Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), has spurred a global health crisis. To date, there are no proven options for ...prophylaxis for those who have been exposed to SARS-CoV-2, nor therapy for those who develop COVID-19. Immune (i.e., "convalescent") plasma refers to plasma that is collected from individuals following resolution of infection and development of antibodies. Passive antibody administration through transfusion of convalescent plasma may offer the only short-term strategy for conferring immediate immunity to susceptible individuals. There are numerous examples in which convalescent plasma has been used successfully as postexposure prophylaxis and/or treatment of infectious diseases, including other outbreaks of coronaviruses (e.g., SARS-1, Middle East respiratory syndrome MERS). Convalescent plasma has also been used in the COVID-19 pandemic; limited data from China suggest clinical benefit, including radiological resolution, reduction in viral loads, and improved survival. Globally, blood centers have robust infrastructure for undertaking collections and constructing inventories of convalescent plasma to meet the growing demand. Nonetheless, there are nuanced challenges, both regulatory and logistical, spanning donor eligibility, donor recruitment, collections, and transfusion itself. Data from rigorously controlled clinical trials of convalescent plasma are also few, underscoring the need to evaluate its use objectively for a range of indications (e.g., prevention vs. treatment) and patient populations (e.g., age, comorbid disease). We provide an overview of convalescent plasma, including evidence of benefit, regulatory considerations, logistical work flow, and proposed clinical trials, as scale-up is brought underway to mobilize this critical resource.
NVX-CoV2373 is a vaccine containing a full-length stabilized recombinant spike protein trimer that is administered in two doses 3 weeks apart along with a saponin-based adjuvant. In a randomized ...trial, approximately 20,000 participants received the vaccine and 10,000 a placebo. Vaccine efficacy against infection was 90%, and reactogenicity was similar to that of other Covid-19 vaccines.
Thyroid cancer cell lines are valuable models but have been neglected in pancancer genomic studies. Moreover, their misidentification has been a significant problem. We aim to provide a validated ...dataset for thyroid cancer researchers.
We performed next-generation sequencing (NGS) and analyzed the transcriptome of 60 authenticated thyroid cell lines and compared our findings with the known genomic defects in human thyroid cancers.
Unsupervised transcriptomic analysis showed that 94% of thyroid cell lines clustered distinctly from other lineages. Thyroid cancer cell line mutations recapitulate those found in primary tumors (e.g.,
,
, or gene fusions). Mutations in the
promoter (83%) and
(71%) were highly prevalent. There were frequent alterations in
,
, and of members of the SWI/SNF chromatin remodeling complex, mismatch repair, cell-cycle checkpoint, and histone methyl- and acetyltransferase functional groups. Copy number alterations (CNA) were more prevalent in cell lines derived from advanced versus differentiated cancers, as reported in primary tumors, although the precise CNAs were only partially recapitulated. Transcriptomic analysis showed that all cell lines were profoundly dedifferentiated, regardless of their derivation, making them good models for advanced disease. However, they maintained the BRAF
versus RAS-dependent consequences on MAPK transcriptional output, which correlated with differential sensitivity to MEK inhibitors. Paired primary tumor-cell line samples showed high concordance of mutations. Complete loss of p53 function in
heterozygous tumors was the most prominent event selected during
immortalization.
This cell line resource will help inform future preclinical studies exploring tumor-specific dependencies.
To quantify the frequency of rib fracture and chest wall (CW) pain and identify the dose-volume parameters that predict CW toxicity after stereotactic body radiotherapy (SBRT).
The records of ...patients treated with SBRT between 2000 and 2008 were reviewed, and toxicity was scored according to Common Terminology Criteria for Adverse Events v3.0 for pain and rib fracture. Dosimetric data for CW and rib were analyzed and related to the frequency of toxicity. The risks of CW toxicity were then further characterized according to the median effective concentration (EC(50)) dose-response model.
A total of 347 lesions were treated with a median follow-up of 19 months. Frequency of Grade I and higher CW pain and/or fracture for CW vs. non-CW lesions was 21% vs. 4%, respectively (p < 0.0001). A dose of 50 Gy was the cutoff for maximum dose (Dmax) to CW and rib above which there was a significant increase in the frequency of any grade pain and fracture (p = 0.03 and p = 0.025, respectively). Volume of CW receiving 15 Gy - 40 Gy was highly predictive of toxicity (R(2) > 0.9). According to the EC(50) model, 5 cc and 15 cc of CW receiving 40 Gy predict a 10% and 30% risk of CW toxicity, respectively.
Adequate tumor coverage remains the primary objective when treating lung or liver lesions with SBRT. To minimize toxicity when treating lesions in close proximity to the CW, Dmax of the CW and/or ribs should remain <50 Gy, and <5 cc of CW should receive ≥ 40 Gy.
The opportunities for healthy choices in homes, neighborhoods, schools, and workplaces can have decisive impacts on health. We review scientific evidence from promising interventions focused on the ...social determinants of health and discuss how such interventions can improve population health and reduce health disparities. We found sufficient evidence of successful outcomes to support disparity-reducing policy interventions targeted at education and early childhood; urban planning and community development; housing; income enhancements and supplements; and employment. Cost-effectiveness evaluations show that these interventions lead to long-term societal savings, but the interventions require more routine attention to cost considerations. We discuss challenges to implementation, including the need for long-term financing to scale up effective interventions for implementation at the local, state, and national levels.
We evaluated heart disease death rates among American Indians and Alaska Natives (AI/ANs) and Whites after improving identification of AI/AN populations.
Indian Health Service (IHS) registration data ...were linked to the National Death Index for 1990 to 2009 to identify deaths among AI/AN persons aged 35 years and older with heart disease listed as the underlying cause of death (UCOD) or 1 of multiple causes of death (MCOD). We restricted analyses to IHS Contract Health Service Delivery Areas and to non-Hispanic populations.
Heart disease death rates were higher among AI/AN persons than Whites from 1999 to 2009 (1.21 times for UCOD, 1.30 times for MCOD). Disparities were highest in younger age groups and in the Northern Plains, but lowest in the East and Southwest. In AI/AN persons, MCOD rates were 84% higher than UCOD rates. From 1990 to 2009, UCOD rates declined among Whites, but only declined significantly among AI/AN persons after 2003.
Analysis with improved race identification indicated that AI/AN populations experienced higher heart disease death rates than Whites. Better prevention and more effective care of heart disease is needed for AI/AN populations.
Transposon-directed insertion site sequencing (TraDIS) is a high-throughput method coupling transposon mutagenesis with short-fragment DNA sequencing. It is commonly used to identify essential genes. ...Single gene deletion libraries are considered the gold standard for identifying essential genes. Currently, the TraDIS method has not been benchmarked against such libraries, and therefore, it remains unclear whether the two methodologies are comparable. To address this, a high-density transposon library was constructed in
K-12. Essential genes predicted from sequencing of this library were compared to existing essential gene databases. To decrease false-positive identification of essential genes, statistical data analysis included corrections for both gene length and genome length. Through this analysis, new essential genes and genes previously incorrectly designated essential were identified. We show that manual analysis of TraDIS data reveals novel features that would not have been detected by statistical analysis alone. Examples include short essential regions within genes, orientation-dependent effects, and fine-resolution identification of genome and protein features. Recognition of these insertion profiles in transposon mutagenesis data sets will assist genome annotation of less well characterized genomes and provides new insights into bacterial physiology and biochemistry.
Incentives to define lists of genes that are essential for bacterial survival include the identification of potential targets for antibacterial drug development, genes required for rapid growth for exploitation in biotechnology, and discovery of new biochemical pathways. To identify essential genes in
, we constructed a transposon mutant library of unprecedented density. Initial automated analysis of the resulting data revealed many discrepancies compared to the literature. We now report more extensive statistical analysis supported by both literature searches and detailed inspection of high-density TraDIS sequencing data for each putative essential gene for the
model laboratory organism. This paper is important because it provides a better understanding of the essential genes of
, reveals the limitations of relying on automated analysis alone, and provides a new standard for the analysis of TraDIS data.
In this study, 1219 HIV-uninfected, heterosexual adults in Botswana were randomly assigned to tenofovir–emtricitabine (TDF–FTC) or placebo. The TDF–FTC group had a lower incidence of HIV infection ...but increased rates of side effects, including a significant loss of bone density.
Biomedical strategies to prevent sexual transmission of human immunodeficiency virus (HIV) remain limited.
1
In animal models, preexposure prophylaxis with tenofovir disoproxil fumarate (TDF) or with the combination of TDF and emtricitabine (TDF–FTC) can prevent infections with HIV or hybrid simian–human immunodeficiency virus after vaginal or rectal challenge.
2
,
3
In humans, daily preexposure prophylaxis with TDF–FTC has been shown to reduce transmission of HIV by 44% among men who have sex with men
4
; however, the findings from studies in heterosexual populations have been mixed.
5
–
8
Botswana has the world's second highest prevalence of HIV infection, estimated in 2008 to be . . .
The combination of CDK4/6 inhibitors with antiestrogen therapies significantly improves clinical outcomes in ER-positive advanced breast cancer. To identify mechanisms of acquired resistance, we ...analyzed serial biopsies and rapid autopsies from patients treated with the combination of the CDK4/6 inhibitor ribociclib with letrozole. This study revealed that some resistant tumors acquired RB loss, whereas other tumors lost PTEN expression at the time of progression. In breast cancer cells, ablation of
, through increased AKT activation, was sufficient to promote resistance to CDK4/6 inhibition
and
. Mechanistically,
loss resulted in exclusion of p27 from the nucleus, leading to increased activation of both CDK4 and CDK2. Because
loss also causes resistance to PI3Kα inhibitors, currently approved in the post-CDK4/6 setting, these findings provide critical insight into how this single genetic event may cause clinical cross-resistance to multiple targeted therapies in the same patient, with implications for optimal treatment-sequencing strategies. SIGNIFICANCE: Our analysis of serial biopsies uncovered RB and PTEN loss as mechanisms of acquired resistance to CDK4/6 inhibitors, utilized as first-line treatment for ER-positive advanced breast cancer. Importantly, these findings have near-term clinical relevance because
loss also limits the efficacy of PI3Kα inhibitors currently approved in the post-CDK4/6 setting.
.
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