MicroRNA-874 targets phosphomevalonate kinase and inhibits cancer cell growth via the mevalonate pathway.

The microRNA (miR) miR-874, a potential tumour suppressor, causes cell death via target gene suppression in various cancer types. Mevalonate pathway inhibition also causes cell death in breast cancer. However, the relationship between the mevalonate pathway and miR-874-induced apoptosis or its association with the tumour suppressor p53 has not been elucidated. We identified phosphomevalonate kinase (PMVK), a key mevalonate pathway enzyme, and sterol regulatory element-binding factor 2 (SREBF2), the master cholesterol biosynthesis regulator, as direct miR­874 targets. Next-generation sequencing analysis revealed a significant miR-874-mediated downregulation of PMVK and SREBF2 gene expression and p53 pathway enrichment. Luciferase reporter assays showed that miR-874 directly regulated PMVK and SREBF2. miR-874-induced apoptosis was p53 dependent, and single-cell RNA sequencing analysis demonstrated that miR-874 transfection resulted in apoptosis and p53 pathway activation. Downregulation of PMVK expression also caused cell cycle arrest and p53 pathway activation, which was rescued by geranylgeranyl pyrophosphate (GGPP) supplementation. Analysis of The Cancer Genome Atlas (TCGA) database indicated a negative correlation between miR-874 and PMVK expression and between miR-874 and SREBF2 expression. These findings suggest that miR-874 suppresses the mevalonate pathway by targeting SREBF2 and PMVK, resulting in GGPP depletion, which activates the p53 pathway and promotes cycle arrest or apoptosis.

Proteogenomic landscape and clinical characterization of GH-producing pituitary adenomas/somatotroph pituitary neuroendocrine tumors.

The clinical characteristics of growth hormone (GH)-producing pituitary adenomas/somatotroph pituitary neuroendocrine tumors (GHomas/somatotroph PitNETs) vary across patients. In this study, we aimed to integrate the genetic alterations, protein expression profiles, transcriptomes, and clinical characteristics of GHomas/somatotroph PitNETs to identify molecules associated with acromegaly characteristics. Targeted capture sequencing and copy number analysis of 36 genes and nontargeted proteomics analysis were performed on fresh-frozen samples from 121 sporadic GHomas/somatotroph PitNETs. Targeted capture sequencing revealed GNAS as the only driver gene, as previously reported. Classification by consensus clustering using both RNA sequencing and proteomics revealed many similarities between the proteome and the transcriptome. Gene ontology analysis was performed for differentially expressed proteins between wild-type and mutant GNAS samples identified by nontargeted proteomics and involved in G protein-coupled receptor (GPCR) pathways. The results suggested that GNAS mutations impact endocrinological features in acromegaly through GPCR pathway induction. ATP2A2 and ARID5B correlated with the GH change rate in the octreotide loading test, and WWC3, SERINC1, and ZFAND3 correlated with the tumor volume change rate after somatostatin analog treatment. These results identified a biological connection between GNAS mutations and the clinical and biochemical characteristics of acromegaly, revealing molecules associated with acromegaly that may affect medical treatment efficacy.

Neoadjuvant therapy strategies for advanced gastric cancer: Current innovations and future challenges.

Gastric cancer, which has a high incidence and poor prognosis, remains a therapeutic challenge. Recently, neoadjuvant therapy has attracted increasing attention due to high recurrence rate and low survival rate after resection in most patients with advanced stage. Clinical trials show that neoadjuvant approaches confer a significant survival advantage for resectable locally advanced gastric cancer. The specific advantages of chemoradiotherapy compared with chemotherapy have not been clarified; optimal regimens and cycles, particularly in the preoperative setting, should be studied further; and trials aimed at determining the role of targeted and immunological therapies should be conducted.

Clinical and pathological staging of gastric cancer: Current perspectives and implications.

Accurate categorization of invasive depth and lymph node metastasis or optimization of TNM categories is fundamentally critical for prognostic assessment and decision making regarding subsequent therapies after surgery for gastric cancer. Improving the precision of the TNM staging is the ongoing goal. The evolution of the staging system indicates that there is no "ideal staging". Every update has criticized the lack of a standard approach for the stages to date. T staging depends on the accurate determination of the depth of infiltration based on pathological continuous sections. N staging is susceptible to the influence of lymph node detection, and insufficient lymph node detection can lead to N staging migration. M staging is required to improve the detection rate of peritoneal positive free cancer cells to determine the high risk factors of peritoneal metastasis. At present, the quality of standardized pathological diagnosis of gastric cancer requires improvement. Based on a review of the literature and experience from multiple gastric cancer centers, we present a new development in TNM staging and a way to improve clinical and pathological quality control of gastric cancer.

Pseudomyxoma Peritonei Originating from Transverse Colon Mucinous Adenocarcinoma: A Case Report and Literature Review.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare neoplasm involving the peritoneum. Most PMPs are low-grade appendicular mucinous neoplasms (LAMNs). There have been no reports of PMP originating from a transverse colonic mucinous adenocarcinoma and causing metastatic mucinous adenocarcinoma. Case Presentation. We report a 46-year-old woman who presented with a right abdominal mass of more than 4-month duration. Transverse colonic mucinous adenocarcinoma, PMP, and ovarian metastatic mucinous adenocarcinoma were diagnosed. The patient's diet was normal, and she had no abdominal pain or bloating. The abdomen mass increased in the month before treatment. After chemotherapy, the transverse colon mass and ovarian giant cyst were resected and about 2000 mL of gelatinous tumor tissue was removed. Postoperative histology confirmed PMP from the transverse colonic mucinous adenocarcinoma, ovarian metastatic mucinous adenocarcinoma, and mesocolon metastatic cancer. Multiple lung metastases appeared 8 months after surgery. The patient died 29 months after surgery because of an inability to eat and poor nutrition. A systematic literature review of the management and outcome of all known similar cases is also presented. CONCLUSIONS: This is the first report of PMP originating from a transverse colonic mucinous adenocarcinoma. It was diagnosed during resective surgery, involved ovarian metastasis, and survival was short. We did an extensive literature review in order to describe the clinical characteristics, histopathological findings, genetic profile, and potential treatments of PMP caused by nonappendiceal mucinous adenocarcinoma.

A novel lymph node staging system for gastric cancer including modified Union for cancer Control/American Joint Committee on cancer and Japanese Gastric Cancer Association criteria.

BACKGROUND: The TNM system of the International Union for Cancer Control/American Joint Committee on Cancer (UICC/AJCC) and the Japanese Gastric Cancer Association (JGCA) systems are the most used lymph node (LN) staging systems in gastric cancer. This study estimated the influence of anatomic location-based node stations on survival and proposed a new staging method based on both the number and anatomical distribution of metastatic LNs (mLNs). METHODS: Stage I-III gastric cancer patients with radical gastrectomy were retrospectively evaluated. Overall survival (OS) was estimated in 1786 patients with UICC/AJCC stage N1-N3b disease and compared with estimates obtained using JGCA group 1-3 mLN staging. RESULTS: The OS of UICC/AJCC stage N1-N3b patients with group 2 JGCA mLNs was significantly worse than that of patients with only group 1 mLNs. The OS of the patients with group 2 mLNs was similar to that of patients with group 1 mLNs but in the next more advanced UICC/AJCC-N stage. The OS of patients with group 3 mLNs was worse than that of patients with any UICC/AJCC-N stage and was similar to that of N3b patients with group 2 mLNs. A new pathological node (pN) staging classification was developed that advanced the N-staging of patients with group 2 mLNs. It was a better indicator of prognosis than the eighth UICC/AJCC-N and the thirteenth JGCA group staging systems. CONCLUSIONS: A simple, accurate pN staging system including both the number and location of mLNs had improved homogeneity, discriminatory ability, and gradient monotonicity.

Methanol-assisted synthesis of Ni3+-doped ultrathin NiZn-LDH nanomeshes for boosted alkaline water splitting.

The construction of nanoporous structure combined with the optimization of electronic structure toward electrocatalysts could be a promising and effective approach to boosting their catalytic performance. Herein, we rationally synthesized a novel Ni3+-doped ultrathin NiZn layered double hydroxide nanomesh supported on nickel foam (Ni(ii,iii)Zn-LDH/NF-nm) by a facile one-step methanol-assisted hydrothermal method. Results show that methanol can not only trigger the generation of ultrathin nanomesh structure, but adjust portion of Ni2+ to Ni3+ and thus to result in the Ni3+-doped NiZn-LDH nanomesh material. The nanoporous feature endows Ni(ii,iii)Zn-LDH/NF-nm with abundant exposed catalytic active sites and fast mass transfer for alkaline water electrolysis. More importantly, the Ni3+ doping can facilitate the available formation of highly active NiOOH phase on the surface for the oxygen evolution reaction (OER), accompanied by increased oxygen vacancies that can greatly enhance the electronic conductivity, leading to the improved intrinsic activity and the accelerated electrocatalytic OER reaction kinetics. As expected, the as-prepared Ni(ii,iii)Zn-LDH/NF-nm has relatively low overpotentials of 320 and 370 mV to drive large current densities of 100 and 500 mA cm-2, respectively, and a small Tafel slope of 63.9 mV dec-1, extremely superior to RuO2/NF and NiZn-LDH/NF-ns counterpart. Meanwhile, the electrolyzer assembled for overall water splitting by Ni(ii,iii)Zn-LDH/NF-nm yields the outstanding catalytic activity and stability. This work highlights a feasible strategy to design and develop high-efficiency water splitting electrocatalysts via engineering on composition and nanostructure.

Benefits of Surgery After Neoadjuvant Intraperitoneal and Systemic Chemotherapy for Gastric Cancer Patients With Peritoneal Metastasis: A Meta-Analysis.

BACKGROUND: Conversion therapy is intended to allow achieving R0 resection after chemotherapy for tumors initially considered unresectable or partially resectable. Neoadjuvant intraperitoneal and systemic chemotherapy (NIPS) is the current conversion therapy for gastric cancer (GC) patients with peritoneal metastasis. This meta-analysis evaluated the effectiveness and safety of NIPS-combined surgery for GC patients with peritoneal metastasis. METHODS: Standard methods were used to select and analyze studies that included GC patients with peritoneal metastasis assigned to two groups, either NIPS-combined surgery or a NIPS-only control. Publications were retrieved from PubMed, EMBASE, Medline, and the Cochrane Central Register. Overall survival, conversion therapy success and R0 resection rates, and adverse events were analyzed using Stata 11.0. RESULTS: Eight of the 14 studies that were evaluated after screening the titles and abstracts of 327 retrieved publications met the selection criteria. The eight retrospective studies included 373 patients with GC and peritoneal metastasis included 265 with NIPS-combined surgery and 109 with NIPS only. Survival was significantly better with NIPS-combined surgery than with NIPS only (hazard ratio = 0.440, 95% confidence interval [CI]: 0.274-0.704; P = 0.0001; odds ratio = 1.960; 95% CI: 1.247-3.083; P = 0.004). Subgroup analysis revealed significantly better survival with S-1 Joint intravenous paclitaxel and intraperitoneal paclitaxel compared with other NIPS regimens. NIPS regimens had a higher conversion rate (effect size [ES] = 0.656; 95% CI: 0.495-0.817; P < 0.05), higher percentage of patients with R0 surgery (ES = 0.633; 95% CI: 0.568-0.699; P < 0.05), less severe adverse reactions to chemotherapy (ES = 0.030; 95% CI: 0.020-0.040; P < 0.05), and fewer postoperative complications (ES = 0.040; 95% CI: 0.020-0.050; P < 0.05). CONCLUSIONS: NIPS-combined surgical treatment was effective and safe for treating GC with peritoneal metastasis. Higher quality trials, better patient selection, and multicenter randomized controlled trials are needed to support standard treatment guidelines.

Clinicopathological Characteristics and Prognosis of Upper Gastric Cancer Patients in China: A 32-Year Single-Center Retrospective Clinical Study.

PURPOSE: Upper or proximal gastric cancer occurs in the upper third of the stomach between the cardia and a line connecting the greater and lesser curvatures. As it differs from other gastric cancers in pathology and prognosis, we evaluated patient and disease characteristics that might guide improved treatment and survival of upper gastric cancer. METHODS: We conducted a retrospective analysis of 649 patients with upper gastric cancer and 1551 patients with lower gastric cancer and R0 radical surgery at our institution between January 1980 and December 2012. RESULTS: Survival after radical surgery for upper gastric cancer was 77.8% at 1 year, 49.6% at 3 years, and 41.1% at 5 years. The corresponding rates for lower gastric cancer were 85.9%, 60.0%, and 57.2% (p < 0.001). Upper gastric cancer had a poor prognosis. Sex (p = 0.036), tumor diameter (p = 0.001), macroscopic type (p < 0.001), pTM stage (p < 0.001), tissue differentiation type (p = 0.003), and serosal invasion (p = 0.034) were independently associated with lymph node metastasis. The macroscopic type (p = 0.045), lymphovascular tumor emboli (p = 0.021), and pTNM stage were independently associated with recurrence and metastasis. Survival of 333 patients with D2 total gastrectomy was 81.3% at 1 year, 54.4% at 3 years, and 45.2% at 5 years. The corresponding rates for 316 proximal gastrectomy patients were 75.4%, 44.9%, and 36.7%. Radical total gastrectomy had better survival than radical proximal resection. CONCLUSIONS: Upper gastric cancers were more aggressive, had a worse prognosis, and were more prone to recurrence and metastasis compared with lower gastric cancers. Survival was better after total gastrectomy than after proximal resection.