tbuckley/cabot-search huggingface dataset:
Treatment of carcinoma in situ of the glans penis with topical chemotherapy agents.
Authors: Hussain M Alnajjar, Wayne Lam, Marco Bolgeri, Rowland Rees, Matthew Perry, Nicholas Watkin
Journal: Journal of Clinical Oncology (2012)

e15100 Background: To establish the response rate of 5-flurouracil (5-FU) and imiquimod (IQ) in the treatment of penile CIS in a large contemporary series in a supra-network center. The use of topical agents in the treatment of CIS of the penis has been well described in the literature. Previous studies have been limited by small sample size and imprecise end-points. Methods: Retrospective review of all primary and recurrent cases of penile CIS treated with 5-FU and IQ identified from a prospective database over a 10- year period. Therapy was standardised in all cases with application to the lesion for 12 hours every 48 hours for 28 days. 5-FU was the first line therapy and IQ used as second line topical agent. The primary end-point was defined as complete response (CR = resolution of lesion), partial response (PR = lesion reduced in size and or visibility) or no response (NR = no improvement in lesion size and or visibility). The secondary end-points included local toxicity and adverse events. Results: A total of 86 patients were diagnosed with CIS of the penis over the 10-year period. 44/86 (51%) received topical chemotherapy. Mean follow-up was 34 months. The response rates, local toxicity and adverse events were analysed. The overall complete response rate for topical agents was 57% (Table). Conclusions: Topical chemotherapy agents are moderately effective first line therapy in the treatment of penile CIS. Toxicity and adverse events were low with our treatment protocol. The issue of long-term surveillance and assessment of partial responders remains a challenge. Topical chemotherapy should remain a first line treatment option for penile CIS. [Table: see text]
Development of an assay for <i>KRAS</i> mutation as a predictive marker for cetuximab in colorectal cancer
Authors: T. Yokota, K. Muro, N. Shibata, T. Ura, D. Takahari, K. Shitara, Y. Yatabe
Journal: Journal of Clinical Oncology (2009)

e15048 Background: The activating KRAS mutation is an important predictive marker for anti-EGFR therapy against colorectal cancer (CRC), although valid assays using pathological specimens have not been yet established. We present a rapid, sensitive assay for KRAS genotyping using small biopsy specimens. Methods: We used Cycleave PCR to detect the KRAS mutation in CRC with a chimeric DNA-RNA-DNA probe labeled with fluorescent dye and quencher, with results obtained within 4 hours. Template DNA was extracted from formalin-fixed, paraffin-embedded specimens, which are surgically resected or biopsied in clinical practice. Results: To evaluate Cycleave PCR accuracy for detecting the KRAS mutation, we compared with results of reverse transcriptase-PCR-coupled direct sequencing (RT-PCR-DS) of metastatic lung tumor specimens from CRC patients. KRAS mutations were present in 40 (43%) of 94 patients, including 28 (30%) and 8 (9%) in codon 12 and codon 13 mutations, respectively. Concordant results between Cycleave PCR and RT-PCR-DS in KRAS codon 12 and 13 were found in 35/36 (97%) and 23/23 (100%), respectively. We also applied this method to surgical specimens in clinical practice. Although 8 from 73 patients (11%) could not be evaluated with Cycleave PCR, corresponding biopsy specimens could be used alternatively. Because biopsy specimens were fixed by formalin for a shorter period, fixation of surgical specimens for longer time may have contributed to PCR failure. Indeed, over- fixation by formalin impaired PCR amplification of KRAS in time-dependently. Furthermore, results of 4 randomly selected biopsy specimens using Cycleave PCR were consistent with those of surgical specimens. Conclusions: Cycleave PCR even using biopsy specimens is accurate, rapid, and useful to detect KRAS mutations in CRC patients. This study also called attention to specimen selection, as over-fixation by formalin may lead to failure of the gene examination due to template DNA fragmentation. This method can be applied to examine BRAF genotyping as well as KRAS. KRAS/BRAF genotyping by Cycleave PCR leads to individualized therapy using cetuximab for CRC patients. No significant financial relationships to disclose.
Gynecology. Medical and Surgical. Outlines for Students and Practitioners.
Journal: JAMA (1905)

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 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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
MDM2 inhibitor AMG-232 and radiation therapy in treating patients with soft tissue sarcoma with wild-type TP53: A phase IB study (NRG-DT001).
Authors: Meng XU WELLIVER, Brian Andrew Van Tine, Peter Houghton, Michelle A. Rudek, Raphael E. Pollock, John Michael Kane, Gary K. Schwartz, Peixin Zhang, David G. Kirsch, Paul Wakely, Steve B. Jiang, Shahanawaz Jiwani, Alan D. Rogers, Dian Wang
Journal: Journal of Clinical Oncology (2019)

TPS11076 Background: Over-expression of mdm2 is a major block to p53 activation in soft tissue sarcoma (STS). AMG-232 specifically inhibits human MDM2-p53 interactions in vitro and in vivo, thereby activating p53. Resistance mechanisms to MDM2 inhibition by AMG-232 is through accumulation of MDM2 and MDMX. However, DNA damaging agents, such as radiotherapy (RT), promote MDMX degradation and lead to sustained p53 activation, which is critically important for radiation-induced tumor cell killing in STS. Indeed, preclinical studies reveal that AMG-232 synergizes with RT in vitro and in vivo when treating STS with wild type (WT) P53 gene . Since a majority of STS harbor WT TP53 gene and RT is part of the standard of care in treating STS; it is the next rational step to test the safety and efficacy of combination of AMG-232 and RT followed by surgery. In this clinical trial, we hypothesize that preoperative AMG-232 plus RT is safe and well tolerated in 2 separate cohorts: (A) extremity and body wall; (B) abdomen/pelvis/retroperitoneum. Methods: A key feature of this trial is to incorporate TP53 NGS sequencing result as one of the eligibility criteria. Adult patients with pathologically proven grade 2-3 STS with size ≥ 5 cm are eligible to enroll if there is a planned definitive surgical resection of the primary tumor. There must be sufficient tissue to submit to central laboratory for NGS sequencing of the TP53 gene, which is an integral biomarker. Only those with tumors harboring WT p53 gene will be allowed to continue protocol treatment. The primary objective is to evaluate the safety and tolerability of AMG-232 in combination with standard-dose RT in STS in two separate cohort; as well as to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of AMG-232 in combination with RT. We define DLT as grade 4-5 toxicities attributable to AMG-232 for up to 4 weeks after the completion of combination treatment (prior to surgery) as well as any AMG-232 related grade 3 toxicity that should lead to &gt; 2 weeks treatment delay or ≥ two dose reductions. There are 3 dose levels for AMG-232: dose level 1 is 120 mg daily for 3 days per week; dose level 2 is 120 mg daily 4 days per week and dose level 5 is 120 mg daily 5 days a week. If patients did not tolerate dose level 1, AMG-232 will be de-escalated to a lower level, which is 120 mg daily 2 days a week. The trial was open since 11/2017; 3 patients have been enrolled to cohort A and 2 patients in cohort B at dose level 1. The first patient has a tumor with WT p53 gene and has completed protocol treatment safely. Clinical trial information: NCT03217266.
Amount and Type of Dietary Fat, Postprandial Glycemia, and Insulin Requirements in Type 1 Diabetes: A Randomized Within-Subject Trial
Authors: Kirstine J. Bell, Chantelle Z. Fio, Stephen Twigg, Sally-Anne Duke, Gregory Fulcher, Kylie Alexander, Margaret McGill, Jencia Wong, Jennie Brand-Miller, Garry M. Steil
Journal: Diabetes Care (2019)

OBJECTIVE The American Diabetes Association recommends individuals with type 1 diabetes (T1D) adjust insulin for dietary fat; however, optimal adjustments are not known. This study aimed to determine 1) the relationship between the amount and type of dietary fat and glycemia and 2) the optimal insulin adjustments for dietary fat. RESEARCH DESIGN AND METHODS Adults with T1D using insulin pump therapy attended the research clinic on 9–12 occasions. On the first six visits, participants consumed meals containing 45 g carbohydrate with 0 g, 20 g, 40 g, or 60 g fat and either saturated, monounsaturated, or polyunsaturated fat. Insulin was dosed using individual insulin/carbohydrate ratio as a dual-wave 50/50% over 2 h. On subsequent visits, participants repeated the 20–60-g fat meals with the insulin dose estimated using a model predictive bolus, up to twice per meal, until glycemic control was achieved. RESULTS With the same insulin dose, increasing the amount of fat resulted in a significant dose-dependent reduction in incremental area under the curve for glucose (iAUCglucose) in the early postprandial period (0–2 h; P = 0.008) and increase in iAUCglucose in the late postprandial period (2–5 h; P = 0.004). The type of fat made no significant difference to the 5-h iAUCglucose. To achieve glycemic control, on average participants required dual-wave insulin bolus: for 20 g fat, +6% insulin, 74/26% over 73 min; 40 g fat, +6% insulin, 63/37% over 75 min; and 60 g fat, +21% insulin, 49/51% over 105 min. CONCLUSIONS This study provides clinical guidance for mealtime insulin dosing recommendations for dietary fat in T1D.
Prenatal exposure to traffic-related air pollution, the gestational epigenetic clock, and risk of early-life allergic sensitization
Authors: Hind Sbihi, Meaghan J. Jones, Julie L. MacIsaac, Michael Brauer, Ryan W. Allen, Malcolm R. Sears, Padmaja Subbarao, Piush J. Mandhane, Theo J. Moraes, Meghan B. Azad, Allan B. Becker, Jeffrey R. Brook, Michael S. Kobor, Stuart E. Turvey
Journal: Journal of Allergy and Clinical Immunology (2019)
Role of Voltage-Gated Sodium Channels in the Mechanism of Ether-Induced Unconsciousness
Authors: Nicholas Denomme, Jacob M. Hull, George A. Mashour
Journal: Pharmacological Reviews (2019)

Despite continuous clinical use for more than 170 years, the mechanism of general anesthetics has not been completely characterized. In this review, we focus on the role of voltage-gated sodium channels in the sedative–hypnotic actions of halogenated ethers, describing the history of anesthetic mechanisms research, the basic neurobiology and pharmacology of voltage-gated sodium channels, and the evidence for a mechanistic interaction between halogenated ethers and sodium channels in the induction of unconsciousness. We conclude with a more integrative perspective of how voltage-gated sodium channels might provide a critical link between molecular actions of the halogenated ethers and the more distributed network-level effects associated with the anesthetized state across species.
Single-Cell Analysis of Human Mononuclear Phagocytes Reveals Subset-Defining Markers and Identifies Circulating Inflammatory Dendritic Cells
Authors: Charles-Antoine Dutertre, Etienne Becht, Sergio Erdal Irac, Ahad Khalilnezhad, Vipin Narang, Shabnam Khalilnezhad, Pei Y. Ng, Lucas L. van den Hoogen, Jing Yao Leong, Bernett Lee, Marion Chevrier, Xiao Meng Zhang, Pearly Jean Ai Yong, Geraldine Koh, Josephine Lum, Shanshan Wu Howland, Esther Mok, Jinmiao Chen, Anis Larbi, Henry Kun Kiaang Tan, Tony Kiat Hon Lim, Panagiota Karagianni, Athanasios G. Tzioufas, Benoit Malleret, Joshua Brody, Salvatore Albani, Joel van Roon, Timothy Radstake, Evan W. Newell, Florent Ginhoux
Journal: Immunity (2019)
Complement Activation in Patients With Probable Systemic Lupus Erythematosus and Ability to Predict Progression to American College of Rheumatology–Classified Systemic Lupus Erythematosus
Authors: Rosalind Ramsey‐Goldman, Roberta Vezza Alexander, Elena M. Massarotti, Daniel J. Wallace, Sonali Narain, Cristina Arriens, Christopher E. Collins, Amit Saxena, Chaim Putterman, Kenneth C. Kalunian, Tyler O'Malley, Thierry Dervieux, Arthur Weinstein
Journal: Arthritis & Rheumatology (2019)

Objective To evaluate the frequency of cell‐bound complement activation products ( CB ‐ CAP s) as a marker of complement activation in patients with suspected systemic lupus erythematosus ( SLE ) and the usefulness of this biomarker as a predictor of the evolution of probable SLE into SLE as classified by the American College of Rheumatology ( ACR ) criteria. Methods Patients in whom SLE was suspected by lupus experts and who fulfilled 3 ACR classification criteria for SLE (probable SLE ) were enrolled, along with patients with established SLE as classified by both the ACR and the Systemic Lupus International Collaborating Clinics ( SLICC ) criteria, patients with primary Sjögren's syndrome ( SS ), and patients with other rheumatic diseases. Individual CB ‐ CAP s were measured by flow cytometry, and positivity rates were compared to those of commonly assessed biomarkers, including serum complement proteins (C3 and C4) and autoantibodies. The frequency of a positive multianalyte assay panel ( MAP ), which includes CB ‐ CAP s, was also evaluated. Probable SLE cases were followed up prospectively. Results The 92 patients with probable SLE were diagnosed more recently than the 53 patients with established SLE , and their use of antirheumatic medications was lower. At the enrollment visit, more patients with probable SLE were positive for CB ‐ CAP s (28%) or MAP (40%) than had low complement levels (9%) ( P = 0.0001 for each). In probable SLE , MAP scores of &gt;0.8 at enrollment predicted fulfillment of a fourth ACR criterion within 18 months (hazard ratio 3.11, P &lt; 0.01). Conclusion Complement activation occurs in some patients with probable SLE and can be detected with higher frequency by evaluating CB ‐ CAP s and MAP than by assessing traditional serum complement protein levels. A MAP score above 0.8 predicts transition to classifiable SLE according to ACR criteria.
Whole–Genome Sequencing of Childhood Cancer Survivors Treated with Cranial Radiation Therapy Identifies 5p15.33 Locus for Stroke: A Report from the St. Jude Lifetime Cohort Study
Authors: Yadav Sapkota, Yin Ting Cheung, Wonjong Moon, Kyla Shelton, Carmen L. Wilson, Zhaoming Wang, Daniel A. Mulrooney, Jinghui Zhang, Gregory T. Armstrong, Melissa M. Hudson, Leslie L. Robison, Kevin R. Krull, Yutaka Yasui
Journal: Clinical Cancer Research (2019)

Abstract Purpose: To identify genetic factors associated with risk of stroke among survivors of childhood cancer treated with cranial radiotherapy (CRT). Experimental Design: We analyzed whole-genome sequencing (36.8-fold) data of 686 childhood cancer survivors of European ancestry [median (range), 40.4 (12.4–64.7) years old; 54% male] from the St. Jude Lifetime Cohort study treated with CRT, of whom 116 (17%) had clinically diagnosed stroke. Association analyses (single-variant and Burden/SKAT tests) were performed, adjusting for demographic characteristics and childhood cancer treatment exposures. Results: We identified a genome-wide significant association between 5p15.33 locus and stroke [rs112896372: HR = 2.55; P = 1.42 × 10–8], with a stronger association (HR = 3.68) among survivors treated with CRT dose 25–50 Gray (Gy) and weaker associations among those treated with CRT doses &amp;lt;20 or 20–25 or &amp;gt;50 Gy (HRs = 2.14, 2.40, and 2.28). The association was replicated in 90 CRT-exposed African survivors (HR = 3.05; P = 0.034). In CRT-exposed Europeans, rs112896372 significantly (P &amp;lt; 0.001) improved predictive ability (AUC = 0.717) for determining stroke risk than nongenetic factors alone (AUC = 0.663) at 30 years since diagnosis, with significant improvement among African survivors (P = 0.047). SNP rs112896372 was further evaluated in three independent datasets including 1,641 European (HR = 1.54; P = 0.055) and 316 African survivors (HR = 1.88; P = 0.283) not treated with CRT, and 166,988 males in the UK Biobank (OR = 1.0012; P = 0.042). Conclusions: A novel locus 5p15.33 is associated with stroke risk among childhood cancer survivors, with a possible CRT dose-specific effect. The locus is of potential clinical utility in characterizing individuals who may benefit from surveillance and intervention strategies.
Cysticercosis and taeniasis cases diagnosed at two referral medical institutions, Belgium, 1990 to 2015
Authors: Veronique Dermauw, Steven Van Den Broucke, Lieselotte Van Bockstal, Leon Luyten, Kim Luyckx, Emmanuel Bottieau, Pierre Dorny
Journal: Eurosurveillance (2019)

Background Few case reports on human infections with the beef tapeworm Taenia saginata and the pork tapeworm, Taenia solium , diagnosed in Belgium have been published, yet the grey literature suggests a higher number of cases. Aim To identify and describe cases of taeniasis and cysticercosis diagnosed at two Belgian referral medical institutions from 1990 to 2015. Methods In this observational study we retrospectively gathered data on taeniasis and cysticercosis cases by screening laboratory, medical record databases as well a uniform hospital discharge dataset. Results A total of 221 confirmed taeniasis cases were identified. All cases for whom the causative species could be determined (170/221, 76.9%) were found to be T. saginata infections. Of those with available information, 40.0% were asymptomatic (26/65), 15.4% reported diarrhoea (10/65), 9.2% reported anal discomfort (6/65) and 15.7% acquired the infection in Belgium (11/70). Five definitive and six probable cases of neurocysticercosis (NCC), and two cases of non-central nervous system cysticercosis (non-CNS CC) were identified. Common symptoms and signs in five of the definitive and probable NCC cases were epilepsy, headaches and/or other neurological disorders. Travel information was available for 10 of the 13 NCC and non-CNS CC cases; two were Belgians travelling to and eight were immigrants or visitors travelling from endemic areas. Conclusions The current study indicates that a non-negligible number of taeniasis cases visit Belgian medical facilities, and that cysticercosis is occasionally diagnosed in international travellers.
Levering Mechanically Activated Piezo Channels for Potential Pharmacological Intervention
Authors: Bailong Xiao
Journal: The Annual Review of Pharmacology and Toxicology (2019)

The mechanically activated Piezo channels, including Piezo1 and Piezo2 in mammals, function as key mechanotransducers for converting mechanical force into electrochemical signals. This review highlights key evidence for the potential of Piezo channel drug discovery. First, both mouse and human genetic studies have unequivocally demonstrated the prominent role of Piezo channels in various mammalian physiologies and pathophysiologies, validating their potential as novel therapeutic targets. Second, the cryo-electron microscopy structure of the 2,547-residue mouse Piezo1 trimer has been determined, providing a solid foundation for studying its structure-function relationship and drug action mechanisms and conducting virtual drug screening. Third, Piezo1 chemical activators, named Yoda1 and Jedi1/2, have been identified through high-throughput screening assays, demonstrating the drugability of Piezo channels. However, the pharmacology of Piezo channels is in its infancy. By establishing an integrated drug discovery platform, we may hopefully discover and develop a fleet of Jedi masters for battling Piezo-related human diseases.
Systemic Delivery of CRISPR/Cas9 Targeting HPV Oncogenes Is Effective at Eliminating Established Tumors
Authors: Luqman Jubair, Sora Fallaha, Nigel A.J. McMillan
Journal: Molecular Therapy (2019)

The recent advancements in CRISPR/Cas9 engineering have resulted in the development of more targeted and potentially safer gene therapies. The challenge in the cancer setting is knowing the driver oncogenes responsible, and the translation of these therapies is hindered by effective and safe delivery methods to target organs with minimal systemic toxicities, on-target specificity of gene editing, and demonstrated lack of long-term adverse events. Using a model system based on cervical cancer, which is driven by the ongoing expression of the human papillomavirus E6 and E7 proteins, we show that CRISPR/Cas9 delivered systemically in vivo using PEGylated liposomes results in tumor elimination and complete survival in treated animals. We compared treatment and editing efficiency of two Cas9 variants, wild-type (WT) Cas9 and the highly specific FokI-dCas9, and showed that the latter was not effective. We also explored high-fidelity repair but found that repair was inefficient, occurring in 6%–8% of cells, whereas non-homologous end joining (NHEJ) was highly efficient, occurring in ∼80% of the cells. Finally, we explored the post gene-editing events in tumors and showed that cell death is induced by apoptosis. Overall, our work demonstrates that in vivo CRISPR/Cas editing treatment of preexisting tumors is completely effective despite the large payloads.