EV20-mediated delivery of cytotoxic auristatin MMAF exhibits potent therapeutic efficacy in cutaneous melanoma.

Abstract Cutaneous melanoma is one of the cancers with the fastest rising incidence and in its advanced metastatic form is a highly lethal disease. Despite the recent approval of several new drugs, the 5-year overall survival rate for advanced cutaneous melanoma is still below 20% and therefore, the development of novel treatments remains a primary need. Antibody-Drug Conjugates are an emerging novel class of anticancer agents, whose preclinical and clinical development has recently seen a remarkable increase in different tumors, including melanoma. Here, we have coupled the anti-HER-3 internalizing antibody EV20 to the cytotoxic drug monomethyl auristatin F (MMAF) to form a novel antibody-drug conjugate (EV20/MMAF). In a panel of human melanoma cell lines, this novel ADC shows a powerful, specific and target-dependent cell killing activity, independently of BRAF status. Efficacy studies demonstrated that a single administration of EV20/MMAF leads to a long-lasting tumor growth inhibition. Remarkably, the effect of this novel ADC was superior to the BRAF inhibitor vemurafenib in preventing kidney, liver and lung melanoma metastases. Overall, these results highlight EV20/MMAF as a novel ADC with promising therapeutic efficacy, warranting extensive pre-clinical evaluation in melanoma with high levels of HER-3 expression

LGALS3BP antibody-drug-conjugate and its use for the treatment of cancer

The present invention relates to a special type of non-internalizing binding moiety- drug-conjugates that specifically target LGALS3BP. From one aspect, the invention relates to an antibody-drug-conjugate comprising an antibody capable of binding to LGALS3BP, said antibody being conjugated to cytotoxic drugs. The invention also comprises methods of the treatment of LGALS3BP-expressing cancer, including administering to a patient the disclosed drug conjugates and pharmaceutical preparations

Secreted Gal-3BP is a novel promising target for non-internalizing Antibody–Drug Conjugates

Abstract Galectin-3-binding protein (Gal-3BP) has been identified as a cancer and metastasis-associated, secreted protein that is expressed by the large majority of cancers. The present study describes a special type of non-internalizing antibody-drug-conjugates that specifically target Gal-3BP. Here, we show that the humanized 1959 antibody, which specifically recognizes secreted Gal-3BP, selectively localized around tumor but not normal cells. A site specific disulfide linkage with thiol-maytansinoids to unpaired cysteine residues of 1959, resulting in a drug-antibody ratio of 2, yielded an ADC product, which cured A375m melanoma bearing mice. ADC products based on the non-internalizing 1959 antibody may be useful for the treatment of several human malignancies, as the cognate antigen is abundantly expressed and secreted by several cancers, while being present at low levels in most normal adult tissues

Public toilets have reduced enteric pathogen hazards in San Francisco

Uncontained fecal wastes in cities may present exposure risks to the public. We collected discarded feces from public spaces in San Francisco, CA for analysis by RT-qPCR for a range of enteric pathogens. Out of 59 samples, we found 12 (20%) were of human origin and 47 (80%) were non-human; 30 of 59 stools were positive for ≥1 of the 35 pathogens assessed, including pathogenic E. coli, Shigella, norovirus, Cryptosporidium, and Trichuris. Using quantitative enteric pathogen estimates and data on observed fecal waste from a public reporting system, we modeled pathogens removed from the environment attributable to a recently implemented program of public toilet construction. We estimated that each new public toilet reduced the annual number of enteric pathogens released into the immediate environment (within 500 m walking distance), including 6.3 x 1012 enteropathogenic E. coli (95% CI: 4.0 x 1012–7.9 x 1012), 3.2 x 1011 enteroaggregative E. coli (95% CI: 1.3 x 1011–6.3 x 1011), and 3.2 x 108 Shigella (6.3 x 107–2.5 x 109). Improving access to public sanitation can reduce enteric pathogen hazards in cities. Interventions must also consider the hygienic disposal of animal waste to reduce microbial hazards with zoonotic infection potential

Cross-syndrome comparison of real-world executive functioning and problem solving using a new problem-solving questionnaire

Background. Individuals with neurodevelopmental disorders like Williams syndrome and Down syndrome exhibit executive function impairments on experimental tasks (Lanfranchi, Jerman, Dal Pont, Alberti, & Vianello, 2010; Menghini, Addona, Costanzo, & Vicari, 2010), but the way that they use executive functioning for problem solving in everyday life has not hitherto been explored. The study aim is to understand cross-syndrome characteristics of everyday executive functioning and problem solving. Methods. Parents/carers of individuals with Williams syndrome (n=47) or Down syndrome (n=31) of a similar chronological age (m =17 years 4 months and 18 years respectively) as well as those of a group of younger typically developing children (n=34; m=8 years 3 months) completed two questionnaires: the Behavior Rating Inventory of Executive Function (BRIEF; Gioia, Isquith, Guy, & Kenworthy, 2000) and a novel Problem-Solving Questionnaire. Results. The rated likelihood of reaching a solution in a problem solving situation was lower for both syndromic groups than the typical group, and lower still for the Williams syndrome group than the Down syndrome group. The proportion of group members meeting the criterion for clinical significance on the BRIEF was also highest for the Williams syndrome group. While changing response, avoiding losing focus and maintaining perseverance were important for problem-solving success in all groups, asking for help and avoiding becoming emotional were also important for the Down syndrome and Williams syndrome groups respectively. Keeping possessions in order was a relative strength amongst BRIEF scales for the Down syndrome group. Conclusion. Results suggest that individuals with Down syndrome tend to use compensatory strategies for problem solving (asking for help and potentially, keeping items well ordered), while for individuals with Williams syndrome, emotional reactions disrupt their problem- solving skills. This paper highlights the importance of identifying syndrome-specific problem-solving strengths and difficulties to improve effective functioning in everyday life

Proceedings of the Thirteenth International Society of Sports Nutrition (ISSN) Conference and Expo

Meeting Abstracts: Proceedings of the Thirteenth International Society of Sports Nutrition (ISSN) Conference and Expo Clearwater Beach, FL, USA. 9-11 June 201

Transtornos neuroconductuales en niños, adolescentes y adultos jóvenes con síndrome de Down

El término diagnóstico-dual se refiere a una persona que tiene retraso mental y un trastorno psiquiátrico. La mayoría de los niños con síndrome de Down no tienen trastornos psiquiátricos o neuroconductuales. Los datos de la prevalencia actual de comorbilidad neuroconductual y psiquiátrica en niños con síndrome de Down están entre el 18 y el 38%. Hemos apreciado que es útil distinguir entre las situaciones que se inician antes de la pubertad de las que se presentan en la etapa postpuberal, ya que se trata de períodos biológicamente distintos, cada uno con su propia vulnerabilidad frente a trastornos psiquiátricos específicos. Debido a que se está reconociendo de forma creciente que pueden coexistir síntomas psiquiátricos junto con el retraso mental, y que no se encuentran irremisiblemente asociados al trastorno cognitivo, se considera que estas situaciones son tratables, en parte, conforme a un modelo médico. Uno de los objetivos más huidizos pero fundamentales de la intervención farmacológica en estos trastornos es mejorar la regulación fisiológica, la estabilidad emocional y el procesamiento neurocognitivo

Trastornos neuroconductuales en niños, adolescentes y adultos jóvenes con síndrome de Down: Segunda parte

El término diagnóstico-dual se refiere a una persona que tiene retraso mental y un trastorno psiquiátrico. La mayoría de los niños con síndrome de Down no tienen trastornos psiquiátricos o neuroconductuales. Los datos de la prevalencia actual de comorbilidad neuroconductual y psiquiátrica en niños con síndrome de Down están entre el 18 y el 38%. Hemos apreciado que es útil distinguir entre las situaciones que se inician antes de la pubertad de las que se presentan en la etapa postpuberal, ya que se trata de períodos biológicamente distintos, cada uno con su propia vulnerabilidad frente a trastornos psiquiátricos específicos. Debido a que se está reconociendo de forma creciente que pueden coexistir síntomas psiquiátricos junto con el retraso mental, y que no se encuentran irremisiblemente asociados al trastorno cognitivo, se considera que estas situaciones son tratables, en parte, conforme a un modelo médico. Uno de los objetivos más huidizos pero fundamentales de la intervención farmacológica en estos trastornos es mejorar la regulación fisiológica, la estabilidad emocional y el procesamiento neurocognitivo

HER3 targeting with an antibody‐drug conjugate bypasses resistance to anti‐HER2 therapies

Despite impressive clinical benefit obtained with anti‐HER2‐targeted therapies, in advances stages, especially in the metastatic setting, HER2‐positive tumors remain incurable. Therefore, it is important to develop novel strategies to fight these tumors, especially when they become resistant to available therapies. We show here that the anti‐HER3 antibody–drug conjugate EV20/MMAF exerted potent anti‐tumoral properties against several models of primary resistance and secondary resistance to common anti‐HER2 available therapies, including trastuzumab, lapatinib, neratinib, and trastuzumab‐emtansine. HER3 was expressed in these HER2+ breast cancer cells and knockdown experiments demonstrated that HER3 expression was required for the action of EV20/MMAF. In mice injected with trastuzumab‐resistant HER2+ cells, a single dose of EV20/MMAF caused complete and long‐lasting tumor regression. Mechanistically, EV20/MMAF bound to cell surface HER3 and became internalized to the lysosomes. Treatment with EV20/MMAF caused cell cycle arrest in mitosis and promoted cell death through mitotic catastrophe. These findings encourage the clinical testing of EV20/MMAF for several indications in the HER2+ cancer clinic, including situations in which HER2+ tumors become refractory to approved anti‐HER2 therapies.AP: Ministry of Economy and Competitiveness of Spain (BFU2015‐71371‐R), the Instituto de Salud Carlos III through the Spanish Cancer Centers Network Program (RD12/0036/0003) and CIBERONC, the Scientific Foundation of the Spanish Association Against Cancer (AECC), ALMOM, and the CRIS Cancer Foundation. Work carried out in AP and AO laboratories receives support from the European Community through the Regional Development Funding Program (FEDER). GS: Fondazione‐AIRC (IG GRANT 2016, Id 18467). EC is the recipient of an AIRC fellowship. LGS is recipient of a predoctoral contract (BES‐2016‐077748).Peer reviewe

Application of phylodynamics to identify spread of antimicrobial-resistant Escherichia coli between humans and canines in an urban environment

The transmission of antimicrobial resistant bacteria in the urban environment is poorly understood. We utilized genomic sequencing and phylogenetics to characterize the transmission dynamics of antimicrobial resistant Escherichia coli (AMR-Ec) cultured from putative canine (caninep) and human feces present on urban sidewalks in San Francisco, California. We isolated a total of fifty-six AMR-Ec isolates from human (n = 20) and caninep (n = 36) fecal samples from the Tenderloin and South of Market (SoMa) neighborhoods of San Francisco. We then analyzed phenotypic and genotypic antimicrobial resistance (AMR) of the isolates, as well as clonal relationships based on cgMLST and single nucleotide polymorphisms (SNPs) of the core genomes. Using Bayesian inference, we reconstructed the transmission dynamics between humans and caninesp from multiple local outbreak clusters using the marginal structured coalescent approximation (MASCOT). Our results provide evidence for multiple sharing events of AMR-Ec between humans and caninesp. In particular, we found one instance of likely transmission from caninesp to humans as well as an additional local outbreak cluster consisting of one caninep and one human sample. Based on this analysis, it appears that non-human feces act as an important reservoir of clinically relevant AMR-Ec within the urban environment for this study population. This work showcases the utility of genomic epidemiology to reconstruct potential pathways by which antimicrobial resistance spreads