Notes

NF1 manages mesenchymal glioblastoma plasticity and aggressiveness from the AP-1 transcription issue FOSL1.
Treatment for metastatic melanoma includes targeted and/or immunotherapy. Although many patients respond, only a subset has complete response. learn more As late-stage patients often have multiple tumors in difficult access sites, non-invasive techniques are necessary for the development of predictive/prognostic biomarkers. PET/CT scans from 52 patients with stage III/IV melanoma were assessed and CT image parameters were evaluated as prognostic biomarkers. Analysis indicated patients with high standard deviation or high mean of positive pixels (MPP) had worse progression-free survival (P = 0.00047 and P = 0.0014, respectively) and worse overall survival (P = 0.0223 and P = 0.0465, respectively). Whole-exome sequencing showed high MPP was associated with BRAF mutation status (P = 0.0389). RNA-sequencing indicated patients with immune "cold" signatures had worse survival, which was associated with CT biomarker, MPP4 (P = 0.0284). Multiplex immunofluorescence confirmed a correlation between CD8 expression and image biomarkers (P = 0.0028). IMPLICATIONS CT parameters have the potential to be cost-effective biomarkers of survival in melanoma, and reflect the tumor immune-microenvironment. link2 VISUAL OVERVIEW http//mcr.aacrjournals.org/content/molcanres/19/6/950/F1.large.jpg.Epigenetic regulators can modulate the effects of cancer therapeutics. To further these observations, we discovered that the bromodomain PHD finger transcription factor subunit (BPTF) of the nucleosome remodeling factor (NURF) promotes resistance to doxorubicin, etoposide, and paclitaxel in the 4T1 breast tumor cell line. BPTF functions in promoting resistance to doxorubicin and etoposide, but not paclitaxel, and may be selective to cancer cells, as a similar effect was not observed in embryonic stem cells. link3 Sensitization to doxorubicin and etoposide with BPTF knockdown (KD) was associated with increased DNA damage, topoisomerase II (TOP2) crosslinking and autophagy; however, there was only a modest increase in apoptosis and no increase in senescence. Sensitization to doxorubicin was confirmed in vivo with the syngeneic 4T1 breast tumor model using both genetic and pharmacologic inhibition of BPTF. The effects of BPTF inhibition in vivo are autophagy dependent, based on genetic autophagy inhibition. Finally, treatment of 4T1, 66cl4, 4T07, MDA-MB-231, but not ER-positive 67NR and MCF7 breast cancer cells with the selective BPTF bromodomain inhibitor, AU1, recapitulates genetic BPTF inhibition, including in vitro sensitization to doxorubicin, increased TOP2-DNA crosslinks and DNA damage. Taken together, these studies demonstrate that BPTF provides resistance to the antitumor activity of TOP2 poisons, preventing the resolution of TOP2 crosslinking and associated autophagy. These studies suggest that BPTF can be targeted with small-molecule inhibitors to enhance the effectiveness of TOP2-targeted cancer chemotherapeutic drugs. IMPLICATIONS These studies suggest NURF can be inhibited pharmacologically as a viable strategy to improve chemotherapy effectiveness.Pancreatic ductal adenocarcinoma (PDA), a leading cause of cancer-related death in the United States, has a high metastatic rate, and is associated with persistent immune suppression. AXL, a member of the TAM (TYRO3, AXL, MERTK) receptor tyrosine kinase family, is a driver of metastasis and immune suppression in multiple cancer types. Here we use single-cell RNA-sequencing to reveal that AXL is expressed highly in tumor cells that have a mesenchymal-like phenotype and that AXL expression correlates with classic markers of epithelial-to-mesenchymal transition. We demonstrate that AXL deficiency extends survival, reduces primary and metastatic burden, and enhances sensitivity to gemcitabine in an autochthonous model of PDA. PDA in AXL-deficient mice displayed a more differentiated histology, higher nucleoside transporter expression, and a more active immune microenvironment compared with PDA in wild-type mice. Finally, we demonstrate that AXL-positive poorly differentiated tumor cells are critical for PDA progression and metastasis, emphasizing the potential of AXL as a therapeutic target in PDA. IMPLICATIONS These studies implicate AXL as a marker of undifferentiated PDA cells and a target for therapy.
Vaccine hesitancy is a complex public health issue referring to concerns about safety, efficacy, or need for vaccination. Using pneumococcal vaccination, which is recommend in anti-CD20-treated multiple sclerosis (MS) patients, as a model, we assessed vaccination behavior in patients with MS to prepare for the upcoming SARS-CoV-2 vaccination challenge.

By a medical chart review, we retrospectively identified patients with MS treated with ocrelizumab at the University Hospital Bern in 2018-2020. Pneumococcal vaccination was discussed with the patients during clinical visits and highlighted in the after-visit summary addressed to the general practitioner before ocrelizumab initiation as part of our clinical standard of care.

Pneumococcal vaccination was performed in 71/121 (58.7%) of patients, and 50/121 (41.3%) patients were not vaccinated. Patients who did not get a pneumococcal vaccination were younger (no vaccination vs vaccination; mean [95% CI] 40.1 [36.1-44.1] vs 45.4 [41.9-48.8],
= 0.028) and had more frequently a relapsing remitting disease course (no vaccination vs vaccination, n [%]; 43/50 [86.0%] vs 49/71 [69.0%],
= 0.031). Furthermore, patients who did not get vaccination had more frequently a history of comorbid psychiatric disorder (no vaccination vs vaccination, n (%); 12/50 [24.0] vs 7/71 [9.8],
= 0.035).

Our study demonstrated that in our single-center cohort, 41.3% of patients with MS do not get the recommended pneumococcal vaccination. Future research should focus on vaccine hesitancy in the vulnerable cohort of patients with MS to improve the safety of MS immunotherapies.
Our study demonstrated that in our single-center cohort, 41.3% of patients with MS do not get the recommended pneumococcal vaccination. Future research should focus on vaccine hesitancy in the vulnerable cohort of patients with MS to improve the safety of MS immunotherapies.
The transepithelial transport of electrolytes, solutes, and water in the kidney is a well-orchestrated process involving numerous membrane transport systems. Basolateral potassium channels in tubular cells not only mediate potassium recycling for proper Na
,K
-ATPase function but are also involved in potassium and pH sensing. Genetic defects in
cause EAST/SeSAME syndrome, characterized by renal salt wasting with hypokalemic alkalosis associated with epilepsy, ataxia, and sensorineural deafness.

A candidate gene approach and whole-exome sequencing determined the underlying genetic defect in eight patients with a novel disease phenotype comprising a hypokalemic tubulopathy with renal salt wasting, disturbed acid-base homeostasis, and sensorineural deafness. Electrophysiologic studies and surface expression experiments investigated the functional consequences of newly identified gene variants.

We identified mutations in the
gene encoding KCNJ16, which along with KCNJ15 and KCNJ10, constitutes the major basolateral potassium channel of the proximal and distal tubules, respectively. Coexpression of mutant KCNJ16 together with KCNJ15 or KCNJ10 in
oocytes significantly reduced currents.

Biallelic variants in
were identified in patients with a novel disease phenotype comprising a variable proximal and distal tubulopathy associated with deafness. Variants affect the function of heteromeric potassium channels, disturbing proximal tubular bicarbonate handling as well as distal tubular salt reabsorption.
Biallelic variants in KCNJ16 were identified in patients with a novel disease phenotype comprising a variable proximal and distal tubulopathy associated with deafness. Variants affect the function of heteromeric potassium channels, disturbing proximal tubular bicarbonate handling as well as distal tubular salt reabsorption.The US Food and Drug Administration (FDA) issued orders in July 2020 authorising Philip Morris Products S.A. to market its heated tobacco product (HTP) IQOS inside the USA with claims that it reduces exposure to some dangerous substances. FDA's 'reduced-exposure' orders explicitly prohibit the marketing of IQOS with claims that IQOS will reduce harm or the risk of tobacco-related diseases. Under US law, FDA's IQOS orders are problematic because FDA disregarded valid scientific evidence that IQOS increases exposure to other dangerous toxins and that Philip Morris Products S.A. failed to demonstrate that consumers understand the difference between reduced-exposure and reduced-harm claims. Unfortunately, both 'reduced-exposure' and 'reduced-harm' are classified as 'modified risk tobacco products' under US law. Exploiting this confusion, Philip Morris International used the FDA decision as the basis for marketing and public relations campaigns outside the USA to press governments to reverse policies that ban or regulate the sales and marketing of HTPs, including IQOS. Parties to the WHO Framework Convention on Tobacco Control should reject tobacco companies' unsubstantiated explicit or implied claims of reduced harm associated with HTPs and resist Philip Morris International's and other companies' calls to relax HTP regulations based on the FDA's actions. Instead, parties should adopt policies aligned with the Framework Convention on Tobacco Control when dealing with HTPs and other novel tobacco products.
Tobacco tax increase is considered as one of the most effective means to reduce tobacco consumption and its consequences. An increase in taxes, which results in an increase in the price of tobacco products, reduces consumption. Historically, a number of studies estimated the responsiveness of quantity demanded to a change in price-the price elasticity of demand-of tobacco products in Bangladesh. However, the government's stronger commitment to reducing tobacco use, rising standard of living, rapidly changing cultural norms due to globalisation, and the substantial fall in tobacco use seen in GATS 2017 necessitate an updated measure of price elasticity of tobacco use, which will allow for more accurate answers to questions of tobacco tax policy in the country. This study endeavours to fill this gap in the literature on demand for tobacco products in Bangladesh.

To estimate the price elasticity of demand for tobacco products, namely cigarettes,
and smokeless tobacco (SLT) products with the 2016 household expenditure and improve health equity.

Our results suggest that the demand for smoking tobacco products is responsive to price changes. Therefore, substantial increase in the prices of tobacco products through taxation will result in significant reduction in tobacco use, particularly among the low expenditure households, while increasing government revenue.
Our results suggest that the demand for smoking tobacco products is responsive to price changes. Therefore, substantial increase in the prices of tobacco products through taxation will result in significant reduction in tobacco use, particularly among the low expenditure households, while increasing government revenue.
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