Hierarchical cluster analysis and nonlinear mixed-effects modelling for candidate biomarker detection in preclinical models of cancer.

Background: Preclinical models of cancer can be of translational benefit when assessing how different biomarkers are regulated in response to particular treatments. Detection of molecular biomarkers in preclinical models of cancer is difficult due inter-animal variability in responses, combined with limited accessibility of longitudinal data.

Methods: Nonlinear mixed-effects modelling (NLME) was used to analyse tumour growth data based on expected tumour growth rates observed 7 days after initial doses (DD7) of Radiotherapy (RT) and Combination of RT with DNA Damage Response Inhibitors (DDRi).

Preclinical Characterization of AZD9574, a Blood-Brain Barrier Penetrant Inhibitor of PARP1.

Purpose: We evaluated the properties and activity of AZD9574, a blood-brain barrier (BBB) penetrant selective inhibitor of PARP1, and assessed its efficacy and safety alone and in combination with temozolomide (TMZ) in preclinical models.

Experimental Design: AZD9574 was interrogated in vitro for selectivity, PARylation inhibition, PARP-DNA trapping, the ability to cross the BBB, and the potential to inhibit cancer cell proliferation. In vivo efficacy was determined using subcutaneous as well as intracranial mouse xenograft models.

Case report: atypical Silver-Russell syndrome patient with hand dystonia: the valuable support of the consensus statement to the wide syndromic spectrum.

The amount of Insulin Growth Factor 2 (IGF2) controls the rate of embryonal and postnatal growth. The and adjacent are the imprinted genes of the telomeric cluster in the 11p15 chromosomal region regulated by differentially methylated regions (DMRs) or imprinting centers (ICs): H19/IGF2:IG-DMR (IC1). Dysregulation due to IC1 Loss-of-Methylation (LoM) or Gain-of-Methyaltion (GoM) causes Silver-Russell syndrome (SRS) or Beckwith-Wiedemann syndrome (BWS) disorders associated with growth retardation or overgrowth, respectively.

Radiation in Combination with Immune Checkpoint Blockade and DNA Damage Response Inhibitors in Mice: Dosage Optimization in MC38 Syngeneic Tumors via Modelling and Simulation.

Clinical trials assessing the impact of radiotherapy (RT) in combination with DNA damage response pathway inhibitors (DDRis) and/or immune checkpoint blockade are currently ongoing. However, current methods for optimizing dosage and schedule are limited. A mathematical model was developed to capture the impacts of RT in combination with DDRi and/or anti-PD-L1 [immune checkpoint inhibitor (ICI)] on tumor immune interactions in the MC38 syngeneic tumor model.

An integrated modelling approach for targeted degradation: insights on optimization, data requirements and PKPD predictions from semi- or fully-mechanistic models and exact steady state solutions.

The value of an integrated mathematical modelling approach for protein degraders which combines the benefits of traditional turnover models and fully mechanistic models is presented. Firstly, we show how exact solutions of the mechanistic models of monovalent and bivalent degraders can provide insight on the role of each system parameter in driving the pharmacological response. We show how on/off binding rates and degradation rates are related to potency and maximal effect of monovalent degraders, and how such relationship can be used to suggest a compound optimization strategy.

Impact of the COVID-19 pandemic on voluntary terminations of pregnancy in an Italian metropolitan area.

Purpose: The COVID-19 pandemic and national lockdown from 9 March to 4 May 2020 changed social, familial, and sexual relationships, as well as how citizens interact with the health services. How these profound changes have affected sexuality, contraception and voluntary terminations of pregnancy is still largely undescribed. The main objective of this study was therefore to find out whether the COVID-19 pandemic and ensuing lockdown affected the demand for legal abortion.

Maternal Uniparental Disomy of Chromosome 20 (UPD(20)mat) as Differential Diagnosis of Silver Russell Syndrome: Identification of Three New Cases.

Silver Russell Syndrome (SRS, MIM #180860) is a rare growth retardation disorder in which clinical diagnosis is based on six features: pre- and postnatal growth failure, relative macrocephaly, prominent forehead, body asymmetry, and feeding difficulties (Netchine-Harbison clinical scoring system (NH-CSS)). The molecular mechanisms consist in (epi)genetic deregulations at multiple loci: the loss of methylation (LOM) at the paternal :IG-DMR (chr11p15.5) (50%) and the maternal uniparental disomy of chromosome 7 (UPD(7)mat) (10%) are the most frequent causes.

Molecular Etiology Disclosed by Array CGH in Patients With Silver-Russell Syndrome or Similar Phenotypes.

Silver-Russell syndrome (SRS) is an imprinting disorder primarily caused by genetic and epigenetic aberrations on chromosomes 11 and 7. SRS is a rare growth retardation disorder often misdiagnosed due to its heterogeneous and non-specific clinical features. The Netchine-Harbison clinical scoring system (NH-CSS) is the recommended tool for differentiating patients into clinical SRS or unlikely SRS.

A Monocentric Retrospective Study about the Correlation between Histology and Cytology of Thyroid Indeterminate Nodules Classified as TIR 3A and TIR 3B, according to 2014 Italian Consensus for Classification and Reporting of Thyroid Cytology.

Background: In 2014, the Italian Consensus for Classification and Reporting of Thyroid Cytology (ICCRTC) reviewed the previous cytological classification proposed in 2007 including the subdivision of TIR 3 category into low risk (TIR 3A) and high risk (TIR 3B). In Italian literature, different rates of malignancy have been correlated to these subcategories.

Objectives: The aim of the study is to present our experience on this subclassification for the assessment of the malignancy risk of indeterminate thyroid nodules.

Discrepant molecular and clinical diagnoses in Beckwith-Wiedemann and Silver-Russell syndromes.

Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS) are two imprinting disorders associated with opposite molecular alterations in the 11p15.5 imprinting centres. Their clinical diagnosis is confirmed by molecular testing in 50-70% of patients.

A group study on the effects of a short multi-domain cognitive training in healthy elderly Italian people.

Background: Alongside physiological cognitive ageing, nowadays there is an alarming increase in the incidence of dementia that requires communities to invest in its prevention. The engagement in cognitively stimulating activities and strong social networks has been identified among those protective factors promoting successful cognitive ageing. One aspect regarding cognitive stimulation concerns the relevance of the frequency of an external intervention.

The association of cognitive reserve with motor and cognitive functions for different stages of Parkinson's disease.

Introduction: The cognitive reserve (CR) theory has been proposed to account for the mismatch between the degree of neuropathological changes and clinical outcome in dementias. Recently, it has also been applied to Parkinson's disease (PD) with promising results, but mostly just focusing on separate proxy measures of CR, such as education, working and leisure time activities, instead of adopting a more comprehensive approach. Using the Cognitive Reserve Index questionnaire (CRIq), this study examined the association of CR with motor functions and cognition in patients with medium-low (1-9 years) and medium-high (>9 years) PD duration.

Optimization of Vagal Stimulation Protocol Based on Spontaneous Breathing Rate.

Controlled breathing maneuver is being widely applied for cardiovascular autonomic control evaluation and cardiac vagal activation through reduction of breathing rate (BR). However, this maneuver presented contradictory results depending on the protocol and the chosen BR. These variations may be related to the individual intrinsic profile baseline sympathetic tonus, as described before by others.

Autoinflammatory diseases as a cause of acute abdominal pain in the emergency department.

Autoinflammatory diseases (AIDs) usually present with acute abdominal pain and fever, both of which are also the main causes of referral in the emergency department. As some patients with acute abdominal pain may be discharged from the emergency department without a definitive diagnosis, it is not surprising that, due to their rarity, most cases of AID remain undiagnosed or are misdiagnosed as acute appendicitis. Indeed, the diagnosis of familial Mediterranean fever and autoinflammatory syndromes requires a high index of suspicion and careful assessment of clinical history.

Taurine Administration Recovers Motor and Learning Deficits in an Angelman Syndrome Mouse Model.

Angelman syndrome (AS, MIM 105830) is a rare neurodevelopmental disorder affecting 1:10-20,000 children. Patients show moderate to severe intellectual disability, ataxia and absence of speech. Studies on both post-mortem AS human brains and mouse models revealed dysfunctions in the extra synaptic gamma-aminobutyric acid (GABA) receptors implicated in the pathogenesis.

Clinical Manifestations and Metabolic Outcomes of Seven Adults With Silver-Russell Syndrome.

Context: There is little information on the long-term natural history of Silver-Russell syndrome (SRS).

Objective: To describe the phenotypes and metabolic status in adults with SRS.

Design: Clinical and metabolic evaluations in adults with a molecular diagnosis of SRS.

Association between autonomic control indexes and mortality in subjects admitted to intensive care unit.

This study checks whether autonomic markers derived from spontaneous fluctuations of heart period (HP) and systolic arterial pressure (SAP) and from their interactions with spontaneous or mechanical respiration (R) are associated with mortality in patients admitted to intensive care unit (ICU). Three-hundred consecutive HP, SAP and R values were recorded during the first day in ICU in 123 patients. Population was divided into survivors (SURVs, n = 83) and non-survivors (NonSURVs, n = 40) according to the outcome.

Effects of laparoscopic radical prostatectomy on intraoperative autonomic nervous system control of hemodynamics.

Background: Laparoscopic radical prostatectomy induces hemodynamic changes that have been supposed due to autonomic nervous system activity. The aim of this study is to measure the sympathetic and vagal modulation on hemodynamic response to steep Trendelenburg and pneumoperitoneum for laparoscopic surgery.

Methods: Autonomic nervous system modulation was assessed noninvasively through heart rate variability and arterial pressure variability analysis in patients undergoing elective laparoscopic radical prostatectomy and in awake volunteers during head-down tilt.

Pulse photoplethysmographic amplitude and heart rate variability during laparoscopic cholecystectomy: A prospective observational study.

Background: Surgical stress affects the autonomic nervous system by increasing sympathetic outflow. One method of monitoring sympathetic activity is pulse photoplethysmographic analysis. From this two indices can be derived - autonomic nervous system state (ANSS) and ANSS index (ANSSi).

Quantifying Net Synergy/Redundancy of Spontaneous Variability Regulation via Predictability and Transfer Entropy Decomposition Frameworks.

Indexes assessing the balance between redundancy and synergy were hypothesized to be helpful in characterizing cardiovascular control from spontaneous beat-to-beat variations of heart period (HP), systolic arterial pressure (SAP), and respiration (R). Net redundancy/synergy indexes were derived according to predictability and transfer entropy decomposition strategies via a multivariate linear regression approach. Indexes were tested in two protocols inducing modifications of the cardiovascular regulation via baroreflex loading/unloading (i.

Mechanical ventilatory modes and cardioventilatory phase synchronization in acute respiratory failure patients.

Cardioventilatory phase synchronization was studied in ten critically ill patients admitted in intensive care unit (ICU) for acute respiratory failure under two mechanical ventilatory modes: (i) pressure controlled ventilation (PCV); (ii) pressure support ventilation (PSV). The two modalities were administered to the same patient in different times in a random order. Cardioventilatory phase interactions were typified by plotting the relative position of a heartbeat, detected from the electrocardiogram and collected in n groups, within m ventilatory cycles as a function of the progressive cardiac beat number via the synchrogram.