Elastin recoil is driven by the hydrophobic effect.

Elastin is an extracellular matrix material found in all vertebrates. Its reversible elasticity, robustness, and low stiffness are essential for the function of arteries, lungs, and skin. It is among the most resilient elastic materials known: During a human lifetime, arterial elastin undergoes in excess of 2 × 109 stretching/contracting cycles without replacement, and slow oxidative hardening has been identified as a limiting factor on human lifespan. For over 50 y, the mechanism of entropic recoil has been controversial. Herein, we report a combined NMR and thermomechanical study that establishes the hydrophobic effect as the primary driver of elastin function. Water ordering at the solvent:protein interface was observed as a function of stretch using double quantum 2H NMR, and the most extensive thermodynamic analysis performed to date was obtained by measuring elastin length and volume as a function of force and temperature in normal water, heavy water and with cosolvents. When stretched, elastin's heat capacity increases, water is ordered proportional to the degree of stretching, the internal energy decreases, and heat is released in excess of the work performed. These properties show that recoil in elastin under physiological conditions is primarily driven by the hydrophobic effect rather than by configurational entropy as is the case for rubber. Consistent with this conclusion are decreases in the thermodynamic signatures when cosolvents that alter the hydrophobic effect are introduced. We propose that hydrophobic effect-driven recoil, as opposed to a configurational entropy mechanism where hardening from crystallization can occur, is the origin of elastin's unusual resilience.

Charting the Evolution of Chemoenzymatic Strategies in the Syntheses of Complex Natural Products.

Bolstered by recent advances in bioinformatics, genetics, and enzyme engineering, the field of chemoenzymatic synthesis has enjoyed a rapid increase in popularity and utility. This Perspective explores the integration of enzymes into multistep chemical syntheses, highlighting the unique potential of biocatalytic transformations to streamline the synthesis of complex natural products. In particular, we identify four primary conceptual approaches to chemoenzymatic synthesis and illustrate each with a number of landmark case studies. Future opportunities and challenges are also discussed.

Undiagnosed and missed active pulmonary tuberculosis during mass gatherings: a prospective cross-sectional study from the Hajj pilgrimage.

Mass gatherings increase the risk of infectious diseases transmission including tuberculosis (TB). The Hajj pilgrimage to Mecca, Saudi Arabia, is attended by over 2 million pilgrims many of whom are from high TB-burden countries, and has been linked to increased risk of TB acquisition among travellers. We investigated the burden of undiagnosed and missed active pulmonary TB (PTB) among Hajj pilgrims symptomatic for cough. The study was conducted among hospitalised and non-hospitalised travellers attending the Hajj pilgrimage in 2016 and 2017. Questionnaires were used to collect relevant data and sputum samples were collected from participants and processed using the Xpert MTB-RIF assay. Non-hospitalised pilgrims (n = 1510) originating from 16 high and medium TB-burden countries were enrolled. Undiagnosed, rifampicin-sensitive, active PTB was identified in 0.7%. Comorbidities (adjOR = 5.9 [95% CI = 1.2-27.8]), close contact with a TB case (adjOR = 5.9 [95% CI = 1.2-27.8]), cough in household (adjOR = 4.46 [95% CI = 1.1-19.5]), and previous TB treatment (adjOR = 10.1 [95% CI = 4.1-98.1]) were independent risk factors for TB. Of the hospitalised pilgrims (n = 304), 2.9% were positive for PTB, and 2.3% were missed, including a rifampicin-resistant case. History of TB treatment was associated with increased risk of TB (adjOR = 8.1 [95% CI = 1.3-48.7]). International mass gatherings may play an important role in the global epidemiology of TB. Preventive measures should be directed to reducing the risk of TB importation and transmission during Hajj and other similar events.

Transferrin-Targeted Liposomes in Glioblastoma Therapy: A Review.

Glioblastoma (GBM) is a highly aggressive brain tumor, and its treatment is further complicated by the high selectivity of the blood-brain barrier (BBB). The scientific community is urgently seeking innovative and effective therapeutic solutions. Liposomes are a promising new tool that has shown potential in addressing the limitations of chemotherapy, such as poor bioavailability and toxicity to healthy cells. However, passive targeting strategies based solely on the physicochemical properties of liposomes have proven ineffective due to a lack of tissue specificity. Accordingly, the upregulation of transferrin receptors (TfRs) in brain tissue has led to the development of TfR-targeted anticancer therapeutics. Currently, one of the most widely adopted methods for improving drug delivery in the treatment of GBM and other neurological disorders is the utilization of active targeting strategies that specifically target this receptor. In this review, we discuss the role of Tf-conjugated liposomes in GBM therapy and present some recent studies investigating the drug delivery efficiency of Tf-liposomes; in addition, we address some challenges currently facing this approach to treatment and present some potential improvement possibilities.

Co-Delivery of Ylang Ylang Oil of Cananga odorata and Oxaliplatin Using Intelligent pH-Sensitive Lipid-Based Nanovesicles for the Effective Treatment of Triple-Negative Breast Cancer.

Smart pH-responsive niosomes loaded with either Oxaliplatin (Ox), Ylang ylang essential oil (Y-oil), or co-loaded with both compounds (Ox-Y) (Ox@NSs, Y@NSs, and Ox-Y@NSs, respectively) were formulated utilizing the thin film method. The developed nanocontainers had a spherical morphology with mean particle sizes lower than 170 nm and showed negative surface charges, high entrapment efficiencies, and a pH-dependent release over 24 h. The prepared pH-responsive niosomes' cytotoxicity was tested against the invasive triple-negative breast cancer (MDA-MB-231) cells, compared to free OX and Y-oil. All niosomal formulations loaded with Ox and/or Y-oil significantly improved cytotoxic activity relative to their free counterparts. The Ox-Y@NSs demonstrated the lowest IC50 (0.0002 µg/mL) when compared to Ox@NSs (0.006 µg/mL) and Y@NSs (18.39 µg/mL) or unloaded Ox (0.05 µg/mL) and Y-oil (29.01 µg/mL). In addition, the percentages of the MDA-MB-231 cell population in the late apoptotic and necrotic quartiles were profoundly higher in cells treated with the smart Ox-Y@NSs (8.38% and 5.06%) than those exposed to free Ox (7.33% and 1.93%) or Y-oil (2.3% and 2.13%) treatments. Gene expression analysis and protein assays were performed to provide extra elucidation regarding the molecular mechanism by which the prepared pH-sensitive niosomes induce apoptosis. Ox-Y@NSs significantly induced the gene expression of the apoptotic markers Tp53, Bax, and Caspase-7, while downregulating the antiapoptotic Bcl2. As such, Ox-Y@NSs are shown to activate the intrinsic pathway of apoptosis. Moreover, the protein assay ascertained the apoptotic effects of Ox-Y@NSs, generating a 4-fold increase in the relative protein quantity of the late apoptotic marker Caspase-7. Our findings suggest that combining natural essential oil with synthetic platinum-based drugs in pH-responsive nanovesicles is a promising approach to breast cancer therapy.

CTP-based estimated ischemic core: A comparative multicenter study between Olea and RAPID software.

BACKGROUND AND PURPOSE: CTP is increasingly used to assess eligibility for endovascular therapy (EVT) in patients with large vessel occlusions (LVO). There remain variability and inconsistencies between software packages for estimation of ischemic core. We aimed to use heterogenous data from four stroke centers to perform a comparative analysis for CTP-estimated ischemic core between RAPID (iSchemaView) and Olea (Olea Medical). METHODS: In this retrospective multicenter study, patients with anterior circulation LVO who underwent pretreatment CTP, successful EVT (defined TICI ≥ 2b), and follow-up MRI included. Automated CTP analysis was performed using Olea platform [rCBF < 25% and differential time-to-peak (dTTP)>5s] and RAPID (rCBF < 30%). The CTP estimated core volumes were compared against the final infarct volume (FIV) on post treatment MRI-DWI. RESULTS: A total of 151 patients included. The CTP-estimated ischemic core volumes (mean ± SD) were 18.7 ± 18.9 mL on Olea and 10.5 ± 17.9 mL on RAPID significantly different (p < 0.01). The correlation between CTP estimated core and MRI final infarct volume was r = 0.38, p < 0.01 for RAPID and r = 0.39, p < 0.01 for Olea. Both software platforms demonstrated a strong correlation with each other (r = 0.864, p < 0.001). Both software overestimated the ischemic core volume above 70 mL in 4 patients (2.6%). CONCLUSIONS: Substantial variation between Olea and RAPID CTP-estimated core volumes exists, though rates of overcalling of large core were low and identical. Both showed comparable core volume correlation to MRI infarct volume.

Truths and myths about superfoods in the era of the COVID-19 pandemic.

Nowadays, during the current COVID-19 pandemic, consumers increasingly seek foods that not only fulfill the basic need (i.e., satisfying hunger) but also enhance human health and well-being. As a result, more attention has been given to some kinds of foods, termed "superfoods," making big claims about their richness in valuable nutrients and bioactive compounds as well as their capability to prevent illness, reinforcing the human immune system, and improve overall health.This review is an attempt to uncover truths and myths about superfoods by giving examples of the most popular foods (e.g., berries, pomegranates, watermelon, olive, green tea, several seeds and nuts, honey, salmon, and camel milk, among many others) that are commonly reported as having unique nutritional, nutraceutical, and functional characteristics.While superfoods have become a popular buzzword in blog articles and social media posts, scientific publications are still relatively marginal. The reviewed findings show that COVID-19 has become a significant driver for superfoods consumption. Food Industry 4.0 innovations have revolutionized many sectors of food technologies, including the manufacturing of functional foods, offering new opportunities to improve the sensory and nutritional quality of such foods. Although many food products have been considered superfoods and intensively sought by consumers, scientific evidence for their beneficial effectiveness and their "superpower" are yet to be provided. Therefore, more research and collaboration between researchers, industry, consumers, and policymakers are still needed to differentiate facts from marketing gimmicks and promote human health and nutrition.

Enhancing Atorvastatin In Vivo Oral Bioavailability in the Presence of Inflammatory Bowel Disease and Irritable Bowel Syndrome Using Supercritical Fluid Technology Guided by wbPBPK Modeling in Rat and Human.

Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are common disorders that can change the body's physiology and drugs pharmacokinetics. Solid dispersion (SD) preparation using supercritical fluid technology (SFT) has many advantages. Our study aimed to explore the effect of IBS and IBD on atorvastatin (ATV) pharmacokinetics, enhance ATV oral bioavailability (BCS II drug) using SFT, and analyze drug-disease-formulation interaction using a whole-body physiologically based pharmacokinetic (wbPBPK) model in rat and human. A novel ATV formulation was prepared using SFT and characterized in vitro and in vivo in healthy, IBS, and IBD rats. The resulting ATV plasma levels were analyzed using a combination of conventional and wbPBPK approaches. The novel formulation increased ATV solubility by 20-fold and resulted in a zero-order release of up to 95%. Both IBS and IBD increased ATV exposure after oral and intravenous administration by more than 30%. The novel SFT formulation increased ATV bioavailability by 28, 14, and 18% in control, IBD, and IBD rat groups and resulted in more consistent exposure as compared to raw ATV solution. Higher improvements in ATV bioavailability of more than 2-fold upon receiving the novel SFT formulation were predicted by the human wbPBPK model as compared to receiving the conventional tablets. Finally, the established wbPBPK model could describe ATV ADME in the presence of IBS and IBD after oral administration of raw ATV and using the novel SFT formula and can help scale the optimized ATV dosing regimens in the presence of IBS and IBD from rats to humans.

Epidemiology of Facial Profiles, Occlusal Features, and Orthodontic Treatment Need among Adolescence: A Cross-sectional Study.

AIMS: This study aimed to investigate the incidence and severity of malocclusion and orthodontic treatment needs among randomly selected high school students. METHODS: A multistage stratified random-sampling study was conducted on 1,036 high school students in Sana'a city. The World Dental Federation and World Health Organization method of occlusal traits and the index of orthodontic treatment need were adopted for measurements. Clinically, the molar relationship and facial profile were examined. Assessment of whether examiner or subject perceived the need for orthodontic treatment was made using the esthetic component index. All data were analyzed using the Chi-square test with a significance level of p <0.05. RESULTS: Normal, convex, and concave facial-profile measurements were found in 81.9, 12.1, and 6.15% of sampled students, respectively. Asymmetrical molar relationship was observed in 16.1% of samples, and most of them were of class I/class II relationships. Increased overjet was noticed in 90.9% of students. Anterior crossbite, deepbite, anterior openbite, posterior openbite, posterior crossbite, and scissor bite accounted for 12.2, 12.8, 3.5, 1.3, 6.6, and 0.6%, respectively. According to the index orthodontic treatment need, 38.9% of students needed some form of orthodontic treatment. Among these cases, 24.3% "definitely" needed treatment, and 59.9% of students needed orthodontic treatment. CONCLUSION: Our findings suggested a call for a more conservative treatment approach in dealing with malocclusion problems among high school students in all zones of Sana'a governorate, Yemen. CLINICAL SIGNIFICANCE: A limited number of surveys were performed in Sana'a Governorate to investigate orthodontic treatment needs, facial profiles, and occlusal features among adolescents. The results of this study could guide us to develop a preventive system that minimizes its adverse effects and the need for costly orthodontic treatments.

Dynamics in natural and designed elastins and their relation to elastic fiber structure and recoil.

Elastin fibers assemble in the extracellular matrix from the precursor protein tropoelastin and provide the flexibility and spontaneous recoil required for arterial function. Unlike many proteins, a structure-function mechanism for elastin has been elusive. We have performed detailed NMR relaxation studies of the dynamics of the minielastins 24x' and 20x' using solution NMR, and of purified bovine elastin fibers in the presence and absence of mechanical stress using solid state NMR. The low sequence complexity of the minielastins enables us to determine average dynamical timescales and degrees of local ordering in the cross-link and hydrophobic modules separately using NMR relaxation by taking advantage of their residue-specific resolution. We find an extremely high degree of disorder, with order parameters for the entirety of the hydrophobic domains near zero, resembling that of simple chemical polymers and less than the order parameters that have been observed in other intrinsically disordered proteins. We find that average backbone order parameters in natural, purified elastin fibers are comparable to those found in 24x' and 20x' in solution. The difference in dynamics, compared with the minielastins, is that backbone correlation times are significantly slowed in purified elastin. Moreover, when elastin is mechanically stretched, the high chain disorder in purified elastin is retained, showing that any change in local ordering is below that detectable in our experiment. Combined with our previous finding of a 10-fold increase in the ordering of water when fully hydrated elastin fibers are stretched by 50%, these results support the hypothesis that stretch induced solvent ordering, i.e., the hydrophobic effect, is a key player in the elastic recoil of elastin as opposed to configurational entropy loss.

Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia.

Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0-49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2-5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1-46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an 'AP-4 deficiency syndrome'. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.

Exploring the role of social support and social media for lifestyle interventions to prevent weight gain with young adults: Focus group findings.

BACKGROUND: Young adults gain more weight annually than other adults and may be destined for future obesity. Effective interventions are needed, and social support may be a key element for success. The present study explores how best to leverage social media to support young adults with their health goals in a healthy lifestyle programme. METHOD: Young adults aged 18-25 years were recruited from the community to a series of four focus groups led by an experienced facilitator who used a discussion guide developed a priori. The discussion explored their opinions regarding which social media platforms were appropriate for providing social support, the types of support that were relevant (family and friends versus strangers) and factors that would encourage peer-to-peer communication in a healthy lifestyle intervention. Sessions were audio-taped, transcribed and analysed using the qualitative software, nvivo, version 11 (QSR International Pty Ltd., Melbourne, VIC, Australia). Themes were generated using an inductive approach informed by the Theory of Social Identity and Social Influence Model of Consumer Participation. RESULTS: Thirty-three people (12 male) participated. Facebook was the most popular platform for facilitating social support as a result of its private group capabilities and already being embedded into their daily routines. The preference was to be grouped with strangers who shared similar goals in smaller groups of participants. The discussions highlighted the integral role of a credible and relatable health coach to serve as a mentor, mediator and role model. CONCLUSIONS: The learnings from this research will be applied to optimise engagement within social media support groups in lifestyle interventions.

Physiologically-based pharmacokinetic model for alectinib, ruxolitinib, and panobinostat in the presence of cancer, renal impairment, and hepatic impairment.

Renal (RIP) and hepatic (HIP) impairments are prevalent conditions in cancer patients. They can cause changes in gastric emptying time, albumin levels, hematocrit, glomerular filtration rate, hepatic functional volume, blood flow rates, and metabolic activity that can modify drug pharmacokinetics. Performing clinical studies in such populations has ethical and practical issues. Using predictive physiologically-based pharmacokinetic (PBPK) models in the evaluation of the PK of alectinib, ruxolitinib, and panobinostat exposures in the presence of cancer, RIP, and HIP can help in using optimal doses with lower toxicity in these populations. Verified PBPK models were customized under scrutiny to account for the pathophysiological changes induced in these diseases. The PBPK model-predicted plasma exposures in patients with different health conditions within average 2-fold error. The PBPK model predicted an area under the curve ratio (AUCR) of 1, and 1.8, for ruxolitinib and panobinostat, respectively, in the presence of severe RIP. On the other hand, the severe HIP was associated with AUCR of 1.4, 2.9, and 1.8 for alectinib, ruxolitinib, and panobinostat, respectively, in agreement with the observed AUCR. Moreover, the PBPK model predicted that alectinib therapeutic cerebrospinal fluid levels are achieved in patients with non-small cell lung cancer, moderate HIP, and severe HIP at 1-, 1.5-, and 1.8-fold that of healthy subjects. The customized PBPK models showed promising ethical alternatives for simulating clinical studies in patients with cancer, RIP, and HIP. More work is needed to quantify other pathophysiological changes induced by simultaneous affliction by cancer and RIP or HIP.

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease.

Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disorder with no current cure. One of the important therapeutic approaches of AD is the inhibition of ß-site APP cleaving enzyme-1 (BACE1), which is involved in the rate-limiting step of the cleavage process of the amyloid precursor protein (APP) leading to the generation of the neurotoxic amyloid ß (Aß) protein after the γ-secretase completes its function. The produced insoluble Aß aggregates lead to plaques deposition and neurodegeneration. BACE1 is, therefore, one of the attractive targets for the treatment of AD. This approach led to the development of potent BACE1 inhibitors, many of which were advanced to late stages in clinical trials. Nonetheless, the high failure rate of lead drug candidates targeting BACE1 brought to the forefront the need for finding new targets to uncover the mystery behind AD. In this review, we aim to discuss the most promising classes of BACE1 inhibitors with a description and analysis of their pharmacodynamic and pharmacokinetic parameters, with more focus on the lead drug candidates that reached late stages of clinical trials, such as MK8931, AZD-3293, JNJ-54861911, E2609, and CNP520. In addition, the manuscript discusses the safety concerns and insignificant physiological effects, which were highlighted for the most successful BACE1 inhibitors. Furthermore, the review demonstrates with increasing evidence that despite tremendous efforts and promising results conceived with BACE1 inhibitors, the latest studies suggest that their clinical use for treating Alzheimer's disease should be reconsidered. Finally, the review sheds light on alternative therapeutic options for targeting AD.

Severe hypercalcemia and a pelvic brown tumor in an adolescent with primary hyperparathyroidism: a case report.

BACKGROUND: Primary hyperparathyroidism may present in a myriad of manners, varying from an incidental asymptomatic biochemical finding to gastrointestinal, psychiatric, renal, and bone manifestations. While hyperparathyroidism remains a rare diagnosis in the pediatric population, the initial approach to diagnosis and management of hypercalcemia in children is imperative for the general pediatrician. Herein, we describe an adolescent who presented with a lytic bone lesion and severe, symptomatic hypercalcemia due to primary hyperparathyroidism. CASE PRESENTATION: A 14-year-old male presented with vomiting, constipation, abdominal pain, and lethargy. He had an elevated total corrected calcium of 4.3 mmol/L. He was found to have a large pelvic lytic tumor consistent with a brown tumor due to primary hyperparathyroidism. He received pharmacologic therapy for stabilization of his hypercalcemia, including intravenous saline, intravenous bisphosphonates, and calcitonin. He subsequently received definitive therapy via parathyroidectomy and his post-operative course was complicated by hungry bone syndrome. Long-term follow-up has found full resolution of the lytic lesion and restored calcium homeostasis. CONCLUSIONS: We present this case to highlight the possible presentations of hypercalcemia and hyperparathyroidism that are essential for a general pediatrician to recognize to ensure prompt diagnosis and management. Evaluation for hypercalcemia should be considered in patients with suggestive symptoms and physical exam findings. To our knowledge, this patient represents the first reported pediatric case of a pelvic brown tumor in an adolescent. While the multi-systemic complications of hyperparathyroidism may be quite severe, swift and appropriate management may mitigate these clinical outcomes.

Interocular difference thresholds are mediated by binocular differencing, not summing, channels.

Patterns in the two eyes' views that are not identical in hue or contrast often elicit an impression of luster, providing a cue for discriminating them from perfectly matched patterns. Here we attempt to determine the mechanisms for detecting interocular differences in luminance contrast, in particular in relation to the possible contributions of binocular differencing and binocular summing channels. Test patterns were horizontally oriented multi-spatial-frequency luminance-grating patterns subject to variable amounts of interocular difference in grating phase, resulting in varying degrees of local interocular contrast difference. Two types of experiment were conducted. In the first, subjects discriminated between a pedestal with an interocular difference that ranged upward from zero (i.e., binocularly correlated) and a test pattern that contained a bigger interocular difference. In the second type of experiment, subjects discriminated between a pedestal with an interocular difference that ranged downward from a maximum (i.e., binocularly anticorrelated) and a test pattern that contained smaller interocular difference. The two types of task could be mediated by a binocular differencing and a binocular summing channel, respectively. However, we found that the results from both experiments were well described by a simpler model in which a single, linear binocular differencing channel is followed by a standard nonlinear transducer that is expansive for small signals but strongly compressive for large ones. Possible reasons for the lack of involvement of a binocular summing channel are discussed in the context of a model that incorporates the responses of both monocular and binocular channels.

Immune checkpoint inhibitors in advanced non-small cell lung cancer.

The emergence of immune checkpoint inhibitors for the treatment of cancer has led to major changes to the therapeutic landscape of lung cancer. Improvements in overall survival relative to standard chemotherapy have been observed in the first-line and second-line therapy settings for patients with advanced non-small cell lung cancer (NSCLC) who are treated with immune checkpoint inhibitors. Consequently, every patient with advanced-stage NSCLC is now a candidate for immune checkpoint inhibitor therapy. However, it is clear that the benefit from therapy is not universal, and identification of biomarkers to select therapy has assumed importance. In addition to programmed cell death receptor ligand 1 expression, both tissue-based and blood-based markers are under evaluation to select patients. In an era of increasing costs of care and potential for toxicities related to immune checkpoint inhibition, proper patient selection is critical to the optimal use of this new class of agents. In addition, development of novel combination approaches has also emerged as an important way to improve the efficacy of immune checkpoint inhibition. Studies in earlier stages of NSCLC are already underway with the hope of improving the cure rate. In this article, the authors review the current landscape of immune checkpoint inhibitors in the treatment of advanced NSCLC. Cancer 2018;124:248-61. © 2017 American Cancer Society.

Iron overload in patients with myelodysplastic syndromes: An updated overview.

Myelodysplastic syndromes (MDS) encompass a heterogeneous group of clonal hematopoietic stem cell disorders characterized by a broad clinical spectrum related to ineffective hematopoiesis leading to unilineage or multilineage cytopenias, with a high propensity for transformation to acute myeloid leukemia. Iron overload has been recently identified as one of the important conditions complicating the management of these diverse disorders. The accumulation of iron is mainly related to chronic transfusions; however, evidence suggests a possible role for ineffective erythropoiesis and increased intestinal absorption of iron, related to altered hepcidin and growth differentiation factor-15 levels in the development of hemosiderosis in patients with MDS. In addition to its suggested role in the exacerbation of ineffective erythropoiesis, multiple reports have identified a prognostic implication for the development of iron overload in patients with MDS, with an improvement in overall survival after the initiation of iron chelation therapy. This review includes a detailed discussion of iron overload in patients with MDS whether they are undergoing supportive therapy or curative hematopoietic stem cell transplantation, with a focus on the mechanism, diagnosis, and effect on survival as well as the optimal management of this highly variable complication.

The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment.

Bipolar affective disorder is a common neuropsychiatric disorder. Although its neurobiological underpinnings are incompletely understood, the dopamine hypothesis has been a key theory of the pathophysiology of both manic and depressive phases of the illness for over four decades. The increased use of antidopaminergics in the treatment of this disorder and new in vivo neuroimaging and post-mortem studies makes it timely to review this theory. To do this, we conducted a systematic search for post-mortem, pharmacological, functional magnetic resonance and molecular imaging studies of dopamine function in bipolar disorder. Converging findings from pharmacological and imaging studies support the hypothesis that a state of hyperdopaminergia, specifically elevations in D2/3 receptor availability and a hyperactive reward processing network, underlies mania. In bipolar depression imaging studies show increased dopamine transporter levels, but changes in other aspects of dopaminergic function are inconsistent. Puzzlingly, pharmacological evidence shows that both dopamine agonists and antidopaminergics can improve bipolar depressive symptoms and perhaps actions at other receptors may reconcile these findings. Tentatively, this evidence suggests a model where an elevation in striatal D2/3 receptor availability would lead to increased dopaminergic neurotransmission and mania, whilst increased striatal dopamine transporter (DAT) levels would lead to reduced dopaminergic function and depression. Thus, it can be speculated that a failure of dopamine receptor and transporter homoeostasis might underlie the pathophysiology of this disorder. The limitations of this model include its reliance on pharmacological evidence, as these studies could potentially affect other monoamines, and the scarcity of imaging evidence on dopaminergic function. This model, if confirmed, has implications for developing new treatment strategies such as reducing the dopamine synthesis and/or release in mania and DAT blockade in bipolar depression.

Effects of psilocybin therapy on personality structure.

OBJECTIVE: To explore whether psilocybin with psychological support modulates personality parameters in patients suffering from treatment-resistant depression (TRD). METHOD: Twenty patients with moderate or severe, unipolar, TRD received oral psilocybin (10 and 25 mg, one week apart) in a supportive setting. Personality was assessed at baseline and at 3-month follow-up using the Revised NEO Personality Inventory (NEO-PI-R), the subjective psilocybin experience with Altered State of Consciousness (ASC) scale, and depressive symptoms with QIDS-SR16. RESULTS: Neuroticism scores significantly decreased while Extraversion increased following psilocybin therapy. These changes were in the direction of the normative NEO-PI-R data and were both predicted, in an exploratory analysis, by the degree of insightfulness experienced during the psilocybin session. Openness scores also significantly increased following psilocybin, whereas Conscientiousness showed trend-level increases, and Agreeableness did not change. CONCLUSION: Our observation of changes in personality measures after psilocybin therapy was mostly consistent with reports of personality change in relation to conventional antidepressant treatment, although the pronounced increases in Extraversion and Openness might constitute an effect more specific to psychedelic therapy. This needs further exploration in future controlled studies, as do the brain mechanisms of postpsychedelic personality change.