Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Online First

Denosumab, a fully humanized monoclonal neutralizing antibody inhibiting the RANK/RANKL/OPG signaling pathway, is widely used for treating patients with bone metastases. However, its use in cancer patients with bone metastases is burdened by the risk of all grades of hypocalcemia, with the severe grade being rare. In the literature, several cases of severe symptomatic hypocalcemia have been reported, particularly in patients with breast and prostate cancers. In this report, we present a rare case of asymptomatic hypocalcemia in a 78 years-old patient with sigmoid cancer and bone metastases.

Hypocalcemia was detected two weeks after the first denosumab administration, during routine biochemical evaluation. The patient reported only a mild nonspecific paresthesia after medical questioning, without relevant clinical symptoms. Despite the severity of the hypocalcemia, serum calcium levels began to improve after a short period of low-dose calcium and calcitriol therapy, though complete stabilization and normalization occurred after several weeks.

This case highlight the importance to consider severe paucisymptomatic or asymptomatic hypocalcemia as a possible side effect in bone-metastatic patients treated with denosumab. It is advisable to monitor serum calcium levels even in the absence of typical hypocalcemia-related symptoms.

This study aims to investigate the function and potential mechanism of Tanshinone IIA in uric acid-induced HK-2 fibrosis models.

An in vitro model of fibrosis was constructed using uric acid stimulation. RT-qPCR and Western blot were used to evaluate the levels of inflammatory cytokines. The detection of ROS and ELISA assay were used to analyze the changes in oxidative stress.

Tanshinone IIA inhibited the increase in inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-18 and the formation of NLRP3 inflammasome induced by uric acid stimulation. In addition, Tanshinone IIA treatment reduced the production of ROS and MDA, promoting the expression of SOD and CAT, thereby protecting HK-2 cells from oxidative stress damage. Besides, the expression of TGF-β, FN, and COL-1 was significantly reduced by the treatment of Tanshinone IIA. Mechanistically, Tanshinone IIA inhibited the expression of inflammatory cytokines and the formation of the NLRP3 inflammasome by targeting NRF2.

Tanshinone IIA exerts a protective role in uric acid-induced HK-2 fibrosis models by targeting the NRF2-NLRP3 signaling pathway to reduce the occurrence of inflammation and oxidative stress.

The purpose of this study was to comprehensively evaluate the association of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) with neurological adverse events using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database, with the aim of guiding the rational use of statins.

The number and clinical characteristics of adverse events (AEs) to statins in the FAERS database between 2012 and March, 2023, were extracted. Neurological AEs were defined by the system organ classes (SOCs) of “Nervous System Disorders (10029205)” and the corresponding PT. Disproportionality was calculated using the reporting dominance ratio (ROR), proportional reporting ratio (PRR), and information component (IC025).

Between January, 2012 and March, 2023, a total of 90,357 AEs were reported for the three statins (atorvastatin, resuvastatin, and simvastatin). The majority of reports on AEs came from the United States (n=7284). A total of 8409 reports described neurological AEs following the use of the three statins, with atorvastatin accounting for more than half of the reports (n=4430). The mean age of patients who developed neurological AEs was 55 years and older. The prevalence was similar in female patients (2230/4480) and male patients (1999/4480). Disproportionate analyses showed that at the SOC level, only the correlation between atorvastatin and neurological AEs suggested a positive signal (ROR: 9.77 (9.56-9.99); IC025: 3.28; PRR (χ²): 9.76 (16.07)) and in total, there were 32 PTs with a positive signal. The median time for neurological AEs was 71 days (IQR: 14-559 days), and the most common AEs were other serious effects (important medical event) (OT) (n=2283) and hospitalization (HO) (n=715).

This study suggests that atorvastatin may be associated with an increased risk of neurological AEs. This study provides realistic evidence of the potential risk of statin-related adverse events.

The diagnostic workup of an adrenal mass should always rule out the possibility of an adrenal metastasis, especially in a patient followed-up for a known primitive cancer. Sometimes, however, the incidental finding of a bulky lesion in a cancer patient can lead to the unexpected diagnosis of metastasis from a second occult cancer. Here, we report the case of a voluminous, isolated left adrenal metastasis from unknown and persistently occult hepatocellular carcinoma (HCC), incidentally found during the follow-up for squamous carcinoma of the tongue.

A 72-year-old HBV/HCV-negative male patient with a history of alcohol abuse was referred to our hospital for gastric bleeding. Some weeks before, the patient was operated on for a locally advanced squamous cell carcinoma of the tongue, which required cervical lymph node neck dissection, temporary tracheostomy, jejunostomy, and plastic reconstruction. Subsequent diagnostic imaging revealed a left adrenal mass sized 9x15 cm with suspicious features. The hormonal workout was negative for pheochromocytoma and a hyperfunctioning adrenal lesion. The patient underwent laparotomic left adrenalectomy. The exploration of the liver was compatible with alcoholic cirrhosis and did not reveal any other palpable lesion. The adrenal mass histologically turned out to be a poorly differentiated G3 HCC. Subsequent radiological exams were unable to identify the primary liver lesion or any other neoplasms. Conversely, α-FP levels were initially high but reduced after treatment with sorafenib. After 2 years of follow-up, the patient is alive and well, albeit with evidence of locoregional inter-aortocaval lymphadenopathy. The primary HCC has never been identified, thus suggesting the hypothesis of a diffuse cirrhosis-like HCC.

The suspicion of an adrenal metastasis in a patient with primary cancer with a low potential for adrenal metastatic spreading must raise the diagnostic suspect for another synchronous occult cancer beyond that for primary adrenal cancer. HCC can rarely first manifest as a metastatic adrenal lesion.

Recurrent Pregnancy Loss (RPL) and Polycystic Ovary Syndrome (PCOS) are both common diseases involving women of childbearing age, and their pathogenesis is still not sufficiently known.

This study aimed to explore the relationship between RPL and PCOS in bioinformatics.

Two expression chips, GSE86241 (obtained from 8 PCOS patients and 9 healthy controls) and GSE73025 (obtained from 5 RPL patients and 5 healthy controls), were downloaded from the Gene Expression Omnibus (GEO) database. We used the GEO database to analyze the gene expression profiles of PCOS and RPL to identify the intersection of abnormal miRNA expression, predicted the target genes of the intersecting miRNAs from miRDB, miRTarBase, and TargetScan databases, and then incorporated the miRNA-mRNA modulation network. By using the string database, the PPI network was built, which could screen the Hub genes and enrich them for analysis. Ultimately, the critical miRNA-mRNA regulatory network was set on the basis of the relationship between hub genes and miRNA.

A total of 39 significantly altered miRNAs of PCOS and 137 significantly altered miRNAs of RPL were obtained, three miRNAs (miR-767-5p, miR-3196, and miR-187-3p), five signaling pathways (PI3K-Akt, p53, Toll-like receptor, C-type lectin receptor, and TNF signaling pathways), and six Hub genes (CASP8, PIK3R1, ADAMTS2, ADAMTS3, COL3A1, and MDM2) were found to be related to the development and progression of two diseases. More importantly, all Hub genes were regulated by miR-767-5p.

This research clarifies the possible relationship between miRNA and mRNA with PCOS and RPL for the first time. It provides a basis for illustrating the pathogenic mechanism and a target of therapies for these two diseases.