Repeated intravenous doses of human umbilical cord-derived mesenchymal stromal cells for bronchopulmonary dysplasia: results of a phase 1 clinical trial with 2-year follow-up.

BACKGROUND: Currently, there is a lack of effective treatments or preventive strategies for bronchopulmonary dysplasia (BPD). Pre-clinical studies with mesenchymal stromal cells (MSCs) have yielded encouraging results. The safety of administering repeated intravenous doses of umbilical cord tissue-derived mesenchymal stromal cells (UC-MSCs) has not yet been tested in extremely-low-gestational-age newborns (ELGANs). AIMS: to test the safety and feasibility of administering three sequential intravenous doses of UC-MSCs every 7 days to ELGANs at risk of developing BPD. METHODS: In this phase 1 clinical trial, we recruited ELGANs (birth weight ≤1250 g and ≤28 weeks in gestational age [GA]) who were on invasive mechanical ventilation (IMV) with FiO2 ≥ 0.3 at postnatal days 7-14. Three doses of 5 × 106/kg of UC-MSCs were intravenously administered at weekly intervals. Adverse effects and prematurity-related morbidities were recorded. RESULTS: From April 2019 to July 2020, 10 patients were recruited with a mean GA of 25.2 ± 0.8 weeks and a mean birth weight of 659.8 ± 153.8 g. All patients received three intravenous UC-MSC doses. The first dose was administered at a mean of 16.6 ± 2.9 postnatal days. All patients were diagnosed with BPD. All patients were discharged from the hospital. No deaths or any serious adverse events related to the infusion of UC-MSCs were observed during administration, hospital stays or at 2-year follow-up. CONCLUSIONS: The administration of repeated intravenous infusion of UC-MSCs in ELGANs at a high risk of developing BPD was feasible and safe in the short- and mid-term follow-up.

CircRNAome of Childhood Acute Lymphoblastic Leukemia: Deciphering Subtype-Specific Expression Profiles and Involvement in TCF3::PBX1 ALL.

Childhood B-cell acute lymphoblastic leukemia (B-ALL) is a heterogeneous disease comprising multiple molecular subgroups with subtype-specific expression profiles. Recently, a new type of ncRNA, termed circular RNA (circRNA), has emerged as a promising biomarker in cancer, but little is known about their role in childhood B-ALL. Here, through RNA-seq analysis in 105 childhood B-ALL patients comprising six genetic subtypes and seven B-cell controls from two independent cohorts we demonstrated that circRNAs properly stratified B-ALL subtypes. By differential expression analysis of each subtype vs. controls, 156 overexpressed and 134 underexpressed circRNAs were identified consistently in at least one subtype, most of them with subtype-specific expression. TCF3::PBX1 subtype was the one with the highest number of unique and overexpressed circRNAs, and the circRNA signature could effectively discriminate new patients with TCF3::PBX1 subtype from others. Our results indicated that NUDT21, an RNA-binding protein (RBP) involved in circRNA biogenesis, may contribute to this circRNA enrichment in TCF3::PBX1 ALL. Further functional characterization using the CRISPR-Cas13d system demonstrated that circBARD1, overexpressed in TCF3::PBX1 patients and regulated by NUDT21, might be involved in leukemogenesis through the activation of p38 via hsa-miR-153-5p. Our results suggest that circRNAs could play a role in the pathogenesis of childhood B-ALL.

Engaging primary care physicians is critical in the screening and diagnosis of colorectal cancer at safety-net hospital systems.

Background: Primary care physicians (PCP) play a key role in offering colorectal cancer (CRC) screenings, particularly amongst underserved populations. Given potential delays in or omission of CRC screening in the absence of a PCP, we aimed to determine stage of CRC at diagnosis in an underserved population. Methods: A retrospective chart review was conducted at two Los Angeles County safety-net hospitals. Inclusion criteria were a CRC diagnosis between 2018 and 2021 and age between 50 and 75 years at diagnosis time. The primary outcome was the cancer stage at diagnosis. Results: A total of 373 patients were included, of those, 52.5 % had a PCP. Compared to others, PCP was similar in age, racial composition, and primary spoken language (Table 1). Of patients with a PCP, 52.0% were diagnosed by screening. After screening, the most common indication for colonoscopy were blood per rectum (24.9 %) and imaging findings (18.0 %). Patients with a PCP had a significantly lower rate of late stage CRC than those without a PCP (42.4 % vs. 68.0 %, p < 0.001). After adjustment, having a PCP was associated with significantly reduced odds of late stage CRC (Adjusted Odds Ratio 0.83, 95 % Confidence Interval [0.68-1.04]). Having a PCP was not associated with any adjusted increase in number of adenomas or tumor size. Conclusions: Patients with a PCP, irrespective of undergoing screening, were diagnosed at earlier CRC stages. This underlines the crucial role of PCPs in CRC and diagnosis, reinforcing the need for their active involvement in these processes.

Clinical and financial outcomes of hospitalizations for cardiac device infection during the COVID-19 pandemic in the US.

BACKGROUND: Cardiac device infection (CDI) can occur in up to 2.2% of patients after device placement, with mortality rates exceeding 15%. Although device removal is standard management, the COVID-19 pandemic has been associated with resource diversion and decreased patient presentation for cardiovascular disease. We ascertained the association of the COVID-19 pandemic with outcomes and resource utilization after admission for CDI. METHODS: The 2016-2020 National Inpatient Sample was used to retrospectively study all adult admissions for CDI. Patients admitted between March and December, 2020 were classified as the pandemic cohort, with the rest pre-pandemic. The primary outcome was major adverse events (MAE), with secondary outcomes of overall length of stay (LOS), post-device removal LOS, time to device replacement, and hospitalization costs. MAE was a combination of in-hospital mortality and select complications. Multivariable regression models were developed to determine the relationship between the pandemic and the aforementioned outcomes. RESULTS: Of an estimated 190,160 patients, 14.3% comprised the pandemic cohort; 2.4% of these patients were COVID-19 positive. The pandemic cohort was older, less commonly female, and had higher rates of congestive heart failure. After adjustment, the pandemic was not associated with altered odds of MAE, device removal, or subsequent device replacement. The pandemic was, however, associated with decreased adjusted overall LOS (ß -0.38 days) and days to device replacement (ß -0.83 days). The pandemic was likewise associated with $2,000 increased adjusted hospitalization costs. CONCLUSION: The pandemic did not have a significant impact on clinical outcomes in patients admitted for CDI, despite higher hospitalization costs and decreased length of stay.

The shape of cancer relapse: Topological data analysis predicts recurrence in paediatric acute lymphoblastic leukaemia.

Although children and adolescents with acute lymphoblastic leukaemia (ALL) have high survival rates, approximately 15-20% of patients relapse. Risk of relapse is routinely estimated at diagnosis by biological factors, including flow cytometry data. This high-dimensional data is typically manually assessed by projecting it onto a subset of biomarkers. Cell density and "empty spaces" in 2D projections of the data, i.e. regions devoid of cells, are then used for qualitative assessment. Here, we use topological data analysis (TDA), which quantifies shapes, including empty spaces, in data, to analyse pre-treatment ALL datasets with known patient outcomes. We combine these fully unsupervised analyses with Machine Learning (ML) to identify significant shape characteristics and demonstrate that they accurately predict risk of relapse, particularly for patients previously classified as 'low risk'. We independently confirm the predictive power of CD10, CD20, CD38, and CD45 as biomarkers for ALL diagnosis. Based on our analyses, we propose three increasingly detailed prognostic pipelines for analysing flow cytometry data from ALL patients depending on technical and technological availability: 1. Visual inspection of specific biological features in biparametric projections of the data; 2. Computation of quantitative topological descriptors of such projections; 3. A combined analysis, using TDA and ML, in the four-parameter space defined by CD10, CD20, CD38 and CD45. Our analyses readily extend to other haematological malignancies.

Immune stress suppresses innate immune signaling in preleukemic precursor B-cells to provoke leukemia in predisposed mice.

The initial steps of B-cell acute lymphoblastic leukemia (B-ALL) development usually pass unnoticed in children. Several preclinical studies have shown that exposure to immune stressors triggers the transformation of preleukemic B cells to full-blown B-ALL, but how this takes place is still a longstanding and unsolved challenge. Here we show that dysregulation of innate immunity plays a driving role in the clonal evolution of pre-malignant Pax5+/- B-cell precursors toward leukemia. Transcriptional profiling reveals that Myd88 is downregulated in immune-stressed pre-malignant B-cell precursors and in leukemic cells. Genetic reduction of Myd88 expression leads to a significant increase in leukemia incidence in Pax5+/-Myd88+/- mice through an inflammation-dependent mechanism. Early induction of Myd88-independent Toll-like receptor 3 signaling results in a significant delay of leukemia development in Pax5+/- mice. Altogether, these findings identify a role for innate immunity dysregulation in leukemia, with important implications for understanding and therapeutic targeting of the preleukemic state in children.

Intraosseous injection of mesenchymal stem cells for the treatment of osteonecrosis of the immature femoral head and prevention of head deformity: A study in a pig model.

BACKGROUND: Cell therapy has been proposed as part of the therapeutic arsenal to assist bone formation and remodeling in the early stages of osteonecrosis of the femoral head. The purpose of this study is to determine the effects of intraosseous inoculation of mesenchymal stem cells on bone formation and remodeling in an established experimental model of osteonecrosis of the femoral head in immature pigs. METHODS: Thirty-one 4-week-old immature Yorkshire pigs were used. Experimental osteonecrosis of the femoral head was created in the right hip of all included animals (n = 31). The month after surgery, hip and pelvis radiographs were taken to confirm osteonecrosis of the femoral head. Four animals were excluded following surgery. Two groups were established: (A) mesenchymal stem cell-treated group (n = 13) and (B) saline-treated group (n = 14). One month after surgery the mesenchymal stem cell-group received an intraosseous injection of 10 × 106 mesenchymal stem cell (5 cc) and the saline-treated group of 5 cc of physiological saline solution. Osteonecrosis of the femoral head progression was assessed by monthly X-rays (1-, 2-, 3- and 4-months post-surgery). The animals were sacrificed 1 or 3 months following the intraosseous injection. Repair tissue and osteonecrosis of the femoral head were histologically evaluated immediately after sacrifice. RESULTS: At time of sacrifice, radiographic images showed evident osteonecrosis of the femoral head with associated severe femoral head deformity in 11 of the 14 animals (78%) in the saline group and in only 2 of the 13 animals (15%) in the mesenchymal stem cell group. Histologically, the mesenchymal stem cell group showed less osteonecrosis of the femoral head and less flattening. In the saline group, there was pronounced femoral head flattening and the damaged epiphyseal trabecular bone was largely replaced with fibrovascular tissue. CONCLUSION: Intraosseous mesenchymal stem cells inoculation improved bone healing and remodeling in our immature pig osteonecrosis of the femoral head model. This work supports further investigation to determine whether mesenchymal stem cells enhance the healing process in immature osteonecrosis of the femoral head.

Effect of surgical timing on outcomes after cholecystectomy for mild gallstone pancreatitis.

BACKGROUND: Retrospective and single-center studies have demonstrated that early cholecystectomy is associated with shorter length of stay in patients with mild gallstone pancreatitis. However, these studies are not powered to detect differences in adverse events. Using a nationally representative cohort, we evaluated the association of timing for cholecystectomy with clinical outcomes and resource use in patients with gallstone pancreatitis. METHODS: All adult hospitalizations for gallstone pancreatitis were tabulated from the 2016-2019 Nationwide Readmissions Database. Using International Classification of Disease, 10th Revision codes, patient comorbidities and operative characteristics were determined. Patients with end-organ dysfunction or cholangitis were excluded to isolate those with only mild gallstone pancreatitis. Major adverse events were defined as a composite of 30-day mortality and perioperative (cardiovascular, respiratory, neurologic, infectious, and thromboembolic) complications. Timing of laparoscopic cholecystectomy was divided into Early (within 2 days of admission) and Late (>2 days after admission) cohorts. Multivariable logistic and linear regression were then used to evaluate the association of cholecystectomy timing with major adverse events and secondary outcomes of interest, including postoperative hospital duration of stay, costs, non-home discharge, and readmission rate within 30 days of discharge. RESULTS: Of an estimated 129,451 admissions for acute gallstone pancreatitis, 25.6% comprised the Early cohort. Compared to patients in the Early cohort, Late cohort patients were older (56 [40-69] vs 53 [37-66] years, P < .001), more likely male (36.6 vs 32.8%, P < .001), and more frequently underwent preoperative endoscopic retrograde cholangiopancreatography (22.2 vs 10.9%, P < .001). In addition, the Late cohort had higher unadjusted rates of major adverse events and index hospitalization costs, compared to Early. After risk adjustment, late cholecystectomy was associated with higher odds of major adverse events (adjusted odds ratio 1.40, 95% confidence interval 1.29-1.51) and overall adjusted hospitalization costs by $2,700 (95% confidence interval 2,400-2,800). In addition, compared to the Early group, those in the Late cohort had increased odds of 30-day readmission (adjusted odds ratio 1.12, 95% confidence interval 1.03-1.23) and non-home discharge (adjusted odds ratio 1.42, 95% confidence interval 1.31-1.55). CONCLUSION: Cholecystectomy >2 days after admission for mild gallstone pancreatitis was independently associated with increased major adverse events, costs, 30-day readmissions, and non-home discharge. Given the significant clinical and financial consequences, reduced timing to surgery should be prioritized in the overall management of this patient population.

Factors Associated With Early Amputation in Patients With Chronic Limb Threatening Ischemia.

INTRODUCTION: Despite advancements in revascularization procedures, early amputation (EA) among patients with chronic limb threatening ischemia (CLTI) are still common. The present study evaluated clinical outcomes of patients with CLTI and factors associated with EA. METHODS: The 2016-2019 Nationwide Readmission Database was queried to identify all adults (≥18 years) with CLTI of lower extremities undergoing limb salvage (LS) procedures. The primary outcome of the study was EA within 90 days of discharge. Secondary outcomes included infectious complication, length of stay (LOS), cumulative hospitalization cost and non-home discharge. RESULTS: Of 103,703 patients who initially underwent surgical or endovascular revascularization, 10,439 (10.1%) subsequently underwent major amputation within 90 days of discharge. Following risk adjustment, factors associated with higher odds of EA were male sex, low-income quartile, tissue loss due to ulceration or gangrene, end-stage renal disease, and diabetes. Compared to those undergoing open revascularization, patients with endovascular limb salvage had a higher likelihood of having early amputation (AOR 1.41, 95% CI 1.31-1.51). Patients undergoing EA had greater odd of infectious complication, incremental LOS, incremental cost and non-home discharge. CONCLUSIONS: We identified several risk factors to be associated with EA in patients with CLTI. These findings may supplement the objective performance goals for limb-related outcomes and facilitate institutional limb salvage programs.

The use of surgical intervention for lower gastrointestinal bleeding and its association with clinical outcomes and resource use.

BACKGROUND: To assess the use of surgical intervention for lower gastrointestinal bleeding and evaluate its associated factors. METHODS: The 2016 to 2019 National Inpatient Sample was queried to identify non-elective adult (≥18 years) hospitalizations for lower gastrointestinal bleeding. The International Classification of Diseases, 10th Revision, codes were used to ascertain patient characteristics, including signs of hemodynamic instability, potential lower gastrointestinal bleed source, and transfusion of blood products, as well as endoscopic, radiologic, and surgical intervention. Multivariable regression analyses were used to elucidate factors associated with operative management of lower gastrointestinal bleeding and evaluate its associated mortality, length of stay, and hospitalization costs. RESULTS: Of an estimated 364,495 patients, 1.7% underwent an operation for lower gastrointestinal bleeding. Compared to those managed conservatively, patients who underwent surgical intervention more commonly had diverticular-related bleeding, signs of hypovolemia, and less frequently underwent endoscopic intervention. After the adjustment of patient and hospital characteristics, ischemic colitis (adjusted odds ratio 7.5, 95% confidence interval 1.8-30.9, ref: hemorrhoids), hemodynamic instability (adjusted odds ratio 1.7, 95% confidence interval 1.5-2.0), and angiographic embolization (adjusted odds ratio 4.9, 95% confidence interval 3.9-6.0, ref: no endoscopic/radiologic intervention) were associated with greater odds of surgical intervention. Additionally, surgical intervention portended greater odds of in-hospital mortality (adjusted odds ratio 6.2, 95% confidence interval 4.5-8.5), a longer length of stay (8.5 days, 95% confidence interval 8.0-9.0), and greater hospitalization cost ($29.1K, 95% confidence interval 26.7K-31.5K). CONCLUSION: Operative management of lower gastrointestinal bleeding is rare and associated with significant morbidity and mortality compared to those managed conservatively. However, when surgical intervention is indicated, preoperative patient characteristics should be used to identify those at greater risk of an operation to facilitate early surgical consultation and inform expectations during the perioperative period.

Revisiting the concept of childhood preleukemia.

Preleukemic has been used to describe children with a propensity to develop B cell acute lymphoblastic leukemia (B-ALL). However, leukemia-predisposing mutations can also be present in differentiated cells unable to transform. We postulate that preleukemia should only be used when such mutations arise in progenitors capable of evolving to B-ALL.

Clonal heterogeneity and rates of specific chromosome gains are risk predictors in childhood high-hyperdiploid B-cell acute lymphoblastic leukemia.

B-cell acute lymphoblastic leukemia (B-ALL) is the commonest childhood cancer. High hyperdiploidy (HHD) identifies the most frequent cytogenetic subgroup in childhood B-ALL. Although hyperdiploidy represents an important prognostic factor in childhood B-ALL, the specific chromosome gains with prognostic value in HHD-B-ALL remain controversial, and the current knowledge about the hierarchy of chromosome gains, clonal heterogeneity and chromosomal instability in HHD-B-ALL remains very limited. We applied automated sequential-iFISH coupled with single-cell computational modeling to identify the specific chromosomal gains of the eight typically gained chromosomes in a large cohort of 72 primary diagnostic (DX, n = 62) and matched relapse (REL, n = 10) samples from HHD-B-ALL patients with either favorable or unfavorable clinical outcome in order to characterize the clonal heterogeneity, specific chromosome gains and clonal evolution. Our data show a high degree of clonal heterogeneity and a hierarchical order of chromosome gains in DX samples of HHD-B-ALL. The rates of specific chromosome gains and clonal heterogeneity found in DX samples differ between HHD-B-ALL patients with favorable or unfavorable clinical outcome. In fact, our comprehensive analyses at DX using a computationally defined risk predictor revealed low levels of trisomies +18+10 and low levels of clonal heterogeneity as robust relapse risk factors in minimal residual disease (MRD)-negative childhood HHD-B-ALL patients: relapse-free survival beyond 5 years: 22.1% versus 87.9%, P < 0.0001 and 33.3% versus 80%, P < 0.0001, respectively. Moreover, longitudinal analysis of matched DX-REL HHD-B-ALL samples revealed distinct patterns of clonal evolution at relapse. Our study offers a reliable prognostic sub-stratification of pediatric MRD-negative HHD-B-ALL patients.

PIMS-TS immunophenotype: description and comparison with healthy children, Kawasaki disease and severe viral and bacterial infections.

BACKGROUND: A new clinical syndrome named Paediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2 (PIMS-TS) has been described. This new disease is a leading cause of hospital and paediatric intensive care unit (PICU). It has been related to immunity dysregulation. METHODS: Prospective-retrospective observational study to describe the innate cell signature and immunophenotype of children admitted to PICU because of PIMS-TS (from March 2020 to September 2020). The immunophenotype was done through the expression analysis of these proteins of mononuclear cells: CD64, CD18, CD11a and CD11b. They were compared with previous healthy controls and children admitted to PICU because of bacterial infection, viral infection and Kawasaki disease (KD). Two hundred and forty-seven children were studied: 183 healthy controls, 25 viral infections, 20 bacterial infections, 6 KD and 13 PIMS-TS. RESULTS: PIMT-TS showed the lowest percentage of lymphocytes and monocytes with higher relative numbers of CD4+ (p = .000). Monocytes and neutrophils in PIMS-TS showed higher levels of CD64 expression (p = .000). Also, CD11a and CD11b were highly expressed (p =,000). CONCLUSION: We observed a differential cell innate signature in PIMS-TS. These findings are consistent with a proinflammatory status (CD64 elevated expression) and lymphocyte trafficking to tissues (CD11a and CD11b). More studies should be carried out to confirm our results.

The Multi-Kinase Inhibitor EC-70124 Is a Promising Candidate for the Treatment of FLT3-ITD-Positive Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Patients with AML harboring a constitutively active internal tandem duplication mutation (ITDMUT) in the FMS-like kinase tyrosine kinase (FLT3) receptor generally have a poor prognosis. Several tyrosine kinase/FLT3 inhibitors have been developed and tested clinically, but very few (midostaurin and gilteritinib) have thus far been FDA/EMA-approved for patients with newly diagnosed or relapse/refractory FLT3-ITDMUT AML. Disappointingly, clinical responses are commonly partial or not durable, highlighting the need for new molecules targeting FLT3-ITDMUT AML. Here, we tested EC-70124, a hybrid indolocarbazole analog from the same chemical space as midostaurin with a potent and selective inhibitory effect on FLT3. In vitro, EC-70124 exerted a robust and specific antileukemia activity against FLT3-ITDMUT AML primary cells and cell lines with respect to cytotoxicity, CFU capacity, apoptosis and cell cycle while sparing healthy hematopoietic (stem/progenitor) cells. We also analyzed its efficacy in vivo as monotherapy using two different xenograft models: an aggressive and systemic model based on MOLM-13 cells and a patient-derived xenograft model. Orally disposable EC-70124 exerted a potent inhibitory effect on the growth of FLT3-ITDMUT AML cells, delaying disease progression and debulking the leukemia. Collectively, our findings show that EC-70124 is a promising and safe agent for the treatment of AML with FLT3-ITDMUT.

Transient Inhibition of the JAK/STAT Pathway Prevents B-ALL Development in Genetically Predisposed Mice.

Preventing development of childhood B-cell acute lymphoblastic leukemia (B-ALL), a disease with devastating effects, is a longstanding and unsolved challenge. Heterozygous germline alterations in the PAX5 gene can lead to B-ALL upon accumulation of secondary mutations affecting the JAK/STAT signaling pathway. Preclinical studies have shown that this malignant transformation occurs only under immune stress such as exposure to infectious pathogens. Here we show in Pax5+/- mice that transient, early-life administration of clinically relevant doses of ruxolitinib, a JAK1/2 inhibitor, significantly mitigates the risk of B-ALL following exposure to infection; 1 of 29 animals treated with ruxolitinib developed B-ALL versus 8 of 34 untreated mice. Ruxolitinib treatment preferentially targeted Pax5+/- versus wild-type B-cell progenitors and exerted unique effects on the Pax5+/- B-cell progenitor transcriptional program. These findings provide the first in vivo evidence for a potential strategy to prevent B-ALL development. SIGNIFICANCE: JAK/STAT inhibition suppresses tumorigenesis in a B-ALL-susceptible mouse model, presenting a novel approach to prevent B-ALL onset.

Engraftment characterization of risk-stratified AML in NSGS mice.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Disease heterogeneity is well documented, and patient stratification determines treatment decisions. Patient-derived xenografts (PDXs) from risk-stratified AML are crucial for studying AML biology and testing novel therapeutics. Despite recent advances in PDX modeling of AML, reproducible engraftment of human AML is primarily limited to high-risk (HR) cases, with inconsistent or very protracted engraftment observed for favorable-risk (FR) and intermediate-risk (IR) patients. We used NSGS mice to characterize the engraftment robustness/kinetics of 28 AML patient samples grouped according to molecular/cytogenetic classification and assessed whether the orthotopic coadministration of patient-matched bone marrow mesenchymal stromal cells (BM MSCs) improves AML engraftment. PDX event-free survival correlated well with the predictable prognosis of risk-stratified AML patients. The majority (85-94%) of the mice were engrafted in bone marrow (BM) independently of the risk group, although HR AML patients showed engraftment levels that were significantly superior to those of FR or IR AML patients. Importantly, the engraftment levels observed in NSGS mice by week 6 remained stable over time. Serial transplantation and long-term culture-initiating cell (LTC-IC) assays revealed long-term engraftment limited to HR AML patients, fitter leukemia-initiating cells (LICs) in HR AML samples, and the presence of AML LICs in the CD34- leukemic fraction, regardless of the risk group. Finally, orthotopic coadministration of patient-matched BM MSCs and AML cells was dispensable for BM engraftment levels but favored peripheralization of engrafted AML cells. This comprehensive characterization of human AML engraftment in NSGS mice offers a valuable platform for in vivo testing of targeted therapies in risk-stratified AML patient samples.

Increased Hypothalamic Anti-Inflammatory Mediators in Non-Diabetic Insulin Receptor Substrate 2-Deficient Mice.

Insulin receptor substrate (IRS) 2 is a key mediator of insulin signaling and IRS-2 knockout (IRS2-/-) mice are a preclinical model to study the development of diabetes, as they develop peripheral insulin resistance and beta-cell failure. The differential inflammatory profile and insulin signaling in the hypothalamus of non-diabetic (ND) and diabetic (D) IRS2-/- mice might be implicated in the onset of diabetes. Because the lipid profile is related to changes in inflammation and insulin sensitivity, we analyzed whether ND IRS2-/- mice presented a different hypothalamic fatty acid metabolism and lipid pattern than D IRS2-/- mice and the relationship with inflammation and markers of insulin sensitivity. ND IRS2-/- mice showed elevated hypothalamic anti-inflammatory cytokines, while D IRS2-/- mice displayed a proinflammatory profile. The increased activity of enzymes related to the pentose-phosphate route and lipid anabolism and elevated polyunsaturated fatty acid levels were found in the hypothalamus of ND IRS2-/- mice. Conversely, D IRS2-/- mice have no changes in fatty acid composition, but hypothalamic energy balance and markers related to anti-inflammatory and insulin-sensitizing properties were reduced. The data suggest that the concurrence of an anti-inflammatory profile, increased insulin sensitivity and polyunsaturated fatty acids content in the hypothalamus may slow down or delay the onset of diabetes.