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Antiretroviral drug exposure in lymph nodes is heterogeneous and drug dependent.

INTRODUCTION: HIV reservoirs and infected cells may persist in tissues with low concentrations of antiretrovirals (ARVs). Traditional pharmacology methods cannot assess variability in ARV concentrations within morphologically complex tissues, such as lymph nodes (LNs). We evaluated the distribution of six ARVs into LNs and the proximity of these ARVs to CD4+ T cells and cell-associated RT-SHIV viral RNA. METHODS: Between December 2014 and April 2017, RT-SHIV infected (SHIV+; N = 6) and healthy (SHIV-; N = 6) male rhesus macaques received two selected four-drug combinations of six ARVs over 10…

Eradication of Biofilm-Like Microcolony Structures of Borrelia burgdorferi by Daunomycin and Daptomycin but not Mitomycin C in Combination with Doxycycline and Cefuroxime.

Lyme disease, caused by Borrelia burgdorferi, is the most common vector-borne disease in the United States and Europe. While the majority of … ptomycin were more active than mitomycin C in single drug comparison at 10 and 20 μM, as well as in drug combinations with doxycycline and cefuroxime. In addition, daunomycin was more active than doxorubicin which correlated with their ability to stain and accumulate in B. burgdorferi. The two drug combination of doxycycline and cefuroxime was unable to eradicate b …

Novel drug targets for personalized precision medicine in relapsed/refractory diffuse large B-cell lymphoma: a comprehensive review.

Diffuse large B-cell lymphoma (DLBCL) is a clinically heterogeneous lymphoid malignancy and the most common subtype of non-Hodgkin's lymphoma in adults, with one of the highest mortality rates in most developed areas of the world. More than half of DLBLC patients can be cured with standard R-CHOP regimens, however approximately 30 to 40 % of patients will develop relapsed/refractory disease that remains a major cause of morbidity and mortality due to the limited therapeutic options.Recent advances in gene expression profiling have led to the identification of at least three distinct molecular

Interactions between antiretroviral drugs and drugs used for the therapy of the metabolic complications encountered during HIV infection.

Treatment of HIV infection with potent combination antiretroviral therapy has resulted in major improvement in overall survival, immune function and the incidence of opportunistic infections. However, HIV infection and treatment has been associated with the development of metabolic complications, including hyperlipidaemia, diabetes mellitus, hypertension, lipodystrophy and osteopenia. Safe pharmacological treatment of these complications requires an understanding of the drug-drug interactions between antiretroviral drugs and the drugs used in the treatment of metabolic complications. Since for

Beyond susceptibility: pharmacokinetic and pharmacodynamic constraints of existing oral antibiotics in extensively drug-resistant typhoid fever.

Salmonella Typhi is an invasive pathogen with sustained bacteraemia and intracellular persistence, requiring therapy that achieves systemic exposure and intracellular penetration. Clinical efficacy should remain central to therapeutic decision-making, while pharmacokinetic/pharmacodynamic (PK/PD) analyses provide complementary insights into dose optimization and the pharmacological limitations of candidate therapies. Oral therapy remains central to typhoid fever management, particularly in South and Southeast Asia, where most patients are managed in the outpatient setting. However, the emergen

Perspectives on 10 years of Immune Checkpoint Inhibitors in Merkel Cell Carcinoma: A Podcast.

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer with a poor prognosis, particularly in patients with advanced disease. The introduction of immune checkpoint inhibitors (ICIs) approximately 10 years ago has dramatically improved outcomes for patients with advanced MCC. Current US Food and Drug Administration-approved ICIs in this setting include the PD-L1 inhibitor avelumab and PD-1 inhibitors pembrolizumab and retifanlimab. In this podcast, we summarize key studies of ICIs in advanced MCC, including clinical trials and real-world studies, and discuss clinical evidence related

Personalized Combination Therapy in Bladder Cancer: cAMP Modulators Synergize with 5-FU and Modulate Redox Programs.

BACKGROUND/OBJECTIVES: Repurposed cAMP-elevating agents may personalize fluoropyrimidine therapy by exploiting pathway-specific vulnerabilities. METHODS: We tested the PDE3 inhibitor milrinone and the β2-agonist terbutaline alone or combined with 10 μM 5-fluorouracil (5-FU) in UM-UC-5 (bladder), A549 (lung), and PC-3 (prostate) cells. Viability, migration, clonogenicity, and intracellular ROS (DCFDA) were measured; drug interactions used Chou-Talalay/CompuSyn. RESULTS: In UM-UC-5, both agents reduced viability, migration, and clonogenicity and synergized with 5-FU (CI < 1 across Fa ≈ 0.42-0.

An evaluation of afamitresgene autoleucel for the treatment of advanced synovial sarcoma and myxoid round cell liposarcoma.

INTRODUCTION: Synovial sarcoma (SyS) and myxoid round-cell liposarcoma (MRCL) are rare, aggressive soft tissue sarcomas with poor outcomes at the advanced and metastatic stage. Novel therapeutic strategies are urgently needed. Afamitresgene autoleucel (afami-cel) is the first Food and Drug Administration (FDA)-approved, affinity-enhanced T-cell receptor (TCR) therapy targeting the cancer-testis antigen MAGE-A4 in HLA-A*02-positive patients. AREAS COVERED: This review summarizes clinical evidence from one early-phase study and the pivotal phase 2 SPEARHEAD-1 trial. Afami-cel achieved objective

Challenges and strategies of non-coding RNA therapies in addressing tumor heterogeneity in head and neck cancers.

Head and neck cancers (HNCs) are characterized by substantial genetic, epigenetic, transcriptional, and microenvironmental heterogeneity, which contributes to variable responses and limited durability of non-coding RNA (ncRNA)-based therapies. Although previous reviews have extensively catalogued dysregulated miRNAs, lncRNAs, and circRNAs in HNC, less attention has been paid to how tumor heterogeneity dynamically reshapes ncRNA-target relationships and therapeutic responses. Here, we introduce heterogeneity-driven target drift as a conceptual framework linking multidimensional tumor heterogene

Dual-target antibacterial agents: Bridging molecular relationships to synergistic mechanisms.

Antimicrobial resistance (AMR) has emerged as a critical global health crisis, exacerbated by the stagnation of novel antibiotic discovery and declining efficacy of existing clinical agents. Dual-target antibacterial strategy has emerged as a promising approach to address this challenge. This review systematically summarizes the cutting-edge advances in dual-target antibacterial agents, covering their core design strategies, structure-activity relationships, preclinical and clinical efficacy/safety profiles, and dual-target mechanism validation. We classify these agents by key target combinati

Repression of PRMT activities sensitize human homologous recombination-proficient ovarian and breast cancer cells to PARP inhibitor treatment.

Therapeutic epigenetic modulation is currently being evaluated in the clinic to sensitize homologous recombination (HR)-proficient tumors to PARP inhibitors. To broaden its clinical applicability and identify more effective combination strategies, we conducted a drug screen combining PARP inhibitors with 74 well-characterized epigenetic modulators targeting five major classes of epigenetic enzymes. Notably, both type I PRMT inhibitors and PRMT5 inhibitors scored highly in combination efficacy and clinical prioritization. PRMT inhibition significantly enhanced PARP inhibitor-induced DNA damage

Discovery of multitargeting single agents as a novel route to the potential treatment of neurodegenerative diseases.

There are no cures for neurodegenerative diseases. The biggest hurdle to treating these disorders is that their clinical manifestation is rooted in multiple physiological processes. Therefore, efficacious pharmaceutical options will likely require two or more agents with different mechanisms of action. However, drug combinations have significant drawbacks, including overlapping toxicities and unique pharmacokinetic properties, particularly the rate and extent of central nervous system (CNS) penetration. A single agent with multiple mechanisms of action could overcome these drawbacks. We have r…

Emerging biologic targets in type 2 and non-type 2 asthma.

PURPOSE OF REVIEW: Severe asthma continues to be a significant cause of global morbidity and mortality despite the dramatic change in landscape of asthma management dramatically over the last two decades, However, there are a variety of novel therapeutic agents under investigation whose goals are to enable patients with severe asthma to achieve remission. RECENT FINDINGS: New strategies in drug development include an ultra-long-acting mechanism with reduced administration frequency, biologics used in combinations, oral therapies and novel therapeutic targets. These targets include bruton tyro

PARP inhibitors induce a senescence phenotype in non-small cell lung carcinoma cell lines.

Several anticancer treatments have been shown to activate the DNA damage repair pathway but also, in some cases, to lead to therapy-induced … ncer therapies induce a senescence phenotype as it could lead to not only treatment failure but alsodrug combinations targeting this pathway to further enhance anticancer treatment efficacy.

Stewardship Challenges, PK/PD Evidence, and Prescribing Appropriateness for Recently Approved Antibiotics in Pediatric Practice.

The rise of multidrug-resistant (MDR) pathogens in the pediatric population represents a significant global health challenge, compounded by a historically stagnant antibiotic pipeline for children. While several novel antibiotics have been approved for adults in recent decades, pediatric labeling is often deferred due to the complexities of developmental pharmacology and due to a certain precautionary prudence in introducing new drugs onto the market for this population. This review explores the landscape of the most recent antibiotics, including advanced cephalosporins (ceftaroline, cefideroc

The combination therapy with venetoclax in therapeutic strategy of acute lymphoblastic leukemia.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is characterized by the malignant transformation and proliferation of lymphoid progenitor cells in the bone marrow, blood, and extramedullary sites. Leukemic cells can develop drug resistance both before and after treatment, complicating disease management. Combination therapy with Venetoclax has been shown to enhance the efficacy of standard anti-leukemia drugs. Therefore, this study aims to review combination treatment strategies as potential therapeutic alternatives, drawing on evidence from previous published literature. METHODS: This narrativ

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… Fig. 4 Comparison of response rates for venetoclax drug combinations. …

Effects of the HDAC6/8 Inhibitor MC1568, Alone and in Combination With Fluconazole, in Non-Albicans Candida Species Infections.

Fungal infections pose a severe health risk, particularly in immunocompromised individuals, with Candida species being a leading cause of bloodstream infections. The rise of non-albicans Candida (NAC) infections, accounting for 35%-65% of candidemia cases, underscores the urgent need for novel antifungal strategies. Current treatments, including echinocandins and azoles, are increasingly challenged by drug-resistant strains. This study evaluated the antifungal efficacy of three clinically approved histone deacetylase inhibitors (HDACi)-Vorinostat, Romidepsin, and Tucidinostat-along with the HD

Current Management and Investigational Therapeutic Strategies in Penile Squamous Cell Carcinoma: A Narrative Review.

Penile squamous cell carcinoma (PSCC) is a rare and aggressive genitourinary malignancy requiring integrated multidisciplinary management. This narrative review provides an updated overview of the diagnostic and therapeutic pathway of PSCC from localized disease, where surgery remains the cornerstone of treatment, to locally advanced disease, where multimodal strategies integrating chemotherapy and radiotherapy with surgery are required, and finally to metastatic disease, where systemic therapy becomes the mainstay of treatment. Platinum-based chemotherapy remains the established systemic back

Regional surveillance of carbapenem-resistant Klebsiella pneumoniae responsible for bloodstream infections in Hebei province.

OBJECTIVE: To investigate the epidemiological characteristics of CRKP responsible for BSIs in Hebei Province, China. METHODS: A total of 100 CRKP isolates were obtained across 15 hospitals in eight cities in Hebei Province, China, between 2022 and 2024. Polymerase chain reaction and short-read whole-genome sequencing were used to characterize the molecular profiles of the strains. RESULTS: All isolates exhibited high-level resistance to β-lactam antibiotics, including a 100% resistance rate to carbapenems and resistance rates of > 97% to β-lactamase inhibitor combinations. The blaKPC was the

Rapid and robust diagnosis of bloodstream infections by single-cell analysis.

Sepsis, a common consequence of bloodstream infection (BSI), is a leading cause of global mortality and morbidity. Diagnosis is challenging and slow due to extremely low pathogen loads and reliance on time-consuming blood culture, necessitating empiric therapy that worsens outcomes and antimicrobial resistance. Here, we introduce sedimentation-assisted tandem rocking and enrichment for analysis and monitoring (STREAM), a platform that efficiently isolates and enriches pathogens near their natural doubling times directly from whole blood. By integrating STREAM with single-cell analysis, we achi