Deciphering the mechanistic links between aging and cancer remains a central challenge in biomedical research. This review begins by presenting recent epidemiological data on cancer incidence across age groups, underscoring the complex and paradoxical interplay between aging and cancer. A systematic analysis follows four core signaling pathways that underpin both aging and cancer: (i) nutrient sensing and energy metabolism pathways, (ii) stress response and genome maintenance pathways, (iii) inflammatory and microenvironmental pathways, and (iv) sirtuin-mediated epigenetic and transcriptional modulation pathways. Each pathway is analyzed regarding its distinct and overlapping roles in aging and cancer, with exploration of strategies for comodulating these shared mechanisms to simultaneously mitigate both conditions. Established and emerging druggable targets within these pathways are highlighted, offering new perspectives for future therapeutic development. Current integrative strategies to achieve concurrent antiaging and anticancer effects include targeting cellular nutrient sensing and metabolism, enhancing genomic integrity, suppressing chronic inflammation, clearing senescent cells, and modulating epigenetic programs. Finally, the impact of aging on cancer therapy, particularly immunotherapy, is discussed, along with a review of representative aging-related pathways and genes and their roles in modulating immunotherapy efficacy. Analysis of agents targeting each pathway spanning preclinical studies, clinical trials, and clinically approved drugs reveals disparities in the research progress between anti-aging and anticancer applications. Consequently, a promising future strategy for drug discovery lies in repurposing well-established anticancer agents for antiaging interventions, as well as translating insights from aging research into novel antitumor therapies, thereby achieving synergistic benefits in both fields.

Immune checkpoint inhibitors (ICIs) have significantly improved overall survival in metastatic urothelial carcinoma (mUC). However, predictive biomarkers for therapeutic response remain insufficiently defined. Although some genomic alterations have been implicated in modulating tumor immunogenicity and ICI sensitivity in other cancers, evidence in mUC remains limited and warrants further investigation.

We retrospectively analyzed 67 patients with mUC treated with ICIs and performed targeted next-generation sequencing using a 440-gene cancer panel. Tumor mutational burden (TMB), genomic alterations, and clinical outcomes were evaluated to identify biomarkers associated with ICI response. Functional studies were conducted using urothelial carcinoma cell lines co-cultured with peripheral blood mononuclear cells (PBMCs) with or without anti-programmed death-ligand 1 (PD-L1) treatment to evaluate tumor viability, cytokine responses, and antigen presentation. Gene knockdown and overexpression experiments, quantitative PCR, immunofluorescence, and western blotting were used to assess cytokine production, antigen presentation machinery components, and major histocompatibility complex (MHC) class I expression. In vivo validation was performed using CRISPR/Cas9-mediated knockout syngeneic murine models treated with anti-PD-L1 to assess tumor growth, immune infiltration, and therapeutic response through immunohistochemistry and flow cytometry.

Responders to ICI monotherapy exhibited significantly higher TMB and enriched mutations in PIK3CA, ADAMTSL1, NSD1, and PRKDC. Hotspot PIK3CA mutations correlated with elevated TMB across multiple TCGA pan-cancer, breast and colorectal cohorts. Functionally, PIK3CA-mutant tumor cells demonstrated enhanced cytotoxicity when co-cultured with PBMCs and anti-PD-L1, whereas PIK3CA knockdown abolished this effect. Silencing PIK3CA reduced expression of pro-inflammatory cytokines (interferon-γ, tumor necrosis factor-α, interleukin (IL)-2, IL-6) and CD8⁺ effector molecules (granzyme B, perforin A), while PIK3CA E545K overexpression restored these immune mediators. Mechanistically, PIK3CA mutations enhanced antigen presentation via the IRF1-NLRC5-MHC-I axis, increasing HLA-A and B2M expression. In vivo, PIK3CA-deficient tumors displayed diminished response to anti-PD-L1 therapy, reduced CD8⁺ T-cell infiltration, and attenuated MHC-I expression.

This study is the first to identify PIK3CA mutation as an immune-modulating driver that enhances tumor immunogenicity through activating IRF1-NLRC5-MHC-I pathway in urothelial carcinoma.

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States. While the gut microbiota has been shown to influence CRC development, the specific contribution of bacteria to DNA methylation and carcinogenesis remains underexplored.

We colonize two groups of GF Apc^Min/+ mice with two consortia, one harboring a pks⁺ E. coli strain with "low-pks" activity (DSMZ) and the second with a clinical isolate exhibiting "high-pks" activity (UM149). These colonized mice are exposed to DSS-induced colitis, and analyzed for tumor burden, DNA methylation, and transcriptional changes. We find that colonization with C13-UM149 leads to more tumors, increased cell proliferation, and higher DNA damage compared to C13-DSMZ (p < 0.05). Methylation analyses show that C13-DSMZ causes extensive promoter hypermethylation and altered gene expression. Differential DNA methylation in mice colonized with either C13-DSMZ or C13-UM149 is associated with changes in pathways controlling tumor suppression, cell proliferation, inflammation, and Wnt signaling. In C13-DSMZ mice, hypermethylation is associated with gene expression involved in tumor suppression in both tumors and normal tissue, whereas hypomethylation is linked to expression of genes promoting Wnt signaling. In C13-UM149 mice, methylation changes were connected to genes involved in epithelial proliferation, extracellular matrix remodeling, and inflammatory responses.

These findings demonstrate that intestinal bacteria with distinct pks activities differentially modulate DNA methylation thereby influencing gene expression and tumor development. This highlights bacterial modulation of epigenetic responses as a potential mechanism underlying CRC progression.

Autoantibodies (ABs) against intracellular proteins, including glutamate-decarboxylase 65 (anti-GAD65), are increasingly recognized in autoimmune and limbic encephalitis (AE/LE). Anti-GAD65 LE frequently progresses to severe temporal lobe epilepsy (TLE), neuropathologically characterized by hippocampal sclerosis (HS) and variable infiltration of cytotoxic T lymphocytes (CTLs). Recently, we have identified Drebrin (DBN) as a new intracellular target protein of ABs in index patients with suspected AE. Here, we aim to characterize key molecular and cellular signatures of hippocampal tissue from anti-GAD65- (GAD65-TLE) versus anti-DBN-positive TLE (DBN-TLE) patients correlated to clinical parameters.

We examined hippocampal neuropathology and performed exploratory single-nucleus RNA sequencing (snRNA-seq) of hippocampal tissue from DBN- and GAD65-TLE patients, integrated with key clinical data from a large patient cohort.

Although the hippocampi of the two patient groups were neuropathologically virtually indistinguishable, exploratory snRNA-seq revealed distinct transcriptional programs. DBN-TLE patients (n = 2) showed transcriptional signatures enriched for forkhead box (Fox) transcription factor family, whereas GAD65-TLE patients (n = 2) displayed transcriptional signatures enriched for transcripts related to NF-κB- signaling. In a larger cohort, DBN-TLE patients (n = 22) showed significantly more favorable pharmacological responsiveness than GAD65-TLE patients (n = 35), who were largely pharmacoresistant. Notably, in a T cell-mediated mouse model for LE, similar inflammatory programs were dynamically regulated.

These findings provide a discovery-based transcriptomic signatures of rare autoimmune hippocampal tissue, revealing distinct immune-associated transcriptional states in anti-DBN- versus anti-GAD65-positive AE/TLE patients despite virtually indistinguishable hippocampal pathology in both groups and support further investigations of disease-specific therapeutic strategies.

Globally, colorectal cancer continues to be a major cause of cancer-related death. Clinical application of 5‑fluorouracil (5‑FU) is constrained by reduced bioavailability and dose‑limiting toxicity. To overcome these restrictions, a ternary drug delivery system was developed in this study. Chitosan and β‑cyclodextrin were physically assembled into a pseudopolyrotaxane complex, and 5‑FU was incorporated by solvent evaporation to form a solid dispersion. The resulting nanocomposite had a mean hydrodynamic diameter of 187 nm and a zeta potential of + 32.5 mV. Fourier transform infrared spectroscopy revealed peak shifts consistent with non‑covalent interactions. X‑ray diffraction confirmed amorphization of 5‑FU within the formulation. The ternary system released 5‑FU more rapidly at pH 5.5 than at pH 7.4. In HCT‑116 colorectal cancer cells, the 5‑FU/chitosan/β‑cyclodextrin formulation showed an IC₅₀ of 16.5 µM, compared with 42.5 µM for free 5‑FU and 27.5 µM for the binary 5‑FU/β‑cyclodextrin complex. Gene expression analysis indicated upregulation of P53 and Caspase‑3 and downregulation of BCL2 and VEGF. A complementary in silico analysis of 5-FU-responsive genes (from public dataset GSE183977) identified a protein‑protein interaction network enriched in apoptosis and cell‑cycle pathways, with IL6, MYC, EGR1, and ATF3 as central hub genes. The obtained results show that incorporation of 5‑FU into a chitosan/β‑cyclodextrin matrix improves its activity against colorectal cancer cells. This effect is attributed to enhanced solubility, pH‑responsive release, and modulation of apoptotic and angiogenic pathways.

Neonatal sepsis continues to be a leading cause of mortality, frequently presenting with vague clinical characteristics. Rarely, it might present with hyperleukocytosis, which closely resembles congenital leukemia and creates a diagnostic difficulty. A preterm male neonate born at 34 weeks' gestation with a birth weight of 1.8 kg was delivered to a 27-year-old G2, P1 woman in a nonconsanguineous marriage. The neonate developed respiratory distress shortly after birth. Laboratory evaluation revealed a total leukocyte count of 108 × 10³/µL (108 × 10⁹/L), raising concern for congenital leukemia. However, peripheral blood smear showed cytoplasmic vacuolation and toxic granules without any blast cells, and flow cytometry excluded malignancy and leukocyte adhesion deficiency. Blood culture grew Acinetobacter baumannii A diagnosis of sepsis-induced hyperleukocytosis was made. The leukocyte count normalized with broad-spectrum antibiotics, and the neonate recovered fully. Hyperleukocytosis in neonates is not always indicative of congenital leukemia. Differentiating between malignant and reactive causes is crucial as management and prognosis differ widely.

An otherwise healthy female infant presented with left-sided, rapidly progressive, severe periorbital swelling, erythema and proptosis for 7 days' duration. Imaging revealed multiple fluid-filled lobulated pockets in both intraconal and extraconal orbital spaces suggestive of multiple orbital abscesses which had an extension to the nasal cavity. Surgical drainage of the abscess was done along with administration of intravenous antibiotics. Diagnostic lacrimal system probing revealed soft stop warranting a nasal endoscopy during which a membranous thick-walled outpouching from the inferior meatus was noted. It was a congenital nasolacrimal duct cyst. Transnasal endoscopic complete marsupialisation of the cyst was done followed by successful silicone intubation. The child recovered well with resolution of orbital signs and no recurrence at follow-up. This case underscores the importance of early recognition of a congenital nasolacrimal duct cyst which can complicate vision and life-threatening complications.

Emerging data suggest fecal microbiota transplantation (FMT) may improve cancer patients' responses to immune checkpoint blockade not only by enriching beneficial bacteria but also by depleting harmful taxa. Here, we discuss the "supplementation" and new "depletion" FMT paradigms in cancer management and highlight key knowledge gaps to be addressed to move this field forward.

To identify clinical characteristics that may be associated with persistence or progression of mild sleep-disordered breathing (SDB) in children who are observed without surgery.

This is a secondary analysis of the control arm of the Pediatric Adenotonsillectomy Trial for Snoring (PATS), which randomized 458 children aged 3.0 to 12.9 years with mild SDB (snoring with obstructive apnea-hypopnea index [oAHI] < 3 events/hour) to early adenotonsillectomy (eAT) versus watchful waiting with supportive care (WWSC). Participants were assessed at baseline and 12 months with the Pediatric Sleep Questionnaire-Sleep-Related Breathing Disorder (PSQ-SRBD) scale and polysomnography (PSG). We tested for factors predictive of either (1) PSG progression defined by a 12-month oAHI ≥ 3 or (2) symptom persistence or progression defined by a 12-month PSQ-SRBD score ≥ 0.33.

A total of 234 participants were observed (mean age 6.2 years, 111 [47%] female, 65 [28%] Black or African American, 37 [16%] Hispanic). Overall, only 13% (n = 20/150) progressed to an oAHI ≥ 3 on repeat PSG, whereas over half (n = 110/192, 57%) had symptom persistence/progression. Of the children with persistent or progressive symptoms, 18% (n = 16/103) progressed to oAHI ≥ 3. In unadjusted analyses, PSG progression was associated with Black race (OR 2.71, 95% CI 1.03-7.17) and higher baseline PSQ-SRBD (OR 1.74, 95% CI 1.03-3.08). Symptom persistence/progression was predicted by asthma (OR 2.70 [95% CI 1.29, 6.01]), ADHD (OR 3.73 [95% CI 1.13, 16.88]), and tobacco smoke exposure (OR 2.41 [95% CI 1.08-5.82]), while children with larger tonsils (grade III-IV) had lower odds of progression (OR 0.42 [95% CI 0.22-0.78]).

A high symptom burden is common after a year of WWSC for mild SDB, but only a minority of children progressed on PSG. Black race and several clinical characteristics and symptom scores were associated with higher likelihood of progression.

ClinicalTrials.gov Identifier: NCT0256204.

Can clinical information predict persistence or progression of mild sleep-disordered breathing in children who are observed for 1 year without adenotonsillectomy?

Polysomnographic progression to obstructive sleep apnea occurs in a minority (13%) of those observed while symptom persistence or progression is more common (57%). Children who are Black or who have asthma, attention-deficit hyperactivity disorder, environmental tobacco exposure, and a high symptom burden could be considered stronger candidates than their peers for earlier adenotonsillectomy for symptomatic mild sleep-disordered breathing.

Angiotensin-converting enzyme 2 (ACE2) is a key regulator of the renin-angiotensin-aldosterone system (RAAS). It also acts as a receptor for SARS-CoV-2 and stabilises the B0AT1 amino acid transporter at the cell surface. Therefore, surface expression of ACE2 is crucial for these physiological processes. ACE2 is released as a soluble, catalytically active form, partly through ectodomain shedding. This process mainly involves the sheddases ADAM10 and ADAM17, but the exact regulatory mechanisms remain unclear. We assessed 11 naturally occurring single-point mutations in the ACE2 stalk region. Most variants showed significantly reduced release compared to wild-type (WT) ACE2; however, the single point mutations P734L and G726R significantly increased their release. ACE2_P734L also exhibits higher surface expression, directly increasing the surface levels of B0AT1. Despite B0AT1 and ACE2 forming a tight tetrameric complex, this did not affect ACE2 shedding. This suggests that complex formation does not restrict sheddase access. Overall, these data identify the ACE2 stalk region as a major determinant of shedding efficiency. Naturally occurring variants in this region can substantially affect the release of soluble ACE2, potentially contributing to interindividual differences that are relevant for pathophysiological processes.