Successful synthesis of a glial-specific blood-brain barrier shuttle peptide following a fragment condensation approach on a solid-phase resin.

Successful manual synthesis of the TD2.2 peptide acting as a blood-brain barrier shuttle was achieved. TD2.2 was successfully synthesised by sequential condensation of four protected peptide fragments on solid-phase settings, after several unsuccessful attempts using the stepwise approach. These fragments were chosen to minimise the number of demanding amino acids (in terms of coupling, Fmoc removal) in each fragment that are expected to hamper the overall synthetic process. Thus, the hydrophobic amino acids as well as Arg(Pbf) were strategically spread over multiple fragments rather than having them congested in one fragment. This study shows how a peptide that shows big challenges in the synthesis using the common stepwise elongation methodology can be synthesised with an acceptable purity. It also emphasises that choosing the right fragment with certain amino acid constituents is key for a successful synthesis. It is worth highlighting that lower amounts of reagents were required to synthesise the final peptide with an identical purity to that obtained by the automatic synthesiser.

Spinal Muscular Atrophy: An Evolving Scenario through New Perspectives in Diagnosis and Advances in Therapies.

Spinal muscular atrophy (SMA) linked to 5q is a recessive motor neuron disease characterized by progressive and diffuse weakness and muscular atrophy. SMA is the most common neurodegenerative disease in childhood with an incidence of approximately 1 in 6000-10,000 live births, being long considered a leading cause of hereditary mortality in infancy, worldwide. The classification of SMA is based on the natural history of the disease, with a wide clinical spectrum of onset and severity. We are currently in a new therapeutic era, that, thanks to the widespread use of the newly approved disease-modifying therapies and the possibility of an early administration, should lead to a deep change in the clinical scenario and, thus, in the history of SMA. With the aim to achieve a new view of SMA, in this review we consider different aspects of this neuromuscular disease: the historical perspective, the clinical features, the diagnostic process, the psychological outcome, innovation in treatments and therapies, the possibility of an early identification of affected infants in the pre-symptomatic phase through newborn screening programs.

Mothers' and Children's Mental Health During the COVID-19 Pandemic Lockdown: The Mediating Role of Parenting Stress.

The present study, carried out during the first peak of the COVID-19 outbreak in Italy, aimed at investigating the mental health of mothers and children during the nationwide lockdown. More specifically, the study investigated children's depression and mothers' individual distress and parenting stress, in comparison with normative samples. The mediating effect of mothers' parenting stress on the relationship between mothers' individual distress and children's depression was also explored. Finally, the study analyzed whether children's biological sex and age moderated the structural paths of the proposed model. A sample of 206 Italian mothers and their children completed an online survey. Mothers were administered self-report questionnaires investigating individual distress and parenting stress; children completed a standardized measure of depression. Mothers' individual distress and parenting stress and children's depression were higher than those recorded for the normative samples. Mothers' parenting stress was found to mediate the association between mothers' individual distress and children's depression. With respect to children, neither biological sex nor age emerged as significant moderators of this association, highlighting that the proposed model was robust and invariant. During the current and future pandemics, public health services should support parents-and particularly mothers-in reducing individual distress and parenting stress, as these are associated with children's depression.

BRCA1/2 pathogenetic variant carriers and reproductive decisions: Gender differences and factors associated with the choice of preimplantation genetic diagnosis (PGD) and prenatal diagnosis (PND).

PURPOSE: To investigate the way carriers of a BRCA1/2 pathogenetic variant make their reproductive decisions and to examine the factors associated with the choice of preimplantation genetic diagnosis (PGD) and prenatal diagnosis (PND). METHODS: We conducted a comprehensive literature search in PubMed, Scopus, and Web of Science in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method. RESULTS: A total of 16 articles published from 2000 to 2021 were included in this review. Data were overall collected from 3564 participants (86% females). Three important themes were identified across studies: changes in family planning, factors associated with family plans, and with acceptance or regret of PGD and PND. CONCLUSION: This review may contribute to the knowledge of the experience of those who have a BRCA1/2 mutation and want a child. These results may help genetic counselors and healthcare professionals that support people with a BRCA pathogenetic variant with reproductive issues.

COVID-19 and home confinement: A study on fathers, father-child relationships and child adjustment.

BACKGROUND: The purpose of this study was to explore fathers' adjustment and father-child relationships during the first peak of the coronavirus disease 2019 (COVID-19) outbreak (April 2020). More particularly, the study analysed paternal perceptions of changes concerning familial economic conditions and children's psychological difficulties (viz., emotional problems and hyperactivity) during the lockdown produced by the current pandemic. Furthermore, we investigated the following correlates of fathers' parenting stress: socio-demographic condition, paternal individual stress, anxiety, depression and changes in the father-child relationship during the outbreak. METHODS: A total of 102 fathers (mean age = 41.60 years; SD = 11.54) with minor children were recruited through an online survey and reported data about their socio-economic condition, anxiety, and depressive levels, parenting stress, offspring's adjustment, and changes in their relationship with their children. RESULTS: As for the economic conditions, participants were equally distributed between those who did not perceive changes and those who perceived a worsening. With regard to changes in the child's psychological difficulties, results showed that levels of children's emotional problems and inattention/hyperactivity had significantly increased during the lockdown period. A multiple linear regression analysis highlighted that the principal predictor of paternal parenting stress was living in the regions most affected by the COVID-19 pandemic, followed by high levels of paternal anxiety symptomatology and high levels of worsening of the relationship with the child during the pandemic. CONCLUSIONS: Overall, our study suggests to consider the effects of COVID-19 on fathers as well, as they have been rather overlooked by previous research that has mainly focused on mothers, and to plan specific interventions able to also take them into account.

Metaplastic breast cancer: an old histotype but a current therapeutic problem.

Metaplastic breast cancer (MPBC) is a rare and aggressive tumor type in great need of satisfactory therapies. Although most cases of MPBC are 'triple negative', they are nonetheless related to worse outcomes compared with other triple-negative invasive tumors. MPBC presents high levels of genetic and molecular heterogeneity, suggesting that novel targeted therapies can be exploited. Overexpression of PD-L1 and high levels of tumor-infiltrating lymphocytes have also been observed in these tumors, suggesting a role for immunotherapy. We present an updated literature revision on clinical, histopathological and molecular features of MPBC and their significance to prognosis and therapy options. We discuss emerging efforts to improve and personalize prognostic and therapeutic approaches, exploiting the molecular signature of MPBC with targeted therapies and immunotherapies.

Quantum dots functionalized with gH625 attenuate QDs oxidative stress and lethality in Caenorhabditis elegans: a model system.

Nanomaterials have revolutionized many scientific fields and are widely applied to address environmental problems and to develop novel health care strategies. However, their mechanism of action is still poorly understood. Several nanomaterials for medical applications are based on quantum dots (QDs). Despite their amazing physico-chemical properties, quantum dots display significant adverse effects. In the present study, the effects of QDs on the motor nervous system of nematodes Caenorhabditis elegans have been investigated as a non-mammalian alternative model. We also explored the possibility of modifying the toxicity of QDs by coating with a cell-penetrating peptide gH625 and thus we analysed the effects determined by QDs-gH625 complexes on the nematodes. With this work, we have demonstrated, by in vivo experiments, that the peptide gH625 is able to reduce the side effects of metallic nanoparticle making them more suitable for medical applications.

Enhancing the Potency of Antimicrobial Peptides through Molecular Engineering and Self-Assembly.

Healthcare-associated infections resulting from bacterial attachment and biofilm formation on medical implants are posing significant challenges in particular with the emergence of bacterial resistance to antibiotics. Here, we report the design, synthesis and characterization of self-assembled nanostructures, which integrate on their surface antibacterial peptides. The antibacterial WMR peptide, which is a modification of the native sequence of the myxinidin, a marine peptide isolated from the epidermal mucus of hagfish, was used considering its enhanced activity against Gram-negative bacteria. WMR was linked to a peptide segment of aliphatic residues (AAAAAAA) containing a lipidic tail (C19H38O2) attached to the ε-amino of a terminal lysine to generate a peptide amphiphile (WMR PA). The self-assembly of the WMR PA alone, or combined with coassembling shorter PAs, was studied using spectroscopy and microscopy techniques. The designed PAs were shown to self-assemble into stable nanofiber structures and these nanoassemblies significantly inhibit biofilm formation and eradicate the already formed biofilms of Pseudomonas aeruginosa (Gram-negative bacteria) and Candida albicans (pathogenic fungus) when compared to the native WMR peptide. Our results provide insights into the design of peptide based supramolecular assemblies with antibacterial activity, and establish an innovative strategy to develop self-assembled antimicrobial materials for biomedical applications.

The role of depression and emotion regulation on parenting stress in a sample of mothers with cancer.

PURPOSE: The aim of the current study was to investigate if and to what extent depression and emotional regulation strategies (namely, cognitive reappraisal and expressive suppression) might lead to parenting stress in a sample of mothers with cancer and in a sample of healthy mothers. METHODS: A sample of mothers with cancer (clinical group; n = 64) and a sample of healthy mothers (control group; n = 80) were administered self-report questionnaires investigating parenting stress (the parenting stress index), depressive symptoms (the Zung depression self-rating scale) and emotion regulation strategies (the emotion regulation questionnaire). RESULTS: Depressive levels represented the most significant predictor of maternal parenting stress in both groups (p < .001). In addition, cognitive reappraisal (p < .05) but not expressive suppression significantly predicted parenting stress exclusively in the group of mothers with cancer. Finally, cognitive reappraisal was negatively and significantly associated with time since cancer diagnosis to survey. CONCLUSIONS: This study highlights that depressive levels and cognitive reappraisal may play a significant role in parenting stress. The systematic assessment of these variables in women with an oncological diagnosis might help mental health professionals to identify those mothers at risk of developing higher levels of parenting stress ensuring adequate support and preventing negative effects on the parent-child relationship.

Psychological aspects, risk and protective factors related to BRCA genetic testing: a review of the literature.

PURPOSE: The primary aim of the present study was to conduct a systematic review of short-, intermediate- and long-term psychological effects, such as anxiety, depression and distress, on individuals undergoing genetic testing to determine BRCA1 and BRCA2 gene mutation. The different instruments used for the measurement of each construct were reported. In addition, risk and protective factors associated with psychological outcomes of genetic tests were explored. METHODS: Bibliographic databases were searched for studies published over the period 1998-2018. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method, 21 articles were selected for the current review. RESULTS: Overall, the collected data revealed rather diverse results, although most studies reported higher levels of distress, anxiety and depression in carriers, as compared to non-carriers. The two genders were not equally represented, with men constituting only 6% of the sample. Risk factors and protective factors that may influence psychological outcomes and adjustment to genetic tests are highlighted and discussed in this review. CONCLUSIONS: The increased risk of developing cancer associated with positive genetic testing results may be experienced as traumatic by many patients, although not all individuals with positive genetic testing results will experience increased distress. Hence, future studies should consider specific risk factors in order to select those who are more likely to be in need of psychological support. Finally, it is necessary to increase the number of male samples to better understand the male experience related to genetic testing outcomes.

Marine Antimicrobial Peptides: Nature Provides Templates for the Design of Novel Compounds against Pathogenic Bacteria.

The discovery of antibiotics for the treatment of bacterial infections brought the idea that bacteria would no longer endanger human health. However, bacterial diseases still represent a worldwide treat. The ability of microorganisms to develop resistance, together with the indiscriminate use of antibiotics, is mainly responsible for this situation; thus, resistance has compelled the scientific community to search for novel therapeutics. In this scenario, antimicrobial peptides (AMPs) provide a promising strategy against a wide array of pathogenic microorganisms, being able to act directly as antimicrobial agents but also being important regulators of the innate immune system. This review is an attempt to explore marine AMPs as a rich source of molecules with antimicrobial activity. In fact, the sea is poorly explored in terms of AMPs, but it represents a resource with plentiful antibacterial agents performing their role in a harsh environment. For the application of AMPs in the medical field limitations correlated to their peptide nature, their inactivation by environmental pH, presence of salts, proteases, or other components have to be solved. Thus, these peptides may act as templates for the design of more potent and less toxic compounds.

Crizotinib-induced cardiotoxicity: the importance of a proactive monitoring and management.

Crizotinib is a multitarget tyrosine kinase inhibitor and it represents the standard of care in patients with anaplastic lymphoma kinase translocated non-small-cell lung cancer. Crizotinib is generally well tolerated and the most frequent adverse events include gastrointestinal effects, visual disorders, edema, fatigue and liver enzyme abnormalities. However, due to the increasing clinical experience with crizotinib, other toxicities are emerging, such as Q-wave T-wave interval prolongation and bradycardia. In the current review we will focus on the management of crizotinib-related cardiotoxicity.

Modeling interactions between Human Equilibrative Nucleoside Transporter-1 and other factors involved in the response to gemcitabine treatment to predict clinical outcomes in pancreatic ductal adenocarcinoma patients.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy, characterized by largely unsatisfactory responses to the currently available therapeutic strategies. In this study we evaluated the expression of genes involved in gemcitabine uptake in a selected cohort of patients with PDAC, with well-defined clinical-pathological features. METHODS: mRNA levels of hENT1, CHOP, MRP1 and DCK were evaluated by means of qRT-PCR in matched pairs of tumor and adjacent normal tissue samples collected from PDAC patients treated with gemcitabine after surgical tumor resection. To detect possible interaction between gene expression levels and to identify subgroups of patients at different mortality/progression risk, the RECursive Partitioning and Amalgamation (RECPAM) method was used. RESULTS: RECPAM analysis showed that DCK and CHOP were most relevant variables for the identification of patients with different mortality risk, while hENT1 and CHOP were able to identify subgroups of patients with different disease progression risk. CONCLUSION: hENT1, CHOP, MRP1 and DCK appear correlated to PDAC, and this interaction might influence disease behavior.

Lipid exchange and flip-flop in solid supported bilayers.

Inter- and intrabilayer transfer of phospholipid molecules was investigated by neutron reflectometry. The structure of solid supported lipid bilayers exposed to a solution of isotopically labeled vesicles was monitored as a function of temperature, time, and vesicle concentration. Lipid interbilayer exchange was shown to be the time limiting process, while lipid intrabilayer movement, the so-called flip-flop, was too fast to be visualized within the experimental acquisition time. The exchange process was characterized by an Arrhenius-like behavior and the activation energy of the process was concentration-independent. The results are discussed and compared extensively with the literature available on the topic.

Needle Insertion Difficulty Algorithm (NIDA): A novel pilot study to predict Huber needle insertion difficulty in totally implanted devices.

Safeguarding of venous assets in cancer patients provides for positioning vascular devices. In totally implanted central venous access devices, hereinafter referred as TIVADs, it's necessary introducing Huber needle, into subcutaneous port, to use it. This procedure is not easy for all implanted devices. The procedural difficulty is to be attributed both to the type of the implanted port and to the skill of the clinician. The degree of patient satisfaction is variable and related with the clinician performing the maneuver. It follows a professional dissatisfaction of the clinician and a hesitation of the patient. Moreover, the incorrect positioning of the Huber needle into the port, could lead to the infusion of antiblastic drugs into the subcutaneous tissue with the consequent tissue damage due to extravasation of the drugs. Evaluation of different characteristics of TIVADs, allowed grouping them, in different types, setting up the S.P.I.A. method (Subcutaneous Port Investigator Assessment). Collected data from medical records concerning: primary pathology, port's permanence and using, Huber needle insertion failed events, if a vascular access expert/specialist clinician has been called, weight gain or loss were recruited. These data made it possible to determine the types of implanted ports that were most difficult to insert the Huber needle, creating the N.I.D.A. (Needle Inserting Difficulty Algorithm) as a prognostic index of Huber needle inserting into the port. In particular, the type of implanted port, that is, if it was a brachial or thoracic implant (p < 0.001), the SPIA type, if type 1, 2, or 3 (p < 0.001) and the experience of the clinician (p < 0.001) were considered as predictors of a successful first attempt and then can perform the NIDA. The relevant aspects in the success of the procedure are therefore the type of port (thoracic or brachial), the SPIA type, and the experience of the clinician in the successful insertion of the Huber needle into the port at the first attempt.

Differential sensing with arrays of de novo designed peptide assemblies.

Differential sensing attempts to mimic the mammalian senses of smell and taste to identify analytes and complex mixtures. In place of hundreds of complex, membrane-bound G-protein coupled receptors, differential sensors employ arrays of small molecules. Here we show that arrays of computationally designed de novo peptides provide alternative synthetic receptors for differential sensing. We use self-assembling α-helical barrels (αHBs) with central channels that can be altered predictably to vary their sizes, shapes and chemistries. The channels accommodate environment-sensitive dyes that fluoresce upon binding. Challenging arrays of dye-loaded barrels with analytes causes differential fluorophore displacement. The resulting fluorimetric fingerprints are used to train machine-learning models that relate the patterns to the analytes. We show that this system discriminates between a range of biomolecules, drink, and diagnostically relevant biological samples. As αHBs are robust and chemically diverse, the system has potential to sense many analytes in various settings.

Strategies for Improving Peptide Stability and Delivery.

Peptides play an important role in many fields, including immunology, medical diagnostics, and drug discovery, due to their high specificity and positive safety profile. However, for their delivery as active pharmaceutical ingredients, delivery vectors, or diagnostic imaging molecules, they suffer from two serious shortcomings: their poor metabolic stability and short half-life. Major research efforts are being invested to tackle those drawbacks, where structural modifications and novel delivery tactics have been developed to boost their ability to reach their targets as fully functional species. The benefit of selected technologies for enhancing the resistance of peptides against enzymatic degradation pathways and maximizing their therapeutic impact are also reviewed. Special note of cell-penetrating peptides as delivery vectors, as well as stapled modified peptides, which have demonstrated superior stability from their parent peptides, are reported.

Immune-based combinations for metastatic triple negative breast cancer in clinical trials: current knowledge and therapeutic prospects.

INTRODUCTION: Immune checkpoint inhibitor (ICI) monotherapy appears to be effective in a small cohort of patients with metastatic triple negative breast cancer (mTNBC). This supports the exploration of strategies for increasing the efficacy of immunotherapy. To enhance overall response and clinical outcomes, several immune-based combinations are being investigated. AREAS COVERED: The authors present a synopsis of current, state-of-art immune-based combinations in this setting and reflect on future possibilities. They shed light on recently presented and published clinical trials and ongoing studies. A literature search was conducted in October 2021; in addition, abstracts of international cancer meetings were reviewed. EXPERT OPINION: Clinical trials suggest that ICI monotherapy could be beneficial in a minority of mTNBC patients; conversely, several immune-based combinations have reported notable results in recently presented or published studies. Some of these combination strategies have been approved for mTNBC - as in the case of chemoimmunotherapy in PD-L1 positive patients. Numerous trials are investigating novel ICI-based combinations and their results are eagerly awaited.

Pemigatinib in Intrahepatic Cholangiocarcinoma: A Work in Progress.

Cholangiocarcinoma (CCA) is the second most frequent primary liver cancer, following hepatocellular carcinoma (HCC). Progress in the molecular understanding of CCA has led to the development of several agents, including FGFR inhibitors, such as pemigatinib, whose approval has marked a new era in this hepatobiliary malignancy. However, a number of questions remain unanswered, including the development of secondary resistance and the role of combination therapies, including FGFR inhibitors. Herein, we specifically focus on the current challenges and future research directions of pemigatinib use in CCA patients.

COVID-19 and chronic disease patients: Perceived stress, worry, and emotional regulation strategies.

OBJECTIVE: The current study aimed at investigating the perceived impact of the COVID-19 pandemic on Italian individuals with a preexisting medical condition. Specifically, the study analyzed: (a) if different conditions were associated with different levels of distress, different levels of worry, and different emotion regulation strategies (i.e., cognitive reappraisal, expressive suppression); and (b) if distress levels were associated with levels of worry about COVID-19, emotion regulation strategies, and changes to medical treatment due to the pandemic. METHOD: This cross-sectional study involved 124 individuals (79.8% female; mean age = 48.88 years; SD = 14.95) with a diagnosis of chronic disease. The questionnaires, administered during the peak of the first wave of the COVID-19 pandemic in Italy (April-May 2020), comprised the Perceived Stress Scale, the Emotion Regulation Questionnaire, a COVID-19 worry questionnaire, and a questionnaire designed to collect anamnestic and sociodemographic data. RESULTS: Higher levels of expressive suppression and worries related to COVID-19, and changes to medical treatment due to the pandemic, were associated with higher perceived stress in patients with a preexisting chronic disease. No differences emerged in the study variables according to the type of chronic disease. CONCLUSIONS: The results highlight the importance of considering expressive suppression, levels of worry about COVID-19, and changes to scheduled medical treatment. Screening procedures based on these factors may be useful for identifying individuals with a preexisting medical condition at higher risk of distress, in order to offer them specific and remotely delivered psychological support. (PsycInfo Database Record (c) 2021 APA, all rights reserved).