A nonnatural peptide targeting the A-kinase anchoring function of PI3Kγ for therapeutic cAMP modulation in pulmonary cells.

A-kinase anchoring proteins (AKAPs) are key orchestrators of cAMP signaling that act by recruiting protein kinase A (PKA) in proximity of its substrates and regulators to specific subcellular compartments. Modulation of AKAPs function offers the opportunity to achieve compartment-restricted modulation of the cAMP/PKA axis, paving the way to new targeted treatments. For instance, blocking the AKAP activity of phosphoinositide 3-kinase γ (PI3Kγ) improves lung function by inducing cAMP-mediated bronchorelaxation, ion transport, and antiinflammatory responses.

Two cases of misleading Epstein-Barr virus infection and the role of EBV-DNA.

Two atypical cases of infectious mononucleosis in two teenagers with initially negative serology and non-evocative blood examinations are reported. The first patient had recently traveled to Africa, and Epstein-Barr virus negative serology led us to make many extensive investigations. The second patient complained of asthenia for a month, and PET/CT was performed to suspicion of lymphoma.

It Takes Two to Tango! Protein-Protein Interactions behind cAMP-Mediated CFTR Regulation.

Over the last fifteen years, with the approval of the first molecular treatments, a breakthrough era has begun for patients with cystic fibrosis (CF), the rare genetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). These molecules, known as CFTR modulators, have led to unprecedented improvements in the lung function and quality of life of most CF patients. However, the efficacy of these drugs is still suboptimal, and the clinical response is highly variable even among individuals bearing the same mutation.

A PI3Kγ mimetic peptide triggers CFTR gating, bronchodilation, and reduced inflammation in obstructive airway diseases.

Cyclic adenosine 3',5'-monophosphate (cAMP)-elevating agents, such as β-adrenergic receptor (β-AR) agonists and phosphodiesterase (PDE) inhibitors, remain a mainstay in the treatment of obstructive respiratory diseases, conditions characterized by airway constriction, inflammation, and mucus hypersecretion. However, their clinical use is limited by unwanted side effects because of unrestricted cAMP elevation in the airways and in distant organs. Here, we identified the A-kinase anchoring protein phosphoinositide 3-kinase γ (PI3Kγ) as a critical regulator of a discrete cAMP signaling microdomain activated by β-ARs in airway structural and inflammatory cells.

Reply to Ialongo et al. Vitamin D, SARS-CoV-2 and Causal Associations in Transversal Studies: The Time-Series Analysis to Reveal Potential Confounders. Comment on "Gaudio et al. Vitamin D Levels Are Reduced at the Time of Hospital Admission in Sicilian SARS-CoV-2-Positive Patients. 2021, , 3491".

We read the comment by Ialongo et al. [..

Vitamin D Levels Are Reduced at the Time of Hospital Admission in Sicilian SARS-CoV-2-Positive Patients.

The coronavirus disease 2019 (COVID-19) pandemic poses a worldwide healthcare challenge that needs an efficient response. Unfortunately, to date there is no highly effective treatment, so a deep understanding of COVID-19 risk factors could be an important step in treating the disease. Vitamin D affects the immune system in many different ways, and other authors already found that COVID-19 patients have low levels of vitamin D.

Sequencing radium 223 and other life-prolonging agents in castration-resistant prostate cancer patients.

Radium 223 (RA223) is currently administered as part of a therapeutic sequence with the other life-prolonging agents (LPAs) for metastatic castration-resistant prostate cancer (mCRPC). We retrospectively reviewed the clinical records of patients who had received at least three LPAs including RA223. Median overall survival (OS) from the start of first-line treatment was 39.

Therapeutic peptides for the treatment of cystic fibrosis: Challenges and perspectives.

Cystic fibrosis (CF) is the most common amongst rare genetic diseases, affecting more than 70.000 people worldwide. CF is characterized by a dysfunctional chloride channel, termed cystic fibrosis conductance regulator (CFTR), which leads to the production of a thick and viscous mucus layer that clogs the lungs of CF patients and traps pathogens, leading to chronic infections and inflammation and, ultimately, lung damage.

Potential therapeutic applications of AKAP disrupting peptides.

The 3'-5'-cyclic adenosine monophosphate (cAMP)/PKA pathway represents a major target for pharmacological intervention in multiple disease conditions. Although the last decade saw the concept of highly compartmentalized cAMP/PKA signaling consolidating, current means for the manipulation of this pathway still do not allow to specifically intervene on discrete cAMP/PKA microdomains. Since compartmentalization is crucial for action specificity, identifying new tools that allow local modulation of cAMP/PKA responses is an urgent need.

A National Multicenter Study on overall survival in elderly metastatic castrate-resistant prostate cancer patients treated with Radium-223.

Background: Radium-223 prolongs overall survival (OS) and delays time to the first symptomatic skeletal events in patients with symptomatic metastatic castration-resistant prostate cancer (mCRPC). There is a lack of evidence on the safety and efficacy of Radium-223 treatment in the very elderly population.

Aims: Aim of this multicentre study is to analyze mCRPC patients treated with Radium-223 in terms of OS and to assess whether there are differences between young and elderly, as well as to verify efficacy and safety in patients ≥ 75 years of age.

Mechanisms of Anthracycline-Induced Cardiotoxicity: Is Mitochondrial Dysfunction the Answer?

Cardiac side effects are a major drawback of anticancer therapies, often requiring the use of low and less effective doses or even discontinuation of the drug. Among all the drugs known to cause severe cardiotoxicity are anthracyclines that, though being the oldest chemotherapeutic drugs, are still a mainstay in the treatment of solid and hematological tumors. The recent expansion of the field of Cardio-Oncology, a branch of cardiology dealing with prevention or treatment of heart complications due to cancer treatment, has greatly improved our knowledge of the molecular mechanisms behind anthracycline-induced cardiotoxicity (AIC).

Radium-223 treatment in castration resistant bone metastatic prostate cancer. Should be the primary tumor always treated?

Introduction: Radium-223 (223Ra) improves symptoms and survival in patients with bone metastatic castration-resistant prostate cancer (mCRPC).

Study Aim: To evaluate the impact of a previous radical prostatectomy (RP) on the outcome of 223Ra therapy in mCRPC patients. The primary prostate tumor left untreated could progress during 223Ra treatment.

Can radium 223 be a conservative non-surgical management of medication-related osteonecrosis of the jaw?

Osteonecrosis of the jaw (ONJ) is a rare and severe necrotic bone disease reflecting a compromise in the body's osseous healing mechanisms and unique to the craniofacial region. Radium 223 dichloride (Ra223) is the only targeted alpha therapy able to extend survival in patients with bone metastases from prostate cancer. Mechanism of action and data currently available focused mainly on osteoblastic metastases from prostate cancer.

A strange case of dyspnoea.

Acquired neuralgic amyotrophy, described for the first time by Parsonage and Turner, is a rare idiopathic disease that may occur in otherwise normal healthy individuals. It typically begins with sudden, unilateral shoulder pain that may also involve the neck and/or arm. Less frequently, the disease involves nerves other than those of the brachial plexus, such as phrenic nerves, resulting in dyspnoea.

Hematologic toxicity of radium-223 in elderly patients with metastatic Castration Resistant Prostate Cancer: a real-life experience.

Background: Treatment with radium-223 has been shown to increase survival and to delay skeletal events related to bone metastases of patients with metastatic Castration Resistant Prostate Cancer (mCRPC). This treatment has also proved to be well tolerated, and hematological toxicity, in particular anemia, represents the most represented adverse event.

Materials And Methods: We evaluated the hematologic toxicity of Ra-223 treatment in a real-life experience of 38 patients from two Italian cancer centers, with bone metastases from mCRPC.

Therapeutic effect of RA223 in the management of breast cancer bone metastases.

Radium 223 dichloride (Ra223) is the only targeted alpha therapy able to extend survival in patients with bone metastases from prostate cancer. Mechanism of action and data currently available focused mainly on osteoblastic metastases from prostate cancer. Phase 1 and 2 trials documented a clinical efficacy also in breast cancer patients with predominately bone disease, highlighting a reduction in alkaline phosphatase and other bone biomarkers.

Inhaled Biologicals for the Treatment of Cystic Fibrosis.

Background: Cystic Fibrosis (CF), one of the most frequent genetic diseases, is characterized by the production of viscous mucus in several organs. In the lungs, mucus clogs the airways and traps bacteria, leading to recurrent/resistant infections and lung damage. For cystic fibrosis patients, respiratory failure is still lethal in early adulthood since available treatments display incomplete efficacy.

Ra223 in Bone Metastases with Osteolytic Activity.

Radium 223 dichloride (Ra223) is the only targeted alpha therapy able to extend survival in patients with bone metastases from prostate cancer. Mechanism of action and data currently available focused mainly on osteoblastic metastases from prostate cancer. In our institution, a patient with breast cancer affected by osteolytic metastases was treated with off-label use of Ra223.

PI3K Signaling in Chronic Obstructive Pulmonary Disease: Mechanisms, Targets, and Therapy.

Chronic Obstructive Pulmonary Disease (COPD) is a progressive respiratory disorder characterized by irreversible chronic inflammation and airflow obstruction. It affects more than 64 million patients worldwide and it is predicted to become the third cause of death in the industrialized world by 2030. Currently available therapies are not able to block disease progression and to reduce mortality, underlying the need for a better understanding of COPD pathophysiological mechanisms to identify new molecular therapeutic targets.

The Clinical Efficacy of Radium-223 for Bone Metastasis in Patients with Castration-Resistant Prostate Cancer: An Italian Clinical Experience.

Background/aim: Prostate cancer frequently causes bone metastases and skeletal events that impair quality of life (QoL) and survival. The alpha emitter radium-223 is a new drug that improves treatment in men with castration-resistant prostate cancer (CRPC) and bone metastases. Our aim was to evaluate the effectiveness of radium-223.

PI3Ks in Diabetic Cardiomyopathy.

Diabetic cardiomyopathy is a heart disease in diabetic patients, identified as ventricular dysfunction in the absence of coronary artery disease and hypertension. The molecular mechanisms underlying diabetic cardiomyopathy are still poorly understood. The protein and lipid kinase phosphoinositide 3-kinases (PI3Ks) have been suggested to regulate cardiac injury during diabetes.

Therapeutic Targeting of PDEs and PI3K in Heart Failure with Preserved Ejection Fraction (HFpEF).

Purpose Of Review: Heart Failure with preserved Ejection Fraction (HFpEF) is a prevalent disease with considerable individual and societal burden. HFpEF patients often suffer from multiple pathological conditions thatcomplicate management and adversely affect outcome, including pulmonary hypertension and chronic obstructive pulmonary disease (COPD). To date, no treatment proved to be fully effective in reducing morbidity and mortality in HFpEF, possibly due to an incomplete understanding of the underlying molecular mechanisms.

Expiratory CT scan in patients with normal inspiratory CT scan: a finding of obliterative bronchiolitis and other causes of bronchiolar obstruction.

Expiratory CT scan is usually obtained as supplement to normal inspiratory CT scan to recognize air-trapping, which is expression of small airways obstruction. In some patients the air-trapping may be the only sign of an early-stage small airways disease in an otherwise normal lung.The purpose of this article is to illustrate pathologic conditions, namely obliterative bronchiolitis, in which expiratory CT scan can be abnormal despite normal inspiratory CT examination, and to highlight indications for this technique in patients with clinical and functional suspect of bronchiolar obstruction.