SV-IV Peptide1–16 reduces coagulant power in normal Factor V and Factor V Leiden

Native Factor V is an anticoagulant, but when activated by thrombin, Factor X or platelet proteases, it becomes a procoagulant. Due to these double properties, Factor V plays a crucial role in the regulation of coagulation/anticoagulation balance

Tuning Local Hydration Enables a Deeper Understanding of Protein-Ligand Binding: The PP1-Src Kinase Case

Water plays a key role in biomolecular recognition and binding. Despite the development of several computational and experimental approaches, it is still challenging to comprehensively characterize water-mediated effects on the binding process. Here, we investigate how water affects the binding of Src kinase to one of its inhibitors, PP1. Src kinase is a target for treating several diseases, including cancer. We use biased molecular dynamics simulations, where the hydration of predetermined regions is tuned at will. This computational technique efficiently accelerates the SRC-PP1 binding simulation and allows us to identify several key and yet unexplored aspects of the solvent's role. This study provides a further perspective on the binding phenomenon, which may advance the current drug design approaches for the development of new kinase inhibitors

An inhibitor of HIV-1 protease modulates constitutive eIF2α dephosphorylation to trigger a specific integrated stress response.

Inhibitors of the HIV aspartyl protease [HIV protease inhibitors (HIV-PIs)] are the cornerstone of treatment for HIV. Beyond their well-defined antiretroviral activity, these drugs have additional effects that modulate cell viability and homeostasis. However, little is known about the virus-independent pathways engaged by these molecules. Here we show that the HIV-PI Nelfinavir decreases translation rates and promotes a transcriptional program characteristic of the integrated stress response (ISR). Mice treated with Nelfinavir display hallmarks of this stress response in the liver, including α subunit of translation initiation factor 2 (eIF2α) phosphorylation, activating transcription factor-4 (ATF4) induction, and increased expression of known downstream targets. Mechanistically, Nelfinavir-mediated ISR bypassed direct activation of the eIF2α stress kinases and instead relied on the inhibition of the constitutive eIF2α dephosphorylation and down-regulation of the phophatase cofactor CReP (Constitutive Repressor of eIF2α Phosphorylation; also known as PPP1R15B). These findings demonstrate that the modulation of eIF2α-specific phosphatase cofactor activity can be a rheostat of cellular homeostasis that initiates a functional ISR and suggest that the HIV-PIs could be repositioned as therapeutics in human diseases to modulate translation rates and stress responses

Hydatid disease of the liver: thirty years of surgical experience.

Hydatid disease of the liver is a relatively frequent disease. Although the natural history is almost completely known, several complications may occur. The aim of this study was to show that radical surgical resection of the hepatic hydatid cyst is a safe and very effective technique, based on our results after 30-year experience. A review of most significant studies was carried out. We retrospectively evaluated our surgical cases. From January 1973 to December 2003 we treated 216 patients, 98 males and 118 females. Survival was compared with the Kaplan-Meier test, using log-rank analysis to compare data. Differences with a p value less than 0.05 were considered significant. A total of 279 cysts were excised. We performed pericystectomy in 122 cases, 73 of which closed. We also performed 19 atypical resections, 10 segmentectomies, 20 lobectomies and 2 percutaneous treatments. In more than 90% of cases, preoperative data collection was completed by preoperative ultrasound. The cumulative morbidity was 13%. The recurrence rate amounted to 4.3% at 5 years and 7% at 10 years: of these, 6 occurred after non-radical surgery and 2 after total pericystectomy or liver resection (p < 0.001). Technical advances and accumulated experience permit safe treatment of hepatic hydatid cysts by radical resection, with an almost zero recurrence rate, making it the treatment of choice over partial resection. The utility of percutaneous treatment remains confined to limited indications, such as laparoscopy

Boost operators in Coulomb-gauge QCD: the pion form factor and Fock expansions in phi radiative decays

In this article we rederive the Boost operators in Coulomb-Gauge Yang-Mills theory employing the path-integral formalism and write down the complete operators for QCD. We immediately apply them to note that what are usually called the pion square, quartic... charge radii, defined from derivatives of the pion form factor at zero squared momentum transfer, are completely blurred out by relativistic and interaction corrections, so that it is not clear at all how to interpret these quantities in terms of the pion charge distribution. The form factor therefore measures matrix elements of powers of the QCD boost and Moeller operators, weighted by the charge density in the target's rest frame. In addition we remark that the decomposition of the eta' wavefunction in quarkonium, gluonium, ... components attempted by the KLOE collaboration combining data from phi radiative decays, requires corrections due to the velocity of the final state meson recoiling against a photon. This will be especially important if such decompositions are to be attempted with data from J/psi decays.Comment: 14 pages, 4 figure

Standard wide local excision or bilateral reduction mammoplasty in large-breasted women with small tumours: Surgical and patient-reported outcomes.

Introduction Oncoplastic breast surgery is used to extend the role of breast-conserving surgery (BCS) to women with an unfavourable tumour to breast volume ratio. However, large-breasted women with a relatively small breast cancer may be offered bilateral reduction mammoplasty (BRM) despite being suitable for standard BCS as the more complex surgery may have advantages in terms of patient satisfaction and reduced adverse effects of radiotherapy.Patient and methods This retrospective study evaluated surgical and patient-reported outcome measures (PROMs) in large-breasted women with early ( 0.05).Conclusion Limitations of this study mean it can only be regarded as hypothesis-generating. Nonetheless, the trends merit a prospective study to investigate the optimal management of smaller breast cancers in larger-breasted women

Bilateral mammoplasty for cancer: Surgical, oncological and patient-reported outcomes.

Introduction Bilateral mammoplasty (BM) can optimise oncological safety and aesthetic outcomes in women with large or ptotic breasts whose tumour to breast volume ratio or tumour location pose a challenge to standard breast-conserving therapy (BCT) and for whom mastectomy (with or without reconstruction) may be the only alternative.Methods We undertook a comprehensive analysis of surgical outcomes (complications according to the Clavien Dindo classification), acute radiation morbidity (Radiation Therapy Oncology Group classification), oncological outcomes, and patient satisfaction (BREAST-Q questionnaire) in women who underwent BM for breast cancer (BC) from June 2009-November 2014.Results 168 women were included. Median age was 55 years (range:33-84) and median tumour size at imaging 35 mm (range:0-170). Median specimen weight was 242 g (range 39-1824). The wise pattern technique was used in 87.5% of procedures. At least one complication occurred in 68 (40.5%) women, mostly Clavien Dindo grade 1. Grade 3 complications were infrequent (8.9%) but occurred mainly on the therapeutic mammoplasty (TM) side (p < 0.05). Complications were associated with higher BMI, specimen weight and longer time to radiotherapy (p < 0.05). Median follow-up was 37 months (range: 13-77). Local recurrence occurred in 3 (1.8%), distant metastases in 5 (3.0%), and 10 (6.0%) women have died. The median score for 'satisfaction with breasts' was 77 (range: 0-100).Conclusions This study provides concurrent data on surgical, oncological and patient-reported outcomes. It offers evidence that BM is an effective treatment for breast cancer in large- or ptotic-breasted women

Cardiovascular comorbidities and pharmacological treatments of covid-19 patients not requiring hospitalization

Introduction: The Coronavirus disease 2019 (COVID-19) outbreak is a whole Earth health emergency related to a highly pathogenic human coronavirus responsible for severe acute respiratory syndrome (SARS-CoV-2). Despite the fact that the majority of infected patients were managed in outpatient settings, little is known about the clinical characteristics of COVID-19 patients not requiring hospitalization. The aim of our study was to describe the clinical comorbidity and the pharmacological therapies of COVID-19 patients managed in outpatient settings. Materials and Methods: We performed an observational, retrospective analysis of laboratory-confirmed COVID-19 patients managed in outpatient settings in Naples, Italy between March 9 and May 1, 2020. Data were sourced from the prospectively maintained Health Search (HS)/Thales database, shared by 128 primary care physicians (PCPs) in Naples, Italy. The clinical features and pharmacological therapies of COVID-19 patients not requiring hospitalization and managed in outpatient settings have been described. Results: A total of 351 laboratory-confirmed COVID-19 patients (mean age 54 ± 17 years; 193 males) with outpatient management were evaluated. Hypertension was the most prevalent comorbidity (35%). The distribution of cardiovascular comorbidities showed no gender-related differences. A total of 201 patients (57.3%) were treated with at least one experimental drug for COVID-19. Azithromycin, alone (42.78%) or in combination (27.44%), was the most widely used experimental anti-COVID drug in outpatient settings. Low Molecular Weight Heparin and Cortisone were prescribed in 24.87% and 19.4% of the study population, respectively. At multivariate regression model, diabetes (risk ratio (RR): 3.74; 95% CI 1.05 to 13.34; p = 0.04) and hypertension (RR: 1.69; 95% CI 1.05 to 2.7; p = 0.03) were significantly associated with the experimental anti-COVID drug administration. Moreover, only diabetes (RR: 2.43; 95% CI 1.01 to 5.8; p = 0.03) was significantly associated with heparin administration. Conclusions: Our data show a high prevalence of hypertension, more likely treated with renin– angiotensin–aldosterone system (RASS) inhibitors, among COVID-19 patients not requiring hospitalization. Experimental COVID-19 therapies have been prescribed to COVID-19 patients considered at risk for increased venous thromboembolism based on concomitant comorbidities, in particular diabetes and hypertension