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1. Off-Therapy Response After Nucleos(t)ide Analogue Withdrawal in Patients With Chronic Hepatitis B: An International, Multicenter, Multiethnic Cohort (RETRACT-B Study)

Author

Hirode, G. Choi, H.S.J. Chen, C.-H. Su, T.-H. Seto, W.-K. Van Hees, S. Papatheodoridi, M. Lens, S. Wong, G. Brakenhoff, S.M. Chien, R.-N. Feld, J. Sonneveld, M.J. Chan, H.L.Y. Forns, X. Papatheodoridis, G.V. Vanwolleghem, T. Yuen, M.-F. Hsu, Y.-C. Kao, J.-H. Cornberg, M. Hansen, B.E. Jeng, W.-J. Janssen, H.L.A. RETRACT-B Study Group

Abstract

Background & Aims: Functional cure, defined based on hepatitis B surface antigen (HBsAg) loss, is rare during nucleos(t)ide analogue (NA) therapy and guidelines on finite NA therapy have not been well established. We aim to analyze off-therapy outcomes after NA cessation in a large, international, multicenter, multiethnic cohort of patients with chronic hepatitis B (CHB). Methods: This cohort study included patients with virally suppressed CHB who were hepatitis B e antigen (HBeAg)–negative and stopped NA therapy. Primary outcome was HBsAg loss after NA cessation, and secondary outcomes included virologic, biochemical, and clinical relapse, alanine aminotransferase flare, retreatment, and liver-related events after NA cessation. Results: Among 1552 patients with CHB, cumulative probability of HBsAg loss was 3.2% at 12 months and 13.0% at 48 months of follow-up. HBsAg loss was higher among Whites (vs Asians: subdistribution hazard ratio, 6.8; 95% confidence interval, 2.7–16.8; P < .001) and among patients with HBsAg levels 30%). Incidence rate of hepatic decompensation and hepatocellular carcinoma was 0.48 per 1000 person-years and 0.29 per 1000 person-years, respectively. Death occurred in 7/19 decompensated patients and 2/14 patients with hepatocellular carcinoma. Conclusions: The best candidates for NA withdrawal are virally suppressed, HBeAg- negative, noncirrhotic patients with CHB with low HBsAg levels, particularly Whites with

Published
2022

2. Historical epidemiology of hepatitis C virus in select countries-volume 4

Author

Maaroufi, A., Vince, A., Himatt, S. M., Mohamed, R., Fung, J., Opare-Sem, O., Workneh, A., Njouom, R., Al ghazzawi, I., Abdulla, M., Kaliaskarova, K. S., Owusu-Ofori, S., Abdelmageed, M. K., Adda, D., Akin, O., Al Baqali, A., Al Dweik, N., Al Ejji, K., Al Kaabi, S., Al Naamani, K., Al Qamish, J., Al Sadadi, M., Al Salman, J., AlBadri, M., Al- Busafi, S. A., Al-Romaihi, H. E., Ampofo, W., Antonov, K., Anyaike, C., Arome, F., Bane, A., Blach, S., Borodo, M. M., Brandon, S. M., Bright, B., Butt, M. T., Cardenas, I., Chan, H. L. Y., Chen, C. J., Chen, D. S., Chen, P. J., Chien, R. N., Chuang, W. L., Cuellar, D., Derbala, M., Elbardiny, A. A., Estes, C., Farag, E., Gamkrelidze, I., Garcia, V., Genov, J., Ghandour, Z., Ghuloom, M., Gomez, B., Gunter, J., Habeeb, J., Hajelssedig, O., Hamoudi, W., Hrstic, I., Hu, C. C., Huang, C. F., Hui, Y. T., Jahis, R., Jelev, D., John, A. K., Kamel, Y., Kao, J. H., Khamis, J., Khattabi, H., Khoudri, I., Konysbekova, A., Kotzev, I., Lai, M. S., Lao, W. C., Layden, J., Lee, M. H., Lesi, O., Li, M., Lo, A., Loo, C. K., Lukšić, B., Malu, A. O., Mateva, L., Mitova, R., Morović, M., Murphy, K., Mustapha, B., Nde, H., Nersesov, A., Ngige, E., Njoya, O., Nonković, D., Obekpa, S., Oguche, S., Okolo, E. E., Omede, O., Omuemu, C., Ondoa, P., Phillips, R. O., Prokopenko, Y. N., Razavi, H., Razavi-Shearer, D., Redae, B., Reic, T., Rinke de Wit, T., Rios, C., Robbins, S., Roberts, L. R., Sanad, S. J., Schmelzer, J. D., Sharma, M., Simonova, M., Su, T. H., Sultan, K., Tan, S. S., Tchernev, K., Tsang, O. T. Y., Tsang, S., Tzeuton, C., Ugoeze, S., Uzochukwu, B., Vi, R., Wani, H. U., Wong, V. W. S., Yacoub, R., Yesmembetov, K. I., Youbi, M., Yuen, M. F., Razavi-Shearer, K., APH - Quality of Care, APH - Personalized Medicine, AII - Infectious diseases, Global Health, and APH - Methodology

Subjects
Hepatology, Health Policy, Disease Management, Hepatitis C, Chronic, Global Health, Antiviral Agents, Liver Transplantation, 03 medical and health sciences, 0302 clinical medicine, Infectious Diseases, Virology, Prevalence, Humans, 030211 gastroenterology & hepatology, 030212 general & internal medicine, Hepatitis C
Abstract

Due to the introduction of newer, more efficacious treatment options, there is a pressing need for policy makers and public health officials to develop or adapt national hepatitis C virus (HCV) control strategies to the changing epidemiological landscape. To do so, detailed, country-specific data are needed to characterize the burden of chronic HCV infection. In this study of 17 countries, a literature review of published and unpublished data on HCV prevalence, viraemia, genotype, age and gender distribution, liver transplants and diagnosis and treatment rates was conducted, and inputs were validated by expert consensus in each country. Viraemic prevalence in this study ranged from 0.2% in Hong Kong to 2.4% in Taiwan, while the largest viraemic populations were in Nigeria (2 597 000 cases) and Taiwan (569 000 cases). Diagnosis, treatment and liver transplant rates varied widely across the countries included in this analysis, as did the availability of reliable data. Addressing data gaps will be critical for the development of future strategies to manage and minimize the disease burden of hepatitis C.

Published
2017
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3. Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study

Author

Razavi-Shearer, D. Gamkrelidze, I. Nguyen, M.H. Chen, D.-S. Van Damme, P. Abbas, Z. Abdulla, M. Abou Rached, A. Adda, D. Aho, I. Akarca, U. Al Ali, F.H. Lawati, F.A.L. Naamani, K.A.L. Alashgar, H.I. Alavian, S.M. Alawadhi, S. Albillos, A. Al-Busafi, S.A. Aleman, S. Alfaleh, F.Z. Aljumah, A.A. Anand, A.C. Anh, N.T. Arends, J.E. Arkkila, P. Athanasakis, K. Bane, A. Ben-Ari, Z. Berg, T. Bizri, A.R. Blach, S. Brandão Mello, C.E. Brandon, S.M. Bright, B. Bruggmann, P. Brunetto, M. Buti, M. Chan, H.L.Y. Chaudhry, A. Chien, R.-N. Choi, M.S. Christensen, P.B. Chuang, W.-L. Chulanov, V. Clausen, M.R. Colombo, M. Cornberg, M. Cowie, B. Craxi, A. Croes, E.A. Cuellar, D.A. Cunningham, C. Desalegn, H. Drazilova, S. Duberg, A.-S. Egeonu, S.S. El-Sayed, M.H. Estes, C. Falconer, K. Ferraz, M.L.G. Ferreira, P.R. Flisiak, R. Frankova, S. Gaeta, G.B. García-Samaniego, J. Genov, J. Gerstoft, J. Goldis, A. Gountas, I. Gray, R. Guimarães Pessôa, M. Hajarizadeh, B. Hatzakis, A. Hézode, C. Himatt, S.M. Hoepelman, A. Hrstic, I. Hui, Y.-T.T. Husa, P. Jahis, R. Janjua, N.Z. Jarcuška, P. Jaroszewicz, J. Kaymakoglu, S. Kershenobich, D. Kondili, L.A. Konysbekova, A. Krajden, M. Kristian, P. Laleman, W. Lao, W.-C.C. Layden, J. Lazarus, J.V. Lee, M.-H. Liakina, V. Lim, Y.-S.S. Loo, C.-K.K. Lukšic, B. Malekzadeh, R. Malu, A.O. Mamatkulov, A. Manns, M. Marinho, R.T. Maticic, M. Mauss, S. Memon, M.S. Mendes Correa, M.C. Mendez-Sanchez, N. Merat, S. Metwally, A.M. Mohamed, R. Mokhbat, J.E. Moreno, C. Mossong, J. Mourad, F.H. Müllhaupt, B. Murphy, K. Musabaev, E. Nawaz, A. Nde, H.M. Negro, F. Nersesov, A. Nguyen, V.T.T. Njouom, R. Ntagirabiri, R. Nurmatov, Z. Obekpa, S. Ocama, P. Oguche, S. Omede, O. Omuemu, C. Opare-Sem, O. Opio, C.K. Örmeci, N. Papatheodoridis, G. Pasini, K. Pimenov, N. Poustchi, H. Quang, T.D. Qureshi, H. Ramji, A. Razavi-Shearer, K. Redae, B. Reesink, H.W. Rios, C.Y. Rjaskova, G. Robbins, S. Roberts, L.R. Roberts, S.K. Ryder, S.D. Safadi, R. Sagalova, O. Salupere, R. Sanai, F.M. Sanchez-Avila, J.F. Saraswat, V. Sarrazin, C. Schmelzer, J.D. Schréter, I. Scott, J. Seguin-Devaux, C. Shah, S.R. Sharara, A.I. Sharma, M. Shiha, G.E. Shin, T. Sievert, W. Sperl, J. Stärkel, P. Stedman, C. Sypsa, V. Tacke, F. Tan, S.S. Tanaka, J. Tomasiewicz, K. Urbanek, P. van der Meer, A.J. Van Vlierberghe, H. Vella, S. Vince, A. Waheed, Y. Waked, I. Walsh, N. Weis, N. Wong, V.W. Woodring, J. Yaghi, C. Yang, H.-I. Yang, C.-L. Yesmembetov, K. Yosry, A. Yuen, M.-F. Yusuf, M.A.M. Zeuzem, S. Razavi, H. The Polaris Observatory Collaborators

Abstract

Background: The 69th World Health Assembly approved the Global Health Sector Strategy to eliminate viral hepatitis by 2030. Although no virological cure exists for hepatitis B virus (HBV) infection, existing therapies to control viral replication and prophylaxis to minimise mother-to-child transmission make elimination of HBV feasible. We aimed to estimate the national, regional, and global prevalence of HBsAg in the general population and in the population aged 5 years in 2016, as well as coverage of prophylaxis, diagnosis, and treatment. Methods: In this modelling study, we used a Delphi process that included a literature review in PubMed and Embase, followed by interviews with experts, to quantify the historical epidemiology of HBV infection. We then used a dynamic HBV transmission and progression model to estimate the country-level and regional-level prevalence of HBsAg in 2016 and the effect of prophylaxis and treatment on disease burden. Findings: We developed models for 120 countries, 78 of which were populated with data approved by experts. Using these models, we estimated that the global prevalence of HBsAg in 2016 was 3·9% (95% uncertainty interval [UI] 3·4–4·6), corresponding to 291 992 000 (251 513 000–341 114 000) infections. Of these infections, around 29 million (10%) were diagnosed, and only 4·8 million (5%) of 94 million individuals eligible for treatment actually received antiviral therapy. Around 1·8 (1·6–2·2) million infections were in children aged 5 years, with a prevalence of 1·4% (1·2–1·6). We estimated that 87% of infants had received the three-dose HBV vaccination in the first year of life, 46% had received timely birth-dose vaccination, and 13% had received hepatitis B immunoglobulin along with the full vaccination regimen. Less than 1% of mothers with a high viral load had received antiviral therapy to reduce mother-to-child transmission. Interpretation: Our estimate of HBV prevalence in 2016 differs from previous studies, potentially because we took into account the effect of infant prophylaxis and early childhood vaccination, as well as changing prevalence over time. Although some regions are well on their way to meeting prophylaxis and prevalence targets, all regions must substantially scale-up access to diagnosis and treatment to meet the global targets. Funding: John C Martin Foundation. © 2018 Elsevier Ltd

Published
2018

4. Novel small molecules disrupting Hec1/Nek2 interaction ablate tumor progression by triggering Nek2 degradation through a death-trap mechanism

Author

Zhu J, Eva Y.-H. P. Lee, Lopez R, Hu Cm, Chamberlin Ar, Guikai Wu, Wen-Hwa Lee, Qiu Xl, Xuning Emily Guo, Chien R, Wang Yv, Chen W, Bryan Ngo, Kim Y, and Tsai Cy

Subjects
Models, Molecular, Cancer Research, Indoles, Mutant, Molecular Conformation, Gene Expression, Mitosis, Plasma protein binding, Protein Serine-Threonine Kinases, Biology, Article, Inhibitory Concentration 50, Cell Line, Tumor, Neoplasms, Valerates, Genetics, Animals, Humans, NIMA-Related Kinases, Phosphorylation, Binding site, Molecular Biology, Binding Sites, Kinase, Nuclear Proteins, Prognosis, Cytoskeletal Proteins, Disease Models, Animal, Thiazoles, Tumor progression, Benzamides, Proteolysis, Cancer cell, Disease Progression, Cancer research, Heterografts, Protein Binding
Abstract

Hec1 (Highly Expressed in Cancer 1) or Nek2 (NIMA-related kinase 2) is often overexpressed in cancers with poor prognosis. Both are critical mitotic regulators and phosphorylation of Hec1 S165 by Nek2 is required for proper chromosome segregation. Therefore, inactivation of Hec1 and Nek2 by targeting their interaction with small molecules represents an ideal strategy for tackling these types of cancers. Here, we showed that new derivatives of INH (Inhibitor for Nek2 and Hec1 binding) bind to Hec1 at amino acids 394–408 on W395, L399 and K400 residues, effectively blocking Hec1 phosphorylation on S165 by Nek2, and killing cancer cells at the nanomolar range. Mechanistically, the D-box (destruction-box) region of Nek2 specifically binds to Hec1 at amino acids 408–422, immediately adjacent to the INH binding motif. Subsequent binding of Nek2 to INH-bound Hec1 triggered proteasome-mediated Nek2 degradation, whereas the Hec1 binding defective Nek2 mutant, Nek2 R361L, resisted INH-induced Nek2 degradation. This finding unveils a novel drug-action mechanism where the binding of INHs to Hec1 forms a virtual death-trap to trigger Nek2 degradation and eventually cell death. Furthermore, analysis of the gene expression profiles of breast cancer patient samples revealed that co-elevated expressions of Hec1 and Nek2 correlated with the shortest survival. Treatment of mice with this kind of tumor with INHs significantly suppressed tumor growth without obvious toxicity. Taken together, the new INH derivatives are suitable for translation into clinical application.

Published
2014
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5. Global prevalence and genotype distribution of hepatitis C virus infection in 2015: A modelling study

Author

Blach, S. Zeuzem, S. Manns, M. Altraif, I. Duberg, A.-S. Muljono, D.H. Waked, I. Alavian, S.M. Lee, M.-H. Negro, F. Abaalkhail, F. Abdou, A. Abdulla, M. Abou Rached, A. Aho, I. Akarca, U. Al Ghazzawi, I. Al Kaabi, S. Al Lawati, F. Al Namaani, K. Al Serkal, Y. Al-Busafi, S.A. Al-Dabal, L. Aleman, S. Alghamdi, A.S. Aljumah, A.A. Al-Romaihi, H.E. Andersson, M.I. Arendt, V. Arkkila, P. Assiri, A.M. Baatarkhuu, O. Bane, A. Ben-Ari, Z. Bergin, C. Bessone, F. Bihl, F. Bizri, A.R. Blachier, M. Blasco, A.J. Brandao Mello, C.E. Bruggmann, P. Brunton, C.R. Calinas, F. Chan, H.L.Y. Chaudhry, A. Cheinquer, H. Chen, C.-J. Chien, R.-N. Choi, M.S. Christensen, P.B. Chuang, W.-L. Chulanov, V. Cisneros, L. Clausen, M.R. Cramp, M.E. Craxi, A. Croes, E.A. Dalgard, O. Daruich, J.R. De Ledinghen, V. Dore, G.J. El-Sayed, M.H. Ergor, G. Esmat, G. Estes, C. Falconer, K. Farag, E. Ferraz, M.L.G. Ferreira, P.R. Flisiak, R. Frankova, S. Gamkrelidze, I. Gane, E. Garcia-Samaniego, J. Khan, A.G. Gountas, I. Goldis, A. Gottfredsson, M. Grebely, J. Gschwantler, M. Guimaraes Pessoa, M. Gunter, J. Hajarizadeh, B. Hajelssedig, O. Hamid, S. Hamoudi, W. Hatzakis, A. Himatt, S.M. Hofer, H. Hrstic, I. Hui, Y.-T. Hunyady, B. Idilman, R. Jafri, W. Jahis, R. Janjua, N.Z. Jarčuška, P. Jeruma, A. Jonasson, J.G. Kamel, Y. Kao, J.-H. Kaymakoglu, S. Kershenobich, D. Khamis, J. Kim, Y.S. Kondili, L. Koutoubi, Z. Krajden, M. Krarup, H. Lai, M.-S. Laleman, W. Lao, W.-C. Lavanchy, D. Lazaro, P. Leleu, H. Lesi, O. Lesmana, L.A. Li, M. Liakina, V. Lim, Y.-S. Luksic, B. Mahomed, A. Maimets, M. Makara, M. Malu, A.O. Marinho, R.T. Marotta, P. Mauss, S. Memon, M.S. Mendes Correa, M.C. Mendez-Sanchez, N. Merat, S. Metwally, A.M. Mohamed, R. Moreno, C. Mourad, F.H. Mullhaupt, B. Murphy, K. Nde, H. Njouom, R. Nonkovic, D. Norris, S. Obekpa, S. Oguche, S. Olafsson, S. Oltman, M. Omede, O. Omuemu, C. Opare-Sem, O. Ovrehus, A.L.H. Owusu-Ofori, S. Oyunsuren, T.S. Papatheodoridis, G. Pasini, K. Peltekian, K.M. Phillips, R.O. Pimenov, N. Poustchi, H. Prabdial-Sing, N. Qureshi, H. Ramji, A. Razavi-Shearer, D. Razavi-Shearer, K. Redae, B. Reesink, H.W. Ridruejo, E. Robbins, S. Roberts, L.R. Roberts, S.K. Rosenberg, W.M. Roudot-Thoraval, F. Ryder, S.D. Safadi, R. Sagalova, O. Salupere, R. Sanai, F.M. Sanchez Avila, J.F. Saraswat, V. Sarmento-Castro, R. Sarrazin, C. Schmelzer, J.D. Schreter, I. Seguin-Devaux, C. Shah, S.R. Sharara, A.I. Sharma, M. Shevaldin, A. Shiha, G.E. Sievert, W. Sonderup, M. Souliotis, K. Speiciene, D. Sperl, J. Starkel, P. Stauber, R.E. Stedman, C. Struck, D. Su, T.-H. Sypsa, V. Tan, S.-S. Tanaka, J. Thompson, A.J. Tolmane, I. Tomasiewicz, K. Valantinas, J. Van Damme, P. Van Der Meer, A.J. Van Thiel, I. Van Vlierberghe, H. Vince, A. Vogel, W. Wedemeyer, H. Weis, N. Wong, V.W.S. Yaghi, C. Yosry, A. Yuen, M.-F. Yunihastuti, E. Yusuf, A. Zuckerman, E. Razavi, H. The Polaris Observatory HCV Collaborators

Abstract

Background The 69th World Health Assembly approved the Global Health Sector Strategy to eliminate hepatitis C virus (HCV) infection by 2030, which can become a reality with the recent launch of direct acting antiviral therapies. Reliable disease burden estimates are required for national strategies. This analysis estimates the global prevalence of viraemic HCV at the end of 2015, an update of—and expansion on—the 2014 analysis, which reported 80 million (95% CI 64–103) viraemic infections in 2013. Methods We developed country-level disease burden models following a systematic review of HCV prevalence (number of studies, n=6754) and genotype (n=11 342) studies published after 2013. A Delphi process was used to gain country expert consensus and validate inputs. Published estimates alone were used for countries where expert panel meetings could not be scheduled. Global prevalence was estimated using regional averages for countries without data. Findings Models were built for 100 countries, 59 of which were approved by country experts, with the remaining 41 estimated using published data alone. The remaining countries had insufficient data to create a model. The global prevalence of viraemic HCV is estimated to be 1·0% (95% uncertainty interval 0·8–1·1) in 2015, corresponding to 71·1 million (62·5–79·4) viraemic infections. Genotypes 1 and 3 were the most common cause of infections (44% and 25%, respectively). Interpretation The global estimate of viraemic infections is lower than previous estimates, largely due to more recent (lower) prevalence estimates in Africa. Additionally, increased mortality due to liver-related causes and an ageing population may have contributed to a reduction in infections. Funding John C Martin Foundation. © 2017 Elsevier Ltd

Published
2017

6. The present and future disease burden of hepatitis C virus infections with today's treatment paradigm

Author

Chan, H. L. Y., Chen, C. J., Omede, O., Al Qamish, J., Al Naamani, K., Bane, A., Tan, S. S., Simonova, M., Cardenas, I., Derbala, M., Akin, O., Phillips, R. O., Abdelmageed, M. K., Abdulla, M., Adda, D., Al Baqali, A., Al Dweik, N., Al Ejji, K., Al ghazzawi, I., Al Kaabi, S., Al Sadadi, M., Al Salman, J., AlBadri, M., Al-Busafi, S. A., Al-Romaihi, H. E., Ampofo, W., Antonov, K., Anyaike, C., Arome, F., Blach, S., Borodo, M. M., Brandon, S. M., Bright, B., Butt, M. T., Chen, D. S., Chen, P. J., Chien, R. N., Chuang, W. L., Cuellar, D., Elbardiny, A. A., Estes, C., Farag, E., Fung, J., Gamkrelidze, I., Garcia, V., Genov, J., Ghandour, Z., Ghuloom, M., Gomez, B., Gunter, J., Habeeb, J., Hajelssedig, O., Hamoudi, W., Himatt, S. M., Hrstic, I., Hu, C. C., Huang, C. F., Hui, Y. T., Jahis, R., Jelev, D., John, A. K., Kaliaskarova, K. S., Kamel, Y., Kao, J. H., Khamis, J., Khattabi, H., Khoudri, I., Konysbekova, A., Kotzev, I., Lai, M. S., Lao, W. C., Layden, J., Lee, M. H., Lesi, O., Li, M., Lo, A., Loo, C. K., Lukšić, B., Maaroufi, A., Malu, A. O., Mateva, L., Mitova, R., Mohamed, R., Morović, M., Murphy, K., Mustapha, B., Nersesov, A., Ngige, E., Njouom, R., Njoya, O., Nonković, D., Obekpa, S., Oguche, S., Okolo, E. E., Omuemu, C., Ondoa, P., Opare- Sem, O., Owusu-Ofori, S., Prokopenko, Y. N., Razavi, H., Razavi-Shearer, D., Razavi-Shearer, K., Redae, B., Reic, T., Rinke de Wit, T., Rios, C., Robbins, S., Roberts, L. R., Sanad, S. J., Schmelzer, J. D., Sharma, M., Su, T. H., Sultan, K., Tchernev, K., Tsang, O. T. Y., Tsang, S., Tzeuton, C., Ugoeze, S., Uzochukwu, B., Vi, R., Vince, A., Wani, H. U., Wong, V. W. S., Workneh, A., Yacoub, R., Yesmembetov, K. I., Youbi, M., Yuen, M. F., and Nde, H.

Subjects
parasitic diseases, hepatitis C, incidence, mortality, prevalence, treatment, geographic locations
Abstract

Factors influencing the morbidity and mortality associated with viremic hepatitis C virus (HCV) infection change over time and place, making it difficult to compare reported estimates. Models were developed for 17 countries (Bahrain, Bulgaria, Cameroon, Colombia, Croatia, Dominican Republic, Ethiopia, Ghana, Hong Kong, Jordan, Kazakhstan, Malaysia, Morocco, Nigeria, Qatar and Taiwan) to quantify and characterize the viremic population as well as forecast the changes in the infected population and the corresponding disease burden from 2015 to 2030. Model inputs were agreed upon through expert consensus, and a standardized methodology was followed to allow for comparison across countries. The viremic prevalence is expected to remain constant or decline in all but four countries (Ethiopia, Ghana, Jordan and Oman) ; however, HCV-related morbidity and mortality will increase in all countries except Qatar and Taiwan. In Qatar, the high-treatment rate will contribute to a reduction in total cases and HCV- related morbidity by 2030. In the remaining countries, however, the current treatment paradigm will be insufficient to achieve large reductions in HCV- related morbidity and mortality.

Published
2017

7. Strategies to manage hepatitis C virus infection disease burden

Author

Chen, D. S., Hamoudi, W., Mustapha, B., Layden, J., Nersesov, A., Reic, T., Garcia, V., Rios, C., Mateva, L., Njoya, O., Al-Busafi, S. A., Abdelmageed, M. K., Abdulla, M., Adda, D., Akin, O., Al Baqali, A., Al Dweik, N., Al Ejji, K., Al ghazzawi, I., Al Kaabi, S., Al Naamani, K., Al Qamish, J., Al Sadadi, M., Al Salman, J., AlBadri, M., Al-Romaihi, H. E., Ampofo, W., Antonov, K., Anyaike, C., Arome, F., Bane, A., Blach, S., Borodo, M. M., Brandon, S. M., Bright, B., Butt, M. T., Cardenas, I., Chan, H. L. Y., Chen, C. J., Chen, P. J., Chien, R. N., Chuang, W. L., Cuellar, D., Derbala, M., Elbardiny, A. A., Estes, C., Farag, E., Fung, J., Gamkrelidze, I., Genov, J., Ghandour, Z., Ghuloom, M., Gomez, B., Gunter, J., Habeeb, J., Hajelssedig, O., Himatt, S. M., Hrstic, I., Hu, C. C., Huang, C. F., Hui, Y. T., Jahis, R., Jelev, D., John, A. K., Kaliaskarova, K. S., Kamel, Y., Kao, J. H., Khamis, J., Khattabi, H., Khoudri, I., Konysbekova, A., Kotzev, I., Lai, M. S., Lao, W. C., Lee, M. H., Lesi, O., Li, M., Lo, A., Loo, C. K., Lukšić, B., Maaroufi, A., Malu, A. O., Mitova, R., Mohamed, R., Morović, M., Murphy, K., Nde, H., Ngige, E., Njouom, R., Nonković, D., Obekpa, S., Oguche, S., Okolo, E. E., Omede, O., Omuemu, C., Ondoa, P., Opare-Sem, O., Owusu-Ofori, S., Phillips, R. O., Prokopenko, Y. N., Razavi, H., Razavi-Shearer, D., Razavi-Shearer, K., Redae, B., Rinke de Wit, T., Robbins, S., Roberts, L. R., Sanad, S. J., Sharma, M., Simonova, M., Su, T. H., Sultan, K., Tan, S. S., Tchernev, K., Tsang, O. T. Y., Tsang, S., Tzeuton, C., Ugoeze, S., Uzochukwu, B., Vi, R., Vince, A., Wani, H. U., Wong, V. W. S., Workneh, A., Yacoub, R., Yesmembetov, K. I., Youbi, M., Yuen, M. F., and Schmelzer, J. D.

Subjects
diagnosis, disease burden, elimination, epidemiology, hepatitis C, scenarios, strategy
Abstract

The hepatitis C virus (HCV) epidemic was forecasted through 2030 for 17 countries in Africa, Asia, Europe, Latin America and the Middle East, and interventions for achieving the Global Health Sector Strategy on viral hepatitis targets —“WHO Targets” (65% reduction in HCV-related deaths, 90% reduction in new infections and 90% of infections diagnosed by 2030) were considered. Scaling up treatment and diagnosis rates over time would be required to achieve these targets in all but one country, even with the introduction of high SVR therapies. The scenarios developed to achieve the WHO Targets in all countries studied assumed the implementation of national policies to prevent new infections and to diagnose current infections through screening.

Published
2017

8. Novel small molecules disrupting Hec1/Nek2 interaction ablate tumor progression by triggering Nek2 degradation through a death-trap mechanism

Author

Hu, C-M, Zhu, J, Guo, XE, Chen, W, Qiu, X-L, Ngo, B, Chien, R, Wang, YV, Tsai, CY, Wu, G, Kim, Y, Lopez, R, Chamberlin, AR, Lee, EY-HP, and Lee, W-H

Subjects
Indoles, Oncology and Carcinogenesis, Clinical Sciences, Molecular Conformation, Mitosis, Gene Expression, Cell Line, Inhibitory Concentration 50, Models, Neoplasms, Breast Cancer, Valerates, Animals, Humans, NIMA-Related Kinases, Oncology & Carcinogenesis, Phosphorylation, Cancer, Tumor, Binding Sites, Animal, Nuclear Proteins, Molecular, Protein-Serine-Threonine Kinases, Prognosis, Thiazoles, Cytoskeletal Proteins, 5.1 Pharmaceuticals, Disease Models, Benzamides, Proteolysis, Disease Progression, Heterografts, Protein Binding
Abstract

© 2015 Macmillan Publishers Limited. All rights reserved. Hec1 (highly expressed in cancer 1) or Nek2 (NIMA-related kinase 2) is often overexpressed in cancers with poor prognosis. Both are critical mitotic regulators, and phosphorylation of Hec1 S165 by Nek2 is required for proper chromosome segregation. Therefore, inactivation of Hec1 and Nek2 by targeting their interaction with small molecules represents an ideal strategy for tackling these types of cancers. Here we showed that new derivatives of INH (inhibitor for Nek2 and Hec1 binding) bind to Hec1 at amino acids 394-408 on W395, L399 and K400 residues, effectively blocking Hec1 phosphorylation on S165 by Nek2, and killing cancer cells at the nanomolar range. Mechanistically, the D-box (destruction-box) region of Nek2 specifically binds to Hec1 at amino acids 408-422, immediately adjacent to the INH binding motif. Subsequent binding of Nek2 to INH-bound Hec1 triggered proteasome-mediated Nek2 degradation, whereas the Hec1 binding defective Nek2 mutant, Nek2 R361L, resisted INH-induced Nek2 degradation. This finding unveils a novel drug-action mechanism where the binding of INHs to Hec1 forms a virtual death-trap to trigger Nek2 degradation and eventually cell death. Furthermore, analysis of the gene expression profiles of breast cancer patient samples revealed that co-elevated expressions of Hec1 and Nek2 correlated with the shortest survival. Treatment of mice with this kind of tumor with INHs significantly suppressed tumor growth without obvious toxicity. Taken together, the new INH derivatives are suitable for translation into clinical application.

Published
2015
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9. Response

Author

Gradishar Wj, Chien R, Gutierrez Hr, Yu Tm, Hornberger J, and Alvarado

Subjects
Cancer Research, Oncology, business.industry, Medicine, business
Published
2012
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10. Signaling mechanisms for the activation of an embryonic gene program during the hypertrophy of cardiac ventricular muscle

Author

Chien R

Subjects
Regulation of gene expression, Expression vector, Transgene, Transfection, Biology, medicine.disease, Cell biology, Muscle hypertrophy, Ventricular hypertrophy, embryonic structures, Gene expression, otorhinolaryngologic diseases, cardiovascular system, medicine, Signal transduction, hormones, hormone substitutes, and hormone antagonists
Abstract

To study the signaling mechanisms which mediate ventricular hypertrophy, we utilized the induction of the ANF gene as a marker of the hypertrophic response. The induction of the atrial natriuretic factor gene (ANF) is one of the most conserved features of ventricular hypertrophy, occurring in multiple species (mouse, rat, hamster, canine, and human) in response to diverse stimuli (hormonal, mechanical, pressure/volume overload, genetic, IHSS, hypertension, etc.). The ANF gene is expressed in both the atrial and ventricular compartments during embryonic development, but shortly after birth ANF expression is down-regulated to negligible levels in the adult myocardium. Since the reactivation of ANF gene expression in the hypertrophied ventricle is a hallmark of the activation of an embryonic gene program, it has also become of interest to determine if similar mechanisms activate ANF expression during hypertrophy and the initial stages of cardiogenesis. A combination of co-transfection, microinjection, and transgenic approaches has been coupled to well characterized cultured cell systems and in vivo murine models employing normal and transgenic mice. The microinjection of oncogenic RAS proteins into living myocardial cells does not lead to the activation of cell proliferation, but activates ANF gene expression, as assessed by immunofluorescence. Co-transfection of mutant and wild-type RAS expression vectors with a ANF-luciferase fusion gene supports a direct effect of activated RAS on ANF gene transcription. Co-transfection of a dominant negative RAS vector effectively inhibits the induction of the ANF gene during α adrenergic mediated hypertrophy of ventricular muscle cells, thereby establishing that a RAS-mediated pathway is required for ANF induction. Studies in transgenic mice have suggested that the cis sequences within the ANF gene which control atrial specificity and inducibility during in vivo hypertrophy can be segregated. Transient assays in cultured ventricular cells transfected with a series of ANF-luciferase fusion genes have identified a 638 bp fragment of the ANF promoter which can confer inducibility during α adrenergic agonist and endothelin-1-mediated hypertrophy of cultured neonatal rat ventricular cells. Recent studies have systematically mutated the Egr-1; CRE; AP-1; AP-2; and A-T-rich sites within a 323 bp ANF gene fragment that mediates inducibility, to identify the cis regulatory elements and their correspondng factors that control ANF expression during myocardial cell hypertrophy. These and related studies will be discussed in the context of elucidating the molecular signals which control ANF gene expression during this important adaptive response of the myocardium.

Published
1992
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11. Global prevalence and genotype distribution of hepatitis C virus infection in 2015:a modelling study

Author

Hans Van Vlierberghe, Soo Aleman, Naveed Z. Janjua, Henry Lik-Yuen Chan, Olufunmilayo A. Lesi, Irena Hrstić, Abdullah M. Assiri, William Rosenberg, Moon sing Lai, Vladimir Chulanov, Jan Sperl, Beat Müllhaupt, Michael Manns, William Sievert, Sabahattin Kaymakoglu, Cesar Yaghi, Evy Yunihastuti, Pierre Van Damme, Jon G. Jonasson, Antonio Javier Blasco, Young Sik Kim, S. Olafsson, Rohani Jahis, Christoph Sarrazin, Manik Sharma, Aasim Yusuf, Omer Hajelssedig, Javier García-Samaniego, Boris Lukšić, Peter Stärkel, Stefan Zeuzem, Stephen Oguche, E. A. Croes, Abdullah S. Alghamdi, Richard Njouom, CE Omuemu, Carlos E Brandão Mello, Adam Mahomed, Behzad Hajarizadeh, Ogu Omede, Said A. Al-Busafi, Sarah Robbins, Peer Brehm Christensen, Ammal M. Metwally, Béla Hunyady, Gamal Esmat, Ivane Gamkrelidze, Maheeba Abdulla, Suzanne Norris, Sarah Blach, Harald Hofer, Maria C Mendes Correa, Devin Razavi-Shearer, Matti Maimets, Chien-Jen Chen, Peter Jarcuska, Marian Oltman, Francesco Negro, Ilias Gountas, Ayman Yosry, Sona Frankova, Adrian Goldis, Laurentius A. Lesmana, Ivan Schréter, Danute Speiciene, Kevork M. Peltekian, Berhane Redae, Stuart K. Roberts, Valentina Liakina, Seyed M Alavian, Wai-cheung C Lao, Ziv Ben-Ari, Imad Al Ghazzawi, Cheryl Brunton, Rudolf E. Stauber, Akram Khan, Tung-Hung Su, Manal H El-Sayed, Kimberly Murphy, Kyriakos Souliotis, Adriana Vince, Ramazan Idilman, Christophe Moreno, Angelos Hatzakis, Lewis R. Roberts, Richard Phillips, Jason Grebely, Michael Gschwantler, Hugo Cheinquer, Vana Sypsa, Samir Shah, Wolfgang Vogel, M. Blachier, Abate Bane, Henri Leleu, Saeed Hamid, Ohene Opare-Sem, Hamad Al-Romaihi, Wan-Long Chuang, Alexander J. Thompson, Agita Jeruma, Robert Flisiak, Catherine A.M. Stedman, Ingo van Thiel, Carole Seguin-Devaux, Jonathan Schmelzer, Juan F.Sanchez Avila, Rui Tato Marinho, Muhammad S. Memon, Nina Weis, Rosmawati Mohamed, Florian Bihl, Moon Seok Choi, David Kershenobich, Vic Arendt, Yee Tak Hui, Mei Hsuan Lee, N. N. Pimenov, Saad Al Kaabi, Ken Pasini, Henrik Krarup, Stefan Mauss, Shahin Merat, Khalid Al Namaani, Rong-Nan Chien, Perttu Arkkila, Henk W. Reesink, Françoise Roudot-Thoraval, Paul Marotta, Shirley Owusu-Ofori, Fadi H. Mourad, Abdul Rahman Bizri, Chris Estes, Heiner Wedemeyer, Faisal M. Sanai, Mihály Makara, Stephen D. Ryder, Mel Krajden, Laura Cisneros, Adriaan J. van der Meer, Eli Zuckerman, Matthew E. Cramp, Rui Sarmento-Castro, Magnus Gottfredsson, Gregory J. Dore, Huma Qureshi, Yasser Kamel, Olga Sagalova, Rifaat Safadi, Wim Laleman, Solomon Obekpa, Karolin Falconer, Edward Gane, Philip Bruggmann, Fernando Bessone, Jia-Horng Kao, Daniel Lavanchy, Riina Salupere, Anne Øvrehus, Ulus Salih Akarca, Monique Andersson, Man-Fung Yuen, Ala I. Sharara, Olav Dalgard, Homie Razavi, Gamal Shiha, Paulo R. Ferreira, George V. Papatheodoridis, Anatoly Shevaldin, Jawad Khamis, Waseem Hamoudi, Kathryn Razavi-Shearer, Vincent Ws Wong, Loreta A. Kondili, Maria Lucia Gomes Ferraz, Wasim Jafri, Pablo Lázaro, Faisal Abaalkhail, David H. Muljono, Youssif Al Serkal, Imam Waked, Zaher Koutoubi, Oidov Baatarkhuu, Nahum Méndez-Sánchez, Abraham O. Malu, Daniel Struck, Helen Nde, Alnoor Ramji, Ahmed Abdou, Antoine Abou Rached, Michael Li, Diana Nonković, Jorge Daruich, Ezequiel Ridruejo, Gül Ergör, Ann-Sofi Duberg, Krzysztof Tomasiewicz, Filipe Calinas, Hossein Poustchi, Layla Al-Dabal, Jessie Gunter, Mark W. Sonderup, Colm Bergin, Mario G. Pessoa, Jonas Valantinas, Asad Chaudhry, Junko Tanaka, Tsendsuren S. Oyunsuren, Soek Siam Tan, Vivek A. Saraswat, Young-Suk Lim, Ibrahim Altraif, Victor de Ledinghen, Faryal Al Lawati, Mette Rye Clausen, Ieva Tolmane, Antonio Craxì, Abdulrahman Aljumah, Elmoubashar Farag, Inka Aho, Sayed Himatt, Nishi Prabdial-Sing, Blach S., Zeuzem S., Manns M., Altraif I., Duberg A.-S., Muljono D.H., Waked I., Alavian S.M., Lee M.-H., Negro F., Abaalkhail F., Abdou A., Abdulla M., Abou Rached A., Aho I., Akarca U., Al Ghazzawi I., Al Kaabi S., Al Lawati F., Al Namaani K., Al Serkal Y., Al-Busafi S.A., Al-Dabal L., Aleman S., Alghamdi A.S., Aljumah A.A., Al-Romaihi H.E., Andersson M.I., Arendt V., Arkkila P., Assiri A.M., Baatarkhuu O., Bane A., Ben-Ari Z., Bergin C., Bessone F., Bihl F., Bizri A.R., Blachier M., Blasco A.J., Brandao Mello C.E., Bruggmann P., Brunton C.R., Calinas F., Chan H.L.Y., Chaudhry A., Cheinquer H., Chen C.-J., Chien R.-N., Choi M.S., Christensen P.B., Chuang W.-L., Chulanov V., Cisneros L., Clausen M.R., Cramp M.E., Craxi A., Croes E.A., Dalgard O., Daruich J.R., De Ledinghen V., Dore G.J., El-Sayed M.H., Ergor G., Esmat G., Estes C., Falconer K., Farag E., Ferraz M.L.G., Ferreira P.R., Flisiak R., Frankova S., Gamkrelidze I., Gane E., Garcia-Samaniego J., Khan A.G., Gountas I., Goldis A., Gottfredsson M., Grebely J., Gschwantler M., Guimaraes Pessoa M., Gunter J., Hajarizadeh B., Hajelssedig O., Hamid S., Hamoudi W., Hatzakis A., Himatt S.M., Hofer H., Hrstic I., Hui Y.-T., Hunyady B., Idilman R., Jafri W., Jahis R., Janjua N.Z., Jarcuska P., Jeruma A., Jonasson J.G., Kamel Y., Kao J.-H., Kaymakoglu S., Kershenobich D., Khamis J., Kim Y.S., Kondili L., Koutoubi Z., Krajden M., Krarup H., Lai M.-S., Laleman W., Lao W.-C., Lavanchy D., Lazaro P., Leleu H., Lesi O., Lesmana L.A., Li M., Liakina V., Lim Y.-S., Luksic B., Mahomed A., Maimets M., Makara M., Malu A.O., Marinho R.T., Marotta P., Mauss S., Memon M.S., Mendes Correa M.C., Mendez-Sanchez N., Merat S., Metwally A.M., Mohamed R., Moreno C., Mourad F.H., Mullhaupt B., Murphy K., Nde H., Njouom R., Nonkovic D., Norris S., Obekpa S., Oguche S., Olafsson S., Oltman M., Omede O., Omuemu C., Opare-Sem O., Ovrehus A.L.H., Owusu-Ofori S., Oyunsuren T.S., Papatheodoridis G., Pasini K., Peltekian K.M., Phillips R.O., Pimenov N., Poustchi H., Prabdial-Sing N., Qureshi H., Ramji A., Razavi-Shearer D., Razavi-Shearer K., Redae B., Reesink H.W., Ridruejo E., Robbins S., Roberts L.R., Roberts S.K., Rosenberg W.M., Roudot-Thoraval F., Ryder S.D., Safadi R., Sagalova O., Salupere R., Sanai F.M., Sanchez Avila J.F., Saraswat V., Sarmento-Castro R., Sarrazin C., Schmelzer J.D., Schreter I., Seguin-Devaux C., Shah S.R., Sharara A.I., Sharma M., Shevaldin A., Shiha G.E., Sievert W., Sonderup M., Souliotis K., Speiciene D., Sperl J., Starkel P., Stauber R.E., Stedman C., Struck D., Su T.-H., Sypsa V., Tan S.-S., Tanaka J., Thompson A.J., Tolmane I., Tomasiewicz K., Valantinas J., Van Damme P., Van Der Meer A.J., Van Thiel I., Van Vlierberghe H., Vince A., Vogel W., Wedemeyer H., Weis N., Wong V.W.S., Yaghi C., Yosry A., Yuen M.-F., Yunihastuti E., Yusuf A., Zuckerman E., Razavi H., Polaris Observ HCV Collaborators, Negro, Francesco, and Ege Üniversitesi

Subjects
Viremia/epidemiology, Population ageing, medicine.medical_specialty, CIENCIAS MÉDICAS Y DE LA SALUD, Delphi Technique, Genotype, Voxilaprevir, Genotype, Global Health, Hepatitis C, Eradication, Modelling study, Medicina Clínica, ddc:616.07, Global Health, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Cost of Illness, Epidemiology, Journal Article, medicine, Global health, Prevalence, Humans, Viremia, 030212 general & internal medicine, Disease Eradication, Disease burden, ddc:616, Hepatology, Hepatitis C, Chronic/epidemiology, business.industry, Gastroenterology, Hepatitis C, Glecaprevir, Hepatitis C, Chronic, medicine.disease, Viremia/epidemiology/genetics, Pibrentasvir, Global Health/statistics & numerical data, HCV, HEPATITIS C, 030211 gastroenterology & hepatology, Medicina Critica y de Emergencia, Human medicine, business, Chronic/epidemiology/genetics/prevention & control, Demography
Abstract

WOS: 000426979400014, PubMed ID: 28404132, Background The 69th World Health Assembly approved the Global Health Sector Strategy to eliminate hepatitis C virus (HCV) infection by 2030, which can become a reality with the recent launch of direct acting antiviral therapies. Reliable disease burden estimates are required for national strategies. This analysis estimates the global prevalence of viraemic HCV at the end of 2015, an update of-and expansion on-the 2014 analysis, which reported 80 million (95% CI 64-103) viraemic infections in 2013. Methods We developed country-level disease burden models following a systematic review of HCV prevalence (number of studies, n=6754) and genotype (n=11 342) studies published after 2013. A Delphi process was used to gain country expert consensus and validate inputs. Published estimates alone were used for countries where expert panel meetings could not be scheduled. Global prevalence was estimated using regional averages for countries without data. Findings Models were built for 100 countries, 59 of which were approved by country experts, with the remaining 41 estimated using published data alone. The remaining countries had insufficient data to create a model. The global prevalence of viraemic HCV is estimated to be 1.0% (95% uncertainty interval 0.8-1.1) in 2015, corresponding to 71.1 million (62.5-79.4) viraemic infections. Genotypes 1 and 3 were the most common cause of infections (44% and 25%, respectively). Interpretation The global estimate of viraemic infections is lower than previous estimates, largely due to more recent (lower) prevalence estimates in Africa. Additionally, increased mortality due to liver-related causes and an ageing population may have contributed to a reduction in infections., John C Martin Foundation, John C Martin Foundation.

Published
2017
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