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In 2023, the U.S. Food and Drug Administration has approved 29 small molecule drugs. These newly approved small molecule drugs possess the distinct scaffolds, thereby exhibiting diverse mechanisms of action and binding modalities. Moreover, the marketed drugs have always been an important source of new drug development and creative inspiration, thereby fostering analogous endeavors in drug discovery that potentially extend to the diverse clinical indications. Therefore, conducting a comprehensive evaluation of drug approval experience and associated information will facilitate the expedited identification of highly potent drug molecules. In this review, we comprehensively summarized the relevant information regarding the clinical applications, mechanisms of action and chemical synthesis of 29 small molecule drugs, with the aim of providing a promising structural basis and design inspiration for pharmaceutical chemists., (© 2024 Wiley Periodicals LLC.)

Chemotherapies are commonly used in cancer therapy, their applications are limited to low specificity, severe adverse reactions, and long-term medication-induced drug resistance. Poly(ADP-ribose) polymerase (PARP) inhibitors are a novel class of antitumor drugs developed to solve these intractable problems based on the mechanism of DNA damage repair, which have been widely applied in the treatment of ovarian cancer, breast cancer, and other cancers through inducing synthetic lethal effect and trapping PARP-DNA complex in BRCA gene mutated cancer cells. In recent years, PARP inhibitors have been widely used in combination with various first-line chemotherapy drugs, targeted drugs and immune checkpoint inhibitors to expand the scope of clinical application. However, the intricate mechanisms underlying the drug resistance to PARP inhibitors, including the restoration of homologous recombination, stabilization of DNA replication forks, overexpression of drug efflux protein, and epigenetic modifications pose great challenges and desirability in the development of novel PARP inhibitors. In this review, we will focus on the mechanism, structure-activity relationship, and multidrug resistance associated with the representative PARP inhibitors. Furthermore, we aim to provide insights into the development prospects and emerging trends to offer guidance for the clinical application and inspiration for the development of novel PARP inhibitors and degraders., (© 2024 Wiley Periodicals LLC.)

In 2022, the U.S. Food and Drug Administration approved a total of 16 marketing applications for small molecule drugs, which not only provided dominant scaffolds but also introduced novel mechanisms of action and clinical indications. The successful cases provide valuable information for optimizing efficacy and enhancing pharmacokinetic properties through strategies like macrocyclization, bioequivalent group utilization, prodrug synthesis, and conformation restriction. Therefore, gaining an in-depth understanding of the design principles and strategies underlying these drugs will greatly facilitate the development of new therapeutic agents. This review focuses on the research and development process of these newly approved small molecule drugs including drug design, structural modification, and improvement of pharmacokinetic properties to inspire future research in this field., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

In 2023, the U.S. Food and Drug Administration has approved 55 novel medications, consisting of 17 biologics license applications and 38 new molecular entities. Although the biologics license applications including antibody and enzyme replacement therapy set a historical record, the new molecular entities comprising small molecule drugs, diagnostic agent, RNA interference therapy and biomacromolecular peptide still account for over 50 % of the newly approved medications. The novel and privileged scaffolds derived from drugs, active molecules and natural products are consistently associated with the discovery of new mechanisms, the expansion of clinical indications and the reduction of side effects. Moreover, the structural modifications based on the promising scaffolds can provide the clinical candidates with the improved biological activities, bypass the patent protection and greatly shorten the period of new drug discovery. Therefore, conducting an appraisal of drug approval experience and related information will expedite the identification of more potent drug molecules. In this review, we comprehensively summarized the pertinent information encompassing the clinical application, mechanism, elegant design and development processes of 28 small molecule drugs, and expected to provide the promising structural basis and design inspiration for pharmaceutical chemists., Competing Interests: Declaration of competing interest All authors have approved the final submission to the journal. The authors declare no conflict of interest., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

The objective of this study was to explore the effects of different amounts of biochar on the migration process and characteristics of NO 3 - -N in loessial soil. In this study, six groups of mixed soil samples with biochar and loessial soil mass ratios of 0% (T0), 1% (T1), 2% (T2), 3% (T3), 4% (T4), and 5% (T5) were used as research objects. NO 3 - -N was used as the tracer. Through the indoor soil column solute transport simulation tests, the effects of different biochar application amounts on the NO 3 - -N transport process in loessial soil were simulated and studied. The results showed that the breakthrough curve of NO 3 - -N in loessial soil shifted to the right with the increasing of biochar application, and the peak value gradually decreased. The initial penetration time, complete penetration time, and total penetration time increased with the increasing of biochar application amount. The total penetration time of NO 3 - in the T1, T2, T3, T4, and T5 treatments was 1.26, 2.31, 2.72, 3.22, and 3.57 times that of T0, respectively. The R 2 was > 0.997 and RMSE was < 2.083 of the two-zone model (TRM). Compared with the convection-dispersion equation (CDE), the TRM model had higher fitting accuracy and could better simulate the NO 3 - -N migration process in loessial soil after the application of different contents of biochar. The analysis of the fitting parameters of the TRM model showed that the average pore velocity, hydrodynamic dispersion coefficient, and water content ratio in the movable zone gradually decreased with the increasing of biochar application, whereas the dispersion and mass exchange coefficient showed an increasing trend. The results showed that biochar application could effectively enhance the ability of loessial soil to fix NO 3 - -N, reduce the leakage of NO 3 - -N to groundwater, and play an important role in maintaining soil fertility and preventing groundwater pollution.

Background: Programmed death 1 (PD-1) inhibitor demonstrated durable antitumor activity in advanced esophageal squamous cell carcinoma (ESCC), but the clinical benefit of perioperative immunotherapy in ESCC remains unclear. This study evaluated the efficacy and safety of neoadjuvant chemoradiotherapy (nCRT) combined with the PD-1 inhibitor toripalimab in patients with resectable ESCC., Methods: From July 2020 to July 2022, 21 patients with histopathologically confirmed thoracic ESCC and clinical staged as cT1-4aN1-2M0/cT3-4aN0M0 were enrolled. Eligible patients received radiotherapy (23 fractions of 1.8 Gy, 5 fractions a week) with concurrent chemotherapy of paclitaxel/cisplatin (paclitaxel 45 mg/m 2 and cisplatin 25 mg/m 2 ) on days 1, 8, 15, 22, 29 and two cycles of toripalimab 240 mg every 3 weeks after nCRT for neoadjuvant therapy before surgery, four cycles of toripalimab 240 mg every 3 weeks for adjuvant therapy after surgery. The primary endpoint was the major pathological response (MPR) rate. The secondary endpoints were safety and survival outcomes., Results: A total of 21 patients were included, of whom 20 patients underwent surgery, 1 patient refused surgery and another patient was confirmed adenocarcinoma after surgery. The MPR and pathological complete response (pCR) rates were 78.9% (15/19) and 47.4% (9/19) for surgery ESCC patients. 21 patients (100.0%) had any-grade treatment-related adverse events, with the most common being lymphopenia (100.0%), leukopenia (85.7%), neutropenia (52.4%). 14 patients (66.7%) had adverse events of grade 3 with the most common being lymphopenia (66.7%). The maximum standardized uptake value and total lesion glycolysis of positron emission tomography/CT after neoadjuvant therapy well predicted the pathological response. The peripheral CD4+%, CD3+HLA-DR+/CD3+%, CD8+HLA-DR+/CD8+%, and IL-6 were significant differences between pCR and non-pCR groups at different times during neoadjuvant therapy. Three patients had tumor relapse and patients with MPR have longer disease-free survival than non-MPR patients., Conclusions: nCRT combined with perioperative toripalimab is effective and safe for locally advanced resectable ESCC. Long-term survival outcomes remain to be determined., Trial Registration Number: NCT04437212., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Following nearly two decades of development, significant advancements have been achieved in PROTAC technology. As of the end of 2022, more than 20 drugs have entered clinical trials, with ARV-471 targeting estrogen receptor (ER) showing remarkable progress by entering phase III clinical studies. In 2022, significant progress has been made on multiple targets. The first reversible covalent degrader designed to target the KRAS G12C mutant protein, based on cyclopropionamide, has been reported. Additionally, the activity HDCA1 degrader surpassed submicromolar levels during the same year. A novel FEM1B covalent ligand called EN106 was also discovered, expanding the range of available ligands. Furthermore, the first PROTAC drug targeting SOS1 was reported. Additionally, the first-in-class degraders that specifically target BRD4 isoforms (BRD4 L and BRD4 S) have recently been reported, providing a valuable tool for further investigating the biological functions of these isoforms. Lastly, a breakthrough was also achieved with the first degrader targeting both CDK9 and Cyclin T1. In this review, we aimed to update the PROTAC degraders as potential anticancer agents covering articles published in 2022. The design strategies, degradation effects, and anticancer activities were highlighted, which might provide an updated sight to develop novel PROTAC degraders with great potential as anticancer agents as well as favorable drug-like properties., Competing Interests: Declaration of competing interest There is no conflict of interest about this article to declare., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

The interleukin-1 receptor associated kinase 4 (IRAK-4) is a member of serine-threonine kinase family, which plays an important role in the regulation of interleukin-1 receptors (IL-1R) and Toll-like receptors (TLRs) related signaling pathways. At present, the IRAK-4 mediated inflammation and related signaling pathways contribute to inflammation, which are also responsible for other autoimmune diseases and drug resistance in cancers. Therefore, targeting IRAK-4 to develop single-target, multi-target inhibitors and proteolysis-targeting chimera (PROTAC) degraders is an important direction for the treatment of inflammation and related diseases. Moreover, insight into the mechanism of action and structural optimization of the reported IRAK-4 inhibitors will provide the new direction to enrich the clinical therapies for inflammation and related diseases. In this comprehensive review, we introduced the recent advance of IRAK-4 inhibitors and degraders with regards to structural optimization, mechanism of action and clinical application that would be helpful for the development of more potent chemical entities against IRAK-4., Competing Interests: Declaration of competing interest All authors have approved the final submission to the journal. The authors declare no conflict of interest., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Under physiological or pathological conditions, transient receptor potential (TRP) channel vanilloid type 1 (TRPV1) and TRP ankyrin 1 (TRPA1) possess the ability to detect a vast array of stimuli and execute diverse functions. Interestingly, increasing works have reported that activation of TRPV1 and TRPA1 could also be beneficial for ameliorating postoperative ileus (POI). Increasing research has revealed that the gastrointestinal (GI) tract is rich in TRPV1/TRPA1, which can be stimulated by capsaicin, allicin and other compounds. This activation stimulates a variety of neurotransmitters, leading to increased intestinal motility and providing protective effects against GI injury. POI is the most common emergent complication following abdominal and pelvic surgery, and is characterized by postoperative bowel dysfunction, pain, and inflammatory responses. It is noteworthy that natural herbs are gradually gaining recognition as a potential therapeutic option for POI due to the lack of effective pharmacological interventions. Therefore, the focus of this paper is on the TRPV1/TRPA1 channel, and an analysis and summary of the processes and mechanism by which natural herbs activate TRPV1/TRPA1 to enhance GI motility and relieve pain are provided, which will lay the foundation for the development of natural herb treatments for this disease., Competing Interests: Declaration of Competing Interest The authors have declared that there is no conflict of interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Following transected spinal cord injury (SCI), there is a critical need to restore nerve conduction at the injury site and activate the silent neural circuits caudal to the injury to promote the recovery of voluntary movement. In this study, we generated a rat model of SCI, constructed neural stem cell (NSC)-derived spinal cord-like tissue (SCLT), and evaluated its ability to replace injured spinal cord and repair nerve conduction in the spinal cord as a neuronal relay. The lumbosacral spinal cord was further activated with tail nerve electrical stimulation (TNES) as a synergistic electrical stimulation to better receive the neural information transmitted by the SCLT. Next, we investigated the neuromodulatory mechanism underlying the action of TNES and its synergism with SCLT in SCI repair. TNES promoted the regeneration and remyelination of axons and increased the proportion of glutamatergic neurons in SCLT to transmit brain-derived neural information more efficiently to the caudal spinal cord. TNES also increased the innervation of motor neurons to hindlimb muscle and improved the microenvironment of muscle tissue, resulting in effective prevention of hindlimb muscle atrophy and enhanced muscle mitochondrial energy metabolism. Tracing of the neural circuits of the sciatic nerve and tail nerve identified the mechanisms responsible for the synergistic effects of SCLT transplantation and TNES in activating central pattern generator (CPG) neural circuits and promoting voluntary motor function recovery in rats. The combination of SCLT and TNES is expected to provide a new breakthrough for patients with SCI to restore voluntary movement and control their muscles., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Due to the long-term and widespread use of antibiotics in clinic, the problem of bacterial resistance is increasingly serious, and the development of new drugs to treat drug-resistant bacteria has gradually become the mainstream direction of antibiotic research. The oxazolidinone-containing drugs linezolid, tedizolid phosphate and contezolid have been approved to the market, which are effective against a variety of Gram-positive bacterium infections. Moreover, there are also many antibiotics containing oxazolidinone fragment under clinical investigation that show good pharmacokinetic and pharmacodynamic properties with unique mechanism of action against resistant bacteria. In this review, we summarized the oxazolidinone-based antibiotics already on the market or in clinical trials and the representative bioactive molecules, and mainly focused on their structural optimizations, development strategies and structure-activity relationships in hope of insight into the reasonable design for medical chemists to develop new oxazolidinone antibiotics with highly potency and fewer side effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Purpose: Neoadjuvant chemoradiotherapy (nCRT) is a standard treatment option for patients with stage III oesophageal cancer. Approximately 30% of oesophageal cancer patients will have a pathological complete response (pCR) after nCRT. However, available clinical methods cannot accurately predict pCR for patients. We aimed to find more indicators that could be used to predict the pathological response to nCRT., Method: A total of 84 patients with stage III oesophageal squamous cell cancer were enrolled in this study. Ten patients failed to have surgery as a result of progressive disease (PD). Among the patients who underwent surgery, 32 patients had a pathologic complete response (pCR), whereas 42 patients showed no or partial response (npCR) after nCRT. Routine blood test results and lymphocyte subset assessments before and after nCRT were retrospectively analysed. Univariate and multivariate analyses were used to identify independent predictors of the clinical curative effect of nCRT. Eventually, nomograms were established for predicting the PD and pCR rates., Results: The numbers of lymphocytes, B lymphocytes, T lymphocytes, Th lymphocytes, Ts lymphocytes, and NK cells and the percentages of B lymphocytes and NK cells were decreased significantly after nCRT ( P < 0.0001), whereas the percentages of T lymphocytes and Ts lymphocytes increased ( P < 0.0001). Univariate analysis showed that age, the length of the lesion, the level of haemoglobin before nCRT, and the amount of change in haemoglobin were related to PD, and the percentage of NK cells after nCRT was related to pCR. Multivariate logistic analysis demonstrated that the length of the lesion, the neutrophil-to-lymphocyte ratio (NLR) before nCRT, and the amount of change in haemoglobin were independent predictors of PD, whereas the percentage of NK cells after nCRT was an independent predictor of pCR., Conclusion: Lymphocyte subsets changed dramatically during nCRT, and these changes together with baseline and posttreatment lymphocyte subsets have predictive value in determining the response to nCRT for oesophageal cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhou, Lin, Xu, Wang, Rong, Zhang, Shen, Xu, Qin, Ye, Ma and Bai.)

Background: The cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) plays critical functions in innate immune responses via the production of the second messenger cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), which stimulates the adaptor stimulator of interferon genes (STING). However, the clinical relevance and prognostic value of the cGAS-STING pathway in human cancers remains largely unexplored., Methods: A gene signature related to the cGAS-STING score was identified. The pan-cancer landscape of cGAS-STING expression was calculated using the RNAseq data acquired from the TCGA cohort. Tumor-infiltrating immune cells (TIICs) were determined by the ssGSEA method. Kaplan-Meier curves, Cox regression analyses, and the area under the curve (AUC) were employed to decipher the predictive value of cGAS-STING risk score and TIICs across several human cancers., Results: Most tumor tissues displayed a higher cGAS-STING score compared with their corresponding nontumor tissues, except for prostate adenocarcinoma (PRAD) and uterine corpus endometrial carcinoma (UCEC). Higher cGAS-STING score was closely associated with poor clinical outcome of kidney renal clear cell carcinoma (KIRC) and kidney renal papillary cell carcinoma (KIRP), whereas the cGAS-STING score predicted a better prognosis in pheochromocytoma and paraganglioma (PCPG). Enrichment analysis showed that cGAS-STING was profoundly implicated in diverse immune-related pathways in KIRC, KIRP, and PCPG. Significant positive correlations were noticed between cGAS-STING score and TIICs, including activated CD8+ T cells, activated CD4+ T cells, monocytes, and mast cells. Finally, the cGAS-STING score was revealed to be an independent prognostic factor for KIRC patients and possessed a strong predictive power for the prognostic evaluation of KIRC and KIRP patients., Conclusions: We constructed a cGAS-STING gene signature to predict survival and tumor immunity across human cancers, which can serve as a novel prognostic indicator and therapeutic target, especially in KIRC and KIRP., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2022 Zheng Wu et al.)

Objective: An otoacoustic emission (OAE) is a low-level sound emitted by the cochlea. OAEs are able to objectively evaluate the auditory perception and reflect the functional status of the auditory system. With the characteristics of non-invasiveness, high reliability, and easy manipulation, OAEs have gained wide popularity in clinical audiology and anesthesiology. This review aims to summarize the application of OAE in anesthesia., Materials and Methods: This study collected data from the databases Web of Science-Clarivate Analytics, PubMed, and Google Scholar in English, covering research in the last 40 years. The keywords were defined as anesthesia, cochlea, OAEs, distortion product otoacoustic emissions, transient evoked otoacoustic emissions, bispectral index, auditory evoked potentials, and depth of anesthesia. Documents that matched defined keywords were selected and reviewed., Results: Research showed that the types and doses of anesthetic drugs impacted OAEs. Ketamine-based anesthesia has a greater effect on OAE sensitivity over time compared to isoflurane. A higher dose of ketamine-xylazine significantly reduced the amplitude of OAEs. According to those characteristics, OAEs could be used as an objective evaluation method for the effect of anesthetics and have great potential to be applied for anesthetic drug dose control during surgery. OAEs also have been used to detect the cochlear function during anesthesia, which may cause irreversible damage to the cochlea., Conclusions: Studies reported that OAEs have been used in anesthesia. However, the existing studies have mainly focused on the influence of anesthetic types or dosages on OAEs. Considering the characteristics of OAEs, such as a convenient measurement, less susceptibility to interference, and fast detection speed, the application of OAE has a great potential in the anesthesia field.

In order to ascertain the distribution characteristics of soil heavy metal pollution and main pollution sources in a small watershed in the southern mountainous area of Ningxia and to ensure the quality of the soil environment, the contents of heavy metals Pb, Ni, Zn, Mn, Cu, Cr, and Cd in 260 surface soil samples (0-20 cm) were collected and determined. Based on the soil background value in Ningxia, the soil heavy metal pollution status and potential ecological risk were evaluated through the single factor index, Nemera composite index, and potential ecological risk index, and the method of combining positive definite matrix factor analysis (PMF) and Kriging interpolation was used to analyze the soil heavy metal spatial distribution and source. The results showed that the average contents of ω (Pb), ω (Ni), ω (Zn), ω (Mn), ω (Cu), ω (Cr), and ω (Cd) were 31.42, 36.22, 62.89, 546.18, 22.26, 61.90, and 0.18 mg·kg -1 , respectively. Except for Ni, the other elements were higher than the background value of Ningxia but lower than the background value of agricultural soil pollution risk selection criteria and green food environmental quality standards. The Nemera composite index showed that the proportions of mild, moderate, and severe heavy metal pollution were 71.92%, 19.23%, and 1.54%, respectively. The potential ecological risks were mainly minor risks, accounting for 98.85%. In addition, there were a very small number of samples with medium potential ecological risk levels, accounting for 1.15% of the total number of samples. Source analysis showed that the main sources of soil heavy metals in the small watershed in the mountainous area of southern Ningxia were mixed sources of fertilization and industrial emissions (12.6%), agricultural activity sources (23.5%), natural parent material sources (27.6%), mixed sources of pesticide use and mining development emissions (17.7%), and atmospheric deposition sources (18.6%).

Axon regeneration and remyelination of the damaged region is the most common repair strategy for spinal cord injury. However, achieving good outcome remains difficult. Our previous study showed that porcine decellularized optic nerve better mimics the extracellular matrix of the embryonic porcine optic nerve and promotes the directional growth of dorsal root ganglion neurites. However, it has not been reported whether this material promotes axonal regeneration in vivo. In the present study, a porcine decellularized optic nerve was seeded with neurotrophin-3-overexpressing Schwann cells. This functional scaffold promoted the directional growth and remyelination of regenerating axons. In vitro, the porcine decellularized optic nerve contained many straight, longitudinal channels with a uniform distribution, and microscopic pores were present in the channel wall. The spatial micro topological structure and extracellular matrix were conducive to the adhesion, survival and migration of neural stem cells. The scaffold promoted the directional growth of dorsal root ganglion neurites, and showed strong potential for myelin regeneration. Furthermore, we transplanted the porcine decellularized optic nerve containing neurotrophin-3-overexpressing Schwann cells in a rat model of T10 spinal cord defect in vivo. Four weeks later, the regenerating axons grew straight, the myelin sheath in the injured/transplanted area recovered its structure, and simultaneously, the number of inflammatory cells and the expression of chondroitin sulfate proteoglycans were reduced. Together, these findings suggest that porcine decellularized optic nerve loaded with Schwann cells overexpressing neurotrophin-3 promotes the directional growth of regenerating spinal cord axons as well as myelin regeneration. All procedures involving animals were conducted in accordance with the ethical standards of the Institutional Animal Care and Use Committee of Sun Yat-sen University (approval No. SYSU-IACUC-2019-B034) on February 28, 2019., Competing Interests: None

Directional axon regeneration and remyelination are crucial for repair of spinal cord injury (SCI), but existing treatments do not effectively promote those processes. Here, we propose a strategy for construction of niche-specific spinal white matter-like tissue (WMLT) using decellularized optic nerve (DON) loaded with neurotrophin-3 (NT-3)-overexpressing oligodendrocyte precursor cells. A rat model with a white matter defect in the dorsal spinal cord of the T10 segment was used. The WMLT transplantation group showed significant improvement in coordinated motor functions compared with the control groups. WMLT transplants integrated well with host spinal cord white matter, effectively addressing several barriers to directional axonal regeneration and myelination during SCI repair. In WMLT, laminin was found to promote development of oligodendroglial lineage (OL) cells by binding to laminin receptors. Interestingly, laminin could also guide linear axon regeneration via interactions with specific integrins on the axon surface. The WMLT developed here utilizes the unique microstructure and bioactive matrix of DON to create a niche rich in laminin, NT-3 and OL cells to achieve significant structural repair of SCI. Our protocol can help to promote research on repair of nerve injury and construction of neural tissues and organoids that form specific cell niches., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors.)

Background: Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is a currently widely used strategy for locally advanced esophageal cancer (EC). However, the conventional imaging methods have certain deficiencies in the evaluation and prediction of the efficacy of nCRT. This study aimed to explore the value of functional imaging in predicting the response to neoadjuvant chemoradiotherapy (nCRT) in locally advanced esophageal squamous cell carcinoma (ESCC)., Methods: Fifty-four patients diagnosed with locally advanced ESCC from August 2017 to September 2019 and treated with nCRT were retrospectively analyzed. DW-MRI scanning was performed before nCRT, at 10-15 fractions of radiotherapy, and 4-6 weeks after the completion of nCRT. 18 F-FDG PET/CT scans were performed before nCRT and 4-6 weeks after the completion of nCRT. These 18 F-FDG PET/CT and DW-MRI parameters and relative changes were compared between patients with pathological complete response (pCR) and non-pCR., Results: A total of 8 of 54 patients (14.8%) were evaluated as disease progression in the preoperative assessment. The remaining forty-six patients underwent operations, and the pathological assessments of the surgical resection specimens demonstrated pathological complete response (pCR) in 10 patients (21.7%) and complete response of primary tumor (pCR-T) in 16 patients (34.8%). The change of metabolic tumor volume (∆MTV) and change of total lesion glycolysis (∆TLG) were significantly different between patients with pCR and non-pCR. The SUVmax-T post , MTV-T post , and TLG-T post of esophageal tumors in 18 F-FDG PET/CT scans after neoadjuvant chemoradiotherapy and the ∆ SUVmax-T and ∆MTV-T were significantly different between pCR-T versus non-pCR-T patients. The esophageal tumor apparent diffusion coefficient (ADC) increased after nCRT; the ADC during , ADC post and ∆ADC during were significantly different between pCR-T and non-pCR-T groups. ROC analyses showed that the model that combined ADC during with TLG-T post had the highest AUC (0.914) for pCR-T prediction, with 90.0% and 86.4% sensitivity and specificity, respectively., Conclusion: 18 F-FDG PET/CT is useful for re-staging after nCRT and for surgical decision. Integrating parameters of 18 F-FDG PET/CT and DW-MRI can identify pathological response of primary tumor to nCRT more accurately in ESCC., (© 2021. The Author(s).)

In order to evaluate the pollution of polycyclic aromatic hydrocarbons (PAHs) in the topsoil of the core area of the Ningdong Energy and Chemical Industry Base, 146 representative topsoil samples were collected using the grid method and the contents of 16 priority PAHs were analyzed. The results showed that the content of ΣPAHs in topsoil ranged from ND to 123.12 mg·kg -1 with an average of 10.19 mg·kg -1 . There were three high PAHs distribution areas in the northwest, southwest, and east of the core area. The source apportionment showed that the sources of PAHs in the Ningdong base were complex, and the main pollution sources were petroleum, coal combustion, traffic, and gasoline, which contributed 39.4%, 33.3%, 19.2%, and 8.1% to the total PAHs sources, respectively. The ecological risk assessment of the quality basis and quality standard method showed that the ecological impact of PAHs in the core area was slight and the possibility of negative ecological effects was low. The results of the health risk assessment showed that the order of exposure of the topsoil PAHs was skin contact > swallowing > respiratory inhalation, and the topsoil PAHs in the core area of the Ningdong base posed no potential carcinogenic risk to people of different ages.

Background: Cisplatin-based induction chemotherapy plus concurrent chemoradiotherapy in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma has been recommended in the National Comprehensive Cancer Network Guidelines. However, cisplatin is associated with poor patient compliance and has notable side-effects. Lobaplatin, a third-generation platinum drug, has shown promising antitumour activity against several malignancies with less toxicity. In this study, we aimed to evaluate the efficacy of lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy over a cisplatin-based regimen in patients with locoregional, advanced nasopharyngeal carcinoma., Methods: In this open-label, non-inferiority, randomised, controlled, phase 3 trial done at five hospitals in China, patients aged 18-60 years with previously untreated, non-keratinising stage III-IVB nasopharyngeal carcinoma; Karnofsky performance-status score of at least 70; and adequate haematological, renal, and hepatic function were randomly assigned (1:1) to receive intravenously either lobaplatin-based (lobaplatin 30 mg/m 2 on days 1 and 22, and fluorouracil 800 mg/m 2 on days 1-5 and 22-26 for two cycles) or cisplatin-based (cisplatin 100 mg/m 2 on days 1 and 22, and fluorouracil 800 mg/m 2 on days 1-5 and 22-26 for two cycles) induction chemotherapy, followed by concurrent lobaplatin-based (two cycles of intravenous lobaplatin 30 mg/m 2 every 3 weeks plus intensity-modulated radiotherapy) or cisplatin-based (two cycles of intravenous cisplatin 100 mg/m 2 every 3 weeks plus intensity-modulated radiotherapy) chemoradiotherapy. Total radiation doses of 68-70 Gy (for the sum of the volumes of the primary tumour and enlarged retropharyngeal nodes), 62-68 Gy (for the volume of clinically involved gross cervical lymph nodes), 60 Gy (for the high-risk target volume), and 54 Gy (for the low-risk target volume), were administered in 30-32 fractions, 5 days per week. Randomisation was done centrally at the clinical trial centre of Sun Yat-sen University Cancer Centre by means of computer-generated random number allocation with a block design (block size of four) stratified according to disease stage and treatment centre. Treatment assignment was known to both clinicians and patients. The primary endpoint was 5-year progression-free survival, analysed in both the intention-to-treat and per-protocol populations. If the upper limit of the 95% CI for the difference in 5-year progression-free survival between the lobaplatin-based and cisplatin-based groups did not exceed 10%, non-inferiority was met. Adverse events were analysed in all patients who received at least one cycle of induction chemotherapy. This trial is registered with the Chinese Clinical Trial Registry, ChiCTR-TRC-13003285 and is closed., Findings: From June 7, 2013, to June 16, 2015, 515 patients were assessed for eligibility and 502 patients were enrolled: 252 were randomly assigned to the lobaplatin-based group and 250 to the cisplatin-based group. After a median follow-up of 75·3 months (IQR 69·9-81·1) in the intention-to-treat population, 5-year progression-free survival was 75·0% (95% CI 69·7-80·3) in the lobaplatin-based group and 75·5% (70·0 to 81·0) in the cisplatin-based group (hazard ratio [HR] 0·98, 95% CI 0·69-1·39; log-rank p=0·92), with a difference of 0·5% (95% CI -7·1 to 8·1; p non-inferiority =0·0070). In the per-protocol population, the 5-year progression-free survival was 74·8% (95% CI 69·3 to 80·3) in the lobaplatin-based group and 76·4% (70·9 to 81·9) in the cisplatin-based group (HR 1·04, 95% CI 0·73 to 1·49; log-rank p=0·83), with a difference of 1·6% (-6·1 to 9·3; p non-inferiority =0·016). 63 (25%) of 252 patients in the lobaplatin-based group and 63 (25%) of 250 patients in the cisplatin-based group had a progression-free survival event in the intention-to-treat population; 62 (25%) of 246 patients in the lobaplatin-based group and 58 (25%) of 237 patients in the cisplatin-based group had a progression-free survival event in the per-protocol population. The most common grade 3-4 adverse events were mucositis (102 [41%] of 252 in the lobaplatin-based group vs 99 [40%] of 249 in the cisplatin-based group), leucopenia (39 [16%] vs 56 [23%]), and neutropenia (25 [10%] vs 59 [24%]). No treatment-related deaths were reported., Interpretation: Lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy resulted in non-inferior survival and fewer toxic effects than cisplatin-based therapy. The results of our trial indicate that lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy might be a promising alternative regimen to cisplatin-based treatment in patients with locoregional, advanced nasopharyngeal carcinoma., Funding: National Science and Technology Pillar Program, International Cooperation Project of Science and Technology Program of Guangdong Province, Planned Science and Technology Project of Guangdong Province, and Cultivation Foundation for the Junior Teachers at Sun Yat-sen University., Translation: For the Chinese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: To evaluate the characteristics of drug-related problems (DRPs) in cancer pain patients, and to identify the impact of pharmacists' intervention in cancer pain associated DRPs., Methods: In this investigative, single-arm intervention study, clinical pharmacists identified DRPs in cancer pain patients and provided interventions based on medication information, direct patient-pharmacist interview, and ward rounds with multi-disciplinary team (MDT). Types and causes of DRPs, interventions, acceptance and outcome were sorted based on Pharmaceutical Care Network Europe (PCNE) DRP classification V9.0, which includes 3 primary domains for problems, 9 for causes, 5 for interventions, 3 for acceptance, and 4 for DRPs status., Results: Totally, 42 cancer pain patients were enrolled, and 47 DRPs in 33 (78.6%) patients were identified by clinical pharmacists. The major type of DRPs was treatment effectiveness (30; 63.8%) and treatment safety (17; 36.2%). For the "treatment effectiveness" category, the "effect of drug treatment not optimal" was dominant category (27/30; 90%). A total of 66 DRP causes were identified, and most of DRPs were caused by "drug selection" (27; 40.9%) and "dose selection" (16; 24.2%). Within the "drug selection" category, "no or incomplete drug treatment in spite of existing indication" was dominant category (25/27; 92.6%). According to DRPs, 159 interventions were provided by clinical pharmacists and 99.4% of interventions were accepted by prescribers or patients. Finally, 44 (93.6%) DRPs were solved., Conclusions: In cancer pain patients, insufficient pain control mainly caused by inappropriate selection and dosage of analgesics. Clinical pharmacists' interventions dramatically ameliorate these problems and bring about positive effects in cancer pain pharmacotherapy.

With the acceleration of urbanization and industrialization, the content and pollution of polycyclic aromatic hydrocarbons (PAHs) in urban soils have been sources of widespread concern. Taking Shizuishan City as an example, the spatial distribution characteristics of PAHs in 156 surface soil samples (0-20 cm) from eight urban functional areas were analyzed. Single factor and Nemero composite indices, as well as a lifetime cancer risk increment model were used to evaluate PAHs pollution in soils. The sources of PAHs were analyzed using the positive matrix factorization (PMF) model. The results showed that the mean value of PAHs in the surface soil of Shizuishan City was 489.82 ng·g -1 and the coefficient of variation of 15 PAHs except for Pyr were more than 100%, indicating strong variation. The PAH contents of urban surface soils in different functional areas showed the following:traffic area (1217.61 ng·g -1 ) > industrial area (809.58 ng·g -1 ) > park (273.66 ng·g -1 ) > cultural and educational area (268.18 ng·g -1 ) > commercial area (240.05 ng·g -1 ) > agricultural area (226.81 ng·g -1 ) > medical area (211.90 ng·g -1 ) > residential area (183.49 ng·g -1 ). The Nemero composite index showed that 82.58% of the samples had no pollution, and the proportion of slight, mild, and moderate pollution were 6.45%, 4.52%, and 0.65%, respectively. Only 5.8% of the samples had serious pollution. The results of health risk assessment showed that skin contact and ingestion were the main routes of PAH exposure in soil, and the health risk was acceptable. Source analysis showed that the main sources of PAHs in Shizuishan City were traffic emissions, coal combustion, mixed biomass/heavy oil combustion, and oil sources, with contribution rates of 10.5%, 36.6%, 50.3%, and 2.6% respectively, and most of the high values were distributed in industrial or coal production areas. These results could provide reference for the study of soil pollution in industrial cities, and play an important role in preventing soil pollution, ensuring the environmental quality of the soil and human health and safety.

Accumulating evidence suggests that abnormal fatty acid composition is related to the development of Alzheimer's disease (AD). However, there is no consistency in the fatty acid profile and metabolism associated with AD pathogenesis. This study aims to define the characteristics of fatty acid composition and metabolism in AD. Using 6-month-old APP/PS1 transgenic mice with wild-type mice as a control, we examined the serum lipids, brain fatty acid composition, and the expression levels of various genes involved in liver fatty acid β-oxidation. The results of our study demonstrate that APP/PS1 mice present decreased serum free fatty acids, altered brain fatty acid profiles, and minimal change in liver fatty acid β-oxidation. Our results suggest that abnormal fatty acid compositions and contents may play potential roles in AD progression. This study provides further evidence for the metabolic basis of AD pathogenesis., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: More than half of cancer patients affected by cancer experience pain of moderate-tosevere intensity. Therefore, facilitating appropriate and safe administration of analgesics is crucial to the comprehensive management of cancer patients. In this article, we assessed medication adherence, pain relief, drug related problems (DRPs) and analgesics adverse events (AEs) in cancer pain patients based on a model of clinical pharmacy services., Methods: In this prospective, single-arm intervention study, cancer pain patients admitted to our institution were eligible. According to different adherence, heterogeneity of pain, and individual treatment strategy, clinical pharmacists (CPs) provided comprehensive pain assessment and medication education for patients, as well as provided consultation and recommendation for physicians. CPs' pharmacy services were assessed through medication adherence, numbers of DRPs, acceptance of recommendation, pain intensity (PI), daily interference and AEs., Results: A total of 42 patients were enrolled between November, 2018 and November, 2019. Compared to baseline, patients' medication adherence evaluated with a medication adherence scale showed a significantly improvement at 14 and at 28 days after receiving CPs' interventions (8 score vs. 7 score at 14 days and at 28 days, P<0.01). During the 28-day follow-up, a total of 63 interventions were put forward according to 57 identified DRPs in 33 patients (78.6%), and approximately 95% (60/63) of the interventions were accepted by physicians. PI and daily interference significantly improved on the third day after the interventions of CPs, and the improvement continued until day 28 (P<0.01). AEs caused by opioids occurred in 19 patients (45.2%), and the most common one was constipation (14 patients, 33.3%)., Conclusions: CPs' comprehensive interventions for cancer pain patients were efficacious in improving their medication adherence and pain relief, as well as reducing incidence of AEs. Therefore, this promising model should be replicated in other medical centers.

Tissue engineering produces constructs with defined functions for the targeted treatment of damaged tissue. A complete spinal cord injury (SCI) model is generated in canines to test whether in vitro constructed neural network (NN) tissues can relay the excitatory signal across the lesion gap to the caudal spinal cord. Established protocols are used to construct neural stem cell (NSC)-derived NN tissue characterized by a predominantly neuronal population with robust trans-synaptic activities and myelination. The NN tissue is implanted into the gap immediately following complete transection SCI of canines at the T10 spinal cord segment. The data show significant motor recovery of paralyzed pelvic limbs, as evaluated by Olby scoring and cortical motor evoked potential (CMEP) detection. The NN tissue survives in the lesion area with neuronal phenotype maintenance, improves descending and ascending nerve fiber regeneration, and synaptic integration with host neural circuits that allow it to serve as a neuronal relay to transmit excitatory electrical signal across the injured area to the caudal spinal cord. These results suggest that tissue-engineered NN grafts can relay the excitatory signal in the completely transected canine spinal cord, providing a promising strategy for SCI treatment in large animals, including humans., Competing Interests: The authors declare no conflict of interest., (© 2019 The Authors. Published by WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.)

A total of 119 surface soil samples (depth of 0-20 cm) were collected from a Chinese wolfberry demonstration garden in Zhongning of Ningxia, and samples were analyzed for seven heavy metals (Pb, Ni, Zn, Mn, Cu, Cr, and Cd). The single factor index, comprehensive index, and potential ecological risk were used to assess the soil heavy metal contamination with the soil background values of Ningxia as the evaluation standards. The absolute principal component scores and multivariate linear regression (APCS-MLR) model as well as geostatistic analysis were combined to identify and apportion the pollution sources of soil heavy metals. The results showed that the average concentrations of Pb, Ni, Zn, Mn, Cu, Cr, and Cd in soils were 34.78, 52.376, 83.692, 641.114, 38.130, 87.257, and 0.149 mg·kg -1 , respectively. The mean concentrations of heavy metals were higher than the local soil background values but lower than the risk screening values for soil contamination of agricultural land. The comprehensive index results showed that the pollution degree of soil heavy metals was at the slightly polluted level in 81.51% of the samples, at the moderately polluted level in 16.81% of the samples, and at the unpolluted level in 1.68% of the samples. The comprehensive index values for potential ecological hazards were less than 60 in 13.45% of the samples, and these values were associated with a slight potential for ecological risks. The comprehensive index values for potential ecological hazards were less than 120 and more than 60 in 86.55% of the samples, and these values were associated with a moderate potential for ecological risks. The four main pollution sources of soil heavy metals in the study area included natural sources, industrial activity, traffic, and agricultural activity. Natural sources were the main source of Ni and Cr with average contribution rates of 55.49% and 64.66%, respectively. Industrial activity was the main source of Pb and Mn with average contribution rates of 46.93% and 42.53%, respectively. Traffic was the main source of Zn and Cu with average contribution rates of 43.51% and 53.71%, respectively. Agricultural activity was the main source of Cd with an average contribution rate of 76.79%. The study results indicated that soil heavy metals have tended to concentrate in the Chinese wolfberry demonstration garden, and the sources of heavy metals were complex and obviously influenced by human activities. Controls should be strengthened for sources that contribute to soil heavy metals to ensure the sustainable utilization of soil resources in the Chinese wolfberry land.

The study aimed to develop a novel dose conversion platform by improving linear-quadratic (LQ) model to more accurately describe radiation response for high fraction/acute doses. This article modified the LQ model via piecewise fitting the biological dose curve using different fractionated dose and optimizing the consistency between mathematical model and experimental data to gain a more reasonable transform. That mathematical development of the LQ model further amended certain deviations of various cell curves with high doses and implied the rationality of the present model at low dose range. The modified biologically effective dose model that solved the dilemma of inaccurate LQ model had been used in comparing between hypofractionated and conventional fractioned dose. It has been verified that the calculated values are similar in the treatment of same efficacy, no matter what α/β is, and provided a more rational explanation for significant differences among various hypofractionations. The equivalent uniform dose based on the subsection function could represent arbitrary inhomogeneous dose distributions including high-dose fractions, providing a foundation for the implementation of detailed evaluation of different cell dose effects., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Locally applied radiation to the tumor is reported to stimulate systemic immune response. During radiotherapy to the abdominal cancer, spleen often receives certain dose, though as an important immune organ, little is known about the impact of splenic irradiation (SI) on systemic immune and local tumor control. Through a mice model, we found that the combination of SI with tumor irradiation (TI) helped in local control. The analysis of the tumor infiltrating leucocytes demonstrated that SI plus TI brought more T cell aggregation in the tumor microenvironment (TME), which helped in tumor control. Increased T cell infiltration may be partly due to higher expression of T cell chemokine in the TME and more expression of CXCR3 on the T cells in the spleen after SI. SI produced more IL-1β in the spleen, IL-1β stimulated the expression of CXCR3 on the T cells, and enhanced their migration ability. Taken together, radiation to the spleen combined with TI helped in local control through promoting T cell infiltration, and may be a considerable means to enhance the immunomodulatory of radiotherapy., (Copyright © 2019. Published by Elsevier Inc.)

Endogenous immune response participates in tumor control, and radiotherapy has immune modulatory capacity, but the role of immune modulation in the tumor microenvironment invoked by radiotherapy in radiosensitivity is poorly defined. In the present study, a radio-resistant melanoma cell line was obtained after repeated irradiation to the parental tumor in C57BL/6 mice. Radiotherapy resulted in aggregation of CD8 + and CD3 + T cells, and decrease of myeloid-derived suppressor cells and dendritic cells in the parental tumor, but not in the resistant tumors. CD4 + T cells and B cells did not change significantly. The CD8 + T cell infiltration after radiotherapy is important for tumor response, because in the nude mice and CD8 + T cell-depleted C57BL/6 mice, the parental and resistant tumor has similar radiosensitivity. Patients with good radiation response had more CD8 + T cells aggregation after radiotherapy. Radiotherapy resulted in robust transcription of T cell chemoattractant in the parental cells, and the expression of CCL5 was much higher. These results reveal a novel mechanism of radioresistance, tumor cells inhibit the infiltration of CD8 + T cell after radiotherapy and become radioresistant. Increasing CD8 + T cell infiltration after RT may be an effective way to improve tumor radiosensitivity.

It is important to accurately assess the regional spatial distribution and variation of soil carbon and its fractions due to its great significance in soil carbon cycling and soil quality. The objectives of this study were to investigate the spatial variability of soil carbon and its fractions using classical and geostatistical statistics. Topsoil samples (0-20 cm) from 119 sites in Wolfberry Field were collected from a grid of 100 m×100 m in Zhongning County. The GS+7.0 software was used to fit a semivariance model to determine the optimal theoretical model and parameters. The spatial distribution characteristics of soil carbon and its fractions were studied by ordinary kriging. The classical statistical analyses showed that the average concentrations of total carbon, inorganic carbon, organic carbon, active organic carbon, medium active organic carbon, and high active organic carbon were 28.74, 18.72, 10.09, 1.81, 1.48, and 0.73 g·kg -1 , respectively. The variation coefficient of total carbon and inorganic carbon were 7.69% and 9.13%, indicating a strong variation, while the other soil carbon fractions showed moderate variation with the coefficients of variations ranging from 14.77%-52.05%. The geostatistical analyses revealed that the semivariogram of organic carbon was best fit by the spherical model, while the other five kinds of carbon fractions were best fit by the exponential model. The nugget coefficients of total carbon and organic carbon were 48.99% and 34.35%, which demonstrated moderate spatial dependence. The nugget coefficients of inorganic carbon, active organic carbon, medium active organic carbon, and high active organic carbon were 8.17%, 0.25%, 12.18%, and 0.08%, which demonstrated strong spatial dependence. The ordinary kriging interpolation map indicated that the spatial distribution patterns were similar for total carbon, organic carbon, medium active organic carbon, and high active organic carbon, which increased from southeast to northwest. Inorganic carbon and active organic carbon presented an irregular plaque distribution in the study area. Spatial interpolation maps could provide useful information for environmental management and the sustainable use of land resources in this region.

Surface soil samples (0-20 cm) from eight different functional areas in Yinchuan city were collected. There were 10 samples respectively in each functional area. The urban soil heavy metals (Zn, Cd, Pb, Mn, Cu and Cr) pollution characteristics and sources in eight different functional areas were evaluated by mathematical statistics and geostatistical analysis method. Meanwhile, the spatial distributions of heavy metals based on the geography information system (GIS) were plotted. The average values of total Zn, Cd, Pb, Mn, Cu and Cr were 74.87, 0.15, 29.02, 553.55, 40.37 and 80.79 mg x kg(-1), respectively. The results showed that the average value of soil heavy metals was higher than the soil background value of Ningxia, which indicated accumulation of the heavy metals in urban soil. The single factor pollution index of soil heavy metals was in the sequence of Cu > Pb > Zn > Cr > Cd > Mn. The average values of total Zn, Cd, Pb and Cr were higher in north east, south west and central city, while the average values of Mn and Cu were higher in north east and central city. There was moderate pollution in road and industrial area of Yinchuan, while the other functional areas showed slight pollution according to Nemoro synthesis index. The pollution degree of different functional areas was as follows: road > industrial area > business district > medical treatment area > residential area > public park > development zone > science and education area. The results indicated that the soil heavy metal pollution condition in Yinchuan City has been affected by human activities with the development of economy.

Objective . To compare adjuvant radiotherapy and salvage radiotherapy after radical resection for treatment of esophageal squamous cell carcinoma (ESCC). Methods . Data from 155 patients with locally advanced ESCC who underwent radical resection and received postoperative radiotherapy from 2005 to 2011 were reviewed. Seventy-nine patients received adjuvant radiotherapy and 76 received salvage radiotherapy after locoregional recurrence. Results . The median disease-free survival (DFS) and overall survival (OS) were significantly higher in the adjuvant radiotherapy group than the salvage radiotherapy group (DFS 25.73 months versus 10.73 months, P < 0.001; OS 33.33 months versus 26.22 months, P = 0.006). The independent prognostic factors for DFS were performance status (PS) before radiotherapy and pathological stage in the adjuvant radiotherapy group, compared with lymph node metastasis, tumor location, and adjuvant chemotherapy in the salvage radiotherapy group. The independent prognostic factors for OS were age and PS in both groups. No differences in median DFS and OS between the groups were observed in patients aged > 65 years or with PS ≥ 2. Conclusion . Compared to salvage radiotherapy, postoperative adjuvant radiotherapy can prolong DFS and OS for patients with radically resected local advanced ESCC but cannot improve survival for patients aged > 65 years or with PS ≥ 2.

Application of methanol (MeOH) inhibits photorespiration and enhances growth and yield in C3 plants. However, the underlying cellular and molecular mechanisms are not clear. In this study, we investigated the effects of foliar application of MeOH (30%, v/v) on glycolate oxidase (GO) activity and photorespiratory intermediates in cotton leaves in a field experiment. MeOH treatment significantly inhibited GO activity (by 30% compared with the controls). We also found that endogenous glyoxylate, a photorespiratory intermediate, increased and glycine decreased significantly in MeOH-treated plants. Serine increased significantly in MeOH-treated plants. These results thus demonstrated that exogenous MeOH can modulate GO activity and the production of photorespiratory intermediates, and sheds new lights on our current understanding of how exogenous MeOH inhibits photorespiration and enhances the growth and yield of C3 plants such as cotton., (© The Author 2014. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The aim of this study was to analyze the risk factors and prognosis for patients with esophageal perforation occurring during or after radiotherapy for esophageal carcinoma. We retrospectively analyzed 322 patients with esophageal carcinoma. These patients received radiotherapy for unresectable esophageal tumors, residual tumors after operation, or local recurrence. Of these, 12 had radiotherapy to the esophagus before being admitted, 68 patients had concurrent chemoradiotherapy (CRT), and 18 patients had esophageal perforation after RT (5.8%). Covered self-expandable metallic stents were placed in 11 patients. Two patients continued RT after stenting and control of infection; one of these suffered a new perforation, and the other had a massive hemorrhage. The median overall survival was 2 months (0-3 months) compared with 17 months in the non-perforation group. In univariate analysis, the Karnofsky performance status (KPS) being ≤ 70, age younger than 60, T4 stage, a second course of radiotherapy to the esophagus, extracapsular lymph nodes (LN) involving the esophagus, a total dose >100 Gy (biologically effective dose-10), and CRT were risk factors for perforation. In multivariate analysis, age younger than 60, extracapsular LN involving the esophagus, T4 stage, and a second course of radiotherapy to the esophagus were risk factors. In conclusion, patients with T4 stage, extracapsular LN involving the esophagus, and those receiving a second course of RT should be given particular care to avoid perforation. The prognosis after perforation was poor., (© The Author 2014. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Determining spatial distributions and analyses contamination condition of soil heavy metals play an important role in evaluation of the quality of agricultural ecological environment and the protection of food safety and human health. Topsoil samples (0-20 cm) from 223 sites in farmland were collected at two scales of sampling grid (1 m x 1 m, 10 m x 10 m) in the Yellow River irrigation area of Ningxia. The objectives of this study were to investigate the spatial variability of total copper (Cu), total zinc (Zn), total chrome (Cr), total cadmium (Cd) and total lead (Pb) on the two sampling scales by the classical and geostatistical analyses. The single pollution index (P(i)) and the Nemerow pollution index (P) were used to evaluate the soil heavy metal pollution. The classical statistical analyses showed that all soil heavy metals demonstrated moderate variability, the coefficient of variation (CV) changed in the following sequence: Cd > Pb > Cr > Zn > Cu. Geostatistical analyses showed that the nugget coefficient of Cd on the 10 m x 10 m scale and Pb on the 1 m x 1 m scale were 100% with pure nugget variograms, which showed weak variability affected by random factors. The nugget coefficient of the other indexes was less than 25%, which showed a strong variability affected by structural factors. The results combined with P(i) and P indicated that most soil heavy metals have slight pollution except total copper, and in general there were the trend of heavy metal accumulation in the study area.

The purpose of this study was to analyze the clinical outcomes of simultaneous modulated accelerated radiotherapy (SMART) in patients with nasopharyngeal carcinoma (NPC). A total of 97 patients who underwent SMART for NPC between August 2005 and November 2011 were evaluated. The prescribed dose was 69.9 Gy/30 fractions at 2.33 Gy/fraction to the primary gross tumor volume (PGTV) including the nasopharynx gross target volume and the positive neck lymph nodes, and 60 Gy/30 fraction at 2.0 Gy/fraction to the PCTV1; 54 Gy/30 fractions at 1.8 Gy/fraction was given to the PCTV2. Among 59 patients with local advanced disease, 31 patients received concurrent chemoradiotherapy (chemo-RT) with a regimen consisting of 135 mg/m(2) paclitaxel on Day 1 and 25 mg/m(2) cisplatin on Days 1-3. The median follow-up period was 42 months. The local control rate (LCR), distant metastases-free survival (DMFS) and overall survival (OS) rates were 93.3%, 90.3% and 91.6% at 3 years, and 87.6%, 87.9% and 85.7% at 5 years, respectively. There was no significant difference in outcome with respect to these three indicators for Stage III and IV disease treated with/without concurrent chemoradiotherapy (P > 0.05). Acute toxicities included Grade 3 mucositis, skin desquamation, and leucopenia, which occurred in 78 (80.4%), 8 (8.2%), and 45 (46.4%) patients, respectively. No patient had a Grade 3-4 late toxicity. SMART was associated with a favorable outcome for NPC with acceptable toxicity. The local-regional control was excellent but distant metastasis remains the main risk. The combination of SMART and chemotherapy needs to be optimized through further studies to enhance outcomes for locally advanced diseases., (© The Author 2014. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Purpose: To compare the quality of computed tomography (CT) and magnetic resonance imaging (MRI) in target delineation of hepatocellular carcinoma., Patients and Methods: Thirty-one patients with hepatocellular carcinoma received CT and MRI (including diffusion-weighted imaging [DWI]) before surgery. The maximal measurement on axial imaging and pathologic examination were extracted for statistical analysis., Results: CT, MRI, DWI-based tumour size correlated well with pathologic sizes, r=0.974, 0.969, 0.964 respectively. But Wilcoxon signed-ranked test showed that differences did exist. CT overestimated the tumour size by 2.9mm compared to pathology (95% CI: -13.2 to 7.4mm). The agreement of MRI-pathology seemed to be worse than CT, with a mean difference of 3.6mm (95% CI: -14.7 to 7.7mm). The worst agreement was in DWI-pathology, with a mean difference of 5mm (95% CI: -17.9 to 7.9mm). But significant difference was found neither between CT and MRI (P=0.477) nor between MRI and DWI (P=0.079)., Conclusions: CT and MRI-based tumour size correlated well with pathologic size, but differences did exist. Most of the lesions were overestimated by CT and MRI. CT and MRI were similar in the guidance of target delineation, and DWI had added little value to MRI. A margin of 10mm around the gross tumour volume to become the clinical target volume is likely not sufficient., (Copyright © 2013 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

Purpose: To analyze the effectiveness and toxicities in the re-irradiation of locally recurrent nasopharyngeal carcinoma (NPC) using intensity-modulated radiotherapy (IMRT)., Methods: This is a retrospective analysis of 54 NPC patients with local recurrence re-irradiated with IMRT. The re-staging for rT1, rT2, rT3, rT4 were 3 (5.6%), 8 (14.8%), 9 (16.7%), 34 (63%) respectively. The average dose to GTV was 69.95 Gy (49.8-76.58 Gy), the average BED(3Gy) was 116.8 Gy (83.5-127.9 Gy). V₉₅ was 96%, and D₉₅ was 65.75 Gy. 33.3% of them received concurrent chemoradiotherapy., Results: Median overall survival (OS) was 21 months (1-93 mon). The 1-, 2-year local progression free survival (LPFS) rate was 84.5%, 64% and OS rate was 71.7%, 44.3%. Severe late adverse events (SLAE) occurred in 48.1% of patients, including 31.5% with ulcer or necrosis of the nasopharyngeal mucosa, 20.4% with difficulty in feeding, 18.5% with temporal lobe necrosis, 11.1% with massive hemorrhage. 15.4% died of local regional progression, 5.8% died of distant metastasis, 25% died of SLAE, 9.6% died of both local regional progression and SLAE that could not be differentiated, 5.8% died of other medical complications. Concurrent chemoradiotherapy was the independent negative prognostic factors for LPFS; PTV>100 ml was a predictive factor of poor OS; patients with invasion of post-styloid space were at higher risk of SLAE., Conclusions: The present study demonstrated that IMRT with 70Gy was efficient for local tumor control. However, we observed a high frequency of serious late complications. More optimized combination treatment and patient selection are required to achieve excellent local control without significant late morbidities in locally recurrent NPC.

The purpose of this investigation was to analyze the correlation between CT size and gross pathologic size for subjects with primary hepatocellular carcinoma (HCC). This analysis included 174 patients with HCC who underwent surgery. Enhanced computed tomography (CT) was performed up to 30 days before surgery. After resection, the size of the tumor on gross pathologic examination was recorded. The maximal measurement in one dimension on axial imaging and pathologic examination was extracted for statistical analysis. The clinical and pathologic sizes were compared using a percent size difference (%Δsize) as an end point. A regression analysis was applied to study the association between pathologic and radiographic size. The median radiographic and pathologic size were 70.58 ± 38.9 mm and 68.59 ± 40.56 mm, respectively. The radiographic size was larger than or equal to the pathologic size in 110/174 tumors (63.2%), and smaller in 64/174 (36.8%) tumors. Overall, the radiographic and pathologic sizes were positively correlated (r = 0.983, P = 0.000). CT seemed to overestimate the tumor size by 2.16 mm compared to final pathology (P = 0.024). The median %Δsize was 3.3%. Pathologic tumor size was significantly underestimated in patients with a tumor size 3-5 cm (P = 0.011), Grade I HCC (P = 0.023), with clear boundary (P = 0.013). We concluded that CT size and pathologic size were positively correlated, but differences did exist. Utilizing the radiographic tumor when planning radiation would have covered 63.2% of gross tumors. For a radiographic tumor size < 50 mm, utilizing a 3-mm margin around the radiographic tumor would have covered 90% of gross lesions, while a margin of 5 mm would have covered 95%, and a margin of 15 mm would have covered 100%.

Aim of the Study: Different carcinomas have different characteristics, which may play a crucial role in diagnosis and treatment. Our study was aimed at understanding the development pattern of bone metastasis from hepatocellular carcinoma, based on its imaging characteristics, so as to provide a more targeted treatment., Material and Methods: Forty two patients (123 lesions) with hepatocellular carcinoma hospitalized from June 2006 to June 2011 underwent radiotherapy for bone metastasis in our department. Clinical and imaging data were analyzed retrospectively (based on CT imaging, also with reference to MRI, ECT, or PET-CT, etc.)., Results: One hundred of 123 lesions were vertebral metastases; 23 were non-vertebral. The major form of bone destruction was osteolytic change. Metastasis in the vertebral body was found in 87.8%, and lesions were well distributed in various sections. Vertebral appendix metastasis accounted for 52%, where lesions could be independent of vertebral body metastasis. Formation of a soft tissue mass in bone metastasis was found in 68.6% of all patients. The center of the mass from a vertebral body metastasis was mostly located at the site of the lesion; masses from the vertebral appendix and the pelvis, on the other hand, often presented as a "peripheral mass". Masses were not formed in lesions with pure osteoblastic changes., Conclusions: The most common radiographic feature is an osteolytic lesion, either replaced by soft tissue mass, or invaded by soft tissue mass from the vicinity, which often cause compression syndrome. Vertebral appendix metastasis can exist independently from vertebral body metastasis, which should be paid more attention to avoid missed diagnosis.

Aims: To carry out a meta-analysis to compare fluorine-18 deoxyglucose ((18)FDG) positron emission tomography (PET), magnetic resonance imaging (MRI) and bone scintigraphy imaging for the diagnosis of bone metastases in patients with lung cancer., Materials and Methods: MEDLINE, EMBASE, Scopus and other databases were searched for relevant original articles published between January 1995 and January 2010. Inclusion criteria were as follows: (18)FDG PET, MRI or (99m)Tc-MDP bone scintigraphy was carried out to detect bone metastases in patients with lung cancer; sufficient data were presented to construct a 2×2 contingency table; histopathological analysis and/or close clinical and imaging follow-up and/or radiographic confirmation by multiple imaging modalities were used as the reference standard. Two reviewers independently extracted data. META-DiSc was used to obtain pooled estimates of sensitivity, specificity, diagnostic odds ratio (DOR), summary receiver operating characteristic (SROC) curves and the *Q index., Results: In total, 14 articles that consisted of 34 studies fulfilled all inclusion criteria. On a per-patient basis, the pooled sensitivity estimates for PET, MRI and bone scintigraphy were 91.9, 80.0 and 91.8%, respectively. The sensitivity for PET and bone scintigraphy were significantly higher than for MRI (P<0.05). There was no significant difference between PET and bone scintigraphy (P>0.05). The pooled specificity estimates for PET, MRI and bone scintigraphy were 96.8, 90.6 and 68.8%, respectively. The specificity for PET was significantly higher than for MRI and bone scintigraphy (P<0.05), and the specificity for MRI was significantly higher than for bone scintigraphy (P<0.05). The pooled DOR estimates for PET, MRI and bone scintigraphy were 365.5, 53.8 and 34.4, respectively. The DOR for PET was significantly higher than for MRI and bone scintigraphy (P<0.05). There was no significant difference between MRI and bone scintigraphy (P>0.05). The SROC curve for PET showed better diagnostic accuracy than for MRI and bone scintigraphy. The SROC curve for MRI was better than for bone scintigraphy. The *Q index estimates for PET, MRI and bone scintigraphy were 0.933, 0.903 and 0.857, respectively. The *Q index for PET and MRI were significantly higher than for bone scintigraphy (P<0.05). There was no significant difference between PET and MRI (P>0.05). On a per-lesion basis, the pooled sensitivity estimates for PET, MRI and bone scintigraphy were 95.0, 83.8 and 71.5%, respectively. The sensitivity for PET was significantly higher than for MRI and bone scintigraphy (P<0.05), and the sensitivity for MRI was significantly higher than for bone scintigraphy (P<0.05). The pooled specificity estimates for PET, MRI and bone scintigraphy were 94.6, 96.3 and 91.0%, respectively. The specificity for MRI was significantly higher than for PET and bone scintigraphy (P<0.05), and the specificity for PET was significantly higher than for bone scintigraphy (P<0.05). The pooled DOR estimates for PET, MRI and bone scintigraphy were 431.9, 158.1 and 9.0, respectively. The DOR for PET was significantly higher than for MRI and bone scintigraphy (P<0.05) and the DOR for MRI was significantly higher than for bone scintigraphy (P<0.05). The SROC curve for PET and MRI showed better diagnostic accuracy than for bone scintigraphy. There was no significant difference between PET and MRI. The *Q index estimates for PET, MRI and bone scintigraphy were 0.953, 0.962 and 0.778, respectively. The *Q index for PET and MRI were significantly higher than for bone scintigraphy (P<0.05). There was no significant difference between PET and MRI (P>0.05)., Conclusion: (18)FDG PET was found to be the best modality to detect bone metastasis in patients with lung cancer, both on a per-patient basis and a per-lesion basis; MRI had the highest specificity on a per-lesion basis. For the subgroup analysis of (18)FDG PET, PET/computed tomography was shown to be better than PET and there were no significant differences between using (68)Ge and computed tomography for attenuation correction on a per-patient basis., (Copyright © 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Purpose: To perform a systematic review to compare FDG-PET, CT, and MRI imaging for diagnosis of local residual or recurrent nasopharyngeal carcinoma., Materials and Methods: MEDLINE, EMBASE, the CBMdisc databases and some other databases were searched for relevant original articles published from January 1990 to June 2007. Inclusion criteria were as follows: Articles were reported in English or Chinese; FDG-PET, CT, or MRI was used to detect local residual or recurrent nasopharyngeal carcinoma; histopathologic analysis and/or close clinical and imaging follow-up for at least 6 months were the reference standard. Two reviewers independently extracted data. A software called "Meta-DiSc" was used to obtain pooled estimates of sensitivity, specificity, diagnostic odds ratio (DOR), summary receiver operating characteristic (SROC) curves, and the Q* index., Results: Twenty-one articles fulfilled all inclusion criteria. The pooled sensitivity estimates for PET (95%) were significantly higher than CT (76%) (P<0.001) and MRI (78%) (P<0.001). The pooled specificity estimates for PET (90%) were significantly higher than CT (59%) (P<0.001) and MRI (76%) (P<0.001). The pooled DOR estimates for PET (96.51) were significantly higher than CT (7.01) (P<0.001) and MRI (8.68) (P<0.001). SROC curve for FDG-PET showed better diagnostic accuracy than CT and MRI. The Q* index for PET (0.92) was significantly higher than CT (0.72) (P<0.001) and MRI (0.76) (P<0.01). For PET, the sensitivity and diagnostic OR for using qualitative analysis were significantly higher than using both qualitative and quantitative analyses (P<0.01). For CT, the sensitivity, specificity, diagnostic OR, and the Q* index for dual-section helical and multi-section helical were all significantly higher than nonhelical and single-section helical (P<0.01). And the sensitivity for 'section thickness <5 mm' was significantly lower than ' =5 mm' (P<0.01), while the specificity was significantly higher (P<0.01). For MRI, there were no significant differences found between magnetic field strength <1.5 and > or =1.5 T (P>0.05)., Conclusion: FDG-PET was the best modality for diagnosis of local residual or recurrent nasopharyngeal carcinoma. The type of analysis for PET imaging and the section thickness for CT would affect the diagnostic results. Dual-section helical and multi-section helical CT were better than nonhelical and single-section helical CT.

Aim: To explore whether intensity modulated radiation therapy (IMRT) in combination with chemotherapy could increase radiation dose to gross tumor volume without severe acute radiation related toxicity by decreasing the dose to the surrounding normal tissue in patients with locally advanced pancreatic cancer., Methods: Twenty-one patients with locally advanced pancreatic cancer were evaluated in this clinical trial. Patients would receive the dose of IMRT from 21Gy to 30Gy in 7 to 10 fractions within two weeks after conventional radiotherapy of 30Gy in 15 fractions over 3 weeks. The total escalation tumor dose would be 51, 54, 57, 60Gy, respectively. 5-fluororacil (5-FU) or gemcitabine was given concurrently with radiotherapy during the treatment course., Results: Sixteen patients who had completed the radiotherapy plan with doses of 51Gy (3 cases), 54Gy (3 cases), 57Gy (3 cases) and 60Gy (7 cases) were included for evaluation. The median levels of CA19-9 prior to and after radiotherapy were 716 U/ml and 255 U/ml respectively (P<0.001) in 13 patients who demonstrated high levels of CA19-9 before radiotherapy. Fourteen patients who suffered from pain could reduce at least 1/3-1/2 amount of analgesic intake and 5 among these patients got complete relief of pain. Ten patients improved in Karnofsky performance status (KPS). The median follow-up period was 8 months and one-year survival rate was 35%. No patient suffered more than grade III acute toxicities induced by radiotherapy., Conclusion: Sixty Gy in 25 fractions over 5 weeks with late course IMRT technique combined with concurrent 5-FU chemotherapy can provide a definitely palliative benefit with tolerable acute radiation related toxicity for patients with advanced pancreatic cancer.

Background/aims: To observe if octreotide can augment the effects of hepatic arterial occlusion for transplanted cancer in rat's liver., Methodology: Walker 256 carcinosarcoma was transplanted into rat's liver to create the liver cancer model. Hepatic arterial ligation was used to block the hepatic arterial blood supply. Rats bearing tumor were divided into three groups: control group, HAL (hepatic arterial ligation) group, and HAL plus octreotide group. Change of tumor volume and tumor growth inhibiting rate after therapy were evaluated. Hoechst 33342 labeling assay was used to analyze the blood perfusion of tumor (the labeled cells' number presenting blood perfusion). Expression of vascular endothelial growth factor and matrix metalloproteinase-1 mRNA was detected by in situ hybridization, and the level of serum vascular endothelial growth factor was assayed by ELISA., Results: Six days after hepatic arterial ligation, the mean tumor volume in control group, HAL group, and HAL plus octreotide group was 0.103 +/- 0.043 cm3, 0.030 +/- 0.018 cm3, and 0.016 +/- 0.005 cm3, respectively. The tumor volume in the two behind groups was smaller than that in the control group (P < 0.01), and the tumor growth-inhibiting rate was 70.8%, and 84.5%, respectively. Compared with the HAL group, the tumor volume in HAL plus octreotide group decreased significantly (P < 0.05). Hoechst 33342 labeled cells' number in control group, HAL group, and HAL plus octreotide group was 369.7 +/- 30.2, 344.1 +/- 26.0, and 323.2 +/- 40.4, respectively. The number in HAL combined with octreotide group decreased significantly compared with that in control group (P < 0.05), which suggested that the blood perfusion of tumor in HAL plus octreotide group decreased significantly. The expression of vascular endothelial growth factor and matrix metalloprotenase-1 mRNA decreased slightly, but not significantly in HAL plus octreotide group compared with that in HAL group (P > 0.05)., Conclusions: The results suggest that octreotide can promote the effects of hepatic arterial occlusion therapy for transplanted cancer in rat's liver. Decreasing the blood perfusion of tumor after hepatic arterial blockage maybe one of its major mechanisms.

Aim: To investigate the influence of hepatic arterial blockage on blood perfusion of transplanted cancer in rat liver and the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-1 (MMP-1), and to explore the mechanisms involved in transarterial embolization (TAE)-induced metastasis of liver cancer preliminarily., Methods: Walker 256 carcinosarcoma was transplanted into rat liver to establish the liver cancer model. Hepatic arterial ligation (HAL) was used to block the hepatic arterial blood supply and simulate TAE. Blood perfusion of tumor in control, laparotomy control, and HAL group was analyzed by Hoechst 33342 labeling assay, the serum VEGF level was assayed by ELISA, the expression of VEGF and MMP-1 mRNA was detected by in situ hybridization., Results: Two days after HAL, the number of Hoechst 33342 labeled cells which represent the blood perfusion of tumor directly and hypoxia of tumor indirectly in HAL group decreased significantly compared with that in control group (329+/-29 vs 384+/-19, P<0.01). The serum VEGF level in the HAL group increased significantly as against that of the control group (93 ng.L(-1)+/-44 ng.L(-1) vs 55 ng.L(-1)+/-19 ng.L(-1), P<0.05). The expression of VEGF and MMP-1 mRNA in the tumor tissue of the HAL group increased significantly compared with that of the control and the laparotomy control groups (P<0.05). The blood perfusion data of the tumor, represented by the number of Hoechst 33342 labeled cells, showed a good linear inverse correlation with the serum VEGF level (r=-0.606, P<0.05) and the expression of VEGF mRNA in the tumor tissue ( r =-0.338, P<0.01)., Conclusion: Blockage of hepatic arterial blood supply results in decreased blood perfusion and increased expression of metastasis-associated genes VEGF and MMP-1 of transplanted liver cancer in rats. Decreased blood perfusion and hypoxia may be the major cause of up-regulated expression of VEGF.

Unlabelled: This report investigated the hemodynamic changes of both nitroglycerin and Salvia miltiorrhiza (Co.) concerning pulmonary capillary-wedge (PCW), mean pulmonary artery pressure (MPAP), cardiac output (CO), cardiac index (CI), systemic mean pressure (SMP), and heart rate (HR). In 20 patients with heart diseases of normal cardiac function, nitroglycerin were compared with Salvia miltiorrhiza (Co.) using Swan-Ganz Catheter, which were self-compared., Result: (1) Both drugs had the similar vaso-dilating effects, reduced the filling pressure of left ventricle and increased the cardiac output but different in the time of appearance and duration, particularly concerning CO and CI. (2) The effect of Salvia miltiorrhiza (Co.) was markedly superior to the nitroglycerin. The action of former was more persistent and the improvement of cardiac function was better than that of latter.