tbuckley/cabot-search huggingface dataset:
Two-Photon Intravital Fluorescence Lifetime Imaging of the Kidney Reveals Cell-Type Specific Metabolic Signatures
Authors: Takashi Hato, Seth Winfree, Richard Day, Ruben M. Sandoval, Bruce A. Molitoris, Mervin C. Yoder, Roger C. Wiggins, Yi Zheng, Kenneth W. Dunn, Pierre C. Dagher
Journal: Journal of the American Society of Nephrology (2017)

In the live animal, tissue autofluorescence arises from a number of biologically important metabolites, such as the reduced form of nicotinamide adenine dinucleotide. Because autofluorescence changes with metabolic state, it can be harnessed as a label-free imaging tool with which to study metabolism in vivo Here, we used the combination of intravital two-photon microscopy and frequency-domain fluorescence lifetime imaging microscopy (FLIM) to map cell-specific metabolic signatures in the kidneys of live animals. The FLIM images are analyzed using the phasor approach, which requires no prior knowledge of metabolite species and can provide unbiased metabolic fingerprints for each pixel of the lifetime image. Intravital FLIM revealed the metabolic signatures of S1 and S2 proximal tubules to be distinct and resolvable at the subcellular level. Notably, S1 and distal tubules exhibited similar metabolic profiles despite apparent differences in morphology and autofluorescence emission with traditional two-photon microscopy. Time-lapse imaging revealed dynamic changes in the metabolic profiles of the interstitium, urinary lumen, and glomerulus-areas that are not resolved by traditional intensity-based two-photon microscopy. Finally, using a model of endotoxemia, we present examples of the way in which intravital FLIM can be applied to study kidney diseases and metabolism. In conclusion, intravital FLIM of intrinsic metabolites is a bias-free approach with which to characterize and monitor metabolism in vivo, and offers the unique opportunity to uncover dynamic metabolic changes in living animals with subcellular resolution.
Checkpoint Blockade in Lung Cancer and Mesothelioma
Authors: Lysanne A. Lievense, Daniel H. Sterman, Robin Cornelissen, Joachim G. Aerts
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

In the last decade, immunotherapy has emerged as a new treatment modality in cancer. The most success has been achieved with the class of checkpoint inhibitors (CPIs), antibodies that unleash the antitumor immune response. After the success in melanoma, numerous clinical trials are being conducted investigating CPIs in lung cancer and mesothelioma. The programmed death protein (PD) 1-PD ligand 1/2 pathway and cytotoxic T lymphocyte-associated protein 4 are currently the most studied immunotherapeutic targets in these malignancies. In non-small cell lung cancer, anti-PD-1 antibodies have become part of the approved treatment arsenal. In small cell lung cancer and mesothelioma, the efficacy of checkpoint inhibition has not yet been proven. In this Concise Clinical Review, an overview of the landmark clinical trials investigating checkpoint blockade in lung cancer and mesothelioma is provided. Because response rates are around 20% in the majority of clinical trials, there is much room for improvement. Predictive biomarkers are therefore essential to fully develop the potential of CPIs. To increase efficacy, multiple clinical trials investigating the combination of cytotoxic T lymphocyte-associated protein 4 inhibitors and PD-1/PD ligand 1 blockade in lung cancer and mesothelioma are being conducted. Given the potential benefit of immunotherapy, implementation of current and new knowledge in trial designs and interpretation of results is essential for moving forward.
Abstract P1-07-06: Immune signatures define and affect prognosis in triple-negative breast cancer subtypes
Authors: G Bottai, G Balazs, A Nagy, L Pusztai, Z Szallasi, JS Reis-Filho, L Santarpia
Journal: Cancer Research (2017)

Abstract Background: The tumor immune microenvironment is formed by many distinct and interacting cell populations, and its composition may predict patient's prognosis and response to therapies. Triple negative breast cancer (TNBC) is a heterogeneous disease in which different genomic subgroups have been described (Lehmann, et al. J Clin Invest.2011). Our aim was to integrate the composition of the tumor immune microenvironment with the molecular TNBC subtypes. Methods: We retrospectively analyzed the composition and the functional orientation of the immune microenvironment of 963 TNBC tumors clustered in 4 main TNBC subgroups (Basal-Like [BL1/2], Immunomodulatory [IM], Mesenchymal/Mesenchymal Stem-Like [MS], Androgen Receptor [AR]) from independent cohorts using transcriptomic profiling. TNBC were stratified based on 9 different immune signatures (Natural Killer [NK], Dendritic Cells [DC], T-Cells [TC], B-Cells [BC], T-Cytotoxic [TC], Interferon [IF], Nuclear Factor-kB [NF-kB], anti-tumor Macrophages [M1] and pro-tumor Macrophages [M2]. We validated our findings using immunohistochemistry. Results: We report that TNBC molecular subgroups and specific microenvironmental immune signatures are highly correlated. The IM was enriched of almost all the immune modules. On overall TNBC population, the TC (P = 0.01), IF (P = 0.007) and M1 (P = 0.001) signatures were associated with good prognosis. The BL subgroup with a good prognosis was characterized by overexpression of genes specific to M1-macrophages (P = 0.004) and TC-lymphocytes (P = 0.01). In contrast, the poor-prognosis MS expresses markers of cells of monocytic origin and significantly associated with the M2 signature (P = 0.01). The MS subgroup also displays an inflammatory and immunosuppressive signature. Pathological examination revealed that the MS subtype is characterized by a high density of pro-tumor macrophages that likely produce chemokines and cytokines which favor tumor-associated inflammation, resulting in a poor prognosis. In contrast, the AR exhibits low immune and inflammatory signatures. Conclusions: The distinct immune orientations of the TNBC molecular subtypes pave the way for tailored immunotherapies. Citation Format: Bottai G, Balazs G, Nagy A, Pusztai L, Szallasi Z, Reis-Filho JS, Santarpia L. Immune signatures define and affect prognosis in triple-negative breast cancer subtypes [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-07-06.
Reasons for changing hormonal therapy of advanced breast cancer.
Authors: Katarina Petrakova, Lubos B. Petruzelka, Vit Kandrnal
Journal: Journal of Clinical Oncology (2012)

e11047 Background: Blood levels of tumor markers are widely used to assess response/progression to breast cancer treatment and guide therapy change in the real world setting compared to clinical trials where treatment efficacy is assessed by imaging methods. Our aim was to describe management of ER+ advanced breast cancer and reasons for treatment change in postmenopausal patients (pt) with hormone sensitive advanced breast cancer in the Czech Republic. Methods: The study was a retrospective, multi-centre, observational study that collected data from postmenopausal pt with hormone sensitive advanced breast cancer that have been treated with minimum two hormonal agents according to approved SmPC. Data collection started in February 2011in 16 centres in the Czech republic. The target number of enrolled pt was 400. Standard descriptive statistical methods were used for data analysis. Confidence intervals are reported where applicable. Results: We present an interim analysis of the study based on 169 pt enrolled till 21 st July 2011. 150 pt have evaluable data. Median age was 55 years. Median time from diagnosis of BC to metastatic dissemination is 44.0 months (mean time 62.5 months). BC was diagnosed in Stage I in 12.0%, Stage II 43.3%, Stage III 24.0% and Stage IV 20.7%. Rebiopsy was done in 27.0% of pt who developed metastases (M). 63,5% pt were diagnosed with bone M, 45,3% with lymph node and soft tissue M, 22,3% with lung M, only 9,5% with liver M. 65% pt were treated with hormonotherapy in the first line and 84,2% in the second line. The main reason for hormonotherapy change was the progression according to examination (63%), elevation of tumor markers (13%), progression of symptoms (8%) intolerance of the treatment (3%) and other reasons (13%). Conclusions: Pt treated in the first line with hormonotherapy in daily practice in the Czech Republic are mostly pt without organ M. Pt with organ M are treated first with chemotherapy. Increase of tumor markers is the reason for treatment change in 13% of pt, progression of symptoms in 8%.
Abstract P6-11-12: Subgroup Analysis by prior treatment and disease burden in MONARCH 1: A phase 2 study of monotherapy abemaciclib, a CDK4 &amp; 6 inhibitor, in patients with HR+/HER2 metastatic breast cancer (MBC) following chemotherapy
Authors: H Rugo, S Nanda, A Koustenis
Journal: Cancer Research (2017)

Abstract Background: The MONARCH 1 (NCT0210249) study demonstrated durable single agent activity of abemaciclib in patients (pts) with HR+/HER2- breast cancer, with an objective response rate of 19.7% and median duration of response of 8.6 months1. The MONARCH 1 study population was heavily pretreated and had a high disease burden: all pts had previously received endocrine therapy and chemotherapy, had median of 3 prior systemic therapies for metastatic disease 90.2% had visceral disease and 85.6% had ≥ 2 metastatic sites. Methods: MONARCH 1 was a phase 2 single-arm study designed to evaluate safety and efficacy of abemaciclib monotherapy in women with HR+/HER2- MBC whose disease progressed on/after endocrine therapy and chemotherapy. Abemaciclib (200 mg) was administered orally on a continuous schedule every 12 hours until disease progression. The primary objective planned to evaluate investigator-assessed objective response rate (ORR= complete response [CR] + partial response [PR]) in a sample size of approximately 128 pts) using RECIST v1.1. Subgroup analyses evaluating ORR by prior treatment and disease burden were performed. Results: A total of 132 pts were treated with abemaciclib monotherapy. Analyses of subgroups based on prior treatment and disease burden are summarized in Table 1. Conclusions: Abemaciclib monotherapy administered on a continuous schedule has consistent single agent activity across the subgroups analyzed. Table 1. Objective Response Rate Subgroup Analyses Number of PatientsObjective Response (CR + PR) n(%)ITT13226 (19.7)Number of Prior chemotherapies for metastatic disease 16714 (20.9)26411 (17.2)311 (100.0)Taxane use in the metastatic setting Yes9119 (20.9)No417 (17.1)Capecitabine use in the metastatic setting Yes7616 (21.1)No5610 (17.9)Number of prior endocrine therapies for metastatic disease 0173 (17.6)1489 (18.8)2 or more6714 (20.9)Fulvestrant use in the metastatic setting Yes6715 (22.4)No6511 (16.9)Number of metastatic sites 1194 (21.1)24610 (21.7)3 or more6712 (17.9)Liver metastases Yes9320 (21.5)No396 (15.4)References: 1. Dickler, M. et al. American Society of Clinical Oncology (ASCO), abstract #510 (2016). Citation Format: Rugo H, Nanda S, Koustenis A. Subgroup Analysis by prior treatment and disease burden in MONARCH 1: A phase 2 study of monotherapy abemaciclib, a CDK4 &amp; 6 inhibitor, in patients with HR+/HER2 metastatic breast cancer (MBC) following chemotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-11-12.
Migraine and the Risk of Carotid Artery Dissection in the IPSYS Registry
Authors: Patrick D. Lyden
Journal: JAMA Neurology (2017)

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 Neurology 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 Neurology journal
Genome Editing in Cardiovascular Biology
Authors: Timon Seeger, Matthew Porteus, Joseph C. Wu
Journal: Circulation Research (2017)

ViewpointsG enome editing has emerged as a powerful tool in re- search and is entering the stage of therapeutic applications.In the cardiovascular field, its role in basic and translational research is well established.However, biological and technical barriers currently hamper the therapeutic potential of genome editing for cardiovascular diseases.This viewpoint discusses possible routes for promoting therapeutic use of genome editing in the cardiovascular system.
A Phase II Study of the Combination of Lenalidomide and Rituximab in Patients with Treatment-NaïVe and Relapsed Chronic Lymphocytic Leukemia
Authors: Paolo Strati, Philip A Thompson, Michael Keating, Christina Hinojosa, Diana Rodriguez, Xuemei Wang, Naval G. Daver, Nitin Jain, Jan A. Burger, Zeev Estrov, William G. Wierda, Hagop M. Kantarjian, Susan Obrien, Alessandra Ferrajoli
Journal: Blood (2016)
PP28. THE EFFECT OF PHOTODYNAMIC THERAPY FOR RECURRENT PITUITARY ADENOMAS: A DOUBLE-BLIND RANDOMISED CONTROLLED TRIAL
Authors: Mr Ian Anderson, Mr Simon Thomson
Journal: Neuro-Oncology (2017)

While pituitary tumours are histologically benign lesions, long-term control is difficult to achieve, even in patients who have undergone surgery. Tumour remnants are typically inaccessible, infiltrating the dura or of a consistency that precludes safe removal. Radiotherapy is the mainstay of adjuvant treatment for growing residuum and is able to provide tumour control in the majority of cases, however it is not without limitations and some lesions prove radio-resistant. Photodynamic therapy (PDT) has been employed as an adjuvant therapy in many malignancies and has been endorsed by the American Food and Drug Administration (FDA) for the treatment of oesophageal and non-small cell lung cancer. A photosensitising agent is administered which is then taken up preferentially and retained by tumour cells. It is subsequently activated by administered light of a particular wavelength, in the presence of oxygen. This results in the formation of highly reactive singlet oxygen, which is cytotoxic. The activated oxygen can cause direct cytoplasmic and mitochondrial damage to the tumour cells as well as indirect action through the destruction and collapse of the tumour vasculature. 14 patients with histologically confirmed pituitary adenomas and MRI-proven evidence of disease recurrence were randomised to either IV Photofrin (2mg/Kg Body Weight) or placebo (0.9% Sodium Chloride, 0.8ml/Kg Body Weight) followed by endonasal light therapy. Patients remained under clinical and radiological surveillance, as per the usual Departmental protocols. 7 patients were randomised each to the PDT and placebo groups. The allocated treatment was received in all cases. The duration of time elapsed since administration of treatment varies as patients were recruited over a 7-year period but is now in the range: 9.8 to 16.4 years post-treatment. 5 of the 14 patients have now died; three in the PDT group and two in the placebo group, none of the deaths were found to relate to the pituitary tumours nor to the treatments administered. There were three of the 14 patients for whom no imaging was available for assessment since the files have been destroyed by the hospital. 7 patients in the placebo cohort and 4 in the PDT cohort had full sets of MRI scans for assessment. Tumour behaviour varied markedly in both cohorts; some lesions showing continued enlargement while others regressed substantially. While the results of this study do not achieve statistical significance, there is no suggestion within the available results that photodynamic therapy is superior to placebo, indeed the placebo group tended to out-perform the PDT group.
Urothelial cancer: Gender discrepancies and impact on overall survival.
Authors: Jeanne Michelle du Manoir, Sue Richter, Srikala S. Sridhar
Journal: Journal of Clinical Oncology (2012)

e15020 Background: Gender differences for disease course and survival in various cancers exist. Gender disparity for both stage at diagnosis and overall survival (OS) has been observed in urothelial cancer (UC). We report a single institution analysis of UC patients treated with chemotherapy to further investigate gender differences in outcomes. Methods: We identified 190 bladder cancer pts treated with chemotherapy (adjuvant of palliative) since 2002. Age and stage at diagnosis, sex, smoking status, radiation/chemical exposures, bloodwork as a measure of organ dysfunction, ECOG performance status (PS), pathology, chemotherapies, presenting symptoms, other malignancies, and survival info was collected. Baseline demographics were compared by z test for significance and outcomes using chi square statistic. Survival was determined by censored Kaplan-Meier methods. Results: Average age and stage at diagnosis, and PS were similar for both genders. Males had significantly more exposure to smoking (58% vs 48%, p&lt;0.05) and radiation/chemical exposures (28% vs 10%, p&lt;0.05). Invasive urothelial carcinoma was the predominant histological diagnosis for both genders, but males were found to have significantly more subtypes or other pathologies (22.2% vs 14%, p&lt;0.05). Males were found to have more malignancies diagnosed prior to or concurrently with their UC diagnosis (27.8% vs 20%, p&lt;0.05). Standard Gem-Cis was given more often to males (70% vs 49%, p&lt;0.01) despite no differences in age, organ dysfunction or PS between genders. Receiving alternative chemotherapy in the first-line setting was associated with a poorer 3-year OS (p&lt;0.05) for either sex, as was stage of diagnosis, presence of visceral disease, creatinine, and ECOG PS (p&lt;0.05). Conclusions: Our data suggests that poorer outcomes in females was associated with not receiving standard chemotherapy (Gem-Cis) as frequently as males, despite similar baseline characteristics. Both males and females had significantly improved OS when they received Gem-Cis as the first regimen of chemotherapy. This study reinforces the importance of administering cisplatin as initial chemotherapy to improve outcomes in UC.
Abstract P3-07-07: Inhibition of death-associated protein kinase 1 enhances chemotherapy action against triple-negative breast cancer
Authors: D Zhao, J Zhao, A Mazumadar, L Bollu, J Shepherd, Y Ma, Y Zhang, JL Hill, MI Savage, PH Brown
Journal: Cancer Research (2017)

Abstract Background: Triple negative breast cancers (TNBCs) are the most aggressive ER negative breast cancers with limited therapy strategies and poor prognosis. P53 gene is frequently mutated in approximately 80% of TNBCs. To identify novel molecular targets for ER negative breast cancer, particularly the more aggressive TNBC, we conducted a human kinome screen and identified death-associated protein kinase 1 (DAPK1) as one of the kinases that are highly expressed in ER negative breast cancer. Deletion or inhibition of DAPK1 suppresses growth of p53-mutant but not p53-wildtype breast cancer cells. Here we investigate whether DAPK1 inhibition will enhance chemotherapy action against p53-mutant TNBCs. Experimental design and methods: We performed experiments to test cell growth of p53-mutant TNBCs that were treated with DAPK1 siRNA or DAPK1 inhibitors in combination with different doses of chemotherapy drugs including 5-FU (5-Fluorouracil), doxorubicin, cisplatin, PARP inhibitor (BMN673), paclitaxel, gemcitabine and vinorelbine. Results: Our results show that DAPK1 inhibitors enhance the growth inhibitory effects of cisplatin and PARP inhibitor in p53-mutant TNBCs. Furthermore, combined DAPK1 inhibition (via siRNA knockdown) with cisplatin synergistically inhibits cell growth of p53-mutant TNBCs. Conclusion: DAPK1 is a novel, promising target for the treatment of triple-negative p53-mutant breast cancer. Our studies demonstrate that DAPK1 inhibition sensitizes TNBCs to the cytotoxic effects of cisplatin or the PARP inhibitor. We are now conducting studies to determine whether DAPK1 inhibition will sensitize TNBC tumors and patient-derived TNBC xenografts to the effects of cisplatin and PARP inhibition. These studies suggest that the combination of DAPK1 inhibition with drugs that interfere with DNA repair will be useful for the treatment of the most aggressive form of breast cancer, triple-negative breast cancer. Funding: This study was funded by a Susan G. Komen Promise grant (SAB12-00006 to P.H. Brown), a MD Anderson Knowledge Gap Moonshot grant (to P.H. Brown) and a Breast Cancer Research Foundation grant (BCRF 15101807, 2015–2016 to P.H. Brown). Citation Format: Zhao D, Zhao J, Mazumadar A, Bollu L, Shepherd J, Ma Y, Zhang Y, Hill JL, Savage MI, Brown PH. Inhibition of death-associated protein kinase 1 enhances chemotherapy action against triple-negative breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-07-07.
Time-Interval Data in a Pediatric In-Hospital Resuscitation Study
Authors: John A. Stewart
Journal: JAMA (2017)

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