CAF cellular glycolysis: linking cancer cells with the microenvironment

Cancers have long being hallmarked as cells relying heavily on their glycolysis for energy generation in spite of having functional mitochondria. The metabolic status of the cancer cells have been revisited time and again to get better insight into the overall carcinogenesis process which revealed the apparent crosstalks between the cancer cells with the fibroblasts present in the tumour microenvironment. This review focuses on the mechanisms of transformations of normal fibroblasts to cancer-associated fibroblasts (CAF), the participation of the CAF in tumour progression with special interest to the role of CAF cellular glycolysis in the overall tumorigenesis. The fibroblasts, when undergoes the transformation process, distinctly switches to a more glycolytic phenotype in order to provide the metabolic intermediates necessary for carrying out the mitochondrial pathways of ATP generation in cancer cells. This review will also discuss the molecular mechanisms responsible for this metabolic make over promoting glycolysis in CAF cells. A thorough investigation of the pathways and molecules involved will not only help in understanding the process of activation and metabolic reprogramming in CAF cells but also might open up new targets for cancer therapy.     

Computerized tumor multinucleation index (MuNI) is prognostic in p16+ oropharyngeal carcinoma

BACKGROUNDPatients with p16⁺ oropharyngeal squamous cell carcinoma (OPSCC) are potentially cured with definitive treatment. However, there are currently no reliable biomarkers of treatment failure for p16⁺ OPSCC. Pathologist-based visual assessment of tumor cell multinucleation (MN) has been shown to be independently prognostic of disease-free survival (DFS) in p16⁺ OPSCC. However, its quantification is time intensive, subjective, and at risk of interobserver variability.METHODSWe present a deep-learning–based metric, the multinucleation index (MuNI), for prognostication in p16⁺ OPSCC. This approach quantifies tumor MN from digitally scanned H&E-stained slides. Representative H&E-stained whole-slide images from 1094 patients with previously untreated p16⁺ OPSCC were acquired from 6 institutions for optimization and validation of the MuNI.RESULTSThe MuNI was prognostic for DFS, overall survival (OS), or distant metastasis–free survival (DMFS) in p16⁺ OPSCC, with HRs of 1.78 (95% CI: 1.37–2.30), 1.94 (1.44–2.60), and 1.88 (1.43–2.47), respectively, independent of age, smoking status, treatment type, or tumor and lymph node (T/N) categories in multivariable analyses. The MuNI was also prognostic for DFS, OS, and DMFS in patients with stage I and stage III OPSCC, separately.CONCLUSIONMuNI holds promise as a low-cost, tissue-nondestructive, H&E stain–based digital biomarker test for counseling, treatment, and surveillance of patients with p16⁺ OPSCC. These data support further confirmation of the MuNI in prospective trials.FUNDINGNational Cancer Institute (NCI), NIH; National Institute for Biomedical Imaging and Bioengineering, NIH; National Center for Research Resources, NIH; VA Merit Review Award from the US Department of VA Biomedical Laboratory Research and Development Service; US Department of Defense (DOD) Breast Cancer Research Program Breakthrough Level 1 Award; DOD Prostate Cancer Idea Development Award; DOD Lung Cancer Investigator-Initiated Translational Research Award; DOD Peer-Reviewed Cancer Research Program; Ohio Third Frontier Technology Validation Fund; Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering; Clinical and Translational Science Award (CTSA) program, Case Western Reserve University; NCI Cancer Center Support Grant, NIH; Career Development Award from the US Department of VA Clinical Sciences Research and Development Program; Dan L. Duncan Comprehensive Cancer Center Support Grant, NIH; and Computational Genomic Epidemiology of Cancer Program, Case Comprehensive Cancer Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, the US Department of VA, the DOD, or the US Government.     

Alterations in Brain Polyribosomal RNA Translation and Lymphocyte Proliferation in Prenatal Ethanol-Exposed Rats

The long-term effects of prenatal ethanol exposure on the properties of brain polysomes and the proliferative responses of lymphocytes to mitogenic stimulation in adult offspring were assessed. Female Sprague-Dawley rats either ingested the control or 6.6% ethanol-containing Lieber-DeCarli liquid diet during the 3rd trimester of pregnancy. Controls were age-matched and pair-fed. At 42 to 72 days of age, ethanol effects were evaluated on the (1) polysomal properties in the cerebral hemispheres, cerebellum, and hippocampal regions of the brain after translation in a messenger RNA (mRNA)-dependent rabbit reticulocyte lysate system and (2) immunologic functions of lymphocytes cultured from spleen cells by measuring their responses to mitogenic stimulation. Results showed long-term adverse effects of in utero ethanol exposure on the polysomal RNA translation in each of the three brain regions tested with free polysomal mRNAs affected more than the bound polysomal mRNAs. Of these, the hippocampal region appeared to sustain the most injurious effects. In addition, a suppression of the mitogen-induced lymphocyte proliferative responses were present under these conditions. The degree of suppression varied with the specific mitogen used. Data suggest that the ethanol effects on the CNS and lymphocyte proliferation are most possibly irreversible, and in the case of the CNS, a post-translational modification by ethanol is indicated. The reduced lymphocyte responses are suggestive of a possible interference by ethanol of the synthesis of interleukin-2 (IL-2) and/or a reduced binding of IL-2 with its receptor (IL-2 receptors).     

Severe OSA Leading to Long Pauses in 24-h Holter ECG Reversed with CPAP

Introduction Sleep-related problems like sleep apnea are increasing tremendously mostly owing to the disordered lifestyle the present generation is leading which is added like a topping on the base of obesity and metabolic syndrome. The burden on the society is huge taking into consideration the work-time loss and health-related financial issues arising out of these sleep disorders with obstructive sleep apnea (OSA) leading the way. Early diagnosis can prevent several complications of OSA. Cardiovascular diseases, including various arrhythmias, arising due to OSA, are described previously.Case Presentation Herein, an interesting case of OSA, whose pacemaker installation to rectify the long pause could be avoided by simple correction of his OSA using continuous positive airway pressure, is presented. This 49-year-old male patient was diagnosed with severe OSA by using polysomnography and all his significant sinus pauses (highest one with 7.8 sec) during holter ECG monitoring were found to be occurring at night and correcting his OSA with continuous positive airway pressure (CPAP) treatment reverted all those sinus pauses and the need for any further intervention with pacemaker was discarded.Discussion OSA is caused by either partial or complete obstruction of the upper airway, and there is the simultaneously attenuated upper airway dilator muscle tone while the patient is sleeping. The gold standard test designed for the assessment of OSA is polysomnography, as approved by the American Academy of Sleep Medicine and CPAP has been found to be universally beneficial in treating OSA related complications. Physiologically, the ACC/AHA guidelines recommend pacing only in patients with prolonged asymptomatic pauses occurring during wakefulness. This case report proved the above mentioned claim of CPAP treatment.     

Electrochromic Os-based metallo-supramolecular polymers: electronic state tracking by in situ XAFS,IR, and impedance spectroscopies

In this study, the electronic states of Os-based metallo-supramolecular polymers (poly(OsL)²⁺) during electrochromism were tracked by in situ X-ray absorption fine structure (XAFS), infrared (IR), and impedance spectroscopies. The XAFS spectra suggested electronic charge migration in the polymer, and the in situ spectra revealed reversible changes caused by electrochemical redox reactions. The IR spectra of the polymers showed an IVCT band, and we also confirmed the reversible changes by applying a voltage to the redox cell. During the impedance measurements, we found a drastic decrease in the charge transfer resistance (R_CT) of the polymer films near the electrochemical redox potential.

In this study, the electronic states of Os-based metallo-supramolecular polymers (poly(OsL)²⁺) during electrochromism were tracked by in situ X-ray absorption fine structure (XAFS), infrared (IR), and impedance spectroscopies.     

Coupling of Proton Binding in Extracellular Domain to Channel Gating in Acid-Sensing Ion Channel

Protonation of several amino acid residues in the extracellular domain (ECD) of acid-sensing ion channel (ASIC) causes conformational changes that lead to opening of the channel. It is not clear how conformational changes in ECD are coupled to channel gating. Here, we show that the loop connecting β9 and α4 at the base of the thumb region of ECD interacts with post-TM1 to stabilize the channel in the closed state. Flexibility of these two regions is important for optimum gating of the channel. In ASIC1a, when Y71 (post-TM1) and W287 (β9–α4 loop) were mutated to cysteine, they formed disulfide bond in the closed state. Breaking of the disulfide bond by reducing agent dithiothreitol (DTT) or tris(2-carboxyethyl)phosphine (TCEP) potentiated the current significantly. Engineered cysteine G288C reacted with sulfhydryl-specific methanethiosulfonate ethyltrimethylammonium (MTSET) in the open state but not in closed/steady desensitized state, suggesting gating-associated conformational movement of this loop. We also identified a salt bridge between highly conserved R64 at TM1 and D432 at TM2 that is important for optimum gating. Based on our results and other published work, we propose that proton binding in ECD is followed by the displacement of the β9–α4 loop of the thumb, leading to the rotation of TM1. Conformational movement propagates to TM2 and the channel gate opens by the concomitant movement of TM2 and breaking of the salt bridge between R64 and D432.