Comprehensive Analysis of Bortezomib-Induced Adverse Events Using the Japanese Real-World Database

Background: Bortezomib is used as first-line therapy for multiple myeloma. Observational studies based on the FDA Adverse Event Reporting System (FAERS) database analysis and systematic reviews indicate that the incidence of peripheral neuropathy and tumor lysis syndrome (TLS) tends to be higher with bortezomib than that of other drugs. In a comprehensive analysis assessing drugs that cause peripheral neuropathy in Japanese patients, the incidence of bortezomib-induced adverse events (AEs) was reportedly high. However, a comprehensive assessment of bortezomib is lacking. Objectives: The purpose of this study was to determine the frequency of bortezomib AEs in Japanese patients and to determine the incidence, time to onset, and post hoc outcomes of unique AEs using the Japanese Adverse Drug Event Report (JADER) database. Method: To investigate the association between bortezomib and AEs, we analyzed the JADER database, which contains spontaneous AE reports submitted to the Pharmaceuticals and Medical Devices Agency from April 2004 to December 2020. Criteria indicating the presence of an AE signal were met when the following requirements were fulfilled: proportional reporting ratios (PRR) ≥ 2 and χ2 ≥ 4. Time to onset and post-event outcomes were analyzed for characteristic AEs. Results: Among 26 extracted AEs, 13 presented AE signals. The post-exposure outcomes of 12 AEs showed fatal outcomes at rates exceeding 10%, including cardiac failure (30%), lung disorder (24%), pneumonia (18%), and TLS (10%). Furthermore, a histogram of time to onset revealed that the 12 AEs were concentrated from the beginning to approximately one month after bortezomib administration. The median onset times for cardiac failure, lung disorder, pneumonia, and TLS were 28, 13, 42, and 5 days, respectively. Conclusions: Cardiac failure, lung disorder, pneumonia, and TLS had a higher rate of fatal clinical outcomes after onset than other AEs. These AEs exhibited a greater onset tendency in the early post-dose period. This study suggests that there is a need to monitor signs of cardiac failure, lung disorder, pneumonia, and TLS, potentially resulting in serious outcomes.

High-mobility group box1 peptide ameliorates bronchopulmonary dysplasia via suppressing inflammation and fibrosis in a mouse model

Bronchopulmonary dysplasia (BPD) is a chronic lung disorder that affect approximately 40% of preterm infants, with no established curative therapy. The administration of mesenchymal stem cells (MSCs) to BPD patients has shown promising outcomes. Previously, we demonstrated that a synthesized peptide originating from high mobility group box-1 protein (HMGB1) induces a regenerative cascade through activating endogenous MSCs. Here, we tested whether the HMGB1 peptide can ameliorate BPD-related lung injury. In a mouse BPD model established via hyperoxia exposure, three shots of HMGB1 peptide significantly improved survival and suppressed inflammation and fibrosis in the lung. Single-cell RNA-sequencing of the lung further showed that the peptide significantly suppressed a hyperoxia-induced inflammatory signature in macrophages and fibrotic signature in fibroblasts. These changes in the transcriptome were also confirmed at the protein level. Taken together, our data show that treatment with the HMGB1 peptide suppressed inflammation and fibrosis, thus preventing BPD progression. This study serves as a foundation for the development of new effective therapies for BPD.

A Review of Placenta and Umbilical Cord-Derived Stem Cells and the Immunomodulatory Basis of Their Therapeutic Potential in Bronchopulmonary Dysplasia

Bronchopulmonary dysplasia (BPD) is a devastating lung disorder of preterm infants as a result of an aberrant reparative response following exposures to various antenatal and postnatal insults. Despite sophisticated medical treatment in this modern era, the incidence of BPD remains unabated. The current strategies to prevent and treat BPD have met with limited success. The emergence of stem cell therapy may be a potential breakthrough in mitigating this complex chronic lung disorder. Over the last two decades, the human placenta and umbilical cord have gained increasing attention as a highly potential source of stem cells. Placenta-derived stem cells (PDSCs) and umbilical cord-derived stem cells (UCDSCs) display several advantages such as immune tolerance and are generally devoid of ethical constraints, in addition to their stemness qualities. They possess the characteristics of both embryonic and mesenchymal stromal/stem cells. Recently, there are many preclinical studies investigating the use of these cells as therapeutic agents in neonatal disease models for clinical applications. In this review, we describe the preclinical and clinical studies using PDSCs and UCDSCs as treatment in animal models of BPD. The source of these stem cells, routes of administration, and effects on immunomodulation, inflammation and regeneration in the injured lung are also discussed. Lastly, a brief description summarized the completed and ongoing clinical trials using PDSCs and UCDSCs as therapeutic agents in preventing or treating BPD. Due to the complexity of BPD, the development of a safe and efficient therapeutic agent remains a major challenge to both clinicians and researchers.

A Mini-Review and Perspective on Anti-hypoxic Hypothesis of COVID-19

A novel coronavirus emerged in Wuhan, China; in December 2019 and has widely affected the global community. After months of extensive effort, much remains to be understood of the pathogenesis of Coronavirus Disease 2019 (COVID-19). The available evidence raises a critical question : Is COVID-19 a lung disorder leading to circulatory problems, or a systemic disorder that leads to lung problems?. If the latter scenario is correct, investigations on hypoxia conditions and the development of anti-hypoxia agents may lead to potential front-line treatments in combination with antivirals for hypoxemic COVID-19 patients. Hence, anti-hypoxic agents may become a potential part of combination therapy in hypoxemic respiratory failure and COVID-19.

Caplan’s Syndrome (rheumatoid pneumoconiosis), a rare disease entity: case report

Caplan’s syndrome, known as rheumatoid pneumoconiosis, was first described by Anthony Caplan in 1953, who identified a rare lung disorder found in coal mine workers with rheumatoid arthritis. Although Caplan’s syndrome was found in patients with a variety of pneumoconioses, it mostly affects individuals with long exposure to crystalline silica. We present a case of Caplan’s syndrome in a patient with advanced stage of rheumatoid arthritis and silicosis.