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Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can assess tumour vascularity, which depends on the process of angiogenesis and affects tumour response to treatment. Our study explored the associations between DCE-MRI parameters and the expression of plasma angiogenic factors in human papilloma virus (HPV)-negative oropharyngeal cancer, as well as their predictive value for response to concurrent chemoradiotherapy (cCRT).

Malignant transformation of normal gastric cells is a complex and multistep process, resulting in development of heterogeneous tumours. Susceptible genetic background, accumulation of genetic changes, and environmental factors play an important role in gastric carcinogenesis. Single nucleotide polymorphisms (SNPs) in mitotic segregation genes could be responsible for inducing the slow process of accumulation of genetic changes, leading to genome instability.

Career selection in medicine is a complex and underexplored process. Most medical career studies performed in the U.S. focused on the effect of demographic variables and medical education debt on career choice. Considering ongoing U.S. physician workforce shortages and the trilateral adaptive model of career decision making, a robust assessment of professional attitudes and work-life preferences is necessary. The objective of this study was to explore and define the dominant viewpoints related to career choice selection in a cohort of U.S. IM residents. We administered an electronic Q-sort in which 218 IM residents sorted 50 statements reflecting the spectrum of opinions that influence postgraduate career choice decisions. Participants provided comments that explained the reasoning behind their individual responses. In the final year of residency training, we ascertained participating residents' chosen career. Factor analysis grouped similar sorts and revealed four distinct viewpoints. We characterized the viewpoints as "Fellowship-Bound-Academic," "Altruistic-Longitudinal-Generalist," "Inpatient-Burnout-Aware," and "Lifestyle-Focused-Consultant." There is concordance between residents who loaded significantly onto a viewpoint and their ultimate career choice. Four dominant career choice viewpoints were found among contemporary U.S. IM residents. These viewpoints reflect the intersection of competing priorities, personal interests, professional identity, socio-economic factors, and work/life satisfaction. Better appreciation of determinants of IM residents' career choices may help address workforce shortages and enhance professional satisfaction.

Abstract Background Loss of DNA mismatch repair (MMR) in humans, mainly due to mutations in the hMLH1 gene, is linked to hereditary nonpolyposis colorectal cancer (HNPCC). Because not all MLH1 alterations result in loss of MMR function, accurate characterization of variants and their classification in terms of their effect on MMR function is essential for reliable genetic testing and effective treatment. To date, in vivo assays for functional characterization of MLH1 mutations performed in various model systems have used episomal expression of the modified MMR genes. We describe here a novel approach to determine accurately the functional significance of hMLH1 mutations in vivo, based on co-expression of human MLH1 and PMS2 in yeast cells. Methods Yeast MLH1 and PMS1 genes, whose protein products form the MutLα complex, were replaced by human orthologs directly on yeast chromosomes by homologous recombination, and the resulting MMR activity was tested. Results The yeast strain co-expressing hMLH1 and hPMS2 exhibited the same mutation rate as the wild-type. Eight cancer-related MLH1 variants were introduced, using the same approach, into the prepared yeast model, and their effect on MMR function was determined. Five variants (A92P, S93G, I219V, K618R and K618T) were classified as non-pathogenic, whereas variants T117M, Y646C and R659Q were characterized as pathogenic. Conclusion Results of our in vivo yeast-based approach correlate well with clinical data in five out of seven hMLH1 variants and the described model was thus shown to be useful for functional characterization of MLH1 variants in cancer patients found throughout the entire coding region of the gene.

Abstract Background Autosomal dominant polycystic kidney disease (ADPKD) is a genetically heterogeneous disorder caused by mutations in at least two different loci. Prior to performing mutation screening, if DNA samples of sufficient number of family members are available, it is worthwhile to assign the gene involved in disease progression by the genetic linkage analysis. Methods We collected samples from 36 Slovene ADPKD families and performed linkage analysis in 16 of them. Linkage was assessed by the use of microsatellite polymorphic markers, four in the case of PKD1 (KG8, AC2.5, CW3 and CW2) and five for PKD2 (D4S1534, D4S2929, D4S1542, D4S1563 and D4S423). Partial PKD1 mutation screening was undertaken by analysing exons 23 and 31–46 and PKD2 . Results Lod scores indicated linkage to PKD1 in six families and to PKD2 in two families. One family was linked to none and in seven families linkage to both genes was possible. Partial PKD1 mutation screening was performed in 33 patients (including 20 patients from the families where linkage analysis could not be performed). We analysed PKD2 in 2 patients where lod scores indicated linkage to PKD2 and in 7 families where linkage to both genes was possible. We detected six mutations and eight polymorphisms in PKD1 and one mutation and three polymorphisms in PKD2. Conclusion In our study group of ADPKD patients we detected seven mutations: three frameshift, one missense, two nonsense and one putative splicing mutation. Three have been described previously and 4 are novel. Three newly described framesfift mutations in PKD1 seem to be associated with more severe clinical course of ADPKD. Previously described nonsense mutation in PKD2 seems to be associated with cysts in liver and milder clinical course.

In recent decades, universities have made significant progress toward environmental sustainability and have likewise tightened their budgets and restructured economic models in the name of financial sustainability. However, institutions of higher education have failed to address issues of social sustainability and social injustice, many of which are increasing in number and severity on college campuses. This article takes a student activist perspective on these issues, suggesting that a comprehensive and intersectional approach toward university sustainability (with particular re-affirmation of the social sustainability pillar) can empower students and their allies, raise awareness about the causes of these issues, and allow a more constructive environment for collaborative approaches and policy formation on college campuses.

Between 2005 and 2020, total contraceptive use among married women in Rwanda increased from 17% to 64%. The aim of this study is to better understand how the Rwandan government's mobilization and demand generation efforts have impacted community norms and interpersonal discourse surrounding family planning. Eight focus group discussions with family planning providers and 32 in-depth interviews with experienced modern contraceptive users were conducted in 2018 in the two Rwandan districts with the highest and the lowest contraceptive prevalence rates. Results suggest that outspoken government support, mass media, and community meetings were valuable sources of information about family planning. Information received through these channels generated interpersonal dialogue about contraceptives through both conversation and observation; however, rumors and misinformation remained a significant barrier to use. A once taboo subject is now normative among married couples. Continuing to address common fears and misinformation through communication channels such as mass media and community meetings may help to further increase contraceptive uptake in Rwanda.

Despite remarkable progress in proteomic methods, including improved detection limits and sensitivity, these methods have not yet been established in routine clinical practice. The main limitations, which prevent their integration into clinics, are high cost of equipment, the need for highly trained personnel, and last, but not least, the establishment of reliable and accurate protein biomarkers or panels of protein biomarkers for detection of neoplasms. Furthermore, the complexity and heterogeneity of most solid tumours present obstacles in the discovery of specific protein signatures, which could be used for early detection of cancers, for prediction of disease outcome, and for determining the response to specific therapies. However, cancer proteome, as the end-point of pathological processes that underlie cancer development and progression, could represent an important source for the discovery of new biomarkers and molecular targets for tailored therapies.

Evidence has shown that certain methylation markers derived from blood can mirror corresponding methylation signatures in internal tissues. In the current study, we aimed to investigate two strong epigenetic predictors for life span, derived from blood DNA methylation data, in tissue samples of solid cancer patients. Using data from the Cancer Genome Atlas (TCGA) and the German DACHS study, we compared a mortality risk score (MRscore) and DNAmPhenoAge in paired tumor and adjacent normal tissue samples of patients with lung (N = 69), colorectal (n = 299), breast (n = 90), head/neck (n = 50), prostate (n = 50), and liver (n = 50) cancer. To explore the concordance across tissue and blood, we additionally assessed the two markers in blood samples of colorectal cancer (CRC) cases and matched controls (n = 93) in the DACHS+ study. The MRscore was significantly elevated in tumor tissues compared to normal tissues of all cancers except prostate cancer, for which an opposite pattern was observed. DNAmPhenoAge was consistently higher in all tumor tissues. The MRscore discriminated lung, colorectal, and prostate tumor tissues from normal tissues with very high accuracy [AUCs of 0.87, 0.99 (TCGA) /0.94 (DACHS), and 0.92, respectively]. DNAmPhenoAge accurately discriminated five types of tumor tissues from normal tissues (except prostate cancer), with AUCs of 0.82–0.93. The MRscore was also significantly higher in blood samples of CRC cases than in controls, with areas under the curve (AUC) of 0.74, whereas DNAmPhenoAge did not distinguish cases from controls, with AUC of 0.54. This study provides compelling evidence that blood‐derived DNAm markers could reflect methylation changes in less accessible tissues. Further research should explore the potential use of these findings for cancer diagnosis and early detection. [ABSTRACT FROM AUTHOR]

Ginger is considered by many people to be the outstanding member among 1400 other species in the family Zingiberaceae. Not only it is a valuable spice used by cooks throughout the world to impart unique flavour to their dishes but it also has a long track record in some Chinese and Indian cultures for treating common human ailments such as colds and headaches. Ginger has recently attracted considerable attention for its anti-inflammatory, antibacterial and antifungal properties. However, ginger as a crop is also susceptible to at least 24 different plant pathogens, including viruses, bacteria, fungi and nematodes. Of these, Pythium spp. (within the kingdom Stramenopila, phyllum Oomycota) are of most concern because various species can cause rotting and yield loss on ginger at any of the growth stages including during postharvest storage. Pythium gracile was the first species in the genus to be reported as a ginger pathogen, causing Pythium soft rot disease in India in 1907. Thereafter, numerous other Pythium spp. have been recorded from ginger growing regions throughout the world. Today, 15 Pythium species have been implicated as pathogens of the soft rot disease. Because accurate identification of a pathogen is the cornerstone of effective disease management programs, this review will focus on how to detect, identify and control Pythium spp. in general, with special emphasis on Pythium spp. associated with soft rot on ginger. [ABSTRACT FROM AUTHOR]

While bleeding canker of European beech trees (Fagus sylvatica) has long been recognized as a problem in Europe and North America, the cause in the northeastern United States has not been clear. To resolve this, we surveyed for disease prevalence on European beech, identified the pathogens involved, proved their pathogenicity, compared protocols for pathogen detection, and conducted a soil assay to determine pathogen presence in soil surrounding established trees in residential and commercial landscapes in New York, Pennsylvania, Maryland, Connecticut and Massachusetts. Approximately 40% of surveyed trees had bleeding cankers. While Phytophthora cactorum, P. gonapodyides, P. cambivora and two newly described species, P. citricola I and P. plurivora, were recovered from symptomatic tissue, P. citricola I and P. cactorum were most prevalent. All caused disease when artificially inoculated into European beech sapling stems, although P. cambivora and P. gonapodyides produced significantly smaller lesions. Recovery of the pathogen from symptomatic tissue using selective media, the preferred method of diagnosis, was significantly higher in the fall. ELISA detection was more successful and worked regardless of season, but did not allow identification to the species level. All five Phytophthora species were found in soil surveys; P. cambivora was most common, followed by P. cactorum and P. citricola I. These results provide a foundation for building management strategies to protect valuable specimens of European beech. [ABSTRACT FROM AUTHOR]

Background & Aims: Impaired mucosal defense plays an important role in the pathogenesis of Crohn’s disease (CD), one of the main subtypes of inflammatory bowel disease (IBD). Deleted in malignant brain tumors 1 (DMBT1) is a secreted scavenger receptor cysteine-rich protein with predominant expression in the intestine and has been proposed to exert possible functions in regenerative processes and pathogen defense. Here, we aimed at analyzing the role of DMBT1 in IBD. Methods: We studied DMBT1 expression in IBD and normal tissues by quantitative reverse transcription–polymerase chain reaction, immunohistochemistry, and mRNA in situ hybridization. Genetic polymorphisms within DMBT1 were analyzed in an Italian IBD case–control sample. Dmbt1 −/− mice were generated, characterized, and analyzed for their susceptibility to dextran sulfate sodium–induced colitis. Results: DMBT1 levels correlate with disease activity in inflamed IBD tissues. A highly significant fraction of the patients with IBD displayed up-regulation of DMBT1 specifically in the intestinal epithelial surface cells and Paneth cells. A deletion allele of DMBT1 with a reduced number of scavenger receptor cysteine-rich domain coding exons is associated with an increased risk of CD (P = .00056; odds ratio, 1.75) but not for ulcerative colitis. Dmbt1 −/− mice display enhanced susceptibility to dextran sulfate sodium–induced colitis and elevated Tnf, Il6, and Nod2 expression levels during inflammation. Conclusions: DMBT1 may play a role in intestinal mucosal protection and prevention of inflammation. Impaired DMBT1 function may contribute to the pathogenesis of CD. [Copyright &y& Elsevier]

European beech (Fagus sylvatica L.) is an important forest tree species which was always considered being non-problematic with regard to its susceptibility to pathogens and insects. However during the past decade, in Europe and the north-eastern USA an increasing number of trees and stands were showing symptoms typical for Phytophthora diseases: increased crown transparency, abnormally small and often yellowish foliage, a dieback of the crown, tongue-shaped necroses of the inner bark and the cambium with tarry or rusty spots on the surface of the bark either extending up to 7m from the stem base (collar rot) or occurring isolated higher up the stem (aerial bleeding cankers), fine root destructions and necrotic lesions on suberized roots. Large-scale investigations on both continents using specific isolation methods and ELISA kits for detection, and morphological and physiological parameters as well as ITS-DNA sequence analysis for identification demonstrated that several Phytophthora species were regularly involved as inciting agents of the decline. The most important species were Phytophthora citricola, P. cambivora and P. cactorum in Europe, and P. inflata in the USA. Their pathogenicity to beech was shown by stem inoculation and soil infestation tests performed by various groups. A small-scale nursery survey in Germany revealed that beech fields are regularly infested with various Phytophthora species. Options for disease management and control are discussed, and an emphasis is put on the prevention of disease spread via infested nursery stock. [Copyright &y& Elsevier]

Alterations of multiple oncogenes and tumor suppressor genes, together with genetic instability, are responsible for carcinogenesis in gastric cancer. The microsatellite mutator phenotype is the cause of many somatic frameshift and point mutations in non-coding repetitive sequences and in coding regions associated with cell proliferation and apoptosis. Genetic mutations in hMLH1 and transcriptional silencing of its promoter by hypermethylation lead to the inactivation of the mismatch repair system. In our study, we screened for mutations the hMLH1 gene in patients expressing the microsatellite instability genotype by using single-strand conformational polymorphism analysis and direct sequencing. Seven changes were identified; of these, three (A92P, E433Q, and K618A) were germline mutations and the other four (IVS5 453 + 79 A > G, I219V, 1039 - 7 del (T)n, and IVS15 1668 -19 A > G) germline polymorphisms. A92P and E433Q are novel, previously unidentified mutations. In addition, we found a rather complex distribution of mutations and polymorphisms in individual patients and in two cases also a methylated hMLH1 promoter. [ABSTRACT FROM AUTHOR]

Summary: Background: DNA methylation biomarkers in colorectal cancer (CRC) tissue hold potential as prognostic indicators. However, individual studies have yielded heterogeneous results, and external validation is largely absent. We conducted a comprehensive external validation and meta-analysis of previously suggested gene methylation biomarkers for CRC prognosis. Methods: We performed a systematic search to identify relevant studies investigating gene methylation biomarkers for CRC prognosis until March 2024. Our external validation cohort with long-term follow-up included 2303 patients with CRC from 22 hospitals in southwest Germany. We used Cox regression analyses to assess associations between previously suggested gene methylation biomarkers and prognosis, adjusting for clinical variables. We calculated pooled hazard ratios (HRs) and their 95% confidence intervals (CIs) using random-effects models. Findings: Of 151 single gene and 29 multiple gene methylation biomarkers identified from 121 studies, 37 single gene and seven multiple gene biomarkers were significantly associated with CRC prognosis after adjustment for clinical variables. Moreover, the directions of these associations with prognosis remained consistent between the original studies and our validation analyses. Seven single biomarkers and two multi-biomarker signatures were significantly associated with CRC prognosis in the meta-analysis, with a relatively strong level of evidence for CDKN2A, WNT5A, MLH1, and EVL. Interpretation: In a comprehensive evaluation of the so far identified gene methylation biomarkers for CRC prognosis, we identified candidates with potential clinical relevance for further investigation. Funding: The German Research Council, the Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany, the German Federal Ministry of Education and Research.

Abstract Obesity is a major comorbidity for the development and worsening of asthma. It is associated with increased disease incidence, reduced response to inhaled and systemic steroids, increased asthma exacerbations, and poor disease control. Over the past two decades, we have learned that there are clinical asthma phenotypes associated with obesity, which have unique immune, inflammatory, and metabolic disease mechanisms. The objectives of this review are to provide a brief overview of the associations and gaps between these chronic inflammatory diseases and the role that traditional therapies have on treating patients with obesity-related asthma, and to describe new clinical research of therapeutic developments targeting mechanisms that are more specific to this patient population.

Em face do aumento significativo de investidores pessoas físicas e da multiplicação de produtos e serviços sustentáveis, sob a sigla ESG (ou ASG) em bolsa de valores brasileira, justifica-se estudo sobre regulação jurídica do mercado de fundos de investimentos, que engloba tanto prestadores de serviço (gestores e administradores), quanto consumidores (pessoas físicas). Objetiva-se compreensão sobre relação entre Democracia e Mercado Financeiro, no âmbito da sociedade hipercomplexa e da economia de mercado global, analisando-se especificamente: (i) – funcionamento do mercado financeiro a partir de teorias de Democracia Econômica, que refletem poder decisório na organização da atividade empresarial; (ii) – a responsabilidade jurídica do administrador e gestor de fundos de investimento na incorporação de critérios ASG, a partir do dever fiduciário. Emprega-se o método indutivo com auxílio de pesquisa bibliográfica. Conclui-se que: 1 – os critérios ASG, representativos da cooperação entre Estado-Empresa para consecução dos Objetivos de Desenvolvimento Sustentável (ODS), não contribuem de forma direta para a democratização do mercado financeiro, mas sim indireta, a partir da introdução de procedimentos de cooperação que promovem a transparência e diálogo, a exemplo do disclosure, que abordam publicamente questões ambientais, sociais e de governança, temas essenciais à democracia nos moldes atuais; 2 – responsabilidade jurídica sobre a incorporação de critérios ASG e a escolha de ativos não deve estar adstrita ao critério risco-retorno, pois há novo universo normativo incidente sobre a atuação dos gestores/administradores de fundos de investimento, inclusive por meio de normas transnacionais, as quais englobam uma nova ética direcionada aos ODS, complementar aos deveres fiduciários tradicionais.