IDH2 inhibition enhances proteasome inhibitor responsiveness in hematological malignancies

Proteasome inhibitors (PIs) are extensively used for the therapy of multiple myeloma (MM) and mantle-cell lymphoma (MCL). However, patients continuously relapse or are intrinsically resistant to this class of drugs. Here, to identify targets that synergize with PIs, we carried out a functional screening in MM cell lines using a short hairpin RNA library against cancer driver genes. Isocitrate dehydrogenase 2 (IDH2) was identified as a top candidate, showing a synthetic lethal activity with the PI carfilzomib (CFZ). Combinations of FDA approved PIs with a pharmacological IDH2 inhibitor (AGI-6780) triggered synergistic cytotoxicity in MM, MCL, and Burkitt's lymphoma (BL) cell lines. CFZ/AGI-6780 treatment increased death of primary CD138+ cells from MM patients and exhibited a favorable cytotoxicity profile towards peripheral blood mononuclear cells and bone marrow-derived stromal cells. Mechanistically, CFZ/AGI-6780 combination significantly decreased tricarboxylic acid (TCA) cycle activity and ATP levels, as a consequence of enhanced IDH2 enzymatic inhibition. Specifically, CFZ treatment reduced the expression of nicotinamide phosphoribosyltransferase (NAMPT), thus limiting IDH2 activation through the NAD+-dependent deacetylase SIRT3. Consistently, combination of CFZ with either NAMPT or SIRT3 inhibitors impaired IDH2 activity and increased MM cell death. Finally, inducible IDH2 knockdown enhanced the therapeutic efficacy of CFZ in a subcutaneous xenograft model of MM, resulting in inhibition of tumor progression and extended survival. Taken together, these findings indicate that NAMPT/SIRT3/IDH2 pathway inhibition enhances the therapeutic efficacy of PIs, thus providing compelling evidence for treatments with lower and less toxic doses and broadening the application of PIs to other malignancies

Modeling effects of impulse noise on application-layer FEC in DSL channels

Internet Protocol Television (IPTV) services rely on the existing IP network infrastructure to deliver high quality video. In order to achieve reliable services, the nature of the underlying transmission channel has to be taken into account. Erasures on access networks such as present in Digital Subscriber Lines (DSL) have to be overcome. Impulse noise, e.g. Repetitive Electrical Impulse Noise (REIN), is one of the dominant error sources in the signal band of DSL channels and can be characterized as fixed-length error bursts. One countermeasure in IPTV system design to increase the robustness against impulse noise impairments is the implementation of Forward Error Correction on the Application-Layer (AL-FEC). In this paper a mathematical model is derived which describes the effect of the REIN channel on the performance of AL-FEC schemes. The effects on the application layer are modeled by a Markov chain with a memory proportional to the error burst length. Extensive empirical simulation campaigns, in the context of AL-FEC protected IPTV services, are used to prove the correctness of the proposed model and additionally, the runtime behavior of the model is analyzed

Mobile TV with long time interleaving and fast zapping

The main challenge for provisioning of Mobile TV services is to overcome long burst errors as are often found in mobile reception conditions. Long time interleaving can be implemented by means of Application Layer FEC (AL-FEC) to increase the time diversity of the signal and thereby its robustness against burst errors. The main obstacle of long time interleaving for streaming services is the increase in service tune-in time, which significantly decreases the Quality of Experience (QoE) of end users. That is why today's Mobile TV systems are provisioned in a way to minimize the time interleaving length to provide an acceptable tune-in time, though the service robustness would significantly benefit from a longer interleaving length. This paper presents a new way of service provisioning that marries fast zapping and long time interleaving by combining Layer-Aware FEC and layered media codecs with unequal time interleaving and an appropriate transmission scheduling. The effect of the proposed scheme on the QoE as well as the service tune-in time is analyzed. Simulation results within a Gilbert-Elliot channel report the benefit of the proposed scheme, which for the first time enables broadcast services with fast tune-in and at the same time long time interleaving

Tracing and analysis of 288 early SARS-CoV-2 infections outside China: A modeling study

Background In the early months of 2020, a novel coronavirus disease (COVID-19) spread rapidly from China across multiple countries worldwide. As of March 17, 2020, COVID-19 was officially declared a pandemic by the World Health Organization. We collected data on COVID-19 cases outside China during the early phase of the pandemic and used them to predict trends in importations and quantify the proportion of undetected imported cases. Methods and findings Two hundred and eighty-eight cases have been confirmed out of China from January 3 to February 13, 2020. We collected and synthesized all available information on these cases from official sources and media. We analyzed importations that were successfully isolated and those leading to onward transmission. We modeled their number over time, in relation to the origin of travel (Hubei province, other Chinese provinces, other countries) and interventions. We characterized the importation timeline to assess the rapidity of isolation and epidemiologically linked clusters to estimate the rate of detection. We found a rapid exponential growth of importations from Hubei, corresponding to a doubling time of 2.8 days, combined with a slower growth from the other areas. We predicted a rebound of importations from South East Asia in the successive weeks. Time from travel to detection has considerably decreased since first importation, from 14.5 +/- 5.5 days on January 5, 2020, to 6 +/- 3.5 days on February 1, 2020. However, we estimated 36% of detection of imported cases. This study is restricted to the early phase of the pandemic, when China was the only large epicenter and foreign countries had not discovered extensive local transmission yet. Missing information in case history was accounted for through modeling and imputation. Conclusions Our findings indicate that travel bans and containment strategies adopted in China were effective in reducing the exportation growth rate. However, the risk of importation was estimated to increase again from other sources in South East Asia. Surveillance and management of traveling cases represented a priority in the early phase of the epidemic. With the majority of imported cases going undetected (6 out of 10), countries experienced several undetected clusters of chains of local transmissions, fueling silent epidemics in the community. These findings become again critical to prevent second waves, now that countries have reduced their epidemic activity and progressively phase out lockdown.Author summaryWhy was this study done? Originating from China, COVID-19 outbreak has now become a global pandemic, with more than 4 million cases reported across all continents. Underdetection of imported cases from China in the early phase of the epidemic played a crucial role in the spreading of the virus across and within countries. We quantified importations over time in light of the implemented travel ban in China and assessed delay and rate of detection of the first imported cases responsible for seeding the epidemic across multiple countries. What did the researchers do and find? We collected information on all international cases outside China officially confirmed in the period from January 3 to February 13, 2020. We developed a statistical model to predict trends in importations and predicted a rebound effect in importations from South East Asia. By analyzing clusters of local transmission, we estimated the detection rate at 36%. What do these findings mean? Travel bans adopted in China contributed to reducing the growth rate of exportations; however, they did not prevent international seeding. The majority of imported cases went undetected, generating extensive chains of local transmission in countries outside China. This led to silently spreading epidemics in seeded countries

Preparedness and vulnerability of African countries against importations of COVID-19: a modelling study

Background The novel coronavirus disease 2019 (COVID-19) epidemic has spread from China to 25 countries. Local cycles of transmission have already occurred in 12 countries after case importation. In Africa, Egypt has so far confirmed one case. The management and control of COVID-19 importations heavily rely on a country's health capacity. Here we evaluate the preparedness and vulnerability of African countries against their risk of importation of COVID-19.Methods We used data on the volume of air travel departing from airports in the infected provinces in China and directed to Africa to estimate the risk of importation per country. We determined the country's capacity to detect and respond to cases with two indicators: preparedness, using the WHO International Health Regulations Monitoring and Evaluation Framework; and vulnerability, using the Infectious Disease Vulnerability Index. Countries were clustered according to the Chinese regions contributing most to their risk.Findings Countries with the highest importation risk (ie, Egypt, Algeria, and South Africa) have moderate to high capacity to respond to outbreaks. Countries at moderate risk (ie, Nigeria, Ethiopia, Sudan, Angola, Tanzania, Ghana, and Kenya) have variable capacity and high vulnerability. We identified three clusters of countries that share the same exposure to the risk originating from the provinces of Guangdong, Fujian, and the city of Beijing, respectively.Interpretation Many countries in Africa are stepping up their preparedness to detect and cope with COVID-19 importations. Resources, intensified surveillance, and capacity building should be urgently prioritised in countries with moderate risk that might be ill-prepared to detect imported cases and to limit onward transmission. Funding EU Framework Programme for Research and Innovation Horizon 2020, Agence Nationale de la Recherche. Copyright (C) 2020 Elsevier Ltd. All rights reserved

Lancet

Background The novel coronavirus disease 2019 (COVID-19) epidemic has spread from China to 25 countries. Local cycles of transmission have already occurred in 12 countries after case importation. In Africa, Egypt has so far confirmed one case. The management and control of COVID-19 importations heavily rely on a country's health capacity. Here we evaluate the preparedness and vulnerability of African countries against their risk of importation of COVID-19. Methods We used data on the volume of air travel departing from airports in the infected provinces in China and directed to Africa to estimate the risk of importation per country. We determined the country's capacity to detect and respond to cases with two indicators: preparedness, using the WHO International Health Regulations Monitoring and Evaluation Framework; and vulnerability, using the Infectious Disease Vulnerability Index. Countries were clustered according to the Chinese regions contributing most to their risk. Findings Countries with the highest importation risk (ie, Egypt, Algeria, and South Africa) have moderate to high capacity to respond to outbreaks. Countries at moderate risk (ie, Nigeria, Ethiopia, Sudan, Angola, Tanzania, Ghana, and Kenya) have variable capacity and high vulnerability. We identified three clusters of countries that share the same exposure to the risk originating from the provinces of Guangdong, Fujian, and the city of Beijing, respectively. Interpretation Many countries in Africa are stepping up their preparedness to detect and cope with COVID-19 importations. Resources, intensified surveillance, and capacity building should be urgently prioritised in countries with moderate risk that might be ill-prepared to detect imported cases and to limit onward transmission

Recombinant vesicular stomatitis vaccine against Nipah virus has a favorable safety profile: Model for assessment of live vaccines with neurotropic potential.

Nipah virus (NiV) disease is a bat-borne zoonosis responsible for outbreaks with high lethality and is a priority for vaccine development. With funding from the Coalition of Epidemic Preparedness Innovations (CEPI), we are developing a chimeric vaccine (PHV02) composed of recombinant vesicular stomatitis virus (VSV) expressing the envelope glycoproteins of both Ebola virus (EBOV) and NiV. The EBOV glycoprotein (GP) mediates fusion and viral entry and the NiV attachment glycoprotein (G) is a ligand for cell receptors, and stimulates neutralizing antibody, the putative mediator of protection against NiV. PHV02 is identical in construction to the registered Ebola vaccine (Ervebo) with the addition of the NiV G gene. NiV ephrin B2 and B3 receptors are expressed on neural cells and the wild-type NiV is neurotropic and causes encephalitis in affected patients. It was therefore important to assess whether the NiV G alters tropism of the rVSV vector and serves as a virulence factor. PHV02 was fully attenuated in adult hamsters inoculated by the intramuscular (IM) route, whereas parental wild-type VSV was 100% lethal. Two rodent models (mice, hamsters) were infected by the intracerebral (IC) route with graded doses of PHV02. Comparator active controls in various experiments included rVSV-EBOV (representative of Ebola vaccine) and yellow fever (YF) 17DD commercial vaccine. These studies showed PHV02 to be more neurovirulent than both rVSV-EBOV and YF 17DD in infant animals. PHV02 was lethal for adult hamsters inoculated IC but not for adult mice. In contrast YF 17DD retained virulence for adult mice inoculated IC but was not virulent for adult hamsters. Because of the inconsistency of neurovirulence patterns in the rodent models, a monkey neurovirulence test (MNVT) was performed, using YF 17DD as the active comparator because it has a well-established profile of quantifiable microscopic changes in brain centers and a known reporting rate of neurotropic adverse events in humans. In the MNVT PHV02 was significantly less neurovirulent than the YF 17DD vaccine reference control, indicating that the vaccine will have an acceptable safety profile for humans. The findings are important because they illustrate the complexities of phenotypic assessment of novel viral vectors with tissue tropisms determined by transgenic proteins, and because it is unprecedented to use a heterologous comparator virus (YF vaccine) in a regulatory-enabling study. This approach may have value in future studies of other novel viral vectors

Function of GH/IGF-I axis in aging: Multicenter study in 152 healthy elderly subjects with different degrees of physical activity: Italian Association for Research on Brain Aging (AIRIC) Multicenter Study Group

We evaluated somatotropic function in 142 healthy elderly subjects (54 men and 88 women), aged 60-90 years and in 10 non-professional, but regularly training elderly distance runners (7 men and 3 women), aged 60-71 years. In the healthy elderly, basal plasma growth hormone (GH) and insulin-like growth factor-I (IGF-I) median levels were 0.6 \u3bcg/L (25th and 75th centiles = 0.3, 1.3) and 100.5 \u3bcg/L (25th and 75th centiles = 63, 140), respectively. About 53% of the elderly had plasma IGF-I levels within the 3rd-97th centiles of young adult subjects. Basal GH and IGF-I were not correlated with each other nor, with the degree of physical activity, evaluated by a self-administered questionnaire; however, basal GH showed a very weak positive correlation with age while IGF-I showed a highly significant negative correlation. The peak GH response to GHRH (1\u3bc/kg, iv), did not correlate with age, BMI and physical activity in 87/142 subjects investigated, but was highly correlated with basal GH levels. Correlation coefficients of plasma growth hormone binding protein (GHBP) with basal GH levels and peak GH levels following GHRH were r=-029 and r=-0.36, respectively, but statistical significance was not reached. In the 'runners' median values of both basal and GHRH-induced GH peak were higher than those recorded in the healthy elderly, but IGF-I levels were not significantly different and they too declined with age. These data suggest that: 1) plasma IGF-I rather than basal or stimulated GH is a better index for evaluating the effect of aging on the GH/GF system; 2) while usual physical activity in itself does not influence somatotropic function, endurance training is related to higher basal GH levels, but fails to oppose the age- related decline of plasma IGF-I levels

Function of GH/IGF-I axis in aging: Multicenter study in 152 healthy elderly subjects with different degrees of physical activity: Italian Association for Research on Brain Aging (AIRIC) Multicenter Study Group

We evaluated somatotropic function in 142 healthy elderly subjects (54 men and 88 women), aged 60-90 years and in 10 non-professional, but regularly training elderly distance runners (7 men and 3 women), aged 60-71 years. In the healthy elderly, basal plasma growth hormone (GH) and insulin-like growth factor-I (IGF-I) median levels were 0.6 μg/L (25th and 75th centiles = 0.3, 1.3) and 100.5 μg/L (25th and 75th centiles = 63, 140), respectively. About 53% of the elderly had plasma IGF-I levels within the 3rd-97th centiles of young adult subjects. Basal GH and IGF-I were not correlated with each other nor, with the degree of physical activity, evaluated by a self-administered questionnaire; however, basal GH showed a very weak positive correlation with age while IGF-I showed a highly significant negative correlation. The peak GH response to GHRH (1μ/kg, iv), did not correlate with age, BMI and physical activity in 87/142 subjects investigated, but was highly correlated with basal GH levels. Correlation coefficients of plasma growth hormone binding protein (GHBP) with basal GH levels and peak GH levels following GHRH were r=-029 and r=-0.36, respectively, but statistical significance was not reached. In the 'runners' median values of both basal and GHRH-induced GH peak were higher than those recorded in the healthy elderly, but IGF-I levels were not significantly different and they too declined with age. These data suggest that: 1) plasma IGF-I rather than basal or stimulated GH is a better index for evaluating the effect of aging on the GH/GF system; 2) while usual physical activity in itself does not influence somatotropic function, endurance training is related to higher basal GH levels, but fails to oppose the age- related decline of plasma IGF-I levels