Growth differentiation factor 11 (GDF11) – a promising anti‐ageing factor – is highly concentrated in platelets

Recent research suggests that growth differentiation factor 11 (GDF11) could reverse age‐related diseases and that its blood concentration decreases with age. This poses plasma from young donors as a therapeutic GDF11 source to treat age‐related diseases. In addition, the tissue source of circulating GDF11 remains unknown. We analysed GDF11 levels in paired samples of serum, plasma and platelet lysate (PL) from 23 volunteers. Plasma and PL were collected by plateletpheresis. Here, we show that GDF11 is highly concentrated in platelets and that the circulating levels reported in previous studies could be biased as a result of serum sample manipulation.     

Squalene synthase as a chemotherapeutic target in Trypanosoma cruzi and Leishmania mexicana

Trypanosoma cruzi and Leishmania parasites have a strict requirement for specific endogenous sterols (ergosterol and analogs) for survival and growth and cannot use the abundant supply of cholesterol present in their mammalian hosts. Squalene synthase (SQS, E.C. 2.5.1.21) catalyzes the first committed step in sterol biosynthesis and is currently under intense study as a possible target for cholesterol-lowering agents in humans, but it has not been investigated as a target for anti-parasitic chemotherapy. SQS is a membrane-bound enzyme in both T. cruzi epimastigotes and Leishmania mexicana promastigotes with a dual subcellular localization, being almost evenly distributed between glycosomes and mitochondrial/microsomal vesicles. Kinetic studies showed that the parasite enzymes display normal Michaelis-Menten kinetics and the values of the kinetic constants are comparable to those of the mammalian enzyme. We synthesized and purified 3-(biphenyl-4-yl)-3-hydroxyquinuclidine (BPQ-OH), a potent and specific inhibitor of mammalian SQS and found that it is also a powerful non-competitive inhibitor of T. cruzi and L. mexicana SQS, with K(i)'s in the range of 12-62 nM. BPQ-OH induced a dose-dependent reduction of proliferation the extracellular stages of these parasites with minimal growth inhibitory concentrations (MIC) of 10-30 microM. Growth inhibition and cell lysis induced by BPQ-OH in both parasites was associated with complete depletion of endogenous squalene and sterols, consistent with a blockade of de novo sterol synthesis at the level of SQS. BPQ-OH was able to eradicate intracellular T. cruzi amastigotes from Vero cells cultured at 37 degrees C, with a MIC of 30 microM with no deleterious effects on host cells. Taken together, these results support the notion that SQS inhibitors could be developed as selective anti-trypanosomatid agents.     

The multi-specific VH-based Humabody CB213 co-targets PD1 and LAG3 on T cells to promote anti-tumour activity

Background Improving cancer immunotherapy long-term clinical benefit is a major priority. It has become apparent that multiple axes of immune suppression restrain the capacity of T cells to provide anti-tumour activity including signalling through PD1/PD-L1 and LAG3/MHC-II.Methods CB213 has been developed as a fully human PD1/LAG3 co-targeting multi-specific Humabody composed of linked V_H domains that avidly bind and block PD1 and LAG3 on dual-positive T cells. We present the preclinical primary pharmacology of CB213: biochemistry, cell-based function vs. immune-suppressive targets, induction of T cell proliferation ex vivo using blood obtained from NSCLC patients, and syngeneic mouse model anti-tumour activity. CB213 pharmacokinetics was assessed in cynomolgus macaques.Results CB213 shows picomolar avidity when simultaneously engaging PD1 and LAG3. Assessing LAG3/MHC-II or PD1/PD-L1 suppression individually, CB213 preferentially counters the LAG3 axis. CB213 showed superior activity vs. αPD1 antibody to induce ex vivo NSCLC patient T cell proliferation and to suppress tumour growth in a syngeneic mouse tumour model, for which both experimental systems possess PD1 and LAG3 suppressive components. Non-human primate PK of CB213 suggests weekly clinical administration.Conclusions CB213 is poised to enter clinical development and, through intercepting both PD1 and LAG3 resistance mechanisms, may benefit patients with tumours escaping front-line immunological control.Subject terms: Antibody fragment therapy, Cancer immunotherapy, Drug development     

The Myotis chiloensis Guano Virome: Viral Nucleic Acid Enrichments for High-Resolution Virome Elucidation and Full Alphacoronavirus Genome Assembly

Bats are widespread mammals of the order Chiroptera. They are key for ecosystem functioning, participating in crucial processes. Their unique ability amongst mammals to fly long distances, their frequently large population sizes, and their longevity favor infectious agent persistence and spread. This includes a large variety of viruses, encompassing many important zoonotic ones that cause severe diseases in humans and domestic animals. Despite this, the understanding of the viral ecological diversity residing in bat populations remains unclear, which complicates the determination of the origins of zoonotic viruses. To gain knowledge on the viral community of a widely distributed insectivorous bat species, we characterized the guano virome of a native Chilean bat species (Myotis chiloensis (Waterhouse, 1840)). By applying a novel enrichment strategy, we were able to secure a consequent percentage of viral reads, providing unprecedented resolution for a bat virome. This in turn enabled us to identify and assemble a new bat alphacoronavirus from Chilean bats closely related to PEDV, an important viral pathogen with high mortality rates in suckling piglets. This study highlights the importance of applying and improving high-resolution virome studies in this vital order to ultimately enhance epidemiological surveillance for potentially zoonotic pathogens.     

Anesthetic management in mastocytosis

Mastocytosis is a heterogeneous grouping of entities characterized by proliferation of mast cells in one or more organs or tissues. The skin is the most frequently affected organ, followed by bone marrow. The relevance of this disease to anesthesia lies in the fact that many drugs used can trigger massive release of chemical mediators of mast cells. We report the case of a patient diagnosed with cutaneous mastocytosis who underwent testicular biopsy with intradural anesthesia. We review the fundamental aspects of the disease and the principles of anesthetic management.     

Chest physiotherapy in lung resection patients: state of the art

The role of chest physiotherapy in limiting postoperative pulmonary complications and in the recovery of pulmonary function and exercise capacity after lung surgery is still unclear because of the lack of conclusive, well-designed clinical trials. In this article the available literature on these topics is reviewed, and the effects of respiratory physiotherapy, instituted preoperatively or administered after surgery to patients undergoing lung resection, are commented on. The authors conclude that chest physiotherapy improves preoperative exercise capacity; this is a parameter highly predictive of postoperative pulmonary complications. Also physiotherapy administered during the immediate period after lung resection probably decreases frequency of pulmonary complications. Finally, further investigation is required for a better understanding of the effects of long-term chest physiotherapy after hospital discharge in lung resection patients.     

Nitric oxide in pulmonary arteriovenous malformations and Fontan procedure

Pulmonary arteriovenous malformations are a well documented complication of superior cavopulmonary (Glenn) connections. We report the successful management of a case of severe hypoxemia in the early postoperative period of a patient who underwent the Fontan operation. The patient had previously been diagnosed with pulmonary arteriovenous malformations; the use of inhaled nitric oxide was followed up with reversal of life-threatening hypoxemia. At 6-month postoperative follow-up, the patient was asymptomatic with near normal aortic saturation.     

Jaundice and chronic pancreatitis: common bile duct compression by pancreatic pseudocyst

In chronic pancreatitis, obstructive jaundice solely due to common bile duct compression by a pancreatic pseudocyst is highly unusual. In most of these cases, the jaundice is due to fibrotic stricture of the intrapancreatic portion of the common bile duct. We report two cases of obstructive jaundice in chronic pancreatitis with pseudocyst. Operative findings and follow-up during the postoperative period demonstrated compression by the pseudocyst over the common bile duct as the only etiologic factor of the jaundice. We believe that intraoperative cholangiography should be performed after drainage of a pseudocyst to correctly assess the etiology of obstruction.