Targeting rapid TKI-induced AXL upregulation overcomes adaptive ERK reactivation and exerts antileukemic effects in FLT3/ITD acute myeloid leukemia.

Acute myeloid leukemia (AML) patients with the FMS-related receptor tyrosine kinase 3 internal tandem duplication (FLT3/ITD) mutation have a poorer prognosis, and treatment with FLT3 tyrosine kinase inhibitors (TKIs) has been hindered by resistance mechanisms. One such mechanism is known as adaptive resistance, in which downstream signaling pathways are reactivated after initial inhibition. Past work has shown that FLT3/ITD cells undergo adaptive resistance through the reactivation of extracellular signal-regulated kinase (ERK) signaling within 24 h of sustained FLT3 inhibition.

Inhibition of NOTCH4 sensitizes FLT3/ITD acute myeloid leukemia cells to FLT3 tyrosine kinase inhibition.

Internal tandem duplication mutations of FLT3 (FLT3/ITD) confer poor prognosis in AML. FLT3 tyrosine kinase inhibitors (TKIs) alone have limited and transient clinical efficacy thus calling for new targets for more effective combination therapy. In a loss-of-function RNAi screen, we identified NOTCH4 as one such potential target whose inhibition proved cytotoxic to AML cells, and also sensitized them to FLT3 inhibition.

RAS G12C Inhibitors: Three Birds with One Stone.

In this issue, Rubinson, Tanaka, and colleagues demonstrate that differences among G12C inhibitors rely on their ability to covalently bind not only G12C mutant KRAS but also NRAS and HRAS, proposing sotorasib as a potent NRAS G12C inhibitor. See related article by Rubinson et al., p.

Strains Display Varying Susceptibility to Grazing by the Soil Amoeba .

Recent studies have shown that can survive in different environments, including soils, and they can maintain populations in sterile soil for a long period of time. This indicates that growth-supporting nutrients are available; however, when grown in non-sterile soils, populations decline, suggesting that other biological factors play a role in controlling populations in soil. Free-living protozoa can affect the bacterial population by grazing.

FLT3 tyrosine kinase inhibitors synergize with BCL-2 inhibition to eliminate FLT3/ITD acute leukemia cells through BIM activation.

Tyrosine kinase inhibitors (TKIs) targeting FLT3 have shown activity but when used alone have achieved limited success in clinical trials, suggesting the need for combination with other drugs. We investigated the combination of FLT3 TKIs (Gilteritinib or Sorafenib), with Venetoclax, a BCL-2 selective inhibitor (BCL-2i), on FLT3/ITD leukemia cells. The combination of a FLT3 TKI and a BCL-2i synergistically reduced cell proliferation and enhanced apoptosis/cell death in FLT3/ITD cell lines and primary AML samples.

Acetylcholinesterase is not a generic marker of extracellular vesicles.

Acetylcholinesterase (AChE) activity is found in abundance in reticulocytes and neurons and was developed as a marker of reticulocyte EVs in the 1970s. Easily, quickly, and cheaply assayed, AChE activity has more recently been proposed as a generic marker for small extracellular vesicles (sEV) or exosomes, and as a negative marker of HIV-1 virions. To evaluate these proposed uses of AChE activity, we examined data from different EV and virus isolation methods using T-lymphocytic (H9, PM1 and Jurkat) and promonocytic (U937) cell lines grown in culture conditions that differed by serum content.

Mechanical properties of the Papio anubis tympanic membrane: Change significantly from infancy to adulthood.

Mechanical properties of the tympanic membrane (TM) are important for studying the transfer function of the auditory system. However, nearly all reported human data are limited to adults because of the unavailability of temporal bones from children. In this study, we used the baboon (Papio anubis), a genetically close human relative, as a model to address the occurrence of age-dependent changes of the human TM.

Combination of ATO with FLT3 TKIs eliminates FLT3/ITD+ leukemia cells through reduced expression of FLT3.

Acute myeloid leukemia (AML) patients with FLT3/ITD mutations have a poor prognosis. Monotherapy with selective FLT3 tyrosine kinase inhibitors (TKIs) have shown transient and limited efficacy due to the development of resistance. Arsenic trioxide (ATO, AsO) has been proven effective in treating acute promyelocytic leukemia (APL) and has shown activity in some cases of refractory and relapsed AML and other hematologic malignances.

Distribution of Diverse Escherichia coli between Cattle and Pasture.

Escherichia coli is widely considered to not survive for extended periods outside the intestines of warm-blooded animals; however, recent studies demonstrated that E. coli strains maintain populations in soil and water without any known fecal contamination. The objective of this study was to investigate whether the niche partitioning of E.

Factors affecting sound energy absorbance in acute otitis media model of chinchilla.

Acute otitis media (AOM) is a rapid-onset infection of the middle ear which results in middle ear pressure (MEP), middle ear effusion (MEE), and structural changes in middle ear tissues. Previous studies from our laboratory have identified that MEP, MEE, and middle ear structural changes are three factors affecting tympanic membrane (TM) mobility and hearing levels (Guan et al., 2014, 2013).

Practically delineating bacterial species with genealogical concordance.

Bacterial species are commonly defined by applying a set of predetermined criteria, including DNA-DNA hybridization values, 16S rRNA gene sequence similarity, phenotypic data as well as genome-based criteria such as average nucleotide identity or digital DNA-DNA hybridization. These criteria mostly allow for the delimitation of taxa that resemble typical bacterial species. Their application is often complicated when the objective is to delineate new species that are characterized by significant population-level diversity or recent speciation.

Morphological changes in the round window membrane associated with Haemophilus influenzae-induced acute otitis media in the chinchilla.

Objective: The round window membrane (RWM) encloses the round window, the opening into the scala tympani (ST) from the middle ear. During the course of acute otitis media (AOM), structural changes of the RWM can occur that potentially affect sound transmission into and out of the cochlea. The relationship between such structural changes and conductive hearing loss during AOM has remained unclear.

Giant obscurins regulate the PI3K cascade in breast epithelial cells via direct binding to the PI3K/p85 regulatory subunit.

Obscurins are a family of giant cytoskeletal proteins, originally identified in striated muscles where they have structural and regulatory roles. We recently showed that obscurins are abundantly expressed in normal breast epithelial cells where they play tumor and metastasis suppressing roles, but are nearly lost from advanced stage breast cancer biopsies. Consistent with this, loss of giant obscurins from breast epithelial cells results in enhanced survival and growth, epithelial to mesenchymal transition (EMT), and increased cell migration and invasion in vitro and in vivo.

Draft Genome Sequences of Eight Nontypeable Haemophilus influenzae Strains Previously Characterized Using an Electrophoretic Typing Scheme.

Nontypeable Haemophilus influenzae is an important cause of human disease. Strains were selected for genome sequencing to represent the breadth of nontypeable strains within the species, as previously defined by the electrophoretic mobility of 16 metabolic enzymes.

Draft Genome Sequences of Six Nontypeable Haemophilus influenzae Strains That Establish Bacteremia in the Infant Rat Model of Invasive Disease.

Haemophilus influenzae is an important cause of invasive disease. The infant rat is the accepted model of invasive H. influenzae disease.

Antisera Against Certain Conserved Surface-Exposed Peptides of Nontypeable Haemophilus influenzae Are Protective.

Nontypeable Haemophilus influenzae (NTHi) cause significant disease, including otitis media in children, exacerbations of chronic obstructive pulmonary disease, and invasive disease in susceptible populations. No vaccine is currently available to prevent NTHi disease. The interactions of NTHi and the human host are primarily mediated by lipooligosaccharide and a complex array of surface-exposed proteins (SEPs) that act as receptors, sensors and secretion systems.

Population Genomics of the Euryhaline Teleost Poecilia latipinna.

Global climate change and increases in sea levels will affect coastal marine communities. The conservation of these ecologically important areas will be a challenge because of their wide geographic distribution, ecological diversity and species richness. To address this problem, we need to better understand how the genetic variation of the species in these communities is distributed within local populations, among populations and between distant regions.

Morphological changes in the tympanic membrane associated with Haemophilus influenzae-induced acute otitis media in the chinchilla.

Objective: The tympanic membrane (TM) couples sound waves entering the outer ear canal to mechanical vibrations of the ossicular chain in the middle ear. During acute otitis media (AOM), dynamic structural changes in the TM can occur, which potentially affect sound transmission. It has remained unclear whether TM changes contribute significantly to the conductive hearing loss associated with human AOM.

Comparison of transcription of the Haemophilus influenzae iron/heme modulon genes in vitro and in vivo in the chinchilla middle ear.

Background: Haemophilus influenzae is a significant cause of childhood otitis media, and also has an absolute growth requirement for heme. Recent microarray studies using three H. influenzae isolates were used to propose a putative core of genes responsive to iron and heme levels.

The role of the RNA chaperone Hfq in Haemophilus influenzae pathogenesis.

Background: The RNA binding protein Hfq of Haemophilus influenzae is highly homologous to Hfq from other bacterial species. In many of these other bacteria, Hfq affects the expression of a broad range of genes and enhances the ability to respond to stressful environments. However, the role of Hfq in H.

Haemophilus influenzae OxyR: characterization of its regulation, regulon and role in fitness.

To prevent damage by reactive oxygen species, many bacteria have evolved rapid detection and response systems, including the OxyR regulon. The OxyR system detects reactive oxygen and coordinates the expression of numerous defensive antioxidants. In many bacterial species the coordinated OxyR-regulated response is crucial for in vivo survival.

Signature-tagging of a bacterial isolate demonstrates phenotypic variability of the progeny in vivo in the absence of defined mutations.

Awareness of the high degree of redundancy that occurs in several nutrient uptake pathways of Haemophilus influenzae led us to attempt to develop a quantitative STM method that could identify both null mutants and mutants with decreased fitness that remain viable in vivo. To accomplish this task we designed a modified STM approach that utilized a set of signature tagged wild-type (STWT) strains (in a single genetic background) as carriers for mutations in genes of interest located elsewhere in the genome. Each STWT strain differed from the others by insertion of a unique, Q-PCR-detectable, seven base pair tag into the same redundant gene locus.