Therapeutic liposomal combination to enhance chemotherapy response and immune activation of tumor microenvironment.

Multiple oxaliplatin-resistance mechanisms have been proposed such as increase of anti-inflammatory M2 macrophages and lack of cytotoxic T-cells. Thereby oxaliplatin chemotherapy promotes an immunosuppressive tumor microenvironment and inhibits anti-tumor efficacy. It has been shown that toll-like receptor (TLR) agonists are capable of triggering broad inflammatory responses, which may potentially reduce oxaliplatin-resistance and improve the efficacy of chemotherapy. In this study, we established colorectal tumor-bearing zebrafish and mice, and investigated the effects of TLR agonists and oxaliplatin in macrophage function and anti-tumor T cell immunity as well as tumor growth control in vivo. To increase the potential of this strategy as well minimize side effects, neutral liposomes carrying oxaliplatin and cationic liposomes co-loaded with TLR agonists Poly I:C and R848 were employed for maximum immune activation. Both of two liposomal systems exhibited good physicochemical properties and excellent biological activities in vitro. The combination strategy delivered by liposomes showed more pronounced tumor regression and correlated with decreased M2 macrophage numbers in both zebrafish and mice. Increasing numbers of dendritic cells, DC maturation and T cell infiltration mediated via immunogenic cell death were observed in treated mice. Our study offers valuable insights into the potential of liposomal combination therapy to improve cancer treatment by reprogramming the tumor microenvironment and enhancing immune responses.

Dual-Targeting Nanoliposome Improves Proinflammatory Immunomodulation of the Tumor Microenvironment.

Immunotherapies targeting immune checkpoints have revolutionized cancer treatment by normalizing the immunosuppressive microenvironment of tumors and reducing adverse effects on the immune system. Indoleamine 2,3-dioxygenase (IDO) inhibitors have garnered attention as a promising therapeutic agent for cancer. However, their application alone has shown limited clinical benefits. Cabozantinib, a multitarget tyrosine kinase inhibitor, holds immunomodulatory potential by promoting infiltration and activation of effector cells and inhibiting suppressive immune cells. Despite its potential, cabozantinib as a monotherapy has shown limited efficacy in terms of objective response rate. In this study, IDO-IN-7 and cabozantinib are coencapsulated into liposomes to enhance tumor accumulation and minimize adverse effects. The liposomal combination exhibits potent cytotoxicity and inhibits the function of IDO enzyme. Furthermore, the dual-targeted treatment effectively inhibits tumor development and reverses the suppressive tumor microenvironment by regulating both adaptive and innate branch of immune system. This is evidenced by pronounced infiltration of T cells and B cells, a decrease of regulatory T lymphocytes, a shift to a proinflammatory phenotype of tumor-associated macrophages, and increases levels of neutrophils. This is the first developed of a liposome-delivered combination of IDO inhibitors and cabozantinib, and holds great potential for future clinical application as a promising anticancer strategy.

Is adenosine deaminase (ADA) activity in saliva and serum a more accurate disease detection tool than traditional redox balance parameters in early-lactating dairy cows?

Enzyme adenosine deaminase (ADA) is a marker of inflammation in domestic animals, but it is unclear whether it is a reliable marker of oxidative stress, especially in the transition period in dairy cows. This study aims to assess if ADA and redox status measurements in saliva provide the same utility to detect disease condition as that obtained from serum. Sixty-eight multiparous Holstein cows, between 2 and 3 weeks postpartum were selected. Five study groups were established: control (healthy), and cows with ketosis, mastitis, laminitis, and metritis. The parameters measured were ADA activity, total oxidants (TOS), antioxidants (TAC), and OSi ratio.Regarding redox status, no significant differences arise in both saliva and serum being the correlations negative and not significant. In saliva, ADA activity in healthy cows differs from those with pathological processes, having the lowest activities. In serum, ADA activity is similar in the healthy and ketosis cows, showing the lowest activities meanwhile animals with mastitis, laminitis, or metritis have significantly higher activities. In conclusion, the measurement of ADA activities and redox status in saliva does not give consistent results, being preferable to measure them in serum during the transition period.

Effective combination of liposome-targeted chemotherapy and PD-L1 blockade of murine colon cancer.

Therapeutic cancer drug efficacy can be limited by insufficient tumor penetration, rapid clearance, systemic toxicity and (acquired) drug resistance. The poor therapeutic index due to inefficient drug penetration and rapid drug clearance and toxicity can be improved by using a liposomal platform. Drug resistance for instance against pemetrexed, can be reduced by combination with docetaxel. Here, we developed a specific liposomal formulation to simultaneously deliver docetaxel and pemetrexed to enhance efficacy and safety. Hydrophobic docetaxel and hydrophilic pemetrexed were co-encapsulated into pH-sensitive liposomes using a thin-film hydration method with high efficiency. The physicochemical properties, toxicity, and immunological effects of liposomes were examined in vitro. Biodistribution, anti-tumor efficacy, and systemic immune response were evaluated in vivo in combination with PD-L1 immune checkpoint therapy using two murine colon cancer models. In cellular experiments, the liposomes exhibited strong cytotoxicity and induced immunogenic cell death. In vivo, the treatment with the liposome-based drug combination inhibited tumor development and stimulated immune responses. Liposomal encapsulation significantly reduced systemic toxicity compared to the delivery of the free drug. Tumor control was strongly enhanced when combined with anti-PDL1 immunotherapy in immunocompetent mice carrying syngeneic MC38 or CT26 colon tumors. We showed that treatment with liposome-mediated chemotherapy of docetaxel and pemetrexed combined with anti-PD-L1 immunotherapy is a promising strategy for the treatment of colon cancers.

Combining Photodynamic Therapy with Immunostimulatory Nanoparticles Elicits Effective Anti-Tumor Immune Responses in Preclinical Murine Models.

Photodynamic therapy (PDT) has shown encouraging but limited clinical efficacy when used as a standalone treatment against solid tumors. Conversely, a limitation for immunotherapeutic efficacy is related to the immunosuppressive state observed in large, advanced tumors. In the present study, we employ a strategy, in which we use a combination of PDT and immunostimulatory nanoparticles (NPs), consisting of poly(lactic-co-glycolic) acid (PLGA)-polyethylene glycol (PEG) particles, loaded with the Toll-like receptor 3 (TLR3) agonist poly(I:C), the TLR7/8 agonist R848, the lymphocyte-attracting chemokine, and macrophage inflammatory protein 3α (MIP3α). The combination provoked strong anti-tumor responses, including an abscopal effects, in three clinically relevant murine models of cancer: MC38 (colorectal), CT26 (colorectal), and TC-1 (human papillomavirus 16-induced). We show that the local and distal anti-tumor effects depended on the presence of CD8+ T cells. The combination elicited tumor-specific oncoviral- or neoepitope-directed CD8+ T cells immune responses against the respective tumors, providing evidence that PDT can be used as an in situ vaccination strategy against cancer (neo)epitopes. Finally, we show that the treatment alters the tumor microenvironment in tumor-bearing mice, from cold (immunosuppressed) to hot (pro-inflammatory), based on greater neutrophil infiltration and higher levels of inflammatory myeloid and CD8+ T cells, compared to untreated mice. Together, our results provide a rationale for combining PDT with immunostimulatory NPs for the treatment of solid tumors.

Novel Fluorinated Poly (Lactic-Co-Glycolic acid) (PLGA) and Polyethylene Glycol (PEG) Nanoparticles for Monitoring and Imaging in Osteoarthritis.

Polymeric nanoparticles (NPs) find many uses in nanomedicine, from drug delivery to imaging. In this regard, poly (lactic-co-glycolic acid) (PLGA) and polyethylene glycol (PEG) particles are the most widely applied types of nano-systems due to their biocompatibility and biodegradability. Here we developed novel fluorinated polymeric NPs as vectors for multi-modal nanoprobes. This approach involved modifying polymeric NPs with trifluoroacetamide (TFA) and loading them with a near-infrared (NIR) dye for different imaging modalities, such as magnetic resonance imaging (MRI) and optical imaging. The PLGA-PEG-TFA NPs generated were characterized in vitro using the C28/I2 human chondrocyte cell line and in vivo in a mouse model of osteoarthritis (OA). The NPs were well absorbed, as confirmed by confocal microscopy, and were non-toxic to cells. To test the NPs as a drug delivery system for contrast agents of OA, the nanomaterial was administered via the intra-articular (IA) administration method. The dye-loaded NPs were injected in the knee joint and then visualized and tracked in vivo by fluorine-19 nuclear magnetic resonance and fluorescence imaging. Here, we describe the development of novel intrinsically fluorinated polymeric NPs modality that can be used in various molecular imaging techniques to visualize and track OA treatments and their potential use in clinical trials.

Liposome-Based Drug Delivery Systems in Cancer Immunotherapy.

Cancer immunotherapy has shown remarkable progress in recent years. Nanocarriers, such as liposomes, have favorable advantages with the potential to further improve cancer immunotherapy and even stronger immune responses by improving cell type-specific delivery and enhancing drug efficacy. Liposomes can offer solutions to common problems faced by several cancer immunotherapies, including the following: (1) Vaccination: Liposomes can improve the delivery of antigens and other stimulatory molecules to antigen-presenting cells or T cells; (2) Tumor normalization: Liposomes can deliver drugs selectively to the tumor microenvironment to overcome the immune-suppressive state; (3) Rewiring of tumor signaling: Liposomes can be used for the delivery of specific drugs to specific cell types to correct or modulate pathways to facilitate better anti-tumor immune responses; (4) Combinational therapy: Liposomes are ideal vehicles for the simultaneous delivery of drugs to be combined with other therapies, including chemotherapy, radiotherapy, and phototherapy. In this review, different liposomal systems specifically developed for immunomodulation in cancer are summarized and discussed.

Effective chemoimmunotherapy by co-delivery of doxorubicin and immune adjuvants in biodegradable nanoparticles.

Chemoimmunotherapy is an emerging combinatorial modality for the treatment of cancers resistant to common first-line therapies, such as chemotherapy and checkpoint blockade immunotherapy. We used biodegradable nanoparticles as delivery vehicles for local, slow and sustained release of doxorubicin, two immune adjuvants and one chemokine for the treatment of resistant solid tumors. Methods: Bio-compatible poly(lactic-co-glycolic acid)-PEG nanoparticles were synthesized in an oil/water emulsion, using a solvent evaporation-extraction method. The nanoparticles were loaded with a NIR-dye for theranostic purposes, doxorubicin cytostatic agent, poly (I:C) and R848 immune adjuvants and CCL20 chemokine. After physicochemical and in vitro characterization the nanoparticles therapeutic efficacy were carried-out on established, highly aggressive and treatment resistant TC-1 lung carcinoma and MC-38 colon adenocarcinoma models in vivo. Results: The yielded nanoparticles average size was 180 nm and -14 mV surface charge. The combined treatment with all compounds was significantly superior than separate compounds and the compounds nanoparticle encapsulation was required for effective tumor control in vivo. The mechanistic studies confirmed strong induction of circulating cancer specific T cells upon combined treatment in blood. Analysis of the tumor microenvironment revealed a significant increase of infiltrating leukocytes upon treatment. Conclusion: The multi-drug loaded nanoparticles mediated delivery of chemoimmunotherapy exhibited excellent therapeutic efficacy gain on two treatment resistant cancer models and is a potent candidate strategy to improve cancer therapy of solid tumors resistant to first-line therapies.

Critical mercury concentration in tropical soils: Impact on plants and soil biological attributes.

Mercury is a toxic element that becomes a problem when present at high concentrations in soils. Mercury toxicity in soils varies depending on chemical species, concentration, exposure routes, and organism vulnerability. There is little information regarding the toxicity of Hg in tropical soils, especially for establishing safe levels of this pollutant. The purpose of this study was to investigate Hg concentrations in two tropical soils and their effect on oats and common beans, as well as on soil biological attributes. The experiment was carried out in a greenhouse, following ISO 11.269-2 and OECD-208 guidelines. Oat and common bean were cultivated in a Typic Hapludox (TyHpx) and Rhodic Acrudox (RhAcx) contaminated with HgCl2 at the following concentrations: 0, 2.5, 5.0, 10.0, 20.0, 40.0, and 80.0 mg of Hg kg-1 of dry soil. The biological variables analyzed were seedling emergence, vegetative growth, chlorophyll content (SPAD index), gas exchange (photosynthetic rate, internal CO2 concentration, transpiration rate, and stomatal conductance), and Hg concentration and accumulation in shoot dry matter. Microbial biomass carbon, soil basal respiration, and metabolic quotient (qCO2) were also analyzed. Due to the sorptive characteristics of TyHpx, it had higher Hg concentrations than RhAcx. Mercury showed toxic effects on both oat and common bean species. However, common bean was affected only at concentrations higher than 20 mg kg-1. The microbial community showed high sensitivity to soil Hg concentrations, but external factors, such as the plant species cultivated, influenced the sensitivity of the community. The microbiota was most sensitive in pots with common bean, and this effect was more pronounced at low clay and low organic matter contents (TyHpx). In this study, the concentration of 0.36 mg kg-1 was critical for Hg in these soils, based on its deleterious effects on oat and common bean and on biological soil attributes.

Physicochemical properties of novel protein kinase inhibitors in relation to their substrate specificity for drug transporters.

INTRODUCTION: Small molecule tyrosine and serine-threonine kinase inhibitors (TKIs and STKIs) are emerging drugs that interfere with downstream signaling pathways involved in cancer proliferation, invasion, metastasis and angiogenesis. The understanding of their pharmacokinetics, the identification of their transporters and the modulating activity exerted on transporters is pivotal to predict therapy efficacy and to avoid unwarranted drug treatment combinations. AREAS COVERED: Experimental or in silico data were collected and summarized on TKIs and STKIs physico-chemical properties, which influence their transport, metabolism and efficacy, and TKIs and STKIs as influx transporter substrates and inhibitors. In addition, the uptake by tumor cell influx transporters and some factors in the tumor microenvironment affecting the uptake of TKIs and STKIs by cancer cells are briefly covered. EXPERT OPINION: Membrane transporters play an important role in the pharmacokinetics and hence the efficacy of anticancer drugs, including TKIs and STKIs. These drugs are substrates and inhibitors of various transporters. Drug resistance may be bypassed not only by identifying the proper transporter but also by selective combinations, which may either downregulate or increase transporter activity. However, care has to be taken because this profile might be disease, drug and patient specific.

Moderate hyperhomocysteinemia provokes dysfunction of cardiovascular autonomic system and liver oxidative stress in rats.

Hyperhomocysteinemia (HHcy) is associated with cardiovascular disease, atherosclerosis and reactive oxygen species generation. Thus, our aim was to investigate whether there was an association between HHcy, blood pressure, autonomic control and liver oxidative stress. Male Wistar rats were divided into 2 groups and treated for 8weeks: one group (control, CO) received tap water, while the other group (methionine, ME) was given a 100mg/kg of methionine in water by gavage. Two catheters were implanted into the femoral artery and vein to record arterial pressure (AP) and heart rate (HR) and drug administration. Signals were recorded by a data acquisition system. Baroreflex sensitivity was evaluated by HR responses to AP changes induced by vasoactive drugs. HR variability and AP variability were performed by spectral analysis in time and frequency domains to evaluate the contribution of the sympathetic and parasympathetic modulation. Lipid peroxidation and antioxidant enzyme activities were evaluated by measuring superoxide dismutase, catalase and glutathione peroxidase in liver homogenates. The ME group presented a significant increase in systolic arterial pressure (118±9 vs 135±6mmHg), diastolic arterial pressure (81±6 vs. 92±4) and mean arterial pressure (95±7 vs. 106±6). In addition, pulse interval variability presented a significant decrease (41%), while the low frequency component of AP was significantly increased (delta P=6.24mmHg(2)) in the ME group. We also found a positive association between lipid peroxidation and cardiac sympathetic modulation, sympathetic and vagal modulation ratio and systolic pressure variability. Collectively, these findings showed that HHcy induced dysfunction of cardiovascular autonomic system and liver oxidative stress.

Increased incidence of esophageal atresia in northwest Tuscany: years 1994-2007.

AIM: Esophageal atresia (EA) and imperforate anus are congenital disorders with an incidence that ranges between 1/4000 and 1/5000 births. The aim of this work was to assess the incidence of these malformations in northwest Tuscany and the associated anomalies in comparison with the data published by the Tuscan Congenital Diseases Registry. METHODS: A retrospective study was made analyzing the cases of these malformations in the years 1994-2007 on a total of 25051 births at the Division of Neonatology of S. Chiara Hospital, Pisa. RESULTS: The authors found 14 cases of EA and 5 cases of imperforate anus. In these case histories of EA and imperforate anus the incidence was 1/1800 and 1/5000 respectively in comparison with the data issued by the Tuscan Congenital Diseases Registry with an incidence of 1/6644 and 1/1403 in all Tuscany. Five cases of EA (35%) and 2 cases of imperforate anus (40%) were associated with other congenital malformations. CONCLUSION: Our retrospective study shows a higher incidence of EA in northwest Tuscany than in all the rest of Tuscany unlike the incidence of imperforate anus that it is the same of the rest of Tuscany. In both cases isolated form is most frequent than syndromic one.

Homocysteine thiolactone induces cardiac dysfunction: role of oxidative stress.

This study investigates the cardiac functioning in male Wistar rats after treatments with methionine and homocysteine thiolactone (HcyT). The rats were distributed into 3 groups and treated for 8 weeks. Group I was the control (CO) group, given water, group II was treated with methionine, and group III with HcyT (100 mg/kg). Morphometric and functional cardiac parameters were evaluated by echocardiography. Superoxide dismutase (SOD), catalase, and glutathione S-transferase activities, chemiluminescence, thiobarbituric acid reactive substances, and immunocontent were measured in the myocardium. Hyperhomocysteinemiawas observed in rats submitted to the both treatments. The results showed diastolic function was compromised in HcyT group, seen by the increase of E/A (peak velocity of early (E) and late (A) diastolic filling) ratio, decrease in deceleration time of E wave and left ventricular isovolumic relaxation time. Myocardial performance index was increased in HcyT group and was found associated with increased SOD immunocontent. HcyT group demonstrated an increase in SOD, catalase, and glutatione S-transferase activity, and chemiluminescence and thiobarbituric acid reactive substances. Overall, these results indicated that HcyT induces a cardiac dysfunction and could be associated with oxidative stress increase in the myocardium.

RETIRED: Postural health in women: the role of physiotherapy.

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[Perceptions of social actors about the care delivered by the optical laboratory in the primary school health care program (PROASE) in the municipality of Ribeirao Preto]. / Percepções dos atores sociais sobre o atendimento prestado pelo laboratório óptico do programa de assistência primária de saúde escolar (PROASE) no município de Ribeirão Preto.

This study aimed at evaluating the care delivered by the Optical Laboratory of the Program of Primary Care to Schoolchildren (PROASE) according to the perceptions of relatives and teachers of children who had acquired glasses from 1991 to 1995 in the municipality of Ribeirão Preto. The content analysis technique was used for data analysis and, in order to observe the meanings shown in the qualitative material, the thematic analysis technique was utilized. It was concluded that that the social actors showed a positive attitude concerning the importance of the program and clearly expressed that PROASE has given relevant contribution to the health of schoolchildren.

Normothermic perfusion and lung function after cardiopulmonary bypass: effects in pulmonary risk patients.

Fifty patients at risk for postoperative lung dysfunction and undergoing elective coronary revascularization have been randomly assigned to receive normothermic (36 degrees C) perfusion with warm heart protection (NP group) or hypothermic (28 degrees C) perfusion with cold heart protection (HP group). Lung function before and after cardiopulmonary bypass (CPB) was studied through the determination of the intrapulmonary shunt (Qs/Qt), the alveoloarterial oxygen gradient (A-a delta O2), and the artero-alveolar carbon dioxide gradient (a-A delta CO2). The Qs/Qt after CPB was significantly lower in the NP group (27.1 +/- 2.6 vs 35.7 +/- 2.3) as well as the A-a delta O2 (50.2 +/- 1.5 vs 57.6 +/- 2.4), both data returned to comparable between the groups after 3 h in the intensive care unit. The a-A delta CO2 was significantly lower after CPB in the NP group (5.2 +/- 0.74 vs 8.2 +/- 0.8). Hospital stay and mortality were comparable in the two groups; intubation time and rate of early extubation showed a trend in favour of the NP group; the rate of patients suffering hypoxia and/or hypercapnia after extubation was significantly lower in the NP group (12%) versus the HP group (44%). Normothermia seems to exert a protective effect against lung dysfunction after CPB. The absence of a rewarming injury associated with reperfusion, a limitation of the hypothermic-induced vasoconstriction due to local cooling of the lung and a better compliance of the normothermic lung are hypothesized as beneficial effects of the 'all-warm' strategy.

Circulating diphtheria antitoxin levels in children aged 11-14 years in relation to the vaccinal history.

Diphtheria antitoxin level in serum samples obtained from 204 healthy children aged 11-14 years was determined by means of an indirect haemagglutination technique and related to the vaccinal history of the subjects. Irrespective of the time since the last toxoid inoculation, the mean antitoxin titre per ml of serum in the individuals who had received incomplete/irregular anti-diphtheria vaccination in childhood was significantly higher when the number of toxoid doses was higher (from two to more than four doses); the same was not observed for individuals given primary vaccination (three toxoid doses) according to the schedule for childhood vaccination in Italy (regular vaccinees) and one or more booster doses. Between 8 and 13 years after the last of three toxoid doses, a significantly negative association between mean antitoxin titre and time was observed only in irregularly vaccinated children (r = -0.82; p less than 0.05); nevertheless, up to thirteen years after the last vaccine dose, more than 95% of the children exhibited protective levels of antitoxin (greater than 0.125 turkey red blood cells passive haemagglutination units per ml). No significant decrease in mean antitoxin titre was observed between 4 and 10 years after the last of four either regularly or irregularly administered toxoid doses.