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Abstract Background Telehealth services are essential to expand healthcare coverage for all in the era of modern technology. Knowledge, willingness, and involvement with the service are also significantly important in the utilization of the service. This study investigated factors associated with knowledge, perceived benefits, perceived concerns, and predisposition to use telehealth services in Bangladesh. This web-based survey was conducted among 1266 adults in Bangladesh. Respondents were enrolled by following a convenience sampling technique. Results Demographic, telehealth service, and perceived health related information were significantly associated with respondents’ knowledge, perceived benefits, perceived concerns, and predispositions. The knowledge was significantly positively correlated with the perceived benefit (p

BackgroundObesity and frailty are prevalent geriatric conditions that share some pathophysiological mechanisms and are associated with adverse clinical outcomes. The relationship between frailty, obesity, and polymorphism remains inadequately explored. Single nucleotide polymorphisms (SNPs) offer insights into genetic predispositions that may influence the development of both frailty and obesity.MethodsWe aimed at investigating whether SNPs associated with frailty also play a role in obesity. Data were collected from the FRASNET cross-sectional study, which included community-dwelling older individuals residing in Milan and nearby areas. Participants were recruited through random sampling. They underwent multidimensional geriatric assessments, which included the collection of blood samples for SNP analysis. Frailty was assessed using the frailty index, and body composition was evaluated using bioelectrical impedance analysis and anthropometric measures.ResultsSNPs related to frailty and linked to the renin–angiotensin system (CYP11B2 rs1799998, AGT rs5051, and AGTR1 rs2131127), apoptosis pathways (CASP8 rs6747918), growth hormone signaling (GHR rs6180), inflammation (TLR4 rs5030717, CD33 rs3865444, and FN1 rs7567647), adducin (ADD3 rs3731566), and the 9p21–23 region (rs518054) were found to be associated with various measures of obesity in community-dwelling older adults.ConclusionsFrailty-related SNPs contribute to obesity in community-dwelling older adults. We identified a novel association between adducin SNPs and visceral fat, which has not been previously reported. Detecting genetic predispositions to obesity and frailty early could aid in identifying individuals at risk, facilitating the adoption of preventive interventions. This represents an initial step toward promoting early intervention strategies.

Summary: Infection is a commonplace, usually self-limiting, condition but can lead to sepsis, a severe life-threatening dysregulated host response. We investigate the individual phenotypic predisposition to developing uncomplicated infection or sepsis in a large cohort of non-infected patients undergoing major elective surgery. Whole-blood RNA sequencing analysis was performed on preoperative samples from 267 patients. These patients developed postoperative infection with (n = 77) or without (n = 49) sepsis, developed non-infectious systemic inflammatory response (n = 31), or had an uncomplicated postoperative course (n = 110). Machine learning classification models built on preoperative transcriptomic signatures predict postoperative outcomes including sepsis with an area under the curve of up to 0.910 (mean 0.855) and sensitivity/specificity up to 0.767/0.804 (mean 0.746/0.769). Our models, confirmed by quantitative reverse-transcription PCR (RT-qPCR), potentially offer a risk prediction tool for the development of postoperative sepsis with implications for patient management. They identify an individual predisposition to developing sepsis that warrants further exploration to better understand the underlying pathophysiology.

IntroductionGenetic disposition is a major etiologic factor in childhood cancer. More than 100 cancer predisposing syndromes (CPS) are known. Surveillance protocols seek to mitigate morbidity and mortality. To implement recommendations in patient care and to ascertain that the constant gain of knowledge forces its way into practice specific pediatric CPS programs were established.Patients and methodsWe retrospectively analyzed data on children, adolescents, and young adults referred to our pediatric CPS program between October 1, 2021, and March 31, 2023. Follow-up ended on December 31, 2023.ResultsWe identified 67 patients (30 male, 36 female, 1 non-binary, median age 9.5 years). Thirty-five patients were referred for CPS surveillance, 32 for features suspicious of a CPS including café-au-lait macules (n = 10), overgrowth (n = 9), other specific symptoms (n = 4), cancer suspicious of a CPS (n = 6), and rare neoplasms (n = 3). CPS was confirmed by clinical criteria in 6 patients and genetic testing in 7 (of 13). In addition, 6 clinically unaffected at-risk relatives were identified carrying a cancer predisposing pathogenic variant. A total of 48 patients were eventually diagnosed with CPS, surveillance recommendations were on record for 45. Of those, 8 patients did not keep their appointments for various reasons. Surveillance revealed neoplasms (n = 2) and metachronous tumors (n = 4) by clinical (n = 2), radiological examination (n = 2), and endoscopy (n = 2). Psychosocial counselling was utilized by 16 (of 45; 35.6%) families.ConclusionsThe diverse pediatric CPSs pose several challenges necessitating interdisciplinary care in specified CPS programs. To ultimately improve outcome including psychosocial well-being joint clinical and research efforts are necessary.

The increase in the number of dogs as pets poses the challenge for veterinary specialists to find new approaches to prevent their morbidity and early mortality. Age and breed are considered to be the main risk criteria for the formation of tumours in dogs, so the aim of this study was to investigate the impact of these and a number of other factors on the susceptibility to cancer in this species. The research was based on the analysis of a single database of veterinary clinics in Bishkek, which includes 328 confirmed cases of cancer in dogs. The most common breeds were German (n=48) and Central Asian Shepherds (n=23), Rottweilers (n=18), Dachshunds (n=18), Poodles (n=17), Shar Pei (n=14), Pekingese (n=14), and a group of outbred dogs (n=70). Benign neoplasms were recorded in 140 cases, accounting for 54.3% of the total number of tumours in pure-bred dogs. Benign tumours predominated in large breed dogs (n=75), or 53.6% of the total number of benign tumours, and the highest growth of malignant tumours was detected in small breed dogs (59%) (n=29). Dogs, regardless of breed, were more vulnerable to tumour formation between the ages of 6 and 12 years. The database analysis revealed that females were more likely to develop cancer than males, with mammary tumours being the main diagnosis in females (36.3%). Small dog breeds had a higher risk of developing mammary tumours than large dogs. The obtained results revealed breed-specific features of the manifestation of morphological types of tumours in dogs and made it possible to determine the critical periods of their formation

Background Telehealth is comprised of telecommunications and electronic information systems to support and maintain long-distance healthcare services. Although it has not been thoroughly explored, the intention of using the service among the general public is critical to its success. We investigated the factors associated with the intention to utilize telehealth services among the general population of Bangladesh. Methods This cross-sectional study was conducted between May 22, 2021 and June 15, 2021 in Bangladesh, where the total number of participants was 1038. The Pearson chi-square test and Kruskal-Wallis H tests were used to examine the unadjusted relationship between the explanatory variables and the intention to use telehealth services. A multinomial logistic regression model was fitted to determine the adjusted association. Shapiro-Wilk tests were used to check the normality of continuous data. Data were processed and analyzed by software STATA-16. Results The probability of utilizing the service increased significantly with increasing knowledge, perceived benefit, and predisposition levels among respondents. However, when perceived concern increased, the likelihood of utilizing the service dropped significantly. Age, marital status, educational status, profession, residence, and perceived health status were significantly associated with the participants’ intention to utilize the telehealth service. Conclusions The influencing aspects of telehealth service utilization should be recognized by the respective authorities. Possible activities to enhance usability among people are also recommended.

Asthma, which affects some 300 million people worldwide and caused 455,000 deaths in 2019, is a significant burden to suffers and to society. It is the most common chronic disease in children and represents one of the major causes for years lived with disability. Significant efforts are made by organizations such as WHO in improving the diagnosis, treatment and monitoring of asthma. However asthma prevention has been less studied. Currently there is a concept of pre- diabetes which allows a reduction in full blown diabetes if diet and exercise are undertaken. Similar predictive states are found in Alzheimer's and Parkinson's diseases. In this paper we explore the possibilities for asthma prevention, both at population level and also investigate the possibility of defining a state of pre-asthma, in which intensive treatment could reduce progression to asthma. Since asthma is a heterogeneous condition, this paper is concerned with allergic asthma. A subsequent one will deal with late onset eosinophilic asthma.

European forest ecosystems are increasingly exposed to stressors such as storm, drought episodes and mass attack of forest insect pests. Sustainable forest management requires a fundamental understanding of causal relationships between forest structures and the occurrence of disturbance events, as well as a well-functioning transfer of scientific knowledge into practice. Risk or predisposition assessment, phenological models or prediction of deficits in stand water supply can serve as decision support for prophylactic and protective measures in forestry. This overview addresses the theoretical approaches to insect pest-related mortality in forests that form the basis for such models. Many insect herbivore species benefit from increased temperatures and drought. For example, there is a clear correlation between bark beetle infestation and summer temperatures, storm damage and precipitation deficits. Drought stress is one of the main factors predisposing conifer forests to bark beetle infestation and significantly impacts interactions among Picea abies, Ips typographus and its associated ophiostomatoid fungi. A multi-year study focused on the effects of drought on the defence capacity and attractiveness of Norway spruce to I. typographus. The empirical dataset gained in field and laboratory experiments provides new insights into defence responses of this important tree species against biotic infestations under drought.

Children and minors in most criminal legislations in the world enjoy a privileged status due to their psychological and physical immaturity. While children belong to the category of completely criminally irresponsible persons, minors are subject to liability, but under specific conditions, defined by the Criminal Code of the Republic of Serbia and the Law on juvenile offenders and the criminal protection of minors. The latest events that have taken place in the Republic of Serbia have encouraged thinking about whether the age limit for criminal responsibility should be reduced, whether punitive measures should be tightened and what preventive measures should be taken to reduce the issue of children and minors committing crimes and prevent tragedies like the tragedy from happening again in the model elementary school "Vladislav Ribnikar" in Belgrade.

Familial non-medullary thyroid carcinoma (FNMTC) accounts for 3% to 9% of all thyroid cancer cases, yet its genetic mechanisms remain unknown. Our study aimed to screen and identify novel susceptibility genes for FNMTC. Whole-exome sequencing (WES) was conducted on a confirmed FNMTC pedigree, comprising four affected individuals across two generations. Variants were filtered and analyzed using ExAC and 1000 Genomes Project, with candidate gene pathogenicity predicted using SIFT, PolyPhen, and MutationTaster. Validation was performed through Sanger sequencing in affected pedigree members and sporadic patients (TCGA database) as well as general population data (gnomAD database). Ultimately, we identified the mutant PPP4R3A (NC_000014.8:g.91942196C>T, or NM_001366432.2(NP_001353361.1):p.(Asp409Asn), based on GRCH37) as an FNMTC susceptibility gene. Subsequently, a series of functional experiments were conducted to investigate the impact of PPP4R3A and its Asp409Asn missense variant in thyroid cancer. Our findings demonstrated that wild-type PPP4R3A exerted tumor-suppressive effects via the Akt-mTOR-P70 S6K/4E-BP1 axis. However, overexpression of the PPP4R3A Asp409Asn mutant resulted in loss of tumor-suppressive function, ineffective inhibition of cell invasion, and even promotion of cell proliferation and migration by activating the Akt/mTOR signaling pathway. These results indicated that the missense variant PPP4R3A Asp409Asn is a candidate susceptibility gene for FNMTC, providing new insights into the diagnosis and intervention of FNMTC.

Aim: For the last 20 years a large amount of data was gathered showing a genetic predisposition to overweight and obesity. The aim of this study was to demonstrate a personalized, genetic-based approach in normalizing the patients’ weight and eating habits.

A family with multiple members diagnosed with prostate cancer was identified, and genetic variants were analyzed. Three brothers were diagnosed with prostate cancer. Germline variants in BRCA1, BRCA2, TINF2, and CD19 were found through next-generation DNA sequencing using a hereditary cancer panel. The BRCA1 G275D variant was present in patients, but absent in the healthy member. An ELAC2 variant was found in 1 patient. Several mutations were predicted to be deleterious by a set of computation programs. Multiple gene mutations might contribute to the overall predisposition to prostate cancer in the family. Even in cases with potentially deleterious variants in BRCA1 or BRCA2, there could be diverse clinical manifestations.

Background: Bone metastasis is the most common metastatic destination in advanced breast cancer, presenting a poor prognosis and clinical challenges in management. To date, the mechanism of bone metastasis in breast cancer remains largely unclear. Methods: Differentially expressed genes in primary tumours that developed bone metastases were systematically analysed using both TCGA-BRCA and E-MTAB-4003 databases. Adaptive phenotype in the subsequent bone lesions was analysed in the GSE46161 database. A series of biomarkers including homing, immune escape, angiogenesis, and factors involved in both osteoblastogenesis and osteoclastogenesis were included to dissect the molecular events underlying bone metastasis in breast cancer. Results: Upregulated expressions of GDF11 expression is positively correlated with colonization, osteoblastogenesis and osteoclastogenesis, whilst CD151 is positively associated with angiogenesis and immune escape. PAFAH1B2 expression is inversely correlated with the angiogenic process. Reduced YTHDF2 may facilitate cancer cell homing, osteoclastogenesis and immune escape in breast cancer. DPP9, FAS, ZNF519, RPP14 and FAU were evaluated for their potential involvement in for the homing to bone, escaping from immune surveillance, angiogenesis, osteoblastic activity and osteoclastic activity in the multi-step process of bone metastasis. Conclusion: GDF11, CD151, PAFAH1B2 and YTHDF2 may play a pivotal role in the predisposition of metastasis to the bone from breast cancer, whilst DPP9, FAS, ZNF519, RPP14 and FAU may be actively involved in the adaptative colonisation of metastatic breast cancer cells in bone.

BackgroundPredisposition to myeloid malignancies is a field at the border of hematology and genetics. Knowledge in this domain has so rapidly increased that WHO defined in 2016 the new “Myeloid Neoplasms with Germline Predisposition” category of tumors. High throughput sequencing is frequently performed in tumors either for diagnosis or prognosis, but this approach may identify potential germline variants that have to be confirmed on non-infiltrated tissues.MethodIn this study, we systematically compared NGS data from genetic analysis performed on all sample types (bone marrow, blood, saliva, skin fibroblasts and hair follicles) in 29 patients, and 44 of their relatives (blood and saliva).ResultsWe showed that saliva was usable for relatives, but only for 24% (7/29) of our patients. Most of patients’ saliva were either “non-contributive” (14/29 i.e., 48% because clearly or probably infiltrated) or “inconclusive” (8/29 corresponding to 28%).ConclusionThe recommendations for the use of saliva we present here focus on the importance of collecting saliva during remission when possible. Moreover, we propose hair follicles as an alternative to skin biopsy, that remains the gold standard especially in case of allogenic hematopoietic stem cells transplantation. Technological progresses have revolutionized the diagnosis of predisposition to solid or hematological malignancies, and it is very likely that new techniques will help to manage the familial predisposition in the future.

Plain English Summary The French Bulldog is currently a hugely popular dog breed in the UK. However, the breed is linked with a range of serious health issues. Using veterinary clinical data from the VetCompass Programme at the Royal Veterinary College, this study aimed to compare the frequency of common disorders in French Bulldogs against that of all remaining dogs to identify health strengths and weaknesses in French Bulldogs. This overall view of breed health can assist owners, breeders and veterinarians to take appropriate actions to improve the health of French Bulldogs. From an overall population of 905,544 dogs, random samples of 2,781 French Bulldogs and 21,850 non-French Bulldogs were included in the analysis. French Bulldogs were younger (1.51 years versus 4.48 years) and lighter (12.45 kg versus 13.80 kg) than non-French Bulldogs. French Bulldogs had increased risk of 20/43 (46.5 %) specific disorders and decreased risk of 11/43 (25.6 %) specific disorders compared to non-French Bulldogs. The disorders with greatest relative risk in French Bulldogs compared to non-French Bulldogs were narrowed nostrils (x 42.14), Brachycephalic Obstructive Airway Syndrome (x 30.89), ear discharge (x 14.40), skin fold dermatitis (x 11.18) and difficulty giving birth [dystocia] (x 9.13). When the disorders were grouped into broad disease categories, French Bulldogs had increased risk of 12/32 (37.5 %) disorder groups and reduced risk of 6/32 (18.8 %) disorder groups compared to non-French Bulldogs. This study suggests that the health of French Bulldogs is very different, and largely much poorer, that the health of the wider non-French Bulldog population. Many of these differences are closely associated with the extreme body shape that defines the French Bulldog breed. Shifting the body shape of French Bulldogs to become more moderate, and hence less extreme, is proposed as a logical opportunity to reduce the current serious and common health issues in the French Bulldog breed.

Abstract Background Stratifying patients with sepsis was the basis of the predisposition, infection, response and organ dysfunction (PIRO) concept, an attempt to resolve the heterogeneity in treatment response. The purpose of this study is to perform an independent validation of the PIRO staging system in an international cohort and explore its utility in the identification of patients in whom time to antibiotic treatment is particularly important. Methods Prospective international cohort study, conducted over a 6-month period in five Portuguese hospitals and one Australian institution. All consecutive adult patients admitted to selected wards or the intensive care, with infections that met the CDC criteria for lower respiratory tract, urinary, intra-abdominal and bloodstream infections were included. Results There were 1638 patients included in the study. Patients who died in hospital presented with a higher PIRO score (10 ± 3 vs 8 ± 4, p

Feng Xiao, Jianrong Zhou School of Nursing, Chongqing Medical University, Chongqing, 400016, People’s Republic of ChinaCorrespondence: Jianrong ZhouSchool of Nursing, Chongqing Medical University, No. 1 Changda Road, Jiulongpo District, Chongqing, 400016, People’s Republic of ChinaEmail jianrong_zhou@21cn.comBackground: Nasopharyngeal carcinoma (NPC) is mainly concentrated in East and Southeast Asia. This study aims to elucidate the potential associations of functional SNPs in the fat mass and obesity associated gene (FTO) with NPC risk and radiotherapy outcomes in a Chinese population.Methods: Functional SNP rs1477196 G>A, rs9939609 T>A, rs7206790 C>G, and rs8047395 A>G were genotyped and evaluated for their associations with NPC risk and radiotherapy outcomes.Results: Both rs9939609 (allele A versus allele T: OR=1.59; 95% CI=1.17– 2.17; P-value=0.003) and rs8047395 (allele G versus allele A: OR=0.76; 95% CI=0.64– 0.9; P-value=0.002) were significantly associated with risk of NPC. GTEx showed risk allele A of rs9939609 and rs8047395 were significantly associated with higher FTO mRNA levels in skeletal muscle tissue, which also corroborated our findings. Meanwhile, both rs1477196 (allele A versus allele G: OR=1.64; 95% CI=1.09– 2.49; P-value=0.019) and rs9939609 (allele A versus allele T: OR=0.61; 95% CI=0.43– 0.87; P-value=0.006) were significantly associated with complete remission (CR) of NPC.Conclusion: Our study identified that FTO polymorphisms contributed to the susceptibility and radiotherapy efficacy of NPC. These results shed light on the potential of establishing markers for predicting risk and personalized treatment of NPC.Keywords: nasopharyngeal carcinoma, FTO, predisposition, radiotherapy

Background: Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures that imposes heavy burden on individuals, families, and also on healthcare systems. As the better understanding of economic aspects of epilepsy will lead to better development of epilepsy care this study was conducted to estimate the cost of illness in epilepsy per patient per year in a tertiary care hospital in New Delhi. Aims and Objectives: The aim of study was to study the direct, indirect and total cost of illness in epilepsy per patient per year in a tertiary care hospital. Materials and Methods: Patients with epilepsy attending the Department of Neurology at Batra Hospital and Medical Research Centre in New Delhi were included in this study. All epilepsy patients fulfilling the inclusion and exclusion criteria were included in the study. The cost of illness was estimated as total, direct and indirect costs of illness per year for each patient. The information was collected on a properly formed format which consists of the demographic details of the patient, general biodata of patient, information about the direct medical costs and direct non-medical costs and information about indirect costs. The results are presented in Mean ± SD frequencies and percentages. The Kruskal-Wallis test was used to compare the costs of illness among different strata. The Mann-Whitney U test was used to compare the costs of illness between strata. The p-value

Alexandra Capellini,1,* Matthew Williams,1,* Kenan Onel,1– 3 Kuan-Lin Huang1– 3 1Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, USA, New York, NY, 10029, USA; 2Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, USA, New York, NY, 10029, USA; 3Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, USA, New York, NY, 10029, USA*These authors contributed equally to this workCorrespondence: Kenan Onel; Kuan-Lin HuangDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, Box 1498, New York, NY, 10029, USATel +1 212-824-6134Email kenan.onel@mssm.edu; kuan-lin.huang@mssm.eduAbstract: The canonical model for hereditary cancer predisposition is a cancer predisposition gene (CPG) that drives either one or both of two fundamental hallmarks of cancer, defective genomic integrity and deregulated cell proliferation, ultimately resulting in the accumulation of mutations within cells. Thus, the genes most commonly associated with cancer-predisposing genetic syndromes are tumor suppressor genes that regulate DNA repair (eg, BRCA1, BRCA2, MMR genes) and/or cell cycle (eg, APC, RB1). In recent years, however, the spectrum of high-penetrance CPGs has expanded considerably to include genes in non-canonical pathways such as oncogenic signaling, metabolism, and protein translation. We propose here that, given the variety of pathways that may ultimately affect genome integrity and cell proliferation, the model of cancer genetic predisposition needs to be expanded to account for diverse mechanisms. This synthesis calls for modeling and multi-omic studies applying novel experimental and computational approaches to understand cancer genetic predisposition.Keywords: cancer, genetics, predisposition, multi-omics, genomics, oncogenesis

Acute myeloid leukaemia (AML) is a heterogeneous myeloid malignancy characterized by recurrent clonal events, including mutations in epigenetically relevant genes such as DNMT3A, ASXL1, IDH1/2, and TET2. Next-generation sequencing analysis of a mother and son pair who both developed adult-onset diploid AML identified a novel germline missense mutation DNMT3A p.P709S. The p.P709S protein-altering variant resides in the highly conserved catalytic DNMT3A methyltransferase domain. Functional studies demonstrate that the p.P709S variant confers dominant negative effects when interacting with wildtype DNMT3A. LINE-1 pyrosequencing and reduced representation bisulphite sequencing (RBBS) analysis demonstrated global DNA hypomethylation in germline samples, not present in the leukaemic samples. Somatic acquisition of IDH2 p.R172K mutations, in concert with additional acquired clonal DNMT3A events in both patients at the time of AML diagnosis, confirms the important pathogenic interaction of epigenetically active genes, and implies a strong selection and regulation of methylation in leukaemogenesis. Improved characterization of germline mutations may enable us to better predict malignant clonal evolution, improving our ability to provide customized treatment or future preventative strategies.

Introduction. Despite a long history of the disease, genital prolapse still have not been definitively solved. A relevance of pelvic organ prolapse in women has been increasing in recent years largely due to a change in the quality of life and desire to sustain their youth. The number of studies pinpointing the cause of the disease in connective tissue dysplasia (CTD) has been increasing annually.Aim: to conduct a systematic analysis and determine most common signs of CTD in women with genital prolapse.Materials and methods. CTD criteria and the relationship with genital prolapse were analyzed. The study was conducted using questionnaires and including clinical studies examining residents of the Belgorod region (135 women). The main group included 91 patients who had signs of pelvic organ prolapse, and control group consisted of 44 healthy women. CTD intensity score proposed by T.Yu. Smolnova et al. (2003) was used to assess signs of dysplasia in women examined allowing to build up three groups in which each symptom was evaluated as severity score.Results. Asthenic constitution was noted in high percentage of women suffering from genital prolapse (16.70 ± 0.38 %) compared with healthy women (2.30 ± 0.15 %; p = 0.016). Mild bruising, increased tissue bleeding tended to rise in main vs. control group (16.50 ± 0.37 % in main group and 0.0 in control group; p = 0.016). Signs of varicose veins and hemorrhoids requiring no surgical treatment were found in 33.00 ± 0.47 % and 4.50 ± 0.21 % in main vs. control group (p = 0.0002), respectively. Genital prolapse and hernia in first-line relatives were recorded in 9.90 ± 0.30 % in main group (p = 0.031), women without signs of prolapse did not indicate prolapse in close relatives.Conclusion. Asthenic constitution, hernias, varicose veins and hemorrhoids, female pelvic and hernial prolapse in close female relatives, a tendency to mild bruising, skeletal anomalies, elastosis skin were among common CTD signs in women with genital prolapse.

Paraoxonase 1 (PON1) is a well recognised member of human endogeneous free radical scavenging systems and its polymorphism and enzyme activity are attributed to various different cancer formations. We aimed to study the Paraoxonase 1 (PON1) polymorphism and enzyme activity in colorectal cancer patients. Peripheral blood samples for DNA extraction were collected from 54 colorectal cancer patients and 85 healthy individuals. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) techniques were used for determination of the PON1192 polymorphism. The frequency of AA genotype was greater than BB and AB genotypes in all groups (n:65 with 46.8%; n:15 with 10.8% and n:59 with 42.4%, respectively). In both tumor groups, PON activities were significantly lower than the control group (p

Obesity is recognized as a significant risk factor for Alzheimer’s disease (AD). Studies have supported the notion that obesity accelerates AD-related pathophysiology in mouse models of AD. The majority of studies, to date, have focused on the use of early-onset AD models. Here, we evaluate the impact of genetic risk factors on late-onset AD (LOAD) in mice fed with a high fat/high sugar diet (HFD). We focused on three mouse models created through the IU/JAX/PITT MODEL-AD Center. These included a combined risk model with APOE4 and a variant in triggering receptor expressed on myeloid cells 2 (Trem2R47H). We have termed this model, LOAD1. Additional variants including the M28L variant in phospholipase C Gamma 2 (Plcg2M28L) and the 677C > T variant in methylenetetrahydrofolate reductase (Mthfr677C >T) were engineered by CRISPR onto LOAD1 to generate LOAD1.Plcg2M28L and LOAD1.Mthfr677C >T. At 2 months of age, animals were placed on an HFD that induces obesity or a control diet (CD), until 12 months of age. Throughout the study, blood was collected to assess the levels of cholesterol and glucose. Positron emission tomography/computed tomography (PET/CT) was completed prior to sacrifice to image for glucose utilization and brain perfusion. After the completion of the study, blood and brains were collected for analysis. As expected, animals fed a HFD, showed a significant increase in body weight compared to those fed a CD. Glucose increased as a function of HFD in females only with cholesterol increasing in both sexes. Interestingly, LOAD1.Plcg2M28L demonstrated an increase in microglia density and alterations in regional brain glucose and perfusion on HFD. These changes were not observed in LOAD1 or LOAD1.Mthfr677C >T animals fed with HFD. Furthermore, LOAD1.Plcg2M28L but not LOAD1.Mthfr677C >T or LOAD1 animals showed transcriptomics correlations with human AD modules. Our results show that HFD affects the brain in a genotype-specific manner. Further insight into this process may have significant implications for the development of lifestyle interventions for the treatment of AD.

Desmopathy of the collateral ligaments of the distal interphalangeal joint (CL-DIPJ) has been increasingly relevant in equine sports medicine. However, the risk factors for the development of such desmopathy are not well established. In the literature, what has been described about it, is based on the clinical conditions observed in animals diagnosed with this disorder. Considering this scenario, the aim of this study was to verify which possible extrinsic or intrinsic risk factors may influence the occurrence of disorders in the collateral ligaments of the distal interphalangeal joint in polo horses. Twenty-five horses from the same equestrian team, all competing in polo, were evaluated via ultrasonography. The outcome was defined as changes in echogenicity and/or boundaries of the CL-DIPJ of the thoracic limbs of the horses evaluated. The intrinsic factors considered in this study were age, the presence of angular deviations and gender. As extrinsic factors, the parameters taken into consideration were the handicap in which the animals played and the type of training to which these horses were previously submitted in their professional athletic career. The prevalence ratio was used to verify the association between risk factor and outcome. The result of this evaluation was considered significant when the confidence interval value did not involve the value 1. Positive and significant association was observed only for age. Playing in different handicaps did not influence the presence of ligament disorders. The other factors evaluated revealed a positive but not significant association. Thus, it was concluded that animals aged nine years or older present a higher risk of CL-DIPJ disorders.

This study aimed at investigating the reasons of Indonesia EFL learners in using morphologically- changed English words in writing and finding out the number of Morphologically Changed English Words tend to be used by Indonesian EFL learners at English study Program at FKIP UMP. The number of sample was 36 Indonesian EFL Learners at the third semester of English Study Program at FKIP UMP. This research was a descriptive study. The technique used for collecting the data was distributing questionnaire. The data was analyzed by using percentage analysis and explained descriptively. The results of this study showed that the majority of respondents had more than one reason for a predisposition using morphologically changed English Words in writing. What triggers the use of them was classified into 9 categories; Entertainment, Habit, Efficiency; Saving time and space, Simplification (Easeness), Esthetics, Narsistics, Self-Contentment, Uniqueness, and Trend/Environment. Self-contentment Reasoning is the most dominant reason that the respondents had. There were 1 sentence, 8 phrases, and 20 words tend to be changed morphologically by Indonesian EFL learners as language users. This research was hoped to give the contribution to sociolinguistic aspect that tries to investigate personal use of the language in society in written and it might be dealt with discourse analysis either. It also informed the language phonemenom happened among Indonesian EFL learners as language users and hoped to help other people understand the original language intention by EFL learners when writing such forms for avoiding misunderstanding.

In our philosophical exploration we shall originally analyze dialectical contradictions of predispositions and skills as a source of memory phenomenon development; the patterns leading to the human professional activity evolution, as well as the identification of obstacles and barriers. The area of human orientation in the world of changing opportunities under the influence of the information society formation, hyper-reality and Smart Society in the cognitive innovation perspective, which is defined in the twenty-first century in the novelties of the labor market, new professions, in the processes of technological development, digitization, and transition to the virtual world of communication networks and the Internet, is justified. Moreover, studies of the memory environment reveal a search for "a certain space of inclination," as well as "corresponding features of each block" of the memory environment, determining the patterns of individual professional selection and prospects of a figure, as the subject not only of professional activity in particular, but of life in general. The correlation of the activity approach developments within the development of the subject’s life as well as the model of predisposition realization by M. Achtnich mentioned as holistic and optimal one, maintained by the specific-historical conditions of the figure, have mostly determined the key problem, which this article is devoted to. The purpose of this scientific exploration is the philosophical understanding of predisposition and skill dialectic in human professional activity (on the example of models by Martin Achtnich and Gregory Popov). The achievements of the theoretical model of Gregory Popov represent the significant results of the solution of the issue, to which P. Drucker reached himself in his formulation of "Smart Approach." It is the aforementioned concept that stands now decisive for the prospects of a "smart society" dispute in various activity spheres. Furthermore, the following disposition considers the praxeological perspective of knowledge of the patterns of the "inclination-skills" contradiction resolving application based on the models of G. Popov and P. Druker.

We tested the association between PON1 L55M, Q192R and I102V polymorphic variants and PC risk in Polish men. DNA from 110 consecutive, newly diagnosed patients hospitalized because of PC and DNA from 110 men – volunteers, healthy at the time of the study. PCR-RFLP method. In our study the average age at PC diagnosis of 55MM genotype carriers from families fulfilling Hereditary Prostate Criteria (HPC) was statistically significantly lower (by 7 years) than the average age at the disease diagnosis of 55MM carriers from families without HPC (54.6 ±6.7 vs. 61.9 ±5.4, respectively, p = 0.03). The probability of 5-year survival for the 55MM carriers was 81.3%, compared to 95.7% for non-carriers (p = 0.08, tendency). This is the first study in Polish men evaluating the impact of PON1 genetic polymorphisms on prostate cancer development and its clinical course. PON1 55MM variant may be probably associated with younger age at PC onset in men from families with HPC and with a shorter survival. However, more extensive studies on a larger number of PC patients, possibly from various populations, are necessary to confirm, and extend our findings.

Abstract Background Multigene panels are routinely used to assess for predisposing germline mutations in families at high breast cancer risk. The number of variants of unknown significance thereby identified increases with the number of sequenced genes. We aimed to determine whether tumor sequencing can help refine the analysis of germline variants based on second somatic genetic events in the same gene. Methods Whole-exome sequencing (WES) was performed on whole blood DNA from 70 unrelated breast cancer patients referred for genetic testing and without a BRCA1, BRCA2, TP53, or CHEK2 mutation. Rare variants were retained in a list of 735 genes. WES was performed on matched tumor DNA to identify somatic second hits (copy number alterations (CNAs) or mutations) in the same genes. Distinct methods (among which immunohistochemistry, mutational signatures, homologous recombination deficiency, and tumor mutation burden analyses) were used to further study the role of the variants in tumor development, as appropriate. Results Sixty-eight patients (97%) carried at least one germline variant (4.7 ± 2.0 variants per patient). Of the 329 variants, 55 (17%) presented a second hit in paired tumor tissue. Of these, 53 were CNAs, resulting in tumor enrichment (28 variants) or depletion (25 variants) of the germline variant. Eleven patients received variant disclosure, with clinical measures for five of them. Seven variants in breast cancer-predisposing genes were considered not implicated in oncogenesis. One patient presented significant tumor enrichment of a germline variant in the oncogene ERBB2, in vitro expression of which caused downstream signaling pathway activation. Conclusion Tumor sequencing is a powerful approach to refine variant interpretation in cancer-predisposing genes in high-risk breast cancer patients. In this series, the strategy provided clinically relevant information for 11 out of 70 patients (16%), adapted to the considered gene and the familial clinical phenotype.

ABSTRACT: Patients with acute renal failure often have a negative energy balance, which promotes metabolic changes predisposing to complications. The objective of this study was to evaluate laboratory parameters of 30 dogs with severe acute renal failure, to assess their relationship with the possibility of developing acute pancreatitis due to the negative energy balance, and to correlate these findings with the degree of renal failure. Serum concentrations of urea, creatinine, beta-hydroxybutyrate, triglycerides, amylase, total lipase, and canine pancreatic lipase were compared between healthy dogs and dogs with severe acute renal failure. A greater serum concentration of beta-hydroxybutyrate and greater activity of pancreatic enzymes, particularly canine pancreatic lipase, as well as a stronger correlation between the latter and serum creatinine concentrations, were related to the occurrence of acute pancreatitis in patients with severe acute renal failure. A greater degree of renal failure implied a greater predisposition to acute pancreatitis.

Juvenile idiopathic arthritis (JIA) is a multifactorial immune-mediated inflammatory disease in childhood, the most common type of rheumatic disease in children. It is characterized by the polygenic type of hereditary predisposition.Objective: to study the association of STAT4 rs7574865 G/T and IRF5 rs2004640 G/T polymorphisms with the predisposition to certain JIA subtypes in the Russian pediatric population.Patients and methods. The investigation enrolled 177 patients, including 66 patients diagnosed with JIA and 111 healthy unrelated volunteers (a control group). Of the 66 patients with JIA there were 30 (45%) with oligoarthritis: 20 (67%) with human leukocyte antigen B27(HLA-B27)-positive JIA (that was associated with enthesitis, HLA-B27 positive JIA (JIA-B27), 10 (33%) with anterior uveitis concurrent with antinuclear antibody-positive JIA (JIA-uveitis); 20 (30%) with polyarticular JIA (JIA-poly), seronegative for rheumatoid factor; and 16 (24%) with systemic JIA (JIA-sys). As a control for genotyping STAT4 rs7574865 G/T and IRF5 rs2004640 G/T polymorphisms, the investigators studied 103 and 111 DNA samples from healthy adult volunteers, respectively. STAT4 rs7574865 G/T and IRF5 rs2004640 G/T polymorphisms were investigated using allele-specific real-time polymerase chain reaction (RT-PCR).Results and discussion. In the oligoarticular JIA group, the frequency of the STAT4 T allele was significantly higher than that in the control group (38.3 and 20.4%, respectively; p=0.004). This allele was also significantly more common in the JIA-B27 (35.0 and 20.4%, respectively; p=0.044) and JIA-uveitis (45.0 and 20.4%, respectively; p=0.021) groups compared with the control one. No significant differences were found in the frequency of the mutant STAT4 T allele between the control group and the JIA-sys and JIA-poly groups. Regression analysis showed that the identification of the STAT4 T allele was associated with the high risk of a predisposition to oligoarticular JIA as a whole (odds ratio, OR 2.43; 95% confidence interval (CI) 1.23–4.70; p=0.007), as well as to the antinuclear antibody-positive oligoarticular JIA with uveitis (JIA-uveitis): the risk in T allele carriers was 3.2 times higher than that in the control (OR 3.19; 95% CI 1.09–9.06; p= ). A high risk for predisposition was also found in the JIA-B27 subgroup compared with the control (OR 2.10; 95% CI 0.38–4.60; p=0.070). There were no statistical differences in the frequency of genotypes and alleles of the IRF5 rs2004640 G/T polymorphism between the entire group of JIA as a whole and its individual clinical types, as well as the control group.Conclusion. This pilot study confirmed that the STAT4 rs7574865 G/T polymorphism was associated with the risk of oligoarticular JIA, mainly that of JIA-uveitis and JIA-B27.

Objective: sto study the clinical picture, psychopathological dynamics and significant pathogenetic factors of computer addiction development (CA).Materials and methods: the study included 93 patients with CA. The control group (CG) was represented by 50 healthy volunteers. Methods: clinical, psychological, paraclinical (brain MRI; EEG; daily excretion level of adrenaline, norepinephrine, dopamine; blood serotonin level; molecular genetic studies), statistical.Results: It is established, that the clinical picture of CA is represented by episodes of computer activity (CAct) and non-episode periods. Their features form a single syndrome of addiction to CAct. Increase of symptoms’ severity and their complication occur due to addition of the altered reactivity syndrome. The clinical-dynamic model of CA development is characterized by phasing with the presence of the initial stage and the stage of the expanded clinical picture. The disorder has a predisposition. The personality component of the predisposition includes the predominance of accentuations of unstable and schizoid types, low rates of internality in both groups. The morphofunctional component includes Val158Met polymorphism features of the COMT gene as predominance (59.1 %) of homozygotes for the Val allele and a high frequency of CNS structural anomalies (55 patients; 62.5 %). The gender component characterizes the predominance of males in CA. Some pathogenetic mechanisms of CA are established: impaired catecholamine and serotonin neuromediation, impaired bioelectrical brain activity with a high prevalence (47.0 %) of paroxysmal activity.Conclusions: Based on the identified pathogenetic mechanisms, the following approaches to the CA treatment are recommended: psychotherapy, psychopharmacotherapy, and their combination.

Abstract Background Rotator cuff disease is a widespread musculoskeletal pathology and a major cause of shoulder pain. Studies on familial predisposition suggest that genetic plays a role in the pathogenesis of rotator cuff disease. Several genes are responsible for rotator cuff disease. The aim of this study was to perform a systematic review on genetic association between rotator cuff disease and genes variations. Methods A systematic review of the literature was performed, in accordance with the PRISMA guidelines. PubMed, Medline, CINAHL, Cochrane, Embase and Google Scholar databases were searched comprehensively using the keywords: “Rotator cuff”, “Gene”, “Genetic”, “Predisposition”, “Single-nucleotide polymorphism” and “Genome-wide association”. Results 8 studies investigating genes variations associated with rotator cuff tears were included in this review. 6 studies were case-control studies on candidate genes and 2 studies were GWASs. A significant association between SNPs and rotator cuff disease was found for DEFB1, FGFR1, FGFR3, ESRRB, FGF10, MMP-1, TNC, FCRL3, SASH1, SAP30BP, rs71404070 located next to cadherin8. Contradictory results were reported for MMP-3. Conclusion Further investigations are warranted to identify complete genetic profiles of rotator cuff disease and to clarify the complex interaction between genes, encoded proteins and environment. This may lead to individualized strategies for prevention and treatment of rotator cuff disease. Level of evidence Level IV, Systematic Review.

Introduction: Breed predisposition to cutaneous mast cell tumours (MCT) in a population of dogs in Poland affected by various skin tumours was assessed, and the distribution of MCT characteristics such as histological grading, sex, age, and location, in predisposed breeds was evaluated.

COVID-19 conspiracy theories have proliferated during the global pandemic, and their rapid spread among certain groups may jeopardize the public health response (e.g., undermining motivation to engage in social distancing and willingness to vaccinate against the virus). Using survey data from two waves of a nationally representative, longitudinal study of life in lockdown in the United Kingdom (N = 1,406), we analyze the factors associated with belief in three origin theories related to COVID-19, namely that it 1) originated in a meat market in Wuhan, China; 2) was developed in a lab in Wuhan, China; and 3) is caused by 5G mobile networks. Our findings suggest that political-psychological predispositions are strongly associated with belief in conspiracy theories about the virus, though the direction and effect sizes of these predictors vary depending on the specific content of each origin theory. For instance, belief in the Chinese lab conspiracy theory is strongly associated with right-wing authoritarianism (RWA), social dominance orientation (SDO), and general conspiracy ideation, as well as less reliable news sources, distrust in scientists, and anxiety about the pandemic. Belief in the 5G network conspiracy theory is strongly associated with SDO, distrust in scientists, while less strongly with conspiracy ideation and information from social networks/media; RWA is strongly negatively associated with belief in the 5G conspiracy theory, with older and more wealthy individuals somewhat less likely to endorse it. The meat market origin theory is predicted by intolerance of uncertainty, ethnocentrism, COVID-19 anxiety, and less so by higher income, while distrust in scientists is negatively associated with this origin story. Finally, belief in COVID-19 conspiracy theories is associated with negative public health behaviors such as unwillingness to social distance and vaccinate against the virus. Crucially, our findings suggest that the specific content of COVID-19 conspiracy theories likely determines which individuals may be most likely to endorse them.

Propose: Cytochrome P450 family 2 subfamily R member 1 (CYP2R1) variations can affect the activity of 25-hydroxylase, resulting in the deficiency of 25(OH)D, which leads to an increased incidence and mortality of coronary heart disease (CHD). The purpose is to assess the influence of CYP2R1 variants on CHD risk among the Chinese Han population.Methods: A total of 508 CHD patients and 510 healthy controls were enrolled. The MassARRAY platform completed genotyping of CYP2R1 variants. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated using logistic regression analysis.Results: Rs6486205 (OR = 1.25, 95% CI: 1.05–1.50, p = 0.014), rs10741657 (OR = 1.29, 95% CI: 1.08–1.54, p = 0.005), and rs2060793 (OR = 1.27, 95% CI: 1.06–1.51, p = 0.009) were associated with the increased susceptibility to CHD in the whole subjects. Interestingly, the relationships between these variants and CHD risk were observed in the subjects with age >60 years, males or non-smoker. Additionally, the haplotypes Ars10741657Ars2060793 and Grs10741657Grs2060793 had the higher risk of CHD, and the combination (rs6486205 and rs10741657) was the best multi-locus model.Conclusion: Our study suggested the contribution of CYP2R1 polymorphisms to the increased CHD predisposition in the Chinese Han population. Furthermore, the risk association was related to confounding factors for CHD, including age, sex, and smoking. These findings might help to strengthen the understanding of the CYP2R1 gene in the occurrence of CHD.

Xiao F, Zhou J. Pharmgenomics Pers Med. 2021;14:1239–1245. At the authors request, the Editor and Publisher of Pharmacogenomics and Personalised Medicine wish to retract the published article. The authors have advised that despite the research being approved and authorized by the Ethics Committee of the School of Nursing of Chongqing Medical University, it also needed to be approved and authorized by the Ethics Committee of Chongqing Medical University. However, the authors were not aware of this requirement and failed to acquire the appropriate authorization prior to commencement of the study and have requested to retract the article. The authors wish to apologise for this error. Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”. This retraction relates to this paper

Objectives: To study Epstein-Barr virus (EBV) antibody patterns in twin individuals with rheumatoid arthritis (RA) and their healthy co-twins, and to determine the heritability of antibody responses against the EBV encoded EBNA1 protein.Methods: Isotypes of EBNA1 antibodies were measured in 137 RA affected- and 150 healthy twin pairs. We estimated the effect of RA and RA predisposition, anti-citrullinated antibodies (ACPA), IgM rheumatoid factor (RF), the shared epitope (SE) and the PTPN22-T allele (PTPN22) on the level of EBNA1 antibodies. We also determined the heritability of EBNA1 antibody levels.Results: IgA-EBNA1 antibody levels were increased in twins from RA discordant twin pairs irrespective of RA, ACPA or IgM-RF status. The IgG-EBNA1 antibody level was elevated in healthy co-twins from RA discordant twin pairs but not in RA affected twins. The IgM-EBNA1 antibody level was elevated in both RA twins and their healthy co-twins. The effect of RA on the IgA-EBNA1 antibody level was reversed when SE was present and with no effect of PTPN22. The heritability of IgA-, IgG- and IgM-EBNA1 antibody level was 40.6, 65.5, and 54.3%, with no effect of environment shared by the twins.Conclusion: EBNA1 antibody levels are distinctively different between patients with RA and healthy subjects but also between relatives of RA strongly predisposed to RA and healthy subjects. The high level of IgA EBNA1 antibodies associated with RA and a family predisposition to RA is attributable to both genetics incl. the shared epitope and environmental variation.

Estrogen is a female sex steroid hormone that plays a significant role in physiological functions. Evidence suggests that estrogen-signaling pathways are closely linked to cancer development and progression. The novel G protein-coupled estrogen receptor (GPER or GPR30) has been shown to influence cancer predisposition and progression, although results of related studies remain equivocal. Thus, this meta-analysis aimed to estimate the relationship between GPER gene polymorphisms and GPER expression levels, with cancer predisposition and progression. The pooled results showed that two GPER polymorphisms, rs3808350 and rs3808351, were significantly associated with cancer predisposition, especially in the Asian population, but no significant association was detected for rs11544331. In parallel, we also found that cancer aggressiveness and progression correlated with rs3808351 and GPER expression in cancerous tissues. Altogether, our findings suggest that GPER plays a pivotal role in cancer pathogenesis and progression. We suggest that rs3808350 and rs3808351 may be used as a prospective biomarker for cancer screening; while rs3808351 and GPER expression can be used to examine the prognosis of patients with cancer. Further biological studies are warranted to confirm our findings.

The maintenance of genomic stability is crucial for species survival, and its failure is closely associated with tumorigenesis. The Fanconi anemia (FA) pathway, involving 22 identified genes, plays a central role in repairing DNA interstrand cross-links. Importantly, a germline defect in any of these genes can cause Fanconi’s anemia, a heterogeneous genetic disorder, characterized by congenital growth abnormalities, bone marrow failure, and predisposition to cancer. On the other hand, the breast cancer susceptibility genes, BRCA1 and BRCA2, also known as FANCS and FANCD1, respectively, are involved in the FA pathway; hence, researchers have studied the association between the FA pathway and cancer predisposition. Here, we mainly focused on and systematically reviewed the clinical and mechanistic implications of the predisposition of individuals with abnormalities in the FA pathway to cancer, especially breast cancer.

Abstract Background The domestic dog is one of the most diverse mammalian species, exhibiting wide variations in morphology, behaviour and morbidity across breeds. Therefore, it is not unexpected that breeds should also exhibit variation in mortality and longevity. While shorter longevity per se may not necessarily be a welfare issue, a generally foreshortened lifespan in a breed that is accompanied by a high prevalence of a particular cause of death may reveal potentially serious welfare concerns and highlight scope to improve breed welfare. Survey data gathered directly from owners offer useful insights into canine longevity and mortality that can support the overall evidence base for welfare reforms within breeds. Results Mortality data on 5663 deceased dogs registered with the UK Kennel Club were collected from an owner-based survey. The most commonly reported causes of death were old age (13.8%), unspecified cancer (8.7%) and heart failure (4.9%); with 5.1% of deaths reported as unknown cause. Overall median age at death was 10.33 years (interquartile range: 7.17–12.83 years). Breeds varied widely in median longevity overall from the West Highland Terrier (12.71 years) to the Dobermann Pinscher (7.67 years). There was also wide variation in the prevalence of some common causes of death among breeds, and in median longevity across the causes of death. Conclusion Substantial variation in the median lifespan and the prominent causes of death exists across breeds. This study has identified some breeds with both a low median lifespan and also a high proportional mortality for one or more specific causes of death that should be considered as both potential welfare concerns as well as opportunities for improvement.

Abstract Background Canine breeds may be considered good animal models for the study of genetic predisposition to cancer, as they represent genetic clusters. From epidemiologic and case collection studies it emerges that some breeds are more likely to develop lymphoma or specific subtypes of lymphoma but available data are variable and geographically inconsistent. This study was born in the context of the European Canine Lymphoma Network with the aim of investigating the breed prevalence of canine lymphoma in different European countries and of investigating possible breed risk of lymphoma overall and/or different lymphoma subtypes. Results A total of 1529 canine nodal lymphoma cases and 55,529 control cases from 8 European countries/institutions were retrospectively collected. Odds ratios for lymphoma varied among different countries but Doberman, Rottweiler, boxer and Bernese mountain dogs showed a significant predisposition to lymphoma. In particular, boxers tended to develop T-cell lymphomas (either high- or low-grade) while Rottweilers had a high prevalence of B-cell lymphomas. Labradors were not predisposed to lymphoma overall but tended to develop mainly high-grade T-cell lymphomas. In contrast with previous studies outside of Europe, the European golden retriever population did not show any possible predisposition to lymphoma overall or to specific subtypes such as T-zone lymphoma. Conclusion Further prospective studies with more precise and consistent subtype identification are needed to confirm our retrospective results and to create the basis for the investigation of possible genes involved in different predispositions.

Abstract Background The human helminth infections include ascariasis, trichuriasis, hookworm infections, schistosomiasis, lymphatic filariasis (LF) and onchocerciasis. It is estimated that almost 2 billion people worldwide are infected with helminths. Whilst the WHO treatment guidelines for helminth infections are mostly aimed at controlling morbidity, there has been a recent shift with some countries moving towards goals of disease elimination through mass drug administration, especially for LF and onchocerciasis. However, as prevalence is driven lower, treating entire populations may no longer be the most efficient or cost-effective strategy. Instead, it may be beneficial to identify individuals or demographic groups who are persistently infected, often termed as being “predisposed” to infection, and target treatment at them. Methods The authors searched Embase, MEDLINE, Global Health, and Web of Science for all English language, human-based papers investigating predisposition to helminth infections published up to October 31st, 2017. The varying definitions used to describe predisposition, and the statistical tests used to determine its presence, are summarised. Evidence for predisposition is presented, stratified by helminth species, and risk factors for predisposition to infection are identified and discussed. Results In total, 43 papers were identified, summarising results from 34 different studies in 23 countries. Consistent evidence of predisposition to infection with certain species of human helminth was identified. Children were regularly found to experience greater predisposition to Ascaris lumbricoides, Schistosoma mansoni and S. haematobium than adults. Females were found to be more predisposed to A. lumbricoides infection than were males. Household clustering of infection was identified for A. lumbricoides, T. trichiura and S. japonicum. Ascaris lumbricoides and T. trichiura also showed evidence of familial predisposition. Whilst strong evidence for predisposition to hookworm infection was identified, findings with regards to which groups were affected were considerably more varied than for other helminth species. Conclusion This review has found consistent evidence of predisposition to heavy (and light) infection for certain human helminth species. However, further research is needed to identify reasons for the reported differences between demographic groups. Molecular epidemiological methods associated with whole genome sequencing to determine ‘who infects whom’ may shed more light on the factors generating predisposition.

Abstract Background Thyroid cancer is a common malignant disease of the endocrine system with increasing incidence rates over the last few decades. In this study, we sought to analyze the possible association of 45 single nucleotide polymorphisms (SNPs) with thyroid cancer in a population from Rio Grande do Norte, Brazil. Methods Based on histological analysis by a pathologist, 80 normal thyroid specimens of tissue adjacent to thyroid tumors were obtained from the biobank at the Laboratory of Pathology of Liga Norte Riograndense Contra o Câncer, Natal, RN. Patient samples were then genotyped using the MassARRAY platform (Sequenon, Inc) followed by statistical analysis employing the SNPassoc package in R program. The genotypic frequencies of all 45 SNPs obtained from the International HapMap Project database and based on data from the ancestral populations of European and African origin were used to compose the control study group. Results In our study, the following 9 SNPs showed significant differences in their frequency when comparing the study and control groups: rs3744962, rs258107, rs1461855, rs4075022, rs9943744, rs4075570, rs2356508, rs17485896, and rs2651339. Furthermore, the SNPs rs374492 C/T and rs258107 C/T were associated with a relative risk for thyroid carcinoma of 3.78 (p = 6.27 × 10e−5) and 2.91 (p = 8.27 × 10e−5), respectively, after Bonferroni’s correction for multiple comparisons. Conclusions These nine polymorphisms could be potential biomarkers of predisposition to thyroid carcinoma in the population from Rio Grande do Norte. However, complementary studies including a control group with samples obtained from healthy subjects in Rio Grande do Norte state, should be conducted to confirm these results.

Aim: to study the relationship between homocysteine, cysteine and glutathione in blood serum and various single nucleotide polymorphisms (SNPs) of genes involved in folate metabolism in patients with proliferative breast disease and breast cancer. Material and methods. The study included 112 patients with proliferative breast lesions and breast cancer in Transbaikalia. The control group consisted of 144 women having no breast cancer. Blood levels of homocysteine, cysteine and glutathione were evaluated by HPLC (high performance liquid chromatography). Genotyping was performed by polymerase chain reaction with the detection of amplification product in real-time. Results. Molecular-genetic testing revealed no association between breast disease and genetic polymorphisms of MTHFR(C677T), MTHFR(A1298C), MTR(A2756G), MTRR(A66G) in women with proliferative breast lesions and breast cancer, however, in contrast to the control group, the concentrations of homocysteine and glutathione were increased.

Abstract Background The landscape of cancer-predisposing genes has been extensively investigated in the last 30 years with various methodologies ranging from candidate gene to genome-wide association studies. However, sequencing data are still poorly exploited in cancer predisposition studies due to the lack of statistical power when comparing millions of variants at once. Method To overcome these power limitations, we propose a knowledge-based framework founded on the characteristics of known cancer-predisposing variants and genes. Under our framework, we took advantage of a combination of previously generated datasets of sequencing experiments to identify novel breast cancer-predisposing variants, comparing the normal genomes of 673 breast cancer patients of European origin against 27,173 controls matched by ethnicity. Results We detected several expected variants on known breast cancer-predisposing genes, like BRCA1 and BRCA2, and 11 variants on genes associated with other cancer types, like RET and AKT1. Furthermore, we detected 183 variants that overlap with somatic mutations in cancer and 41 variants associated with 38 possible loss-of-function genes, including PIK3CB and KMT2C. Finally, we found a set of 19 variants that are potentially pathogenic, negatively correlate with age at onset, and have never been associated with breast cancer. Conclusions In this study, we demonstrate the usefulness of a genomic-driven approach nested in a classic case-control study to prioritize cancer-predisposing variants. In addition, we provide a resource containing variants that may affect susceptibility to breast cancer.

Intensive development of DNA analysis technologies and largescale genome-wide association studies have led to accumulation of a large array of data on the relationship between genetic factors and various phenotypic manifestations, including monogenic and polygenic hereditary diseases. This greatly has extended the capabilities of clinical diagnostics and predictive medicine in the field of socially significant diseases. For example, a role of agenetic component of the risk for such a multifactorial and polyetiologic disease as stroke is now actively explored. Large-scale studies have revealed both general and specific genetic markers associated only with a certain type and subtype of stroke. This review analyzes the current state of the problem of using genetic markers for diagnosis of stroke predisposition, complex issues associated with multiplicity of risk factors for stroke, and possible development in this area.

Objective ― The aim of the work was to study the contribution of the immune response mediator genes polymorphism (TNFA rs1800629, LTA rs909253, IL1B rs16944, IL2-IL21 rs6822844, IL2RA rs2104286, IL6 rs1800795, IL10 rs1800872, MIF rs755622, CTLA4 rs3087243, NFKB1 rs28362491, PTPN22 rs2476601, PADI4 rs2240336) to the formation of the predisposition to juvenile idiopathic arthritis (JIA) and its clinical variants. Material and Methods ― The JIA group included 330 patients and the control group – 342 volunteers without autoimmune diseases from the Republic of Bashkortostan, Russia. Genotyping was conducted by the real-time polymerase chain reaction. Results ― Taking into account the differences by sex, it was established, that the alleles/genotypes of the TNFA rs1800629, LTA rs909253, IL2-IL21 rs6822844, PTPN22 rs2476601 polymorphic loci and the TNFA rs1800629*G – LTA rs909253*G haplotype are associated with the development of JIA as a whole (p

Early-life stressful experiences are critical for plasticity and development, shaping adult neuroendocrine response and future health. Stress response is mediated by the autonomous nervous system and the hypothalamic–pituitary–adrenal (HPA) axis while various environmental stimuli are encoded via epigenetic marks. The stress response system maintains homeostasis by regulating adaptation to the environmental changes. Pre-conceptual and in utero stressors form the fetal epigenetic profile together with the individual genetic profile, providing the background for individual stress response, vulnerability, or resilience. Postnatal and adult stressful experiences may act as the definitive switch. This review addresses the issue of how preconceptual in utero and postnatal events, together with individual differences, shape future stress responses. Putative markers of early-life adverse effects such as prematurity and low birth weight are emphasized, and the epigenetic, mitochondrial, and genomic architecture regulation of such events are discussed.

The next-generation sequencing era has repeatedly demonstrated that the amount of acquired somatic mutations in paediatric cancers can rarely account for the total incidence of any cancer subtype. In addition, many cancer-related mutations can be found in healthy individuals. These findings strongly suggest that additional genetic or epigenetic variation is required for malignant transformation, particularly in children who have significantly less environmental exposure and resulting genetic damage. Current studies now suggest that 3–33% of paediatric cancer patients have a predisposition to cancer. These germline genetic or epigenetic changes are frequently found in molecular mechanisms regulating normal human development which have long informed our understanding of developmental biology. Blockade of development is a mechanism of transformation consistent with the higher number of immature cancer cell types in paediatric patients. Thus, while nearly every cancer is a combination of germline variation and somatic mutation, the relative contribution to tumourigenesis in paediatrics is weighted toward germline changes. This review will explore how paediatric predisposition to leukaemia is influenced by germline genetic and epigenetic variability of variable penetrance. Improved understanding of these critical developmental mechanisms will lead to improved surveillance and perhaps guide a new class of therapeutics aimed at promoting normal differentiation rather than widespread cytotoxicity.