tbuckley/cabot-search huggingface dataset:
Patients with primary hyperoxaluria type 2 have significant morbidity and require careful follow-up
Authors: Sander F. Garrelfs, Gill Rumsby, Hessel Peters-Sengers, Florian Erger, Jaap W. Groothoff, Bodo B. Beck, Michiel J.S. Oosterveld, Alessandra Pelle, Thomas Neuhaus, Brigitte Adams, Pierre Cochat, Eduardo Salido, Graham W. Lipkin, Bernd Hoppe, Sally-Anne Hulton
Journal: Kidney International (2019)

Primary hyperoxaluria type 2 is a rare inherited disorder of glyoxylate metabolism causing nephrocalcinosis, renal stone formation and ultimately kidney failure. Previously, primary hyperoxaluria type 2 was considered to have a more favorable prognosis than primary hyperoxaluria type 1, but earlier reports are limited by low patient numbers and short follow up periods. Here we report on the clinical, genetic, and biochemical findings from the largest cohort of patients with primary hyperoxaluria type 2, obtained by a retrospective record review of genetically confirmed cases in the OxalEurope registry, a dataset containing 101 patients from eleven countries. Median follow up was 12.4 years. Median ages at first symptom and diagnosis for index cases were 3.2 years and 8.0 years, respectively. Urolithiasis was the most common presenting feature (82.8% of patients). Genetic analysis revealed 18 novel mutations in the <i>GRHPR</i> gene. Of 238 spot-urine analyses, 23 (9.7%) were within the normal range for oxalate as compared to less than 4% of 24-hour urine collections. Median intra-individual variation of 24-hour oxalate excretion was substantial (34.1%). At time of review, 12 patients were lost to follow-up; 45 of the remaining 89 patients experienced chronic kidney disease stage 2 or greater and 22 patients had reached stage 5. Median renal survival was 43.3 years, including 15 kidney transplantations in 11 patients (1 combined with liver transplantation). Renal outcome did not correlate with genotype, biochemical parameters or initially present nephrocalcinosis. Thus, primary hyperoxaluria type 2 is a disease with significant morbidity. Accurate diagnosis by 24-hour urine analysis and genetic testing are required with careful follow-up.
OS3.1 Antiepileptic drugs and their association with depression, anxiety and subjective cognitive impairment in glioma patients
Authors: P B van der Meer, M J B Taphoorn, M J van den Bent, L Dirven, J A F Koekkoek
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Epileptic seizures are a common symptom in glioma patients and generally treated with antiepileptic drugs (AEDs), which are considered to have the potential of mood-modulating and neurocognitive adverse effects. This observational study aimed to assess the independent association between AEDs and depression, anxiety and subjective cognitive impairment in glioma patients. MATERIAL AND METHODS Use of AEDs was defined as a categorical variable (none or at least one). Depression and anxiety were measured with the Hospital Anxiety and Depression Scale, while subjective cognitive impairment was measured with the Medical Outcomes Study-Cognitive Functioning Scale. Hierarchical multivariable logistic regression analyses were performed for each outcome separately. Besides use of AEDs, other confounding variables such as seizure severity and Karnofsky Performance Status score were included. Analyses were repeated for the two most commonly prescribed AEDs separately, levetiracetam or valproic acid, with the same confounding variables. RESULTS A total of 272 grade II-IV glioma patients were included in the study, of which 68% used at least one AED. Prevalence of depression was 10% for patients taking 0 AEDs and increased significantly to 21% (adjusted Odds Ratio [aOR]=2.4 [95%Confidence Interval {CI}=1.0–5.8]) for those taking ≥1. Prevalence was not significantly different between patients using 0 and using ≥1 AEDs for both anxiety (19% versus 26%, aOR=1.1 [95%CI=0.6–2.2]) and subjective cognitive impairment (16% versus 21%, aOR=1.2 [95%CI=0.6–2.5]). Although prevalences of depression (13% versus 23%, aOR=1.6 [95%CI=0.8–3.2]) and anxiety (17% versus 31%, aOR=1.8 [95%CI=0.9–3.3]), but not subjective cognitive impairment (20% versus 18%, aOR=1.7 [95%=0.4–1.4]), differed significantly between patients not using and using levetiracetam, these associations were not independent. No significant differences were found between patients not using and using valproic acid on the three outcome measures. CONCLUSION After adjustment of confounders, only depression was associated with the use of AED’s. No such relation was found for anxiety or subjective cognitive impairment. Use of levetiracetam or valproic acid were not independently related to depression, anxiety or subjective cognitive impairment.
Erratum: Corrigendum: BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus
Authors: Corinne Stoetzel, Virginie Laurier, Erica E Davis, Jean Muller, Suzanne Rix, José L Badano, Carmen C Leitch, Nabiha Salem, Eliane Chouery, Sandra Corbani, Nadine Jalk, Serge Vicaire, Pierre Sarda, Christian Hamel, Didier Lacombe, Muriel Holder, Sylvie Odent, Susan Holder, Alice S Brooks, Nursel H Elcioglu, Eduardo D Silva, Béatrice Rossillion, Sabine Sigaudy, Thomy J L de Ravel, Richard Alan Lewis, Bruno Leheup, Alain Verloes, Patrizia Amati-Bonneau, André Mégarbané, Olivier Poch, Dominique Bonneau, Philip L Beales, Jean-Louis Mandel, Nicholas Katsanis, Hélène Dollfus
Journal: Nature Genetics (2006)
An osteopontin‐derived peptide inhibits human hair growth at least in part by decreasing fibroblast growth factor‐7 production in outer root sheath keratinocytes
Authors: M. Alam, M. Bertolini, J. Gherardini, A. Keren, L. Ponce, J. Chéret, J. Alenfall, P. Dunér, A.H. Nilsson, A. Gilhar, R. Paus
Journal: British Journal of Dermatology (2019)

Given that unwanted hair growth (hirsutism, hypertrichosis) can cause major psychological distress, new pharmacological treatment strategies with safe and effective hair growth inhibitors that do not destroy the hair follicle (HF) and its stem cells need to be developed. To establish if osteopontin‐derived fragments may modulate human hair growth given that human HFs express the multifunctional, immunomodulatory glycoprotein, osteopontin. Our hypothesis was tested ex vivo and in vivo by using a newly generated, toxicologically well‐characterized, modified osteopontin‐derived peptide (FOL‐005), which binds to the HF. In organ‐cultured human HFs and scalp skin, and in human scalp skin xenotransplants onto SCID mice, FOL‐005 treatment (60 nmol L−1 to 3 μmol L−1) significantly promoted premature catagen development without reducing the number of keratin 15‐positive HF stem cells or showing signs of drug toxicity. Genome‐wide DNA microarray, quantitative reverse‐transcriptase polymerase chain reaction and immunohistochemistry revealed decreased expression of the hair growth promoter, fibroblast growth factor‐7 (FGF7) by FOL‐005, while cotreatment of HFs with recombinant FGF7 partially abrogated FOL‐005‐induced catagen promotion. With caveats in mind, our study identifies this osteopontin‐derived peptide as an effective, novel inhibitory principle for human hair growth ex vivo and in vivo, which deserves systematic clinical testing in hirsutism and hypertrichosis. What's already known about this topic? The treatment of unwanted hair growth (hypertrichosis, hirsutism) lacks pharmacological intervention, with only few and often unsatisfactory treatments available. Osteopontin is prominently expressed in human HFs and has been reported to be elevated during catagen in the murine hair cycle. What does this study add? We tested the effects on hair growth of a novel, osteopontin‐derived fragment (FOL‐005) ex vivo and in vivo. In human hair follicles, high‐dose FOL‐005 significantly reduces hair growth both ex vivo and in vivo. What is the translational message? High‐dose FOL‐005 may provide a new therapeutic opportunity as a treatment for unwanted hair growth.
P12.08 Immunocytokines are a novel immunotherapeutic approach against glioblastoma
Authors: T Weiss, E Puca, M Weller, D Neri, P Roth
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Glioblastoma is the most common malignant primary brain tumor in adults with an urgent need for novel treatment options. The administration of pro-inflammatory cytokines could be a potent immunotherapeutic approach to shift the balance between tumor-associated immunosuppression and immune activation. However, the systemic administration of therapeutically active doses of pro-inflammatory cytokines is not feasible due to toxic side effects and there is a need for strategies that enable a targeted delivery of pro-inflammatory cytokines to the tumor site. METHODS We investigated different antibody-cytokine fusion products that enable a targeted delivery of interleukin (IL)-2, IL-12 or tumor necrosis factor (TNF)-α to the tumor site by binding to a tumor-specific epitope of fibronectin. We investigated the expression of this tumor-specific epitope ex vivo in tumor-bearing mouse brains and human glioblastoma samples. Subsequently, we assessed the anti-tumor activity of IL-2, IL-12 or TNF-α fused to an antibody targeting this tumor-specific epitope in orthotopic syngeneic mouse glioma models. RESULTS The tumor-specfic extra domain B of fibronectin is expressed in murine glioma models and human glioblastoma samples. A fluorochrome-labeled antibody targeting this tumor-specific epitope accumulated at the tumor site in the brain in vivo upon systemic administration. IL-2, IL-12, or TNF-α fused to this antibody conferred a survival benefit in orthotopic tumor-bearing mice and cured a fraction of tumor-bearing mice. Mechanistically, antibody-fused TNF-α induced tumor necrosis and increased the activation of tumor-infiltrating natural killer (NK) cells, whereas antibody-fused IL-12 mainly boosted an anti-tumor immune response mediated by NK cells and T cells. CONCLUSION We demonstrate the expression of a tumor-specific epitope of fibronectin in glioblastoma and exploit this for the targeted delivery of IL-2, IL-12 or TNF-α to the tumor site. Our preclinical assessments indicate potent anti-tumor activity in orthotopic, syngneic glioma mouse models and reveal the mode of action for the different immunocytokines. Based on these findings, we initiated a phase I/II clinical trial in patients with recurrent glioma to investigate the targeted delivery of TNF-α (ClinicalTrials.gov identifier NCT03779230).
P14.03 Adult medulloblastoma: Influence of risk stratification and molecular subtypes on chemotherapy efficacy
Authors: O Absalyamova, G Kobiakov, G Agabekyan, M Ryzhova, N Kobiakov, K Lodygina, A Poddubsky, A Korshunov
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Incidence of medulloblastoma (MB) in adults is about 1%. Optimal treatment for adult medulloblastoma has not been defined. Published datasets were acquired over a long period of time, during which there were changes in surgical technique, radiotherapy, chemotherapy regimens; often disease stage was not considered in the analyses. Recently discovered molecular subgroups are not taken into account in studies concerning treatment of medulloblastoma in adults. MATERIAL AND METHODS Study includes 64 patients with medulloblastoma (median age 26.5 years (15–62)), who were first admitted to Burdenko Neurosurgery Institute for surgery from 2000 to 2017. 100 % patients included in the study received radiotherapy - craniospinal irradiation, 36 Gy (20 x 1.8 Gy) with boost to primary site (2 cm around tumor bed) up to 55 Gy total dose. 41 patients (64%) received chemotherapy (ChT). Chemotherapy was started 4–6 weeks after finishing craniospinal irradiation, the regimen included cisplatin 25 mg/m2 days 1–4+etoposide 100 mg/m2 days 1–4+cyclophosphamide 600 mg/m2 days 1–4; the cycles repeating every 28 days, 6 cycles in total. Treatment volume didn’t correspond with risk group and/or molecular genetic subgroup (these parameters were determined retrospectively). Median follow-up time is 4.45 years. RESULTS 53% patients had classic histology MB, 27% - desmoplastic, 20% - large cell/anaplastic. High risk (HR), standard risk (SR) and unspecified risk (UR) groups included 23, 16 and 25 patients respectively. Molecular subgroup testing was performed in 39 cases: SHH-activated - 59%, WNT-activated - 18%, GROUP4 - 23%. Median time to tumor progression (MTTP) in patients who received radio-chemotherapy versus radiotherapy alone was 4.3 and 2.64 years, respectively (p=0.264). The differences in MTTP were the most pronounced in SR and UR patients who received radio-chemotherapy (5.5 and 6.0 months, respectively) versus radiotherapy alone (1.5 and 2.0 months, respectively). HR patients showed the least difference in MTTP for radiotherapy (2.0 years) versus radio-chemotherapy (2.5 years), p=0.093. The SHH-subgroup patients had MTTP of 3.1 years (3.1 and 3.0 years for ChT+ and ChT-, respectively). GROUP4 patients had MTTP of 4.3 years (4.3 and 1.5 years for ChT+ and ChT-, respectively). All WNT-subgroup patients received chemotherapy, MTTP was 9.0 years. Median overall survival cannot be defined in any of the subgroups. CONCLUSION Chemotherapy in adult medulloblastoma patients increases MTTP in SR and UR patients. Low efficacy of chemotherapy for high risk medulloblastoma urges search for more efficacious treatment protocols. WNT-activated adult medulloblastoma has the highest MTTP among other molecular subgroups.
P11.24 CR13626, an oral tyrosine kinase inhibitor crossing the blood brain barrier, reduces tumour growth and prolongs survival in a mouse model of glioblastoma
Authors: C Galimberti, M Montagna, T Piepoli, O Letari, G Caselli, R Artusi, M Colovic, S Persiani, L C Rovati
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Glioblastoma multiforme (GBM) is the most malignant primary brain cancer. Several mutations and alterations of key cellular pathways including tyrosine kinases (TKs) are involved in GBM etiopathogenesis. Currently there is no cure for GBM. Tumour heterogeneity and the presence of the blood brain barrier (BBB), with efflux transporters, are some of the causes of failure of novel therapeutic agents. Thus, appropriate target selectivity and pharmacokinetics (including brain penetration) are critical issues for the generation of potential drug candidates. The main in-vitro and in-vivo properties and antitumour activity of CR13626, a novel brain penetrant TK inhibitor, are presented. MATERIAL AND METHODS CR13626 inhibitory activity against a panel of 173 kinases was assessed. The effect on cellular proliferation was verified in different 2D human glioblastoma cell lines (U87MG, U373, U87MG vIII) and in a U87MG 3D spheroid model by ViaCount assays. The in-vivo antitumour activity was determined in a mouse model of glioblastoma based on the orthotopic injection of U87MG-Luciferase GBM cells in nude mice: oral treatment started on day 9 post-implantation and continued for 10 days (50 mg/kg/daily). Tumour progression was evaluated through the measurement of bioluminescence (BLI) at the end of dosing (day 19) and during follow-up (day 26–33). Survival was also monitored. The pharmacokinetics and brain exposure of CR13626 were assessed by LC/MS/MS in plasma and brain homogenate tissues of CD1 and tumour-bearing nude mice. RESULTS CR13626 potently inhibited FYN, YES, KDR and EGFR kinases, relevant for GBM development, with IC50 values of 69 nM, 3.6 nM, 82 nM and 6 nM, respectively. The compound reduced the proliferation of different human glioblastoma cell lines (GI50 1–3 µM). In CD1 mice, CR13626 had a good oral bioavailability (72%) and brain penetration (brain/plasma ratio of 1.4). In-vivo BLI analysis indicated a time-dependent reduction of tumour growth, reaching 60% on the last BLI evaluation 33 days post-implantation (i.e. 15 days after the end of dosing). Tumour growth inhibition translated into an increase of 25% of the median survival time of animals treated with CR13626 compared to the vehicle group (p&lt;0.05). The observed antitumour effects agreed with the exposure of tumour-bearing mice to CR13626, which was above the TKs in-vitro IC50 values. CONCLUSION The combined abilities of CR13626 to inhibit the activity of TKs involved in GBM development, to cross the BBB, and to reduce tumour growth in-vivo leading to increased survival, warrant its further development as a drug candidate in GBM.
A protocol integrating remote patient monitoring patient reported outcomes and cardiovascular biomarkers
Authors: Chrisandra Shufelt, Eldin Dzubur, Sandy Joung, Garth Fuller, Kelly N. Mouapi, Irene Van Den Broek, Mayra Lopez, Shivani Dhawan, Corey W. Arnold, William Speier, Mitra Mastali, Qin Fu, Jennifer E. Van Eyk, Brennan Spiegel, C. Noel Bairey Merz
Journal: npj Digital Medicine (2019)

Abstract We describe the protocol, design, and methodology of the P rediction, R isk, and E valuation of M ajor A dverse C ardiac E vents (PRE-MACE) study as a multicomponent remote patient monitoring in cardiology. Using biosensor, biomarkers, and patient-reported outcomes in participants with stable ischemic heart disease, the PRE-MACE study is designed to measure cross-sectional correlations and establish the ability of remote monitoring to predict major adverse cardiovascular event (MACE) biomarkers and incident MACE at baseline and 12-month follow-up. It will further assess the adherence and cost-effectiveness of remote monitoring and blood sampling over the initial months. Despite medication and lifestyle changes, patients with cardiovascular disease can experience MACE due to undertreatment, poor adherence, or failure to recognize clinical or biochemical changes that presage MACE. Identifying patients using remote monitoring to detect MACE forerunners has potential to improve outcomes, avoid MACE, and reduce resource utilization. Data collection will include: (1) continuous remote monitoring using wearable biosensors; (2) biomarker measurements using plasma and at-home micro-sampling blood collection; and (3) patient-reported outcomes to monitor perceived stress, anxiety, depression, and health-related quality of life. Two hundred participants will be followed for 90 days with a subset ( n = 80) monitored for 180 days. All participants will be followed up for MACE at 12 months.The PRE-MACE study will utilize remote monitoring with biosensors, biomarkers, and patient-reported outcomes to identify intermediate biomarkers of MACE in patients with stable ischemic heart disease. If shown to be effective, this intervention can be utilized between health visits to predict MACE and reduce financial impact of MACE.
Inter‐rater reliability and agreement hidradenitis suppurativa instruments
Authors: L. Thorlacius, A. Garg, P.T. Riis, S.M. Nielsen, V. Bettoli, J.R. Ingram, V. Marmol, L. Matusiak, J.C. Pascual, J. Revuz, K. Sartorius, T. Tzellos, H.H. Zee, C.C. Zouboulis, D.M. Saunte, A.B. Gottlieb, R. Christensen, G.B.E. Jemec
Journal: British Journal of Dermatology (2019)

Hidradenitis suppurativa (HS) is a long-lasting skin disease with flares of painful boils in areas where skin meets skin, such as the armpits and groins. It affects somewhere between 1 and 40 people out of 1000 worldwide. When trying to measure the effect of a treatment in a clinical trial, so-called ‘outcome measurement instruments’ are used. These are ways of estimating ‘how much’ disease is present. It is obviously important that outcome measurement instruments measure the right thing and do not vary at random. It has previously been shown that outcome measurement instruments used in HS trials lack proof of their reliability. This study therefore aimed to find out how consistently 12 HS-experienced dermatologists would score 24 patients with HS, using nine different instruments. The study showed that one called Hurley staging was an acceptable instrument in terms of consistency of scores. However, Hurley staging is suited only for severity staging e.g. to guide the most appropriate treatment in each stage. For instruments designed to measure changes in disease severity, low agreement between the rating dermatologists was found. Therefore, the results question whether HS physical signs are best measured by traditional instruments based on a physician counting individual HS lesions (affected patches). As a result, other assessment methods of physical signs in HS, using technology such as ultrasound, should also be considered.
Use of tumour necrosis factor-α inhibitors and the risk of serious infection in paediatric inflammatory bowel disease in Denmark: a nationwide cohort study
Authors: Viktor Wintzell, Henrik Svanström, Mads Melbye, Tine Jess, Ola Olén, Jonas F Ludvigsson, Björn Pasternak
Journal: The Lancet. Gastroenterology & hepatology (2019)
From old issues to new directions in experimental psychology and economics
Authors: Vernon L. Smith
Journal: Behavioral and Brain Sciences (2001)

The rhetoric of hypothesis testing implies that game theory is not testable if a negative result is blamed on any auxiliary hypothesis such as “rewards are inadequate.” This is because either the theory is not falsifiable (since a larger payoff can be imagined, one can always conclude that payoffs were inadequate) or it has no predictive content (the appropriate payoff cannot be prespecified).
Chemotherapy combined with antiangiogenesis drugs in stage IV sarcoma patients: Efficacy data from the largest cohort study from China.
Authors: Zhiwu Ren, Zhichao Liao, Jilong Yang
Journal: Journal of Clinical Oncology (2019)

e22505 Background: Chemotherapy agents such as doxorubicin are not curative and new therapies for metastatic sarcomas are urgently needed. Several anti-angiogenesis therapeutic drugs such as Apatinib and Endostar have been widely used as monotherapy or combined treatments. We performed a retrospective study with the largest Chinese sarcoma cohort to investigate the efficacy of different anti-angiogenesis strategies. Methods: Data of NCT03121833 and NCT03121846 were collected. The information of 119 sarcoma patients in stage IV treated in Tianjin Medical University Cancer Hospital from Oct. 2009 to Aug. 2018 was collected. These sarcoma patients received chemotherapy, anti-angiogenesis therapies, or combined treatments. Chemotherapy was administered with single-agent Adriamycin or combination regimens according to NCCN guideline. Endostar was given at a dose of 15mg once daily by intravenous infusion for 14 days combined with chemotherapy regimens. Apatinib were given at a starting dose of 500 mg daily. Efficacy was evaluated according to RECIST1.1. Treatment-related adverse effects (AEs) were also evaluated. Results: 119 patients (46 bone sarcomas and 73 soft tissue sarcomas) were enrolled into four groups according to different treatment strategies (Table). The ORR had no significantly difference but DCR was significantly different, with the highest rate in chemotherapy plus apatinib group. The mPFS and mOS had no significantly difference. All the AEs were manageable. Conclusions: Chemotherapy combined with anti-angiogenesis drugs such as Apatinib and Endostar significantly increase the response rate. Apatinib is effective and well tolerated for advanced sarcoma patients. As for Apatinib treatment, the patients who suffered hypertension, hand-foot-skin reaction or proteinuria have significant longer OS than those without these AEs, which is first report in sarcoma patients. Clinical trial information: NCT03121833; NCT03121846. [Table: see text]