tbuckley/cabot-search huggingface dataset:
Association of <i>CYP1A1</i> A4889G and T6235C polymorphisms with the risk of breast cancer in Brazilian women.
Authors: Camila Borges Martins Oliveira, Cassio Cardoso-Filho, Leonardo Da Silveira Bossi, Maria Salete Costa-Gurgel, Gustavo Jacob Lourenco, Carmen Silvia Passos Lima
Journal: Journal of Clinical Oncology (2013)

e11551 Background: Estrogen, activated by cytochrome P450 enzymes (CYP1A1), participates in the breast cancer (BC) development. G and C variant alleles of CYP1A1 A4889G and T6235C polymorphisms encode enzymes with increased activity in activation of this compound when compared with the respective wild alleles. This study aimed to clarify the roles of the polymorphisms in the risk of BC. Methods: CYP1A1 A4889G and T6235C genotypes of 742 sporadic breast cancer (SBC) patients (median age: 52 years, 638 Caucasians, 104 non-Caucasians) and 742 healthy women (median age: 40 years, 638 Caucasians, 104 non-Caucasians) were obtained in genomic DNA by PCR and enzymatic digestion. Results: Patient’s and control’s samples were in HW equilibrium at CYP1A1 A4889G (χ2= 0.15, P= 0.70; χ2= 1.15, P= 0.28) and T6235C (χ2= 2.65, P= 0.10; χ2= 1.93, P= 0.16) loci. The frequency of CYP1A1 4889AG+GG genotypes was higher in patients than in controls (29.0% versus 23.2%, P= 0.004). Carriers of the G allele were under a 1.50 (95% CI: 1.14-1.97)-fold increased risk for SBC than those with the wild AA genotype. The frequencies of 4889AG+GG genotypes in Caucasian SBC patients were higher than those found in Non-Caucasian (30.4% vs 20.2%, P= 0.03), and also in controls (30.4% vs 23.2%, P= 0.002). Carriers of G allele were under a 1.61 (95% CI: 1.20-2.15)-fold increased risk for SBC than others. A higher frequency of the CYP1A1 4889AG+GG genotypes was also seen in patients with an earlier median age at first full-term pregnancy (FFTP), compared to those who had the first pregnancy with a later medium age (33.8% vs 26.1%, P=0.03), and also when compared to controls (33.8% vs 23.2%, P= 0.001). Women with the CYP1A1 4889AG+GG genotypes and with earlier FFTP were under a 1.87 (95% CI: 1.32-2.67)-fold increased risk for SBC than others. The CYP1A1 6235CC genotype was more common in pre-obese or obese SBC patients than in underweight or normal SBC patients (6.8% vs 4.0%, P= 0.04). Conclusions: Our data suggest that CYP1A1 A4889G and T6235C polymorphisms alter BC risk in Brazilian women. We believe that women with variant alleles of the referred polymorphisms should receive additional medical attention for disease prevention and early diagnosis.
Intracellular metabolism of antibody-drug conjugates: identification and quantitation of released drugs
Authors: Stephen C. Alley, Nicole M. Okeley, Russell J. Sanderson, Vajira Nanayakkara, Robin L. Campbell, Toni B. Kline, Svetlana O. Doronina, Scott C. Jeffrey, Dennis Benjamin, Peter D. Senter
Journal: Cancer Research (2006)

1992  Antibody-drug conjugates (ADCs) target drugs to the lysosomes of antigen-positive cells. To exert their biological activity, these drugs must be cleaved from the antibody and then reach their cellular targets. We have used protease-sensitive linkers and non-cleavable linkers to tether the potent antimitotic agents monomethylauristatin E and F to reduced disulfides of the anti-CD30 monoclonal antibody cAC10. These ADCs are active against a wide variety of CD30 positive cell lines in vitro and in vivo. cAC10- maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbamyl-MMAE employs a protease-sensitive, self-immolative spacer that was designed to release MMAE. In cells, we find that MMAE is indeed released and that it is the exclusive cellular metabolite. In contrast, cAC10-maleimidocaproyl-MMAF has no obvious drug release mechanism but has potent cytotoxic activity. We have found that a prominent cellular metabolite is the cysteine adduct of maleimidocaproyl-MMAF. While cysteine-maleimidocaproyl-MMAF is weakly potent as a free drug, likely due to poor cellular uptake, specific intracellular delivery demonstrated that cysteine-maleimidocaproyl-MMAF is a potent intracellular metabolite, showing the value of antibody-targeted delivery. The source of the cysteine appears to be from the antibody following lysosomal proteolysis rather than from free intracellular cysteine. Additional non-cleavable drug-linkers attached through lysines and cysteines similarly released drugs in the form of lysine-linker-drug and cysteine-linker-drug, respectively. Despite the requirement for antibody degradation in the lysosome to release drug, we find this to be a rapid and efficient process. The amount of cellular ADC metabolism is not completely accounted for by cysteine-maleimidocaproyl-MMAF, and the balance might be from larger cysteine-containing antibody peptides linked to maleimidocaproyl-MMAF. These results demonstrate that a variety of cleavable and non-cleavable linkage systems can be used to build auristatin ADCs, and that upon internalization these ADCs are rapidly metabolized to discrete, high-potency cytotoxic agents.
Response to: ‘Association between proton pump inhibitors therapy and fracture risk in patients with rheumatoid arthritis’ by Lai <i>et al</i>
Authors: Gulsen Ozen, Kaleb Michaud
Journal: Annals of the Rheumatic Diseases (2019)

Response to: 'Association between proton pump inhibitors therapy and fracture risk in patients with rheumatoid arthritis' by Lai et alWe appreciate Lai et al 1 for sharing their data and emphasising the lack of association between proton pump inhibitor (PPI) use and fracture risk in a different patient population.We agree that the adverse association found with PPI use and fracture in the previous studies has not been repeated in many other well-designed studies.Our study has tested this association for the first time in a disease state like rheumatoid arthritis (RA) where the risk of osteoporosis and fractures are already increased. 2As Lai et al emphasise our study is consistent with the prior studies in the general population that PPIs are not associated with increased fracture risk in patients with RA.However, we have to indicate that we did not evaluate different PPI doses and types which may have different risk estimates.We also agree that there is not enough evidence to recommend routine bone density testing neither for RA patients nor patients without any inflammatory disease unless they have other risk factors.Despite this, we want to emphasise that our study did not evaluate other potential health effects of PPIs in RA patients such as increased risk of community-acquired pneumonia, 3 and Clostridioides difficile and other enteric infections. 4 5Although PPI use is quite common in RA due to common use of nonsteroidal anti-inflammatory drugs, glucocorticoids or antiplatelets, we believe that the necessity of PPIs and other medications should be regularly reviewed in RA to minimise polypharmacy and accordingly potential drug interactions and other adverse events of these medications.
An Organ-On-A-Chip Engineered Platform to Study the Microbiota–Gut–Brain Axis in Neurodegeneration
Authors: Manuela Teresa Raimondi, Diego Albani, Carmen Giordano
Journal: Trends in Molecular Medicine (2019)

After decades of research, the etiology of neurodegenerative disorders such as Alzheimer's or Parkinson's disease is still mostly unknown. Recent findings indicate that the microorganisms in the human gut might be involved in neurodegenerative pathways. Here, we discuss an innovative groundbreaking bioengineering approach that could make a difference in this intriguing scenario.
Noninvasive Imaging to Assess Atherosclerotic Plaque Composition and Disease Activity
Authors: Marwa Daghem, Rong Bing, Zahi A. Fayad, Marc R. Dweck
Journal: JACC. Cardiovascular imaging (2019)

Cardiovascular disease is one of the leading causes of mortality and morbidity worldwide. Atherosclerosis imaging has traditionally focused on detection of obstructive luminal stenoses or measurements of plaque burden. However, with advances in imaging technology it has now become possible to noninvasively interrogate plaque composition and disease activity, thereby differentiating stable from unstable patterns of disease and potentially improving risk stratification. This manuscript reviews multimodality imaging in this field, focusing on carotid and coronary atherosclerosis and how these novel techniques have the potential to complement current imaging assessments and improve clinical decision making.
Abstract #1969: Ubc9 promotes breast tumor metastasis in a sumoylation-independent manner
Authors: Shoumin Zhu, Yin-Yuan Mo
Journal: Cancer Research (2009)

Ubc9 is an E2 conjugating enzyme that transfers the activated SUMO (small ubiquitin-related modifier) to protein substrates, and thus it plays a critical role in sumoylation-mediated cellular pathways. However, Ubc9 may also exert its function independent of sumoylation. We have previously reported that Ubc9 promotes tumor growth in the xenograft mouse model using breast cancer cell line MCF-7 in part through regulation of Bcl-2 expression. In this study, we show that ectopic expression of wild type Ubc9 (Ubc9-WT) promotes cell invasion and metastasis. Surprisingly, the SUMO defective mutant Ubc9 (Ubc9-DN) also causes the same phenotype, indicating that the ability of Ubc9 to promote invasion and metastasis is separable from its ability to conjugate SUMO to protein substrates. Of considerable interest, several microRNAs such as miR-224 are regulated by Ubc9. While ectopic expression of Ubc9 causes downregulation of miR-224, and suppression of Ubc9 by Ubc9-siRNAs leads to its upregulation. We further demonstrate that miR-224 can inhibit cell invasion and directly targets CDC42 and CXCR4 which are well known for their role in cell migration and metastasis. Together, these results demonstrate a molecular link between Ubc9 and the metastasis genes such as CDC42 and CXCR4, and thus provide new insight into the mechanism of Ubc9-mediated tumor metastasis. (supported by grants CA102630 from NCI and postdoctoral fellowship from IDPH ).  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1969.
Precision Therapy for Aggressive Endometrial Cancer by Reactivation of Protein Phosphatase 2A
Authors: Kaitlin Haines, Gloria S. Huang
Journal: Cancer Research (2019)

Abstract Critically important to reducing uterine cancer mortality is the development of more effective therapy for aggressive endometrial cancers, including uterine serous cancer and uterine carcinosarcoma, which together account for over half of deaths due to endometrial cancer. About one-third of these aggressive endometrial cancers harbor mutations in the protein phosphatase 2A (PP2A) Aα scaffold subunit encoded by PPP2R1A. In this issue, the study by Taylor and colleagues elucidates the role of a highly recurrent PP2A-Aα–subunit mutation PPP2R1A P179R as a biological driver of aggressive endometrial cancer. Compelling data demonstrate that the P179R mutation alters PP2A-Aα protein conformation, impairing holoenzyme formation and reducing PP2A phosphatase activity to promote endometrial cancer progression. Restoration of wild-type PPP2R1A in P179R-mutant endometrial cancer cells increases phosphatase activity and inhibits tumor growth in vivo. Furthermore, a small-molecule activator of PP2A (SMAP) phenocopies restoration of wild-type PPP2R1A to suppress tumor growth. These promising results are an important advance toward effective precision therapy for aggressive endometrial cancer. See related article by Taylor et al., p. 4242
Imaging with FLT-PET demonstrates that PF-477736, an inhibitor of CHK1 kinase, overcomes a cell cycle checkpoint induced by gemcitabine in PC-3 xenografts
Authors: G. A. McArthur, J. Raleigh, A. Blasina, C. Cullinane, D. Dorow, N. Conus, R. J. Hicks, J. Kornmann, E. Chen, T. J. McCarthy, K. Anderes
Journal: Journal of Clinical Oncology (2006)

3045 Background: The development of strategies to monitor the molecular and cellular response to novel agents that target the cell cycle is vital to provide proof of mechanism and biological activity of these compounds. The protein kinase CHK1 is activated following DNA damage in the S and G2-phases of the cell cycle and mediates cell cycle arrest. In vitro studies demonstrate that inhibition of CHK1 can overcome cell cycle arrest induced by DNA damage and enhance cytotoxic activity of DNA damaging agents. In vivo studies show that combining DNA damaging agents with a CHK1 inhibitor potentiates antitumor activity. We hypothesize that functional imaging with 18F-fluorine-L-thymidine (FLT), a PET-tracer where tumor uptake is maximal in the S and G2 phases of the cell cycle can be used to non-invasively monitor the induction and therapeutic inhibition of a cell cycle checkpoint in vivo. Methods: Nude mice harbouring PC-3 xenografts were treated with vehicle controls, gemcitabine, the CHK1-inhibitor PF-477736 or gemcitabine + PF-477736. FLT-PET scans were performed and tumors harvested for ex-vivo biomarkers to assess S-phase, M-phase and DNA-repair. Results: Gemcitabine induced a 8.3 ±0.8 fold increase in tumoral uptake of FLT at 21 hours that correlated with a 3.3 ±0.2-fold increase in thymidine kinase activity and S-phase arrest as demonstrated by BrdU incorporation and elevated expression of cyclin-A. Treatment with PF-477736 at 17 hours after gemcitabine abrogated the early FLT-flare at 21 hours by 82% (p&lt;0.001). This was associated with both an increased fraction of cells in mitosis and G1-phase of the cell cycle as determined by phos-histone H3 and flow cytometry. Furthermore, the combination of gemcitabine and PF-477736 enhanced DNA damage as measured by phos-gamma-H2AX and significantly delayed tumor growth when compared to tumors treated with gemcitabine alone. Conclusion: These data clearly indicate that the CHK1-inhibitor PF-477736 can overcome the cell cycle checkpoint induced by gemcitabine and increase associated DNA damage in tumors in-vivo. The PET studies indicate that functional imaging with FLT-PET is a promising strategy to monitor responses to therapeutic agents that target cell cycle checkpoints. [Table: see text]
Institutional Review Boards (IRBs) Render “Coercion as Subjection” Implausible
Authors: Ilene Wilets, Glenn Martin, Theodore Bania
Journal: The American Journal of Bioethics (2019)

Millum and Garnett’s target article (2019) asserts that payment for research participation can be coercive, placing potential research participants in a position in which they have no choice but to...
Repurposing antimycotic ciclopirox olamine as a promising anti-ischemic stroke agent
Authors: Hongxuan Feng, Linghao Hu, Hongwen Zhu, Lingxue Tao, Lei Wu, Qinyuan Zhao, Yemi Gao, Qi Gong, Fei Mao, Xiaokang Li, Hu Zhou, Jian Li, Haiyan Zhang
Journal: Acta Pharmaceutica Sinica B (2019)

Ischemic stroke is a severe disorder resulting from acute cerebral thrombosis. Here we demonstrated that post-ischemic treatment with ciclopirox olamine (CPX), a potent antifungal clinical drug, alleviated brain infarction, neurological deficits and brain edema in a classic rat model of ischemic stroke. Single dose post-ischemic administration of CPX provided a long-lasting neuroprotective effect, which can be further enhanced by multiple doses administration of CPX. CPX also effectively reversed ischemia-induced neuronal loss, glial activation as well as blood-brain barrier (BBB) damage. Employing quantitative phosphoproteomic analysis, 130 phosphosites in 122 proteins were identified to be significantly regulated by CPX treatment in oxygen glucose deprivation (OGD)-exposed SH-SY5Y cells, which revealed that phosphokinases and cell cycle-related phosphoproteins were largely influenced. Subsequently, we demonstrated that CPX markedly enhanced the AKT (protein kinase B, PKB/AKT) and GSK3β (glycogen synthase kinase 3β) phosphorylation in OGD-exposed SH-SY5Y cells, and regulated the cell cycle progression and nitric oxide (NO) release in lipopolysaccharide (LPS)-induced BV-2 cells, which may contribute to its ameliorative effects against ischemia-associated neuronal death and microglial inflammation. Our study suggests that CPX could be a promising compound to reduce multiple ischemic injuries; however, further studies will be needed to clarify the molecular mechanisms involved.
Abstract 10592: Impact of Pulmonary Hypertension on In-Hospital Outcomes in Patients Undergoing Transcatheter Mitral Valve Repair With Mitraclip
Authors: Abdelrahman Ahmed, Emmanuel Akintoye, Oluwole Adegbala, Ahmed Yassin, Ahmed Subahi, Hossam Abubakar, Lamin Bangura, Sajid Ali, Mustafa Ajam, Adel Elmoghrabi, Antonio Smith, Yasir Abdelgadir, Amir kaki, Mahir Elder, Mohamed Shokr, Luis Afonso
Journal: Circulation (2018)

Introduction: In-hospital outcomes of transcatheter mitral valve repair (TMVR) with Mitraclip in patients with mitral valve regurgitation and pulmonary hypertension (PH) are not well studied. Metho...
Exercise-Induced Cardiac Troponin I Increase and Incident Mortality and Cardiovascular Events
Authors: Vincent L. Aengevaeren, Maria T.E. Hopman, Paul D. Thompson, Esmée A. Bakker, Keith P. George, Dick H.J. Thijssen, Thijs M.H. Eijsvogels
Journal: Circulation (2019)

Blood concentrations of cardiac troponin above the 99th percentile are a key criterion for the diagnosis of acute myocardial injury and infarction. Troponin concentrations, even below the 99th percentile, predict adverse outcomes in patients and the general population. Elevated troponin concentrations are commonly observed after endurance exercise, but the clinical significance of this increase is unknown. We examined the association between postexercise troponin I concentrations and clinical outcomes in long-distance walkers. We measured cardiac troponin I concentrations in 725 participants (61 [54-69] yrs) before and immediately after 30 to 55 km of walking. We tested for an association between postexercise troponin I concentrations above the 99th percentile (>0.040 µg/L) and a composite end point of all-cause mortality and major adverse cardiovascular events (myocardial infarction, stroke, heart failure, revascularization, or sudden cardiac arrest). Continuous variables were reported as mean ± standard deviation when normally distributed or median [interquartile range] when not normally distributed. Participants walked 8.3 [7.3-9.3] hours at 68±10% of their maximum heart rate. Baseline troponin I concentrations were >0.040 µg/L in 9 participants (1%). Troponin I concentrations increased after walking (P<.001), with 63 participants (9%) demonstrating a postexercise troponin concentration >0.040 µg/L. During 43 [23-77] months of follow-up, 62 participants (9%) experienced an end point; 29 died and 33 had major adverse cardiovascular events. Compared with 7% with postexercise troponin I ≤0.040 µg/L (log-rank P<.001), 27% of participants with postexercise troponin I concentrations >0.040 µg/L experienced an end point. The hazard ratio was 2.48 (95% CI, 1.29-4.78) after adjusting for age, sex, cardiovascular risk factors (hypertension, hypercholesterolemia or diabetes mellitus), cardiovascular diseases (myocardial infarction, stroke, or heart failure), and baseline troponin I concentrations. Exercise-induced troponin I elevations above the 99th percentile after 30 to 55 km of walking independently predicted higher mortality and cardiovascular events in a cohort of older long-distance walkers. Exercise-induced increases in troponin may not be a benign physiological response to exercise, but an early marker of future mortality and cardiovascular events.
Abstract #1197: Leukocyte cell-derived chemotaxin 2 (LECT2) gene expression can influence intravasation and metastatic ability of hepatoma cells through in vivo study
Authors: Ching-Yao Yang, Yu-Ling Wu, Wei-Jiunn Lee, Wan-Chin Chung, Chieh-Hsiu Lu, Min-Liang Kuo
Journal: Cancer Research (2009)

Background: In our previous study, LECT2 was identified to have correlation with vascular invasion status of human hepatocellular carcinoma through suppression subtractive hybridization and cDNA microarray. We also found LECT2 gene expression level was correlated with invasion ability of hepatoma cell lines. Purpose: We would like to study whether gene expression level of LECT2 can also influence the vascular invasion or metastatic ability of hepatoma cells through in vivo experiments. Methods: LECT2 gene overexpression and knockdown hepatoma cell lines was established in SK-Hep1 and Huh7 cells, respectively. Intravasation CAM assay, and experiments of orthotopic liver injection of cancer cells in SCID mice were performed to evaluate the influence of LECT2 gene expression on these cells. Results: In intravasation CAM assay, we found LECT2 gene overexpression can inhibit intravasation ability of SK-Hep1 cells. When LECT2 gene was knockdown in Huh7 cells, the intravasation ability was increased significantly. After orthotopic liver injection of Huh shLECT2 cells or Huh7 Luc (control) cells, we found prominent difference of metastatic nodules in both liver and lung. Prominent increase of the culture rate of cancer cells from the aspirated IVC blood of the SCID mice was noted in LECT2 knockdown group. Conclusion: The different expression level of LECT2 gene can influence the intravasation and metastatic ability of hepatoma cells through in vivo study.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1197.