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Immune Privilege of the Eye: A Delicate Balance Between Clarity and Chaos - PubMed
16 hours ago
- Ocular immune privilege maintains a balance to prevent inflammation and preserve vision through mechanisms like anatomical barriers and immunomodulatory mediators.
- Disruption of ocular immune privilege, not complete loss, contributes to diseases such as uveitis, diabetic retinopathy, and corneal transplantation issues.
- Diseases involve altered immune homeostasis, increased inflammation, impaired barriers, and reduced local immune restraint, varying by ocular compartment.
- Immune privilege is dynamic and conditional, explaining why pathologies like tumors and allergies behave uniquely in ocular tissues.
- Understanding preserved or lost immune elements can enhance ocular pathology insights and guide targeted immune therapies.
LRRC71 is essential for sperm motility, fertilization and male fertility - PubMed
16 hours ago
- LRRC71 is essential for sperm motility, fertilization, and male fertility in mice, and its knockout leads to asthenozoospermia.
- LRRC71 knockout disrupts mitochondrial sheaths in sperm, impairing both glycolysis and oxidative phosphorylation pathways, resulting in reduced ATP content.
- LRRC71 knockout sperm show defective fertilization capacity and fail to migrate into the oviduct, with down-regulation of key metabolic and fertilization-related proteins.
- A novel heterozygous variant of LRRC71 was identified in an asthenozoospermia patient, highlighting its potential clinical relevance in male infertility.
- Despite failed in vitro fertilization, successful intracytoplasmic sperm injection was achieved in LRRC71 knockout mice, suggesting it as a diagnostic and therapeutic target.
Ganaxolone, an approved therapy for CDKL5-Deficiency Disorder, is an inhibitor of PTP1B - PubMed
16 hours ago
- Ganaxolone is an FDA-approved therapy for CDKL5-Deficiency Disorder (CDD) used to treat seizures in patients aged 2 years and older.
- The study reveals that ganaxolone acts as a PTP1B inhibitor, similar in potency to known inhibitors like MSI-1436, in both in vitro and cellular models.
- Inhibition of PTP1B in CDKL5-KO cells enhances TRKB/BDNF signaling, restores cellular morphology, and suggests targeting PTP1B as a therapeutic strategy for CDD.
Treatment outcomes of adult B-cell ALL with post-transplant relapse in the era of immunotherapeutic agents - PubMed
16 hours ago
- Outcomes improved in Ph-negative adult B-cell ALL after post-transplant relapse with immunotherapies (inotuzumab ozogamicin and blinatumomab), showing a rise in 2-year overall survival from 19% to 51% and complete remission rates from 36% to 77%.
- Safety profiles for these agents in the post-transplant setting were acceptable, with specific concerns noted for VOD/SOS in patients undergoing a second transplant after inotuzumab, especially with a short interval (<2.5 months).
- No significant survival improvement was observed in Ph-positive ALL patients, indicating differential impact based on genetic subtype.
- The study highlights the importance of timing and disease status at first transplant as prognostic factors, supporting the integration of these immunotherapies into treatment strategies for relapsed cases.
Distinct genomic and immunologic tumor evolution in germline TP53-driven breast cancers - PubMed
16 hours ago
- Germline TP53 alterations cause Li-Fraumeni Syndrome (LFS), with breast cancer as the most common cancer in LFS females.
- LFS breast cancers (LFS-BC) typically undergo biallelic loss of TP53 and show no recurrent oncogenic variants except ERBB2 amplification.
- Compared to sporadic premenopausal breast cancer, LFS-BC exhibits a high burden of short amplified aneuploid segments.
- Pro-apoptotic p53 target genes BAX and TP53I3 fail to up-regulate in LFS-BC, unlike in sporadic breast cancer.
- LFS-BC has lower CD8+ T-cell infiltration but higher levels of proliferating cytotoxic T-cells compared to sporadic breast cancer.
- Progression from in situ to invasive LFS-BC is marked by increased chromosomal instability and decreased proliferating cytotoxic T-cells.
Pharmacological mechanisms underlying neurovascular alterations related to resistant and refractory migraine: CGRP pathways and beyond - PubMed
16 hours ago
- Migraine is a leading global cause of disability, but 40% of patients do not respond to available treatments, including CGRP-targeted therapies.
- Non-response is linked to clinical, genetic, and epigenetic factors affecting pharmacokinetics and pharmacodynamics, with CGRP and other neuropeptides playing a key role.
- Understanding neurovascular mechanisms and exploring combination therapies may help overcome resistance and refractoriness, requiring further research for personalized treatments.
REDD1 deficiency alleviates podocyte PANoptosis and restores autophagy in diabetic kidney disease - PubMed
16 hours ago
- REDD1 deficiency in diabetic mice improved kidney function and reduced podocyte loss and PANoptosis markers.
- Knocking down REDD1 in podocytes suppressed high glucose-induced PANoptosis, mitochondrial damage, and cytoskeletal disorganization.
- REDD1 deletion restored autophagy and TFEB expression in diabetic kidneys and promoted TFEB nuclear translocation in podocytes.
- REDD1 knockout inhibited stratifin (SFN) expression, and SFN knockdown or RIPK3 inhibitor GSK-872 alleviated PANoptosis and autophagy dysfunction.
- SFN overexpression reversed the protective effects of REDD1 knockdown on PANoptosis and autophagy in high glucose conditions.
- The study suggests REDD1 as a potential therapeutic target to slow diabetic kidney disease progression by inhibiting podocyte PANoptosis and restoring autophagy.
Targeting lipophagy in atherosclerosis: Molecular mechanisms, pathogenesis and therapeutic interventions (Review) - PubMed
16 hours ago
- Atherosclerosis is a chronic inflammatory disease driven by lipid accumulation and cholesterol imbalance in arterial walls.
- Lipophagy is a selective autophagy process that degrades lipid droplets and regulates cellular lipid homeostasis.
- Key regulatory networks of lipophagy include mTORC1/AMPK pathways, TFEB, and FXR/CREBP signaling axes.
- In macrophages, lipophagy can stabilize plaques by promoting cholesterol efflux but may also contribute to necrotic core formation if dysregulated.
- In vascular smooth muscle cells, lipophagy influences phenotype switching and calcification, and in endothelial cells, it reduces oxidative stress and inflammation.
- Therapeutic interventions include drugs like statins and metformin, natural compounds, and Traditional Chinese Medicine formulas.
- Future strategies should focus on cell-type-specific targeting of lipophagy, particularly the sirtuin 1-TFEB axis, for safer clinical applications.
Real-world outcomes of cilta-cel versus BCMA-targeting bispecific antibodies in relapsed/refractory multiple myeloma - PubMed
16 hours ago
- Real-world outcomes comparison between cilta-cel and BCMA-targeting bispecific antibodies for relapsed/refractory multiple myeloma.
- Publication reference includes PMID 42169674 and DOI 10.1080/10428194.2026.2673104.
- Article mentions availability of full text sources and research materials.
Acellular Dermal Matrix-assisted Implant-based Breast Reconstruction: Surgical and Patient-reported Outcomes From the Mastectomy Reconstruction Outcomes Consortium Study - PubMed
16 hours ago
- The study evaluated SurgiMend ADM in immediate 2-stage subpectoral implant-based breast reconstruction compared to no ADM using data from the Mastectomy Reconstruction Outcomes Consortium.
- Composite clinical success, defined as a BREAST-Q score decline of ≤4 points at 1 year and no major complications within 2 years, was significantly higher with SurgiMend (32.4% vs. 21.1%; difference 11.2%, P=0.02).
- Major complications were lower in the SurgiMend group (33.7% vs. 46.7%) after propensity-adjusted analysis, and patient-reported BREAST-Q scores were higher at 1 year (44.5% vs. 39.1%).
- The study concludes that SurgiMend is associated with fewer complications and better patient-reported outcomes, supporting its safety and effectiveness in postmastectomy reconstruction.
- Disclosures note funding and employment ties to Integra LifeSciences, with SurgiMend having FDA 'approvable pending good manufacturing practice' status but not yet marketed in the U.S.
Physiologically Based Pharmacokinetic Modeling of Elexacaftor/Tezacaftor/Ivacaftor in Infants With Cystic Fibrosis - PubMed
16 hours ago
- The study uses physiologically based pharmacokinetic (PBPK) modeling to predict the pharmacokinetics of elexacaftor/tezacaftor/ivacaftor in infants aged 1 month to under 2 years with cystic fibrosis.
- Simulations suggest that doses extrapolated from ivacaftor monotherapy generally match adult drug exposures in infants, except for lower exposures in those aged 1-2 months and potentially higher exposures in infants weighing ≥ 14 kg.
- The findings provide preliminary dosing guidance for infants under 2 years, pending larger clinical studies, and recommend therapeutic drug monitoring to optimize treatment.
ELN orchestrates prometastatic and immunosuppressive niche in bladder cancer via TGFB1 autocrine signaling - PubMed
16 hours ago
- ELN, secreted by cancer-associated fibroblasts, promotes metastasis and immune evasion in bladder cancer.
- ELN binds to TGFBR2, activating SMAD2/3 and triggering TGF-β1 secretion, forming a feed-forward loop that enhances metastatic capacity and immunosuppression.
- Blocking the ELN-TGFBR2 interaction suppresses metastasis and restores anti-tumor immunity, suggesting a new therapeutic strategy to improve immunotherapy outcomes.
HMGB1-mediated formation of IL-33-abundant NETs drives lung-to-kidney injury in severe pneumonia-associated acute kidney injury - PubMed
16 hours ago
- Severe pneumonia-associated acute kidney injury (SP-AKI) has a high incidence (53.6%) and mortality (24.2%) in a multicenter cohort.
- Elevated levels of HMGB1, NETs, and IL-33 in circulation are linked to SP-AKI, indicating their role in disease progression.
- HMGB1 in the lungs triggers the formation of NETs that are enriched with IL-33, which then migrate to the kidneys.
- In the kidneys, these NETs activate ST2/NF-κB signaling, leading to inflammation, apoptosis, and kidney injury.
- Interventions targeting HMGB1, IL-33, ST2, or NET formation (via PAD4 inhibition) reduce both lung and kidney damage in models.
- A self-sustaining feed-forward loop exists where HMGB1 amplifies NET-mediated IL-33 release, exacerbating injury.
- NETs are redefined as cross-organ pathogenic carriers, highlighting new therapeutic targets for SP-AKI.
Genetic Drivers of Sensitivity or Resistance to RAS(ON) Multi-Selective Inhibitors in NRAS-Mutated Melanoma - PubMed
16 hours ago
- RAS(ON) multi-selective inhibitors like RMC-7977 and daraxonrasib show potent anti-proliferative activity against NRAS-mutated melanoma.
- Resistance to RMC-7977 monotherapy in preclinical models arises via mutations in Ppia (CYPA) or Map2k1 (MEK1).
- Daraxonrasib demonstrated anti-tumor activity in one NRAS-mutated melanoma patient, but progressive disease in another with co-occurring NRAS and MAP2K1 mutations.
- The findings support daraxonrasib's potential for treating NRAS-mutated melanoma and highlight monotherapy resistance mechanisms.
- Combination therapies may be needed to improve outcomes for patients with NRAS-mutated melanoma.
Comparative effectiveness of mirikizumab and risankizumab in patients with ulcerative colitis: A propensity-matched cohort study - PubMed
16 hours ago
- Mirikizumab showed lower corticosteroid use (31.9% vs. 44.4%) and higher fecal calprotectin response compared to risankizumab in ulcerative colitis patients.
- No difference was found in therapy change or colectomy rates between the two treatments; adverse events were low.
- The study suggests mirikizumab may be more effective for inducing remission, especially in bio-exposed patients.
Prognostic implications of tissue-based homologous recombination deficiency in metastatic gastric cancer treated with immune checkpoint inhibitor plus chemotherapy - PubMed
16 hours ago
- This study included 139 metastatic gastric cancer (mGC) patients treated with first-line nivolumab plus chemotherapy, of whom 116 underwent tissue-based next-generation sequencing (NGS).
- HRD-positive tumors (14.7% of sequenced patients) were significantly associated with longer progression-free survival (PFS; median 23.1 vs. 9.6 months, p=0.032) and overall survival (OS; median not reached vs. 17.9 months, p=0.027) compared to HRD-negative tumors.
- HRD positivity remained an independent favorable prognostic factor for OS in multivariate analysis (HR: 0.247; 95% CI 0.071-0.859; p=0.028).
- HRD-positive tumors showed higher frequencies of high tumor mutational burden (TMB) and microsatellite instability-high (MSI-high) status.
- An exploratory analysis of ctDNA-based HRD in a small subset (n=24) did not demonstrate a statistically significant association with survival outcomes.
- The study suggests tissue-based HRD positivity may provide complementary prognostic information in mGC patients treated with first-line immune checkpoint inhibitor plus chemotherapy.
Repurposing Syrosingopine for Cancer Therapy: Lactate Trapping and ISR Sensitization as Metabolic Vulnerabilities - PubMed
16 hours ago
- Syrosingopine repurposed as a dual lactate transporter (MCT1/MCT4) inhibitor to exploit the Warburg effect in cancer.
- Mechanism involves lactate trapping, NAD+ depletion, and bioenergetic stress, enhancing synthetic lethality with mitochondrial inhibitors.
- Advanced delivery systems improve intratumoral drug accumulation and modulate the immunosuppressive tumor microenvironment.
- Preclinical data show efficacy, but context-dependent toxicities such as liver fibrosis risk may limit therapeutic windows.
- Clinical translation requires biomarker-guided trials, nanoformulation optimization, metabolic imaging, and safety monitoring for metabolic plasticity.
In vivo gene therapy with CAR-T cells - PubMed
16 hours ago
- In vivo CAR-T therapy involves generating CAR-T cells inside the body rather than ex vivo manufacturing.
- Proof-of-concept clinical studies show feasibility and therapeutic potential for this approach.
- Ex vivo CAR-T cells are effective for lymphoid hematologic malignancies but face logistic complexities that limit accessibility.
- In vivo methods present unique technical, biological, and safety challenges to address.
Clinicogenomic Landscape of MTAP-Deleted Thoracic Malignancies Across US and Japanese Nationwide Cohorts: Impact of Concurrent CDKN2A Alterations and Driver Mutations - PubMed
16 hours ago
- MTAP deletion frequency in lung cancer was similar between adenocarcinoma and squamous cell carcinoma in both U.S. and Japanese cohorts, but rare in small cell lung cancer.
- In thymic tumors, MTAP deletion was mostly seen in thymic carcinoma, not thymoma, and was strongly linked to CDKN2A/B deletions.
- MTAP deletion often co-occurred with actionable driver mutations like EGFR, ALK, and ERBB2, but showed an inverse association with RB1 mutations.
- Associations with lower tumor mutational burden and shorter overall survival in EGFR-mutated lung cancer were tied to driver enrichment and CDKN2A loss, respectively.
- Findings support the global development of MTAP-targeted synthetic lethal therapies for thoracic malignancies, especially combined with targeted agents.
SERCA2 deficiency in tubular epithelial cells drives ferroptosis in acute kidney injury regulating endoplasmic reticulum mitochondrial calcium homeostasis via voltage dependent anion channel 1 oligome
16 hours ago
- SERCA2 expression is reduced in proximal tubules of patients and animal models with acute kidney injury (AKI).
- SERCA2 deficiency disrupts endoplasmic reticulum calcium homeostasis, promoting VDAC1 oligomerization via impaired mitochondria-associated endoplasmic reticulum membranes.
- This leads to mitochondrial permeability transition pore opening, calcium overload, oxidative stress, and ferroptosis in tubular epithelial cells.
- SERCA2 activation or inhibition of VDAC1 oligomerization attenuates AKI injury, identifying this axis as a therapeutic target.

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Hasty Briefsbeta

Immune Privilege of the Eye: A Delicate Balance Between Clarity and Chaos - PubMed

LRRC71 is essential for sperm motility, fertilization and male fertility - PubMed

Ganaxolone, an approved therapy for CDKL5-Deficiency Disorder, is an inhibitor of PTP1B - PubMed

Treatment outcomes of adult B-cell ALL with post-transplant relapse in the era of immunotherapeutic agents - PubMed

Distinct genomic and immunologic tumor evolution in germline TP53-driven breast cancers - PubMed

Pharmacological mechanisms underlying neurovascular alterations related to resistant and refractory migraine: CGRP pathways and beyond - PubMed

REDD1 deficiency alleviates podocyte PANoptosis and restores autophagy in diabetic kidney disease - PubMed

Targeting lipophagy in atherosclerosis: Molecular mechanisms, pathogenesis and therapeutic interventions (Review) - PubMed

Real-world outcomes of cilta-cel versus BCMA-targeting bispecific antibodies in relapsed/refractory multiple myeloma - PubMed

Acellular Dermal Matrix-assisted Implant-based Breast Reconstruction: Surgical and Patient-reported Outcomes From the Mastectomy Reconstruction Outcomes Consortium Study - PubMed

Physiologically Based Pharmacokinetic Modeling of Elexacaftor/Tezacaftor/Ivacaftor in Infants With Cystic Fibrosis - PubMed

ELN orchestrates prometastatic and immunosuppressive niche in bladder cancer via TGFB1 autocrine signaling - PubMed

HMGB1-mediated formation of IL-33-abundant NETs drives lung-to-kidney injury in severe pneumonia-associated acute kidney injury - PubMed

Genetic Drivers of Sensitivity or Resistance to RAS(ON) Multi-Selective Inhibitors in NRAS-Mutated Melanoma - PubMed

Comparative effectiveness of mirikizumab and risankizumab in patients with ulcerative colitis: A propensity-matched cohort study - PubMed

Prognostic implications of tissue-based homologous recombination deficiency in metastatic gastric cancer treated with immune checkpoint inhibitor plus chemotherapy - PubMed

Repurposing Syrosingopine for Cancer Therapy: Lactate Trapping and ISR Sensitization as Metabolic Vulnerabilities - PubMed

In vivo gene therapy with CAR-T cells - PubMed

Clinicogenomic Landscape of MTAP-Deleted Thoracic Malignancies Across US and Japanese Nationwide Cohorts: Impact of Concurrent CDKN2A Alterations and Driver Mutations - PubMed

SERCA2 deficiency in tubular epithelial cells drives ferroptosis in acute kidney injury regulating endoplasmic reticulum mitochondrial calcium homeostasis via voltage dependent anion channel 1 oligome