Oncolytic adenovirus coding for shedding-resistant MICA enhances immune responses against tumors.

Cancer immunotherapies strive to overcome tumor-induced immune suppression and activate antitumor immune responses. Although cytotoxic T lymphocytes (CTLs) play a pivotal role in this process, natural killer (NK) cells have also demonstrated remarkable tumor-killing abilities, given their ability to discriminate tumor cells from normal cells and mediate specific antitumoral cytotoxicity. NK cells activation depends on a balance between activation and inhibition signals from several ligands/receptors. Among them, MICA/NKG2D axis is a master regulator of NK activation. MHC class I chain-related polypeptide A (MICA) expression is upregulated by many tumor cell lines and primary tumors and serves as a ligand for the activating NK group 2D (NKG2D) receptor on NK cells and subpopulations of T cells. However, cancer cells can cleave MICA, making it soluble and de-targeting tumor cells from NK cells, leading to tumor immune escape.In this study, we present ICOVIR15KK-MICAMut, an oncolytic adenovirus (OAdv) armed with a transgene encoding a non-cleavable MICA to promote NK-mediated cell-killing capacity and activate the immune response against cancer cells. We first demonstrated the correct MICA overexpression from infected cells. Moreover, our MICA-expressing OAdv promotes higher NK activation and killing capacity than the non-armed virus in vitro. In addition, the armed virus also demonstrated significant antitumor activity in immunodeficient mice in the presence of human PBMCs, indicating the activation of human NK cells. Finally, OAdv-MICA overexpression in immunocompetent tumor-bearing mice elicits tumor-specific immune response resulting in a greater tumor growth control.In summary, this study highlights the significance of NK cells in cancer immunotherapy and presents an innovative approach using a modified oncolytic virus to enhance NK cell activation and antitumor immune response. These findings suggest promising potential for future research and clinical applications.

A glycerophospholipid-specific pocket in the RVFV class II fusion protein drives target membrane insertion.

The Rift Valley fever virus (RVFV) is transmitted by infected mosquitoes, causing severe disease in humans and livestock across Africa. We determined the x-ray structure of the RVFV class II fusion protein Gc in its postfusion form and in complex with a glycerophospholipid (GPL) bound in a conserved cavity next to the fusion loop. Site-directed mutagenesis and molecular dynamics simulations further revealed a built-in motif allowing en bloc insertion of the fusion loop into membranes, making few nonpolar side-chain interactions with the aliphatic moiety and multiple polar interactions with lipid head groups upon membrane restructuring. The GPL head-group recognition pocket is conserved in the fusion proteins of other arthropod-borne viruses, such as Zika and chikungunya viruses, which have recently caused major epidemics worldwide.

Recent developments in radiotherapy for small-cell lung cancer: a review by the Oncologic Group for the Study of Lung Cancer (Spanish Radiation Oncology Society).

Small-cell lung cancer (SCLC) accounts for 13% of all lung tumours. The standard treatment in patients with limited-stage disease is radiotherapy combined with chemotherapy. In extensive SCLC, the importance of consolidation thoracic radiotherapy in patients with a good treatment response has become increasingly recognized. In both limited and extensive disease, prophylactic cranial irradiation is recommended in patients who respond to treatment. New therapeutic approaches such as immunotherapy are being increasingly incorporated into the treatment of SCLC, although more slowly than in non-small cell lung cancer (NSCLC). Diverse radiation dose and fractionation schemes, administered in varying combinations with these new drugs, are being investigated. In the present study we review and update the role of radiotherapy in the treatment of SCLC. We also discuss the main clinical trials currently underway in order to identify future trends.

Targeted therapy combined with radiotherapy in non-small-cell lung cancer: a review of the Oncologic Group for the Study of Lung Cancer (Spanish Radiation Oncology Society).

In recent years, major advances in our understanding of the molecular biology of lung cancer, together with significant improvements in radiotherapy technologies, have revolutionized the treatment of non-small cell lung cancer (NSCLC). This has led to the development of new therapies that target molecular mutations specific to each tumor type, acting on the cell surface antigens or intracellular signaling pathways, or directly affecting cell survival. At the same time, ablative dose radiotherapy can be delivered safely in the context of metastatic disease. In this article, the GOECP/SEOR (Oncological Group for Study of Lung Cancer/Spanish Society of Radiation Oncology) reviews the role of new targeted therapies used in combination with radiotherapy in patients with locally advanced (stage III) NSCLC and in patients with advanced, metastatic (stage IV) NSCLC.

Contact topical anesthesia versus general anaesthesia in strabismus surgery.

OBJECTIVE: To evaluate the anesthetic block provided by contact topical anesthesia (CTA) in strabismus surgery in adult patients. To analyze postoperative pain and surgical outcome obtained by CTA compared with general anesthesia (GA). METHODOLOGY: Prospective longitudinal cohort study of adult patients undergoing strabismus surgery by CTA or GA. The intensity of pain perceived by patients during the course of surgery and in the postoperative period was measured using Numerical Pain Scale. The success of the surgical outcome, considered as a residual ocular deviation<10 prism diopters, was evaluated. RESULTS: Twenty-three patients were operated using CTA and 26 using AG. During the course of surgery, pain intensity experienced by patients in ATC group was 3.17±2.44. There were no differences between CTA group and AG group in the intensity of pain in the immediate postoperative period (2.13±2.39 vs. 2.77±2.18, respectively; P=.510) and during the first postoperative day (3.22±2.84 vs. 3.17±2.73; P=.923). Surgical success was significantly higher in the CTA group than in the GA group (78.3 vs. 73.1%; P=.019). CONCLUSIONS: CTA provides adequate sensory block to perform strabismus surgery. The control of postoperative pain is similar to that obtained with AG. Conservation of ocular motility providing CTA enables better surgical outcome.

Nanoobjects formed by ionic PAMAM dendrimers: hydrophilic/lipophilic modulation and encapsulation properties.

In this paper, we present the preparation and properties of some ionic PAMAM derivatives, which combine hydrophilic and lipophilic carboxylic acid chains as counter-ions for all protonable inner and outer amino groups. The amphiphilic nature of the final ionic codendrimers and, hence, their self-assembling features can be modulated by using different ratios between hydrophilic and lipophilic chains. In the bulk, these new materials self-organize into smectic A liquid crystal phases. In water, they self-assemble into different types of nano-objects depending on the molecular composition. The study of the morphology of these nano-structures, their cytotoxicity and their capability to encapsulate a lipophilic anticancer drug are reported herein. Some of these nanoobjects are non-cytotoxic and present good drug trapping ability, which make them interesting nanocarriers for applications in nanotechnology and biomedicine.

Hidatidosis vertebral: a propósito de un caso / Vertebral hydatidosis: case report

La hidatidosis causada por el echinococcus granulosus puede afectar cualquier órgano del cuerpo siendo el pulmón y el hígado los más comúnmente afectados. El compromiso vertebral por el echinococcus granulosus es de escasa prevalencia, comprendiendo con menos de 1% del compromiso óseo. Presentamos el caso de una mujer de 50 años que consultó en Servicio de Traumatología por cuadro de dolor lumbar progresivo, de cinco meses de evolución, irradiado a extremidad inferior derecha y posterior compromiso neurológico de extremidad. El estudio imagenológico reveló espondilodiscitis T12-L1 que posterior a estudio de biopsia confirmó este cuadro. El tratamiento es mixto, tanto ortopédico como quirúrgico. El nivel de recurrencia es alto, reportándose entre 30 y 40%. El objetivo de este caso es proponer diagnóstico diferencial de masa vertebral de origen desconocido y detallar el manejo de esta patología.

Hydatidosis caused by echinococcus granulosus may affect any organ in the body, with the lungs and the liver as the most commonly affected organs. Vertebral compromise resulting from echinococcus granulosus has a low prevalence and accounts for less than 1% of bone compromise. We report the case of a 50 year-old female who presented at the Trauma Service with progressive low back pain with 5 months of duration that irradiated to the right lower limb, and led to neurologic compromise of the limb. Imaging studies showed spondylodiscitis at T12-L1, confirmed by a biopsy. Treatment of this condition is both orthopedic and surgical. The recurrence rate is high, between 30 and 40%. The objective of describing this case is to propose the differential diagnosis of a vertebral mass of unknown origin and provide details as to how to manage this condition.

[Vertebral hydatidosis: case report]. / Hidatidosis vertebral: a propósito de un caso.

Hydatidosis caused by echinococcus granulosus may affect any organ in the body, with the lungs and the liver as the most commonly affected organs. Vertebral compromise resulting from echinococcus granulosus has a low prevalence and accounts for less than 1% of bone compromise. We report the case of a 50 year-old female who presented at the Trauma Service with progressive low back pain with 5 months of duration that irradiated to the right lower limb, and led to neurologic compromise of the limb. Imaging studies showed spondylodiscitis at T12-L1, confirmed by a biopsy. Treatment of this condition is both orthopedic and surgical. The recurrence rate is high, between 30 and 40%. The objective of describing this case is to propose the differential diagnosis of a vertebral mass of unknown origin and provide details as to how to manage this condition.

Contact topical anesthesia for strabismus surgery in adult patients.

OBJECTIVE: To analyze the effectiveness and usefulness of contact topical anesthesia in strabismus surgery in adult patients. MATERIAL AND METHODS: A prospective study was conducted on 20 patients undergoing strabismus surgery using contact topical anesthesia and sedation with remifentanil. The intensity of pain was recorded using a numeric pain rating scale at the time of anesthesia implementation, during the surgical procedure, 30 min afterwards, and during the first postoperative day. The incidence of oculocardiac reflex, postoperative nausea and vomiting, corneal ulcers, patient satisfaction (numerically from 0 to 10) and the degree of residual ocular deviation were also assessed. RESULTS: The operation was performed successfully in all patients. Average pain intensity was 1.40 ± 1.73 during anesthesia implementation, 4.20 ± 2.57 during the surgical procedure, 2.50 ± 2.54 30 min after surgery, and 3.55 ± 2.89 during the first postoperative day. Oculocardiac reflex was observed in 7 patients (35%), postoperative nausea and vomiting in 4 (20%), and corneal ulcer in 4 (20%). The patient satisfaction was 9.53 ± 2.51. More than two-thirds (70%) of patients had a residual ocular deviation less than 10 prism diopters. CONCLUSIONS: Contact topical anesthesia is a safe and effective alternative for strabismus surgery in adult patients. Contact topical anesthesia provides adequate pain control, lower incidence of postoperative nausea and vomiting and oculocardiac reflex, and optimal setting of ocular alignment.

Use of a new ocular insert versus conventional mydriasis in cataract surgery.

BACKGROUND: To compare the efficacy and safety of a new ocular insert versus conventional mydriasis in cataract surgery. METHODS: We selected 70 patients undergoing cataract surgery. Thirty five patients (Group 1) received instillation of mydriatic drops (tropicamide 1%, phenylephrine 10%, and cyclopentolate 1%) prior to surgery, and 35 patients (Group 2) had a Mydriasert insert (Théa Pharma) (0.28 mg of tropicamide and 5.4 mg of phenylephrine hydrochloride) placed in the inferior fornix. Pupil size before and after surgery, blood pressure, and heart rate were measured. RESULTS: Before surgery, pupil diameter was 9.44 ± 1.17 mm in Group 1 and 9.05 ± 1.54 in Group 2 (P > 0.05). Twenty four hours after surgery, pupil diameter was 5.20 ± 1.54 mm in Group 1 and 3.33 ± 1.15 in Group 2 (P < 0.001). There were no statistically significant differences in blood pressure or heart rate between groups. CONCLUSIONS: The effect of the Mydriasert insert was similar to conventional mydriatic agents. Pupil size was restored to normal faster when using the Mydriasert insert compared with conventional mydriatic agents for pupil dilation.

Comparison of pharmacokinetic profiles of PM02734 loaded lipid nanoparticles and cyclodextrins: in vitro and in vivo characterization.

PM02734 is a chemically synthesized depsipeptide derived from the marine kahalalides family with a broad spectrum of activity against solid tumors in vitro and in vivo, but presenting low bioavailability. In this work, solid lipid nanoparticles made of Precirol ATO 5 have been developed using a hot homogenization method followed by high shear homogenization and ultrasonication. These solid lipid nanoparticles show suitable size (around 150 nm) and encapsulation efficiency (nearly 70%) for the oral administration of the compound PM02734. A physical-chemical stability study was performed after 6 months of storage at different thermical conditions, concluding that solid lipid nanoparticles stored at 4 degrees C were more stable than solid lipid nanoparticles stored at 25 degrees C. The pharmacokinetic profile of drug-loaded solid lipid nanoparticles was also evaluated in Beagle dogs and compared with that of a cyclodextrin-based delivery system by means of AUC, C(max) and T(max) parameter estimation. Solid lipid nanoparticle based formulation provided a sustained release of the drug for a longer period of time than the cyclodextrins.

Clareamento dentário integrado: uma alternativa estética / Integrated dental bleaching: an esthetic approach

A Odontologia neste início de século tem demonstrado inúmeros avanços em todas as áreas de atuação, mas atenção ímpar tem sido dada à estética, independentemente da especialidade e da região de atuação na cavidade bucal. Nesse contexto, a cor dos dentes constitui o fator isolado mais importante no equilíbrio estético do sorriso porque a desarmonia de cor é mais imediata e rapidamente percebida do que as outras anomalias estéticas. Dessa forma, o clareamento dentário é um procedimento cada vez mais solicitado pelos pacientes que procuram os recursos da Odontologia Estética. Um paciente adulto, do sexo masculino, apresentou-se na Clínica da Universidade Estadual de Maringá (UEM) insatisfeito com seu sorriso devido ao escurecimento severo do dente 11. Na anamnese, o paciente relatou que esse dente havia sido submetido a um tratamento endodôntico há aproximadamente 11 anos, disse também que o escurecimento dentário aconteceu de forma lenta e progressiva. Após o exame radiográfico, observou-se que o tratamento endodôntico apresentava-se insatisfatório, com presença de restos pulpares no interior do canal radicular. Inicialmente, foi realizado o retratamento endodôntico do dente e, após quinze dias, o tratamento consistiu de clareamento dentário associando-se as técnicas de clareamento interno (Opalescence Endo 35 por cento, Ultradent) e externo (Opalescence XtraBoost 38 por cento, Ultradent). Como resultado, restabeleceu-se a estética do sorriso de forma conservadora e proporcionou-se um conforto psicológico ao paciente. Pretende-se, com esse artigo, enfatizar a eficácia do clareamento dentário , ressaltando a importância do diagnóstico correto e do plano de tratamento adequado para a obtenção de resultados estéticos satisfatórios.

Nowadays, dentistry has been demonstrating many advances in all working fields, but more attention has been given to esthetics, regardless of specialty and operation region in the oral cavity. In this context, the tooth color becomes the most important factor in the smile esthetic balance, once the color disharmony is more immediate and quickly perceived than other esthetic anomalies. Therefore, the tooth bleaching is an increasingly procedure requested by patients that look for the resources of cosmetic dentistry. An adult male patient presented at the Maringá State University (UEM), unhappy with his smile due to the severe darkening of the tooth 11. At medical history, the patient reported that this tooth had its endodontic treatment done 11 years ago, and also said that the dental darkening happened slowly and gradually. After the radiographic examination, it was observed that the endodontic treatment was unsatisfactory due to the presence of pulp residual tissue inside the root canal. Initially, the endodontic retreatment of the tooth was performed and after two weeks the treatment consisted of tooth bleaching associating internal (Opalescence Endo 35% Ultradent) and external bleaching techniques (Opalescence Xtra Boost 38% Ultradent). According to this case report, the esthetic excellence could be obtained through the correct diagnosis and appropriate treatment approach. The association of bleaching systems and agents is a conservative technique that avoids prosthetic treatments such as dental veneers and fixed prosthesis.

[Fungal infections in oncohematology: the role of prophylaxis]. / Infecciones fungicas en oncohematologia: el rol de la profilaxis.

Fungal infections in patients with oncohematological diseases present a changing scene due to various circumstances such as: a better control of bacterial infections, the prophylactic use of antifungal agents such as fluconazole, the emergence of pathogens other than Candida spp., infections in non-neutropenic patients during graft-versus-host disease (GVHD), the use of other therapies that cause an increased immunosuppression (dexamethasone in high doses, fludarabine, rituximab, etc.), among others. Acute leukemia, hematopoietic transplant, GVHD, and treatment with purine analogs (fludarabine, cladribine) or alemtuzumab are considered to be the clinical scenarios with the highest risk. The ongoing management of fungal infections includes prophylaxis, empirical treatment of patients with fever not responsive to antibiotics, preemptive therapy, and specific treatment.

[Diagnosis and treatment of benign breast lesions during pregnancy]. / Diagnóstico y tratamiento de las lesiones benignas de la mama en el embarazo.

OBJECTIVES: To retrospectively study the diagnosis and treatment of benign breast disease during pregnancy and breastfeeding at our department. To review the relevant literature. MATERIALS AND METHODS: From January 2001 to March 2005, a total of 91 pregnant or breastfeeding women (age range: 23-36 years) were diagnosed with benign breast pathology. All patients presented with palpable nodules or inflammatory symptoms. Ultrasound-guided fine-needle cytology was performed in all cases and percutaneous core biopsy was considered necessary in three cases. Abscesses were drained when present. Patients provided their informed consent before all procedures. RESULTS: Tumors were detected in 28 cases (30%): fibroadenomas (n = 12), lactating adenomas (n = 9), galactoceles (n = 5), and papillomas (n = 2). Conservative treatment with ultrasound follow-up was employed in all cases except one, which required surgical treatment in the third trimester. On 63 occasions (70%), the pathology was inflammatory, including abscesses in 24 cases (38%); abscesses were drained using fine-needle aspiration (n = 16) or pig-tail catheter (n = 3), according to protocol, depending on the size of the abscess (less than or greater than 3 cm). In 5 cases the abscesses were drained surgically. CONCLUSIONS: The most common benign breast pathology during pregnancy is inflammatory and is satisfactorily managed with antibiotics and percutaneous drainage with good esthetic results. Ultrasound is the diagnostic technique of choice, together with cytology; percutaneous biopsy is only performed in uncertain cases to minimize the risk of fistulas. Management of tumors after histological confirmation should be conservative with close follow-up. These tumors cause no problems for the child, the mother, or breastfeeding.

Compatibility and stability of the novel anticancer agent ES-285 x HCl formulated with 2-hydroxypropyl-beta-cyclodextrin in infusion devices.

ES-285 x HCl is a novel marine-derived anticancer agent isolated from the clam Spisula polynyma. The compound is pharmaceutically formulated as a lyophilised product containing 25 or 50 mg ES-285 x HCl and 500 or 1000 mg 2-hydroxypropyl-beta-cyclodextrin per dosage unit and requires reconstitution with sterile water for injection before intravenous administration. The aim of this study was to determine the stability and compatibility of ES-285 x HCl in infusion devices. ES-285 x HCl was shown to be stable at concentrations of 10-1400 microg/ml after dilution in 5% dextrose in water and compatible with PE infusion containers and PE and silicone tubing. No sorption on- or into the administration set was observed at concentrations equal to or above 20 microg/ml. In conclusion, ES-285 x HCl infusion solutions can be administered without stability or sorption problems using a PE infusion container and PE or silicone tubing in concentrations equal or above 20 microg/ml in 3-hour or 24-hour infusion administration schedules.