Alveolar rhabdomyosarcoma is a life-threatening myogenic cancer of children and adolescent young adults, driven primarily by the chimeric transcription factor PAX3-FOXO1. The mechanisms by which ...PAX3-FOXO1 dysregulates chromatin are unknown. We find PAX3-FOXO1 reprograms the
-regulatory landscape by inducing
super enhancers. PAX3-FOXO1 uses super enhancers to set up autoregulatory loops in collaboration with the master transcription factors MYOG, MYOD, and MYCN. This myogenic super enhancer circuitry is consistent across cell lines and primary tumors. Cells harboring the fusion gene are selectively sensitive to small-molecule inhibition of protein targets induced by, or bound to, PAX3-FOXO1-occupied super enhancers. Furthermore, PAX3-FOXO1 recruits and requires the BET bromodomain protein BRD4 to function at super enhancers, resulting in a complete dependence on BRD4 and a significant susceptibility to BRD inhibition. These results yield insights into the epigenetic functions of PAX3-FOXO1 and reveal a specific vulnerability that can be exploited for precision therapy.
PAX3-FOXO1 drives pediatric fusion-positive rhabdomyosarcoma, and its chromatin-level functions are critical to understanding its oncogenic activity. We find that PAX3-FOXO1 establishes a myoblastic super enhancer landscape and creates a profound subtype-unique dependence on BET bromodomains, the inhibition of which ablates PAX3-FOXO1 function, providing a mechanistic rationale for exploring BET inhibitors for patients bearing PAX-fusion rhabdomyosarcoma.
.
Information about the impact of diabetic neuropathy (DN) on outcomes after pancreas transplantation (PT) is scarce. We assessed the independent relationship between DN markers with both graft ...survival and incident cardiovascular disease (CVD) after transplantation.
A cohort study in individuals with type 1 diabetes and end-stage kidney disease who underwent PT between 1999 and 2015 was conducted. DN was assessed with vibration perception thresholds (VPTs) and orthostatic hypotension (pre-PT and 6 mo, 2-3, 5-6, and 8-10 y after transplantation). Pretransplantation and posttransplantation DN markers were related with graft failure/dysfunction and incident CVD during follow-up.
We included 187 participants (70% men, age 39.9 ± 7.1 y, diabetes duration 27.1 y), with a median follow-up of 11.3 y. Abnormal VPTs (≥25 V) were observed in 53%. After transplantation, VPTs improved (22.4 ± 8.4 pretransplant versus 16.1 ± 6.1 V at 8-10 y post-PT; P < 0.001); additionally, the prevalence of abnormal VPTs decreased (53% pretransplant versus 24.4% at 8-10 y; P < 0.001). After adjusting for age, sex, diabetes duration, blood pressure, body mass index, and previous CVD, pretransplant VPTs ≥25 V were independently associated with pancreas graft failure/dysfunction (hazard ratio HR, 2.01 1.01-4.00) and incident CVD (HR, 2.57 1.17-5.64). Furthermore, persistent abnormal VPTs after 6 mo posttransplantation were associated with the worst outcomes (HR, 2.80 1.25-6.23 and HR, 3.19 1.14-8.96, for graft failure/dysfunction and incident CVD, respectively).
In individuals with type 1 diabetes and end-stage kidney disease, PT was associated with an improvement of VPTs. This simple and widely available DN study was independently associated with pancreas graft function and CVD posttransplantation.
The interpretation of the available seismic lines of the South-Central-Pyrenean fold and thrust belt, conveniently tied with the exploration wells, define the main structural features of this realm ...of the Pyrenees. In particular, they define the geometry and areal extension of the autochthonous foreland underneath the sole thrust. The mapping of several selected structural lines brings constraints for the structural interpretation of the South-Central Pyrenees, including the cut-off lines between selected stratigraphic horizons of the autochthonous foreland and the branch line between basement-involved thrust sheets and the sole thrust. The thrust salient which characterizes at surface the geometry of the South-Pyrenean fold and thrust belt contrasts with the linear trend of these structural lines at subsurface. This salient has been the result of a secondary progressive curvature developed since Middle Eocene times by thrust displacement gradients during overthrusting of the South-Pyrenean thrust sheets above a Paleogene autochthonous sequence. Displacement gradients resulted from the uneven distribution of weak salt layers, mostly the Triassic and the Upper Eocene ones. The minimum amount of South-directed displacement from early Middle Eocene times to Late Oligocene is 52km, which would be significantly higher if internal shortening by folding and cleavage/fracture development as well as hanging-wall erosion is added. KEYWORDS Pyrenees. Seismic data. Cut-off and branch lines.
Tacrolimus is pivotal in pancreas transplants but poses challenges in maintaining optimal levels due to recipient differences. This study aimed to explore the utility of time spent below the ...therapeutic range and intrapatient variability in predicting rejection and
donor-specific antibody (dnDSA) development in pancreas graft recipients. This retrospective unicentric study included adult pancreas transplant recipients between January 2006 and July 2020. Recorded variables included demographics, immunosuppression details, HLA matching, biopsy results, dnDSA development, and clinical parameters. Statistical analysis included ROC curves, sensitivity, specificity, and predictive values. A total of 131 patients were included. Those with biopsy-proven acute rejection (BPAR, 12.2%) had more time (39.9% ± 24% vs. 25.72% ± 21.57%,
= 0.016) and tests (41.95% ± 13.57% vs. 29.96% ± 17.33%,
= 0.009) below therapeutic range. Specific cutoffs of 31.5% for time and 34% for tests below the therapeutic range showed a high negative predictive value for BPAR (93.98% and 93.1%, respectively). Similarly, patients with more than 34% of tests below the therapeutic range were associated with dnDSA appearance (38.9% vs. 9.4%,
= 0.012; OR 6.135, 1.346-27.78). In pancreas transplantation, maintaining optimal tacrolimus levels is crucial. Suboptimal test percentages below the therapeutic range prove valuable in identifying acute graft rejection risk.
Evaluate the weight trajectories after pancreas transplantation (PT) and their relationships with pancreas graft outcomes in type 1 diabetes (T1D).
Retrospective cohort study. T1D individuals who ...underwent PT were recruited (T1D-PT; n = 194) and divided into three groups according to transplantation date: 1999–2004 (n = 57), 2005–2009 (n = 79), 2010–2015 (n = 58). For weight comparisons, a random sample of T1D without renal impairment was also recruited during 2015 (n = 61; T1D-control).
The median follow-up for the T1D-PT group was 11.1 years. Despite significant weight loss at 6 months (65.7 ± 12.4 vs. 64.1 ± 11.4 Kg; p < 0.001), a stepped increase was seen thereafter (60 months: 68.0 ± 14.0 Kg; p < 0.001). Participants from the 2010–2015 period showed higher weight gain (p < 0.001), outweighing that observed in the T1D-control (60 months: +4.69 ± 8.49 vs. −0.97 ± 4.59 Kg; p = 0.003). Weight gain between 6 and 36 months was directly associated with fasting glucose and HbA1c at 36 months, and with HbA1c at 60 months (p < 0.05). However, in Cox-regression models adjusted for age, sex, and several recipient and PT-related variables, the third tertile of weight gain between 6 and 36 months showed a non-significant increase in the graft failure/dysfunction (HR 2.33 0.75–7.27).
Weight gain post-PT was associated with glucose-related biochemical markers of graft dysfunction, which needs confirmation in further studies.
The advent of Machine Perfusion (MP) as a superior form of preservation and assessment for cold storage of both high-risk kidney's and the liver presents opportunities in the field of beta-cell ...replacement. It is yet unknown whether such techniques, when applied to the pancreas, can increase the pool of suitable donor organs as well as ameliorating the effects of ischemia incurred during the retrieval process. Recent experimental models of pancreatic MP appear promising. Applications of MP to the pancreas, needs refinement regarding perfusion protocols and organ viability assessment criteria. To address the "Role of pancreas machine perfusion to increase the donor pool for beta cell replacement," the European Society for Organ Transplantation (ESOT) assembled a dedicated working group comprising of experts to review literature pertaining to the role of MP as a method of improving donor pancreas quality as well as quantity available for transplant, and to develop guidelines founded on evidence-based reviews in experimental and clinical settings. These were subsequently refined during the Consensus Conference when this took place in Prague.
Simultaneous pancreas-kidney transplantation (SPKT) leads to increased survival and quality of life, and is an alternative treatment for insulin-dependent diabetes mellitus and end-stage kidney ...disease. Due to the particularities of this population (often with multiple comorbidities) and of the surgery (only performed in a few centers), a comprehensive analysis of patients' experience along the SPKT process is crucial to improve patient care and add value to this procedure. Therefore, we applied a systematic and iterative methodology with the participation of both patients and professional teams working together to explore and identify unmet needs and value-adding steps along the transplant patient journey at an established pancreas transplant program. Four main steps (to comprehend, to explore, to experiment and to assess) led to several interventions around three major areas: Administration and logistics, information and communication, and perceived quality of assistance. As a result, both displacements to the hospital for diagnostic purposes and the time delay involved in joining the patient waiting list for transplantation were reduced in parallel to the administrative procedures. In conclusion, the methodological implementation of key organizational changes has great impact on overall patient experience. Further quantitative analysis from the patient's perspective will consolidate our program and may add new prototype service design components.
Besides their physiological role in bile formation and fat digestion, bile acids (BAs) synthesised from cholesterol in hepatocytes act as signalling molecules that modulate hepatocellular carcinoma ...(HCC). Trafficking of cholesterol to mitochondria through steroidogenic acute regulatory protein 1 (STARD1) is the rate-limiting step in the alternative pathway of BA generation, the physiological relevance of which is not well understood. Moreover, the specific contribution of the STARD1-dependent BA synthesis pathway to HCC has not been previously explored.
STARD1 expression was analyzed in a cohort of human non-alcoholic steatohepatitis (NASH)-derived HCC specimens. Experimental NASH-driven HCC models included MUP-uPA mice fed a high-fat high-cholesterol (HFHC) diet and diethylnitrosamine (DEN) treatment in wild-type (WT) mice fed a HFHC diet. Molecular species of BAs and oxysterols were analyzed by mass spectrometry. Effects of NASH-derived BA profiles were investigated in tumour-initiated stem-like cells (TICs) and primary mouse hepatocytes (PMHs).
Patients with NASH-associated HCC exhibited increased hepatic expression of STARD1 and an enhanced BA pool. Using NASH-driven HCC models, STARD1 overexpression in WT mice increased liver tumour multiplicity, whereas hepatocyte-specific STARD1 deletion (Stard1ΔHep) in WT or MUP-uPA mice reduced tumour burden. These findings mirrored the levels of unconjugated primary BAs, β-muricholic acid and cholic acid, and their tauroconjugates in STARD1-overexpressing and Stard1ΔHep mice. Incubation of TICs or PMHs with a mix of BAs mimicking this profile stimulated expression of genes involved in pluripotency, stemness and inflammation.
The study reveals a previously unrecognised role of STARD1 in HCC pathogenesis, wherein it promotes the synthesis of primary BAs through the mitochondrial pathway, the products of which act in TICs to stimulate self-renewal, stemness and inflammation.
Effective therapy for hepatocellular carcinoma (HCC) is limited because of our incomplete understanding of its pathogenesis. The contribution of the alternative pathway of bile acid (BA) synthesis to HCC development is unknown. We uncover a key role for steroidogenic acute regulatory protein 1 (STARD1) in non-alcoholic steatohepatitis-driven HCC, wherein it stimulates the generation of BAs in the mitochondrial acidic pathway, the products of which stimulate hepatocyte pluripotency and self-renewal, as well as inflammation.
Display omitted
•Human non-alcoholic fatty liver disease and steatohepatitis-driven HCC tissue specimens exhibit increased STARD1 expression.•STARD1 overexpression promotes, whereas STARD1 ablation curtails, NASH-driven HCC.•STARD1 stimulates bile acid synthesis through activation of the alternative mitochondrial pathway.•Bile acids stimulate pluripotency, stemness and inflammation-related genes in tumour-initiating stem-like cells.
Abstract
BACKGROUND AND AIMS
‘Stress hyperglycaemia’ is a condition characterized by elevated blood glucose levels during stress or illness. It is often multifactorial and leads to transient insulin ...resistance and/or insulin deficiency in critical ill patients. Patients with stress hyperglycaemia could be potential pancreas donors, although there is some concern about the influence of donor insulin use on pancreas graft survival. Studies have reported that stress hyperglycaemia increases the risk toward the development of type 2 diabetes (T2D) on the long term, but the patient profiles were of those not usually considered for pancreas donation. The objective of our study was to assess the impact of insulin requirements during intensive care unit (ICU) in surviving patients who otherwise would be potentially eligible for pancreas donation. The risk of T2D at 3 years after discharge was assessed to understand the pancreas function recovery after stress hyperglycaemia.
METHOD
we developed a retrospective study including patients admitted in the ICU between March 2011 and December 2017 due to severe neurological acute conditions subarachnoid haemorrhage (SAH), head trauma, non-SAH haemorrhage or stroke. Inclusion criteria were as follows: severe neurological condition requiring need for intubation, age <56 years and survival at discharge. Exclusion criteria included: obesity (BMI ≥30), diagnosis of diabetes prior to admission, HVB, HVC or HIV positive and lost to follow-up <3 years. Baseline characteristics, length of hospital and ICU stay, peak AST/ALT and amilase/lipase, insulin use during admission as well as variables associated with hyperglycaemia (use of parenteral nutrition, infections, use of corticosteroids or propofol sedation) were collected from patient's electronic medical records of our institution. Primary endpoint was diagnosis of T2D at 3 years after discharge (HbA1C ≥6.5% or fasting plasma glucose ≥126 mg/dL).
RESULTS
A total of 76 patients were included, with insulin requirement during ICU admission reported in only 5 (6.6%). Median age was 45 years (IQR 35–52), 50% were males, median Charlson index was 0, and 25 (32.9%) had present or past smoking habit. Hypertension was present in 11 (14.5%) and dyslipidaemia in 7 (9.2%). The main admission cause was SAH in 45 patients (59.2%) followed by head trauma in 21 (27.6%). As for hyperglycaemic factors, during admission, 6 (7.9%) received parenteral nutrition, 48 (63%) had an infectious complication, 51 (67%) received corticosteroids and 49 (64.5%) were under propofol sedation. A total of 55 (72.4%) received noradrenaline. Median amylase, lipase, AST and ALT peak were 115 U/L (69.5–233), 70 U/L (34–222), 51 U/L (33.25–101.5) and 94 U/L (35.5–165), respectively. Median ICU and hospital stay were 10 (5–17.75) and 29 (19–42.75) days, respectively. Those who required insulin had longer ICU stay compared with the median of the overall cohort (25 versus 10 days); all of them received corticosteroids and were diagnosed with SAH. At 3 years of follow-up, only three patients (3.9%) were diagnosed with T2D, but none of them had received insulin during admission. One patient was diagnosed 7 months after discharge and the other two were diagnosed 1 year after discharge. Three patients died during the follow-up, but any of them also required insulin during admission.
CONCLUSION
Insulin requirement in patients with severe neurological acute conditions who could meet criteria for pancreas donation was less common than expected, despite large use of corticoids, infectious complications and propofol sedation as hyperglycaemic factors. Remarkably, only three patients were diagnosed of T2D during the follow-up and none of them received insulin during admission. Prospective studies are needed in order to understand pancreas recovery after stress hyperglycaemia.
PDF
