Cholangiographic Features in the Diagnosis and Management of Obstructive Icteric Type Hepatocellular Carcinoma

In 11 years and 3 months, 2037 patients with HCC were seen and 48 patients (2.4%) were diagnosed to have obstructive icteric type HCC. Five patients were terminally ill and were not investigated further. Forty three patients were initially investigated by endoscopic retrograde cholangiography (ERC) or percutaneous transhepatic cholangiogram (PTC) and classified as having obstructive icteric type 1, 2, or 3 HCC based on the cholangiographic findings. The obstruction in type 1 HCC was due to intraluminal tumour casts and/or tumour fragments obstructing the hepatic ductal confluence or common bile duct, while intraluminal blood clots, from haemobilia, filling the biliary tree was the cause in type 2 HCC. The pathology in type 3 HCC was extraluminal obstruction by extensive tumour encasement of the intra–hepatic biliary ductal system and/or extrinsic compression of the hepatic and common bile ducts by tumour(s) and/or malignant lymph nodes. At the initial ERC/PTC, 10 patients (5 resected, 50%) had obstructive icteric type 1 and 23 patients (0 resected) had obstructive icteric type 3 HCC. Of the 10 patients initially classified according to cholangiography to have obstructive icteric type 2 HCC, subsequent investigations revealed that 6 patients had type 1 HCC (4 resectable, 67%) and 4 patients had type 3 HCC (0 resectable). The classification of the obstructive icteric type HCC into types 1, 2, and 3, based on the initial cholangiographic appearances has simplified and rationalized our management strategy for this condition

Constraints on a Massive Dirac Neutrino Model

We examine constraints on a simple neutrino model in which there are three massless and three massive Dirac neutrinos and in which the left handed neutrinos are linear combinations of doublet and singlet neutrinos. We examine constraints from direct decays into heavy neutrinos, indirect effects on electroweak parameters, and flavor changing processes. We combine these constraints to examine the allowed mass range for the heavy neutrinos of each of the three generations.Comment: latex, 29 pages, 7 figures (not included), MIT-CTP-221

Bitter Melon (Momordica charantia) Extract Inhibits Tumorigenicity and Overcomes Cisplatin-Resistance in Ovarian Cancer Cells Through Targeting AMPK Signaling Cascade

OBJECTIVE: Acquired chemoresistance is a major obstacle in the clinical management of ovarian cancer. Therefore, searching for alternative therapeutic modalities is urgently needed. Bitter melon (Momordica charantia) is a traditional dietary fruit, but its extract also shows potential medicinal values in human diabetes and cancers. Here, we sought to investigate the extract of bitter melon (BME) in antitumorigenic and cisplatin-induced cytotoxicity in ovarian cancer cells. METHODS: Three varieties of bitter melon were used to prepare the BME. Ovarian cancer cell lines, human immortalized epithelial ovarian cells (HOSEs), and nude mice were used to evaluate the cell cytotoxicity, cisplatin resistance, and tumor inhibitory effect of BME. The molecular mechanism of BME was examined by Western blotting. RESULTS: Cotreatment with BME and cisplatin markedly attenuated tumor growth in vitro and in vivo in a mouse xenograft model, whereas there was no observable toxicity in HOSEs or in nude mice in vivo. Interestingly, the antitumorigenic effects of BME varied with different varieties of bitter melon, suggesting that the amount of antitumorigenic substances may vary. Studies of the molecular mechanism demonstrated that BME activates AMP-activated protein kinase (AMPK) in an AMP-independent but CaMKK (Ca2+/calmodulin-dependent protein kinase)-dependent manner, exerting anticancer effects through activation of AMPK and suppression of the mTOR/p70S6K and/or the AKT/ERK/FOXM1 (Forkhead Box M1) signaling cascade. CONCLUSION: BME functions as a natural AMPK activator in the inhibition of ovarian cancer cell growth and might be useful as a supplement to improve the efficacy of cisplatin-based chemotherapy in ovarian cancer.published_or_final_versio

A numerical study of multi-soliton configurations in a doped antiferromagnetic Mott insulator

We evaluate from first principles the self-consistent Hartree-Fock energies for multi-soliton configurations in a doped, spin-1/2, antiferromagnetic Mott insulator on a two-dimensional square lattice. We find that nearest-neighbor Coulomb repulsion stabilizes a regime of charged meron-antimeron vortex soliton pairs over a region of doping from 0.05 to 0.4 holes per site for intermediate coupling 3 < U/t <8. This stabilization is mediated through the generation of ``spin-flux'' in the mean-field antiferromagnetic (AFM) background. Holes cloaked by a meron-vortex in the spin-flux AFM background are charged bosons. Our static Hartree-Fock calculations provide an upper bound on the energy of a finite density of charged vortices. This upper bound is lower than the energy of the corresponding charged stripe configurations. A finite density of charge carrying vortices is shown to produce a large number of unoccupied electronic levels in the Mott-Hubbard charge transfer gap. These levels lead to significant band tailing and a broad mid-infrared band in the optical absorption spectrum as observed experimentally. At very low doping (below 0.05) the doping charges create extremely tightly bound meron-antimeron pairs or even isolated conventional spin-polarons, whereas for very high doping (above 0.4) the spin background itself becomes unstable to formation of a conventional Fermi liquid and the spin-flux mean-field is energetically unfavorable. Our results point to the predominance of a quantum liquid of charged, bosonic, vortex solitons at intermediate coupling and intermediate doping concentrations.Comment: 12 pages, 25 figures; added references, modified/eliminated some figure

Monoubiquitination of syntaxin 3 leads to retrieval from the basolateral plasma membrane and facilitates cargo recruitment to exosomes

Syntaxin 3 (Stx3), a SNARE protein located and functioning at the apical plasma membrane of epithelial cells, is required for epithelial polarity. A fraction of Stx3 is localized to late endosomes/lysosomes, although how it traffics there and its function in these organelles is unknown. Here we report that Stx3 undergoes monoubiquitination in a conserved polybasic domain. Stx3 present at the basolateral—but not the apical—plasma membrane is rapidly endocytosed, targeted to endosomes, internalized into intraluminal vesicles (ILVs), and excreted in exosomes. A nonubiquitinatable mutant of Stx3 (Stx3-5R) fails to enter this pathway and leads to the inability of the apical exosomal cargo protein GPRC5B to enter the ILV/exosomal pathway. This suggests that ubiquitination of Stx3 leads to removal from the basolateral membrane to achieve apical polarity, that Stx3 plays a role in the recruitment of cargo to exosomes, and that the Stx3-5R mutant acts as a dominant-negative inhibitor. Human cytomegalovirus (HCMV) acquires its membrane in an intracellular compartment and we show that Stx3-5R strongly reduces the number of excreted infectious viral particles. Altogether these results suggest that Stx3 functions in the transport of specific proteins to apical exosomes and that HCMV exploits this pathway for virion excretion

The interplay of intrinsic and extrinsic bounded noises in genetic networks

After being considered as a nuisance to be filtered out, it became recently clear that biochemical noise plays a complex role, often fully functional, for a genetic network. The influence of intrinsic and extrinsic noises on genetic networks has intensively been investigated in last ten years, though contributions on the co-presence of both are sparse. Extrinsic noise is usually modeled as an unbounded white or colored gaussian stochastic process, even though realistic stochastic perturbations are clearly bounded. In this paper we consider Gillespie-like stochastic models of nonlinear networks, i.e. the intrinsic noise, where the model jump rates are affected by colored bounded extrinsic noises synthesized by a suitable biochemical state-dependent Langevin system. These systems are described by a master equation, and a simulation algorithm to analyze them is derived. This new modeling paradigm should enlarge the class of systems amenable at modeling. We investigated the influence of both amplitude and autocorrelation time of a extrinsic Sine-Wiener noise on: $(i)$ the Michaelis-Menten approximation of noisy enzymatic reactions, which we show to be applicable also in co-presence of both intrinsic and extrinsic noise, $(ii)$ a model of enzymatic futile cycle and $(iii)$ a genetic toggle switch. In $(ii)$ and $(iii)$ we show that the presence of a bounded extrinsic noise induces qualitative modifications in the probability densities of the involved chemicals, where new modes emerge, thus suggesting the possibile functional role of bounded noises

Electronic Structure Calculation by First Principles for Strongly Correlated Electron Systems

Recent trends of ab initio studies and progress in methodologies for electronic structure calculations of strongly correlated electron systems are discussed. The interest for developing efficient methods is motivated by recent discoveries and characterizations of strongly correlated electron materials and by requirements for understanding mechanisms of intriguing phenomena beyond a single-particle picture. A three-stage scheme is developed as renormalized multi-scale solvers (RMS) utilizing the hierarchical electronic structure in the energy space. It provides us with an ab initio downfolding of the global band structure into low-energy effective models followed by low-energy solvers for the models. The RMS method is illustrated with examples of several materials. In particular, we overview cases such as dynamics of semiconductors, transition metals and its compounds including iron-based superconductors and perovskite oxides, as well as organic conductors of kappa-ET type.Comment: 44 pages including 38 figures, to appear in J. Phys. Soc. Jpn. as an invited review pape

Multiwavelength Constraints on the Origin of a Nearby Repeating Fast Radio Burst Source in a Globular Cluster

Since fast radio bursts (FRBs) were discovered, their precise origins have remained a mystery. Multiwavelength observations of nearby FRB sources provide one of the best ways to make rapid progress in our understanding of the enigmatic FRB phenomenon. We present results from a sensitive, broadband multiwavelength X-ray and radio observational campaign of FRB 20200120E, the closest known extragalactic repeating FRB source. At a distance of 3.63 Mpc, FRB 20200120E resides in an exceptional location, within a ~10 Gyr-old globular cluster in the M81 galactic system. We place deep limits on both the persistent X-ray luminosity and prompt X-ray emission at the time of radio bursts from FRB 20200120E, which we use to constrain possible progenitors for the source. We compare our results to various classes of X-ray sources and transients. In particular, we find that FRB 20200120E is unlikely to be associated with: ultraluminous X-ray bursts (ULXBs), similar to those observed from objects of unknown origin in other extragalactic globular clusters; giant flares, like those observed from Galactic and extragalactic magnetars; or most intermediate flares and very bright short X-ray bursts, similar to those seen from magnetars in the Milky Way. We show that FRB 20200120E is also unlikely to be powered by a persistent or transient ultraluminous X-ray (ULX) source or a young, extragalactic pulsar embedded in a Crab-like nebula. We also provide new constraints on the compatibility of FRB 20200120E with accretion-based FRB models involving X-ray binaries and models that require a synchrotron maser process from relativistic shocks to generate FRB emission. These results highlight the power that multiwavelength observations of nearby FRBs can provide for discriminating between potential FRB progenitor models.Comment: 58 pages, 10 figures, 7 tables, submitte