IgA Nephropathy is an autoimmune disease characterized by the accumulation of immunoglobulin A antibody in the glomeruli, leading to formation of immune complexes that result in inflammation and tissue damage. The immune response, including complement system overactivation, results in a gradual loss of kidney function and disease progression. Current IgAN treatments are limited, prompting investigation into how complement activation or inhibition treatments, such as iptacopan, could potentially restore renal function in patients with IgAN. Treatment is expected to reduce complement-mediated kidney injury and related biomarkers. This study aims to evaluate the impact of iptacopan on IgAN immunopathology by assessing changes in mesangial C3c deposition and other biomarkers over a 9 month period. This is a phase 2, multicenter, single-arm, open-label interventional trial evaluating iptacopan in adults with IgA nephropathy receiving standard of care background treatment. Participants undergo a screening period followed by a baseline kidney biopsy, then receive oral iptacopan (200 mg twice daily) for 9 months without dose adjustment. Assessment and outcome measures focus on baseline-to-Month 9 biopsy-based immunopathological changes in adults with IgA nephropathy receiving iptacopan and supportive care. The primary outcome is focused on overall reduction in mesangial C3c deposition, with secondary measures including levels of CD86-positive cells and changes in IgA and IgG staining.

The calcium-binding proteins S100A8 and S100A9 (calprotectin) are established modulators and biomarkers of inflammation in human skin diseases such as psoriasis and atopic dermatitis. However, how S100A8 and S100A9 regulate the inflammatory and phagocytic responses in acne vulgaris in sebocytes remains unknown. Acne vulgaris is an inflammatory skin disease associated with dysregulated immune responses to Cutibacterium acnes (C. acnes). We have previously shown that human sebocytes function as innate immune cells capable of regulating inflammatory response and phagocytosing C. acnes. Given the role of S100A8/A9 complex in innate immunity and antimicrobial defense, we investigated its function in sebocyte responses to C. acnes. Using human SEB-1 cells, we found that C. acnes induce dose-dependent expression of S100A8 and S100A9 at both transcriptional and protein levels. siRNA-mediated knockdown of S100A8 and/or S100A9 significantly reduced secretion of the pro-inflammatory cytokines IL-6 and IL-8, while TNFα production was largely unaffected. Notably, S100A8 knockdown markedly impaired C. acnes uptake, as measured by flow cytometry, identifying S100A8 as a key regulator of sebocyte phagocytosis. Together, these findings demonstrate that S100A8/A9 coordinate both inflammatory signaling and phagocytosis in sebocytes response to C. acnes, highlighting their potential as therapeutic targets in acne vulgaris.

South Asian populations face a disproportionately high burden of Type 2 Diabetes (T2D), with nearly a fourfold increased risk and earlier onset compared to other groups. Despite this, U.S. screening guidelines typically recommend routine screening beginning at age 35, potentially delaying detection in high-risk populations. This study uses community-based glucose screening data to assess whether earlier screening is warranted for South Asians. A cross-sectional analysis was conducted on 1,153 non-fasting random blood glucose (RBG) measurements collected at BPSHI student-run clinics across California Gurdwaras. RBG values were analyzed by age and sex and compared to national reference benchmarks to identify metabolic risk patterns and gaps in screening practices. Mean RBG levels exceeded national reference values. Elevated rates of unmanaged diabetes were observed among younger individuals, while rates were lower in middle-aged groups and similar in older populations. No significant sex-based differences were found, suggesting age is a more relevant factor for screening strategies. These findings support reconsidering screening thresholds for South Asians. Lowering the screening age to 25 and flagging RBG values ≥140 mg/dL for confirmatory HbA1c testing may improve early detection in this high-risk population.

Cushing’s disease results from hormone-secreting corticotroph tumors in the pituitary gland that release excess ACTH, disrupting normal endocrine balance and causing chronically elevated glucocorticoid levels. Tumor cells often display upregulated histone deacetylase (HDAC) expression, which silences gene activity and supports tumor growth and progression. Current drug treatments that target HDACs inhibit their enzymatic function but do not destroy the proteins, which results in continued partial activity and limited effectiveness. An alternative therapeutic approach focused on fully eliminating HDAC (specifically HDAC2), using targeted protein degradation mechanisms and the ubiquitin-proteasome pathway. This project was to create a system to accurately measure endogenous HDAC2 levels within cells, utilizing a corticotroph tumor cell model called AtT-20 cells. The cells’ HDAC2 gene was modified and a small peptide label called HiBiT was tagged to endogenous proteins. A NanoLuc-based split luciferase reporting system was utilized, where the HiBiT tag was designed to bind with LgBiT, a complementary protein fragment. When combined, the fragments reassembled into an active luciferase enzyme, and adding furimazine substrate triggers a light-producing reaction. The brightness of the emitted light reflects the amount of HDAC2 present, quantifying the protein’s abundance in living cells. This method can be used to screen and identify HDAC degraders and supports the development of new therapeutic strategies for Cushing’s disease.

Purpose: To assess risk factors contributing to the progression of primary open angle glaucoma (POAG) in African-American (AA) patients when compared to Caucasian patients. Methods: Eyes had at least 6 visual fields over 3 years. Demographic, ocular, and systemic data were collected for each. Disease progression was analyzed using visual field data and was defined as a rate of change of mean deviation (MD) > 0.5 decibels (dB) per year. The AA and Caucasian eyes were matched 1:1 for age (<5 years), baseline MD (<2 dB), and sex. Univariate analysis was conducted using logistic regression and odds ratios were calculated for each variable. Results: A total of 990 eyes were evaluated. 12% of AA eyes and 14% of Caucasian eyes showed glaucoma progression. For AA and Caucasian patients, both peak intraocular pressure (IOP) and IOP fluctuation (measured by standard deviation) contributed to an increased risk of glaucoma progression. For each mmHg increase in peak IOP, there was a 7% (AA) and 26% (Caucasian) greater risk of progression. For each mmHg increase in IOP fluctuation, there was an increase of 52% (AA) and 253% (C). A thicker retinal nerve fiber layer (RNFL) decreased the risk of progression by 6% in AA patients and 15% in Caucasian patients. Conclusions: Risk factors for glaucoma progression are similar in African American and Caucasian patients. IOP-related factors (peak and fluctuation) as well as structural factors (RNFL) were shown to affect the likelihood of disease progression in both demographics.

Triple-negative breast cancer (TNBC) is a subtype defined by the absence of estrogen receptor, progesterone receptor, and HER2 amplification, associated with early recurrence, metastasis, and poor overall survival. Increasing evidence implicates metabolic dysregulation as a major promoter of tumor growth and therapeutic resistance. We have developed a novel biguanide analogue (JD006) with potent activity against diverse metabolic mechanisms involved in cancer progression, producing suppression of cancer cell proliferation in a dose-dependent manner (p<0.001). Mechanistically, treatment induces AMPK phosphorylation and attenuates mTORC1 signaling, evidenced by reduced phosphorylation of S6 ribosomal protein and 4E-BP1. Furthermore, JD006 induces apoptosis through the intrinsic pathway by reducing levels of Bcl-2, Bcl-xL, and Bax. Combined with a selective CDK4/6 inhibitor, JD006 produces additive and synergistic antiproliferative effects in vitro, with enhanced suppression of Rb phosphorylation compared to either agent alone. In orthotopic and xenograft TNBC models, combination therapy significantly impedes tumor growth relative to single-agent treatment (p<0.001). These findings support a therapeutic paradigm in which simultaneous disruption of mitochondrial bioenergetics, apoptosis promotion and cyclin D–CDK4/6–Rb signaling exploits a key metabolic-cell cycle dependency in TNBC, providing a strong preclinical rationale for combining next-generation biguanides with CDK4/6 inhibitors for this high-risk breast cancer subtype.

This abstract has been withheld from publication.

Pancreatic ductal adenocarcinoma (PDAC) remains a malignancy with high cancer-related mortality. Although most patients experience aggressive disease in large part due to immunosuppressive tumor microenvironment including an abundance of CD66+ tumor associated neutrophils, however a subgroup of less than 5% of patients have exceptional clinical outcomes, > 5 year survival. This suggests potential biologic differences within the tumor microenvironment (TME) that may account for better clinical responses. We wanted to define stromal and immune features associated with exceptional versus non-exceptional PDAC. PDAC tumor was taken from 10 exceptional and 10 non-exceptional patients were analyzed using a multiplex immunohistochemistry panel, quantified with image cytometry, and compared using unpaired t-tests. Specifically, we evaluated TME master regulator focal adhesion kinase (FAK), fibroblast activation protein (FAP), CD66b. Patients with exceptional outcomes demonstrated significantly lower FAK+ expression than non-exceptional patients (p=0.01). FAP+ expression trended lower in the exceptional group (p=0.31). CD66b expression trended lower in the exceptional group (p=0.30). Overall, exceptional PDAC outcomes were associated with a reduced FAK , FAP, and CD66b expression., These findings support the potential central role for FAK as a key stromal regulator of immune exclusion and further study of the differences in the TME having a potential correlation to favorable clinical behavior in PDAC. These immunosuppressant cells, sp