tbuckley/cabot-search huggingface dataset:
Inconsistent symptom clusters for functional gastrointestinal disorders in Asia: is Rome burning?
Authors: Gerald J Holtmann, Nicholas J Talley
Journal: Gut (2018)

On 18 July 64 AD, the great fire of Rome destroyed much of the ancient city, starting in the slums in the southern part and rapidly spreading north.1 The Emperor Nero was long blamed for the disaster but there is little evidence that he actually set the fire. However, he was displeased by the architectural design of the ancient Rome and the disaster provided a welcome opportunity for him to change the city building codes.

Fast forward 2000 years; the Rome criteria today are considered the global ‘gold standard’ for the diagnosis and categorisation of functional GI disorders (FGID) including the IBS and functional dyspepsia (FD), and Rome IV was released to acclaim in 2016.2 The Rome criteria are consensus and expert opinion based and anatomical region or structure focused (eg, oesophageal disorders, gastroduodenal disorders, bowel disorders, centrally mediated pain disorders and anorectal disorders)2 rather than a strictly evidence, pathophysiology or symptom-based nosology.

Undoubtedly, major progress has been achieved since the Rome criteria were first introduced in 1994.3 They were originally developed to provide guidance on positively diagnosing patients with FGIDs and are now also intended to guide therapy; subsequently, they have shaped the conduct of clinical trials particularly by defining clear inclusion and exclusion criteria.4 Most importantly, the Rome criteria have led to increased awareness and ultimately greater research interest, paving the path for systematic studies into the underlying pathophysiology, epidemiology and treatment. Thanks to the Rome criteria, arguably many more patients are now properly diagnosed by healthcare professionals although the uptake in general practice has been suboptimal.5 Regulatory authorities such as the Federal Drug Administration (FDA) and the European Agency for the Evaluation of Medicinal Products rely on the Rome criteria when clinical trials are planned and assessed. Equally pharmaceutical companies rely on …
CRAN-10. PEDIATRIC CRANIOPHARYNGIOMA IN ASSOCIATION WITH FAMILIAL ADENOMATOUS POLYPOSIS
Authors: Nathan A Dahl, Drew Pratt, Chandan Kumar, Sandra Camelo-Piragua, Rajen J Mody, Seth Septer, Todd Hankinson, Carl Koschmann, Lindsey Hoffman
Journal: Neuro-Oncology (2018)

Familial adenomatous polyposis (FAP) is a cancer predisposition syndrome that is driven by germline loss-of-function of the APC gene and phenotypically characterized by intestinal polyposis and a variety of extra-intestinal bone and soft tissue tumors. Though craniopharyngioma is not classically associated with FAP, six cases have been reported in adults, all demonstrating ectopic location and adamantinomatous histology. We report the first case of craniopharyngioma associated with FAP in a pediatric patient. A seven-year-old girl with known FAP presented with headache and vomiting and was found on head CT to have partially calcified, cystic mass involving the posterior fossa. MRI delineated a primary suprasellar mass with cystic extension to the pre-pontine space. The cyst was surgically decompressed, and pathology demonstrated an adamantinomatous craniopharyngioma with nuclear β-catenin expression. We performed whole exome sequencing of paired germline and tumor DNA, confirming a CTNNB1 activating point mutation and recapitulation of her germline APC frameshift variant. Whole transcriptome analysis of tumor RNA revealed overexpression of multiple Wnt/β-catenin and SHH pathway genes. This case represents the first FAP-associated craniopharyngioma in childhood and the first characterized with somatic and germline exome sequencing, expanding our understanding of the molecular underpinnings driving tumorigenesis in this unique patient.
EMBR-10. GENOMIC COMPLEXITY AND EVOLUTION OF EMBRYONAL TUMORS WITH MULTILAYERED ROSETTES (ETMR)
Authors: Sander Lambo, Sebastian M Waszak, Tobias Rausch, Susanne Groebner, Christin Schmidt, Sebastian Brabetz, Stefan M Pfister, Andrey Korshunov, Marcel Kool
Journal: Neuro-Oncology (2018)

Embryonal Tumors with Multilayered Rosettes (ETMRs) are aggressive pediatric brain tumors mainly occurring in infants. In order to develop alternative treatment strategies for this deadly disease there is an urgent need for better understanding the mechanisms driving these tumors. We therefore analyzed a cohort of 60 ETMRs using whole genome and panel sequencing, DNA methylation, mRNA expression profiling, and miRNA sequencing. The genetic hallmark of ETMRs is amplification of miRNA cluster C19MC fused to TTYH1 present in ~90% of all ETMRs. ETMRs lacking the C19MC amplification are biologically highly similar to tumors with C19MC amplification, indicating that they do not represent a distinct subgroup. DNA sequencing revealed germline mutations affecting DNA repair genes or miRNA processing genes in a subset of cases, while tumor specific mutations included genes involved in the TP53-, SHH- WNT-, or miRNA processing pathways. Prevalence of mutations in miRNA processing pathways are specifically high in tumors without C19MC amplification, however overall recurrence of mutations is low within our cohort. We also detect high recurrence of genomic instability shown by pluriploidy, large abundance of CNVs, highly upregulated DNA repair pathways and chromothripsis primarily centered around the C19MC amplicon. Structural variations throughout the genome, including the C19MC amplicon, are highly conserved from primary tumor to relapse while other mutations show low conservation. These results suggest ETMR is an entity driven by structural variations rather than single nucleotide variants and could lead to new treatment options, specifically targeting genomic instability, to be tested in preclinical model systems of ETMR.
Radiation esophageal stent.
Authors: Arnold M. Herskovic, Mark Rivard, Richard I Rothstein, Zella Hussein, Jennifer Saunders, Kathleen Corcoran, Claude Clerc, John Favreau
Journal: Journal of Clinical Oncology (2017)

e15514 Baclground:Self-expanding metal stents (SEMS) produce palliative dysphagia relief for esophageal cancers (EC) which is enhanced by brachytherapy. We present a brachytherapy stent designed to deliver radiation to ECs with brachytherapy sources in the porcine esophagus. Methods: A radioactive carrier stent containing I 125 seeds was designed to deliver 60 Gy to 5mm depth over 2 months. One dummy,non-radioactive seeds, and 3 radioactive stents were implanted into the esophagus of Yucatan minipigs. Stents were left in place for up to 43 days after implant, and one pig survived 10 weeks after stent removal. Animals were monitored biweekly via endoscopy and fluoroscopic imaging throughout the study collecting tissue at necropsy. Results: Swine esophageal tissue received doses ranging from 39-48 Gy at the prescription depth of 5mm and 132-160 Gy at the mucosal surface. Tissues were assessed pathologically at 0, 1, and 10 weeks after stent removall. Endoscopic assessment of all irradiated animals found increasingly pronounced and permanent infolding of the proximal stent flare over time, eventually resulting in early stent removal. At stent removal, all animals had numerous benign mucosal polyps ( &lt; 5mm) at both stent flares which mostly resolved. within 6 weeks of removal, At gross necropsy, small amounts of necrotic tissue as well as mucosal polyps were observed along the entire length of the tissue adjacent to the radioactive stent (mostly adjacent to the stent flares). No systemic effects related to radiation were observed. Conclusions: We demonstrated that brachytherapy stent delivery is feasible and reasonably safe for irradiated healthy tissue. Although irradiation &gt; 130 Gy affected the mucosal tissue, stent-related injury appeared to cause more substantial damage to the tissue. Both experimental and control animals showed the most marked tissue reaction at the non radiative stent flares. Tissue reactions along the stent body were consistent with stent related tissue erosion possibly enhanced by radiation exposure, . One animal, assessed up to 10 weeks after stent removal showed nearly complete healing of the esophageal tissue. Future studies will assess safety in a larger cohort of animals with escalated RT doses and different radionuclides.
Стан судинного ендотелію у пацієнтів з хронічними запальними захворюваннями кишечника i різним нутритивним статусом
Authors: I.S. Konenko, V.A. Karachinova, M.V. Stoykevich, I.A. Klenina
Journal: GASTROENTEROLOGY (2018)

Актуальність. Визначення ендотеліальної функції за допомогою неінвазивних методів відіграє основну роль у прогнозуваннi перебігу різних захворювань, ризику розвитку ускладнень та оцінцi лікування. Мета: оцінка ендотеліальної функції в пацієнтів iз хронічними запальними захворюваннями кишечника (ХЗЗК) залежно від їхнього нутритивного статусу шляхом визначення стану судинного ендотелію в пробі з реактивною гіперемією та вмісту метаболітів оксиду азоту (МОА) в сироватці крові. Матеріали та методи. Сто двадцять пацієнтів iз ХЗЗК (81 — iз неспецифічним виразковим колітом (НВК) та 39 пацієнтів із хворобою Крона (ХК)) були розподілені на групи залежно від антропометричних характеристик: І — зі зниженим нутритивним статусом (n = 70); ІІ — iз нормальним (n = 20); ІІІ — iз підвищеним нутритивним статусом (n = 30). У сироватці крові пацієнтів вимірювали рівень МОА за В.А. Метельською. Для оцінки ендотеліальної функції визначали ендотелійзалежну вазодилатацію плечової артерії в пробі з реактивною гіперемією. Результати. На основі проведених досліджень встановлено вірогідне зниження вмісту МОА в сироватці крові: у пацієнтів iз НВК — у 1,7 раза (р &lt; 0,01) та з ХК — в 1,9 раза (р &lt; 0,001). Зниження вмісту МОА в сироватці крові не залежало від нутритивного статусу пацієнтів iз ХЗЗК. Порушення функції судинного ендотелію виявлено в 76,7 % випадків: зниження функції ендотелію — у 49,2 %, дисфункція — у 27,5 %. Зміни функції судинного ендотелію зареєстровано в 75,7 % пацієнтів І групи, 75 % — ІІ та у 83,4 % пацієнтів ІІІ групи, переважно внаслiдок зниження функції ендотелію. Висновки. Показано, що в 71 % пацієнтів iз ХЗЗК відбувається вірогідне зниження вмісту МОА в сироватці крові, що не залежить від їхнього нутритивного статусу. У хворих iз НВК спостерігалися більш виражені зміни у частотi виявлених порушень та більш значне зростання діаметра плечової артерії порівняно iз пацієнтами з ХК. Зниження нутритивного статусу супроводжувалося змінами функції судинного ендотелію в 75,4 % випадків.
Raltitrexed as salvage therapy for metastatic colorectal cancer: A multicenter retrospective study
Authors: I. Ghanem, A. Viudez, E. García-Torralba, J. Torres-Tenor, A. Carmona, R. Vera, N. Rodriguez-Salas, F. Ayala de la Peña, O. Higuera, J. Feliu
Journal: Annals of Oncology (2018)

Introduction: Raltitrexed is used as an alternative to fluoropyrimidines (FP) for the treatment of colorectal cancer patients. We previously reported a retrospectively unicentric study analyzing the activity and tolerance of raltitrexed as salvage therapy for advanced colorectal cancer. Here, we report an update and an enlargement of the sample size as a multicenter study. Methods: From January 2008 to June 2017, 134 metastatic colorectal cancer patients (p) treated with raltitrexed as salvage therapy at three Spanish Hospitals, monotherapy (72p; 54%) or combined with oxaliplatin (29p; 22%), mitomycin (26p; 19%), or other therapies (7p; 5%) were identified. Clinical characteristics, tolerability and efficacy were collected. Results: One hundred and thirty-four p (70 men; 52%) with a median age of 67 years (range 28-86) and ECOG 0-1 (92p; 69%) or ECOG 2 (42p; 31%) were included. Fifty-seven p (42%) had received adjuvant therapy, 77p (57%) two previous lines for metastatic disease, and 57p (43%) three or more lines. Median time from metastatic diagnosis to first administration of raltitrexed was 24.9 months. All patients were previously treated with FP, irinotecan and oxaliplatin, 121p (90%) antiangiogenic therapy, 61p (45%) anti-EGFR therapy, 11p (8%) mitomycin, 7p (5%) regorafenib and 4p (3%) TAS 102. The most common sites of metastases were liver in 99p (74%) and lung in 95p (71%). Median number of cycles was 3 (1-37) and dose adjustment was done in forty-five p (34%), most of them (27p; 20%) at first cycle. One hundred and thirty-two p were evaluated for toxicity: 122p (91%) presented some adverse event (AE), grade 3-4 AE were observed in 35 p (26%). The most frequent AE were asthenia in 99 p (74%) and anemia in 79 p (59%). One p (0.7%) presented complete response, 2p (1.5%) partial response, 16p (12%) stable disease, 96 p (72%) progressive disease, and 19p (14%) were not evaluated. The median progression free survival and median overall survival were 2.4 (95% CI, 2.15 to 2.64) and 5.1 months (95% CI, 4.02 to 6.18) respectively. Conclusion: Despite acceptable tolerance, in our multicenter retrospective study, raltitrexed does not seem to have activity as salvage therapy for metastatic colorectal cancer.
Characteristics of colorectal cancer in the elderly patients about 60 cases
Authors: H. Aliane, S. Ghomari-Bezzar, A. Belhadj, N. Madani, N. Charif
Journal: Annals of Oncology (2018)

Introduction: Older people constitute a heterogeneous population, according to World Health Organization, the elderly person is defined as any individual with a chronological age equal to or higher than 60 years. In most cases, colorectal carcinoma is a disease of the elderly. Occurs mostly in the elderly people of more than 65 years and it poses public health problem. For several years geriatric evaluation has shown multiple benefits and we are witnessing a significant improvement in the oncological management of these patients. Methods: This is a retrospective study conducted in the Medical Oncology Department CHU Tlemcen for patients aged 65 years and over with colorectal carcinoma. The objective of this study is the geriatric evaluation before treatment and establish the different epidemiological, clinical, endoscopic, histological and therapeutic profile of colorectal cancer and survival without recurrence in this population. Results: We collected 60 cases of which 56% were men. The mean age was 71.3 years [65-91], The majority of patients had comorbidities associated with diabetes (20%), hypertension (34%), heart disease (8%) and 38% had others, 18% had a family history of cancers. The mean time to consultation was 9.1 months [1-36], The reason for consultation was rectorrhagia (45%), abdominal pain (25%), constipation (11%), diarrhea (10%) and occlusive syndrome (8%). Endoscopic appearance of the tumor was dominated by the burgeoning ulcerative appearance in the majority of cases, the tumour was colic in 72%. The well differentiated lieberkuhnal adenocarcinoma was the dominant histological type (89%). Tumor resection with node dissection was performed in 80% of cases. The tumor was classified as stage I (14%), II (14%), III (47%) and IV (25%). The metastases were synchronous at diagnosis in 25% of cases and metachronous in 15%, they were liver metastases (42%), peritoneal carcinomatosis (27%), pulmonary (21%) and other (10%). Before treatment evaluating oncogeriatric was done in patients older than 75 years the score G8 was superior than 14 in 69% of cases which 28% were classified as fragile according to BALDUCCI. The toxicity score of HURRIA was low for standard dose monochemotherapy in 46%. 51% of patients had an indication of adjuvant chemotherapy however only 45% received the recommended protocol. The evolution was marked by 15% of recurrences and 36% of deaths. Conclusion: Elderly patients with colorectal cancer deserve to be treated in the same way as younger subjects. These treatments must be targeted and adapted according to age and associated co-morbidities, only a collaboration of oncologists and geriatricians strengthened in a multidisciplinary consultation that will facilitate the care of these patients.
PCLN-05. A BIOBANK OF PATIENT-DERIVED MOLECULARLY CHARACTERIZED ORTHOTOPIC PEDIATRIC BRAIN TUMOR MODELS FOR PRECLINICAL RESEARCH
Authors: Sebastian Brabetz, Susanne N Groebner, Natalie Jaeger, Till Milde, Jonas Ecker, Florian Selt, Olaf Witt, Jessica M Rusert, Jan Koster, Sarah E Leary, Xiao-Nan Li, Robert J Wechsler-Reya, James M Olson, Stefan M Pfister, Marcel Kool
Journal: Neuro-Oncology (2018)

Identification of multiple distinct subtypes of pediatric brain tumors raises the need for more and better preclinical models reflecting these subtypes. Orthotopic patient-derived xenograft (PDX) models generated by injection of human tumor cells into the brain of NSG mice offer the unique possibility to test novel substances in primary patient tissue in an in vivo environment. Extensive molecular characterization of PDX and matching primary tumor/blood are needed to see how well the PDX represents the original disease, to learn about targetable oncogenic drivers in each model, and to establish or confirm predictive biomarkers. In an ongoing world-wide effort we have generated and fully characterized thus far 130 PDX models reflecting 22 distinct molecular subtypes of pediatric brain tumors. PDX models always retain their molecular subtype as assessed by DNA methylation analysis and in the vast majority of cases also the mutations and copy number alterations when compared to their primary tumors. Most aggressive tumors, such as those having MYC(N) amplifications, are overrepresented in the cohort, but also subtypes which have not been available for preclinical testing before due to lack of genetically engineered mouse models or suitable cell lines are included. All models and corresponding molecular data will become available for the community for preclinical research. Our repertoire of PDX models and corresponding molecular characterizations allow researchers to find the right models for their specific scientific questions. It provides an unprecedented resource to study tumor biology and paves the way for improving treatment strategies for children with malignant brain tumors.
Abstract 13418: Atherosclerotic Risk Factors and Biomarkers Among Diabetics with Subclavian Stenosis: The Penn Diabetes Health Study
Authors: Scott Lilly, Timothy W Churchill, Atif N Qasim, Claire K Mulvey, Muredach P Reilly, Luis H Eraso
Journal: Circulation (2012)

Introduction:  Subclavian stenosis (SS) is clinically defined as >15 mm difference in the brachial systolic arm pressures. Previous epidemiologic studies have identified an increased incidence of SS among those with diabetes, though there is little data regarding risk factor or biomarker correlates in the diabetic population. We hypothesized that SS would be prevalent in the diabetic population and be associated with biomarkers formerly linked to peripheral arterial disease.    Methods:  Within the Penn Diabetes Heart Study (PDHS, N = 1856, 36% women, 61% Caucasian), a cross-sectional study of diabetic individuals without clinical cardiovascular disease, we used ANOVA, the chi-square test and logistic regression to compare CVD risk factors and biomarkers among those with and without SS (defined as brachial arm pressure difference > 15 mm Hg).    Results:  SS was present in 12.2% in the PDHS cohort. Those with SS were more likely to be female (46.7% vs 34.7%) and have a greater body mass index (BMI) (33.9 vs 32.5 lb/in2; both p    Conclusion:  The prevalence of SS among diabetics without overt cardiovascular disease is higher than that reported in non-diabetic populations, and occurred more frequently in tandem with other indices of peripheral, but not coronary, atherosclerosis. In addition, the relationship between leptin, body mass index and SS has not formerly been reported, and provides a framework for the mechanistic investigation of the link between obesity and SS.
Therapeutic Effects of Adipose Stem Cells from Diabetic Mice for the Treatment of Type 2 Diabetes
Authors: Mengmeng Wang, Lili Song, Charlie Strange, Xiao Dong, Hongjun Wang
Journal: Molecular Therapy (2018)

To assess the potential therapeutic effects of adipose tissue-derived mesenchymal stem cells (ASCs) for the treatment of type 2 diabetes (T2D), we compared the phenotype and functionality of ASCs isolated from high-fat diet and streptozotocin (STZ)-induced T2D and the leptin receptor-deficient (db/db) mice with cells from healthy C57BL/6 mice. ASCs from T2D or db/db mice showed similar expression patterns of cellular markers and abilities to differentiate into adipocytes, osteoblasts, and chondrocytes. However, the rate of proliferation was reduced. ASCs from db/db mice secreted less hepatocyte growth factor (HGF). T2D mice receiving a single intravenous injection of T2D or db/db ASCs showed increased insulin sensitivity, reduced inflammation and fat content in adipose tissue and the liver and increased pancreatic β cell mass through 5 weeks post-infusion. Our data show that, although ASCs from T2D or db/db mice had inferior proliferative capacity compared to cells from healthy controls, improved insulin sensitivity and less β cell death was seen in T2D mice receiving mesenchymal stem cell (MSC) therapy. This study offers evidence that ASCs from diabetic donors have the potential to be used for cell therapy in the treatment of insulin resistance and T2D. To assess the potential therapeutic effects of adipose tissue-derived mesenchymal stem cells (ASCs) for the treatment of type 2 diabetes (T2D), we compared the phenotype and functionality of ASCs isolated from high-fat diet and streptozotocin (STZ)-induced T2D and the leptin receptor-deficient (db/db) mice with cells from healthy C57BL/6 mice. ASCs from T2D or db/db mice showed similar expression patterns of cellular markers and abilities to differentiate into adipocytes, osteoblasts, and chondrocytes. However, the rate of proliferation was reduced. ASCs from db/db mice secreted less hepatocyte growth factor (HGF). T2D mice receiving a single intravenous injection of T2D or db/db ASCs showed increased insulin sensitivity, reduced inflammation and fat content in adipose tissue and the liver and increased pancreatic β cell mass through 5 weeks post-infusion. Our data show that, although ASCs from T2D or db/db mice had inferior proliferative capacity compared to cells from healthy controls, improved insulin sensitivity and less β cell death was seen in T2D mice receiving mesenchymal stem cell (MSC) therapy. This study offers evidence that ASCs from diabetic donors have the potential to be used for cell therapy in the treatment of insulin resistance and T2D.
Long Noncoding RNA CRYBG3 Blocks Cytokinesis by Directly Binding G-Actin
Authors: Hailong Pei, Wentao Hu, Ziyang Guo, Huaiyuan Chen, Ji Ma, Weidong Mao, Bingyan Li, Aiqing Wang, Jianmei Wan, Jian Zhang, Jing Nie, Guangming Zhou, Tom K. Hei
Journal: Cancer Research (2018)

Abstract The dynamic interchange between monomeric globular actin (G-actin) and polymeric filamentous actin filaments (F-actin) is fundamental and essential to many cellular processes, including cytokinesis and maintenance of genomic stability. Here, we report that the long noncoding RNA LNC CRYBG3 directly binds G-actin to inhibit its polymerization and formation of contractile rings, resulting in M-phase cell arrest. Knockdown of LNC CRYBG3 in tumor cells enhanced their malignant phenotypes. Nucleotide sequence 228-237 of the full-length LNC CRYBG3 and the ser14 domain of β-actin is essential for their interaction, and mutation of either of these sites abrogated binding of LNC CRYBG3 to G-actin. Binding of LNC CRYBG3 to G-actin blocked nuclear localization of MAL, which consequently kept serum response factor (SRF) away from the promoter region of several immediate early genes, including JUNB and Arp3, which are necessary for cellular proliferation, tumor growth, adhesion, movement, and metastasis. These findings reveal a novel lncRNA-actin-MAL-SRF pathway and highlight LNC CRYBG3 as a means to block cytokinesis and to treat cancer by targeting the actin cytoskeleton. Significance: Identification of the long noncoding RNA LNC CRYBG3 as a mediator of microfilament disorganization marks it as a novel therapeutic antitumor strategy. Cancer Res; 78(16); 4563–72. ©2018 AACR.