Hypocalcemia Event Associated with Denosumab: A Real-World Study from FDA Adverse Event Reporting System (FAERS) Database.

BACKGROUND AND OBJECTIVE: Denosumab is widely used for osteoporosis and cancer treatment. However, hypocalcemia induced by denosumab is a frequent adverse event. The objective of this study is to comprehensively investigate the safety signals and the occurrence of hypocalcemia in real-world patient cases reported through the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). METHODS: Reports from January 1, 2017 to December 31, 2021 were extracted from the FAERS. Only cases of hypocalcemia suspected to denosumab were eligible in pharmacovigilance study. Denosumab-related hypocalcemia safety signal were identified to characterize their clinical features. A safety signal for hypocalcemia was evaluated using reporting odds ratios (ROR). RESULTS: Among the 102,413 cases related to denosumab, 1042 cases were reported with denosumab-related hypocalcemia. The affected patients were mainly elderly (median age 70 years) and male (n = 568, 63.5%). In available data, the median onset time of 23 (range 0-1601) days. Most patients required drug interruption (n = 226, 72.9%) and can achieve a recovered-resolved state (n = 318, 62.1%). For the whole database, denosumab exhibited a safety signal for hypocalcemia (ROR = 14.09, 95% Cl 13.18, 15.06). In the sensitivity analyses, denosumab also showed a safety signal for hypocalcemia in cancer (ROR = 21.28, 95% Cl 18.79, 24.11) and osteoporosis (ROR = 9.29, 95% Cl 6.80, 12.59). Compared with bisphosphonates, denosumab still has safety signal for hypocalcemia (ROR = 1.88, 95% Cl 1.67, 2.11). CONCLUSIONS: This pharmacovigilance database analysis indicates a high safety signal for hypocalcemia associated with denosumab, particularly in cancer patients.

Airway delivery of Streptococcus salivarius is sufficient to induce experimental pulmonary hypertension in rats.

BACKGROUND AND PURPOSE: The causal relationship between altered host microbiome composition, especially the respiratory tract microbiome, and the occurrence of pulmonary hypertension (PH) has not yet been studied. An increased abundance of airway streptococci is seen in patients with PH compared with healthy individuals. This study aimed to determine the causal link between elevated airway exposure to Streptococcus and PH. EXPERIMENTAL APPROACH: The dose-, time- and bacterium-specific effects of Streptococcus salivarius (S. salivarius), a selective streptococci, on PH pathogenesis were investigated in a rat model established by intratracheal instillation. KEY RESULTS: Exposure to S. salivarius successfully induced typical PH characteristics, such as elevated right ventricular systolic pressure (RVSP), right ventricular hypertrophy (Fulton's index) and pulmonary vascular remodelling, in a dose- and time-dependent manner. Moreover, the S. salivarius-induced characteristics were absent in either the inactivated S. salivarius (inactivated bacteria control) treatment group or the Bacillus subtilis (active bacteria control) treatment group. Notably, S. salivarius-induced PH is characterized by elevated inflammatory infiltration in the lungs, in a pattern different from the classic hypoxia-induced PH model. Moreover, in comparison with the SU5416/hypoxia-induced PH model (SuHx-PH), S. salivarius-induced PH causes similar histological changes (pulmonary vascular remodelling) but less severe haemodynamic changes (RVSP, Fulton's index). S. salivarius-induced PH is also associated with altered gut microbiome composition, suggesting potential communication of the lung-gut axis. CONCLUSION AND IMPLICATIONS: This study provides the first evidence that the delivery of S. salivarius in the respiratory tract could cause experimental PH in rats.

Prediction and prognosis of adverse maternal and foetal/neonatal outcomes in pulmonary hypertension: an observational study and nomogram construction.

BACKGROUND: Pregnant women with pulmonary hypertension (PH) have higher mortality rates and poor foetal/neonatal outcomes. Tools to assess these risk factors are not well established. METHODS: Predictive and prognostic nomograms were constructed using data from a "Development" cohort of 420 pregnant patients with PH, recorded between January 2009 and December 2018. Logistic regression analysis established models to predict the probability of adverse maternal and foetal/neonatal events and overall survival by Cox analysis. An independent "Validation" cohort comprised data of 273 consecutive patients assessed from January 2019 until May 2022. Nomogram performance was evaluated internally and implemented with online software to increase the ease of use. RESULTS: Type I respiratory failure, New York Heart Association functional class, N-terminal pro-brain natriuretic peptide [Formula: see text] 1400 ng/L, arrhythmia, and eclampsia with pre-existing hypertension were independent risk factors for maternal mortality or heart failure. Type I respiratory failure, arrhythmia, general anaesthesia for caesarean section, New York Heart Association functional class, and N-terminal pro-brain natriuretic peptide [Formula: see text] 1400 ng/L were independent predictors of pulmonary hypertension survival during pregnancy. For foetal/neonatal adverse clinical events, type I respiratory failure, arrhythmia, general anaesthesia for caesarean section, parity, platelet count, fibrinogen, and left ventricular systolic diameter were important predictors. Nomogram application for the Development and Validation cohorts showed good discrimination and calibration; decision curve analysis demonstrated their clinical utility. CONCLUSIONS: The nomogram and its online software can be used to analyse individual mortality, heart failure risk, overall survival prediction, and adverse foetal/neonatal clinical events, which may be useful to facilitate early intervention and better survival rates.

Neurotransmitters: Potential Targets in Glioblastoma.

For decades, glioblastoma multiforme (GBM), a type of the most lethal brain tumor, has remained a formidable challenge in terms of its treatment. Recently, many novel discoveries have underlined the regulatory roles of neurotransmitters in the microenvironment both physiologically and pathologically. By targeting the receptors synaptically or non-synaptically, neurotransmitters activate multiple signaling pathways. Significantly, many ligands acting on neurotransmitter receptors have shown great potential for inhibiting GBM growth and development, requiring further research. Here, we provide an overview of the most novel advances concerning the role of neurotransmitters in the normal neural and the GBM microenvironments, and discuss potential targeted drugs used for GBM treatment.

Serum metabonomic study of the effects of Huofeitong tablet on rats with COPD.

Chronic obstructive pulmonary disease (COPD) is a common respiratory disease. The Huofeitong tablet (HFTT), a Chinese compound medicine, exhibits an unambiguous therapeutic effect on COPD. However, the mechanism of its therapeutic effect on COPD is unclear. This study aimed to investigate the effect of HFTT on COPD and its mechanism. The changes in pulmonary function and the inflammatory factors in rats were determined via histopathology and bronchoalveolar lavage fluid. The mechanism of HFTT in COPD treatment was revealed using UPLC-Q-TOF-MS/MS and multivariate statistical analysis. Results showed that after HFTT treatment, the lung function began to recover, the lung tissue improved, and the TNF-α and IL-6 levels decreased, suggesting that HFTT had a therapeutic effect on COPD. In addition, 12 potential biomarkers, including malonate, urea-1-carboxylate, pyruvate, l-cysteate, glutathione, 2-deoxy-α-d-ribose1-phosphate, 3-fumarylpyruvate, 3-maleylpyruvate, 2-inosose, urate, allantoin, and inosine were screened. They associated with COPD development and concentrated in glutathione metabolism, glyoxylate and dicarboxylate metabolism, secondly concentrated in pyruvate metabolism, glycolysis/gluconeogenesis, pentose phosphate pathway, citrate cycle, glycine, serine and threonine metabolism, inositol phosphate, and purine metabolism. This study contributes to the development and application of HFTT in COPD treatment and provides a theoretical basis for COPD diagnosis, prevention, and treatment.

Cardioprotective effects of timosaponin B-II isolated from Anemarrhena rhizome in a zebrafish model.

Timosaponin B-II (TB-II; (25S)-26-(ß-D-glucopyranosyloxy)-3ß-[(2-O-ß-D-glucopyranosyl-ß-D-galactopyranosyl) oxy]-5ß-furostan-22-ol is extracted from Anemarrhena. Its anti-inflammation, anti-oxidation, and anti-asthma properties have been widely explored. However, its effect on the heart has not been reported. In this study, we used zebrafish as a research model to determine the effects of TB-II on the heart and its toxic and anti-inflammatory effects. To explore the cause of cardioprotective effects of TB-II, we used transgenic zebrafish with macrophages and neutrophils labeled with fluorescent protein. We found for the first time that TB-II had a protective effect on the zebrafish heart. It did not affect the survival and hatching rates of zebrafish embryos, indicating its low toxicity. Results showed that TB-II may have cardioprotective effects, which might be related to its anti-inflammatory effects.

BRCA1 R71K missense mutation contributes to cancer predisposition by increasing alternative transcript levels.

Mutation screening of the breast and ovarian cancer predisposition genes BRCA1 and BRCA2 is becoming an increasingly important part of clinical practice. Classification of rare non-truncating sequence variants in the BRCA1 and BRCA2 genes is problematic because it is not known whether these subtle changes alter function sufficiently to predispose cells to cancer development. The BRCA1 331G > A substitution mutation, which occurs at the last nucleotide of exon 5, results in an Arg-to-Lys change at codon 71 (R71K). cDNA analysis indicated that the R71K mutation significantly increases the level of a transcript, characterized by a 22 bp deletion in exon 5, which putatively produces a truncated BRCA1 protein of 63 amino acids. The mutation completely abolishes normal splicing as the mutant allele does not generate any normal transcript. Analysis of a tumor specimen indicates loss of heterozygosity. These results support the conclusion that BRCA1 331G > A (R71K) is a deleterious mutation.

NF-kappaB regulates androgen receptor expression and prostate cancer growth.

Prostate cancers that progress during androgen-deprivation therapy often overexpress the androgen receptor (AR) and depend on AR signaling for growth. In most cases, increased AR expression occurs without gene amplification and may be due to altered transcriptional regulation. The transcription factor nuclear factor (NF)-kappaB, which is implicated in tumorigenesis, functions as an important downstream substrate of mitogen-activated protein kinase, phosphatidylinositol 3-kinase, AKT, and protein kinase C and plays a role in other cancer-associated signaling pathways. NF-kappaB is an important determinant of prostate cancer clinical biology, and therefore we investigated its role in the regulation of AR expression. We found that NF-kappaB expression in prostate cancer cells significantly increased AR mRNA and protein levels, AR transactivation activity, serum prostate-specific antigen levels, and cell proliferation. NF-kappaB inhibitors decrease AR expression levels, prostate-specific antigen secretion, and proliferation of prostate cancer cells in vitro. Furthermore, inhibitors of NF-kappaB demonstrated anti-tumor activity in androgen deprivation-resistant prostate cancer xenografts. In addition, levels of both NF-kappaB and AR were strongly correlated in human prostate cancer. Our data suggest that NF-kappaB can regulate AR expression in prostate cancer and that NF-kappaB inhibitors may have therapeutic potential.

Genome-wide analysis of gene expression associated with MYCN in human neuroblastoma.

Molecular mechanisms through which MYCN expression contributes to the malignant phenotype of neuroblastoma are unknown. We performed a genome-widegene expression analysis of 40 well-characterized neuroblastic tumors and 12 cell lines to identify genes and biological pathways associated with MYCN expression. Gene expression was validated by reverse transcription-PCR and immunohistochemistry using tissue arrays. Two hundred twenty-two of 62,839 oligonucleotide probe sets detected expression of genes that were strongly associated with MYCN expression. Differentially expressed genes included examples of known oncogenes, genes associated with neural differentiation, and genes related to cell proliferation. Expression of a subset of these genes was altered after transfection of a neuroblastoma cell line, SK-N-ER, with a MYCN expressing gene construct when protein synthesis was inhibited and have consensus MYCN binding E-box sequences in their promotor regions, suggesting they represent direct targets. Several novel genes/expressed sequences were identified as overexpressed and most likely coamplified with MYCN in a subset of cases. A classification model to identify neuroblastomas with high levels of MYCN expression was developed based on expression profiles. The identification of coexpressed and coamplified genes associated with MYCN overexpression in neuroblastoma suggests biochemical pathways that contribute to the malignant behavior of these tumors and forms a basis for molecular classification.

Novel regions of allelic imbalance identified by genome-wide analysis of neuroblastoma.

Several nonrandom chromosomal abnormalities have been associated with neuroblastoma (NB). However, the relationship of each genetic event to the clinical course of disease is not firmly established. We have performed a genome-wide allelic scan of NB to identify regions with frequent allelic imbalance (AI) and correlate the allelotype with clinical features of disease. Nineteen tumors from patients across the spectrum of NB were used. Genome-wide allelotype was performed using 169 fluorescently labeled microsatellite markers from the Weber 9a human screening set (Research Genetics, Huntsville, AL) and 48 independent markers for high-density analysis of selected regions. Eleven chromosomal regions had AI in >25% of tumors including loci known previously to be frequently altered such as 1p36 (10 of 19; 52%), 2p (9 of 19; 47%), 17q (8 of 19; 42%), 11q23 (8 of 19; 42%), 14q32 (7 of 19; 37%), 19q (6 of 19; 31%), 7q (6 of 19; 31%), 9p21 (5 of 19; 26%), and three novel regions of frequent AI at 10p11-p15 (7 of 19; 40%), 12q24.1 (5 of 19; 26%), and 8qcen-q24 (5 of 19; 26%). AI of four regions (8q, 10p, 19q, and 12q) allowed the distinction of two genetic groups that matched clinical significant subgroups of NB. AI at 12q24 and 19q13 was found exclusively in high-risk local-regional tumors, whereas AI at 10p11 and 8q appeared to be specific for stage 4 tumors with MCYN amplification. Spontaneously remitting or quiescent tumors were intact at all of the regions described above.