Lipid Profile and Serum Characteristics of the Blind Subterranean Mole Rat, Spalax

to underground life resulted in structural and molecular-genetic differences comparing to above-ground mammals. These differences include higher myocardial maximal oxygen consumption, increased lung diffusion capacity, increased blood vessels density, and unique expression patterns of cancer and angiogenesis related genes such as heparanase, vascular endothelial growth factor, and P53. revealed special features in this mammal. pursue underground, dietary components, and evolutionary genetic adaptations. Unfolding the genetic basis of these differences will probably result in unique treatments for a variety of human diseases such as dyslipedemias, inflammation and cancer

Quantitative trait loci conferring grain mineral nutrient concentrations in durum wheat 3 wild emmer wheat RIL population

Mineral nutrient malnutrition, and particularly deficiency in zinc and iron, afflicts over 3 billion people worldwide. Wild emmer wheat, Triticum turgidum ssp. dicoccoides, genepool harbors a rich allelic repertoire for mineral nutrients in the grain. The genetic and physiological basis of grain protein, micronutrients (zinc, iron, copper and manganese) and macronutrients (calcium, magnesium, potassium, phosphorus and sulfur) concentration was studied in tetraploid wheat population of 152 recombinant inbred lines (RILs), derived from a cross between durum wheat (cv. Langdon) and wild emmer (accession G18-16). Wide genetic variation was found among the RILs for all grain minerals, with considerable transgressive effect. A total of 82 QTLs were mapped for 10 minerals with LOD score range of 3.2–16.7. Most QTLs were in favor of the wild allele (50 QTLs). Fourteen pairs of QTLs for the same trait were mapped to seemingly homoeologous positions, reflecting synteny between the A and B genomes. Significant positive correlation was found between grain protein concentration (GPC), Zn, Fe and Cu, which was supported by significant overlap between the respective QTLs, suggesting common physiological and/or genetic factors controlling the concentrations of these mineral nutrients. Few genomic regions (chromosomes 2A, 5A, 6B and 7A) were found to harbor clusters of QTLs for GPC and other nutrients. These identified QTLs may facilitate the use of wild alleles for improving grain nutritional quality of elite wheat cultivars, especially in terms of protein, Zn and Fe

Restoration of energy homeostasis by SIRT6 extends healthy lifespan

Aging leads to a gradual decline in physical activity and disrupted energy homeostasis. The NAD+-dependent SIRT6 deacylase regulates aging and metabolism through mechanisms that largely remain unknown. Here, we show that SIRT6 overexpression leads to a reduction in frailty and lifespan extension in both male and female B6 mice. A combination of physiological assays, in vivo multi-omics analyses and 13C lactate tracing identified an age-dependent decline in glucose homeostasis and hepatic glucose output in wild type mice. In contrast, aged SIRT6-transgenic mice preserve hepatic glucose output and glucose homeostasis through an improvement in the utilization of two major gluconeogenic precursors, lactate and glycerol. To mediate these changes, mechanistically, SIRT6 increases hepatic gluconeogenic gene expression, de novo NAD+ synthesis, and systemically enhances glycerol release from adipose tissue. These findings show that SIRT6 optimizes energy homeostasis in old age to delay frailty and preserve healthy aging

Hematologic malignancies in pregnancy : Management guidelines from an international consensus meeting

Purpose: The incidence of hematologic malignancies during pregnancy is 0.02%. However, this figure is increasing, as women delay conception until a later age. Systemic symptoms attributed to the development of a hematologic cancermay overlapwith physiologic changes of pregnancy. A favorable prognosis is contingent upon early diagnosis and treatment. Therefore, a high index of suspicion is required by health care providers. Although timely, accurate diagnosis followed by appropriate staging is essential and should not be delayed due to pregnancy, management guidelines are lacking due to insufficient evidence-based research. Consequently, treatment is delayed, posing significant risks to maternal and fetal health, and potential pregnancy termination. This report provides guidelines for clinical management of hematologic cancers during the perinatal period, which were developed by a multidisciplinary team including an experienced hematologist/oncologist, a high-risk obstetrics specialist, a neonatologist, and experienced nurses, social workers, and psychologists. Methods: These guidelines were developed by experts in the field during the first International Consensus Meeting of PrenatalHematologicMalignancies, which took place in Leuven, Belgium, onMay 23, 2014. Results and Conclusion: This consensus summary equips health care professionals with novel diagnostic and treatment methodologies that aimfor optimal treatment of themother, while protecting fetal and pediatric health

Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal encephalopathy

This is the author accepted manuscript. The final version is available from Oxford University Press via the DOI in this record.The corrigendum to this article is in ORE: http://hdl.handle.net/10871/33588Cellular distribution and dynamics of mitochondria are regulated by several motor proteins and a microtubule network. In neurons, mitochondrial trafficking is crucial because of high energy needs and calcium ion buffering along axons to synapses during neurotransmission. The trafficking kinesin proteins (TRAKs) are well characterized for their role in lysosomal and mitochondrial trafficking in cells, especially neurons. Using whole exome sequencing, we identified homozygous truncating variants in TRAK1 (NM_001042646:c.287-2A > C), in six lethal encephalopathic patients from three unrelated families. The pathogenic variant results in aberrant splicing and significantly reduced gene expression at the RNA and protein levels. In comparison with normal cells, TRAK1-deficient fibroblasts showed irregular mitochondrial distribution, altered mitochondrial motility, reduced mitochondrial membrane potential, and diminished mitochondrial respiration. This study confirms the role of TRAK1 in mitochondrial dynamics and constitutes the first report of this gene in association with a severe neurodevelopmental disorder.D.M.E. and J.K. are supported by the Office of Naval Research (ONR) Grant N000141410538. M.S. is supported by the BBSRC (BB/K006231/1), a Wellcome Trust Institutional Strategic Support Award (WT097835MF, WT105618MA), and a Marie Curie Initial Training Network (ITN) action PerFuMe (316723). M.C.V.M., J.S., H.P., C.F., T.V. and W.A.G. are supported by the NGHRI Intramural Research Program. G.R. is supported by the Kahn Family Foundation and the Israeli Centers of Excellence (I-CORE) Program (ISF grant no. 41/11)

Insights on the mechanism of formation of protein microspheres in a biphasic system

Microspheres of bovine serum albumin (BSA) and silk fibroin are produced by applying ultrasound in a biphasic system consisting of an aqueous protein solution and an organic solvent. The protein microspheres are dispersed in an aqueous media where the protein remains at the interface covering the organic solvent. This only occurs when high shear forces are applied that induce changes to force the protein to the interface. Fourier transform infrared results indicate a large increase in the content of the β-sheet during the formation of silk fibroin microspheres. Molecular dynamics simulations show a clear adaption on the 3D structure of BSA when stabilized at the interface, without major changes in secondary structure. Further studies demonstrate that high water content, oil solvents, and larger peptides with separated and clear hydrophobic and hydrophilic areas lead to more stable and smaller spheres. This is the first time that these results are presented. We also present herein the rationale to produce tailored protein microspheres with a controlled size, controlled charge, and increased stability.This work was supported by Lidwine Project-Multifunctional medical textiles for wound (e.g., Decubitus) prevention and improved wound healing NMP2-CT-2006-026741. H.F. thanks POPH/FSE for cofinancing and FCT for Fellowship SFRH/BPD/38939/2007. We acknowledge Silvia Cappellozza from "Sezione Specializzata per la Bachicoltura" for the supply of silk cocoons

Monoclonal gammopathy of renal significance (MGRS): Real-world data on outcomes and prognostic factors

Monoclonal gammopathy of renal significance (MGRS) is a recognized clinical entity. Literature regarding treatment and its outcomes in MGRS is sparse due to the rarity and misdiagnosis of MGRS. We retrospectively analyzed 280 adults with an MGRS diagnosis from 2003 to 2020 across 19 clinical centers from 12 countries. All cases required renal biopsy for the pathological diagnosis of MGRS. Amyloidosis-related to MGRS (MGRS-A) was present in 180 patients; nonamyloidosis MGRS (MGRS-NA), including a broad spectrum of renal pathologies, was diagnosed in 100 patients. The median overall survival in the studied cohort was 121.0 months (95% CI: 105.0–121.0). Patients with MGRS-A had a shorter overall survival than patients with MGRS-NA (HR = 0.41, 95%CI: 0.25–0.69; p = 0.0007). Both hematologic and renal responses were associated with longer survival. Achievement of ≥VGPR was generally predictive of a renal response (OR = 8.03 95%CI: 4.04–115.96; p < 0.0001), one-fourth of patients with ≥VGPR were renal nonresponders. In MGRS-A, factors associated with poor prognosis included elevated levels of creatinine, beta-2-microglobulin, and hemodialysis at diagnosis. In MGRS-NA, only age >65 years was associated with increased risk of death. Treatments provided similar hematologic response rates in both types of MGRS. Autologous stem cell transplantation led to better response than other treatments. This multicenter and international effort is currently the largest report on MGRS

Side-by-Side In(OH)3 and In2O3 Nanotubes: Synthesis and Optical Properties

A simple and mild wet-chemical approach was developed for the synthesis of one-dimensional (1D) In(OH)3 nanostructures. By calcining the 1D In(OH)3 nanocrystals in air at 250 °C, 1D In2O3 nanocrystals with the same morphology were obtained. TEM results show that both 1D In(OH)3 and 1D In2O3 are composed of uniform nanotube bundles. SAED and XRD patterns indicate that 1D In(OH)3 and 1D In2O3 nanostructures are single crystalline and possess the same bcc crystalline structure as the bulk In(OH)3 and In2O3, respectively. TGA/DTA analyses of the precursor In(OH)3 and the final product In2O3 confirm the existence of CTAB molecules, and its content is about 6%. The optical absorption band edge of 1D In2O3 exhibits an evident blueshift with respect to that of the commercial In2O3 powders, which is caused by the increasing energy gap resulted from decreasing the grain size. A relatively strong and broad purple-blue emission band centered at 440 nm was observed in the room temperature PL spectrum of 1D In2O3 nanotube bundles, which was mainly attributed to the existence of the oxygen vacancies

Observational study of lenalidomide in patients with mantle cell lymphoma who relapsed/progressed after or were refractory/intolerant to ibrutinib (MCL-004).

BACKGROUND: The observational MCL-004 study evaluated outcomes in patients with relapsed/refractory mantle cell lymphoma who received lenalidomide-based therapy after ibrutinib failure or intolerance. METHODS: The primary endpoint was investigator-assessed overall response rate based on the 2007 International Working Group criteria. RESULTS: Of 58 enrolled patients (median age, 71 years; range, 50-89), 13 received lenalidomide monotherapy, 11 lenalidomide plus rituximab, and 34 lenalidomide plus other treatment. Most patients (88%) had received ≥ 3 prior therapies (median 4; range, 1-13). Median time from last dose of ibrutinib to the start of lenalidomide was 1.3 weeks (range, 0.1-21.7); 45% of patients had partial responses or better to prior ibrutinib. Primary reasons for ibrutinib discontinuation were lack of efficacy (88%) and ibrutinib toxicity (9%). After a median of two cycles (range, 0-11) of lenalidomide-based treatment, 17 patients responded (8 complete responses, 9 partial responses), for a 29% overall response rate (95% confidence interval, 18-43%) and a median duration of response of 20 weeks (95% confidence interval, 2.9 to not available). Overall response rate to lenalidomide-based therapy was similar for patients with relapsed/progressive disease after previous response to ibrutinib (i.e., ≥PR) versus ibrutinib-refractory (i.e., ≤SD) patients (30 versus 32%, respectively). The most common all-grade treatment-emergent adverse events after lenalidomide-containing therapy (n = 58) were fatigue (38%) and cough, dizziness, dyspnea, nausea, and peripheral edema (19% each). At data cutoff, 28 patients have died, primarily due to mantle cell lymphoma. CONCLUSION: Lenalidomide-based treatment showed clinical activity, with no unexpected toxicities, in patients with relapsed/refractory mantle cell lymphoma who previously failed ibrutinib therapy. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02341781 . Date of registration: January 14, 2015

Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma

BACKGROUND: Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)–directed CAR T-cell therapy, is effective in heavily pretreated patients with relapsed or refractory multiple myeloma. We investigated cilta-cel in earlier treatment lines in patients with lenalidomide-refractory disease. METHODS: In this phase 3, randomized, open-label trial, we assigned patients with lenalidomide-refractory multiple myeloma to receive cilta-cel or the physician’s choice of effective standard care. All the patients had received one to three previous lines of treatment. The primary outcome was progression-free survival. RESULTS: A total of 419 patients underwent randomization (208 to receive cilta-cel and 211 to receive standard care). At a median follow-up of 15.9 months (range, 0.1 to 27.3), the median progression-free survival was not reached in the cilta-cel group and was 11.8 months in the standard-care group (hazard ratio, 0.26; 95% confidence interval [CI], 0.18 to 0.38; P<0.001). Progression-free survival at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group. More patients in the cilta-cel group than in the standard-care group had an overall response (84.6% vs. 67.3%), a complete response or better (73.1% vs. 21.8%), and an absence of minimal residual disease (60.6% vs. 15.6%). Death from any cause was reported in 39 patients and 46 patients, respectively (hazard ratio, 0.78; 95% CI, 0.5 to 1.2). Most patients reported grade 3 or 4 adverse events during treatment. Among the 176 patients who received cilta-cel in the as-treated population, 134 (76.1%) had cytokine release syndrome (grade 3 or 4, 1.1%; no grade 5), 8 (4.5%) had immune effector cell–associated neurotoxicity syndrome (all grade 1 or 2), 1 had movement and neurocognitive symptoms (grade 1), 16 (9.1%) had cranial nerve palsy (grade 2, 8.0%; grade 3, 1.1%), and 5 (2.8%) had CAR-T–related peripheral neuropathy (grade 1 or 2, 2.3%; grade 3, 0.6%). CONCLUSIONS: A single cilta-cel infusion resulted in a lower risk of disease progression or death than standard care in lenalidomide-refractory patients with multiple myeloma who had received one to three previous therapies. (Funded by Janssen and Legend Biotech; CARTITUDE-4 ClinicalTrials.gov number, NCT04181827. opens in new tab.