tbuckley/cabot-search huggingface dataset:
Abstract 132: African polyherbal formulation alleviates benzene-induced leukemia in Wistar rats
Authors: Olufemi E. Akanni, Ayodeji Faremi, Aminat O. Agboola, Adekemi R. Akanni, Oluseyi E. Bamisaye
Journal: Cancer Research (2017)

Abstract Background: Chemotherapy and radiotherapy are effective cancer treatment options but they are accompanied by serious side effects. Therefore, more effective therapies are sorely needed. This study investigated the chemotherapeutic effects of a polyherbal formulation on benzene induced leukemia in Wistar rats. The polyherbal formulation is composed of fruits such as Orange, Lime, Lemon, Pineapple, Grape and Vegetables like; Pumpkin leave, Garden egg in honey medium. Method: Leukemia was induced by injecting 0.2 ml of benzene solution intravenously through the tail at 48 h intervals for four weeks. Leukemia developed in 92% of rats within 2 to 4 weeks after the last benzene injection and further observed for leukemia development in appropriate rat groups. Leukemia burden was assessed using indicator parameters such as total leukocyte, red blood cell count, hematocrit, and hemoglobin concentration. Immunophenotyping enumeration of CD 19 expression also corroborated the leukemia assessment by providing specific cellular marker for differentiation of the developed leukemia type. Exactly 0.48 ml of the polyherbal formulation was administered orally by gavage using oral cannular once daily post leukemia induction for four weeks. Results: Leukemia induction reflected in significant reduction in hematocrit, hemoglobin concentration, red cell count and a marked and a significant increase in leukocyte count and CD 19 expression over the control (p &amp;lt; 0.05). There is significant difference between the leukemia group treated with polyherbal formulation and the leukemia positive control group untreated. Conclusion: This study reveals profound chemotherapeutic activity of the polyherbal formulation against experimentally developed leukemia by reversing the induced leukemia in the positive control rat group, hence the ability of the polyherbal formulation in alleviating the cancer symptoms. Table 1.Hematological parameters in polyherbal formulation treated leukemia bearing Wistar rats.Estimated parametersNegative control rats (Mean±SD)Leukemia Positive rats. (Mean±SD)Polyherbal formulation treated leukemic rats (Mean±SD)CD 19 (X 109/L)47.59±1.3989.41±1.7262.32 + 1.42*Total Leukocyte count (X 109/L)6.84 + 0.3011.08 + 0.317.45 + 0.65*Red blood cells(X 1012/L)6.30 + 0.383.5 + 0.385.10 + 0.03*Hematocrit (L/L)0.43 + 0.170.26. + 0.200.37 + 0.08*Hemoglobin (g/dl)13.62 + 0.696.63 + 0.9611.80 + 2.96*Platelets (X 109/L)554.80 + 92.23389.50 + 146.10425.10 + 60.8**Significance at p&amp;lt;0.05 Citation Format: Olufemi E. Akanni, Ayodeji Faremi, Aminat O. Agboola, Adekemi R. Akanni, Oluseyi E. Bamisaye. African polyherbal formulation alleviates benzene-induced leukemia in Wistar rats [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 132. doi:10.1158/1538-7445.AM2017-132
A phenotypically and functionally distinct human T <sub>H</sub> 2 cell subpopulation is associated with allergic disorders
Authors: Erik Wambre, Veronique Bajzik, Jonathan H. DeLong, Kimberly O’Brien, Quynh-Anh Nguyen, Cate Speake, Vivian H. Gersuk, Hannah A. DeBerg, Elizabeth Whalen, Chester Ni, Mary Farrington, David Jeong, David Robinson, Peter S. Linsley, Brian P. Vickery, William W. Kwok
Journal: Science Translational Medicine (2017)

A unique T helper cell signature in allergic patients isolates the pathogenic cells and provides a target for disease intervention.
Abstract 689: Immune checkpoint targeting to improve immunotherapy in neuroblastoma
Authors: Myrna L. Ortiz-Ruiz
Journal: Cancer Research (2017)

Abstract Neuroblastoma (NB) is the most common extracranial solid tumor in children. Current treatments accounts only for at the most 40% of survival rate in high-risk NB patients. Hence, there is a need to develop new strategies that disrupt immunosuppressive signals in the tumor microenvironment in order to achieve robust anti-tumor immune responses. Co-inhibitory signals through receptors such as PD-1 can lead to the inactivation of T cells. On the other hand, co-stimulatory signals through receptors such as 41BB can enhance T cell activity against tumors. These receptors can serve as tools to develop strategies to optimize and enhance T cell anti-tumor functions. In this study, we used 9464D NB tumor mouse model to evaluate antibody treatment as a possible immunotherapy strategy. We further examine the infiltration and function of T cells after targeting checkpoints in 9464D NB tumor bearing mice. Blockade of various receptors in mice bearing 9464D tumor showed that anti-PD1 and anti-41BB delayed tumor growth. Combination therapy with anti-PD1 and anti-41BB antibodies significantly delayed tumor growth compared to single antibody treatment. This combination therapy led to a higher infiltration of CD8+ cells within the tumor. Splenocytes from 9464D tumor bearing mice treated with anti-PD1 and anti-41BB are tumor specific. In conclusion, our findings intend to design the best complement therapy to improve survival of patients with advanced NB. Our data demonstrates that tumor reactive T cells in NB tumors may express different checkpoint receptors including PD1 and 41BB. 9464D tumor bearing mice that received a combination of anti-PD1 and anti-41BB antibodies have smaller tumor size compared to single antibody therapy. Future direction includes examine T cells activation after combination therapy of BMT and immunecheckpoint targeting. Also we want to test adoptive transfer of T cells in tumor bearing mice after BMT. Further we want to measure the infiltration of other immune cells, such as myeloid cells and Tregs, in the tumor environment and possible target immune suppressive populations to see the effects in tumor growth. Citation Format: Myrna L. Ortiz-Ruiz. Immune checkpoint targeting to improve immunotherapy in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 689. doi:10.1158/1538-7445.AM2017-689
Abstract 1792: Immune system pathway activation for prediction of the response to neoadjuvant chemotherapy in triple-negative breast cancer
Authors: Takeshi Sawada, Riet Hilhorst, Savithri Rangarajan, Masayuki Yoshida, Kenji Tamura, Rinie van Beuningen, Rob Ruijtenbeek, Hitoshi Tsuda, Fumiaki Koizumi
Journal: Cancer Research (2017)

Abstract Background: Triple-negative breast cancer patients (TNBCs) who receive neoadjuvant chemotherapy (NAC) generally show a response to NAC, but about 5% experience progressive disease (PD). Although TNBCs that respond to NAC have been well-studied, reports about TNBCs with PD during NAC are absent. We aimed to compare kinase activity profiles of TNBCs of both groups to identify a biological predictor of NAC non-responders. Methods: Tyrosine kinase activity profiles of lysates of fresh frozen cancer tissues from NAC non-responders and responders, the latter represented by TNBCs who did not receive NAC, were determined with a peptide microarray system (Cancer Res. 2009; 69(14):5987-95). Tumor infiltrating lymphocytes (TILs) were counted in these tissues. Results: Among 740 TNBCs, 20 NAC non-responders were identified. For the 7 samples from PD confirmed patients and 10 TNBCs not receiving NAC, no correlation was observed between NAC response and age, menopausal status, tumor size or axillary lymph node status. Kinase activity measurements showed large differences in overall tyrosine kinase activity between responders and non-responders. 35 peptides had significantly (p &amp;lt; 0.05) higher phosphorylation in the responder group. Kinases that phosphorylate these peptides (upstream kinases) were identified from literature. Among others, the immune related kinases Zap70, Syk and JAK2 were identified as upstream kinases. Pathway analysis yielded evidence for increased activity in the responder group in immune-related pathways and in pathways involved in development and signal transduction. Responders had a significantly higher (p = 0.0053) TILs count. Conclusion: Kinases related to the immune system are less activated in NAC non-responders. The low TILs count in the non-responders confirmed that activation of the immune system in non-responders is lower than in NAC responders. These data merit a further investigation of the use of kinase activity profiling either alone or in combination with TIL scoring for the prediction of the response to NAC in TNBC with a larger patient cohort. Citation Format: Takeshi Sawada, Riet Hilhorst, Savithri Rangarajan, Masayuki Yoshida, Kenji Tamura, Rinie van Beuningen, Rob Ruijtenbeek, Hitoshi Tsuda, Fumiaki Koizumi. Immune system pathway activation for prediction of the response to neoadjuvant chemotherapy in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1792. doi:10.1158/1538-7445.AM2017-1792
Abstract 4378: Gastric cancer organoid culture shows preserved genomic stability in long-term passage
Authors: Sarah Siu Kuen Yue, Helen Hoi Ning Yan, Hoi Cheong Siu, Siu Lun Ho, Wai Yin Tsui, Dessy Chan, Annie Shuk Yee Chan, Bernard Chi Hang Lee, Anthony Kin Wang Chan, Suet Yi Leung
Journal: Cancer Research (2017)

Abstract With recent advances in 3D organoid culture techniques, normal epithelial and tumor cells can be directly cultured from clinical specimens in vitro and expanded long-term with a very high success rate. Thus, this constitutes a good platform for various mechanistic functional studies and clinical applications. A previous karyotyping and gene expression profiling study has indicated that organoid culture of normal epithelial cells can be propagated for long periods of time without genomic alterations. However, data on the genomic stability of tumor organoids in long-term culture are not yet available. We have successfully established organoid cultures derived from either primary tumor or lymph node metastasis from 4 gastric cancer patients. For each sample, we performed long-term culture for at least 6 months. DNA was extracted from blood, as well as the early and late passages of these organoids, and submitted for whole-exome sequencing (WES), achieving a mean coverage approaching 50X. Somatic mutations detected in early versus late passage gastric cancer organoids were compared. Furthermore, we examined the organoids for copy number variations based on the coverage and loss of heterozygosity (LOH) information derived from exome sequencing. We detected between 80 to 228 somatic mutations in the 4 early passage organoids, in which over 84-99% of them were retained during long-term culture. We detected 16, 20, 31 and 98 new mutations in the 4 long-term cultures, respectively. The one case with a substantially large number of new mutations (n=98) appeared to have emerged from a subclone of TP53 wild-type cells in a TP53 mutant tumor. Notably, the C&amp;gt;T mutation was the most dominant mutation spectrum in this case, constituting 48%. Despite the presence of frequent long segment LOH and chromosomal aberrations in early passage organoids, indicating the presence of chromosomal instability, these patterns of aberrations were stably maintained in long-term passage. Overall, with the current organoid culture protocol, tumor genomes are mostly stably maintained with the accumulation of only a small number of new mutations. Our results indicate that this is a reliable and stable in vitro cell culture model for various cancer-related and clinical studies. Citation Format: Sarah Siu Kuen Yue, Helen Hoi Ning Yan, Hoi Cheong Siu, Siu Lun Ho, Wai Yin Tsui, Dessy Chan, Annie Shuk Yee Chan, Bernard Chi Hang Lee, Anthony Kin Wang Chan, Suet Yi Leung. Gastric cancer organoid culture shows preserved genomic stability in long-term passage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4378. doi:10.1158/1538-7445.AM2017-4378
Mandela doctor’s book is withdrawn for possible breach of confidentiality
Authors: Pat Sidley
Journal: BMJ (2017)

A new book on the final days of the late South African president Nelson Mandela by his personal doctor has been withdrawn from sale by Penguin Random House South Africa.

It has been alleged that the book, Mandela’s Last Days , breached doctor-patient confidentiality, as permission was not granted by Mandela’s executors or his widow for his medical information to be made public. The book was launched on 18 July, known as Mandela Day (Mandela’s birthday), and was withdrawn less than a week later on 24 July.

The book’s author, Vejay Ramlakan, was the surgeon general …
Abstract 256: Delta tocopherol inhibits urothelial tumorigenesis in the UPII mutant Ha-ras transgenic mouse model and induces apoptosis via activation of the ATF4/CHOP-DR5 pathway
Authors: Christopher A. Blair, Maggie Wu, Tim Huynh, Hanze Hu, Arman Walia, Chung S. Yang, Xiaolin Zi
Journal: Cancer Research (2017)

Abstract Epidemiological studies have reported that Vitamin E intake was inversely related to the risk of multiple cancers including human urinary bladder cancer. Tocopherols (T) are the major forms of vitamin E in the U.S. diet, exist as α-T, β-T, γ-T and δ-T. Compared to α-T, the anti-cancer effect of other Ts and their mechanisms of action remain largely unknown. We have shown that δ-T is the most effective one among the Ts in reducing the viabilities of bladder cancer cell lines with IC50s of under 10 μM, whereas there is no or minimal effect of α-T at a concentration of up to 50 μM on the viability of bladder cancer cell lines. δ-T treatment of bladder cancer cell lines, RT4 and UMUC-3, resulted in apoptosis via marked induction of death receptor-5 (DR5) expression and then activation of caspase 3, 8, and 9 leading to PARP cleavage and apoptotic morphology. siRNA knockdown of DR5 expression significantly attenuated the apoptotic effects of δ-T in bladder cancer cells. Consistent with the above results, δ-T treatment significantly upregulated the expression of ER stress sensors PERK and IRE1α, as well as downstream components GRP78, ATF4, and CHOP. These results suggested that δ-T can induce endoplasmic reticulum stress and the Unfolded Protein Response, triggering its apoptotic effect. Furthermore, homozygous male UPII mutant Ha-ras transgenic mice that mimic the development and progression of human urothelial cell carcinoma (UCC) with H-ras activation were fed with vehicle control diet (n=20) or diet supplemented with δ-T (0.2% in diet) for 150 days (n=18). The δ-T diet significantly decreased the mean bladder weights (serves as a surrogate of tumor weight) of survived Ha-ras mutant mice by 56% (control vs δ-T, 0.259 ± 0.015 gram vs. 0.114 ± 0.012 gram, P&amp;lt;0.0001) with no significant difference in overall body mass and no detectable indication of toxicity. Our results suggest that δ-T is a potent anti-cancer agent and deserves further investigation in preventing the recurrence and progression of non-muscle-invasive UCC. Citation Format: Christopher A. Blair, Maggie Wu, Tim Huynh, Hanze Hu, Arman Walia, Chung S. Yang, Xiaolin Zi. Delta tocopherol inhibits urothelial tumorigenesis in the UPII mutant Ha-ras transgenic mouse model and induces apoptosis via activation of the ATF4/CHOP-DR5 pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 256. doi:10.1158/1538-7445.AM2017-256
Abstract 2885: Activation of IL1α signaling by HER2 overexpression promotes breast cancer stem cells
Authors: Shou Liu, Ji shin Lee, Hexin Chen
Journal: Cancer Research (2017)

Abstract Breast cancer is a heterogeneous disease and only a small proportion of cells known as cancer stem cells (CSCs) have ability to generate tumor. Recently, it has been reported that HER2 overexpression increase breast cancer stem cells (BCSCs). However, the underlying mechanism is not clearly known. In this study, we explored the molecular mechanism how HER2 increase BCSCs. Our data has demonstrated HER2 induces BCSCs by indirectly activating NF-kB and STAT3 signaling. To figure out the direct target of HER2, we did the microarray and found that HER2 upregulates the expressions of IL1a and IL6, two major cytokines which directly activates NFkB and STAT3, respectively. Interestingly, we found that IL1a also indirectly activates STAT3. IL1α induced STAT3 was blocked when IL6 was knock out from cells. We found that HER2 enhances IL1α transcription by activating PU.1 which is known transcription factor of IL1a. Finally, we studied effect of IL1a on tumorigenesis, and found that IL1α KO dramatically attenuates the tumor growth in NOD/SCID mice. Taken together, we found that HER2 induces BCSCs by upregulating IL1a and IL6 expression. We for first time demonstrating that IL1α plays a critical role in HER2-induced expansion of BCSC population and may be a potential therapeutic target for HER2 positive breast cancer. Citation Format: Shou Liu, Ji shin Lee, Hexin Chen. Activation of IL1α signaling by HER2 overexpression promotes breast cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2885. doi:10.1158/1538-7445.AM2017-2885
FRI0553 The efficacy of 2-years denosumab treatment for glucocorticoid-induced osteoporosis (GIOP)
Authors: K Akashi, K Nishimura, G Kageyama, S Ichikawa, T Shirai, Y Yamamoto, Y Ichise, H Yamada, I Naka, D Waki, T Okano, S Takahashi, Y Ueda, S Sendo, A Onishi, J Saegusa, A Morinobu
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Osteoporosis is one of the important adverse effects in the glucocorticoids treatment for the patients with rheumatoid arthritis (RA) and connective tissue diseases (CTDs). Although the usefulness of denosmab for primary osteoporosis has been well-established, the efficacy for GIOP remains unclear. <h3>Objectives</h3> This study aimed to clarify the therapeutic effects of denosumab for GIOP. <h3>Methods</h3> We evaluated bone mineral density (BMD) and serum markers of bone metabolism (BAP, NTx, TRACP-5b and P1NP) of patients who had been treated with over 5mg of predonisolone for RA and CTDs, and denosumab for GIOP, for two years in Kobe University Hospital. BMD and serum markers were evaluated every six months for 2 years from the baseline. The changes of those data from baseline were analyzed by Student9s t test using GraphPad Prism 5 software and p&lt;0.05 was considered statistically significant. <h3>Results</h3> Number of the patients were 53 (male: 4 cases, female: 49 cases), and their characteristics at the beginning of denosumab treatment were as below; age: 64.19±12.0 years old, dose of prednisolon: 10.59±9.97mg/day, BMD of lumber spine: 0.768±0.112g/cm<sup>3</sup>, T-score of lumber spine: -2.28±1.01, BMD of femoral neck: 0.540±0.085g/cm<sup>3</sup>, T-score of femoral neck: -2.28±0.76. After 2-years denosumab treatment, T-scores of lumber spine (0.54±0.39 gain) and femoral neck (0.13±0.26 gain) were significantly increased from baseline (Figure; mean ± SEM. *:p&lt;0.05). In addition, the serum markers of bone metabolism, both absorption and formation, were significantly suppressed with denosumab. <h3>Conclusions</h3> Denosumab can suppress bone metabolic turnover, and increase lumber spine and femoral neck T-scores of GIOP patients. <h3>Disclosure of Interest</h3> None declared
Abstract 982: Development of homogeneous dual-drug ADCs: Application to the co-delivery of auristatin payloads with complementary antitumor activities
Authors: Matthew R. Levengood, Xinqun Zhang, Kim K. Emmerton, Joshua H. Hunter, Peter D. Senter
Journal: Cancer Research (2017)

Abstract A common theme in treating cancer is the use of combination chemotherapy, where multiple drugs with different mechanisms of action are combined to elicit synergistic activity or overcome differential drug sensitivities. Antibody-drug conjugates (ADCs) have emerged as a powerful approach for treating cancer, combining the tumor targeting specificity of monoclonal antibodies with the potent cell-killing activity of cytotoxic drugs. Like other therapies, these agents are increasingly being tested in combination with unconjugated, clinically approved anticancer agents. In addition, emerging data demonstrates that insensitivity to a particular ADC can be overcome through delivery of a different payload using the same antibody. For these reasons, the development of ADCs that can deliver two complementary payloads to a tumor would likely be a significant advancement in ADC technology. To enable dual-drug conjugation, we utilized a multiplexing drug carrier that contains cysteine residues with orthogonal protecting groups and identified novel conditions for utilization of these protecting groups on a folded protein. Sequential cysteine unmasking enables discrimination between conjugation sites to allow for site-specific drug conjugation. This strategy provides homogeneous ADCs bearing 16 total drugs per antibody, split evenly between the two drug linkers. Importantly, this strategy is flexible, as it does not require engineered antibodies or custom enzymes for drug-linker conjugation. To demonstrate the potential benefits of ADC dual drug delivery, this strategy was applied to the construction of ADCs bearing two classes of auristatin drug linkers that have different physiochemical properties and complementary anti-cancer activities. Dual-auristatin ADCs were tested in cell line and xenograft models that have differential sensitivities to the individual auristatin components, including those with heterogeneous antigen expression or high levels of drug efflux transporters. The data from these studies demonstrate that the dual-auristatin ADCs were active on cells and tumors that are refractory to treatment with either of the individual component drugs. This work highlights the potential for delivering two synergistic or complementary payloads on a single ADC and presents a flexible method for constructing dual-drug ADCs with site-specific and homogeneous drug loading. Citation Format: Matthew R. Levengood, Xinqun Zhang, Kim K. Emmerton, Joshua H. Hunter, Peter D. Senter. Development of homogeneous dual-drug ADCs: Application to the co-delivery of auristatin payloads with complementary antitumor activities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 982. doi:10.1158/1538-7445.AM2017-982