tbuckley/cabot-search huggingface dataset:
Factor H autoantibody is associated with atypical hemolytic uremic syndrome in children in the United Kingdom and Ireland
Authors: Vicky Brocklebank, Sally Johnson, Thomas P. Sheerin, Stephen D. Marks, Rodney D. Gilbert, Kay Tyerman, Meredith Kinoshita, Atif Awan, Amrit Kaur, Nicholas Webb, Shivaram Hegde, Eric Finlay, Maggie Fitzpatrick, Patrick R. Walsh, Edwin K.S. Wong, Caroline Booth, Larissa Kerecuk, Alan D. Salama, Mike Almond, Carol Inward, Timothy H. Goodship, Neil S. Sheerin, Kevin J. Marchbank, David Kavanagh
Journal: Kidney International (2017)

Factor H autoantibodies can impair complement regulation, resulting in atypical hemolytic uremic syndrome, predominantly in childhood. There are no trials investigating treatment, and clinical practice is only informed by retrospective cohort analysis. Here we examined 175 children presenting with atypical hemolytic uremic syndrome in the United Kingdom and Ireland for factor H autoantibodies that included 17 children with titers above the international standard. Of the 17, seven had a concomitant rare genetic variant in a gene encoding a complement pathway component or regulator. Two children received supportive treatment; both developed established renal failure. Plasma exchange was associated with a poor rate of renal recovery in seven of 11 treated. Six patients treated with eculizumab recovered renal function. Contrary to global practice, immunosuppressive therapy to prevent relapse in plasma exchange-treated patients was not adopted due to concerns over treatment-associated complications. Without immunosuppression, the relapse rate was high (five of seven). However, reintroduction of treatment resulted in recovery of renal function. All patients treated with eculizumab achieved sustained remission. Five patients received renal transplants without specific factor H autoantibody-targeted treatment with recurrence in one who also had a functionally significant CFI mutation. Thus, our current practice is to initiate eculizumab therapy for treatment of factor H autoantibody-mediated atypical hemolytic uremic syndrome rather than plasma exchange with or without immunosuppression. Based on this retrospective analysis we see no suggestion of inferior treatment, albeit the strength of our conclusions is limited by the small sample size.
Functional significance of missense variants in BRCA1
Authors: Vesna Dapic, Catherine M. Phelan, Bonnie Tice, Reyna Favis, Elaine Kwan, Francis Barany, Steven A. Narod, Alvaro N. Monteiro
Journal: Cancer Research (2004)

1314   BRCA1 is a tumor suppressor gene product involved in transcriptional regulation, DNA-damage repair, cell-cycle control and the maintenance of genomic integrity. Germ-line mutations in the  BRCA1  gene predispose individuals to breast and ovarian cancer. Cancer-associated BRCA1 mutations abolish its transcriptional activity, indicating that this activity is crucial for the maintenance of the normal phenotype. Development of cancer requires the loss of the wild type allele, since the inherited mutation predisposing allele is recessive. A substantial number of  BRCA1  germ-line mutations encode for missense variants. Classification and predictive risk assessment are difficult due to a lack of information about their impact on the BRCA1 tumor suppressor function. Classification of missense variants into cancer-predisposing mutations or benign polymorphisms is crucial for identifying individuals at risk. In this study, we have investigated 13 missense variants for their ability to activate transcription in both yeast and mammalian transcriptional assays. Five variants (H1402Y, H1421Y, S1512I, M1628T, T1720A) were able to activate transcription comparably to the wild-type BRCA1 and are likely to be benign polymorphisms. Eight variants (L1407P, M1628V, T1685I, G1706A, A1752P, G1788V, V1809F and W1837R) showed significantly reduced ability to activate transcription similar to the known deleterious controls and likely represent cancer-associated variants. This study contributes to a better understanding of BRCA1 unclassified variants and has important implications for carriers of these mutations.
Cascade Screening for Familial Hypercholesterolemia and the Use of Genetic Testing
Authors: Joshua W. Knowles, Daniel J. Rader, Muin J. Khoury
Journal: JAMA (2017)

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An endogenous DNA adduct as a prognostic biomarker for hepatocarcinogenesis and its prevention by Theaphenon E in mice
Authors: Ying Fu, Shana Silverstein, Justine N. McCutcheon, Marcin Dyba, Raghu G. Nath, Monika Aggarwal, Heidi Coia, Angela Bai, Jishen Pan, Jiji Jiang, Bhaskar Kallakury, Hongkun Wang, Yu‐Wen Zhang, Giuseppe Giaccone, Aiwu Ruth He, Fung‐Lung Chung
Journal: Hepatology (2017)

Hepatocellular carcinoma (HCC) is the third leading cause of cancer–related deaths worldwide, mainly because of its poor prognosis. A valid mechanism‐based prognostic biomarker is urgently needed. γ‐hydroxy‐1, N 2 ‐propanodeoxyguanosine (γ‐OHPdG) is an endogenously formed mutagenic DNA adduct derived from lipid peroxidation. We examined the relationship of γ‐OHPdG with hepatocarcinogenesis in two animal models and its potential role as a prognostic biomarker for recurrence in HCC patients. Bioassays were conducted in xeroderma pigmentosum group A knockout mice and diethylnitrosamine‐injected mice, both prone to HCC development. γ‐OHPdG levels in the livers of these animals were determined. The effects of antioxidant treatments on γ‐OHPdG and hepatocarcinogenesis were examined. Using two independent sets of HCC specimens from patients, we examined the relationship between γ‐OHPdG and survival or recurrence‐free survival. γ‐OHPdG levels in liver DNA showed an age‐dependent increase and consistently correlated with HCC development in all three animal models. Theaphenon E treatment significantly decreased γ‐OHPdG levels in the liver DNA of xeroderma pigmentosum group A knockout mice and remarkably reduced HCC incidence in these mice to 14% from 100% in the controls. It also effectively inhibited HCC development in the diethylnitrosamine‐injected mice. Using clinical samples from two groups of patients, our study revealed that higher levels of γ‐OHPdG are strongly associated with low survival ( P &lt; 0.0001) and low recurrence‐free survival ( P = 0.007). Conclusion: These results support γ‐OHPdG as a mechanism‐based, biologically relevant biomarker for predicting the risk of HCC and its recurrence. (H epatology 2018;67:159‐170).
Renal Tubular Cell-Derived Extracellular Vesicles Accelerate the Recovery of Established Renal Ischemia Reperfusion Injury
Authors: Jesus H. Dominguez, Yunlong Liu, Hongyu Gao, James M. Dominguez, Danhui Xie, K. J. Kelly
Journal: Journal of the American Society of Nephrology (2017)

Ischemic renal injury is a complex syndrome; multiple cellular abnormalities cause accelerating cycles of inflammation, cellular damage, and sustained local ischemia. There is no single therapy that effectively resolves the renal damage after ischemia. However, infusions of normal adult rat renal cells have been a successful therapy in several rat renal failure models. The sustained broad renal benefit achieved by relatively few donor cells led to the hypothesis that extracellular vesicles (EV, largely exosomes) derived from these cells are the therapeutic effector in situ We now show that EV from adult rat renal tubular cells significantly improved renal function when administered intravenously 24 and 48 hours after renal ischemia in rats. Additionally, EV treatment significantly improved renal tubular damage, 4-hydroxynanoneal adduct formation, neutrophil infiltration, fibrosis, and microvascular pruning. EV therapy also markedly reduced the large renal transcriptome drift observed after ischemia. These data show the potential utility of EV to limit severe renal ischemic injury after the occurrence.
Brief Report: Deficiency of Complement 1r Subcomponent in Early‐Onset Systemic Lupus Erythematosus: The Role of Disease‐Modifying Alleles in a Monogenic Disease
Authors: Erkan Demirkaya, Qing Zhou, Carolyne K. Smith, Michael J. Ombrello, Natalie Deuitch, Wanxia L. Tsai, Patrycja Hoffmann, Elaine F. Remmers, Masaki Takeuchi, Yong Hwan Park, JaeJin Chae, Kenan Barut, Dogan Simsek, Amra Adrovic, Sezgin Sahin, Salim Caliskan, Settara C. Chandrasekharappa, Sarfaraz A. Hasni, Amanda K. Ombrello, Massimo Gadina, Daniel L. Kastner, Mariana J. Kaplan, Ozgur Kasapcopur, Ivona Aksentijevich
Journal: Arthritis & Rheumatology (2017)

To identify a genetic cause of early-onset systemic lupus erythematosus (SLE) in a large consanguineous family from Turkey and to study the mechanisms of the disease.
Metastatic melanoma outcomes in the era of commercially available targeted therapy and immunotherapy.
Authors: Chloe Goldman, Jeremy Tchack, Eric Michael Robinson, Sung Won Han, Judy Zhong, Una Moran, Eleazar Vega-Saenz de Miera, Farbod Darvishian, David Polsky, Russell S. Berman, Richard L. Shapiro, Iman Osman, Anna C. Pavlick, Melissa Wilson
Journal: Journal of Clinical Oncology (2016)

e21017 Background: In the past 5 years, the treatment of metastatic melanoma has rapidly evolved with the commercial approval of immune and targeted therapies. While each therapeutic development has demonstrated improved prognosis in clinical trials, few studies have examined the evolution of prognosis and toxicity profiles among a more diverse patient population. This study assesses whether survival and toxicity profiles reported in clinical trials, which typically exclude patients with CNS involvement, poor performance status, and other co-morbidities, are recapitulated within a commercial access population. Methods: Patients diagnosed with stage IV melanoma from July 2006 to December 2013, prospectively enrolled in the NYU Melanoma program database, and treated with ipilimumab, pembrolizumab, or vemurafenib were followed. Kaplan-Meier survival analysis and Fisher tests were performed to assess differences in patient and disease characteristics between clinical trial and commercial cohorts. Results: Patients receiving commercial therapy had a lower overall survival (OS) compared to those on trial when assessed across all treatment types (median OS (mOS) 5.3 months vs mOS 11.1 months, respectively, p < 0.04). Patients on clinical trial had better ECOG performance status compared to commercial patients at time of stage IV diagnosis (p = 0.01). Although no differences in immune-related adverse events (irAEs) were observed between trial and commercial cohorts, grade 1 or 2 irAEs conferred increased mOS (20.3 months), compared to severe irAEs (12.4 months) and no irAEs (9.0 months), in patients receiving immunotherapy independent of clinical trial and commercial stratification (p < 0.001). No relationship between toxicity and OS was observed with vemurafenib treatment. Across all therapies, independent of trial or commercial status, metastatic brain involvement conferred poor prognosis (p < 0.001). Conclusions: Our data demonstrate that patients receiving drugs commercially may represent a different clinical population with poor prognostic features compared to those on clinical trial. Both irAEs and CNS involvement may be prognostic of treatment benefit overall in melanoma patients.
Dermatux: Phase IV trial of C-FOLFIRI in 1st-line metastatic colorectal cancer receiving a pre-defined skin care.
Authors: Carl Christoph Schimanski, Frank Staib, Thomas Goehler, Holger Frithjof Hebart, Michael Neise, Jochen Rudi, Thomas Geer, Peter Ehscheidt, Thomas Flohr, Alexander H. Schmittel, Peter R. Galle, Markus H. Moehler
Journal: Journal of Clinical Oncology (2016)

e15048 Background: Dose- and treatment limiting cetuximab-induced skin rash ≥ 3° occur in 18% of colorectal cancer (CRC) patients. Survival, response and toxicity parameters were re-evaluated under a pre-defined skin prophylaxis consistent of vitamin K1 ointment and oral doxycycline. Methods: This is a national, phase IV, multicenter, 1st-line CRC trial (N = 165, KRAS wt, EGFR +, ECOG 0/1) in UICC stage 4 patients. Patients received irinotecan 180 mg/m² (d1) , folinic acid 400 mg/m² (d1), and 5-FU 400 mg/m² (d1, d2) and cetuximab ( 400 mg² (d1), then 250 mg/m² qw). Concurrently, patients received 0.1% vitamin K1 ointment qd and oral doxycycline 100 mg bid. Upon occurrence of rash ≥ 3°, an additional topical corticoid ointment bid and cetuximab dose-reduction according the license were applied. If rash 4° occurred, cetuximab was stopped. Primary objective: 1-year PFS rate; secondary objectives: rash ≥ 2°, time to occurrence of rash ≥ 2°, paronychia and skin fissures, response rate (RR), progression free survival (PFS), overall survival (OS), secondary resection of liver metastasis and safety. Results: 20 centers recruited 55 patients, no SUSARs occurred. Recruitment started Q1 2011 and ended in Q3 2013 due to poor accrual. Follow-up will end Q3 2017. Patient characteristics were in line with CRYSTAL trial except for an older age (median 65 years) and a predomination of colonic origin (74.1%). 1-year PFS rate was 25.9%, median OS 21.8 and median PFS 8.5 m (months). ORR was 63% and disease control rate 88.9%. Rash ≥ 2° occurred in 42.6%; time to onset was 6.3 w (weeks). Paronchychia ≥ 2° occurred in 22.2% with a median time to onset of 16.9 w. Skin fissures ≥ 2° occurred in 31.5% of cases with a median time to onset of 18.3 w. Skin side effects rapidly improved under protocol escalation measures. Conclusions: 1-y PFS was 25.9%. PFS and OS were in line and DCR (88.9% vs. 74%) was increased as compared to historical data. As compared to historical data, rash ≥ 2° was decreased to 42.6% (vs. 62-82%); time to onset doubled (6 vs. 2.7 w), whilst time to onset of paronychia ≥ 2° and skin fissures ≥ 2° doubled and tripled, respectively. As a result only 4 patients needed to abandon anti-EGFR treatment due to skin toxicity. Clinical trial information: NCT01315990.
Phase I study of BPM 31510 in advanced solid tumors: Omics-based molecular correlation to outcome for patient stratification.
Authors: Manish A. Shah, Vivek Subbiah, Niven R. Narain, Rangaprasad Sarangarajan, Michael Kiebish, Vivek Vishnudas, Eric M Grund, Yezhou Sun, Gregory M Miller, Leonardo O Rodrigues, Viacheslav R Akmaev, Susan Brouwer, Janice Stevens, Ralph Zinner, Peter Paul Yu
Journal: Journal of Clinical Oncology (2016)

2550 Background: BPM 31510 targets the metabolic machinery of cancer cells to reverse the Warburg effect. The current study evaluates BPM 31510 as a 6-day continuous infusion as a single agent and in combination with 3 standard weekly chemotherapy regimens. The study was designed to determine the Phase II dose and infer multi-omic patient-centric signatures identifying molecular predictive markers of clinical benefit and patient stratification. Methods: Eligible patients (pts) (aged ≥ 18 y) were relapsed/refractory to standard therapy. The monotherapy arm received IV BPM 31510 for 6 d in continuous infusion in 28-d cycles, and combination arms (gemcitabine, 5-FU or docetaxel) were primed for 3 wks followed by weekly dosing in a 6 wk cycle. Doses were escalated in a 3+3 schema. Endpoints were safety, PK and multi-omics analysis. Tumor response is evaluated at wk 2 and then after every 2 cycles. Results: As of 10 Dec 2015, 85 pts have been enrolled. DLTs were reported at 171mg/kg in mono and at 137mg/kg in the gemcitabine arm (maximum administered dose) and were coagulopathy-related. Six of 66 pts (24%) maintained a minimum of Stable Disease for ≥ 4 cycles. Molecular signatures of response and safety were derived from the integrated omics and AI profiling of the Interrogative BiologyÒ platform. Biomarker candidates correlating with favorable clinical response and safety were identified. pK levels of BPM 31510 was a driver of favorable response. These molecular correlates were independent of tumor type and prior therapy indicating a broad anti-tumor effect of BPM 31510. Novel multi-omic panels could stratify response before and 24h post treatment with AUC > 0.85. Conclusions: BPM 31510 is well tolerated as a monotherapy and in combination with chemotherapeutic agents and associated with early anti-tumor activity. The MTD of 110mg/kg in the gemcitabine arm is being established and used in a planned Phase II pancreatic cancer trial. Dose-escalation in the other 3 arms is ongoing to determine phase II doses. Molecular signatures will be utilized in phase II trials to guide the patient stratification and selection for a variety of cancer types that will guide the development plan for BPM 31510 as anticancer agent. Clinical trial information: NCT01957735.
PD-L1 Expression and Immune Escape in Melanoma Resistance to MAPK Inhibitors
Authors: Hojabr Kakavand, Robert V. Rawson, Gulietta M. Pupo, Jean Y. H. Yang, Alexander M. Menzies, Matteo S. Carlino, Richard F. Kefford, Julie R. Howle, Robyn P.M. Saw, John F. Thompson, James S. Wilmott, Georgina V. Long, Richard A. Scolyer, Helen Rizos
Journal: Clinical Cancer Research (2017)

Abstract Purpose: To examine the relationship between immune activity, PD-L1 expression, and tumor cell signaling, in metastatic melanomas prior to and during treatment with targeted MAPK inhibitors. Experimental Design: Thirty-eight tumors from 17 patients treated with BRAF inhibitor (n = 12) or combination BRAF/MEK inhibitors (n = 5) with known PD-L1 expression were analyzed. RNA expression arrays were performed on all pretreatment (PRE, n = 17), early during treatment (EDT, n = 8), and progression (PROG, n = 13) biopsies. HLA-A/HLA-DPB1 expression was assessed by IHC. Results: Gene set enrichment analysis (GSEA) of PRE, EDT, and PROG melanomas revealed that transcriptome signatures indicative of immune cell activation were strongly positively correlated with PD-L1 staining. In contrast, MAPK signaling and canonical Wnt/-β-catenin activity was negatively associated with PD-L1 melanoma expression. The expression of PD-L1 and immune activation signatures did not simply reflect the degree or type of immune cell infiltration, and was not sufficient for tumor response to MAPK inhibition. Conclusions: PD-L1 expression correlates with immune cells and immune activity signatures in melanoma, but is not sufficient for tumor response to MAPK inhibition, as many PRE and PROG melanomas displayed both PD-L1 positivity and immune activation signatures. This confirms that immune escape is common in MAPK inhibitor–treated tumors. This has important implications for the selection of second-line immunotherapy because analysis of mechanisms of immune escape will likely be required to identify patients likely to respond to such therapies. Clin Cancer Res; 23(20); 6054–61. ©2017 AACR.
ST. GEORGE'S HOSPITAL: TWO CASES OF PARACENTESIS OF THE BLADDER FROM THE RECTUM: WITH REMARKS
Authors: T. Holmes
Journal: BMJ (1856)

adherent, to be associated with ascites; that they are, fur- ther, more difficult of diagnosis from tumours of other parts,t and are commonly of a slower growth, consequently less quickly fatal if left to themselves, there can, I think, be no question as to the propriety of refraining from any
Symptoms of endometrial cancer.
Authors: Janelle B. Pakish, Karen H. Lu, Charlotte C. Sun, Jennifer K. Burzawa, Anthony Greisinger, Frances A Smith, Bryan Fellman, Diana L Urbauer, Pamela T. Soliman
Journal: Journal of Clinical Oncology (2015)

e16501 Background: The majority of women with endometrial cancers (EC) present at an early stage with an associated 5-year survival rate of > 90%. High rates of early detection are attributed to warning symptoms; however, the prevalence of such symptoms has not been well defined. Methods: A cross-sectional study was conducted to assess the prevalence of symptoms in EC patients at a large cancer center compared to healthy controls. Controls included patients seen for an annual visit (AV) or for a gynecologic problem visit (PV) including irregular bleeding, vaginal discharge, or pain. A self-administered questionnaire was given to all participants addressing EC associated symptoms, at the time of initial clinic visit. Odds ratios were used to compare prevalence of symptoms between EC patients and controls. Logistic regression was used to determine impact of menopausal status and obesity on symptom prevalence. Results: The EC (n = 75) group was significantly older than the AV (n = 203) and PV (n = 151) controls (59.7 vs 49.8 vs 51.0 y, p < 0.01), had a higher BMI (35.5 vs 29.4 vs 30.9 kg/m2, p < 0.01), and a higher proportion were postmenopausal (76 vs 53.7 vs 52.0%, p < 0.01). EC was associated with postmenopausal bleeding (OR 32.99 and 5.83, p < 0.01) and vaginal discharge (OR 8.8 and 3.3, < 0.01) compared the AV and PV groups. Control groups were then stratified by obesity. Heavy menses was associated with obesity in the PV group (OR 2.19, p = 0.01). When the symptom of heavy menses was evaluated among both obese cancer patients and obese controls, there was no difference between the groups. Conclusions: Symptoms of postmenopausal bleeding and abnormal vaginal discharge were significantly higher in EC compared to controls. The presence of such symptoms should raise concern for malignant disease and prompt immediate evaluation. Symptoms in EC compared to AV and PV controls AV PV OR 95% CI p-value OR 95% CI p-value Menstrual Symptoms Postmenopausal bleeding 32.99 13.61-79.97 < 0.01 5.83 2.54-13.40 < 0.01 Irregular menses 1.51 0.89-2.59 0.13 0.99 0.57-1.72 0.96 Heavy menses 1.73 1.0-2.98 0.05 1.23 0.7-2.18 0.47 Non-Menstrual Symptoms Pain 4.31 2.46-7.55 < 0.01 1.75 0.99-3.1 0.05 Pelvic pressure 6.38 3.32-12.23 < 0.01 1.58 0.89-2.81 0.12 Abnormal discharge 8.80 4.73-16.37 < 0.01 3.3 1.85-5.91 < 0.01