POPULARITY
Listen to a blog summary of a research paper published by Oncotarget in Volume 13, entitled, "Bladder cancer survival in patients with NOD2 or CDKN2A variants.” _______________________________ Genitourinary cancers are a group of cancers that affect components of the urinary tract, including the bladder and kidneys. Worldwide, bladder and kidney cancer impact men at disproportionately higher rates than women. While incidence and mortality rates of bladder cancer in most western European countries have been consistently decreasing, some countries in the region, such as Poland, have seen an increase. Bladder cancer is the 4th most common malignancy in Polish men and the 14th most common malignancy in Polish women. There is currently a need to identify more effective bladder cancer biomarkers and therapeutic targets to develop new effective treatments that improve patient outcomes. “The association between the NOD2 c.3020insC allele and CDKN2A missense variant c.442G>A (p.P.A148T) and survival of patients with bladder or kidney cancer remains controversial.” In April of 2022, researchers from Pomeranian Medical University, University of Newcastle and NSW Health Pathology published the first larger-scale study in Poland to describe the clinical characteristics and survival of bladder cancer patients and kidney cancer patients associated with variants in NOD2 and CDKN2A. Their research paper was published in Oncotarget on April 22, 2022, and entitled, “Bladder cancer survival in patients with NOD2 or CDKN2A variants.” Full blog - https://www.impactjournals.com/journals/blog/oncotarget/gene-variants-investigated-in-polish-bladder-and-kidney-cancer/ DOI - https://doi.org/10.18632/oncotarget.28226 Correspondence to - Elżbieta Złowocka-Perłowska - elzunik@wp.pl Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28226 Keywords - bladder cancer, kidney cancer, NOD2, CDKN2A, survival About Oncotarget Oncotarget is a peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/OncotargetYouTube LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Oncotarget is published by Impact Journals, LLC: https://www.ImpactJournals.com Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957
In the US, few people receive vaccination for tuberculosis (TB), a disease that hasn’t been a major killer here for many decades. But while we in the US mostly experience TB as a relatively rare but real threat in its multidrug resistant form, particularly in pts with HIV--or in Victorian novels--TB still kills 2 million people a year. There is a vaccine for TB, a live attenuated vaccine called BCG for Bacille Calmette-Guerin. In fact it’s the most widely used vaccine on earth, and an estimated 4 billion people have received it since was first administered to a baby whose mother died of TB a few hours after giving birth in the summer of 1921. This connection of this vaccine to COVID caught our attention when a friend suggested a few weeks ago that Russia and other parts of the world where BCG vaccination is routine might be shielded from the worst COVID outbreaks. In the intervening weeks, as Russia grapples with its own COVID epidemic, that possibilty seems less tenable, but it did lead us down an interesting research path. Host: Elizabeth Esty, MD Research By: Elizabeth Esty, MD Sound Editing By: Nate Novotny References: Miller A, Reandelar MJ, Fasciglione K, Roumenova V, Li Y, Otazu GH. Correlation between Universal BCG Vaccination Policy and Reduced Morbidity and Mortality for COVID-19: An Epidemiological Study. Epidemiology; 2020. doi:10.1101/2020.03.24.20042937 Kleinnijenhuis J, Quintin J, Preijers F, et al. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proceedings of the National Academy of Sciences. 2012;109(43):17537-17542. doi:10.1073/pnas.1202870109 Arts RJW, Moorlag SJCFM, Novakovic B, et al. BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity. Cell Host & Microbe. 2018;23(1):89-100.e5. doi:10.1016/j.chom.2017.12.010 Further Reading: https://www.who.int/news-room/commentaries/detail/bacille-calmette-gu%C3%A9rin-(bcg)-vaccination-and-covid-19 https://clinicaltrials.gov/ct2/show/NCT04328441 https://www.mpg.de/14491738/0219-mpin-116799-modified-tuberculosis-vaccine-as-a-therapy-for-cancer-of-the-bladder
Hosts: Vincent Racaniello, Dickson Despommier, and Daniel Griffin The TWiP trio solve the case of the Woman from Washington Heights, and reveal how helminth infection protects mice deficient in the Crohn's disease gene NOD2 from intestinal disease by inhibiting colonization with an inflammatory bacterial species. Subscribe to TWiP (free) in iTunes, by the RSS feed or by email Links for this episode: Helminth infection promotes colonization resistance (Science) NOD2 (Wikipedia) Image credit Letters read on TWiP 112 This episode is sponsored by CuriosityStream, a subscription streaming service that offers over 1,400 documentaries and nonfiction series from the world's best filmmakers. Get unlimited access starting at just $2.99 a month, and for our audience, the first two months are completely free if you sign up at curiositystream.com/microbe and use the promo code MICROBE. Become a patron of TWiP. Case Study for TWiP 112 A case here at CUMC, 59 yo male, past medical history of childhood polio, presents with worsening lower extremity weakness, bowel and urinary incontinence. 2 year before worsening back pain, weakness, could not work. Cannot walk up one flight of stairs since 1 month; 1 week prior to admission had fever, no headaches, diarrhea, cough, or any other symptoms. Splits time between Washington Heights and Mexico. Construction worker. Rural town in southern Mexico, 10 months of the year. Worked in the corn growing area. Has been exposed to bugs. Stopped working in cornfields 20 years ago. Has son and daughter, visits them. Lives with wife, stays in Mexico, she is fine. HIV negative. Eats home prepared foods, no dietary restrictions. Physical exam: not febrile, vital signs all good, neurological: upper strength good, weakness in hip flexors, ⅗; quadriceps, but ⅕ in lower extremities ⅖ in right. Sensory has decreased as well. Possibly spinal lesion. Labs: elevated glucose, ESR 33, CRP 2.2, whites 8, 30.6 hematocrit, guaiac negative. Imaging: MRI of spine shows normal vertebrae, T9/10 inflammation of spinal cord, mass lesion, compromise of canal. Brain MRI: hydrocephalus. Problem with recirculation of CSF. Send your case diagnosis, questions and comments to twip@microbe.tv
Identification of inflammatory response regulators sheds light on disease.
Genome-wide association studies identified the autophagy gene IRGM to be strongly associated with Crohn's disease (CD) but its impact in ulcerative colitis (UC), its phenotypic effects and potential epistatic interactions with other IBD susceptibility genes are less clear which we therefore analyzed in this study. Genomic DNA from 2060 individuals including 817 CD patients, 283 UC patients, and 961 healthy, unrelated controls (all of Caucasian origin) was analyzed for six IRGM single nucleotide polymorphisms (SNPs) (rs13371189, rs10065172 = p.Leu105Leu, rs4958847, rs1000113, rs11747270, rs931058). In all patients, a detailed genotype-phenotype analysis and testing for epistasis with the three major CD susceptibility genes NOD2, IL23R and ATG16L1 were performed. Our analysis revealed an association of the IRGM SNPs rs13371189 (p = 0.02, OR 1.31 [95% CI 1.05-1.65]), rs10065172 = p.Leu105Leu (p = 0.016, OR 1.33 [95% CI 1.06-1.66]) and rs1000113 (p = 0.047, OR 1.27 [95% CI 1.01-1.61]) with CD susceptibility. There was linkage disequilibrium between these three IRGM SNPs. In UC, several IRGM haplotypes were weakly associated with UC susceptibility (p
Genome-wide association studies identified PTPN2 (protein tyrosine phosphatase, non-receptor type 2) as susceptibility gene for inflammatory bowel diseases (IBD). However, the exact role of PTPN2 in Crohn's disease (CD) and ulcerative colitis (UC) and its phenotypic effect are unclear. We therefore performed a detailed genotype-phenotype and epistasis analysis of PTPN2 gene variants. Genomic DNA from 2131 individuals of Caucasian origin (905 patients with CD, 318 patients with UC, and 908 healthy, unrelated controls) was analyzed for two SNPs in the PTPN2 region (rs2542151, rs7234029) for which associations with IBD were found in previous studies in other cohorts. Our analysis revealed a significant association of PTPN2 SNP rs2542151 with both susceptibility to CD (p = 1.95×10⁻⁵; OR 1.49 [1.34-1.79]) and UC (p = 3.87×10⁻², OR 1.31 [1.02-1.68]). Moreover, PTPN2 SNP rs7234029 demonstrated a significant association with susceptibility to CD (p = 1.30×10⁻³; OR 1.35 [1.13-1.62]) and a trend towards association with UC (p = 7.53×10⁻²; OR 1.26 [0.98-1.62]). Genotype-phenotype analysis revealed an association of PTPN2 SNP rs7234029 with a stricturing disease phenotype (B2) in CD patients (p = 6.62×10⁻³). Epistasis analysis showed weak epistasis between the ATG16L1 SNP rs2241879 and PTPN2 SNP rs2542151 (p = 0.024) in CD and between ATG16L1 SNP rs4663396 and PTPN2 SNP rs7234029 (p = 4.68×10⁻³) in UC. There was no evidence of epistasis between PTPN2 and NOD2 and PTPN2 and IL23R. In silico analysis revealed that the SNP rs7234029 modulates potentially the binding sites of several transcription factors involved in inflammation including GATA-3, NF-κB, C/EBP, and E4BP4. Our data confirm the association of PTPN2 variants with susceptibility to both CD and UC, suggesting a common disease pathomechanism for these diseases. Given recent evidence that PTPN2 regulates autophagosome formation in intestinal epithelial cells, the potential link between PTPN2 and ATG16L1 should be further investigated.
Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 12/19
Im Rahmen der vorliegenden Arbeit wurden 855 Individuen mit Morbus Crohn, 481 Individuen mit Colitis ulcerosa und ein Kontrollkollektiv aus 1029 unverwandten, gesunden Individuen hinsichtlich drei verschiedener Einzelnukleotidpolymorphismen im Gen für den Toll-like Rezeptor 9 (TLR9) untersucht. Ziel war es, zu ermitteln, ob Assoziationen dieser SNPs mit Morbus Crohn oder Colitis ulcerosa oder mit klinischen Subtypen der beiden Erkrankungen vorliegen, und ob Interaktionen mit anderen krankheitsassoziierten Genen stattfinden. Es wurden für die vorliegende Arbeit drei Polymorphismen ausgewählt, mithilfe derer in Kombination mit den SNPs -1237 C/T und 2848 G/A, für die die Studienpopulation bereits typisiert war, zwischen den elf häufigsten beschriebenen 5-Punkt TLR9-Haplotypen differenziert werden kann. Es handelt sich dabei um die beiden Promotorpolymorphismen -1923 A/C und -1486 C/T sowie den Polymorphismus 1174A/G im Intron 1 des TLR9-Gens. Als wichtigstes Ergebnis der vorliegenden Arbeit kann eine hier erstmals beschriebene Assoziation des Polymorphismus 1174 A/G mit Colitis ulcerosa betrachtet werden. Für den SNP 1174 A/G konnte ein signifikant selteneres Auftreten des A-Allels bei Patienten mit Colitis ulcerosa gegenüber der Kontrollgruppe (p=0,035) oder Patienten mit Morbus Crohn (p=0,002) gezeigt werden. Signifikant war auch das seltenere Vorkommen des Genotyps AA bei Patienten mit Colitis ulcerosa (p=0,012 gegenüber Kontrollgruppe bzw. p=0,004 gegenüber Patientengruppe Morbus Crohn) Dies kann im Sinne eines protektiven Effekts des 1174 A/G A-Allels gegenüber Colitis ulcerosa interpretiert werden. Die im Rahmen dieser Arbeit beobachtete Assoziation des TLR9-Polymorphismus 1174 A/G mit Colitis ulcerosa kann als Hinweis darauf verstanden werden, dass TLR9 nicht nur, wie bereits beschrieben eine Rolle in der Pathogenese des Morbus Crohn spielt, sondern auch Bedeutung für die Colitis ulcerosa hat. Der Polymorphismus -1486 C/T scheint mit weiteren Suszeptibilitätsvarianten für Morbus Crohn zu interagieren, und das Krankheitsrisiko zu erhöhen. Es handelt sich hierbei jedoch um sehr schwache Effekte, so dass Aussagen über die Krankheitsrelevanz vor Ausschluss anderer Einflüsse (z.B. Kopplungsungleichgewichte) nicht getroffen werden können. Zusammen mit den Beobachtungen bzgl. Interaktionen zwischen dem Polymorphismus -1237 T/C im TLR9 und Polymorphismen im NOD2 und IL23R {Török, 2009}, unterstützen diese Ergebnisse aus genetischer Sicht jedoch eine Rolle von TLR9 in der Pathogenese Chronisch-entzündlicher Darmerkrankungen. Ein wichtiger Punkt bleibt allerdings die nähere Abgrenzung der funktionellen Relevanz der beschriebenen Assoziationen, was eine große Herausforderung für künftige Untersuchungen darstellt.
The carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) acts as a receptor for adherent-invasive E. coli (AIEC) and its ileal expression is increased in patients with Crohn's disease (CD). Given its contribution to the pathogenesis of CD, we aimed to investigate the role of genetic variants in the CEACAM6 region in patients with inflammatory bowel diseases (IBD). In this study, a total of 2,683 genomic DNA samples (including DNA from 858 CD patients, 475 patients with ulcerative colitis (UC), and 1,350 healthy, unrelated controls) was analyzed for eight CEACAM6 SNPs (rs10415946, rs1805223 = p.Pro42Pro, rs4803507, rs4803508, rs11548735 = p.Gly239Val, rs7246116 = pHis260His, rs2701, rs10416839). In addition, a detailed haplotype analysis and genotype-phenotype analysis were performed. Overall, our genotype analysis did not reveal any significant association of the investigated CEACAM6 SNPs and haplotypes with CD or UC susceptibility, although certain CEACAM6 SNPs modulated CEACAM6 expression in intestinal epithelial cell lines. Despite its function as receptor of AIEC in ileal CD, we found no association of the CEACAM6 SNPs with ileal or ileocolonic CD. Moreover, there was no evidence of epistasis between the analyzed CEACAM6 variants and the main CD-associated NOD2, IL23R and ATG16L1 variants. This study represents the first detailed analysis of CEACAM6 variants in IBD patients. Despite its important role in bacterial attachment in ileal CD, we could not demonstrate a role for CEACAM6 variants in IBD susceptibility or regarding an ileal CD phenotype. Further functional studies are required to analyze if these gene variants modulate ileal bacterial attachment.
Background: The aims were to analyze two novel NOD2 variants (rs2066843 and rs2076756) in a large cohort of patients with inflammatory bowel disease and to elucidate phenotypic consequences. Methodology/Principal Findings: Genomic DNA from 2700 Caucasians including 812 patients with Crohn's disease (CD), 442 patients with ulcerative colitis (UC), and 1446 healthy controls was analyzed for the NOD2 SNPs rs2066843 and rs2076756 and the three main CD-associated NOD2 variants p.Arg702Trp (rs2066844), p.Gly908Arg (rs2066847), and p.Leu1007fsX1008 (rs2066847). Haplotype and genotype-phenotype analyses were performed. The SNPs rs2066843 (p = 3.01×10−5, OR 1.48, [95% CI 1.23-1.78]) and rs2076756 (p = 4.01×10−6; OR 1.54, [95% CI 1.28-1.86]) were significantly associated with CD but not with UC susceptibility. Haplotype analysis revealed a number of significant associations with CD susceptibility with omnibus p values
Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 11/19
Thu, 17 Dec 2009 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/10980/ https://edoc.ub.uni-muenchen.de/10980/1/Beynon_Vanessa.pdf Beynon, Vanessa ddc:610, ddc:600, Medizinische Fakultät
Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 09/19
Thu, 4 Dec 2008 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/9396/ https://edoc.ub.uni-muenchen.de/9396/1/Cotofana_Sebastian.pdf Cotofana, Sebastian
Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 07/19
Thu, 8 Nov 2007 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/7652/ https://edoc.ub.uni-muenchen.de/7652/1/Mair_Anja.pdf Mair, Anja
The IL23R gene has been identified as a susceptibility gene for inflammatory bowel disease (IBD) in the North American population. The aim of our study was to test this association in a large German IBD cohort and to elucidate potential interactions with other IBD genes as well as phenotypic consequences of IL23R variants. Genomic DNA from 2670 Caucasian individuals including 833 patients with Crohn's disease (CD), 456 patients with ulcerative colitis (UC), and 1381 healthy unrelated controls was analyzed for 10 IL23R SNPs. Genotyping included the NOD2 variants p.Arg702Trp, p.Gly908Arg, and p.Leu1007fsX1008 and polymorphisms in SLC22A4/OCTN1 (1672 C-->T) and SLC22A5/OCTN2 (-207 G-->C). All IL23R gene variants analyzed displayed highly significant associations with CD. The strongest association was found for the SNP rs1004819 [P = 1.92x10(-11); OR 1.56; 95 % CI (1.37-1.78)]. 93.2% of the rs1004819 TT homozygous carriers as compared to 78% of CC wildtype carriers had ileal involvement [P = 0.004; OR 4.24; CI (1.46-12.34)]. The coding SNP rs11209026 (p.Arg381Gln) was protective for CD [P = 8.04x10(-8); OR 0.43; CI (0.31-0.59)]. Similar, but weaker associations were found in UC. There was no evidence for epistasis between the IL23R gene and the CD susceptibility genes CARD15 and SLC22A4/5. IL23R is an IBD susceptibility gene, but has no epistatic interaction with CARD15 and SLC22A4/5. rs1004819 is the major IL23R variant associated with CD in the German population, while the p.Arg381Gln IL23R variant is a protective marker for CD and UC.
Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 02/19
Die Studie sollte Aufschluss über den Zusammenhang zwischen der 3020insC Mutation des NOD2/CARD15-Gens und chronisch marginalen Parodontitiden erbringen. Untersucht wurden 80 Patienten mit chronischer Parodontitis und 122 gesunde Patienten. Ein Zusammenhang konnte nicht nachgewiesen werden.
The recent identification of the CARD15/NOD2 gene as a susceptibility locus for Crohn's disease represents an important step towards the delineation of the immuno-pathogenesis of inflammatory bowel disease. CARD15 functions as an intracellular receptor for bacterial components and thus represents an important link between inflammatory bowel disease and innate immunity. Three major CARD15/NOD2 gene mutations have been associated with Crohn's disease in Caucasians in several independent studies. Together, they explain about 20% of the genetic susceptibility for Crohn's disease. Genotype-phenotype analyses demonstrated an association of these mutations with ileum-specific disease, an increased incidence of the fibrostenotic phenotype and an earlier age of disease onset. Beside these associations, no other relationship between the CARD15/NOD2 genotype and disease behavior or response to treatment has been detailed so far. Thus, the clinical impact of knowing the patient's genotype is limited at this time. Screening for CARD15 mutations in order to identify high-risk individuals or to introduce an individualized disease management is therefore currently not recommended. Copyright (C) 2003 S. Karger AG, Basel.