Synthesis, Photophysical Properties, Theoretical Studies, and Living Cancer Cell Imaging Applications of New 7-(Diethylamino)quinolone Chalcones.

In this article, three unsymmetrical 7-(diethylamino)quinolone chalcones with D-π-A-D and D-π-A-π-D type push-pull molecular arrangements were synthesized via a Claisen-Schmidt reaction. Using 7-(diethylamino)quinolone and vanillin as electron donor (D) moieties, these were linked together through the α,ß-unsaturated carbonyl system acting as a linker and an electron acceptor (A). The photophysical properties were studied, revealing significant Stokes shifts and strong solvatofluorochromism caused by the ICT and TICT behavior produced by the push-pull effect. Moreover, quenching caused by the population of the TICT state in THF-H2O mixtures was observed, and the emission in the solid state evidenced a red shift compared to the emission in solution. These findings were corroborated by density functional theory (DFT) calculations employing the wb97xd/6-311G(d,p) method. The cytotoxic activity of the synthesized compounds was assessed on BHK-21, PC3, and LNCaP cell lines, revealing moderate activity across all compounds. Notably, compound 5b exhibited the highest activity against LNCaP cells, with an LC50 value of 10.89 µM. Furthermore, the compounds were evaluated for their potential as imaging agents in living prostate cells. The results demonstrated their favorable cell permeability and strong emission at 488 nm, positioning them as promising candidates for cancer cell imaging applications.

Implantable Phakic Contact Lens: vault evaluation five years after surgery.

PURPOSE: To evaluate the stability of the postoperative vault of the Intraocular Phakic Contact Lens (IPCL) five years after implantation. SETTING: Clínica de Ojos Dr. Nano, Olivos (Buenos Aires), Argentina. DESIGN: Retrospective case-series study. METHODS: Myopic patients operated with the IPCL lens for spherical correction in which preoperative data were compared with different scenarios of postoperative vault at 1, 3 and 5 years after surgery. The main parameter to be evaluated was the vault obtained 5 years after surgery. RESULTS: A total of 140 eyes of 72 patients, aged 31.9 ±2.8 years old (21-50) were included. Most of the eyes (78.6 %) obtained a vault between 250 to 750 µm, while in 15% of the eyes it was less than 250, and 6.4% were greater than 750 µm. The vault evaluated 1, 3 and 5 years after surgery remained stable. Sub-capsular cataracts were detected in two eyes, with vault < 250 µm. A total of 50 eyes (35.7 %) had cysts in the sulcus (5 cases in the group of eyes with vault > 750 µm). No changes were detected in relation to intraocular pressure or endothelial cell count. CONCLUSION: In eyes implanted with the IPCL lens over 5 years, it has been observed that the vault remained stable over time. The proportion of eyes with cysts was higher in eyes with vaults larger than 750 µm.

Novel Blood Biomarkers for Response Prediction and Monitoring of Stereotactic Ablative Radiotherapy and Immunotherapy in Metastatic Oligoprogressive Lung Cancer.

Up to 80% of patients under immune checkpoint inhibitors (ICI) face resistance. In this context, stereotactic ablative radiotherapy (SABR) can induce an immune or abscopal response. However, its molecular determinants remain unknown. We present early results of a translational study assessing biomarkers of response to combined ICI and SABR (I-SABR) in liquid biopsy from oligoprogressive patients in a prospective observational multicenter study. Cohort A includes metastatic patients in oligoprogression to ICI maintaining the same ICI due to clinical benefit and who receive concomitant SABR. B is a comparative group of oligometastatic patients receiving only SABR. Blood samples are extracted at baseline (T1), after the first (T2) and last (T3) fraction, two months post-SABR (T4) and at further progression (TP). Response is evaluated by iRECIST and defined by the objective response rate (ORR)-complete and partial responses. We assess peripheral blood mononuclear cells (PBMCs), circulating cell-free DNA (cfDNA) and small RNA from extracellular vesicles. Twenty-seven patients could be analyzed (cohort A: n = 19; B: n = 8). Most were males with non-small cell lung cancer and one progressing lesion. With a median follow-up of 6 months, the last ORR was 63% (26% complete and 37% partial response). A decrease in cfDNA from T2 to T3 correlated with a good response. At T2, CD8+PD1+ and CD8+PDL1+ cells were increased in non-responders and responders, respectively. At T2, 27 microRNAs were differentially expressed. These are potential biomarkers of response to I-SABR in oligoprogressive disease.

Conventional and new proposals of GnRH therapy for ovarian, breast, and prostatic cancers.

For many years, luteinizing hormone-releasing hormone or gonadotropin-releasing hormone (GnRH) analogs have been used to treat androgen or estrogen-dependent tumors. However, emerging evidence shows that the GnRH receptor (GnRH-R) is overexpressed in several cancer cells, including ovarian, endometrial, and prostate cancer cells, suggesting that GnRH analogs could exert direct antitumoral actions in tumoral tissues that express GnRH-R. Another recent approach based on this knowledge was the use of GnRH peptides for developing specific targeted therapies, improving the delivery and accumulation of drugs in tumoral cells, and decreasing most side effects of current treatments. In this review, we discuss the conventional uses of GnRH analogs, together with the recent advances in GnRH-based drug delivery for ovarian, breast, and prostatic cancer cells.

Self-assembling peptides as immunomodulatory biomaterials.

Self-assembling peptides are a type of biomaterial rapidly emerging in the fields of biomedicine and material sciences due to their promise in biocompatibility and effectiveness at controlled release. These self-assembling peptides can form diverse nanostructures in response to molecular interactions, making them versatile materials. Once assembled, the peptides can mimic biological functions and provide a combinatorial delivery of therapeutics such as cytokines and drugs. These self-assembling peptides are showing success in biomedical settings yet face unique challenges that must be addressed to be widely applied in the clinic. Herein, we describe self-assembling peptides' characteristics and current applications in immunomodulatory therapeutics.

Estradiol and Estrone Have Different Biological Functions to Induce NF-κB-Driven Inflammation, EMT and Stemness in ER+ Cancer Cells.

In general, the risk of being diagnosed with cancer increases with age; however, the development of estrogen-receptor-positive (ER+) cancer types in women are more closely related to menopausal status than age. In fact, the general risk factors for cancer development, such as obesity-induced inflammation, show differences in their association with ER+ cancer risk in pre- and postmenopausal women. Here, we tested the role of the principal estrogens in the bloodstream before and after menopause, estradiol (E2) and estrone (E1), respectively, on inflammation, epithelial-to-mesenchymal transition (EMT) and cancer stem cell enrichment in the human ER+ cervical cancer cell line HeLa. Our results demonstrate that E1, contrary to E2, is pro-inflammatory, increases embryonic stem-transcription factors (ES-TFs) expression and induces EMT in ER+ HeLa cells. Moreover, we observed that high intratumoural expression levels of 17ß-Hydroxysteroid dehydrogenase (HSD17B) isoforms involved in E1 synthesis is a poor prognosis factor, while overexpression of E2-synthetizing HSD17B isoforms is associated with a better outcome, for patients diagnosed with ER+ ovarian and uterine corpus carcinomas. This work demonstrates that E1 and E2 have different biological functions in ER+ gynaecologic cancers. These results open a new line of research in the study of ER+ cancer subtypes, highlighting the potential key oncogenic role of E1 and HSD17B E1-synthesizing enzymes in the development and progression of these diseases.

Efecto de la cobertura vegetal en escarabajos coprófagos (Coleoptera: Scarabaeinae) y sus funciones ecológicas en un bosque andino de Colombia / Effect of vegetation cover on dung beetles (Coleoptera: Scarabaeinae) and their ecological functions in an Andean forest of Colombia

Resumen Introducción: Los escarabajos coprófagos cumplen funciones importantes en los ecosistemas terrestres, pero las presiones antrópicas los afectan negativamente. Estos efectos están bien documentados en los bosques neotropicales de tierras bajas, pero se han estudiado poco en los bosques andinos. Objetivo: Evaluar cómo los atributos de los ensambles de escarabajos coprófagos y tres de sus funciones ecológicas difieren en tres tipos de cobertura vegetal, y determinar las relaciones entre atributos y funciones, y entre funciones. Métodos: Los escarabajos coprófagos se capturaron con trampas pitfall y se midieron las funciones ecológicas a través de un experimento de campo en la hacienda "El Ocaso" (Colombia), en tres tipos de cobertura vegetal: bosque secundario, bosque mixto y pastos para ganado (tres sitios independientes por cobertura). Los atributos del ensamble que se evaluaron fueron: abundancia, número de especies, biomasa y longitud corporal media ponderada; las funciones medidas fueron: remoción de estiércol, excavación del suelo y dispersión secundaria de semillas. Resultados: Se encontró que tanto los atributos del ensamble como las funciones ecológicas se vieron afectados negativamente en las coberturas vegetales más alteradas, particularmente en los pastos ganaderos. La mayoría de los atributos de ensamblaje se correlacionaron positivamente con las funciones; la excavación del suelo y la dispersión secundaria de semillas tuvieron una fuerte correlación positiva con la remoción de estiércol. Conclusiones: Los ensambles de escarabajos coprófagos juegan importantes funciones ecológicas y son sensibles a las alteraciones del ecosistema. Este estudio muestra cómo los escarabajos coprófagos y sus funciones se ven afectados negativamente cuando el bosque se transforma en pastizales para ganado en los ecosistemas forestales andinos poco estudiados y altamente fragmentados.

Abstract Introduction: Dung beetles perform important functions in terrestrial ecosystems, but anthropic pressures affect them negatively. These effects are well documented in neotropical lowland forests but have been studied little in Andean forests. Objective: To evaluate how the attributes of the dung beetle assemblages and three of their ecological functions differ in three types of vegetation cover, and to determine the relationships between attributes and functions, and among functions. Methods: Dung beetles were captured with pitfall traps, and ecological functions were measured through a field experiment in the farm "El Ocaso" (Colombia), in three types of vegetation cover: secondary forest, mixed forest and cattle pasture (three independent sites per cover). The assemblage attributes that were evaluated were abundance, number of species, biomass, and weighted mean body length; functions measured were dung removal, soil excavation, and secondary seed dispersal. Results: It was found that both the assemblage attributes and the ecological functions were negatively affected in the more disturbed vegetation covers, particularly in cattle pastures. Most of the assemblage attributes correlated positively with functions; soil excavation and secondary seed dispersal had a strong positive correlation with dung removal. Conclusions: Dung beetle assemblages play important ecological functions and they are sensitive to ecosystem disturbances. This study shows how dung beetles and their functions are affected negatively when forest is transformed to cattle pasture in the understudied and highly fragmented Andean forest ecosystems.

Cervicovaginal cytology, HPV testing and vaginal flora in transmasculine persons receiving testosterone.

BACKGROUND: Testosterone is one of the strategies that transmasculine persons can elect in order to align physical traits to their gender identity. Previous studies have shown morphologic changes in the genital tract associated with testosterone. Here, we aim to evaluate cervicovaginal cytology specimens (Pap tests) and high-risk HPV (HR-HPV) testing from transmasculine individuals receiving testosterone. METHODS: This is a retrospective cohort of 61 transmasculine individuals receiving testosterone from 2013 to 2021. Cytologic diagnoses from 65 Pap tests were correlated with HPV status and histologic follow-up and compared with the institutional data and a cohort of cisgender women with atrophic changes. RESULTS: The median age was 28 years and median time of testosterone use was 3 years. Transmasculine persons showed significantly higher rates of HSIL (2%) and unsatisfactory (16%) when compared with the institutional data and atrophic cohort of cisgender women. After reviewing slides of 46 cases, additional findings were noted: atrophy was present in 87%, glycogenated cells were seen in 30%, and Lactobacilli were substantially decreased in 89%. Among 32 available HPV tests, 19% were positive for HR-HPV and 81% were negative. On histologic follow-up, all HR-HPV-positive cases with abnormal cytology showed HSIL, while none of the HPV-negative cases revealed HSIL. CONCLUSION: Our study cohort demonstrated a high percentage of abnormal Pap tests in transmasculine persons receiving testosterone. Testosterone seems to induce changes in squamous cells and shifts in vaginal flora. HR-HPV testing can be a useful adjunct in the workup of abnormal Pap tests from transmasculine individuals.

Activation of Adaptive and Innate Immune Cells via Localized IL2 Cytokine Factories Eradicates Mesothelioma Tumors.

PURPOSE: IL2 immunotherapy has the potential to elicit immune-mediated tumor lysis via activation of effector immune cells, but clinical utility is limited due to pharmacokinetic challenges as well as vascular leak syndrome and other life-threatening toxicities experienced by patients. We developed a safe and clinically translatable localized IL2 delivery system to boost the potency of therapy while minimizing systemic cytokine exposure. EXPERIMENTAL DESIGN: We evaluated the therapeutic efficacy of IL2 cytokine factories in a mouse model of malignant mesothelioma. Changes in immune populations were analyzed using time-of-flight mass cytometry (CyTOF), and the safety and translatability of the platform were evaluated using complete blood counts and serum chemistry analysis. RESULTS: IL2 cytokine factories enabled 150× higher IL2 concentrations in the local compartment with limited leakage into the systemic circulation. AB1 tumor burden was reduced by 80% after 1 week of monotherapy treatment, and 7 of 7 of animals exhibited tumor eradication without recurrence when IL2 cytokine factories were combined with anti-programmed cell death protein 1 (aPD1). Furthermore, CyTOF analysis showed an increase in CD69+CD44+ and CD69-CD44+CD62L- T cells, reduction of CD86-PD-L1- M2-like macrophages, and a corresponding increase in CD86+PD-L1+ M1-like macrophages and MHC-II+ dendritic cells after treatment. Finally, blood chemistry ranges in rodents demonstrated the safety of cytokine factory treatment and reinforced its potential for clinical use. CONCLUSIONS: IL2 cytokine factories led to the eradication of aggressive mouse malignant mesothelioma tumors and protection from tumor recurrence, and increased the therapeutic efficacy of aPD1 checkpoint therapy. This study provides support for the clinical evaluation of this IL2-based delivery system. See related commentary by Palanki et al., p. 5010.

Peptide Targeted Gold Nanoplatform Carrying miR-145 Induces Antitumoral Effects in Ovarian Cancer Cells.

One of the recent attractive therapeutic approaches for cancer treatment is restoring downregulated microRNAs. They play an essential muti-regulatory role in cellular processes such as proliferation, differentiation, survival, apoptosis, cell cycle, angiogenesis, and metastasis, among others. In this study, a gold nanoplatform (GNPF) carrying miR-145, a downregulated microRNA in many cancer types, including epithelial ovarian cancer, was designed and synthesized. For targeting purposes, the GNPF was functionalized with the FSH33 peptide, which provided selectivity for ovarian cancer, and loaded with the miR-145 to obtain the nanosystem GNPF-miR-145. The GNPF-mir-145 was selectively incorporated in A2780 and SKOV3 cells and significantly inhibited cell viability and migration and exhibited proliferative and anchor-independent growth capacities. Moreover, it diminished VEGF release and reduced the spheroid size of ovarian cancer through the damage of cell membranes, thus decreasing cell viability and possibly activating apoptosis. These results provide important advances in developing miR-based therapies using nanoparticles as selective vectors and provide approaches for in vivo evaluation.

Clinically translatable cytokine delivery platform for eradication of intraperitoneal tumors.

Proinflammatory cytokines have been approved by the Food and Drug Administration for the treatment of metastatic melanoma and renal carcinoma. However, effective cytokine therapy requires high-dose infusions that can result in antidrug antibodies and/or systemic side effects that limit long-term benefits. To overcome these limitations, we developed a clinically translatable cytokine delivery platform composed of polymer-encapsulated human ARPE-19 (RPE) cells that produce natural cytokines. Tumor-adjacent administration of these capsules demonstrated predictable dose modulation with spatial and temporal control and enabled peritoneal cancer immunotherapy without systemic toxicities. Interleukin-2 (IL2)-producing cytokine factory treatment eradicated peritoneal tumors in ovarian and colorectal mouse models. Furthermore, computational pharmacokinetic modeling predicts clinical translatability to humans. Notably, this platform elicited T cell responses in NHPs, consistent with reported biomarkers of treatment efficacy without toxicity. Combined, our findings demonstrate the safety and efficacy of IL2 cytokine factories in preclinical animal models and provide rationale for future clinical testing in humans.

Anemia in Pregnancy: Screening and Clinical Management Strategies.

ABSTRACT: Screening recommendations for anemia during pregnancy, etiologies of inherited and noninherited forms of anemia, their impact on maternal-fetal outcomes, and the clinical management of pregnant patients presenting with these conditions are reviewed. Anemia during pregnancy can cause adverse perinatal outcomes including preterm labor, premature rupture of membranes, and increased maternal and fetal mortality. Physiologic (dilutional) anemia and iron deficiency anemia are the two most common noninherited forms of anemia, and some cases may be the result of an underlying comorbidity such as diabetes or lupus. Aplastic anemia and autoimmune hemolytic anemia are uncommon forms of noninherited anemias that also merit discussion. Inherited forms of anemia include sickle cell disease, alpha-thalassemia, and beta-thalassemia. Timely diagnosis and treatment of anemia during pregnancy, whether inherited or noninherited, is imperative to protect mother and baby from potential adverse outcomes associated with these conditions.

Histologic Findings in Gynecologic Tissue From Transmasculine Individuals Undergoing Gender-Affirming Surgery.

CONTEXT.­: Gender-affirming surgery is part of a multidisciplinary approach in gender transitioning. Deeper histologic examination may strengthen care for transmasculine individuals and increase the understanding of the influence of hormonal therapy in specific organs. OBJECTIVE.­: To evaluate and catalogue histologic findings of tissue obtained from gender-affirming gynecologic surgery and cervical cytology specimens. DESIGN.­: This is an institutional review board-approved retrospective study that included transmasculine individuals who underwent gender-affirming gynecologic surgery from January 2015 to June 2020. All surgical gynecologic pathology and cervical cytology slides were reviewed by 2 pathologists. RESULTS.­: Fifty-five patients were included, which represented 40 uteri, 35 bilateral ovaries, 15 vaginectomy specimens, and 24 cervical cytology results. The median age was 27 years (range, 18-56), and 94% (50 of 53) of patients were receiving testosterone for at least 1 year. Seventy-five percent (30 of 40) of endometria were inactive, while 25% (10 of 40) showed evidence of cycling. Transitional cell metaplasia was the most common finding in the cervix (17 of 40) and vagina (15 of 15), reflecting a high percentage (4 of 24) of unsatisfactory or ASC-US (atypical squamous cells of undetermined significance) cervical cytologies. Prostatic-type glands were identified in 20% (8 of 40) of cervices and 67% (10 of 15) of vaginectomy specimens. Multiple bilateral cystic follicles and evidence of follicular maturation were present in 57% (20 of 35) of cases. Four cases showed paratubal epididymis-like mesonephric remnant hypertrophy. CONCLUSIONS.­: A comprehensive evaluation of tissue from gender-affirming surgery increases knowledge of the changes following androgen therapy in transmasculine individuals and may contribute to optimal patient care by raising awareness of normal histologic variations in this population.

Overlap of Granulomatosis With Polyangiitis and IgA Nephropathy.

Acute glomerulonephritis is a constellation of renal disorders which are precipitated by an immunologic mechanism triggering inflammation and proliferation of glomerular tissue resulting in damage to the basement membrane, mesangium, or capillary endothelium. Two of the most well-known manifestations of glomerulonephritis are granulomatosis with polyangiitis (GPA) and IgA nephropathy (IgAN). To our knowledge, these diseases are often found separately and are rarely diagnosed in the same patient. Here, we discuss a case of a 35-year-old male who presented and was diagnosed with simultaneous GPA and IgAN. His renal biopsy was significant for extensive, crescentic, and necrotizing glomerulonephritis and IgA staining on immunofluorescence indicating severe renal damage. Despite full immunosuppressive therapy, our patient failed to recover his renal function. In our case, we hope to raise awareness of these disorders and early recognition of the clinical features. We believe that this case would prompt providers to pursue diagnostic workups to detect these diseases early on, especially when symptoms progressively worsen and become systemic. As demonstrated in our patient, delay in diagnosis can lead to irreversible damage to a patient's renal function, especially when two types of glomerulonephritis are present.

El lenguaje de la insuficiencia cardiaca con fracción de eyección preservada en los últimos treinta años: un análisis bibliométrico / The language of heart failure with ejection fraction preserved in the last thirty years: a bibliometric analysis

Resumen Introducción: Los estudios bibliométricos permiten realizar un análisis cuantitativo y cualitativo de la producción científica en un campo determinado. En el área de la cardiología, la producción científica ha crecido sustancialmente durante las últimas décadas; sin embargo, existe poca información acerca del manejo integral de la insuficiencia cardiaca con fracción de eyección preservada (ICFEp). Objetivo: Realizar un análisis bibliométrico que proporcione una evaluación detallada del nivel de producción científica de la ICFEp. Método: Estudio bibliométrico descriptivo en el que se realizó una búsqueda en la literatura científica en los últimos 30 años respecto a la ICFEp, para lo cual se utilizó la estrategia de búsqueda "heart failure" AND "preserved ejection fraction" entre 1988 y 2018 en las bases de datos Web of Science, Scopus y Medline a partir de FABUMED y PubReMiner. Resultados: Se encontraron 2830, 4136 y 7943 publicaciones en las bases de datos Medline, Scopus y Web of Science, respectivamente. Los países destacados por su volumen de publicación fueron los Estados Unidos, el Reino Unido y Alemania. En Latinoamérica, los países más productivos fueron Brasil, Argentina y Chile, mientras que Colombia solo tuvo una publicación. Conclusiones: Este análisis bibliométrico es pionero en señalar la evolución de la investigación científica de la ICFEp en los últimos 30 años. Los resultados obtenidos representan un incentivo a la comunidad científica para priorizar la investigación sobre la ICFEp con el fin de mejorar el abordaje integral de los pacientes y, con ello, su calidad de vida.

Abstract Introduction: Bibliometric studies are defined as the quantitative and qualitative analysis of scientific production in each field. The scientific production in the area of cardiology has had a substantial growth during the last decades. Despite this, there is currently little information about heart failure with preserved ejection fraction (HFpEF). Objective: To provide a detailed assessment of the current status and level of scientific production of HFpEF over the past 30 years. Method: Bibliometric study based in scientific literature concerning HFpEF for the period of 1988 - 2018 using the terms "heart failure" AND "preserved ejection fraction" in the databases of the Web of Science, Scopus and Medline using FABUMED and PubReMiner. Results: We found 2830, 4136 and 7943 publications in Medline, Scopus and Web of Science databases, respectively. The countries with higher scientific production in general were: United States, United Kingdom and Germany. In Latin America, the most productive countries were Brazil, Argentina and Chile. Colombia only had one publication. Conclusions: This is the first bibliometric analysis to highlight the production, evolution and current situation of scientific research about the HFpEF in the last 30 years, a call is made to the scientific community worldwide and especially in our country, Colombia, to focus in the scientific production on this subject. The above mentioned, in order to clarify the pathophysiology, reduce morbidity, mortality and improve the quality of life of patients suffering from HFpEF.

Clinical translation of immunomodulatory therapeutics.

Immunomodulatory therapeutics represent a unique class of drug products that have tremendous potential to rebalance malfunctioning immune systems and are quickly becoming one of the fastest-growing areas in the pharmaceutical industry. For these drugs to become mainstream medicines, they must provide greater therapeutic benefit than the currently used treatments without causing severe toxicities. Immunomodulators, cell-based therapies, antibodies, and viral therapies have all achieved varying amounts of success in the treatment of cancers and/or autoimmune diseases. However, many challenges related to precision dosing, off-target effects, and manufacturing hurdles will need to be addressed before we see widespread adoption of these therapies in the clinic. This review provides a perspective on the progress of immunostimulatory and immunosuppressive therapies to date and discusses the opportunities and challenges for clinical translation of the next generation of immunomodulatory therapeutics.

Diabetic Ketoacidosis Secondary to New Onset Type 1 Diabetes Mellitus Related to Pembrolizumab Therapy.

Pembrolizumab is an immunoglobulin G4 (IgG4) monoclonal antibody used in the treatment of various types of cancers. Despite its efficacy, pembrolizumab does not specifically target cancer cells which often leads to common side effects seen in immunotherapies such as diarrhea, rash, fatigue, nausea, decreased appetite, pruritus, and endocrinopathies. Type 1 diabetes mellitus (T1DM) has been reported in 0.1% of the patients in pembrolizumab clinical trials. In this case report, we discuss a 65-year-old Caucasian male with a history of metastatic head and neck cancer that was previously treated with pembrolizumab and was subsequently admitted to the intensive care unit (ICU) due to new onset diabetic ketoacidosis (DKA). Based on the timing of his presentation and the pre-hospital/inpatient workup, notably a normal hemoglobin A1C (HbA1c) 72 hours prior to admission and a significant increase thereafter, it was concluded that his presentation of diabetic ketoacidosis was secondary to his most recent infusion of pembrolizumab. With immunotherapies like programmed cell death (PD1) receptor antibodies becoming a more common first-line treatment for various cancers, this case hopes to raise awareness about the possible endocrinologic-related adverse events to its use and may help guide outpatient management.

Metformin Reduces NGF-Induced Tumour Promoter Effects in Epithelial Ovarian Cancer Cells.

Epithelial ovarian cancer (EOC) is a lethal gynaecological neoplasm characterized by rapid growth and angiogenesis. Nerve growth factor (NGF) and its high affinity receptor tropomyosin receptor kinase A (TRKA) contribute to EOC progression by increasing the expression of c-MYC, survivin and vascular endothelial growth factor (VEGF) along with a decrease in microRNAs (miR) 23b and 145. We previously reported that metformin prevents NGF-induced proliferation and angiogenic potential of EOC cells. In this study, we sought to obtain a better understanding of the mechanism(s) by which metformin blocks these NGF-induced effects in EOC cells. Human ovarian surface epithelial (HOSE) and EOC (A2780/SKOV3) cells were stimulated with NGF and/or metformin to assess the expression of c-MYC, ß-catenin, survivin and VEGF and the abundance of the tumor suppressor miRs 23b and 145. Metformin decreased the NGF-induced transcriptional activity of MYC and ß-catenin/T-cell factor/lymphoid enhancer-binding factor (TCF-Lef), as well as the expression of c-MYC, survivin and VEGF in EOC cells, while it increased miR-23b and miR-145 levels. The preliminary analysis of ovarian biopsies from women users or non-users of metformin was consistent with these in vitro results. Our observations shed light on the mechanisms by which metformin may suppress tumour growth in EOC and suggest that metformin should be considered as a possible complementary therapy in EOC treatment.

Immune-modulatory alginate protects mesenchymal stem cells for sustained delivery of reparative factors to ischemic myocardium.

Paracrine factors secreted by mesenchymal stem cells (MSCs) have been previously shown to improve cardiac function following acute myocardial infarction (MI). However, cell therapy activates the innate immune response, leading to the rapid elimination of transplanted cells and only short-term therapeutic delivery. Herein, we describe a new strategy to deliver sustained paracrine-mediated MSC therapy to ischemic myocardium. Using an immune evasive, small molecule modified alginate, we encapsulated rat MSC cells in a core-shell hydrogel capsule and implanted them in the pericardial sac of post-MI rats. Encapsulated cells allowed diffusion of reparative paracrine factors at levels similar to non-encapsulated cells in vitro. Encapsulation enabled sustained cell survival with localization over the heart for 2 weeks. The effect of the experimental group on ventricular function and fibrosis was compared with blank (cell free) capsules and unencapsulated MSCs injected into infarcted myocardium. MSC capsules improved post-MI ventricular function ∼2.5× greater than MSC injection. After 4 weeks, post-MI fibrosis was reduced ∼2/3 with MSC capsules, but unchanged with MSC injection. MSC encapsulation with alginate core-shell capsules sustains cell survival and potentiates efficacy of therapy.