tbuckley/cabot-search huggingface dataset:
Absence of linkage between chromosome 11p15 markers and manic- depressive illness in a Belgian pedigree
Authors: J Mendlewicz, M Leboyer, A De Bruyn, A Malafosse, S Sevy, D Hirsch, C Van Broeckhoven, J Mallet
Journal: American Journal of Psychiatry (1991)

The original finding of genetic linkage in an Old Order Amish pedigree has been contradicted by the results of several subsequent studies. Using the same genetic parameter values, diagnostic criteria, and 11p15 genetic markers as those used to study the initial Amish population, the authors performed a linkage study of a four-generation informative pedigree in Belgium.Recombinant DNA technology was used to analyze three markers for the chromosome 11p15 location: the genes for tyrosine hydroxylase (TH) and insulin (INS) and the c-Harvey-ras oncogene (HRAS). Diagnoses of the relatives of a proband with bipolar affective disorder were determined with the Schedule for Affective Disorders and Schizophrenia--Lifetime Version and based on the Research Diagnostic Criteria. Relatives were considered affected if they had bipolar disorder, unipolar disorder, or cyclothymia; a diagnostic hierarchy was developed to include unipolar disorder and cyclothymia in the linkage analysis.Pairwise analyses of the disease locus and each of the three polymorphisms excluded the possibility of close linkage between manic-depressive illness and the three chromosome 11p15 markers. Multipoint linkage analysis combining the information from all three genes also excluded linkage.The conflict between the original results from the Amish study and the many negative reports on chromosome 11 linkage of manic-depression has been interpreted as indicating genetic heterogeneity, but heterogeneity has not been documented for the 11p15 locus. Conversely, the linkage approach has major drawbacks, so other genetic strategies should also be considered.
A phase I trial of antifibronecitin <sup>131</sup>I-L19-small immunoprotein (L19-SIP) in solid tumors and lymphoproliferative disease
Authors: G. Del Conte, D. Tosi, A. Fasolo, C. Chiesa, P. Erba, C. M. Grana, H. D. Menssen, G. Mariani, E. Bombardieri, L. Gianni
Journal: Journal of Clinical Oncology (2008)

2575 Background: L19-SIP is a human recombinant antibody-fragment consisting of the variable regions of the L19 mAb directed against the extra-domain B (ED-B) of fibronectin that is overexpressed in tumoral vasculature. We explored the targeting potential of 131I-L19-SIP for both tumor imaging and radioimmunotherapy (RIT). Methods: 131I-L19-SIP (4 mg; 74–193 MBq) was administered iv for dosimetry and pharmacokinetics (PK). Patients (pts) with high tumor uptake (lesion/red marrow absorbed dose ratio ≥10) received a single therapeutic dose of about 3,700 MBq (n=11) or 5,550 MBq (n=7) of 131I-L19-SIP. Dosimetry was based on dual-head gamma-camera planar imaging. Results: 37 pts (median age 59 yr [range 34–82], median ECOG PS 0 [range 0–1], median prior chemotherapies 2 [range 0–5]) with the following cancers were enrolled: colorectal (8), melanoma (7), thymoma (4), mesothelioma (4), prostate (2), pancreatic (2), lymphomas (2), other (8). Eighteen pts (48.6%) were eligible for RIT. Blood elimination profile in the first 13 pts: T1/2α 13 h, T1/2 β 39 h, with an extremely low interpatient variability. Dosimetry estimates as median absorbed doses (Gy): heart wall 2.8, kidneys 3.7, liver 3.0, lungs 1.98, testes 4.2, stomach 0.67, red marrow 0.85, tumor lesions 12.24. Imaging was excellent and in some cases revealed lesions undetected by MRI or CT. Main toxicities of RIT: short-lived grade 3/4 thrombocytopenia (4 pts) and uncomplicated grade 4 neutropenia (1 pt). One objective response was recorded according to RECIST criteria. A clinical benefit was seen in 4 additional pts: stabilization of ≥3 months in 1 thymoma pt, clinical evidence of long-term tumor shrinkage in 1 melanoma pt, stabilization of rapidly progressive skin lesions in 1 melanoma pt, and pain palliation in 1 breast cancer pt with brachial plexus neoplastic infiltration. Furthermore, a substantial decrease of [18F]FDG uptake was observed for several lesions in 3 out of 4 mesothelioma pts. Conclusions: Good tolerability and high tumor uptake combined with low red marrow absorbed dose justify testing the feasibility of further increase of the 131I-L19-SIP dose for RIT. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bayer HealthCare Pharma, USA
Phase II study of NK012 in relapsed small cell lung cancer.
Authors: E. Raefsky, D. R. Spigel, J. R. Infante, J. C. Bendell, S. F. Jones, A. J. Lipman, D. Trent, S. Kawamura, F. A. Greco, J. D. Hainsworth, H. A. Burris
Journal: Journal of Clinical Oncology (2011)

7079 Background: NK012 is a topoisomerase I (TI) inhibitor designed as a micelle-forming macromolecule to release a gradual and sustained concentration of SN-38, the active metabolite of irinotecan. Phase I studies have shown safety and antitumor activity of NK012 in patients (pts) with refractory tumors including small-cell lung cancer (SCLC). This phase II trial was designed to evaluate NK012 in pts with sensitive relapsed (SR) and refractory relapsed (RR) SCLC. Methods: Pts with relapsed SCLC following 1 chemotherapy regimen for extensive-stage SCLC or chemoradiation for limited-stage SCLC were eligible. Pts had measurable disease, an ECOG performance status (PS) of 0-2, and adequate organ function. Pts with untreated brain metastases or prior TI therapy were excluded. NK012 was given IV over 30 minutes once every 28 days at a dose based on pretreatment UGT1A1 genotyping: 28 mg/m2 (wild-type [wt]/wt and wt/*28) or 18 mg/m2 (*28/*28). Pts were restaged every 8 weeks and remained on therapy until disease progression or unacceptable toxicity. The trial used a two-stage design to assess the objective response rate (ORR) in both SR (H1 30%, α.10, β.20) and RR cohorts (H1 20%, α.05, β.20). Results: 40 SR pts were enrolled over 11 months. The RR cohort remains open to enrollment. Pt characteristics of the SR pts: median age 62 years, female 48%, ECOG 0-1 95%. Pts received a median of 4 cycles (range 1-10) of NK012. The ORR assessed in 37 SR pts was 22% including 2 complete responses; the disease control rate (DCR=ORR+stable disease) was 68%. Survival analyses are in progress. NK012 was well-tolerated with the following grade 3/4 toxicities (> 5%): neutropenia (44%, 1 pt with febrile neutropenia), thrombocytopenia (13%), anemia (5%), diarrhea (8%), and no treatment-related deaths. Conclusions: NK012 exhibited positive efficacy in pts with sensitive relapsed SCLC with a 22% ORR and a 68%DCR. Toxicity was expected and manageable with relatively low rates of serious toxicity. NK012 is currently in a phase I platinum combination study.
Whole exome sequencing of circulating and disseminated tumour cells in patients with metastatic breast cancer
Authors: D. Peeters, A. Brouwer, K. Op de Beeck, G. Van de Weyer, P. Pauwels, M. Peeters, P. Vermeulen, S. Van Laere, G. Van Camp, L.Y. Dirix
Journal: Annals of Oncology (2015)
Testosterone in Androgen Receptor Signaling and DNA Repair: Enemy or <i>Frenemy</i>?
Authors: Melvin Lee Kiang Chua, Robert G. Bristow
Journal: Clinical Cancer Research (2016)

Androgen suppression mediates transcriptional downregulation of DNA repair genes. Stimulation with supraphysiologic levels of dihydrotestosterone induces formation of lethal DNA breaks through recruitment of topoisomerase II enzymes to fragile DNA sites. Bipolar castration and stimulation that contributes to increasing DNA damage represents a novel strategy of sensitizing prostate cancer to cytotoxic therapies, including radiotherapy. Clin Cancer Res; 22(13); 3124-6. ©2016 AACRSee related article by Hedayati et al., p. 3310.
Pegylated liposomal doxorubicin (PLD) with bevacizumab (B) in second-line treatment of ovarian cancer (OC): Pharmacokinetics (PK), safety, and preliminary outcome results
Authors: F. M. Muggia, L. Boyd, L. Liebes, A. Downey, C. Muller, B. Pothuri, S. Blank, T. Rutledge, D. Fishman, C. Verschraegen
Journal: Journal of Clinical Oncology (2009)

5548 Background: PLD activity in platinum-resistant OC is modest. B, with its activity in platinum(Plat)-sensitive and Plat-resistant patients (pts), has not been combined with PLD. PLD intratumoral concentrations, if affected by B, might be reflected in PLD PK. This phase II study of PLD + B was started in 2007 to accrue 48 pts, unless 4 serious (&gt; grade 3) adverse events (AEs) supervened. Methods: Improvement in progression-free survival (PFS) at 6 m from 25 to 40% at 6 m in Plat-resistant OC is primary endpoint. PK of PLD alone at 1h, d 7 and d 21 (cycle 1) vs with B (cycle 2), safety, and response rates (RECIST and CA125 criteria) were secondary endpoints. Dosing: PLD 30 mg/m 2 followed by B 15 mg/kg on cycles 2–7 (with option to continue) d 1 every 3 w. Pts recurring within 6 m of platinum-based treatment for OC after &lt; 3 prior regimens (but no PLD or B) were eligible. Exclusions: bowel obstruction, prior perforation, uncontrolled hypertension, or vascular disease. Hematologic, mucocutaneous and renal toxicities were evaluated prior to each cycle, MUGA scans every third cycle; disease status by CA125 and/or RECIST every third cycle. Results: 21 of 24 pts enrolled to date are evaluable. Median age is 65, range 52–83; most had 2 prior chemotherapy regimens. Median 6 (range 3–12) cycles were given with 6 off study with progression at 3–7 cycles. RECIST and CA125 responses are under review; in 11 pts with baseline CA125 of &gt; 40 IU/mL, median increase was 31% by cycle 2; later falling to -57%. AEs did not exceed grade 3; hand-foot syndrome led to PLD dose reduction in 8 pts (33%); asymptomatic decreases in left ventricular ejection fraction (LVEF) &gt;10% in 3 pts were noted, with treatment discontinuation in 1. The mean (±SEM) secondary PK parameter estimates for Cmax, AUC, and elimination half life were 4.5 ± 0.5 ug/mL, 651.7 ± 61 ug/mL x h, and 93.3 ± 19.7 h, respectively. Conclusions: Cycles 1 and 2 PLD PK do not differ. PLD + B is tolerable with PLD dose modifications. Declines in LVEF in 1 institution have uncertain causality. Midway into the trial, safety and time on study encourage completion for study primary endpoint. [Table: see text]
Radioembolization of unresectable hepatic metastases using yttrium-90 microspheres in heavily pretreated colorectal cancer.
Authors: M. E. Hill, M. F. Mulcahy, R. Lewandowski, A. Rademaker, R. Salem
Journal: Journal of Clinical Oncology (2011)

559 Background: Yttrium-90 (Y90) microsphere liver-directed treatment has previously demonstrated the ability to provide disease stabilization to patients with liver-dominant metastatic colorectal cancer. Methods: We conducted a retrospective analysis of 36 patients with metastatic colorectal cancer who had undergone Y90 liver-directed therapy between November 2001 and March 2009. All patients had previously received 5-fluorouracil, irinotecan, and oxaliplatin and had unresectable hepatic metastases, with or without extrahepatic metastases. Results: Thirty-six patients with a mean age of 58 were included in the analysis. Twenty patients had both hepatic and extrahepatic metastatic disease and 16 had liver-confined metastatic disease at the time of first Y90 treatment. Radiologic response rate with stabilization of liver metastases was 72%. Median survival from time of diagnosis of liver metastases and from time of first Y90 treatment was 31.7 months and 9.4 months, respectively. One patient is still alive. Nine patients received only one Y90 treatment, 20 patients received two treatments, and 7 patients received three treatments. One-year survival from first Y90 treatment was 47%, and 53% of these patients had no extrahepatic metastatic disease prior to therapy, 41% had minimal extrahepatic disease, and 6% had significant extrahepatic disease. Fifty-three percent of patients survived less than one year after the first Y90 treatment. Of these, 36.8% had no evidence of extrahepatic metastatic disease prior to first Y90 therapy, 31.6% had a small volume of extrahepatic disease, and 31.6% had extensive extrahepatic disease. Conclusions: Liver-directed therapy with Y90 was observed to control the growth of unresectable metastatic liver disease in the majority of patients with heavily-pretreated colorectal cancer. A significantly smaller proportion of patients who survived a year or more had extensive extrahepatic mestastatic disease at the time of first Y90 treatment than those who survived less than a year. This suggests a potential survival advantage of Y90 liver-directed treatment in patients with primary liver metastatic disease and minimal extrahepatic disease. [Table: see text]
Loss of Glis2/NPHP7 causes kidney epithelial cell senescence and suppresses cyst growth in the Kif3a mouse model of cystic kidney disease
Authors: Dongmei Lu, Alysha Rauhauser, Binghua Li, Chongyu Ren, Kayla McEnery, Jili Zhu, Moumita Chaki, Komal Vadnagara, Sarah Elhadi, Anton M. Jetten, Peter Igarashi, Massimo Attanasio
Journal: Kidney International (2016)
PTPS-26PIN1, A THERAPEUTIC TARGET IN HEDGEHOG-DRIVEN MEDULLOBLASTOMA
Authors: Tao Xu, Honglai Zhang, Sung Soo Park, Sandra Camelo-Piragua, Andrzej Dlugosz, Sriram Venneti, Rork Kuick, Takafumi Uchida, Jean-Francois Rual
Journal: Neuro-Oncology (2015)

Medulloblastoma is the most common malignant brain tumor of childhood. Therapeutic approaches to medulloblastoma have led to significant improvements, but are achieved at a high cost to quality of life. Aberrant upregulation of the hedgehog (Hh) pathway drives cerebellar tumorigenesis in ∼30% of medulloblastoma patients. Hh pathway inhibitors such as the SMO antagonist Vismodegib are currently being tested in Hh-activated medulloblastoma and the preliminary results are encouraging. However, resistance to SMO inhibition can be acquired, leading to relapse. Alternative therapeutic approaches are needed. We aim to uncover novel Hh signal modulators that are essential in medulloblastoma to maintain tumorigenic potential. Using our proteomic platform for systematic protein interaction mapping, we discovered a novel interaction between GLI1, a key transcription factor for the mediation of Hh signals, and PIN1, a peptidylprolyl cis/trans isomerase that regulates the post-phosphorylation conformation of its substrates. Our results support a molecular model in which PIN1 protects GLI1 from ITCH-driven proteasomal degradation, thus contributing to the positive regulation of Hh signals. Most importantly, our in vivo functional analyses of PIN1 in mouse models of Hh-driven medulloblastoma demonstrate that the loss-of-PIN1 impairs tumor development and increases survival by 3 fold, from 57 to 158 days (P < 0.0001), establishing PIN1 as a key factor in Hh-driven medulloblastoma tumorigenesis. Finally, in human medulloblastoma tumor samples, the GLI1 and PIN1 proteins are correlated in their expression, supporting the relevance of the GLI1/PIN1 interaction in this disease context. In summary, the discovery of the GLI1/PIN1 interaction uncovers PIN1 as a novel therapeutic target in medulloblastoma tumorigenesis. If our hypothesis is validated, i.e., PIN1 inhibitors can improve survival in mouse models of Hh-driven medulloblastoma, our project will strongly justify testing the clinical relevance of PIN1 blockade in medulloblastoma patients.
Coverage by selective neonatal BCG vaccination should be monitored
Authors: N. Hicks, A Hamilton
Journal: BMJ (1996)

EDITOR,—Meirion R Evans raises important points relating to the provision and uptake of neonatal BCG vaccination by babies at increased risk of tuberculosis.1 This matter has been addressed in Dudley, where we have increased the uptake of neonatal BCG vaccination in identified ethnic minority babies to 93.5% and have introduced a system for monitoring the coverage among ethnic minority groups.

The department of public …
Appropriateness of Testing for Anti–Tumor Necrosis Factor Agent and Antibody Concentrations, and Interpretation of Results
Authors: Gil Y. Melmed, Peter M. Irving, Jennifer Jones, Gilaad G. Kaplan, Patricia L. Kozuch, Fernando S. Velayos, Leonard Baidoo, Miles P. Sparrow, Brian Bressler, Adam S. Cheifetz, Shane M. Devlin, Laura E. Raffals, Niels Vande Casteele, Diane R. Mould, Jean-Fred Colombel, Marla Dubinsky, William J. Sandborn, Corey A. Siegel
Journal: Clinical Gastroenterology and Hepatology (2016)
Convergence of Implementation Science, Precision Medicine, and the Learning Health Care System
Authors: David A. Chambers, W. Gregory Feero, Muin J. Khoury
Journal: JAMA (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Outbreak in meldonium positive laboratory tests: are we missing something?
Authors: Alice Panchaud, Chantal Csajka
Journal: British Journal of Sports Medicine (2016)

As clinicians facing the challenges associated with the interpretation of drug concentrations or clinical laboratory measures in our daily practice, the outbreak of adverse analytical findings reported on meldonium makes us wonder if the information on meldonium available to date is sufficient to adequately interpret such findings. An adequate interpretation of a drug concentration requires knowledge of its pharmacokinetic characteristics and profile over time, and this has not been studied fully for meldonium.

Available studies suggest that meldonium is eliminated mainly by the kidneys. Single dose administration showed …
Efficacy of irinotecan in combination with 5-fluorouracil (FOLFIRI) in metastatic gastric adenocarcinoma (MGA)
Authors: P. Afchain, E. Samalin, S. Thezenas, F. Abbas, O. Romano, R. Guimbaud, Y. Becouarn, F. Desseigne, E. Mitry, M. Ychou
Journal: Journal of Clinical Oncology (2008)

15539 Background: The most commonly used schedules for MGA are 5FU in combination with CDDP with or without Epirubicin (ECF) or Docetaxel (TCF). Irinotecan combined with 5FU (FOLFIRI regimen) was reported as active and well tolerated in a French randomized phase II study (Bouché, JCO 2004). The aim of this retrospective study was to evaluate the FOLFIRI regimen in a larger series of MGA patients (pts). Methods: Between 05/99 and 03/07, 219 pts from 13 French centers (162 males (72%), median age: 62 years, range: 25–88) were treated with at least one cycle of FOLFIRI. Primary tumour sites were 127 (58%) stomach and 92 (42%) gastroesophageal junction. The WHO status was 0 or 1 in 81% of pts and 95 (43%) pts were asymptomatic. One hundred forty two pts (65%) were treated in first- line (including 42 pts previously exposed to chemotherapy as (neo)adjuvant therapy). The 77 others pts (35%) received FOLFIRI as second- (n = 60) or later- (n=17) line for MGA. Results: Median number of chemotherapy cycles was 6 (range: 1–28). Grade 3 or 4 toxicities per patient were respectively: neutropenia 19%, mucositis 2%, nausea 5%, vomiting 6%, diarrhea 5%. There was one toxic death due to neutropenia. For the 147 pts treated as first-line, response rate was 34.7% (95% CI: 24.8 - 44.6, 92 measurable pts), median PFS was 5.8 months and median overall survival was 12.9 months (1-yr survival: 55%). For the 92 pts treated as second- or later-line, response rate was 18.2% (95% CI: 7.8 - 28.6, 55 measurable pts), median PFS was 4.0 months and median overall survival was 9.5 months (1-yr survival: 39%). Conclusions: These retrospective data 1- confirm the interesting activity and good tolerance of FOLFIRI regimen in MGA as first-line as well as later-line; 2- justify the ongoing prospective multicenter French phase III study, comparing FOLFIRI followed at progression by ECC (Epirubicine, Cisplatin, Capecitabine) versus the opposite sequence in MGA. No significant financial relationships to disclose.
Neoplastic transformation of normal hematopoietic cells by constitutively activating mutations of c-kit receptor tyrosine kinase
Authors: H Kitayama, T Tsujimura, I Matsumura, K Oritani, H Ikeda, J Ishikawa, M Okabe, M Suzuki, K Yamamura, Y Matsuzawa, Y Kitamura, Y Kanakura
Journal: Blood (1996)
421PD Prospective monitoring of lung function tests with CO and NO diffusion during high dose thoracic radiotherapy for lung cancer: The CONORT study
Authors: F. Mornex, C. Fontaine-Delaruelle, I. Selmaji, C. Prevost, N. Girard, V. Zarza, C. Viart-Ferber, S. Couraud
Journal: Annals of Oncology (2015)
Genomic Profiles of Diversification and Genotype–Phenotype Association in Island Nematode Lineages
Authors: Angela McGaughran, Christian Rödelsperger, Dominik G. Grimm, Jan M. Meyer, Eduardo Moreno, Katy Morgan, Mark Leaver, Vahan Serobyan, Barbara Rakitsch, Karsten M. Borgwardt, Ralf J. Sommer
Journal: Molecular Biology and Evolution (2016)

Understanding how new species form requires investigation of evolutionary forces that cause phenotypic and genotypic changes among populations. However, the mechanisms underlying speciation vary and little is known about whether genomes diversify in the same ways in parallel at the incipient scale. We address this using the nematode, Pristionchus pacificus, which resides at an interesting point on the speciation continuum (distinct evolutionary lineages without reproductive isolation), and inhabits heterogeneous environments subject to divergent environmental pressures. Using whole genome re-sequencing of 264 strains, we estimate FST to identify outlier regions of extraordinary differentiation (∼1.725 Mb of the 172.5 Mb genome). We find evidence for shared divergent genomic regions occurring at a higher frequency than expected by chance among populations of the same evolutionary lineage. We use allele frequency spectra to find that, among lineages, 53% of divergent regions are consistent with adaptive selection, whereas 24% and 23% of such regions suggest background selection and restricted gene flow, respectively. In contrast, among populations from the same lineage, similar proportions (34–48%) of divergent regions correspond to adaptive selection and restricted gene flow, whereas 13–22% suggest background selection. Because speciation often involves phenotypic and genomic divergence, we also evaluate phenotypic variation, focusing on pH tolerance, which we find is diverging in a manner corresponding to environmental differences among populations. Taking a genome-wide association approach, we functionally validate a significant genotype–phenotype association for this trait. Our results are consistent with P. pacificus undergoing heterogeneous genotypic and phenotypic diversification related to both evolutionary and environmental processes.