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R-2-hydroxyglutarate (R-2HG), a metabolite produced by mutant isocitrate dehydrogenases (IDHs), was recently reported to exhibit anti-tumor activity. However, its effect on cancer metabolism remains largely elusive. Here we show that R-2HG effectively attenuates aerobic glycolysis, a hallmark of cancer metabolism, in (R-2HG-sensitive) leukemia cells. Mechanistically, R-2HG abrogates fat-mass- and obesity-associated protein (FTO)/N6-methyladenosine (m6A)/YTH N6-methyladenosine RNA binding protein 2 (YTHDF2)-mediated post-transcriptional upregulation of phosphofructokinase platelet (PFKP) and lactate dehydrogenase B (LDHB) (two critical glycolytic genes) expression and thereby suppresses aerobic glycolysis. Knockdown of FTO, PFKP, or LDHB recapitulates R-2HG-induced glycolytic inhibition in (R-2HG-sensitive) leukemia cells, but not in normal CD34+ hematopoietic stem/progenitor cells, and inhibits leukemogenesis in vivo; conversely, their overexpression reverses R-2HG-induced effects. R-2HG also suppresses glycolysis and downregulates FTO/PFKP/LDHB expression in human primary IDH-wild-type acute myeloid leukemia (AML) cells, demonstrating the clinical relevance. Collectively, our study reveals previously unrecognized effects of R-2HG and RNA modification on aerobic glycolysis in leukemia, highlighting the therapeutic potential of targeting cancer epitranscriptomics and metabolism.STING-dependent cytosolic DNA sensing in dendritic cells (DCs) initiates antitumor immune responses, but how STING signaling is metabolically regulated in the tumor microenvironment remains unknown. Here, we show that oxidative stress is required for STING-induced DC antitumor function through a process that directs SUMO-specific protease 3 (SENP3) activity. DC-specific deletion of Senp3 drives tumor progression by blunting STING-dependent type-I interferon (IFN) signaling in DCs and dampening antitumor immune responses. DC-derived reactive oxygen species (ROS) trigger SENP3 accumulation and the SENP3-IFI204 interaction, thereby catalyzing IFI204 deSUMOylation and boosting STING signaling activation in mice. Consistently, SENP3 senses ROS to facilitate STING-dependent DC activity in tissue samples from colorectal cancer patients. Our results reveal that oxidative stress as a metabolic regulator promotes STING-mediated DC antitumor immune responses and highlights SENP3 as an overflow valve for STING signaling induction in the metabolically abnormal tumor microenvironment.

Staging guidelines for lung cancer recommend endobronchial ultrasound (EBUS) and systematic biopsy of at least three mediastinal lymph node (LN) stations for accurate staging. A four-point ultrasonographic score (Canada Lymph Node Score [CLNS]) was developed to determine the probability of malignancy in each LN. A LN with a CLNS of< 2 is considered low probability for malignancy. We hypothesized that, in patients with cN0 non-small cell lung cancer, LNs with CLNS of< 2 may not require routine biopsy because they represent true node-negative disease.

Do LNs considered triple normal on CT scanning, PET scanning, and CLNS evaluation require routine biopsy?

LNs were evaluated for ultrasonographic features at the time of EBUS and the CLNS was applied. Triple-normal LNs were defined as cN0 on CT scanning (short axis,< 1cm), PET scanning (no hypermetabolic activity), and EBUS (CLNS,< 2). Specificity and negative predictive value (NPV) were calculated against the gold standard pathologic diagnosis from surgically excised specimens.

In total, 143 LNs from 57 cN0 patients were assessed. Triple-normal LNs showed a specificity and NPV of 60%(95%CI, 51.2%-68.3%) and 93.1%(95%CI, 85.6%-97.4%), respectively. After pathologic assessment, only 5.6%(n= 8/143) of triple-normal nodes were proven to be malignant.

At the time of staging for lung cancer, combining CT scanning, PET scanning, and CLNS criteria can identify triple-normal LNs that have a high NPV for malignancy. This raises the question of whether triple-normal LNs require routine sampling during EBUS and transbronchial needle aspiration. A prospective trial is required to confirm these findings.

At the time of staging for lung cancer, combining CT scanning, PET scanning, and CLNS criteria can identify triple-normal LNs that have a high NPV for malignancy. This raises the question of whether triple-normal LNs require routine sampling during EBUS and transbronchial needle aspiration. A prospective trial is required to confirm these findings.Tobacco, like other popular commodities, both reflected the rhythms of early modern empires and contributed to them. People, goods, and ideas crossing the Atlantic Ocean often traveled as freight in vessels bound upon other business, and much of that was tobacco business. Using a variety of historical examples, the current article explores tobacco's economic, cultural, and labor-related worlds to show how one plant shaped institutions of human enslavement, altered colonial ecologies, offered new sensory possibilities, and ruined fortunes. Although now perhaps better known within medical contexts as a significant, preventable cause of death, tobacco as it is understood today is also a highly political, economic, and cultural product, characteristics that have shaped human relationships to the commodity over the centuries. The 17th and 18th centuries, for example, saw a dramatic rise in tobacco consumption in Europe alongside an influx of colonial natural products across the continent. The tobacco trade offered power and profit to some, exploitation and enslavement to others. It underwrote the rise of prominent merchant and political families while shaping the daily routines of countless enslaved men, women, and children tasked with growing the plant. Tobacco leaves also offered hopes of medical treatment and trustworthy business dealings, as well as a moment of respite on a long voyage. At every stage of its evolution into a global commodity, tobacco's meanings and roles changed, becoming more fully integrated into European empire and its structures of power and profit in the process.

Diffuse alveolar hemorrhage (DAH) is an uncommon complication of hematopoietic stem cell transplantation (HCT) that carries high morbidity and mortality. Limited contemporary data are available regarding the incidence, outcomes, and risk factors for DAH.

What are the incidence, outcomes, and risk factors for DAH developing after HCT?

This was a single-center retrospective cohort study of patients who underwent HCT between January 1, 2005, and December 31, 2016. The incidence and outcomes of DAH development were evaluated. A multivariate logistic regression model was used to analyze differences between survivors and nonsurvivors.

Of 4,350 patients undergoing first-time HCT, DAH was diagnosed in 99 (2.3%). DAH was seen in 40 of 3,536 autologous HCT recipients (1.1%) and 59 of 814 allogeneic HCT recipients (7.2%). Mean age was 53 ± 13 years, and median time of DAH diagnosis was 126days (interquartile range, 19-349days) after HCT. In-hospital mortality and mortality 1 year after DAH diagnosis were 55.6%anechanical ventilation, thrombocytopenia, and elevated INR are all associated with worse outcomes.Pulmonary nodules are a frequent, incidental finding on CT scans, ranging from up to 8.4% on abdominal scans and up to 48% on CT angiograms. Incidental findings are sometimes disregarded or overshadowed by critical situations and may not be disclosed or documented on discharge. The costs and risks associated with incidental findings are not insignificant, including the risk of a delayed diagnosis of lung cancer. A medical center commitment to prevent overlooked incidental pulmonary nodules led to the development of an incidental pulmonary nodule program. The program, led by an advanced practice nurse, established processes to identify patients with incidental lung nodules on CT scans and developed criteria for further follow-up with the primary care provider and the patient. Improvements with consistent use of Fleischner guidelines in scan reports by radiologists and increased ownership in informing patients of incidental nodules by ED and trauma providers have occurred. As the frequency of chest CT imaging is increasing, the number of incidental nodules identified will also increase. A lung nodule surveillance process would greatly benefit every lung nodule clinic or hospital system for management of pulmonary nodules.COPD is a clinically heterogeneous syndrome characterized by injury to airways, airspaces, and lung vasculature and usually caused by tobacco smoke and/or air pollution exposure. COPD is also independently associated with nonpulmonary comorbidities (eg, cardiovascular disease) and malignancies (eg, GI, bladder), suggesting a role for systemic injury. Since not all those with exposure develop COPD, there has been a search for plasma and lung biomarkers that confer increased cross-sectional and longitudinal risk. This search typically focuses on clinically relevant COPD outcomes such as FEV1, FEV1 decline, CT measurements of emphysema, or exacerbation frequency. The rapid advances in omics technology and the molecular phenotyping of COPD cohorts now permit large-scale evaluation of genetic, transcriptomic, proteomic, and metabolic biomarkers. TebipenemPivoxil This review focuses on protein biomarkers associated with clinically relevant COPD outcomes. The prototypic COPD protein biomarker is alpha-1 antitrypsin; however, this biomarker only accounts for 1% to 5% of COPD. This article reviews and summarizes the evidence for other validated biomarkers for each COPD outcome, and discusses their advantages, weaknesses, and required regulatory steps to move the biomarker from the bench into clinic. Although we highlight the emergence of many novel biomarkers (eg, fibrinogen, soluble receptor for advanced glycation, surfactant protein D, club cell secretory protein), there is increasing evidence that individual biomarkers only explain a fraction of the increased COPD risk and that multiple biomarker panels are needed to completely explain clinical variation and risk in individuals and populations.

The provision of palliative care for severe COPD remains low, resulting in unmet needs in patients and carers.

What are the palliative care needs of patients living with severe COPD and their caregivers? What views of accessing and providing palliative care and factors influence these experiences. To what extent have palliative care and COPD services been integrated?

A multicentre qualitative study was undertaken in COPD services and specialist palliative care in the United Kingdom involving patients with severe COPD, their carers, and health professionals. Data were collected using semistructured interviews and were analyzed using framework analysis. Themes were integrated using the constant comparison process, enabling systematic data synthesis.

Four themes were generated from interviews with 20 patients, six carers, and 25 health professionals management of exacerbations, palliative care needs, access to palliative care and pathways, and integration of palliative care support. Uncertainty and fear s being implemented for nonmalignant diseases including COPD throughout the United Kingdom, although models of working vary. A theoretical model was developed to illustrate the concept and pathway of the integration of palliative care support. A standardized screening and needs assessment tool is required to improve timely palliative care and to address the significant needs of this population.