Drinking water quality impacts oocyte viability and embryo development.

Normal reproductive function and fertility is considered a "sixth vital sign" because disruptions to this sensitive physiological system can forewarn other health issues, including exposure to environmental toxicants. We found that female mice exhibited profound loss of embryos during pre-implantation and fetal development coincident with a change to the source of their drinking water. When female mice were provided with tap water from the building in which they were housed (Water 2), instead of tap water from a neighboring building which was their previous supply (Water 1), ovulated oocytes were degenerated or had impaired meiotic maturation, and failed to form embryos. The harmful effects of Water 2 exposure were not reversible even following a recovery period; however, carbon-filtration of Water 2 removed the toxic contaminant. Water composition analysis to identify the responsible toxicant(s) found that trace elements were present at expected levels and phthalates were undetectable. Per- and Poly-fluoroalkyl Substances (PFAS), a family of persistent organic pollutants were detected at ∼4 ng/L. To investigate further, female mice were given drinking water categorized by level of PFAS contamination (0.6 ng/L, 2.8 ng/L, or 4.4 ng/L) for 9 weeks. Compared to mice consuming purified MilliQ water, mice consuming PFAS-contaminated water had decreased oocyte quality, impaired embryogenesis and reduced cell numbers in blastocysts. PFAS concentration in the drinking water was negatively correlated with oocyte viability. Importantly, the levels of PFAS detected in the tap water are within current "safe level" guidelines, and further research is needed to determine whether PFAS are responsible for the observed reproductive toxicity. However, this research demonstrating that water deemed suitable for human consumption has detrimental effects on mammalian embryo development has important implications for public health and water quality policies.

REPRODUCTIVE AGEING: BGP-15 mitigates adverse impacts of aging on sperm quality, fertility, and offspring health in male mice.

In Brief: Aging in men is associated with diminished sperm quality and a higher incidence of altered fetal development and miscarriage in resultant pregnancies. This study in mice identifies a therapeutic compound that, when administered to aged males, improves sperm quality, subsequent embryo development and post-natal offspring health. Abstract: Aging in men is associated with diminished sperm quality and a higher incidence of altered fetal development and miscarriage in resultant pregnancies. We used a mouse model of advanced paternal age to characterize embryonic development in older male mice and tested whether pre-conception treatment with the mitochondrial activator BGP-15 improves reproductive outcomes in old males. Like older men, reproductively old male mice had higher levels of sperm DNA damage and delayed pre-implantation development, associated with a reduced fetal weight and placental weight. Analysis of neonatal outcomes of in vivo-conceived offspring found that pups sired by old males were smaller, had delayed locomotor development, and increased mortality. BGP-15 treatment for 5 days prior to conception reduced sperm DNA oxidation levels and improved on-time embryo development after IVF and pup survival. BGP-15 treatment for 3 weeks prior to conception improved on-time pre-implantation embryo development and fetal viability and increased fetal size in pregnancies sired by old males. These results validate that ageing negatively affects male fertility and offspring physiology and indicates that pre-conception treatment with BGP-15 has the potential to improve sperm quality as well as early embryo development and post-natal health.

Circulating tumor extracellular vesicles to monitor metastatic prostate cancer genomics and transcriptomic evolution.

Extracellular vesicles (EVs) secreted by tumors are abundant in plasma, but their potential for interrogating the molecular features of tumors through multi-omic profiling remains widely unexplored. Genomic and transcriptomic profiling of circulating EV-DNA and EV-RNA isolated from in vitro and in vivo models of metastatic prostate cancer (mPC) reveal a high contribution of tumor material to EV-loaded DNA/RNA, validating the findings in two cohorts of longitudinal plasma samples collected from patients during androgen receptor signaling inhibitor (ARSI) or taxane-based therapy. EV-DNA genomic features recapitulate matched-patient biopsies and circulating tumor DNA (ctDNA) and associate with clinical progression. We develop a novel approach to enable transcriptomic profiling of EV-RNA (RExCuE). We report how the transcriptome of circulating EVs is enriched for tumor-associated transcripts, captures certain patient and tumor features, and reflects on-therapy tumor adaptation changes. Altogether, we show that EV profiling enables longitudinal transcriptomic and genomic profiling of mPC in liquid biopsy.

Feammox bacterial biofilm formation in HFMB.

Nitrogen pollution has been increasing with the development of industrialization. Consequently, the excessive deposition of reactive nitrogen in the environment has generated the loss of biodiversity and eutrophication of different ecosystems. In 2005, a Feammox process was discovered that anaerobically metabolizes ammonium. Feammox with the use of hollow fiber membrane bioreactors (HFMB), based on the formation of biofilms of bacterial communities, has emerged as a possible efficient and sustainable method for ammonium removal in environments with high iron concentrations. This work sought to study the possibility of implementing, at laboratory scale, an efficient method by evaluating the use of HFMB. Samples from an internal circulation reactor (IC) incubated in culture media for Feammox bacteria. The cultures were enriched in a batch reactor to evaluate growth conditions. Next, HFMB assembly was performed, and Feammox parameters were monitored. Also, conventional PCR and scanning electron microscopy (SEM) analysis were performed to characterize the bacterial communities associated with biofilm formation. The use of sodium acetate presented the best performance for Feammox activity. The HFMB operation showed an ammonium (NH4+) removal of 50%. SEM analysis of the fibers illustrated the formation of biofilm networks formed by bacteria, which were identified as Albidiferax ferrireducens, Geobacter spp, Ferrovum myxofaciens, Shewanella spp., and Anammox. Functional genes Archaea/Bacteria ammonia monooxygenase, nrxA, hzsB, nirS and nosZ were also identified. The implementation of HFMB Feammox could be used as a sustainable tool for the removal of ammonium from wastewater produced because of anthropogenic activities.

Case report: Exceptional and durable response to Radium-223 and suspension of androgen deprivation therapy in a metastatic castration-resistant prostate cancer patient.

Despite the development of new therapies in the last few years, metastatic prostate cancer (PCa) is still a lethal disease. Radium-223 (Ra-223) is approved for patients with advanced castration-resistant prostate cancer (CRPC) with bone metastases and no visceral disease. However, patients' outcomes are heterogenous, and there is lack of validated predictive biomarkers of response, while biomarkers for early identification of patients who benefit from treatment are limited. This case report describes a remarkable and durable response to Ra-223 in a CRPC patient with bone metastases who had rapidly progressed to many previous therapies; this response is now lasting for 5 years even after having stopped backbone androgen deprivation therapy (ADT). Here, we present the clinical course of this exceptional response, as well as comprehensive genomic and histopathology analyses on sequential biopsies acquired before and after therapy. Additionally, we review current knowledge on predictive and response biomarkers to Ra-223 in metastatic prostate cancer.

A Signal-Finding Study of Abemaciclib in Heavily Pretreated Patients with Metastatic Castration-Resistant Prostate Cancer: Results from CYCLONE 1.

PURPOSE: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors radically changed the treatment paradigm for breast cancer. Similar to estrogen receptor in breast cancer, androgen receptor signaling activates cyclin D-CDK4/6, driving proliferation and resistance to hormonal manipulation in prostate cancer. This study was designed to detect signals of clinical activity for abemaciclib in treatment-refractory metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Eligible patients had progressive mCRPC, measurable disease, and previously received ≥1 novel hormonal agent(s) and 2 lines of taxane chemotherapy. Abemaciclib 200 mg twice daily was administered on a continuous dosing schedule. Primary endpoint was objective response rate (ORR) without concurrent bone progression. This study was designed to detect a minimum ORR of 12.5%. RESULTS: At trial entry, 40 (90.9%) of 44 patients had objective radiographic disease progression, 4 (9.1%) had prostate-specific antigen (PSA)-only progression, and 20 (46.5%) had visceral metastases (of these, 60% had liver metastases). Efficacy analyses are as follows: ORR without concurrent bone progression: 6.8%; disease control rate: 45.5%; median time to PSA progression: 6.5 months [95% confidence interval (CI), 3.2-NA]; median radiographic PFS; 2.7 months (95% CI, 1.9-3.7); and median OS, 8.4 months (95% CI, 5.6-12.7). Most frequent grade ≥3 treatment-emergent adverse events (AE) were neutropenia (25.0%), anemia, and fatigue (11.4% each). No grade 4 or 5 AEs were related to abemaciclib. CONCLUSIONS: Abemaciclib monotherapy was well tolerated and showed clinical activity in this heavily pretreated population, nearly half with visceral metastases. This study is considered preliminary proof-of-concept and designates CDK4/6 as a valid therapeutic target in prostate cancer.

Dynamics of Mitochondrial DNA Copy Number and Membrane Potential in Mouse Pre-Implantation Embryos: Responses to Diverse Types of Oxidative Stress.

Mitochondria undergo a myriad of changes during pre-implantation embryo development, including shifts in activity levels and mitochondrial DNA (mtDNA) replication. However, how these distinct aspects of mitochondrial function are linked and their responsiveness to diverse stressors is not well understood. Here, we show that mtDNA content increased between 8-cell embryos and the blastocyst stage, with similar copy numbers per cell in the inner cell mass (ICM) and trophectoderm (TE). In contrast, mitochondrial membrane potential (MMP) was higher in TE than ICM. Culture in ambient oxygen (20% O2) altered both aspects of mitochondrial function: the mtDNA copy number was upregulated in ICM, while MMP was diminished in TE. Embryos cultured in 20% O2 also exhibited delayed development kinetics, impaired implantation, and reduced mtDNA levels in E18 fetal liver. A model of oocyte mitochondrial stress using rotenone showed only a modest effect on on-time development and did not alter the mtDNA copy number in ICM; however, following embryo transfer, mtDNA was higher in the fetal heart. Lastly, endogenous mitochondrial dysfunction, induced by maternal age and obesity, altered the blastocyst mtDNA copy number, but not within the ICM. These results demonstrate that mitochondrial activity and mtDNA content exhibit cell-specific changes and are differentially responsive to diverse types of oxidative stress during pre-implantation embryogenesis.

Coupling of the Feammox - Anammox pathways by using a sequential discontinuous bioreactor.

Treating nitrogenous compounds in wastewater is a contemporary challenge, prompting novel approaches for ammonium (NH4+) conversion to molecular nitrogen (N2). This study explores the classic anaerobic ammonium oxidation process (Anammox) coupled to the iron-dependent anaerobic ammonium oxidation process (Feammox) in a sequential discontinuous bioreactor (SBR) for NH4+ removal. Feammox and Anammox cultures were individually enriched and combined, optimizing the coupling, and identifying key variables influencing the enrichment process. Adding sodium acetate as a carbon source significantly reduces Fe3+ to Fe2+, indicating Feammox activity. Both Anammox and Feammox processes were successfully operated in SBRs, achieving efficient NH4+ removal (Anammox: 64.6 %; Feammox: 43.4 %). Combining these pathways in a single SBR enhances the NH4+ removal capacity of 50.8 %, improving Feammox efficiency. The Feammox process coupled with Anammox may generate the nitrite (NO2-) needed for Anammox. This research contributes to biotechnological advancements for sustainable nitrogenous compound treatment in SBRs.

Sex influences blood pressure but not blood pressure variability in response to dietary sodium and potassium in salt-resistant adults.

Dietary sodium and potassium have been shown to affect blood pressure (BP) but their influence on BP variability (BPV) is less studied as is the influence of sex. The aim of this study was to compare 24 h BP and short-term BPV in response to varying dietary levels of sodium and potassium in healthy non-obese normotensive salt-resistant adults. We hypothesized that high sodium would increase short-term BP and BPV while the addition of high potassium would counteract this increase. Furthermore, we hypothesized that women would experience greater increases in BPV under high sodium conditions compared to men while potassium would attenuate this response. Thirty-seven participants (17 M/20 W; 27 ± 5 years old; BMI 24.3 ± 3 kg/m2) completed seven days each of the following randomized diets: moderate potassium/low sodium (MK/LS), moderate potassium/high sodium (MK/HS) and high potassium/high sodium (HK/HS). BP and short-term BPV were assessed using 24 h ambulatory BP monitoring starting on day 6. BPV was calculated using the average real variability (ARV) index. Twenty-four hour, daytime, and nighttime systolic BP (SBP) were lower in women compared to men regardless of diet. However, 24 h and daytime SBP were lowered in women on the HK/HS diet compared to the MK/HS diet. There were no significant effects of diet or sex for 24 h, daytime or nighttime SBP ARV. However, men exhibited a higher 24 hDBP ARV than women regardless of diet. In conclusion, a high potassium diet lowered BP under high sodium conditions in women alone while men exhibited higher short-term BPV that was not influenced by diet.

Melatonin supplementation does not alter vascular function or oxidative stress in healthy normotensive adults on a high sodium diet.

High sodium diets (HSD) can cause vascular dysfunction, in part due to increases in reactive oxygen species (ROS). Melatonin reduces ROS in healthy and clinical populations and may improve vascular function. The purpose was to determine the effect of melatonin supplementation on vascular function and ROS during 10 days of a HSD. We hypothesized that melatonin supplementation during a HSD would improve vascular function and decrease ROS levels compared to HSD alone. Twenty-seven participants (13 M/14 W, 26.7 ± 2.9 years, BMI: 23.6 ± 2.0 kg/m2 , BP: 110 ± 9/67 ± 7 mmHg) were randomized to a 10-day HSD (6900 mg sodium/d) supplemented with either 10 mg of melatonin (HSD + MEL) or a placebo (HSD + PL) daily. Brachial artery flow-mediated dilation, a measure of macrovascular function, (HSD + PL: 7.1 ± 3.8%; HSD + MEL: 6.7 ± 3.4%; p = 0.59) and tissue oxygenation index (TSI) reperfusion rate, a measure of microvascular reactivity, (HSD + PL: 0.21 ± 0.06%/s; HSD + MEL: 0.21 ± 0.08%/s; p = 0.97) and TSI area under the curve (HSD + PL: 199899 ± 10,863 a.u.; HSD + MEL: 20315 ± 11,348 a.u.; p = 0.17) were similar at the end of each condition. Neither nitroxide molarity (HSD + PL: 7.8 × 10-5 ± 4.1 × 10-5 mol/L; HSD + MEL: 8.7 × 10-5 ± 5.1 × 10-5 mol/L; p = 0.55) nor free radical number (HSD + PL: 8.0 × 1015 ± 4.4 × 1015 ; HSD + MEL: 9.0 × 1015 ± 4.9 × 1015 ; p = 0.51) were different between conditions. Melatonin supplementation did not alter vascular function or ROS levels while on a HSD in this sample of young healthy normotensive adults.

Prevalence of immune-related adverse events and anti-tumor efficacy in advanced/metastatic urothelial carcinoma following immune-checkpoint inhibitor treatment

Purpose We evaluated the prevalence of immune-related adverse events and anti-tumor efficacy in advanced/metastatic urothelial carcinoma following immune-checkpoint inhibitors (ICIs) treatment. Methods We conducted a multicenter retrospective study of patients with advanced/metastatic urothelial carcinoma treated with ICIs in four Spanish institutions. irAEs were classified using Common Terminology Criteria for Adverse Event (CTCAE) v.5.0 guidelines. The primary endpoint was overall survival (OS). Other endpoints were overall response rate (ORR) and progression-free survival (PFS). irAEs were evaluated as a time-dependent covariate to avoid immortal time bias. Results A total of 114 patients were treated with ICIs between May 2013 and May 2019, 105 (92%) of whom received ICIs as monotherapy. irAEs of any grade were experienced in 56 (49%) patients and 21 (18%) patients had grade ≥ 3 toxicity. The most frequent irAEs were gastrointestinal and dermatological toxicities, reported in 25 (22%) and 20 (17%) patients, respectively. Patients with grade 1–2 irAEs had significantly longer OS compared to those without grade 1–2 irAEs (median 18.2 vs. 8.7 months, HR = 0.61 [95% CI 0.39–0.95], p = 0.03). No association with efficacy was observed for patients with grade ≥ 3 irAEs. No difference in PFS was observed after adjusting for the immortal time bias. ORR was higher in patients who developed irAEs (48% vs 17%, p < 0.001). Conclusions Our findings suggest that development of irAEs was associated with higher ORR, and patients who developed grade 1–2 irAEs had longer OS. Prospective studies are necessary to confirm our findings (AU)

Melatonin supplementation reduces nighttime blood pressure but does not affect blood pressure reactivity in normotensive adults on a high-sodium diet.

High-sodium diets (HSDs) can cause exaggerated increases in blood pressure (BP) during physiological perturbations that cause sympathetic activation, which is related to cardiovascular risk. Melatonin supplementation has been shown to play a role in BP regulation. Our aim was to examine the effects of melatonin taken during an HSD on 24-h BP and BP reactivity during isometric handgrip (IHG) exercise, postexercise ischemia (PEI), and the cold pressor test (CPT). Twenty-two participants (11 men/11 women, 26.5 ± 3.1 yr, BMI: 24.1 ± 1.8 kg/m2, BP: 111 ± 9/67 ± 7 mmHg) were randomized to a 10-day HSD (6,900 mg sodium/day) that was supplemented with either 10 mg/day of melatonin (HSD + MEL) or placebo (HSD + PL). Twenty-four-hour ambulatory BP monitoring was assessed starting on day 9. Mean arterial pressure (MAP) was quantified during the last 30 s of IHG at 40% of maximal voluntary contraction and CPT, and during 3 min of PEI. Melatonin did not change 24-h MAP (HSD + PL: 83 ± 6 mmHg; HSD + MEL: 82 ± 5 mmHg; P = 0.23) but decreased nighttime peripheral (HSD + PL: 105 ± 10 mmHg; HSD + MEL: 100 ± 10 mmHg; P = 0.01) and central systolic BP (HSD + PL: 97 ± 9 mmHg; HSD + MEL: 93 ± 8 mmHg; P = 0.04) on the HSD compared with the HSD + PL. The absolute and percent change in MAP during IHG was not different between conditions (all P > 0.05). In conclusion, melatonin supplementation did not alter BP reactivity to the perturbations tested on an HSD but may be beneficial in lowering BP in young healthy normotensive adults.NEW & NOTEWORTHY BP reactivity was assessed during isometric handgrip (IHG) exercise, postexercise ischemia (PEI), and the cold pressor test (CPT) after 10 days of a high-sodium diet with and without melatonin supplementation. Melatonin did not alter BP reactivity in healthy normotensive men and women. However, melatonin did decrease nighttime peripheral and central systolic BP, suggesting it may be beneficial in lowering BP even in those with a normal BP.

Selective HIF2A Inhibitors in the Management of Clear Cell Renal Cancer and Von Hippel-Lindau-Disease-Associated Tumors.

Von Hippel-Lindau (VHL) loss is the hallmark event characterizing the clear cell renal cancer subtype (ccRCC). Carriers of germinal VHL mutations have an increased prevalence of kidney cysts and ccRCC as well as hemangioblastoma, pheochromocytoma and pancreatic neuroendocrine tumors. In both sporadic and inherited ccRCC, the primary mechanism of VHL-mediated carcinogenesis is the abnormal stabilization of hypoxia-inducible factors (HIF1A and HIF2A). While HIF1A acts as a tumor suppressor and is frequently lost through inactivating mutations/14q chromosome deletions, HIF2A acts as an oncogene promoting the expression of its target genes (VEGF, PDGF, CAIX Oct4, among others). Selective HIF2a inhibitors block the heterodimerization between HIF2A and ARNT, stopping HIF2A-induced transcription. Several HIF2A inhibitors have entered clinical trials, where they have shown a favorable toxicity profile, characterized by anemia, fatigue and edema and promising activity in heavily pretreated ccRCC patients. Belzutifan, a second-generation HIF2a inhibitor, was the first to receive FDA approval for the treatment of unresectable ccRCC in VHL syndrome. In this review, we recapitulate the rationale for HIF2a blockade in ccRCC, summarize the development of HIF2a inhibitors from preclinical models up to its introduction to the clinic with emphasis on Belzutifan, and discuss their role in VHL disease management.

Intraorbital lymphatic-venous malformation in an adult patient: is sirolimus the key?

Intraorbital lymphatic-venous malformations are rare lesions that represent a therapeutic challenge given their location and high rate of recurrence, with only a few cases in adult patients having been published in the literature. We present the case of a 30-year-old male with a right intraorbital lymphatic-venous malformation treated with sirolimus at a dose of 4 mg/day with complete clinical and radiologic remission. Mild cold-like symptoms ensued during the first week of treatment and elevation of liver function enzymes and D-dimer occurred in the context of acute SARS-CoV-2 pneumonia. No major adverse effects were documented. After 18 months of treatment, the patient remains asymptomatic and ophthalmologic examinations including optical coherence tomography and visual field test are within normal values.

Prevalence of immune-related adverse events and anti-tumor efficacy in advanced/metastatic urothelial carcinoma following immune-checkpoint inhibitor treatment.

PURPOSE: We evaluated the prevalence of immune-related adverse events and anti-tumor efficacy in advanced/metastatic urothelial carcinoma following immune-checkpoint inhibitors (ICIs) treatment. METHODS: We conducted a multicenter retrospective study of patients with advanced/metastatic urothelial carcinoma treated with ICIs in four Spanish institutions. irAEs were classified using Common Terminology Criteria for Adverse Event (CTCAE) v.5.0 guidelines. The primary endpoint was overall survival (OS). Other endpoints were overall response rate (ORR) and progression-free survival (PFS). irAEs were evaluated as a time-dependent covariate to avoid immortal time bias. RESULTS: A total of 114 patients were treated with ICIs between May 2013 and May 2019, 105 (92%) of whom received ICIs as monotherapy. irAEs of any grade were experienced in 56 (49%) patients and 21 (18%) patients had grade ≥ 3 toxicity. The most frequent irAEs were gastrointestinal and dermatological toxicities, reported in 25 (22%) and 20 (17%) patients, respectively. Patients with grade 1-2 irAEs had significantly longer OS compared to those without grade 1-2 irAEs (median 18.2 vs. 8.7 months, HR = 0.61 [95% CI 0.39-0.95], p = 0.03). No association with efficacy was observed for patients with grade ≥ 3 irAEs. No difference in PFS was observed after adjusting for the immortal time bias. ORR was higher in patients who developed irAEs (48% vs 17%, p < 0.001). CONCLUSIONS: Our findings suggest that development of irAEs was associated with higher ORR, and patients who developed grade 1-2 irAEs had longer OS. Prospective studies are necessary to confirm our findings.

Closing the Gaps in Care of Dyslipidemia: Revolutionizing Management with Digital Health and Innovative Care Models.

Although great progress has been made in the diagnostic and treatment options for dyslipidemias, unawareness, underdiagnosis and undertreatment of these disorders remain a significant global health concern. Growth in digital applications and newer models of care provide novel tools to improve the management of chronic conditions such as dyslipidemia. In this review, we discuss the evolving landscape of lipid management in the 21st century, current treatment gaps and possible solutions through digital health and new models of care. Our discussion begins with the history and development of value-based care and the national establishment of quality metrics for various chronic conditions. These concepts on the level of healthcare policy not only inform reimbursements but also define the standard of care. Next, we consider the advances in atherosclerotic cardiovascular disease risk score calculators as well as evolving imaging modalities. The impact and growth of digital health, ranging from telehealth visits to online platforms and mobile applications, will also be explored. We then evaluate the ways in which machine learning and artificial intelligence-driven algorithms are being utilized to address gaps in lipid management. From an organizational perspective, we trace the redesign of medical practices to incorporate a multidisciplinary team model of care, recognizing that atherosclerotic cardiovascular disease risk is multifaceted and requires a comprehensive approach. Finally, we anticipate the future of dyslipidemia management, assessing the many ways in which atherosclerotic cardiovascular disease burden can be reduced on a population-wide scale.

Update in collecting duct carcinoma: Current aspects of the clinical and molecular characterization of an orphan disease.

Collecting duct renal cell carcinoma (cdRCC), which until recently was thought to arise from the collecting ducts of Bellini in the renal medulla, is a rare and aggressive type of non-clear renal cell carcinoma (ncRCC), accounting for 1% of all renal tumors and with nearly 50% of patients being diagnosed with Stage IV disease. The median overall survival in this setting is less than 12 months. Several regimens of chemotherapies had been used based on morphologic and cytogenetic similarities with urothelial cell carcinoma described previously, although the prognosis still remains poor. The use of targeted therapies also did not result in favorable outcomes. Recent works using NGS have highlighted genomic alterations in SETD2, CDKN2A, SMARCB1, and NF2. Moreover, transcriptomic studies have confirmed the differences between urothelial carcinoma and cdRCC, the possible true origin of this disease in the distal convoluted tubule (DCT), differentiating from other RCC (e.g., clear cell and papillary) that derive from the proximal convoluted tubule (PCT), and enrichment in immune cells that may harbor insights in novel treatment strategies with immunotherapy and target agents. In this review, we update the current aspects of the clinical, molecular characterization, and new targeted therapeutic options for Collecting duct carcinoma and highlight the future perspectives of treatment in this setting.

OXIDATIVE STRESS AND REPRODUCTIVE FUNCTION: Reactive oxygen species in the mammalian pre-implantation embryo.

In brief: Reactive oxygen species are generated throughout the pre-implantation period and are necessary for normal embryo formation. However, at pathological levels, they result in reduced embryo viability which can be mediated through factors delivered by sperm and eggs at conception or from the external environment. Abstract: Reactive oxygen species (ROS) occur naturally in pre-implantation embryos as a by-product of ATP generation through oxidative phosphorylation and enzymes such as NADPH oxidase and xanthine oxidase. Biological concentrations of ROS are required for crucial embryonic events such as pronuclear formation, first cleavage and cell proliferation. However, high concentrations of ROS are detrimental to embryo development, resulting in embryo arrest, increased DNA damage and modification of gene expression leading to aberrant fetal growth and health. In vivo embryos are protected against oxidative stress by oxygen scavengers present in follicular and oviductal fluids, while in vitro, embryos rely on their own antioxidant defence mechanisms to protect against oxidative damage, including superoxide dismutase, catalase, glutathione and glutamylcysteine synthestase. Pre-implantation embryonic ROS originate from eggs, sperm and embryos themselves or from the external environment (i.e. in vitro culture system, obesity and ageing). This review examines the biological and pathological roles of ROS in the pre-implantation embryo, maternal and paternal origins of embryonic ROS, and from a clinical perspective, we comment on the growing interest in combating increased oxidative damage in the pre-implantation embryo through the addition of antioxidants.

Restoring Sperm Quality Post-Cryopreservation Using Mitochondrial-Targeted Compounds.

While critical for male fertility preservation, cryopreservation damage reduces sperm quality and fertilization potential. This study investigated whether the addition of mitochondrial-targeted, antioxidant compounds, also known as Mitochondrial activators, to the cryopreservation medium could protect sperm quality during cryopreservation. For this, semen samples from men undergoing IVF/ICSI treatment, which were donated for research, underwent cryopreservation in the absence or presence of BGP-15, MitoQ and L-carnitine. Fresh semen and thawed sperm samples from the same participant were analyzed for indicators of sperm quality: sperm viability, kinetics, mitochondrial reactive oxygen species (ROS) levels, Mitochondrial Membrane Potential (MMP) and DNA damage. Cryopreservation significantly reduced sperm viability and motility and predicted mucous penetration. BGP-15, MitoQ and L-carnitine improved sperm motility, whilst the addition of L-Carnitine prevented the loss of sperm viability during cryopreservation. Both BGP-15 and L-carnitine reduced sperm DNA oxidative damage, but only BGP-15 significantly reduced DNA fragmentation. More importantly, BGP-15 increased sperm predictive mucous penetration and MMP and reduced DNA oxidation. Our results show that the addition of BGP-15 or L-carnitine to the cryopreservation medium improves sperm quality post-thawing, highlighting the potential of mitochondrial antioxidants to improve long-term fertility preservation in males.