tbuckley/cabot-search huggingface dataset:
Inhibitory Control of Prefrontal Cortex by the Claustrum
Authors: Jesse Jackson, Mahesh M. Karnani, Boris V. Zemelman, Denis Burdakov, Albert K. Lee
Journal: Neuron (2018)

The claustrum is a small subcortical nucleus that has extensive excitatory connections with many cortical areas. While the anatomical connectivity from the claustrum to the cortex has been studied intensively, the physiological effect and underlying circuit mechanisms of claustrocortical communication remain elusive. Here we show that the claustrum provides strong, widespread, and long-lasting feedforward inhibition of the prefrontal cortex (PFC) sufficient to silence ongoing neural activity. This claustrocortical feedforward inhibition was predominantly mediated by interneurons containing neuropeptide Y, and to a lesser extent those containing parvalbumin. Therefore, in contrast to other long-range excitatory inputs to the PFC, the claustrocortical pathway is designed to provide overall inhibition of cortical activity. This unique circuit organization allows the claustrum to rapidly and powerfully suppress cortical networks and suggests a distinct role for the claustrum in regulating cognitive processes in prefrontal circuits.
Abstract 1781: HPN536, a T cell-engaging, mesothelin/CD3-specific TriTAC for the treatment of solid tumors
Authors: Richard Austin, Wade Aaron, Patrick Baeuerle, Manasi Barath, Adrie Jones, Susan D. Jones, Che-Leung Law, Kathryn Kwant, Bryan Lemon, Anna Muchnik, Kenneth Sexton, Laurie Tatalick, Holger Wesche, Timothy Yu
Journal: Cancer Research (2018)

Abstract Mesothelin (MSLN) is a GPI-linked tumor antigen overexpressed in a variety of solid tumors, including ovarian, pancreatic, lung and triple-negative breast cancer. Normal tissue expression is restricted to single-cell, mesothelial layers lining the pleural, pericardial, and peritoneal cavities. Overexpression of MSLN is associated with poor prognosis in lung adenocarcinoma and triple-negative breast cancer. MSLN has been used as cancer target antigen for numerous modalities, including immunotoxins, vaccines, antibody drug conjugates and CAR-T cells. Early signs of clinical efficacy have validated MSLN as target, but therapies with improved efficacy are still needed to address the significant, unmet medical need posed by MSLN-expressing cancers. HPN536 is a ~50-kDa antibody derivative called TriTAC (Tri-specific T cell Activating Construct) designed to simultaneously bind to MSLN on tumor cells and to CD3ε on T cells with an affinity of 1 nM and 14 nM, respectively. Transient bispecific binding leads to the formation of an immunological cytolytic synapse, T cell activation and redirected tumor cell killing. A third domain of HPN536 binds non-covalently to serum albumin with an affinity of 8 nM to extend serum half-life life. Because TriTACs are built using single domain antibodies, TriTACs are much smaller than full size antibodies and are anticipated to demonstrate improved penetration of human tumors compared to full sized antibodies. HPN536 is produced by eukaryotic cell culture and secreted as a highly stable, single polypeptide. It binds with similar affinity to human and cynomolgus MSLN, albumin and CD3. When incubated in co-cultures with resting, human or cynomolgus T cells and human tumor cells, T cells are induced to release cytokines, to proliferate, and to specifically lyse MSLN-positive target cells with EC50 values at single-digit picomolar concentrations. In an exploratory toxicological study in non-human primates, HPN536 was well tolerated and showed pharmacokinetics in support of weekly dosing in humans. Preclinical characterization suggests that HPN536 is an efficacious and safe novel therapeutic candidate for the convenient treatment of patients with MSLN-expressing malignancies. Citation Format: Richard Austin, Wade Aaron, Patrick Baeuerle, Manasi Barath, Adrie Jones, Susan D. Jones, Che-Leung Law, Kathryn Kwant, Bryan Lemon, Anna Muchnik, Kenneth Sexton, Laurie Tatalick, Holger Wesche, Timothy Yu. HPN536, a T cell-engaging, mesothelin/CD3-specific TriTAC for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1781.
Abstract 3908: miR-3132 induces TRAIL and cell death in mutant p53-expressing cancer cells
Authors: Amriti R. Lulla, Margret B. Einarson, Yan Zhou, Avital Lev, David T. Dicker, Wafik S. El-Deiry
Journal: Cancer Research (2018)

Abstract Tumor suppressor p53, guardian of the genome, is frequently mutated or functionally dysregulated in more than 50% of human tumors. p53 mutation is a later event in tumorigenesis and a number of p53 mutants have “Gain of Function” (GOF) properties that have been shown to promote invasive and more aggressive phenotypes in cancer cells. Mutant p53 has been an attractive and promising therapeutic target for advanced stages of tumors. Further understanding the GOF properties of mutant p53 may help with design of novel strategies to target mutant p53 and/or key GOF pathways. We developed a novel functional high throughput screening (HTS) assay to identify miRNAs that selectively target GOF in mutant p53-expressing cell lines. Of the 2754 miRNA mimics screened, we identified 56 miRNAs that selectively reduced cell viability in TP53 R175H (mutant) cells. The current study characterizes the role of our lead mimic, miR-3132 in mutant p53 cells. We found that expression of miR-3132 is lost in cancer cells and that miR-3132 expression is correlated to p53 status, with mutant p53 cells expressing lower levels of miR-3132 than those with wild-type p53. Restoring expression of miR-3132 via mimics induces anti-proliferative and pro-apoptotic effects in a broad panel of colorectal (CRC), breast and lung cancer cell lines. In addition, miR-3132 induces TRAIL-dependent cell death in mutant p53-expressing cells. All cell lines show potent upregulation of cleaved caspases -8, -9 and -3, at 72 hrs post transfection with miR-3132. DNA damaging agents and serum starvation endogenously increase mature miR-3132 levels in wild-type p53 cells. However, this increase is blunted in mutant p53 cells, indicating that p53 could have a role in modulating either the transcriptional or post-transcriptional levels of miR-3132. In summary, we have identified miR-3132 as a TRAIL and cell death-inducing miRNA whose regulation is dependent on p53. Our ongoing work aims at finding the key targets of miR-3132 that explain the cellular response, TRAIL induction and subsequent cell death. Our long-term goal is to develop miR-3132 as a novel single or combinatorial anti-cancer agent for mutant p53 cancer cells. Citation Format: Amriti R. Lulla, Margret B. Einarson, Yan Zhou, Avital Lev, David T. Dicker, Wafik S. El-Deiry. miR-3132 induces TRAIL and cell death in mutant p53-expressing cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3908.
Abstract 3842: Potent antitumor activity of the HSP90 inhibitor SNX-2112 in type 1 papillary renal cell carcinoma
Authors: Roma Pahwa, Abhigya Giri, Carole Sourbier, Craig Thomas, W Marston Linehan, Len Neckers, Ramaprasad Srinivasan
Journal: Cancer Research (2018)

Abstract Papillary renal-cell carcinoma (pRCC) is the second most common form of kidney cancer, accounting for 15 to 20% of all cases. There are currently no treatment options of proven benefit for patients with advanced pRCC. The type 1 subset of pRCC tumors are associated with gain of chromosome 7 and activating mutations of MET that could lead to aberrant MET pathway activation resulting in cell proliferation and anti-apoptotic signaling. While MET kinase inhibitors are active in some patients with type 1 pRCC, primary and acquired resistance is common, prompting us to investigate possible therapeutic alternatives. Heat shock protein 90 (Hsp90), which stabilizes numerous oncogenic proteins, including MET and several downstream mediators of MET activity, is an important regulator of cell proliferation and survival, and has attracted wide interest as a novel target for cancer therapy. Hsp90 inhibitors were also identified as molecules of interest based on antitumor activity against patient derived type 1 pRCC cell lines following quantitative high throughput screening (qHTS) with small molecule libraries. We hypothesized that inhibition of Hsp90 might provide a novel therapeutic approach for patients with pRCC tumors with MET pathway activation. SNX-2112 was chosen as a candidate Hsp90 inhibitor for further evaluation. Our data demonstrate that inhibition of the Hsp90 pathway is lethal to pRCC cell lines with MET pathway activation, and that treatment with SNX-2112 leads to the degradation of MET/pMET and its downstream signaling intermediates p-AKT, AKT, p-ERK. Furthermore, SNX-2112 leads to inhibition of critical downstream transcriptional targets of AKT and ERK, including VEGF, c-Myc and BIRC5. SNX-2112 has potent anti-tumor activity in vitro, inhibiting proliferation, clonogenicity and 3D-anchorage independent colony formation of MET activated pRCC cell lines. These data demonstrate that Hsp90 inhibition is a promising therapeutic strategy in Type 1 pRCC and is worthy of further preclinical and clinical evaluation. Citation Format: Roma Pahwa, Abhigya Giri, Carole Sourbier, Craig Thomas, W Marston Linehan, Len Neckers, Ramaprasad Srinivasan. Potent antitumor activity of the HSP90 inhibitor SNX-2112 in type 1 papillary renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3842.
Abstract 982: Pharmacological DNA-PK inhibition induces ATM/p53 dependent premature senescence with immunomodulatory phenotype in irradiated cancer cells
Authors: Yige Guo, Qing Sun, Xiaohong Liu, Janusz Puc, Frank Czauderna, Frank Zenke, Andree Blaukat, Lyubomir T. Vassilev
Journal: Cancer Research (2018)

Abstract A new generation, clinical-stage DNA-PK inhibitor, M3814, potently and selectively blocks one of the two major pathways for repair of DNA double strand breaks (DSB) and synergizes with ionizing radiation (IR) and DSB-inducing chemotherapy. We show that by inhibiting DNA-PK catalytic activity in the presence of DNA DSBs, M3814 simultaneously suppresses DNA repair and a negative regulatory signal to ATM, leading to enhanced activation of the ATM dependent signaling, including CHK2 and p53-dependent cell cycle arrest. Combination treatment of proliferating p53 wild-type cancer cells (A549, A375, H460) with a single dose of ionizing radiation (2-5Gy) and sustained exposure to M3814 induced a complete G1/S and G2/M cell cycle block. Within 4-7 days of treatment cells acquired a typical senescence phenotype with large/flat morphology and β-Gal staining. Live cell imaging and BrdU labeling in A549 cells demonstrated that this phenotype is not reversible following M3814 removal, in contrast to a fully reversible senescence-like phenotype caused by selective p53 activation by MDM2 inhibitor Nutlin-3a. Isogenic p53-null A549 cells lost the ability to fully arrest their cell cycle, confirming the role of p53 in senescence induction. Analysis of mRNA from IR/M3814 induced senescent A549 and A375 cells by the Nanostring PanCancer Immune profiling panel revealed activation of a large group of genes from several immune response pathways, including interferon, cytokine/chemokine, and complement. Eighteen genes were commonly upregulated &amp;gt;3-150 fold compared to controls. These substantial changes in gene expression were built gradually and correlated with the development of senescence phenotype. Several proteins from the induced subset were measured in the cell media (MesoScale Discovery) and confirmed that they are secreted by senescent cells in the absence of M3814. Culture media from M3814-induced senescent cells showed increased immunomodulatory effect on human PBMC-derived immune cells, suggesting increased probability for clearance of IR+M3814 induced senescent cancer cells by the immune system. Citation Format: Yige Guo, Qing Sun, Xiaohong Liu, Janusz Puc, Frank Czauderna, Frank Zenke, Andree Blaukat, Lyubomir T. Vassilev. Pharmacological DNA-PK inhibition induces ATM/p53 dependent premature senescence with immunomodulatory phenotype in irradiated cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 982.
Abstract 2518: Folate hydrolase-1 is a novel target for J591-brachytherapy in Merkel cell carcinoma
Authors: Barbara Meier, Marigdalia K. Ramirez-Fort, Kristina Lachance, Candice D. Church, Sean S. Mahase, Joseph M. Jenrette, Christopher S. Lange, Lars E. French, Paul Nghiem, Neil H. Bander
Journal: Cancer Research (2018)

Abstract Folate hydrolase-1 (FOLH1) is a type II transmembrane protein. Oncologically, FOLH1 is upregulated throughout prostate cancer cells; it is also luminally expressed by the neovasculature of most solid tumors but not by normal vessels. J591, a monoclonal antibody (AB), is specific to, and is effectively endocytosed after extracellular binding to, FOLH1. J591 is presently being developed in clinical trials as a vehicle for AB-based brachytherapy in FOLH1+ cancers. Merkel cell carcinoma (MCC) is a rare, neuroendocrine tumor; metastatic (m) MCC is associated with poor survival. We characterized FOLH1 expression in MCC to determine its target potential for J591-brachytherapy. Paraffin sections from primary (p) and mMCC were deparaffinized and rehydrated. Samples were stained with 3E6 (DAKO), a mouse IgG1 monoclonal anti-human FOLH1. Mouse IgG1 (10 ug/mL in 1% bovine serum albumin) was used as an isotype-matched negative control. Anti-CD31 (IgG1) was used as a positive control. Kaplan-Meier survival curves were calculated based on patient outcome data and FOLH1 expression. 81 MCC tumors were evaluated. 67% (54/81) of all cases with 77% (24/31) of pMCC and 60% (30/50) of mMCC tumors demonstrated FOLH1+ neovessels. No cellular staining of tumor cells was identified. 34 patients with FOLH1 +/- MCC were demographically homogeneous in terms of sex, age, immunosuppression status, prior therapies, stage at diagnosis, and local or distant recurrences. No significant differences were detected based on FOLH1 status, in regards to MCC specific survival (P=0.905), or overall survival (P=0.687), as measured from time of diagnosis. FOLH1 is expressed in the majority of pMCC and mMCC cases and is nonprognostic. Our findings support further investigation of targeted therapy with J591-brachytherapy for the management of MCC. Citation Format: Barbara Meier, Marigdalia K. Ramirez-Fort, Kristina Lachance, Candice D. Church, Sean S. Mahase, Joseph M. Jenrette, Christopher S. Lange, Lars E. French, Paul Nghiem, Neil H. Bander. Folate hydrolase-1 is a novel target for J591-brachytherapy in Merkel cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2518.
Aberrant Ventricular Conduction of Escaped Beats
Authors: Alfredpick
Journal: Circulation (1956)

Escape beats recorded in clinical electrocardiograms sometimes differ in contour and QRS duration from conducted beats, and this in spite of their having a relatively short cycle length. This suggests a location of the subsidiary pacemaker above the bifurcation of the common A-V bundle. While this, unlike other types of aberrant ventricular conduction, cannot be explained on a functional basis, recent investigations on the structure of the normal A-V junction suggest that paraspecific A-V connections may act as preferential pathways to the ventricles in some A-V nodal escape beats. Difficulties and guides in differentiating A-V nodal from ventricular escapes under such circumstances are pointed out. On the basis of clinical, electrocardiographic and anatomic facts such a normal preferential A-V conduction must be distinguished from an abnormal accessory A-V conduction causing the pre-excitation (Wolff-Parkinson-White) syndrome. However, the two may occur in association.
Basigin Mediates Pulmonary Hypertension by Promoting Inflammation and Vascular Smooth Muscle Cell Proliferation
Authors: KimioSatoh, TaijyuSatoh, NobuhiroKikuchi, JunichiOmura, RyoKurosawa, KotaSuzuki, KoichiroSugimura, TatsuoAoki, KotaroNochioka, ShunsukeTatebe, SaoriMiyamichi-Yamamoto, MasanobuMiura, ToruShimizu, ShoheiIkeda, NobuhiroYaoita, YoshihiroFukumoto, TatsuroMinami, SatoshiMiyata, KazufumiNakamura, HiroshiIto, KenjiKadomatsu, HiroakiShimokawa
Journal: Circulation Research (2014)

Rationale:Cyclophilin A (CyPA) is secreted from vascular smooth muscle cells (VSMCs) by oxidative stress and promotes VSMC proliferation. However, the role of extracellular CyPA and its receptor Basigin (Bsg, encoded by Bsg) in the pathogenesis of pulmonary hypertension (PH) remains to be elucidated. Objective:To determine the role of CyPA/Bsg signaling in the development of PH. Methods and Results:In the pulmonary arteries of patients with PH, immunostaining revealed strong expression of CyPA and Bsg. The pulmonary arteries of CyPA+/− and Bsg+/− mice exposed to normoxia did not differ in morphology compared with their littermate controls. In contrast, CyPA+/− and Bsg+/− mice exposed to hypoxia for 4 weeks revealed significantly reduced right ventricular systolic pressure, pulmonary artery remodeling, and right ventricular hypertrophy compared with their littermate controls. These features were unaltered by bone marrow reconstitution. To further evaluate the role of vascular Bsg, we harvested pulmonary VS...
Iron Overload Augments Angiotensin II–Induced Cardiac Fibrosis and Promotes Neointima Formation
Authors: NobukazuIshizaka, KanSaito, HaruoMitani, IeharuYamazaki, MasatakaSata, Shin-ichiUsui, IchiroMori, MinoruOhno, RyozoNagai
Journal: Circulation (2002)

Background— Abnormal iron deposition may cause oxidant-induced damage in various organs. We have previously reported that continuous administration of angiotensin II to rats results in an overt iron deposition in the renal tubular epithelial cells, which may have a role in angiotensin II–induced renal damage. In the present study, we investigated the role of iron in the development of cardiac injury induced by angiotensin II. Methods and Results— Angiotensin II was continuously infused to rats at a dose of 0.7 mg/kg per day for 7 consecutive days. No iron deposits were observed in the hearts of untreated rats, whereas iron deposition was seen in the cells in the subepicardial and granulation regions after angiotensin II infusion. Concomitant administration of deferoxamine, an iron chelator, significantly reduced the extent of cardiac fibrosis, which suggests that iron deposition aggravates the cardiac fibrosis induced by angiotensin II. Iron overload caused by the administration of iron-dextran resulted i...
Abstract LB-179: The feasibility of delivering a cancer education program in correctional facilities
Authors: Pamela Valera, Daniel Mackey, Zi Lian, William McLaughlin
Journal: Cancer Research (2018)

Abstract Introduction. Cancer 101, a cancer education program, is a critical resource to increase cancer knowledge, awareness, and cancer prevention activities to improve cancer health and survival rates. The purpose of this study was to test the feasibility of delivering the Cancer 101 curriculum to incarcerated adult males to improve cancer knowledge and increase cancer prevention activities. Methods. Cancer 101 curriculum was pilot tested for adaptation with representatives from the target audience in a New York and Pennsylvania prison facilities and based on their feedback modifications were implemented. Three prison facilities participated in adapting Cancer 101 for this study; participation in the Cancer 101 educational intervention was limited to individuals who were current smokers or former smokers. Pre-test and post-test surveys were used to assess knowledge of, perceived attitudes regarding and benefits of cancer prevention activities at baseline and immediately after completing the Cancer 101 educational intervention. To determine whether cancer knowledge improved after participating in the Cancer 101 program, a paired t-test procedure was conducted; since improvement was expected, a one-tailed alpha of .05 was specified. Results. The mean cancer knowledge scores differed prior to and after completing the Cancer 101 intervention, t(165) = -14.65, p &amp;lt; .000. Mean cancer knowledge scores prior to the Cancer 101 intervention (M = 28.42, SD = 4.21) were significantly lower than after the intervention (M = 32.68, SD = 3.36). Therefore, the intervention had a positive effect on cancer knowledge. Participants also reported that the primary reasons for participating in the Cancer 101 intervention were to develop knowledge about cancer and the skills to participate in cancer prevention activities and to educate other inmates and family members about cancer. Participants demonstrated significant increases in cancer knowledge and interest in partaking in cancer prevention activities. Discussion. A prison-based Cancer 101 educational intervention provides opportunities for inmates to increase cancer knowledge, as well as promote action for cancer control during incarceration. Citation Format: Pamela Valera, Daniel Mackey, Zi Lian, William McLaughlin. The feasibility of delivering a cancer education program in correctional facilities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-179.
A tribute to Lloyd Hollingsworth “Holly” Smith Jr. (1924–2018)
Authors: Robert M. Wachter, Talmadge E. King
Journal: Journal of Clinical Investigation (2018)

in his home in Marin County, California.He was 94.It is difficult to imagine a fuller life than Holly Smith's, or one whose impact on an institution -in this case, the University of California, San Francisco (UCSF) -and its people, was more profound.Holly Smith (Figure 1) was born in Easley, South Carolina, a town with a population of about 3,000 in the northwest corner of the state.While his father, Lloyd H. Smith, was an attorney and cotton farmer, there was plenty of medicine and science in his family tree.His grandfather had been the town's physician, and his uncle, Hugh Hollingsworth Smith, MD, helped to develop the yellow fever vaccine while working at the Rockefeller Foundation in the 1930s (1).After attending Washington and Lee College, in 1943, at the age of 19, Holly was accepted (without an interview) into Harvard Medical School (2).Following his superb performance at Harvard, he completed his residency in medicine at Massachusetts General Hospital, after which he entered the Army, where his work during the Korean War included some of the early experiments with the artificial kidney.After returning to the US, he conducted seminal studies on pyrimidine and oxalate metabolism, some of the latter while on sabbati-