Systemic therapies of Hepatocellular carcinoma (HCC): from preclinical to clinical studies

Introduzione Attualmente i principali punti critici del trattamento dell’HCC avanzato sono: 1) la mancanza di predittori di risposta alla terapia con sorafenib, 2) lo sviluppo resistenze al sorafenib, 3) la mancanza di terapie di seconda linea codificate. Scopo della tesi 1) ricerca di predittori clinico-laboratoristici di risposta al sorafenib in pazienti ambulatoriali con HCC; 2) valutazione dell’impatto della sospensione temporanea-definitiva del sorafenib in un modello murino di HCC mediante tecniche ecografiche; 3) valutazione dell’efficacia della capecitabina metronomica come seconda linea dell’HCC non responsivo a sorafenib. Risultati Studio-1: 94 pazienti con HCC trattato con sorafenib: a presenza di metastasi e PVT-neoplastica non sembra inficiare l’efficacia del sorafenib. AFP basale <19 ng/ml è risultata predittrice di maggiore sopravvivenza, mentre lo sviluppo di nausea di una peggiore sopravvivenza. Studio -2: 14 topi con xenografts di HCC: gruppo-1 trattato con placebo, gruppo-2 trattato con sorafenib con interruzione temporanea del farmaco e gruppo-3 trattato con sorafenib con sospensione definitiva del sorafenib. La CEUS targettata per il VEGFR2 ha mostrato al giorno 13 valori maggiori di dTE nel gruppo-3 confermato da un aumento del VEGFR2 al Western-Blot. I tumori del gruppo-2 dopo 2 giorni di ritrattamento, hanno mostrato un aumento dell’elasticità tissutale all’elastonografia. Studio-3:19 pazienti trattati con capecitabina metronomica dopo sorafenib. Il TTP è stato di 5 mesi (95% CI 0-10), la PFS di 3,6 mesi (95% CI 2,8-4,3) ed la OS di 6,3 mesi (95% CI 4-8,6). Conclusioni Lo sviluppo di nausea ed astenia ed AFP basale >19, sono risultati predittivi di una minore risposta al sorafenib. La sospensione temporanea del sorafenib in un modello murino di HCC non impedisce il ripristino della risposta tumorale, mentre una interruzione definitiva tende a stimolare un “effetto rebound” dell’angiogenesi. La capecitabina metronomica dopo sorafenib ha mostrato una discreta attività anti-neoplastica ed una sicurezza accettabile.introduction The main critical points of the treatment of advanced HCC are: 1 ) the lack of predictors of response to sorafenib , 2 ) the development of resistance to sorafenib , 3) the lack of second-line therapies. The aim of the study was: 1 ) to look for clinical-laboratoristic predictors of HCC response to sorafenib treatment , 2) to evaluate the impact of the temporary/permanent discontinuation of sorafenib in HCC xenografts using ultrasound-based techniques , 3) to evaluate the efficacy of metronomic capecitabine as second-line treatment in HCC patients after sorafenib. results Study-1: 94 HCC patients treated with sorafenib. The presence of metastasis and neoplastic-PVT appear not to affect the efficacy of sorafenib. Baseline AFP <19 ng / ml was a predictor of better survival. Study-2: 14 HCC-mice: group-1 treated with placebo, group -2 treated with sorafenib with temporary interruption and group-3 treated with sorafenib with permanent discontinuation. Targeted CEUS for VEGFR2 showed higher values of DTE at day 13 in the group-3 confirmed by Western -Blot analyses. Group -2 showed an increase in tissue elasticity after 2 days of re-treatment at sonoelastography. Study-3: 19 patients treated with metronomic capecitabine after sorafenib. The TTP was 5 months (95 % CI 0-10 ) and the OS was 6.3 months (95 % CI 4-8 , 6) . conclusions The development of nausea and fatigue, as well as a baseline AFP > 19 , are predictive of a lower response to sorafenib. The temporary suspension of sorafenib in a mouse model of HCC does not prevent the restoration of tumor response, while a permanent discontinuation tends to stimulate a "rebound effect" of angiogenesis. The metronomic capecitabine in patients with HCC after sorafenib showed a good anti-neoplastic activity and an acceptable safety profile

Sustainability and Well-Being: The Perception of Younger Generations and Their Expectations

The paper aims at analyzing the level of knowledge and the perception of the concepts of sustainability and well-being of high school students in Tuscany. It is an explorative study carried out during specific events held in high schools with the support of the teachers; during the events, students were asked to fill a questionnaire designed to elicit their relation with these topics as well as the level of involvement of their families. The results provide an interesting starting point for a debate about what the expectations of younger generations are and what we can do to match them. The debate moves from the assessment of the importance of sustainability and well-being indicators and the relevance of perceived threats. Moreover, the results put the role of institutions (and in particular that of public schools) under scrutiny to develop the level of awareness and to promote knowledge transfer

Sustainability and Food: a Text Analysis of the Scientific Literature

The paper analyses the evolution of the research debate related to sustainability and to the relation between food and sustainability. A number of text analysis techniques were combined for the investigation of scientific papers. The results stress how discourse analysis of sustainability in the pre-Rio period is mostly associated with agriculture and with a vision where the ecological and environmental aspects are dominant. In the post-Rio phase, the discussion about sustainability, though still strongly linked to environmental issues, enters a holistic dimension that includes social elements. The themes of energy and the sustainability of urban areas become central, and the scientific debate stresses the importance of indicators within an assessment approach linked to the relevance of planning and intervention aspects. The focus on the role of food within the debate on sustainability highlights a food security oriented approach in the pre-Rio phase, with a particular attention towards agriculture and third world Countries. In the post-Rio period, the focus of the analysis moves towards developed Countries. Even though food security remains a strongly significant element of the debate, the attention shifts towards consumers and food choices

Cal State San Bernardino Social Work Students\u27 Attitudes Toward Domestic Minor Sex-Trafficked (DMST) Youth

Domestic Minor Sex Trafficking (DMST) affects hundreds of thousands of youth every year. In the past, DMST youth were often viewed by law enforcement and the criminal justice system as offenders and were usually arrested for solicitation even though they were minors. While new laws have begun to identify youth as victims, it has not yet been ensured that social workers have adopted this perspective. This quantitative study\u27s purpose was to examine Cal State University San Bernardino (CSUSB) Bachelor of Social Work (BASW) and Master of Social Work (MSW) students\u27 attitudes toward DMST youth. Participants completed an online questionnaire using Qualtrics software. Data were analyzed using SPSS version 21, using statistical tests including frequencies, Pearson\u27s R, and ANOVA. The hypothesis that knowledge, exposure to curriculum, and past experiences impacted students\u27 stigmatization of DMST youth was not supported by the data. Instead, results indicated that CSUSB social work students did not stigmatize the DMST population. Because these findings cannot be generalized to social workers in the field, future research should explore whether social workers currently working with DMST youth stigmatize this population. These findings also have implications for the CSUSB School of Social Work as they revealed that some students lacked education about this population and, consequently, felt unprepared to work with this population

Process-specific cues for recruitment in sedimentary environments: Geochemical signals?

The most biologically and geochemically active marine sediments are characterized by steep chemical gradients within the top centimeters of sediment (Berner, 1980). A common feature of these environments is disruptions of surface sediments by both physical and biotic forces. Growth and mortality rates for new recruits are affected by many of these surface perturbations. At the same time, these disturbances also impose a discontinuity in concentration across the sediment-water interface, and accordingly, a change in surface chemistry. In this paper we present evidence that the cue used by juveniles to distinguish between recently disturbed and undisturbed surfaces may be disruption of geochemical gradients that are typical of nearshore benthic systems. New juveniles exposed to ammonium concentrations typical of disturbed surface sediments exhibit behaviors consistent with rejection of the habitat. Conversely, new juveniles placed onto sediments containing ammonium levels typical of undisturbed surficial sediments rapidly initiate burrowing activity, a sign of acceptability. We also present a numerical model, which assesses the dynamics of small-scale chemical shifts that accompany sediment disruption, to determine (a) what is the magnitude of surface chemistry changes associated with disturbance (i.e. what is the signal strength)? and (b) what are the spatial and temporal scales associated with the return to the undisturbed condition ( recovery )? Model results show that the signal strength, and the return to acceptable conditions, are strongly influenced by the initial gradient. Model predictions of the time required to recover indicate that times to recovery are longer than the interval between disturbance events, but are of the same temporal scale (minutes to hours). Thus, our results suggest that the dynamics of surficial gradients provide a strong signal over appropriate time scales that may reveal the intensity of disturbance and the likelihood of mortality for juveniles. As such, transport-reaction processes which govern porewater concentrations in surficial sediments may also play a role in recruitment processes

TRPV1 channels are critical brain inflammation detectors and neuropathic pain biomarkers in mice

The capsaicin receptor TRPV1 has been widely characterized in the sensory system as a key component of pain and inflammation. A large amount of evidence shows that TRPV1 is also functional in the brain although its role is still debated. Here we report that TRPV1 is highly expressed in microglial cells rather than neurons of the anterior cingulate cortex and other brain areas. We found that stimulation of microglial TRPV1 controls cortical microglia activation per se and indirectly enhances glutamatergic transmission in neurons by promoting extracellular microglial microvesicles shedding. Conversely, in the cortex of mice suffering from neuropathic pain, TRPV1 is also present in neurons affecting their intrinsic electrical properties and synaptic strength. Altogether, these findings identify brain TRPV1 as potential detector of harmful stimuli and a key player of microglia to neuron communication

Generation Y, wine and alcohol. A semantic differential approach to consumption analysis in Tuscany.

Abstract The aim of the study is the elicitation of the consumer's semantic perception of different alcoholic beverages in order to provide information for the definition of communication strategies for both the private sector (and specifically the wine industry) and the public decision maker. Such information can be seen as the basis of a wider social marketing construct aimed at the promotion of responsible drinking among young consumers. The semantic differential approach was used in this study. The data collection was based on a survey to 430 consumers between 18 and 35 years old in Tuscany, Italy. The database was organized in a three-way structure, indexing the data in a multiway matrix. The data were processed using a Multiple Factor Analysis (MFA). Moreover, homogeneous clusters of consumers were identified using a Hierarchical Clustering on Principal Components (HCPC) approach. The results of the study highlight that beer and spirits are mainly perceived as "Young", "Social", "Euphoric", "Happy", "Appealing" and "Trendy" beverages, while wine is associated mostly with terms such as "Pleasure", "Quality" and "Comfortable". Furthermore, the cluster analysis allowed for the identification of three groups of individuals with different approaches to alcohol drinking. The results of the study supply a useful information framework for the elaboration of specific communication strategies that, based on the drinking habits of young consumers and their perception of different beverages, can use a language that is very close to the consumer typologies. Such information can be helpful for both private and public communication strategies

Taking Pain Out of NGF: A “Painless” NGF Mutant, Linked to Hereditary Sensory Autonomic Neuropathy Type V, with Full Neurotrophic Activity

During adulthood, the neurotrophin Nerve Growth Factor (NGF) sensitizes nociceptors, thereby increasing the response to noxious stimuli. The relationship between NGF and pain is supported by genetic evidence: mutations in the NGF TrkA receptor in patients affected by an hereditary rare disease (Hereditary Sensory and Autonomic Neuropathy type IV, HSAN IV) determine a congenital form of severe pain insensitivity, with mental retardation, while a mutation in NGFB gene, leading to the aminoacid substitution R100W in mature NGF, determines a similar loss of pain perception, without overt cognitive neurological defects (HSAN V). The R100W mutation provokes a reduced processing of proNGF to mature NGF in cultured cells and a higher percentage of neurotrophin secreted is in the proNGF form. Moreover, using Surface Plasmon Resonance we showed that the R100W mutation does not affect NGF binding to TrkA, while it abolishes NGF binding to p75NTR receptors. However, it remains to be clarified whether the major impact of the mutation is on the biological function of proNGF or of mature NGF and to what extent the effects of the R100W mutation on the HSAN V clinical phenotype are developmental, or whether they reflect an impaired effectiveness of NGF to regulate and mediate nociceptive transmission in adult sensory neurons. Here we show that the R100 mutation selectively alters some of the signaling pathways activated downstream of TrkA NGF receptors. NGFR100 mutants maintain identical neurotrophic and neuroprotective properties in a variety of cell assays, while displaying a significantly reduced pain-inducing activity in vivo (n = 8–10 mice/group). We also show that proNGF has a significantly reduced nociceptive activity, with respect to NGF. Both sets of results jointly contribute to elucidating the mechanisms underlying the clinical HSAN V manifestations, and to clarifying which receptors and intracellular signaling cascades participate in the pain sensitizing action of NGF

Quality of life and upper limb disability in Charcot-Marie-Tooth disease: A pilot study

Charcot-Marie-Tooth (CMT) patients present mainly lower limbs disability, with slowly progressive distal muscle weakness and atrophy, but hands impairment is a relevant problem affecting the quality of life (QoL). The evaluation of the upper limb is of primary importance. Often these patients present subclinical disorders or report difficulties in manipulating objects, with little evidence in the most used outcome measures. We aim to investigate the impact of hand impairment in the perceived QoL of CMT persons and secondly whether the Disability of Arm, Shoulder and Hand (DASH) scale can be useful in assessing upper limb abilities in CMT. We recruited 23 patients with confirmed genetic diagnosis of CMT. We performed a clinical evaluation with Sollerman Hand Function Test (SHFT), Thumb Opposition Test (TOT) and CMT examination score (CMTES). We completed the clinical assessment with DASH scale and the Short form 36 (SF36) questionnaire for a subjective evaluation of upper limb disability and quality of life. All patients also underwent an instrumental evaluation with a hand-held dynamometer measuring hand grip and tripod pinch and a sensor-engineered glove test (SEGT) to evaluate finger opposition movements in a quantitative spatial-temporal way. As expected, we found significant differences between CMT and control group performances in both clinical and instrumental assessment. Concerning QoL, we found that total score of SF36 and the SF36 Physical Composite Score (PCS) correlate with all clinical and instrumental Outcome Measures (OMs), particularly with Tripod pinch strength and TOT, which are considered major determinants of manual dexterity in CMT. DASH scale correlates with most clinical and instrumental OMs. Not surprisingly, we also found a correlation with DASH work, because CMT affects young patients engaged in work activities. However, we found a low correlation with the TOT and the dynamometer suggesting that DASH may not be the best scale for remote monitoring of upper limb disorders in CMT patients. Nevertheless, the results of our study confirm the usefulness of SF36 in recognizing the impact of upper limb disability in these subjects suggesting its use even in the remote monitoring of physical functioning

Revealing the Therapeutic Potential of Botulinum Neurotoxin Type A in Counteracting Paralysis and Neuropathic Pain in Spinally Injured Mice

Botulinum neurotoxin type A (BoNT/A) is a major therapeutic agent that has been proven to be a successful treatment for different neurological disorders, with emerging novel therapeutic indications each year. BoNT/A exerts its action by blocking SNARE complex formation and vesicle release through the specific cleavage of SNAP-25 protein; the toxin is able to block the release of pro-inflammatory molecules for months after its administration. Here we demonstrate the extraordinary capacity of BoNT/A to neutralize the complete paralysis and pain insensitivity induced in a murine model of severe spinal cord injury (SCI). We show that the toxin, spinally administered within one hour from spinal trauma, exerts a long-lasting proteolytic action, up to 60 days after its administration, and induces a complete recovery of muscle and motor function. BoNT/A modulates SCI-induced neuroglia hyperreactivity, facilitating axonal restoration, and preventing secondary cells death and damage. Moreover, we demonstrate that BoNT/A affects SCI-induced neuropathic pain after moderate spinal contusion, confirming its anti-nociceptive action in this kind of pain, as well. Our results provide the intriguing and real possibility to identify in BoNT/A a therapeutic tool in counteracting SCI-induced detrimental effects. Because of the well-documented BoNT/A pharmacology, safety, and toxicity, these findings strongly encourage clinical translation