tbuckley/cabot-search huggingface dataset:
Tingling and numbness in the arm
Authors: Muhammad A Zamir, Jamaal Raoof
Journal: BMJ (2019)

A 35 year old bricklayer presented with a six day history of numbness and tingling in his left arm. The pain was noticeably worse at night when lying on his left side and exacerbated by abducting the arm. He had no history of trauma and did not use machinery at work. He had no other medical conditions.

Clinical examination showed minor swelling of the left hand compared with the right, with reduced sensation to pain and fine touch at the ulnar aspect …
Abstract 4278: A comparison of drug sensitivity in isogenic tumor cell lines confirms that cytoprotective autophagy confers intrinsic resistance to cisplatin
Authors: Jingwen Xu, Nipa Patel, Tareq Saleh, Yingliang Wu, Santiago Lima, David A. Gewirtz
Journal: Cancer Research (2019)

Abstract Although autophagy inhibition often increases tumor cell sensitivity to chemotherapy and radiation, these observations do not provide definitive proof that autophagy is actually an intrinsic mechanism of resistance since virtually all tumor cells undergo autophagy in response to therapy. To directly address whether autophagy induction can confer chemoresistance, the current studies utilized a paired set of isogenic cell lines in which (cisplatin-induced) autophagy was either cytoprotective (crp53 cells where p53 was knocked out) or nonprotective (parental p53 wt cells) in function, but where the overall extent of autophagy was essentially identical. Cisplatin sensitivity was significantly lower in the crp53 cells where cisplatin-induced autophagy was protective compared to the parental p53 wt cells where cisplatin-induced autophagy was nonprotective, in support of the premise that cytoprotective autophagy could confer a relative degree of intrinsic resistance to chemotherapy. Accordingly, we can draw the following conclusions: (i) radiation and chemotherapy can promote both protective and nonprotective autophagy in tumor cells; (ii) although p53 can act as an autophagic switch, it cannot be reliably predicted whether autophagy will be protective or nonprotective based solely on p53 function; and (iii) even in the case(s) where autophagy is cytoprotective, it cannot be assumed that autophagy will confer drug or radiation resistance, but only that autophagy inhibition may, in select cases, increase drug or radiation sensitivity. These findings highlight the complexity of efforts to exploit autophagy inhibition as a therapeutic strategy to enhance tumor response to chemotherapy and radiation. Citation Format: Jingwen Xu, Nipa Patel, Tareq Saleh, Yingliang Wu, Santiago Lima, David A. Gewirtz. A comparison of drug sensitivity in isogenic tumor cell lines confirms that cytoprotective autophagy confers intrinsic resistance to cisplatin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4278.
A new prognostic score for biliary tract cancer: a multicenter experience
Authors: P. Ziranu, E. Lai, A. Casadei Gardini, A. Pretta, L. Faloppi, K. Andrikou, G. Astara, G. Orsi, V. Impera, S. Mariani, N. Liscia, P. Soro, F. Musio, S. Camera, S. Tolu, C. Madeddu, E. Massa, V. Pusceddu, L. Demurtas, M. Puzzoni, S. Cascinu, M. Scartozzi
Journal: Annals of Oncology (2019)
Drug delivery micelles with efficient near-infrared photosensitizer for combined image-guided photodynamic therapy and chemotherapy of drug-resistant cancer
Authors: Shijie Zhen, Xiaoqing Yi, Zujin Zhao, Xiaoding Lou, Fan Xia, Ben Zhong Tang
Journal: Biomaterials (2019)

The combination of photodynamic therapy (PDT) and chemotherapy (CT) offers a promising approach for the tumor eradication for overcoming multidrug resistance (MDR), which is a major obstacle to effective cancer treatment. However, for PDT, simultaneously achieving near-infrared (NIR) emission and efficient reactive oxygen species (ROS) generation with low dark toxicity is urgently needed but remains challenging. Herein, a series of novel fluorophores with strong NIR emission, hybridized local and charge transfer characteristics, good two-photon absorption, high photostability, low dark cytotoxicity and excellent ROS generation ability are developed. By encapsulating the NIR fluorophore (DEB-BDTO) as a photosensitizer along with a drug resistance inhibitor tariquidar (TQR) within a polymeric prodrug (PMP), a reduction-sensitive drug co-delivery system (DEB/[email protected] micelles) is constructed. The DEB/[email protected] micelles exhibit a prominent synergistic lethal effect of PDT and CT on SKOV-3 cells and SKOV-3/MDR cells, and can apparently enhance the inhibition of tumor growth compared with sole PDT or CT in the tumor-bearing mouse model. Both in vitro and in vivo experiments prove that the new NIR fluorophores are excellent photosensitizers and can furnish an efficient combination therapy of image-guided PDT and CT within drug delivery micelles, which is particularly useful for eradicating multidrug resistance cancer.
Abstract 4961: Gut microbiota modulates adoptive cell therapy via CD8α dendritic cells and IL-12
Authors: Mireia Uribe-Herranz, Kyle Bittinger, Stavros Rafail, Stefano Pierini, Sonia Guedan, Frederic Bushman, Carl June, Andrea Facciabene
Journal: Cancer Research (2019)

Abstract Adoptive T cell therapy (ACT) is a promising new modality for malignancies. Here, we report that adoptive T cell efficacy in tumor-bearing mice is significantly affected by differences in the native composition of the gut microbiome or treatment with antibiotics, or by heterologous fecal transfer. Depletion of bacteria with vancomycin decreased the rate of tumor growth in mice from The Jackson Laboratory receiving ACT, whereas treatment with neomycin and metronidazole had no effect, indicating the role of specific bacteria in host response. Vancomycin treatment induced an increase in systemic CD8α+ DCs, which sustained systemic adoptively transferred antitumor T cells in an IL-12-dependent manner. In subjects undergoing allogeneic hematopoietic cell transplantation, we found that oral vancomycin also increased IL-12 levels. Collectively, our findings demonstrate an important role played by the gut microbiota in the antitumor effectiveness of ACT and suggest potentially new avenues to improve response to ACT by altering the gut microbiota. Citation Format: Mireia Uribe-Herranz, Kyle Bittinger, Stavros Rafail, Stefano Pierini, Sonia Guedan, Frederic Bushman, Carl June, Andrea Facciabene. Gut microbiota modulates adoptive cell therapy via CD8α dendritic cells and IL-12 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4961.
Abstract 1036: WISP-1 promotes epithelial-mesenchymal transition in oral squamous cell carcinoma via the miR-153-3p/Snail axis
Authors: An-Chen Chang, Chih-Hsin Tang
Journal: Cancer Research (2019)

Abstract Oral squamous cell carcinoma (OSCC) is the most common oral malignancy and approximately 50% of patients with OSCC present with regional regional lymph node metastasis. The first step in the ‘invasion-metastasis cascade’ is the phenomenon of epithelial-to-mesenchymal transition (EMT), whereby epithelial cells of the primary tumor lose their apical-basal polarity and transition to a mesenchymal phenotype, gaining the ability to migrate and invade basement membrane and blood vessels. WNT1-inducible signaling pathway protein-1 (WISP-1/CCN4) is an extracellular matrix-related protein that belongs to the CCN family, capable of stimulating bone remodeling and tumor progression. Our previous research showed that WISP-1 promotes cell migration and VEGF-C-dependent lymphangiogenesis in OSCC cells. This investigation further examined the role of WISP-1 in regulating EMT. First, we analyzed data from the cancer genome atlas (TCGA) database, to determine the clinical importance of WISP-1 in oral cancer. We found that WISP-1 expression was significantly associated with clinical disease stage and regional lymph node metastasis. Moreover, we found higher levels of WISP-1 expression in serum samples obtained from 62 patients with OSCC compared with samples from healthy controls. Treatment of the OSCC cell line SCC4 with WISP-1 increased EMT by downregulating expression of the epithelial marker E-cadherin and upregulating the mesenchymal marker Snail. We also observed that WISP-1 regulated the expression of EMT markers via the FAK, ILK and AKT signal transduction pathways. Computational analysis confirmed that microRNA (miR)-29c directly targets the 3′ untranslated region (3′ UTR) of Snail. Treatment of SCC4 cells with WISP-1 inhibited miR-29c expression, while miR-29c mimic prevented WISP-1-induced enhancement of Snail expression, revealing an inverse correlation between miR-29c and Snail expression during WISP-1 treatment. Our findings provide insight into WISP-1-mediated regulation of EMT in OSCC. Citation Format: An-Chen Chang, Chih-Hsin Tang. WISP-1 promotes epithelial-mesenchymal transition in oral squamous cell carcinoma via the miR-153-3p/Snail axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1036.
Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses
Authors: Sarah Spencer, Sevgi Köstel Bal, William Egner, Hana Lango Allen, Syed I. Raza, Chi A. Ma, Meltem Gürel, Yuan Zhang, Guangping Sun, Ruth A. Sabroe, Daniel Greene, William Rae, Tala Shahin, Katarzyna Kania, Rico Chandra Ardy, Marini Thian, Emily Staples, Annika Pecchia-Bekkum, William P.M. Worrall, Jonathan Stephens, Matthew Brown, Salih Tuna, Melanie York, Fiona Shackley, Diarmuid Kerrin, Ravishankar Sargur, Alison Condliffe, Hamid Nawaz Tipu, Hye Sun Kuehn, Sergio D. Rosenzweig, Ernest Turro, Simon Tavaré, Adrian J. Thrasher, Duncan Ian Jodrell, Kenneth G.C. Smith, Kaan Boztug, Joshua D. Milner, James E.D. Thaventhiran
Journal: The Journal of Experimental Medicine (2019)

IL-6 excess is central to the pathogenesis of multiple inflammatory conditions and is targeted in clinical practice by immunotherapy that blocks the IL-6 receptor encoded by IL6R. We describe two patients with homozygous mutations in IL6R who presented with recurrent infections, abnormal acute-phase responses, elevated IgE, eczema, and eosinophilia. This study identifies a novel primary immunodeficiency, clarifying the contribution of IL-6 to the phenotype of patients with mutations in IL6ST, STAT3, and ZNF341, genes encoding different components of the IL-6 signaling pathway, and alerts us to the potential toxicity of drugs targeting the IL-6R.
Abstract 5: Pre-clinical development of CDK9 inhibitor - LS007 for the treatment of acute myeloid leukemia
Authors: Wang Hui, Wang Shudong
Journal: Cancer Research (2019)

Abstract Acute myeloid leukemia (AML) is the most common form of acute leukaemia with an increasing incidence and dismal long-term prognosis with age. The most aggressive subtype, MLL-AML, is characterized by translocations of the mixed-lineage leukaemia gene (MLL) in chromosome band 11q23 and resistance to conventional chemotherapy with a short overall survival of only 9 months. Cyclin-dependent 9 (CDK9) activity is required for MLL-driven oncogenic transcription. Inhibition of CDK9 directly targets the transcriptional machinery required for MLL-fusion proteins (e.g. MLL-AF4, MLL-AF9 and MLL-ENL), thereby leading to apoptosis. We have developed a highly effective drug candidate - LS007 that inhibited CDK9 with a Ki = 4 nM. It suppressed proliferation and induced apoptosis in a range of AML cell lines and patient samples. LS007 was highly efficacious against several AML cell line xenografts and patient-derived xenografts, and well tolerated in mice after oral administration. In a Molm-13 xenograft model, after 21 days of orally daily dosing at 25 mg/kg and 50 mg/kg LS007 inhibited tumor growth (p &amp;lt; 0.001) with T/C = 44 % and 18 %, respectively. Similarly, in a HL-60 xenograft model, LS007 exhibited a significant tumor growth inhibition at 45 mg/kg and 60 mg/kg daily by oral administration with T/C = 40 % and 20 %, respectively. The pharmacokinetic profiles of LS007 was further assessed in the cynomolgus monkeys. After oral doses at the dose of 2, 4 and 8 mg/kg, LS007 was detected in the plasma with the maximum concentration (Cmax) from 55.9 to 279.5 ng/mL and the area under the plasma drug concentration-time graph (AUC) up to 1862.7 h·ng/mL. The mean terminal half-life (T 1/2) was around 3 h. LS007 possessed the favorable pharmacokinetic profiles with oral bioavailability F = 56% in the cynomolgus monkey (at dose 4 mg/kg), suggesting its therapeutic potential as an orally bioavailable anti-AML agent. The GLP- toxicological studies of LS007 in the cynomolgus monkey were completed, and the maximum tolerated doses were identified, which were used to estimate the safe starting dose for the Phase I clinical trials. With its excellent anti-cancer efficacy along with appreciable absorption and safety profiles, LS007 offers a very exciting prospect as a clinical development candidate. The application of Investigational New Drug (IND) has been approved allowing the commencement of clinical trials of LS007 in patients with AML. Citation Format: Wang Hui, Wang Shudong. Pre-clinical development of CDK9 inhibitor - LS007 for the treatment of acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5.
Safety, Efficacy, and Pharmacokinetic Profiles of Intravenous Rigosertib in Japanese Patients with Recurrent/Relapsed or Refractory Myelodysplastic Syndromes: A Multicenter, Open-Label Phase I Clinical Study
Authors: Michinori Ogura, Yukio Kobayashi, Shiro Kubonishi, Michihiro Hidaka, Toshiki Uchida, Yasushi Takamatsu
Journal: Blood (2016)
Abstract 2434: Noninvasive Monitoring of Atherosclerotic Plaque with Radiolabeled Annexin V and Matrix Metalloproteinase Inhibitor in Spontaneous Atherosclerotic Mice
Authors: Yared Tekabe, Evis Harja, Ann Marie Schmidt, Stan Majewski, Ashish Gupta, Andrew Weisenberger, Marija Sedlar, Jagat Narula, Lynne Johnson
Journal: Circulation (2006)

Introduction: Vascular apoptosis and extracellular matrix degradation render atherosclerotic plaques vulnerable to rupture. We assessed the hypothesis that molecular imaging can be used as a noninv...
Updated results of a phase II randomized trial with high dose proton pump inhibitors and metronomic capecitabine as salvage treatment for patients with advanced gastrointestinal tumours
Authors: M. Roberto, G. Arrivi, A. Milano, C. D’Antonio, A. Romiti, R. Falcone, F. Mazzuca, S. Fais, P. Marchetti
Journal: Annals of Oncology (2019)
Abstract 1114: Upregulation of ALCAM is a marker for non-small-cell lung cancer brain metastases
Authors: Desiree Loreth, Justine Münsterberg, Cecile Maire, Stefan Werner, Monja Gandrass, Christian Bernreuther, Jolanthe Kropidlowski, Manfred Westphal, Stefan Steurer, Katrin Lamszus, Markus Glatzel, Klaus Pantel, Harriet Wikman
Journal: Cancer Research (2019)

Abstract Non-small-cell lung cancer (NSCLC) is the most common cause of cancer-related death with still a 5-year survival rate of &amp;lt;10%. Every second patient with advanced NSCLC will develop brain metastases and in 50% of those the brain is the only site of tumor relapse (oligo-metastasis). Cancer cells need to have specific properties to access and colonize the brain microenvironment leading to the question which metastatic factors foster brain metastasis formation. Different cell adhesion molecules (CAMs) have been shown to be involved in the process of metastasis in different tumor entities. The activated leukocyte cell adhesion molecule (ALCAM) is a type I transmembrane protein of the immunoglobulin superfamily and involved in the maintenance of cell-cell contacts and has a possible role in the “homing” of metastatic cells in distant organs. ALCAM is also involved in the leukocyte transmigration across the blood-brain barrier. Here we therefore investigated the role of ALCAM in NSCLC brain metastases formation. Our studies on patient material revealed that the ALCAM protein expression in brain metastases (n=71) is significantly increased (50.7% positive, p=0.023) compared to the primary tumor (21.7% positive, n=47). Analysis of matched pairs of primary tumors and brain metastases confirmed this observation, as in 33% a de novo ALCAM expression in the matching brain metastases could be observed. Additionally, patients with a strong ALCAM expression in either their primary tumors or brain metastases showed a significantly shortened overall survival (p=0.017 and p=0.035 respectively). In vitro analysis of the effect of ALCAM knock out in the H460 lung cancer cell line showed no effect on proliferation, migration or colony-forming behavior. However, cell adhesion was severely hampered in the knock out cells. Currently in vivo mice experiments are running. Together these findings indicate an important role for ALCAM in brain metastasis formation. Citation Format: Desiree Loreth, Justine Münsterberg, Cecile Maire, Stefan Werner, Monja Gandrass, Christian Bernreuther, Jolanthe Kropidlowski, Manfred Westphal, Stefan Steurer, Katrin Lamszus, Markus Glatzel, Klaus Pantel, Harriet Wikman. Upregulation of ALCAM is a marker for non-small-cell lung cancer brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1114.
Abstract 3216: CKD-516, a novel vascular disrupting agent, enhances anticancer activity of anti-PD-1 antibody in SMAD4-deficient colon cancer model
Authors: Soo Jin Kim, Hark Kyun Kim, Keun Ho Ryu, Chung Il Hong
Journal: Cancer Research (2019)

Abstract CKD-516 is a potent vascular disrupting agent (VDA), selectively acting on tumor vessels. A clinical study of CKD-516 combined with irinotecan is undergoing in colorectal cancer. There have been exponential gains in immune-oncology (I-O) in recent times through the development of immune checkpoint inhibitors (ICIs). ICIs demonstrated durable response and some patients achieved disease control for several years. However, there are still critical unmet medical needs for the combination therapies due to limited response rate of ICIs. The first step of the cancer-immunity cycle is dendritic cells (DCs) maturation which is necessary for the anticancer immunity. It is well known that mature DCs play critical roles in priming immune responses in cancer patients. We found that CKD-516 is able to induce DC maturation through Rho signaling pathway in DCs. A tumor suppressor gene, SMAD4 is associated with several cancers including stomach cancer, colorectal cancer, and pancreas cancer. The loss of SMAD4 is a poor prognostic biomarker in these cancer types and its mutation is related to poor clinical outcome on immunotherapies. A SMAD4-deficient mouse colorectal cancer cell line (3349LM) was primary cultured from a spontaneous intestinal adenocarcinoma formed in a Villin-Cre;Smad4(F/F);Trp53(F/F) mouse. CKD-516 showed a synergistic effect with anti-PD-1 antibody in 3349LM syngeneic model. In addition, 3349LM is also a MSS type cancer. Thus, CKD-516 displayed a therapeutic potential for several cancer patients who do not respond to immunotherapy. In summary, CKD-516 is a novel VDA with immune boosting effect. In SMAD4 deficient cancer model, CKD-516 has shown synergistic effects in combination with PD-1 antibody. Therefore, these data suggest that CKD-516 potentiates the anticancer activity of immunotherapy. Citation Format: Soo Jin Kim, Hark Kyun Kim, Keun Ho Ryu, Chung Il Hong. CKD-516, a novel vascular disrupting agent, enhances anticancer activity of anti-PD-1 antibody in SMAD4-deficient colon cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3216.
Prevention of progression of pulmonary hypertension by the Nur77 agonist 6-mercaptopurine: role of BMP signalling
Authors: Kondababu Kurakula, Xiao-Qing Sun, Chris Happé, Denielli da Silva Goncalves Bos, Robert Szulcek, Ingrid Schalij, Karien C. Wiesmeijer, Kirsten Lodder, Ly Tu, Christophe Guignabert, Carlie J.M. de Vries, Frances S. de Man, Anton Vonk Noordegraaf, Peter ten Dijke, Marie-José Goumans, Harm Jan Bogaard
Journal: European Respiratory Journal (2019)

Pulmonary arterial hypertension (PAH) is a progressive fatal disease characterised by abnormal remodelling of pulmonary vessels, leading to increased vascular resistance and right ventricle failure. This abnormal vascular remodelling is associated with endothelial cell dysfunction, increased proliferation of smooth muscle cells, inflammation and impaired bone morphogenetic protein (BMP) signalling. Orphan nuclear receptor Nur77 is a key regulator of proliferation and inflammation in vascular cells, but its role in impaired BMP signalling and vascular remodelling in PAH is unknown.We hypothesised that activation of Nur77 by 6-mercaptopurine (6-MP) would improve PAH by inhibiting endothelial cell dysfunction and vascular remodelling.Nur77 expression is decreased in cultured pulmonary microvascular endothelial cells (MVECs) and lungs of PAH patients. Nur77 significantly increased BMP signalling and strongly decreased proliferation and inflammation in MVECs. In addition, conditioned medium from PAH MVECs overexpressing Nur77 inhibited the growth of healthy smooth muscle cells. Pharmacological activation of Nur77 by 6-MP markedly restored MVEC function by normalising proliferation, inflammation and BMP signalling. Finally, 6-MP prevented and reversed abnormal vascular remodelling and right ventricle hypertrophy in the Sugen/hypoxia rat model of severe angioproliferative PAH.Our data demonstrate that Nur77 is a critical modulator in PAH by inhibiting vascular remodelling and increasing BMP signalling, and activation of Nur77 could be a promising option for the treatment of PAH.
Total neoadjuvant treatment of “ugly” rectal cancers in Slovenia
Authors: V. Velenik, N. Boc, J. Ocvirk, E. Brecelj, B. Krebs, F. Anderluh, A. Jeromen, I. Oblak, A. Secerov-Ermenc, J. But-Hadzic
Journal: Annals of Oncology (2019)