Fostamatinib effectiveness and safety for immune thrombocytopenia in clinical practice.

Fostamatinib, a recently approved syk inhibitor used in adult primary immune thrombocytopenia (ITP), has been shown to be safe and effective in this disorder. However, clinical trial results may not be similarly reproduced in clinical practice. Here 138 ITP patients (both primary and secondary) from 42 Spanish centers who had been treated with fostamatinib were evaluated prospectively and retrospectively. The median age of our cohort (55.8% women) was 66 years (interquartile range, IQR, 56-80 years). The median time since ITP diagnosis at fostamatinib initiation was 51 months (IQR, 10-166 months). The median number of therapies prior to fostamatinib initiation was 4 (IQR, 2-5), including eltrombopag (76.1%), romiplostim (57.2%) and intravenous immunoglobulins (IVIG) (44.2%). Fifty-eight patients (42.0%) had signs/symptoms of bleeding in the month prior to treatment initiation. 79.0% of patients responded to fostamatinib with 53.6% complete responses (platelet count > 100 x 109 /L). Eighty-three patients (60.1%) received fostamatinib monotherapy achieving a high response rate (85.4%). The proportion of time in response during the 27-month period examined was 83.3%. The median time to platelet response was 11 days (IQR, 7-21 days). Sixty-seven patients (48.5%) experienced adverse events, mainly grade 1-2, the commonest of which were diarrhea (n = 28) and hypertension (n = 21). One patient had deep venous thrombosis and one patient developed acute myocardial infarction. Fostamatinib was shown to be effective with good safety profile in patients with primary and secondary ITP across a wide age spectrum in this real-world study.

Colorimetric Evaluation of a Reintegration via Spectral Imaging-Case Study: Nasrid Tiling Panel from the Alhambra of Granada (Spain).

Color reintegration is a restoration treatment that involves applying paint or colored plaster to an object of cultural heritage to facilitate its perception and understanding. This study examines the impact of lighting on the visual appearance of one such restored piece: a tiled skirting panel from the Nasrid period (1238-1492), permanently on display at the Museum of the Alhambra (Spain). Spectral images in the range of 380-1080 nm were obtained using a hyperspectral image scanner. CIELAB and CIEDE2000 color coordinates at each pixel were computed assuming the CIE 1931 standard colorimetric observer and considering ten relevant illuminants proposed by the International Commission on Illumination (CIE): D65 plus nine white LEDs. Four main hues (blue, green, yellow, and black) can be distinguished in the original and reintegrated areas. For each hue, mean color difference from the mean (MCDM), CIEDE2000 average distances, volumes, and overlapping volumes were computed in the CIELAB space by comparing the original and the reintegrated zones. The study reveals noticeable average color differences between the original and reintegrated areas within tiles: 6.0 and 4.7 CIEDE2000 units for the yellow and blue tiles (with MCDM values of 3.7 and 4.5 and 5.8 and 7.2, respectively), and 16.6 and 17.8 CIEDE2000 units for the black and green tiles (with MCDM values of 13.2 and 12.2 and 10.9 and 11.3, respectively). The overlapping volume of CIELAB clouds of points corresponding to the original and reintegrated areas ranges from 35% to 50%, indicating that these areas would be perceived as different by observers with normal color vision for all four tiles. However, average color differences between the original and reintegrated areas changed with the tested illuminants by less than 2.6 CIEDE2000 units. Our current methodology provides useful quantitative results for evaluation of the color appearance of a reintegrated area under different light sources, helping curators and museum professionals to choose optimal lighting.

Optical properties of dental zirconia, bovine dentin, and enamel-dentin structures.

OBJECTIVE: To evaluate the optical properties and the relative translucency parameter of Ceramill ZI White (3Y-TZP) and Ceramill Zolid FX White (5Y-PSZ) zirconia ceramic systems and compare them with those of the bovine dentin and enamel/dentin structures. MATERIALS AND METHODS: 3Y-TZP and 5Y-PSZ zirconia ceramic systems were evaluated. A 0.5-mm-thick 3Y-TZP (3Y-NC.5), 0.5-mm-thick (5Y-NC.5), and 1.4-mm-thick (5Y-C.14) were used. A 0.5-mm-thick dentin specimens and 1.4-mm-thick enamel/dentin specimens (n = 5) were obtained from anterior bovine maxillary teeth. Scattering, absorption, transmittance, and albedo coefficient were calculated using Kubelka-Munk's model. Data were statistically analyzed using Kruskal-Wallis and Mann-Whitney tests (p < 0.001), and goodness-of-fit coefficient (GFC). Relative translucency parameter differences were evaluated using translucency thresholds. RESULTS: Reflectance, scattering, absorption, and transmittance properties were wavelength dependent. Good matches (GFC ≥ 0.999) in spectral reflectance were observed between 0.5-mm-thick dentin and 1.4-mm-thick enamel/dentin, and 3Y-NC.5 and 5Y-NC.5. Scattering was the main optical extinction process during light interaction with zirconia and dental structures, as indicated by albedo coefficient. Translucency differences were acceptable only for 3Y-NC.5 and the dentin structure, and 5Y-C.14 and the enamel/dentin structure. CONCLUSIONS: Optical properties of 3Y-TZP and 5Y-PSZ dental zirconia differed from each other and from bovine dental structures. Nevertheless, 3Y-TZP showed similar relative translucency parameter to bovine dentin. CLINICAL SIGNIFICANCE: To achieve the best esthetic results in restorative dentistry, it is crucial for clinicians to know about the optical properties of 3Y-TZP and 5Y-PSZ and to be able to compare these properties with those of dental structures.

Chroma-dependence of CIEDE2000 acceptability thresholds for dentistry.

OBJECTIVES: Determine visual 50:50% color difference acceptability thresholds (AT) for regions of the dental color space with varying chromaticity. METHODS: A 40-observer panel belonging to two different groups (dentists and laypersons) evaluated 144 dental resin composites pairs (divided in three different sets of 48 pairs according to chroma value: Low Chroma (LC), Medium Chroma (MC) and High Chroma (HC) placed 40 cm away and inside of a viewing cabinet (D65 Standard light source; diffuse/0° geometry). A Takagi-Sugeno-Kang (TSK) fuzzy approximation was used for fitting the data points and calculate the 50:50% acceptability thresholds in CIEDE2000. A paired t-test was used to evaluate the statistical significance between thresholds differences and Bonferroni correction was applied. RESULTS: The CIEDE2000 50:50% AT were ∆E00 = 2.84, ∆E00 = 2.31 and ∆E00 = 1.80 for LC, MC and HC sets of sample pairs, respectively. The 50:50% AT values were statistically significant between the different sets of sample pairs, as well as the 50:50% AT values obtained for different observer groups. CONCLUSIONS: 50:50% CIEDE2000 acceptability thresholds for dentistry are significantly different depending on the chromaticity of the samples. Observers show higher acceptability for more achromatic samples (low chroma value) than for more chromatic samples. CLINICAL SIGNIFICANCE: The difference in the AT for distinct regions of the dental color space can assist professionals as a quality control tool to assess clinical performance and interpret visual and instrumental findings in clinical dentistry, dental research, and subsequent standardization processes.

Daratumumab-based therapies in transplant-ineligible patients with untreated multiple myeloma and hepatic dysfunction: A systematic review of subgroup analyses.

INTRODUCTION: There is subgroup analysis suggesting a lack of benefit of daratumumab use in multiple myeloma (MM) and hepatic disease (HD). The objectives of this study were to conduct a systematic review and interpretation of daratumumab-based regimen efficacy in transplant-ineligible patients with untreated MM and HD. METHODS: A systematic search in Pubmed® database about randomized clinical trials (RCTs) with subgroup analysis regarding hepatic function for overall survival (OS) or progression-free survival (PFS) were developed. Two methodologies were applied. One of them considered statistical interaction, prespecification, biological support and consistency of subgroup results. Second methodology was two-part validated tool: preliminary questions to reject subset analysis without minimal relevance, and a checklist relating a recommendation for applicability in clinical practice. RESULTS: It was included three records. About first methodology, statistical interaction among subgroups was found for PFS in one RCT. Subsets were prespecified in all RCTs. Biological support of efficacy differences could be reasonable. Inconsistent results were found. Second methology directly rejected applicability of subset analysis in two records. Checklist recommended "null" application of results in the remaining RCT. CONCLUSIONS: No consistent heterogeneity for daratumumab-based regimen efficacy was observed among subgroups regarding hepatic function in transplant-ineligible patients with untreated MM. Patients with normal hepatic function and HD could benefit from these treatments.

Recent Advances in the Knowledge of the Mechanisms of Leptin Physiology and Actions in Neurological and Metabolic Pathologies.

Excess body weight is frequently associated with low-grade inflammation. Evidence indicates a relationship between obesity and cancer, as well as with other diseases, such as diabetes and non-alcoholic fatty liver disease, in which inflammation and the actions of various adipokines play a role in the pathological mechanisms involved in these disorders. Leptin is mainly produced by adipose tissue in proportion to fat stores, but it is also synthesized in other organs, where leptin receptors are expressed. This hormone performs numerous actions in the brain, mainly related to the control of energy homeostasis. It is also involved in neurogenesis and neuroprotection, and central leptin resistance is related to some neurological disorders, e.g., Parkinson's and Alzheimer's diseases. In peripheral tissues, leptin is implicated in the regulation of metabolism, as well as of bone density and muscle mass. All these actions can be affected by changes in leptin levels and the mechanisms associated with resistance to this hormone. This review will present recent advances in the molecular mechanisms of leptin action and their underlying roles in pathological situations, which may be of interest for revealing new approaches for the treatment of diseases where the actions of this adipokine might be compromised.

Changes in Lipid Metabolism Enzymes in Rat Epididymal Fat after Chronic Central Leptin Infusion Are Related to Alterations in Inflammation and Insulin Signaling.

Leptin inhibits food intake and reduces the size of body fat depots, changing adipocyte sensitivity to insulin to restrain lipid accrual. This adipokine may modulate the production of cytokines that could diminish insulin sensitivity, particularly in visceral adipose tissue. To explore this possibility, we examined the effects of chronic central administration of leptin on the expression of key markers of lipid metabolism and its possible relationship with changes in inflammatory- and insulin-signaling pathways in epididymal adipose tissue. Circulating non-esterified fatty acids and pro- and anti-inflammatory cytokines were also measured. Fifteen male rats were divided into control (C), leptin (L, icv, 12 µg/day for 14 days), and pair-fed (PF) groups. We found a decrease in the activity of glucose-6-phosphate dehydrogenase and malic enzyme in the L group, with no changes in the expression of lipogenic enzymes. A reduction in the expression of lipoprotein lipase and carnitine palmitoyl-transferase-1A, together with a decrease in the phosphorylation of insulin-signaling targets and a low-grade inflammatory pattern, were detected in the epididymal fat of L rats. In conclusion, the decrease in insulin sensitivity and increased pro-inflammatory environment could regulate lipid metabolism, reducing epididymal fat stores in response to central leptin infusion.

Color stability and degree of conversion of gingiva-colored resin-based composites.

OBJECTIVES: To evaluate gingiva-colored resin-based composites' (GCRBC) color stability and degree of conversion (DC%). METHODS: Eight discs (8 × 1 mm) of 20 shades of GCRBC were prepared. Color coordinates were measured against a gray background with a calibrated spectroradiometer, CIE D65 illuminant and the CIE 45°/0° geometry at baseline and after 30 days of storage in distilled water, coffee, and red wine. Color differences ( ∆ E 00 ) between final and baseline conditions were calculated. An ATR-FTIR spectrometer with a diamond tip was used to calculate DC%. The results were analyzed statistically using ANOVA and Tukey post-hoc test. The level of significance was p < 0.05. RESULTS: DC% and color stability correlated with each other and with the GCRBC brand. DC% ranged between 43% and 96%, highest values correspond to flowable composites. All composites have experienced color changes after immersion in water, wine and coffee. However, the magnitude of the color change has varied widely depending on the immersion medium and the GCRBC. Color changes generated by the wine were, globally, greater than those induced by coffee (p < 0.001) and above the acceptability thresholds. CONCLUSIONS: The DC% of GCRBCs is sufficient to achieve adequate biocompatibility and physicomechanical properties, but the high susceptibility to staining could compromise aesthetic long-term results. CLINICAL SIGNIFICANCE: The degree of conversion and the color stability of gingiva-colored resin-based composites correlated with each other. All composites have experienced color changes after immersion in water, wine and coffee. Color changes generated by wine were, globally, greater than those induced by coffee and above the acceptability thresholds that could compromise aesthetic long-term results.

Clinical and pharmacoeconomic impact of subgroup analysis in onco-hematological patients.

Subgroup analysis evaluates a health intervention in subpopulations according to a characteristic or factor. It can be useful for generating new hypotheses or conducting new studies. However, subgroup analysis presents several limitations and it should be considered cautiously. The development of new onco-hematological drugs is accelerating in recent years and the impact of subgroup analysis on clinical decision-making is increasing. The interpretation of subgroup analyses can be controversial in some cases, negatively affecting patients and healthcare systems. This work is a review of the clinical and pharmacoeconomic impact of subgroup analysis in onco-hematological patients. The study describes some illustrative examples of inadequate interpretations about subset analysis: combination of pembrolizumab plus chemotherapy in lung cancer, inhibitors of cyclin-dependent kinases in breast cancer, daratumumab-based regimens in newly diagnosed multiple myeloma, combination of nivolumab with ipilimumab in melanoma and docetaxel in prostate cancer. Subgroup analysis can have a significant impact on the data selection for the development of studies; efficacy, safety, and convenience of treatments in onco-hematological patients; efficiency of therapies in health systems; and therapeutic positioning of antineoplastic drugs. There is a strong need to establish homogeneous criteria for the assessment of subgroup analysis and to develop new tools for its consideration.

Belantamab mafodotin for relapsed or refractory multiple myeloma.

Objective: Refractory multiple myeloma (MM) presents poor responses to therapies. New drugs for highly pretreated MM are a hope for this clinical context with limited treatment options. We developed a comparative commentary on the evidence about the use of belantamab mafodotin in heavily pretreated relapsed or refractory MM with respect to other therapies. Data sources: Regimen data were extracted from pivotal clinical trials. Data summary: Response rates were the main efficacy outcomes reported in trials. Overall response was achieved by approximately 30% of patients trated with belantamab mafodotin. Response rates of different regimens must be supported by more relevant data, such as overall survival or progression-free survival. Subgroups of patients with extramedullary disease and revised International Staging System III should be thoroughly evaluated in phase III comparative clinical trials with larger sample sizes. Belantamab mafodotin presented specific adverse events (visual disturbances and kerathopathies). Grade 3-4 adverse events involved high percentages of patients treated with the different schemes. The budgetary impact of different treatments for heavily pretreated refractory MM would be very high. Literature suggested increased efficiency of belantamab mafodotin versus chimeric antigen receptor T-cell therapies. Conclusions: Belantamab mafodotin and other regimens are promising drugs for MM, especially for triple-class refractory patients. Comparative studies are necessary to perform a reliable therapeutic positioning.

Visual and instrumental coverage error of two dental shade guides: an in vivo study.

OBJECTIVES: This study aims to evaluate in vivo the color agreement between natural teeth and dental shade guides by means of visual and instrumental coverage error ([Formula: see text]) index. MATERIALS AND METHODS: The color of the middle third of 735 incisors was visually determined by two evaluators using the Vita Classical (VC) and Vita 3D Master (V3DM) shade guides. The color match between the natural tooth and the shade tab was rated as poor (P), good (G), or optimum (O) by each observer. CIE color coordinates of the target teeth and shade tabs of VC and V3DM were instrumentally measured using a clinical spectrophotometer. Visual ([Formula: see text]) and instrumental ([Formula: see text]) coverage error indexes were computed using CIELAB and CIEDE2000 metrics for both shade guides. For [Formula: see text] calculation, only the concordant inter-observer determination on tooth shade rated as O-O or O-G was used. The results were evaluated using perceptibility (PT, [Formula: see text]= 1.2, [Formula: see text]= 0.8) and acceptability (AT, [Formula: see text]= 2.7, [Formula: see text]= 1.8) color thresholds for dentistry. RESULTS: VC and V3DM exhibited [Formula: see text] (2.5, 3.2, and 3.2, 2.7 CIELAB units; 1.9, 2.3, and 2.8, 2.4 CIEDE2000 units, respectively, for O-O and O-G match) and [Formula: see text] (4.7, 4.8, and 4.1, 4.6 CIELAB units; 3.3, 3.4, and 3.4, 3.6 CIEDE2000 units, respectively, for O-O and O-G match) values greater than 50:50% AT for both color difference formulas. [Formula: see text] contributes more than 50% (53.2-82.4% range) to the [Formula: see text] value. This contribution depends on the shade guide used and the quality of the visual rating. CONCLUSIONS: The evaluated shade guides exhibited visual coverage errors above acceptability thresholds, largely due to the contribution of the instrumental coverage error to the visual coverage error. CLINICAL RELEVANCE: It necessary to further improve commercially available dental shade guides to facilitate achievement of satisfactory esthetics results in clinical practice.

Magnetic resonance imaging-guided stereotactic body radiotherapy for prostate cancer (mirage): a phase iii randomized trial.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is becoming increasingly used in treating localized prostate cancer (PCa), with evidence showing similar toxicity and efficacy profiles when compared with longer courses of definitive radiation. Magnetic resonance imaging (MRI)-guided radiotherapy has multiple potential advantages over standard computed tomography (CT)-guided radiotherapy, including enhanced prostate visualization (abrogating the need for fiducials and MRI fusion), enhanced identification of the urethra, the ability to track the prostate in real-time, and the capacity to perform online adaptive planning. However, it is unknown whether these potential advantages translate into improved outcomes. This phase III randomized superiority trial is designed to prospectively evaluate whether toxicity is lower after MRI-guided versus CT-guided SBRT. METHODS: Three hundred men with localized PCa will be randomized in a 1:1 ratio to SBRT using CT or MRI guidance. Randomization will be stratified by baseline International Prostate Symptom Score (IPSS) (≤15 or > 15) and prostate gland volume (≤50 cc or > 50 cc). Five fractions of 8 Gy will be delivered to the prostate over the course of fourteen days, with or without hormonal therapy and elective nodal radiotherapy (to a dose of 5 Gy per fraction) as per the investigator's discretion. The primary endpoint is the incidence of physician-reported acute grade ≥ 2 genitourinary (GU) toxicity (during the first 90 days after SBRT), as assessed by the CTCAE version 4.03 scale. Secondary clinical endpoints include incidence of acute grade ≥ 2 gastrointestinal (GI) toxicity, 5-year cumulative incidences of physician-reported late grade ≥ 2 GU and GI toxicity, temporal changes in patient-reported quality of life (QOL) outcomes, 5-year biochemical recurrence-free survival and the proportion of fractions of MRI-guided SBRT in which online adaptive radiotherapy is used. DISCUSSION: The MIRAGE trial is the first randomized trial comparing MRI-guided with standard CT-guided SBRT for localized PCa. The primary hypothesis is that MRI-guided SBRT will lead to an improvement in the cumulative incidence of acute grade ≥ 2 GU toxicity when compared to CT-guided SBRT. The pragmatic superiority design focused on an acute toxicity endpoint will allow an early comparison of the two technologies. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04384770. Date of registration: May 12, 2020. https://clinicaltrials.gov/ct2/show/NCT04384770 PROTOCOL VERSION: Version 2.1, Aug 28, 2020.

The PI-3-Kinase P110α Catalytic Subunit of T Lymphocytes Modulates Collagen-Induced Arthritis.

The phosphatidylinositol 3-kinase (PI3K) family of enzymes plays a determinant role in inflammation and autoimmune responses. However, the implication of the different isoforms of catalytic subunits in these processes is not clear. Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory disease that entails innate and adaptive immune response elements in which PI3K is a potential hub for immune modulation. In a mouse transgenic model with T-cell-specific deletion of p110α catalytic chain (p110α-/-ΔT), we show the modulation of collagen-induced arthritis (CIA) by this isoform of PI3K. In established arthritis, p110α-/-ΔT mice show decreased prevalence of illness than their control siblings, higher IgG1 titers and lower levels of IL-6 in serum, together with decreased ex vivo Collagen II (CII)-induced proliferation, IL-17A secretion and proportion of naive T cells in the lymph nodes. In a pre-arthritis phase, at 13 days post-Ag, T-cell-specific deletion of p110α chain induced an increased, less pathogenic IgG1/IgG2a antibodies ratio; changes in the fraction of naive and effector CD4+ subpopulations; and an increased number of CXCR5+ T cells in the draining lymph nodes of the p110α-/-ΔT mice. Strikingly, T-cell blasts in vitro obtained from non-immunized p110α-/-ΔT mice showed an increased expression of CXCR5, CD44 and ICOS surface markers and defective ICOS-induced signaling towards Akt phosphorylation. These results, plus the accumulation of cells in the lymph nodes in the early phase of the process, could explain the diminished illness incidence and prevalence in the p110α-/-ΔT mice and suggests a modulation of CIA by the p110α catalytic chain of PI3K, opening new avenues of intervention in T-cell-directed therapies to autoimmune diseases.

PI3-Kinase p110α Deficiency Modulates T Cell Homeostasis and Function and Attenuates Experimental Allergic Encephalitis in Mature Mice.

Class I phosphoinositide 3-kinases (PI3K) are involved in the development of normal and autoimmune responses, including Experimental Autoimmune Encephalomyelitis (EAE), a mouse model for human multiple sclerosis (MS). Here, the role of the ubiquitously expressed class IA PI3K p110α catalytic subunits in EAE has been analyzed using a model of Cre/flox mediated T cell specific deletion of p110α catalytic chain (p110αΔT). Comparison of two month-old (young) and six month-old (mature) p110αΔT mice and their wild type (WT) counterparts indicated loss of spleen CD4+ T cells that increased with age, indicating a role of p110α in their homeostasis. In contrast, CD4+ T regulatory (Treg) cells were enhanced in mature p110αΔT mice when compared to WT mice. Since Myelin Oligodendrocyte Glycoprotein (MOG) peptide-induced EAE is dependent on, or mediated by CD4+ T cells and CD4+ T cell-derived cytokines and controlled by Treg cells, development of EAE in young and mature WT or p110αΔT mice was analyzed. EAE clinical symptoms and disease scores in six month p110αΔT mice were significantly lower than those of mature WT, or young WT and p110αΔT mice. Furthermore, ex vivo antigen activation of lymph node cells from MOG immunized mature p110αΔT mice induced significantly lower levels of IFN-γ and IL-17A than young p110αΔT or young and mature WT mice. Other cytokines including IL-2, IL-10 or TNF-α showed no significant differences between p110αΔT and WT mature mice. Our data show a lower incidence of MOG-induced EAE in mature p110αΔT mice linked to altered T cell homeostasis and lower secretion of inflammatory cytokines.

An Immunological Approach to the Biocompatibility of Mesoporous SiO2-CaO Nanospheres.

Mesoporous bioactive glass nanospheres (NanoMBGs) have high potential for clinical applications. However, the impact of these nanoparticles on the immune system needs to be addressed. In this study, the biocompatibility of SiO2-CaO NanoMBGs was evaluated on different mouse immune cells, including spleen cells subsets, bone marrow-derived dendritic cells (BMDCs), or cell lines like SR.D10 Th2 CD4+ lymphocytes and DC2.4 dendritic cells. Flow cytometry and confocal microscopy show that the nanoparticles were rapidly and efficiently taken up in vitro by T and B lymphocytes or by specialized antigen-presenting cells (APCs) like dendritic cells (DCs). Nanoparticles were not cytotoxic and had no effect on cell viability or proliferation under T-cell (anti-CD3) or B cell (LPS) stimuli. Besides, NanoMBGs did not affect the balance of spleen cell subsets, or the production of intracellular or secreted pro- and anti-inflammatory cytokines (TNF-α, IFN-γ, IL-2, IL-6, IL-10) by activated T, B, and dendritic cells (DC), as determined by flow cytometry and ELISA. T cell activation surface markers (CD25, CD69 and Induced Costimulator, ICOS) were not altered by NanoMBGs. Maturation of BMDCs or DC2.4 cells in vitro was not altered by NanoMBGs, as shown by expression of Major Histocompatibility Complex (MHC) and costimulatory molecules (CD40, CD80, CD86), or IL-6 secretion. The effect of wortmannin and chlorpromazine indicate a role for phosphoinositide 3-kinase (PI3K), actin and clathrin-dependent pathways in NanoMBG internalization. We thus demonstrate that these NanoMBGs are both non-toxic and non-inflammagenic for murine lymphoid cells and myeloid DCs despite their efficient intake by the cells.

Systematic Review of Gender Bias in the Clinical Trials of New Long-Acting Antipsychotic Drugs.

PURPOSE/BACKGROUND: This article evaluates gender bias in the published clinical trials of new long-acting antipsychotics. METHODS/PROCEDURES: We conducted a review of controlled clinical trials of the new prolonged-release antipsychotics (aripiprazole, risperidone, or paliperidone) for the treatment of schizophrenia published in MEDLINE over the last 10 years and available in full text in English. The study followed the corresponding international recommendations. RESULTS: We identified 132 trials, and of these, 40 met the inclusion and exclusion criteria. We found that only 36.41% of the total patients were women. The separate analysis of the main variable between the subpopulations of men and women was carried out in only 6 of the 40 works included. In contrast, in 15 trials, this analysis was performed on secondary variables, generally related to safety. Only 3 of the 40 trials discussed the results separately according to sex. CONCLUSIONS: The clinical trials of long-acting atypical antipsychotic drugs show a far-from-negligible gender bias. Women are underrepresented, and the main and secondary variables are not analyzed separately according to gender. This is despite international recommendations establishing these criteria as part of a package of minimum requirements for meeting scientific validity and making results apt to extrapolate to the general population of patients.

Morbid obesity-related changes in the expression of lipid receptors, transporters, and HSL in human sperm.

OBJECTIVE: To study the location and expression of receptors (SR-BI/CLA-1, SR-BII, and LDLr) and transporter (ABCA1) involved in uptake and efflux of cholesterol in human spermatozoa and assess whether obesity alters its location/expression and whether this could be related to infertility. DESIGN: Observational study. SETTING: None PATIENT(S): Ten controls and 20 obese patients. INTERVENTION(S): Anthropometric parameters. Serum and semen samples were collected. MAIN OUTCOME MEASURE(S): Spermatozoon concentration, immunolocalization, and protein expression in semen. RESULTS: Spermatozoon concentration and motility was decreased in morbidly obese patients. SR-BI/CLA-1, SR-BII, LDLr, and ABCA1 are located in the spermatozoon cell membrane and the localization does not change between obese patients and controls. Control spermatozoa showed high SR-BI expression, and less expression for the rest of the receptors analyzed, indicating that SR-BI/CLA-1 is relevant in human spermatozoon cholesterol uptake/efflux. On the contrary, spermatozoa of obese patients showed less SR-BI/CLA-1 expression than controls, and more intense positive staining for SR-BII, LDLr, and ABCA1. Finally, human sperm expresses the 130- and 82-kDa hormone-sensitive lipase (HSL) isoforms. The 130-kDa isoform is expressed in the control sperm, and the expression disappears in the obese patients. CONCLUSION(S): The presence of lipid receptors/transporters and HSL in human spermatozoa suggests their role in the process of maturation/capacitation. The changes in the expression of lipid receptors/transporters and the lack of the 130-kDa HSL isoform in obese patients prevent the hydrolysis of cholesterol esters internalized by these receptors, and favor their accumulation in the cytoplasm of the spermatozoa that could contribute to lipotoxicity and infertility.

Ellagic acid protects from myelin-associated sphingolipid loss in experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE), the most common model for multiple sclerosis, is characterized by inflammatory cell infiltration into the central nervous system and demyelination. Previous studies have demonstrated that administration of some polyphenols may reduce the neurological alterations of EAE. In this work, we show that ellagic acid, a polyphenolic compound, is beneficial in EAE, most likely through stimulation of ceramide biosynthesis within the brain. EAE was induced in Lewis rats by injection of guinea-pig spinal cord tissue along with Freund's complete adjuvant containing Mycobacterium tuberculosis. Clinical signs first appeared at day 8 post-immunization and reached a peak within 3 days, coincident with reduction of myelin basic protein (MBP) in the cortex. Sphingolipids, the other major components of myelin, also decreased at the acute phase of EAE, both in the cerebral cortex and in the spinal cord. In rats receiving ellagic acid in the drinking water from 2 days before immunization, the onset of the disease was delayed and clinical signs were reduced. This amelioration of clinical signs was accompanied by sustained levels of both MBP and sphingolipid in the cortex, without apparent changes in infiltration of inflammatory CD3+ T-cells, microglial activation, or weight loss, which together suggest a neuroprotective effect of ellagic acid. Finally, in glioma and oligodendroglioma cells we demonstrate that urolithins, the ellagic acid metabolites that circulate in plasma, stimulate the synthesis of ceramide. Together these data suggest that ellagic acid consumption protects against demyelination in rats with induced EAE, likely by a mechanism involving sphingolipid synthesis.

Combination of melatonin and rapamycin for head and neck cancer therapy: Suppression of AKT/mTOR pathway activation, and activation of mitophagy and apoptosis via mitochondrial function regulation.

Head and neck squamous cell carcinoma (HNSCC) clearly involves activation of the Akt mammalian target of rapamycin (mTOR) signalling pathway. However, the effectiveness of treatment with the mTOR inhibitor rapamycin is often limited by chemoresistance. Melatonin suppresses neoplastic growth via different mechanisms in a variety of tumours. In this study, we aimed to elucidate the effects of melatonin on rapamycin-induced HNSCC cell death and to identify potential cross-talk pathways. We analysed the dose-dependent effects of melatonin in rapamycin-treated HNSCC cell lines (Cal-27 and SCC-9). These cells were treated with 0.1, 0.5 or 1 mmol/L melatonin combined with 20 nM rapamycin. We further examined the potential synergistic effects of melatonin with rapamycin in Cal-27 xenograft mice. Relationships between inhibition of the mTOR pathway, reactive oxygen species (ROS), and apoptosis and mitophagy reportedly increased the cytotoxic effects of rapamycin in HNSCC. Our results demonstrated that combined treatment with rapamycin and melatonin blocked the negative feedback loop from the specific downstream effector of mTOR activation S6K1 to Akt signalling, which decreased cell viability, proliferation and clonogenic capacity. Interestingly, combined treatment with rapamycin and melatonin-induced changes in mitochondrial function, which were associated with increased ROS production, increasing apoptosis and mitophagy. This led to increase cell death and cellular differentiation. Our data further indicated that melatonin administration reduced rapamycin-associated toxicity to healthy cells. Overall, our findings suggested that melatonin could be used as an adjuvant agent with rapamycin, improving effectiveness while minimizing its side effects.

Melatonin, clock genes and mitochondria in sepsis.

After the characterization of the central pacemaker in the suprachiasmatic nucleus, the expression of clock genes was identified in several peripheral tissues including the immune system. The hierarchical control from the central clock to peripheral clocks extends to other functions including endocrine, metabolic, immune, and mitochondrial responses. Increasing evidence links the disruption of the clock genes expression with multiple diseases and aging. Chronodisruption is associated with alterations of the immune system, immunosenescence, impairment of energy metabolism, and reduction of pineal and extrapineal melatonin production. Regarding sepsis, a condition coursing with an exaggerated response of innate immunity, experimental and clinical data showed an alteration of circadian rhythms that reflects the loss of the normal oscillation of the clock. Moreover, recent data point to that some mediators of the immune system affects the normal function of the clock. Under specific conditions, this control disappears reactivating the immune response. So, it seems that clock gene disruption favors the innate immune response, which in turn induces the expression of proinflammatory mediators, causing a further alteration of the clock. Here, the clock control of the mitochondrial function turns off, leading to a bioenergetic decay and formation of reactive oxygen species that, in turn, activate the inflammasome. This arm of the innate immunity is responsible for the huge increase of interleukin-1ß and entrance into a vicious cycle that could lead to the death of the patient. The broken clock is recovered by melatonin administration, that is accompanied by the normalization of the innate immunity and mitochondrial homeostasis. Thus, this review emphasizes the connection between clock genes, innate immunity and mitochondria in health and sepsis, and the role of melatonin to maintain clock homeostasis.