A novel signature integrated endoplasmic reticulum stress and apoptosis related genes to predict prognosis for breast cancer.

Background: Breast cancer (BC) is the primary cause of cancer mortality. Herein, we aimed to establish and verify a prognostic model consisting of endoplasmic reticulum stress and apoptosis related genes (ERAGs) to predict patient survival. Methods: The Cancer Genome Atlas (TCGA) database was used to download gene expression and clinical data to identify the differentially expressed genes (DEGs). Using univariate Cox regression analysis and the Least Absolute Shrinkage and Selection Operator (LASSO)-penalized Cox proportional hazards regression analysis, the prognostic ERAGs were screened. The predictive performance was evaluated using Kaplan-Meier (KM) survival and receiver operating characteristic (ROC) curve analysis. Furthermore, a nomogram model incorporating clinical parameters and risk scores was constructed and subsequently evaluated using ROC and KM analysis. The correlation analysis, mutation analysis, functional enrichment analysis, and immune infiltration analysis were employed to investigate the specific mechanism of ERAGs. We also used Quantitative Real-Time PCR (RT-qPCR) to verify the differential expression of DE-ERAGs between the breast cancer cell line and mammary epithelial cell line. Results: We constructed a prognostic signature comprising 16 ERAGs. ROC, KM analysis and the nomogram model demonstrated high effectiveness in accurately predicting the overall survival (OS) of BRCA patients. The results of these analysis could provide reference for further mechanism exploration. Conclusion: We developed and assessed a novel molecular predictive model for breast cancer that focuses on endoplasmic reticulum stress and apoptosis in this study. It is a valuable complement to the existing prognostic prediction models for breast cancer.

A novel fluorescence-electrochemiluminescence dual-mode sensing platform for high-precision BRAF gene detection.

In this study, we innovatively synthesized bipyridine ruthenium cluster nanosheets (RuMOFNCs), a novel metal-organic framework material that exhibits both fluorescence and electrochemiluminescence. Gold nanoparticles (AuNPs) were anchored onto RuMOFNCs via bipyridine chelation, enhancing optical signals and creating sites for attaching biologically functional probes. We employed tetraferrocene-modified DNA probes, linked via gold-sulfur (Au-S) bonds, to construct a dual-mode fluorescence-electrochemiluminescence biosensor. This sensor, exploiting exonuclease III (Exo III)-mediated cyclic amplification, inhibits the electron transfer from RuMOFNC to tetraferrocene, resulting in amplified fluorescence and electrochemiluminescence signals. The sensor demonstrates exceptional sensitivity for detecting the BRAF gene, with fluorescence and electrochemiluminescence detection limits of 10.3 aM (range: 0.1 fM to 1 nM) and 3.1 aM (range: 1 aM to 10 pM), respectively. These capabilities are attributed to RuMOFNCs' luminescence properties, tetraferrocene's quenching effect, and the specificity of base pairing. This study's findings hold substantial promise for biomedical research and clinical diagnostics, particularly in precision medicine and early disease detection.

Fat intake modifies association between cigarette smoking and lung cancer in a prospective cohort study: A potential explanation for the lung cancer paradox.

BACKGROUND & AIMS: It remains unclear why the association between cigarette smoking and lung cancer was substantially stronger in Western countries than in Asian countries. As experimental studies have revealed that fat intake modulates tobacco carcinogen metabolism and the growth of transplanted or carcinogen-induced lung tumors in mice, the present study sought to investigate whether the association between cigarette smoking and lung cancer was modified by intake of total fat and types of fat (saturated, monounsaturated, and polyunsaturated fats) in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. METHODS: During a median follow-up of 8.9 years, 1,425 cases of lung cancer were documented from 100,864 participants eligible for the present analysis. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: After adjustment for established or suspected confounders, the strength of the association between cigarette smoking and lung cancer was remarkably larger among individuals with high fat intake. HRs (95% CIs) comparing current with never smokers were 23.0 (13.4, 39.6), 32.7 (20.3, 52.8), and 59.8 (30.2, 118.2) for the tertile 1 (≤13.48 g/day), tertile 2 (13.49-21.89 g/day), and tertile 3 (≥21.90 g/day) of saturate fat intake, respectively. A similar pattern of the non-significant interaction was observed when the accumulated amount of cigarette smoking (1-19, 20-39, and ≥40 vs. 0 pack-years) was entered into the regression models. CONCLUSIONS: The present study showed that lung cancer risk associated with both the status and accumulated amount of cigarette smoking was remarkably stronger in individuals with high intakes of fat, particularly saturated fat. However, this interaction was not statistically significant and thus warrants further investigations in other studies.

TRIM56: a promising prognostic immune biomarker for glioma revealed by pan-cancer and single-cell analysis.

Tripartite-motif 56 (TRIM56) is a member of the TRIM family, and was shown to be an interferon-inducible E3 ubiquitin ligase that can be overexpressed upon stimulation with double-stranded DNA to regulate stimulator of interferon genes (STING) to produce type I interferon and thus mediate innate immune responses. Its role in tumors remains unclear. In this study, we investigated the relationship between the expression of the TRIM56 gene and its prognostic value in pan-cancer, identifying TRIM56 expression as an adverse prognostic factor in glioma patients. Therefore, glioma was selected as the primary focus of our investigation. We explored the differential expression of TRIM56 in various glioma subtypes and verified its role as an independent prognostic factor in gliomas. Our research revealed that TRIM56 is associated with malignant biological behaviors in gliomas, such as proliferation, migration, and invasion. Additionally, it can mediate M2 polarization of macrophages in gliomas. The results were validated in vitro and in vivo. Furthermore, we utilized single-cell analysis to investigate the impact of TRIM56 expression on cell communication between glioma cells and non-tumor cells. We constructed a multi-gene signature based on cell markers of tumor cells with high TRIM56 expression to enhance the prediction of cancer patient prognosis. In conclusion, our study demonstrates that TRIM56 serves as a reliable immune-related prognostic biomarker in glioma.

Comparison of clinical efficacy of 3D-printed artificial vertebral body and conventional titanium mesh cage in spinal reconstruction after total en bloc spondylectomy for spinal tumors: a systematic review and meta-analysis.

Propose: This meta-analysis aimed to determine whether 3D-printed artificial vertebral bodies (AVBs) have superior clinical efficacy compared to conventional titanium mesh cages (TMCs) for spinal reconstruction after total en bloc spondylectomy (TES) for spinal tumors. Methods: Electronic databases, including PubMed, OVID, ScienceDirect, Embase, CINAHL, Web of Science, Cochrane Library, WANFANG, and CNKI, were searched to identify clinical trials investigating 3D-printed AVB versus conventional TMC from inception to August 2023. Data on the operation time, intraoperative blood loss, preoperative and postoperative visual analogue scale (VAS) scores, preoperative and postoperative Frankel classification of spinal cord injury, vertebral body subsidence, and early complications were collected from eligible studies for a meta-analysis. Data were analyzed using Review Manager 5.4 and Stata 14.0. Results: Nine studies assessing 374 patients were included. The results revealed significant differences between the 3D-printed AVB and conventional TMC groups with regard to operation time (P = 0.04), intraoperative blood loss (P = 0.004), postoperative VAS score (P = 0.02), vertebral body subsidence (P < 0.0001), and early complications (P = 0.02). Conversely, the remaining preoperative VAS score and Frankel classifications (pre-and postoperative) did not differ significantly between the groups. Conclusion: The 3D-printed AVB in spinal reconstruction after TES for spinal tumors has the advantages of a short operative time, little intraoperative blood loss, weak postoperative pain, low occurrence of vertebral body subsidence and early complications, and a significant curative effect. This could provide a strong basis for physicians to make clinical decisions. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023441521, identifier CRD42023441521.

EGF-driven EGFR/miR-27b-3p/FOXO1 promotes rat FSH synthesis and secretion.

The adenopituitary secretes follicle-stimulating hormone (FSH), which plays a crucial role in regulating the growth, development, and reproductive functions of organisms. Investigating the process of FSH synthesis and secretion can offer valuable insights into potential areas of focus for reproductive research. Epidermal growth factor (EGF) is a significant paracrine/autocrine factor within the body, and studies have demonstrated its ability to stimulate FSH secretion in animals. However, the precise mechanisms that regulate this action are still poorly understood. In this research, in vivo and in vitro experiments showed that the activation of epidermal growth factor receptor (EGFR) by EGF induces the upregulation of miR-27b-3p and that miR-27b-3p targets and inhibits Foxo1 mRNA expression, resulting in increased FSH synthesis and secretion. In summary, this study elucidates the precise molecular mechanism through which EGF governs the synthesis and secretion of FSH via the EGFR/miR-27b-3p/FOXO1 pathway.

NRAS Mutant Dictates AHCYL1-Governed ER Calcium Homeostasis for Melanoma Tumor Growth.

Calcium homeostasis is critical for cell proliferation, and emerging evidence shows that cancer cells exhibit altered calcium signals to fulfill their need for proliferation. However, it remains unclear whether there are oncogene-specific calcium homeostasis regulations that can expose novel therapeutic targets. Here, from RNAi screen, we report that adenosylhomocysteinase like protein 1 (AHCYL1), a suppressor of the endoplasmic reticulum (ER) calcium channel protein inositol trisphosphate receptor (IP3R), is selectively upregulated and critical for cell proliferation and tumor growth potential of human NRAS-mutated melanoma, but not for melanoma expressing BRAF V600E. Mechanistically, AHCYL1 deficiency results in decreased ER calcium levels, activates the unfolded protein response (UPR), and triggers downstream apoptosis. In addition, we show that AHCYL1 transcription is regulated by activating transcription factor 2 (ATF2) in NRAS-mutated melanoma. Our work provides evidence for oncogene-specific calcium regulations and suggests AHCYL1 as a novel therapeutic target for RAS mutant-expressing human cancers, including melanoma. IMPLICATIONS: Our findings suggest that targeting the AHCYL1-IP3R axis presents a novel therapeutic approach for NRAS-mutated melanomas, with potential applicability to all cancers harboring RAS mutations, such as KRAS-mutated human colorectal cancers.

Molecular Regulation and Oncogenic Functions of TSPAN8.

Tetraspanins, a superfamily of small integral membrane proteins, are characterized by four transmembrane domains and conserved protein motifs that are configured into a unique molecular topology and structure in the plasma membrane. They act as key organizers of the plasma membrane, orchestrating the formation of specialized microdomains called "tetraspanin-enriched microdomains (TEMs)" or "tetraspanin nanodomains" that are essential for mediating diverse biological processes. TSPAN8 is one of the earliest identified tetraspanin members. It is known to interact with a wide range of molecular partners in different cellular contexts and regulate diverse molecular and cellular events at the plasma membrane, including cell adhesion, migration, invasion, signal transduction, and exosome biogenesis. The functions of cell-surface TSPAN8 are governed by ER targeting, modifications at the Golgi apparatus and dynamic trafficking. Intriguingly, limited evidence shows that TSPAN8 can translocate to the nucleus to act as a transcriptional regulator. The transcription of TSPAN8 is tightly regulated and restricted to defined cell lineages, where it can serve as a molecular marker of stem/progenitor cells in certain normal tissues as well as tumors. Importantly, the oncogenic roles of TSPAN8 in tumor development and cancer metastasis have gained prominence in recent decades. Here, we comprehensively review the current knowledge on the molecular characteristics and regulatory mechanisms defining TSPAN8 functions, and discuss the potential and significance of TSPAN8 as a biomarker and therapeutic target across various epithelial cancers.

Targeting transcription factors through an IMiD independent zinc finger domain.

Immunomodulatory imide drugs (IMiDs) degrade specific C2H2 zinc finger degrons in transcription factors, making them effective against certain cancers. SALL4, a cancer driver, contains seven C2H2 zinc fingers in four clusters, including an IMiD degron in zinc finger cluster two (ZFC2). Surprisingly, IMiDs do not inhibit growth of SALL4 expressing cancer cells. To overcome this limit, we focused on a non-IMiD degron, SALL4 zinc finger cluster four (ZFC4). By combining AlphaFold and the ZFC4-DNA crystal structure, we identified a potential ZFC4 drug pocket. Utilizing an in silico docking algorithm and cell viability assays, we screened chemical libraries and discovered SH6, which selectively targets SALL4-expressing cancer cells. Mechanistic studies revealed that SH6 degrades SALL4 protein through the CUL4A/CRBN pathway, while deletion of ZFC4 abolished this activity. Moreover, SH6 led to significant 62% tumor growth inhibition of SALL4+ xenografts in vivo and demonstrated good bioavailability in pharmacokinetic studies. In summary, these studies represent a new approach for IMiD independent drug discovery targeting C2H2 transcription factors in cancer.

The marine Penicillium sp. GGF16-1-2 metabolite dicitrinone G inhibits pancreatic angiogenesis by regulating the activation of NLRP3 inflammasome.

Citrinin derivatives have been found to have various pharmacological activities, such as anti-inflammatory, anti-tumor, and antioxidant effects. Dicitrinone G (DG) was a new citrinin dimer isolated from marine-derived fungus Penicillium sp. GGF 16-1-2 which has potential activity. Here, we aim to investigate whether DG has anti-pancreatic cancer activity. In xenograft tumor model, 2 × 106 BXPC-3 cells were injected into the hind flank of NU/NU nude mice by subcutaneously for 2 weeks followed by treating with DG (0.25, 0.5, 1 mg/kg) and 5-FU (30 mg/kg) for 4 weeks. Tumor volume and weight were measured, and the expression of CD31, IL-18, NLRP3, and Caspase-1 in tumor tissue were detected. In vitro, HUVECs were treated with conditioned medium (CM) derived from BXPC-3 cells, the effects of DG on angiogenesis were detected by tube formation and western blot analysis. In vivo studies showed that the tumor growth and angiogenesis were greatly suppressed. The tumor weight inhibition rates of DG and 5-FU groups were about 42.36%, 38.94%, 43.80%, and 31.88%. Furthermore, the expression of CD31 and Caspase-1 were decreased. In vitro, CM derived from BXPC-3 cells which treated with DG could inhibit the tube formation and expression of pro-angiogenic NICD in HUVECs. Our study suggests that DG could suppress angiogenesis via the NLRP3/IL-18 pathway and may have the potential to inhibit tumor development.

Small molecular CD73 inhibitors: Recent progress and future perspectives.

The occurrence and development of the tumor are very complex biological processes. In recent years, a large number of research data shows that CD73 is closely related to tumor growth and metastasis. It has been confirmed that the cascade hydrolysis of extracellular ATP to adenosine is one of the most important immunosuppressive regulatory pathways in the tumor microenvironment. The metabolite adenosine can mediate immunosuppression by activating adenosine receptor (such as A2A) on effector Immune cells and enable tumor cells to achieve immune escape. Therefore, attenuating or completely removing adenosine-mediated immunosuppression in the tumor microenvironment by inhibiting CD73 is a promising approach in the treatment of solid tumors. This paper focuses on the research progress of CD73 enzyme and CD73 small molecule inhibitors, and is expected to provide some insights into the development of small-molecule antitumor drugs targeting CD73.

Discovery of (quinazolin-6-yl)benzamide derivatives containing a 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline moiety as potent reversal agents against P-glycoprotein-mediated multidrug resistance.

P-glycoprotein (P-gp) is an important factor leading to multidrug resistance (MDR) in cancer treatment. The co-administration of anticancer drugs and P-gp inhibitors has been a treatment strategy to overcome MDR. In recent years, tyrosine kinase inhibitor Lapatinib has been reported to reverse MDR through directly interacting with ABC transporters. In this work, a series of P-gp inhibitors (1-26) was designed and synthesized by integrating the quinazoline core of Lapatinib into the molecule framework of the third-generation P-gp inhibitor Tariquidar. Among them, compound 14 exhibited better MDR reversal activity than Tariquidar. The docking results showed compound 14 displayed the L-shaped molecular conformation. Importantly, compound 14 increased the accumulation of Adriamycin (ADM) and rhodamine 123 (Rh123) in MCF7/ADM cells. Besides, compound 14 significantly increased ADM-induced apoptosis and inhibited the proliferation, migration and invasion of MCF7/ADM cells. It was also demonstrated that compound 14 significantly inhibited the growth of MCF7/ADM xenograft tumors by increasing the sensitivity of ADM. In summary, compound 14 has the potential to overcome MDR caused by P-gp.

Depletion of tet2 results in age-dependent changes in DNA methylation and gene expression in a zebrafish model of myelodysplastic syndrome.

Introduction: Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic disorders characterized by ineffective hematopoiesis, cytopenias, and dysplasia. The gene encoding ten-eleven translocation 2 (tet2), a dioxygenase enzyme that catalyzes the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine, is a recurrently mutated tumor suppressor gene in MDS and other myeloid malignancies. Previously, we reported a stable zebrafish line with a loss-of-function mutation in the tet2 gene. The tet2m/m-mutant zebrafish developed a pre-MDS state with kidney marrow dysplasia, but normal circulating blood counts by 11 months of age and accompanying anemia, signifying the onset of MDS, by 24 months of age. Methods: In the current study, we collected progenitor cells from the kidney marrows of the adult tet2m/m and tet2wt/wt fish at 4 and 15 months of age and conducted enhanced reduced representation of bisulfite sequencing (ERRBS) and bulk RNA-seq to measure changes in DNA methylation and gene expression of hematopoietic stem and progenitor cells (HSPCs). Results and discussion: A global increase in DNA methylation of gene promoter regions and CpG islands was observed in tet2m/m HSPCs at 4 months of age when compared with the wild type. Furthermore, hypermethylated genes were significantly enriched for targets of SUZ12 and the metal-response-element-binding transcription factor 2 (MTF2)-involved in the polycomb repressive complex 2 (PRC2). However, between 4 and 15 months of age, we observed a paradoxical global decrease in DNA methylation in tet2m/m HSPCs. Gene expression analyses identified upregulation of genes associated with mTORC1 signaling and interferon gamma and alpha responses in tet2m/m HSPCs at 4 months of age when compared with the wild type. Downregulated genes in HSPCs of tet2-mutant fish at 4 months of age were enriched for cell cycle regulation, heme metabolism, and interleukin 2 (IL2)/signal transducer and activator of transcription 5 (STAT5) signaling, possibly related to increased self-renewal and clonal advantage in HSPCs with tet2 loss of function. Finally, there was an overall inverse correlation between overall increased promoter methylation and gene expression.

[Research Progress of Lung Cancer Vaccines].

With the development of medical technology, tumor vaccines as a novel precise immunotherapy approach have gradually received attention in clinical applications. Against the backdrop of the global corona virus disease 2019 (COVID-19) outbreak, vaccine technology has further advanced. Depending on the types of antigens, tumor vaccines can be divided into whole-cell vaccines, peptide vaccines, messenger ribonucleic acid (mRNA) vaccines, recombinant virus vaccines, etc. Although some tumor vaccines have been marketed and achieved certain therapeutic effects, the results of tumor vaccines in clinical trials have been unsatisfactory in the past period. With the maturation of next-generation sequencing (NGS) technology and the continuous development of bioinformatics, dynamic monitoring of the entire process of tumor subpopulation development has become a reality, which has laid a solid foundation for personalized, neoantigen-centered therapeutic tumor vaccines. This article reviews the recent developments of tumor vaccines of different types, starts with lung cancer and summarizes the achievements of tumor vaccines in clinical applications, and provides an outlook for the future development of antigen-centered tumor vaccines.
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Paraneoplastic anti-GAD65 extralimbic encephalitis presented with epilepsy: A case report.

RATIONALE: Autoimmunity targeting glutamic acid decarboxylase 65 (GAD65) is associated with type 1 diabetes mellitus as well as various neurological diseases. In the central nervous system, GAD65 autoimmunity usually presents with limbic encephalitis, whereas extralimbic encephalitis (ELE) has only been reported in a few cases. Moreover, anti-GAD65 ELE in the paraneoplastic context has not yet been reported. PATIENT CONCERNS: A 60-year-old man presented with intermittent cough and sputum for 10 years, with no other diseases. The patient presented with recurrent seizures that were resistant to antiepileptic drugs (AEDs). Chest computed tomography and pathological results confirmed the diagnosis of small cell lung cancer. Paraneoplastic testing found a high level of GAD65 antibodies in his serum, and cerebrospinal fluid analysis revealed lymphocytic pleocytosis, indicating autoimmune encephalitis. Brain magnetic resonance imaging showed multifocal T2 fluid-attenuated inversion recovery hyperintensities in the extralimbic areas including the subcortex and deep white matter of the bilateral frontal lobe, parietal lobe, and insula lobes. DIAGNOSES: Finally, a diagnosis of anti-GAD65 autoimmune ELE with a paraneoplastic etiology from the small cell lung cancer was suspected. INTERVENTIONS: The patient refused any tumor-suppressive treatment or immunotherapy for potential side effects and only received AEDs levetiracetam, sodium valproate, and diazepam. OUTCOMES: The epilepsy of the patient was resistant to AEDs, and the patient died a week after discharge due to disease progression. LESSONS: Anti-GAD65 autoimmune encephalitis can be extralimbic, can present with isolated epilepsy, and extralimbic anti-GAD65 encephalitis can occur with an underlying malignancy.

Identification of Key Novel lncRNAs RP11-400N13.3 and RP11-197K6.1 that Construct ceRNA Networks Associated with Recurrence and Metastasis in Colon Cancer.

BACKGROUND: Colon adenocarcinoma (COAD) is a major cause of cancer mortality worldwide. The occurrence and development of colon cancer is regulated by complex mechanisms that require further exploration. Recently, long non-coding RNAs (lncRNAs) were found to be related to the mortality of colon cancer patients through their participation in competing endogenous RNA (ceRNA) networks. Therefore, screening the lncRNAs involved in colon cancer may contribute to clarifying the complex mechanisms. METHODS: In this study, we explored the potential lncRNAs associated with colon cancer by establishing a ceRNA network using bioinformatics, followed by biological verification. RESULTS: RP11-197K6.1 and RP11-400N13.3 were screened out owing to their involvement in the expression of CDK2NA, a gene that potentially prevents colon cancer cells from high oxygen levels. CONCLUSIONS: Our work explored the mechanisms of recurrence and metastasis in colon cancer and provided potential targets for drug development.

Trans-vaccenic acid reprograms CD8+ T cells and anti-tumour immunity.

Diet-derived nutrients are inextricably linked to human physiology by providing energy and biosynthetic building blocks and by functioning as regulatory molecules. However, the mechanisms by which circulating nutrients in the human body influence specific physiological processes remain largely unknown. Here we use a blood nutrient compound library-based screening approach to demonstrate that dietary trans-vaccenic acid (TVA) directly promotes effector CD8+ T cell function and anti-tumour immunity in vivo. TVA is the predominant form of trans-fatty acids enriched in human milk, but the human body cannot produce TVA endogenously1. Circulating TVA in humans is mainly from ruminant-derived foods including beef, lamb and dairy products such as milk and butter2,3, but only around 19% or 12% of dietary TVA is converted to rumenic acid by humans or mice, respectively4,5. Mechanistically, TVA inactivates the cell-surface receptor GPR43, an immunomodulatory G protein-coupled receptor activated by its short-chain fatty acid ligands6-8. TVA thus antagonizes the short-chain fatty acid agonists of GPR43, leading to activation of the cAMP-PKA-CREB axis for enhanced CD8+ T cell function. These findings reveal that diet-derived TVA represents a mechanism for host-extrinsic reprogramming of CD8+ T cells as opposed to the intrahost gut microbiota-derived short-chain fatty acids. TVA thus has translational potential for the treatment of tumours.

Successful lung transplantation for artificial stone-associated accelerated silicosis: a case report.

This report focuses on the occupational health risks associated with the use of artificial stones containing high levels of crystalline silica in the production of kitchen countertops. It presents the case of a 43-yr-old man who developed severe silicosis due to his occupation involving cutting and polishing quartz stone raw materials. A retrospective analysis of the patient's medical records and occupational history was conducted. The diagnosis of severe silicosis, moderate restrictive lung disease, and bilateral pneumothorax was based on clinical manifestations, pulmonary function test, radiological findings, and histological reports. The patient underwent lung transplantation, and his pulmonary function improved post-surgery. The study highlights the significant health risks associated with procedures involving artificial stones and emphasizes the importance of awareness and protective measures for employees and workers. Clinicians should be cautious when diagnosing respiratory symptoms in patients with a history of occupational exposure to artificial stones containing high levels of crystalline silica.

Exploring the potential relationship between frozen shoulder and Dupuytren's disease through bioinformatics analysis and machine learning.

Background: Frozen shoulder (FS) and Dupuytren's disease (DD) are two closely related diseases, but the mechanism of their interaction is unknown. Our study sought to elucidate the molecular mechanism of these two diseases through shared gene and protein interactions. Methods: GSE75152 and GSE140731 data were downloaded from the Gene Expression Omnibus (GEO) database, and shared genes between FS and DD were selected by using R packages. Then, we used Cytoscape software and the STRING database to produce a protein-protein interaction (PPI) network. Important interaction networks and hub genes were selected through MCODE and cytoHubba algorithms. To explore the potential mechanisms of the development of the two diseases, the hub genes were further enriched by GO and KEGG analyses. We predicted the transcription factors (TFs) of hub genes with Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining (TRRUST). Moreover, we identified candidate genes for FS with DD with cytoHubba and machine learning algorithms. Finally, we analyzed the role of immunocyte infiltration in FS and constructed the relationship between candidate genes and immunocytes in FS. Results: We identified a total of 321 shared genes. The results of GO and KEGG enrichment of shared genes showed that extracellular matrix and collagen fibril tissue play a certain role in the occurrence and development of disease. According to the importance of genes, we constructed the key PPI network of shared genes and the top 15 hub genes for FS with DD. Then, we predicted that five TFs are related to the hub genes and are highly expressed in the FS group. Machine learning results show that the candidate genes POSTN and COL11A1 may be key for FS with DD. Finally, immune cell infiltration revealed the disorder of immunocytes in FS patients, and expression of candidate genes can affect immunocyte infiltration. Conclusion: We identified a PPI network, 15 hub genes, and two immune-related candidate genes (POSTN and COL11A1) using bioinformatics analysis and machine learning algorithms. These genes have the potential to serve as diagnostic genes for FS in DD patients. Furthermore, our study reveals disorder of immunocytes in FS.

Neoadjuvant chemoradiation therapy combined with immunotherapy for microsatellite stable ultra-low rectal cancer (CHOICE II): study protocol of a multicentre prospective randomised clinical trial.

INTRODUCTION: Neoadjuvant chemoradiotherapy (nCRT) could bring tumour shrinking and downstaging and increase the probability of organ preservation for patients with low rectal cancer. But for ultra-low rectal cancer, there is little possibility for organ preservation. Immunotherapy has been shown to have significant survival benefits in microsatellite instability-high patients but poor response in microsatellite stable (MSS) patients. Studies have demonstrated that radiotherapy and immunotherapy have synergistic effects in cancer treatment. There is no existing evidence about the clinical efficacy of immunotherapy combined with nCRT for patients with MSS ultra-low rectal cancer. METHOD AND ANALYSIS: This trial is an open-labelled multicentre prospective randomised controlled trial (NCT05215379) with two parallel groups and allocation ratio 1:1 (nCRT+immunotherapy vs nCRT group). Eligible participants will be aged 18-75 years, with a desire for anus preservation, confirmed cT1-3aN0-1M0 rectal adenocarcinoma, confirmed MSS type, inferior margin of ≤5 cm from the anal verge. The primary endpoint of this trial is complete clinical response (cCR) rate. Immunotherapy is added after 1 week of chemoradiotherapy for two cycles, and then the patients will be administered two cycles of immunotherapy and CAPOX. The evaluations will be carried out after the completion of the whole neoadjuvant therapy. We expect the programme to improve the cCR rate and the quality of life for patients with ultra-low rectal cancer. ETHICS AND DISSEMINATION: This trial was approved by the Ethics committee of Changhai Hospital and other medical centres (Grant number:CHEC2022-118). The results of this study will provide further insight into the clinical efficacy of immunotherapy in combination with nCRT in patients with MSS ultra-low rectal cancer. TRIAL REGISTRATION NUMBER: NCT05215379.