Using single-species and algal communities to determine long-term adverse effects of silver nanoparticles on freshwater phytoplankton.

The physical and chemical properties of silver nanoparticles (AgNPs) have led to their increasing use in various fields such as medicine, food, and industry. Evidence has proven that AgNPs cause adverse effects in aquatic ecosystems, especially when the release of Ag is prolonged in time. Several studies have shown short-term adverse effects of AgNPs on freshwater phytoplankton, but few studies have analysed the impact of long-term exposures on these populations. Our studies were carried out to assess the effects of AgNPs on growth rate, photosynthesis activity, and reactive oxygen species (ROS) generation on the freshwater green algae Scenedesmus armatus and the cyanobacteria Microcystis aeruginosa, and additionally on microcystin (MC-LR) generation from these cyanobacteria. The tests were conducted both in single-species cultures and in phytoplanktonic communities exposed to 1 ngL-1 AgNPs for 28 days. The results showed that cell growth rate of both single-species cultures decreased significantly at the beginning and progressively reached control-like values at 28 days post-exposure. This effect was similar for the community-cultured cyanobacteria, but not for the green algae, which maintained a sustained decrease in growth rate. While gross photosynthesis (Pg) increased in both strains exposed in single cultures, dark respiration (R) and net photosynthesis (Pn) decreased in S. armatus and M. aeruginosa, respectively. These effects were mitigated when both strains were exposed under community culture conditions. Similarly, the ROS generation shown by both strains exposed in single-species cultures was mitigated when exposure occurred in community cultures. MC-LR production and release were significantly decreased in both single-species and community exposures. These results can supply helpful information to further investigate the potential risks of AgNPs and ultimately help policymakers make better-informed decisions about their utilization for environmental restoration.

Miliarial-type gout in association with chronic use of glucocorticoids.

A 59-year-old male patient with long-standing tophaceous gout (more than 30 years) characterized by polyarticular involvement and recurrent disseminated tophi formation; his past medical history is relevant for poor adherence to urate-lowering medications, as well as persistent use of self-prescribed systemic glucocorticoids. Despite achieving therapeutic goals for serum uric acid levels, new tophi formation with an intradermal location in the form of "miliarial-type gout" was documented. Due to functional limitations, the patient underwent surgical resection of the olecranon bursa. This case illustrates a widespread and recurrent tophi formation associated with long-standing gout and regular and sustained glucocorticoid use, despite an adequate disease control based on serum urate levels and involving an intradermal location of tophi presenting as "miliarial-type" lesions. In addition, the coexistence of urate and cholesterol crystal deposition disease in olecranon gouty bursitis is presented. Finally, a sonographic extended field of view of lesions distributed along the patient's extremities is presented as a novel characterization of this condition.

Adverse effects of iron-based nanoparticles on freshwater phytoplankton Scenedesmus armatus and Microcystis aeruginosa strains.

Zero-valent nano-iron particles (nZVI) are increasingly present in freshwater aquatic environments due to their numerous applications in environmental remediation. However, despite the broad benefits associated with the use and development of nZVI nanoparticles, the potential risks of introducing them into the aquatic environment need to be considered. Special attention should be focused on primary producer organisms, the basal trophic level, whose impact affects the rest of the food web. Although there are numerous acute studies on the acute effects of these nanoparticles on photosynthetic primary producers, few studies focus on long-term exposures. The present study aimed at assessing the effects of nZVI on growth rate, photosynthesis activity, and reactive oxygen activity (ROS) on the freshwater green algae Scenedesmus armatus and the cyanobacteria Microcystis aeruginosa. Moreover, microcystin production was also evaluated. These parameters were assessed on both organisms singly exposed to 72 h-effective nZVI concentration for 10% maximal response for 28 days. The results showed that the cell growth rate of S. armatus was initially significantly altered and progressively reached control-like values at 28 days post-exposure, while M. aeruginosa did not show any significant difference concerning control values at any time. In both strains dark respiration (R) increased, unlike net photosynthesis (Pn), while gross photosynthesis (Pg) only slightly increased at 7 days of exposure and then became equal to control values at 28 days of exposure. The nZVI nanoparticles generated ROS progressively during the 28 days of exposure in both strains, although their formation was significantly higher on green algae than on cyanobacteria. These data can provide additional information to further investigate the potential risks of nZVI and ultimately help decision-makers make better informed decisions regarding the use of nZVI for environmental remediation.

Identification of APOB variants in samples from the brazilian population with hypercholesterolemic phenotype

BACKGROUND AND AIMS: Apolipoprotein B plays a crucial role in regulating plasma cholesterol by mediating the interaction of low-density lipoprotein (LDL) with LDL receptors in the liver. Inherited mutations in this gene may increase the risk of developing premature atherosclerotic cardiovascular disease, especially in individuals with familial hypercholesterolemia type 2 (FH2). The aim of this study is to identify APOB variants that may indicate pathogenicity in a sample of the Brazilian population using a data bank exome sequencing study by NGS in a Brazilian population phenotypically diagnosed by clinical and laboratory profile. This finding is going to improve genetic hypercholesteremia diagnosis. METHODS: High-quality DNA samples (n»300) were sequenced using an exon-targeted gene sequencing (ETGS) strategy to identify variants in FHrelated genes. Pathogenicity classification was based on criteria established by the American College of Medical Genetics and Genomics (ACMG), also using information from ClinVar and pathogenicity scores from previous association studies. RESULTS: A total of 121 variants were identified in APOB, of which four are novel variants missense (p.Thr626Asn, p.Ile2750Thr, p.Gln2078Lys and p.Met4184Arg). After curating pathogenicity scores, variants were classified according to the ACMG criteria. Among them four as pathogenic or likely pathogenic (p.Pro2739Leu, p.His1923Arg, p.Pro994Leu and p.Pro877Leu), and 21 variants had uncertain significance. Additionally, 92 previously known variants with uncertain significance were classified as benign or likely benign. The results were submitted to Clinvar for actualization of pathogenicity. CONCLUSIONS: These results improve the molecular diagnosis associating APOB variants with the clinical phenotype of hypercholesterolemia.

Functional analysis of ldlr genetic variants identified in hypercholesterolemic patients in brazil, USING CRISPR/CAS9

BACKGROUND AND AIMS: Introduction: The familial hypercholesterolemia (FH) is one of the main causes of cardiovascular diseases, and it is mainly caused by genetic variants at the low-density lipoprotein receptor (LDLR). Although ultrasequencing technology has allowed the identification of several genetic variants, few of them was functional analyzed. The CRISPR/ Cas9 tool promotes precise genetic editing and allows the creation of experimental models, therefore contributing to the functional validation process. Aim: To use the CRISPR/Cas9 tool to perform in vitro functional analysis of LDLR variants identified in FH patients. METHODS: Two missense LDLR variants were selected within a group of variants identified in FH patients, based on in silico data, the affected protein domain and MAF. Three sgRNAs were designed for each of the variants c.551G>A and c.1118G>A, to analyze the accuracy of the sgRNAs. The sgRNAs were inserted on PX458 plasmid, cloned, purified in E. coli DH5a, and then co-transfected with the DNA template at HepG2 cells. The DNAs templates were designed to contain the selected variants. RESULTS: HepG2 cells co-transfected with PX458 constructs and DNA templates showed considerably transfection rate, being possible to visualize it at fluorescence microscopy. However, it was noted that single transfection of sgRNAs showed a higher transfection efficiency than cotransfection. CONCLUSIONS: We designed sgRNA for c.551G>A and c.1118G>A variants, being able to analyze the transfection efficiency. In further steps, we will select new sgRNAs for LDLR variants that have not been described yet, and functional analysis will be performed to determine the clinical relevance of these variants.

Pheochromocytoma: A three-decade clinical experience in a multicenter study.

OBJECTIVE: To analyze the clinical and analytical features, diagnostic tests, therapies, and outcomes of pheochromocytoma (PCC). DESIGN AND METHODS: A multicenter retrospective study in surgically treated patients with PCC followed in 3 Spanish tertiary referral hospitals. RESULTS: A total of 106 patients (61 [57.5%] women, mean age 52.3 ±â€¯14.8 years) were evaluated. At diagnosis, PCC was symptomatic in 62% and sporadic in 83%. Patients with familial PCC were significantly younger than those with sporadic disease (40.8 ±â€¯14.2 years vs 54.5 ±â€¯13.9 years, p < .001). Familial PCCs were more frequently associated with MEN2A (n = 8). Levels of 24-h urinary fractionated metanephrines were positively related to tumor size. The maximum tumor diameter was 4.3 cm (3-6 cm); 27.7% of the patients had tumors ≥6 cm. Incidental PCCs were significantly smaller than symptomatic PCCs (3.4 cm [2.4-5.0 cm] vs 5.6 cm [4.0-7.0 cm], p < .001). Scintigraphy by ¹²³I-metaiodobenzylguanidine showed a high sensitivity (81.9%). Preoperative alpha blockade with phenoxybenzamine was used in 93.6% and doxazosin in the rest. Laparoscopic surgery was used in 2/3 of the patients, with a low conversion (1.9%) to open surgery. Perioperative complications appeared in approximately 20% of patients, mainly hypertensive crisis (9.4%). Recurrent disease appeared in 10%, and malignant PCC was uncommon (6.3%). CONCLUSIONS: PCCs surgically treated in Spain are usually large, symptomatic, and sporadic tumors diagnosed around the sixth decade of life. Hereditary PCC is usually associated with MEN2A. The main type of surgical technique used is laparoscopic surgery, and the prevalence of metastatic PCC is low.

A generative co-design framework for healthcare innovation: development and application of an end-user engagement framework.

Background Continual improvements to health systems, products, and services are necessary for improvements in health. However, many of these improvements are not incorporated into everyday practice. When designing new health systems, products, and services, involving members of the healthcare community and the public with personal healthcare experience can help to make sure that improvements will be useful and relevant to others like them. Methods Together with healthcare workers and family members with healthcare experience, we developed and applied a step-by-step guide to involving those with personal experience in the design of health system improvements. Results Our guide has three phases- 'Pre-Design', 'Co-Design', and 'Post-Design'. This paper describes each of these phases and illustrates how we applied them to our own project, which is to use virtual healthcare methods to improve care for children with chronic healthcare conditions and their families. In our own work, we found that healthcare workers and family members with personal healthcare experiences were able to use their knowledge and creativity to help us imagine how to improve care for children with chronic healthcare conditions and their families. We have created action items from these family member- and healthcare worker-identified needs, which we will use to shape our virtual healthcare system. Conclusions This paper may be useful for those seeking to involve members of the healthcare community and the public in the creation of better healthcare systems, products, and services. Background Challenges with the adoption, scale, and spread of health innovations represent significant gaps in the evidence-to-practice cycle. In the health innovation design process, a lack of attention paid to the needs of end-users, and subsequent tailoring of innovations to meet these needs, is a possible reason for this deficit. In the creative field of health innovation, which includes the design of healthcare products, systems (governance and organization mechanisms), and services (delivery mechanisms), a framework for both soliciting the needs of end-users and translating these needs into the design of health innovations is needed. Methods To address this gap, our team developed and applied a seven-step methodological framework, called A Generative Co-Design Framework for Healthcare Innovation. This framework was developed by an interdisciplinary team that included patient partners. Results This manuscript contributes a framework and applied exemplar for those seeking to engage end-users in the creative process of healthcare innovation. Through the stages of 'Pre-Design', 'Co-Design', and 'Post-Design', we were able to harness the creative insights of end-users, drawing on their experiences to shape a future state of care. Using an expository example of our own work, the DigiComp Kids project, we illustrate the application of each stage of the Framework. Conclusions A Generative Co-Design Framework for Healthcare Innovation provides healthcare innovators, applied health science researchers, clinicians, and quality improvement specialists with a guide to eliciting and incorporating the viewpoints of end-users while distilling practical considerations for healthcare innovation and design.

The silent variants of pituitary tumors: demographic, radiological and molecular characteristics.

INTRODUCTION: Tumors of the anterior pituitary gland (PTs) are mostly benign tumors with a low prevalence, which has nevertheless increased with advances in brain radiology techniques. Nearly half of PTs are not associated with a clinical endocrine syndrome. These tumors have been indistinctly named non-functioning pituitary adenomas (NFPAs) or silent pituitary tumors (SPTs) and the mechanisms of silencing are not fully known. AIM: To study the frequency and characterize the silent variant of PTs in a large local series, and to assess their pituitary adenohypophyseal gene expression. METHODS: This observational, cross-sectional study was performed in a Pituitary Tumor Center of Excellence and involved 268 PTs. After identifying the different subtypes according to the immunohistochemical (IHC) expression of adenohypophyseal hormones, we studied their gene expression by RT-qPCR. RESULTS: We found that silent tumors were larger and more invasive, but not more proliferative than their functional counterparts. The RT-qPCR complements the IHC typification of PTs, reducing the proportion of null-cell subtype. Finally, some silent PT subtype variants showed lower specific adenohypophyseal hormone gene expression than their functional counterparts, which may contribute to the absence of endocrine manifestations. CONCLUSIONS: This paper highlights the importance of identifying the silent variant of the PTs subtypes. As expected, silent tumors were larger and more invasive than their functioning counterparts. However, there was no difference in the proliferation activity between them. Finally, the lower specific gene expression in the silent than in the functioning counterparts of some PTs subtypes gives insights into the silencing mechanisms of PTs.

Feocromocitoma: experiencia clínica de tres décadas en un estudio multicéntrico / Pheochromocytoma: A three-decade clinical experience in a multicenter study

Objetivo Analizar las características clínicas y analíticas, las pruebas diagnósticas, los tratamientos y los resultados del feocromocitoma (FCC). Diseño y métodos Estudio multicéntrico retrospectivo en pacientes con FCC tratados quirúrgicamente y seguidos en 3 hospitales terciarios de referencia españoles. Resultados Se analizó a un total de 106 pacientes (61 [57,5%] mujeres, edad media 52,3 ± 14,8 años). En el diagnóstico, el FCC fue sintomático en el 62% de los casos y esporádico en el 83%. Los pacientes con FCC familiar eran significativamente más jóvenes que aquellos que presentaban la enfermedad esporádica (40,8 ± 14,2 años vs. 54,5 ± 13,9 años, p < 0,001). El FCC familiar se asociaba con mayor frecuencia a la MEN2A (n = 8). Los niveles de metanefrinas en orina de 24h se relacionaron positivamente con el tamaño del tumor. El diámetro tumoral máximo fue 4,3cm (3-6cm); el 27,8% de los pacientes tenían tumores ≥ 6cm. Los FCC incidentales eran significativamente más pequeños que los FCC sintomáticos (3,4cm [2,4-5,0cm] vs. 5,6cm [4,0-7,0cm], p < 0,001). La gammagrafía con 123I-metaiodobencilguanidina mostró una alta sensibilidad (81,9%). En el 93,6% de los casos se usó el bloqueo alfa preoperatorio con fenoxibenzamina y con doxazosina en los demás casos. En 2/3 de los pacientes se empleó la cirugía laparoscópica, con una baja tasa de conversión (1,9%) a cirugía abierta. Aproximadamente en el 20% de los pacientes aparecieron complicaciones perioperatorias, principalmente crisis hipertensivas (9,4%). La enfermedad recurrente apareció en el 10% de los casos y el FCC maligno fue raro (6,3%). Conclusiones Los FCC tratados quirúrgicamente en España suelen ser tumores grandes, sintomáticos y esporádicos diagnosticados alrededor de la sexta década de vida. El FCC hereditario está generalmente asociado con MEN2A. La cirugía laparoscópica es el tipo principal de técnica quirúrgica utilizada y la prevalencia del FCC metastásico es baja (AU)

Objective To analyze the clinical and analytical features, diagnostic tests, therapies, and outcomes of pheochromocytoma (PCC). Design and methods A multicenter retrospective study in surgically treated patients with PCC followed in 3 Spanish tertiary referral hospitals. Results A total of 106 patients (61 [57.5%] women, mean age 52.3 ± 14.8 years) were evaluated. At diagnosis, PCC was symptomatic in 62% and sporadic in 83%. Patients with familial PCC were significantly younger than those with sporadic disease (40.8 ± 14.2 years vs. 54.5 ± 13.9 years, p<.001). Familial PCCs were more frequently associated with MEN2A (n=8). Levels of 24-h urinary fractionated metanephrines were positively related to tumor size. The maximum tumor diameter was 4.3cm (3-6cm); 27.7% of the patients had tumors ≥6cm. Incidental PCCs were significantly smaller than symptomatic PCCs (3.4cm [2.4-5.0cm] vs. 5.6cm [4.0-7.0cm], p<.001). Scintigraphy by 123I-metaiodobenzylguanidine showed a high sensitivity (81.9%). Preoperative alpha blockade with phenoxybenzamine was used in 93.6% and doxazosin in the rest. Laparoscopic surgery was used in 2/3 of the patients, with a low conversion (1.9%) to open surgery. Perioperative complications appeared in approximately 20% of patients, mainly hypertensive crisis (9.4%). Recurrent disease appeared in 10%, and malignant PCC was uncommon (6.3%). Conclusion PCCs surgically treated in Spain are usually large, symptomatic, and sporadic tumors diagnosed around the sixth decade of life. Hereditary PCC is usually associated with MEN2A. The main type of surgical technique used is laparoscopic surgery, and the prevalence of metastatic PCC is low (AU)

Pheochromocytoma: A three-decade clinical experience in a multicenter study. / Feocromocitoma: experiencia clínica de tres décadas en un estudio multicéntrico.

OBJECTIVE: To analyze the clinical and analytical features, diagnostic tests, therapies, and outcomes of pheochromocytoma (PCC). DESIGN AND METHODS: A multicenter retrospective study in surgically treated patients with PCC followed in 3 Spanish tertiary referral hospitals. RESULTS: A total of 106 patients (61 [57.5%] women, mean age 52.3 ± 14.8 years) were evaluated. At diagnosis, PCC was symptomatic in 62% and sporadic in 83%. Patients with familial PCC were significantly younger than those with sporadic disease (40.8 ± 14.2 years vs. 54.5 ± 13.9 years, p<.001). Familial PCCs were more frequently associated with MEN2A (n=8). Levels of 24-h urinary fractionated metanephrines were positively related to tumor size. The maximum tumor diameter was 4.3cm (3-6cm); 27.7% of the patients had tumors ≥6cm. Incidental PCCs were significantly smaller than symptomatic PCCs (3.4cm [2.4-5.0cm] vs. 5.6cm [4.0-7.0cm], p<.001). Scintigraphy by 123I-metaiodobenzylguanidine showed a high sensitivity (81.9%). Preoperative alpha blockade with phenoxybenzamine was used in 93.6% and doxazosin in the rest. Laparoscopic surgery was used in 2/3 of the patients, with a low conversion (1.9%) to open surgery. Perioperative complications appeared in approximately 20% of patients, mainly hypertensive crisis (9.4%). Recurrent disease appeared in 10%, and malignant PCC was uncommon (6.3%). CONCLUSIONS: PCCs surgically treated in Spain are usually large, symptomatic, and sporadic tumors diagnosed around the sixth decade of life. Hereditary PCC is usually associated with MEN2A. The main type of surgical technique used is laparoscopic surgery, and the prevalence of metastatic PCC is low.

En reconocimiento a la labor de los revisores. ¿Cómo podemos mejorar? / Recognizing the reviewer's contribution. How can we improve?

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Is Somatostatin Receptor and Dopamine Receptor profiling useful in the management of silent somatotroph tumors?

Silent somatotroph tumors (sSTs) are pituitary neuroendocrine tumors (PitNETs) which do not give rise to the clinical syndrome of acromegaly. Differently to their functioning counterparts, the adjuvant medical treatment with somatostatin analogues (SSAs) or dopamine receptors agonists (DAs) has been scarcely addressed in these tumors. As preliminary results of an ongoing research on silencing mechanisms involved in the pathogenesis of sSTs, we have characterized by qRT-PCR the expression of SSTRs and DRDs in a large series of 18 silent and 68 functioning STs. Although the expression of SSTR2 and SSTR5 was lower in sSTs than in functioning ones, we found a negative correlation between SSTR2 and the tumor size of the sSTs. Additionally, levels of expression of DRD2 were similar between the two subtypes suggesting a possible basis for the treatment of these tumors with SSAs and DAs.

Heavy metals immobilization capability of two iron-based nanoparticles (nZVI and Fe3O4): Soil and freshwater bioassays to assess ecotoxicological impact.

The contamination by heavy metals constitutes an environmental problem of great importance in the last decades, and demands of society for clean environments are increasingly evident. To achieve this goal, several strategies have appeared for the in situ remediation of soil contamination caused by heavy metals. This study evaluated two types of iron-based nanoparticles, zero-valent iron nanoparticles (nZVI) and Fe3O4 nanoparticles, for the effective immobilization of Furthermore, we conducted a set of ecotoxicological bioassays: Microtox® Test, Caenorhabditis elegans Test, and Phytoplankton Toxicity Tests, on selected soil and aquatic test organisms to both, i) evaluate the potential ecotoxicological risks associated with nanoparticles treatment, and ii) to define sensitive organisms to be used as suitable bioindicators of heavy metals pollution. The application of 5% nZVI significantly reduced the amount of bioavailable heavy metals, which was effective from an ecotoxicity point of view as a reduction of the toxicity of was observed. Among the bioassays used, C. elegans seems the most effective reference organism in detecting changes in the toxicity of and therefore, C. elegans was found to be a sensitive heavy metals pollution bioindicator. When the Combination index (CI) was obtained to determine combined heavy metals interactions, the results indicated that toxicity would be higher than that expected for Pb, Cd and Zn individually considered, due to the proved antagonistic interactions of those toxicants. The obtained results suggested that nZVI nanoparticles are susceptible to be used as a soil remediation strategy for heavy metal pollution, although a short reactive lifespan must be considered, and therefore its effectiveness in long periods remains to be elucidated.

Mating system and intrapopulational genetic diversity of Copernicia prunifera (Arecaceae): a native palm from Brazilian semiarid.

The aim of this study was to investigate the mating system and genetic diversity of the palm Copernicia prunifera using inter-simple sequence repeat markers. We found that the C. prunifera has multiple inflorescences with hermaphroditic flowers and pollen viability of 62%. Outcrossing rates at the population level (N = 267) produced a multilocus outcrossing rate (tm) of 0.878 and a single-locus outcrossing rate (ts) of 0.738, indicating that C. prunifera has a mixed mating system that is preferentially allogamous. The rate of mating among relatives (tm - ts) was low, indicating limited outcrossing between closely related individuals. The fixation index between seed trees (F) was negative (0.200), suggesting an absence of inbreeding, while the correlation of selfing (rs) was high (0.914). The values of the diversity indices among adults and progenies did not differ statistically (HE = 0.319 and I = 0.470; HE = 0.337 and I = 0.505, respectively). In testing for the presence of genetic bottlenecks using the infinite allele model and the stepwise mutation model, we observed a reduction in the effective population, as well as a deficit in heterozygosity (P < 0.0001). The results of this study inform management strategies for the conservation and genetic improvement of the C. prunifera palm.

Anthropization as a determinant factor in the genetic structure of Copernicia prunifera (Arecaceae).

This study uses ISSR molecular markers to characterize the demographic pattern, and spatial genetic structure (SGS) at different life stages of development (cohorts) in a natural population of Copernicia prunifera in the Rio Grande do Norte State, Brazil. All individuals were sampled and georeferenced in a 0.55-ha plot. The demographic analyses showed a clustered pattern in the first-distance classes and a random or segregated pattern at higher distance classes for all cohorts. Among the three studied life stages, juveniles showed the greatest value for Nei's genetic diversity index (HE = 0.369), while the lowest was found among reproductive adults (HE = 0.341). Greater genetic differentiation was found within life stages (98.61%) than among stages (1.39%). The total population (N = 161) showed positive and significant kinship in the first-distance class (12.3 m). The juveniles showed significant kinship up to 10.5 m. Non-reproductive adults had a positive kinship in the first-distance class (11.0 m) and a random distribution of genotypes in the remaining classes, while reproductive adults showed a random spatial distribution of genotypes. Tests for genetic bottleneck showed that the number of loci with excess observed heterozygosity was greater than expected. The SGS results reflected the restricted seed dispersion of the species, and the genetic bottleneck reflected the reduction of genotypes as a result of the anthropization of C. prunifera natural environments.

Human Menstrual Blood-Derived Mesenchymal Stem Cells as Potential Cell Carriers for Oncolytic Adenovirus.

Antitumor efficacy of systemically administered oncolytic adenoviruses (OAdv) is limited due to diverse factors such as liver sequestration, neutralizing interactions in blood, elimination by the immune system, and physical barriers in tumors. It is therefore of clinical relevance to improve OAdv bioavailability and tumor delivery. Among the variety of tumor-targeting strategies, the use of stem cells and specifically bone marrow-derived mesenchymal stem cells (BM-MSCs) is of particular interest due to their tumor tropism and immunomodulatory properties. Nonetheless, the invasive methods to obtain these cells, the low number of MSCs present in the bone marrow, and their restricted in vitro expansion represent major obstacles for their use in cancer treatments, pointing out the necessity to identify an alternative source of MSCs. Here, we have evaluated the use of menstrual blood-derived mesenchymal stem cells (MenSCs) as cell carriers for regional delivery of an OAdv in the tumor. Our results indicate that MenSCs can be isolated without invasive methods, they have an increased proliferation rate compared to BM-MSCs, and they can be efficiently infected with different serotype 5-based capsid-modified adenoviruses, leading to viral replication and release. In addition, our in vivo studies confirmed the tumor-homing properties of MenSCs after regional administration.

A multivariable prediction model for pegvisomant dosing: monotherapy and in combination with long-acting somatostatin analogues.

BACKGROUND: Effective treatment of acromegaly with pegvisomant (PEGV), a growth hormone receptor antagonist, requires an appropriate dose titration. PEGV doses vary widely among individual patients, and various covariates may affect its dosing and pharmacokinetics. OBJECTIVE: To identify predictors of the PEGV dose required to normalize insulin-like growth factor I (IGF-I) levels during PEGV monotherapy and in combination with long-acting somatostatin analogues (LA-SSAs). DESIGN: Two retrospective cohorts (Rotterdam + Liège Acromegaly Survey (LAS), total n = 188) were meta-analyzed as a form of external replication to study the predictors of PEGV dosing in addition to LA-SSA, the LAS (n = 83) was used to study the predictors of PEGV monotherapy dosing. Multivariable regression models were used to identify predictors of the PEGV dose required to normalize IGF-I levels. RESULTS: For PEGV dosing in combination with LA-SSA, IGF-I levels, weight, height and age, were associated with the PEGV normalization dosage (P ≤ 0.001, P ≤ 0.001, P = 0.028 and P = 0.047 respectively). Taken together, these characteristics predicted the PEGV normalization dose correctly in 63.3% of all patients within a range of ±60 mg/week (21.3% within a range of ±20 mg/week). For monotherapy, only weight was associated with the PEGV normalization dose (P ≤ 0.001) and predicted this dosage correctly in 77.1% of all patients within a range of ±60 mg/week (31.3% within a range of ±20 mg/week). CONCLUSION: In this study, we show that IGF-I levels, weight, height and age can contribute to define the optimal PEGV dose to normalize IGF-I levels in addition to LA-SSA. For PEGV monotherapy, only the patient's weight was associated with the IGF-I normalization PEGV dosage.