Apoptosis Protein Research Articles

Advancing Systemic Therapy in Chondrosarcoma: New Horizons.

The systemic treatment landscape for advanced and metastatic chondrosarcoma, a malignancy with limited responsiveness to conventional therapies, has always been notoriously challenging. While standard chemotherapy offers minimal benefits, certain subtypes, such as mesenchymal and dedifferentiated chondrosarcomas, have shown some response to systemic therapies initially developed for other sarcomas. Investigational strategies are focusing on molecular targets, including mutations in the isocitrate dehydrogenase gene (IDH), signaling pathways, such as hedgehog and death receptor 5 (DR5) and immune modulation. IDH mutations, notably found in conventional and dedifferentiated chondrosarcomas, have prompted the evaluation of IDH inhibitors, which have demonstrated promising efficacy in preclinical and early clinical trials, despite limited data in chondrosarcoma. Additionally, the hedgehog pathway, implicated in chondrosarcoma progression, has been targeted with inhibitors, although clinical translation has shown mixed results. Immunotherapy, including programmed cell death 1 (PD-1) checkpoint inhibitors and chimeric antigen receptor-T (CAR-T) cells, is also being investigated but faces challenges due to the immunosuppressive tumour microenvironment. Among new approaches, DR5 agonists such as INBRX-109 have shown single-agent efficacy, with minimal toxicity, opening possibilities for use in combination therapies to improve outcomes. Given the heterogenous and treatment-resistant nature of chondrosarcoma, we highlight the need for multi-omics and genetic profiling to guide personalized, combination therapies that target multiple carcinogenic pathways. The integration of multi-targeted approaches could enhance efficacy, address tumour heterogeneity, and overcome resistance, presenting a hopeful direction for systemic therapy in this challenging cancer. The investigation of combination regimens with IDH inhibitors, immunotherapy and DR5 agonists hold promise for transforming the management of advanced chondrosarcoma.

Musculoskeletal immune-related adverse events of PD-(L)1 inhibitors in melanoma: a systematic review and meta-analysis.

Immune checkpoint inhibitors (ICIs) are first-line treatment for melanoma. The incidence of musculoskeletal immune-related adverse events (MSK irAEs) remains unclear. To estimate the relative risk of MSK irAEs in melanoma patients treated with ICIs targeting programmed cell death-1 or its ligand PD-(L)1 as compared to placebo. We performed a systematic literature review including phase III randomized controlled trials of adult melanoma patients comparing a PD-(L)1 inhibitor to a placebo arm. Outcomes of interest included arthralgias, arthritis, back pain and myalgias. Meta-analysis was performed to estimate the pooled relative risk of MSK irAEs over the treatment course. Four RCTs met the inclusion criteria (n = 3,041 subjects). Use of PD-(L)1 inhibitors was associated with an increased risk of developing arthralgias (RR 1.30 [95% CI: 1.13-1.49]) and myalgias (RR 1.48 [95% CI: 1.17-1.87]) as compared to placebo. Back pain and arthritis were not reported. Use of PD-(L)1 inhibitors is associated with a significantly increased risk of arthralgias and myalgias in melanoma patients. The risk of back pain and arthritis is unknown. MSK irAEs can impact quality of life and should be considered, particularly in the adjuvant setting when risks and benefits are carefully weighed.

Association of T-Cell Phenotypes With Peri-Coronary Inflammation in People With and Without HIV and Without Cardiovascular Disease.

Persistent immune activation is linked to elevated cardiovascular diseases in people with HIV on antiretroviral therapy. The fat attenuation index (FAI) is a measure of peri-coronary inflammation that independently predicts cardiovascular disease risk in people without HIV. Whether FAI is associated with immune activation is unknown. Peripheral blood T-cell activation and homing phenotypes were measured in people with HIV (n=58) and people without HIV (n=16) without known cardiovascular disease who underwent coronary computed tomography angiography and had FAI measurements. A cross-sectional analysis of an observational cohort was performed. The primary aim was to evaluate associations of T-cell activation and phenotypes with the outcome variables, FAI values of the right coronary artery and left anterior descending artery, which were assessed using multivariable regression models adjusted for age, natal sex, race, low-density lipoprotein cholesterol, body mass index, and use of lipid-lowering medication. T cells from people with HIV showed greater activation, as measured by cluster of differentiation (CD) 38/human leukocyte antigen - DR isotype coexpression on CD4 central memory and terminally-differentiated effector memory subsets and on CD8 effector memory (TEM), than did cells from people without HIV. Expression of the chemokine receptor C-C Chemokine Receptor 2 was reduced on CD4 central memory and TEM and CD8 TEM and terminally-differentiated effector memory subsets in people with HIV. Among all participants, PD-1 (programmed cell death 1) in CD8 central memory was associated with worsened peri-coronary inflammation of the right coronary artery, whereas perforin/granzyme B on CD8 TEM was associated with improved peri-coronary inflammation of the right coronary artery and left anterior descending artery in adjusted analyses. When accounting for HIV serostatus, CD38/human leukocyte antigen - DR isotype coexpression on CD8 central memory, TEM, and terminally-differentiated effector memory cells was associated with more peri-coronary inflammation of the left anterior descending artery. The associations between T-cell activation with FAI are novel and suggest that T-cell activation may be an important driver of peri-coronary inflammation, occurring at an early stage of atherosclerosis, even before the development of clinical disease.

Integrative multi-omics analysis reveals a novel subtype of hepatocellular carcinoma with biological and clinical relevance

BackgroundHepatocellular carcinoma (HCC) is a highly heterogeneous tumor, and the development of accurate predictive models for prognosis and drug sensitivity remains challenging.MethodsWe integrated laboratory data and public cohorts to conduct a multi-omics analysis of HCC, which included bulk RNA sequencing, proteomic analysis, single-cell RNA sequencing (scRNA-seq), spatial transcriptomics sequencing (ST-seq), and genome sequencing. We constructed a tumor purity (TP) and tumor microenvironment (TME) prognostic risk model. Proteomic analysis validated the TP-TME-related signatures. Joint analysis of scRNA-seq and ST-seq revealed characteristic clusters associated with TP high-risk subtypes, and immunohistochemistry confirmed the expression of key genes. We conducted functional enrichment analysis, transcription factor activity inference, cell-cell interaction, drug efficacy analysis, and mutation information analysis to identify a novel subtype of HCC.ResultsOur analyses constructed a robust HCC prognostic risk prediction model. The patients with TP-TME high-risk subtypes predominantly exhibit hypoxia and activation of the Wnt/beta-catenin, Notch, and TGF-beta signaling pathways. Furthermore, we identified a novel subtype, XPO1+Epithelial. This subtype expresses signatures of the TP risk subtype and aligns with the biological behavior of high-risk patients. Additional analyses revealed that XPO1+Epithelial is influenced primarily by fibroblasts via ligand-receptor interactions, such as FN1-(ITGAV+ITGB1), and constitute a significant component of the TP-TME subtype. Moreover, XPO1+Epithelial interact with monocytes/macrophages, T/NK cells, and endothelial cells through ligand-receptor pairs, including MIF-(CD74+CXCR4), MIF-(CD74+CD44), and VEGFA-VEGFR1R2, respectively, thereby promoting the recruitment of immune-suppressive cells and angiogenesis. The ST-seq cohort treated with Tyrosine Kinase Inhibitors (TKIs) and Programmed Cell Death Protein 1 (PD-1) presented elevated levels of TP and TME risk subtype signature genes, as well as XPO1+Epithelial, T-cell, and endothelial cell infiltration in the treatment response group. Drug sensitivity analyses indicated that TP-TME high-risk subtypes, including sorafenib and pembrolizumab, were associated with sensitivity to multiple drugs. Further exploratory analyses revealed that CTLA4, PDCD1, and the cancer antigens MSLN, MUC1, EPCAM, and PROM1 presented significantly increase expression levels in the high-risk subtype group.ConclusionsThis study constructed a robust prognostic model for HCC and identified novel subgroups at the single-cell level, potentially assisting in the assessment of prognostic risk for HCC patients and facilitating personalized drug therapy.

An Azomethine Derivative, BCS3, Targets XIAP and cIAP1/2 to Arrest Breast Cancer Progression Through MDM2-p53 and Bcl-2-Caspase Signaling Modulation

Background: Breast cancer influences more than 2 million women worldwide annually. Since apoptotic dysregulation is a cancer hallmark, targeting apoptotic regulators encompasses strategic drug development for cancer therapy. One such class of apoptotic regulators is inhibitors of apoptosis proteins (IAP) which are a class of E3 ubiquitin ligases that actively function to support cancer growth and survival. Methods: The current study reports design, synthesis, docking analysis (based on binding to IAP-BIR3 domains), anti-proliferative and anti-tumor potential of the azomethine derivative, 1-(4-chlorophenyl)-N-(4-ethoxyphenyl)methanimine (BCS3) on breast cancer (in vitro and in vivo) and its possible mechanisms of action. Results: Strong selective cytotoxic activity was observed in MDA-MB-231, MCF-7, and MDA-MB-468 breast cancer cell lines that exhibited IC50 values, 1.554 µM, 5.979 µM, and 6.462 µM, respectively, without affecting normal breast cells, MCF-10A. For the evaluation of the cytotoxic potential of BCS3, immunofluorescence, immunoblotting, and FACS (apoptosis and cell cycle) analyses were conducted. BCS3 antagonized IAPs, thereby causing MDM2-p53 and Bcl-2-Caspase-mediated intrinsic and extrinsic apoptosis. It also modulated p53 expression causing p21-CDK1/cyclin B1-mediated cell cycle arrest at S and G2/M phases. The in vitro findings were consistent with in vivo findings as observed by reduced tumor volume and apoptosis initiation (TUNEL assay) by IAP downregulation. BCS3 also produced potent synergistic effects with doxorubicin on tumor inhibition. Conclusions: Having witnessed the profound anti-proliferative potential of BCS3, the possible adverse effects related to anti-cancer therapy were examined following OECD 407 guidelines which confirmed its systemic safety profile and well tolerability. The results indicate the promising effect of BCS3 as an IAP antagonist for breast cancer therapy with fewer adverse effects.

Efficacy and Safety of Immune Checkpoint Inhibitors on Advanced Cervical Cancer: A Systematic Review and Meta-analysis.

This study aims to evaluate the efficacy and safety of immune checkpoint inhibitors (ICIs) in patients with histologically proven advanced cervical cancer. MEDLINE (through PubMed), Web of Science, Embase, and the Cochrane Library were comprehensively searched. Eligible studies were clinical trials investigating the efficacy and safety on ICIs in patients with confirmed advanced cervical cancer. Response rates and adverse events rates were pooled using either a random-effects model or a fixed-effects model based on the I2 value. A total of 12 clinical trials with 523 women diagnosed with advanced cervical cancer were included. Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors were identified. The pooled objective response (OR) rate, complete response (CR) rate, partial response (PR) rate, and stable disease (SD) rate of PD1 antibodies were 0.24 (95% CIs: 0.11-0.39; I2=90%, P<0.01), 0.03 (95% CIs: 0.02-0.05; I2=0%, P =0.92), 0.20 (95% CIs: 0.08-0.36; I2=91%, P<0.01), 0.31 (95% CIs: 0.23-0.40; I2=79%, P<0.01), respectively. Adverse events (AEs) rate of any grade was 0.81 (95% CIs: 0.72-0.88; I2=83%, P<0.01). This study indicates that PD-1/PD-L1 inhibitors reveal acceptable clinical responses and tolerable adverse events in the treatment of advanced cervical cancer. Well-designed clinical trials investigating the efficacy and safety of immune checkpoint inhibitors (ICIs) are needed.

Overcoming Resistance Mechanisms to Melanoma Immunotherapy.

The advent of immune checkpoint inhibition has revolutionized treatment of advanced melanoma. While most patients derive survival benefit from established immunotherapies, notably monoclonal antibodies blocking cytotoxic T-lymphocyte antigen 4 and programmed cell death protein 1, a subset does not optimally respond due to the manifestation of innate or acquired resistance to these therapies. Combination regimens have proven efficacious relative to single-agent blockade, but also yield high-grade treatment toxicities that are often dose-limiting for patients. In this review, we discuss the significant strides made in the past half-decade toward expanding the melanoma immunotherapy treatment paradigm. These include newly approved therapies, adoption of neoadjuvant immunotherapy, and studies in the clinical trials pipeline targeting alternative immune checkpoints and key immunoregulatory molecules. We then review how developments in molecular and functional diagnostics have furthered our understanding of the tumor-intrinsic and -extrinsic mechanisms driving immunotherapy resistance, as well as highlight novel biomarkers for predicting treatment response. Throughout, we discuss potential approaches for targeting these resistance mechanisms in rational combination with established immunotherapies to improve outcomes for patients with melanoma.

Salidroside overcomes cisplatin resistance in ovarian cancer via the inhibition of CRNDE-mediated autophagy.

Cisplatin (DDP) resistance significantly affects the survival rate of patients with ovarian cancer (OC). Autophagy is recognized as a common cause of resistance to DDP. This study aimed to investigate the impact of salidroside on OC progression and explore its potential regulatory effects on DDP resistance and autophagy. A DDP-resistant A2780 (A2780/DDP) cell line was induced by exposure to increasing DDP concentrations. The protein levels of autophagy proteins (p62, Beclin-1, ATG5, and LC3 II/LC3 I), apoptosis proteins (cleaved caspase-3 and cleaved caspase-9), and PI3K/AKT/mTOR pathway were determined by western blotting. Autophagic vacuoles in cells were observed with LC3 dyeing with confocal fluorescent microscopy. Cell viability and apoptosis were evaluated by cell counting kit-8 assays and flow cytometry. RT-qPCR was conducted to measure the relative levels of various lncRNAs in A2780 or A2780/DDP cells. A xenograft model was established by subcutaneous injection of 1 × 107 A2780 cells into the posterior flank of nude mice. Tumor size and weight were recorded. The expression of Ki67, cleaved caspase-3 and LC3 in tumor tissues was assessed by immunohistochemistry staining. The biodistribution of DDP in organs and blood of normal nude mice and tumors of tumor-bearing mice was detected using the ICP-MS. Hematoxylin-eosin staining was used to assess the histopathological changes of kidney, liver, and spleen sections. For in vitro analysis, autophagy was enhanced in DDP-resistant A2780 cells. Additionally, salidroside inhibits DDP resistance to A2780 cells via autophagy inhibition. Mechanistically, salidroside downregulated CRNDE in DDP-resistant A2780 cells. CRNDE knockdown inhibited autophagy, while CRNDE overexpression reversed the protective effects of salidroside. Additionally, salidroside activated the PI3K/AKT/mTOR pathway in DDP-resistant A2780 cells, and inhibition of PI3K reversed the effect of salidroside on inhibiting autophagy and apoptosis of A2780/DDP cells. For in vivo analysis, salidroside inhibited tumor growth, autophagy, and nephrotoxicity of DDP. Additionally, salidroside downregulated CRNDE and activated PI3K/AKT/mTOR signaling in vivo. Salidroside prevents autophagy-mediated DDP resistance in OC by downregulating lncRNA CRNDE and activating the PI3K/AKT/mTOR pathway.

Dissecting the link between PD-1/PD-L1-based immunotherapy and cancer pain: mechanisms, research implications, and artificial intelligence perspectives

Cancer-related pain represents one of the most common complaints of cancer patients especially for those with advanced-stage of disease and/or bone metastases. More effective therapeutic strategies are needed not only to improve the survival of cancer patients but also to relieve cancer-related pain. In the last decade, immune checkpoint inhibitor (ICI)-based immunotherapy targeting programmed cell death-1 (PD-1) and its ligand 1 (PD-L1) has revolutionized cancer care. Beyond its anticancer role, PD-1/PD-L1 axis pathway is involved in many other physiological processes. PD-L1 expression is found in both malignant tissues and normal tissues including the dorsal root ganglion, and spinal cord. Through its interaction with PD-1, PD-L1 can modulate neuron excitability, leading to the suppression of inflammatory, neuropathic, and bone cancer pain. Therefore, since the intricate relationship between immunotherapy and pain should be largely dissected, this comprehensive review explores the complex relationship between PD-1/PD-L1-based immunotherapy and cancer-related pain. It delves into the potential mechanisms through which PD-1/PD-L1 immunotherapy might modulate pain pathways, including neuroinflammation, neuromodulation, opioid mechanisms, and bone processes. Understanding these mechanisms is crucial for developing future research directions in order to optimize pain management strategies in cancer patients. Finally, this article discusses the role of artificial intelligence (AI) in advancing research and clinical practice in this context. AI-based strategies, such as analyzing large datasets and creating predictive models, can identify patterns and correlations between PD-1/PD-L1 immunotherapy and pain. These tools can assist healthcare providers in tailoring treatment plans and pain management strategies to individual patients, ultimately improving outcomes and quality of life for those undergoing PD-1/PD-L1-based immunotherapy.

E3 ubiquitination ligase XIAP lightens diabetes-induced cognitive impairment by inactivating TXNIP-ERS-mediated neuronal injury.

Diabetes-induced cognitive dysfunction (DCD) is a neurological disorder associated with diabetes, characterized by cognitive impairment driven by neuronal injury from chronic high glucose (HG) exposure. This study aims to elucidate the role and mechanisms of the X-linked inhibitor of apoptosis protein (XIAP)/thioredoxin-interacting protein (TXNIP) in hippocampal neuron cell death and cognitive function within DCD models. A diabetic rat model was established using a high-fat/sucrose diet and streptozotocin injection. Primary hippocampal neurons were stimulated with HG to mimic diabetic conditions. Cognitive and memory functions were assessed using the Morris water maze (MWM) and novel object recognition test (ORT).

Sea Hare Hydrolysate Reduces PD‐L1 Levels in Cancer Cells and Mitigates Rheumatoid Arthritis Ina Collagen‐Induced Arthritis Mouse Model

ABSTRACTOur previous study highlighted the anticancer potential of sea hare hydrolysate (SHH), particularly its role in regulating macrophage polarization and inducing pyroptotic death in lung cancer cells through the inhibition of signal transducer and activator of transcription 3 (STAT3). These findings prompted us to investigate additional features of immune‐oncology (I‐O) agents or adjuvants, such as programmed cell death protein 1 (PD‐1)/programmed death ligand 1 (PD‐L1) inhibition and their association with rheumatoid arthritis (RA) risk, to explore the potential of SHH as an I‐O agent or adjuvant. In this study, we investigated the effects of SHH on PD‐L1 levels in various cancer cell types and assessed its effectiveness in treating RA, a common side effect of I‐O agents. Our results showed a marked reduction in PD‐L1 levels in multiple cancer cell lines and decreased PD‐1 and PD‐L1 levels in tumor‐associated macrophages. In a mouse model with collagen‐induced arthritis (CIA), SHH exhibited anti‐inflammatory effects comparable to methotrexate (MTX), a first‐line treatment for RA. Both the SHH and MTX groups had significantly lower arthritis scores and paw thickness compared to the CIA group. Additionally, SHH or MTX treatment effectively reduced elevated levels of anticollagen type II (CII) antibodies and proinflammatory cytokines (IL‐1β, IL‐6, and TNF‐α). Histopathological analysis revealed that SHH and MTX treatments notably mitigated arthritic inflammation, synovial hyperplasia, and loss of articular cartilage and bone. Micro‐CT scans showed reduced articular destruction in the SHH and MTX groups. These findings indicate that SHH treatment decreases PD‐L1 levels in cancer cells and reduces the severity of CIA by exerting anti‐inflammatory effects. Therefore, SHH holds promise as an I‐O agent without side effects such as exacerbation of RA.

Electrochemical immunosensor for the predictive cancer biomarker SLFN11 using reduced graphene oxide/MIL-101(Cr)-NH2 composite

SLFN11 is a predictive cancer biomarker essential for identifying tumors that are sensitive to DNA-damaging agents, facilitating more personalized and effective treatment approaches. Detecting this biomarker can guide therapeutic decisions and improve outcomes for cancer patients. However, existing detection methods for SLFN11 are complex and require advanced techniques. In this study, we introduce the first immunosensor designed for on-site detection of SLFN11. An advanced electrochemical immunosensor platform utilizing a composite of graphene oxide (GO) and chromium-based metal organic framework (MIL-101 (Cr)-NH2) was developed. The integration of GO and MIL-101(Cr)-NH2 was characterized through FT-IR, XRD, SEM, and XPS, affirming the formation of the composite. The subsequent electrochemical reduction to rGO/MIL-101(Cr)-NH2 significantly improved the electrochemical performance and stability. A glutaraldehyde cross-linker was then utilized to attach the SLFN11-specific antibody to the amine groups of the MOF-modified electrodes. This led to the development of rapid, sensitive, portable, and cost-effective immunosensor for SLFN11 at concentrations as low as 8.9 pg/mL which holds promise for early cancer diagnosis. High specificity was achieved, with minimal cross-reactivity observed with other cancer biomarkers such as pepsinogen I, claudin 18.2 and Programmed cell death protein 1. Demonstrating practical applicability, the electrochemical immunosensor validated by commercial ELISA kit showed successful detection in serum samples with high recovery rates and reproducibility. This research highlights the potential of rGO/MOFs composites in electrochemical biosensors developments for early cancer diagnostics and personalized medicine.

Prognostic and clinicopathological significance of survivin in gynecological cancer

Survivin belongs to the inhibitor of apoptosis protein (IAP) family and is encoded by the baculoviral inhibitor of apoptosis repeat-containing, or BIRC5, gene. It is preferentially expressed in cancers with functional complexity in cell signaling cascades such as extracellular signal-regulated kinases (ERK), mitogen-activated protein kinases (MAPK), heat shock protein-90 (HSP90), epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase (PI3K), signal transducer and activator of transcription (STAT), hypoxia-inducible factor-1 alpha (HIF-1α), vascular endothelial growth factor (VEGF), and others. Survivin plays a role in cell division and cell death, properties that have attracted a large body of research to decipher its therapeutic and prognostic significance in cancer. Survivin has tumor-promoting effects in endometrial (EC) and ovarian (OC) cancers, and its upregulation in endometrial cancer has been associated with poor overall survival (OS). While survivin protein is abundantly expressed in OC, it is barely detectable in normal ovarian tissue or benign ovarian tumors. Survivin expression is also a marker for cervical intraepithelial neoplasia (CIN) and high-risk human papillomavirus, and a predictor of viral clearance and prognosis in uterine cervical cancer (UCC). Furthermore, nuclear survivin expression is very low in normal vulvar squamous epithelium and increases to become abundant in vulvar invasive squamous cell carcinoma (ISCC), conferring resistance to apoptosis in vulvar carcinogenesis. In this review, we discuss in detail the impact of survivin signaling on gynecological cancers and provide insight on its therapeutic and diagnostic potential, existing research gaps, and areas for future research.

Synthesis and Anti-gastric Cancer Activity by Targeting FGFR1 Pathway of Novel Asymmetric Bis-chalcone Compounds.

Bis-chalcone compounds with symmetrical structures, either isolated from natural products or chemically synthesized, have multiple pharmacological activities. Asymmetric Bis-chalcone compounds have not been reported before, which might be attributed to the synthetic challenges involved, and it remains unknown whether these compounds possess any potential pharmacological activities. The aim of this study is to investigate the synthesis route of asymmetric bis-chalcone compounds and identify potential candidates with efficient anti-tumor activity. The two-step structural optimization of the bis-chalcone compounds was carried out sequentially, guided by the screening of the compounds for their growth inhibitory activity against gastric cancer cells by MTT assay. The QSAR model of compounds was established through random forest (RF) algorithm. The activities of the optimal compound J3 on growth inhibition, apoptosis, and apoptosis-inducing protein expression in gastric cancer cells were investigated sequentially by colony formation assay, flow cytometry, and western blotting. Further, the inhibitory effects of J3 on the FGFR1 signaling pathway were explored by Western Blotting, shRNA, and MTT assays. Finally, the in vivo anti-tumor activity and mechanism of J3 were studied through nude mice xenograft assay, western blotting. 27 asymmetric bis-chalcone compounds, including two types (N and J) were sequentially designed and synthesized. Some N-class compounds have good inhibitory activity on the growth of gastric cancer cells. The vast majority of J-class compounds optimized on the basis of N3 exhibit excellent inhibitory activity on gastric cancer cell growth. We established a QSAR model (R2 = 0.851627) by applying random forest algorithms. The optimal compound J3, which had better activity, concentration-dependently inhibited the formation of gastric cancer cell colonies and led to cell apoptosis by inducing the expression of the pro-apoptotic protein cleaved PARP in a dose-dependent manner. J3 may exert anti-gastric cancer effects by inhibiting the activation of FGFR1/ERK pathway. Moreover, at a dose of 10 mg/kg/day, J3 inhibited tumor growth in nude mice by nearly 70% in vivo with no significant toxic effect on body weight and organs. In summary, this study outlines a viable method for the synthesis of novel asymmetric bischalcone compounds. Furthermore, the compound J3 demonstrates substantial promise as a potential candidate for an anti-tumor drug.

Co-treatment with erythropoietin derived HBSP and caspase-3 siRNA: A promising approach to prevent fibrosis after acute kidney injury.

Acute kidney injury (AKI) is a risk factor of chronic kidney disease, without specific treatment. This study investigated the effect of co-treatment using erythropoietin-derived helix B surface peptide (HBSP) and caspase-3 small interfering RNA (CASP3siRNA) on preventing fibrosis post AKI in order to achieve better efficacy by different action mechanisms. Ischemia-reperfusion (IR) in mice was induced by clamping bilateral renal pedicles for 30 min followed by 2-week reperfusion, with HBSP and/or CASP3siRNA administered at the onset of IR. Serum creatinine, apoptosis, active caspase-3 and high mobility group protein B1 (HMGB1) in kidneys were decreased by HBSP, CASP3siRNA or both, with increased PCNA. α-SMA expression and collagen I deposition were also reduced by CASP3siRNA and both. Most interestingly, the co-treatment further reduced tubulointerstitial damage and fibrosis, but raised PCNA compared to CASP3siRNA. EPOR/βcR was reduced by HBSP, and positively correlated with Sirius red staining, whereas EPOR was unchanged. In TCMK-1 cells, H2O2 raised apoptosis and α-SMA were reduced by HBSP, while the same was occurred to HMGB1. However, HMGB1 was further increased by EPOR siRNA under H2O2 stimulation with/without HBSP treatment. In conclusion, this study demonstrated synergistic long-term renoprotection post IR-AKI by HBSP and CASP3siRNA, which may be due to co-inhibiting inflammation and stimulating repair at early stage, and subsequently preventing fibrosis.

Multiomics reveals tumor microenvironment remodeling in locally advanced gastric and gastroesophageal junction cancer following neoadjuvant immunotherapy and chemotherapy

BackgroundPerioperative chemotherapy is the standard of care for patients with locally advanced gastric and gastroesophageal junction cancer. Recent evidence demonstrated the addition of programmed cell death protein 1 (PD-1) inhibitors...

Expression of Immune Checkpoint Regulator Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) and Programmed Cell Death Protein Ligand 1 (PD-L1) in Invasive Ductal Carcinoma Breast.

Despite significant advancement in the diagnostic and therapeutic aspects of breast carcinoma, the prognosis remains dismal. Recently, with advances in its understanding, various immune system-based management strategies have been developed. CTLA-4 suppresses lymphocyte reactivity, IL-2 secretion, and IL-2 receptor expression and triggers cell cycle arrest. PD-L1 inhibits the proliferation and cytotoxicity of T cells and inhibits release of cytokines. Hence, we planned to evaluate the immunoexpression of CTLA-4 and PD-L1 in invasive ductal carcinoma breast and seek correlation between their immunopositivity and the clinicopathological parameters. This was a retrospective study conducted on archival material of 50 cases of breast carcinoma tissue microarrays. Clinicopathological details were recorded. All cases were evaluated for immunohistochemical expression of CTLA-4 and PD-L1. Cytoplasmic expression of CTLA-4 and membranous expression of PD-L1 were considered positive and staining intensity was recorded as mild, moderate, and intense. Data was recorded and analyzed. Immunopositivity for CTLA-4 was seen in 92% of cases of breast carcinoma. CTLA-4 staining intensity showed significant association with TNM staging of breast carcinomas (p = 0.036). Age group of the breast carcinoma cases showed a statistically significant correlation with PD-L1 immunoexpression (p = 0.002). No significant correlation was found between all other clinicopathological characteristics and CTLA-4 or PD-L1 immunostaining. Our study shows that CTLA-4 is a more important immune checkpoint regulator in breast carcinomas in comparison to PD-L1. Thus, anti-CTLA-4 immunotherapy might prove to be of immense help in the treatment of invasive ductal carcinoma breast showing overexpression of CTLA-4.

High-resolution crystal structure of PD-1 in complex with retifanlimab, the FDA-approved immune checkpoint blocking antibody for treating Merkel cell carcinoma

Retifanlimab is a humanized monoclonal antibody that specifically targets programmed cell death protein 1 (PD-1), an essential immune checkpoint that modulates T-cell immune responses. Several anti-PD-1 antibodies have been market-approved, marking a significant advancement in the treatment of diverse tumor types by restoring the T-cell immune response. Recently, the US FDA approved retifanlimab for treating metastatic or recurrent locally advanced Merkel cell carcinoma. We present the crystal structure of PD-1 in complex with the retifanlimab Fab at a resolution of 1.54 Å to elucidate the structural basis for the mechanism of action of this antibody. This work clarifies the detailed interactions and conformational alterations that occur upon antibody binding. The epitope of retifanlimab partially overlaps with the ligand binding site, and its binding induced unique conformations of the flexible loops within PD-1, including BC, C'D, and FG loops, thereby optimizing interactions with the antibody. A thorough analysis of its interaction with PD-1 and other FDA-approved anti-PD-1 antibodies may provide valuable insights into the rational design of enhanced therapies to regulate immune responses in cancer treatment.

NK cell-derived exosomes inhibit survival of Mycobacterium tuberculosis by promoting apoptosis in mice

AimTo investigate anti-Mycobacterium tuberculosis (Mtb) influences exerted by natural killer cell-derived exosomes (NK-exo) on mice and to elucidate underlying immunologic mechanisms. MethodsWe established tuberculosis (TB) model in mouse by injecting Mtb H37Ra (1 × 106 colony counting (CFU), i.v.) into tail vein for 14 days. The survival rate of Mtb was assessed through CFU, apoptosis rates were measured utilizing flow cytometry, and inflammation relief was quantified via HE staining. Expressions of apoptosis, inflammation, and pyroptosis-related proteins were quantified by Western blotting and RT-qPCR. ELISA was utilized for detecting inflammatory cytokines production. Intracellular reactive oxygen species (ROS) levels were assessed through DCFH-DA fluorescent probe assay. ResultsNK-exo treatment reduced Mtb load in lung and spleen tissues and alleviated inflammation in mice lung tissues. NK-exo intervention increased protein levels of markers associated with apoptosis, PARP and caspase-3/8/9, downregulating the concentrations of pro-inflammatory cytokines, comprising IL-1β, TNF-α, IL-6, along with protein expressions of biomarkers, ASC, NLRP3, GSDMD, associated to inflammation and pyroptosis. NK-exo also elevated ROS levels without affecting lactate dehydrogenase (LDH) release from macrophages. ConclusionNK-exo exhibits anti-tuberculosis activity in experimental TB mice. The underlying mechanism involve regulating caspase-dependent apoptotic signaling pathway to promote cell apoptosis, as well as modulating NLRP3 signaling pathway to suppress the inflammatory response.

Checkpoint based immunotherapy in non-small cell lung cancer: a real-world retrospective study

IntroductionImmune checkpoint inhibitor (ICI)-based immunotherapy targeting programmed cell death 1 (PD-1) or its ligand 1 (PD-L1) has radically changed the management of many types of solid tumors including non-small cell lung cancer (NSCLC). Many clinical trials have demonstrated that ICIs improve the survival and the quality of life of patients with advanced non oncogene NSCLC as compared to standard therapies. However, not all patients achieve a clinical benefit from this immunotherapeutic approach. As a result, real-word validation of the efficacy and safety of ICIs can be useful for defining potential predictive biomarkers as well as for overcoming limitations linked to clinical trial restrictions.MethodsWe retrospectively retrieved the clinical data of patients with advanced non oncogene NSCLC treated with ICIs (anti-PD-1 or anti-PD-L1) as single agent or in combination with chemotherapy at “San Giovanni di Dio e Ruggi D’Aragona” University Hospital from January 2016 to December 2023. Potential correlations between clinical-pathological characteristics and safety or survival outcomes were investigated employing the Fisher’s exact test, Mann-Whitney U test, the Kruskal-Wallis method and log-rank test, as applicable. Multivariate survival analyses were performed using the Cox proportional hazards model.ResultsClinical data of 129 patients were retrieved. At a median follow-up of 29.70 months, progression-free survival (PFS) and overall survival (OS) were 5.27 months and 8.43 months, respectively. At the multivariate analyses, smoking status, presence of bone metastases and the occurrence of immune-related adverse events (irAEs) were correlated with both PFS and OS. Moreover, patients treated with anti-PD-1-based therapy achieved an increased clinical benefit than those treated with anti-PD-L1.DiscussionIn this study we described our real-world experience of ICIs for the treatment of patients with advanced non oncogene NSCLC. A decreased OS in our study population was reported as compared to that of patients included in the clinical trials. Noteworthy, correlations between clinical-pathological characteristics and survival outcomes emerged. Nevertheless, the potential integration of clinical-pathological characteristics as predictive biomarkers in more accurate therapeutic algorithms as well as the underlying biological mechanisms should be further validated in ad hoc studies.