Comparable survival outcome between transplantation from haploidentical donor and matched related donor or unrelated donor for severe aplastic anemia patients aged 40 years and older: A retrospective multicenter cohort study

This retrospective multicenter cohort study aimed to compare the outcome of haploidentical hematopoietic stem cell transplantation (HID-HSCT) with matched sibling donor (MSD) and unrelated donor (URD) transplantation in severe aplastic anemia (SAA) patients 40 years of age and older. With a median follow-up time of 17.6 months, 85 consecutive patients were enrolled in the study, and the median patient age was 45 years (40, 58). The cumulative engraftment rates of neutrophil and platelet were 98.8 ± 0.0% and 92.9 ± 0.1%. The cumulative incidences of Grade 2-4 acute graft-versus-host disease (aGvHD) and chronic graft-versus-host disease (cGvHD) at 3 years were 14.1 ± 0.1% and 17.3 ± 0.2%. The 3-year estimated overall survival (OS) and failure-free survival (FFS) were 91.2 ± 3.2% and 89.7 ± 3.5%. In multivariate analysis, the only factor associated with inferior survival was an ECOG score ≥2. HID-HSCT was associated with a higher incidence of GvHD, but the difference of 3-year estimated OS between HID group and the other two cohorts was not significant (86.7 ± 6.4% for HID vs 92.1% ± 4.4% for MSD and 100% for URD, P = .481). HID-HSCT might be a feasible alternative option for selected SAA patients aged 40 years and older without a matched donor.     

误诊为尿路上皮癌的膀胱平滑肌肉瘤1例并文献分析

目的探讨膀胱平滑肌肉瘤的临床表现、病理学特征、治疗及预后,提高对该病的认知和诊疗水平。方法回顾分析1例膀胱平滑肌肉瘤患者的临床资料及诊疗过程并复习相关国内外文献。结果患者经术前各项检查明确手术指征,充分完善术前准备后行腹腔镜下根治性膀胱全切+乙状结肠代膀胱术。术后病理结果示:(膀胱)间叶性恶性肿瘤,倾向平滑肌肉瘤,免疫组化SMA(+)、Vimentin(+)、Galdesmon(-)、Bcl2(-)、Ki67(约15%)、Desmin(-)、CD34(血管+)、P53(灶+)、EMA(-)、S-100(-)、CDK4(-)、CK(-)。术后辅以AI方案化疗:异磷酰胺(130 mg/m^2)、多柔比星(20 mg/m^2)。随访10个月未见肿瘤转移及复发,治疗效果明显。结论膀胱平滑肌肉瘤系一种极其少见的侵袭性间质瘤,临床和影像学表现均不典型,临床上很容易误诊,其治疗方法可考虑以手术联合化疗为主。     

FBP1 is highly expressed in human hypertrophic scars and increases fibroblast proliferation,apoptosis, and collagen expression

Purpose: FBP1, one of the far-upstream element binding proteins(FBPs), is a distal upstream binding protein of c-myc, which is highly expressed in tumor tissues. This study aimed to investigate FBP1 expression in human hypertrophic scars and to determine the effects of FBP1 on fibroblasts. Materials and methods: Human normal skin and scar specimens were collected during clinical surgery. One portion of each tissue specimen was embedded in paraffin and sliced to observe differences in histological features and FBP1 expression by immunohistochemistry and western blotting. The other portion of each tissue specimen was cultured to obtain fibroblasts. Fibroblasts from the second to the sixth passage were used for the experiments, which were divided into the following two groups: an experimental group, whose cells were transfected with an siRNA targeting FBP1, and a control group, whose cells where not transfected. MTT and TUNEL assays were performed, respectively, to assess fibroblast proliferation and apoptosis, and western blotting was performed to assess protein expression. Results: We obtained fibroblasts by primary tissue culture and found that FBP1 was highly expressed in hypertrophic scars. MTT assay showed that an siRNA targeting FBP1 significantly reduced fibroblast proliferation in siRNA-treated cells compared to control cells. TUNEL assay showed that there was no difference in apoptosis between the two groups; however, western blotting showed that collagen I, collagen III, c-myc, caspase-3, and caspase-9 expression levels were all decreased in the experimental group. Conclusion: FBP1 is highly expressed in human hypertrophic scars and increases fibroblast proliferation, apoptosis and collagen expression.     

Selected Abstracts from the 13th Annual Meeting of the Clinical Immunology Society: 2022 Annual Meeting: Immune Deficiency and Dysregulation North American Conference

Journal of Clinical Immunology - Coronavirus disease 2019 (COVID-19) exhibits a wide spectrum of clinical manifestations, ranging from asymptomatic to critical conditions. Understanding the...     

Inherited IFNAR1 Deficiency in a Child with Both Critical COVID-19 Pneumonia and Multisystem Inflammatory Syndrome

Journal of Clinical Immunology - Inborn errors of immunity (IEI) and autoantibodies to type I interferons (IFNs) underlie critical COVID-19 pneumonia in at least 15% of the patients, while the...     

从高血压到脑卒中的脑血管血流动力学指标变化规律

目的:探讨从高血压到脑卒中的脑血管血流动力学指标(cerebralvascu-larhemodynmic,CVHD)的变化规律。方法:队列人群中随访发生的371例有高血压病史的脑卒中患者按年龄、性别随机选择其它组别,分成血压正常组、临界高血压组、高血压组、脑卒中前高血压组和脑卒中后遗症组。分析和观察CVHD的分布和变化规律。结果:5组人群的CVHD积分中位数分别为95.5,90.0,78.75,40.0和51.25分,其中<75分的百分率分别为19.9%,36.8%,46.3%,78.7%和69.5%;从血压正常到脑卒中发病前,脑血管血流速度呈明显的降低趋势,外周阻力和特性阻抗等动力学指标呈明显的升高趋势。结论:随着高血压的发生和发展,脑血管功能异常逐渐加重,当总积分值下降至40分左右,为脑卒中发病前的“超高危”状态,是脑卒中发生的重要预警信号。     

鸦胆子油药理作用研究概况

鸦胆子系苦木科植物鸦胆子Brucea javanica（L．）Merr．的干燥成熟果实。始载于《本草纲目拾遗》。由于鸦胆子油抗癌作用，近年来在临床应用和药理作用基础方面研究受到广泛重视。现就其药理研究综述如下：     

Cdc42 Deficiency Causes Ciliary Abnormalities and Cystic Kidneys

Ciliogenesis and cystogenesis require the exocyst, a conserved eight-protein trafficking complex that traffics ciliary proteins. In culture, the small GTPase Cdc42 co-localizes with the exocyst at primary cilia and interacts with the exocyst component Sec10. The role of Cdc42 in vivo, however, is not well understood. Here, knockdown of cdc42 in zebrafish produced a phenotype similar to sec10 knockdown, including tail curvature, glomerular expansion, and mitogen-activated protein kinase (MAPK) activation, suggesting that cdc42 and sec10 cooperate in ciliogenesis. In addition, cdc42 knockdown led to hydrocephalus and loss of photoreceptor cilia. Furthermore, there was a synergistic genetic interaction between zebrafish cdc42 and sec10, suggesting that cdc42 and sec10 function in the same pathway. Mice lacking Cdc42 specifically in kidney tubular epithelial cells died of renal failure within weeks of birth. Histology revealed cystogenesis in distal tubules and collecting ducts, decreased ciliogenesis in cyst cells, increased tubular cell proliferation, increased apoptosis, increased fibrosis, and led to MAPK activation, all of which are features of polycystic kidney disease, especially nephronophthisis. Taken together, these results suggest that Cdc42 localizes the exocyst to primary cilia, whereupon the exocyst targets and docks vesicles carrying ciliary proteins. Abnormalities in this pathway result in deranged ciliogenesis and polycystic kidney disease.Cilia are thin rod-like organelles, found on the surface of many eukaryotic cells, with complex functions in signaling, cell differentiation, and growth control. Cilia extend outward from the basal body, a cellular organelle related to the centriole. In kidney cells, a single primary cilium projects from the basal body, is nonmotile, and exhibits an axoneme microtubule pattern of 9+0. In the mammalian kidney, primary cilia have been observed on renal tubule cells in the parietal layer of the Bowman capsule, the proximal tubule, the distal tubule, and in the principal, but not intercalated, cells of the collecting duct.¹Multiple proteins that, when mutated, result in the development of polycystic kidney disease (PKD) have been localized to renal primary cilia. These include polycystin-1 and -2, the causal proteins in autosomal dominant PKD (ADPKD) (reviewed by Smyth et al.²). Research into pkd2 function in zebrafish has further strengthened the idea that polycystin-2 functions in cilia. Knockdown of pkd2 by morpholino (MO)^3–5 or in mutants^5,6 produces phenotypes that are consistent with a role in cilia function, such as curved tails, pronephric cysts, and edema.Although we are beginning to identify the roles ciliary proteins play in diverse biologic processes, relatively little is known about how these proteins are transported to the cilium.⁷ The exocyst, originally identified in Saccharomyces cerevisiae,⁸ is a highly conserved 750-kD eight-protein complex known for the targeting and docking of vesicles carrying membrane proteins.⁹ It is composed of Sec3, Sec5, Sec6, Sec8, Sec10, Sec15, Exo70, and Exo84 (also known as EXOC1–8).¹⁰ Notably, in addition to being found near the tight junction, exocyst proteins were localized to the primary cilium in kidney cells.^11,12 Sec10 and Sec15 are the most vesicle-proximal of the exocyst components. Sec10 directly binds to Sec15, which, in turn, directly binds Sec4/Rab8, a Rab GTPase found on the surface of transport vesicles. Sec10 then acts as a “linker” by binding the other exocyst components through Sec5.¹³ Our previous studies suggested that the exocyst would no longer be able to bind Sec15, and thereby target/dock transport vesicles, without Sec10, and would, instead, disintegrate and be degraded. Importantly, we showed that knockdown of Sec10 in Madin-Darby canine kidney (MDCK) cells abrogated ciliogenesis, while Sec10 overexpression enhanced ciliogenesis. Furthermore, Sec10 knockdown caused abnormal cystogenesis when the cells were grown in a collagen matrix and decreased the levels of other exocyst components and the intraflagellar transport protein 88. This was in contrast to knockdown of exocyst components Sec8 and Exo70, which had no effect on ciliogenesis, cystogenesis, or levels of other exocyst components.¹² On the basis of these data, and its known role in trafficking proteins to the plasma membrane,^14–17 we proposed that Sec10 and the exocyst are required to build primary cilia by targeting and docking vesicles carrying ciliary proteins.A possible mechanism to target the exocyst to nascent primary cilia, so it can participate in ciliogenesis, is through the Par complex. We previously showed that the exocyst co-localizes with Par3¹² and directly interacts with Par6,¹⁸ both components of the Par complex, which also includes atypical PKC. Cdc42 is associated with the Par complex.^19,20 In addition to their well studied function at cell-cell contacts, the Par complex has been immunolocalized to primary cilia and is necessary for ciliogenesis.^21,22 The exocyst is regulated by multiple Rho and Rab family GTPases (reviewed by Lipschutz and Mostov⁹), including Cdc42, which regulates polarized exocytosis via interactions with the exocyst in yeast.²³ Using inducible MDCK cell lines that express constitutively active or dominant negative forms of Cdc42,^24,25 we established that Cdc42 is centrally involved in three-dimensional collagen gel cystogenesis and tubulogenesis.²⁶ Whether and how Cdc42 might participate in ciliogenesis and cooperate with the exocyst in ciliary membrane trafficking are open questions.Toward this end, we showed, in cell culture, that Cdc42 co-immunoprecipitated and co-localized with Sec10 and that Cdc42 was necessary for ciliogenesis in renal tubule cells, in that Cdc42-dominant negative expression, small hairpin RNA knockdown of Cdc42, and small hairpin RNA knockdown of Tuba, a guanine nucleotide exchange factor (GEF) for Cdc42, all inhibited ciliogenesis. Exocyst Sec8 and polycystin-2 also no longer localized to the primary cilium, or the ciliary region, after Cdc42 and Tuba knockdown.¹⁸ As noted, we showed that Sec10 directly binds to Par6, and others have shown that Cdc42 also directly binds to Par6.^27,28 Knockdown of both Sec10²⁹ and Cdc42 increased mitogen-activated protein kinase (MAPK) activation.¹⁸Here, using two different living organisms, we confirm and extend our in vitro findings. We show that cdc42 knockdown in zebrafish phenocopies many aspects of sec10 and pkd2 knockdown—including curved tail, glomerular expansion, and MAPK activation—suggesting, in conjunction with our previous data,^12,18,29 that cdc42 may be required for sec10 (and possibly pkd2) function in vivo. Other ciliary phenotypes include hydrocephalus and loss of photoreceptor cilia. We also demonstrate a synergistic genetic interaction between zebrafish cdc42 and sec10 for these cilia-related phenotypes, indicating that cdc42 and sec10 function in the same pathway. Demonstrating that the phenotypes were not due to off-target effects from the cdc42 MOs, we rescued the phenotypes with mouse Cdc42 mRNA. Cdc42 kidney-specific knockout mice died of kidney failure within weeks of birth; histologic examination revealed cystogenesis in distal tubules and collecting ducts and decreased ciliogenesis in cyst cells. Cdc42 conditional knockout kidneys showed increased tubular epithelial cell proliferation, increased apoptosis, increased interstitial fibrosis, and MAPK pathway activation, all features of the nephronophthisis form of PKD. These data, along with our previously published results, support a model in which Cdc42 localizes the exocyst to the primary cilium, whereupon the exocyst then targets and docks vesicles carrying proteins necessary for ciliogenesis; if this does not occur, the result is abnormal ciliogenesis and PKD.