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Background Recurrence of hepatitis B virus (HBV) infection in the liver graft is a grave complication following liver transplantation for HBV cirrhosis. Hepatitis B immunoglobulin (HBIg) seems effective in increasing survival after liver transplantation. HBIg and anti-viral drugs are given alone or in combination for its prevention. Objectives To assess the benefits and harms of different regimens for preventing HBV reactivation following liver transplantation. Search strategy We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until February 2010. We attempted to identify further trials by reviewing the reference lists and contacting the principal authors of identified trials. Selection criteria Randomised clinical trials addressing benefits and harms of lamivudine or adefovir dipivoxil alone or in combination with hepatitis B immunoglobulins (HBIg) for preventing recurrent HBV infection in patients who are liver transplanted due to HBV infection with or without hepatocellular carcinoma. Data collection and analysis Two authors independently assessed the trials for risk of bias and extracted data. We contacted study authors whenever information was lacking. We collected information on adverse events. The primary outcomes were all-cause mortality and reappearance of hepatitis B surface antigen in serum after liver transplantation. Relative risks were calculated from individual trials. Main results Four trials, recruiting 136 participants, were included. Two trials compared lamivudine alone versus HBIg alone. Randomisation was performed one week after transplantation in one of the trials and after six months after transplantation in another; from transplantation until randomisation, HBIg alone was given to all patients in the two trials. A third trial compared combination treatment with lamivudine and HBIg versus lamivudine alone after one month of combination treatment, and a fourth trial compared the combination of lamivudine and HBIg versus a combination of lamivudine and adefovir dipivoxil after at least 12-month of lamivudine and HBIg combination treatment. Statistically significant differences were not detected in any of the comparisons and outcomes. All trials were open-labelled, and none of the trials were adequately powered to show a difference in HBV recurrence. No meta-analyses were performed since the identified trials assessed different comparisons. Authors' conclusions This review could not derive clear evidence from randomised clinical trials for the treatment of patients with chronic HBV following liver transplantation for preventing recurrence of HBV infection. Large randomised clinical trials comparing long-term combination treatment to each of the monotherapy alone, including the newer antiviral drugs, are needed.

To localise the immunogenic part of infliximab and evaluate the clinical usefulness of measuring antibodies against infliximab fragments.Observational study.A specialised inflammatory bowel disease (IBD) centre in a tertiary hospital.Serum was collected from patients with IBD and controls. Antibodies against whole infliximab (ATI) and against the digested Fc, F(ab')(2) and F(ab') fragments were measured by a specifically developed ELISA and by western blotting. A separate ELISA was used to determine infliximab levels in serum.109 serum samples from 62 infliximab-treated patients were tested along with 64 control samples. Anti-F(ab')(2) antibodies were found in 28/42 (67%) samples with positive ATI, all from infliximab-exposed patients. Anti-F(ab')(2) antibodies were also present in 26 of the remaining 67 (39%) samples from exposed patients despite absent ATI. No specific anti-Fc antibodies were detected. Low trough infliximab level and high ATI level was found in 10/12 patients (83%) with complete loss of response to infliximab, but in only 5/14 patients (36%, p=0.02) who regained response to intensified infliximab regimen and in 2/24 patients (8%, p0.001) in maintained remission while on 5 mg/kg/8 week infliximab treatment. Although Anti-F(ab')(2) antibodies showed similar test characteristics to ATI in patients losing response to infliximab, they were also detected in 61% of patients in maintained remission, thereby limiting their clinical usefulness. No cross reactivity to adalimumab was noted.F(ab')(2) is the immunogenic fragment of infliximab. However, ATI level in serum--combined with measurement of trough infliximab level--is better correlated with the clinical response to infliximab or with its loss.

Pericarditis as a presenting sign of infective endocarditis is rare. Here we describe 2 cases and an additional 19 cases of pericarditis as a presenting sign of infective endocarditis reported during the last 40 y. 71% of patients were young males (mean age 43.2 y). The most commonly reported underlying conditions were diabetes mellitus type 2 (5 patients, 24%), and substance or alcohol abuse (4 patients, 19%). The native aortic valve was the most frequently involved valve. The most common symptoms were fever, cough or dyspnoea, and chest pain. Overt tamponade was diagnosed in 47% of the patients. However, pulsus paradoxus and pericardial friction rub were rare. A heart murmur was heard in 12 patients (57%). Staphylococcus aureus was the most commonly isolated pathogen concomitantly from blood and pericardial fluid. 16 patients (76%) were operated. Six underwent a pericardial procedure, 5 underwent valve replacement, 4 both, and 1 patient was operated for pseudoaneurysm. Mortality rates were 60% and 31% of patients treated with antibiotics alone versus antibiotics and surgical intervention, respectively. In patients presenting with pericarditis with or without cardiac tamponade, the possibility of infective endocarditis should be considered. Optimal therapy should consist of antibiotics and surgical intervention.

The occurrence of three cases of meningococcal disease among children in a small community, two of whom attended the same day-care centre, prompted a programme of mass antibiotic prophylaxis. Nasopharyngeal and throat swabs were obtained on three occasions from all children registered at the day-care centre. Serogroup B Neisseria meningitidis was isolated from 13 of 61 children before prophylaxis, from three children after 2 weeks, and from 19 children after 3 months. Repetitive extragenic palindromic PCR analysis identified several meningococcal strains before treatment, one of which became predominant after 3 months. Mass antibiotic prophylaxis initially suppressed meningococcal carriage, but the carriage rate subsequently rebounded.

Hepatocellular carcinoma (HCC) is the fifth most common tumor and the third leading cause of cancer-related deaths. Loss of TGF-β signaling has been associated with development of HCC. Cancer preventive effects of Vitamin D (VD) have been implicated in multiple cancers, however a clear role for Vitamin D in specific high risk populations remains undefined for HCC. Therefore, we examined for a potential chemopreventive role of VD in HCC in the context of TGF-β inactivation. Methods: (1) We screened for somatic mutation of the TGF-β pathway and VD related genes in 202 HCCs from The Cancer Genome Atlas (TCGA). (2) Wild type, Sptbn1+/- and Smad3+/- mice were fed with low VD (200 IU VD/kg) or high VD diet (10,000 IU VD/kg) for 9 weeks. Liver tissues were subjected to microarray analyses and further evaluation by quantitative PCR. (3) Wild type, Sptbn1+/- and Smad3+/- mice were injected Diethylnitrosamine (DEN) and at 8 month, 26 mice receiving low VD (200 IU VD/kg) and 26 mice receiving high VD (10,000 IU VD/kg) chow. HCC development was assessed at 4 months after VD treatment. (4) Reverse Phase Protein Array (RPPA) was performed to analyze expression profiles of 164 proteins of mouse liver tumors. (5) Liver samples from patients with HCV cirrhosis receiving VD supplements were examined to evaluate expression of TGF-β, Wnt and VD pathway molecules by immunohistochemistry. Results: (1) We observed a high rate of somatic mutation in TGF-β and VD pathway related genes in the TCGA genomic analysis. (2) None of the VD treated mice developed HCC but high VD treatment increased TLR7 mRNA expression about 3-fold in liver from Smad3+/- mice compared with livers from WT mice. (3) Smad3+/- mice with low VD showed 3-fold larger HCC formation, compared to the high VD group (Smad3+/-) that did not develop significant tumors. However, correction of VD in the Chow after 10 months did not reverse HCC formation. (4) RPPA data revealed that the tumor suppressor protein PDCD4 was reduced in Smad3+/- mice with low VD treatment. However, oncoproteins such as β-catenin, Stat5A and Bcl2-XL were induced in the same sample. (5) Expression of β2SP and TβRII were higher in HCV cirrhosis patients receiving VD supplementation compared to non-treated group. Conclusions: Loss of TGF-β signaling pathway developed HCC and VD deficiency promotes tumor growth in the context of Smad3 disruption potentially through regulation of TLR7 expression. However, after 10 months restoring VD does not have any significant effect on altering tumors. Therefore VD could be a potential candidate for prevention in early identified HCC high risk individuals who has inactivation of TGF-β/Smad3 signaling. Citation Format: Ji-hyun Shin, Lior H. Katz, Nina M. Munoz, Andrea Cortes, Vivek Shukla, Sang-Bae Kim, Franklin Herlong, Keigo Machida, Hidekazu Tsukamoto, Kirti Shetty, Aiwu R. He, Lynt B. Johnson, Asif Rashid, Jian Chen, Ju-Seog Lee, Lopa Mishra. Vitamin D deficiency regulates TLR7 to promote hepatocellular cancer in TGF-β/Smad3 heterozygous mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 892. doi:10.1158/1538-7445.AM2015-892

Objective: Genome-wide analysis enables predictive modeling of genetic pathways driving many cancers. While somatic mutations and patterns reflecting key pathways have been identified for many cancers, an integrated analysis of driver mutations identified through mouse/human genetics have yet to be comprehensively defined for hepatocellular cancer (HCC). Previously our group and others have identified that loss of TGF-β signaling leads to spontaneous HCC development, through mouse models and human genetics. Patients with hepatocellular cancer have a poor survival of 9-11 months. Recent clinical studies show that targeting TGF-β improves survival up to 21 months, yet prognostic significances are undefined. The relationships between patterns of mutations and transcriptomic phenotypes for the TGF-β pathway are unclear. Methods: (1) We analyzed the transcriptome of 488 hepatocellular cancers and screened for mutations in the TGF-β pathway in 202 HCCs from The Cancer Genome Atlas (TCGA). (2) Increased levels of TGF-β-related genes were designated as an “activated” signature that is associated with hepatic fibrosis. Conversely, decreased levels of TGF-β-related genes were defined as an “inactivated” signature, which was associated with the loss of TGF-β tumor suppressor function. (3) We further performed high-fidelity (80x) whole-genome sequence analysis and transcriptome sequencing analysis of eight additional HCCs to define the role of TGF-β in their development and characterize a potential novel “driver mutations” in HCV- and alcohol-associated hepatocellular cancer. (4) We validated the clinical relevance of β2SP alterations in 22 human liver specimens. Results: (1) Transcriptomic analyses revealed aberrant TGF-β superfamily profiles in 72% of hepatocellular cancers, with mutations in 38% of patients. (2) HCCs characterized by the “inactivated” TGF-β signature were associated with a significantly poorer survival particularly in early stage HCCs, compared to HCCs with the “activated” TGF-β signature (p = 0.0027). (3) We observed the greatest number of functional mutations in the SPTBN1 gene (6%), which encodes a tumor suppressor TGF-β/Smad3 adaptor protein. (4) Furthermore, we found a strong association between DNA damage response genes and the TGF-β pathway at both transcriptomic and genomic levels. Conclusions: The TGF-β pathway plays a pivotal role in liver tumorigenesis and the molecular signatures we characterize here appear to have prognostic significance. The additional association with the DNA repair pathway supports new approaches to developing biomarkers. Targeting of TGF-β, has the potential for improving survival of liver cancer. Citation Format: Jian Chen, Jiun-Sheng Chen, Jianping Zhang, Liem Phan, Nina M. Muñoz, Lior H Katz, YoungJin Gi, Vipin Kumar Menon, Ji-Hyun Shin, Yun Seong Jeong, Wilma Jogunoori, Patrizia Farci, Kirti Shetty, Xiaoping Su, Tej K Pandita, Jon White, Bibhuti Mishra, Fausto Zamboni, Xifeng Wu, Asif Rashid, Shulin Li, Milind Javle, Mien-Chie Hung, Franklin Herlong, Marta Davila, John Stroehlein, Kenna R Shaw, Xuemei Wang, Jeffrey S Morris, Rehan Akbani, Lopa Mishra. Genomic landscape of human cancer reveals dysregulated TGF-β signaling with prognostic significance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3900. doi:10.1158/1538-7445.AM2015-3900

Hepatocellular carcinoma (HCC) is the third most common cause of cancer related death worldwide. Vitamin D (VD) has been implicated in the prevention of multiple cancers- some with inactivation of TGF-β signaling. Recently, inactivation of TGF-β signaling has been associated with HCC. We analyzed whole genome data for TGF-β signaling and examined the role of VD in the context of TGF-β inactivation in HCC. Methods: Databases of HCC Genomics (COSMIC) and transcriptomics (TCGA) were analyzed. The effect of calcitriol on cell proliferation was measured in HCC cell lines; Hep-G2 and MEF cells, with knocked down TGF-β/β2-spectrin (β2SP). Wild-type (WT), Sptbn1+/- and Smad3+/- mice were fed with diets containing 200 IU VD/kg or 10,000 IU VD/kg for 9 weeks. Hepatocyte proliferation was analyzed through Ki67 staining. The expression of cyclin D1 was evaluated by Western blotting. A whole genome gene expression profiling array was performed from liver samples of those mice using Illumina MouseWG-6 v2.0 gene expression arrays®. Lastly, liver samples from patients with HCC who had received VD supplementation were evaluated by immunohistochemistry. Results: Whole genome data revealed aberrant TGF-β signaling in ∼70% of HCCs. Treatment with calcitriol suppressed the growth of HCC cell lines, regardless of their TGF-β pathway status. Inhibition of proliferation was noted in WT MEFs as well as in the Sptbn1+/- and Sptbn1-/- cells. High dose VD reduced hepatic proliferation and cyclin D1 levels in Sptbn1+/- and Smad3+/- mutants, and in WT mice. The microarray data demonstrated the most significant changes in gene expression were associated with acute phase inflammatory response (p Citation Format: Lior H. Katz, Andrea Cortes, Vivek Shukla, Keigo Machida, Hidekazu Tsukamoto, Kirty Shetty, Aiwu R. He, Lynt B. Johnson, Jian Chen, Randa El-Zein, Ju-Seog Lee, Lopa Mshra. Vitamin D for prevention of liver cancer in the setting of disrupted TGF-β signaling pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4111. doi:10.1158/1538-7445.AM2014-4111

Background: It has been demonstrated that elevated alcohol intake affects the permeability of the gut allowing endotoxins such as LPS to enter into the portal circulation and to promote liver ethanol toxicity. It has also been shown that increased ethanol intake and LPS challenge impairs liver function and affects liver tumor formation. Hence, with the aim of generating a mouse model of alcoholic liver disease that would rapidly develop steatosis, inflammation and fibrosis, we formulated a regimen that combined chronic injections of low dose LPS with ethanol feeding to mice with impaired TGF-β signaling through constitutive disruption of β2-spectrin (Sptbn1+/-) , Smad3 (Smad3+/-) or both. Methods: Wild type, Sptbn1+/-, Smad3+/- and Sptbn1+/-;Smad3+/- female mice between 8-10 weeks of age were fed orally with a Lieber-DeCarli-based diet containing 6.7% ethanol, and 2-4 weeks later they were injected with 2mg/kg LPS via i.p. 3 times/week for up to 20 weeks or death, whichever occurred first. Survival analysis was done using the Gehan-Breslow-Wilcoxon test. Results: Unexpectedly, the mice treated with chronic low dose LPS and fed the alcohol-containing diet only developed a mild liver phenotype, i.e. steatosis but not hepatitis or fibrosis. Instead, these mice developed very aggressive T-cell lymphomas with massive abdominal and thoracic hemorrhages to which the TGF-β mutant mice succumbed more rapidly than the wild type mice. The median survival of the mutants oscillated between 39 to 42 weeks vs. undefined of the wild type mice. We found statistically significant decreased survival of the mutant mice vs. the wild type (p-values between 0.0015 and 0.028). Conclusions: To our knowledge, this is the first report of a mouse model of aggressive T-cell lymphoma based on chronic challenge with low dose LPS and alcohol feeding. We are currently assessing the cross-talk of the LPS/TLR4 and TGF-β pathways in T-cells from these mice to understand the molecular mechanism underlying the accelerated rate of lymphoma development in these mice. Citation Format: Nina M. Muñoz, Lior H. Katz, Mihai I. Gagea, Asif Rashid, Lopa Mishra. Generation of a T-cell lymphoma mouse model based on chronic LPS challenge and TGF-β signaling disruption. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3921. doi:10.1158/1538-7445.AM2014-3921

Background: Hepatocellular cancer (HCC) is the 3rd leading cause of cancer death in the world, that is difficult to treat due to late diagnosis and few viable targeted therapeutics. A large number of studies have demonstrated that the TGF-β pathway plays a fundamental role in the biology of the GI tract, and as such, several components of the pathway are commonly targeted in various GI cancers. TGF-β signaling is regulated by the ubiquitin-proteasome pathway, in which E3 ubiquitin ligases recognize and target proteins for degradation by the proteasome. Numerous E3 ubiquitin ligases have been identified as negative regulators of different components of the TGF-β pathway. More recently, Praja and Keap1 have been identified as E3 ligases that ubiquitinates β2-spectrin (β2SP) in a TGF-β-dependent manner. Accordingly, Praja E3 ligase activity regulates TGF-β signaling by controlling β2SP abundance through ubiquitin-mediated degradation. Hypothesis: Specific E3 ligases, which disrupt TGF-β/β2SP/Smad3 tumor suppressor pathway lead to uncontrolled activation of chromatin and tumor formation. Therefore, small molecule inhibitors that specifically target these E3 ligases could present a novel therapeutic approach for liver cancer. Materials & Methods: Broad genome datasets including 110 cases of HCC patients were retrieved from The Cancer Genome Atlas (TCGA) and analyzed. 23 HCC and normal liver tissue specimens were immunostained with anti-Praja1 antibody. Whole mount in situ hybridization histochemistry (ISHH) assay was used to determine knock down Praja1in zebrafish embryos. A small chemical compound library was screened for E3 ligase inhibitors targeting Praja1. Results: (1) Broad genome analysis reveals that E3 ubiquitin ligases regulating the TGF-β pathway are altered in GI cancers mainly by increase in mRNA and that they negatively correlate with patient survival. (2) Praja1 expression is dramatically raised in human HCCs with loss of TGF-β signaling. (3) Praja1 inhibits TGF-β/Smad3 tumor suppressor function and increases c-Myc activities. (4) Inhibition of Praja1 leads to apoptosis and suppresses its oncogenic activities. (5) Small chemical inhibitors suppress Praja1 activities and restores TGF-β tumor suppressor function in HCC cells. (6) Small chemical inhibitors induce apoptosis and inhibit HCC cell growth and tumorigenesis. Conclusions: E3 ubiquitin ligases that modulate the TGF-β pathway are frequently increased in HCC. Praja1 presents a therapeutic target- it disrupts the TGF-β tumor suppressor pathway, and its overexpression promotes cancer cell survival and proliferation. Small molecule inhibitors such as triterpenoids that specifically target Praja1 could be very useful in HCC therapy, through targeting c-Myc, restoring TGF-β tumor suppressor function. This study may lead to new therapeutics targeting this lethal cancer and potentially a Phase I clinical trial in HCC. Citation Format: Jian Chen, Jiun-Sheng Chen, YoungJin Gi, Lior H Katz, Ji-Hyun Shin, Liem Phan, Wilma Jogunoori, Vivek Shukla, Bibhuti Mishra, Shulin Li, Milind Javle, Mien-Chie Hung, Lopa Mishra. Targeting TGF-β regulated E3 ligases: a novel therapeutic approach for primary liver cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2784. doi:10.1158/1538-7445.AM2014-2784

Introduction: Advanced colorectal cancer (CRC) remains lethal and difficult to treat with over 140,000 new cases a year in the United States. One contributing factor that has emerged is the rapid development of cancers in small, sessile adenomas(polyps) (less than 1cm), which might be overlooked. Results: Using whole genome and whole exome sequence (WGS) analyses of four pairs of colorectal adenoma (early CRC) tissue samples along with their normal counterparts, we observe dramatic genomic instability in two of the samples, suggesting that these two adenomas could be on the brink of overt CRC. We proceeded to analyze a further 20 samples through RNA sequence and/or immunohistochemical analysis. The two polyps are associated with hyper mutated profile of multiple genes including Carcinoembryonic antigen (CEA) and CEACAM6 in one of the samples. Analyses of the expression levels of CEA and TGF-β signaling pathway members in 20 early adenomas and normal colon tissues demonstrate a marked increase in CEA expression in 25% of adenoma samples linked to a concomitant loss of TGF-β signaling. We proceeded to mechanistic studies examining CEA and it role in inactivating the tumor suppressive arm of transforming growth factor-β (TGF-β) signaling, providing crucial new information for CEA in promoting aggressive CRC. We found that CEA interacts directly with the transforming growth factor-β (TGF-β) receptor 1 (TBR1) with inhibition of downstream TGF-β tumor suppressor signaling through its B3 domain. Moreover, we previously found that deletion of Smad3/4 adaptor β2SP results in loss of TGF-β signaling, with dramatic and spontaneous formation of adenomas as well as CRC. Ectopic expression of CEA also induces CRC metastases, potentially indirectly through activation of STAT3 and stimulating production of IL-6, IL-10 and others, in addition to inactivating TGF-β tumor suppressor signaling. Conclusions: Our data suggest that enhanced CEA levels and oncogenic mutations in the colon adenomas can be used as prognostic markers for early detection of aggressive CRC and the B3 domain of CEA can be targeted by monoclonal antibody/peptide inhibitors/small molecule inhibitors targeting CEA and CRC cell proliferation. Citation Format: Avijit Majumdar, Jian Chen, Sue Hwa Lin, Lior Katz, Gottumukkala Subba Raju, Kirti Shetty, Jon White, Xifeng Wu, Asif Rashid, John S. McMurray, Kenna R. Shaw, Xiaoping Su, Brian Weston, Selvi Thirumurthi, Aiwu Ruth He, Lopa Mishra. Genome & exome analysis of early colon cancers reveals new targets. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4703. doi:10.1158/1538-7445.AM2014-4703

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. Vitamin D (VD) has been implicated in the prevention of multiple cancers, some of which are characterized by inactivation of TGF-β signaling. Recently, inactivation of TGF-β signaling has been associated with development of HCC. We examined the potential role of VD in HCC chemoprevention in the context of TGF-β inactivation in a mouse model. Methods: Wild type, Sptbn1+/- and Smad3+/- male mice were treated with 50 mg/kg of the chemical carcinogen diethylnitrosamine (DEN) via i.p. injection at 14 days of age. At 8 months, the animals were changed from regular chow (2,200 IU/kg VD) to one of two diets: lower than normal VD (200 IU/kg) or high VD (10,000 IU/kg). At one year of age, the livers were harvested for tissue analysis. Several metrics were assessed including expression levels of 164 proteins from liver tumors by Reverse Phase Protein Array (RPPA). Results: Twenty three mice were treated with lower than normal dose VD while 26 received high dose VD. We did not find significant differences in blood calcium levels in animals on either diet. As expected, high VD intervention after 8 months of DEN injection did not affect the total number of tumors the mice developed; however, the lower than normal VD regimen promoted tumor growth in the context of Smad3 disruption (liver-to-body weight ratio 18.37% in Smad3+/- mice treated with low dose VD vs. 6.25% in Smad3+/- animals treated with high dose, p=0.028). Furthermore, RPPA data revealed that the lower than normal VD intake in DEN-treated Smad3 heterozygous null mice results in repression of tumor suppressing genes such as PDCD4 and concomitant up-regulation of tumor promoting genes like Stat5A, Bcl2-XL, PDGFRB and PEA15. Conclusions: Remarkably, lower than normal VD in the context of Smad3 disruption promotes tumor growth possibly through repression of tumor suppressing genes such as PDCD4 and up-regulation of oncogenes like Stat5A, Bcl2-XL, PDGFRB and PEA15. These results suggest that VD treatment strategies could potentially be significant for chemoprevention and treatment of HCC in the context of inactivation of TGF-β signaling in patient populations with underlying deficiency of VD. Citation Format: Nina M. Muñoz, Lior H. Katz, Keigo Machida, Hidekazu Tsukamoto, Kirty Shetty, Aiwu R. He, Lynt B. Johnson, Asif Rashid, Sang Bae Kim, Ju-Seog Lee, Lopa Mishra. Vitamin D deficiency promotes hepatocellular carcinoma tumor growth in TGF-β impaired mice by Smad3 heterozygous deletion. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 248. doi:10.1158/1538-7445.AM2014-248

It is difficult to detect bioterrorism attacks and to identify the castoff biological agent. The principal enigmas are the wide variety of the clinical symptoms associated with various biological agents and the fact that the attack is likely to be a covert event. The first and major indication of a bioterrorism attack could be the presence of affected patients. It is, however, extremely important to detect and identify an attack using a biological agent as early as possible. Therefore, it is crucial to be alert to such possibilities and to maintain high levels of suspicion. The aim of this article is to list all the clues, which will help us highlight the suspicion that a disease or clinical symptoms are the result of a bioterrorism attack and not a "natural" outbreak. These clues involve the recognition of a wide range of clinical patterns pertinent to biological agent attacks on the individual victim and the overall integrated epidemiological picture. Further signs also include the identification of the roots of transmission, the contagious patterns of bioterrorism agents and possible unusual findings in laboratory tests and in animals.

Infection with Burkholderia mallei (formerly Pseudomonas mallei) can cause a subcutaneous infection known as "farcy" or can disseminate to condition known as Glanders. It is primarily a disease affecting horses, donkeys and mules. In humans, Glanders can produce four types of disease: localized form, pulmonary form, septicemia, and chronic form. Necrosis of the tracheobronchial tree and pustular skin lesions characterize acute infection with B. mallei. Other symptoms include febrile pneumonia, if the organism was inhaled, or signs of sepsis and multiple abscesses, if the skin was the port of entry. Glanders is endemic in Africa, Asia, the Middle East, and Central and South America. Glanders has low contiguous potential, but because of the efficacy of aerosolized dissemination and the lethal nature of the disease, B. mallei was considered a candidate for biological warfare. During World War I, Glanders was believed to have been spread to infect large numbers of Russian horses and mules on the Eastern front. The Japanese infected horses, civilians and prisoners of war during World War II. The USA and the Soviet Union have shown interest in B. mallei in their biological warfare program. The treatment is empiric and includes mono or poly-therapy with Ceftazidime, Sulfadiazine, Trimethoprim + Sulfamethoxazol, Gentamicin, Imipenem etc. Aggressive control measures essentially eliminated Glanders from the west. However, with the resurgent concern about biological warfare, B. mallei is now being studied in a few laboratories worldwide. This review provides an overview of the disease and presents the only case reported in the western world since 1949.

There are hundreds of potential agents that could be used in biological warfare or bioterrorism: bacteria, viruses and toxins. There are no similarities between clinical presentations of organisms or toxins belonging to specific microbial families. Therefore, it is important for the physician, required to cope with an unusual disease or outbreak among his patients, to become familiar with the various symptoms that victims of biological warfare or bioterrorism may present.To describe the six most common groups of symptoms expected in the above setting. The most common symptoms will be described as they appear in nature, because of a fortunate lack of experience with the majority of these agents in biological warfare. Hence, variations of these presentations may be possible.The six most common presentations reviewed are: 1) respiratory tract symptoms; 2) hemorrhagic fevers; 3) meningitis and encephalitis; 4) flaccid paralyses; 5) fever syndromes with rash; and 6) diarrheal syndromes. Additional presentations may be possible due to alterations made in these organisms or development of new agents and mixtures. A list is provided of features that may alert a physician of the possibility of biological warfare or bioterrorism.Knowledge of the principal clinical presentations of victims of biological warfare or bioterrorism is essential to all physicians. This knowledge may contribute to the early recognition of a cluster of patients, an epidemic, an unusual disease, or biological warfare; quick referral to the emergency department, leading to early microbiological diagnosis; and rapid notification of the Ministry of Health. All these, and the institution of appropriate measures, will ultimately contribute to the survival of individual patients and at-risk populations.

The threat of a disease outbreak resulting from biologic warfare has been of concern for the Israeli health system for many years. In order to be prepared for such an event the health system has formulated doctrines for various biologic agents and defined the logistic elements for the procurement of drugs. During the last 4 years, and especially after the West Nile fever epidemic in 2000, efforts to prepare the healthcare system and the relevant organizations were accelerated. The Director-General of the Ministry of Health nominated a Supreme Steering Committee to fill in the gaps and upgrade the preparedness of the health system for an unusual disease outbreak. This committee and its seven subcommittees established appropriate guidelines, communication routes among different organizations, and training programs for medical personnel. The anthrax outbreak in the United States found the healthcare system in the hub of the preparation process, and all modes of action were intensified. Further work by hospitals, primary care clinics and all other institutes should be increased to maintain a state of proper preparedness.

AIM: To evaluate the impact of antiviral treatment on cytomegalovirus (CMV)-positive ulcerative colitis patients. METHODS: We performed a systematic review and meta-analysis (MA) of comparative cohort and case-control studies published between January 1966 and March 2013. Studies focusing on colectomy series and studies including only less than 3 patients in the treated or non-treated arm were excluded. The primary outcome was colectomy within 30 d of diagnosis. Secondary outcomes included colectomy during the follow-up period Subgroup analyses by method of detection of CMV, study design, risk of bias and country of origin were performed. Quality of studies was evaluated according to modified New-Castle Ottawa Scale. RESULTS: After full-text review, nine studies with a total of 176 patients were included in our MA. All the included studies were of low to moderate quality. Patients who have received antiviral treatment had a higher risk of 30-d colectomy (OR = 2.40; 95%CI: 1.05-5.50; I2 = 37.2%). A subgroup analysis including only patients in whom CMV diagnosis was based did not demonstrate a significant difference between the groups (OR = 3.41; 95%CI: 0.39-29.83; I2 = 56.9%). Analysis of long-term colectomy rates was possible for 6 studies including 110 patients. No statistically significant difference was found between the treated and untreated groups (OR = 1.71; 95%CI: 0.71-4.13; 6 studies, I2 = 0%). Analysis of mortality rate was not possible due to a very limited number of cases. Stratification of the outcomes by disease severity was not possible. CONCLUSION: No positive association between antiviral treatment and a favorable outcome was demonstrated. These findings should be interpreted cautiously due to primary studies’ quality and potential biases.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer related death worldwide. One third of patients with cirrhosis will develop HCC, thus comprising a well-characterized population at high-risk for the development of this deadly, yet potentially preventable cancer. Vitamin D (VD) has been implicated in the prevention of multiple cancers- some with inactivation of TGF-beta signaling. Recently, inactivation of TGF-beta signaling has been associated with HCC. The identification of subgroups of patients responsive to treatment is vital for preventing this disease effectively. In an effort to understand the role of Vit D in HCC and to identify clear responders, we analyzed the role of Vit D in the context of TGF-beta inactivation. Methods: The effect of calcitriol on cell proliferation was measured in HCC cell lines as well as in Hep-G2 cells that were knocked down to the adaptor protein β2-spectrin (Spnb2). To evaluate in vivo effects of VD on animals predisposed to developing liver cancer, Spnb2+/− mice were fed with special diets containing 1000 IU VD/kg/D or 10,000 IU VD/kg/D. After 6 weeks, the animals were euthanized and hepatocyte proliferation and the content of fat in the liver were analyzed through Ki67 staining and oil red staining, respectively. The expression of cyclin D1 was evaluated by Western blotting (WB). Lastly, liver samples from patients with HCC who had received VD supplementation in the diet were also evaluated by immunohistochemistry. Results: We observed a dramatic response to treatment with calcitriol as indicated by a significant increase in the expression of CYP24A1. Additionally, treatment with VD and calcitriol suppressed the growth of HCC cell lines. Absence of Spnb2 caused more prominent suppression of the growth of Hep-G2. From our animal studies we found that steatosis and hepatocyte proliferation were higher in Spnb2+/− mice fed with a low dose of VD, and that the high dose VD significantly reduced both parameters. The increased proliferation in Spnb2+/− mice fed with a low dose of VD was associated with higher levels of cyclin D1 expression, which was restored the level almost to that seen in the wild type mice with the higher dose of VD. Lastly, VD supplementation to patients with HCC was associated with higher expression of β2-spectrin (p Conclusions: VD suppresses the proliferation of several HCC cell lines, and in agreement with this, high doses of VD in the diet suppress hepatocyte proliferation and steatosis in the HCC prone Spnb2+/− mice. Our data also indicate that VD administration appears to restore the expression of key cell cycle proteins even in the setting of TGF-β signaling disruption. Taken together, these preliminary results suggest that VD treatment strategies could potentially be pivotal in preventing obesity-induced HCC. Citation Format: Lior H. Katz, Vivek Shukla, Sara Peleg, Kirti shetty, Jian Chen, Steven Curley, Powel H. Brown, Lopa Mishra. Vitamin D as a chemoprophylactic agent for liver cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3692. doi:10.1158/1538-7445.AM2013-3692

Background: A crucial factor in protection from liver injury, fibrosis and cancer by agents such as alcohol, aflatoxins and viral hepatitis is the enforcement of genomic stability. However, sensors for genotoxicity leading to aberrant DNA repair remain elusive. Because inactivation of the TGF-β pathway results in DNA damage, alcohol toxicity and HCC, TGF-β has been implicated as a critical promoter of genomic stability and tumor suppression; however, the framework by which this occurs is not known. We performed Whole-genome (WGS) and Exome sequencing (WES) on 6 pairs human HCC samples and identified inactivation of TGF-beta pathway members as a prominent characteristic of alcohol induced HCC, potentially through inactivation of a TGF-b adaptor, β2SP. We therefore hypothesized that the TGF-β/β2SP/Smad3 pathway is crucial for protection against aldehyde genotoxicity through enforcing genomic stability. Materials & Methods: We performed Whole-genome (WGS) and Exome sequencing (WES) on 6 pairs human HCC samples. β2SP mutant mice were treated with alcohol to determine their susceptibility to aldehyde-induced developmental abnormalities. Primary MEFs from β2SP+/+, β2SP+/− and β2SP−/− mice were treated with colcemid for cytogenetic analysis, and they were also treated with multiple DNA damaging agents and γ-irradiation to evaluate Mdc1, NBS1 and Rad51 foci formation. ChIP assays were performed to determine the recruitment of β2SP/Smad3/Smad4 at FancD2 promoter. Results: (1) Through our WGS and WES analyses, we discovered a novel inactivating mutation of TGF-β/β2SP pathway in alcohol-associated HCC. This β2SP mutation results in functional disruption of TGF-β signaling. (2) Alcohol treatment in the absence of β2SP mice results in teratogenicity and spontaneous fetal alcohol-like phenotype (FAS). (3) Loss of β2SP results in premature replicative senescence and marked hypersensitivity to DNA interstrand crosslinking agents, such as mitomycin C (MMC). (4) DNA damage response induces nuclear localization of β2SP in a TGF-β-dependent manner. (5) Suppression of β2SP impairs the recruitment of DNA repair proteins in the nucleus and consequently the repair of DNA double-strand breaks. (6) Loss of β2SP correlates with loss of FANCD2 expression, but not of any of the other 12 Fanconi anemia complementation factors. Moreover, our results indicate that β2SP/Smad3/Smad4 regulate expression of FANCD2 at the transcriptional level. (7) The expression of β2SP and FANCD2 is correlated in alcoholic hepatitis and cirrhotic livers. Conclusions: Through whole genome and Exome sequencing we found a novel inactivating mutation in β2SP which results in loss of TGF-β signaling pathway. Importantly, these results could potentially lead to new therapeutics targeting toxin-induced DNA damage and tumorigenesis. Citation Format: Vivek Shukla, Jian Chen, Jiun-Sheng Chen, Ying Li, Lior Katz, Avijit Majumdar, Lei Li, Walter Hittleman, Xiaoping Su, Junjie Chen, Xifeng Wu, Patrizia Farci, Lopa Mishra. High resolution characterization of human hepatocellular cancer (HCC) reveals a novel inactivating mutation in the TGF-β pathway that promotes alcohol induced HCC. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1775. doi:10.1158/1538-7445.AM2013-1775

Objective To examine the prevalence, etiology, risk factors, and outcomes of liver abnormality in pregnancy, in a tertiary medical center, and to study the potential impact of artificial reproduction techniques (ART) on the incidence and the outcome of pregnancy-related liver abnormality. Design A retrospective case-control study using an electronic database and patients' files. Setting Tertiary referral center. Patient(s) Women in the third trimester of pregnancy who were hospitalized for delivery. Intervention(s) None. Main Outcome Measure(s) Development of significant elevation of alanine aminotransferase (ALT ≥100 IU/L). Secondary outcomes included development of maternal and fetal complications. Result(s) The upper limit of normal of ALT was ≥1.5 times and it occurred in 440 (1.6%) pregnancies; of those, 228 (0.8%) had ALT ≥100 IU/L. The etiology of significant liver test abnormality was idiopathic in 47% of patients. Compared with spontaneous pregnancies (295/23,793), ART was significantly associated with liver test abnormality (145/4, 520). The presence of ALT ≥100 IU/L in the third trimester was associated with higher rates of cesarean sections, prematurity, low birthweight, and fetal complications. Conclusion(s) A definite etiology was not determined in about half of pregnancy-associated liver test abnormality. The ART was significantly associated with liver test elevation. Significant liver test abnormality in the third trimester may have an impact on maternal and fetal/neonatal outcomes.

Backgrounds: Green tea catechins (GTCs) have been shown to provide anti-carcinogenic effects in several laboratory studies. Although the effect of green tea consumption on the risk of gastric cancer has been studied in epidemiological studies, the results remain controversial. The anti-carcinogenic mechanisms of GTCs have not been fully evaluated in rodent models of gastric cancer. Previous reports indicate that transgenic INS-GASmice are hypergastrinemic and induced corpus gastritis and eventually developed gastric cancer at over 20 months old. Aim: The aim of our study was to investigate the molecular effects of GTCs on gastritis and premalignant lesions in INS-GAS mice. Methods: Thirty eight, male INSGAS mice on a FVB background were used in this study. Mice were divided into two groups: A GTCs group and control. Mice in the GTCs group were allowed free access to drinking water containing 2000ppm of GTCs from the age of 9 weeks. Mice were euthanized at the age of 13 or 37 weeks. Histological scores (inflammation and dysplasia) were graded on a blinded basis by pathologist on a scale from 0 to 4. The mRNA expressions of IFN-gamma and TNF-alpha in the corpus of stomachs were evaluated using quantitative PCR. Statistical analysis was performed using a Mann-Whitney U test. Results: Body weights in mice supplemented with GTCs were significantly lower than that of controls at both 13 and 37 weeks of age (p < 0.05). Treated and control mice developed minimal to mild corpus gastritis, although dysplasia was evident. The histological score of dysplasia in mice supplemented with GTCs was significantly lower than that in controls at 37 weeks of age (p < 0.05). GTCs supplementation did not affect the inflammation score. The mRNA level of IFN-gamma in mice administrated GTCs was significantly lower than that of controls at 13 weeks of age (p < 0.05), although it did not reach statistical significance at 34 weeks of age (p = 0.056). GTCs supplementation did not alter TNF-alpha mRNA expression levels between both groups. Conclusions: Administration of GTCs attenuated progression of gastric dysplasia in INS-GAS male mice. These results demonstrated that IFN-gamma dependent mechanisms may be involved in the protective role of GTCs in development of gastritis and premalignant lesions in this rodent model.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer related mortality worldwide. In view of its limited therapeutic options, strategies for HCC prevention are urgently needed. Vitamin D (VD) and calcitriol have anti-proliferative and other anti neoplastic activities. Low levels of VD are associated with increased risk for cancer, and calcitriol can be active agent in cancer treatment. Therefore, VD might be a strong candidate for HCC prevention. We show that vitamin D can prevent the development of HCC in cell lines, reduce proliferation in animal models and modify cell cycle protein levels in human livers. Methods: 1) Hep3B HCC cells were treated with either calcitriol, or two synthetic VD analogs - EB1089 and QW-1624F. Growth was measured using an MTS assay. 2) Livers were harvested from 12 months-old wild-type (WT) mice fed standard Purina chow, and age-matched β2spectrin (≥2SP)+/− mice after 6 weeks of feeding with a semi-purified AIN-93 diet containing 1000 IU VD/kg or 10,000 IU VD/kg. Hepatocyte proliferation (Ki67 staining) and fat content (Oil red staining) were assessed as well as cell cycle proteins (by Western blot). 3) Human liver tissue from healthy and cirrhotic livers as well as from HCC patients were stained for TGF ≤ Receptor II (TBRII) and for β2SP with and without treatment with VD. Results: 1) HCC cell lines - Doses of 10-1000nM of calcitriol or vitamin D analogs suppress the growth of HCC cells. 2) Serum levels of VD in WT and β2SP+/− mice on regular diet were 25.6+/− 2.9 ng/mL and 21.7+/− 8 ng/mL, respectively (p=NS). High dose vitamin D in the diet increased significantly serum levels of vitamin D in β2SP+/− mice to 49.6+/− 12.7 (p=0.0036). Proliferation and steatosis were higher in hepatocytes from β2SP+/− mice fed low dose VD as compared to the wild-type mice fed standard diet. However, high dose VD reduced hepatocyte proliferation and steatosis in β2SP+/− mice. Levels of cyclin D1 were increased in the β2SP+/− mice fed with regular diet as compared to the wild type mice. However, high-dose VD restored the levels of cyclin D1 almost to that of the WT (p=0.069). 3) Normal human hepatocytes have active TGF-β signaling as demonstrated by high levels of β2SP and TBRII staining, while cirrhotic liver cells and HCC cells have reduced β2SP and TBRII staining. VD treatment partially restores TGF-β signaling with similar β2SP and TBRII staining to that in normal hepatocytes. A potential mechanism through KLF-4 modulation may contribute to it. A disappearance of an MRI detected nodule was observed in one of the patients treated with Vitamin D with restoration of TGF-β markers. Conclusions: 1) Calcitriol and its analogs suppress proliferation of HCC cell lines. 2+3) High doses of VD in the diet suppress hepatocyte proliferation and hepatic steatosis in susceptible mice. Possible mechanism can be the effect of VD on cell cycle proteins through the TGF-β pathway as seen in humans. These findings emphasize the use of vitamin D as a novel preventive treatment for HCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1619. doi:1538-7445.AM2012-1619

Summary. To assess the effects of prophylactic lamivudine on reactivation and mortality following immunosuppressive therapy in hepatitis B surface antigen (HBsAg)-positive patients, we performed a meta-analysis. Systematic review and meta-analysis of randomized and nonrandomized prospective controlled trials and retrospective comparative case series were identified through The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and LILACS. The primary outcomes were virological reactivation, clinical reactivation and mortality. Secondary outcomes included hepatitis B virus (HBV)-related mortality, liver histology, discontinuation or disruption of immunosuppressive therapy, lamivudine-resistant HBV strains and adverse events. A total of 21 studies were included, two of which were randomized controlled trials. Clinical and virological reactivation were significantly reduced in the lamivudine group [odds ratio (OR) 0.09; 95% confidence interval (CI) 0.05–0.15 and OR 0.04; 95% CI 0.01–0.14 respectively]. All-cause mortality was significantly reduced in the lamivudine group (OR 0.36; 95% CI 0.23–0.56) which translates to only 11 patients who need to be treated to prevent one death. Lamivudine significantly reduced HBV-related mortality, and discontinuations or disruptions of the immunosuppressive treatment. No adverse effects of lamivudine were recorded, and resistance to lamivudine occurred in low rates. We demonstrated a clear benefit of lamivudine in terms of clinical and virological HBV reactivation, overall mortality, HBV-related mortality and interruptions or discontinuations in the immunosuppressive treatment. Lamivudine should be administered prophylactically to HBsAg-positive patients who are about to receive immunosuppressive therapy.