Preclinical Evaluation of Ureidosulfamate Carbonic Anhydrase IX/XII Inhibitors in the Treatment of Cancers

Carbonic anhydrases (CAs) are a family of enzymes involved in the pH regulation of metabolically active cells/tissues. Upregulation of the CAIX/XII isoforms is associated with hypoxic tumours and clinically linked with malignant progression, treatment resistance and poor prognosis. The elucidation of the crystal structure of the catalytic domains of CAIX/XII provided the basis for the generation of CAIX/XII selective inhibitors based on the sulfonamide, sulfamate and coumarins chemical structures. Ureido-substituted benzenesulfonamide CAIX/XII inhibitors have shown significant potential, with U-104 (SLC-0111) currently present in clinical Phase I/II. Ureido-substituted sulfamate CAIX/XII inhibitors have received less attention despite encouraging preclinical test results. In triple-negative breast cancer (TNBC), ureidosulfamates revealed a significant antitumour (FC9-398A) and antimetastatic potential (S4). In small cell lung cancer (SCLC), a cancer cell type very sensitive to a dysregulation in CAIX signaling, S4 treatment was particularly effective when combined with cisplatin with no evidence of acquired cisplatin-resistance. These successful anticancer strategies should provide a solid basis for future studies on ureido-substituted sulfamates

Hunting in times of change: Uncovering indigenous strategies in the Colombian amazon using a role-playing game

Despite growing industrialization, the shift to a cash economy and natural resource overexploitation, indigenous people of the Amazon region hunt and trade wildlife in order to meet their livelihood requirements. Individual strategies, shaped by the hunters' values and expectations, are changing in response to the region's economic development, but they still face the contrasting challenges of poverty and overhunting. For conservation initiatives to be implemented effectively, it is crucial to take into account people's strategies with their underlying drivers and their adaptive capabilities within a transforming socio-economic environment. To uncover hunting strategies in the Colombian Amazon and their evolution under the current transition, we co-designed a role-playing game together with the local stakeholders. The game revolves around the tension between ecological sustainability and food security—hunters' current main concern. It simulates the mosaic of activities that indigenous people perform in the wet and dry season, while also allowing for specific hunting strategies. Socio-economic conditions change while the game unfolds, opening up to emerging alternative potential scenarios suggested by the stakeholders themselves. Do hunters give up hunting when given the opportunity of an alternative income and protein source? Do institutional changes affect their livelihoods? We played the game between October and December 2016 with 39 players—all of them hunters—from 9 different communities within the Ticoya reserve. Our results show that providing alternatives would decrease overall hunting effort, but impacts are not spatially homogenous. Legalizing trade could lead to overhunting except when market rules and competition come into place. When it comes to coupled human-nature systems, the best way forward to produce socially just and resilient conservation strategies might be to trigger an adaptive process of experiential learning and scenario exploration. The use of games as “boundary objects” can guide stakeholders through the process, eliciting the plurality of their strategies, their drivers and how outside change affects them

Effect of first line cancer treatment on the ovarian reserve and follicular density in girls under the age of 18 years

The Child Cancer Foundation in Denmark, The Novo Nordisk Foundation and the EU interregional project ReproHigh/ReproUnion are thanked for having funded this study.Objective: To study the impact of first-line antineoplastic treatment on the ovarian reserve in young girls returning for ovarian tissue cryopreservation (OTC) in connection with a relapse. Design: Retrospective case-control study. Setting: University hospitals. Patients: Sixty-three girls under the age of 18 years who underwent OTC before (group 1: 31 patients) and after (group 2: 32 patients) their initial cancer treatment. Intervention(s): None. Main Outcome Measure(s): Follicular densities (follicles/mm3) measured from an ovarian cortical biopsy before OTC. The ovarian volume (mL) of entire ovaries excised for OTC was also monitored. Result(s):There was no statistically significant difference in the mean age or follicular density between groups 1 and 2 (334 ± 476/mm3 vs. 327 ± 756/mm3). In contrast, the ovarian volume and total number of ovarian cortex chips cryopreserved were statistically significantly lower in patients who received gonadotoxic treatment before OTC (mean ± standard deviation [SD]: ovarian volume, 5.3 ± 3.1 mL vs. 2.9 ± 2.1 mL, respectively; number of cortex chips: 21.3 ± 8.1 vs. 15.2 ± 7.1, respectively). The reduction in the estimated ovarian reserve ranged from 10% to 20% in children to around 30% in adolescent girls (>10 years). Conclusion(s): Girls under the age of 10 tolerate a gonadotoxic insult better than adolescents, who may experience up to a 30% reduction in the ovarian reserve via first-line gonadotoxic treatment, which at present is considered to have little effect on the follicle pool. This information will improve counseling of young female cancer patients in deciding whether to undergo fertility preservation treatment.PostprintPeer reviewe

Fertility preservation in pre-pubertal girls with cancer : the role of ovarian tissue cryopreservation

Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.With increasing numbers of survivors of cancer in young people future fertility and ovarian function are important considerations that should be discussed before treatment commences. Some young people, by nature of the treatment they will receive, are at high risk of premature ovarian insufficiency and infertility. For them, ovarian tissue cryopreservation (OTC) is one approach to fertility preservation that remains both invasive and for young patients experimental. There are important ethical and consent issues that need to be explored and accepted before OTC can be considered established in children with cancer. In this review we have discussed a framework for patient selection which has been shown to be effective in identifying those patients at high risk of premature ovarian insufficiency (POI) and who can be offered OTC safely.PostprintPeer reviewe

مطالعه اثرات α توکوفرول و هورمون محرک فوليکولی روی بلوغ فوليکول‌های پره آنترال موش‌های نابالغ و اووسيت محصور در آن

زمينه و هدف: بلوغ اووسيت در محيطin vitro (IVM) راه تازه‌ای برای کاهش هزينه و تقليل اثرات جانبی تحريکات گنادوتروپين برای لقاح در محيط in vitro (IVF)است. برای ارزيابی بهتر ماهيت و اثرات هورمون‌های مختلف و پارامترهای مهم روی رشد و حفظ اووسيت‌ها در محيط in vitro، مطالعه حاضر انجام شد. هدف از انجام اين پژوهش مطالعه اثرات α توکوفرول و هورمون محرک فوليکولی روی بلوغ فوليکول‌های پره آنترال موش‌های نابالغ و اووسيت محصور در آن بود. روش کار: برای انجام آزمايش، فوليکول‌های پره آنترال سالم از تخمدان‌های موش‌های ماده 6 هفته‌ای جدا و در محيط in vitro کشت داده شدند. فوليکول‌های پره آنترال در طول دوره 6 روزه کشت در حضور غلظتهای 5، 20، 40، 60، 100، 180،140 و mIU/ml220 از FSH و غلظت‌های 20، 40، 80، 240، 300 و nmol/ml 400 از α توکوفرول (ويتامين E) قرار گرفتند. فوليکول‌ها داخل انکوباتور با درجه حرارتC °37، رطوبت %92 و CO2 برابر %5 در هوا قرارگرفتند. اثرات مواد مختلف روی بلوغ اووسيت، گسيختگی وزيکول ژرمينال، تغيير قطر فوليکولها و ميزان ماندگاری آنها مورد بررسی قرار گرفت. نوع مطالعه تحقيقی بود و آناليز‌های آماری با استفاده از نرم‌افزار SPSS و آزمون ANOVA يکطرفه انجام گرفت. يافته‌ها: در غلظت FSH IU/l100 افزايش قابل توجهی در قطر فوليکولی (µm 5 ±190)،‌ ميزان زيست پذيری(4 ± 91٪)، GVBD(3 ± 81٪) و بلوغ اووسيت(6 ± 59٪) مشاهده شد. α توکوفرول بقاء فوليکولی را افزايش داد اما روی قطر، GVBD و ميزان بلوغ اووسيت اثری نداشت. در حاليکه محيط حاوی ترکيب α توکوفرول و FSH افزايش قابل توجهی در تمام پارامترها شامل قطر فوليکولی (µm 5 ±210)،‌ ميزان زيست پذيری( 3 ± 95٪)، GVBD(3 ± 93٪) و بلوغ اووسيت(5 ± 76٪) نشان داد. نتيجه‌گيری: FSH و ويتامين E هر يک به تنهايی ميزان بلوغ فوليکول و اووسيت داخل آن را افزايش می‌دهند اما ترکيب آنها تآثير قابل توجه‌تری روی سرعت رشد فوليکول‌ها و اووسيت محصور در آن دارد

Event analytics

The process analysis toolkit (PAT) integrates the expressiveness of state, event, time, and probability-based languages with the power of model checking. PAT is a self-contained reasoning system for system specification, simulation, and verification. PAT currently supports a wide range of 12 different expressive modeling languages with many application domains and has attracted thousands of registered users from hundreds of organizations. In this invited talk, we will present the PAT system and its vision on “Event Analytics” (EA) which is beyond “Data Analytics”. The EA research is based on applying model checking to event planning, scheduling, prediction, strategy analysis and decision making. Various new EA research directions will be discussed.No Full Tex

Efecto de adicionar ácido ascórbico al medio de vitrificación de folículos preantrales bovinos

The aim of this study was to evaluate the effect of adding ascorbic acid (AA) to the vitrification medium of bovine preantral follicles (PFs) subjected previously to cooling at 4 °C for 4 h or 24 h. Ovaries were collected from Nelore heifers at 14 months of age. In the laboratory, ovarian fragments were removed from the cortical region and distributed to fragments as fresh control (C0h), and fragments to cooling at 4 ºC for 4 and 24 hours in TCM-199 plus HEPES and antibiotics. Of the cooled fragments, two were fixed as controls for each cooling time (C4h, C24h), and the remaining fragments were distributed in four vitrification treatments, using the TCM-199 medium associated with ethylene glycol and dimethyl sulfoxide (V), sucrose (VSUC) or ascorbic acid (VAA), and the treatment with ethylene glycol, dimethyl sulfoxide, sucrose and AA (VSUC+AA). After 72 h, fragments were warmed and fixed for histological analysis and mechanical follicular isolation. No difference (p>0.05) between C0h and C4h for morphologically normal PFs was detected (99.3 and 96.0%, respectively). Vitrification reduced the morphological integrity and follicular viability in all treatments compared to C0h; nevertheless, VAA treatment maintained the follicular viability like C24h (p>0.05). It is concluded that bovine PFs were conserved efficiently at 4 °C during 4 h, and the addition of ascorbic acid to the vitrification medium improved survival rates and kept the morphological integrity of the follicles.El objetivo del estudio fue evaluar el efecto de la adición de ácido ascórbico (AA) al medio de vitrificación de folículos preantrales (FPs) bovinos previamente enfriados a 4 °C durante 4 o 24 h. Se recolectaron ovarios de novillas Nelore a los 14 meses de edad. En el laboratorio se extrajeron fragmentos de ovario de la región cortical y se distribuyeron a fragmentos para control fresco (C0h), y fragmentos para refrigeración a 4 ºC por 4 y 24 horas en TCM-199 más HEPES y antibióticos. De los fragmentos enfriados, dos se fijaron como controles para cada tiempo de enfriamiento (C4h, C24h), y los restantes se distribuyeron en cuatro tratamientos de vitrificación, utilizando el medio TCM-199 asociado con etilenglicol y dimetilsulfóxido (V), sacarosa (VSUC) o ácido ascórbico (VAA), y el tratamiento con etilenglicol, dimetilsulfóxido, sacarosa y AA (VSUC+AA). Después de 72 h, los fragmentos se calentaron y fijaron para el análisis histológico y el aislamiento folicular mecánico. No se detectó diferencia (p>0.05) entre C0h y C4h para FPs morfológicamente normales (99.3 y 96.0%, respectivamente). La vitrificación redujo la integridad morfológica y la viabilidad folicular en todos los tratamientos en comparación con C0h; sin embargo, el tratamiento VAA mantuvo la viabilidad folicular similar a C24h (p>0.05). Se concluye que los FAs bovinos se conservaron eficientemente a 4 °C durante 4 h, y la adición de ácido ascórbico al medio de vitrificación mejoró las tasas de supervivencia y mantuvo la integridad morfológica folicular