tbuckley/cabot-search huggingface dataset:
Expression of the epidermal growth factor receptor (EGFR) pathway in cervical cancer (CC) patients (pts)
Authors: S. Movva, H. Arias-Pulido, A. Chavez, N. Joste, L. Lomo, S. J. Lee, C. F. Verschraegen
Journal: Journal of Clinical Oncology (2009)

5519 Background: EGFR, a membrane tyrosine kinase receptor that regulates multiple functions such as cell growth, differentiation, gene expression and development through at least 3 pathways, is overexpressed in a wide variety of solid tumors, including CC. The downstream activation of the EGFR pathways has not been studied extensively. The aim of this study is to assess the correlation between EGFR-HER-2-HER-3-HER-4 status, downstream pathways (STAT 3, survivin, RAS) with pt characteristics, overall survival and recurrence free survival in pts diagnosed with invasive CC. Methods: Receptor expressions were assessed by immunohistochemistry on 80 pts from our clinic. Tumors were scored by percentage of cells stained multiplied by intensity for a score range of 0–300 by two pathologists. Median EGFR score was 140. Pts were categorized as low expressor (EGFR score lower than 140) or as high expressor (EGFR score greater than 140). Differences in receptor expression were compared using the Log-rank test for overall (OS) and recurrence-free survivals (RFS) and by Chi-square analyses for the clinical parameters (age, stage, histology, and grade). Results: A total of 80 pts data was analyzed. Mean age of the sample was 48 years. 23% of pts had well differentiated tumors. 80% had squamous histology. 39% had stage IIB or higher. 25% died of cancer. By Log-rank test, standard prognostic factors (age, stage, grade, and histology) showed the expected differences in survival, confirming the validity of the sample. However there were no correlations between the clinical parameters, OS, or RFS with EGFR expression. Data on HER-2–3-4, STAT3, survivin and RAS will be presented at the meeting. Conclusions: Although no correlation has been found between clinical outcome and EGFR expression, EGFR inhibitors of the extracellular domain are expected to be useful for the treatment of CC that overexpress this receptor. These results will serve as baseline data needed to test cetuximab and other EGFR inhibitors in pts with CC. No significant financial relationships to disclose.
Antisense oligonucleotides increase <i>Scn1a</i> expression and reduce seizures and SUDEP incidence in a mouse model of Dravet syndrome
Authors: Zhou Han, Chunling Chen, Anne Christiansen, Sophina Ji, Qian Lin, Charles Anumonwo, Chante Liu, Steven C. Leiser, None Meena, Isabel Aznarez, Gene Liau, Lori L. Isom
Journal: Science Translational Medicine (2020)

Antisense oligonucleotide administration reduces seizures and SUDEP incidence in a mouse model of Dravet syndrome.
Value of stable disease (SD) in drug development of targeted therapies (TGT)
Authors: T. Vidaurre, J. Wilkerson, S. E. Bates, R. Simon, A. T. Fojo
Journal: Journal of Clinical Oncology (2009)

2509 It has been widely asserted that the efficacy of TGT cannot be assessed by traditional response measures since they are not expected to cause tumor shrinkage. Despite the lack of substantiating data, this idea has become conventional wisdom, often guiding clinical trial design. Aware the acceptance of SD as a measure of activity led to its being increasingly reported with traditional cytotoxic agents (CTX), we set about to methodically compare the occurrence of SD in phase II trials of TGT and CTX. We systematically catalogued response assessments in 147 phase II studies reported between 10/06 and 3/08 in 5 journals (Cancer, BJC, CCR, JCO, and Lancet Oncology). Eighty used CTX, 59 used TGT and 8 used both “classes” of agents. Thirty-eight properties including CR, PR, SD, PFS, and OS were recorded for each study. CTX and TGT studies were comparable with similar distribution of histologies and similar PFS and OS in these patients with refractory tumors. For CTX vs. TGT, the median numbers of pts/study was 47.1 vs. 51.9; median PFS, 5.55 vs. 4.54 mos; and median OS, 12.55 vs. 12.88 mos. SD was defined by duration in only 31% of studies, a median duration of 9.5 weeks. SD rates were nearly identical for the two therapy groups - 34.6% for CTX and 33.1% for TGT- and their distribution by histology was similar, suggesting properties other than therapy are responsible for SD. Correlations or lack thereof between %SD and PFS or OS were similar for both CTX and TGT. The overall response rate (CR + PR) was higher with CTX than with TGT (29.4% vs. 13.3%) and demonstrated a strong correlation (p&lt;0.0001) of uncertain importance with PFS and OS for all therapies. Examination of 33 NSCLC studies (16 CTX/17 TGT) found similar results. We conclude that SD as currently defined and measured in not a property of TGT but of the phase II patient population and is similarly found with CTX. Responses are observed with TGT as with CTX, and this analysis suggests that even for TGT it is a measure of activity that should be sought. Assertions that SD is a particular characteristic of TGT should be replaced by definitions that seek clinically meaningful SD. No significant financial relationships to disclose.
Evaluation of erlotinib treatment after gefitinib failure in Japanese recurrent non-small cell lung cancer patients
Authors: A. Hata, S. Nanjo, R. Kaji, S. Hujita, N. Katakami, T. Nishimura, K. Ishihara, H. Yoshioka, H. Hayashi, T. Ishida
Journal: Journal of Clinical Oncology (2009)

e19008 Background: Both gefitinib (G) and erlotinib (E) belong to the family of epidermal growth factor receptor-tyrosine kinase inhibitors that has shown positive results in the treatment of advanced/recurrent non-small-cell lung cancer (NSCLC). Recent studies suggested a distinction in efficacy between G and E. In fact, there is a subgroup of patients who had clinically meaningful benefit with E therapy after G failure, but little is known about the factors that predict disease control or the risk factors that develop toxicity in these patients. Our aim is to evaluate the efficacy and toxicity of E after G failure in the largest scale study to date. Methods: We retrospectively evaluated the efficacy and toxicity of E therapy and analyzed factors that contributed to disease control in patients had experienced G failure. EGFR mutational analysis was performed in evaluable cases. Results: From January 2008 to December 2008, seventy-seven patients were treated with E after G failure in our institutions. Of these 77 patients, 11 had a partial response (PR) and 21 had a stable disease (SD), resulting in a best response rate of 14% and a disease control rate (DCR) of 42%. Thirty of 56 (54%) patients who had benefited from prior G therapy achieved disease control, while only 2 of 20 (10%) patients who had experienced initial progressive disease to G therapy obtained SD (P&lt;0.001) . Twenty-seven of 48 (56%) patients with performance status (PS) 0/1 achieved disease control, but a DCR of PS 2/3/4 patients was only 17% (5 of 29) (P&lt;0.001). EGFR mutation status, smoking history, and gender had little relationship to disease control. In 4 of 11 patients who achieved PR, E was effective for brain metastases. The most common side effects of E therapy were skin rash and diarrhea, as described in previous studies. Notably in approximately 30% of poor PS patients, grade 3 to 4 non-hematological toxicity including severe general malaise and anorexia was observed. Conclusions: E may be effective as a salvage therapy for some Japanese NSCLC patients after G failure, especially in those who had benefited from prior G treatment and/or those who maintain a good PS. Interestingly, E was effective for brain metastases of some patients after G failure. No significant financial relationships to disclose.
Evaluation of the Edmonton Symptoms Assesment Scale (ESAS) symptoms improvement (SI) assessment as a prognostic factor for survival in advanced cancer patients (pts) undergoing palliative care (PC): An observational prospective study
Authors: T. Gamucci, F. Narducci, I. Sperduti, L. Mentuccia, T. Trapasso, E. Magnolfi, R. Grande, G. Cianci, D. Gemma, G. Trombetta
Journal: Journal of Clinical Oncology (2009)

9591 Background: ESAS is a validated tool for physical symptoms assessment in PC practice which evaluates symptoms through a numeric scale ( 0–10). The use of SI as a prognostic factor is controversial. To this purpose, an observational prospective study in advanced cancer pts previously treated with anti-cancer treatments and now undergoing only PC was conducted. Methods: Pts were considered eligible if no longer able to receive any anticancer treatment; they were scheduled to undergo ESAS assessment: 1) at the hospitalization time-point (TH); 2) at the hospital discharge time-point (TD). Symptoms’ scores were divided into 3 severity-classes (SC): mild (0–3, MI), moderate (4–6, MO) and severe (≥7, S). Differences across symptoms’ classes between TH and TD was analyzed with the paired-data McNemar-test, according to tumor types. KM method was used for survival calculation, according to ESAS score classes, and logrank test for curves comparison. Uni/multi-variate survival analysis including age, sex, tumour, symptoms number and score class, PaP (Palliative Prognostic)-score, KPS, were carried out using the Cox regression model. Results: ESAS was administered to 68 pts, gastrointesinal (GI)/lung (NSCLC): 39/29, median age: 69-yrs, KPS ≤50/&gt;50: 27 (39.7 %)/ 41 (60.3%), PaP-score A/B/C: 26 (38.2%)/37 (54.4%)/C (7.4%). A statistically significant reduction of S-SC rates was observed, as shown in the Table . SI correlates with survival improvement: PaP score (HR 2.95, 95% CI 1.35–6.41, p=0.006) and anorexia (HR 3.21, 95% CI 1.33–7.72, p=0.009) appear to be prognostic factors for survival at the multivariate analaysis for GI pts; asthenia is the only significant variable (HR 5.11 CI 95% 1.86–14.03, p=.0.002) for NSCLC pts. Conclusions: SI according to ESAS after PC treatment represents an important prognostic factor for survival in pts no longer suitable to receive any anticancer active therapies. [Table: see text] No significant financial relationships to disclose.
The reimagination of school-based physical activity research in the COVID-19 era
Authors: Deirdre M. Harrington, Michelle O’Reilly
Journal: PLoS Medicine (2020)

Deirdre Harrington and Michelle O'Reilly discuss the article "Effectiveness and cost-effectiveness of the GoActive intervention to increase physical activity among UK adolescents: A cluster randomised controlled trial" by Kirsten Corder and colleagues.
The XPO1 Inhibitor KPT-8602 Synergizes with Dexamethasone in Acute Lymphoblastic Leukemia
Authors: Delphine Verbeke, Sofie Demeyer, Cristina Prieto, Charles E. de Bock, Jolien De Bie, Olga Gielen, Kris Jacobs, Nicole Mentens, Bronte Manouk Verhoeven, Anne Uyttebroeck, Nancy Boeckx, Kim De Keersmaecker, Johan Maertens, Heidi Segers, Jan Cools
Journal: Clinical Cancer Research (2020)

Abstract Purpose: KPT-8602 (Eltanexor) is a second-generation exportin-1 (XPO1) inhibitor with potent activity against acute lymphoblastic leukemia (ALL) in preclinical models and with minimal effects on normal cells. In this study, we evaluated whether KPT-8602 would synergize with dexamethasone, vincristine, or doxorubicin, three drugs currently used for the treatment of ALL. Experimental Design: First, we searched for the most synergistic combination of KPT-8602 with dexamethasone, vincristine, or doxorubicin in vitro in both B-ALL and T-ALL cell lines using proliferation and apoptosis as a readout. Next, we validated this synergistic effect by treatment of clinically relevant B- and T-ALL patient-derived xenograft models in vivo. Finally, we performed RNA-sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) to determine the mechanism of synergy. Results: KPT-8602 showed strong synergism with dexamethasone on human B-ALL and T-ALL cell lines as well as in vivo in three patient-derived ALL xenografts. Compared with single-drug treatment, the drug combination caused increased apoptosis and led to histone depletion. Mechanistically, integration of ChIP-seq and RNA-seq data revealed that addition of KPT-8602 to dexamethasone enhanced the activity of the glucocorticoid receptor (NR3C1) and led to increased inhibition of E2F-mediated transcription. We observed strong inhibition of E2F target genes related to cell cycle, DNA replication, and transcriptional regulation. Conclusions: Our preclinical study demonstrates that KPT-8602 enhances the effects of dexamethasone to inhibit B-ALL and T-ALL cells via NR3C1- and E2F-mediated transcriptional complexes, allowing to achieve increased dexamethasone effects for patients.
Distinguishing Wants vs Preferences for End-of-Life Care: Can You Tell Me What You Want, What You Really, Really Want?
Authors: Davene R. Wright
Journal: JAMA Network Open (2020)

Gwen M. Bernacki, MD, MHSA; Ruth A. Engelberg, PhD; J. Randall Curtis, MD, MPH; Manjula Kurella Tamura, MD; Lyndia C. Brumback, PhD; Danielle C. Lavallee, PharmD, PhD; Elizabeth K. Vig, MD, MPH; Ann M. O’Hare, MD, MA
Generated SecPen_NY-ESO-1_ubiquitin-pulsed dendritic cell cancer vaccine elicits stronger and specific T cell immune responses
Authors: Yunkai Yang, Xiaohan Guo, Bo Hu, Peng He, Xiaowu Jiang, Zuohuan Wang, Huaxing Zhu, Lina Hu, Minghua Yu, Meiqing Feng
Journal: Acta Pharmaceutica Sinica B (2020)

Dendritic cell-based cancer vaccines (DC vaccines) have been proved efficient and safe in immunotherapy of various cancers, including melanoma, ovarian and prostate cancer. However, the clinical responses were not always satisfied. Here we proposed a novel strategy to prepare DC vaccines. In the present study, a fusion protein SNU containing a secretin-penetratin (SecPen) peptide, NY-ESO-1 and ubiquitin was designed and expressed. To establish the DC vaccine (DC-SNU), the mouse bone marrow-derived DCs (BMDCs) were isolated, pulsed with SNU and maturated with cytokine cocktail. Then peripheral blood mononuclear cells (PBMCs) from C57BL/6 mice inoculated intraperitoneally with DC-SNU were separated and cocultured with MC38/MC38NY-ESO-1 tumor cells or DC vaccines. The results show that SNU was successfully expressed. This strategy made NY-ESO-1 entering cytoplasm of BMDCs more efficiently and degraded mainly by proteasome. As we expected, mature BMDCs expressed higher CD40, CD80 and CD86 than immature BMDCs. Thus, the PBMCs released more IFN-γ and TNF-α when stimulated with DC-SNU in vitro again. What's more, the PBMCs induced stronger and specific cytotoxicity towards MC38NY-ESO-1 tumor cells. Given the above, it demonstrated that DC-SNU loaded with SecPen and ubiquitin-fused NY-ESO-1 could elicit stronger and specific T cell immune responses. This strategy can be used as a platform for DC vaccine preparation and applied to various cancers treatment.
Nine typical injury patterns in German professional male football (soccer): a systematic visual video analysis of 345 match injuries
Authors: Christian Klein, Patrick Luig, Thomas Henke, Hendrik Bloch, Petra Platen
Journal: British Journal of Sports Medicine (2020)

Aim We aimed to systematically analyse the videos of acute injuries in professional men’s football and describe typical injury patterns. Methods Injuries were registered with the German statutory accident insurance for professional athletes as part of occupational accident reporting. Following each season (2014–2017), video footage of the two highest divisions in German male football was searched for moderate and severe acute match injuries. Two raters then independently assessed the injuries for: game situation, player and opponent behaviour, referee decision, and injury mechanisms. Results The total data set included 7493 acute injuries. Of these, 857 (11%) were moderate or severe match injuries. The video search yielded 345 (40%) clearly identifiable injuries and of those 170 (49%) were contact injuries. We describe nine typical injury patterns: one each for head and shoulder injuries, two for thigh and ankle, and three for knee injuries. The nine patterns are called: (1) Head-to-head injury. (2) Collision-and-fall shoulder injury. (3) Sprinter’s thigh injury. (4) Perturbation-and-strain thigh injury. (5) Tackle knee injury. (6) Tackle-and-twist knee injury. (7) Non-contact knee injury. (8) Attacked ankle injury. (9) Collision-and-twist ankle injury. Thigh injuries occurred primarily in non-contact situations (44/81), mostly while the player was sprinting (23/44). Knee injuries were often caused by direct external impact (49/84)—mainly suffered by the tackler during a tackle (17/49). Conclusion The nine common injury patterns in football differed substantially in their mechanisms and causes.
Sixty seconds on . . . management consultants
Authors: Gareth Iacobucci
Journal: BMJ (2020)

They’ve only gone and snared themselves another huge contract from the UK government.

It emerged this week that McKinsey & Co was paid a whopping £563 400 (€627 000; $740 900) for six weeks’ work to decide the “vision, purpose, and narrative” of England’s new public health body, the National Institute for Health Protection.1

Indeed. And the …
Patients Recovered From COVID-19 Show Ongoing Subclinical Myocarditis as Revealed by Cardiac Magnetic Resonance Imaging
Authors: Ming-Yen Ng, Vanessa M. Ferreira, Siu Ting Leung, Jonan Chun Yin Lee, Ambrose Ho-Tung Fong, Raymond Wai To Liu, Johnny Wai Man Chan, Alan Ka Lun Wu, Kwok-Cheung Lung, Andrew M. Crean, Ivan Fan-Ngai Hung, Chung-Wah Siu
Journal: JACC. Cardiovascular imaging (2020)
<i>Notes from the Field: Candida auris</i> and Carbapenemase-Producing Organism Prevalence in a Pediatric Hospital Providing Long-Term Transitional Care — Chicago, Illinois, 2019
Authors: Tristan D. McPherson, Kelly A. Walblay, Elissa Roop, David Soglin, Ann Valley, Latania K. Logan, Snigdha Vallabhaneni, Stephanie R. Black, Massimo Pacilli
Journal: MMWR Morbidity and Mortality Weekly Report (2020)
Lung innervation in the eye of a cytokine storm: neuroimmune interactions and COVID-19
Authors: Francesco De Virgiliis, Simone Di Giovanni
Journal: Nature Reviews Neurology (2020)

COVID-19 is an infectious disease caused by the coronavirus SARS-CoV-2, which was first reported in Wuhan, China, in December 2019 and has caused a global pandemic. Acute respiratory distress syndrome (ARDS) is a common feature of severe forms of COVID-19 and can lead to respiratory failure, especially in older individuals. The increasing recognition of the neurotropic potential of SARS-CoV-2 has sparked interest in the role of the nervous system in respiratory failure in people with COVID-19. However, the neuroimmune interactions in the lung in the context of ARDS are poorly understood. In this Perspectives article, we propose the concept of the neuroimmune unit as a critical determinant of lung function in the context of COVID-19, inflammatory conditions and ageing, focusing particularly on the involvement of the vagus nerve. We discuss approaches such as neurostimulation and pharmacological neuromodulation to reduce tissue inflammation with the aim of preventing respiratory failure. Acute respiratory distress syndrome is a common occurrence in COVID-19, an infectious disease caused by the coronavirus SARS-CoV-2. In this article, the authors consider how lung innervation might crosstalk with the immune system to modulate lung function and influence outcomes in COVID-19.
Effect of collaborative care between traditional and faith healers and primary health-care workers on psychosis outcomes in Nigeria and Ghana (COSIMPO): a cluster randomised controlled trial
Authors: Oye Gureje, John Appiah-Poku, Toyin Bello, Lola Kola, Ricardo Araya, Dan Chisholm, Oluyomi Esan, Benjamin Harris, Victor Makanjuola, Caleb Othieno, LeShawndra Price, Soraya Seedat
Journal: The Lancet (2020)
Perioperative oral eltrombopag versus intravenous immunoglobulin in patients with immune thrombocytopenia: a non-inferiority, multicentre, randomised trial
Authors: Donald M Arnold, Nancy M Heddle, Richard J Cook, Cyrus Hsia, Mark Blostein, Erin Jamula, Michelle Sholzberg, Yulia Lin, Jeannine Kassis, Loree Larratt, Alan Tinmouth, Sufia Amini, Martin Schipperus, Wendy Lim, Prakash Vishnu, Margaret Warner, Julie Carruthers, Na Li, Shannon Lane, John G Kelton
Journal: The Lancet Haematology (2020)
A phase I study of flavopiridol using an alternative schedule in patients (pts) with advanced solid tumors
Authors: B. Ramaswamy, M. Phelps, R. Baiocchi, T. Bekaii-Saab, D. Wilkins, D. Arbogast, A. Campbell, A. L. Doyle, M. Grever, M. Shah
Journal: Journal of Clinical Oncology (2009)

2580 Background: A phase I study of flavopiridol, a cyclin-dependent kinase inhibitor, using an alternative schedule was conducted in pts with solid tumors given its promising activity in pts with chronic lymphocytic leukemia (CLL). Methods: Using standard 3x3 ph I dose escalation design, NCI-sponsored trial was performed to determine the safety and dose-limiting toxicity (DLT) of flavopiridol given as a 30-min IV loading dose followed by a 4-hr infusion weekly for 4 wks repeated every 6 wks. DLT was defined as Gr 4 hematologic toxicity (HT) for &gt; 7 days, &gt; Gr 3 non-HT except Gr 3 fatigue or diarrhea resolving &lt;4 days and cytokine release syndrome (CRS) &gt; Gr 3 despite steroids. Blood samples were obtained at pre-dose and 0.5, 1, 3, 4.5, 6, 8, 24, and 48-hr after start of first bolus dose for pharmacokinetics (PK). Results: 26 pts with advanced solid tumors with a median age of 63 (44–75) yrs were enrolled. Median no. of doses was 7.5 (1–24). Table 1 outlines the PK parameters, DLTs and CRS. Due to a grade 5 CRS/death in cohort 3, the protocol was amended to include 20 mg IV dexamethasone prior to flavopiridol to prevent CRS (cohorts 2B, 1B). Of the 20 evaluable pts, 35% had stable- and 65% had progressive-disease. Results of serum cytokines (IL-2, IL-4, IL-6, TNF-a, IFN-g, IL-10) levels will be presented. Conclusions: There was a higher frequency of CRS, despite prophylactic steroids seen our pts with solid tumors compared to previous studies with CLL and this correlated with AUC. PK and toxicity profile in our pt population differs from pts with hematologic malignancies administered flavopiridol on the same schedule. Protein binding and serum albumin levels are under evaluation as potential contributors. This work is supported by NCI U01-CA76576. [Table: see text] [Table: see text]