tbuckley/cabot-search huggingface dataset:
Diallyl trisulfide inhibits in vitro angiogenesis in endothelial cells in association with caspase-dependent apoptosis and inactivation of Akt.
Authors: Dong Xiao, Mengfeng Li, Shivendra V. Singh
Journal: Cancer Research (2006)

5608  Garlic-derived organosulfur compounds such as diallyl sulfide (DAS), diallyl disulfide (DADS) and diallyl trisulfide (DATS) have been shown to afford significant protection against cancer in animal models induced by a variety of chemical carcinogens. Evidence is accumulating to indicate that garlic-derived OSC analogues can also suppress proliferation of cancer cells by causing apoptosis and/or cell cycle arrest. We now demonstrate, for the first time, that DATS is a potent inhibitor of in vitro angiogenic features of human umbilical vein endothelial cells (HUVEC). Survival of HUVEC was reduced significantly in the presence of DATS in a concentration-dependent manner as determined by trypan blue dye exclusion assay. DATS was significantly more effective than either DAS or DADS against proliferation of HUVEC. The DATS-mediated suppression of HUVEC survival was associated with apoptosis induction characterized by accumulation of sub-diploid cells, cytoplasmic histone associated DNA fragmentation, and cleavage of caspase-3 and poly(ADP-ribose)polymerase (PARP). The DATS-induced cleavage of caspase-3 and PARP as well as DNA fragmentation was significantly attenuated on treatment with pan caspase inhibitor zVAD-fmk and specific inhibitors of caspase-9 and caspase-8. The DATS treatment inhibited capillary-like tube structure formation and migration by HUVEC in association with suppression of vascular endothelial growth factor (VEGF) secretion as determined by an ELISA assay and VEGF receptor-2 protein level as determined by immunoblotting, and inactivation of Akt kinase as determined by immunoprecipitation-kinase assay. The DATS treatment also caused activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N- terminal kinase (JNK), but not p38 mitogen activated protein kinase (p38 MAPK). The DATS-mediated apoptosis induction and inhibition of HUVEC tube formation was partially but statistically significantly attenuated by pharmacologic inhibition of ERK1/2 but not JNK or p38 MAPK. In conclusion, the present study indicates that the DATS-mediated inhibition of in vitro angiogenesis in HUVEC is associated with caspase-dependent apoptosis, inactivation of Akt, suppression of VEGF secretion, down-regulation of VEGF-R2 protein expression, and activation of ERK1/2. We speculate that apoptosis induction alone can’t fully explain DATS-mediated inhibition of angiogenesis in HUVEC. Supported in part by NCI grants CA113363, CA101753 and CA115498.
Liver Progenitors and Adult Cell Plasticity in Hepatic Injury and Repair: Knowns and Unknowns
Authors: Sungjin Ko, Jacquelyn O. Russell, Laura M. Molina, Satdarshan P. Monga
Journal: Annual Review of Pathology Mechanisms of Disease (2019)

The liver is a complex organ performing numerous vital physiological functions. For that reason, it possesses immense regenerative potential. The capacity for repair is largely attributable to the ability of its differentiated epithelial cells, hepatocytes and biliary epithelial cells, to proliferate after injury. However, in cases of extreme acute injury or prolonged chronic insult, the liver may fail to regenerate or do so suboptimally. This often results in life-threatening end-stage liver disease for which liver transplantation is the only effective treatment. In many forms of liver injury, bipotent liver progenitor cells are theorized to be activated as an additional tier of liver repair. However, the existence, origin, fate, activation, and contribution to regeneration of liver progenitor cells is hotly debated, especially since hepatocytes and biliary epithelial cells themselves may serve as facultative stem cells for one another during severe liver injury. Here, we discuss the evidence both supporting and refuting the existence of liver progenitor cells in a variety of experimental models. We also debate the validity of developing therapies harnessing the capabilities of these cells as potential treatments for patients with severe and chronic liver diseases.
Time to ATRA in suspected newly diagnosed acute promyelocytic leukemia and association with early death rate at a non-cancer center institution: Are we meeting the target?
Authors: Gulam Abbas Manji, Samira Khan Manji, Sheetal Karne, Jeff Chao
Journal: Journal of Clinical Oncology (2012)

6615 Background: ATRA administration in suspected APL patients (sAPL) is thought to impact early death rate (EDR) (Tallman and Manji, Blood Cells Mol Dis. 2011). Delay in ATRA therapy at specialized centers was associated with EDR (Altman et al Blood 2011). EDR within this study was significantly lower compared to the SEER database (12% vs 17.3%) and hence may not reflect overall delay in ATRA therapy. We determined time to ATRA therapy in sAPL, and fraction of sAPL that did not have disease. Methods: Retrospective analysis of patients that received ATRA for newly diagnosed s APL between 01/01/98-12/31/11 at Albany Medical Center. Time to hematologist evaluation, ATRA ordered and administered, and mortality data was collected from cancer registry, medical record, and chemo-pharmacy database. Results: A total of 39 patients with newly diagnosed sAPL were administered ATRA (46% male, mean age 50y). APL diagnosis: 29/39 (75%) true APL (APL); 9/10 ATRA-treated non-APL (A-nAPL); and one patient for whom cytogenetic data unavailable. EDR amongst APL was 5/29 (17%) compared to 2/9 (22%) within A-nAPL. Time variables were compared between APL patients that died early (&lt;30d) to those that survived 30 days, and included: time to hematologist response (0.9d vs. 0.4d); time to ATRA ordered (2.9d vs. 2.0d); time to ATRA administered (3.4d v. 2.2d); and time elapsed between hematologist response to ATRA administered (2.5d v. 1.9d), respectively. Cryoprecipitate was administered to 1/5 (20%) patients who expired within 30d compared to 10/23 (43%) who survived. Overall mortality for APL was 9/29 (31%) compared to 4/9 (44%) for A-nAPL group. Compared to recent reports, time to ATRA administration in our institution was later (2.0d vs. 2.4d). Conclusions: Our data indicate that APL patients who survived 30d received ATRA early. EDR at our institution is comparable to that reported by SEER database and may be attributed to delay in ATRA administration. Higher fraction of patients that survived 30d received cryoprecipitate. Hence aggressive blood product support may contribute to improved survival. Timing at which these products were administered is currently being evaluated.
Soft‐Nanoparticle Functionalization of Natural Hydrogels for Tissue Engineering Applications
Authors: Kamil Elkhoury, Carina S. Russell, Laura Sanchez‐Gonzalez, Azadeh Mostafavi, Tyrell J. Williams, Cyril Kahn, Nicholas A. Peppas, Elmira Arab‐Tehrany, Ali Tamayol
Journal: Advanced Healthcare Materials (2019)

Abstract Tissue engineering has emerged as an important research area that provides numerous research tools for the fabrication of biologically functional constructs that can be used in drug discovery, disease modeling, and the treatment of diseased or injured organs. From a materials point of view, scaffolds have become an important part of tissue engineering activities and are usually used to form an environment supporting cellular growth, differentiation, and maturation. Among various materials used as scaffolds, hydrogels based on natural polymers are considered one of the most suitable groups of materials for creating tissue engineering scaffolds. Natural hydrogels, however, do not always provide the physicochemical and biological characteristics and properties required for optimal cell growth. This review discusses the properties and tissue engineering applications of widely used natural hydrogels. In addition, methods of modulation of their physicochemical and biological properties using soft nanoparticles as fillers or reinforcing agents are presented.
Nuclear karyopherin alpha-2 (KPNA2) expression predicts poor survival in patients with advanced breast cancer.
Authors: Peter Wild, Oleg Gluz, Robert Meiler, Raihana Diallo-Danebrock, Evelyn Ting, Svjetlana Mohrmann, Gerhart Schuett, Edgar Dahl, Thomas Fuchs, Alexander Herr, Markus Frick, Christopher Poremba, Ulrike Nitz, Arndt Hartmann
Journal: Cancer Research (2008)

977  Purpose: Intensive lymph node involvement indicates poor prognosis in breast cancer patients. The significance of other molecular prognostic factors in this subgroup is unclear. Karyopherin alpha-2 (KPNA2) has been reported as an important factor of tumorgenesis and progression of breast cancer. The aim of the present study was to evaluate the impact of KPNA2 expression on prognosis of patients with high risk breast cancer (HRBC) and response to intensive chemotherapy within the randomized WSG-AM-01 trial.  Methods: KPNA2 nuclear expression (> 10% vs.  9 positive lymph nodes) randomized to tandem high dose vs. conventional dose-dense chemotherapy. Results were correlated with clinical outcome (median follow-up 63.3 months) by Kaplan-Meier and multivariate Cox regression analysis including molecular subtypes, determined by k-clustering (k=5).  Results: KPNA2 overexpression (n=74, 39%) significantly correlated with shorter event-free (EFS) and overall survival (OS) in both therapy arms by univariate analysis. Multivariate analysis showed that the overexpression of KPNA2 was an independent negative prognostic factor for overall survival (hazard ratio=1.89, 95% CI=1.06-3.35, p=0.03). This predictive value was independent of basal-like and HER2 subtypes, and was significantly associated with KPNA2 immunoreactivity.  Conclusion: Our data suggest the use of nuclear KPNA2 expression as novel prognostic marker in node-positive patients. KPNA2 expression may be also considered as a marker of global chemoresistance, which can not be overcome by conventional dose-modification of chemotherapy in HRBC patients.
Glyoxalase 1 Prevents Chronic Hyperglycemia Induced Heart-Explant Derived Cell Dysfunction
Authors: Melanie Villanueva, Connor Michie, Sandrine Parent, Georges N Kanaan, Ghazaleh Rafatian, Pushpinder Kanda, Bin Ye, Wenbin Liang, Mary-Ellen Harper, Darryl R Davis
Journal: Theranostics (2019)

Decades of work have shown that diabetes increases the risk of heart disease and worsens clinical outcomes after myocardial infarction.Because diabetes is an absolute contraindication to heart transplant, cell therapy is increasingly being explored as a means of improving heart function for these patients with very few other options.Given that hyperglycemia promotes the generation of toxic metabolites, the influence of the key detoxification enzyme glyoxalase 1 (Glo1) on chronic hyperglycemia induced heart explant-derived cell (EDC) dysfunction was investigated.Methods: EDCs were cultured from wild type C57Bl/6 or Glo1 over-expressing transgenic mice 2 months after treatment with the pancreatic beta cell toxin streptozotocin or vehicle.The effects of Glo1 overexpression was evaluated using in vitro and in vivo models of myocardial ischemia.Results: Chronic hyperglycemia reduced overall culture yields and increased the reactive dicarbonyl cell burden within EDCs.These intrinsic cell changes reduced the angiogenic potential and production of pro-healing exosomes while promoting senescence and slowing proliferation.Compared to intra-myocardial injection of normoglycemic cells, chronic hyperglycemia attenuated cell-mediated improvements in myocardial function and reduced the ability of transplanted cells to promote new blood vessel and cardiomyocyte growth.In contrast, Glo1 overexpression decreased oxidative damage while restoring both cell culture yields and EDC-mediated repair of ischemic myocardium.The latter was associated with enhanced production of pro-healing extracellular vesicles by Glo1 cells without altering the pro-healing microRNA cargo within.Conclusions: Chronic hyperglycemia decreases the regenerative performance of EDCs.Overexpression of Glo1 reduces dicarbonyl stress and prevents chronic hyperglycemia-induced dysfunction by rejuvenating the production of pro-healing extracellular vesicles.
The Fibrosis Burden of Systemic Sclerosis
Authors: Michael P. Keane
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

modulation in other cell types that are known to be involved in lung fibrogenesis, including structural (epithelial) and immune (macrophages and T cells) cells, need to be better clarified.3. ERs are ubiquitously expressed receptors that are involved in physiological and pathological processes, including carcinogenesis, and therefore the side effects of modulating their activity require further consideration.In addition, pulmonary hypertension and embolism have been associated with oral contraceptives through estrogen-induced obliterative and thrombotic vascular lesions, and estrogens exert proinflammatory and oxidative stress effects (1).Despite the above concerns, this study represents the first attempt to provide a pathogenic linkage between sex hormones and lung collagen deposition, and to explain the female survival bias in lung fibrosis.Linking ER and other hormone analogs with accelerated aging, senescence, and metabolic disorders, which are often seen in patients with fibrotic lung disease, would be an interesting future approach-the best is yet to come.
Blood biomarker modulation with dasatinib (D) and cetuximab (C) in patients (pts) with advanced solid malignancies
Authors: A. Egloff, T. M. Feinstein, S. C. Joyce, L. A. Kelly, M. C. Panelli, T. Yang, J. M. Siegfried, J. R. Grandis, A. Argiris
Journal: Journal of Clinical Oncology (2009)

6034 Background: Src is implicated in the resistance to epidermal growth factor receptor (EGFR) inhibitors. We studied biomarkers in the context of a phase I clinical trial of D, a small molecule inhibitor of several kinases, including Src, and C, a chimeric IgG1 monoclonal anti-EGFR antibody (Esteve et al. ASCO 2008; A14668). Methods: Plasma levels of EGFR, amphiregulin (AR), transforming growth factor-α (TGF-α), COX-2 and hepatocyte growth factor (HGF) were measured using a multiplex enzyme-linked immunosorbant assay (Searchlight TM) at day 0 and day 15. Blood mononuclear cell pSrc/Src levels were measured by Odyssey western blotting at day 0 (no C) and day 15 (with C) prior to and 2, 4, 8 and 24 hours after D. Clinical results were tested for association with biomarkers. The same biomarkers were also measured in plasma collected through an Early Detection Research Network- (EDRN-) sponsored effort from 22 squamous cell carcinoma of the head and neck (SCCHN) pts and 32 cancer-free matched controls. Results: 25 pts had baseline levels, 16 with paired samples. At day 15, EGFR plasma levels significantly decreased (p &lt; 0.001), while AR (p &lt; 0.001) and TGF-α (p &lt; 0.001) significantly increased compared to pretreatment levels. HGF and COX 2 plasma levels did not change with treatment. Pre-daily D pSrc levels on day 0 and day 15 did not differ. pSrc levels decreased from pre-daily D levels by 8 hours post-D at day 0 (p = 0.036, n = 21) and day 15 (p = 0.027, n = 13) and returned to pre-D levels by 24 hours. In 17 pts evaluable for response, only low baseline levels of TGF-α were associated with an increased likelihood of disease control (p = 0.020). Elevated HGF at baseline was seen in treatment pts and SCCHN control pts compared to cancer-free controls (p = 0.006 and p = 0.001, respectively). Otherwise, there was no significant difference in plasma biomarker levels compared to the matched EDRN. Conclusions: D and C significantly decreased plasma levels of EGFR and increased EGFR ligands (AR and TGF-α). Similar data has been shown in vitro, suggesting that C binding to EGFR leads to fewer available receptors for ligand binding. pSrc transiently decreased after D dosing. We will evaluate C plus D and validate these biomarkers in a planned phase II trial in SCCHN. [Table: see text]
Changes in thymidine phosphorylase expression in response to neoadjuvant chemotherapy for primary breast cancer
Authors: F. Puglisi, M. Mansutti, A. Minisini, S. Russo, G. Cardellino, C. Andreetta, E. Rijavec, S. Pizzolitto, M. Pandolfi, C. Di Loreto
Journal: Journal of Clinical Oncology (2006)

655 Background: Thymidine phosphorilase (TP) is a key enzyme involved in nucleoside metabolism. Recently, it has been hypothesized that TP modulation could enhance the therapeutic activity of TP-targeting chemotherapy such as capecitabine. In addition, some evidence exists that anticancer agents could upregulate TP. The present study analyzed TP immunohistochemical expression in response to neoadjuvant chemotherapy for primary breast cancer. Methods: Fifty-five women with operable breast cancer (T ≥ 2 cm, N0–1, M0) were treated with anthracycline-based (all cases) and anthracycline/taxane-based (n= 40 cases) neoadjuvant chemotherapy. Tumor samples from diagnostic large core biopsy (n=55) and from surgery (n=53) were available for histological evaluation and immunohistochemical analysis of TP. Immunohistochemistry was performed at a single central laboratory using a primary mouse anti-TP monoclonal antibody (Roche molecular biochemicals).TP expression was evaluated on tumor cells (nuclear and cytoplasmic staining) and on stromal cells. The intensity of cytoplasmic immunoreactivity was scored as 0, 1, 2 or 3 denoting negative, weak, moderate and strong staining, respectively. Results: An increase in TP cytoplasmic expression was observed in 35.89% (95% CI: 0.21–0.52%) of tumor samples after neoadjuvant chemotherapy. In particular, increases in cytoplasmic TP score were more common after taxane-containing regimens (40.74%, 95% CI: 0.22–0.61%) than after regimens without taxanes (25%, 95% CI: 0.05–0.57%). No significant changes of TP expression were found in nuclei of tumor cells after neoadjuvant chemotherapy. Similarly, no significant changes of TP expression were observed in stromal cells. There was no significant association between clinical or pathological response rate and TP changes in both tumor and stromal cells. Conclusions: This study provides further evidence that, at least in breast cancer, TP is upregulated after anthracycline and/or taxane-containing chemotherapy. According to these results, a strong rationale exists in combining TP-inducing and TP-targeting anticancer agents. No significant financial relationships to disclose.
Abstract #291: Spontaeous development of lung adenocarcinoma in mice lacking the tumor suppressor gene, CADM1/TSLC1
Authors: Yoshinori Murakami, Masayoshi Nagata, Daisuke Yamada, Mika Sakurai-Yageta, Miwako Iwai, Takashi Obana, Taketo Kawai, Mari Masuda, Yumi Tsuboi, Hiromi Ichihara, Tomoko Maruyama, Akihiko Ito
Journal: Cancer Research (2009)

Disruption of cell adhesion is a critical step in the development and progression of human cancer. The CADM1/TSLC1 on chromosomal region 11q23 was initially identified as a tumor suppressor gene in non-small cell lung cancer (NSCLC) for its suppressor activity of tumorigenicity in nude mice by functional complementation. The CADM1 encodes an immunoglobulin-superfamily cell adhesion molecule that is expressed in the brain, testis, lung and many other epithelial tissues. In contrast, the CADM1 is inactivated in 30-60% of various human cancers, including NSCLC. We have demonstrated that CADM1 associates with an actin-binding protein, 4.1B/DAL-1, and members of the membrane-associated guanylate kinase homologs (MAGuKs). To further investigate the physiological roles of CADM1, we generated Cadm1 gene-deficient C57BL6 mice by disrupting exon 1. We have previously demonstrated that Cadm1-/- mice were born normally but Cadm1-/- male mice were infertile. The number of sperm in the semen decreased to less than 0.01% of that in the Cadm1+/+ mice by disruption of spermatogenic cell adhesion, indicating that CADM1 is indispensable for spermatogenesis. Here, we demonstrate that 10 of 30 Cadm1-/- mice (33%) developed lung adenomas and adenocarcinomas at 15 months of age. In lung adenoma, normal bronchiolo-alveolar structure disappeared and was completely replaced by the tumor cells with mild atypical nuclei showing nest-like arrangement. In lung adenocarcinoma, tumor cells with severe atypia and nuclear pleomorphism were detected. The average volume of these tumors was 39 mm3. In contrast, only three of 31 (10%) Cadm+/+ mice showed micro-adenomas of 0.005 mm3 in average volume. The incidence of tumor-bearing mice in Cadm1-/- mice (13/35; 37%) was also significantly higher than that in Cadm1+/+ mice (2/30; 7%), when sacrificed at 18 months of age. Moreover, high incidence of tumor formation was observed in Cadm1+/- mice, where lung tumors showed loss of CADM1 expression, suggesting that the Cadm1 gene is inactivated by 2-hit. Whereas no mutation was observed in the Kras2, Egfr and Tp53 genes in the tumors, we found loss of expression of 4.1N as well as CADM4, a molecule homologous to CADM1, in almost all tumors examined. Furthermore, activation of several receptor thyrosine kinases and its downstream pathways were detected in western blotting as well as expression profile analyses. These findings indicate that CADM1 acts as a strong tumor suppressor in the lung but that additional alterations both in cell adhesion and signal transduction cascade are required for lung tumor development.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 291.
Immune microenvironment modulation unmasks therapeutic benefit of radiotherapy and checkpoint inhibition
Authors: Jared M. Newton, Aurelie Hanoteau, Hsuan-Chen Liu, Angelina Gaspero, Falguni Parikh, Robyn D. Gartrell-Corrado, Thomas D. Hart, Damya Laoui, Jo A. Van Ginderachter, Neeraja Dharmaraj, William C. Spanos, Yvonne Saenger, Simon Young, Andrew G. Sikora
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Immune checkpoint inhibitors (ICIs) for solid tumors, including those targeting programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), have shown impressive clinical efficacy, however, most patients do not achieve durable responses. One major therapeutic obstacle is the immunosuppressive tumor immune microenvironment (TIME). Thus, we hypothesized that a strategy combining tumor-directed radiation with TIME immunomodulation could improve ICI response rates in established solid tumors. <h3>Methods</h3> Using a syngeneic mouse model of human papillomavirus (HPV)-associated head and neck cancer, mEER, we developed a maximally effective regimen combining PD-1 and CTLA-4 inhibition, tumor-directed radiation, and two existing immunomodulatory drugs: cyclophosphamide (CTX) and a small-molecule inducible nitric oxide synthase (iNOS) inhibitor, L-n6-(1-iminoethyl)-lysine (L-NIL). We compared the effects of the various combinations of this regimen on tumor growth, overall survival, establishment of immunologic memory, and immunologic changes with flow cytometry and quantitative multiplex immunofluorescence. <h3>Results</h3> We found PD-1 and CTLA-4 blockade, and radiotherapy alone or in combination, incapable of clearing established tumors or reversing the unfavorable balance of effector to suppressor cells in the TIME. However, modulation of the TIME with cyclophosphamide (CTX) and L-NIL in combination with dual checkpoint inhibition and radiation led to rejection of over 70% of established mEER tumors and doubled median survival in the B16 melanoma model. Anti-tumor activity was CD8<sup>+</sup> T cell-dependent and led to development of immunologic memory against tumor-associated HPV antigens. Immune profiling revealed that CTX/L-NIL induced remodeling of myeloid cell populations in the TIME and tumor-draining lymph node and drove subsequent activation and intratumoral infiltration of CD8<sup>+</sup> effector T cells. <h3>Conclusions</h3> Overall, this study demonstrates that modulation of the immunosuppressive TIME is required to unlock the benefits of ICIs and radiotherapy to induce immunologic rejection of treatment-refractory established solid tumors.