Clinical and biomarker analyses of sintilimab plus gemcitabine and cisplatin as first-line treatment for patients with advanced biliary tract cancer.

The prognosis of biliary tract cancer (BTC) remains unsatisfactory. This single-arm, phase II clinical trial (ChiCTR2000036652) investigated the efficacy, safety, and predictive biomarkers of sintilimab plus gemcitabine and cisplatin as the first-line treatment for patients with advanced BTCs. The primary endpoint was overall survival (OS). Secondary endpoints included toxicities, progression-free survival (PFS), and objective response rate (ORR); multi-omics biomarkers were assessed as exploratory objective. Thirty patients were enrolled and received treatment, the median OS and PFS were 15.9 months and 5.1 months, the ORR was 36.7%. The most common grade 3 or 4 treatment-related adverse events were thrombocytopenia (33.3%), with no reported deaths nor unexpected safety events. Predefined biomarker analysis indicated that patients with homologous recombination repair pathway gene alterations or loss-of-function mutations in chromatin remodeling genes presented better tumor response and survival outcomes. Furthermore, transcriptome analysis revealed a markedly longer PFS and tumor response were associated with higher expression of a 3-gene effector T cell signature or an 18-gene inflamed T cell signature. Sintilimab plus gemcitabine and cisplatin meets pre-specified endpoints and displays acceptable safety profile, multiomics potential predictive biomarkers are identified and warrant further verification.

Sauchinone inhibits breast cancer cell proliferation through regulating microRNA-148a-3p/HER-2 axis.

BACKGROUND: Sauchinone is extracted from the root of Saururus chinensis and exhibits potent antitumor effects in various human cancers. However, how sauchinone is involved in breast cancer has not been well studied. METHODS: Cells apoptosis, cell proliferation, and cycle distribution were evaluated. Xenograft tumor mouse model was constructed to investigate the roles of sauchinone. The relevant protein expression was detected by western blot. RESULTS: We found that sauchinone significantly reduced proliferation and survival, also induced apoptosis of MCF-7 and Bcap-37 cells in vitro. Sauchinone significantly increased miR-148a-3p expression, and human epidermal growth factor receptor (HER)-2 targeted on miR-148a-3p. Sauchinone exposure downregulated HER-2 expression whose overexpression partly eliminated the inhibitory effect of sauchinone. Further, sauchinone efficiently inhibited breast cancer progression through downregulating HER-2 expression in vivo. CONCLUSION: Our results indicate that sauchinone efficiently inhibits breast cancer progression through regulating miR-148a-3p/HER-2 axis, suggesting that sauchinone could be an effective anticancer agent for breast cancer.

A genomic and transcriptomic study toward breast cancer.

Background: Breast carcinoma is well recognized to be having the highest global occurrence rate among all cancers, being the leading cause of cancer mortality in females. The aim of this study was to elucidate breast cancer at the genomic and transcriptomic levels in different subtypes so that we can develop more personalized treatments and precision medicine to obtain better outcomes. Method: In this study, an expression profiling dataset downloaded from the Gene Expression Omnibus database, GSE45827, was re-analyzed to compare the expression profiles of breast cancer samples in the different subtypes. Using the GEO2R tool, different expression genes were identified. Using the STRING online tool, the protein-protein interaction networks were conducted. Using the Cytoscape software, we found modules, seed genes, and hub genes and performed pathway enrichment analysis. The Kaplan-Meier plotter was used to analyze the overall survival. MicroRNAs and transcription factors targeted different expression genes and were predicted by the Enrichr web server. Result: The analysis of these elements implied that the carcinogenesis and development of triple-negative breast cancer were the most important and complicated in breast carcinoma, occupying the most different expression genes, modules, seed genes, hub genes, and the most complex protein-protein interaction network and signal pathway. In addition, the luminal A subtype might occur in a completely different way from the other three subtypes as the pathways enriched in the luminal A subtype did not overlap with the others. We identified 16 hub genes that were related to good prognosis in triple-negative breast cancer. Moreover, SRSF1 was negatively correlated with overall survival in the Her2 subtype, while in the luminal A subtype, it showed the opposite relationship. Also, in the luminal B subtype, CCNB1 and KIF23 were associated with poor prognosis. Furthermore, new transcription factors and microRNAs were introduced to breast cancer which would shed light upon breast cancer in a new way and provide a novel therapeutic strategy. Conclusion: We preliminarily delved into the potentially comprehensive molecular mechanisms of breast cancer by creating a holistic view at the genomic and transcriptomic levels in different subtypes using computational tools. We also introduced new prognosis-related genes and novel therapeutic strategies and cast new light upon breast cancer.

Emerging Nondopaminergic Medications for Parkinson's Disease: Focusing on A2A Receptor Antagonists and GLP1 Receptor Agonists.

Parkinson's disease (PD) is a severe neurodegenerative disease characterized by classic motor features associated with the loss of dopaminergic neurons and appearance of Lewy bodies in the substantia nigra. Due to the complexity of PD, a definitive diagnosis in the early stages and effective management of symptoms in later stages are difficult to achieve in clinical practice. Previous research has shown that colocalization of A2A receptors (A2AR) and dopamine D2 receptors (D2R) may induce an antagonistic interaction between adenosine and dopamine. Clinical trials have found that the A2AR antagonist istradefylline decreases dyskinesia in PD and could be used as an adjuvant to levodopa treatment. Meanwhile, the incretin hormone glucagon-like peptide 1 (GLP1) mainly facilitates glucose homeostasis and insulin signaling. Preclinical experiments and clinical trials of GLP1 receptor (GLP1R) agonists show that they may be effective in alleviating neuroinflammation and sustaining cellular functions in the central nervous system of patients with PD. In this review, we summarize up-to-date findings on the usefulness of A2AR antagonists and GLP1R agonists in PD management. We explain the molecular mechanisms of these medications and their interactions with other neurotransmitter receptors. Furthermore, we discuss the efficacy and limitations of A2AR antagonists and GLP1R agonists in clinical practice.

Axonal variants of Guillain-Barré syndrome: an update.

Axonal variants of Guillain-Barré syndrome (GBS) mainly include acute motor axonal neuropathy, acute motor and sensory axonal neuropathy, and pharyngeal-cervical-brachial weakness. Molecular mimicry of human gangliosides by a pathogen's lipooligosaccharides is a well-established mechanism for Campylobacter jejuni-associated GBS. New triggers of the axonal variants of GBS (axonal GBS), such as Zika virus, hepatitis viruses, intravenous administration of ganglioside, vaccination, and surgery, are being identified. However, the pathogenetic mechanisms of axonal GBS related to antecedent bacterial or viral infections other than Campylobacter jejuni remain unknown. Currently, autoantibody classification and serial electrophysiology are cardinal approaches to differentiate axonal GBS from the prototype of GBS, acute inflammatory demyelinating polyneuropathy. Newly developed technologies, including metabolite analysis, peripheral nerve ultrasound, and feature selection via artificial intelligence are facilitating more accurate diagnosis of axonal GBS. Nevertheless, some key issues, such as genetic susceptibilities, remain unanswered and moreover, current therapies bear limitations. Although several therapies have shown considerable benefits to experimental animals, randomized controlled trials are still needed to validate their efficacy.

Cyclic adenosine monophosphate in acute ischemic stroke: some to update, more to explore.

The development of effective treatment for ischemic stroke, which is a common cause of morbidity and mortality worldwide, remains an unmet goal because the current first-line treatment management interventional therapy has a strict time window and serious complications. In recent years, a growing body of evidence has shown that the elevation of intracellular and extracellular cyclic adenosine monophosphate (cAMP) alleviates brain damage after ischemic stroke by attenuating neuroinflammation in the central nervous system and peripheral immune system. In the central nervous system, upregulated intracellular cAMP signaling can alleviate immune-mediated damage by restoring neuronal morphology and function, inhibiting microglia migration and activation, stabilizing the membrane potential of astrocytes and improving the cellular functions of endothelial cells and oligodendrocytes. Enhancement of the extracellular cAMP signaling pathway can improve neurological function by activating the cAMP-adenosine pathway to reduce immune-mediated damage. In the peripheral immune system, cAMP can act on various immune cells to suppress peripheral immune function, which can alleviate the inflammatory response in the central nervous system and improve the prognosis of acute cerebral ischemic injury. Therefore, cAMP may play key roles in reducing post-stroke neuroinflammatory damage. The protective roles of the cAMP indicate that the cAMP enhancing drugs such as cAMP supplements, phosphodiesterase inhibitors, adenylate cyclase agonists, which are currently used in the treatment of heart and lung diseases. They are potentially able to be applied as a new therapeutic strategy in ischemic stroke. This review focuses on the immune-regulating roles and the clinical implication of cAMP in acute ischemic stroke.

Obesity-associated miR-27a upregulation promotes hepatocellular carcinoma metastasis through suppressing SFRP1.

BACKGROUND: Obesity was a recognized risk factor for the development and progression of hepatocellular carcinoma (HCC). However, the effects and mechanisms by which obesity promotes HCC metastasis remain poorly understood. MATERIALS AND METHODS: We cultured adipocyte induced by preadipocyte 3T3-L1 in vitro and established HCC metastasis model in obesity mouse in vivo to mimic the tumor microenvironment in obese status. The mechanisms underlying obesity-associated miR-27a upregulation promoting HCC metastasis were investigated. RESULTS: In this study, we showed that miR-27a was upregulated in adipocytes, obese mouse model and clinical samples, and the increased miR-27a level promoted migration and invasion in HCC cells, increased the number of metastasis nodes in obese mouse model, and was associated with poor clinical outcomes. Overexpressed secreted frizzled-related protein 1 in HCC cells and tissues significantly alleviated the upregulation of ß-catenin and matrix metalloproteinase-7 induced by high level of miR-27a. Meanwhile, the E-cadherin expression decreased and Vimentin expression increased, linking with high level of ß-catenin in high-fat group. CONCLUSION: Taken together, our results have elucidated the critical role of extracellular miR-27a as a pro-metastatic factor in HCC and revealed that obesity-associated miR-27a upregulation promoted HCC metastasis through activated Wnt/ß-catenin signaling by suppressing secreted frizzled-related protein 1. Our findings shed light on the novel mechanism underlying HCC metastasis and provided miR-27a as a promising target for obese liver cancer therapy.

Research and Clinical Application of Three-Dimensional Location of Amygdaloid Body.

Accurately representing the spatial location of the amygdaloid body can lay an anatomical basis for the neurosurgery operation for amputation of the amygdaloid body through lateral fissure approach. As we know, there are a number of nerve nucleuses and essential structures locating around amygdaloid body in our brain, especially optic tract. However, only few research had been done to protect these tissues or nerve nucleuses. Thus, we reconstructed the three-dimensional images of the amygdaloid body of the human brain and established a coordinate system. The morphological parameters of the amygdaloid body and the three-dimensional coordinate data were measured. The spherical coordinates (R, θ, ϕ) were constructed by calculating the azimuth angle, elevation angle, and the distance from the coordinates origin to each amygdaloid body centroid. Sixty people brain MRI images without any visible organic disease were used in our research to investigate the average level of related parameters. The authors selected a proper coordinate origin and measured the value of anteroposterior diameter, right-and-left diameter, vertical diameter of the amygdaloid body, and the distance from the optic tract to amygdaloid body. The authors also measured the three-dimensional coordinate data of each centroid of the amygdaloid body in order to provide anatomical suggestion for surgery. The authors confirmed the nearest point from the foremost edge of the brain ventricle temporal horn to the lateral fissure, then viewed it as the coordinate origin. By means of coordinate translation, the authors got various morphological parameters and the coordinate values of each centroid of the amygdaloid body. Spherical coordinates were calculated from the three-dimensional coordinate values. The distances between the different layers of the amygdaloid body and the optic tract were also measured. The reconstruction of the three-dimensional coordinates of amygdaloid body is part of the digital engineering of the human body. The measurement of the parameters provides an important theoretical basis for the clinical amygdaloid body destruction surgery. Finally, the authors get conclusions as follows. There are no significant differences in the measured values of r1, r2, and r3 between the upper and lower diameters, the left and right diameters, the anteroposterior diameter of the amygdaloid body. The measured values of men and women are not statistically significant (P > 0.05). Spherical coordinates (R, θ, ϕ) calculated from the three-dimensional coordinate values and values from different sexes of the amygdaloid body are not statistically significant, either (P > 0.05). The distance between the different levels of the amygdaloid body and the optic tract (h1, h2, h3, h4, h5, h6, and h7) are not statistically significant (P > 0.05).

Extensive paranasal sinus mucoceles: a 15-year review of 82 cases.

PURPOSE: The aim of the study was to report the clinical characteristics, management, and outcome of patients with extensive paranasal sinus mucoceles. MATERIALS AND METHODS: In a retrospective study, 82 patients with intracranial or intraorbital extension due to paranasal sinus mucoceles who were surgically treated between 1993 and 2007 were studied. In addition, clinical data, presenting symptoms, clinical features, management, and outcome were analyzed. RESULTS: The study population included 42 males and 40 females, with a mean age of 52.7 years (range, 15-87 years). The most common presenting symptoms were ptosis (27/82, 32.9%) and periorbital swelling (24/82, 29.3%). The main radiologic finding on computed tomography scan was bony defect of lamina papyracea and/or medial superior orbital rim. Sixty-six patients underwent endoscopic sinus surgery; among them, 3 patients had recurrence (3/77, 3.9%) during follow-up periods. CONCLUSION: In our study, a majority of patients with extensive paranasal sinus mucoceles exhibited ophthalmologic symptoms before treatment (81/82, 98.8%). Computed tomography scanning was a feasible tool for preoperative assessment. A satisfactory outcome can be achieved after surgical treatment of endoscopic sinus surgery.