Computational pathology identifies immune-mediated collagen disruption to predict clinical outcomes in gynecologic malignancies.

BACKGROUND: The role of immune cells in collagen degradation within the tumor microenvironment (TME) is unclear. Immune cells, particularly tumor-infiltrating lymphocytes (TILs), are known to alter the extracellular matrix, affecting cancer progression and patient survival. However, the quantitative evaluation of the immune modulatory impact on collagen architecture within the TME remains limited. METHODS: We introduce CollaTIL, a computational pathology method that quantitatively characterizes the immune-collagen relationship within the TME of gynecologic cancers, including high-grade serous ovarian (HGSOC), cervical squamous cell carcinoma (CSCC), and endometrial carcinomas. CollaTIL aims to investigate immune modulatory impact on collagen architecture within the TME, aiming to uncover the interplay between the immune system and tumor progression. RESULTS: We observe that an increased immune infiltrate is associated with chaotic collagen architecture and higher entropy, while immune sparse TME exhibits ordered collagen and lower entropy. Importantly, CollaTIL-associated features that stratify disease risk are linked with gene signatures corresponding to TCA-Cycle in CSCC, and amino acid metabolism, and macrophages in HGSOC. CONCLUSIONS: CollaTIL uncovers a relationship between immune infiltration and collagen structure in the TME of gynecologic cancers. Integrating CollaTIL with genomic analysis offers promising opportunities for future therapeutic strategies and enhanced prognostic assessments in gynecologic oncology.

The role of cells that are part of our immune system in altering the structure of the protein collagen within cancers is not fully understood, particularly within cancers that affect women such as ovarian, cervical and uterine cancers. Here, we developed a computer-based method called CollaTIL to explore how immune cells influence collagen in these tumors and affect their growth. We found that a higher presence of immune cells leads to less organized collagen in the tumor. Conversely, when there are fewer immune cells, the collagen tends to be more structured. Additionally, CollaTIL identifies patterns that predict patient outcomes in these cancers. These findings not only enhance our understanding of tumor biology but also may be useful in helping clinicians to predict which patients are at risk of their disease progressing.

Amyloid ß Induces Lipid Droplet-Mediated Microglial Dysfunction in Alzheimer's Disease.

Several microglia-expressed genes have emerged as top risk variants for Alzheimer's disease (AD). Impaired microglial phagocytosis is one of the main proposed outcomes by which these AD-risk genes may contribute to neurodegeneration, but the mechanisms translating genetic association to cellular dysfunction remain unknown. Here we show that microglia form lipid droplets (LDs) upon exposure to amyloid-beta (Aß), and that their LD load increases with proximity to amyloid plaques in brains from human patients and the AD mouse model 5xFAD. LD formation is dependent upon age and disease progression and is more prominent in the hippocampus in mice and humans. Despite variability in LD load between microglia from male versus female animals and between cells from different brain regions, LD-laden microglia exhibited a deficit in Aß phagocytosis. Unbiased lipidomic analysis identified a substantial decrease in free fatty acids (FFAs) and a parallel increase in triacylglycerols (TAGs) as the key metabolic transition underlying LD formation. We demonstrate that DGAT2, a key enzyme for the conversion of FFAs to TAGs, promotes microglial LD formation, is increased in microglia from 5xFAD and human AD brains, and that inhibiting DGAT2 improved microglial uptake of Aß. These findings identify a new lipid-mediated mechanism underlying microglial dysfunction that could become a novel therapeutic target for AD.

Condyloma lata mimicking vulvar carcinoma in an immunocompromised patient: A case report.

Background: Syphilis is a sexually transmitted infection with increasing incidence in the United States. Presentations of syphilis vary widely and can be easily mistaken for other diagnoses, including cancer, especially in atypical cases. Case description: At her delivery after no prenatal care, a 35-year-old woman was found to have exophytic vulvar and perianal lesions, inguinal lymphadenopathy, and a new diagnosis of HIV, with a strong clinical concern for vulvar and/or anal carcinoma. She was subsequently diagnosed with presumed late latent syphilis and began weekly intramuscular penicillin G benzathine treatment. CT imaging demonstrated a perineal plaque-like area with bilateral inguinal, external iliac and retroperitoneal lymphadenopathy. She was seen in gynecologic oncology clinic one week after her initial presentation with notable improvement in the vulvar lesions, raising suspicion for condyloma lata rather than invasive or preinvasive disease on the vulva, however concern remained for dysplasia in the perianal lesion. Another week later, she underwent an exam under anesthesia with vulvar and perianal biopsies revealing chronic inflammation and granulomatous change without evidence of malignancy or dysplasia. At the four week post operative visit, there was almost complete resolution of the lesions. Conclusion: Syphilis should be considered in the differential diagnosis of atypical vulvar lesions.

Surveillance of gynecologic cancer patients post-COVID-19 vaccine: Are CA-125 levels reliable?

Objective: The COVID-19 vaccine is known to instigate an inflammatory response that impacts cancer testing. We aimed to evaluate carbohydrate antigen 125 (CA-125) trends in gynecologic oncology patients in surveillance following COVID-19 vaccination to inform clinical practice. Methods: This was a single institution retrospective study of patients who received a COVID-19 vaccine while undergoing surveillance of gynecologic cancers with serial serum CA-125 measurements. CA-125 levels from the three months before and after vaccination were included in analysis. Differences between mean and median pre- and post-vaccination CA-125 levels for each patient were calculated. The mean and median of these differences were calculated, as well as the distribution of change. Demographic and cancer-related variables were also recorded. Results: Twenty-six patients who received a COVID-19 vaccine and were followed with surveillance serum CA-125 levels were identified. The mean age was 68.2 years; 92 % received a two-vaccine series. Forty-six percent had endometrial cancer and 54 % had ovarian cancer. The mean change from pre- to post-vaccine mean CA-125 level was 0.16 (±7.17) U/mL and the median change from pre- to post-vaccine median CA-125 level was -0.30 (IQR 3.66) U/mL. The range in change from pre- to post-vaccine mean was -16.50 to 24.00 U/mL, with 73 % of patients between -4 and +4 U/mL. Conclusion: We found no clinically significant change in CA-125 level after patients under surveillance for gynecologic cancers were vaccinated against COVID-19, suggesting that that the vaccine does not impact the utility of CA-125 as a tool to monitor disease in this population.

Factors Associated with New Uptake of Long-Acting Reversible Contraceptives Since the Affordable Care Act Among Privately Insured Women in Pennsylvania.

BACKGROUND: The Affordable Care Act eliminated out-of-pocket costs for contraceptives, including highly effective long-acting reversible contraception (LARC), for most insured women. Patient characteristics associated with new LARC uptake after the Affordable Care Act have not been well-studied. We hypothesized that awareness of no-cost intrauterine device (IUD) coverage would be associated with new LARC use. METHODS: Data included were from 883 women not using a LARC at baseline who participated in the MyNewOptions study, a 2-year study of privately insured women in Pennsylvania. Multivariable analysis assessed whether the following baseline characteristics predicted new LARC use over 2 years: awareness of no-cost IUD coverage, future pregnancy intention, baseline contraceptive use, contraceptive attitudes, and sociodemographic characteristics. RESULTS: At baseline, 54.4% of participants were using prescription methods; 21.1% nonprescription methods; 12.1% natural family planning, withdrawal, or spermicide alone; and 12.5% no method. A minority (7.2%) was aware of no-cost coverage for IUDs. Over 2 years, 7.2% of participants became new LARC users, but awareness of no-cost coverage for IUDs was not associated with new LARC use (adjusted odds ratio, 0.84; 95% confidence interval, 0.27-2.55). New LARC use was associated with already using prescription methods, not intending pregnancy within the next 5 years, prior unintended pregnancy, and desire to change method if cost were not a factor. CONCLUSIONS: Among privately insured women, wanting to switch methods if cost were not a factor was associated with new LARC uptake, although awareness of no-cost IUD coverage was not. Providing women with information about their contraceptive coverage benefits may help women to seek and obtain the methods better aligned with their personal needs.

Sensing of Bacterial Cyclic Dinucleotides by the Oxidoreductase RECON Promotes NF-κB Activation and Shapes a Proinflammatory Antibacterial State.

Bacterial and host cyclic dinucleotides (cdNs) mediate cytosolic immune responses through the STING signaling pathway, although evidence suggests that alternative pathways exist. We used cdN-conjugated beads to biochemically isolate host receptors for bacterial cdNs, and we identified the oxidoreductase RECON. High-affinity cdN binding inhibited RECON enzyme activity by simultaneously blocking the substrate and cosubstrate sites, as revealed by structural analyses. During bacterial infection of macrophages, RECON antagonized STING activation by acting as a molecular sink for cdNs. Bacterial infection of hepatocytes, which do not express STING, revealed that RECON negatively regulates NF-κB activation. Loss of RECON activity, via genetic ablation or inhibition by cdNs, increased NF-κB activation and reduced bacterial survival, suggesting that cdN inhibition of RECON promotes a proinflammatory, antibacterial state that is distinct from the antiviral state associated with STING activation. Thus, RECON functions as a cytosolic sensor for bacterial cdNs, shaping inflammatory gene activation via its effects on STING and NF-κB.

A Lupus-Associated Mac-1 Variant Has Defects in Integrin Allostery and Interaction with Ligands under Force.

Leukocyte CD18 integrins increase their affinity for ligand by transmitting allosteric signals to and from their ligand-binding αI domain. Mechanical forces induce allosteric changes that paradoxically slow dissociation by increasing the integrin/ligand bond lifetimes, referred to as catch bonds. Mac-1 formed catch bonds with its ligands. However, a Mac-1 gene (ITGAM) coding variant (rs1143679, R77H), which is located in the ß-propeller domain and is significantly associated with systemic lupus erythematosus risk, exhibits a marked impairment in 2D ligand affinity and affinity maturation under mechanical force. Targeted mutations and activating antibodies reveal that the failure in Mac-1 R77H allostery is rescued by induction of cytoplasmic tail separation and full integrin extension. These findings demonstrate roles for R77, and the ß-propeller in which it resides, in force-induced allostery relay and integrin bond stabilization. Defects in these processes may have pathological consequences, as the Mac-1 R77H variant is associated with increased susceptibility to lupus.