Mycobacterium paratuberculosis: A HERV Turn-On for Autoimmunity, Neurodegeneration, and Cancer?

Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections that, over millions of years, became integrated into the human genome. While normally inactive, environmental stimuli such as infections have contributed to the transcriptional reactivation of HERV-promoting pathological conditions, including the development of autoimmunity, neurodegenerative disease and cancer. What infections trigger HERV activation? Mycobacterium avium subspecies paratuberculosis (MAP) is a pluripotent driver of human disease. Aside from granulomatous diseases, Crohn's disease, sarcoidosis and Blau syndrome, MAP is associated with autoimmune disease: type one diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis (RA) and autoimmune thyroiditis. MAP is also associated with Alzheimer's disease (AD) and Parkinson's disease (PD). Autoimmune diabetes, MS and RA are the diseases with the strongest MAP/HERV association. There are several other diseases associated with HERV activation, including diseases whose epidemiology and/or pathology would prompt speculation for a causal role of MAP. These include non-solar uveal melanoma, colon cancer, glioblastoma and amyotrophic lateral sclerosis (ALS). This article further points to MAP infection as a contributor to autoimmunity, neurodegenerative disease and cancer via the un-silencing of HERV. We examine the link between the ever-increasing number of MAP-associated diseases and the MAP/HERV intersection with these diverse medical conditions, and propose treatment opportunities based upon this association.

Comprehensive Echographic Evaluation of Insulinoma, From Bedside to Endoscopic Ultrasonography: A Case Report and Brief Review of the Literature.

Insulinoma is a neuroendocrine tumor of the pancreas, and its identification with bedside ultrasonography (US) is extremely rare. With the aim of providing a comprehensive description of the main US characteristics of this rare form of neuroendocrine neoplasm, we are here describing an interesting case of a young woman with insulinoma, identified by using both bedside and endoscopic ultrasounds.

Correlation between antibodies against the pathogenic pHERV-W envelope protein and the inflammatory phase of multiple sclerosis.

The role of retroviral envelope proteins belonging to the Human Endogenous Retroviral family 'W' (HERV-W), specifically syncytin-1 and pathogenic HERV-W (pHERV-W), as potential risk factors in multiple sclerosis (MS) has been established. This study aimed to investigate the humoral response to syncytin-1 and pHERV-W-derived peptides in a group of relapsing remitting MS patients categorized as having acute or stable disease. Furthermore, an inhibition assay was conducted to assess the extent of cross-reactivity between the two epitopes. The findings revealed that MS patients in the acute phase exhibited a higher specific antibody response to the pHERV-W env epitope compared to syncytin-1. This suggests a potential pathogenic role for pHERV-W env during the inflammatory stages of central nervous system involvement, and these antibody responses could serve as useful biomarkers for monitoring the progression of the disease.

Endogenous retrovirus group FRD member 1 is a potential biomarker for prognosis and immunotherapy for kidney renal clear cell carcinoma.

Introduction: The activation of endogenous retroviral (ERV) genes in kidney renal clear cell carcinoma (KIRC) suggests the necessity for further research on their functions. Methods: In this study, KIRC and healthy cohorts were obtained from TGGA and GEO datasets. Subsequently, differential analysis and functional annotation were conducted using GO, KEGG, and GSEA. Clinical outcomes were then observed and utilized in the development of a nomogram. Results: We observed the general low expression of ERVFRD-1 in KIRC tumors compared to normal tissue (P < 0.001) across multiple cohorts. Differential analysis and functional annotation using GO, KEGG, GSEA analysis revealed significant involvement of ERVFRD-1 in tumor immunoregulation: a close relation to the infiltration levels of mast cells and Treg cell (P < 0.001) and occurrence with a variety of immune markers. Methylation status was then applied to uncover potential mechanisms of ERVFRD-1 in KIRC. Notably, higher expression levels of ERVFRD-1 were associated with extended overall survival, disease-specific survival, and progression-free survival. Finally, based on Cox regression analysis, we constructed a nomogram incorporating ERVFRD-1, pathologic T, and age, which exhibited promising predictive power in assessing the survival outcomes of KIRC patients. Discussion: To sum up, our study suggests that ERVFRD-1 plays a role in regulating immunological activity within the tumor microenvironment and is associated with overall survival in KIRC patients. ERVFRD-1 may therefore be a sensitive biomarker for diagnosis, immunotherapy, and prognosis assessment of KIRC.

Fecal Microbiota Transplantation in Irritable Bowel Syndrome: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Irritable bowel syndrome (IBS) poses a significant challenge due to its poorly understood pathogenesis, substantial morbidity, and often inadequate treatment outcomes. The role of fecal microbiota transplantation (FMT) in managing IBS symptoms remains inconclusive. This systematic review and meta-analysis aimed to ascertain the effectiveness of FMT in relieving symptoms in IBS patients. A thorough search was executed on PubMed/Medline and Embase databases until 14 June 2023, including all studies on FMT use in IBS patients. We examined the efficiency of FMT in reducing patients' symptoms overall and in particular subgroups, classified by placebo preparation, FMT preparation, frequency, and route of administration. Among 1015 identified studies, seven met the inclusion criteria for the meta-analysis. The overall symptomatology of FMT-treated IBS patients did not significantly differ from the control group (Odds Ratio (OR) = 0.99, 95% Confidence Interval (CI) 0.39-2.5). Multiple doses of FMT compared with non-FMT placebo, or single-donor FMT therapy compared with autologous FMT placebo also showed no significant benefit (OR = 0.32, 95%CI (0.07-1.32), p = 0.11, and OR = 1.67, 95%CI (0.59-4.67), p = 0.32, respectively). However, a single dose of multiple-donor FMT administered via colonoscopy (lower gastrointestinal (GI) administration) significantly improved patient symptoms compared with autologous FMT placebo (OR = 2.54, 95%CI (1.20-5.37), p = 0.01, and OR = 2.2, 95%CI (1.20-4.03), p = 0.01, respectively). The studies included in the analysis showed a low risk of bias and no publication bias. In conclusion, lower GI administration of a single dose of multiple-donor FMT significantly alleviates patient complaints compared with the autologous FMT used as a placebo. The underlying mechanisms need to be better understood, and further experimental studies are desired to fill the current gaps.

A Multigene-Panel Study Identifies Single Nucleotide Polymorphisms Associated with Prostate Cancer Risk.

The immune system plays a critical role in modulating cancer development and progression. Polymorphisms in key genes involved in immune responses are known to affect susceptibility to cancer. Here, we analyzed 35 genes to evaluate the association between variants of genes involved in immune responses and prostate cancer risk. Thirty-five genes were analyzed in 47 patients with prostate cancer and 43 healthy controls using next-generation sequencing. Allelic and genotype frequencies were calculated in both cohorts, and a generalized linear mixed model was applied to test the relationship between prostate cancer risk and nucleotide substitution. Odds ratios were calculated to describe the association between each single nucleotide polymorphism (SNP) and prostate cancer risk. Significant changes in allelic and genotypic distributions were observed for IL4R, IL12RB1, IL12RB2, IL6, TMPRSS2, and ACE2. Furthermore, a generalized linear mixed model identified statistically significant associations between prostate cancer risk and SNPs in IL12RB2, IL13, IL17A, IL4R, MAPT, and TFNRS1B. Finally, a statistically significant association was observed between IL2RA and TNFRSF1B and Gleason scores, and between SLC11A1, TNFRSF1B and PSA values. We identified SNPs in inflammation and two prostate cancer-associated genes. Our results provide new insights into the immunogenetic landscape of prostate cancer and the impact that SNPs on immune genes may have on affecting the susceptibility to prostate cancer.

Bacillus Calmette-Guérin Tokyo-172 vaccine provides age-related neuroprotection in actively induced and spontaneous experimental autoimmune encephalomyelitis models.

Multiple sclerosis is the most common immune-mediated disorder affecting the central nervous system in young adults but still has no cure. Bacillus Calmette-Guérin (BCG) vaccine is reported to have non-specific anti-inflammatory effects and therapeutic benefits in autoimmune disorders including multiple sclerosis. However, the precise mechanism of action of BCG and the host immune response to it remain unclear. In this study, we aimed to investigate the efficacy of the BCG Tokyo-172 vaccine in suppressing experimental autoimmune encephalomyelitis (EAE). Groups of young and mature adult female C57BL/6J mice were BCG-vaccinated 1 month prior or 6 days after active EAE induction using myelin oligodendrocyte glycoprotein (MOG)35-55 peptide. Another group of 2D2 TCRMOG transgenic female mice was BCG-vaccinated before and after the onset of spontaneous EAE. BCG had an age-associated protective effect against active EAE only in wild-type mice vaccinated 1 month before EAE induction. Furthermore, the incidence of spontaneous EAE was significantly lower in BCG vaccinated 2D2 mice than in non-vaccinated controls. Protection against EAE was associated with reduced splenic T-cell proliferation in response to MOG35-55 peptide together with high frequency of CD8+ interleukin-10-secreting T cells in the spleen. In addition, microglia and astrocytes isolated from BCG-vaccinated mice showed polarization to anti-inflammatory M2 and A2 phenotypes, respectively. Our data provide new insights into the cell-mediated and humoral immune mechanisms underlying BCG vaccine-induced neuroprotection, potentially useful for developing better strategies for the treatment of MS.

Subendotyping of Dermatophagoides pteronyssinus-Induced Rhinitis and Its Impact on Respiratory Comorbidities.

BACKGROUND: The impact of delayed hypersensitivity to Dermatophagoides pteronyssinus (DP) on comorbidities of allergic rhinitis (AR) is unknown. OBJECTIVE: The primary end point was to test the hypothesis that DP-induced AR could be divided into 2 subendotypes on the basis of presence or absence of a delayed-type mite sensitization detected by the positive result of atopy patch test for DP (DP-APT). The second end point was to evaluate differences in the long-term risk of respiratory comorbidities and nasal airway response to mite exposure. METHODS: In a prospective observational study, we included 472 patients with DP-induced AR. A total of 343 patients had positive results of skin prick test/serum specific IgE and DP-APT and were assigned to a subendotype with both IgE- and T-cell-mediated mite sensitization (BMSS). The remaining 129 patients without delayed-type mite sensitization were included in the subendotype with only IgE-mediated mite sensitization. Nasal allergen provocation test with active anterior rhinomanometry, paranasal sinuses computed tomography scan, nasal endoscopy, and spirometry were performed. RESULTS: At baseline, BMSS showed a larger increase in nasal airway resistance, total nasal score, and visual analogue scale score to mite exposure. During a 15-year follow-up, 56 patients developed chronic rhinosinusitis with nasal polyps, with higher incidence in BMSS than in the subendotype with only IgE-mediated mite sensitization (50 patients, 14.6% vs 6 patients, 12.4%; P < .001). BMSS also showed a higher incidence of conjunctivitis (25.7% vs 12.4%; P < .01). The rate of adult-onset asthma did not differ between groups, but patients with BMSS showed a more frequent link to chronic rhinosinusitis with nasal polyps (6 of 29 patients, 20.7% vs 0 of 10 patients, 0%). DP-APT independently predicted chronic rhinosinusitis with nasal polyps and conjunctivitis. CONCLUSIONS: Two subendotypes with significantly different clinical outcome can be identified among patients with DP-induced AR according to the presence of delayed-type mite sensitization detected by positive DP-APT result.

An Unusual Case of Severe Hypertension Presenting With Leg Weakness, Hypokalemia, and Hyperreninemic Aldosteronism.

Takayasu's arteritis is a rare vasculitis characterized by granulomatous inflammation of the large vessels, typically occurring in the second or third decade of life and preferentially affecting females. It commonly involves large vessels such as the aorta and its major branches (carotid and iliac arteries). Visceral arterial involvement is uncommon and reported in only a minority of patients. Clinical manifestations of Takayasu arteritis are heterogeneous and could include nonspecific symptoms such as fever of unknown origin, asthenia, myalgias, intermittent claudication, angina, and mild arterial hypertension. The rarity of this disease and the extreme heterogeneity of clinical manifestations often lead to delays in diagnosis, lasting more than three years in some patients. Improving knowledge of its diagnostic workup could help clinicians in prompt clinical suspicion and early diagnosis. Here, we aim to describe a particular case of a 40-year-old woman with severe hypertension symptomatic for dizziness, gait instability, leg weakness, and diffuse cramps caused by renovascular hypertension as the first clinical manifestation of Takayasu's arteritis involving the right renal artery.

Antibodies against HSV-1 and Curli Show the Highest Correlation in Parkinson's Disease Patients in Comparison to Healthy Controls.

Parkinson's disease (PD) is a neurodegenerative disorder involving the accumulation of alpha-synuclein (α-syn)/Lewy bodies in the brain and -enteric nervous system. The etiology of the disease is not well understood, but bacterial and viral infections may contribute to the pathogenesis of PD. It has been suggested that the gastrointestinal (GI) complications observed in PD patients may arise from bacterial dysbiosis, leading to curli/α-syn deposits in the enteric nervous system. Enteric bacteria secrete curli, a functional amyloid peptide involved in adhesion to surfaces, cell invasion, and biofilm formation. However, these bacterial amyloids can initiate additional α-syn deposits through immune system activation and cross-seeding. In this study, we investigate the humoral response against α-syn, curli peptides, and various bacterial and viral immunogen peptides in PD patients, and compare them with those in healthy controls (HCs). Polyclonal IgG antibodies (Abs) were detected against peptides derived from α-syn (α-syn100−114), curli (Curli133−141), Porphyromonas gingivalis Pg (RgpA800−812, Kpg328−339), Aggregatibacter actinomycetemcomitans (LtxA1429−445, LtxA264−80), Mycobacterium avium subsp. paratuberculosis (MAP3865c125−133, MAP1,4-a-gbp157−173 and MAP_402718−32), Epstein−Barr virus (EBNA1400−413, BOLF1305−320), and Herpes Simplex virus 1 (UI4222−36), as investigated by indirect ELISA of 51 serum samples from PD and 58 sex and age-matched HCs. Significant differences in OD (optical density) values and Abs positivity between PD patients and HCs were observed for Kpg (82.3% vs. 10.3%), followed by RgpA (60.7% vs. 24.1%), curli (51% vs. 22.4%), and UI42 (43.1% vs. 25.8%) in PD, compared to HCs sera (p < 0.001). No significant difference was found in the ODs obtained from other tested peptides in PD patients, compared to HCs. Significant positive correlations between OD values obtained by ELISA were observed for UI42 and curli (r = 0.811, p < 0.0001), Kpg and RgpA (r = 0.659, p < 0.0001), followed by LtxA1 and LtxA2 (r = 0.653, p < 0.0001). The correlation between the HY scale (Hoehn and Yahr Scale) and LtxA1 (r = 0.306, p < 0.028) and HY and Kpg (r = 0.290, p < 0.038) were significantly positive. This study reports a significantly increased humoral response against curli, Pg, and HSV-1 in PD patients, implying that they could be important factors in the pathogenesis of the disease. In addition, the high positive correlation between UI42 and curli may suggest the involvement of HSV-1 in GI dysbiosis. Therefore, the role of each individual pathogen and curli in PD needs to be further investigated.

Relationship between cytokine release and stress hyperglycemia in patients hospitalized with COVID-19 infection.

Introduction: Stress hyperglycemia is a frequent finding in patients with COVID-19 infection and could affect the outcome of disease. Cytokines released in response to infection could have adverse effects on insulin sensitivity and pancreatic beta-cell function. The aim of the study was to examine the relationships of stress hyperglycemia with cytokines and clinical outcomes in hospitalized patients with COVID-19. Methods: In a cross-sectional analysis of 150 patients hospitalized for COVID-19 infection who were included in the GIRA-COVID database, we identified patients with stress hyperglycemia by calculation of the Stress Hyperglycemia Ratio (SHR) and use of a cut-off of 1.14. Plasma levels of cytokines principally involved in COVID-19 infection-related cytokine storm were measured. Outcome variables were use of mechanical ventilation and death within 60 days from hospital admission. Results: Patients with SHR > 1.14 had significantly higher plasma insulin, HOMA-index, and levels of interleukin-10 (IL-10), interleukin-10/tumor necrosis factor-a ratio (IL-10/TNF-α), and CXC motif chemokine ligand 10 (CXCL10) than patients with SHR ≤ 1.14. IL-10, IL-10/TNF-α ratio, CXCL10, and IFN-γ were significantly and directly related with SHR in univariate analysis and multivariate logistic regression models showed that IL-10, IL-10/TNF-α ratio, and CXCL10 were independently associated with SHR>1.14. In a multivariate logistic model, stress hyperglycemia predicted use of mechanical ventilation (OR 2.453; CI 1.078-6.012) and death (OR 2.281; CI 1.049-7.369) independently of diabetes and other major confounders. Conclusions: In patients hospitalized for COVID-19 infection, stress hyperglycemia is associated with worse clinical outcomes and is independently related to levels of cytokines that might impair glucose homeostasis.

Antibody Response to HML-2 May Be Protective in Amyotrophic Lateral Sclerosis.

OBJECTIVES: Reactivation of HERV-K(HML-2) has been found in subsets of individuals with amyotrophic lateral sclerosis (ALS). This study examines the antibody response against HML-2 in ALS and analyzes its clinical relevance. METHODS: Antibodies to HML-2 envelope (env) were analyzed using a peptide array for epitope mapping and by a peptide enzyme-linked immunosorbent assay (ELISA) in 242 healthy donors, and 243 ALS and 85 multiple sclerosis (MS) individuals. Extracellular levels of HML-2 were analyzed by digital polymerase chain reaction (PCR). RESULTS: Antibodies in the sera of ALS individuals recognized more HML-2 env peptides compared to healthy controls (p < 0.0001). ALS individuals had higher levels of HML-2 than healthy donors (p = 0.02) and higher antibody levels against a select HML-2 env peptide compared to healthy donors or individuals with multiple sclerosis (p < 0.0001). 55.14% of ALS compared to 21.16% of healthy donors and 13.10% of MS individuals had antibodies against the HML-2 peptide (AUC = 0.769, p < 0.0001). Levels of extracellular HML-2 DNA in serum (p = 0.02) and the number of HML-2 env peptides recognized by ALS sera (p = 0.02) correlated with disease duration. Among ALS individuals, lower levels of HML-2 antibodies were associated with a definite diagnosis per EL Escorial criteria (p = 0.03), and with a lower predicted (p = 0.02) and observed survival (p = 0.03). INTERPRETATION: There is a differential antibody response against specific epitopes of HML-2 env in ALS and controls, suggesting epitope spreading, likely due to persistent antigenic exposure following reactivation of the viral genes. Low levels of antibodies to HML-2 env in ALS are associated with poor prognosis and decreased survival probability. ANN NEUROL 2022;92:782-792.

Bisphenols induce human genomic damage and modulate HERVs/env expression.

Bisphenol A (BPA), a recognized endocrine-disrupting chemical, is used in the production of epoxy and polycarbonate resins. Since human exposure to BPA has been associated with increased cancer susceptibility, the market has shifted to products often labeled as "BPA free" containing BPA analogs such as bisphenol F (BPF) and bisphenol S (BPS). However, the European legislation on BPF and BPS is still unclear. This study analyzed the effects of BPA, BPF, and BPS exposure on human peripheral blood mononuclear cells by using in vitro micronucleus assay. Furthermore, it investigated the impact of bisphenols exposure on human endogenous retroviruses (HERVs) expression, which is implicated with the pathogenesis of several human diseases. The micronucleus assay revealed a significant genotoxic effect in peripheral blood cells after exposure to BPA and BPF at concentrations of 0.1, 0.05, and 0.025 µg/ml, and to BPS at 0.1 and 0.05 µg/ml. In addition, BPA exposure seems to upregulate the expression of HERVs, while a downregulation was observed after BPF and BPS treatments. Overall, our data showed the toxic effect of BPA and its analogs on circulating cells in the blood and demonstrated that they could modulate the HERVs expression.

A rapid phage assay for detection of viable Mycobacterium avium subsp. paratuberculosis in milk.

Paratuberculosis is an incurable gastroenteritis among ruminants that is promoted by Mycobacterium avium subsp. paratuberculosis (MAP), an acid-fast mycobacterium. To accelerate the detection of viable pathogen, a conventional (peptide mediated magnetic separation: PMS) and novel (phage-bead qPCR: PBQ) phage based assay was optimized. A superior limit of detection (LOD) of 10 MAP per 10 mL milk was suggested for PBQ compared to 100 cells/10 mL for PMS-phage assay. Via PBQ, viable MAP was found in 48.78% out 41 unpasteurized sheep and goat milk samples. Sheep milk samples (n = 29) that were tested by PMS-phage assay contained no viable MAP. The absence of viable MAP in milk collected from 21 of the recent sheep animals was also confirmed by PBQ after a 2-week gap. Although, the two phage assays comparably detected no viable MAP in the milk samples, MAP DNA and antibodies against MAP were recognized in milk and sera of some of these animals within two instances of sampling representing that some sheep animals were MAP shedders. In conclusion, PBQ and PMS-phage could be promising methods for the assessment of MAP viability in milk samples. However, PBQ was privileged over the PMS-phage assay due to the lower LOD, rapidity, higher sensitivity, lack of need to M. smegmatis and consequent virucidal treatment that are essential in PMS-phage assay for making lawn and inactivation of exogenous mycobacteriophages respectively.

Risk of Chronic Rhinosinusitis With Nasal Polyps in Endotypes of Dermatophagoides pteronyssinus-Induced Rhinitis.

BACKGROUND: Observation of the natural history of two emerging endotypes of allergic rhinitis, local-sensitization rhinitis (LAR) and dual-allergic rhinitis (DAR), compared with systemic-sensitization rhinitis (AR), could improve knowledge of the role of allergy in chronic rhinosinusitis with nasal polyps (CRSwNP). OBJECTIVE: To test the hypothesis that endotypes of Dermatophagoides pteronyssinus (DP)-induced rhinitis were risk factors for CRSwNP and adult-onset asthma and to investigate whether delayed hypersensitivity to DP, assessed by atopy patch test, could be a contributing factor. METHODS: We conducted a prospective observational study over 15 years on a cohort of 999 patients: 468 with AR, 333 with LAR, and 198 with DAR. The latter endotype was characterized by the coexistence of seasonal disease caused by systemic sensitization to pollen in patients with DP-induced LAR. The study design included a physical visit; ear, nose, and throat examination with anterior rhinoscopy; skin prick test; serum-specific IgE; DP-atopy patch test; nasal allergen provocation test with DP; paranasal sinuses computed tomography scan; nasal endoscopy; and spirometry. RESULTS: During 15 years of follow-up, 194 patients developed CRSwNP with a higher rate of LAR (28.2%) and DAR (22.2%) than AR (12%). For LAR and DAR, 7.5% and 10.6% of patients developed adult-onset asthma temporally linked to CRSwNP in 68% and 71.4% of cases, respectively. A total of 858 patients with rhinitis had delayed hypersensitivity to DP. Moreover, DP-ATP was an independent predictive factor for CRSwNP and had elevated positive and negative predictive values for localized allergic disease of the nasal mucosa. CONCLUSIONS: Endotypes of DP-induced allergic rhinitis represent risk factors for CRSwNP. Patients with local-sensitization rhinitis and DAR are more at risk than those with AR. In these emerging endotypes, progression toward CRSwNP is often associated with the development of adult-onset asthma. Chronic rhinosinusitis with nasal polyps shows several possible indicators for type 2 endotype. Delayed hypersensitivity to DP is an independent predictive factor for CRSwNP.

HERV-K and HERV-H Env Proteins Induce a Humoral Response in Prostate Cancer Patients.

A higher expression of human endogenous retroviruses (HERVs) has been associated with several malignancies, including prostate cancer, implying a possible use as a diagnostic or prognostic cancer biomarker. For this reason, we examined the humoral response against different epitopes obtained from the envelope protein of HERV-K (HERV-K env-su19-37, HERV-K env-su109-126), HERV-H (HERV-H env-su229-241, HERV-H env387-399) and HERV-W (HERV-W env-su93-108, HERV-W env-su248-262) in the plasma of patients affected by prostate cancer (PCa), and compared to that of benign prostate hyperplasia (BPH) and a borderline group of patients with atypical small acinar proliferation (ASAP) and prostate intraepithelial neoplasia (PIN) and healthy controls. A significant antibody response was observed against HERV-K env-su109-126 (p = 0.004) and HERV-H env-su229-241 (p < 0.0001) in PCa patients compared to HCs, BPH and borderline cohorts, whilst no significance difference was found in the antibodies against HERV-W env-su93-108 and HERV-W env-su248-262 in patients with PCa. Our results provided further proof of the association between HERV-K and PCa and added new evidence about the possible involvement of HERV-H in PCa pathogenesis, highlighting their possibility of being used as biomarkers of the disease.

TDP-43 and HERV-K Envelope-Specific Immunogenic Epitopes Are Recognized in ALS Patients.

The human endogenous retrovirus-K (HERV-K) and TAR DNA-binding protein 43 (TDP-43) have been associated with the pathophysiology of amyotrophic lateral sclerosis (ALS). Given these findings, we investigated the humoral response against HERV-K envelope surface (env-su) glycoprotein antigens and TDP-43 in the plasma of ALS patients and healthy controls (HCs). The measured levels of Abs against the different epitopes' fragments were significantly elevated in ALS patients, both in long-survivor (LS) and newly diagnosed (ND) patients, compared to HCs. We observed a positive correlation between HERV-K and TDP-43 antibodies (Abs) levels, which seemed to strengthen with disease progression, that was not found in HCs. The TDP-43 and HERV-K epitopes identified in this study are highly immunogenic and recognized by the humoral response of ALS patients. Increased circulating levels of Abs directed against specific HERV-K- and TDP-43-derived epitopes could serve as possible biomarkers.

Polyphenols Rich Diets and Risk of Type 2 Diabetes.

Type 2 diabetes is an increasing health concern worldwide. Both genetic and environmental risk factors as improper dietary habits or physical inactivity are known to be crucial in the pathogenesis of type 2 diabetes. Polyphenols are a group of plant-derived compounds with anti-inflammatory and antioxidant properties that are associated with a low prevalence of metabolic conditions characterized by insulin resistance, including obesity, diabetes, and hypertension. Moreover, there is now full awareness that foods that are rich in phytochemicals and polyphenols could play an important role in preserving human cardiovascular health and substantial clinical evidence indicates that regular dietary consumption of such foods affects favorably carbohydrate metabolism. This review briefly summarizes the evidence relating dietary patterns rich in polyphenols with glucose metabolism and highlights the potential benefits of these compounds in the prevention of type 2 diabetes.

Beware of Drug Interactions Treating Iatrogenic Mycobacterium bovis Endocarditis from Intravesical BCG Instillation.

We report a case of mechanical mitral valve endocarditis associated with miliary disseminated bacillus Calmette-Guerin (BCG) infection following intravesical instillations for minimally invasive bladder cancer in a 65-year-old man. The diagnosis was established by echocardiographic evidence of vegetation on the prosthetic mitral valve, miliary lesions in the lungs and evidence of bloodstream infection sustained by Mycobacterium. We successfully treated the patient with the classical regimen of quadruple antituberculous therapy. LEARNING POINTS: To consider endocarditis as an extra-pulmonary manifestation of Mycobacterium bovis infection, especially in the presence of predisposing heart conditions and risk factors.To be careful of drug interactions among warfarin, rifampin and amiodarone.

Whole-exome Sequencing of Prostate Cancer in Sardinian Identify Recurrent UDP-glucuronosyltransferase Amplifications.

Globally, prostate cancer is the third most common cancer in the world, and the second most common cancer in men. However, rates for incidence and mortality vary considerably with race, ethnicity, and geography. Over 97 significantly mutated genes that have been identified in prostate cancer; however, a lack of genomic prostate cancer studies focusing on different racial and ethnic groups and racial mixing pose a serious challenge to universalize these findings. The Sardinian population is an isolated Mediterranean population that has a high frequency of centenarians and a much lower incidence of prostate cancer than found in males in mainland Europe. Here, we conducted a genomic prostate cancer study on a Sardinian cohort diagnosed with local prostate cancer. Our data reveals a low rate of ERG fusion in Sardinian prostate cancer. Interestingly, we identified a novel BTBD7-SLC2A5 fusion that occurred in 13% of the patients. We also found that the UGT2B4 on 4q13.2 was amplified in 20% of the Sardinian patients but rarely amplified in patients of other population. These observations underscore the importance of the inter-population molecular heterogeneity of prostate cancer. In addition, we examined the expression of UGT2B4 in 497 prostate cancer patients derived from The Cancer Genome Atlas database. We found that high expression of UGT2B4 was associated with low-grade prostate cancer and upregulation of UGT2B4 in tumors was associated with upregulation of metabolism pathways such as 'de novo' IMP biosynthetic process, glutamine and monocarboxylic acid metabolism. These data provide insight into clinical relevance and functional mechanism of UGT2B4. Further understanding functional mechanism of UGT2B4 amplification and BTBD7-SLC2A5 fusion will aid in developing drugs to benefit the prostate cancer patients.