Integrative analysis of genomic aberrations in the context of trancriptomic alterations will lead to a more comprehensive perspective on prostate cancer progression. Genome-wide copy number changes ...were monitored using array comparative genomic hybridization of laser-capture microdissected prostate cancer samples spanning stages of prostate cancer progression, including precursor lesions, clinically localized disease, and metastatic disease. A total of 62 specific cell populations from 38 patients were profiled. Minimal common regions (MCR) of alterations were defined for each sample type, and metastatic samples displayed the most number of alterations. Clinically localized prostate cancer samples with high Gleason grade resembled metastatic samples with respect to the size of altered regions and number of affected genes. A total of 9 out of 13 MCRs in the putative precursor lesion, high-grade prostatic intraepithelial neoplasia (PIN), showed an overlap with prostate cancer cases (amplifications in 3q29, 5q31.3-q32, 6q27, and 8q24.3 and deletions in 6q22.31, 16p12.2, 17q21.2, and 17q21.31), whereas postatrophic hyperplasia (PAH) did not exhibit this overlap. Interestingly, prostate cancers that do not overexpress ETS family members (i.e., gene fusion-negative prostate cancers) harbor differential aberrations in 1q23, 6q16, 6q21, 10q23, and 10q24. Integrative analysis with matched mRNA profiles identified genetic alterations in several proposed candidate genes implicated in prostate cancer progression.
The ongoing evolution of Ebolaviruses poses significant challenges to the development of immunodiagnostics for detecting emergent viral variants. There is a critical need for the discovery of ...monoclonal antibodies with distinct affinities and specificities for different Ebolaviruses. We developed an efficient technology for the rapid discovery of a plethora of antigen-specific monoclonal antibodies from immunized animals by mining the VH:VL paired antibody repertoire encoded by highly expanded B cells in the draining popliteal lymph node (PLN). This approach requires neither screening nor selection for antigen-binding. Specifically we show that mouse immunization with Ebola VLPs gives rise to a highly polarized antibody repertoire in CD138(+) antibody-secreting cells within the PLN. All highly expanded antibody clones (7/7 distinct clones/animal) were expressed recombinantly, and shown to recognize the VLPs used for immunization. Using this approach we obtained diverse panels of antibodies including: (i) antibodies with high affinity towards GP; (ii) antibodies which bound Ebola VLP Kissidougou-C15, the strain circulating in the recent West African outbreak; (iii) non-GP binding antibodies that recognize wild type Sudan or Bundibugyo viruses that have 39% and 37% sequence divergence from Ebola virus, respectively and (iv) antibodies to the Reston virus GP for which no antibodies have been reported.
Efficient energy storage systems based on lithium-ion batteries represent a critical technology across many sectors including consumer electronics, electrified transportation, and a smart grid ...accommodating intermittent renewable energy sources. Nanostructured electrode materials present compelling opportunities for high-performance lithium-ion batteries, but inherent problems related to the high surface area to volume ratios at the nanometer-scale have impeded their adoption for commercial applications. Here, we demonstrate a materials and processing platform that realizes high-performance nanostructured lithium manganese oxide (nano-LMO) spinel cathodes with conformal graphene coatings as a conductive additive. The resulting nanostructured composite cathodes concurrently resolve multiple problems that have plagued nanoparticle-based lithium-ion battery electrodes including low packing density, high additive content, and poor cycling stability. Moreover, this strategy enhances the intrinsic advantages of nano-LMO, resulting in extraordinary rate capability and low temperature performance. With 75% capacity retention at a 20C cycling rate at room temperature and nearly full capacity retention at -20 degrees C, this work advances lithium-ion battery technology into unprecedented regimes of operation.
Survival rates for pediatric patients suffering from mixed lineage leukemia (MLL)-rearranged leukemia remain below 50% and more targeted, less toxic therapies are urgently needed. A screening method ...optimized to discover cytotoxic compounds selective for MLL-rearranged leukemia identified CCI-006 as a novel inhibitor of MLL-rearranged and CALM-AF10 translocated leukemias that share common leukemogenic pathways. CCI-006 inhibited mitochondrial respiration and induced mitochondrial membrane depolarization and apoptosis in a subset (7/11, 64%) of MLL-rearranged leukemia cell lines within a few hours of treatment. The unresponsive MLL-rearranged leukemia cells did not undergo mitochondrial membrane depolarization or apoptosis despite a similar attenuation of mitochondrial respiration by the compound. In comparison to the sensitive cells, the unresponsive MLL-rearranged leukemia cells were characterized by a more glycolytic metabolic phenotype, exemplified by a more pronounced sensitivity to glycolysis inhibitors and elevated HIF1α expression. Silencing of HIF1α expression sensitized an intrinsically unresponsive MLL-rearranged leukemia cell to CCI-006, indicating that this pathway plays a role in determining sensitivity to the compound. In addition, unresponsive MLL-rearranged leukemia cells expressed increased levels of MEIS1, an important leukemogenic MLL target gene that plays a role in regulating metabolic phenotype through HIF1α. MEIS1 expression was also variable in a pediatric MLL-rearranged ALL patient dataset, highlighting the existence of a previously undescribed metabolic variability in MLL-rearranged leukemia that may contribute to the heterogeneity of the disease. This study thus identified a novel small molecule that rapidly kills MLL-rearranged leukemia cells by targeting a metabolic vulnerability in a subset of low HIF1α/low MEIS1-expressing MLL-rearranged leukemia cells.
Although BRAF inhibitor monotherapy yields response rates >50% in
-mutant melanoma, only approximately 5% of patients with
colorectal cancer respond. Preclinical studies suggest that the lack of ...efficacy in
colorectal cancer is due to adaptive feedback reactivation of MAPK signaling, often mediated by EGFR. This clinical trial evaluated BRAF and EGFR inhibition with dabrafenib (D) + panitumumab (P) ± MEK inhibition with trametinib (T) to achieve greater MAPK suppression and improved efficacy in 142 patients with
colorectal cancer. Confirmed response rates for D+P, D+T+P, and T+P were 10%, 21%, and 0%, respectively. Pharmacodynamic analysis of paired pretreatment and on-treatment biopsies found that efficacy of D+T+P correlated with increased MAPK suppression. Serial cell-free DNA analysis revealed additional correlates of response and emergence of
and
mutations on disease progression. Thus, targeting adaptive feedback pathways in
colorectal cancer can improve efficacy, but MAPK reactivation remains an important primary and acquired resistance mechanism.
This trial demonstrates that combined BRAF + EGFR + MEK inhibition is tolerable, with promising activity in patients with
colorectal cancer. Our findings highlight the MAPK pathway as a critical target in
colorectal cancer and the need to optimize strategies inhibiting this pathway to overcome both primary and acquired resistance.
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Shear-assisted processing and extrusion (ShAPE) is used to consolidate Al-4.2Mg-1.6Zr-0.25Si-0.1Fe (wt.%) powders. The extruded alloy exhibits: (i) near-zero porosity; (ii) an attractive combination ...of tensile yield strength (~220 MPa), ultimate strength (330 MPa) and elongation (>20%); and (iii) excellent thermal stability at 400 °C. The ultra-fine grain size in the gas-atomized powders – created and stabilized by primary L12-Al3Zr submicron precipitates - is maintained after consolidation and subsequent exposure at 400 °C, contributing twice as much to strength as Mg in solid-solution. Electron microscopy reveals the microstructure of the L12-Al3Zr precipitates, and other precipitates (Mg2Si and Al3Fe) and dispersoids (oxides).
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Gastrointestinal (GI) illness is the most commonly reported health concern among Peace Corps Volunteers (PCVs) serving in Guatemala. This project identified water types and treatment and storage ...practices used by PCVs and measured select water quality parameters in their household water.
A survey about water types and practices was conducted of PCVs in Guatemala. The water type most frequently consumed in the household ("primary drinking water") and other water types present in the household ("secondary water") were tested for free chlorine residual (FCR) and for the presence of
and total coliforms. A negative binomial regression model was used to analyze data on incidence of self-reported GI illness.
(commercially purified water in a 5-gal bottle) was the water type most frequently (64%) reported as primary drinking water in 39 PCV households. Most (74%) PCVs reported drinking water other than primary drinking water ≥1 day per week; the incidence rate of GI illness per PCV per month was significantly lower among PCVs who reported never consuming water other than primary drinking water compared to those who did (0.4 and 1.6 GI illnesses per PCV per month, respectively) (
< 0.05).
was not detected in any primary drinking water sample, but was detected in 35% of secondary water samples. Total coliforms were detected in more than two-thirds of primary drinking water and secondary water samples. Nearly all water samples had an FCR of < 0.2 mg/L.
Consuming primary drinking water exclusively likely contributes to reducing the rate of GI illness among PCVs. However, most PCVs reported drinking multiple water types, which may include contaminated secondary water types in the household. All water intended for consumption, including secondary sources within and outside the household, should be properly treated and safely stored.
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