Artificial neural network-based diagnostic models for lung cancer combining conventional indicators with tumor markers.

This study set out to establish a lung cancer diagnosis and prediction model uses conventional laboratory indicators combined with tumor markers, so as to help early screening and auxiliary diagnosis of lung cancer through a convenient, fast, and cheap way, and improve the early diagnosis rate of lung cancer. A total of 221 patients with lung cancer, 100 patients with benign pulmonary diseases, and 184 healthy subjects were retrospectively studied. General clinical data, the results of conventional laboratory indicators, and tumor markers were collected. Statistical Product and Service Solutions 26.0 was used for data analysis. The diagnosis and prediction model of lung cancer was established by artificial neural network - multilayer perceptron. After correlation and difference analysis, five comparison groups (lung cancer-benign lung disease group, lung cancer-health group, benign lung disease-health group, early-stage lung cancer-benign lung disease group, and early-stage lung cancer-health group) obtained 5, 28, 25, 16, and 25 valuable indicators for predicting lung cancer or benign lung disease, and then established five diagnostic prediction models, respectively. The area under the curve (AUC) of each combined diagnostic prediction model (0.848, 0.989, 0.949, 0.841, and 0.976) was higher than that of the diagnostic prediction model established only using tumor markers (0.799, 0.941, 0.830, 0.661, and 0.850), and the difference in the lung cancer-health group, the benign lung disease-health group, the early-stage lung cancer-benign lung disease group, and early-stage lung cancer-health group was statistically significant (P < 0.05). The artificial neural network-based diagnostic models for lung cancer combining conventional indicators with tumor markers have high performance and clinical significance in assisting the diagnosis of early lung cancer.

SPDEF enhances cancer stem cell-like properties and tumorigenesis through directly promoting GALNT7 transcription in luminal breast cancer.

BACKGROUND: Luminal breast cancer (BC) is the predominant subtype of breast cancer with a sustained risk of late recurrence and death. Understanding the molecular mechanisms for the oncogenesis of luminal BC would improve the prognosis for this large subset of patients. SPDEF was reported to be dysregulated in breast cancers. However, the biological functions and underlying molecular mechanism of SPDEF in luminal BC remains largely unknown. The aim of the present study was to elucidate the potential roles of SPDEF underlying subtype-specific functions in BC, especially in luminal subtypes. METHODS: The expressions and clinicopathological characteristics of SPDEF in luminal BC patients were evaluated bioinformatically. In vitro and in vivo assays were performed to investigate the oncogenic function and stemness maintenance of SPDEF in luminal BC. Chromatin immunoprecipitation (ChIP) and dual luciferase reporter assays were conducted to determine the transcription regulation of GALNT7 by SPDEF. GALNT7 levels in serum from luminal BC patients were further detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: SPDEF is markedly upregulated in luminal BC and positively associated with tumor progression and poor prognosis. Furthermore, we confirmed that SPDEF enhanced the proliferation, migration, invasion and stemness of luminal BC cells in vitro as well the tumorigenicity in vivo. Mechanistically, we demonstrated the stimulative effect of SPDEF on the progression and stemness of luminal BC, which is mediated by its directly transcriptional target GALNT7. Clinically, we verified that the GALNT7 can be used as a noninvasive diagnostic marker. Noteworthy, the combined detection of serum GALNT7 and traditional tumor markers can enhance diagnostic accuracy thus is of vital importance in the early diagnosis of luminal BC. CONCLUSIONS: Our study reveals a novel mechanism by which SPDEF transcriptionally activates GALNT7 via directly binding to its promoter to promote cell proliferation, motility and stemness, and led to luminal BC tumorigenesis and poor prognosis.

Sex Differences in Association Between Gut Microbiome and Essential Hypertension Based on Ambulatory Blood Pressure Monitoring.

BACKGROUND: Sex differences in the pathogenesis of hypertension exist. While gut microbiota (GM) has been associated with hypertension, it is unclear whether there are sex-linked differences in the association between GM and hypertension. METHODS: We conducted a cross-sectional study to investigate the sex differences in associations between GM characterized by shotgun sequencing, GM-derived short-chain fatty acids, and 24-hour ambulatory blood pressure in 241 Hong Kong Chinese (113 men and 128 women; mean age, 54±6 years). RESULTS: The hypertensive group was associated with GM alterations; however, significant differences in ß-diversity and GM composition in hypertensive versus normotensive groups were only observed in women and not in men under various statistical models adjusting for the following covariates: age, sex, body mass index, sodium intake estimated by spot urine analysis, blood glucose, triglycerides, low- and high-density lipoprotein cholesterol, smoking, menopause, and fatty liver status. Specifically, Ruminococcus gnavus, Clostridium bolteae, and Bacteroides ovatus were significantly more abundant in the hypertensive women, whereas Dorea formicigenerans was more abundant in the normotensive women. No bacterial species were found to be significantly associated with hypertension in men. Furthermore, total plasma short-chain fatty acids and propionic acid were independent predictors of systolic and diastolic blood pressure in women but not men. CONCLUSIONS: GM dysregulation was strongly associated with 24-hour ambulatory blood pressure in women but not men, which may be mediated through propionic acid. Our work suggests that sex differences may be an important consideration while assessing the role of GM in the development and treatment of hypertension.

Age-dependent accumulation of oligomeric SNCA/α-synuclein from impaired degradation in mutant LRRK2 knockin mouse model of Parkinson disease: role for therapeutic activation of chaperone-mediated autophagy (CMA).

Parkinson disease (PD) is an age-related neurodegenerative disorder associated with misfolded SNCA/α-synuclein accumulation in brain. Impaired catabolism of SNCA potentiates formation of its toxic oligomers. LRRK2 (leucine-rich repeat kinase-2) mutations predispose to familial and sporadic PD. Mutant LRRK2 perturbs chaperone-mediated-autophagy (CMA) to degrade SNCA. We showed greater age-dependent accumulation of oligomeric SNCA in striatum and cortex of aged LRRK2R1441G knockin (KI) mice, compared to age-matched wildtype (WT) by 53% and 31%, respectively. Lysosomal clustering and accumulation of CMA-specific LAMP2A and HSPA8/HSC70 proteins were observed in aged mutant striatum along with increased GAPDH (CMA substrate) by immunohistochemistry of dorsal striatum and flow cytometry of ventral midbrain cells. Using our new reporter protein clearance assay, mutant mouse embryonic fibroblasts (MEFs) expressing either SNCA or CMA recognition 'KFERQ'-like motif conjugated with photoactivated-PAmCherry showed slower cellular clearance compared to WT by 28% and 34%, respectively. However, such difference was not observed after the 'KFERQ'-motif was mutated. LRRK2 mutant MEFs exhibited lower lysosomal degradation than WT indicating lysosomal dysfunction. LAMP2A-knockdown reduced total lysosomal activity and clearance of 'KFERQ'-substrate in WT but not in mutant MEFs, indicating impaired CMA in the latter. A CMA-specific activator, AR7, induced neuronal LAMP2A transcription and lysosomal activity in MEFs. AR7 also attenuated the progressive accumulation of both intracellular and extracellular SNCA oligomers in prolonged cultures of mutant cortical neurons (DIV21), indicating that oligomer accumulation can be suppressed by CMA activation. Activation of autophagic pathways to reduce aged-related accumulation of pathogenic SNCA oligomers is a viable disease-modifying therapeutic strategy for PD.Abbreviations: 3-MA: 3-methyladenine; AR7: 7-chloro-3-(4-methylphenyl)-2H-1,4-benzoxazine; CMA: chaperone-mediated autophagy; CQ: chloroquine; CSF: cerebrospinal fluid; DDM: n-dodecyl ß-D-maltoside; DIV: days in vitro; ELISA: enzyme-linked immunosorbent assay; FACS: fluorescence-activated cell sorting; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GWAS: genome-wide association studies; HSPA8/HSC70: heat shock protein 8; KFERQ: CMA recognition pentapeptide; KI: knockin; LAMP1: lysosomal-associated membrane protein 1; LAMP2A: lysosomal-associated membrane protein 2A; LDH: lactate dehydrogenase; LRRK2: leucine-rich repeat kinase 2; MEF: mouse embryonic fibroblast; NDUFS4: NADH:ubiquinone oxidoreductase core subunit S4; NE: novel epitope; PD: Parkinson disease; RARA/RARα: retinoic acid receptor, alpha; SNCA: synuclein, alpha; TUBB3/TUJ1: tubulin, beta 3 class III; WT: wild-type.

The Aqueous Extract of Rhizome of Gastrodia elata Protected Drosophila and PC12 Cells against Beta-Amyloid-Induced Neurotoxicity.

This study aims to investigate the neuroprotective effect of the rhizome of Gastrodia elata (GE) aqueous extract on beta-amyloid(A ß )-induced toxicity in vivo and in vitro. Transgenic Drosophila mutants with A ß -induced neurodegeneration in pan-neuron and ommatidia were used to determine the efficacy of GE. The antiapoptotic and antioxidative mechanisms of GE were also studied in A ß -treated pheochromocytoma (PC12) cells. In vivo studies demonstrated that GE (5 mg/g Drosophila media)-treated Drosophila possessed a longer lifespan, better locomotor function, and less-degenerated ommatidia when compared with the A ß -expressing control (all P < 0.05). In vitro studies illustrated that GE increased the cell viability of A ß -treated PC12 cells in dose-dependent manner, probably through attenuation of A ß -induced oxidative and apoptotic stress. GE also significantly upregulated the enzymatic activities of catalase, superoxide dismutase, and glutathione peroxidase, leading to the decrease of reactive oxidation species production and apoptotic marker caspase-3 activity. In conclusion, our current data presented the first evidence that the aqueous extract of GE was capable of reducing the A ß -induced neurodegeneration in Drosophila, possibly through inhibition of apoptosis and reduction of oxidative stress. GE aqueous extract could be developed as a promising herbal agent for neuroprotection and novel adjuvant therapies for Alzheimer's disease.