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Chron’s Disease is a chronic inflammatory intestinal disease, first described at the beginning of the last century. The disease is characterized by the alternation of periods of flares and remissions influenced by a complex pathogenesis in which inflammation plays a key role. Crohn’s disease evolution is mediated by a complex alteration of the inflammatory response which is characterized by alterations of the innate immunity of the intestinal mucosa barrier together with a remodeling of the extracellular matrix through the expression of metalloproteins and increased adhesion molecules expression, such as MAcCAM-1. This reshaped microenvironment enhances leucocytes migration in the sites of inflammation, promoting a T H 1 response, through the production of cytokines such as IL-12 and TNF-α. IL-12 itself and IL-23 have been targeted for the medical treatment of CD. Giving the limited success of medical therapies, the treatment of the disease is invariably surgical. This review will highlight the role of inflammation in CD and describe the surgical approaches for the prevention of the almost inevitable recurrence.

Key Points Single-celled eukaryotes (protists) constitute a tremendously diverse group of microorganisms. These species exhibit a wide range of nutritional modes (many species possess multiple nutritional modes simultaneously) and are essential components at several trophic levels within food webs. Genetic analyses of protists have lagged behind those of other microbial taxa because protists have much larger genomes and more complicated gene expression patterns. Consequently, we have very limited knowledge about gene number, identity and function within many protistan lineages. Widespread application of targeted gene sequencing (most notably, of small-subunit rRNA genes) has greatly improved our knowledge of eukaryote phylogeny and provided a framework for an emerging taxonomy incorporating morphological and molecular information. A recently developed alternative approach to provide genetic information for ecologically important protistan taxa is transcriptome sequencing of cultured species. Transcriptomes are providing vital databases of genes for species that lack sequenced genomes. Transcriptomic studies of cultures and natural assemblages of phototrophic protists (phytoplankton) are revealing complex metabolic responses to environmental conditions (such as nutrient limitation and light regime), pathways that are involved in toxin production by some harmful algal species and changes in gene expression that are related to shifts in nutritional mode for mixotrophic species. The application of transcriptomic approaches to the study of protistan symbioses, predator–prey interactions and protist–bacterium interactions are beginning to reveal the molecular signalling that is involved in the recognition and response between microorganisms, providing insights into the origin of eukaryotic organelles and the structure of aquatic food webs. We now have an improved understanding of the physiological responses of ecologically relevant protistan species and trophic groups to environmental changes. This understanding, which has been garnered through omics studies, is being harnessed to improve the predictive capabilities of global biogeochemical models. Protists are an important part of the marine food web. In this Review, Caron et al . summarize recent insights from transcriptomic studies of cultured and free-living protists and discuss how these findings highlight the functions and interactions of these single-celled eukaryotes in the global oceans. Protists, which are single-celled eukaryotes, critically influence the ecology and chemistry of marine ecosystems, but genome-based studies of these organisms have lagged behind those of other microorganisms. However, recent transcriptomic studies of cultured species, complemented by meta-omics analyses of natural communities, have increased the amount of genetic information available for poorly represented branches on the tree of eukaryotic life. This information is providing insights into the adaptations and interactions between protists and other microorganisms and macroorganisms, but many of the genes sequenced show no similarity to sequences currently available in public databases. A better understanding of these newly discovered genes will lead to a deeper appreciation of the functional diversity and metabolic processes in the ocean. In this Review, we summarize recent developments in our understanding of the ecology, physiology and evolution of protists, derived from transcriptomic studies of cultured strains and natural communities, and discuss how these novel large-scale genetic datasets will be used in the future.

Background Ipilimumab, a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4, has demonstrated an improvement in overall survival in two phase III trials of patients with advanced melanoma. The primary objective of the current trial was to prospectively explore candidate biomarkers from the tumor microenvironment for associations with clinical response to ipilimumab. Methods In this randomized, double-blind, phase II biomarker study (ClinicalTrials.gov NCT00261365), 82 pretreated or treatment-naïve patients with unresectable stage III/IV melanoma were induced with 3 or 10 mg/kg ipilimumab every 3 weeks for 4 doses; at Week 24, patients could receive maintenance doses every 12 weeks. Efficacy was evaluated per modified World Health Organization response criteria and safety was assessed continuously. Candidate biomarkers were evaluated in tumor biopsies collected pretreatment and 24 to 72 hours after the second ipilimumab dose. Polymorphisms in immune-related genes were also evaluated. Results Objective response rate, response patterns, and safety were consistent with previous trials of ipilimumab in melanoma. No associations between genetic polymorphisms and clinical activity were observed. Immunohistochemistry and histology on tumor biopsies revealed significant associations between clinical activity and high baseline expression of FoxP3 (p = 0.014) and indoleamine 2,3-dioxygenase (p = 0.012), and between clinical activity and increase in tumor-infiltrating lymphocytes (TILs) between baseline and 3 weeks after start of treatment (p = 0.005). Microarray analysis of mRNA from tumor samples taken pretreatment and post-treatment demonstrated significant increases in expression of several immune-related genes, and decreases in expression of genes implicated in cancer and melanoma. Conclusions Baseline expression of immune-related tumor biomarkers and a post-treatment increase in TILs may be positively associated with ipilimumab clinical activity. The observed pharmacodynamic changes in gene expression warrant further analysis to determine whether treatment-emergent changes in gene expression may be associated with clinical efficacy. Further studies are required to determine the predictive value of these and other potential biomarkers associated with clinical response to ipilimumab.

Diminished ovarian reserve (DOR) lacks strong plasma biomarkers, and recent studies have implicated lipid remodeling in its pathophysiology. In our previous study, we noted elevated circulating levels of semaphorin 3A (SEMA3A) in women with DOR, especially among those who achieved beta-human chorionic gonadotropin (β-hCG) positivity following in vitro fertilization. In this study, we explored whether there are correlations between increased SEMA3A levels and the lipid profile in DOR compared to healthy controls. We performed integrated untargeted metabolomics of plasma lipid and amide classes in women with DOR and healthy controls. Group differences and associations with SEMA3A and reproductive hormones were analyzed using ANCOVA or partial Spearman correlations adjusted for age, body mass index (BMI), and group, with multiple testing controlled by the two-stage Benjamini-Krieger-Yekutieli false discovery rate (BKY FDR) (q ≤ 0.05). Discrimination was evaluated using the area under the receiver operating characteristic curve (ROC AUC) with DeLong's test and FDR correction. Multiple lipid species, particularly glycerophospholipids and ether lipids, varied between groups and demonstrated fair to good discrimination, confirming lipid profile alterations consistent with lipid remodeling. Circulating SEMA3A showed no significant correlation with individual lipid species after adjusting for covariates and controlling for FDR. In contrast, reproductive hormones, including anti Müllerian hormone (AMH), follicle-stimulating hormone (FSH), prolactin (PRL), and tyroid-stimulating hormone (TSH), exibited coherent association with lipid species, particularly within triacylglycerol pathways. Plasma lipidomics in DOR revealed a reproducible remodeling signature; however, SEMA3A did not align with these systemic lipid changes, suggesting context-dependent, likely local ovarian or vascular signaling. Larger, prospective studies with harmonized sampling and complementary matrices (e.g., follicular fluid) are needed to clarify the role of SEMA3A and validate lipid-based signatures relevant to DOR.

Itch is a common side-effect of treatment with anti-EGFR antibodies and tyrosine-kinase inhibitors. We designed a pilot single-centre study to assess the effects of aprepitant—a neurokinin receptor inhibitor—for management of severe pruritus induced by biological drugs. In this single-group, prospective study, we consecutively enrolled 45 outpatients with metastatic solid tumours treated with biological drugs at the Campus Bio-Medico Hospital of Rome, Rome, Italy, between September, 2010, and November, 2011. We classified patients into two groups: a refactory group, for patients with pruritis refractory to standard treatment, or a naive group, for patients who had not been previously treated for pruritis. Aprepitant (125 mg on day 1; 80 mg on day 3; 80 mg on day 5) was given to patients in the refractory group after at least 1 week of standard systemic treatment. In the naive group, aprepitant was given in the same schedule as the refractory group, after first onset of severe pruritus. Intensity of itch was evaluated by Visual Analogue Scale (VAS) score. The primary endpoint was change in median VAS score. This trial is registered with ClinicalTrials.gov, number NCT01683552. Median VAS in the refractory group was 8·00 (95% CI 7·93–8·57) at baseline and 1·00 (0·00–2·00) after 1 week of treatment with aprepitant (p<0·0001). In the naive group, VAS score was 8·00 (7·43–8·37) at baseline and 0·00 (0·06–1·08) after 1 week of treatment (p<0·0001). 41 (91%) patients responded to aprepitant (ie, had a >50% reduction in intensity of pruritis) and pruritus recurred in only six (13%) patients. No adverse events related to aprepitant occurred. Aprepitant decreases severe pruritus induced by biological treatments; it is an old drug, widely available, and therefore easy to add to the armamentarium of supportive treatment. Although to our knowledge no other studies of the anti-itch activity of aprepitant are planned, the results of our trial warrant confirmation in phase 2 and 3 trials. None.

Colorectal carcinoma is the second leading cause of cancer-related deaths, and indeed, rectal cancer accounting for approximately one third of newly diagnosed patients. Gold standard in the treatment of rectal cancer is a multimodality approach, aiming at a good control of the local disease. Distant recurrences are the major cause of mortality. Currently, Locally Advanced Rectal Cancer (LARC) patients undergo a combined treatment of chemotherapy and radiotherapy, followed by surgery. Eventually, more chemotherapy, namely adjuvant chemotherapy (aCT), may be necessary. Total Neoadjuvant Therapy (TNT) is an emerging approach aimed to reduce distant metastases and improve local control. Several ongoing studies are analyzing whether this new approach could improve oncological outcomes. Published results were encouraging, but the heterogeneity of protocols in use, makes the comparison and interpretation of data rather complex. One of the major concerns regarding TNT administration is related to its effect on larger and more advanced cancers that might not undergo similar down-staging as smaller, early-stage tumors. This minireview, based on a systematic literature search of randomized clinical trials and meta-analysis, summarizes current knowledge on TNT. The aim was to confirm or refute whether or not current practice of TNT is based on relevant evidence, to establish the quality of that evidence, and to address any uncertainty or variation in practice that may be occurring. A tentative grouping of general study characteristics, clinical features and treatments characteristics has been undertaken to evaluate if the reported studies are sufficiently homogeneous in terms of subjects involved, interventions, and outcomes to provide a meaningful idea of which patients are more likely to gain from this treatment.

Acute myeloid leukemia (AML) primary cells express high levels of phosphorylated Akt, a master regulator of cellular functions regarded as a promising drug target. By means of reverse phase protein arrays, we examined the response of 80 samples of primary cells from AML patients to selective inhibitors of the phosphatidylinositol 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) axis. We confirm that >60% of the samples analyzed are characterized by high pathway phosphorylation. Unexpectedly, however, we show here that targeting Akt and mTOR with the specific inhibitors Akti 1/2 and Torin1, alone or in combination, result in paradoxical Akt phosphorylation and activation of downstream signaling in 70% of the samples. Indeed, we demonstrate that cropping Akt or mTOR activity can stabilize the Akt/mTOR downstream effectors Forkhead box O and insulin receptor substrate-1, which in turn potentiate signaling through upregulation of the expression/phosphorylation of selected growth factor receptor tyrosine kinases (RTKs). Activation of RTKs in turn reactivates PI3K and downstream signaling, thus overruling the action of the drugs. We finally demonstrate that dual inhibition of Akt and RTKs displays strong synergistic cytotoxic effects in AML cells and downmodulates Akt signaling to a much greater extent than either drug alone, and should therefore be explored in AML clinical setting.

Visual impairment (VI) can significantly interfere in the child’s daily activities and quality of life, having a negative effect on their development and learning. The aim of the study was to determine the prevalence of VI and associated demographic factors in students examined during the program “Moçambique te vejo melhor”. This study was cross-sectional and retrospective, based on the 2018/19 edition of the program. Eye examinations were performed in secondary school students, aged between 12 and 20 years, of five districts in Nampula province. The examination included visual acuity, non-cycloplegic refraction and assessment of the anterior and posterior segment and ocular adnexa. The prevalence of uncorrected, presenting and best-corrected VI found was 18.3%, 10.8%, and 5.0%, respectively. Refractive error (RE) had a prevalence of 24.7%, and the age groups between 15–17 years and 18–20 years were significantly associated with myopia (with OR: 4.9 and OR: 8.8, respectively), as well as the 11th and 12th grade (OR: 8.1 and OR: 10.7, respectively), and Malema district had association with myopia (ORa: 0.4) and hyperopia (ORa: 0.4 and OR: 0.3) as a protective factor. The prevalence of RE and VI was relatively high, showing the need for greater intervention at the school level.

Background The management of breast cancer (BC) skin metastases represents a therapeutic challenge. Electrochemotherapy (ECT) combines the administration of bleomycin with temporary permeabilization induced by locally administered electric pulses. Preliminary experience with ECT in BC patients is encouraging. Methods A total of 125 patients with BC skin metastases who underwent ECT between 2010 and 2013 were enrolled onto a multicenter retrospective cohort study. The treatment was administered following the European Standard Operative Procedures of Electrochemotherapy. Tumor response was clinically assessed adapting the Response Evaluation Criteria in Solid Tumors, and toxicity was evaluated according to Common Terminology Criteria for Adverse Events 4.0. Cox regression analysis was used to identify predictive factors. Results Response was evaluable in 113 patients for 214 tumors (median 1 per patient, range 1–3). The overall response rate after 2 months was 90.2 %, while the complete response (CR) rate was 58.4 %. In multivariate analysis, small tumor size ( P  < 0.001), absence of visceral metastases ( P  = 0.001), estrogen receptor positivity ( P  = 0.016), and low Ki-67 index ( P  = 0.024) were significantly associated with CR. In the first 48 h, 10.4 % of patients reported severe skin pain. Dermatologic toxicity included grade 3 skin ulceration (8.0 %) and grade 2 skin hyperpigmentation (8.8 %). Tumor 1-year local progression-free survival was 86.2 % (95 % confidence interval 79.3–93.8) and 96.4 % (95 % confidence interval 91.6–100) in the subgroup of those with CR. Conclusions In this study, small tumor size, absence of visceral metastases, estrogen receptor positivity, and low Ki-67 index were predictors of CR after ECT. Patients who experienced CR had durable local control. ECT represents a valuable skin-directed therapy for selected patients with BC.