tbuckley/cabot-search huggingface dataset:
Collagen Formation Assessed by N‐Terminal Propeptide of Type 3 Procollagen Is a Heritable Trait and Is Associated With Liver Fibrosis Assessed by Magnetic Resonance Elastography
Authors: Cyrielle Caussy, Meera Bhargava, Ida F. Villesen, Natasja S. Gudmann, Diana J. Leeming, Morten A. Karsdal, Claire Faulkner, Denny Bao, Amy Liu, Min‐Tzu Lo, Ricki Bettencourt, Shirin Bassirian, Lisa Richards, David A. Brenner, Chi‐Hua Chen, Claude B. Sirlin, Rohit Loomba
Journal: Hepatology (2019)

N‐terminal propeptide of type 3 procollagen (PRO‐C3) is a biomarker of liver fibrosis in nonalcoholic fatty liver disease (NAFLD). This study examines the association between PRO‐C3 concentration and liver fibrosis assessed by magnetic resonance elastography (MRE)–measured stiffness (MRE‐stiffness) and the heritability of PRO‐C3 concentration in a cohort of twins and families with and without NAFLD. We performed a cross‐sectional analysis of a well‐characterized prospective cohort of 306 participants, including 44 probands with NAFLD‐cirrhosis and their 72 first‐degree relatives, 24 probands with NAFLD without advanced fibrosis and their 24 first‐degree relatives, and 72 controls without NAFLD and their 72 first‐degree relatives. Liver steatosis was assessed by magnetic resonance imaging proton density fat fraction, and liver fibrosis was assessed by MRE‐stiffness. Serum PRO‐C3 was assessed by competitive, enzyme‐linked immunosorbent assay. We assessed the familial correlation of PRO‐C3 concentration, the shared gene effects between PRO‐C3 concentration and liver steatosis and fibrosis, and the association between PRO‐C3 concentration and genetic variants in the patatin‐like phospholipase domain–containing 3 ( PNPLA3 ), transmembrane 6 superfamily member 2 ( TM6SF2 ), membrane‐bound O‐acyltransferase domain–containing ( MBOAT ), and glucokinase regulator ( CGKR ) genes. In multivariable‐adjusted models including age, sex, body mass index, and ethnicity, serum PRO‐C3 correlated strongly with liver fibrosis ( r 2 = 0.50, P &lt; 0.001) and demonstrated robust heritability ( h 2 , 0.36; 95% confidence interval [CI], 0.07, 0.59; P = 0.016). PRO‐C3 concentration and steatosis had a strong genetic correlation (shared genetic determination: 0.62; 95% CI, 0.236, 1.001; P = 0.002), whereas PRO‐C3 concentration and fibrosis had a strong environmental correlation (shared environmental determination: 0.55; 95% CI, 0.317, 0.717; P &lt; 0.001). PRO‐C3 concentrations were higher in carriers of the TM6SF2 rs58542926‐T allele compared with noncarriers: 15.7 (± 10.5) versus 10.8 (± 5.7) ng/L ( P = 0.047). Conclusion : Serum PRO‐C3 correlates with MRE‐assessed fibrosis, is heritable, shares genetic correlation with liver steatosis and shares environmental correlation with liver fibrosis. PRO‐C3 concentration appears to be linked to both fibrosis and steatosis and increased in carriers of the TM6SF2 rs58542926 risk allele.
AQP4 Aggregation State Is a Determinant for Glioma Cell Fate
Authors: Laura Simone, Francesco Pisani, Maria G. Mola, Manuela De Bellis, Giuseppe Merla, Lucia Micale, Antonio Frigeri, Angelo L. Vescovi, Maria Svelto, Grazia P. Nicchia
Journal: Cancer Research (2019)

Abstract The glial water channel protein aquaporin-4 (AQP4) forms heterotetramers in the plasma membrane made of the M23-AQP4 and M1-AQP4 isoforms. The isoform ratio controls AQP4 aggregation into supramolecular structures called orthogonal arrays of particles (AQP4-OAP). The role of AQP4 aggregation into OAP in malignant gliomas is still unclear. In this study, we demonstrate that AQP4 aggregation/disaggregation into OAP influences the biology of glioma cells. Selective expression of the OAP-forming isoform M23-AQP4 (AQP4-OAP) triggered cell shape changes in glioma cells associated with alterations to the F-actin cytoskeleton that affected apoptosis. By contrast, expression of M1-AQP4 (AQP4-tetramers), which is unable to aggregate into OAP, ameliorated glioma cell invasiveness, improved cell migration, and increased methalloproteinase-9 activity. Two prolines (254 and 296) at the C-terminus tail were shown to be important in mediating the relationship between the actin cytoskeleton and AQP4-OAP and AQP4-tetramers. In conclusion, this study demonstrates that AQP4 aggregation state might be an important determinant in orienting glioma cells to persist or perish. AQP4 disaggregation may potentiate invasiveness potential, whereas AQP4 aggregation may activate the apoptotic path. This study shows a new perspective on the role of AQP4 in brain tumors not necessarily associated with edema formation but with AQP4 aggregation/disaggregation dynamics and their link with the actin cytoskeleton. Significance: This study demonstrates how AQP4 aggregation influences plasma membrane dynamics to alter cell proliferation, invasiveness, migration, and apoptotic potential in glioma cells.
Plasticity of adult hepatocytes and readjustment of cell fate: a novel dogma in liver disease
Authors: Francisco Javier Cubero, Maria Luz Martinez-Chantar
Journal: Gut (2019)

Acute liver failure (ALF) is a life-threatening syndrome characterised by rapid hepatocellular necrosis due to various types of insults including drugs, autoimmune disorders or viral infections, and thus represents a disease with high mortality and elevated societal costs. At present, most ALF treatment strategies are rather aimed at simply preventing complications and decelerating disease progression. Unfortunately, the only curative treatment for ALF at present is liver transplantation, an option which is limited due to financial constraints, shortage of donor livers and immunosuppression-related complications.1 Therefore, novel therapeutic avenues for patients with ALF are urgently needed.

Normally, mature hepatocytes can orchestrate liver regeneration on loss of liver mass. When severe liver insult occurs, however, hepatocytes are unable to differentiate and hepatic progenitor cells (HPCs) are activated. HPCs, embryonic stem cells (ES) and induced pluripotent stem cells (iPS) have been considered a potential source for cell replacement in the injured liver since they possess hepatic differentiation capacity.2 However, their clinical applicability remains still controversial. For long, it has been widely assumed that hepatocytes do not contribute directly to the progenitor or stem cell compartment. Recently, Chen and colleagues2 reported the dedifferentiation of progenitor cells from isolated mature hepatocytes, refuting the current dogma.

Yet to be explored was the identification of molecular cascades that specifically dedifferentiate mature hepatocytes and activate a ‘fetal programme’. The Hippo/Yes-associated protein (YAP)-signalling pathway plays an essential role by determining cellular fates in the mammalian liver. Hippo signalling controls the phosphorylation of the transcriptional co-activator YAP whose constitutive activation in …
Tailored Melt Electrowritten Scaffolds for the Generation of Sheet‐Like Tissue Constructs from Multicellular Spheroids
Authors: Rebecca McMaster, Christiane Hoefner, Andrei Hrynevich, Carina Blum, Miriam Wiesner, Katharina Wittmann, Tim R. Dargaville, Petra Bauer‐Kreisel, Jürgen Groll, Paul D. Dalton, Torsten Blunk
Journal: Advanced Healthcare Materials (2019)

Abstract Melt electrowriting (MEW) is an additive manufacturing technology that is recently used to fabricate voluminous scaffolds for biomedical applications. In this study, MEW is adapted for the seeding of multicellular spheroids, which permits the easy handling as a single sheet‐like tissue‐scaffold construct. Spheroids are made from adipose‐derived stromal cells (ASCs). Poly(ε‐caprolactone) is processed via MEW into scaffolds with box‐structured pores, readily tailorable to spheroid size, using 13–15 µm diameter fibers. Two 7–8 µm diameter “catching fibers” near the bottom of the scaffold are threaded through each pore (360 and 380 µm) to prevent loss of spheroids during seeding. Cell viability remains high during the two week culture period, while the differentiation of ASCs into the adipogenic lineage is induced. Subsequent sectioning and staining of the spheroid‐scaffold construct can be readily performed and accumulated lipid droplets are observed, while upregulation of molecular markers associated with successful differentiation is demonstrated. Tailoring MEW scaffolds with pores allows the simultaneous seeding of high numbers of spheroids at a time into a construct that can be handled in culture and may be readily transferred to other sites for use as implants or tissue models.
Intraductal carcinoma of the prostate in prostate biopsy samples: Correlation with pathological features after radical prostatectomy and prognostic value in high-risk prostate cancer patients.
Authors: Sha Zhu
Journal: Journal of Clinical Oncology (2019)

123 Background: Intraductal carcinoma of the prostate (IDC-P) is a biologically aggressive form of prostate cancer. We investigated the correlation between IDC-P in prostate biopsy samples (Pbx) and several pathological features after radical prostatectomy (RP), also its prognostic value in high-risk prostate cancer patients. Methods: Totally, 455 patients diagnosed with PCa during 2010 to 2017 in West China Hospital were included in this study. Chi-squared test and binary logistic regression were used in discovering the correlation between IDC-P and post-RP pathological features. Kaplan Meier curve, log-rank test, Cox’s proportional hazards model and C-index were applied in the investigation of the prognostic value of IDC-P on 418 high-risk patients. Results: The detection rate of IDC-P in Pbx is 7.91%. IDC-P was an independent predictor of SVI ( p= 0.014), EPE ( p&lt; 0.001), cT stage ( p= 0.001), PSM of urethra end ( p= 0.042). Patients with IDC-P in PBx specimens manifested poorer BFS than those without IDC-P ( p&lt; 0.001), and IDC-P pattern 2 (HR: 4.429, p= 0.020) was associated with worse prognosis than IDC-P pattern 1 (HR: 3.225, p= 0.047). Further analyses also demonstrated that the addition of IDC-P in several nomograms could improve their C-index. Conclusions: IDC-P is associated with several post-RP pathological features after radical prostatectomy. Also, IDC-P can effectively predict the patients’ BFS, and the addition of it can increase the C-index of several nomograms.
Clinical features and outcomes of secondary somatic malignancy (SSM) arising from teratoma in late relapse germ cell tumor (GCT).
Authors: Nathan Colin Wong, Shawn Dason, Lucas W. Dean, Sumit Isharwal, Mark Donoghue, Liwei Jia, Gabriella Joseph, William D. Tap, Samuel Aaron Funt, Deaglan Joseph McHugh, Hikmat Al-Ahmadie, Victor E. Reuter, Dean F. Bajorin, Robert J. Motzer, George J. Bosl, Joel Sheinfeld, David B. Solit, Darren R. Feldman
Journal: Journal of Clinical Oncology (2019)

518 Background: Late relapse (&gt;2 years) GCT is associated with an increased rate of SSM. We report our experience with SSM in the setting of late relapse and determine predictors of overall survival (OS). Methods: From 1985 to 2018, 46 patients with GCT and SSM at late relapse were identified. Clinical and pathologic parameters were reviewed. The Kaplan-Meier method was used to estimate OS from time of relapse and a Cox proportional hazards model to assess predictors of OS. Results: Of 46 men (44 testicular primary, 2 mediastinal primary), median time to late relapse with SSM was 10.4 years (range, 2.3 - 38.1). Most (n=27, 59%) were symptomatic at presentation but 11 were detected by elevated tumor markers (AFP 8, HCG 2, both 1) and 8 by surveillance imaging. SSMs were adenocarcinoma (25), sarcoma (14), poorly differentiated neoplasm (3), Wilms (2), PNET (1) and glioma (1). Median time to relapse was longer for adenocarcinoma vs other histotypes of SSM (14.6 vs 4.1 years, p &lt; 0.001). The initial site of relapse was the retroperitoneum (RP, 26), pelvis (7), lung (6), retrocrural space (3), mediastinum (2), neck (1) and duodenum (1). Only 10 of 26 men with late relapse in the RP had undergone prior RPLND (all at outside institutions; variable templates) with histology in 7/10 showing teratoma. The other 16 men had received chemotherapy only (8), orchiectomy only for stage I (3), RPLND aborted due to cardiac arrest (1), and unknown (4). All 46 late relapses were managed with surgical resection; 26 also received chemotherapy (16 SSM-directed, 10 GCT-directed). Overall, 12 patients died and the median OS was 14.2 years. On univariable analysis, symptomatic presentation (HR = 3.1), SSM at multiple sites (HR = 3.9), extra-RP disease (HR: 3.9), and incomplete/no resection of SSM (HR = 3.6) predicted mortality. On multivariable analysis, only extra-RP disease was independently associated with inferior OS (5-year OS, 82 vs 52%, p = 0.017). Conclusions: SSM is an important potential complication of late relapse GCT and seems to be associated with the lack of resection of retroperitoneal metastases. Early identification and complete surgical resection prior to SSM arising in extra-RP sites is critical to optimizing outcomes.
Results of a phase I pharmacokinetic study of intraperitoneal bortezomib (B) and carboplatin (C) in patients with persistent or recurrent ovarian cancer (OC): An NRG/Gynecologic Oncology Group study.
Authors: Don S. Dizon, William E. Brady, Heather A. Lankes, Danielle A Jandial, Stephen B. Howell, Russell J. Schilder, Jan Hendrik Beumer, Susan M. Christner, Sandra Strychor, Matthew A. Powell, Andrea R. Hagemann, Kathleen N. Moore, Joan L. Walker, Paul DiSilvestro, Paula M. Fracasso
Journal: Journal of Clinical Oncology (2015)

5515 Background: Intraperitoneal therapy (IP) has been shown to improve survival outcomes for women with optimally cytoreduced, newly diagnosed, advanced OC, but whether IP has a role for recurrent OC is unknown. Preclinicial data show IP administration of the proteasome inhibitor bortezomib (B) prior to IP carboplatin (C) increased cellular platinum accumulation and results in synergistic cytotoxicity. Hence, we conducted this phase I trial of an IP regimen consisting of B+C in women with recurrent or persistent disease. Methods: We enrolled 33 pts with recurrent or persistent OC, GOG PS ≤ 2, with ≤ 4 prior regimens. After DLT at DL1 (B 0.5 mg/m2]/C AUC 5), the protocol was amended to fixed C AUC4 with dose escalation of B: DL-1 (0.5); 1a (0.9); 2a (1.3), 3a (1.7), 4a (2.1), 5a (2.5). Treatment was delivered every 21 days for six cycles. Pharmacokinetics (PK) of B (by LC-MS/MS) and C (ultrafilterable, by AAS) were studied in cycle 1. Results: Of enrolled pts, 32/33 were evaluable for safety. Two patients experienced DLT at DL1 (G3 abdominal pain, G4 thrombocytopenia and G3 lung infection). At C AUC4, we escalated BTZ to DL5a without DLT. Grade 3/4 related toxicities included fatigue, abdominal pain, nausea, vomiting, and diarrhea; however, all were relatively infrequent. The overall response rate in patients with measurable disease (n = 21) was 19% (1 CR, 3PR). At DL5a (n = 5), the ORR was 20% (0CR, 1PR). PK revealed IP and peripheral blood plasma B Cmax and AUC increased linearly with dose. The B IP to peripheral geometric mean ratios (range) were (N = 26): Cmax 304 (317-2840), and AUC 139 (15-1867) and appeared independent of dose. Ultrafilterable platinum IP to peripheral geometric mean ratios (range) were (N = 9): Cmax 49 (18-101) and AUC 17 (6-54). Conclusions: IP administration of B+C was feasible and showed promising activity in this phase I trial of heavily pre-treated women with OC. PK analysis showed a favorable exposure ratio of the peritoneal cavity relative to peripheral blood plasma. Further evaluation of this novel IP combination should be conducted. Clinical trial information: NCT01074411.
Abstract PD8-04: Neoadjuvant chemotherapy for breast cancer: Nodal downstaging is highly correlated with pathological complete response
Authors: P Blumencranz, M Habibi, T Treece, L Blumencranz, E Yoder, W Audeh, E Carter, L McNaughton, J Roussos, S Shivers, G Acs, C Cox, Group MINT Investigators
Journal: Cancer Research (2019)

Abstract Background: Neoadjuvant chemotherapy (NAC) is employed in patients with larger tumors to attempt to downstage locally advanced cancers to allow breast conservation and to assess in vivo tumor response. The Multi-Institutional Neoadjuvant Therapy MammaPrint Project I (MINT) study asked a secondary question of whether complete nodal downstaging could also be achieved with NAC. Methods: This analysis included 147 eligible invasive breast cancer patients with high tumor burdens, classified as cT2-4N0-3M0 (T2 greater than 3.5cm if N0). Patients who had a positive core biopsy and/or fine needle aspiration (FNA) on an axillary node prior to starting NAC were included in this analysis. Those who had a surgical sentinel lymph node biopsy were not included. Nodal involvement was established following neoadjuvant treatment by axillary lymph node dissection (ALND). Results: This population was 54% postmenopausal, average age 53 yrs (range 25 to 80 yrs). Tumor characteristics were 91% invasive ductal carcinoma; 65% T2, 29% T3, 6% T4; 87% LN1, 13% LN2-3; 3% low grade, 38% intermediate grade, 59% high grade; 65% ER-positive, 49% PR-positive, and 28% HER2-positive by immunohistochemistry; 84% High Risk (HR) and 16% Low Risk (LR) by MammaPrint (MP). After NAC, 45% (66/147) of these LN-positive patients were down-staged to ypN0 and also achieved a complete pathological response in the primary tumor. The potential for down-staging was inversely-related to tumor burden, where 47% (60/128) of N1, 35% (6/17) of N2, and 0% (0/2) of N3 patients were down-staged to ypN0. There were 3 patients who were down-staged (2 N2 to N1, and 1 N3 to N2), but not to ypN0. At surgery, 34% (44/128) of patients had no change, and 19% (24/129) progressed in LN staging. Pre vs Post NAC Nodal StagePre NAC Nodal StageypN0ypN1ypN2ypN3TotalcN16044222128cN2626317cN3 112Total6646296147 Conclusions: We confirmed that upon achieving a complete response of the primary tumor that there was also a pathologic complete response in the LN. About 53% of patients had no change or progression of LN involvement following NAC. Citation Format: Blumencranz P, Habibi M, Treece T, Blumencranz L, Yoder E, Audeh W, Carter E, McNaughton L, Roussos J, Shivers S, Acs G, Cox C, MINT Investigators Group. Neoadjuvant chemotherapy for breast cancer: Nodal downstaging is highly correlated with pathological complete response [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD8-04.
Does anterolateral ligament rupture affect functional outcomes in patients who underwent an anterior cruciate ligament reconstruction?
Authors: Burak Gunaydin, Ali Turgut, Abdulkadir Sari, Cagatay Tekin, Bekir Eray Kilinc, Ibrahim Kusak, Gulcan Gucer Sahin, Onder Kalenderer, Yavuz Selim Kabukcuoglu
Journal: International Journal of Surgery (2019)
Cost-effectiveness of measles control during elimination in Ontario, Canada, 2015
Authors: Lauren C Ramsay, Natasha S Crowcroft, Shari Thomas, Elena Aruffo, Alexandra Teslya, Jane M Heffernan, Effie Gournis, Joanne Hiebert, Valerie Jaeger, Manisa Jiaravuthisan, Jennifer Sharron, Alberto Severini, Shelley L Deeks, Jonathan Gubbay, Tony Mazzulli, Beate Sander
Journal: Eurosurveillance (2019)

BackgroundGiven that measles is eliminated in Canada and measles immunisation coverage in Ontario is high, it has been questioned whether Ontario's measles outbreak response is worthwhile.AimOur objective was to determine cost-effectiveness of measles containment protocols in Ontario from the healthcare payer perspective.MethodsWe developed a decision-analysis model comparing Ontario's measles containment strategy (based on actual 2015 outbreak data) with a hypothetical 'modified response'. The modified scenario assumed 10% response costs with reduced case and contact tracing and no outbreak-associated vaccinations; it was based on local and provincial administrative and laboratory data and parameters from peer-reviewed literature. Short- and long-term health outcomes, quality-adjusted life years (QALYs) and costs discounted at 1.5%, were estimated. We conducted one- and two-way sensitivity analyses.ResultsThe 2015 outbreak in Ontario comprised 16 measles cases and an estimated 3,369 contacts. Predictive modelling suggested that the outbreak response prevented 16 outbreak-associated cases at a cost of CAD 1,213,491 (EUR 861,579). The incremental cost-effectiveness ratio was CAD 739,063 (EUR 524,735) per QALY gained for the outbreak response vs modified response. To meet the commonly accepted cost-effectiveness threshold of CAD 50,000 (EUR 35,500) per QALY gained, the outbreak response would have to prevent 94 measles cases. In sensitivity analyses, the findings were robust.ConclusionsOntario's measles outbreak response exceeds generally accepted cost-effectiveness thresholds and may not be the most efficient use of public health resources from a healthcare payer perspective. These findings should be balanced against benefits of increased vaccine coverage and maintaining elimination status.
Brain metastastasis in human epidermal growth factor 2 (HER-2) overexpression gastric cancer.
Authors: Luigi Cavanna, Pietro Seghini, Camilla di Nunzio, Emanuele Michieletti, Elisa Maria Stroppa, Adriano Zangrandi, Patrizia Mordenti, Fabio Fornari
Journal: Journal of Clinical Oncology (2015)

e15019 Background: Central nervous system (CNS) metastases from the gastrointestinal tract (GIT) cancers are relatively rare, and occur in 0.16 – 0.69% of the patients with gastric cancer. Overexpression of the human epidermal growth factor 2 (HER-2) is associated with on aggressive metastatic phenotype poor prognosis in the absence of HER-2 targeted-therapy, and increased incidence of CNS metastases in patients with breast cancer. However, the prognostic impact of HER-2 overexpression is not so well-characterized in gastric adenocarcinoma. The purpose of this retrospective study is to assess the incidence of CNS metastases in patients with gastric cancer and to evaluate the relation of CNS metastases with HER-2 overexpression Methods: Between 2007 and 2011, 200 patients with gastric cancer were admitted to the general hospital of Piacenza (Italy). These cases were retrospectively analyzed to evaluate CNS metastases. The metastases were diagnosed on imaging techniques performed in symptomatic patients. Histological samples of patients with CNS metastases were reviewed and tested for HER-2, and patients were considered to have HER-2 gastric cancer if the their tumor samples were scored as 3+ on immunohistochemistry or if they were fluorescence in situ hybridization (FISH) positive Results: Seven of 200 patients (3.5 %) with gastric cancer were found to have CNS metastases on imaging studies and six out of seven (85.71 %) patients with gastric cancer and CNS metastases, had HER-2 positive disease. These patients tended also to have an advanced initial disease stage, a more aggressive behaviour and poor prognosis. Conclusions: Despite the limitations of a retrospective study, these results suggest that there is a CNS recurrence susceptibility in patients with HER-2 positive gastric cancer. These data should be confirmed in prospective studies with a more extensive series of patients.
Review: Exercise rehabilitation improves outcomes by a small amount in chronic heart failure
Authors: Dinesh Kumbhare
Journal: Annals of Internal Medicine (2019)

Source Citation Palmer K, Bowles KA, Paton M, Jepson M, Lane R. Chronic heart failure and exercise rehabilitation: a systematic review and meta-analysis. Arch Phys Med Rehabil. 2018;99:2570-82. 29698639