Search

Background/Purpose The long-term disease course and efficacy of maintenance therapies have rarely been investigated in Asian patients with neuromyelitis optica spectrum disorder (NMOSD). Methods Medical records of patients fulfilling the 2015 International Consensus Diagnostic Criteria for NMOSD at three medical centers in Taiwan were systematically analyzed. Linear regression analysis was performed to investigate factors related to annualized relapse rate (ARR); survival analysis was used to estimate the relapse-free intervals among therapies. Results A total of 557 relapses affecting 648 regions (202 optic neuritis, 352 acute myelitis, and 94 brain syndromes) in 204 patients were analyzed during a follow-up period of 69.5 months (range, 1–420). Up to 36.1% of myelitis-onset patients and 24.0% of optic neuritis-onset patients exhibited a limited form disease, defined as having one or more relapses confined to the same region. The median ARR was significantly lower in patients with limited form disease than those with relapses involving multiple regions (0.30 vs. 0.47, respectively). An older age at disease onset was associated with a lower ARR (p = 0.023). Kaplan–Meier analysis showed that the estimated time (months) to next relapse was longest in rituximab-treatment group (58.0 ± 13.2), followed by immunosuppressant (48.5 ± 4.8) or prednisone (29.6 ± 4.6) groups, and shortest in those without maintenance therapy (27.6 ± 4.2) (p = 8.1 × 10−7). Conclusion Limited form disease and older age at disease onset are associated with a lower relapse rate in NMOSD. Compared to no maintenance therapy, rituximab and immunosuppressant significantly reduce the relapse risks.

Background Along with increasing research on acupuncture for chronic pain, the validity of sham acupuncture (SA) has also been argued. Methods Nine databases were searched for randomized controlled trials (RCTs) from the inception dates of the databases to July 5, 2022. With Markov Chain Monte Carlo methods, a Bayesian multiple-treatment network meta-analysis (NMA) with random-effects model was conducted. Results A total of 62 RCTs with 6,806 patients and four kinds of treatments (real acupuncture [RA], non-acupuncture [NA], penetrative SA [PSA], and non-penetrative SA [NPSA]) were included. The results indicated that both NPSA and PSA were not superior to NA in improving chronic pain (NPSA: mean difference [MD]= –4.77, 95% confidence interval [CI] –11.09 to 1.52; PSA: MD= –4.96, 95% CI –10.38 to 0.48). After NPSA and PSA were combined into the SA group, the weak trend of pain relief from SA was still not statistically significant (MD= –4.91, 95% CI –9.93 to 0.05). NPSA and PSA had similar effects (MD= 0.18, 95% CI –5.45 to 5.81). RA was significantly associated with pain relief, compared with NPSA and PSA (NPSA: MD= –12.03, 95% CI –16.62 to –7.41; PSA: MD= –11.85, 95% CI –15.48 to –8.23). The results were generally consistent regardless of pain phenotype, frequency, duration, acupuncture methods, analgesic intake, or detection bias. Conclusion These results suggested that acupuncture was significantly associated with reduced chronic pain. The two kinds of placebo acupuncture, NPSA and PSA, have similar effects. Both NPSA and PSA, with a weak but not significant effect, are appropriate to be inert placebo controls in RCTs for chronic pain.

The size of the optical zoom system is important in smartphone camera design, especially as it governs the thickness of the smartphone. We present the optical design of a miniaturized 10× periscope zoom lens for smartphones. To achieve the desired level of miniaturization, the conventional zoom lens can be replaced with a periscope zoom lens. In addition to this change in the optical design, the quality of the optical glass, which also affects the performance of the lens, must be considered. With advancements in the optical glass manufacturing process, aspheric lenses are becoming more widely used. In this study, aspheric lenses are incorporated into a design for a 10× optical zoom lens with a lens thickness of less than 6.5 mm and an eight-megapixel image sensor. Furthermore, tolerance analysis is carried out to prove its manufacturability.

High-entropy alloy (HEA) nanocrystals have attracted extensive attention in catalysis. However, there are no effective strategies for synthesizing them in a controllable and predictable manner. With quinary HEA nanocrystals made of platinum-group metals as an example, we demonstrate that their structures with spatial compositions can be predicted by quantitatively knowing the reduction kinetics of metal precursors and entropy of mixing in the nanocrystals under dropwise addition of the mixing five–metal precursor solution. The time to reach a steady state for each precursor plays a pivotal role in determining the structures of HEA nanocrystals with homogeneous alloy and core-shell features. Compared to the commercial platinum/carbon and phase-separated counterparts, the dendritic HEA nanocrystals with a defect-rich surface show substantial enhancement in catalytic activity and durability toward both hydrogen evolution and oxidation. This quantitative study will lead to a paradigm shift in the design of HEA nanocrystals, pushing away from the trial-and-error approach.

Despite significant advances in targeted and immune therapy for non-small cell lung cancer (NSCLC), effective therapies for wild-type epidermal growth factor receptor/anaplastic lymphoma kinase ( EGFR/ALKWT) with low expression of programmed death ligand-1 (PD-L1) NSCLC remain elusive. Numerous studies have shown that ferroptosis plays an essential role in antitumor activity. To identify the molecular regulation patterns associated with ferroptosis, 351 EGFR/ALKWT NSCLC samples with low-level PD-L1 were extracted from The Cancer Genome Atlas (TCGA) and clustered using the k-means clustering technique. The two clusters associated with ferroptosis showed significantly different prognoses. In total, 169 differential expression genes (DEGs) were identified. Cluster differential analysis revealed that Cluster 1 had a significantly poorer overall survival (OS) and was associated with more negative immune regulation. In addition, TCGA samples were randomly assigned in a 7:3 ratio to a training group or testing group. A signature of eight genes associated with ferroptosis was established in the training cohort using DEGs and validated in the test cohort and three independent cohorts (GSE72049, GSE41271, and GSE50081). The 5-year area under the curve (AUC) was 0.713, which was significantly higher than that of other predictors, including TNM stage and age. Furthermore, the risk score was associated with immune function, immune infiltration, and immunotherapy response, with high-risk patients having a worse prognosis, an immune-suppressing phenotype, and a poor response to immune checkpoint inhibitors. This study aims to contribute to our understanding of the biological role of ferroptosis in EGFR/ALKWT NSCLC with low-level PD-L1, laying the groundwork for the development of novel therapeutic strategies.

Neuronal intranuclear inclusion disease (NIID), caused by an expansion of GGC repeats in the 5′-untranslated region of NOTCH2NLC, is an important but underdiagnosed cause of adult-onset leukoencephalopathies. The present study aimed to investigate the prevalence, clinical spectrum and brain MRI characteristics of NIID in adult-onset nonvascular leukoencephalopathies and assess the diagnostic performance of neuroimaging features. One hundred and sixty-one unrelated Taiwanese patients with genetically undetermined nonvascular leukoencephalopathies were screened for the NOTCH2NLC GGC repeat expansions using fragment analysis, repeat-primed PCR, Southern blot analysis and/or nanopore sequencing with Cas9-mediated enrichment. Among them, 32 (19.9%) patients had an expanded NOTCH2NLC allele and were diagnosed with NIID. We enrolled another two affected family members from one patient for further analysis. The size of the expanded NOTCH2NLC GGC repeats in the 34 patients ranged from 73 to 323 repeats. Skin biopsies from five patients all showed eosinophilic, p62-positive intranuclear inclusions in the sweat gland cells and dermal adipocytes. Among the 34 NIID patients presenting with nonvascular leukoencephalopathies, the median age at symptom onset was 61 years (range, 41–78 years) and the initial presentations included cognitive decline (44.1%; 15/34), acute encephalitis-like episodes (32.4%; 11/34), limb weakness (11.8%; 4/34) and parkinsonism (11.8%; 4/34). Cognitive decline (64.7%; 22/34) and acute encephalitis-like episodes (55.9%; 19/34) were also the most common overall manifestations. Two-thirds of the patients had either bladder dysfunction or visual disturbance. Comparing the brain MRI features between the NIID patients and individuals with other undetermined leukoencephalopathies, corticomedullary junction curvilinear lesions on diffusion weighted images were the best biomarkers for diagnosing NIID with high specificity (98.4%) and sensitivity (88.2%). However, this diffusion weighted imaging abnormality was absent in 11.8% of the NIID patients. When only fluid-attenuated inversion recovery images were available, the presence of white matter hyperintensity lesions either in the paravermis or middle cerebellar peduncles also favoured the diagnosis of NIID with a specificity of 85.3% and sensitivity of 76.5%. Among the MRI scans of 10 patients, performed within 5 days of the onset of acute encephalitis-like episodes, five showed cortical hyperintense lesions on diffusion weighted images and two revealed focal brain oedema. In conclusion, NIID accounts for 19.9% (32/161) of patients with adult-onset genetically undiagnosed nonvascular leukoencephalopathies in Taiwan. Half of the NIID patients developed encephalitis-like episodes with restricted diffusion in the cortical regions on diffusion weighted images at the acute stage. Corticomedullary junction hyperintense lesions, white matter hyperintensities in the paravermis or middle cerebellar peduncles, bladder dysfunction and visual disturbance are useful hints to diagnosing NIID.

This study aimed to assess the clinical characteristics affecting outcomes after immune checkpoint inhibitors (ICI) therapies in non-small cell lung cancer (NSCLC) patients, and the underlying mechanism in tumor immune micro-environment (TIME).A total of 144 patients treated with ICI-based strategies were retrospectively analyzed. Expression of 10 immune antibodies in tumor tissues from other 60 untreated NSCLC patients were sequentially tested using multiplexed immunofluorescence (mIF) staining method. Correlation of clinical characteristics with ICI treatment outcomes and TIME characteristics were analyzed.Multivariate logistic and cox regression indicated that BoM negatively affected disease control rate (OR = 0.32, 95%CI: 0.13-0.82, P = 0.018), progression free survival (HR = 3.44, 95% CI:1.97-6.00, P 0.001) and overall survival (HR = 3.24, 95% CI:1.62-6.50, P = 0.001), irrespective of programmed death-ligand 1 (PD-L1) expression. BoM patients were with significantly lower PD-L1, and this heterogeneity of TIME was then confirmed in the mIF staining, where 36 (61.0%) patients were clustered into immune-subtype A, with low expression of all the detected immune markers, similar to "cold" tumors, and 23 (39.0%) in cluster B with likely "hot" tumors. More patients in immune-subtype A were non-smokers (63.9% vs. 39.1% P = 0.063), with BoM (66.7% vs. 21.7%, P = 0.001), in stage IV(88.9% vs. 65.2%, P = 0.045), and with adenocarcinoma (91.7% vs. 69.6%, P = 0.037). Multivariate logistic regression indicated that BoM was independently associated with the "cold" immune characteristics (OR = 0.19, 95% CI:0.04-0.84, P = 0.028). Combination therapy with chemotherapy /antiangiogenesis or use of bisphosphonate during ICI treatment significantly improved clinical outcomes in BoM patients.BoM displays adverse impact on clinical outcomes after ICI treatments in NSCLC patients. The "cold" characteristics of TIME may be the underlying mechanism for the attenuated efficacy of ICIs in bone metastatic NSCLC patients.

To observe the efficacy of acupuncture on symptom burden in patients with gastric cancer during adjuvant chemotherapy after gastrectomy.A total of 58 patients were randomized into a high-dose acupuncture group (19 cases, 5 cases dropped off), a low-dose acupuncture group (20 cases, 6 cases dropped off) and a control group (19 cases, 2 cases dropped off). Conventional chemotherapy and antiemetic treatment were adopted in the control group. On the basis of the treatment in the control group, acupuncture was applied 7 times each chemotherapy cycle for totally 21 times in the high-dose acupuncture group, and 3 times each chemotherapy cycle for totally 9 times in the low-dose acupuncture group. Baihui (GV 20), Zusanli (ST 36), Neiguan (PC 6), etc. were selected in the two acupuncture groups, as well as back-The symptom burden was worst within 7 days of each cycle of chemotherapy in the 3 groups. After the 3rd chemotherapy cycle, the total score of ESAS in the low-dose acupuncture group was lower than the control group (Acupuncture shows promising effect in controlling symptom burden during adjuvant chemotherapy in gastric cancer patients after gastrectomy.

Background and ObjectivesThe GGC repeat expansion in the 5′ untranslated region of NOTCH2NLC was recently identified as the cause of neuronal intranuclear inclusion disease (NIID), which may manifest with peripheral neuropathy. The aim of this study is to investigate its contribution to inherited neuropathy.MethodsThis cohort study screened patients with molecularly undiagnosed Charcot-Marie-Tooth disease (CMT) and healthy controls for the GGC repeat expansion in NOTCH2NLC using repeat-primed PCR and fragment analysis. The clinical and electrophysiologic features of the patients harboring the GGC repeat expansion were scrutinized. Skin biopsy with immunohistochemistry staining and electric microscopic imaging were performed.ResultsOne hundred twenty-seven unrelated patients with CMT, including 66 cases with axonal CMT (CMT2), and 200 healthy controls were included. Among them, 7 patients with CMT carried a variant NOTCH2NLC allele with GGC repeat expansion, but it was absent in controls. The sizes of the expanded GGC repeats ranged from 80 to 104 repeats. All 7 patients developed sensory predominant neuropathy with an average age at disease onset of 37.1 years (range 21–55 years). Electrophysiologic studies revealed mild axonal sensorimotor polyneuropathy. Leukoencephalopathy was absent in the 5 patients who received a brain MRI. Skin biopsy from 2 patients showed eosinophilic, ubiquitin- and p62-positive intranuclear inclusions in the sweat gland cells and dermal fibroblasts. Two of the 7 patients had a family history of NIID.DiscussionThe NOTCH2NLC GGC repeat expansions are an underdiagnosed and important cause of inherited neuropathy. The expansion accounts for 10.6% (7 of 66) of molecularly unassigned CMT2 cases in the Taiwanese CMT cohort.Classification of EvidenceThis study provides Class III evidence that in Taiwanese patients with genetically undiagnosed CMT, 10.6% of the CMT2 cases have the GGC repeat expansion in NOTCH2NLC.

The clinicopathological value of microRNA-141-3p (miR-141-3p) and its prospective target genes in endometrial carcinoma (EC) remains unclear. The present study determined the expression level of miR-141-3p in EC via quantitative real-time PCR (RT-qPCR). RT-qPCR showed a markedly higher expression level of miR-141-3p in EC tissues than in non-EC endometrium tissues (P < 0.0001). The microarray and miRNA-seq data revealed upregulation of miR-141-3p. Integrated analysis based on 675 cases of EC and 63 controls gave a standardized mean difference of 1.737, confirmed the upregulation of miR-141-3p. The Kaplan-Meier survival curve showed that a higher expression of miR-141-3p positively corelated with a poorer prognosis. Combining the predicted targets and downregulated genes in EC, we obtained 271 target genes for miR-141-3p in EC. Two potential targets, PPP1R12A and PPP1R12B, were downregulated at both the mRNA and protein levels. This study indicates that the overexpression of miR-141-3p may play an important part in the carcinogenesis of EC. The overexpression of miR-141-3p may be a risk factor for the prognosis of patients with EC., Graphical Abstract

Along with increasing research on acupuncture for chronic pain, the validity of sham acupuncture (SA) has also been argued.Nine databases were searched for randomized controlled trials (RCTs) from the inception date to July 5, 2022. Using Markov Chain Monte Carlo methods, a Bayesian multiple treatment network meta-analysis (NMA) with random-effects model was conducted.A total of 62 RCTs with 6806 patients and four kinds of treatments (real acupuncture (RA), non-acupuncture (NA), penetrative SA (PSA) and non-penetrative SA (NPSA)) were included. The results indicated that both NPSA and PSA were not superior to NA in improving chronic pain (NPSA: MD -4.77 [95% CI, -11.09 to 1.52]; PSA: MD, -4.96 [95% CI, -10.38 to 0.48]). After combining NPSA and PSA into the SA group, the weak trend of pain relief from SA was still not statistically significant (MD, -4.91 [95% CI, -9.93 to 0.05]). NPSA and PSA had similar effects (MD, 0.18 [95% CI, -5.45 to 5.81]). RA was significantly associated with pain relief, compared with NPSA and PSA (NPSA: MD, -12.03 [95% CI, -16.62 to -7.41]; PSA: MD, -11.85 [95% CI, -15.48 to -8.23]). The results were generally consistent regardless of pain phenotype, frequency, duration, acupuncture methods, analgesic intake, or detection bias.These results suggested that acupuncture was significantly associated with reduced chronic pain. The two kinds of placebo acupuncture, NPSA and PSA, have similar effects. Both NPSA and PSA, with a weak but not significant effect, are appropriate to be inert placebo controls in RCTs for chronic pain.

Sorafenib is a multikinase inhibitor for the standard treatment of advanced liver cancer patients. However, acquired resistance to sorafenib is responsible for a poor prognosis. Therefore, uncovering the molecular mechanisms underlying sorafenib sensitization can provide biomarkers for sorafenib treatment and improve sorafenib activity in a precise medication. Here, we report that epigenetic suppression of Dicer by the HOXB-AS3/EZH2 complex is responsible for sorafenib resistance. We observed that Dicer expression is inversely correlated with EZH2 levels, HOXB-AS3 expression, sorafenib resistance, and cancer stem cell properties in liver cancer patients. Furthermore, ectopic expression of Dicer induced liver cancer cells resensitization to sorafenib. Mechanistically, we found HOXB-AS3 physically interacts with EZH2 and recruits EZH2 to the Dicer promoter, resulting in epigenetic suppression of Dicer expression. These findings reveal that HOXB-AS3/EZH2 complex-mediated Dicer suppression plays an important role in sorafenib resistance and cancer stemness and provide potential therapeutic strategies for diagnosing and treating liver cancer patients.

Background Whereas there are many pharmacological interventions prescribed for patients with advanced anaplastic lymphoma kinase (ALK)- rearranged non-small cell lung cancer (NSCLC), comparative data between novel generation ALK-tyrosine kinase inhibitors (TKIs) remain scant. Here, we indirectly compared the efficacy and safety of first-line systemic therapeutic options used for the treatment of ALK-rearranged NSCLC. Methods We included all phase 2 and 3 randomised controlled trials (RCTs) comparing any two or three treatment options. Eligible studies reported at least one of the following outcomes: progression free survival (PFS), overall survival (OS), objective response rate (ORR), or adverse events of grade 3 or higher (Grade ≥ 3 AEs). Subgroup analysis was conducted according to central nervous system (CNS) metastases. Results A total of 9 RCTs consisting of 2484 patients with 8 treatment options were included in the systematic review. Our analysis showed that alectinib (300 mg and 600 mg), brigatinib, lorlatinib and ensartinib yielded the most favorable PFS. Whereas there was no significant OS or ORR difference among the ALK-TKIs. According to Bayesian ranking profiles, lorlatinib, alectinib 600 mg and alectinib 300 mg had the best PFS (63.7%), OS (35.9%) and ORR (37%), respectively. On the other hand, ceritinib showed the highest rate of severe adverse events (60%). Conclusion Our analysis indicated that alectinib and lorlatinib might be associated with the best therapeutic efficacy in first-line treatment for major population of advanced NSCLC patients with ALK-rearrangement. However, since there is little comparative evidence on the treatment options, there is need for relative trials to fully determine the best treatment options as well as the rapidly evolving treatment landscape.

Background and ObjectivesTo investigate the frequency, spectrum, and molecular functional effect of glycosyltransferase 8 domain-containing protein 1 (GLT8D1) variations in Taiwanese patients with amyotrophic lateral sclerosis (ALS).MethodsWe performed genetic analyses of GLT8D1 in 410 unrelated patients with ALS by Sanger sequencing. The 410 patients were selected from a cohort of 477 unrelated patients with ALS after excluding variations in common ALS disease genes. Functional effects of the GLT8D1 variation were investigated by in vitro functional analysis.ResultsWe identified a novel heterozygous missense variation in GLT8D1, p.I290M (c.870C>G), in 1 single patient with familial ALS. The patient with the p.I290M variation had a spinal-onset ALS with disease onset at age 60 years and a survival of 6 years. Functional studies demonstrated that the variant I290M GLT8D1 protein was mislocalized to the endoplasmic reticulum (ER), provoked ER stress and unfolded protein response, compromised the glycosyltransferase activity, and led to an increased cytotoxicity.DiscussionGLT8D1 variations account for 0.2% (1/477) of the patients with ALS in Taiwan. These findings expand the spectrum of GLT8D1 variation and support the pathogenic role of GLT8D1 variations in ALS.

Haochuan Ma,1,&ast; Zhiyong Xu,1,&ast; Rui Zhou,1,&ast; Yihong Liu,2 Yanjuan Zhu,1– 4 Xuesong Chang,2 Yadong Chen,2 Haibo Zhang1– 5 1The Second Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 2Department of Oncology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou, People’s Republic of China; 3Guangdong-Hong Kong-Macau Joint Laboratory on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 4Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, People’s Republic of China; 5State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haibo ZhangDepartment of Oncology, Guangdong Provincial Hospital of Traditional Chinese Medicine, No. 111, Dade Road, Guangzhou, Guangdong, 510120, People’s Republic of ChinaTel +86-20-81887233Fax +86-20-81874903Email haibozh@gzucm.edu.cnPurpose: This study was designed to construct and validate a nomogram that was available for predicting cancer-specific survival (CSS) in patients with pulmonary large-cell neuroendocrine carcinoma (LCNEC).Patients and Methods: Using the US Surveillance, Epidemiology, and End Results (SEER) database, we identified patients pathologically diagnosed as LCNEC from 1975 to 2016. Univariate and multivariate Cox regression was conducted to assess prognostic factors of CSS. A novel nomogram model was constructed and validated by the concordance index (C-index), calibration curves and decision curve analysis (DCA).Results: A total of 624 LCNEC patients were enrolled. Five prognostic factors for CSS were identified and merged to establish nomograms. In the training and validation cohorts, calibration curves displayed the nomogram predictions are in a good agreement with the actual survival. The C-Index of the training and validation cohorts were both higher than 0.8, and the DCA results showed that the nomogram has clinical validity and utility.Conclusion: The proposed nomogram resulted in accurate CSS prognostic prediction for patients with LCNEC.Keywords: pulmonary large-cell neuroendocrine carcinoma, prognosis, nomogram, SEER database, cancer-specific survival

To compare the reduction of residual dentine thickness of two different post preparation methods on the mandibular second molars with a C-shaped root canal configuration.A total of 26 extracted right mandibular second molars with a C-shaped root canal configuration were selected and paired based on similar canal morphology. Each of the paired teeth was randomly allocated to the heat and ultrasonic instruments group (HU group) or Peeso Reamer (Mani, Utsonomiya, Japan) group (PR group) (n = 13) and received post preparation with different instruments after the same endodontic treatment. The reduction of residual dentine thickness and the minimal remaining dentine thickness at the apical sections at 4 or 7 mm below the cementoenamel junction (CEJ) were recorded. The data were analysed using an independent samples t test (α = 0.05).The reduction of residual dentine thickness for the HU group was less than that for the PR group in the two sections. Moreover, at the section 7 mm below the CEJ, the teeth reduction of the distolingual wall in the HU group (0.022 ± 0.007 mm) was significantly lower than that in the PR group (0.101 ± 0.013 mm) (P0.01).Using heat and ultrasonic instruments to perform post preparation could follow the original canal configuration to save more tooth structure in the remaining root canal wall, minimise the reduction of residual dentine thickness and decrease the incidence of root canal perforation.

The GGC repeat expansion in the 5' untranslated region ofThis cohort study screened patients with molecularly undiagnosed Charcot-Marie-Tooth disease (CMT) and healthy controls for the GGC repeat expansion inOne hundred twenty-seven unrelated patients with CMT, including 66 cases with axonal CMT (CMT2), and 200 healthy controls were included. Among them, 7 patients with CMT carried a variantTheThis study provides Class III evidence that in Taiwanese patients with genetically undiagnosed CMT, 10.6% of the CMT2 cases have the GGC repeat expansion in

δ-Aminolevulinic acid (δ-ALA) plays a vital role in the diagnosis and clinical screening of diseases like lead poisoning, hepatic porphyria, and hereditary tyrosinemia type-1. However, because of the drawbacks of the existing methods, such as tedious pre-separations and analytical interference, it poses a serious challenge for an efficient, specific, and simple δ-ALA detection strategy. In this work, matrix-isopotential synchronous fluorescence spectrometry (MISFS) and the first derivative technique are combined for the direct determination of δ-ALA in urine samples. The proposed approach promises the detection of δ-ALA in urine samples with unknown background fluorescence, alleviating complicated and tedious pre-separation processes. Here, the fluorescent derivatization of δ-ALA was based on the Hantzsch reaction. MISF spectra were scanned along a matrix-isopotential trajectory, which combines the points of equal intensity in theoretical 3D contours. The contours were constructed from the excitation and emission spectra of δ-ALA and urine. The unknown background signal of the urine was suppressed by the first order derivative technique. Maximum sensitivity and appropriate selectivity were ensured by the study of the experimental variables in the δ-ALA bands, centered at its excitation and emission maxima (392.6 nm and 464.5 nm). The limits of detection and quantification, calculated according to IUPAC definitions, were 5.4 ppb and 18 ppb, respectively. The average recoveries were 97.2% ± 2.6%. For within-run precisions, the inter-day and intra-day CVs were 5.3% and 3.6%, respectively. The results achieved by the proposed method were consistent with those obtained by the conventional HPLC-FLD method.

A remarkable intermolecular dehydrative coupling reaction with the formation of a C-C bond was found for the vinylidene complex 2 a, yielding the dinuclear bisvinylidene complex 4 a. Complex 2 a containing 1-hydroxyindan moiety was first formed from the reaction of o-propynyl benzaldehyde 1 a with [Ru]-Cl ([Ru]=Cp(PPh3 )2 Ru) by a cyclization process. For analogous aldehyde 1 b containing an additional 1,3-dioxolane group on the aryl ring, similar intermolecular coupling yields the dinuclear bisvinylidene complex 4 b. However, the fluoro group on the aryl ring in aldehyde 1 c inhibits the coupling reaction, giving only the vinylidene complex 2 c. For the reactions of [Ru]-Cl in MeOH with compounds 1 f, 1 g and 1 h, each with a ketone functionality, cyclization gives vinylidene complexes 2 f, 2 g and 2 h, respectively. However, no similar intermolecular coupling was observed, instead, the intramolecular dehydration yields 8 f, 8 g and 8 h, respectively. In CDCl3 , catalytic cyclization is observed for the o-propynylphenyl ketone 1 h with [Ru]-Cl at 50 °C giving the isochromene products 14 h. Furthermore, treatment of the o-propynylaryl α,β-unsaturated ketones 1 k-m and 1 n with [Ru]-Cl in MeOH affords the corresponding vinylidene complexes 10 k-m and 11 n each with 1-benzosuberone moiety in the presence of NH4 PF6 . These intramolecular cyclization products were formed by the addition of Cβ onto the terminal carbon of the alkene moiety. All these reaction products were characterized by spectroscopic methods. In addition, structures of complexes 4 a, and 10 l were confirmed by single crystal X-ray diffraction analysis.

Patients with EGFR gene mutation often obtain de novo resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) or develop secondary resistance to EGFR-TKIs after taking EGFR-TKI therapy. Traditional Chinese medicine (TCM) with different treatment principles, in combination with EGFR-TKIs, plays an important role in the treatment of cancers including resistant non-small cell lung cancer (NSCLC). However, inappropriate use of TCM herbs may induce resistance to gefitinib. Therefore, it is of a great value to evaluate which TCM treatment principle should be combined with EGFR-TKIs, and which one should be avoided, and find out the potential mechanisms. The lentiviral transfection assay was used for overexpression of PIK3CA mutation gene in PC-9 cells to construct PC-9-PIK3CA-mutation (PC-9-PIK3CA-M) cells. Cell proliferation, apoptosis, and the expression of EGFR/PI3K/AKT and EGFR/RAS/RAF/ERK in PC-9-PIK3CA-M and H1975 cells treated by the typical cooling-heat drug, Qing-kai-ling (QKL) and Tan-re-qing (TRQ), or the typical warming-yang drug, Shen-fu (SF) and gefitinib treatment, were detected by MTT, Annexin V/PI double labeling, and Western blot assays, respectively. Tumor xenograft and immunohistochemistry experiments were carried out to confirm the in vitro findings. PC-9-PIK3CA-M cells were less sensitive to gefitinib, when compared with PC-9 cells. QKL injection and TRQ injection, not SF injection, combined with gefitinib induced significantly increased cell growth inhibition and apoptosis in PC-9-PIK3CA-M and H1975 cells. SF injection antagonized the effect of gefitinib in promoting cancer cell apoptosis. QKL injection and TRQ injection increased the sensitivity of gefitinib by inhibiting the phosphorylation of AKT or ERK in H1975 and PC-9-PIK3CA-M cells. Similar findings were observed in vivo in H1975 xenograft mouse model. QKL and TRQ, with cooling-heat TCM treatment principle, should be combined with gefitinib in the treatment of NSCLC. Furthermore, warming-yang drug SF should be avoided to be used together with EGFR-TKIs.

TPS220 Background: For advanced colorectal cancer (CRC), fluoropyrimidine-based chemotherapy (5-FU or capecitabine combined with oxaliplatin) with VEGF inhibitors (bevacizumab) is standard first-line treatment. However, once this treatment had been used, the second line treatment is limited. Although continuation of bevacizumab after first progression can improve PFS and OS, the benefit of bevacizumab may be reduced compared with who never pre-treated with bevacizumab (the ML18147 study). Anlotinib is an oral small molecule tyrosine kinases inhibitor, targeting VEGF receptors 1/2/3, FGF receptors 1-4, PDGF receptors α/β and c-kit. mXELIRI is a chemotherapy regimen consisting of irinotecan and capecitabine. The trial is to investigate the efficacy and safety of anlotinib combined with mXELIRI as second-line treatment in advanced colorectal cancer pre-treated with bevacizumab plus standard chemotherapy. Methods: This is a multi-center, prospective, single-arm, 2-part, phase Ib/II study. Eligible pts are aged 18-75 years with histologically and radiographically confirmed mCRC who had progressed or intolerant with bevacizumab plus FOLFOX or CAPEOX regimen chemotherapy treatment. ECOG performance status 0 - 1, and adequate organ function. Treatment: anlotinib (8mg, 10mg or 12mg), po, qd, on days 1-14 every 3 weeks; irinotecan 180-200 mg/m2, iv, on day 1 every 3 weeks; capecitabine, 800 mg/m2, po, bid, on days 1-14 every 3 weeks. For the phase 1b segment, a standard 3+3 dose-escalation design is used to determine the maximum tolerated dose or recommended phase 2 dose (RP2D) of anlotinib. 3 patients are enrolled and treated per dose level (8mg,10mg,12mg). If no DLT, dose is escalated for the next cohort of 3 patients; If 1 DLT, 3 additional patients are treated at this level with dose escalation only if no additional DLTs；If ≥ 2 DLTs, prior dose level is defined as MTD. MTD decided when 6 patients are treated at a dose level with < 2 DLTs. Primary endpoint is objective response rate (ORR) according to RECIST v1.1. Secondary endpoints are progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DOR) and quality of life (QoL). Based on a one-sided one sample log-rank test with 2.5% Type I error, 80% power to detect an improvement in ORR from 5.4% to 15%, there will be 94 patients consider 20% of patients fall off. Research Sponsor: Guangdong Provincial Hospital of Chinese Medicine Clinical trial information: NCT05035914.

Background: Traditional Chinese Medicine (TCM) prescriptions should be decided according to the TCM treatment principle, and the warming-yang or cooling-heat should be the guide of treatment principle outline. Methods: In order to identify which treatment principle, warming-yang or cooling-heat should be combined with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC), we combined the typical warming-yang drug, Shen-fu (SF), and the typical cooling-heat drug, Qing-kai-ling (QKL) with gefitinib in resistant NSCLC models. Results: The results demonstrated that QKL combined with gefitinib induced significantly increased cell viability inhibition and apoptosis in A549 cell line and significantly smaller tumor volume and lower tumor weight in H1975 xenograft transplanted nude mice. On the contrary, SF combined with gefitinib had significant antagonism effect on both cell viability inhibition and apoptosis in vitro , and on tumor weight in vivo . EGFR phosphorylation inhibition and the downstream PI3K/AKT and RAS/RAF/ERK pathway inhibition served an important role in the synergism effect between QKL and gefitinib in H1975 xenograft transplanted nude mice. Conclusions: The present study indicated that cooling-heat TCM treatment principle may reverse or delay NSCLC resistance to EGFR-TKIs, and combination of them warrants further study.

Light-matter interactions have always been a fundamentally significant topic that has attracted much attention. It is important to reveal a fluorophore-plasmon interaction on the nanoscale. However, as a powerful investigative tool, fluorescence spectroscopy still suffers from a limited spectral resolution and the susceptibility to interfering substances. In this work, excitation-emission synchronization-mediated surface-plasmon-coupled emission (EES-SPCE) is proposed to break the bottleneck. By actively screening the energy transitions for observation, an improved spectral resolution has been achieved, which is advantageous to the investigation of the fluorophore-plasmon interactions under different coupling modes. The spectral information related to the plasmonic interactions through tuning vibrational energy levels is clearly distinguished at directional emission angles. EES-SPCE is demonstrated to selectively and efficiently extract the coupled emission from the vibrational resolution, which would open up the opportunity to improve the capability of spectral feature identification and signal collection for practical applications of plasmonic fluorescence spectroscopy.

We present an optical design for the lens depth of a periscope-type 3 × zoom lens with 8-megapixel sensor in mobile phone. In the practice application, the lens depth of zoom lens must be less than the thickness of the mobile phone mechanism. The lens depth is thus the upper size limit of the prism thickness or the maximum surface aperture in the Y-direction of the zoom lens. The zoom lens in the designed system has an F-number of F/3.5 to F/5.5, a focal length of 4.514 mm to 13.442 mm, the half field angle in the x-direction is 23.96° to 8.488°, and the half field angle in the y-direction is 14.035° to 4.798°. The smallest lens depth of the zoom lens is 5.377 mm. These results show that the depth of a periscope-type zoom lens can be embedded in the mobile phone.

The crustal structure of collisional orogen is critical for deciphering the crustal evolution and geodynamics of an orogen. Metamorphic rocks and post-collisional magmatic rocks are the key subjects to probe the crustal structure. In this study, we conducted an integrated study of zircon U Pb age, Hf and O isotopes for migmatites and post-collisional granites in the southern segment of the Tongbai orogen. Zircon U−Pb dating yields protolith ages of 755 ± 55 to 713 ± 6 Ma and metamorphic ages of 162 ± 11 Ma to 138 ± 2 Ma for the migmatites and intrusion ages of 137 ± 2 Ma for the post-collisional granites. The inherited magmatic cores in the migmatites exhibit similar Hf isotopic compositions to the metamorphic zircons. Their eHf(t) values range from 13.5 to −9.5 with crust Hf model ages of 787 Ma to 2233 Ma, indicating that the protoliths were derived from reworking of Paleoproterozoic crust with the addition of juvenile components during the Neoproterozoic. Zircon δ18O of inherited magmatic cores are of −1.45‰ to 5.90‰, signifying the protoliths were formed by remelting of hydrothermally altered low δ18O rocks. By comparison, the post-collisional granites mostly show normal mantle-like O zircon isotope compositions and have lower eHf(t) and eNd(t) values than the migmatite rocks. These features suggest that the granites were formed by fusion of the ancient crust that might have suffered insufficient water-rock interaction. The discrepancies in O–Hf–Nd isotopic compositions of the studied migmatites and granites might be inherited from their precursors. It is thus inferred that the precursors of the granites might lie at the shoulder of the Neoproterozoic rift and thus might have experienced slight water-rock hydrothermal alteration and crust-mantle interaction; whereas the protoliths of the metamorphic rocks might be located at or near the rift center and thus had suffered intensive water-rock hydrothermal alteration and crust-mantle interaction. Prior to the late Mesozoic magmatism, the Tongbai orogen would have an uncoupled double-layered crust, where the upper layer consists of the metamorphic rocks and the lower is the sources of the post-collisional granites. They were stacked by the Permian-Triassic orogeny. The final architecture of the Tongbai orogen might be constituted by the emplacement of the voluminous granites from the deeper crust and the formation of the migmatites in the Tongbai complex. This configuration might widespread for other collisional orogens.

Droplet digital polymerase chain reaction (ddPCR) has shown sufficient concordance in detecting plasma epidermal growth factor receptor (EGFR) status in non-small cell lung cancer (NSCLC), compared to tumor tissues. However, the clinical significance of the quantitative plasma mutated EGFR concentration remains unknown. The purpose of this study was to explore the relationship of plasma mutated EGFR concentration with tumor burden in advanced NSCLC patients.Using ddPCR, plasma DNA samples prior to administration of therapies from 113 consecutive NSCLC patients were analyzed for EGFR L858R substitution and deletion of exon19 (ex19del). Plasma EGFR status was compared to tumor EGFR status to determine concordance. Then, we assessed the correlation of plasma mutated EGFR concentrations with tumor burden and other tumor characteristics.Compared to tumor EGFR, the concordance rate of plasma and tissue EGFR status was 86.73%. Of the 64 patients who harbored tumor EGFR mutation, plasma mutated EGFR concentrations significantly correlated with number of metastatic sites (Spearman's r=0.4954, p0.0001), number of lesions (Spearman's r=0.4484, p=0.0002), and sum of measurable lesions' diameters (Spearman's r=0.3539, p=0.0048). Number of metastatic sites was independently associated with mutated EGFR concentration in multiple linear regression. Besides, plasma mutated EGFR concentrations were significantly higher in those with extensive tumor burden (median concentration, 386.9 vs. 13.4copies/mL; p0.0001) and stage IV disease (median concentration, 244.2 vs. 0copies/mL; p=0.0252). In conclusion, mutated plasma EGFR concentration determined by ddPCR analysis significantly correlated with tumor burden.

// Yong Li 1, * , Yi-Hong Liu 1, * , Xian Chen 1 , Yan-Juan Zhu 1 , Hai-Bo Zhang 1 , Yan Li 1 , Jian-Ping Bai 1 , Li-Rong Liu 1 , Yan-Chun Qu 1 and Xin Qu 1 1 Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, Guangdong, China * Yong Li and Yi-Hong Liu contributed equally to this work Correspondence to: Hai-Bo Zhang, email: bubu400865@sohu.com Keywords: long non-coding RNAs, HULC, cancer, overall survival Received: April 18, 2017 Accepted: May 03, 2017 Published: June 13, 2017 SUMMARY Some studies investigated the association between highly up-regulated in liver cancer (HULC) and the overall survival (OS) of cancer. However, the results were conflicted and inconclusive. Therefore, we performed this meta-analysis to determine the association between HULC and the OS of cancer. A comprehensive online search was conducted on Online electronic databases (PubMed, EMBASE, and Wanfang database) from the earliest date to Aug 30, 2016. The strength of the association was calculated with the HRs and respective 95% CIs. The expression of HULC was significantly associated with OS of cancers (HR = 2.12; 95% CI 1.61 – 2.79; P

Progress in the treatment options for small cell lung cancer (SCLC) remains poor. Concerns exist regarding the efficacy of bevacizumab in SCLC. The present study aimed to evaluate the efficacy of bevacizumab in extensive stage (ES)-SCLC. A meta-analysis on studies conducted and listed on the Medline, Cochrane Trials, ASCO, ESMO and ClinicalTrial databases, and Chinese databases prior to April 2015 was performed. All clinical trials in which patients with ES-SCLC were treated with bevacizumab were considered. Survival rates at specific time points were extracted from the reported survival curves. Hazard ratios (HR) for progression-free survival (PFS) and overall survival (OS), rates for PFS, OS, overall response rate (ORR), and side-effects were synthesized using random-effects or fixed-effects model. Two randomized control trials (RCT) (176 patients) and six single-arm trials (292 patients) were identified. In RCTs, no statistically significant differences were observed in PFS [HR, 0.70; 95% confidence interval (CI), 0.41-1.19; P=0.19] or OS (HR, 1.21; 95% CI, 0.84-1.75; P=0.31). In the first-line trials, pooled 6-month and 1-year PFS rates were 57% (95% CI, 39-76%) and 10% (95% CI, 4-16%), respectively. Synthesized 1-year and 2-year OS rates were 45% (95% CI, 36-54%) and 10% (95% CI, 6-14%), respectively. Reported median PFS and OS times for pretreated patients were 2.7-4.0 months and 6.3-7.4 months, respectively. Pooled ORRs were 71% (95% CI, 59-82%) in the first-line trials and 18% (95% CI, 11-25%) in the second-line trials. The most common types of reported toxicities were chemotherapy-associated, including neutropenia, leukopenia, fatigue and thrombocytopenia. According to the RCTs, bevacizumab did not appear to improve the PFS or OS for patients with ES-SCLC, with low quality of evidence. Due to the disappointing pooled efficacy in the single-arm trials, more clinical studies on bevacizumab in SCLC may not be valuable, although the evidence was with low quality.

TPS151 Background: The standard third-line treatment of mCRC is regofenib, fruquintinib or TAS-102. However, the efficacy was not satisfied. Because VEGF and EGFR share the downstream signal pathway, targeting these two pathways may have synergistic efficacy. Preclinical studies have confirmed the effect of the combination of regorafenib and cetuximab. The subsequent phase Ⅰb study in advanced cancer showed the combination is effective. Fruquintinib is the same anti-VEGF drugs and was approved in China. Our department has treated one patient of advanced colorectal cancer, no standard regimen after third-line treatment. The efficacy is SD and PFS time exceeded 6 months. Therefore this study explores the safety and efficacy of fruquintinib combined with cetuximab. Methods: This is a single-center, non-random, prospective, open exploratory study. Eligible pts were diagnosed as advanced RAS/BRAF wild-type colorectal cancer and had received at least two prior regimens of standard therapies. The purpose of phase Ⅰ is to confirm the safety and the appropriate dose of fruquintinib combined with cetuximab. The phase Ⅱa investigate the safety and the efficacy of fruquintinib combined with cetuximab. Phase I: The dose of cetuximab is 500mg/m2 every two weeks which is clinically tolerable, so the dose need not be adjusted. fruquintinib is taken once daily for the first 21 days of each 28-day cycle and the dose adjustment is required due to the side effects. The standard dose of fruquintinib is 5mg/d, but the side effects are serious. The dose of 3mg/d is the minimum effective dose, therefore the initial dose of fruquintinib starts from 4mg, and three patients are enrolled. If DLT appeared in less than three patients, the dose elevated to 5mg/d. Three patients were enrolled in the 5mg/d dose group. If DLT appeared in less than three patients, the right dose of fruquintinib was 5mg/d. If DLT appeared in all three patients of the 5mg/d, fruquintinib was declined to 4mg/d combined with cetuximab to carry out a phase Ⅱa study. Fruquintinib initial dose is 4mg/d. If DLT was present in all three patients, the dose was reduced to 3mg/d. The standard dose of fruquintinib (3mg/d) was determined to be MDT, and the subsequent phase Ⅱa study was conducted by giving fruquintinib 3mg/d. The phase Ⅱa study is cetuximab 500mg/m2 biweekly combined with fruquintinib according to the confirmed dose in phase Ⅰ, taking it once daily for the first 21 days of each 28-day cycle. The number of cases is 20.Response assessment via CT/MRI is to be done q8 wks (RECIST 1.1). Continue until disease progression or unacceptable toxicity. The primary objective is to estimate safety, grade 3/4 adverse, and DLT. Secondary objectives include ORR, PFS, and OS. Final analysis to be done 6 mo after enrollment of the final pt. Clinical trial information: ChiCTR2000038227 . Research Sponsor: None

Based on the conclusions of the European Food Safety Authority (EFSA), the four polycyclic aromatic hydrocarbons (PAH4) chrysene (Chr), benzo(a)anthracene (BaA), benzo(a)pyrene (BaP), and benzo(b)fluoranthene (BbF) are new markers for the occurrence of PAHs in food. Vegetable oils are extremely easily contaminated by PAHs, due to the raw material pollution and the imperfections of processing techniques. Therefore, it is of great importance to establish an efficient method for the rapid determination of PAH4 in vegetable oils. In this research, second-derivative nonlinear variable-angle-matrix isopotential synchronous fluorescence spectroscopic approach has been proposed for the simultaneous and rapid determination of PAH4 in vegetable oils with ultrasonic-assisted extraction. This method is capable of resolving the spectra of these four PAHs well. The limits of detection (LODs) for Chr, BaA, BaP, and BbF were 13.0, 8.64, 0.16, and 7.68 μg kg−1, respectively. The recoveries in various oil samples for Chr, BaA, BaP, and BbF were 86.2 ± 15.3, 93.8 ± 11.7, 93.9 ± 12.1, and 94.3 ± 7.4 %, respectively, at the spiked levels of 10∼400 μg kg−1. The relative standard deviations (RSDs) achieved for Chr, BaA, BaP, and BbF were 3.0, 8.4, 6.3, and 7.2 %, respectively. The established method is simple, economical, and reliable, as well as provides an attractive alternative for the simultaneous and rapid determination of PAH4 in vegetable oils.

Background To study a case of para-Bombay phenotype caused by compound heterozygous mutation of the FUT1 gene. Methods We performed an agglutination examination to anti-H serum. Secretor status was determined in order to assess the presence of soluble blood group substances. Genotyping of ABO and FUT1 genes were also performed. Results Our results showed the presence of A and H antigens in the saliva. Based on these results, the patient in the present case was diagnosed to have a para-Bombay A phenotype. Direct DNA sequencing of the patient's ABO gene indicated A1v/O1vgenotype. FUT1 gene sequence analysis revealed that the patient harbored the compound heterozygous mutations c.881_882delTT (p.Phe294Cysfs) and c.551_552delAG (p.Glu184Valfs). Conclusions In summary, our findings support that the occurrence of a heterozygous mutation in FUT1, 547delAG/880delTT, is the most common mutation in Taiwanese.