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Background: Renal medullary carcinoma (RMC) is a highly aggressive cancer in need of new therapeutic strategies. The neddylation pathway can protect cells from DNA damage induced by the platinum‐based chemotherapy used in RMC. We investigated if neddylation inhibition with pevonedistat will synergistically enhance antitumour effects of platinum‐based chemotherapy in RMC. Methods: We evaluated the IC50 concentrations of the neddylation‐activating enzyme inhibitor pevonedistat in vitro in RMC cell lines. Bliss synergy scores were calculated using growth inhibition assays following treatment with varying concentrations of pevonedistat and carboplatin. Protein expression was assessed by western blot and immunofluorescence assays. The efficacy of pevonedistat alone or in combination with platinum‐based chemotherapy was evaluated in vivo in platinum‐naïve and platinum‐experienced patient‐derived xenograft (PDX) models of RMC. Results: The RMC cell lines demonstrated IC50 concentrations of pevonedistat below the maximum tolerated dose in humans. When combined with carboplatin, pevonedistat demonstrated a significant in vitro synergistic effect. Treatment with carboplatin alone increased nuclear ERCC1 levels used to repair the interstrand crosslinks induced by platinum salts. Conversely, the addition of pevonedistat to carboplatin led to p53 upregulation resulting in FANCD2 suppression and reduced nuclear ERCC1 levels. The addition of pevonedistat to platinum‐based chemotherapy significantly inhibited tumour growth in both platinum‐naïve and platinum‐experienced PDX models of RMC (p <.01). Conclusions: Our results suggest that pevonedistat synergises with carboplatin to inhibit RMC cell and tumour growth through inhibition of DNA damage repair. These findings support the development of a clinical trial combining pevonedistat with platinum‐based chemotherapy for RMC. [ABSTRACT FROM AUTHOR]

Background: Cancer treatment of prepubertal patients impacts future fertility due to the abolition of spermatogonial stem cells (SSCs). In macaques, spermatogenesis could be regenerated by intratesticular transplantation of SSCs, but no studies have involved cytotoxic treatment before puberty and transplantation after puberty, which would be the most likely clinical scenario. Objectives: To evaluate donor‐derived functional sperm production after SSC transplantation to adult monkeys that had received testicular irradiation during the prepubertal period. Materials and methods: We obtained prepubertal testis tissue by unilaterally castrating six prepubertal monkeys and 2 weeks later irradiated the remaining testes with 6.9 Gy. However, because spermatogenic recovery was observed, we irradiated them again 14 months later with 7 Gy. Three of the monkeys were treated with GnRH‐antagonist (GnRH‐ant) for 8 weeks. The cryopreserved testis cells from the castrated testes were then allogeneically transplanted into the intact testes of all monkeys. Tissues were harvested 10 months later for analyses. Results: In three of the six monkeys, 61%, 38%, and 11% of the epididymal sperm DNA were of the donor genotype. The ability to recover donor‐derived sperm production was not enhanced by the GnRH‐ant pretreatment. However, the extent of filling seminiferous tubules during the transplantation procedure was correlated with the eventual production of donor spermatozoa. The donor epididymal spermatozoa from the recipient with 61% donor contribution were capable of fertilizing rhesus eggs and forming embryos. Although the transplantation was done into the rete testis, two GnRH‐ant‐treated monkeys, which did not produce donor‐derived epididymal spermatozoa, displayed irregular tubular cords in the interstitium containing testicular spermatozoa derived from the transplanted donor cells. Discussion and Conclusion: The results further support that sperm production can be restored in non‐human primates from tissues cryopreserved prior to prepubertal and post‐pubertal gonadotoxic treatment by transplantation of these testicular cells after puberty into seminiferous tubules. [ABSTRACT FROM AUTHOR]

Ostruthin, isolated from Paramignya trimera, was used as a scaffold to design its alkyl triphenylphosphonium derivatives. With the optimal reaction conditions in hand, five alkyl triphenylphosphonium ostruthin derivatives (1–5) were synthesized. Ostruthin and its derivatives were tested for cytotoxicity against human PANC‐1 pancreatic, Hela cervical, and HepG2 liver cancer cell lines. Ostruthin and its hexyl and heptyl triphenylphosphonium derivatives (4 and 5) showed strong preferential cytotoxicity against PANC‐1 cells with the PC50 values of 10.3 and 14.4 μM, respectively. In addition, compounds 4 and 5 also exhibited potent cytotoxicity towards HeLa cells with the IC50 values of 24.8 and 18.5 μM, respectively. The hexyl triphenylphosphonium group in 4 was found to slightly enhance cytotoxicity against HepG2 cells. Further, the morphological changes and the live‐cell imaging result suggested the anticancer potential against HeLa cells of the synthesized ostruthin derivative 5. [ABSTRACT FROM AUTHOR]

The article presents a cross-sectional study on clinical, radiographic, and genetic characteristics of hypohidrotic ectodermal dysplasia (HED) . Topics include X-ray analyses for patients showed that alveolar ridges in their both jaws were extremely low and mandible was small but normal in shape, and the studied cohort had typical features of HED such as hypotrichosis, hypohidrosis and hypodontia, and mutations in the ectodysplasin A (EDA) gene stated to be present in most tested cases.

Insulin resistance is a prominent feature in heart failure, while hyperglycemia impairs cardiac contraction. We propose that decreased insulin-mediated glucose uptake by the heart preserves cardiac function in response to metabolic and hemodynamic stress. To test this hypothesis, we fed rats a high-sucrose diet (HSD). Energy substrate metabolism and cardiac work were determined ex vivo in a sequential protocol simulating metabolic and hemodynamic stress. Compared to chow-fed, control rats, HSD impaired myocardial insulin responsiveness and induced profound metabolic changes in the heart, characterized by reduced rates of glucose uptake (7.91 ±0.30 vs. 10.73±0.67 µmol/min/g dry weight; P<0.001) but increased rates of glucose oxidation (2.38±0.17 vs. 1.50±0.15 (i.mol/min/g dry weight; P<0.001) and oleate oxidation (2.29±0.11 vs. 1.96±0.12 µmol/min/g dry weight; P<0.05). Tight coupling of glucose uptake and oxidation and improved cardiac efficiency were associated with a reduction in glucose 6-phosphate and oleoyl-CoA levels, as well as a reduction in the content of uncoupling protein 3. Our results suggest that insulin resistance lessens fuel toxicity in the stressed heart. This calls for a new exploration of the mechanisms regulating substrate uptake and oxidation in the insulin-resistant heart. [ABSTRACT FROM AUTHOR]

The flow-field immediately downstream of a collapsible tube during oscillation onset starting from the collapsed state was measured using two-dimensional high-speed particle image velocimetry. Both tube and fluid were chosen to produce oscillation at the lowest possible Reynolds number, of just over 300. The flow was examined in the plane formed by the tube axis extended into the downstream pipe and the major axis of the tube collapse cross-section. The resulting time-series of spatial fields of 2D velocity vectors was analysed by frequency content and by proper orthogonal decomposition. Areas of the flow where oscillation initially occurs were identified. Flow disturbances centred at various frequencies were identified, some associated with the growing oscillation arising from the instability of the fluid–structure interaction between the main flow and the tube and others associated with the instability of the confined twin jets emanating from the collapsed-tube throat. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

An abstract of the article "Direct Carbon-Carbon Bond Formation via Reductive Soft Enolization: A syn-Selective Mannich Addition of α-Iodo Thioesters" by Ngoc Truong and colleagues is presented.

Aim: Mental health problems are a growing challenge in tertiary institutions warranting psycho-educational intervention programmes such as mental health first aid (MHFA) that provide training to identify and support affected individuals. The present study assesses the impact of MHFA interventions on tertiary students and staff. Specifically, we examine (1) MHFA application rates and the types of mental health issues encountered, (2) how MHFA was provided, (3) application of the MHFA action plan, and (4) perceived outcomes of MHFA., Methods: MHFA-trained staff within a tertiary institution were electronically surveyed. Quantitative data were analysed using descriptive statistics, whereas abductive coding yielded qualitative themes., Results: Ninety participants completed the questionnaire (26%). Fifty-seven percentage of respondents had applied MHFA within the tertiary context. All participants reported applying MHFA in response to anxiety or depression at least once. Anxiety (37%) and depression (27%) were the most frequently encountered mental health issues. All participants had administered MHFA face-to-face, with telephone calls (35%) and text messaging (33%) also frequently employed. On average, participants reported completing 4.2 (out of 5) MHFA action plan actions, with 47% completing all actions. Most participants believed that their intervention was helpful (88%) with 65% of recipients seeking professional assistance. Recipients experienced perceived positive affective responses, which were also associated with approach strategies., Conclusions: MHFA is widely applied in the tertiary context through a variety of modes. Most interventions featured at least four of the recommended MHFA action plan actions. The outcomes of MHFA were largely positive, suggesting that MHFA is an effective early intervention in the tertiary context., (© 2020 John Wiley & Sons Australia, Ltd.)

Background: In male pre-pubertal cancer patients, radiation and chemotherapy impact future fertility by eradication of spermatogonial stem cells (SSCs). In macaques, spermatogenesis could be regenerated by intratesticular transplantation of SSCs, but only a small percentage of spermatozoa produced were of donor origin. Transient hormone suppression with a GnRH antagonist (GnRH-ant) enhanced spermatogenic recovery from transplanted SSCs., Objectives: To evaluate donor-derived and endogenous spermatogenic recovery after SSC transplantation into irradiated monkeys and to test whether hormone suppression around the time of transplantation facilitates spermatogenic recovery., Materials and Methods: Testes of 15 adult rhesus monkeys were irradiated with 7 Gy and 4 months later transplanted, to one of the testes, with cryopreserved testicular cells containing SSCs from unrelated monkeys. Monkeys were either treated with GnRH-ant for 8 weeks before transplantation, GnRH-ant from 4 weeks before to 4 weeks after transplantation, or with no GnRH-ant. Tissues were harvested 10 months after transplantation., Results: Two of the 15 monkeys, a control and a pre-transplantation GnRH-ant-treated, showed substantially higher levels of testicular spermatogenesis and epididymal sperm output in the transplanted side as compared to the untransplanted. Over 84% of epididymal spermatozoa on the transplanted side had the donor genotype and were capable of fertilizing eggs after intracytoplasmic sperm injection forming morulae of the donor paternal origin. Low levels of donor spermatozoa (~1%) were also identified in the epididymis of three additional monkeys. Transplantation also appeared to enhance endogenous spermatogenesis., Discussion and Conclusion: We confirmed that SSC transplantation can be used for restoration of fertility in male cancer survivors exposed to irradiation as a therapeutic agent. The success rate of this procedure, however, is low. The success of filling the tubules with the cell suspension, but not the GnRH-ant treatment, was related to the level of colonization by transplanted cells., (© 2020 American Society of Andrology and European Academy of Andrology.)

Academic performance on a standardized oral comprehensive exam (OCE) was compared for students taught basic science in a problem-based learning (PBL) curriculum and a lecture-based learning (LBL) curriculum. The OCE was administered to the graduating classes of 1991-1994 (n approximately 20/class) six months after completion of their basic science courses. The OCE contained six components including: Organization and Thoroughness, Diagnosis, Primary Treatment Plan, Alternate Treatment Plan, Science and Medical Knowledge, and Dental Knowledge. Six to eight examiners graded each of the students by using a standardized scoring system and by subjective comments. The class of 1991 was taught by LBL, classes of 1993 and 1994 by PBL, and the class of 1992 by an incomplete PBL teaching method. Mean OCE scores were not significantly different between classes; however, the Science and Medical Knowledge component score was significantly better for the class of 1994 than for 1991 (p < 0.05). There was a non-significant 40 percent increase (p = 0.07) in honors and a 269 percent (p < 0.001) increase in cumulative positive examiner comments between 1991 and 1994.