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Heparin Doesn't Dent VTE Risk After Knee Scoping, Leg Casting (CME/CE)

Headlines from MedPage Today® - Tue, 12/06/2016 - 11:00am
(MedPage Today) -- Higher doses or longer treatment not recommended

Infantile Spasms Dx Often Comes Slowly

Headlines from MedPage Today® - Tue, 12/06/2016 - 10:30am
(MedPage Today) -- Less than a third offered first-line treatment within a week of onset

Does Patient Safety Suffer at End of Residents' Rotations?

Headlines from MedPage Today® - Tue, 12/06/2016 - 10:00am
(MedPage Today) -- F. Perry Wilson, MD, explores a new study of handoffs

HIV-Positive Patients Fit for Autologous Cell Transplant (CME/CE)

Headlines from MedPage Today® - Tue, 12/06/2016 - 10:00am
(MedPage Today) -- Cell subsets that define immune recovery merge over time

Transplant Still Top Therapy in Multiple Myeloma (CME/CE)

Headlines from MedPage Today® - Tue, 12/06/2016 - 9:30am
(MedPage Today) -- Newly diagnosed patients treated with drugs alone more likely to progress

Chemo-Free Induction for Mantle Cell Impresses (CME/CE)

Headlines from MedPage Today® - Tue, 12/06/2016 - 8:32am
(MedPage Today) -- Response rate of 100% with ibrutinib-rituximab combination

Big biology projects warm up to preprints

news@nature - Tue, 12/06/2016 - 8:21am

Consortium backed by US National Institutes of Health is first major biology programme to mandate online publication of results ahead of peer review.

Nature News doi: 10.1038/nature.2016.21074

ALL Study Fails to Support Chemo Change (CME/CE)

Headlines from MedPage Today® - Tue, 12/06/2016 - 8:15am
(MedPage Today) -- Reduced intensity treatment was less effective in preventing relapse

Morning Break: Superbug at Pig Farm; Saving Kids' Hearing; Nut Nuttiness

Headlines from MedPage Today® - Tue, 12/06/2016 - 8:01am
(MedPage Today) -- Health news and commentary from around the Web, gathered by the MedPage Today staff

Deforestation spikes in Brazilian Amazon

news@nature - Tue, 12/06/2016 - 7:21am

Illegal land clearing hits highest levels since 2008 as environmental policies come under attack.

Nature News doi: 10.1038/nature.2016.21083

Targeting Drug Resistance in Chronic Myeloid Leukemia: A Dissertation

eScholarship@UMMS - Mon, 12/05/2016 - 9:44pm

Inhibiting BCR-ABL kinase activity with tyrosine kinase inhibitors (TKIs) has been the frontline therapy for CML. Resistance to TKIs frequently occurs, but the mechanisms remain elusive.

First, to uncover survival pathways involved in TKI resistance in CML, I conducted a genome-wide RNAi screen in human CML cells to identify genes governing cellular sensitivity to the first generation TKI called IM (Gleevec). I identified genes converging on and activating the MEK/ERK pathway through transcriptional up-regulation of PRKCH. Combining IM with a MEK inhibitor synergistically kills TKI-resistant CML cells and CML stem cells.

Next, I performed single cell RNA-seq to compare expression profiles of CML stem cells and hematopoietic stem cells isolated from the same patient. Among the genes that are preferentially expressed in CML stem cells is PIM2, which encodes a pro-survival serine-threonine kinase that phosphorylates and inhibits the pro-apoptotic protein BAD. Inhibiting PIM2 function sensitizes CML stem cells to IM-induced apoptosis and prevents disease relapse in a CML mouse model.

Last, I devised a CRISPR-Cas9 based strategy to perform insertional mutagenesis at a defined genomic location in murine hematopoietic Ba/F3 cells. As proof of principle, we showed its capability to perform unbiased, saturated point mutagenesis in a 9 amino acid region of BCR-ABL encompassing the socalled “gatekeeper” residue, an important determinant of TKI binding. We found that the ranking order of mutations from the screen correlated well with their prevalence in IM-resistant CML patients.

Overall, my findings reveal novel resistance mechanisms in CML and provide alternative therapeutic strategies.

Systematic Analysis of Duplications and Deletions in the Malaria Parasite P. falciparum: A Dissertation

eScholarship@UMMS - Mon, 12/05/2016 - 9:44pm

Duplications and deletions are a major source of genomic variation. Duplications, specifically, have a significant impact on gene genesis and dosage, and the malaria parasite P. falciparum has developed resistance to a growing number of anti-malarial drugs via gene duplication. It also contains highly duplicated families of antigenically variable allelic genes. While specific genes and families have been studied, a comprehensive analysis of duplications and deletions within the reference genome and population has not been performed. We analyzed the extent of segmental duplications (SD) in the reference genome for P. falciparum, primarily by a whole genome self alignment. We discovered that while 5% of the genome identified as SD, the distribution within the genome was partition clustered, with the vast majority localized to the subtelomeres. Within the SDs, we found an overrepresentation of genes encoding antigenically diverse proteins exposed to the extracellular membrane, specifically the var, rifin, and stevor gene families. To examine variation of duplications and deletions within the parasite populations, we designed a novel computational methodology to identify copy number variants (CNVs) from high throughput sequencing, using a read depth based approach refined with discordant read pairs. After validating the program against in vitro lab cultures, we analyzed isolates from Senegal for initial tests into clinical isolates. We then expanded our search to a global sample of 610 strains from Africa and South East Asia, identifying 68 CNV regions. Geographically, genic CNV were found on average in less than 10% of the population, indicating that CNV are rare. However, CNVs at high frequency were almost exclusively duplications associated with known drug resistant CNVs. We also identified the novel biallelic duplication of the crt gene – containing both the chloroquine resistant and sensitive allele. The synthesis of our SD and CNV analysis indicates a CNV conservative P. falciparum genome except where drug and human immune pressure select for gene duplication.

The Exocyst Subunit Sec6 Interacts with Assembled Exocytic Snare Complexes: A Dissertation

eScholarship@UMMS - Mon, 12/05/2016 - 9:44pm

In eukaryotic cells, membrane-bound vesicles carry cargo between intracellular compartments, to and from the cell surface, and to the extracellular environment. Many conserved families of proteins are required for properly localized vesicle fusion, including the multi-subunit tethering complexes and the SNARE complexes. These protein complexes work together to promote proper vesicle fusion in other trafficking pathways. Contrary to these other pathways, our lab previously suggested that the exocyst subunit Sec6, a component of the exocytosis-specific tethering complex, inhibited Sec9:Sso1 SNARE complex assembly due to interactions in vitro with the SNARE protein Sec9 (Sivaram et al., 2005).

My goal for this project was to test the hypothesis that Sec6 inhibited SNARE complex assembly in vivo. I therefore chose to generate Sec6:Sec9 loss-of-binding mutants, and study their effect both in vitro and in vivo. I identified a patch of residues on Sec9 that, when mutated, are sufficient to disrupt the novel Sec6-SNARE interaction. Additionally, I found that the previous inhibitory role for Sec6 in SNARE assembly was due to a data mis-interpretation; my re-interpretation of the data shows that Sec6 has a mild, if any, inhibitory effect on SNARE assembly. My results suggest a potential positive role for Sec6 in SNARE complex assembly, similar to the role observed for other tether-SNARE interactions.

Requirement and Function of Hippo Pathway Signaling in the Mammalian Gastrointestinal Tract: A Dissertation

eScholarship@UMMS - Mon, 12/05/2016 - 9:43pm

In cancer, aberrant activation of developmental signaling pathways such as the Hippo Pathway has been shown to drive proliferation and invasion of cancer cells. Therefore, understanding the normal function of the Hippo Pathway during embryonic development can provide critical insight into how aberrant activity contributes to tumorigenesis. This dissertation explores the role of the Hippo Pathway members YAP and TAZ in gastrointestinal (GI) development and tumorigenesis. I use mouse genetics to systematically dissect the roles of YAP/TAZ in the endoderm-derived gastrointestinal epithelia and mesoderm-derived gastrointestinal mesenchyme during mammalian development. In the GI epithelium, I demonstrate that YAP/TAZ are dispensable for development and homeostasis. However, YAP/TAZ are required for Wnt pathway-driven tumorigenesis. I find that YAP/TAZ are direct transcriptional targets of Wnt/TCF4 signaling. In the GI mesenchyme, I describe a previously unknown requirement for YAP/TAZ activity during mammalian GI development. YAP/TAZ are involved in normal GI mesenchymal differentiation and function as transcriptional co-repressors in a progenitor cell population. In this way, YAP/TAZ act as molecular gatekeepers prior to Hedgehog-mediated differentiation into smooth muscle cells. This work unveils a previously unknown requirement for Hippo pathway signaling in the mammalian GI tract and a novel mechanism wherein YAP/TAZ function as transcriptional co-repressors to maintain a mesenchymal progenitor cell population.

Less Hair 'Down There' May Up Risk for Sexually Transmitted Infection

Headlines from MedPage Today® - Mon, 12/05/2016 - 5:30pm
(MedPage Today) -- Pubic hair grooming might cause skin micro-tears

Less Hair 'Down There' May Up Risk for Sexually Transmitted Infection

Headlines from MedPage Today® - Mon, 12/05/2016 - 5:30pm
(MedPage Today) -- Pubic hair grooming might cause skin micro-tears

VR's Future in Medicine: HealthLeaders Media

Headlines from MedPage Today® - Mon, 12/05/2016 - 5:00pm
(MedPage Today) -- Also, more monitoring needed for U.S. blood systems

VR's Future in Medicine: HealthLeaders Media

Headlines from MedPage Today® - Mon, 12/05/2016 - 5:00pm
(MedPage Today) -- Also, more monitoring needed for U.S. blood systems

Preemies Fare Better with Noninvasive Respiratory Care (CME/CE)

Headlines from MedPage Today® - Mon, 12/05/2016 - 4:33pm
(MedPage Today) -- Meta-analysis supports CPAP and nasal intermittent positive pressure ventilation

Preemies Fare Better with Noninvasive Respiratory Care (CME/CE)

Headlines from MedPage Today® - Mon, 12/05/2016 - 4:33pm
(MedPage Today) -- Meta-analysis supports CPAP and nasal intermittent positive pressure ventilation
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