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Environmental Pollution (Barking, Essex... Jun 2024Mercuric chloride (HgCl) is a widespread inorganic mercury with digestive toxicity. The pancreas is an important digestive organ in animals, and pancreatic fibrosis (PF)...
Mercuric chloride (HgCl) is a widespread inorganic mercury with digestive toxicity. The pancreas is an important digestive organ in animals, and pancreatic fibrosis (PF) is a major pathological feature of chronic pancreatitis, which can be caused by heavy metals. Selenium (Se) is an essential trace element for the animal organism, performing biological functions in the form of selenoproteins, as well as alleviating the toxicity of heavy metals. In this study, we explored the specific mechanisms underlying the protective effect of Se on HgCl-induced pancreatic injury in chickens. Morphological observation and serum biochemical analysis showed that Se attenuated HgCl-caused pancreatic tissue damage and elevated glucose concentration and α-amylase activity. Next, the expression of oxidative stress indicators such as MDA and GSH-Px as well as inflammation-related markers including IL-1β, IL-6, and TNF-α were detected. Results showed that Se had an inhibitory effect on HgCl-induced oxidative stress and inflammation. Furthermore, we found that Se alleviated HgCl-induced PF by detecting the expression of markers related to PF including TGF-β1, α-SMA, COL1A1, and FN1. Mechanistically, Se attenuated HgCl-induced PF via the MAPK signaling pathway. Importantly, several selenoproteins, especially those with antioxidant activity, were involved in the protective effect of Se on HgCl toxicity. In conclusion, our findings demonstrated that Se inhibited HgCl-induced oxidative stress and inflammation and alleviated chicken PF through the MAPK signaling pathway, in which some antioxidant selenoproteins were involved.
PubMed: 38942272
DOI: 10.1016/j.envpol.2024.124448 -
Stem Cell Reports Jun 2024Genetic differences between pluripotent stem cell lines cause variable activity of extracellular signaling pathways, limiting reproducibility of directed differentiation...
Genetic differences between pluripotent stem cell lines cause variable activity of extracellular signaling pathways, limiting reproducibility of directed differentiation protocols. Here we used human embryonic stem cells (hESCs) to interrogate how exogenous factors modulate endogenous signaling events during specification of foregut endoderm lineages. We find that transforming growth factor β1 (TGF-β1) activates a putative human OTX2/LHX1 gene regulatory network which promotes anterior fate by antagonizing endogenous Wnt signaling. In contrast to Porcupine inhibition, TGF-β1 effects cannot be reversed by exogenous Wnt ligands, suggesting that induction of SHISA proteins and intracellular accumulation of Fzd receptors render TGF-β1-treated cells refractory to Wnt signaling. Subsequently, TGF-β1-mediated inhibition of BMP and Wnt signaling suppresses liver fate and promotes pancreas fate. Furthermore, combined TGF-β1 treatment and Wnt inhibition during pancreatic specification reproducibly and robustly enhance INSULIN cell yield across hESC lines. This modification of widely used differentiation protocols will enhance pancreatic β cell yield for cell-based therapeutic applications.
PubMed: 38942030
DOI: 10.1016/j.stemcr.2024.05.010 -
Artificial Intelligence in Medicine Jun 2024Pancreatic cancer does not show specific symptoms, which makes the diagnosis of early stages difficult with established image-based screening methods and therefore has...
Pancreatic cancer does not show specific symptoms, which makes the diagnosis of early stages difficult with established image-based screening methods and therefore has the worst prognosis among all cancers. Although endoscopic ultrasonography (EUS) has a key role in diagnostic algorithms for pancreatic diseases, B-mode imaging of the pancreas can be affected by confounders such as chronic pancreatitis, which can make both pancreatic lesion segmentation and classification laborious and highly specialized. To address these challenges, this work proposes a semi-supervised multi-task network (SSM-Net) to leverage unlabeled and labeled EUS images for joint pancreatic lesion classification and segmentation. Specifically, we first devise a saliency-aware representation learning module (SRLM) on a large number of unlabeled images to train a feature extraction encoder network for labeled images by computing a contrastive loss with a semantic saliency map, which is obtained by our spectral residual module (SRM). Moreover, for labeled EUS images, we devise channel attention blocks (CABs) to refine the features extracted from the pre-trained encoder on unlabeled images for segmenting lesions, and then devise a merged global attention module (MGAM) and a feature similarity loss (FSL) for obtaining a lesion classification result. We collect a large-scale EUS-based pancreas image dataset (LS-EUSPI) consisting of 9,555 pathologically proven labeled EUS images (499 patients from four categories) and 15,500 unlabeled EUS images. Experimental results on the LS-EUSPI dataset and a public thyroid gland lesion dataset show that our SSM-Net clearly outperforms state-of-the-art methods.
PubMed: 38941908
DOI: 10.1016/j.artmed.2024.102919 -
Cancer Epidemiology Jun 2024Data on social inequalities in cancer mortality are sparse, especially in low- and middle-income countries. We aimed to analyze the socioeconomic inequalities in cancer...
INTRODUCTION
Data on social inequalities in cancer mortality are sparse, especially in low- and middle-income countries. We aimed to analyze the socioeconomic inequalities in cancer mortality in Costa Rica between 2010 and 2018.
METHODS
We linked 9-years of data from the National Electoral Rolls, National Birth Index and National Death Index to classify deaths due to cancer and socioeconomic characteristics of the district of residence, as measured by levels of urbanicity and wealth. We analyzed the fifteen most frequent cancer sites in Costa Rica among the 2.7 million inhabitants aged 20 years and older. We used a parametric survival model based on a Gompertz distribution.
RESULTS
Compared to urban areas, mixed and rural area residents had lower mortality from pancreas, lung, breast, prostate, kidney, and bladder cancers, and higher mortality from stomach cancer. Mortality from stomach, lung and cervical cancer was higher, and mortality from colorectal cancer, non-Hodgkin lymphoma and leukemia was lower in the most disadvantaged districts, compared to the wealthiest ones.
CONCLUSION
We observed marked disparities in cancer mortality in Costa Rica in particular from infection- and lifestyle- related cancers. There are important opportunities to reduce disparities in cancer mortality by targeting cancer prevention, early detection and opportune treatment, mainly in urban and disadvantaged districts.
PubMed: 38941875
DOI: 10.1016/j.canep.2024.102604 -
Journal of Molecular Endocrinology Jun 2024Pregnancy requires metabolic adaptations in order to meet support fetal growth with nutrient availability. In this study, the influence of pregnancy on metabolically...
Pregnancy requires metabolic adaptations in order to meet support fetal growth with nutrient availability. In this study, the influence of pregnancy on metabolically active organs (adipose tissues in particular) was investigated. Our results showed that maternal weight and adipose mass presented dynamic remodeling in the periparturient mice. Meanwhile, pregnancy mice displayed obvious glucose intolerance and insulin resistance in late pregnancy as compared to non-pregnancy, which were partially reversed at parturition. Further analysis revealed that different fat depots exhibited site-specific adaptions of morphology and functionality as pregnancy advanced. Brown and inguinal white adipose tissue (BAT and IngWAT) exhibited obviously decreased thermogenic activity; by contrast, gonadal white adipose tissue (GonWAT) displayed remarkably increased lipid mobilization. Notably, we found that mammary gland differentiation was enhanced in IngWAT, followed by BAT, but not in GonWAT. These result indicated that brown and white adipose tissues might synergistically play a crucial role in maintaining the maxicum of energy supply for mother and fetus, which facilitates the mammary duct luminal epithelium development as well as the growth and development of fetus. Accompanied with adipose adaptation, however, our results revealed that the liver and pancreas also displayed significant metabolic adaptability, which together tended to trigger the risk of maternal metabolic diseases. Importantly, pregnancy-dependent obesity in our mice model resembled the disturbed metabolic phenotypes of pregnant women such as hyperglyceridemia and hypercholesterolemia. Our findings in this study could provide valuable clues for better understanding the underlying mechanisms of metabolic maladaptation, and facilitate the development of the prevention and treatment of metabolic diseases.
PubMed: 38941267
DOI: 10.1530/JME-24-0012 -
Archives of Animal Nutrition Jun 2024Dietary fibre is mainly classified according to its chemical characteristics but structure and particle size of fibre-rich feedstuff can also be decisive for digestion...
Dietary fibre is mainly classified according to its chemical characteristics but structure and particle size of fibre-rich feedstuff can also be decisive for digestion and performance. So far, only few studies investigated this in pigs. This experiment aimed to compare coarse and finely ground dried hemp plants and apple pomace regarding performance and ileal and total tract nutrient digestibility of growing pigs. Coarse or finely ground apple pomace or dried hemp plants were added to the diet of 56 nine weeks old growing pigs (DanBred x Duroc), housed in flat decks with each 2 animals. The growing pigs received the experimental diets for three weeks while performance was recorded. Eight pigs per group were sacrificed and digesta and organ tissue sampled. The stomach health was evaluated by visually scoring of the mucosa integrity. Apparent ileal (AID) and total tract digestibility (ATTD) were calculated using titanium dioxide as marker. Statistical analyses were performed using two-way ANOVA ( < 0.05). The highest feed intake (fibre particle size, = 0.018) and bodyweight gain (fibre particle size, = 0.018; fibre source x particle size interaction, = 0.040), was observed in animals fed finely ground apple pomace, while the feed conversion ratio was 8-12% lower in pigs fed finely ground fibre sources ( = 0.012). No differences in stomach mucosa integrity were detected between the groups. The relative pancreas ( = 0.045), stomach ( < 0.001), and jejunum ( = 0.010) weights were higher in animals fed diets containing apple pomace. In contrast, the relative liver, caecum and colon weights were not affected by fibre source or particle size. The AID of protein and amino acids was not affected, while ATTD was increased by fibre source (hemp vs. apple pomace) reducing faecal nitrogen excretion. The AID of calcium was increased when diets contained apple pomace ( < 0.001), while zinc AID and ATTD were enhanced when diets contained dried hemp ( = 0.016; = 0.016, respectively). Our results suggest that the structure as well as the chemical characteristics should be considered in a future fibre evaluation system in pigs.
PubMed: 38941242
DOI: 10.1080/1745039X.2024.2368284 -
Magyar Sebeszet Jun 2024Bevezetés: A posztoperatív pancreasfistula mind proximalis, mind distalis pancreatectomia után a legjelentősebb sebészi szövődménynek számít. A...
Bevezetés: A posztoperatív pancreasfistula mind proximalis, mind distalis pancreatectomia után a legjelentősebb sebészi szövődménynek számít. A szakirodalomban nincs egyértelműen ajánlott, megbízható módszer ezen probléma kiküszöbölésére, emiatt történnek újítások szerte a világon. Jelen közleményünkben a technikai innovációinkról számolunk be. Anyag és módszerek: 2013. január 1-jétől 2023. november 30-ig terjedő időszakban 205 Whipple-műtétet végeztünk nyitottan, mely során a pancreatojejunalis anastomosist az általunk módosított dohányzacskó-öltéses módszerrel készítettük el. 2019. január 1. és 2023. november 30. között pedig 30 betegnél történt nyitott distalis pancreatectomia, amikor a pancreascsonkot az általunk kifejlesztett technikával, szabad rectus fascia-peritoneum grafttal fedtük, majd azt cirkuláris öltéssel rögzítettük. Közleményünkben ezen két módszerrel elért eredményeket ismertetjük. Eredmények: a demográfiai adatok megfeleltek a betegségnél szokásosnak. A posztoperatív ápolási idő és a transzfúzió igény terén észlelt különbségek tükrözték a kétféle beavatkozás eltérő invazivitását. A releváns pancreasfistula kialakulási rátája kedvező képet mutatott, Whipple-műtét után 7,3% volt, míg distalis pancreatectomát követően nem fejlődött ki. A reoperációs és a halálozási arányok megfeleltek az elvártaknak és korreláltak a műtétek kiterjedtségével. Következtetés: pancreas resectiók utáni komplikációk csökkentésére tett törekvéseink során a módosított dohányzacskó-öltéses pancreatojejunostomia és a pancreascsonk fedésére kidolgozott módszerünk egyaránt kedvező eredményekkel járt.
Topics: Humans; Pancreatic Fistula; Postoperative Complications; Female; Male; Pancreatectomy; Middle Aged; Pancreaticojejunostomy; Aged; Pancreaticoduodenectomy; Treatment Outcome; Adult
PubMed: 38941151
DOI: 10.1556/1046.2024.20002 -
Sheng Li Xue Bao : [Acta Physiologica... Jun 2024The purpose of the present study was to investigate the modeling time of type 2 diabetes mellitus (T2DM) mouse model induced by high fat diet (HFD) alone and the effects...
The purpose of the present study was to investigate the modeling time of type 2 diabetes mellitus (T2DM) mouse model induced by high fat diet (HFD) alone and the effects of HFD on the pathology and function of organs related to glucose and lipid metabolism. C57BL/6 mice were fed with normal diet (NC group) or HFD (HFD group). The time of successful T2DM modeling was evaluated by measuring body weight, fasting blood glucose and glucose tolerance at time points of 0, 4, 8, 12, 16 and 20 weeks. The functional and pathological changes of glucose and lipid metabolism related organs were evaluated by detecting insulin tolerance, plasma lipid levels, vascular function, as well as HE staining of pancreas and liver. The results showed that compared with the NC group, the HFD group had significantly increased body weight after 8 weeks of HFD. After 16 weeks of HFD, the HFD group exhibited impaired fasting glucose tolerance. After 20 weeks of HFD, the HFD group mice reached diabetic state, showing impaired glucose tolerance and insulin resistance, islet volume reduction and vacuolar degeneration; Large number of lipid droplets appeared in liver cells, and the level of AMPK phosphorylation in liver tissue was significantly increased in the HFD groups, compared with the NC group; There was endothelial dependent diastolic dysfunction in the thoracic aorta of the HFD group; Compared with the NC group, the HFD group mice showed a significant increase in urinary protein levels. These results suggest that T2DM mouse model can be successfully established by HFD induction alone for 20 weeks. The model is characterized by insulin resistance, fatty liver, hyperlipidemia, vascular dysfunction, renal dysfunction and pathological changes of islet and liver cells, which are similar to those of T2DM patients. Therefore it can be used as an ideal animal model for T2DM research.
Topics: Animals; Diabetes Mellitus, Type 2; Mice; Diet, High-Fat; Mice, Inbred C57BL; Male; Disease Models, Animal; Insulin Resistance; Lipid Metabolism; Diabetes Mellitus, Experimental; Liver
PubMed: 38939933
DOI: No ID Found -
Journal of Medical Economics Jun 2024AimsWe aimed to describe the clinical, economic, and societal burdens of cystic fibrosis (CF) and impact of CF transmembrane conductance regulator modulator (CFTRm)...
AimsWe aimed to describe the clinical, economic, and societal burdens of cystic fibrosis (CF) and impact of CF transmembrane conductance regulator modulator (CFTRm) treatment on people with CF, caregivers, and healthcare systems.Material and MethodsThis retrospective study used linked real-world data from Swedish national population-based registries and the Swedish CF Quality Registry to assess clinical, economic, and societal burden and CFTR impact in CF. Records from people with CF and a ten-fold control population without CF matched by sex, birth year, and location were compared during 2019. Outcomes for a subset aged >6 years initiating lumacaftor/ivacaftor (LUM/IVA) in 2018 were compared 12 months pre- and post-treatment initiation.ResultsPeople with CF (n = 743) had >10 times more inpatient and outpatient specialist visits annually vs controls (n = 7406). Those aged >18 had an additional 77·7 (95% CI: 70·3, 85·1) days of work absence, at a societal cost of €11,563 (95% CI: 10,463, 12,662), while caregivers of those aged <18 missed an additional 6.1 (5.0, 7.2) workdays. With LUM/IVA treatment, people with CF (n = 100) had significantly increased lung function (mean change in ppFEV [3·8 points; 95% CI: 1·1, 6·6]), on average 0·5 (95% CI: -0·8, -0·2) fewer pulmonary exacerbations and 45·2 (95% CI: 13·3, 77·2) fewer days of antibiotics. Days of work lost by caregivers of people with CF aged <18 decreased by 5·4 days (95% CI: 2·9, 7·9).ConclusionCF is associated with a high clinical economic and societal burden in Sweden. Improvements in clinical status observed in people with CF treated with LUM/IVA were reflected in reduced caregiver and societal burden.
PubMed: 38939921
DOI: 10.1080/13696998.2024.2373000 -
Molecular Therapy. Nucleic Acids Jun 2024Small interfering RNAs (siRNAs) are revolutionizing the treatment of liver-associated indications. Yet, robust delivery to extrahepatic tissues remains a challenge....
Small interfering RNAs (siRNAs) are revolutionizing the treatment of liver-associated indications. Yet, robust delivery to extrahepatic tissues remains a challenge. Conjugating lipids (e.g., docosanoic acid [DCA]) to siRNA supports extrahepatic delivery, but tissue accumulation remains lower than that achieved in liver by approved siRNA therapeutics. Early evidence suggests that functionalizing DCA with a head group (e.g., phosphatidylcholine [PC]) may enhance delivery to certain tissues. Here, we report the first systematic evaluation of the effect of PC head group chemistry on the extrahepatic distribution of DCA-conjugated siRNAs. We show that functionalizing DCA with a PC head group enhances siRNA accumulation in heart, muscle, lung, pancreas, duodenum, urinary bladder, and fat. Varying the size of the linker between the phosphate and choline moiety of the PC head group altered the extrahepatic accumulation of siRNA, with the optimal linker length being different for different tissues. Increasing PC head group valency also improved extrahepatic accumulation in a tissue-specific manner. This study demonstrates the structural impact of the PC moiety on the biodistribution of lipid-conjugated siRNA and introduces multiple novel PC variants for the chemical optimization of DCA-conjugated siRNA. These chemical variants can be used in the context of other lipids to increase the repertoire of conjugates for the extrahepatic distribution of siRNAs.
PubMed: 38938759
DOI: 10.1016/j.omtn.2024.102230