Pan-cancer analysis of heterogeneity of tumor mutational burden and genomic mutation under treatment pressure.

BACKGROUND: High tumor mutational burden (TMB) is one of the widely researched predictive biomarkers of immune checkpoint inhibitors and has been shown to be closely related with response to immunotherapy in multiple cancer types. However, for patients who have failed conventional therapy and are about to undergo immunotherapy, there is no consensus recommendation on the timing of tumor sampling for TMB analysis, and the effects of different therapies on TMB have not been clarified. This retrospective observational study aimed to investigate the heterogeneity of TMB and genomic mutation under the treatment pressure. PATIENTS AND METHODS: We retrospectively collected the available genomic and therapeutic information from 8051 samples across 15 tumor types (>50 samples/tumor) found in 30 published studies and investigated the distribution and heterogeneity of TMB under treatment across diverse cohorts. RESULTS: This integrated analysis has shown anticancer treatments increased TMB. Significant effects of treatment on TMB were more frequently observed in tumor types with lower treatment-naïve TMB, including breast, prostate, and pediatric cancers. For different cancer therapies, chemotherapy was prone to be correlated with an increased TMB in most cancer types. Meanwhile, the fraction of the TMB-high category of breast, prostate, and bladder cancers and glioma increased significantly after chemotherapy. Several actionable genes including ERS1 and NF1 in breast cancer, as well as some prognostic markers including TERT in bladder cancer and IDH1 in glioma, were significantly changed in post-chemotherapy tumors compared to treatment-naïve tumors. CONCLUSION: Our study reveals the heterogeneity of TMB under treatment across diverse cancer types and provides evidences that chemotherapy was associated with increases in TMB as well as the fraction of TMB-high category, suggesting that resampling tumor tissues for calculating post-chemotherapy TMB could be a better option for predicting the response to immunotherapy, especially for tumors with initially low TMB.

[The effect of unexpected follicular development in artificial cycles on the clinical outcomes in frozen thawed embryo transfer based on propensity score matching].

Objective: To study the effect of unexpected follicular development in artificial cycles on the clinical outcomes in frozen thawed embryo transfer based on propensity score matching(PSM). Methods: The retrospective cohort study analyzed the clinical data of 7 064 cycles (5 716 patients) of artificial cycle frozen-thawed embryo transfer (AC-FET) in the Reproduction Center of the Third Affiliated Hospital of Zhengzhou University from January 1, 2016 to December 31, 2020. The clinical data were divided into three groups according to the degree of follicular development in AC-FET: no follicular growth group (group A, 6 349 cycles), small follicular growth group (group B, 248 cycles), and large follicular growth group (group C, 467 cycles). Differences in clinical outcomes between the small follicle growth group (Group B) and the large follicle growth group (Group C) were compared with the no follicle growth group (Group A) after PSM and logistic regression to adjust for confounding factors at baseline. A binary logistic regression model was used to analyze the factors related to the unanticipated follicular development in AC-FET. Results: Age [M(Q1,Q3)] was [31.0 (28.0, 36.0)] years in Group A, [34.5 (30.0, 40.0)] years in Group B, and [36.0 (31.0, 41.0)] years in Group C. After adjusting for confounders, the differences between Groups A and B in clinical pregnancy rate (P=0.169), live birth rate (P=0.318), early abortion rate (P=0.470), and miscarriage rate (P=0.783) were not statistically significant. The differences in clinical pregnancy rate (P=0.743), live birth rate (P=0.486) and miscarriage rate (P=0.080) between Groups A and C were not statistically significant, while early miscarriage rate (P=0.034) differences were statistically significant. The age, BMI, basal AFC, AMH and starting dose of estrogen were correlates of the emergence of non-expected small follicles in Groups B and A. The adjusted OR (AOR) values (95%CI) were 1.03 (1.01-1.06), 0.93 (0.90-0.98), 0.97 (0.95-0.99), 0.96 (0.95-0.97), and 0.59 (0.45-0.77), all P<0.05. Age, basal AFC, AMH and starting dose of estrogen were the associated factors of the appearance of non-expected large follicles in Groups C and A. The AOR values (95%CI) were 1.03 (1.01-1.05), 0.93 (0.91-0.95), 0.96 (0.95-0.97), and 0.52 (0.42-0.64), all P<0.05. Conclusions: In AC-FET, the clinical outcome of small follicular growth is similar to that of unfollicular growth; Compared with the growth without follicles, the growth and development of large follicles can reduce the early abortion rate; Patients with older age, less AFC, lower AMH, and lower initial dose of estrogen could be more likely to have unanticipated follicular development during endometrial preparation.

[Analysis for the breast cancer screening among urban population in Hebei province, 2018-2019].

From 2018 to 2019, 3 453 cases of high-risk population were screened by the Cancer Screening Program in Urban China (CanSPUC) in Hebei Province, with the age of (53.94±8.00). 147 and 686 cases of breast cancer positive and suspicious positive patients were found, with the positive rate and suspicious positive rate of 4.26% and 19.87% respectively. The suspicious positive rate of 45-49 years old age group was the highest (28.32%), and the positive rate of over 70 years old age group was the highest (7.32%). The positive detection rate of mammography combined with ultrasound was 5.16%, which was higher than that of ultrasound alone (2.46%) (χ²=30.28,P<0.001) or mammography alone (3.06%) (χ²=14.56,P<0.001).

[The application of pediatric voice handicap index in children with voice disorders].

Objective: To access the influence of voice disorders on children's voice-related quality of life through the parental version of pediatric voice handicap index (pVHI). Methods: From April 2017 to March 2018, a total of 192 children with voice disorders (dysphonic group) and 111 children without voice disorders (control group) were enrolled in this work. Parents of children in both groups were asked for fill out the questionnaire containing the parental version of pVHI and the data of non-normal distribution were analyzed by Mann-Whitney U test. Spearman test was used for correlation analysis. Results: (1)Vocal cord nodule was the most common voice disorder in children, and boys were more susceptible to voice disorder than girls in this study (70.3%(135/192) vs 29.7%(57/192)). (2)The most common voice abuse or misuse habit was "Shouting loudly". (3)In dysphonic group, the scores of function, physiology, emotion and total were higher than those in control group (all P<0.05). (4)In dysphonic group, there was a weak correlation between the parents' overall evaluation of the children's voice status and the three dimensions of the parental version of pVHI (function: r=0.339, physiology: r=0.334, emotion: r=0.208, all P<0.001). Conclusions: Voice disorders can cause a negative impact on children's quality of life. Parental version of pVHI can be used to assess the voice-related quality of life in children with voice disorders.

[Reconsidering on the drug therapy of adult laryngopharyngeal reflux disease].

The treatment for laryngopharyngeal reflux diseases consist of general treatment, medical therapy and surgical treatment, among which, drug therapy is still the main effective way. Proton pump inhibitor is adopted as the first drug for patients with laryngopharyngeal reflux disease only caused by acid reflux. With standardized treatment, the majority of symptoms in laryngopharyngeal reflux disease could be alleviated effectively. PPI therapy, while seeming logical, is less useful in patients with reflux hypersensitivity, weak acid or non acid reflux, neuropsychic factors and gastroesophageal reflux disease. This article aims to investigate bewilderment and challenge faced by clinicians when managing adult laryngology reflux disease with medical therapy.

Long noncoding RNA LINC00313 modulates papillary thyroid cancer tumorigenesis via sponging miR-4429.

Mounting evidence indicates that long noncoding RNAs (lncRNAs) play a critical role in tumorigenesis. LncRNA LINC00313 has been found to be up-regulated and associated with poor prognosis in lung cancer. However, the potential role and clinical value of LINC00313 in human papillary thyroid cancer (PTC) remain elusive and therefore require examination. The aim of this study is to investigate the role of LINC00313 in papillary thyroid cancer (PTC). We found its expression was significantly up-regulated in PTC tissues and cell lines and that this up-regulation correlated with poor prognosis. In vitro experiments indicated that down-regulation of LINC00313 inhibited proliferation and the migratory and colony-forming abilities of PTC cells. Moreover, silencing LINC00313 induced cell cycle arrest and apoptosis in the PTC cells. In addition, mechanism studies showed that LINC00313 down-regulates miR-4429 expression, and that miR-4429 over-expression can abrogate the oncogenic role of LINC00313 in PTC cells. In summary, our data revealed that LINC00313 acts as an oncogene in PTC via sponging miR-4429, and this suggests that LINC00313 may be successfully applied as a therapeutic target in PTC.

Linc-ROR promotes endometrial cell proliferation by activating the PI3K-Akt pathway.

OBJECTIVE: To observe the expressions of Linc-ROR and proteins in the PI3K-Akt pathway in an ectopic lesion of adenomyosis. PATIENTS AND METHODS: The expression of Linc-ROR in the ectopic endometrium, eutopic endometrium, and normal endometrium of adenomyosis was detected by qRT-PCR. Western blot was used to detect the protein expressions of PI3K-Akt in endometriosis and lesion endometriosis. Cell counting kit-8 (CCK-8) assay was utilized to detect cell proliferative activity. After interfering or overexpressing Linc-ROR, protein expressions of the PI3K-Akt pathway were detected by Western blot. RESULTS: Linc-ROR expression in the ectopic endometrium of adenomyosis was higher than that in the eutopic endometrium and normal endometrium, and the expression level of PTEN in adenomyosis tissues was decreased, whilst expression levels of Akt, p-Akt, p-PTEN were increased. Clinical data of enrolled patients indicated that there was a relationship between Linc-ROR expression and the type and severity of dysmenorrhea of adenomyosis. However, no relationship was observed between Linc-ROR expression and age, cesarean section, uterine surgery, and menstrual cycle. Cell counting kit-8 (CCK-8) assay showed that the proliferative activity of cells was significantly decreased after knockdown of Linc-ROR in the adenomyosis cells. Western blot revealed that the expression level of PTEN increased but the expression levels of p-Akt, p-PTEN and p-PDK1 decreased. Overexpression of Linc-ROR obtained the opposite results. CONCLUSIONS: Linc-ROR is highly expressed in the ectopic endometrium of adenomyosis, and it can promote the proliferative activity of endometrial cells by activating the PI3K-Akt pathway.

The role of routine screening in blood-borne pathogens in Chinese patients undergoing joint arthroplasty.

OBJECTIVES: Surgeons face a substantial risk of infection because of the occupational exposure to blood-borne pathogens (BBPs) from patients undergoing high-risk orthopaedic procedures. This study aimed to determine the seroprevalence of four BBPs among patients undergoing joint arthroplasty in Shanghai, China. In addition, we evaluated the significance of pre-operative screening by calculating a cost-to-benefit ratio. METHODS: A retrospective observational study of pre-operative screening for BBPs, including hepatitis B and C viruses (HBV and HCV), human immunodeficiency virus (HIV) and Treponema pallidum (TP), was conducted for sequential patients in the orthopaedic department of a large urban teaching hospital between 01 January 2009 and 30 May 2016. Medical records were analysed to verify the seroprevalence of these BBPs among the patients stratified by age, gender, local origin, type of surgery, history of previous transfusion and marital status. RESULTS: Of the subjects who underwent arthroplasty surgery in our institution, pre-operative screening tests were available for 96.1% (11 609 patients). The seroprevalence of HBV, HCV, HIV and TP was 5.47%, 0.45%, 0.08% and 3.6%, respectively. A total of 761 seropositive cases (68.4%) were previously undiagnosed. Pre-operative screening for HIV resulted in a low cost to benefit ratio, followed by HCV and HBV. CONCLUSION: Routine HCV and HIV screening prior to joint arthroplasty is not a cost-effective strategy. Considering the high rate of undiagnosed patients and the shortage of protective options, targeted pre-operative screening for HBV and syphilis should be considered for the protection of healthcare workers in China who have not been vaccinated.Cite this article: Bone Joint Res 2017;6:566-571.

[Effect of TSC2 gene expression downregulation by lentivirus induced RNA interference on U937 cell line and its mechanism].

Objective: To investigate the effect of biology and mTOR pathway activity of down-regulated TSC2 gene expression on U937 leukemia cells. Methods: Gene expression was down-regulated by lentivirus induced RNA interference on TSC2 high expressed U937 cell line; the proliferation, apoptosis and differentiation were detected by CCK-8 assay, colony formation assay and flow cytometry; the gene expression level and protein kinase activity were detected by qRT-PCR and Western blot. Results: Down-regulated expression of TSC2 gene promoted U937 cell proliferation and colony formation ability (P<0.05) . The proportion in G(0)/G(1) phase of TSC2 down-regulated U937 cell was much lower than that of the control cells [ (52.53±3.75) % vs (75.10±4.33) %, t=6.829, P=0.002], the S phase [ (22.43±1.00) % vs (15.47±1.20) %, t=-5.581, P=0.019] and G(2)/M phase [ (25.03±4.34) % vs (14.33±0.91) %, t=-5.413, P=0.013] was remarkably higher than that of the control cells (P<0.05) . There were no statistically significant differences in cell apoptosis and differentiation (P>0.05) . Down-regulation of TSC2 led to the increased activity of mTOR, 4EBP1 and S6K1, but did not influence the activity of AKT. The expressions of proliferation related cyclinD1, c-myc and PTEN were also up-regulated after TSC2 silenced, but the expressions of P27KIP and BCL-XL were not changed. Conclusion: Downregulation of TSC2 could promote the proliferation of U937 cells through up-regulation of mTOR activity.

Morphology, Molecular Characteristics, and Demonstration of a Definitive Host for Sarcocystis rommeli from Cattle (Bos taurus) in China.

Sarcocysts of Sarcocystis rommeli were found for the first time in 6 of 34 (17.6%) cattle (Bos taurus) in China. With light microscopy, sarcocysts of S. rommeli were up to 1,130 µm long, with a striated, 4-8-µm-thick cyst wall. Using transmission electron microscopy, the villar protrusions (vp) were 4.7-5.2 × 0.2-0.3 µm, and 0.3-0.5 µm apart from each other. The vp contained microtubules extending from the top of the vp to the middle of the ground substance layer (gsl). A BLAST search of the near full-length 18S rRNA and partial mitochondrial cox1 sequences of S. rommeli revealed 98.7% identity and 99.2% identity with sequences of Sarcocystis bovini in GenBank, respectively. Two domestic cats (Felis catus) fed sarcocysts of S. rommeli shed oocysts/sporocysts in their feces with a prepatent period of 14 to 15 days; the partial mitochondrial cox1 sequences of these oocysts/sporocysts shared the high identities, that is, 99.4% and 99.5%, with cox1 sequences of S. rommeli sarcocysts and S. bovini sarcocysts, respectively. This is the first demonstration of a definitive host for S. rommeli.

Prognostic value of miR-141 downregulation in gastric cancer.

Previous research has shown that microRNA-141 (miR-141) expression levels are associated with survival in several types of cancer. In the present study, we investigated the clinical significance and prognostic value of miR-141 in gastric cancer. Paired tissue specimens (tumor and adjacent normal mucosa) from 95 patients with gastric cancer were obtained at the Department of General Surgery, Xiangya Hospital, Central South University from March 2009 to February 2014. The levels of miR-141 in cancerous and corresponding non-cancerous tissues were detected by quantitative reverse transcription-polymerase chain reaction. Associations between clinicopathological parameters and miR-141 expression were evaluated using chi-square tests. Overall survival was calculated and survival curves were plotted using the Kaplan-Meier method; differences between groups were compared using log-rank tests. Compared to the matched normal gastric mucosa, gastric cancer tissues had significantly lower miR-141 expression levels (P < 0.001). This decreased miR-141 expression was significantly associated with tumor differentiation (P = 0.044), positive lymph node metastasis (P = 0.010), distant metastasis (P < 0.001), and advanced tumor-node-metastasis (TNM) stage (P < 0.001). Furthermore, a significant relationship was found between miR-141 expression and overall survival (P = 0.012, log-rank test). Cox regression analysis revealed that lymph node metastasis (P = 0.003), distant metastasis (P = 0.001), TNM stage (P < 0.001), and miR- 141 expression (P = 0.007) were independent prognostic factors in patients with gastric cancer. Our data provide evidence that the downregulation of miR-141 may contribute to the aggressive progression and poor prognosis of human gastric cancer.

Dysregulated choline metabolism in T-cell lymphoma: role of choline kinase-α and therapeutic targeting.

Cancer cells have distinct metabolomic profile. Metabolic enzymes regulate key oncogenic signaling pathways and have an essential role on tumor progression. Here, serum metabolomic analysis was performed in 45 patients with T-cell lymphoma (TCL) and 50 healthy volunteers. The results showed that dysregulation of choline metabolism occurred in TCL and was related to tumor cell overexpression of choline kinase-α (Chokα). In T-lymphoma cells, pharmacological and molecular silencing of Chokα significantly decreased Ras-GTP activity, AKT and ERK phosphorylation and MYC oncoprotein expression, leading to restoration of choline metabolites and induction of tumor cell apoptosis/necropotosis. In a T-lymphoma xenograft murine model, Chokα inhibitor CK37 remarkably retarded tumor growth, suppressed Ras-AKT/ERK signaling, increased lysophosphatidylcholine levels and induced in situ cell apoptosis/necropotosis. Collectively, as a regulatory gene of aberrant choline metabolism, Chokα possessed oncogenic activity and could be a potential therapeutic target in TCL, as well as other hematological malignancies with interrupted Ras signaling pathways.

A case-control study indicates that the TRIB1 gene is associated with pancreatic cancer.

Pancreatic cancer is a malignant neoplasm originating from transformed cells arising in tissues that form the pancreas. To investigate whether the tribbles homolog 1 (Drosophila) gene (TRIB1) is associated with pancreatic cancer in the Chinese Han population, we conducted this case-control study and genotyped 3 single nucleotide polymorphisms (rs2980879, rs2980874, and rs2235108) of the TRIB1 gene in 182 patients and 359 normal controls of Chinese Han origin and analyzed their association. The results showed that the rs2980879 polymorphism was associated with pancreatic cancer [allele: P = 0.023434, genotype: P = 0.03005; odds ratio (OR) and 95% confidence interval (CI) = 0.727788 (0.552664-0.958404)], whereas the rs2980874 polymorphism had no association with pancreatic cancer [allele: P = 0.749885, genotype: P = 0.699533; OR and 95%CI = 1.041981 (0.809196-1.341734)], and the rs2235108 polymorphism was not associated with the disease [allele: P = 0.629475, genotype: P = 0.547534, OR and 95%CI = 1.128290 (0.690829-1.842770)]. Haplotype analyses and linkage disequilibrium tests were also conducted, and the results showed that these 3 loci are not in the same block. In conclusion, our study indicated that the TRIB1 gene is associated with pancreatic cancer. More studies with larger samples are needed in order to support this finding.

Polymorphisms of the vitamin D receptor gene and the risk of inflammatory bowel disease: a meta-analysis.

The gene encoding vitamin D receptor (VDR) is recognized as a promising candidate for indicating the development of inflammatory bowel disease (IBD). Four genetic polymorphisms (ApaI, BsmI, FokI, TaqI) in VDR have been widely evaluated to determine their association with IBD, and the results of these evaluations are often inconsistent. Therefore, we conducted a meta-analysis to shed some light on this issue and explored the sources of the heterogeneity between studies. We identified six articles for ApaI (cases/controls: 1902/1468), eight for TaqI (3053/2145), and five each for BsmI (1512/1616) and FokI (2315/1676). Data were analyzed under the random-effects model, and heterogeneity was explored by subgroup analyses. Overall, except for TaqI in allelic comparison [odds ratio (OR) = 0.90, 95% confidence interval (CI): 0.83-0.98], ApaI, BsmI, and FokI polymorphisms showed no significant associations with IBD across different genetic models of inheritance. However, subgroup analyses indicated significance for the association of ApaI with Crohn's disease (CD) risk (AA versus aa: OR = 1.40; 95%CI = 1.05-1.88), for BsmI in East Asians (BB plus Bb versus bb: OR = 1.77, 95%CI = 1.14-2.74), for TaqI in Caucasians (TT plus Tt versus tt: OR = 0.79, 95%CI = 0.63- 1.00), and with ulcerative colitis (UC) risk (T versus t: OR = 0.89, 95%CI = 0.80-0.99). There was a low probability of publication bias for all studied polymorphisms. Pooling previous individual studies on IBD, our findings demonstrated that the ApaI polymorphism may increase the risk of CD, whereas the TaqI polymorphism may decrease the risk of UC, especially in Caucasians. Moreover, this study leaves open the question of divergent genetic profiles across different ethnic groups.

Meta-analysis demonstrates lack of an association of microsomal epoxide hydrolase 1 polymorphisms with esophageal cancer risk.

Epoxide hydrolases metabolize exogenous chemicals, including carcinogens such as polycyclic aromatic hydrocarbons. The relationship between microsomal epoxide hydrolase 1 (EPHX1) polymorphisms and esophageal cancer risk has been investigated in various ethnic populations, but the results have been contradictory. We investigated the association of EPHX1 Tyr113His and His139Arg polymorphisms with esophageal cancer via a comprehensive meta-analysis. Publications before August 20, 2012 were included. Eight studies concerning Tyr113His polymorphism associated with 1158 esophageal cancer cases and 1868 controls were identified; 7 studies concerning association of His139Arg with 901 esophageal cancer cases and 1615 controls were also included. A random-effect model was applied, irrespective of between-study heterogeneity. Data and study quality were assessed in duplicate. No significant association was found in either the allele or genotype models for Tyr113His or His139Arg polymorphism with risk for esophageal cancer. Lack of association was also identified in stratified analyses by ethnicity. No publication bias was observed. We conclude that current evidence does not demonstrate association of EPHX1 Tyr113His or His139Arg polymorphisms with risk for development of esophageal cancer.

Lack of association between the interleukin 6 gene -174G>C polymorphism and colorectal cancer: evidence from a meta-analysis.

Interleukin 6 (IL6) is a pleiotropic cytokine involved in physiological processes and in a variety of human malignancies. It is thus a logical candidate for being a causative factor underlying colorectal cancer (CRC). The association between the IL6 -174G>C polymorphism and CRC has been widely evaluated; yet, there is a lack of agreement between studies on the role of this polymorphism in CRC. We performed a meta-analysis to evaluate this association signal. Articles published before May 10, 2012 were included in the meta-analysis. A total of 11 populations incorporating 6481 cases and 7935 controls were included in our analysis. A random-effect model was applied irrespective of between-study heterogeneity. Data and study quality were assessed in duplicate. Overall, the association of the -174G>C polymorphism with CRC was not significant in an allelic comparison model [odds ratio (OR) = 0.99; 95% confidence interval (95%CI) = 0.90-1.09; P = 0.827], a homozygote model (OR = 0.98; 95%CI = 0.83-1.15; P = 0.805), a dominant model (OR = 0.99; 95%CI = 0.87-1.13; P = 0.906), or a recessive model (OR = 0.97; 95%CI = 0.88-1.08; P = 0.610). Furthermore, the analyses of subgroups created based on common study design, genotyping methods, and ethnicity failed to find a significant association of this polymorphism with CRC. Therefore, our results collectively suggest that the IL6 -174G>C polymorphism might not be a potential candidate for CRC risk.

Differential progressive remodeling of coronary and cerebral arteries and arterioles in an aortic coarctation model of hypertension.

OBJECTIVES: Effects of hypertension on arteries and arterioles often manifest first as a thickened wall, with associated changes in passive material properties (e.g., stiffness) or function (e.g., cellular phenotype, synthesis and removal rates, and vasomotor responsiveness). Less is known, however, regarding the relative evolution of such changes in vessels from different vascular beds. METHODS: We used an aortic coarctation model of hypertension in the mini-pig to elucidate spatiotemporal changes in geometry and wall composition (including layer-specific thicknesses as well as presence of collagen, elastin, smooth muscle, endothelial, macrophage, and hematopoietic cells) in three different arterial beds, specifically aortic, cerebral, and coronary, and vasodilator function in two different arteriolar beds, the cerebral and coronary. RESULTS: Marked geometric and structural changes occurred in the thoracic aorta and left anterior descending coronary artery within 2 weeks of the establishment of hypertension and continued to increase over the 8-week study period. In contrast, no significant changes were observed in the middle cerebral arteries from the same animals. Consistent with these differential findings at the arterial level, we also found a diminished nitric oxide-mediated dilation to adenosine at 8 weeks of hypertension in coronary arterioles, but not cerebral arterioles. CONCLUSION: These findings, coupled with the observation that temporal changes in wall constituents and the presence of macrophages differed significantly between the thoracic aorta and coronary arteries, confirm a strong differential progressive remodeling within different vascular beds. Taken together, these results suggest a spatiotemporal progression of vascular remodeling, beginning first in large elastic arteries and delayed in distal vessels.