FAT1 upregulation is correlated with an immunosuppressive tumor microenvironment and predicts unfavorable outcome of immune checkpoint therapy in non-small cell lung cancer.

Background: Previous studies found that FAT1 was recurrently mutated and aberrantly expressed in multiple cancers, and the loss function of FAT1 promoted the formation of cancer-initiating cells in several cancers. However, in some types of cancer, FAT1 upregulation could lead to epithelial-mesenchymal transition (EMT). The role of FAT1 in cancer progression, which appears to be cancer-type-specific, is largely unknown. Methods: QRT-PCR and immunochemistry were used to verify the expression of FAT1 in non-small cell lung cancer (NSCLC). QRT-PCR and Western blot were used to detect the influence of siFAT1 knockdown on the expression of potential targets of FAT1 in NSCLC cell lines. GEPIA, KM-plotter, CAMOIP, and ROC-Plotter were used to evaluate the association between FAT1 and clinical outcomes based on expression and clinical data from TCGA and immune checkpoint inhibitors (ICI) treated cohorts. Results: We found that FAT1 upregulation was associated with the activation of TGF-ß and EMT signaling pathways in NSCLC. Patients with a high FAT1 expression level tend to have a poor prognosis and hard to benefit from ICI therapy. Genes involved in TGF-ß/EMT signaling pathways (SERPINE1, TGFB1/2, and POSTN) were downregulated upon knockdown of FAT1. Genomic and immunologic analysis showed that high cancer-associated fibroblast (CAF) abundance, decreased CD8+ T cells infiltration, and low TMB/TNB were correlated with the upregulation of FAT1, thus promoting an immunosuppressive tumor microenvironment (TME) which influence the effect of ICI-therapy. Conclusion: Our findings revealed the pattern of FAT1 upregulation in the TME of patients with NSCLC, and demonstrated its utility as a biomarker for unfavorable clinical outcomes, thereby providing a potential therapeutic target for NSCLC treatment.

Coronary Artery Fistula and Severe Coronary Artery Stenosis: A Case Report and an Insight for Potential Pathogenesis of Coronary Artery Atherosclerosis.

Coronary artery fistulae (CAF) are a rare anomaly characterized by abnormal connections between a coronary artery and a cardiac chamber or a great vessel, with most patients remaining asymptomatic. Despite being predisposed to severe complications like heart failure, patients with CAF infrequently experience severe stenosis in the coronary artery. This study delineates a case involving a 46-year-old male presenting with a fistula bridging the right coronary artery (RCA) and right atrium (RA), manifesting a pronounced 99% stenosis at the right extremity of the coronary artery proximal to the fistula. Concurrently, the individual exhibits six conventional risk factors: age over 40, male gender, hypertension, diabetes, smoking, and hypertriglyceridemia. Following pharmaceutical intervention, the patient was discharged and subjected to extended follow-up. This case highlights the dual processes of "accelerating damage" and "retarding renewal" in the progression of atherosclerosis. Factors such as shear stress, smoking, and hypertension are posited to expedite endothelial cell damage, while aging and diabetes may impede the renewal and repair of these cells. Together with the concept of secondary atherosclerotic plaque healing, this case prompts the introduction of a "Double Endothelial Healings" hypothesis, proposing a potential pathogenetic mechanism for coronary artery atherosclerosis.

Cancer-associated fibroblasts: protagonists of the tumor microenvironment in gastric cancer.

Enhanced knowledge of the interaction of cancer cells with their environment elucidated the critical role of tumor microenvironment in tumor progression and chemoresistance. Cancer-associated fibroblasts act as the protagonists of the tumor microenvironment, fostering the metastasis, stemness, and chemoresistance of cancer cells and attenuating the anti-cancer immune responses. Gastric cancer is one of the most aggressive cancers in the clinic, refractory to anti-cancer therapies. Growing evidence indicates that cancer-associated fibroblasts are the most prominent risk factors for a poor tumor immune microenvironment and dismal prognosis in gastric cancer. Therefore, targeting cancer-associated fibroblasts may be central to surpassing resistance to conventional chemotherapeutics, molecular-targeted agents, and immunotherapies, improving survival in gastric cancer. However, the heterogeneity in cancer-associated fibroblasts may complicate the development of cancer-associated fibroblast targeting approaches. Although single-cell sequencing studies started dissecting the heterogeneity of cancer-associated fibroblasts, the research community should still answer these questions: "What makes a cancer-associated fibroblast protumorigenic?"; "How do the intracellular signaling and the secretome of different cancer-associated fibroblast subpopulations differ from each other?"; and "Which cancer-associated fibroblast subtypes predominate specific cancer types?". Unveiling these questions can pave the way for discovering efficient cancer-associated fibroblast targeting strategies. Here, we review current knowledge and perspectives on these questions, focusing on how CAFs induce aggressiveness and therapy resistance in gastric cancer. We also review potential therapeutic approaches to prevent the development and activation of cancer-associated fibroblasts via inhibition of CAF inducers and CAF markers in cancer.

Fibroblast regulates angiogenesis in assembled oral cancer organoid: A possible role of NNMT.

OBJECTIVE: Tumour angiogenesis is affected by various cell types in the tumour microenvironment (TME), including cancer cells and cancer-associated fibroblasts (CAFs). Here, an assembled organoid model was generated to investigate the mechanism by which the TME regulates angiogenesis in oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Secretion of vascular endothelial growth factor-A (VEGFA) was analysed to compare the proangiogenic properties of OSCC cells and corresponding CAFs. Cell aggregates consisting of endothelial cells (ECs), CAFs and cancer cells were generated to construct assembled organoids. Nicotinamide N-methyltransferase (NNMT) was pharmacologically or genetically inhibited to block the activation of CAFs. ATAC-seq was employed to test the transcriptional network of fibroblasts overexpressing NNMT. RESULTS: Compared with cancer cells, CAFs secreted more VEGFA. Coculture with CAFs more effectively promoted the sprouting of ECs. Blockade of CAF activation via inhibition of NNMT drastically reduced the expression of CD31 in the assembled organoids. Overexpression of NNMT enhanced the transcription of genes related to angiogenesis in fibroblasts. Specifically, NNMT orchestrated the enrichment of the transcription factor JUNB at the promoter of VEGFA. CONCLUSIONS: We clarify that stromal NNMT enables the steady reproduction of angiogenesis in assembled oral cancer organoids, providing a novel target for exploiting antiangiogenic therapy.

Combined intake of caffeine and low-dose glucose to reduce exercise-related hypoglycaemia in individuals with type 1 diabetes on ultra-long-acting insulin degludec: A randomized, controlled, double-blind, cross-over trial.

AIM: To evaluate whether caffeine combined with a moderate amount of glucose reduces the risk for exercise-related hypoglycaemia compared with glucose alone or control in adult people with type 1 diabetes using ultra-long-acting insulin degludec. MATERIALS AND METHODS: Sixteen participants conducted three aerobic exercise sessions (maximum 75 min) in a randomized, double-blind, cross-over design. Thirty minutes before exercise, participants ingested a drink containing either 250 mg of caffeine + 10 g of glucose + aspartame (CAF), 10 g of glucose + aspartame (GLU), or aspartame alone (ASP). The primary outcome was time to hypoglycaemia. RESULTS: There was a significant effect of the condition on time to hypoglycaemia (χ2 = 7.674, p = .0216). Pairwise comparisons revealed an 85.7% risk reduction of hypoglycaemia for CAF compared with ASP (p = .044). No difference was observed between GLU and ASP (p = .104) or between CAF and GLU (p = .77). While CAF increased glucose levels during exercise compared with GLU and ASP (8.3 ± 1.9 mmol/L vs. 7.7 ± 2.2 mmol/L vs. 5.8 ± 1.4 mmol/L; p < .001), peak plasma glucose levels during exercise did not differ between CAF and GLU (9.3 ± 1.4 mmol/L and 9.1 ± 1.6 mmol/L, p = .80), but were higher than in ASP (6.6 ± 1.1 mmol/L; p < .001). The difference in glucose levels between CAF and GLU was largest during the last 15 min of exercise (p = .002). Compared with GLU, CAF lowered perceived exertion (p = .023). CONCLUSIONS: Pre-exercise caffeine ingestion combined with a low dose of glucose reduced exercise-related hypoglycaemia compared with control while avoiding hyperglycaemia.

All-solid-state 3-µm single-frequency Er:CaF2 laser with a stable and switchable wavelength.

We have demonstrated a 3-µm all-solid-state single-frequency laser with a stable center frequency and a switchable wavelength using the intra-cavity Fabry-Perot etalon method. Experimentally, the central wavelengths of the laser for the single-longitudinal mode are 2728 and 2794 nm, with maximum output powers of 268 and 440 mW, respectively. The corresponding single-longitudinal mode linewidths are 25 and 11 MHz. In particular, the central wavelengths of the single-longitudinal mode laser remain almost constant as the incident pump power increases. To the best of our knowledge, this study represents the first instance of using a laser diode to directly pump Er:CaF2 block single crystals for single-frequency lasers in the 3 µm region. Additionally, it achieves the highest output power of a 3-µm all-solid-state single-longitudinal mode.

Cancer-associated fibroblasts drive colorectal cancer cell progression through exosomal miR-20a-5p-mediated targeting of PTEN and stimulating interleukin-6 production.

BACKGROUND: This study evaluated the clinical relevance of a set of five serum-derived circulating microRNAs (miRNAs) in colorectal cancer (CRC). Additionally, we investigated the role of miR-20a-5p released by exosomes derived from cancer-associated fibroblasts (CAFs) in the context of CRC. METHODS: The expression levels of five circulating serum-derived miRNAs (miR-20a-5p, miR-122-5p, miR-139-3p, miR-143-5p, and miR-193a-5p) were quantified by real-time quantitative PCR (RT-qPCR), and their associations with clinicopathological characteristics in CRC patients were assessed. The diagnostic accuracy of these miRNAs was determined through Receiver Operating Characteristic (ROC) curve analysis. CAFs and normal fibroblasts (NFs) were isolated from tissue samples, and subsequently, exosomes derived from these cells were isolated and meticulously characterized using electron microscopy and Western blotting. The cellular internalization of fluorescent-labeled exosomes was visualized by confocal microscopy. Gain- and loss-of-function experiments were conducted to elucidate the oncogenic role of miR-20a-5p transferred by exosomes derived from CAFs in CRC progression. The underlying mechanisms were uncovered through luciferase reporter assay, Western blotting, enzyme-linked immunosorbent assays, as well as proliferation and migration assays. RESULTS: The expression levels of serum-derived circulating miR-20a-5p and miR-122-5p were significantly higher in CRC and were positively correlated with advanced stages of tumorigenesis and lymph node metastasis (LNM). In contrast, circulating miR-139-3p, miR-143-5p, and miR-193a-5p were down-regulated in CRC and associated with early tumorigenesis. Except for miR-139-3p, they showed a negative correlation with LNM status. Among the candidate miRNAs, significantly elevated levels of miR-20a-5p were observed in both cellular and exosomal fractions of CAFs. Our findings indicated that miR-20a-5p induces the expression of EMT markers, partly by targeting PTEN. Exosomal miR-20a secreted by CAFs emerged as a key factor enhancing the proliferation and migration of CRC cells. The inhibition of miR-20a impaired the proliferative and migratory potential of CAF-derived exosomes in SW480 CRC cells, suggesting that the oncogenic effects of CAF-derived exosomes are mediated through the exosomal transfer of miR-20a. Furthermore, exosomes originating from CAFs induced increased nuclear translocation of the NF-kB p65 transcription factor in SW480 CRC cells, leading to increased interleukin-6 (IL-6) production. CONCLUSIONS: We established a set of five circulating miRNAs as a non-invasive biomarker for CRC diagnosis. Additionally, our findings shed light on the intricate mechanisms underpinning the oncogenic impacts of CAF-derived exosomes and underscore the pivotal role of miR-20a-5p in CRC progression.

TSPAN8+ myofibroblastic cancer-associated fibroblasts promote chemoresistance in patients with breast cancer.

Cancer-associated fibroblasts (CAFs) are abundant stromal cells in the tumor microenvironment that promote cancer progression and relapse. However, the heterogeneity and regulatory roles of CAFs underlying chemoresistance remain largely unclear. Here, we performed a single-cell analysis using high-dimensional flow cytometry analysis and identified a distinct senescence-like tetraspanin-8 (TSPAN8)+ myofibroblastic CAF (myCAF) subset, which is correlated with therapeutic resistance and poor survival in multiple cohorts of patients with breast cancer (BC). TSPAN8+ myCAFs potentiate the stemness of the surrounding BC cells through secretion of senescence-associated secretory phenotype (SASP)-related factors IL-6 and IL-8 to counteract chemotherapy. NAD-dependent protein deacetylase sirtuin 6 (SIRT6) reduction was responsible for the senescence-like phenotype and tumor-promoting role of TSPAN8+ myCAFs. Mechanistically, TSPAN8 promoted the phosphorylation of ubiquitin E3 ligase retinoblastoma binding protein 6 (RBBP6) at Ser772 by recruiting MAPK11, thereby inducing SIRT6 protein destruction. In turn, SIRT6 down-regulation up-regulated GLS1 and PYCR1, which caused TSPAN8+ myCAFs to secrete aspartate and proline, and therefore proved a nutritional niche to support BC outgrowth. By demonstrating that TSPAN8+SIRT6low myCAFs were tightly associated with unfavorable disease outcomes, we proposed that the combined regimen of anti-TSPAN8 antibody and SIRT6 activator MDL-800 is a promising approach to overcome chemoresistance. These findings highlight that senescence contributes to CAF heterogeneity and chemoresistance and suggest that targeting TSPAN8+ myCAFs is a promising approach to circumvent chemoresistance.

Stabilizing tumor resident mast cells restores T cell infiltration and sensitizes sarcomas to PD-L1 inhibition.

PURPOSE: To explore the cellular crosstalk of tumor resident mast cells (MCs) in controlling the activity of cancer-associated fibroblasts (CAFs) to overcome TME abnormalities, enhancing the efficacy of immune checkpoint inhibitors (ICIs) in sarcoma. EXPERIMENTAL DESIGN: We used a coculture system followed by further validation in mouse models of fibrosarcoma and osteosarcoma with or without administration of the MC stabilizer and antihistamine ketotifen. To evaluate the contribution of ketotifen in sensitizing tumors to therapy, we performed combination studies with doxorubicin chemotherapy and anti-PD-L1 (B7-H1, clone 10F.9G2) treatment. We investigated the ability of ketotifen to modulate the TME in human sarcomas in the context of a repurpose phase II clinical trial. RESULTS: Inhibition of MC activation with ketotifen successfully suppressed CAF proliferation and stiffness of the extracellular matrix accompanied by an increase in vessel perfusion in fibrosarcoma and osteosarcoma as indicated by ultrasound shear wave elastography imaging. The improved tissue oxygenation increased the efficacy of chemo-immunotherapy, supported by enhanced T cell infiltration and acquisition of tumor antigen-specific memory. Importantly, the effect of ketotifen in reducing tumor stiffness was further validated in sarcoma patients highlighting its translational potential. CONCLUSIONS: Our study suggests the targeting of MCs with clinically administered drugs, such as antihistamines, as a promising approach to overcome resistance to immunotherapy in sarcomas.

Clinical Evaluation of Coronally Advanced Flap with or without a Platelet-Rich Fibrin Membrane for the Root Coverage.

Aim: To evaluate "coronally advanced flap" with or without "a platelet-rich fibrin membrane for the root coverage." Materials and Methods: All the clinical parameters were assessed at different time intervals (at baseline, 1, 3, and 6 months) in both experimental and control group. Following "clinical parameters" were recorded using "UNC-15" "Probe-Plaque Index (PI)" (Silness and Loe, 1964), "Gingival Index" (GI) (Loe and Silness, 1963), "Recession depth (RD)," "Recession width (RW)," "Clinical attachment level (CAL)," and "Width of keratinized gingiva (WKG)". Results: At final evaluation (i.e., mean change from baseline to 6 months), "the decrease in Plaque Index was 2.5% higher in Group B (66.0%) as compared to Group A (63.5%). The decrease in Gingival Index was 6.1% higher in Group B (91.4%) as compared to Group A (85.3%), and the decrease in recession width was 4.0% higher in Group B (75.2%) as compared to Group A (71.2%). The decrease in clinical attachment level was 4.4% higher in Group B (53.2%) as compared to Group A (48.4%). The increase in width of keratinized gingiva was 1.9% higher in Group A (28.8%) as compared to Group B (26.9%)." Conclusion: The controlled, randomized, split mouth design showed that CAF surgery, either by alone or in combination with PRF, is an efficient treatment method for covering denuded roots. "This design was used to treat bilateral isolated Miller's class I and II recessions in gingival part. When compared to the CAF approach, the results from a combination of CAF and PRF after a 6-month period showed additional advantages in addition to mean root coverage in the treatment of Miller's classes I and II recessions in gingival part."

Caffeic acid attenuates memory dysfunction and restores the altered activity of cholinergic, monoaminergic and purinergic in brain of cadmium chloride exposure rats.

Objectives This study aims to evaluate the neuroprotective effect of caffeic acid (CAF) against cadmium chloride (CdCl2) in rats via its effect on memory index as well as on altered enzymatic activity in the brain of CdCl2-induced neurotoxicity. Methods The experimental rats were divided into seven groups (n=6 rats per group) of healthy rats (group 1), CdCl2 -induced (CD) (3 mg/kg BW) rats (group 2), CD rats + Vitamin C (group 3), CD rats + CAF (10 and 20 mg/kg BW respectively) (group 4 & 5), and healthy rat + CAF (10 and 20 mg/kg BW respectively) (group 6 & 7). Thereafter, CdCl2 and CAF were administered orally to the experimental rats in group 2 to group 5 on daily basis for 14 days. Then, the Y-maze test was performed on the experimental rats to ascertain their memory index. Results CdCl2 administration significantly altered cognitive function, the activity of cholinesterase, monoamine oxidase, arginase, purinergic enzymes, nitric oxide (NOx), and antioxidant status of Cd rats (untreated) when compared with healthy rats. Thereafter, CD rats treated with vitamin C and CAF (10 and 20 mg/kg BW) respectively exhibited an improved cognitive function, and the observed altered activity of cholinesterase, monoamine oxidase, arginase, purinergic were restored when compared with untreated CD rats. Also, the level of brain NOx and antioxidant status were significantly (p<0.05) enhanced when compared with untreated CD rats. In the same vein, CAF administration offers neuro-protective effect in healthy rats vis-à-vis improved cognitive function, reduction in the activity of some enzymes linked to the progression of cognitive dysfunction, and improved antioxidant status when compared to healthy rats devoid of CAF. Conclusions This study demonstrated the neuroprotective effect of CAF against CdCl2 exposure and in healthy rats.

Surgical management of multiple coronary artery to coronary sinus fistulas with giant left circumflex artery and multivalvular infective endocarditis.

Coronary artery fistula (CAF) is characterized as a congenital or acquired abnormal communication between a coronary artery and any of the four chambers of the heart (coronary-cameral fistula) or great vessels (coronary arteriovenous fistula) bypassing the capillaries within myocardium. CAF is a rare disease, challenging to diagnose and treat depending on the anatomical location and type of the fistula and accompanying diseases. This study aims to report a case with multiple coronary artery to coronary sinus (CS) fistulas with giant left circumflex artery and multivalvular infective endocarditis.

Tumor cell-intrinsic epigenetic dysregulation shapes cancer-associated fibroblasts heterogeneity to metabolically support pancreatic cancer.

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) involves a significant accumulation of cancer-associated fibroblasts (CAFs) as part of the host response to tumor cells. The origins and functions of transcriptionally diverse CAF populations in PDAC remain poorly understood. Tumor cell-intrinsic genetic mutations and epigenetic dysregulation may reshape the TME; however, their impacts on CAF heterogeneity remain elusive. SETD2, a histone H3K36 trimethyl-transferase, functions as a tumor suppressor. Through single-cell RNA sequencing, we identify a lipid-laden CAF subpopulation marked by ABCA8a in Setd2-deficient pancreatic tumors. Our findings reveal that tumor-intrinsic SETD2 loss unleashes BMP2 signaling via ectopic gain of H3K27Ac, leading to CAFs differentiation toward lipid-rich phenotype. Lipid-laden CAFs then enhance tumor progression by providing lipids for mitochondrial oxidative phosphorylation via ABCA8a transporter. Together, our study links CAF heterogeneity to epigenetic dysregulation in tumor cells, highlighting a previously unappreciated metabolic interaction between CAFs and pancreatic tumor cells.

Machine learning developed a fibroblast-related signature for predicting clinical outcome and drug sensitivity in ovarian cancer.

Ovarian cancer (OC) is the leading cause of gynecological cancer death. Cancer-associated fibroblasts (CAF) is involved in wound healing and inflammatory processes, tumor occurrence and progression, and chemotherapy resistance in OC. GSE184880 dataset was used to identify CAF-related genes in OC. CAF-related signature (CRS) was constructed using integrative 10 machine learning methods with the datasets from the Cancer Genome Atlas, GSE14764, GSE26193, GSE26712, GSE63885, and GSE140082. The performance of CRS in predicting immunotherapy benefits was verified using 3 immunotherapy datasets (GSE91061, GSE78220, and IMvigor210) and several immune calculating scores. The Lasso + StepCox[forward] method-based predicting model having a highest average C index of 0.69 was referred as the optimal CRS and it had a stable and powerful performance in predicting clinical outcome of OC patients, with the 1-, 3-, and 5-year area under curves were 0.699, 0.708, and 0.767 in the Cancer Genome Atlas cohort. The C index of CRS was higher than that of tumor grade, clinical stage, and many developed signatures. Low CRS score demonstrated lower tumor immune dysfunction and exclusion score, lower immune escape score, higher PD1&CTLA4 immunophenoscore, higher tumor mutation burden score, higher response rate and better prognosis in OC, suggesting a better immunotherapy response. OC patients with low CRS score had a lower half maximal inhibitory concentration value of some drugs (Gemcitabine, Tamoxifen, and Nilotinib, etc) and lower score of some cancer-related hallmarks (Notch signaling, hypoxia, and glycolysis, etc). The current study developed an optimal CRS in OC, which acted as an indicator for the prognosis, stratifying risk and guiding treatment for OC patients.

Reductions of Arenes using a Magnesium-Dinitrogen Complex.

In this contribution, we present "Birch-type", and other reductions of simple arenes by the potassium salt of an anionic magnesium dinitrogen complex, [{K(TCHPNON)Mg}2(µ-N2)] (TCHPNON = 4,5-bis(2,4,6-tricyclohexylanilido)-2,7-diethyl-9,9-dimethyl-xanthene), which acts as a masked dimagnesium(I) diradical in these reactions. This reagent is non-hazardous, easy-to-handle, and readily provides access to 1,4-cyclohexadiene reduction products under relatively mild reaction conditions. This system works effectively to reduce benzene, naphthalene and anthracene through magnesium-bound "Birch-type" reduction intermediates. Cyclohexadiene products can be subsequently released from the magnesium centres by protonolysis with methanol. In contrast, the reduction of substituted arenes is less selective and involves competing reaction pathways. For toluene and 1,3,5-triphenylbenzene, the structural authentication of "Birch-type" reduction intermediates is conclusive, although the formation of corresponding 1,4-cyclohexadiene derivatives was low yielding. Reduction of anisole did not yield an isolable "Birch-type" intermediate, but instead gave a C-O activation product. Treating triphenylphosphine with [{K(TCHPNON)Mg}2(µ-N2)] resulted in the extrusion of both biphenyl and dinitrogen to afford a magnesium(II) phosphanide [{K(TCHPNON)Mg(µ-PPh2)}2]. Reduction of fluorobenzene proceeded via C‒F activation of the arene, and isolation of the magnesium(II) fluoride [{K(TCHPNON)Mg(µ-F)}2]. Finally, the two-electron reduction of 1,3,5,7-cyclooctatetraene (COT) with [{K(TCHPNON)Mg}2(µ-N2)] yielded a complex, [{K(TCHPNON)Mg}2(µ-COT)], incorporating the aromatic dianion (COT2-).

Cancer-associated fibroblasts-derived exosomal METTL3 promotes the proliferation, invasion, stemness and glutaminolysis in non-small cell lung cancer cells by eliciting SLC7A5 m6A modification.

Cancer-associated fibroblasts (CAFs) can promote the crosstalk between cancer cells and tumor microenvironment by exosomes. METTL3-mediated N6-methyladenine (m6A) modification has been proved to promote the progression of non-small cell lung cancer (NSCLC). Here, we focused on the impacts of CAFs-derived exosomes and METTL3-mediated m6A modification on NSCLC progression. Functional analyses were conducted using Cell Counting Kit-8, EdU, colony formation, sphere formation and transwell assays, respectively. Glutamine metabolism was evaluated by detecting glutamate consumption, and the production of intercellular glutamate and α-ketoglutarate (α-KG). qRT-PCR and western blotting analyses were utilized to measure the levels of genes and proteins. Exosomes were isolated by kits. The methylated RNA immunoprecipitation assay detected the m6A modification profile of Amino acid transporter LAT1 (SLC7A5) mRNA. The NSCLC mouse model was established to conduct in vivo experiments. We found that CAFs promoted the proliferation, invasion, stemness and glutaminolysis in NSCLC cells. METTL3 was enriched in CAFs and was packaged into exosomes. After knockdown of METTL3 in CAF exosomes, it was found the oncogenic effects of CAFs on NSCLC cells were suppressed. CAFs elevated m6A levels in NSCLC cells. Mechanistically, exosomal METTL3-induced m6A modification in SLC7A5 mRNA and stabilized its expression in NSCLC cells. Moreover, SLC7A5 overexpression abolished the inhibitory effects of exosomal METTL3-decreased CAFs on NSCLC cells. In addition, METTL3 inhibition in CAF exosomes impeded NSCLC growth in vivo. In all, CAFs-derived exosomal METTL3 promoted the proliferation, invasion, stemness and glutaminolysis in NSCLC cells by inducing SLC7A5 m6A modification.

Deciphering the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer.

Although heterogeneity of FAP+ Cancer-Associated Fibroblasts (CAF) has been described in breast cancer, their plasticity and spatial distribution remain poorly understood. Here, we analyze trajectory inference, deconvolute spatial transcriptomics at single-cell level and perform functional assays to generate a high-resolution integrated map of breast cancer (BC), with a focus on inflammatory and myofibroblastic (iCAF/myCAF) FAP+ CAF clusters. We identify 10 spatially-organized FAP+ CAF-related cellular niches, called EcoCellTypes, which are differentially localized within tumors. Consistent with their spatial organization, cancer cells drive the transition of detoxification-associated iCAF (Detox-iCAF) towards immunosuppressive extracellular matrix (ECM)-producing myCAF (ECM-myCAF) via a DPP4- and YAP-dependent mechanism. In turn, ECM-myCAF polarize TREM2+ macrophages, regulatory NK and T cells to induce immunosuppressive EcoCellTypes, while Detox-iCAF are associated with FOLR2+ macrophages in an immuno-protective EcoCellType. FAP+ CAF subpopulations accumulate differently according to the invasive BC status and predict invasive recurrence of ductal carcinoma in situ (DCIS), which could help in identifying low-risk DCIS patients eligible for therapeutic de-escalation.

Acute myocardial infarction due to giant coronary artery aneurysm and arteriovenous fistula: a challenging case report and review of the literature.

BACKGROUND: A coronary artery aneurysm (CAA) is an abnormal dilation of a coronary artery segment often accompanied by coronary artery fistula (CAF), leading to communication between a coronary artery and a cardiac chamber or a part of the coronary venous system. Both CAAs and CAFs can present with symptoms and signs of myocardial ischemia and infarction. CASE PRESENTATION: We describe the case of a 46-year-old woman with non-ST-elevation myocardial infarction (NSTEMI) caused by a "giant" CAA. Various imaging modalities revealed a thrombus-containing aneurysm located at the right-posterior cardiac border, with established arteriovenous communication with the distal part of left circumflex artery (LCx). After initial treatment with dual antiplatelet therapy, a relapse of pain was reported along with a new increase in troponin levels, electrocardiographic abnormalities, reduced left ventricular ejection fraction (LVEF) and thrombus enlargement. Surgical excision of the aneurysm was favored, revealing its true size of 6 cm in diameter. Τhe aneurysm was excised without complications. The patient remained asymptomatic during follow-up. CONCLUSIONS: Management of rare entities such as "giant" CAAs and CAFs can be challenging. Cases such as this can serve as precedents to facilitate treatment plans and develop consistent recommendations, emphasizing the importance of personalized strategies for future patients.

Pain and Post-traumatic Stress Disorder Symptoms: Dyadic Relationships Between Canadian Armed Forces Members/Veterans with Chronic Pain and their Offspring.

Chronic pain and mental health issues occur at higher rates in Veterans than the general population. One widely recognized mental health issue faced by Veterans is post-traumatic stress disorder (PTSD). Trauma symptoms and pain frequently co-occur and are mutually maintained due to shared mechanisms. Many Veterans are also parents. Parental physical and mental health issues significantly predict children's chronic pain and related functioning, which can continue into adulthood. Only one US-based study has examined pain in the offspring of Veterans, suggesting heightened risk for pain. Research to date has not examined the associations between trauma and pain, and the dyadic influences of these symptoms, among Veterans and their children. The current study aimed to describe pain characteristics in Canadian Armed Forces (CAF) Members/Veterans with chronic pain and their offspring (youth and adult children aged 9-38). Cross-lagged Panel Models (CLPM) were conducted to examine dyadic relationships between pain interference and trauma symptoms of CAF Members/Veterans and their offspring. Over half of adult offspring and over one quarter of youth offspring reported chronic pain. Results revealed effects between one's own symptoms of PTSD and pain interference. No significant effects of parents on offspring or offspring on parents were found. The findings highlight the interconnection between pain and PTSD consistent with mutual maintenance models, and a lack of significant interpersonal findings suggestive of resiliency in this unique population. PERSPECTIVE: We characterized chronic pain in offspring of Canadian Armed Forces Members/Veterans with chronic pain and examined dyadic relationships between PTSD symptoms and chronic pain interference. Findings revealed that PTSD symptoms and pain interference were related within Veterans and offspring, but no dyadic relationships were found, which could reflect resiliency.

Glyphosate-based herbicide worsens alterations induced by cafeteria diet on rat uterus.

Exposure to glyphosate-based herbicides (GBH) and consumption of cafeteria (CAF) diet, which are widespread in Western society, seem to be associated with endometrial hyperplasia (EH). Here, we aimed to evaluate the effects of a subchronic low dose of a GBH added to CAF diet on the rat uterus. Female Wistar rats were fed from postnatal day (PND)21 until PND240 with chow (Control) or CAF diet. Since PND140, rats also received GBH (2 mg of glyphosate/kg/day) or water through food, yielding four experimental groups: Control, CAF, GBH and CAF+GBH. On PND240, CAF and CAF+GBH animals showed an increased adiposity index. Respect to Control group, no changes on the serum levels of 17ß-estradiol and progesterone were found. However, progesterone levels were higher in CAF+GBH group than in CAF and GBH groups. In the uterus, both studied factors alone and in combination induced morphological and molecular changes associated with EH. Furthermore, the addition of GBH provoked an increased thickness of subepithelial stroma in rats fed with CAF diet. As a consequence of GBH exposure, CAF+GBH rats exhibited an increased density of abnormal gland area, considered preneoplastic lesions, as well as a reduced PTEN and p27 expression, both tumor suppressor molecules that inhibit cell proliferation, respect to Control rats. These results indicate that the addition of GBH exacerbates the CAF-effects on uterine lesions and that the PTEN/p27 signaling pathway seems to be involved. Further studies focusing on the interaction between unhealthy diets and environmental chemicals should be encouraged to better understand uterine pathologies.