Umbria is located in Central Italy and took the name from its ancient inhabitants, the Umbri, whose origins are still debated. Here, we investigated the mitochondrial DNA (mtDNA) variation of 545 present-day Umbrians (with 198 entire mitogenomes) and 28 pre-Roman individuals (obtaining 19 ancient mtDNAs) excavated from the necropolis of Plestia. We found a rather homogeneous distribution of western Eurasian lineages across the region, with few notable exceptions. Contemporary inhabitants of the eastern part, delimited by the Tiber River and the Apennine Mountains, manifest a peculiar mitochondrial proximity to central-eastern Europeans, mainly due to haplogroups U4 and U5a, and an overrepresentation of J (30%) similar to the pre-Roman remains, also excavated in East Umbria. Local genetic continuities are further attested to by six terminal branches (H1e1, J1c3, J2b1, U2e2a, U8b1b1 and K1a4a) shared between ancient and modern mitogenomes. Eventually, we identified multiple inputs from various population sources that likely shaped the mitochondrial gene pool of ancient Umbri over time, since early Neolithic, including gene flows with central-eastern Europe. This diachronic mtDNA portrait of Umbria fits well with the genome-wide population structure identified on the entire peninsula and with historical sources that list the Umbri among the most ancient Italic populations. Due to its acknowledged potential, archaeogenetics is broadly applied to study ancient civilizations, demographic histories and migration events. Markedly, advances in high-throughput genotyping technology have highlighted how the present-day genetic variation of human populations is the outcome of past population movements. In prehistoric times, the Mediterranean area experienced three significant migration waves whose legacy is retrieved in the mitochondrial pool of modern and ancient populations: the Paleolithic hunter-gatherers who survived and re-expanded from glacial refuges, the Neolithic farming societies that moved from the East, and the herders from the Pontic-Caspian steppes inaugurating the Bronze Age 1-13 .
Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), a cell surface receptor, is expressed on normal epithelial tissue and highly expressed in cancers of high unmet medical need, such as non-small cell lung, pancreatic, and colorectal cancer. CEACAM receptors undergo homo- and heterophilic interactions thereby regulating normal tissue homeostasis and angiogenesis, and in cancer, tumor invasion and metastasis. CEACAM6 expression on malignant plasma cells inhibits antitumor activity of T cells, and we hypothesize a similar function on epithelial cancer cells. The interactions between CEACAM6 and its suggested partner CEACAM1 on T cells were studied. A humanized CEACAM6-blocking antibody, BAY 1834942, was developed and characterized for its immunomodulating effects in co-culture experiments with T cells and solid cancer cells and in comparison to antibodies targeting the immune checkpoints programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and T cell immunoglobulin mucin-3 (TIM-3). The immunosuppressive activity of CEACAM6 was mediated by binding to CEACAM1 expressed by activated tumor-specific T cells. BAY 1834942 increased cytokine secretion by T cells and T cell-mediated killing of cancer cells. The in vitro efficacy of BAY 1834942 correlated with the degree of CEACAM6 expression on cancer cells, suggesting potential in guiding patient selection. BAY 1834942 was equally or more efficacious compared to blockade of PD-L1, and at least an additive efficacy was observed in combination with anti-PD-1 or anti-TIM-3 antibodies, suggesting an efficacy independent of the PD-1/PD-L1 axis. In summary, CEACAM6 blockade by BAY 1834942 reactivates the antitumor response of T cells. This warrants clinical evaluation.
Background The coronavirus disease 2019 (COVID-19) pandemic has challenged researchers performing clinical trials to develop innovative approaches to mitigate infectious risk while maintaining rigorous safety monitoring. Methods In this report we describe the implementation of a novel exclusively remote randomized clinical trial (ClinicalTrials.gov NCT04354428) of hydroxychloroquine and azithromycin for the treatment of the SARS-CoV-2–mediated COVID-19 disease which included cardiovascular safety monitoring. All study activities were conducted remotely. Self-collected vital signs (temperature, respiratory rate, heart rate, and oxygen saturation) and electrocardiographic (ECG) measurements were transmitted digitally to investigators while mid-nasal swabs for SARS-CoV-2 testing were shipped. ECG collection relied on a consumer device (KardiaMobile 6L, AliveCor Inc.) that recorded and transmitted six-lead ECGs via participants’ internet-enabled devices to a central core laboratory, which measured and reported QTc intervals that were then used to monitor safety. Results Two hundred and thirty-one participants uploaded 3245 ECGs. Mean daily adherence to the ECG protocol was 85.2% and was similar to the survey and mid-nasal swab elements of the study. Adherence rates did not differ by age or sex assigned at birth and were high across all reported race and ethnicities. QTc prolongation meeting criteria for an adverse event occurred in 28 (12.1%) participants, with 2 occurring in the placebo group, 19 in the hydroxychloroquine group, and 7 in the hydroxychloroquine + azithromycin group. Conclusions Our report demonstrates that digital health technologies can be leveraged to conduct rigorous, safe, and entirely remote clinical trials.
This research addresses the problem of optimizing simultaneously the container vessels berthing schedule and quay cranes assignment for each berthed container vessel. A mixed integer linear programming (MILP) mathematical model is developed to achieve the lowest total flow time of the group of anchored vessels waiting for service, considering port resources usage constraints. The research extended to study the efficiency of the use of port resources such as berth length, number of available quay cranes in the port and the maximum allowable quay cranes that can serve a vessel. Experiments were carried out using the developed model to study the effect of number of quay cranes, berth length and the maximum allowable cranes per vessel on vessels total flow time as well as the interaction between these factors in affecting the total flow time. The utilization of berth and quay cranes were studied at the berthing schedule that minimizes the total flow time. It was concluded from the results that increasing the number of quay cranes will not contribute to improving the total vessel flow time unless a sufficient berth that can accommodate more vessels is present. Moreover, a reduced quay crane utilization will occur with increasing the number of quay cranes. Also, increasing the maximum allowable quay cranes for vessels in service contribute to improving vessels total flow time and quay carne utilization.
Background Human papillomavirus (HPV) is the main cause of cervical, anal and oro-pharyngeal cancer worldwide. The HPV vaccine can prevent over 90% of HPV-related malignancies but vaccination rates in the United State (US) vary significantly by region. In this study, we assessed whether state-level politics is associated with receipt of HPV vaccination in the US, and if the association is modified by sex and age. Methods This study analyzed data from the Center for Disease Control and Prevention’s (CDC) Behavioral Risk Factors Surveillance System (BRFSS) survey. Persons ages 18 to 36 years of age, who lived in 17 states that included the supplementary “Adult Human Papillomavirus (HPV)” module questionnaire in 2016, 2017 or 2018, were included. We compared self-reported receipt of HPV vaccination among persons living in Republican versus Democratic states, based on state electoral college votes in the 2016 US presidential election. Mantel-Haenszel stratified analysis was used to estimate prevalence ratios and to assess for effect modification and control for confounding. Results Overall, 36,334 survey respondents were included in the analysis, 22.7% of whom reported prior receipt of the HPV vaccine, 28.1% in Democratic states and 20.4% in Republican states. When adjusted for race, living in a Democratic state was associated with a higher prevalence of prior receipt of the HPV vaccine in comparison to living in a Republican state. This association was strongest for men less than 26 years of age (PR 1.77, 95% CI: 1.58, 1.98) but remained significant for men ages 26 – 36 years (PR 1.51, 95% CI: 1.24, 1.85), women less than 26 years of age (PR 1.20, 95% CI: 1.13, 1.27), and women ages 26 – 36 years (PR 1.69, 95% CI: 1.57, 1.83). Conclusion Overall HPV vaccine coverage was low in adults 18–36 years of age. The strong association between state-level voting patterns and prior receipt of the HPV vaccine suggests that HPV vaccine coverage is lower in Republican states when compared to Democratic states. Further public health efforts are needed to promote HPV vaccine uptake among young men and women, particularly in Republican voting states. Disclosures All Authors: No reported disclosures
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