What's new about the tumor microenvironment of urothelial carcinoma?

Urothelial carcinoma is a significant global health concern that accounts for a substantial part of cancer diagnoses and deaths worldwide. The tumor microenvironment is a complex ecosystem composed of stromal cells, soluble factors, and altered extracellular matrix, that mutually interact in a highly immunomodulated environment, with a prominent role in tumor development, progression, and treatment resistance. This article reviews the current state of knowledge of the different cell populations that compose the tumor microenvironment of urothelial carcinoma, its main functions, and distinct interactions with other cellular and non-cellular components, molecular alterations and aberrant signaling pathways already identified. It also focuses on the clinical implications of these findings, and its potential to translate into improved quality of life and overall survival. Determining new targets or defining prognostic signatures for urothelial carcinoma is an ongoing challenge that could be accelerated through a deeper understanding of the tumor microenvironment.

Curettage or Resection? A Review on the Surgical Treatment of Low-Grade Chondrosarcomas.

Introduction Low-grade chondrosarcomas (LG-CS), including atypical cartilaginous tumors (ACT), are locally aggressive lesions. The focus of the discussion sits on the differential diagnosis between benign lesions or aggressive cartilaginous tumors and on their treatment: intralesional curettage or wide resection. This study presents the results obtained in the surgical treatment of 21 cases of LG-CS. Methods This retrospective study includes 21 consecutive patients from a single center with LG-CS who underwent surgery from 2013 to 2021. Fourteen were located in the appendicular skeleton, and seven in the axial (shoulder blade, spine, or pelvis). Mortality rate, recurrence, metastatic disease, overall survival, recurrence-free survival, and metastatic disease-free survival were analyzed for each type of procedure and each disease location. Operative complications and residual tumors were also recorded in cases where resection was performed. Survival was calculated using the Kaplan-Meier method. Results Thirteen patients underwent intralesional curettage (11 appendicular and 2 axial lesions), and eight underwent wide resection (5 axial and 3 appendicular). There were six recurrences during the follow-up, 43% of the axial lesions recurred, rising to 100% in axial curetted ones. Appendicular LG-CS recurred in 21% of cases, and only 18% of curetted appendicular lesions were not eradicated. The overall survival for the entire follow-up is 90.5%, and the 5-year survival rate is 83% (12 patients have adequate follow-up). Recurrence-free and metastasis-free survival were higher in resection cases, with 75% and 87.5%, vs. curettage 69.2% and 76.9%, respectively. In 9% of cases, the preoperative biopsy was inconsistent with the pathology of the surgical specimen. Discussion LG-CS and ACT are described as having high survival and low potential for metastatic disease. For this reason, these lesions are subject to a change in treatment philosophy to reflect these characteristics. Intra-lesional curettage is advocated as a less invasive technique for eradicating atypical cartilage tumors and has fewer and less severe complications, which was in accordance with our findings. Diagnosis, however, is challenging; misgrading is frequent and should be considered. Because of this risk of under-treating higher-grade lesions, some authors still defend wide-resection as the treatment of choice. We observed a trend towards longer survival, less recurrence, and metastatic disease with wide resection. Metastatic disease was higher than expected, present in 19% of cases, and always associated with local recurrence. Conclusion LG-CS is still a diagnostic and treatment challenge; patient selection is fundamental. Overall survival is high, independent of treatment choice or lesion location. We found a higher rate of metastatic disease than described in the literature; this, coupled with a misgrading rate of 9%, reflects the difficulty of preoperative diagnosis and the risk of treating high-grade chondrosarcomas as a low-grade lesion. More studies should be carried out with larger samples to obtain statistically robust results.

Efecto de las Técnicas Instrumentales KineticXer® en la Modificación de Parámetros Séricos y Mecánicos en Usuarios Sedentarios con Dolor Lumbar Inespecífico / Effect of KineticXer® Instrumental Techniques in the Modification of Serum and Mechanical Parameters in Sedentary Users with Nonspecific Low Back Pain

Introducción. El dolor lumbar es una de las causas mas comunes de discapacidad en el mundo, existen diferentes tratamientos conservadores dentro de la kinesiología para el manejo de este. La presente investigación describe los efectos de la aplicación de técnicas de liberación miofascial instrumental y, cómo éstas modifican parámetros mecánicos y la expresión de parámetros séricos, tales como: Leucocitos, Bilirrubina y Fierro en estudiantes sedentarios que presenten dolor lumbar inespecífico de la Universidad de las Américas. Objetivo. Describir el efecto de la técnica de liberación miofascial instrumental en la modificación de parámetros mecánicos y séricos en usuarios sedentarios con dolor lumbar inespecífico. Métodos. Analítico experimental. Resultado. Fueron intervenidos 14 participantes sedentarios con dolor lumbar inespecífico, los resultados no fueron significativos en los cambios serios, por el contrario, fueron significativo en los cambios mecánicos. Conclusión. Las técnicas de liberación miofascial instrumental pueden ser una herramienta eficaz para el manejo del dolor lumbar inespecífico, pero faltan mas estudios para demostrar sus efectos a nivel sérico.

Introduction. Low back pain is one of the most common causes of disability in the world, there are different conservative treatments within kinesiology for its management. The present research describes the effects of the application of instrumental myofascial release techniques and how they modify mechanical parameters and the expression of serum parameters, such as: Leukocytes, Biliverdin and Iron in sedentary students with non-specific lumbar pain from the University of Las Américas. Objective. To describe the effect of the instrumental myofascial release technique in the modification of mechanical and serum parameters in sedentary users with nonspecific low back pain. Methods. Case series Results. 14 sedentary participants with non-specific lumbar pain were operated on, the results were not significant in the serious changes, on the contrary, they were significant in the mechanical changes. Conclusion. Instrumental myofascial release techniques can be an effective tool for the management of nonspecific low back pain, but more studies are needed to demonstrate their effects at the serum level.

Insulin-degrading enzyme: an ally against metabolic and neurodegenerative diseases.

Insulin-degrading enzyme (IDE) function goes far beyond its known proteolytic role as a regulator of insulin levels. IDE has a wide substrate promiscuity, degrading several proteins such as amyloid-ß peptide, glucagon, islet amyloid polypeptide (IAPP), and insulin-like growth factors, which have diverse physiological and pathophysiological functions. Importantly, IDE plays other non-proteolytic functions such as: a chaperone/dead-end chaperone, an E1-ubiquitin activating enzyme, and a proteasome modulator. It also responds as a heat shock protein, regulating cellular proteostasis. Notably, amyloidogenic proteins such as IAPP, amyloid-ß, and α-synuclein have been reported as substrates for IDE chaperone activity. This is of utmost importance as failure of IDE may result in increased protein aggregation, a key hallmark in the pathogenesis of beta cells in type 2 diabetes mellitus and of neurons in neurodegenerative diseases such as Alzheimer's and Parkinson's disease. In this review, we focus on the biochemical and biophysical properties of IDE and the regulation of its physiological functions. We further raise the hypothesis that IDE plays a central role in the pathological context of dysmetabolic and neurodegenerative diseases and discuss its potential as a therapeutic target. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Neurological manifestations of adult-onset Still's disease-case-based review.

Adult-onset Still's disease (AOSD) is a rare inflammatory disorder in which pathophysiology is yet to be fully understood. We report the case of a 66-year-old male that presents with fever, arthralgia, and laboratory abnormalities suggestive of a systemic inflammatory disease. During a diagnostic workout, the patient developed neurological symptoms, namely a sudden confounding syndrome and hearing loss that improved with corticosteroid therapy. After exclusion of malignancy, infection-namely nervous system infection-and other rheumatic diseases, AOSD diagnosis was made using the Yamaguchi criteria. In some rare cases, neurological symptoms are present and the diagnosis may become even more challenging if the clinicians are not aware of these rare manifestations of AOSD. Therefore, the authors present the case of a patient with neurological manifestations of AOSD.

Parada cardíaca por origem aórtica anômala de uma artéria coronária: estarão os pacientes mais velhos realmente seguros? / Cardiac arrest due to an anomalous aortic origin of a coronary artery: are older patients really safe?

RESUMO Os autores relatam um raro caso de uso de Suporte Avançado de Vida no contexto de uma parada cardíaca ocorrida em razão de uma origem aórtica anômala da artéria coronária direita em um paciente de 49 anos de idade. O paciente foi admitido com dor torácica e dispneia, evoluindo rapidamente para taquicardia ventricular sem pulso e parada cardiopulmonar. Considerou-se um infarto agudo do miocárdio e, na ausência de um laboratório de hemodinâmica no hospital, realizou-se trombólise. Subsequentemente, uma angiografia coronária revelou ausência de lesões angiográficas nas artérias coronárias e origem anômala da artéria coronária direita do seio de Valsalva oposto. Uma angiografia coronária por tomografia computadorizada confirmou o achado e determinou um trajeto entre a artéria pulmonar e a aorta. O paciente foi submetido à cirurgia cardíaca com realização de ponte de mamária para a artéria coronária direita, sem qualquer novo episódio de arritmia.

ABSTRACT The authors report a rare case of successful Advanced Life Support in the context of cardiac arrest due to the presence of an anomalous aortic origin of the right coronary artery in a 49-year-old patient. The patient was admitted due to chest pain and dyspnea, with rapid evolution of pulseless ventricular tachycardia and cardiopulmonary arrest. Acute myocardial infarction was considered, and in the absence of a hemodynamic laboratory in the hospital, thrombolysis was performed. Subsequently, coronary angiography revealed no angiographic lesions in the coronary arteries and an anomalous right coronary artery originating from the opposite sinus of Valsalva. Coronary computed tomography angiography confirmed this finding and determined the course between the pulmonary artery and the aorta. The patient underwent cardiac surgery with a bypass graft to the right coronary artery, with no recurrent episodes of arrythmia.

Hsp27 reduces glycation-induced toxicity and aggregation of alpha-synuclein.

α-synuclein (aSyn) is a major player in Parkinson's disease and a group of other disorders collectively known as synucleinopathies, but the precise molecular mechanisms involved are still unclear. aSyn, as virtually all proteins, undergoes a series of posttranslational modifications during its lifetime, which can affect its biology and pathobiology. We recently showed that glycation of aSyn by methylglyoxal (MGO) potentiates its oligomerization and toxicity, induces dopaminergic neuronal cell loss in mice, and affects motor performance in flies. Small heat-shock proteins (sHsps) are molecular chaperones that facilitate the folding of proteins or target misfolded proteins for clearance. Importantly, sHsps were shown to prevent aSyn aggregation and cytotoxicity. Upon treating cells with increasing amounts of methylglyoxal, we found that the levels of Hsp27 decreased in a dose-dependent manner. Therefore, we hypothesized that restoring the levels of Hsp27 in glycating environments could alleviate the pathogenicity of aSyn. Consistently, we found that Hsp27 reduced MGO-induced aSyn aggregation in cells, leading to the formation of nontoxic aSyn species. Remarkably, increasing the levels of Hsp27 suppressed the deleterious effects induced by MGO. Our findings suggest that in glycating environments, the levels of Hsp27 are important for modulating the glycation-associated cellular pathologies in synucleinopathies.

Dimension and morphology of the mandibular condyle in class I patients in cone beam computed tomography / Dimensión y morfología del cóndilo mandibular en pacientes de clase I en tomografía computarizada de haz cónico

To evaluate the anterior-posterior (A-P)/medial-lateral (M-L) dimension, and morphology of the mandibular condyle in patients aged 18 to 65 years with Class I skeletal pattern on Cone Beam CT scans. Materials and Methods: Seventy one scans were evaluated using RealScan 2.0 software. The dimension was determined by points A (most anterior in the sagittal plane), P (most posterior in the sagittal plane), M (most interior in the coronal plane), L (most exterior in the coronal plane). The morphology of the condyle was evaluated in two coronal and sagittal planes, being classified as: round, flat, convex or mixed. The size of the condyle was analyzed by descriptive statistics and the morphology by frequency distribution. For the bivariate analysis, the Student's t-test was applied. Results: Measurements were obtained for the A-P diameter of the right condyle (RC) (8.72mm ± 1.25mm) and the left condylar (LC) (8.50mm ± 1.50mm), the M-L diameter of the RC (19.24mm ± 2.03mm) and the LC (18.97mm ± 1.87mm). There were significant differences in the male M-L dimension of the LC compared to the female (p=0.002). The most prevalent morphology of RC (35.21) and IQ (23.94) in the coronal plane was round. Conclusion: The A-P dimension of the right and left condyle is similar in both genders; however, there are differences in the M-L dimension of the left male condyle. The most prevalent morphology of the right and left condyle was round in the sagittal plane with the exception of the coronal plane.

Evaluar la dimensión antero- posterior (A-P)/medio-lateral (M­L), y la morfología del cóndilo mandibular en pacientes de 18 a 65 años con patrón esquelético Clase I en tomografías computarizadas Cone Beam. Material y Métodos: 71 tomografías fueron evaluadas mediante el software RealScan 2.0. La dimensión fue determinada por los puntos A (más anterior en el plano sagital), P (más posterior en el plano sagital), M (más interno en el plano coronal), L (más externo en plano coronal). Se evaluó la morfología del cóndilo en dos planos coronal y sagital, clasificándose en: redonda, aplanada, convexa y mixta. La dimensión del cóndilo fue analizada por estadística descriptiva y la morfología mediante distribución de frecuencias. Para el análisis bivariado, se aplicó la prueba de t de Student. Resultado: Se obtuvieron las medidas del diámetro A-P del cóndilo derecho (CD) (8,72mm ± 1,25mm) y el izquierdo (CI) (8,50mm ± 1,50mm), el diámetro M-L del CD (19,24mm ± 2,03mm) y el CI (18,97mm ± 1,87mm). Hubo diferencias significativas en la dimensión M-L del CI del sexo masculino en comparación al femenino (p=0.002). La morfología más prevalente del CD (35,21) y CI (23,94) en plano coronal fue de tipo redonda. Conclusión: La dimensión A-P del cóndilo derecho e izquierdo es similar en ambos sexos; sin embargo, existen diferencias en la dimensión M-L del cóndilo izquierdo del sexo masculino. La morfología del cóndilo derecho e izquierdo más prevalente fue la redonda en plano sagital a excepción del plano coronal.

Estudio comparativo del espacio aéreo faríngeo según deformidades dentofaciales en radiografías cefalométricas / Comparative study of pharyngeal airway space according to dentofacial deformities in cephalometric radiographs

RESUMEN Objetivo: Comparar la dimensión del espacio aéreo faríngeo superior e inferior en las deformidades esqueléticas clase I, II y III determinadas en radiografías cefalométricas. Material y métodos: Se realizó un estudio de tipo retrospectivo donde se analizó 106 radiografías cefalométricas, tomadas en el centro radiográfico del Centro Universitario de Salud de la Universidad Peruana de Ciencias Aplicadas entre los años 2011 y 2014. A través del programa Nemoceph® se marcaron los puntos y trazados cefalométricos principales para determinar la de-formidad esquelética (según Steiner) y la dimensión de las vías aéreas superior e inferior (según McNamara). Resultados: La mayor dimensión en promedio (17,68 mm), se encontró en el espacio aéreo faríngeo superior (EAFS) con en la deformidad dentofacial clase III (DDF clase III) y la menor dimensión en promedio (13,71 mm) en la DDF clase II. En el espacio aéreo faríngeo inferior (EAFI), el mayor promedio (15,98mm) se presenta en la DDF clase III y el menor promedio (13,19mm) en la DDF clase II. Al comparar la dimensión del espacio faríngeo (EAF) entre las DDF, se encontró que existe diferencias estadísticamente significativas entre el EAFS de las DDF II y III, con un valor de p = 0,001; y en el inferior entre DDF III con DDF I y DDF III con DDFII con valores de p=0,0236 y p=0,0042 respectivamente. Conclusiones: En este estudio se encontró que existe diferencias estadísticamente significativas en el espacio aéreo faríngeo superior e inferior entre las tres clases de deformidades esqueléticas.

SUMMARY Objectives: Compare the dimension of the upper and lower pharyngeal airspace between the skeletal deformities class I, II and III in cephalometric radiographs. Material and methods: A retrospective type of study was made where there were analyzed 106 side radiogra-phies, taken in the X-ray center of the University health Center of the Peruvian University of Applied Sciences UPC between the years 2011 and 2014. Through the program Nemoceph® the main cephalometrics points and tracings were marked to be able to obtain the skeletal deformity (Steiner) and the dimension of the upper and lower airspace (McNamara). Results: In the upper pharyngeal airspace it was found that the highest aver-age dimension was 17.68 mm founded in the dentofacial deformation class III, and the lowest in class II with a value of 13.71 mm. Fort the lower airspace, the highest average was 15.98mm and the lowest 13.19mm, also founded in skeletal deformation Class III and Class II respectively. While comparing the size of the pharyngeal space between classes of deformity, it was found that there is statistically significant difference between the upper airspace of skeletal deformities class II and III with a value of p = 0.001; and in the lower, between classes III - I and III - II with values of p=0.0236 and p=0.0042 respectively. Conclusions: In this study it was found that there is a statistically significant difference in the upper and lower pharingeal airspace between the three dentofacial skeletal deformities.

Cardiac arrest due to an anomalous aortic origin of a coronary artery: are older patients really safe? / Parada cardíaca por origem aórtica anômala de uma artéria coronária: estarão os pacientes mais velhos realmente seguros?

The authors report a rare case of successful Advanced Life Support in the context of cardiac arrest due to the presence of an anomalous aortic origin of the right coronary artery in a 49-year-old patient. The patient was admitted due to chest pain and dyspnea, with rapid evolution of pulseless ventricular tachycardia and cardiopulmonary arrest. Acute myocardial infarction was considered, and in the absence of a hemodynamic laboratory in the hospital, thrombolysis was performed. Subsequently, coronary angiography revealed no angiographic lesions in the coronary arteries and an anomalous right coronary artery originating from the opposite sinus of Valsalva. Coronary computed tomography angiography confirmed this finding and determined the course between the pulmonary artery and the aorta. The patient underwent cardiac surgery with a bypass graft to the right coronary artery, with no recurrent episodes of arrythmia.

Os autores relatam um raro caso de uso de Suporte Avançado de Vida no contexto de uma parada cardíaca ocorrida em razão de uma origem aórtica anômala da artéria coronária direita em um paciente de 49 anos de idade. O paciente foi admitido com dor torácica e dispneia, evoluindo rapidamente para taquicardia ventricular sem pulso e parada cardiopulmonar. Considerou-se um infarto agudo do miocárdio e, na ausência de um laboratório de hemodinâmica no hospital, realizou-se trombólise. Subsequentemente, uma angiografia coronária revelou ausência de lesões angiográficas nas artérias coronárias e origem anômala da artéria coronária direita do seio de Valsalva oposto. Uma angiografia coronária por tomografia computadorizada confirmou o achado e determinou um trajeto entre a artéria pulmonar e a aorta. O paciente foi submetido à cirurgia cardíaca com realização de ponte de mamária para a artéria coronária direita, sem qualquer novo episódio de arritmia.

Odontogenic Carcinosarcoma: Clinicopathologic Features of 2 Cases.

This study reports 2 odontogenic carcinosarcomas, including the clinicopathologic and immunoprofile characteristics of these rare tumors. The first case occurred in a 22-year-old male presenting a bilobular mass involving the gingiva and bone of the premolar region of the left mandible, with paresthesia of the lower lip. Microscopic examination revealed a tumor similar to ameloblastic fibrosarcoma, with atypical mesenchymal cells; however, the odontogenic epithelium also showed atypia. In the second case, a 16-year-old female had a painless, asymptomatic, large intraosseous mandibular lesion. The patient received radiotherapy to treat a rhabdomyosarcoma of the parotid 13 years before. The tumor was composed of atypical spindle cells, positive for vimentin and smooth muscle actin, intermingled with malignant odontogenic epithelium. Both epithelial and mesenchymal components of the tumors showed high index of p53- and Ki67-positive cells. The first case was diagnosed as odontogenic carcinosarcoma possibly originated from an ameloblastic fibrosarcoma, and the second as de novo odontogenic carcinosarcoma possibly caused by previous radiotherapy.

Extracellular aggregated alpha synuclein primarily triggers lysosomal dysfunction in neural cells prevented by trehalose.

Cell-to-cell propagation of aggregated alpha synuclein (aSyn) has been suggested to play an important role in the progression of alpha synucleinopathies. A critical step for the propagation process is the accumulation of extracellular aSyn within recipient cells. Here, we investigated the trafficking of distinct exogenous aSyn forms and addressed the mechanisms influencing their accumulation in recipient cells. The aggregated aSyn species (oligomers and fibrils) exhibited more pronounced accumulation within recipient cells than aSyn monomers. In particular, internalized extracellular aSyn in the aggregated forms was able to seed the aggregation of endogenous aSyn. Following uptake, aSyn was detected along endosome-to-lysosome and autophagosome-to-lysosome routes. Intriguingly, aggregated aSyn resulted in lysosomal activity impairment, accompanied by the accumulation of dilated lysosomes. Moreover, analysis of autophagy-related protein markers suggested decreased autophagosome clearance. In contrast, the endocytic pathway, proteasome activity, and mitochondrial homeostasis were not substantially affected in recipient cells. Our data suggests that extracellularly added aggregated aSyn primarily impairs lysosomal activity, consequently leading to aSyn accumulation within recipient cells. Importantly, the autophagy inducer trehalose prevented lysosomal alterations and attenuated aSyn accumulation within aSyn-exposed cells. Our study underscores the importance of lysosomes for the propagation of aSyn pathology, thereby proposing these organelles as interventional targets.

Synergism between gabapentin-tramadol in experimental diabetic neuropathic pain.

Neuropathic pain is associated with several conditions such as surgery, cancer, and diabetes and can be induced experimentally. Among the drugs used as monotherapy are gabapentin and tramadol. The purpose of this study was to evaluate the coadministration of gabapentin and tramadol, by isobolographic analysis, in three different algesiometric assays in experimental diabetic neuropathic pain induced by streptozocin in mice. In all the behavioral tests, gabapentin or tramadol produced a dose-dependent antinociception and their coadministration resulted in a positive interaction. This effect can be explained by principles of multimodal analgesia, whereby the different mechanisms of action of each drug contribute to the combined effect in a supra-additive manner. The findings of the present study suggest that the combination of gabapentin and tramadol could be a useful strategy for the treatment of pain induced by diabetic neuropathy.

Antinociception induced by rosuvastatin in murine neuropathic pain.

BACKGROUND: Neuropathic pain, and subsequent hypernociception, can be induced in mice by paclitaxel (PTX) administration and partial sciatic nerve ligation (PSNL). Its pharmacotherapy has been a clinical challenge, due to a lack of effective treatment. In two models of mouse neuropathic pain (PTX and PSNL) the antinociception induced by rosuvastatin and the participation of proinflammatory biomarkers, interleukin (IL)- 1ß, TBARS and glutathione were evaluated. METHODS: A dose-response curve for rosuvastatin ip was obtained on cold plate, hot plate and Von Frey assays. Changes on spinal cord levels of IL-1ß, glutathione and lipid peroxidation were measured at 7 and 14days in PTX and PSNL murine models. RESULTS: PTX or PSNL were able to induce in mice peripheral neuropathy with hypernociception, either to 7 and 14days. Rosuvastatin induced a dose dependent antinociception in hot plate, cold plate and Von Frey assays. The increased levels of IL-1ß or TBARS induced by pretreatment with PTX or PSNL were reduced by rosuvastatin. The reduction of spinal cord glutathione, by PTX or PSNL, expressed as the ratio GSH/GSSG, were increased significantly in animals pretreated with rosuvastatin. The anti-inflammatory properties of statins could underlie their beneficial effects on neuropathic pain by reduction of proinflammatory biomarkers and activation of glia. CONCLUSION: The findings of this study suggest a potential usefulness of rosuvastatin in the treatment of neuropathic pain.

Mandibular condyle dimensions in Peruvian patients with class II and class III skeletal patterns

OBJECTIVE: to compare condylar dimensions of young adults with class II and class III skeletal patterns using cone-beam computed tomography (CBCT). MATERIALS AND METHODS: 124 CBCTs from 18-30 year-old patients, divided into 2 groups according to skeletal patterns (Class II and Class III) were evaluated. skeletal patterns were classified by measuring the ANB angle of each patient. the anteroposterior diameter (A and P) of the right and left mandibular condyle was assessed from a sagittal view by a line drawn from point A (anterior) to P (posterior). the coronal plane allowed the evaluation of the medio-lateral diameter by drawing a line from point M (medium) to L (lateral); all distances were measured in mm. RESULTS: In class II the A-P diameter was 9.06±1.33 and 8.86±1.56 for the right and left condyles respectively, in class III these values were 8.71±1.2 and 8.84±1.42. in class II the M-L diameter was 17.94±2.68 and 17.67±2.44 for the right and left condyles respectively, in class III these values were 19.16±2.75 and 19.16±2.54. CONCLUSION: class III M-L dimensions showed higher values than class II, whereas these differences were minimal in A-P.

Adenosine A2A Receptors Modulate α-Synuclein Aggregation and Toxicity.

Abnormal accumulation of aggregated α-synuclein (aSyn) is a hallmark of sporadic and familial Parkinson's disease (PD) and related synucleinopathies. Recent studies suggest a neuroprotective role of adenosine A2A receptor (A2AR) antagonists in PD. Nevertheless, the precise molecular mechanisms underlying this neuroprotection remain unclear. We assessed the impact of A2AR blockade or genetic deletion (A2AR KO) on synaptic plasticity and neuronal cell death induced by aSyn oligomers. We found that impairment of LTP associated with aSyn exposure was rescued in A2AR KO mice or upon A2AR blockade, through an NMDA receptor-dependent mechanism. The mechanisms underlying these effects were evaluated in SH-SY5Y cells overexpressing aSyn and rat primary neuronal cultures exposed to aSyn. Cell death in both conditions was prevented by selective A2AR antagonists. Interestingly, blockade of these receptors did not interfere with aSyn oligomerization but, instead, reduced the percentage of cells displaying aSyn inclusions. Altogether, our data raise the possibility that the well-documented effects of A2AR antagonists involve the control of the latter stages of aSyn aggregation, thereby preventing the associated neurotoxicity. These findings suggest that A2AR represent an important target for the development of effective drugs for the treatment of PD and related synucleinopathies.

Isostructural Re(I)/(99m)Tc(I) tricarbonyl complexes for cancer theranostics.

Merging classical organic anticancer drugs with metal-based compounds in one single molecule offers the possibility of exploring new approaches for cancer theranostics, i.e. the combination of diagnostic and therapeutic modalities. For this purpose, we have synthesized and biologically evaluated a series of Re(I)/(99m)Tc(I) tricarbonyl complexes (Re1­Re4 and Tc1­Tc4, respectively) stabilized by a cysteamine-based (N,S,O) chelator and containing 2-(4'-aminophenyl)benzothiazole pharmacophores. With the exception of Re1, all the Re complexes have shown a moderate cytotoxicity in MCF7 and PC3 cancer cells (IC50 values in the 15.9­32.1 µM range after 72 h of incubation). The cytotoxic activity of the Re complexes is well correlated with cellular uptake that was quantified using the isostructural (99m)Tc congeners. There is an augmented cytotoxic effect for Re3 and Re4 (versusRe1 and Re2), and the highest cellular uptake for Tc3 and Tc4, which display a long ether-containing linker to couple the pharmacophore to the (N,S,O)-chelator framework. Moreover, fluorescence microscopy clearly confirmed the cytosolic accumulation of the most cytotoxic compound (Re3). Biodistribution studies of Tc1­Tc4 in mice confirmed that these moderately lipophilic complexes (logDo/w = 1.95­2.32) have a favorable bioavailability. Tc3 and Tc4 presented a faster excretion, as they undergo metabolic transformations, in contrast to complexes Tc1 and Tc2. In summary, our results show that benzothiazole-containing Re(I)/(99m)Tc(I) tricarbonyl complexes stabilized by cysteamine-based (N,S,O)-chelators have potential to be further applied in the design of new tools for cancer theranostics.

(Poly)phenols protect from α-synuclein toxicity by reducing oxidative stress and promoting autophagy.

Parkinson's disease (PD) is the most common movement neurodegenerative disorder and is associated with the aggregation of α-synuclein (αSyn) and oxidative stress, hallmarks of the disease. Although the precise molecular events underlying αSyn aggregation are still unclear, oxidative stress is known to contribute to this process. Therefore, agents that either prevent oxidative stress or inhibit αSyn toxicity are expected to constitute potential drug leads for PD. Both pre-clinical and clinical studies provided evidence that (poly)phenols, pure or in extracts, might protect against neurodegenerative disorders associated with oxidative stress in the brain. In this study, we analyzed, for the first time, a (poly)phenol-enriched fraction (PEF) from leaves of Corema album, and used in vitro and cellular models to evaluate its effects on αSyn toxicity and aggregation. Interestingly, the PEF promoted the formation of non-toxic αSyn species in vitro, and inhibited its toxicity and aggregation in cells, by promoting the autophagic flux and reducing oxidative stress. Thus, C. album (poly)phenols appear as promising cytoprotective compounds, modulating central events in the pathogenesis of PD, such as αSyn aggregation and the impairment of autophagy. Ultimately, the understanding of the molecular effects of (poly)phenols will open novel opportunities for the exploitation of their beneficial effects and for drug development.