Quantifying evidence for phenotypic specificity (PP4) for syndromic phenotypes: Large-scale integration of rare germline FH variants from diagnostic laboratory testing for HLRCC (Hereditary Leiomyomatosis and Renal Cell Cancer) and renal cancer.

Purpose: Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is a rare cancer susceptibility syndrome exclusively attributable to pathogenic variants in FH (HGNC:3700). This paper quantitatively weights the phenotypic context (PP4/PS4) of such very rare variants in FH.

Methods: We collated clinical diagnostic testing data on germline FH variants from 387 individuals with HLRCC and 1,780 individuals with renal cancer, and compared the frequency of 'very rare' variants in each phenotypic cohort against 562,295 population controls.

Recent advances in the design of small molecules targeting human ClpP.

Human mitochondrial ClpP (hClpP), a pivotal protease regulating mitochondrial protein homeostasis, has emerged as an important target for anticancer drug development. In recent years, significant progress has been made in designing small molecules targeting hClpP, primarily classified into activators and inhibitors. Activators specifically stimulate ClpP proteolytic activity by mimicking the mechanism of its chaperone protein ClpX, with representative compounds, such as imipridone derivatives (ONC201/206/212) and their optimized products (ZK53, 7k, etc.

Successful Identification and Treatment of Cancer of Unknown Primary Originating From Gastric Cancer Using Comprehensive Genomic Profiling and Immune Checkpoint Inhibitor Therapy: A Case Report.

Background: Cancer of unknown primary (CUP) is a challenging malignancy characterized by metastatic tumors with an unidentified primary site, even after extensive pathological and radiographic evaluation. Recent advancements in gene expression profiling and comprehensive genomic profiling (CGP) using next-generation sequencing (NGS) have enabled the identification of potential tissue origins, thereby facilitating personalized treatment strategies. Although most cases of CUP present as adenocarcinomas or poorly differentiated tumors, the treatment remains largely empirical, with limited success from molecularly tailored therapies.

Semiopen Ag@Au Plasmonic Nanotube Arrays Synergizing Molecular Confinement and Multimodal SERS for Lung Cancer Breath Diagnostics.

Exhaled breath analysis offers noninvasive, early lung cancer detection via volatile organic compound (VOC) biomarkers, surpassing blood-based methods. Surface-enhanced Raman spectroscopy (SERS) is ideal for this purpose, combining molecular fingerprint specificity with single-molecule sensitivity. However, conventional SERS substrates face a fundamental limitation: while porous materials such as metal-organic frameworks effectively adsorb VOCs through their subnanometer pores (0.

Advances in Artemisinin-based Therapies: Innovations in Synthesis, Drug Delivery, and Expanding Therapeutic Applications.

Artemisinin, a natural compound derived from Artemisia annua, has significantly impacted the treatment of malaria and has shown promise in various other therapeutic applications. This review explores the molecular structure of artemisinin and its derivatives, as well as advancements in synthetic and semi-synthetic production methods, and their broader therapeutic effects beyond malaria, including potential uses in cancer, neurological disorders, and viral infections. It also discusses contemporary drug delivery innovations, such as nanoparticles and liposomal systems, which aim to enhance the bioavailability and targeted action of artemisinin, while addressing issues of drug resistance, particularly in parasitic diseases like malaria.

Characterization of Early Viral Populations in Infants Acquiring HIV Through Perinatal and Breastmilk Transmission: A Review of what is Currently Known and the Gaps that Need to be Addressed to Guide Passive HIV Immunization of Breastfeeding Infants.

Newborns represent only 1% of the population. Yet, HIV vertical transmissions represent 10% of all new infections globally, even though antiretroviral therapy (ART) has been shown to reduce the risk of vertical transmission to less than 2%. While vaccines still represent the most efficient and cost-effective intervention to eradicate new infections, HIV immunogens that can effectively elicit broad-spectrum protection are still at least a decade away.

New Indazole Derivatives as Potential Scaffolds for the Development of Anticancer, Antiviral, and Anti-tuberculosis Chemotherapeutic Compounds.

Introduction: Chemotherapy remains essential despite advances in immunotherapy, radiotherapy, and biological therapy. However, the wide range of chemical drugs is limited by a narrow therapeutic index, low selectivity, and the development of resistance. In this regard, new high-efficiency drugs are in extremely high demand.

Grafting of Resveratrol-Chitosan Nanoparticles as a Promising Radiosensitizer and Protector in DMBA-Induced Breast Cancer in Mice.

Introduction: Breast cancer is the most common malignancy among women and the second leading cause of cancer-related deaths worldwide. Resveratrol, a polyphenolic stilbene derivative found in grapes, red wine, and other plants, possesses anti-cancer properties. Various studies have reported the potential of different nanomaterials to act as radiosensitizers against tumor cells.

Regulation of sub-Tg solid-state surface crosslinking of reactive polyarylene ether substrate into loose nanofiltration membranes for dyes desalination.

The scalable fabrication of high performance dyes desalination loose nanofiltration (LNF) membrane through facile thermal annealing remains challenging due to the susceptible pore collapse. Herein, we have developed a metal ion mediated sub-Tg thermal crosslinking protocol, which can convert the phase inverted reactive polymeric ultrafiltration substrate into LNF membrane showing high permselectivity as well as resistance to both extremely acid and alkaline solution. The original ultrafiltration substrate was composed of scalable-produced reactive polyarylene ether amidoxime (PEA) that was pre-crosslinked with ferric ions.

Copine family members: Their molecular mechanisms in tumor progression and therapy resistance and their value in tumor diagnosis and prognosis evaluation.

Malignant tumors present a major global health burden, as they generally have a poor prognosis, and the efficacy of available treatments is limited. Copine family members (CPNEs) play crucial roles in the regulation of tumor cell proliferation, metastasis, and therapeutic resistance, as well as in tumor diagnosis and prognostic risk stratification. CPNEs can facilitate tumor cell survival by regulating cell cycle progression and cell death.

Natural Agents Modulating Ferroptosis in Cancer: Molecular Pathways and Therapeutic Perspectives.

Ferroptosis, a controlled cell death influenced by iron-dependent lipid peroxidation, presents potential therapeutic targets for cancer treatment due to its unique molecular pathways and potential drug resistance. Natural compounds, such as polyphenols, flavonoids, terpenoids and alkaloids, can influence ferroptosis via important signalling pathways, such as Nrf2/Keap1, p53, and GPX4. These are promising for combinational therapy due to their ability to cause ferroptotic death in cancer cells, exhibit tumour-specific selectivity and reduce systemic toxicity.

Bio-ethical issues of research in Sub-Saharan Africa.

This paper examines bioethical considerations of research conducted in Sub-Saharan Africa (SSA), where a notable scarcity persists in literature addressing region-specific bioethical issues. Although bioethics-related activities have encountered challenges surpassing existing protocol safeguards, emerging evidence demonstrates growing recognition of integrated scientific and ethical principles within African medical research. Maintaining research continuity in resource-limited settings necessitates bridging critical gaps between informed consent procedures and participants' actual understanding.

KRAS mutations in Non-Small Cell Lung Cancer: translational aspects, current therapies and challenges for future research.

Mutations in the KRAS gene are prominent oncogenic drivers in non-small cell lung cancer (NSCLC), with multiple pathophysiological, clinical and prognostic implications. Although historically considered an "undruggable" target, recent research led to the development of specific KRAS-G12C inhibitors, like sotorasib and adagrasib which are currently approved for clinical use in patients affected by advanced NSCLC. However, the clinical utility of these drugs is often limited by resistance development through several biological mechanisms, including additional KRAS mutations, activation of compensatory pathways and metabolic reprogramming.

Laser Interstitial Thermal Therapy (LITT) in pediatric neurosurgery: Single center retrospective analysis of 41 consecutive procedures.

Introduction: Laser Interstitial Thermal Therapy under MRI control has emerged as a safe and efficient alternative to microsurgery in epilepsy and neurooncology procedures. Yet it has been used only recently in seldom European centers. Here, we report our 4 years' experience with LITT in children (complications, epileptic and oncologic outcomes).

Targeting the KRAS-p38-ATF4 axis enhances the therapeutic sensitivity of the peptide PDBAG1 in ovarian cancer via stress response modulation.

We previously screened a peptide PDBAG1 that remarkably inhibited triple-negative breast cancer, and found that its target was C1QBP. Recently, C1QBP has been reported as a potential tumor marker in ovarian cancer, which of the mortality rate ranks first among malignant tumors of the female reproductive tract. However, it is unclear whether and how PDBAG1 plays a regulatory role in ovarian cancer.

Platinum-group metal half-sandwich complexes of sugar-isoxazol(in)e conjugates - synthesis and evaluation of their antineoplastic and antimicrobial activities.

Platinum-group metal half-sandwich complexes are considered to be potential replacements of the clinically widely used platins which have several side effects and tend to cause resistance to develop. In our previous works, we used a range of 2-pyridyl-substituted N- and C-glycosyl heterocycles as N,N-chelating ligands to prepare ruthenium(II), osmium(II), iridium(III) and rhodium(III) polyhapto arene/arenyl half-sandwich complexes. Some of these complexes, particularly with the C-glucopyranosyl isoxazole derived ligand in its O-perbenzoylated form, exhibited greater anticancer efficiency than cisplatin and had minimal or negligible effects on non-transformed fibroblasts.

Targeted deletion of Cyp24a1 in the intestine reduces mucosal injury and preserves epithelial proliferation after 5-fluorouracil treatment.

Vitamin D has been proposed to attenuate chemotherapy-induced gastrointestinal mucositis (GM). In the intestine, local catabolism of active vitamin D [1,25-dihydroxyvitamin D₃] is mediated by the enzyme Cyp24a1. This study assessed whether deletion of Cyp24a1 specifically in intestinal epithelial cells can protect against 5-fluorouracil (5-FU)-induced intestinal injury and microbiome disruption in mice.

Metastasis-directed radiotherapy without systemic therapy for oligometastatic clear-cell renal-cell carcinoma: primary efficacy analysis of a single-arm, single-centre, phase 2 trial.

Background: Select patients with metastatic clear-cell renal-cell carcinoma can be treated without systemic therapy, yet few studies have explored this population. We investigated the efficacy of metastasis-directed therapy without systemic therapy in oligometastatic clear-cell renal-cell carincoma.

Methods: This investigator-initiated single-arm, phase 2 trial enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-2, histologically confirmed clear-cell renal-cell carcinoma, and one to five metastases.

Clinical applications of cell-free DNA-based liquid biopsy analysis.

Liquid biopsies, particularly those involving circulating tumor DNA (ctDNA) from patient blood, have emerged as crucial and minimally invasive adjuncts to standard tissue-based testing. ctDNA testing enables the identification of actionable mutations for targeted therapy and can be routinely used when tissue samples are unavailable for genotyping. Compared to tissue-based testing, ctDNA testing has the advantages of capturing spatial or temporal genomic heterogeneity and facilitating repeated assessments.

Remodeling the sarcoma microenvironment by simultaneous targeting of urokinase-type plasminogen activator receptors and epidermal growth factor receptors to promote antitumor activity.

We evaluated the antitumor effects of remodeling the MC17 mouse sarcoma microenvironment (SME) by targeting urokinase-type plasminogen activator receptor (uPAR)- and epidermal growth factor receptor (EGFR)-expressing cells. Specifically, we used eBAT (a bispecific ligand-targeted toxin directed to EGFR and uPAR), and its mouse counterpart, meBAT, to ablate uPAR- and/or EGFR-expressing cells. We chose the MC17 model because the cells are resistant to eBAT, allowing us to exclusively evaluate the role of uPAR- and EGFR-expressing cells in the SME.

Male Reproductive Senescence in Mammals Is Pervasive and Aligned With the Slow-Fast Continuum.

Reproductive senescence, the decline in any component of offspring recruitment with increasing age, has been well documented in mammalian females. Male reproductive senescence, however, is much less understood, partly due to the past complexities of getting reliable paternity assignment in the wild. Through a standardised literature search, we compiled age-specific reproductive data on both mating and reproductive success on 57 species encompassing 73 populations.

ADSL deficiency is a secondary mitochondrial disease affecting organelle homeostasis and ERK2/AKT signaling in a linear genotype-phenotype relation.

Adenylosuccinate lyase deficiency (ADSLd) is a rare autosomal recessive purine metabolism disorder with several clinical manifestations. While toxic substrate accumulation is a known hallmark, no additional molecular mechanisms have been established. Here, we show that ADSLd is associated with mitochondrial dysfunction, including increased fragmentation, impaired respiration, and reduced ATP production.

Influence of dietary components on the gut microbiota of middle-aged adults: the gut-Mediterranean connection.

Background: A plant-focused, healthy dietary pattern, such as the Mediterranean diet enriched with dietary fiber, polyphenols, and polyunsaturated fats, is well known to positively influence the gut microbiota. Conversely, a processed diet high in saturated fats and sugars negatively impacts gut diversity, potentially leading to weight gain, insulin resistance, and chronic, low-grade inflammation. Despite this understanding, the mechanisms by which the Mediterranean diet impacts the gut microbiota and its associated health benefits remain unclear.

Deciphering pancreatobiliary intraductal oncocytic papillary neoplasms: integrative analysis of histomorphologic patterns, immunophenotypic markers, and emerging molecular biomarkers.

Purpose: We reviewed recent advancements in the characterization of intraductal oncocytic papillary neoplasm (IOPN) of the pancreas, with a specific focus on developments in immunohistochemical markers, molecular pathology, and pathogenic mechanisms over the past ten years (2015-2024). Through comprehensive analysis of current literature, we aimed to elucidate the evolving understanding of IOPN's biological behavior and diagnostic features, while identifying potential areas for future research in this distinctive pancreatic neoplasm.

Methods: English-language articles on IOPN were searched from Pubmed from the first report of IOPN of the pancreas in 2015 to 2024.