tbuckley/cabot-search huggingface dataset:
Indocyanine green and poly I:C containing thermo-responsive liposomes used in immune-photothermal therapy prevent cancer growth and metastasis
Authors: Li Xu, Wei Zhang, Hae-Bin Park, Minseok Kwak, Junghwan Oh, Peter C. W. Lee, Jun-O Jin
Journal: Journal for ImmunoTherapy of Cancer (2019)

Efficient cancer therapy is sought not only for primary tumor treatment but also for the prevention of metastatic cancer growth. Immunotherapy has been shown to prevent cancer metastasis by inducing antigen-specific immune responses. Indocyanine green (ICG) has a peak spectral absorption at about 800 nm, which makes it a photothermal reagent for direct treatment of solid tumors by photothermal therapy (PTT). Since PTT alone cannot fully induce antigen-specific immune response for prevention of cancer metastasis, the combination of PTT and immunotherapy has been developed as a new strategy of cancer treatment.Thermal responsive liposomes (TRL) were synthesized by incorporating ICG into the lipid bilayer and encapsulating the water-soluble immune stimulatory molecule polyinosinic:polycytidylic acid (poly I:C) in the hydrophilic core. The poly I:C- and ICG-containing TRLs (piTRLs) were analyzed according to size, and their photothermal effect was evaluated following laser irradiation at 808 nm. Moreover, the temperature-dependent release of poly I:C was also measured. For cancer therapy, CT-26 (carcinoma) and B16 (melanoma) cells were subcutaneously inoculated to build the 1st transplanted tumor in BALB/c and C57BL/6 mice, respectively. These mice received a 2nd transplantation with the same cancer cells by intravenous inoculation, for evaluation of the anti-metastatic effects of the liposomes after PTT.Near-infrared (NIR) laser irradiation increased the temperature of piTRLs and effectively released poly I:C from the liposomes. The increased temperature induced a photothermal effect, which promoted cancer cell apoptosis and dissolution of the 1st transplanted tumor. Moreover, the released poly I:C from the piTRL induced activation of dendritic cells (DCs) in tumor draining lymph node (tdLN). Cancer cell apoptosis and DC-activation-mediated cancer antigen-specific immune responses further prevented growth of lung metastatic cancer developed following intravenous transplantation of cancer cells.These results demonstrated the potential usage of a piTRL with laser irradiation for immuno-photothermal therapy against various types of cancer and their metastases.
The protein-tyrosine phosphatase SHP1 is downregulated with disease progression in Philadelphia (Ph) chromosome positive chronic myelogenous leukemia (CML), and effect not mediated by DNA methylation
Authors: Koyu Hoshino, Hui Yang, Andreia A. Canalli, Blanca Sanchez-Gonzalez, Hagop Kantarjian, Jean-Pierre Issa, Nicholas Donato, Guillermo Garcia-Manero
Journal: Cancer Research (2004)

4436  CML is molecularly defined by the presence of the BCR-ABL oncoprotein. This protein has unregulated protein tyrosine kinase activity that results in uncontrolled proliferation by altering main signal transduction networks that regulate proliferation and apoptosis. Clinically, CML is divided into three different phases: initial phase known as chronic (CP), that is followed by an accelerated phase (AP), and a final fatal phase known as blastic (BP). SHP1 (also known as PTPN6, HCP, SH-PTP1) is a SH2 containing non-receptor protein-tyrosine phosphatase that modulates multiple signal transduction cascades, and has been shown to negatively regulate BCR-ABL kinase activity. Here, we studied the levels of SHP1 in patients with CML in different phases of the disease. Thirty patients (10 with CP, 10 with AP, and 10 with BP) were studied. As controls, we studied 6 bone marrows from healthy volunteers, 3 cases of acute lymphocytic leukemia (ALL) and 11 leukemia derived cell lines. The levels of SHP1, GAPDH, and c-ABL were studied using real-time polymerase chain reaction (PCR). Mean value, standard deviation (SD) and two sided p values are presented on table. Overall, the values of SHP1 were significantly higher in patients with CP than in those with AP, BP, cell lines, and normal healthy volunteers. To study the mechanisms of gene silencing, we then analyzed the frequency of SHP1 DNA methylation in cell lines and clinical samples. Methylation of a cluster of CpG sites near the proximal SHP1 promoter has been recently shown to occur in leukemias, including CML (Oka et al. Cancer Res 2002;62:6390-6394). SHP1 methylation was analyzed using the combined bisulfite restriction assay (COBRA). Nine out of 11 cell lines including K562 were methylated (range 11% to 47%), but, interestingly, in the imatinib resistant cell line K562R was not methylated. Subsequently, SHP1 methylation was analyzed in 106 patients: 78 with CP Ph + CML, 4 AP Ph+ CML, 4 BP Ph+ CML, 9 Ph negative CML, 9 ALL, 2 acute myelogenous leukemia (AML) and 1 normal. SHP1 methylation using COBRA was found in 5 (6%) pts with CP CML, 1 AP, 1 BP, and in 0 pts with Ph negative CML, AML, or ALL. These data indicates that, in contrast to cell line data, SHP1 methylation is an infrequent event. In summary, SHP1 levels are low in healthy volunteers and that they are up-regulated in patients with chronic phase disease and decrease as CML transitions into the accelerated and blastic phases. This implies that escape into accelerated phase is partially mediated by SHP1 an effect not mediated by aberrant DNA methylation in clinical samples.
Volume Standards for High-risk Cancer Surgery
Authors: Yuman Fong, Marco G. Patti
Journal: JAMA Surgery (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 Surgery 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 Surgery journal
The role of human RecQL4 helicase protein interactions in genomic stability
Authors: Mirella L. Meyer-Ficca, Ralph G. Meyer, Elaine L. Jacobson, Myron K. Jacobson
Journal: Cancer Research (2005)

1789  The unique biopolymer poly(ADP-ribose) (PAR) is synthesized by members of the poly(ADP-ribose) polymerase (PARP) family as a posttranslational modification of many cellular target proteins. PARP-1, a major PAR synthetic activity, is activated in response to DNA strand breaks. Once synthesized, PAR is rapidly degraded by action of poly(ADP-ribose) glycohydrolase (PARG). Cellular PAR metabolism modulates cellular responses to genotoxic stress by stimulating DNA repair or inducing cell death and is therefore an important factor for the maintenance of genomic integrity. Reduced poly(ADP-ribosyl)ation capacity, e.g. in PARP-1-/- mice, leads to a decrease in genomic stability and to an increase in tumor formation. In addition to PARP-1 and PARP-2, which are DNA strand break activated, numerous genes code for PARP enzymes that catalyze PAR synthesis in both nuclear and extranuclear compartments of the cell independent of the presence of DNA damage. Only one gene coding for PARG has been identified in mammalian cells. We recently described the human PARG gene structure (Meyer et al., Gene, 314: 181-190, 2003) and have shown that several cellular PARG protein isoforms of 111kDa (hPARG111), 102 kDa (hPARG102) and 99 kDa (hPARG99) are synthesized by translation of alternatively spliced messages (Meyer-Ficca et al., Exp Cell Res, 297: 521-532, 2004). The different isoforms localize to different cellular compartments and are therefore able to function in PAR homeostasis throughout the cell: hPARG111 is nuclear, while hPARG102 and hPARG99 appear to be cytoplasmic. Here we describe the detection of an additional human PARG splice variant coding for a 60 kDa protein (hPARG60), which also has a cytoplasmic subcellular distribution. To assess the functions of the different PARG isoforms in more detail, constructs allowing for the overexpression of fusion proteins of green fluorescent protein to the PARG isoforms were generated. Transient overexpression of these proteins in HEK293 cells increased the total cellular PAR degrading activity by 4-5 fold. The accumulation of PAR after DNA damage was markedly reduced. Overexpression of the longer PARG isoforms (hPARG111 and hPARG102) in HeLa cells induced distinct changes in nuclear morphology, while overexpression of the 60 kDa PARG isoform was cytotoxic. These finding support the concept that PAR homeostasis involving the coordination of cellular PARPs and PARGs play important roles not only in cellular responses to DNA damage, but also for the maintenance of genomic integrity in the absence of genotoxic stress. (Supported in part by NIH Grant CA-43894)
Background-free and doxycycline-inducible transgene integration at specific loci in cancer cell lines
Authors: Iacovos Michael, Claudio Monetti, Hoon Ki Sung, Koichiro Nishino, Andras Nagy
Journal: Cancer Research (2008)

2936  Background: Functional and comparative analysis of various genes, mutations and isoforms in tumour progression is complicated due to the extreme variability of transgene expression levels in each cell line. This is attributed to the highly variable number of transgene copies integrated into the genome and to the different genomic position effects on gene expression due to random integration. Recombinase-mediated site-specific integration can overcome these limitations by introducing the target gene of interest (GOI) into pre-determined chromosomal loci.  Methods: In this study we used the ΦC31 integrase in order to mediate non-reversible cassette integration. We designed a cassette “docking site” that contains an attP site as well as a selection system. An incoming vector, carrying an attB site as well as the GOI, can be specifically integrated into the docking site after ΦC31-mediated recombination. We established a collection of incoming vectors for high-throughput applications by incorporating the Gateway system allowing for simplified cloning of the GOI(s). Furthermore, we combined the ΦC31-mediated site-specific integration strategy with a new tightly regulated tetracycline induction system, composed of a second-generation reverse tetracycline transactivator and a second-generation tetracycline response element driving the expression of the GOI.  Results: As a proof of principle study, after integrating the docking site cassette randomly in the prostate cancer cell lines PC-3 and DU145, we were able to achieve ΦC31-mediated integration of incoming vectors containing different GOI (i.e. encoding for green fluorescent, transmembrane or secreted protein). After drug selection, we showed that isogenic clones expressed comparable levels of protein in each case (e.g. similar fluorescence levels) and that only site-specific integration of the incoming vector occurred. In addition, we were able to apply this system in a high throughput format for 24- and 96-well plates. Finally, we showed that we could induce and tightly control the expression of the GOI both in vitro and in vivo in xenografts studies.  Conclusions: This novel system will allow easy and precise integration of a GOI in the genome, eliminating the need for extended screening, and facilitating the design of complex cassette-exchange strategies. It is directly applicable to high-throughput studies requiring inducible and comparable expression levels of a series of transgenes (e.g. pro- and/or anti- angiogenic factors) for determining their effect in tumour progression.
Abstract MP86: Hemodynamic and Metabolomic Change From Lifestyle Driven Weight Loss in Obese Adolescents
Authors: Justin P Zachariah, Jane W Newburger, Gary F Mitchell
Journal: Circulation (2016)

Background: While bariatric surgery is known to induce hemodynamic and metabolic pathway alterations, lifestyle-driven weight loss in obese adolescents are not well characterized with respect to hemodynamic and metabolomic effects. We studied aortic function and urine metabolomics changes in obese adolescent volunteers attending weight loss summer camps. Methods: Adolescents (n=45, 71% girls, mean age 15±1 year) attending long-standing weight loss camps over 3 summers volunteered to have weight, long term diet and activity history, and vascular tonometry after overnight fast at camp entry and exit. A subset (n=32) also gave urine entry and exit urine samples for metabolomic analysis (Metabolon, Durham NC). Camp administrators followed pre-existing protocols encouraging campers toward 5 hours or more of structured activity and free play as well as nutritionist-designed meal plan restricted to age-sex specific calorie goals. Paired students T-tests were used to assess changes in anthropometrics and hemodynamics. Osmolality-adjusted metabolomic changes were analyzed using principal components analysis; paired T-test with multiple comparison adjustment by Storey-Tibshirani false discovery rate thresholding; and Random Forest decision tree ensembles with selection of the top 30 biochemicals in variable importance gleaned from the Mean Decrease Accuracy metric, which randomly permutes a given chemical and reassesses predictive accuracy throughout the tree ensembles, and then grouped into pathway categories. Results: Median camp length was 6 weeks (25%,75% IQR 5,7). Campers on average lost body 11±4% of body weight (99±20 to 88±17 kilograms, p&lt;0.0001). Supine systolic blood pressure declined from 115±11 to 111±12 mmHg (p&lt;0.01), diastolic blood pressure from 57±8 to 52±7 mmHg (p&lt;0.0001), and heart rate from 73±10 to 62±11 beats per minute (p&lt;0.0001). Carotid femoral pulse wave velocity decreased from 5.4±0.7 to 5.1±0.6 meters per second (p&lt;0.0001). This change in arterial stiffness was not dependent on changes in heart rate nor distending pressure. Augmentation index did not significantly change from 17±11% to 16±9% (p=0.5). On urine metabolomic analysis, altered biochemical pathways included lipid metabolism, bile acids, and carbohydrate excretion. Conclusions: Diet and activity driven weight loss in excess weight adolescents is associated with salutary hemodynamic improvement and specific metabolic alterations, paralleling findings after bariatric surgery. More investigation into the mechanisms of lifestyle driven weight loss is warranted.
Gut microbiome alteration in MORDOR I: a community-randomized trial of mass azithromycin distribution
Authors: T. Doan, A. Hinterwirth, L. Worden, A. M. Arzika, R. Maliki, A. Abdou, S. Kane, L. Zhong, M. E. Cummings, S. Sakar, C. Chen, C. Cook, E. Lebas, E. D. Chow, I. Nachamkin, T. C. Porco, J. D. Keenan, T. M. Lietman
Journal: Nature Medicine (2019)
Abstract P6-21-06: Target N-Ras for degradation by flunarizine to treat basal-like breast cancer
Authors: Z-Y Zheng, J Li, F Li, Y Zhu, K Cui, ST Wong, EC Chang, Y-h Liao
Journal: Cancer Research (2019)

Abstract Background:Basal-like breast cancer (BLBC) is an aggressive form of breast cancer that are usually triple negative for ER, PR, and HER2. There is no effective targeted therapy for BLBC due to the lack of a druggable driver. Ras GTPases are powerful drivers for tumorigenesis. We have shown that wild type N-Ras, but not K- or H-Ras, is overexpressed in BLBC and driving itsgrowth and transforming activities. However, there is currently no treatment that directly target Ras. This study thus screened existing pharmacologically active and approved compounds for the new ability to induce N-Ras degradation in BLBC. Methods:Compounds in the LOPAC library were screened by an automated microscopy system for the ability to reduce GFP-N-Ras signals in the cells. Isolated compounds were then examined to identify those that can degrade endogenous N-Ras in BLBC cells without impacting levels of other Ras proteins. Final candidate compounds were further examined to determine by which proteolytic pathway N-Ras is induced to be degraded. The potentials of the identified compound to treat BLBC were assessed by examining cell growth and soft agar colony formation in vitroand tumor growth in vivo. Results:We identified flunarizine (FLN), previously approved for treating migraine and epilepsy. The FLN-induced N-Ras degradation was not affected by a 26S-proteasome inhibitor. Rather, it was blocked by autophagy inhibitors. Furthermore, N-Ras can be seen co-localized with active autophagosomes upon FLN treatment, suggesting that FLN alters the autophagy pathway to degrade N-Ras. Importantly, FLN treatment recapitulated the effect of N-RASsilencingin vitroby selectively inhibiting the growth of BLBC cells, but not that of breast cancer cells of other subtypes. In addition, in vivoFLN inhibited tumor growth of a BLBC xenograft model. Conclusion:This proof-of-principle study presents evidence that the autophagy pathway can be coerced by small molecule inhibitors, such as FLN, to degrade Ras as a strategy to treat cancer. FLN has low toxicity and should be further investigated to enrich the toolbox of cancer therapeutics against BLBC. Citation Format: Zheng Z-Y, Li J, Li F, Zhu Y, Cui K, Wong ST, Chang EC, Liao Y-h. Target N-Ras for degradation by flunarizine to treat basal-like breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-21-06.
Making Machine Learning Models Clinically Useful
Authors: Nigam H. Shah, Arnold Milstein, Steven C. Bagley, PhD
Journal: JAMA (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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Caring for people at the end of life: How do cancer caregivers differ from other caregivers?
Authors: Afaf Girgis, Amy Pickar Abernethy, David C Currow
Journal: Journal of Clinical Oncology (2012)

9128 Background: The size of the population in receipt of cancer care is growing as the population ages and grows, with many receiving outpatient care, living for longer and wishing to be cared for at home. Hence, cancer is now one of the most common health conditions in receipt of informal care giving. Methods: The South Australian Health Omnibus is an annual, face-to-face, cross-sectional, whole-of-population, multi-stage, systematic area sampling survey which seeks a minimum of 3,000 respondents each year state-wide. From 2000-2007, questions about end of life were asked. This study compares people who cared for someone with cancer until death (cancer caregivers) with caregivers of people with other life limiting illnesses (non-cancer caregivers). Results: 4,665/14,624 (31.9%; participation rate 71.6%) had someone close to them die from an “expected” death in the 5 years prior to being surveyed. One in 10 (10%; 1,504/14,624) provided hands-on (day-to-day or intermittent) care; the majority (79.5%) having cared for someone with cancer. Compared to non-cancer caregivers, cancer caregivers cared for someone who was significantly younger (mean age 66 vs 74 years; p&lt;0.0001), and to have had a palliative care service involved in the care of that person (64.9% vs 39%; p=0.000). Whilst not statistically significant, cancer caregivers were somewhat less likely to be the spouse of the person they cared for (11.8% vs 16.8%); more likely to be of non-English speaking background (11% vs 7.5%); more likely to report that the deceased was comfortable in the last 2 weeks of life (44.1% vs 31.7%); and prepared to care again for someone with a life-limiting illness (81.3% vs 71.4%). Conclusions: Caring for someone with cancer at the end of life appears to be fundamentally different to other caregiver populations, particularly in relation to age of, and relationship to, the patient, which may contribute to their substantially greater utilisation of palliative care services. Being a younger caregiver increases the likelihood of them caring again in the future.
Trial of zoledronic acid and interleukin-2 to expand tumoricidal γδ T cells in vivo in patients with refractory neuroblastoma.
Authors: Joseph Gerald Pressey, Julia M Adams, David R Kelly, Lawrence S Lamb
Journal: Journal of Clinical Oncology (2013)

TPS10073 Background: CD3+ γδ+ T cells comprise 2 to 5% of the circulating T cells. Vγ9Vδ2+ cells are the dominant circulating γδ T cell and recognize non-peptide phosphoantigens and stress-associated NKG2D ligands expressed on malignant cells. Strategies that incorporate the tumoricidal properties of γδ T cells represent a promising means of harnessing the innate immune system to treat malignancies including neuroblastoma (NB). Indeed, γδ T cells from both healthy volunteers and NB patients exert a potent cytotoxic effect on NB cell lines and autologous NB in vitro following expansion and activation in culture. Vγ9Vδ2+ cells can also be induced to proliferate in vivo. By blocking farnesyl pyrophosphate synthase in the mevalonate pathway of isoprenoid synthesis in monocytes, the aminobisphosphonate zoledronic acid (ZOL) promotes the accumulation of isopentenyl pyrophosphate which is sensed by γδ T cells. IL-2 is also required for robust expansion γδ T cells. Methods: The trial is a prospective, non-randomized trial that assesses two dose levels of recombinant IL-2 (aldesleukin) in combination with ZOL. To be eligible for the study patients must be 2 to 21 years of age with refractory neuroblastoma with no known curative therapeutic options. Patients must also have adequate organ function and performance status. ZOL is given intravenously on day 1, and aldesleukin is given subcutaneously on days 1 to 5 and 15 to 19 of every 28 day cycle. The single-institution study is being conducted at the University of Alabama at Birmingham. Correlative studies include evaluating the absolute count, phenotype, activation, and effector/memory progression of γδ T cells by flow cytometry and the biological function of autologous expanded/activated γδ T cells by in vitro cytotoxicity assays employing established human NB cell lines. In order to determine the ability of in vivo expanded/activated γδ T cells to infiltrate NB tissue, bone marrow core biopsies obtained before and after the first course of therapy from patients with bone marrow metastasis are assayed for T cell infiltration by immunohistochemistry. The study has currently enrolled 1 of the planned 6 patients. Clinical trial information: NCT01404702.