Serum biomarkers for the prediction of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a leading cause of global cancer death. Major etiologies of HCC relate to chronic viral infections as well as metabolic conditions. The survival rate of people with HCC is very low and has been attributed to late diagnosis with limited treatment options. Combining ultrasound and the biomarker alpha-fetoprotein (AFP) is currently one of the most widely used screening combinations for HCC. However, the clinical utility of AFP is controversial, and the frequency and operator-dependence of ultrasound lead to a variable degree of sensitivity and specificity across the globe. In this review, we summarize recent developments in the search for non-invasive serum biomarkers for early detection of HCC to improve prognosis and outcome for patients. We focus on tumor-associated protein markers, immune mediators (cytokines and chemokines), and micro-RNAs in serum or circulating extracellular vesicles and examine their potential for clinical application.Fil: Debes, José D.. Erasmus MC Rotterdam; Países Bajos. University of Minnesota; Estados UnidosFil: Romagnoli, Pablo Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Grupo Vinculado Centro de Investigación en Medicina Traslacional Severo R. Amuchástegui - Cimetsa | Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Grupo Vinculado Centro de Investigación en Medicina Traslacional Severo R. Amuchástegui - Cimetsa | Instituto de Investigación Médica Mercedes y Martín Ferreyra. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Grupo Vinculado Centro de Investigación en Medicina Traslacional Severo R. Amuchástegui - Cimetsa; Argentina. Instituto Universitario de Ciencias Biomédicas de Córdoba; ArgentinaFil: Prieto, Jhon. Centro de Enfermedades Hepáticas y Digestivas; ColombiaFil: Arrese, Marco. Pontificia Universidad Católica de Chile; ChileFil: Mattos, Angelo Z.. Universidade Federal de Ciencias Da Saúde de Porto Alegre; BrasilFil: Boonstra, André. Erasmus MC Rotterdam; Países Bajo

AdS Duals of Matrix Strings

We review recent work on the holographic duals of type II and heterotic matrix string theories described by warped AdS_3 supergravities. In particular, we compute the spectra of Kaluza-Klein primaries for type I, II supergravities on warped AdS_3xS^7 and match them with the primary operators in the dual two-dimensional gauge theories. The presence of non-trivial warp factors and dilaton profiles requires a modification of the familiar dictionary between masses and ``scaling'' dimensions of fields and operators. We present these modifications for the general case of domain wall/QFT correspondences between supergravities on warped AdS_{d+1}xS^q geometries and super Yang-Mills theories with 16 supercharges.Comment: 7 pages, Proceedings of the RTN workshop ``The quantum structure of spacetime and the geometric nature of fundamental interactions'', Leuven, September 200

Holographic Renormalization

We systematically develop the procedure of holographic renormalization for RG flows dual to asymptotically AdS domain walls. All divergences of the on-shell bulk action can be cancelled by adding covariant local boundary counterterms determined by the near-boundary behavior of bulk fields. This procedure defines a renormalized action from which correlation functions are obtained by functional differentiation. The correlators are finite and well behaved at coincident points. Ward identities, corrected for anomalies, are satisfied. The correlators depend on parts of the solution of the bulk field equations which are not determined by near-boundary analysis. In principle a full nonlinear solution is required, but one can solve linearized fluctuation equations to define a bulk-to-boundary propagator from which 2-point correlation functions are easily obtained. We carry out the procedure explicitly for two known RG flows obtained from the maximal gauged D=5 supergravity theory, obtaining new results on correlators of vector currents and related scalar operators and giving further details on a recent analysis of the stress tensor sector.Comment: 46 pages; v2: minor improvements and one ref adde

Assessment of <i>TLL1 </i>variant and risk of hepatocellular carcinoma in Latin Americans and Europeans

Introduction and Objectives: Tolloid like protein 1 (TLL1) rs17047200 has been reported to be associated with HCC development and liver fibrosis. However, to our knowledge, no studies have been performed on Latin Americans and comparative differences between TLL1 rs17047200 in HCC patients from Latin America and Europe are undefined. Materials and Methods: Cross-sectional analysis performed on Latin American and European individuals. We analyzed TLL1 rs17047200 on DNA from 1194 individuals, including 420 patients with HCC (86.0 % cirrhotics) and 774 without HCC (65.9 % cirrhotics). Results: TLL1 rs17047200 genotype AT/TT was not associated with HCC development in Latin Americans (OR: 0.699, 95 %CI 0.456-1.072, p = 0.101) or Europeans (OR: 0.736, 95 %CI 0.447-1.211, p = 0.228). TLL1 AT/TT was not correlated with fibrosis stages among metabolic dysfunction-associated steatotic liver disease (MASLD) patients from Latin America (OR: 0.975, 95 %CI 0.496-1.918, p = 0.941). Among Europeans, alcohol-related HCC had lower TLL1 AT/TT frequencies than cirrhosis (18.3 % versus 42.3 %, OR: 0.273, 95 %CI 0.096-0.773, p = 0.015). Conclusions: We found no evidence that the TLL1 rs17047200 AT/TT genotype is a risk factor for HCC development in Latin Americans or Europeans. A larger study integrating ethnic and etiology backgrounds is needed to determine the importance of the TLL1 SNP in HCC development.</p

MBOAT7 rs641738 Variant Is Not Associated with an Increased Risk of Hepatocellular Carcinoma in a Latin American Cohort

Background: The rs641738 C &gt; T single-nucleotide polymorphism of MBOAT7 has been associated with hepatocellular carcinoma (HCC) and nonalcoholic fatty liver disease (NAFLD). Latin Americans have high rates of HCC and NAFLD, but no assessment between MBOAT7 and HCC has been performed in this population. Aims: We provide the first assessment of the impact of MBOAT7 on HCC risk in Latin Americans. Methods: Patients were prospectively recruited into the ESCALON network, designed to collect samples from Latin American patients with HCC in 6 South American countries (Argentina, Ecuador, Brazil, Chile, Peru, and Colombia). A European cohort and the general Hispanic population of gnomAD database were included for comparison. Associations between HCC and MBOAT7 were evaluated using logistic regression. Results:In total, 310 cases of HCC and 493 cases of cirrhosis without HCC were assessed. The MBOAT7 TT genotype was not predictive of HCC in Latin Americans (TT vs CC OR adjusted = 1.15, 95% CI 0.66–2.01, p = 0.610) or Europeans (TT vs CC OR adjusted = 1.20, 95% CI 0.59–2.43, p = 0.621). No significant association was noted on subgroup analysis for NAFLD, viral hepatitis, or alcohol-related liver disease. The TT genotype was increased in the NAFLD-cirrhosis cohort of Latin Americans compared to a non-cirrhotic NAFLD cohort (TT vs CC + CT OR = 2.75, 95% CI 1.10–6.87, p = 0.031). Conclusion: The rs631738 C &gt; T allele of MBOAT7 was not associated with increased risk of HCC in Latin Americans or Europeans. An increase in the risk of cirrhosis was noted with the TT genotype in Latin Americans with NAFLD. Graphical Abstract: [Figure not available: see fulltext.]</p

Holography and Defect Conformal Field Theories

We develop both the gravity and field theory sides of the Karch-Randall conjecture that the near-horizon description of a certain D5-D3 brane configuration in string theory, realized as AdS_5 x S^5 bisected by an AdS_4 x S^2 "brane", is dual to N=4 Super Yang-Mills theory in R^4 coupled to an R^3 defect. We propose a complete Lagrangian for the field theory dual, a novel "defect superconformal field theory" wherein a subset of the fields of N=4 SYM interacts with a d=3 SU(N) fundamental hypermultiplet on the defect preserving conformal invariance and 8 supercharges. The Kaluza-Klein reduction of wrapped D5 modes on AdS_4 x S^2 leads to towers of short representations of OSp(4|4), and we construct the map to a set of dual gauge-invariant defect operators O_3 possessing integer conformal dimensions. Gravity calculations of and are given. Spacetime and N-dependence matches expectations from dCFT, while the behavior as functions of lambda = g^2 N at strong and weak coupling is generically different. We comment on a class of correlators for which a non-renormalization theorem may still exist. Partial evidence for the conformality of the quantum theory is given, including a complete argument for the special case of a U(1) gauge group. Some weak coupling arguments which illuminate the duality are presented.Comment: 47 pages, LaTeX, 2 figures, feynmf. v2: fixed minor errors, added references. v3: fixed more typo

Intersecting D3-branes and Holography

We study a defect conformal field theory describing D3-branes intersecting over two space-time dimensions. This theory admits an exact Lagrangian description which includes both two- and four-dimensional degrees of freedom, has (4,4) supersymmetry and is invariant under global conformal transformations. Both two- and four-dimensional contributions to the action are conveniently obtained in a two-dimensional (2,2) superspace. In a suitable limit, the theory has a dual description in terms of a probe D3-brane wrapping an AdS_3 x S^1 slice of AdS_5 x S^5. We consider the AdS/CFT dictionary for this set-up. In particular we find classical probe fluctuations corresponding to the holomorphic curve wy=c\alpha^{\prime}. These fluctuations are dual to defect fields containing massless two-dimensional scalars which parameterize the classical Higgs branch, but do not correspond to states in the Hilbert space of the CFT. We also identify probe fluctuations which are dual to BPS superconformal primary operators and to their descendants. A non-renormalization theorem is conjectured for the correlators of these operators, and verified to order g^2.Comment: 46 pages, 5 figures, Latex, minor corrections to section 4.2, version published in Phys. Rev.

CRK9 contributes to regulation of mitosis and cytokinesis in the procyclic form of Trypanosoma brucei

<p>Abstract</p> <p>Background</p> <p>The <it>Trypanosoma brucei </it>cell cycle is regulated by combinations of cyclin/CRKs (cdc2 related kinases). Recently, two additional cyclins (CYC10, CYC11) and six new CRK (CRK7-12) homologues were identified in the <it>T. brucei </it>genome database <abbrgrp><abbr bid="B1">1</abbr><abbr bid="B2">2</abbr></abbrgrp>.</p> <p>Results</p> <p>Individual RNAi knockdowns of these new proteins in the procyclic form of <it>T. brucei </it>showed no apparent phenotype except for the CRK9 depletion, which enriched the cells in G2/M phase. But a similar CRK9 knockdown in the bloodstream form caused no apparent phenotype. CRK9 lacks the typical PSTAIRE motif for cyclin binding and the phenylalanine "gatekeeper" but binds to cyclin B2 <it>in vitro </it>and localizes to the nucleus in both forms of <it>T. brucei</it>. CRK9-depleted procyclic-form generated no detectable anucleate cells, suggesting an inhibition of cytokinesis by CRK9 depletion as well. The knockdown enriched cells with one nucleus, one kinetoplast and two closely associated basal bodies with an average distance of 1.08 mm in between, which was shorter than the control value of 1.36 μm, and the cells became morphologically deformed and rounded with time.</p> <p>Conclusion</p> <p>CRK9 may play a role in mediating the segregation between the two kinetoplast/basal body pairs prior to cytokinetic initiation. Since such a segregation over a relatively significant distance is essential for cytokinetic initiation only in the procyclic but may not be in the bloodstream form, CRK9 could be specifically involved in regulating cytokinetic initiation in the procyclic form of <it>T. brucei</it>.</p