卡非佐米治疗多发性骨髓瘤的耐药机制研究进展

治疗多发性骨髓瘤(multiple myeloma,MM)的药物主要以蛋白酶体抑制剂(proteasome inhibitors,PIs)、免疫调节剂(immunomodulatory drugs,IMiDs)为主。近年来包括CD38单抗、CAR-T细胞治疗以及其他一些新药的使用,显著提高了MM患者的治疗疗效,改善了患者的生存期。其中PIs仍然是MM治疗的基本药物。卡非佐米(carfilzomib,CFZ)作为新一代的PIs,相较于硼替佐米(bortezomib,BTZ)以及伊沙佐米(ixazomib,IXZ),由于其治疗机制的不同,更多地使用于复发难治性MM(relapsed or refractory multiple myeloma,RRMM)以及耐药MM的患者,且其疗效已被大量数据证实。但随着卡非佐米的临床应用,部分患者出现耐药现象。本文将根据近些年对于卡非佐米耐药的研究,从自噬水平、药物代谢、蛋白酶体结构及数量、基因的修饰、细胞代谢5个方面分析卡非佐米的耐药机制,并据此给出可能的新的治疗方案。根据上述新的治疗方案有望增强卡非佐米的疗效,减少耐药现象的出现,延长患者的生存时间。

Dynamic variations in COVID-19 with the SARS-CoV-2 Omicron variant in Kazakhstan and Pakistan

Background The ongoing coronavirus disease 2019(COVID-19)pandemic caused by the severe acute respiratory syndrome-coronavirus 2(SARS-CoV-2)and the Omicron variant presents a formidable challenge for control and prevention worldwide,especially for low-and middle-income countries(LMICs).Hence,taking Kazakhstan and Pakistan as examples,this study aims to explore COVID-19 transmission with the Omicron variant at different contact,quarantine and test rates.Methods A disease dynamic model was applied,the population was segmented,and three time stages for Omicron transmission were established:the initial outbreak,a period of stabilization,and a second outbreak.The impact of population contact,quarantine and testing on the disease are analyzed in five scenarios to analysis their impacts on the disease.Four statistical metrics are employed to quantify the model’s performance,including the correlation coefficient(CC),normalized absolute error,normalized root mean square error and distance between indices of simulation and observation(DISO).Results Our model has high performance in simulating COVID-19 transmission in Kazakhstan and Pakistan with high CC values greater than 0.9 and DISO values less than 0.5.Compared with the present measures(baseline),decreasing(increasing)the contact rates or increasing(decreasing)the quarantined rates can reduce(increase)the peak values of daily new cases and forward(delay)the peak value times(decreasing 842 and forward 2 days for Kazakhstan).The impact of the test rates on the disease are weak.When the start time of stage Ⅱ is 6 days,the daily new cases are more than 8 and 5 times the rate for Kazakhstan and Pakistan,respectively(29,573 vs.3259;7398 vs.1108).The impact of the start times of stageⅢon the disease are contradictory to those of stageⅡ.Conclusions For the two LMICs,Kazakhstan and Pakistan,stronger control and prevention measures can be more effective in combating COVID-19.Therefore,to reduce Omicron transmission,strict management of population movement should be employed.Moreover,the timely application of these strategies also plays a key role in disease control.

Dietary exposure to di-isobutyl phthalate increases urinary 5-methyl-2′-deoxycytidine level and affects reproductive function in adult male mice

Phthalates are a large family of ubiquitous environmental pollutants suspected of being endocrine disruptors. Epidemiological studies have associated phthalate metabolites with decreased reproductive parameters and linked phthalate exposure with the level of urinary 5-methyl-2′-deoxycytidine（5mdC, a product of methylated DNA）. In this study, adult male mice were exposed to 450 mg di-isobutyl phthalate（DiBP）/（kg·day） via dietary exposure for 28 days. Mono-isobutyl phthalate（Mi BP, the urinary metabolite） and reproductive function parameters were determined. The levels of 5mdC and 5-hydroxymethyl-2′-deoxycytidine（5hmdC） were measured in urine to evaluate if their contents were also altered by DiBP exposure in this animal model. Results showed that DiBP exposure led to a significant increase in the urinary 5mdC level and significant decreases in sperm concentration and motility in the epididymis, accompanied with reduced testosterone levels and downregulation of the P450 cholesterol side-chain cleavage enzyme（P450scc） gene in the mice testes. Our findings indicated that exposure to DiBP increased the urinary 5mdC levels,which supported our recent epidemiological study about the associations of urinary 5mdC with phthalate exposure in the male human population. In addition, DiBP exposure impaired male reproductive function, possibly by disturbing testosterone levels; P450scc might be a major steroidogenic enzyme targeted by DiBP or other phthalates.

Cross-reactivity of eight SARS-CoV-2 variants rationally predicts immunogenicity clustering in sarbecoviruses

A steep rise in Omicron reinfection cases suggests that this variant has increased immune evasion ability.To evaluate its antigenicity relationship with other variants,antisera from guinea pigs immunized with spike protein of SARS-CoV-2 variants of concern(VOCs)and variants of interest(VOIs)were cross-tested against pseudotyped variants.The neutralization activity against Omicron was markedly reduced when other VOCs or VOIs were used as immunogens,and Omicron(BA.1)-elicited sera did not efficiently neutralize the other variants.However,a Beta or Omicron booster,when administered as the 4th dose 3-months after the 3rd dose of any of the variants,could elicit broad neutralizing antibodies against all of the current variants including Omicron BA.1.Further analysis with 280 available antigen–antibody structures and quantification of immune escape from 715 reported neutralizing antibodies provide explanations for the observed differential immunogenicity.Three distinct clades predicted using an in silico algorithm for clustering of sarbecoviruses based on immune escape provide key information for rational design of vaccines.