Efficacy and safety of Zolbetuximab plus chemotherapy for advanced CLDN18.2-positive gastric or gastro-oesophageal adenocarcinoma: a meta-analysis of randomized clinical trials.

BACKGROUND: The benefit of adding Zolbetuximab to the treatment in patients with Claudin-18 isoform 2 (CLDN18.2)-positive, human epidermal growth factor receptor 2-negative, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GC/GEJ) is not yet fully elucidated. METHODS: We searched PubMed, Embase and Cochrane databases for randomized controlled trials (RCTs) that investigated Zolbetuximab plus chemotherapy versus chemotherapy alone for GC or GEJ adenocarcinoma. We computed hazard-ratios (HRs) or odds-ratios (ORs) for binary endpoints, with 95% confidence intervals (CIs). RESULTS: Three studies and 1,233 patients were included. Comparing with Zolbetuximab plus chemotherapy versus chemotherapy alone, progression-free survival (PFS) rate (HR 0.64; 95% CI 0.49-0.84; p < 0.01) and overall survival (OS) rate (HR 0.72; 95% CI 0.62-0.83; p < 0.01) were significant in favor of the Zolbetuximab group. Regarding effectiveness, the Objective Response Rate (ORR) was (OR 1.15; 95% CI 0.87-1.53; p = 0.34). CONCLUSIONS: In this comprehensive systematic review and meta-analysis of RCTs, the incorporation of Zolbetuximab alongside chemotherapy offers a promising prospect for reshaping the established treatment paradigms for patients diagnosed with advanced CLDN18.2-positive GC/GEJ cancer.

The Essential Oil from Conyza bonariensis (L.) Cronquist (Asteraceae) Exerts an In Vitro Antimelanoma Effect by Inducing Apoptosis and Modulating the MAPKs, NF-κB, and PKB/AKT Signaling Pathways.

The characterization and cytotoxicity of the essential oil from Conyza bonariensis (L.) aerial parts (CBEO) were previously conducted. The major compound was (Z)-2-lachnophyllum ester (EZ), and CBEO exhibited significant ROS-dependent cytotoxicity in the melanoma cell line SK-MEL-28. Herein, we employed the Molegro Virtual Docker v.6.0.1 software to investigate the interactions between the EZ and Mitogen-Activated Protein Kinases (MAPKs), the Nuclear Factor kappa B (NF-κB), and the Protein Kinase B (PKB/AKT). Additionally, in vitro assays were performed in SK-MEL-28 cells to assess the effect of CBEO on the cell cycle, apoptosis, and these signaling pathways by flow cytometry and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay using MAPKs inhibitors. CBEO induced a significant increase in the sub-G1 peak, as well as biochemical and morphological changes characteristic of apoptosis. The in-silico results indicated that EZ interacts with Extracellular Signal-Regulated Kinase 1 (ERK1), c-Jun N-terminal Kinase 1 (JNK1), p38α MAPK, NF-κB, and PKB/AKT. Moreover, CBEO modulated the ERK1/2, JNK, p38 MAPK, NF-κB, and PKB/AKT activities in SK-MEL-28 cells. Furthermore, CBEO's cytotoxicity against SK-MEL-28 cells was significantly altered in the presence of MAPKs inhibitors. These findings support the in vitro antimelanoma effect of CBEO through apoptosis induction, and the modulation of ERK, JNK, p38 MAPK, NF-κB, and PKB/AKT activities.

PD-1/PD-L1 Inhibitors plus Chemotherapy Versus Chemotherapy Alone for Resectable Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: The benefit of adding programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors to the treatment of early-stage non-small cell lung cancer (NSCLC), both neoadjuvant therapy (NAT) and adjuvant therapy (AT), is not yet fully elucidated. Methods: We searched PubMed, Embase, and Cochrane databases for randomized controlled trials (RCT) that investigated PD-1/PD-L1 inhibitors plus chemotherapy for resectable stage NSCLC. We computed hazard ratios (HRs) or odds ratios (ORs) for binary endpoints, with 95% confidence intervals (CIs). Results: A total of seven RCTs comprising 3915 patients with resectable stage NSCLC were randomized to chemotherapy with or without PD-1/PD-L1 inhibitors as NAT or AT. As NAT, the PD-1/PD-L1 inhibitors plus chemotherapy group demonstrated significantly improved overall survival (HR 0.66; 95% CI 0.51-0.86) and event-free survival (HR 0.53; 95% CI 0.43-0.67) compared with the chemotherapy alone group. There was a significant increase in favor of the PD-1/PD-L1 inhibitors plus chemotherapy group for major pathological response (OR 6.40; 95% CI 3.86-10.61) and pathological complete response (OR 8.82; 95% CI 4.51-17.26). Meanwhile, as AT, disease-free survival was significant in favor of the PD-1/PD-L1 inhibitors plus chemotherapy group (HR 0.78; 95% CI 0.69-0.90). Conclusions: In this comprehensive systematic review and meta-analysis of RCTs, the incorporation of PD-1/PD-L1 inhibitors alongside chemotherapy offers a promising prospect for reshaping the established treatment paradigms for patients diagnosed with resectable stages of NSCLC. Moreover, our analyses support that neoadjuvant administration with these agents should be encouraged, in light of the fact that it was associated with an increased survival and pathological response, at the expense of a manageable safety profile.

Chemical Composition, In Vitro Antitumor Effect, and Toxicity in Zebrafish of the Essential Oil from Conyza bonariensis (L.) Cronquist (Asteraceae).

The essential oil from Conyza bonariensis (Asteraceae) aerial parts (CBEO) was extracted by hydrodistillation in a Clevenger-type apparatus and was characterized by gas chromatography-mass spectrometry. The antitumor potential was evaluated against human tumor cell lines (melanoma, cervical, colorectal, and leukemias), as well as non-tumor keratinocyte lines using the MTT assay. The effect of CBEO on the production of Reactive Oxygen Species (ROS) was evaluated by DCFH-DA assay, and a protection assay using the antioxidant N-acetyl-L-cysteine (NAC) was also performed. Moreover, the CBEO toxicity in the zebrafish model was assessed. The majority of the CBEO compound was (Z)-2-lachnophyllum ester (57.24%). The CBEO exhibited selectivity towards SK-MEL-28 melanoma cells (half maximal inhibitory concentration, IC50 = 18.65 ± 1.16 µg/mL), and induced a significant increase in ROS production. In addition, the CBEO's cytotoxicity against SK-MEL-28 cells was reduced after pretreatment with NAC. Furthermore, after 96 h of exposure, 1.5 µg/mL CBEO induced death of all zebrafish embryos. Non-lethal effects were observed after exposure to 0.50-1.25 µg/mL CBEO. Additionally, significant alterations in the activity of enzymes associated with oxidative stress in zebrafish larvae were observed. These results provide evidence that CBEO has a significant in vitro antimelanoma effect by increasing ROS production and moderate embryotoxicity in zebrafish.

Surgical versus non-surgical treatment of flail chest: a meta-analysis of randomized controlled trials.

PURPOSE: Conflicting evidence exists on the choice of surgical or non-surgical treatment of flail chest injuries. We aimed to perform a meta-analysis comparing outcomes in patients presenting flail chest undergoing surgical or non-surgical treatment. METHODS: Embase, PubMed, and Cochrane databases were searched for randomized controlled trials (RCTs) comparing surgery to no surgery in patients with acute unstable chest wall injuries. We computed weighted mean differences (WMDs) for continuous outcomes and risk ratios (RRs) for binary endpoints, with 95% confidence intervals (CIs). Random effects meta-analyses were performed. Heterogeneity was assessed using I2 statistics. RESULTS: Six RCTs (544 patients) were included, and surgical treatment was used in 269 (49.4%). Compared to no surgery, surgery reduced mechanical ventilation days (WMD - 4.34, 95% CI - 6.98, - 1.69; p < 0.01; I2 = 87%; GRADE: very low; PI - 13.51, 4.84); length of intensive care unit stay (WMD - 4.62, 95% CI - 7.19, - 2.05; p < 0.01; I2 = 78%; GRADE: low; PI - 12.86, 3.61) and the incidence of pneumonia (RR 0.50, 95% CI 0.31, 0.81; p = 0.005; I2 = 54%; GRADE: moderate; PI 0.13, 1.91). No difference in mortality (RR 0.56, 95% CI 0.19, 1.65; p = 0.27; I2 = 23%; GRADE: moderate; PI 0.04, 7.25), length of hospital stay (WMD - 5.39, 95% CI - 11.38, - 0.60; p = 0.08; I2 = 89%; GRADE: very low; PI - 11.38, 0.60), or need for tracheostomy (RR 0.59, 95% CI 0.34, 1.03; p = 0.06; I2 = 54%; GRADE: moderate; PI 0.11, 3.24) was found. CONCLUSIONS: Our results suggest that surgical treatment is advantageous compared to non-surgical treatment for patients with flail chest secondary to rib fractures.

Cancer mortality in Guarapari, Espiríto Santo State, Brazil, with areas of high natural radioactivity.

Guarapari, a municipality of the state of Espírito Santo, Brazil, reported higher mortality rates for the most common cancers from 1996 to 2000. This municipality has beaches with high natural radioactivity. To verify whether this excessive cancer mortality rate still exist in Guarapari, mortality rates for all causes, cancers, and the most prevalent cancers in this municipality were studied from 2000 to 2018 and compared with those observed in the state. Data on all-cause mortality, all-cancer mortality, and mortality from cancer of the esophagus, stomach, larynx, trachea, bronchi and lung, prostate, breast, and leukemias were collected in Brazilian Health Informatics Department (DATASUS) from 2000 to 2018. Mortality rates were calculated by direct method. Standardized age-adjusted rates (SAAR) were calculated based on standard of the World Health Organization (WHO) world population. Crude mortality rates were calculated for each municipality and SAAR for the state and nine municipalities where natural radioactivity was evaluated. Mortality rates from all causes, all cancers, and different cancers observed in Guarapari did not differ significantly from those observed in the state or municipalities with more than 100,000 inhabitants. Radioactivity levels and mortality rates showed no correlation in nine municipalities where natural radioactivity was known. In conclusion, results showed that mortality from cancer and all causes in Guarapari did not differ from those observed in the state and that there was no correlation between the levels of natural radioactivity and mortality from cancer in areas where natural radioactivity was evaluated.

Efficacy of the argon plasma coagulation in patients with weight regain after gastric bypass: a randomized control trial.

Background and study aims Endoscopic procedure using argon plasma coagulation (APC) promotes a progressive reduction in gastrojejunal anastomosis diameter. The present study aimed to evaluate the efficacy of the APC in patients with weight regain in the postoperative periods of gastric bypass. Patients and methods This was a randomized controlled trial conducted with 66 patients who were randomly assigned selected (using lottery method) and divided into two groups: study group (SG), 38 patients (APC treatment); and control group (CG), 28 patients (only endoscopy procedure). We considered 30 days,180 days, and one year as short-term, medium-term, and long-term, respectively. The parameters analyzed were total weight loss (TWL), excess weight loss (%EWL), total weight loss (%TWL), and reduction of weight regain (%RWR). Furthermore, a biopsy for neoplastic histological changes was carried out for the APC group. For statistical analysis, values of P  < 0.05 were considered significant. Results The %TWL and %RWR were higher in the SG in short, medium, and long terms, when compared to the same periods in the CG ( P  < 0.001). One year after follow-up, the final weight did not reach the statistical difference between groups. Biopsy performed in SG 1 year after APC did not reveal neoplastic histological changes. Conclusions APC effectively treats weight regain after bariatric surgery in the short and medium-term. An important "new" weight gain was observed in the long-term, showing that obesity is a chronic disease that requires multidisciplinary and family care for life. Also, APC is a safe procedure with low adverse event rates.

Reversible Iron Oxyfluoride (FeOF)-Graphene Composites as Sustainable Cathodes for High Energy Density Lithium Batteries.

Two large barriers are impeding the wide implementation of electric vehicles, namely driving-range and cost, primarily due to the low specific energy and high cost of mono-valence cathodes used in lithium-ion batteries. Iron is the ideal element for cathode materials considering its abundance, low cost and toxicity. However, the poor reversibility of (de)lithiation and low electronic conductivity prevent iron-based high specific energy multi-valence conversion cathodes from practical applications. In this work, a sustainable FeOF nanocomposite is developed with extraordinary performance. The specific capacity and energy reach 621 mAh g-1 and 1124 Wh kg-1 with more than 100 cycles, which triples the specific capacity, and doubles the specific energy of current mono-valence intercalation LiCoO2 . This is the result of an effective approach, combing the nanostructured FeOF with graphene, realized by making the (de)lithiation reversible by immobilizing FeOF nanoparticles and the discharge products over the graphene surface and providing the interparticle electric conduction. Importantly, it demonstrates that introducing small amount of graphene can create new materials with desired properties, opening a new avenue for altering the (de)lithiation process. Such extraordinary performance represents a significant breakthrough in developing sustainable conversion materials, eventually overcoming the driving range and cost barriers.

Synthetic Naphthoquinone Derivatives as Anticancer Agents in Ovarian Cancer: Cytotoxicity Assay and Investigation of Possible Biological Mechanisms Action.

In this study, eight naphthoquinone derivatives were synthesized in yields ranging from 52 to 96% using easy, fast, and low-cost methodologies. All naphthoquinone derivatives were screened for their in vitro anti-proliferative activities against OVCA A2780 cancer cell lines. Amongst all analysed compounds, derivatives 3-5 presented the most prominent cytotoxic potential. Naphthoquinones 3 and 4, bearing sulfur-containing groups, were identified as having high potential for ROS production, in particular the superoxide anion. Furthermore, 3 and 4 compounds caused a decrease in the cell population in G0/G1 and induced more than 90% of the cell population to apoptosis. Compound 5 did not act in any of these processes. Finally, compounds 3-5 were tested for their inhibitory ability against PI3K and MAPK. Compounds 3 and 4 do not inhibit the PI3K enzyme. On the other hand, the naphthoquinone-polyphenol 5 was only able to inhibit the percentage of cells expressing pERK.

Evaluation of the breathing mode by infrared thermography

Abstract Objectives: To analyze breathing modes with infrared thermography. Methods: Cross-sectional observational exploratory study conducted in 20 female participants with a mean age of 26.0-years. The thermograms were made following the principles of the American Academy of Thermology and the Brazilian Thermology Society. The camera FLIR A315 (FLIR Inc., Santa Barbara, CA) was used for the tests. The recordings consisted of the participants breathing normally through the nose for 2 min and simulating oral/oronasal breathing for another 2min. The thermograms were analyzed with the FLIR Tools software. An ellipse was placed between the nostrils and the lip commissures to obtain the mean temperatures. The collection was made by two independent researchers, and the normalized non-dimensional temperature was calculated. Results: The temperature in nasal breathing is higher than in oral/oronasal breathing both for inhaling and exhaling when measured in the region of the mouth. The exhaling temperatures were higher than the inhaling ones in oral/oronasal breathing (through the nose and the mouth) and nasal breathing (only through the nose). The temperature difference between exhaling and inhaling (ΔT) was greater in oral/oronasal breathing when measured in the region of the mouth. Conclusion: The thermographic assessment of breathing modes may be made by comparing the mean temperatures of the mouth, using an ellipse. Level of evidence: Study without consistently applied reference standards.

Geografia das respostas sociais para as pessoas idosas em Portugal / Geography of social care for older people in Portugal

Resumo: Este estudo analisa a distribuição geográfica das respostas sociais dirigidas à população idosa em Portugal continental, e compara os padrões espaciais dos equipamentos dos sectores público, solidário e lucrativo. Os resultados mostram uma distribuição heterogénea e uma tendência para a concentração espacial das estruturas do sector privado em áreas mais urbanizadas. Conclui-se que a crescente liberalização do sector constitui um risco para a equidade territorial dos cuidados sociais.

Abstract: This study analyses the geographical distribution of social care for older adults in mainland Portugal, and compares the spatial patterns of public, non-profit and profit institutions. The results show a heterogeneous distribution and a tendency towards spatial concentration of private sector structures in more urbanised areas. We conclude that the increasing liberalisation of the sector constitutes a risk to the territorial equity of social care provision.

Analysis of the efficacy of prophylactic tranexamic acid in preventing postpartum bleeding: systematic review with meta-analysis of randomized clinical trials

Abstract Background Postpartum Hemorrhage (PPH) is one of the main causes of maternal mortality, mainly in the poorest regions of the world, drawing attention to the need for strategies for preventing it. This study aims to evaluate the efficacy of prophylactic administration of Tranexamic Acid (TXA) in decreasing blood loss in pregnant women in delivery, preventing PPH. Methods Systematic review of randomized clinical trials. We searched for publications in PubMed, EMBASE and Cochrane Library databases, with the uniterms "postpartum, puerperal hemorrhage" and "tranexamic acid", published between January of 2004 and January of 2020. The eligibility criteria were trials published in English with pregnant women assessed during and after vaginal or cesarean delivery about the effect of prophylactic use of TXA on bleeding volume. The random-effects model was applied with the DerSimonian-Laird test and the Mean Difference (MD) was calculated for continuous variables together with each 95% CI. This systematic review was previously registered in the PROSPERO platform under the registration n° CRD42020187393. Results Of the 630 results, 16 trials were selected, including one with two different doses, performing a total of 6731 patients. The intervention group received a TXA dose that varied between 10 mg.kg−1 and 1g (no weight calculation). The TXA use was considered a protective factor for bleeding (MD: -131.07; 95% CI: -170.00 to -92.78; p= 0.000) and hemoglobin variation (MD: -0.417; 95% CI: -0.633 to -0.202; p= 0.000). In the subgroup analysis related to the cesarean pathway, the effect of TXA was even greater. Conclusion The prophylactic use of tranexamic acid is effective in reducing the post-partum bleeding volume. PROSPERO registration ID CRD42020187393.

Cancer mortality in Guarapari, Espiríto Santo State, Brazil, with areas of high natural radioactivity / Mortalidade por câncer em Guarapari, Espírito Santo, Brasil, em áreas de alta radioatividade natural / Mortalidad por cáncer en Guarapari, Espírito Santo, Brasil, en áreas de alta radiactividad natural

Guarapari, a municipality of the state of Espírito Santo, Brazil, reported higher mortality rates for the most common cancers from 1996 to 2000. This municipality has beaches with high natural radioactivity. To verify whether this excessive cancer mortality rate still exist in Guarapari, mortality rates for all causes, cancers, and the most prevalent cancers in this municipality were studied from 2000 to 2018 and compared with those observed in the state. Data on all-cause mortality, all-cancer mortality, and mortality from cancer of the esophagus, stomach, larynx, trachea, bronchi and lung, prostate, breast, and leukemias were collected in Brazilian Health Informatics Department (DATASUS) from 2000 to 2018. Mortality rates were calculated by direct method. Standardized age-adjusted rates (SAAR) were calculated based on standard of the World Health Organization (WHO) world population. Crude mortality rates were calculated for each municipality and SAAR for the state and nine municipalities where natural radioactivity was evaluated. Mortality rates from all causes, all cancers, and different cancers observed in Guarapari did not differ significantly from those observed in the state or municipalities with more than 100,000 inhabitants. Radioactivity levels and mortality rates showed no correlation in nine municipalities where natural radioactivity was known. In conclusion, results showed that mortality from cancer and all causes in Guarapari did not differ from those observed in the state and that there was no correlation between the levels of natural radioactivity and mortality from cancer in areas where natural radioactivity was evaluated.

Taxas de mortalidade maiores para os cânceres mais frequentes foram registradas entre 1996 e 2000 em Guarapari, um município do Espírito Santo, Brasil, onde se localizam praias com alta radioatividade natural. Para verificar a existência desse excesso de mortalidade por câncer em Guarapari, taxas de mortalidade por todas as causas, todos os cânceres e pelos cânceres mais prevalentes no município foram estudadas entre 2000 e 2018 e comparadas com aquelas observadas no estado. Dados de mortalidade por todas as causas, por câncer e por câncer de esôfago, estômago, laringe, traqueia, brônquios e pulmão, próstata, mama e leucemias foram coletados no Departamento de Informática do SUS (DATASUS) de 2000 a 2018. As taxas de mortalidade foram calculadas pelo método direto. As taxas padronizadas ajustadas por idade (TPAI) foram calculadas com base na população mundial padrão da Organização Mundial da Saúde (OMS). Foram calculadas taxas brutas de mortalidade para cada município e as TPAI para o estado e para os nove municípios onde foi avaliada a radioatividade natural. A mortalidade por todas as causas, todos os cânceres e pelos diferentes cânceres investigados em Guarapari não diferiu significativamente daqueles observados no estado ou em municípios com mais de 100 mil habitantes. Não houve correlação entre os níveis de radioatividade e as taxas de mortalidade nos nove municípios onde a radioatividade natural era conhecida. Em conclusão, os resultados mostraram que a mortalidade por câncer e por todas as causas em Guarapari não diferiu daquelas observadas no restante do estado. Além disso, não houve correlação entre os níveis de radioatividade natural e a mortalidade por câncer nas áreas onde a radioatividade natural foi avaliada.

Las mayores tasas de mortalidad por cáncer se registraron entre 1996 y 2000 en Guarapari, un municipio del estado de Espírito Santo, Brasil, donde existen playas con alta radiactividad natural. Para verificar la existencia de mayor mortalidad por cáncer en Guarapari, se estudiaron las tasas de mortalidad por distintas causas, por los tipos de cáncer y por los tipos más prevalentes en este municipio entre 2000 y 2018, y se las compararon con las observadas en todo el estado. Los datos sobre la mortalidad por distintas causas, por cáncer y por cáncer de esófago, estómago, laringe, tráquea, bronquios y pulmón, próstata, mama y leucemias se recogieron del Departamento de Informática de SUS (DATASUS) sobre el periodo de 2000 a 2018. Las tasas de mortalidad se calcularon utilizando el método directo. Las tasas estandarizadas ajustadas por edad (TEAE) se calcularon con base en las de la población mundial estándar de la Organización Mundial de Salud (OMS). Se calcularon las tasas brutas de mortalidad para cada municipio y las TEAE para el estado y para los nueve municipios donde se evaluó la radiactividad natural. La mortalidad por distintas causas, por los tipos de cáncer y por los diferentes tipos de cáncer investigados en Guarapari no difirió significativamente de la observada en el estado o en los municipios con más de 100.000 habitantes. No hubo correlación entre los niveles de radiactividad y las tasas de mortalidad en los nueve municipios donde existe radiactividad natural. Se concluye que la mortalidad por cáncer y por distintas causas en Guarapari no difiere de los resultados observados en todo el estado. Además, no hubo correlación entre los niveles de radiactividad natural y la mortalidad por cáncer en las áreas donde se evaluó la radiactividad natural.

A 9-aminoacridine derivative induces growth inhibition of Ehrlich ascites carcinoma cells and antinociceptive effect in mice.

Acridine derivatives have been found with anticancer and antinociceptive activities. Herein, we aimed to evaluate the toxicological, antitumor, and antinociceptive actions of N'-(6-chloro-2-methoxyacridin-9-yl)-2-cyanoacetohydrazide (ACS-AZ), a 9-aminoacridine derivative with antimalarial activity. The toxicity was assessed by acute toxicity and micronucleus tests in mice. The in vivo antitumor effect of ACS-AZ (12.5, 25, or 50 mg/kg, intraperitoneally, i.p.) was determined using the Ehrlich tumor model, and toxicity. The antinociceptive efficacy of the compound (50 mg/kg, i.p.) was investigated using formalin and hot plate assays in mice. The role of the opioid system was also investigated. In the acute toxicity test, the LD50 (lethal dose 50%) value was 500 mg/kg (i.p.), and no detectable genotoxic effect was observed. After a 7-day treatment, ACS-AZ significantly (p < 0.05) reduced tumor cell viability and peritumoral microvessels density, suggesting antiangiogenic action. In addition, ACS-AZ reduced (p < 0.05) IL-1ß and CCL-2 levels, which may be related to the antiangiogenic effect, while increasing (p < 0.05) TNF-α and IL-4 levels, which are related to its direct cytotoxicity. ACS-AZ also decreased (p < 0.05) oxidative stress and nitric oxide (NO) levels, both of which are crucial mediators in cancer known for their angiogenic action. Moreover, weak toxicological effects were recorded after a 7-day treatment (biochemical, hematological, and histological parameters). Concerning antinociceptive activity, ACS-AZ was effective on hotplate and formalin (early and late phases) tests (p < 0.05), characteristic of analgesic agents with central action. Through pretreatment with the non-selective (naloxone) and µ1-selective (naloxonazine) opioid antagonists, we observed that the antinociceptive effect of ACS-AZ is mediated mainly by µ1-opioid receptors (p < 0.05). In conclusion, ACS-AZ has low toxicity and antitumoral activity related to cytotoxic and antiangiogenic actions that involve the modulation of reactive oxygen species, NO, and cytokine levels, in addition to antinociceptive properties involving the opioid system.

GENES EXPRESSION AND SERUM BIOMARKERS FOR DIAGNOSIS OF HEPATOCELLULAR CARCINOMA, CIRRHOSIS AND HEPATITIS C.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Risk factors for HCC include hepatitis C (HCV) and B (HBV) virus infection, alcoholic cirrhosis and genetic alterations that can affect several cellular pathways. OBJECTIVE: This study purposed to analyze the gene and serum protein expression of vascular endothelial growth factor (VEGF), angiogenesis, alpha fetoprotein, cystatin B (CSTB), ß-catenin and glypican-3 (GPC3) in groups with HCC, cirrhosis or HCV and controls, and their relation with clinical staging in the HCC and cirrhosis groups, as well its sensitivity and specificity values. METHODS: A total of 230 individuals were distributed in Group 1 (G1) - 80 patients with HCC; Group 2 (G2) - 76 patients with cirrhosis due to any etiology; Group 3 (G3) - 33 patients with HCV; Group 4 (G4 - controls) - 41 individuals without clinical or biochemical signs of any liver disease. Gene expression was analyzed by qRT-PCR and serum proteins were performed using the ELISA method. RESULTS: Increased VEGF and angiogenesis, alpha fetoprotein expression could be observed in BCLC stage-D patients compared to stage-B patients, and stage-C patients showed higher expression of ß-catenin, compared to stage-B patients (P<0.05). For VEGF and GPC3, discriminatory power was observed between HCC patients and controls (AUC =0.71; 0.82, respectively). CSTB showed discriminatory power in the comparison between patients with HCV and controls (AUC =0.74). CONCLUSION: The present study confirms the sensitivity of serum CSTB in the diagnosis of hepatitis C, and gene expression of VEGF and serum GPC3, confer both sensitivity and specificity for the diagnosis of HCC.

Expressão gênica e biomarcadores séricos para diagnóstico de carcinoma hepatocelular, cirrose e hepatite C / Genes expression and serum biomarkers for diagnosis of hepatocellular carcinoma, cirrhosis and hepatitis c

ABSTRACT Background: Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Risk factors for HCC include hepatitis C (HCV) and B (HBV) virus infection, alcoholic cirrhosis and genetic alterations that can affect several cellular pathways. Objective: This study purposed to analyze the gene and serum protein expression of vascular endothelial growth factor (VEGF), angiogenesis, alpha fetoprotein, cystatin B (CSTB), β-catenin and glypican-3 (GPC3) in groups with HCC, cirrhosis or HCV and controls, and their relation with clinical staging in the HCC and cirrhosis groups, as well its sensitivity and specificity values. Methods: A total of 230 individuals were distributed in Group 1 (G1) - 80 patients with HCC; Group 2 (G2) - 76 patients with cirrhosis due to any etiology; Group 3 (G3) - 33 patients with HCV; Group 4 (G4 - controls) - 41 individuals without clinical or biochemical signs of any liver disease. Gene expression was analyzed by qRT-PCR and serum proteins were performed using the ELISA method. Results: Increased VEGF and angiogenesis, alpha fetoprotein expression could be observed in BCLC stage-D patients compared to stage-B patients, and stage-C patients showed higher expression of β-catenin, compared to stage-B patients (P<0.05). For VEGF and GPC3, discriminatory power was observed between HCC patients and controls (AUC =0.71; 0.82, respectively). CSTB showed discriminatory power in the comparison between patients with HCV and controls (AUC =0.74). Conclusion The present study confirms the sensitivity of serum CSTB in the diagnosis of hepatitis C, and gene expression of VEGF and serum GPC3, confer both sensitivity and specificity for the diagnosis of HCC.

RESUMO Contexto: Carcinoma hepatocelular (CHC) é o tipo mais comum de câncer de fígado. Os fatores de risco para CHC incluem infecção pelo vírus da hepatite C (VHC) e B (VHB), cirrose alcoólica e alterações genéticas que podem afetar diversas vias celulares. Objetivo: Este estudo teve como objetivo analisar a expressão gênica e proteica sérica de VEGF, AFP, CSTB, β-catenina e GPC3 em grupos com CHC, cirrose ou VHC e controles, e sua relação com o estadiamento clínico nos grupos CHC e cirrose, bem como sua valores de sensibilidade e especificidade. Métodos: Duzentos e trinta indivíduos foram distribuídos no Grupo 1 (G1) - 80 pacientes com CHC; Grupo 2 (G2) - 76 pacientes com cirrose de qualquer etiologia; Grupo 3 (G3) - 33 pacientes com VHC; Grupo 4 (G4 - Controles) - 41 indivíduos sem sinais clínicos ou bioquímicos de qualquer doença hepática. A expressão gênica foi analisada por qRT-PCR e as proteínas séricas foram realizadas pelo método ELISA. Resultados: Aumento da expressão de VEGF e AFP pode ser observado em pacientes BCLC estágio D em comparação com pacientes estágio B, e pacientes estágio C apresentaram maior expressão de CTNNB1, em comparação com pacientes estágio B (P<0,05). Para VEGF e GPC3, foi observado poder discriminatório entre pacientes com CHC e controles (AUC = 0,71; 0,82, respectivamente). O CSTB mostrou poder discriminatório na comparação entre pacientes com VHC e controles (AUC =0,74). Conclusão: O presente estudo confirma a sensibilidade do CSTB sérico no diagnóstico da hepatite C, e a expressão gênica de VEGF e GPC3 sérica conferem sensibilidade e especificidade para o diagnóstico de CHC.

Genetic polymorphisms related to the vitamin D pathway in patients with cirrhosis with or without hepatocellular carcinoma (HCC).

Objective: To evaluate the association of genetic polymorphisms of vitamin D transporter protein (DBPrs4588 and DBP-rs7041) and cytochrome P450-24A1 (CYP24A1-rs6013897) in patients with cirrhosis with or without hepatocellular carcinoma (HCC), including demographic/clinical/biochemical profiles. Methods: A total of 383 individuals were studied, considering the total group (TotalG) of patients with cirrhosis (TotalG: N = 158) with or without HCC, distributed into Group 1 (G1): cirrhosis and HCC; Group 2 (G2): isolated cirrhosis; and 225 individuals without hepatopathies (G3). Polymorphisms were analysed by real-time polymerase chain reaction. An alpha error of 5% was admitted. Results: CYP24A1-rs6013897 predominated the genotype with at least one polymorphic allele (_/T) in G1 (98.3%) versus G2 (88.8%; p = 0.0309). There was a moderate positive correlation between vitamin D and parathyroid hormone in patients (TotalG: R 2 = 0.3273). Smoking, alcoholism and diabetes mellitus (DM) stood out as independent factors for cirrhosis, as well as for cirrhosis with HCC, except for smoking, adding, in this case, advanced age, male gender, polymorphic allele of CYP24A1-rs6013897, viral hepatitis and high levels of serum gamma-glutamyl transferase (GGT), alpha-fetoprotein (AFP) and creatinine. An increase in survival was observed in the presence of the polymorphic allele of DBP-rs7041 (p = 0.0282). Conclusion: CYP24A1-rs6013897 is associated with cirrhosis and HCC as a predictor, while DBP-rs4588 is associated with reduced vitamin D, and DBP-rs7041 provides increased survival, suggesting a protective characteristic. Advanced age, alcoholism, DM, viral hepatitis and high levels of GGT, AFP and creatinine are also confirmed as predictors of HCC and cirrhosis, while smoking, alcoholism and DM for isolated cirrhosis only.

Investigating VEGF. miR-145-3p, and miR-101-3p Expression in Patients with Cholangiocarcinoma.

INTRODUCTION: Cholangiocarcinoma (CCA) is the second most common type of primary liver cancer. Several factors, such as epigenetic changes in promoter genes, gene expression, and microRNAs (miR), can contribute to genomic instability in cancer. This study aimed at evaluating the expression of VEGF, miRs 145-3p, and 101-3p in patients with CCA and their potential as biomarkers for diagnosis and prognosis of CCA. MATERIAL AND METHODS: Sixty two patients were studied. Out of these 62 patients, 41 cases had confirm CCA and 21 cases had hepatopathies complications. The RNA was extracted from a paraffined tissue block, and then the synthesis of cDNA was performed. The analysis of the expression of VEGF, miR-145-3p, and miR-101-3p was carried out by polymerase chain reaction in real time.  Results: The findings revealed that miRs 145-3p and 101-3p were under expressed in the case group compared to the control group (0.46; 0.17; P = 0.0001, respectively). VEGF was overexpressed in the case group compared to the control group (11.8; P = 0.0001). An increase in miR-145-3p expression level was observed in patients with perihilar CCA compared to those with distal CCA (0.51 ± 0.41; 0.17 ± 0.13; P = 0.0698). Survival rate analysis showed that 41.9% of patients with intrahepatic CCA and 31.5% of patients with extrahepatic CCA were free from death within 11 months, leading to a significant difference (P> 0.05). CONCLUSION: The underexpression of miRNAs, tumor suppressors, the overexpression of VEGF, smoking, and aging were associated with CCA based on our findings. It seems that the reduced expression of the studies miRNAs and increased expression of VEGF can contribute to a decrease in survival rate of patients with tumor in their intrahepatic bile ducts.

Evaluation of doxorubicin in three-dimensional culture of breast cancer cells and the response in PI3K/AKT/PTEN signaling pathways: a pilot study.

Breast cancer (BC) has a high mortality rate, which is attributed to the absence of effective treatment markers. Doxorubicin (DOX) was evaluated by molecular docking in vitro in cultured BC spheroids and its association with genes involved in the PI3K/AKT/PTEN signaling pathway. Spheroids were obtained from a primary BC. The selected compound was used for molecular docking experiments. Spheroids were treated with DOX for 1 (D1) and 9 (D9) days. qPCR was used to evaluate PIK3CA, HIF-1α, VEGF-A, PTEN expression. Treatment with DOX (1 µM) significantly increased the number of spheroids (D1), whereas exposure to chemotherapy at 2 µM on D9 was more effective. DOX treatment resulted in significantly higher expression of VEGF-A, HIF-1α and PIK3CA by D1 and HIF-1α and PTEN were upregulated by D9. Compared to treatment on D1 with D9 (1 µM) had significantly higher PTEN and lower PIK3CA gene expression. The genes HIF-1α and PTEN were more expressed with 2 µM of DOX while VEGF-A was downregulated. D1 vs. D9 exhibited reduced VEGF-A, HIF-1α, and PIK3CA expression and upregulation of PTEN expression. DOX effects at the molecular mechanisms can be involved the modulation of genes related to angiogenesis cell proliferation and tumor growth in BC tissue spheroids.