Genetic predisposition to melanoma Hawkes, Jason E; Truong, Amanda; Meyer, Laurence J
Seminars in oncology,
10/2016, Volume:
43, Issue:
5
Journal Article
Peer reviewed
Malignant melanoma is a rare, often fatal form of skin cancer with a complex multigenic etiology. The incidence of melanoma is increasing at an alarming rate. A number of heritable factors contribute ...to a patient's overall melanoma risk, including response to ultraviolet light, nevus number, and pigmentation characteristics, such as eye and hair color. Approximately 5%-10% of melanoma cases are familial, yet the majority of familial cases lack identifiable germ-line mutations in known susceptibility genes. Additionally, most familial melanomas lack germ-line mutations in genes that are commonly mutated in sporadic melanoma. Candidate and systematic genome-wide association studies have led to an improved understanding of the risk factors for melanoma and the identification of susceptibility genes. In this review, we provide an overview of the major risk factors and known genes implicated in familial melanoma susceptibility.
MMT: assume a can opener Meyer, Laurence
Business economics (Cleveland, Ohio),
2020/1, Volume:
55, Issue:
1
Journal Article
Peer reviewed
The key assumptions in the debate between MMTers and CMEers are about the relationship between monetary and fiscal institutions.
CMEers
assume the
Treasury and the Fed are independent.
MMTers
assume ...either that the Fed is consolidated into the Treasury
, or that, whenever the Treasury wants to spend money, the Fed adds reserves to the Treasury’s account at the Fed. MMT is also wrong at the very start in its assumption that the money supply is the instrument of monetary policy; the federal funds rates is. The fact that MMT’s assumptions are wrong means that all the conclusions that follow from them must also be wrong. For example, with respect to crowding out, not only don’t interest rates rise with an increase in government spending in MMT, they actually fall, indeed, all the way to zero! This analysis of the effect of government spending on rates is wildly off the mark. It is also not comforting that the MMT framework would have Congress accept responsibility for the current Fed mandates Nonetheless, MMT has highlighted a central policy question: whether the large spending programs called for to meet unmet social needs can be financed without adverse consequences.
Combination antiretroviral therapy (cART) reduces HIV-associated morbidities and mortalities but cannot cure the infection. Given the difficulty of eradicating HIV-1, a functional cure for ...HIV-infected patients appears to be a more reachable short-term goal. We identified 14 HIV patients (post-treatment controllers PTCs) whose viremia remained controlled for several years after the interruption of prolonged cART initiated during the primary infection. Most PTCs lacked the protective HLA B alleles that are overrepresented in spontaneous HIV controllers (HICs); instead, they carried risk-associated HLA alleles that were largely absent among the HICs. Accordingly, the PTCs had poorer CD8+ T cell responses and more severe primary infections than the HICs did. Moreover, the incidence of viral control after the interruption of early antiretroviral therapy was higher among the PTCs than has been reported for spontaneous control. Off therapy, the PTCs were able to maintain and, in some cases, further reduce an extremely low viral reservoir. We found that long-lived HIV-infected CD4+ T cells contributed poorly to the total resting HIV reservoir in the PTCs because of a low rate of infection of naïve T cells and a skewed distribution of resting memory CD4+ T cell subsets. Our results show that early and prolonged cART may allow some individuals with a rather unfavorable background to achieve long-term infection control and may have important implications in the search for a functional HIV cure.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Virus-specific CD8+ T cells play a central role in HIV-1 natural controllers to maintain suppressed viremia in the absence of antiretroviral therapy. These cells display a memory program that confers ...them stemness properties, high survival, polyfunctionality, proliferative capacity, metabolic plasticity, and antiviral potential. The development and maintenance of such qualities by memory CD8+ T cells appear crucial to achieving natural HIV-1 control. Here, we show that targeting the signaling pathways Wnt/transcription factor T cell factor 1 (Wnt/TCF-1) and mTORC through GSK3 inhibition to reprogram HIV-specific CD8+ T cells from noncontrollers promoted functional capacities associated with natural control of infection. Features of such reprogrammed cells included enrichment in TCF-1+ less-differentiated subsets, a superior response to antigen, enhanced survival, polyfunctionality, metabolic plasticity, less mTORC1 dependency, an improved response to γ-chain cytokines, and a stronger HIV-suppressive capacity. Thus, such CD8+ T cell reprogramming, combined with other available immunomodulators, might represent a promising strategy for adoptive cell therapy in the search for an HIV-1 cure.
The University of California Santa Cruz (UCSC) Genome Browser (http://genome.ucsc.edu) offers online public access to a growing database of genomic sequence and annotations for a wide variety of ...organisms. The Browser is an integrated tool set for visualizing, comparing, analysing and sharing both publicly available and user-generated genomic datasets. As of September 2012, genomic sequence and a basic set of annotation 'tracks' are provided for 63 organisms, including 26 mammals, 13 non-mammal vertebrates, 3 invertebrate deuterostomes, 13 insects, 6 worms, yeast and sea hare. In the past year 19 new genome assemblies have been added, and we anticipate releasing another 28 in early 2013. Further, a large number of annotation tracks have been either added, updated by contributors or remapped to the latest human reference genome. Among these are an updated UCSC Genes track for human and mouse assemblies. We have also introduced several features to improve usability, including new navigation menus. This article provides an update to the UCSC Genome Browser database, which has been previously featured in the Database issue of this journal.
The University of California, Santa Cruz Genome Browser (http://genome.ucsc.edu) offers online access to a database of genomic sequence and annotation data for a wide variety of organisms. The ...Browser also has many tools for visualizing, comparing and analyzing both publicly available and user-generated genomic data sets, aligning sequences and uploading user data. Among the features released this year are a gene search tool and annotation track drag-reorder functionality as well as support for BAM and BigWig/BigBed file formats. New display enhancements include overlay of multiple wiggle tracks through use of transparent coloring, options for displaying transformed wiggle data, a 'mean+whiskers' windowing function for display of wiggle data at high zoom levels, and more color schemes for microarray data. New data highlights include seven new genome assemblies, a Neandertal genome data portal, phenotype and disease association data, a human RNA editing track, and a zebrafish Conservation track. We also describe updates to existing tracks.
IMPORTANCE: Selecting effective antidepressants for the treatment of major depressive disorder (MDD) is an imprecise practice, with remission rates of about 30% at the initial treatment. OBJECTIVE: ...To determine whether pharmacogenomic testing affects antidepressant medication selection and whether such testing leads to better clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS: A pragmatic, randomized clinical trial that compared treatment guided by pharmacogenomic testing vs usual care. Participants included 676 clinicians and 1944 patients. Participants were enrolled from 22 Department of Veterans Affairs medical centers from July 2017 through February 2021, with follow-up ending November 2021. Eligible patients were those with MDD who were initiating or switching treatment with a single antidepressant. Exclusion criteria included an active substance use disorder, mania, psychosis, or concurrent treatment with a specified list of medications. INTERVENTIONS: Results from a commercial pharmacogenomic test were given to clinicians in the pharmacogenomic-guided group (n = 966). The comparison group received usual care and access to pharmacogenomic results after 24 weeks (n = 978). MAIN OUTCOMES AND MEASURES: The co–primary outcomes were the proportion of prescriptions with a predicted drug-gene interaction written in the 30 days after randomization and remission of depressive symptoms as measured by the Patient Health Questionnaire–9 (PHQ-9) (remission was defined as PHQ-9 ≤ 5). Remission was analyzed as a repeated measure across 24 weeks by blinded raters. RESULTS: Among 1944 patients who were randomized (mean age, 48 years; 491 women 25%), 1541 (79%) completed the 24-week assessment. The estimated risks for receiving an antidepressant with none, moderate, and substantial drug-gene interactions for the pharmacogenomic-guided group were 59.3%, 30.0%, and 10.7% compared with 25.7%, 54.6%, and 19.7% in the usual care group. The pharmacogenomic-guided group was more likely to receive a medication with a lower potential drug-gene interaction for no drug-gene vs moderate/substantial interaction (odds ratio OR, 4.32 95% CI, 3.47 to 5.39; P < .001) and no/moderate vs substantial interaction (OR, 2.08 95% CI, 1.52 to 2.84; P = .005) (P < .001 for overall comparison). Remission rates over 24 weeks were higher among patients whose care was guided by pharmacogenomic testing than those in usual care (OR, 1.28 95% CI, 1.05 to 1.57; P = .02; risk difference, 2.8% 95% CI, 0.6% to 5.1%) but were not significantly higher at week 24 when 130 patients in the pharmacogenomic-guided group and 126 patients in the usual care group were in remission (estimated risk difference, 1.5% 95% CI, −2.4% to 5.3%; P = .45). CONCLUSIONS AND RELEVANCE: Among patients with MDD, provision of pharmacogenomic testing for drug-gene interactions reduced prescription of medications with predicted drug-gene interactions compared with usual care. Provision of test results had small nonpersistent effects on symptom remission. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03170362
In France, the first pandemic peak fell disproportionately on the most disadvantaged, as they were overrepresented in contaminations and in developing severe forms of the virus. At that time, and ...especially during lockdown, the French healthcare system was severely disrupted and limited. The issue of social differences in the use of healthcare by people experiencing symptoms of Covid-19 arose. Based on a random sample of 135,000 persons, we selected respondents who reported Covid-19-like symptoms (cough, fever, dyspnea, anosmia and/or ageusia) during the first lockdown (n = 12,422). The aim of this study was to determine if the use of health care services was likely to contribute to widen Covid-19 social inequalities. Use of health care services was classified in three categories: (1) no consultation, (2) out-of-hospital consultation(s) and (3) in-hospital consultation(s). We estimated odds ratio of utilization of health care using multinomial regressions, adjusted on social factors (age, gender, class, ethno-racial status, social class, standard of living and education), contextual variables, health variables, and symptoms characteristics. Altogether, 37.8% of the individuals consulted a doctor for their symptoms; 32.1% outside hospital and 5.7% in hospital. Use of health care services was strongly associated with social position2: the most disadvantaged social groups and racially minoritized immigrants were more likely to use health care, particularly for in-hospital consultation(s). The highest utilization of health care were found among older adults (OR 9.51, 95%CI 5.02-18.0 compared to the youngest age group), the racially minoritized first-generation immigrants (OR 1.61, 95%CI 1.09-2.36 compared to the mainstream population), the poorest (OR 1.31, 95%CI 1.00-1.72) and the least educated (OR 2.20, 95%CI 1.44-3.38). To conclude, we found that the use of health care services counteracted the potential impact of social inequalities in exposure and infection to the Covid-19.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The University of California, Santa Cruz (UCSC) Genome Browser website (http://genome.ucsc.edu/) provides a large database of publicly available sequence and annotation data along with an integrated ...tool set for examining and comparing the genomes of organisms, aligning sequence to genomes, and displaying and sharing users' own annotation data. As of September 2009, genomic sequence and a basic set of annotation 'tracks' are provided for 47 organisms, including 14 mammals, 10 non-mammal vertebrates, 3 invertebrate deuterostomes, 13 insects, 6 worms and a yeast. New data highlights this year include an updated human genome browser, a 44-species multiple sequence alignment track, improved variation and phenotype tracks and 16 new genome-wide ENCODE tracks. New features include drag-and-zoom navigation, a Wiki track for user-added annotations, new custom track formats for large datasets (bigBed and bigWig), a new multiple alignment output tool, links to variation and protein structure tools, in silico PCR utility enhancements, and improved track configuration tools.
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