Route to Functionalized Tetrahydrobenzo[d]azepines via Re2O7-Mediated Intramolecular Friedel-Crafts Reaction.

We describe a Re2O7-mediated intramolecular dehydrative Friedel-Crafts reaction for the efficient synthesis of various benzo-fused heterocycles such as benzazepines and benzazocines. This process is characterized by a broad substrate scope, mild reaction conditions, high efficiency, and high atom economy. The potential application of this methodology was exemplified by the facile preparation of a NMDA antagonist as well as a key intermediate en route to SKF 38393.

[Zi Huangjing TM Preparation Relieves Cancer-Related Fatigue During Chemotherapy: A Prospective Single-Arm Multicenter Clinical Trial].

Objective: To primarily explore the efficacy of Zi Huangjing TM preparation in patients with cancer-related fatigue (CRF) during chemotherapy. Methods: This study was designed as a prospective, single-arm, multicenter clinical trial. According to the plan of the study, patients with malignant tumors who had received at least one cycle of chemotherapy and had moderate-to-severe CRF (Piper Fatigue Scale score≥4) were enrolled. All the enrolled patients took Zi Huangjing TM preparation (2.1 g, twice a day) every day during the two subsequent cycles of chemotherapy and were followed up. During the period, the enrolled patients independently completed the Piper Fatigue Scale and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) scale, and part of their biochemical and immunological indicators were measured at the baseline, before the second cycle of chemotherapy (day 21), and before the third cycle of chemotherapy (day 42). The primary endpoint was the change in Piper Fatigue Scale scores between the baseline and day 42. Results: Eventually, 47 patients completed the entire study. After treatment, the mean score of the Piper Fatigue Scale assessed before the third cycle of chemotherapy (day 42) was 3.21±1.67, which was significantly lower than that at baseline (5.89±1.36) ( P=0.000), and the patients' CRF was significantly improved. In terms of quality of life, the patient's global quality of life, physical functions, role function, emotional function, cognitive function, and social function were significantly improved. In terms of symptom management, the patient's symptoms, such as fatigue, nausea and vomiting, insomnia, and appetite loss also significantly improved. No severe adverse reactions (grades 3 and 4) occurred during the observation period of this study. After evaluation, the adverse reactions that the patients actually had were considered to be related to chemotherapy, but unrelated to Zi Huangjing TM preparation. Conclusion: According to our preliminary investigation, Zi Huangjing TM preparation is safe and has the potential therapeutic effect of improving CRF in cancer patients during chemotherapy. However, further larger-scale randomized controlled clinical studies are needed to confirm the efficacy of Zi Huangjing TM in improving CRF.

Rapid titration with oral sustained-release morphine plus subcutaneous morphine in a multi-center, randomized control study of cancer patients with moderate to severe cancer pain.

BACKGROUND: Pain is one of the most common concomitant symptoms among cancer patients. Pharmacologic agents are regarded as a cornerstone of cancer pain management. 'Dose titration' with short-acting morphine is widely accepted. Such a titration method is very complicated. The analgesic background establishment is often delayed. Titration based on sustained-release opioids is also recommended, but the onset of analgesic effect requires hours, whereas the rescue analgesia is always needed. This study evaluated the optimized morphine titration scheme with a simultaneous combination of sustained-release morphine and subcutaneous morphine. METHODS: In a multicenter, 7-day, randomized controlled study, patients with moderate to severe cancer pain were assigned to receive either sustained-release morphine and subcutaneous morphine simultaneously (rapid titration) or only subcutaneous morphine to dose titration. The primary outcome was the safety and the number of times of rescue therapy as needed in the first 24 h. RESULTS: A total of 108 patients with moderate to severe cancer pain were included in the study. The number of times of rescue analgesics in the first 24 h significantly reduced in the rapid titration group (0.4 ± 0.48 vs. 2.3 ± 0.78, P = 0.000). No differences in the intensity of opioid-related symptoms were found between the two groups. CONCLUSIONS: Rapid titration is safe and efficient, which could significantly decrease rescue analgesics in the first 24 h and achieve better analgesic efficacy for cancer pain patients.

MiR-429 inhibits oral squamous cell carcinoma growth by targeting ZEB1.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is the sixth most common human malignancy worldwide. To develop new therapeutics requires elucidation of the underlying mechanism of OSCC pathogenesis. The role of miR-429 in OSCC remains unknown. MATERIAL/METHODS: The level of miR-429 and ZEB1 in OSCC tissues and cell lines was measured by qRT-PCR. MiR-429 was down-regulated by miRNAs antisense oligonucleotides (ASO) transfection and up-regulated by miRNAs mimics. Cell proliferation was analyzed by MTT assay. Cell apoptosis was revealed by FACS analysis. Targeted genes were predicted by a bioinformatics algorithm and confirmed by a dual luciferase reporter assay. RESULTS: MiR-429 was down-regulated in OSCC tissues, and miR-429 overexpression inhibited OSCC cell lines growth and vice versa. Further, we found that miR-429 could inhibit zinc finger E-boxbinding homeobox 1 (ZEB1) expression, and that miR-429 and ZEB1 expression in OSCC tissues were negatively correlated. CONCLUSIONS: Our data demonstrate the tumor suppressor role of miR-429 in OSCC, and may provide a potential therapeutic target that warrants further investigation.

Late-Stage C-H Nitration of Unactivated Arenes by Fe(NO3)3·9H2O in Hexafluoroisopropanol.

Operationally simple and generally applicable arene nitration with cheap and easily accessible chemicals has been a long-sought transformation in the synthetic organic community. In this work, we realized this goal with nontoxic and inexpensive Fe(NO3)3·9H2O as the nitro source and easily recyclable solvent hexafluoroisopropanol as the promotor via a network of hydrogen-bonding interactions. As a result of the relative mildness and high reliability of this protocol, late-stage nitration of various highly functionalized natural products and commercially available drugs was realized.

Re2O7/HReO4 Mediated Intramolecular Hydroacyloxylation of Unactivated Alkenes: A Dual Hydrogen-Bonding Effect.

This publication describes the application of Re2O7 in hexafluoroisopropanol (HFIP) for the activation of inert as well as electronically deactivated olefins to facilitate a challenging intramolecular hydroacyloxylation reaction. Both HFIP and an internal carboxy group have been proven to be crucial for the successful implementation of this transformation; these are proposed to assist the formation and stabilization of the key cationic intermediate via hydrogen-bonding interactions with perrhenate anion (ReO4-).

Aggregation-Induced Enhancement Electrochemiluminescence of Ag Nanoribbons as a Signal Probe for Ultrasensitive Detection of the Halogenase Gene Segment from Aspergillus Ochratoxin.

Here, an electrochemiluminescence (ECL) biosensor was developed based on aggregation-induced enhancement ECL of Ag nanoribbons (Ag NRs) as a signal probe and the mismatched bases-fueled DNA walker as the amplification strategy for ultrasensitive detection of the halogenase gene segment (target) from aspergillus ochratoxin to evaluate fungi capable of producing ochratoxin in dairy products. Compared with the existing agminated NCs, the Ag NRs displayed dramatically enhanced ECL emission due to effective electron transfer and less energy dissipation of excited-state Ag NRs based on the metallophilic interaction of Ag(I)-Ag(I). Impressively, the target was conversed mismatched bases-DNA walker to trigger a significant ECL response through toehold-mediated strand displacement amplification. Thus, the strategy realized trace analysis of the halogenase gene segment with a detection limit of 45 aM, which ushered a new detection method for toxin determination in the previous stage of toxin biosynthesis to protect people from toxic damage.

The Relationship of Special Education Teacher Performance on Observation Instruments With Student Outcomes.

In this study, we examined the relationship of special education teachers' performance on the Recognizing Effective Special Education Teachers (RESET) Explicit Instruction observation protocol with student growth on academic measures. Special education teachers provided video-recorded observations of three instructional lessons along with data from standardized, curriculum-based academic measures at the beginning, middle, and end of the school year for the students in the instructional group. Teachers' lessons were evaluated by external, trained raters. Data were analyzed using many-faceted Rasch measurement (MFRM), correlation, and multiple regression. Teacher performance on the overall protocol did not account for statistically significant variance in student growth beyond that of students' beginning of the year academic performance. Teacher performance on an abbreviated protocol comprised of items that had average or higher item difficulties on the MFRM analysis accounted for an additional 4.5% of variance beyond that of beginning of the year student performance. Implications for further research are discussed.

Modular engineering of gold-silver nanocluster supermolecular structure endow strong electrochemiluminescence for ultrasensitive bioanalysis.

Here, the gold-silver nanocluster supramolecular network (AuAg NCs) is synthesized by the assembly of Au nanoclusters (Au NCs) and Ag NCs via host-guest complexation between 6-aza-2-thiothymine as the stabilizer of Au NCs and L-arginine as the stabilizer of Ag NCs in solution, whose electrochemiluminescence (ECL) emission is not only exceptionally stronger than that of discrete monometallic NCs, but also more significant than that of agminated monometallic NCs. The dramatically enhanced ECL emission of self-assembled AuAg NCs originates from the synergistic effect of aggregation-induced enhancement and silver effect in gold catalysis. As a proof of concept, the self-assembled AuAg NCs is successfully applied in the ultrasensitive detection of breast cancer biomarker microRNAs-21 (miR-21), which guides a new pathway for creating high-quality nano-optical elements in chemical sensors, biological imaging, and lightemitting devices.

Incidence of chemotherapy-induced nausea and vomiting among cancer patients receiving moderately to highly emetogenic chemotherapy in cancer centers in Sichuan, China.

PURPOSE: Nausea and vomiting are the most painful and feared side effects for patients during chemotherapy. Currently, most studies focus on the occurrence of CINV during the risk phase. We initiated this real-world study to understand the actual occurrence of CINV throughout all phases, to provide a basis to prevent CINV in patients during chemotherapy and improve their quality of life. METHODS: This prospective real-world study was conducted at 17 major cancer centers in Sichuan, China. Cancer patients who were about to receive moderately/highly emetogenic chemotherapy were included in the study. Occurrences of nausea and vomiting were recorded using patient diaries, and physicians are responsible for recording patient clinical data. RESULTS: A total of 1,139 patients were included in this study between August 2018 and April 2019. In this study, the incidence of acute CINV was 55.3%, delayed CINV was 62.3%, and CINV beyond the risk period was 36%. All phases overall, the overall complete control (CC) rate of CINV was 30.1 and 32.1% for highly and moderately emetogenic chemotherapy regimens, respectively. The median CC time for CINV was 7 days, but only 21.5% of these patients used antiemetic regimens according to the NCCN guideline. CONCLUSION: In the real world, the incidence of CINV is high in patients receiving chemotherapy, and nausea and vomiting may occur beyond the risk period; the low level of standardized antiemetic treatment in compliance with the guideline might have been the main reason for unsatisfactory prevention and control of CINV in this study.

Pressure-Engineered Optical and Charge Transport Properties of Mn2+/Cu2+ Codoped CsPbCl3 Perovskite Nanocrystals via Structural Progression.

In this work, compared with the corresponding pure CsPbCl3 nanocrystals (NCs) and Mn2+-doped CsPbCl3 NCs, Mn2+/Cu2+-codoped CsPbCl3 NCs exhibited improved photoluminescence (PL) and photoluminescence quantum yields (PL QYs) (57.6%), prolonged PL lifetimes (1.78 ms), and enhanced thermal endurance (523 K) as a result of efficient Mn2+ doping (3.66%) induced by the addition of CuCl2. Furthermore, we applied pressure on Mn2+/Cu2+-codoped CsPbCl3 NCs to reveal that a red shift of photoluminescence followed by a blue shift was caused by band gap evolution and related to the structural phase transition from cubic to orthorhombic. Moreover, we also found that under the preheating condition of 523 K, such phase transition exhibited obvious morphological invariance, accompanied by significantly enhanced conductivity. The pressure applied to the products treated with high temperature enlarged the electrical difference and easily intensified the interface by closer packaging. Interestingly, defect-triggered mixed ionic and electronic conducting (MIEC) was observed in annealed NCs when the applied pressure was 2.9 GPa. The pressure-dependent ionic conduction was closely related to local nanocrystal amorphization and increased deviatoric stress, as clearly described by in situ impedance spectra. Finally, retrieved products exhibited better conductivity (improved by 5-6 times) and enhanced photoelectric response than those when pressure was not applied. Our findings not only reveal the pressure-tuned optical and electrical properties via structural progression but also open up the promising exploration of more amorphous all-inorganic CsPbX3-based photoelectric applications.

Tumor suppressor role of miR-876-5p in gastric cancer.

Gastric cancer (GC) is the second most common cancer cause of cancer-related mortality worldwide. Recent studies have demonstrated the function of microRNAs (miRNAs) in the pathogenesis of GC. miR-876-5p demonstrated an antitumor role in hepatocellular carcinoma and lung cancer; however, the function of miR-876-5p has not yet been fully identified in GC. Thus, the present study aimed to investigate the role of miR-876-5p in GC. The results of the present study demonstrated low expression levels of miR-876-5p in GC tumor tissues. Furthermore, overexpression of miR-876-5p inhibited GC cell proliferation and promoted apoptosis, whilst miR-876-5p knockdown promoted GC cell proliferation and decreased cisplatin sensitivity of GC cells. Transforming growth factor ß-receptor 1 was demonstrated to be a potential target gene of miR-876-5p. Overall, the results of the present study suggest that miR-876-5p plays an antitumor role in GC.

Barbigerone, a natural isoflavone, induces apoptosis in murine lung-cancer cells via the mitochondrial apoptotic pathway.

Barbigerone is a naturally occurring isoflavone with antioxidant activity. In present study, we investigated the antitumor activity of barbigerone against murine lung cancer cells LL/2 and the possible mechanism in vitro. Our results showed that barbigerone inhibited LL/2 cells proliferation in a concentration- and time-dependent manner and caused apoptotic death of LL/2 cells. Barbigerone-induced apoptosis was characterized by enhanced mitochondrial cytochrome c release, activation of caspase-3,-9, but not caspase-8. Exposure of LL/2 cells to barbigerone resulted in upregulation of Bcl-2-associated protein (Bax) and down-regulation of Bcl-2. In addition, proliferation inhibitory effect of barbigerone was associated with decreased level of phosphorylated p42/44 mitogen-activated protein kinase (p42/44 MAPK) and phosphorylated Akt. Moreover, barbigerone exhibit less toxicity to non-cancer cells than tumor cells. In conclusion, our results indicated that barbigerone can inhibit murine lung cancer cell proliferation by inducing apoptosis via mitochondrial apoptotic pathway and by decreasing phosphorylated p42/44 MAPK and Akt. Its potential to be a candidate of anti-cancer agent is worth being further investigated.

Chloroquine inhibits colon cancer cell growth in vitro and tumor growth in vivo via induction of apoptosis.

The present study was to investigate the anticancer effect of chloroquine on proliferation of mouse colon cancer cell line CT26 in vivo and in vitro and the possible mechanism. We found that chloroquine inhibited CT26 proliferation by concentration- and time-dependent manner. This effect was associated with apoptosis induction and decreased level of phosphorylated p42/44 mitogen-activated protein kinase and phosphorylated Akt. The in vivo study showed chloroquine-reduced tumor volume and prolonged survival time in CT26-bearing mice. These observations indicated chloroquine could inhibit CT26 proliferation by inducing apoptosis both in vitro and in vivo, providing its chemotherapeutic potential of human cancers.

Novel ROR1 inhibitor ARI-1 suppresses the development of non-small cell lung cancer.

Limited drug response and severe drug resistance confer the high mortality of non-small-cell lung cancer (NSCLC), a leading cause of cancer death worldwide. There is an urgent need for novel treatment against NSCLC. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is aberrantly overexpressed and participats in NSCLC development and EGFR-TKIs-induced drug resistance. Increasing evidences indicate that oncogenic ROR1 is a potential target for NSCLC therapy. However, nearly no ROR1 inhibitor was reported until now. Here, combining the computer-aided drug design and cell-based activity screening, we discover (R)-5,7-bis(methoxymethoxy)-2-(4-methoxyphenyl)chroman-4-one (ARI-1) as a novel ROR1 inhibitor. Biological evaluation demonstrates that ARI-1 specifically targets the extracellular frizzled domain of ROR1 and potently suppresses NSCLC cell proliferation and migration by regulating PI3K/AKT/mTOR signaling in a ROR1-dependent manner. Moreover, ARI-1 significantly inhibits tumor growth in vivo without obvious toxicity. Intriguingly, ARI-1 is effective to EGFR-TKIs-resistant NSCLC cells with high ROR1 expression. Therefore, our work suggests that the ROR1 inhibitor ARI-1 is a novel drug candidate for NSCLC treatment, especially for EGFR-TKIs-resisted NSCLC with high ROR1 expression.

Foundations for Self-Determination in Early Childhood: Preliminary Preschool Study.

Foundations for self-determination begin in early childhood for children with disabilities with the onset of self-regulation and engagement in activities at home, school, and in the community. This article describes the development and preliminary results of an intervention model that encourages collaborative practices for parents and teachers around short-term goal setting to adjust environments for young children with special needs or at risk for delay. The Foundations Intervention was used with 48 children in authentic early childhood settings and involved parents, teachers, and a facilitator to enhance children's self-regulation and engagement at home and school. Results showed feasibility of the intervention; positive child outcomes in goal attainment, self-regulation, and engagement measures were also evident. When parents and teachers communicated about a child's strengths and needs within routines at home and school, this appeared to strengthen parent and teacher connections and helped children become more engaged or regulated in daily activities.

Cell growth inhibition, G2/M cell cycle arrest, and apoptosis induced by chloroquine in human breast cancer cell line Bcap-37.

Chloroquine is an antimalarial drug that has been used in the treatment and prophylaxis of malaria since the 1950s. The present study was undertaken to examine the effects of chloroquine on Bcap-37 human breast cancer cells' growth, cell cycle modulation, apoptosis induction, and associated molecular alterations in vitro. The chloroquine treatment decreased the viability of Bcap-37 cells in a concentration- and time-dependent manner, which correlated with G(2)/M phase cell cycle arrest. The chloroquine-mediated cell cycle arrest was associated with a decrease in protein levels/activity of polo-like kinase 1 (Plk1), phosphorylated cell division cycle 25C (Cdc25C), phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2), phosphorylated Akt. The chloroquine-treated Bcap-37 cells exhibited a marked decrease in the level of mitochondrial transmembrane potential (DeltaPsim), which was accompanied by the activation of caspase-3 and cleaved poly(ADP-ribose) polymerase (PARP). Exposure of Bcap-37 cells to chloroquine also resulted in the induction of spindle abnormalities. In conclusion, the findings in this study suggested that chloroquine might have potential anticancer efficacy, which could be attributed, in part, to its proliferation inhibition and apoptosis induction of cancer cells through modulation of apoptosis and cell cycle-related proteins expressions, down-regulation of mitochondrial transmembrane potential (DeltaPsim), and induction of spindle abnormalities.

ROR1 expression as a biomarker for predicting prognosis in patients with colorectal cancer.

There is a lack of reliable prognosis biomarker in the current treatment of colorectal cancer. The receptor-tyrosine-kinase-like orphan receptor 1 (ROR1) is overexpressed and associated with poor prognosis in certain tumors. This study aimed to explore the prognostic significance of ROR1 in colorectal cancer. Western blot analysis and immunohistochemistry showed that the expression of ROR1 in colorectal cancer was significantly higher than that in the adjacent normal tissues. ROR1 expression was positively associated with the clinical stage and lymph-node metastasis (p < 0.01). Kaplan-Meier survival analysis revealed that patients with higher ROR1 expression had a significantly shorter overall survival (p < 0.01). Multivariate Cox regression analysis confirmed that ROR1 is an independent prognostic marker in colorectal cancer (p = 0.002, HR = 2.08, 95% CI: 1.314-3.292). Thus, our study demonstrated that ROR1 expression is correlated with malignant attributes and may serve as a novel prognostic marker and therapeutic target for colorectal cancer.

ROR1 is a novel prognostic biomarker in patients with lung adenocarcinoma.

Currently, there is no reliable biomarker to clinically predict the prognosis of lung adenocarcinoma (ADC). The receptor-tyrosine-kinase like orphan receptor 1 (ROR1) is reported to be overexpressed and associated with poor prognosis in several tumors. This study aimed to examine the expression of ROR1 and evaluate its prognostic significance in human lung ADC patients. In this present study, Western blot analysis and immunohistochemistry were performed to characterize expression of ROR1 protein in lung ADC patients. The results revealed that ROR1 protein expression was significantly higher in lung ADC tissues than that in their adjacent non-tumor tissues. Patients at advanced stages and those with positive lymph node metastasis expressed higher level of ROR1 (P < 0.001). Moreover, Chi-square test showed that ROR1 expression was correlated to gender (P = 0.028), the 7th edition of the American Joint Committee on Cancer tumor-node-metastasis (AJCC TNM) staging system and lymph node metastasis (P < 0.001). Kaplan-Meier survival analysis indicated an association of high ROR1 expression with worse overall survival (OS) in lung ADC patients (P < 0.001). Multivariate COX regression analysis further confirmed that ROR1 is an independent prognostic predictor (P < 0.001, HR = 4.114, 95% CI: 2.513-6.375) for OS. Therefore, ROR1 expression significantly correlates with malignant attributes of lung ADC and it may serve as a novel prognostic marker in lung ADC patients.