Potencial remineralizante del fluoruro diamino de plata al 38% en dentina de dientes temporales afectada por caries / Remineralizing potential of 38% silver diamine fluoride in dentin affected by dental caries

Introducción: la caries es una enfermedad compleja que afecta a cualquier edad. La prevalencia es mayor en la primera dentición, sobre todo en población con baja percepción económica. El fluoruro diamino de plata (FDP) al 38% ha sido utilizado como una alter- nativa de tratamiento para esta enfermedad. Funciona como una solución remineralizante y cariostática. Objetivo: evaluar el efecto remineralizante del FDP al 38% en dentina afectada por lesiones de caries en molares temporales. Material y métodos: estudio clínico, epidemiológico, descriptivo, longitudinal y experimental. Se llevó a cabo en molares de primera dentición de niños de tres a cinco años de edad. Los niños seleccionados tenían molares con lesiones cariosas dentinarias, Pitts las denomina D3. No se incluyeron niños con dientes que presentaron patologías pulpares irreversibles. La aplicación del FDP al 38% la efectuó un operador entrenado para esta finalidad. Se utilizaron los criterios de Nyvad para determinar el grado de dureza de la dentina y con ello deducir su remineraliza- ción. Se observó la permanencia de la remineralización efectuada por un periodo de cinco meses. Resultado y conclusión: el FDP es un compuesto eficaz en 91% de los casos en un periodo de cinco meses o más (AU)

Introduction: dental caries is a complex disease that affects any age. The prevalence is higher in primary dentition, especially in a population with low economic perception. 38% silver diamine fluoride (FDP) has been used as an alternative treatment for this disease. It works as a remineralizing and cariostatic solution. Objective: to evaluate the remineralizing effect of 38% FDP on dentin affected by dental caries, in temporary molars. Material and methods: clinical, epidemiological, descriptive, longitudinal and experimental study. It was carried out in temporary molars of children between three and five years of age. The selected children presented molars with dental carious lesions, Pitts calls them D3. Children with teeth that presented irreversible pulp pathologies were not included. The application of the FDP to 38% was carried out by an operator trained for this purpose. The Nyvad criteria were used to determine the degree of hardness of the dentin and thereby deduce its remineralization. The permanence of the remineralization carried out was observed for a period of five months. Result and conclusion: the FDP is an effective compound in 91% of the cases, in a period of five months or more (AU)

Vorasidenib, a Dual Inhibitor of Mutant IDH1/2, in Recurrent or Progressive Glioma; Results of a First-in-Human Phase I Trial.

PURPOSE: Lower grade gliomas (LGGs) are malignant brain tumors. Current therapy is associated with short- and long-term toxicity. Progression to higher tumor grade is associated with contrast enhancement on MRI. The majority of LGGs harbor mutations in the genes encoding isocitrate dehydrogenase 1 or 2 (IDH1/IDH2). Vorasidenib (AG-881) is a first-in-class, brain-penetrant, dual inhibitor of the mutant IDH1 and mutant IDH2 enzymes. PATIENTS AND METHODS: We conducted a multicenter, open-label, phase I, dose-escalation study of vorasidenib in 93 patients with mutant IDH1/2 (mIDH1/2) solid tumors, including 52 patients with glioma that had recurred or progressed following standard therapy. Vorasidenib was administered orally, once daily, in 28-day cycles until progression or unacceptable toxicity. Enrollment is complete; this trial is registered with ClinicalTrials.gov, NCT02481154. RESULTS: Vorasidenib showed a favorable safety profile in the glioma cohort. Dose-limiting toxicities of elevated transaminases occurred at doses ≥100 mg and were reversible. The protocol-defined objective response rate per Response Assessment in Neuro-Oncology criteria for LGG in patients with nonenhancing glioma was 18% (one partial response, three minor responses). The median progression-free survival was 36.8 months [95% confidence interval (CI), 11.2-40.8] for patients with nonenhancing glioma and 3.6 months (95% CI, 1.8-6.5) for patients with enhancing glioma. Exploratory evaluation of tumor volumes in patients with nonenhancing glioma showed sustained tumor shrinkage in multiple patients. CONCLUSIONS: Vorasidenib was well tolerated and showed preliminary antitumor activity in patients with recurrent or progressive nonenhancing mIDH LGG.

γ-secretase inhibitors, DAPT and RO4929097, promote the migration of Human Glioma Cells via Smad5-downregulated E-cadherin Expression.

Malignant gliomas are a type of central nervous system cancer with extremely high mortality rates in humans. γ-secretase has been becoming a potential target for cancer therapy, including glioma, because of the involvement of its enzymatic activity in regulating the proliferation and metastasis of cancer cells. In this study, we attempted to determine whether γ-secretase activity regulates E-cadherin to affect glioma cell migration. The human glioma cell lines, including LN18 and LN229, and the γ-secretase inhibitors, including N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) and RO4929097, were used in this study. It was shown that γ-secretase activity inhibition by DAPT and RO4929097 could promote LN18 and LN229 glioma cell migration via downregulating E-cadherin mRNA and protein expressions, but not via affecting E-cadherin protein processing. In addition, γ-secretase activity inhibition was regulated by bone morphogenetic proteins-independent Smad5 activation in glioma cells. Moreover, endogenous Smad1 in glioma cells was found to play an important role in regulating E-cadherin expression and subsequent cell migration but did not affect DAPT-stimulated effects. These results help further elucidate the molecular mechanisms of γ-secretase activity regulation involved in controlling glioma cell malignancy. Information about a potential role for Smad1/5 activity upregulation and subsequent E-cadherin downregulation during inhibition of γ-secretase activity in the development of gliomas is therefore relevant for future research.

Anthelmintic activity of aminoalcohol and diamine derivatives against the gastrointestinal nematode Teladorsagia circumcincta.

Gastrointestinal nematodes (GIN) infections are a serious problem in livestock production due to the great economic losses they cause. Their control is increasingly difficult because of the rapid development of drug resistance and the limited number of available drugs. Therefore, this study evaluated 18 aminoalcohol and 16 diamine derivatives against eggs, first and third stage larvae from a susceptible and a resistant isolate of Teladorsagia circumcincta collected from sheep. The effectiveness of the in vitro anthelmintic activity of the compounds was evaluated using three different procedures: Egg Hatch Test (EHT), Larval Mortality Test (LMT) and Larval Migration Inhibition Test (LMIT). Those compounds with activities higher than 90 % in the initial screening at 50 µM were selected to determine their half maximal effective concentration (EC50). In parallel, cytotoxicity assays were conducted on Caco2 and HepG2 cell lines to calculate Selectivity Indexes (SI) for each compound. The diamine 30 presented the best results in preventing egg hatching, displaying the lowest EC50 value (1.01 ±â€¯0.04 µM) of all compounds tested and the highest SI (21.21 vs. Caco-2 cells). For the LMIT, the diamine 34 showed the highest efficacy, with EC50 values of 2.67 ±â€¯0.08 and 3.02 ±â€¯0.09 µM on the susceptible and resistant isolate of the parasite, respectively.

Inhibition of notch enhances the anti-atherosclerotic effects of LXR agonists while reducing fatty liver development in ApoE-deficient mice.

Liver X receptor (LXR) activation can achieve satisfactory anti-atherosclerotic activity, but can also lead to the development of fatty liver and hypertriglyceridemia. In contrast, Notch inhibition can suppress both atherosclerosis and the hepatic accumulation of lipids. In the present study, we sought to assess whether combining LXR ligand agonists (T317) with Notch receptor inhibitors (DAPT) would lead to enhanced anti-atherosclerotic activity while overcoming the adverse events associated with LXR ligand agonist therapy. The impact of the combined T317 + DAPT therapeutic regimen on atherosclerosis, fatty liver development, and hypertriglyceridemia was assessed using ApoE deficient (ApoE-/-) mice. The results of this analysis suggested that DAPT was able to improve the anti-atherosclerotic activity of T317 without reducing the stability of lesion plaques while simultaneously reducing blood lipids in treated ApoE-/- mice. This combination T317 + DAPT treatment was also linked with a significant upregulation of ABCA1 and the stimulation of reverse cholesterol transport (RCT), as well as with decreases in the levels of intercellular cell adhesion molecule-1 (ICAM-1) and p-p65, and with altered M1/M2 macrophage proportions within atherosclerotic plaques. Importantly, DAPT was also able to reduce T317-mediated lipid accumulation within the liver owing to its ability to reduce SREBP-1 expression while simultaneously increasing that of Pi-AMPKα and PPARα. Together, our results suggest that administering Notch receptor inhibitors to ApoE-/- mice may be an effective means of enhancing the anti-atherosclerotic activity of LXR ligand agonists while simultaneously limiting associated fatty liver and hypertriglyceridemia development in these animals.

Inhibitors of metalloprotease, γ-sectretase, protein kinase C and Rho kinase inhibit wild-type adenoviral replication.

Adenoviruses cause upper respiratory infections, conjunctivitis, keratitis, and gastrointestinal illness. These can be fatal in immunocompromised individuals. Adenoviruses have also been engineered into viral vectors to deliver therapeutic genes or induce immunity as vaccine carriers. The success of ocular gene therapy is driven partly by the immunologic and biochemical influences of the intraocular environment. We have shown that versican and hyaluronan modulate adenoviral vector transgene expression through CD44 signaling. Herein we explored the role of these pathways on virus replication and viral protein expression of wild type adenovirus. We report that the addition of vitreous humor (which contains both versican and hyaluronan) increases viral hexon protein levels. Vitreous humor also increased wild type adenovirus DNA replication in vitro. Metalloproteinase and γ-secretase inhibitors, which inhibit CD44 proteolytic activation, blocked adenoviral replication in vitro. Similarly, protein kinase C and RhoA kinase inhibitors, both proteins associated with CD44 mediated pathways, also inhibited wild type adenoviral replication in vitro. Application of metalloproteinase and γ-secretase inhibitors to human conjunctival explants sharply decreased adenoviral vector gene expression. Our results demonstrate that pharmacologic delivery of these inhibitors is easily achievable. The inhibition of these enzymes should be explored as potential therapies of wild type adenoviral infections.

DAPT inhibits titanium particle-induced osteolysis by suppressing the RANKL/Notch2 signaling pathway.

Artificial prosthesis is wildly used in clinical medicine for degenerative disease such as osteoclast-related diseases. However, the material wear particles released from the surface of prostheses cause prosthetic loosening as a result of aseptic osteolysis in long-term use. Therefore, it is important to find an agent that inhibits the formation and function of osteoclast for therapeutic use. Notch signaling pathway plays a lot of roles in cell proliferation, differentiation, and apoptosis. However, the role of Notch signaling pathway in osteoclastogenesis remains unclear. The aim of this study is to assess the effects of γ-secretase inhibitor DAPT on osteoclastogenesis via Notch signaling pathway in vitro and titanium particle-induced osteolysis in vivo. In animal experiments, the inhibitory effect of DAPT on titanium particle-induced osteolysis in a mouse calvaria model was demonstrated. Interestingly, few resorption pits were observed following administration of DAPT and almost no osteoclasts formed at high concentration of DAPT. in vitro experiments revealed the mechanism of the effects of DAPT on osteoclastogenesis. DAPT inhibited the formation and function of osteoclast by blocking RANKL-induced Notch2-NF-κB complex signaling pathway. In conclusion, these results indicated that DAPT could prevent and cure titanium particle-induced prosthetic loosening and other osteoclast-related diseases.

[1,2,5]Oxadiazolo[3,4-b]pyrazine-5,6-diamine Derivatives as Mitochondrial Uncouplers for the Potential Treatment of Nonalcoholic Steatohepatitis.

Small molecule mitochondrial uncouplers are emerging as a new class of molecules for the treatment of nonalcoholic steatohepatitis. We utilized BAM15, a potent protonophore that uncouples the mitochondria without depolarizing the plasma membrane, as a lead compound for structure-activity profiling. Using oxygen consumption rate as an assay for determining uncoupling activity, changes on the 5- and 6-position of the oxadiazolopyrazine core were introduced. Our studies suggest that unsymmetrical aniline derivatives bearing electron withdrawing groups are preferred compared to the symmetrical counterparts. In addition, alkyl substituents are not tolerated, and the N-H proton of the aniline ring is responsible for the protonophore activity. In particular, compound 10b had an EC50 value of 190 nM in L6 myoblast cells. In an in vivo model of NASH, 10b decreased liver triglyceride levels and showed improvement in fibrosis, inflammation, and plasma ALT. Taken together, our studies indicate that mitochondrial uncouplers have potential for the treatment of NASH.

Bidirectional linkage between the B-cell receptor and NOTCH1 in chronic lymphocytic leukemia and in Richter's syndrome: therapeutic implications.

NOTCH1 mutations in chronic lymphocytic leukemia (CLL) lead to accumulation of NOTCH1 intracellular domain (NICD) and prolong signaling. These mutations associate with a more aggressive disease compared to wild-type (WT) CLL. In this work we demonstrate a bidirectional functional relationship between NOTCH1 and the B cell receptor (BCR) pathways. By using highly homogeneous cohorts of primary CLL cells, activation of NOTCH1 is shown to increase expression of surface IgM, as well as LYN, BTK, and BLNK, ultimately enhancing BCR signaling responses, including global mRNA translation. Upon BCR cross-linking, NOTCH1 itself is actively translated and increased on cell surface. Furthermore, BCR ligation induces calcium mobilization that can facilitate ligand-independent NOTCH1 activation. These data suggest that the two pathways are functionally linked, providing a rationale for dual inhibition strategies. Consistently, addition of the γ-secretase inhibitor DAPT to ibrutinib significantly potentiates its effects, both in vitro and in a short-term patient-derived xenograft model. While this observation may find limited applications in the CLL field, it is more relevant for Richter's Syndrome (RS) management, where very few successful therapeutic options exist. Treatment of RS-patient-derived xenografts (RS-PDX) with the combination of ibrutinib and DAPT decreases disease burden and increases overall survival.

Inhibition of CD44 intracellular domain production suppresses bovine articular chondrocyte de-differentiation induced by excessive mechanical stress loading.

CD44 fragmentation is enhanced in chondrocytes of osteoarthritis (OA) patients. We hypothesized that mechanical stress-induced enhancement of CD44-intracellular domain (CD44-ICD) production plays an important role in the de-differentiation of chondrocytes and OA. This study aimed to assess the relationship between CD44-ICD and chondrocyte gene expression. Monolayer cultured primary bovine articular chondrocytes (BACs) were subjected to cyclic tensile strain (CTS) loading. ADAM10 inhibitor (GI254023X) and γ-secretase inhibitor (DAPT) were used to inhibit CD44 cleavage. In overexpression experiments, BACs were electroporated with a plasmid encoding CD44-ICD. CTS loading increased the expression of ADAM10 and subsequent CD44 cleavage, while decreasing the expression of SOX9, aggrecan, and type 2 collagen (COL2). Overexpression of CD44-ICD also resulted in decreased expression of these chondrocyte genes. Both GI254023X and DAPT reduced the production of CD44-ICD upon CTS loading, and significantly rescued the reduction of SOX9 expression by CTS loading. Chemical inhibition of CD44-ICD production also rescued aggrecan and COL2 expression following CTS loading. Our findings suggest that CD44-ICD is closely associated with the de-differentiation of chondrocytes. Excessive mechanical stress loading promoted the de-differentiation of BACs by enhancing CD44 cleavage and CD44-ICD production. Suppression of CD44 cleavage has potential as a novel treatment strategy for OA.

Inhibitor of γ-secretase alleviates middle ear inflammation by regulating Th2 response in OVA-mediated allergic OME in vivo.

Otitis media with effusion (OME) often occurs in infants and young children, which is related to allergic reactions. Notch signaling pathway plays an important role in allergic responses. In this study, we aimed to investigate the role of Notch signaling pathway in the ovalbumin (OVA)-mediated allergic OME in vivo. OVA-induced OME rats were treated with a control vehicle or a γ-secretase inhibitor, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) suppressing the Notch signaling. We studied the effect of Notch signaling pathway in OME model, including histopathological assessment, the expression of Th1 cytokines (IFN-γ), Th2 cytokines (IL-4, IL-5), key transcription factors (T-bet, GATA-3) by quantitative real-time polymerase chain reaction (qRT-PCR). In addition, the level of Notch ligand (Jagged1) and the downstream target gene Hes1 were also evaluated by qRT-PCR and immunofluorescent staining. We observed that the production of Th2 cytokines was increased, the level of Th1 cytokines was decreased in OME experimental model. Likewise, Th2-cytokine(IL-4)level was reduced, but the level of Th1 cytokines(IFN-γ) was no changes. Additionally, administration of DAPT induced a decrease in the expression of GATA-3 mRNA, however, no influence on T-bet mRNA production. These results suggest that there is an imbalance with Th1/Th2 in OVA-mediated allergic OME. DAPT treatment can block the Notch signaling pathway and relieve the middle ear inflammation through modulating the level of Th2 responses in OVA-induced allergic OME.

pH sensitive peptide functionalized nanoparticles for co-delivery of erlotinib and DAPT to restrict the progress of triple negative breast cancer.

Although a variety of drug delivery strategies have been designed for enhancing the treatment of Triple negative breast cancer (TNBC), combating with TNBCs is still dramatically challenged by the selection of appropriate therapeutic targets and insufficient tumor accumulation or inner penetration of chemotherapeutics. To address these issues, the classical EGFR-inhibitor, erlotinib (EB), was selected as the model drug here and PLA-based nano-platform (NP-EB) was prepared for tumor site drug delivery. Given the significant role of Notch-EGFR interplay in raising severe resistance to EGFR inhibition of EB, gamma secretase inhibitor (GSI)-DAPT was further entrapped into the core of nanoparticles to inhibit the activation of Notch signaling (NP-EB/DART). For achieving the goal of tumor targeting drug delivery, we developed a new peptide CF and decorating it on the surface of EB/DART-dual loaded nanoparticles (CF-NP-EB/DART). Such CF peptide was designed by conjugating two separated peptide CREKA, tumor-homing peptide, and F3, cell penetrating peptide, to together via a pH-sensitive hydrazone bond. By this way, the tumor unspecific property of F3 was sealed and significantly reduced the site effects. However, after the nanoparticles reach the tumor site, the pH-sensitive linkage can be broken down by the unique acidic environment of tumor, and subsequently discovered the F3 peptide to penetrate into tumor cells.

In vitro testing of a first-in-class tri-alkylnorspermidine-biaryl antibiotic in an anti-biofilm silicone coating.

Biofilm-related infection is among the worst complication to prosthetic joint replacement procedures; once established on the implant surface, biofilms show strong recalcitrance to clinical antibiotic therapy, frequently requiring costly revision procedures and prolonged systemic antibiotics for their removal. A well-designed active release coating might assist host immunity in clearing bacterial contaminants within the narrow perioperative window and ultimately prevent microbial colonization of the joint prosthesis. A first-in-class compound (CZ-01127) was tested as the active release agent in a silicone (Si) coating using an in vitro dynamic flow model of surgical site contamination and compared with analogous coatings containing clinical gold-standard antibiotics vancomycin and gentamicin; the CZ-01127 coating outperformed both vancomycin and gentamicin coatings and was the only to decrease the methicillin-resistant Staphylococcus aureus (MRSA) inocula below detectable limits for the first 3 days. The antimicrobial activity of CZ-01127, and for comparison vancomycin and gentamicin, were characterized against both planktonic and biofilm MRSA using the minimum inhibitory concentration (MIC) assay, serial passages, and serial dilution tests against established biofilms grown with a CBR 90 CDC biofilm reactor. Despite a similar MIC (1 µg/ml) and behavior in a 25-day serial passage analysis, CZ-01127 displayed much greater bactericidal activity against established biofilms and was the only to decrease biofilm colony forming units (CFUs) below detectable limits at the highest concentration tested (500 µg/ml). Coating release profiles were characterized using ATR-FTIR and displayed burst release kinetics within the decisive period of the perioperative window suggesting the silicon carrier is broadly useful for screening antibiotic compound for local delivery applications. STATEMENT OF SIGNIFICANCE: With an aging population, an increasing number of people are undergoing total joint replacement procedures in which diseased joint tissues are replaced with permanent metallic implants. Some of these procedures are burdened by costly and debilitating infections. A promising approach to prevent infections is the use of an antimicrobial coating on the surface of the implant which releases antibiotics into the surgical site to prevent infection. In this study, we tested a new antibiotic compound formulated in a silicone coating. Data showed that this compound was more effective at killing pathogenic methicillin resistant Staphylococcus aureus (MRSA) bacteria than two clinical gold-standard antibiotics-vancomycin and gentamicin-and could be a promising agent for antimicrobial coating technologies.

De-escalation of anti-platelet therapy in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a narrative review.

OBJECTIVE: Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor is the cornerstone of treatment in patients with acute coronary syndromes (ACS) and in those undergoing percutaneous coronary intervention (PCI). In current clinical situation, availability of different oral P2Y12 inhibitors (clopidogrel, prasugrel, and ticagrelor) has enabled physicians to switch among therapies owing to specific clinical scenarios. Although optimum time, loading dose and interval of transition between P2Y12 inhibitors is still controversial and needs further evidence, switching between oral inhibitors frequently occurs in clinical practice for several reasons. DATA SOURCES: This review was based on data in articles published in PubMed up to June 2018, with the following keywords "antiplatelet therapy", "ACS", "PCI", "ticagrelor", and "clopidogrel". STUDY SELECTION: Original articles and critical reviews on de-escalation strategy in ACS patients after PCI were selected. References of the retrieved articles were also screened to search for potentially relevant papers. RESULTS: Safety concerns associated with switching between antiplatelet agents, has prompted the use of clopidogrel for patients with ACS especially after PCI as a de-escalation strategy. Practical considerations for de-escalating therapies in patients with ACS such as reducing dose of P2Y12 inhibitors or shortening duration of DAPT (followed by aspirin or P2Y12 receptor inhibitor monotherapy) as potential options are yet to be standardized and validated. CONCLUSIONS: Current review will provide an overview of the pharmacology of common P2Y12 inhibitors, definitions of de-escalation and different de-escalating strategies and its outcomes, along with possible direction to be explored in de-escalation.

DAPT Plus Cilostazol is Better Than Traditional DAPT or Aspirin Plus Ticagrelor as Elective PCI for Intermediate-to-Highly Complex Cases: Prospective, Randomized, PRU-Based Study in Taiwan.

PURPOSE: Current treatment guidelines do not recommend different antiplatelet treatments for patients in different coronary risk categories; nor do they consider ethnic differences in responses to individual drugs. OBJECTIVES: We performed a prospective, single-blind, randomized, comparative study of Taiwanese patients with stable angina and scheduled stent implantation for intermediate-to-highly complex coronary lesions and compared the platelet reactivity unit (PRU) levels and 24-month outcomes of groups receiving three different antiplatelet treatments. METHODS: Patients (N = 334) were randomized into three treatment groups (aspirin + clopidogrel, aspirin + ticagrelor, or aspirin + clopidogrel + cilostazol) for 6 months of treatment and were then switched to aspirin only. PRU levels were determined 24 h, 7 days, and 1 month after stent implantation. Clinical outcomes and adverse events were recorded over 24 months. RESULTS: Clopidogrel treatment reached full effect after 1 month. Ticagrelor decreased PRU levels more than did clopidogrel but often to levels that increased the risk of hemorrhage. The addition of cilostazol to clopidogrel decreased PRU levels earlier and more strongly than clopidogrel alone but not as strongly as did ticagrelor. Ticagrelor treatment caused fewer major adverse cardiovascular events (MACEs) and more episodes of minor bleeding than the other two treatments. CONCLUSIONS: Clopidogrel appears safer than ticagrelor in Taiwanese patients with stable angina after stent implantation for intermediate-to-highly complex coronary lesions. The addition of cilostazol to clopidogrel may provide a more rapid decrease in PRU to therapeutic levels without increasing the risk of hemorrhage. CLINICAL TRIAL REGISTRATION NUMBER: NCT02101411.

Casuística de 10 pacientes con queratitis por Acanthamoeba / A report of 10 patients with Acanthamoeba keratitis

CASOS CLÍNICOS: Presentamos 10 casos de queratitis por Acanthamoeba tratados en nuestro hospital entre 2008 y 2017. Todos eran portadores de lentes de contacto. Como tratamiento todos recibieron una biguanida junto a una diamidina. En 3 casos la infección no superaba el estroma superficial, respondiendo al tratamiento tópico. En 7 alcanzaba el estroma profundo, precisando 6 de ellos una queratoplastia penetrante, 3 «en caliente» por riesgo de perforación o extensión ocular. La agudeza visual mejoró en todos los casos. CONCLUSIÓN: La profundidad de la infección al diagnóstico aparece como el principal factor de riesgo para necesitar una queratoplastia penetrante

CLINICAL CASES: Cases are presented of 10 patients with Acanthamoeba keratitis treated between 2008 and 2017. All were contact lens wearers. All of them received treatment with a biguanide combined with a diamidine. In 3 cases the infestation did not exceed the superficial stroma, responding to topical treatment. In 7, the infection reached the deep stroma, with 6 of these cases requiring penetrating keratoplasty (PKP), 3 of them therapeutic PKP because of perforation risk or ocular spreading. The visual acuity improved in all the cases. CONCLUSION: The infestation depth at the time of diagnosis appears to be the main risk factor for requiring a PKP

Gremlin activates the Notch pathway linked to renal inflammation.

Preclinical studies suggest that Gremlin participates in renal damage and could be a potential therapeutic target for human chronic kidney diseases. Inflammation is a common characteristic of progressive renal disease, and therefore novel anti-inflammatory therapeutic targets should be investigated. The Notch signaling pathway is involved in kidney development and is activated in human chronic kidney disease, but whether Gremlin regulates the Notch pathway has not been investigated. In cultured tubular cells, Gremlin up-regulated gene expression of several Notch pathway components, increased the production of the canonical ligand Jagged-1, and caused the nuclear translocation of active Notch-1 (N1ICD). In vivo administration of Gremlin into murine kidneys elicited Jagged-1 production, increased N1ICD nuclear levels, and up-regulated the gene expression of the Notch effectors hes-1 and hey-1 All these data clearly demonstrate that Gremlin activates the Notch pathway in the kidney. Notch inhibition using the γ-secretase inhibitor DAPT impaired renal inflammatory cell infiltration and proinflammatory cytokines overexpression in Gremlin-injected mice and in experimental models of renal injury. Moreover, Notch inhibition blocked Gremlin-induced activation of the canonical and noncanonical nuclear factor-κB (NF-κB) pathway, identifying an important mechanism involved in the anti-inflammatory actions of Notch inhibition. In conclusion, Gremlin activates the Notch pathway in the kidney and this is linked to NF-κB-mediated inflammation, supporting the hypothesis that Notch inhibition could be a potential anti-inflammatory strategy for renal diseases.

Effect of an experimental mouth rinse containing NaF and TiF4 on tooth erosion and abrasion in situ.

OBJECTIVE: This study compared the effect of an experimental NaF/TiF4 mouth rinse with a commercial tin/F mouth rinse on the prevention of tooth wear in situ. METHODS: Fifteen subjects took part in this crossover and double-blind study, in which they wore a palatal appliance with 8 bovine teeth samples (4 enamel and 4 root dentine) in each of 3 phases (5 days each). Half of the samples were subjected to erosive challenges, and the other half to erosive plus abrasive challenges. The phases corresponded to the use of 1) Experimental solution containing NaF/TiF4 (189 ppm Ti+4, 500 ppm F-, pH 4.4); 2) commercial solution containing SnCl2/NaF/AmF (800 ppm Sn+2, 500 ppm F-, pH 4.5, Elmex®/GABA, positive control); 3) distilled water (negative control). Erosive challenges were performed using 0.1% citric acid (pH 2.5) for 90 s 4 times per day. The abrasion was done using a toothbrush and slurry of fluoride toothpaste, for 15 s 2 times per day. Thereafter, the subjects rinsed with the tested mouth rinse for 60s. Tooth wear was measured using contact profilometry (µm) and submitted to a two-way RM ANOVA/Bonferroni test (p < 0.05). RESULTS: No significant differences were detected between the experimental and the commercial mouth rinses, regardless of the challenge. Both fluoride mouth rinses were able to significantly reduce tooth wear compared to the negative control (p < 0.0001). No significant differences were detected with respect to tooth wear between the challenges (erosion and erosion plus abrasion). CONCLUSION: The experimental NaF/TiF4 mouth rinse has a similar protective effect to the commercial one against tooth wear in situ. CLINICAL SIGNIFICANCE: The experimental NaF/TiF4 solution protected against tooth wear in situ, regardless of the challenge (erosion or erosion plus abrasion), for both enamel and dentine, similarly to a commercial solution (tin/F-Elmex®) applied for this proposal. This result supports the conduction of clinical trials and a possible application of this solution in the future.

A phase I, open-label, two-stage study to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the oral AKT inhibitor GSK2141795 in patients with solid tumors.

Background We sought to determine the recommended phase II dose (RP2D) and schedule of GSK2141795, an oral pan-AKT kinase inhibitor. Patients and Methods Patients with solid tumors were enrolled in the dose-escalation phase. Pharmacokinetic (PK) analysis after a single dose (Cycle 0) informed dose escalation using accelerated dose titration. Once one grade 2 toxicity or dose-limiting toxicity was observed in Cycle 1, the accelerated dose titration was terminated and a 3 + 3 dose escalation was started. Continuous daily dosing was evaluated along with two intermittent regimens (7 days on/7 days off and 3 times per week). In the expansion phase at RP2D, patients with endometrial or prostate cancer, as well as those with select tumor types with a PIK3CA mutation, AKT mutation or PTEN loss, were enrolled. Patients were evaluated for adverse events (AEs), PK parameters, blood glucose and insulin levels, and tumor response. Results The RP2D of GSK2141795 for once-daily dosing is 75 mg. The most common (>10%) treatment-related AEs included diarrhea, fatigue, vomiting, and decreased appetite. Most AEs were low grade. The frequency of hyperglycemia increased with dose; however, at the RP2D, grade 3 hyperglycemia was only reported in 4% of patients and no grade 4 events were observed. PK characteristics were favorable, with a prolonged half-life and low peak-to-trough ratio. There were two partial responses at the RP2D in patients with either a PIK3CA mutation or PTEN loss. Conclusion GSK2141795 was safe and well-tolerated, with clinical activity seen as monotherapy at the RP2D of 75 mg daily. NCT00920257.