IL-38 blockade induces anti-tumor immunity by abrogating tumor-mediated suppression of early immune activation.

Immune checkpoint inhibitors that overcome T cell suppressive mechanisms in tumors have revolutionized the treatment of cancer but are only efficacious in a small subset of patients. Targeting suppressive mechanisms acting on innate immune cells could significantly improve the incidence of clinical response by facilitating a multi-lineage response against the tumor involving both adaptive and innate immune systems. Here, we show that intra-tumoral interleukin (IL)-38 expression is a feature of a large frequency of head and neck, lung and cervical squamous cancers and correlates with reduced immune cell numbers. We generated IMM20324, an antibody that binds human and mouse IL-38 proteins and inhibits the binding of IL-38 to its putative receptors, interleukin 1 receptor accessory protein-like 1 (IL1RAPL) and IL-36R. In vivo, IMM20324 demonstrated a good safety profile, delayed tumor growth in a subset of mice in an EMT6 syngeneic model of breast cancer, and significantly inhibited tumor expansion in a B16.F10 melanoma model. Notably, IMM20324 treatment resulted in the prevention of tumor growth following re-implantation of tumor cells, indicating the induction of immunological memory. Furthermore, exposure of IMM20324 correlated with decreased tumor volume and increased levels of intra-tumoral chemokines. Together, our data suggest that IL-38 is expressed in a high frequency of cancer patients and allows tumor cells to suppress anti-tumor immunity. Blockade of IL-38 activity using IMM20324 can re-activate immunostimulatory mechanisms in the tumor microenvironment leading to immune infiltration, the generation of tumor-specific memory and abrogation of tumor growth.

Mid-Term Outlook Following Modified Senning's Operation for the Correction of Transposition of the Great Arteries: A Case Series and Review of Literature.

At the time of writing, two patients who underwent modified Senning's operation (MSO) for the treatment of transposition of great arteries (TGAs) were followed up. At the time of surgery, the patients were three months and 15 years old, respectively. The duration of the follow-up was three years, during which there was a good prognosis, and hence no further invasive treatments were required. There was normal functioning of the right ventricle (RV) in both patients, with the exception of a minor baffle leak in the three-month-old patient. At the annual three-year follow-up, the tricuspid regurgitation (systemic atrioventricular valve) status was moderate in the three-year-old child and mild in the 18-year-old girl. Both patients maintained sinus rhythm and are assigned classification as New York Heart Association (NYHA) Classes I and II. This study aims to assess the midterm outlook after MSO in order to identify and manage future long-term complications. Our report shows a positive outcome in terms of survival and functional activities among children with d-TGA; however, there is a strong need for future research to evaluate the prognosis in the long term (LT) and to assess the functioning of RV.

Detecting and Quantifying Residual Intracardiac Shunts Using Oximetric Step-Up Methods: A Prospective Observational Study.

Background & aims  Intracardiac shunts are abnormal channels of blood circulation within the heart that develop either as an additional blood flow pathway or as a replacement for the normal channels of blood circulation. They are the commonest types of congenital heart defects. Various methods are available in the present times to identify, localize or quantify left-to-right intracardiac shunts. Methods may vary in sensitivity, indicators, or types of equipment available. One such method used in almost all cardiac centers for a long time has been oximetry run to detect step-up differences in oxygen saturation values. In the oximetry run the main approach to detect and estimate the left-to-right (L-->R) shunts requires the oxygen concentration expressed as a proportion of saturation to be evaluated in blood samples which are obtained from the right atrium (RA) and pulmonary artery (PA), respectively. A left-to-right shunt can be considered if there is a significant increase (step-up) in blood saturation. A significant step-up is defined as a substantial rise in blood oxygen content or saturation that is higher than normal values. Methods  Using a prospective observational design, this article investigates the application of the step-up method in detecting intracardiac shunts. The study was conducted between 2021 and 2022 on 35 pediatric cardiac patients (males/females, 24/11) diagnosed with post-tricuspid shunts. The pulmonary artery and right atrium were sampled before and after cardiopulmonary bypass surgery and analyzed using a blood gas test. As a result, nearly 91% of the patients had a saturation below 8%. However, the difference between PA oxygen saturation (SO2) & RASO2 before and after surgery was significant. As a result, the difference in O2 saturation helped detect the residual ventricular septal defect (VSD) after the surgery. Results  There were no deaths or complications in this study. There were no re-interventions for post-tricuspid shunt surgery, though one patient had a step-up of >15% and residual VSD status was moderate to large on two-dimensional (2D) echocardiography. Conclusion A combination of physical findings, chest radiography, electrocardiogram (ECG), and echocardiography is routinely done for all these patients undergoing pediatric cardiac surgery. Echocardiography can detect the occurrence of shunt but does not calculate the shunt ratio. Transesophageal or epicardial echocardiography is the standard of care but has its limitations like perception difference between the operating surgeon and the person performing echocardiography. In this study, we have added an oximetry analysis of blood-gas samples before and after surgery and compared it to 2D echocardiography to test the validation of oximetry in isolation and comparison to 2D echocardiography.

Measurement of Pro-Islet Amyloid Polypeptide (1-48) in Diabetes and Islet Transplants.

Context: Islet amyloid is a feature of ß-cell failure in type 2 diabetes (T2D) and type 1 diabetes (T1D) recipients of islet transplants. Islet amyloid contains islet amyloid polypeptide (IAPP; amylin), a circulating peptide that is produced in ß cells by processing of its precursor, proIAPP1-67, via an intermediate form, proIAPP1-48. Elevated proinsulin to C-peptide ratios in the plasma of persons with diabetes suggest defects in ß-cell prohormone processing. Objective: Determine whether plasma levels of precursor forms of IAPP are elevated in diabetes. Design, Setting, and Patients: We developed an immunoassay to detect proIAPP1-48 in human plasma, and we determined the ratio of proIAPP1-48 to mature IAPP in subjects with T1D, T2D, recipients of islet transplants, and healthy controls. Results: The proIAPP1-48 immunoassay had a limit of detection of 0.18 ± 0.06 pM and cross-reactivity with intact proIAPP1-67 <15%. Healthy individuals had plasma concentrations of proIAPP1-48 immunoreactivity of 1.5 ± 0.2 pM and a proIAPP1-48 to total IAPP ratio of 0.28 ± 0.03. Plasma concentrations of proIAPP1-48 immunoreactivity were not significantly different in subjects with T2D but were markedly increased in T1D recipients of islet transplants. Children and adults with T1D had reduced mature IAPP levels relative to age-matched controls but an elevated ratio of proIAPP1-48 to total IAPP. Conclusion: The ß cells in T1D and islet transplants have impaired processing of the proIAPP1-48 intermediate. The ratio of proIAPP1-48-to-IAPP immunoreactivity may have value as a biomarker of ß-cell stress and dysfunction.