Novel and selective inactivators of Triosephosphate isomerase with anti-trematode activity

International audienceTrematode infections such as schistosomiasis and fascioliasis cause signifcant morbidity in an estimated 250 million people worldwide and the associated agricultural losses are estimated at more than US$ 6 billion per year. Current chemotherapy is limited. Triosephosphate isomerase (TIM), an enzyme of the glycolytic pathway, has emerged as a useful drug target in many parasites, including Fasciola hepatica TIM (FhTIM). We identifed 21 novel compounds that selectively inhibit this enzyme. Using microscale thermophoresis we explored the interaction between target and compounds and identifed a potent interaction between the sulfonyl-1,2,4-thiadiazole (compound 187) and FhTIM,which showed an IC50 of 5µM and a Kd of 66nM. In only 4hours, this compound killed the juvenile form of F. hepatica with an IC50 of 3µM, better than the reference drug triclabendazole (TCZ). Interestingly, we discovered in vitro inhibition of FhTIM by TCZ, with an IC50 of 7µM suggesting a previously uncharacterized role of FhTIM in the mechanism of action of this drug. Compound 187 was also active against various developmental stages of Schistosoma mansoni. The low toxicity in vitro in diferent cell types and lack of acute toxicity in mice was demonstrated for this compound, as was demonstrated the efcacy of 187 in vivo in F. hepatica infected mice. Finally, we obtained the frst crystal structure ofFhTIM at 1.9Å resolution which allows us using docking to suggest a mechanism of interaction between compound 187 and TIM. In conclusion, we describe a promising drug candidate to control neglected trematode infections in human and animal health

Programa de internacionalización de los productos de “Finca La Isla”.

Dentro del proyecto 3J04 “Inteligencia Cultural y Comercial para los Negocios Internacionales”, se realizó el programa de internacionalización de varios productos naturales de la empresa “Finca La Isla”. Estos van desde: Miel, Jengibre, Vainilla, Cúrcuma, Canela, entre otros. El proyecto se centró en la exportación de la miel en dos destinos: Alemania y Turquía, centrándose en las ferias Internacionales de la Anuga 2023, en Cologne, y Apimondia 2022 en Estambul. El proyecto nos llevó a crear un brochure, en donde se pueden encontrar diferentes aspectos económicos, culturales, sociales, políticos, y de mercado, para que el empresario tenga en cuenta todo antes de iniciar la inversión. Nos dividimos en dos equipos de trabajo, cada uno enfocado en un paísITESO, A.C

Dose volume histogram constraints in patients with soft tissue sarcomas of the extremities and the superficial trunk treated with surgery and perioperative HDR brachytherapy

Background: Wound healing complications (WHC), osteoradionecrosis (ORN), and nerve damage (ND) are common adverse effects in adult patients with soft tissue sarcomas of the extremities and the superficial trunk treated with surgery and perioperative high dose rate brachytherapy (PHDRB) alone or combined with external beam radiotherapy (EBRT). Rationale: Analysis of the treatment factors contributing to these complications can potentially minimize their occurrence and severity. Patients: A total of 169 patients enrolled in two parallel prospective studies were included in this analysis. Previously Unirradiated cases (Group 1; n = 139) were treated with surgical resection, 16–24 Gy of PHDRB and 45 Gy of EBRT. Adjuvant chemotherapy was given to selected patients with high-grade tumors. Previously irradiated cases (Group 2; n = 30) were treated with surgical resection and 32– 40 Gy of PHDRB without further EBRT. Methods: Patient factors, tumor factors, surgical factors, PHDRB factors and EBRT factors were analyzed using Cox univariate and multivariate analysis. Results: In Previously Unirradiated cases, WHC, ORN and ND occurred in 38.8%, 5.0% and 19.4%. Multivariate analysis indicated that WHC increased with CTV size (p = 0.02) and CTV2cm3 Physical dose (p = 0.02). ORN increased with Bone2cm3 EQD2 67 Gy (p = 0.01) and ND was more frequent in patients with TV100 DVH-based dose (tissue volume encompassed by the 100% isodose) 84 Gy (p < 0.01). In Previously Irradiated cases, WHC, ORN and ND occurred in 63.3%, 3.3% and 23.3%. Multivariate analysis showed that WHC was more frequent in patients with Skin2cm3 Lifetime EQD2 84 Gy (p = 0.01) and ND was more frequent after CTVD90 Physical Doses 40 Gy (p < 0.01). Conclusions: WHC in Previously Unirradiated patients can be minimized by using a more conservative CTV definition together with a meticulous implant technique and planning aimed to minimize hyperdose CTV2cm3 areas. In Previously Irradiated patients WHC may be mimimized considering Lifetime EQD2 Skin2cm3 doses. ORN can be reduced by using the Bone2cm3 EQD2 constraint. ND occurs more frequently in patients with large tumors receiving high treated volume doses, but no specific constraints can be recommended due to the lack of peripheral nerve definition during brachytherapy planning

New and noteworthy bird records from the east slope of the andes of colombia

We present significant new information on the distribution and status of 138 speciesof birds from the Andean East Slope of Colombia, based upon fieldwork between1990 and 2000 at 28 sites from central Dpto. Boyacá south to the Ecuador border.The first Colombian specimens of two species (Campylopterus villaviscensio, NapoSabrewing; Myrmotherula spodionota, Foothill Antwren) are reported. Three othertaxa (Ocreatus underwoodii addae, Piculus leucolaemus leucolaemus andMyiophobus p. phoenicomitra), the first two sometimes considered species distinctfrom known Colombian forms, represent first reports from Colombia based uponsightings or photographs; we add several more sightings of two species (Pipreolachlorolepidota, Iridisornis analis) previously known from single sight records. Inall, we report 35 species from the Andean East Slope of Colombia for the first time,southward range extensions on this slope for 47 species, northward extensions for21, upward or downward altitudinal extensions for 19, filling in of major discontinuitiesin distribution for 22; for ten of the latter, known from very few reports, new informationindicates a continuous distribution and far greater abundance than previouslysupposed. Range extensions and previously undiscovered populations of severalrestricted-range, Vulnerable, Near-threatened and Threatened species help toemphasize the importance of implementing conservation measures in the face of the increasing colonization pressures and insecurity. Based on our observations, wepresent several recommendations for setting conservation priorities in this rich butstill relatively poorly known region

Programa de internacionalización de los productos de Finca La Isla

Dentro del proyecto 3J04 “Inteligencia Cultural y Comercial para los Negocios Internacionales”, se realizó el programa de internacionalización de varios productos naturales de la empresa “Finca La Isla”. Estos van desde: Miel, Jengibre, Vainilla, Cúrcuma, Canela, entre otros. El proyecto se centró en la exportación de la miel en dos destinos: Alemania y Turquía, centrándose en las ferias Internacionales de la Anuga 2023, en Colonia, y Apimondia 2022 en Estambul. El proyecto nos llevó a crear un brochure, en donde se pueden encontrar diferentes aspectos económicos, culturales, sociales, políticos, y de mercado, para que el empresario tenga en cuenta todo antes de iniciar la inversión. Nos dividimos en dos equipos de trabajo, cada uno enfocado en un país.ITESO, A.C

The discovery BPD (D-BPD) program: Study protocol of a prospective translational multicenter collaborative study to investigate determinants of chronic lung disease in very low birth weight infants

Background: Premature birth is a growing and serious public health problem affecting more than one of every ten infants worldwide. Bronchopulmonary dysplasia (BPD) is the most common neonatal morbidity associated with prematurity and infants with BPD suffer from increased incidence of respiratory infections, asthma, other forms of chronic lung illness, and death (Day and Ryan, Pediatr Res 81: 210-213, 2017; Isayama et la., JAMA Pediatr 171:271-279, 2017). BPD is now understood as a longitudinal disease process influenced by the intrauterine environment during gestation and modulated by gene-environment interactions throughout the neonatal and early childhood periods. Despite of this concept, there remains a paucity of multidisciplinary team-based approaches dedicated to the comprehensive study of this complex disease. Methods: The Discovery BPD (D-BPD) Program involves a cohort of infants < 1,250 g at birth prospectively followed until 6 years of age. The program integrates analysis of detailed clinical data by machine learning, genetic susceptibility and molecular translation studies. Discussion: The current gap in understanding BPD as a complex multi-trait spectrum of different disease endotypes will be addressed by a bedside-to-bench and bench-to-bedside approach in the D-BPD program. The D-BPD will provide enhanced understanding of mechanisms, evolution and consequences of lung diseases in preterm infants. The D-BPD program represents a unique opportunity to combine the expertise of biologists, neonatologists, pulmonologists, geneticists and biostatisticians to examine the disease process from multiple perspectives with a singular goal of improving outcomes of premature infants. Trial registration: Does not apply for this study.Fil: Ofman, Gaston. University of Alabama at Birmingahm; Estados UnidosFil: Caballero, Mauricio Tomás. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Álvarez Paggi, Damián Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Marzec, Jacqui. National Institute of Environmental Health Sciences; Estados UnidosFil: Nowogrodzki, Florencia. No especifíca;Fil: Cho, Hye Youn. National Institute of Environmental Health Sciences; Estados UnidosFil: Sorgetti, Mariana. No especifíca;Fil: Colantonio, Guillermo. No especifíca;Fil: Bianchi, Alejandra. No especifíca;Fil: Prudent, Luis M.. Fundación para la Salud Materno Infantil; ArgentinaFil: Vain, Néstor Eduardo. Fundación para la Salud Materno Infantil; Argentina. Sanatorio de la Trinidad Palermo.; ArgentinaFil: Mariani, Gonzalo Luis. Hospital Italiano; ArgentinaFil: Digregorio, Jorge. Sanatorio de la Trinidad Palermo.; ArgentinaFil: Lopez Turconi, Elba. No especifíca;Fil: Osio, Cristina. Sanatorio "Otamendi y Miroli S. A."; ArgentinaFil: Galletti, Maria Fernanda. Hospital Italiano; ArgentinaFil: Quiros, Mariangeles. Clinica y Maternidad Suizo Argentina; ArgentinaFil: Brum, Andrea. Sanatorio de la Trinidad Palermo.; ArgentinaFil: Lopez Garcia, Santiago. No especifíca;Fil: Garcia, Silvia. Sanatorio "Otamendi y Miroli S. A."; ArgentinaFil: Bell, Douglas. National Institute of Environmental Health Sciences; Estados UnidosFil: Jones, Marcus H.. Pontificia Universidade Católica do Rio Grande do Sul; BrasilFil: Tipple, Trent E.. University of Alabama at Birmingahm; Estados UnidosFil: Kleeberger, Steven R.. National Institute of Environmental Health Sciences; Estados UnidosFil: Polack, Fernando Pedro. University of Alabama at Birmingahm; Estados Unido

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Hospital-based proton therapy implementation during the COVID pandemic: early clinical and research experience in a European academic institution

Introduction A rapid deploy of unexpected early impact of the COVID pandemic in Spain was described in 2020. Oncology practice was revised to facilitate decision-making regarding multimodal therapy for prevalent cancer types amenable to multidisciplinary treatment in which the radiotherapy component searched more efcient options in the setting of the COVID-19 pandemic, minimizing the risks to patients whilst aiming to guarantee cancer outcomes. Methods A novel Proton Beam Therapy (PBT), Unit activity was analyzed in the period of March 2020 to March 2021. Institutional urgent, strict and mandatory clinical care standards for early diagnosis and treatment of COVID-19 infection were stablished in the hospital following national health-authorities’ recommendations. The temporary trends of patients care and research projects proposals were registered. Results 3 out of 14 members of the professional staf involved in the PBR intra-hospital process had a positive test for COVID infection. Also, 4 out of 100 patients had positive tests before initiating PBT, and 7 out of 100 developed positive tests along the weekly mandatory special checkup performed during PBT to all patients. An update of clinical performance at the PBT Unit at CUN Madrid in the initial 500 patients treated with PBT in the period from March 2020 to November 2022 registers a distribution of 131 (26%) pediatric patients, 63 (12%) head and neck cancer and central nervous system neoplasms and 123 (24%) re-irradiation indications. In November 2022, the activity reached a plateau in terms of patients under treatment and the impact of COVID pandemic became sporadic and controlled by minor medical actions. At present, the clinical data are consistent with an academic practice prospectively (NCT05151952). Research projects and scientifc production was adapted to the pandemic evolution and its infuence upon professional time availability. Seven research projects based in public funding were activated in this period and preliminary data on molecular imaging guided proton therapy in brain tumors and post-irradiation patterns of blood biomarkers are reported. Conclusions Hospital-based PBT in European academic institutions was impacted by COVID-19 pandemic, although clinical and research activities were developed and sustained. In the post-pandemic era, the benefts of online learning will shape the future of proton therapy education

Study protocol for the multicentre cohorts of Zika virus infection in pregnant women, infants, and acute clinical cases in Latin America and the Caribbean: The ZIKAlliance consortium

Background: The European Commission (EC) Horizon 2020 (H2020)-funded ZIKAlliance Consortium designed a multicentre study including pregnant women (PW), children (CH) and natural history (NH) cohorts. Clinical sites were selected over a wide geographic range within Latin America and the Caribbean, taking into account the dynamic course of the ZIKV epidemic. Methods: Recruitment to the PW cohort will take place in antenatal care clinics. PW will be enrolled regardless of symptoms and followed over the course of pregnancy, approximately every 4 weeks. PW will be revisited at delivery (or after miscarriage/abortion) to assess birth outcomes, including microcephaly and other congenital abnormalities according to the evolving definition of congenital Zika syndrome (CZS). After birth, children will be followed for 2 years in the CH cohort. Follow-up visits are scheduled at ages 1-3, 4-6, 12, and 24 months to assess neurocognitive and developmental milestones. In addition, a NH cohort for the characterization of symptomatic rash/fever illness was designed, including follow-up to capture persisting health problems. Blood, urine, and other biological materials will be collected, and tested for ZIKV and other relevant arboviral diseases (dengue, chikungunya, yellow fever) using RT-PCR or serological methods. A virtual, decentralized biobank will be created. Reciprocal clinical monitoring has been established between partner sites. Substudies of ZIKV seroprevalence, transmissio