tbuckley/cabot-search huggingface dataset:
Micropapillary pattern (MPP) is an excellent predictor of a poor prognosis in lung adenocarcinoma, and even stronger evidence is loss of SP-A expression in MPP.
Authors: Hideaki Tsutsumida, Norishige Yamada, Shinichi Kitajima, Masamichi Goto, Mitsuharu Nomoto, Joeji Wakimoto, Ichiro Kubota, Yasunobu Hirotsu, Suguru Yonezawa
Journal: Cancer Research (2006)

5258  Micropapillary pattern (MPP) is known as a poor prognosis factor in cancers of ovaries, breasts and urinary bladders. MPP is detected also in lung cancer, but there is still a few studies investigating the roles of MPP in lung adenocarcinoma. Herein we clarify the character of MPP and suggest that MPP could be an excellent predictor of a poor prognosis in small size lung adenocarcinoma. Adenocarcinomas with MPP were examined from 185 cases of surgically removed small size ( 1%) was observed in 21 cases (11.4%), which correlated with lymphatic invasion (p
Ubiquitin modification of cyclin G1 protein stability
Authors: Mary Horne, Colleen Cowan, Robert Dallapiazza, Jennifer Duven
Journal: Cancer Research (2007)

5192  Cyclins G1 and G2 are unconventional cyclins correlated with cell cycle arrest that associate with active protein phosphatase 2A (PP2A). Cyclin G-family mRNAs are low in proliferating cells, but significantly upregulated during stress-induced cell cycle exit. Upon stress, the cyclin G1 gene is transactivated by p53, but the G2 gene is a target of the growth inhibitory transcription factor FOXO3a.We reported thatectopic expression of either cyclin G1 or G2 induces cell cycle arrest.Supporting our hypothesis that upregulation of G1 or G2 promotes growth arrest, multiple microarray studies of others have repeatedly correlated their elevation coincident with diverse cell cycle-inhibitory signals. Though cyclins G1 and G2 are close homologs, they differ in their subcellular localization and ability to associate with some binding partners. In a previous collaborative study we determined that cyclin G1 is an unstable protein subjected to proteasomal degradation in the presence of the E3 ubiquitin (Ub) ligase and p53 antagonist Mdm2, and that the level of G1 expression impacts its cell cycle effects. We showed that G1 associates with PP2A, p53, and Mdm2 . In the present study we investigated the regulation of cyclin G1 stability compared to G2, and evaluated the importance of G1 expression to growth inhibitory responses elicited by ectopic expression of the Mdm2 antagonist, p19ARF. Here we show that cyclin G1 is a polyubiquitinated protein that interacts with the 26S proteasome subunit S5a, and is targeted for degradation in the presence of abundant Mdm2. Inhibition of poly-Ub chain formation via ectopic expression of Ub-lysine mutants (K48R) increased the abundance of cyclin G1, and its association with both Mdm2 and PP2A. We used pulldown assays to map the respective regions required for cyclin G1-Mdm2 interactions and hypothesize that, because G1 is reduced in the presence of active Mdm2, it directly contributes to cyclin G1 downregulation. To determine the importance of site-specific ubiquitin modification of cyclin G1 for its stability and associated cell cycle inhibitory activity, we generated several cyclin G1 point mutants. We identified mutants that are stabilized in the presence of Mdm2 and appears to exhibit increased intrinsic cell cycle inhibitory activity. Using shRNA-mediated knockdown of endogenous G1, we have preliminary evidence that the growth-arrest response elicited by ectopic expression of p19ARF is blunted upon cyclin G1 down-regulation. We are evaluating the cellular effects of these G1 mutations and the contribution of endogenous cyclins G1 and G2 to cell cycle arrest. Ub-modification of cell cycle regulatory proteins is central to growth control, and many human cancers exhibit alterations in p53 signaling pathways. Thus determining how cyclin G1 abundance is modulated (in the presence or absence of cyclin G2 expression), and the effect this has on tumor suppressor function is clearly warranted.
Methotrexate withdrawal in patients with rheumatoid arthritis who achieve low disease activity with tofacitinib modified-release 11 mg once daily plus methotrexate (ORAL Shift): a randomised, phase 3b/4, non-inferiority trial
Authors: Stanley B Cohen, Janet Pope, Boulos Haraoui, Fedra Irazoque-Palazuelos, Mariusz Korkosz, Annette Diehl, Jose L Rivas, Tatjana Lukic, Shixue Liu, Lori Stockert, Noriko Iikuni, Edward C Keystone
Journal: The Lancet Rheumatology (2019)
Concepts for prevention of complications in implant therapy
Authors: Georgios E. Romanos, Rafael Delgado‐Ruiz, Anton Sculean
Journal: Periodontology 2000 (2019)

Abstract The use of dental implants is nowadays a well‐accepted and highly predictable treatment modality for restoring the dentition and reestablishing the masticatory function of edentulous and partially edentulous patients. Despite the high predictability and excellent long‐term survival rates reported for implant therapy, complications may still occur and can jeopardize both short‐ and long‐term success. The present paper provides an overview on the most important aspects related to the etiology, prevention, and management of complications associated with implant therapy. Data from the literature indicate that a number of factors, such as surgical trauma, implant diameter, type of implant‐abutment connection, abutment disconnection and reconnection, presence of microgap, and implant malpositioning, can substantially influence the biologic processes of bone remodeling and biofilm formation, thus increasing the rate of short‐ and long‐term hard‐ and soft‐tissue complications. Other factors, such as excess cement at cement‐retained prosthetic restorations, abutment mobility, and infections (e.g. peri‐implant mucositis and peri‐implantitis) caused by bacterial biofilm, are further causes for complications and failures. More recent evidence also indicates that besides the need for sufficient bone volume surrounding the implant, the presence of an adequate width and thickness of attached mucosa may improve biofilm control and limit crestal bone resorption. Furthermore, emerging evidence points also to the pivotal role of human factors as one of the most important causes of complications in implant dentistry. It can be concluded that clinicians need to consider all biologic and biomechanical factors affecting implant placement and survival, as well as undergo adequate training to improve their surgical skills to control and prevent implant complications. Careful patient selection and control of environmental and systemic factors, such as smoking, diabetes etc., coupled with an accurate surgical and prosthetic planning, enable a better prevention and control of infections.
The effect of hospital and physician volume on racial differences in disease recurrence following surgery for prostate cancer
Authors: Kyna Gooden, Daniel Howard, William Carpenter, April Carson, Yhenneko Jallah, Paul Godley
Journal: Cancer Research (2007)

3416  Recurrence following radical prostatectomy is higher among African Americans compared to Caucasians. Previous studies have shown that hospital and physician volume, proxies for experience, are associated with improved outcomes and disease-free survival following major surgical procedures. This study investigated racial differences in recurrence following surgery for prostate cancer as they may be associated with hospital and physician volume. Data from the Surveillance, Epidemiology, and End-Results (SEER)-Medicare database were examined for 962 African American and 7387 Caucasian men who were diagnosed with prostate cancer during 1993-1999 and received surgery within 6 months of diagnosis. Analysis controlled for age at diagnosis, cancer stage, and Gleason grade. Cox regression models were employed to estimate the relationships between volume, disease-recurrence, and race, grouping hospital and physician volume by quartiles. During 1993-1999, African American men were more likely to experience disease recurrence than Caucasian men (Hazard Ratio (HR)=1.32; 95%CI: 1.15, 1.51). Examination of this disparity revealed that the racial differences in recurrence were greater among high volume hospitals (High HR=1.66; 95%CI: 1.31, 2.09) than low volume hospitals (Low HR=1.24, 95%CI: 0.92, 1.68). The disparity in recurrence was even lower among those receiving care at Medium (Medium HR=1.12, 95%CI: 0.81, 1.53) and Medium High volume hospitals (Medium High HR=1.19, 95%CI: 0.84,1.68). Thus, contrary to expectation, hospitals performing the most surgeries for prostate cancer had larger racial differences in recurrence than hospitals performing the least surgeries. Those hospitals that were in the medium volume categories exhibited little evidence for racial differences in recurrence. Stratification by physician volume revealed an increase in racial differences between Low, Medium, and Medium High Volume physicians (Low HR=1.00; 95%CI: 0.76, 1.33; Medium HR=1.20, 95%CI: 0.91, 1.58; Medium High HR=1.67, 95%CI: 1.25, 2.22). However, patients of the highest volume physicians showed slightly lower racial differences than those of the Medium volume Physicians (High HR=1.11, 95%CI: 0.59, 2.11). In summary, racial differences in recurrence following surgery for prostate cancer did not consistently decrease with increasing hospital and physician volume as expected. Instead, this study suggests that racial differences in recurrence persist among patients of high volume or experienced hospitals, and patients of medium high volume physicians.
Intraductal cholangioscopy for the diagnosis of pancreaticobiliary maljunction
Authors: Carolina Mangas-Sanjuan, Maryana Bozhychko, Luis Compañy, Francisco Ruiz, Juan Martinez, Juan Antonio Casellas, José Ramón Aparicio
Journal: Endoscopy (2019)

An 8-year-old girl was admitted to our department because of acute pancreatitis. She had undergone laparoscopic cholecystectomy 2 weeks previously. A 13-mm dilatation of the common bile duct (CBD) and a biliary tract obstruction next to the papilla were observed on magnetic resonance imaging (MRI) during hospitalization ([Fig. 1]). After endoscopic sphincterotomy was carried out during endoscopic retrograde cholangiopancreatography (ERCP), proteinaceous material was removed from the distal end of the bile duct ([Fig. 2]), with resolution of the biliary obstruction. When radiographic contrast dye was injected into the distal bile duct, the pancreatic duct, a dilated CBD similar to a choledochal cyst, and a long common channel were observed ([Fig. 3]). Therefore, a pancreaticobiliary maljunction (PBM) was suspected. Subsequently, an intraductal cholangioscopy using the SpyGlass DS Direct Visualization System (Boston Scientific Co., Natick, Massachusetts, USA) was performed to confirm a PBM type I, in which the pancreatic duct enters the CBD ([Fig. 4]; [Video 1]).
AlleleAnalyzer: a tool for personalized and allele-specific sgRNA design
Authors: Kathleen C. Keough, Svetlana Lyalina, Michael P. Olvera, Sean Whalen, Bruce R. Conklin, Katherine S. Pollard
Journal: Genome biology (2019)

The CRISPR/Cas system is a highly specific genome editing tool capable of distinguishing alleles differing by even a single base pair. Target sites might carry genetic variations that are not distinguishable by sgRNA designing tools based on one reference genome. AlleleAnalyzer is an open-source software that incorporates single-nucleotide variants and short insertions and deletions to design sgRNAs for precisely editing 1 or multiple haplotypes of a sequenced genome, currently supporting 11 Cas proteins. It also leverages patterns of shared genetic variation to optimize sgRNA design for different human populations. AlleleAnalyzer is available at https://github.com/keoughkath/AlleleAnalyzer .
NMDA receptor 2B promoter methylation predicts poor prognosis in esophageal squamous cell carcinoma
Authors: Myoung Kim, Keishi Yamashita, Xiaofei Chang, Young Chae, Marianna Zahurak, Guojun Wu, David Sidransky
Journal: Cancer Research (2007)

1136  NMDAR family members are endogenously expressed neurotoxic molecules that can be activated in a variety of normal neurophysiological processes. We previously identified NMDAR2B as a putative tumor suppressor gene, and reported a cancer-specific methylation of the promoter in esophageal squamous cell carcinoma (ESCC). The CpG island analyzed was directly upstream of the transcription start site (TSS). In this study, we investigated the methylation status of NMDAR2B promoter at three different sites (P1, P2, and P3) of 1 kb upstream of the TSS where two CpG islands reside. Three independent modalities for methylation analysis (bisulfite-sequencing, COBRA, and TaqMan MSP) were performed to analyze total 67 ESCC tissues that included 43 primary tumors with well characterized clinicopathological parameters including patient outcome. Using an optimized cut-off value by quantitative-methylationspecific PCR (Q-MSP), we found that patients with higher NMDA receptor 2B methylation ratios in the proximal region (P1) demonstrated poorer 5-year disease-specific survival rates than those without NMDA receptor 2B methylation (P=0.006). A significant correlation was also seen between NMDAR2B promoter methylation and the presence of vascular permeation. These results suggest that NMDAR2B promoter methylation could be a clinically applicable marker for ESCC progression.
Biweekly combination therapy with gemcitabine and carboplatin compared with gemcitabine monotherapy in patients over 80 years old with advanced non-small-cell lung cancer: Subgroup analysis of the prospective randomized phase II study.
Authors: Hideki Kusagaya, Naoki Inui, Masato Karayama, Yuichi Ozawa, Yutaro Nakamura, Shigeki Kuroishi, Koshi Yokomura, MIkio Toyoshima, Toshihiro Shirai, Masafumi Masuda, Takashi Yamada, Kazumasa Yasuda, Takafumi Suda, Kingo Chida
Journal: Journal of Clinical Oncology (2013)

e20658 Background: Chemotherapy regimens for the elderly with non-small-cell lung cancer (NSCLC) are still controversial, especially for patients over 80 years. We previously reported that biweekly combination therapy with gemcitabine and low-dose carboplatin was well tolerated and active in elderly patients aged ≥76 years with NSCLC (Lung Cancer 77, 2012). Here we present a subanalysis of more elder patients aged ≥80 years. Methods: We conducted a phase II trial comparing biweekly combination therapy with gemcitabine (1000mg/m2) plus carboplatin (AUC 3) and monotherapy with weekly gemcitabine (1000mg/m2) in chemotherapy-naïve NSCLC patients aged ≥76 years. We performed a retrospective subgroup analysis comparing patients aged &lt; 80 and those ≥ 80 years. We focused on patients treated with combination therapy. The primary endpoint was overall response rate and secondary endpoints were safety and progression free survival (PFS). Results: Sixteen patients were aged &lt; 80 years (median 77.5, range, 76-79 years) and 15 patients were aged ≥80 years (median 83, range 81-88 years). Overall response rates were 25% (95% CI: 7.3-52.4%) for patients aged &lt;80 years and 20% (95% CI: 4.3-48.1%) for patients aged ≥80 years. The median PFS in patients aged &lt;80 years was 3.5 months (95% CI: 3.2-5.6), compared with 3.6 months (95% CI: 2.8-5.0) in patients aged ≥80 years. Additionally, the prevalence of grade 3 or 4 hematologic and non-hematologic toxicity, the completion of four cycles chemotherapy, and the need for withdrawing treatment were not significantly different between the two groups. Conclusions: In elderly patients with NSCLC, even aged ≥80 years, combination therapy with biweekly gemcitabine and low-dose carboplatin may be an efficacious treatment with a favorable toxicity profile. Clinical trial information: NCT00881296.
Clinical significance of MLL-AF4 fusion transcript expression in the absence of a cytogenetically detectable t(4;11)(q21;q23) chromosomal translocation.
Authors: Fatih M. Uckun, Kim Herman-Hatten, Mya-Lisa Crotty, Martha G. Sensel, Harland N. Sather, Lisa Tuel-Ahlgren, Mireille B. Sarquis, Bruce Bostrom, James B. Nachman, Peter G. Steinherz, Paul S. Gaynon, Nyla Heerema
Journal: Blood (1998)
A phase I dose-escalation study of the HSP90 inhibitor AUY922 and erlotinib for patients with EGFR-mutant lung cancer with acquired resistance (AR) to EGFR tyrosine kinase inhibitors (EGFR TKIs).
Authors: Melissa Lynne Johnson, Helena Alexandra Yu, Eric M Hart, Rebekah Worden, Alfred Rademaker, Rajesh Gupta, Claire Miller, Jyoti D. Patel, Mark G. Kris, Vincent A. Miller, Gregory J. Riely
Journal: Journal of Clinical Oncology (2012)

3083 Background: AUY922 is a highly potent, non-geldanamycin analog, HSP90 inhibitor that degrades mutated EGFR and MET. Preclinical studies demonstrate that HSP90 inhibitors have anti-tumor activity in EGFR mutant, EGFR TKI-sensitive and TKI-resistant lung cancer xenograft models. To prevent disease flare after stopping EGFR TKIs in patients (pts) with EGFR mutated lung cancer, erlotinib (E) is often continued with subsequent lines of treatment for AR. This phase I study will determine the maximally tolerated dose (MTD) of AUY922 and E for pts with mutated EGFR and RECIST progression on EGFR TKIs. Methods: All pts have EGFR mutant lung cancer, with development of AR (per Jackman, JCO 2010) after treatment with an EGFR TKI. Pts underwent repeat tumor biopsies after development of AR and prior to study entry. Pts receive AUY922 IV weekly and E oral daily in 28-day cycles, with dose escalation using standard 3+3 design. Pharmacokinetics, serial ophthalmology evaluations and weekly assessment for toxicity are required. Tumor tissue from re-biopsy at study entry is analyzed for EGFR T790M and MET. Results: Since April 2011, 11 pts have been enrolled, in 4 of 5 planned cohorts (AUY922 25 mg/m 2 + E 75 mg; AUY922 25 mg/m 2 + E 150 mg; AUY922 37.5 mg/m 2 + E 150 mg; AUY922 55 mg/m 2 +E 150 mg). Prior to developing AR, pts were treated with EGFR TKIs for a median of 9 months (range 8-32). Of 9 pts with tissue analyzed thus far, 6 had EGFR T790M. Pts have received a median of two cycles (range 1-7), and 5 remain on study. There have been no dose-limiting toxicities. Adverse events reported in ≥ 20% of pts were diarrhea, nausea, vomiting, fatigue, and rash, all graded 1 or 2. No cardiovascular, renal or hepatic toxicities have been observed. Three pts have reported “flashing lights” and 2 pts transient night blindness, all grade 1. Dose escalation continues. No partial responses have been seen in 6 evaluable pts, 4 patients have confirmed stable disease at 8 wks. Conclusions: AUY922 and E is a well-tolerated combination at dose levels up to AUY922 55 mg/m 2 + E 150 mg. Further dose-escalation, MTD, and correlation with markers of AR will be reported. Supported by Novartis, Inc.
Frequent loss of hPMS2 and hMSH6 expression in non-familial (sporadic) young patients with colorectal cancer
Authors: Ajay Goel, Jennifer Spiegel, Takeshi Nagasaka, Sung-Kwan Shin, Sheryl Livingston, Richard Meyer, Warren Lichliter, C. Richard Boland
Journal: Cancer Research (2007)

133  Colorectal cancer (CRC) occurs rarely in young individuals ( 2/5 markers were unstable, as MSI-low (MSI-L) if only 1 marker was unstable, or microsatellite stable (MSS) if no marker was unstable. Results: The mean age of the patient cohort was 34.4 years (range 16-47 years); 52% were female and 48% were male. 72% of the CRCs were located distally, and only 28% proximal. 17% (14 of 82) of the CRCs were MMR-deficient, based upon loss of expression of MMR proteins. Unlike Lynch syndrome, only 43% (6/14) of these MMR-deficient CRCs demonstrated loss of expression of one of the two major DNA MMR proteins, hMLH1 or hMSH2 (3 each for hMLH1 and hMSH2), together with the associated loss of hPMS2 or hMSH6 expression. Unexpectedly, 8/14 (57%) of the MMR-deficient CRCs exhibited the exclusive loss of either hPMS2 (n = 3) or hMSH6 (n = 5), without evidence for the loss of expression of the partnering major MMR protein. While all 6 tumors with hMLH1 or hMSH2 loss were MSI-H, only 4/8 tumors with an isolated loss of hMSH6 (1/4) or hPMS2 (3/3) were MSI-H. Conclusions: We found isolated loss of hMSH6 and hPMS2 proteins in 10% of young patients with non-familial CRC. These findings suggest that these patients have germline mutations in hMSH6 associated with a low level of MSI-H, and that some of these apparently non-familial patients may have germline mutations in hPMS2. More importantly, the observation that tumors associated with isolated loss of hMSH6 or hPMS2 develop without loss of hMSH2 and hMLH1 raises unanswered questions about the molecular pathways through which these tumors develop.
A Cohesin-Mediated Intrachromosomal Loop Drives Oncogenic ROR lncRNA to Accelerate Tumorigenesis
Authors: Jiayan Fan, Yangfan Xu, Xuyang Wen, Shengfang Ge, Renbing Jia, He Zhang, Xianqun Fan
Journal: Molecular Therapy (2019)

Long noncoding RNAs (lncRNAs) are an important class of pervasive noncoding RNA involved in a variety of biological functions. Numerous studies have demonstrated their important regulatory role in human disease, especially cancer. However, the mechanism underlying the transcription of lncRNAs is not fully elucidated. Here, a comparison of local chromatin structure of the ROR lncRNA locus revealed a cohesin-complex-mediated intrachromosomal loop that is juxtaposed with an upstream enhancer to the ROR promoter, enabling activation of endogenous ROR lncRNA in tumor cells. This chromosomal interaction was not observed in normal control cells. Knockdown of SMC1 by RNAi or deletion of the enhancer DNA by CRISPR/Cas9 abolished the intrachromosomal interaction, resulting in ROR lncRNA silencing and inhibition of the tumor progression in animals carrying tumor xenografts. Our results reveal a novel mechanism by which the cohesin-orchestrated intrachromosomal looping may serve as a critical epigenetic driver to activate transcription of ROR lncRNA, subsequently inducing tumorigenesis. Our data represent a novel chromosomal folding pattern of lncRNA regulation, thereby providing a novel alternative concept of chromosomal interaction in lncRNA-triggered tumorigenesis.
Distributed Biological Foundries for Global Health
Authors: Jose Gomez‐Marquez, Kimberly Hamad‐Schifferli
Journal: Advanced Healthcare Materials (2019)

Abstract Historically, many industries such as manufacturing have undergone a trend away from centralized, large‐scale production toward a more distributed form. Currently, this same trend is witnessed in biological manufacturing and bioprocessing, with the rise of biological foundries where one can synthesize, grow, isolate, and purify a broad range of biologics. The adoption of distributed practices for biological processing has significant implications for healthcare, diagnostics, and therapies. This essay discusses the many diverse factors that have facilitated this growth, ranging from the establishment of available biological components, or “parts,” low‐cost programmable hardware, and others. Currently existing examples of distributed biological foundries are also identified, separating the discussion into those that are accessible only by elite users and the more recent emerging foundries that are more accessible to the general population. Taking lessons from other fields, it is argued that this trend toward distributed biological manufacturing is inevitable, so adapting to this trend is important for the progress of creating new therapeutics, sensors, diagnostics, and reagents for biomedical applications.