tbuckley/cabot-search huggingface dataset:
Post-finasteride syndrome
Authors: Shelly L Gray, Todd P Semla
Journal: BMJ (2019)

Efforts to explain persistent symptoms are undermined by poor long term data on harms Finasteride, a 5α-reductase inhibitor, was approved in 1992 for the treatment of benign prostatic hyperplasia; a lower dose (1 mg) was approved in 1997 for male pattern baldness. A second 5α-reductase inhibitor, dutasteride, was approved in 2001 for benign prostatic hyperplasia. Emerging post-marketing reports of persistent depression and sexual side effects have led to growing concerns about the safety of 5α-reductase inhibitors and prompted product labelling changes in many regulatory jurisdictions.1234 Since 2008, at least 17 countries including the United Kingdom and the United States have warned prescribers of the potential for depression, sexual side effects, or both with finasteride.5 Post-finasteride syndrome is an ill defined and controversial syndrome associated with a constellation of sexual, physical, and psychological symptoms that develop during or after finasteride exposure and persist after discontinuation (box 1).35 The incidence of post-finasteride syndrome is unknown, as are the biological mechanisms, but we know that 5α-reductase inhibitors reduce synthesis of brain neurosteroids, which affect mood, cognition, and libido.36 Box 1 ### Symptoms of post-finasteride syndrome #### Sexual Libido … RETURN TO TEXT
Amphiregulin activates PTHrP gene expression through the P1-promoter in hypercalcemia inducing lung squamous cell carcinomas
Authors: Ryan Gonterman, Jennifer Gilmore, John Foley
Journal: Cancer Research (2008)

82  Parathyroid hormone-related protein (PTHrP) is the causative factor of the paraneoplastic syndrome humoral hypercalcemia of malignancy (HHM), a complication of lung squamous-cell carcinomas (SCC). The epidermal growth factor receptor (EGFR) has been implicated in activating PTHrP gene expression in lung and breast cancer, as well as cultured keratinocytes. Inhibition of autocrine EGFR signaling has been shown to reduce plasma total calcium concentrations in a lung SCC xenograft model of hypercalcemia. The purpose of this study was to identify the mechanism by which the EGFR is stimulated and how PTHrP gene expression is increased. The tumor-necrosis factor α-converting enzyme (TACE) is the metalloprotease that cleaves EGFR ligands, including amphiregulin (AREG), making them accessible to the EGFR, was detected at high levels in a panel of lung SCCs. These cells were also evaluated by quantitative real-time PCR (QRT-PCR) for mRNA expression of the EGFR ligands; AREG, transforming growth factor-α (TGFα), and heparin binding-epidermal growth factor (HB-EGF). AREG transcript levels were at least 10-fold higher than that of HB-EGF and TGFα, suggesting that AREG is the predominant ligand in lung SCCs. Furthermore, ELISA easily detected AREG in the media of lung SCCs, whereas HB-EGF and TGFα were below the threshold of detection. Exogenous stimulation of lung SCC cells with the prototypical ligand EGF and AREG resulted in a difference in phosphorylation of the EGFR. EGF causes phosphorylation of numerous tyrosine residues, including residue 1045, which is coupled to the ubiquitin pathway and regulates receptor turnover. In contrast, addition of AREG phosphorylated a limited number of tyrosine residues and not 1045. Consistent with this observation, addition of exogenous EGF lead to rapid receptor turnover, whereas stimulation with AREG had no effect on EGFR levels. PTHrP mRNA levels were increased ~10-fold by 3-hours by exogenous EGF and declined after 6-hours. In contrast, addition of AREG generated a prolonged 10-fold increase in PTHrP mRNA up to 10-hours post ligand addition. Finally, we examined how EGFR signaling regulates PTHrP gene expression. We determined that blockade of EGFR signaling does not affect PTHrP mRNA stability, but rather, EGFR signaling regulates PTHrP gene expression through a transcriptional mechanism. Of the three PTHrP promoters (P1, P2, P3), P1-derived transcripts could be completely eliminated by an EGFR inhibitor, and exogenous AREG stimulated P1 mRNA by ~5-fold. Taken together, we provide evidence that autocrine AREG stimulation of EGFR results in prolonged activation of the receptor, transcriptional regulation of the P1 promoter, and high levels of PTHrP gene expression, which together are likely contributing factors to HHM and other cancer-associated bone pathologies.
A common ATM polymorphism associates with bilateral breast cancer
Authors: Katri Heikkinen, Katrin Rapakko, Sanna-Maria Karppinen, Hannele Erkko, Pentti Nieminen, Robert Winqvist
Journal: Cancer Research (2005)

4072  ATM kinase has an essential role in maintaining genomic integrity. Loss of both ATM alleles results in ataxia-telangiectasia (A-T), a rare autosomal recessive neuro-immunologic disorder associated with cancer susceptibility. Individuals heterozygous for germline ATM mutations have been reported to have an increased risk for malignancy, female breast cancer in particular. In the current study, a full mutation analysis of the ATM gene was carried out in patients from 121 breast or breast-ovarian cancer families. A cis position ATM combination allele was found associated with bilateral breast cancer (OR 10.2, 95% CI 3.1-33.8, p=0.001). Although based on a relatively small number of cases, the ATM expression levels of lymphoblast cell lines from heterozygous carriers of this combination allele were lower than from non-carriers (p=0.09). Lowered gene expression levels may have direct influence on the activities in DNA damage recognition and response pathways, and other genome integrity maintenance functions. Based on the results, we propose a cancer risk modifying effect for the studied ATM composite allele.
Mutational spectra of trans-1,2-dihydroxy-1,2-dihydro-6-hydroxylaminochrysene (1,2-DHD-6-NHOH-C), a putative ultimate carcinogenic metabolite of the environmental mammary carcinogen 6-nitrochrysene (6-NC), in a lacI mammary epithelial cell line
Authors: Yuan-Wan Sun, Zhong-Lin Zhao, Joseph Guttenplan, Wieslawa Kosinska, Jacek Krzeminski, Shantu Amin, Karam El-Bayoumy
Journal: Cancer Research (2007)

894  The cause of most breast cancers remains unknown. Environmental pollutants [e.g. nitroaromatics (NO2-PAH)] that are known to induce mammary cancer in rodents must be regarded as potential human carcinogens; a representative example is 6-NC. We previously showed that trans-1,2-dihydroxy-1,2-dihydro-6-nitrochrysene (1,2-DHD-6-NC) is the proximate mutagen/carcinogen and the structure of the major DNA adduct in the mammary gland of rats treated with 6-NC is derived from nitroreduction of 1,2-DHD-6-NC suggesting that the corresponding hydroxylamine 1,2-DHD-6-NHOH-C is the ultimate mutagenic/carcinogenic metabolite. Therefore 1,2-DHD-6-NHOH-C was synthesized and its mutation frequency and mutation spectra (MS) were assessed in cultured lacI rat mammary epithelial cells. The results were compared with those obtained in the mammary gland of rats treated with 6-NC. The MS of 6-NC in vivo and in vitro (in cultured lacI rat mammary epithelial cells) were similar in thatthe two major classes of mutations were AT→GC and AT→TA base-pair substitutions (ca. 30% of each). A similar MS was induced by 1,2-DHD-6-NHOH-C in vitro, with AT→GC and AT→TA substitutions representing the major types of mutations (about 25% each, of the total mutations). Also these two major mutations are different from those induced by other metabolites (e.g. 1,2-DHD-6-NC) which we tested previously. These results further support the hypothesis that 1,2-DHD-6-NHOH-C is the ultimate mutagen of 6-NC. It may be relevant that AT→GC substitutions have also been reported in significant percentages among mutations in the p53 gene in human breast tumors.  Since enantiomeric derivatives of numerous PAH including chrysene have distinctly different biological activities, we hypothesize that the stereochemical course of 6-NC metabolism plays a critical role in its mutagenic properties. Thus, in an initial study, the metabolite 1,2-DHD-6-NC, obtained from incubations of 6-NC with rat liver microsomes, was resolved to produce 88% of [R,R]- and 12% of [S,S]-enantiomers; circular dichroism was used to characterize each enantiomer. Resolution was achieved by either derivatization of 1,2-DHD-6-NC with (-)-menthoxyacetyl group followed by HPLC (Lichrosorb silica 60 A° ) separation or by a chiral stationary phase HPLC [(S,S) Whelk-O1, Regis Inc.]. Future studies will be aimed at determining the mutagenic and carcinogenic properties of each 1,2-DHD-6-NHOH-C enantiomer. Support: grant # CA35519.
Intravascular Polarimetry in Patients With Coronary Artery Disease
Authors: Kenichiro Otsuka, Martin Villiger, Antonios Karanasos, Laurens J.C. van Zandvoort, Pallavi Doradla, Jian Ren, Norman Lippok, Joost Daemen, Roberto Diletti, Robert-Jan van Geuns, Felix Zijlstra, Gijs van Soest, Jouke Dijkstra, Seemantini K. Nadkarni, Evelyn Regar, Brett E. Bouma
Journal: JACC. Cardiovascular imaging (2019)

The aims of this first-in-human pilot study of intravascular polarimetry were to investigate polarization properties of coronary plaques in patients and to examine the relationship of these features with established structural characteristics available to conventional optical frequency domain imaging (OFDI) and with clinical presentation. Polarization-sensitive OFDI measures birefringence and depolarization of tissue together with conventional cross-sectional optical frequency domain images of subsurface microstructure. Thirty patients undergoing polarization-sensitive OFDI (acute coronary syndrome, n = 12; stable angina pectoris, n = 18) participated in this study. Three hundred forty-two cross-sectional images evenly distributed along all imaged coronary arteries were classified into 1 of 7 plaque categories according to conventional OFDI. Polarization features averaged over the entire intimal area of each cross section were compared among plaque types and with structural parameters. Furthermore, the polarization properties in cross sections (n = 244) of the fibrous caps of acute coronary syndrome and stable angina pectoris culprit lesions were assessed and compared with structural features using a generalized linear model. The median birefringence and depolarization showed statistically significant differences among plaque types (p < 0.001 for both, one-way analysis of variance). Depolarization differed significantly among individual plaque types (p < 0.05), except between normal arteries and fibrous plaques and between fibrofatty and fibrocalcified plaques. Caps of acute coronary syndrome lesions and ruptured caps exhibited lower birefringence than caps of stable angina pectoris lesions (p < 0.01). In addition to clinical presentation, cap birefringence was also associated with macrophage accumulation as assessed using normalized SD. Intravascular polarimetry provides quantitative metrics that help characterize coronary arterial tissues and may offer refined insight into coronary arterial atherosclerotic lesions in patients.
A Large Panel of Isogenic APP and PSEN1 Mutant Human iPSC Neurons Reveals Shared Endosomal Abnormalities Mediated by APP β-CTFs, Not Aβ
Authors: Dylan Kwart, Andrew Gregg, Claudia Scheckel, Elisabeth A. Murphy, Dominik Paquet, Michael Duffield, John Fak, Olav Olsen, Robert B. Darnell, Marc Tessier-Lavigne
Journal: Neuron (2019)
Cardiovascular risk profile of breast cancer patients treated with anthracycline-taxane containing adjuvant chemotherapy and/or trastuzumab
Authors: L. W. Jones, M. Haykowsky, C. J. Peddle, A. A. Joy, E. N. Pituskin, L. M. Tkachuk, K. S. Courneya, D. J. Slamon, J. R. Mackey
Journal: Journal of Clinical Oncology (2006)

666 Background: With improving longevity, post-treatment cardiovascular disorders will become an increasingly important indicator of competing mortality in early-stage breast cancer. As such, we conducted a pilot study to comprehensively evaluate the CVD profile of a subset of early-stage breast cancer patients treated with adjuvant taxane-anthracycline containing chemotherapy and/or trastuzumab. Methods: Twenty-six breast cancer patients (mean 20 months post chemotherapy) who participated in Breast Cancer International Research Group 006 clinical trial and 10 healthy age-matched women were studied. We measured 14 metabolic and vascular established CVD risk factors, BMI, VO 2peak and left ventricular systolic function. All assessments were performed within a 14-day period. Results: Cardiac abnormalities were suggested by LVEF &lt;50% in 10% of patients, LVEF remained &gt;10% below pre-treatment values in 38% while 50% presented with resting sinus tachycardia. BNP was significantly elevated in 40% and was correlated with LVEF (r = -0.72, p=&lt;.001). For the majority of CVD risk factors, similar proportions of patients and controls (35% to 60%) were classified as ‘undesirable.’ A significantly higher proportion of patients were classified with low VO 2peak (46% vs. 0%, p&lt;0.01), being overweight/obese (72% vs. 50%, p&lt;0.05), and having resting sinus tachycardia (50% vs. 0%, p&lt;0.01) compared with controls. VO 2peak and BMI were correlated with CV risk factors (r = -0.64 to 0.63, p&lt;0.05; r = -0.63 to 0.67, p&lt;0.05, respectively). Exploratory analyses revealed several differences between CVD risk factors based on chemotherapy regimen. Conclusions: Breast cancer survivors treated with adjuvant chemotherapy are at a higher risk of developing late-occurring CVD than age matched controls due to direct and indirect treatment-related toxicity. No significant financial relationships to disclose.
Unraveling the role of oxytocin in the motivational structure of conflict
Authors: René Hurlemann, Nina Marsh
Journal: Behavioral and Brain Sciences (2019)

Abstract Current psychological perspectives emphasize “attack” and “defense” as the behavioral mechanisms underlying conflict. Here, we extend this view by highlighting the relevance of pathological altruism and the neuroendocrine pathways associated with hostile behaviors. Specifically, we elucidate the modulatory role of the neuropeptide hormone oxytocin in motivating extraordinary levels of in-group commitment that can promote extreme behaviors and endure conflict with out-groups.
A phase II study of fludarabine (F), cyclophosphamide (C), and mitoxantrone (M) plus rituximab (R) (FCM-R) in previously untreated patients (pts) with CLL ≤ 70 years (yrs)
Authors: S. Faderl, W. Wierda, S. O’Brien, A. Ferrajoli, M. Detry, F. Ravandi, H. M. Kantarjian, B. O’Neal, M. J. Keating
Journal: Journal of Clinical Oncology (2006)

6607 Background: Rituximab plus chemotherapy has demonstrated higher and better quality responses (MRD-negative) than chemotherapy alone. FCR produced overall response rates of 95% and complete remissions in 73%. Responses were lower in pts ≥ 70 years and β2M levels &gt; 2 × ULN, and myelosuppression-associated complications were more frequent. High response rates of 60% and 88% have been reported with FCM in pts with relapsed and untreated CLL. We here report results of FCM plus rituximab and pegfilgrastim in patients ≤ 70 yrs. with previously untreated CLL. Methods: Pts ≤ 70 yrs with untreated, symptomatic CLL (NCI-WG criteria) were eligible. Pts were excluded for β2M &gt; 2 × ULN and ECOG PS &gt; 2. For course 1, doses of fludarabine were 25 mg/m 2 i.v. daily d2–4, cyclophosphamide 250 mg/m 2 i.v. daily d2–4, mitoxantrone 6 mg/m 2 i.v. d2, and rituximab 375 mg/m 2 i.v. d1. Pegfilgrastim was 6 mg s.c. on d4. Courses were repeated q4–6 wks. For courses 2–6, FCM started day 1 with rituximab 500 mg/m 2 . Study endpoints included evaluation of efficacy (clinical and 2-color flow [CD5/CD19] response rate after 3 and 6 cycles) and toxicity. Results: Twenty-three pts have been treated, 19 are evaluable for response after 3 and 11 pts after 6 cycles. Median age: 57 yrs (38–69). Twelve pts (52%) were male. Rai stage ≥ 3 was present in 17%. Median β2M was 2.7 mg/dL (1.4–4) and median WBC 59.9 × 10 9 /L (5.6–355). Unfavorable FISH abnormalities were present in 3/17 (18%), unmutated IgV H in 9/12 (75%), and ZAP-70 immunohistochemistry was positive in 10/14 (71%) pts. After 3 cycles, all 19 pts responded (4 [21%] CR, 5 [26%] nPR, 10 [53%] PR). Six pts (32%) had &lt;1% CD5/CD19-positive cells in the marrow. Response rates after 6 cycles: 2 (18%) CR, 1 (9%) nPR), 8 (73%) PR (PR due only to failure to recover counts in 7 pts) for an OR rate of 100%. Six pts (55%) had &lt; 1% CD5/CD19-positive marrow cells at 6 months. Only 2 pts stopped prematurely because of persistent neutropenia. Conclusions: FCM-R achieves high clinical response rates. The frequency of pts with flow cytometry response &lt; 1% CD5/CD19-positive cells was similar to FCR. Myelosuppression-related complications were infrequent. Use of hematopoietic growth factors with chemoimmunotherapy regimens is recommended. [Table: see text]
Bioinorganics and Wound Healing
Authors: Benjamin Dalisson, Jake Barralet
Journal: Advanced Healthcare Materials (2019)

Abstract Wound dressings and the healing enhancement (increasing healing speed and quality) are two components of wound care that lead to a proper healing. Wound care today consists mostly of providing an optimal environment by removing waste and necrotic tissues from a wound, preventing infections, and keeping the wounds adequately moist. This is however often not enough to re‐establish the healing process in chronic wounds; with the local disruption of vascularization, the local environment is lacking oxygen, nutrients, and has a modified ionic and molecular concentration which limits the healing process. This disruption may affect cellular ionic pumps, energy production, chemotaxis, etc., and will affect the healing process. Biomaterials for wound healing range from simple absorbents to sophisticated bioactive delivery vehicles. Often placing a material in or on a wound can change multiple parameters such as pH, ionic concentration, and osmolarity, and it can be challenging to pinpoint key mechanism of action. This article reviews the literature of several inorganic ions and molecules and their potential effects on the different wound healing phases and their use in new wound dressings.
Abstract 17349: Induction of Cardiopoiesis From Human Adipose-Derived Mesenchymal Stem Cells Using Microencapsulated-Modified-Messenger RNA
Authors: Mark Li, Raman Deep Singh, Andre Terzic, Atta Behfar
Journal: Circulation (2017)

Introduction: Current efforts in cardiac regenerative medicine have utilized different stem cell products to institute resuscitation of cardiac function. One example is cardiopoietic stem cells, wh...
Targeted DNA methylation in cell fate determination
Authors: Shu-Huei Hsiao, Kuan-Der Lee, Min-Jen Tseng, Wei-Sheng Sun, Chia-Chen Hsu, Hao-Chun Chang, Yi-Chen Hung, Ching-Chu Yen, Yu-Chen Zhou, Yu-Chih Lin, I-Wen Teng, Yein-Ling Lie, Kun-Tu Yeh, Shaw-Jeng Tsai, Hsiao-Fang Sun, Yu-Sun Chang, Tim Huang, Yu-Wei Leu
Journal: Cancer Research (2008)

4298  Locus-specific DNA methylation was developed to epigenomically modify the bivalent loci identified by ChIP-on-chip (trimethylated lysine 27 histone 3) and DNA methylation hybridization microarray to direct the cell fate of mesenchymal stem cell (MSC) and cancer cells. Trip10 was identified as bivalent locus, which methylation status was increased during MSC-to-liver/neuron differentiation but decreased during MSC-to-adipocyte differentiation. Trip10 promoter was mostly hypermethylated in breast (n=94) and brain tumor specimen (n=47), but hypomethylated in liver cancer samples (n=37). Overexpressed Trip10 in IMR32 (neuroblastoma) promoted tumor growth, as indicated by colony formation assay and subsequent tumor formation in subcutaneously injected immuno-deficient mice. However, outgrowth of tumor was suppressed when Trip10 was overexpressed in CP70 cells. Consistent with other reports, we found Trip10 interacted with Cdc42 and Huntingtin to regulate cell cycle/growth and apoptosis. If the bivalent nature of Trip10 were true, we hypothesized that methylation of Trip10 should be sufficient to change the cell fate. We evaluated this hypothesis by pre-depositing DNA methylation within the Trip10 promoter in MSC. Compared to the mock-treated MSC, those Trip10 methylated MSC exhibited accelerated MSC-to-neuron differentiation accompanied with reduced cell death after differentiation. Therefore, methylation of the bivalent loci is sufficient to determine the cell fate of somatic stem cells. Similar strategy was applied to specifically target the estrogen receptor non-expressing (ER-) breast cancer cell line, MDA-MB-231. While most of the ER target loci were methylated and silenced in ER- cells as compared with the methylation status in ER+ cells, there were 19 genes actually activated. We reasoned that these 19 loci were crucial for the survival or the oncogenic activity of MDA-MB-231. Tailored methylation of these 19 loci led to increased cell death of MDA-MB-231 but not in cells including MCF7, HepG2, CP70, IMR32, and MSC. It is thus concluded that we have developed a new method that can epigenetically tailor the cell fate of stem cells or kill the targeted tumor cells specifically. (Supported in part by NSC 95-3112-B-194-001, NSC 94-2320-B-194-006, NSC 94-2320-B-194-003)
Limited utility of surveillance imaging for detection of relapse in non-Hodgkin lymphoma.
Authors: Quoc Van Truong, Nilay Shah, Mark Knestrick, Brendan F. Curley, Michael Craig, Mehdi Hamadani
Journal: Journal of Clinical Oncology (2013)

8557 Background: Surveillance imaging with computerized tomography (CT) and positron emission tomography with CT (PET/CT) scans during follow-up after first-line therapies in patients with non-Hodgkin lymphoma (NHL) is commonly used in practice. However, most guidelines do not recommend surveillance imaging. We aimed to determine the value of routine imaging for the detection of first relapse in NHL patients in complete remission (CR) after first-line therapies. Methods: We retrospectively analyzed NHL patients referred to our center, who achieved CR after first-line therapies and subsequently relapsed. We evaluated whether the relapse was detected solely by routine CT or PET/CT or by patient-reported symptoms. Subgroup analysis was performed according to baseline histology (indolent vs. aggressive NHL). Data were also collected to determine the number of additional imaging, number of false positive scans, invasive procedures and iatrogenic complications, directly resulting from an abnormality detected on surveillance imaging. Results: Seventy-seven patients with first relapse of NHL between January 1, 2000 and December 31, 2010 were included. Majority of the relapses were detected by patient-reported symptoms as opposed to surveillance imaging (79.2% (n=61) vs. 20.8% (n=16); p&lt;0.0001). There was no overall survival difference between the two groups (p=0.08). Patient-reported symptoms led to the detection of majority of relapses in aggressive (86.4% (n=45) vs. 13.6% (n=6); p&lt;0.0001) and indolent NHL (69.7% (n=32) vs. 30.3% (n=10); p=0.037). There were greater number of scans done after a suspected relapse in the imaging versus symptoms group (1.94 versus 0.97; p=0.0004). Surveillance imaging led to 2 false positive scans/invasive procedures with one case of iatrogenic pneumothorax. Conclusions: Our limited retrospective analysis suggests that there is a limited role of surveillance imaging by CT or PET/CT for the detection of relapse in patients with NHL. There was no difference in survival outcome in our study between the two groups.
Platelet Factor 4 (PF4)-Mediated Neutrophil Extracellular Trap Compaction Limits Endothelial Injury and Promotes Survival Following Lipopolysaccharide Challenge
Authors: Kandace Gollomp, Ian Johnston, Minna Kim, Li Zhai, Guohua Zhao, M. Anna Kowalska, Mortimer Poncz
Journal: Blood (2017)