tbuckley/cabot-search huggingface dataset:
Identification of single nucleotide variants in gastrointestinal stromal tumor KIT/PDGFRA wild-type (WT GISTs) by massively parallel sequencing.
Authors: V. Indio, M. A. Pantaleo, A. Astolfi, R. Casadio, P. Paterini, S. Formica, P. Martelli, R. Moore, N. Thiessen, M. di Battista, F. Catena, D. Santini, M. C. Heinrich, C. Gnocchi, A. P. Dei Tos, G. Biasco
Journal: Journal of Clinical Oncology (2011)

10046 Background: Recently SDH variations were identified in KIT and PDGFRA wild type GISTs. However the causative genomic alterations of these GISTs still remain unknown. Massively parallel sequencing allows identifying novel putative variants. Methods: Whole transcriptome paired-end RNA sequencing was performed by Illumina GAIIx system using a 75 bases paired-end strategy on tumor samples of two young adults patients (P1 and P2) affected by gastric WT-GIST (age 28 and 30 years). Sequences were aligned with BWA against exon+junction references. SNVmix2 was used for SNP calling, identifying by this 2045 and 1780 coding non-synonymous novel single nucleotide variants (SNVs) in P1 and P2, respectively. After checking misalignments by SAMTools, the variants were filtered to increasing SNPcall confidence: SNVs with quality read score > 30 (error probability of 0.1%), total coverage > 40, and ratio between coverage of alterate base and total coverage >0.3 were labeled high confidence. Single point mutations were translated at the protein level and their likelihood of being disease-associated was computed with SNP&GO and confirmed with Sanger sequencing. Results: In both patients common mutations in SDHA and different private SNV were highlighted. Among the private disease-related SNVs we identified mutations in MYH9 (myosin heavy chain 9) and TPI1 (triosephosphate isomerase 1) in patient P1, and a mutation in OGDHL (oxoglutarate dehydrogenase-like) in P2. MYH9 is involved in cell motility and cytokinesis, while OGDHL is an enzyme of the Krebs cycle, as the SDH complex, and TPI1 is involved in glycolysis. Ongoing validation by Sanger sequencing on DNA from tumor and peripheral blood (PB) already confirmed the presence of heterozygous MYH9 K1775E in P1 and OGDHL V815M in P2, both in tumor and PB, showing that these mutations are germinal. Conclusions: Massively parallel RNA sequencing, followed by data analysis, allows to discover novel single nucleotide variants and to identify new potential target genes in WT-GIST.
Gastrointestinal metastasis from breast cancer: Report of five patients from a retrospective analysis of 740 cases at a single institute and review of the literature.
Authors: M. Ambroggi, P. Mordenti, E. M. Stroppa, E. Nobili, C. Biasini, L. Cavanna
Journal: Journal of Clinical Oncology (2011)

e11529 Background: Luminal gastrointestinal (GI) metastasis from breast cancer are rare, reports are fragmentary and poor. The purpose of this study was to assess the GI involvement from breast cancer in a retrospective study at a single institution and to review the literature. Methods: Between January 2007 and December 2010 a total of 740 patients with breast cancer were treated at our institute, patients’ records and report database were analysed. Institutional Review Board approval was obtained for this study. We also performed a review of the literature. A search of the literature using PubMed, CancerLit (National Cancer Institute); Embase was performed using the terms “breast cancer, GI metastases, GI tract, palliative surgery”. Articles and abstracts were also identified by back-referencing from original and relevant papers. Selected for the present review were papers published in English before December 2010. Results: 5 of 740 patients (0.67 %) showed GI metastasis from breast cancer, 3 patients had gastric involvement, 1 jejunum, and 2 rectum. Reviewing the literature, we found 105 patients affected by GI metastasis from breast cancer: the most frequent site of metastasis was the stomach (37 %), then the esophagus (21 %), small intestine (15 %), colon (15 %), rectum (9 %), oropharynx (2 %) and anum (1 %). The majority of the patients underwent chemotherapy, and endocrine therapy, someone surgery, and 1 patient affected by esophageal involvement underwent pneumatic dilatation. Conclusions: In conclusion, GI metastases from breast cancer are rare, but possible: each site of the GI tract can be involved, from the mouth to the anum, and a very late recurrence is also possible. So, a cito-histological diagnosis is mandatory, to differentiate GI metastasis from breast cancer from other diseases and to allow a definite and adequate treatment.
Risk Factors, Protective Factors, and Current Recommendations to Reduce Sudden Infant Death Syndrome
Authors: Rebecca F. Carlin, Rachel Y. Moon
Journal: JAMA Pediatrics (2016)

Sudden infant death syndrome remains the leading cause of death in infants aged 1 month to 1 year in the United States.While its exact cause is unknown, sudden infant death syndrome is believed to be multifactorial, ie, occurs in infants with underlying biological vulnerability who experience an exogenous stressor, such as prone/side sleeping or soft bedding, during a critical developmental period. Much genetic and physiologic evidence points to impaired arousal responses to hypercarbia and hypoxia, which ultimately leads to asphyxia. Known risk factors for infants include prone and side sleeping, soft bedding, bed sharing, inappropriate sleep surfaces (including sofas), exposure to tobacco smoke, and prematurity; protective factors include breastfeeding, pacifier use, room sharing, and immunizations.Despite our improved understanding of the physiologic mechanisms that cause sudden infant death, the mainstay of risk reduction continues to be a safe sleep environment, as most infants who die suddenly and unexpectedly do so in unsafe sleep environments.
ULK1-mediated phosphorylation of ATG14 promotes autophagy and is impaired in Huntington’s disease models
Authors: Mitchell S. Wold, Junghyun Lim, Véronik Lachance, Zhiqiang Deng, Zhenyu Yue
Journal: Molecular Neurodegeneration (2016)

Autophagy is a bulk degradation pathway for long-lived proteins, protein aggregates, and damaged organelles. ULK1 protein kinase and Vps34 lipid kinase are two key autophagy regulators that are critical for autophagosome biogenesis. However, it isn't fully understood how ULK1 regulates Vps34, especially in the context of disease. Polyglutamine expansion in huntingtin (Htt) causes aberrant accumulation of the aggregated protein and disrupts various cellular pathways including autophagy, a lysosomal degradation pathway, underlying the pathogenesis of Huntington's disease (HD). Although autophagic clearance of Htt aggregates is under investigation as therapeutic strategy for HD, the precise mechanism of autophagy impairment remains poorly understood. Moreover, in-vivo assays of autophagy have been particularly challenging due to lack of reliable and robust molecular biomarkers. We generated anti-phosphorylated ATG14 antibody to determine ATG14-mediated autophagy regulation; we employed Huntington's disease (HD) genetic cell models and animal models as well as autophagy reporter animal model to understand autophagy signaling and regulation in vivo. We applied biochemical analysis and molecular biology approaches to dissect the alteration of autophagy kinase activity and regulation. Here, we demonstrate that ULK1 phosphorylates ATG14 at serine 29 in an mTOR-dependent manner. This phosphorylation critically regulates ATG14-Vps34 lipid kinase activity to control autophagy level. We also show that ATG14-associated Vps34 activity and ULK1-mediated phosphorylation of ATG14 and Beclin 1 are compromised in the Q175 mouse model of Huntington's disease. Finally, we show that ATG14 phosphorylation is decreased during general proteotoxic stress caused by proteasomal inhibition. This reduction of the specific phosphorylation of ATG14 and Beclin 1 is mediated, in part, by p62-induced sequestration of ULK1 to an insoluble cellular fraction. We show that increased ULK1 levels and phosphor-mimetic mutant ATG14 facilitate the clearance of polyQ mutant in cells. Our study identifies a new regulatory mechanism for ATG14-Vps34 kinase activity by ULK1, which can be used as valuable molecular markers for in-vivo autophagic activity as well as potential therapeutic target for the clearance of polyglutamine disease protein.
Triple-negative breast cancer: A single-institution retrospective analysis.
Authors: P. K. Julka, S. Mallick, S. Pandit, N. P. Joshi, A. Gandhi, H. Kunhiparambath, D. Sharma, G. K. Rath
Journal: Journal of Clinical Oncology (2011)

e11543 Background: Triple negative breast cancer (TNBC) is a distinct entity associated with adverse outcomes. We explore our institutional results. Methods: We retrospectively analysed our database between 2000 & 2010. The estrogen receptor (ER) & progesterone receptor (PR) status was negative by immunohistochemistry (IHC) while Her2 status was negative by IHC or confirmed negative by fluorescent in-situ hybridisation for equivocal cases. Adjuvant radiation was 50 Gy in 25 fractions after modified radical mastectomy (MRM) or 66 Gy equivalent after wide local excision (WLE). Adjuvant chemotherapy was anthracycline or taxane-anthracycline based. Treatment at relapse consisted of chemotherapy, surgery & radiation as required. Palliative chemotherapy included single agent or combination chemotherapy with paclitaxel, carboplatin, gemcitabine, ixabepilone & capecitabine. Survival outcomes (overall [OS] & disease free survival [DFS]) were calculated using the Kaplan Meier method. These were correlated with age, menopausal status, clinical & pathological ‘T’ & ‘N’ stage (T1 & T2 vs. T3 &T4 or N0 vs. Node positive disease) lymphovascular space invasion, extracapsular spread & type of chemotherapy. Log-rank test was used to compare survival distribution. The data was analysed using SPSS 16. Results: One ninety six patients were analysed. TNBCs formed 22% of all breast cancer cases noted. Median follow up was 19.4 months (range: 1-135) Median age at presentation was 45 years (range: 27-58 years). The 5 year OS was 73% & 5 year DFS was 60%. Earlier clinical ‘T’ & ‘N’ stage (p=0.054 & p=0.095) & taxane chemotherapy (p=0.06) showed a trend for better coverall survival. Earlier pathological ‘T’ stage (p=0.004) & taxane chemotherapy (p=0.006) had significantly better DFS while there was a trend for earlier pathological ‘N’ stage (p=0.076). Other variables did not correlate significantly with survival data. Conclusions: Clinical and pathological stage remain important predictors of survival for this disease defined on the basis of ER, PR & Her2 status. Taxanes seem to offer better disease free as well as overall survival.
Ofatumumab and High-Dose Methylprednisolone Is An Effective Salvage Treatment for Heavily Pretreated, Unfit or Refractory Patients with Chronic Lymphocytic Leukemia: Single Institution Experience
Authors: Januario E Castro, Juan Sebastian Barajas-Gamboa, Johanna Melo-Cardenas, Rosa N Paz, Cesar Bernal-Corzo, Amine Ale-Ali, Danelle F. James, Thomas J. Kipps
Journal: Blood (2010)
Risk factor for axillary lymph node metastases in microinvasive breast cancer.
Authors: S. Ahn
Journal: Journal of Clinical Oncology (2011)

17 Background: Sentinel lymph node biopsy (SLNB) in patients with ductal carcinoma in situ (DCIS) was controversial. Usually we didn’t SLNB when we performed conserving operation with small sized DCIS. But sometimes we can find DCIS with microinvasive breast cancer (MIC) after operation. Must do reoperation in all patients? We determined the incidence of positive axillary lymph node (ALN) in patients with MIC and the predictive factors of ALN metastases in these patients. Methods: Between July 1989 and December 2008, 9.635 patients had operation on invasive breast cancer in Asan Medical Center. Among these patients 319 patients had MIC. The research conducted on the 293 patients except who didn’t performed axillary lymph node dissection or SLN biopsy. We retrospectively checked clinical and pathologic variables. Results: There were 22 cases of ALN metastases identified in this group of patients (7.5%). Lymphatic invasion (p&lt;0.001) and positive estrogen receptor status (p=0.03) were independent significant predictors of axillary metastases. Conclusions: Microinvasive breast cancer is associated with a low rate of lymph node metastases. Some breast cancer patients with MIC at low likelihood of lymph node metastases may be spared lymph node evaluation.
The chemosensory brain requires a distributed cellular mechanism to harness information and resolve conflicts – is consciousness the forum?
Authors: Richard Lathe
Journal: Behavioral and Brain Sciences (2016)

The central nervous system (CNS) evolved from a chemosensory epithelium, but a simple epithelium has limited means to resolve conflicts between early drives (e.g., approach vs. avoid). Understanding the role of "consciousness" as a resolution device, with specific focus on chemosensation and the olfactory system, is of appeal. I argue that consciousness is not the adjudicator, but is instead the forum that brings conflicting (conscious) inputs into a form that allows them to be (unconsciously) compared/contrasted, guiding rational action.
Digital Imaging - a Web Based Exercise for Blood Cell and Bone Marrow Morphology as Part of a National Quality Assesment Scheme.
Authors: Emma Wells, John Ardern, Michelle Brereton, Lois Hickman, John Burthem, Rebecca Bromilow, Len Seal, Barbara De La Salle, Paul McTaggart, John Parker-Williams, Keith Hyde
Journal: Blood (2004)
Pathologic response rate (pCR) and near-pathologic response rate (near-pCR) with docetaxel-carboplatin (TCarb) in early triple-negative breast cancer.
Authors: P. Kern, H. C. Kolberg, A. Kalisch, C. Liedtke, F. Otterbach, R. Kimmig, C. M. Kurbacher
Journal: Journal of Clinical Oncology (2011)

277 Background: Triple-negative breast cancer (TNBC) is associated with a poor prognosis unless a pathological complete response is achieved (Liedtke C et al. 2008: J Clin Oncol 26:1275-1281) or almost achieved (Symmans WF. 2007: J Clin Oncol 25:4414-4422). Sensitivity to platin compounds has been demonstrated in BRCA1-positive settings (Byrski T et al. 2010: J Clin Oncol 20:28:375-9; Silver DP. 2010: J Clin Oncol 28:1145-1153) with only limited numbers of patients (Byrski T et al. 2010: J Clin Oncol 20:28:375-9) or in sporadic breast cancer with heterogeneous cohorts (Sikov WM et al 2009: J Clin Oncol 27:4693-4700; Chang HR et al. 2010: Cancer 15; 116:4227-4237). Methods: This pivotal trial was to assess the efficacy of platinum and taxane-based combination therapy without the use of anthracyclines. 27 patients with primary TNBC (majority of them cT2, two cT3 and one cT4a) had to be unsuitable for standard anthracycline-based chemotherapy. They received 6 cycles, respectively in two cases only 5 cycles, of carboplatin AUC 6 and docetaxel 75 mg/m 2 q3w. The primary endpoint was the pCR-rate, secondary endpoint toxicity. Results: 20 out of 27 (74%) patients had pathological complete response (52%) or near-complete response (22%)—ypT1mic and ypT1a—both being associated with a good prognosis. Seven remaining patients had still good partial response, leaving only low residual cancer burden, which was defined as ypT1. Treatment was well-tolerated: grade III and IV toxicities were neutropenia, thrombopenia, oedema, nausea, joint pain, nail changes, fatigue, hypertension, and alopecia. Conclusions: These results show a high efficacy of carboplatin AUC6 and docetaxel 75 mg/m 2 q3w and good feasibility as primary chemotherapy for TNBC with a pCR- and near-pCR-rate of 74% and total response rate of 100%. The incorporation of anthracyclines and parp-inhibitors into further trial designs could enhance the efficacy of these compounds. The omission of exposure to anthracyclines in patients with considerable heart disease risks seems to be feasible with a good pCR-rate, the latter being a surrogate-marker for long-term survival.
Use of speed and extent of PSA response during the first three cycles of docetaxel chemotherapy in metastatic castrate-resistant prostate cancer to predict overall survival.
Authors: R. B. Goody, D. M. Mitchell, J. McAleese, J. M. O'Sullivan
Journal: Journal of Clinical Oncology (2011)

48 Background: Docetaxel chemotherapy has an established role in the management of metastatic castrate-resistant prostate carcinoma (CRPC). With an overall survival benefit demonstrated with second line agents, identifying non-responders to docetaxel at an early stage would allow timely consideration of therapy change.We wished to assess PSA response rates to sequential cycles of docetaxel chemotherapy to determine after which cycle men should be considered nonresponders.We also wished to assess if previous therapy with diethylstilbestrol (DES) influenced subsequent response to docetaxel. Methods: Retrospective case review of all men with CRPC receiving docetaxel chemotherapy between January 2007 and April 2010 at our institution was performed. PSA immediately prior to cycle 1 (baseline) and subsequent cycles were noted and evaluated for response compared to baseline PSA. Results: 86 men with a median age of 65 years (47-81) received an average of 5 cycles (1-10) of docetaxel chemotherapy. 67 (77%) had a documented fall in PSA below baseline during chemotherapy with 56 (65%) and 43 (50%) having a PSA response of &gt;30% and &gt;50% respectively. A PSA level lower than baseline was seen in 54%, 63% and 72% of men after cycles 1, 2 and 3 respectively. Limited PSA falls below baseline were seen in 3 (3.4%) and 2 (2.3%) men after cycles 4 and 5 respectively. All PSA responses of &gt;50% had occurred by the start of cycle 4. Of the 14 men who had received DES prior to starting docetaxel, only 3 (21%) had &gt;50% reduction in PSA. The median overall survival for men achieving a PSA response &gt;50% below baseline was 20 mths and was significantly better than the median overall survival of 10mths for those with no PSA response &gt;50% (p&lt;0.0001). Site of metastatic disease also correlated with survival. Conclusions: In our population, men who fail to document a PSA response to the first 3 cycles of docetaxel chemotherapy are highly unlikely to do so after this time. Response defined as a fall below baseline and the extent of PSA decline below baseline are all correlated with survival. More modest PSA responses are seen in men pre-treated with DES than those who have not received DES. No significant financial relationships to disclose.
Young Adults Presenting with Extramedullary Acute Myeloid Leukemia Have A Unique Sensitivity to High Doses of Anthracyclines: Subset Analysis of ECOG 1900,
Authors: Hugo F. Fernandez, Zhuoxin Sun, Mark R. Litzow, Selina M. Luger, Elisabeth Paietta, Janis Racevskis, Gordon W. Dewald, Rhett P Ketterling, John M. Bennett, Jacob M. Rowe, Hillard M. Lazarus, Martin S. Tallman
Journal: Blood (2011)
P0019 : Adiponectin and related adipocytokines in steatotic and non-steatotic liver transplantation
Authors: M.B. Jiménez Castro, A. Casillas Ramírez, M.E. Cornide Petronio, M. Mendes Braz, J. Gracia Sancho, L. Torrens, J. Rodés, C. Peralta
Journal: Journal of Hepatology (2015)
Locoregional recurrence risk factor and indications for postmastectomy radiotherapy in Japanese patients with tumors 5 cm or larger.
Authors: T. Nagao, T. Kinoshita, N. Tamura, T. Hojo, M. Morota, Y. Kagami
Journal: Journal of Clinical Oncology (2011)

127 Background: Locoregional recurrence (LRR) after mastectomy reduces the patient’s quality of life and survival. There is a consensus that postmastectomy radiotherapy (PMRT) helps achieve locoregional control and reduces LRR. However, in patients with large tumors, the question of which variables affect the likelihood of LRR and the role of PMRT has been the subject of substantial controversy. This study investigated what are risk factors for LRR and the efficacy of PMRT in this Japanese patient population. Methods: This study examined 589 cases of invasive breast carcinoma with tumors 5 cm or larger from 1998 to 2008. We divided the study population into 3 groups: patients with negative nodes, 1-3 positive nodes, and ≥4 positive nodes. The relationship between various clinicopathological variables and LRR was examined and the relationship between LRR and PMRT was estimated. Results: During the median follow-up was 44.2 months, 38 (6.5%) patients experienced LRR. In the multivariate analysis, independent predictors of LRR include pectoral invasion in patients with 1-3 positive nodes, and severity lymphatic invasion, estrogen receptor-negative status, and nodal ratio of positive/excised nodes ≥ 0.50 in patients with ≥4 positive nodes. In patients without positive nodes, none of the examined variables were significantly associated with LRR. PMRT did not improve the outcome of the patients at highest risk who had these variables. Conclusions: The efficacy of PMRT in patients with large tumors was not shown. In the context of systemic therapy and adequate lymph node dissection, PMRT by itself had a limited role in providing locoregional control. Due to the very low incidence of LRR observed, PMRT was not necessary for patients with large tumors without lymph node metastasis. The indication for PMRT in patients with metastatic nodes remains controversial.
Vascular endothelial growth factor (VEGF)–targeting therapies for endocrine-refractory or -resistant metastatic breast cancer (MBC): Preliminary results of a systematic review and meta-analysis.
Authors: A. D. Wagner, C. Thomssen, J. Haerting, S. Unverzagt
Journal: Journal of Clinical Oncology (2011)

e11564 Background: Individual trial results of VEGF-targeting therapies in MBC are highly variable. Methods: This review was conducted according to a published protocol, following the guidelines of the Cochrane Collaboration. Objective: To assess the effect of VEGF-targeting therapies in addition to chemotherapy (ctx) in patients (pts) with MBC. Primary endpoint: Progression-free-survival (PFS).Secondary endpoints: overall survival (OS), response rates (ORR), toxicity and quality of life. Search strategy: We searched the Cochrane Central Register of Controlled Trials; MEDLINE; EMBASE; Cochrane Breast Cancer Group Specialised Register; proceedings from ASCO; ECCO; San Antonio Breast Cancer Conference; St. Gallen Breast Cancer Conference until 12/ 2010. Selection criteria: Randomized controlled trials on VEGF-targeting drugs in MBC. Register data is included for assessment of toxicity. As individual patient data was not provided, aggregate data was used for the analysis. Results: Eligible data is limited to 3 trials using ctx with or without bevacizumab (bev) in 1st line, and 2 trials using bev in 2nd line. Prognostic factors are well balanced. Pooled hazard ratios (HR) for the comparison of 1st line ctx with versus without bev (2,695 pts) are 0.69 [95% CI 0.63 -0.76] for PFS, with significant heterogeneity; and 0.93 [95% CI 0.84-1.04] for OS; for 2nd line ctx (1,146 pts) it is 0.85 [95% CI 0.73-0.98] for PFS, all in favour of treatment with bev. Data on OS in 2nd line is incomplete. ORRs are significantly improved. Conclusions: Adding bev to 1st and 2nd line ctx significantly improves PFS and ORRs in MBC. The impact on OS in 1st line is non-significant. Individual patient data are required to address the role of potential predictive factors, subsequent treatments and crossover. Supported by BMBF grant number: 01KG0926.