tbuckley/cabot-search huggingface dataset:
Dissecting p53 tumor suppressor function using transactivation mutant knock-in mice
Authors: Laura D. Attardi, Thomas Johnson
Journal: Cancer Research (2006)

276  The p53 protein plays a central role as a tumor suppressor. Although p53 is clearly a transcriptional activator capable of transactivating target genes, a number of other activities have been ascribed to p53 using in vitro assays. To define the contribution of transactivation to p53 function in vivo, we generated a knock-in mouse strain in which the wild-type p53 locus is substituted with a mutant significantly compromised for transactivation, p53QS. Using mouse embryo fibroblasts (MEFs), we confirmed that that p53QS is greatly impaired in activation of most p53 target genes examined. To assess p53QS activity in p53 biological function, we assayed apoptotic responses of E1A-expressing MEFs to different cellular stresses. Whereas wild-type p53 can induce apoptosis in response to diverse stresses, p53QS showed selectivity in its action. Specifically, p53QS was completely defective in inducing apoptosis in response to DNA damage, and very effective at inducing apoptosis in response to hypoxia. These findings suggest that p53 acts via distinct mechanisms to induce cell death in different contexts, and that hypoxia-induced apoptosis does not require p53 transactivation function. Analysis of the p53QS mutant provides a unique means to assess the relative contribution of DNA damage-induced and hypoxia-induced, p53-dependent apoptosis for tumor suppression. Toward this end, we have transformed MEFs with E1A and ras and compared p53QSΠexpressing cells with p53-expressing cells. We have determined that p53QS, despite being transactivation defective, has tumor suppressor activity. Together, these results suggest the importance of transactivation-independent activities of p53 for its function in vivo. Additional investigation of the p53QS mutant mice will provide a powerful means for further dissecting the functions of p53 critical for apoptosis and tumor suppression in different settings.
Updated CDC Recommendation for Serologic Diagnosis of Lyme Disease
Authors: Paul Mead, Jeannine Petersen, Alison Hinckley
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

Lyme disease is a tickborne zoonosis for which serologic testing is the principal means of laboratory diagnosis. In 1994, the Association of State and Territorial Public Health Laboratory Directors, CDC, the Food and Drug Administration (FDA), the National Institutes of Health (NIH), the Council of State and Territorial Epidemiologists, and the National Committee for Clinical Laboratory Standards convened the Second National Conference on Serologic Diagnosis of Lyme Disease (1).
Working Formulation (WF) and Revised European-American classification of Lymphoma (REAL): Inter-observer agreement in conflicting lymphoma cases
Authors: S. Latifzadeh, T. Riahi, V. Entezari
Journal: Journal of Clinical Oncology (2006)

17567 Background: Immunophenotypic and genetic studies play an increasingly important role in diagnosis and classification of lymphoid neoplasm. This study tried to re-evaluate a number of conflicting lymphoma cases which were reported by WF previously, with REAL classification and to measure the agreement between these two methods of classification. Methods: In a three year period, a panel of expert pathologists evaluated referral cases by WF. Those cases (n = 60, Mean age = 40.9 ± 16.4) whose evaluations did not reached to a definitive pathologic diagnosis or there was a discrepancy between their pathologic and clinical findings were reviewed in Keil institute of hematopathology in Germany based on REAL classification. The primary and secondary diagnoses each were classified in five subgroups with equivalent clinical risks (see Table ). Results: Disagreement was detected in 23 cases (38%), while exact kappa statistic was 0.50. Sixteen cases (70%) of difference belonged to group of low grade lymphoma (kappa = 0.35) in which 11 cases (69%) changed to aggressive lymphoma and one case changed to highly aggressive subgroups. Four cases (25%) of difference occurred in the group of low probability lymphoma in which neoplasia was documented. High grade and Hodgkin lymphoma subgroups showed a high level of agreement (kappa = 0.84 and 0.74 respectively). Conclusions: Based on this study’s results, it can be concluded that there is a moderate agreement between WF and REAL classifications in conflicting lymphoma cases. WF underestimates clinical risk of low grade lymphoma in a considerable amount of patients but in high grade lymphoma the disagreement is not so high. [Table: see text] No significant financial relationships to disclose.
Role of Population Receptive Field Size in Complex Visual Dysfunctions
Authors: Pieter B. de Best, Noa Raz, Nitzan Guy, Tamir Ben-Hur, Serge O. Dumoulin, Yoni Pertzov, Netta Levin
Journal: JAMA Neurology (2019)

The neuronal mechanism of visual agnosia and foveal crowding that underlies the behavioral symptoms of several classic neurodegenerative diseases, including impaired holistic perception, navigation, and reading, is still unclear. A better understanding of this mechanism is expected to lead to better treatment and rehabilitation.To use state-of-the-art neuroimaging protocols to assess a hypothesis that abnormal population receptive fields (pRF) in the visual cortex underlie high-order visual impairments.Between April 26 and November 21, 2016, patients and controls were recruited from the Hadassah-Hebrew University medical center in a cross-sectional manner. Six patients with posterior cortical atrophy (PCA) were approached and 1 was excluded because of an inability to perform the task. Participants underwent functional magnetic resonance imaging-based cortical visual field mapping and pRF evaluation and performed a masked repetition priming task to evaluate visuospatial perception along the eccentricity axis. The association between pRF sizes and behavioral impairments was assessed to evaluate the role of abnormal pRF sizes in impaired visual perception. Posterior cortical atrophy is a visual variant of Alzheimer disease that is characterized by progressive visual agnosia despite almost 20/20 visual acuity. Patients with PCA are rare but invaluable for studying visual processing abnormalities following neurodegeneration, as atrophy begins in visual cortices but initially spares other brain regions involved in memory and verbal communication.Participants underwent a magnetic resonance imaging scan.Population receptive field sizes and their association with visual processing along the fovea-to-periphery gradient.Five patients with PCA (4 men [80%]; mean [SEM] age, 62.9 [3.5] years) were compared with 8 age-matched controls (1 man [25%]; mean [SEM] age, 63.7 [3.7] years) and demonstrated an atypical pRF mapping that varied along the eccentricity axis, which presented as abnormally small peripheral and large foveal pRFs sizes. Abnormality was seen in V1 (peripheral, 4.4° and 5.5°; foveal, 5.5° and 4.5° in patients and controls, respectively; P < .05) as well as in higher visual regions, but not in intermediate ones. Behaviorally, an atypical fovea-to-periphery gradient in visual processing was found that correlated with their pRF properties (r = 0.8; P < .01 for the correlation between pRF and behavioral fovea-to-periphery slopes).High-order visuocognitive functions may depend on abnormalities in basic cortical characteristics. These results may fundamentally change approaches to rehabilitation in such conditions, emphasizing the potential of low-level visual interventions.
Enhanced cancer therapy through synergetic photodynamic/immune checkpoint blockade mediated by a liposomal conjugate comprised of porphyrin and IDO inhibitor
Authors: Zeqian Huang, Gaofei Wei, Zishan Zeng, Yanjuan Huang, Liangfeng Huang, Yifeng Shen, Xiaoqi Sun, Congjun Xu, Chunshun Zhao
Journal: Theranostics (2019)

Cancer metastases is still a hurdle for good prognosis and live quality of breast cancer patients. Treatment strategies that can inhibit metastatic cancer while treating primary cancer are needed to improve the therapeutic effect of breast cancer. Methods: In this study, a dual functional drug conjugate comprised of protoporphyrin IX and NLG919, a potent indoleamine-2,3-dioxygenase (IDO) inhibitor, is designed to combine photodynamic therapy and immune checkpoint blockade to achieve both primary tumor and distant metastases inhibition. Liposomal delivery is applied to improve the biocompatibility and tumor accumulation of the drug conjugate (PpIX-NLG@Lipo). A series of in vitro and in vivo experiments were carried out to examine the PDT effect and IDO inhibition activity of PpIX-NLG@Lipo, and subsequently evaluate its anti-tumor capability in the bilateral 4T1 tumor-bearing mice. Results: The in vitro and in vivo experiments demonstrated that PpIX-NLG@Lipo possess strong ability of ROS generation to damage cancer cells directly through PDT. Meanwhile, PpIX-NLG@ Lipo can induce immunogenic cell death to elicit the host immune system. Furthermore, PpIX-NLG@Lipo interferes the activity of IDO, which can amplify PDT-induced immune responses, leading to an increasing amount of CD8+ T lymphocytes infiltrated into tumor site, finally achieve both primary and distant tumor inhibition. Conclusion: This work presents a novel conjugate approach to synergize photodynamic therapy and IDO blockade for enhanced cancer therapy through simultaneously inhibiting both primary and distant metastatic tumor.
Lymphoid neoplasms in Shanghai, China: Relative frequency of subtypes of NHL diagnosed according to the WHO classification.
Authors: Sherilyn A. Gross, Xiaoqin Wang, John Ryder, Xiong Zheng Zhu, Liming Bao, Hua Fu, Richard D. Irons
Journal: Cancer Research (2006)

5364  The relative frequency of subtypes of lymphoid neoplasms was determined in a prospective series of 380 patients presenting at 28 Shanghai hospitals over a 2-year period. Diagnosis was established in a single laboratory, analyzing morphologic, immunophenotypic, cytogenetic and molecular data, according to the World Health Organization (WHO) revised classification. Precursor B- and T-cell leukemias represented 19.7% and 2.6% of total lymphoid neoplasms, respectively. The frequency of Hodgkin lymphoma was 11.6%. For comparison, the remaining non-Hodgkin lymphoma (NHL) subtypes (N=251) were classified according to the Revised European-American Lymphoma (REAL) system. The most prevalent NHL subtypes in Shanghai were: diffuse large B-cell lymphoma 30.3%, small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) 11.6%, follicular lymphoma 9.2%, peripheral T-cell lymphoma 9.2%, aggressive NK cell leukemia 6%, marginal zone B-cell lymphoma 5.6% and angioimmunoblastic T-cell lymphoma 5.6%. Although a low incidence has been reported in some Asian populations, SLL/CLL was the second most commonly encountered NHL subtype, indicating that chronic lymphoid neoplasms are not rare in Shanghai. Consistent with previous reports, our findings indicate a decrease in the frequency of follicular lymphoma and an increase in T-cell neoplasms compared to the West. Aggressive NK cell leukemia, angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma were prominent subtypes of T-cell NHL, which comprised 31.8% of NHL (REAL). This study was supported by a grant from the Benzene Health Research Consortium.
A novel approach to neoadjuvant chemoradiation for soft tissue sarcoma using cisplatin and adriamycin.
Authors: Ashley Brown, Christina Henson, Terence S. Herman, William C. Dooley, Alexis Schutz, Zeeshan Mirza, Hassan Hatoum, Jeremy White, Vipul Pareek, Patricia Pius
Journal: Journal of Clinical Oncology (2019)

e22515 Background: Soft tissue sarcomas (STS) are heterogeneous solid tumors of mesenchymal cell origin, often difficult to manage. Local recurrence of extremity STS with surgery alone ranges from 5-20% with amputation ; 40% with wide excision. Neoadjuvant therapies are used to improve surgical outcomes. There is currently no recognized optimal neoadjuvant chemoradiation regimen prior to resection of STS. At our institution, we have piloted a neoadjuvant regimen of daily Cisplatin with infusional Adriamycin concurrent with radiation to assess its impact on surgical outcomes and tumor control. Methods: Patients diagnosed with STS of any site were treated neoadjuvantly with Cisplatin 6mg/m 2 IV over 3-5 mins given 20 to 30 minutes before radiation (5 days) for 6 weeks. Adriamycin was given in the inpatient setting at 12.5 mg/m 2 IV over 24 hours on days 1-4, weeks 1 and 4. The radiation dose was 54 Gy in 30 fractions. More than 50% of patients were treated with IMRT planning. Results: Since 2011, 12 STS patients were treated preoperatively with this regimen. Of these patients, 9 underwent surgery. Six of the 9 surgical patients received this neoadjuvant protocol followed by resection in the upfront setting. All of the 6 upfront patients had negative surgical margins; all of these patients had grade 3 tumors. Necrosis was reported based on the FNCLCC grading system. The average percent of necrosis was 96.3% (95% confidence interval 50.4%, 99.8%). Toxicity: Reported according to the RTOG/EORTC Radiation toxicity grading system. Of all patients, grade 1-2 skin toxicity predominated (75%). No grade 4 toxicity reported. Hematologic toxicity: Of all patients, grade 2-3 hematologic toxicity during neoadjuvant chemotherapy was reported in 83% of patients; grade 4 in 1 patient. No febrile neutropenia occurred. Post-operative complications: Seroma/hematoma formation was the most common post-operative complication in the surgical patients. No severely delayed healing was noted. Survival:Nine of 12 patients were dead (6 of 9 surgical patients) at the time of this analysis, all of metastatic disease. Mean time to DM 7.4 months. Mean OS 10 months. Conclusions: Our novel regimen achieved high necrosis rates, and all surgical patients achieved negative margin status. These factors are prognostic and correlate with local control. The predominant pattern of failure was distant. With its acceptable toxicity, this regimen of neoadjuvant Cisplatin, Adriamycin and radiation should be examined in a randomized fashion versus neoadjuvant radiation alone to determine the long term outcomes.
Caspase-6 activation and lamin A cleavage occur in resveratrol-evoked apoptosis of colon cancer cell line (HCT116) cells
Authors: Shao C. Lee, Marie-Veronique Clement, Sanjiv K. Yadav, Soofern Lee, Shazib Pervaiz
Journal: Cancer Research (2005)

3492  Background Paclitaxel is an microtubule inhibitors, whose action results in the formation of stable bundles of microtubules within the cell, increasing tubulin polymerization, thus inhibiting the formation of mitotic spindle and cell cycle,finally inducing the cell apoptosis.It has been demonstrated that paclitaxel induced apoptosis in several cancers(such as ovarian and breast cancer as well as leukemic cells).However,it is not clear how paclitaxel induces apoptosis in human osteosarcoma and whether the apoptosis is related to apoptosis-regulated gene Bcl-2 and Bax.The objective of the current study was to investigate the apoptosis in human osteosarcoma cells induced by paclitaxel,and the relationship between this apoptosis and expression of Bcl-2 and Bax. Methods MG63 OS cells were treated with various concentrations of paclitaxel.Proliferation was determined by cell count in a cytometer chamber.Viability was assessed by typan blue dye exclusion.The cell morphologic alterations were visualized using light and transmitting electron microscope. The percentage of apoptosis of osteosarcoma cell MG63 was measured by TdT-mediated dUTP Nick End Labeling technique(TUNEL) staining method and flowcytometry using Annexin V/PI double staining method after 0, 24, 48,72 and 96 hours of culture in the presence or absence of paclitaxel. The expression of apoptosis-regulated gene Bcl-2 and Bax were detected using immunohistochemical staining. Results A time-dependent and dose-dependent cell growth inhibition was shown after exposure to paclitaxel.Paclitaxel induced MG63 cells to undergo apoptosis with typical apoptosis characteristics, including morphological changes of chromatin condensation, chromatin crescent formation,nucleus fragmentation.The DNA-cleavage was detected by using TUNEL assay.The cells treated with paclitaxel showed initially G2/M phase arrest,which was followed by apoptosis.Paclitaxel could reduce the expression of apoptosis-regulated gene Bcl-2 and improved the expression of apoptosis-regulated gene Bax. Conclusions Paclitaxel is able to induce the apoptosis in human osteosarcoma cells through the initiation of G2/M phase arrest and inhibiting mitosis in both a time-dependent and dose-dependent manner.This apoptosis maybe mediated by down-expression of apoptosis-regulated gene Bcl-2 and up-expression of apoptosis-regulated gene Bax.
Women’s Representation Among Lead Investigators of Clinical Trials in Oncology
Authors: Ethan B. Ludmir, Walker Mainwaring, Austin B. Miller, Timothy A. Lin, Amit Jethanandani, Andres F. Espinoza, Emma B. Holliday
Journal: JAMA Oncology (2019)

This database study assesses the number of female lead investigators of randomized clinical trials registered in ClinicalTrials.gov.
A novel approach for generation of fully human monoclonal antibodies using single cell PCR and in vitro translation
Authors: Alexander Lifke, Anna Macha, Hans Krell, Valeria Lifke
Journal: Cancer Research (2008)

2554  Since the establishment of hybridoma technology, monoclonal antibodies have been playing a pivotal role in basic research, diagnostics and human healthcare. Hybridoma technology and phage display, represent two common approaches for the generation of monoclonal antibodies. Both of these methods comprise some drawbacks. In the hybridoma technology, obtaining of stable clones is a major hurdle, thus diminishing diversity of the antibodies, since only a limited number of B-cells are successfully fused. In the phage display approach, there is the issue of mis- and/or dis-optimal pairings of heavy and light chains, resulting in cross reacting antibodies. A possibility to overcome these drawbacks consists of a method based on the amplification of cognate IgH and IgL chains of an IgG isotype from a single B-cell in combination with in vitro translation. The high sensitivity of this method can be exploited to amplify even minute amounts of mRNA from single cells. This method permits the investigation of the expressed antibody from each B-cell, thus providing higher diversity as opposed to the hybridoma technology. Furthermore, since the cognate antibody chains are obtained from mature B-cells after antigen contact, selectively high specific and accurately paired antibodies can be generated. This confers a high advantage over the generation of unspecific antibodies via phage display.  In this study, a multiplex semi nested PCR for amplification of cognate IgH and IgL chains from a single CD19 positive human B-cell isolated from human PBMCs was established. The Fab PCR product was subsequently translated in vitro. The expression was examined using ELISA and western blot. The genes encoding the IgH and IgL were amplified by single cell RT-PCR and the combined with regulatory elements for in vitro transcription and translation by overlapping PCR technique. The in vitro translation of such a linear mRNA template has previously been described by Nakano et al. The IgG-specific PCR amplification established in this study, was optimized and modified resulting in an 10 fold increase in measured OD-values in comparison to values reported by Nakano et al.  To accomplish this, three different PCR-based approaches were established: a two step PCR approach, a nested and a semi nested PCR approach. The nested PCR approach proved to be highly sensitive and resulted in high recovery ratios of the amplified heavy and light chains. However, the obtained Fab products could not be translated in vitro. The two step approach lead to the generation of functional Fab fragments with a plasmid template positive control, but was insensitive with single B-cell templates. On the other hand, the expression of functional and stable Fab fragments was observed after in vitro translation of PCR products obtained via the semi nested approach. With single B-cell templates, production of Fab protein was in the range of 180 to 310 ng/mL.
Reply to Zhipeng Mai's Letter to the Editor re: Taimur T. Shah, Max Peters, David Eldred-Evans, et al. Early-Medium-Term Outcomes of Primary Focal Cryotherapy to Treat Nonmetastatic Clinically Significant Prostate Cancer from a Prospective Multicentre Registry. Eur Urol 2019;76:98–105
Authors: Taimur T. Shah, Max Peters, Manit Arya, Hashim U. Ahmed
Journal: European Urology (2019)
Abstract #521: Poly(ADP-ribose) polymerase-1 polymorphisms, expression and activity in a panel of human tumor cell lines
Authors: Tomasz Zaremba, Patrick Ketzer, Elizabeth Plummer, Sally Coulthard, Michael Cole, Nicola Curtin
Journal: Cancer Research (2009)

Background: (PARP-1) is a DNA-binding enzyme activated by DNA breaks and involved in DNA repair, genomic stability, transcription control, cell death and proliferation. PARP activity is reported to be higher in various cancers than adjacent normal tissue. Contrastingly, the prevalence of some cancers is reported to be greater in individuals with a single nucleotide polymorphism (SNP) V762A (T2444C) in the catalytic domain that causes a reduction inPARP-1 activity. We aimed to resolve these opposing observations by determining PARP-1 genotype, PARP-1 protein levels, and PARP-1 activity in a panel of 20 human cancer cell lines.Methods: We studied 5 neuroblastoma cell lines (TR14, NB1691, NGP, LS, SK-N-BE2C), 3 breast cancer cell lines (T47D, MCF-7, MDA-MB-231), 7 leukaemia cell lines (Nalm 6, PreB 697, HL-60, K562, CCRF-CEM, Jurkat, Molt-4), Burkitt\#8217;s lymphoma cell line (Raji), thyroid carcinoma cell line (ML-1), colorectal carcinoma cell line (LoVo), hereditary spherocytosis cell line (TK-6) and bone marrow stromal cell line (HS-5). The T2444C SNPwas detected by pyrosequencing and the (CA)n microsatellite in the promoter was analyzed by capillary-electrophoresis. PARP-1 activity and expression were determined using GCLP validated immunoblot andWestern blot, respectively. Results: Analysis of the active site (T2444C) SNP revealed that most of the cell lines had the wild genotype (T/T), PreB and LoVo cells were heterozygous (T/C) while LS and Jurkat cells were homozygous variant (C/C). A long (CA)15-20 polymorphism in the promoter region may result in increased PARP-1 expression but most of the cells had short microsatellites 56% CA11/CA11, 28% CA11/CA15, 6% CA11/CA12, 6% CA13/CA14, and only 6% CA15/CA15.There was a wide variation in PARP activity in the cell line panel with a 35-fold difference between the lowest (2460 pmol PAR/106 HS5 cells) and the highest activity (85750 pmol PAR/106 NGP cells). There was less variation in PARP-1 protein expression with a 3.5-fold difference between the lowest (2.0 ng/\#956;g for HS5 cells) and the highest (7.1 ng/\#956;g for ML-1 cells). The mean activity in the cancer cells was 45 fold higher than mean activity in normal human lymphocytes (Proc Annu Meet Am Assoc Cancer Res 2008 #540) and the PARP-1 protein levels were 23-fold higher. Conclusion: Overall our data showed significant upregulation of PARP-1 expression and activity in cancer cell lines compared to human lymphocytes. However, we did not find any significant correlation between PARP-1 expression and length of the (CA)n-microsatellite in the promoter or activity with either PARP-1 protein levels or the T2444C SNP between the cell lines. This suggests that post-translational mechanisms contribute significantly to the increase in activity.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 521.