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Curcumin and resveratrol are bioactive natural compounds displaying anti-inflammatory, anti-oxidant and anti-cancer properties. In this study, we compared the cytotoxic effects of these molecules and the molecular mechanisms involved against Her-2/neu-positive breast and salivary cancer cell lines. We found that both curcumin and resveratrol were efficient in reducing cancer cell survival and that they differently affected autophagy, ROS and activation of the PI3K/AKT/mTOR pathway. Moreover, we found that resveratrol and curcumin in combination exerted a stronger cytotoxic effect in correlation with the induction of a stronger ER stress and the upregulation of pro-death UPR molecule CHOP. This effect also correlated with the induction of pro-survival autophagy by curcumin and its inhibition by resveratrol. In conclusion, this study unveils new molecular mechanisms underlying the anti-cancer effects of resveratrol, curcumin and their combination, which can help to design new therapeutic strategies based on the use of these polyphenols.

This pilot study compared the effects of two attentional focus strategies on fitness parameters and body composition in outpatients with obesity. This was a randomized, controlled study that enrolled 94 obese individuals and allocated them into an internal focus group (IF) or an external focus group (EF) while performing six weeks of a home-based training program. The home-based exercise program was the same for both groups except for the instructions that shifted the attention to an external or an internal condition. At the beginning and after the intervention period, participants were assessed for functional performance using the Functional Movement Screen (FMS), body balance using the Modified Balance Error Scoring System (M-BESS) and muscular strength with the Handgrip Strength Test (HST) and the Five-Repetition Sit-To-Stand (FRSTS) test. Concerning body composition and anthropometric parameters, the body mass index (BMI) and fat mass percentage (FM%) were calculated. Significant improvements, main interactions and effects of time and groups were highlighted in the EF group as compared to the IF group in FMS (35% vs. 21%), M-BESS (42% vs. 18%), HST (13% vs. 7%) and FRSTS (23% vs. 12%) measures, while FM% (5%) and BMI (6% vs. 5%) showed a similar improvement overtime (p < 0.001). In conclusion, our findings provide initial evidence that a 6-week training program performed following external focus instruction is able to promote significant enhancements in movement efficiency, balance and muscular strength as compared to an internal focus cue. Fitness coaches and therapists might consider integrating a specific attentional focus strategy when designing rehabilitation programs in subjects with obesity.

// Alessia Garufi 1 , 2 , * , Gianandrea Traversi 1 , 2 , * , Maria Saveria Gilardini Montani 3 , Valerio D’Orazi 4 , Giuseppa Pistritto 5 , Mara Cirone 3 and Gabriella D’Orazi 1 , 2 1 IRCCS Regina Elena National Cancer Institute, Department of Research, Rome 00144, Italy 2 University ‘G. d’Annunzio’, Department of Medical and Biotechnological Sciences, Chieti 66013, Italy 3 Sapienza University, Department of Experimental Medicine, Rome 00161, Italy 4 Department of Surgical Sciences, Rome 00161, Italy 5 University Tor Vergata, Department of Systems Medicine, Rome 00133, Italy * These authors contributed equally to this work Correspondence to: Gabriella D’Orazi, email: gdorazi@unich.it Keywords: chemoresistance; reactive oxygen species (ROS); high glucose (HG); cancer; nuclear factor erythroid 2-related factor 2 (NRF2) Received: April 23, 2019 Accepted: July 05, 2019 Published: July 23, 2019 ABSTRACT Resistance to chemotherapy represents a major obstacle to successful treatment. The generation of reactive oxygen species (ROS) has been directly linked to the cytotoxic effects of several antitumor agents, including Adriamycin (ADR), and modulation of the oxidative balance has been implicated in the development and/or regulation of resistance to chemotherapeutic drugs. We recently showed that high glucose (HG) markedly diminished the cancer cell death induced by anticancer agents such as ADR. In the present study we attempted to evaluate the mechanism that impaired the cytotoxic effect of ADR in HG. We found that, in colon cancer cells, HG attenuated ADR-induced ROS production that consequently diminished ADR-induced H2AX phosphorylation and micronuclei (MN) formation. Mechanistically, HG attenuation of ADR-induced ROS production correlated with increased antioxidant response promoted by NRF2 activity. Thus, pharmacologic inhibition of NRF2 pathway by brusatol re-established the ADR cytotoxic effect impaired by HG. Together, the data provide new insights into chemotherapeutic-resistance mechanisms in HG condition dictated by increased NRF2-induced antioxidant response and how they may be overcome in order to restore chemosensitivity and ADR-induced cell death.

In the article by De Amicis et al. entitled "Patients with Severe Obesity during the COVID- 19 Pandemic: How to Maintain an Adequate Multidisciplinary Nutritional Rehabilitation Program?" [Obes Facts. 2021, DOI: 10.1159/000513283], the author list is incorrect. The correct author list is: De Amicis R. Cancello R. Capodaglio P. Gobbi M. Brunani A. Gilardini L. Castelnuovo G. Molinari E. Barbieri V. Mambrini S.P. Battezzati A. Bertoli S. © 2021 S. Karger AG. All rights reserved.

Background: The COVID-19 pandemic is spreading all over the world, particularly in developed countries where obesity is also widespread. There is a high frequency of increased BMI in patients admitted to intensive care for SARS-CoV-2 infection with a major severity in patients with an excess of visceral adiposity. Patients at risk of severe SARS-CoV-2 acute respiratory syndrome are characterised by the high prevalence of pre-existing diseases (high blood pressure and cardiovascular disease, diabetes, chronic respiratory disease, or cancer), most of them typically present in severely obese patients. Indeed, the biological role of adipose tissue in sustaining SARS-CoV-2 infection is not completely elucidated. Summary: The forced isolation due to pandemic containment measures abruptly interrupted the rehabilitation programs to which many patients with severe obesity were enrolled. People affected by obesity, and especially those with severe obesity, should continue clinical rehabilitation programs, taking extra measures to avoid COVID-19 infection and reinforcing the adoption of preventive procedures. In this review, the available data on obesity and COVID-19 are discussed along with evidence-based strategies for maintaining the necessary continuous rehabilitation programs. Key Messages: Greater attention is needed for obese and severely obese patients in the face of the current COVID-19 pandemic, which represents a huge challenge for both patients and healthcare professionals. The adoption of new strategies to guarantee adequate and continuous multidisciplinary nutritional rehabilitation programs will be crucial to control the severity of SARS-CoV-2 infection in high-risk populations as well as the worsening of obesity-linked complications. Health authorities should be urged to equip hospitals with tools for the diffusion of telemedicine to maintain physician-patient communication, which is fundamental in chronic and complicated obese patients.

Polyphenols have been shown to possess several beneficial properties, including properties involved in the prevention or treatment of cancer. Among these polyphenols, a leading role is played by dihydroxyphenylethanol (DPE), the most powerful antioxidant compound contained in the olive oil. DPE has been previously reported to induce endoplasmic reticulum (ER) stress and to reduce cell survival in colon cancer, one of the most common and aggressive cancers in developed countries. In this study, we further investigated the activation of UPR by DPE and explored the roles of the three UPR sensors, inositol-requiring enzyme (IRE) 1 alpha, protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor (ATF6), in the cell death–survival decision of wt and mutp53 colon cancer cells and the underlying mechanisms involved. We also unveiled a new interplay between ATF6 and wt, as well as mutp53, which may have important implications in cancer therapy.

p53 is the most frequently mutated or inactivated gene in cancer, as its activity is not reconcilable with tumor onset and progression. Moreover, mutations in the p53 gene give rise to mutant proteins such as p53-R273H that, besides losing the wild type p53 (wtp53) capacity to safeguard genome integrity, may promote carcinogenesis, mainly due to its crosstalk with pro-oncogenic pathways. Interestingly, the activation of oncogenic pathways is interconnected with reactive oxygen species (ROS) and the release of pro-inflammatory cytokines that contribute to create an inflammatory/pro-tumorigenic milieu. In this study, based on experiments involving p53-R273H silencing and transfection, we showed that this mutant p53 (mutp53) promoted cancer cell survival by increasing intracellular ROS level and pro-inflammatory/immune suppressive cytokine release, activating mTOR, reducing autophagy and mitophagy and downregulating uncoupling protein 2 (UCP2). Interestingly, p53-R273H transfection into cancer cells carrying wtp53 induced none of these effects and resulted in p21 upregulation. This suggests that wtp53 may counteract several pro-tumorigenic activities of p53-R273H and this could explain the lower aggressiveness of cancers carrying heterozygous mutp53 in comparison to those harboring homozygous mutp53.

Colon cancer is one of the most common cancers, currently treated with traditional chemotherapies or alternative therapies. However, these treatments are still not enough effective and induce several side effects, so that the search of new therapeutic strategies is needed. The use of Poly-(ADP-ribose)-polymerase (PARP) inhibitors, although originally approved against BRCA-1 or BRCA-2 mutated cancers, has been extended, particularly in combination with other treatments, to cure cancers that do not display defects in DNA repair signaling pathways. The role of p53 oncosuppressor in the regulating the outcome of PARP inhibitor treatment remains an open issue. In this study, we addressed this topic by using a well-tolerated PARP 1/2/3 inhibitor, namely AZD2461, against colon cancer cell lines with different p53 status. We found that AZD2461 reduced cell proliferation in wtp53 and p53-/- cancer cells by increasing ROS and DNA damage, while R273H mutant (mut) p53 counteracted these effects. Moreover, AZD2461 improved the reduction of cell proliferation by low dose radiation (IR) in wtp53 cancer cells, in which a down-regulation of BRCA-1 occurred. AZD2461 did not affect cell proliferation of mutp53 colon cancer cells also in combination with low dose radiation, suggesting that only wt p53 or p53 null colon cancer cells could benefit AZD2461 treatment.

Programmed death ligand 1 (PD-L1) up-regulation on antigen presenting cells induces T cell dysfunction, strongly impairing immune response. Human Herpesviruses (HHV) 6B is a β-herpesvirus that, although displays a higher tropism for T cells, can infect other immune cells including monocytes and dendritic cells (DCs) and neuronal cells. We have previously shown that HHV-6B infection of primary monocytes reduced autophagy and induced Endoplasmic Reticulum (ER) stress/ Unfolded Protein Response (UPR), impairing their survival and differentiation into DCs. In this study, we found that PD-L1 expression was up-regulated by HHV-6B on the surface of infected monocytes and that its extracellular release also increased, effects known to lead to an impairment of anti-viral immune response. At molecular level, PD-L1 up-regulation correlated with the activation of a positive regulatory circuit between the increase of intracellular ROS and the activation of STAT1 and STAT3 induced by HHV-6B, accompanied by a high release of pro-inflammatory/immune suppressive cytokines. In conclusion, this study unveils new strategies put in place by HHV-6B to induce immune dysfunction and the underlying molecular pathways that could be targeted to counteract such immune suppressive effects.

PEL is a rare B cell lymphoma associated with KSHV that mainly arises in immune-deficient individuals. The search for new drugs to treat this cancer is still ongoing given its aggressiveness and the poor response to chemotherapies. In this study, we found that DMF, a drug known for its anti-inflammatory properties which is registered for the treatment of psoriasis and relapsing–remitting MS, could be a promising therapeutic strategy against PEL. Indeed, although some mechanisms of resistance were induced, DMF activated NRF2, reduced ROS and inhibited the phosphorylation of STAT3 and the release of the pro-inflammatory and immune suppressive cytokines IL-6 and IL-10, which are known to sustain PEL survival. Interestingly, we observed that DMF displayed a stronger cytotoxic effect against fresh PEL cells in comparison to PEL cell lines, due to the activation of ERK1/2 and autophagy in the latter cells. This finding further encourages the possibility of using DMF for the treatment of PEL.

Background Two different systems for the screening and diagnosis of hypertension (HTN) in children currently coexist, namely, the guidelines of the 2017 American Academy of Pediatrics (AAP) and the 2016 European Society for Hypertension (ESH). The two systems differ in the lowered cut-offs proposed by the AAP versus ESH. Objectives We evaluated whether the reclassification of hypertension by the AAP guidelines in young people who were defined non-hypertensive by the ESH criteria would classify differently overweight/obese youth in relation to their cardiovascular risk profile. Methods A sample of 2929 overweight/obese young people (6–16 years) defined non-hypertensive by ESH (ESH–) was analysed. Echocardiographic data were available in 438 youth. Results Using the AAP criteria, 327/2929 (11%) young people were categorized as hypertensive (ESH–/AAP+). These youth were older, exhibited higher body mass index, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), triglycerides, total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C) ratio, blood pressure, left ventricular mass index and lower HDL-C (p Conclusions The reclassification of hypertension by the AAP guidelines in young people overweight/obese defined non-hypertensive by the ESH criteria identified a significant number of individuals with high blood pressure and abnormal cardiovascular risk. Our data support the need of a revision of the ESH criteria.

(1) Background. Visceral adiposity index (VAI) has been recently identified as a new cardiometabolic risk marker reflecting abdominal fat distribution and dyslipidaemia. The aim of the present paper was to evaluate the relationship between VAI, daily energy intake and metabolic syndrome (MetS) in a cohort of obese Caucasian children and adolescents, aged 8 to 15 years. (2) Methods. Consecutive Italian children and adolescents with obesity, according to World Health Organization were enrolled. Anthropometric parameters and blood pressure were measured. Fasting blood samples have been analyzed for lipids, insulin and glucose levels. MetS was diagnosed using identification and prevention of dietary- and lifestyle-induced health effects in children and infants (IDEFICS) or International Diabetes Federation (IDF) criteria according to age. Homeostatic model assessment index (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), A body shape index (ABSI) and VAI were calculated. Multivariable logistic regression analyses with sex, age and each anthropometric parameter (body mass index (BMI) z-score, ABSI, waist-to-height ratio (WHR)) or VAI was performed to predict MetS. Receiver operation curve (ROC) analysis was used to define the optimal VAI cut-off to identify MetS. Multiple regression was performed to predict the BMI z-score and VAI from daily energy intake after adjusting for age and sex. (3) Results. Six hundred and thirty-seven (313 boys and 324 girls) children and adolescents with obesity with median age 11 (interquartile range 10&ndash, 13) years were included in the analysis. MetS was diagnosed in 79 patients. VAI correlated with BMI, WHR, ABSI, HOMA-IR, QUICKI, systolic blood pressure, low- and high-density lipoprotein cholesterol, triglycerides and triglycerides-to-HDL ratio (p &lt, 0.050). Optimal VAI cut-off (AUC) values to identify MetS were 1.775 (0.774), 1.685 (0.776) and 1.875 (0.797) in the whole population, boys and girls, respectively. Energy intake was positively associated with BMI z-score but no association was found with VAI. (4) Conclusion. VAI is a promising tool to identify MetS in children and adolescents with obesity and should be used in the management of abdominal obesity together with dietary assessment.

Summary Obesity is an evolutionary, chronic, and relapsing disease that consists of a pathological accumulation of adipose tissue able to increase morbidity for high blood pressure, type 2 diabetes, metabolic syndrome, and obstructive sleep apnea in adults, children, and adolescents. Despite intense research over the last 20 years, obesity remains today a disease with a complex and multifactorial etiology. Recently, long non‐coding RNAs (lncRNAs) are emerging as interesting new regulators as different lncRNAs have been found to play a role in early and late phases of adipogenesis and to be implicated in obesity‐associated complications onset. In this review, we discuss the most recent advances on the role of lncRNAs in adipocyte biology and in obesity‐associated complications. Indeed, more and more researchers are focusing on investigating the underlying roles that these molecular modulators could play. Even if a significant number of evidence is correlation‐based, with lncRNAs being differentially expressed in a specific disease, recent works are now focused on deeply analyzing how lncRNAs can effectively modulate the disease pathogenesis onset and progression. LncRNAs possibly represent new molecular markers useful in the future for both the early diagnosis and a prompt clinical management of patients with obesity.

This study shows that pancreatic cancer cells undergoing cell death by valproic acid (VPA) treatment activated dendritic cells (DCs) more efficiently than those treated with trichostatin A (TSA), as demonstrated by CD86 and CD80 surface expression. Surprisingly though, DCs cultured in the presence of supernatant derived from VPA-treated cancer cells showed a reduced allostimulatory capacity and an increased release of IL10 and IL8 cytokines in comparison with those exposed to TSA-treated cell culture supernatant. Searching for molecular mechanisms leading to such differences, we found that VPA treatment dysregulated choline metabolism and triggered a stronger endoplasmic reticulum (ER) stress in pancreatic cancer cells than TSA, upregulating CCAAT/enhancer-binding protein homologous protein, and activated cyclooxygenase-2, thus promoting the release of prostaglandin (PG) E2. Interestingly, dysfunctional DCs cultured in the presence of VPA-treated cells culture supernatant showed a higher level of intracellular reactive oxygen species, 4-hydroxy-trans-2-nonenal protein adducts, and ER stress, as evidenced by the upregulation of spliced X-box binding protein 1 (XBP1s), effects that were reduced when DCs were exposed to supernatant of cancer cells treated with Celecoxib before VPA. Celecoxib prevented PGE2 release, restoring the function of DCs exposed to VPA-treated cells culture supernatant, and a similar effect was obtained by silencing XBP1s in DCs treated with VPA-treated cells culture supernatant. These results suggest that PGE2 could be one of the yet unidentified factors able to transfer the stress from cancer cells to DCs, resulting in an impairment of their function.

A major objective of the metabolic-nutritional-psychological multidisciplinary rehabilitation of obese subjects is providing a nutritional education aimed at achieving a weight loss and the improvement of obesity-related cardio-metabolic diseases. The impact of nutrition knowledge in healthy eating patterns and weight loss is still debated. The aim of this study was to identify whether the increase in nutrition knowledge is associated with weight loss.Two hundred fifty-six obese patients (80% women, mean age 57.5±12.4 years) were consecutively recruited among those referred for a three-month metabolic-nutritional-psychologic rehabilitation program. Education level and time of the onset of obesity were collected. Before and at the end of the intervention, anthropometric measures and body composition were assessed and the Moynihan Questionnaire (MQ) and the International Physical Activity Questionnaire administered. The weight loss maintenance was evaluated in patients who attended the 6-month follow-up visit.Nutrition knowledge was poor/sufficient in 97 out of 256 obese patients. The MQ Score was associated with the education level but not with age, gender and Body Mass Index. After rehabilitation, there was an increase in nutrition knowledge (mean score change -12±10.5%, P0.0001) in the whole group of patients as well as in those with poor knowledge, 77% of whom reached a good/high level of knowledge on healthy diet. The improvement in knowledge was greater in patients with a weight loss ≥5% (P0.05 vs. patients with a lower weight loss). Weight maintenance at follow-up, was associated with a better improvement in the nutritional knowledge during the previous rehabilitation.Weight-management programs should include a strong component of nutrition education to alleviate knowledge inequalities and promote more effective weight loss and control. The MQ may be a useful tool to verify the nutritional education carried out during the rehabilitation of obese subjects.

BACKGROUND A major objective of the metabolic-nutritional-psychological multidisciplinary rehabilitation of obese subjects is providing a nutritional education aimed at achieving a weight loss and the improvement of obesity-related cardio-metabolic diseases. The impact of nutrition knowledge in healthy eating patterns and weight loss is still debated. The aim of this study was to identify whether the increase in nutrition knowledge is associated with weight loss. METHODS Two hundred fifty-six obese patients (80% women, mean age 57.5±12.4 years) were consecutively recruited among those referred for a three-month metabolic-nutritional-psychologic rehabilitation program. Education level and time of the onset of obesity were collected. Before and at the end of the intervention, anthropometric measures and body composition were assessed and the Moynihan Questionnaire (MQ) and the International Physical Activity Questionnaire administered. The weight loss maintenance was evaluated in patients who attended the 6-month follow-up visit. RESULTS Nutrition knowledge was poor/sufficient in 97 out of 256 obese patients. The MQ Score was associated with the education level but not with age, gender and Body Mass Index. After rehabilitation, there was an increase in nutrition knowledge (mean score change -12±10.5%, P

Abstract Background Tumor progression and tumor response to anticancer therapies may be affected by activation of oncogenic pathways such as the antioxidant one induced by NRF2 (nuclear factor erythroid 2-related factor 2) transcription factor and the pathways modified by deregulation of oncosuppressor p53. Often, oncogenic pathways may crosstalk between them increasing tumor progression and resistance to anticancer therapies. Therefore, understanding that interplay is critical to improve cancer cell response to therapies. In this study we aimed at evaluating NRF2 and p53 in several cancer cell lines carrying different endogenous p53 status, using a novel curcumin compound since curcumin has been shown to target both NRF2 and p53 and have anti-tumor activity. Methods We performed biochemical and molecular studies by using pharmacologic of genetic inhibition of NRF2 to evaluate the effect of curcumin compound in cancer cell lines of different tumor types bearing wild-type (wt) p53, mutant (mut) p53 or p53 null status. Results We found that the curcumin compound induced a certain degree of cell death in all tested cancer cell lines, independently of the p53 status. At molecular level, the curcumin compound induced NRF2 activation, mutp53 degradation and/or wtp53 activation. Pharmacologic or genetic NRF2 inhibition further increased the curcumin-induced cell death in both mutp53- and wtp53-carrying cancer cell lines while it did not increase cell death in p53 null cells, suggesting a cytoprotective role for NRF2 and a critical role for functional p53 to achieve an efficient cancer cell response to therapy. Conclusions These findings underline the prosurvival role of curcumin-induced NRF2 expression in cancer cells even when cells underwent mutp53 downregulation and/or wtp53 activation. Thus, NRF2 inhibition increased cell demise particularly in cancer cells carrying p53 either wild-type or mutant suggesting that p53 is crucial for efficient cancer cell death. These results may represent a paradigm for better understanding the cancer cell response to therapies in order to design more efficient combined anticancer therapies targeting both NRF2 and p53.

HHV-6A and HHV-6B are neurotropic viruses able to dysregulate autophagy and activate ER stress/UPR in several cell types. The appropriate functioning of these processes is required for cell homeostasis, particularly in post-mitotic cells such as neuronal cells. Interestingly, neurodegenerative diseases such as Alzheimer's disease (AD) are often accompanied by autophagy dysregulation and abnormal UPR activation. This study demonstrated for the first time that HHV-6A infection of astrocytoma cells and primary neurons reduces autophagy, increases Aβ production and activates ER stress/UPR promoting tau protein hyper-phosphorylation. Our results support previous studies suggesting that HHV-6A infection may play a role in AD and unveil the possible underlying molecular mechanisms involved.

Human Herpes Virus-6 (HHV-6), Epstein-Barr Virus (EBV) and Kaposi Sarcoma Herpes Virus (KSHV) are viruses that share with other member of the Herpesvirus family the capacity to interfere with the autophagic process. In this paper, mainly based on the findings of our laboratory, we describe how, through different mechanisms, these viruses converge in reducing autophagy to impair DC immune function and how, by infecting and dysregulating autophagy in different cell types, they promote the pathologies associated with their infection, from the neurodegenerative diseases such Alzheimer’s disease to cancer.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of KS, an aggressive neoplasm that mainly occurs in immune-compromised patients. Spindle cells represent the main feature of this aggressive malignancy and arise from KSHV-infected endothelial cells undergoing endothelial to mesenchymal transition (EndMT), which changes their cytoskeletal composition and organization. As in epithelial to mesenchymal transition (EMT), EndMT is driven by transcription factors such as SNAI1 and ZEB1 and implies a cellular reprogramming mechanism regulated by several molecular pathways, particularly PI3K/AKT/MTOR. Here we found that KSHV activated MTOR and its targets 4EBP1 and ULK1 and reduced bulk macroautophagy and mitophagy to promote EndMT, activate ER stress/unfolded protein response (UPR), and increase the release of the pro-angiogenic and pro-inflammatory chemokine CCL2 by HUVEC cells. Our study suggests that the manipulation of macroautophagy, mitophagy and UPR and the interplay between the three could be a promising strategy to counteract EndMT, angiogenesis and inflammation, the key events of KSHV-driven sarcomagenesis.

HDAC inhibitors (HDACi) represent promising anti-cancer treatments, as the acetylation of histone and non-histone proteins is often dysregulated in cancer and contributes to cancer onset and progression. HDACi have been also reported to increase the cytotoxicity of DNA-damaging agents, such as radiation or cisplatin. In this study, we found that TSA and, even more effectively, VPA synergized with AZD2461, PARP1, 2 and 3 inhibitor (PARPi) to induce DNA damage and reduce pancreatic cancer cell survival. At a molecular level, VPA and TSA down-regulated CHK1 and RAD51, which is correlated with the interruption of the cross-talk between mutp53 and HSP70. Moreover, VPA and to a lesser extent TSA reactivated wtp53 in these cells, which contributed to CHK1 and RAD51 reduction. These findings suggest that the combination of HDACi and PARPi might improve the treatment of pancreatic cancer, which remains one of the most aggressive and therapy-resistant cancers.

The induction of DNA damage together with the interference with DNA repair represents a promising strategy in cancer treatment. Here we show that the PARP-1/2/3 inhibitor AZD2461 in combination with the CHK1 inhibitor UCN-01 altered the DNA damage response and reduced cell proliferation in PEL cells, an aggressive B cell lymphoma highly resistant to chemotherapies. AZD2461/UCN-01 combination activated p53/p21 and downregulated c-Myc in these cells, leading to a reduced expression level of RAD51, molecule involved in DNA repair. The effect of AZD2461/UCN-01 on c-Myc and p53/p21 was inter-dependent and, besides impairing cell proliferation, contributed to the activation of the replicative cycle of KSHV, carried in a latent state in PEL cells. Finally, we found that the pharmacological or genetic inhibition of p21 counteracted the viral lytic cycle activation and further reduced PEL cell proliferation, suggesting that it could induce a double beneficial effect in this setting. This study unveils that, therapeutic approaches, based on the induction of DNA damage and the reduction of DNA repair, could be used to successfully treat this malignant lymphoma.

The aim of this study was to determine the effects of two different home-based training interventions on functional parameters and body composition in obese patients. Sixty-four obese patients were recruited at the IRCCS Istituto Auxologico Italiano and randomly assigned into a movement quality group (MQ) and a conventional training group (CT). In the MQ, the training protocol combined various stimuli based on whole-body movement patterns, mobility, motor control and diaphragmatic breathing. The CT included traditional bodyweight resistance-training exercises. All patients were tested for movement efficiency (Functional Movement Screen, FMS), postural control (Modified Balance Error Scoring System, M-BESS), breathing pattern (Total Faulty Breathing Scale, TFBS), muscular strength (Handgrip Strength Test, HST and Five Repetition Sit to Stand, FRSTS) and body composition (Waist Circumference, WC, Body Mass Index, BMI, Body fat mass percentage, Fat Mass) before and after a 6-week period of training. Significant interactions and main effects of time (p &lt, 0.0001) were found in MQ compared to CT in the FMS, M-BESS and TFBS parameters, while muscular strength (HST, FRSTS) and body composition parameters improved similarly in both groups with a main effect of time (p &lt, 0.05). These findings suggest that a 6-week movement quality training is effective in ameliorating postural control and movement efficiency with similar improvements in muscular strength and body composition compared with a mere traditional home-based training. Fitness coaches and practitioners might consider the MQ intervention as a valuable alternative to conventional training when treating obesity.

OBJECTIVE: To investigate in a large sample of overweight/obese (OW/OB) children and adolescents the prevalence of prediabetic phenotypes such as impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), and to assess their association with cardiometabolic risk (CMR) factors including hepatic steatosis (HS). METHODS: Population data were obtained from the CARdiometabolic risk factors in children and adolescents in ITALY study. Between 2003 and 2013, 3088 youths (972 children and 2116 adolescents) received oral glucose tolerance test (OGTT) and were included in the study. In 798 individuals, abdominal ultrasound for identification of HS was available. RESULTS: The prevalence of IFG (3.2 vs. 3.3%) and IGT (4.6 vs. 5.0%) was similar between children and adolescents. Children with isolated IGT had a 2-11 fold increased risk of high LDL-C, non-HDL-C, Tg/HDL-C ratio, and low insulin sensitivity, when compared to those with normal glucose tolerance (NGT). No significant association of IFG with any CMR factor was found in children. Among adolescents, IGT subjects, and to a lesser extent those with IFG, showed a worse CMR profile compared to NGT subgroup. In the overall sample, IGT phenotype showed a twofold increased risk of HS compared to NGT subgroup. CONCLUSIONS: Our study shows an unexpected similar prevalence of IFG and IGT between children and adolescents with overweight/obesity. The IGT phenotype was associated with a worse CMR profile in both children and adolescents. Phenotyping prediabetes conditions by OGTT should be done as part of prediction and prevention of cardiometabolic diseases in OW/OB youth since early childhood.