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Background: Drug resistance and the lack of molecular therapeutic target are the main challenges in the management of osteosarcomas (OSs). Identification of novel genetic alteration(s) related with OS recurrence and chemotherapeutic resistance would be of scientific and clinical significance. Methods: To identify potential genetic alterations related with OS recurrence and chemotherapeutic resistance, the biopsies of a 20-year-old male osteosarcoma patient were collected at primary site (p-OS) and from its metastatic tumor (m-OS) formed after 5 months of adjuvant chemotherapy. Both OS specimens were subjected to cancer-targeted next generation sequencing (NGS) and their cell suspensions were cultured under three-dimensional condition to establish spheroid therapeutic model. Transcript-oriented Sanger sequencing for GPC3, the detected mutated gene, was performed on RNA samples of p-OS and m-OS tissues and spheroids. The effects of anti-GPC3 antibody and its combination with cisplatin on m-OS spheroids were elucidated. Results: NGS revealed 4 mutations (GPC3, SOX10, MDM4 and MAPK8) and 6 amplifications (MDM2, CDK4, CCND3, RUNX2, GLI1 and FRS2) in p-OS, and 3 mutations (GPC3, SOX10 and EGF) and 10 amplifications (CDK4, CCND3, MDM2, RUNX2, GLI1, FRS2, CARD11, RAC1, SLC16A7 and PMS2) in m-OS. Among those alterations, the mutation abundance of GPC3 was the highest (56.49%) in p-OS and showed 1.54 times increase in m-OS. GPC3 transcript-oriented Sanger sequencing confirmed the mutation at 1046 in Exon 4, and immunohistochemical staining showed increased GPC3 production in m-OS tissues and its spheroids. EdU cell proliferation and Calcein/PI cell viability assays revealed that of the anti-OS first line drugs (doxorubicin, cisplatin, methotrexate, ifosfamide and carboplatin), 10 μM carboplatin exerted the best inhibitory effects on the p-OS but not the m-OS spheroids. 2 μg/mL anti-GPC3 antibody effectively committed m-OS spheroids to death by itself (76.43%) or in combination with cisplatin (92.93%). Conclusion: This study demonstrates increased abundance and up-regulated expression of mutant GPC3 in metastatic osteosarcoma and its spheroids with multidrug resistance. As GPC3-targeting therapy has been used to treat hepatocellular carcinomas and it is also effective to OS PDSs, GPC3 would be a novel prognostic parameter and therapeutic target of osteosarcomas.

Extracellular ATP and its ultimate degradation product adenosine are potent extracellular signaling molecules that elicit a variety of pathophysiological pathways in retina through the activation of P2 and P1 purinoceptors, respectively. Excessive build-up of extracellular ATP accelerates pathologic responses in retinal diseases, whereas accumulation of adenosine protects retinal cells against degeneration or inflammation. This mini-review focuses on the roles of ATP and adenosine in three types of blinding diseases including age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy (DR). Several agonists and antagonists of ATP receptors and adenosine receptors (ARs) have been developed for the potential treatment of glaucoma, DR and AMD: antagonists of P2X7 receptor (P2X7R) (BBG, MRS2540) prevent ATP-induced neuronal apoptosis in glaucoma, DR, and AMD; A1 receptor (A1R) agonists (INO-8875) lower intraocular pressure in glaucoma; A2A receptor (A2AR) agonists (CGS21680) or antagonists (SCH58261, ZM241385) reduce neuroinflammation in glaucoma, DR, and AMD; A3 receptor (A3R) agonists (2-Cl-lB-MECA, MRS3558) protect retinal ganglion cells (RGCs) from apoptosis in glaucoma.

AIM: To analyze the control effect of orthokeratology(OK)combined with atropine of low concentration on moderate to low myopia in adolescents.METHODS: Totally 76(152 eyes)adolescents with moderate to low myopia who were admitted to the department from January 2016 were enrolled. According to the voluntary principle, they were divided into orthokeratology group(OK group, n=36 cases, 72 eyes)and orthokeratology combined with atropine of low concentration group(combination group, n=40 cases, 80 eyes). The OK glasses were given for the two groups. The combination group was additionally given 0.1g/L atropine eye drops. All were followed up for 1a. The changes of uncorrected visual acuity, diopter, axial length, intraocular pressure, tear film function and corneal parameters were measured before and after wearing glasses. The incidence of complications was statistically analyzed.RESULTS: There were no significant differences in uncorrected visual acuity, diopter, axial length and intraocular pressure between the two groups before wearing glasses and at 1a of wearing glasses(P>0.05). The change of uncorrected visual acuity before wearing glasses and at 1a of wearing glasses of combination group was higher than that of OK group while the differences in diopter and axial length were lower than those of OK group(PP>0.05). At 1a of wearing glasses, LLT and BUT of combination group were higher than those of OK group while OSI was lower than that of OK group(PP>0.05). At 1a of wearing glasses, the changes of above indexes of combination group were lower than those of OK group(PP>0.05).CONCLUSION:OK glasses combined with atropine of low concentration can improve the uncorrected visual acuity of adolescents with moderate to low myopia, control the increase of diopter and axial length. And there is significant negative influence on corneal morphology and tear film function, and with high safety.

AIM: To investigate camera-assisted measurement in evaluating the accuracy of Hirschberg Test in measuring squint angle of concomitant strabismus.METHODS:The clinical data of 105 patients with concomitant strabismus who were admitted to the hospital during the period from January 2016 to January 2018 were collected. After admission, they were given traditional Hirschberg Test and picture Hirschberg Test for squint angle examination.Taking the prism cover test as golden standard, the deviation values between squint angle measured by golden standard and those measured by the traditional Hirschberg Test and the picture Hirschberg Test were recorded.The influence of Kappa angle on the deviation value was analyzed.The application value of camera-assisted measurement in squint angle of concomitant strabismus was analyzed.RESULTS:There was a significant difference in the value of squint angle measured by traditional Hirschberg Test, picture Hirschberg Test and prism cover test test(PPPPPPPCONCLUSION: The deviation of camera-assisted measurement picture Hirschberg Test is lower than that of traditional Hirschberg Test for the measurement of squint angle of concomitant strabismus, and it is more suitable for young patients who cannot cooperate with.

Abstract Esophageal cancer is one of the most common tumor in the world, and the morbidity rate is as high as 100/100 000 in some parts of China. Therefore, it is important and urgent to explore the pathogenesis of esophageal cancer and find new therapeutic targets for esophageal cancer. In this study, we found that a novel tumor suppressor SPINK5 is significantly reduced in the development of esophageal cancer, and is closely related to the pathological differentiation and lymph node metastasis of esophageal cancer via bioinformatics analysis and esophageal cancer tissue array. Further studies have found that SPINK5 is closely related to Wnt/β‐catenin signaling pathway by bioinformatics analysis and western blot. In esophageal cancer cells, SPINK5 overexpression can inhibit Wnt/β‐catenin signaling pathway. Combined with LiCl or MG‐132 treatment, SPINK5 can inhibit GSK3β phosphorylation and promote β‐catenin protein degradation, thus inhibit Wnt/β‐catenin signaling pathway. In vivo study, SPINK5 overexpression can significantly inhibit the growth of esophageal cancer cells. Our study shows that SPINK5 can inhibit the proliferation, migration, and invasion of esophageal cancer cells by inhibiting Wnt/β‐catenin signaling pathway, and thus plays an important role in the development of esophageal cancer, and may serve as a treatment target of esophageal cancer.

Objective Approximately 50% of amyotrophic lateral sclerosis (ALS) patients have cognitive and behavioural dysfunction in varying degrees and forms. Previous studies have shown that cognitive and behavioural changes may indicate a poor prognosis, and cognitive function gradually deteriorates over the course of disease, but the results of different studies have been inconsistent. In addition, there are relatively limited long-term follow-up studies tracking death as an endpoint. The purpose of this study was to investigate the clinical prognostic characteristics of ALS patients with cognitive behavioural changes through long-term follow-up in a cohort. Methods A total of 87 ALS patients from 2014 to 2015 in the Third Hospital of Peking University were selected and divided into a pure ALS group, an ALS with behavioural variant of frontotemporal dementia (ALS-bvFTD) group, and an ALS with cognitive and behaviour changes group. All patients were followed up for 60 months. The main end point was death and tracheotomy. Results There was no significant difference in survival curve between pure ALS and ALS with cognitive and behavioural change group, but the survival time of ALS-bvFTD group was significantly lower than the other two groups (P < 0.001). For those who was followed up to the endpoint, the survival time of the ALS-bvFTD group was significantly shorter than that of the pure ALS group (t = 5.33, p < 0.001) or the ALS with cognitive and behaviour changes group (t = 4.25, p < 0.001). The progression rate of ALS Functional Rating Scale–Revised (FRS-R) scores from recruitment to endpoint was significantly faster in the ALS-bvFTD group than in the pure ALS group (z = 2.68, p = 0.01) or the ALS with cognitive and behavioural changes group (z = 2.75, p = 0.01). There was no significant difference in survival time (t = 0.52, P = 0.60) or FRS-R score progression rate (z = 0.31, p = 0.76) between the pure ALS group and the ALS with cognitive and behavioural changes group. The total Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen (ECAS) score was positively correlated with survival time (r = 0.38, p = 0.01). Conclusion ALS-bvFTD patients have shorter survival time. The total ECAS score may be correlated with survival time.

It is generally believed that eye movements are completely spared in amyotrophic lateral sclerosis (ALS). Although a series of eye movement abnormalities has been recognized in recent years, the findings are highly controversial, and bulbar disabilities should be considered in relation to eye movement abnormalities. The present study aimed to determine whether eye movement abnormalities are present in ALS and, if so, to investigate their characteristics and their association with bulbar disability in ALS patients. A total of 60 patients and 30 controls were recruited and underwent the standardized evaluations of the oculomotor system using videonystagmography. Square-wave jerks (OR: 16.20, 95% CI: 3.50–74.95, p < 0.001) and abnormal cogwheeling during smooth pursuit (OR: 14.04, 95% CI: 3.00–65.75, p = 0.001) were more frequently observed in ALS patients than in the control subjects. In subgroup analyses, square-wave jerks (OR: 26.51, 95% CI: 2.83–248.05, p = 0.004) and abnormal cogwheeling during smooth pursuit (OR: 6.56, 95% CI: 1.19–36.16, p = 0.031) were found to be more common in ALS patients with bulbar involvement (n = 44) than in those without bulbar involvement (n = 16). There were no significant differences in the investigated eye movement parameters between bulbar-onset (n = 12) and spinal-onset patients (n = 48). ALS patients showed a range of eye movement abnormalities, affecting mainly the ocular fixation and smooth pursuit systems. Our pioneering study indicates that the region of involvement could better indicate the pathophysiological essence of the abnormalities than the type of onset pattern in ALS. Eye movement abnormalities may be potential clinical markers for objectively evaluating upper brainstem or supratentorial cerebral lesion neurodegeneration in ALS.

Nitrous acid (HONO), a vital precursor of atmospheric hydroxyl radicals (OH), has been extensively investigated to understand its characteristics and formation mechanisms. However, discerning fundamental mechanisms across diverse environments remains challenging. This study utilizes measurements from Mount Lao, a coastal mountain in eastern China, and an observation-based chemical box model (OBM) to examine HONO budgets and their subsequent impacts on atmospheric oxidizing capacity. The model incorporates additional HONO sources, including direct emissions, heterogeneous conversions of NO 2 on aerosol and ground surfaces, and particulate nitrate photolysis. The observed mean HONO concentration was 0.46 ± 0.37 ppbv. The updated model reproduced daytime HONO concentrations well during dust and photochemical pollution events. During dust events, daytime HONO formation was dominated by photo-enhanced heterogeneous reactions of NO 2 on aerosol surfaces (> 50 %), whereas particulate nitrate photolysis (34 %) prevailed during photochemical pollution events. Nevertheless, the model uncovers a significant unidentified marine HONO source in a "sea case", with its HONO production rate reaching up to 0.70 ppbv h -1 at noon. Without considering this unidentified source, an extraordinarily high photolysis coefficient of nitrate and/or a heterogeneous uptake coefficient of NO 2 would be required to match observed HONO concentrations. This missing marine HONO source affected the peak O 3 production rate and OH radical concentration by 36 % and 28 %, respectively, at the observation site. Given the limited HONO observation data in coastal and marine settings, the unidentified HONO source may cause an underestimation of the atmosphere's oxidizing capacity. This study highlights the necessity for further investigation of the role of HONO in atmospheric chemistry in coastal and marine environments. [ABSTRACT FROM AUTHOR]

Hypoxia-inducible factor 1 can sufficiently control the progress of neurological symptoms after ischemic stroke owing to their actions associated with its downstream genes. In this study, we evaluated the role of HIF-1α in attenuating brain damage after endothelin-1 injection. Focal cerebral ischemia in mice were induced by endothelin-1 microinjection. Hypoxia-inducible factor 1 activator, dimethyloxalylglycine (DMOG), and HIF-1α inhibitor, acriflavine (ACF), were used to evaluate the hypoxia-inducible factor 1 activity during cerebral ischemia. The expression levels of HIF-1α, glial fibrillary acidic protein (GFAP), interleukin-10 (IL-10), inducible nitric oxide synthase (iNOS), phosphorylated I-kappa-B-alpha/total I-kappa-B-alpha (p-IκBα/IκBα) and nuclear factor kappa B (NF-kB) were assessed. Besides, mRNA levels of IL-10, tumor necrosis factor- alpha (TNF-α), and NF-kB were also analyzed. Results showed a noticeable increase in hypoxia-inducible factor 1 and IL-10 levels in the DMOG group with a decline in iNOS, TNF-α, and NF-kB levels, implying the anti-inflammatory role of hypoxia-inducible factor 1 activator following stroke. These findings were further corroborated by GFAP immunostaining that showed astrocytic activation to be inhibited 12 days post-ischemia, as well as histological and TEM analyses that demonstrated hypoxia-inducible factor 1 induction to alleviate neuronal soma damage and cell death. Based on our study, HIF-1α could be a potential therapeutic target for ischemic stroke.

Due to the vast number of potential isomers, the chemical synthesis of large carbohydrates is challenging. Here the authors report the synthesis of mycobacterial arabinogalactan, a biologically important natural product composed of 92 monosaccharide units, the largest synthetic polysaccharide to date.

This paper proposes a generalized distance measure and its similarity measures between single valued neutrosophic multisets (SVNMs). Then, the similarity measures are applied to a medical diagnosis problem with incomplete, indeterminate and inconsistent information. This diagnosis method can deal with the diagnosis problem with indeterminate and inconsistent information which cannot be handled by the diagnosis method based on intuitionistic fuzzy multisets (IFMs).

This paper introduces the concept of a single valued neutrosophic multiset (SVNM) as a generalization of an intuitionistic fuzzy multiset (IFM) and some basic operational relations of SVNMs, and then proposes the Dice similarity measure and the weighted Dice similarity measure for SVNMs and investigates their properties. Fi nally, the Dice similarity measure is applied to a medical diagnosis problem with SVNM information. This diagnosis method can deal with the medical diagnosis problem with indeterminate and inconsistent information which cannot be handled by the diagnosis method based on IFMs.