Qualitative Alterations Research Articles

Differential diagnosis of cacosmia and dysgeusia in COVID-19 pandemic. Clinical case report

Olfactory and gustatory dysfunctions were presented in a high percentage of COVID-19 cases. Most of them are represented by quantitative disorders. Qualitative alterations were established in a small proportion. During the Covid-19 pandemic, there is a need to make a differential diagnosis (DD) of olfactory and gustatory disorders. Clinical case of a 64-year-old man presented with dairy food cacosmia and dysgeusia for the last two weeks, and night sweats. From medical history we found that our patient recovered from COVID-19 infection, one month ago. Based on some studies, patients with COVID-19 infection, presented moderate to severe olfactory or gustatory dysfunctions for long-term, in convalescent period. It’s important to make a DD of smell and taste impairements and choose the necessary treatment. Esophageal candidiasis was diagnosed in our patient. After 21 days of antifungal treatment cacosmia and dysgeusia disappeared. HIV test was negative. Some studies presented that COVID-19 infection is linked with a continuous reduction in lymphocytes along the disease. We hypothesized that immunodeficiency in COVID-19 infection and antibiotic therapy could be the trigger for esophageal candidiasis in our case. Our case report highlighted the importance of smell and taste disorders DD, in COVID-19 pandemic. Dairy food cacosmia and dysgeusia can be a sign of esophageal candidiasis. That's why, convalescent COVID-19 infection patients should be monitored for a long-term period.

Assessment of the Anti-Cancer Efficiency of Silver Moringa oleifera Leaves Nano-extract against Colon Cancer Induced Chemically in Rats.

Background:Colorectal cancer (CRC) categorized as the most common type of gastrointestinal cancers affected both genders equally. Chemotherapeutic drugs became limited due to their deleterious side effects. Therefore, efficiency of M. oleifera leaves extract increased by incorporating silver nanoparticles (Ag-NPs) then studied against colon cancer induced by azoxymethane (AOM) in rats. Methods:Different hematological and biochemical measurements in addition to specific tumor and inflammatory markers were quantified. Histopathological examination for Colonic tissues was performed. Native proteins and isoenzyme patterns were electrophoretically detected in addition to assaying expression of Tumor Protein P53 (TP53) and Adenomatous Polyposis Coli (APC) genes in colonic tissues.Results: M. oleifera nano-extract restored levels of the hematological and biochemical measurements in addition to levels of tumor and inflammatory markers to normalcy in both of nano-extract simult- and post-treated groups. Also, it minimized severity of the histopathological alterations in the simult-treated group and prevented it completely in the post-treated group. The lowest similarity index (SI%) values were noticed with electrophoretic protein (SI=61.54%), lipid (SI=0.00%) and calcium (SI=75.00%) moieties of protein patterns, catalase (SI=85.71%), peroxidase (SI=85.71%), α-esterase (SI=50.00%) and β-esterase (SI=50.00%) isoenzymes in addition to altering the relative quantities of total protein and isoenzyme bands in colon of cancer induced group. Moreover, levels of TP53 and APC gene expression increased significantly (P≤0.05) in colon cancer induced group. The nano-extract prevented the qualitative and quantitative alterations in the different electrophoretic patterns in addition to restoring levels of the gene expressions to normalcy in both of simult- and post-treated groups. Conclusion: M. oleifera nano-extract exhibited ameliorative effect against the biochemical, physiological and molecular alterations induced by AOM in nano-extract simult- and post-treated groups.

Morphological and mechanical changes induced by quercetin in human T24 bladder cancer cells

Quercetin is a flavonoid found in a great variety of foods such as vegetables and fruits. This compound has been shown to inhibit the proliferation of various types of cancer cells, as well as the growth of tumors in animal models. In the present study, we analyze morphological and mechanical changes produced by quercetin in T24 bladder cancer cells. Decreased cell viability and cell number were observed following quercetin treatment at 40 μM and 60 μM, respectively, as observed by the MTT assay and trypan blue exclusion test, supporting the hypothesis of quercetin anticancer effect. These assays also allowed us to determine the 40, 60, and 80 μM quercetin concentrations for the following analyses, Lactate Dehydrogenase assay (LDH); Nuclear Morphometric Analysis (NMA); and atomic force microscopy (AFM). The LDH assay showed no cytotoxic effect of quercetin on T24 cancer cells. The AFM showed morphological changes following quercetin treatment, namely decreased cell body, cytoplasmic retraction, and membrane condensation. Following quercetin treatment, the NMA evidenced an increased percentage of nuclei characteristic to the apoptotic and senescence processes. Cells also presented biophysical alterations consistent with cell death by apoptosis, as increased roughness and aggregation of membrane proteins, in a dose-dependent manner. Cellular elasticity, obtained through force curves, showed increased stiffness after quercetin treatment. Data presented herein demonstrate, for the first time, in a quantitative and qualitative form, the morphological and mechanical alterations induced by quercetin on bladder cancer cells.

Compositional distinction of gut microbiota between Han Chinese and Tibetan populations with liver cirrhosis

BackgroundLiver cirrhosis (LC) is caused by numerous chronic liver diseases and its complications are associated with qualitative and quantitative alterations of the gut microbiota. Previous studies have revealed the characteristics of gut microbiota in Han Chinese patients with LC and different compositions of gut microbiota were reported between the Tibetan and Han Chinese populations. This study was designed to evaluate the unique features of the gut microbiota of Tibetans and compare the differences of gut microbiota between Tibetan and Han Chinese patients with LC.MethodsThirty-six patients with liver cirrhosis and nineteen healthy volunteers, from both Tibetan and Han Chinese populations, were enrolled and fecal samples were collected for 16S rRNA gene sequencing analyses.ResultsSignificant differences were found in the gut microbiota of healthy volunteers and between Tibetan and Han Chinese patients with LC. In the Han Chinese patients with cirrhosis (HLC) group the relative abundances of the phylum Bacteroidetes was significantly reduced (P < 0.001), whereas in the Tibetan patients with cirrhosis (TLC) group Firmicutes and Actinobacteria were highly enriched (P = 0.01 and 0.03, respectively). At the genus level, the relative abundances of Anaerostipes (P < 0.001), Bifidobacterium (P = 0.03), and Blautia (P = 0.004) were prevalent, while Alloprevotella, Dorea, Prevotella_2, Prevotella_7 and Prevotella_9 were decreased in the TLC group compared to the HLC group (P < 0.01).ConclusionOur findings showed how the intestinal bacterial community shifted in Tibetan patients with cirrhosis.

Reflexing Suspicious β-Region Findings on Capillary Serum Protein Electrophoresis to Immunofixation or Immunosubtraction for Detecting Monoclonal Proteins.

Monoclonal immunoglobulins (M-proteins) that migrate in the β region on serum protein electrophoresis (SPEP) are often cloaked by this region's normal constituents. The present study interrogates the utility of using both quantitative and qualitative alterations in β-region bands for detection of β-migrating M-proteins. Consecutive SPEP cases analyzed by capillary electrophoresis were searched to identify the initial workup on 1,841 patients with increased total β regions, suspicious β-region findings resulting in reflex immunofixation (IFE), or immunosubtraction (ISUB). To augment quantitative information, separate β1 and β2 measurements were established and retrospectively used to evaluate their sensitivity for M-protein detection. We identified M-proteins in 205 (11.1%) cases, including immunoglobulin A (IgA) (54%), IgG (24%), IgM (13%), and free light chain (9%) isotypes. Of the 15 cases flagged by separate β1 and β2 measurements that were not identified by total β-region measurement, 1 progressed to myeloma. Of the 56 β-migrating M-proteins identified by qualitative features but without increase in any of the β-region measurements, 1 progressed to myeloma. A combination of separate measurements for β1 and β2 regions together with detection of β-region distortions increase sensitivity for identifying β-migrating M-proteins via reflex IFE or ISUB.

Novel nanomedicines to overcome cancer multidrug resistance.

Chemotherapy remains a powerful tool to eliminate malignant cells. However, the efficacy of chemotherapy is compromised by the frequent emergence of intrinsic and acquired multidrug resistance (MDR). These chemoresistance modalities are based on a multiplicity of molecular mechanisms of drug resistance, including : 1) Impaired drug uptake into cancer cells; 2) Increased expression of ATP-binding cassette efflux transporters; 3) Loss of function of pro-apoptotic factors; 4) Enhanced DNA repair capacity; 5) Qualitative or quantitative alterations of specific cellular targets; 6) Alterations that allow cancer cells to tolerate adverse or stressful conditions; 7) Increased biotransformation or metabolism of anticancer drugs to less active or completely inactive metabolites; and 8) Intracellular and intercellular drug sequestration in well-defined organelles away from the cellular target. Hence, one of the major aims of cancer research is to develop novel strategies to overcome cancer drug resistance. Over the last decades, nanomedicine, which focuses on targeted delivery of therapeutic drugs into tumor tissues using nano-sized formulations, has emerged as a promising tool for cancer treatment. Therefore, nanomedicine has been introduced as a reliable approach to improve treatment efficacy and minimize detrimental adverse effects as well as overcome cancer drug resistance. With rationally designed strategies including passively targeted delivery, actively targeted delivery, delivery of multidrug combinations, as well as multimodal combination therapy, nanomedicine paves the way towards efficacious cancer treatment and hold great promise in overcoming cancer drug resistance. Herein, we review the recent progress of nanomaterials used in medicine, including liposomal nanoparticles, polymeric nanoparticles, inorganic nanoparticles and hybrid nanoparticles, to surmount cancer multidrug resistance. Finally, the future perspectives of the application of nanomedicine to reverse cancer drug resistance will be addressed.

Emerging Complexity in CD4+T Lineage Programming and Its Implications in Colorectal Cancer

The intestinal immune system has the difficult task of protecting a large environmentally exposed single layer of epithelium from pathogens without allowing inappropriate inflammatory responses. Unmitigated inflammation drives multiple pathologies, including the development of colorectal cancer. CD4+T cells mediate both the suppression and promotion of intestinal inflammation. They comprise an array of phenotypically and functionally distinct subsets tailored to a specific inflammatory context. This diversity of form and function is relevant to a broad array of pathologic and physiologic processes. The heterogeneity underlying both effector and regulatory T helper cell responses to colorectal cancer, and its impact on disease progression, is reviewed herein. Importantly, T cell responses are dynamic; they exhibit both quantitative and qualitative changes as the inflammatory context shifts. Recent evidence outlines the role of CD4+T cells in colorectal cancer responses and suggests possible mechanisms driving qualitative alterations in anti-cancer immune responses. The heterogeneity of T cells in colorectal cancer, as well as the manner and mechanism by which they change, offer an abundance of opportunities for more specific, and likely effective, interventional strategies.

Quantitative and qualitative alterations of plasma clusterin, paraoxonase 1, myeloperoxidase and HDL’s apolipoproteins are aggravated by hyperglycemia in peripheral artery disease patients with diabetes

Background and Aims: Peripheral artery disease (PAD), the atherosclerotic disorder that affects arteries of the lower limbs, has increasing incidence worldwide, the major risk factors being dyslipidemia and diabetes mellitus (DM). Some of the key players in the atheroma formation are dysfunctional high-density lipoproteins (HDL), whose components that contribute to PAD evolution are less known. We aimed to identify alterations of HDL constituents which associate with PAD aggravation.

Dissection of pleiotropic effects of variants in and adjacent to F8 exon 19 and rescue of mRNA splicing and protein function

The pathogenic significance of nucleotide variants commonly relies on nucleotide position within the gene, with exonic changes generally attributed to quantitative or qualitative alteration of protein biosynthesis, secretion, activity, or clearance. However, these changes may exert pleiotropic effects on both protein biology and mRNA splicing due to the overlapping of the amino acid and splicing codes, thus shaping the disease phenotypes. Here, we focused on hemophilia A, in which the definition of F8 variants' causative role and association to bleeding phenotypes is crucial for proper classification, genetic counseling, and management of affected individuals. We extensively characterized a large panel of hemophilia A-causing variants (n = 30) within F8 exon 19 by combining and comparing in silico and recombinant expression analyses. We identified exonic variants with pleiotropic effects and dissected the altered protein features of all missense changes. Importantly, results from multiple prediction algorithms provided qualitative results, while recombinant assays allowed us to correctly infer the likely phenotype severity for 90% of variants. Molecular characterization of pathogenic variants was also instrumental for the development of tailored correction approaches to rescue splicing affecting variants or missense changes impairing protein folding. A single engineered U1snRNA rescued mRNA splicing of nine different variants and the use of a chaperone-like drug resulted in improved factor VIII protein secretion for four missense variants. Overall, dissection of the molecular mechanisms of a large panel of HA variants allowed precise classification of HA-affected individuals and favored the development of personalized therapeutic approaches.

Communication and social interaction in the cannabinoid-type 1 receptor null mouse: Implications for autism spectrum disorder.

Clinical and preclinical findings have suggested a role of the endocannabinoid system (ECS) in the etiopathology of autism spectrum disorder (ASD). Previous mouse studies have investigated the role of ECS in several behavioral domains; however, none of them has performed an extensive assessment of social and communication behaviors, that is, the main core features of ASD. This study employed a mouse line lacking the primary endocannabinoid receptor (CB1r) and characterized ultrasonic communication and social interaction in CB1-/- , CB1+/- , and CB1+/+ males and females. Quantitative and qualitative alterations in ultrasonic vocalizations (USVs) were observed in CB1 null mice both during early development (i.e., between postnatal days 4 and 10), and at adulthood (i.e., at 3months of age). Adult mutants also showed marked deficits in social interest in the three-chamber test and social investigation in the direct social interaction test. These behavioral alterations were mostly observed in both sexes and appeared more marked in CB1-/- than CB1+/- mutant mice. Importantly, the adult USV alterations could not be attributed to differences in anxiety or sensorimotor abilities, as assessed by the elevated plus maze and auditory startle tests. Our findings demonstrate the role of CB1r in social communication and behavior, supporting the use of the CB1 full knockout mouse in preclinical research on these ASD-relevant core domains. LAY SUMMARY: The endocannabinoid system (ECS) is important for brain development and neural function and is therefore likely to be involved in neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). Here we investigated changes in social behavior and communication, which are core features of ASD, in male and female mice lacking the chief receptor of this system. Our results show that loss of this receptor results in several changes in social behavior and communication both during early development and in adulthood, thus supporting the role of the ECS in these ASD-core behavioral domains.

A note on psychological continuity theories of identity and neurointerventions

An important concern sometimes voiced in the neuroethical literature is that swift and radical changes to the parts of a person’s mental life essential for sustaining his/her numerical identity can...

Characteristics of 809 Patients with Essential Thrombocythemia in Real-World Clinical Practice: A Chart Review Study in the United States

Background: Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by elevated platelet counts and proliferation of mature megakaryocytes in the bone marrow. The quantitative and qualitative platelet alterations in ET may lead to increased risks of thrombosis and bleeding. Risk factors for thrombotic complications include age >60 years, prior history of venous or arterial thrombosis, JAK2 V617F mutation, and cardiovascular risk factors. The current management of ET with cytoreductive therapy is largely directed at lowering the risk of thrombotic complications. This study aimed to characterize patients with ET treated with cytoreductive therapy in real-world clinical practice.Methods: Data were extracted from medical charts of patients with ET who were managed with cytoreductive therapy between June 1, 2011, and September 15, 2016, at participating community oncology/hematology clinics. Physician and patient characteristics, medical history, diagnostic tests and results, and signs and symptoms at ET diagnosis were reported descriptively.Results: 50 hematologists and oncologists participated in the study. The participating physicians had a mean (SD) of 17.5 (7.3) years of practice, and treated a mean (SD) of 31.6 (22.4) patients with ET in the past 5 years. A total of 809 patients with ET who received cytoreductive therapy from the 50 hematologists and oncologists were included. Patients were predominantly white (75.4%) with a mean (SD) age of 68.7 (11.5) years, and 48.9% were male. The majority (81.1%) of patients were referred to the participating physicians. Physicians reported that 64.5% of patients were diagnosed using World Health Organization criteria. However, less than half (48.8%) of patients had undergone a bone marrow biopsy at the time of diagnosis. Overall, 708 (87.5%) patients underwent JAK2 mutation testing; among these patients, 512 (72.3%) were positive. Physicians also noted JAK2 exon 12 mutation testing in 24 (3.0%) patients, however, none were positive. Reflex CALR and MPL molecular testing was conducted in 26.3% of patients, with 7.0% and 4.6% positive, respectively. Per physician assessment, 41.7%, and 42.5% were low and high risk, respectively; risk category was unknown in 15.8% of patients. At diagnosis, 11.4% and 19.5% of patients had a history of arterial thrombosis and venous thrombosis, respectively, and 64.4% of patients had ≥1 cardiovascular risk factor (arterial hypertension, 28.2%; smoking, 26.9%; hypercholesterolemia, 26.5%; overweight, 23.6%; diabetes, 15.3%). The most common ET signs and symptoms were fatigue (53.2%), headache (20.4%), and splenomegaly (15.1%); 90.3% of patients had platelet counts ≥600 × 109/L and 55.9% had white blood cell counts ≥10 × 109/L. For their first-line cytoreductive therapy, 755 patients (93.3%) received hydroxyurea (HU), 30 (3.7%) anagrelide, 10 (1.2%) ruxolitinib, 10 (1.2%) pegylated interferon or interferon alfa, and 4 (0.5%) other.Conclusions: Patients with ET receiving cytoreductive therapy had substantial clinical burden of disease (eg, symptoms, elevated blood counts) at the time of diagnosis. Furthermore, a large proportion of these patients were at high risk of a thrombotic event because of age ≥60 years, prior thrombosis, ≥1 risk factor for cardiovascular event, or having a JAK2 mutation. DisclosuresYu:Incyte Corporation: Employment, Equity Ownership. Colucci:Incyte Corporation: Employment, Equity Ownership. Paranagama:Incyte Corporation: Employment, Equity Ownership. Sivaraman:Incyte Corporation: Employment, Equity Ownership. Atanasov:Incyte Corporation: Consultancy. Hanna:Incyte Corporation: Consultancy. Tang:Incyte Corporation: Consultancy. Parasuraman:Incyte Corporation: Employment, Equity Ownership.

Activity-mediated accumulation of potassium induces a switch in firing pattern and neuronal excitability type.

During normal neuronal activity, ionic concentration gradients across a neuron's membrane are often assumed to be stable. Prolonged spiking activity, however, can reduce transmembrane gradients and affect voltage dynamics. Based on mathematical modeling, we investigated the impact of neuronal activity on ionic concentrations and, consequently, the dynamics of action potential generation. We find that intense spiking activity on the order of a second suffices to induce changes in ionic reversal potentials and to consistently induce a switch from a regular to an intermittent firing mode. This transition is caused by a qualitative alteration in the system's voltage dynamics, mathematically corresponding to a co-dimension-two bifurcation from a saddle-node on invariant cycle (SNIC) to a homoclinic orbit bifurcation (HOM). Our electrophysiological recordings in mouse cortical pyramidal neurons confirm the changes in action potential dynamics predicted by the models: (i) activity-dependent increases in intracellular sodium concentration directly reduce action potential amplitudes, an effect typically attributed solely to sodium channel inactivation; (ii) extracellular potassium accumulation switches action potential generation from tonic firing to intermittently interrupted output. Thus, individual neurons may respond very differently to the same input stimuli, depending on their recent patterns of activity and/or the current brain-state.

Spontaneous and Successful Pregnancies After Premature Ovarian Insufficiency: Case Series

Premature ovarian insufficiency (POI) formerly referred to as premature menopause, premature ovarian failure or primary ovarian failure (POF) implies quantitative and qualitative alterations in the functional integrity of the ovarian follicles leading to irregularity of menses, clinical manifestations of signs and symptoms of menopause and impaired fertility performance. This phenomenon tends to occur in about 1% of the women population in their reproductive years and arbitrarily below the age of 40 years. We hereby present case series of seven subjects who were specifically complaining of infertility or low fertility from a total of 242 women with presumed diagnosis of premature ovarian insufficiency. These were extracted from a pool of 10,090 clients that were documented over a year’s period i.e. from January 1, 2020 up to December 31, 2020. Our patients achieved spontaneous pregnancies and underwent a normal course of the pregnancies that culminated in uneventful childbirths. The deliveries invariably took place in private setups. We maintained a close contact telemetrically and physically; and followed them up during their course of the delivery and the postpartum period since they were denoted as very high risk pregnancy. To the best of our knowledge, there is no isolated similar case report or publication in the Ethiopian setting. The objective of the case series presentation is linked with the intention of adding to the world literature highlighting its relevance, desire to create more awareness and establish the basis for further inspiration to develop future undertakings in the understanding of diminished ovarian reserve vis-a-vis premature ovarian insufficiency and spontaneous pregnancy

Cold atmospheric plasma coupled with air abrasion in liquid medium for the treatment of peri-implantitis model grown with a complex human biofilm: an in vitro study

ObjectiveTreatment of implants with peri-implantitis is often unsuccessful due to residual microbial biofilm hindering re-osseointegration. The aim of this study was to treat biofilm-grown titanium (Ti) implants with different modalities involving air abrasion (AA) and cold atmospheric plasma (CAP) to compare the effectiveness in surface decontamination and the alteration/preservation of surface topography.Materials and methodsSaliva collected from a peri-implantitis patient was used to in vitro develop human biofilm over 35 implants with moderately rough surface. The implants were then mounted onto standardized acrylic blocks simulating peri-implantitis defects and treated with AA (erythritol powder), CAP in a liquid medium, or a combination (COM) of both modalities. The remaining biofilm was measured by crystal violet (CV). Surface features and roughness before and after treatment were assessed by scanning electron microscope (SEM). The data were statistically analyzed using Kruskal-Wallis followed by Tukey’s multiple comparison test.ResultsIn the present peri-implantitis model, the human complex biofilm growth was successful as indicated by the statistical significance between the negative and positive controls. All the treatment groups resulted in a remarkable implant surface decontamination, with values very close to the negative control for AA and COM. Indeed, statistically significant differences in the comparison between the positive control vs. all the treatment groups were found. SEM analysis showed no post-treatment alterations on the implant surface in all the groups.ConclusionsDecontamination with AA delivering erythritol with or without CAP in liquid medium demonstrated compelling efficacy in the removal of biofilm from implants. All the tested treatments did not cause qualitative alterations to the Ti surface features. No specific effects of the CAP were observed, although further studies are necessary to assess its potential as monotherapy with different settings or in combination with other decontamination procedures.Clinical relevanceCAP is a promising option in the treatment of peri-implantitis because it has potential to improve the elimination of bacterial plaque from implant surfaces, in inaccessible pockets or during open-flap debridement, and should stimulate the process of the re-osseointegration of affected dental implants by not altering surface features and roughness.

Prevalence of dry eyes in patients with type 2 diabetes mellitus having meibomian gland dysfunction

Purpose: The purpose of this study was to know the prevalence of dry eyes in patients with Type 2 Diabetes mellitus having meibomian gland dysfunction. Materials and Methods: The study was conducted in patients visiting tertiary care hospital. This study included a total of 200 patients presenting with ocular discomfort, with history of Type 2 Diabetes mellitus. The patients were assessed for Meibomian gland dysfunction by noting the symptoms under slit lamp examination. Dry eyes were suspected on the basis of history including ocular discomfort, redness, blurred vision, gritty eyes and other sensation that improved with blinking. The examination for the dry eye was done using schirmer’s test and tear break up time. Results: A total of 130 out of 200 enrolled patients had meibomian gland dysfunction. The most common symptom being dryness(55%), foreign body sensation(30%), redness(10%), gritty sensation(5%). Conclusion: The above study shows that the incidence of dry eyes is more in patients with Type 2 diabetes mellitus having Meibomian gland dysfunction. Meibomian glands are important contributors for maintenance of healthy ocular surface. Meibomian gland dysfunction can cause qualitative and quantitative alteration in meibum with negative impact on the ocular surface. Keywords: Dry eye, Meibomian gland dysfunction.

Nutritional Regulation of Mammary Gland Development and Milk Synthesis in Animal Models and Dairy Species.

In mammals, milk is essential for the growth, development, and health. Milk quantity and quality are dependent on mammary development, strongly influenced by nutrition. This review provides an overview of the data on nutritional regulations of mammary development and gene expression involved in milk component synthesis. Mammary development is described related to rodents, rabbits, and pigs, common models in mammary biology. Molecular mechanisms of the nutritional regulation of milk synthesis are reported in ruminants regarding the importance of ruminant milk in human health. The effects of dietary quantitative and qualitative alterations are described considering the dietary composition and in regard to the periods of nutritional susceptibly. During lactation, the effects of lipid supplementation and feed restriction or deprivation are discussed regarding gene expression involved in milk biosynthesis, in ruminants. Moreover, nutrigenomic studies underline the role of the mammary structure and the potential influence of microRNAs. Knowledge from three lactating and three dairy livestock species contribute to understanding the variety of phenotypes reported in this review and highlight (1) the importance of critical physiological stages, such as puberty gestation and early lactation and (2) the relative importance of the various nutrients besides the total energetic value and their interaction.

Effect of Tocilizumab on LDL and HDL Characteristics in Patients with Rheumatoid Arthritis. An Observational Study.

BackgroundIn patients with rheumatoid arthritis (RA), qualitative alterations of low and high-density lipoproteins (LDL and HDL, respectively) might partially explain their increased cardiovascular risk. Tocilizumab has been associated with an increase in lipids, including triglyceride (TG) and cholesterol levels. The aim of this study is to evaluate the effect of tocilizumab on certain LDL and HDL characteristics (oxidized LDL levels, HDL-associated enzymes, chemical composition of both total HDL and HDL3c subpopulation, and their capacity to promote cellular cholesterol efflux) at baseline and 3 months after the start of treatment in patients with RA.MethodsTwenty-eight RA patients (ACR/EULAR 2010 criteria) with indication of treatment with tocilizumab were included in the present study. Clinical assessment [Health assessment questionnaire (HAQ)], disease activity score 28 (DAS28), high-sensitivity C reactive protein (hsCRP) concentration, lipid profile, and lipoprotein (a) [Lp(a)] levels were evaluated in all patients at baseline and after 3 months of treatment with tocilizumab. Lipoprotein characteristics were evaluated through the levels of oxidized LDL (OxLDL), the activity of paraoxonase (PON) 1, the composition of total HDL and small, dense HDL3c subpopulation, and their ability to promote cellular cholesterol efflux.ResultsAfter 3 months of treatment with tocilizumab, HAQ (− 23%, p < 0.05), DAS28 (− 49%, p < 0.001), and hsCRP (− 94%, p < 0.01) levels decreased significantly. Total cholesterol (TC), LDL-C, non-HDL-C, and apo B levels showed a significant increase after treatment (TC: + 7.0%, p < 0.01; LDL-C: + 10%, p < 0.01; non-HDL-C: + 9.9%, p < 0.01; and apo B: + 9.6%, p < 0.05). Decreases in Lp(a) and OxLDL levels were also observed after treatment [Lp(a): − 50%, p < 0.01; and oxLDL: − 5.4%, p < 0.05]. The latter was in accordance with the increment detected in PON activity. No changes were observed in HDL capacity to promote cholesterol efflux (p > 0.05) in the whole group.ConclusionsTreatment with tocilizumab reduced hsCRP levels and displayed positive effects on certain lipoprotein-related parameters, such as a potent decrease inLp(a) and a reduction in OxLDL levels. Moreover, HDL capacity to promote cellular cholesterol efflux was maintained after 3 months of treatment.

Allosteric Kinase Inhibitors Reshape MEK1 Kinase Activity Conformations in Cells and In Silico.

Mutations at different stages of the mitogen-activated protein kinase (MAPK) signaling pathway lead to aberrant activation of the involved protein kinase entities. These oncogenic modifications alter signal propagation which converge on the gatekeeper kinases MEK1/2, transmitting the input signal to ERK1/2. Thus, targeted MEK inhibition causes qualitative alterations of carcinogenic MAPK signals. Phosphorylation of the MEK1 activation loop at the positions S218 and S222 by RAF kinases triggers the conformational alignment of MEK’s catalytic pocket to enable ATP-binding and substrate phosphorylation. We have extended a kinase conformation (KinCon) biosensor platform to record MEK1 activity dynamics. In addition to MEK phosphorylation by BRAF, the integration of the phosphorylation-mimetic mutations S218D/S222D triggered opening of the kinase. Structural rearrangement may involve the flexibility of the N terminal MEK1 A-helix. Application of the allosterically acting MEK inhibitors (MEKi) trametinib, cobimentinib, refametinib, and selumetinib converted activated MEK1 KinCon reporters back into a more closed inactive conformation. We confirmed MEK1 KinCon activity dynamics upon drug engagement using the patient-derived melanoma cell line A2058, which harbors the V600E hotspot BRAF mutation. In order to confirm biosensor dynamics, we simulated structure dynamics of MEK1 kinase in the presence and absence of mutations and/or MEKi binding. We observed increased dynamics for the S218D/S222D double mutant particularly in the region of the distal A-helix and alpha-C helix. These data underline that MEK1 KinCon biosensors have the potential to be subjected to MEKi efficacy validations in an intact cell setting.

Obesity-Associated Inflammation: Does Curcumin Exert a Beneficial Role?

Curcumin is a lipophilic polyphenol, isolated from the plant turmeric of Curcuma longa. Curcuma longa has always been used in traditional medicine in Asian countries because it is believed to have numerous health benefits. Nowadays it is widely used as spice component and in emerging nutraceutical food worldwide. Numerous studies have shown that curcumin possesses, among others, potential anti-inflammatory properties. Obesity represents a main risk factor for several chronic diseases, including type 2 diabetes, cardiovascular disease, and some types of cancer. The establishment of a low-grade chronic inflammation, both systemically and locally in adipose tissue, occurring in obesity most likely represents a main factor in the pathogenesis of chronic diseases. The molecular mechanisms responsible for the onset of the obesity-associated inflammation are different from those involved in the classic inflammatory response caused by infections and involves different signaling pathways. The inflammatory process in obese people is triggered by an inadequate intake of nutrients that produces quantitative and qualitative alterations of adipose tissue lipid content, as well as of various molecules that act as endogenous ligands to activate immune cells. In particular, dysfunctional adipocytes secrete inflammatory cytokines and chemokines, the adipocytokines, able to recruit immune cells into adipose tissue, amplifying the inflammatory response also at systemic level. This review summarizes the most recent studies focused at elucidating the molecular targets of curcumin activity responsible for its anti-inflammatory properties in obesity-associated inflammation and related pathologies.