Therkildsenchristiansen4738

BNIP3 is a mitophagy receptor with context-dependent roles in cancer, but whether and how it modulates melanoma growth in vivo remains unknown. Here, we found that elevated BNIP3 levels correlated with poorer melanoma patient's survival and depletion of BNIP3 in B16-F10 melanoma cells compromised tumor growth in vivo. BNIP3 depletion halted mitophagy and enforced a PHD2-mediated downregulation of HIF-1α and its glycolytic program both in vitro and in vivo. Mechanistically, we found that BNIP3-deprived melanoma cells displayed increased intracellular iron levels caused by heightened NCOA4-mediated ferritinophagy, which fostered PHD2-mediated HIF-1α destabilization. These effects were not phenocopied by ATG5 or NIX silencing. Restoring HIF-1α levels in BNIP3-depleted melanoma cells rescued their metabolic phenotype and tumor growth in vivo, but did not affect NCOA4 turnover, underscoring that these BNIP3 effects are not secondary to HIF-1α. These results unravel an unexpected role of BNIP3 as upstream regulator of the pro-tumorigenic HIF-1α glycolytic program in melanoma cells.The absolute number of Never Events is used by UK regulators to help assess hospital safety performance, without account of hospital workload. We applied funnel plots, as an established means of taking workload into account, to published Never Event data for 151 acute Trusts in NHS England, matched to finished consultant episodes for 3 years, 2017-2020. Trusts with excess event rates should have the most Never Events if absolute number is a valid way to judge performance. The absolute number of Never Events was correlated with workload (r2 = 0.51, p less then 0.001), but the five Trusts above the upper 95% confidence limit did not have the highest number of Never Events. However, a limitation to interpretation was that the data were skewed; 12 out of 151 Trusts lay below the lower 95% limit. This skew probably arises because funnel plots pool all Never Events and workload data; whereas, ideally, different Never Events should use as denominator only the relevant workload actions that could cause them. We conclude that the manner in which Never Event data are currently used by regulators, in part to judge or rate hospitals, is mathematically invalid. The focus should shift from identifying 'outlier' hospitals to reducing the overall national mean Never Event rate through shared learning and an integrated system-wide approach.Nitro groups are often associated with synthetically manufactured compounds such as medicines and explosives, and rarely with natural products. Loquat emits a nitro compound, (2-nitroethyl)benzene, as a flower scent. The nitro compound exhibits fungistatic activity and is biosynthesised from l-phenylalanine via (E/Z)-phenylacetaldoxime. Although aldoxime-producing CYP79s have been intensively studied, it is unclear what enzymes form nitro groups from aldoximes either in plants or in other organisms. Here, we report the identification of two cytochrome P450s that are likely to be involved in (2-nitroethyl)benzene biosynthesis in loquat through differential gene expression analysis using RNA-seq and functional identification using yeast and tobacco. CYP79D80 and CYP94A90 catalysed the formation of (E/Z)-phenylacetaldoxime from l-phenylalanine and (2-nitroethyl)benzene from the aldoxime, respectively. Expression profiles of CYP79D80 and CYP94A90 were correlated with the emission of (2-nitroethyl)benzene from loquat flowers. CYP94A90 also functioned as a fatty acid ω-hydroxylase as do other CYP94A fatty acid ω-hydroxylases. The CYP94As tested from other plants were all found to catalyse the formation of (2-nitroethyl)benzene from (E/Z)-phenylacetaldoxime. CYP79D80 and CYP94A90 are likely to operate in concert to biosynthesise (2-nitroethyl)benzene in loquat. CYP94A90 and other CYP94As are 'promiscuous fatty acid ω-hydroxylases', catalysing the formation of nitro groups from aldoximes, and are widely distributed in dicot plants.

Nelfinavir (NFV), an HIV-1 protease inhibitor, has been shown to sensitize cancer cells to chemoradiation (CRT). The objectives of this phase 1 trial were to evaluate safety and identify the recommended phase 2 dose of NFV added to concurrent CRT for locally advanced cervical cancer.

Two dose levels of NFV were evaluated 875 mg orally twice daily (dose level 1 [DL1]) and 1250 mg twice daily (DL2). NFV was initiated 7 days before CRT and continued through CRT completion. Toxicity, radiographic responses, and pathologic responses were evaluated. Serial tumor biopsies (baseline, after NFV monotherapy, on NFV + CRT, and posttreatment) were evaluated by immunohistochemistry, NanoString, and reverse-phase-protein-array analyses.

NFV sensitized cervical cancer cells to radiation, increasing apoptosis and tumor suppression in vivo. find more Patients (n = 13) with International Federation of Gynecology and Obstetrics stage IIA through IVA squamous cell cervical carcinoma were enrolled, including 7 patients at DL1 and 6 patients at DL2. At DL1, expansion to 6 patients was required after a patient developed a dose-limiting toxicity, whereas no dose-limiting toxicities occurred at DL2. Therefore, DL2 was established as the recommended phase 2 dose. All patients at DL2 completed CRT, and 1 of 6 experienced grade 3 or 4 anemia, nausea, and diarrhea. One recurrence was noted at DL2, with disease outside the radiation field. Ten of 11 evaluable patients remained without evidence of disease at a median follow-up of 50 months. NFV significantly decreased phosphorylated Akt levels in tumors. Cell cycle and cancer pathways also were reduced by NFV and CRT.

NFV with CRT is well tolerated. The response rate is promising compared with historic controls in this patient population and warrants further investigation.

NFV with CRT is well tolerated. The response rate is promising compared with historic controls in this patient population and warrants further investigation.Concerns regarding both the limited generalizability and the slow pace of traditional randomized trials have led to calls for greater use of real-world evidence (RWE) in the evaluation of new treatments or products. RWE studies often rely on real-world data (RWD), including data extracted from healthcare records or data captured by mobile phones or other consumer devices. Global assessments of RWD sources are not helpful in assessing whether any specific RWD element is fit for any specific purpose. Instead, evidence generators and evidence consumers should clearly identify the specific health state or clinical phenomenon of interest and then consider each step between that clinical phenomenon and its representation in a research database. We propose specific questions regarding potential error or bias affecting each of those steps Would a person experiencing this clinical phenomenon present for care in this setting or interact with this recording device? Would this clinical phenomenon be accurately recognized or assessed? How might the recording environment or tools affect accurate and consistent recording of this clinical phenomenon? Can data elements from different sources be harmonized, both technically (same format) and semantically (same meaning)? Can the original data elements be consistently reduced to a useful clinical phenotype? Addressing these questions requires a range of clinical, organizational, and technical expertise.