bluuebunny/crossref_metadata_2025 huggingface dataset:
Sustained hepatitis C virus clearance and increased hepatitis B surface antigen seroclearance in patients with dual chronic hepatitis C and B during posttreatment follow-up
Authors: Yu Ming-Lung , Lee Chuan-Mo , Chen Chi-Ling , Chuang Wan-Long , Lu Sheng-Nan , Liu Chen-Hua , Wu Shun-Sheng , Liao Li-Ying , Kuo Hsing-Tao , Chao You-Chen , Tung Shui-Yi , Yang Sien-Sing , Kao Jia-Horng , Su Wei-Wen , Lin Chih-Lin , Yang Hung-Chih , Chen Pei-Jer , Chen Ding-Shinn , Liu Chun-Jen
Published: January 2013

Patients dually infected with hepatitis C virus (HCV)/hepatitis B virus (HBV) have a higher risk of developing advanced liver disease or hepatocellular carcinoma compared with monoinfected patients. Yet, there is a similar rate of sustained virologic response (SVR) after peginterferon alfa-2a and ribavirin combination therapy in these patients compared with HCV-monoinfected patients and a high hepatitis B surface antigen (HBsAg) seroclearance rate. The durability of hepatitis C and B clearance in coinfected patients was investigated in a 5-year follow-up study. Patients with active HCV genotype 1, both HBV-coinfected (n = 97) and HBV-monoinfected (n = 110), underwent 48-week combination therapy with peginterferon alfa-2a plus ribavirin. In patients with active HCV genotype 2 or 3, both HBV-coinfected (n = 64) and monoinfected (n = 50) patients underwent 24-week combination therapy. A total of 295 (91.9%) patients completed treatment and 24 weeks posttreatment follow-up; 264 (89.5%) patients agreed to receive additional follow-up for up to 5 years after the end of treatment. After a median follow-up of 4.6 ± 1.0 years, six of the 232 patients achieving SVR developed HCV RNA reappearance, including five HCV genotype 1/HBV-coinfected patients and one HCV genotype 2/3-monoinfected patient. Subgenomic analysis of the HCV core gene indicated that five patients developed delayed recurrence of HCV infection. Overall, the cumulative recurrence rate of HCV infection was 2.3% (0.4%/year; 95% confidence interval [CI], 0.9%-5.5%). The cumulative HBsAg seroclearance rate was 30.0% (95% CI, 21.5%-42.0%); with 33.1% (95% CI, 21.8%-50.1%) in the 48-week combination therapy group and 24.3% (95% CI, 13.7%-42.9%) in the 24-week therapy group.

Conclusion

: Peginterferon alfa-2a and ribavirin therapy provides good HCV SVR durability and a high accumulative HBsAg seroclearance rate in patients who are coinfected with HCV and HBV.
Dendritic Cells Limit Fibroinflammatory Injury in Nonalcoholic Steatohepatitis in Mice
Authors: Henning Justin R. , Graffeo Christopher S. , Rehman Adeel , Fallon Nina C. , Zambirinis Constantinos P. , Ochi Atsuo , Barilla Rocky , Jamal Mohsin , Deutsch Michael , Greco Stephanie , Ego-Osuala Melvin , Bin-Saeed Usama , Rao Raghavendra S. , Badar Sana , Quesada Juan P. , Acehan Devrim , Miller George
Published: January 2013

Nonalcoholic steatohepatitis (NASH) is the most common etiology of chronic liver dysfunction in the United States and can progress to cirrhosis and liver failure. Inflammatory insult resulting from fatty infiltration of the liver is central to disease pathogenesis. Dendritic cells (DCs) are antigen-presenting cells with an emerging role in hepatic inflammation. We postulated that DCs are important in the progression of NASH. We found that intrahepatic DCs expand and mature in NASH liver and assume an activated immune phenotype. However, rather than mitigating the severity of NASH, DC depletion markedly exacerbated intrahepatic fibroinflammation. Our mechanistic studies support a regulatory role for DCs in NASH by limiting sterile inflammation through their role in the clearance of apoptotic cells and necrotic debris. We found that DCs limit CD8+ T-cell expansion and restrict Toll-like receptor expression and cytokine production in innate immune effector cells in NASH, including Kupffer cells, neutrophils, and inflammatory monocytes. Consistent with their regulatory role in NASH, during the recovery phase of disease, ablation of DC populations results in delayed resolution of intrahepatic inflammation and fibroplasia.

Conclusion

: Our findings support a role for DCs in modulating NASH. Targeting DC functional properties may hold promise for therapeutic intervention in NASH. (HEPATOLOGY 2013;58:589–602)
Bone marrow monosomy 7: Hematologic and clinical manifestations in childhood and adolescence
Authors: Hutter John J. , Hecht Frederick , Kaiser‐Mccaw Barbara , Hays Taru , Baranko Paul , Cohen Jesse , Durie Brian
Published: January 2013

The hematologic manifestations and clinical course are described for six children and adolescents with bone marrow monosomy 7. One child with secondary acute myelogenous leukemia had monosomy 7 plus a marker chromosome; the remaining patients had marrow monosomy 7 as the only karyotypic abnormality. The hematologic abnormalities were diverse, but the majority of patients had a smoldering preleukemic or myeloproliferative phase. Leukemic blasts were either undifferentiated or demonstrated evidence of myeloid differentiation. All patients responded poorly to antileukemic therapy. Bone marrow monosomy 7 was observed in one patient with severe marrow hypoplasia. Antileukemic therapy in another patient with > 30 per cent marrow blasts was associated with the development of a bone marrow myeloproliferative disorder with persistence of the monosomy 7 karyotype. We speculate that monosomy 7 may be a specific marker for a pluripotent hematopoetic stem cell abnormality that is associated with either blastic leukemia or a myeloproliferative disorder.
Phenotyping of canine lymphoma with monoclonal antibodies directed at cell surface antigens: Classification, morphology, clinical presentation and response to chemotherapy
Authors: Appelbaum Frederick R. , Sale George E. , Storb Rainer , Charrier Keith , Deeg H. Joachim , Graham Ted , Wulff Jan C.
Published: January 2013

Forty cases of naturally occurring canine lymphoma were studied using a panel of murine monoclonal antibodies which identify defined subsets of normal canine lymphocytes. The distribution of phenotypes was similar to that which is seen in man in that the majority (78 per cent) of canine lymphomas were of B‐cell origin but a definite minority were phenotypically of T‐cell (10 per cent) or non‐B, non‐T‐cell (12 per cent) origin. The expression of Ia‐like antigens was restricted to B‐cell neoplasms. Within each histologic subgroup of canine lymphomas there was considerable heterogeneity of cell surface marker expression. Immunophenotype appeared to correlate with clinical presentation. Finally, the reactivity of lymphoma cells with murine monoclonal antibody DLy‐6, an antibody which appears to react with a differentiation antigen on canine B and T cells, strongly predicted the outcome of initial induction chemotherapy in that all ten evaluable dogs with DLy‐6− tumors achieved complete responses to initial chemotherapy while only four of 11 dogs with DLy‐6+ tumors responded completely.
A report on a prospective trial of no initial therapy in patients with asymptomatic favourable prognosis non‐Hodgkin's lymphoma
Authors: Mead G. M. , Macbeth F. R. , Ryall R. D. H. , Williams C. J. , Whitehouse J. M. A.
Published: January 2013

Thirty‐one (58 per cent) of a group of fifty‐three unselected patients with stage II–IV favourable prognosis non‐Hodgkin's lymphoma were regarded as being eligible for a prospective study of no initial therapy. Seventeen of these patients (55 per cent) have required no treatment for periods from 6 + −47 + months, (median 18 months) and fourteen patients have been treated with chemotherapy for progressive disease after a period varying from 3–40 months (median 9·5 months). Selected asymptomatic patients with non‐bulky disease may be suitable for no initial therapy. Randomized prospective trials will be needed to test whether survival is affected by delaying therapy.
In situ immunologic characterization of follicular lymphomas
Authors: Ancelin E. , Delsol G. , Familiades J. , Mason D. Y. , Kuhlein E. , Al Saati T. , Laurent G. , Huguet‐Rigal F.
Published: January 2013

Surface markers were studied in a series of follicular lymphomas with immunofluorescence on frozen sections (39 cases) and on cell suspensions (21 cases), and with immunoperoxidase on frozen sections using a panel of 15 monoclonal antibodies (17 cases).

With immunofluorescence on frozen sections, 22/39 cases showed monotypic sIg (IgMK: 14 cases, IgML: 7 cases, M: 1 case). In the remaining 17 cases the neoplastic follicles were negative. Nevertheless, even if sIg is not detected, the absence of an extracellular immunoglobulin network is indicative of the neoplastic, and not of the reactive nature of lymphoid follicles.

The results obtained with immunofluorescence on frozen sections and on cell suspensions were identical in about half of the cases. In 9/21 cases monotypic sIg were detected by only one of these two methods.

All the 17 cases studied with immunoperoxidase on frozen sections using monoclonal antibodies demonstrated monotypic sIg. On low magnification 6/17 sIg+ exhibited a nodular staining pattern while 7/17 cases this staining was diffuse. In 4/17 cases the staining pattern for heavy and light chains was different. A thin mantle zone, with sIgM plus sIgD cells, was observed in only 4 cases. Anti‐HLA‐DR and Leu‐10 were positive in all cases. T cells positive for OKT3 were mainly distributed in the interfollicular areas; OKT4 + cells outnumbered OKT8 + cells. Within the neoplastic follicles, T cells stained mainly for OKT4 and OKT8 + cells were scarce. Leu‐7 + cells predominated within the neoplastic nodules in 5 cases. With the anti‐dendritic reticulum cell monoclonal antibody, all 17 cases showed a network, usually more loosely arranged than in reactive follicles. In 4 cases, of follicular and diffuse lymphoma, this network was extremely dissociated and in some areas these cells were scanty or lacking.

We concluded that immunoperoxidase on frozen sections, using monoclonal antibodies, appears to be the most reliable method for the immunological phenotyping of follicular lymphomas.
Growth fractions in malignant non‐Hodgkin's lymphomas (NHL) as determinedin situwith the monoclonal antibody Ki‐67
Authors: Gerdes Johannes , Dallenbach Frederike , Lennert Karl , Lemke Hilmar , Stein Harald
Published: January 2013

The proportion of proliferating cells in malignant non‐Hodgkin's lymphomas (NHL) was determinedin situby immunostaining with the monoclonal antibody Ki‐67, which reacts with a nuclear antigen that is present only in proliferating cells. A highly significant correlation could be demonstrated between the proportion of Ki‐67 positive cells and the classification into high and low‐grade NHL according to the Kiel classification. 93·8 per cent of high‐grade and 88·5 per cent of low‐grade malignancies were correctly allocated to these groups using the percentage of Ki‐67 positive cells as discriminant parameter. On the basis of the medians, the degree of proliferation also paralleled the succession of entities within the Kiel classification. Within most of these different entities, however, the ranges of Ki‐67 positive cells varied considerably, indicating that the growth fractions within these groups are rather heterogeneous. Thus it might be useful to determine the growth fraction of each individual case of NHL, because this might be of prognostic value.
Risk of advanced gastric precancerous lesions in Helicobacter pylori infected subjects is influenced by ABO blood group and cagA status
Authors: Rizzato Cosmeri , Kato Ikuko , Plummer Martyn , Muñoz Nubia , Stein Angelika , Jan van Doorn Leen , Franceschi Silvia , Canzian Federico
Published: January 2013

A higher incidence of stomach cancer in ABO blood type A individuals than in those with blood type O has been known for a long time. We studied this association in relation to Helicobacter pylori (Hp) of different cagA status. For our study, we used baseline gastric histopathology data and DNAs from frozen gastric biopsies of 2,077 subjects enrolled in a chemoprevention trial for gastric precancerous lesions in Venezuela. We analyzed six single nucleotide polymorphisms in the ABO gene, and we assessed the presence of the Hp cagA gene. Odds ratios (ORs) for risk of advanced precancerous gastric lesions were calculated using individuals with normal gastric epithelium or non‐atrophic gastritis as a reference. Among individuals carrying a cagA negative Hp infection or no Hp infection, those with blood type A had a lower risk of intestinal metaplasia (IM) and dysplasia than those with blood type O (OR=0.60; 95% CI 0.38–0.94). In carriers of cagA positive Hp strains, individuals with blood type A had a higher risk of IM or dysplasia than those with blood type O (OR=1.42, 95% CI 1.09–1.86) and a higher risk if compared to subjects carrying cagA negative strain and non‐A blood group (OR=3.82, 95% CI=2.80–5.20). The interaction between Hp cagA status and blood type was statistically significant (p=0.0006). We showed that SNPs in the ABO gene, predictive of ABO blood groups, are associated with risk of advanced precancerous gastric lesions in individuals infected with Hp, but the assessment of the risk is strictly dependent on cagA status.
Human liver carboxylesterase 1 outperforms alpha‐fetoprotein as biomarker to discriminate hepatocellular carcinoma from other liver diseases in Korean patients
Authors: Na Keun , Jeong Seul‐Ki , Lee Min Jung , Cho Sang Yun , Kim Sun A , Lee Min‐Ji , Song Si Young , Kim Hoguen , Kim Kyung Sik , Lee Hyun Woong , Paik Young‐Ki
Published: January 2013

Although alpha‐fetoprotein (AFP) is currently the major serologic biomarker for hepatocellular carcinoma (HCC), it cannot efficiently distinguish this cancer from other forms of liver disease in early diagnosis due to its low sensitivity. The aim of this study is to compare sensitivity and specificity of human carboxylesterase 1 (hCE1) and AFP biomarker. Antibody‐based assays for hCE1 and AFP were used to test both biomarkers with respect to diagnostic efficiency, Youden's index and the area under the curve (AUC) through receiver operating characteristic (ROC) analysis in plasma from 208 patients with HCC (n=57), liver cirrhosis (n=27), chronic hepatitis (n=37), cholangiocarcinoma (n=22), gastric cancer (n=31) and pancreatic cancer (n=34), along with 52 healthy donors (HDs). The levels of hCE1 were significantly higher in patients with HCC than HDs and the other diseases (p<0.005), further verified by AUC values and Youden's index. In the set of HCC versus liver cirrhosis the AUC values were 0.744 (AFP), 0.918 (hCE1) and 0.938 (combination of AFP and hCE1), respectively. These results indicate that hCE1 is not only a more potent and specific marker in distinguishing cancer from liver diseases, in particular cirrhosis, but the combination of hCE1 and AFP shows also synergistic potential for greater sensitivity and specificity in early diagnosis. Therefore the antibody‐based hCE1 assay appears to have high diagnostic efficiency for discriminating HCC from other forms of liver disease. It is now feasible to further validate this novel plasma‐based biomarker in the large cohort we assembled.
Up‐regulation of proliferative and migratory genes in regulatory T cells from patients with metastatic castration‐resistant prostate cancer
Authors: Huen Ngar‐Yee , Pang Alan Lap‐Yin , Tucker Jo A. , Lee Tin‐Lap , Vergati Matteo , Jochems Caroline , Intrivici Chiara , Cereda Vittore , Chan Wai‐Yee , Rennert Owen M. , Madan Ravi A. , Gulley James L. , Schlom Jeffrey , Tsang Kwong Y.
Published: January 2013

A higher frequency of regulatory T cells (Tregs) has been observed in peripheral blood mononuclear cells (PBMC) of patients with different types of solid tumors and hematological malignancies as compared to healthy donors. In prostate cancer patients, Tregs in PBMC have been shown to have increased suppressive function. Tumor‐induced biological changes in Tregs may enable tumor cells to escape immunosurveillance. We performed genome‐wide expression analyses comparing the expression levels of more than 38,500 genes in Tregs with similar suppressive activity, isolated from the peripheral blood of healthy donors and patients with metastatic castration‐resistant prostate cancer (mCRPC). The differentially expressed genes in mCRPC Tregs are involved in cell cycle processes, cellular growth and proliferation, immune responses, hematological system development and function and the interleukin‐2 (IL‐2) and transforming growth factor‐β (TGF‐β) pathways. Studies revealed that the levels of expression of genes responsible for T‐cell proliferation (C‐FOS, C‐JUN and DUSP1) and cellular migration (RGS1) were greater in Tregs from mCRPC patients as compared to values observed in healthy donors. Increased RGS1 expression in Tregs from mCRPC patients suggests a decrease in these Tregs' migratory ability. In addition, the higher frequency of CD4+CD25highCD127– Tregs in the peripheral blood of mCRPC patients may be the result of an increase in Treg proliferation capacity. Results also suggest that the alterations observed in gene expression profiles of Tregs in mCRPC patients may be part of the mechanism of tumor escape from host immune surveillance.
Calcium intake is not related to breast cancer risk among Singapore Chinese women
Authors: Li Jingmei , Koh Woon‐Puay , Jin Ai‐Zhen , Yuan Jian‐Min , Yu Mimi C. , Butler Lesley M.
Published: January 2013

There is experimental evidence that calcium protects against breast cancer development. Prospective epidemiologic studies supporting a protective effect of calcium on breast cancer risk have mainly been limited to Western populations. We examined the association between calcium intake and breast cancer risk in the Singapore Chinese Health Study, a large population‐based prospective cohort. Calcium intake and supplement use was assessed by in‐person interviewer using a validated food frequency questionnaire. After a mean follow‐up of 14.2±3.5 years, 823 cohort participants developed invasive breast cancer. Multivariate proportional hazards regression models were fitted to examine the associations between calcium intake and breast cancer risk. Vegetables were the primary food source of calcium in this study population, followed by dairy products, grains and soy foods. Calcium intake was not associated with breast cancer risk, comparing highest quartile (>345.6 mg/1,000 kcal/day) to lowest quartile (<204.5 mg/1,000 kcal/day) of intake. There was no evidence of effect modification by menopausal status, body mass index, dietary vitamin D or stage of disease at diagnosis. Our findings do not support a hypothesis for calcium in breast cancer chemoprevention, contrary to findings from previous studies among Western populations with higher calcium intake primarily from dairy products and supplements.
Elevated levels of mitochondrial mortalin and cytosolic HSP70 in blood as risk factors in patients with colorectal cancer
Authors: Rozenberg Perri , Kocsis Judit , Saar Moran , Prohászka Zoltán , Füst George , Fishelson Zvi
Published: January 2013

Mortalin/GRP75 is a ubiquitous mitochondrial chaperone related to the cytosolic heat shock protein 70 (HSP70). It protects cells from senescence and apoptosis and is overexpressed in cancer cells. Cell resistance to complement‐dependent cytotoxicity depends on mortalin and during complement attack mortalin is released from cells. Our goal was to determine whether cancer patients have circulating mortalin in blood. The significance of mortalin in blood to survival prospects of colorectal cancer patients was evaluated. Occurrence of extracellular soluble HSP70 (sHSP70) is documented. We developed a sensitive ELISA for mortalin. The association between mortalin level and survival was subjected to the Cox proportional hazards analysis (univariate and multivariate analyses). Mortalin concentration in serum of colorectal cancer patients was 10–214 ng/ml. Survival data of the patients were known from an earlier study of sHSP70 in these samples. Cox regression analysis indicated that high mortalin (>60 ng/ml) is a risk factor for shorter survival. Serum levels of sHSP70 and mortalin in patients were independent variables. Concurrence of high sHSP70 and mortalin was associated with rapid disease progression (HR = 4, 2.04–8.45, p < 0.001). Addition of high sHSP70 and mortalin to a baseline model of age, sex and TNM stage, significantly (p < 0.001) enhanced the risk score to 8 (3.26–20.46). This is the first demonstration of circulating mortalin in cancer patients. Analysis of mortalin in blood, and even more so of mortalin and sHSP70, adds a high prognostic value to the TNM stage and will identify colorectal cancer patients at high risk of poor survival.
Establishment of tumor‐specific copy number alterations from plasma DNA of patients with cancer
Authors: Heitzer Ellen , Auer Martina , Hoffmann Eva Maria , Pichler Martin , Gasch Christin , Ulz Peter , Lax Sigurd , Waldispuehl‐Geigl Julie , Mauermann Oliver , Mohan Sumitra , Pristauz Gunda , Lackner Carolin , Höfler Gerald , Eisner Florian , Petru Edgar , Sill Heinz , Samonigg Hellmut , Pantel Klaus , Riethdorf Sabine , Bauernhofer Thomas , Geigl Jochen B. , Speicher Michael R.
Published: January 2013

With the increasing number of available predictive biomarkers, clinical management of cancer is becoming increasingly reliant on the accurate serial monitoring of tumor genotypes. We tested whether tumor‐specific copy number changes can be inferred from the peripheral blood of patients with cancer. To this end, we determined the plasma DNA size distribution and the fraction of mutated plasma DNA fragments with deep sequencing and an ultrasensitive mutation‐detection method, i.e., the Beads, Emulsion, Amplification, and Magnetics (BEAMing) assay. When analyzing the plasma DNA of 32 patients with Stage IV colorectal carcinoma, we found that a subset of the patients (34.4%) had a biphasic size distribution of plasma DNA fragments that was associated with increased circulating tumor cell numbers and elevated concentration of mutated plasma DNA fragments. In these cases, we were able to establish genome‐wide tumor‐specific copy number alterations directly from plasma DNA. Thus, we could analyze the current copy number status of the tumor genome, which was in some cases many years after diagnosis of the primary tumor. An unexpected finding was that not all patients with progressive metastatic disease appear to release tumor DNA into the circulation in measurable quantities. When we analyzed plasma DNA from 35 patients with metastatic breast cancer, we made similar observations suggesting that our approach may be applicable to a variety of tumor entities. This is the first description of such a biphasic distribution in a surprisingly high proportion of cancer patients which may have important implications for tumor diagnosis and monitoring.
RAS promotes tumorigenesis through genomic instability induced by imbalanced expression of Aurora‐A and BRCA2 in midbody during cytokinesis
Authors: Yang Gong , Mercado‐Uribe Imelda , Multani Asha S. , Sen Subrata , Shih Ie‐Ming , Wong Kwong‐Kwok , Gershenson David M. , Liu Jinsong
Published: January 2013

The oncogene RAS is known to induce genomic instability, leading to cancer development; the underlying mechanism, however, remains poorly understood. To better understand how RAS functions, we measured the activity of the functionally related genes Aurora‐A and BRCA2 in ovarian cancer cell lines and tumor samples containing RAS mutations. We found that Aurora‐A and BRCA2 inversely controlled RAS‐associated genomic instability and ovarian tumorigenesis through regulation of cytokinesis and polyploidization. Overexpression of mutated RAS ablated BRCA2 expression but induced Aurora‐A accumulation at the midbody, leading to abnormal cytokinesis and ultimately chromosomal instability via polyploidy in cancer cells. RAS regulates the expression of Aurora‐A and BRCA2 through dysregulated protein expression of farnesyl protein transferase β and insulin‐like growth factor binding protein 3. Our results suggest that the imbalance in expression of Aurora‐A and BRCA2 regulates RAS‐induced genomic instability and tumorigenesis.
Nonsynonymous polymorphisms in FAT4 gene are associated with the risk of esophageal cancer in an Eastern Chinese population
Authors: Du Jiangbo , Ji Jian , Gao Yong , Xu Lin , Xu Jing , Zhu Chen , Gu Haiyong , Jiang Jie , Li Huizhang , Ma Hongxia , Hu Zhibin , Jin Guangfu , Guo Wei , Chen Xiaofei , Shen Hongbing
Published: January 2013

FAT4 plays a crucial role in carcinogenesis as a key component of the Hippo signaling pathway. We hypothesized that potential functional polymorphisms in the FAT4 gene may modify the risk of esophageal cancer. To test this hypothesis, we evaluated the association between four nonsynonymous polymorphisms (rs1039808, rs12508222, rs1567047 and rs1014867) in FAT4 and esophageal cancer risk in a case–control study of 2,139 esophageal cancer cases and 2,273 controls in a Chinese population. We found that the T allele of rs1014867 (Pro4972Ser) was significantly associated with a decreased risk of esophageal cancer (odds ratio [OR]=0.77, 95% confidence interval [95% CI]=0.66–0.90; p=1.42 × 10−3). We also observed a borderline significant association between rs1039808 (Ala807Val) and esophageal cancer risk (OR=0.90, 95% CI=0.82–1.00; p=0.050), which was more prominent in non‐drinkers (OR=0.82, 95% CI=0.71–0.94; p=6.53 × 10−3). Furthermore, we detected a significant interaction between rs1039808 genotypes and alcohol drinking on esophageal cancer risk (p=0.013). These findings indicate that the nonsynonymous variants rs1014867 (Pro4972Ser) and rs1039808 (Ala807Val) of FAT4 may contribute to esophageal cancer susceptibility.
The novel phosphoinositide 3‐kinase–mammalian target of rapamycin inhibitor, BEZ235, circumvents erlotinib resistance of epidermal growth factor receptor mutant lung cancer cells triggered by hepatocyte growth factor
Authors: Sano Takako , Takeuchi Shinji , Nakagawa Takayuki , Ishikawa Daisuke , Nanjo Shigeki , Yamada Tadaaki , Nakamura Takahiro , Matsumoto Kunio , Yano Seiji
Published: January 2013

Acquired resistance to epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR–TKIs), such as gefitinib and erlotinib, is a critical problem in the management of patients with EGFR mutant lung cancer. Several mechanisms have been reported involved in this acquired resistance, including hepatocyte growth factor (HGF) activation of an alternative pathway. PI3K and mTOR are downstream molecules of receptor tyrosine kinases, such as EGFR and Met, and are thought to be ideal targets for controlling various tumor types. We assessed whether BEZ235, a dual inhibitor of PI3K and mTOR, could overcome the EGFR–TKI resistance induced by HGF in an EGFR mutant lung cancer model. Exogenous and endogenous HGF triggered resistance to erlotinib in the PC‐9 and HCC827, EGFR mutant lung cancer cell lines. BEZ235 alone inhibited the viability of PC‐9 and HCC827 cells in vitro, irrespective of the presence or the absence of HGF. Using a xenograft model of severe combined immunodeficient mice with HGF‐gene‐transfected PC‐9 cells (PC‐9/HGF), we found that BEZ235 inhibited tumor growth, whereas erlotinib did not. BEZ235 monotherapy also inhibited the phosphorylation of Akt and p70S6K/S6RP, downstream molecules of PI3K and mTOR, respectively, as well as suppressing tumor‐cell proliferation and angiogenesis of PC‐9/HGF tumors. These results suggest that BEZ235, even as monotherapy, may be useful in managing HGF‐induced EGFR–TKI resistance in EGFR mutant lung cancer.
Novel signatures of cancer‐associated fibroblasts
Authors: Bozóky Benedek , Savchenko Andrii , Csermely Péter , Korcsmáros Tamás , Dúl Zoltán , Pontén Fredrik , Székely László , Klein George
Published: January 2013

Increasing evidence indicates the importance of the tumor microenvironment, in particular cancer‐associated fibroblasts, in cancer development and progression. In our study, we developed a novel, visually based method to identify new immunohistochemical signatures of these fibroblasts. The method employed a protein list based on 759 protein products of genes identified by RNA profiling from our previous study, comparing fibroblasts with differential growth‐modulating effect on human cancers cells, and their first neighbors in the human protein interactome. These 2,654 proteins were analyzed in the Human Protein Atlas online database by comparing their immunohistochemical expression patterns in normal versus tumor‐associated fibroblasts. Twelve new proteins differentially expressed in cancer‐associated fibroblasts were identified (DLG1, BHLHE40, ROCK2, RAB31, AZI2, PKM2, ARHGAP31, ARHGAP26, ITCH, EGLN1, RNF19A and PLOD2), four of them can be connected to the Rho kinase signaling pathway. They were further analyzed in several additional tumor stromata and revealed that the majority showed congruence among the different tumors. Many of them were also positive in normal myofibroblast‐like cells. The new signatures can be useful in immunohistochemical analysis of different tumor stromata and may also give us an insight into the pathways activated in them in their true in vivo context. The method itself could be used for other similar analysis to identify proteins expressed in other cell types in tumors and their surrounding microenvironment.
ADAMTS4 and its proteolytic fragments differentially affect melanoma growth and angiogenesis in mice
Authors: Rao Nithya , Ke Zhiyuan , Liu Hongrui , Ho Chao‐Jin , Kumar Saran , Xiang Wei , Zhu Yizhun , Ge Ruowen
Published: January 2013

The metalloproteinase ADAMTS4 (ADAMTS, a disintegrin‐like and metalloproteinase with thrombospondin motif)/aggrecanase‐1 is highly expressed in cartilage and has been implicated in human arthritis. Although abundantly expressed in many types of cancer, its role in cancer remains unknown. In this work, we demonstrate for the first time that full‐length ADAMTS4 and its catalytically more active N‐terminal 53 kDa autocatalytic fragment both promote B16 melanoma growth and angiogenesis in mice. In contrast, overexpression of its catalytically inactive E362A mutant or truncated fragments containing only the C‐terminal ancillary domains suppresses melanoma growth and angiogenesis under similar conditions. Structure–function mapping revealed that the single thrombospondin‐type 1 repeat domain is essential and sufficient for the antitumorigenic activity displayed by the catalytically inactive ADAMTS4 isoforms. Suppression of tumor growth and angiogenesis in mice is accompanied by a significant increase in tumor cell apoptosis, whereas tumor cell proliferation is not affected. Importantly, we identified and demonstrated the presence of novel proteolytic fragments of ADAMTS4 containing essentially only the C‐terminal ancillary domains in cultured cells, and also in human cancer tissues, coexisting with full‐length and catalytically active N‐terminal fragments. The contrasting functions toward tumor growth in mice by the wild‐type proteinase and its catalytically inactive mutant correlate with their contrasting influences on angiogenesis signaling pathway molecules in B16 melanoma in mice. Our results suggest a complex role for ADAMTS4 in cancer with the functional balance of protumorigenic and antitumorigenic isoforms likely to act as an important parameter in determining the net influence of this metalloproteinase on tumor growth in vivo.
Comparative effects of teriparatide and risedronate in glucocorticoid-induced osteoporosis in men: 18-month results of the EuroGIOPs trial
Authors: Glüer Claus-C , Marin Fernando , Ringe Johann D , Hawkins Federico , Möricke Rüdiger , Papaioannu Nikolaos , Farahmand Parvis , Minisola Salvatore , Martínez Guillermo , Nolla Joan M , Niedhart Christopher , Guañabens Nuria , Nuti Ranuccio , Martín-Mola Emilio , Thomasius Friederike , Kapetanos Georgios , Peña Jaime , Graeff Christian , Petto Helmut , Sanz Beatriz , Reisinger Andreas , Zysset Philippe K
Published: January 2013

Data on treatment of glucocorticoid-induced osteoporosis (GIO) in men are scarce. We performed a randomized, open-label trial in men who have taken glucocorticoids (GC) for ≥3 months, and had an areal bone mineral density (aBMD) T-score ≤ –1.5 standard deviations. Subjects received 20 μg/d teriparatide (n = 45) or 35 mg/week risedronate (n = 47) for 18 months. Primary objective was to compare lumbar spine (L1–L3) BMD measured by quantitative computed tomography (QCT). Secondary outcomes included BMD and microstructure measured by high-resolution QCT (HRQCT) at the 12th thoracic vertebra, biomechanical effects for axial compression, anterior bending, and axial torsion evaluated by finite element (FE) analysis from HRQCT data, aBMD by dual X-ray absorptiometry, biochemical markers, and safety. Computed tomography scans were performed at 0, 6, and 18 months. A mixed model repeated measures analysis was performed to compare changes from baseline between groups. Mean age was 56.3 years. Median GC dose and duration were 8.8 mg/d and 6.4 years, respectively; 39.1% of subjects had a prevalent fracture, and 32.6% received prior bisphosphonate treatment. At 18 months, trabecular BMD had significantly increased for both treatments, with significantly greater increases with teriparatide (16.3% versus 3.8%; p = 0.004). HRQCT trabecular and cortical variables significantly increased for both treatments with significantly larger improvements for teriparatide for integral and trabecular BMD and bone surface to volume ratio (BS/BV) as a microstructural measure. Vertebral strength increases at 18 months were significant in both groups (teriparatide: 26.0% to 34.0%; risedronate: 4.2% to 6.7%), with significantly higher increases in the teriparatide group for all loading modes (0.005 < p < 0.015). Adverse events were similar between groups. None of the patients on teriparatide but five (10.6%) on risedronate developed new clinical fractures (p = 0.056). In conclusion, in this 18-month trial in men with GIO, teriparatide showed larger improvements in spinal BMD, microstructure, and FE-derived strength than risedronate.
Compensatory regulation of the Snai1 and Snai2 genes during chondrogenesis
Authors: Chen Ying , Gridley Thomas
Published: January 2013

Endochondral bone formation is a multistep process during which a cartilage primordium is replaced by mineralized bone. Several genes involved in cartilage and bone development have been identified as target genes for the Snail family of zinc finger transcriptional repressors, and a gain-of-function study has demonstrated that upregulation of Snai1 activity in mouse long bones caused a reduction in bone length. However, no in vivo loss-of-function studies have been performed to establish whether Snail family genes have an essential, physiological role during normal bone development. We demonstrate here that the Snai1 and Snai2 genes function redundantly during embryonic long bone development in mice. Deletion of the Snai2 gene, or limb bud–specific conditional deletion of the Snai1 gene, did not result in obvious defects in the skeleton. However, limb bud–specific Snai1 deletion on a Snai2 null genetic background resulted in substantial defects in the long bones of the limbs. Long bones of the Snai1/Snai2 double mutants exhibited defects in chondrocyte morphology and organization, inhibited trabecular bone formation, and delayed ossification. Chondrocyte proliferation was markedly reduced, and transcript levels of genes encoding cell cycle regulators, such as p21Waf1/Cip1, were strikingly upregulated in the Snai1/Snai2 double mutants, suggesting that during chondrogenesis Snail family proteins act to control cell proliferation by mediating expression of cell-cycle regulators. Snai2 transcript levels were increased in Snai1 mutant femurs, whereas Snai1 transcript levels were increased in Snai2 mutant femurs. In addition, in the mutant femurs the Snai1 and Snai2 genes compensated for each other's loss not only quantitatively, but also by expanding their expression into the other genes' normal expression domains. These results demonstrate that the Snai1 and Snai2 genes transcriptionally compensate temporally, spatially, and quantitatively for each other's loss, and demonstrate an essential role for Snail family genes during chondrogenesis in mice.
Isolation of a novel strain of Planomicrobium chinense from diesel contaminated soil of tropical environment
Authors: Das Reena , Tiwary Bhupendra N.
Published: January 2013

A novel bacterial strain (B6) degrading high concentration of diesel oil [up to 2.5% (v/v)] was isolated from a site contaminated with petroleum hydrocarbons in the state of Chhattisgarh, India. The strain demonstrated efficient degradation for diesel oil range alkanes (C14 to C36 i.e., mostly linear chain alkanes). It was identified to be 99% similar to Planomicrobium chinense on the basis of partial 16S rRNA gene sequencing and biochemical characteristics. The efficiency of degradation was optimized at pH 7.2 and temperature at 32 °C. GC analysis demonstrated complete mineralization of higher chain alkanes into lower chain alkanes within 96 h. The organism also displayed surface tension reduction by producing stable emulsification on the onset of stationary phase. A multidimensional characteristics of the strain to grow at a high temperature range, resistance to various heavy metals as well as tolerance to moderate concentration of NaCl makes it suitable for bioremediation of soil contaminated with diesel oil in tropical environment.
Edaphobacillus lindanitolerans gen. nov., sp. nov., isolated from hexachlorocyclohexane (HCH) contaminated soil
Authors: Lal Devi , Khan Fazlurrahman , Gupta Sanjay Kumar , Schumann Peter , Lal Rup
Published: January 2013

A Gram‐staining‐positive, aerobic, cocco‐bacilli‐shaped, non‐motile, non‐spore forming, cream colored strain bacterium (strain MNA4T) was isolated from hexachlorocyclohexane (HCH) contaminated soil. Strain MNA4T showed the highest 16S rRNA gene sequence similarity of 97.47% with type species of the newly defined genus Bhargavaea cecembensis. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain MNA4T belonged to a clade represented by Bhargavaea cecembensis, Bacillus beijingensis and Bacillus ginsengi. DNA‐DNA hybridization values of the strain MNA4T with close relatives were well below the 70% threshold value recommended for delineation of species. The major fatty acids were anteiso C15:0, anteiso C17:0, iso C16:0 and iso C15:0. The strain was found to contain respiratory quinones MK‐8, MK‐9 and MK‐7 in an approximate molar ratio of 85:7:5. Polar lipid profile consisted of diphosphatidylglycerol, phosphatidylglycerol and two unknown phospholipids. The DNA G + C content was 55.6 mol%. Peptidoglycan type was A4α (L‐Lys – L‐Ala – D‐Asp). Phylogenetic analysis, fatty acids profile, phenotypic properties and chemotaxonomic data of strain MNA4T indicated that it represents a novel species of a novel genus for which the name Edaphobacillus lindanitolerans gen. nov., sp. nov., is proposed. The type strain is MNA4T (=CCM 7584T = DSM 22424T).
Purification and characterization of a novel acid phosphatase from the split gill mushroom Schizophyllum commune
Authors: Zhang Guo‐Qing , Chen Qing‐Jun , Sun Jian , Wang He‐Xiang , Han Chun‐Hua
Published: January 2013

A monomeric acid phosphatase (ACP) with a molecular mass of 72.5 kDa was purified from fresh fruiting bodies of cultured Schizophyllum commune mushroom. The isolation procedure entailed ion exchange chromatography on DEAE‐cellulose, CM‐cellulose, and Q‐sepharose, and gel filtration by fast protein liquid chromatography on Superdex 75. It demonstrated a unique N‐terminal amino acid sequence of NAPWAQIDEV, which exhibited 60% amino acid identity to that of S. commune hypothetical histidine ACP based on its genome sequence, but less than 30% amino acid identity to that of other fungal ACPs previously reported. The ACP exhibited an optimum temperature at 50 °C, an optimum pH at pH 4.6, and was considerably stable at a pH range of 4.0 to 9.0, and a temperature range of 20–40 °C. The Km of the purified enzyme for ρ‐nitrophenyl phosphate (ρNPP) was 0.248 mM and the Vmax was 9.093 × 10−3 μM/min. ACP activity was strongly inhibited by Al3+ and Fe3+, but enhanced by Co2+, Mg2+, and Ca2+ at a concentration of 0.5 mM.
Physical insight of superconductivity of Nb2AlC: in situ Raman spectrometry investigation
Authors: Xiang Huimin , Wang Xiaohui , Wang Jingyang , Zhou Yanchun
Published: January 2013

Superconductivity of Nb2AlC has been previously reported, but the origin is not clear. In this paper, in situ Raman spectra of Nb2AlC are measured in the temperature range from 80 to 380 K at ambient pressure. The line‐width of E2g (ω1) mode increases with temperature which originates from the anharmonic phonon–phonon scattering. On the contrary the line‐widths of E2g (ω2) and A1g (ω4) modes decrease continuously at elevated temperature. The phenomenon is explained by the electron–phonon coupling. The origin of superconductivity is therefore interpreted by the coupling of Nb 4d electrons with E2g (ω2) and A1g (ω4) phonon modes. Copyright © 2013 John Wiley & Sons, Ltd.
Selectivity tuning via temperature pulsing using low thermal mass liquid chromatography and monolithic columns
Authors: Pursch Matthias , Eckerle Patric , Gu Binghe , Luong Jim , Cortes Hernan J.
Published: January 2013

Low thermal mass LCwas applied to the capillary LC separation of a complex insecticide mixture by increasing temperature and decreasing gradients, as well as fast selected temperature pulses to increase resolution of overlapped components. The technology was applied using a new generation of capillary monolithic stationary phases. Considerable peak shifts and selectivity changes were observed for given temperature conditions. The concept of temperature pulsing during an elution profile shows promise for increasing resolution in difficult separations and can provide a relatively simple means to solve coelution problems.
Lipophilicity of oils and fats estimated by TLC
Authors: Naşcu‐Briciu Rodica D. , Sârbu Costel
Published: January 2013

A representative series of natural toxins belonging to alkaloids and mycotoxins classes was investigated by TLC on classical chemically bonded plates and also on oils‐ and fats‐impregnated plates. Their lipophilicity indices are employed in the characterization and comparison of oils and fats. The retention results allowed an accurate indirect estimation of oils and fats lipophilicity. The investigated fats and oils near classical chemically bonded phases are classified and compared by means of multivariate exploratory techniques, such as cluster analysis, principal component analysis, or fuzzy‐principal component analysis. Additionally, a concrete hierarchy of oils and fats derived from the observed lipophilic character is suggested. Human fat seems to be very similar to animal fats, but also possess RP‐18, RP‐18W, and RP‐8.
Simultaneous separation of hydrophobic and polar bases using a silica hydride stationary phase
Authors: Yang Yuanzhong , Matyska Maria T. , Boysen Reinhard I. , Pesek Joseph J. , Hearn Milton T. W.
Published: January 2013

In this study, the retention behavior of selected hydrophobic and polar bases on a minimally modified silica hydride phase was investigated. From these results and the associated retention plots, significant differences in the chromatographic dependencies of these two classes of basic compounds were evident. The polar bases exhibited strong retention with mobile phases of high organic solvent content, but displayed weak retention with mobile phases of high water content. In contrast, the hydrophobic bases showed “U‐shape” retention dependencies, indicative of the interplay of both RP and normal‐phase retention characteristics. These studies have demonstrated that hydrophobic and polar bases can be simultaneously separated on the same column either under typical RP‐like or aqueous normal‐phase‐like conditions, respectively, with distinctive selectivity. Finally, the effects of temperature on the RP and aqueous normal phase modality of separations with these analytes were investigated, where discrete changes in retention behavior were also observed.
Survival of Barrow's goldeneyes during remigial molt and fall staging
Authors: Hogan Danica , Thompson Jonathan E. , Esler Daniel
Published: January 2013

Postbreeding survival of waterfowl is rarely quantified, despite potential for constraints during this stage of the annual cycle that may subsequently affect population dynamics. We estimated survival of radio‐marked adult male Barrow's goldeneyes (Bucephala islandica) during remigial molt and fall staging at Cardinal and Leddy Lakes in the Boreal Transition Zone of northwestern Alberta, Canada. Daily survival rate (DSR) was high during remigial molt (DSR = 0.9987, 95% CI: 0.9967–1.0000), corresponding to a 39‐day period survival rate (PSR) of 0.95 (95% CI: 0.88–1.00). During fall staging, DSR was markedly lower (DSR = 0.9938, 95% CI: 0.9898–0.9978), corresponding to a PSR of 0.68 (95% CI: 0.53–0.87) over the 62‐day period between the end of remigial molt and fall migration. Half of fall staging mortalities observed on Cardinal Lake were directly attributed to hunting. We conclude that remigial molt is a period with high survival in the annual cycle of Barrow's goldeneyes at our study sites. However, in light of low fall staging survival, Barrow's goldeneye harvest management strategies should be carefully evaluated with intent to reduce risk of localized high mortality at significant staging sites in western Canada. © 2013 The Wildlife Society.
Nonlinear Brønsted and Hammett Correlations Associated with Reactions of 4‐Chloro‐7‐nitrobenzofurazan with Anilines in Dimethyl Sulfoxide Solution
Authors: Jmaoui I. , Boubaker T. , Goumont R.
Published: January 2013

The kinetics and mechanism of nucleophilic aromatic substitution reactions of 4‐chloro‐7‐nitrobenzofurazan 1 with 4‐X‐substituted anilines 2a–g (X = OH, OCH3, CH3, H, I, Cl, and CN) are investigated in a dimethyl sulfoxide (Me2SO) solution at 25°C. The Hammett plot of log k1 versus σ is nonlinear for all the anilines studied due to positive deviations of the electron‐donating substituents. However, the corresponding Yukawa–Tsuno plot resulted in a good linear correlation with σ+r (σ+−σ). The corresponding Brønsted‐type plot is also nonlinear, i.e., the slope (βnuc) changes from 1.60 to 0.56 as the basicity of anilines decreases. These results indicate a change in a mechanism from a polar SNAr process for less basic nucleophiles (X = I, Cl, and CN) to a single electron transfer for more basic nucleophiles (X = OH, OCH3, and CH3). The satisfactory log k1 versus Eo correlation obtained for the reactions of 1 with anilines 2a–d in the present system is consistent with the proposed mechanism. Interestingly, the βnuc = 1.60 value measured for 1 in Me2SO reflects one of the highest coefficients Brønsted ever observed for SNAr reactions. © 2013 Wiley Periodicals, Inc. Int J Chem Kinet 45: 152–160, 2013
Fiber optic probes for linear and nonlinear Raman applications – Current trends and future development
Authors: Latka Ines , Dochow Sebastian , Krafft Christoph , Dietzek Benjamin , Popp Jürgen
Published: January 2013

This review focuses on fiber optic probes for linear and nonlinear Raman spectroscopy, especially for medical applications. It aims at providing an overview over contemporary technology, recent first clinical trials, and helps identifying future developments necessary to bring the emerging technology to clinical end users. After a short introduction to linear and nonlinear Raman spectroscopic modalities, general design considerations will be discussed and compared to common fiber probe setups. Subsequently, examples for medical applications of fiber optic Raman probes will be given concentrating on probes for linear Raman spectroscopy as these devices are technologically more mature compared to their counterparts based on nonlinear Raman spectroscopy. The review also includes a brief summary of first multimodal fiber optic probes and highlights their benefits for clinical applications. Finally, probes are introduced which employ either nonlinear Raman spectroscopy or surface enhanced spectroscopy.