Adamsgoldstein0189
Pancreatic neuroendocrine tumor (PNET), a heterogenous type of neoplasm with limited treatment options, is relatively rare and to date, the genetic background has remained to be fully elucidated. The present study aimed to determine the mutational landscape of PNET with and without liver metastasis, as well as its clinical application value for treatment. Fresh tumor tissues were collected from 14 patients with PNET following surgery, 4 of whom had developed liver metastasis. Subsequently, targeted next-generation sequencing of 612 cancer-associated genes and comprehensive analysis were performed on the tumor tissues. The results identified 63 somatic mutations in 53 genes in the 14 patients with PNET, amongst which menin 1 was identified as the most recurrently mutated gene. The analysis also identified several novel recurrently mutated genes, including adrenoceptor alpha 2B, ARVCF delta catenin family member, carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase and neuregulin 1. Among the 53 mutated genes, 11 were enriched in the PI3K/AKT signaling pathway (adjusted P=7.12x10-5). In addition, 4 patients with PNET with liver metastasis had distinctly different mutational profiles compared with those without liver metastasis; 13 genes were discovered to be exclusively mutated in the liver metastasis group of the patients with PNET, including ATRX chromatin remodeler, thioredoxin reductase 2, anus kinase 3, ARVCF delta catenin family member, integrin subunit alpha V and RAD50 double strand break repair protein. In addition, two potentially actionable alterations in BRCA2 DNA repair-associated (p.Q548Q) and neurofibromin 1 (p.Q1188X) were identified using the OncoKB database. In conclusion, the present study generated a comprehensive mutational profile of 14 patients with PNET and further described the features of patients with liver metastasis, which highlights potential targets for drug development of PNET.Cervical cancer is the most common gynecological cancer in women worldwide. Human papillomavirus (HPV) is required but not sufficient for developing cervical cancer. HPV E6 and E7 proteins are able to directly interact with certain nuclear receptors; however, whether steroid hormone receptors mediate cervical carcinogenesis is not completely understood. The present study demonstrated via immunohistochemistry that estrogen receptor α (ERα) and androgen receptor (AR) expression were decreased in a sequential manner from healthy cervical tissues to cervical intraepithelial neoplasia tissues and further to cervical cancer (CC) tissues, whereas microRNA (miR)-130a-3p expression levels were higher in CC tissues compared with healthy tissues. Both ERα and AR were direct targets of miR-130a-3p, as determined by performing luciferase reporter assays and western blotting. Functionally, compared with the corresponding control groups, miR-130a-3p knockdown, ERα overexpression and AR overexpression significantly inhibited CC cell proliferation and invasion, as demonstrated by the results obtained from the Cell Counting Kit-8 and Transwell assays in vitro. In addition, antagomiR-130a decreased tumor size and weight in vivo compared with control antagomiR as determined via the xenograft tumor growth assay. Therefore, the results suggested that miR-130a-3p might contribute to tumor progression by suppressing ERα and AR, and serve as a promising candidate target for the treatment of patients with CC.Minocycline (MH) is a broad-spectrum antimicrobial agent and semisynthetic tetracycline derivative, which has been widely used in the clinic due to its efficacy. Having the strongest anti-microbial effect, MH exceeded the traditional scope of antibiotics and its previously unknown antifungal activity is also gradually being discovered. To preliminarily investigate the inhibitory effect of MH on Candida albicans (C. albicans), changes of cell growth, hyphal formation and transition, biofilm production and signaling pathway gene expression of C. albicans in the presence of MH were assessed in the present study. An XTT reduction assay was performed to quantitatively detect the metabolic activity of biofilms and evaluate the inhibition of MH on this. The results suggested that biofilm formation was clearly inhibited by 67% (P less then 0.0001) in the presence of 250 µg/ml MH, while mature biofilms were not significantly affected. In addition, MH inhibited the transition from yeast to hypha in a dose-dependent manner. Furthermore, reverse transcription-quantitative PCR revealed that several hyphae- and adhesion-specific genes associated with the Ras/cyclic (c)AMP/protein kinase A (PKA) pathway were differentially expressed following MH treatment, including downregulation of ras family GTPase (RAS1), adenylyl cyclase-associated protein 1 (CAP1), thiamin pyrophosphokinase 1 (TPK1), adenylate cyclase (CDC35), transcription factor (TEC1), agglutinin-like protein 3 (ALS3) and hyphal wall protein 1 (HWP1) and upregulation of EFG1 (enhanced filamentous growth protein 1 gene) and PDE2 (high-affinity phosphodiesterase gene). The most obviously changed genes were TPK1, HWP1 and RAS1, downregulated by 0.33-, 0.48- and 0.55-fold, respectively. It was suggested that MH is associated with alterations in the morphology of C. albicans, such as the repression of hypha and biofilm formation of cells, and MH affected the Ras/cAMP pathway to regulate the expression of cAMP-associated genes.Vasodilator-stimulated phosphoprotein (VASP) is essential for osteoclast differentiation, and reduced VASP expression results in depressed osteoclast differentiation. Previously, we demonstrated the importance of VASP and Ras-related C3 botulinum toxin substrate 1 interactions in osteosarcoma cell migration and metastasis using Mg-63 and Saos2 cells. However, the molecular details of the functional role of VASP in cell motility and migration remain to be elucidated. The present study demonstrated that VASP affects the expression of αV-integrin, tartrate-resistant acid phosphatase (TRAP) and lamellipodia protrusion in RAW 264.7 murine macrophage cells. The RAW 264.7 mouse monocyte macrophage cell line was used as an osteoclast precursor. RAW 264.7 cells were treated with 50 ng/ml of receptor activator of nuclear factor κ-Β ligand (RANKL) in order to induce cell differentiation (osteoclastogenesis). Small interfering RNA (siRNA) was used to silence VASP, and RT-PCR and western blotting were used to determine the expression for genes and proteins, respectively. TRAP staining as a histochemical marker for osteoclast and fluorescent microscopy for lamellipodia protrusion was performed. RANKL treatment significantly increased the gene and protein expression of VASP, αV-integrin and TRAP in RAW 264.7 cells. WNK463 Silencing of VASP significantly reduced the RANKL-induced expression of αV-integrin, TRAP and lamellipodia protrusion. In addition, knockdown of VASP attenuated RANKL-stimulated activation of NF-κB, c-Fos and nuclear factor of activated T cells cytoplasmic 1 transcription factors, and the phosphorylation of the p65 and IκBα. These results suggest the critical role of VASP in regulating osteoclast differentiation, which should be further explored in osteosarcoma research.
In osteoarthritis (OA) there is a need for automated screening systems for early detection of structural progressors. We built a comprehensive machine learning (ML) model that bridges major OA risk factors and serum levels of adipokines/related inflammatory factors at baseline for early prediction of at-risk knee OA patient structural progressors over time.
The patient- and gender-based model development used baseline serum levels of six adipokines, three related inflammatory factors and their ratios (36), as well as major OA risk factors [age and bone mass index (BMI)]. Subjects (677) were selected from the Osteoarthritis Initiative (OAI) progression subcohort. The probability values of being structural progressors (PVBSP) were generated using our previously published prediction model, including five baseline structural features of the knee, i.e. two X-rays and three magnetic resonance imaging variables. To identify the most important variables amongst the 47 studied in relation to PVBSP, we employed theng the gender-based model generalizability. This study offers a new automated system for identifying early knee osteoarthritis structural progressors, which will significantly improve clinical prognosis with real time patient monitoring.
driver mutations are found in up to 15% of patients with colorectal cancer (CRC) and lead to constitutive activation of
kinase and sustained
pathway signaling.
mutations define a sub-population characterized by a poor prognosis and dismal median survival. Following successful outcomes with
inhibition in
mutant metastatic melanoma, this approach was evaluated in metastatic colorectal cancer (mCRC). The development and combination of targeted therapies against multiple signaling pathways has proved particularly successful, with improved survival and response rates.
This review addresses the development of therapeutic strategies with inhibitors targeting MAPK/ERK and
signaling in
V600E mutated mCRC, focusing on encorafenib, binimetinib and cetuximab. A pharmacological and clinical review of these drugs and the therapeutic approaches behind their optimization are presented.
Exploiting knowledge of the mechanisms of resistance to
inhibitors has been crucial to developing effective therapeutic strategies in
mutant mCRC. The BEACON trial is a successful example of this approach, using encorafenib and cetuximab with or without binimetinib in patients with previously treated
V600E mutant mCRC, showing an impressive improvement in clinical outcomes and tolerable toxicity compared with chemotherapy, establishing a new standard of care in this setting.
Exploiting knowledge of the mechanisms of resistance to BRAF inhibitors has been crucial to developing effective therapeutic strategies in BRAF-V600E mutant mCRC. The BEACON trial is a successful example of this approach, using encorafenib and cetuximab with or without binimetinib in patients with previously treated BRAF V600E mutant mCRC, showing an impressive improvement in clinical outcomes and tolerable toxicity compared with chemotherapy, establishing a new standard of care in this setting.
Clinical decision making is challenging in men with metastatic prostate cancer (mPC), as heterogeneity in treatment options and patient characteristics have resulted in multiple scenarios with little or no evidence. The South East Asia Expert Panel 2019 addressed some of these challenges.
Based on evidence in the literature and expert interviews, 19 statements were formulated for key challenges in the treatment of men with castration-sensitive and -resistant prostate cancer in clinical practice. A modified Delphi process was used to reach consensus among experts in the panel and develop clinical practice recommendations.
The majority of the panel preferred a risk-based stratification and recommended abiraterone or enzalutamide as first-line therapy for symptomatic chemotherapy naïve patients. Abiraterone is preferred over enzalutamide as a first-line treatment in these patients. However, the panel did not support the use of abiraterone in high risk lymph-node positive only (N+M0) or in non-metastatic (N0M0) patients.
