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Supplementary Table 4 from CHR-2797: An Antiproliferative Aminopeptidase Inhibitor that Leads to Amino Acid Deprivation in Human Leukemic Cells

CHR-2797 is a novel metalloenzyme inhibitor that is converted into a pharmacologically active acid product (CHR-79888) inside cells. CHR-79888 is a potent inhibitor of a number of intracellular aminopeptidases, including leucine aminopeptidase. CHR-2797 exerts antiproliferative effects against a range of tumor cell lines in vitro and in vivo and shows selectivity for transformed over nontransformed cells. Its antiproliferative effects are at least 300 times more potent than the prototypical aminopeptidase inhibitor, bestatin. However, the mechanism by which inhibition of these enzymes leads to proliferative changes is not understood. Gene expression microarrays were used to profile changes in mRNA expression levels in the human promyelocytic leukemia cell line HL-60 treated with CHR-2797. This analysis showed that CHR-2797 treatment induced a transcriptional response indicative of amino acid depletion, the amino acid deprivation response, which involves up-regulation of amino acid synthetic genes, transporters, and tRNA synthetases. These changes were confirmed in other leukemic cell lines sensitive to the antiproliferative effects of CHR-2797. Furthermore, CHR-2797 treatment inhibited phosphorylation of mTOR substrates and reduced protein synthesis in HL-60 cells, both also indicative of amino acid depletion. Treatment with CHR-2797 led to an increase in the concentration of intracellular small peptides, the substrates of aminopeptidases. It is suggested that aminopeptidase inhibitors, such as CHR-2797 and bestatin, deplete sensitive tumor cells of amino acids by blocking protein recycling, and this generates an antiproliferative effect. CHR-2797 is orally bioavailable and currently undergoing phase II clinical investigation in the treatment of myeloid leukemia. [Cancer Res 2008;68(16):6669–79]

Supplementary Methods and Materials from CHR-2797: An Antiproliferative Aminopeptidase Inhibitor that Leads to Amino Acid Deprivation in Human Leukemic Cells

International audience; This study analysed the effects of increasing the longitudinal bending stiffness (LBS) of runners’ habitual shoes on the metabolic energetic demand, lower limb muscle activation and stride spatiotemporal parameters during a prolonged running session through classical group investigation, as well as a more individualised approach. Eleven recreational male participants ran overground for 40 min at 95% of their ventilatory anaerobic threshold with their own shoes or their shoes with higher LBS (stiff carbon plate inserted under insole). The net energetic cost of running, lower leg muscle activation and spatiotemporal parameters were measured during the prolonged running. The variables of interest were analysed for 1 min in seven time intervals. There were no main effects of LBS or interaction effects with running duration on the group averaged variables. Overall, the participant-specific metabolic effects induced by an increased shoe LBS were not beneficial. Beneficial metabolic effects were more likely to occur when the increased LBS induced a decrease or no change in the ground contact time relative to their habitual shoes, as well as for taller runners. Increasing the LBS in runners’ habitual shoes did not induce systematic metabolic effects for all the runners and may not be beneficial for performance purposes if the runners’ shoe habits were too disrupted.

Background The anterolateral thigh (ALT) flap is a workhorse flap in head and neck cancer reconstruction. The anteromedial thigh (AMT) flap was developed as a rescue or alternative flap whenever the ALT flap is not available; however, the harvest of AMT flap seems to be more challenging in the sense that perforators have multiple variations. This study was designed to compare the outcome of the AMT and ALT flaps in head and neck cancer reconstruction. Methods A total of 1,547 ALT and 57 AMT flaps were used for head and neck cancer reconstruction between March 1, 2008 and February 28, 2017. Differences in patient and operative characteristics were compared between the patients undergoing AMT and ALT flap reconstruction. The primary outcome of the free flap was its survival or failure, while the second outcome was the associated complications. Results Compared to those who had ALT flap reconstruction, the patients who underwent AMT flap reconstruction had a higher rate of conditions that required reconstruction after previous cancer ablation and recurrence but a lower rate of primary cancer and deeply located cancer. Analysis of the 40 well-balanced pairs of propensity-score-matched patient cohorts revealed that the AMT flaps were associated with a significantly higher failure rate than the ALT flaps (15.0 vs. 0.0%, respectively; p = .026). Conclusion This study revealed that AMT flaps were associated with a significantly higher failure rate than ALT flaps in head and neck cancer reconstruction in the cohort of total patients and the propensity-score-matched cohorts.

Agricultural residues of Rose flowers (Rosa x hybrida L.) are abundant, cheap, and renewable. These lignocellulosic remains are composed of cellulose, hemicellulose, and lignin. They are an attractive feedstock to produce various value-added products, as microcrystalline cellulose (MCC). The objective of this study was to obtain MCC from residual Rose stems (RS) using a successive alkaline peroxide treatment. X-ray diffraction, Fourier-transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and scanning electron microscopy (SEM) were used to determine the degree of crystallinity, structure characteristics, thermal properties, and morphology, respectively, of MCC. The properties of RS-MCC were compared with those of commercial MCC. The degree of crystallinity of RS-MCC was 70.21%. The X-ray diffraction patterns reveal the presence of Type I cellulose. FTIR showed the absence of non-cellulosic components, mainly lignin, present in the amorphous regions of the RS fibers. Results are promising for taking advantage of agricultural residues as a source of MCC, which could be used as a reinforcing agent in polymeric matrices.

International audience

Fractura de columna cervical con extensa artrodesis previa Tratamiento mediante triple corporectomía más artrodesis circunferencial

Sport shoes are expected to contribute to performance. A common indicator of running performance is running economy (RE; Fletcher, Esau, & MacIntosh, 2009), and a number of studies have investigate...

1,4-Dioxane (dioxane) is a groundwater contaminant of emerging concern for which bioremediation may become a practical remediation strategy. Therefore, it is important to advance our heuristic understanding of geochemical parameters that are most influential on the potential success of intrinsic bioremediation of dioxane-impacted sites. Here, Pearson's and Spearman's correlation and linear regression analyses were conducted to discern associations between 1,4-dioxane biodegradation activity measured in aerobic microcosms and groundwater geochemical parameters at four different contaminated sites. Dissolved oxygen, which is known to limit dioxane biodegradation, was excluded as a limiting factor in this analysis. Biodegradation activity was positively associated with dioxane concentrations (p

Introducción La fusión quirúrgica de la columna lumbar es un método muy utilizado para el tratamiento de la inestabilidad segmentaria lumbar dolorosa. En la actualidad, las dos técnicas de fusión instrumentada más utilizadas son la fusión posterolateral con tornillos pediculares y la fusión circunferencial mediante asociación de caja intersomática. Si bien hay evidencia de que la asociación de dispositivos intersomáticos aumenta la tasa de fusión, la mayoría de los estudios no discriminan si esta se produce solo de forma posterolateral o si se asocia una fusión anterior. El objetivo de este trabajo es determinar si existe fusión ósea real a nivel de las cajas intersomáticas o si estas actúan solo como espaciadores. Material y métodos Se analizaron 28 pacientes con patología de la columna lumbar sometidos a artrodesis lumbar circunferencial en un solo nivel entre mayo de 2007 y enero de 2012, mediante tomografía computarizada posquirúrgica para valorar la presencia o no de artrodesis anterior. Se efectuó un estudio de valor terapéutico, descriptivo, de observación (nivel de evidencia IV); mediante evaluación estadística se realizó un análisis de frecuencias para describir la proporción de casos con fusión anterior. Resultados Se detectó una tasa de fusión del 92,86% y falta de fusión radiológica anterior en el 7,14% de los pacientes. Conclusiones Hay una alta tasa de fusión anterior a nivel de las cajas intersomáticas; de este modo, se demuestra que dichos dispositivos actúan como medios de fusión y no solo como espaciadores.

This study investigated the removal of parabens, N,N-diethyl-m-toluamide (DEET), and phthalates by ozonation. The second-order rate constants for the reaction between selected compounds with ozone at pH 7 were of (2.2 +/-0.2) X 10(6) to (2.9 +/-0.3) X 10(6) M 1/s for parabens, (2.1+/- 0.3) to (3.9 +/-0.5) M-1/s for phthalates, and (5.2 +/-0.3) M-1/s for DEET. The rate constants for the reaction between selected compounds with hydroxyl radical ranged from (2.49 +/-0.06) x 10(9) to (8.5 +/-0.2) x 10(9) M-1/s. Ozonation of selected compounds in secondary wastewater and surface waters revealed that ozone dose of 1 and 3 mg/L yielded greater than 99% depletion of parabens and greater than 92% DEET and phthalates, respectively. In addition, parabens were found to transform almost exclusively through the reaction with ozone, while DEET and phthalates were transformed almost entirely by hydroxyl radicals (.OH).

Ion transporters are emerging targets of increasing importance to the pharmaceutical industry because of their relevance to a wide range of numerous indications of cardiovascular, metabolic, and inflammatory diseases. However, traditional ion transporter assay technologies using radioactive or fluorescent ligands and substrates or manual patch clamping suffer from several problems: limited sensitivity and robustness, significant numbers of false positives and false negatives, and cost. The authors describe a novel method for the measurement of ion transporters using cell-free electrophysiology based on the SURFE (2) R (surface electrogenic event reader) technology platform. The main advantages of the method described here are high sensitivity and simple handling. Material for assays is mainly a simple membrane preparation, which can be stored over weeks and months. Thus, the application of the method does not depend on a permanently running cell-culture lab. The application of the technology itself uses a bench-top system and chips loaded with membrane fragments. The SURFE (2) R technology was used to establish an Na+/Ca2+-exchanger assay. The assay performance, as judged by the Z' value of 0.73 and the signal-to-background ratio of 7.6, suggests that this is a reliable and robust assay. The authors compared the technology with patch-clamp experiments: The measurement of activity of 17 different inhibitors and the determination of an IC (50)value indicated a good correlation between SURFE (2) R technology and patch clamp results. Using the SURFE (2) R technology, results were obtained with 20 times higher throughput and required less-qualified personnel compared with manual patch clamping.

Objectives To determine the efficacy of a three-fold reduced dose (RD, 27 mg) of intravesical bacille Calmette-Gue´rin (BCG) against the standard dose (81 mg) in patients with superficial bladder cancer, assessing recurrence, progression and differences in toxicity. Patients and methods Five hundred patients with superficial bladder cancer (Ta, T1, Tis) were enrolled and randomly assigned to be treated after transurethral resection of all visible lesions with intravesical BCG Connaught strain (weekly×six and thereafter fortnightly×six) either with the standard or RD instillation. Results All but one of the 500 patients were evaluable for efficacy and toxicity (252 in the standard arm and 247 in the RD arm). The median follow-up was 69 months (maximum 104); 71 (28%) patients in the standard arm and 76 (31%) in the RD arm developed recurrences; the median time to recurrence has not yet been attained, but at 5 years the mean (sd) percentage of recurrence-free patients was 70.5 (3.12) and 70.4 (3.1) for the standard and RD arms, respectively. In patients presenting with multifocal tumours, the standard dose was more effective against recurrences than the RD (P=0.0151). In those with G3 and high-risk tumours overall, the superiority of the standard dose was marginal (P=0.060 and P=0.082). Twenty-nine (11.5%) tumours in the standard arm and 33 (13.3%) in the RD arm progressed to invasive disease; the median time to progression has not yet been attained, but the percentage of progression-free patients at 5 years was 88.8 (2.23) and 86.9 (2.31) for the standard and RD arms, respectively. The standard dose was more effective than the RD against progression only in patients with multifocal disease (P=0.048). Twelve (4.8%) cystectomies were performed in the standard and 15 (6.1%) in the RD arm. Currently, 106 (21.2%) patients have died, but only 38 (7.6%) from bladder cancer, i.e. 20 (7.9%) in the standard and 18 (7.5%) in RD arm. Overall the disease-specific death rate was lower for those patients who completed the scheduled treatment. The cause-specific survival at 5 years did not differ between the arms (P=0.76) but there was a trend toward better cause-specific survival for patients with multifocal tumours in the standard arm. Toxicity differed between the arms, significantly more patients having no toxicity in the RD arm, and fewer having delayed instillations or withdrawing. However, severe systemic toxicity occurred even in patients treated with the RD, in a similar proportion to those receiving the standard dose. Conclusion Overall, the RD gave similar results for recurrence and progression but with significantly less toxicity. However, patients with multifocal tumours fared better with the standard dose and there was a trend towards better recurrence rates in patients with high-risk tumours. We recommend continuing to use the standard dose for high-risk tumours, while we consider the reduced dose safe and effective for intermediate-risk lesions and for maintenance schedules.

Purpose: Although radical cystectomy is the standard therapy for invasive bladder cancer, cisplatin based multi-drug chemotherapy has proved to be effective for advanced transitional cell urothelial carcinoma. The potential for bladder preservation with neoadjuvant chemotherapy is currently under investigation.Materials and Methods: A phase 2 protocol is presented for conservative treatment of muscle invasive transitional cell carcinoma of the bladder consisting of primary cisplatin, methotrexate and vinblastine chemotherapy followed by reevaluation for bladder sparing surgery and surveillance. A total of 61 patients completed the protocol with a mean followup of 41.4 months.Results: Initial complete response to chemotherapy associated with tumor stage, size and configuration was noted in 20 patients (33 percent). Bladder preservation, intended only for the complete response group, was achieved in 16 patients (26 percent) but only 11 (18 percent) were alive with the bladder intact at study closure...

Vis plečiantis internete skelbiamam turiniui ir žinioms, bibliotekoms atsiveria galimybės teikti savo duomenis ir naujoviškai pristatyti savo rinkinius. Konceptualiai giminingą informaciją galima sieti semantiškai, taip praturtinant vartotojus gausesniais duomenų rinkiniais ir naujoviškomis paieškos galimybėmis, atsirandančiomis dėl medijoms, vie­tiniams metaduomenims ir išoriniams informacijos šaltiniams būdingų tarpusavio ryšių. Šiame straipsnyje pristatomi CONTENTUS projekte plėtojami bibliotekoms ir multimedijos archyvams skirti sprendimai, susiję su įvairialypių duomenų šaltinių integravimo ir inovatyvių semantinės paieškos koncepcijų teikimo iššūkiais.

Fractura de columna cervical con extensa artrodesis previa Tratamiento mediante triple corporectomia mas artrodesis circunferencial

From November 1984 to April 1989,122 patients with clinical T2-4a Nx-2 MO transitional cell carcinoma of the bladder were entered in a prospective randomized trial to compare survival between a control group of 60 patients treated only with radical cystectomy (arm A) and a group of 62 patients treated with 3 cycles of 100 mg./rn.' neoadjuvant cisplatin before radical cystectomy (arm B). Secondary objectives of the trial were comparison of the disease-free interval and time to death, significance of response of the primary tumor to cisplatin, pattern of relapse and toxicity. As of April 1993 after a median followup of 78.2 months (range 48 to 101) no difference in survival between the control patients and those who received neoadjuvant cisplatin has been observed. The overall direct survival is 37.3% for arm A and 35.5% for arm B. The survival rate of the 109 patients who complied with the protocol is 38.2% for 55 patients of the control group and 40.7% for 54 patients of the cisplatin group. Survival rates of patients theoretically rendered free of disease by radical cystectomy (complete response pTO-4a, pNO-2, MO) is 43.7% for 40 control patients and 47.8% for 41 cisplatin treated patients. The time to relapse in complete response patients was significantly longer (p = 0.0298) for those who received cisplatin (arm A 13.1 months versus arm B 30.3 months). The time to death (cause specific) did not differ significantly between both groups overall (p = 0.1349) but it was significantly different between controls and responders (p = 0.0501). Preoperative cisplatin downstaged the primary tumor in 19 patients (33.9%), of whom 11 (19.6%) had no tumor in the cystectomy specimen (pTO) and 8 (14.3%) had superficial tumor (pl'is pTa pT1). In 6 patients (9.7%) disease progressed during chemotherapy. The survival of the responders was significantly better than that of nonresponders (p = 0.0142), with specific death rate of 26.3% and 62.5%, respectively, and a median time to death of 43 months for responders and 30.5 months for nonresponders. Patients without nodal involvement (pNO) or with only 1 micrometastasis (pN1) fared significantly better (p = 0.0001) than those with major node invasion (pN2-4), irrespective of the treatment received. The survival rate is 48.6% for patients with pNO disease, 37.5% for pN1 and 5% for pN2-4. Toxicity of cisplatin was minimal and there were no differences in perioperative morbidity between the arms. In conclusion, 3 cycles of neoadjuvant cisplatin did not improve the overall survival of patients undergoing cystectomy for muscle infiltrating transitional cell bladder cancer, although they did prolong significantly the disease-free interval (p = 0.0298). Moreover a subgroup of patients whose primary tumor was downstaged by cisplatin showed a significant survival advantage over nonresponders (p = 0.0142). More than 50% of patients with invasive but nonmetastatic urothelial carcinoma of the bladder do not survive for 5 years after radical cystectomy and die of distant metastases despite good local control of the disease.' Combination therapy with preoperative radiation has not added any benefit to overall patient survival.2 Since most of the failures Seem to be caused by subclinical unrecognized disseminated disease at the time of local treatment, some clinicians have argued that systemic chemotherapy might be required to eradicate micrometastases and thereby improve survival."

From November 1984 to April 1989, 122 patients with clinical T2-4a Nx-2 M0 transitional cell carcinoma of the bladder were entered in a prospective randomized trial to compare survival between a control group of 60 patients treated only with radical cystectomy (arm A) and a group of 62 patients treated with 3 cycles of 100 mg./m2. neoadjuvant cisplatin before radical cystectomy (arm B). Secondary objectives of the trial were comparison of the disease-free interval and time to death, significance of response of the primary tumor to cisplatin, pattern of relapse and toxicity. As of April 1993 after a median followup of 78.2 months (range 48 to 101) no difference in survival between the control patients and those who received neoadjuvant cisplatin has been observed. The overall direct survival is 37.3% for arm A and 35.5% for arm B. The survival rate of the 109 patients who complied with the protocol is 38.2% for 55 patients of the control group and 40.7% for 54 patients of the cisplatin group. Survi...

The preliminary results of a randomized, multicentre, prospective trial conducted by the Spanish Oncology Group (CUETO) are presented. The primary aim of the trial was to determine whether or not lowering the dose of bacillus Calmette-Guerin (BCG) could reduce toxicity without compromising efficacy. From February 1991 to June 1992, 500 patients with superficial bladder cancer (TaG2-3, T1G1-3) entered the trial. Of these patients, 252 were included in group A (BCG, 81 mg) and 248 in group B (BCG, 27 mg). There were no significant differences in clinical and pathological characteristics between the two groups. Following treatment, significant differences arose between groups A and B in local severe toxicity (22.6 vs. 4.2%, respectively; p < 0.01). Systemic toxicity was more common in group A than in group B (p < 0.01): pulmonary effects (2.3 vs. 0.4%), fever (26.9 vs. 12.9%) and malaise (16.2 vs. 8.4%), all p < 0.01. Regarding efficacy, 204 patients in group A and 210 in group B were evaluated after a mean follow-up of 18.6 months. No significant differences in recurrence rate (18.1 vs. 19.5%) or progression rate (2.4 vs. 4.8%) were found. However, in patients with superficial bladder cancer with high risk of recurrence and progression (carcinoma in situ and G3), caution must be exercised in selecting the dose.

We present a case of renal vasculitis (polyarteritis nodosa) in a 36-year-old female prostitute having undetected HIV infection (AIDS-related complex) and chronic B-hepatitis. The pathogenesis and significance of the association between these entities are reviewed.

Objective To study the clinical, histological, and immuno-histochemical findings of small cell carcinoma (SCC) of the urinary bladder, and also to delineate its behaviour in comparison with transitional cell carcinomas of the bladder. Materials and methods A retrospective review of 552 patients with bladder cancer yielded six cases (1%) of small cell carcinoma which were histologically identical to pulmonary small cell anaplastic carcinoma. Clinical data and follow-up were collected. Aside from the conventional histological parameters, an immunohistochemical study with AE1–AE3 and Cam 5.2 keratins, epithelial membrane antigen, neuron-specific enolase, chromogranin, synaptophysin, ACTH, calcitonin, and prostatic specific antigen was performed. Results The clinical presentation did not differ from conventional transitional cell carcinoma, haematuria being the most frequent complaint (four cases). All the cases presented as flat tumours. On light microscopy, there were oat cell (four cases), intermediate (one case) and mixed oat-cellJintermediate (one case) variants. Three cases were associated with transitional cell carcinoma. Dysplastic changes were observed in the adjacent urothelium in one case only. At the time of diagnosis, all tumours were deeply invasive (pT3). Three cases were Stage III and three Stage IV, with involvement of regional lymph nodes and metastases to the liver (two cases) and lung (one case). Immunohistochemically, epithelial markers were variably expressed as AE1-AE3 keratin (5J6), Cam 5.2 keratin (2/6) and epithelial membrane antigen (3/6). Neuron specific enolase was demonstrated in every case. Chromogranin, however, was expressed in only one case. Synaptophysin, ACTH, calcitonin, and prostatic specific antigen all gave negative results. All the patients died of the disease and the overall length of survival was very poor (range 5–2 5 months, mean 13.3). Conclusion Small cell carcinomas show the same histological patterns as their pulmonary counterpart. Immunohistochemistry reveals a wide spectrum of activity, enolase and keratins being the most constant. The present study confirms that the overall prognosis of this tumour is very poor.

CONTENTUS ist ein Anwendungsszenario des Forschungsprogramms THESEUS, welches durch das Bundesministerium fur Wirtschaft und Technologie gefordert wird. Die Deutsche Nationalbibliothek (DNB) leitet das Projekt. Weitere Partner sind die Deutsche Thomson OHG (DTO, ein Tochterunternehmen von Technicolor), das Institut fur Rundfunktechnik (IRT), das Fraunhofer Institut fur Nachrichtentechnik - Heinrich-Hertz-Institut (HHI), das Fraunhofer Institut fur Intelligente Analyse- und Informationssysteme (IAIS), das Hasso-Plattner-Institut (HPI) und die mufin GmbH.