Relationship between MLH1, PMS2, MSH2 and MSH6 gene-specific alterations and tumor mutational burden in 1057 microsatellite instability-high solid tumors

Microsatellite instability-high (MSI-H) and tumor mutational burden (TMB) are predictive biomarkers for immune-checkpoint inhibitors (ICIs). Still, the relationship between the underlying cause(s) of MSI and TMB in tumors remains poorly defined. We investigated associations of TMB to mismatch repair (MMR) protein expression patterns by immunohistochemistry (IHC) and MMR mutations in a diverse sample of tumors. Hypothesized differences were identified by the protein/gene affected/mutated and the tumor histology/primary site. Overall, 1057 MSI-H tumors were identified from the 32 932 tested. MSI was examined by NGS using 7000+ target microsatellite loci. TMB was calculated using only nonsynonymous missense mutations sequenced with a 592-gene panel; a subset of MSI-H tumors also had MMR IHC performed. Analyses examined TMB by MMR protein heterodimer impacted (loss of MLH1/PMS2 vs. MSH2/MSH6 expression) and gene-specific mutations. The sample was 54.6% female; mean age was 63.5 years. Among IHC tested tumors, loss of co-expression of MLH1/PMS2 was more common (n = 544/705, 77.2%) than loss of MSH2/MSH6 (n = 81/705, 11.5%; P < .0001), and was associated with lower mean TMB (MLH1/PMS2: 25.03 mut/Mb vs MSH2/MSH6 46.83 mut/Mb; P < .0001). TMB also varied by tumor histology: colorectal cancers demonstrating MLH1/PMS2 loss had higher TMBs (33.14 mut/Mb) than endometrial cancers (20.60 mut/Mb) and other tumors (25.59 mut/Mb; P < .0001). MMR gene mutations were detected in 42.0% of tumors; among these, MSH6 mutations were most common (25.7%). MSH6 mutation patterns showed variability by tumor histology and TMB. TMB varies by underlying cause(s) of MSI and tumor histology; this heterogeneity may contribute to differences in response to ICI.     

后路枕骨髁螺钉技术研究进展

正枕骨、寰椎和枢椎共同构成了枕颈部活动的结构功能单位,即枕颈交界区~([1-2])。炎症、创伤、肿瘤及畸形等因素会导致枕颈交界区失稳,从而引起颈脊髓或神经根的损伤、麻痹及难以忍受的疼痛,甚至危及生命~([3-4])。后路内固定融合技术是治疗枕颈部失稳的重要手段,目前常用术式为枕骨螺钉技术,该技术较钢丝固定技术有更好的生物力学稳定     

项韧带骨化相关因素及其组织学变化

目的：探讨脊髓型颈椎病患者项韧带骨化的相关因素及其组织学改变特点.方法：将45例脊髓型颈椎病患者根据项韧带有无骨化分为两组,观察并统计两组患者的年龄、性别组成、颈椎椎间退变和颈椎稳定性情况,对各指标与项韧带骨化的关系进行相关性分析,同时观察项韧带骨化的组织学改变.结果：统计分析表明,项韧带骨化和颈椎椎间退行性改变及颈椎不稳定之间具有相关性（P＜0.05）;同时还与患者年龄、性别组成有相关性（P＜0.05）.项韧带骨化的组织学改变以软骨内化骨为主.结论：项韧带骨化与颈椎退行性改变及颈椎椎间关节不稳定具有相关性,组织学改变以软骨内化骨为主.     

X chromosomal and autosomal loss of heterozygosity and microsatellite instability in human cervical carcinoma

The study analyzes tumor material and normal tissue from 27 patients with pure squamous cell carcinoma of the uterine cervix for loss of heterozygosity (LOH) and microsatellite instability (MSI) on 14 autosomal and 11 X chromosomal loci. Overall, 4-40% of the informative cases showed LOH at autosomal regions with the highest frequency at 3p (21-40%) and a marked frequency at 2q35-q37.1 (12.5%) and 17p13.3 (10%), representing regions with putative tumor suppressor gene (TSG) function. The frequency of X chromosomal LOH ranged from 4% to 20%, with a maximum at Xq28 (20%) and Xq11.2-q12 (17%), again indicating alterations in TSG. A 12% LOH was seen at Xq21.33-q22.3, a region encoding a protein with a regulatory function in the cell cycle via cyclin-dependent kinases. MSI was detected in autosomal regions in up to 7% in regions linked to the X chromosome in up to 11%, probably indicating alterations of mismatch repair mechanisms. Our results and those obtained from the literature suggest that autosomal LOH and MSI in carcinomas of the cervix uteri are predominantly found at regions with putative TSG function. Beside TSG alterations, X chromosomal LOH is probably more strongly connected to disturbances in cell cycle regulation.     

Mitotic and meiotic detection of radiation-induced translocations in mouse stem cell spermatogonia using fluorescencein situ hybridization

The efficiency of two methods of detection of translocations induced in mouse stem cell spermatogonia by X-ray doses of 2, 5 and 7 Gy was compared: classical multivalent analysis at diakinesis-metaphase I of meiosis and observation via fluorescencein situ hybridization analysis of mitotic or meiotic stages. Specific DNA libraries for chromosomes 1, 11 and 13 were used. The results obtained indicate that (a) chromosomes 1, 11 and 13 are more involved in multivalent formation than expected on the basis of DNA content and (b) if the mitotic FISH analysis data are corrected for the observed over-representation, the frequencies of induced translocations are similar to those recorded in the classical multivalent studies, suggesting equal scoring efficiencies in both systems.     

Chromosomal Rearrangements in Three Infertile Men

Summary:  Three chromosomal rearrangements: a balanced reciprocal translocation, t(14;10) (q22;q13), a Y-autosome translocation, t(Y;16) (q11;p13) and a deleted Y chromosome, Yq- were detected among 100 infertile men. The autosomal translocation, associated with oligozoospermia was found to be familial with various effects on the female carriers and the proband's father. The patients with the chromosome Y abberations were found to be azoospermic and might have lost the genes necessary for normal sperma-togenesis.
Zusammenfassung:  Unter 100 infertilen Männern wurden drei Chromosomenneuan-ordnungen entdeckt: eine balancierte reziproke Translokation, t(14;10) (q22;q13), eine Y-autosome Translokation, t(Y;16) (q11;p13) und eine Deletion des Y-Chromosoms, Yq-. Die autosomale Translokation bei Oligozoospermie zeigte sich familiär mit verschiedenen Auswirkungen bei den weiblichen Überträgern und dem Vater des Probanden. Die Patien-ten mit chromosomalen Y-Aberrational wiesen eine Azoospermie auf und scheinen die zur normalen Spermatogenese notwendigen Gene verloren zu haben.     

Tendon Graft—Ulna Fixation in Distal Radio-Ulnar Joint Stabilisation; Biomechanical Comparison of Three Graft-Bone Fixation Methods

A common distal radio-ulnar joint (DRUJ) stabilisation procedure uses a tendon graft running from the lip of the radial sigmoid notch to the ulnar fovea and through a bony tunnel to the ulnar shaft, before being wrapped round the distal ulna and sutured to itself. Such graft fixation can be challenging and requires a considerable tendon length. The graft length could be reduced by fixing the graft to the ulna using a bone anchor or interference screw. The aim of this study was to compare the strength of three distal ulna graft fixation methods (tendon wrapping and suturing, bone anchor and interference screw). Four human cadaveric ulnae were used. A tendon strip was run through a tunnel in the distal ulna and secured by: (1) wrapping round the shaft and suturing it to itself, (2) a bone anchor and (3) an interference screw in the bone tunnel. Load to failure was determined using a custom-made apparatus and an Instron machine. Maximum failure load was highest for the bone anchor fixation (99.3 ± 23.7 N) followed by the suturing (96.2 ± 12.1 N), and the interference screw fixation (46.9 ± 5.6 N). There was no significant difference between the tendon suturing and bone anchor methods, but the tendon suturing was statistically significantly higher compared to the interference screw (P = 0.028). In performing anatomical stabilisation of the DRUJ fixation of the tendon graft to the distal ulna with a bone anchor provides the most secure fixation. This may make the stabilisation technique less demanding and require a smaller tendon graft.