Disruption of proteome by an oncogenic fusion kinase alters metabolism in fibrolamellar hepatocellular carcinoma.

Fibrolamellar hepatocellular carcinoma (FLC) is a usually lethal primary liver cancer driven by a somatic dysregulation of protein kinase A. We show that the proteome of FLC tumors is distinct from that of adjacent nontransformed tissue. These changes can account for some of the cell biological and pathological alterations in FLC cells, including their drug sensitivity and glycolysis.

A Playbook for Implementing Medicaid Expansion: Louisiana's Experience.

Policy Points Twelve states have yet to expand Medicaid under the Affordable Care Act (ACA). Louisiana offers a model of steps that states and counties can take to rapidly enroll eligible persons while balancing eligibility integrity and doing so within a limited administrative budget. In a post-COVID-19 health care landscape, Medicaid expansion can improve and protect population health and boost state economies, even amid budget shortfalls.

Identification of Novel Therapeutic Targets for Fibrolamellar Carcinoma Using Patient-Derived Xenografts and Direct-from-Patient Screening.

To repurpose therapeutics for fibrolamellar carcinoma (FLC), we developed and validated patient-derived xenografts (PDX) from surgical resections. Most agents used clinically and inhibitors of oncogenes overexpressed in FLC showed little efficacy on PDX. A high-throughput functional drug screen found primary and metastatic FLC were vulnerable to clinically available inhibitors of TOPO1 and HDAC and to napabucasin.

Characterization of the full-length human Grb7 protein and a phosphorylation representative mutant.

It is well known the dimerization state of receptor tyrosine kinases (RTKs), in conjunction with binding partners such as the growth factor receptor bound protein 7 (Grb7) protein, plays an important role in cell signaling regulation. Previously, we proposed, downstream of RTKs, that the phosphorylation state of Grb7SH2 domain tyrosine residues could control Grb7 dimerization, and dimerization may be an important regulatory step in Grb7 binding to RTKs. In this manner, additional dimerization-dependent regulation could occur downstream of the membrane-bound kinase in RTK-mediated signaling pathways.

Medicaid's Role in Health Reform and Closing the Coverage Gap.

Medicaid coverage matters for millions of low-income Americans, and especially for those with ongoing and serious health challenges. A source of comprehensive and affordable coverage, Medicaid has long been a cornerstone of federal and state efforts to improve access and health outcomes for very poor and medically vulnerable populations. The Affordable Care Act (ACA) leveraged Medicaid's role in serving the poor to broaden the program's reach to millions of low-income uninsured adults, and positioned the program as a fundamental component of the newly established continuum of public and private coverage.

Grb7 protein RA domain oligomerization.

The growth factor receptor bound protein 7 (Grb7) is an adaptor protein that is often coamplified with the erythroblastosis oncogene B 2 receptor in 20% to 30% of breast cancer patients. Grb7 overexpression has been linked to increased cell migration and cancer metastasis. The ras associating and pleckstrin homology domain region of Grb7 has been reported to interact with various other downstream signaling proteins such as four and half Lin11, Isl-1, Mec-3 (LIM) domains isoform 2 and filamin α.

Grb7 and Hax1 may colocalize partially to mitochondria in EGF-treated SKBR3 cells and their interaction can affect Caspase3 cleavage of Hax1.

Growth factor receptor bound protein 7 (Grb7) is a signal-transducing adaptor protein that mediates specific protein-protein interactions in multiple signaling pathways. Grb7, with Grb10 and Grb14, is members of the Grb7 protein family. The topology of the Grb7 family members contains several protein-binding domains that facilitate the formation of protein complexes, and high signal transduction efficiency.

Grb7 and Filamin-a associate and are colocalized to cell membrane ruffles upon EGF stimulation.

Grb7 is an adaptor molecule mediating signal transduction from multiple cell surface receptors to diverse downstream pathways. Grb7, along with Grb10 and Grb14, make up the Grb7 protein family. This protein family has been shown to be overexpressed in certain cancers and cancer cell lines.

Dimerization in the Grb7 protein.

In previous studies, we showed that the tyrosine phosphorylation state of growth factor receptor-bound protein 7 (Grb7) affects its ability to bind to the transcription regulator FHL2 and the cortactin-interacting protein, human HS-1-associated protein-1. Here, we present results describing the importance of dimerization in the Grb7-Src homology 2 (SH2) domain in terms of its structural integrity and the ability to bind phosphorylated tyrosine peptide ligands. A tyrosine phosphorylation-mimic mutant (Y80E-Grb7-SH2) is largely dimerization deficient and binds a tyrosine-phosphorylated peptide representative of the receptor tyrosine kinase (RTK) erbB2 with differing thermodynamic characteristics than the wild-type SH2 domain.

Water-refined solution structure of the human Grb7-SH2 domain in complex with the erbB2 receptor peptide pY1139.

We report a refinement in implicit water of the previously published solution structure of the Grb7-SH2 domain bound to the erbB2 receptor peptide pY1139. Structure quality measures indicate substantial improvement, with residues in the most favored regions of the Ramachandran plot increasing by 14 % and with WHAT IF statistics (Vriend, G. J.

Dx for a careful approach to moving dual-eligible beneficiaries into managed care plans.

Policy makers are moving rapidly to develop and test reforms aimed at doing a better job of managing the costs and care for people dually eligible for Medicare and Medicaid. This commentary underscores the importance of pursuing new initiatives to address care coordination and spending concerns. It then focuses on key issues raised by proposals that would shift dual-eligible beneficiaries into managed care plans.

Grb7 binds to Hax-1 and undergoes an intramolecular domain association that offers a model for Grb7 regulation.

Adaptor proteins mediate signal transduction from cell surface receptors to downstream signaling pathways. The Grb7 protein family of adaptor proteins is constituted by Grb7, Grb10, and Grb14. This protein family has been shown to be overexpressed in certain cancers and cancer cell lines.

The intertwining of structure and function: proposed helix-swapping of the SH2 domain of Grb7, a regulatory protein implicated in cancer progression and inflammation.

Grb7 is a multidomain intracellular signaling protein that links activated tyrosine kinases with downstream signaling targets. Best known for its regulatory role in cell migration and tumor metastasis, Grb7 also regulates inflammation by coupling NF-kappaB-inducing kinase with erbB/EGFR family receptors. The "adaptor" role of Grb7 in these processes depends upon binding to membrane-associated tyrosine kinases through its C-terminal SH2 domain.

Beyond Incrementalism? SCHIP and the politics of health reform.

When Congress enacted the State Children's Health Insurance Program (SCHIP) in 1997, it was heralded as a model of bipartisan, incremental health policy. However, despite the program's achievements in the ensuing decade, SCHIP's reauthorization triggered political conflict, and efforts to expand the program stalemated in 2007. The 2008 elections broke that stalemate, and in 2009 the new Congress passed, and President Barack Obama signed, legislation reauthorizing SCHIP.

Florida's medicaid reform: informed consumer choice?

Florida is among the first states to implement Medicaid reform using a competitive consumer choice model. Using data from a 2006-07 Kaiser Family Foundation survey of Medicaid recipients newly enrolled in Florida's reform program, we examine how well they understood the changes taking place and their experiences in selecting a health plan. We find important gaps in people's understanding of major components of the reform: About 30 percent were not aware that they were enrolled in reform, and more than half had trouble understanding plan information.

The cell migration protein Grb7 associates with transcriptional regulator FHL2 in a Grb7 phosphorylation-dependent manner.

Grb7 is an adaptor molecule that can mediate signal transduction from multiple cell surface receptors to various downstream signaling pathways. Grb7, along with Grb10 and Grb14, make up the Grb7 protein family. This protein family has been shown to be overexpressed in certain cancers and cancer cell lines.

Isolation, characterization, and biological evaluation of syn and anti diastereomers of [(99m)Tc]technetium depreotide: a somatostatin receptor binding tumor imaging agent.

The early and later eluting [(99m)TcO]depreotide products on RP-HPLC were confirmed to be the anti and syn diastereomers, respectively, based on proton NMR and circular dichroism spectroscopy. NMR provided evidence of a folded, conformationally constrained structure for the syn diastereomer. The syn diastereomer is predominant (anti/syn approximately 10:90) in the [(99m)TcO]depreotide preparation and shows a slightly higher affinity (IC50 = 0.

Alternative splicing of the voltage-gated Ca2+ channel beta4 subunit creates a uniquely folded N-terminal protein binding domain with cell-specific expression in the cerebellar cortex.

Ca2+ channel beta subunits regulate cell-surface expression and gating of voltage-dependent Ca2+ channel alpha1 subunits. Based on primary sequence comparisons, beta subunits are predicted to be modular structures composed of five domains (A-E) that are related to the large family of membrane-associated guanylate kinase proteins. The crystal structure of the beta subunit core B-D domains has been reported recently; however, little is known about the structures of the A and E domains.

Can States stretch the Medicaid dollar without passing the buck? Lessons from Utah.

In 2002, Utah became the first state to reduce benefits and increase cost sharing for existing Medicaid beneficiaries, to finance a primary care benefit expansion for previously ineligible, low-income adults. Through a 2004 survey of beneficiaries, we found that expansion enrollees were predominantly poor and that most suffered from chronic conditions or disabilities, or both. Parents whose coverage was reduced to finance the expansion were extremely poor, were in poor health, and faced major financial challenges.

Solution structure of the N-terminal A domain of the human voltage-gated Ca2+channel beta4a subunit.

Ca2+ channel beta subunits regulate trafficking and gating (opening and closing) of voltage-dependent Ca2+ channel alpha1 subunits. Based on primary sequence comparisons, they are thought to be modular structures composed of five domains (A-E) that are related to the large family of membrane associated guanylate-kinase (MAGUK) proteins. The crystal structures of the beta subunit core, B-D, domains have recently been reported; however, very little is known about the structures of the A and E domains.

Keeping Medicaid viable. Interview by Terese Hudson Thrall.

As the Medicaid program enters its fourth decade, it remains a safety net for Americans in need and for the nation itself, says Barbara Lyons, deputy director of the Kaiser Family Foundation's Commission on Medicaid and the Uninsured. In a question-and-answer interview, Lyons discusses whether it can stay that way--and why it must.

Solution structure of the human Grb14-SH2 domain and comparison with the structures of the human Grb7-SH2/erbB2 peptide complex and human Grb10-SH2 domain.

Grb14 is an adapter protein that is known to be overexpressed in estrogen receptor positive breast cancers, and in a number of prostate cancer cell lines. Grb14 has been demonstrated to bind to a number of activated receptor tyrosine kinases (RTKs) and to modulate signals transduced through these receptors. The RTKs to which Grb14 binds include the insulin receptor (IR), the fibroblast growth factor receptor (FGFR), the platelet-derived growth factor receptor (PDGFR), and the tunica endothelial kinase (Tek/Tie2) receptor.