Anticancer Therapeutic Strategies Targeting p53 Aggregation.

p53 is a tumor suppressor protein that is mutated in more than 50% of cancer cases. When mutated, it frequently results in p53 oncogenic gain of function (GOF), resulting in a greater tendency to aggregate in the phase separation and phase transition pathway. GOFs related to p53 aggregation include chemoresistance, which makes therapy even more difficult. The therapies available for the treatment of cancer are still quite limited, so the study of new molecules and therapeutic targets focusing on p53 aggregates is a promising strategy against cancer. In this review, we classify anticancer molecules with antiaggregation properties into four categories: thiol alkylating agents, designed peptides, agents with chaperone-based mechanisms that inhibit p53 aggregation, and miscellaneous compounds with anti-protein aggregation properties that have been studied in neurodegenerative diseases. Furthermore, we highlight autophagy as a possible degradation pathway for aggregated p53. Here, considering cancer as a protein aggregation disease, we review strategies that have been used to disrupt p53 aggregates, leading to cancer regression.

Royal jelly reduce DNA damage induced by alkylating agent in mice.

Royal jelly (RJ) is a creamy white-yellow liquid that is secreted by the mandibular and hypopharyngeal glands of bees to nourish the larvae. RJ has gained increasing interest in recent years owing to its antioxidant potential. However, little is known about adequate RJ dosing and its effects on genetic material. Thus, the aim of this study was to evaluate the in vivo effects of RJ on genotoxicity and mutagenicity induced by the alkylating agent methyl methanesulfonate (MMS). In this study, 3-month-old Swiss albino male mice (N = 66) were divided into 11 groups for experimentation. Experiments were performed by administering lyophilized RJ (150 mg/kg, 300 mg/kg, and 1000 mg/kg) or water via gavage as pre- and posttreatment processes with the alkylating agent MMS. After treatment, blood samples were collected from the mice via an incision at the end of the tail to conduct comet assays at times of 24 h and 48 h posttreatment. The mice were then euthanized to remove the bone marrow for a micronucleus test. Overall, regardless of dose, RJ did not exhibit genotoxic, mutagenic activity and the administration of high doses, mainly in the form of posttreatment, presented antigenotoxic and antimutagenic actions. Further, a dose-response correlation was observed in the RJ posttreatment groups. These results demonstrate that RJ administration was effective in reversing the damage caused by the alkylating agent MMS.

Molecular alterations that precede the establishment of the hallmarks of cancer: An approach on the prevention of hepatocarcinogenesis.

Chronic liver injury promotes the molecular alterations that precede the establishment of cancer. Usually, several decades of chronic insults are needed to develop the most common primary liver tumor known as hepatocellular carcinoma. As other cancer types, liver cancer cells are governed by a common set of rules collectively called the hallmarks of cancer. Although those rules have provided a conceptual framework for understanding the complex pathophysiology of established tumors, therapeutic options are still ineffective in advanced stages. Thus, the molecular alterations that precede the establishment of cancer remain an attractive target for therapeutic interventions. Here, we first summarize the chemopreventive interventions targeting the early liver carcinogenesis stages. After an integrative analysis on the plethora of molecular alterations regulated by anticancer agents, we then underline and discuss that two critical processes namely oxidative stress and genetic alterations, play the role of 'dirty work laborer' in the initial cell damage and drive the transformation of preneoplastic into neoplastic cells, respectively; besides, the activation of cellular senescence works as a key mechanism in attempting to prevent the onset and establishment of liver cancer. Whereas the detrimental effects of the binomial made up of oxidative stress and genetic alterations are either eliminated or reduced, senescence activation is promoted by anticancer agents. We argue that collectively, oxidative stress, genetic alterations, and senescence are key events that influence the fate of initiated cells and the establishment of the hallmarks of cancer.

Stability in solution and chemoprotection by octadecavanadates(IV/V) in E. coli cultures.

Two mixed-valence octadecavanadates, (NH4)2(Me4N)5[VIV12VV6O42I]·Me4NI·5H2O (V18I) and [{K6(OH2)12VIV11VV7O41(PO4)·4H2O}n] (V18P), were synthesized and characterized by single-crystal X-ray diffraction analysis and FTIR, Raman, 51V NMR, EPR and UV/Vis/NIR spectroscopies. The chemoprotective activity of V18I and V18P towards the alkylating agent diethyl sulfate was assessed in E. coli cultures. The complex V18I was nontoxic in concentrations up to 5.0 mmol L-1, while V18P presented moderate toxicity in the concentration range 0.10 - 10 mmol L-1. Conversely, a ca. 35% enhancement in culture growth as compared to cells treated only with diethyl sulfate was observed upon addition of V18I (0.10 to 2.5 mmol L-1), while the combination of diethyl sulfate with V18P increased the cytotoxicity presented by diethyl sulfate alone. 51V NMR and EPR speciation studies showed that V18I is stable in solution, while V18P suffers partial breakage to give low nuclearity oxidometalates of vanadium(V) and (IV). According to the results, the chemoprotective effect depends strongly on the direct reactivity of the polyoxidovanadates (POV) towards the alkylating agent. The reaction of diethyl sulfate with V18I apparently produces a new, rearranged POV instead of poorly-reactive breakage products, while V18P shows the formation and subsequent consumption of low-nuclearity species. The correlation of this chemistry with that of other mixed-valence polyoxidovanadates, [H6VIV2VV12O38PO4]5- (V14) and [VIV8VV7O36Cl]6- (V15), suggests a relationship between stability in solution and chemoprotective performance.

The numerical probability of carcinogenicity to humans of some pharmaceutical drugs: Alkylating agents, topoisomerase inhibitors or poisons, and DNA intercalators.

The nonclinical branch of regulatory pharmacology has traditionally relied on the sensitivity and specificity of regulatorily recommended bioassays. Nonetheless, any predictive testing (eg, safety pharmacology) with less than 100% sensitivity or 100% specificity is prone to deliver false positive or negative results (namely, outcomes discordant to the clinical gold standard). It was recently suggested that the statistics-based and regulatory pertinent "predictive values approach" (PVA) might help to reach a more predictive use of preclinical testing data. To resolve the associated probability of carcinogenicity to humans, the PVA was applied to 37 pharmaceuticals bearing inadequate epidemiological evidence of carcinogenicity, but identifiable as unequivocal mutagens. According to current knowledge, a 98.9% (or more) probability of carcinogenicity to humans was reckoned for those 37 genotoxic drugs. Accordingly, these pharmaceutical drugs might be either scientifically or regulatorily regarded as "carcinogenic to humans." In the USA, European Union, or Canada as examples, the great majority of these 37 pharmaceuticals are authorized for medical use in humans. From the results of the present appraisal, the following is suggested (1) for the pharmaceuticals listed in this report, to include significant carcinogenicity warnings in their prescribing information; (2) to conduct pharmacoepidemiology studies or risk-benefit analyses (if warranted), and (3) based on the respective risk-benefit analyses, to re-evaluate the authorization of hydralazine and phenoxybenzamine as antihypertensives, oxcarbazepine as an anticonvulsant, and phenazopyridine as a urinary tract antimicrobial or analgesic. For the four latter drugs (eg, phenoxybenzamine), a 99.5% probability of carcinogenicity to humans was estimated.

Maternal exposure to busulfan reduces the cell number in the somatosensory cortex associated with delayed somatic and reflex maturation in neonatal rats.

Busulfan is a bifunctional alkylating agent used for myeloablative conditioning and in the treatment of chronic myeloid leukemia due to its ability to cause DNA damage. However, in rodent experiments, busulfan presented a potential teratogenic and cytotoxic effect. Studies have evaluated the effects of busulfan on fetuses after administration in pregnancy or directly on pups during the lactation period. There are no studies on the effects of busulfan administration during pregnancy on offspring development after birth. We investigated the effects of busulfan on somatic and reflex development and encephalic morphology in young rats after exposure in pregnancy. The pregnant rats were exposed to busulfan (10 mg/kg, intraperitoneal) during the early developmental stage (days 12-14 of the gestational period). After birth, we evaluated the somatic growth, maturation of physical features and reflex-ontogeny during the lactation period. We also assessed the effects of busulfan on encephalic weight and cortical morphometry at 28 days of postnatal life. As a result, busulfan-induced pathological changes included: microcephaly, evaluated by the reduction of cranial axes, delay in reflex maturation and physical features, as well as a decrease in the morphometric parameters of somatosensory and motor cortex. Thus, these results suggest that the administration of a DNA alkylating agent, such as busulfan, during the gestational period can cause damage to the central nervous system in the pups throughout their postnatal development.

Comparable stx2a expression and phage production levels between Shiga toxin-producing Escherichia coli strains from human and bovine origin.

Shiga toxin-producing Escherichia coli (STEC) can cause diarrhoea and severe diseases in humans, such as haemolytic uraemic syndrome. STEC virulence is considered to correlate with the amount of Shiga toxins (Stx) produced, especially Stx2, whose subtype Stx2a is most frequently associated with high virulence. Stx are encoded in prophages, which play an important role in STEC pathogenesis. The aim of this study was to evaluate stx2a expression levels and Stx2a phage production using qPCR and the double-agar-layer method in 29 STEC strains, corresponding to serotypes O26:H11 (6), O91:H21 (1), O145:H- (11) and O157:H7 (11), isolated from cattle and humans. Results were then tested for possible associations with serotype, origin or some genetic features. We observed heterogeneous levels of stx2a expression and Stx2a phage production. However, statistical comparisons identified a higher stx2a expression in response to mitomycin C in strains isolated from cattle than in those from humans. At the same time, compared to stx2a /stx2c strains, stx2a strains showed a higher increase in phage production under induced conditions. Notably, most of the strains studied, regardless of serotype and origin, carried inducible Stx2a phages and evidenced expression of stx2a that increased along with phage production levels under induced conditions.

In vivo induction of hepatocellular carcinoma by diethylnitrosoamine and pharmacological intervention in Balb C mice using Bergenia ciliata extracts / Indução in vivo de carcinoma hepatocelular por dietilnitrosoamina e intervenção farmacológica em camundongos balb c usando extratos de Bergenia ciliata

Abstract Background Hepatocellular carcinoma is the most frequent primary malignancy of liver and accounts for as many as one million deaths worldwide in a year. Objectives The aim of the present study was to evaluate the anti-cancerous efficiency of Bergenia ciliata rhizome against diethylnitrosoamine induced hepatocarcinogenesis in Balb C mice. Methods One percent diethylnitrosoamine was prepared by using 99 ml of normal saline NaCl (0.9 percent) solution to which was added 1 ml of concentrated diethylnitrosoamine (DEN) solution (0.01 μg/μl). Extract of Bergenia ciliata was prepared by maceration technique. Mice were classified into four groups as follows: Group 1 a control group (N=7) received saline solution (3.5 μl/mg), group 2 (N=14) received diethylnitrosoamine (3.5 μl/mg) intraperitoneally once in a week for eight consecutive weeks, group 3 (N=7) received plant extract (150 mg/kg (Body weight)) once in a week, while group 4 (N=7) was given combination of diethylnitrosoamine (3.5 μl/mg) and plant extract (150 mg/kg (Body weight)). After eight weeks of DEN induction group 2 mice were divided into two subgroups containing seven mice each, subgroup 1 was sacrificed while subgroup 2 was treated with plant extract (150 mg/kg (Body weight)) once in a week for eight consecutive weeks. Results The model of DEN injected hepatocellular carcinomic (HCC) mice elicited significant decline in levels of albumin with concomitant significant elevations in tumor markers aspartate aminotransferase, alanine aminotransferase (ALT), lactate dehydrogenase (LDH), alpha feto protein (AFP), gamma glutamyl transferase (Y-GT), 5 nucleotidase (5NT), glucose-6-phosphate dehydrogenase (G6PDH) and bilirubin. The intraperitoneal administration of B. ciliata as a protective agent, produced significant increase in albumin levels with significant decrease in the levels of tumor markers aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), alpha feto protein (AFP), gamma glutamyl transferase (Y-GT), 5 nucleotidase (5NT), glucose-6-phosphate dehydrogenase (G6PDH) and bilirubin. Conclusion Bergenia ciliata has potent antioxidant activity, radical scavenging capacity and anticancerous properties. Bergenia ciliata extracts may provide a basis for development of anti-cancerous drug.

Resumo Antecedentes O carcinoma hepatocelular é a neoplasia primária mais frequente do fígado e é responsável por até um milhão de mortes em todo o mundo em um ano. Objetivos O objetivo do presente estudo foi avaliar a eficiência anticancerígena do rizoma de Bergenia ciliata contra a hepatocarcinogênese induzida por dietilnitrosoamina em camundongos balb c. Métodos Um por cento de dietilnitrosoamina foi preparado usando 99 ml de solução salina normal (0,9 por cento) à qual foi adicionado 1 ml de solução concentrada de dietilnitrosoamina (DEN) (0,01 μg / μl). O extrato de Bergenia ciliata foi preparado pela técnica de maceração. Os ratos foram classificados em quatro grupos: Grupo 1 grupo controle (N = 7) recebeu solução salina (3,5 mL / mg), grupo 2 (N = 14) recebeu dietilnitrosoamina (3,5 mL / mg) por via intraperitoneal uma vez por semana para oito semanas consecutivas, o grupo 3 (N = 7) recebeu extrato vegetal (150 mg / kg (peso corporal)) uma vez por semana, enquanto o grupo 4 (N = 7) recebeu combinação de dietilnitrosoamina (3,5 μl / mg) e extrato (150 mg / kg (peso corporal). Após oito semanas do grupo de indução DEN 2 ratos foram divididos em dois subgrupos contendo sete ratos cada, subgrupo 1 foi sacrificado enquanto subgrupo 2 foi tratado com extrato vegetal (150 mg / kg)) uma vez por semana durante oito semanas consecutivas. Resultados O modelo de camundongos hepatocelulares carcinômicos (CHC) injetados com DEN provocou declínio significativo nos níveis de albumina com elevações significativas concomitantes nos marcadores tumorais: aspartato aminotransferase, alanina aminotransferase (ALT), lactato desidrogenase (LDH), proteína alfa feto (AFP), gama glutamiltransferase (Y-GT), 5 nucleotidase (5NT), glicose-6-fosfato ehidrogenase (G6PDH) e bilirrubina. A administração intraperitoneal de B. ciliata como agente protetor produziu um aumento significativo nos níveis de albumina com uma diminuição significativa nos níveis dos marcadores tumorais: aspartato aminotransferase, alanina aminotransferase (ALT), lactato desidrogenase (LDH), proteína alfa feto (AFP), gama glutamiltransferase (Y-GT), 5 nucleotidase (5NT), glicose-6-fosfato desidrogenase (G6PDH) e bilirrubina. Conclusão Bergenia ciliata possui atividade antioxidante potente, capacidade de eliminação de radicais livres e propriedades anticancerígenas. Extratos de Bergenia ciliata podem fornecer uma base para o desenvolvimento de drogas anti-cancerígenas.

XEN Gel Stent to Treat ICE Syndrome: 4 Cases.

PRéCIS:: This case series reports safe, effective implantation of XEN gel stents to treat iridocorneal endothelial (ICE) syndrome. The stents continue to function well and have not been occluded by membranes or peripheral anterior synechiae, but continued follow-up is necessary. PURPOSE: ICE syndrome-related glaucoma is often refractory to medical treatment, and traditional surgical treatment has lower success rates than typical for other types of glaucoma. We present a series of patients who were treated with XEN gel stent implantation. PATIENTS AND METHODS: Retrospective case series of 4 patients with ICE syndrome who underwent XEN with subconjunctival mitomycin C injection. RESULTS: Average preoperative intraocular pressure was 28.5 mm Hg on 3.8 glaucoma medications, and average postoperative intraocular pressure was 10.5 mm Hg on 1.0 medication. No patients required return to the operating room for additional procedures over an average of 6.9 months of follow-up. One patient had shallow anterior chamber that resolved with conservative management. Another had shallow anterior chamber that resolved with anterior chamber reformation with viscoelastic and developed nonappositional choroidal effusions that had resolved at most recent follow-up of 7 months after surgery. No XEN implants have been occluded by membrane formation or peripheral anterior synechiae. CONCLUSIONS: XEN is a safe and effective option for surgical management of ICE syndrome-related glaucoma. Further follow-up surveillance is necessary.

In vivo induction of hepatocellular carcinoma by diethylnitrosoamine and pharmacological intervention in Balb C mice using Bergenia ciliata extracts.

BACKGROUND: Hepatocellular carcinoma is the most frequent primary malignancy of liver and accounts for as many as one million deaths worldwide in a year. OBJECTIVES: The aim of the present study was to evaluate the anti-cancerous efficiency of Bergenia ciliata rhizome against diethylnitrosoamine induced hepatocarcinogenesis in Balb C mice. METHODS: One percent diethylnitrosoamine was prepared by using 99 ml of normal saline NaCl (0.9 percent) solution to which was added 1 ml of concentrated diethylnitrosoamine (DEN) solution (0.01 µg/µl). Extract of Bergenia ciliata was prepared by maceration technique. Mice were classified into four groups as follows: Group 1 a control group (N=7) received saline solution (3.5 µl/mg), group 2 (N=14) received diethylnitrosoamine (3.5 µl/mg) intraperitoneally once in a week for eight consecutive weeks, group 3 (N=7) received plant extract (150 mg/kg (Body weight)) once in a week, while group 4 (N=7) was given combination of diethylnitrosoamine (3.5 µl/mg) and plant extract (150 mg/kg (Body weight)). After eight weeks of DEN induction group 2 mice were divided into two subgroups containing seven mice each, subgroup 1 was sacrificed while subgroup 2 was treated with plant extract (150 mg/kg (Body weight)) once in a week for eight consecutive weeks. RESULTS: The model of DEN injected hepatocellular carcinomic (HCC) mice elicited significant decline in levels of albumin with concomitant significant elevations in tumor markers aspartate aminotransferase, alanine aminotransferase (ALT), lactate dehydrogenase (LDH), alpha feto protein (AFP), gamma glutamyl transferase (Y-GT), 5 nucleotidase (5NT), glucose-6-phosphate dehydrogenase (G6PDH) and bilirubin. The intraperitoneal administration of B. ciliata as a protective agent, produced significant increase in albumin levels with significant decrease in the levels of tumor markers aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), alpha feto protein (AFP), gamma glutamyl transferase (Y-GT), 5 nucleotidase (5NT), glucose-6-phosphate dehydrogenase (G6PDH) and bilirubin. CONCLUSION: Bergenia ciliata has potent antioxidant activity, radical scavenging capacity and anticancerous properties. Bergenia ciliata extracts may provide a basis for development of anti-cancerous drug.

Diethylnitrosamine enhances hepatic tumorigenic pathways in mice fed with high fat diet (Hfd).

Obesity has been implicated in the genesis of metabolic syndromes including insulin resistance and Type 2 Diabetes Mellitus (T2DM). Given the association between T2DM and the risk of hepatocellular carcinoma (HCC), our specific goal was to determine whether the liver of HFD-induced T2DM mice is more sensitive to the carcinogen diethylnitrosamine (DEN), due to a modification of the molecular pathways implicated in the early stages of HCC pathogenesis. C57BL/6 male mice (five-week-old) were divided into 4 groups: C, C + DEN, HFD and HFD + DEN. Mice were euthanized twenty-five weeks after DEN-injection. Livers of HDF-fed mice showed a higher proliferative index than Control groups. In line with this, HFD groups showed an increase of nuclear ß-catenin, and interestingly, DEN treatment led to a slight increase in the expression of this protein in HFD group. Based on these results, and to confirm this effect, we analyzed ß-catenin target genes, finding that DEN treatment in HFD group led to a significant increase of Vegf, c-myc, c-jun and cyclin D1 expression levels. According to our results, the expression of TCF4 showed to be significantly increased in HFD + DEN vs. HFD. In this regard, the ß-catenin/TCF4 complex enhanced its association with pSmads 2/3, as we observed an increase of nuclear Smads expression in HFD + DEN, suggesting a possible role of TGF-ß1/Smads signaling pathway in this phenomenon. Our results show that the liver of HFD fed model that resembles early T2DM pathology in mice, is more sensitive to DEN, by inducing both Wnt/ß-catenin and TGF ß1/Smads tumorigenic pathways.

Prognostic Factors and Management of Patients with Choanal Atresia.

OBJECTIVE: To analyze prognostic factors in the management of patients with choanal atresia. STUDY DESIGN: This is a review of 114 patients operated on for choanal atresia in a tertiary care center between November 1986 and November 2016, including clinical characteristics, surgical management, and postoperative course with final nasal patency. The data were collected in a database that was updated over time. RESULTS: Among the 114 patients, 78 were female, 77 presented with unilateral choanal atresia, and 37 presented with bilateral unilateral choanal atresia, corresponding to 151 nasal fossae. Forty-seven patients had associated abnormalities (41.2%), including CHARGE, diagnosed in 20 children (17.5%). At the end of follow-up, 91 patients (79.8%) had normal choanal patency. The identified risk factors of surgical failure were age <6 months (P = .004), weight <5 kg (P = .007), and bilateral choanal atresia (P < .001). The type of atresia, presence of associated abnormalities, surgical approach, stenting, and use of mitomycin were not significantly linked with the surgical results. CONCLUSIONS: This series highlights the importance of the timing of surgery, which is guided by the clinical ability of the infant to tolerate the procedure. Endoscopic approaches are widely performed, but a transpalatal approach, necessary in some cases of bilateral choanal atresia, does not alter the results. Unilateral choanal atresia surgery should be delayed after age 6 months and/or weight >5 kg when possible.

Mitomycin C in the endoscopic treatment of tracheal stenosis: a prospective cohort study / Mitomicina C no tratamento endoscópico de estenose traqueal: estudo prospectivo de coorte

ABSTRACT Objective: To evaluate the efficacy of mitomycin C (MMC) in the endoscopic treatment of tracheal stenosis. Methods: Patients with laryngotracheal, tracheal, or tracheobronchial stenosis were treated with dilation and topical MMC. The inclusion criteria were as follows: being ineligible for surgery (for medical reasons) at the time of evaluation; membranous stenosis responding well to dilation; and postoperative stenosis at the anastomosis site. Etiology of stenosis and indication for treatment with MMC, as well as site, length, and percentage of stenosis, together with presence of tracheostomy and duration of follow-up, were analyzed. The outcomes evaluated were symptom-free interval ≥ 12 months, number of dilations with topical application of MMC, and complications. Results: Twenty-two patients (15 men and 7 women) were treated between 2003 and 2010. Stenosis was due to endotracheal intubation in 15 patients and surgery in 8. Pure tracheal stenosis was encountered in 13 patients, subglottic stenosis was encountered in 4, tracheobronchial stenosis was encountered in 3, and complex stenosis was encountered in 2. The length of stenosis ranged from 0.5 cm to 2.5 cm, and the percentage of stenosis ranged from 40% to 100%. Nine patients had undergone tracheostomy and had a Montgomery T-tube in situ. Treatment was successful in 14 patients, who remained free of symptoms for at least 12 months. The number of topical applications of MMC ranged from 1 to 5, and complications included fungal infection, keloid scarring, granuloma, and mediastinal emphysema. Conclusions: MMC appears to be effective in the endoscopic treatment of tracheal stenosis.

RESUMO Objetivo: Avaliar a eficácia da mitomicina C (MMC) no tratamento endoscópico de estenose traqueal. Métodos: Pacientes com estenose laringotraqueal, traqueal ou traqueobrônquica foram tratados por meio de dilatação e MMC tópica. Foram empregados os seguintes critérios de inclusão: pacientes inaptos para cirurgia (por motivos médicos) no momento da avaliação; estenose membranosa com boa resposta a dilatação e estenose pós-operatória no local da anastomose. Foram analisadas as seguintes variáveis: etiologia da estenose; indicação de tratamento com MMC; local e extensão da estenose, bem como a porcentagem de estenose; presença de traqueostomia e tempo de seguimento. Os desfechos avaliados foram 12 meses ou mais sem sintomas, número de dilatações com aplicação de MMC tópica e complicações. Resultados: Vinte e dois pacientes (15 homens e 7 mulheres) foram tratados entre 2003 e 2010. As causas da estenose foram intubação endotraqueal em 15 pacientes e cirurgia em 8. A estenose traqueal pura foi observada em 13 pacientes, a subglótica, em 4, a traqueobrônquica, em 3 e a complexa, em 2. A extensão da estenose variou de 0,5 a 2,5 cm, e a porcentagem de estenose variou de 40 a 100%. Nove pacientes haviam sido submetidos a traqueostomia e apresentavam tubo T de Montgomery in situ. O tratamento teve êxito em 14 pacientes, que permaneceram sem sintomas durante pelo menos 12 meses. O número de aplicações de MMC tópica variou de 1 a 5, e as complicações foram infecção fúngica, queloide, granuloma e enfisema mediastinal. Conclusões: A MMC é aparentemente eficaz no tratamento endoscópico de estenose traqueal.

Hibiscus acetosella extract protects against alkylating agent-induced DNA damage in mice.

Hibiscus acetosella was shown to exert beneficial effects in humans and animal models however, the effects of this plant on DNA are unknown. The aim of this study was to determine the antigenotoxic and antimutagenic effects of H. acetosella extracts on alkylating agent methyl methanesulfonate (MMS) in vivo in mice. Initially, we performed analysis of phenolic compounds in extracts of H. acetosella by high-performance liquid chromatography (HPLC). Next, mice were divided into 8 groups and treated with distilled water or plant extract (0.1 ml/10 g) by gavage for 15 days, followed by intraperitoneal (ip) administration of saline solution or MMS (40 mg/Kg b.w) on day 16. Caffeic acid, following by gallic acid, gallocatechin, coumaric acid, and 3,4-dihydroxybenzoic acid were found to be present in extracts of H. acetosella leaves. In peripheral blood analysis of groups receiving pretreatment with H. acetosella at doses of 50 or 100 mg/kg plus MMS decreased DNA damage as evidenced by comet assay and Micronucleus assays relative to MMS alone. These results suggested that H. acetosella extracts exerted protective effects dose dependent against genotoxicity and mutagenicity induced by alkylating agents.

Atorvastatin Downregulates In Vitro Methyl Methanesulfonate and Cyclophosphamide Alkylation-Mediated Cellular and DNA Injuries.

Statins are 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, and this class of drugs has been studied as protective agents against DNA damages. Alkylating agents (AAs) are able to induce alkylation in macromolecules, causing DNA damage, as DNA methylation. Our objective was to evaluate atorvastatin (AVA) antimutagenic, cytoprotective, and antigenotoxic potentials against DNA lesions caused by AA. AVA chemopreventive ability was evaluated using antimutagenicity assays (Salmonella/microsome assay), cytotoxicity, cell cycle, and genotoxicity assays in HepG2 cells. The cells were cotreated with AVA and the AA methyl methanesulfonate (MMS) or cyclophosphamide (CPA). Our datum showed that AVA reduces the alkylation-mediated DNA damage in different in vitro experimental models. Cytoprotection of AVA at low doses (0.1-1.0 µM) was observed after 24 h of cotreatment with MMS or CPA at their LC50, causing an increase in HepG2 survival rates. After all, AVA at 10 µM and 25 µM had decreased effect in micronucleus formation in HepG2 cells and restored cell cycle alterations induced by MMS and CPA. This study supports the hypothesis that statins can be chemopreventive agents, acting as antimutagenic, antigenotoxic, and cytoprotective components, specifically against alkylating agents of DNA.

Trypan Blue for the Assessment of Filtering Bleb Function During Cataract Surgery.

PURPOSE: Phacoemulsification has been cited as a possible cause of bleb failure in eyes with prior trabeculectomy. No method has been developed to directly evaluate the risk of bleb failure after phacoemulsification. We investigate the use of trypan blue during cataract surgery in the setting of a preexisting trabeculectomy to evaluate the functional status of the bleb and predict postoperative bleb function. MATERIALS AND METHODS: In total, 14 patients contributing 1 eye each with a history of prior trabeculectomy with mitomycin C undergoing phacoemulsification with intraocular lens implantation were enrolled in this prospective, nonrandomized clinical trial. At the time of phacoemulsification, trypan blue was instilled into the anterior chamber before capsulorhexis creation. Staining of the bleb was grouped as being mild or diffuse using intraoperative photographs. These eyes were followed for 1 year postoperatively and evaluated for intraocular pressure (IOP) control. RESULTS: The change in IOP was not significantly different between the 2 groups (P=0.14). A trend towards greater need for IOP-lowering medications was noted (P<0.10) in eyes with mild bleb staining. No statistically significant difference in rates of decreased bleb function was noted at 1-year follow-up after phacoemulsification. CONCLUSION: The intensity of bleb staining with trypan blue during phacoemulsification is not associated with changes in IOP postoperatively. A trend towards decreased need for IOP-lowering medications was noted in eyes with diffuse bleb staining at 1 year after cataract surgery.

Comparison among adjuvant treatments for primary pterygium: a network meta-analysis.

PURPOSE: Pterygium is a frequent ocular disease, where the major challenge is the high level of recurrence after its surgical removal. We performed a network meta-analysis to identify, among several adjuvant treatments for primary pterygium, which is the best to prevent recurrence. METHODS: A search was conducted using PubMed, Scientific Electronic Library Online, Latin American and Caribbean Centre on Health Sciences and Cochrane Eyes and Vision Group Trials Register between 1993 and 2015 for randomisedclinical trials (RCTs) comparing adjuvant treatments following primary pterygium surgery. RESULTS: 24 RCTs that studied 1815 eyes of 1668 patients were included and allowed direct and indirect comparison among 14 interventions through network meta-analysis. The rank from the best to worse treatment to prevent recurrence is: conjunctival autograft + ciclosporin 0.05% eye drops, bare sclera + intraoperativemitomycin C (MMC) <0.02%, bare sclera + beta therapy (2500 cGy single dose), conjunctival autograft + beta therapy (1000 cGy single dose), bare sclera + MMC 0.02% eye drops, conjunctival autograft, bare sclera + intraoperative MMC >0.02%, bare sclera + ciclosporin 0.05% eye drops, bare sclera + intraoperative 5-fluorouracil 5%, amniotic membrane transplantation, bare sclera + intraoperative MMC 0.02%, conjunctival autograft + bevacizumab 0.05% eye drops, bare sclera + bevacizumab 0.05% eye drops and bare sclera alone. CONCLUSION: The best adjuvant treatment to prevent recurrence after primary pterygium surgery is the association of conjunctival autograft and ciclosporin 0.05% eye drops. Bare sclera technique alone should be discontinued since it is associated with high recurrence rates.

Mitomycin C in the endoscopic treatment of tracheal stenosis: a prospective cohort study.

OBJECTIVE: To evaluate the efficacy of mitomycin C (MMC) in the endoscopic treatment of tracheal stenosis. METHODS: Patients with laryngotracheal, tracheal, or tracheobronchial stenosis were treated with dilation and topical MMC. The inclusion criteria were as follows: being ineligible for surgery (for medical reasons) at the time of evaluation; membranous stenosis responding well to dilation; and postoperative stenosis at the anastomosis site. Etiology of stenosis and indication for treatment with MMC, as well as site, length, and percentage of stenosis, together with presence of tracheostomy and duration of follow-up, were analyzed. The outcomes evaluated were symptom-free interval ≥ 12 months, number of dilations with topical application of MMC, and complications. RESULTS: Twenty-two patients (15 men and 7 women) were treated between 2003 and 2010. Stenosis was due to endotracheal intubation in 15 patients and surgery in 8. Pure tracheal stenosis was encountered in 13 patients, subglottic stenosis was encountered in 4, tracheobronchial stenosis was encountered in 3, and complex stenosis was encountered in 2. The length of stenosis ranged from 0.5 cm to 2.5 cm, and the percentage of stenosis ranged from 40% to 100%. Nine patients had undergone tracheostomy and had a Montgomery T-tube in situ. Treatment was successful in 14 patients, who remained free of symptoms for at least 12 months. The number of topical applications of MMC ranged from 1 to 5, and complications included fungal infection, keloid scarring, granuloma, and mediastinal emphysema. CONCLUSIONS: MMC appears to be effective in the endoscopic treatment of tracheal stenosis.

Hipertensão arterial no tratamento do câncer / Hypertension in cancer treatment

A hipertensão arterial sistêmica (HAS) é uma condição clínica multifatorial caracterizada por elevação sustentada dos níveis pressóricos. No Brasil, a hipertensão arterial atinge 32,5% (36 milhões) de indivíduos adultos, mais de 60% idosos, contribuindo direta ou indiretamente para 50% das mortes por doença cardiovascular. A HAS é uma das comorbidades mais frequentemente observadas em pacientes com câncer. Algumas drogas são diretamente relacionadas ao desenvolvimento ou piora da HAS como os agentes alquilantes e os inibidores do fator de crescimento endotelial. O controle adequado dos níveis de pressão arterial (PA) em pacientes com câncer visa aumentar a tolerância dos doentes à quimioterapia, reduzir a incidência de lesões em órgãos-alvo e, em última análise, reduzir a mortalidade geral. A PA deve ser aferida semanalmente durante o primeiro ciclo e a cada duas a três semanas após. O diagnóstico e tratamento da HAS devem seguir as recomendações atuais da 7aDiretriz Brasileira de Hipertensão e, quando possível, realizados antes do tratamento oncológico. Os IECA e BRA são anti-hipertensivos usados com maior frequência para o tratamento da HAS associada aos inibidores de fator de crescimento endotelial (iVEGF). Os bloqueadores de canal de cálcio não diidropiridínicos, como o verapamil e o diltiazem, são contraindicados com o uso concomitante de iVEGF. A descontinuação definitiva deve ser o último recurso. Os oncologistas e cardiologistas devem desenvolver abordagens em conjunto para manejar a HAS de forma eficaz e segura, com objetivo de manter o benefício do tratamento oncológico e de diminuir a morbidade e mortalidade cardiovascular

Systemic arterial hypertension (SAH) is a multifactorial condition, characterized by a sustained elevation in blood pressure. In Brazil, arterial hypertension affects 32.5% (36 million) adult individuals, more of 60% of whom are elderly, directly or indirectly contributing to 50% of deaths due to cardiovascular disease. SAH is one of the most commonly observed comorbidities in people with cancer. Some drugs are directly related to the development or worsening of SAH, such as alkylating agents and endothelial growth factor inhibitors. Adequate control of blood pressure (BP) in patients with cancer aims to increase patients' tolerance to chemotherapy, reduce the incidence of target organ damage and, ultimately, reduce overall mortality. BP must be measured every week in the first cycle and every two-three weeks after. The diagnosis and treatment of SAH should follow the current recommendations of the VII Brazilian Guideline on Hypertension, and where possible, should be performed before the oncological treatment. ACE inhibitors and ARBs are the most commonly used antihypertensive drugs for the treatment of SAH associated with vascular endothelial growth factor inhibitors (VEGFI). Non-dihydropyridine calcium channel blockers, such as Verapamil and Diltiazem, are contraindicated with the concomitant use of VEGFI. Definitive suspension should be the final resort. Oncologists and cardiologists must develop joint approaches to manage the SAH effectively and safely, with the objective of maintaining the benefit of the oncological treatment and reducing cardiovascular morbidity and mortality

Primary Trabeculectomy Outcomes by Glaucoma Fellows in a Tertiary Hospital in Brazil.

PURPOSE: To examine outcomes of trabeculectomy with mitomycin C for uncontrolled glaucoma when performed by glaucoma trainee surgeons. MATERIALS AND METHODS: Retrospective case series of patients who underwent trabeculectomy with mitomycin C. Primary outcome was to assess the rate of failure, which was defined as intraocular pressure in 2 consecutive visits >18 or <5 mm Hg or intraocular pressure reduction <30% from baseline, additional glaucoma surgery, or loss of light perception. The secondary outcome was to investigate risk factors for failure and surgical complications. RESULTS: One hundred forty-three eyes from 126 glaucoma patients underwent primary trabeculectomy between 2013 and 2014 at University of Campinas. Mean follow-up time was 1.47±0.96 years. Kaplan-Meier analysis showed cumulative survival rates of 70.1%, 62.5%, and 57.8%, after 1, 2, and 3 years, respectively. Multivariate analysis with generalized estimating equations revealed that neovascular glaucoma [odd ratios (OR): 5.05, P=0.043], suture lysis (OR: 8.89, P=0.011), and early bleb leak (OR: 4.63, P=0.011) were risk factors for failure. CONCLUSIONS: A success rate of approximately 60% was obtained 3 years after primary trabeculectomy performed by trainees. Patients with neovascular glaucoma, who underwent suture lysis and who presented an early bleb leak had an increased risk for failure during follow-up.