FAT1 is frequently mutated in head and neck squamous cell carcinoma (HNSCC), but the biological and clinical effects of FAT1 mutations in HNSCC remain to be fully elucidated. We investigated the landscape of altered protein and gene expression associated with FAT1 mutations and clinical outcomes of patients with HNSCC. FAT1 mutation was stratified with clinical information from The Cancer Genome Atlas HNSCC databases with more than 200 proteins or phosphorylated sites. FAT1 mutation was significantly more prevalent among HPV, female, and older patients and was enriched in oral, larynx, and hypopharynx primary tumors. FAT1 mutation was also significantly associated with lower FAT1 gene expression and increased protein expression of HER3 pY1289, IRS1, and CAVEOLIN1. From an independent International Cancer Genome Consortium dataset, FAT1 mutation in oral cancer cooccurred with top mutated genes TP53 and CASP8. Poorer overall survival or progression-free survival was observed in patients with FAT1 mutation or altered HER3 pY1289, IRS1, or CAVEOLIN1. Pathway analysis revealed dominant ERBB/neuregulin pathways linked to FAT1 mutations in HNSCC, and protein signature panels uncovered the heterogeneity of patient subgroups. Decreased pEGFR, pHER2, and pERK and upregulated pHER3 and HER3 proteins were observed in two FAT1 knockout HNSCC cell lines, supporting that FAT1 alterations lead to altered EGFR/ERBB signaling. In squamous cancers of the lung and cervix, a strong association of FAT1 and EGFR gene expressions was identified. Collectively, these results suggest that alteration of FAT1 appears to involve mostly HPV HNSCC and may contribute to resistance to EGFR-targeted therapy.
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Yu Zhao;
Chong Cui;
Kun Zhang;
Jialin Liu;
Jinfu Xu;
Eric Nisenbaum;
Yixiang Huang;
Guoyou Qin;
Bing Chen;
Michael Hoffer;
Susan H. Blanton;
Fred Telischi;
Joshua M. Hare;
Sylvia Daunert;
Bhavarth Shukla;
Savita G. Pahwa;
Dushyantha T. Jayaweera;
Paul E. Farmer;
Carlos del Rio;
Xuezhong Liu;
Yilai Shu
The COVID-19 outbreak spread rapidly throughout the globe, with worldwide infections and deaths continuing to increase dramatically. To control disease spread and protect healthcare workers, accurate information is necessary. We searched PubMed and Google Scholar for studies published from December 2019 to March 31, 2020 with the terms “COVID-19,” “2019-nCoV,” “SARS-CoV-2,” or “Novel Coronavirus Pneumonia.” The main symptoms of COVID-19 are fever (83–98.6%), cough (59.4–82%), and fatigue (38.1–69.6%). However, only 43.8% of patients have fever early in the disease course, despite still being infectious. These patients may present to clinics lacking proper precautions, leading to nosocomial transmission, and infection of workers. Potential COVID-19 cases must be identified early to initiate proper triage and distinguish them quickly from similar infections. Early identification, accurate triage, and standardized personal protection protocols can reduce the risk of cross infection. Containing disease spread will require protecting healthcare workers.
As perinatally HIV-infected (PHIV) women reach reproductive age, there is an increasing number who become pregnant. This is a retrospective cohort study of HIV-infected women who delivered from June 2007 to July 2012 at our institution. Maternal demographics, HIV characteristics, and obstetric and neonatal outcomes were compared. 20 PHIV and 80 SHIV pregnancies were reviewed. The groups had similar CD4+ counts, prevalence of AIDS, and use of antiretrovirals (ARV) at initiation of obstetrical care. PHIV women were significantly more likely to be younger, have a detectable viral load (35% versus 74%, P < 0.01), and have HIV-genotype resistance (40% versus 12%, P < 0.01) than the SHIV women. The median gestational age at delivery (38 weeks) and rates of obstetrical and neonatal complications were similar between the groups. While the overall rate of cesarean delivery (CD) was similar, the rates for CD due to HIV were higher in the PHIV group (64% versus 22%, P < 0.01). There was one case (5.3%) of mother-to-child transmission in the PHIV group versus two cases (2.6%) in the SHIV group. In our population, PHIV pregnant women have a higher rate of HIV-genotype resistance and higher rate of detectable viral load leading to a higher rate of CD secondary to HIV.
Background: Recent reports have demonstrated a decline in bacterial bloodstream infections (BSIs) following adherence to central line insertion practices; however, declines have been less evident for BSIs due to Candida species. Methods: We conducted active, population-based laboratory surveillance for candidemia in metropolitan Atlanta, GA and Baltimore, MD over a 5-year period.We calculated annual candidemia incidence and antifungal drug resistance rates. Results: We identified 3,848 candidemia cases from 2008-2013. Compared with 2008, candidemia incidence per 100,000 person-years decreased significantly by 2013 in both locations (GA: 14.1 to 9.5, p<0.001; MD: 30.9 to 14.4, p<0.001). A total of 3,255 cases (85%) had a central venous catheter (CVC) in place within 2 days before the BSI culture date. In both locations, the number of CVC-associated cases declined (GA: 473 to 294; MD: 384 to 151). Candida albicans (CA, 36%) and Candida glabrata (CG, 27%) were the most common species recovered. In both locations, the proportion of cases with fluconazole resistance decreased (GA: 8.0% to 7.1%, -10%; MD: 6.6%to 4.9%, -25%), while the proportion of cases with an isolate resistant to an echinocandin increased (GA: 1.2%to 2.9%, +147%; MD: 2.0% to 3.5%, +77%). Most (74%) echinocandin-resistant isolates were CG; 17 (<1%) isolates were resistant to both drug categories (multidrug resistant [MDR], 16/17 were CG). The proportion of CG cases with MDR Candida increased from 1.8% to 2.6%. Conclusions: We observed a significant decline in the incidence of candidemia over a five-year period, and increases in echinocandin-resistant and MDR Candida. Efforts to strengthen infection control practices may be preventing candidemia among high-risk patients. Further surveillance for resistant Candida is warranted.
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Meredith A. Benson;
Elizabeth A. Ohneck;
Chanelle Ryan;
Francis Alonzo, III;
Hannah Smith;
Apurva Narechania;
Sergios-Orestis Kolokotronis;
Sarah Satola;
Anne-Catrin Uhlemann;
Robert Sebra;
Gintaras Deikus;
Bo Shopsin;
Paul J. Planet;
Victor J. Torres
Staphylococcus aureus has evolved as a pathogen that causes a range of diseases in humans. There are two dominant modes of evolution thought to explain most of the virulence differences between strains. First, virulence genes may be acquired from other organisms. Second, mutations may cause changes in the regulation and expression of genes. Here we describe an evolutionary event in which transposition of an IS element has a direct impact on virulence gene regulation resulting in hypervirulence. Whole-genome analysis of a methicillin-resistant S. aureus (MRSA) strain USA500 revealed acquisition of a transposable element (IS256) that is absent from close relatives of this strain. Of the multiple copies of IS256 found in the USA500 genome, one was inserted in the promoter sequence of repressor of toxins (Rot), a master transcriptional regulator responsible for the expression of virulence factors in S. aureus. We show that insertion into the rot promoter by IS256 results in the derepression of cytotoxin expression and increased virulence. Taken together, this work provides new insight into evolutionary strategies by which S. aureus is able to modify its virulence properties and demonstrates a novel mechanism by which horizontal gene transfer directly impacts virulence through altering toxin regulation. Copyright
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Abuzaid A. Abuzaid;
Abdalmohsin M. Abdoon;
Mohamed A. Aldahan;
Abdullah G. Alzahrani;
Raaft F. Alhakeem;
Abdullah M. Asiri;
Mohamed H. Alzahrani;
Ziad Memish
Despite the great efforts by health authorities in Kingdom of Saudi Arabia (KSA), Cutaneous leishmaniasis (CL) continues to be a major public health problem in the country. Many risk factors make KSA prone to outbreaks and epidemics; among these, rapid urbanization and the huge population movement are the most important. The disease is endemic in many parts of KSA, with the majority of cases concentrated in six regions, including Al-Qaseem, Riyadh, Al-Hassa, Aseer, Ha'il, and Al-Madinah. Leishmania major (L. major) and Leishmania tropica (L. tropica) are the main dermotropic species, and Phlebotomus papatasi (vector of L. major) and Phlebotomus sergenti (vector of L. tropica) are the proved vectors of the disease. Psammomys obesus and Meriones libycus have been defined as the principal reservoir hosts of zoonotic CL in Al-Hassa oasis, Al-Madinah, and Al-Qaseem provinces. Clinically, males are affected more than females, and there is no variation between the Saudis and expatriates in terms of number of reported cases, but the disease tends to run a more severe course among non-Saudis. Face is the most commonly affected site, and ulcerative pattern accounts for 90% of lesions. Despite local and international recommendations of using laboratory diagnostics to confirm CL cases, most cases in KSA are diagnosed and treated on clinical grounds and local epidemiology. However, systemic parenteral sodium stibogluconate (SSG) is the first line of therapy and used to treat all CL patients irrespective of their clinical presentation or the incriminated species. In brief, more efforts are needed to combat this disease. Several aspects of the disease require more evaluation through encouragement of national and regional studies. Development of evidence based national diagnostic and management guidelines, as well as algorithms, is urgently needed to improve the practice of diagnosing and treating CL in KSA.
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Bohdan Nosyk;
Jeong Eun Min;
Xiao Zang;
Daniel J Feaster;
Lisa Metsch;
Brandon D L Marshall;
Carlos del Rio;
Reuben Granich;
Bruce R Schackman;
Julio S G Montaner
With efficacious behavioral, biomedical, and structural interventions available, combination implementation strategies are being implemented to combat HIV/AIDS across settings internationally. However, priority statements from national and international bodies make it unclear whether the objective should be the reduction in HIV incidence or the maximization of health, most commonly measured with quality-adjusted life years (QALYs). Building off a model-based evaluation of HIV care interventions in British Columbia, Canada, we compare the optimal sets of interventions that would be identified using HIV infections averted, and QALYs as the primary outcome in a cost-effectiveness analysis. We found an explicit focus on averting new infections undervalues the health benefits derived from antiretroviral therapy, resulting in suboptimal and potentially harmful funding recommendations.
OBJECTIVES: Emotional stress may disproportionally affect young women with ischemic heart disease. We sought to examine whether mental stress-induced myocardial ischemia (MSIMI), but not exercise-induced ischemia, is more common in young women with previous myocardial infarction (MI) than in men.
METHODS: We studied 98 post-MI patients (49 women and 49 men) aged 38 to 60 years. Women and men were matched for age, MI type, and months since MI. Patients underwent technetium-99m sestamibi perfusion imaging at rest, after mental stress, and after exercise/pharmacological stress. Perfusion defect scores were obtained with observer-independent software. A summed difference score (SDS), the difference between stress and rest scores, was used to quantify ischemia under both stress conditions.
RESULTS: Women 50 years or younger, but not older women, showed a more adverse psychosocial profile than did age-matched men but did not differ for conventional risk factors and tended to have less angiographic coronary artery disease. Compared with age-matched men, women 50 years or younger exhibited a higher SDS with mental stress (3.1 versus 1.5, p = .029) and had twice the rate of MSIMI (SDS ≥3 52% versus 25%), whereas ischemia with physical stress did not differ (36% versus 25%). In older patients, there were no sex differences in MSIMI. The higher prevalence of MSIMI in young women persisted when adjusting for sociodemographic and life-style factors, coronary artery disease severity, and depression.
CONCLUSIONS: MSIMI post-MI is more common in women 50 years or younger compared with age-matched men. These sex differences are not observed in post-MI patients who are older than 50 years.
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Swann Arp Adams;
Catherine L. Rohweder;
Jennifer Leeman;
Daniela B. Friedman;
Ziya Gizlice;
Robin C. Vanderpool;
Natoshia Askelson;
Alicia Best;
Susan A. Flocke;
Karen Glanz;
Linda K. Ko;
Michelle Kegler
While colorectal cancer (CRC) screening rates have been increasing in the general population, rates are considerably lower in Federally Qualified Health Centers (FQHCs), which serve a large proportion of uninsured and medically vulnerable patients. Efforts to screen eligible patients must be accelerated if we are to reach the national screening goal of 80% by 2018 and beyond. To inform this work, we conducted a survey of key informants at FQHCs in eight states to determine which evidence-based interventions (EBIs) to promote CRC screening are currently being used, and which implementation strategies are being employed to ensure that the interventions are executed as intended. One hundred and forty-eight FQHCs were invited to participate in the study, and 56 completed surveys were received for a response rate of 38%. Results demonstrated that provider reminder and recall systems were the most commonly used EBIs (44.6%) while the most commonly used implementation strategy was the identification of barriers (84.0%). The mean number of EBIs that were fully implemented at the centers was 2.4 (range 0–7) out of seven. Almost one-quarter of respondents indicated that their FQHCs were not using any EBIs to increase CRC screening. Full implementation of EBIs was correlated with higher CRC screening rates. These findings identify gaps as well as the preferences and needs of FQHCs in selecting and implementing EBIs for CRC screening.
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Heather A. Prentice;
Matthew A. Price;
Travis R. Porter;
Emmanuel Cormier;
Michael J. Mugavero;
Anatoli Kamali;
Etienne Karita;
Shabir Lakhi;
Eduard J. Sanders;
Omu Anzala;
Pauli N. Amornkul;
Susan Allen;
Eric Hunter;
Richard A. Kaslow;
Jill Gilmour;
Jianming Tang
In HIV-1 infection, plasma viral load (VL) has dual implications for pathogenesis and public health. Based on well-known patterns of HIV-1 evolution and immune escape, we hypothesized that VL is an evolving quantitative trait that depends heavily on duration of infection (DOI), demographic features, human leukocyte antigen (HLA) genotypes and viral characteristics. Prospective data from 421 African seroconverters with at least four eligible visits did show relatively steady VL beyond 3 months of untreated infection, but host and viral factors independently associated with cross-sectional and longitudinal VL often varied by analytical approaches and sliding time windows. Specifically, the effects of age, HLA-B*53 and infecting HIV-1 subtypes (A1, C and others) on VL were either sporadic or highly sensitive to time windows. These observations were strengthened by the addition of 111 seroconverters with 2-3 eligible VL results, suggesting that DOI should be a critical parameter in epidemiological and clinical studies.