CAR T-Cell therapy for the management of mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a subtype of Non-Hodgkin lymphoma (NHL) of mature B-cells characterized by translocation, which is typically due to excess expression of Cyclin D1. Although with the progress in our knowledge of the causes for MCL and available treatments for MCL, this cancer is still incurable. Age, male gender, rapid advancement, significant nodal involvement, elevated serum lactate dehydrogenase level, and prognostic indications including increased expression of Ki-67 and presence of TP53 mutation, are symbols of poor outcome. Advanced immunotherapy using chimeric antigen receptor (CAR)-T cells is advantageous for patients suffering from B-cell malignancies and MCL. Targeting B-cell antigens on the cell surface is a feasible approach in re-occurring (R/R) MCL because of significant responses obtained in other B-cell cancers. USFDA has approved brexucabtagene autoleucel (Tecartus, KTE-X19), a novel CAR T-cell therapy to be used in patients with MCL who have not responded to previous treatments or have relapsed. The FDA approved this new treatment depending on the outcomes of the ZUMA-2 clinical trial. Serious adverse reactions, moderate anti-tumor activity, allergen withdrawal, antigen escape, limited tumor infiltration, and trafficking are major barriers to successful CAR T-cell therapy. This review is a brief synopsis of the development of CAR T-cell therapy for MCL.

Nivolumab and relatlimab for the treatment of melanoma.

Melanoma is a highly lethal type of skin cancer. Although an early diagnosis, in combination with surgery for nonmetastatic melanomas, significantly increases the probability of survival, there are no efficacious treatments for metastatic melanoma. Nivolumab and relatlimab are monoclonal antibodies that selectively interact with and block the proteins programmed cell death protein 1 (PD-1) and lymphocyte activation protein 3 (LAG-3), respectively, and thus, their activation by their cognate ligands. The combination of these immunotherapy drugs was approved in 2022 by the United States Food and Drug Administration (FDA) for the treatment of melanoma. Data from clinical trials indicated that, compared to nivolumab monotherapy, nivolumab and relatlimab produced more than a 2-fold median increase in progression-free survival (PFS) and a higher response rate in melanoma patients. This is an important finding as the response of patients to immunotherapies is limited due to dose-limiting toxicities and secondary drug resistance. This review article will discuss the pathogenesis of melanoma and the pharmacology of nivolumab and relatlimab. In addition, we will provide i) a summary of the anticancer drugs that inhibit LAG-3 and PD-1 in cancer patients and ii) our perspective about the use of nivolumab in combination with relatlimab to treat melanoma.

Comparative efficacy of different Chinese patent medicines in preventing restenosis after percutaneous coronary intervention: a systematic review and Bayesian network meta-analysis of randomized clinical trials.

Background: Chinese patent medicines (CMPs) have curative effectiveness in preventing coronary restenosis. However, the relative efficacy between different CPMs has not been sufficiently investigated. Methods: Randomized clinical trials were searched from electronic databases including PubMed, Web of Science, Cochrane Library, Embase, CNKI, VIP, WanFang, SinoMed, Chinese Clinical Trial Registry, and ClinicalTrials.gov. Bayesian network meta-analysis was performed to analyze CPMs' efficacy in preventing angiographic restenosis, recurrence angina, acute myocardial infarction, and target lesion revascularization after percutaneous coronary intervention. Results: This network meta-analysis included 47 trials with 5,077 patients evaluating 11 interventions. Regarding angiographic restenosis, the efficacy of CPMs (except Xuezhikang capsule) combined with standard treatment (Std) was superior to Std alone, and Guanxin Shutong capsule plus Std reduced the risk of angiographic restenosis by 76% (relative risk 0.24, 95% confidence interval 0.11-0.45, and very low to moderate certainty of evidence), most likely the best intervention. Fufang Danshen dripping pill combined with Std showed superiority over other interventions for relieving recurrence angina, which can reduce the risk by 83% (RR 0.17, 95% CI 0.04-0.51, very low to moderate certainty of evidence) compared to Std alone. In acute myocardial infarction after percutaneous coronary intervention, compared with Std alone, Danhong injection plus Std displayed a significant effect (RR 0.11, 95% CI 0.00-0.69, very low to moderate certainty of evidence) and was the best treatment probably. Chuanxiongqin tablet plus Std was the most effective treatment for reducing target lesion revascularization by 90% (RR 0.10, 95% CI 0.00-0.60, very low to moderate certainty of evidence) compared with Std alone. Conclusion: The results indicated that CPMs combined with Std reduced the risk of coronary restenosis after percutaneous coronary intervention. However, the results should be interpreted cautiously due to significant data limitations.

Enhanced external counterpulsation ameliorates endothelial dysfunction and elevates exercise tolerance in patients with coronary artery disease.

Purpose: Enhanced external counterpulsation (EECP) is a new non-drug treatment for coronary artery disease (CAD). However, the long-term effect of EECP on endothelial dysfunction and exercise tolerance, and the relationship between the changes in the endothelial dysfunction and exercise tolerance in the patients with coronary heart disease are still unclear. Methods: A total of 240 patients with CAD were randomly divided into EECP group (n = 120) and control group (n = 120). All patients received routine treatment of CAD as the basic therapy. Patients in the EECP group received 35 1-h daily sessions of EECP during 7 consecutive weeks while the control group received the same treatment course, but the cuff inflation pressure was 0-10 mmHg. Peak systolic velocity (PSV), end diastolic velocity (EDV), resistance index (RI), and inner diameter (ID) of the right carotid artery were examined using a Color Doppler Ultrasound and used to calculate the fluid shear stress (FSS). Serum levels of human vascular endothelial cell growth factor (VEGF), vascular endothelial cell growth factor receptor 2 (VEGFR2), and human angiotensin 2 (Ang2) were determined by enzyme-linked immunosorbent assay (ELISA). Exercise load time, maximal oxygen uptake (VO2max ), metabolic equivalent (METs), anaerobic threshold (AT), peak oxygen pulse (VO2max/HR) were assessed using cardiopulmonary exercise tests. Results: After 1 year follow-up, the EDV, PSV, ID, and FSS were significantly increased in the EECP group (P < 0.05 and 0.01, respectively), whereas there were no significant changes in these parameters in the control group. The serum levels of VEGF and VEGFR2 were elevated in the EECP and control groups (all P < 0.05). However, the changes in VEGF and VEGFR2 were significantly higher in the EECP group than in the control group (P < 0.01). The serum level of Ang2 was decreased in the EECP group (P < 0.05) and no obvious changes in the control group. As for exercise tolerance of patients, there were significant increases in the exercise load time, VO2max, VO2max/HR, AT and METs in the EECP group (all P < 0.05) and VO2max and METs in the control group (all P < 0.05). Correlation analyses showed a significant and positive correlations of VEGF and VEGFR2 levels with the changes in FSS (all P < 0.001). The correlations were still remained even after adjustment for confounders (all Padjustment < 0.001). Linear regression displays the age, the medication of ACEI (angiotensin-converting enzyme inhibitors) or ARB (angiotensin receptor blockers), the diabetes and the changes in VEGF and VEGFR2 were positively and independently associated with the changes in METs after adjustment for confounders (all Padjustment < 0.05). Conclusion: The data of our study suggested that EECP is a useful therapeutic measurement for amelioration of endothelial dysfunction and long-term elevation of exercise tolerance for patients with coronary heart disease. Clinical trial registration: [http://www.chictr.org.cn/], identifier [ChiCTR1800020102].

An integrated flexible film as cathode for High-Performance Lithium-Sulfur battery.

Poor cycling stability and low volumetric capacity of sulfur cathode prevents practical application of Lithium-sulfur (Li-S) batteries. Herein, we demonstrate a strategy to address the two drawbacks of sulfur cathode by synthesizing a compact and flexible film cathode with bilayer structure using a two-step vacuum filtration method. Two layers make up the sulfur cathode, active layer (sulfur-acethlene black (SC) spheres) and barrier layer (three dimensional MnO2-graphene oxide-multi-walled carbon nanotubes (MnO2-GO-CNTs) composites), which are integrated together by reduced graphene oxide (rGO) through self-binding. The rGO sheets provide an electrical conductive framework and a stable architecture to accommodate volume changes of sulfur. SC spheres stacked orderly between the rGO layers facilitate fast Li+ storage and energy release. Polar MnO2-GO-CNTs composites with large specific surface area have not only afforded efficient sites for chemically binding polysulfides, but also provided fast electron transfer for accelerating polysulfides redox reaction. Consequently, the integrated film cathode exhibits an unprecedented cycling stability of ~0.0279% capacity decay per cycle over more than 600 cycles at 1C and high volumetric capacity of 1021.9 Ah L-1 at 2C. Meanwhile, a foldable Li-S battery based on this flexible cathode is fabricated and shows excellent mechanical and electrochemical properties. The integrated flexible sulfur cathode of this study sheds light on the design strategies for application in flexible high volumetric capacity system.

Grb7 is over-expressed in cervical cancer and facilitate invasion and inhibit apoptosis in cervical cancer cells.

Growth factor receptor bound protein-7 (Grb7) is a multi-domain adaptor protein that is co-opted by numerous tyrosine kinases involved in various cellular signaling. The objective of this study was to investigate the expression of Grb7 and its clinicopathological significance in cervical cancer. Utilising immunohistochemical staining, we examined the expression of Grb7 in 120 cases of human cervical cancer tissue and 10 cases of adjacent non-cancerous cervical tissue. The positive rate of Grb7 protein expression was 34.2%, which was significantly higher than that in adjacent non-cancerous cervical tissue (0%, p<0.05). The expression of Grb7 was found to be correlated with age, tumor size, serosal invasion, differentiated degree, tumor stage, early or advanced stage and lymph node metastasis. Kaplan-Meier survival analysis showed that patients with positive Grb7 protein expression had a lower overall survival rate than patients without Grb7 expression. In addition, Grb7 plays an important role in promoting tumor progression, including invasion and anti-apoptosis, in cervical cancer cell line. Down-regulation of Grb7 repressed the expression of MMP-9 and Bcl-2, and increased the expression of Bax in Grb7 knockdown Hela cells. Cell invasion assay showed decreased number of Grb7 knockdown Hela cells (18.7±2.1) compared to Hela cells (65.3±2.5, P<0.05). Our results indicated that Grb7 over-expression may facilitate invasion and inhibit apoptosis in cervical cancer and Grb7 is a potentially molecular target of cervical cancer chemotherapy.

[Analysis of Volatile Oils from Different Processed Products of Zingiber officinale Rhizome by GC-MS].

OBJECTIVE: To analyze the volatile components in different processed products of Zingiber officinale rhizome, and to make clear the effect of different heating degree on them. METHODS: The volatile components were extracted from four kinds of processed products by applying steam distillation, and then were analyzed by GC-MS. RESULTS: There were totally 43 components of volatile oil identified from four kinds of processed products of Zingiber officinale rhizome. Fresh product, dried product, and charcoal product of Zingiber officinale rhizome each had 27 components of volatile oil, while sand fried product contained 24 components. Fresh Zingiber officinale rhizome contained 22. 59% of zingiberene, 20. 87% of a-citral and 11. 01% of ß-phellandrene, respectively. After processing in different heating degree, the volatile components changed greatly in both of their quantity and quality, For instance, dried Zingiber officinale rhizome contained 40. 48% of α-citral and 8-phellandrene content was slightly lower at 10. 38%. 32.73% of 3,7,11-trimethyl-l, 6, 10-dodecatriene,16. 38% of murolan-3, 9 (11)-diene-10-peroxy and 3. 36% of cubebene newly emerged in the sand fried Zingiber officinale rhizome, and eudesm-4 (14) and ß-bisabolol, etc. However, ß-phellandrene content was only 1. 95%. The zingiberene and ß-sesquiphellandrene were the highest in charcoal product, besides, new components such as α-cedrene, decanal and γ-elemene appeared. CONCLUSION: Volatile components in different processed products of Zingiber officinale rhizome were different in both of their kinds and contents. This method is suitable for the analysis of volatile components in Zingiber officinale rhizome, and this study can provide the experimental evidence for quality evaluation and clinical application for ginger processed products.

[Optimization of wine-roasting technology of coptidis rhizoma using orthogonal design].

OBJECTIVE: To optimize the processing technology of Coptidis Rhizoma roasting with yellow rice wine. METHODS: The total content of four kinds of alkaloids was used as index. Orthogonal design was applied to study the processing technology of Coptidis Rhizoma roasting with yellow rice wine. L9 (3(4)) orthogonal table was decided with three factors: roasting temperature, roasting time and the amount of yellow rice wine. RESULTS: Of the three factors, only B factor (roasting time) had obvious effect on the total content of four kinds of alkaloids. CONCLUSION: The optimal processing technology is as follows: Coptidis Rhizoma should be roasted with 15% yellow rice wine for 30 min at 150 degrees C.

A novel and simple hollow-fiber assay for in vivo evaluation of nonpeptidyl thrombopoietin receptor agonists.

Preclinical in vivo assessment of the pharmacologic activity of nonpeptidyl thrombopoietin receptor (TPOR) agonists is very difficult because of the high species specificity of such agonists. In this study, we have developed a novel and simple in vivo hollow-fiber assay to preclinically evaluate TPOR agonists. The 32D-mpl cell line was generated by stable transfection of human TPOR into 32D lymphoblast cells and shown to be a specific model for nonpeptide TPOR agonists in vitro. Stably transfected 32D-mpl cells were then sealed in hollow fibers and implanted into nude mice. Cells in hollow fibers specifically responded to TPOR agonists, including thrombopoietin and eltrombopag, a nonpeptide small-molecule TPOR agonist, but not to granulocyte colony-stimulating factor or erythropoietin. Oral administration of eltrombopag stimulated 32D-mpl cell proliferation, prevented 32D-mpl cell apoptosis, and stimulated the phosphorylation of cellular signaling transducers and activators of transcription in a TPOR- and dose-dependent manner. These results indicate that the hollow-fiber assay is a specific and efficient model for rapidly evaluating the in vivo activity of small-molecule TPOR agonists.

YHHU0895, a novel synthetic small-molecule microtubule-destabilizing agent, effectively overcomes P-glycoprotein-mediated tumor multidrug resistance.

P-glycoprotein-mediated multidrug resistance (MDR) is a major limiting factor in the efficacy of most microtubule-targeting agents. Here, we investigated the novel, synthetic, and small-molecule microtubule-destabilizing agent, 2-(2-amino-5-(1-ethyl-1H-indol-5-yl) pyrimidin-4-yl) phenol (YHHU0895), for its anti-tumor activity and potential for overcoming P-glycoprotein-mediated MDR. YHHU0895 inhibited purified tubulin polymerization through binding to tubulin at the colchicine-binding site and significantly inhibited human tumor cell proliferation. Notably, P-glycoprotein-overexpressing KBV200 and K562/ADR cells, which are strongly resistant to colchicine, vinorelbine and paclitaxel, were sensitive to YHHU0895 both in vitro and in vivo. These findings indicate that YHHU0895 is a novel type of microtubule-destabilizing agent that has the potential for the treatment of patients with drug resistance mediated by P-glycoprotein.

Synthesis and biological evaluation of 2,4,5-substituted pyrimidines as a new class of tubulin polymerization inhibitors.

Members of a series of 2,4,5-substituted pyrimidine derivatives were synthesized, and their interactions with tubulin and their antiproliferative activities against the human hepatocellular carcinoma cells of liver (BEL-7402) were evaluated. One member of this family, the indole-pyrimidine 4k, having an indole-aryl-substituted aminopyrimidine structure, was observed to be an excellent inhibitor of tubulin polymerization (IC(50) = 0.79 µM) and to display significantly high antiproliferative activities against several cancer cell lines with IC(50) values ranging from 16 to 62 nM. This substance displayed a high propensity to arrests cells at the G(2)/M phase of the cell cycle (EC(50) = 20 nM). In addition, 4k was found to competitively inhibit colchicine binding to tubulin, indicating that it binds to the colchicine-binding site of tubulin. The observations made in this investigation demonstrate that 2,4,5-substituted pyrimidines represent a new class of tubulin polymerization inhibitors with significant antiproliferative activity.

Synthesis and biological evaluation of novel 2,4,5-substituted pyrimidine derivatives for anticancer activity.

A series of novel 2,4,5-substituted pyrimidine derivatives were synthesized and evaluated for inhibition against the human hepatocellular carcinoma BEL-7402 cancer cell line. Several compounds showed potent inhibition with an IC(50) value less than 0.10 microM. Structure-activity relationships for this class of compounds at the 2- and 5-position of the pyrimidine scaffold have been elucidated. The most active compound 7gc showed good inhibition of several different human cancer cell lines with IC(50) values from 0.024 to 0.55 microM.