tbuckley/cabot-search huggingface dataset:
Proteolytic cleavage of Beclin 1 exacerbates neurodegeneration
Authors: Gregor Bieri, Kurt M. Lucin, Caitlin E. O’Brien, Hui Zhang, Saul A. Villeda, Tony Wyss-Coray
Journal: Molecular Neurodegeneration (2018)

Neuronal cell loss contributes to the pathology of acute and chronic neurodegenerative diseases, including Alzheimer's disease (AD). It remains crucial to identify molecular mechanisms sensitizing neurons to various insults and cell death. To date, the multifunctional, autophagy-related protein Beclin 1 has been shown to be both necessary and sufficient for neuronal integrity in neurodegenerative models associated with protein aggregation. Interestingly, besides its role in cellular homeostasis, Beclin 1 has also been ascribed a role in apoptosis. This makes it critical to elucidate whether Beclin 1 regulates neuronal death and survival across neurodegenerative conditions independent of protein clearance. Here, we provide experimental evidence for a direct functional link between proteolytic cleavage of Beclin 1 and apoptotic neuronal cell loss in two independent models of neurodegeneration in vivo.Proteolytic cleavage of Beclin 1 was characterized in lysates of human AD brain samples. We developed viral tools allowing for the selective neuronal expression of the various Beclin 1 forms, including Beclin 1 cleavage products as well as a cleavage-resistant form. The effect of these Beclin 1 forms on survival and integrity of neurons was examined in models of acute and chronic neurodegeneration in vitro and in vivo. Markers of neuronal integrity, neurodegeneration and inflammation were further assessed in a Kainic acid-based mouse model of acute excitotoxic neurodegeneration and in a hAPP-transgenic mouse model of AD following perturbation of Beclin 1 in the susceptible CA1 region of the hippocampus.We find a significant increase in caspase-mediated Beclin 1 cleavage fragments in brain lysates of human AD patients and mimic this phenotype in vivo using both an excitotoxic and hAPP-transgenic mouse model of neurodegeneration. Surprisingly, overexpression of the C-terminal cleavage-fragment exacerbated neurodegeneration in two distinct models of degeneration. Local inhibition of caspase activity ameliorated neurodegeneration after excitotoxic insult and prevented Beclin 1 cleavage. Furthermore, overexpression of a cleavage-resistant form of Beclin 1 in hippocampal neurons conferred neuroprotection against excitotoxic and Amyloid beta-associated insults in vivo.Together, these findings indicate that the cleavage state of Beclin 1 determines its functional involvement in both neurodegeneration and neuroprotection. Hence, manipulating the cleavage state of Beclin 1 may represent a therapeutic strategy for preventing neuronal cell loss across multiple forms of neurodegeneration.
Abstract 10935: Cardiac-Specific Deletion of Suppressor of Cytokine Signaling-3 Prevents Doxorubicin-Induced Cardiomyopathy in Mice
Authors: Sachiko Kyogoku, Hideo Yasukawa, Takanobu Nagata, Toyoharu Oba, Hideki Ohshima, Tomoko Minami, Toshitaka Yajima, Masahiko Hoshijima, Hiroki Aoki, Kirk U Knowlton, Tsutomu Imaizumi
Journal: Circulation (2012)

Background: JAK-STAT activating cytokines can prevent the development of cardiomyopathy induced by doxorubicin (DOX). We previously showed that the suppressor of cytokine signaling-3 (SOCS3) is an intrinsic negative regulator of JAK-STAT signaling. Here, we created cardiac-specific SOCS3-knockout mice (SOCS3-CKO) to investigate whether myocardial SOCS3 would play a role in the development of DOX-induced cardiomyopathy. Methods and Results: DOX-induced cardiomyopathy was induced in wild-type mice (WT) after a single intraperitoneal injection of DOX (15 mg/kg). Western blot analysis revealed that transient STAT3 phosphorylation was associated with SOCS3 induction in WT hearts after DOX administration. At 2 days after DOX administration, real-time PCR of mouse hearts revealed increases in JAK-STAT-activating cytokines including granulocyte-colony stimulating factor (8.5 fold), interleukin-11 (3.0 fold), and leukemia inhibitory factor (2.1 fold). The activation of the STAT3-SOCS3 pathway was closely correlate...
Phase I study of epigenetic priming using azacitidine prior to neoadjuvant chemotherapy in patients with resectable esophageal and gastric adenocarcinoma.
Authors: Bryan J. Schneider, Manish A. Shah, Allyson J. Ocean, Elizabeta C. Popa, Andrew Schreiner, Paul J. Christos, Alice Mercado, Romae Palmer, Jeffrey L. Port, Nasser K. Altorki, Joseph M Scandura
Journal: Journal of Clinical Oncology (2014)

4047 Background: Epigenetic silencing of tumor suppressor genes (TSGs) is an acquired abnormality observed in cancer and is prototypically linked to DNA methylation. 5-Azacitidine (V) is a cytosine analog and a DNA hypomethylating agent (DHA). Reactivated expression of TSGs is commonly implicated in the clinical activity of DHAs since TSGs often regulate apoptosis, DNA repair, and checkpoint control. We postulated that pre-treatment (priming) with V would increase the efficacy of neoadjuvant chemotherapy by reactivating TSGs during administration of cytotoxics. The study was conducted to identify a tolerable dose of V prior to epirubicin (E), oxaliplatin (O), capecitabine (X), (EOX) neoadjuvant chemotherapy. Methods: Eligible patients (pts) had locally-advanced, resectable esophageal/gastric adenocarcinoma, no prior therapy, ECOG 0-2 and adequate organ function. V (75mg/m2) was given subcutaneously for 3 (Dose Level, DL 1) or 5 (DL 2) days with EOX (E 50 mg/m2, O 130 mg/m2, X 625 mg/m2 bid x 21 d) beginning on the last day of V. Cycles were repeated every 21 days. Residual tumor was resected after cycle 3. Standard 3+3 methodology guided V dose escalation. DNA methylation at control and biomarker regions was measured by digital droplet, bisulfite qPCR in tumor samples prior to therapy and at resection. Results: 10 pts were mostly male (9M:1F), median age 54 yrs (40-84) and esophageal (3), gastric (5), or GEJ (2) tumors. 9 pts completed the planned 3 cycles; 3 on DL1, 7 on DL2. A MTD was not identified. One DLT was identified (DL2) during cycle 2: Grade 4 dehydration and hypokalemia. Other toxicities included grade 4 neutropenia (n = 4), pulmonary embolus (n = 1) and grade 3 nausea (n = 3). Overall response rate was 60% (CR/PR: 2/4) by PERCIST and included 2 pathologic CR and a third with only a microscopic tumor focus found at resection. Responding pts with informative DNA methylation abnormalities at baseline demonstrated significant DNA hypomethylation at CDKN2A, HPP1, ESR1 and TIMP3 in the resected specimen. Conclusions: Neoadjuvant V-EOX was well tolerated with significant clinical and epigenetic responses. Research was partially, supported by a grant from Celgene, Inc. Clinical trial information: NCT01386346.
FDA breakthrough therapy designation of oncology products: The first-year experience.
Authors: Yangmin M. Ning, Tamy Kim, Virginia Ellen Maher, Amna Ibrahim, Anthony J. Murgo, Ann T. Farrell, Patricia Keegan, Robert L. Justice, Richard Pazdur
Journal: Journal of Clinical Oncology (2014)

e17502 Background: Breakthrough Therapy (BT) designation is a new regulatory program introduced in Section 902 of the Food and Drug Administration Safety and Innovation Act of 2012. Its goal is to expedite the development and review of investigational products intended to treat serious or life-threatening diseases. Designation of a BT requires preliminary clinical evidence indicating that the product may provide substantial improvement over available or existing therapies on one or more clinically significant endpoints. FDA’s Office of Hematology and Oncology Products (OHOP) received its first BT request in October 2012. Methods: We reviewed all BT requests submitted to OHOP from 10/30/2012 to 10/31/2013. The BT designation results were based on the recommendation of the review Division in consultation with the Medical Policy Council. For products that did not receive a BT designation for the proposed use, we categorized the identified deficiencies. Results: OHOP received 50 BT designation requests in the first year of implementation of the program and completed assessments of 43 of the requests. Fourteen requests were granted BT designation, 29 were denied, and 7 were withdrawn by the sponsors. Among the 14 BT designations, 3 submitted marketing applications within approximately 3 months of the designation and 2 received approval 5-6 months after submission. Of the 29 requests that were denied, 24 had preliminary clinical evidence that did not indicate a substantial improvement over existing therapies for their intended clinical use and 5 had limited clinical data that prevented reliable assessments. Conclusions: Since implementation of the program, FDA/OHOP has granted 14 BT designations. While BT designation resulted in an expedited review of the two products which were subsequently approved, it is too early to determine the long-term impact of this program on development and approval of oncology products. Lack of clear preliminary clinical evidence for substantial improvement over existing therapies and/or limited clinical data were responsible for the denial of BT designation requests. In many instances, additional clinical data could be provided for reconsideration of BT designation.
Resemblance of breast cancer to known viral cancers.
Authors: Bernard Friedenson
Journal: Journal of Clinical Oncology (2014)

e22076 Background: In women at high risk for breast cancer, immune responses occur before breast cancer but do not prevent disease. Previous work found every breast cancer genome had acquired mutations in immune and antiviral defenses. Acquired mutations can deregulate immunity or favor cancer associated infections. But dense extracellular and intracellular structures still remain to physically block infection. If infection can cause breast cancer, why don’t these barriers prevent it? Do the same barriers fail in known viral cancers? Methods: Cervical cancers caused by human papilloma viruses (HPVs) were used as a working model for cancer due to viral infection. Functional effects of ~6,000 gene mutations in cervical cancers were researched in depth. Functions damaged in this model viral cancer were then compared to functions damaged by ~3,000 mutations in 21 complete breast cancer genomes and by ~5,000 mutations in 103 breast cancer exomes. DNA sequences were from publicly available data. Results: Comparing breast cancers to the HPV cervical cancer model highlighted many mutations in identical or related genes that encode structural barriers to microbial infection. Breast and viral cancers had damage to genes encoding the same infection barriers. Genes needed to produce and circulate a mucus blanket around the cell were almost always damaged. Under the mucus layer, other infection barriers had gene damage. Mutations altered genes for the dense, tightly packed cytoplasm and could degrade its architecture. Every known virus infection interacts with actin and every breast cancer had damage to actin or related genes. The nuclear envelope, its pore complexes, the nuclear skeleton and chromatin arrangements are additional formidable infection barriers with gene damage in most breast cancers. Most breast cancers also had damaged genes for cell-cell and extracellular matrix attachments, potentially allowing abnormal cell shapes and opening easier routes for infectious particles. Conclusions: Breast cancers have striking similarities to viral cancers with damage to hundreds of identical or closely related genes. Genes encoding immune defenses and physical barriers against infection are always damaged. Infections may play a larger role in breast cancer than previously thought.
Pre-Transplant Genetic Susceptibility in Adult Allogeneic Hematopoietic Cell Transplant Recipients: Incidence and Clinical Relevance in Transplant-Associated Thrombotic Microangiopathy
Authors: Eleni Gavriilaki, Tasoula Touloumenidou, Ioanna Sakellari, Ioannis Batsis, Despina Mallouri, Fotis Psomopoulos, Maria Kotouza, Maria Koutra, Evangelia Yannaki, Apostolia Papalexandri, Maria Stamouli, Andreas Holbro, Ioannis Baltadakis, Maria Liga, Alexandros Spyridonidis, Panagiotis Tsirigotis, Nikolaos Charchalakis, Jakob R. Passweg, Kostas Stamatopoulos, Achilles Anagnostopoulos
Journal: Blood (2018)
Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage
Authors: Dvir Aran, Agnieszka P. Looney, Leqian Liu, Esther Wu, Valerie Fong, Austin Hsu, Suzanna Chak, Ram P. Naikawadi, Paul J. Wolters, Adam R. Abate, Atul J. Butte, Mallar Bhattacharya
Journal: Nature Immunology (2019)
Correlation of IMP3 expression and survival in metastatic renal cell carcinoma with sarcomatoid features (SmRCC).
Authors: Srinivas Kiran Tantravahi, Dan Albertson, Archana M. Agarwal, Alli M. Straubhar, Austin Poole, David D. Stenehjem, Ting Liu, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2014)

e15569 Background: SmRCC is a rare variant of RCC associated with poor outcome. No definitive treatments exist. Expression of IMP3, a member of insulin-like growth factor-II mRNA binding protein, has been reported to be associated with poor prognosis in localized clear cell RCC. Here we report the correlation of IMP3 expression and survival in SmRCC. Methods: From a single institutional database (years 2000-2012), we identified pts with SmRCC receiving systemic therapy. Overall survival (OS) was assessed in the overall cohort and in subgroups divided by clinicopathologic characteristics, including the extent of sarcomatoid features, and MSKCC risk criteria. Sarcomatoid component of the tumor was classified by predominant (≥20%) and non-predominant (<20%). Immunohistochemistry (IHC) analysis was performed for mammalian target of rapamycin (mTOR) signaling, phosphorylated ribosomal protein S6, proviral integration site proteins (PIM 1,2,3), Beta-catenin, E-cadherin, phosphatase and tensin homolog (PTEN), U3 small nucleolar ribonucleoprotein (IMP-3), p53, and epithelial membrane antigen (EMA). Results: 24 pts with SmRCC were evaluated. 19pts were available for IHC analysis, with a median age 57 years (range 39-74) and10 pts were male. The pts received the following therapies: cytotoxic chemotherapy (1 pt), immunotherapy (4 pts), targeted therapy (12 pts), and no treatment (2 pts). Pts belonged to the following risk categories: 8 intermediate and 11 poor risk. Median OS of the entire cohort was 249 days (95% CI 113-430 days). IMP3 was expressed in 12 (63%) pts, and 14 (74%) pts had sarcomatoid predominant SmRCC. Although IMP3 expression correlated with predominant sarcomatoid features (p=0.0195), median OS more strongly correlated with IMP3 expression (137 vs 430 days, p=0.1444; HR 2.26, 95% CI 0.76-7.57), than the sarcomatoid predominance (234 vs 286 days for dominant vs non-dominant, p=0.8009; HR 0.87, 95% CI 0.30-2.83). Other IHC markers did not correlate with survival and sarcomatoid predominance. Conclusions: IMP-3 expression is correlated with poor OS, although not statistically significant due to small sample size. Further validation is necessary in a larger set of pts.
PTPN11 Mutations Confer Unique Metabolic Properties and Increase Resistance to Venetoclax and Azacitidine in Acute Myelogenous Leukemia
Authors: Brett M. Stevens, Courtney L Jones, Amanda Winters, James Dugan, Diana Abbott, Michael R. Savona, Stephen W. Fesik, Daniel A Pollyea, Craig T Jordan
Journal: Blood (2018)
Effect of the sonic hedgehog inhibitor GDC-0449 on an in vitro isogenic cellular model simulating odontogenic keratocysts
Authors: Jiemei Zhai, Heyu Zhang, Jianyun Zhang, Ran Zhang, Yingying Hong, Jiafei Qu, Feng Chen, Tiejun Li
Journal: International Journal of Oral Science (2019)

Odontogenic keratocysts (OKCs) are common cystic lesions of odontogenic epithelial origin that can occur sporadically or in association with naevoid basal cell carcinoma syndrome (NBCCS). OKCs are locally aggressive, cause marked destruction of the jaw bones and have a propensity to recur. PTCH1 mutations (at ∼80%) are frequently detected in the epithelia of both NBCCS-related and sporadic OKCs, suggesting that PTCH1 inactivation might constitutively activate sonic hedgehog (SHH) signalling and play a major role in disease pathogenesis. Thus, small molecule inhibitors of SHH signalling might represent a new treatment strategy for OKCs. However, studies on the molecular mechanisms associated with OKCs have been hampered by limited epithelial cell yields during OKC explant culture. Here, we constructed an isogenic PTCH1R135X/+ cellular model of PTCH1 inactivation by introducing a heterozygous mutation, namely, c.403C>T (p.R135X), which has been identified in OKC patients, into a human embryonic stem cell line using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system. This was followed by the induction of epithelial differentiation. Using this in vitro isogenic cellular model, we verified that the PTCH1R135X/+ heterozygous mutation causes ligand-independent activation of SHH signalling due to PTCH1 haploinsufficiency. This activation was found to be downregulated in a dose-dependent manner by the SHH pathway inhibitor GDC-0449. In addition, through inhibition of activated SHH signalling, the enhanced proliferation observed in these induced cells was suppressed, suggesting that GDC-0449 might represent an effective inhibitor of the SHH pathway for use during OKC treatment.
Lenalidomide in the treatment of relapsed primary central nervous system lymphoma (PCNSL).
Authors: Caroline Houillier, Sylvain Choquet, Valerie Touitou, Nadine Martin-Duverneuil, Khê Hoang-Xuan
Journal: Journal of Clinical Oncology (2014)

2079 Background: Lenalidomide is an immunomodulator agent that exhibits efficacy in multiple myeloma and haematological malignancies including refractory/relapsed diffuse large B-cell (DLBC) systemic lymphoma (Witzig et al, Ann Oncol 2011). Methods: Retrospective review of PCNSL patients treated with lenalidomide at the Pitié-Salpêtrière hospital. Inclusion criteria were: (1) immunocompetent status (2) pathologically proven diagnosis of DLBC-PCNSL, (3) recurrent or refractory disease after at least two prior chemotherapy treatments, including intravenous high-dose methotrexate and cytarabine based regimens, (4) lenalidomide administered orally, at a dose of 25 mg/day on days 1-21 of a 28-days cycle. MRI scans were performed monthly. Response was evaluated according to the IPCG criteria. Results: Between June 2011 and March 2013, 6 patients (4 women and 2 men) met the inclusion criteria. Lenalidomide was given as 3rd line in 4 patients, as 4th line in 1 and 5th line in 1. Median age was 73.5 years (range 64-78) and median Karnofsky Performance Status was 60 (range 40-70). Two patients achieved complete response (CR). Patient 1 received a total of 9 monthly cycles of lenalidomide without any steroids and is still in remission after a follow-up of 18 months from the start of the treatment. Patient 2 achieved a CR and was off-steroids at the time of CR, but relapsed during the third cycle and died after 14 weeks. Patient 3 achieved a partial response after one cycle but died suddenly during the second cycle. Patients 4, 5, and 6 progressed and died 2, 5, and 6 months respectively after the start of lenalidomide. One of them who suffered from an oculo-cerebral relapse demonstrated a partial ocular response while progressing in the brain. Apart from the sudden death of unknown cause, the treatment was well tolerated. None of the patients experienced any grade III or IV toxicity. Conclusions: These results suggest that lenalidomide exhibits activity in heavily pre-treated PCNSL and is well tolerated in elderly patients. Lenalidomide efficacy on PCNSL needs to be evaluated prospectively, alone or in association with other cytotoxic agents. A phase II trial combining rituximab and lenalidomide for recurrent PCNSL is on-going in France (NCT01956695).
PTEN-opathies: from biological insights to evidence-based precision medicine
Authors: Lamis Yehia, Joanne Ngeow, Charis Eng
Journal: Journal of Clinical Investigation (2019)

The tumor suppressor phosphatase and tensin homolog (PTEN) classically counteracts the PI3K/AKT/mTOR signaling cascade. Germline pathogenic PTEN mutations cause PTEN hamartoma tumor syndrome (PHTS), featuring various benign and malignant tumors, as well as neurodevelopmental disorders such as autism spectrum disorder. Germline and somatic mosaic mutations in genes encoding components of the PI3K/AKT/mTOR pathway downstream of PTEN predispose to syndromes with partially overlapping clinical features, termed the "PTEN-opathies." Experimental models of PTEN pathway disruption uncover the molecular and cellular processes influencing clinical phenotypic manifestations. Such insights not only teach us about biological mechanisms in states of health and disease, but also enable more accurate gene-informed cancer risk assessment, medical management, and targeted therapeutics. Hence, the PTEN-opathies serve as a prototype for bedside to bench, and back to the bedside, practice of evidence-based precision medicine.
Safety and activity of sintilimab in patients with relapsed or refractory classical Hodgkin lymphoma (ORIENT-1): a multicentre, single-arm, phase 2 trial
Authors: Yuankai Shi, Hang Su, Yongping Song, Wenqi Jiang, Xiuhua Sun, Wenbin Qian, Wei Zhang, Yuhuan Gao, Zhengming Jin, Jianfeng Zhou, Chuan Jin, Liqun Zou, Lugui Qiu, Wei Li, Jianmin Yang, Ming Hou, Shan Zeng, Qingyuan Zhang, Jianda Hu, Hui Zhou, Yan Xiong, Peng Liu
Journal: The Lancet Haematology (2019)
Real-World Outcomes with Bortezomib-Containing Regimens and Lenalidomide Plus Dexamethasone for the Treatment of Transplant Ineligible MM Patients: A Multi-Institutional Report from the National Myeloma Canada Research Network (MCRN) Database
Authors: Victor Jimenez-Zepeda, Donna E Reece, McCurdy R Arleigh, Esther Masih-Khan, Eshetu G Atenafu, Michael Sebag, Julie Stakiw, Kevin Song, Richard Leblanc, Tony Reiman, Martha L Louzada, Rami Kotb, Engin Gul, Christopher P. Venner
Journal: Blood (2018)
Rate of Spleen Length Progression Is a Marker of Outcome in Patients With Primary Sclerosing Cholangitis
Authors: Franziska Jung, Nora Cazzagon, Eik Vettorazzi, Christophe Corpechot, Olivier Chazouilleres, Lionel Arrivé, Ansgar W. Lohse, Christoph Schramm, Hanno Ehlken
Journal: Clinical Gastroenterology and Hepatology (2019)
Oncologists’ proficiency in identifying psychological distress in cancer patients: Hits and misses.
Authors: Brindha Sitaram, Rehna Willam, Nitya Dhruve, Iyengar Prapti
Journal: Journal of Clinical Oncology (2014)

e20572 Background: The past decade has seen a plethora of evidence defining the magnitude of Psychological distress of cancer patients, its clinical implications and impact on cancer outcomes. In the Indian scenario, a nation wide study reported 40% of cancer patients are in severe psychological distress and 52% of them experience mild to moderate distress. Considering the magnitude of the problem, it is compelling to understand the ability of the oncologists to identify Psychological distress in their patients and to facilitate timely psychosocial care for them. The present study is an effort in this direction. Methods: Patients referred to psycho-oncology service (N=138) were screened for Psychological well-being using: Distress Thermometer (DT). Cancer patients (N=116) not referred to the service were also Screened using the same measure. Results: The Distress score on DT between the two groups was 86% and 71.6% (χ2=7.6, p = 0.006) indicating significant number of non-referred patients had distress above the cut off point. In the referred groups 14.4% of patients had a distress levels below the cut off point compared to 28.4% of non-referred patients. Conclusions: Although oncologists were successful in identifying Psychological distress of patients there were considerable number of hits and misses. This makes a case for routine distress screening of patients and to integrate Psycho-oncology into mainstream cancer care. Empowering oncologists in identifying psychological distress would perhaps facilitate timely professional assistance to ameliorate patients’ distress.