tbuckley/cabot-search huggingface dataset:
OTU-04 Artificial intelligence for real-time polyp localisation in colonoscopy withdrawal videos
Authors: Omer F Ahmad, Patrick Brandao, Sarmed S Sami, Evangelos Mazomenos, Anita Rau, Rehan J Haidry, Roser Vega, Ed Seward, Tom Vercauteren, Danail Stoyanov, Laurence B Lovat
Journal: Endoscopy (2019)

<h3>Introduction</h3> Artificial intelligence (AI) can potentially improve adenoma detection rates. Previous work focussed on still images and selected video sequences which may be subject to bias and lack clinical utility. This study assesses whether a convolutional neural network (CNN) developed using still images and short video sequences from a multicentre dataset using different processors generalises effectively to locate polyps in a new video dataset consisting of complete colonoscopy withdrawals (caecum to rectum). <h3>Methods</h3> Our group previously developed a CNN using 4664 polyp test frames from the MICCAI 2015 polyp dataset. Here, we created a new dataset using 17 complete colonoscopy withdrawal videos, previously unseen by the CNN, containing 83 polyps consisting of 83,716 frames (14,634 polyp &amp; 69,082 non-polyp) using Olympus EVIS LUCERA CV290(SL) processors and colonoscopes. White light frames were annotated by drawing bounding boxes around polyps. Size, morphology, histopathology and location was recorded for each polyp (table 1). Low quality frames (e.g. blurred) were excluded. Half the procedures were randomly selected to create a testing set. A true positive was scored if the CNN prediction overlapped with the bounding box. A false positive indicated a non-overlapping location. <h3>Results</h3> The CNN operated at real-time video-rate achieving a sensitivity of 91.6% and positive predictive value 75.3% in the MICCAI test set. When the MICCAI trained CNN was tested on our previously unseen colonoscopy procedures, it achieved a sensitivity of 76.6% and specificity of 78.9%. This CNN was fine-tuned by using polyp positive frames from our training dataset. This improved sensitivity to 84.5% and specificity to 92.5%. <h3>Conclusion</h3> Whilst the CNN achieved excellent results on the public still image dataset, it is more challenging to generalise results to complete colonoscopy withdrawals. Fine-tuning using our dataset improved performance. Furthermore, our procedures were performed by experts, including a significant proportion of right sided flat elevated and subtle sessile serrated lesions which were not evaluated in recent publications. AI development should include complete colonoscopy withdrawals to reflect true clinical practice and focus specifically on identifying challenging polyps that may be overlooked.
EGFR gene mutation and epithelial to mensenchymal transition (EMT) markers in advanced NSCLC patients treated with erlotinib.
Authors: Mary J. Fidler, Manish J Dave, Sanjib Basu, Thomas A. Hensing, Mark Pool, Brett Mahon, Jeffrey A Borgia, Kelly Kaiser Walters, Diana Escarzaga, Marta Batus, Philip D. Bonomi
Journal: Journal of Clinical Oncology (2012)

e18117 Background: TTF-1 is a transcription factor involved in regulating epithelial to mesenchymal transition (EMT). Previous work in a clinically enriched non-small cell lung cancer (NSCLC) population suggested low probability of an EGFR activating gene mutation in the absence of TTF-1 positivity (Somaiah ASCO 2011). This study's goal was to validate the relationship of TTF-1 and other immunohistochemical (IHC) markers of EMT to the presence of an EGFR activating gene mutation in a diverse group of NSCLC patients treated with erlotinib. Methods: Patients receiving erlotinib at two midwest institutions were retrospectively analyzed by IHC for TTF-1 (Greater than 5% of tumor cells with moderate (2+) or strong (3+) nuclear staining considered positive) and for PTEN, Ecadherin,vimentin, beta catinin, and snail (frequency(0-4) times intensity(0-4)). Exon 19 and L858R mutations were detectedusing single-strand conformation polymorphism and sequence-specific polymerase chain reaction (PCR)).Fisher’s exact testand logistic regression wereused to correlate TTF-1(positive or negative) and the remaining EMT markers with the presence of EGFR mutation. Results: 216 patients were analyzed for EGFR activating gene mutations: 15% squamous, 80% smokers. EGFR mutation was found in 11.6% of cases. TTF-1 was present in 8% of squamous cell patients and 71% of adenocarcinoma patients. TTF-1 correlated with prolonged progression free survival (log rank p=.004). TTF-1 positivity was strongly correlated with the presence of mutation (p=.0006, negative predictive value=97.7%). Increasing Ecadherin and increasing PTEN expression by IHC correlated with the presence of EGFR gene mutation when measured on continuum (p=.006 and p=.04, respectively). Conclusions: Though retrospective, our work confirms the negative predictive value of TTF-1 for an EGFR activating gene mutation in a NSCLC cohort representative of a North American population.Though high PTEN and Ecadherin expression also correlated with EGFR mutation, TTF-1 positivity may be a more straight-forward marker that can select patients who should be screened for the mutation prior to initiation of first line therapy.
Incidence of venous thromboembolism in lung cancer and its effect on survival.
Authors: Mohammad Mozayen, Anteneh A. Tesfaye, Manas ranjan Sarangi, Jyothsna Talluri, Khalil Katato
Journal: Journal of Clinical Oncology (2012)

7102 Background: Lung cancer is a major risk factor of venous thromboembolism (VTE). The incidence of VTE in different histological patterns of lungs cancer and its impact at the disease outcome is not well studied. We aim to evaluate the incidence rate of VTE in lung cancer and its effect on survival. Methods: Patients (pts) with lung cancer diagnosis from cancer database of community hospital were reviewed. Pts’ medical records were checked for VTE over 3 years after diagnosis. Pts’ demographics, pathology, TNM stage and overall survival were studied. Development of VTE was primary outcome and 3 year overall survival was the secondary outcome. Results: A total 2,164 pts with lung cancer between 1995 and 2008 were included. Median age of the study population was 70 years. Males were 53%, African Americans were 7%. 200 pts (9%) were diagnosed with VTE. Out of 1783 pts with non-small cell lung cancer (NSCLC), 176 pts (9.9%) had VTE whereas out of 381 pts with small cell lung cancer (SCLC) 24 pts (6.3%) had VTE (p=0.015). Among NSCLC pts, 13.5% of pts with adenocarcinoma had VTE, whereas 6.6% of pts with squamous cell carcinoma had VTE (p&lt;0.05). The incidence of VTE in stages I, II, III, IV of all pts were (8.4%, 7.3%, 13%, 7.5%) (p=0.007) respectively. In NSCLC, three years overall survival of pts with and without VTE was 22% and 24% respectively (p=0.34). In SCLC, three years overall survival of pts with and without VTE was 21% and 11% respectively (p=0.09). Conclusions: There is a higher incidence of VTE in non-small cell lung cancer than in small cell lung cancer. Among the NSCLC, VTE’s incidence was higher in adenocarcinoma than squamous carcinoma. VTE maybe higher at advanced stages (stage III) in both NSCLC and SCLC combined. There was no significant difference in the 3 years overall survival of lung cancer patients with and without VTE.
The miR-26a/AP-2α/Nanog signaling axis mediates stem cell self-renewal and temozolomide resistance in glioma
Authors: Wenhuan Huang, Zhe Zhong, Chang Luo, Yuzhong Xiao, Limin Li, Xing Zhang, Liu Yang, Kai Xiao, Yichong Ning, Li Chen, Qing Liu, Xiang Hu, Jian Zhang, Xiaofeng Ding, Shuanglin Xiang
Journal: Theranostics (2019)

Aberrant expression of transcription factor AP-2α has been functionally associated with various cancers, but its clinical significance and molecular mechanisms in human glioma are largely elusive. Methods: AP-2α expression was analyzed in human glioma tissues by immunohistochemistry (IHC) and in glioma cell lines by Western blot. The effects of AP-2α on glioma cell proliferation, migration, invasion and tumor formation were evaluated by the 3-(4,5-dimethyNCthiazol-2-yl)-25-diphenyltetrazolium bromide (MTT) and transwell assays in vitro and in nude mouse models in vivo. The influence of AP-2α on glioma cell stemness was analyzed by sphere-formation, self-renewal and limiting dilution assays in vitro and in intracranial mouse models in vivo. The effects of AP-2α on temozolomide (TMZ) resistance were detected by the MTT assay, cell apoptosis, real-time PCR analysis, western blotting and mouse experiments. The correlation between AP-2α expression and the expression of miR-26a, Nanog was determined by luciferase reporter assays, electrophoretic mobility shift assay (EMSA) and expression analysis. Results: AP-2α expression was downregulated in 58.5% of glioma tissues and in 4 glioma cell lines. AP-2α overexpression not only reduced the proliferation, migration and invasion of glioma cell lines but also suppressed the sphere-formation and self-renewal abilities of glioma stem cells in vitro. Moreover, AP-2α overexpression inhibited subcutaneous and intracranial xenograft tumor growth in vivo. Furthermore, AP-2α enhanced the sensitivity of glioma cells to TMZ. Finally, AP-2α directly bound to the regulatory region of the Nanog gene, reduced Nanog, Sox2 and CD133 expression. Meanwhile, AP-2α indirectly downregulated Nanog expression by inhibiting the interleukin 6/janus kinase 2/signal transducer and activator of transcription 3 (IL6/JAK2/STAT3) signaling pathway, consequently decreasing O6-methylguanine methyltransferase (MGMT) and programmed death-ligand 1 (PD-L1) expression. In addition, miR-26a decreased AP-2α expression by binding to the 3' untranslated region (UTR) of AP-2α and reversed the tumor suppressive role of AP-2α in glioma, which was rescued by a miR-26a inhibitor. TMZ and the miR-26a inhibitor synergistically suppressed intracranial GSC growth. Conclusion: These results suggest that AP-2α reduces the stemness and TMZ resistance of glioma by inhibiting the Nanog/Sox2/CD133 axis and IL6/STAT3 signaling pathways. Therefore, AP-2α and miR-26a inhibition might represent a new target for developing new therapeutic strategies in TMZ resistance and recurrent glioma patients.
Engineering of a Lectibody Targeting High-Mannose-Type Glycans of the HIV Envelope
Authors: Krystal Teasley Hamorsky, J. Calvin Kouokam, Matthew W. Dent, Tiffany N. Grooms, Adam S. Husk, Steven D. Hume, Kenneth A. Rogers, Francois Villinger, Mary Kate Morris, Carl V. Hanson, Nobuyuki Matoba
Journal: Molecular Therapy (2019)

High-mannose-type glycans (HMGs) are aberrantly enriched on HIV envelope glycoproteins. However, there is currently no drug selectively targeting HIV-associated HMGs. Here, we describe a novel HMG-targeting "lectibody," a recombinant Fc-fusion protein comprising human IgG1 Fc and a novel actinohivin lectin variant (Avaren) obtained by structure-guided modifications for improved overall surface charge properties (AvFc). AvFc was engineered and produced using a rapid and scalable plant-based transient overexpression system. The lectibody exhibited potent antiviral activity against HIV-1 groups M and O primary viruses, as well as HIV-2 and simian immunodeficiency virus (SIV) strains, without affecting normal human blood cells. Furthermore, the lectibody induced Fc-mediated cell killing activity against HIV-1-infected cells and selectively recognized SIVmac239-infected macaque mesenteric lymph node cells in vitro. AvFc showed an extended serum half-life in rats and rhesus macaques, while no discernible toxicity was observed upon repeated systemic dosing in mice. These results highlight AvFc's potential as a biotherapeutic targeting HIV-associated HMGs of cell-free virions, as well as productively infected cells, providing a foundation for new anti-HIV strategies. Efficient and cost-effective bioproduction in greenhouse facilities may open unique possibilities for further development of AvFc. High-mannose-type glycans (HMGs) are aberrantly enriched on HIV envelope glycoproteins. However, there is currently no drug selectively targeting HIV-associated HMGs. Here, we describe a novel HMG-targeting "lectibody," a recombinant Fc-fusion protein comprising human IgG1 Fc and a novel actinohivin lectin variant (Avaren) obtained by structure-guided modifications for improved overall surface charge properties (AvFc). AvFc was engineered and produced using a rapid and scalable plant-based transient overexpression system. The lectibody exhibited potent antiviral activity against HIV-1 groups M and O primary viruses, as well as HIV-2 and simian immunodeficiency virus (SIV) strains, without affecting normal human blood cells. Furthermore, the lectibody induced Fc-mediated cell killing activity against HIV-1-infected cells and selectively recognized SIVmac239-infected macaque mesenteric lymph node cells in vitro. AvFc showed an extended serum half-life in rats and rhesus macaques, while no discernible toxicity was observed upon repeated systemic dosing in mice. These results highlight AvFc's potential as a biotherapeutic targeting HIV-associated HMGs of cell-free virions, as well as productively infected cells, providing a foundation for new anti-HIV strategies. Efficient and cost-effective bioproduction in greenhouse facilities may open unique possibilities for further development of AvFc.
What is the behavior of Breslow’s thickness?
Authors: Gelcio L. Q. Mendes, Sergio Koifman
Journal: Journal of Clinical Oncology (2013)

9097 Background: Localized cutaneous melanomas (CM) have their clinical course predicted by microscopic findings in the tumor specimen, mostly Breslow’s thickness (BTL), ulceration and mitoses. It is not certain whether BTL has a linear relationship with overall survival (OS) or relapse-free survival (RFS). The aim of this study was to evaluate BTL´s linear (LC) and its non-linear component (NLC) with relation to survival. Methods: All consecutive cases of CM treated from 1997 to 2006 at a single institution were identified, individuals with stage I or II tumors, minimum follow up of one month and known BTL were selected, socio-demographic data, clinical and pathological findings, treatment and outcomes were abstracted. Information about ulceration was missing in more that 30% of cases and it was not evaluated, there was no information about mitotic rate. Survival was estimated by the Kaplan-Meier method. Multivariate analyses were performed by the Cox model. BTL was evaluated as a continuous variable, and the LC and NLC by the technique of smoothing, using p-splines. Results: There were 1465 cases of CM, 51 with no follow up, 137 had no information about BTL and 202 had advanced stages. This analysis is based on 1075 cases. In the Cox model, the variables associated OS were age [hazard ratio (HR) 1.02, 95% CI 1.01 to 1.03], sex (HR 1.56, 95% CI 1.2 to 2.04) and BTL (HR=1.079, 95% CI 1.065 to 1.094). The variables associated with RFS were age (HR 1.017, 95% CI 1.009 to 1.024), sex (HR 1.372, 95% CI 1.104 to 1.704) and BTL (1.068, 95% CI 1.057 to 1.080). In the analysis of LC and NLC of BTL, it was found that both LC and NLC were statistically significant for OS and RFS. There was an increase in the HR as BTL increased in those lesions thinner than 4mm, then such increase was not as evident and lesions with more than 10mm had a similar OS and RFS (plateau). Conclusions: BTL is one of the most powerful prognostic criteria of patients with stage I and II CM. The risk of death increases linearly for thin lesions up to 4mm, lesions thicker than 10mm behave as a uniform group with no further decrease in OS or RFS as the lesion becomes larger. In conclusion, BTL may not behave as a linear function, it has a LC for thinner lesions, but for thicker lesions, above 10mm, further increase in BTL may add no more risk.
MicroRNA biomarkers in whole blood for detection of pancreatic cancer.
Authors: Nicolai Aagaard Schultz, Christian Dehlendorff, Benny Vittrup Jensen, Jon K. Bjerregaard, Kaspar Nielsen, Stig Egil Bojesen, Dan Calatayud, Svend Erik Nielsen, Mette K. N. Yilmaz, Niels Henrik Hollander, Klaus Kaae Andersen, Julia S. Johansen
Journal: Journal of Clinical Oncology (2013)

4052 Background: There is a great need for biomarkers for early diagnosis of patients with pancreatic cancer (PC) to improve their poor prognosis. The aims were (1) to describe differences in miRNA expression in whole blood between patients with PC, healthy subjects (HS) and patients with chronic pancreatitis (CP); and (2) to identify panels of miRNAs for early diagnosis of PC. Methods: Case-control study. 409 patients with PC, 33 patients with other periampullary cancers (PAC) and 25 patients with CP were included prospectively in the Danish BIOPAC biomarker study. 312 blood donors were included as HS. MiRNA expressions in pretreatment 2.5 ml whole blood samples collected in PAXgene RNA tubes were investigated in three independent cohorts: “Discovery Study” (PC n=143, CP n=18, HS n=69); “Training Study” (PC n=180, HS n=199); and “Validation Study” (PC n=86, PAC n=33, CP n=7, HS n=44). TaqMan Human MicroRNA assay was used to screen 754 miRNAs in the “Discovery Study”. Fluidigm BioMark PCR System was used in the “Training Study” (38 miRNAs) and “Validation Study” (13 miRNAs). Results: The “Discovery Study” demonstrated that 38 miRNAs (out of a total of 754 miRNAs) in whole blood were significantly deregulated between patients with PC and controls. These miRNAs were tested in the “Training Study” and two diagnostic indexes were constructed including 4 miRNAs in bPANmiRC index I (= miR-150 + miR-636 – miR-145 – miR-223) or 10 miRNAs in bPANmiRC index II (= 6.9275 – 0.2134xmiR-122 – 0.3560xmiR-34a – 0.8577xmiR-145 + 1.0043xmiR-636 – 0.6725xmiR-223 + 0.7018xmiR-26b – 0.3233xmiR-885.5p + 1.1304xmiR-150 – 0.2204xmiR-126* - 0.1730xmiR-505) (AUC 0.86/0.93, sensitivity 85%/85% and specificity 64%/85%). Conclusions: We identified two diagnostic indexes, using 4 or 10 miRNAs in peripheral whole blood, with a potential clinical value in the evaluation of patients with uncharacteristic symptoms to identify PC at an early stage.
Different mechanisms involved in the activity of BAY 43-9006 (Sorafenib) in human pancreatic cancer cell lines
Authors: Paola Ulivi, Chiara Arienti, Anna Tesei, Francesco Fabbri, Wainer Zoli, Ivan Vannini, Silvia Carloni, Giovannni Brigliadori, Dino Amadori, Daniele Calistri, Rosella Silvestrini
Journal: Cancer Research (2008)

2809  Aim: To analysethe molecular mechanisms underlying the activity of sorafenib (BAY-43-9006) in human pancreatic cancer cell lines characterized by different basal activation of the RAF --> MEK --> MAPK pathway.  Methods: The study was carried out on four commercial cell lines (t3m4, Capan 1, Capan 2, MiaPaca 2).Cell viability was determined using the sulforhodamine B colorimetric assay. Cell cycle perturbations were analyzed by flow cytometry using propidium iodide and apoptosis was evaluated by TUNEL and Annexin-V assays. Mitochondrial membrane depolarization was assessed by JC-1 assay using flow cytometry. The expression of proliferation and apoptotic markers was assessedby western blot and Real Time PCR analyses.  Results: Sorafenib exerted an antiproliferative effect on all the four pancreatic cell lines, with a time-dependent induction of cell cycle perturbations and apoptosis. Mechanisms of apoptosis induction were analyzed in Capan 1 and in t3m4 cell lines characterized by high and low basal levels, respectively, of MEK and MAPK phosphorylation. In Capan 1, sorafenib activity was associated withthe inhibition of the MEK/MAPK pathway, the induction of apoptosis in up to 35% of cells after 72 h of treatment, dephosphorylation of BAD Ser122, upregulation of PUMA, and caspase-3 and -9 cleavage. Antiapoptotic Mcl-1 and Bcl-2 proteins were upregulated. In t3m4 cell line, sorafenib showed MEK/MAPK-independent activity involving a rapid decrease in Mcl-1 expression, BAD Ser 122 phosphorylation, and AKT expression and phosphorylation. These events were accompanied by an early induction of apoptosis starting after 8 h of treatment, which reached 60% at the longest times of treatment, upregulation of PUMA, and caspase-3 and -9 cleavage.  Conclusions: Sorafenib would seem to induce apoptosis through different mechanisms involving the MEK/MAPK pathway in cells basally expressing these phosphorylated proteins, or the AKT and Mcl-1 pathways in cells expressing very low levels of the activated form of MEK/MAPK.
Mohammad Afzal Mir
Authors: Anne Freeman, Farooq Mir, Deborah Komianos, Bob Ryder
Journal: BMJ (2019)

Afzal Mir will be remembered for many years to come as an inspirational teacher by the thousands of doctors who have passed through his unit as medical students and junior doctors. He will be remembered fondly by all his friends and colleagues as a true gentleman, a generous host, and, above all, as an outstanding clinician. He will be lovingly remembered by his wife and three children as a truly wonderful family man.

Afzal was born on 6 May 1936 in Trehgam, Kashmir, the son of M Abdullah Mir, a farmer, and his wife, Taj. He was the third born of 10 children. At school he was top of his year all the way through. He won a scholarship to study medicine at G R Medical College in Gwalior, where he received the scholarship of merit during all five years in medical school, together with first prize and certificates of honour in anatomy and physiology, and in forensic medicine. He graduated MB BS from Vikram University, Ujjain, in 1962. Vikram University was the awarding body for three medical schools, and Afzal graduated fifth out of a total of 500 students. His internship was at S M H S Hospital in Srinagar, Kashmir.

In May 1962, Afzal and four friends left Kashmir in a bid to escape for a better future. They walked across the border in the thick of night in their office shoes …