IDO1 + Paneth cells promote immune escape of colorectal cancer

Abstract: Tumors have evolved mechanisms to escape anti-tumor immunosurveillance. They limit humoral and cellular immune activities in the stroma and render tumors resistant to immunotherapy. Sensitizing tumor cells to immune attack is an important strategy to revert immunosuppression. However, the underlying mechanisms of immune escape are still poorly understood. Here we discover Indoleamine-2,3-dioxygenase-1 (IDO1)+ Paneth cells in the stem cell niche of intestinal crypts and tumors, which promoted immune escape of colorectal cancer (CRC). Ido1 expression in Paneth cells was strictly Stat1 dependent. Loss of IDO1+ Paneth cells in murine intestinal adenomas with tumor cell-specific Stat1 deletion had profound effects on the intratumoral immune cell composition. Patient samples and TCGA expression data suggested corresponding cells in human colorectal tumors. Thus, our data uncovered an immune escape mechanism of CRC and identify IDO1+ Paneth cells as a target for immunotherapy

IDO1 + Paneth cells promote immune escape of colorectal cancer

Abstract: Tumors have evolved mechanisms to escape anti-tumor immunosurveillance. They limit humoral and cellular immune activities in the stroma and render tumors resistant to immunotherapy. Sensitizing tumor cells to immune attack is an important strategy to revert immunosuppression. However, the underlying mechanisms of immune escape are still poorly understood. Here we discover Indoleamine-2,3-dioxygenase-1 (IDO1)+ Paneth cells in the stem cell niche of intestinal crypts and tumors, which promoted immune escape of colorectal cancer (CRC). Ido1 expression in Paneth cells was strictly Stat1 dependent. Loss of IDO1+ Paneth cells in murine intestinal adenomas with tumor cell-specific Stat1 deletion had profound effects on the intratumoral immune cell composition. Patient samples and TCGA expression data suggested corresponding cells in human colorectal tumors. Thus, our data uncovered an immune escape mechanism of CRC and identify IDO1+ Paneth cells as a target for immunotherapy

Association of respiratory symptoms and lung function with occupation in the multinational Burden of Obstructive Lung Disease (BOLD) study

Background Chronic obstructive pulmonary disease has been associated with exposures in the workplace. We aimed to assess the association of respiratory symptoms and lung function with occupation in the Burden of Obstructive Lung Disease study. Methods We analysed cross-sectional data from 28 823 adults (≥40 years) in 34 countries. We considered 11 occupations and grouped them by likelihood of exposure to organic dusts, inorganic dusts and fumes. The association of chronic cough, chronic phlegm, wheeze, dyspnoea, forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1)/FVC with occupation was assessed, per study site, using multivariable regression. These estimates were then meta-analysed. Sensitivity analyses explored differences between sexes and gross national income. Results Overall, working in settings with potentially high exposure to dusts or fumes was associated with respiratory symptoms but not lung function differences. The most common occupation was farming. Compared to people not working in any of the 11 considered occupations, those who were farmers for ≥20 years were more likely to have chronic cough (OR 1.52, 95% CI 1.19–1.94), wheeze (OR 1.37, 95% CI 1.16–1.63) and dyspnoea (OR 1.83, 95% CI 1.53–2.20), but not lower FVC (β=0.02 L, 95% CI −0.02–0.06 L) or lower FEV1/FVC (β=0.04%, 95% CI −0.49–0.58%). Some findings differed by sex and gross national income. Conclusion At a population level, the occupational exposures considered in this study do not appear to be major determinants of differences in lung function, although they are associated with more respiratory symptoms. Because not all work settings were included in this study, respiratory surveillance should still be encouraged among high-risk dusty and fume job workers, especially in low- and middle-income countries.publishedVersio

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

The role of CDHR5 in intestinal tissue homeostasis and tumorigenesis

Das Protocadherin CDHR5 ist ein Transmembranprotein und lokalisiert in der mikrovillären Bürstengrenze von Cholangiozyten, Kolonozyten, Enterozyten und Nierenepithelzellen. Dabei verlinkt CDHR5 Mikrovilli. Die Expression von CDHR5 ist in veränderten humanen Kryptaherden, Adenomen, Karzinomen und Lebermetastasen herunterreguliert und suggeriert daher eine tumorunterdrückende Rolle. Um diese Hypothese zu bestätigen, wurden CDHR5-defiziente Mäuse (CDHR5 /) generiert umso die Funktion dieses Zelladhäsionsproteins im Normalgewebe und Tumorgewebe zu untersuchen. CDHR5-defiziente Mäuse waren lebensfähig und zeigten keine auffällige Darmpathologie aber dafür einige den Darm betreffende Phänotypen wie eine Verkürzung der Mikrovilli, eine Fehllokalisation von anderen Proteinen in der mikrovillären Bürstengrenze, eine undichte Darmbarriere und eine Hyperplasie von sekretorischen Darmzellen. Mit dem chemischen AOM/DSS-Protokoll wurde Dickdarmkrebs in CDHR5-defizienten Mäusen induziert und dieser zeigte eine Zunahme in der Größe des Tumors sowie einen invasiven Charakter, begleitet von einer Zunahme von Stammzellen, sowie einer Akkumulation von aktiviertem Stat3 und ß-Catenin im Nucleus und folgend einer Translation vom Epithel zum Mesenchym. Die Expression von Stat3 und ß-Catenin war hochreguliert. Die Expression von Survivin, welches von beiden reguliert wird, war ebenfalls erhöht aber im Gegensatz dazu war die Expression von p21, das durch ß-Catenin unterdrückt wird, reduziert. Die Analyse von Zelllinien im gesunden Darmgewebe sowie im Tumorgewebe zeigte eine erhöhte Anzahl von sekretorischen Zellen in CDHR5-defizienten Mäusen, was auf eine Reduzierung im Notch Signalweg hindeutet. Demzufolge sind reduzierte Werte von den Proteinen, NICD und Hes1 im gesunden Darm sowie in Tumoren von CDHR5-defizienten Mäusen beobachtet worden. Des Weiteren demonstrierten in silico Analysen eine positive Korrelation von CDHR5 und wichtigen Notch Genen im humanen Dickdarmkrebs. Diese Daten zeigen, dass CDHR5 als Tumorsuppressor im Dickdarmkrebs zu sehen ist und auch einen neuen Knotenpunkt zwischen dem Wnt Signalweg und dem Notch Signalweg in der Homöostase des Darms und in der Tumorgenese darstellt.The protocadherin CDHR5 is a transmembrane cell adhesion protein in the microvillar brush border (BB) of cholangiocytes, colonocytes, enterocytes and kidney epithelial cells where it bridges microvilli. CDHR5 is downregulated in human altered crypt foci, adenomas, carcinomas and colorectal cancer (CRC) liver metastasis suggesting a tumor suppressive role. To evaluate this hypothesis, we generated CDHR5-deficient mice (CDHR5 /) and investigated the function of this cell adhesion protein in intestinal tissue homeostasis and autochthonous colorectal tumors. CDHR5-deficient mice were viable without obvious intestinal pathology but revealed distinct intestinal phenotypes such as shortening of microvilli, mislocalization of brush border proteins, mucosal barrier defect and secretory hyperplasia. Tumor induction in CDHR5-deficient mice with the chemical AOM/DSS protocol resulted in an increased tumor burden. Tumors displayed characteristics of invasive carcinomas with enhanced cancer stemness, nuclear accumulation of activated Stat3 and ß-Catenin and epithelial to mesenchymal (EMT) transition. Expression of the Stat3/ß-Catenin target Survivin was also upregulated whereas p21, which is repressed by ß-Catenin, was reduced. Analysis of cell lineage determination demonstrated increased numbers of secretory cells in the intestine and in tumors of CDHR5-deficient mice, which is characteristic for reduced Notch signaling. Consistently, NICD and Hes1 protein levels were reduced in the intestinal mucosa and in tumors of CDHR5-deficient mice. In silico analyses showed a positive correlation of CDHR5 and major Notch targets on RNA level in human cancer. These data demonstrate that CDHR5 functions as a tumor suppressor in CRC and provides a node for Wnt and Notch signaling in intestinal tissue homeostasis and colorectal cancer.Abweichender Titel laut Übersetzung der Verfasserin/des VerfassersArbeit an der Bibliothek noch nicht eingelangt - Daten nicht geprüftMedizinische Universität Wien, Diss., 2019(VLID)442177

Prognostic value of blood glucose levels in diabetic patients upon admission and its outcomes in patients with acute coronary syndrome

Background: Coronary heart disease (CHD) is the main leading cause of morbidity and mortality in patients with diabetes mellitus. Hyperglycemia on admission was associated with a worse outcome for all patients admitted with ACS. Aim: To correlate the relationship between hyperglycemia with acute coronary syndrome and poor outcome. Methodology: Clinical evaluation of the patients were carried out on arrival to Emergency Department regarding: Initial assessment of patient general condition either stable or not through; ABCDE (air way and cervical spine control, breathing, circulation, neurological dysfunction and exposure). Then determine the characters and types of chest pain. Assess the condition of the patients either stable or unstable which will determine the needed investigations and plane of management. Results: the mortality was higher in patients with RBG more than 300 mg/dl (68.4 %), (10.5 %) of the patients had ranged from 250 ─ < 300 mg/dl, and the patients had ranged from 200 ─ < 250 mg/dl were (10.5 %). The patients had ranged from 160 ─ < 200 mg/dl were (5.3) and there were (5.3) of the patients had ranged from 70 ─ < 160mg/dl. Conclusions: The data from this study have shown that hyperglycemia on admission was associated with a worse outcome for all patients admitted with ACS

Effect of Resilience on Health-Related Quality of Life during the COVID-19 Pandemic: A Cross-Sectional Study

The unprecedented outbreak of coronavirus disease 2019 (COVID-19) has caused a huge global health and economic crisis. The aim of the study was to examine the extent to which the resilience of a person is associated with the quality of life (QoL) of adults amongst Saudi Arabia. A cross-sectional study was conducted among a sample of adults in Saudi Arabia. A total of 385 adults voluntarily participated in and completed the survey. The quality of life was measured using the “World Health Organization QoL”. The “Connor-Davidson Resilience Scale” instrument was also used to assess resilience during the COVID-19 pandemic. Amongst the 385 participants, 179 (46%) showed a good QoL, and 205 (54%) reported a relatively poor QoL. The resilience was found to be significantly associated with QoL. The study further revealed that gender-based differences were dominant in the QoL; the men respondents reported a significantly higher QoL in all the domains in comparison to the women respondents. The gender, income, and psychological health and interaction effect of resilience and age explained 40% of the variance in the total score of QoL. In reference to the predictors of the physical health domain of QoL, resilience, gender, and psychological health were significantly associated with the physical health domain of the QoL (R2 = 0.26, p = 0.001). It was also noted that gender was not associated with the social relationships and environmental domains of QoL (p &gt; 0.05). Findings showed a statistically significant association between the score of QoL and resilience, age, gender, income, and psychological health. These findings highlight the significant contribution of gender-based differences, psychological health, and resilience on the domains of QoL

Psychological trauma in different mechanisms of traumatic injury: A hospital-based cross-sectional study.

BackgroundPsychological distress following traumatic injury can influence the patient health, well-being and quality of life; however, this impact may partly vary according to the type and severity of injury. We aimed to study the predominant distress causing cluster and individual symptoms of Post-Traumatic Stress Disorders (PTSD) at the clinical and subthreshold level in patients with traumatic injuries, based on the mechanism of injury (MOI).MethodsA hospital based cross-sectional study was conducted at a Level 1 Trauma Center utilizing PTSD Checklist to diagnose PTSD after one month of the traumatic event. All patients suffering from psychological distresses were assessed by a clinical psychologist in the trauma section. PTSD diagnostic criteria from DSM-5 were used to classify the patients. The inclusion criteria comprised of adult trauma patients who were directly involved in traumatic injuries and admitted under the Trauma Surgery services for a minimum of one day; have ability to provide written informed consent and can be assessed with the PCL-5 checklist after 4 weeks post-injury.ResultsTwo hundred patients completed PCL-5 checklist, of them 26 (13.0%) were positive for PTSD and 174 (87%) had subthreshold scores. The mean age of participants was 34.4±11.8 years and males constituted 90.5%. Road traffic injury (RTI) was most the frequent injury mechanism (59%). PTSD positive patients with RTI, fall of heavy objects, pedestrian injury and assaults had highest average scores on clusters of negative alterations in mood and cognitions (16.9, 18.0, 18.5, 17.0 respectively), followed by hyperarousal. Symptom of always being on the guard and having repeated unwanted or disturbing memories of the incident, was reported by nearly 100% PTSD positive patients. Patients with subthreshold scores also reported distressing symptoms on all four clusters of PTSD.ConclusionsPatients with different MOI showed a broad range of psychological problems with respect to symptom clusters. Negative alteration in mood and cognition followed by hyperarousal caused higher level of distress in patients post traumatic injuries. Subthreshold symptoms of PTSD are more common and deserve more attention

IDO1 + Paneth cells promote immune escape of colorectal cancer

Abstract: Tumors have evolved mechanisms to escape anti-tumor immunosurveillance. They limit humoral and cellular immune activities in the stroma and render tumors resistant to immunotherapy. Sensitizing tumor cells to immune attack is an important strategy to revert immunosuppression. However, the underlying mechanisms of immune escape are still poorly understood. Here we discover Indoleamine-2,3-dioxygenase-1 (IDO1)+ Paneth cells in the stem cell niche of intestinal crypts and tumors, which promoted immune escape of colorectal cancer (CRC). Ido1 expression in Paneth cells was strictly Stat1 dependent. Loss of IDO1+ Paneth cells in murine intestinal adenomas with tumor cell-specific Stat1 deletion had profound effects on the intratumoral immune cell composition. Patient samples and TCGA expression data suggested corresponding cells in human colorectal tumors. Thus, our data uncovered an immune escape mechanism of CRC and identify IDO1+ Paneth cells as a target for immunotherapy