Adult haematopoietic stem cells lacking Hif-1α self-renew normally

The haematopoietic stem cell (HSC) pool is maintained under hypoxic conditions within the bone marrow (BM) microenvironment. Cellular responses to hypoxia are largely mediated by hypoxia-inducible factors, Hif-1 and Hif-2. The oxygen-regulated alpha subunits of Hif-1 and Hif-2 (namely, Hif-1α and Hif-2α) form dimers with their stably expressed beta subunits, and control the transcription of downstream hypoxia-responsive genes to facilitate adaptation to low oxygen tension. An initial study concluded that Hif-1α is essential for HSC maintenance, whereby Hif-1α-deficient HSCs lost their ability to self-renew in serial transplantation assays. In another study, we demonstrated that Hif-2α is dispensable for cell-autonomous HSC maintenance, both under steady-state conditions and following transplantation. Given these unexpected findings, we set out to revisit the role of Hif-1α in cell-autonomous HSC functions. Here we demonstrate that inducible acute deletion of Hif-1α has no impact on HSC survival. Notably, unstressed HSCs lacking Hif-1α efficiently self-renew and sustain long-term multilineage haematopoiesis upon serial transplantation. Finally, Hif-1α-deficient HSCs recover normally after hematopoietic injury induced by serial administration of 5-fluorouracil. We therefore conclude that despite the hypoxic nature of the BM microenvironment, Hif-1α is dispensable for cell-autonomous HSC maintenance

JAK2-mutant hematopoietic cells display metabolic alterations that can be targeted to treat myeloproliferative neoplasms

Increased energy requirement and metabolic reprogramming are hallmarks of cancer cells. We show that metabolic alterations in hematopoietic cells are fundamental to the pathogenesis of mutant JAK2-driven myeloproliferative neoplasms (MPNs). We found that expression of mutant JAK2 augmented and subverted metabolic activity of MPN cells, resulting in systemic metabolic changes in vivo, including hypoglycemia, adipose tissue atrophy, and early mortality. Hypoglycemia in MPN mouse models correlated with hyperactive erythropoiesis and was due to a combination of elevated glycolysis and increased oxidative phosphorylation. Modulating nutrient supply through high-fat diet improved survival, whereas high-glucose diet augmented the MPN phenotype. Transcriptomic and metabolomic analyses identified numerous metabolic nodes in JAK2-mutant hematopoietic stem and progenitor cells that were altered in comparison with wild-type controls. We studied the consequences of elevated levels of Pfkfb3, a key regulatory enzyme of glycolysis, and found that pharmacological inhibition of Pfkfb3 with the small molecule 3PO reversed hypoglycemia and reduced hematopoietic manifestations of MPNs. These effects were additive with the JAK1/2 inhibitor ruxolitinib in vivo and in vitro. Inhibition of glycolysis by 3PO altered the redox homeostasis, leading to accumulation of reactive oxygen species and augmented apoptosis rate. Our findings reveal the contribution of metabolic alterations to the pathogenesis of MPNs and suggest that metabolic dependencies of mutant cells represent vulnerabilities that can be targeted for treating MPNs

Hif-1α and Hif-2α synergize to suppress AML development but are dispensable for disease maintenance

Leukemogenesis occurs under hypoxic conditions within the bone marrow (BM). Knockdown of key mediators of cellular responses to hypoxia with shRNA, namely hypoxia-inducible factor-1α (HIF-1α) or HIF-2α, in human acute myeloid leukemia (AML) samples results in their apoptosis and inability to engraft, implicating HIF-1α or HIF-2α as therapeutic targets. However, genetic deletion of Hif-1α has no effect on mouse AML maintenance and may accelerate disease development. Here, we report the impact of conditional genetic deletion of Hif-2α or both Hif-1α and Hif-2α at different stages of leukemogenesis in mice. Deletion of Hif-2α accelerates development of leukemic stem cells (LSCs) and shortens AML latency initiated by Mll-AF9 and its downstream effectors Meis1 and Hoxa9. Notably, the accelerated initiation of AML caused by Hif-2α deletion is further potentiated by Hif-1α codeletion. However, established LSCs lacking Hif-2α or both Hif-1α and Hif-2α propagate AML with the same latency as wild-type LSCs. Furthermore, pharmacological inhibition of the HIF pathway or HIF-2α knockout using the lentiviral CRISPR-Cas9 system in human established leukemic cells with MLL-AF9 translocation have no impact on their functions. We therefore conclude that although Hif-1α and Hif-2α synergize to suppress the development of AML, they are not required for LSC maintenanc

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Hypermethylierung-assoziierte Dysregulation der WNT-Antagonisten SFRP 1, 2, 4 und 5 beim Multiplen Myelom

There is increasing evidence that epigenetic changes, especially DNA methylation affecting promoter-associated CpG islands, play an important role in the pathogenesis of hematopoietic malignancies. In this study, we detected simultaneous hypermethylation of multiple WNT inhibitors in both MM cell lines and primary samples from patients with MM and MGUS. Our data are in accordance with a recent study by Chim et al. and confirm that concurrent promoter hypermethylation of SFRP genes is a common epigenetic event in MM. We found that aberrant methylation of at least one gene occurred in 48/76 (63.2%) samples. SFRP 1 and SFRP 2 were the most frequently affected genes. Hypermethylation of SFRP genes could be observed in all MM stages and also in 2/3 cases with MGUS indicating that epigenetic dysregulation of WNT antagonists may be an early event in the pathogenesis of malignant plasma cell disorders. In contrast, SFRP 5 hypermethylation was only detected in stage III MM or in PCL, and the association between hypermethylation of SFRP 5 and PCL was statistically significant (p=0.0046). There were no correlations between the methylation status of any SFRP gene with the clinical parameters age and gender, white blood cell count, haemoglobin, platelet count, creatinine or calcium. Epigenetic silencing of the SFRP genes may contribute to dysregulation of the WNT pathway in plasma cells. Further studies are warranted to elucidate the functional consequences of aberrant WNT signaling by downregulation of the SFRP genes in the pathogenesis of MM. Additionally, the increasing evidence for the important role of DNA methylation changes in malignant plasma cell disorders may serve as a basis for the use of epigenetically targeted therapeutic approaches in MM in the future. This study and the results of the group of Roman-Gomez et al. indicate the function of the SFRPs is not redundant in hematologic malignancies, in contrast to the findings in solid tumors. Further studies are needed to eluciate the diffenrence role of the SFRPs

Arı sokmalarına karşı oluşan reaksiyonlar

Arı venomlarına karşı gelişen reaksiyonlar, ciddi sonuçlarının olabilmesi nedeniyle önemli bir sağlık sorunu oluşturmaktadır. Reaksiyonlar arı sokmasının olduğu bölgede, lokal veya sistemik olarak ortaya çıkabilir. Reaksiyonlar IgE bağımlı veya IgE bağımsız mekanizmalara bağlı olabilir. Bu derlemede, arı sokmalarında oluşan lezyonların ve reaksiyonların sınıflandırılması, tanı ve tedavi yöntemleri sunulmaktadı

Review of Postoperative Pain Assessment Records of Nurses. 8th Congress of the European Operating Room Nurses Association

Erden Sevilay, Arslan Sevban, Deniz Sevgi, Kaya Pınar, Gezer Derya (2017) A Review of Postoperative Pain Assessment Records of Nurses. 8th Congress of the European Operating Room Nurses Association (EORNA),Rodos, YUNANİSTAN, (Poster Bildiri)

A density functional theory study of partial oxidation of propylene on Cu2O(001) and CuO(001) surfaces

This work theoretically investigates propylene epoxidation reaction on Cu2O(001) and CuO(001) surfaces using periodical DFT method to determine the active copper species within the reaction mechanism. The transition states and energy profiles are calculated for the formation of surface intermediates such as oxametallopropylene (OMP) over Cu2O(0 0 1) and oxygen bridging (OB) over CuO(0 0 1) and allylic H-stripping reaction (AHS) over both surfaces as well as for formation of products. Propylene oxide (PO) and acetone are obtained through OMP and OB surface intermediates and acrolein generation is observed through allylic H-stripping reaction (AHS). The calculations revealed that the corresponding surface intermediates for epoxidation reaction need to overcome an activation barrier of 13 kcal/mol over CuO surface whereas they occur without an energy barrier over Cu2O surface indicating the higher activity of Cu+ species. Acrolein is also found to be a thermodynamically more favorable product for both surfaces especially over CuO surface due to the presence of more surface oxygen atoms on which the basicity has been evaluated by the adsorption of sulfur dioxide. This indicates that the lattice oxygen inherent in both surface types does not participate in PO production

A review of postoperative pain assessment records of nurses

In conclusion, our study results showed that pain assessment was not carried out in accordance with the pain guidelines and pain assessment and analgesia records were missing. What is desired and expected is that pain which should be paid attention and followed as much as vital signs should be evaluated ideally and recorded. Although the education level of more than half of the nurses in the study was graduate or undergraduate, they were not aware of the importance of pain records. In this context, hospital policies and procedures should be formed and patient record should be made apparent with electronic patient recording system. Online pain management courses should be prepared, bed side visits per day should be performed in the supervision of pain nurse, awareness should be provided by giving training and feedback to the other nurses along with the clinical head nurses. The pivotal role of pain assessment records in the effective pain management therapy should be emphasized in the training

Assessment of Learning Needs in Patients Hospitalized In the General Surgery Clinic

Background: A planned patient training suited to the needs and personal characteristics of the patient is one of the most important factors in meeting the goal of a discharge training. The findings in the literature indicate that a training suited to the patients’ learning needs helps them overcome difficulties related to their diseases; increases their compliance to and satisfaction with the treatment; and decreases unplanned re-admissions to hospital. Aims: This study was conducted to assess the learning needs of the patients hospitalized in surgery clinics. Methodology:This descriptive and cross-sectional study was conducted with 57 patients in the General Surgery Clinic. Data were obtained using the “Patient Information Form,” and the Turkish version of the ‘’Patient Learning Needs Scale (PLNS) ’’ by the researhers. Results: The mean total PLNS score was 215.6±27.9, indicating that the patients’ learning needs were at an extremely significant level within the total scale. The most significant learning needs of the patients were treatment and complications (mean=39.7±3.9, level of significance=4.41), while the least important were the feelings related to condition (mean=19.9±3.8, level of significance 3.98). The study results indicated that the learning needs of general surgery patients are very high before their discharge from the hospital, and that treatment and complications were the main subjects where patients needed to be informed. Conclusion:The effective management of complications and participation of the patients in this process can be ensured through the assessment of patient learning needs by surgery nurses according to the patients’ own priorities. Thus, a key implication arising from this study is, raising awareness of educational roles of surgical nurses