Zoledronic Acid Prevents Bone Resorption Caused by the Combination of Radium-223, Abiraterone Acetate, and Prednisone in an Intratibial Prostate Cancer Mouse Model.

An increased risk of non-pathological fractures in patients with prostate cancer and bone metastases has been associated with combination treatment with radium-223, abiraterone, and prednisone/prednisolone in the absence of bone-protecting agents. Here, we investigated possible mechanisms leading to this outcome using an intratibial LNCaP model mimicking prostate cancer bone metastases. Male NOD.scid mice were inoculated intratibially with LNCaP prostate cancer cells and treated with vehicle, radium-223, abiraterone, prednisone, zoledronic acid, or their combinations for 28 days. Serum TRACP 5b and PSA levels were measured. Bone structure, quality, and formation rate of non-tumor-bearing and tumor-bearing tibiae were analyzed by microCT, 3-point bending assay, and dynamic histomorphometry, respectively. Radium-223 incorporation into bone was also measured. Radium-223/abiraterone/prednisone combination treatment induced a transient increase in bone resorption indicated by elevated TRACP 5b levels, which was inhibited by concurrent treatment with zoledronic acid. Furthermore, radium-223/abiraterone/prednisone combination reduced periosteal and trabecular new bone formation and the number of osteoblasts, but bone structure or biomechanical quality were not affected. The abiraterone/prednisone treatment decreased radium-223 incorporation into tumor-bearing bone, possibly explaining the lack of additional antitumor efficacy. In conclusion, radium-223/abiraterone/prednisone combination increased bone resorption, which may have been one of the mechanisms leading to an increased fracture risk in patients with mCRPC.

Investigating the Causality Between Financial Development and Carbon Emissions: A Quantile-Based Analysis.

The relationship between financial development and environmental sustainability has received significant attention in academic discourse. This study explores the crucial role of financial development in addressing the challenge of increasing CO2 emissions. Using quantile-on-quantile and nonparametric causality-in-quantile methodologies, this research investigates the impacts and causal links between financial market and institution development and CO2 emissions levels in five major polluting countries from 1990 to 2019. The findings provide strong evidence regarding the impact of financial institutions and financial market development on CO2 emissions, demonstrating the presence of shocks and nonparametric causality from financial institutions and financial market development to CO2 emissions quantiles. However, the effects of financial institution shocks and nonparametric causality are diverse and asymmetric across the sample. Positive and negative shocks are observed in India, while only negative shocks are observed in China, the USA, Russia, and Japan. Moreover, the findings reveal that the influence of financial market development on CO2 emissions varies across countries, with both positive and negative shocks transmitted to CO2 emissions in the USA, Russia, and Japan, indicating higher volatility in these countries compared to China and India, where only negative shocks are observed. Therefore, our recommendation emphasizes the prioritization of environmentally conscious financial products and the enhancement of the financial system's capacity to mitigate positive shocks contributing to increased CO2 emissions. Implementing this strategy requires collective efforts to embrace sustainable financial practices that consider the environmental impact of financial activities.

Enhanced Antitumor Efficacy of Radium-223 and Enzalutamide in the Intratibial LNCaP Prostate Cancer Model.

Radium-223 dichloride and enzalutamide are indicated for metastatic castration-resistant prostate cancer and their combination is currently being investigated in a large phase 3 clinical trial. Here, we evaluated the antitumor efficacy of radium-223, enzalutamide, and their combination in the intratibial LNCaP model mimicking prostate cancer metastasized to bone. In vitro experiments revealed that the combination of radium-223 and enzalutamide inhibited LNCaP cell proliferation and showed synergistic efficacy. The combination of radium-223 and enzalutamide also demonstrated enhanced in vivo antitumor efficacy, as determined by measuring serum PSA levels in the intratibial LNCaP model. A decreasing trend in the total area of tumor-induced abnormal bone was associated with the combination treatment. The serum levels of the bone formation marker PINP and the bone resorption marker CTX-I were lowest in the combination treatment group and markedly decreased compared with vehicle group. Concurrent administration of enzalutamide did not impair radium-223 uptake in tumor-bearing bone or the ability of radium-223 to inhibit tumor-induced abnormal bone formation. In conclusion, combination treatment with radium-223 and enzalutamide demonstrated enhanced antitumor efficacy without compromising the integrity of healthy bone. The results support the ongoing phase 3 trial of this combination.

Integrated Features for Optimizing Machine Learning Classifiers of Pediatric and Young Adults With a Post-Traumatic Headache From Healthy Controls.

Post-traumatic headache (PTH) is a challenging clinical condition to identify and treat as it integrates multiple subjectively defined symptoms with underlying physiological processes. The precise mechanisms underlying PTH are unclear, and it remains to be understood how to integrate the patient experience with underlying biology when attempting to classify persons with PTH, particularly in the pediatric setting where patient self-report may be highly variable. The objective of this investigation was to evaluate the use of different machine learning (ML) classifiers to differentiate pediatric and young adult subjects with PTH from healthy controls using behavioral data from self-report questionnaires that reflect concussion symptoms, mental health, pain experience of the participants, and structural brain imaging from cortical and sub-cortical locations. Behavioral data, alongside brain imaging, survived data reduction methods and both contributed toward final models. Behavioral data that contributed towards the final model included both the child and parent perspective of the pain-experience. Brain imaging features produced two unique clusters that reflect regions that were previously found in mild traumatic brain injury (mTBI) and PTH. Affinity-based propagation analysis demonstrated that behavioral data remained independent relative to neuroimaging data that suggest there is a role for both behavioral and brain imaging data when attempting to classify children with PTH.

Towards a deeper understanding of pain: How machine learning and deep learning algorithms are needed to provide the next generation of pain medicine for use in the clinic.

As our definition of pain evolves, the factors implicit in defining and predicting pain status grow. These factors each have unique data characteristics and their outcomes each have unique target attributes. The clinical characterization of pain does not, as defined in the most recent IASP definition, require any tissue pathology, suggesting that the experience of pain can be uniquely psychological in nature. Predicting a persons pain status may be optimized through integration of multiple independent observations; however, how they are integrated has direct relevance towards predicting chronic pain development, clinical application, and research investigation. The current challenge is to find clinically-mindful ways of integrating clinical pain rating scales with neuroimaging of the peripheral and central nervous system with the biopsychocial environment and improving our capacity for diagnostic flexibility and knowledge translation through data modeling. This commentary addresses how our current knowledge of pain phenotypes and risk factors interacts with statistical models and how we can proceed forward in a clinically responsible way.

Evidence of Chronic Complement Activation in Asymptomatic Pediatric Brain Injury Patients: A Pilot Study.

Physical insult from a mild Traumatic Brain Injury (mTBI) leads to changes in blood flow in the brain and measurable changes in white matter, suggesting a physiological basis for chronic symptom presentation. Post-traumatic headache (PTH) is frequently reported by persons after an mTBI that may persist beyond the acute period (>3 months). It remains unclear whether ongoing inflammation may contribute to the clinical trajectory of PTH. We recruited a cohort of pediatric subjects with PTH who had an acute or a persistent clinical trajectory, each around the 3-month post-injury time point, as well as a group of age and sex-matched healthy controls. We collected salivary markers of mRNA expression as well as brain imaging and psychological testing. The persistent PTH group showed the highest levels of psychological burden and pain symptom reporting. Our data suggest that the acute and persistent PTH cohort had elevated levels of complement factors relative to healthy controls. The greatest change in mRNA expression was found in the acute-PTH cohort wherein the complement cascade and markers of vascular health showed a prominent role for C1Q in PTH pathophysiology. These findings (1) underscore a prolonged engagement of what is normally a healthy response and (2) show that a persistent PTH symptom trajectory may parallel a poorly regulated inflammatory response.

Additive Benefits of Radium-223 Dichloride and Bortezomib Combination in a Systemic Multiple Myeloma Mouse Model.

Osteolytic bone disease is a hallmark of multiple myeloma (MM) mediated by MM cell proliferation, increased osteoclast activity, and suppressed osteoblast function. The proteasome inhibitor bortezomib targets MM cells and improves bone health in MM patients. Radium-223 dichloride (radium-223), the first targeted alpha therapy approved, specifically targets bone metastases, where it disrupts the activity of both tumor cells and tumor-supporting bone cells in mouse models of breast and prostate cancer bone metastasis. We hypothesized that radium-223 and bortezomib combination treatment would have additive effects on MM. In vitro experiments revealed that the combination treatment inhibited MM cell proliferation and demonstrated additive efficacy. In the systemic, syngeneic 5TGM1 mouse MM model, both bortezomib and radium-223 decreased the osteolytic lesion area, and their combination was more effective than either monotherapy alone. Bortezomib decreased the number of osteoclasts at the tumor-bone interface, and the combination therapy resulted in almost complete eradication of osteoclasts. Furthermore, the combination therapy improved the incorporation of radium-223 into MM-bearing bone. Importantly, the combination therapy decreased tumor burden and restored body weights in MM mice. These results suggest that the combination of radium-223 with bortezomib could constitute a novel, effective therapy for MM and, in particular, myeloma bone disease.

Chemical composition of the leaf oils from two morphotypes of Psidium cattleyanum at four phenological stages.

The chemical composition of volatile oil extracted from leaves of two morphotypes of Psidium cattleyanum Sabine from southern Brazil was evaluated at four phenological stages. In addition, plant material was evaluated at four different locations of the Planalto Serrano Region of Santa Catarina state, Brazil. Major components found were: 1,8-cineole, α-pinene, α-eudesmol, (E)-caryophyllene and p-cymene in red morphotype whereas 1,8-cineole, α-pinene, myrcene, (E)-caryophyllene and valerianol were found in the yellow morphotype. The differences observed in the chemical composition in red and yellow morphotypes may help in the differentiation between the two morphotypes in the absence of fruits. Also, important differences were observed mainly for 1,8-cineole and α-pinene percentage at different phenological stages.

Revisión sistemática del síndrome de Münchhausen por poderes o trastorno facticio impuesto a otro: psicobiografía de la perpetradora, el proceso de peregrinación hospitalaria y signos de alarma en la víctima / The Münchhausen syndrome by proxy: a systematic review. psychobiography of the perpetrator, hospital pilgrimage process and victims' red flags

INTRODUCCIÓN: En 1977, Roy Medow acuña y describe el síndrome de Münchhausen por poderes como una enfermedad mental en la que una cuidadora miente al doctor sobre la salud de su hijo mediante la fabricación de signos físicos, la alteración del historial médico o la inducción de síntomas. En la actualidad, es recogido en el DSM-5 bajo el nombre de trastorno facticio impuesto a otro. Se estima que afecta a 0.2 - 2 cada 100.000 niños menores de 16 años. OBJETIVO: Aportar información sobre la psicobiografía de la perpetradora diagnosticada de trastorno facticio impuesto a otro, con el objetivo de establecer un perfil de sospecha en aquellas presentaciones médicas inusuales en la práctica clínica. MÉTODOS: Revisión sistemática de los artículos publicados desde el año 2000 en la base de datos PubMed, que incorporen los términos "Münchhausen syndrome by proxy" y "factitious disorder". Se incluyeron libros y documentos, artículos de revistas científicas y revisiones en inglés y castellano. Se excluyeron aquellos artículos con una muestra menor a 20 casos analizados. RESULTADOS: La perpetradora se dibuja generalmente como la madre de la víctima en la mayoría de los casos, con unos antecedentes vividos de maltrato infantil y de abusos de distinta índole. Gran parte de estas, recibieron atención psiquiátrica en la infancia, y también en la vida adulta. Suelen presentar comorbilidades psicopatológicas, en especial el trastorno facticio impuesto a uno mismo y los trastornos de personalidad, sobresaliendo el límite. Por otro lado, la víctima es habitualmente un menor de 5 años, con una morbimortalidad importante. La peregrinación hospitalaria, la necesidad de ingresos hospitalarios prolongados, así como la realización de intervenciones invasivas, son consecuencias evidentes en estos menores. CONCLUSIONES: Si bien es cierto que en esta revisión se han arrojado cifras al respecto, no sería correcto utilizar estos resultados categóricamente, ya que se han dado casos en la literatura médica de perpetradoras que no eran figuras femeninas, y de víctimas que no eran menores. Para futuros estudios, sería interesante observar a nivel retrospectivo la aparición de patología psiquiátrica en las víctimas y valorar la posibilidad de la repetición de determinados roles de maltrato

BACKGROUND: In 1977, Roy Medow named and described Münchhausen's syndrome by proxy as a mental illness in which a caregiver lies to the doctor about his child's health situation by making physical signs, altering the medical history or inducing symptoms. Currently, it is collected in DSM-5 under the name of factitious disorder imposed on another. It is estimated to affect 0.2 - 2 per 100,000 children under the age of 16. OBJECTIVE: Provide information about the psychobiography of the perpetrator diagnosed with factitious disorder imposed on another, with the aim of establishing a suspicious profile in those unusual medical presentations in clinical practice. METHODS: Systematic review of articles published since 2000 in the PubMed database, incorporating the terms "Münchhausen syndrome by proxy" and "factitious disorder". Books and documents, articles from scientific journals and reviews were included, in both English and Spanish. Those articles whose sample was less than 20 analyzed cases were excluded. RESULTS: The perpetrator is generally portrayed as the victim's mother in most cases, with a vivid history of child abuse and abuse of various kinds. Most of them received psychiatric care in childhood, and also during adult life. They usually present psychopathological comorbidities, especially factitious disorder imposed on self and personality disorders, especially the Borderline personality disorder. On the other hand, the victim is usually a child under the age of 5, with significant morbimortality. Hospital pilgrimage, the need for prolonged hospital admissions, as well as invasive procedures, are obvious consequences in these minors. CONCLUSIONS: Although it is true that figures have been produced in this review, it would not be correct to use these results categorically, since there have been cases in the medical literature of perpetrators who were not female figures, and of victims who were not minors. For future studies, it would be interesting to retrospectively observe the appearance of psychiatric pathology in victims and assess the possibility of the repetition of certain roles of abuse

Spruce Galactoglucomannan-Stabilized Emulsions Enhance Bioaccessibility of Bioactive Compounds.

The increasing public awareness of health and sustainability has prompted the development of functional foods rich in health-promoting ingredients. Processing technologies and sustainable multifunctional ingredients are needed for structuring these formulations. Spruce galactoglucomannan (GGM), the main hemicelluloses in softwood cell walls, are an abundantly available, emerging sustainable food hydrocolloid that have the ability to efficiently emulsify and stabilize oil-in-water emulsions. In this study, we illustrate how this lignocellulosic stabilizer affects the digestion of polyunsaturated fatty acids (PUFAs) in vitro. A 100% decrease in the initial TAG content was observed during the in vitro digestion, suggesting that complete hydrolysis of the TAGs was achieved by the digestive enzymes. Besides, no release of mono-, di-, and oligosaccharides or phenolic compounds from GGM was detected. Our results demonstrate that the GGM-stabilized emulsion could potentially deliver lipophilic bioactive ingredients and enhance their bioaccessibility. In addition, this bio-stabilizer itself would remain stable in the upper gastrointestinal track and serve as a prebiotic for gut microbiota. We anticipate GGM to complement or even replace many of the conventional carriers of bioactive components in future health care products and functional foods.

The Mode-of-Action of Targeted Alpha Therapy Radium-223 as an Enabler for Novel Combinations to Treat Patients with Bone Metastasis.

Bone metastasis is a common clinical complication in several cancer types, and it causes a severe reduction in quality of life as well as lowering survival time. Bone metastases proceed through a vicious self-reinforcing cycle that can be osteolytic or osteoblastic in nature. The vicious cycle is characterized by cancer cells residing in bone releasing signal molecules that promote the differentiation of osteoclasts and osteoblasts either directly or indirectly. The increased activity of osteoclasts and osteoblasts then increases bone turnover, which releases growth factors that benefit metastatic cancer cells. In order to improve the prognosis of patients with bone metastases this cycle must be broken. Radium-223 dichloride (radium-223), the first targeted alpha therapy (TAT) approved, is an osteomimetic radionuclide that is incorporated into bone metastases where its high-linear energy transfer alpha radiation disrupts both the activity of bone cells and cancer cells. Therefore, radium-223 treatment has been shown preclinically to directly affect cancer cells in both osteolytic breast cancer and osteoblastic prostate cancer bone metastases as well as to inhibit the differentiation of osteoblasts and osteoclasts. Clinical studies have demonstrated an increase in survival in patients with metastatic castration-resistant prostate cancer. Due to the effectiveness and low toxicity of radium-223, several novel combination treatment strategies are currently eliciting considerable research interest.

Human Immune System Increases Breast Cancer-Induced Osteoblastic Bone Growth in a Humanized Mouse Model without Affecting Normal Bone.

Bone metastases are prevalent in many common cancers such as breast, prostate, and lung cancers, and novel therapies for treating bone metastases are needed. Human immune system-engrafted models are used in immuno-oncology (IO) studies for subcutaneous cancer cell or patient-derived xenograft implantations that mimic primary tumor growth. Novel efficacy models for IO compounds on bone metastases need to be established. The study was performed using CIEA NOG (NOG) mice engrafted with human CD34+ hematopoietic stem cells (huNOG) and age-matched immunodeficient NOG mice. Bone phenotyping was performed to evaluate baseline differences. BT-474 human breast cancer cells were inoculated into the tibia bone marrow, and cancer-induced bone changes were monitored by X-ray imaging. Bone content and volume were analyzed by dual X-ray absorptiometry and microcomputed tomography. Tumor-infiltrating lymphocytes (TILs) and the expression of immune checkpoint markers were analyzed by immunohistochemistry. Bone phenotyping showed no differences in bone architecture or volume of the healthy bones in huNOG and NOG mice, but the bone marrow fat was absent in huNOG mice. Fibrotic areas were observed in the bone marrow of some huNOG mice. BT-474 tumors induced osteoblastic bone growth. Bone lesions appeared earlier and were larger, and bone mineral density was higher in huNOG mice. huNOG mice had a high number of human CD3-, CD4-, and CD8-positive T cells and CD20-positive B cells in immune-related organs. A low number of TILs and PD-1-positive cells and low PD-L1 expression were observed in the BT-474 tumors at the endpoint. This study reports characterization of the first breast cancer bone growth model in huNOG mice. BT-474 tumors represent a "cold" tumor with a low number of TILs. This model can be used for evaluating the efficacy of combination treatments of IO therapies with immune-stimulatory compounds or therapeutic approaches on bone metastatic breast cancer.

Duration of ß-adrenoceptor blockade associated with once-daily oral administration of atenolol in healthy dogs.

OBJECTIVE To test the hypothesis that once-daily oral administration of atenolol would attenuate the heart rate response to isoproterenol for 24 hours. ANIMALS 20 healthy dogs. PROCEDURES A double-blind randomized placebo-controlled crossover study was conducted. Dogs were assigned to receive atenolol (1 mg/kg, PO, q 24 h) or a placebo for 5 to 7 days. After a washout period of 7 days, dogs then received the other treatment. Heart rate at rest (HRr) and heart rate induced by administration of isoproterenol (HRi) as a constant rate infusion (0.2 µg/kg/min for 5 to 7 minutes) were obtained by use of ECG 0, 0.25, 3, 6, 12, 18, and 24 hours after administration of the final dose of atenolol or the placebo. A mixed-model ANOVA was used to evaluate effects of treatment, time after drug or placebo administration, treatment-by-time interaction, period, and sequence on HRr and HRi. RESULTS Effects of sequence or period were not detected. There was a significant effect of treatment and the treatment-by-time interaction on HRi. Atenolol significantly attenuated HRi for 24 hours but did so maximally at 3 hours (least squares mean ± SE, 146 ± 5 beats/min and 208 ± 5 beats/min for atenolol and placebo, respectively). The effect at 24 hours was small (193 ± 5 beats/min and 206 ± 5 beats/min for atenolol and placebo, respectively). Atenolol had a small but significant effect on HRr. CONCLUSIONS AND CLINICAL RELEVANCE This study of healthy dogs receiving atenolol supported a recommendation for a dosing interval < 24 hours.

The MATRIX, a novel tool exploring dynamic psychotherapy: Preliminary psychometric properties.

Most measures in the field of psychodynamic psychotherapy are bound to a specific theory, and usually focus only on patient processes or therapist interventions. The MATRIX is a newly developed research tool that focuses on events within both the patient and the therapist individually, as well as on dyadic events, and provides the simple and meaningful coding of content for therapy session transcripts in psychotherapy. The present study describes the inter-rater reliability and construct validity of the MATRIX. Reliability of the MATRIX was assessed by applying it to 805 fragments of psychodynamic-oriented psychotherapy sessions. Three independent experts coded fragments, and the tool was examined for reliability. Validity in identifying the theoretical inclinations was assessed by applying the MATRIX to 30 segments (containing 1309 fragments) of sessions that reflect different theoretical orientations. Findings evinced high inter-rater reliability for all dimensions. The MATRIX was found to have high degree of validity for differentiating the theoretical inclinations of segments of sessions. The MATRIX is a reliable and valid measure that may enable moment-to-moment, quantitative, analysis of psychodynamic psychotherapy.

Radium-223 Inhibits Osseous Prostate Cancer Growth by Dual Targeting of Cancer Cells and Bone Microenvironment in Mouse Models.

Purpose: Radium-223 dichloride (radium-223, Xofigo), a targeted alpha therapy, is currently used for the treatment of patients with castration-resistant prostate cancer (CRPC) with bone metastases. This study examines the mode-of-action and antitumor efficacy of radium-223 in two prostate cancer xenograft models.Experimental Design: Mice bearing intratibial LNCaP or LuCaP 58 tumors were randomized into groups (n = 12-17) based on lesion grade and/or serum PSA level and administered radium-223 (300 kBq/kg) or vehicle, twice at 4-week intervals. X-rays and serum samples were obtained biweekly. Soft tissue tumors were observed macroscopically at sacrifice. Tibiae were analyzed by gamma counter, micro-CT, autoradiography and histology.Results: Radium-223 inhibited tumor-induced osteoblastic bone growth and protected normal bone architecture, leading to reduced bone volume in LNCaP and abiraterone-resistant LuCaP 58 models. Furthermore, radium-223 resulted in lower PSA values and reduced total tissue and tumor areas, indicating that treatment constrains prostate cancer growth in bone. In addition, radium-223 suppressed abnormal bone metabolic activity as evidenced by decreased number of osteoblasts and osteoclasts and reduced level of the bone formation marker PINP. Mode-of-action studies revealed that radium-223 was deposited in the intratumoral bone matrix. DNA double-strand breaks were induced in cancer cells within 24 hours after radium-223 treatment, and PSA levels were significantly lower 72 hours after treatment, providing further evidence of the antitumor effects.Conclusions: Taken together, radium-223 therapy exhibits a dual targeting mode-of-action that induces tumor cell death and suppresses tumor-induced pathologic bone formation in tumor microenvironment of osseous CRPC growth in mice. Clin Cancer Res; 23(15); 4335-46. ©2017 AACR.

Estudio de correlación entre variables clínicas y biomecánicas en pacientes con fibromialgia / Study of correlation between clinical and biomechanical variables in patients with fibromyalgia

Objetivo: Realizar un análisis biomecánico del equilibrio y la marcha en pacientes con fibromialgia para establecer una correlación con el estado funcional percibido. Material y método: Estudio transversal con 42 pacientes diagnosticados de fibromialgia (40 mujeres y 2 hombres). Se excluyeron personas con patologías concomitantes que alterasen la marcha y equilibrio. Se compararon los resultados del estado funcional medido mediante el Cuestionario de Impacto de la Fibromialgia (FIQ), con sus valoraciones biomecánicas del equilibrio medido con la aplicación NedSVE/IBV y cinética de la marcha con el sistema NedAMH/IBV. Resultados: Un 43% de los sujetos presentaba alteración en la valoración global de la prueba de Romberg Ojos Cerrados (ROC). Se encontró una correlación significativa entre el FIQ y la estabilidad medio lateral en la prueba de ROC (p=0,020). La valoración cinética de la marcha de todos los sujetos obtuvo parámetros dentro de la normalidad. No se encontraron correlaciones entre las variables del análisis cinético de la marcha y el resultado de la FIQ. Conclusión: Los hallazgos indican una buena correlación entre la FIQ con fibromialgia y su equilibrio postural medido con posturografía, pero no con los del análisis cinético de la marcha (AU)

Objective: To perform a biomechanical analysis of balance and gait in patients with fibromyalgia to establish a correlation with perceived functional status. Material and methods: A cross-sectional study of 42 patients diagnosed with fibromyalgia (40 women and 2 men). Subjects with concomitant conditions affecting balance and gait were excluded. Functional status results measured by the Fibromyalgia Impact Questionnaire (FIQ) were compared with the biomechanical assessments of balance measured with the NedSVE/IBV application and gait kinetics with the NedAMH/IBV system. Results: Forty-three percent of subjects had abnormalities on the overall assessment of the Romberg eyes closed (REC) test. A significant correlation was found between FIQ and lateral medial stability on the REC test (p=0.020). Gait kinetics assessment of all subjects obtained parameters within the normal range. No correlations were found between variables in the gait kinetics analysis and the FIQ result. Conclusion: Our findings indicate a good correlation of the FIQ with fibromyalgia and postural balance measured with posturography, but not with the results of gait kinetics analysis (AU)

Survival benefit with radium-223 dichloride in a mouse model of breast cancer bone metastasis.

BACKGROUND: Bone metastases are associated with increased morbidity and poor prognosis in breast cancer patients. Radium-223 dichloride is a calcium mimetic that localizes to bone, providing targeted therapy for skeletal metastasis. METHODS: We investigated the mode of action of radium-223 dichloride using breast cancer cell, osteoclast, and osteoblast cultures as well as a mouse model of breast cancer bone metastasis. A single dose of radium-223 dichloride was used in three different settings mimicking the prevention or treatment of bone metastasis. Disease progression was monitored using fluorescence and radiographic imaging and histological analyses. The effect of radium-223 dichloride alone and in combination with doxorubicin or zoledronic acid on survival of mice was analyzed by Kaplan-Meier methods. All statistical tests used were two-sided. RESULTS: Radium-223 dichloride incorporated into bone matrix and inhibited proliferation of breast cancer cells and differentiation of osteoblasts and osteoclasts (all P values < .001) in vitro. In an established bone metastasis setting, radium-223 dichloride prevented tumor-induced cachexia (0/14 vs 7/14 control mice) and decreased osteolysis by 56% and tumor growth by 43% (all P values < .05). Radium-223 dichloride induced double-strand DNA breaks in cancer cells in vivo. Finally, radium-223 dichloride extended survival as a monotherapy (29.2 days, 95% confidence interval [CI] = 26.6 to 31.8 days, P = .039) and in combination with zoledronic acid (31.4 days, 95% CI = 28.8 to 34.0 days, P = .004) or doxorubicin (31.5 days, 95% CI = 29.5 to 33.5 days, P < .001) compared to the vehicle group (24.9 days, 95% CI = 23.4 to 26.4 days). Similar but even more pronounced effects were observed when radium-223 dichloride was administered in a preventive or micrometastatic setting. CONCLUSIONS: Our findings strongly support the development of radium-223 dichloride for the treatment of breast cancer patients with or at high risk of developing bone metastases.

Improved statistical modeling of tumor growth and treatment effect in preclinical animal studies with highly heterogeneous responses in vivo.

PURPOSE: Preclinical tumor growth experiments often result in heterogeneous datasets that include growing, regressing, or stable growth profiles in the treatment and control groups. Such confounding intertumor variability may mask the true treatment effects especially when less aggressive treatment alternatives are being evaluated. EXPERIMENTAL DESIGN: We developed a statistical modeling approach in which the growing and poorly growing tumor categories were automatically detected by means of an expectation-maximization algorithm coupled within a mixed-effects modeling framework. The framework is implemented and distributed as an R package, which enables model estimation and statistical inference, as well as statistical power and precision analyses. RESULTS: When applied to four tumor growth experiments, the modeling framework was shown to (i) improve the detection of subtle treatment effects in the presence of high within-group tumor variability; (ii) reveal hidden tumor subgroups associated with established or novel biomarkers, such as ERß expression in a MCF-7 breast cancer model, which remained undetected with standard statistical analysis; (iii) provide guidance on the selection of sufficient sample sizes and most informative treatment periods; and (iv) offer flexibility to various cancer models, experimental designs, and treatment options. Model-based testing of treatment effect on the tumor growth rate (or slope) was shown as particularly informative in the preclinical assessment of treatment alternatives based on dietary interventions. CONCLUSIONS: In general, the modeling framework enables identification of such biologically significant differences in tumor growth profiles that would have gone undetected or had required considerably higher number of animals when using traditional statistical methods.

Coagulation factor IX mediates serotype-specific binding of species A adenoviruses to host cells.

Human species A adenoviruses (HAdVs) comprise three serotypes: HAdV-12, -18, and -31. These viruses are common pathogens and cause systemic infections that usually involve the airways and/or intestine. In immunocompromised individuals, species A adenoviruses in general, and HAdV-31 in particular, cause life-threatening infections. By combining binding and infection experiments, we demonstrate that coagulation factor IX (FIX) efficiently enhances binding and infection by HAdV-18 and HAdV-31, but not by HAdV-12, in epithelial cells originating from the airways or intestine. This is markedly different from the mechanism for HAdV-5 and other human adenoviruses, which utilize coagulation factor X (FX) for infection of host cells. Surface plasmon resonance experiments revealed that the affinity of the HAdV-31 hexon-FIX interaction is higher than that of the HAdV-5 hexon-FX interaction and that the half-lives of these interactions are profoundly different. Moreover, both HAdV-31-FIX and HAdV-5-FX complexes bind to heparan sulfate-containing glycosaminoglycans (GAGs) on target cells, but binding studies utilizing cells expressing specific GAGs and GAG-cleaving enzymes revealed differences in GAG dependence and specificity between these two complexes. These findings add to our understanding of the intricate infection pathways used by human adenoviruses, and they may contribute to better design of HAdV-based vectors for gene and cancer therapy. Furthermore, the interaction between the HAdV-31 hexon and FIX may also serve as a target for antiviral treatment.

[First record of Telenomus podisi (Ashmead) and Trissolcus urichi (Crawford) (Hymenoptera: Scelionidae) parasitizing eggs of the rice stem bug, Tibraca limbativentris (Stål) (Hemiptera: Pentatomidae), in Santa Catarina, Brazil]. / Primeiro relato de ocorrência de Telenomus podisi (Ashmead) e Trissolcus urichi (Crawford) (Hymenoptera : Scelionidae) como Parasitóides de ovos do Percevejo-do-Colmo-do-Arroz, Tibraca limbativentris (Stål) (Hemiptera: Pentatomidae), em Santa Catarina.

We report the first occurrence of Telenomus podisi (Ashmead) and Trissolcus urichi (Crawford) parasitizing eggs of the Rice Stem Bug, Tibraca limbativentris (Stål), in Santa Catarina, Brazil. These species have a high potential of parasitization, pointing them as an alternative for biological control of T. limbativentris.