In vivo migration of labeled autologous natural killer cells to liver metastases in patients with colon carcinoma

BACKGROUND: Besides being the effectors of native anti-tumor cytotoxicity, NK cells participate in T-lymphocyte responses by promoting the maturation of dendritic cells (DC). Adherent NK (A-NK) cells constitute a subset of IL-2-stimulated NK cells which show increased expression of integrins and the ability to adhere to solid surface and to migrate, infiltrate, and destroy cancer. A critical issue in therapy of metastatic disease is the optimization of NK cell migration to tumor tissues and their persistence therein. This study compares localization to liver metastases of autologous A-NK cells administered via the systemic (intravenous, i.v.) versus locoregional (intraarterial, i.a.) routes. PATIENTS AND METHODS: A-NK cells expanded ex-vivo with IL-2 and labeled with (111)In-oxine were injected i.a. in the liver of three colon carcinoma patients. After 30 days, each patient had a new preparation of (111)In-A-NK cells injected i.v. Migration of these cells to various organs was evaluated by SPET and their differential localization to normal and neoplastic liver was demonstrated after i.v. injection of (99m)Tc-phytate. RESULTS: A-NK cells expressed a donor-dependent CD56(+)CD16(+)CD3(- )(NK) or CD56(+)CD16(+)CD3(+ )(NKT) phenotype. When injected i.v., these cells localized to the lung before being visible in the spleen and liver. By contrast, localization of i.a. injected A-NK cells was virtually confined to the spleen and liver. Binding of A-NK cells to liver neoplastic tissues was observed only after i.a. injections. CONCLUSION: This unique study design demonstrates that A-NK cells adoptively transferred to the liver via the intraarterial route have preferential access and substantial accumulation to the tumor site

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons

Exploring Effortful Control as a Moderator of the Relationship Between Negative Affect and Child Psychopathology

The present study examined unique and interactive effects of effortful control (self-report vs. task-based) on the relationship between negative affect and dimensions of psychopathology in a group of children from the ABCD Study® aged 9-11 (n = 5,432). Results demonstrate that the reactive temperament factor of negative affect showed strong and positive significant associations with both dimensions of psychopathology, while the regulative factor of effortful control showed a significant negative association with both dimensions of psychopathology via Flanker, and a significant positive association with both dimensions of psychopathology via the EATQ-R. These findings raise the possibility that early assessment of effortful control may aid in the identification of early risk profiles for psychopathology and that interventions aimed at maximizing flexible deployment of effort control could help to reduce children’s risk of developing psychopathological symptoms

Linking RDoC and HiTOP: A new interface for advancing psychiatric nosology and neuroscience

The Research Domain Criteria (RDoC) and the Hierarchical Taxonomy of Psychopathology (HiTOP) represent major dimensional frameworks proposing two alternative approaches to accelerate progress in the way psychopathology is studied, classified, and treated. RDoC is a research framework rooted in neuroscience aiming to further the understanding of transdiagnostic biobehavioral systems underlying psychopathology and ultimately inform future classifications. HiTOP is a dimensional classification system, derived from the observed covariation among symptoms of psychopathology and maladaptive traits, which seeks to provide more informative research and treatment targets (i.e., dimensional constructs and clinical assessments) than traditional diagnostic categories. This article argues that the complementary strengths of RDoC and HiTOP can be leveraged in order to achieve their respective goals. RDoC’s biobehavioral framework may help elucidate the underpinnings of the clinical dimensions included in HiTOP, whereas HiTOP may provide psychometrically robust clinical targets for RDoC-informed research. We present a comprehensive mapping between dimensions included in RDoC (constructs and subconstructs) and HiTOP (spectra and subfactors) based on narrative review of the empirical literature. The resulting RDoC-HiTOP interface sheds light on the biobehavioral correlates of clinical dimensions and provides a broad set of dimensional clinical targets for etiological and neuroscientific research. We conclude with future directions and practical recommendations for using this interface to advance clinical neuroscience and psychiatric nosology. Ultimately, we envision that this RDoC-HiTOP interface has the potential to inform the development of a unified, dimensional, and biobehaviorally-grounded psychiatric nosology

Il parto nel feto macrosoma. Revisione della letteratura

La stima ecografica del peso fetale ha un ampio margine di errore con sensibilità insoddisfacente per elevato numero di falsi positivi. Non è in grado di fornire basi sufficienti per processi decisionali clinici, sia nella politica di induzione al parto che nella programmazione del taglio cesareo che appare indicato solo per pesi >4.500 g in diabetiche e >5.000 g nelle non diabetiche. La stima del peso fetale può essere utilizzata per un’adeguata informazione alla coppia e presenza di medici competenti in sala parto. Sono necessarie un’attenta valutazione clinica della paziente e del mobile fetale e la corretta condotta ostetrica durante il travaglio ed il parto. In prospettiva lo sviluppo di nuove metodiche e nuove formule matematiche per il calcolo del peso fetale potrebbero migliorare l’accuratezza diagnostica degli ultrasuoni. Il rilievo di lesioni del plesso brachiale dopo parto apparentemente non complicato impone la necessità di evitare eccessive ed inopportune trazioni sulla testa fetale al momento del disimpegno delle spalle, così come i casi di lesioni del plesso brachiale dopo taglio cesareo elettivo mettono in evidenza l’esistenza di fattori intrauterini causa delle stesse

A novel 7-modified camptothecin analog overcomes breast cancer resistance protein-associated resistance in a mitoxantrone-selected colon carcinoma cell line

We selected a mitoxantrone-resistant HT29 colon carcinoma cell line (HT29/MIT) that exhibited a very high degree of resistance to the selecting agent and marked resistance to topotecan and SN38, but limited resistance to doxorubicin. The development of drug resistance was independent of expression of P-glycoprotein or multidrug resistance-associated protein but was associated with high up-regulation of the breast carcinoma resistance protein (BCRP) as shown by Western blot analysis. BCRP overexpression was associated with a reduced intracellular accumulation of topotecan, a known substrate for BCRP. Conversely, a lipophilic 7-modified camptothecin analogue (ST1481) displayed a complete lack of cross-resistance in HT29/MIT cells, suggesting that the drug was not a substrate for BCRP because no defects in intracellular accumulation were found. This conclusion is consistent with the antitumor efficacy of ST1481 against a BCRP-expressing tumor. These results may have therapeutic implications because the antitumor efficacy of ST1481 is in part related to a good bioavailability after oral administration, and the drug is currently under Phase I clinical evaluation