To develop an evidence-based clinical practice guideline to assist in clinical decision making for patients with advanced hepatocellular carcinoma (HCC).
ASCO convened an Expert Panel to conduct a ...systematic review of published phase III randomized controlled trials (2007-2020) on systemic therapy for advanced HCC and provide recommended care options for this patient population.
Nine phase III randomized controlled trials met the inclusion criteria.
Atezolizumab + bevacizumab (atezo + bev) may be offered as first-line treatment of most patients with advanced HCC, Child-Pugh class A liver disease, Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1, and following management of esophageal varices, when present, according to institutional guidelines. Where there are contraindications to atezolizumab and/or bevacizumab, tyrosine kinase inhibitors sorafenib or lenvatinib may be offered as first-line treatment of patients with advanced HCC, Child-Pugh class A liver disease, and ECOG PS 0-1. Following first-line treatment with atezo + bev, and until better data are available, second-line therapy with a tyrosine kinase inhibitor may be recommended for appropriate candidates. Following first-line therapy with sorafenib or lenvatinib, second-line therapy options for appropriate candidates include cabozantinib, regorafenib for patients who previously tolerated sorafenib, or ramucirumab (for patients with α-fetoprotein ≥ 400 ng/mL), or atezo + bev where patients did not have access to this option as first-line therapy. Pembrolizumab or nivolumab are also reasonable options for appropriate patients following sorafenib or lenvatinib. Consideration of nivolumab + ipilimumab as an option for second-line therapy and third-line therapy is discussed. Further guidance on choosing between therapy options is included within the guideline. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.
Retrovirus Restriction Factors Goff, Stephen P.
Molecular Cell,
12/2004, Volume:
16, Issue:
6
Book Review, Journal Article
Peer reviewed
Open access
A number of cellular genes have recently been identified that actively inhibit retrovirus replication and so protect cells from infection. The genes target many distinct steps in the viral life ...cycle: entry, viral DNA synthesis, intracellular movement of viral nucleic acids, and viral gene expression. These restriction systems constitute newly appreciated components of an innate immunity that may be important for survival of a host exposed to retrovirus infection. It may someday be possible to enhance or activate these systems to induce antiviral states.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cells have evolved multiple mechanisms to inhibit viral replication. To identify previously unknown antiviral activities, we screened mammalian complementary DNA (cDNA) libraries for genes that ...prevent infection by a genetically marked retrovirus. Virus-resistant cells were selected from pools of transduced clones, and an active antiviral cDNA was recovered. The gene encodes a CCCH-type zinc finger protein designated ZAP. Expression of the gene caused a profound and specific loss of viral messenger RNAs (mRNAs) from the cytoplasm without affecting the levels of nuclear mRNAs. The finding suggests the existence of a previously unknown machinery for the inhibition of virus replication, targeting a step in viral gene expression.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Many mammalian species express restriction factors that confer host resistance to retroviral infection. Here we show that HIV-1 sensitivity to restriction factors is modulated by cyclophilin A ...(CypA), a host cell protein that binds the HIV-1 capsid protein (CA). In certain nonhuman primate cells, the CA-CypA interaction is essential for restriction: HIV-1 infectivity is increased >100-fold by cyclosporin A (CsA), a competitive inhibitor of the interaction, or by an HIV-1 CA mutation that disrupts CypA binding. Conversely, disruption of CA-CypA interaction in human cells reveals that CypA protects HIV-1 from the Ref-1 restriction factor. These findings suggest that HIV-1 has co-opted a host cell protein to counteract restriction factors expressed by human cells and that this adaptation can confer sensitivity to restriction in unnatural hosts. Manipulation of HIV-1 CA recognition by restriction factors promises to advance animal models and new therapeutic strategies for HIV-1 and AIDS.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Dopaminergic (DA) neurons of substantia nigra in the midbrain control voluntary movement, and their degeneration is the cause of Parkinson's disease. The complete set of genes required to ...specifically determine the development of midbrain DA subgroups is not known yet. We report here that mice lacking the bicoid-related homeoprotein Pitx3 fail to develop DA neurons of the substantia nigra. Other mesencephalic DA neurons of the ventral tegmental area and retrorubral field are unaltered in their dopamine expression and histological organization. These data suggest that Pitx3-dependent gene expression is specifically required for the differentiation of DA progenitors within the mesencephalic DA system.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Subsurface fluvial deposits in coastline‐proximal settings record the spatiotemporal evolution of the coastal landscape and may be viable repositories of sediment for future coastal restoration ...projects. However, quantitative linkages between the geomorphic form and stratigraphic expression of coastal plain fluvial elements remain lacking, complicating coastal stratigraphic interpretations and subsurface resource assessment. This study explores the expression and preservation of fluvial coastal plain geomorphic features through outcrop‐scale seismic stratigraphic analysis of ultra‐high‐resolution chirp acoustic reflection data from the north‐western Gulf of Mexico inner continental shelf, offshore the Brazos River, Texas, USA. The chirp data exhibit decimetre‐scale vertical resolution within the upper 35 m of the shelf, evincing the preservation of two distinct types of coexisting fluvial channel‐forms: Type 1, a 1 km wide and 9 m deep single‐storey channel belt filled with sand‐rich lateral accretion deposits and channel fills; and Type 2, numerous 10 to 800 m wide and 1 to 20 m deep incisional floodplain channels filled with extensive drapes of overbank‐derived sediments. The chirp data resolve fluvial geomorphic elements including lateral accretion surfaces, levées, floodplain deposits and abandoned channel fills. Rollover of lateral accretion surfaces, widespread draping of seismic reflectors within channel fills, and quantitative comparison between the interpreted stratigraphic forms and analogous features on the nearby Texas Coastal Plain suggest near‐complete stratigraphic preservation of the geomorphic form of both channel belt and floodplain channel elements. Rapid aggradation of the coastal plain by the Brazos River in this region during the Holocene transgression is hypothesized as a mechanism for the high degree of preservation achieved. This study proposes the first recognition criteria for the seismic stratigraphic expression of coastal floodplain channels and provides direct linkages between the geomorphic and stratigraphic expression of a coastal plain fluvial landscape, promoting improved coastal stratigraphic interpretations and assessment of subsurface lithofacies distributions.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
We have generated and analysed null mutations in the mouse genes encoding three structurally related receptors with tyrosine kinase activity: Tyro 3, Axl, and Mer. Mice lacking any single receptor, ...or any combination of two receptors, are viable and fertile, but male animals that lack all three receptors produce no mature sperm, owing to the progressive death of differentiating germ cells. This degenerative phenotype appears to result from a failure of the tropic support that is normally provided by Sertoli cells of the seminiferous tubules, whose function depends on testosterone and additional factors produced by Leydig cells. Tyro 3, Axl and Mer are all normally expressed by Sertoli cells during postnatal development, whereas their ligands, Gas6 and protein S, are produced by Leydig cells before sexual maturity, and by both Leydig and Sertoli cells thereafter. Here we show that the concerted activation of Tyro 3, Axl and Mer in Sertoli cells is critical to the role that these cells play as nurturers of developing germ cells. Additional observations indicate that these receptors may also be essential for the tropic maintenance of diverse cell types in the mature nervous, immune and reproductive systems.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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