Texture analysis of apparent diffusion coefficient maps: can it identify nonresponse to neoadjuvant chemotherapy for additional radiation therapy in rectal cancer patients?

Background: Neoadjuvant chemotherapy (NCT) alone can achieve comparable treatment outcomes to chemoradiotherapy in locally advanced rectal cancer (LARC) patients. This study aimed to investigate the value of texture analysis (TA) in apparent diffusion coefficient (ADC) maps for identifying non-responders to NCT. Methods: This retrospective study included patients with LARC after NCT, and they were categorized into nonresponse group (pTRG 3) and response group (pTRG 0-2) based on pathological tumor regression grade (pTRG). Predictive texture features were extracted from pre- and post-treatment ADC maps to construct a TA model using RandomForest. The ADC model was developed by manually measuring pre- and post-treatment ADC values and calculating their changes. Simultaneously, subjective evaluations based on magnetic resonance imaging assessment of TRG were performed by two experienced radiologists. Model performance was compared using the area under the curve (AUC) and DeLong test. Results: A total of 299 patients from two centers were divided into three cohorts: the primary cohort (center A; n = 194, with 36 non-responders and 158 responders), the internal validation cohort (center A; n = 49, with 9 non-responders) and external validation cohort (center B; n = 56, with 33 non-responders). The TA model was constructed by post_mean, mean_change, post_skewness, post_entropy, and entropy_change, which outperformed both the ADC model and subjective evaluations with an impressive AUC of 0.997 (95% confidence interval [CI], 0.975-1.000) in the primary cohort. Robust performances were observed in internal and external validation cohorts, with AUCs of 0.919 (95% CI, 0.805-0.978) and 0.938 (95% CI, 0.840-0.985), respectively. Conclusions: The TA model has the potential to serve as an imaging biomarker for identifying nonresponse to NCT in LARC patients, providing a valuable reference for these patients considering additional radiation therapy.

Genome-Wide Identification of the WRKY Gene Family and Functional Characterization of CpWRKY5 in Cucurbita pepo.

The WRKY gene family is crucial for regulating plant growth and development. However, the WRKY gene is rarely studied in naked kernel formation in hull-less Cucurbita pepo L. (HLCP), a natural mutant that lacks the seed coat. In this research, 76 WRKY genes were identified through bioinformatics-based methods in C. pepo, and their phylogenetics, conserved motifs, synteny, collinearity, and temporal expression during seed coat development were analyzed. The results showed that 76 CpWRKYs were identified and categorized into three main groups (I-III), with Group II further divided into five subgroups (IIa-IIe). Moreover, 31 segmental duplication events were identified in 49 CpWRKY genes. A synteny analysis revealed that C. pepo shared more collinear regions with cucumber than with melon. Furthermore, quantitative RT-PCR (qRT-PCR) results indicated the differential expression of CpWRKYs across different varieties, with notable variations in seed coat development between HLCP and CP being attributed to differences in CpWRKY5 expression. To investigate this further, CpWRKY5-overexpression tobacco plants were generated, resulting in increased lignin content and an upregulation of related genes, as confirmed by qRT-PCR. This study offers valuable insights for future functional investigations of CpWRKY genes and presents novel information for understanding the regulation mechanism of lignin synthesis.

Clinicopathological role of Cyclin A2 in uterine corpus endometrial carcinoma: Integration of tissue microarrays and ScRNA-Seq.

BACKGROUND: The comprehensive expression level and potential molecular role of Cyclin A2 (CCNA2) in uterine corpus endometrial carcinoma (UCEC) remains undiscovered. METHODS: UCEC and normal endometrium tissues from in-house and public databases were collected for investigating protein and messenger RNA expression of CCNA2. The transcription factors of CCNA2 were identified by the Cistrome database. The prognostic significance of CCNA2 in UCEC was evaluated through univariate and multivariate Cox regression as well as Kaplan-Meier curve analysis. Single-cell RNA-sequencing (scRNA-seq) analysis was performed to explore cell types in UCEC, and the AUCell algorithm was used to investigate the activity of CCNA2 in different cell types. RESULTS: A total of 32 in-house UCEC and 30 normal endometrial tissues as well as 720 UCEC and 165 control samples from public databases were eligible and collected. Integrated calculation showed that the CCNA2 expression was up-regulated in the UCEC tissues (SMD = 2.43, 95% confidence interval 2.23∼2.64). E2F1 and FOXM1 were identified as transcription factors due to the presence of binding peaks on transcription site of CCNA2. CCNA2 predicted worse prognosis in UCEC. However, CCNA2 was not an independent prognostic factor in UCEC. The scRNA-seq analysis disclosed five cell types: B cells, T cells, monocytes, natural killer cells, and epithelial cells in UCEC. The expression of CCNA2 was mainly located in B cells and T cells. Moreover, CCNA2 was active in T cells and B cells using the AUCell algorithm. CONCLUSION: CCNA2 was up-regulated and mainly located in T cells and B cells in UCEC. Overexpression of CCNA2 predicted unfavorable prognosis of UCEC.

Preparation, evaluation and application of MRI detectable sunitinib-loaded calcium alginate/poly(acrylic acid) hydrogel microspheres.

Transcatheter arterial chemoembolization (TACE) is an effective method for the treatment of unresectable hepatocellular carcinoma. Although many embolic agents have been developed in TACE, there are few ideal embolic agents that combine drug loading, imaging properties and vessel embolization. Here, we developed novel magnetic embolic microspheres that could simultaneously load sunitinib malate (SU), be detected by magnetic resonance imaging (MRI) and block blood vessels. Calcium alginate/poly (acrylic acid) hydrogel microspheres (CA/PAA-MDMs) with superparamagnetic iron oxide nanoparticles (SPIONs) modified by citric acid were prepared by a drip and photopolymerization method. The embolization and imaging properties of CA/PAA-MDMs were evaluated through a series of experiments such as morphology, X-ray diffraction and X-ray photoelectron spectroscopy, magnetic responsiveness analysis, elasticity, cytotoxicity, hemolysis test, in vitro MRI evaluation, rabbit ear embolization and histopathology. In addition, the ability of drug loading and drug release of CA/PAA-MDMs were investigated by using sunitinib (SU) as the model drug. In conclusion, CA/PAA-MDMs showed outstanding drug loading capability, excellent imaging property and embolization effect, which would be expected to be used as a potential biodegradable embolic agent in the clinical interventional therapy.

B-Type Natriuretic Peptide Inhibits the Expression and Function of SERCA2a in Heart Failure.

B-type natriuretic peptide (BNP) possesses protective cardiovascular properties; however, there has not been sufficient serious consideration of the side effects of BNP. As for sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a), it was once considered a new target for the treatment of heart failure (HF). Nevertheless, clinical trials of SERCA2a gene therapy in HF have finally become unsuccessful. Research has found that elevated BNP levels and decreased SERCA2a expression are two important HF characteristics, which are always negatively correlated. We hypothesize that BNP inhibits SERCA2a expression and, therefore, exerts negative effects on SERCA2a expression and function.The effects of BNP on endogenous SERCA2a expression and function were tested in mice with HF induced by transverse aortic constriction and neonatal rat cardiomyocytes (NRCM). Furthermore, to verify the effects of BNP on exogenous SERCA2a gene transduction efficacy, BNP was added to the myocardium and cardiomyocytes infected with an adenovirus overexpressing SERCA2a.In vivo, BNP levels were increased, SERCA2a expression was reduced in both the BNP intervention and HF groups, and BNP reduced the overexpressed exogenous SERCA2a protein in the myocardium. Our in vitro data showed that BNP dose-dependently inhibited the total and exogenous SERCA2a expression in NRCM by activating the cGMP-dependent protein kinase G. BNP also inhibited the effects of SERCA2a overexpression on Ca2+ transience in NRCM.The expression and function of endogenous and exogenous SERCA2a are inhibited by BNP. The opposite relationship between BNP and SERCA2a should be given serious attention in the treatment of HF via BNP or SERCA2a gene therapy.

Tumor-infiltrating immune cells and survival in head and neck squamous cell carcinoma: a retrospective computational study.

The immune infiltration profiles of the tumor microenvironment have effects on the prognosis of head and neck squamous cell carcinoma (HNSCC). Whereas, HNSCC is a heterogeneous group of tumors, but past work has not taken this into consideration. Herein, we investigate the associations between survival and the function of immune cells in different tumorigenic sites of HNSCC. 1149 samples of HNSCC were collected from publicly accessible databases. Based on gene expression data, CIBERSORTx was applied to determine the proportion of 22 immune cell subpopulations. In the Cox regression model, the associations between overall survival, disease-free survival, and immune cells were examined, modeling gene expression and immune cell proportion as quartiles. Consensus cluster analysis was utilized to uncover immune infiltration profiles. Regardless of tumor sites, CD8+ T cells and activated CD4 memory T cells were associated with favorable survival, while eosinophils were the opposite. The survival of the hypopharynx, oral cavity, and larynx subsites was somewhat affected by immune cells, while the survival of the oropharynx subsite potentially was the most impacted. High expression of TIGIT, CIITA, and CXCR6 was linked to better survival, mainly in the oropharynx subsite. Immune cell clusters with four distinct survival profiles were discovered, of which the cluster with a high CD8+ T cell content had a better prognosis. The immune-infiltration pattern is related to the survival of HNSCC to varying degrees depending on the tumor sites; forthcoming studies into immune-mediated infiltration profiles will lay the groundwork for treating HNSCC with precision therapy.

Targeting JMJD1C to selectively disrupt tumor Treg cell fitness enhances antitumor immunity.

Regulatory T (Treg) cells are critical for immune tolerance but also form a barrier to antitumor immunity. As therapeutic strategies involving Treg cell depletion are limited by concurrent autoimmune disorders, identification of intratumoral Treg cell-specific regulatory mechanisms is needed for selective targeting. Epigenetic modulators can be targeted with small compounds, but intratumoral Treg cell-specific epigenetic regulators have been unexplored. Here, we show that JMJD1C, a histone demethylase upregulated by cytokines in the tumor microenvironment, is essential for tumor Treg cell fitness but dispensable for systemic immune homeostasis. JMJD1C deletion enhanced AKT signals in a manner dependent on histone H3 lysine 9 dimethylation (H3K9me2) demethylase and STAT3 signals independently of H3K9me2 demethylase, leading to robust interferon-γ production and tumor Treg cell fragility. We have also developed an oral JMJD1C inhibitor that suppresses tumor growth by targeting intratumoral Treg cells. Overall, this study identifies JMJD1C as an epigenetic hub that can integrate signals to establish tumor Treg cell fitness, and we present a specific JMJD1C inhibitor that can target tumor Treg cells without affecting systemic immune homeostasis.

Synthesis and protection: a controllable electrochemical approach to polypyrrole-coated copper azide with superior safety for MEMS.

Traditional lead-based primary explosives present challenges in application to micro-energetics-on-a-chip. It is highly desired but still remains challenging to design a primary explosive for the development of powerful yet safe energetic films. Copper-based azides (Cu(N3)2 or CuN3, CA) are expected to be ideal alternatives owing to their properties such as excellent device compatibility, excellent detonation performance, and low environmental pollution. However, the significantly high electrostatic sensitivity of CA limits its use in micro-electro-mechanical systems (MEMS). This study presents an in situ electrochemical approach to preparing and modifying a CA film with excellent electrostatic safety using a Cu chip. Herein, a CA film is prepared by employing Cu nanorod arrays as precursors. Next, polypyrrole (PPy) is directly coated on the surface of the CA materials to produce a CA@PPy composite energetic film using the electrochemical process. The results show that CuN3 is first generated and gradually oxidized to Cu(N3)2, essentially forming enclosed nest-like structures during electrochemical azidation. The microstructure and composition of the product can be regulated by varying the current density and reaction time, which leads to controllable heat output of the CA from 521 to 1948 J g-1. Notably, the composite energetic film exhibits excellent electrostatic sensitivity (2.69 mJ) owing to the excellent conductivity of PPy. Thus, this study offers novel ideas for the further advances of composite energetic materials and applications in MEMS explosive systems.

Integrative transcriptome and single-cell sequencing technology analysis of the potential therapeutic benefits of oleanolic acid in liver injury and liver cancer.

BACKGROUND: Oleanolic acid has important hepatoprotective effects and inhibits liver tissue carcinogenesis. The aim of this study was to investigate the mechanism of action of oleanolic acid in inhibiting liver injury and liver cancer. METHOD: In this study, we applied differential gene analysis and gene enrichment analysis to identify the targets of oleanolic acid for the treatment of liver injury. And this study also applied Cibersort and GSVA methods to investigate the targets of oleanolic acid in liver injury. Based on oleanolic acid targets, we explored the major targets and further explored the role of the major targets in liver cancer. This study used the oncoPredict and the TIDE algorithm to predict the effect of oleanolic acid on drug resistance. Finally, the binding effect of oleanolic acid to relevant targets was explored using molecular docking techniques. RESULT: In this study, oleanolic acid was found to inhibit liver injury and promote liver regeneration mainly by promoting elevated expression of HMOX1. Oleanolic acid can inhibit oxidative stress and promotes Ferroptosis in liver injury. In liver cancer, we identified that the main target of oleanolic acid is HMOX1 and HDAC1. And we determined that HMOX1 promotes Ferroptosis in liver cancer. This reduced the sensitivity of liver cancer to targeted therapies and immunotherapy. Molecular docking showed high binding of oleanolic acid to HDAC1 and HMOX1. CONCLUSIONS: Oleanolic acid is an antioxidant by promoting high expression of HMOX1 and promotes the development of Ferroptosis in liver cancer and liver injury.

Gut microbial structural variation associates with immune checkpoint inhibitor response.

The gut microbiota may have an effect on the therapeutic resistance and toxicity of immune checkpoint inhibitors (ICIs). However, the associations between the highly variable genomes of gut bacteria and the effectiveness of ICIs remain unclear, despite the fact that merely a few gene mutations between similar bacterial strains may cause significant phenotypic variations. Here, using datasets from the gut microbiome of 996 patients from seven clinical trials, we systematically identify microbial genomic structural variants (SVs) using SGV-Finder. The associations between SVs and response, progression-free survival, overall survival, and immune-related adverse events are systematically explored by metagenome-wide association analysis and replicated in different cohorts. Associated SVs are located in multiple species, including Akkermansia muciniphila, Dorea formicigenerans, and Bacteroides caccae. We find genes that encode enzymes that participate in glucose metabolism be harbored in these associated regions. This work uncovers a nascent layer of gut microbiome heterogeneity that is correlated with hosts' prognosis following ICI treatment and represents an advance in our knowledge of the intricate relationships between microbiota and tumor immunotherapy.

Prognostic factors and predictive nomogram models for early death in elderly patients with hepatocellular carcinoma: a population-based study.

Background: Owing to an aging society, there has been an observed increase in the average age of patients diagnosed with hepatocellular carcinoma (HCC). Consequently, this study is centered on identifying the prognostic factors linked with early death among this elderly demographic diagnosed with HCC. Additionally, our focus extends to developing nomograms capable of predicting such outcomes. Methods: The Surveillance, Epidemiology and End Results (SEER) database underpinned this study, showcasing participants aged 75 and above diagnosed with HCC within the timeframe from 2010 to 2015. These participants were divided randomly, at a 7:3 ratio, into training and validation cohorts. Univariable and multivariable logistic regressions were applied to the training cohort in the identification of prognostic indicators of early death, forming the basis for nomogram development. To measure the efficacy of these nomograms within both cohorts, we resorted to Receiver Operating Characteristic (ROC) curves, along with GiViTI calibration belt and Decision Curve Analysis (DCA). Results: The study involved 1,163 elderly individuals diagnosed with HCC, having reported instances of 397 all-cause early deaths and 356 HCC-specific early deaths. The sample group was divided into two cohorts: a training group consisting of 815 individuals, and a validation cohort, comprised of 348 individuals. Multifactorial analysis identified grade, T-stage, surgery, radiation, chemotherapy, bone and lung metastasis as significant predictors of mortality from all causes. Meanwhile, race, grade, T-stage, surgery, radiation, chemotherapy, and bone metastasis were revealed to be estimative factors for cancer-specific mortality. Subsequently, these factors were used to develop nomograms for prediction. GiViTI calibration belt corroborated the acceptable coherence of the nomograms, DCA confirmed their valuable clinical applicability, and ROC curves evidenced satisfactory discriminative capacity within both training and validation cohorts. Conclusion: The nomograms utilized in this study proved instrumental in detecting early death among elderly individuals afflicted with HCC. This tool could potentially assist physicians in formulating individualized treatment strategies.

China special issue on gastrointestinal tumors-Radiological features of pathological complete response in mismatch repair deficient colorectal cancer after neoadjuvant PD-1 blockade: A post hoc analysis of the PICC phase II trial.

Neoadjuvant programmed cell death protein 1 (PD-1) blockade exhibits promising efficacy in patients with mismatch repair deficient (dMMR) colorectal cancer (CRC). However, discrepancies between radiological and histological findings have been reported in the PICC phase II trial (NCT03926338). Therefore, we strived to discern radiological features associated with pathological complete response (pCR) based on computed tomography (CT) images. Data were obtained from the PICC trial that included 36 tumors from 34 locally advanced dMMR CRC patients, who received neoadjuvant PD-1 blockade for 3 months. Among the 36 tumors, 28 (77.8%) tumors achieved pCR. There were no statistically significant differences in tumor longitudinal diameter, the percentage change in tumor longitudinal diameter from baseline, primary tumor sidedness, clinical stage, extramural venous invasion status, intratumoral calcification, peritumoral fat infiltration, intestinal fistula and tumor necrosis between the pCR and non-pCR tumors. Otherwise, tumors with pCR had smaller posttreatment tumor maximum thickness (median: 10 mm vs 13 mm, P = .004) and higher percentage decrease in tumor maximum thickness from baseline (52.9% vs 21.6%, P = .005) compared to non-pCR tumors. Additionally, a higher proportion of the absence of vascular sign (P = .003, odds ratio [OR] = 25.870 [95% CI, 1.357-493.110]), nodular sign (P < .001, OR = 189.000 [95% CI, 10.464-3413.803]) and extramural enhancement sign (P = .003, OR = 21.667 [2.848-164.830]) was observed in tumors with pCR. In conclusion, these CT-defined radiological features may have the potential to serve as valuable tools for clinicians in identifying patients who have achieved pCR after neoadjuvant PD-1 blockade, particularly in individuals who are willing to adopt a watch-and-wait strategy.

A nomogram for individually predicting the overall survival in colonic adenocarcinoma patients presenting with perineural invasion: a population study based on SEER database.

Background: Colonic adenocarcinoma, representing the predominant histological subtype of neoplasms in the colon, is commonly denoted as colon cancer. This study endeavors to develop and validate a nomogram model designed for predicting overall survival (OS) in patients with colon cancer, specifically those presenting with perineural invasion (PNI). Methods: The Surveillance, Epidemiology, and End Results (SEER) database supplied pertinent data spanning from 2010 to 2015, which facilitated the randomization of patients into distinct training and validation cohorts at a 7:3 ratio. Both univariate and multivariate analyses were employed to construct a prognostic nomogram based on the training cohort. Subsequently, the nomogram's accuracy and efficacy were rigorously evaluated through the application of a concordance index (C-index), calibration plots, decision curve analysis (DCA), and receiver operating characteristic (ROC) curves. Results: In the training cohorts, multivariable analysis identified age, grade, T-stage, N-stage, M-stage, chemotherapy, tumor size, carcinoembryonic antigen (CEA), marital status, and insurance as independent risk factors for OS, all with P-values less than 0.05. Subsequently, a new nomogram was constructed. The C-index of this nomogram was 0.765 (95% CI: 0.755-0.775), outperforming the American Joint Committee on Cancer (AJCC) TNM staging system's C-index of 0.686 (95% CI: 0.674-0.698). Calibration plots for 3- and 5-year OS demonstrated good consistency, while DCA for 3- and 5-year OS revealed excellent clinical utility in the training cohorts. Comparable outcomes were observed in the validation cohorts. Furthermore, we developed a risk stratification system, which facilitated better differentiation among three risk groups (low, intermediate, and high) in terms of OS for all patients. Conclusion: In this study, we have devised a robust nomogram and risk stratification system to accurately predict OS in colon cancer patients exhibiting PNI. This innovative tool offers valuable guidance for informed clinical decision-making, thereby enhancing patient care and management in oncology practice.

Genetic characteristics and clinical-specific survival prediction in elderly patients with gallbladder cancer: a genetic and population-based study.

Background: Biliary system cancers are most commonly gallbladder cancers (GBC). Elderly patients (≥ 65) were reported to suffer from an unfavorable prognosis. In this study, we analyzed the RNA-seq and clinical data of elderly GBC patients to derive the genetic characteristics and the survival-related nomograms. Methods: RNA-seq data from 14 GBC cases were collected from the Gene Expression Omnibus (GEO) database, grouped by age, and subjected to gene differential and enrichment analysis. In addition, a Weighted Gene Co-expression Network Analysis (WGCNA) was performed to determine the gene sets associated with age grouping further to characterize the gene profile of elderly GBC patients. The database of Surveillance, Epidemiology, and End Results (SEER) was searched for clinicopathological information regarding elderly GBC patients. Nomograms were constructed to predict the overall survival (OS) and cancer-specific survival (CSS) of elderly GBC patients. The predictive accuracy and capability of nomograms were evaluated through the concordance index (C-index), calibration curves, time-dependent operating characteristic curves (ROC), as well as area under the curve (AUC). Decision curve analysis (DCA) was performed to check out the clinical application value of nomograms. Results: Among the 14 patients with GBC, four were elderly, while the remaining ten were young. Analysis of gene differential and enrichment indicated that elderly GBC patients exhibited higher expression levels of cell cycle-related genes and lower expression levels of energy metabolism-related genes. Furthermore, the WGCNA analysis indicated that elderly GBC patients demonstrated a decrease in the expression of genes related to mitochondrial respiratory enzymes and an increase in the expression of cell cycle-related genes. 2131 elderly GBC patients were randomly allocated into the training cohort (70%) and validation cohort (30%). Our nomograms showed robust discriminative ability with a C-index of 0.717/0.747 for OS/CSS in the training cohort and 0.708/0.740 in the validation cohort. Additionally, calibration curves, AUCs, and DCA results suggested moderate predictive accuracy and superior clinical application value of our nomograms. Conclusion: Discrepancies in cell cycle signaling and metabolic disorders, especially energy metabolism, were obviously observed between elderly and young GBC patients. In addition to being predictively accurate, the nomograms of elderly GBC patients also contributed to managing and strategizing clinical care.

Determination and characterization of molecular heterogeneity and precision medicine strategies of patients with pancreatic cancer and pancreatic neuroendocrine tumor based on oxidative stress and mitochondrial dysfunction-related genes.

Background: Mitochondria are significant both for cellular energy production and reactive oxygen/nitrogen species formation. However, the significant functions of mitochondrial genes related to oxidative stress (MTGs-OS) in pancreatic cancer (PC) and pancreatic neuroendocrine tumor (PNET) are yet to be investigated integrally. Therefore, in pan-cancer, particularly PC and PNET, a thorough assessment of the MTGs-OS is required. Methods: Expression patterns, prognostic significance, mutation data, methylation rates, and pathway-regulation interactions were studied to comprehensively elucidate the involvement of MTGs-OS in pan-cancer. Next, we separated the 930 PC and 226 PNET patients into 3 clusters according to MTGs-OS expression and MTGs-OS scores. LASSO regression analysis was utilized to construct a novel prognostic model for PC. qRT-PCR(Quantitative real-time PCR) experiments were performed to verify the expression levels of model genes. Results: The subtype associated with the poorest prognosis and lowerest MTGs-OS scores was Cluster 3, which could demonstrate the vital function of MTGs-OS for the pathophysiological processes of PC. The three clusters displayed distinct variations in the expression of conventional cancer-associated genes and the infiltration of immune cells. Similar molecular heterogeneity was observed in patients with PNET. PNET patients with S1 and S2 subtypes also showed distinct MTGs-OS scores. Given the important function of MTGs-OS in PC, a novel and robust MTGs-related prognostic signature (MTGs-RPS) was established and identified for predicting clinical outcomes for PC accurately. Patients with PC were separated into the training, internal validation, and external validation datasets at random; the expression profile of MTGs-OS was used to classify patients into high-risk (poor prognosis) or low-risk (good prognosis) categories. The variations in the tumor immune microenvironment may account for the better prognoses observed in high-risk individuals relative to low-risk ones. Conclusions: Overall, our study for the first time identified and validated eleven MTGs-OS remarkably linked to the progression of PC and PNET, and elaborated the biological function and prognostic value of MTGs-OS. Most importantly, we established a novel protocol for the prognostic evaluation and individualized treatment for patients with PC.

CT-based deep learning model for the prediction of DNA mismatch repair deficient colorectal cancer: a diagnostic study.

BACKGROUND: Stratification of DNA mismatch repair (MMR) status in patients with colorectal cancer (CRC) enables individual clinical treatment decision making. The present study aimed to develop and validate a deep learning (DL) model based on the pre-treatment CT images for predicting MMR status in CRC. METHODS: 1812 eligible participants (training cohort: n = 1124; internal validation cohort: n = 482; external validation cohort: n = 206) with CRC were enrolled from two institutions. All pretherapeutic CT images from three dimensions were trained by the ResNet101, then integrated by Gaussian process regression (GPR) to develop a full-automatic DL model for MMR status prediction. The predictive performance of the DL model was evaluated using the area under the receiver operating characteristic curve (AUC) and then tested in the internal and external validation cohorts. Additionally, the participants from institution 1 were sub-grouped by various clinical factors for subgroup analysis, then the predictive performance of the DL model for identifying MMR status between participants in different groups were compared. RESULTS: The full-automatic DL model was established in the training cohort to stratify the MMR status, which presented promising discriminative ability with the AUCs of 0.986 (95% CI 0.971-1.000) in the internal validation cohort and 0.915 (95% CI 0.870-0.960) in the external validation cohort. In addition, the subgroup analysis based on the thickness of CT images, clinical T and N stages, gender, the longest diameter, and the location of tumors revealed that the DL model showed similar satisfying prediction performance. CONCLUSIONS: The DL model may potentially serve as a noninvasive tool to facilitate the pre-treatment individualized prediction of MMR status in patients with CRC, which could promote the personalized clinical-making decision.

Research into the characteristic molecules significantly affecting liver cancer immunotherapy.

Background: The past decade has witnessed unprecedented scientific breakthroughs, including immunotherapy, which has great potential in clinical applications for liver cancer. Methods: Public data were obtained from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases and analyzed with R software. Results: The LASSO and SVM-RFE machine learning algorithms identified 16 differentially expressed genes (DEGs) related to immunotherapy, namely, GNG8, MYH1, CHRNA3, DPEP1, PRSS35, CKMT1B, CNKSR1, C14orf180, POU3F1, SAG, POU2AF1, IGFBPL1, CDCA7, ZNF492, ZDHHC22, and SFRP2. Moreover, a logistic model (CombinedScore) was established based on these DEGs, showing an excellent prediction performance for liver cancer immunotherapy. Patients with a low CombinedScore might respond better to immunotherapy. Gene Set Enrichment Analysis showed that many metabolism pathways were activated in patients with a high CombinedScore, including butanoate metabolism, bile acid metabolism, fatty acid metabolism, glycine serine and threonine metabolism, and propanoate metabolism. Our comprehensive analysis showed that the CombinedScore was negatively correlated with the levels of most tumor-infiltrating immune cells and the activities of key steps of cancer immunity cycles. Continually, the CombinedScore was negatively associated with the expression of most immune checkpoints and immunotherapy response-related pathways. Moreover, patients with a high and a low CombinedScore exhibited diverse genomic features. Furthermore, we found that CDCA7 was significantly correlated with patient survival. Further analysis showed that CDCA7 was positively associated with M0 macrophages and negatively associated with M2 macrophages, suggesting that CDCA7 could influence the progression of liver cancer cells by affecting macrophage polarization. Next, single-cell analysis showed that CDCA7 was mainly expressed in prolif T cells. Immunohistochemical results confirmed that the staining intensity of CDCA7 was prominently increased in the nucleus in primary liver cancer tissues compared to adjacent non-tumor tissues. Conclusions: Our results provide novel insights into the DEGs and factors affecting liver cancer immunotherapy. Meanwhile, CDCA7 was identified as a potential therapeutic target in this patient population.

Effects of Metformin on Risk and Prognosis of Biliary Tract Cancer: A Systematic Review and Meta-Analysis.

Background and Objectives: Metformin has been found to potentially reduce the risk and improve the prognosis of a variety of tumors, but these findings remain controversial in biliary tract cancer (BTC). Therefore, this systematic review and meta-analysis was conducted to investigate the association between metformin and BTC. Materials and Methods: Two independent researchers comprehensively searched PubMed, Embase, the Cochrane Library, and Web of Science for eligible studies published from their inception to 31 March 2022. Comparisons of risk, overall survival (OS), and disease-free survival (DFS) for patients with BTC were selected as the endpoints of interest and pooled by random or fixed-effects models. Results: Eleven studies with a total of 24,788,738 participants were eligible for this analysis. The overall pooled effects showed no significant differences in biliary tract cancer risk (hazard ratio (HR) = 0.82, 95% confidence interval (CI): 0.50-1.35, p = 0.436), OS (HR = 0.88, 95% CI: 0.74-1.04, p = 0.135), or DFS (HR = 1.03, 95% CI: 0.79-1.34, p = 0.829) between metformin users and non-users. When restricting participants to those with diabetes, a similar negative result was found, demonstrating that metformin use was not significantly associated with a lower risk of developing BTC compared with a lack of metformin use (HR = 0.65, 95% CI: 0.39-1.07, p = 0.089); notably, the included studies exhibited significant heterogeneity in the selection of participants and the definition of metformin users. Conclusions: Metformin may not be able to reduce the risk of BTC and improve prognosis in certain populations. Based on the limited quantity and quality of the included studies, the present results should be interpreted within their limitations, and further studies are warranted to determine the optimal timing, dose, duration, and scenario of metformin administration.

Detection of Complement C1q B Chain Overexpression and Its Latent Molecular Mechanisms in Cervical Cancer Tissues Using Multiple Methods.

Aim: The aim of this study is to demonstrate the expression and clinicopathological significance of complement C1q B chain (C1QB) in cervical cancer. Methods: In total, 120 cervical cancer tissues, as well as 20 samples each of high-grade squamous intraepithelial lesions (HSILs), low-grade squamous intraepithelial lesions (LSILs), and benign cervical tissue, were collected to evaluate the expression of C1QB protein via immunohistochemical staining. We conducted an integrated analysis of C1QB mRNA expression in cervical cancer using public microarrays and RNA-seq data sets by calculating standard mean differences (SMDs). Simultaneously, we explored the relations of C1QB with clinicopathological parameters and the expression of P16, Ki-67, and P53. Results: The expression of C1QB protein was higher in cervical cancer samples than that in benign cervical tissue, LSIL, and HSIL samples (p < 0.05). A combined SMD of 0.65 (95% CI: [0.52, 0.79], p < 0.001) revealed upregulation of C1QB mRNA in cervical cancer. C1QB expression may also be related to the depth of infiltration, lymphovascular invasion, and perineural invasion in cervical cancer (p < 0.05). We also found that C1QB protein expression was positively correlated with P16 and Ki-67 expression in cervical cancer (p < 0.05). The gene set enrichment analysis showed that C1QB may participate in apoptosis and autophagy. A relationship was predicted between C1QB expression and drug sensitivity to cisplatin, paclitaxel, and docetaxel. Conclusion: We confirmed the overexpression of C1QB in cervical cancer at both mRNA and protein levels for the first time. C1QB may serve as an oncogene in the tumorigenesis of cervical cancer, but this possibility requires further study.