tbuckley/cabot-search huggingface dataset:
Maternal ω3 docosapentaenoic acid inhibits infant allergic dermatitis through TRAIL‐expressing plasmacytoid dendritic cells in mice
Authors: So‐ichiro Hirata, Takahiro Nagatake, Kento Sawane, Koji Hosomi, Tetsuya Honda, Sachiko Ono, Noriko Shibuya, Emiko Saito, Jun Adachi, Yuichi Abe, Junko Isoyama, Hidehiko Suzuki, Ayu Matsunaga, Takeshi Tomonaga, Hiroshi Kiyono, Kenji Kabashima, Makoto Arita, Jun Kunisawa
Journal: Allergy (2020)

Abstract Background Maternal dietary exposures are considered to influence the development of infant allergies through changes in the composition of breast milk. Cohort studies have shown that ω3 polyunsaturated fatty acids (PUFAs) in breast milk may have a beneficial effect on the preventing of allergies in infants; however, the underlying mechanisms remain to be investigated. We investigated how the maternal intake of dietary ω3 PUFAs affects fatty acid profiles in the breast milk and their pups and reduced the incidence of allergic diseases in the pups. Methods Contact hypersensitivity (CHS) induced by 2,4‐dinitrofluorobenzene (DNFB) and fluorescein isothiocyanate was applied to the skin in pups reared by mother maintained with diets mainly containing ω3 or ω6 PUFAs. Skin inflammation, immune cell populations, and expression levels of immunomodulatory molecules in pups and/or human cell line were investigated by using flow cytometric, immunohistologic, and quantitative RT‐PCR analyses. ω3 PUFA metabolites in breast milk and infant's serum were evaluated by lipidomics analysis using LC‐MS/MS. Results We show that maternal intake of linseed oil, containing abundant ω3 α‐linolenic acid, resulted in the increased levels of ω3 docosapentaenoic acid (DPA) and its 14‐lipoxygenation products in the breast milk of mouse dams; these metabolites increased the expression of TNF‐related apoptosis‐inducing ligand (TRAIL) on plasmacytoid dendritic cells (pDCs) in their pups and thus inhibited infant CHS. Indeed, the administration of DPA‐derived 14‐lipoxygenation products to mouse pups ameliorated their DNFB CHS. Conclusion These findings suggest that an inhibitory mechanism in infant skin allergy is induced through maternal metabolism of dietary ω3 PUFAs in mice.
Twin Anemia Polycythemia Sequence
Authors: Joana Araújo Pereira, Marina Sousa Gomes
Journal: New England Journal of Medicine (2020)

Physical examination at birth of monochorionic, diamniotic twins born at 31 weeks of gestation showed a pallid first twin and a plethoric second twin. Findings on transabdominal ultrasonography that had been performed at 30 weeks of gestation were suggestive of twin anemia polycythemia sequence.
Prevalence and Family-Related Factors Associated With Suicidal Ideation, Suicide Attempts, and Self-injury in Children Aged 9 to 10 Years
Authors: Danielle C. DeVille, Diana Whalen, Florence J. Breslin, Amanda S. Morris, Sahib S. Khalsa, Martin P. Paulus, Deanna M. Barch
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Although suicide is a leading cause of death for children in the United States, and the rate of suicide in childhood has steadily increased, little is known about suicidal ideation and behaviors in children. <h3>Objective</h3> To assess the overall prevalence of suicidal ideation, suicide attempts, and nonsuicidal self-injury, as well as family-related factors associated with suicidality and self-injury among preadolescent children. <h3>Design, Setting, and Participants</h3> Cross-sectional study using retrospective analysis of the baseline sample from the Adolescent Brain Cognitive Development (ABCD) study. This multicenter investigation used an epidemiologically informed school-based recruitment strategy, with consideration of the demographic composition of the 21 ABCD sites and the United States as a whole. The sample included children aged 9 to 10 years and their caregivers. <h3>Main Outcomes and Measures</h3> Lifetime suicidal ideation, suicide attempts, and nonsuicidal self-injury as reported by children and their caregivers in a computerized version of the Kiddie Schedule for Affective Disorders and Schizophrenia. <h3>Results</h3> A total of 11 814 children aged 9 to 10 years (47.8% girls; 52.0% white) and their caregivers were included. After poststratification sociodemographic weighting, the approximate prevalence rates were 6.4% (95% CI, 5.7%-7.3%) for lifetime history of passive suicidal ideation; 4.4% (95% CI, 3.9%-5.0%) for nonspecific active suicidal ideation; 2.4% (95% CI, 2.1%-2.7%) for active ideation with method, intent, or plan; 1.3% (95% CI, 1.0%-1.6%) for suicide attempts; and 9.1% (95% CI, 8.1-10.3) for nonsuicidal self-injury. After covarying by sex, family history, internalizing and externalizing problems, and relevant psychosocial variables, high family conflict was significantly associated with suicidal ideation (odds ratio [OR], 1.12; 95% CI, 1.07-1.16) and nonsuicidal self-injury (OR, 1.09; 95% CI, 1.05-1.14), and low parental monitoring was significantly associated with ideation (OR, 0.97; 95% CI, 0.95-0.98), attempts (OR, 0.91; 95% CI, 0.86-0.97), and nonsuicidal self-injury (OR, 0.95; 95% CI, 0.93-0.98); these findings were consistent after internal replication. Most of children's reports of suicidality and self-injury were either unknown or not reported by their caregivers. <h3>Conclusions and Relevance</h3> This study demonstrates the association of family factors, including high family conflict and low parental monitoring, with suicidality and self-injury in children. Future research and ongoing prevention and intervention efforts may benefit from the examination of family factors.
Multimodality management of brain metastasis from colorectal cancer.
Authors: Zhaohui Jin, William Breen, Rui Jin, Paul D. Brown, Joleen Marie Hubbard
Journal: Journal of Clinical Oncology (2020)

204 Background: More than 50% of colorectal cancer (CRC) patients will develop metastatic disease. Brain metastasis (BM) from colorectal cancer is uncommon (0.6-1.36%). This study aims to investigate the patient characteristics, treatment modalities and prognostic factors in this rare population. Methods: 104 patients with brain metastasis disease from CRC were identified from over 30,000 colorectal cancer patients at the Mayo Clinic Rochester between 1/1994 and 6/2019. A retrospective review was conducted by using data from electronic medical records (EMR). Statistical analysis utilized the Kaplan-Meier method, Log-rank test, and Cox proportional hazards models. Results: Among the 104 patients, 62 were male (59.6%) and 42 were female (40.4%). Median age at CRC diagnosis was 58.4 and at BM diagnosis was 61. Thirty-three patients had right-sided colon cancers, 27 patients had left-sided colon cancers and 39 patients had rectal cancer. Median time from CRC diagnosis to BM was 30.7 months. The majority of patients (58.7%) presented with a solitary brain lesion. Eighty-six patients (82.7%) had extracranial metastatic disease at BM diagnosis. Median survival was 7.0 months (95% CI 2.6-16.9) from BM diagnosis. Age &lt;70, solitary BM, surgery, radiation, and chemotherapy were associated with statistically significant improved survival on univariate and multivariate analysis. Multi-modality treatment including surgical brain lesion resection, postoperative stereotactic radiation (SRS) with/without whole brain radiation (WBRT), and chemotherapy significantly improved median overall survival (Table). Conclusions: Although BM from CRC carries poor prognosis, multi-modality treatment (surgery, radiation and systemic chemotherapy) for patients with limited BM improves clinical outcome. [Table: see text]
Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line therapy in patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.
Authors: Rui-hua Xu, Hendrik-Tobias Arkenau, Yung-Jue Bang, Crystal S. Denlinger, Ken Kato, Josep Tabernero, Jin Wang, Jiang Li, Henry Castro, Markus H. Moehler
Journal: Journal of Clinical Oncology (2020)

TPS458 Background: First-line standard of care in patients with locally advanced or metastatic G/GEJ adenocarcinoma is fluoropyrimidine- and platinum (plat)-based combination chemotherapy. Despite improved chemotherapy regimens, outcomes remain poor and survival is low. Tislelizumab, an investigational humanized IgG4 monoclonal antibody with high affinity and binding specificity for PD-1, was engineered to minimize binding of FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Previous reports from early phase studies suggested tislelizumab, as a single agent and combined with chemotherapy, was generally well tolerated and had antitumor activity in patients with advanced solid tumors, including G/GEJ cancer. Methods: This randomized, placebo-controlled phase 3 study (NCT03777657) is designed to evaluate plat/fluoropyrimidine + tislelizumab vs plat/fluoropyrimidine + placebo as first-line therapy for patients with locally advanced or metastatic G/GEJ adenocarcinoma. Adult patients (n≈720) from ~160 centers will be randomized 1:1 to receive tislelizumab (200 mg IV Q3W) or placebo in combination with chemotherapy. Oxaliplatin (130 mg/m² IV Q3W) + capecitabine (1000 mg/m 2 orally BID for 2 weeks) or cisplatin (80 mg/m² IV Q3W) + 5-fluorouracil (800 mg/m 2 /day IV on Days 1-5 Q3W) will be used as backbone chemotherapy on an individual basis. Chemotherapy will be administered for up to 6 cycles; capecitabine maintenance therapy is optional for patients who received capecitabine and oxaliplatin. Progression-free and overall survival are primary endpoints of the study. Secondary endpoints will include overall response rate, quality-of-life outcomes, and the safety/tolerability profile of combination therapy. Exploratory endpoints include disease control rate, time to response, and an analysis of potential predictive biomarkers including PD-L1 expression; the VENTANA PD-L1 (SP263) assay will be used for PD-L1 expression analysis. This study is actively enrolling. Clinical trial information: NCT03777657.
Phase I dose-escalation trial of trifluridine/tipiracil (TAS-102) and temozolomide in the treatment of advanced neuroendocrine tumors.
Authors: Nataliya Volodymyrivna Uboha, Sam Joseph Lubner, Noelle K. LoConte, Daniel Mulkerin, Jens C. Eickhoff, Dustin A. Deming
Journal: Journal of Clinical Oncology (2020)

615 Background: Systemic chemotherapy plays a role in treating neuroendocrine tumors. Trifluridine/tipiracil (FTD/TPI), known as TAS-102, is an antineoplastic agent that is non-cross resistant with 5-fluorouracil and capecitabine and that has a different toxicity profile. We are presenting results from a phase 1 portion of the study evaluating safety of FTD/TPI in combination with TMZ in patients in neuroendocrine tumors. Methods: Phase 1 portion to the study utilized “3+3” design to determine maximum tolerated doses (MTD) of FTD/TPI and TMZ when administered in combination. Patients with advanced NETs of any grade were eligible for participation. FTD/TPI was taken twice a day on days 1-5 and 8-12 and TMZ was taken daily on days 8-12 of a 28 day cycle. 3 dose levels (Lv) were evaluated. FTD/TPI was started at a goal dose of 35 mg/m 2 twice daily. Three doses of TMZ were studied: 100, 150 and 200 mg/m 2 . Growth factor support was required during DLT evaluation period for all patients starting with the fourth subject on study. Results: Sixteen evaluable subjects (6 females, median age 64) enrolled in the phase 1 portion of the study (4 on Lv1, 6 on Lv2, 6 on Lv3). 3/16 had high-grade tumors, 8/16 had non-GI or unknown primary. No DLTs were observed on Lv1. One DLT was observed on Lv2 (grade 3 fatigue and inability to resume treatment) and 1 DLT on Lv3 (grade 4 thrombocytopenia). Overall the treatment was well tolerated. 7 subjects had grade ≥3 AEs at least possibly related to treatment, with neutropenia and lymphopenia being the most common. 4 subjects required dose reductions. 7 subjects remain on active treatment. 4 subjects discontinued treatment due to AEs and 1 due to clinical disease progression. Efficacy data is being collected and will be presented at the meeting. Conclusions: This study established MTD of FTD/TPI (35mg/m 2 twice daily) and TMZ (200 mg/m 2 ). This regimen is well tolerated. Enrollment into expansion cohort for patients with advanced Grade 1-2 pancreatic NETs is ongoing (NCT02943733). Clinical trial information: NCT02943733.
Hypoxia induced LUCAT1/PTBP1 axis modulates cancer cell viability and chemotherapy response
Authors: Lin Huan, Tianan Guo, Yangjun Wu, Linguo Xu, Shenglin Huang, Ye Xu, Linhui Liang, Xianghuo He
Journal: Molecular Cancer (2020)

Hypoxic tumors are refractory to DNA damage drugs. However, the underlying mechanism has yet to be elucidated. We aimed to identify lncRNAs that upregulated under hypoxia and their effects on colorectal cancer (CRC).CRC cells were treated with 1% O2 to identify lncRNAs that upregulated under hypoxia. We integrated these lncRNAs with RNA-seq of 4 paired CRC tissues and TCGA data to get candidate lncRNAs. Multiple in vitro and in vivo assays were used to explore the role of LUCAT1 in CRC.We identified a hypoxia-induced lncRNA LUCAT1 that facilitated the growth of CRC cells and contributed to drug resistance of CRC cells both in vitro and in vivo. Mechanically, LUCAT1 interacts with polypyrimidine tract binding protein 1 (PTBP1) in CRC cells, facilitates the association of a set of DNA damage related genes with PTBP1, thus resulting in altered alternative splicing of these genes. Moreover, ectopic expression of PTBP1 in CRC cells with knockdown of LUCAT1 abrogated the effects induced by LUCAT1 knockdown. Chemotherapeutics drug combined with LUCAT1 knockdown via antisense oligonucleotides (ASO) would get a better outcome in vivo, compared with group treated with chemotherapeutic drug only. Notably, LUCAT1 is upregulated in CRC tissues, compared to adjacent normal tissues; and CRC patients with higher LUCAT1 have a worse prognosis and poorly responded to chemotherapy in the clinic.Our data suggested CRC cells utilizes LUCAT1 to develop resistance to DNA damage drugs, and disrupting the LUCAT1/PTBP1 axis might be a promising therapeutic strategy for refractory hypoxic tumors.
Genomic profiling of a clinically annotated cohort of locoregionally advanced head and neck cancers (HNC) treated with definitive chemoradiotherapy.
Authors: Tanguy Y. Seiwert, Michaela K. Keck, Zhixiang Zuo, Arun Khattri, Christopher Brown, Thomas Stricker, Damian Rieke, Mark W. Lingen, Ezra E. W. Cohen, Kevin P. White, Everett E. Vokes
Journal: Journal of Clinical Oncology (2012)

5517 Background: Recent advances in genomic technology and sequencing have allowed the near comprehensive characterization of genetic abnormalities in HNC, but their correlation with clinical outcome remains to be determined. We analysed a clinically annotated cohort of locoregionally advanced HNC for copy number changes and mutations and correlated with outcome in an exploratory fashion. Methods: 120 head and neck cancers (frozen tissue) and matching normal tissues/blood from patients with locoregionally advanced HNC treated with definitive chemoradiation +/- induction at the University of Chicago were obtained from our tissue bank. DNA, RNA, protein were extracted. Barcoded, multiplexed sequencing libraries for 500 head and neck cancer associated genes (Agilent capture) were built and sequenced on Illumina HiSeq next generation sequencers. 150 commonly copy number altered and HNC relevant genes were analysed for copy number alterations (CNA) using the Nanostring nCounter platform. Respective genetic aberrations in curated pathways were allocated to tumor subgroups. Exploratory analysis correlated data with induction response and progression free survival. Confirmatory HPV testing was performed using an E6, nested, multiplex PCR. Results: ≥80% of targeted sequences were successfully captured and sequenced. Commonly mutated genes included: TP53, CDKN2A, PIK3CA, NOTCH1. Of note PIK3CA mutations were enriched in HPV(+) tumors. Commonly copy number altered genes included amplifications of VEGF1, CCND1, MYC, EGFR, MDM4, CTTN, as well as PIK3CA, and deletions of CDKN2A, SUCLG2, FHIT, TGFBR2, PTPRD, IKBKG, TRAF6, and RASSF1. CCND1, and MYC were commonly co-amplified and correlated with poor progression free survival, representing a distinct HNC phenotype. Analysis for additional genes and influence on induction response will be presented. Conclusions: Targeted, medium throughput genomic profiling is feasible, and provides the majority of HNC specific genetic aberrations at a comparably low cost. Impact on outcome (CCND1/MYC amplification) and potential treatment targets (PIK3CA mutations in HPV(+) tumors) were identified.
Effect of weight, obesity, and other co-morbidities on mortality of colon cancer patients.
Authors: Kevin Sing, Valerie Tran, Donna McClish, Khalid Matin
Journal: Journal of Clinical Oncology (2020)

25 Background: There have been reports implicating underweight status as well as obesity with lower survival in colorectal cancer patients, but data has been inconsistent. Methods: In this retrospective observational study, we gathered pre-treatment data on BMI and other co-morbidities from 423 colon cancer patients who underwent surgical resection (stages I to III) or were metastatic at diagnosis (stage IV) at VCU Medical Center from 2005 to 2018 and analyzed their survival outcomes. Results: Compared to patients with a normal BMI, patients with underweight status (BMI &lt; 18.5) have a trend towards higher all-cause mortality (HR 1.66, 95% CI 0.67-4.12). Patients with overweight BMI (25-29.9) and obese BMI ( &gt; 30) have a trend towards improved mortality (HR 0.67, 95% CI 0.46-0.98) (HR 0.75, 95% CI 0.53-1.07) respectively. The p-value was 0.0675. We also found that pre-existing diabetes mellitus is associated with increased all-cause mortality (HR 1.43, CI 1.03 to 1.98, p &lt; 0.05), as well as the use of aspirin at diagnosis (HR 1.60, CI 1.16 to 2.21, p &lt; 0.05). Conclusions: Our results are similar to previous findings that patients with underweight status have worse mortality outcome, suggesting the importance of nutritional status prior to starting treatment. We also found that overweight and obese patients have trends towards improved survival compared to normal weight patients. Future focus can be directed to see whether overweight or obesity status past diagnosis affect survival trends. Aspirin use at diagnosis in our study population is associated with worse mortality outcome; literature is conflicting with outcomes and pre-diagnosis aspirin use. Our findings are similar for both locoregional colon cancers as well as metastatic disease. Research should be directed at seeing what kind of interventions such as nutrition or rehabilitation can be used to ameliorate the increased mortality trend in the underweight status group of patients.
Abstract 17150: LDL-C Response to Portfolio Foods Containing High Levels of Phytosterols, Whole Food Fiber, and Alpha-Linoleic Acid in Statin Reluctant Patients: Impact of CYP7A1-rs3808607 and APOE Isoforms
Authors: Stephen L Kopecky, Elizabeth Klodas, Soumya Alias, Jessica Bauman, Stephanie Jew, Peter J Jones
Journal: Circulation (2018)

Introduction: Up to 20% of outpatients receiving HMG-CoA reductase inhibitors (statins) experience treatment reluctance on the basis of side effects, leaving a large population at increased risk of CVD. We hypothesized that a practical food-based approach can be utilized to lower LDL-C in statin reluctant patients and that the lipid response can be predicted based upon CYP7A1-rs3808607 (CYP7A1) and APOE genetic isoforms. Methods: This was a multicenter, randomized, double-blind, free-living cross-over study composed of 2 phases of 4 wk each, separated by a 4 wk washout. Participants (n=54) received an assortment of individually packaged, shelf stable snacks along with printed instructions to ingest 2 servings of the foods per day as a substitute for similar items they were eating already. No other dietary or behavior adjustments were requested. Treatment products supplied at least 1800 mg alpha-linoleic acid (ALA), 5 g of fiber and 1g of phytosterols per serving. Control products were calorie-matched like items drawn from the general grocery marketplace. Lipid parameters were measured and averaged over 2 d at baseline and at 4 wk of each phase. Ingestion of study foods was confirmed by C18:3n3 serum level assessment. Single nucleotide polymorphisms and APOE isoform were assessed by Taqman genotyping assay. Results: As compared to control, LDL-C decreased 8.8% in the treatment arm (p&lt;0.0001, range -37.6% to +20.5%) and total cholesterol fell 5.1% (p&lt;0.004). No significant change was seen in HDL-C, TG or fasting glucose levels. LDL-C was reduced by diet in CYP7A1 T/T homozygotes (-0.3924+0.1271mmol/l, p = 0.0033) and APOE4 carriers ( -0.3808+0.098 mmol/l, p = 0.0003). Conclusions: Significant LDL-C reductions can be affected through a simple food intervention supplying high levels of phytosterols, fiber and ALA. CYP7A1 and APOE isoforms influence the variability in LDL-C response and can help identify individual patients especially appropriate for a food-based LDL-C lowering approach. Given the large number of patients unable/unwilling to take statins, our findings have significant impact for management of this challenging population.
The Reg4-CD44ICD pathway and tumor aggression in early-stage colon adenocarcinoma.
Authors: Jared Sninsky, Kumar Bishnupuri, Ivan Gonzalez, Nikolaos Trikalinos, Ling Chen, Brian Dieckgraefe
Journal: Journal of Clinical Oncology (2020)

234 Background: Reg4, or regenerating islet-derived protein 4, is highly expressed in gastrointestinal malignancies and acts as a mitogenic factor. Our prior work suggests a direct invitro interaction between Reg4 and CD44, a non-kinase transmembrane glycoprotein over-expressed in cancer stem cells. Reg4 is hypothesized to activate CD44 proteolytic cleavage to release intra-cytoplasmic domain of CD44 (CD44ICD). The goal of this study was to demonstrate clinical validity of the Reg4-CD44/CD44ICD pathway in stage II/III colon cancer and its association with disease recurrence and clinical parameters of aggression. Methods: We constructed a tissue microarray (TMA) consisting of 94 stage II/III matched colon adenocarcinoma patients, 23 of which had recurrent disease after potentially curative treatment. The TMA was immunohistochemically stained for Reg4, CD44, and CD44ICD proteins with specific antibodies. Spearman’s correlation, Chi-square tests, and Kaplan-Meier analyses were used to identify protein associations with tumor characteristics, recurrence and overall survival. Results: Expression of Reg4, CD44, and CD44ICD was associated with tumor location, size, tumor grade, mismatch repair (MMR) status, and disease recurrence. TMA data analysis supported our proposed mechanism of Reg4-mediated release of CD44ICD into the cytoplasm. A significant correlation was observed between Reg4 and CD44 (r 2 = 0.23, P = 0.028), CD44 and CD44ICD (r 2 = 0.36, p = 0.0004), and Reg4 and CD44ICD (r 2 = 0.45, p = &lt; 0.0001). Reg4 expression was associated with larger tumor size (r 2 = 0.23, p = 0.026) . No association was observed between Reg4, CD44, or CD44ICD expression with disease recurrence. In patients who recurred, Reg4-positive patients had a median survival of 4 years vs. 7 years for Reg4-negative patients (p = 0.04). Our lab has performed in vitroexperiments with CD44ICD interfering peptides blocking the pro-proliferative effect of Reg4. Conclusions: These results suggest that Reg4-positive tumors, while not at higher risk of recurrence, are associated with decreased survival in established recurrent colon adenocarcinoma. Inhibition of the Reg4-CD44/CD44ICD pathway may be a future therapeutic target.