Deep brain stimulation (DBS) is a reversible and adjustable neurostimulation technique, and has been established as a significant therapeutic modality in functional neurosurgery although its mechanisms are not yet fully understood. The primary indications for DBS include movement disorders such as Parkinson's disease (PD) and dystonia, essential tremor (ET), and Huntington's disease (HD). In recent years, its application has expanded to encompass the treatment of various other neurological and psychiatric conditions, including epilepsy, depression, obsessive-compulsive disorder (OCD), Alzheimer's disease (AD), and Tourette syndrome (TS), although the indications for DBS currently approved by the Food and Drug Administration (FDA) are PD, dystonia, ET, OCD, and epilepsy. In this review, we summarize the prevailing hypotheses regarding the mechanisms through which DBS ameliorates neurological and psychiatric disorders. We also describe the advancements in DBS for treating PD, dystonia, epilepsy, and other brain disorders. Furthermore, we outline the limitations associated with DBS treatment to date. Through this comprehensive analysis, we aim to enhance the understanding of DBS applications in neurological and psychiatric diseases and suggest potential avenues for technological advancement.
This study used UK Biobank data from ∼500 000 participants to examine how smoking intensity and duration jointly shape the risk of 12 smoking-related cancers. We modeled excess relative risks (ERRs) per pack-year, separating the effect of smoking intensity while holding total pack-years constant to compare low-intensity/long-duration with high-intensity/short-duration patterns. For the same cumulative exposure, cancer risk increases differed across these smoking patterns, indicating that pack-years alone do not fully capture carcinogenic risk. We further evaluated time since cessation (TSC) and found that longer TSC was associated with lower ERR/pack-year for most cancers. Lifestyle factors modified these associations: participants with favorable behaviors (e.g., regular physical activity and healthier diet) generally had lower ERRs/pack-year than those with unfavorable behaviors. Overall, our findings show that smoking pattern and cessation history meaningfully influence pan-cancer risk beyond cumulative exposure, supporting the incorporation of detailed smoking histories-intensity, duration, and cessation-into risk stratification, screening eligibility, and prevention strategies.
This year marks the 50th anniversary of the Ebola virus identification, but the 2026 outbreak of Bundibugyo ebolavirus disease has exposed important limitations in Ebola preparedness strategies that remain largely focused on Zaire ebolavirus. Although major advances in diagnostics, vaccines, and therapeutics have followed the 2014–2016 West African Ebola epidemic, most licensed countermeasures were developed against Zaire ebolavirus and may provide limited protection against other ebolavirus species, including Bundibugyo ebolavirus. Herein, we examine the epidemiological significance of Bundibugyo ebolavirus and review current and emerging diagnostics, vaccines, antibody therapies, and antiviral strategies, with emphasis on their species coverage and limitations. We further discuss how diagnostic blind spots and limited species-inclusive countermeasures contributed to challenges during the current outbreak. Future Ebola preparedness should adopt a broader framework encompassing multiple ebolavirus species with epidemic potential.
The impact of high-altitude environments on the three core large-scale brain networks (default mode network (DMN), executive control network (ECN), and salience network (SN)) remains poorly understood. This study included 64 ultra-high-altitude residents (U-HA, 3600 m), 51 high-altitude residents (HA, 1500 m), and 49 low-altitude residents (LA, 400 m). Large-scale networks (DMN, SN, and bilateral ECN) were identified by group independent component analysis. The within- and between-network functional connectivity (FC) was quantified. Groups were compared using one-way analysis of variance. Partial correlations assessed the associations between network FC and oxygen saturation and HA residence duration after controlling confounders. The HA and U-HA groups exhibited higher medial prefrontal cortex (mPFC)-left posterior parietal cortex (PPC)/right dorsolateral prefrontal cortex (dlPFC), posterior cingulate cortex (PCC)-right anterior insula (AI), left and right dlPFC, and left dlPFC-dorsal anterior cingulate cortex (dACC) FC than the LA group (FDR-corrected, LSD post hoc). The blood oxygen saturation negatively correlated with the above FC, surviving correction for age, sex, education, and motion. Our findings may indicate that HA hypoxia is associated with reduced functional segregation between the DMN and ECN, as well as enhanced coupling of the bilateral ECN and SN-ECN.
RNA modifications are essential in regulating gene expression at the post-transcriptional level. Recent studies, including our own, have highlighted that RNA modifications, such as N6-methyladenosine (m6A) and methyl-5-cytosine (m5C), play a crucial role in tumorigenesis, metabolism, and anti-tumor immunity. Targeting RNA modification machinery may represent a promising therapeutic strategy in cancer. Intriguingly, emerging evidence reveals numerous modifications in mitochondrial RNA (mt-RNA), expanding the concept of epitranscriptomics to mitochondria. The mammalian mitochondrion possesses its own genome, which encodes 22 transfer RNAs (tRNAs), 2 ribosomal RNAs (rRNAs), and 13 proteins necessary for energy production via oxidative phosphorylation (OxPhos). The mitochondrial transcriptome is produced from large polycistronic transcripts, implying that mitochondrial gene expression is predominantly regulated post-transcriptionally. In this review, we summarize all currently known mt-RNA modifications, their potential regulatory machinery, as well as their biological functions in tumorigenesis and metabolism. Additionally, given that this field is still in its infancy, we discuss several critical knowledge gaps and propose future research directions to clarify the mechanistic and clinical significance in the study of mt-RNA modifications.
The locus coeruleus (LC), a cluster of noradrenergic neurons in the dorsal pons, is the brain’s main source of norepinephrine (NE), crucial for memory, cognition, and stress response. NE dysregulation has been linked to mood disorders, chronic stress, and neurodegenerative diseases such as Alzheimer’s disease (AD). Amyloid-β42 (Aβ42) is a key protein in AD pathology, and forms plaques that trigger neurodegeneration. Studies show elevated Aβ42 levels are associated with anxiety symptoms, even in cognitively normal individuals. Previous research suggests a positive correlation between NE and Aβ42, with Aβ42 present in NE-producing LC neurons. NE may affect Aβ42 levels through adrenergic receptors on neurons or microglia. However, the exact role of NE in modulating Aβ42 remains unclear. Using the NE depletion models, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4) lesions and dopamine β-hydroxylase (DBH) knockout (KO) mice, researchers found reduced Aβ42 levels without changes in amyloid precursor protein processing. A newer model, DBH internal ribosome entry site-Cre × floxed tyrosine hydroxylase (DBH-IRES-Cre × floxed-TH) preserved dopamine (DA) but eliminated NE in adrenergic neurons, further supporting the specific influence of NE on Aβ42. Findings indicate that decreased Aβ42 in NE-depleted mice stems not from altered DA but from NE loss. This highlights the NE-mediated regulation of endogenous Aβ42 and the role of NE in AD-related pathology.
Exosomes, extracellular vesicles packed with diverse bioactive molecules, show significant promise as therapeutic agents for corneal disorders. This review provides an overview of the current landscape and future outlook of exosome-based therapies in ophthalmology, with a focus on corneal disease. We summarize the fundamental biology and characteristics of corneal exosomes and discuss their roles in maintaining corneal homeostasis and driving disease processes. The therapeutic potential of exosomes in corneal ulcers, dry eye disease (DED), scarring, and dystrophies is evaluated, highlighting preclinical evidence that exosomes can promote epithelial wound healing, modulate inflammation and fibrosis, and support tissue regeneration, as well as emerging clinical studies that begin to assess their safety and feasibility. We also address critical aspects of exosome isolation, characterization, engineering, and delivery strategies that are relevant for clinical translation. Despite encouraging preclinical findings, significant challenges remain, particularly in standardizing manufacturing and quality control, ensuring safety, and achieving consistent therapeutic efficacy. Future research should focus on optimizing exosome production and delivery, rationally engineering them to enhance therapeutic performance, and exploring their potential as biomarkers. Overall, exosome-based therapies hold substantial promise for transforming the management of corneal diseases, but further rigorous translational and clinical studies are required to realize their full potential.
Data on the clinical characteristics and outcomes of patients with pleural infection are limited. This retrospective study aimed to describe the clinical characteristics and outcomes associated with community-acquired pleural infection (CAPI) and hospital-acquired pleural infection (HAPI) in a large Chinese tertiary-care hospital in Beijing over 11 years. The study included 832 patients, of whom 84.9
Hereditary spherocytosis (HS) and thalassemia are both common hemolytic anemias, yet their pathogenesis is different. HS arises from erythrocyte membrane abnormalities, while thalassemia stems from defective hemoglobin synthesis. They both typically manifest in childhood, and diagnosis is often straightforward based on typical clinical manifestations and laboratory findings. Here, we report a unique case of co-occurring hematological disorders: HS and α-globin gene triplication, in a 2-year-old Chinese boy. The child had a history of longtime hemolytic disease and carried a novel heterozygous mutation which was not detected in either parent. The previously undescribed c.149-1G>A splicing mutation is speculated to affect pre-mRNA splicing. The coexistence of these conditions, along with a novel heterozygous mutation in the SPTB gene, highlights the complexity of genetic contributions to hemolytic anemias and underscores the importance of genetic testing in diagnosing and understanding these disorders.
KMT2A (formerly MLL) gene rearrangements are common and clinically significant in acute leukemias, with outcomes influenced by the fusion partner. Over 100 fusion partners are known, but new ones continue to emerge. This study identified three novel partners-myocardin-related transcription factor B (MRTFB), sorbin and SH3 domain-containing 1 (SORBS1), and scavenger receptor cysteine-rich family member with 5 domains (SSC5D)-in pediatric and adult acute leukemia cases. Three cases were analyzed: a boy with B-cell precursor acute lymphoblastic leukemia, a girl with acute myelomonocytic leukemia, and a woman with therapy-related acute myeloid leukemia (AML). Diagnostics included cytogenetic analysis, fluorescence in situ hybridization (FISH), multiplex reverse transcription-polymerase chain reaction (RT-PCR), whole genome sequencing (WGS), and confirmation of breakpoints by Sanger sequencing, with validation at DNA and RNA levels, using patient-specific primers. WGS identified three novel in-frame fusions: KMT2A::MRTFB, KMT2A::SORBS1, and KMT2A::SSC5D, all within the major KMT2A breakpoint region. All patients achieved complete remission with tailored therapy, including chemotherapy and hematopoietic stem cell transplantation where indicated. Follow-up demonstrated durable remissions ranging from 9 to 23 months at the time of reporting. This study expands the catalog of KMT2A fusion partners, highlighting MRTFB, SORBS1, and SSC5D as novel leukemia-associated genes. The findings underscore the value of WGS for comprehensive detection of rare genetic events, enabling improved molecular classification and prognostic assessment in KMT2A-rearranged leukemias.
Glioblastoma (GBM), the most aggressive central nervous system (CNS) malignancy, currently lacks curative therapeutic options. While immunotherapy has revolutionized treatment for many cancers, GBM remains refractory to immune-based interventions due to the absence of effective immunotherapeutic targets. Here, through CRISPR screening, we identify Niemann–Pick C1-like 1 (NPC1L1) as a previously unrecognized key driver of GBM progression. Mechanistically, NPC1L1 modulates cholesterol metabolism to concurrently enhance tumor cell stemness and suppress CD8+ T-cell activation, thus inducing tumor progression. Notably, combined treatment with ezetimibe (NPC1L1 inhibitor) and anti-PD-1 antibody elicited potent antitumor activity in GBM orthotopic mouse models. Collectively, these findings establish NPC1L1 as a critical regulator of GBM pathogenesis, underscoring the translational potential of targeting NPC1L1-mediated cholesterol metabolism for developing novel GBM immunotherapies.
Congenital muscular dystrophies (CMDs) are a genetically heterogeneous group of disorders. Variants in the INPP5K gene, which encodes a phosphoinositide phosphatase, are a rare cause of CMD. The condition is commonly associated with muscle weakness, early-onset cataracts, and intellectual disability, and prior reports have primarily identified missense, frameshift, or deletion variants. We describe the first Chinese case of INPP5K-related muscular dystrophy in a 28-year-old male with a mild phenotype, notably lacking intellectual disability. His presentation included bilateral cataracts at age 5 and adolescent onset limb girdle weakness. Muscle magnetic resonance imaging (MRI) revealed a characteristic pattern of selective fatty infiltration, with severe involvement of gluteal and thigh muscles and striking sparing of the rectus femoris, sartorius, and gracilis. Genetic analysis identified compound heterozygous novel INPP5K variants: a missense c.274C>T, p.(Arg92Cys) and a synonymous c.261G>A, p.(Lys87=) change. Functional studies confirmed the synonymous variant causes aberrant splicing (exon 3 skipping), leading to a frameshift and premature termination p.(Leu52SerfsTer49). According to American College of Medical Genetics and Genomics guidelines, the c.274C>T and c.261G>A variants were classified as likely pathogenic and pathogenic, respectively. This first report of a Chinese patient with INPP5K-related muscular dystrophy broadens both the genetic and clinical spectrum of the disorder. We identify the first disease-causing synonymous variant (via aberrant splicing) and a novel hypomorphic missense variant p.(Arg92Cys), the combination of which explains the attenuated phenotype lacking intellectual disability. Our case highlights the critical role of RNA analysis in diagnosing non-canonical variants and confirms the universal diagnostic relevance of the characteristic muscle MRI pattern.
Pontocerebellar hypoplasia type 12 (PCH12) is an ultra-rare, perinatal lethal, neurodegenerative disorder with microcephaly and arthrogryposis. Previous reports have associated PCH12 with complete loss-of-function variants in COASY identified in 14 fetuses and newborns from eight unrelated families. In contrast, COASY partial loss-of-function variants have been linked to COASY protein-associated neurodegeneration (CoPAN), a subtype of neurodegeneration with brain iron accumulation (NBIA). Emerging evidence suggests that COASY-related disorders may represent a phenotypic continuum between PCH12 and CoPAN. Using exome sequencing, we identified a previously reported missense variant (c.641C>T, p.Ala214Val) as well as a previously unreported rare nonsense variant (c.1015C>T, p.Arg339*) in a compound heterozygous state in the COASY gene in a patient presenting with clinical features consistent with PCH12. The p.Ala214Val variant has only been described in combination with another missense variant (p.Arg499Cys) in two siblings with CoPAN. The presence of p.Ala214Val in trans with the truncating p.Arg339* variant in this patient is associated with a severe perinatal lethal phenotype resembling PCH12. This case broadens the reported genetic and phenotypic spectrum of COASY-associated disorders and highlights the importance of continued genotype-phenotype correlation investigation.
Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening hematological emergency defined by severe ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13) deficiency. However, TTP-like syndromes without ADAMTS13 reduction can occur in systemic infections such as human immunodeficiency virus (HIV), posing significant diagnostic and therapeutic challenges, particularly in high-risk and underdiagnosed populations. We report the case of a 45-year-old transgender woman who presented to the emergency department with abdominal and lumbar pain, severe anemia, and thrombocytopenia. Laboratory tests revealed schistocytes, elevated lactate dehydrogenase (LDH), and indirect hyperbilirubinemia, prompting a high PLASMIC score and the initiation of plasma exchange for suspected TTP. Subsequent investigations revealed a preserved ADAMTS13 activity and uncovered a previously undiagnosed advanced HIV infection, along with Epstein-Barr virus (EBV) and human herpesvirus 8 (HHV-8) viremia. Despite timely initiation of antiretroviral therapy and comprehensive supportive care, the patient experienced progressive clinical deterioration and died during hospitalization. This case illustrates a multifactorial secondary thrombotic microangiopathy (TMA) mimicking primary TTP, triggered by advanced HIV and possibly exacerbated by estrogen-associated prothrombotic risk. It highlights the importance of early virologic screening and broad diagnostic reasoning in high-risk patients with overlapping prothrombotic conditions, where identifying the underlying cause of secondary TMA is critical to improving outcomes and preventing missed opportunities for life-saving intervention.
Immune checkpoint inhibitor (ICI)-based immunotherapy has emerged as an effective strategy for stage III non-small cell lung cancer (NSCLC). However, predictive biomarkers of response remain limited. DNA polymerase epsilon (POLE) mutations, although rare in NSCLC, are associated with an increased tumor mutational burden and enhanced neoantigen presentation, both of which may promote immune sensitivity. A 52-year-old woman was diagnosed with stage IIIA NSCLC. Tumor programmed death-ligand 1 (PD-L1) expression was negative. Molecular profiling revealed a somatic POLE mutation (NM_006231.4 (POLE): c.1270C>G (p.Leu424Val)), without additional tumor alterations. A perioperative chemo-immunotherapy approach was implemented. After three cycles of neoadjuvant carboplatin, pemetrexed, and pembrolizumab, computed tomography (CT) scan revealed a significant response. Then, the patient underwent to curative-intent surgery. Histopathological examination demonstrated a pathological complete response (pCR). Adjuvant pembrolizumab (thirteen cycles) was administered without relevant toxicities. At 18-month follow-up, the patient remained disease-free with good performance status. In conclusion, we report the case of pCR in a POLE-mutated NSCLC patient treated with perioperative chemo-immunotherapy. Incorporating a POLE evaluation could improve the integrated decision-making process for patients with NSCLC in the perioperative setting. Prospective studies are warranted to validate this observation.
Hepatocellular carcinoma (HCC) remains a lethal malignancy with limited therapeutic targets. P53 and DNA damage-regulated gene 1 (PDRG1) has emerged as an oncogene in multiple cancers, yet its role and regulatory mechanism in HCC remain unclear. Here, we demonstrated that PDRG1 expression was significantly upregulated in HCC tissues compared to normal liver, correlating with advanced tumor stage, higher grade, and poor patient survival. Functionally, PDRG1 knockdown suppressed HCC cell proliferation, migration, and invasion in vitro and inhibited tumor growth and lung metastasis in vivo, whereas PDRG1 overexpression exerted opposite effects. Mechanistically, PDRG1 activated Wnt/β-catenin signaling, elevating levels of β-catenin, c-Myc, and phosphorylated GSK-3β, and the oncogenic effects of PDRG1 were reversed by the Wnt pathway inhibitor XAV939. Furthermore, transcription factor Specificity Protein 1 (SP1) bound directly to the PDRG1 promoter at the E3 site (–1927 to–1917) and activated its transcription. The pro-tumor effects of SP1 were rescued by PDRG1 silencing, indicating that SP1 acts through PDRG1. Collectively, our study identifies SP1 as an upstream transcriptional activator of PDRG1 and defines the SP1/PDRG1/Wnt/β-catenin axis as a key regulatory pathway promoting HCC progression, suggesting its potential as a prognostic biomarker and therapeutic target.
