Treatment Resistance Research Articles

Targeting LHPP in neoadjuvant chemotherapy resistance of gastric cancer: insights from single-cell and multi-omics data on tumor immune microenvironment and stemness characteristics

Gastric cancer (GC) is a highly heterogeneous and complex malignancy, often characterized by tumor stemness and immune evasion mechanisms, which contribute to a poor response to neoadjuvant chemotherapy (NAC) and treatment resistance. In this study, we performed a comprehensive analysis using single-cell and multi-omics approaches on 375 GC samples from The Cancer Genome Atlas database, along with 141 clinical samples from patients who underwent NAC. We identified key gene modules associated with stemness and immune traits, and developed a novel stem cell-immune risk score. This score effectively distinguished responders from non-responders to chemotherapy, and was significantly associated with overall survival. Through multi-omics analysis, we further elucidated the role of phospholysine phosphohistidine inorganic pyrophosphatase (LHPP) in the tumor immune microenvironment. Our findings showed that high LHPP expression was closely linked to the increased infiltration of antitumor immune cells, such as CD8+ T cells, and significantly suppressed the development of stemness characteristics in GC. Additionally, single-cell sequencing data revealed that tumor epithelial cells with low LHPP expression exhibited heightened stemness and demonstrated the strongest communication with CD8+-exhausted T cells. We also observed that LHPP inhibited stemness and chemotherapy resistance in GC cells by regulating the phosphorylation of GSK-3β. In conclusion, LHPP plays a critical regulatory role in the stemness features and tumor immune microenvironment of GC, presenting a promising biomarker and potential therapeutic target for personalized treatment of GC.

Condensates as a Culprit in RAS Activation and Inhibitor Resistance.

Therapy resistance is a significant cause of death in patients treated with targeted cancer therapy in diverse oncogene-driven cancers. A better understanding of resistance mechanisms can lay the foundation for improving existing and developing new therapies. A recent elegant study published in Nature Chemical Biology sheds light on a new resistance mechanism. The authors define a novel role for ARAF, a member of the RAF protein family (ARAF, BRAF, and CRAF), that is distinct from its previously understood role as a RAS effector and MEK protein kinase in the MAPK pathway. They describe how ARAF sequesters active RAS at the plasma membrane in phase-separated condensates to sustain signaling and prevent inactivation by the RAS GTPase-activating protein neurofibromin 1. This study underscores emerging roles for biomolecular condensates in cancer and highlights important implications for disrupting protein condensates to address treatment resistance to RAS (and RAS pathway)-targeted therapies. The study also illuminates evolutionary functional distinction between the RAF proteins and indicates unique biology for ARAF in normal physiology and disease.

Olverembatinib in chronic myeloid leukemia-Review of historical development, current status, and future research.

Once considered an incurable disease with a poor prognosis (median survival, 3-6 years), chronic myeloid leukemia (CML) is now managed with a diverse clinical armamentarium that includes BCR::ABL1 tyrosine kinase inhibitors (TKIs), which have largely normalized life expectancy in most patients in the chronic phase of the disease (CML-CP). Clinical challenges remain, including ABL1 mutation-driven treatment resistance (under the selection pressures exerted by TKIs), as well as treatment intolerance, which can involve potentially serious arterial occlusive events. Olverembatinib is a third-generation TKI approved in China for TKI-resistant CML-CP and accelerated-phase CML with the T135I mutation, as well as for CML-CP resistant to or intolerant of first- and/or second-generation TKIs. Olverembatinib exhibits a broad coverage of ABL1 mutants, including the gatekeeper T315I variant and compound mutations. In preclinical models, olverembatinib inhibited multiple downstream protein kinases, which has potentially opened avenues for future management of other malignancies, including acute myeloid and lymphoid leukemias, gastrointestinal tumors, and others. The pharmacokinetic profile of olverembatinib is compatible with alternate-day dosing. In clinical trials, olverembatinib exerted potent antileukemic effects in heavily pretreated patients with CML, including those with ponatinib or asciminib resistance or intolerance, and was well tolerated. Future studies include the phase 3 registrational POLARIS-1 (NCT06051409; in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia), POLARIS-2 (NCT06423911; in patients with CML with or without the T315I mutation), and POLARIS-3 (NCT06640361; in patients with succinate dehydrogenase-deficient gastrointestinal stromal tumors) clinical trials.

Running from depression: a review of aerobic exercise as an adjunctive treatment for mood disorders

Background: Mood disorders, including major depressive disorder (MDD) and anxiety disorders, significantly impact global mental health, contributing to disability and reduced quality of life. While pharmacotherapy and psychotherapy are standard treatments, many patients experience residual symptoms or treatment resistance. Aerobic exercise has emerged as a promising adjunctive intervention due to its psychological and neurobiological benefits. This review examines its efficacy, mechanisms, optimal implementation strategies, and integration into psychiatric care.Methods: A narrative literature review was conducted using PubMed, Embase, and other relevant databases, focusing on studies published up to 2025. Keywords such as "aerobic exercise," "depression," "anxiety," "psychiatric disorders," and "neurobiological mechanisms" were used to identify studies assessing clinical outcomes, neurobiological effects, and adherence factors.Results: Aerobic exercise significantly reduces depression and anxiety symptoms across diverse populations, with moderate-to-large effect sizes in randomized controlled trials. Mechanistically, it enhances neurotransmitter balance, increases brain-derived neurotrophic factor (BDNF), regulates the hypothalamic-pituitary-adrenal (HPA) axis, and improves cognitive function. Optimal outcomes are observed with moderate-intensity exercise (60–80% HRmax), performed three times per week for at least 8–12 weeks. Supervised and group-based interventions improve adherence, particularly in psychiatric populations.Conclusions: Aerobic exercise represents a viable, low-cost, and effective adjunct to traditional psychiatric treatments. However, methodological limitations, lack of long-term data, and adherence challenges remain. Future research should focus on standardized protocols, personalized exercise prescriptions, and large-scale, multi-center trials to maximize clinical integration and optimize patient outcomes.

Exploring the molecular pathways of miRNAs in testicular cancer: from diagnosis to therapeutic innovations.

Cancer diagnostics highlight the critical requirement for sensitive and accurate tools with functional biomarkers for early tumor detection, diagnosis, and treatment. With a high burden of morbidity and mortality among young men worldwide and an increasing prevalence, Testicular cancer (TC) is a significant death-related cancer. Along with patient history, imaging, clinical presentation, and laboratory data, histological analysis of the testicular tissue following orchiectomy is crucial. Although some patients in advanced stages who belong to a poor risk group die from cancer, surgical treatments and chemotherapeutic treatment offer a high possibility of cure in the early stages. Testicular tumors lack useful indicators despite their traditional pathological classification, which highlights the need to find and use blood tumor markers in therapy. Regretfully, the sensitivity and specificity of the currently available biomarkers are restricted. Novel non-coding RNA molecules, microRNAs (miRNAs), have recently been discovered, offering a potential breakthrough as viable biomarkers and diagnostic tools. They act as fundamental gene regulators at the post-transcriptional level, controlling cell proliferation, differentiation, and apoptosis. This article aims to comprehensively explore the role of miRNAs in the pathophysiology, diagnosis, and treatment of TC, with a focus on their regulatory mechanisms within key signaling pathways such as TGF-β, PTEN/AKT/mTOR, EGFR, JAK/STAT, and WNT/β-catenin. By investigating the potential of miRNAs as diagnostic and prognostic biomarkers and therapeutic targets, this study seeks to address challenges such as treatment resistance and evaluate the clinical importance of miRNAs in improving patient outcomes. Additionally, the work aims to explore innovative approaches, including nanoparticle-based delivery systems, to enhance the efficacy of miRNA-based therapies. Ultimately, this research aims to provide insights into future directions for precision medicine in TC, bridging the gap between molecular discoveries and clinical applications.

Targeting ferroptosis: a novel pathway in oral, oropharyngeal, hypopharyngeal, and laryngeal cancers.

Malignancies of the oral cavity, oropharynx, hypopharynx, and larynx rank as the seventh most prevalent cancers globally, characterized by high morbidity and mortality. Despite advancements in conventional therapies, these cancers often demonstrate recurrence and treatment resistance. This review investigates ferroptosis, an iron-dependent regulated cell death mechanism, as a novel therapeutic target to overcome resistance and recurrence in these cancers. A narrative review study was conducted using online databases, including PubMed, Google Scholar, Scopus, and Web of Science. The search incorporated keywords such as "ferroptosis", "oral squamous cell carcinoma", "oropharyngeal cancer", "hypopharyngeal cancer", "laryngeal cancer", "iron metabolism", and "lipid peroxidation". Studies focusing on molecular mechanisms, ferroptosis regulation, and therapeutic applications were included. Key findings highlighted the involvement of genes like CA9, CAV1, and SLC7 A11 in oral squamous cell carcinoma (OSCC), contributing to progression and resistance. Ferroptosis inducers such as resveratrol and quercetin effectively promoted ferroptosis in OSCC by targeting pathways like p53/SLC7 A11. In hypopharyngeal and oropharyngeal cancers, agents like ascorbic acid and RSL3 enhanced lipid peroxidation, while laryngeal cancers showed resistance through molecules like SLC3 A2 and KPNA2, which could be counteracted with targeted therapies. Nanotechnology-based approaches, including photodynamic therapy and nanofiber membranes, offer potential for localized and effective ferroptosis induction. Ferroptosis holds promise as a therapeutic strategy for treating head and neck cancers by addressing treatment resistance and recurrence. Future research should focus on optimizing combination therapies, understanding molecular heterogeneity, and translating preclinical findings into clinical applications to improve patient outcomes.

HBO1 determines epithelial-mesenchymal transition and promotes immunotherapy resistance in ovarian cancer cells.

Epithelial-mesenchymal transition (EMT) plays critical roles in tumor progress and treatment resistance of ovarian cancer (OC), resulting in the most deadly gynecological cancer in women. However, the cell-intrinsic mechanism underlying EMT in OC remains less illuminated. SKOV3, the OC cell line, was treated with TGF-β to induce EMT or with SB431542, an inhibitor of the TGF-β signaling pathway, to reduce migration. The function of HBO1 in EMT was confirmed by knock-down or overexpression of HBO1 in SKOV3 cells. The role of HBO1 in cell proliferation and apoptosis of SKOV3 cells was analyzed by flow cytometry. The whole-genome transcriptome was used to compare significantly different genes in control and HBO1-KD SKOV3 cells. T-cell cytotoxicity assays were measured by an IVIS spectrum. The chromatin binding of HBO1 was investigated using CUT&Tag-seq. Here, we show that HBO1, a MYST histone acetyltransferase (HAT), is a cell-intrinsic determinant for EMT in OC cells. HBO1 is greatly elevated during TGF-β-triggered EMT in SKOV3 OC cells as well as in later stages of clinical OC samples. HBO1 Knock-down (KD) in SKOV3 cells blocks TGF-β-triggered EMT, migration, invasion and tumor formation in vivo. Interestingly, HBO1 KD in SKOV3 cells suppresses their resistance to CAR-T cells. Mechanistically, HBO1 co-binds the gene sets responsible for EMT with SMAD4 and orchestrates a gene regulatory network critical for tumor progression in SKOV3 cells. HBO1 plays an essential onco-factor to drive EMT and promote the immunotherapy resistance in ovarian cancer cells. Together, we reveal a critical role of HBO1 mediated epigenetic mechanism in OC progression, providing an insight into designing new therapy strategies.

Rheumatoid Arthritis: Pathogenesis, Therapeutic Strategies, Advances, and Structural Activity Relationships of Synthesized Agents.

Rheumatoid arthritis (RA) is the most prevalent form of inflammatory arthritis, characterized by chronic inflammation of the synovial membrane. Current therapeutic options have advanced RA management significantly, yet limitations like adverse effects and treatment resistance underscore the need for novel therapeutic agents. Recent advancements have introduced promising candidates, including BTK inhibitors, JAK inhibitors, TLR4 inhibitors, COX-2 inhibitors, and LOX inhibitors, which target specific pathways implicated in RA pathogenesis. This manuscript provides a comprehensive overview of RA, emphasizing its pathophysiology, diagnostic approaches, and therapeutic strategies. Special attention is given to the structural-activity relationships (SAR) and mechanistic insights underlying emerging pharmacological interventions. Moreover, current challenges and future directions in RA drug discovery are critically examined, highlighting innovative wet-lab approaches to address unmet clinical needs.

Comparative Genomic Analysis of Key Oncogenic Pathways in Hepatocellular Carcinoma Among Diverse Populations

Background/Objectives: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, with significant racial and ethnic disparities in incidence, tumor biology, and clinical outcomes. Hispanic/Latino (H/L) patients tend to be diagnosed at younger ages and more advanced stages than Non-Hispanic White (NHW) patients, yet the molecular mechanisms underlying these disparities remain poorly understood. Key oncogenic pathways, including RTK/RAS, TGF-beta, WNT, PI3K, and TP53, play pivotal roles in tumor progression, treatment resistance, and response to targeted therapies. However, ethnicity-specific alterations within these pathways remain largely unexplored. This study aims to compare pathway-specific mutations in HCC between H/L and NHW patients, assess tumor mutation burden, and identify ethnicity-associated oncogenic drivers using publicly available datasets. Findings from this analysis may inform precision medicine strategies for improving early detection and targeted therapies in underrepresented populations. Methods: We conducted a bioinformatic analysis using publicly available HCC datasets to assess mutation frequencies in RTK/RAS, TGF-beta, WNT, PI3K, and TP53 pathway genes. This study included 547 patients, consisting of 69 H/L patients and 478 NHW patients. Patients were stratified by ethnicity (H/L vs. NHW) to evaluate differences in mutation prevalence. Chi-squared tests were used to compare mutation frequencies, while Kaplan–Meier survival analysis assessed overall survival differences associated with pathway-specific alterations in both populations. Results: Significant differences were observed in the RTK/RAS pathway-related genes, particularly in FGFR4 mutations, which were more prevalent in H/L patients compared to NHW patients (4.3% vs. 0.6%, p = 0.02). Additionally, IGF1R mutations exhibited borderline significance (7.2% vs. 2.9%, p = 0.07). In the PI3K pathway, INPP4B alterations were more frequent in H/L patients than in NHW patients (4.3% vs. 1%, p = 0.06), while, in the TGF-beta pathway, TGFBR2 mutations were more common in H/L patients (2.9% vs. 0.4%, p = 0.07), suggesting potential ethnicity-specific variations. Survival analysis revealed no significant differences in overall survival between H/L and NHW patients, indicating that molecular alterations alone may not fully explain survival disparities and suggesting a role for additional factors such as immune response, environmental exposures, or access to targeted therapies. Conclusions: This study provides one of the first ethnicity-focused analyses of key oncogenic pathway alterations in HCC, revealing distinct molecular differences between H/L and NHW patients. The findings suggest that RTK/RAS (FGFR4, IGF1R), PI3K (INPP4B), and TGF-beta (TGFBR2) pathway alterations may play a distinct role in HCC among H/L patients, while their prognostic significance in NHW patients remains unclear. These insights emphasize the importance of incorporating ethnicity-specific molecular profiling into precision medicine approaches to improve early detection, targeted therapies, and clinical outcomes in HCC, particularly for underrepresented populations.

ELAINE 3: phase 3 study of lasofoxifene plus abemaciclib to treat ER+/HER2-, ESR1-mutated, metastatic breast cancer.

Endocrine therapy (ET) is recommended for patients with estrogen receptor-positive (ER+) metastatic breast cancer (mBC), but most patients will develop treatment resistance, often due to mutations in the ER-α-coding gene, ESR1. Therapeutic options are limited for endocrine-resistant mBC, particularly following treatment with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). Lasofoxifene had anti-tumor activity in two separate phase 2, open-label studies (ELAINE 1 and 2) when given as monotherapy or combined with abemaciclib. The phase 3, randomized ELAINE 3 trial will evaluate the efficacy and safety of lasofoxifene/abemaciclib versus fulvestrant/abemaciclib for locally advanced or metastatic, ER+/HER2- breast cancer with an ESR1 mutation that progressed after ET-CDK4/6i treatment. Enrollment is planned for up to 500 patients to evaluate progression-free survival as the primary endpoint.Clinical trial registration: www.clinicaltrials.gov identifier is NCT05696626.

Resistance in Lung Cancer Immunotherapy and How to Overcome It: Insights from the Genetics Perspective and Combination Therapies Approach

Lung cancer with the highest number of new cases diagnosed in Europe and in Poland, remains an example of malignancy with a very poor prognosis despite the recent progress in medicine. Different treatment strategies are now available for cancer therapy based on its type, molecular subtype and other factors including overall health, the stage of disease and cancer molecular profile. Immunotherapy is emerging as a potential addition to surgery, chemotherapy, radiotherapy or other targeted therapies, but also considered a mainstay therapy mode. This combination is an area of active investigation in order to enhance efficacy and overcome resistance. Due to the complexity and dynamic of cancer’s ecosystem, novel therapeutic targets and strategies need continued research into the cellular and molecular mechanisms within the tumour microenvironment. From the genetic point of view, several signatures ranging from a few mutated genes to hundreds of them have been identified and associated with therapy resistance and metastatic potential. ML techniques and AI can enhance the predictive potential of genetic signatures and model the prognosis. Here, we present the overview of already existing treatment approaches, the current findings of key aspects of immunotherapy, such as immune checkpoint inhibitors (ICIs), existing molecular biomarkers like PD-L1 expression, tumour mutation burden, immunoscore, and neoantigens, as well as their roles as predictive markers for treatment response and resistance.

ADORA2B promotes proliferation and migration in head and neck squamous cell carcinoma and is associated with immune infiltration

BackgroundAdenosine A2B receptor (ADORA2B), a G protein-coupled receptor, is implicated in tumor progression and immune regulation in various cancers. However, its specific role in head and neck squamous cell carcinoma (HNSC) remains largely unexplored. This study aims to elucidate the expression profile, prognostic value, immune modulatory role, and therapeutic potential of ADORA2B in HNSC.MethodsComprehensive bioinformatics analyses were performed using TCGA and GEO datasets to evaluate ADORA2B expression, clinical correlations, and prognostic significance in HNSC. Weighted gene co-expression network analysis (WGCNA) and functional enrichment analyses were conducted to explore ADORA2B-associated pathways. Immune infiltration was assessed via ESTIMATE and single-sample gene set enrichment analysis (ssGSEA). Immune checkpoint blockade (ICB) therapy sensitivity and drug sensitivity were analyzed using the IMvigor210 and NCI-60 databases, respectively. In vitro experiments, including siRNA-mediated ADORA2B knockdown, CCK-8 assays, colony formation, and wound healing assays, were performed to validate the oncogenic role of ADORA2B.ResultsADORA2B was significantly overexpressed in HNSC tumor tissues compared to adjacent normal tissues, and its expression correlated with advanced clinical stage as well as poor overall survival (OS) and progression-free survival (PFS). Functional enrichment analyses revealed significant downregulation of immune-related pathways in high ADORA2B expression groups. High ADORA2B expression was associated with a more immunosuppressive tumor microenvironment (TME), characterized by lower immune and stromal scores and reduced immune cell infiltration. Immunotherapy response analysis demonstrated that patients with high ADORA2B expression exhibited poorer outcomes following ICB therapy. Drug sensitivity analysis identified several agents, including Ixazomib citrate, Masitinib, and others, as potential therapeutic candidates for high ADORA2B expression patients. In vitro experiments confirmed that ADORA2B knockdown significantly inhibited HNSC cell proliferation, colony formation, and migration, underscoring its critical role in tumor progression.ConclusionADORA2B is a key oncogenic driver in HNSC, contributing to tumor proliferation, migration, and an immunosuppressive TME. Its high expression is associated with poor prognosis and reduced immunotherapy efficacy. Targeting ADORA2B may enhance therapeutic outcomes and overcome treatment resistance, highlighting its potential as a diagnostic, prognostic, and therapeutic biomarker.

The Role of GREMLIN1, a Bone Morphogenetic Protein Antagonist, in Cancer Stem Cell Regulation

Cancer remains a leading cause of death globally, characterized by uncontrolled cell proliferation, tumor growth and metastasis. Bone morphogenetic proteins (BMPs) and their growth differentiation factor (GDF) relatives are crucial regulators of developmental processes such as limb, kidney and lung formation, cell fate determination, cell proliferation, and apoptosis. Cancer stem cells (CSCs) are a subpopulation of self-renewing cells within tumors that possess stemness properties and a tumor cell-forming capability. The presence of CSCs in a tumor is linked to growth, metastasis, treatment resistance and cancer recurrence. The tumor microenvironment in which CSCs exist also plays a critical role in the onset, progression and treatment resistance in many cancers. Growth factors such as BMPs and GDFs counterbalance transforming growth factor-beta (TGF-β) in the maintenance of CSC pluripotency and cancer cell differentiation. BMP signaling typically functions in a tumor suppressor role in various cancers by inducing CSC differentiation and suppressing stemness characteristics. This differentiation process is vital, as it curtails the self-renewal capacity that characterizes CSCs, thereby limiting their ability to sustain tumor growth. The interplay between BMPs and their secreted antagonists, such as GREM1, Noggin and Chordin, adds another layer of complexity to CSC regulation. Human cancers such as gastric, colorectal, glioblastoma, and breast cancer are characterized by GREMLIN1 (GREM1) overexpression, leading to inhibition of BMP signaling, facilitating the maintenance of pluripotency in CSCs, thus promoting tumorigenesis. GREM1 overexpression may also contribute to CSC immune evasion, further exacerbating patient prognoses. In addition to BMP inhibition, GREM1 has been implicated as a target of fibroblast growth factor (FGF) → Sonic hedgehog (Shh) signaling, as well as the Wnt/Frizzled pathway, both of which may contribute to the maintenance of CSC stemness. The complex role of BMPs and their antagonists in regulating CSC behavior underscores the importance of a balanced BMP signaling pathway. This article will summarize current knowledge of BMP and GREM1 regulation of CSC function, as well as conflicting data on the exact role of GREM1 in modulating CSC biology, tumor formation and cancer. Targeting this pathway by inhibiting GREM1 using neutralizing antibodies or small molecules may hold early-stage promise for novel therapeutic strategies aimed at reducing CSC burden in cancers and improving patient outcomes.

Experimental System Design and Modelling of EGFR Extracellular Domain and Its Mutant Binding to Antibody Interacting Partner

The EGFR pathway is activated by ligand binding, and EGFR overexpression is linked to malignancies like colorectal and head and neck cancer. This pathway is targeted by monoclonal antibodies such as Cetuximab; however, drug resistance can arise, frequently because of EGFR gene alterations like mutation, particularly in domain III, which inhibits Cetuximab binding. EGFR and MEGFR (R497K mutated EGFR) plasmids were transfected into Chinese hamster ovary (CHO) cells, which do not express EGFR. Real-time PCR was performed using probes that were specifically developed for the R497K mutation. Furthermore, Cetuximab binding to EGFR and MEGFR was examined using molecular modeling. According to molecular modeling, the R497K mutation modifies the domain III structure, which lowers the binding affinity of Cetuximab. Curiously, Cetuximab also showed binding to MEGFR’s domain IV. Real-time PCR showed that the probes specifically identified MEGFR in transfected CHO cells. The R497K mutation may result in treatment resistance by decreasing Cetuximab binding or increasing competitive ligand binding. Therefore, for individualized treatment, it is essential to find EGFR mutations in patient tumor samples. The R497K mutation may be successfully detected by the designed oligonucleotide probes, allowing for the early identification of potential resistance and directing the development of suitable treatment strategies.

CXCR4/CXCL12 blockade therapy; a new horizon in TNBC therapy.

The only subtype of breast cancer (BC) without specific therapy is triple-negative breast cancer (TNBC), which represents 15-20% of incidence cases of BC. TNBC encompasses transformed and nonmalignant cells, including cancer-associated fibroblasts (CAF), endothelial vasculature, and tumor-infiltrating cells. These nonmalignant cells, soluble factors (e.g., cytokines), and the extracellular matrix (ECM) form the tumor microenvironment (TME). The TME is made up of these nonmalignant cells, ECM, and soluble components, including cytokines. Direct cell-to-cell contact and soluble substances like cytokines (e.g., chemokines) may facilitate interaction between cancer cells and the surrounding TME. Through growth-promoting cytokines, TME not only enables the development of cancer but also confers therapy resistance. New treatment targets will probably be suggested by comprehending the processes behind tumor development and progression as well as the functions of chemokines in TNBC. In this light, several investigations have shown the pivotal function of the C-X-C motif chemokine ligand 12 (CXCL12 or SDF-1) axis and chemokine receptor type 4 (CXCR4) in the pathophysiology of TNBC. This review provides an overview of the CXCR4/CXCL12 axis' function in TNBC development, metastasis, angiogenesis, and treatment resistance. A synopsis of current literature on targeting the CXCR4/CXCL12 axis for treating and managing TNBC has also been provided.

Combination Treatment of Rituximab and Therapeutic Vaccines Affords Superior Tumor Suppression and Relapse Prevention for Non-Hodgkin Lymphoma.

Lymphoma, a common malignancy of the lymphatic system, presents considerable health challenges and imposes a significant economic burden. Despite advancements in chemotherapy and immunotherapy that have improved survival rates, issues such as high relapse rates and treatment resistance remain pressing concerns. This study presents a novel therapeutic strategy that combines rituximab with a therapeutic vaccine for human B-cell non-Hodgkin lymphoma, evaluated in a humanized mouse model. This combination therapy synergistically achieves superior tumor suppression and relapse prevention. By harnessing the tumor-killing efficacy of monoclonal antibodies and the T cell-mediated immunity elicited by vaccines, this approach represents a promising advancement in achieving significantly improved cancer treatment outcomes.

Ad-SGE-DKK3 Gene Therapy Overcomes Resistance to Immune Checkpoint Blockade in Pleural Mesothelioma.

Immune checkpoint inhibitors (ICIs) have limited efficacy in pleural mesothelioma. We investigated the role of Dickkopf WNT Signaling Pathway Inhibitor 3 (DKK3) in overcoming treatment resistance. We performed preclinical studies to elucidate DKK3's role in ICI-resistant mouse mesothelioma. Based on these findings, we conducted a single-arm, phase II clinical trial of a combination of Ad-SGE-DKK3 and nivolumab for chemotherapy-refractory epithelioid pleural mesothelioma, with objective response rate (ORR) as the primary outcome. DKK3 was significantly reduced in human epithelioid mesothelioma. Overexpression of DKK3 in cancer cells activated the p53 pathway, enhanced glycolysis, increased surface PD-L1, and reduced extracellular vesicle secretion and Colony Stimulating Factor 1 (CSF1). DKK3 sensitized the tumor-immune microenvironment to ICIs and enabled eradication of tumors by PD-1 blockade. In our trial, twelve patients received intratumoral Ad-SGE-DKK3 plus intravenous nivolumab. ORR was 16.6% and 41.7% had stable disease, for a 58.3% rate of durable clinical response (DCB). Median overall survival was 14.5 months, and median progression-free survival was 4.5 months. Grade 3 adverse events occurred in 41.7% of patients. Serial tumor biopsies and serum analyses revealed that DCB patients had increased tumor-infiltrating bulk and effector memory CD8 T cells, reduced circulating memory CD8 T cells, and sustained lower soluble mesothelin and CSF1 levels compared to progressors. Combination Ad-SGE-DKK3 plus nivolumab demonstrated a tolerable safety profile and potential efficacy in patients with chemotherapy-refractory epithelioid pleural mesothelioma. gov identifier: NCT04013334.

Understanding Enzalutamide-Resistance Based on a Functional Single-Cell Approach.

Anti-androgen or castration therapies are the mainstay treatment for metastatic prostate cancers (PCa). Although effective at first, androgen-dependent PCa (ADPC) universally develops therapy resistance, thereby evolving into an incurable disease called castration-resistant PCa (CRPC). Currently, mechanisms underlying the emergence of CRPC from ADPC are largely unclear. We used single-cell RNA-sequencing (scRNA-Seq) to determine the transcription heterogeneity of a therapy-naïve ADPC cell line-LNCaP and how it responded to the anti-androgen drug, enzalutamide. Based on the results, we used single-cell/colony-based cloning to isolate a pre-enzalutamide cell subset, displaying low and/or no expression of androgen receptor (ARlow/-). We found that most LNCaP cells expressed enzalutamide-target androgen receptor (AR+), while a small subpopulation (~10%) expressed low or no AR (ARlow/-). Gene set enrichment analysis (GSEA) revealed that AR+ and ARlow/- cells were enriched with significantly different gene expressions and signaling pathways. Unexpectedly, ARlow/- cells displayed robust transcriptional response, including upregulations of genes and pathways involved in clinical CRPC. Next, we isolated ARlow/- and AR+ cells from enzalutamide-naïve LNCaP cells and functionally confirmed the enzalutamide-resistant phenotype of ARlow/- cells in vitro and in xenograft models in vivo. Through xenograft-based single-nucleus RNA-Seq, we further found that the ARlow/- cells were selected, while the AR+ cells were de-selected in vivo by enzalutamide. Also, we found that the selection and expansion of ARlow/- clone were recapitulated in another enzalutamide-resistant cell model. In summary, our single-cell-based sequencing and functional tests suggest a clonal selection and expansion model of enzalutamide resistance, in which the pretreatment AR-low subpopulation is selected and expanded to confer treatment resistance.

Single-cell RNA sequencing in diffuse large B-cell lymphoma: tumor heterogeneity, microenvironment, resistance, and prognostic markers

Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous malignancy with challenges in treatment resistance and relapse. Single-cell RNA sequencing (scRNA-seq) has provided important insights into tumor heterogeneity, microenvironment interactions, resistance mechanisms, and prognostic biomarkers. This review summarizes key findings from scRNA-seq studies, which have deepened our understanding of DLBCL and contributed to the development of precision therapeutic strategies. Integrating scRNA-seq with spatial transcriptomics and single-cell multi-omics may further elucidate disease mechanisms and identify novel therapeutic targets, supporting the advancement of precision medicine in DLBCL.

Antimicrobial stewardship interventions in hospitalized adults with community-acquired pneumonia: a systematic review and meta-analysis.

This systematic review and meta-analysis evaluate the effectiveness of ASPs in managing community-acquired pneumonia (CAP), focusing on antibiotic optimization and resistance mitigation. Comprehensive literature searches were conducted in PubMed, Scopus, and Web of Science using PICOS criteria. Studies involving adults with CAP exposed to ASPs were included. Data on clinical, economic, diagnostic, and treatment outcomes were extracted. Random-effects meta-analysis using R software pooled effect sizes. Outcomes reported in at least three studies were analyzed for robustness. ASPs did not significantly impact in-hospital mortality, length of stay, 30-day readmissions, sample collection rates, or intravenous antibiotic duration. However, notable improvements included shorter time to clinical stability and a 31% reduction in 30-day mortality. Legionella urinary antigen testing frequency increased nearly threefold, and the time from admission to antibiotic initiation was reduced. Enhanced adherence to timely antibiotic administration and recommended regimens was observed, though outcome variability persisted. ASPs significantly improve CAP management by enhancing clinical stability and accelerating antibiotic initiation. Multifaceted strategies, including rapid diagnostics and clinician education, yield clinical benefits. However, outcome variability suggests a need for tailored interventions. Future research should isolate specific ASP components influencing prescriber behavior. Ongoing investment in education, diagnostics, and interdisciplinary collaboration is vital to optimize CAP treatment and combat antibiotic resistance.