tbuckley/cabot-search huggingface dataset:
Which app should I use?
Authors: Stephen Armstrong
Journal: British Journal of Sports Medicine (2017)

There are well over 150 000 health apps available in Europe1—from those designed to improve general wellness to apps that monitor medical conditions, apps for clinicians, and apps that function as medical devices. There have been more than 102 billion down-loads of health apps worldwide yet there is little regulation or guidance available for doctors or patients on quality, safety, or efficacy.

Since the UK government founded the Cochrane Centre in 1992, evidence based medicine has been at the heart of healthcare.2 With the burgeoning apps market, however, things are different.

“There's a huge and growing number of health apps out there, and with that comes a wide variation in quality, testing, and evaluation,” says Sarah Williams, senior health information officer at Cancer Research UK. “As with any new technology there's a lot we still need to understand about whether they can be effective, especially in the long term, and, perhaps more importantly, whether they're helping the people who really need it.”

Technically any app that makes efficacy claims needs to be able to produce some evidence to support its claims under the European Directive on Misleading Advertising. This may, however, not include the high quality evidence from randomised controlled trials that clinicians have come to expect.

“People are increasingly using apps to monitor, manage, and even treat conditions but have no information on whether or how the apps have been calibrated, and it's hard to find any information on the research used in development,” explains Patricia Wilkie, chair of the National Association for Patient Participation. “It's a very murky area.”

“People choose health apps the same way as they choose any apps—quality of design and how easy they are to use,” explains Satish Misra, cardiology fellow at the Johns Hopkins Hospital in Baltimore and managing editor …
A Nanosystem of Amphiphilic Oligopeptide-Drug Conjugate Actualizing Both αvβ3 Targeting and Reduction-Triggered Release for Maytansinoid
Authors: Yanqin Liang, Suxin Li, Xiaoyou Wang, Bo He, Bing He, Wenbing Dai, Hua Zhang, Xueqing Wang, Yiguang Wang, Demin Zhou, Qiang Zhang
Journal: Theranostics (2017)

To design a prodrug-based self-assembling nanosystem with both ligand targeting and stimuli-responsive features, and elucidate the superiority of each targeting strategy and the synergistic effect between them, we synthesized four small molecule amphiphilic peptide-drug conjugates (APDCs) using maytansinoid (DM1) as a cytotoxic agent, cRGDfK as a homing peptide, and disulfide (SS) or thioether (SMCC) as linker. Owing to their amphiphilicity, the APDCs could self-assemble into nanoparticles (APDC@NPs) which were evaluated in vitro in three different cell lines and in vivo in tumor-bearing C57BL/6 mice. The RSSD@NPs showed the strongest interaction with αvβ3 integrin, highest cell uptake and intracellular free drug level, and best antitumor efficacy in vitro and in vivo, while it shared the same goodness with other test nanosystems in terms of high drug loading, EPR effect and free of potentially toxic polymers. Especially, the in vivo efficacy of RSSD@NPs was 2 fold of free DM1 which is too cytotoxic to be a drug, while the active targeted APDC@NPs demonstrated acceptable system, tissue and blood compatibility. In αvβ3-positive cells or tumors, the RGD targeting contributed much more than disulfide in anticancer effect. The maximum synergism of the two strategies reached to 22 fold in vitro and 3 fold in vivo. Generally, the active targeting, prodrug and nanosystem could significantly decrease the toxicity of free DM1 and improve its therapy outcome via combining active targeting, prodrug and nanopreparation, especially the dual targeting strategies and their synergism.
Abstract 1599: Antibody-based inhibition of CSF-1R as a component of combination immunotherapy in preclinical models
Authors: David I. Bellovin, Nebiyu Wondyfraw, Barbara Sennino, Quinn Walker, Susan Johnson, Anita Levin, Emma Masteller, Susannah D. Barbee, Robert Sikorski, Tom Brennan
Journal: Cancer Research (2017)

Abstract The colony stimulating factor 1 receptor (CSF-1R) signaling pathway promotes tumor progression via the recruitment, differentiation, and survival of immuno-suppressive tumor-associated macrophages (TAMs). FivePrime has developed cabiralizumab (FPA008), an IgG4 antibody against CSF-1R that blocks the ability of both CSF-1 and IL-34 to bind and activate this receptor, thereby modulating the immune response to tumorigenesis. In order to investigate the impact of CSF-1R signaling inhibition in preclinical models, we generated a surrogate antibody, cmFPA008, which targets mouse CSF-1R and demonstrates equivalent affinity and ligand-blocking ability as FPA008. Utilizing a combination of flow cytometry and immunofluorescence analyses, we have identified alterations in the tumor microenvironment that occur upon CSF-1R inhibition, including significant reduction of immunosuppressive TAMs and an increase in tumor PD-L1 expression. Interestingly, we observe a transient increase in CD8+ T cell number and activation upon TAM depletion, followed by a subsequent increase in MDSC populations that corresponds with reduction of the CD8+ T cell numbers. Moreover, we have used murine syngeneic tumor models to examine the anti-tumor impact of CSF-1R inhibition in combination with other immuno-oncology agents. Our results show that, when added to PD-1/PD-L1 blockade, cmFPA008 can significantly enhance anti-tumor efficacy. We are currently exploring the effects of combining cmFPA008-induced TAM depletion with additional immuno-oncology agents, including T cell agonists. Our preclinical results demonstrate that inhibition of the CSF-1R pathway can combine with various immuno-oncology agents with distinct mechanisms of action. FivePrime has initiated a clinical trial in collaboration with Bristol-Myers Squibb (BMS) to investigate the use of cabiralizumab in combination with nivolumab (anti-PD-1, OPDIVO®) in six different tumor types. Citation Format: David I. Bellovin, Nebiyu Wondyfraw, Barbara Sennino, Quinn Walker, Susan Johnson, Anita Levin, Emma Masteller, Susannah D. Barbee, Robert Sikorski, Tom Brennan. Antibody-based inhibition of CSF-1R as a component of combination immunotherapy in preclinical models [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 1599. doi:10.1158/1538-7445.AM2017-1599
Abstract 613: Development of FPA154, a novel tetravalent anti-GITR antibody, for the treatment of solid tumors
Authors: Susannah D. Barbee, Amanda Chen, Susan Johnson, David I. Bellovin, John C. Timmer, Nebiyu Wondyfraw, Mikayel Mkrtichyan, Amir S. Razai, Kyle S. Jones, Chelsie Y. Hata, Denise Gonzalez, Quinn Deveraux, Brendan P. Eckelman, Luis Borges
Journal: Cancer Research (2017)

Abstract Glucocorticoid-induced TNFR-related (GITR, TNFRSF18) is a member of the TNFR superfamily with pleiotropic T cell modulatory activity. We are developing a novel anti-GITR antibody with enhanced agonist activity for the treatment of solid tumors. Our candidate molecule, FPA154, is constructed with single-domain antibodies (sdAbs) in a tetravalent format, with an effector-competent IgG1 Fc domain. Both FPA154 and the mouse-reactive surrogate molecule (cmFPA154, mIgG2a isotype) bind to cell-surface GITR with high affinity. GITR is most highly expressed in vivo on activated and intratumoral Treg, and our data indicates that FPA154 and cmFPA154 potently mediate ADCC activity against Treg expressing high levels of GITR. In contrast, activated effector T cells express modest levels of cell-surface GITR, and FPA154 and cmFPA154 drive GITR-induced NF-κB activation. This activity is independent of Fc-mediated crosslinking, which is normally required for bivalent GITR antibodies to induce GITR signaling. cmFPA154 has potent antitumor activity in several syngeneic mouse tumors, both as a monotherapy treatment and in combination with anti-PD-1. In summary, FPA154 is a promising candidate with multiple mechanisms of action that contribute to generation of an antitumor immune response mediated by different T cell subsets. Citation Format: Susannah D. Barbee, Amanda Chen, Susan Johnson, David I. Bellovin, John C. Timmer, Nebiyu Wondyfraw, Mikayel Mkrtichyan, Amir S. Razai, Kyle S. Jones, Chelsie Y. Hata, Denise Gonzalez, Quinn Deveraux, Brendan P. Eckelman, Luis Borges. Development of FPA154, a novel tetravalent anti-GITR antibody, for the treatment of solid tumors [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 613. doi:10.1158/1538-7445.AM2017-613
Abstract 4508: Penfluridol-induced endoplasmic reticulum stress leads to autophagy-mediated pancreatic tumor growth suppression
Authors: Alok Ranjan, Sharavan Ramachandran, Nehal Gupta, Sanjay Srivastava
Journal: Cancer Research (2017)

Abstract Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States. Experimental and clinical evidences suggested that high basal state autophagy in pancreatic tumors could induce resistance to chemotherapies. Recently, we have demonstrated that penfluridol suppresses pancreatic tumor growth by autophagy-mediated apoptosis both in vitro and in vivo. (Ranjan and Srivastava, Scientific Reports: 2016;6:26165; PMID: 27189859), however the mechanism of autophagy induction by penfluridol was not clear. Several studies have established that endoplasmic reticulum (ER) stress could lead to autophagy and inhibit tumor progression. In the current study, we demonstrated that penfluridol induced ER stress in BxPC-3, AsPC-1 and Panc-1, pancreatic cancer cell lines as indicated by up regulation of ER stress markers such as BIP, CHOP and IRE1α after treatment with penfluridol in a concentration-dependent manner. Inhibiting ER stress by pre-treatment with pharmacological inhibitors such as sodium phenylbutyrate and mithramycin or by silencing CHOP using CHOPsiRNA, blocked penfluridol-induced autophagy. These results clearly indicated that penfluridol induced ER stress lead to autophagy in our model. Western blot analysis of subcutaneously implanted AsPC-1 and BxPC-3 tumors as well as orthotopically implanted Panc-1 tumors demonstrated upregulation of BIP, CHOP and IRE1α expression in the tumors lysates from penfluridol treated mice as compared to tumors from control mice. Altogether, our study established that penfluridol induced ER stress mediated autophagy in pancreatic tumor. Our study opened a new therapeutic target for advanced chemotherapies against pancreatic cancer. (Supported in part by RO1 grant CA129038, awarded by National Cancer Institute, NIH). Citation Format: Alok Ranjan, Sharavan Ramachandran, Nehal Gupta, Sanjay Srivastava. Penfluridol-induced endoplasmic reticulum stress leads to autophagy-mediated pancreatic tumor growth suppression [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 4508. doi:10.1158/1538-7445.AM2017-4508
Abstract 3884: A tumor stem cell marker DCLK1 promotes hepatocellular carcinoma by regulating β-catenin, EMT and clonogenic properties of hepatocytes
Authors: Naushad Ali, Charles B. Nguyen, Parthasarathy Chandrakesan, Randal May, Danny Dhanasekaran, Michael S. Bronze, Courtney W. Houchen
Journal: Cancer Research (2017)

Abstract Introduction: Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related deaths worldwide with a 5-year survival rate of &amp;lt;15%. Chronic viral hepatitis, NASH, and cirrhosis are major risk factors for the HCC development. Thus, HCC represents a major public health issue worldwide. Currently, sorafenib is the only FDA-approved drug used for HCC treatment. Unfortunately, it increases patient's survival by only 3 months. Tumor stem cells (TSCs) are likely responsible for resistance to chemotherapy, relapse, and metastasis. We have demonstrated that a TSC marker, doublecortin-like kinase (DCLK1), is induced during hepatic injury, cirrhosis and HCC and its overexpression in HCC patient’s liver significantly reduces survival. Therefore, understanding of the mechanism(s) hepatic TSCs regulation is important for the development of effective therapy against HCC. Methods: Hepatoma Huh7 cells and primary human hepatocytes were infected with lentiviruses expressing recombinant RFP-DCLK1 fusion protein. The RFP-DCLK1-positive cells were isolated using FACS and subjected to immunofluorescence confocal microscopy, clonogenic assay, Western blot and xenograft in mice. Results: DCLK1-overexpressing human hepatocytes formed spheroids but not the control cells. DCLK1 overexpression induced accumulation of active β-catenin in the perinuclear and nuclear regions in Huh7 cells with concomitant increase in c-Myc. The DCLK1-negative cells lacked active β-catenin and total β-catenin was observed only in their cell membranes. Hepatic β-catenin mRNA levels were unaffected during various stages of HCC. Analysis of HCC patients’ liver tissues (n= 369) suggested that elevated DCLK1 mRNAs expression significantly correlates with increased levels of MMP2, vimentin, Zeb2, Twist1 and VEGF-C which are involved in epithelial-to-mesenchymal transition (EMT) and tumor invasion. Huh7-derived tumors also exhibited high level expression of these factors. Conclusions: These observations suggest that DCLK1 induces tumor/cancer stem cell-like properties and EMT in liver cells. DCLK1 appears to enhance active β-catenin levels and its cellular localization to the nucleus. Thus, the DCLK1 represents an important target for HCC therapy. Citation Format: Naushad Ali, Charles B. Nguyen, Parthasarathy Chandrakesan, Randal May, Danny Dhanasekaran, Michael S. Bronze, Courtney W. Houchen. A tumor stem cell marker DCLK1 promotes hepatocellular carcinoma by regulating β-catenin, EMT and clonogenic properties of hepatocytes [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 3884. doi:10.1158/1538-7445.AM2017-3884
Abstract 563: Quantitative EMT expression score for predicting survival outcome
Authors: Jason T. George, Mohit K. Jolly, Herbert Levine
Journal: Cancer Research (2017)

Abstract Tumor aggressiveness and subsequent metastasis still remain as major limitations to curative treatments for cancer patients. The epithelial to mesenchymal transition (EMT) is a process that occurs naturally during embryogenesis and has been linked to metastasis in many cancer types. EMT is characterized by phenotypic changes that allow for tissue extravasation and migration of cancer cells into the bloodstream. These changes may be linked to specific patterns in the gene expression signature of cells undergoing EMT. Recent theoretical efforts have predicted the existence of a stable, hybrid (E/M) phenotype which has also been observed experimentally in single cells. However, the effects of this hybrid phenotype on cancer patient survival have not been well characterized. The ability to quantify a patient’s EMT status via a simple test involving a small collection of prognostic genes would provide an important tool for clinical risk stratification and treatment in the context of many cancer types. Here, we apply iterative statistical methods to generate an EMT score based on gene expression samples. We use this score to characterize the degree of the hybrid phenotype signature present in test samples. Predictions from our model are verified against cell lines with known EMT status. Lastly, we apply our model to clinical samples in order to assess survival differences in various EMT groups. We demonstrate that in many cases, EMT status successfully classifies patients into groups with statistically significant differences in survival, which is of immediate clinical relevance. Citation Format: Jason T. George, Mohit K. Jolly, Herbert Levine. Quantitative EMT expression score for predicting survival outcome [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 563. doi:10.1158/1538-7445.AM2017-563
Abstract 5236: The dynamic interplay between the cancer genome mutating enzyme APOBEC3B and DNA substrates
Authors: Ozlem Demir, Jeffrey R. Wagner, Ke Shi, Michael A. Carpenter, Surajit Banerjee, Nadine M. Shaban, Kayo Kurahashi, Daniel J. Salamango, Jennifer L. McCann, Gabriel J. Starrett, Justin V. Duffy, Daniel Harki, Hideki Aihara, Rommie E. Amaro, Reuben S. Harris
Journal: Cancer Research (2017)

Abstract The APOBEC3 (A3) family of enzymes catalyze deamination of cytosines to uracils (C-to-U) in single-stranded (ss)DNA, and is an important part of innate immune responses against viruses and transposons. Recent data also indicate that APOBEC3B (A3B) is a major source of genomic mutations in multiple cancers and a contributor to the evolution of drug resistance. A3B is therefore a promising anti-cancer target. Using existing structural information and structural modeling, we generated a model for wild-type A3B in complex with ssDNA and used molecular dynamics to monitor the dynamics of the native interactions of wild-type A3B with ssDNA. The details of A3B-ssDNA interaction and its implications for potential inhibitor design will be presented. Citation Format: Ozlem Demir, Jeffrey R. Wagner, Ke Shi, Michael A. Carpenter, Surajit Banerjee, Nadine M. Shaban, Kayo Kurahashi, Daniel J. Salamango, Jennifer L. McCann, Gabriel J. Starrett, Justin V. Duffy, Daniel Harki, Hideki Aihara, Rommie E. Amaro, Reuben S. Harris. The dynamic interplay between the cancer genome mutating enzyme APOBEC3B and DNA substrates [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 5236. doi:10.1158/1538-7445.AM2017-5236
Expansion of cytotoxic CD56 bright natural killer cells during T-cell deficiency after allogeneic hematopoietic stem cell transplantation
Authors: Gertjan Lugthart, Marieke Goedhart, Merle M. van Leeuwen, Janine E. Melsen, Cornelia M. Jol-van der Zijde, Carly Vervat, Monique M. van Ostaijen-ten Dam, Anja M. Jansen-Hoogendijk, Maarten J.D. van Tol, Arjan C. Lankester, Marco W. Schilham
Journal: Journal of Allergy and Clinical Immunology (2017)
Abstract 2583: A model for capturing and integrating complex molecular alterations related to clinically relevant efficacy evidence
Authors: Cara M. Statz, Sara E. Patterson, Taofei Yin, Susan M. Mockus
Journal: Cancer Research (2017)

Abstract The ability to capture data relevant to different types of oncology-related variations, including single nucleotide variations, deletions, insertions, copy number variations, and fusions in a single system is crucial to a comprehensive understanding of cancer biology. However, collectively linking these varied types of molecular alterations to capture their compound impact to clinically relevant efficacy evidence within a database can prove challenging. Thus, we have built the JAX Clinical Knowledgebase (JAX-CKB), a flexible relational database that allows curation of complex molecular profiles and provides the ability to associate these profiles with documented efficacy evidence, thereby providing a more detailed overview of therapeutic relevance. To demonstrate the utility of creating complex molecular signatures in relation to efficacy evidence, the JAX-CKB was queried to first determine the overall degree of efficacy evidence content related to complex profiles. Additionally, two specific types of complex molecular profiles were queried, which included EML4-ALK plus a missense mutation(s) and BRAF V600E plus any type of molecular alteration(s). Within the JAX-CKB, there are 1,383 unique efficacy evidence lines linked to complex molecular profiles. The complex molecular profiles consisting of EML4-ALK and one or more additional missense mutations were associated with 174 unique efficacy evidence lines. Of the 174 lines, 69 were annotated with a resistant response type, while 68 were annotated with a sensitive response type. The combination of BRAF V600E with one or more molecular alterations was linked to 229 unique efficacy evidence lines. The majority of the lines, 118, were specific to a resistant response type and 83 were associated with sensitivity. Comprehensive genomic profiling of cancer patient samples can often reveal complex molecular signatures. The JAX-CKB is an inclusive knowledgebase that allows one to interpret these complex signatures and rapidly identify appropriate targeted therapies, which could be critical in a clinical setting. Citation Format: Cara M. Statz, Sara E. Patterson, Taofei Yin, Susan M. Mockus. A model for capturing and integrating complex molecular alterations related to clinically relevant efficacy evidence [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 2583. doi:10.1158/1538-7445.AM2017-2583
Abstract 1867: Near infrared fluorescent imaging of brain tumor with IR780 dye incorporated phospholipid nanoparticles
Authors: Shihong Li, Jennifer Johnson, Anderson Peck, Qian Xie
Journal: Cancer Research (2017)

Abstract Background: Near-IR fluorescence (NIRF) imaging is becoming a promising approach in preclinical tumor detection and clinical image-guided oncological surgery. While heptamethine cyanine dye IR780 has excellent tumor targeting and imaging potential, its hydrophobic properties limit its clinical use. In this study, we developed nanoparticle formulations to facilitate the use of IR780 for fluorescent imaging of malignant brain tumor. Methods: Self-assembled IR780-liposomes and IR780-phospholipid micelles were prepared and their NIRF properties were characterized. The intracellular accumulation of IR780-nanoparticles in glioma cells were determined using confocal microscopy. The in vivo brain tumor targeting and NIRF imaging capacity of IR780-nanoparticles were evaluated using U87MG glioma ectopic and orthotopic xenograft models and a spontaneous glioma mouse model driven by RAS/RTK activation. Results: The loading of IR780 into liposomes or phospholipid micelles was efficient. The particle diameter of IR780-liposomes and IR780-phospholipid micelles were 95 nm and 26 nm, respectively. While stock solutions of each preparation were maintained at ready-to-use condition, the IR780-phospholipid micelles were more stable. In tissue culture cells, IR780-nanoparticles prepared by either method accumulated in mitochondria, however, in animals the IR780-phospholipid micelles showed enhanced intra-tumoral accumulation in U87MG ectopic tumors. Moreover, IR780-phospholipid micelles also showed preferred intracranial tumor accumulation and potent NIRF signal intensity in glioma orthotopic models at a real-time, non-invasive manner. Conclusion: The IR780-phospholipid micelles demonstrated tumor-specific NIRF imaging capacity in glioma preclinical mouse models, providing great potential for clinical imaging and image-guided surgery of brain tumors. Citation Format: Shihong Li, Jennifer Johnson, Anderson Peck, Qian Xie. Near infrared fluorescent imaging of brain tumor with IR780 dye incorporated phospholipid nanoparticles [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 1867. doi:10.1158/1538-7445.AM2017-1867