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Proliferation is one of the significant hallmarks of gallbladder cancer, which is a relatively rare but fatal malignance. Aim of this study was to examine the biological impact and molecular mechanism of the candidate hub-gene on the proliferation and tumorigenesis of gallbladder cancer. We analyzed the differentially expressed genes and the correlation between these genes with MKI67, and showed that KIF11 is one of the major upregulated regulators of proliferation in gallbladder cancer (GBC). The Gene Ontology, Gene Sets Enrichment Analysis and KEGG Pathway analysis indicated that KIF11 may promote GBC cell proliferation through the ERBB2/PI3K/AKT signaling pathway. Gain-of-function and loss-of-function assay demonstrated that KIF11 regulated GBC cell cycle and cancer cell proliferation in vitro. GBC cells exhibited G2M phase cell cycle arrest, cell proliferation and clone formation ability reduction after treatment with Monastrol, a specific inhibitor of KIF11. Xenograft model showed that KIF11 promotes GBC growth in vivo. Rescue experiments showed that KIF11-induced GBC cell proliferation dependented on ERBB2/PI3K/AKT pathway. Moreover, we found that H3K27ac signals are enriched among the promoter region of KIF11 in the UCSC Genome Browser Database. Differentially expressed analysis showed that EP300, a major histone acetyltransferase modifying H3K27ac signal, is highly expressed in gallbladder cancer and correlation analysis illustrated that EP300 is positively related with KIF11 in almost all the cancer types. We further found that KIF11 was significantly downregulated in a dose-dependent and time-dependent manner after histone acetylation inhibitor treatment. The present results highlight that high KIF11 expression promotes GBC cell proliferation through the ERBB2/PI3K/AKT signaling pathway. The findings may help deepen our understanding of mechanism underlying GBC cancer development and development of novel diagnostic and therapeutic target.

The incidence of hepatocellular carcinoma (HCC) is extremely high, and China accounts for approximately 50% of global liver cancer cases. Previous studies reported that CDC20 is involved in the occurrence and progression of a variety of malignant tumors. So, whether CDC20 will affect the development of HCC, we have conducted in-depth research on this. We selected Hep3B and HepG2 for cell culture, and performed siRNA transfection, lentiviral infection, western blot, MTS determination, cell cycle determination, apoptosis test, immunodeficiency test, clone survival test and subcutaneous parthenogenesis in nude mice. Knockdown of CDC20 greatly enhanced the radiation efficacy on the growth retardation in HepG2, and protein level of CDC20 was decreased for the activation of P53 by radiation. Downregulation of CDC20 combined with radiation can inhibit proliferation, aggravate DNA damage, increase G2/M arrest, and promote apoptosis of HCC cells to a greater extent, and the relative survival fraction of HCC cells was gradually reduced with radiation dose increased in P53 mutated Hep3B cells. After knocking down CDC20 in HCC, Bcl-2 was down-regulated and Bax expression increased. Down-regulation of CDC20 can inhibit further invasion by promoting the radiosensitivity of HCC. In this study, we found that that CDC20 was highly expressed in HCC and participated in radio resistance of HCC cells with P53 mutation Bcl-2/Bax via signaling pathway. This study is the first to present evidence that CDC20 may play a role in improving the efficacy of radiotherapy in HCC.

Programmed cell death-1/programmed cell death-ligand 1 (PD-[L]1) inhibitors plus bevacizumab (or biosimilars) or tyrosine kinase inhibitors (TKIs) have been widely used for the first-line treatment of patients with unresectable hepatocellular carcinoma (uHCC). However, no head-to-head trials have compared the efficacy outcomes between these two combination regimens. Therefore, an unanchored matching-adjusted indirect comparison (MAIC) was conducted to evaluate the comparative efficacy of tislelizumab plus lenvatinib versus sintilimab plus bevacizumab biosimilar. Individual patients from the BGB-A317-211 study (NCT04401800) for tislelizumab plus lenvatinib were adjusted to match the population from the ORIENT-32 (NCT03794440) for sintilimab plus bevacizumab biosimilar through an unanchored MAIC. Odds Ratios (ORs) of objective response rates (ORR) and disease control rates (DCR), and hazard ratios (HRs) of progression-free survival (PFS) and overall survival (OS) were evaluated to quantify the relative treatment effect between the two treatment regimens after population matching. Sensitivity analyses were performed by sequentially removing one variable in the matching and adjusting the population through simulated treatment comparison (STC). After matching, baseline characteristics were balanced between the tislelizumab plus lenvatinib group (effective sample size [ESS] = 49, ESS/N = 79.03%) and sintilimab plus bevacizumab biosimilar group (N = 380). MAIC analysis indicated that tislelizumab plus lenvatinib group showed significantly higher ORR per RECIST v1.1 (OR = 2.56, 95% CI 1.40-4.63; = 0.0027), higher DCR (OR = 3.81, 95% CI 1.62-11.20; = 0.0013), longer PFS (HR = 0.56, 95% CI 0.37-0.84, = 0.0054), and improved OS (HR = 0.43, 95% CI 0.25-0.74, = 0.0023), compared to sintilimab plus bevacizumab biosimilar group. Sensitivity analysis by two different methods supported the findings from the primary MAIC analysis. This MAIC analysis demonstrated that tislelizumab plus lenvatinib achieved superior efficacy, with higher ORR and longer PFS and OS compared to sintilimab plus bevacizumab biosimilar in untreated Chinese patients with uHCC.

This study analysed the data of 101 countries from the World Bank’s Financial Inclusion and Financial Availability Survey databases for the years 2011, 2014, 2017, and 2021. It constructed a new financial inclusion evaluation index system using digital empowerment and established a dual fixed-effect panel data regression model to examine the impact of financial inclusion on employment. The study also considered the moderating effect of education on financial inclusion affecting employment. The results indicate that financial inclusion is beneficial to improving employment levels. The level of education development is proportional to the level of employment, and it has a regulatory effect of promoting the financial inclusion’s positive impact on employment level. The heterogeneity analysis demonstrates that the effect of financial inclusion on improving employment levels is greater in female groups. The promotion of financial inclusion is the largest in low- and middle-income countries, followed by high-income countries, indicating that financial inclusion must have a certain economic foundation to fully play its role, and it has more obvious benefits for relatively poor and weak areas than for high-income areas. The conclusions of this study have implications for improving employment and augmenting financial inclusion.

γ-Secretase inhibitors (GSIs) increase B cell maturation antigen (BCMA) density on malignant plasma cells and enhance antitumour activity of BCMA chimeric antigen receptor (CAR) T cells in preclinical models. We aimed to evaluate the safety and identify the recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat (LY3039478) for individuals with relapsed or refractory multiple myeloma. We conducted a phase 1, first-in-human trial combining crenigacestat with BCMA CAR T-cells at a single cancer centre in Seattle, WA, USA. We included individuals aged 21 years or older with relapsed or refractory multiple myeloma, previous autologous stem-cell transplant or persistent disease after more than four cycles of induction therapy, and Eastern Cooperative Oncology Group performance status of 0–2, regardless of previous BCMA-targeted therapy. To assess the effect of the GSI on BCMA surface density on bone marrow plasma cells, participants received GSI during a pretreatment run-in, consisting of three doses administered 48 h apart. BCMA CAR T cells were infused at doses of 50 × 106 CAR T cells, 150 × 106 CAR T cells, 300 × 106 CAR T cells, and 450 × 106 CAR T cells (total cell dose), in combination with the 25 mg crenigacestat dosed three times a week for up to nine doses. The primary endpoints were the safety and recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat, an oral GSI. This study is registered with ClinicalTrials.gov, NCT03502577, and has met accrual goals. 19 participants were enrolled between June 1, 2018, and March 1, 2021, and one participant did not proceed with BCMA CAR T-cell infusion. 18 participants (eight [44%] men and ten [56%] women) with multiple myeloma received treatment between July 11, 2018, and April 14, 2021, with a median follow up of 36 months (95% CI 26 to not reached). The most common non-haematological adverse events of grade 3 or higher were hypophosphataemia in 14 (78%) participants, fatigue in 11 (61%), hypocalcaemia in nine (50%), and hypertension in seven (39%). Two deaths reported outside of the 28-day adverse event collection window were related to treatment. Participants were treated at doses up to 450 × 106 CAR+ cells, and the recommended phase 2 dose was not reached. Combining a GSI with BCMA CAR T cells appears to be well tolerated, and crenigacestat increases target antigen density. Deep responses were observed among heavily pretreated participants with multiple myeloma who had previously received BCMA-targeted therapy and those who were naive to previous BCMA-targeted therapy. Further study of GSIs given with BCMA-targeted therapeutics is warranted in clinical trials. Juno Therapeutics—a Bristol Myers Squibb company and the National Institutes of Health.

Background Esophageal cancer (EC) is the ninth most common cancer worldwide that kills about 300,000 people each year. Esophageal squamous cell carcinoma (ESCC) is the main type of EC. Long non-coding RNAs (lncRNAs) have been proven to be severely dysregulated in EC, but the functions of more lncRNAs still need to be explored. Methods To explore the new molecular mechanism of ESCC development, the online biology databases (GEO, lncRNASNP2, Starbase, TargetScan) were employed to investigate the novel pathways implicated. To assess the expression levels of FLG-AS1, miR-23a-3p, and associated genes, we utilized RT-qPCR. The expression of HOXD10 was evaluated through western blotting analysis. To elucidate the regulatory interactions among FLG-AS1, miR-23a-3p, and HOXD10, a combination of dual luciferase assays, silencing techniques, and overexpression studies were conducted. The migratory and invasive capabilities of the cells were examined using a transwell apparatus. Cell viability was measured employing the CCK-8 assay, while apoptosis was detected through Annexin V/PI double staining methodology. Concentrations of glucose and lactic acid were determined utilizing appropriate biochemical kits. Results FLG-AS1 and HOXD10 exhibited low expression levels in ESCC cells, whereas miR-23a-3p was found to be highly expressed. FLG-AS1 was observed to reduce the free level of miR-23a-3p by directly binding to it, and in turn, miR-23a-3p inhibited the expression of HOXD10 by targeting its mRNA. The overexpression of FLG-AS1 and HOXD10 resulted in the attenuation of anaerobic glycolysis, as well as a decrease in the migratory and invasive capabilities of ESCC cells, effectively reversing their resistance to cisplatin. Conversely, the upregulation of miR-23a-3p yielded opposing effects. Furthermore, ESCC patients exhibiting elevated levels of FLG-AS1 and HOXD10, alongside reduced expression of miR-23a-3p, demonstrated a significantly higher 5-year survival rate post-surgery. Conclusion FLG-AS1 effectively inhibits the progression of ESCC and counters cisplatin resistance through the modulation of the miR-23a-3p/HOXD10 axis. This is a new mechanism affecting ESCC and will provide new ideas for the targeted therapy of ESCC.

Lung cancer is the most malignant tumor in the worldwide. About 3%‐5% non‐small cell lung cancer (NSCLC) patients carry anaplastic lymphoma kinase (ALK) gene fusions and receive great benefits from ALK‐targeted therapy. However, drug resistance inevitably occurs even with the most potent inhibitor drug lorlatinib. About half of the resistance are caused by alteration in ALK proteins for earlier ALK TKI drugs and near one‐third of loratinib resistant cases are caused by compound mutations without current effective treatment strategy in clinic. Novel strategies are in great need to overcome drug resistance. Lately, two novel strategies have been developed and attracted great attentions for their potentials to overcome drug resistance problems: (1) developed small compact macrocyclic ALK kinase inhibitors and (2) developed ALK targeted proteolysis‐targeting chimera (PROTAC) drugs. The macrocyclic molecules are small and compact in size, brain barrier permeable, and highly potent against lorlatinib‐resistant compound mutations. Developed ALK targeted PROTAC molecules could degrade oncogenic ALK driver proteins. Some showed superiority in killing ALK positive cancer cells and inhibiting the growth of cells expressing G1202R resistant ALK proteins comparing to inhibitor drugs. The update on these two treatment strategies was reviewed. Acquired resistance mutations including G1202R and L1196M, alone or in compound form, in ALK proteins lead to drug resistance to ALK‐targeted therapy. Two novel strategies showed great potential in overcoming such resistance: (1) More effective inhibition by small and compact macrocyclic inhibitors; (2) Degradation of oncogenic ALK proteins including those with resistant mutations by ALK targeted proteolysis‐targeting chimeras.

Background and study aims Fail to reach the bilioenteric anastomosis is the main cause of treatment failure during single-balloon enteroscopy-assisted endoscopic retrograde cholangiopancreatography (SBE-assisted ERCP) in patients after bilioenteric Roux-en-Y anastomosis. We aim to evaluate factors influencing the endoscopic insertion failure. Patients and methods We retrospectively reviewed the clinical data of 231 cases undergoing SBE-assisted ERCP from January 2016 to December 2021. Treatment details and outcomes were studied to analyze the factors involved in endoscopic insertion failure. Results The enteroscopy success rate and procedural success rate were 88.3% and 84.4%. Incidence of postoperative adverse events was 3.9%. No serious adverse events occurred. Risk factors of endoscopic insertion failure include first ERCP attempt, side to side anastomosis at the Rou-Y anastomosis, the use of Endo-GIA anastomosis, three bowel lumens seen at the Rou-Y anastomosis under endoscopy, steep angle of the afferent loop at the Rou-Y anastomosis with a U-shape, length of the afferent loop ≥ 50 cm, and twisted afferent loop. Among which the multifactorial analysis suggested that the presence of three bowel lumens at the Rou-Y anastomosis and twisted afferent loop were independent risk factors for enteroscopy failure. For case with twisted afferent loop, the use of a transparent cap with X-ray-assisted guidance during insertion is an effective strategy to improve the success rate. Conclusions SBE-assisted ERCP is safe and effective in patients after bilioenteric Roux-en-Y anastomosis. The severity of afferent loop twisting and Rou-Y anastomosis shape were risk factors for endoscopic insertion failure. Surgeons should take into account the feasibility of postoperative ERCP treatment at the time of operation.

Background Lenvatinib is widely used in treatment of unresectable hepatocellular carcinoma (uHCC), but the benefit of its combination with immunotherapy needs to be verified. This study evaluated the efficacy and safety of tislelizumab plus lenvatinib in systemic treatment-naïve patients with uHCC. Methods In this multicenter, single-arm, phase 2 study, systemic treatment-naïve patients with uHCC received tislelizumab 200 mg every three weeks plus lenvatinib (bodyweight ≥ 60 kg: 12 mg; < 60 kg: 8 mg; once daily). Dose-limiting toxicities (DLTs) were evaluated in safety run-in phase to determine whether to enter the expansion phase. The primary endpoint was objective response rate (ORR) assessed by independent review committee (IRC) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). Based on Simon’s two-stage design, > 6 responders were needed in stage 1 ( n  = 30) to continue the study, and ≥ 18 responders were needed by the end of stage 2 ( n  = 60) to demonstrate statistical superiority to a historical control of lenvatinib monotherapy. Results Sixty-four patients were enrolled. No DLTs were reported. The study achieved statistical superiority ( p  = 0.0003) with 23 responders assessed by IRC per RECIST v1.1 in the first 60 patients of the efficacy evaluable analysis set ( n  = 62). After a median follow-up of 15.7 months, confirmed ORR and disease control rate were 38.7% (24/62, 95% confidence interval [CI], 26.6–51.9) and 90.3% (56/62, 95% CI, 80.1–96.4), respectively. Median progression-free survival was 8.2 months (95% CI, 6.8–not evaluable). Overall survival rate at 12 months was 88.6% (95% CI, 77.7–94.4). Grade ≥ 3 treatment-related adverse events occurred in 18 (28.1%) patients. Conclusions Tislelizumab plus lenvatinib demonstrated promising antitumor activity with favourable tolerability as first-line therapy for patients with uHCC. Trial registration ClinicalTrials.gov (NCT 04401800).

APCs (aliphatic polycarbonates) are one of the most important types of biodegradable polymers and widely used in the fields of solid electrolyte, biological medicine and biodegradable plastics. Zinc-based catalysts have the advantages of being low cost, being non-toxic, having high activity, and having excellent environmental and biological compatibility. Zinc (II) acetylacetonate (Zn(Acac)2) was first reported as a highly effective catalyst for the melt transesterification of biphenyl carbonate with 1,4-butanediol to synthesize poly(1,4-butylene carbonate)(PBC). It was found that the weight-average molecular weight of PBC derived from Zn(Acac)2 could achieve 143,500 g/mol with a yield of 85.6% under suitable reaction conditions. The Lewis acidity and steric hindrance of Zn2+ could obviously affect the catalytic performance of Zn-based catalysts for this reaction. The main reasons for the Zn(Acac)2 catalyst displaying a higher yield and Mw than other zinc-based catalysts should be ascribed to the presence of the interaction between acetylacetone ligand and Zn2+, which can provide this melt transesterification reaction with the appropriate Lewis acidity as well as the steric hindrance.