tbuckley/cabot-search huggingface dataset:
Pooled survival analysis of series using the liver-first approach to the management of colorectal cancer with synchronous liver-limited metastases demonstrates wide variation in outcome.
Authors: Santhalingam Jegatheeswaran, Ajith K. Siriwardena
Journal: Journal of Clinical Oncology (2013)

e14547 Background: Options for the management of patients with colorectal cancer with synchronous liver-limited metastatic disease include synchronous (liver and bowel) resection or sequential surgery: either the classic bowel-first approach or the newer liver-first strategy. This latter approach is popular but has little evidence underlying it. This study undertakes a pooled analysis of protocol and outcome of all reports of the liver-first approach for synchronous metastases. Methods: PubMed, Embase, science citation index, social sciences citation index and the Derwent innovations index were searched using terms describing colorectal cancer, liver metastases and surgery. The literature search identified 417 articles of which 4 cohort study reports described the liver-first approach and reported survival data and constitute the study population. A pre-defined protocol for data extraction was utilised to retrieve data on design, distribution of primary and hepatic metastatic disease, chemotherapy, surgery, patients completing treatment algorithm, outcome and survival. Data were extracted to populate a PRIZMA quality-control chart. Results: The 4 studies comprised 121 patients starting treatment of whom 90 (74%) completed the specified treatment protocol (83 rectal primary, 33 colon primary and primary site unreported in 5). Disease progression during the protocol period occurred in 23 (19%). Ninety six (79%) of the starting cohort of 121 reached the stage of liver resection with disease progression or death during chemotherapy being the principal causes of failure. Preferred algorithm was systemic chemotherapy (median 3 to 6 cycles) followed by hepatectomy with colorectal resection as the last step. There was wide variation between the reports in terms of their survival data. Conclusions: The liver-first approach is technically feasible in patients with colorectal cancer and synchronous hepatic metastases. About 20% will fail to complete the full treatment protocol because of disease progression. To date, there are no data to suggest superiority of outcome over the classic approach or synchronous surgery.
Association Between Early Hypertension Control and Cardiovascular Disease Incidence in Veterans With Diabetes
Authors: Sridharan Raghavan, Yuk-Lam Ho, Vinay Kini, Mary K. Rhee, Jason L. Vassy, David R. Gagnon, Kelly Cho, Peter W.F. Wilson, Lawrence S. Phillips
Journal: Diabetes Care (2019)

OBJECTIVE Guidelines for hypertension treatment in patients with diabetes diverge regarding the systolic blood pressure (SBP) threshold at which treatment should be initiated and treatment goal. We examined associations of early SBP treatment with atherosclerotic cardiovascular disease (ASCVD) events in U.S. adults with diabetes. RESEARCH DESIGN AND METHODS We studied 43,986 patients with diabetes who newly initiated antihypertensive therapy between 2002 and 2007. Patients were classified into categories based on SBP at treatment initiation (130–139 or ≥140 mmHg) and after 2 years of treatment (100–119, 120–129, 130–139, 140–159, and ≥160 mmHg). The primary outcome was composite ASCVD events (fatal and nonfatal myocardial infarction and stroke), estimated using inverse probability of treatment-weighted Poisson regression and multivariable Cox proportional hazards regression. RESULTS Relative to individuals who initiated treatment when SBP was 130–139 mmHg, those with pretreatment SBP ≥140 mmHg had higher ASCVD risk (hazard ratio 1.10 [95% CI 1.02, 1.19]). Relative to those with pretreatment SBP of 130–139 mmHg and on-treatment SBP of 120–129 mmHg (reference group), ASCVD incidence was higher in those with pretreatment SBP ≥140 mmHg and on-treatment SBP 120–129 mmHg (adjusted incidence rate difference [IRD] 1.0 [−0.2 to 2.1] events/1,000 person-years) and in those who achieved on-treatment SBP 130–139 mmHg (IRD 1.9 [0.6, 3.2] and 1.1 [0.04, 2.2] events/1,000 person-years for those with pretreatment SBP 130–139 mmHg and ≥140 mmHg, respectively). CONCLUSIONS In this observational study, patients with diabetes initiating antihypertensive therapy when SBP was 130–139 mmHg and those achieving on-treatment SBP &amp;lt;130 mmHg had better outcomes than those with higher SBP levels when initiating or after 2 years on treatment.
One small step for mice, one giant leap for GWAS?
Authors: Mark A. Herman, Jonathan E. Campbell, David A. D’Alessio
Journal: Journal of Clinical Investigation (2019)

Genome-wide association studies (GWAS) have provided a wealth of information on potential disease-associated genes in the human population. In particular, several loci have been associated with type 2 diabetes (T2D). However, due to the complexity of the disease, it has been a challenge to unravel the exact effects of specific loci on T2D pathogenesis. In this issue of the JCI, Keller and colleagues developed a systems genetic approach to identify insulin secretion–associated genes in nondiabetic mice followed by tissue-level and functional phenotyping. Several of the loci identified were syntenic with human T2D-related loci, indicating that this approach may be feasible for discerning genetic variation in nondiabetic individuals that may lead to the development of T2D.
Prognostic Significance of Baseline FLT3-ITD Mutant Allele Burden in Acute Myeloid Leukemia Treated with Intensive Chemotherapy with/without Sorafenib
Authors: Fevzi Yalniz, Hagop M. Kantarjian, Tapan M. Kadia, Guillermo Garcia-Manero, Keyur Patel, Sanam Loghavi, Koji Sasaki, Naval G. Daver, Courtney D. DiNardo, Naveen Pemmaraju, Nicholas J Short, Musa Yilmaz, Prithviraj Bose, Kiran Naqvi, Sherry A. Pierce, Jorge E. Cortes, Farhad Ravandi
Journal: Blood (2018)
Homologous Recombination-Based Genome Editing by Clade F AAVs Is Inefficient in the Absence of a Targeted DNA Break
Authors: Geoffrey L. Rogers, Hsu-Yu Chen, Heidy Morales, Paula M. Cannon
Journal: Molecular Therapy (2019)

Adeno-associated virus (AAV) vectors are frequently used as donor templates for genome editing by homologous recombination. Although modification rates are typically under 1%, they are greatly enhanced by targeted double-stranded DNA breaks (DSBs). A recent report described clade F AAVs mediating high-efficiency homologous recombination-based editing in the absence of DSBs. The clade F vectors included AAV9 and a series isolated from human hematopoietic stem and progenitor cells (HSPCs). We evaluated these vectors by packaging homology donors into AAV9 and an AAVHSC capsid and examining their ability to insert GFP at the CCR5 and AAVS1 loci in human HSPCs and cell lines. As a control, we used AAV6, which effectively edits HSPCs but only when combined with a targeted DSB. Each AAV vector promoted GFP insertion in the presence of matched CCR5 or AAVS1 zinc-finger nucleases (ZFNs), but none supported detectable editing in the absence of the nucleases. Rates of editing with ZFNs correlated with transduction efficiencies for each vector, implying no differences in the ability of donor sequences delivered by the different vectors to direct genome editing. Our results, therefore, do not support that clade F AAVs can perform high-efficiency genome editing in the absence of a DSB.
Paneth Cell Dysfunction Mediates Alcohol‐related Steatohepatitis Through Promoting Bacterial Translocation in Mice: Role of Zinc Deficiency
Authors: Wei Zhong, Xiaoyuan Wei, Liuyi Hao, Tai‐Du Lin, Ruichao Yue, Xinguo Sun, Wei Guo, Haibo Dong, Tianjiao Li, Ali R. Ahmadi, Zhaoli Sun, Qibin Zhang, Jiangchao Zhao, Zhanxiang Zhou
Journal: Hepatology (2019)

Microbial dysbiosis is associated with alcohol-related hepatitis (AH), with the mechanisms yet to be elucidated. The present study aimed to determine the effects of alcohol and zinc deficiency on Paneth cell (PC) antimicrobial peptides, α-defensins, and to define the link between PC dysfunction and AH.Translocation of pathogen-associated molecular patterns (PAMPs) was determined in patients with severe AH and in a mouse model of alcoholic steatohepatitis. Microbial composition and PC function were examined in mice. The link between α-defensin dysfunction and AH was investigated in α-defensin-deficient mice. Synthetic human α-defensin 5 (HD5) was orally given to alcohol-fed mice to test the therapeutic potential. The role of zinc deficiency in α-defensin was evaluated in acute and chronic mouse models of zinc deprivation. Hepatic inflammation was associated with PAMP translocation and lipocalin-2 (LCN2) and chemokine (C-X-C motif) ligand 1 (CXCL1) elevation in patients with AH. Antibiotic treatment, lipopolysaccharide injection to mice, and in vitro experiments showed that PAMPs, but not alcohol, directly induced LCN2 and CXCL1. Chronic alcohol feeding caused systemic dysbiosis and PC α-defensin reduction in mice. Knockout of functional α-defensins synergistically affected alcohol-perturbed bacterial composition and the gut barrier and exaggerated PAMP translocation and liver damage. Administration of HD5 effectively altered cecal microbial composition, especially increased Akkermansia muciniphila, and reversed the alcohol-induced deleterious effects. Zinc-regulated PC homeostasis and α-defensins function at multiple levels, and dietary zinc deficiency exaggerated the deleterious effect of alcohol on PC bactericidal activity.Taken together, the study suggests that alcohol-induced PC α-defensin dysfunction is mediated by zinc deficiency and involved in the pathogenesis of AH. HD5 administration may represent a promising therapeutic approach for treating AH.
Cannabidiol attenuates seizures and EEG abnormalities in Angelman syndrome model mice
Authors: Bin Gu, Manhua Zhu, Madison R. Glass, Marie Rougié, Viktoriya D. Nikolova, Sheryl S. Moy, Paul R. Carney, Benjamin D. Philpot
Journal: Journal of Clinical Investigation (2019)

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by intellectual disability, lack of speech, ataxia, EEG abnormalities, and epilepsy. Seizures in individuals with AS are common, debilitating, and often drug resistant. Thus, there is an unmet need for better treatment options. Cannabidiol (CBD), a major phytocannabinoid constituent of cannabis, has shown antiseizure activity and behavioral benefits in preclinical and clinical studies for some disorders associated with epilepsy, suggesting that the same could be true for AS. Here, we show that acute CBD (100 mg/kg) treatment attenuated hyperthermia- and acoustically induced seizures in a mouse model of AS. However, neither acute CBD nor a 2-week-long course of CBD administered immediately after a kindling protocol could halt the proepileptogenic plasticity observed in AS model mice. CBD had a dose-dependent sedative effect but did not have an impact on motor performance. CBD abrogated the enhanced intracortical local field potential power, including the delta and theta rhythms observed in AS model mice, indicating that CBD administration could also help normalize the EEG deficits observed in individuals with AS. We believe our results provide critical preclinical evidence supporting CBD treatment of seizures and alleviation of EEG abnormalities in AS and will thus help guide the rational development of CBD as a treatment for AS.
Ventricular stroke work and vascular impedance refine the characterization of patients with aortic stenosis
Authors: Eyal Ben-Assa, Jonathan Brown, Zahra Keshavarz-Motamed, Jose M. de la Torre Hernandez, Benjamin Leiden, Max Olender, Faouzi Kallel, Igor F. Palacios, Ignacio Inglessis, Jonathan J. Passeri, Pinak B. Shah, Sammy Elmariah, Martin B. Leon, Elazer R. Edelman
Journal: Science Translational Medicine (2019)

High left ventricular stroke work and low vascular impedance predict better quality of life after valve intervention in patients with aortic stenosis.
Reducing Hospital Admissions for Paracentesis: A Quality Improvement Intervention
Authors: Shazia Mehmood Siddique, Stefanie Porges, Meghan Lane-Fall, Shivan J. Mehta, William Schweickert, Joan Kinniry, April Taylor, James D. Lewis, Shaz Iqbal, David Goldberg, Judy A. Shea, Robert Stetson, Mary Coniglio, Maarouf Hoteit, Neil Fishman, Vandana Khungar
Journal: Clinical Gastroenterology and Hepatology (2019)
When Improving Symptoms Is Not Enough—Is It Time for Next-Generation Interventions for Obsessive-Compulsive Disorder?
Authors: David Mataix-Cols, Lorena Fernández de la Cruz, Christian Rück
Journal: JAMA Psychiatry (2019)

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H. Michael Shepard, Dennis J. Slamon, and Axel Ullrich honored with the 2019 Lasker~DeBakey Clinical Medical Research Award
Authors: Corinne L. Williams
Journal: Journal of Clinical Investigation (2019)

The characterization of tumor-specific proteins and genes has led to the development of several targeted therapies that have improved and extended the lives of patients with a variety of cancers.The 2019 Lasker~DeBakey Clinical Medical Research Award recognizes H. Michael Shepard, Dennis J. Slamon, and Axel Ullrich (Figure 1) for their contributions to the development of the HER2-targeting monoclonal antibody (mAb), Herceptin (also known as trastuzumab), the first of its kind to effectively target a cancerassociated protein and increase survival of women with HER2 + breast cancer.
Sociocultural memory development research drives new directions in gadgetry science
Authors: Penny Van Bergen, John Sutton
Journal: Behavioral and Brain Sciences (2019)

Sociocultural developmental psychology can drive new directions in gadgetry science. We use autobiographical memory, a compound capacity incorporating episodic memory, as a case study. Autobiographical memory emerges late in development, supported by interactions with parents. Intervention research highlights the causal influence of these interactions, whereas cross-cultural research demonstrates culturally determined diversity. Different patterns of inheritance are discussed.
Dynamics of Genomic, Epigenomic, and Transcriptomic Aberrations during Stepwise Hepatocarcinogenesis
Authors: Byul A Jee, Ji-Hye Choi, Hyungjin Rhee, Sarah Yoon, So Mee Kwon, Ji Hae Nahm, Jeong Eun Yoo, Youngsic Jeon, Gi Hong Choi, Hyun Goo Woo, Young Nyun Park
Journal: Cancer Research (2019)

Hepatocellular carcinoma (HCC) undergoes a stepwise progression from liver cirrhosis to low-grade dysplastic nodule (LGDN), high-grade dysplastic nodule (HGDN), early HCC (eHCC), and progressed HCC (pHCC). Here, we profiled multilayered genomic, epigenomic, and transcriptomic aberrations in the stepwise hepatocarcinogenesis. Initial DNA methylation was observed in eHCC (e.g., DKK3, SALL3, and SOX1) while more extensive methylation was observed in pHCC. In addition, eHCCs showed an initial loss of DNA copy numbers of tumor suppressor genes in the 4q and 13q regions, thereby conferring survival benefits to cancer cells. Transcriptome analysis revealed that HGDNs expressed endoplasmic reticulum (ER) stress-related genes, while eHCC started to express oncogenes. Furthermore, integrative analysis indicated that expression of the serine peptidase inhibitor, Kazal type 1 (SPINK1), played a pivotal role in eHCC development. Significant demethylation of SPINK1 was observed in eHCC compared to HGDN. The study also demonstrated that ER stress may induce SPINK1 demethylation and expression in liver cancer cells. In conclusion, these results reveal the dynamics of multiomic aberrations during malignant conversion of liver cancer, thus providing novel pathobiological insights into hepatocarcinogenesis. SIGNIFICANCE: Multiomics profiling and integrative analyses of stepwise hepatocarcinogenesis reveal novel mechanistic and clinical insights into hepatocarcinogenesis.
Clinicopathologic characteristics, prognostication and treatment outcomes for myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U): Mayo Clinic-Moffitt Cancer Center study of 135 consecutive patients
Authors: Abhishek A. Mangaonkar, David M. Swoboda, Giacomo Coltro, Terra L. Lasho, Paul J. Novotny, Prateek Pophali, Ryan M. Carr, Moritz Binder, Christy M. Finke, Naseema Gangat, Aref Al-Kali, Kebede H. Begna, Kaaren K. Reichard, Rhett P. Ketterling, Najla H. Al Ali, Pardis Vafaii, Ling Zhang, Eric Padron, Chetasi Talati, Mrinal M. Patnaik
Journal: Leukemia (2019)
Dasatinib (D) in patients (pts) with chronic myelogenous leukemia (CML) in myeloid blast crisis (MBC) who are imatinib-resistant (IM-R) or IM-intolerant (IM-I): Results of the CA180006 ‘START-B’ study
Authors: J. E. Cortes, D. W. Kim, G. Rosti, P. Rousselot, E. Bleickardt, R. Zink, C. Sawyers
Journal: Journal of Clinical Oncology (2006)

6529 Background: Dasatinib (D) (BMS-354825) is an oral, multitargeted tyrosine kinase inhibitor of Bcr-Abl and SRC with activity against IM-R cell lines. In a phase I study, there was preliminary evidence that D was active in MBC-CML patients (pts). Methods: START B is an open-label study of D in IM-R or IM-I MBC carried out in 46 sites worldwide. From December 2004 to May 2005, 124 MBC pts were accrued. D was given orally at 70 mg twice a day (BID) with dose escalation to 100 mg BID for poor initial response or dose reductions to 50 mg and 40 mg BID for toxicity. Pts had weekly blood counts and monthly bone marrow evaluations, including cytogenetics. The primary endpoint was confirmed (minimum 4 weeks duration) major hematologic response (MaHR). Results: Data are currently available on the first 74 pts (68 IM-R, 6 IM-I). Median age was 55 years, 55% were male. Other prior therapy included interferon in 55% of pts and bone marrow transplant (BMT) in 12%. Prior IM dose was &gt;600 mg/day in 49% of pts and 47% of pts received IM for &gt; 3 years. At baseline, the WBC count was ≥20 × 10 3 /mm 3 in 46%, the platelet count was &lt; 100 × 10 3 /mm 3 in 72% of pts and 35% of pts had ≥ 50% bone marrow blasts. Mutations in the BCR-ABL domain were found in 27/63 (43%) pts. Median duration of therapy was 3.5 months. D doses were reduced in 35% pts, temporarily interrupted in 58% pts, and escalated in 41% pts. With a minimum of 6-month follow-up, hematologic response was seen in 39 (53%) pts: confirmed MaHR in 24 (32%) pts, Complete in 18 (24%) and No Evidence of Leukemia in 6 (8%). Major cytogenetic responses were documented in 22 (30%) pts and was complete in 20 (27%). The median time to MaHR was 56 days. There was no loss of response in pts with MaHR; the duration of MaHR ranged from 1.2+ to 7.8+ months. The median PFS had not been reached. Severe myelosuppression was very common. Non-hematologic toxicities were usually mild to moderate. Most common Grade 3–4 toxicities included diarrhea in (7%), pleural effusion (9%), nausea (4%). Peripheral edema was reported in 14% of pts (0% Grade 3–4), and rash in 11% of the pts (0% Grade 3–4). Conclusions: Dasatinib was highly effective in IM-R pts with MBC with durable MaHR. Data on all 124 pts will be presented at the meeting. [Table: see text]
Hydroxyapatite mineral enhances malignant potential in a tissue-engineered model of ductal carcinoma in situ (DCIS)
Authors: Frank He, Nora L. Springer, Matthew A. Whitman, Siddharth P. Pathi, Yeonkyung Lee, Sunish Mohanan, Stephen Marcott, Aaron E. Chiou, Bryant S. Blank, Neil Iyengar, Patrick G. Morris, Maxine Jochelson, Clifford A. Hudis, Pragya Shah, Jennie A.M.R. Kunitake, Lara A. Estroff, Jan Lammerding, Claudia Fischbach
Journal: Biomaterials (2019)
Abstract 11621: History of Asthma Increases the Risk for Incident Cardiovascular Disease in Postmenopausal Women
Authors: Fady Y Marmoush, Mary B Roberts, Rami Nassir, Matthew Allison, Milagros Rosal, Charles B Eaton
Journal: Circulation (2015)

Hypothesis and Objectives: The state of chronic Inflammation associated with asthma may contribute to the development of cardiovascular disease (CVD) in adulthood. This study evaluated prospectively the association between history of asthma and CVD in a cohort of postmenopausal women. Methods: Study participants are postmenopausal women (n= 90,168) who are free of cardiovascular disease at baseline, evaluated from 1993-1998. We used self-report of physician diagnosed asthma to define the exposure. Information on treatment for asthma in addition to CVD risk factors were collected. The association between asthma and the incidence of CVD and coronary heart disease (CHD) was evaluated using cox proportional hazards models. Results: Among 90,168 women in the study sample, 6,921 (7.68%) reported asthma at baseline. Baseline characteristics were similar between the asthma and no asthma groups although asthmatics were more obese (36% vs 27%; p&lt;0.0001) and had higher hypertension rates (38% vs 31%; p&lt;0.0001). As compared to the no asthma group with CVD and CHD rates of 8,078 (9.7%) and 5,800 (6.97%), respectively, the asthma group had higher rates of CVD and CHD, 803 (11.6%) and 595 (8.6%) respectively. When adjusted to age plus all CVD risk factors, the HR for CVD events was 1.21 (95% CI 1.12-1.31) and for CHD events was 1.24 (95% CI 1.14 - 1.36). The association remained significant in different models (see table). Conclusion: Asthma was associated with a modestly increased risk for CVD and CHD in postmenopausal women. Further studies needed to explore this association.