Monotherapy Research Articles

Protective effects of long term antiplatelet and anticoagulant therapy in hospitalized patients with inflammatory bowel disease

BACKGROUND Inflammatory bowel disease (IBD), with its rising prevalence rates is associated with an increased risk of cardiovascular and thromboembolic events. Antiplatelets and/or anticoagulants agents are often prescribed but the literature on the impact of long-term anticoagulation and/or antiplatelet use among patients hospitalized with IBD is scarce. The aim of this study is to assess the outcomes of patients hospitalized with IBD on antiplatelet and/or anticoagulant agents. AIM To investigate the effects of long-term use of antiplatelets/anticoagulants on clinical outcomes in patients hospitalized with IBD. METHODS We conducted a retrospective cohort study using the Nationwide Inpatient Sample database, including all adult IBD patients hospitalized in the United States from 2016 to 2019. Patient cohorts were stratified based on antiplatelet/anticoagulant therapy status. Multivariate regression analysis was done to assess outcomes, adjusting for potential confounders. The primary outcome was mortality, whereas length of stay (LOS), total parenteral nutrition, acute kidney injury, sepsis, shock, gastrointestinal bleeding, need for colonoscopy/sigmoidoscopy, abdominal surgery and total hospitalization charges were secondary outcomes. RESULTS Among 374744 hospitalized IBD patients, antiplatelet or anticoagulant therapy alone was associated with significantly lower in-hospital mortality and reduced healthcare utilization, including shorter LOS and decreased hospitalization costs. Combined therapy was associated with a protective effect on mortality, but did not reach statistical significance. Notably, therapy did not exacerbate disease severity or complications, although higher odds of gastrointestinal bleeding were observed. CONCLUSION Our study highlights the potential benefits of long-term anticoagulation/antiplatelet therapy in hospitalized IBD patients, with improved mortality outcomes and healthcare utilization. While concerns regarding gastrointestinal bleeding exist, the overall safety profile suggests a role for these agents in mitigating thromboembolic risks without exacerbating disease severity. Further research is needed to look at optimal treatment strategies and addressing limitations to guide clinical decision-making in this population.

Oncogenic EML4-ALK assemblies suppress growth factor perception and modulate drug tolerance

Drug resistance remains a challenge for targeted therapy of cancers driven by EML4-ALK and related fusion oncogenes. EML4-ALK forms cytoplasmic protein condensates, which result from networks of interactions between oncogene and adapter protein multimers. While these assemblies are associated with oncogenic signaling, their role in drug response is unclear. Here, we use optogenetics and live-cell imaging to find that EML4-ALK assemblies suppress transmembrane receptor tyrosine kinase (RTK) signaling by sequestering RTK adapter proteins including GRB2 and SOS1. Furthermore, ALK inhibition, while suppressing oncogenic signaling, simultaneously releases the sequestered adapters and thereby resensitizes RTK signaling. Resensitized RTKs promote rapid and pulsatile ERK reactivation that originates from paracrine ligands shed by dying cells. Reactivated ERK signaling promotes cell survival, which can be counteracted by combination therapies that block paracrine signaling. Our results identify a regulatory role for RTK fusion assemblies and uncover a mechanism of tolerance to targeted therapies.

Remission rate, toxicity and pharmacokinetics of venetoclax-based induction regimens in untreated pediatric acute myeloid leukemia

The efficacy and safety of venetoclax in newly diagnosed pediatric acute myeloid leukemia (AML) are not well-established as they are in adults. Children newly diagnosed with AML were recommended for induction therapy with venetoclax and chemotherapy or hypomethylating agents (HMAs) as per for the ChiCTR1900027146 trial. Venetoclax was administered at a consistent dose of 200 mg/m2/day for 28 days, with adjustments when used concurrently with azoles. The study measured both the remission rates and the safety assessments of venetoclax. We enrolled 45 newly diagnosed pediatric patients with AML. The complete remission rates were 94.7% in the low/middle-risk group and 80.8% in the high-risk group; MRD-negative rates were 52.6% and 38.5% in the low/middle-risk group and high-risk group, respectively. Venetoclax based combination therapy was well tolerated by the majority of patients. The median duration of venetoclax dosing was 18 days (range 9–28), with hematological toxicity and infection being the most common adverse events. Venetoclax-based induction regimens demonstrated a high response rate and safety profile in newly diagnosed pediatric AML cases. This underscores the significance of venetoclax as a viable treatment option for untreated AML, extending beyond its role as salvage therapy for refractory/relapsed AML.

Comparative effectiveness of cognitive behavioural therapy, modafinil, and their combination for treating fatigue in multiple sclerosis (COMBO-MS): a randomised, statistician-blinded, parallel-arm trial

Fatigue is one of the most disabling symptoms reported by people with multiple sclerosis. Although behavioural and pharmacological interventions might be partly beneficial, their combined effects have not been evaluated for multiple sclerosis fatigue, or examined with sufficient consideration of characteristics that might affect treatment response. In this comparative effectiveness research trial, we compared the effectiveness of cognitive behavioural therapy (CBT), modafinil, and their combination for treating multiple sclerosis fatigue. This randomised, analyst-blinded, parallel-arm, comparative effectiveness trial was done at two universities in the USA. Adults (aged ≥18 years) with multiple sclerosis and problematic fatigue (Fatigue Severity Scale [FSS] score ≥4) were randomly assigned (1:1:1), using a web-based treatment assignment system with minimisation, to receive CBT, modafinil, or both for 12 weeks. Statisticians were masked to group assignment, but participants, study neurologists, CBT interventionalists, and coordinators were not masked to treatment assignment. The primary outcome was the change in Modified Fatigue Impact Scale (MFIS) from baseline to 12 weeks, assessed using multiple linear regression, adjusted for age, sex, study site, anxiety, pain, baselines MFIS score, and physical activity. Analyses were done by intent to treat. The trial was registered with clinicaltrials.gov, NCT03621761, and is completed. Between Nov 15, 2018, and June 2, 2021, 336 participants were randomly assigned treatment (114 assigned to CBT, 114 assigned to modafinil, and 108 assigned to combination therapy). At 12 weeks, CBT (n=103), modafinil (n=107), and combination therapy (n=102) were associated with clinically meaningful within-group MFIS reductions of 15·20 (SD 11·90), 16·90 (15·90), and 17·30 (16·20) points, respectively. Change in MFIS scores from baseline to 12 weeks did not differ between groups: relative to combination therapy, the adjusted total mean difference in MFIS change score was 1·88 (95% CI -2·21 to 5·96) for CBT and 1·20 (-2·83 to 5·23) for modafinil. Most common adverse events for modafinil-containing treatment groups included insomnia (eight [7%] for modafinil and eight [7%] for combination therapy) and anxiety (three [3%] for modafinil and nine [8%] for combination therapy). Modafinil, CBT, and combination therapy were associated with similar reductions in the effects of multiple sclerosis fatigue at 12 weeks. Combination therapy was not associated with augmented improvement compared with the individual interventions. Further research is needed to determine whether effects of these interventions on multiple sclerosis-related fatigue is influenced by sleep hygiene and sleepiness. No serious adverse events related to the study drug were encountered. Patient-Centered Outcomes Research Institute and National Multiple Sclerosis Society.

T-cell Responses to Individualized Neoantigen Therapy mRNA-4157 (V940) Alone or in Combination with Pembrolizumab in the Phase 1 KEYNOTE-603 Study.

mRNA-4157 (V940) is an individualized neoantigen therapy targeting up to 34 patient-specific tumor neoantigens to induce T-cell responses and potentiate antitumor activity. We report mechanistic insights into the immunogenicity of mRNA-4157 via characterization of T-cell responses to neoantigens from the first-in-human, phase 1, KEYNOTE-603 study (NCT03313778) in patients with resected non-small cell lung cancer (Part A: 1-mg mRNA-4157, n = 4) or resected cutaneous melanoma (Part D: 1-mg mRNA-4157 + 200-mg pembrolizumab, n = 12). Safety, tolerability, and immunogenicity were assessed. All patients experienced ≥1 treatment-emergent adverse event; there were no grade 4/5 adverse events or dose-limiting toxicities. mRNA-4157 alone induced consistent de novo and strengthened preexisting T-cell responses to targeted neoantigens. Following combination therapy, sustained mRNA-4157-induced neoantigen-specific T-cell responses and expansion of cytotoxic CD8 and CD4 T cells were observed. These findings show the potential of a novel mRNA individualized neoantigen therapy approach in oncology. Significance: The safety and immunogenicity results from this phase 1 study of mRNA-4157 as adjuvant monotherapy or combination therapy with pembrolizumab show generation of de novo and enhancement of existing neoantigen-specific T-cell responses and provide mechanistic proof of concept to support further development of mRNA-4157 for patients with resected solid tumors. See related commentary by Berraondo et al., p. 2021.

Effects of sitagliptin and L-theanine combination therapy on testicular tissue in rats with experimental diabetes

This study examines the impact of the combination of sitagliptin and L-theanine on the testis tissue of rats with experimental diabetes. Diabetes mellitus, a chronic metabolic illness, significantly reduces quality of life and can cause male infertility by decreasing sperm count, motility, and testosterone levels. Rats were allocated to five separate groups: control, diabetes, L-theanine, sitagliptin, and combination therapy. The measurements encompassed blood glucose levels, body weight, serum insulin levels, and the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). The histological examination of testicular tissue was conducted using H&E, PASH, caspase-12, and PCNA staining techniques, in addition to a TUNEL assay to detect apoptosis. Levels of oxidative stress indicators, including glutathione peroxidase (GPX), malondialdehyde (MDA), and catalase, were also evaluated. The results showed that the group of individuals with diabetes had significantly higher levels of blood glucose, apoptotic indices, GPX, catalase, and MDA levels and activities in comparison with the control group. Although both the L-theanine and sitagliptin groups exhibited some improvement, the combination therapy demonstrated the most significant decrease in histopathological damage and apoptotic markers. These results indicate that the combination of sitagliptin and L-theanine may significantly decrease testicular damage caused by diabetes, making it a promising therapeutic strategy.

SMYD family in cancer: epigenetic regulation and molecular mechanisms of cancer proliferation, metastasis, and drug resistance.

Epigenetic modifiers (miRNAs, histone methyltransferases (HMTs)/demethylases, and DNA methyltransferases/demethylases) are associated with cancer proliferation, metastasis, angiogenesis, and drug resistance. Among these modifiers, HMTs are frequently overexpressed in various cancers, and recent studies have increasingly identified these proteins as potential therapeutic targets. In this review, we discuss members of the SET and MYND domain-containing protein (SMYD) family that are topics of extensive research on the histone methylation and nonhistone methylation of cancer-related genes. Various members of the SMYD family play significant roles in cancer proliferation, metastasis, and drug resistance by regulating cancer-specific histone methylation and nonhistone methylation. Thus, the development of specific inhibitors that target SMYD family members may lead to the development of cancer treatments, and combination therapy with various anticancer therapeutic agents may increase treatment efficacy.

Safety and Efficiency of Anti-VEGF with Dexamethasone Intravitreal Implant for Non-Ischemic Retinal Vein Occlusion: A Prospective, Case-controlled, Cohort Study.

This study aimed to assess the efficacy and safety of anti-VEGF combined with dexamethasone implant for the retinal vein occlusion patients with macular edema. In this prospective, case-controlled, cohort clinical trial (Register ID: ChiCTR2400080048), patients with non-ischemic retinal vein occlusion were enrolled from the Sanmenxia Central Hospital from August 2020 to April 2023. The patients were randomized into two groups. All the patients received ranibizumab intravitreal injection in the first 3 consecutive months. For the ranibizumab group, anti-VEGF injections were as needed thereafter in case of recurrence of macular edema; For the combination group, the patients received an intravitreal dexamethasone implant injection at 15 days after the first ranibizumab injection. The primary outcome measurements were improvement in best corrected visual acuity (BCVA) and reduction in central macular thickness (CMT). The secondary outcomes were recurrence of macular edema, number of intravitreal injections, and injection interval. Safety profiles were also recorded. A total of 124 patients were included, of which 73 patients completed all follow-ups. Both the ranibizumab monotherapy and the combination therapy significantly improved BCVA at all time points, compared to the baseline. The combined group achieved more BCVA improvement in 3 months, 6 months, and 12 months, compared to the ranibizumab alone group. Compared to the baseline, both groups achieved significant reductions in CMT at all follow-ups. However, the combination group showed more CMT reduction at 1 week post injection, compared to the ranibizumab group. The combination group had a significantly longer injection interval, lower injection time, and recurrence of macular edema. Ocular hypertension was the most common adverse events. Lastly, intraocular pressure was all well controlled by 1-3 glaucoma medications without surgical intervention. The combination therapy could significantly improve the BCVA and reduce the CMT with a good safety profile.

Efficacy and Safety of a Fixed-Dose Combination Gel with Adapalene 0.1% and Clindamycin 1% for the Treatment of Acne Vulgaris (CACTUS): A Randomized, Controlled, Assessor-Blind, PhaseIII Clinical Trial.

Combination therapy is required for the treatment of moderate acne vulgaris. However, patient compliance in applying multiple topical formulations is poor. To assess the efficacy and safety of a fixed-dose combination gel with adapalene 0.1% and clindamycin 1% (adapalene-clindamycin) relative to adapalene 0.1% monotherapy and clindamycin 1% monotherapy in patients with moderate facial acne vulgaris. This was a randomized, controlled, assessor-blind, phaseIII study conducted in patients with moderate facial acne vulgaris. A total of 1617 patients were enrolled. At week12, patients in the adapalene-clindamycin gel treatment group showed a significant reduction in the percentage change from baseline in total lesion count (- 66.85%), compared with adapalene alone (- 50.82%) or clindamycin gel alone (- 57.61%). The difference in the least square means of the adapalene-clindamycin gel group and adapalene group, or clindamycin gel group was - 16.08% (95%CI - 19.95% to - 12.21%) and - 9.38% (95%CI - 13.25% to - 5.51%;), respectively. At week12, 19.28% of participants who received adapalene-clindamycin gel achieved at least 2-grade improvement in IGA, versus 7.74% with adapalene gel (OR 3.05, 95%CI 1.93, 4.80) and 14.77% with clindamycin gel (OR 1.42, 95%CI 0.97, 2.07). The study also achieved all its secondary endpoints. Adverse event rates were mostly mild to moderate and comparable across the three treatment groups. Adapalene 0.1%-clindamycin 1% combination gel is well tolerated and demonstrated superior efficacy over 0.1% adapalene gel monotherapy and 1% clindamycin gel monotherapy for the treatment of moderate acne vulgaris. ClinicalTrials.gov identifier NCT03615768.

Combined dapagliflozin and roxadustat effectively protected heart and kidney against cardiorenal syndrome-induced damage in rodent through activation of cell stress-Nfr2/ARE signalings and stabilizing HIF-1α

BackgroundThis study tested whether combined dapagliflozin (DAPA) and roxadustat (ROX) therapy was superior to a singular therapy in protecting heart and kidney functions in rats with cardiorenal syndrome (CRS). Methods and resultsAn in vitro study demonstrated that the cell survival (PI3K/Akt/mTOR)/cell stress (ERK1/2, JNK/p-38) signaling was significantly activated by combination therapy with ROX-DAPA (all p<0.001). Additionally, these two signaling pathways further significantly upregulated the hypoxia-induced factor (HIF)-1α which, in turn, significantly upregulated Nrf2/ARE (HO-1/NQO-1) and angiogenesis/cell-growth factors (EPO/SDF-1α/VEGF/FGF/IGF-2) and downregulated hypoxia-inducible factor prolyl-4-hydroxylase-1 (all p<0.001). Adult-male SD rats were categorized into Groups 1 (sham-operated control)/2 (CRS)/3 (CRS+ROX)/4 (CRS+DAPA)/5 (CRS+ROX+DAPA). By Day 60 after rodent CRS induction, the levels of BUN/creatinine and the ratio of urine protein to creatinine were lowest in Group 1, highest in Group 2, and significantly lower in Group 5 than in Groups 3 and 4; however, they were similar in the latter two groups, whereas the left-ventricular-ejection-fraction exhibited the opposite trend of creatinine among the groups (all p<0.0001). The protein expression levels of cell-survival (p-PI3K/p-Akt-p-mTOR)/cell-stress (p-JNK/p-p38/p-ERK1/2)/Nrf2-ARE (HO-1/NQO-1/SIRT1/SIRT3) signaling factors and angiogenesis factors (HIF-1α/VEGF/SDF-1α/FGF/IGF-2/EPO) significantly and progressively increased from Groups 1–5 (all p<0.0001). ConclusionCombined DAPA-ROX therapy has a synergistic effect on protecting heart and kidney functions against CRS-induced damage in rodents.

Modulating versatile pathways using a cleavable PEG shell and EGFR-targeted nanoparticles to deliver CRISPR-Cas9 and docetaxel for triple-negative breast cancer inhibition.

Human antigen R (HuR), an RNA-binding protein, is implicated in regulating mRNA stability and translation in cancer, especially in triple-negative breast cancer (TNBC), a highly aggressive form. CRISPR/Cas9-mediated HuR knockout (HuR CRISPR) presents a promising genetic therapeutic approach, but it encounters transfection limitations. Docetaxel (DTX), an effective cytotoxic agent against metastatic breast cancer (BC), faces challenges related to vehicle-associated adverse events in DTX formulations. Therefore, we designed multifunctional nanoparticles with pH-sensitive PEG derivatives and targeting peptides to enable efficient HuR CRISPR and DTX delivery to human TNBC MDA-MB-231 cells and tumor-bearing mice. Our findings indicated that these nanoparticles displayed pH-responsive cytotoxicity, precise EGFR targeting, efficient tumor penetration, successful endosomal escape, and accurate nuclear and cytoplasmic localization. They also demonstrated the ability to spare normal cells and prevent hemolysis. Our study concurrently modulated multiple pathways, including EGFR, Wnt/β-catenin, MDR, and EMT, through the regulation of EGFR/PI3K/AKT, HuR/galectin-3/GSK-3β/β-catenin, and P-gp/MRPs/BCRP, as well as YAP1/TGF-β/ZEB1/Slug/MMPs. The combined treatment arrested the cell cycle at the G2 phase and inhibited EMT, effectively impeding tumor progression. Tissue distribution, biochemical assays, and histological staining revealed the enhanced safety profile of pH-responsive PEG- and peptide-modified nanoformulations in TNBC mice. The DTX-embedded and peptide-modified nanoparticles mitigated the side effects of DTX, enhanced cytotoxicity in TNBC MDA-MB-231 cells, and exhibited remarkable antitumor efficacy and safety in TNBC-bearing mice with HuR CRISPR deletion. Collectively, the combination therapy of DTX and CRISPR/Cas9 offers an effective platform for delivering antineoplastic agents and gene-editing systems to combat tumor resistance and progression in TNBC.

Combination therapy of dexamethasone, rituximab, and cyclosporine for adults with primary immune thrombocytopenia: a prospective observational study

ABSTRACT Background To assess the effectiveness of the combination of dexamethasone, rituximab, and cyclosporine in treating adults with primary immune thrombocytopenia (ITP). Research design and methods This prospective study enrolled consecutive adult patients diagnosed with ITP at the 967th Hospital of the Chinese People’s Liberation Army Joint Service Support Force Hospital between November 2019 and February 2023. Results Twenty-eight patients (13 males, median age 43.5 years) were included. All patients previously experienced ineffective or relapsed ITP, with a median disease duration of 26.5 (range, 7-72) months. At baseline, the median platelet (PLT) count was 13.5 × 109/L (8.25-20 × 109/L). Following treatment, the PLT counts were significantly increased at weeks 1, 3, and 4. The early response rates at weeks 1 and 4 were 82.1% (23/28 patients) and 71.4% (20/28 patients), respectively. The 1-, 3-, and 6-month response rates were 71.4% (20/28), 67.9% (19/28), and 75% (21/28). The treatment-free survival rates at 12 and 24 months were 82.35% (14/17) and 71.43% (10/14), respectively. Six patients experienced transient adverse reactions. Conclusions The combination of dexamethasone, rituximab, and cyclosporine may present a promising therapeutic option for patients with refractory ITP, with good tolerability and mild adverse reactions.

Neutrophil-to-Lymphocyte Ratio as a Biomarker for Clinical Response After Autologous Hematopoietic Stem Cell Transplantation in Systemic Sclerosis.

Systemic sclerosis is a complex disease that affects various target organs, making it difficult to assess response and determine remission or relapse. A baseline Neutrophil-to-Lymphocyte Ratio (NLR) >2.95 is associated with severe progressive skin and lung disease and decreased 5-year survival in systemic sclerosis (SSc). However, it is unknown whether NLR changes in response to treatment. To retrospectively evaluate NLR changes as a biomarker for treatment response in SSc. Progressive diffuse SSc patients who were treated with autologous hematopoietic stem cell transplantation (AHSCT group), with combination therapy of rituximab and mycophenolate mofetil (combination group) or CAR-T cell therapy (CAR-T group) were recruited, along with healthy controls (HC group). NLR, modified Rodnan Skin Score (mRSS) and forced vital capacity (FVC)% predicted were repeatedly assessed over 2 years. Fifteen patients were recruited in the AHSCT group, 15 in the combination group, and six patients in the CAR-T group. Baseline mean NLR was high (>2.95) in AHSCT, combination groups, and CAR-T compared with HC. All treatment arms showed a statistically significant decrease in mRSS values and an increase in FVC% at each time point up to 12 months. In a linear mixed model, NLR significantly decreased up to 24 months only in the AHSCT group. NLR correlated with mRSS and FVC exclusively in the AHSCT group. NLR increased above 3 in two patients who experienced a relapse after AHSCT. NLR is a simple biomarker that correlated with outcome measures in SSc following AHSCT, but not with conventional therapy or CAR-T therapy. It is suggested that a decrease in NLR following AHSCT may indicate remission, whereas an increase may be associated with exacerbation. Further research is needed to validate these novel findings.

Efficacy and Safety of Nivolumab With Ipilimumab in Elderly Patients With Advanced Renal Cell Carcinoma.

Nivolumab and ipilimumab (NIVO+IPI) is standard therapy for patients with intermediate and poor risk advanced renal cell carcinoma (RCC). However, the efficacy and safety of NIVO+IPI in elderly patients aged >75 years remains unclear. This study aimed to determine the efficacy and safety of first-line NIVO+IPI treatment in patients aged >75 years with advanced RCC. This study included 59 patients with advanced RCC who received NIVO+IPI as first-line therapy between September 2018 and December 2023. Objective response rates (ORRs), along with progression-free survival (PFS) and overall survival (OS) were compared between patients aged <75 years and ≥75 years, to assess survival outcomes. A total of 46 (78.0%) and 13 (22.0%) patients were classified into <75 years and ≥75 years groups, respectively, at NIVO+IPI initiation. The ORRs were 45.7% for <75 years and 53.8% for ≥75 years (p=0.2422). No significant differences in PFS (p=0.0729) were observed between groups. In contrast, patients aged ≥75 years had better OS than those aged <75 years (p=0.0212). However, no significant difference was observed in the OS between the two groups of patients with clear cell histology (p=0.0532). The incidence of immune-related adverse events higher than Grade 3 was not significantly different between the two groups (p=0.5016). NIVO and IPI combination therapy is both safe and efficacious in patients aged ≥75 years with advanced RCC.

Comparative assessment of intravitreal steroid implant with combination therapy for diabetic macular edema.

Comparative assessment of intravitreal steroid implant with combination therapy for diabetic macular edema.

Adavosertib in Combination with Olaparib in Patients with Refractory Solid Tumors: An Open-Label, Dose-Finding, and Dose-Expansion Phase Ib Trial.

Adavosertib is a first-in-class, selective small-molecule inhibitor of Wee1. Olaparib is an inhibitor of poly(ADP-ribose) polymerase (PARP). Preclinical data suggest that adavosertib enhances the antitumor effect of PARP inhibitors. The safety, tolerability, and efficacy of adavosertib plus olaparib were evaluated in patients with refractory solid tumors to define the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Eligible patients in part A (dose finding) had a refractory solid tumor for which there is no established treatment and had received ≥ 1 prior course of systemic therapy; in part B (dose expansion), patients had platinum-sensitive extensive-stage or relapsed small-cell lung cancer (SCLC). Patients received adavosertib [once (qd) or twice daily (bid)] for 3 consecutive days with 4 days off treatment (3/4), or 5 consecutive days with 2 days off (5/2), plus olaparib (bid) for 14 or 21 days of a 21-day cycle. A total of 130 patients were enrolled in the study, 120 in part A and 10 in part B. The MTD for adavosertib bid was 175 mg (days 1-3, 8-10/21-day cycle) plus continuous olaparib 200 mg bid; the once-daily MTD (and RP2D) was adavosertib 200 mg (days 1-3, 8-10/21-day cycle) plus continuous olaparib 200 mg bid. In the MTD/RP2D cohort, one patient (7%) experienced a dose-limiting toxicity (DLT) of thrombocytopenia. The most common treatment-related adverse events (TRAEs) in the cohorts in which MTD/RP2D for bid dosing and RP2D for qd dosing were determined were fatigue (64.3% and 15.4%, respectively), diarrhea (42.9% and 30.8%), decreased appetite (35.7% and 23.1%), nausea (35.7% and 15.4%), and anemia (35.7% and 38.5%). In the SCLC dose-expansion cohort, TRAEs occurred in eight patients (88.9%), including thrombocytopenia (66.7%) and anemia (55.6%). In part A, objective response rate (ORR) was 14.8% [95% confidence interval (CI) 8.7-22.9] overall; for the cohorts in which MTD/RP2D for bid dosing and RP2D for qd dosing were determined, ORR was 30.8% (9.1-61.4) and 9.1% (0.2-41.3), respectively. ORR was 11.1% [95% CI 0.3-48.2; one partial response (PR)], disease control rate was 22.2% (2.8-60.0; one PR, one stable disease), and median progression-free survival was 1.5 months (1.3-4.2) in the SCLC dose-expansion cohort. Adverse events and DLTs observed in the bid MTD and once-daily MTD/RP2D dosing schedules were manageable and consistent with known adavosertib and olaparib safety profiles. Limited antitumor activity was observed with adavosertib plus olaparib combination therapy. ClinicalTrials.gov, NCT02511795 (registration: 28 July 2015).

Pharmacological activation of STAT1-GSDME pyroptotic circuitry reinforces epigenetic immunotherapy for hepatocellular carcinoma.

Genomic screening uncovered interferon-gamma (IFNγ) pathway defects in tumours refractory to immune checkpoint blockade (ICB). However, its non-mutational regulation and reversibility for therapeutic development remain less understood. We aimed to identify ICB resistance-associated druggable histone deacetylases (HDACs) and develop a readily translatable combination approach for patients with hepatocellular carcinoma (HCC). We correlated the prognostic outcomes of HCC patients from a pembrolizumab trial (NCT03419481) with tumourous cell expressions of all HDAC isoforms by single-cell RNA sequencing. We investigated the therapeutic efficacy and mechanism of action of selective HDAC inhibition in 4 ICB-resistant orthotopic and spontaneous models using immune profiling, single-cell multiomics and chromatin immunoprecipitation-sequencing and verified by genetic modulations and co-culture systems. HCC patients showing higher HDAC1/2/3 expressions exhibited deficient IFNγ signalling and poorer survival on ICB therapy. Transient treatment of a selective class-I HDAC inhibitor CXD101 resensitised HDAC1/2/3high tumours to ICB therapies, resulting in CD8+T cell-dependent antitumour and memory T cell responses. Mechanistically, CXD101 synergised with ICB to stimulate STAT1-driven antitumour immunity through enhanced chromatin accessibility and H3K27 hyperacetylation of IFNγ-responsive genes. Intratumoural recruitment of IFNγ+GZMB+cytotoxic lymphocytes further promoted cleavage of CXD101-induced Gasdermin E (GSDME) to trigger pyroptosis in a STAT1-dependent manner. Notably, deletion of GSDME mimicked STAT1 knockout in abolishing the antitumour efficacy and survival benefit of CXD101-ICB combination therapy by thwarting both pyroptotic and IFNγ responses. Our immunoepigenetic strategy harnesses IFNγ-mediated network to augment the cancer-immunity cycle, revealing a self-reinforcing STAT1-GSDME pyroptotic circuitry as the mechanistic basis for an ongoing phase-II trial to tackle ICB resistance (NCT05873244).

An Update on Recent Clinical Trial Data in Bloodstream Infection

Bloodstream infections (BSIs) remain a significant source of morbidity and mortality globally, exacerbated by an ageing population and rising antimicrobial resistance (AMR). This review offers an updated evaluation of randomized clinical trials (RCTs) in BSI management from 2018 onwards, focusing on the evolving landscape of diagnostics and treatment. New rapid diagnostic technologies and shorter antimicrobial courses have transformed clinical practice, reducing the time to appropriate therapy and hospital stays. Several RCTs demonstrated that rapid phenotypic and genotypic tests shorten the time to optimal therapy, especially when paired with antimicrobial stewardship. Ongoing trials are investigating novel antimicrobial regimens and the safety of early oral switch strategies, particularly for Gram-positive and Gram-negative BSIs. Recent RCTs on Staphylococcus aureus BSI (SAB) and multidrug-resistant Gram-negative bacteria highlight advances in treatment but emphasize the need for further study into the efficacy of combination therapies and the utility of rapid diagnostics in different healthcare settings. The review also explores challenges in trail design, with adaptive and pragmatic appropriates improving the efficacy of clinical trials. Finally, this paper identifies gaps in the research, including the need for further investigation into oral step-down therapy, optimal durations, and the role of rapid diagnostics in resource-limited settings.

Inhibitors of the mTOR signaling pathway can play an important role in breast cancer immunopathogenesis.

This study explores the critical role of inhibitors targeting the mammalian target of rapamycin (mTOR) signaling pathway in breast cancer research and treatment. The mTOR pathway, a central regulator of cellular processes, has been identified as a crucial factor in the development and progression of breast cancer. The essay explains the complex molecular mechanisms through which mTOR inhibitors, such as rapamycin and its analogs, exert their anticancer effects. These inhibitors can stop cell growth, proliferation, and survival in breast cancer cells by blocking critical signaling pathways within the mTOR pathway. Furthermore, the essay discusses the implications of using mTOR inhibitors as a comprehensive therapeutic strategy. It emphasizes the potential benefits of combining mTOR inhibitors with other treatment approaches to enhance the effectiveness of breast cancer treatment. The evolving landscape of breast cancer research underscores the significance of mTOR as a therapeutic target and highlights ongoing efforts to improve and optimize mTOR inhibitors for clinical use. In conclusion, the essay asserts that inhibitors of the mTOR signaling pathway offer a promising approach in the fight against breast cancer. These inhibitors provide a focused and effective intervention targeting specific dysregulations within the mTOR pathway. As research advances, the integration of mTOR inhibitors into customized combination therapies holds excellent potential for shaping a more effective and personalized approach to breast cancer treatment, ultimately leading to improved outcomes for individuals affected by this complex and diverse disease.

‘Effectiveness of various sulbactam-based combination antibiotic therapy in the management of ventilator-associated pneumonia caused by carbapenem-resistant Acinetobacter baumannii in a tertiary care Health centre’

ObjectiveCarbapenem-resistant Acinetobacter baumannii (CRAB) is a common cause of ventilator-associated pneumonia (VAP). Some in vitro data favour various combination antibiotic therapy. However, there is a need for more in vivo studies for the management of VAP caused by CRAB. This retrospective study was done to evaluate the effectiveness of various combination antibiotic therapy including sulbactam on outcomes of VAP caused by CRAB. MethodsAdult patients (age ≥18 years) diagnosed with VAP caused by CRAB were included. Patients with polymicrobial infections were excluded from the study. Patients with CRAB associated VAP who were given sulbactam based antibiotic combinations were observed for outcomes. The primary outcome was 28-day mortality after diagnosis of VAP caused by CRAB. Reduction in serum HsCRP (High sensitivity C-reactive protein) during treatment and requirement of inotropes were the secondary outcomes. Outcomes were compared between various sulbactam based antibiotic combination therapies. ResultsA total of 103 patients were included. A total of 44 (42.7 %) patients received sulbactam and minocycline or sulbactam and polymyxin B dual antibiotic combination, and 59 (57.3 %) patients received sulbactam, polymyxin B and minocycline triple antibiotic combination. The percentage difference in 28 days mortality was 27.51 % (95 % CI 8.03 %–44.06 %; p = 0.005) in dual vs triple sulbactam based antibiotic combination therapy. The percentage difference in requirement of inotropes during therapy and HsCRP reduction after 7 days of therapy was 23.65 % (95 % CI 6.43 %–38.3 %; p = 0.007) and 25.1 % (95%CI 10.1 %–38.2 %; p < 0.001) respectively when compared between dual vs triple sulbactam based antibiotic combination therapy. ConclusionTreatment with sulbactam, polymyxin B and minocycline combination antibiotic therapy was associated with significantly lower 28-day mortality. Moreover, the lower requirement of inotropes during treatment and a significant reduction in HsCRP level favours this combination antibiotic therapy in VAP caused by CRAB.