Predicted climate change-induced increases in heat waves and hypoxic events will have profound effects on fishes, yet the capacity of parents to alter offspring phenotype via non-genetic inheritance ...and buffer against these combined stressors is not clear. This study tested how prolonged adult zebrafish exposure to combined diel cycles of thermal stress and hypoxia affect offspring early survival and development, parental investment of cortisol and heat shock proteins (HSPs), larval offspring stress responses, and both parental and offspring heat and hypoxia tolerance. Parental exposure to the combined stressor did not affect fecundity, but increased mortality, produced smaller embryos and delayed hatching. The combined treatment also reduced maternal deposition of cortisol and increased embryo hsf1, hsp70a, HSP70, hsp90aa and HSP90 levels. In larvae, basal cortisol levels did not differ between treatments, but acute exposure to combined heat stress and hypoxia increased cortisol levels in control larvae with no effect on larvae from exposed parents. In contrast, whereas larval basal hsf1, hsp70a and hsp90aa levels differed between parental treatments, the combined acute stressor elicited similar transcriptional responses across treatments. Moreover, the combined acute stressor only induced a marked increase in HSP47 levels in the larvae derived from exposed parents. Finally, combined hypoxia and elevated temperatures increased both thermal and hypoxia tolerance in adults and conferred an increase in offspring thermal but not hypoxia tolerance. These results demonstrate that intergenerational acclimation to combined thermal stress and hypoxia elicit complex carryover effects on stress responsiveness and offspring tolerance with potential consequences for resilience.
shows a strict host tropism for reticulocytes. We identified transferrin receptor 1 (TfR1) as the receptor for
reticulocyte-binding protein 2b (PvRBP2b). We determined the structure of the N-terminal ...domain of PvRBP2b involved in red blood cell binding, elucidating the molecular basis for TfR1 recognition. We validated TfR1 as the biological target of PvRBP2b engagement by means of TfR1 expression knockdown analysis. TfR1 mutant cells deficient in PvRBP2b binding were refractory to invasion of
but not to invasion of
Using Brazilian and Thai clinical isolates, we show that PvRBP2b monoclonal antibodies that inhibit reticulocyte binding also block
entry into reticulocytes. These data show that TfR1-PvRBP2b invasion pathway is critical for the recognition of reticulocytes during
invasion.
The maternal match hypothesis predicts that maternal exposure to a stressor may help prepare offspring to cope with the same disturbance in later life. Although there is support for this hypothesis, ...the signals involved in non-genetic inheritance are unclear. In this study, we tested how adult zebrafish exposure to diel cycles of thermal stress (27-36°C), hypoxia (20-85% dissolved oxygen) or the combined treatment affects maternal and embryonic levels of cortisol and heat shock proteins (HSPs). While parental exposure to the thermal, hypoxic or combined treatment for 2 weeks did not affect whole-body cortisol levels, the combined exposure increased ovarian cortisol levels by 4-fold and reduced embryonic cortisol content by 60%. The combined treatment also elicited 3- and 19-fold increases in embryo transcripts involved in cortisol breakdown (11bhsd2) and export (abcb4), respectively. The thermal stress and combined exposure also elicited marked increases in ovary and embryo hsp70a (20- to 45-fold) and HSP70 (3- to 7-fold), and smaller increases in ovary and embryo hsp90aa and hsp47 (2- to 4-fold) and in embryo HSP90 and HSP47 (2- to 6-fold). In contrast, except for increases in ovary hsp90aa (2-fold) and embryo HSP90 (3-fold), the hypoxia treatment had little effect on HSP expression and transfer. Overall, while the embryonic deposition of HSPs largely paralleled the ovarian cellular stress response, the inverse relationship between ovary and embryo cortisol levels suggests the existence of barriers against cortisol deposition in response to environmental stressors. We conclude that the endocrine and cellular stress responses make stressor-specific and distinct contributions to non-genetic inheritance.
Fluctuating incubation temperatures may have significant effects on fish embryogenesis; yet most laboratory-based studies use constant temperatures. For species that experience large, natural ...seasonal temperature changes during embryogenesis, such as lake whitefish (Coregonus clupeaformis), seasonal temperature regimes are likely optimal for development. Anthropogenic activities can increase average and/or variability of natural incubation temperatures over large (e.g. through climate change) or smaller (e.g. thermal effluent discharge) geographic scales. To investigate this, we incubated lake whitefish embryos under constant (2, 5, or 8°C) and fluctuating temperature regimes. Fluctuating temperature regimes had a base temperature of 2°C with: 1) seasonal temperature changes that modeled natural declines/inclines; 2) tri-weekly +3°C, 1h temperature spikes; or 3) both seasonal temperature changes and temperature spikes. We compared mortality to hatch, morphometrics, and heart rate at three developmental stages. Mortality rate was similar for embryos incubated at constant 2°C, constant 5°C, or with seasonal temperatures, but was significantly greater at constant 8°C. Embryos incubated constantly at >2°C had reduced body growth and yolk consumption compared to embryos incubated with seasonal temperature changes. When measured at the common base temperature of 2°C, embryos incubated at constant 2°C had lower heart rates than embryos incubated with both seasonal temperature changes and temperature spikes. Our study suggests that incubating lake whitefish embryos with constant temperatures may significantly alter development, growth, and heart rate compared to incubating with seasonal temperature changes, emphasizing the need to include seasonal temperature changes in laboratory-based studies.
The T790M mutation in the epidermal growth factor receptor gene causes most acquired resistance to firstor second-line epidermal growth factor receptor-tyrosine kinase inhibitors in advanced ...non-small-cell lung cancer. The results of T790M testing can guide subsequent treatment. Despite the availability of guidelines from international organisations, T790M testing practices in Hong Kong must be streamlined and adapted to the Hospital Authority setting. To address this issue, a panel of experts in oncology and pathology met for discussion of key topics regarding T790M testing practices in Hong Kong, including the appropriate timing of testing and re-testing, as well as optimal testing methods. All panel members voted on the results of the discussion to achieve consensus. Items supported by a majority vote were adopted as consensus statements regarding current best practices for T790M testing in Hong Kong. Among the topics discussed, the panel agreed that T790M testing should be initiated upon radiological progression, including symptomatic disease progression or central nervous system-only progression. The experts also preferred initial testing with liquid biopsy, using the widely available digital polymerase chain reaction platform. This document provides the final consensus statements, as well as a testing and treatment workflow, for clinicians in Hong Kong to use as guidance in T790M testing.
Linear erythematous rash over the trunk Kunaseelan, Shangari; Al‐Jabri, Majid; Goh, Daniel YT ...
Journal of paediatrics and child health,
12/2022
Journal Article
Intravenous anti–PD-L1 durvalumab therapy can safely be combined with intravesical bacillus Calmette-Guerin (BCG) treatments or a short-course of bladder-focused external beam radiation therapy (6 Gy ...× 3) in BCG-unresponsive non–muscle-invasive bladder cancer patients. Encouraging preliminary efficacy requires validation.
Novel treatments and trial designs remain a high priority for bacillus Calmette-Guerin (BCG)-unresponsive non–muscle-invasive bladder cancer (NMIBC) patients.
To evaluate the safety and preliminary efficacy of anti–PD-L1 directed therapy with durvalumab (D), durvalumab plus BCG (D + BCG), and durvalumab plus external beam radiation therapy (D + EBRT).
A multicenter phase 1 trial was conducted at community and academic sites.
Patients received 1120 mg of D intravenously every 3 wk for eight cycles. D + BCG patients also received full-dose intravesical BCG weekly for 6 wk with BCG maintenance recommended. D + EBRT patients received concurrent EBRT (6 Gy × 3 in cycle 1 only).
Post-treatment cystoscopy and urine cytology were performed at 3 and 6 –mo, with bladder biopsies required at the 6-mo evaluation. The recommended phase 2 dose (RP2D) for each regimen was the primary endpoint. Secondary endpoints included toxicity profiles and complete response (CR) rates.
Twenty-eight patients were treated in the D (n = 3), D + BCG (n = 13), and D + EBRT (n = 12) cohorts. Full-dose D, full-dose BCG, and 6 Gy fractions × 3 were determined as the RP2Ds. One patient (4%) experienced a grade 3 dose limiting toxicity event of autoimmune hepatitis. The 3-mo CR occurred in 64% of all patients and in 33%, 85%, and 50% within the D, D + BCG, and D + EBRT cohorts, respectively. Twelve-month CRs were achieved in 46% of all patients and in 73% of D + BCG and 33% of D + EBRT patients.
D combined with intravesical BCG or EBRT proved feasible and safe in BCG-unresponsive NMIBC patients. Encouraging preliminary efficacy justifies further study of combination therapy approaches.
Durvalumab combination therapy can be safely administered to non–muscle-invasive bladder cancer patients with the goal of increasing durable response rates.
Since 2016 there has been a 20-fold increase in known burns injury from personal mobility device (PMD) related fires. The root cause is the failure of high-density lithium ion (Li-ion) battery packs ...powering the PMDs. This failure process, known as thermal runaway, is well documented in applied science journals. Importantly, the liberation of hydrogen fluoride from failing Li-ion batteries may contribute to unrecognized chemical burns. A clinical gap in knowledge exists in the understanding of the explosive nature of Li-ion batteries. We reviewed the electrochemical pathophysiology of a failing Li-ion cell as it impacts clinical management of burn injuries. This retrospective study was carried out in two major institutions in Singapore. All admitted PMD-related burns and follow up appointments were captured and reviewed from 2016 - 2020. Thirty patients were admitted to tertiary hospitals, 43% of patients were in the pediatric population and 57% were adult patients, aged from 0.3 to 77 years. TBSA of burns ranged from 0 to 80% with a mean 14.5%. 73% of cases presented with inhalation injury, 8 of whom did not suffer any cutaneous burns. 50% of patients sustained both cutaneous and inhalation burn injuries. 27% of patients sustained major burns of >20% TBSA, with 2 in the pediatric group. Mortali ty rate was 10% from PMD-related fires. This cause of burn injury has proven to be fa tal. Prevention of PMD-related fires by ensuring proper battery utilization, adherence to PMD sanctions for battery standards and public education is vital to reducing the morbidity and mortality of this unique type of thermal injury.
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