Germline DNA copy number variation in familial and early-onset breast cancer

Introduction: Genetic factors predisposing individuals to cancer remain elusive in the majority of patients with a familial or clinical history suggestive of hereditary breast cancer. Germline DNA copy number variation (CNV) has recently been implicated in predisposition to cancers such as neuroblastomas as well as prostate and colorectal cancer. We evaluated the role of germline CNVs in breast cancer susceptibility, in particular those with low population frequencies (rare CNVs), which are more likely to cause disease." Methods: Using whole-genome comparative genomic hybridization on microarrays, we screened a cohort of women fulfilling criteria for hereditary breast cancer who did not carry BRCA1/BRCA2 mutations. Results: The median numbers of total and rare CNVs per genome were not different between controls and patients. A total of 26 rare germline CNVs were identified in 68 cancer patients, however, a proportion that was significantly different (P = 0.0311) from the control group (23 rare CNVs in 100 individuals). Several of the genes affected by CNV in patients and controls had already been implicated in cancer. Conclusions: This study is the first to explore the contribution of germline CNVs to BRCA1/2-negative familial and early-onset breast cancer. The data suggest that rare CNVs may contribute to cancer predisposition in this small cohort of patients, and this trend needs to be confirmed in larger population samples.Brazilian National Institute of Science and Technology in Oncogenomics [FAPESP 2008/57887-9, CNPq 573589/08-9, FAPESP (2009/00898-1)]Brazilian National Institute of Science and Technology in Oncogenomic

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Surface Physicochemical and Structural Analysis of Functionalized Titanium Dioxide Films

Titanium and its alloys are recognized as acceptable materials for many applications. The properties of titanium dioxide (TiO2) thin films are directly related to the structural characteristics of the material, which can be modified with tailor-made functional groups. Reactive bifunctional groups can be bound with hydroxyl-terminated TiO2, leading to the formation of self-assembled monolayers or multilayer films. The understanding of such interactions is necessary to design functional oxide coatings for a large variety of applications. In this study, nanosized TiO2 films were synthesized by the sol-gel method and deposited by spin coating technique upon titanium substrate. Subsequently, TiO2 thin films were functionalized with (3-aminopropyl)trimethoxysilane (APTMS), 3-(4-aminophenyl)propionic acid (APPA), 3-mercaptopropionic acid (MPA) or polyethylene glycol (PEG). Surface characterization by XPS, surface roughness, and contact angle indicated successful functionalization and allowed for identification of the preferential conformation of each molecule. APPA and APTMS presented free amine groups indicating the attachment to the surface by carboxyl and silane groups, respectively. Mercapto coupling from MPA showed the formation of S-Ti bonds. PEG-coated surface revealed polymerization of several hydroxyl groups that crosslinked with each other. Analyzing the mode of attachment at the interface of the metal oxide and functional group may help in the development of improved functional materials

Cutaneous/Mucocutaneous Leishmaniasis Treatment for Wound Healing: Classical versus New Treatment Approaches

Cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (ML) show clinical spectra that can range from a localized lesion (with a spontaneous healing process) to cases that progress to a generalized systemic disease with a risk of death. The treatment of leishmaniasis is complex since most of the available drugs show high toxicity. The development of an effective topical drug formulation for CL and ML treatment offers advantages as it will improve patient’s compliance to the therapy given the possibility for self-administration, as well as overcoming the first pass metabolism and the high costs of currently available alternatives. The most common dosage forms include solid formulations, such as membranes and semi-solid formulations (e.g., ointments, creams, gels, and pastes). Topical treatment has been used as a new route of administration for conventional drugs against leishmaniasis and its combinations, as well as to exploit new substances. In this review, we discuss the advantages and limitations of using topical drug delivery for the treatment of these two forms of leishmaniasis and the relevance of combining this approach with other pharmaceutical dosage forms. Emphasis will also be given to the use of nanomaterials for site-specific delivery

Antimycotic nail polish based on humic acid-coated silver nanoparticles for onychomycosis

Background: The objective of this work has been the development of silver nanoparticles (AgNPs) coated with humic acid (HA) and their incorporation into an enamel for antifungal activity. AgNPs were synthesized by chemical reduction using sodium borohydride (NaBH4) as a reducing agent and coated with HA. Uncoated AgNPs were synthesized as control. AgNPs and HAAgNPs were characterized by ultravioletvisible spectrophotometry (UVVis), differential scanning calorimetry (DSC), dynamic light scattering (DLS), Fouriertransform infrared spectroscopy (FTIR), atomic force microscopy (AFM) and Xray diffraction (XRD). Size of AgNPs and HAAgNPs was recorded within the nanorange, showing HAAgNPs higher stability than noncoated particles by presenting a single plasmatic band around 400 nm. Results Thermal analysis showed conjugated endothermic peaks, which confirms the compatibility HAAgNPs. FTIR depicted absorptions between 1300 and 1000 cm1 (C = C, Ar H, respectively) demonstrating that HA is adsorbed onto AgNPs. TGA showed that HA does not alter the reduction in mass loss of AgNPs, while it was found by XRD that adding HA promoted the formation of more amorphous AgNPs. The effectiveness of HAAgNPs was evaluated against three different fungal species. Minimum inhibitory concentration (MIC) assays showed that ca. 0.5mM of AgNPs were able to inhibit dermatophyte species growth. HAAgNPs were incorporated into a commercial enamel at a concentration of 8% and their organoleptic characteristics, drying time, centrifugation test and thermal stress, were evaluated. Enamels with AgNPs kept their physicochemical properties over 21days of storage. Conclusion HAAgNPs nail polish is thus proposed as an innovative material for onychomycosis infections.This research was financed by the Coordenação Aperfeiçoamento de Pessoal de Nivel Superior (CAPES), Fundação de Amparo à Pesquisa do Estado de Sergipe (FAPITEC) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). EBS wishes to acknowledge the sponsorship of the project UIDB/04469/2020 (strategic fund) from the Portuguese Science and Technology Foundation, Ministry of Science and Education (FCT/MEC) through national funds, co-financed by FEDER, under Partnership Agreement PT2020.info:eu-repo/semantics/publishedVersio