Multinational evaluation of genetic diversity indicators for the Kunming-Montreal Global Biodiversity Framework.

Under the recently adopted Kunming-Montreal Global Biodiversity Framework, 196 Parties committed to reporting the status of genetic diversity for all species. To facilitate reporting, three genetic diversity indicators were developed, two of which focus on processes contributing to genetic diversity conservation: maintaining genetically distinct populations and ensuring populations are large enough to maintain genetic diversity. The major advantage of these indicators is that they can be estimated with or without DNA-based data.

Opposing Patterns of Altitude-Driven Pollinator Turnover in the Tropical and Temperate Americas.

AbstractAbiotic factors (e.g., temperature, precipitation) vary markedly along elevational gradients and differentially affect major groups of pollinators.

Acute inpatient rehabilitation for COVID-19 survivors: A retrospective case series.

Background: Patients with Coronavirus Disease 2019 (COVID-19) who required mechanical ventilation and had prolonged hospital stay present with medical instability and functional impairments after the acute hospitalization.

Objective: To present the rehabilitation outcome of three patients with COVID-19 admitted to an inpatient rehabilitation unit using a case series method.

Methods: Subjects included three consecutive male patients admitted to the rehabilitation unit with a diagnosis of deconditioning and critical illness myopathy.

Adaptation to lower latitudes and lower elevations precedes the evolution of hummingbird pollination in western North American Penstemon.

Premise: A switch in pollinator can occur when a plant lineage enters a new habitat where the ancestral pollinator is less common, and a novel pollinator is more common. Because pollinator communities vary according to environmental tolerances and availability of resources, there may be consistent associations between pollination mode and specific regions and habitats. Such associations can be studied in lineages that have experienced multiple pollinator transitions, representing evolutionary replicates.

Volume-assured pressure support mode for noninvasive ventilation: can it improve overnight adherence in children with neuromuscular disease?

Purpose: Volume-assured pressure support in noninvasive ventilation (VAPS-NIV) is a newer mode providing automatic pressure support adjustment to ensure a constant alveolar ventilation. Previous studies have shown that NIV effectiveness depends on patient adherence and tolerance. The aim of this study was to determine the adherence and efficacy of VAPS-NIV compared to spontaneous-time (S/T) mode in pediatric patients with neuromuscular disease (NMD).

Recommended antimicrobial therapy for common inpatient infections: a comparative review of guidelines across 51 hospital trusts in England.

Background: The number of different antimicrobial recommendations between hospital trusts for the same indication in England is unknown.

Aim: We aimed to evaluate the heterogeneity of antimicrobial recommendations for seven common inpatient infections across hospital trusts in England and evaluate changes to recommendations following introduction of national (National Institute for Healthcare and Excellence, NICE) and international (WHO) antimicrobial guidelines.

Methods: Guidelines published on the MicroGuide smartphone application were collected from December 2017 to February 2018 and re-evaluated between December 2019 and February 2020.

Mesenchymal niche remodeling impairs hematopoiesis via stanniocalcin 1 in acute myeloid leukemia.

Acute myeloid leukemia (AML) disrupts the generation of normal blood cells, predisposing patients to hemorrhage, anemia, and infections. Differentiation and proliferation of residual normal hematopoietic stem and progenitor cells (HSPCs) are impeded in AML-infiltrated bone marrow (BM). The underlying mechanisms and interactions of residual hematopoietic stem cells (HSCs) within the leukemic niche are poorly understood, especially in the human context.

Ibuprofen intercalation and release from different layered double hydroxides.

Aim: The chemical composition of layered double hydroxides (LDHs) affects their structure and properties. The method of ibuprofen (IBU) intercalation into LDHs may modify its release, reduce adverse effects and decrease the required dosing frequency.

Methodology: This study investigates the effects of four different LDHs; MgAl-LDH, MgFe-LDH, NiAl-LDH and NiFe-LDH on in vitro release of IBU intercalated by coprecipitation and anionic-exchange.

Versatile humanized niche model enables study of normal and malignant human hematopoiesis.

The BM niche comprises a tightly controlled microenvironment formed by specific tissue and cells that regulates the behavior of hematopoietic stem cells (HSCs). Here, we have provided a 3D model that is tunable in different BM niche components and useful, both in vitro and in vivo, for studying the maintenance of normal and malignant hematopoiesis. Using scaffolds, we tested the capacity of different stromal cell types to support human HSCs.

Epigenetic Reprogramming Sensitizes CML Stem Cells to Combined EZH2 and Tyrosine Kinase Inhibition.

Unlabelled: A major obstacle to curing chronic myeloid leukemia (CML) is residual disease maintained by tyrosine kinase inhibitor (TKI)-persistent leukemic stem cells (LSC). These are BCR-ABL1 kinase independent, refractory to apoptosis, and serve as a reservoir to drive relapse or TKI resistance. We demonstrate that Polycomb Repressive Complex 2 is misregulated in chronic phase CML LSCs.

Osteosarcoma: Cells-of-Origin, Cancer Stem Cells, and Targeted Therapies.

Osteosarcoma (OS) is the most common type of primary solid tumor that develops in bone. Although standard chemotherapy has significantly improved long-term survival over the past few decades, the outcome for those patients with metastatic or recurrent OS remains dismally poor and, therefore, novel agents and treatment regimens are urgently required. A hypothesis to explain the resistance of OS to chemotherapy is the existence of drug resistant CSCs with progenitor properties that are responsible of tumor relapses and metastasis.

Effect of hypoxia-inducible factors in normal and leukemic stem cell regulation and their potential therapeutic impact.

Introduction: Hypoxia inducible factors (HIF-1α and HIF-2α) are the main mediators of hypoxic responses that operate in both normal and pathological conditions. Recent evidence indicates that HIF-1α and HIF-2α could have overlapping, unique and even sometimes opposing activities in both normal physiology and disease. Despite an increase in our understanding of the different pathways regulated by HIF-1α and HIF-2α, the role played by each factor in HSC maintenance and leukemogenesis is still controversial.

Specialty substance use disorder services following brief alcohol intervention: a meta-analysis of randomized controlled trials.

Background And Aims: Brief alcohol interventions in medical settings are efficacious in improving self-reported alcohol consumption among those with low-severity alcohol problems. Screening, Brief Intervention and Referral to Treatment initiatives presume that brief interventions are efficacious in linking patients to higher levels of care, but pertinent evidence has not been evaluated. We estimated main and subgroup effects of brief alcohol interventions, regardless of their inclusion of a referral-specific component, in increasing the utilization of alcohol-related care.

Antimicrobial clay-based materials for wound care.

The historical use of clay minerals for the treatment of wounds and other skin ailments is well documented and continues within numerous human cultures the world over. However, a more scientific inquiry into the chemistry and properties of clay minerals emerged in the 19th century with work investigating their role within health gathering pace since the second half of the 20th century. This review gives an overview of clay minerals and how their properties can be manipulated to facilitate the treatment of infected wounds.

Writing implementation research grant proposals: ten key ingredients.

Background: All investigators seeking funding to conduct implementation research face the challenges of preparing a high-quality proposal and demonstrating their capacity to conduct the proposed study. Applicants need to demonstrate the progressive nature of their research agenda and their ability to build cumulatively upon the literature and their own preliminary studies. Because implementation science is an emerging field involving complex and multilevel processes, many investigators may not feel equipped to write competitive proposals, and this concern is pronounced among early stage implementation researchers.

Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival.

Recent evidence suggests chronic myeloid leukemia (CML) stem cells are insensitive to kinase inhibitors and responsible for minimal residual disease in treated patients. We investigated whether CML stem cells, in a transgenic mouse model of CML-like disease or derived from patients, are dependent on Bcr-Abl. In the transgenic model, after retransplantation, donor-derived CML stem cells in which Bcr-Abl expression had been induced and subsequently shut off were able to persist in vivo and reinitiate leukemia in secondary recipients on Bcr-Abl reexpression.

BCR-ABL enhances differentiation of long-term repopulating hematopoietic stem cells.

In a previously developed inducible transgenic mouse model of chronic myeloid leukemia, we now demonstrate that the disease is transplantable using BCR-ABL(+) Lin(-)Sca-1(+)c-kit(+) (LSK) cells. Interestingly, the phenotype is more severe when unfractionated bone marrow cells are transplanted, yet neither progenitor cells (Lin(-)Sca-1(-)c-kit(+)), nor mature granulocytes (CD11b(+)Gr-1(+)), nor potential stem cell niche cells (CD45(-)Ter119(-)) are able to transmit the disease or alter the phenotype. The phenotype is largely independent of BCR-ABL priming before transplantation.

Targeted therapy in haematological malignancies.

The recent and rapid development of molecularly targeted therapy is best illustrated by advances in the management of haematological malignancy. In myeloid diseases we have seen dramatic improvements in the overall survival and quality of life for patients with chronic myeloid leukaemia treated with ABL and Src/ABL kinase inhibitors and we are poised to discover whether JAK2 inhibitors may offer similar benefit in myeloproliferative diseases. For acute myeloid leukaemia, the introduction of ATRA and myelotarg have had major impacts on the design of therapy regimens and many novel targeted agents, including farnesyl transferase, FLT3 and histone deacetylase inhibitors, are now in clinical trial.

Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells.

Imatinib mesylate (IM), a potent inhibitor of the BCR/ABL tyrosine kinase, has become standard first-line therapy for patients with chronic myeloid leukemia (CML), but the frequency of resistance increases in advancing stages of disease. Elimination of BCR/ABL-dependent intracellular signals triggers apoptosis, but it is unclear whether this activates additional cell survival and/or death pathways. We have shown here that IM induces autophagy in CML blast crisis cell lines, CML primary cells, and p210BCR/ABL-expressing myeloid precursor cells.

Optimization of methods for the detection of BCR-ABL activity in Philadelphia-positive cells.

Objective: The recent success in treating chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKI), such as imatinib mesylate (IM), has created a demand for reproducible methods to accurately assess inhibition of BCR-ABL activity within CML cells, including rare stem and progenitor cells, either in vitro or in vivo. The purpose of this study was to develop an enzyme-linked immunosorbent (ELISA) method to measure total tyrosine phosphorylation (P-Tyr) in small samples of cells that express BCR-ABL and to compare to more established methods.

Materials And Methods: The assay was first validated in BCR-ABL wild-type and mutant vs BCR-ABL-negative cell lines.

Combined BCR-ABL inhibition with lentiviral-delivered shRNA and dasatinib augments induction of apoptosis in Philadelphia-positive cells.

Objective: This study investigated two approaches, short hairpin RNA (shRNA) and the potent ABL inhibitor, dasatinib, alone and together, to achieve complete inhibition of BCR-ABL activity in Philadelphia-positive (Ph(+)) cells.

Materials And Methods: shRNA specific for BCR-ABL b3a2 were delivered, by lentiviral transduction or electroporation, to K562 cells, with or without dasatinib. mRNA and protein knockdown were measured by quantitative reverse transcriptase polymerase chain reaction, flow cytometry, and Western blotting.

BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergizes with tyrosine kinase inhibitors.

Chronic myeloid leukemia (CML), a hematopoietic stem-cell disorder, cannot be eradicated by conventional chemotherapy or the tyrosine kinase inhibitor imatinib mesylate (IM). To target CML stem/progenitor cells, we investigated BMS-214662, a cytotoxic farnesyltransferase inhibitor, previously reported to kill nonproliferating tumor cells. IM or dasatinib alone reversibly arrested proliferation of CML stem/progenitor cells without inducing apoptosis.

Patterns of smoking and methadone dose in drug treatment patients.

Cigarette smoking prevalence is very high, and cessation rates are very low, among people in methadone treatment. This may in part be due to interactions between methadone administration and cigarette smoking. The present study explores relationships between methadone dose timing and smoking rates.

Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction.

Dasatinib (BMS-354825), a novel dual SRC/BCR-ABL kinase inhibitor, exhibits greater potency than imatinib mesylate (IM) and inhibits the majority of kinase mutations in IM-resistant chronic myeloid leukemia (CML). We have previously demonstrated that IM reversibly blocks proliferation but does not induce apoptosis of primitive CML cells. Here, we have attempted to overcome this resistance with dasatinib.