tbuckley/cabot-search huggingface dataset:
Antitumor activity of NK012 combined with cisplatin against small-cell lung cancer and intestinal mucosal changes in tumor-bearing mouse after treatment
Authors: T. Nagano, M. Yasunaga, K. Goto, Y. Koga, J. Kuroda, Y. Nishimura, T. Sugino, Y. Nishiwaki, Y. Matsumura
Journal: Journal of Clinical Oncology (2009)

e13522 Background: The novel SN-38-incorporating polymeric micelles NK012 has been shown to have significant antitumor activity against several cancer mouse models compared with CPT-11. The phase I study demonstrated that patients treated with NK012 did not develop grade 3/4 diarrhea, one of the major adverse effects of CPT-11. The aim of this study is to investigate the advantages of NK012 combined with cisplatin (cis-dichlorodiammineplatinum (II): CDDP) over CPT-11/CDDP, one of the most active regimens against small-cell and non-small-cell lung cancers in the clinic, in mice bearing a small-cell lung cancer (SCLC) xenograft in terms of antitumor activity and toxicity, particularly intestinal toxicity. Methods: Cytotoxic effects were evaluated in human SCLC cell lines (H69, H82, vascular endothelial growth factor [VEGF]-secreting cells, SBC-3/VEGF and its mock transfectant SBC-3/Neo). In vivo antitumor effects were evaluated in SBC-3/Neo-and SBC-3/VEGF-bearing mice after NK012/CDDP or CPT-11/CDDP administration on days 0, 7, and 14. Drug distribution was analyzed by high-performance liquid chromatography or fluorescence microscopy, and the small intestine was pathologically examined. Results: The in vitro growth inhibitory effects of NK012 were 198- to 532-fold more potent than those of CPT-11. A significant difference in the relative tumor volume on day 30 was found between NK012/CDDP and CPT- 11/CDDP treatments (P=0.0058). Inflammatory changes in the small intestinal mucosa were rare in all NK012-treated mice, but were commonly observed in CPT-11-treated mice. Moreover, a large amount of CPT-11 was excreted into the feces and high CPT-11 concentration was detected in the small intestinal epithelium. On the other hand, a small amount of NK012 was found in the feces and NK012 was weakly and uniformly distributed in the mucosal interstitium. Conclusions: NK012/CDDP combination may be a promising candidate regimen against lung cancer without severe diarrhea toxicity, and therefore warrants further clinical evaluation. No significant financial relationships to disclose.
A Fluorescent Oligothiophene-Bis-Triazine ligand interacts with PrP fibrils and detects SDS-resistant oligomers in human prion diseases
Authors: Thibaut Imberdis, Adeline Ayrolles-Torro, Alysson Duarte Rodrigues, Joan Torrent, Maria Teresa Alvarez-Martinez, Gabor G. Kovacs, Jean-Michel Verdier, Mike Robitzer, Véronique Perrier
Journal: Molecular Neurodegeneration (2016)

Prion diseases are characterized by the accumulation in the central nervous system of an abnormally folded isoform of the prion protein, named PrP(Sc). Aggregation of PrP(Sc) into oligomers and fibrils is critically involved in the pathogenesis of prion diseases. Oligomers are supposed to be the key neurotoxic agents in prion disease, so modulation of prion aggregation pathways with small molecules can be a valuable strategy for studying prion pathogenicity and for developing new diagnostic and therapeutic approaches. We previously identified thienyl pyrimidine compounds that induce SDS-resistant PrP(Sc) (rSDS-PrP(Sc)) oligomers in prion-infected samples.Due to the low effective doses of the thienyl pyrimidine hits, we synthesized a quaterthiophene-bis-triazine compound, called MR100 to better evaluate their diagnostic and therapeutic potentials. This molecule exhibits a powerful activity inducing rSDS-PrP(Sc) oligomers at nanomolar concentrations in prion-infected cells. Fluorescence interaction studies of MR100 with mouse PrP fibrils showed substantial modification of the spectrum, and the interaction was confirmed in vitro by production of rSDS-oligomer species upon incubation of MR100 with fibrils in SDS-PAGE gel. We further explored whether MR100 compound has a potential to be used in the diagnosis of prion diseases. Our results showed that: (i) MR100 can detect rSDS-oligomers in prion-infected brain homogenates of various species, including human samples from CJD patients; (ii) A protocol, called "Rapid Centrifugation Assay" (RCA), was developed based on MR100 property of inducing rSDS-PrP(Sc) oligomers only in prion-infected samples, and avoiding the protease digestion step. RCA allows the detection of both PK-sensitive and PK-resistant PrP(Sc) species in rodents samples but also from patients with different CJD forms (sporadic and new variant); (iii) A correlation could be established between the amount of rSDS-PrP(Sc) oligomers revealed by MR100 and the duration of the symptomatic phase of the disease in CJD patients; and (iv) Bioassay experiments showed that MR100 can trap prion infectivity more efficiently than P30 drug.MR100 is a powerful tool not only for studying the prion aggregation pathways regarding oligomeric and sPrP(Sc) species, but also for developing alternative methods for the detection of prion-infected samples. Considering our bioassay results, MR100 is a promising molecule for the development of prion decontamination approaches.
The utility of a real-time RT-PCR assay for the detection of metastases greater than 0.2 mm in sentinel lymph nodes of breast cancer patients confirmed by detailed histological analysis
Authors: M. Kurosumi, Y. Kobayashi, H. Takei
Journal: Journal of Clinical Oncology (2009)

628 Background: Analysis using real time RT-PCR for the detection of metastases in lymph nodes (LN) increases sampling but is associated with a risk of too much sensitivity as compared to histological analysis. Determining the appropriate cutoff value is important in introducing this system to routine clinical practice. Our study confirms the reliability of the cutoff values of a real-time RT-PCR assay (GeneSearch, Veridex LLC) to detect metastases larger than 0.2 mm by detailed 0.2 mm frozen section histological diagnosis. Methods: 129 sentinel and non-sentinel lymph nodes were obtained by sentinel LN biopsy from 79 breast cancer patients. All LNs were cut in half. One half of each LN was used for routine intra-operative diagnosis. The other LN half had sections cut every 0.2 mm for histological analysis. All frozen sections were H&amp;E stained and examined by on-site pathologists. These sections were then re-stained immunohistochemically using a pancytokeratin antibody (AE1/AE3) for detecting submicrometastses. All remaining tissue between the histology sections was assayed by the real-time RT-PCR assay using the genetic markers mammaglobin (MG) and cytokeratin-19 (CK-19) (note: tissue processing method was investigational and off-label). Cutoff values were pre-set in a large US study (n = 304). Results: Compared to the histological diagnosis using 0.2 mm interval frozen sections, the real-time RT-PCR results were as follows; sensitivity of 100.0% (34/34), specificity of 93.7% (89/95), and overall accuracy of 95.3% (123/129). Submicrometastases were recognized by IHC in 3 of 95 samples (2 solitary and 1 multiple sites) diagnosed as negative by H&amp;E-stain sections, and 3 samples were negative for RT-PCR. Conclusions: Results of 0.2 mm interval histological analysis suggest a near perfect sensitivity of the real time RT-PCR assay, allowing reliable detection of LN metastases larger than 0.2 mm. In addition, at least three samples with submicrometastases detected by immunohistochemistry for pancytokeratin were above the preset cutoff values of this real time RT-PCR assay. [Table: see text]
Circulating DF3 and CA125 antigen levels in serum from patients with epithelial ovarian carcinoma.
Authors: H Sekine, D F Hayes, T Ohno, K A Keefe, E Schaetzl, R C Bast, R Knapp, D W Kufe
Journal: Journal of Clinical Oncology (1985)

The murine monoclonal antibody (MAb), designated DF3, reacts with a 300-kilodalton (kd) mammary epithelial antigen. A sequential double-determinant enzyme-linked immunoassay (EIA) has been developed to monitor circulating DF3 antigen. Previous studies have demonstrated that the use of the DF3 EIA provides a new and potentially useful marker to follow the clinical course of patients with metastatic breast cancer. In the present study, we have monitored circulating DF3 antigen in the serum of patients with epithelial ovarian carcinomas and non-ovarian gynecologic malignancies. Twenty-one of 45 patients (47%) with ovarian carcinoma had elevated DF3 antigen levels (greater than or equal to 30 U/mL). In contrast, three of 20 patients (15%) with non-ovarian gynecologic malignancies, and only four of 59 control women (7%) had elevation of circulating DF3 antigen. The difference between DF3 antigen values from patients with ovarian cancer and from controls was significant (P less than .001). The elevation of circulating DF3 antigen in ovarian cancer patients has also been confirmed by transblot assays. MAb DF3 reactivity occurred predominately with circulating antigens of molecular weights (mol wt) ranging from 300 to 450 kd. Furthermore, DF3 antigen levels have been shown to correlate with progression of disease in six patients with ovarian cancer and after resection of disease in two others. The half-life of circulating DF3 antigen was approximately 45 to 60 days. The results also demonstrate that DF3 antigen is distinct from CA125, a glycoprotein associated with coelomic epithelium and developmental amnion. The use of both the DF3 EIA and the immunoradiometric assay previously described to detect circulating CA125 suggests that determining levels of both markers may enhance the sensitivity of monitoring the course of ovarian cancer. Furthermore, the use of both assays may be useful in distinguishing ovarian cancer from other malignancies.
당뇨병 환자와 비당뇨병 환자의 화농성 간농양 비교
Authors: 이창재 ( Chang Jae Lee ), 정동식 ( Dong Sik Jung ), 정석희 ( Suk Hee Jung ), 백정환 ( Jung Hoan Baik ), 이정현 ( Jung Hyun Lee ), 조용락 ( Young Rak Cho ), 고병성 ( Byoung Soung Go ), 이성욱 ( Sung Wook Lee ), 한상영 ( Sang Young Han ), 이동현 ( Dong Hyun Lee )
Journal: Clinical and Molecular Hepatology (2005)

목적: 최근 연구에 따르면 현재 K. pneumoniae가 간농양의 가장 흔한 균으로 보고되고 있다. 또한 당뇨성 간농양에서 공기방울 형성 간농양 발생률이 매우 높다한다. 공기방울 형성 간농양은 합병증과 사망률이 공기방울 비형성군에 비해 높다. 또한 전체적 합병증 발생률에서도 당뇨성 간농양 환자에서 높다. 이에 저자들을 간농양 환자를 대상으로 당뇨병 환자의 빈도를 알아보고, 비당뇨성 간농양과 비교하여 원인균, 임상적 차이, 합병증 발생률 등을 알아보고자 했다. 대상과 방법: 1997년 1월부터 2004년 7월까지 병원에 입원하여 방사선학적 검사 혹은 수술에 의해 간농양이 확인되거나, 경피적 천자나 수술을 통한 배농액 배양, 혹은 혈액검사에서 원인균이 증명된 145명의 간농양 환자 중 결핵성 간농양 2예, 아메바성 간농양 2예, 호산구성 간농양 1예를 제외한 화농성 간농양으로 진단 받은 140명을 대상으로 하였다. 결과: 화농성 간농양을 가진 140명의 환자(남:83, 여:57) 중 당뇨병을 가진 환자는 37명(남:25, 여:12)으로 26%를 차지하였다. 환자의 평균 나이는 당뇨군에서 59.47세, 비당뇨군에서 55.89세로 당뇨군에서 높았다. 또한 두 군 모두 50대에 발병률이 가장 높았다. 공기방울 형성 간농양은 당뇨군에서 16%, 비당뇨군 0%로 당뇨군에서만 발생하였다. 농양강에서 배양률은 당뇨군에서 41%, 비당뇨군에서 40%였고, 농양강내 세균 배양상 K. pneumoniae가 당뇨군에서 53%, 비당뇨군에서 51%로 두 군 모두 가장 많이 검출되었다. E. coli가 당뇨군에서 20%, 비당뇨군에서 12%로 두 군 모두 간농양내 배양으로 두 번째로 많이 검출되었다. 합병증 발생률은 당뇨군에서 40.5%, 비당뇨군에서 25.2%로 당뇨군에서 발생률이 높았다. 늑막삼출이 당뇨군에서 60%, 비당뇨군에서 42.3%로 두 군 모두 합병증 중 가장 많았다. 합병증 발생률은 당뇨성 간농양 중 공기방울 형성 간농양군에서 67%, 공기방울 비형성 간농양군에서 29%로 공기방울 형성군에서 많이 발생하였다. HbA1C은 공기방울 형성군에서 9.3, 공기방울 비형성군에서 9.18이었다. 결론: 간농양의 주된 원인균은 당뇨군, 비당뇨군 모두 K. pneumoniae가 가장 많이 배양되는 균이었다. 합병증 발생률은 당뇨군에서 높았고, 공기방울 형성 간농양은 당뇨군에서 발생률이 훨씬 높았다. 합병증 발생은 공기방울 형성군이 공기방울 비형성군에 비해 의미 있게 높았다. 혈당이 잘 조절될수록 합병증 발생률이 낮고, 인슐린으로 혈당을 조절한 경우 공기방울 형성 간농양 발생률이 낮았다. 당뇨성 간농양 치료에 혈당조절이 중요한 인자이고 특히 인슐린으로 혈당을 조절하는 것이 합병증 발생을 예방하는 데 중요한 인자로 사료된다.
PWE-417 Incentivising laparoscopic deliberate practice in core surgical training
Authors: LG Nicol, R Partridge, J Cleland, S Moug, A Paisley, I Ahmed, KG Walker
Journal: Gut (2015)

<h3>Introduction</h3> Frequent practice using a laparoscopic simulator is known to improve subsequent live operating skills. Achieving automation of motor movements prior to live training frees the trainee’s attention for higher skills. Despite this, trainees don’t avail themselves of opportunity for practice. We incentivised frequent laparoscopic practise within two Core Surgical Training (CST) programmes. <h3>Method</h3> 27 CST’s in their first general/urology/paediatric post were given a take-home laparoscopic simulator with instrument tracking software and assigned 6 online modules. Support was provided via social media and a helpdesk. Achievement of metric targets and uploading specified data merited an eCertificate. On production of this certificate, supervisors progressed trainees from camera-holding to operating (the incentive). Trainee views of the intervention and laparoscopic practice were assessed by questionnaires. <h3>Results</h3> Metric results show improvement across all domains for those who completed 1 or more modules (presented graphically). Trainee self-rated anxiety of laparoscopic operating was reduced post-study. 94% of participants thought simulator practise was worthwhile, 76% would recommend the programme. 88% reported improved confidence and motor skills. 41% of participants completed &gt;1 modules. 19% completed all. Comments indicated reasons for this, including the need to integrate simulation into curricular structures. Metric results showed improvement in 5 domains Motion smoothness, acceleration, speed, distance between instruments,% time off screen + time to completion. <h3>Conclusion</h3> The message from this feasibility study, the first to “incentivise” laparoscopic practice, indicates that simply incentivising practice with 24/7 access to simulators and targets, doesn9t result in frequent deliberate practice by trainees, though performance improves in those who do engage. Trainee feedback provides clear indicators of what to address to maximise uptake. It would suggest that to fully engage trainees, laparoscopic practice must be fully integrated into training and progress assessed within training. <h3>Disclosure of interest</h3> L. Nicol: None Declared, R. Partridge Conflict with: Founder of E-O surgical, J. Cleland: None Declared, S. Moug: None Declared, A. Paisley: None Declared, I. Ahmed: None Declared, K. Walker: None Declared. <h3>References</h3> Nagendran M, <i>et al</i>. Laparoscopic surgical box model training for surgical trainees with no prior laparoscopic experience. Cochrane Database Syst Rev. 2014;1 Dawe SR, <i>et al</i>. A Systematic Review of Surgical Skills Transfer After Simulation-Based Training Laparoscopic Cholecystectomy and Endoscopy. Ann Surg. 2014;259(2) Zapf MA, Ujiki MB. Surgical resident evaluations of portable laparoscopic box trainers incorporated into a simulation-based minimally invasive surgery curriculum. Surg Innov. 2015;22(1):83–7
P0902 : Exposure-response analyses for efficacy (SVR12) for the direct acting antiviral regimen of ABT-450/R, ombitasvir with dasabuvir +/− ribavirin in subjects with HCV genotype 1 infection
Authors: A. Khatri, S. Mensing, T. Podsadecki, W. Awni, R. Menon, S. Dutta
Journal: Journal of Hepatology (2015)
Gonadal hormones after chemotherapy with or without radiotherapy in male lymphoma survivors
Authors: C. E. Kiserud, A. Fosså, T. Bjøro, H. Holte, M. Cvancarova, S. D. Fosså
Journal: Journal of Clinical Oncology (2008)

8594 Background: Endocrine gonadal function may be reduced in male survivors treated for malignant lymphoma (mLSs). We investigated gonadal hormones in a large cohort of mLSs. Methods: mLSs ≤ 50 years at diagnosis when admitted at the Norwegian Radium Hospital from 1980 to 2002 were eligible for this cross sectional study. Gonadal hormones [testosterone, SHBG (Sex hormone-binding globulin), LH (Luteine Hormone) and FSH (Follicle-stimulating Hormone)] were assessed in 301 patients. Treatment was categorized according to type of regimen and cumulative doses: 1: No chemotherapy / low gonadotoxic chemotherapy (“Low”), 2: Medium gonadotoxic chemotherapy (“Med”), 3: High gonadotoxic chemotherapy (“High”). Radiotherapy was not considered. Blood samples were also grouped into three categories: 1: gonadal hormones within normal range (Testosterone 9.0–31.0 nmol/l, FSH<12.0 U/l, LH<10.0 U/l, SHBG 15.0–85.0 nmol/l), 2: isolated elevated FSH (> 12.0 U/l), 3: either elevated LH (>10.0 U/l) or low testosterone (< 9.0 nmol/l) or both, with or without elevated FSH (hypogonadal). Descriptive analyses, chi-square test and multinominal logistic regression were used with p<0.05 considered significant. Results: Median age at diagnosis was 33 years, with median observation time 15 years from diagnosis. One hundred and forty eight (49%) had gonadal hormones within normal range, 59 (20%) had elevated FSH, 94 (31%) were hypogonadal. There was a statistically significant association between treatment group and gonadal function (p<0.001). After treatment with “Low” 77% had normal gonadal hormones, whereas the comparable numbers were 47% after “Med” and 14 % after ”High”. Patients treated with “Med” were 3 times more likely to be hypogonadal than those treated with “Low”, whereas after “High” the chance of being hypogonadal was 13 times higher compared to treatment with “Low”. Hypogonadism was less frequent for mLSs being < 20 years at diagnosis (p=0.014). Conclusions: In males, chemotherapy of malignant lymphoma is followed by endocrine hypogonadism in nearly one third of long-term survivors with a statistically significant association to the type of regimen and/or cumulative dose. The role of androgen substitution in mLSs has to be explored in clinical studies. No significant financial relationships to disclose.
Inhibition of JAK/STAT pathway in airway epithelium as a potential targeted therapy of asthma
Authors: Anna Bujak, Patrycja Nejman-Gryz, Pawel Gunerka, Monika Lamparska-Przybysz, Maciej Wieczorek, Ryszarda Chazan, Aleksandra Stanczak
Journal: European Respiratory Journal (2014)

INTRODUCTION  Epithelial cells play an important role in immune response and eosinophilic airway inflammation, contributing to the pathogenesis of asthma. JAK/STAT pathway is involved in transduction of signal from cytokines9 receptors and expression of downstream cytokines and chemokines. Therefore, inhibition of JAKs seems to be a promising approach for the therapy of asthma.  MATHERIALS AND METHODS  JAKs inhibitors: baricitinib, tofacitinib and gandotinib were used to study a role of JAK/STAT pathway in airway epithelium. Their activity among the JAKs kinases was assessed by ATP-based enzymatic assay. Their biological potency was evaluated in Primary Bronchial Tracheal Epithelial Cells (PBTEC) by WB and ELISA.  RESULTS  Baricitinib has a great potency to inhibit JAK1/JAK2, tofacitinib inhibits JAK2/JAK3, while gandotinib is a potent JAK2 inhibitor.  We showed significant inhibition of STAT6 phosphorylation in cytokines9 stimulated PBTEC after treatment with tofacitinib and baricitinib at concentration of 0,5μM, and gandotinib at 1μM. We showed corresponding decrease of eotaxin-3 secretion by cells treated with tofacitinib (IC50  CONCLUSION  In airway epithelium model we observed distinct effect on eotaxin-3 release of JAKs inhibitors with higher activity towards JAK3 (tofacitinib) and JAK1 (baricitinib) from that of gandonitinib, the selective JAK2 inhibitor. Our results confirm that targeting JAK/STAT pathway represents a promising strategy for the therapy of asthma.
Mature results of a randomized phase II study of OGX-011 in combination with docetaxel/prednisone versus docetaxel/prednisone in patients with metastatic castration-resistant prostate cancer
Authors: K. N. Chi, S. J. Hotte, E. Yu, D. Tu, B. Eigl, I. Tannock, F. Saad, S. North, J. Powers, E. Eisenhauer
Journal: Journal of Clinical Oncology (2009)

5012 Background: Clusterin is a cytoprotective chaperone protein associated with CRPC progression. OGX is a 2'-methoxyethyl antisense that potentiates chemotherapy in xenografts and inhibits clusterin expression at doses of &lt;640 mg. Methods: Pts with CRPC and chemo-naive received docetaxel (DOC) 75mg/m 2 q3w + OGX 640mg IV weekly + prednisone (Arm A) or DOC + prednisone (Arm B) in a single stage randomized phase II design. Primary endpoint was PSA response rate (RR). Progression-free survival (PFS) and overall survival (OS) were secondary endpoints. Planned sample size was 40/arm: Arm A the hypotheses (PSA RR&lt;40% vs. &gt;60%) could be tested at 10% β and 10% α, Arm B the true PSA RR could be estimated with half-width of the 90% CI&lt;13% if PSA RR=40%. Results: 82 pts (41 Arm A, 41 Arm B) were randomized from 09/05–12/06. At this analysis time, all pts are off therapy and 49 have died. One pt was ineligible but included in ITT survival analysis. Baseline characteristics were similar: median age 69 (49–87), PSA &gt;100 μg/L in 51%, Hgb ≥100 g/L in 98%, alk phos &gt;ULN in 44%, LDH &gt;ULN in 36%, ECOG performance status (PS) 0:1 in 51%:49%, bone/lymph node/visceral metastases in 69%/50%/28%. Median cycles for Arm A and B was 9 and 7. Adverse events associated with OGX included fatigue, fever, rigors, diarrhea and rash. Mean serum clusterin change on day 1 cycle 2 was -18% in Arm A and +8% in Arm B (p = 0.0005). PSA RR was 58% (Arm A) and 54% (Arm B). PSA declines at 12 weeks of any/&gt;30%/&gt;50% was observed in 87%/65%/45% (Arm A) and 68%/58%/34% (Arm B). PSA/objective disease progression as best response occurred in 0%/4% (Arm A), and 3%/17% (Arm B). PFS for Arms A and B was 7.3 (5.3–8.8) and 6.1 months (3.7–8.6). Median OS for Arms A and B was 27.5 (19.2-∞) and 16.9 months (12.7–26.0) (unadjusted HR = 0.60 [0.34–1.06], p = 0.07). Variables predictive of OS on multivariate analysis: PS 0 vs 1 (p = 0.0002), presence of visceral metastasis (p = 0.006) and treatment assignment (HR = 0.54 [0.29–0.97], p = 0.04). Conclusions: The PSA RR in both arms met criterion for further study. OGX reduced serum clusterin and OS appears superior with DOC/OGX. This combination warrants further evaluation. Supported by a grant from the NCI-Canada/Canadian Cancer Society. [Table: see text]