Lineage plasticity has emerged as an important mechanism of treatment resistance in prostate cancer. Treatment-refractory prostate cancers are increasingly associated with loss of luminal prostate ...markers, and in many cases induction of developmental programs, stem cell-like phenotypes, and neuroendocrine/neuronal features. Clinically, lineage plasticity may manifest as low PSA progression, resistance to androgen receptor (AR) pathway inhibitors, and sometimes small cell/neuroendocrine pathologic features observed on metastatic biopsy. This mechanism is not restricted to prostate cancer as other malignancies also demonstrate lineage plasticity during resistance to targeted therapies. At present, there is no established therapeutic approach for patients with advanced prostate cancer developing lineage plasticity or small cell neuroendocrine prostate cancer (NEPC) due to knowledge gaps in the underlying biology. Few clinical trials address questions in this space, and the outlook for patients remains poor. To move forward, urgently needed are: (i) a fundamental understanding of how lineage plasticity occurs and how it can best be defined; (ii) the temporal contribution and cooperation of emerging drivers; (iii) preclinical models that recapitulate biology of the disease and the recognized phenotypes; (iv) identification of therapeutic targets; and (v) novel trial designs dedicated to the entity as it is defined. This Perspective represents a consensus arising from the NCI Workshop on Lineage Plasticity and Androgen Receptor-Independent Prostate Cancer. We focus on the critical questions underlying lineage plasticity and AR-independent prostate cancer, outline knowledge and resource gaps, and identify strategies to facilitate future collaborative clinical translational and basic studies in this space.
In a single-group trial, 48 children with severe heart failure received a ventricular assist device designed for children. Survival rates were significantly higher in this group than among ...propensity-score–matched children receiving support with extracorporeal membrane oxygenation.
Systolic heart failure causes 280,000 deaths in adults annually in the United States.
1
Heart failure is much less common among children than among adults, but it is highly lethal, with 46% of children with heart failure dying or undergoing transplantation within 5 years after diagnosis, according to one estimate.
2
The survival rate among children after heart transplantation is estimated at 83% at 3 years,
3
,
4
but the limited availability of donor hearts for children prolongs the waiting period,
5
resulting in a high rate of death among children on waiting lists.
6
–
8
Options for mechanical circulatory support as a bridge to . . .
To provide evidence-based guidance on the clinical management of cancer cachexia in adult patients with advanced cancer.
A systematic review of the literature collected evidence regarding ...nutritional, pharmacologic, and other interventions, such as exercise, for cancer cachexia. PubMed and the Cochrane Library were searched for randomized controlled trials (RCTs) and systematic reviews of RCTs published from 1966 through October 17, 2019. ASCO convened an Expert Panel to review the evidence and formulate recommendations.
The review included 20 systematic reviews and 13 additional RCTs. Dietary counseling, with or without oral nutritional supplements, was reported to increase body weight in some trials, but evidence remains limited. Pharmacologic interventions associated with improvements in appetite and/or body weight include progesterone analogs and corticosteroids. The other evaluated interventions either had no benefit or insufficient evidence of benefit to draw conclusions on efficacy. Limitations of the evidence include high drop-out rates, consistent with advanced cancer, as well as variability across studies in outcomes of interest and methods for outcome assessment.
Dietary counseling may be offered with the goals of providing patients and caregivers with advice for the management of cachexia. Enteral feeding tubes and parenteral nutrition should not be used routinely. In the absence of more robust evidence, no specific pharmacological intervention can be recommended as the standard of care; therefore, clinicians may choose not to prescribe medications specifically for the treatment of cancer cachexia. Nonetheless, when it is decided to trial a drug to improve appetite and/or improve weight gain, currently available pharmacologic interventions that may be used include progesterone analogs and short-term (weeks) corticosteroids.
Purpose
Current reports on acute kidney injury (AKI) in the intensive care unit (ICU) show wide variation in occurrence rate and are limited by study biases such as use of incomplete AKI definition, ...selected cohorts, or retrospective design. Our aim was to prospectively investigate the occurrence and outcomes of AKI in ICU patients.
Methods
The Acute Kidney Injury–Epidemiologic Prospective Investigation (AKI-EPI) study was an international cross-sectional study performed in 97 centers on patients during the first week of ICU admission. We measured AKI by Kidney Disease: Improving Global Outcomes (KDIGO) criteria, and outcomes at hospital discharge.
Results
A total of 1032 ICU patients out of 1802 57.3 %; 95 % confidence interval (CI) 55.0–59.6 had AKI. Increasing AKI severity was associated with hospital mortality when adjusted for other variables; odds ratio of stage 1 = 1.679 (95 % CI 0.890–3.169;
p
= 0.109), stage 2 = 2.945 (95 % CI 1.382–6.276;
p
= 0.005), and stage 3 = 6.884 (95 % CI 3.876–12.228;
p
< 0.001). Risk-adjusted rates of AKI and mortality were similar across the world. Patients developing AKI had worse kidney function at hospital discharge with estimated glomerular filtration rate less than 60 mL/min/1.73 m
2
in 47.7 % (95 % CI 43.6–51.7) versus 14.8 % (95 % CI 11.9–18.2) in those without AKI,
p
< 0.001.
Conclusions
This is the first multinational cross-sectional study on the epidemiology of AKI in ICU patients using the complete KDIGO criteria. We found that AKI occurred in more than half of ICU patients. Increasing AKI severity was associated with increased mortality, and AKI patients had worse renal function at the time of hospital discharge. Adjusted risks for AKI and mortality were similar across different continents and regions.
Mycobacterium tuberculosis, the leading cause of death due to infection, has a dynamic and immunomodulatory cell envelope. The cell envelope structurally and functionally varies across the length of ...the cell and during the infection process. This variability allows the bacterium to manipulate the human immune system, tolerate antibiotic treatment and adapt to the variable host environment. Much of what we know about the mycobacterial cell envelope has been gleaned from model actinobacterial species, or model conditions such as growth in vitro, in macrophages and in the mouse. In this Review, we combine data from different experimental systems to build a model of the dynamics of the mycobacterial cell envelope across space and time. We describe the regulatory pathways that control metabolism of the cell wall and surface lipids in M. tuberculosis during growth and stasis, and speculate about how this regulation might affect antibiotic susceptibility and interactions with the immune system.
Severe acute respiratory syndrome virus (SARS-CoV-2) has infected millions of people worldwide. Our goal was to identify risk factors associated with admission and disease severity in patients with ...SARS-CoV-2.
This was an observational, retrospective study based on real-world data for 7,995 patients with SARS-CoV-2 from a clinical data repository.
Yale New Haven Health (YNHH) is a five-hospital academic health system serving a diverse patient population with community and teaching facilities in both urban and suburban areas.
The study included adult patients who had SARS-CoV-2 testing at YNHH between March 1 and April 30, 2020.
Primary outcomes were admission and in-hospital mortality for patients with SARS-CoV-2 infection as determined by RT-PCR testing. We also assessed features associated with the need for respiratory support.
Of the 28605 patients tested for SARS-CoV-2, 7995 patients (27.9%) had an infection (median age 52.3 years) and 2154 (26.9%) of these had an associated admission (median age 66.2 years). Of admitted patients, 2152 (99.9%) had a discharge disposition at the end of the study period. Of these, 329 (15.3%) required invasive mechanical ventilation and 305 (14.2%) expired. Increased age and male sex were positively associated with admission and in-hospital mortality (median age 80.7 years), while comorbidities had a much weaker association with the risk of admission or mortality. Black race (OR 1.43, 95%CI 1.14-1.78) and Hispanic ethnicity (OR 1.81, 95%CI 1.50-2.18) were identified as risk factors for admission, but, among discharged patients, age-adjusted in-hospital mortality was not significantly different among racial and ethnic groups.
This observational study identified, among people testing positive for SARS-CoV-2 infection, older age and male sex as the most strongly associated risks for admission and in-hospital mortality in patients with SARS-CoV-2 infection. While minority racial and ethnic groups had increased burden of disease and risk of admission, age-adjusted in-hospital mortality for discharged patients was not significantly different among racial and ethnic groups. Ongoing studies will be needed to continue to evaluate these risks, particularly in the setting of evolving treatment guidelines.
Summary Background The effect of many contemporary chemotherapeutic drugs on pregnancy and livebirth is not well established. We aimed to establish the effects of these drugs on pregnancy in male and ...female survivors of childhood cancer not exposed to pelvic or cranial radiotherapy. Methods We used data from a subset of the Childhood Cancer Survivor Study cohort, which followed 5-year survivors of the most common types of childhood cancer who were diagnosed before age 21 years and treated at 27 institutions in the USA and Canada between 1970 and 1999. We extracted doses of 14 alkylating and similar DNA interstrand crosslinking drugs from medical records. We used sex-specific Cox models to establish the independent effects of each drug and the cumulative cyclophosphamide equivalent dose of all drugs in relation to pregnancies and livebirths occurring between ages 15 years and 44 years. We included siblings of survivors as a comparison group. Findings We included 10 938 survivors and 3949 siblings. After a median follow-up of 8 years (IQR 4–12) from cohort entry or at age 15 years, whichever was later, 4149 (38%) survivors reported having or siring a pregnancy, of whom 3453 (83%) individuals reported at least one livebirth. After a median follow-up of 10 years (IQR 6–15), 2445 (62%) siblings reported having or siring a pregnancy, of whom 2201 (90%) individuals reported at least one livebirth. In multivariable analysis, survivors had a decreased likelihood of siring or having a pregnancy versus siblings (male survivors: hazard ratio HR 0·63, 95% CI 0·58–0·68; p<0·0001; female survivors: 0·87, 0·81–0·94; p<0·0001) or of having a livebirth (male survivors: 0·63, 0·58–0·69; p<0·0001; female survivors: 0·82, 0·76–0·89; p<0·0001). In male survivors, reduced likelihood of pregnancy was associated with upper tertile doses of cyclophosphamide (HR 0·60, 95% CI 0·51–0·71; p<0·0001), ifosfamide (0·42, 0·23–0·79; p=0·0069), procarbazine (0·30, 0·20–0·46; p<0·0001) and cisplatin (0·56, 0·39–0·82; p=0·0023). Cyclophosphamide equivalent dose in male survivors was significantly associated with a decreased likelihood of siring a pregnancy (per 5000 mg/m2 increments: HR 0·82, 95% CI 0·79–0·86; p<0·0001). However, in female survivors, only busulfan (<450 mg/m2 HR 0·22, 95% CI 0·06–0·79; p=0·020; ≥450 mg/m2 0·14, 0·03–0·55; p=0·0051) and doses of lomustine equal to or greater than 411 mg/m2 (0·41, 0·17–0·98; p=0·046) were significantly associated with reduced pregnancy; cyclophosphamide equivalent dose was associated with risk only at the highest doses in analyses categorised by quartile (upper quartile vs no exposure: HR 0·85, 95% CI 0·74–0·98; p=0·023). Results for livebirth were similar to those for pregnancy. Interpretation Greater doses of contemporary alkylating drugs and cisplatin were associated with a decreased likelihood of siring a pregnancy in male survivors of childhood cancer. However, our findings should provide reassurance to most female survivors treated with chemotherapy without radiotherapy to the pelvis or brain, given that chemotherapy-specific effects on pregnancy were generally few. Nevertheless, consideration of fertility preservation before cancer treatment remains important to maximise the reproductive potential of all adolescents newly diagnosed with cancer. Funding National Cancer Institute, National Institutes of Health, and the American Lebanese–Syrian Associated Charities.
Summary Background Treatment-resistant major depression is common and potentially life-threatening in elderly people, in whom little is known about the benefits and risks of augmentation ...pharmacotherapy. We aimed to assess whether aripiprazole is associated with a higher probability of remission than is placebo. Methods We did a randomised, double-blind, placebo-controlled trial at three centres in the USA and Canada to test the efficacy and safety of aripiprazole augmentation for adults aged older than 60 years with treatment-resistant depression (Montgomery Asberg Depression Rating Scale MADRS score of ≥15). Patients who did not achieve remission during a pre-trial with venlafaxine extended-release (150–300 mg/day) were randomly assigned (1:1) to the addition of aripiprazole (target dose 10 mg maximum 15 mg daily) daily or placebo for 12 weeks. The computer-generated randomisation was done in blocks and stratified by site. Only the database administrator and research pharmacists had knowledge of treatment assignment. The primary endpoint was remission, defined as an MADRS score of 10 or less (and at least 2 points below the score at the start of the randomised phase) at both of the final two consecutive visits, analysed by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00892047. Findings From July 20, 2009, to Dec 30, 2013, we recruited 468 eligible participants, 181 (39%) of whom did not remit and were randomly assigned to aripiprazole (n=91) or placebo (n=90). A greater proportion of participants in the aripiprazole group achieved remission than did those in the placebo group (40 44% vs 26 29% participants; odds ratio OR 2·0 95% CI 1·1–3·7, p=0·03; number needed to treat NNT 6·6 95% CI 3·5–81·8). Akathisia was the most common adverse effect of aripiprazole (reported in 24 26% of 91 participants on aripiprazole vs 11 12% of 90 on placebo). Compared with placebo, aripiprazole was also associated with more Parkinsonism (15 17% of 86 vs two 2% of 81 participants), but not with treatment-emergent suicidal ideation (13 21% of 61 vs 19 29% of 65 participants) or other measured safety variables. Interpretation In adults aged 60 years or older who do not achieve remission from depression with a first-line antidepressant, the addition of aripiprazole is effective in achieving and sustaining remission. Tolerability concerns include the potential for akathisia and Parkinsonism. Funding National Institute of Mental Health, UPMC Endowment in Geriatric Psychiatry, Taylor Family Institute for Innovative Psychiatric Research, National Center for Advancing Translational Sciences, and the Campbell Family Mental Health Research Institute.
Insulin-like peptides (ILPs) couple growth, metabolism, longevity, and fertility with changes in nutritional availability. In
Drosophila, several ILPs called Dilps are produced by the brain ...insulin-producing cells (IPCs), from which they are released into the hemolymph and act systemically. We show here that in response to nutrient deprivation, brain Dilps are no longer secreted and accumulate in the IPCs. We further demonstrate that the larval fat body, a functional homolog of vertebrate liver and white fat, couples the level of circulating Dilps with dietary amino acid levels by remotely controlling Dilp release through a TOR/RAPTOR-dependent mechanism. We finally use ex vivo tissue coculture to demonstrate that a humoral signal emitted by the fat body transits through the hemolymph and activates Dilp secretion in the IPCs. Thus, the availability of nutrients is remotely sensed in fat body cells and conveyed to the brain IPCs by a humoral signal controlling ILP release.
C99 is the transmembrane carboxyl-terminal domain of the amyloid precursor protein that is cleaved by γ-secretase to release the amyloid-β polypeptides, which are associated with Alzheimer's disease. ...Nuclear magnetic resonance and electron paramagnetic resonance spectroscopy show that the extracellular amino terminus of C99 includes a surface-embedded "N-helix" followed by a short "N-loop" connecting to the transmembrane domain (TMD). The TMD is a flexibly curved a helix, making it well suited for processive cleavage by γ-secretase. Titration of C99 reveals a binding site for cholesterol, providing mechanistic insight into how cholesterol promotes amyloidogenesis. Membrane-buried GXXXG motifs (G, Gly; X, any amino acid), which have an established role in oligomerization, were also shown to play a key role in cholesterol binding. The structure and cholesterol binding properties of C99 may aid in the design of Alzheimer's therapeutics.
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