Macrophage Checkpoint Nanoimmunotherapy Has the Potential to Reduce Malignant Progression in Bioengineered In Vitro Models of Ovarian Cancer.

Most ovarian carcinoma (OvCa) patients present with advanced disease at the time of diagnosis. Malignant, metastatic OvCa is invasive and has poor prognosis, exposing the need for improved therapeutic targeting. High CD47 (OvCa) and SIRPα (macrophage) expression has been linked to decreased survival, making this interaction a significant target for therapeutic discovery. Even so, previous attempts have fallen short, limited by CD47 antibody specificity and efficacy. Macrophages are an important component of the OvCa tumor microenvironment and are manipulated to aid in cancer progression via CD47-SIRPα signaling. Thus, we have leveraged lipid-based nanoparticles (LNPs) to design a therapy uniquely situated to home to phagocytic macrophages expressing the SIRPα protein in metastatic OvCa. CD47-SIRPα presence was evaluated in patient histological sections using immunohistochemistry. 3D tumor spheroids generated on a hanging drop array with OVCAR3 high-grade serous OvCa and THP-1-derived macrophages created a representative model of cellular interactions involved in metastatic OvCa. Microfluidic techniques were employed to generate LNPs encapsulating SIRPα siRNA (siSIRPα) to affect the CD47-SIRPα signaling between the OvCa and macrophages. siSIRPα LNPs were characterized for optimal size, charge, and encapsulation efficiency. Uptake of the siSIRPα LNPs by macrophages was assessed by Incucyte. Following 48 h of 25 nM siSIRPα treatment, OvCa/macrophage heterospheroids were evaluated for SIRPα knockdown, platinum chemoresistance, and invasiveness. OvCa patient tumors and in vitro heterospheroids expressed CD47 and SIRPα. Macrophages in OvCa spheroids increased carboplatin resistance and invasion, indicating a more malignant phenotype. We observed successful LNP uptake by macrophages causing significant reduction in SIRPα gene and protein expressions and subsequent reversal of pro-tumoral alternative activation. Disrupting CD47-SIRPα interactions resulted in sensitizing OvCa/macrophage heterospheroids to platinum chemotherapy and reversal of cellular invasion outside of heterospheroids. Ultimately, our results strongly indicate the potential of using LNP-based nanoimmunotherapy to reduce malignant progression of ovarian cancer.

Azithromycin as a Possible Cause of Linear IgA Bullous Dermatosis.

We present a rare case of linear IgA bullous dermatosis (LABD) in a 72-year-old male associated with the use of azithromycin. LABD presents as subepidermal blisters due to IgA antibodies targeting BPAG2, a component of hemidesmosomes. LABD is a rare diagnosis and may be idiopathic, associated with illness, or medication-induced. The patient experienced a rash five days after completing a course of azithromycin for pneumonia. The diagnosis of LABD was confirmed with a biopsy and direct immunofluorescence. Lesions resolved over two weeks with an oral prednisone taper and topical clobetasol. This case represents just one of two previously reported cases in the literature of azithromycin-associated LABD. While LABD is well known to be induced by certain medications, this is only the second report of it being associated with the use of a macrolide. We propose that macrolides be included as a potential cause of medication-induced LABD.

Cracking the case: The diagnosis and treatment of a complex high-grade endometrial carcinoma with hepatoid, endometrioid, serous features and somatically derived yolk sac tumor component in a 50 year old female.

•Alpha-fetoprotein secreting tumors in gynecologic cancers have a broad differential.•Surgical pathology may provide a more comprehensive picture of tumor heterogeneity than initial biopsy.•Yolk Sac Tumor components intermixed with carcinoma points towards a somatic derivative rather than a collision tumor.•Alpha-fetoprotein can be trended over time to gauge response to treatment of cancers that produce the protein.

Oral Low-Dose Naltrexone in the Treatment of Frontal Fibrosing Alopecia and Lichen Planopilaris: An Uncontrolled Open-Label Prospective Study.

Background Frontal fibrosing alopecia (FFA) and lichen planopilaris (LPP) is scarring alopecias with limited evidence supporting their treatment options. We investigated the use of low-dose naltrexone (3 mg oral daily) as adjunctive therapy in the treatment of FFA and LPP. Methods A single-center, uncontrolled open-label prospective study was performed, with 26 patients who took low-dose naltrexone for one year included in the per-protocol analysis. Both patient-reported (pruritus and burning/pain) and physician-assessed (erythema, scale, and scalp involvement) outcomes were analyzed. Results There were decreases in erythema and scale for the overall longitudinal outcomes using linear mixed effects model analysis. However, only erythema had a significant decrease at 12 months compared with baseline. Mean erythema decreased by 0.93 at 12 months compared with baseline on a 0-3-point scale (p<0.0001, 95% mean CI [-1.32, -0.53]). There was no statistically significant difference comparing 12 months to baseline for the other outcomes including pruritus, burning/pain, and scalp involvement. Limitations include the possibility of spontaneous stabilization, concurrent medications, a small sample size with limited racial diversity, and mild subjective symptoms at baseline. Conclusion Our study supports further investigation of oral low-dose naltrexone as adjunctive therapy in the treatment of FFA and LPP if there is prominent erythema, and possibly scale.

The Proteolytic Landscape of Ovarian Cancer: Applications in Nanomedicine.

Ovarian cancer (OvCa) is one of the leading causes of mortality globally with an overall 5-year survival of 47%. The predominant subtype of OvCa is epithelial carcinoma, which can be highly aggressive. This review launches with a summary of the clinical features of OvCa, including staging and current techniques for diagnosis and therapy. Further, the important role of proteases in OvCa progression and dissemination is described. Proteases contribute to tumor angiogenesis, remodeling of extracellular matrix, migration and invasion, major processes in OvCa pathology. Multiple proteases, such as metalloproteinases, trypsin, cathepsin and others, are overexpressed in the tumor tissue. Presence of these catabolic enzymes in OvCa tissue can be exploited for improving early diagnosis and therapeutic options in advanced cases. Nanomedicine, being on the interface of molecular and cellular scales, can be designed to be activated by proteases in the OvCa microenvironment. Various types of protease-enabled nanomedicines are described and the studies that focus on their diagnostic, therapeutic and theranostic potential are reviewed.

Biokinetic models for Group VB elements.

This paper reviews biokinetic data for the Group VB elements vanadium, niobium, and tantalum, and presents biokinetic models describing their systemic behaviour. The model for systemic niobium in adults was developed earlier and described in Publication 134 of the International Commission on Radiological Protection. The model for niobium is used as a starting point for the development of models for vanadium and tantalum. Published biokinetic data for vanadium, including comparisons with niobium, indicate that the initial distribution of vanadium is broadly similar to that of niobium but that vanadium is less firmly fixed in most tissues and is excreted more rapidly than niobium. Biokinetic data for tantalum are more limited but suggest that its systemic behaviour closely resembles that of niobium at early times after administration. The model for niobium is proposed for application to tantalum in view of the suggested biological similarities of tantalum and niobium, their generally strong coherence in nature due to similar ionic radii and identical valence states, and the difficulties in developing parameter values directly from available data for tantalum. The proposed model for vanadium relies largely on vanadium-specific information and varies considerably from the model for niobium.