Hirsutella sinensis intensifies testicular function and spermatogenesis in male mice with high-fat diet-induced obesity.

BACKGROUND: Hirsutella sinensis (HS) is a mycelium isolated from the fruiting body of the medicinal mushroom Cordyceps sinensis . This study explored whether HS treatment affects reproductive dysfunction in a high-fat diet (HFD)-induced mouse model and regulates various mechanisms, focusing on oxidative stress, apoptosis, inflammation, and autophagy. METHODS: Twenty-four C57BL/6J (B6) mice were randomly divided into a standard chow diet (NCD)- or HFD-fed group for 24 weeks. During the final 8 weeks, half of the HFD-fed mice were orally administered HS (HFD + HS). Biochemical markers, including glucose, insulin, triglycerides, and total cholesterol, were assessed, and hormones, including testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH), were analyzed. Liver and testicular histology, as well as sperm quality markers such as sperm motility, sperm count, and percentage of sperm with normal morphology, were observed. The activities of the testicular antioxidants superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx) and the products of lipid peroxidation, such as malondialdehyde (MDA), were measured. The protein expression levels of apoptosis-, autophagy- and inflammation-related markers were measured. RESULTS: The HFD-fed mice had abnormal sex hormone levels, poor sperm quality, and a destroyed testicular structure, with increased oxidative stress and apoptosis in the testis. HS supplementation in HFD-fed mice attenuated testicular apoptosis by suppressing the Bax/Bcl-xl ratio and cleaved caspase 3 protein expression. The HS-treated mice exhibited improved reproductive function, possibly due to reduced oxidative stress and apoptosis, suggesting that HS has a protective effect against HFD-induced testicular damage. CONCLUSION: Male mice supplemented with HS exhibited attenuated poor semen quality and reduced testosterone levels brought about by HFD-induced obesity by reducing oxidative stress.

Assessing the diversity and determinants of health-related quality of life measures in patients with acute heart failure.

AIMS: Heart failure with reduced ejection fraction (HFrEF) significantly impacts health-related quality of life (HR-QoL). Existing HR-QoL questionnaires can show inconsistencies, potentially misrepresenting patient self-reports. This study examines the variation in HR-QoL measurement tools for HFrEF patients, identifying related determinants. METHODS AND RESULTS: We retrospectively analysed 134 hospitalized patients with acute decompensated HFrEF at a Taiwanese tertiary centre's Heart Failure Post-Acute-Care (HF-PAC) programme. Participants completed the EuroQol-5 dimension (EQ-5D) questionnaire, the EQ-5D visual analogue scale (VAS), and the Minnesota Living with Heart Failure Questionnaire (MLHFQ). Utility values were obtained from the EQ-5D questionnaire. Demographic features were depicted using descriptive statistics, while multivariate regression was used to ascertain relationships between HR-QoL measurements and determinants. Average scores for EQ-5D, MLHFQ, EQ-5D utility, and VAS were 6.1 ± 1.6, 21.8 ± 21.3, 81.7 ± 27.0, and 59.5 ± 14.6, respectively. Significant correlations were observed among the three tools. The New York Heart Association functional class showed a notable association with all tool scores. Other associations encompassed EQ-5D with coronary artery disease, mineralocorticoid receptor antagonists, and the 6 min walk test; EQ-5D VAS with chronic kidney disease; and MLHFQ with age. CONCLUSIONS: This study illuminates the variance in HR-QoL measurement tools for Taiwanese HFrEF patients. Using a range of these tools is beneficial in unveiling diverse determinants and approaching comprehensive patient-centred care. However, for a more precise HR-QoL assessment in Taiwanese HFrEF patients, recalibrating the EQ-5D-derived utility scores might be necessary, emphasizing the importance of patient-specific considerations within the HF-PAC programme.

The intervention of artificial intelligence to improve the weaning outcomes of patients with mechanical ventilation: Practical applications in the medical intensive care unit and the COVID-19 intensive care unit: A retrospective study.

Patients admitted to intensive care units (ICU) and receiving mechanical ventilation (MV) may experience ventilator-associated adverse events and have prolonged ICU length of stay (LOS). We conducted a survey on adult patients in the medical ICU requiring MV. Utilizing big data and artificial intelligence (AI)/machine learning, we developed a predictive model to determine the optimal timing for weaning success, defined as no reintubation within 48 hours. An interdisciplinary team integrated AI into our MV weaning protocol. The study was divided into 2 parts. The first part compared outcomes before AI (May 1 to Nov 30, 2019) and after AI (May 1 to Nov 30, 2020) implementation in the medical ICU. The second part took place during the COVID-19 pandemic, where patients were divided into control (without AI assistance) and intervention (with AI assistance) groups from Aug 1, 2022, to Apr 30, 2023, and we compared their short-term outcomes. In the first part of the study, the intervention group (with AI, n = 1107) showed a shorter mean MV time (144.3 hours vs 158.7 hours, P = .077), ICU LOS (8.3 days vs 8.8 days, P = .194), and hospital LOS (22.2 days vs 25.7 days, P = .001) compared to the pre-intervention group (without AI, n = 1298). In the second part of the study, the intervention group (with AI, n = 88) exhibited a shorter mean MV time (244.2 hours vs 426.0 hours, P = .011), ICU LOS (11.0 days vs 18.7 days, P = .001), and hospital LOS (23.5 days vs 40.4 days, P < .001) compared to the control group (without AI, n = 43). The integration of AI into the weaning protocol led to improvements in the quality and outcomes of MV patients.

Pharmacodynamic effects of the PARP inhibitor talazoparib (MDV3800, BMN 673) in patients with BRCA-mutated advanced solid tumors.

PURPOSE: Talazoparib is an inhibitor of the poly (ADP-ribose) polymerase (PARP) family of enzymes and is FDA-approved for patients with (suspected) deleterious germline BRCA1/2-mutated, HER2­negative, locally advanced or metastatic breast cancer. Because knowledge of the pharmacodynamic (PD) effects of talazoparib in patients has been limited to studies of PARP enzymatic activity (PARylation) in peripheral blood mononuclear cells, we developed a study to assess tumoral PD response to talazoparib treatment (NCT01989546). METHODS: We administered single-agent talazoparib (1 mg/day) orally in 28-day cycles to adult patients with advanced solid tumors harboring (suspected) deleterious BRCA1 or BRCA2 mutations. The primary objective was to examine the PD effects of talazoparib; the secondary objective was to determine overall response rate (ORR). Tumor biopsies were mandatory at baseline and post-treatment on day 8 (optional at disease progression). Biopsies were analyzed for PARylation, DNA damage response (γH2AX), and epithelial‒mesenchymal transition. RESULTS: Nine patients enrolled in this trial. Four of six patients (67%) evaluable for the primary PD endpoint exhibited a nuclear γH2AX response on day 8 of treatment, and five of six (83%) also exhibited strong suppression of PARylation. A transition towards a more mesenchymal phenotype was seen in 4 of 6 carcinoma patients, but this biological change did not affect γH2AX or PAR responses. The ORR was 55% with the five partial responses lasting a median of six cycles. CONCLUSION: Intra-tumoral DNA damage response and inhibition of PARP enzymatic activity were confirmed in patients with advanced solid tumors harboring BRCA1/2 mutations after 8 days of talazoparib treatment.

Spatial variability of nitrogen cycling in the sediments of the Danshuie River Estuary (Northern Taiwan).

Dissolved N species, TOC and total N (TN) in sediment cores (SC) collected from an eutrophic estuary were analyzed to understand the N geochemical variation in SC of the eutrophic estuary. Extremely higher concentrations of ammonium (6550 µM) and DON (2050 µM) were observed in pore water of the upper estuary and both concentrations generally accounted for 65-99 % and 1-34 % of the dissolved total N pool, respectively, in the three sediment pore waters. The DON and TN concentrations decreased with increasing depth in SC of the upper estuary, opposite the ammonium profile, suggesting that the mineralization of DON and TN provided the ammonium source to the SC. While, the TN mineralization was more profound than the DON mineralization in SC of the middle and lower estuary. The mineralization rate of DON and TN obviously differed from the different depth intervals of the three SC.

Aspergillus coinfection in critically Ill patients with severe dengue.

In 2014-2015, a significant outbreak of dengue fever occurred in southern Taiwan, with a subsequent decline in dengue incidence. Despite this, there is emerging concern about virus-associated aspergillosis, yet limited research has explored coinfections involving dengue and aspergillosis. We conducted a retrospective study at a single center in Southern Taiwan, specifically focusing on dengue patients admitted to the intensive care unit during the period between July and November 2015. Among the 142 dengue patients studied, only 8.06 % (10/142) underwent serum galactomannan testing, with a single patient undergoing bronchoalveolar lavage (BAL) galactomannan assay. Out of those tested, 20 % (2/10) returned positive serum galactomannan results. Herein, we present two consecutive cases of coinfection involving dengue and pulmonary aspergillosis in immunocompetent patients.

The association between tyrosine kinase inhibitors and fatal arrhythmia in patients with non-small cell lung cancer in Taiwan.

Objective: As a standard therapy, tyrosine kinase inhibitors (TKIs) improved survival in patients with non-small cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) mutation. However, treatment-related cardiotoxicity, particularly arrhythmia, cannot be ignored. With the prevalence of EGFR mutations in Asian populations, the risk of arrhythmia among patients with NSCLC remains unclear. Methods: Using data from the Taiwanese National Health Insurance Research Database and National Cancer Registry, we identified patients with NSCLC from 2001 to 2014. Using Cox proportional hazards models, we analyzed outcomes of death and arrhythmia, including ventricular arrhythmia (VA), sudden cardiac death (SCD), and atrial fibrillation (AF). The follow-up duration was three years. Results: In total, 3876 patients with NSCLC treated with TKIs were matched to 3876 patients treated with platinum analogues. After adjusting for age, sex, comorbidities, and anticancer and cardiovascular therapies, patients receiving TKIs had a significantly lower risk of death (adjusted HR: 0.767; CI: 0.729-0.807, p < 0.001) than those receiving platinum analogues. Given that approximately 80% of the studied population reached the endpoint of mortality, we also adjusted for mortality as a competing risk. Notably, we observed significantly increased risks of both VA (adjusted sHR: 2.328; CI: 1.592-3.404, p < 0.001) and SCD (adjusted sHR: 1.316; CI: 1.041-1.663, p = 0.022) among TKI users compared with platinum analogue users. Conversely, the risk of AF was similar between the two groups. In the subgroup analysis, the increasing risk of VA/SCD persisted regardless of sex and most cardiovascular comorbidities. Conclusions: Collectively, we highlighted a higher risk of VA/SCD in TKI users than in patients receiving platinum analogues. Further research is needed to validate these findings.

Assessment of Tyrosine Kinase Inhibitors and Survival and Cardiovascular Outcomes of Patients With Non-Small Cell Lung Cancer in Taiwan.

Importance: Tyrosine kinase inhibitors (TKIs) have been recognized as the standard treatment for patients with non-small cell lung cancers (NSCLCs) and epidermal growth factor receptor (EGFR) sequence variation. Although TKIs have been reported to cause cardiotoxicity, they are widely administered owing to the high prevalence of EGFR sequence variation in Taiwan. Objective: To compare the outcomes of death and major adverse cardiac and cerebrovascular events among patients with NSCLC who use and do not use TKIs in a national cohort. Design, Setting, and Participants: Using data from the Taiwanese National Health Insurance Research Database and National Cancer Registry, patients treated for NSCLC from 2011 to 2018 were identified, and their outcomes were analyzed, including death and major adverse cardiac and cerebrovascular events (MACCEs; such as heart failure, acute myocardial infarction, and ischemic stroke) after adjusting for age, sex, cancer stage, comorbidities, anticancer therapies, and cardiovascular drugs. The median follow-up duration was 1.45 years. The analyses were performed from September 2022 to March 2023. Exposures: TKIs. Main Outcomes and Measures: Cox proportional hazards models were used to estimate death and MACCEs in patients treated with and without TKIs. Given that death may reduce the incidence of cardiovascular events, the competing risk method was used to calculate the MACCE risk after adjustment for all potential confounders. Results: Overall, 24 129 patients treated with TKIs were matched with 24 129 patients who did not receive TKIs (24 215 [50.18%] were female; and the mean [SD] age was 66.93 [12.37] years). Compared with those not receiving TKIs, the TKI group presented with a significantly lower hazard ratio (HR) of all-cause death (adjusted HR, 0.76; 95% CI, 0.75-0.78; P < .001), and the reason for death was primarily cancer. In contrast, the HR of MACCEs significantly increased (subdistribution HR, 1.22; 95% CI, 1.16-1.29; P < .001) in the TKI group. Furthermore, afatinib use was associated with a significantly reduced risk of death among patients receiving various TKIs (adjusted HR, 0.90; 95% CI, 0.85-0.94; P < .001) compared with those receiving erlotinib and gefitinib, although the outcomes of MACCEs were similar between the 2 groups. Conclusions and Relevance: In this cohort study of patients with NSCLC, TKI use was associated with reduced HRs of cancer-related death but increased HRs of MACCEs. These findings suggest the importance of close monitoring of cardiovascular problems in individuals receiving TKIs.

Risk factors for reintubation and mortality among patients who had unplanned extubation.

BACKGROUND: Unplanned extubation (UE) occurs among 2%-16% of patients with mechanical ventilation (MV). Failed UE requiring reintubation could be associated with several adverse events. AIMS: The aim of this study was to investigate the outcomes and prognostic factors of patients with UE in intensive care units (ICUs). METHODS: We prospectively registered the patients who had UE and retrospectively reviewed the electronic medical records for 96-bed ICUs between 1 January 2009, and 31 December 2020. RESULTS: A total of 392 patients had UE, and 234 patients (59.7%) were ≥65 years (older adult group). The median Acute Physiology and Chronic Health Evaluation (APACHE) II score were 17 and the median Glasgow Coma Scale score was 10. In total, 205 patients (52.3%) were reintubated within 48 h (due to failed UE) and 75 patients (19.1%) died during hospitalization. Multivariate analyses were performed to evaluate those factors predicting failed UE and mortality. These analyses demonstrated that higher positive end-expiratory pressure (PEEP) and the admission APACHE II scores predicted failed UE. A higher fraction of inspiration O2 (FiO2 ) and minute ventilation; lower haemoglobin (Hb); and higher instances of liver cirrhosis, cancer, and failed UE were independently associated with hospital mortality. CONCLUSION: We concluded that among patients who had UE, higher FiO2 or minute ventilation, or under MV or with lower Hb, liver cirrhosis, cancer, and failed UE tended to have higher mortality. RELEVANCE TO CLINICAL PRACTICE: Patients with high disease severity indices who have an increased risk of UE required special attention to techniques to prevent endotracheal tubes from accidental removal.

XPF activates break-induced telomere synthesis.

Alternative Lengthening of Telomeres (ALT) utilizes a recombination mechanism and break-induced DNA synthesis to maintain telomere length without telomerase, but it is unclear how cells initiate ALT. TERRA, telomeric repeat-containing RNA, forms RNA:DNA hybrids (R-loops) at ALT telomeres. We show that depleting TERRA using an RNA-targeting Cas9 system reduces ALT-associated PML bodies, telomere clustering, and telomere lengthening. TERRA interactome reveals that TERRA interacts with an extensive subset of DNA repair proteins in ALT cells. One of TERRA interacting proteins, the endonuclease XPF, is highly enriched at ALT telomeres and recruited by telomeric R-loops to induce DNA damage response (DDR) independent of CSB and SLX4, and thus triggers break-induced telomere synthesis and lengthening. The attraction of BRCA1 and RAD51 at telomeres requires XPF in FANCM-deficient cells that accumulate telomeric R-loops. Our results suggest that telomeric R-loops activate DDR via XPF to promote homologous recombination and telomere replication to drive ALT.

Comparison of the risk of gastrointestinal perforation between patients with and without rheumatoid arthritis: A nationwide cohort study in Asia.

Objectives: Patients with rheumatoid arthritis (RA) may have an increased risk for gastrointestinal perforation (GIP) caused by medications or chronic inflammation. However, the risk of GIP between patients with and without RA remains unclear. Therefore, we conducted this study to clarify it. Methods: Using the Taiwan National Health Insurance Research Database, we identified patients with and without RA matched at 1:1 ratio by age, sex, and index date between 2000 and 2013 for this study. Comparison of the risk of GIP between the two cohorts was performed by following up until 2014 using Cox proportional hazard regression analyses. Results: In total, 11,666 patients with RA and an identical number of patients without RA were identified for this study. The mean age (±standard deviation) and female ratio were 55.3 (±15.2) years and 67.6% in both cohorts. Patients with RA had a trend of increased risk for GIP than patients without RA after adjusting for underlying comorbidities, medications, and monthly income [adjusted hazard ratio (AHR) 1.42; 95% confidence interval (CI) 0.99-2.04, p = 0.055]. Stratified analyses showed that the increased risk was significant in the female population (AHR 2.06; 95% CI 1.24-3.42, p = 0.005). Older age, malignancy, chronic obstructive pulmonary disease, and alcohol abuse were independent predictors of GIP; however, NSAIDs, systemic steroids, and DMARDs were not. Conclusion: RA may increase the risk of GIP, particularly in female patients. More attention should be paid in female population and those with independent predictors above for prevention of GIP.

Curcumin Remedies Testicular Function and Spermatogenesis in Male Mice with Low-Carbohydrate-Diet-Induced Metabolic Dysfunction.

Increasing reports on the significance of dietary patterns in reproduction have arisen from both animal and human studies, suggesting an interactive association between nutrition and male fertility. The aim of this study was to investigate the effects of curcumin supplementation on low-carbohydrate-diet-induced metabolic dysfunction, testicular antioxidant capacity, apoptosis, inflammation and spermatogenesis in male mice. Male C57BL/6 mice were fed a normal diet (AIN-93M group, n = 12) and a low-carbohydrate diet for 12 weeks (LC group, fed with low-carbohydrate diet, n = 48), and mice randomly chosen from the LC group were later fed their original diet (LC group, n = 12). This diet was changed to AIN-93M feed (LC/AIN-93M group, n = 12), a ketogenic diet (LC/KD group, n = 12), or a ketogenic diet treated with curcumin supplementation for the final 6 weeks (LC/KDCu group, n = 12). A poor sperm morphology and mean testicular biopsy score (MTBS) were observed in the LC and LC/KD groups, but they were eliminated by the normal diet or ketogenic diet with curcumin. The LC group exhibited a lower testicular testosterone level and a lower 17ß-HSD activity and protein expression. This also enhanced apoptosis protein expressions in testis tissue, including Bax/BCl2, cleaved caspase 3, PARP and NF-κB. Meanwhile, we found a statistically significant increase in lipid peroxidation and decreased superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase levels in the LC group. Our study indicated that a replacement of a normal diet or ketogenic diet supplemented with curcumin attenuated poor semen quality and reduced testosterone levels by the LC diet by reducing oxidative stress.

Effects of Iron Supplementation on Testicular Function and Spermatogenesis of Iron-Deficient Rats.

Iron deficiency is the most common micronutrient deficiency in the world. Previous studies have shown that iron deficiency increases oxidative stress and decreases antioxidant enzymes, and studies of male infertility indicated that oxidative stress may affect male reproductive functions. The aim of this study was to investigate the effects of iron supplementation on spermatogenesis and testicular functions in iron-deficient rats. Three-week-old male Sprague Dawley (SD) rats were randomly divided into two groups: an iron-adequate control (AI group, 35 ppm FeSO4) and an iron-deficient group (ID group, <5 ppm FeSO4). After three weeks, the iron-deficient group was divided into an original iron-deficient group and five iron-supplemented groups, the latter fed diets containing different doses of FeSO4 (6, 12, 18, 24, and 35 ppm). After five weeks, blood and testis tissue were analyzed. We presented as median (interquartile range, IQR) for continuous measurements and compared their differences using the Kruskal−Wallis test followed by the Mann−Whitney U test among groups. The results showed that as compared with the AI group, the ID group had significantly lower serum testosterone and poorer spermatogenesis (The medians (QR) were 187.4 (185.6−190.8) of AI group vs. 87.5 (85.7−90.4) of ID group in serum testosterone, p < 0.05; 9.3 (8.8−10.6) of AI group vs. 4.9 (3.4−5.4) of ID group in mean testicular biopsy score (MTBS], p < 0.05); iron supplementation reversed the impairment of testis tissue. In the testosterone biosynthesis pathway, iron supplementation improved the lowered protein expressions of hydroxysteroid dehydrogenases caused by iron deficiency. Additionally, decreased activities of glutathione peroxidase and catalase, and increased cleaved-caspase 8 and caspase 3 expression, were found in the iron-deficient rats. The iron-supplemented rats that received > 12 ppm FeSO4 exhibited improvements in antioxidant levels. In conclusion, iron supplementation can abrogate testis dysfunction due to iron deficiency through regulation of the testicular antioxidant capacity.

Is a Ketogenic Diet Superior to a High-Fat, High-Cholesterol Diet Regarding Testicular Function and Spermatogenesis?

The study aimed to determine effects of a ketogenic diet on metabolic dysfunction, testicular antioxidant capacity, apoptosis, inflammation, and spermatogenesis in a high-fat and high-cholesterol diet-induced obese mice model. Forty-two male C57BL/6 mice were fed either a normal diet (NC group) or a high-fat and high-cholesterol (HFC) diet (HFC group) for 16 weeks, and mice from the HFC group were later randomly divided into two groups: the first were maintained on the original HFC diet, and the second were fed a medium-chain triacylglycerol (MCT)-based ketogenic diet for 8 weeks (KD group). A poor semen quality was observed in the HFC group, but this was eliminated by the ketogenic diet. Both the HFC and KD groups exhibited enhanced apoptosis protein expressions in testis tissue, including caspase 3 and cleaved PARP, and higher inflammation protein expressions, including TNF-α and NF-κB. However, the KD group exhibited a statistically-significant reduction in lipid peroxidation and an increased glutathione peroxidase level as compared with the HFC group. The HFC diet induced obesity in mice, which developed body weight gain, abnormal relative organ weights, metabolic dysfunction, and liver injury. Overall, the results showed that a ketogenic diet attenuated oxidative stress and improved the semen quality reduced by the HFC diet.

Does Coenzyme Q10 Supplementation Improve Testicular Function and Spermatogenesis in Male Mice with Chronic Kidney Disease?

The aim of the study was to examine the potential effects of coenzyme Q10 (CoQ10) on reproductive function in a chronic kidney disease (CKD) mouse model. Nine-week-old mice were randomly assigned to two groups: sham surgery (n = 18) and CKD surgery (n = 18). After surgery, the study groups received CoQ10 (10 mg/kg body weight dissolved in corn oil by oral gavage) or corn oil as a vehicle daily for 8 weeks. The groups that underwent 5/6 nephrectomy developed significant elevations of serum BUN and creatinine levels. The CoQ10 treatment significantly increased the serum and testicular CoQ10 levels and alleviated the poor semen quality from incomplete spermatogenesis. The testosterone concentration, in addition to the protein expression of enzymes related to testosterone biosynthesis, was also elevated, and the CKD-induced decrease in antioxidant activity in the testes was significantly ameliorated. The results suggest that CoQ10 could act against CKD-induced testicular dysfunction through improvements in the sperm function, testicular morphology, testosterone levels and related biosynthesis pathways, in addition to antioxidant activity.

Safety, Antitumor Activity, and Biomarker Analysis in a Phase I Trial of the Once-daily Wee1 Inhibitor Adavosertib (AZD1775) in Patients with Advanced Solid Tumors.

PURPOSE: The Wee1 kinase inhibitor adavosertib abrogates cell-cycle arrest, leading to cell death. Prior testing of twice-daily adavosertib in patients with advanced solid tumors determined the recommended phase II dose (RPh2D). Here, we report results for once-daily adavosertib. PATIENTS AND METHODS: A 3 + 3 dose-escalation design was used, with adavosertib given once daily on days 1 to 5 and 8 to 12 in 21-day cycles. Molecular biomarkers of Wee1 activity, including tyrosine 15-phosphorylated Cdk1/2 (pY15-Cdk), were assessed in paired tumor biopsies. Whole-exome sequencing and RNA sequencing of remaining tumor tissue identified potential predictive biomarkers. RESULTS: Among the 42 patients enrolled, the most common toxicities were gastrointestinal and hematologic; dose-limiting toxicities were grade 4 hematologic toxicity and grade 3 fatigue. The once-daily RPh2D was 300 mg. Six patients (14%) had confirmed partial responses: four ovarian, two endometrial. Adavosertib plasma exposures were similar to those from twice-daily dosing. On cycle 1 day 8 (pre-dose), tumor pY15-Cdk levels were higher than baseline in four of eight patients, suggesting target rebound during the day 5 to 8 dosing break. One patient who progressed rapidly had a tumor WEE1 mutation and potentially compensatory PKMYT1 overexpression. Baseline CCNE1 overexpression occurred in both of two responding patients, only one of whom had CCNE1 amplification, and in zero of three nonresponding patients. CONCLUSIONS: We determined the once-daily adavosertib RPh2D and observed activity in patients with ovarian or endometrial carcinoma, including two with baseline CCNE1 mRNA overexpression. Future studies will determine whether CCNE1 overexpression is a predictive biomarker for adavosertib.

A High Phosphorus Diet Impairs Testicular Function and Spermatogenesis in Male Mice with Chronic Kidney Disease.

Hyperphosphatemia is a serious complication in chronic kidney disease (CKD) that occurs due to insufficient excretion of phosphorus during failure of renal function. Both CKD and an excessive phosphorus intake have been reported to increase oxidative stress and result in poor male fertility, but little is known about the reproductive function of the CKD under a poorly controlled phosphate intake. Eight-week-old C57BL/6 mice (n = 66) were randomly divided into four groups: a sham operation group received a chow diet as control (SC group, n = 14), CKD-induced mice received a chow diet (CKDC group, n = 16), control mice received a high phosphorus (HP) diet (SP group, n = 16), and CKD-induced mice received a HP diet (CKDP group, n = 20). CKD was induced by performing a 5/6 nephrectomy. The chow diet contained 0.6% phosphorus, while the HP diet contained 2% phosphorus. Impaired testicular function and semen quality found in the CKD model may result from increased oxidative stress, causing apoptosis and inflammation. The HP diet aggravated the negative effects of testicular damage in the CKD-induced mice.

Metformin Ameliorates Testicular Function and Spermatogenesis in Male Mice with High-Fat and High-Cholesterol Diet-Induced Obesity.

The aim of this study was to investigate the effects of metformin supplementation on metabolic dysfunction, testicular antioxidant capacity, apoptosis, inflammation and spermatogenesis in male mice with high-fat and high-cholesterol diet-induced obesity. Forty male C57BL/6 mice were fed a normal diet (NC group, n = 10) or a high-fat and high-cholesterol diet (HFC group, n = 30) for 24 weeks, and mice randomly chosen from the HFC group were later treated with metformin for the final 8 weeks of HFC feeding (HFC + Met group, n = 15). Compared with the HFC group, the obese mice supplemented with metformin exhibited improved blood cholesterol, glucose and insulin resistance. The HFC group diminishes in the sperm motility and normal sperm morphology, while the poorer maturity of testicular spermatogenesis was improved by metformin treatment. The HFC group exhibited a higher estradiol level and a lower 17ß-HSD protein expression. Further analyses showed that metformin treatment increased the activities of superoxide dismutase, catalase and glutathione peroxidase and reduced lipid peroxidation. Nevertheless, both the HFC and HFC + Met groups exhibited increased expressions of apoptosis and inflammation proteins in the testis. Metformin treatment ameliorated obesity-induced poor testicular spermatogenesis and semen quality through increasing the testosterone level and antioxidant capacity.

Assessment of miniaturized ultrasound-powered implants: an in vivo study.

OBJECTIVE: Therapeutic applications of implantable active medical devices have improved the quality of patient life. Numerous on-going research in the field of neuromodulation and bioelectronic medicine are exploring the use of these implants for treating diseases and conditions. Miniaturized implantable medical devices that are wirelessly powered by ultrasound (US) can be placed close to the target sites deep inside the body for effective therapy with less invasiveness. In this study, we assessed the long-term in vivo performance of miniaturized US powered implants (UPI) using a rodent model. APPROACH: Prototype UPI devices were implanted in rodents and powered wirelessly using an unfocused US transmitter over 12 weeks, and the corresponding device output was recorded. Structural integrity of UPI before and after implantation was studied using scanning electron microscopy (SEM). We also conducted qualitative histological assessment of skin and muscle surrounding the UPI and compared it to naïve control and US exposed tissues. MAIN RESULTS: We found that it is feasible to power UPI devices wirelessly with US over long-term. The encapsulation of UPIs did not degrade over time and the tissues surrounding the UPI were comparable to both naïve control and US exposed tissues. SIGNIFICANCE: This study is the first to assess the long-term performance of miniaturized UPI devices using a rodent model over 12-weeks. The set of tests used in this study can be extended to assess other US-powered miniaturized implants.

Investigation of somatic single nucleotide variations in human endogenous retrovirus elements and their potential association with cancer.

Human endogenous retroviruses (HERVs) have been investigated for potential links with human cancer. However, the distribution of somatic nucleotide variations in HERV elements has not been explored in detail. This study aims to identify HERV elements with an over-representation of somatic mutations (hot spots) in cancer patients. Four HERV elements with mutation hotspots were identified that overlap with exons of four human protein coding genes. These hotspots were identified based on the significant over-representation (p<8.62e-4) of non-synonymous single-nucleotide variations (nsSNVs). These genes are TNN (HERV-9/LTR12), OR4K15 (HERV-IP10F/LTR10F), ZNF99 (HERV-W/HERV17/LTR17), and KIR2DL1 (MST/MaLR). In an effort to identify mutations that effect survival, all nsSNVs were further evaluated and it was found that kidney cancer patients with mutation C2270G in ZNF99 have a significantly lower survival rate (hazard ratio = 2.6) compared to those without it. Among HERV elements in the human non-protein coding regions, we found 788 HERVs with significantly elevated numbers of somatic single-nucleotide variations (SNVs) (p<1.60e-5). From this category the top three HERV elements with significantly over-represented SNVs are HERV-H/LTR7, HERV-9/LTR12 and HERV-L/MLT2. Majority of the SNVs in these 788 HERV elements are located in three DNA functional groups: long non-coding RNAs (lncRNAs) (60%), introns (22.2%) and transcriptional factor binding sites (TFBS) (14.8%). This study provides a list of mutational hotspots in HERVs, which could potentially be used as biomarkers and therapeutic targets.