A Proteomics Approach Identifies RREB1 as a Crucial Molecular Target of Imidazo-Pyrazole Treatment in SKMEL-28 Melanoma Cells.

Cutaneous melanoma is the most dangerous and deadly form of human skin malignancy. Despite its rarity, it accounts for a staggering 80% of deaths attributed to cutaneous cancers overall. Moreover, its final stages often exhibit resistance to drug treatments, resulting in unfavorable outcomes. Hence, ensuring access to novel and improved chemotherapeutic agents is imperative for patients grappling with this severe ailment. Pyrazole and its fused systems derived thereof are heteroaromatic moieties widely employed in medicinal chemistry to develop effective drugs for various therapeutic areas, including inflammation, pain, oxidation, pathogens, depression, and fever. In a previous study, we described the biochemical properties of a newly synthesized group of imidazo-pyrazole compounds. In this paper, to improve our knowledge of the pharmacological properties of these molecules, we conduct a differential proteomic analysis on a human melanoma cell line treated with one of these imidazo-pyrazole derivatives. Our results detail the changes to the SKMEL-28 cell line proteome induced by 24, 48, and 72 h of 3e imidazo-pyrazole treatment. Notably, we highlight the down-regulation of the Ras-responsive element binding protein 1 (RREB1), a member of the zinc finger transcription factors family involved in the tumorigenesis of melanoma. RREB1 is a downstream element of the MAPK pathway, and its activation is mediated by ERK1/2 through phosphorylation.

Eculizumab as a therapeutic approach for severe crescentic recurrence of immunoglobulin A nephropathy after kidney transplantation.

Crescentic forms of immunoglobulin A nephropathy (IgAN) are rare but can be associated with rapid kidney failure and a high rate of end-stage renal disease despite immunosuppression therapy. Complement activation has emerged as a key driver of glomerular injury in IgAN. Therefore, complement inhibitors may be a rational treatment option in patients unresponsive to first-line immunosuppressive therapy. Here, we describe the case of a 24-year-old woman presenting with crescentic IgAN recurrence a few months after living kidney transplantation. Considering the dramatic graft failure accompanied by malignant hypertension and thrombotic microangiopathy features worsening after a first-line of high-dose steroids and 3 sessions of plasma exchanges, eculizumab was started as a rescue therapy. For the first time, the clinical response to eculizumab was highly successful, with a complete graft recovery without any relapse after 1 year of treatment. Further clinical studies are strongly needed to specify which patients might benefit from terminal complement blockade.

Evaluation of the Biological Properties of an Optimized Extract of Polygonum cuspidatum Using Ultrasonic-Assisted Extraction.

Phytochemicals are natural compounds found in plants that have potential health benefits such as antioxidants, anti-inflammatory and anti-cancer properties, and immune reinforcement. Polygonum cuspidatum Sieb. et Zucc. is a source rich in resveratrol, traditionally consumed as an infusion. In this study, P. cuspidatum root extraction conditions were optimized to increase antioxidant capacity (DPPH, ABTS+), extraction yield, resveratrol concentration, and total polyphenolic compounds (TPC) via ultrasonic-assisted extraction using a Box-Behnken design (BBD). The biological activities of the optimized extract and the infusion were compared. The optimized extract was obtained using a solvent/root powder ratio of 4, 60% ethanol concentration, and 60% ultrasonic power. The optimized extract showed higher biological activities than the infusion. The optimized extract contained 16.6 mg mL-1 resveratrol, high antioxidant activities (135.1 µg TE mL-1 for DPPH, and 230.4 µg TE mL-1 for ABTS+), TPC (33.2 mg GAE mL-1), and extraction yield of 12.4%. The EC50 value (effective concentration 50) of the optimized extract was 0.194 µg mL-1, which revealed high cytotoxic activity against the Caco-2 cell line. The optimized extract could be used to develop functional beverages with high antioxidant capacity, antioxidants for edible oils, functional foods, and cosmetics.

Breakthrough COVID-19 cases despite prophylaxis with 150 mg of tixagevimab and 150 mg of cilgavimab in kidney transplant recipients.

The cilgavimab-tixagevimab combination retains a partial in vitro neutralizing activity against the current SARS-CoV-2 variants of concern (omicron BA.1, BA.1.1, and BA.2). Here, we examined whether preexposure prophylaxis with cilgavimab-tixagevimab can effectively protect kidney transplant recipients (KTRs) against the omicron variant. Of the 416 KTRs who received intramuscular prophylactic injections of 150 mg tixagevimab and 150 mg cilgavimab, 39 (9.4%) developed COVID-19. With the exception of one case, all patients were symptomatic. Hospitalization and admission to an intensive care unit were required for 14 (35.9%) and three patients (7.7%), respectively. Two KTRs died of COVID-19-related acute respiratory distress syndrome. SARS-CoV-2 sequencing was carried out in 15 cases (BA.1, n = 5; BA.1.1, n = 9; BA.2, n = 1). Viral neutralizing activity of the serum against the BA.1 variant was negative in the 12 tested patients, suggesting that this prophylactic strategy does not provide sufficient protection against this variant of concern. In summary, preexposure prophylaxis with cilgavimab-tixagevimab at the dose of 150 mg of each antibody does not adequately protect KTRs against omicron. Further clarification of the optimal dosing can assist in our understanding of how best to harness its protective potential.

Two calix[4]pyrroles as potential therapeutics for castration-resistant prostate cancer.

Macrocyclic compounds meso-(p-acetamidophenyl)-calix[4]pyrrole and meso-(m-acetamidophenyl)-calix[4]pyrrole have previously been reported to exhibit cytotoxic properties towards lung cancer cells. Here, we report pre-clinical in vitro and in vivo studies showing that these calixpyrrole derivatives can inhibit cell growth in both PC3 and DU145 prostatic cancer cell lines. We explored the impact of these compounds on programmed cell death, as well as their ability to inhibit cellular invasion. In this study we have demonstrated the safety of these macrocyclic compounds by cytotoxicity tests on ex-vivo human peripheral blood mononuclear cells (PBMCs), and by in vivo subcutaneous administration. Preliminary in vivo tests demonstrated no hepato-, no nephro- and no genotoxicity in Balb/c mice compared to controls treated with cisplatin. These findings suggest these calixpyrroles might be novel therapeutic tools for the treatment of prostate cancer and of particular interest for the treatment of androgen-independent castration-resistant prostate cancer.

Sexual violence experiences among adolescent and young adult males: a review to empower healthcare providers.

PURPOSE OF REVIEW: Despite 3-17% of adolescent and young adult males (AYAMs) experiencing sexual violence, there is a paucity of information regarding their sexual violence experiences leaving them vulnerable to dangerous and detrimental sequelae. RECENT FINDINGS: There is underreporting and under-discussion of AYAMs' experiences of sexual violence, with disclosure influenced by societal perceptions of male sexuality, shame, and fear of discrimination. AYAMs experience sexual violence from individuals known to them, with many experiencing physical violence, threats, coercion, and electronic harassment. Intersectionality, previous traumas, inappropriate childhood exposures to sexually explicit situations, select online media consumption, and adverse childhood experiences (ACEs) increase the risk of sexual violence. AYAMs who experience sexual violence are at increased risk of re-victimization, perpetrating sexual violence, experiencing bodily harm, contracting sexually transmitted infections (STIs), and experiencing internalizing and externalizing symptoms, which can lead to significant morbidity and mortality. Research on male-specific protective and resilience factors is scarce and represents an ongoing need. SUMMARY: After reviewing AYAMs' experiences of sexual violence, including risk and protective factors, media influences, detrimental sequelae, and resilience factors, we provide a screening framework to empower the healthcare provider (HCP) to champion tailored prevention, screening, intervention, and advocacy efforts to support AYAMs.

Intravenous immunoglobulin as a preventive strategy against BK virus viremia and BKV-associated nephropathy in kidney transplant recipients-Results from a proof-of-concept study.

BK virus (BKV) replication occurs frequently in kidney transplant recipients (KTR), potentially leading to BKV-associated nephropathy (BKVAN) and graft loss. Patients with high titers of BKV-neutralizing antibodies (NAbs) are protected against BKV replication, and intravenous immunoglobulin (IVIg) infusion can increase NAb titers. We investigated whether early IVIg administration prevents BKV replication in patients with low NAb titers (<4 log10 against the BKV-specific genotype). Based on NAb titers on the day of transplantation, KTR followed in the Strasbourg University Hospital (n = 174) were retrospectively divided into the following 3 risk categories for BKV replication: (1) patients with low NAb titers ("high-risk") who received IVIg for the first 3 posttransplant months (n = 44), (2) patients with low NAb titers ("high-risk") who did not undergo IVIg treatment (n = 41), and (3) patients with high NAb titers ("low-risk") who did not receive IVIg (n = 89). At 12 posttransplant months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%) was similar to that observed in the low-risk group (10.1%) and markedly lower than that of the untreated high-risk group (36.6%; P < .001). Similar results were observed with regard to BKVAN. We conclude that IVIg may be a valuable strategy for preventing BKV replication.

In-depth virological assessment of kidney transplant recipients with COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread widely, causing coronavirus disease 2019 (COVID-19) and significant mortality. However, data on viral loads and antibody kinetics in immunocompromised populations are lacking. We aimed to determine nasopharyngeal and plasma viral loads via reverse transcription-polymerase chain reaction and SARS-CoV-2 serology via enzyme-linked immunosorbent assay and study their association with severe forms of COVID-19 and death in kidney transplant recipients. In this study, we examined hospitalized kidney transplant recipients with nonsevere (n = 21) and severe (n = 19) COVID-19. SARS-CoV-2 nasopharyngeal and plasma viral load and serological response were evaluated based on outcomes and disease severity. Ten recipients (25%) displayed persistent viral shedding 30 days after symptom onset. The SARS-CoV-2 viral load of the upper respiratory tract was not associated with severe COVID-19, whereas the plasma viral load was associated with COVID-19 severity (P = .010) and mortality (P = .010). All patients harbored antibodies during the second week after symptom onset that persisted for 2 months. We conclude that plasma viral load is associated with COVID-19 morbidity and mortality, whereas nasopharyngeal viral load is not. SARS-CoV-2 shedding is prolonged in kidney transplant recipients and the humoral response to SARS-CoV-2 does not show significant impairment in this series of transplant recipients.

A CROSS-SECTIONAL STUDY OF THE ASSOCIATION BETWEEN THE 1-HOUR ORAL GLUCOSE TOLERANCE TEST AND THE METABOLIC SYNDROME IN A HIGH-RISK SAMPLE WITH IMPAIRED FASTING GLUCOSE.

Objective: The aim of this study was to evaluate the association between the 1-hour oral glucose tolerance test (OGTT) (≥155 mg/dL) and metabolic syndrome (MS) in a sample with previous impaired fasting glucose (IFG). Methods: Three hundred and twenty four Peruvian subjects with a history of IFG ≥100 mg/dL were selected for a cross-sectional study. They underwent a 75 g OGTT and were assigned to different groups according to the result. We evaluated the association between 1-hour OGTT and MS. Results: The mean age was 56.5 ± 12.6 years and 191 (61.5%) were female. During the OGTT, we found 28 (8.6%) subjects with diabetes, 74 (22.8%) with IGT, and 222 (68.5%) with a normal glucose tolerance test with a 2-hour glucose <140 mg/dL (NGT). In the NGT group, 124 (38.3%) had 1-hour glucose levels <155 mg/dL, while 98 (30.2%) had 1-hour glucose levels ≥155 mg/dL. Evaluating the association between the 1-hour value in the OGTT and MS, we found that subjects with a 1-hour glucose ≥155 mg/dL were more than twice as likely to have MS as those with a 1-hour glucose <155 mg/dL (odds ratio = 2.64, 95% confidence interval: 1.52 to 4.57). In addition, body mass index, fasting glycemia, triglycerides, and waist circumferences were significantly higher in subjects with 1-hour glucose levels ≥155 mg/dL compared to those with 1-hour glucose levels <155 mg/dL (P<.05). Conclusion: Among subjects with IFG, performing an OGTT was helpful to identify subjects with 1-hour glucose levels ≥155 mg/dL and NGT who were significantly more likely to have MS and a worse cardiometabolic risk profile. Abbreviations: AST = aspartate aminotransferase; BMI = body mass index; CI = confidence interval; IFG = impaired fasting glucose; IGT = impaired glucose tolerance; LDL = low-density lipoprotein; MS = metabolic syndrome; NGT = normal glucose tolerance; OGTT = oral glucose tolerance test; OR = odds ratio; T2DM = type 2 diabetes; TG = triglycerides.

Biocatalytic Potential of Native Basidiomycetes from Colombia for Flavour/Aroma Production.

Aromas and flavours can be produced from fungi by either de novo synthesis or biotransformation processes. Herein, the biocatalytic potential of seven basidiomycete species from Colombia fungal strains isolated as endophytes or basidioma was evaluated. Ganoderma webenarium, Ganoderma chocoense, and Ganoderma stipitatum were the most potent strains capable of decolourizing ß,ß-carotene as evidence of their potential as biocatalysts for de novo aroma synthesis. Since a species' biocatalytic potential cannot solely be determined via qualitative screening using ß,ß-carotene biotransformation processes, we focused on using α-pinene biotransformation with mycelium as a measure of catalytic potential. Here, two strains of Trametes elegans-namely, the endophytic (ET-06) and basidioma (EBB-046) strains-were screened. Herein, T. elegans is reported for the first time as a novel biocatalyst for the oxidation of α-pinene, with a product yield of 2.9 mg of cis-Verbenol per gram of dry weight mycelia used. The EBB-046 strain generated flavour compounds via the biotransformation of a Cape gooseberry medium and de novo synthesis in submerged cultures. Three aroma-producing compounds were identified via GC-MS-namely, methyl-3-methoxy-4H-pyran-4-one, hexahydro-3-(methylpropyl)-pyrrolo[1,2-a]pyrazine-1,4-dione, and hexahydro-3-(methylphenyl)-pyrrolo[1,2-a]pyrazine-1,4-dione.

Teenage pregnancy prevention: the role of young men.

PURPOSE OF REVIEW: Although teenage pregnancy is declining in many parts of the world, it remains associated with considerable social, health, and economic outcomes. Pregnancy prevention efforts focus primarily on young women, with minimal attention to young men. This review highlights recent literature pertaining to the role of young men in pregnancy prevention. RECENT FINDINGS: Young men have varying views on contraception as well as which partner(s) should be responsible for its use. Limited contraception knowledge reduces young men's sexual health communication as well as their contraception use. Healthcare providers play a major role as one of the main sources of sexual health information for young men, but there are gaps in young men's sexual health care so new guidelines have emerged. SUMMARY: Recent literature highlights young men's range of views on contraception as well as their low sexual health knowledge and sexual health communication. To address teenage pregnancy and improve young men's overall wellness, healthcare providers should routinely address sexual health. Healthcare providers may use our newly proposed acronym, HIS BESTT, (Hello. Initiate. Sexual health assessment. Both condoms and female dependent methods. Examine genitals. STI screening. Talking to partner(s). Talking to parent(s) or guardians), to incorporate current clinical recommendations.

Pre-existing donor-specific antibodies are detrimental to kidney allograft only when persistent after transplantation.

Donor-specific antibodies (DSA) increase the risk of allograft rejection and graft failure. They may be present before transplant or develop de novo after transplantation. Here, we studied the evolution of preformed DSA and their impact on graft outcome in kidney transplant recipients. Using the Luminex Single Antigen assay, we analyzed the sera on the day of transplantation of 239 patients who received a kidney transplant. Thirty-seven patients (15.5%) had pre-existing DSA detected the day of transplantation. After 5 years, the pre-existing DSA disappeared in 22 patients whereas they persisted in 12. Variables associated with DSA persistence were age <50 years (P = 0.009), a history of previous transplantation (P = 0.039), the presence of class II DSA (P = 0.009), an MFI of preformed DSA >3500 (P < 0.001), and the presence of two or more DSA (P < 0.001). DSA persistence was associated with a higher risk of graft loss and antibody-mediated rejection. Previously undetected preformed DSA are deleterious to graft survival only when they persist after transplantation.

The Effect of Resveratrol on Cell Viability in the Burkitt's Lymphoma Cell Line Ramos.

Resveratrol is a polyphenolic natural compound produced by a variety of crops. Currently, resveratrol is considered a multi-target anti-cancer agent with pleiotropic activity, including the ability to prevent the proliferation of malignant cells by inhibiting angiogenesis and curtailing invasive and metastatic factors in many cancer models. However, the molecular mechanisms mediating resveratrol-specific effects on lymphoma cells remain unknown. To begin tackling this question, we treated the Burkitt's lymphoma cell line Ramos with resveratrol and assessed cell survival and gene expression. Our results suggest that resveratrol shows a significant anti-proliferative and pro-apoptotic activity on Ramos cells, inducing the DNA damage response, DNA repairing, and modulating the expression of several genes that regulate the apoptotic process and their proliferative activity.