tbuckley/cabot-search huggingface dataset:
A Biomarker-enriched, Randomized Phase II Trial of Adavosertib (AZD1775) Plus Paclitaxel and Carboplatin for Women with Platinum-sensitive <i>TP53</i>-mutant Ovarian Cancer
Authors: Amit M. Oza, Maria Estevez-Diz, Eva-Maria Grischke, Marcia Hall, Frederik Marmé, Diane Provencher, Denise Uyar, Johanne I. Weberpals, Robert M. Wenham, Naomi Laing, Michael Tracy, Tomoko Freshwater, Mark A. Lee, Ji Liu, Jingjun Qiu, Shelonitda Rose, Eric H. Rubin, Kathleen Moore
Journal: Clinical Cancer Research (2020)

Preclinical studies show that adavosertib, a WEE1 kinase inhibitor, sensitizes TP53-mutant cells to chemotherapy. We hypothesized that adavosertib, plus chemotherapy, would enhance efficacy versus placebo in TP53-mutated ovarian cancer.Following safety run-in, this double-blind phase II trial (NCT01357161) randomized women with TP53-mutated, platinum-sensitive ovarian cancer to oral adavosertib (225 mg twice daily for 2.5 days/21-day cycle) or placebo, plus carboplatin (AUC5) and paclitaxel (175 mg/m2), until disease progression or for six cycles. The primary endpoints were progression-free survival (PFS) by enhanced RECIST v1.1 [ePFS (volumetric)] and safety. Secondary/exploratory objectives included PFS by RECIST v1.1 (single dimension), objective response rate, overall survival, and analysis of tumor gene profile versus sensitivity to adavosertib.A total of 121 patients were randomized to adavosertib (A+C; n = 59) and placebo (P+C; n = 62) plus chemotherapy. Adding adavosertib to chemotherapy improved ePFS [median, 7.9 (95% confidence interval (CI), 6.9-9.9) vs. 7.3 months (5.6-8.2); HR 0.63 (95% CI, 0.38-1.06); two-sided P = 0.080], meeting the predefined significance threshold (P < 0.2). Clinical benefit was observed following A+C for patients with different TP53 mutation subtypes, identifying possible response biomarkers. An increase in adverse events was seen with A+C versus P+C: greatest for diarrhea (adavosertib 75%; placebo 37%), vomiting (63%; 27%), anemia (53%; 32%), and all grade ≥3 adverse events (78%; 65%).Establishing an optimal strategy for managing tolerability and identifying specific patient populations most likely to benefit from treatment may increase clinical benefit. Future studies should consider additional adavosertib doses within the chemotherapy treatment cycle and the potential for maintenance therapy.
Plk1 - A novel therapeutic target for nasopharyngeal carcinoma
Authors: Wei Shi, Carlo Bastianutto, Nehad Alajez, Angela Hui, Fei-Fei Liu
Journal: Cancer Research (2007)

5390  Introduction   Polo-like kinase 1 (PLK1) is a critical regulator of the many stages of mitosis. Accumulating evidence indicates that over-expression of Plk1 correlates with clinical outcome. In this work, we evaluate for the first time, the expression of Plk1 in primary human nasopharyngeal carcinoma (NPC) biopsies, and demonstrate its potential role as a therapeutic target.  Experimental Procedures  Plk1 expression was assessed using immunohistochemistry in 40 NPC archival samples linked to outcome data. Plk1 was targeted using siRNA to evaluate both functional significance, as well as its therapeutic potential in NPC. RNA interference was achieved using a pooled small interfering RNA (siPlk1) to knock down the expression of PLK1 in the Epstein-Barr Virus (EBV)-positive NPC cell line C666-1.  Results  Plk1 immunoexpression was observed in 28 of 40 specimens (70%), which in turn, was associated with a higher likelihood of recurrence (p=0.018). SiPlk1 (30nM) reduced C666-1 viability in a time and dose-dependent manner. The cytotoxic effect was enhanced with the addition of radiation (6 Gy), down to 15% viability at day 7. This cytotoxicity appeared to be mediated by apoptosis (33.5% at 48 hours), along with activation of caspases 3/7 (2.1-fold increase over control). Cell cycle analysis demonstrated an increase in the G2/M cell population to 30.6%. Immunofluorescence demonstrated the G2/M arrest being associated with aberrant spindle formation, resulting in mitotic arrest.Western blotting corroborated that down-regulation of Plk1 was associated with an increase in Cyclin B1 expression, consistent with the known downstream targets of Plk1. Finally, the therapeutic potential of Plk1 was assessed using an in vivo tumor-formation assay. Transfection of C666-1 cells with SiPlk1 delayed tumor formation by 44 days, compared to control mice. When combined with radiation (6 Gy), this resulted in a further delay in tumor development of up to 75 days, compared to the 60 days in the siCNTR-treated group.  Conclusion  Our data demonstrate over-expression of Plk1 in human NPC samples, which was associated with a higher risk of recurrent disease. In addition, targeting Plk1 was effective in reducing NPC survival both in vitro and in vivo, particularly when combined with ionizing radiation, indicating that Plk1 likely represents an important target for NPC therapy.
The Cost, Price, and Debt of Medical Education
Authors: David A. Asch, Justin Grischkan, Sean Nicholson
Journal: New England Journal of Medicine (2020)

By 2018, the mean price of a U.S. medical education was about $300,000; 75% of students took on loans, and their average debt at graduation was $200,000. Various policies aim to combat the problem, but policies targeting cost, price, or debt have different consequences.
Metabolic Signatures of Distinct Endothelial Phenotypes
Authors: Sébastien J. Dumas, Melissa García-Caballero, Peter Carmeliet
Journal: Trends in Endocrinology and Metabolism (2020)

Angiogenesis is crucial for the development of the blood vasculature during embryogenesis, but also contributes to cancer and other diseases. While therapeutic targeting of endothelial cells (ECs) through growth factor inhibition is limited by insufficient efficacy and resistance, a new paradigm for modulating angiogenesis by targeting EC metabolism has emerged. Findings from the past decade highlight how ECs adapt their metabolism to proliferate or migrate during vessel sprouting, or to maintain the vascular barrier and protect themselves against oxidative stress in the high-oxygen environment they are exposed to in healthy conditions. We overview key endothelial metabolic pathways underlying the different EC phenotypes, as well as potential opportunities for targeting EC metabolism in therapeutic settings.
Response to letter regarding “Stereotactic radiosurgery for nonfunctioning pituitary adenomas: meta-analysis and International Society of Stereotactic Radiosurgery (ISRS) practice opinion”
Authors: Rupesh Kotecha, Shoji Yomo, John H Suh
Journal: Neuro-Oncology (2020)

Response to letter regarding "Stereotactic radiosurgery for nonfunctioning pituitary adenomas: meta-analysis and International Society of Stereotactic Radiosurgery (ISRS) practice opinion"We would like to thank the editors for the opportunity to respond to the issues raised by Xu and colleagues and to clarify the key aspects of our meta-analysis of nonfunctioning pituitary adenomas (NFAs) treated with stereotactic radiotherapy. 1We would also like to thank the authors themselves for broadening the discussion and seeking methodologic clarification.As described in the Methods, a comprehensive review of the literature yielded several series which consisted of updates on prior reports from the same institution or multiinstitutional studies with inclusion of already published patient cohorts.In these situations, duplicate studies were assessed for any updated data on treatment efficacy or toxicity with the latest report of the largest number of patients included in the final analysis: 35 unique studies.The intent of this was to minimize duplication to the greatest extent possible.In fact, we did provide a very detailed and specific evaluation of this issue in the discussion as a potential limitation.Taken verbatim, "every effort was made to prevent overlap of data across studies, and if multi-institutional patient level data were available, this was given preference over individual studies as they would incorporate data from centers which did not always publish individual outcomes.Also, different multi-institutional reports had overlapping time periods of data collection and therefore were included in order to evaluate the maximum number of patients, with partial but unknown quantity of overlap with subsequent studies." 1 Because individual patient level data from each publication are simply unavailable and unobtainable, the best that can be achieved is minimization of overlap, not complete negation of it.
Prediction of an Adverse Cardiovascular Response to Physical Exercise From Resting Echocardiography Imaging in Young Adults With Suboptimal Blood Pressure
Authors: M Alsharqi, O J Huckstep, W Williamson, A Mohamed, C Tan, W Lapidaire, F Telles, L Arnold, C Monteiro, H Dawes, C Foster, A J Lewandowski, P Leeson
Journal: Circulation (2019)
GI symptoms and fever increase the risk of severe illness and death in patients with COVID-19
Authors: Jue Liu, Liyuan Tao, Xia Liu, Hongyan Yao, Shicheng Yu, Qiqi Wang, Jiaojiao Zhang, Zhancheng Gao, Rongmeng Jiang, Wenzhan Jing, Min Liu
Journal: Gut (2020)

PostScriptGI symptoms and fever increase the risk of severe illness and death in patients with COVID-19 COVID-19 pandemic has become a major public health problem globally.Fever is the most common symptom.Besides fever, GI symptoms has also been reported in patients with COVID-19, such as diarrhoea, nausea, vomiting and abdominal pain and affect up to 28% of patients. 1-5 Several previous studies assessed the association between GI symptoms and disease severity and yielded inconsistent results. 1 2 6 In this retrospective cohort study, we explored whether GI symptoms and fever increased the risk of severe illness or death in patients with COVID-19.We analysed 29 393 laboratoryconfirmed COVID-19 patients diagnosed before 21 March 2020 in cities outside of Wuhan in mainland China.The study was supported by the National Health Commission of China.The final data of follow-up were 17 April 2020.We excluded clinically diagnosed cases who were not laboratory confirmed and patients who were not discharged from hospital by 17 April 2020.The diagnosis of laboratory-confirmed COVID-19 case, severe cases (including critical cases) and death was conducted by local healthcare workers according to the national diagnosis and treatment protocol for COVID-19 released by the National Health Commission. 7The definition of having GI symptoms were patients with COVID-19 who had one of the following symptoms (nausea, vomiting, diarrhoea or abdominal pain).We used χ 2 test or Fisher's exact test to compare the characteristics of four COVID-19 groups divided by GI symptoms and fever.Log-binomial regression models were used to estimate the crude and adjusted risk ratios (aRRs) and 95% CIs of severe cases and death for patients with GI symptoms and fever, after adjusting for potential confounders.Two-sided p values of less than 0.05 were deemed to be statistically significant.Characteristics of patients with COVID-19 with and without GI symptoms and fever are listed in table 1.The median age was 47 years (IQR 34-57).The most frequent symptom was fever (69.9%).Overall, 2289 (7.8%) patients had GI symptoms.Five hundred and four (1.7%) patients had GI symptoms and no fever, 18 771 (63.9%) patients had fever and no GI symptoms, 1785 (6.1%) patients had both GI symptoms and fever on August 10,
Estimation of Excess Deaths Associated With the COVID-19 Pandemic in the United States, March to May 2020
Authors: Daniel M. Weinberger, Jenny Chen, Ted Cohen, Forrest W. Crawford, Farzad Mostashari, Don Olson, Virginia E. Pitzer, Nicholas G. Reich, Marcus Russi, Lone Simonsen, Anne Watkins, Cecile Viboud
Journal: JAMA Internal Medicine (2020)

<h3>Importance</h3> Efforts to track the severity and public health impact of coronavirus disease 2019 (COVID-19) in the United States have been hampered by state-level differences in diagnostic test availability, differing strategies for prioritization of individuals for testing, and delays between testing and reporting. Evaluating unexplained increases in deaths due to all causes or attributed to nonspecific outcomes, such as pneumonia and influenza, can provide a more complete picture of the burden of COVID-19. <h3>Objective</h3> To estimate the burden of all deaths related to COVID-19 in the United States from March to May 2020. <h3>Design, Setting, and Population</h3> This observational study evaluated the numbers of US deaths from any cause and deaths from pneumonia, influenza, and/or COVID-19 from March 1 through May 30, 2020, using public data of the entire US population from the National Center for Health Statistics (NCHS). These numbers were compared with those from the same period of previous years. All data analyzed were accessed on June 12, 2020. <h3>Main Outcomes and Measures</h3> Increases in weekly deaths due to any cause or deaths due to pneumonia/influenza/COVID-19 above a baseline, which was adjusted for time of year, influenza activity, and reporting delays. These estimates were compared with reported deaths attributed to COVID-19 and with testing data. <h3>Results</h3> There were approximately 781 000 total deaths in the United States from March 1 to May 30, 2020, representing 122 300 (95% prediction interval, 116 800-127 000) more deaths than would typically be expected at that time of year. There were 95 235 reported deaths officially attributed to COVID-19 from March 1 to May 30, 2020. The number of excess all-cause deaths was 28% higher than the official tally of COVID-19–reported deaths during that period. In several states, these deaths occurred before increases in the availability of COVID-19 diagnostic tests and were not counted in official COVID-19 death records. There was substantial variability between states in the difference between official COVID-19 deaths and the estimated burden of excess deaths. <h3>Conclusions and Relevance</h3> Excess deaths provide an estimate of the full COVID-19 burden and indicate that official tallies likely undercount deaths due to the virus. The mortality burden and the completeness of the tallies vary markedly between states.
Trainee doctor who slapped and throttled his wife is struck off after GMC appeal
Authors: Clare Dyer
Journal: BMJ (2020)

A doctor who throttled and slapped his wife and exerted coercive control over her has been struck off the UK medical register after the General Medical Council (GMC) successfully appealed against an earlier suspension.

Muhammad Saqib Saeed was suspended from the register for 12 months by a medical practitioners tribunal in 2019 after he was given a 22 month prison sentence suspended for two years. …
Ultrasound-mediated delivery enhances therapeutic efficacy of MMP sensitive liposomes
Authors: Marieke Olsman, Viktoria Sereti, Kristine Andreassen, Sofie Snipstad, Annemieke van Wamel, Rasmus Eliasen, Sigrid Berg, Andrew J. Urquhart, Thomas L. Andresen, Catharina de Lange Davies
Journal: Journal of Controlled Release (2020)

To improve therapeutic efficacy of nanocarrier drug delivery systems, it is essential to improve their uptake and penetration in tumour tissue, enhance cellular uptake and ensure efficient drug release at the tumour site. Here we introduce a tumour targeting drug delivery system based on the ultrasound-mediated delivery of enzyme sensitive liposomes. These enzyme sensitive liposomes are coated with cleavable poly(ethylene glycol) (PEG) which will be cleaved by two members of the enzyme matrix metalloproteinase family (MMP-2 and MMP-9). Cleavage of the PEG coat can increase cellular uptake and will destabilize the liposomal membrane which can result in accelerated drug release. The main aim of the work was to study the effect of focused ultrasound and microbubbles on the delivery and therapeutic efficacy of the MMP sensitive liposome. The performance of the MMP sensitive liposome was compared to a non-MMP sensitive version and Doxil-like liposomes. In vitro, the cellular uptake and cytotoxicity of the liposomes were studied, while in vivo the effect of ultrasound and microbubbles on the tumour accumulation, biodistribution, microdistribution, and therapeutic efficacy were investigated. For all tested liposomes, ultrasound and microbubble treatment resulted in an improved tumour accumulation, increased extravasation, and increased penetration of the liposomes from blood vessels into the extracellular matrix. Surprisingly, penetration depth was independent of the ultrasound intensity used. Ultrasound-mediated delivery of free doxorubicin and the Doxil-like and MMP sensitive liposome resulted in a significant reduction in tumour volume 28 days post the first treatment and increased median survival. The MMP sensitive liposome showed better therapeutic efficacy than the non-MMP sensitive version indicating that cleaving the PEG-layer is important. However, the Doxil-like liposome outcompeted the MMP and non-MMP sensitive liposome, both with and without the use of ultrasound and microbubbles.
Recommended physical activity and all cause and cause specific mortality in US adults: prospective cohort study
Authors: Min Zhao, Sreenivas P Veeranki, Costan G Magnussen, Bo Xi
Journal: BMJ (2020)

Abstract Objective To determine the association between recommended physical activity according to the 2018 physical activity guidelines for Americans and all cause and cause specific mortality using a nationally representative sample of US adults. Design Population based cohort study. Setting National Health Interview Survey (1997-2014) with linkage to the National Death Index records to 31 December 2015. Participants 479 856 adults aged 18 years or older. Exposures Participant self-reports of the amount of leisure time spent in aerobic physical activity and muscle strengthening activity each week were combined and categorised into four groups: insufficient activity, aerobic activity only, muscle strengthening only, and both aerobic and muscle strengthening activities according to the physical activity guidelines. Main outcome measures All cause mortality and cause specific mortality (cardiovascular disease, cancer, chronic lower respiratory tract diseases, accidents and injuries, Alzheimer’s disease, diabetes mellitus, influenza and pneumonia, and nephritis, nephrotic syndrome, or nephrosis) obtained from the National Death Index records. Results During a median follow-up of 8.75 years, 59 819 adults died from all causes, 13 509 from cardiovascular disease, 14 375 from cancer, 3188 from chronic lower respiratory tract diseases, 2477 from accidents and injuries, 1470 from Alzheimer’s disease, 1803 from diabetes mellitus, 1135 from influenza and pneumonia, and 1129 from nephritis, nephrotic syndrome, or nephrosis. Compared with those who did not meet the physical activity guidelines (n=268 193), those who engaged in recommended muscle strengthening activity (n=21 428; hazard ratio 0.89, 95% confidence interval 0.85 to 0.94) or aerobic activity (n=113 851; 0.71, 0.69 to 0.72) were found to be at reduced risk of all cause mortality; and even larger survival benefits were found in those engaged in both activities (n=76 384; 0.60, 0.57 to 0.62). In addition, similar patterns were reported for cause specific mortality from cardiovascular disease, cancer, and chronic lower respiratory tract diseases. Conclusions Adults who engage in leisure time aerobic and muscle strengthening activities at levels recommended by the 2018 physical activity guidelines for Americans show greatly reduced risk of all cause and cause specific mortality. These data suggest that the physical activity levels recommended in the guidelines are associated with important survival benefits.
Targeted screening for lung cancer is here but who do we target and how?
Authors: David Baldwin, Emma O'Dowd, Kevin Ten Haaf
Journal: Thorax (2020)

In October 2019, an Independent Review of Adult Screening Programmes in England was published, authored by Mike Richards.1 Two key recommendations were that targeted screening programmes should be given equal weight to population screening programmes and that there should be a single advisory body covering both population and targeted screening programmes. The review identified the importance of defining individual risk of cancer to identify a target population at sufficient risk of the condition to be cost-effective. Secretary of State for Health and Social Care, Matt Hancock has asked the chief medical officers of the four UK countries to agree a mechanism for overseeing the new ‘targeted programmes’.2 Screening for lung cancer with low radiation dose CT (LDCT) is the largest of these programmes and is a considerable challenge to implement. In other countries the distinction between population and targeted screening is emphasised less but the criteria used to select eligible people remain crucial in determining cost-effectiveness.3 4 Targeting avoids subjecting people at low risk, who have little chance of developing the disease and benefiting from screening, to similar harms as those who are more likely to develop the disease and potentially benefit. Multivariable models have been shown to have better sensitivity and specificity than selection based on age and tobacco smoking alone, the most common criteria currently used on a global basis.5 6 In the UK, the first trial to use a multivariable model to define eligibility was the UK Lung Screening Trial (UKLS).7 The cancer detection rate was 2.1%, but there was some concern that the threshold risk (5% over 5 years) was too high.8 UK pilots have used both the Liverpool Lung Project version 2 (LLPv2), as was used in UKLS, and the Prostate Lung Colorectal and Ovarian (modified 2012) (PLCO …
Injured Brains of Medical Minds. Views from Within, by Ed Narinder Kapur
Authors: S. A Spence
Journal: BMJ (1997)

Ed Narinder Kapur Oxford University Press, £27, pp 421 ISBN 0 19 852144

“You would certainly make very clever doctors of men who from their earliest years, besides acquiring scientific knowledge, had come in contact with very many cases, and who had themselves suffered from every malady, and were not constitutionally very healthy.” Thus said Plato, and thus begins Narinder Kapur's odyssey through the disordered brain states of medical doctors and scientists who have suffered cerebral pathology. A variety of patients, anonymous and named, describe what it is like to be “on the other side.”

These papers are gathered from over the past century, with the emphasis being on more recent times. The opportunistic, sporadic occurrence …
Human Oral Motion‐Powered Smart Dental Implant (SDI) for In Situ Ambulatory Photo‐biomodulation Therapy
Authors: Moonchul Park, Sayemul Islam, Hye‐Eun Kim, Jonathan Korostoff, Markus B. Blatz, Geelsu Hwang, Albert Kim
Journal: Advanced Healthcare Materials (2020)

Abstract Peri‐implant disease is an inflammatory condition affecting the soft and hard tissues surrounding a dental implant. However, current preventative methods are insufficient due to the limited bioactivity on the dental implant and poor patient compliance. Recently, photo‐biomodulation (PBM) therapy that can recover and regenerate peri‐implant soft tissue has attracted considerable attention in dentistry. In this paper, a seamless human oral motion‐powered dental implant system (called Smart Dental Implant or SDI) is presented as an ambulatory PBM therapy modality. SDI allows the in situ light delivery, which is enabled by the energy harvesting from dynamic human oral motions (chewing and brushing) via an engineered piezoelectric dental crown, an associated circuit, and micro light emitting diodes (LEDs). The SDI also offers adequate mechanical strength as the clinical standards. Using primary human gingival keratinocytes (HGKs) as a model host organism and Pseudomonas aeruginosa lipopolysaccharides (LPS) as a model inflammatory stimulus, effective SDI‐mediated PBM therapy is demonstrated. A new class of dental implants could be an ambulatory PBM therapy platform for the prevention of peri‐implant disease without patient dependency, warranting long‐lasting dental implants.