tbuckley/cabot-search huggingface dataset:
The BH3-only proapoptotic protein Bim directly links the microtubule poison Paclitaxel to mitochondrial damage and apoptosis
Authors: Rui Li, Tarsem Moudgil, Helen J. Ross, Hong-Ming Hu
Journal: Cancer Research (2004)

5611  Lung cancer is the second most common cancer in the United States, and it claimed more lives than colorectal, breast, and prostate cancer combined. When used alone or in combination with platinum-based drugs or topoisomerase inhibitors, Paclitaxel has proved to be one of the most efficacious chemotherapeutic agents available and it is widely used for lung cancer patients. Paclitaxel induces stabilization of microtubule formation, blockade of G2/M cell cycle transition and leads to subsequent cell death. However, the cell death pathway in lung cancer cells targeted by Paclitaxel is still poorly understood. Recently we have observed a significant difference in the susceptibility to Paclitaxel killing among a panel of short-term cultured non-small cell lung cancer (NSCLC) cell lines. We hypothesized that the difference in killing susceptibility might be explained by the differential expression of BH3 only proteins of Bcl-2 family. To this end, we screened the expression levels of Bim, Bmf, Bax, Bak, Bcl-2 and Bcl-xl in 6 NSCLC cell lines established in our institute and 4 established breast and 2 prostate cancer cell lines. Our results demonstrated that Paclitaxel killing directly correlated to the expression of Bim but not other bcl-2 family members. Paclitaxel induced apoptotic cell death of the NSCLC cell line expressing the highest level of Bim, as determined by the morphological analysis, nuclear fragmentation, activation of caspase-3 and 9, and release of mitochondrial proteins, Cyt c, Smac and AIF. Our results also showed that expression of exogenous Bim in a Bim-negative cell line increased its susceptibility to Paclitaxel killing and it correlated with significant increase of caspase-3 like activity. To obtain the direct evidence that Bim does play an important role in Paclitaxel-induced cell death, we chose the RNA interference approach to inhibit Bim expression in different tumor cell lines to determine whether the suppression of Bim expression could decrease the sensitivity to Paclitaxel killing. Our results demonstrated that knock down Bim expression in Bim positive NSCLC cell line decreased its sensitivity to Paclitaxel-mediated killing. A similar observation was found in a panel of established breast and prostate cancer cell lines. Taking together, we have identified an essential requirement of Bim expression for Paclitaxel killing of NSCLC cells, possibly breast and prostate cancer cells. Microtubule localized Bim appears to be well situated to serve as the important sentinel for stress induced by the damage of microtubule and initiate apoptosis of cells at G2/M phase of cell cycle via intrinsic mitochondrial pathway.
Slow-Cycling Cancer Stem Cells Regulate Progression and Chemoresistance in Colon Cancer
Authors: Daisuke Shiokawa, Hiroaki Sakai, Hirokazu Ohata, Toshiaki Miyazaki, Yusuke Kanda, Shigeki Sekine, Daichi Narushima, Masahito Hosokawa, Mamoru Kato, Yutaka Suzuki, Haruko Takeyama, Hideki Kambara, Hitoshi Nakagama, Koji Okamoto
Journal: Cancer Research (2020)

Cancer chemoresistance is often attributed to the presence of cancer stem cell (CSC)-like cells, but whether they are homogeneously chemoresistant remains unclear. We previously showed that in colon tumors, a subpopulation of LGR5+ CSC-like cells driven by TCF1 (TCF7), a Wnt-responsive transcription factor, were responsible for tumorigenicity. Here we demonstrate that the tumorigenic subpopulation of mouse LGR5+ cells exists in a slow-cycling state and identify a unique 22-gene signature that characterizes these slow-cycling CSC. Seven of the signature genes are specifically expressed in slow-cycling LGR5+ cells from xenografted human colon tumors and are upregulated in colon cancer clinical specimens. Among these seven, four genes (APCDD1, NOTUM, PROX1, and SP5) are known to be direct Wnt target genes, and PROX1 was expressed in the invasive fronts of colon tumors. PROX1 was activated by TCF1 to induce CDKN1C and maintain a slow-cycling state in colon cancer organoids. Strikingly, PROX1 was required for recurrent growth after chemotherapeutic treatment, suggesting that inhibition of slow-cycling CSC by targeting the TCF1-PROX1-CDKN1C pathway is an effective strategy to combat refractory colon cancer in combination with conventional chemotherapy. SIGNIFICANCE: These findings illustrate the importance of a slow-cycling CSC subpopulation in colon cancer development and chemoresistance, with potential implications for the identified slow-cycling CSC signatures and the TCF1-PROX1-CDKN1C pathway as therapeutic targets.
ERK1/2 Signaling Induces Upregulation of ANGPT2 and CXCR4 to Mediate Liver Metastasis in Colon Cancer
Authors: Jelena Urosevic, María Teresa Blasco, Alicia Llorente, Anna Bellmunt, Antoni Berenguer-Llergo, Marc Guiu, Adrià Cañellas, Esther Fernandez, Ivan Burkov, Maria Clapés, Mireia Cartanà, Cristina Figueras-Puig, Eduard Batlle, Angel R. Nebreda, Roger R. Gomis
Journal: Cancer Research (2020)

Carcinoma development in colorectal cancer is driven by genetic alterations in numerous signaling pathways. Alterations in the RAS-ERK1/2 pathway are associated with the shortest overall survival for patients after diagnosis of colorectal cancer metastatic disease, yet how RAS-ERK signaling regulates colorectal cancer metastasis remains unknown. In this study, we used an unbiased screening approach based on selection of highly liver metastatic colorectal cancer cells in vivo to determine genes associated with metastasis. From this, an ERK1/2-controlled metastatic gene set (EMGS) was defined. EMGS was associated with increased recurrence and reduced survival in patients with colorectal cancer tumors. Higher levels of EMGS expression were detected in the colorectal cancer subsets consensus molecular subtype (CMS)1 and CMS4. ANGPT2 and CXCR4, two genes within the EMGS, were subjected to gain-of-function and loss-of-function studies in several colorectal cancer cell lines and then tested in clinical samples. The RAS-ERK1/2 axis controlled expression of the cytokine ANGPT2 and the cytokine receptor CXCR4 in colorectal cancer cells, which facilitated development of liver but not lung metastases, suggesting that ANGPT2 and CXCR4 are important for metastatic outgrowth in the liver. CXCR4 controlled the expression of cytokines IL10 and CXCL1, providing evidence for a causal role of IL10 in supporting liver colonization. In summary, these studies demonstrate that amplification of ERK1/2 signaling in KRAS-mutated colorectal cancer cells affects the cytokine milieu of the tumors, possibly affecting tumor-stroma interactions and favoring liver metastasis formation. SIGNIFICANCE: These findings identify amplified ERK1/2 signaling in KRAS-mutated colorectal cancer cells as a driver of tumor-stroma interactions that favor formation of metastases in the liver.
Boron neutron capture therapy: Current status and future perspectives
Authors: Mayya Alexandrovna Dymova, Sergey Yurjevich Taskaev, Vladimir Alexandrovich Richter, Elena Vladimirovna Kuligina
Journal: Cancer Communications (2020)

Abstract The development of new accelerators has given a new impetus to the development of new drugs and treatment technologies using boron neutron capture therapy (BNCT). We analyzed the current status and future directions of BNCT for cancer treatment, as well as the main issues related to its introduction. This review highlights the principles of BNCT and the key milestones in its development: new boron delivery drugs and different types of charged particle accelerators are described; several important aspects of BNCT implementation are discussed. BCNT could be used alone or in combination with chemotherapy and radiotherapy, and it is evaluated in light of the outlined issues. For the speedy implementation of BCNT in medical practice, it is necessary to develop more selective boron delivery agents and to generate an epithermal neutron beam with definite characteristics. Pharmacological companies and research laboratories should have access to accelerators for large‐scale screening of new, more specific boron delivery agents.
Correspondence on: ‘Interleukin-6 blockade with sarilumab in severe COVID-19 pneumonia with systemic hyperinflammation—an open-label cohort study’ by Della-Torre<i>et al</i>
Authors: Chao Cheng, Fangjie Zhang
Journal: Annals of the Rheumatic Diseases (2020)

We read with deep interest the article by Della-Torre et al ,1 which was aimed at assessing the safety and efficacy of interleukin (IL)-6 blockade with sarilumab in patients with severe COVID-19 pneumonia and systemic hyperinflammation. The results indicated that at day 28, overall clinical improvement and mortality were not significantly different between sarilumab and standard of care. Sarilumab was associated with faster recovery in a subset of patients who showed minor lung consolidation at baseline. This conclusion might be of great significance for alleviating the current COVID-19 pandemic.

However, we noticed that most of the patients in this study met the diagnostic criteria for acute respiratory distress syndrome (ARDS,2 according to the baseline demographic and clinical characteristics of the patients’ cohort, there were 22 patients with a PaO2/FiO2 ratio of 100–200 and 30 patients with a PaO2/FiO2 …
In cancer-associated VTE, apixaban was noninferior to dalteparin for recurrence and did not increase major bleeding
Authors: Irbaz Bin Riaz, Ariela L. Marshall, Robert G. Badgett
Journal: Annals of Internal Medicine (2020)

ACP Journal Club18 August 2020In cancer-associated VTE, apixaban was noninferior to dalteparin for recurrence and did not increase major bleedingIrbaz Bin Riaz, MD, MS, Ariela L. Marshall, MD, Robert G. Badgett, MDIrbaz Bin Riaz, MD, MSMayo Clinic, Rochester, Minnesota, USA (I.B.R., A.L.M.)University of Kansas School of Medicine, Wichita, Kansas, USA (I.B.R., R.G.B.)Search for more papers by this author, Ariela L. Marshall, MDMayo Clinic, Rochester, Minnesota, USA (I.B.R., A.L.M.)Search for more papers by this author, Robert G. Badgett, MDUniversity of Kansas School of Medicine, Wichita, Kansas, USA (I.B.R., R.G.B.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJ202008180-021 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationAgnelli G, Becattini C, Meyer G, et al. Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med. 2020;382:1599-607. https://pubmed.ncbi.nlm.nih.gov/32223112Clinical Impact RatingsHematology: Oncology: References1 Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018;378:615-24. [PMID: 29231094] Google Scholar2 Young AM, Marshall A, Thirlwall J, et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT D). J Clin Oncol. 2018;36:2017-23. [PMID: 29746227] Google Scholar3 openMetaAnalysis Contributors. Cancer associated thromboembolism treatment. Updated 8 June 2020. http://openmetaanalysis.github.io/cat/ (accessed 9 Jun 2020). Google Scholar Author, Article, and Disclosure InformationAffiliations: Mayo Clinic, Rochester, Minnesota, USA (I.B.R., A.L.M.)University of Kansas School of Medicine, Wichita, Kansas, USA (I.B.R., R.G.B.)Disclosures: The commentators have disclosed no conflicts of interest. The forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M19-3045.This article was published at Annals.org on 4 August 2020. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byFSPBO-DQN: SeGAN based segmentation and Fractional Student Psychology Optimization enabled Deep Q Network for skin cancer detection in IoT applications 18 August 2020Volume 173, Issue 4Page: JC21KeywordsApixabanCancer treatmentDeep vein thrombosisDrug interactionsDrugsHemorrhageLung and intrathoracic tumorsPulmonary embolismThrombosisVenous thromboembolism ePublished: 18 August 2020 Issue Published: 18 August 2020 Copyright & PermissionsCopyright © 2020 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Serum potassium in the <scp>PARADIGM‐HF</scp> trial
Authors: João Pedro Ferreira, Ulrik M. Mogensen, Pardeep S. Jhund, Akshay S. Desai, Jean‐Lucien Rouleau, Michael R. Zile, Patrick Rossignol, Faiez Zannad, Milton Packer, Scott D. Solomon, John J.V. McMurray
Journal: European Journal of Heart Failure (2020)

The associations between potassium level and outcomes, the effect of sacubitril-valsartan on potassium level, and whether potassium level modified the effect of sacubitril-valsartan in patients with heart failure and a reduced ejection fraction were studied in PARADIGM-HF. Several outcomes, including cardiovascular death, sudden death, pump failure death, non-cardiovascular death and heart failure hospitalization, were examined.A total of 8399 patients were randomized to either enalapril or sacubitril-valsartan. Potassium level at randomization and follow-up was examined as a continuous and categorical variable (≤3.5, 3.6-4.0, 4.1-4.9, 5.0-5.4 and ≥5.5 mmol/L) in various statistical models. Hyperkalaemia was defined as K+ ≥5.5 mmol/L and hypokalaemia as K+ ≤3.5 mmol/L. Compared with potassium 4.1-4.9 mmol/L, both hypokalaemia [hazard ratio (HR) 2.40, 95% confidence interval (CI) 1.84-3.14] and hyperkalaemia (HR 1.42, 95% CI 1.10-1.83) were associated with a higher risk for cardiovascular death. However, potassium abnormalities were similarly associated with sudden death and pump failure death, as well as non-cardiovascular death and heart failure hospitalization. Sacubitril-valsartan had no effect on potassium overall. The benefit of sacubitril-valsartan over enalapril was consistent across the range of baseline potassium levels.Although both higher and lower potassium levels were independent predictors of cardiovascular death, potassium abnormalities may mainly be markers rather than mediators of risk for death.
Neuromuscular Controller Models for Quantifying Standing Balance in Older People: A Systematic Review
Authors: Fredrik Olsson, Kjartan Halvorsen, Anna Cristina Aberg
Journal: IEEE Reviews in Biomedical Engineering (2021)

Objective quantification of the balancing mechanisms in humans is strongly needed in health care of older people, yet is largely missing among current clinical balance assessment methods. Hence, the main goal of this literature review is to identify methods that have the potential to meet that need. We searched in the PubMed and IEEE Xplore databases using predefined criteria, screened 1064 articles, and systematically reviewed and categorized methods from 73 studies that deal with identification of neuromuscular controller models of human upright standing from empirical data. These studies were then analyzed with the particular aim to understand to what degree such methods would be useful solutions for assessing the balance of older individuals aged above 60 years. The 16 studies that included an older subject population were especially examined with this in mind. The majority of the reviewed articles focused on research questions related to the general function of human balance control rather than clinical applicability. Further efforts need to be made to adapt these methods for more accessible and mobile technologies and to ensure that the outcomes are valid for balance assessment of a general older population.
The Paradoxical Effects of COVID-19 on Cancer Care: Current Context and Potential Lasting Impacts
Authors: Alex Broom, Katherine Kenny, Alexander Page, Nicole Cort, Eric S. Lipp, Aaron C. Tan, David M. Ashley, Kyle M. Walsh, Mustafa Khasraw
Journal: Clinical Cancer Research (2020)

Abstract Coronavirus disease 2019 (COVID-19) has fundamentally disrupted the practice of oncology, shifting care onto virtual platforms, rearranging the logistics and economics of running a successful clinical practice and research, and in some contexts, redefining what treatments patients with cancer should and can receive. Since the start of the pandemic in early 2020, there has been considerable emphasis placed on the implications for patients with cancer in terms of their vulnerability to the virus and potential exposure in healthcare settings. But little emphasis has been placed on the significant, and potentially enduring, consequences of COVID-19 for how cancer care is delivered. In this article, we outline the importance of a focus on the effects of COVID-19 for oncology practice during and potentially after the pandemic, focusing on key shifts that are already evident, including: the pivot to online consultations, shifts in access to clinical trial and definitions of “essential care,” the changing economics of practice, and the potential legacy effects of rapidly implemented changes in cancer care. COVID-19 is reshaping oncology practice, clinical trials, and delivery of cancer care broadly, and these changes might endure well beyond the short- to mid-term of the active pandemic. Therefore, shifts in practice brought about by the pandemic must be accompanied by improved training and awareness, enhanced infrastructure, and evidence-based support if they are to harness the positives and offset the potential negative consequences of the impacts of COVID-19 on cancer care.
Article on prostate cancer should have adhered to agreed staging terminology
Authors: M. Hehir, L. Walker
Journal: BMJ (1996)

Physicians working group, whose members included paediatricians, paediatric nephrologists, radiologists, microbiologists, general practitioners, paediatric urologists, and a parent.2The article makes no reference to the vital importance of the child's age to management, despite clear evidence that younger children are at far greater risk of developing renal scars with a urinary tract infection, infants under 1 year being especially vulnerable.This explains the
Abstract 5660: Characterisation of novel CD73 antibodies as a therapeutic method of adenosine regulation
Authors: Grainne Gernon, Suzanne Grooby, Louise Tonkin, Anja-Christina Bitterwolf, Lorna Stewart, Marcel Deken, Pritom Shah, Katherine Ewings, Zoe Johnson
Journal: Cancer Research (2020)

Abstract CD73 is a membrane-bound nucleotidase receptor which is frequently overexpressed in the tumour microenvironment and can be found on both tumour and immune cell types. Its function is to catalyse the conversion of adenosine monophosphate (AMP) to adenosine and phosphate and it has been proposed as a therapeutic target in cancer due to adenosines role in tumour immune suppression. Using multiple approaches, a series of novel CD73 antibodies have been characterised for their therapeutic potential and benchmarked against agents currently undergoing clinical evaluation Inhibition of CD73 activity was evaluated using an Amplex Red-based coupled adenosine assay against both human and mouse CD73, and kinetics of antibody binding were determined using BioLayer Interferometry. Cellular assays were then utilised to further evaluate the antibodies in vitro. The ability of the CD73 antibodies to internalise was evaluated using two different methods, a Fab-ZAP killing assay and the IncuCyteTM FabFluor internalisation assay. The antibodies have also undergone functional studies, investigating the ability of the CD73 antibodies to disrupt the production of adenosine in tumour cells. We demonstrate that the novel CD73 antibodies inhibit CD73 function by two different mechanisms; direct inhibition of enzyme activity and modulation of cell surface expression, both of a which have therapeutic potential to disrupt CD73-mediated adenosine production and therefore reduce antitumor immune responses. Ongoing studies are investigating the in vitro and in vivo efficacy of the clone selected for further development as a monotherapy and in combination with a novel small molecule inhibitor in murine models of cancer. Citation Format: Grainne Gernon, Suzanne Grooby, Louise Tonkin, Anja-Christina Bitterwolf, Lorna Stewart, Marcel Deken, Pritom Shah, Katherine Ewings, Zoe Johnson. Characterisation of novel CD73 antibodies as a therapeutic method of adenosine regulation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5660.
Abstract 14717: Prognostic Importance of Borderline Pulmonary Hypertension Associated With Connective Tissue Diseases
Authors: Yoshiyuki Orihara, Masanori Asakura, Yuki Matsumoto, Tomotaka Ando, Yoshitaka Okuhara, Kazunori Kashiwase, Masaharu Ishihara, Tohru Masuyama
Journal: Circulation (2018)

Background: Pulmonary hypertension (PH) is a lethal complication in patients with connective tissue disease (CTD). Recently, great deal of attenton has been focused on poor prognosis in patients wi...
The Old Dilemma
Authors: Jack Coulehan
Journal: Annals of Internal Medicine (2020)

Ad Libitum18 August 2020The Old DilemmaJack Coulehan, MDJack Coulehan, MDCenter for Medical Humanities, Compassionate Care, and Bioethics at Stony Brook University, Stony Brook, New York (J.C.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M19-0935 Audio Reading - “The Old Dilemma” Audio. Michael A. Lacombe, MD, Annals Associate Editor, reads “The Old Dilemma” by Jack Coulehan, MD Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail The blade of ethics rips close to your skin.... Author, Article, and Disclosure InformationAffiliations: Center for Medical Humanities, Compassionate Care, and Bioethics at Stony Brook University, Stony Brook, New York (J.C.)Current Author Address: Jack Coulehan, MD; e-mail, john.[email protected]edu. PreviousarticleNextarticle Advertisement Audio Reading - “The Old Dilemma” Audio. Michael A. Lacombe, MD, Annals Associate Editor, reads “The Old Dilemma” by Jack Coulehan, MD Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics 18 August 2020Volume 173, Issue 4Page: 261 ePublished: 18 August 2020 Issue Published: 18 August 2020 Copyright & PermissionsCopyright © 2020 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...