Search Results (39)

Drug-resistant epilepsy is often associated with a neurodevelopmental disorder, focal cortical dysplasia (FCD). As demonstrated by numerous studies, defects in perisomatic inhibition may play a role in the formation of seizures. In our previous study, we observed an increase in parvalbumin-immunopositive perisomatic input. It has been observed that other perisomatic inhibitory cells expressing cannabinoid receptor type-1 (CB1R) and containing cholecystokinin (CCK) sprout in epileptic hippocampi. Therefore, we have investigated whether CB1R-immunopositive innervation has also changed in FCD. FCDIIB surgical samples were compared to controls with short post-mortem delay. The perisomatic input contacting principal cells was examined by NeuN-CB1R double immunostaining. Quantification in 3D was performed using a confocal fluorescence microscope. The results show that the CB1R-immunopositive synaptic input of principal cells is significantly larger in FCD cases. This condition may be an adaptive response to abnormal activity, or it may be a pre-existing pathology that is exacerbated by seizures. The reorganisation of the perisomatic inhibitory system has the potential to further increase the seizure probability in both cases. It should be noted that alterations in both PV- and CCK-CB1R-expressing basket cells may be implicated in seizure generation. Full article

Platinum group metals (PGM) are essential for clean-energy technologies, including proton exchange membrane (PEM) electrolyzers for hydrogen production and PEM fuel cells for hydrogen use, as well as catalytic, electronic, and advanced industrial applications. However, their supply is exposed to geological concentration, co-product dependence, and market volatility. This study evaluates the medium-term cost-based accessibility of known primary PGM resources using a cumulative availability curve. The analysis combines resource estimates and allocated production-cost data for 61 known PGM-bearing deposits and projects, with costs expressed in 2022 USD per metric ton of combined PGM output. Because PGM deposits differ in ore type, processing route, and co-product setting, the results are interpreted by deposit cluster rather than only by country or aggregate cost threshold. The low-cost portion of the curve is dominated by Ni–Cu sulphide by-product systems, but this cluster represents only 1.87% of the compiled resource base. In contrast, UG2/Merensky/Great Dyke reef-type systems account for 72.95%, and Platreef/Northern Limb and Platreef-type systems account for 19.82%. Thus, most known primary PGM resources occur outside the low-cost by-product segment. Cluster-weighted PGM basket-price benchmarks are used instead of individual metal-price comparisons. Several cluster-level cost ranges fall below or near indicative April 2025 basket-price benchmarks, but these comparisons are not project-level profitability tests. Overall, the cumulative availability curve provides a deposit-cluster-based framework for evaluating known primary PGM availability and informing critical-material policy, recycling strategy, supply-chain planning, hydrogen-technology deployment, and responsible resource development. Full article

Background and Clinical Significance: Lambert–Eaton myasthenic syndrome (LEMS) is mediated by antibodies against P/Q-type voltage-gated calcium channels (VGCCs) and is classified as paraneoplastic (T-LEMS) or non-paraneoplastic (NT-LEMS). Cerebellar degeneration is recognized in T-LEMS, but pathological confirmation in NT-LEMS has not been reported. Case Presentation: A 79-year-old man developed progressive ataxic gait and dysarthria at age 76 and was diagnosed with LEMS based on repetitive nerve stimulation findings and anti-P/Q-type VGCC antibodies. No malignancy was identified during more than 40 months of surveillance, and comprehensive autopsy revealed no occult tumor. After hospitalization for erythroderma and pneumonia, he died of respiratory failure. Postmortem examination revealed severe Purkinje cell loss with Bergmann gliosis in the anterior lobe and tuber vermis, accompanied by torpedoes and empty baskets, without significant inflammation. These findings indicate that NT-LEMS can reach the same VGCC-associated Purkinje cell endpoint previously documented only in paraneoplastic LEMS, despite different upstream triggers. Conclusions: This first autopsy-confirmed case of NT-LEMS with cerebellar degeneration supports a shared, non-inflammatory VGCC-mediated pathway of Purkinje cell injury across LEMS subtypes. Full article

Squamous cell lung cancer (SqCLC) accounts for 20–30% of non-small cell lung cancer (NSCLC) and remains associated with a poorer prognosis compared with adenocarcinoma. Despite advances in treatment, 5-year overall survival for advanced (stage IV) disease remains below 10–15%. Unlike non-squamous NSCLC, SqCLC is characterized by a high tumor mutational burden and complex genomic landscape dominated by alterations in tumor suppressor genes and lineage survival pathways including TP53, CDKN2A, PIK3CA, FGFR1, SOX2, and the NFE2L2/KEAP1 oxidative stress pathway, as well as dysregulation of the NOTCH signaling pathway, but it harbors relatively few actionable oncogenic drivers, resulting in limited treatments for targeted therapy. HER2 alterations can occur by multiple mechanisms, including activating mutations, gene amplifications, and protein overexpression. They comprise a very small percentage of NSCLC, with HER2 mutations reported in approximately 1–3% and HER2 amplifications observed roughly in 2–4%. While HER2 alterations are well characterized in lung adenocarcinoma, the prevalence, genomic context, and clinical significance of HER2 alterations in SqCLC remain incompletely defined. Advances in next-generation sequencing have led to improved ability to detect HER2 alterations and facilitated the development of HER2 targeted therapies. Available treatments for advanced/metastatic SqCLC have been historically limited to platinum-doublet chemotherapy, with immune checkpoint inhibitors such as anti-PD-1/PD-L1 newly emerging in the past decade. Selective HER2 tyrosine kinase inhibitors and HER2 antibody/drug conjugates have shown improved efficacy in HER2-altered NSCLC as shown in DESTINY-LUNG02 and BEAMION LUNG-1 trials; however, most of the enrolled patients had non-squamous histology, with minimal or no SqCLC-specific efficacy data reported. Future progress in HER2-altered SqCLC will require inclusion of SqCLC in HER2 basket trials, incorporation of comprehensive molecular profiling and standardized HER2 testing in squamous histology. This review summarizes the current state of knowledge of HER2 biology in SqCLC and highlights areas for future directions for precision oncology in SqCLC. Full article

Three packaging methods were applied to fresh red apricots: P1 (plastic basket), P2 (breathable foam box), and P3 (perforated corrugated carton). To evaluate the effects of different packaging methods on apricot quality during simulated transportation and subsequent cold storage, fruit quality parameters were measured at 0 h, after 48 h of simulated vibration, and on days 3, 6, and 9 of cold storage. The results showed that, compared with P2 and P3, P1 more effectively maintained fruit surface color and firmness, delayed declines in soluble solids content (SSC), titratable acidity (TA), ascorbic acid content, and moisture content, and reduced water loss and overall weight loss. P1 also suppressed the increase in respiration rate, enhanced peroxidase (POD) and catalase (CAT) activities, suppressed increases in polyphenol oxidase (PPO) activity and hydrogen peroxide (H₂O₂) accumulation, and reduced lipid peroxidation. Additionally, P1 alleviated damage to the cell wall, maintained the structural integrity of the pulp cell walls, and improved the percentage of sound fruit. Transmission electron microscopy (TEM) confirmed that P1 delayed the degradation of the pulp cell wall and maintained the structural integrity of fruit cells. In conclusion, P1 (plastic basket) was the optimal packaging method for maintaining postharvest quality of fresh apricots during simulated transportation and cold storage. Full article

The CFEM (Common in Fungal Extracellular Membrane) domain defines a family of cysteine-rich proteins unique to fungi, playing pivotal roles in host–pathogen interactions. However, the repertoire and functions of CFEM proteins in the broad-host-range necrotrophic pathogen Sclerotinia sclerotiorum remain largely unexplored. Through genome-wide bioinformatic analysis, we identified 13 CFEM-containing proteins (SsCFEM1–13) in S. sclerotiorum. Characterization revealed substantial diversity in their physicochemical properties, domain architecture, and predicted subcellular localization. Ten proteins possess a secretion signal, with six predicted to be GPI-anchored and three classified as high-confidence effectors. Members lacking transmembrane domains were predicted to adopt the conserved CFEM “helical-basket” fold. Phylogenetic analysis grouped SsCFEMs into two distinct clades and indicated a complex evolutionary history involving both conserved ancestry and lineage-specific expansion. Transcriptomic profiling showed that most genes were upregulated during early infection of various host plants, with SsCFEM8 exhibiting particularly strong and consistent induction. Crucially, transient expression assays in Nicotiana benthamiana revealed that several SsCFEM proteins, notably SsCFEM4 and SsCFEM9, function as cell death suppressors, validating their predicted effector roles and identifying key virulence candidates. This study provides the first comprehensive catalog and functional prediction of the CFEM protein family in S. sclerotiorum, establishing a foundation for future mechanistic studies on their roles in the pathogenesis of this devastating fungal pathogen. Full article

This study presents the development of a three-dimensional (3D) filament assembly model for predicting the air permeability of woven fabrics composed of spun yarns. To address the limitations of conventional single-line yarn models, the proposed framework incorporates fiber-level geometric representations using non-uniform rational B-splines (NURBS) and simulates multiple weave patterns—including plain, basket, twill, and rib—under various set density configurations. Each yarn was modeled with accurate filament distribution and cross-sectional layering, enabling the construction of realistic unit-cell-based CAD geometries. Computational fluid dynamics (CFD) simulations were performed using the k-ε turbulence model in SolidWorks Flow Simulation and validated against experimental measurements conducted under ISO 9237:1995 conditions. The filament assembly model achieved high predictive accuracy, exhibiting a lower of percentage prediction errors than the single-line yarn path model, thereby more effectively capturing airflow behavior through inter-yarn and intra-yarn pores. These findings highlight the capability of integrated CAD/CFD methodologies for virtual prototyping of breathable textiles and provide a robust foundation for high-precision performance prediction in functional and technical fabric design. Full article

Background/Objectives: Tissue-agnostic therapy has transformed oncology by enabling treatment selection based on molecular alterations rather than tumor origin. Since 2017, nine U.S. Food and Drug Administration approvals across six biomarker classes have defined this paradigm. Thoracic and head and neck (H&N) cancers have been underrepresented in the registrational evidence supporting these approvals. This review systematically evaluated biomarker representation, histologic distribution, and clinical applicability of tissue-agnostic therapies in thoracic and H&N malignancies. Methods: A narrative systematic review was conducted using PubMed, ClinicalTrials.gov, and regulatory documents for all tissue-agnostic approvals between January 2017 and October 2025. Data were extracted from pivotal trials, including total enrollment, objective response rate (ORR), histologic distribution, and thoracic/H&N representation. Emerging biomarkers and resistance mechanisms were assessed from phase I–III studies and basket trials. Results: Nine tissue-agnostic approvals encompassing six biomarkers were identified: MSI-H/dMMR, TMB-High, NTRK, RET, BRAF V600E, and HER2 (IHC 3+). Across pivotal datasets (3800 patients), thoracic and H&N cancers accounted for fewer than 8% (n = 290) of enrolled patients. Thoracic representation was dominated by non-small-cell lung cancer (NSCLC) in RET, NTRK, and HER2 programs (150 patients, 4%), while small-cell lung, mesothelioma, and thymic carcinomas contributed <1% combined. H&N cancers comprised 140 patients (3–4%), primarily secretory salivary carcinoma in NTRK trials (n = 12–20), thyroid carcinoma in BRAF (n = 36) and RET (n = 45) programs, and rare HER2-positive salivary duct carcinomas. Conventional HNSCC and sinonasal cancers were limited to 1–2 cases per trial. Only two of nine trials (22%) reported prespecified CNS endpoints, and RNA-based fusion testing was employed in <40%, underscoring diagnostic variability and limited applicability. Conclusions: Although tissue-agnostic therapy has expanded the reach of precision oncology, thoracic and H&N cancers remain underrepresented in registrational evidence. Most approvals rely on single-arm basket studies with small, heterogeneous subsets that preclude histology-specific conclusions. Future research should prioritize histology-enriched trial designs, standardized molecular diagnostics, and real-world validation to establish reliable, equitable standards of care for these underrepresented malignancies. Full article

Background/Objectives: A concussive head injury increases the likelihood of temporal lobe epilepsy through mechanisms that are not entirely understood. This study aimed to investigate how two key histopathological features shared by both TLE (temporal lobe epilepsy) and head injury—mossy fiber sprouting and hilar excitatory cell loss—contribute to the modulation of dentate gyrus excitability. Methods: A computational approach was used to explore the impact of specific levels of mossy fiber sprouting and mossy cell loss, while avoiding the confounding effects of concurrent changes. The dentate gyrus model consists of 500 granule cells, 15 mossy cells, 6 basket cells and 6 hilar perforant path-associated cells. Results: My simulations demonstrate a correlation between the degree of mossy fiber sprouting and the number of spikes in dentate gyrus granule cells (correlations coefficient R = 0.95, p < 0.0001) and other cells (correlations coefficient R = 0.99, p < 0.0001). The mean values (standard deviation, SD) and 95% CI for granule cell activity in the control group and percentage 10–50% of mossy fiber sprouting groups are 376.4 (16.7) (95% CI, 374.9–377.8) vs. 463.5 (24.3) (95% CI, 461.4–465.6) vs. 514.8 (32.5) (95% CI, 511.9–517.6) vs. 555.0 (40.4) (95% CI, 551.5–558.6) vs. 633.4 (51.8) (95% CI, 628.8–637.9) vs. 701.7 (66.2) (95% CI, 695.9–707.5). The increase in mossy fiber sprouting was significantly statistically associated with an increase in granule cell activity (p < 0.01). The removal of mossy cells led to a reduction in excitability within the model network (for granule cells, correlations coefficient R = −0.40, p < 0.0001). Conclusions: These results are generally consistent with experimental observations, which indicate a high degree of mossy fiber sprouting in animals with a higher frequency of seizures. Whereas unlike the strong hyperexcitability effects induced by mossy fiber sprouting, the removal of mossy cells led to reduced granule cell responses to perforant path activation. Full article

A copolymer of 3-hydroxybutyrate (3HB) and 3-hydoxyhexanoate (3HHx), PHBHHx, is a practical biodegradable plastic, and at present, the copolymer is produced at commercial scale via heterotrophic cultivation of an engineered strain of a facultative hydrogen-oxidizing bacterium, Cupriavidus necator, using vegetable oil as the carbon source. In our previous report, we investigated PHBHHx production from CO₂ via pH-stat jar cultivation of the newly created recombinants of C. necator under autotropic conditions, feeding the inorganic substrate gas mixture (H₂/O₂/CO₂ = 80:10:10 v/v%) into a recycled-gas closed-circuit (RGCC) culture system. The dry cell weight (DCW) and PHBHHx concentration with the best strain MF01/pBPP-ccr_MeJ_Ac-emd increased to 59.62 ± 3.18 g·L⁻¹ and 49.31 ± 3.14 g·L⁻¹, respectively, after 216 h. In this study, we investigated the high-concentration production of PHBHHx with a shorter cultivation time by using a jar fermenter equipped with a basket-shaped agitator to enhance oxygen transfer in the culture medium and by continuously supplying the gases with higher O₂ concentrations to maintain the gas composition within the reservoir at a constant ratio. The concentrations of ammonium and phosphate in the culture medium were maintained at low levels. As a result, the DCW and PHBHHx concentrations increased to 109.5 ± 0.30 g·L⁻¹ and 85.2 ± 0.62 g·L⁻¹ after 148 h, respectively. The 3HHx composition was 10.1 ± 0.693 mol%, which is suitable for practical applications. Full article

Background/Objectives: In recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), the overall prognosis is poor, and systemic treatment options remain limited. While precision therapy approaches have revolutionized treatment strategies in several tumor types, molecularly informed therapies in R/M HNSCC are rare, primarily due to the low number of actionable genetic alterations identified through next-generation sequencing (NGS) panels. There is an urgent need to establish precision therapy approaches in R/M HNSCC using innovative predictive testing. Methods: We report the case of a 43-year-old patient with recurrent oral cancer who was extensively pretreated and comprehensively characterized using both descriptive and functional testing. Results: NGS revealed no targetable alterations. A tumor tissue slice radiosensitivity assay suggested radioresistance, arguing against re-irradiation. Kinome profiling identified upregulated Src-family kinases (SFK), and SFK inhibition reduced kinase activity in vitro. Most notably, mRNA analysis demonstrated high Trop-2 overexpression, confirmed by immunohistochemistry (3+ in 100% of tumor cells). Following six cycles of the Trop-2-directed antibody–drug conjugate Sacituzumab govitecan (SG), the patient had an impressive clinical response. Conclusions: Tumor characterization beyond genetic profiling can identify novel treatment options in therapy-refractory HNSCC. This is the first report of “real-world” data on promising antitumor efficacy of SG in a heavily pretreated oral cancer patient with Trop-2 overexpression. Consistent with the findings of the Basket TROPiCS-03 study, SG appears to be a promising novel therapy option for R/M HNSCC after failure of immunotherapy and chemotherapy, particularly in patients with Trop-2 overexpression. Full article

Background/Objectives: The oncofetal membrane protein Claudin 6 (CLDN6) is an attractive target for T cell-based therapies. There is a lack of detailed analyses on the age-dependent expression of CLDN6 in normal tissues is lacking, which limits the expansion of CLDN6 CAR-T cell clinical trials to pediatric populations. Methods: We analyzed CLDN6 expression in extracranial solid tumors and normal tissues of children using RNA-sequencing data from over 500 pediatric solid tumor samples, qRT-PCR and immunohistochemistry (IHC) in more than 100 fresh-frozen tumor samples and, approximately, 250 formalin-fixed paraffin-embedded (FFPE) samples. We examined normal tissue expression via qRT-PCR in 32 different infant tissues and via IHC in roughly 290 tissues from donors across four age groups, as well as in fetal autopsy samples. Results: In fetal tissues, we detected CLDN6 expression primarily in the epithelial cells of several organs, including the skin, lungs, kidneys, intestinal tract, and pancreas, but not in undifferentiated blastemal cells. Postnatally, we found CLDN6-positive epithelial progenitors only during the first few weeks of life. In older-age groups, isolated clusters of CLDN6-positive progenitors were present, but in scarce quantities. In tumor tissues, we found strong and homogeneous CLDN6 expression in desmoplastic small round cell tumors and germ cell tumors. Wilms tumors demonstrated heterogeneous CLDN6 expression, notably absent in the blastemal component. Conclusions: These findings highlight an organ-specific presence of CLDN6-positive epithelial precursors that largely disappear in terminally differentiated epithelia within weeks after birth. Therefore, our data support CLDN6 as a viable therapeutic target in pediatric patients and justify their inclusion in basket studies for anti-CLDN6-based therapies. Full article

The regulatory approvals of tumor-agnostic therapies have led to the re-evaluation of the drug development process. The conventional models of drug development are histology-based. On the other hand, the tumor-agnostic drug development of a new drug (or combination) focuses on targeting a common genomic biomarker in multiple cancers, regardless of histology. The basket-like clinical trials with multiple cohorts allow clinicians to evaluate pan-cancer efficacy and toxicity. There are currently eight tumor agnostic approvals granted by the Food and Drug Administration (FDA). This includes two immune checkpoint inhibitors, and five targeted therapy agents. Pembrolizumab is an anti-programmed cell death protein-1 (PD-1) antibody that was the first FDA-approved tumor-agnostic treatment for unresectable or metastatic microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) solid tumors in 2017. It was later approved for tumor mutational burden-high (TMB-H) solid tumors, although the TMB cut-off used is still debated. Subsequently, in 2021, another anti-PD-1 antibody, dostarlimab, was also approved for dMMR solid tumors in the refractory setting. Patients with fusion-positive cancers are typically difficult to treat due to their rare prevalence and distribution. Gene rearrangements or fusions are present in a variety of tumors. Neurotrophic tyrosine kinase (NTRK) fusions are present in a range of pediatric and adult solid tumors in varying frequency. Larotrectinib and entrectinib were approved for neurotrophic tyrosine kinase (NTRK) fusion-positive cancers. Similarly, selpercatinib was approved for rearranged during transfection (RET) fusion-positive solid tumors. The FDA approved the first combination therapy of dabrafenib, a B-Raf proto-oncogene serine/threonine kinase (BRAF) inhibitor, plus trametinib, a mitogen-activated protein kinase (MEK) inhibitor for patients 6 months or older with unresectable or metastatic tumors (except colorectal cancer) carrying a BRAF^V600E mutation. The most recent FDA tumor-agnostic approval is of fam-trastuzumab deruxtecan-nxki (T-Dxd) for HER2-positive solid tumors. It is important to identify and expeditiously develop drugs that have the potential to provide clinical benefit across tumor types. Full article

Nuclear pore complexes (NPCs) are highly dynamic macromolecular protein structures that facilitate molecular exchange across the nuclear envelope. Aberrant NPC functioning has been implicated in neurodegeneration. The translocated promoter region (Tpr) is a critical scaffolding nucleoporin (Nup) of the nuclear basket, facing the interior of the NPC. However, the role of Tpr in adult neural stem/precursor cells (NSPCs) in Alzheimer’s disease (AD) is unknown. Using super-resolution (SR) and electron microscopy, we defined the different subcellular localizations of Tpr and phospho-Tpr (P-Tpr) in NSPCs in vitro and in vivo. Elevated Tpr expression and reduced P-Tpr nuclear localization accompany NSPC differentiation along the neurogenic lineage. In 5xFAD mice, an animal model of AD, increased Tpr expression in DCX+ hippocampal neuroblasts precedes increased neurogenesis at an early stage, before the onset of amyloid-β plaque formation. Whereas nuclear basket Tpr interacts with chromatin modifiers and NSPC-related transcription factors, P-Tpr interacts and co-localizes with cyclin-dependent kinase 1 (Cdk1) at the nuclear chromatin of NSPCs. In hippocampal NSPCs in a mouse model of AD, aberrant Tpr expression was correlated with altered NPC morphology and counts, and Tpr was aberrantly expressed in postmortem human brain samples from patients with AD. Thus, we propose that altered levels and subcellular localization of Tpr in CNS disease affect Tpr functionality, which in turn regulates the architecture and number of NSPC NPCs, possibly leading to aberrant neurogenesis. Full article

Background. Renal medullary carcinoma (RMC) is one of most aggressive renal cell carcinomas and novel therapeutic strategies are therefore needed. Recent comprehensive molecular and immune profiling of RMC tissues revealed a highly inflamed phenotype, suggesting the potential therapeutic role for immune checkpoint therapies. We present the first prospective evaluation of an immune checkpoint inhibitor in a cohort of patients with RMC. Methods. A cohort of patients with locally advanced or metastatic RMC was treated with pembrolizumab 200 mg intravenously every 21 days in a phase II basket trial (ClinicalTrials.gov: NCT02721732). Responses were assessed by irRECIST. Tumor tissues were evaluated for PD-L1 expression and for tumor-infiltrating lymphocyte (TIL) levels. Somatic mutations were assessed by targeted next-generation sequencing. Results. A total of five patients were treated. All patients had advanced disease, with the majority of patients (60%) having metastatic disease at diagnosis. All patients had rapid disease progression despite pembrolizumab treatment, with a median time to progression of 8.7 weeks. One patient (patient 5) experienced sudden clinical progression immediately after treatment initiation and was thus taken off trial less than one week after receiving pembrolizumab. Conclusions. This prospective evaluation showed no evidence of clinical activity for pembrolizumab in patients with RMC, irrespective of PD-L1 or TIL levels. Full article