tbuckley/cabot-search huggingface dataset:
ATRT-04. A FUNCTIONAL SCREENING OF THE KINOME IDENTIFIES THE POLO-LIKE KINASE 4 (PLK4) AS A POTENTIAL THERAPEUTIC TARGET FOR ATYPICAL TERATOID/RHABDOID TUMORS (AT/RT), AND POSSIBLY, OTHER EMBRYONAL TUMORS OF THE BRAIN
Authors: Simone Sredni, Mario Suzuki, Jian-Ping Yang, Jacek Topczewski, Alexandre de Andrade, Anders Bailey, Jeffrey Gross, Akihide Kondo, David Piper, Tadanori Tomita
Journal: Neuro-Oncology (2017)

BACKGROUND: Atypical teratoid / rhabdoid tumors (AT/RT) are deadly embryonal tumors of the brain. With poor survival and modest response to current therapies, more effective and less toxic treatments are needed. We hypothesized that a systematic screening of the kinome will reveal kinases that drive AT/RT and can be targeted by inhibitors. METHODS: We individually mutated 160 kinases in a well characterized rhabdoid tumor cell line (MON) using Lentiviral CRISPR/Cas9. Monitoring the growth of each stably kinase-mutated cell line demonstrated that deficiency in 8 kinases (5%) resulted in significant impairment of cell proliferation. The kinase that most significantly impaired cell growth was validated by next generation sequencing. Its expression was evaluated by microarray gene expression (GE) within 111 pediatric tumors, and functional assays were performed. An inhibitor was tested in AT/RT cell lines and its toxicity evaluated in zebrafish larvae development. RESULTS: The Polo-like kinase 4 (PLK4) was identified as the kinase that resulted in higher impairment of cell proliferation when mutated by CRISPR/Cas9. PLK4 CRISPR-mutated rhabdoid cells demonstrated significant decrease in proliferation, viability and survival. GE showed upregulation of PLK4 in AT/RT and other embryonal tumors of the brain. The PLK4 inhibitor CFI-400945 showed cytotoxic effects on AT/RT cell lines including impairment of invasion and migration while sparing human fibroblasts and developing zebrafish larvae. CONCLUSIONS: PLK4 plays a key role in cell cycle control. It localizes to the centrosomes and is a critical regulator of centriole duplication. Our findings indicate that AT/RT proliferation is highly dependent on PLK4 and suggest that targeting PLK4 with inhibitors may hold a novel strategy to treat AT/RT and possibly other embryonal tumors of the brain. This is the first time PLK4 has been described as a potential target for both brain and pediatric tumors. FUNDING: The Rally Foundation of Childhood Cancer Research in memory of Hailey Trainer.
TPExtreme randomized trial: TPEx versus Extreme regimen in 1st line recurrent/metastatic head and neck squamous cell carcinoma.
Authors: Joel Guigay, Ulrich Keilholz, Ricard Mesia, Nadejda Vintonenko, Jean Bourhis, Anne Auperin
Journal: Journal of Clinical Oncology (2015)

TPS6087 Background: The EXTREME regimen (6 cycles of 5FU–cisplatin-cetuximab followed by cetuximab maintenance) is currently the standard first line in recurrent/metastatic (R/M) HNSCC. The GORTEC trial evaluating the TPEx regimen (4 cycles of docetaxel–cisplatin-cetuximab followed by cetuximab maintenance) demonstrated good results (median OS 14 months, ORR 54%) with acceptable safety profile, excellent dose intensity, high rate of patients who started maintenance. The aim of the current trial is to compare TPEx and EXTREME regimens. Methods: International, randomized, open-label trial. Main inclusion criteria are: histologically confirmed R/M HNSCC not suitable for locoregional treatment, age 18-70 years, PS < 2, creatinine clearance > 60 ml/min, prior total dose of cisplatin < 300 mg/m². The control arm EXTREME : 6 cycles, every 21 days, of cisplatin 100 mg/m² day1, 5FU 4000 mg/m² continuous infusion day1-4, and weekly cetuximab 250 mg/m² (1st loading dose 400 mg/m²) followed by weekly cetuximab 250 mg/m² maintenance. The experimental arm TPEx: 4 cycles, every 21 days, of docetaxel 75 mg/m² day1, cisplatin 75 mg/m² day1, and weekly cetuximab 250 mg/m² (1st loading dose 400 mg/m²), followed by cetuximab 500 mg/m² maintenance every 2 weeks. If cisplatin is not tolerated or its total cumulative dose reaches 600 mg/m², it must be replaced by carboplatin AUC5. G-CSF prophylactic administration is mandatory for each cycle in the TPEx arm. Only patients with CR/PR/SD will continue the cetuximab maintenance until PD or unacceptable toxicity. The primary endpoint is OS. Assuming a 2-sided type I error of 0.05, observing 295 deaths will provide a 80% power to detect a hazard ratio of 0.72. 295 deaths are expected out of 416 patients (208 per arm). Secondary endpoints are ORR, best response rate, PFS, TTP, toxicity and QoL. Tumor response assessments (Weeks 6, 12 and 18, then every 8 weeks until PD) will be reviewed by a blinded central image review committee. HPV central analysis and cost-effectiveness study are ancillary studies. GORTEC (France), AIO-Studien-gGmbH (Germany), TTCC (Spain) joint trial in collaboration with French GETTEC, GERCOR, H&N UNICANCER groups. Unrestricted grant from Merck Serono. Clinical trial information: NCT02268695.
When Respecting Autonomy Is Harmful: A Clinically Useful Approach to the Nocebo Effect
Authors: John T. Fortunato, Jason Adam Wasserman, Daniel Londyn Menkes
Journal: The American Journal of Bioethics (2017)

Nocebo effects occur when an adverse effect on the patient arises from the patient's own negative expectations. In accordance with informed consent, providers often disclose information that results in unintended adverse outcomes for the patient. While this may adhere to the principle of autonomy, it violates the doctrine of "primum non nocere," given that side-effect disclosure may cause those side effects. In this article we build off previous work, particularly by Wells and Kaptchuk (2012 Wells, R. E., and T. J. Kaptchuk. 2012. To tell the truth, the whole truth, may do patients harm: The problem of the nocebo effect for informed consent. American Journal of Bioethics 12:22–29.[Taylor & Francis Online], [Web of Science ®] , [Google Scholar]) and by Cohen (2013 Cohen, S. 2013. Nudging and informed consent. American Journal of Bioethics 13 (6):3–11.[Taylor & Francis Online], [Web of Science ®] , [Google Scholar]), to suggest ethical guidelines that permit nondisclosure in the case when a nocebo effect is likely to occur on of the basis of nonmaleficence. We accept that that autonomy vis-à-vis informed consent must be forestalled, but salvage much of its role by elaborating a practical clinical approach to postencounter follow-up. In doing so, we reconcile a clinically practicable process of determining conditions of disclosure with long-standing ethical commitments to patients.
Age-Related Autonomous Aldosteronism
Authors: Kazutaka Nanba, Anand Vaidya, Gordon H. Williams, Isabel Zheng, Tobias Else, William E. Rainey
Journal: Circulation (2017)

Background: Both aging and inappropriate secretion of aldosterone increase the risk for developing cardiovascular disease; however, the influence of aging on aldosterone secretion and physiology is not well understood. Methods: The relationship between age and adrenal aldosterone synthase (CYP11B2) expression was evaluated in 127 normal adrenal glands from deceased kidney donors (age, 9 months to 68 years). Following immunohistochemistry, CYP11B2-expressing area and areas of abnormal foci of CYP11B2-expressing cells, called aldosterone-producing cell clusters, were analyzed. In a separate ancillary clinical study of 677 participants without primary aldosteronism, who were studied on both high and restricted sodium diets (age, 18–71 years), we used multivariable linear regression to assess the independent associations between age and renin-angiotensin-aldosterone system physiology. Results: In adrenal tissue, the total CYP11B2-expressing area was negatively correlated with age ( r =−0.431, P &lt;0.0001), whereas the total aldosterone-producing cell cluster area was positively correlated with age ( r =0.390, P &lt;0.0001). The integrated ratio of aldosterone-producing cell cluster to CYP11B2-expressing area was most strongly and positively correlated with age ( r =0.587, P &lt;0.0001). When participants in the clinical study were maintained on a high sodium balance, renin activity progressively declined with older age, whereas serum and urinary aldosterone did not significantly decline. Correspondingly, the aldosterone-to-renin ratio was positively and independently associated with older age (adjusted β=+5.54 ng/dL per ng/mL per hour per 10 years, P &lt;0.001). In contrast, when participants were assessed under sodium-restricted conditions, physiological stimulation of aldosterone was blunted with older age (β=−4.6 ng/dL per 10 years, P &lt;0.0001). Conclusions: Aging is associated with a pattern of decreased normal zona glomerulosa CYP11B2 expression and increased aldosterone-producing cell cluster expression. This histopathologic finding parallels an age-related autonomous aldosteronism and abnormal aldosterone physiology that provides 1 potential explanation for age-related cardiovascular risk.
Management of locally advanced non-small cell lung cancer (NSCLC) at a community hospital: A retrospective analysis.
Authors: Laura Jane Spranklin, Jon Willis Heflin, Alejandro R. Calvo
Journal: Journal of Clinical Oncology (2012)

e17506 Background: The optimal management of stage IIIA NSCLC has not been clearly defined. Much of this controversy is due to the heterogenity of this group. The current standard for unresectable stage IIIA disease is concurrent chemoradiotherapy. In patients with resectable stage IIIA disease however, neoadjuvant treatment followed by surgery provides better outcomes but not a significant survival benefit. Our study analyzed the management of stage IIIA NSCLC patients diagnosed at Kettering Health Network (KHN) and the observed 5-year survival as compared to the current NCCN guidelines and national 5-year relative and observed survival using the SEER database and National Cancer Database statistics. Methods: This retrospective study included all patients treated at KHN for Stage IIIA NSCLC from January 2004 to December 2009. 117 cases were analyzed, 53% female and 47% male. 42% were squamous cell, 28% adenocarcinoma, and the final 30% accounting for the remaining histology. 20 patients were not candidates for therapy due to poor performance status or comorbidity. 37 of the 97 patients under active treatment underwent resection at some point during treatment and 60 patients were deemed unresectable. Results: 68% of individuals with unresectable NSCLC received definitive concurrent chemoradiation, 32% received chemotherapy alone. In regards to resectable stage IIIA, 25% were treated with neoadjuvant therapy. 54% received postoperative therapy. 21% were treated with surgery alone due to multiple factors. The observed 5-year survival was 12.2% as compared to 10% nationally. The SEER data 5-year relative survival from 2001 to 2007 for stage IIIA NSCLC is 14%. Conclusions: In this heterogenous group of patients, treatment provided at KHN was individualized and followed national trends. The majority of unresectable stage IIIA NSCLC patients at KHN received the standard approach of concurrent chemoradiation. In terms of resectable stage IIIA NSCLC, approximately 25% were treated with either neoadjuvant chemotherapy or chemoradiotherapy. Overall, the 5-year survival rate for stage IIIA NSCLC at KHN is comparable to other community hospitals however slightly lower than the national average.
Frequent personalised emails match effective medicine for smoking cessation, study finds
Authors: Susan Mayor
Journal: BMJ (2017)

Sending smokers frequent personalised emails providing tips on quitting, motivational messages, and social support achieves similar cessation rates to the most effective medicines, a study has found.1

Telephone counselling has been shown to be effective in helping people to stop smoking, but it can reach only a limited number of patients. Text messaging on mobile phones can also help smokers to quit, but the information and support it can provide is also limited.

The study …
Too soon to assess effects of deemed consent to organ donation in Wales
Authors: John Fabre
Journal: BMJ (2017)

The first full accounting year for deemed consent in Wales was completed last month, and we await with interest the statistics from NHS Blood and Transplant. Margaret McCartney reminds us that it is too early to make claims for or against the deemed consent system in Wales.1 Because Wales has a comparatively small population, any valid assessment will take …
PDTM-21. LARGE SCALE TUMOR MUTATIONAL BURDEN ANALYSIS OF PEDIATRIC TUMORS PROVIDES A DIAGNOSTIC TOOL FOR GERMLINE PREDISPOSITION AND REVEALS NOVEL CANDIDATES FOR IMMUNE CHECKPOINT INHIBITION
Authors: Brittany B Campbell, Paola Angelini, Nicholas Light, Eric Bouffet, Valerie Larouche, David Samuel, Duncan Stearns, Kristina A Cole, Enrico Opocher, Magnus Sabel, Ben George, David Ziegler, Normand Laperriere, Stephen Meyn, David Malkin, Adam Shlien, Uri Tabori
Journal: Neuro-Oncology (2017)

A significant amount of childhood brain tumors emerge from cancer predisposition syndromes. Although tumor sequencing is common practice, it is currently impossible to infer germline mutations from tumor data. Glioblastoma Multiforme arising in children with Biallelic Mismatch Repair Deficiency Syndrome (bMMRD) are ultrahypermutant which is highly specific to this syndrome and confers eligibility for immune checkpoint inhibition therapy (ICI). Our objective was to quantify the frequency of hypermutant tumors in children, determine whether mutational signatures can predict germline mutations, and treat hypermutant tumors with ICIs. Deep panel sequencing (1000x) of 315 genes in 2984 pediatric tumors (585 brain tumors) and 79 842 adult tumors (3910 brain tumors) was performed. An algorithm was devised to determine mutation burden from 2 MB of panel sequencing data and results correlated strongly with mutation burden from exome sequencing (R2 = 0.94). Mutational signatures were analyzed to predict source of hypermutation. Thirteen patients with hypermutant brain tumors identified by panel sequencing were enrolled on an ICI trial. Hypermutant tumors (>10 mut/MB) comprised 5% of all pediatric tumors (n=143). These were highly enriched for replication repair mutations (p<0.0001) and mutation loads correlated with hypermutant adult tumors that have shown demonstrable clinical response to ICI. Hypermutation was found in 5% of childhood and 6% of adult glioblastoma. All cases of GBM greater than 100 Mut/MB harbored MMR/polymerase mutations suggesting germline bMMRD (p =10-7). Clinical data collected on 15 ultrahypermutant tumors revealed germline mutations in replication repair genes in all patients. Of the 22 patients with hypermutant cancers treated with ICI, 16 had brain tumors, and favorable sustained responses are observed. High mutation burden is a sensitive predictor of germline bMMRD. Hypermutant tumors are more common in the pediatric setting than previously appreciated, opening novel therapeutic avenues. ICI shows promise for hypermutant pediatric cancers.
Higher head accelerations observed in female athletes than in male athletes across age
Authors: Jaclyn B Caccese, Thomas A Buckley, Ryan T Tierney, William C Rose, Kristy B Arbogast, Joseph J Glutting, Thomas W Kaminski
Journal: British Journal of Sports Medicine (2017)

Objective To compare linear and rotational acceleration across age and gender in controlled purposeful soccer heading. Design Prospective study. Setting Biomechanics laboratory. Participants One-hundred soccer players (42 male, 58 female, 17.1±3.5 years, 168.5±20.3 cm, 61.5±13.7 kg) classified as collegiate, high school (HS), or youth (12–14 years) male (MS) or female (FS) soccer players. Exclusionary criteria history of neurologic disorder, cervical spine injury, or head injury in the past 6 months. Interventions We implemented a unique soccer heading paradigm that allows for precise control of head impact magnitude, direction, and frequency to model repetitive head impacts in sport. This model consists of controlled soccer heading (12 headers at 11.2 m/s from a JUGS machine) while measuring linear and rotational accelerations using a triaxial accelerometer and gyroscope affixed to the back of the head. Linear accelerations were transformed to the head center-of-gravity using 3D motion capture data and standard rigid body dynamics equations. Outcome measures Linear and rotational accelerations at the head center-of-gravity. Main results [Average±Standard Deviation (95% Confidence Interval)] Collegiate [42.4±11.5 g (36.8–47.9); 3.35±0.87 krad/s 2 (2.9–3.8)], HS [38.5±13.1 g (32.2–44.8); 3.16±1.01 krad/s 2 (2.7–3.7)], and youth [40.5±14.9 g(33.1–47.9); 3.20±1.24 krad/s 2 (2.6–3.8)] FS produced higher linear and rotational accelerations than both the collegiate [26.1±9.5 g(21.7–30.6); 2.13±1.07 krad/s 2 (1.6–2.6)] (linear: p&lt;0.001, p?= 0.012, p=0.002; rotational: p=0.002, p=0.015, p=0.011, respectively) and HS [26.7±5.9 g(23.2–30.1); 2.18±0.40 krad/s 2 (2.0–2.4)] (linear: p=0.002, p=0.045, p?= 0.012; rotational: p=0.011, p=0.052, p=0.040, respectively) MS. Conclusions Collegiate and HS FS have higher head accelerations than their male counterparts, but at the youth level, there are no differences across gender. These data suggest that FS may be exposed to greater cumulative head accelerations from repeated heading of a soccer ball over a career than MS. Competing interests None.
Development of prodrugs for combination chemotherapy
Authors: Khalid Abu Ajaj, Ralph Graeser, Christoph Schaechtele, Felix Kratz
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

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Macromolecular prodrugs are being intensively studied, preclinically as well as clinically. Modern drug antibody conjugates primarily use highly potent drugs such as calicheamicins, maytanosinoids or auristatins, whereas drug conjugates with synthetic polymers or serum proteins use clinically established agents. To date, macromolecular prodrugs that incorporate two anticancer agents and can be released enzymatically as well as pH-dependently have not been described. In this work, we set out to develop a bifunctional maleimide spacer that would allow derivatization with the first drug bound through an enzymatically cleavable linker, the second through an acid-sensitive hydrazone bond.    Starting with 6-maleimidocaproic acid and α- tert -butylester glutamic acid, a bifunctional linker was prepared in an eight-step synthesis that incorporates a protein-binding maleimide group, a methyltrityl (MTT) protected hydrazide moiety as well as an activated Phe-Lys(MTT)-PABOH moiety (PABOH = para -aminobenzyl alcohol). This linker represents a versatile building block that can be derivatized with a spectrum of anticancer drugs. Phe-Lys is a substrate for cathepsin B, a cysteine protease that is over-expressed in solid tumors. As a first example, we bound paclitaxel and doxorubicin to this bifunctional linker enabling the enzymatic cleavage of paclitaxel and the acid-sensitive release of doxorubicin.    For preparing a macromolecular drug conjugate, the novel prodrug was bound through the maleimide moiety to the cysteine-34 position of human serum albumin. In its albumin-bound form, the doxorubicin-paclitaxel prodrug showed a IC50 value of ~11 nM, compared to 64 nM for doxorubicin, ~6 nM for paclitaxel and ~0.5 nM for a 1:1 mixture of doxorubicin and paclitaxel, when tested in a 72 h cytotoxicity assay against HT29 colon tumor cells. The cytotoxic potential of the combined prodrug forms a good basis for evaluating its antitumor efficacy in vivo .
Targeting GPNMB with glembatumumab vedotin: Current developments and future opportunities for the treatment of cancer
Authors: April A.N. Rose, Marco Biondini, Rafael Curiel, Peter M. Siegel
Journal: Pharmacology & Therapeutics (2017)

GPNMB has emerged as an immunomodulator and an important positive mediator of tumor progression and metastasis in numerous solid cancers. Tumor intrinsic GPNMB-mediated effects on cellular signaling, coupled with the ability of GPNMB to influence the primary tumor and metastatic microenvironments in a non-cell autonomous fashion, combine to augment malignant cancer phenotypes. In addition, GPNMB is often overexpressed in a variety of cancers, making it an attractive therapeutic target. In this regard, glembatumumab vedotin, an antibody-drug conjugate (ADC) that targets GPNMB, is currently in clinical trials as a single agent in multiple cancers. In this review, we will describe the physiological functions of GPNMB in normal tissues and summarize the processes through which GPNMB augments tumor growth and metastasis. We will review the pre-clinical and clinical development of glembatumumab vedotin, evaluate on-going clinical trials, explore emerging opportunities for this agent in new disease indications and discuss exciting possibilities for this ADC in the context of combination therapies.
Response by Jolly et al to Letters Regarding Article, “Thrombus Aspiration in ST-Segment-Elevation Myocardial Infarction: An Individual Patient Meta-Analysis: Thrombectomy Trialists Collaboration”
Authors: Sanjit S. Jolly, Stefan James, Vladimír Džavík, John A. Cairns, Ole Frøbert
Journal: Circulation (2017)
Fluorescence in Situ Hybridization (FISH) abnormalities and Baseline Clinical Features at Diagnosis in African American Multiple Myeloma Patients
Authors: Megan H Jagosky, Kyle L Madden, Blake B Goodbar, Virginia Thurston, Manisha Bhutani, Preeya Patel, Myra M Robinson, Rupali Bose, Jill Eddy, Candice G Roth, Lynn S Sanders, James T Symanowski, Tammy D Cogdill, Belinda R. Avalos, Edward A. Copelan, Saad Z Usmani
Journal: Blood (2016)
IL233, A Novel IL-2 and IL-33 Hybrid Cytokine, Ameliorates Renal Injury
Authors: Marta E. Stremska, Sheethal Jose, Vikram Sabapathy, Liping Huang, Amandeep Bajwa, Gilbert R. Kinsey, Poonam R. Sharma, Saleh Mohammad, Diane L. Rosin, Mark D. Okusa, Rahul Sharma
Journal: Journal of the American Society of Nephrology (2017)

CD4+Foxp3+ regulatory T cells (Tregs) protect the kidney during AKI. We previously found that IL-2, which is critical for Treg homeostasis, upregulates the IL-33 receptor (ST2) on CD4+ T cells, thus we hypothesized that IL-2 and IL-33 cooperate to enhance Treg function. We found that a major subset of Tregs in mice express ST2, and coinjection of IL-2 and IL-33 increased the number of Tregs in lymphoid organs and protected mice from ischemia-reperfusion injury (IRI) more efficiently than either cytokine alone. Accordingly, we generated a novel hybrid cytokine (IL233) bearing the activities of IL-2 and IL-33 for efficient targeting to Tregs. IL233 treatment increased the number of Tregs in blood and spleen and prevented IRI more efficiently than a mixture of IL-2 and IL-33. Injection of IL233 also increased the numbers of Tregs in renal compartments. Moreover, IL233-treated mice had fewer splenic Tregs and more Tregs in kidneys after IRI. In vitro, splenic Tregs from IL233-treated mice suppressed CD4+ T cell proliferation better than Tregs from saline-treated controls. IL233 treatment also improved the ability of isolated Tregs to inhibit IRI in adoptive transfer experiments and protected mice from cisplatin- and doxorubicin-induced nephrotoxic injury. Finally, treatment with IL233 increased the proportion of ST2-bearing innate lymphoid cells (ILC2) in blood and kidneys, and adoptive transfer of ILC2 also protected mice from IRI. Thus, the novel IL233 hybrid cytokine, which utilizes the cooperation of IL-2 and IL-33 to enhance Treg- and ILC2-mediated protection from AKI, bears strong therapeutic potential.