Conditionally Replicating Adenovirus Expressing TIMP2 Increases Survival in a Mouse Model of Disseminated Ovarian Cancer

Ovarian cancer remains difficult to treat mainly due to presentation of the disease at an advanced stage. Conditionally-replicating adenoviruses (CRAds) are promising anti-cancer agents that selectively kill the tumor cells. The present study evaluated the efficacy of a novel CRAd (Ad5/3-CXCR4-TIMP2) containing the CXCR4 promoter for selective viral replication in cancer cells together with TIMP2 as a therapeutic transgene, targeting the matrix metalloproteases (MMPs) in a murine orthotopic model of disseminated ovarian cancer. An orthotopic model of ovarian cancer was established in athymic nude mice by intraperitonal injection of the human ovarian cancer cell line, SKOV3-Luc, expressing luciferase. Upon confirmation of peritoneal dissemination of the cells by non-invasive imaging, mice were randomly divided into four treatment groups: PBS, Ad-ΔE1-TIMP2, Ad5/3-CXCR4, and Ad5/3-CXCR4-TIMP2. All mice were imaged weekly to monitor tumor growth and were sacrificed upon reaching any of the predefined endpoints, including high tumor burden and significant weight loss along with clinical evidence of pain and distress. Survival analysis was performed using the Log-rank test. The median survival for the PBS cohort was 33 days; for Ad-ΔE1-TIMP2, 39 days; for Ad5/3-CXCR4, 52.5 days; and for Ad5/3-CXCR4-TIMP2, 63 days. The TIMP2-armed CRAd delayed tumor growth and significantly increased survival when compared to the unarmed CRAd. This therapeutic effect was confirmed to be mediated through inhibition of MMP9. Results of the in vivo study support the translational potential of Ad5/3-CXCR4-TIMP2 for treatment of human patients with advanced ovarian cancer

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance.

Investment in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing in Africa over the past year has led to a major increase in the number of sequences that have been generated and used to track the pandemic on the continent, a number that now exceeds 100,000 genomes. Our results show an increase in the number of African countries that are able to sequence domestically and highlight that local sequencing enables faster turnaround times and more-regular routine surveillance. Despite limitations of low testing proportions, findings from this genomic surveillance study underscore the heterogeneous nature of the pandemic and illuminate the distinct dispersal dynamics of variants of concern-particularly Alpha, Beta, Delta, and Omicron-on the continent. Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve while the continent faces many emerging and reemerging infectious disease threats. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Static Shear Strength of a Non-Prismatic Beam with Transverse Openings

In this study, a predicated formula is been proposed to find the shear strength of non-prismatic beams with or without openings. It depends on the contributions of concrete shear strength considering the beam depth variation and existing openings, shear steel reinforcements and defines the critical shear section, the effect of diagonal shear reinforcement, the effect of inclined tensile steel reinforcement, and the compression chord influence. The verification of the proposed formula has been conducted on the experimental test results of 26 non-prismatic beams with or without openings at the same loading conditions. The results reflect that the predicted formula finds the shear capacity of non-prismatic beams with openings, it is conservative and can be used for designing without the strength reduction factor.</jats:p

Distribution of Hemoglobinopathies and Thalassemias in Qatari Nationals Seen at Hamad Hospital in Qatar

Several reports indicate that haemoglobinopathies and thalassemias are the most common genetic abnormalities in the population of the Arabian- Peninsula. However the exact frequencies of these abnormalities among the Qatari population has not yet been determined. We surveyed the results of all hemoglobin-electrophoresis performed in Hematology laboratory at Hamad Hospital over a period of 78 months (Jan.1994- June.2000) together with the results of all other relevant tests to highlight the distribution of these disorders among the Qatari patients seen at Hamad Hospital. The size of the group analyzed was 3275 of whom 1702 were Qatari and 1573 were non-Qatari residents of different nationalities. The survey of Qatari results revealed that 30.43% of all Qatari patients tested carry fi-thalassemia (minor, intermedia or major), 12.28% carry oc-thalassemia (minor or intermedia) while 0.53% were labeled as having Hereditary Persistence of Fetal Hemoglobin (HPFH). fithalassemia is the most common type of thalassemic disorders seen in the Qatari patients, accounting for 71.25% of all thalassemias encountered in this group. Out of Qatari patients tested 16.33% were found to carry a structurally abnormal hemoglobin variant of one type or another. Sickle cell hemoglobin (Hb-s) is the most common structural hemoglobin variant detected where it is found in 14.63% of those tested and constituting about 83.97% of all structural hemoglobin variants detected. Hb.D was found in 1.41% of those tested and constituted 12.42% of all structural hemoglobin variants detected in this group. Other structurally abnormal hemoglobin variants such as Hb. E and Hb. C were less common. As expected, almost all possible combinations between different types of structural hemoglobin variants and different types of thalassemias could be identified. Considering the fact that the hematology laboratory at Hamad Hospital is the only laboratory in the State of Qatarthat performs hemoglobin- electrophoresis we hope that this study will reflect for the first time a reasonable idea about the prevalence of thalassemia and other types of hemoglobinopathies among the indigenous Qatari population and help to provide a comprehensive baseline information for any proper future epidemiological studies to establish the exact frequencies of these genetic disorders among Qatari nationals and for any future molecularbased studies for elucidation of the molecular basis of these disorders in this population.</jats:p

Ada al-Qur'an di hatiku : rahasia menyatukan hati dengan al-Qur'an

xi, 265 hlm.; 23 c