tbuckley/cabot-search huggingface dataset:
A Randomized Trial Comparing Antibiotics with Appendectomy for Appendicitis
Authors: Francesco Pata, Mauro Podda, Salomone Di Saverio
Journal: New England Journal of Medicine (2021)

Background  Antibiotic therapy has been proposed as an alternative to surgery for the treatment of appendicitis.  Methods  We conducted a pragmatic, nonblinded, noninferiority, randomized trial comparing antibiotic therapy (10-day course) with appendectomy in patients with appendicitis at 25 U.S. centers. The primary outcome was 30-day health status, as assessed with the European Quality of Life-5 Dimensions (EQ-5D) questionnaire (scores range from 0 to 1, with higher scores indicating better health status; noninferiority margin, 0.05 points). Secondary outcomes included appendectomy in the antibiotics group and complications through 90 days; analyses were prespecified in subgroups defined according to the presence or absence of an appendicolith.  Results  In total, 1552 adults (414 with an appendicolith) underwent randomization; 776 were assigned to receive antibiotics (47% of whom were not hospitalized for the index treatment) and 776 to undergo appendectomy (96% of whom underwent a laparoscopic procedure). Antibiotics were noninferior to appendectomy on the basis of 30-day EQ-5D scores (mean difference, 0.01 points; 95% confidence interval [CI], -0.001 to 0.03). In the antibiotics group, 29% had undergone appendectomy by 90 days, including 41% of those with an appendicolith and 25% of those without an appendicolith. Complications were more common in the antibiotics group than in the appendectomy group (8.1 vs. 3.5 per 100 participants; rate ratio, 2.28; 95% CI, 1.30 to 3.98); the higher rate in the antibiotics group could be attributed to those with an appendicolith (20.2 vs. 3.6 per 100 participants; rate ratio, 5.69; 95% CI, 2.11 to 15.38) and not to those without an appendicolith (3.7 vs. 3.5 per 100 participants; rate ratio, 1.05; 95% CI, 0.45 to 2.43). The rate of serious adverse events was 4.0 per 100 participants in the antibiotics group and 3.0 per 100 participants in the appendectomy group (rate ratio, 1.29; 95% CI, 0.67 to 2.50).  Conclusions  For the treatment of appendicitis, antibiotics were noninferior to appendectomy on the basis of results of a standard health-status measure. In the antibiotics group, nearly 3 in 10 participants had undergone appendectomy by 90 days. Participants with an appendicolith were at a higher risk for appendectomy and for complications than those without an appendicolith. (Funded by the Patient-Centered Outcomes Research Institute; CODA ClinicalTrials.gov number, NCT02800785.).
Modeling Pharmacokinetic Natural Product–Drug Interactions for Decision-Making: A NaPDI Center Recommended Approach
Authors: Emily J. Cox, Dan-Dan Tian, John D. Clarke, Allan E. Rettie, Jashvant D. Unadkat, Kenneth E. Thummel, Jeannine S. McCune, Mary F. Paine
Journal: Pharmacological Reviews (2021)

The popularity of botanical and other purported medicinal natural products (NPs) continues to grow, especially among patients with chronic illnesses and patients managed on complex prescription drug regimens. With few exceptions, the risk of a given NP to precipitate a clinically significant pharmacokinetic NP-drug interaction (NPDI) remains understudied or unknown. Application of static or dynamic mathematical models to predict and/or simulate NPDIs can provide critical information about the potential clinical significance of these complex interactions. However, methods used to conduct such predictions or simulations are highly variable. Additionally, published reports using mathematical models to interrogate NPDIs are not always sufficiently detailed to ensure reproducibility. Consequently, guidelines are needed to inform the conduct and reporting of these modeling efforts. This recommended approach from the Center of Excellence for Natural Product Drug Interaction Research describes a systematic method for using mathematical models to interpret the interaction risk of NPs as precipitants of potential clinically significant pharmacokinetic NPDIs. A framework for developing and applying pharmacokinetic NPDI models is presented with the aim of promoting accuracy, reproducibility, and generalizability in the literature. <h3>Significance Statement</h3> Many natural products (NPs) contain phytoconstituents that can increase or decrease systemic or tissue exposure to, and potentially the efficacy of, a pharmaceutical drug; however, no regulatory agency guidelines exist to assist in predicting the risk of these complex interactions. This recommended approach from a multi-institutional consortium designated by National Institutes of Health as the Center of Excellence for Natural Product Drug Interaction Research provides a framework for modeling pharmacokinetic NP-drug interactions.
The very favorable metastatic renal cell carcinoma (mRCC) risk group: Data from the International Metastatic RCC Database Consortium (IMDC).
Authors: Andrew Lachlan Schmidt, Wanling Xie, Chun Loo Gan, Connor Wells, Shaan Dudani, Frede Donskov, Camillo Porta, Cristina Suarez, Bernadett Szabados, Lori Wood, Jose Manuel Ruiz Morales, Ben Tran, Georg A. Bjarnason, Takeshi Yuasa, Benoit Beuselinck, Aaron Richard Hansen, Neeraj Agarwal, Ziad Bakouny, Daniel Yick Chin Heng, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2021)

339 Background: The IMDC criteria have been used as a prognostic tool for patients with mRCC receiving single agent VEGF-targeted drugs, and more recently combination immuno-oncology (IO) +/- VEGF-targeted agents, which improve outcomes over VEGF TKI monotherapy. We sought to identify a subset of patients with very favorable outcomes, for which less intensive therapy might be considered. Methods: Utilizing the IMDC dataset, 1638 patients with IMDC favorable risk disease received first-line systemic therapy. Patients were randomly selected in a 2:1 ratio to the training and testing sets, stratified by year of systemic therapy initiation. Multivariable Cox regression estimated prognostic factors for overall survival (OS). Results: Median age was 63 (range 21-95) years and 98% had received prior nephrectomy. First-line systemic therapy consisted of targeted therapy (91%), IO-combination regimens (8%), or other (1%). From the training data, three variables (primary diagnosis to systemic therapy &lt;3 vs ≥3yr; Karnofsky Performance Status 80 vs &gt;80; presence of brain, liver, or bone metastasis) significantly predicted for OS in the multivariable model (hazard ratio 1.4~1.5, p-values&lt;0.05). The model had similar performance in the test dataset (C-index=0.64). Using the 3 included risk factors, patients were classified to very favorable risk (0 risk factors, 29% of patients) or favorable risk disease (≥1 risk factors, 71% of patients). Clinical outcomes for the two risk groups are presented in the table below. Conclusions: We identified a very favorable risk group in the IMDC criteria in RCC patients treated with first-line therapy. External validation including populations receiving IO containing therapies is ongoing. [Table: see text]
Alternative strategies in cardiac preclinical research and new clinical trial formats
Authors: Fabian Philipp Kreutzer, Anna Meinecke, Kevin Schmidt, Jan Fiedler, Thomas Thum
Journal: Cardiovascular Research (2021)

Abstract An efficient and safe drug development process is crucial for the establishment of new drugs on the market aiming to increase quality of life and life-span of our patients. Despite technological advances in the past decade, successful launches of drug candidates per year remain low. We here give an overview about some of these advances and suggest improvements for implementation to boost preclinical and clinical drug development with a focus on the cardiovascular field. We highlight advantages and disadvantages of animal experimentation and thoroughly review alternatives in the field of three-dimensional cell culture as well as preclinical use of spheroids and organoids. Microfluidic devices and their potential as organ-on-a-chip systems, as well as the use of living animal and human cardiac tissues are additionally introduced. In the second part, we examine recent gold standard randomized clinical trials and present possible modifications to increase lead candidate throughput: adaptive designs, master protocols, and drug repurposing. In silico and N-of-1 trials have the potential to redefine clinical drug candidate evaluation. Finally, we briefly discuss clinical trial designs during pandemic times.
Covid mutations: honest approach needed from politicians and scientists on pandemic outlook
Authors: Milan Dagli
Journal: BMJ (2021)

Over the past year the government has enthusiastically told us about getting control over the pandemic through “ramping up testing,” “world beating tracing,” “breakthrough drugs,” and “game changing vaccinations” to name a few preferred phrases.12

Scientists from the Scientific Advisory Group for Emergencies and other agencies have been more circumspect, using phrases such as “we are going to have to live with this virus for a long time,” …
Abstract IA010: How opposing roles of interferon and pattern recognition receptor signaling in the TME influence immunotherapy
Authors: Andy J. Minn
Journal: Cancer Research (2021)

Abstract Interferon (IFN) signaling pathways are broadly active across multiple cancer types. These pathways are typically associated with pathogen infection, but their roles in cancer are less understood. Emerging evidence indicates that IFN signaling has complex and even dichotomous roles in both cancer and host-pathogen interactions. On the one hand, IFN is often essential for immune activation and for promoting response to cancer immunotherapies. On the other hand, prolonged IFN signaling that accompanies persistent disease can lead to immunotherapy resistance and immunosuppression. This latter role represents a feedback inhibition mechanism that can also be observed in chronic pathogen infections to limit immune-mediated pathology. Thus, how these opposing effects of IFN signaling are controlled and what factors dictate one function over the other are important questions. In this presentation, insight into how opposing functions of IFN and pattern recognition receptor signaling impact cancer immunotherapy will be discussed. This will include evidence for what factors might favor one function of IFN over the other. Finally, work will be presented that illustrates how key interferon-stimulated genes (ISGs) expressed by cancer cells can control whether an immune stimulatory or suppressive tumor immune microenvironment develops. Citation Format: Andy J. Minn. How opposing roles of interferon and pattern recognition receptor signaling in the TME influence immunotherapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr IA010.
Doctors unlawfully denied drug to girl with spinal muscular atrophy, appeal court rules
Authors: Clare Dyer
Journal: BMJ (2021)

Decisions made by two consultants to deny a 10 year old girl with type 3 spinal muscular atrophy the chance of treatment with a potentially life changing drug were “unlawful” and “irrational,” three Court of Appeal judges have ruled.1

Imelda Hughes, a consultant paediatric neurologist at Manchester University Hospitals NHS Foundation Trust, and Mariacristina Scoto, a consultant in neuromuscular translational research at Great Ormond Street Hospital for Children NHS Foundation Trust, decided that Sophie Basma did not meet the criteria for treatment.

The drug nusinersin (Spinraza), which has a list price of £450 000 (€520 000; $630 000) for the first year and £225 000 for subsequent years but is supplied to the NHS at a discount, is the only potentially disease modifying treatment available in the UK for Sophie’s condition. The UK National Institute for Health and Care Excellence issued guidance in October 2019 stating that it should be provided to patients with type 3 spinal muscular atrophy provided that seven criteria were …
New biomarkers from multiomics approaches: improving risk prediction of atrial fibrillation
Authors: Jelena Kornej, Vanessa A Hanger, Ludovic Trinquart, Darae Ko, Sarah R Preis, Emelia J Benjamin, Honghuang Lin
Journal: Cardiovascular Research (2021)

Abstract Atrial fibrillation (AF) is a common cardiac arrhythmia leading to many adverse outcomes and increased mortality. Yet the molecular mechanisms underlying AF remain largely unknown. Recent advances in high-throughput technologies make large-scale molecular profiling possible. In the past decade, multiomics studies of AF have identified a number of potential biomarkers of AF. In this review, we focus on the studies of multiomics profiles with AF risk. We summarize recent advances in the discovery of novel biomarkers for AF through multiomics studies. We also discuss limitations and future directions in risk assessment and discovery of therapeutic targets for AF.
FBW7 suppresses ovarian cancer development by targeting the N6-methyladenosine binding protein YTHDF2
Authors: Fei Xu, Jiajia Li, Mengdong Ni, Jingyi Cheng, Haiyun Zhao, Shanshan Wang, Xiang Zhou, Xiaohua Wu
Journal: Molecular Cancer (2021)

Abstract Background The tumor suppressor FBW7 is the substrate recognition component of the SCF E3-ubiquitin ligase complex that mediates proteolytic degradation of various oncogenic proteins. However, the role of FBW7 in ovarian cancer progression remains inadequately understood. Methods IP-MASS, co-IP, immunohistochemistry, and western blotting were used to identify the potential substrate of FBW7 in ovarian cancer. The biological effects of FBW7 were investigated using in vitro and in vivo models. LC/MS was used to detect the m 6 A levels in ovarian cancer tissues. MeRIP-Seq and RNA-Seq were used to assess the downstream targets of YTHDF2. Results We unveil that FBW7 is markedly down-regulated in ovarian cancer tissues and its high expression is associated with favorable prognosis and elevated m 6 A modification levels. Consistently, ectopic FBW7 inhibits ovarian cancer cell survival and proliferation in vitro and in vivo, while ablation of FBW7 empowers propagation of ovarian cancer cells. In addition, the m 6 A reader protein, YTHDF2, is identified as a novel substrate for FBW7. FBW7 counteracts the tumor-promoting effect of YTHDF2 by inducing proteasomal degradation of the latter in ovarian cancer. Furthermore, YTHDF2 globally regulates the turnover of m 6 A-modified mRNAs, including the pro-apoptotic gene BMF. Conclusions Our study has demonstrated that FBW7 suppresses tumor growth and progression via antagonizing YTHDF2-mediated BMF mRNA decay in ovarian cancer.
Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial
Authors: Eric P Winer, Oleg Lipatov, Seock-Ah Im, Anthony Goncalves, Eva Muñoz-Couselo, Keun Seok Lee, Peter Schmid, Kenji Tamura, Laura Testa, Isabell Witzel, Shoichiro Ohtani, Nicholas Turner, Stefania Zambelli, Nadia Harbeck, Fabrice Andre, Rebecca Dent, Xuan Zhou, Vassiliki Karantza, Jaime Mejia, Javier Cortes
Journal: The Lancet Oncology (2021)
OLI-P: Toxicity and efficacy of local ablative radiotherapy in PSMA-PET staged, oligometastatic prostate cancer—A phase II trial.
Authors: Tobias Hölscher, Michael Baumann, Jörg Kotzerke, Manfred Wirth, Christian Thomas, Daniel Zips, Mechthild Krause, Fabian Lohaus
Journal: Journal of Clinical Oncology (2021)

115 Background: After curative primary therapy, a subset of patients with prostate cancer will have PSA-progression. Modern imaging methods may detect patients with oligometastastic disease at an early time point. Local ablative therapy has shown to improve time to progression compared to standard of care. PSMA-PET hybrid imaging is an emerging method, with a high accuracy and sensitivity to detect oligometastatic disease at low PSA-levels. Methods: At two German centers, patients with PSA progression after local curative treatment had PSMA-PET- hybrid imaging. Patients with up to five PSMA-PET positive metastases were offered to participate in the clinical trial. Further relevant exclusion criteria were ongoing androgen deprivation therapy (ADT), PSA &gt;10 ng/ml or severe comorbidity. The patients had a local ablative radiotherapy (aRT) to all PSMA-PET positive metastases. The primary endpoint was toxicity within two years after aRT. Secondary endpoints included PSA-progression free survival (defined as PSA nadir +1 ng/ml or start of ADT) and therapy-free survival (i.e. time to start ADT). Results: Between 2014 and 2018, 72 patients were included; patients’ characteristics are shown in table. Nine patients were excluded as no aRT was performed. The median follow up for the remaining 63 patients was 34.2 months. Within two years, 67 % (42 of 63 pats) had no report of adverse events. Following events were recorded during follow up: rectal bleeding (Grade 1, n=1), stroke (1), urinary incontinence (grade 2: n=3) secondary malignoma (n=5, primary liver tumor (n=2), bladder cancer, acute leukemia and head and cancer). All adverse events were considered as “not related“ to aRT of the metastases. PSA progression occurred in 44 patients after a median of 14.4 months. After two years, PSA relapse free survival was 38.2 %. ADT was initiated in 36 patients after a median of 26 months; 54 % (n=34 of 63) did not start ADT within two years after aRT. Conclusions: Local ablative radiotherapy in selected patients with PSMA-PET staged oligometastatic prostate cancer is well tolerated and may improve midterm outcome and delay onset of systemic therapy. Clinical trial information: NCT02264379. [Table: see text]
Hydroxynorketamines: Pharmacology and Potential Therapeutic Applications
Authors: Jaclyn N. Highland, Panos Zanos, Lace M. Riggs, Polymnia Georgiou, Sarah M. Clark, Patrick J. Morris, Ruin Moaddel, Craig J. Thomas, Carlos A. Zarate, Edna F. R. Pereira, Todd D. Gould
Journal: Pharmacological Reviews (2021)

Hydroxynorketamines (HNKs) are formed in vivo after (R,S)-ketamine (ketamine) administration. The 12 HNK stereoisomers are distinguished by the position of cyclohexyl ring hydroxylation (at the 4, 5, or 6 position) and their unique stereochemistry at two stereocenters. Although HNKs were initially classified as inactive metabolites because of their lack of anesthetic effects, more recent studies have begun to reveal their biologic activities. In particular, (2R,6R)- and (2S6)-HNK exert antidepressant-relevant behavioral and physiologic effects in preclinical models, which led to a rapid increase in studies seeking to clarify the mechanisms by which HNKs exert their pharmacological effects. To date, the majority of HNK research has focused on the actions of (2R,6R)-HNK because of its robust behavioral actions in tests of antidepressant effectiveness and its limited adverse effects. This review describes HNK pharmacokinetics and pharmacodynamics, as well as the putative cellular, molecular, and synaptic mechanisms thought to underlie their behavioral effects, both following their metabolism from ketamine and after direct administration in preclinical studies. Converging preclinical evidence indicates that HNKs modulate glutamatergic neurotransmission and downstream signaling pathways in several brain regions, including the hippocampus and prefrontal cortex. Effects on other neurotransmitter systems, as well as possible effects on neurotrophic and inflammatory processes, and energy metabolism, are also discussed. Additionally, the behavioral effects of HNKs and possible therapeutic applications are described, including the treatment of unipolar and bipolar depression, post-traumatic stress disorder, chronic pain, neuroinflammation, and other anti-inflammatory and analgesic uses. SIGNIFICANCE STATEMENT: Preclinical studies indicate that hydroxynorketamines (HNKs) exert antidepressant-relevant behavioral actions and may also have analgesic, anti-inflammatory, and other physiological effects that are relevant for the treatment of a variety of human diseases. This review details the pharmacokinetics and pharmacodynamics of the HNKs, as well as their behavioral actions, putative mechanisms of action, and potential therapeutic applications.
Association between percentage of positive biopsy cores and risk of pelvic lymph node involvement in prostate cancer.
Authors: David Dewei Yang, Edward Christopher Dee, Melaku A Arega, Paul L. Nguyen, Peter F. Orio, Martin T. King, Benjamin Harris Kann, James B. Yu, Kiri Cook, Ting Martin Ma, Amar Upadhyaya Kishan, Vinayak Muralidhar
Journal: Journal of Clinical Oncology (2021)

205 Background: Commonly used tools for predicting the risk of pelvic lymph node involvement (LNI) in prostate cancer often do not incorporate information on the percentage of positive biopsy cores (PPB). To better inform the use of elective nodal irradiation in the definitive treatment of prostate cancer, we examined the association between PPB and risk of pathologic pelvic LNI in men with prostate cancer who underwent radical prostatectomy (RP). Methods: We identified 109,577 men from the National Cancer Database who were diagnosed in 2010-2015 with cN0M0 prostate cancer, had 6-24 cores sampled at biopsy, and underwent RP with pathologic nodal evaluation. Multivariable logistic regression was used to examine the association between PPB and the likelihood of having ≥1 positive pelvic lymph node, adjusting for other known clinicopathologic prognostic variables. Results: Overall, 4.0% (4,340) of the cohort was found to have pelvic LNI at the time of RP. Higher PPB was associated with an increased risk of pelvic LNI (adjusted odds ratio [AOR] 1.75 for 25.1-50.0% PPB, 2.63 for 50.1-75.0% PPB, and 4.49 for 75.1-100.0% PPB vs. ≤25.0% PPB, all P&lt;0.001). Notably, men with Gleason 8 disease and ≤25.0% PPB only had a 3.6% risk of pelvic LNI, whereas men with Gleason 9-10 disease and 75.1-100.0% PPB had a 32.6% risk (Table). Other factors associated with the likelihood of pelvic LNI included a higher biopsy Gleason score (AOR 1.43 for Gleason 8 and 2.84 for Gleason 9-10 vs. Gleason 4+3, both P&lt;0.001), more advanced clinical tumor stage (AOR 1.48 for cT2, 1.97 for cT3, and 3.87 for cT4 vs. cT1, all P&lt;0.001), and a higher PSA (AOR 1.90 for 10.0-19.9 ng/mL, 2.40 for 20.0-39.9 ng/mL, and 2.60 for ≥40.0 ng/mL vs. &lt;10.0 ng/mL, all P&lt;0.001), but not more advanced age (AOR 0.98 for &gt;62 years [median] vs. ≤62 years, P=0.59) or black vs. white race (AOR 0.99, P=0.92). Conclusions: There was a statistically significant and clinically relevant association between increasing PPB and a higher risk of pelvic LNI. As the ongoing RTOG 0924 randomized trial matures, clinicians should consider incorporating information on PPB in determining which patients with prostate cancer may benefit from receiving radiation therapy to the pelvic lymph nodes. [Table: see text]