tbuckley/cabot-search huggingface dataset:
Use of optical biomarkers from nondysplastic metaplastic cells on the detection of high-grade dysplasia and adenocarcinoma from Barrett’s esophagus.
Authors: Randall Brand, Sumera Rizvi, Jon M. Davison, Rajan Bista, Kevin Staton, Douglas Hartman, Kenneth Fasanella, Kevin McGrath, Yang Liu
Journal: Journal of Clinical Oncology (2012)

14 Background: Patients with Barrett’s esophagus (BE), defined as presence of intestinal metaplasia (IM) in the esophagus, require surveillance due to an increased risk of developing esophageal adenocarcinoma (EAC). The biggest challenge in the current surveillance methodology (i.e., Seattle protocol) is random sampling with the inability to identify those patients with non-dysplastic BE on surveillance who have occult high grade dysplasia (HGD) or will eventually progress to HGD or EAC. We propose a novel approach based on the concept of field effect to detect HGD or EAC through the analysis of non-dysplastic IM, thus identifying a high risk BE population. Our group uses a unique microscope – spatial-domain low-coherence quantitative phase microscopy (SL-QPM) to detect changes in nuclear structure as small as 0.9 nm, a scale 1000 times smaller than what conventional microscopy detects. We hypothesize that the SL-QPM-derived optical biomarkers of non-dysplastic IM would distinguish BE patients with EAC/HGD from those without neoplasia. Methods: We performed a retrospective study of 60 BE patients who underwent Seattle protocol biopsies: 33 BE patients with IM only and 27 BE patients with HGD or EAC (21 HGD, 6 EAC). H&amp;E stained slides with non-dysplastic IM on review by an expert pathologist were used. The distance between the selected IM biopsy and HGD/EAC was 1 to 4 cm. Forty to 60 columnar cells from each case were analyzed. Results: We identified three optical biomarkers (nuclear optical path length, intra-nuclear uniformity, entropy) that can distinguish non-dysplastic BE from patients with HGD and EAC with statistical significance (P &lt; 0.01). A prediction model combining all three optical biomarkers can distinguish BE patients with HGD/EAC from those with IM only at 89% sensitivity and 76% specificity (accuracy = 0.87). Conclusions: The accurate assessment of nanoscale optical biomarkers by SL-QPM is a promising approach for detecting dysplastic/neoplastic Barrett’s epithelium from non-dysplastic IM. This approach could potentially simplify BE surveillance by identifying a subset of high-risk BE patients that warrant intensive surveillance.
Clinical implications of Mycobacterium chimaera detection in thermoregulatory devices used for extracorporeal membrane oxygenation (ECMO), Germany, 2015 to 2016
Authors: Franziska C. Trudzinski, Uwe Schlotthauer, Annegret Kamp, Kai Hennemann, Ralf M. Muellenbach, Udo Reischl, Barbara Gärtner, Heinrike Wilkens, Robert Bals, Mathias Herrmann, Philipp M. Lepper, Sören L. Becker
Journal: Eurosurveillance (2016)

Mycobacterium chimaera, a non-tuberculous mycobacterium, was recently identified as causative agent of deep-seated infections in patients who had previously undergone open-chest cardiac surgery. Outbreak investigations suggested an aerosol-borne pathogen transmission originating from water contained in heater-cooler units (HCUs) used during cardiac surgery. Similar thermoregulatory devices are used for extracorporeal membrane oxygenation (ECMO) and M. chimaera might also be detectable in ECMO treatment settings. We performed a prospective microbiological study investigating the occurrence of M. chimaera in water from ECMO systems and in environmental samples, and a retrospective clinical review of possible ECMO-related mycobacterial infections among patients in a pneumological intensive care unit. We detected M. chimaera in 9 of 18 water samples from 10 different thermoregulatory ECMO devices; no mycobacteria were found in the nine room air samples and other environmental samples. Among 118 ECMO patients, 76 had bronchial specimens analysed for mycobacteria and M. chimaera was found in three individuals without signs of mycobacterial infection at the time of sampling. We conclude that M. chimaera can be detected in water samples from ECMO-associated thermoregulatory devices and might potentially pose patients at risk of infection. Further research is warranted to elucidate the clinical significance of M. chimaera in ECMO treatment settings.
Leukemia Stem Cells (LSCs) Are Frequent in Childhood Precursor B Acute Lymphoblastic Leukemia (ALL).
Authors: Sebastien Morisot, Alan S Wayne, Osnat Bohana-Kashtan, Ian M Kaplan, Richard Hildreth, Patrick Brown, Maryalice Stetler-Stevenson, Curt I Civin
Journal: Blood (2008)
CD151 as a prognostic indicator in malignancy of the bladder and prostate.
Authors: A. Williams, V. McPherson, C. Martinez, C. Vasquez, S. Chan, J. Gomez-Lemus, K. Rizkalla, V. Chalasani, R. Rajgopal, A. Zijlstra
Journal: Journal of Clinical Oncology (2011)

295 Background: CD151 is a tetraspanin protein linked to cellular growth and motility. Recent work has suggested that CD151 may play a role in metastases in a variety of cancers, but as yet there is no evidence that it plays a role in transitional cell carcinoma of the bladder (TCC) or prostate adenocarcinoma (PCa). We wished to check the protein expression of CD151 in radical cystectomy (RC) and radical prostatectomy (RRP) tumour specimens to look for any association with disease progression and survival. Methods: Tissue was attained from 99 patients who had undergone RRP for PCa (mean follow up 12.4 years) and from 67 patients undergoing RC for TCC (mean follow up 5.75 years). Tissue sections were taken from paraffin embedded slides and imunohistochemical staining performed for CD151. Histological sections from corresponding levels were stained with H&amp;E and compared for CD151 positivity. A database of patient's demographic factors, disease factors and relevant survival information was generated and correlated with disease-free progression and survival. Results: In the RRP group there was a statistically significant difference in CD151 expression between malignant tissue and benign tissue around (p = 0.01) and away from the tumour (p &lt; 0.01). CD151 positivity was statistically associated with biochemical failure p = 0.022 following RRP; Gleason grade and tumor stage were not significantly associated with recurrence in this cohort. CD151 positivity did not correlate with biochemical failure following RC, although tumour stage and nodal status were strong predictors of recurrence. Conclusions: Patients with PCa specimens that stained positively for CD151 were more likely to develop disease recurrence. This study was probably underpowered to show that Gleason score and tumour stage can predict recurrence suggesting that CD151 positivity may be a more sensitive indicator or risk of recurrence in patients following RRP. We speculate that CD151 may have a clinical role in predicting those who may benefit from adjuvant treatment following RRP. While we were able to demonstrate that CD151 seems important in PCa, CD151 does not appear to have any clinical role in predicting recurrence of TCC following RC. No significant financial relationships to disclose.
Impact of Interleukin-10 Gene Promoter Polymorphisms on Clinical Course of Chronic Lymphocytic Leukemia
Authors: Ewa Lech-Maranda, Tadeusz Robak, Miroslaw Majewski, Monika Lewandowska, Grazyna Nowak, Olga Grzybowska-Izydorczyk, Anna Szmigielska-Kaplon, Krzysztof Warzocha
Journal: Blood (2008)
The effect of acute and chronic exposure to acetaldehyde—a mutagenic metabolite of dietary ethanol—on prostate cancer cells: A potential source of race disparity disfavoring black men.
Authors: Lionel Lloyds Banez, Anthony Kyle Davidson, Wiguins Etienne, Emma H Allott, Elizabeth Ellen Calloway, Brant Allen Inman
Journal: Journal of Clinical Oncology (2012)

143 Background: We recently reported that the ADH1B*3 allele, which is specific to African Americans (AA), when combined with ethanol intake may constitute a gene-environment interaction leading to elevated prostate cancer (CaP) and potentially aggressive CaP risk among AA men possibly through intra-prostatic acetaldehyde accumulation. Indeed, studies have shown microsomes from rat ventral prostates biotransform ethanol to acetaldehyde that further metabolizes into oxidative stress-inducing acetyl radicals. In addition, acetaldehyde has been previously shown to enhance proliferation of colon cancer cells. Whether acetaldehyde has the same effect on CaP is unknown. Methods: We subjected DU-145 CaP cells to varying concentrations of acetaldehyde using acute and chronic models of exposure and measured tumor proliferation using MTS assay. Proliferation was measured over 4 days of acetaldehyde treatment in acute and after 2 weeks of treatment in chronic exposure experiments. All experiments were conducted in triplicate. Results were expressed as mean values for each treatment referenced to untreated cells. Doubling times were calculated using least squares fitting exponential regression. Results: In the acute exposure model, proliferation of DU-145 cells was inhibited by 150 uM acetaldehyde by 28% while 1,500uM and higher concentrations resulted in complete inhibition of proliferation. After chronic exposure to acetaldehyde, proliferation of DU-145 cells was inhibited by 500 uM acetaldehyde by 19%. In contrast, chronic exposure with 1,000 uM acetaldehyde resulted in increased proliferation by 9% and shortened tumor doubling time. Conclusions: Acute exposure to acetaldehyde resulted in inhibition of CaP cellular proliferation. Chronic exposure to high acetaldehyde concentrations promoted tumor proliferation likely through selection for more robust CaP cells that survive the repeated chemical insult. Our results suggest that chronic acetaldehyde exposure of existent CaP may potentially promote disease aggressiveness. Uncovering mechanisms for enhanced CaP cell proliferation by acetaldehyde are warranted.
Prognostication by multigene proliferative marker panel compared with Ki-67 in small-intestinal NENs.
Authors: Ben Lawrence, Simon Schimmack, Bernhard Svejda, Ignat Drozdov, Daniele Alaimo, Barton Kenney, Mark Kidd, Irvin M Modlin
Journal: Journal of Clinical Oncology (2012)

242 Background: Ki-67 is the major proliferative marker in clinical use to determine neuroendocrine neoplasm (NEN) prognosis. Ki-67 is unable to predict the outcome of SI-NENs, as the majority have a low (≤2) Ki-67%. Therefore, we aimed to identify a sensitive panel of proliferative markers using qRT-PCR to more accurately define the proliferation of these slow growing tumors. Methods: We identified genes with a mechanistic function in cell cycle progression that were over-expressed in RNA microarrays of SI-NENs (n=8) compared to adjacent normal tissue (n=4) (dCHIP, annotation databases). Timing of marker gene expression (qRT-PCR) in proliferating cell-cycle phases (S, G 2 , M) was determined in flow-sorted SI-NEN cell lines (KRJ-1, H-STS) after propidium iodide staining. RNA expression of candidate proliferative markers was then investigated using an in vivo model and two independent tumor datasets, and transcript level compared to Ki-67% protein expression (immunohistochemical staining). Results: Twenty genes with a mechanistic role in proliferation were identified and 17 confirmed to be expressed in proliferating cell cycle phases. Each tumor expressed a unique profile of the 17 proliferative markers. Both Ki-67 protein and Ki-67 RNA transcript levels failed to differentiate in vivo SI-NEN models or patient samples despite variable proliferative capacity (e.g., WDNETs versus WDNECs). Although most tumors showed low levels of Ki-67 expression, the tumors expressed high levels of select alternative proliferative markers. Hierarchical clustering provided a novel and clinically meaningful prognostic classification. Conclusions: Proliferation of individual SI-NENs is regulated by unique combinations of multiple genes with a mechanistic role in cell-cycle progression. Regulation of proliferation in SI-NENs is therefore complex and cannot accurately be defined by Ki-67 as a single marker. A panel of proliferative RNA markers has potential to significantly improve prognostication in patients with SI-NENs.
Phase II study of docetaxel (D) and oxaliplatin (O) in recurrent metastatic transitional cell cancer (mTCC) of the urothelial tract.
Authors: Gurkamal S. Chatta, Leonard Joseph Appleman, David Friedland, Gail Tribble, Diwakar Davar
Journal: Journal of Clinical Oncology (2012)

296 Background: First-line regimens for mTCC of the bladder are either MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) or the cisplatinum-gemcitabine doublet. There is no approved second-line option for mTCC. Both single agent D and O have response rates of 10 to 20%, and O in cisplatin-resistant patients (pts). Hence the combination of D and O may be useful in recurrent mTCC. Methods: The combination of D and O was primarily tested for efficacy in recurrent mTCC. All pts had histologically proven TCC with measurable disease, and had prior treatment with at least 1 platinum-containing regimen. D 60 mg/m2 followed by O 110 mg/m2 were administered every 3 weeks. Pts were evaluated for response every 2 cycles and were treated either till progression or for a maximum of 6 cycles. Results: 22 pts were enrolled of whom 19 were evaluable for response. Median age was 72 years (range 44 – 87). All pts had prior treatment with at least 1 cytotoxic regimen, with 8 pts having received 2 or more prior regimens. The mean number of cycles administered was 3. Of the 19 pts evaluable for efficacy, objective response was documented in two pts (both partial responses), three had stable disease, and the remaining fourteen progressed on therapy for an overall disease stabilization rate of 26%. Median time to progression (TTP) was 3.0 months (95% CI 0.2 to 5.8) and median overall survival (OS) was 7.0 months (95% CI 4.6 to 9.4). Toxicity, evaluated in all 22 patients, was relatively mild: grade 3-4 diarrhea in 6 patients, grade 3-4 hematological toxicity in 4 pts and grade 3-4 fatigue in 1 pt. No grade 3-4 neuropathy was observed and no toxic deaths were noted. The median follow-up period was 7.0 months (95% CI 4.5 to 9.5). Conclusions: The combination of D and O is active in previously treated pts with mTCC. This regimen appears to be well tolerated with overall mild toxicity. Whilst this study was not powered for assessing survival, the presence of stable disease in 26% of pts suggests that further investigation of the combination in carefully selected pts maybe warranted.
Prognostic factors of cancer recurrence and progression in non-muscle-invasive urothelial carcinoma: A multicenter study of over 4,300 patients.
Authors: T. F. Chromecki, R. S. Svatek, S. Holmäng, P. I. Karakiewicz, M. Mazumdar, A. Dunning, A. M. Kamat, S. T. Tagawa, D. Scherr, S. F. Shariat
Journal: Journal of Clinical Oncology (2011)

249 Background: The outcomes of patients with non-muscle-invasive urothelial carcinoma of the bladder (NMIUCB) remain poorly understood. The aim of our study was to identify prognostic factors of cancer recurrence and progression in patients with primary UCB. Methods: We performed a combined analysis on individual data from 4,325 patients with primary NMIUCB. Results: Within a median follow-up of 64 months, 1,960 patients (45.4%) experienced disease recurrence, 498 (11.5%) experienced progression to muscle-invasive stage, 1,155 (26.7%) died of any cause, and 310 (7.2%) died of their cancer. In multivariable Cox regression analysis, advanced age, higher grade, larger tumor size, higher number of tumors, number of prior recurrences, and type of intravesical therapy were independent predictors of disease recurrence and progression. While treatment intravesical chemotherapy was only associated with decreased/delayed cancer recurrence, intravesical BCG therapy was associated with decreased/delayed cancer recurrence and progression. The predictive accuracies of the models for recurrence and progression were 63.5% and 71.3%, respectively. Conclusions: Even in a heterogenous patient population, BCG therapy appears to decrease frequency and delay time to cancer recurrence and progression in patients with NMIUCB. Predictive tools based on combination of multiple clinical variables which capture the biological and clinical potential of nonmuscle-invasive disease could help with patient counseling and individualized risk assessment for adjuvant intravesical therapy and clinical trial design. [Table: see text] No significant financial relationships to disclose.
Advice on sugar and starch is urged in type 2 diabetes counselling
Authors: Jane Feinmann
Journal: BMJ (2016)

GPs have been urged to help patients with type 2 diabetes make informed choices about their treatment, including advice that reducing their daily intake of sugar and starchy carbohydrate could reverse the disorder.

“I have spent 25 years failing patients with type 2 diabetes whose blood sugar levels got worse as they got steadily heavier—and nothing I could say or do made any difference,” said David Unwin, a GP partner in Southport since 1986, who was recently appointed national champion for collaborative care and support planning in obesity and diabetes at the Royal College of General Practitioners. He was speaking at a meeting at the King’s Fund in London on 30 November.

Currently, around 3.2 million …
SF3B1, a Splicing Factor Gene, Is Infrequently Mutated in Rare Bone Marrow Failure Diseases but Still Associated with Ring Sideroblast Phenotype
Authors: Valeria Visconte, Heesun J. Rogers, Ali Tabarroki, Edy Hasrouni, Fabiola Traina, Yang Liu, Christine L. O'Keefe, Jaroslaw P. Maciejewski, Mikkael A. Sekeres, Fred H. Hsieh, Ramon V Tiu
Journal: Blood (2012)
Abstract #3862: Dual action of roscovitine, a selective CDK inhibitor, on human HeLa cervical cancer cells: Inhibition of phosphorylation of cell cycle regulators and repression of HPV-encoded proteins
Authors: Jozefa Wesierska-Gadek, Andreea Borza, Eva Walzi, Margarita Maurer, Oxana Komina, Stefanie Wandl
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Expression of HPV-18-encoded E6 and E7 oncoproteins, inactivating pRb and p53 tumor suppressor proteins, substantially contributes to the escape of human HeLa cervical carcinoma cells from the proper cell cycle control. The aim of the present study was to assess the action of the pharmacological inhibitor targeting specifically the cyclin-dependent kinases (CDKs) on asynchronously growing and synchronized HeLa cells and to prove whether it would be able to restore the restriction checkpoint. Exposure of asynchronously growing human HeLa cervical carcinoma cells to roscovitine (ROSC), a selective cyclin-dependent kinase (CDK) inhibitor, arrests their progression at the transition between G2/M and/or induces apoptosis. The outcome depends on the ROSC concentration. At higher dose ROSC initiates caspase-dependent apoptosis. Inhibition of the site-specific phosphorylation of survivin and Bad, occurring at high-dose ROSC treatment, precedes the onset of apoptosis and is a prerequisite for cell death. Considering the fact that in HeLa cells the G1/S restriction checkpoint is abolished by HPV-encoded E7 oncoprotein, we addressed the question whether the inhibition of CDKs by pharmacological inhibitors in synchronized cells would be able to block the cell cycle in G1 phase. For this purpose, we attempted to synchronize cells by serum withdrawal or by blocking of the mitotic apparatus using nocodazole. Unlike human MCF-7 cells, HeLa cells do not undergo G1 block after serum starvation, but respond with a slight increase of the ratio of G1 population. Exposure of G1-enriched HeLa cells to ROSC after re-feeding does not block their cell cycle progression at G1-phase, but increases the ratio of S- and G2-phase, thereby mimicking the effect on asynchronously growing cells. A quite different impact is observed after treatment of HeLa cells released from mitotic block. ROSC prevents their cell cycle progression and cells transiently accumulate in G1-phase. Moreover, ROSC represses HPV-encoded E6 oncoprotein that coincides with accumulation of p53 protein. These results show that inhibition of CDKs by ROSC in cells lacking the G1/S restriction checkpoint has different outcomes depending on the cell cycle status prior to the onset of treatment and on the dosage. Our results indicate that ROSC at higher concentration blocks transcription of HPV-encoded proteins.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3862.
Most ApoL1 Is Secreted by the Liver
Authors: Khuloud Shukha, Jessica L. Mueller, Raymond T. Chung, Michael P. Curry, David J. Friedman, Martin R. Pollak, Anders H. Berg
Journal: Journal of the American Society of Nephrology (2016)

Two coding sequence variants in the APOL1 gene (G1 and G2) explain much of the increased risk for FSGS, HIV-associated nephropathy, and hypertension-attributed ESRD among people of recent African ancestry. The ApoL1 protein is expressed in a wide variety of cell tissues. It has been assumed that the majority of circulating ApoL1 is produced by the liver, but this has not been shown. Using mass spectrometry, we genotyped and quantified the circulating ApoL1 in two liver transplant recipients whose native APOL1 genotype differed from the genotype of the deceased donors, allowing us to differentiate liver- from nonliver-produced ApoL1. Our findings confirm that the liver is indeed the main source of circulating ApoL1. However, the liver is not the sole source of circulating ApoL1, because we found that residual amounts of native ApoL1 continued to circulate in the blood, even after the liver transplant.