tbuckley/cabot-search huggingface dataset:
Real-world utilization of docetaxel among men with <i>de novo</i> metastatic castration-sensitive prostate cancer: A population-based study in men aged 66 or older.
Authors: Bobby Shayegan, Christopher J.D. Wallis, Robert James Hamilton, Scott Carlyle Morgan, Ilias Cagiannos, Naveen S. Basappa, Cristiano Ferrario, Geoffrey Gotto, Ricardo Fernandes, Krista Noonan, Tamim Niazi, Sebastien J. Hotte, Fred Saad, Huong Hew, Katherine Chan, Laura Park-Wyllie, Shawn Malone
Journal: Journal of Clinical Oncology (2021)

47 Background: Docetaxel was the first agent, when added to androgen deprivation therapy (ADT), to demonstrate a survival benefit in men with metastatic castration-sensitive prostate cancer (mCSPC). It remains an important guideline recommendation approach in these men. However, real-world experience among patients with de novo metastatic disease is poorly understood. Using population-based data from Ontario Canada, we examined the real-world experience of using docetaxel in mCSPC. Methods: Men aged 66 years and older diagnosed with de novo metastatic prostate cancer between 2014-2019 were captured. The Cancer Activity Level Reporting system tracks information regarding the use of cancer treatments, including details of systemic therapy. We identified patients who received docetaxel intensification to ADT following diagnosis of de novo mCSPC and analyzed the proportion of patients who completed 6 cycles of treatment, required a dose decrease, and who visited the emergency department (ED) or were hospitalized for febrile neutropenia. Results: Over the 5-year study period, 399 men received docetaxel treatment among 3,556 identified with de novo mCSPC. The median age was 72 (IQR 68-76) and mean Charlson comorbidity index was 0.15 (SD +/- 0.72). Of the 399 men, 230 (58%), 202 (51%) and 175 (44%) patients completed at least 4, 5 and 6 cycles of docetaxel, respectively. Dose reduction during docetaxel treatment was required in 173 (43%) patients. Filgrastim was prescribed among 29 (7.3%) patients. Hospitalization or ED visit for febrile neutropenia was observed in 63 (16 %) of patients who received docetaxel. Conclusions: Among men age 66 years and over who received docetaxel and ADT for mCSPC, less than half were able to complete all six prescribed cycles. In addition, over two fifth required dose reductions and 16% experienced febrile neutropenia requiring hospitalization or ED visit. These data highlight the differences in expected outcomes between clinical trial populations (as reported in CHAARTED) and routine use.
Abstract PO-053: Machine learning CADx process for classification of lung nodules below the Lung-RADS 4A threshold in LDCT scans
Authors: Rohan Abraham, Ian Janzen, Saeed Seyyedi, Sukhinder Khattra, John Mayo, Ren Yuan, Renelle Meyers, Stephen Lam, Calum MacAulay
Journal: Clinical Cancer Research (2021)

Abstract Lung Cancer screening trials have demonstrated significant mortality reduction. Low-Dose Computed Tomography (LDCT) screening can frequently discover many small nodules in at risk participants. However classification of these, sub-cm nodules as cancerous or benign is a challenging task even for expert clinicians. In this work we use machine learning (ML) techniques to differentiate, cancerous (clinically confirmed) and benign nodules (&amp;gt;5 years of follow-up). Data for this study is drawn from a screening study (PanCan) from which we selected 613 distinct nodules (141 cancerous, and ~size matched 472 benign). We analyzed texture and shape features (~170) that are extracted from the nodule with and without perimeter transition pixels to control for perimeter effects. Features are also extracted from the ring of parenchyma surrounding the nodule to account for tumor effects on surrounding tissue. From the equivalent location in the opposite lung, parenchymal characteristics were extracted which we use to normalize the nodule texture features in an effort to reduce scanner bias. Our preliminary results for machine learning classification have shown model accuracies of up to ~80% (feature selection and classification algorithm dependent). Radiomic feature data can be combined with patient demographic variables such as age, sex, and smoking status to further improve our models, reaching ~84% classification accuracy. When normalized by the opposite lung, 58% of texture features showed improved classification ability. A single feature from the ring of parenchyma surrounding the nodule achieved 73.5% accuracy. Others have shown that nodule area/volume is a good classifier; for this data set it gave 68% accuracy. Data exploration to study classification accuracies among different subsets of patients reveals a number of interesting trends. We have noted for instance that in patients without emphysema, tumors can be classified with much higher accuracy (&amp;gt;90%) than in those who suffer from it. This and other results detailing classification among specific patient groupings may prove relevant in any potential future clinical implementation of these results. Citation Format: Rohan Abraham, Ian Janzen, Saeed Seyyedi, Sukhinder Khattra, John Mayo, Ren Yuan, Renelle Meyers, Stephen Lam, Calum MacAulay. Machine learning CADx process for classification of lung nodules below the Lung-RADS 4A threshold in LDCT scans [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PO-053.
Recent advances in microneedles-mediated transdermal delivery of protein and peptide drugs
Authors: Ting Liu, Minglong Chen, Jintao Fu, Ying Sun, Chao Lu, Guilan Quan, Xin Pan, Chuanbin Wu
Journal: Acta Pharmaceutica Sinica B (2021)

Proteins and peptides have become a significant therapeutic modality for various diseases because of their high potency and specificity. However, the inherent properties of these drugs, such as large molecular weight, poor stability, and conformational flexibility, make them difficult to be formulated and delivered. Injection is the primary route for clinical administration of protein and peptide drugs, which usually leads to poor patient's compliance. As a portable, minimally invasive device, microneedles (MNs) can overcome the skin barrier and generate reversible microchannels for effective macromolecule permeation. In this review, we highlighted the recent advances in MNs-mediated transdermal delivery of protein and peptide drugs. Emphasis was given to the latest development in representative MNs design and fabrication. We also summarize the current application status of MNs-mediated transdermal protein and peptide delivery, especially in the field of infectious disease, diabetes, cancer, and other disease therapy. Finally, the current status of clinical translation and a perspective on future development are also provided.
Acetylcholine production by group 2 innate lymphoid cells promotes mucosal immunity to helminths
Authors: Luke B. Roberts, Corinna Schnoeller, Rita Berkachy, Matthew Darby, Jamie Pillaye, Menno J. Oudhoff, Naveen Parmar, Claire Mackowiak, Delphine Sedda, Valerie Quesniaux, Bernhard Ryffel, Rachel Vaux, Kleoniki Gounaris, Sylvie Berrard, David R. Withers, William G. C. Horsnell, Murray E. Selkirk
Journal: Science Immunology (2021)

Synthesis of acetylcholine by group 2 innate lymphoid cells is important for optimal immune responses to helminth infection.
Peter Stanley Harper
Authors: Julian Sampson
Journal: BMJ (2021)

Peter Stanley Harper grew up in Barnstaple and developed a keen and lasting love of nature from time spent in the surrounding countryside, but followed his father, Richard, a GP, into medicine. His academic leanings were no doubt influenced by both his father, who wrote two books on the relation between evolution and disease, and by his mother, Margery (born Elkington), who was a French scholar with a first class degree from Oxford and a doctorate from the Sorbonne, but who sacrificed her own career for her husband’s.

During preclinical studies at Oxford, Peter attended additional lectures at the Department of Zoology and became determined to find a way to combine his genetic and clinical interests professionally. At the time there was no established clinical career route to enable this, and after completing undergraduate clinical attachments at St Thomas’ he initially took jobs in paediatrics and internal medicine. In 1967 he moved to Liverpool, soon finding a natural home with Cyril Clarke’s team (later Sir Cyril, president of the Royal College of Physicians). Like Peter, Clarke had a major interest in genetics, developed through his research on the swallow tailed butterfly, and he had recently established the Nuffield Unit of Medical Genetics at the University. Peter then spent two years at Johns Hopkins, Baltimore, USA, with Victor McKusick, completing his doctoral studies on …
Comparative cardiotoxicity of the novel hormonal agents abiraterone and enzalutamide in metastatic castration-resistant prostate cancer using real-world data.
Authors: Jason Hu, Armen G. Aprikian, Marie Vanhuyse, Alice Dragomir
Journal: Journal of Clinical Oncology (2021)

62 Background: Novel hormonal agents (NHAs) such abiraterone (ABI) and enzalutamide (ENZA) have demonstrated similar survival benefits against placebo groups in their respective clinical trials leading to their regulatory approval in both the pre- and post-chemotherapy settings in metastatic castration-resistant prostate cancer (mCRPC). Despite the overall tolerable risk profile, certain signals of cardiovascular toxicity were reported for these agents in clinical trials but little is known about their incidence in clinical practice. The objective was to assess the comparative cardiovascular safety of ABI and ENZA in patients with mCRPC in the real-world. Methods: A retrospective population-based cohort was extracted from Quebec public healthcare administrative databases. Patients were selected on the basis of having received androgen deprivation therapy prior to initiating a novel hormonal agent (ABI or ENZA) between 2012 and 2016. The primary outcome of interest was cardiovascular-related hospitalization (composite outcome that included acute coronary disease, cerebrovascular disease, heart failure, arrhythmia and other cardiovascular causes). Inverse probability of treatment weighting (IPTW) with the propensity score was used to adjust for measured baseline confounders including pre-existing cardiovascular disease. Results: The cohort comprises 2,183 patients, with 1,773 (81.2%) in the ABI group and 410 (18.8%) in the ENZA group. Before IPTW, mean age of the ENZA group was higher than the ABI group (78 vs 76). There were more ENZA patients with pre-existing arrythmia (ABI: 10.7%, ENZA: 15.1%) and diabetes (ABI: 21.5%, ENZA: 25.1%). Crude incidence rates of cardiovascular-related hospitalization were of 10 events per 100 person-years (PYs) and of 7 events per 100 PYs for the ABI and ENZA groups, respectively. After applying IPTW, all baseline variables were well balanced across both groups with standardized differences &lt; 0.05. The ABI group was at greater risk of cardiovascular-related hospitalization compared to the ENZA group (IPTW-hazard ratio (HR): 1.79, 95% confidence interval (95%CI): 1.04-3.09). The risk of hospitalization for heart failure was greater in ABI (IPTW-HR: 3.02, 95%CI: 1.17-7.78). Conclusions: In our study population, there was a greater risk of cardiovascular-related hospitalizations for ABI users relative to ENZA users, in particular for hospitalization for heart failure. Given the lack of evidence from randomized head-to-head comparisons of both agents, these results provide clinicians with additional insight on the cardiovascular risks of mCRPC patients treated with NHAs in the real-world and further large studies are required to corroborate these findings.
FDG PET Findings Post–COVID Vaccinations
Authors: Saba Moghimi, Don Wilson, Patrick Martineau
Journal: Clinical Nuclear Medicine (2021)

Abstract Vaccinations can cause hypermetabolic axillary lymphadenopathy on FDG PET. We present the case of a 71-year-old man who underwent FDG PET/CT for melanoma staging 6 days following a COVID (coronavirus disease) vaccination. Imaging showed a prominent intramuscular mass at the vaccination site, in addition to extensive axillary lymphadenopathy. The mass was compatible with a hematoma at the vaccination site, and the lymphadenopathy was most likely reactive. This case demonstrates unconventional findings in response to a routine vaccination event—findings that, in light of current world events, are likely to be routinely encountered on PET imaging and that should be recognized reactive rather malignant.
Macropinocytosis in Cancer-Associated Fibroblasts Is Dependent on CaMKK2/ARHGEF2 Signaling and Functions to Support Tumor and Stromal Cell Fitness
Authors: Yijuan Zhang, M. Victoria Recouvreux, Michael Jung, Koen M.O. Galenkamp, Yunbo Li, Olga Zagnitko, David A. Scott, Andrew M. Lowy, Cosimo Commisso
Journal: Cancer Discovery (2021)

Although pancreatic ductal adenocarcinoma (PDAC) cells are exposed to a nutrient-depleted tumor microenvironment, they can acquire nutrients via macropinocytosis, an endocytic form of protein scavenging that functions to support cancer metabolism. Here, we provide evidence that macropinocytosis is also operational in the pancreatic tumor stroma. We find that glutamine deficiency triggers macropinocytic uptake in pancreatic cancer-associated fibroblasts (CAF). Mechanistically, we decipher that stromal macropinocytosis is potentiated via the enhancement of cytosolic Ca2+ and dependent on ARHGEF2 and CaMKK2-AMPK signaling. We elucidate that macropinocytosis has a dual function in CAFs-it serves as a source of intracellular amino acids that sustain CAF cell fitness and function, and it provides secreted amino acids that promote tumor cell survival. Importantly, we demonstrate that stromal macropinocytosis supports PDAC tumor growth. These results highlight the functional role of macropinocytosis in the tumor stroma and provide a mechanistic understanding of how nutrient deficiency can control stromal protein scavenging. SIGNIFICANCE: Glutamine deprivation drives stromal macropinocytosis to support CAF cell fitness and provide amino acids that sustain PDAC cell survival. Selective disruption of macropinocytosis in CAFs suppresses PDAC tumor growth.This article is highlighted in the In This Issue feature, p. 1601.
Antiseptic mouthwash for gonorrhoea prevention (OMEGA): a randomised, double-blind, parallel-group, multicentre trial
Authors: Eric P F Chow, Deborah A Williamson, Jane S Hocking, Matthew G Law, Kate Maddaford, Catriona S Bradshaw, Anna McNulty, David J Templeton, Richard Moore, Gerald L Murray, Jennifer A Danielewski, Rebecca Wigan, Marcus Y Chen, Rebecca J Guy, Lei Zhang, Basil Donovan, Andrew E Grulich, John M Kaldor, David M Whiley, Vincent J Cornelisse, Benjamin P Howden, David A Lewis, Tim R H Read, Christopher K Fairley
Journal: The Lancet Infectious Diseases (2021)
Abstract IA016: Cellular senescence in cancer therapy: Friend or foe?
Authors: Marco Demaria
Journal: Cancer Research (2021)

Abstract Most used anti-cancer therapeutic approaches are based on impairing mitosis and targeting highly proliferative cells. The non-specificity of these interventions often leads to transient and chronic side effects, and a general accelerated aging phenotype. Cellular senescence - a complex stress response whereby cells lose irreversibly their capacity to proliferate – is potent tumor suppressive mechanism and a desired outcome of anti-cancer therapies. Our data show that chemotherapy agents induce senescent cells in both mice and humans. However, chemotherapy-induced senescent cells develop a strong secretory phenotype (SASP) and contribute to chemotoxicity in mice including bone marrow suppression, cardiac decline, decreased physical activity and cancer relapse. Interestingly, chemotherapy treatment combined to genetic or pharmacological senolysis delays or prevents the onset of several pathologies. We also show that similar to genotoxic chemotherapy, inhibitors of Cyclin-Dependent Kinases (CDK)-4/6 induce a p53-mediated senescence program. Interestingly, using RNAseq, cytokine arrays and in-tissue analyses we demonstrate that CDKi-induced senescent cells are characterized by a strongly reduced SASP. CDKi-induced senescent cells fail to promote paracrine detrimental effects, and do not lead to adverse effects in mice. Moreover, transient treatment with CDK4/6i in combination with chemotherapy is sufficient to reduce SASP and improve healthspan. Together, our data suggest that modulating the senescence response is a potent strategy to limit the toxicity of ant-cancer treatments. This effect can be achieved either by eliminating detrimental senescent cells or by designing drugs that can promote stable growth arrest without strong paracrine effects. Importantly, the phenotypical characterization of these different senescent cells could predict toxicity and side effects associated to standard oncological drugs. Citation Format: Marco Demaria. Cellular senescence in cancer therapy: Friend or foe? [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 IA016.
Early assessment of diffusion and possible expansion of SARS-CoV-2 Lineage 20I/501Y.V1 (B.1.1.7, variant of concern 202012/01) in France, January to March 2021
Authors: Alexandre Gaymard, Paolo Bosetti, Adeline Feri, Gregory Destras, Vincent Enouf, Alessio Andronico, Sonia Burrel, Sylvie Behillil, Claire Sauvage, Antonin Bal, Florence Morfin, Sylvie Van Der Werf, Laurence Josset, François Blanquart, Bruno Coignard, Simon Cauchemez, Bruno Lina
Journal: Eurosurveillance (2021)

The emergence of SARS-CoV-2 variant 20I/501Y.V1 (VOC-202012/1 or GR/501Y.V1) is concerning given its increased transmissibility. We reanalysed 11,916 PCR-positive tests (41% of all positive tests) performed on 7-8 January 2021 in France. The prevalence of 20I/501Y.V1 was 3.3% among positive tests nationwide and 6.9% in the Paris region. Analysing the recent rise in the prevalence of 20I/501Y.V1, we estimate that, in the French context, 20I/501Y.V1 is 52-69% more transmissible than the previously circulating lineages, depending on modelling assumptions.
Factors Associated With Prescriptions for Branded Medications in the Medicare Part D Program
Authors: Mariana P. Socal, Ge Bai, Gerard F. Anderson
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Branded products of multisource drugs are frequently dispensed in the Medicare Part D program, increasing costs for the program and patients. <h3>Objective</h3> To examine the reasons for dispensing branded multisource drugs in Medicare Part D. <h3>Design, Setting, and Participants</h3> This cross-sectional study examined claims for multisource drugs with more than 1000 branded claims dispensed in Medicare Part D using Medicare Prescription Drug Event data from a 2017 nationwide random sample of 20% of Medicare beneficiaries. Data were analyzed between January and October 2020. <h3>Exposures</h3> Justification for branded dispensing as indicated by each claim's dispense-as-written code. <h3>Main Outcomes and Measures</h3> Mean Medicare Part D program spending and patient out-of-pocket spending for branded and generic products, and generic vs branded spending discounts in program and patient out-of-pocket spending for each multisource drug. <h3>Results</h3> Among 169 million claims for 224 multisource drugs, 8.3 million claims (4.9%) were dispensed with a branded product. Among these claims, 4.9 million claims (59.2%) did not have a recorded reason for branded dispensing; 1.4 million claims (16.9%) occurred because of prescriber requests; and 1.1 million claims (13.5%) occurred because of patient requests. If all branded dispensing requested by prescribers had been substituted by the corresponding generics, the projected savings to the Medicare Part D program and Medicare patients were $997 million (56.0%) and $161 million (64.4%), respectively. If all branded dispensing requested by patients had been substituted by generics, the projected savings to the Medicare Part D program and Medicare patient were $673 million (53.4%) and $109 million (55.1%), respectively. Drugs with the highest proportion of branded dispensing by physician or patient request were typically high cost (eg, drugs with above-median frequencies of branded dispensing: mean [SD] discount on generic vs branded, 73.9% [26.9%] for prescriber requests). <h3>Conclusions and Relevance</h3> Prescribers and patients motivated 30.4% of all branded dispensing of multisource drugs in the Medicare Part D program. Branded dispensing requested by prescribers or patients incurred an incremental annual cost of $1.67 billion to the Medicare program and $270 million to patients when compared with switching to generics. Policy makers should consider ways to discourage prescribers and patients from requesting branded dispensing of multisource drugs because of the higher cost.
Omega-3 fatty acids alter GTP-bound Ras both in vitro and in vivo in WiDr colon carcinoma
Authors: Kristina Rogers, Kyle Smith, Ronald Pardini
Journal: Cancer Research (2007)

3744  Cancer of the colon is the third most common type of cancer and the second most common cause of cancer death in the US. Colorectal cancer evolves from a multi-stepprocess and is a disease that is heavily influenced by environmentalfactors, with diet being one of the most important causative agents. Among dietary factors, there is strong epidemiological,clinical, and experimental data indicating a protective effectfor fish oil-derived n-3 polyunsaturated fatty acids (PUFA) oncolon cancer. In general, dietary lipidsrich in linoleic acid (LA; 18:2n-6), found in vegetableoils, have been shown to enhance the development of colon tumors, whereas n-3 PUFA-enriched diets, containing docosahexaenoicacid (DHA; 22:6n-3), have been shown to reduce colon cancer incidence.  Ras proteins are critical regulators of cell function, including growth, differentiation, and apoptosis, with membrane localization and GTP activation of the protein being required for proliferation and malignant transformation. Because the biological activity of Ras is regulated by posttranslational lipid attachment and its interaction with stimulatory lipids being critical for its activation, we investigated whether docosahexaenoic acid (DHA), found in Dhasco oil, compared with linoleic acid (LA), found in corn oil, alters Ras posttranslational processing, activation, and other effector protein functions.  We have recently demonstrated that treatment with DHA in vitro compared with LA, decreases phosphorylated Shc, p38 MAPK, and ERK in WiDr colon carcinoma. These proteins are important effectors of the Ras signaling pathway and are involved in cell proliferation and growth. We show here that treating with DHA in vitro or feeding Dhasco oil in vivo, compared with LA or corn oil, decreases GTP-bound Ras and reduces cell growth in vitro and tumor growth in vivo in athymic nude mice injected subcutaneously with colon carcinoma. Preliminary data suggest that treating or feeding with DHA also lowers the level of phosphorylated EGFR, which is a membrane receptor in which Ras can receive signals for activation. In light of the central role of Ras in the development of colon cancer, the finding that n-3 (DHA) and n-6 (LA) PUFAs differentially alter Ras activation may partly explain why dietary fish oils and other sources high in omega-3 protects against colon cancer development and progression.