor effect, Signaling pathway     

Distinct histopathological phenotypes of severe alcoholic hepatitis suggest different mechanisms driving liver injury and failure

Intrahepatic neutrophil infiltration has been implicated in severe alcoholic hepatitis (SAH) pathogenesis; however, the mechanism underlying neutrophil-induced injury in SAH remains obscure. This translational study aims to describe the patterns of intrahepatic neutrophil infiltration and its involvement in SAH pathogenesis. Immunohistochemistry analyses of explanted livers identified two SAH phenotypes despite a similar clinical presentation, one with high intrahepatic neutrophils (Neu^hi), but low levels of CD8⁺ T cells, and vice versa. RNA-Seq analyses demonstrated that neutrophil cytosolic factor 1 (NCF1), a key factor in controlling neutrophilic ROS production, was upregulated and correlated with hepatic inflammation and disease progression. To study specifically the mechanisms related to Neu^hi in AH patients and liver injury, we used the mouse model of chronic-plus-binge ethanol feeding and found that myeloid-specific deletion of the Ncf1 gene abolished ethanol-induced hepatic inflammation and steatosis. RNA-Seq analysis and the data from experimental models revealed that neutrophilic NCF1-dependent ROS promoted alcoholic hepatitis (AH) by inhibiting AMP-activated protein kinase (a key regulator of lipid metabolism) and microRNA-223 (a key antiinflammatory and antifibrotic microRNA). In conclusion, two distinct histopathological phenotypes based on liver immune phenotyping are observed in SAH patients, suggesting a separate mechanism driving liver injury and/or failure in these patients.     

Structure Characterization and Impact Effect of Al-Cu Graded Materials Prepared by Tape Casting

With the need of developing new materials, exploring new phenomenon, and discovering new mechanisms under extreme conditions, the response of materials to high-pressure compression attract more attention. However, the high-pressure state deviating from the Hugoniot line is difficult to realize by conventional experiments. Gas gun launching graded materials could reach the state. In our work, the corresponding Al-Cu composites and graded materials are prepared by tape casting and hot-pressing sintering. The microstructure and the acoustic impedance of the corresponding Al-Cu composites are analyzed to explain the impact behavior of Al-Cu graded materials. Computed tomographic testing and three-dimension surface profilometry machine results demonstrated well-graded structure and parallelism of the graded material. Al-Cu GMs with good parallelism are used to impact the Al-LiF target at 2.3 km/s using a two-stage light-gas gun, with an initial shock impact of 20.6 GPa and ramping until 27.2 GPa, deviating from the Hugoniot line.     

Adolescent Knowledge,Attitudes and Practices of Healthy Eating: Findings of Qualitative Interviews among Hong Kong Families

To tackle unhealthy eating among adolescents, it is crucial to understand the dietary knowledge, attitudes, and practices (KAP) on which adolescent eating habits are based. This qualitative study identifies the gaps in KAP by exploring what Chinese adolescents know, perceive, and practice regarding healthy eating to better inform targeted interventions for this important health problem. Parent–adolescent dyads were purposively sampled based on, for example, the dietary intake, age, and gender of the adolescent and household income, and each completed a 30 to 60 min interview. Twelve themes were synthesized: knowledge: (1) dietary recommendations, (2) health outcomes of healthy eating, (3) nutrition content in food, and (4) access to healthy meals; attitudes: (5) outcome expectation for healthy eating, (6) food preferences, and (7) self-efficacy regarding adopting healthy eating; and practices: (8) going grocery shopping for healthy food, (9) eating home-prepared meals. (10) eating out in restaurants or consuming takeaway food, (11) fruit and vegetable consumption, and (12) snacking, perceived unhealthy eating to be low risk, made unhealthy choices regarding snacking and eating out, and had insufficient fruit and vegetable intake. Programs should emphasize the positive short-term health outcomes of healthy eating and empower adolescents to acquire food preparation skills to sustain healthy eating habits.     

Assessment of the Effect of Selenium Supplementation on Production of Selected Cytokines in Women with Hashimoto’s Thyroiditis

The impact of selenium on the course of Hashimoto’s thyroiditis (HT) was mainly assessed by monitoring the titer of antithyroid autoantibodies in most of the studies conducted hitherto. On the other hand, the imbalance in activity of T cells such as Th1, Th2, Th17, and Treg may be relevant in the pathogenesis of this disease. Hence, the assessment of changes in the secretion of cytokines by these cells during selenium supplementation in patients with HT seems to be an important issue and was the main goal of this study. A further aim was to search for correlations among these cytokines, as well as markers of thyroid function, selenium/iodine status in the body, and other biochemical parameters. The group of 29 women with newly diagnosed Hashimoto’s thyroiditis was supplemented with selenium in a dose of 100 µg/day for 6 months. Immunological parameters: interferon γ, tumor necrosis factor α, chemokine CXCL10, interleukin 4, interleukin 1β, interleukin 17, transforming growth factor β, and C-reactive protein, as well as selenium status parameters were determined in serum twice, i.e., before and after supplementation. Selenium supplementation was associated with a change in the production of two cytokines: interferon γ and interleukin 1β, for which a decrease and an increase in concentration were observed, respectively. The partial least squares (PLS) model revealed the presence of many relevant correlations among analyzed parameters. The stage of HT development, degree of thyroid dysfunction, and selenium supplementation of diet are interdependent factors which shape the profile of some cytokines secreted by cells participating in the autoimmunity process.     

Time-Dependent Seismic Fragility of Typical Concrete Girder Bridges under Chloride-Induced Corrosion

Recent studies highlighted the importance of the combined effects of prestress loss and corrosion deterioration for concrete girder bridge structures when the effect of damage on the performance level is estimated. The multi-deterioration mechanisms connected with chloride erosion include the cross-sectional area loss of longitudinal bars and stirrups, the reduction in the ductility, the decrease in the strength of steels and the strength loss of concrete in RC columns. For the corroded RC columns and corroded elastomeric bridge bearings, analytical models of the material degradation phenomena were employed for performing the probabilistic seismic performance analysis, which could obtain the system seismic fragility of aging bridges by considering the failure functionality of multiple correlated components (e.g., columns, bearings). The combined effects of prestress loss and cracking were also considered when developing time-dependent system seismic fragility functions. Here, a typical multi-span reinforced concrete girder bridge was used as a case study for studying the time-variant seismic performance. The results revealed the importance of the joint effects of the multi-deterioration mechanisms when modeling the time-dependent seismic fragility of aging bridge systems, as well as the significance of considering the combined effects of prestress loss and cracking.