Chronic acidosis rewires cancer cell metabolism through PPARα signaling

The mechanisms linking tumor microenvironment acidosis to disease progression are not understood. Here, we used mammary, pancreatic, and colon cancer cells to show that adaptation to growth at an extracellular pH (pH_e) mimicking acidic tumor niches is associated with upregulated net acid extrusion capacity and elevated intracellular pH at physiological pH_e, but not at acidic pH_e. Using metabolic profiling, shotgun lipidomics, imaging and biochemical analyses, we show that the acid adaptation-induced phenotype is characterized by a shift toward oxidative metabolism, increased lipid droplet-, triacylglycerol-, peroxisome content and mitochondrial hyperfusion. Peroxisome proliferator-activated receptor-α (PPARA, PPARα) expression and activity are upregulated, at least in part by increased fatty acid uptake. PPARα upregulates genes driving increased mitochondrial and peroxisomal mass and β-oxidation capacity, including mitochondrial lipid import proteins CPT1A, CPT2 and SLC25A20, electron transport chain components, peroxisomal proteins PEX11A and ACOX1, and thioredoxin-interacting protein (TXNIP), a negative regulator of glycolysis. This endows acid-adapted cancer cells with increased capacity for utilizing fatty acids for metabolic needs, while limiting glycolysis. As a consequence, the acid-adapted cells exhibit increased sensitivity to PPARα inhibition. We conclude that PPARα is a key upstream regulator of metabolic changes favoring cancer cell survival in acidic tumor niches.     

Clinicopathological Profile of Myelomatous Pleural Effusion: Single-center Real-world Experience and Review of Literature

Background

Multiple myeloma (MM) is a hematologic malignancy of plasma cell origin. MM primarily affects bone marrow, but extramedullary sites can also be involved. Myelomatous pleural effusion (MPE) is an atypical and rare complication of MM. We aimed to systematically study the incidence and clinicopathologic profile of patients with MPE in a real-world setting.

US Food and Drug Administration approvals for Bruton tyrosine kinase inhibitors in patients with chronic lymphocytic leukemia: Potential inefficiencies in trial design and evidence generation

The US Food and Drug Administration granted acalabrutinib approval as the second Bruton tyrosine kinase (BTK) inhibitor to treat patients with chronic lymphocytic leukemia and small lymphocytic lymphoma as monotherapy or in combination with obinutuzumab. This approval was based on 2 phase 3 trials: ELEVATE-TN and ASCEND. There are several concerns with the design of these trials, including suboptimal treatment of patients in the control arm, expansion of the trial population, and lack of data regarding efficacy or tolerability compared with ibrutinib, a first-in-class drug. The Food and Drug Administration approval of acalabrutinib for patients with chronic lymphocytic leukemia and small lymphocytic lymphoma represents concerning drug approval patterns in the United States and a weakness in evidence generation.     

Reductions in clinical inflammation and oral neutrophils with improving oral hygiene

Clinical Oral Investigations - This study compared the effects of oral hygiene with a toothpaste formulated with zinc (test) to a fluoride dentifrice (control) for effects on oral polymorphonuclear...     

Age at menopause in India: A systematic review

Background and aimsMenopause is a physiological process in nature and hence, variations in the age of menopause are not expected. Hence, the study was conducted with an objective to calculate the reliable estimates of age at menopause for India, and understand the differentials in women’s age at menopause throughout the country.MethodsA total of 202 studies of age at menopause, covering the period 2009–2020, were accessed from PubMed database and Google. Of these only ten studies met the selection criteria for this paper, which is that the data for these studies must be collected from house-to-house surveys.ResultsThe average age at menopause in India, with minimal publication bias, is 46.6 years (95% CI: 44.83, 48.44). In one study slightly above 1.96 Standard Deviation, was observed, as ascertained by Funnel Plot and Egger’s test. The mean age ranged from a minimum of 44.69 years (95% CI: 35.01, 54.37) to a maximum of 48.95 (95% CI: 42.29, 55.61) years. Furthermore, the age at menopause did not exhibit any significant variation by age at menarche, although the association was positive.ConclusionsThe age at menopause showed positive association with age at menarche. In India, during the period 2009–2020, it was 46.6 years, which significantly lower than the age in some developed countries. The differences may be methodological since no information was found regarding the distribution of age at menopause in the studies that were considered for meta-analysis.