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Rehabilitation plays a crucial role in cancer care, as the functioning of cancer survivors is frequently compromised by impairments that can result from the disease itself but also from the long-term sequelae of the treatment. Nevertheless, the current literature shows that only a minority of patients receive physical and/or cognitive rehabilitation. This lack of rehabilitative care is a consequence of many factors, one of which includes the transportation issues linked to disability that limit the patient’s access to rehabilitation facilities. The recent COVID-19 pandemic has further shown the benefits of improving telemedicine and home-based rehabilitative interventions to facilitate the delivery of rehabilitation programs when attendance at healthcare facilities is an obstacle. In recent years, researchers have been investigating the benefits of the application of virtual reality to rehabilitation. Virtual reality is shown to improve adherence and training intensity through gamification, allow the replication of real-life scenarios, and stimulate patients in a multimodal manner. In our present work, we offer an overview of the present literature on virtual reality-implemented cancer rehabilitation. The existence of wide margins for technological development allows us to expect further improvements, but more randomized controlled trials are needed to confirm the hypothesis that VRR may improve adherence rates and facilitate telerehabilitation.

Overweight and obesity constitute the most impactful lifestyle-dependent risk factors for cancer and have been tightly linked to a higher number of tumor-related deaths nowadays. The excessive accumulation of energy can lead to an imbalance in the level of essential cellular biomolecules that may result in inflammation and cell-cycle dysregulation. Nutritional strategies and phytochemicals are gaining interest in the management of obesity-related cancers, with several ongoing and completed clinical studies that support their effectiveness. At the same time, cyclin-dependent kinases (CDKs) are becoming an important target in breast and ovarian cancer treatment, with various FDA-approved CDK4/6 inhibitors that have recently received more attention for their potential role in diet-induced obesity (DIO). Here we provide an overview of the most recent studies involving nutraceuticals and other dietary strategies affecting cell-cycle pathways, which might impact the management of breast and ovarian cancers, as well as the repurposing of already commercialized chemotherapeutic options to treat DIO.

NONO is an RNA-binding protein involved in transcription, mRNA splicing, DNA repair, and checkpoint activation in response to UV radiation. NONO expression has been found altered in several tumor types, including prostate, colon, breast, melanoma, and in papillary renal carcinoma, in which an X chromosome inversion generates a NONO-TFE3 fusion protein. Upon such rearrangement, NONO loses its C-terminal domain. Through bioinformatics analysis, we identified a putative degron motif, known to be recognized by the Skp1-Cul1-F-box-protein (SCF) complex. Here, we evaluated how this domain could affect NONO protein biology. We showed that NONO interacts with the nuclear FBW7α isoform and its ubiquitination is regulated following modulation of the GSK3β kinase. Mutation of T428A/T432A within the degron impaired polyubiquitination upon FBW7α and GSK3β overexpression. Overall, our data suggest that NONO is likely subjected to proteasome-mediated degradation and add NONO to the list of proteins targeted by FBW7, which is itself often deregulated in cancer.

Gastric cancer represents a diffuse and aggressive neoplasm, whose mortality index is among the highest in the world. Predisposing factors are E-cadherin mutations, Helicobacter pylori infection and a diet rich in salted and smoked food, with a low intake of fresh fruits and vegetables. Here we analyzed the effect of total lipophilic extracts of two Southern Italy tomato varieties, San Marzano and Corbarino, on an in vitro model of gastric cancer, YCC-1, YCC-2 and YCC-3 cell lines, characterized by different aggressiveness. Our results showed a possible role of these two varieties of tomatoes against typical neoplastic features. The treatment with tomato extracts affected cancer cell ability to grow both in adherence and in semisolid medium, reducing also cell migration ability. No toxic effects were observed on non-tumoral cells. We found, on gastric cancer cell lines, effects on both cell cycle progression and apoptosis modulation. The extent of antineoplastic effects, however, did not seem to correlate with the carotenoid content and antioxidant activity of the two tomato varieties. Our data indicate that San Marzano and Corbarino intake might be further considered as nutritional support not only in cancer prevention, but also for cancer patient diet. This article is protected by copyright. All rights reserved.

Doxorubicin (doxo) is an effective anticancer compound in several tumor types. However, as a consequence of oxidative stress induction and ROS overproduction, its high cardiotoxicity demands urgent attention. Vanillin possesses antioxidant, antiproliferative, antidepressant and anti-glycating properties. Therefore, we investigated the potential vanillin protective effects against doxo-induced cardiotoxicity in H9c2 cells. Using multiparametric approach, we demonstrated that vanillin restored both cell viability and damage in response to doxo exposure. Contextually, vanillin decreased sub-G1 appearance and caspase-3 and PARP1 activation, reducing the doxo-related apoptosis induction. From a mechanistic point of view, vanillin hindered doxo-induced ROS accumulation and impaired the ERK phosphorylation. Notably, besides the cardioprotective effects, vanillin did not counteract the doxo effectiveness in osteosarcoma cells. Taken together, our results suggest that vanillin ameliorates doxo-induced toxicity in H9c2 cells, opening new avenues for developing alternative therapeutic approaches to prevent the anthracycline-related cardiotoxicity and to improve the long-term outcome of antineoplastic treatment.

The cholesterol metabolite 24(S)-hydroxycholesterol (24S-OHC) allows cholesterol excretion from the brain and was suggested to be critically involved in physiological as well as neurodegenerative processes. It induces on human neuronal cell cultures a dose dependent toxicity associated with increased reactive oxygen species production. Since glial cells play a key role in assisting neuronal function, here we investigated the effects of increased concentrations of 24S-OHC on a glial cell model (human glioblastoma U-87 MG cells). We determined the content of PGC-1α and TFAM, involved in the biogenesis of mitochondria, both mitochondrial complexes activity and protein amount, lipid and protein oxidative damage, cellular reactive oxygen species (ROS) release and both the activities and amount of the antioxidant enzymes glutathione peroxidase and catalase. Low concentration of 24S-OHC increased cellular content of PGC-1α and TFAM and the activities of mitochondrial complexes I and II, with no marked changes in their protein amount. Interestingly, 24S-OHC at lower concentrations reduced while at higher concentration increased lipid and protein oxidative damage. Conversely, the content of nitro-tyrosine increased only with the highest 24S-OHC concentration. Also, cell H2O2 release was reduced by lower and increased by higher 24S-OHC used concentrations. The cell activity of glutathione peroxidase was reduced by 24S-OHC at higher concentration while that of catalase was reduced by all the assayed concentrations. Further, a dose dependent decrease of both enzymes levels was observed. In conclusion, we demonstrated that 24S-OHC exerts different effects on U-87 MG cells depending on its level. At lower concentrations it stimulates cellular processes critical to maintain redox homeostasis, while at higher dose its effect on the glial cell here used resemble its action on neurons.

Glioblastoma (GB) is the most common and aggressive malignant tumor of the central nervous system. Despite current intensive treatment regimens, consisting of surgical resection followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ) chemotherapy, the prognosis of patients with GB remains extremely poor. Considering that alterations of the p53 tumor suppressor pathway have a key role in both GB development and resistance to TMZ treatment, the re‑activation of p53 could be an effective therapeutic approach against GB. In this study, we challenged p53 wild‑type and mutant GB cell lines with RITA, a molecule originally identified for its ability to restore p53 functions, although it was subsequently shown to act also through p53‑independent mechanisms. We examined the effects of RITA on GB cell viability, through MTS and clonogenic assays, and analyzed cell death through cytoflourimetric analyses. In all the tested GB cell lines, RITA significantly reduced the cell proliferative and clonogenic potential and induced cell accumulation in the S and/or G2/M cell cycle phases and massive p53‑dependent apoptosis. Moreover, RITA was more effective than the well‑known p53 re‑activating molecule, nutlin‑3, and did not affect the viability of normal astrocytes. In addition, RITA decreased survivin expression and induced DNA damage, two mechanisms that likely contribute to its anti‑tumor effects. Furthermore, RITA synergized with TMZ and was able to decrease the expression of MGMT, which is a crucial player in TMZ resistance. Thus, although further studies are warranted to clarify the exact mechanisms of action of RITA, the data of this study suggest the potential of such an approach for GB therapy, which may also help to overcome resistance to TMZ.

The major cause of end-stage renal disease is the diabetic nephropathy. Oxidative stress contributes to the development of type II diabetes mellitus (T2DM). In this study we have evaluated the effect of a diet with a new standardized of red orange and lemon extract (RLE) rich in anthocyanins (ANT) in the progression of the kidney disease on Zucker diabetic fatty rats. Oxidative stress and renal function were analyzed. In diabetic rats, the RLE restored the blood glucose levels, body weight, and normalized the reactive oxygen species (ROS) total pathways. The kidney inflammation, in diabetic rats, has not shown significant change, showing that the oxidative stress rather than to inflammatory processes is a triggering factor in the renal complication associated with T2DM. Therefore, the administration of the RLE prevents this complication and this effect could be related to the inhibition of ROS production.

The KCTD family is an emerging class of proteins that are involved in important biological processes whose biochemical and structural properties are rather poorly characterized or even completely undefined. We here used KCTD5, the only member of the family with a known three-dimensional structure, to gain insights into the intrinsic structural stability of the C-terminal domain and into the mutual dynamic interplay between the two domains of the protein. Molecular dynamics (MD) simulations indicate that, in the simulation timescale (120 ns), the pentameric assembly of the C-terminal domain (CTD) is endowed with a significant intrinsic stability. Moreover, MD analyses also led to the identification of exposed β-strand residues. Being these regions intrinsically sticky, they could be involved in the substrate recognition. More importantly, simulations conducted on the full-length protein provide interesting information of the relative motions between the BTB domain and the CTD of the protein. Indeed, the dissection of the overall motion of the protein is indicative of a large interdomain twisting associated with limited bending movements. Notably, MD data indicate that the entire interdomain motion is pivoted by a single residue (Ser150) of the hinge region that connects the domains. The functional relevance of these motions was evaluated in the context of the functional macromolecular machinery in which KCTD5 is involved. This analysis indicates that the interdomain twisting motion here characterized may be important for the correct positioning of the substrate to be ubiquitinated with respect to the other factors of the ubiquitination machinery.

HCV infection is a major threaten for human health as it affects hundreds of million people worldwide. Here we investigated the conformational properties of the 412–423 fragment of the envelope E2 protein, one of the most immunogenic regions of the virus proteome whose characterization may provide interesting insights for anti-HCV vaccine development. The spectroscopic characterization of the polypeptide unravels its unexpected tendency to form amyloid-like aggregates. When kept in monomeric state, it shows a limited tendency to adopt regular secondary structure. Enhanced molecular dynamics simulations, starting from four distinct conformational states, highlight its structural versatility. Interestingly, all multiform conformational states of the polypeptide detected in crystallographic complexes with antibodies are present in the structural ensemble of all simulations. This observation corroborates the idea that known antibodies recognize this region through a conformational selection mechanism. Accordingly, the design of effective anti-HCV vaccines should consider the intrinsic flexibility of this region. The structural versatility of the 412–423 region is particularly puzzling if its remarkable sequence conservation is considered. It is likely that flexibility and sequence conservation are important features that endow this epitope with the ability to accomplish distinct functions such as immunity escape and interaction with host receptors.

Although rare, mediastinal tumors often present a challenge for both the physicians and the pathologists. Here we focus on the molecular features underlying thymic tumors and lymphomas, which are the most common malignancies occurring in the anterior compartment of the mediastinum. We discuss both established and recently discovered molecular alterations that can overall serve as diagnostic, prognostic, and predictive factors or possibly as targets for therapeutic intervention.

The retinoblastoma (RB) protein family includes RB1/p105, RBL1/p107, and RBL2/p130, which are key factors in cell-cycle regulation and stand at the crossroads of multiple pathways dictating cell fate decisions. The role of RB proteins in apoptosis is controversial because they can inhibit or promote apoptosis depending on the context, on the apoptotic stimuli and on their intrinsic status, impacting on the response to antitumoral treatments. Here we identified RBL2/p130 as a direct substrate of the AKT kinase, a key antiapoptotic factor hyperactive in multiple cancer types. We showed that RBL2/p130 and AKT1 physically interact and AKT phosphorylates RBL2/p130 Ser941, located in the pocket domain, but not when this residue is mutated into Ala. We found that pharmacological inhibition of AKT, through the highly selective AKT inhibitor VIII (AKTiVIII), impairs RBL2/p130 Ser941 phosphorylation and increases RBL2/p130 stability, mRNA expression and nuclear levels in both lung cancer and mesothelioma cell lines, mirroring the more extensively studied effects on the p27 cell-cycle inhibitor. Consistently, AKT inhibition reduced cell viability, induced cell accumulation in G0/G1, and triggered apoptosis, which proved to be largely dependent on RBL2/p130 itself, as shown upon RBL2/p130 silencing. AKT inhibition induced RBL2/p130-dependent apoptosis also in HEK-293 cells, in which re-expression of a short hairpin-resistant RBL2/p130 was able to rescue AKTiVIII-induced apoptosis upon RBL2/p130 silencing. Our data also showed that the combination of AKT and cyclin-dependent kinases (CDK) inhibitors, which converge on the re-activation of RBL2/p130 antitumoral potential, could be a promising anticancer strategy.

Physiological thyroid hormone levels are necessary for normal hepatic function and hepatobiliary complications are commonly found in hyperthyroid animals and humans. Most of thyroid hormone actions are due to the transcription of T3-responsive genes mediated through nuclear receptors. It has been suggested that tissue oxidative stress developing when circulating levels of thyroid hormones increase are responsible for some complications found in hyperthyroidism. Therefore, increasing interest is devoted to the use of antioxidants as therapeutic agents in thyroid related disorders. Vitamin E is among the most commonly consumed dietary supplements due to the belief that it, as antioxidant, may attenuate oxidant-linked diseases. The belief is supported by numerous studies, demonstrating that primary function of the vitamin is to destroy peroxyl radicals, protecting polyunsaturated fatty acids of biological membranes from oxidative damage and cell derangement. However, results are also available indicating that protective vitamin E effects against oxidative damage can be obtained even through different mechanisms.

We investigated thyroid state effect on capacity of rat liver mitochondria to remove exogenously produced H2O2, determining their ability to decrease fluorescence generated by an H2O2 detector system. The rate of H2O2 removal by both non respiring and respiring mitochondria was increased by hyperthyroidism and decreased by hypothyroidism. However, the rate was higher in the presence of respiratory substrates, in particular pyruvate/malate, indicating a respiration-dependent process. Generally, the changes in H2O2 removal rates mirrored those in H2O2 release rates excluding the possibility that endogenous and exogenous H2O2 competed for the removing system. Pharmacological inhibition revealed thyroid state-linked differences in antioxidant enzyme contribution to H2O2 removal which were consistent with those in antioxidant system activities. The H2O2 removal was only in part due to enzymatic systems and that imputable to non-enzymatic processes was higher in hyperthyroid and lower in hypothyroid mitochondria. The levels of cytochrome c and the light emissions, due to luminol oxidation catalyzed by cytochrome/H2O2, exhibited similar changes with thyroid state supporting the idea that non-enzymatic scavenging was mainly due to hemoprotein action, which produces hydroxyl radicals. Further support was obtained showing that the whole antioxidant capacity, which provides an evaluation of capacity of the systems, different from cytochromes, assigned to H2O2 scavenging, was lower in hyperthyroid than in hypothyroid state. In conclusion, our results show that mitochondria from hyperthyroid liver have a high capacity for H2O2 removal, which, however, leading in great part to more reactive oxygen species, results harmful for such organelles.

pRb2/p130 is a key tumor suppressor, whose oncosuppressive activity has mainly been attributed to its ability to negatively regulate cell cycle by interacting with the E2F4 and E2F5 transcription factors. Indeed, pRb2/p130 has been found altered in various cancer types in which it functions as a valuable prognostic marker. Here, we analyzed pRb2/p130 expression in gastric cancer tissue samples of diffuse histotype, in comparison with their normal counterparts. We found a cytoplasmic localization of pRb2/p130 in cancer tissue samples, whereas, in normal counterparts, we observed the expected nuclear localization. pRb2/p130 cytoplasmic delocalization can lead to cell cycle deregulation, but considering the emerging involvement of pRb2/p130 in other key cellular processes, it could contribute to gastric tumorigenesis also through other mechanisms. Our data support the necessity of further investigations to verify the possibility of using pRb2/p130 as a biomarker or potential therapeutic target for diffuse gastric cancer. J. Cell. Physiol. 230: 802–805, 2015. © 2014 Wiley Periodicals, Inc.

Dump your assumptions, and be curious.

PPARs are a class of ligand-activated transcription factors belonging to the superfamily of receptors for steroid and thyroid hormones, retinoids and vitamin D that control the expression of a large number of genes involved in lipid and carbohydrate metabolism and in the regulation of cell proliferation, differentiation and death. The role of PPARs in the CNS has been primarily associated with lipid and glucose metabolism; however, these receptors are also implicated in neural cell differentiation and death, as well as neuronal maturation. Although it has been demonstrated that PPARs play important roles in determining NSCs fate, less is known about their function in regulating NSCs metabolism during differentiation. In order to identify the metabolic events, controlled by PPARs, occurring during neuronal precursor differentiation, the glucose and lipid metabolism was followed in a recognized model of neuronal differentiation in vitro, the SH-SY5Y neuroblastoma cell line. Moreover, PPARs distribution were also followed in situ in adult mouse brains. The concept of adult neurogenesis becomes relevant especially in view of those disorders in which a loss of neurons is described, such as Alzheimer disease, Parkinson disease, brain injuries and other neurological disorders. Elucidating the crucial steps in energetic metabolism and the involvement of PPARγ in NSC neuronal fate (lineage) may be useful for the future design of preventive and/or therapeutic interventions.

HCV-linked pathologies represent worldwide health threats. Over the years, an enormous number of independent studies have been devoted to the understanding of the molecular bases of HCV infection. A significant amount of these investigations has been focused on the structural characterization of the virus proteins with the aim of developing structure-based innovative therapeutic approaches. An analysis of the current Protein Data Bank content unravels that the structural biology of the virus has hitherto covered a large fraction of the HCV proteins (75%). This fraction is even larger if the recently identified intrinsically disordered regions are not considered. The present review recapitulates the state-of-the-art of structural characterizations of HCV individual proteins with a specific focus on their structural versatility/flexibility. This survey indicates there is an accumulating evidence that structural flexibility is a common feature among HCV proteins. This versatility can be detected at different structural level i.e. occurrence of alternative oligomeric states and/or of local and global flexibility. Somewhat surprisingly, some disordered or highly flexible regions of HCV proteins, such as the core and the antigenic fragment 412-423 of E2, present highly conserved sequences among the virus genotypes. The overall versatility of HCV proteins plays an important role in host protein recognition, drug resistance mechanisms, and virus escape from the host immunogenic system. Of particular relevance is the emerging idea that HCV uses local structural flexibility as an alternative tool to sequence variability to evade the immune response of the host organism. We believe that these emerging concepts will be important for the development of anti-HCV vaccines that are eagerly needed.

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide. Although effective therapeutic approaches, based on specific inhibitors of HCV proteins NS3/4A and NS5B, have been recently discovered, their use is limited by the elevated costs of these drugs. Currently, there is neither an effective immune globulin for prophylaxis nor a vaccine for the prevention of hepatitis C. A particularly attracting target is represented by the immunogenic E2 glycoprotein, a key factor for HCV entry in host cells. This protein has been the subject of recent structural studies that have greatly expand our current knowledge of HCV pathogenicity (Khan et al. 2015; Khan et al. 2014; Kong et al. 2013). In this framework, we have recently undertaken studies aimed at evaluating the potential of some regions of the protein as vaccine candidates (Sandomenico et al. 2015, under review). We here investigated the structural/dynamic features of the E2 protein, whose structure has been recently solved by two independent groups in complex with antibodies. Molecular dynamics simulations carried out on the protein core provided interesting information on both global dynamics of the protein and on local features of important regions. Moreover, a combined experimental/computational analysis shows that the epitope I region (residues 412-422) is endowed with an elevated structural versatility. Collectively these findings provide useful information for future studies aimed at designing anti-HCV vaccines.ReferencesKhan AG, Miller MT, and Marcotrigiano J. 2015. HCV glycoprotein structures: what to expect from the unexpected. Current opinion in virology 12:53-58. 10.1016/j.coviro.2015.02.004 Khan AG, Whidby J, Miller MT, Scarborough H, Zatorski AV, Cygan A, Price AA, Yost SA, Bohannon CD, Jacob J, Grakoui A, and Marcotrigiano J. 2014. Structure of the core ectodomain of the hepatitis C virus envelope glycoprotein 2. Nature 509:381-384. 10.1038/nature13117 Kong L, Giang E, Nieusma T, Kadam RU, Cogburn KE, Hua Y, Dai X, Stanfield RL, Burton DR, Ward AB, Wilson IA, and Law M. 2013. Hepatitis C virus E2 envelope glycoprotein core structure. Science 342:10901094. 10.1126/science.1243876

Hepatitis C Virus (HCV) is one of the most persistent human viruses. Although effective therapeutic approaches have been recently discovered, their use is limited by the elevated costs. Therefore, the development of alternative/complementary strategies is an urgent need. The E2 glycoprotein, the most immunogenic HCV protein, and its variants represent natural candidates to achieve this goal. Here we report an extensive molecular dynamics (MD) analysis of the intrinsic properties of E2. Our data provide interesting clues on the global and local intrinsic dynamic features of the protein. Present MD data clearly indicate that E2 combines a flexible structure with a network of covalent bonds. Moreover, the analysis of the two most important antigenic regions of the protein provides some interesting insights into their intrinsic structural and dynamic properties. Our data indicate that a fluctuating β-hairpin represents a populated state by the region E2412−423. Interestingly, the analysis of the epitope E2427−446 conformation, that undergoes a remarkable rearrangement in the simulation, has significant similarities with the structure that the E2430−442 fragment adopts in complex with a neutralizing antibody. Present data also suggest that the strict conservation of Gly436 in E2 protein of different HCV genotypes is likely dictated by structural restraints. Moreover, the analysis of the E2412−423 flexibility provides insights into the mechanisms that some antibodies adopt to anchor Trp437 that is fully buried in E2. Finally, the present investigation suggests that MD simulations should systematically complement crystallographic studies on flexible proteins that are studied in combination with antibodies.

Continuous exposure of homeothermic animals to low environmental temperatures elicits physiological adaptations necessary for animal survival, which are associated to higher generation of pro-oxidants in thermogenic tissues. It is not known whether intermittent cold exposure (cold training) is able to affect tissue responses to continuous cold exposure. Therefore, we investigated whether rat liver responses to continuous cold exposure of 2 days are modified by cold training (1h daily for 5 days per week for 3 consecutive weeks). Continuous cold increased liver oxidative metabolism by increasing tissue content of mitochondrial proteins and mitochondrial aerobic capacity. Cold training did not affect such parameters, but attenuated or prevented the changes elicited by continuous cold exposure. Two-day cold exposure increased lipid hydroperoxide and protein-bound carbonyl levels in homogenates and mitochondria, whereas cold training decreased such effects although it decreased only homogenate protein damage in control rats. The activities of the antioxidant enzymes GPX and GR and H2O2 production were increased by continuous cold exposure. Despite the increase in GPX and GR activities, livers from cold-exposed rats showed increased susceptibility to in vitro oxidative challenge. Such cold effects were decreased by cold training, which in control rats reduced only H2O2 production and susceptibility to stress. The changes of PGC-1, NRF-1, and NRF-2 expression levels were consistent with those induced by cold exposure and cold training in mitochondrial protein content and antioxidant enzyme activities. However, the mechanisms by which cold training attenuates the effects of the continuous cold exposure remain to be elucidated.

We investigated whether reactive oxygen species (ROS) are involved in heart adaptive responses administering a vitamin E-enriched diet to trained rats. Using the homogenates and/or mitochondria from rat hearts we determined the aerobic capacity, tissue level of mitochondrial proteins, and expression of cytochrome c and factors (PGC-1, NRF-1, and NRF-2) involved in mitochondrial biogenesis. We also determined the oxidative damage, glutathione peroxidase (GPX) and reductase activities, glutathione content, mitochondrial ROS release rate, and susceptibility to in vitro oxidative challenge. Glutathione (GSH) content was not affected by both training and antioxidant supplementation. Conversely, antioxidant supplementation prevented metabolic adaptations to training, such as the increases in oxidative capacity, tissue content of mitochondrial proteins, and cytochrome c expression, attenuated some protective adaptations, such as the increase in antioxidant enzyme activities, and did not modify the decrease in ROS release by succinate supplemented mitochondria. Moreover, vitamin E prevented the training-linked increase in tissue capacity to oppose an oxidative attach. The antioxidant effects were associated with decreased levels of PGC-1, NRF-1, and NRF-2 expression. Our results support the idea that some heart adaptive responses to training depend on ROS produced during the exercise sessions and are mediated by the increase in PGC-1 expression which is involved in both the regulation of respiratory capacity and antioxidant protection. However, vitamin inability to prevent some adaptations suggests that other signaling pathways impinging on PGC-1 can modify the response to the antioxidant integration.

pRb2/p130 is a key tumor suppressor, whose oncosuppressive activity has mainly been attributed to its ability to negatively regulate cell cycle by interacting with the E2F4 and E2F5 transcription factors. Indeed, pRb2/p130 has been found altered in various cancer types in which it functions as a valuable prognostic marker. Here, we analyzed pRb2/p130 expression in gastric cancer tissue samples of diffuse histotype, in comparison with their normal counterparts. We found a cytoplasmic localization of pRb2/p130 in cancer tissue samples, whereas, in normal counterparts, we observed the expected nuclear localization. pRb2/p130 cytoplasmic delocalization can lead to cell cycle deregulation, but considering the emerging involvement of pRb2/p130 in other key cellular processes, it could contribute to gastric tumorigenesis also through other mechanisms. Our data support the necessity of further investigations to verify the possibility of using pRb2/p130 as a biomarker or potential therapeutic target for diffuse gastric cancer.

Recent structural investigations have shown that the C-terminal domain (CTD) of the transcription factor RfaH undergoes unique structural modifications that have a profound impact into its functional properties. These modifications cause a complete change in RfaHCTD topology that converts from an α-hairpin to a β-barrel fold. To gain insights into the determinants of this major structural conversion, we here performed computational studies (protein structure prediction and molecular dynamics simulations) on RfaHCTD. Although these analyses, in line with literature data, suggest that the isolated RfaHCTD has a strong preference for the β-barrel fold, they also highlight that a specific region of the protein is endowed with a chameleon conformational behavior. In particular, the Leu-rich region (residues 141–145) has a good propensity to adopt both α-helical and β-structured states. Intriguingly, in the RfaH homolog NusG, whose CTD uniquely adopts the β-barrel fold, the corresponding region is rich in residues as Val or Ile that present a strong preference for the β-structure. On this basis, we suggest that the presence of this Leu-rich element in RfaHCTD may be responsible for the peculiar structural behavior of the domain. The analysis of the sequences of RfaH family (PfamA code PF02357) unraveled that other members potentially share the structural properties of RfaHCTD. These observations suggest that the unusual conformational behavior of RfaHCTD may be rare but not unique.

We studied the effects of ten-day 1%Galdieria sulphurariadietary supplementation on oxidative damage and metabolic changes elicited by acute exercise (6-hour swimming) determining oxygen consumption, lipid hydroperoxides, protein bound carbonyls in rat tissue (liver, heart, and muscle) homogenates and mitochondria, tissue glutathione peroxidase and glutathione reductase activities, glutathione content, and rates of H2O2mitochondrial release. Exercise increased oxidative damage in tissues and mitochondria and decreased tissue content of reduced glutathione. Moreover, it increased State 4 and decreased State 3 respiration in tissues and mitochondria.G. sulphurariasupplementation reduced the above exercise-induced variations. Conversely, alga supplementation was not able to modify the exercise-induced increase in mitochondrial release rate of hydrogen peroxide and in liver and heart antioxidant enzyme activities. The alga capacity to reduce lipid oxidative damage without reducing mitochondrial H2O2release can be due to its high content of C-phycocyanin and glutathione, which are able to scavenge peroxyl radicals and contribute to phospholipid hydroperoxide metabolism, respectively. In conclusion,G. sulphurariaability to reduce exercise-linked oxidative damage and mitochondrial dysfunction makes it potentially useful even in other conditions leading to oxidative stress, including hyperthyroidism, chronic inflammation, and ischemia/reperfusion.

The role of milk and dairy products in cancer prevention was debated for a long time. In some cases they seem to promote some hormones related neoplastic pathologies. Yet, as we here describe, milk and dairy products may be helpful in colorectal cancer prevention, because of their calcium content, showing the capability of inactivating bile acids. Fats seem not to be relevant. In fact, although animal fats generally exert a pro-neoplastic effects, recent findings demonstrated that milk and dairy foods preventive role of colorectal cancer is not affected by their fat content. IGF-1, which was similarly considered a pro-carcinogenic factor, was “exonerated” more than ten years ago, because different authors showed that its effects are not influential in people. Previous investigations led to consider IGF-1 as the principal cause of colorectal cancer, and it was just around the year 2000 that epidemiological studies refuted the pre-existing hypothesis about IGF-1. Hence, milk and dairy products may be advisable, not only because of their nutritional value, but also because of their preventive effect of colorectal cancer. Moreover, their consumption should be encouraged also in cancer patients, because their energy content, together with their micro- and macronutrients, may represent a good eating habit against cachexia. Yet, a special care should be taken with patients developing lactose intolerance and hypolactasia, a possible side effect of 5’FU chemotherapy. Finally, we have to stress that a further care should be taken about cheeses consumption. Their energy density and their saturated fatty acids content is not relevant in predisposing to colorectal cancer, but an excessive intake should be avoided not to develop either overweight/obesity, or hypercholesterolemia.

We studied vitamin E eff ects on metabolic changes and oxidative damage elicited by swim training in rat liver. Training reduced mitochondrial aerobic capacity but increased liver content of mitochondrial proteins, so that tissue aerobic capacity was not diff erent in trained and sedentary animals. Vitamin E supplementation prevented the training-induced mitochondrial changes. Training and vitamin E eff ects were consistent with the changes in tissue content of factors involved in mitochondrial biogenesis (peroxisomal proliferator-activated receptor- γ coactivator and nuclear respiratory factors 1 and 2). Tissue and mitochondrial oxidative damage was reduced by training decreasing the rate of mitochondrial reactive oxygen species (ROS) production and enhancing glutathione levels and glutathione peroxidase and glutathione reductase activities. The eff ects of vitamin E were diff erent when it was administered to sedentary or trained rats. In the former, vitamin E reduced liver preparations oxidative damage decreasing ROS production rate and increasing GSH content without any eff ect on antioxidant enzyme activities. In the latter, vitamin E did not modify ROS production and oxidative damage but decreased antioxidant levels. This decrease was likely responsible for the enhanced susceptibility to in vitro oxidative attack of the hepatic tissue from trained rats following vitamin E supplementation. These results indicate that vitamin E integration, which can be healthy for animals subjected to acute exercise, is not advisable during training because it prevents or reduces the favourable eff ects of the physical activity. They also support the idea that the stimulus for training-induced adaptive responses can derive from the increased ROS production that accompanies the single sessions of the training program.

A final diagnosis of pancreatic cancer was established in 76 consecutive patients during 4 years. The clinical outcome was evaluated retrospectively, as well as clinical presentation and its impact on the rate of resectability. Even though the diagnostic techniques showed a high sensitivity, only 18.4% of patients had a radical resection performed. In 77.6% of the cases a tissue diagnosis had been obtained. However, in only 1/5 of them was the tissue proof obtained preoperatively. This review confirms that the survival of patients with pancreatic cancer is poor, with slight advantages in the few resectable cases. Therefore, an earlier diagnosis should be attempted in high-risk symptomatic patients, selected by means of nonaggressive tests and evaluated by means of more accurate diagnostic techniques, when suitable.

The usefulness of tumor marker assay in pleural effusions for differential diagnosis is still debated. From the observation of common antigens on tissue polypeptide antigen (TPA) and keratins 8, 18 and 19 and vimentin, all substances contained in normal and neoplastic mesothelium, we felt it opportune to evaluate the use of TPA assay in 105 pleural effusions (46 benign and 59 malignant). The values were much higher than those found in blood. In hydrothorax the median value was 454 U/l (range, 59–1923), in exudative effusions 846 U/l (range, 258–4485), in metastatic pleural effusions 1277 U/l (range, 58–32352) and in mesotheliomas 7705 (range, 759–16000). The maximum value found in nonmalignant effusions was 4485 U/l; this value was taken as a cutoff level, so only 29.9 % of the tumors were positive to the test. Our results showed this assay to be not very important for a differential diagnosis of malignant and nonmalignant pleural effusions. Nevertheless, the different TPA patterns in mesotheliomas (66.6 % positive) and metastatic pleural effusions (15.9 %) suggest that further studies are warranted.

Serum concentrations of the CA 19-9 and CA 50 antigens were determined in 129 patients with malignant and benign biliary and pancreatic diseases. Values for the two markers were highly correlated (P less than 0.001). The concentrations of CA 19-9 and CA 50 were positive in 84.6% and 80.7% of patients with pancreatic cancer, respectively. The overall specificity of CA 19-9 (92.4%) was slightly higher than that of CA 50 (88.5%). The sensitivity of CA 50 (91.3%) was greater than that of CA 19-9 (73.9%) in patients with diseases of the biliary tract. Elevated concentrations of CA 19-9 (12.9%) and CA 50 (35.2%) were also found in a number of cases with benign disease, especially in patients with obstructive jaundice. These data suggest that both CA 19-9 and CA 50 can be useful markers of pancreatic cancer in nonjaundiced patients. The joint use of the two markers does not yield a better diagnostic resolution than the use of either one alone.

In 22 patients with radiological evidence of a malignant stricture or an obstruction of the common bile duct, endobiliary tissue specimens were obtained through endoscopic retrograde cholangiopancreatography. An endoscopic papillo(sphinctero)tomy was necessary in 9 of the 22 patients. The following techniques were employed: (1) forceps biopsy of the papillary infundibulum and/or of the common bile duct; (2) brush cytology in the same sites as above; (3) biliary juice cytology obtained by a nasobiliary drainage tube. In 8 patients, two different sampling techniques were used. The final diagnosis was established by means of pathological evaluation of surgical or necroscopic material. The diagnostic adequacy was 100% for biopsy, 88% for brush cytology, and 62% for bile cytology. The sensitivity was 100%, 66%, and 25%, respectively, for the above techniques. From 6 cases without biliary cancer, the specificity was 100%. These data show that biopsy specimens alone provide a definitive preoperative diagnosis in most cases, provided adequate samples are obtained.