Molecular and immune characterization of Chinese early-stage non-squamous non-small cell lung cancer: a multi-omics cohort study.

Background: Albeit considered with superior survival, around 30% of the early-stage non-squamous non-small cell lung cancer (Ns-NSCLC) patients relapse within 5 years, suggesting unique biology. However, the biological characteristics of early-stage Ns-NSCLC, especially in the Chinese population, are still unclear. Methods: Multi-omics interrogation of early-stage Ns-NSCLC (stage I-III), paired blood samples and normal lung tissues (n=76) by whole-exome sequencing (WES), RNA sequencing, and T-cell receptor (TCR) sequencing were conducted. Results: An average of 128 exonic mutations were identified, and the most frequently mutant gene was EGFR (55%), followed by TP53 (37%) and TTN (26%). Mutations in MUC17, ABCA2, PDE4DIP, and MYO18B predicted significantly unfavorable disease-free survival (DFS). Moreover, cytobands amplifications in 8q24.3, 14q13.1, 14q11.2, and deletion in 3p21.1 were highlighted in recurrent cases. Higher incidence of human leukocyte antigen loss of heterozygosity (HLA-LOH), higher tumor mutational burden (TMB) and tumor neoantigen burden (TNB) were identified in ever-smokers than never-smokers. HLA-LOH also correlated with higher TMB, TNB, intratumoral heterogeneity (ITH), and whole chromosomal instability (wCIN) scores. Interestingly, higher ITH was an independent predictor of better DFS in early-stage Ns-NSCLC. Up-regulation of immune-related genes, including CRABP2, ULBP2, IL31RA, and IL1A, independently portended a dismal prognosis. Enhanced TCR diversity of peripheral blood mononuclear cells (PBMCs) predicted better prognosis, indicative of a noninvasive method for relapse surveillance. Eventually, seven machine-learning (ML) algorithms were employed to evaluate the predictive accuracy of clinical, genomic, transcriptomic, and TCR repertoire data on DFS, showing that clinical and RNA features combination in the random forest (RF) algorithm, with area under the curve (AUC) of 97.5% and 83.3% in the training and testing cohort, respectively, significantly outperformed other methods. Conclusions: This study comprehensively profiled the genomic, transcriptomic, and TCR repertoire spectrums of Chinese early-stage Ns-NSCLC, shedding light on biological underpinnings and candidate biomarkers for prognosis development.

Pyxinol Fatty Acid Ester Derivatives J16 against AKI by Selectively Promoting M1 Transition to M2c Macrophages.

Acute kidney injury (AKI) is a common, multicause clinical condition that, if ignored, often progresses to chronic kidney disease (CKD) and end-stage kidney disease, with a mortality rate of 40-50%. However, there is a lack of universal treatment for AKI. Inflammation is the basic pathological change of early kidney injury, and inflammation can exacerbate AKI. Macrophages are the primary immune cells involved in the inflammatory microenvironment of kidney disease. Therefore, regulating the function of macrophages is a crucial breakthrough for the AKI intervention. Our team chemically modified pyxinol, an ocotillol-type ginsenoside, to prepare PJ16 with higher solubility and bioavailability. In vitro, using a model of macrophages stimulated by LPS, it was found that PJ16 could regulate macrophage function, including inhibiting the secretion of inflammatory factors, promoting phagocytosis, inhibiting M1 macrophages, and promoting M1 transition to the M2c macrophage. Further investigation revealed that PJ16 may shield renal tubular epithelial cells (HK-2) damaged by LPS in vitro. Based on this, PJ16 was validated in the animal model of unilateral ureteral obstruction, which showed that it improves renal function and inhibits renal tissue fibrosis by decreasing inflammatory responses, reducing macrophage inflammatory infiltration, and preferentially upregulating M2c macrophages. In conclusion, our study is the first to show that PJ16 resists AKI and fibrosis by mechanistically regulating macrophage function by modulating the phenotypic transition from M1 to M2 macrophages, mainly M2c macrophages.

Assessing colposcopy competencies in medically underserved communities: a multi-center study in China.

BACKGROUND: Colposcopy plays an essential role in diagnosing cervical lesions and directing biopsy; however, there are few studies of the capabilities of colposcopists in medically underserved communities in China. This study aims to fill this gap by assessing colposcopists' competencies in medically underserved communities of China. METHODS: Colposcopists in medically underserved communities across China were considered eligible to participate. Assessments involved presenting participants with 20 cases, each consisting of several images and various indications. Participants were asked to determine transformation zone (TZ) type, colposcopic diagnoses and to decide whether biopsy was necessary. Participants are categorized according to the number of colposcopic examinations, i.e., above or below 50 per annum. RESULTS: There were 214 participants in this study. TZ determination accuracy was 0.47 (95% CI 0.45,0.49). Accuracy for colposcopic diagnosis was 0.53 (95% CI 0.51,0.55). Decision to perform biopsies was 0.73 accurate (95% CI 0.71,0.74). Participants had 0.61 (95% CI 0.59,0.64) sensitivity and a 0.80 (95% CI 0.79,0.82) specificity for detecting high-grade lesions. Colposcopists who performed more than 50 cases were more accurate than those performed fewer across all indicators, with a higher sensitivity (0.66 vs. 0.57, p = 0.001) for detecting high-grade lesions. CONCLUSIONS: In medically underserved communities of China, colposcopists appear to perform poorly at TZ identification, colposcopic diagnosis, and when deciding to biopsy. Colposcopists who undertake more than 50 colposcopies each year performed better than those who perform fewer. Therefore, colposcopic practice does improve through case exposure although there is an urgent need for further pre-professional and clinical training.

Total Neoadjuvant Therapy With PD-1 Blockade for High-Risk Proficient Mismatch Repair Rectal Cancer.

Importance: Total neoadjuvant therapy (TNT) is the standard treatment for locally advanced rectal cancer, especially for patients with high-risk factors. However, the efficacy of TNT combined with immunotherapy for patients with proficient mismatch repair (pMMR) rectal cancer is unknown. Objectives: To evaluate the safety and efficacy of TNT with induction chemoimmunotherapy followed by long-course chemoradiation in patients with high-risk, pMMR rectal cancer and to identify potential molecular biomarkers associated with treatment efficacy. Design, Setting, and Participants: This cohort study was a single-arm phase 2 trial conducted at Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, from June 2020 to October 2021. Biopsies and plasma were collected before treatment for whole-exome sequencing and cell-free DNA sequencing, respectively. Data were analyzed from May 2022 to September 2022. Interventions: Participants received 3 cycles of induction oxaliplatin and capecitabine combined with camrelizumab and radiotherapy (50.6 Gy in 22 fractions) with concurrent capecitabine. Patients without disease progression received 2 cycles of consolidation oxaliplatin/capecitabine. Main Outcomes and Measures: The primary end point was pathologic complete response rate. Results: Of 25 patients enrolled (19 men [76%]; 6 women [24%]; median [IQR] age, 58 [48-64] years), 22 patients (88%) completed the TNT schedule. The pathologic complete response rate was 33.3% (7/21). Twelve patients (48%) achieved clinical complete response, and 4 patients (16%) chose to watch and wait. R0 resection was achieved in 21 of 21 patients, and the major pathologic response rate was 38.1% (8/21). The most common adverse event was nausea (80%, 20/25); grade 3 toxic effects occurred in 9 of 25 patients (36%). Patients with tumor shrinkage of 50% or greater after induction oxaliplatin/capecitabine and camrelizumab or clinical complete response had higher percentages of LRP1B mutation. Mutation of LRP1B was associated with high tumor mutation burden and tumor neoantigen burden. Patients with high tumor mutation burden all benefited from therapy. Conclusions and Relevance: This study found that TNT with induction chemoimmunotherapy followed by long-course chemoradiation was safe and effective for patients with high-risk rectal cancer with pMMR status. Longer follow-up and larger clinical studies are needed to validate this innovative regimen. There is also an urgent need to further validate the predictive value of LRP1B and discover other novel biomarkers with potential predictive value for rectal cancer.

Genotype, cervical intraepithelial neoplasia, and type-specific cervical intraepithelial neoplasia distributions in hrHPV+ cases referred to colposcopy: A multicenter study of Chinese mainland women.

To investigate age and type-specific prevalences of high-risk human papillomavirus (hrHPV) and cervical intraepithelial neoplasia (CIN) in hrHPV+ women referred to colposcopy. This is a retrospective, multicenter study. Participants were women referred to one of seven colposcopy clinics in China after testing positive for hrHPV. Patient characteristics, hrHPV genotyping, colposcopic impressions, and histological diagnoses were abstracted from electronic records. Main outcomes were age-related type-specific prevalences associated with hrHPV and CIN, and colposcopic accuracy. Among 4419 hrHPV+ women referred to colposcopy, HPV 16, 52, and 58 were the most common genotypes. HPV 16 prevalence was 39.96%, decreasing from 42.57% in the youngest group to 30.81% in the eldest group. CIN3+ prevalence was 15.00% and increased with age. As lesion severity increases, HPV16 prevalence increased while the prevalence of HPV 52 and 58 decreased. No age-based trend was identified with HPV16 prevalence among CIN2+, and HPV16-related CIN2+ was less common in women aged 60 and above (44.26%) compared to those younger than 60 years (59.61%). Colposcopy was 0.73 sensitive at detecting CIN2+ (95% confidence interval[CI]: 0.71, 0.75), with higher sensitivity (0.77) observed in HPV16+ women (95% CI: 0.74, 0.80) compared to HPV16- women (0.68, 95% CI: 0.64, 0.71). Distributions of hrHPV genotypes, CIN, and type-specific CIN in Chinese mainland hrHPV+ women referred to colposcopy were investigated for the first time. Distributions were found to be age-dependent and colposcopic performance appears related to HPV genotypes. These findings could be used to improve the management of women referred to colposcopy.

Silencing PKM2 Attenuates Brain Injury Induced by Status Epilepticus by Inhibiting the AKT/mTOR Pathway and the NLRP3 Inflammasome.

PKM2 is a glycolytic pyruvate kinase isoenzyme, and its role in neurological diseases has been published. However, the role and mechanism of PKM2 in the process of status epilepticus have not been reported. The purpose of this study is to explore the role and mechanism of PKM2 in epilepsy. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were used to explore the expression of PKM2 in cells. Enzyme-linked immunosorbent assay kits were used to evaluate the level of inflammatory factors. An epilepsy model was established by intraperitoneal injection of lithium chloride in rats. Various behavioural assays were conducted to explore the learning ability and cognitive level of rats. PKM2 expression was upregulated in Mg2+-induced hippocampal neurons. PKM2 inhibition ameliorated Mg2+-induced hippocampal neuronal inflammation and reduced neuronal apoptosis. In addition, PKM2 silencing inhibited the metabolic dysfunction of Mg2+-induced hippocampal neurons. Subsequent experiments showed that the Akt/mTOR pathway and NLRP3 inflammasome are involved in PKM2-mediated neuronal regulation. More importantly, PKM2 inhibition could alleviate status epilepticus in rats. PKM2 inhibition attenuates Mg2+-induced hippocampal neuronal inflammation, apoptosis and metabolic dysfunction and improves the cognitive ability of rats. Therefore, PKM2 may be an important target for epilepsy treatment.

Enhancing colposcopy training using a widely accessible digital education tool in China.

BACKGROUND: Colposcopy is a cornerstone of cervical cancer prevention; however, there is a global shortage of colposcopists. It is challenging to train a sufficient number of colposcopists through in-person methods, which hinders our ability to adequately diagnose and manage positive cases. A digital platform is needed to make colposcopy training more efficient, scalable, and sustainable; however, current online training programs are generally based on didactic curricula that do not incorporate image analysis training. In addition, long-term assessments of online training are not readily available. Therefore, innovative digital training and an assessment of its effectiveness are needed. OBJECTIVE: This study aimed to evaluate the short- and long-term effects of DECO (an online Digital Education Tool for Colposcopy) on trainees' colposcopy competencies and confidence. STUDY DESIGN: DECO can be used both on laptops and smartphones and comprises 4 training modules (image interpretation; terminology learning; video teaching; and collection of guidelines and typical cases) and 2 test modules. DECO was tested through a pre-post study between September and November 2022. Participants were recruited in China, and DECO training lasted 12 days. Trainees initially learned basic theory before completing training using 200 image-based cases. Pretest, posttest, and follow-up testing included 20 distinct image-based questions, and was conducted on Days 0, 13, and 60. Primary outcomes were competence and confidence scores. Secondary measures were response distributions for colposcopic diagnoses, biopsies, and DECO training satisfaction. Multilevel modeling was used to determine improvement from baseline to posttraining and follow-up for the outcomes of interest. RESULTS: Among 402 participants recruited, 96.8% (n=389) completed pretesting, 84.1% (n=338) posttesting, and 75.1% (n=302) follow-up testing. Colposcopic competence and confidence increased across this study. Diagnostic scores improved on average from 55.3 (53.7-56.9) to 70.4 (68.9-71.9). The diagnostic accuracy for normal/benign lesions, low-grade squamous intraepithelial lesions, and high-grade squamous intraepithelial lesions or worse increased by 16.9%, 13.1%, and 16.9%, respectively. Mean confidence scores increased from 48.1 (45.6-50.6) to 56.2 (54.5-57.9). These improvements remained evident 2 months after training. Trainees were also satisfied with DECO overall. Most found DECO to be scientific (82.5%), easy to use (75.2%), and clinically useful (98.4%), and would recommend it to colleagues (93.2%). CONCLUSION: DECO is a useful, acceptable digital education tool that improves colposcopy competencies and confidence. DECO could make colposcopy training more efficient, scalable, and sustainable because there are no geographic or time limitations. Therefore, DECO could be used to alleviate the shortage of trained colposcopists around the world.

Tislelizumab for squamous lung cancer combined with basal cell carcinoma of the skin: A case report.

INTRODUCTION: Surgery is the preferred treatment for basal cell carcinoma (BCC), locally advanced or metastatic BCC, radiation therapy or systemic therapy can be considered. Programmed death receptor 1 (PD-1) inhibitors are rarely used to treat cutaneous BCC. In the present case, we found that tislelizumab, a PD-1 immunosuppressant, had a positive effect on BCC. PATIENT CONCERNS: A 74-year-old male patient presented with a mass in the left back in October 2021, which was surgically removed and diagnosed as BCC. The patient was diagnosed with squamous lung cancer after presenting with a cough and coughing up a small amount of white, sticky sputum in December 2021. DIAGNOSIS: BCC and squamous lung cancer. INTERVENTIONS: Docetaxel + nedaplatin systemic chemotherapy combined with tislelizumab immunotherapy. OUTCOMES: Both BCC and squamous lung cancer were significantly reduced in size. CONCLUSION: After 2 cycles of immunotherapy with tislelizumab, the lung tumor shrank, the back mass disappeared, and the wound healed.

Establishing a Proteomics-Based Signature of AKR1C3-Related Genes for Predicting the Prognosis of Prostate Cancer.

Aldo-keto reductase family 1 member C3 (AKR1C3) plays an important role in prostate cancer (PCa) progression, particularly in castration-resistant prostate cancer (CRPC). It is necessary to establish a genetic signature associated with AKR1C3 that can be used to predict the prognosis of PCa patients and provide important information for clinical treatment decisions. AKR1C3-related genes were identified via label-free quantitative proteomics of the AKR1C3-overexpressing LNCaP cell line. A risk model was constructed through the analysis of clinical data, PPI, and Cox-selected risk genes. Cox regression analysis, Kaplan-Meier (K-M) curves, and receiver operating characteristic (ROC) curves were used to verify the accuracy of the model, and two external datasets were used to verify the reliability of the results. Subsequently, the tumor microenvironment and drug sensitivity were explored. Moreover, the roles of AKR1C3 in the progression of PCa were verified in LNCaP cells. MTT, colony formation, and EdU assays were conducted to explore cell proliferation and drug sensitivity to enzalutamide. Migration and invasion abilities were measured using wound-healing and transwell assays, and qPCR was used to assess the expression levels of AR target genes and EMT genes. CDC20, SRSF3, UQCRH, INCENP, TIMM10, TIMM13, POLR2L, and NDUFAB1 were identified as AKR1C3-associated risk genes. These risk genes, established using the prognostic model, can effectively predict the recurrence status, immune microenvironment, and drug sensitivity of PCa. Tumor-infiltrating lymphocytes and several immune checkpoints that promote cancer progression were higher in high-risk groups. Furthermore, there was a close correlation between the sensitivity of PCa patients to bicalutamide and docetaxel and the expression levels of the eight risk genes. Moreover, through in vitro experiments, Western blotting confirmed that AKR1C3 enhanced SRSF3, CDC20, and INCENP expression. We found that PCa cells with a high expression of AKR1C3 have high proliferation ability and high migration ability and were insensitive to enzalutamide. AKR1C3-associated genes had a significant role in the process of PCa, immune responses, and drug sensitivity and offer the potential for a novel model for prognostic prediction in PCa.

Multi-omics analysis uncovers tumor ecosystem dynamics during neoadjuvant toripalimab plus nab-paclitaxel and S-1 for esophageal squamous cell carcinoma: a single-center, open-label, single-arm phase 2 trial.

BACKGROUND: Immune checkpoint inhibitors combined with chemotherapy as a neoadjuvant therapy have been applied to the treatment of esophageal squamous cell carcinoma (ESCC). However, the optimal regimen needs to be further explored, particularly for older patients, and the mechanisms by which the immune checkpoint inhibitor combined with chemotherapy modulates the evolution of ESCC are unknown. METHODS: In this single-arm phase 2 trial, patients with resectable (stage II/III/IV without metastasis) ESCC were enrolled and received nanoparticle albumin-bound (nab) paclitaxel for two cycles and oral S-1 for 2 weeks, combined with intravenous toripalimab for two cycles before surgery. Combination postoperative adjuvant therapy was administered. The primary outcome was the major pathological response (MPR). Secondary outcomes included pathological complete response (pCR), overall response rate (ORR), disease control rate (DCR), disease-free survival (DFS), overall survival (OS), improvement in Stooler's dysphagia score and degree of daily living ability (dADL). Biopsies and plasma pre- and post-neoadjuvant therapy were performed using whole-exome sequencing, transcriptome sequencing, immunohistochemistry (IHC) for PD-L1, multiplex immunofluorescence (mIF) and proximity extension assay technology (PEA) for 92 proteins. FINDINGS: From November 2019 to July 2021, 60 patients were enrolled. After neoadjuvant therapy, R0 resection was achieved in 55 (98.21%) patients. MPR was identified in 27 patients (49.09%), and 16 patients (29.09%) achieved pCR. Patients with PR, SD and PD were 37 (61.67%), 21 (35.00%) and 2 (3.33%), respectively. The overall staging, Stooler dysphagia scores and dADL were significantly decreased after treatment. 11 patients (18.3%) experienced grade ≥3 AEs. Compared to PD-L1-Low patients, PD-L1-High patients had a significantly higher ratio of PR. During therapy, the tumor mutation burden (TMB) and tumor neoantigen burden (TNB) were significantly decreased in patients with PR. Differential clonal evolution within tumors was demonstrated by analysis of intratumoral heterogeneity. Transcriptome analyses revealed that the infiltration of CD4+ T lymphocytes at baseline was associated with clinical outcome. During therapy, CD8+ T cells and CD4+ T cells were increased in all patients; however, exhausted cells, nTregs and iTregs were significantly increased in patients with non-MPR. Protein analyses revealed that the levels of IFN-γ, Gal.1 and LAMP3 can predict the clinical benefit. In addition, the expression of CD83, TNFRSF4, TNFSF14, VEGFR2, ADA, ARG1, and HO-1 was associated with serious AEs. More importantly, the integration of CD4+ T cells with plasma protein of IFN-γ, Gal.1 or LAMP3 could further distinguish responders from non-responders. INTERPRETATION: In this study, neoadjuvant therapy with toripalimab, nab-paclitaxel and S-1 was less toxic and showed promising antitumor activity in patients with resectable ESCC. Changes in the genome, transcriptome, PD-L1 expression and serum proteins were comprehensively analyzed and correlated with clinical outcomes, which provides insight into the mechanism of action of toripalimab combined with nab-paclitaxel and S-1 in patients with ESCC. FUNDING: This study was funded by Major projects of the ministry of science and technology of the 13th five-year plan of China [grant number: 2018ZX09201013].

Spatial multi-omics revealed the impact of tumor ecosystem heterogeneity on immunotherapy efficacy in patients with advanced non-small cell lung cancer treated with bispecific antibody.

BACKGROUND: Immunotherapy for malignant tumors has made great progress, but many patients do not benefit from it. The complex intratumoral heterogeneity (ITH) hindered the in-depth exploration of immunotherapy. Conventional bulk sequencing has masked intratumor complexity, preventing a more detailed discovery of the impact of ITH on treatment efficacy. Hence, we initiated this study to explore ITH at the multi-omics spatial level and to seek prognostic biomarkers of immunotherapy efficacy considering the presence of ITH. METHODS: Using the segmentation strategy of digital spatial profiling (DSP), we obtained differential information on tumor and stromal regions at the proteomic and transcriptomic levels. Based on the consideration of ITH, signatures constructed by candidate proteins in different regions were used to predict the efficacy of immunotherapy. RESULTS: Eighteen patients treated with a bispecific antibody (bsAb)-KN046 were enrolled in this study. The tumor and stromal areas of the same samples exhibited distinct features. Signatures consisting of 11 and 18 differentially expressed DSP markers from the tumor and stromal areas, respectively, were associated with treatment response. Furthermore, the spatially resolved signature identified from the stromal areas showed greater predictive power for bsAb immunotherapy response (area under the curve=0.838). Subsequently, our stromal signature was validated in an independent cohort of patients with non-small cell lung cancer undergoing immunotherapy. CONCLUSION: We deciphered ITH at the spatial level and demonstrated for the first time that genetic information in the stromal region can better predict the efficacy of bsAb treatment. TRIAL REGISTRATION NUMBER: NCT03838848.

Integrated tumor genomic and immune microenvironment analysis identifies predictive biomarkers associated with the efficacy of neoadjuvant therapy for triple-negative breast cancer.

BACKGROUND: Although neoadjuvant chemotherapy (NAC) is currently the best therapy for triple-negative breast cancer (TNBC), resistance still occurs in a considerable proportion, thus it is crucial to understand resistance mechanisms and identify predictive biomarkers for patients selection. METHODS: Biopsy samples were collected from 21 patients with TNBC who underwent NAC. Whole-exome sequencing (WES), targeted sequencing, and multiplex immunohistochemistry (mIHC) were carried out on the clinical samples and used to identify and validate potential biomarkers associated with response to NAC. In addition, data on 190 TNBC patients who had undergone chemotherapy were obtained from The Cancer Genome Atlas (TCGA) and analyzed to further validate our findings. RESULTS: Both the tumor mutational burden (TMB) and tumor neoantigen burden (TNB) were significantly higher in responders than in non-responders. Higher response rates and longer survival rates were observed in patients with higher TMB. Patients with higher ratios of CD8 to M2 macrophages had higher response rates and improved survival rates. Finally, the integrated analysis demonstrated that the combination of TMB and the ratio of CD8 T cells to M2 macrophages could further distinguish patients who benefitted from the treatment in both enrolled patients and public data. CONCLUSIONS: The findings of this study indicated that the combination of TMB and the ratio of CD8 T cells to M2 macrophages may be a potential biomarker for improving the recognition of NAC responders, thereby providing a basis for developing precision NAC regimens.

Systematic analysis of microbiota in pregnant Chinese women and its association with miscarriage.

Background: Miscarriage is the most common adverse pregnancy outcome and more than 50% of its incidence remains unexplained. Earlier studies have suggested that maternal microbiota might be associated with miscarriage, but the association is insufficiently understood. Methods: We used 16S ribosomal RNA (rRNA) amplicon sequencing and metagenomic sequencing technology to characterize the bacterial composition of three sites including the rectum, vagina, and cervix of a case group of 63 pregnant women who had miscarried compared to a control group of 24 pregnant women who underwent voluntary elective abortion. Results: The alpha-diversity from the rectum and cervix was significantly decreased in the case group relative to the control group. However, we did not find significant differences in microbial diversity of vaginal samples between the two groups. Lactobacillus was the most predominant genus in the cervix and vaginal samples. Gestational age at the time of surgery was positively associated with the rectum microbiota diversity, with an effect size of 10% (P=0.004). Host factors including gestational age and red blood count (RBC) were associated with the rectal microbiota diversity. Conclusions: We detected a significantly lower rectal microbiota diversity and a pro-inflammatory tendency in the miscarriage group. This is the first study to investigate the association of microbiota from samples collected from three sites and miscarriage. Further studies are warranted to explore further the role of microbiota in miscarriage.

Identification of cuproptosis-related gene signature to predict prognosis in lung adenocarcinoma.

Background: Studies have reported that coppers are involved in the tumorigenesis and development of tumor. In herein, we aimed to construct a prognostic classification system for lung adenocarcinoma (LUAD) associated with cuproptosis. Methods: Samples information of LUAD were acquired from The Cancer Genome Atlas (TCGA) and GSE31210 dataset. Cuproptosis-related genes were screened from previous research. ConsensusClusterPlus was applied to determine molecular subtypes, which evaluated by genome analysis, tumor immune microenvironment analysis, immunotherapy, functional enrichment analysis. Furthermore, univariate Cox analysis combined with Lasso analysis were employed to construct a cuproptosis-related risk model for LUAD. Results: 14 genes related to cuproptosis phenotype were identified, and 2 clusters (C1 and C2) were determined. Among which, C1 had better survival outcome, less advanced stages, enhanced immune infiltration and enriched in TCA related pathways. A 7 cuproptosis-associated genes risk model was constructed, and the performance was verified in the GSE31210 dataset. A higher RiskScore was significantly correlated with worse overall survival, advanced stages. Cox survival analysis showed that RiskScore was an independent predictor. High-risk group patients had weakened immune infiltration, less likely to benefit from immunotherapy and was more sensitived to immunotherapy. Conclusion: The cuproptosis-related gene signature could serve as potential prognostic predictors for LUAD patients and may provide clues for the intervention of cuproptosis induced harm and targeted anti-tumor application.

Status and epidemiological characteristics of high-risk human papillomavirus infection in multiple centers in Shenyang.

The different human papillomavirus (HPV) strains cause warts in various regions of the body. However, considering that the status and genotype distribution of HPV infection in women in Shenyang remain unknown, herein, we investigated the epidemiological characteristics of high-risk HPV (HR-HPV) infection in women in Shenyang, as well as the current state of HPV infection in Shenyang, to provide a theoretical basis for the prevention and treatment of cervical cancer. From December 2018 to December 2021, 6,432 urban and rural women from the Liaoning Cancer Hospital and the Sujiatun Women and Infants' Hospital were assessed via the Thinprep cytology test (TCT) and HR-HPV detection. Of the 5,961 women enrolled, 739 were HPV positive (12.40%) and 562 were TCT positive (9.43%). Statistical analyses identified the following HPV risk factors: high school education or lower [OR = 1.426 (1.199-1.696), p < 0.001], age at first sexual encounter ≤ 19 years [OR = 1.496 (1.008-2.220), p = 0.046], and number of sexual partners > 1 [OR = 1.382 (1.081-1.768), p = 0.010], atypical squamous cells of undetermined significance (ASCUS) and above [OR = 10.788 (8.912-13.060), p < 0.001], non-condom-based contraception [OR = 1.437 (1.103-1.871), p = 0.007], nationalities other than Han [OR = 1.690 (1.187-2.406), p = 0.004], rural residence [OR = 1.210 (1.031-1.419), p = 0.020]. Compared to the HPV infection rate of women aged 56-65, that in women aged 35-45 [OR = 0.687 (0.549-0.860), p = 0.001] and 46-55 [OR = 0.740 (0.622-0.879), p = 0.001] decreased significantly. To conclude, risk factors of HPV infection among female patients include high school age and below, initial sexual encounter at age ≤ 19 years, number of sexual partners > 1, ASCUS and above, non-condom contraception, nationalities other than Han nationality and rural population. Collectively, this study provides insights for the improved prevention and treatment of cervical cancer.

Performance of human papillomavirus E6/E7 mRNA assay for primary cervical cancer screening and triage: Population-based screening in China.

Objective: Cervical cancer screening is very important in the prevention and treatment of cervical cancer. In China, the cervical screening strategy needs to be improved. To explore a suitable cervical screening strategy in China, we evaluated the performance of the human papillomavirus (HPV) E6/E7 mRNA (Aptima HPV (AHPV)) assay in primary screening and different triage strategies for women undergoing routine cervical screening. Methods: A total of 10,002 women aged 35 to 65 years of age were recruited in Liaoning Province and Qingdao City, China. Specimens were tested by liquid-based cytology (LBC) and the AHPV assay, and women who tested positive on any test were referred for colposcopy. Genotyping was performed on all high-risk HPV (HR-HPV)-positive samples. Test characteristics were calculated based on histological review. Results: We identified 109 women with high-grade squamous intraepithelial lesion or worse (HSIL+), including six with cervical cancer. The sensitivity of AHPV was clearly higher than that of LBC (92.7 [95% CI: 87.2, 97.2] vs. 67.9 [95% CI: 59.6, 76.1], p < 0.001). The specificity of AHPV was 93.0 (95% CI: 92.5, 93.5), which was lower than that of LBC (95.2 [95% CI: 94.8, 95.6], p < 0.001). There was no statistical difference between the positive predictive value of AHPV and LBC (13.5 [95% CI: 11.2, 16.2] vs. 14.3 [95% CI: 11.4, 17.6], p = 0.695). The difference of area under the curve (AUC) values between the AHPV test (0.928 [95% CI: 0.904, 0.953]) and LBC test (0.815 [95% CI: 0.771, 0.860]) in detecting HSIL+ was statistically significant (p < 0.001). Finally, among the three triage strategies, both the sensitivity (73.4 [95% CI: 65.1, 81.7]) and AUC (0.851 [95% CI: 0.809, 0.892]) of AHPV genotyping with reflex LBC triage were the greatest. Conclusion: In summary, the AHPV assay is both specific and sensitive for detecting HSIL+ and may be suitable for use in primary cervical cancer screening in China. AHPV genotyping with reflex LBC triage may be a feasible triage strategy.

Comprehensive Analysis of Histone Modifications in Hepatocellular Carcinoma Reveals Different Subtypes and Key Prognostic Models.

Histone modification, an important epigenetic mechanism, is related to the carcinogenesis of hepatocellular carcinoma (HCC). In three datasets, we screened 88 epigenetic-dysregulated PCGs (epi-PCGs) , which were significantly associated with HCC survival and could cluster HCC into three molecular subtypes. These subtypes were associated with prognosis, immunomodulatory alterations, and response to different treatment strategies. Based on 88 epi-PCGs in the TCGA training set, a risk prediction model composed of 4 epi-PCGs was established. The model was closely related to the clinicopathological features and showed a strong predictive ability in different clinical subgroups. In addition, the risk prediction model was an independent prognostic factor for patients with HCC. The significance of epi-PCGs in HCC is revealed by our data analysis.

MC4R Deficiency Causes Dysregulation of Postsynaptic Excitatory Synaptic Transmission as a Crucial Culprit for Obesity.

Melanocortin 4 receptor (MC4R) in the paraventricular nucleus of the hypothalamus (PVH) shows bidirectional characterization in modulating food intake and energy homeostasis. We demonstrate that MC4R knockdown (KD) in the PVH can attenuate AMPA receptor (AMPAR)-mediated postsynaptic responses by altering the phosphorylation of AMPAR GluA1 subunit through the protein kinase A (PKA)-dependent signaling cascade and simultaneously lead to rapid body weight gain. Furthermore, PKA KD in the PVH engendered similar electrophysiological and behavioral phenotypes as in MC4R KD mice. Importantly, we observed that the reduction of AMPAR GluA1 expression not only led to attenuated synaptic responses but also caused body weight gain, suggesting that the aberration of synaptic responses may be one of the crucial pathogeny of obesity. Our study provides the synaptic and molecular explanations of how body weight is regulated by MC4R in the PVH.

Risk Factors Associated With Human Papillomavirus Infection, Cervical Cancer, and Precancerous Lesions in Large-Scale Population Screening.

Cervical cancer is the most common gynecological malignancy and screening for risk factors with early detection has been shown to reduce the mortality. In this study, we aimed to analyze the characteristics and risk factors of human papillomavirus (HPV) infection and precancerous lesions in women and provide clinical evidence for developing strategies to prevent cervical precancerous lesions and cancer in women. Furthermore, we evaluated the influencing factors for high-risk HPV infection. From April 2018 to December 2021, 10,628 women were recruited for cervical cancer screening at Liaoning Cancer Hospital, Shenyang Sujiatun District Women's and Infants Hospital, Benxi Manchu Autonomous County People's Hospital, and Shandong Affiliated Hospital of Qingdao University. The study participants were tested to determine if they were HPV-positive (HPV +) or underwent thinprep cytology test (TCT) for atypical squamous cells of undetermined significance (ASCUS) and above. Furthermore, colposcopies and biopsies were performed for the histopathological examination. Finally, 9991 cases were included in the statistical analysis, and the factors influencing HPV infection and those related to cervical cancer and precancerous lesions were analyzed. HPV + infection, high-grade squamous intraepithelial lesion-positive (CINII +) in cervical high-grade intraepithelial neoplasia, and early cervical cancer diagnosis rates were 12.45, 1.09, and 95.41%, respectively. The potential risk factors for HPV were education ≤ high school [odds ratio (OR) = 1.279 (1.129-1.449), P < 0.001], age at initial sexual activity ≤ 19 years [OR = 1.517 (1.080-2.129), P = 0.016], sexual partners > 1 [OR = 1.310 (1.044-1.644), P = 0.020], ASCUS and above [OR = 11.891 (10.105-13.993), P < 0.001], non-condom contraception [OR = 1.255 (1.059-1.487), P = 0.009], and HSIL and above [OR = 1.541 (1.430-1.662), P < 0.001]. Compared with women aged 56-65 and 35-45 years [OR = 0.810 (0.690-0.950), P = 0.010] the HPV infection rate was significantly lower in those aged 46-55 years [OR = 0.79 (0.683-0.915), P = 0.002]. Furthermore, ≤ high school age [OR = 1.577 (1.042-2.387), P = 0.031], not breastfeeding [OR = 1.763 (1.109-2.804), P = 0.017], ASCUS and above [OR = 42.396 (28.042-64.098), P < 0.001] were potential risk factors for cervical cancer and precancerous lesions. In women with HPV infection, ≤ high school education level, initial sexual activity at ≤ 19 years of age, number of sexual partners > 1, ASCUS and above, non-condom contraception, HSIL and above were risk factors for HPV infection. Compared with women aged 56-65 years, those aged 35-45 and 46-55 years had significantly lower HPV infection rates, and high school age and below, non-breastfeeding, and ASCUS and above were all potential risk factors for cervical cancer and precancerous lesions.

Highly precise breakpoint detection of chromosome balanced translocation in chronic myelogenous leukaemia: Case series.

Chronic myelogenous leukaemia (CML) has a special phenomenon of chromosome translocation, which is called Philadelphia chromosome translocation. However, the detailed connection of this structure is troublesome and expensive to be identified. Low-coverage whole genome sequencing (LCWGS) could not only detect the previously unknown chromosomal translocation, but also provide the breakpoint candidate small region (with an accuracy of ±200 bases). Importantly, the sequencing cost of LCWGS is about US$300. Then, with the Sanger DNA sequencing, the precise breakpoint can be determined at a single base level. In our project, with LCWGS, BCR and ABL1 are successfully identified to be disrupted in three CML patients (at chr22:23,632,356 and chr9:133,590,450; chr22:23,633,748 and chr9:133,635,781; chr22: 23,631,831 and chr9:133,598,513, respectively). Due to the reconnection after chromosome breakage, classical fusion gene (BCR::ABL1) was found in bone marrow and peripheral blood. The precise breakpoints were helpful to investigate the pathogenic mechanism of CML and could better guide the classification of CML subtypes. This LCWGS method is universal and can be used to detect all diseases related to chromosome variation, such as solid tumours, liquid tumours and birth defects.