Cancer cells characteristically consume glucose through Warburg metabolism
, a process that forms the basis of tumour imaging by positron emission tomography (PET). Tumour-infiltrating immune cells ...also rely on glucose, and impaired immune cell metabolism in the tumour microenvironment (TME) contributes to immune evasion by tumour cells
. However, whether the metabolism of immune cells is dysregulated in the TME by cell-intrinsic programs or by competition with cancer cells for limited nutrients remains unclear. Here we used PET tracers to measure the access to and uptake of glucose and glutamine by specific cell subsets in the TME. Notably, myeloid cells had the greatest capacity to take up intratumoral glucose, followed by T cells and cancer cells, across a range of cancer models. By contrast, cancer cells showed the highest uptake of glutamine. This distinct nutrient partitioning was programmed in a cell-intrinsic manner through mTORC1 signalling and the expression of genes related to the metabolism of glucose and glutamine. Inhibiting glutamine uptake enhanced glucose uptake across tumour-resident cell types, showing that glutamine metabolism suppresses glucose uptake without glucose being a limiting factor in the TME. Thus, cell-intrinsic programs drive the preferential acquisition of glucose and glutamine by immune and cancer cells, respectively. Cell-selective partitioning of these nutrients could be exploited to develop therapies and imaging strategies to enhance or monitor the metabolic programs and activities of specific cell populations in the TME.
Background. The clinical relevance of detecting minority drug-resistant human immunodeficiency virus type 1 (HIV-1) variants is uncertain. Methods. To determine the effect of pre-existing minority ...nonnucleoside reverse-transcriptase inhibitor (NNRTI)-resistant variants on the risk of virologic failure, we reanalyzed a case-cohort substudy of efavirenz recipients in AIDS Clinical Trials Group protocol A5095. Minority K103N or Y181C populations were determined by allele-specific polymerase chain reaction in subjects without NNRTI resistance by population sequencing. Weighted Cox proportional hazards models adjusted for recent treatment adherence estimated the relative risk of virologic failure in the presence of NNRTI-resistant minority variants. Results. The evaluable case-cohort sample included 195 subjects from the randomly selected subcohort (51 with virologic failure, 144 without virologic failure), plus 127 of the remaining subjects who experienced virologic failure. Presence of minority K103N or Y181C mutations, or both, was detected in 8 (4.4%), 54 (29.5%), and 11 (6%), respectively, of 183 evaluable subjects in the random subcohort. Detection of minority Y181C mutants was associated with an increased risk of virologic failure in the setting of recent treatment adherence (hazard ratio, 3.45 95% confidence interval, 1.90–6.26) but not in nonadherent subjects (hazard ratio, 1.39 95% confidence interval, 0.58–3.29). Of note, 70% of subjects with minority Y181C variants achieved long-term viral suppression. Conclusions. In adherent patients, pre-existing minority Y181C mutants more than tripled the risk of virologic failure of first-line efavirenz-based antiretroviral therapy. Clinical trials registration. NCT00013520.
Vaccines prevent infectious disease largely by inducing protective neutralizing antibodies against vulnerable epitopes. Several major pathogens have resisted traditional vaccine development, although ...vulnerable epitopes targeted by neutralizing antibodies have been identified for several such cases. Hence, new vaccine design methods to induce epitope-specific neutralizing antibodies are needed. Here we show, with a neutralization epitope from respiratory syncytial virus, that computational protein design can generate small, thermally and conformationally stable protein scaffolds that accurately mimic the viral epitope structure and induce potent neutralizing antibodies. These scaffolds represent promising leads for the research and development of a human respiratory syncytial virus vaccine needed to protect infants, young children and the elderly. More generally, the results provide proof of principle for epitope-focused and scaffold-based vaccine design, and encourage the evaluation and further development of these strategies for a variety of other vaccine targets, including antigenically highly variable pathogens such as human immunodeficiency virus and influenza.
Urothelial carcinomas of the upper urinary tract (UTUCs) are rare, with poorer stage-for-stage prognosis than urothelial carcinomas of the urinary bladder. No international consensus exists on the ...benefit of adjuvant chemotherapy for patients with UTUCs after nephroureterectomy with curative intent. The POUT (Peri-Operative chemotherapy versus sUrveillance in upper Tract urothelial cancer) trial aimed to assess the efficacy of systemic platinum-based chemotherapy in patients with UTUCs.
We did a phase 3, open-label, randomised controlled trial at 71 hospitals in the UK. We recruited patients with UTUC after nephroureterectomy staged as either pT2–T4 pN0–N3 M0 or pTany N1–3 M0. We randomly allocated participants centrally (1:1) to either surveillance or four 21-day cycles of chemotherapy, using a minimisation algorithm with a random element. Chemotherapy was either cisplatin (70 mg/m2) or carboplatin (area under the curve AUC4·5/AUC5, for glomerular filtration rate <50 mL/min only) administered intravenously on day 1 and gemcitabine (1000 mg/m2) administered intravenously on days 1 and 8; chemotherapy was initiated within 90 days of surgery. Follow-up included standard cystoscopic, radiological, and clinical assessments. The primary endpoint was disease-free survival analysed by intention to treat with a Peto-Haybittle stopping rule for (in)efficacy. The trial is registered with ClinicalTrials.gov, NCT01993979. A preplanned interim analysis met the efficacy criterion for early closure after recruitment of 261 participants.
Between June 19, 2012, and Nov 8, 2017, we enrolled 261 participants from 57 of 71 open study sites. 132 patients were assigned chemotherapy and 129 surveillance. One participant allocated chemotherapy withdrew consent for data use after randomisation and was excluded from analyses. Adjuvant chemotherapy significantly improved disease-free survival (hazard ratio 0·45, 95% CI 0·30–0·68; p=0·0001) at a median follow-up of 30·3 months (IQR 18·0–47·5). 3-year event-free estimates were 71% (95% CI 61–78) and 46% (36–56) for chemotherapy and surveillance, respectively. 55 (44%) of 126 participants who started chemotherapy had acute grade 3 or worse treatment-emergent adverse events, which accorded with frequently reported events for the chemotherapy regimen. Five (4%) of 129 patients managed by surveillance had acute grade 3 or worse emergent adverse events. No treatment-related deaths were reported.
Gemcitabine–platinum combination chemotherapy initiated within 90 days after nephroureterectomy significantly improved disease-free survival in patients with locally advanced UTUC. Adjuvant platinum-based chemotherapy should be considered a new standard of care after nephroureterectomy for this patient population.
Cancer Research UK.
The gold‐catalyzed enantioselective hydroazidation and hydroamination reactions of allenes are presented herein. ADC gold(I) catalysts derived from BINAM were critical for achieving high levels of ...enantioselectivity in both transformations. The sense of enantioinduction is reversed for the two different nucleophiles, allowing access to both enantiomers of the corresponding allylic amines using the same catalyst enantiomer.
Chiral allylic azides and amines are obtained by enantioselective hydroazidation and hydroamination of allenes catalyzed by acyclic diaminocarbene gold(I) catalysts derived from BINAM. The sense of enantioinduction is reversed for the two different nucleophiles, allowing easy access to both enantiomers with a single catalyst enantiomer.
There are increasing concerns regarding the role of exposure to ambient air pollution during pregnancy in the development of early childhood cancers.
This population based study examined whether ...prenatal and early life (<1year of age) exposures to ambient air pollutants, including nitrogen dioxide (NO2) and particulate matter with aerodynamic diameters ≤2.5μm (PM2.5), were associated with selected common early childhood cancers in Canada.
2,350,898 singleton live births occurring between 1988 and 2012 were identified in the province of Ontario, Canada. We assigned temporally varying satellite-derived estimates of PM2.5 and land-use regression model estimates of NO2 to maternal residences during pregnancy. Incident cases of 13 subtypes of pediatric cancers among children up to age 6 until 2013 were ascertained through administrative health data linkages. Associations of trimester-specific, overall pregnancy and first year of life exposures were evaluated using Cox proportional hazards models, adjusting for potential confounders.
A total of 2044 childhood cancers were identified. Exposure to PM2.5, per interquartile range increase, over the entire pregnancy, and during the first trimester was associated with an increased risk of astrocytoma (hazard ratio (HR) per 3.9μg/m3=1.38 (95% CI: 1.01, 1.88) and, HR per 4.0μg/m3=1.40 (95% CI: 1.05–1.86), respectively). We also found a positive association between first trimester NO2 and acute lymphoblastic leukemia (ALL) (HR=1.20 (95% CI: 1.02–1.41) per IQR (13.3ppb)).
In this population-based study in the largest province of Canada, results suggest an association between exposure to ambient air pollution during pregnancy, especially in the first trimester and an increased risk of astrocytoma and ALL. Further studies are required to replicate the findings of this study with adjustment for important individual-level confounders.
•Ambient air pollution in pregnancy increases the risk of childhood cancers.•PM2.5 exposure in first trimester was associated with risk of astrocytoma.•First trimester exposure to NO2 increased risk of acute lymphoblastic leukemia.
Prion diseases Johnson, Richard T
Lancet neurology,
10/2005, Letnik:
4, Številka:
10
Journal Article
Recenzirano
Prion diseases are degenerative disorders of the nervous system caused by transmissible particles that contain a pathogenic isoform of the prion protein, a normal constituent of cell membranes. The ...most common human prion disease is Creutzfeldt-Jakob disease (CJD). Most cases are sporadic with unknown mode of transmission, 10–15% of cases are inherited, and a small number have been transmitted by medical procedures. The spread of human prion diseases through consumption of infected material has been implicated historically in kuru and recently in variant CJD. Animal prion diseases (scrapie of sheep, transmissible mink encephalopathy, chronic wasting disease of cervids, and bovine spongiform encephalopathy) all seem to be laterally transmitted by contact with infected animals or by consumption of infected feed. The different modes of transmission of different prion diseases, the unpredictable species barriers, the variable distribution of infectivity in tissues, and strain variations found in some diseases all make risk assessment and predictions of future events difficult.
Aim
The frequency and impact of symptoms experienced by patients with congenital, childhood, and juvenile‐onset myotonic dystrophy (CDM/ChDM/JDM) is not documented. This report identifies symptomatic ...areas with the greatest disease burden in an international population of patients with early‐onset myotonic dystrophy type‐1 (DM1).
Method
We distributed surveys to parents of patients with CDM/ChDM/JDM. Patients with CDM/ChDM/JDM were members of the US National Registry of DM1 Patients and Family Members, the Canadian Neuromuscular Disease Registry, or the Swedish Health System. Surveys inquired about 325 symptoms and 20 themes associated with CDM/ChDM/JDM. Parents identified the importance of each symptom and theme to their affected child. The prevalence of each symptom and theme were compared across subgroups of patients. The statistical analysis was performed using Fisher's exact and Kruskal–Wallis tests.
Results
One hundred and fifty parents returned surveys. The most frequently reported symptomatic themes in children were issues involving communication (81.7%) and problems with hands or fingers (79.6%). Problems with communication and fatigue were the issues that were reported to have the greatest impact on childrens’ lives, while 24.1% of children reported cardiac disorders and 15.8% had problems with anesthesia.
Interpretation
A range of symptoms contribute to the burden of disease faced by children with DM1. Many of these symptoms are under‐recognized.
What this study adds
Communication issues, fatigue, and problems with hands and fingers are important in childhood‐onset myotonic dystrophy.
The age at onset, CTG repeat length, and age of the child affect the severity of symptoms.
Up to 24% of children with childhood‐onset myotonic dystrophy have cardiac problems at a young age.
This article is commented on by Schara on page 652 of this issue.
ABSTRACT
Introduction: The Myotonic Dystrophy Health Index (MDHI) is a disease‐specific patient‐reported outcome measure. Here, we examine the associations between the MDHI and other measures of ...disease burden in a cohort of individuals with myotonic dystrophy type‐1 (DM1). Methods: We conducted a cross‐sectional study of 70 patients with DM1. We examined the associations between MDHI total and subscale scores and scores from other clinical tests. Participants completed assessments of strength, myotonia, motor and respiratory function, ambulation, and body composition. Participants also provided blood samples, underwent physician evaluations, and completed other patient‐reported outcome measures. Results: MDHI total and subscale scores were strongly associated with muscle strength, myotonia, motor function, and other clinical measures. Conclusions: Patient‐reported health status, as measured by the MDHI, is associated with alternative measures of clinical health. These results support the use of the MDHI as a valid tool to measure disease burden in DM1 patients. Muscle Nerve, 2015 Muscle Nerve 53: 183–190, 2016
The commercialization of scientific discoveries within the university‐industry nexus is multifaceted and complex, characterized by dynamic interactions between multiple agents, organizations, and ...institutions. These interactions support a university‐centered entrepreneurial ecosystem (UCEE). Our study investigates agent‐institution dynamics within the UCEE to explore how individual agents seek to commercialize their scientific discoveries. Specifically, relying on 47 narrative interviews, we explore how UCEE agents across three UCEEs in the United States, United Kingdom, and Russia respond and adapt to institutional commercialization mandates during commercialization of their stem cell‐based regenerative medicine discoveries. Our findings emphasize the bi‐directional relationship between individual agents and institutions within a UCEE, facilitating a much‐needed multi‐level perspective on academic entrepreneurship research. We extend recent frameworks that propose how the formative stages of the entrepreneurial process – opportunity evolution – influences ecosystem emergence. Specifically, by investigating the latter stages of the entrepreneurial process – how (science‐based) opportunities are commercialized within UCEEs – we reveal distinct behavioral responses to science commercialization mandates, which underscore how UCEEs evolve. Furthermore, by explicating the importance of UCEE agent behavior during science commercialization, our study shines an important spotlight onto the microfoundations of science commercialization and UCEEs. Our research imparts important policy implications for institutions tasked with commercializing scientific discoveries and policy makers challenged with developing high growth, sustainable UCEEs.
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