tbuckley/cabot-search huggingface dataset:
DualMET andERBB inhibition overcomes intratumor plasticity in osimertinib-resistant-advanced non-small-cell lung cancer (NSCLC)
Authors: A. Martinez-Marti, E. Felip, J. Matito, E. Mereu, A. Navarro, S. Cedrés, N. Pardo, A. Martinez de Castro, J. Remon, J.M. Miquel, A. Guillaumet-Adkins, E. Nadal, G. Rodriguez-Esteban, O. Arqués, R. Fasani, P. Nuciforo, H. Heyn, A. Villanueva, H.G. Palmer, A. Vivancos
Journal: Annals of Oncology (2017)

Third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as osimertinib are the last line of targeted treatment of metastatic non-small-cell lung cancer (NSCLC) EGFR-mutant harboring T790M. Different mechanisms of acquired resistance to third-generation EGFR-TKIs have been proposed. It is therefore crucial to identify new and effective strategies to overcome successive acquired mechanisms of resistance.For Amplicon-seq analysis, samples from the index patient (primary and metastasis lesions at different timepoints) as well as the patient-derived orthotopic xenograft tumors corresponding to the different treatment arms were used. All samples were formalin-fixed paraffin-embedded, selected and evaluated by a pathologist. For droplet digital PCR, 20 patients diagnosed with NSCLC at baseline or progression to different lines of TKI therapies were selected. Formalin-fixed paraffin-embedded blocks corresponding to either primary tumor or metastasis specimens were used for analysis. For single-cell analysis, orthotopically grown metastases were dissected from the brain of an athymic nu/nu mouse and cryopreserved at -80°C.In a brain metastasis lesion from a NSCLC patient presenting an EGFR T790M mutation, we detected MET gene amplification after prolonged treatment with osimertinib. Importantly, the combination of capmatinib (c-MET inhibitor) and afatinib (ErbB-1/2/4 inhibitor) completely suppressed tumor growth in mice orthotopically injected with cells derived from this brain metastasis. In those mice treated with capmatinib or afatinib as monotherapy, we observed the emergence of KRAS G12C clones. Single-cell gene expression analyses also revealed intratumor heterogeneity, indicating the presence of a KRAS-driven subclone. We also detected low-frequent KRAS G12C alleles in patients treated with various EGFR-TKIs.Acquired resistance to subsequent EGFR-TKI treatment lines in EGFR-mutant lung cancer patients may induce genetic plasticity. We assess the biological insights of tumor heterogeneity in an osimertinib-resistant tumor with acquired MET-amplification and propose new treatment strategies in this situation.
Continuation of nonselective beta‐blockers for patients with liver cirrhosis and hemodynamic nonresponse?
Authors: Tilman Sauerbruch
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. Author names in bold designate shared co‐first authorship. TO THE EDITOR: It was with great interest that I read the meticulously written article by Villanueva et al.1 on portal pressure–guided therapy for the prevention of rebleeding from varices. First, this article estimates the sensitivity and specificity of acute response after intravenous propranolol for prediction of the chronic drop of the hepatic venous pressure gradient (HVPG) after 2‐4 weeks of daily intake of nonselective beta‐blockers (NSBBs) with or without isosorbide‐5‐mononitrate (ISMN). The authors should be congratulated for addressing this open question, although later addition of ISMN could bias these findings a bit. They found that 43% (32/75) of their patients were chronic hemodynamic responders (a >20% drop of HVPG from baseline), which is very similar to the percentage we2 detected 2 weeks after daily application of propranolol and ISMN (42% [32/76]). Second, the most interesting finding of the study by Villanueva et al. is the significantly better overall survival in chronic hemodynamic responders to nadolol with or without ISMN compared with hemodynamic nonresponders (see Fig. 4B).1 The nonresponders, as far as I could determine, were kept on nadolol with or without prazosin (nitrates) and ligation of varices. In our previous study,2 which compared an 8‐mm cTIPS (covered transjugular intrahepatic portosystemic stent‐shunt) with HVPG‐guided medical prophylaxis for prevention of rebleeding from varices, we did not find a survival difference between responders and nonresponders when analyzing only the medical group receiving proranolol/ISMN. However, in contrast to the Villanueva et al. study, our nonresponder group received only ligation. Drugs were withdrawn after assessment of nonresponse. This raises the question of whether hemodynamic nonresponders really benefit from further application of a medication (mostly NSBBs), which has not been proven to reduce portal pressure. With respect to the present article and our previous findings, one might hypothesize that these drugs even worsen outcome in nonresponders. It would be interesting to design a specific clinical trial to answer this question properly.
Abstract P191: Calpain-Generated Free PKCα Catalytic Domains Induce HDAC5 Nuclear Export and Regulate Cardiac Gene Transcription
Authors: Yan Zhang, Scot Matkovich, Abhinav Diwan, Min-Young Kang, Gerald W Dorn
Journal: Circulation Research (2011)

Receptor-mediated activation of protein kinase (PK) C is a central pathway regulating cell growth, homeostasis, and programmed death. Recently, we showed that calpain-mediated proteolytic processing of PKC in ischemic myocardium activates PKC signaling in a receptor-independent manner by releasing a persistent and constitutively active free catalytic C-terminal fragment, PKCα-CT. This unregulated kinase provokes cardiomyopathy, but the mechanisms remain unclear. We examined hypothesis that PKCα-CT has transcriptional activity. Using immunoblot analysis and confocal microscopy, we found that PKCα-CT localized in part to nuclei and spontaneously induced cytosolic relocalization HDAC5 of the transcriptional regulator. Co- expression of calpain 1 with full length PKCα can generate PKCα-CT and produced the same HDAC5 cytosolic relocalization, whereas full length PKCα alone had no such effect. HDAC5 cytosolic relocalization induced by PKCα-CT was abolished by the protein kinase inhibitor GO6976, but not by PKD inhibitor CID 755673. The in vivo relevance of these findings was examined in transgenic mice expressing PKCα and PKCα-CT. To assess the consequence on gene expression, we performed global transcriptome profiling by Affymetrix microarrays and mRNA sequencing. The two techniques substantially agreed. Compared to control hearts, 621 mRNAs were regulated at least 1.3 fold in PKCα-CT hearts (P&lt; 0.001), only 59 in full-length PKCα hearts. MEF2-dependent inflammatory pathway genes which are putative HDAC targets were upregulated in PKCα-CT heart: 15 MEF2 target mRNAs were upregulated in PKCα-CT hearts (p&lt;0.001), only one in PKCα hearts. These results reveal that PKCα-CT is a potent regulator of pathological cardiac gene expression by localizing to nuclei and directly promoting nuclei-cytoplasmic shuttling of HDAC5. Receptor-independent effect of PKCα-CT and HDAC phosphorylation in ischemic hearts has broad ramifications for understanding and preventing the pathological transcriptional stress response.
Induced-Pluripotent-Stem-Cell-Derived Primitive Macrophages Provide a Platform for Modeling Tissue-Resident Macrophage Differentiation and Function
Authors: Kazuyuki Takata, Tatsuya Kozaki, Christopher Zhe Wei Lee, Morgane Sonia Thion, Masayuki Otsuka, Shawn Lim, Kagistia Hana Utami, Kerem Fidan, Dong Shin Park, Benoit Malleret, Svetoslav Chakarov, Peter See, Donovan Low, Gillian Low, Marta Garcia-Miralles, Ruizhu Zeng, Jinqiu Zhang, Chi Ching Goh, Ahmet Gul, Sandra Hubert, Bernett Lee, Jinmiao Chen, Ivy Low, Nurhidaya Binte Shadan, Josephine Lum, Tay Seok Wei, Esther Mok, Shohei Kawanishi, Yoshihisa Kitamura, Anis Larbi, Michael Poidinger, Laurent Renia, Lai Guan Ng, Yochai Wolf, Steffen Jung, Tamer Önder, Evan Newell, Tara Huber, Eishi Ashihara, Sonia Garel, Mahmoud A. Pouladi, Florent Ginhoux
Journal: Immunity (2017)
Nivolumab-Induced Development of Pulmonary Sarcoidosis in Renal Cell Carcinoma
Authors: Meng Zhang, Geoffrey Schembri
Journal: Clinical Nuclear Medicine (2017)

A 64-year-old woman with metastatic clear cell renal carcinoma who had been on nivolumab immunotherapy for 10 months was referred for a FDG PET scan to monitor disease progress. New bilateral mediastinal and hilar FDG-avid lymphadenopathy was noted. Pathology on subsequent mediastinal nodal biopsy showed well-formed epithelioid granulomas with no evidence of malignancy consistent with sarcoidosis. This case illustrates that pulmonary sarcoidosis can be induced by immunotherapy in the treatment of renal cell carcinoma.
Intense 99mTc-MDP Activity in an Elongated Sagging Gallbladder With a Partially Calcified Gallstone
Authors: Xiangcheng Wang, Xia Bai, Weina Zhou, Xiyan Hao, Xuemei Wang
Journal: Clinical Nuclear Medicine (2017)

Intense activity was noted in the right middle abdomen on whole-body 99mTc-MDP bone scan images, which were obtained in a 78-year-old woman who had back pain. Further SPECT/CT images demonstrated that the intense activity was located in an elongated gallbladder. Partially calcified gallstone was also revealed on SPECT/CT images. Unexpectedly, the gallbladder activity was from the radioactive bile inside the gallbladder lumen, whereas the partially calcified gallstone was relatively photopenic.
The First Follow-up Data Analysis of Patients with Acquired Bone Marrow Failure Harboring a Small Population of PNH-Type Cells in the Japanese, Multicenter, Prospective Study Optima
Authors: Yasutaka Ueda, Jun-Ichi Nishimura, Chiharu Sugimori, Kohei Hosokawa, Yuji Yonemura, Naoshi Obara, Hideyoshi Noji, Yoshihiko Nakamura, Yukari Shirasugi, Kiyoshi Ando, Tsutomu Shichishima, Haruhiko Ninomiya, Shigeru Chiba, Tatsuya Kawaguchi, Yuzuru Kanakura, Shinji Nakao
Journal: Blood (2016)
Biopsy-Proven Diffuse Mediastinal Prostate Cancer Metastases Negative on 18F-Fluorocholine, Diagnosed on 68Ga-PSMA and 18F-PSMA PET/CT
Authors: Guillaume Chaussé, Tamim Niazi, Gad Solomon Abikhzer, Stephan Michael Probst
Journal: Clinical Nuclear Medicine (2017)

A 72-year-old man with prostate cancer (stage T3b, Gleason score 7) treated by radical prostatectomy was found to have biochemical failure (prostate-specific antigen 8.5 ng/mL) and a suspicious growing nodularity at the left prostate bed on MRI. F-fluorocholine PET/CT failed to demonstrate any site of uptake suggestive of malignancy. A bone scan did exclude bone metastases. Ga-PSMA PET/CT revealed various positive lymph nodes in the supraclavicular, mediastinal, and hilar regions. This was confirmed on F-DCFPyl PET/CT, with the addition of a suspicious right axillary lymph node. Mediastinal biopsy confirmed metastatic prostate cancer.
A study of vistusertib in combination with selumetinib in patients with advanced cancers: TORCMEK phase Ib results.
Authors: Peter Schmid, Martin David Forster, Yvonne J. Summers, Jane Good, Shah-Jalal Sarker, Louise Lim, Kelly Mousa, Gary William Middleton
Journal: Journal of Clinical Oncology (2017)

2548 Background: PI3K/mTOR and MAPK pathways are aberrantly activated in many tumours and interact to promote tumour growth and therapeutic resistance. Activity of single pathway inhibition is limited due to compensatory activation of alternative signalling pathways. Dual pathway inhibition has demonstrated synergistic activity in preclinical models, with broad activity across a range of molecular backgrounds. This study was designed to evaluate the optimal doses and schedule of vistusertib (dual mTOR1/2 inhibitor) and selumetinib (MEK1/2 inhibitor) when given in combination. Methods: Thisphase Ib/IIa trial with a dose escalation part (Ib) in treatment refractory advanced solid tumours and expansion cohorts in TNBC, squamous and non-squamous NSCLC (KRASmt &amp; WT) (IIa). Both, continuous daily (CC) (25, 35, 50mg BD) and intermittent (IC) schedules (50, 100, 125mg BD 2ds on, 5 ds off) of vistusertib were investigated. Selumetinib dose was given at a dose of 75mg BD daily. Treatment was given until PD (RECIST 1.1) or intolerable toxicity. The primary endpoint was DLTs. Secondary endpoints included response, clinical benefit, PFS and PK. Results: 23 evaluable patients were enrolled in the PhaseIb part. For the intermittent schedule, no DLTs were reported at any of the dose levels IC1-3. For the continuous schedule, 2 out of 9 patients treated at dose level C2C developed DLTs (G3 mucositis, dizziness and rash). Dose level C3C was not tolerated with DLTs observed in 2 out of 3 patients (G3 mucositis and G3 LFTs). Separate MDTs were determined for intermittent (I3C) and continuous schedules (C2C). Adverse events were in keeping with established single agent safety profiles. Anti-tumour efficacy was demonstrated at various dose levels and across tumour types including uveal melanoma, breast, cervical, uterine, skin or colorectal cancers. There were no objective responses but confirmed stable disease for &gt; 16 weeks were observed in 7 patients with a duration of response ranging up to 55+ weeks. Conclusions: Based on DLTs, dose intensity and cumulative toxicity, the intermittent schedule I3C was selected as RP2D for expansion cohorts. Preliminary anti-tumour activity was observed. Clinical trial information: NCT02583542.
Convenient Inexpensive Device for Quantitative Hand Feeding of Mice
Authors: Harold P. Morris, J. W. Thompson
Journal: JNCI Journal of the National Cancer Institute (1940)

Journal Article Convenient Inexpensive Device for Quantitative Hand Feeding of Mice Get access Harold P. Morris, Harold P. Morris chemist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar J. W. Thompson J. W. Thompson associate pharmacologist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 1, Issue 3, December 1940, Pages 395–396, https://doi.org/10.1093/jnci/1.3.395 Published: 01 December 1940
Art: The sweetness of life
Authors: Patricia Wynn Davies
Journal: BMJ (2000)

Felix Gonzalez-Torres Serpentine Gallery, London, until 16 July

Works also appear in the children's ward at the Chelsea and Westminster Hospital, on billboards across London, and by night at the Camden Art Centre

Sweets are the artistic medium for the installation Untitled (Rossmore II) at London's Serpentine Gallery. They are green sweets wrapped in cellophane and stacked in a corner. The piece refers to the street in Los Angeles where the artist Felix Gonzalez-Torres and his partner, Ross Laycock, lived before Laycock's death from AIDS in 1991. Five years later, Gonzalez-Torres would also be dead from an AIDS related illness.

The Cuban born artist never spoke publicly about the disease, but his work stands as the most humane of reflections on life and love, on mortality and loss. Untitled (Placebo) is a huge shimmering rectangular lake of chocolate covered toffees individually wrapped in silver cellophane. Visitors are invited to participate in these works and help themselves, sensually consuming with the mouth as well as the eye. Elsewhere they are urged to take posters or offset prints from piles labelled with their “ideal” heights.

Gonzalez-Torres was an artist in the vanguard of the movement to put meaning back into minimalist art. He also believed that “authorship” of a work is a collaboration between the maker, presenter, owner, and viewer, and he left it to the curators to decide whether to replace the candy consumed or to allow visitors to pick away until the artwork eventually disappeared. The Serpentine Gallery replenishes the works each evening, perhaps a comment on life fading away but also being renewed.

As with everything made by this artist, there are multiple layers of meaning. The narrative on death—a smoked mirror on the wall forces you to look at yourself alongside the reflection of a coffin-like lagoon—stands in perfect harmony with a narrative about life. We, the viewers at the edge of the candy spill, decide whether to do forbidden things. Should we flout the conventions of an art gallery, sucking sweets from a stranger and getting something for nothing? Gonzalez-Torres's message, above all, is about choice.

Hope (is the sweet a cure?) and love are never far behind. Untitled 1989/1990 consists of two stacks of paper. The first says, “Somewhere better than this place,” the second, “Nowhere better than this place.” Gonzalez-Torres reached the height of his artistic powers during the darkest days of the AIDS epidemic in the United States and became, at the age of 39, one of its victims. But his depictions of the sweetness of life and the transition, difficult but necessary, to another place in death is utterly even-handed. I came away feeling that the artist must have ended up agreeing with both statements. People make mistakes, make the wrong choices, end up dying. But life is still beautiful.
RV Myocardial Strain During Pre-Load Augmentation Is Associated With Exercise Capacity in Patients With Chronic HF
Authors: Kenya Kusunose, Hirotsugu Yamada, Susumu Nishio, Ayumi Ishii, Yukina Hirata, Hiromitsu Seno, Yoshihito Saijo, Takayuki Ise, Koji Yamaguchi, Shusuke Yagi, Takeshi Soeki, Tetsuzo Wakatsuki, Masataka Sata
Journal: JACC. Cardiovascular imaging (2017)
Abstract 16438: Serum Exosomal Protein Profiling for the Non-invasive Detection of Cardiac Allograft Rejection
Authors: Peter J Kennel, Dawn Maldonado, Raymond Givens, Danielle Brunjes, Estibaliz Castillero, Emily Chen, Isaac George, Donna Mancini, P. Christian Schulze
Journal: Circulation (2015)

Introduction: Exosomes are cell-derived vesicles in the extracellular environment present in biological fluids. Exosomal content is actively assembled containing mRNA, miRNA and proteins. Exosomal-derived molecules have messenger function on target cells. Hypothesis: The serum-derived exosomal proteome is altered in acute cardiac allograft rejection allowing a distinction between non-rejection and acute rejection episodes with specifics for the type of rejection. Methods: Serum samples were collected from heart transplant (HTx) recipients with no rejection (n=10), acute cellular rejection (n=10) and antibody-mediated rejection (n=8) confirmed by myocardial biopsy and histopathology report. Exosome isolation was performed using an isolation kit (Invitrogen). Proteomic analyses were performed by LC-MS/MS analysis using the Fusion Tribrid Orbitrap Mass Spectrometer. To confirm these findings, one of the proteins found by proteomic analysis, C1Q, was compared across samples with ELISA (Abcam). Results: A distinct pattern was detectable separating each group by clustering analysis. A exosomal protein signature totaling 24 proteins (FDR&lt;2%) was found in the rejection group compared to the no rejection group. Further, patients with ACR had a distinctly different exosomal protein signature compared to patients with AMR. Of note, complement factor components such as C1QA (-53%), C1QB (-36%) and immunoglobulin subfractions such as IGHM (+42%) were the most significantly regulated proteins. Confirmatory ELISA testing of exosomal C1Q levels revealed a trend (p=0.077) towards decreased levels of C1Q in the AMR group but no significant difference in the ACR group. Conclusions: These data suggest a distinct exosomal proteome signature in cardiac allograft rejection patients as compared to patients without rejection, mainly involving complement cascade proteins, immunoglobulin fractions and structural proteins. Exosomal proteome analysis shows potential for non-invasive characterization of cardiac allograft rejection with distinct profiles in patients with ACR and AMR.
Abstract 20111: High MCV and Low Platelet Count Indicate Higher Risk to Develop Cardiovascular Events in Patients Undergoing Hemodialysis
Authors: Kaoru Tateno, Yorinobu Takeda, Yoshio Kobayashi
Journal: Circulation (2015)

Patients undergoing hemodialysis (HD) are at high risk of suffering fatal cardiovascular events, and there is a need to specify the most vulnerable cases that should undergo aggressive cardiovascular intervention. Here, we show that routine blood cell count has a prognostic value in HD patients. In a nested case-control study constituted of 167 patients who have had HD on April 2008, we analyzed conventional blood tests at arrival. Primary endpoint was defined as composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and occurrence of critical limb ischemia (CLI). Ten patients met exclusion criteria including renal transplant, and remaining 157 patients were analyzed. We found that those who met the endpoint were older, had higher Ca x P values, higher MCV, lower albumin, or lower platelet counts. Cox hazard analysis revealed that low platelet count was a risk factor independent to other significant factors (age and albumin). Kaplan-Meyer analysis showed that patients in the lowest platelet quartiles had strikingly worse prognosis compared to those with the highest (p&lt;0.05). Sub-analysis showed that occurrence of the endpoint in secondary prevention arm, consisted of 40 patients with history of myocardial infarction, stroke, or healed CLI, were highly influenced by platelet count decrease compared to the remainder 117 patients who were designated as primary prevention arm. On the other hand, in the primary prevention arm, high MCV value was shown to be an independent risk factor. High MCV value had been reported to predict adverse outcome after coronary stenting, and our result expanded this finding to HD patients without any history of vascular diseases. This study also exhibited that low platelet count is an independent risk factor, especially for the secondary prevention arm of HD patients. Importantly, we have reported that platelet count positively correlates with circulating CD34-positive cells in CLI patients, whereas high MCV has been recognized to represent disturbed bone marrow function in various hematologic disorders. These imply that platelet count and MCV values can be surrogate markers of vascular injury and homeostasis, which thereby serve as predictors of adverse cardiovascular events in HD patients.