Tooth loss is an indicator of oral health and may be affected by cannabis use. The authors aimed to examine whether cannabis use and frequency of past-month cannabis use (in days) were associated with tooth loss, especially among racial and/or sexual orientation/gender identity groups, in a cross-sectional, nationally representative sample of Americans. The number of missing teeth was assessed in the 2016, 2018, 2020, and 2022 Behavioral Risk Factor Surveillance System surveys. Past-month cannabis use was assessed as both a binary and continuous variable (days of cannabis use) in 2024. Backwards selection selected covariates for 2 multivariate models. Final models were stratified by race/ethnicity and sexual orientation/gender identity if the interaction with cannabis use was significant. After adjusting for covariates, current cannabis use was associated with 1.157 times higher odds of tooth loss (95% CI=1.065, 1.257), although this relationship was found to differ by racial/ethnic subgroups. Among non-Hispanic Whites, cannabis use was associated with higher odds of tooth loss (OR=1.223, 95% CI=1.119, 1.336), although no significant associations were found among other subgroups. Among those who used cannabis, each 1-day increase in the frequency of past-month cannabis use was associated with 1.009 times higher odds of tooth loss (95% CI=1.003, 1.015). Cannabis use was significantly associated with tooth loss overall and among non-Hispanic Whites specifically. Frequency of cannabis use was significantly associated with tooth loss among those using cannabis. More research may be needed to fully understand the relationship among minority subgroups.
Dermoid cysts are congenital lesions that typically occur along the midline. They usually remain asymptomatic unless ruptured, causing meningitis, hydrocephalus, or cranial nerve deficits. This case presents an exceptionally rare scenario of bilateral, symmetric intradiploic dermoid cysts of the occipital bone, which initially manifested as sensorineural hearing loss (an unusual symptom). A 21-year-old woman presented with right-sided hearing loss. Imaging showed bilateral, symmetric intradiploic cystic lesions within the occipital bone. The right-sided lesion had ruptured into the posterior fossa, releasing lipid-rich contents over the cerebellum. A T1-hyperintense signal along the right vestibular aqueduct suggested the migration of debris into the inner ear. Both lesions were resected with maximal safe resection, targeting the ruptured component and preventing future complications. Histopathological analysis confirmed that both lesions were dermoid cysts. Although typically associated with chemical meningitis, dermoid cyst rupture may rarely present solely with sensorineural hearing loss when fatty debris migrates into the vestibular aqueduct. Bilateral, symmetric intradiploic occipital lesions are rare and may reflect developmental anomalies at paired ossification centers. Surgical removal of the antigenic source, even without acute complications, may prevent delayed sequelae. A tailored resection approach that preserves vital structures, including the transverse sinus, is safe and effective. https://thejns.org/doi/10.3171/CASE2691.
Purtscher-like retinopathy is a rare occlusive microvasculopathy that causes acute, painless visual loss and characteristic retinal lesions. Although typically trauma-related, it can occur in systemic conditions such as nephrotic syndrome (NS), driven by hypercoagulability, complement activation, and microembolization. We report a 3-year-old girl with steroid-resistant NS presenting with sudden vision loss, including inability to fixate and intermittent exotropia, without trauma or hypertension. Fundoscopy revealed bilateral peripapillary retinal whitening with periarteriolar sparing, cotton wool spots, and intraretinal hemorrhages. Laboratory tests showed hypoalbuminemia (1.7 g/dL) and nephrotic-range proteinuria; kidney biopsy suggested podocytopathy. She was receiving prednisolone and cyclosporine (trough 84 ng/mL), which was discontinued due to concern for drug-induced vasculopathy. Treatment included intravenous methylprednisolone pulses followed by oral tapering. Whole-exome sequencing identified a de novo pathogenic WT1 variant (c.1447 + 5G > A), establishing a genetic etiology (NPHS4) for steroid-resistant nephrotic syndrome in this patient. At 6 months, visual acuity improved from light perception to counting fingers at a distance of 2 m. This case highlights the need to consider Purtscher-like retinopathy in NS patients with acute vision loss, particularly in the context of steroid resistance or calcineurin inhibitor therapy. Prompt ophthalmologic evaluation and careful medication review are critical to prevent permanent visual impairment and to optimize recovery.
Multilevel (≥ 2) cervical disc arthroplasty (CDA) has become increasingly popular over the past decade. The authors report the first case of three-level CDA demonstrating divergent bone remodeling, heterotopic ossification (HO), and anterior bone loss (ABL) at separate operative levels, with preserved segmental motion. A 45-year-old man underwent three-level CDA (C4-5, C5-6, C6-7) with the ROTAIO prosthesis for medically refractory cervical myeloradiculopathy secondary to multilevel disc herniation superimposed on congenital stenosis. Surveillance imaging identified grade 2 ABL at C4-5 at 6 months and McAfee class II HO at C6-7 at 18 months; the intervening C5-6 remained unaffected. At the 2-year follow-up, the patient was asymptomatic with mobility preserved across all three levels. The coexistence of HO and ABL at different operative levels within a single patient, despite identical implants and uniform perioperative conditions, implicates level-specific mechanical factors-rather than implant design, material properties, or patient-intrinsic variables-as the principal drivers of bone remodeling after multilevel CDA. Close radiological surveillance is warranted even in asymptomatic patients. https://thejns.org/doi/10.3171/CASE26368.
In individuals with schizophrenia receiving either clozapine or olanzapine, this study examined changes in 1) body weight and other cardiometabolic measures and microbiota biodiversity and composition between commencement and completion of 24-week semaglutide intervention; 2) body weight between commencement and 76-week follow-up. 24-week intervention (16-weeks full-dose (1.0 mg/week) after 8-weeks' titration) of open-label nurse-administered semaglutide in a public mental health setting, with one-year post-intervention follow-up (76-week trial-completion). people with schizophrenia without diabetes receiving clozapine or olanzapine with BMI > 27 kg/m2. %body weight change at 24-weeks, and 76-weeks. Secondary endpoints: %change in waist circumference, HbA1c at 24-weeks and 76-weeks, body composition at 24-weeks. Gut microbiota changes were compared at baseline, 10-weeks and 24-weeks intervention completion. Mean age: 41.5 years (range 18-61), 65.4% female. Intervention completed by 65.4% (n = 17/26). 24-week intervention: intention-to-treat body weight reduction: -9.8% (95% CI: [-12.7%, -6.8%], p < 0.001) or - 10.1 kg (95% CI [-13.6, -6.6]); waist circumference reduction: -7.3% (95% CI: [-10.1%, -4.4%], p < 0.001); HbA1c non-significant reduction: -5.3% (95% CI [-10.4%, 0.1%], p = 0.055). Microbial alpha diversity decreased as time on semaglutide increased, with enrichment of Parasutterella excrementihominis. Trial completion: 88.2% (n = 15/17). Average body weight change baseline-76-weeks: -5.1% (95% CI: [-8.3%, -1.9%], p = 0.001) or - 5.3 kg (95% CI: [-8.9, -1.7]). Semaglutide was associated with significant weight loss in overweight/obese people with schizophrenia. These benefits attenuated following semaglutide discontinuation. Gut microbial compositional differences consistent with improvement in health outcomes may occur in semaglutide-treated people living with schizophrenia.
Androgenic alopecia (AGA) is the most common type of hair loss that occurs due to androgens, specially, dihydrotestosterone (DHT), and the 5-alpha reductase is the key enzyme to control AGA, as it is responsible for the conversion of testosterone to DHT, the more potent form of testosterone involved in the pathogenesis of AGA. Blockers of this enzyme suppress the conversion of androgens to DHT. Dutasteride is one of the 5-alpha reductase inhibitors and is frequently used as an anti-hair loss treatment. Gamma-oryzanol (GO) is an anti-oxidant and anti-5-alpha reductase, which has been introduced as an anti-hair loss treatment by some studies. The nanostructured lipid carriers (NLCs) were developed for targeting the dutasteride and GO in hair follicles. The NLCs were prepared from herbal oils pumpkin seed oil (PSO) and saw palmetto (SP), which also have a 5-alpha reductase inhibitory effect, contributing to the therapeutic effect. NLCs in follicular targeting enable to accumulation of the drugs in the target area (hair follicle cells), reduce the absorption of dutasteride in other organs and tissues, and reduce the side effects. NLCs were prepared by adopting a hot homogenization method and were characterized by particle size analyzer, scanning electron microscope, and X-ray diffraction. An in-vivo study was conducted using C57BL/6 mice to assess NLCs ability in drug delivery and accumulation in hair follicles. NLCs had great potentials for reducing the dutasteride daily dose. Moreover, the accumulation of NLCs was confirmed by histopathological images even after two weeks of the discontinued treatment. NLCs may have facilitated the follicular delivery of the anti-hair loss drugs. Since the NLCs have potential for accumulation in the hair follicles, the interval of formulation usage may have been increased to more than once a week which was of great interest to the practitioners aiming at developing more efficient formulations for androgenetic alopecia.
The Antarctic ozone hole was first reported in 1985, and small ozone losses at the global scale were also observed in the late 1980s. The combination of field and laboratory measurements, together with modeling, quickly established anthropogenic chlorofluorocarbons (CFCs) as the cause of both the Antarctic and global ozone depletion. However, when, where, and why the earliest ozone depletion could have been detected has not been determined. Here, we conduct a thought experiment to investigate when human-induced ozone depletion could have first been detectable, assuming the availability of accurate stratospheric ozone observations from 1950 onward. We find that human-caused ozone depletion was likely identifiable as early as 1957 in the tropical upper stratosphere. This region's low internal variability enables the earliest detection of the anthropogenic signal, even though tropical ozone losses in the upper stratosphere were smaller than those in higher-latitude regions. Our results highlight the key role of considering both internal variability ("noise") and the forced response ("signal") in detection studies. Further, while CFCs are widely recognized as the primary drivers of current ozone depletion, we find that early ozone loss was primarily caused by human-made carbon tetrachloride (CCl4), used mainly as a solvent. These findings suggest that a clear human influence on the stratospheric ozone layer began nearly 70 y ago, even before substantial emissions of CFCs from spray cans or air conditioning.
The aim of this in vitro study was to evaluate the effect of different whey protein beverages on the surface microhardness of three nanohybrid resin composites. A total of 90 disc-shaped specimens were prepared from three nanohybrid resin composites (n = 30 per material) and subdivided into three groups (n = 10) according to the immersion medium: whey concentrate, whey isolate, and distilled water. The specimens were immersed for 10 min twice daily for 30 days. Surface microhardness was measured at baseline and after immersion using a Vickers microhardness tester, and hardness change was calculated as ΔVHN. The data were analyzed using two-way repeated measures ANOVA and post-hoc tests. The analysis revealed that composite type, immersion solution, and their interaction had statistically significant effects on ΔVHN values (p < 0.0001). The highest hardness loss was observed in the injectable composite exposed to whey concentrate (ΔVHN: 10.4 ± 2.1), whereas the lowest change was recorded in the highly filled composite stored in distilled water (ΔVHN: 0.9 ± 0.4). Immersion in whey concentrate resulted in significantly greater hardness loss in all composites compared to distilled water (p < 0.05). Whey isolate also produced significantly greater hardness loss in all composites except the highly filled composite, in which no statistically significant difference was observed (p = 0.076). These findings indicate that whey protein beverages may reduce the surface microhardness of resin composites, with the extent of degradation depending on both material composition and beverage formulation.
The anterior intrapelvic approach (AIP) is increasingly used for pelvic ring and acetabular fractures, yet its learning curve during structured implementation remains poorly defined. This study evaluated the learning curve associated with AIP introduction in a trauma center. A retrospective analysis of a prospectively maintained database was conducted at a level-1 trauma center. Eighty-six consecutive patients treated with AIP by a single senior surgeon (2015-2019) were included. Patients were divided chronologically into two equal groups (first 43 vs. last 43 cases). The primary outcome was operative time. Secondary outcomes included blood loss, reduction quality assessed on postoperative CT (Matta and Matta-Tornetta criteria), and complications. Multivariable analyses were performed to identify independent predictors of operative time and reduction quality. Operative time decreased significantly from 226 ± 93 to 187 ± 83 min (p = 0.04) and remained independently associated with case sequence (p < 0.01). Blood loss decreased by 31% (897 ± 694 vs. 620 ± 436 mL, p = 0.01). Reduction quality remained stable, with anatomical or satisfactory reduction achieved in 86% of cases, without intergroup differences. The overall complication rate was 8%. Early postoperative neurological deficits were more frequent in the initial phase but decreased significantly over time (p = 0.04). No implant failures or loss of reduction were observed. AIP implementation was associated with improved operative efficiency without compromising reduction quality or increasing complications, suggesting a progressive learning curve with an acceptable and improving neurological morbidity profile in a trauma center setting.
People with movement disabilities face difficulties in independent mobility. The main objective of this study was to develop and evaluate a real-time electro-myography (EMG) based wheelchair control framework with upper arm or neck muscles and to investigate feasibility for assistive mobility applications. A feature optimisation framework was employed to extract the most significant features for movement recognition. The proposed model was trained and tested in both offline and real-time control. Feasibility was assessed through classification accuracy, repeatability measures, response latency and preliminary validation involving two individuals with disabilities. With subject-independent methodology, wheelchair activation with upper arm muscles achieved an accuracy of 95% in real time, whereas for neck muscles, it was 98.6% in able-bodied participants. For neck muscles, two participants with disabilities, namely a transhumeral amputee and a mobility-impaired participant because of poliomyelitis were evaluated and achieved an accuracy of 100%. The average system response latency for upper arm movements was found to be 430 ms for able-bodied participants, whereas for neck muscles, it was 360 ms for able-bodied participants and 400 ms for participants with disabilities. The proposed framework demonstrated the feasibility of real-time EMG-based wheelchair control in a controlled environment. However, further studies involving larger and more diverse participant cohorts are needed to evaluate its generalisability and broader clinical applicability. The proposed system may support independent mobility by utilising residual muscle activity for wheelchair control. Upper arm and neck muscles may be used in individuals with transradial limb loss, while neck muscles alone may provide an alternative control interface for individuals with transhumeral limb loss. The approach may also be explored for individuals with low cervical spinal cord injury.The system was designed with low processing time and response latency, enabling real-time control of external assistive devices.The subject-independent control strategy may reduce the need for extensive user-specific training, thereby facilitating practical deployment for new users.By incorporating both upper arm and neck muscle interfaces, the proposed framework may accommodate users with different levels of upper limb impairment, thereby expanding its potential applicability in assistive mobility.
Age-related loss of muscle mass and function contributes to mobility limitations, loss of independence, and other adverse health outcomes. Structural and functional indicators characterize muscle health but may not change in parallel with advancing age. Evidence from rural populations remains limited. This study aimed to examine age-related differences in structural and functional muscle indicators among rural community-dwelling women and to determine whether age-group differences are greater in functional than in structural indicators. This cross-sectional study included 211 community-dwelling women aged 50-89 years residing in rural Asan, Korea. Participants were categorized into four age groups (50-59, 60-69, 70-79, and 80-89 years). Structural indicators included skeletal muscle index (SMI), skeletal muscle mass (SMM), thigh circumference (TC), and calf circumference (CF). Functional indicators included handgrip (HG) strength, isometric knee extensor (KE) strength, and the five-times sit-to-stand test (5×STS). Between-group differences were analyzed using one-way analysis of variance (ANOVA), and domain-level differences were further examined using a mixed-design repeated-measures ANOVA. To facilitate comparison across indicators, variables were normalized to the 50-59 age group (set to 100). Structural and functional indicators showed different magnitudes of age-related change across groups. HG and KE were lower in older groups and showed larger between-group differences than the structural indicators. In contrast, 5×STS time increased across age groups, from 7.0 ± 1.75 s in the 50-59 group to 15.2 ± 6.60 s in the 80-89 group. Relative SMI decreased to 81.5% of the reference group, whereas the relative index for 5×STS (reciprocal time) decreased to 46.0% (all p < 0.001). Structural and functional muscle indicators showed divergent age-related patterns among rural community-dwelling women. The performance-based 5×STS demonstrated substantially greater relative differences than structural indicators, supporting the inclusion of functional assessments alongside structural measures for age-stratified evaluation in rural settings.
Metabolic dysfunction, in particular obesity and type 2 diabetes mellitus, increases susceptibility to pulmonary fibrosis via chronic inflammation, oxidative stress, and the accumulation of senescence. Senescent cells promote secretion of pro-fibrotic mediators that impair lung structure and repair. Here, we investigated whether reducing senescent cell burden using the mitochondria-targeted senolytic agent MitoTam, or weight-loss-induced improvement after bariatric surgery, can attenuate metabolic-associated pulmonary injury. In mice with diet-induced obesity, MitoTam improved glucose homeostasis, reduced adiposity, and markedly decreased senescence markers in lungs. This was accompanied by reduced inflammatory and fibrotic gene expression, diminished myofibroblast accumulation, and alleviated lung hypoxia. MitoTam also lowered senescence and expression of key pro-fibrotic factors, including GDF15, FGF2, TGFβ, and endothelin-1 (EDN1) in subcutaneous adipose tissue, indicating both direct pulmonary and systemic endocrine effects. In patients with class III obesity, laparoscopic sleeve gastrectomy induced substantial body weight loss, improved metabolic parameters, and significantly reduced adipose tissue senescence and pro-fibrotic signaling, including EDN1 expression and its level in the circulation. These findings identify cellular senescence as a modifiable driver linking metabolic dysfunction to pulmonary fibrosis and highlight mitochondria-targeted senolysis with MitoTam as a promising therapeutic approach.
Oral corticosteroids remain a cornerstone of therapy for generalized myasthenia gravis (gMG) but are associated with substantial long-term toxicity. Efgartigimod, a human immunoglobulin G1 (IgG1) antibody Fc fragment targeting the neonatal Fc receptor (FcRn), has demonstrated efficacy in gMG; however, no prospective trial has evaluated whether regularly scheduled efgartigimod administration can safely reduce oral prednisolone (PSL) dosage. We designed a prospective clinical study to evaluate the steroid-sparing effect of efgartigimod in patients with gMG who remain dependent on ≥ 6 mg/day of oral PSL. This is a single-arm, open-label, single-center clinical study. Patients with gMG who are receiving ≥ 6 mg/day of oral PSL on a stable dose for at least 4 weeks prior to enrollment, with any concomitant oral immunosuppressants also at stable doses for at least 4 weeks, and scoring ≥ 5 on the MG Activities of Daily Living (MG-ADL) scale will be enrolled. Efgartigimod will be intravenously administered at 10 mg/kg once weekly for 4 consecutive weeks (one cycle), repeated for four cycles with a 28-day interval between cycles. On the fourth administration day of each cycle, oral PSL will be tapered if MG symptoms have not worsened, defined as no ≥ 1-point increase in the MG-ADL score from both baseline and the first administration day of that cycle. The primary endpoint is the change in PSL dosage from baseline at the end of the study. Secondary endpoints include the proportion of patients achieving minimal manifestations (MM) or better status with PSL ≤ 5 mg/day (MM-5 mg), the time to reach ≤ 5 mg/day, the cumulative PSL dose over the study period, the proportion of patients completing the protocol, changes in MG-ADL and other clinical scales, responder rate to efgartigimod, comparison of clinical course between MG subtypes (anti-acetylcholine receptor (AChR) antibody-positive, anti-muscle-specific kinase (MuSK) antibody-positive, and double-seronegative cases) and between patients who are anti-AChR antibody positive, with and without thymoma, changes in indicators of steroid toxicity (HbA1c, lumbar spine bone mineral density, and blood pressure), and the safety profile. The study will also explore biomarkers predictive of efgartigimod response through proteomic and immunologic analyses of serially collected blood samples.  Graphical abstract available for this article.  TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT), CRB3180028; registered on 1 October 2024 (prospectively registered). Myasthenia gravis is a disease in which the immune system attacks the connections between nerves and muscles. It causes muscle weakness that can affect the eyes, swallowing, breathing, and limbs. In the generalized form of this disease, doctors commonly prescribe steroids such as prednisolone to control symptoms. However, long-term steroid use can cause serious problems, including diabetes, high blood pressure, depression, and bone loss.Efgartigimod is a newer medicine that lowers the level of harmful antibodies in the blood. Previous studies show that it improves symptoms of generalized myasthenia gravis. It is not yet clear whether doctors can use efgartigimod to safely reduce the amount of steroid their patients take.In this study, we will enroll patients with generalized myasthenia gravis who still need at least 6 mg of prednisolone each day. Each patient will receive efgartigimod on a fixed schedule for about 8 months. After every treatment cycle, if symptoms have not worsened, we will reduce the prednisolone dose step by step. Our goal is to bring the dose down to 5 mg per day or lower.We will measure how much we can reduce the steroid dose and whether symptoms stay stable. We will also check whether side effects of long-term steroid use, such as bone loss and elevated blood sugar, improve. In addition, we will analyze blood samples to look for markers that predict who responds best to efgartigimod. The results should help doctors choose better treatments for patients who find it hard to come off steroids.
Short proximal femoral nail antirotation (PFNA) fixation is commonly performed for intertrochanteric fractures and is typically inserted without reaming. However, limited reaming may be required in cases of a narrow femoral canal, severe femoral bowing, or inadvertent selection of an oversized nail. Unlike long nails, reaming for short PFNA is confined to the isthmus, and its effects have not been well described. This study aimed to evaluate the association between limited reaming during short PFNA fixation and clinical outcomes. We conducted a retrospective matched cohort study of patients aged ≥ 65 years who underwent short PFNA fixation for intertrochanteric fractures at a university-affiliated tertiary care center between January 2020 and August 2025. Patients were matched in a 1:3 ratio (limited reamed vs. unreamed) by age, sex, body mass index, ASA classification, and OTA/AO fracture type. Operative variables, perioperative hematologic parameters, transfusion requirements, length of hospital stay (LOS), radiographic fracture healing time, mortality, and postoperative complications were compared. A total of 30 limited reamed and 90 unreamed patients were analyzed, with comparable baseline characteristics. The limited reamed group had a longer operative time (98.2 ± 27.9 vs. 80.0 ± 23.7 min; P = 0.001) and greater intraoperative blood loss (232.3 ± 143.5 vs. 169.2 ± 102.2 mL; P = 0.03). There were no differences in nail diameter, hematocrit decline, total transfusion volume, LOS, fracture healing time, mortality rate, or complications rate between the two groups (all P > 0.05). Follow-up beyond 3 months was 86.7%, and mean follow-up duration was comparable between groups. The unreamed technique should be considered the preferred approach in most cases of short proximal femoral nail antirotation fixation. Limited canal reaming was associated with longer operative time and greater intraoperative blood loss. Therefore, limited reaming should be reserved for situations in which it is necessary to facilitate safe nail insertion, such as in patients with challenging canal anatomy or when an oversized nail is inadvertently selected. Therapeutic Level III.
The complement system is a key driver of geographic atrophy (GA), a disease that leads to progressive, irreversible vision loss. Pharmacological preclinical studies characterizing an antibody fragment, which is a novel complement C3 inhibitor under investigation for GA treatment, are presented. Kinetic parameters were determined for the antibody fragment binding to C3, C3b, and C3 variants associated with GA. Inhibition of membrane attack complex (MAC) formation after classical (CP), alternative (AP), and lectin (LP) pathway activation was determined. Comparisons with the second-generation compstatin derivative (APL-1) were made because of the expected similarity of binding behavior and in vitro potency with pegcetacoplan (which could not be sourced at the time of the study). Diffusion through Bruch's membrane (BrM) was investigated for the antibody fragment and a pegcetacoplan-similar (PEG-s) molecule using enriched porcine BrM in Ussing chamber devices. The antibody fragment showed high (picomolar) affinity for all tested C3 ligands. APL-1 showed lower (single-digit nanomolar) affinity than the antibody fragment, comparable with published values. The antibody fragment exhibited dose-dependent inhibition of MAC formation via CP (half-maximal inhibitory concentration [IC50] 79 nM), AP (344 nM), and LP (67 nM), with enhanced potency for inhibiting CP- and LP-mediated complement activation vs. APL-1. More efficient permeation of the BrM was observed with the antibody fragment than with the PEG-s molecule. The antibody fragment is a potent and specific C3 inhibitor that displays dose-dependent inhibition of MAC formation across all three complement pathways and effectively crosses the BrM. In line with these results, the antibody fragment is being investigated in patients with GA. Graphical abstract available for this article. Geographic atrophy is the late stage of age-related macular degeneration. Geographic atrophy is a disease that causes damage to the retina in the eye and can cause loss of vision and reduce a person’s quality of life. There are currently only a few medicines approved to treat geographic atrophy. The development and progression of geographic atrophy is linked to the components of the immune system that are responsible for inflammation and the formation of destructive protein complexes. This preclinical study used laboratory experiments to investigate how a potential new therapy called an antibody fragment affects these immune system components and to see if it is suitable for the treatment for geographic atrophy. The study found that the antibody fragment bound strongly to its target immune components, and it may prevent the formation of destructive protein complexes. The antibody fragment was also able to readily pass through the membrane found in the eye where the immune components need to be targeted. These promising preclinical results support further investigation of the antibody fragment in people with geographic atrophy.
The t(4;14) chromosomal translocation drives overexpression of the histone methyltransferase NSD2 and defines a high-risk segment of multiple myeloma (MM) patients. Herein, we report the discovery of NSD2-LDD, a cereblon-recruiting and PWWP1-mediated ligand directed degrader (LDD) that selectively and potently eliminates full length and PWWP1 domain containing NSD2 protein isoforms. NSD2-LDD treatment induces global loss of H3K36me2 leading to promoter-proximal spreading of H3K27me3 and re-wiring of cis-regulatory interactions that reverse t(4;14) transcriptional programs. These effects suppress MM disease-associated phenotypes including stromal adhesion, three-dimensional colony growth and paracrine signaling. By integrating patient single cell profiles with model 3D epigenomic and spatial transcriptomics, we delineate t(4;14) disease state together with the tumor-intrinsic reprogramming and resultant remodeling of the bone marrow microenvironment upon NSD2 degradation. In cell line derived xenografts and genetically engineered mouse models of t(4;14), NSD2-LDD extends median survival accompanied by tumoral H3K36me2 loss and niche re-modelling. Although the NSD2-LDD response is restricted to PWWP1-containining models, collectively this work validates NSD2 as a tractable dependency and supports clinical development of NSD2 degradation as a novel, targeted therapeutic strategy in high-risk MM.
 Bariatric surgery, also known as metabolic surgery, is known to improve the metabolic profile of morbidly obese patients in many aspects, thereby improving their quality of life. Obesity is typically associated with subtle changes in thyroid homeostasis. Bariatric procedures, particularly sleeve gastrectomy and Roux-en-Y gastric bypass, are associated with reductions in thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and total triiodothyronine (TT3) levels during the first postoperative year. This study aimed to evaluate the impact of bariatric surgery on thyroid function and thyroxine requirements in patients with and without pre-existing hypothyroidism.  This retrospective cross-sectional study was conducted at the Department of General Surgery, Dubai Health, United Arab Emirates. All patients who underwent bariatric surgery between September 2017 and December 2023 were included. Patients were divided into two groups: (1) those with preoperative hypothyroidism controlled on thyroxine therapy and (2) those with normal thyroid function. Patients with hyperthyroidism or a history of total thyroidectomy were excluded. Thyroid function tests and thyroxine requirements were evaluated preoperatively and at one- and two-year follow-up.  A total of 853 patients were included (mean age: 34.4 ± 11.0 years; 71.1% female). Sleeve gastrectomy accounted for 35.3% of procedures, Roux-en-Y gastric bypass for 55.9%, and redo-/mini-gastric bypass for 8.8%. All procedures resulted in significant weight loss at one and two years postoperatively (p < 0.001). Baseline thyroid function was within reference ranges, and postoperative TSH and free T4 levels remained stable. Among the 46 hypothyroid patients receiving thyroxine therapy, only a small proportion required dose adjustments, with no significant association with the type of surgery (χ²(6) = 3.35, p = 0.763). No correlation was found between BMI reduction and changes in thyroid hormone levels.  This study found no significant association between weight loss following bariatric surgery and changes in thyroid hormone function. No significant alterations in thyroxine requirements were observed. Larger multicenter studies with follow-up beyond two years are needed to further evaluate these findings.
Meningiomas are the most common primary brain tumors, yet the molecular pathways that distinguish grade 1 from grade 2 lesions remain insufficiently understood. Among post-translational modifications, N-terminal arginylation─catalyzed by ATE1─regulates protein stability and cellular stress responses, but its role in meningioma biology has not been explored. Here, we integrated mass-spectrometry-based proteomics, immunoblotting, and transcriptomic reanalysis to investigate pathway regulation across tumor grades. Grade 1 meningiomas displayed higher ATE1 expression and increased arginylation of key chaperones, accompanied by activation of the PERK branch of the unfolded protein response (UPR), enhanced autophagy, and greater engagement of apoptotics pathways. In contrast, grade 2 tumors showed reduced ATE1 levels, diminished BIP arginylation, attenuated UPR-PERK signaling, impaired autophagy, and increased proliferative signaling. Proteins predicted to be substrates of ATE1-mediated degradation were upregulated in grade 2 tumors, suggesting that loss of arginylation may stabilize pro-oncogenic factors. Together, these findings reveal grade-specific remodeling of the N-degron/arginylation axis and highlight protein arginylation as a previously unrecognized modulator of meningioma progression, with potential therapeutic relevance.
HER2-positive (HER2+) breast cancer often develops resistance to therapies like Lapatinib, potentially involving mitochondrial metabolic and redox reprogramming. This study aimed to identify mitochondrial oxidative stress-related genes (MOS-DEGs) as biomarkers of resistance and to characterize their functional nsSNPs and structural impacts. RNA-seq datasets (GSE231524, GSE231525) were analyzed using DESeq2 to identify DEGs, which were intersected with mitochondrial oxidative stress genes to obtain MOS-DEGs. Functional enrichment, PPI analysis, ROC analysis, expression profiling, and survival analysis were performed. nsSNPs were evaluated using multiple predictive tools, and structural impacts were assessed through secondary and 3D modeling. Integrated transcriptomic and clinical analysis identified MTHFD2 and PRDX3 as central MOS-DEGs displaying opposing regulatory roles in mitochondrial redox metabolism. MTHFD2 was significantly upregulated and associated with poor prognosis (HR = 1.53, p = 1.1 × 10⁻16), while PRDX3 exhibited protective expression patterns (HR = 0.73, p = 7.7×10⁻10). ROC analysis suggested their potential as predictors of therapeutic response. nsSNP analysis revealed five deleterious variants in MTHFD2 and four deleterious variants in PRDX3, with rs1471336772 (MTHFD2) and rs747786383 (PRDX3.) identified as the most pathogenic. These variants were predicted to be damaging based on multiple computational scoring systems, including SIFT ≤ 0.05, PolyPhen-2 ≥ 0.85, deleterious CADD scores, and high REVEL scores, and were located within catalytic or redox-active domains. Structural modeling suggested that these substitutions may destabilize conformation, disrupt metal- and cofactor-binding sites, and affect NADPH regeneration or thioredoxin-dependent peroxidase activity. Molecular dynamics predictions indicated potential loss of structural stability and altered flexibility, suggesting possible functional impairment of mitochondrial redox control. This study identifies MTHFD2 and PRDX3 as regulators of mitochondrial oxidative stress in HER2+ breast cancer. Deleterious nsSNPs in these genes may contribute to altered redox balance, potentially influencing metabolic adaptation (MTHFD2) and antioxidant defense (PRDX3).
Rare cancers are molecularly heterogeneous and lack robust clinical evidence to guide treatment. Whether cancer driver gene expression is governed by tumor lineage or specific somatic alterations-and whether this distinction carries clinical relevance-remains poorly characterized, particularly in Asian populations. This study aimed to determine the relative contributions of tumor lineage and DNA mutations to RNA expression of cancer driver genes and to evaluate the clinical implications of genomic alteration status in Asian patients with rare cancers. DNA and RNA were extracted from formalin-fixed paraffin-embedded tumor samples obtained through the MASTER KEY Asia research network. Next-generation sequencing was performed to evaluate genomic alterations and gene expression profiles. RNA expression of cancer driver genes was quantified as TPM Z scores. Elastic net regression with 10-fold cross-validation assessed the relative contributions of tumor lineage and DNA mutations to RNA expression, and findings were independently replicated in another cohort. Integrated DNA and RNA data were available for 128 patients. Tumor lineage was the predominant determinant of RNA expression in 17 of 27 cancer driver genes (63%), whereas ERBB2 and MDM2 demonstrated genomic-predominant regulation, replicated across both cohorts. Alterations in ERBB2 or ARID1A were associated with a lower frequency of disease progression compared with patients without either alteration (P = .01), independently of ERBB2 RNA expression. Functional subclassification of TP53 revealed that gain-of-function mutations were associated with higher rates of disease progression (P = .007) and shorter progression-free survival than loss-of-function variants (hazard ratio, 2.355 [95% CI, 1.086 to 5.105]; P = .029). Tumor mutational burden was not associated with treatment response. These findings demonstrate that genomic alteration status, including TP53 functional subclassification, provides clinically meaningful information beyond transcriptional profiling alone, supporting integrative genomics and transcriptomics analysis for precision oncology in rare cancers.