tbuckley/cabot-search huggingface dataset:
Polycystic Ovarian Disease.
Authors: Walter Futterweit
Journal: Annals of Internal Medicine (1985)

1 Neuroendocrine Regulation of Gonadal Function.- 2 Hormonal Control of Folliculogenesis.- 3 Androgen Transport and Plasma Levels in the Normal Female.- 4 The Pathologic Anatomy of Polycystic Ovarian Disease.- 5 Genetics of Polycystic Ovarian Disease.- 6 Pathophysiology of Polycystic Ovarian Disease.- 7 Clinical Features of Polycystic Ovarian Disease.- 8 Hyperprolactinemia and Polycystic Ovarian Disease.- 9 Laboratory Diagnosis and Differential Diagnosis of Polycystic Ovarian Disease.- 10 Treatment of Polycystic Ovarian Disease.- 11 Hypothesis and Summary.- References.
Thymidylate synthase expression as predictive biomarker of pemetrexed sensitivity in advanced cancer patients.
Authors: Federico Rojo, Manuel Domine, Sandra Zazo, Cristina Chamizo, Gloria Serrano, Cristina Carames, Nuria Perez-Gonzalez, Tatiana Hernandez, Carmen Laura Auz, Nerea Carvajal, Irene Moreno, Jose Ignacio Martin-Valades, Yann Izarzugaza, Alberto Lendinez, Brezo Martinez-Ammoros, Juan Luis Arranz, Juan Madoz, Ana Leon, Francisco Lobo, Jesus Garcia-Foncillas
Journal: Journal of Clinical Oncology (2013)

11089 Background: Although a high level of thymidylate synthase (TS) expression in malignant tumours has been suggested to be related to a reduced sensitivity to the antifolate drug pemetrexed, no direct evidence for such an association has been demonstrated in routine clinical samples from patients treated with this drug. The purpose of this study was to evaluate the impact of quantitative TS expression in tumor cells as predictor of the efficacy in patients with advanced non-small cell lung cancer, small cell lung cancer (SCLC) and mesothelioma treated with pemetrexed in our institution. Methods: 54 patients were included in this study: 40 stage IV NSCLC (26 adenocarcinomas, 11 large cell, and 3 squamous cell carcinoma), 3 SCLC and 11 mesothelioma. 21 patients received platins-pemetrexed as first line NSCLC, 20 pemetrexed in monotherapy as second and further lines and 3 carboplatin-pemetrexed fo extensive disease SCLC. Total RNA was isolated by RNeasy FFPE procedure (Qiagen). The expression of TS was analyzed by RT-qPCR using appropriate mRNA specific primers and probes in LightCycler 480II platform at 45 cycles. TS levels was calibrated to expression in normal tissue. Results: From 54 cases, TS expression data were available in 32 cases, detecting overexpression in 23 (71.8%) and low expression in 9 (28.2%) patients. The response rate for patients with low TS expression was 0.63 compared with 0.15 in patients with overexpression (p=0.015). A significant benefit in time to progression was observed in patients with low expression (median TTP 12 vs. 2 months respectively, p= 0.002), whereas did not impact on overall survival (median OS 20 vs. 19 months respectively, p= 0.595). Conclusions: TS overexpression in tumor cells correlated with a reduced response to pemetrexed-containing chemotherapy and might be used as a predictive biomarker in advanced lung and mesothelioma cancer patients.
Active combination with aprepitant, palonosetron, and dexamethasone for preventing emesis of anthracycline-containing regimens in patients with breast cancer.
Authors: Yoshie Nakayama, Yoshinori Ito, Shunji Takahashi, Kiyohiko Hatake
Journal: Journal of Clinical Oncology (2012)

e19512 Background: Anthracycline and cyclophoshamaide containing regimens for breast cancer are classified as highly emetogenic chemotherapy. Aprepitant (A), palonosetron (P), granisetron (G) or dexamethasone(D) are recommended as antiemetic drugs. However, it is uncertain which combination would be best effective. We have retrospectively examined the efficacy of these antiemetic drugs. Methods: We reviewed the medical records of 501 patients with breast cancer treated with anthracycline and cyclophoshamaide containing regimens between August, 2009 and September, 2010. The combination of GD were G: 3 mg on day1 (i.v.), 2 mg on days 2-6 (p.o.) and D: 16.5 mg on day1 (i.v.), 8mg on days 2-4 (p.o.). The AGD were A: 125 mg on day1 (i.v.), 80 mg on days 2-3 (p.o.), G: 3 mg on day1 (i.v.), 2 mg on days 2-6 (p.o.), and D: 13.2 mg on day1 (i.v.), 4 mg on days 2-4 (p.o.). The APD were A: 125 mg on day1 (i.v.), 80 mg on days 2-3 (p.o.), P: 0.75 mg on day1 ( i.v.), and D: 13.2 mg on day1 (i.v.), 4 mg on days 2-4 (p.o.). Results: The number of patients who were treated with GD, AGD, and APD were 170, 159, and 172, respectively. Complete response (CR) rate in acute phase (0-24h) or delayed phase (24-120h) and complete control (CC) rate in acute or delayed phase in each regimens were summarized in the table. AGD or APD was significantly superior to GD in CR rate of acute or delayed phase (P&lt;0.01). Of note, CC rate of APD in acute phase was significantly superior to AGD (P&lt;0.01). AGD or APD was significantly superior to GD in CC rate in delayed phase. Conclusions: The combination with APD was the most effective antiemetic therapy in patients who were treated with anthracycline and cyclophosphamide containing regimens. [Table: see text]
DAXX Suppresses Tumor-Initiating Cells in Estrogen Receptor–Positive Breast Cancer Following Endocrine Therapy
Authors: Daniel S. Peiffer, Debra Wyatt, Andrei Zlobin, Ali Piracha, Jeffrey Ng, Andrew K. Dingwall, Kathy S. Albain, Clodia Osipo
Journal: Cancer Research (2019)

Abstract Estrogen receptor (ER)-positive breast cancer recurrence is thought to be driven by tumor-initiating cells (TIC). TICs are enriched by endocrine therapy through NOTCH signaling. Side effects have limited clinical trial testing of NOTCH-targeted therapies. Death-associated factor 6 (DAXX) is a newly identified marker whose RNA expression inversely correlates with NOTCH in human ER+ breast tumor samples. In this study, knockdown and overexpression approaches were used to investigate the role of DAXX on stem/pluripotent gene expression, TIC survival in vitro, and TIC frequency in vivo, and the mechanism by which DAXX suppresses TICs in ER+ breast cancer. 17β-Estradiol (E2)-mediated ER activation stabilized the DAXX protein, which was required for repressing stem/pluripotent genes (NOTCH4, SOX2, OCT4, NANOG, and ALDH1A1), and TICs in vitro and in vivo. Conversely, endocrine therapy promoted rapid protein depletion due to increased proteasome activity. DAXX was enriched at promoters of stem/pluripotent genes, which was lost with endocrine therapy. Ectopic expression of DAXX decreased stem/pluripotent gene transcripts to levels similar to E2 treatment. DAXX-mediated repression of stem/pluripotent genes and suppression of TICs was dependent on DNMT1. DAXX or DNMT1 was necessary to inhibit methylation of CpGs within the SOX2 promoter and moderately within the gene body of NOTCH4, NOTCH activation, and TIC survival. E2-mediated stabilization of DAXX was necessary and sufficient to repress stem/pluripotent genes by recruiting DNMT1 to methylate some promoters and suppress TICs. These findings suggest that a combination of endocrine therapy and DAXX-stabilizing agents may inhibit ER+ tumor recurrence. Significance: Estradiol-mediated stabilization of DAXX is necessary and sufficient to repress genes associated with stemness, suggesting that the combination of endocrine therapy and DAXX-stabilizing agents may inhibit tumor recurrence in ER+ breast cancer.
A phase I study of dovitinib (TKI258) in Japanese patients with advanced solid tumors.
Authors: Hiroya Takiuchi, Masahiro Gotoh, Motoki Yoshida, Takayuki Kii, Keishi Yamashita, Yu Sunakawa, Toshikado Kaneta, Matthew Robson, Tomoyuki Kakizume, Yasutsuna Sasaki
Journal: Journal of Clinical Oncology (2012)

3088^ Background: Dovitinib is a tyrosine kinase inhibitor with demonstrated inhibitory activity against FGFRs, VEGFRs, and PDGFRs in vivo. Based on responses observed in renal cell carcinoma, breast cancer, AML, melanoma, and multiple myeloma in clinical studies in the West, we investigated dovitinib in Japanese patients (pts). Methods: This multicenter phase I study determined the maximum tolerated dose (MTD) of dovitinib based on the occurrence of dose-limiting toxicity (DLT) in Japanese pts with advanced solid tumors. Following a 2-day pharmacokinetic (PK) run-in period, dovitinib was administered orally once daily on a 5-days-on/2-days-off schedule in 28-day cycles until disease progression or withdrawal. The planned dose range was 100-600 mg/day. A 2-parameter Bayesian logistic regression model based on the principle of escalation with overdose control was used to estimate the MTD. Results: In total, 28 pts received dovitinib: 100 mg (n = 3), 200 mg (n = 3), 300 mg (n = 7), 400 mg (n = 9), and 500 mg (n = 6). The median age was 58.5 years (range, 30-76); 16 of 28 pts (57%) were male. All pts had stage IV disease, with an ECOG performance status of 0 or 1. Pts completed a median of 3 cycles. One pt is currently ongoing in the study (peritoneal adenocarcinoma, 400-mg cohort, cycle 19), 23 discontinued due to disease progression, and 4 discontinued due to adverse events (AEs). All DLTs were grade 3: anorexia (n = 1; 300 mg), nausea/vomiting (n = 1; 400 mg), liver function disorder (n = 1; 400 mg), and increased alanine transaminase (n = 1; 500 mg). The most common grade 3/4 AEs (occurring in &gt;10% of pts) suspected to be related to study drug were lymphopenia (18%), neutropenia (14%), abnormal hepatic function (14%), decreased white blood cell count (14%), decreased appetite (14%), and hypertension (14%). Best responses were confirmed partial response in 1 pt (4%; peritoneal adenocarcinoma, 400-mg cohort), stable disease in 9 pts (32%), and progressive disease in 10 pts (36%). No treatment-related deaths have been reported. Safety and PK parameters were comparable to those of non-Japanese pts in the global study. Conclusions: The study has completed enrollment. Dovitinib was found to be tolerable at doses up to 500 mg, which was declared as the MTD in Japanese pts.
MMP-2: A novel target for antitumor immune therapy
Authors: E. Godefroy, Y. Guilloux, F. Jotereau, N. Bhardwaj
Journal: Journal of Clinical Oncology (2009)

3053 Background: Over the last two decades, a large array of antigens expressed by melanoma cells (MAA) has been identified and used in various immunization strategies to treat cancer patients. However, the therapeutic efficacy of these approaches remains limited. Because MMP-2 (matrix metalloproteinase-2) activity is critical for melanoma progression, this protein represents a unique antigen for vaccine therapy. Methods: Antigen-specific T cell clones were obtained from healthy donors. CD4 + cells were stimulated with overlapping MMP-2 peptides pulsed with irradiated autologous CD4 - fraction. After 12 days, MMP-2-specific responses were determined by intracellular staining for cytokines. Specific T cells from positive samples were enriched, using the IFNγ-capture assay (Miltenyi), followed by cloning using limiting dilution. Cytokine production was assessed by ELISA, intracellular staining, or cytometric bead array method. Results: We identified 11 novel CD4 MMP-2-derived epitopes, and showed that the corresponding T cells displayed an inflammatory T H 2 profile, i.e., mainly secreting TNF, IL-4 and IL-13 and expressing the T H 2-specific transcription factor GATA-3. In contrast, CD4 + T cells that recognize other associated MAAs were typically T H 1. MMP-2-specific responses were detected in the CD45RO + /CD62L - T cell memory fraction. Interestingly, naïve T cells primed with active MMP-2 gave rise to T H 2 specific cells, while naïve T cells primed with peptides generated IFNγ-secreting specific cells, consistent with a T H 1 profile. Accordingly, we showed that the enzymatic activity of MMP-2 inhibited IL-12 secretion by mature DCs, possibly explaining the T H 2 skewing of MMP-2-specific T cells. Furthermore, MMP-2 specific T H 2 cells were found in at least 18 tumor-infiltrating lymphocyte populations out of the 31 melanoma patients tested. Conclusions: The protease activity of MMP-2 blocks DC maturation, more precisely IL-12 production, which could be responsible for the observed T H 2 lineage commitment of MMP-2-specific T cells. These findings open the way to therapeutic strategies skewing these already frequent and diverse MMP-2-specific responses towards a more efficient antitumor T H 1 phenotype to treat melanoma patients. No significant financial relationships to disclose.
Venous thromboembolism as a relevant toxicity in cancer patients treated in phase I studies.
Authors: Mario Mandala, Federica Grosso, Cristina Vitalini, Irene Corradino, Roberto Labianca, Sonia Colombini, Roberta Sanfilippo, Antonella De Pascale, Silvia Marsoni
Journal: Journal of Clinical Oncology (2012)

e19549 Background: To investigate the risk factors and the relevance of venous thromboembolism (VTE) among the reported toxicities in advanced cancer patients treated in phase I studies. Methods: Patients enrolled and treated in phase I studies conducted by SENDO (Southern Europe New Drugs Organization) Foundation between 2000 and 2010 in 15 experimental centres were considered for the study. Clinical data, including adverse events, were prospectively collected during the studies and retrospectively pooled for VTE analysis. Results: Data of 1,415 pts were considered for analysis. 526 (37.2%) patients were males, median age was 57.3 years (range: 13-85). 85% of patients had metastatic disease, while the remaining had locally advanced irresectable disease. For 706 (49.9%) of the patients the study treatment was with cytotoxic agent(s) only, for 314 with target therapy(ies) only, while the remaining patients received a target therapy in combination with a cytotoxic drug. 56 (3.96%) patients who developed a VTE, almost all (89.3%) during the course of treatment, the remaining during the follow-up. At multivariate analysis gynecologic (HR: 2.7, p&lt; 0.012; 95% CI: 1.241 - 5.889) and gastrointestinal tumors (HR 3.32, p&lt; 0.019; 95% CI: 1.22 - 9.08) as well as cytotoxic plus antiangiogenic agents (HR 2.5, p&lt; 0.038; 95% CI: 1.05 - 5.96) were statistically correlated with VTE development. The adverse events were the main reason for discontinuation in 230 pts. VTE was the fourth most common cause of drug discontinuation among this subgroup of patients. The median time from first drug administration to discontinuation was 1.4 for VTE and 2.3 months for the other AEs, respectively (p=0.02) Conclusions: VTE is a relatively common complication among patients treated in the context of phase I studies and may influence the early drug discontinuation. Tumour site and the combination of chemotherapy and antiangiogenic therapy predict VTE development.
A phase I study of the safety and pharmacokinetics of DSTP3086S, an anti-STEAP1 antibody-drug conjugate (ADC), in patients (pts) with metastatic castration-resistant prostate cancer (CRPC).
Authors: Daniel Costin Danila, Russell Zelig Szmulewitz, Celestia S. Higano, Houston Gilbert, Robert S. Kahn, Katie Wood, Priya Agarwal, Kedan Lin, Omar Kabbarah, Bernard M. Fine, Daniel J. Maslyar, Ulka N. Vaishampayan
Journal: Journal of Clinical Oncology (2013)

5020 Background: Six-transmembrane epithelial antigen of the prostate-1 (STEAP1) protein is a cell-surface antigen overexpressed in human epithelial prostate cancers. The ADC DSTP3086S contains the humanized IgG1 anti-STEAP1 monoclonal antibody linked to the potent anti-mitotic agent MMAE. Methods: This study evaluated safety, pharmacokinetics, and pharmacodynamic activity of intravenous DSTP3086S (0.3-2.8 mg/kg) given every 3 weeks (q3w) to pts with CRPC. A traditional 3+3 design was used to determine maximum-tolerated dose, followed by cohort expansion at the recommended Phase II dose (RP2D). Clinical activity was evaluated per PCWG criteria. Dose escalation results are presented. Results: Twenty-eight pts were enrolled with a median age of 67 (43-76), all ECOG PS 0-1, and with a median of 7 prior systemic regimens (including a median of 4 hormonal and 3 non-hormonal regimens). Pts received a median of 3 doses (range 1-10) of DSTP3086S. Reversible Grade 3 transaminitis DLTs occurred in one pt each in the 2.25 mg/kg and 2.8 mg/kg cohorts. Serious AEs (SAE) related to study drug (3 total) included one DVT (Grade 3) in the 1.5 mg/kg cohort, as well as one GI hemorrhage (Grade 3) and one sepsis event (Grade 5) in the 2.25 mg/kg cohort. The most common related AEs across all doses were fatigue (36%), nausea (32%), constipation (25%), decreased appetite and diarrhea (each 21%), and musculoskeletal pain and vomiting (each 18%). Exposure for total antibody, free MMAE, and conjugated MMAE was dose proportional. Approximately 60% of the tumor samples assessed showed high STEAP1 expression. CTC reductions were most robust at 2.8 mg/kg; 4/4 patients with unfavorable CTCs at baseline (median of 99, range: 21-205) exhibited CTC conversions from unfavorable to favorable (&lt;5) after a single dose of DSTP3086S. CTC conversions were also observed at lower doses. PSA decreases of ≥ 50% were observed in 1 pt at 2.25 mg/kg, and 2 pts at 2.8 mg/kg who also had PCWG2 radiologic responses. Conclusions: DSTP3086S at the RP2D of 2.8 mg/kg q3w has a tolerable safety profile and shows evidence of anti-tumor activity. Enrollment in the expansion cohort is ongoing.
Preclinical study of trabectedin (TR) and poly(ADP-ribose)polymerase 1 (PARP-1) inhibitor combination in soft tissue sarcoma (STS).
Authors: Ymera Pignochino, Federica Capozzi, Carmine Dell' Aglio, Marco Basiricò, Loredana Tarraran, Lorenzo D'Ambrosio, Danilo Galizia, Erica Palesandro, Loretta Gammaitoni, Dario Sangiolo, Maria Serena Benassi, Massimo Aglietta, Giovanni Grignani
Journal: Journal of Clinical Oncology (2012)

10066 Background: TR is an alkylating agent approved in Europe for the treatment of advanced STS as second/third line therapy. TR binds to the minor groove of DNA and interferes with gene transcription and nucleotide excision repair mechanism, inducing DNA double strand breaks (DSBs), and S/G2 cell cycle arrest. There is a strong clinical interest to increase TR activity combining it with other anti-cancer drugs. PARP-1 inhibitors disable DNA base-excision repair mechanism causing the accumulation of DSBs and look like a reasonable TR partner to be explored. We focused our in vitro studies on the effects of the combination of TR with the PARP-1 inhibitor Olaparib (OL). Methods: We explored the activity of TR-OL combination against a panel of different histotypes of STS cell lines, evaluating cell viability after 72h treatment with escalating doses of TR (0-2 nM), OL (0-20 µM), and their constant combination. Following colony formation, cell cycle, apoptosis (annexin V+/PI+) and DNA damage (phospho-histone H2AX - Ser139) were checked. Results: The TR-OL combination strongly affects STS cell viability, showing synergism (Combination Index &lt; 1, based on Chou–Talalay method) on 8 out of 13 cell lines tested. We observed a strong synergism, as a massive reduction of colony growth (402.91, MES-SA, and DMR-SN-8.4.98 lines) induced by the combination if compared with each single agent (78% vs. ~27% : p&lt;0.05). OL potentiates the S/G2 cell-cycle arrest caused by TR at 48h (Control= 29%, TR= 33.4%, OL= 31.5%, TR-OL= 80.9%), and induces a strong increase of the apoptotic cells at 72h (Control= 17.4%, TR= 28.3%, OL= 33.5%, TR-OL= 56.8%). Furthermore, the TR-OL synergism on DNA damage is confirmed by a significant increase of the DSBs marker (Control= 8.7%, TR= 59.5%, OL= 23.8%, TR-OL= 76.5%). Conclusions: These results validate the biological rationale to combine TR and PARP-1 inhibitors in STS and suggest assessing this drug combination in the clinical setting.
Investigating the Relationship Between Type 2 Diabetes and Dementia Using Electronic Medical Records in the GoDARTS Bioresource
Authors: Alex S.F. Doney, Wilfred Bonney, Emily Jefferson, Katherine E. Walesby, Rachel Bittern, Emanuele Trucco, Peter Connelly, Rory J. McCrimmon, Colin N.A. Palmer
Journal: Diabetes Care (2019)

OBJECTIVE To investigate the impact of type 2 diabetes on incidence of major dementia subtypes, Alzheimer and vascular dementia, using electronic medical records (EMR) in the GoDARTS bioresource. RESEARCH DESIGN AND METHODS GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland) comprises a large case-control study of type 2 diabetes with longitudinal follow-up in EMR. Dementia case subjects after recruitment were passively identified in the EMR, and using a combination of case note review, an Alzheimer-specific weighted genetic risk score (wGRS), and APOE4 genotype, we validated major dementia subtypes. We undertook a retrospective matched cohort study to determine the risk of type 2 diabetes status for incident dementia accounting for competing risk of death. RESULTS Type 2 diabetes status was associated with a significant risk of any dementia (cause-specific hazard ratio [csHR] 1.46, 95% CI 1.31–1.64), which was attenuated, but still significant, when competing risk of death was accounted for (subdistribution [sd]HR 1.26, 95% CI 1.13–1.41). The accuracy of EMR-defined cases of Alzheimer or vascular dementia was high—positive predictive value (PPV) 86.4% and PPV 72.8%, respectively—and wGRS significantly predicted Alzheimer dementia (HR 1.23, 95% CI 1.12–1.34) but not vascular dementia (HR 1.02, 95% CI 0.91–1.15). Conversely, type 2 diabetes was strongly associated with vascular dementia (csHR 2.47, 95% C 1.92–3.18) but not Alzheimer dementia, particularly after competing risk of death was accounted for (sdHR 1.02, 95% CI 0.87–1.18). CONCLUSIONS Our study indicates that type 2 diabetes is associated with an increased risk of vascular dementia but not with an increased risk of Alzheimer dementia and highlights the potential value of bioresources linked to EMR to study dementia.
Slc6a8-Mediated Creatine Uptake and Accumulation Reprogram Macrophage Polarization via Regulating Cytokine Responses
Authors: Liangliang Ji, Xinbin Zhao, Bin Zhang, Lan Kang, Wenxin Song, Baohong Zhao, Wei Xie, Ligong Chen, Xiaoyu Hu
Journal: Immunity (2019)
Marcel Waldinger: neuropsychiatrist and researcher who defined premature ejaculation
Authors: Tony Sheldon
Journal: BMJ (2019)

The cover of the 1997 doctoral thesis of Dutch neuropsychiatrist and sexual medicine researcher Marcel Waldinger features a stopwatch.1 Through such low tech means, Waldinger changed medical practice. It was a key tool in achieving international consensus on a definition—and largely accepted best treatment—for lifelong premature ejaculation in men, for which he is credited.

His friend and research collaborator Berend Olivier, professor in psychopharmacology at Utrecht University, explained that men who came to Waldinger’s clinic in The Hague who claimed to be affected by premature ejaculation were sent home with the stopwatch.

Previously the condition had been based on uncertain reporting, but now Waldinger’s patients had to pass an approximate and simple test before he would treat them. Their female partners had to press on the stopwatch when their men achieved orgasm. If this happened less than a minute after entering the vagina they were deemed to be among an estimated 2-5% of all men who are lifelong “premature ejaculators.”

In reality, Marcel spent decades studying thousands of patients in his clinic and abroad, in order to try to understand what is normal. He worked with Aeilko Zwinderman, a statistician at Amsterdam University, before deciding on a cut-off point, an intravaginal ejaculatory latency time of one minute. This prevented overmedicalisation of the condition and is now accepted as …