Mixed lineage leukemia (MLL/KMT2A) rearrangements (MLL-r) are one of the most frequent chromosomal aberrations in acute myeloid leukemia. We evaluated the function of Meningioma 1 (MN1), a co-factor of HOXA9 and MEIS1, in human and murine MLL-rearranged leukemia by CRISPR-Cas9 mediated deletion of MN1. MN1 was required for in vivo leukemogenicity of MLL positive murine and human leukemia cells. Loss of MN1 inhibited cell cycle and proliferation, promoted apoptosis and induced differentiation of MLL-rearranged cells. Expression analysis and chromatin immunoprecipitation with sequencing from previously reported data sets demonstrated that MN1 primarily maintains active transcription of HOXA9 and HOXA10, which are critical downstream genes of MLL, and their target genes like BCL2, MCL1 and Survivin. Treatment of MLL-rearranged primary leukemia cells with anti-MN1 siRNA significantly reduced their clonogenic potential in contrast to normal CD34⁺ hematopoietic progenitor cells, suggesting a therapeutic window for MN1 targeting. In summary, our findings demonstrate that MN1 plays an essential role in MLL fusion leukemias and serve as a therapeutic target in MLL-rearranged acute myeloid leukemia.

Autophagy is a genetically regulated process of adaptation to metabolic stress and was recently shown to be involved in the treatment response of chronic myeloid leukemia (CML). However, in vivo data are limited and the molecular mechanism of autophagy regulators in the process of leukemogenesis is not completely understood. Here we show that Beclin-1 knockdown, but not Atg5 deletion in a murine CML model leads to a reduced leukemic burden and results in a significantly prolonged median survival of targeted mice. Further analyses of murine cell lines and primary patient material indicate that active BCR-ABL directly interacts with BECLIN-1 and phosphorylates its tyrosine residues 233 and 352, resulting in autophagy suppression. By using phosphorylation-deficient and phosphorylation-mimic mutants, we identify BCR-ABL induced BECLIN-1 phosphorylation as a crucial mechanism for BECLIN-1 complex formation: interaction analyses exhibit diminished binding of the positive autophagy regulators UVRAG, VPS15, ATG14 and VPS34 and enhanced binding of the negative regulator Rubicon to BCR-ABL-phosphorylated BECLIN-1. Taken together, our findings show interaction of BCR-ABL and BECLIN-1 thereby highlighting the importance of BECLIN-1-mediated autophagy in BCR-ABL⁺ cells.

Although highly effective, BCR-ABL1 tyrosine kinase inhibitors do not target chronic myeloid leukemia (CML) stem cells. Most patients relapse upon tyrosine kinase inhibitor therapy cessation. We reported previously that combined BCR-ABL1 and BCL-2 inhibition synergistically targets CML stem/progenitor cells. p53 induces apoptosis mainly by modulating BCL-2 family proteins. Although infrequently mutated in CML, p53 is antagonized by MDM2, which is regulated by BCR-ABL1 signaling. We hypothesized that MDM2 inhibition could sensitize CML cells to tyrosine kinase inhibitors. Using an inducible transgenic Scl-tTa-BCR-ABL1 murine CML model, we found, by RT-PCR and CyTOF proteomics increased p53 signaling in CML bone marrow (BM) cells compared with controls in CD45⁺ and linage-SCA-1⁺C-KIT⁺ populations. CML BM cells were more sensitive to exogenous BH3 peptides than controls. Combined inhibition of BCR-ABL1 with imatinib and MDM2 with DS-5272 increased NOXA level, markedly reduced leukemic linage-SCA-1⁺C-KIT⁺ cells and hematopoiesis, decreased leukemia burden, significantly prolonged the survival of mice engrafted with BM cells from Scl-tTa-BCR-ABL1 mice, and significantly decreased CML stem cell frequency in secondary transplantations. Our results suggest that CML stem/progenitor cells have increased p53 signaling and a propensity for apoptosis. Combined MDM2 and BCR-ABL1 inhibition targets CML stem/progenitor cells and has the potential to improve cure rates for CML.

This follow-up study of a randomized, prospective trial included 192 patients with newly diagnosed severe aplastic anemia receiving antithymoglobulin and cyclosporine, with or without granulocyte colony-stimulating factor (G-CSF). We aimed to evaluate the long-term effect of G-CSF on overall survival, event-free survival, probability of secondary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), clinical paroxysmal nocturnal hemoglobinuria, relapse, avascular osteonecrosis and chronic kidney disease. The median follow-up was 11.7 years (95% CI, 10.9-12.5). The overall survival rate at 15 years was 57±12% in the group given G-CSF and 63±12% in the group not given G-CSF (P=0.92); the corresponding event-free survival rates were 24±10% and 23±10%, respectively (P=0.36). In total, 9 patients developed MDS or AML, 10 only a clonal cytogenetic abnormality, 7 a solid cancer, 18 clinical paroxysmal nocturnal hemoglobinuria, 8 osteonecrosis, and 12 chronic kidney disease, without any difference between patients treated with or without G-CSF. The cumulative incidence of MDS, AML or isolated cytogenetic abnormality at 15 years was 8.5±3% for the G-CSF group and 8.2±3% for the non-G-CSF group (P=0.90). The cumulative incidence of any late event including myelodysplastic syndrome or acute myeloid leukemia, isolated cytogenetic abnormalities, solid cancer, clinical paroxysmal nocturnal hemoglobinuria, aseptic osteonecrosis, chronic kidney disease and relapse was 50±12% for the G-CSF group and 49±12% for the non-G-CSF group (P=0.65). Our results demonstrate that it is unlikely that G-CSF has an impact on the outcome of severe aplastic anemia; nevertheless, very late events are common and eventually affect the prognosis of these patients, irrespectively of their age at the time of immunosuppressive therapy (NCT01163942).

Urinary albumin-to-creatinine ratio (ACR) is a marker of diabetic nephropathy and microvascular damage. Metabolic-related traits are observationally associated with ACR, but their causal role is uncertain. Here, we confirmed ACR as a marker of microvascular damage and tested whether metabolic-related traits have causal relationships with ACR. The association between ACR and microvascular function (responses to acetylcholine [ACH] and sodium nitroprusside) was tested in the SUMMIT study. Two-sample Mendelian randomization (MR) was used to infer the causal effects of 11 metabolic risk factors, including glycemic, lipid, and adiposity traits, on ACR. MR was performed in up to 440,000 UK Biobank and 54,451 CKDGen participants. ACR was robustly associated with microvascular function measures in SUMMIT. Using MR, we inferred that higher triglyceride (TG) and LDL cholesterol (LDL-C) levels caused elevated ACR. A 1 SD higher TG and LDL-C level caused a 0.062 (95% CI 0.040, 0.083) and a 0.026 (95% CI 0.008, 0.044) SD higher ACR, respectively. There was evidence that higher body fat and visceral body fat distribution caused elevated ACR, while a metabolically "favorable adiposity" phenotype lowered ACR. ACR is a valid marker for microvascular function. MR suggested that seven traits have causal effects on ACR, highlighting the role of adiposity-related traits in causing lower microvascular function.

Hyponatremiahyposmolarreset osmostatsyndrome of inappropriate antidiuresiselderly

Lai et al. report the case of an elderly gentleman who presented with resolving neurologic findings from a transient ischemic attack and who was found to have hyponatremia with a serum sodium concentration of 123 mmol/L. Hypoosmolality was confirmed, and a diluting defect identified with a urine osmolality that ranged between 167 and 285 mOsm/kg. As the urine osmolality rose to > 400 mOsm/kg with water deprivation, a diagnosis of syndrome of inappropriate antidiuresis (SIAD) from reset osmostat was entertained.

Hyponatremia, the most common electrolyte disorder, is present in 2%–4% of ambulatory patients and up to 22% of geriatric inpatients (1). Clinicians classify hyponatremia into three main categories: hypovolemic (decreased intravascular volume from salt and water loss with inadequate replacement), euvolemic (normal intravascular volume, but increased water dilutes sodium), and hypervolemic (total body water is increased, usually causing edema, while intravascular volume is often decreased). Less frequent causes are pseudohyponatremia (due to decreased water in a fixed volume of plasma, usually due to increased lipids or protein) and water shifting due to increased osmolality (most commonly due to glucose). While the most extreme examples of hypovolemic and hypervolemic states can be determined by physical examination, in many cases the patient is euvolemic clinically.

Nosocomial pneumonia (NP), including ventilator-associated pneumonia (VAP), is increasingly associated with multidrug-resistant Gram-negative pathogens. This study describes the in vitro activity of ceftazidime-avibactam, ceftazidime, and relevant comparator agents against bacterial pathogens isolated from patients with NP, including VAP, enrolled in a ceftazidime-avibactam phase 3 trial. Gram-positive pathogens were included if coisolated with a Gram-negative pathogen. In vitro susceptibility was determined at a central laboratory using Clinical and Laboratory Standards Institute broth microdilution methods. Of 817 randomized patients, 457 (55.9%) had ≥1 Gram-negative bacterial pathogen(s) isolated at baseline, and 149 (18.2%) had ≥1 Gram-positive pathogen(s) coisolated. The most common isolated pathogens were Klebsiella pneumoniae (18.8%), Pseudomonas aeruginosa (15.8%), and Staphylococcus aureus (11.5%). Ceftazidime-avibactam was highly active in vitro against 370 isolates of Enterobacteriaceae, with 98.6% susceptible (MIC₉₀, 0.5 μg/ml) compared with 73.2% susceptible for ceftazidime (MIC₉₀, >64 μg/ml). The percent susceptibility values for ceftazidime-avibactam and ceftazidime against 129 P. aeruginosa isolates were 88.4% and 72.9% (MIC₉₀ values of 16 μg/ml and 64 μg/ml), respectively. Among ceftazidime-nonsusceptible Gram-negative isolates, ceftazidime-avibactam percent susceptibility values were 94.9% for 99 Enterobacteriaceae and 60.0% for 35 P. aeruginosa. MIC₉₀ values for linezolid and vancomycin (permitted per protocol for Gram-positive coverage) were within their respective MIC susceptibility breakpoints against the Gram-positive pathogens isolated. This analysis demonstrates that ceftazidime-avibactam was active in vitro against the majority of Enterobacteriaceae and P. aeruginosa isolates from patients with NP, including VAP, in a phase 3 trial. (This study has been registered at ClinicalTrials.gov under identifier NCT01808092.)

Monoubiquitinated FANCI and FANCD2 constitute the ID complex, which forms a sliding clamp on DNA.

We report the diagnostic challenges and the clinical course of a patient with an extraordinary presentation of B-lymphoblastic leukemia (B-ALL) with eosinophilia. We identified a novel ZBTB20-JAK2 gene fusion as a chimeric RNA transcript using the Archer platform. This gene fusion from the same patient was recently identified by Peterson et al. (2019) at the genomic level using a different sequencing technology platform. The configuration of this gene fusion predicts the production of a kinase-activating JAK2 fusion protein, which would normally lead to a diagnosis of Philadelphia chromosome–like B-ALL (Ph-like B-ALL). However, the unusual presentation of eosinophilia led us to demonstrate the presence of this gene fusion in nonlymphoid hematopoietic cells by fluorescence in situ hybridization (FISH) studies with morphologic correlation. Therefore, we believe this disease, in fact, represents blast crisis arising from an underlying myeloid neoplasm with JAK2 rearrangements. This case illustrates the difficulty in differentiating Ph-like B-ALL and myeloid/lymphoid neoplasm with eosinophilia and gene rearrangements (MLN-EGR) in blast crisis. As currently defined, the diagnosis of MLN-EGR relies on the hematologic presentations and the identification of marker gene fusions (including PCM1-JAK2, ETV6-JAK2, and BCR-JAK2). However, these same gene fusions, when limited to B-lymphoblasts, also define Ph-like B-ALL. Yet, our case does not conform to either condition. Therefore, the assessment for lineage restriction of gene rearrangements to reflect the pathophysiologic difference between B-ALL and MLN-EGR in blast crisis is likely a more robust diagnostic approach and allows the inclusion of MLN-EGR with novel gene fusions.

8p11 myeloproliferative syndrome (EMS) represents a unique World Health Organization (WHO)-classified hematologic malignancy defined by translocations of the FGFR1 receptor. The syndrome is a myeloproliferative neoplasm characterized by eosinophilia and lymphadenopathy, with risk of progression to either acute myeloid leukemia (AML) or T- or B-lymphoblastic lymphoma/leukemia. Within the EMS subtype, translocations between breakpoint cluster region (BCR) and fibroblast growth factor receptor 1 (FGFR1) have been shown to produce a dominant fusion protein that is notoriously resistant to tyrosine kinase inhibitors (TKIs). Here, we report two cases of BCR–FGFR1⁺ EMS identified via RNA sequencing (RNA-seq) and confirmed by fluorescence in situ hybridization (FISH). Sanger sequencing revealed that both cases harbored the exact same breakpoint. In the first case, the patient presented with AML-like disease, and in the second, the patient progressed to B-cell acute lymphoblastic leukemia (B-ALL). Additionally, we observed that that primary leukemia cells from Case 1 demonstrated sensitivity to the tyrosine kinase inhibitors ponatinib and dovitinib that can target FGFR1 kinase activity, whereas primary cells from Case 2 were resistant to both drugs. Taken together, these results suggest that some but not all BCR–FGFR1 fusion positive leukemias may respond to TKIs that target FGFR1 kinase activity.

Posttranscriptional regulation of mRNA is a powerful and tightly controlled process in which cells command the integrity, diversity, and abundance of their protein products. RNA-binding proteins (RBPs) are the principal players that control many intermediary steps of posttranscriptional regulation. Recent advances in this field have discovered the importance of RBPs in hematological diseases. Herein we will review a number of RBPs that have been determined to play critical functions in leukemia and lymphoma. Furthermore, we will discuss the potential therapeutic strategies that are currently being studied to specifically target RBPs in these diseases.

थैलेसीमिया मुख्यत: एक जेनेटिक यानी अनुवांशिक बीमारी है जो माता-पिता से उनके बच्चों में होती है। इस बीमारी में बच्चों में खून की कमी होने लगती है, जो कि सेहत के लिए बहुत हानिकारक होता है।

El confinamiento y la caída del precio del petróleo ponen en juego el futuro de un enorme yacimiento petrolífero argentino

• Read this article in English here

En las próximas semanas, se esclarecerá si el mundo vuelve a los combustibles fósiles tras la pandemia o si da un paso adelante hacia una economía limpia, mientras el FMI (Fondo Monetario Internacional) y Argentina deciden si van a continuar ofreciendo su apoyo a los inmensos yacimientos de petróleo y gas de Vaca Muerta, en Patagonia.

El objetivo del proyecto es explotar el segundo depósito más grande de esquisto del planeta (después de la Cuenca Pérmica, en Texas), pero su futuro es incierto debido al confinamiento forzoso provocado por COVID-19, que ha causado el descenso más drástico en el precio del crudo de los últimos treinta años.

Hematopoietic stem cells from a healthy donor can help patients suffering from acute leukemia. However, the side effects of therapies are often severe. Researchers have now shown how human healthy and cancerous hematopoietic stem cells can be more selectively eliminated using immunotherapy instead of chemotherapy in mice. The aim is to test the new immunotherapy in humans as soon as possible.

Who wants to make sequels forever?

Show's creators were told 'he will never play this role – please do not bring him up ever again'

James Rodriguez has been linked with a sensational switch to David Beckham's MLS franchise, Inter Miami.

Chayse Gannon and his mother, forced to leave dad and baby brother behind, have changed accommodation around Sydney more than 12 times since he was diagnosed in February.

Hematopoietic stem cells from a healthy donor can help patients suffering from acute leukemia. However, the side effects of therapies are often severe. A group of researchers led by the University of Zurich have now shown how human healthy and cancerous hematopoietic stem cells can be more selectively eliminated using immunotherapy instead of chemotherapy in mice. The aim is to test the new immunotherapy in humans as soon as possible.

Moderate, daily coffee consumption does not trigger incident heart arrhythmias, according to an analysis of prospectively collected data from nearly 300,000 residents of the United Kingdom.
Medscape Medical News

It seems Strictly Come Dancing will be introducing a new dancer this year – Gorka...

Mass shooters appear to injure and kill more people when the use semiautomatic rifles instead of handguns, other types of rifles, or shotguns, according to a new analysis in the Journal of The American Medical Association. But the research has significant limitations.

Bristol Myers Squibb and Acceleron Pharma’s Reblozyl (luspatercept) has secured a positivr opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) for use in the treatment of transfusion-dependent anaemia in two adult patient populations.

Six Miami-Dade County residents have been indicted in connection with an alleged $10 million Medicare fraud scheme operated out of Midway Medical, a Miami clinic that purported to specialize in treating HIV/AIDS patients.

Rodrigo Molina, 33, a Brazilian national who resided in Miami, was found guilty by a federal jury on 11 of 16 charged counts related to a $13.5 million money laundering conspiracy. Molina was found guilty on Feb. 25, 2009, following a seven-day jury trial in U.S. District Court for the Southern District of Florida.

Two Miami-area residents pleaded guilty today in connection with a $10 million Medicare fraud scheme involving HIV infusion clinics. Dr. Carmen Del Cueto, 65, and Alexis Dagnesses, 44, each pleaded guilty to one count of conspiracy to commit health care fraud before U.S. District Judge Paul C. Huck. Both defendants admitted to working at Midway Medical Center Inc. (Midway), a Miami clinic that purported to specialize in the treatment of patients with HIV.

Four Miami-area residents were sentenced today in connection with a $10 million Medicare fraud scheme involving HIV infusion clinics. Alexis Dagnesses, 44; Gonzalo Nodarse, 38; Alexis Carrazana, 41; and Dr. Carlos Garrido, 69, all pleaded guilty in March 2009 to one count of conspiracy to commit health care fraud before U.S. District Judge Paul C. Huck.

Eight Miami-Dade County, Fla., residents have been indicted in connection with an alleged $22 million Medicare fraud scheme operated out of Miami businesses purporting to specialize in home health care services. A temporary restraining order freezing assets of the indicted defendants and their companies was also filed.

Miami physician Roberto Rodriguez, 54, was sentenced today to 97 months in prison for his role in a Medicare fraud scheme involving HIV infusion services.

The United States has sued four Hialeah, Fla., tax return preparers –Alberto Alem, Beatriz Sardinas and Pilar Medina and their company, PCPS Corp. – seeking to put them out of business. The civil injunction suit was filed in Miami with the U.S. District Court for the Southern District of Florida. According to the civil injunction complaint, the defendants prepare federal income tax returns with fabricated claims for the federal fuel tax credit.

Representatives of the Financial Fraud Enforcement Task Force met in Miami today for the first of a series of Mortgage Fraud Summits.

The United States has asked a federal court to permanently shut down a Miami tax return preparer and his business.

Six Miami-area residents have been charged for their alleged role in a $13.6 million health care fraud scheme involving a Miami-area HIV infusion clinic, announced the Departments of Justice and Health and Human Services (HHS).

Miami residents Jose and Denisse Martinez were each sentenced today to three years in prison for their role in running a Canton, Mich.,-based drug infusion clinic designed to defraud Medicare.