tbuckley/cabot-search huggingface dataset:
Phase I/II clinical trials of dendritic cell-based immunotherapy in patients with the biochemical relapse of the prostate cancer.
Authors: Radek Spisek, Michal Podrazil, Marek Babjuk, Ladislav Jarolim, Jitka Fucikova, Anna Fialova, Ivo Minarik, Hana Hromadkova, Jirina Bartunkova
Journal: Journal of Clinical Oncology (2013)

e16002 Background: In order to have the highest impact on the control of tumor growth, cancer immunotherapy should be initiated as early in the disease course as possible. In prostate cancer, the effect of cancer immunotherapy at the minimal residual disease stage can be evaluated in patients with the biochemical relapse detected by ultrasensitive PSA measurements. We performed a Phase I/II clinical trial of dendritic cell based immunotherapy in patients with the biochemical relaps of the prostate cancer. Methods: Patients with the prostate cancer in the biochemical failure after radical prostatectomy or primary radiotherapy were enrolled in the study. Study medication consisted of 12 doses of 1x10 7 dendritic cells pulsed with killed prostate cancer cell line LNCap (DCVAC/PCa), injected s.c. in 4 weeks intervals. Primary goal of the study was to assess the safety. Secondary goals were PSA kinetics and presence of tumor antigen specific immune response in the peripheral blood. Study is registered as EudraCT 2009-017259-91. Results: Twenty patients were enrolled in the study and evaluated after receiving complete treatment cycle of DCVAC/PCa. Administration of DCVAC/PCa did not lead to any significant side effects. Continuous cancer immunotherapy by DCVAC/PCa significantly prolonged the PSA doubling time (PSA-DT) in all treated patients, on average there was a 3,43-fold increase of PSA-DT after the completion of the treatment. Seven of 20 patients had stable PSA levels during the treatment duration. Mean PSA-DT increased from 8,15 months before the initiation of cancer immunotherapy to 52,64 months at the completion of 12 doses, p&lt;0.0015. Sustained T cells responses against PSA, NY-ESO1, MAGE A1 and MAGE A3 were detected in the peripheral blood of enrolled patients. Conclusions: This study indicates that the continuous cancer immunotherapy with dendritic cells loaded with killed LNCAP cell line represents efficient treatment modality for prostate cancer patients with biochemical relapse. This study supports the use of immunotherapy early in the course of the disease, provided that relevant surrogate endpoints predictive of improved prognosis of early stage patients will be identified. Clinical trial information: 2009-017259-91.
Role of IGF-1R inhibition on an Src-family kinase bypass resistance pathway: A rational basis for cotargeting IGF-1R and Src kinase in pediatric sarcomas?
Authors: Xiaolin Wan, Choh L Yeung, Christine Heske, Arnulfo Mendoza, Lee J. Helman
Journal: Journal of Clinical Oncology (2013)

10025 Background: Dysregulation of IGF signaling plays a fundamental role in oncogenesis in pediatric sarcomas. We recently completed a Phase II study targeting the IGFI receptor signaling pathway in refractory Ewing’s and other sarcomas. We demonstrated an objective response rate of 16 percent, but most responses were transient lasting less than 18 weeks. The majority of patients, even those with initial responses, do not have long term benefit from IGFIR blockade, indicating the presence of an innately resistant tumor mass or the recruitment of compensatory pathways allowing for continued growth. To improve on these responses, we have been probing these tumors to identify other critical pathways that might allow combined targeting approaches. Methods: Multiple RMS and ES cell lines were treated with IGF1R kinase inhibitors and assayed for up-regulation of various signaling pathways. Combination treatment with IGF1R inhibitors and inhibitors of additional signaling pathways were then tested in vitro and in vivo using standard techniques. For in vivo xenograft studies, treatments began 11 days following orthotopic injection of tumor cells. Results: We have identified repid up-regulation of Src family kinase (SFK) signaling within 4 hours of IGF1R blockade in both RMS and ES cell lines. Of note, combined treatment with IGF1R Ab plus IGF1R kinase inhibitors most potently upregulated SFK signaling. Based on these findings, we tested combined IGF1R blockade with SFK inhibition using the commercially available drug, dasatinib. We show that dual blockade of IGF1R and SFK pathways were synergistic in vitro. Furthermore, in xenograft models of RMS, the combination IGF1R and SFK inhibition led to long-term disease free status for at least 90 days in some mice, never seen in our hands previously using these models. Conclusions: This work identified that IGF-1R inhibition induced activation of Src kinase that may act as a by-pass pathway. Synergistic activity of IGF-1R and SFK kinase inhibitors was observed in vitro and in vivo. Dual IGFI and SFK kinase inhibition may lead to improved therapeutic outcomes.
A Single-Cell Window into Pancreas Cancer Fibroblast Heterogeneity
Authors: Jad I. Belle, David G. DeNardo
Journal: Cancer Discovery (2019)

Abstract Summary: Cancer-associated fibroblasts (CAF) have been implicated in diverse and sometimes divergent tumor modulatory processes that can be explained only by the existence of heterogeneous CAF subsets. In this issue of Cancer Discovery, Elyada and colleagues utilize single-cell transcriptomics to resolve CAF heterogeneity in pancreatic ductal adenocarcinoma and identify a novel antigen-presenting CAF population. See related article by Elyada et al., p. 1102.
Exons 45–55 Skipping Using Mutation-Tailored Cocktails of Antisense Morpholinos in the DMD Gene
Authors: Yusuke Echigoya, Kenji Rowel Q. Lim, Dyanna Melo, Bo Bao, Nhu Trieu, Yoshitaka Mizobe, Rika Maruyama, Kamel Mamchaoui, Jun Tanihata, Yoshitsugu Aoki, Shin’ichi Takeda, Vincent Mouly, William Duddy, Toshifumi Yokota
Journal: Molecular Therapy (2019)
Incorporation of 4-1BB Endowed the Potent CD33 Specific Chimeric Antigen Receptor T Cells with Anti-Exhaustion Capacity and Increased Central Memory Compartment
Authors: Saisai Li, Zhongfei Tao, Yingxi Xu, Jia Liu, Na An, Ying Wang, Zheng Tian, Haiyang Xing, Kejing Tang, Xiaolong Liao, Qing Rao, Min Wang, Jianxiang Wang
Journal: Blood (2017)
Heterogeneity and plasticity in healthy and atherosclerotic vasculature explored by single-cell sequencing
Authors: Kim van Kuijk, Christoph Kuppe, Christer Betsholtz, Michael Vanlandewijck, Rafael Kramann, Judith C Sluimer
Journal: Cardiovascular Research (2019)

Abstract Cellular characteristics and their adjustment to a state of disease have become more evident due to recent advances in imaging, fluorescent reporter mice, and whole genome RNA sequencing. The uncovered cellular heterogeneity and/or plasticity potentially complicates experimental studies and clinical applications, as markers derived from whole tissue ‘bulk’ sequencing is unable to yield a subtype transcriptome and specific markers. Here, we propose definitions on heterogeneity and plasticity, discuss current knowledge thereof in the vasculature and how this may be improved by single-cell sequencing (SCS). SCS is emerging as an emerging technique, enabling researchers to investigate different cell populations in more depth than ever before. Cell selection methods, e.g. flow assisted cell sorting, and the quantity of cells can influence the choice of SCS method. Smart-Seq2 offers sequencing of the complete mRNA molecule on a low quantity of cells, while Drop-seq is possible on large numbers of cells on a more superficial level. SCS has given more insight in heterogeneity in healthy vasculature, where it revealed that zonation is crucial in gene expression profiles among the anatomical axis. In diseased vasculature, this heterogeneity seems even more prominent with discovery of new immune subsets in atherosclerosis as proof. Vascular smooth muscle cells and mesenchymal cells also share these plastic characteristics with the ability to up-regulate markers linked to stem cells, such as Sca-1 or CD34. Current SCS studies show some limitations to the number of replicates, quantity of cells used, or the loss of spatial information. Bioinformatical tools could give some more insight in current datasets, making use of pseudo-time analysis or RNA velocity to investigate cell differentiation or polarization. In this review, we discuss the use of SCS in unravelling heterogeneity in the vasculature, its current limitations and promising future applications.
Wearable sensors for monitoring the internal and external workload of the athlete
Authors: Dhruv R. Seshadri, Ryan T. Li, James E. Voos, James R. Rowbottom, Celeste M. Alfes, Christian A. Zorman, Colin K. Drummond
Journal: npj Digital Medicine (2019)

Abstract The convergence of semiconductor technology, physiology, and predictive health analytics from wearable devices has advanced its clinical and translational utility for sports. The detection and subsequent application of metrics pertinent to and indicative of the physical performance, physiological status, biochemical composition, and mental alertness of the athlete has been shown to reduce the risk of injuries and improve performance and has enabled the development of athlete-centered protocols and treatment plans by team physicians and trainers. Our discussions in this review include commercially available devices, as well as those described in scientific literature to provide an understanding of wearable sensors for sports medicine. The primary objective of this paper is to provide a comprehensive review of the applications of wearable technology for assessing the biomechanical and physiological parameters of the athlete. A secondary objective of this paper is to identify collaborative research opportunities among academic research groups, sports medicine health clinics, and sports team performance programs to further the utility of this technology to assist in the return-to-play for athletes across various sporting domains. A companion paper discusses the use of wearables to monitor the biochemical profile and mental acuity of the athlete.
bcl-2 expression and possibility of bladder preservation using combined modality treatment in muscle-invasive transtional cell carcinoma
Authors: H. A. Gaffar, A. Elfayomy, A. Elmaghraby, M. M. Elnemr, W. H. Elsawy
Journal: Journal of Clinical Oncology (2009)

e16133 Background: whether combined chemoradiotherapeutic approaches can obtain the same local control as radical surgery, reducing the rate of distant metastases and improving survival with preservation of bladder for carefully selected patients. The BCL2 inhibits apoptosis. The apoptosis inhibiting action of BCL2 confirms a poor prognosis by current treatment modalities. To evaluate the combined modality treatment and selective bladder preservation and to evaluate BCL-2 expression that may predict treatment response and survival. Methods: 66 eligible patients with T2–4a NxM0 transitional cell carcinoma received two courses of gemcitabine and cisplatin followed by 45 Gy of pelvic radiotherapy in 1.8 Gy fractions with concomitant cisplatin. Tumor response was evaluated by cystoscopy and biopsy. Those responding completely were given 20 Gy bladder boost; patients with residual tumor were assigned to immediate cystectomy. Immunohistochemistry was used to assess the tumor cell expression of BCL-2. Results: After neoadjuvant chemotherapy, a complete response (CR) observed in 14 patients, a partial response (PR) in 26 and no change (NC) in 26. At cystoscopy after the pelvic irradiation with 45 Gy plus cisplatin, a CR was achieved in 33 patients, a PR in 14 and NC in 19. Immediate cystectomy was performed in 21 patients with PR or NC after neoadjuvant chemoradiotherapy. Bcl-2 was expressed in 35 (53%) of the patients. Bcl-2 immunoreactivity was inversely correlated with of histological grade (p = 0.0232) and was not correlated with gender distribution (p = 0.4666), the clinical stage (T) (p = 0.4325) or response to treatment (p = 0.6234). No significant difference was noted between the cause-specific survival rate of patients with positive Bcl-2 expression and those with negative BCL-2 expression. Conclusions: this combined approach of chemotherapy and radiation therapy with bladder preservation should be considered as an option for muscle-invasive transitional cell carcinoma of bladder. Initial results suggest the possibility of retaining a functioning bladder in many patients, without compromising survival. Assessment of Bcl-2 protein expression may be used to predict a clinical response to this combined modality approach. No significant financial relationships to disclose.
Saving the Endangered Physician-Scientist — A Plan for Accelerating Medical Breakthroughs
Authors: Mukesh K. Jain, Vivian G. Cheung, Paul J. Utz, Brian K. Kobilka, Tadataka Yamada, Robert Lefkowitz
Journal: New England Journal of Medicine (2019)

Physician-scientists have been a driving force in biomedical research and have made broad contributions in both the private and public sectors. In the past four decades, however, the proportion of U.S. physicians engaged in research has dropped.
DJ-1 as a predictor of pathologic complete remission of neoadjuvant chemotherapy with breast cancer patients.
Authors: Takahiko Kawate
Journal: Journal of Clinical Oncology (2012)

10544 Background: DJ-1 is a multifunctional protein which is encoded by the causative gene of familial Parkinson disease (i.e., PARK7), and is associated with carcinogenesis. DJ-1 is also a candidate marker for the presence of breast cancer cells, in which it is secreted in nipple fluid and serum. We previously reported that a DJ-1 expression pattern that is low at the protein level and high at the mRNA level is associated with DJ-1 secretion. This secretory expression pattern correlated with a negative hormone receptor status and with unfavorable clinical outcome in breast cancer patients. However, the association of the DJ-1 secretion pattern with therapeutic effect has yet to be determined. Methods: A total of 299 patients received neoadjuvant chemotherapy and surgery from 2002 to 2010 at our institution. We performed immunohistochemistry and in-situ hybridization of DJ-1 in both the needle biopsy and operative specimens of 147 cases with a follow-up time of 3.1 years. The average degree of staining intensity was evaluated semi-quantitatively using an image analyzer. Univariate and multivariate analyses were used to evaluate the predictive value of the therapeutic effect of neoadjuvant chemotherapy. Results: A low expression of DJ-1 protein was detected in the needle biopsy and operative specimens of 89 of the 147 cases, regardless of a high or maintained mRNA level. The tumor response was evaluated as pathological complete remission (pCR) in 39 cases and as non-pCR in the remaining 108 cases. A low expression of DJ-1 protein, which was detected in 34 (87.2%) pCR cases, was a significant predictor on univariate analysis (P &lt;0.001). On multivariate analysis, a low expression of DJ-1 was shown to be a significant independent predictor similar to established predictors such as estrogen receptor status and human epidermal growth factor receptor 2 score. Conclusions: A low expression of DJ-1 protein can serve as a novel and important predictor of a neoadjuvant chemotherapeutic effect, as well as a promising indicator for serologic diagnosis in breast cancer patients.
Whole-brain radiotherapy in NSCLC patients with brain metastasis: Who benefits and by how much?
Authors: Pooja Jain, Amir H Montazeri, Farida Alam, Chinnamani Eswarvee, David J. Husband, Azman Ibrahim, Zafar I Malik, Penny Schofield, Aditya Shenoy, Asha Sivapalasuntharam, Karen A Whitmarsh, Helen Wong, John Littler
Journal: Journal of Clinical Oncology (2012)

e18068 Background: NSCLC patients with brain metastasis have poor survival even with whole brain radiation therapy (WBRT) alone or in combination with surgery (S+WBRT). The aim of the audit was to identify any prognostic factors which can aid treatment decisions. Methods: A retrospective study of patients with brain metastasis from NSCLC, diagnosed between July 2008 and December 2010 was carried out. Patient characteristics, RPA score at the time of presentation, treatment modality, radiotherapy dose fractionation, time to progression, date of death and primary or secondary presentation were collected. The data was analysed using descriptive statistics; overall survival was calculated using the Kaplan-Meier estimates and compared with the Log-rank test. Multivariate analysis was carried using the Proportional Hazards Model. Results: Of the 156 patients included, 52% presented as primary manifestation and 48% as secondary. The mean age of the audit population was 64.4 year, with 60% of patients falling in the RPA II category. Histology was not available in 27 (18%) of the patients. Majority (79%) were treated with WBRT alone, 3 patients had stereotactic radiosurgery in combination with WBRT and 19% had S+WBRT. 9 (6%) patients did not complete WBRT. Median follow up is 3.8 months (0.5-34.5). Overall survival (OS) for the whole group is 4 months. Better survival was seen with S + WBRT (8 vs. 4 months, p &lt;0.01) and primary presentation (5 vs. 4 months, p=0.009). RPA classification significantly influenced survival in the S + WBRT arm (12 months vs. 7 months for RPA I, p=0.009). On multivariate analysis of the various prognostic factors in the WBRT group, RPA classification and higher RT dose (30 Gy/10#) were associated with better survival (OR 2.3 95%CI 1.6-3.4). Patients treated with SRS have the best survival (11 months). Conclusions: RPA classification is the strongest predictor for outcome following treatment for brain metastasis. These findings can assist in better patient selection and optimising radiotherapy dose fractionation to improve survival outcome. It will be interesting to see if QUARTZ trial supports these findings and clarify the benefit of WBRT in patients with NSCLC.
<i>DDR2</i> mutations in lung cancer in adenocarcinoma and squamous cell carcinoma and association with MET activation.
Authors: Justin P Windham, Yongbao Wang, Rebecca A Hilferty, Marc A Sanidad, Daniel Jones
Journal: Journal of Clinical Oncology (2013)

8115 Background: The discoidin domain receptor tyrosine kinase 2 (DDR2) gene is mutated in a small subset of squamous cell carcinomas (SQCAs) of the lung. Targeting of DDR2 with the inhibitor dasatinib inhibits DDR2-mutated cell line growth and is being investigated in clinical trials for treatment of DDR2-mutated lung tumors. We investigated the frequency and type of DDR2 mutations and their association with other targetable growth factor pathway alterations in non-small cell lung carcinoma (NSCLC). Methods: DNA was extracted from macro-dissected FFPE sections of 105 advanced stage lung carcinomas. Next-generation sequencing was performed using a 36-amplicon panel including the coding regions of DDR2 and exons 11 and 15 of BRAF. DDR2 mutations were confirmed by bidirectional Sanger sequencing. Lung tumors were classified using a standard immunohistochemistry panel. MET pathway activation was assessed with immunohistochemistry using an activation-specific phospho-antibody (pMET, Try1234/1235). MET amplification and ALK rearrangement were assessed using FISH. Mutational analysis for EGFR (exon 18-21), PIK3CA (exons 9 and 20), and KRAS(exons 1-2) was performed using PCR-based DNA sequencing. Results: Heterozygous DDR2 point mutations were identified in 7/105 (6.7%) NSCLCs, including 3/29 (10.3%) SQCAs and 4/69 (5.8%) ACAs, but not in neuroendocrine/large cell carcinomas (0/7). DDR2 mutations were scattered throughout the gene, with 4 present in the discoidin domain and 3 in the kinase domain. MET pathway activation, seen in 25% of DDR2-unmutated cases, was found in 3/6 (50%) DDR2-mutated cases, including 1 SQCA with high-level MET gene amplification. DDR2 mutations were mutually exclusive with BRAF or EGFR mutation or ALK rearrangement, with 1 KRAS-mutated case. Conclusions: DDR2 mutations occur in lung carcinomas with a range of histologic features and in association with MET activation. Dual targeting of the MET and DDR2 kinases in such cases may warrant further investigation.
Opioid use potentiates the virulence of hospital-acquired infection, increases systemic bacterial dissemination and exacerbates gut dysbiosis in a murine model of <i>Citrobacter rodentium</i> infection
Authors: Fuyuan Wang, Jingjing Meng, Li Zhang, Sabita Roy
Journal: Gut Microbes (2019)

Opioid analgesics are frequently prescribed in the United States and worldwide. However, serious side effects such as addiction, immunosuppression and gastrointestinal symptoms limit their use. It was recently demonstrated that morphine treatment results in a significant disruption in gut barrier function, leading to an increased translocation of gut commensal bacteria. Further studies have indicated distinct alterations in the gut microbiome and metabolome following morphine treatment, contributing to the negative consequences that are associated with opioid use. However, it is unclear how opioids modulate gut homeostasis in the context of a hospital-acquired bacterial infection. Citrobacter rodentium is an ideal murine model of human infections with enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC). In the current study, a mouse model of C. rodentium infection was used to investigate the role of morphine in the modulation of gut homeostasis in the context of a hospital-acquired bacterial infection. Morphine treatment resulted in 1) the promotion of C. rodentium systemic dissemination, 2) an increase in the expression of the virulence factors of C. rodentium colonization in intestinal contents, 3) altered gut microbiome, 4) damaged integrity of gut epithelial barrier function, 5) inhibition of the C. rodentium-induced increase in goblet cells, and 6) dysregulated IL-17A immune response. This study demonstrates and further validates a positive correlation between opioid drug use/abuse and an increased risk of infections, suggesting that the overprescription of opioids may increase the susceptibility to hospital-acquired infection.