Deciphering conversational complexity around a diabetic patient in a web based forum

Web based conversational forums have gained momentum as an aid to clinical decision making. This paper, written in an empirical explanatory manner, attempts to understand the flow of information and the process of sense-making in one such forum (Tabula-rasa) through considering a prototype discussion among participants

Pierwotny śródczaszkowy bazaloidalny rak płaskonabłonkowy

Primary intracranial squamous cell carcinoma is extremely rare, with most cases arising from malignant transformation of dysembryogenetic lesions such as epidermoid and dermoid cysts. Intracranial squamous cell neoplasm arising de novo is even rarer and has been reported in only four patients to date. We herein describe a case of primary intracranial squamous cell carcinoma arising de novo in the right frontal lobe in a 35-year-old woman treated with a combination of surgery and postoperative conformal radiation. We have also shed light on the biology and the therapeutic options of this enigmatic tumour.Pierwotny śródczaszkowy rak płaskonabłonkowy jest wyjątkową rzadkością i w większości przypadków rozwija się w wyniku zezłośliwienia zmian o charakterze dysembriogenetycznym, np. torbieli naskórkowej lub skórzastej. Śródczaszkowy rak płaskonabłonkowy powstały de novo jest jeszcze rzadszy – dotąd opisano 4 takie przypadki. W niniejszej pracy przedstawiono przypadek nowotworu powstałego de novo w prawym płacie czołowym u 35-letniej chorej, którą z tego powodu poddano leczeniu chirurgicznemu i pooperacyjnej radioterapii konformalnej. Podano również informacje na temat biologii i możliwości leczenia tego zagadkowego guza

Carlinoside reduces hepatic bilirubin accumulation by stimulating bilirubin-UGT activity through Nrf2 gene expression

Accu mulati on of biliru bin, prima rily because of its insol ubilit y, has bee n found to be associa ted with liver disea ses includ ing jaundice . Free bilir ubin is insol uble; its glucuro nidation by bilirubin -UGT enz yme (UGT1 A1) makes it soluble and elimina tes it throu gh urine and fae ces. Taki ng CCl 4 induced ra t liver dysfun ction m odel, we demonst rated that supp ression of UGT1A 1 activity in ra t liv er increa sed ser um biliru bin level wh ich could be reve rsed by carl inoside (Cln), a flavone glyc oside. Alth ough Cln is a flavone compou nd, it escaped self-glucu ronid ation in the intestin e and readily absorbe d. Kineti c stud y of mic rosoma l UGT1A 1 from HepG 2 cells sugg ested that Cln enhan ced enz yme activity by increa sing V max with out alterin g K m. This altered V max was foun d to be due to UGT1A 1 ove rexpre ssion by Cln wh ich wa s obser ved in both HepG 2 and rat prima ry hepa tocytes . Sin ce Nrf2 is the transc ription factor of UG T1A1, we exam ined whethe r Cln effe ct on UG T1A1 overexp ression is media ted th rough Nrf2. In Nrf2 knock -out cells, Cln cou ld not eleva te UG T1A1 activity indica ting Nrf2 to be its target. Cln signific antly increas ed Nrf2 ge ne expr ession in HepG2 cells wh ich was subse quently locali zed in nuclear region . Resu lts from Ch IP assa y show ed that Cln mar kedly augm ented Nrf2 bindi ng to UGT1A 1 prom oter that con sequentl y enhan ced report er act ivity. Our findings therefor e show that Cln upreg ulated Nr f2 gene expr ession, incr eased its nu clear tran slocation and stimula ted UGT1A 1 prom oter act ivity. Tota l outc ome of these even ts brought about a signific ant increase of biliru bin glucur onida tion. Cln ther efore could be a wor thy choice to int ervene hype rbilir ubinemi a due to liv er dysfunc tion

MLH1-methylated endometrial cancer under 60 years of age as the “sentinel” cancer in female carriers of high-risk constitutional MLH1 epimutation

Objective. Universal screening of endometrial carcinoma (EC) for mismatch repair deficiency (MMRd) and Lynch syndrome uses presence of MLH1 methylation to omit common sporadic cases from follow-up germline testing. However, this overlooks rare cases with high-risk constitutional MLH1 methylation (epimutation), a poorly-recognized mechanism that predisposes to Lynch-type cancers with MLH1 methylation. We aimed to de-termine the role and frequency of constitutional MLH1 methylation among EC cases with MMRd, MLH1- methylated tumors.Methods. We screened blood for constitutional MLH1 methylation using pyrosequencing and real-time methylation-specific PCR in patients with MMRd, MLH1-methylated EC ascertained from (i) cancer clinics (n = 4, <60 years), and (ii) two population-based cohorts; Columbus-area (n = 68, all ages) and Ohio Colo-rectal Cancer Prevention Initiative (OCCPI) (n = 24, <60 years).Results. Constitutional MLH1 methylation was identified in three out of four patients diagnosed between 36 and 59 years from cancer clinics. Two had mono-/hemiallelic epimutation (similar to 50% alleles methylated). One with multiple primaries had low-level mosaicism in normal tissues and somatic second-hits affecting the unmethylated allele in all tumors, demonstrating causation. In the population-based cohorts, all 68 cases from the Columbus-area cohort were negative and low-level mosaic constitutional MLH1 methylation was identified in one patient aged 36 years out of 24 from the OCCPI cohort, representing one of six (similar to 17%) patients <50 years and one of 45 patients (similar to 2%) <60 years in the combined cohorts. EC was the first/dual-first cancer in three pa-tients with underlying constitutional MLH1 methylation.Conclusions. A correct diagnosis at first presentation of cancer is important as it will significantly alter clinical management. Screening for constitutional MLH1 methylation is warranted in patients with early-onset EC or syn-chronous/metachronous tumors (any age) displaying MLH1 methylation.(c) 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/)

An efficient local binary pattern based plantar pressure optical sensor image classification using convolutional neural networks

The objective of this study was to design and produce highly comfortable shoe products guided by a plantar pressure imaging data-set. Previous studies have focused on the geometric measurement on the size of the plantar, while in this research a plantar pressure optical imaging data-set based classification technology has been developed. In this paper, an improved local binary pattern (LBP) algorithm is used to extract texture-based features and recognize patterns from the data-set. A calculating model of plantar pressure imaging feature area is established subsequently. The data-set is classified by a neural network to guide the generation of various shoe-last surfaces. Firstly, the local binary mode is improved to adapt to the pressure imaging data-set, and the texture-based feature calculation is fully used to accurately generate the feature point set; hereafter, the plantar pressure imaging feature point set is then used to guide the design of last free surface forming. In the presented experiments of plantar imaging, multi-dimensional texture-based features and improved LBP features have been found by a convolution neural network (CNN), and compared with a 21-input-3-output two-layer perceptual neural network. Three feet types are investigated in the experiment, being flatfoot (F) referring to the lack of a normal arch, or arch collapse, Talipes Equinovarus (TE), being the front part of the foot is adduction, calcaneus varus, plantar flexion, or Achilles tendon contracture and Normal (N). This research has achieved an 82% accuracy rate with 10 hidden-layers CNN of rotation invariance LBP (RI-LBP) algorithm using 21 texture-based features by comparing other deep learning methods presented in the literature

Beta-Catenin Phosphorylated at Threonine 120 Antagonizes Generation of Active Beta-Catenin by Spatial Localization in trans-Golgi Network

The stability and subcellular localization of beta-catenin, a protein that plays a major role in cell adhesion and proliferation, is tightly regulated by multiple signaling pathways. While aberrant activation of beta-catenin signaling has been implicated in cancers, the biochemical identity of transcriptionally active beta-catenin (ABC), commonly known as unphosphorylated serine 37 (S37) and threonine 41 (T41) β-catenin, remains elusive. Our current study demonstrates that ABC transcriptional activity is influenced by phosphorylation of T120 by Protein Kinase D1 (PKD1). Whereas the nuclear β-catenin from PKD1-low prostate cancer cell line C4-2 is unphosphorylated S37/T41/T120 with high transcription activity, the nuclear β-catenin from PKD1-overexpressing C4-2 cells is highly phosphorylated at T120, S37 and T41 with low transcription activity, implying that accumulation of nuclear β-catenin alone cannot be simply used as a read-out for Wnt activation. In human normal prostate tissue, the phosphorylated T120 β-catenin is mainly localized to the trans-Golgi network (TGN, 22/30, 73%), and this pattern is significantly altered in prostate cancer (14/197, 7.1%), which is consistent with known down regulation of PKD1 in prostate cancer. These in vitro and in vivo data unveil a previously unrecognized post-translational modification of ABC through T120 phosphorylation by PKD1, which alters subcellular localization and transcriptional activity of β-catenin. Our results support the view that β-catenin signaling activity is regulated by spatial compartmentation and post-translational modifications and protein level of β-catenin alone is insufficient to count signaling activity

SARS-CoV-2 receptor binding domain displayed on HBsAg virus–like particles elicits protective immunity in macaques

Authorized vaccines against SARS-CoV-2 remain less available in low- and middle-income countries due to insufficient supply, high costs, and storage requirements. Global immunity could still benefit from new vaccines using widely available, safe adjuvants, such as alum and protein subunits, suited to low-cost production in existing manufacturing facilities. Here, a clinical-stage vaccine candidate comprising a SARS-CoV-2 receptor binding domain–hepatitis B surface antigen virus–like particle elicited protective immunity in cynomolgus macaques. Titers of neutralizing antibodies (>104) induced by this candidate were above the range of protection for other licensed vaccines in nonhuman primates. Including CpG 1018 did not significantly improve the immunological responses. Vaccinated animals challenged with SARS-CoV-2 showed reduced median viral loads in bronchoalveolar lavage (~3.4 log10) and nasal mucosa (~2.9 log10) versus sham controls. These data support the potential benefit of this design for a low-cost modular vaccine platform for SARS-CoV-2 and other variants of concern or betacoronaviruses

FACT Prevents the Accumulation of Free Histones Evicted from Transcribed Chromatin and a Subsequent Cell Cycle Delay in G1

The FACT complex participates in chromatin assembly and disassembly during transcription elongation. The yeast mutants affected in the SPT16 gene, which encodes one of the FACT subunits, alter the expression of G1 cyclins and exhibit defects in the G1/S transition. Here we show that the dysfunction of chromatin reassembly factors, like FACT or Spt6, down-regulates the expression of the gene encoding the cyclin that modulates the G1 length (CLN3) in START by specifically triggering the repression of its promoter. The G1 delay undergone by spt16 mutants is not mediated by the DNA–damage checkpoint, although the mutation of RAD53, which is otherwise involved in histone degradation, enhances the cell-cycle defects of spt16-197. We reveal how FACT dysfunction triggers an accumulation of free histones evicted from transcribed chromatin. This accumulation is enhanced in a rad53 background and leads to a delay in G1. Consistently, we show that the overexpression of histones in wild-type cells down-regulates CLN3 in START and causes a delay in G1. Our work shows that chromatin reassembly factors are essential players in controlling the free histones potentially released from transcribed chromatin and describes a new cell cycle phenomenon that allows cells to respond to excess histones before starting DNA replication

Secretogranin II; a Protein Increased in the Myocardium and Circulation in Heart Failure with Cardioprotective Properties

Background: Several beneficial effects have been demonstrated for secretogranin II (SgII) in non-cardiac tissue. As cardiac production of chromogranin A and B, two related proteins, is increased in heart failure (HF), we hypothesized that SgII could play a role in cardiovascular pathophysiology. Methodology/Principal Findings: SgII production was characterized in a post-myocardial infarction heart failure (HF) mouse model, functional properties explored in experimental models, and circulating levels measured in mice and patients with stable HF of moderate severity. SgII mRNA levels were 10.5 fold upregulated in the left ventricle (LV) of animals with myocardial infarction and HF (p&lt;0.001 vs. sham-operated animals). SgII protein levels were also increased in the LV, but not in other organs investigated. SgII was produced in several cell types in the myocardium and cardiomyocyte synthesis of SgII was potently induced by transforming growth factor-beta and norepinephrine stimulation in vitro. Processing of SgII to shorter peptides was enhanced in the failing myocardium due to increased levels of the proteases PC1/3 and PC2 and circulating SgII levels were increased in mice with HF. Examining a pathophysiological role of SgII in the initial phase of post-infarction HF, the SgII fragment secretoneurin reduced myocardial ischemia-reperfusion injury and cardiomyocyte apoptosis by 30% and rapidly increased cardiomyocyte Erk1/2 and Stat3 phosphorylation. SgII levels were also higher in patients with stable, chronic HF compared to age-and gender-matched control subjects: median 0.16 (Q1-3 0.14-0.18) vs. 0.12 (0.10-0.14) nmol/L, p&lt;0.001. Conclusions: We demonstrate increased myocardial SgII production and processing in the LV in animals with myocardial infarction and HF, which could be beneficial as the SgII fragment secretoneurin protects from ischemia-reperfusion injury and cardiomyocyte apoptosis. Circulating SgII levels are also increased in patients with chronic, stable HF and may represent a new cardiac biomarker