Impact of Metronomic UFT/Cyclophosphamide Chemotherapy and Antiangiogenic Drug Assessed in a New Preclinical Model of Locally Advanced Orthotopic Hepatocellular Carcinoma

AbstractHepatocellular carcinoma (HCC) is an intrinsically chemotherapy refractory malignancy. Development of effective therapeutic regimens would be facilitated by improved preclinical HCC models. Currently, most models consist of subcutaneous human tumor transplants in immunodeficient mice; however, these do not reproduce the extensive liver disease associated with HCC or metastasize. To address this deficiency, we developed an orthotopic model. Human HCC cells were transfected with the gene encoding secretable β-subunit human choriogonadotropin (β-hCG), which was used as a surrogate marker of tumor burden. The HCC cells were implanted into the left liver lobe of severe combined immunodeficient (SCID) mice, after which the efficacy of different therapies was evaluated on established, but liver-confined human Hep3B cell line HCC. Treatments included sorafenib or metronomic chemotherapy using cyclophosphamide (CTX), UFT, an oral 5-fluorouracil prodrug, or doxorubicin either alone or in various combinations, with or without an antiangiogenic agent, DC101, an anti-vascular endothelial growth factor receptor-2 antibody. Sorafenib inhibited tumor growth in a dose-dependent manner but caused severe weight loss in SCID mice, thus necessitating use of DC101 in subsequent experiments. Although less toxicity was observed using either single or doublet metronomic chemotherapy without any added antiangiogenic agent, none, provided survival benefit. In contrast, significantly improved overall survival was observed using various combinations of metronomic chemotherapy regimens such as UFT + CTX with DC101. In conclusion, using this model of liver-confined but advanced HCC suggests that the efficacy of a targeted antiangiogenic drug or metronomic chemotherapy can be mutually enhanced by concurrent combination treatment

Characterization of Rock Mechanical Properties Using Lab Tests and Numerical Interpretation Model of Well Logs

The tight gas reservoir in the fifth member of the Xujiahe formation contains heterogeneous interlayers of sandstone and shale that are low in both porosity and permeability. Elastic characteristics of sandstone and shale are analyzed in this study based on petrophysics tests. The tests indicate that sandstone and mudstone samples have different stress-strain relationships. The rock tends to exhibit elastic-plastic deformation. The compressive strength correlates with confinement pressure and elastic modulus. The results based on thin-bed log interpretation match dynamic Young’s modulus and Poisson’s ratio predicted by theory. The compressive strength is calculated from density, elastic impedance, and clay contents. The tensile strength is calibrated using compressive strength. Shear strength is calculated with an empirical formula. Finally, log interpretation of rock mechanical properties is performed on the fifth member of the Xujiahe formation. Natural fractures in downhole cores and rock microscopic failure in the samples in the cross section demonstrate that tensile fractures were primarily observed in sandstone, and shear fractures can be observed in both mudstone and sandstone. Based on different elasticity and plasticity of different rocks, as well as the characteristics of natural fractures, a fracture propagation model was built

Theoretical study on pp --> p n pi+ reaction at medium energies

The $pp\to p n \pi^+$ reaction is a channel with the largest total cross section for pp collision in COSY/CSR energy region. In this work, we investigate individual contributions from various $N^*$ and $\Delta^{*}$ resonances with mass up to about 2 GeV for the $pp\to p n \pi^+$ reaction. We extend a resonance model, which can reproduce the observed total cross section quite well, to give theoretical predictions of various differential cross sections for the present reaction at $T_p=2.88$ GeV. It could serve as a reference for identifying new physics in the future experiments at HIRFL-CSR.Comment: talk at STORI08, Sept. 2008, Lanzhou, Chin

Contacts between the endoplasmic reticulum and other membranes in neurons

The cytoplasm of eukaryotic cells is compartmentalized by intracellular membranes that define subcellular organelles. One of these organelles, the endoplasmic reticulum, forms a continuous network of tubules and cisternae that extends throughout all cell compartments, including neuronal dendrites and axons. This network communicates with most other organelles by vesicular transport, and also by contacts that do not lead to fusion but allow cross-talk between adjacent bilayers. Though these membrane contacts have previously been observed in neurons, their distribution and abundance has not been systematically analyzed. Here, we have carried out such analysis. Our studies reveal new aspects of the internal structure of neurons and provide a critical complement to information about interorganelle communication emerging from functional and biochemical studies

Pig Liver Xenotransplantation: A Review of Progress Toward the Clinic

Experience with clinical liver xenotransplantation has largely involved the transplantation of livers from nonhuman primates. Experience with pig livers has been scarce. This brief review will be restricted to assessing the potential therapeutic impact of pig liver xenotransplantation in acute liver failure and the remaining barriers that currently do not justify clinical trials. A relatively new surgical technique of heterotopic pig liver xenotransplantation is described that might play a role in bridging a patient with acute liver failure until either the native liver recovers or a suitable liver allograft is obtained. Other topics discussed include the possible mechanisms for the development of the thrombocytopenis that rapidly occurs after pig liver xenotransplantation in a primate, the impact of pig complement on graft injury, the potential infectious risks, and potential physiologic incompatibilities between pig and human. There is cautious optimism that all of these problems can be overcome by judicious genetic manipulation of the pig. If liver graft survival could be achieved in the absence of thrombocytopenia or rejection for a period of even a few days, there may be a role for pig liver transplantation as a bridge to allotransplantation in carefully selected patients

Lymphocyte Homing to Bronchus-associated Lymphoid Tissue (BALT) Is Mediated by L-selectin/PNAd, α4β1 Integrin/VCAM-1, and LFA-1 Adhesion Pathways

Bronchus-associated lymphoid tissue (BALT) participates in airway immune responses. However, little is known about the lymphocyte–endothelial adhesion cascades that recruit lymphocytes from blood into BALT. We show that high endothelial venules (HEVs) in BALT express substantial levels of VCAM-1, in marked contrast to HEVs in other secondary lymphoid tissues. BALT HEVs also express the L-selectin ligand PNAd. Anti–L-selectin, anti-PNAd, and anti–LFA-1 mAbs almost completely block the homing of B and T lymphocytes into BALT, whereas anti–α4 integrin and anti–VCAM-1 mAbs inhibit homing by nearly 40%. α4β7 integrin and MAdCAM-1 are not involved. Importantly, we found that mAbs against α4 integrin and VCAM-1 significantly block the migration of total T cells (80% memory phenotype) but not naive T and B cells to BALT. These results suggest that an adhesion cascade, which includes L-selectin/PNAd, α4β1 integrin/VCAM-1, and LFA-1, targets specific lymphocyte subsets to BALT. This high level of involvement of α4β1 integrin/VCAM-1 is unique among secondary lymphoid tissues, and may help unify lymphocyte migration pathways and immune responses in BALT and other bronchopulmonary tissues

Ozone seasonal evolution and photochemical production regime in the polluted troposphere in eastern China derived from high-resolution Fourier transform spectrometry (FTS) observations

The seasonal evolution of O3 and its photochemical production regime in a polluted region of eastern China between 2014 and 2017 has been investigated using observations. We used tropospheric ozone (O3), carbon monoxide (CO), and formaldehyde (HCHO, a marker of VOCs (volatile organic compounds)) partial columns derived from high-resolution Fourier transform spectrometry (FTS); tropospheric nitrogen dioxide (NO2, a marker of NOx (nitrogen oxides)) partial column deduced from the Ozone Monitoring Instrument (OMI); surface meteorological data; and a back trajectory cluster analysis technique. A broad O3 maximum during both spring and summer (MAM/JJA) is observed; the day-to-day variations in MAM/JJA are generally larger than those in autumn and winter (SON/DJF). Tropospheric O3 columns in June are 1.55x1018moleculescm-2 (56DU (Dobson units)), and in December they are 1.05x1018moleculescm-2 (39 DU). Tropospheric O3 columns in June were ∼ 50% higher than those in December. Compared with the SON/DJF season, the observed tropospheric O3 levels in MAM/JJA are more influenced by the transport of air masses from densely populated and industrialized areas, and the high O3 level and variability in MAM/JJA is determined by the photochemical O3 production. The tropospheric-column HCHO/NO2 ratio is used as a proxy to investigate the photochemical O3 production rate (PO3). The results show that the PO3 is mainly nitrogen oxide (NOx) limited in MAM/JJA, while it is mainly VOC or mixed VOC-NOx limited in SON/DJF. Statistics show that NOx-limited, mixed VOC-NOx-limited, and VOC-limited PO3 accounts for 60.1%, 28.7%, and 11% of days, respectively. Considering most of PO3 is NOx limited or mixed VOC-NOx limited, reductions in NOx would reduce O3 pollution in eastern China