Glioblastoma (GBM) is the most common and malignant primary brain tumor. The extracellular matrix, also known as the matrisome, helps determine glioma invasion, adhesion, and growth. Little ...attention, however, has been paid to glycosylation of the extracellular matrix components that constitute the majority of glycosylated protein mass and presumed biological properties. To acquire a comprehensive understanding of the biological functions of the matrisome and its components, including proteoglycans (PGs) and glycosaminoglycans (GAGs), in GBM tumorigenesis, and to identify potential biomarker candidates, we studied the alterations of GAGs, including heparan sulfate (HS) and chondroitin sulfate (CS), the core proteins of PGs, and other glycosylated matrisomal proteins in GBM subtypes versus control human brain tissue samples. We scrutinized the proteomics data to acquire in-depth site-specific glycoproteomic profiles of the GBM subtypes that will assist in identifying specific glycosylation changes in GBM. We observed an increase in CS 6-O sulfation and a decrease in HS 6-O sulfation, accompanied by an increase in unsulfated CS and HS disaccharides in GBM versus control samples. Several core matrisome proteins, including PGs (decorin, biglycan, agrin, prolargin, glypican-1, and chondroitin sulfate proteoglycan 4), tenascin, fibronectin, hyaluronan link protein 1 and 2, laminins, and collagens, were differentially regulated in GBM versus controls. Interestingly, a higher degree of collagen hydroxyprolination was also observed for GBM versus controls. Further, two PGs, chondroitin sulfate proteoglycan 4 and agrin, were significantly lower, about 6-fold for isocitrate dehydrogenase-mutant, compared to the WT GBM samples. Differential regulation of O-glycopeptides for PGs, including brevican, neurocan, and versican, was observed for GBM subtypes versus controls. Moreover, an increase in levels of glycosyltransferase and glycosidase enzymes was observed for GBM when compared to control samples. We also report distinct protein, peptide, and glycopeptide features for GBM subtypes comparisons. Taken together, our study informs understanding of the alterations to key matrisomal molecules that occur during GBM development. (Data are available via ProteomeXchange with identifier PXD028931, and the peaks project file is available at Zenodo with DOI 10.5281/zenodo.5911810).
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•Differential regulation of core matrisome proteins for GBM versus controls.•A higher degree of collagen hydroxyprolination for GBM versus controls.•Differential regulation of O-glycopeptides for proteoglycans for GBM versus controls.•Increase in glycotransferase and glycosidase enzymes for GBM versus controls.
Glioblastoma (GBM) is the most malignant human brain tumor. It is critical to understand the molecular mechanisms in GBM and identify clinical markers. Extracellular matrix or matrisome is implicated in important neurological processes in brain cancer. But less attention has been paid to matrisomal changes and related glycosylation in GBM. In this manuscript, we performed an in-depth matrisomal, glycomic, and glycoproteomic analysis of control and GBM samples to identify key alterations in matrisomal components, strengthening our knowledge of GBM pathology.
Micronutrient deficiencies compromise immune systems, hinder child growth and development, and affect human potential worldwide. Yet, to our knowledge, the only existing estimate of the global ...prevalence of micronutrient deficiencies is from over 30 years ago and is based only on the prevalence of anaemia. We aimed to estimate the global and regional prevalence of deficiency in at least one of three micronutrients among preschool-aged children (aged 6–59 months) and non-pregnant women of reproductive age (aged 15–49 years).
In this pooled analysis, we reanalysed individual-level biomarker data for micronutrient status from nationally representative, population-based surveys. We used Bayesian hierarchical logistic regression to estimate the prevalence of deficiency in at least one of three micronutrients for preschool-aged children (iron, zinc, and vitamin A) and for non-pregnant women of reproductive age (iron, zinc, and folate), globally and in seven regions using 24 nationally representative surveys done between 2003 and 2019.
We estimated the global prevalence of deficiency in at least one of three micronutrients to be 56% (95% uncertainty interval UI 48–64) among preschool-aged children, and 69% (59–78) among non-pregnant women of reproductive age, equivalent to 372 million (95% UI 319–425) preschool-aged children and 1·2 billion (1·0–1·4) non-pregnant women of reproductive age. Regionally, three-quarters of preschool-aged children with micronutrient deficiencies live in south Asia (99 million, 95% UI 80–118), sub-Saharan Africa (98 million, 83–113), or east Asia and the Pacific (85 million, 61–110). Over half (57%) of non-pregnant women of reproductive age with micronutrient deficiencies live in east Asia and the Pacific (384 million, 279–470) or south Asia (307 million, 255–351).
We estimate that over half of preschool-aged children and two-thirds of non-pregnant women of reproductive age worldwide have micronutrient deficiencies. However, estimates are uncertain due to the scarcity of population-based micronutrient deficiency data.
US Agency for International Development.
IMPORTANCE: Many patients with diabetic peripheral neuropathy experience chronic pain and inadequate relief despite best available medical treatments. OBJECTIVE: To determine whether 10-kHz spinal ...cord stimulation (SCS) improves outcomes for patients with refractory painful diabetic neuropathy (PDN). DESIGN, SETTING, AND PARTICIPANTS: The prospective, multicenter, open-label SENZA-PDN randomized clinical trial compared conventional medical management (CMM) with 10-kHz SCS plus CMM. Participants with PDN for 1 year or more refractory to gabapentinoids and at least 1 other analgesic class, lower limb pain intensity of 5 cm or more on a 10-cm visual analogue scale (VAS), body mass index (calculated as weight in kilograms divided by height in meters squared) of 45 or less, hemoglobin A1c (HbA1c) of 10% or less, daily morphine equivalents of 120 mg or less, and medically appropriate for the procedure were recruited from clinic patient populations and digital advertising. Participants were enrolled from multiple sites across the US, including academic centers and community pain clinics, between August 2017 and August 2019 with 6-month follow-up and optional crossover at 6 months. Screening 430 patients resulted in 214 who were excluded or declined participation and 216 who were randomized. At 6-month follow-up, 187 patients were evaluated. INTERVENTIONS: Implanted medical device delivering 10-kHz SCS. MAIN OUTCOMES AND MEASURES: The prespecified primary end point was percentage of participants with 50% pain relief or more on VAS without worsening of baseline neurological deficits at 3 months. Secondary end points were tested hierarchically, as prespecified in the analysis plan. Measures included pain VAS, neurological examination, health-related quality of life (EuroQol Five-Dimension questionnaire), and HbA1c over 6 months. RESULTS: Of 216 randomized patients, 136 (63.0%) were male, and the mean (SD) age was 60.8 (10.7) years. Additionally, the median (interquartile range) duration of diabetes and peripheral neuropathy were 10.9 (6.3-16.4) years and 5.6 (3.0-10.1) years, respectively. The primary end point assessed in the intention-to-treat population was met by 5 of 94 patients in the CMM group (5%) and 75 of 95 patients in the 10-kHz SCS plus CMM group (79%; difference, 73.6%; 95% CI, 64.2-83.0; P < .001). Infections requiring device explant occurred in 2 patients in the 10-kHz SCS plus CMM group (2%). For the CMM group, the mean pain VAS score was 7.0 cm (95% CI, 6.7-7.3) at baseline and 6.9 cm (95% CI, 6.5-7.3) at 6 months. For the 10-kHz SCS plus CMM group, the mean pain VAS score was 7.6 cm (95% CI, 7.3-7.9) at baseline and 1.7 cm (95% CI, 1.3-2.1) at 6 months. Investigators observed neurological examination improvements for 3 of 92 patients in the CMM group (3%) and 52 of 84 in the 10-kHz SCS plus CMM group (62%) at 6 months (difference, 58.6%; 95% CI, 47.6-69.6; P < .001). CONCLUSIONS AND RELEVANCE: Substantial pain relief and improved health-related quality of life sustained over 6 months demonstrates 10-kHz SCS can safely and effectively treat patients with refractory PDN. TRIAL REGISTRATION: ClincalTrials.gov Identifier: NCT03228420
Background and Aims Bile duct surgery (BDS), percutaneous transhepatic cholangiography (PTC), and endoscopic retrograde cholangiopancreatography (ERCP) are alternative interventions used to treat ...biliary disease. We aim to describe trends in ERCP, BDS, and PTC on a nationwide level in the United States. Methods We used the National Inpatient Sample to estimate age-standardized utilization trends of inpatient diagnostic ERCP, therapeutic ERCP, BDS, and PTC between 1998 and 2013. We calculated average case fatality, length of stay, patient demographic profile (age, gender, payer), and hospital characteristics (hospital size and metropolitan status) for these procedures. Results Total biliary interventions decreased over the study period from 119.8 to 100.1 per 100,000. Diagnostic ERCP utilization decreased by 76%, and therapeutic ERCP utilization increased by 35%. BDS rates decreased by 78%, and PTC rates decreased by 24%. ERCP has almost completely supplanted surgery for the management of choledocholithiasis. Fatality from ERCP, BDS, and PTC have all decreased, whereas mean length of stay has remained stable. The proportion of, Medicare-insured, Medicaid-insured and uninsured patients undergoing biliary procedures has increased over time. The majority of the increase in therapeutic ERCP and decrease in BDS occurred in large, metropolitan hospitals. Conclusions Although therapeutic ERCP utilization has increased over time, the total volume of biliary interventions has decreased. BDS utilization has experienced the most dramatic decrease, possibly a consequence of the increased therapeutic capacity and safety of ERCP. ERCPs are now predominantly therapeutic in nature. Large urban hospitals are leading the shift from surgical to endoscopic therapy of the biliary system.
Lung cancer is one of the most common fatal diseases in the developed world. The disease is rarely cured by currently available therapies, with an overall survival rate of ∼10%. Characterizing novel ...proteins that offer crucial insights into the processes of lung tumour invasion and metastasis may therefore provide much-needed prognostic markers, and influence therapeutic strategies. Aberrant function of the integrin family of heterodimeric cell surface receptors is a common theme in cancer--investigation into novel integrin activity regulators may offer crucial insights into the processes of tumour invasion and metastasis and may reveal insights into potential therapeutic targets. We previously described that depletion of the novel multi-transmembrane domain protein Fam38A, located at the endoplasmic reticulum (ER), inactivates endogenous beta1 integrin affinity, reducing cell adhesion. We now show that depletion of Fam38A, also now known as Piezo1, causes anchorage independence and a switch to a reduced integrin-dependent mode of cell migration/invasion, a novel phenotype for this integrin-regulating protein. Normal lung epithelial cells show increased rates of migration by 2D time-lapse microscopy and increased capacity to invade into matrigel, despite having decreased integrin affinity. We confirm greatly depleted Fam38A expression in small cell lung cancer (SCLC) lines where a form of reduced integrin-dependent migration, i.e. amoeboid migration, is a known phenotype. We propose that loss of Fam38A expression may cause increased cell migration and metastasis in lung tumours.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background and Objectives: Transient thyroid hormone alterations are common during critical illness and are termed non-thyroidal illness syndrome (NTIS). We studied the prevalence of NTIS in the ICU ...setting and its impact on predicting mortality and other outcomes and compared it to the Acute Physiology and Chronic Health Evaluation II (APACHE II) score. Materials and Methods: The study included 119 consecutive patients admitted with a critical illness. APACHE II score was calculated. Total T3, total T4, TSH, free T3, and free T4 were measured at admission and after six weeks of discharge. NTIS and euthyroid groups were studied for ICU, hospital stays, mortality, readmission, and recovery. Predictors of mortality were compared between survivors and non-survivors. Results: The mean age was 60.15 ± 14.50 years with M:F = 84 (71%):35 (29%). NTIS was observed in 84 (71%), low T3 being the most common abnormality in 53 (63%). The occurrence of NTIS was significantly higher among non-survivors (28/30, 93%) versus survivors (56/89, 63%) (P = 0.002). Non-survivors showed significantly lower T3, TSH, and FT3/FT4 ratios and higher readmissions. NTIS group showed significantly greater ICU stay (P = 0.02) and had higher readmission rates (P = 0.032). Baseline T3 had the greatest power to predict mortality. APACHE II score also correlated significantly with mortality (19.60 ± 10.58 vs 11.99 ± 6.80, P < 0.001). The area under the curve (0.677) for the T3 level was lower than the APACHE II score (0.760). After six weeks, 61% had recovered from NTIS. Conclusions: NTIS was common amongst critically ill patients (71.5%), which reversed in 61% at six weeks. Low T3 was the most common abnormality and independently predicted mortality. Free T3/free T4 also significantly predicted mortality. The correlation between thyroid dysfunction and the severity of primary illness makes it an additional attractive low-cost marker of mortality.
Advancements in environmental DNA (eDNA) approaches have allowed for rapid and efficient species detections in diverse environments. Although most eDNA research is focused on leveraging genetic ...diversity to identify taxa, some recent studies have explored the potential for these approaches to detect within‐species genetic variation, allowing for population genetic assessments and abundance estimates from environmental samples. However, we currently lack a framework outlining the key considerations specific to generating, analysing and applying eDNA data for these two purposes. Here, we discuss how various genetic markers differ with regard to genetic information and detectability in environmental samples and how analysis of eDNA samples differs from common tissue‐based analyses. We then outline how it may be possible to obtain species absolute abundance estimates from eDNA by detecting intraspecific genetic variation in mixtures of DNA under multiple scenarios. We also identify the major causes contributing to allele detection and frequency errors in eDNA data, discuss their consequences for population‐level analyses and outline bioinformatic approaches to detect and remove erroneous sequences. This review summarizes the key advances required to harness the full potential of eDNA‐based intraspecific genetic variation to inform population‐level questions in ecology, evolutionary biology and conservation management.
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