Molecular characterization, clinical value, and cancer-immune interactions of genes related to disulfidptosis and ferroptosis in colorectal cancer.

BACKGROUND: This research strived to construct a new signature utilizing disulfidptosis-related ferroptosis (SRF) genes to anticipate response to immunotherapy, prognosis, and drug sensitivity in individuals with colorectal cancer (CRC). METHODS: The data for RNA sequencing as well as corresponding clinical information of individuals with CRC, were extracted from The Cancer Genome Atlas (TCGA) dataset. SRF were constructed with the help of the random forest (RF), least absolute shrinkage and selection operator (LASSO), and stepwise regression algorithms. To validate the SRF model, we applied it to an external cohort, GSE38832. Prognosis, immunotherapy response, drug sensitivity, molecular functions of genes, and somatic mutations of genes were compared across the high- and low-risk groups (categories). Following this, all statistical analyses were conducted with the aid of the R (version 4.23) software and various packages of the Cytoscape (version 3.8.0) tool. RESULTS: SRF was developed based on five genes (ATG7, USP7, MMD, PLIN4, and THDC2). Both univariate and multivariate Cox regression analyses established SRF as an independent, prognosis-related risk factor. Individuals from the high-risk category had a more unfavorable prognosis, elevated tumor mutational burden (TMB), and significant immunosuppressive status. Hence, they might have better outcomes post-immunotherapy and might benefit from the administration of pazopanib, lapatinib, and sunitinib. CONCLUSION: In conclusion, SRF can act as a new biomarker for prognosis assessment. Moreover, it is also a good predictor of drug sensitivity and immunotherapy response in CRC but should undergo optimization before implementation in clinical settings.

Identification of the shared gene signature and biological mechanism between type 2 diabetes and colorectal cancer.

Background: The correlation of type 2 diabetes mellitus (T2DM) with colorectal cancer (CRC) has garnered considerable attention in the scientific community. Despite this, the molecular mechanisms underlying the interaction between these two diseases are yet to be elucidated. Hence, the present investigation aims to explore the shared gene signatures, immune profiles, and drug sensitivity patterns that exist between CRC and T2DM. Methods: RNA sequences and characteristics of patients with CRC and T2DM were retrieved from The Cancer Genome Atlas and Gene Expression Omnibus databases. These were investigated using weighted gene co-expression network analysis (WGCNA) to determine the co-expression networks linked to the conditions. Genes shared between CRC and T2DM were analyzed by univariate regression, followed by risk prognosis assessment using the LASSO regression model. Various parameters were assessed through different software such as the ESTIMATE, CIBERSORT, AND SSGSEA utilized for tumor immune infiltration assessment in the high- and low-risk groups. Additionally, pRRophetic was utilized to assess the sensitivity to chemotherapeutic agents in both groups. This was followed by diagnostic modeling using logistic modeling and clinical prediction modeling using the nomogram. Results: WGCNA recognized four and five modules that displayed a high correlation with T2DM and CRC, respectively. In total, 868 genes were shared between CRC and T2DM, with 14 key shared genes being identified in the follow-up analysis. The overall survival (OS) of patients in the low-risk group was better than that of patients in the high-risk group. In contrast, the high-risk group exhibited higher expression levels of immune checkpoints The Cox regression analyses established that the risk-score model possessed independent prognostic value in predicting OS. To facilitate the prediction of OS and cause-specific survival, the nomogram was established utilizing the Cox regression model. Conclusion: The T2DM + CRC risk-score model enabled independent prediction of OS in individuals with CRC. Moreover, these findings revealed novel genes that hold promise as therapeutic targets or biomarkers in clinical settings.

Management of esophagogastric fistula caused by adjustable gastric band erosion: A case report and literature review.

Laparoscopic adjustable gastric banding (LAGB) is commonly used in the treatment of morbid obesity. However, with clinical application and long-term follow-up, the shortcomings of this procedure were also exposed, bringing about surgery-related complications include dysphagia, intragastric band migration, slippage, and gastric band erosion. Lower esophageal and gastric fistula is a rare but dangerous complication after LAGB. We describe a case of esophagogastric fistula occurring twelve years after a laparoscopic band procedure and its successful management in a multidisciplinary and staged manner, followed by a short review of the literature.

The risk factors of postoperative nausea and vomiting in patients undergoing laparoscopic sleeve gastrectomy and laparoscopic distal gastrectomy: a propensity score matching analysis.

Postoperative nausea and vomiting (PONV) is a common side effect after laparoscopic surgery. The aim of the study is to investigate the variables that could predict PONV in patients who underwent laparoscopic gastrectomy. We divided patients who underwent laparoscopic gastrectomy into PONV and No-PONV groups. Propensity score matching (PSM) was applied to adjust confounding factors for further validation, and ordinal logistic regression analysis was used to identify predictors for PONV. In the ordinal logistic regression analysis, the preoperative neutrophil-to-lymphocyte ratio (NLR) (odds ratio [OR]: 3.19, 95% confidence interval [CI]: 1.38-7.38; p < 0.01) was identified as an independent risk factor for the presence of PONV and a predictor of the severity of PONV (OR: 3.44, 95% CI: 1.67-5.20; p < 0.01) in 94 PSM patients. Besides, NLR was positively correlated with the PONV score (r = 0.534, p < 0.001). In the receiver-operating characteristic (ROC) curve analysis, an NLR with an optimal cutoff value of 1.59 predicted severe PONV with a sensitivity of 72% and specificity of 81%. The NLR was an independent risk factor for the presence of PONV, and a high NLR tends to be positively associated with the severity of PONV after laparoscopic gastrectomy.

Effect of multi-platform extended care on postoperative self-efficacy and quality of life in patients with osteoporotic vertebral compressive fracture.

OBJECTIVES: This study analyzed the effect of multi-platform extended care on postoperative self-efficacy and quality of life in patients with osteoporotic vertebral compressive fracture (OVCF). METHODS: 162 OVCF patients who underwent percutaneous vertebroplasty (PVP) or percutanous kyphoplasty (PKP) surgery in our hospital from January 2018 to June 2019 were classified into a control group (n=78) and an observation group (n=84) based on the admission time. The control group was given conventional health guidance and follow-up by telephone, and the observation group got multi-platform extended care. The postoperative incidence of re-fracture, Oswestry dysfunction index (ODI) before and after intervention, self-efficacy and quality of life were compared between the two groups. RESULTS: Incidence of re-fracture in the observation group was higher than that of the control group (P<0.05). The ODI scores of the two groups 3, 6, and 12 months after operation were lower than those on discharge (P<0.05), and the observation group had lower OD scores than the control group 6 and 12 months after operation (P<0.05). The self-efficacy scores of the two groups 6 months after discharge were higher than that on discharge (P<0.05), and the index in the observation group was higher than that of the control group (P<0.05). In addition, the scores of all dimensions of quality of life in two groups 6 months of discharge were higher than those on discharge (P<0.05), and the scores in the observation group were higher than those of the control group (P<0.05). CONCLUSION: Multi-platform extended care can effectively reduce the risk of postoperative re-fracture in OVCF patients, facilitate the improvement of patients' lumbar function, self-efficacy, and quality of life, and improve the prognosis of patients, which is worthy of clinical promotion.

Decorated Au NPs on agar modified Fe3O4 NPs: Investigation of its catalytic performance in the degradation of methylene orange, and anti-human breast carcinoma properties.

This work describes an eco-friendly approach for in situ immobilization of Au nanoparticles on the surface of Fe3O4 nanoparticles, with help of Agar and ultrasound irradiations, without using any toxic reducing and capping agents. The structure, morphology, and physicochemical properties were characterized by various analytical techniques such as Fourier transformed infrared spectroscopy (FT-IR), field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), energy dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD), inductively coupled plasma (ICP) and vibrating sample magnetometer (VSM). The desired catalyst showed great efficiency in the reductive degradation of methylene orange (MO) dye over NaBH4 at room temperature. The MO was fully reduced in only 70 s and achieved rate constant of 9.6 × 10-2 s-1. The catalyst was reused for 10 runs without significant loss in catalytic activity. Cell viability of Fe3O4/agar/Au NPs was very low against breast adenocarcinoma (MCF7), breast carcinoma (Hs 578Bst), infiltrating ductal cell carcinoma (Hs 319.T), and metastatic carcinoma (MDA-MB-453) cell lines without any cytotoxicity on the normal cell line. According to the above findings, the Fe3O4/agar/Au NPs may be administrated for the treatment of several types of human breast carcinoma in humans.

FAM83D promotes epithelial-mesenchymal transition, invasion and cisplatin resistance through regulating the AKT/mTOR pathway in non-small-cell lung cancer.

PURPOSE: FAM83D has been proposed to act as an oncoprotein in several types of human cancer. Its role and mode of action in human non-small cell lung cancer (NSCLC) metastasis and its impact on chemotherapy are as yet, however, poorly understood. METHODS: FAM83D expression was measured in NSCLC cells and normal lung epithelial cells, as well as in primary NSCLC tissues and corresponding adjacent non-cancerous tissues, using qRT-PCR, Western blotting and immunohistochemistry. FAM83D was stably overexpressed in BEAS2B cells or silenced in A549 and H1299 cells using retroviral or lentiviral vectors. The growth capacity of NSCLC cells was evaluated using MTT and colony formation assays. Epithelial-mesenchymal transition (EMT) was assessed using Western blotting and immunofluorescence. NSCLC cell invasive capacities were assessed using scratch wound healing and Boyden chamber assays. NSCLC cell viability in response to cisplatin treatment was assessed using MTT assays in vitro and a xenograft model in vivo. RESULTS: We found that FAM83D expression levels were significantly elevated in NSCLC cells and tissues, and positively correlated with tumor progression and a poor prognosis. Exogenous FAM83D overexpression promoted, while FAM83D silencing inhibited NSCLC cell proliferation, EMT and invasion. FAM83D silencing also reduced cisplatin resistance. Concordantly, we found that NSCLC patients with a low FAM83D expression benefited most from chemotherapy. Mechanistically, we found that FAM83D activated the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway. Pharmacological treatment with either AKT or mTOR inhibitors reverted FAM83D-induced tumorigenic phenotypes. CONCLUSIONS: Our results suggest a role of FAM83D in NSCLC development. In addition, our results indicate that NSCLC patients exhibiting FAM83D overexpression are likely to benefit from AKT and/or mTOR inhibitor treatment.

Fabrication and characterization of solid lipid nano-formulation of astraxanthin against DMBA-induced breast cancer via Nrf-2-Keap1 and NF-kB and mTOR/Maf-1/PTEN pathway.

In the current experimental study, we scrutinized the chemoprotective effect of astraxanthin against the 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast cancer via Nrf-2-Keap1 and NF-kB and mTOR/Maf-1/PTEN pathway. The double emulsion solvent displacement method was used for the preparation of astraxanthin solid lipid nanoparticles (SLN). SLNs were appraised for entrapment, potential, size, drug-release performance, and gastric stability. DMBA (8 mg/kg) was used for the induction of breast cancer. Tumor weight, body weight, and tumor incidence were estimated at a regular interval. Different biochemical parameters such as Na+/K+, Ca2+, and Mg2+ activity, antioxidant, lipid, glycoprotein, phase I and II biotransformation enzymes, mitochondrial TCA cycle, and carbohydrate metabolizing enzymes were estimated. Keap1-Nrf-2, associated HO-1, and NF-kB expressions were estimated. Moreover, it estimated the mRNA expression of LXR (α,ß), HMG-CoAR, PTEN, Maf1, PI3K, mTOR, Akt, FASN, and ACC1. AX-SLN reduced the tumor incidence, tumor weight, and increased the body weight. AX-SLN exhibited the protective effect against the LPO, enzymic (SOD, CuZnSOD, MnSOD, GPx, and CAT), and nonenzymic (GSH) in the serum, mammary gland, renal, and hepatic tissues. AX-SLN reduced the p-AKT which is accountable for the reduction in the NF-kB expression and also reduced the expression of Keap1 and NF-kB along with increasing the expression of HO-1 and Nrf-2. Further, AX-SLN significantly altered the mRNA of LXR (α,ß), HMG-CoAR, PTEN, Maf1, PI3K, mTOR, Akt, FASN, and ACC1. On the basis of the results, we can conclude that AX-SLN inhibits the mammary gland carcinogenesis via Nrf-2-Keap1, NF-kB, and mTOR/Maf-1/PTEN pathway.

Driving better and safer HER2-specific CARs for cancer therapy.

Given the clinical efficacy of chimeric antigen receptor (CAR)-based therapy in hematological malignancies, CAR T-cell therapy for a number of solid tumors has been actively investigated. Human epidermal growth factor receptor 2 (HER2) is a well-established therapeutic target in breast, as well as other types of cancer. However, HER2 CAR T cells pose a risk of lethal toxicity including cytokine release syndrome from "on-target, off-tumor" recognition of HER2. In this review, we summarize the development of conventional HER2 CAR technology, the alternative selection of CAR hosts, the novel HER2 CAR designs, clinical studies and toxicity. Furthermore, we also discuss the main strategies for improving the safety of HER2 CAR-based cancer therapies.

Potential therapeutic strategy for gastric cancer peritoneal metastasis by NKG2D ligands-specific T cells.

PURPOSE: Despite advancements in its treatment, gastric cancer continues to be one of the leading causes of cancer deaths worldwide. Adoptive transfer of chimeric antigen receptor-modified T cells is a promising antitumor therapy for many cancers. The purpose of this study was to construct a chimeric receptor linking the extracellular domain of NKG2D to the CD28 and CD3zeta chain intracellular domains to target gastric cancers that expressed NKG2D ligands. METHODS: Expression of NKG2D ligands including MICA, MICB, and ULBP1-3 in a gastric cancer cell line and primary gastric cancer cells from ascites samples were analyzed using flow cytometry. Co-culture experiments were performed by incubating chNKG2D T cells with gastric cancer cell lines and with primary human gastric cancer cells isolated from ascites and by measuring cytokine and chemokine release and cytotoxicity. RESULTS: Gastric cancer cell lines and ascites-derived primary human gastric cancer cells expressed high levels of MICA, MICB, and ULBP2. ChNKG2D T cells secreted proinflammatory cytokines and chemokines when cultured with these cancer cells. In addition, chNKG2D T cells lysed gastric cancer cell lines and the ascites-derived primary human gastric cancer cells. CONCLUSION: These data indicate that treatment with chNKG2D-expressing T cells is a potential immunotherapy for gastric cancer with peritoneal metastasis.

Evaluation of biomarker changes after administration of various neoadjuvant chemotherapies in breast cancer.

To assess the changes in estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and Ki-67 expression in breast cancer patients after various neoadjuvant chemotherapies. Data from 138 locally advanced breast cancer patients with histological diagnoses were reviewed. Seventy patients (group 1) were given 4 cycles of 500 mg/m(2) cyclophosphamide and 50 mg/m(2) pirarubicin every 21 days. Sixty-eight patients (group 2) were given 4 cycles of 500 mg/m(2) cyclophosphamide and 75 mg/m(2) docetaxel every 21 days. The biomarker changes of the operated tumor tissues were compared with the initial core biopsies. ER, PR, HER2 and Ki-67 expression changed by 28.6%, 22.9%, 17.1% and 54.3%, respectively, after neoadjuvant chemotherapy in group 1 and 16.2%, 22.1%, 13.2% and 70.6%, respectively, after neoadjuvant chemotherapy in group 2. There were significant differences between the groups regarding ER and Ki-67 status changes, and these changes can be used to inform treatment strategies.

Construction and evaluation of a novel humanized HER2-specific chimeric receptor.

INTRODUCTION: The human epidermal growth factor receptor 2 (HER2) represents one of the most studied tumor-associated antigens (TAAs) for cancer immunotherapy. The monoclonal antibody (mAb) trastuzumab has improved the outcomes of patients with HER2+ breast cancer. However, a large number of HER2+ tumors are not responsive to, or become resistant to, trastuzumab-based therapy, and thus more effective therapies targeting HER2 are needed. METHODS: HER2-specific T cells were generated by the transfer of genes that encode chimeric antigen receptor (CAR). Using a multistep overlap extension PCR method, we constructed a novel, humanized HER2 CAR-containing, chA21 single-chain variable fragment (scFv) region of antigen-specific mAb and T-cell intracellular signaling chains made up of CD28 and CD3ζ. An interferon γ and interleukin 2 enzyme-linked immunosorbent assay and a chromium-51 release assay were used to evaluate the antitumor immune response of CAR T cells in coculture with tumor cells. Furthermore, SKBR3 tumor-bearing nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice were treated with HER2 CAR T cells to evaluate antitumor activity. Human CD3+ T cell accumulation in tumor xenograft was detected by immunohistochemistry. RESULTS: chA21-28z CAR was successfully constructed, and both CD4+ and CD8+ T cells were transduced. The expanded HER2 CAR T cells expressed a central memory phenotype and specifically reacted against HER2+ tumor cell lines. Furthermore, the SKBR3 tumor xenograft model revealed that HER2 CAR T cells significantly inhibited tumor growth in vivo. Immunohistochemical analysis showed robust accumulation of human CD3+ T cells in regressing SKBR3 lesions. CONCLUSIONS: The results of this study show that novel chA21 scFv-based, HER2-specific CAR T cells not only recognized and killed HER2+ breast and ovarian cancer cells ex vivo but also induced regression of experimental breast cancer in vivo. Our data support further exploration of the HER2 CAR T-cell therapy for HER2-expressing cancers.

Aberrant BLID expression is associated with breast cancer progression.

In our previous study, we have found that BH3-like motif containing, cell death inducer (BLID) was a tumor suppressor in breast cancer, and its downregulation was correlated with both poor disease-free and overall survival. In the present study, we aimed to explore the possible role of BLID in breast cancer progression. We found that BLID was strongly expressed in all normal breast tissues, and it became lower and wreaker gradually in the progression from normal, UDH (usual ductal hyperplasia), ADH (atypical ductal hyperplasia), and DCIS (ductal carcinoma in situ) to breast cancer. Statistical analysis demonstrated significant different BLID expressions between proliferative and cancerous breast lesions. Our data suggested that loss of BLID may contribute to the progression of intraductal proliferation lesions to breast cancer. Our finding gives a new clue that BLID might be a potential indicator for progression of breast cancer in the future.

Identification of novel variants of metadherin in breast cancer.

Metadherin (MTDH, also known as AEG-1, and Lyric) has been demonstrated to play a potential role in several significant aspects of tumor progression. It has been reported that overexpression of MTDH is associated with progression of disease and poorer prognosis in breast cancer. However, there are no studies to date assessing variants of the MTDH gene and their potential relationship with breast cancer susceptibility. Thus, we investigated all variants of the MTDH gene and explored the association of the variants with breast cancer development. Our cohort consisted of full-length gene sequencing of 108 breast cancer cases and 100 healthy controls; variants were detected in 11 breast cancer cases and 13 controls. Among the variants detected, 9 novel variants were discovered and 2 were found to be associated with the susceptibility of breast cancer. However, additional studies need to be conducted in larger sample sizes to validate these findings and to further investigate whether these variants are prognostic in breast cancer patients.