Apoptosis Protein Research Articles

Evaluation of prognostic significance of histopathological characteristics and tumor-infiltrating lymphocytes for pancreatic cancer survival

With a 5-year survival of ˂ 10%, pancreatic cancer is one of the leading causes of cancer-related deaths. Given the role of the distribution of tumor-infiltrating lymphocyte (TILs) subtypes in the tumor and its microenvironment in predicting prognosis, the development of new targeted therapies based on T-cell adaptive response has gained considerable attention. This study aimed to examine the peritumoral spread of TILs and its relationship with other prognostic parameters and survival. This study included 60 patients with pancreatic cancer who had undergone surgery with follow-up between 2011 and 2021. Demographic characteristics, tumor histopathological features, peritumoral TILs counts, and intratumoral programmed cell death protein-1 (PD-1) and programmed death ligand − 1 (PD-L1) positivity were evaluated. Furthermore, overall survival and their efficacy in predicting survival according to TNM stage were analyzed. The number of cluster differentiation-3 positive (CD3 P) TILs increased with advancing pathological T stage. CD3 P and CD8 P TIL counts were higher in patients with peripancreatic fatty tissue invasion. Patients with PD-L1 positivity and higher TIL counts had better survival rates. PD-L1-negative patients with a low CD8 positive/total lymph node count (P/T) ratio had a longer survival. Moreover, patients with poorly differentiated tumors with low CD3 P/T and CD8 P/T ratios had a longer survival. The CD3 P/T and CD8 P/T ratios were compatible with the automatic and manual measurements. Age, tumor differentiation, N stage, and peritumoral TIL count and subtype, when evaluated together with the presence of PD-L1 in the tumor tissue, may have prognostic significance for survival in patients with pancreatic cancer.

OSU-T315 overcomes immunosuppression in triple-negative breast cancer by targeting the ILK/NF-κB signaling pathway to enhance immunotherapeutic efficacy

Triple negative breast cancer (TNBC) is an aggressive and immunogenic subtype of breast cancer. The absence of biomarker has given immune checkpoint inhibitors (ICIs) a broad prospect in this type of breast cancer. The infiltration of regulatory T cells (Tregs) expressing transcription factor forkhead box P3 (Foxp3) in the tumor microenvironment (TME) is the key factor leading to ICIs resistance. Therefore, elimination of tumor antigen-specific Tregs may be an important aspect of improving ICIs efficacy. In this study, it based on the Gene Expression Omnibus and The Cancer Genome Atlas database, along with in vivo and in vitro experimental models, to verified that the high expression of integrin-linked kinase (ILK) in TNBC is the key differential factor leading to the high infiltration of Foxp3+-Tregs in the TME. Then, we selected ILK-specific inhibitor, OSU-T315, to intervene in vitro and vivo. Importantly, we found that OSU-T315 blocked the secretion of CCL17/CCL22 in tumor cells by inhibiting the ILK/NF-κB pathway, resulting in the apoptosis of Foxp3+-Tregs and decreased programmed cell death-1 (PD-1) expression. Therefore, our findings indicate a novel mechanism of OSU-T315 with potential therapeutic application in TNBC.

TMED inhibition suppresses cell surface PD-1 expression and overcomes T cell dysfunction

BackgroundBlockade of the programmed cell death protein 1 (PD-1) immune checkpoint (ICB) is revolutionizing cancer therapy, but little is known about the mechanisms governing its expression on CD8 T cells....

Development of pituitary dysfunction and destructive thyroiditis is associated with better survival in non-small cell lung cancer patients treated with programmed cell death-1 inhibitors: a prospective study with immortal time bias correction

Development of pituitary dysfunction and destructive thyroiditis is associated with better survival in non-small cell lung cancer patients treated with programmed cell death-1 inhibitors: a prospective study with immortal time bias correction

Use of Anti-PD1 Blockade After Hedgehog Inhibitors or as First-Line Therapy for Gorlin Syndrome

This case series examines treatment with anti–programmed cell death 1 (PD1) immunotherapy for patients with basal cell nevus syndrome.

A B7-H3–Targeted CD28 Bispecific Antibody Enhances the Activity of Anti–PD-1 and CD3 T-cell Engager Immunotherapies

Abstract T-cell activation is a multistep process requiring T-cell receptor engagement by peptide–MHC complexes (Signal 1) coupled with CD28-mediated costimulation (Signal 2). Tumors typically lack expression of CD28 ligands, so tumor-specific Signal 1 (e.g., neoepitope presentation) without costimulation may be ineffective or even induce T-cell anergy. We designed the bispecific antibody XmAb808 to co-engage the tumor-associated antigen B7-H3 with CD28 to promote T-cell costimulation within the tumor microenvironment. XmAb808 costimulation was measured by its ability to activate and expand T cells and enhance T cell–mediated cancer cell killing in cocultures of human peripheral blood mononuclear cells and cancer cells and in mice engrafted with human peripheral blood mononuclear cells and tumor xenografts. XmAb808 avidly bound cancer cells and stimulated IL2 and IFNγ secretion from T cells cocultured with cancer cells engineered to deliver Signal 1 to T cells via a surface-expressed anti-CD3 antibody. XmAb808 enhanced expression of the antiapoptotic factor Bcl-xL and CD25, promoting survival and IL2-dependent expansion of T cells coupled with increased T cell–mediated cytotoxicity in vitro. XmAb808 combined with an EpCAM×CD3 bispecific antibody to enhance target cell killing through IL2-dependent expansion of CD25+ T cells. This combination also suppressed pancreatic tumor xenograft growth in mice. Furthermore, XmAb808 combined with an anti–programmed cell death protein 1 antibody to suppress breast tumor xenograft growth in mice. XmAb808 as monotherapy and in combination with an anti–programmed cell death protein 1 antibody is currently in clinical development in patients with advanced solid tumors. Our results suggest that XmAb808 may also combine with tumor antigen–targeted anti-CD3 (Signal 1) T-cell engagers.

Cell death in glioblastoma and the central nervous system.

Glioblastoma is the commonest and deadliest primary brain tumor. Glioblastoma is characterized by significant intra- and inter-tumoral heterogeneity, resistance to treatment and dismal prognoses despite decades of research in understanding its biological underpinnings. Encompassed within this heterogeneity and therapy resistance are severely dysregulated programmed cell death pathways. Glioblastomas recapitulate many neurodevelopmental and neural injury responses; in addition, glioblastoma cells are composed of multiple different transformed versions of CNS cell types. To obtain a greater understanding of the features underlying cell death regulation in glioblastoma, it is important to understand the control of cell death within the healthy CNS during homeostatic and neurodegenerative conditions. Herein, we review apoptotic control within neural stem cells, astrocytes, oligodendrocytes and neurons and compare them to glioblastoma apoptotic control. Specific focus is paid to the Inhibitor of Apoptosis proteins, which play key roles in neuroinflammation, CNS cell survival and gliomagenesis. This review will help in understanding glioblastoma as a transformed version of a heterogeneous organ composed of multiple varied cell types performing different functions and possessing different means of apoptotic control. Further, this review will help in developing more glioblastoma-specific treatment approaches and will better inform treatments looking at more direct brain delivery of therapeutic agents.

Spermine Synthase : A Potential Prognostic Marker for Lower-Grade Gliomas.

The objective of this study was to assess the relationship between spermine synthase (SMS) expression, tumor occurrence, and prognosis in lower-grade gliomas (LGGs). A total of 523 LGG patients and 1152 normal brain tissues were included as controls. Mann-Whitney U test was performed to evaluate SMS expression in the LGG group. Functional annotation analysis was conducted to explore the biological processes associated with high SMS expression. Immune cell infiltration analysis was performed to examine the correlation between SMS expression and immune cell types. The association between SMS expression and clinical and pathological features was assessed using Spearman correlation analysis. In vitro experiments were conducted to investigate the effects of overexpressing or downregulating SMS on cell proliferation, apoptosis, migration, invasion, and key proteins in the protein kinase B (AKT)/epithelialmesenchymal transition signaling pathway. The study revealed a significant upregulation of SMS expression in LGGs compared to normal brain tissues. High SMS expression was associated with certain clinical and pathological features, including older age, astrocytoma, higher World Health Organization grade, poor disease-specific survival, disease progression, non-1p/19q codeletion, and wild-type isocitrate dehydrogenase. Cox regression analysis identified SMS as a risk factor for overall survival. Bioinformatics analysis showed enrichment of eosinophils, T cells, and macrophages in LGG samples, while proportions of dendritic (DC) cells, plasmacytoid DC (pDC) cells, and CD8+ T cells were decreased. High SMS expression in LGGs may promote tumor occurrence through cellular proliferation and modulation of immune cell infiltration. These findings suggest the prognostic value of SMS in predicting clinical outcomes for LGG patients.

Computational identification of PDL1 inhibitors and their cytotoxic effects with silver and gold nanoparticles

Immunotherapy is a promising treatment for cancer that aims to boost the immune system’s response to cancer cells. This can be achieved by blocking Programmed cell death protein 1/Programmed death-ligand 1 (PD1/PDL1), which activates T cells. In this work, the aim was to find high-affinity drugs against PDL1 using computational tools and conjugate nanoparticles with them. The cytotoxic activity of the nanoparticle conjugated drugs was then tested. The screening of 100,000 drugs from the ZINC database and FDA-approved drugs was done computationally. The physicochemical properties and toxicity of the drugs were analyzed using SwissADME and ProTox-II, respectively. Silver nanoparticles (AgNPs) and gold nanoparticles (AuNPs) were synthesized using extracts of Catharanthus roseus flowers and Juglans regia shells, respectively. The characterization of AgNPs and AuNPs was performed using UV–Vis spectroscopy, X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). Their conjugation with the drugs Irinotecan, Imatinib, and Methotrexate was also confirmed using UV–Vis, FTIR, and Dynamic light scattering (DLS). The top screened drugs were ZINC1098661 and 3 FDA-approved drugs (Irinotecan, Imatinib, and Methotrexate). Docking studies revealed that Irinotecan had the highest binding affinity towards PDL1 when conjugated with silver nanoparticles (AgNPs) and gold nanoparticles (AuNPs). The Irinotecan-PDL1 complex was confirmed as the most stable through molecular dynamics simulations. The result of the methylthiazol tetrazolium (MTT) assay showed that conjugated AgNPs and AuNPs with Irinotecan had a higher toxic effect on the A549 cancer cell line than AgNPs and AuNPs conjugated with Imatinib. This study provides a promising avenue for further investigation and development of nanoparticle-drug conjugates as a potential cancer immunotherapy strategy.

Silibinin Induces Both Apoptosis and Necroptosis with Potential Anti-tumor Efficacy in Lung Cancer.

Lung cancer incidence is steadily on the rise, posing a growing threat to human health. The search for therapeutic drugs from natural active substance and elucidating their mechanism have been the focus of anti-tumor research. In our work, Silibinin (SiL) was chosen as a possible substance that could inhibit lung cancer. and its effects on inducing tumor cell death have been studied. CCK-8 analysis and morphological observation were used to assess the cytotoxic impacts of SiL on lung cancer cells in vitro. The alterations in mitochondrial membrane potential (MMP) and apoptosis rate of cells were detected by flow cytometry. The level of lactate dehydrogenase (LDH) release out of cells was measured. The expression changes of apoptosis or necroptosis-related proteins were detected using western blotting. Protein interactions among RIPK1, RIPK3 and MLKL were analyzed using the co-immunoprecipitation technique. In vivo, SiL was evaluated for its antitumor effects using LLC tumor-bearing mice with mouse lung cancer. With an increased dose of SiL, the proliferation ability of A549 cells was considerably inhibited, and the accompanying cell morphology changed. The results of flow cytometry showed that after SiL treatment, MMP levels decreased, and the proportion of cells undergoing apoptosis increased. The proteins associated with apoptosis were upregulated and activated. The amount of LDH released from the cells increased following SiL treatment, accompanied by augmented expression and phosphorylation levels of necroptosis-related proteins. The co-IP assay further confirmed necrosome formation induced by SiL. Furthermore, Necrosulfonamide (an MLKL inhibitor) increased the apoptotic rate of SiL-treated cells and aggravated the cytotoxic effect of SiL, indicating that necroptosis blockade could switch cell death to apoptosis and increase the inhibitory effect of SiL on A549 cells. In LLC-bearing mice, gastric administration of SiL significantly inhibited tumor growth. This study helped clarify the anti-tumor mechanism of SiL against lung cancer, elucidating its role in dual induction of apoptosis and necroptosis. In particular, necroptosis blockade could switch cell death to apoptosis and increase the inhibitory effect of SiL. Our work provided an experimental basis for the research on cell death induced by SiL and revealed its possible applications for improving the management of lung cancer.</p>.

Polydatin protects against articular cartilage degeneration by regulating autophagy mediated by the AMPK/mTOR signaling pathway.

Knee osteoarthritis (KOA) is one of the leading causes of disability. Polydatin has a potential effect on KOA treatment but the therapeutic mechanism is not clear. This study aims to investigate the therapeutic action of polydatin in KOA and its mechanism in activating autophagy via the AMP-activated protein kinase (AMPK)/mTOR signaling pathway. After a KOA rat model was established by anterior cruciate ligament transection surgery, model rats were treated with polydatin 40 mg/kg for 30 days. Subsequently, cartilage tissues were collected, and hematoxylin-eosin (HE), Safranin-O, and TUNEL staining, and western blotting were performed to evaluate the pathological damage and autophagy-related protein expression. Then, human chondrocyte C28/I2 cells were stimulated with lipopolysaccharide (LPS), and the effects of polydatin on C28/I2 cell viability, apoptosis, and autophagy-related protein expression were detected by MTT, Flow Cytometry, and western blot. In addition, an AMPK inhibitor (Dorsomorphin 2HCl) was used to probe the cell proliferation and apoptosis of polydatin-administered C28/I2 cells. Polydatin ameliorated the pathological damage in rat cartilage tissues and inhibited cell apoptosis in KOA rats. Meanwhile, in C28/I2 cells, polydatin promoted viability and reduced apoptosis. In addition, the protein expression of collagen II, LC3II/LC3I, Beclin-1, and p-AMPK/AMPK were upregulated, and p62 and p-mTOR/mTOR were downregulated by polydatin treatment. Interestingly, relative results showed that the protective effect of polydatin in LPS-stimulated-C28/I2 cells was blocked by the AMPK/mTOR inhibitor, dorsomorphin 2HCl. Our research showed that polydatin reduced apoptosis and activated autophagy both in vivo and in vitro by the AMPK/mTOR signaling pathway to protect against KOA, which provided the basis for further investigation into the potential therapeutic impact of polydatin on KOA.

Cisplatin- or Carboplatin-Based Chemotherapy Plus Pembrolizumab in Advanced Urothelial Cancer: Exploratory Analysis From the Phase 3 KEYNOTE-361 Study

IntroductionKEYNOTE-361 evaluated first-line pembrolizumab with and without platinum-based chemotherapy versus chemotherapy alone in advanced or metastatic urothelial carcinoma. The primary end points of progression-free survival (PFS) or overall survival (OS) were not met. Exploratory analysis of efficacy by platinum agent (cisplatin or carboplatin) is reported. Patients and MethodsEligible patients were randomly assigned 1:1:1 to receive pembrolizumab 200 mg intravenously every 3 weeks for ≤35 cycles with or without chemotherapy (gemcitabine with investigator's choice of either cisplatin or carboplatin) or chemotherapy alone. This exploratory subset analysis evaluated PFS and objective response rate (ORR) per RECIST v1.1 by blinded independent central review and OS for cisplatin- or carboplatin-based chemotherapy with versus without pembrolizumab for patients assigned to chemotherapy-containing arms of KEYNOTE-361. ResultsOf 1010 patients enrolled, 703 were assigned to receive a chemotherapy-containing regimen (n = 312 cisplatin based; n = 391 carboplatin based). Median follow-up was 31.3 months. For cisplatin-based arms, with versus without pembrolizumab, median OS was 20.1 versus 16.4 months (HR 0.88, 95% CI 0.67-1.15) and median PFS was 8.5 versus 7.1 months (HR 0.67, 0.51-0.89). ORR was 64.1% versus 48.7%, respectively. For carboplatin-based arms, with versus without pembrolizumab, median OS was 15.5 versus 12.3 months (HR 0.84, 95% CI 0.67-1.06) and median PFS was 8.0 versus 6.7 months (HR 0.86, 0.68-1.09). ORR was 47.2% versus 41.8%, respectively. Among patients in the cisplatin-based versus carboplatin-based chemotherapy alone arms, 55.8% versus 41.8% received a subsequent anti–programmed cell death protein 1/ligand 1 therapy. The addition of pembrolizumab did not significantly increase the incidence of adverse events reported. ConclusionResults suggest trends towards OS and PFS improvements with the addition of pembrolizumab to gemcitabine-platinum doublet over gemcitabine-platinum alone regardless of whether cisplatin or carboplatin was the chosen platinum agent. OS may have been influenced by active subsequent therapies. MicroAbstractUntil recently, the standard first-line treatment for advanced urothelial carcinoma included platinum-based chemotherapy containing either cisplatin or carboplatin. This exploratory analysis from the KEYNOTE-361 study describes efficacy outcomes with the addition of pembrolizumab to cisplatin- or carboplatin-based chemotherapy to determine if there are differences in clinical benefit between patients who received cisplatin-based versus carboplatin-based combination therapy.

Hypoxia-inducible factor-2α enhances neutrophil survival to promote cardiac injury following myocardial infarction.

Heart failure is a major cause of mortality following myocardial infarction. Neutrophils are among the first immune cells to accumulate in the infarcted region. Although beneficial functions of neutrophils in heart injury are now appreciated, neutrophils are also well known for their ability to exacerbate inflammation and promote tissue damage. Myocardial infarction induces hypoxia, where hypoxia-inducible factors (HIFs) are activated and play critical roles in cellular functions. In this context, the role of Hif2α in neutrophils during myocardial infarction is unknown. Here, we demonstrate that neutrophil Hif2α deletion markedly attenuates myocardial infarct size, improves cardiac function, reduces neutrophil survival and tissue accumulation, and correlates with increased macrophage engulfment rates. Mechanistic studies revealed that Hif2α promotes neutrophil survival through binding to hypoxia response element (HRE) in the promoter region of Birc2 to regulate expression of the prosurvival factor, cellular inhibitor of apoptosis protein-1 (cIAP1). Inhibition of cIAP1 in neutrophils using the pharmacological agent, Birinapant resulted in increased cell death, establishing a critical role of cIAP1 downstream of Hif2α in neutrophil survival. Taken together, our data demonstrate a protective effect of Hif2α deletion in neutrophils on cardiac injury outcomes through modulation of neutrophil cell survival.NEW & NOTEWORTHY Hif2α in neutrophils increases infarct size, cardiac dysfunction, and ventricular scar after myocardial infarction. Hif2α in neutrophils supports neutrophil survival via cIAP-1 signaling and delays macrophage engulfment.

Next Generation of Solid Target Radionuclide Antibody Conjugates for Tumor Immuno-Therapy.

Immune checkpoint therapy has emerged as an effective treatment option for various types of cancers. Key immune checkpoint molecules, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and lymphocyte activation gene 3 (LAG-3), have become pivotal targets in cancer immunotherapy. Antibodies designed to inhibit these molecules have demonstrated significant clinical efficacy. Nevertheless, the ability to monitor changes in the immune status of tumors and predict treatment response remains limited. Conventional methods, such as assessing lymphocytes in peripheral blood or conducting tumor biopsies, are inadequate for providing real-time, spatial information about T-cell distributions within heterogeneous tumors. Positron emission tomography (PET) using T-cell specific probes represents a promising and noninvasive approach to monitor both systemic and intratumoral immune changes during treatment. This technique holds substantial clinical significance and potential utility. In this paper, we review the applications of PET probes that target immune cells in molecular imaging.

Lactiplantibacillus plantarum 1008 Enhances Testicular Function and Spermatogenesis via the Modulation of Gut Microbiota in Male Mice with High-Fat-Diet-Induced Obesity

Our study was designed to investigate the Lactiplantibacillus plantarum 1008 (LP1008) on testicular antioxidant capacity, spermatogenesis, apoptosis, autophagy, and metabolic function in male mice with high-fat-diet-induced obesity. A total of thirty-six male C57BL/6 mice were fed a normal diet (denoted as the NC group) or a high-fat control diet (denoted as the HFC group) for 16 weeks, then half of the HFC group was randomly chosen and subsequently fed with LP1008 for the final 8 weeks (high-fat diet + LP1008; denoted as the HFP group). The HFP group expressed improved blood cholesterol, insulin resistance, hepatic function, and lipopolysaccharide (LPS) levels compared to the HFC group. Meanwhile, the HFC group displayed decreased testicular testosterone levels, sperm quality, and 17β-HSD protein expression, which were rescued after LP1008 treatment. Moreover, the HFC group had lower superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) enzyme activities. After LP1008 treatment, enhanced antioxidative activities and decreased lipid peroxidation were observed. The HFC group also exhibited aggravated apoptosis, inflammation, and autophagy proteins in the testis, which were ameliorated by LP1008 supplementation. Furthermore, the gut microbiota analysis results revealed that the Firmicutes/Bacteroidetes ratio was significantly elevated in the HFC and HFP groups compared to the NC group and that LP1008 treatment diminished Ruminococcaceae and enhanced Bifidobacteriaceae diversity. In summary, LP1008 treatment strengthened antioxidative enzyme levels and regulated microbiota-ameliorated HFC-induced oxidative stress, apoptosis, inflammation, and autophagy, and thus improved testicular function and semen quality.

Microbiological aspects of cancer progression: A systematic review conducted according to the PRISMA 2020 guidelines and the Cochrane Handbook for Systematic Reviews of Interventions.

The complex interplay between the gut microbiota, cancer treatments and patient characteristics has emerged as a significant area of research. This study sought to examine these relationships in the context of colorectal cancer (CRC).A comprehensive search of relevant studies was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines and the Cochrane Handbook for Systematic Reviews of Interventions. The studies included a variety of treatment modalities and microbiological parameters. A data extraction form, designed specifically for this review, was used to assess a range of variables across all studies.The analysis revealed a multifaceted interaction between the gut microbiota, genetic factors and treatment outcomes. Elderly patients with CRC frequently received single-agent chemotherapy, with outcomes that were comparable to those of younger patients. The presence of tumorigenic bacteria, including Escherichia coli and Bacteroides fragilis, was associated with early colon neoplasia. Additionally, an abundance of Fusobacterium spp. was observed in colonic adenomas, contributing to a pro-inflammatory environment. Although the FcγRIIIa-158 V/V genotype was associated with higher cetuximab-mediated antibodydependent cellular cytotoxicity (ADCC), no direct influence of FcγR polymorphisms on treatment response was noted. Furthermore, the combination of programmed cell death protein-1 (PD-1), BRAF and MEK inhibition showed favorable response rates. The gut microbiome, especially the presence of Fusobacterium spp., had a notable influence on the therapeutic response in CRC.These findings underscore the role of the gut microbiota and genetic factors in cancer treatment outcomes, emphasizing the potential of a holistic approach to cancer management. Future research should exploit these findings in order to develop microbiota-modulating strategies and personalized medicine approaches for the purpose of improving the efficacy of cancer treatment.

The first case of primary malignant melanoma of the esophagus to achieve pathologic complete response after preoperative ipilimumab + nivolumab followed by resection.

Primary malignant melanoma of the esophagus is a rare disease with a poor prognosis. Surgical resection is common, but there is no consensus on perioperative treatment. Studies have reported the efficacy of programmed cell death-1 inhibitors (e.g., nivolumab, pembrolizumab) and anti-cytotoxic T-lymphocyte-associated antigen 4 agents (e.g., ipilimumab) in treating malignant melanoma. Here, we present the first case of primary malignant melanoma of the esophagus with lymph node metastases treated with nivolumab and ipilimumab followed by resection, achieving a pathologic complete response. A 75-year-old man presented with dysphagia. Esophagogastroduodenoscopy revealed a black, elevated lesion in the mid-thoracic esophagus. Biopsy confirmed primary malignant melanoma of the esophagus, showing tumor cells with melanin deposition, positive for HBM45 and S-100 staining. Computed tomography showed enlarged lymph nodes in the subclavian and mediastinum regions, suggesting metastases. After two courses of preoperative chemotherapy with ipilimumab and nivolumab, which significantly shrank the tumor, the patient underwent robot-assisted subtotal esophagectomy and 3-field lymph node dissection. Histopathological examination revealed no tumors or lymph node metastases, confirming a pathologic complete response. Given the rarity and poor prognosis of primary malignant melanoma of the esophagus, this case provides valuable insights for treatment strategies.

The Effect of PD-1/PD-L1 Inhibitor and Statin Combination Therapy on Overall Survival and Gastrointestinal Toxicity.

Immune checkpoint inhibitors (ICIs), such as programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors, have been approved to treat a variety of cancers. Recently, studies have suggested that ICIs and statins are synergistic. However, the addition of statins to ICI therapy may increase the risk of gastrointestinal immune-related adverse events (irAEs). We investigated the effect of combination therapy with PD-1 and/or L1 inhibitors and statins on overall survival and gastrointestinal irAEs. We reviewed the charts of patients with select cancers who received PD-1 and/or PD-L1 inhibitors and statins. The incidence of gastrointestinal irAEs and overall survival were compared with that in a matched control group of patients who received PD-1 and/or PD-L1 inhibitors without statins. Of the 823 patients in the statin group, 707 received PD-1 inhibitors, 86 received PD-L1 inhibitors, and 30 received both. Patients taking any statins (10.8%) and those taking high-intensity statins (15.8%) had higher rates of gastrointestinal irAEs than patients not taking statins (8.7%; P=0.046 and 0.006, respectively). Compared with the nonstatin treatments, statin use was associated with improved overall survival for patients taking PD-1 inhibitors (P<0.001) and for patients with (P=0.021) and without (P<0.001) gastrointestinal irAEs. Synergism of statins with PD-1 and PD-L1 inhibitors continues to be a developing field of interest. Our data demonstrate the survival benefit of combination therapy with PD-1 and/or PD-L1 inhibitors and statins, warranting further investigation.

Causal relationship between hypothyroidism and ulcerative colitis: a bidirectional Mendelian randomization study.

Ulcerative colitis (UC) and Hashimoto's thyroiditis frequently cooccur in patients with multiple autoimmune conditions, but the specific association between UC and hypothyroidism is unknown. We used Mendelian randomization (MR) methods to determine the causal relationship between UC and hypothyroidism. We obtained single nucleotide polymorphisms (SNPs) related to ulcerative colitis (UC) and hypothyroidism from genome-wide association studies (GWAS) available in the public database of the Integrated Epidemiology Unit (IEU). To assess the causal relationship between UC and hypothyroidism, we employed MR-Egger, weighted median, inverse variance weighted (IVW), simple mode, and weighted mode methods. Sensitivity analyses were performed using Cochran's Q test, the horizontal pleiotropy test, and the leave-one-out (LOO) method to assess the reliability of the MR data. The genes corresponding to instrumental variables (IVs) were subjected to Gene Ontology (GO) functional annotation, Kyoto Encyclopedia of the Genome (KEGG) pathway enrichment analysis, and protein-protein interaction (PPI) analysis to explore the mechanisms behind the causal relationships at the gene level. Forward MR analysis indicated that hypothyroidism was associated with an increased risk of UC (IVW: P = 0.02, OR = 9.71, 95% confidence interval (CI) = 1.36-69.46). In contrast, reverse MR did not demonstrate a causal relationship between UC and hypothyroidism (IVW: P = 0.53). Sensitivity analysis proved the reliability of the results. The PPI network revealed CD247, CD80, and STAT4 as central genes. GO and KEGG analyses revealed significant enrichment of the T cell, gamma interferon (IFN-γ), and programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathways. Hypothyroidism was a risk factor for UC. The balance of T-cell differentiation played an important role in the process of hypothyroidism-induced UC, and IL-21 might be the key to finding a cure. Enrichment of PD-1/PD-L1 might attenuate inflammation by suppressing the immune action of T cells.

Altered immunophenotypic expression in the peripheral bladder cancer immune landscape.

Treatments targeting the immune system only benefit a subset of patients with bladder cancer (BC). Biomarkers predictive of BC progression and response to specific therapeutic interventions are required. We evaluated whether peripheral blood immune subsets and expression of clinically relevant immune checkpoint markers are associated with clinicopathologic features of BC. Peripheral blood mononuclear cells isolated from blood collected from 23 patients with BC and 9 age-matched unaffected-by-cancer control donors were assessed using a 21-parameter flow cytometry panel composed of markers of T, B, natural killer and myeloid populations and immune checkpoint markers. Patients with BC had significantly lower numbers of circulating CD19+ B cells and elevated circulating CD4+CD8+ Tcells compared with the control cohort. Immune checkpoint markers programmed cell death protein 1 (PD-1) and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) were elevated in the total peripheral immune cell population in patients with BC. Within the BC cohort, PD-1 expression in T and myeloid cells was elevated in muscle-invasive compared with non-muscle-invasive disease. In addition, elevated T, B and myeloid PD-1 cell surface expression was significantly associated with tumor stage, suggesting that measures of peripheral immune cell exhaustion may be a predictor of tumor progression in BC. Finally, positive correlations between expression levels of the various immune checkpoints both overall and within key peripheral blood immune subsets collected from patients with BC were observed, highlighting likely coregulation of peripheral immune checkpoint expression. The peripheral blood immunophenotype in patients with BC is altered compared with cancer-free individuals. Understanding this dysregulated immune profile will contribute to the identification of diagnostic and prognostic indicators to guide effective immune-targeted, personalized treatments.