Novel strategies in HPV­16­related cervical cancer treatment: An in vitro study of combined siRNA-E5 with oxaliplatin and ifosfamide chemotherapy.

BACKGROUND: Cervical cancer, primarily caused by HPV infection, remains a global health concern. Current treatments face challenges including drug resistance and toxicity. This study investigates combining E5-siRNA with chemotherapy drugs, Oxaliplatin and Ifosfamide, to enhance treatment efficacy in HPV-16 positive cervical cancer cells, targeting E5 oncoprotein to overcome limitations of existing therapies. METHODS: The CaSki cervical cancer cell line was transfected with E5-siRNA, and subsequently treated with Oxaliplatin/Ifosfamide. Quantitative real-time PCR was employed to assess the expression of related genes including p53, MMP2, Nanog, and Caspases. Cell apoptosis, cell cycle progression, and cell viability were evaluated using Annexin V/PI staining, DAPI staining, and MTT test, respectively. Furthermore, stemness ability was determined through a colony formation assay, and cell motility was assessed by wound healing assay. RESULTS: E5-siRNA transfection significantly reduced E5 mRNA expression in CaSki cells compared to the control group. The MTT assay revealed that monotherapy with E5-siRNA, Oxaliplatin, or Ifosfamide had moderate effects on cell viability. However, combination therapy showed synergistic effects, reducing the IC50 of Oxaliplatin from 11.42 × 10-8 M (45.36 µg/ml) to 6.71 × 10-8 M (26.66 µg/ml) and Ifosfamide from 12.52 × 10-5 M (32.7 µg/ml) to 8.206 × 10-5 M (21.43 µg/ml). Flow cytometry analysis demonstrated a significant increase in apoptosis for combination treatments, with apoptosis rates rising from 11.02 % (Oxaliplatin alone) and 16.98 % (Ifosfamide alone) to 24.8 % (Oxaliplatin + E5-siRNA) and 34.9 % (Ifosfamide + E5-siRNA). The sub-G1 cell population increased from 15.7 % (Oxaliplatin alone) and 18 % (Ifosfamide alone) to 21.9 % (Oxaliplatin + E5-siRNA) and 27.1 % (Ifosfamide + E5-siRNA), indicating cell cycle arrest. The colony formation assay revealed a substantial decrease in the number of colonies following combination treatment. qRT-PCR analysis showed decreased expression of stemness-related genes CD44 and Nanog, and migration-related genes MMP2 and CXCL8 in the combination groups. Apoptosis-related genes Casp-3, Casp-9, and pP53 showed increased expression following combination therapy, while BAX expression increased and BCL2 expression decreased relative to the control. CONCLUSION: The study demonstrates that combining E5-siRNA with Oxaliplatin or Ifosfamide enhances the efficacy of chemotherapy in HPV-16 positive cervical cancer cells. This synergistic approach effectively targets multiple aspects of cancer cell behavior, including proliferation, apoptosis, migration, and stemness. The findings suggest that this combination strategy could potentially allow for lower chemotherapy doses, thereby reducing toxicity while maintaining therapeutic efficacy. This research provides valuable insights into targeting HPV E5 as a complementary approach to existing therapies focused on E6 and E7 oncoproteins, opening new avenues for combination therapies in cervical cancer treatment.

Preventive and therapeutic effects of a super-multivalent sialylated filamentous bacteriophage against the influenza virus.

The resurgence of influenza viruses as a significant global threat emphasizes the urgent need for innovative antiviral strategies beyond existing treatments. Here, we present the development and evaluation of a novel super-multivalent sialyllactosylated filamentous phage, termed t-6SLPhage, as a potent entry blocker for influenza A viruses. Structural variations in sialyllactosyl ligands, including linkage type, valency, net charge, and spacer length, were systematically explored to identify optimal binding characteristics against target hemagglutinins and influenza viruses. The selected SLPhage equipped with optimal ligands, exhibited exceptional inhibitory potency in in vitro infection inhibition assays. Furthermore, in vivo studies demonstrated its efficacy as both a preventive and therapeutic intervention, even when administered post-exposure at 2 days post-infection, under 4 lethal dose 50% conditions. Remarkably, co-administration with oseltamivir revealed a synergistic effect, suggesting potential combination therapies to enhance efficacy and mitigate resistance. Our findings highlight the efficacy and safety of sialylated filamentous bacteriophages as promising influenza inhibitors. Moreover, the versatility of M13 phages for surface modifications offers avenues for further engineering to enhance therapeutic and preventive performance.

Napabucasin deactivates STAT3 and promotes mitoxantrone-mediated cGAS-STING activation for hepatocellular carcinoma chemo-immunotherapy.

The immune resistance of tumor microenvironment (TME) causes immune checkpoint blockade therapy inefficient to hepatocellular carcinoma (HCC). Emerging strategies of using chemotherapy regimens to reverse the immune resistance provide the promise for promoting the efficiency of immune checkpoint inhibitors. The induction of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) in tumor cells evokes the adaptive immunity and remodels the immunosuppressive TME. In this study, we report that mitoxantrone (MIT, a chemotherapeutic drug) activates the cGAS-STING signaling pathway of HCC cells. We provide an approach to augment the efficacy of MIT using a signal transducer and activator of transcription 3 (STAT3) inhibitor called napabucasin (NAP). We prepare an aminoethyl anisamide (AEAA)-targeted polyethylene glycol (PEG)-modified poly (lactic-co-glycolic acid) (PLGA)-based nanocarrier for co-delivery of MIT and NAP. The resultant co-nanoformulation can elicit the cGAS-STING-based immune responses to reshape the immunoresistant TME in the mice orthotopically grafted with HCC. Consequently, the resultant co-nanoformulation can promote anti-PD-1 antibody for suppressing HCC development, generating long-term survival, and inhibiting tumor recurrence. This study reveals the potential of MIT to activate the cGAS-STING signaling pathway, and confirms the feasibility of nano co-delivery for MIT and NAP on achieving HCC chemo-immunotherapy.

Paeoniae radix overcomes resistance to EGFR-TKIs via aurora B pathway suppression in lung adenocarcinoma.

Targeted therapies using epidermal growth factor receptor (EGFR) inhibitors have markedly improved survival rates and quality of life for patients with EGFR-mutant lung adenocarcinoma (LUAD). Despite these advancements, resistance to EGFR inhibitors remains a significant challenge, limiting the overall effectiveness of the treatment. This study explored the synergistic effects of combining Paeoniae Radix (PR) with first-generation EGFR-tyrosine kinase inhibitors (TKIs), erlotinib and gefitinib, to overcome this resistance. Transcriptomic analysis of EGFR-mutant LUAD cell lines revealed that PR treatment could potentially reverse the gene signatures associated with resistance to EGFR-TKIs, primarily through the suppression of the Aurora B pathway. Experimental validation demonstrated that combining PR with erlotinib and gefitinib enhanced drug responsiveness by inhibiting Aurora kinase activity and inducing apoptosis in LUAD cells. Additionally, gene expression changes confirmed these combined effects, with the suppression of the Aurora B pathway and upregulation of the apoptotic pathway, which was accompanied by increased expression of multiple pro-apoptotic genes. Our findings contribute to the development of natural product-based therapeutic strategies to mitigate drug resistance in LUAD.

Exploring intranasal drug delivery via nanocarriers: A promising glioblastoma therapy.

Glioblastoma is one of the most recurring types of glioma, having the highest mortality rate among all other gliomas. Traditionally, the standard course of treatment for glioblastoma involved maximum surgical resection, followed by chemotherapy and radiation therapy. Nanocarriers have recently focused on enhancing the chemotherapeutic administration to the brain to satisfy unmet therapeutic requirements for treating brain-related disorders. Due to the significant drawbacks and high recurrence rates of gliomas, intranasal administration of nanocarrier systems presents several advantages. These include low toxicity, non-invasiveness, and the ability to cross the blood-brain barrier. By customizing their size, encasing them with mucoadhesive agents, or undergoing surface modification that encourages movement over the nose's mucosa, we can exceptionally engineer nanocarriers for intranasal administration. Olfactory and trigeminal nerves absorb drugs administered nasally and transport them to the brain, serving as the primary delivery mechanism for nose-to-brain administration. This review sums up the latest developments in chemotherapeutic nanocarriers, such as metallic nanoparticles, polymeric nanoparticles, nanogels, nano vesicular carriers, genetic material-based nanocarriers, and polymeric micelles. These nanocarriers have demonstrated efficient drug delivery from the nose to the brain, effectively overcoming mucociliary clearance. However, challenges persist, such as limitations in targeted chemotherapy and restricted drug loading capacity for intranasal administration. Additionally, the review addresses regulatory considerations and prospects for these innovative drug delivery systems.

Oral toxicity assessment and the mitigation of lung carcinogenesis by phytol and α-bisabolol combination treatment in swiss albino mice: insights into redox enzyme modulation and caspase-dependent cell death mechanisms.

This study examined the safety and potential anti-lung cancer effects of combinations of phytol and α-bisabolol in Swiss albino mice. Both acute and subacute toxicity assessments showed that the combination of phytol and α-bisabolol is safe, with no adverse effects observed at higher concentrations. Hematological, biochemical, and histopathological tests showed no signs of toxicity in the heart, lungs, liver, spleen, and kidneys. The LD50 was greater than 2000 mg/kg, indicating a large safety margin. Histopathological analysis confirmed cancer induction in the B(a)P-induced group, which had significantly altered relative lung weights. Lung weight increased slightly pre and post-treatment, but histopathology showed normal alveolar epithelium. GSH and SOD levels increased significantly in B(a)P-exposed groups, indicating an adaptive antioxidant response. CAT levels increased significantly in the post-treatment group, demonstrating the role of combination of phytol and α-bisabolol in protecting against B(a)P-induced oxidative damage. Upregulation of Bax and downregulation of Bcl-2 caused a pro-apoptotic environment, suggesting a way to inhibit malignant cell survival. Modulation of caspase-3 and caspase-9 showed the complexity of carcinogen-induced apoptotic signaling. In conclusion, phytol and α-bisabolol were found to be safe and organ-protective, and demonstrated no acute or subacute toxicity. They modulate antioxidant defenses and apoptotic pathways, which may help prevent and treat lung cancer.

Cabozantinib enhances CAIX specific CAR-T cells against renal cancer by improving effector functions and augmenting tumor immune microenvironment.

Despite demonstrating promising outcomes in treating hematologic malignancies, the efficacy of chimeric antigen receptor-modified T (CAR-T) cell therapy remains limited when applied to solid tumors due to tumor immune microenvironment (TIME). Strategies to augment CAR-T cell efficacy against solid tumors have been investigated by ameliorating TIME to a certain extent. In this study, Cabozantinib was utilized in combination with CAR-T cells targeting carbonic anhydrase IX (CAIX) for the treatment of renal cancer. Our findings indicate that combination therapy with CAIX-CAR-T and Cabozantinib demonstrated synergistic efficacy against an orthotopic xenograft tumor model and a subcutaneous tumor model of renal cell carcinoma in mice. Mechanistically, it was observed that CAR-T cells combined with Cabozantinib led to an increase in the infiltration of tumor-infiltrating T cells, while reducing tumor-associated macrophages and M2 polarization. Additionally, Cabozantinib blocked the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis by decreasing the expression of PD-L1 in tumor cells and PD-1 in T cells. Furthermore, Cabozantinib promoted CAR-T cell effector function and reduced T cell exhaustion. This combination therapy represents a novel approach to enhancing CAR-T cell efficacy against solid tumors and holds significant promise for advancing CAR-T cell therapy in clinical settings.

Impact of porin deficiency on the synergistic potential of colistin in combination with ß-lactam/ß-lactamase inhibitors against ESBL- and carbapenemase-producing Klebsiella pneumoniae.

Combinations of colistin and ß-lactam/ß-lactamase inhibitors (BLBLIs) have shown in vitro synergy against ß-lactamase-producing strains. However, data are limited and conflicting, potentially attributed to variations among the examined strains. This study investigated whether loss of porins OmpK35 and OmpK36 impacts the synergistic potential of colistin in combination with ceftazidime-avibactam or meropenem-avibactam against ß-lactamase-producing Klebsiella pneumoniae. Genetically modified strains were constructed by introducing blaCTX-M-15, blaKPC-2, and blaOXA-48 chromosomally into K. pneumoniae ATCC 35657, in which the major porin-encoding genes (ompK35, ompK36) were either intact or knocked out. The in vitro activity of colistin in combination with ceftazidime-avibactam or meropenem-avibactam was evaluated by time-lapse microscopy screening and in static time-kill experiments. The deletion of porins in the ß-lactamase-producing strains resulted in 2- to 128-fold increases in MICs for the ß-lactams and BLBLIs. The activity of avibactam was concentration-dependent, and 4- to 16-fold higher concentrations were required to achieve similar inhibition of the ß-lactamases in strains with porin loss. In the screening, synergy was observed for colistin and ceftazidime-avibactam against the CTX-M-15-producing strains and colistin and meropenem-avibactam against the KPC-2- and OXA-48-producing strains. The combination effects were less pronounced in the time-kill experiments, where synergy was rarely detected. No apparent associations were found between the loss of OmpK35 and OmpK36 and combination effects with colistin and BLBLIs, indicating that additional factors determine the synergistic potential of such combinations.

The enhancing effects of selenomethionine on harmine in attenuating pathological cardiac hypertrophy via glycolysis metabolism.

Pathological cardiac hypertrophy, a common feature in various cardiovascular diseases, can be more effectively managed through combination therapies using natural compounds. Harmine, a ß-carboline alkaloid found in plants, possesses numerous pharmacological functions, including alleviating cardiac hypertrophy. Similarly, Selenomethionine (SE), a primary organic selenium source, has been shown to mitigate cardiac autophagy and alleviate injury. To explores the therapeutic potential of combining Harmine with SE to treat cardiac hypertrophy. The synergistic effects of SE and harmine against cardiac hypertrophy were assessed in vitro with angiotensin II (AngII)-induced hypertrophy and in vivo using a Myh6R404Q mouse model. Co-administration of SE and harmine significantly reduced hypertrophy-related markers, outperforming monotherapies. Transcriptomic and metabolic profiling revealed substantial alterations in key metabolic and signalling pathways, particularly those involved in energy metabolism. Notably, the combination therapy led to a marked reduction in the activity of key glycolytic enzymes. Importantly, the addition of the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) did not further potentiate these effects, suggesting that the antihypertrophic action is predominantly mediated through glycolytic inhibition. These findings highlight the potential of SE and harmine as a promising combination therapy for the treatment of cardiac hypertrophy.

Evaluation of the effectiveness and safety of combining PD-1/PD-L1 inhibitors with anti-angiogenic agents in unresectable hepatocellular carcinoma: a systematic review and meta-analysis.

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality globally, particularly when diagnosed at an unresectable stage. Traditional treatments for advanced HCC have limited efficacy, prompting the exploration of combination therapies. This systematic review and meta-analysis evaluate the effectiveness and safety of combining PD-1/PD-L1 inhibitors with anti-angiogenic agents in patients with unresectable HCC. Methods: A comprehensive literature search was conducted in PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science, including studies up to June 2024. Randomized controlled trials (RCTs) comparing combination therapy (PD-1/PD-L1 inhibitors with anti-angiogenic agents) to monotherapy or standard treatments in unresectable HCC patients were included. Data were synthesized using random-effects models, with pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and risk ratios (RRs) for objective response rate (ORR) and adverse events (AEs). Results: Five Phase III RCTs involving 1515 patients were included. Combination therapy significantly improved OS (HR: 0.71, 95% CI: 0.60-0.85) and PFS (HR: 0.64, 95% CI: 0.53-0.77) compared to monotherapy or standard treatments. The pooled OR for ORR was 1.27 (95% CI: 1.57-2.11), indicating a higher response rate with combination therapy. However, the risk of AEs was also higher in the combination therapy group (RR: 1.04, 95% CI: 1.02-1.06). Subgroup analyses revealed consistent benefits across different types of PD-1/PD-L1 inhibitors and anti-angiogenic agents, with no significant publication bias detected. Conclusions: The combination of PD-1/PD-L1 inhibitors with anti-angiogenic agents offers significant benefits in improving OS and PFS in patients with unresectable HCC, although it is associated with an increased risk of adverse events.

Breaking the barrier: Epigenetic strategies to combat platinum resistance in colorectal cancer.

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Platinum-based drugs, such as cisplatin and oxaliplatin, are frontline chemotherapy for CRC, effective in both monotherapy and combination regimens. However, the clinical efficacy of these treatments is often undermined by the development of drug resistance, a significant obstacle in cancer therapy. In recent years, epigenetic alterations have been recognized as key players in the acquisition of resistance to platinum drugs. Targeting these dysregulated epigenetic mechanisms with small molecules represents a promising therapeutic strategy. This review explores the complex relationship between epigenetic changes and platinum resistance in CRC, highlighting current epigenetic therapies and their effectiveness in countering resistance mechanisms. By elucidating the epigenetic underpinnings of platinum resistance, this review aims to contribute to ongoing efforts to improve treatment outcomes for CRC patients.

High efficacy of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in Black adults in the United States, including those with pre-existing HIV resistance and suboptimal adherence.

BRAAVE (NCT03631732), a Phase 3b, multicenter, open-label US study, demonstrated the efficacy of switching to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) among Black individuals with suppressed HIV through 48 weeks. Here, 72-week resistance, adherence, and virologic outcomes are presented. Enrollment criteria permitted nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistance (R), protease inhibitor (PI)-R, and certain nucleos(t)ide reverse transcriptase inhibitor (NRTI)-R (M184V/I allowed; ≥3 thymidine analog mutations [TAMs] excluded); but excluded primary integrase strand transfer inhibitor (INSTI)-R. Pre-existing resistance was determined using historical genotypes and retrospective baseline proviral DNA genotyping. Adherence, virologic outcomes, and viral blips were assessed. Of 489 participants receiving B/F/TAF with ≥1 post-switch HIV-1 RNA measurement: pre-existing NRTI-R (15% of participants), M184V/I (11%), ≥1 TAMs (8%), NNRTI-R (22%), and PI-R (13%) were observed; pre-existing INSTI-R substitutions (2%) were detected post-randomization; mean viral blip frequency was 0.9% across all timepoints (unassociated with virologic failure); 24% of participants had <95% adherence (98% of whom had HIV-1 RNA <50 copies/mL at last visit); none had treatment-emergent study-drug resistance. Overall, 99% of participants, including all with baseline NRTI-R/INSTI-R, had HIV-1 RNA <50 copies/mL at the last visit, demonstrating that B/F/TAF maintained virologic suppression through 72 weeks regardless of pre-existing resistance, viral blips, and suboptimal adherence.

Bioorthogonal Regulated Metabolic Balance for Promotion of Ferroptosis and Mild Photothermal Therapy.

The nanozyme with NADPH oxidase (NOX)-like activity can promote the consumption of NADPH and the generation of free radicals. In consideration of that the upregulation of glucose-6-phosphate dehydrogenase (G6PD) would accelerate the compensation production of NADPH, for inhibition of G6PD activity, our designed bioorthogonal nanozyme can in situ catalyze pro-DHEA to produce G6PD inhibitor and dehydroepiandrosterone (DHEA) drugs to inhibit G6PD activity. Therefore, the well-defined platform can disrupt NADPH homeostasis, leading to the collapse of the antioxidant defense system in the tumor cells. The enzyme-like activity of PdCuFe is further enhanced when irradiated by NIR-II light. The destruction of NADPH homeostasis can promote ferroptosis and, in turn, facilitate mild photothermal therapy. Our design can realize NADPH depletion and greatly improve the therapeutic effect through metabolic regulation, which may provide inspiration for the design of bioorthogonal catalysis.

Formulation Strategies to Overcome Amphotericin B Induced Toxicity.

Fungal infection poses a major global threat to public health because of its wide prevalence, severe mortality rate, challenges involved in diagnosis and treatment, and the emergence of drug-resistant fungal strains. Millions of people are getting affected by fungal infection, and around 3.8 million people face death per year due to fungal infection, as per the latest report. The polyene antibiotic AmB has an extensive record of use as a therapeutic moiety against systemic fungal infection and leishmaniasis since 1960. AmB has broad-spectrum fungistatic and fungicidal activity. AmB exerts its therapeutic activity at the cellular level by binding to fungal sterol and forming hydrophilic pores, releasing essential cellular components and ions into the extracellular fluid, leading to cell death. Despite using AmB as an antifungal and antileishmanial at a broad scale, its clinical use is limited due to drug-induced nephrotoxicity resulting from binding the aggregated form of the drug to mammalian sterol. To mitigate AmB-induced toxicity and to get better anti-fungal therapeutic outcomes, researchers have developed nanoformulations, self-assembled formulations, prodrugs, cholesterol- and albumin-based AmB formulations, AmB-mAb combination therapy, and AmB cochleates. These formulations have helped to reduce toxicity to a certain extent by controlling the aggregation state of AmB, providing sustained drug release, and altering the physicochemical and pharmacokinetic parameters of AmB. Although the preclinical outcome of AmB formulations is quite satisfactory, its parallel result at the clinical level is insignificant. However, the safety and efficacy of AmB therapy can be improved at the clinical stage by continuous investigation and collaboration among researchers, clinicians, and pharmaceutical companies.

Oxytocin with calcium vs. oxytocin for induction of labor in women with term premature rupture of membranes: A randomized controlled trial: Oxytocin with calcium gluconate for labor induction.

BACKGROUND: Intravenous calcium administration has shown promise in enhancing uterine contractions and reducing blood loss during cesarean section, but this regimen has not been compared in vaginal labor induction. OBJECTIVE: To determine the efficacy of oxytocin combined with calcium versus oxytocin alone for inducing labor among women with term premature rupture of membranes (PROM). STUDY DESIGN: This single-blind, randomized control trial was conducted between October 2022 and May 2023 in a tertiary university hospital. Patients diagnosed with PROM were randomly allocated into two groups. The intervention group received a bolus of 10 mL of calcium gluconate followed by a continuous infusion of oxytocin via a pump (n = 210), whereas the control group received only oxytocin infusion (n = 218). The primary outcome was successful vaginal deliveries within 24 hours of labor induction. Secondary outcomes included the interval from labor induction to delivery, vaginal delivery blood loss, and maternal and neonatal complications. RESULTS: Baseline characteristics, including maternal age, BMI, Bishop score before labor induction, were comparable between groups. The rate of vaginal delivery within 24 hours of labor induction was statistically higher in the intervention group (79.52% vs. 70.64%; P = 0.04). Participants in intervention group experienced a shortened interval between induction and delivery (10.48 h vs. 11.25h; P = 0.037), and demonstrated a higher success rate in induction of labor assessed by the onset of active phase (93.80% vs. 87.61%; P = 0.04) without increasing the cesarean rate. Reduced hemorrhage was presented in the intervention group (242.5ml vs. 255.0ml; P = 0.0015) while the maternal and neonatal outcomes were comparable between groups. CONCLUSION: The co-administration of calcium and oxytocin in labor induction among pregnancies with PROM was more efficient and safer than oxytocin alone. Our research suggests that the combination therapy of calcium and oxytocin may offer significant advantages during the process of labor induction and result in better outcomes.

MTA-cooperative PRMT5 inhibitors enhance T cell-mediated antitumor activity in MTAP-loss tumors.

BACKGROUND: Hyperactivated protein arginine methyltransferases (PRMTs) are implicated in human cancers. Inhibiting tumor intrinsic PRMT5 was reported to potentiate antitumor immune responses, highlighting the possibility of combining PRMT5 inhibitors (PRMT5i) with cancer immunotherapy. However, global suppression of PRMT5 activity impairs the effector functions of immune cells. Here, we sought to identify strategies to specifically inhibit PRMT5 activity in tumor tissues and develop effective PRMT5i-based immuno-oncology (IO) combinations for cancer treatment, particularly for methylthioadenosine phosphorylase (MTAP)-loss cancer. METHODS: Isogeneic tumor lines with and without MTAP loss were generated by CRISPR/Cas9 knockout. The effects of two PRMT5 inhibitors (GSK3326595 and MRTX1719) were evaluated in these isogenic tumor lines and T cells in vitro and in vivo. Transcriptomic and proteomic changes in tumors and T cells were characterized in response to PRMT5i treatment. Furthermore, the efficacy of MRTX1719 in combination with immune checkpoint blockade was assessed in two syngeneic murine models with MTAP-loss tumor. RESULTS: GSK3326595 significantly suppresses PRMT5 activity in tumors and T cells regardless of the MTAP status. However, MRTX1719, a methylthioadenosine-cooperative PRMT5 inhibitor, exhibits tumor-specific PRMT5 inhibition in MTAP-loss tumors with limited immunosuppressive effects. Mechanistically, transcriptomic and proteomic profiling analysis reveals that MRTX1719 successfully reduces the activation of the PI3K pathway, a well-documented immune-resistant pathway. It highlights the potential of MRTX1719 to overcome immune resistance in MTAP-loss tumors. In addition, MRTX1719 sensitizes MTAP-loss tumor cells to the killing of tumor-reactive T cells. Combining MRTX1719 and anti-PD-1 leads to superior antitumor activity in mice bearing MTAP-loss tumors. CONCLUSION: Collectively, our results provide a strong rationale and mechanistic insights for the clinical development of MRTX1719-based IO combinations in MTAP-loss tumors.

Monotherapy or combination therapy in PsA: current aspects.

Psoriatic arthritis (PsA) is an immune-mediated inflammatory disease with heterogeneity regarding its clinical features, mainly affecting the skin and the musculoskeletal system; additionally, extra-musculoskeletal manifestations and comorbidities are common, adding complexity to its treatment. In the last decades, a plethora of therapeutic options have been available, including conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs), biological DMARDs (bDMARDs), and targeted synthetic DMARDs (tsDMARDs), and many recommendations have been published regarding the proper use of them in patients with PsA. In rheumatoid arthritis, the combination of conventional with bDMARDs or tsDMARDs is a common and recommended practice, whereas in PsA there is scarce data about the benefit of this combination. This review summarizes all the available data from randomized clinical trials, observational studies, and registries about the value of this therapeutic strategy.

Use of b/tsDMARDs in PsA: with or without csDMARDs Over the last years, many different b/ts DMARDs have been porven to be efficacious in psoriatic arthritis (PsA). Although in rheumatoid arthritis, it is established that most of these drugs work better in combination with conventional synthetic DMARDs (e.g methotrexate), this seems to be slightly different in PsA. Herein, we review the current literature about the combination therapy versus monotherapy of b/ts DMARDs in PsA. We present the results of this narrative review in a structured (per drug category) way, so that it is easier for the reader to find relevant information. There is no doubt that the currently available treatment options in PsA have changed the course of the disease and improved the functional status of the patients. However, as there is still a substantial proportion of patients who do not achieve remission or low disease activity, the need to find effective therapeutic regimens or follow different strategies is growing. In this direction, the combination of a conventional synthetic with biological or targeted synthetic DMARD does not seem to be more effective than the monotherapy of the latter. This seems to be more pronounced in the newer drug categories (anti-IL-17, anti-IL23 and JAKi) compared to the TNFi, where the co-administration of a csDMARD improves their survival.

Combination of immune checkpoint inhibitors and radiotherapy in locally advanced esophagogastric junction adenocarcinoma: A review.

Esophagogastric adenocarcinoma (EGJ-AC) poses a significant global health burden, characterized by high incidence rates and poor prognosis. Despite advancements in treatment modalities, including surgery, chemotherapy, and radiation therapy (RT), locally advanced EGJ-AC management remains challenging. Various preclinical and clinical studies have provided insights into the synergistic effects of combining immune checkpoint inhibitors (ICIs) with RT, further supporting the combination therapy in EGJ-AC. Immunotherapy, particularly ICIs, has emerged as a promising therapeutic approach in various malignancies, including EGJ-AC. This narrative review aims to critically examine the rationale behind combining ICIs with standard treatment modalities, including RT or chemoradiotherapy, in the preoperative setting for locally advanced EGJ-AC. A comprehensive literature search identified eight phase 2 randomized clinical trials evaluating the safety profile and oncologic outcomes of adding ICI agents to neoadjuvant chemoradiotherapy in this population. The results of enrolled trials show that the combination of ICIs with standard treatment modalities is a promising approach for improving survival and pathological response in patients with locally advanced EGJ-AC. This combination treatment was associated with mostly grade 1-2 immune-related toxicities, indicating its safety and tolerability. There were higher rates of complete or major pathologic responses compared to historical controls. Further studies, including large-scale randomized controlled trials, are needed to address remaining questions regarding the efficacy, safety, and long-term outcomes of combination therapy in this population.

Transarterial chemoembolization combined with sintilimab and lenvatinib for the treatment of unresectable hepatocellular carcinoma: a retrospective study.

BACKGROUND: The treatment of unresectable hepatocellular carcinoma (uHCC) challenging due to unfulfilled clinical requirements. OBJECTIVE: To evaluate the safety and efficacy of combining transarterial chemoembolization (TACE) with sintilimab and lenvatinib in the treatment of uHCC. METHODS: We retrospectively analyzed the data of patients with uHCC who were treated with a combination of TACE, sintilimab, and lenvatinib between May 2019 and December 2021 at the Chinese PLA General Hospital. Systemic treatment was started 1 week after TACE was performed. Sintilimab was administered intravenously at a dosage of 200 mg every three weeks, and lenvatinib was given orally at dosages of 8 mg or 12 mg daily, contingent upon the weight of the patients. The primary endpoint was the objective response rate (ORR) as per the mRECIST. Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and treatment-related adverse events (tr-AEs). RESULTS: A total of 32 patients were enrolled in the study. Among them, 9 patients were classified as Barcelona Clinic Liver Cancer-B (BCLC-B), 23 patients were classified as BCLC-C, 14 patients diagnosed with portal vein tumors, and 12 patients were diagnosed with extra hepatic metastases. The ORR and DCR were 75% and 90.6% respectively, with 4 patients exhibiting (12.5%) complete response, 20 patients exhibiting (62.5%) partial response, 5 patients exhibiting (15.6%) stable disease, and 3 patients exhibiting (9.4%) progressive disease. With a median follow-up time of 19.6 months, the median PFS was 9.9 months, and the median OS was 33.3 months. A total of 31 patients experienced different degrees of tr-AEs, of which 2 were grade 3 tr-AEs. CONCLUSION: The combination therapy of TACE, sintilimab, and lenvatinib demonstrates satisfactory efficacy in the treatment of uHCC with manageable tr-AEs.