PERK/CHOP contributes to the CGK733-induced vesicular calcium sequestration which is accompanied by non-apoptotic cell death

Calcium ions (Ca²⁺) are indispensable for the physiology of organisms and the molecular regulation of cells. We observed that CGK733, a synthetic chemical substance, induced non-apoptotic cell death and stimulated reversible calcium sequestration by vesicles in pancreatic cancer cells. The endoplasmic reticulum (ER) stress eukaryotic translation initiation factor 2-alpha kinase 3/C/EBP homologous protein (PERK/CHOP) signaling pathway was shown to be activated by treatment with CGK733. Ionomycin, an ER stress drug and calcium ionophore, can activate PERK/CHOP signaling and accelerate CGK733-induced calcium sequestration. Knockdown of CHOP diminished CGK733-induced vesicular calcium sequestration, but had no effects on the cell death. Proteomic analysis demonstrated that the ER-located calcium-binding proteins, calumenin and protein S100-A11, were altered in CGK733-treated cells compared to non-treated controls. Our study reveals that CGK733-induced intracellular calcium sequestration is correlated with the PERK/CHOP signaling pathway and may also be involved in the dysregulations of calcium-binding proteins.     

The ALK inhibitor ASP3026 eradicates NPM-ALK+ T-cell anaplastic large-cell lymphoma in vitro and in a systemic xenograft lymphoma model

NPM-ALK⁺ T-cell anaplastic large-cell lymphoma (ALCL) is an aggressive type of cancer. Standard treatment of NPM-ALK⁺ ALCL is CHOP polychemotherapy. Although patients initially respond favorably to CHOP, resistance, relapse, and death frequently occur. Recently, selective targeting of ALK has emerged as an alternative therapeutic strategy. ASP3026 is a second-generation ALK inhibitor that can overcome crizotinib resistance in non-small cell lung cancer, and is currently being evaluated in clinical trials of patients with ALK⁺ solid tumors. However, NPM-ALK⁺ ALCL patients are not included in these trials. We studied the effects of ASP3026 on NPM-ALK⁺ ALCL cell lines in vitro and on systemic lymphoma growth in vivo. ASP3026 decreased the viability, proliferation, and colony formation, as well as induced apoptotic cell death of NPM-ALK⁺ ALCL cells. In addition, ASP3026 significantly reduced the proliferation of 293T cells transfected with NPM-ALK mutants that are resistant to crizotinib and downregulated tyrosine phosphorylation of these mutants. Moreover, ASP3026 abrogated systemic NPM-ALK⁺ ALCL growth in mice. Importantly, the survival of ASP3026-treated mice was superior to that of control and CHOP-treated mice. Our data suggest that ASP3026 is an effective treatment for NPM-ALK⁺ ALCL, and support the enrollment of patients with this lymphoma in the ongoing clinical trials.     

Broad neutralization against SARS-CoV-2 variants induced by ancestral and B.1.351 AS03-Adjuvanted recombinant Plant-Derived Virus-Like particle vaccines

Since 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection resulting in the coronavirus disease 2019 (COVID-19) has afflicted hundreds of millions of people in a worldwide pandemic. Several safe and effective COVID-19 vaccines are now available. However, the rapid emergence of variants and risk of viral escape from vaccine-induced immunity emphasize the need to develop broadly protective vaccines. A recombinant plant-derived virus-like particle vaccine for the ancestral COVID-19 (CoVLP) recently authorized by Canadian Health Authorities and a modified CoVLP.B1351 targeting the B.1.351 variant (both formulated with the adjuvant AS03) were assessed in homologous and heterologous prime-boost regimen in mice. Both strategies induced strong and broadly cross-reactive neutralizing antibody (NAb) responses against several Variants of Concern (VOCs), including B.1.351/Beta, B.1.1.7/Alpha, P.1/Gamma, B.1.617.2/Delta and B.1.1.529/Omicron strains. The neutralizing antibody (NAb) response was robust with both primary vaccination strategies and tended to be higher for almost all VOCs following the heterologous prime-boost regimen.     

Outcome of 3-day bleomycin,etoposide and cisplatin chemotherapeutic regimen for patients with malignant ovarian germ cell tumours: A Taiwanese Gynecologic Oncology Group study

BackgroundThe combination of bleomycin, etoposide and cisplatin (BEP) is currently the most widely used treatment for malignant ovarian germ cell tumours (MOGCTs). The aim of this study was to evaluate the efficacy and adverse effects of the 3-day BEP regimen in Taiwan. The prognostic factors of the MOGCT patients were also analysed.Patients and methodsTwo hundred and thirty-nine cases of MOGCTs were identified from the Taiwanese Gynecologic Oncology Group database, and 204 of those who received postoperative BEP chemotherapy were then analysed.ResultsThe estimated rate of no evidence of disease was 94.0% for 204 patients with adjuvant BEP regimen. Seven grade 3/4 haematological adverse effects including four subjects with neutropenia, one with pancytopenia and two with neutropenic fever were recorded in the 853 total courses of chemotherapeutic cycles. The rates of haematological and non-haematological adverse effects were 0.82% and 2.3%, respectively. No treatment-related mortality was noted. In the analysis of prognostic factors, only tumour stage had a significant impact on disease recurrence (95% confidence interval (CI), 4.2–94.4, p < 0.001) and disease-related mortality (95% CI, 2.2–163.9, p = 0.007).ConclusionsThe current 3-day adjuvant BEP regimen was effective and safe for patients with MOGCTs.     

Dendritic cells: therapy and imaging

Background: Dendritic cells (DCs) play a major role in cell-mediated immunotherapy. In this approach, DCs are isolated from cancer patients and pulsed with exogenous and specific tumor antigens in vitro, and the antigen-loaded DCs are then transferred to the hosts to enhance the immune response against tumor targets. Clinical observations and animal studies have shown that tumors can elicit immune responses caused by tumor infiltration of T-lymphocytes. Several pilot clinical trials have been recently conducted using this strategy for treating several types of cancers. Objective: To optimize DC-based therapy with emerging molecular imaging techniques. Methods: A review of the most current literature on DCs and imaging work. Results/conclusion: The translational application of DC-based therapy can be supported greatly through molecular imaging. New discoveries on DC migration and behavior in vivo will lead to new advances in the treatment of a broad range of cancers.     

FDA有关仿制药和抗肿瘤药说明书的2个指导原则介绍

美国食品药品管理局（FDA）于2022年1月发布了“参比制剂（RLD）说明书修订后简化新药申请（ANDA）说明书的修订”供企业用的指导原则草案。该指导原则提供了多种获取RLD说明书变更信息的方法，还告知提交修改后的仿制药说明书的具体资料。2020年11月FDA发布了“联合方案中的抗肿瘤药物的交叉说明书”供企业用的指导原则草案。所谓“交叉说明书”是指被批准用于联合方案的抗肿瘤药物的说明书纳入的相关信息。该指导原则指出，其中新药的交叉说明书“应包括有关联合用药安全有效的信息以及仅限于各自药物的信息”；而其中已批准的药物的交叉说明书，“应包括在联合方案中该药物与其他药物合用的安全有效性信息”。该指导原则还对交叉说明书一些具体项目的内容提出了建议。而我国目前尚没有类似的指导原则。详细介绍FDA这2个指导原则，期望对中国RLD说明书修订后的仿制药说明书的修订以及联合用药方案中的抗肿瘤药的“交叉说明”的实施有帮助；对这两种情况的说明书的监管也有所启迪。     

温和刺激方案在多囊卵巢综合征患者体外受精——胚胎移植中的应用研究

目的探讨温和刺激方案在多囊卵巢综合征(PCOS)患者体外受精-胚胎移植周期中的临床应用。方法选取2015年3月~2017年6月在我院接受体外受精-胚胎移植(IVF-ET)的PCOS患者共80例,将患者随机分为克罗米芬温和刺激方案(A组)40例和短效促性腺激素释放激素激动剂(Gn RHa)长方案(B组)40例,比较两组患者IVF周期的一般情况、促排卵参数、实验室指标及解冻胚胎移植(FET)临床妊娠率。结果 (1)两组患者年龄、不孕年限、基础FSH、基础LH、基础E2、体质量指数(BMI)均无统计学差异(P0.05);(2)A组使用促性腺激素(Gn)天数和Gn用量显著低于B组(P0.05);(3)两组注射人绒毛膜促性腺激素(HCG)日E2、P无显著性差异(P0.05);而HCG日LH水平A组显著高于B组,差异有统计学意义(P0.01);(4)两组获卵数、卵裂率、优质胚胎率差异均无统计学意义(P0.05),而A组正常受精率、冷冻胚胎数低于B组,差异有统计学意义(P0.05);(5)A组中度卵巢过度刺激综合征(OHSS)率明显低于B组,但差异无统计学意义(P0.05);(6)A组FET临床妊娠率高于B组,但差异无统计学意义(P0.05)。结论克罗米芬温和刺激方案在PCOS患者IVF-ET治疗中有较理想的促排效果,可明显减少Gn天数及Gn总量,从而减少患者周期治疗费用;OHSS并发症发生率较低,且能获得理想的临床妊娠率。     

Primary non-Hodgkin’s lymphoma of the gallbladder diagnosed by laparoscopic cholecystectomy

Primary lymphoma of the gallbladder is an exceedingly rare disease. We experienced an asymptomatic case of primary non-Hodgkin’s lymphoma of the gallbladder in a 55-year-old woman in whom laparoscopic cholecystectomy made a definite diagnosis. Abdominal computed tomography revealed a 4-cm gallbladder tumor with markedly enlarged lymph nodes in the retropancreatic area. Despite the marked involvement of lymph nodes, serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 were not elevated. The discrepancy between the imaging findings and the patient’s mild clinical presentation led us to suspect that the tumor was a lymphoma. We examined serum markers of lymphoma, revealing slight elevations of interleukin (IL)-2 receptor and thymidine kinase. Laparoscopic cholecystectomy for a total biopsy was performed successfully, and the results of intraoperative frozen-section examination led us to have a high suspicion of malignant lymphoma. The final diagnosis was large diffuse B-cell lymphoma of the gallbladder with a positive CD20 antibody reaction. The patient received postoperative chemotherapy with R-CHOP (rituximab, 500 mg; cyclophosphamide, 1000 mg; adriamycin, 68 mg; vincristine, 1.9 mg; and prednisone, 80 mg) starting on postoperative day 12. She achieved complete remission and is still in complete remission 3 years and 2 months after the cholecystectomy. In conclusion, gallbladder lymphoma should be added to the differential diagnosis of gallbladder tumors, especially when the imaging findings and clinical presentation are not consistent with typical signs of gallbladder carcinoma, and laparoscopic cholecystectomy is helpful for the confirmation of suspicious cases.     

美罗华联合CHOP方案治疗侵袭性B细胞淋巴瘤

目的:探讨美罗华联合CHOP方案治疗侵袭性B细胞淋巴瘤疗效。方法:选取患者102例,采用数字表法分为常规组和联合组,分别给予CHOP方案和美罗华联合CHOP方案治疗,评价其治疗有效率和不良反应率。结果:联合组治疗有效性(88.24%)高于常规组(66.67%)(P0.05);两组不良反应率(21.57%vs25.49%)差异对比无统计学意义(P0.05)。结论:美罗华联合CHOP方案治疗侵袭性B细胞淋巴瘤相比于常规方案,在不增加患者不良反应率的前提下,可提高患者症状缓解率。