Bite by a juvenile Bothrops venezuelensis (Venezuelan lancehead) resulting in severe envenomation: A case report.

Bothrops venezuelensis is a venomous snake of the Viperidae family. It is associated with a high snakebite-related morbidity and mortality in Venezuela, although clinical case descriptions are scarce. Bites by other Bothrops sp. can result in coagulopathy and acute kidney injury. We describe a bite by a captive juvenile B. venezuelensis that caused local swelling, severe pain, endothelial damage, excessive fibrinolysis (INR >12, aPTT 136s, fibrinogen 0.3g/l) and incoagulable blood within 1.5 hours after the bite. The patient was treated with prothrombin complex factors concentrate, fibrinogen and antivenom (Antivipmyn®, Instituto Bioclon, Mexico) 4.5 h after the bite, which improved coagulation parameters progressively. Subsequently signs of compensated disseminated intravascular coagulation manifested and the patient received fresh frozen plasma and erythrocyte concentrate. The patient developed acute kidney injury with macroscopic hematuria. Fluid overload resulted in pulmonary edema requiring intermittent ventilation and diuretic treatment with furosemide. He was discharged with moderately elevated creatinine 16 days after hospitalization. Creatinine level normalized within another week. This case displays the life-threatening toxicity even after juvenile B. venezuelensis bites and the comparability to bites by other Bothrops sp.

[CME: Ethylene Glycol Intoxication]. / CME: Ethylenglykol-Intoxikation.

CME: Ethylene Glycol Intoxication Abstract. Ethylene glycol is a sweet-tasting alcohol used in common antifreeze and other industrial solutions. Without appropriate therapy, intoxication with ethylene glycol can result in severe metabolic acidosis, acute renal failure, and in death. After gastrointestinal resorption, hepatic metabolism starts with oxidation by alcohol dehydrogenase and results in severe anion gap metabolic acidosis. Other metabolic products are calcium oxalate crystals, which can deposit in several tissues like the kidneys and lead to acute tubular necrosis with reversible renal failure. The crucial therapeutic step is rapid inhibition of alcohol dehydrogenase with fomepizole or ethanol to avoid the formation of toxic metabolites. Additionally, haemodialysis is the most effective way to eliminate ethylene glycol as well as its toxic metabolites. If therapy is initiated rapidly, prognosis is favorable.

Acute Toxicity Associated With the Recreational Use of the Novel Psychoactive Benzofuran N-methyl-5-(2 aminopropyl)benzofuran.

N-methyl-5-(2 aminopropyl)benzofuran (5-MAPB) is a novel psychoactive benzofuran, created by N-methylation of 5-(2-aminopropyl)benzofuran (5-APB), which shares structural features with methylenedioxymethamphetamine (MDMA). To our knowledge, no case of 5-MAPB-related toxicity has been published in the scientific literature. We report a case of oral 5-MAPB exposure confirmed by liquid chromatography-tandem mass spectrometry in a 24-year-old previously healthy white man. Observed symptoms and signs such as paleness, cold and clammy skin, hypertension, elevated high-sensitive troponin T level, tachycardia, ECG change, diaphoresis, mild hyperthermia, mydriasis, tremor, hyperreflexia, clonus, agitation, disorientation, hallucinations, convulsions, reduced level of consciousness, and creatine kinase level elevation (305 IU/L) were compatible with undesired effects related to 5-APB or MDMA exposure. Signs and symptoms resolved substantially within 14 hours with aggressive symptomatic treatment, including sedation with benzodiazepines, external cooling, analgesia and sedation with fentanyl-propofol, and treatment with urapidil, an α-receptor-blocking agent. 5-MAPB showed first-order elimination kinetics with a half-life of 6.5 hours, comparable to the half-life of MDMA. According to the chemical structure, this case report, and users' Web reports, 5-MAPB appears to have an acute toxicity profile similar to that of 5-APB and MDMA, with marked vasoconstrictor effect.

Requirement for CDK6 in MLL-rearranged acute myeloid leukemia.

Chromosomal rearrangements involving the H3K4 methyltransferase mixed-lineage leukemia (MLL) trigger aberrant gene expression in hematopoietic progenitors and give rise to an aggressive subtype of acute myeloid leukemia (AML). Insights into MLL fusion-mediated leukemogenesis have not yet translated into better therapies because MLL is difficult to target directly, and the identity of the genes downstream of MLL whose altered transcription mediates leukemic transformation are poorly annotated. We used a functional genetic approach to uncover that AML cells driven by MLL-AF9 are exceptionally reliant on the cell-cycle regulator CDK6, but not its functional homolog CDK4, and that the preferential growth inhibition induced by CDK6 depletion is mediated through enhanced myeloid differentiation. CDK6 essentiality is also evident in AML cells harboring alternate MLL fusions and a mouse model of MLL-AF9-driven leukemia and can be ascribed to transcriptional activation of CDK6 by mutant MLL. Importantly, the context-dependent effects of lowering CDK6 expression are closely phenocopied by a small-molecule CDK6 inhibitor currently in clinical development. These data identify CDK6 as critical effector of MLL fusions in leukemogenesis that might be targeted to overcome the differentiation block associated with MLL-rearranged AML, and underscore that cell-cycle regulators may have distinct, noncanonical, and nonredundant functions in different contexts.

CDX2-driven leukemogenesis involves KLF4 repression and deregulated PPARγ signaling.

Aberrant expression of the homeodomain transcription factor CDX2 occurs in most cases of acute myeloid leukemia (AML) and promotes leukemogenesis, making CDX2, in principle, an attractive therapeutic target. Conversely, CDX2 acts as a tumor suppressor in colonic epithelium. The effectors mediating the leukemogenic activity of CDX2 and the mechanism underlying its context-dependent properties are poorly characterized, and strategies for interfering with CDX2 function in AML remain elusive. We report data implicating repression of the transcription factor KLF4 as important for the oncogenic activity of CDX2, and demonstrate that CDX2 differentially regulates KLF4 in AML versus colon cancer cells through a mechanism that involves tissue-specific patterns of promoter binding and epigenetic modifications. Furthermore, we identified deregulation of the PPARγ signaling pathway as a feature of CDX2-associated AML and observed that PPARγ agonists derepressed KLF4 and were preferentially toxic to CDX2+ leukemic cells. These data delineate transcriptional programs associated with CDX2 expression in hematopoietic cells, provide insight into the antagonistic duality of CDX2 function in AML versus colon cancer, and suggest reactivation of KLF4 expression, through modulation of PPARγ signaling, as a therapeutic modality in a large proportion of AML patients.

Targeting of KRAS mutant tumors by HSP90 inhibitors involves degradation of STK33.

Previous efforts to develop drugs that directly inhibit the activity of mutant KRAS, the most commonly mutated human oncogene, have not been successful. Cancer cells driven by mutant KRAS require expression of the serine/threonine kinase STK33 for their viability and proliferation, identifying STK33 as a context-dependent therapeutic target. However, specific strategies for interfering with the critical functions of STK33 are not yet available. Here, using a mass spectrometry-based screen for STK33 protein interaction partners, we report that the HSP90/CDC37 chaperone complex binds to and stabilizes STK33 in human cancer cells. Pharmacologic inhibition of HSP90, using structurally divergent small molecules currently in clinical development, induced proteasome-mediated degradation of STK33 in human cancer cells of various tissue origin in vitro and in vivo, and triggered apoptosis preferentially in KRAS mutant cells in an STK33-dependent manner. Furthermore, HSP90 inhibitor treatment impaired sphere formation and viability of primary human colon tumor-initiating cells harboring mutant KRAS. These findings provide mechanistic insight into the activity of HSP90 inhibitors in KRAS mutant cancer cells, indicate that the enhanced requirement for STK33 can be exploited to target mutant KRAS-driven tumors, and identify STK33 depletion through HSP90 inhibition as a biomarker-guided therapeutic strategy with immediate translational potential.

Comprehensive genomic access to vector integration in clinical gene therapy.

Retroviral vectors have induced subtle clonal skewing in many gene therapy patients and severe clonal proliferation and leukemia in some of them, emphasizing the need for comprehensive integration site analyses to assess the biosafety and genomic pharmacokinetics of vectors and clonal fate of gene-modified cells in vivo. Integration site analyses such as linear amplification-mediated PCR (LAM-PCR) require a restriction digest generating unevenly small fragments of the genome. Here we show that each restriction motif allows for identification of only a fraction of all genomic integrants, hampering the understanding and prediction of biological consequences after vector insertion. We developed a model to define genomic access to the viral integration site that provides optimal restriction motif combinations and minimizes the percentage of nonaccessible insertion loci. We introduce a new nonrestrictive LAM-PCR approach that has superior capabilities for comprehensive unbiased integration site retrieval in preclinical and clinical samples independent of restriction motifs and amplification inefficiency.