Immunotherapy for multiple myeloma: new chances and hope

Introduction Multiple myeloma(MM),characterized by the proliferation of monoclonal plasma cells in the bone marrow,has the second highest incidence among hematologic malignancies1.Because of its incurable nature,treatments for MM are aimed primarily at obtaining minimal residual disease(MRD)negativity and achieving persistent control,both of which are believed to be important strategies to prolong survival and improve prognosis in patients with MM.

TRPV6对结肠癌SW480细胞生物学行为及小鼠模型中结肠肿瘤发生的影响

目的:通过观察沉默瞬时受体阳离子通道亚家族V成员6(transient receptor potential cation channel,subfamily V member 6,TRPV6)对结肠癌SW480细胞生物学行为的影响和细胞内钙的浓度变化,以及1,25(OH)_2D_3、CaCl_2及CuCl_2在SD大鼠结肠肿瘤模型建立中的影响,探索TRPV6在结肠癌发生过程中的相关作用,为结肠癌的防治寻找新的靶点。方法:通过构建慢病毒颗粒感染结肠癌SW480细胞,采用免疫组织化学法、Western bolt、PCR技术检测TRPV6蛋白及m RNA的表达,MTT法、迁移及凋亡实验观察结肠癌SW480细胞增殖、迁移及凋亡变化,高速离子成像系统测定结肠癌SW480细胞内的Ca^(2+)浓度变化。以二甲基肼(dimethyl hydrazine,DMH)建立SD大鼠结肠肿瘤模型,分为实验组(DMH组)和干预组[(DMH+1,25(OH)_2D_3组、DMH+CuCl_2组)]、对照组,干预组分别予1,25(OH)_2D_3(37.5 nmol/kg)、CuCl2(375μmol/kg)对模型进行干预。观察各组大鼠结肠腺瘤及腺癌的发生情况,Western blot检测各组结肠组织中TRPV6蛋白的表达情况。结果:TRPV6-RNAi转染结肠癌SW480细胞后,TRPV6 m RNA及蛋白表达减少,细胞Ca^(2+)浓度水平降低,结肠癌SW480细胞的增殖率、迁移能力下降,细胞凋亡率增加,与空白对照组及阴性对照组比较差异具有统计学意义(P<0.05)。对照组大鼠成瘤率为0,DMH+1,25(OH)_2D_3组为100%,DMH组为84.62%,DMH+CuCl_2组为33.33%。各组大鼠大肠中均有TRPV6蛋白的表达,表达情况为DMH+1,25(OH)_2D_3组>DMH组>DMH+CuCl_2组>对照组,差异具有统计学意义(P<0.05)。结论:降低结肠癌SW480细胞Ca^(2+)浓度水平可抑制结肠癌SW480细胞的增殖、迁移能力,诱导细胞凋亡。1,25(OH)_2D_3可以增加实验鼠结肠组织TRPV6蛋白表达,促进结肠肿瘤的形成。CuCl_2可以使实验鼠结肠组织中的TRPV6蛋白表达降低,并抑制结肠肿瘤的形成。

基于GIS的湖南省山洪沟提取技术及其应用

本文基于GIS空间分析技术进行流域信息分析,结合坡度、地形起伏度等地形特征,利用逆流原理对湖南省山洪沟边界信息进行提取,结果表明:1) 湖南省山洪沟多分布在湖南省西北部、南部和中部山区。与降水分布进行对比,发现这些地区降水分布相对集中,且出现强降水的概率较大,出现山洪灾害的风险较高。2) 对山洪沟预测指标进行等级分级,用不同等级值反映了山洪灾害发生的概率,可以看出提取的山洪沟位置信息与实际发生山洪灾害的位置有很好的对应关系。说明山洪沟的分布能在一定程度内反映出山洪灾害的发生地点。3) GIS提取结果与历史普查的山洪灾害发生区域进行叠加分析,相似度较高,较好的验证了山洪沟提取的可靠性。

Dynamic and adaptive membrane lipid remodeling in leaves of sorghum under salt stress

Salt stress limits plant growth and development.In this study,changes in membrane lipids were investigated in leaves of sorghum seedlings subjected to salt stress(150 mmol L^(-1)NaCl).Galactolipids(DGDG and MGDG)accounted for more than 65%of the total glycerolipids in sorghum leaves.The predominance of C36 molecular species in MGDG suggested that sorghum is an 18:3 plant.Under Na Cl treatment,the content of major phospholipids(PC and PE)increased,accompanied by the activation of their metabolism pathways at the transcriptional level.In contrast,the proportion of MGDG and PG dropped drastically,leading to a decreased ratio of plastidic to non-plastidic lipids.An adjustment of glycerolipid pathway between the cytosolic and plastidic compartments was triggered by salt stress,as reflected by the increased conversion of PC to PA,providing precursors for galactolipid synthesis.The elevated DGDG resulted in increased DGDG/MGDG and bilayer/non-bilayer lipid ratios.The double-bond index of PC,PE,and DGDG increased markedly,evidently owing to the increased expression of FAD3 and FAD8.These findings will be helpful for understanding dynamic membrane lipid changes and adaptive lipid remodeling in sorghum response to salt stress.

Mettl3依赖的m^(6)A甲基化调控CD8^(+)T细胞效应分化和记忆形成

Efficient immune responses rely on the proper differentiation of CD8^(+)T cells into effector and memory cells.Here,we show a critical requirement of N^6-Methyladenosine(m^(6)A)methyltransferase Mettl3 during CD8^(+)T cell responses upon acute viral infection.Conditional deletion of Mettl3 in CD8^(+)T cells impairs effector expansion and terminal differentiation in an m^(6)A-dependent manner,subsequently affecting memory formation and the secondary response of CD8^(+)T cells.Our combined RNA-seq and m^(6)AmiCLIP-seq analyses reveal that Mettl3 deficiency broadly impacts the expression of cell cycle and transcriptional regulators.Remarkably,Mettl3 binds to the Tbx21 transcript and stabilizes it,promoting effector differentiation of CD8^(+)T cells.Moreover,ectopic expression of T-bet partially restores the defects in CD8^(+)T cell differentiation in the absence of Mettl3.Thus,our study highlights the role of Mettl3 in regulating multiple target genes in an m^(6)A-dependent manner and underscores the importance of m^(6)A modification during CD8^(+)T cell response.

Tubulointerstitial nephritis antigen-like 1 is a novel matricellular protein that promotes gastric bacterial colonization and gastritis in the setting of Helicobacter pylori infection

The interaction between the gastric epithelium and immune cells plays key roles in H. pylori-associated pathology. Here, we demonstrate a procolonization and proinflammatory role of tubulointerstitial nephritis antigen-like 1 (TINAGL1), a newly discovered matricellular protein, in H. pylori infection. Increased TINAGL1 production by gastric epithelial cells (GECs) in the infected gastric mucosa was synergistically induced by H. pylori and IL-1β via the ERK-SP1 pathway in a cagA-dependent manner. Elevated human gastric TINAGL1 correlated with H. pylori colonization and the severity of gastritis, and mouse TINAGL1 derived from non-bone marrow-derived cells promoted bacterial colonization and inflammation. Importantly, H. pylori colonization and inflammation were attenuated in Tinagl1−/− and Tinagl1ΔGEC mice and were increased in mice injected with mouse TINAGL1. Mechanistically, TINAGL1 suppressed CCL21 expression and promoted CCL2 production in GECs by directly binding to integrin α5β1 to inhibit ERK and activate the NF-κB pathway, respectively, which not only led to decreased gastric influx of moDCs via CCL21-CCR7-dependent migration and, as a direct consequence, reduced the bacterial clearance capacity of the H. pylori-specific Th1 response, thereby promoting H. pylori colonization, but also resulted in increased gastric influx of Ly6Chigh monocytes via CCL2-CCR2-dependent migration. In turn, TINAGL1 induced the production of the proinflammatory protein S100A11 by Ly6Chigh monocytes, promoting H. pylori-associated gastritis. In summary, we identified a model in which TINAGL1 collectively ensures H. pylori persistence and promotes gastritis.

Prognostic value of the Second Revision of the International Staging System (R2-ISS) in a real-world cohort of patients with newlydiagnosed multiple myeloma

To the Editor:Multiple myeloma(MM)is a plasma cell disorder characterized by heterogeneous features.^([1])Accurate risk stratification could predict diverse prognoses of patients with myeloma and attain risk-adapted therapy to extend their lifespan.Recently,the European Myeloma Network(EMN)conducted a large retrospective analysis involving more than 7000 patients with myeloma and developed a new risk model defined as the Second Revision of International Staging System(R2-ISS),with excellent risk distribution among patients enrolled in clinical trials.^([2])The R2-ISS stratifications were based on weighted risk scores of different prognostic factors:ISS II 1.0 point,ISS III 1.5 points,del(17p)1.0 point,elevated lactate dehydrogenase(LDH)1.0 point,t(4;14)1.0 point,and 1q21+0.5 points.

Enhanced production of seed oil with improved fatty acid composition by overexpressing NAD^(+)-dependent glycerol-3-phosphate dehydrogenase in soybean

There is growing interest in expanding the production of soybean oils(mainly triacylglycerol, or TAG) to meet rising feed demand and address global energy concerns. We report that a plastidlocalized glycerol-3-phosphate dehydrogenase(GPDH), encoded by GmGPDHp1 gene, catalyzes the formation of glycerol-3-phosphate(G3 P), an obligate substrate required for TAG biosynthesis.Overexpression of GmGPDHp1 increases soybean seed oil content with high levels of unsaturated fatty acids(FAs), especially oleic acid(C18:1), without detectably affecting growth or seed protein content or seed weight. Based on the lipidomic analyses, we found that the increase in G3 P content led to an elevated diacylglycerol(DAG) pool, in which the Kennedy pathwayderived DAG was mostly increased, followed by PC-derived DAG, thereby promoting the synthesis of TAG containing relatively high proportion of C18:1. The increased G3 P levels induced several transcriptional alterations of genes involved in the glycerolipid pathways. In particular, genes encoding the enzymes responsible for de novo glycerolipid synthesis were largely upregulated in the transgenic lines, in-line with the identified biochemical phenotype. These results reveal a key role for GmGPDHp1-mediated G3 P metabolism in enhancing TAG synthesis and demonstrate a strategy to modify the FA compositions of soybean oils for improved nutrition and biofuel.

46例巨灶型多发性骨髓瘤患者临床特征及预后分析

回顾性分析2013年1月至2019年12月就诊于中国医学科学院血液病医院的46例巨灶型骨髓瘤(MFMM)患者临床特征、化验及检查结果、具体治疗方案、疗效及生存等临床资料,并按照诊断时间、治疗方案匹配,选择92例经典多发性骨髓瘤(MM)患者作为对照组。在1137例MM患者中,符合MFMM诊断标准患者46例(4.0%),中位年龄56岁,与经典MM患者差异无统计学意义(P=0.066);MFMM组41例(89.1%)患者为ISS分期Ⅰ、Ⅱ期,仅5例(10.9%)患者为ISSⅢ期,而对照组49例(53.3%)患者为ISSⅢ期(P<0.05);所有MFMM患者均为R-ISS分期Ⅰ、Ⅱ期。MFMM组20例患者初诊时可见髓外浆细胞瘤,比例明显高于对照组(43.5%比18.5%,P<0.05)。MFMM组较少出现高危遗传学异常,比例低于对照组(15.8%比32.2%,P=0.058);MFMM组患者t(11;14)发生率明显高于对照组(32.4%比9.4%,P<0.05)。MFMM组与对照组患者诱导治疗方案、自体移植率相似,MFMM组中最佳疗效达CR患者比例明显高于对照组(78.3%比60.9%,P<0.05);截至2021年7月,中位随访时间37.9个月,MFMM组患者中位无进展生存期较对照组明显延长(77.5个月比39.8个月,P<0.05),总生存期也显著优于对照组(未达到比68.2个月,P<0.05)。骨髓浆细胞数量、不同新药治疗对MFMM患者生存结局无影响。

Ultra-stable K metal anode enabled by oxygen-rich carbon cloth

The K metal batteries are emerged as promising alternatives beyond commercialized Li-ion batteries.However,suppressing uncontrolled dendrite is crucial to the accomplishment of K metal batteries.Herein,an oxygen-rich treated carbon cloth(TCC)has been designed as the K plating host to guide K homogeneous nucleation and suppress the dendrite growth.Both density function theory calculations and experimental results demonstrate that abundant oxygen functional groups as K-philic sites on TCC can guide K nucleation and deposition homogeneously.As a result,the TCC electrode exhibits an ultra-long-life over 800 cycles at high current density of 3.0 mA·cm^(−2)for 3.0 mA·h·cm^(−2).Furthermore,the symmetrical cells can run stably for 2,000 h with low over-potential less than 20 mV at 1.0 mA·cm^(−2)for 1.0 mA·h·cm^(−2).Even at a higher current of 5.0 mA·cm^(−2),the TCC electrode can still stably cycle for 1,400 h.