tbuckley/cabot-search huggingface dataset:
Pharmacogenomic strategies provide a rational approach to the treatment of cisplatin-resistant patients with advanced non- small cell lung cancer (NSCLC)
Authors: C. Acharya, D. Hsu, B. Balakumaran, K. Walters, V. Vlahovic, R. Riedel, J. Garst, P. Febbo, J. Nevins, A. Potti
Journal: Journal of Clinical Oncology (2007)

7501 Background: Standard treatment for advanced non-small lung cancer (NSCLC) includes platinum-based therapy. Response is however suboptimal and unpredictable. Newer agents, such as pemetrexed, have shown significant activity in the second-line setting, but their role in the first-line setting is unknown. Methods: Using in vitro drug sensitivity data, coupled with Affymetrix microarray data, gene expression signatures predicting sensitivity to cisplatin and pemetrexed were developed, using methods previously described (Nature Medicine, 2006). Signatures were validated with response data from 32 independent ovarian and lung cancer cell lines as well as 59 patient samples. Results: Genomic-derived signatures of cisplatin and pemetrexed sensitivity were shown to accurately predict response in vitro and, in the case of cisplatin, in 59 samples obtained from advanced disease patients previously treated with cisplatin. The accuracy of the cisplatin predictor, using clinical response as the endpoint, was 83.1% (Sensitivity: 100%, Specificity: 57%). In comparison, determination of ERCC1 status (IHC) had a predictive accuracy of 62% (Sensitivity: 82.8%, Specificity: 33.3%). Interestingly, a significant inverse correlation (p = 0.004) was found between the likelihood of cisplatin and pemetrexed sensitivity in the NSCLC cell lines. This relationhip was further validated in another indepedent cohort of 91 patients with NSCLC (p &lt; 0.01). Finally, using novel cell proliferation experiments, we show that tumors from cisplatin refractory patients that are initially sensitive to pemetrexed, if treated with a taxane (docetaxel or paclitaxel) prior to pemetrexed therapy, develop resistance to subsequent pemetrexed therapy. Conclusions: The use of gene expression signatures that predict cisplatin and pemetrexed sensitivity can be incorporated into strategies to refine the selection of chemotherapeutic drugs chosen as first-line therapy in advanced NSCLC. It is critical for future prospective studies to validate the use of pharmacogenomic predictors of chemosensitivity in NSCLC, to optimize response rates and survival benefit. No significant financial relationships to disclose.
Natural killer T cell activation increases iNOS+CD206- M1 macrophage and controls the growth of solid tumor
Authors: Sourav Paul, Sushanta Chhatar, Amrita Mishra, Girdhari Lal
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> NKT cells play an important role in anti-tumor immunity. Alpha-galactosylceramide (α-GalCer), a synthetic glycolipid is presented to natural killer T (NKT) cells by most antigen-presenting cells through CD1d molecules leading to activation of NKT cells. However, the precise mechanisms of how α-GalCer-activated NKT regulate the polarization of the macrophages and effector T cells in the solid tumor are not studied adequately. <h3>Methods</h3> We induced solid tumor in C57BL/6 mice by subcutaneous injection of B16F10 cell line (1 X 10<sup>6</sup> cells) and monitored the tumor growth. Animals were given an intraperitoneal injection of α-GalCer (2 μg/injection) in 200 μl PBS on day + 1, + 5, + 10, + 15, and + 20 (with respect to tumor cell injection). Immune cells were characterized using flow cytometry and immunofluorescence staining. NK cells, Gr1<sup>+</sup> cells, and F4/80<sup>+</sup> macrophages in the mice were depleted by intravenous injection of cell-specific antibodies. Statistical analysis was performed using Student's <i>t</i>-test or one-way ANOVA. <h3>Results</h3> Our results showed that intratumoral NKT cells have a lower frequency of CD69, CD25, CD122, and IFN-γR expression; produced less inflammatory cytokines such as IFN-γ, TNF-α, and GM-CSF; higher frequency CD62L<sup>+</sup> NKT cells; and also showed reduced proliferation as compared to the splenic NKT cells. Mice treated with α-GalCer showed a significantly increased frequency of IFN-γ-producing NKT cells, CD8<sup>+</sup> T cells, and effector Th1 cells. Depletion of NK cells in α-GalCer-treated mice showed a lower frequency of IFN-γ-producing CD4<sup>+</sup> and CD8<sup>+</sup> T cells in the tumor and prevented the α-GalCer-induced tumor growth. NKT cell activation with α-GalCer treatment significantly increased the iNOS<sup>+</sup>CD206<sup>−</sup> M1-macrophages and reduced the iNOS<sup>−</sup>CD206<sup>+</sup> M2-macrophages in the spleen and tumor, and depletion of F4/80<sup>+</sup> macrophages prevented the α-GalCer-induced reduction in the tumor growth. <h3>Conclusions</h3> We showed that activation of NKT cell with α-GalCer modulates the frequency of M1-macrophages and effector Th1 cells in the secondary lymphoid tissues and tumor microenvironment and inhibit tumor growth. The finding suggests that activation of NKT cells with α-GalCer may provide an effective anti-cancer outcome.
Meta-analysis Metastasis
Authors: Joshua D. Wallach
Journal: JAMA Internal Medicine (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Renin-Angiotensin System Inhibition Following Transcatheter Aortic Valve Replacement
Authors: Tania Rodriguez-Gabella, Pablo Catalá, Antonio J. Muñoz-García, Luis Nombela-Franco, Raquel Del Valle, Enrique Gutiérrez, Ander Regueiro, Victor A. Jimenez-Diaz, Henrique B. Ribeiro, Fernando Rivero, Jose Antonio Fernandez-Diaz, Philippe Pibarot, Juan H. Alonso-Briales, Gabriela Tirado-Conte, César Moris, Felipe Diez Del Hoyo, Gustavo Jiménez-Britez, Nicolas Zaderenko, Fernando Alfonso, Itziar Gómez, Manuel Carrasco-Moraleja, Josep Rodés-Cabau, J. Alberto San Román Calvar, Ignacio J. Amat-Santos
Journal: Journal of the American College of Cardiology (2019)
Following Australia’s lead to eradicate cervical cancer
Authors: Keira J Bralsford, Elias Jamieson
Journal: BMJ (2019)

We agree that high vaccine coverage is key to the eradication of cervical cancer1; Australia’s HPV vaccination programme has been a leader in attempting to achieve this. Australia was the first country to introduce a nationwide HPV vaccination programme in 2007. It has among the lowest rates of cervical cancer …
Circumvent anxiety of patients (CAP) while receiving chemotherapy at one-day hospital.
Authors: Joseph Gergi Kattan, Alain Daher, Lama jaoudat Assaker, Yolla Tanios Jreige, Rachide Jamil Aintouri, Rouba Eid
Journal: Journal of Clinical Oncology (2013)

e20500 Background: Transforming patient anxiety to comfort during chemotherapy delivery is the desire of every cancer care givers. For the first time, a beauty clinic services are offered to adult cancer patients, while receiving one-day chemotherapy. Methods: One-day unit at Saint Joseph hospital is an independent department including 12 beds and serving around 160 chemotherapy sessions per month. A professional physiotherapist in beauty care and relaxation massage offers her services for every patient during 15 minutes session at his own bed. CAP program was approved by Saint Joseph ethical committee and supported by Jane Nassar institute. Evaluation questionnaires were filled by randomly selected patients. Results: CAP program was initiated in August 2012. Around 10 patients per day were included. 90% of our patients welcome the program and participate. The majority of patients who refused participation at the first visit accept it during the second session. Men choose hands or feet relaxation massage and women usually face beauty care. 22 patients were randomly selected to fill the CAP-evaluation questionnaire. Among these 22 patients, 2 (9%) refused to participate in the program, one of them did not have a clear reason, the other attributed to a state of uncomfortable and depression. Among the 20 who participated, 90% had at least two sessions, 100% would advise other patients to participate, 95% of them believe that this service adds an advantage to delivered care and provides a restful atmosphere, and all of them encourage the department to continue to provide this service. Conclusions: Psychosocial support is almost lacking in the management of our patients leading to increase their anxiety while receiving chemotherapy. CAP program represents a unique experience and temptation in adult patients to circumvent their anxiety.
End of season influenza vaccine effectiveness in adults and children in the United Kingdom in 2017/18
Authors: Richard Pebody, Abdelmajid Djennad, Joanna Ellis, Nick Andrews, Diogo F P Marques, Simon Cottrell, Arlene J Reynolds, Rory Gunson, Monica Galiano, Katja Hoschler, Angie Lackenby, Chris Robertson, Mark O’Doherty, Mary Sinnathamby, Nikolaos Panagiotopoulos, Ivelina Yonova, Rebecca Webb, Catherine Moore, Matthew Donati, Muhammad Sartaj, Samantha J Shepherd, Jim McMenamin, Simon de Lusignan, Maria Zambon
Journal: Eurosurveillance (2019)

Background In the United Kingdom (UK), in recent influenza seasons, children are offered a quadrivalent live attenuated influenza vaccine (LAIV4), and eligible adults mainly trivalent inactivated vaccine (TIV). Aim To estimate the UK end-of-season 2017/18 adjusted vaccine effectiveness (aVE) and the seroprevalence in England of antibodies against influenza viruses cultured in eggs or tissue. Methods This observational study employed the test-negative case–control approach to estimate aVE in primary care. The population-based seroprevalence survey used residual age-stratified samples. Results Influenza viruses A(H3N2) (particularly subgroup 3C.2a2) and B (mainly B/Yamagata/16/88-lineage, similar to the quadrivalent vaccine B-virus component but mismatched to TIV) dominated. All-age aVE was 15% (95% confidence interval (CI): −6.3 to 32) against all influenza; −16.4% (95% CI: −59.3 to 14.9) against A(H3N2); 24.7% (95% CI: 1.1 to 42.7) against B and 66.3% (95% CI: 33.4 to 82.9) against A(H1N1)pdm09. For 2–17 year olds, LAIV4 aVE was 26.9% (95% CI: −32.6 to 59.7) against all influenza; −75.5% (95% CI: −289.6 to 21) against A(H3N2); 60.8% (95% CI: 8.2 to 83.3) against B and 90.3% (95% CI: 16.4 to 98.9) against A(H1N1)pdm09. For ≥ 18 year olds, TIV aVE against influenza B was 1.9% (95% CI: −63.6 to 41.2). The 2017 seroprevalence of antibody recognising tissue-grown A(H3N2) virus was significantly lower than that recognising egg-grown virus in all groups except 15–24 year olds. Conclusions Overall aVE was low driven by no effectiveness against A(H3N2) possibly related to vaccine virus egg-adaption and a new A(H3N2) subgroup emergence. The TIV was not effective against influenza B. LAIV4 against influenza B and A(H1N1)pdm09 was effective.
Linker histones are fine-scale chromatin architects modulating developmental decisions in Arabidopsis
Authors: Kinga Rutowicz, Maciej Lirski, Benoît Mermaz, Gianluca Teano, Jasmin Schubert, Imen Mestiri, Magdalena A. Kroteń, Tohnyui Ndinyanka Fabrice, Simon Fritz, Stefan Grob, Christoph Ringli, Lusik Cherkezyan, Fredy Barneche, Andrzej Jerzmanowski, Célia Baroux
Journal: Genome biology (2019)

Chromatin provides a tunable platform for gene expression control. Besides the well-studied core nucleosome, H1 linker histones are abundant chromatin components with intrinsic potential to influence chromatin function. Well studied in animals, little is known about the evolution of H1 function in other eukaryotic lineages for instance plants. Notably, in the model plant Arabidopsis, while H1 is known to influence heterochromatin and DNA methylation, its contribution to transcription, molecular, and cytological chromatin organization remains elusive. We provide a multi-scale functional study of Arabidopsis linker histones. We show that H1-deficient plants are viable yet show phenotypes in seed dormancy, flowering time, lateral root, and stomata formation—complemented by either or both of the major variants. H1 depletion also impairs pluripotent callus formation. Fine-scale chromatin analyses combined with transcriptome and nucleosome profiling reveal distinct roles of H1 on hetero- and euchromatin: H1 is necessary to form heterochromatic domains yet dispensable for silencing of most transposable elements; H1 depletion affects nucleosome density distribution and mobility in euchromatin, spatial arrangement of nanodomains, histone acetylation, and methylation. These drastic changes affect moderately the transcription but reveal a subset of H1-sensitive genes. H1 variants have a profound impact on the molecular and spatial (nuclear) chromatin organization in Arabidopsis with distinct roles in euchromatin and heterochromatin and a dual causality on gene expression. Phenotypical analyses further suggest the novel possibility that H1-mediated chromatin organization may contribute to the epigenetic control of developmental and cellular transitions.
Computational Biology Approach to Predict Hypomethylating Agent (HMA) Response Using Genomic and Clinical Characteristics in Myelodsyplastic Syndromes (MDS)
Authors: Leylah M. Drusbosky, Salah-Eddin Komrokji, Najla Al Ali, Neeraj Kumar Singh, Chandan Kumar, Sumanth Vasista, Diwyanshu Sahu, Ganesh Naga, Patil Dattatraya, Taher Abbasi, Shireen Vali, David A Sallman, Rami S. Komrokji, Christopher R. Cogle
Journal: Blood (2017)
Evaluation of a digitally-enabled care pathway for acute kidney injury management in hospital emergency admissions
Authors: Alistair Connell, Hugh Montgomery, Peter Martin, Claire Nightingale, Omid Sadeghi-Alavijeh, Dominic King, Alan Karthikesalingam, Cian Hughes, Trevor Back, Kareem Ayoub, Mustafa Suleyman, Gareth Jones, Jennifer Cross, Sarah Stanley, Mary Emerson, Charles Merrick, Geraint Rees, Chris Laing, Rosalind Raine
Journal: npj Digital Medicine (2019)

Abstract We developed a digitally enabled care pathway for acute kidney injury (AKI) management incorporating a mobile detection application, specialist clinical response team and care protocol. Clinical outcome data were collected from adults with AKI on emergency admission before (May 2016 to January 2017) and after (May to September 2017) deployment at the intervention site and another not receiving the intervention. Changes in primary outcome (serum creatinine recovery to ≤120% baseline at hospital discharge) and secondary outcomes (30-day survival, renal replacement therapy, renal or intensive care unit (ICU) admission, worsening AKI stage and length of stay) were measured using interrupted time-series regression. Processes of care data (time to AKI recognition, time to treatment) were extracted from casenotes, and compared over two 9-month periods before and after implementation (January to September 2016 and 2017, respectively) using pre–post analysis. There was no step change in renal recovery or any of the secondary outcomes. Trends for creatinine recovery rates (estimated odds ratio (OR) = 1.04, 95% confidence interval (95% CI): 1.00–1.08, p = 0.038) and renal or ICU admission (OR = 0.95, 95% CI: 0.90–1.00, p = 0.044) improved significantly at the intervention site. However, difference-in-difference analyses between sites for creatinine recovery (estimated OR = 0.95, 95% CI: 0.90–1.00, p = 0.053) and renal or ICU admission (OR = 1.06, 95% CI: 0.98–1.16, p = 0.140) were not significant. Among process measures, time to AKI recognition and treatment of nephrotoxicity improved significantly ( p &lt; 0.001 and 0.047 respectively).
Decline of programmed death‐1‐positive circulating T regulatory cells predicts more favourable clinical outcome of patients with melanoma under immune checkpoint blockade
Authors: T. Gambichler, U. Schröter, S. Höxtermann, L. Susok, E. Stockfleth, J.C. Becker
Journal: British Journal of Dermatology (2019)

The role of T regulatory lymphocytes (Tregs) and their immunosuppressive mechanisms in the context of programmed death (PD)‐1 blockade is not completely understood. To assess the impact of PD‐1‐blocking antibody treatment on Treg subpopulations in the blood. We studied circulating Treg subpopulations in patients with melanoma under nivolumab or pembrolizumab treatment using flow cytometry and correlated these findings with clinical outcomes. These analyses revealed that the frequency of CD4+ CD25++ CD127− PD‐1+ lymphocytes (PD‐1+ Tregs) significantly decreased after the first cycle of immunotherapy (23% vs. 8·6%, P = 0·043). Compared with patients who did not show a significant decline of PD‐1+ Tregs after the first treatment, those who did had better clinical outcomes with respect to progression‐free survival (PFS, P = 0·022) and melanoma‐specific death (MSD, P = 0·0038). Multivariate analysis confirmed that a significant decline of PD‐1+ Tregs in peripheral blood after the first treatment cycle is a significant predictor of more favourable PFS and MSD (P = 0·04 and 0·017, respectively). Interestingly, the occurrence of immune‐related adverse events was also an independent predictor for decreased risk of MSD (P = 0·047; odds ratio 0·064, 95% confidence interval 0·0042–0·97). We provide preliminary evidence that circulating PD‐1+ Tregs rapidly decline after the initiation of treatment with PD‐1‐blocking antibodies, which is associated with reduced risk of melanoma progression and MSD. Patients showing no decrease of these PD‐1+ Tregs in peripheral blood are characterized by an impaired response to immune checkpoint blockade and worse outcome. What's already known about this topic? Programmed death (PD)‐1‐blocking antibodies are highly effective in melanoma treatment. However, more than half of patients do not benefit from this therapy and to date it is difficult to predict which patients will respond to it. What does this study add? PD‐1‐blocking antibody therapy rapidly results in a decline of circulating PD‐1+ T regulatory cells (Tregs). What is the translational message? Patients showing a decrease of PD‐1+ Tregs appear to have better clinical outcome under PD‐1 treatment.
An LKB1–SIK Axis Suppresses Lung Tumor Growth and Controls Differentiation
Authors: Christopher W. Murray, Jennifer J. Brady, Min K. Tsai, Chuan Li, Ian P. Winters, Rui Tang, Laura Andrejka, Rosanna K. Ma, Christian A. Kunder, Pauline Chu, Monte M. Winslow
Journal: Cancer Discovery (2019)

The kinase LKB1 is a critical tumor suppressor in sporadic and familial human cancers, yet the mechanisms by which it suppresses tumor growth remain poorly understood. To investigate the tumor-suppressive capacity of four canonical families of LKB1 substrates in vivo, we used CRISPR/Cas9-mediated combinatorial genome editing in a mouse model of oncogenic KRAS-driven lung adenocarcinoma. We demonstrate that members of the SIK family are critical for constraining tumor development. Histologic and gene-expression similarities between LKB1- and SIK-deficient tumors suggest that SIKs and LKB1 operate within the same axis. Furthermore, a gene-expression signature reflecting SIK deficiency is enriched in LKB1-mutant human lung adenocarcinomas and is regulated by LKB1 in human cancer cell lines. Together, these findings reveal a key LKB1-SIK tumor-suppressive axis and underscore the need to redirect efforts to elucidate the mechanisms through which LKB1 mediates tumor suppression. SIGNIFICANCE: Uncovering the effectors of frequently altered tumor suppressor genes is critical for understanding the fundamental driving forces of cancer growth. Our identification of the SIK family of kinases as effectors of LKB1-mediated tumor suppression will refocus future mechanistic studies and may lead to new avenues for genotype-specific therapeutic interventions.This article is highlighted in the In This Issue feature, p. 1469.
Sorafenib monotherapy in patients with treatment-naïve metastatic renal cell cancer: preliminary results of a phase II intra-patient dose-escalation study
Authors: S. Srinivas, L. Harshman, R. J. Hauke
Journal: Journal of Clinical Oncology (2009)

e14564 Background: In a phase I dose finding study, the maximum tolerated dose of sorafenib was determined to be 400 mg bid. In subsequent practice, these doses of sorafenib have been associated with minimal or reversible toxicity, which presented an opportunity to explore more intensive dosing. A single institution trial of 44 patients demonstrated complete responses in 26% and partial responses in 36%. 93% of patients were able to be dose escalated. The objective of our study was to confirm these findings. The primary endpoints for this study were safety, feasibility, and toxicity. Secondary endpoints included overall response rate (ORR) and progression- free survival (PFS). Methods: Patients with treatment-naïve metastatic renal cell with clear cell histology were enrolled at Stanford University and the University of Nebraska Medical Center. Cycles consisted of 28 days. Dose limiting toxicity (DLT) was defined as grade 3/ 4 toxicity. Patients received sorafenib 400mg bid for 28 days. If no DLT's were reported after the first cycle, patients were dose escalated to sorafenib 600 mg bid for cycle 2. Patients without DLTs at the end of the second cycle were dose escalated to the highest dose, sorafenib 800 mg bid. Patients continued on therapy until progression or unacceptable toxicity. Results: To date, thirteen patients have been treated. Median age was 63 (47–84) years. The majority (84%) were men. Ten patients had nephrectomy prior to trial initiation. Sites of metastases included lung, nodes, liver, adrenal glands, and bone. Dose escalation was possible in 70% of the patients. Median number of cycles was 7 (3–12). Hand-foot syndrome (skin toxicity) limited escalation in the other 30% of patients. One pathologic complete response was obtained after a patient underwent metastectomy of adrenal gland after 4 cycles. One patient achieved a partial response and seven experienced disease stabilization. Conclusions: This dose-escalation trial is ongoing. Dose escalation has been feasible in 70% of patients. The main toxicity limiting escalation was hand-foot syndrome. Thus far, dose escalation did not result in an increased number of responses as compared to the standard 800mg/d dosing. PFS data will be presented as data matures. [Table: see text]