Search

A series of hierarchical Cd-Ni-MOF micro/nanostructures were fabricated, and the samples which were composed of thin nanosheets alone exhibited the best photocatalytic H2 evolution rate.

Because of the persistence and high toxicity of benzo[a]pyrene (B[a]P), the bioaccumulation and detoxification mechanisms of B[a]P have been studied extensively at the tissue level; but the data at the subcellular level in bivalves have not been reported. The present study was conducted to investigate the effects of B[a]P exposure on bioaccumulation, detoxification, and biomacromolecular damage in gills, digestive glands, and their subcellular fractions of the scallop Chlamys farreri. The subcellular fraction contains cytoplasm, mitochondria, microsome, nucleus, cell membrane, and overall organelle. The results demonstrated that B[a]P accumulation showed a clear time-dose effect. Based on the time-dependent accumulation of B[a]P in subcellular fractions, we speculated that the intracellular migration order of B[a]P was cell membrane, organelle, and nucleus in turn. Considering the difference of B[a]P accumulation may be related to B[a]P metabolism, we have further confirmed that the activities of B[a]P metabolizing enzymes in scallop tissues and subcellular fractions were significantly tempted by B[a]P (p 0.05), including 7-ethoxyresorufin O-deethylase (increased), glutathione-S-transferase (GST; decreased), and superoxide dismutase (increased). First, GST was detected in bivalve cytoplasm and microsome. Second, B[a]P exposure also caused biomacromolecules damage. The results demonstrated that mitochondria and microsome were more vulnerable to lipid peroxidation than cell membrane and nucleus. Taken together, the present study fills some of the gaps in our knowledge of the bioaccumulation and detoxification mechanisms of C. farreri exposed to B[a]P in subcellular fractions and deeply explores the transportation and the main metabolic and damage sites of polycyclic aromatic hydrocarbons (PAHs) in cells, which helped us to comprehensively understand the toxic mechanism of PAHs on bivalves. Environ Toxicol Chem 2022;41:2353-2364. © 2022 SETAC.

Objective. To objectively evaluate the nursing quality of patients with inguinal hernia from the aspects of postoperative pain, self-discipline, and complications, the application of medical data analysis and nursing intervention in patients with inguinal hernia was discussed. Methods. A total of 86 patients with inguinal hernia were selected, and the time distribution was from September 2020 to March 2021. The patients were divided into two groups: in the control group, there were 43 cases, 28 males and 15 females. There were 43 cases in the observation group, 25 males and 18 females. All selected subjects must sign the informed consent form and have the right to know the research content. The patients were diagnosed by abdominal ultrasound, and the demographic data and basic clinical data were recorded. Results. A total of 86 patients were divided into two groups in this study, of which 43 patients used a routine nursing path as the control group and the other 43 patients added medical data analysis and nursing intervention as the observation group on the basis of the routine nursing path. The postoperative pain, self-discipline, complications, and patient satisfaction were compared, and the patients’ satisfaction in the experimental group was significantly higher than that in the control group, while serum swelling and urine retention were significantly lower than those in the control group ( p < 0.05 ). Conclusion. According to the analysis of the routine nursing path and medical data, nursing intervention patients have more stable emotions and less postoperative pain. They can get out of bed early, reduce the occurrence of other complications, and improve the overall curative effect. Systematic nursing intervention can reduce the incidence of postoperative adverse reactions and complications. It is one of the ideal adjuvant treatments for inguinal hernia patients.

Benzo[a]pyrene (B[a]P), a typical PAHs widely existing in the marine environment, has been extensively studied for its immunotoxicity due to its persistence and high toxicity. Nevertheless, the immunotoxicity mechanism remain incompletely understood. In this study, isolated hemocytes of Chlamys farreri were exposed at three concentrations of B[a]P (5, 10 and 15 μg/mL), and the effects of B[a]P on detoxification metabolism, signal transduction, humoral immune factors, exocytosis and phagocytosis relevant proteins and immune function at 0, 6, 12, 24 h were studied. Results illustrated the AhR, ARNT and CYP1A1 were significantly induced by B[a]P at 12 h. Additionally, the content of B[a]P metabolite BPDE increased in a dose-dependent manner with pollutants. Under B[a]P stimulation, the expressions of PTK (Src, Fyn) and PLC-Ca

Retinoid X receptor (RXR) has been found to be a major target in various processes of endocrine disruption from the exposure to organotin compounds (OTCs), including imposex in gastropod mollusks. It was also reported in bivalves that OTCs caused intersex and skewed sex ratio. In order to evaluate the effect of these ligand-like OTCs, we constructed a reconstituted yeast system (CfRE system) based on GAL4 yeast two-hybrid principle using scallop Chlamys farreri retinoid X receptor (CfRXRa) and retinoid X response element (RXRE) to investigate the ligand-induced transactivation of CfRXRa. Responses of CfRXRa to 9-cis retinoic acid (9cRA) and tested four OTCs showed concentration-dependent response which is comparable with reported RXRa in vitro assay of human and gastropods. The detective limits of the CfRE system were found to be 100 nM for 9cRA and 10-1000 nM for the tested OTCs. While the tested non-Sn endocrine disrupting chemicals, including Benzo[a]pyrene, 2,4-Dichlorophenol, Nonylphenol, and Tetrabromobisphenol A, showed no effect on CfRXRa response. The present assay system may provide a valuable tool for screening assessments of unidentified environmental ligand chemicals on bivalve mollusks. It is also useful for comparison of sensitivity differences among species exposed to EDCs.

Purpose This study was aimed to investigate long-term survivals and toxicities of early-stage nasopharyngeal carcinoma (NPC) in endemic area, evaluating the role of chemotherapy in stage II patients.Materials and Methods Totally 187 patients with newly diagnosed NPC and restaged American Joint Committee on Cancer/ International Union Against Cancer 8th T1-2N0-1M0 were retrospectively recruited. All received intensity-modulated radiotherapy (IMRT)±chemotherapy (CT) from 2001 to 2010.Results With 15.7-year median follow-up, 10-year locoregional recurrence-free survival, distant metastasis-free survival (DMFS), disease-specific survival (DSS), and overall survival (OS) were 93.3%, 93.5%, 92.9% and 88.2%, respectively. Multivariable analyses showed cervical lymph nodes positive and pre-treatment prognostic nutritional index ≥ 52.0 could independently predict DMFS (p=0.036 and p=0.011), DSS (p=0.014 and p=0.026), and OS (p=0.002 and p < 0.001); Charlson comorbidity index < 3 points could predict DSS (p=0.011); age > 45 years (p=0.002) and pre-treatment lactate dehydrogenase ≥ 240 U/L (p < 0.001) predicted OS. No grade 4 late toxicity happened; grade 3 late toxicities included subcutaneous fibrosis (4.3%), deafness or otitis (4.8%), skin dystrophy (2.1%), and xerostomia (1.1%). No differences on survivals were shown between IMRT+CT vs. IMRT alone in stage II patients, even in T2N1M0 (p > 0.05). Unsurprising, patients in IMRT+CT had more acute gastrointestinal reaction, myelosuppression, mucositis, late ear toxicity, and cranial nerve injury (all p < 0.05) than IMRT alone group.Conclusion Superior tumor control and satisfying long-term outcomes could be achieved with IMRT in early-stage NPC with mild late toxicities. As CT would bring more toxicities, it should be carefully performed to stage II patients.

The multixenobiotic resistance mechanism (MXR) provides aquatic organisms with the capacity to adapt to polluted environments, which can be inhibited by chemosensitizers. In the present study, the effect of two typical marine persistent organic pollutants, benzo(a)pyrene (BaP) and tetrabromobisphenol A (TBBPA), on the most relevant ABC transporters, ABCB1, ABCC1, and ABCG2 of scallop Chlamys farreri was tested. MXR transporter efflux activity of cultured gill cells of the scallops was evaluated by measuring the intracellular fluorescent intensity of Calcein-AM and rhodamine 123 with flow cytometry. The results showed that ABCB1 and ABCC1 transporters demonstrated increased activity compared with ABCG2 in mediating MXR efflux activity. BaP and TBBPA were able to suppress the efflux transporter activity of ABC transporters significantly, of which BaP revealed block effects by acting on the ABCB1 transporter. Additionally, exposure of BaP and TBBPA only significantly upregulated the expression level of ABCC1 gene. This study demonstrated the promising utility of efflux transporter activity in conjunction with biomarkers such as mRNA levels in identification of chemosensitizer.

Purpose Current guideline recommends a uniform method of delineation of subclinical disease within the primary clinical target volume (CTVp) for all stages of nasopharyngeal carcinoma (NPC). We performed a prospective observational study to investigate the outcomes with a reduced CTVp and radiation dose for early-stage NPC. Methods and Materials Patients with newly diagnosed, biopsy-proven World Health Organization type II-III and American Joint Committee on Cancer/Union for International Cancer Control sixth edition stage T1-2N0-1 disease were enrolled. All patients were treated with intensity modulated radiation therapy alone. We categorized CTVp into CTVp1 (high risk) and CTVp2 (low risk). CTVp1 comprised of gross tumor (on magnetic resonance imaging or contrast-enhanced computed tomography) plus a 5-mm margin (3-mm posteriorly) and was prescribed to 60 Gy in 30 fractions (fr). CTVp2 was generated from CTVp1 plus a 5-mm margin (3 mm posteriorly), excluding the maxillary and cavernous sinuses, and was prescribed to 54 Gy in 30 fr. The prescribed doses to the primary and nodal gross tumor volume (GTVp and GTVn) were 68 Gy in 30 fr and 60 to 66 Gy in 30 fr, respectively. Primary endpoint was local recurrence-free survival. This study was registered in ClinicalTrials.gov , number NCT03839602 . Results From May 2001 to August 2006, 103 patients were recruited and completed IMRT. With a median follow-up of 15.2 years (range, 2.1-18.1 years), only 1 patient had local failure. Ten-year local recurrence-free survival, regional recurrence-free survival, distant metastasis-free survival, and overall survival were 90.3%, 88.3%, 90.3%, and 91.2%, respectively. Among late IMRT-related adverse events, we recorded 2 patients with G1 cranial nerve injury, 3 patients with G3 hearing loss, and 3 patients with G3 subcutaneous fibrosis. No patients had temporal lobe necrosis, brain stem injury, or trismus. Conclusions Decreased CTV margins and radiation doses can achieve long-term tumor control with mild late toxicities for patients with early-stage NPC.

Retinoid X receptor (RXR) and peroxisome proliferators-activated receptors (PPAR) have been shown as important targets of endocrine disrupting effects caused by organotin compounds (OTCs). In vitro methods for non-model species are instrumental in revealing not only mechanism of toxicity but also basic biology. In the present study, we constructed the GAL4 factor-based recombinant yeast systems of RXRα/RXRα (RR), RXRα/PPARα (RPα) and RXRα/PPARγ (RPγ) of the scallop Chlamys farreri to investigate their transcriptional activity under the induction of OTCs (tributyltin chloride, triphenyltin chloride, tripropyltin chloride and bis(tributyltin)oxide), their spiked sediments and five other non‑tin compounds (Wy14643, rosiglitazone, benzyl butyl phthalate, dicyclohexyl phthalate and bis(2-ethylhexyl) phthalate). The results showed that the natural ligand of RXR, 9-cis-retinoic acid (9cRA), induces transcriptional activity in all three systems, while four OTCs induced the transcriptional activity of the RR and RPα systems. None of the five potential non‑tin endocrine disruptors induced effects on the RPα and RPγ systems. The spiked sediment experiment demonstrated the feasibility of the recombinant yeast systems constructed in this study for environmental sample detection. These results suggest that OTCs pose a threat to affect function of RXRα and PPARα of bivalve mollusks. The newly developed GAL4 factor-based yeast two-hybrid system can be used as a valuable tool for identification and quantification of compounds active in disturbing RXR and PPAR of bivalves.

This study provides the first data on pyrethroid residues of seafood in China. A total of 192 seafood samples were randomly selected from four coastal cities of Shandong Province in 2020. The residues of fenpropathrin, cypermethrin and deltamethrin in seafood by GC-MS were ND to 26.82 μg/kg, ND to 19.18 μg/kg and ND to 15.56 μg/kg, respectively. The cumulative risk to general population of different age groups was assessed by the hazard quotient (HQ) and hazard index (HI) approaches, and showed that the maximum value of both HQ (1.81 × 10

Gonadotropin-releasing hormone (GnRH) plays a key role in the control of the reproductive axis in vertebrates, however, little is known about its function in reproductive endocrine regulation in molluscs. In the present study, RNA-seq was used to construct transcriptomes of Ruditapes philippinarum testis and ovaries of control and GnRH suppressed individuals using RNA interference. GnRH suppression caused 112 and 169 enriched KEGG pathways in testis and ovary, with 92 pathways in common in both comparisons. The most enriched KEGG pathways occurred in the "Oxidative phosphorylation", "Dorso-ventral axis formation", "Thyroid hormone synthesis" and "Oxytocin signaling pathway" etc. A total of 1838 genes in testis and 358 genes in ovaries were detected differentially expressed in GnRH suppressed clams. Among the differentially expressed genes, a suit of genes related to regulation of steroid hormones synthesis and gonadal development, were found in both ovary and testis with RNAi of GnRH. These results suggest that GnRH may play an important role in reproductive function in bivalves. This study provides a preliminary basis for studying the function and regulatory mechanism of GnRH in bivalves.

Porcine spermatozoa are stored in the oviductal isthmus after natural mating, and the number of spermatozoa is increased in the oviductal ampulla when the mature cumulus-oocyte complexes (COCs) are transferred into the ampulla. However, the mechanism is unclear. Herein, natriuretic peptide type C (NPPC) was mainly expressed in porcine ampullary epithelial cells, whereas its cognate receptor natriuretic peptide receptor 2 (NPR2) was located on the neck and the midpiece of porcine spermatozoa. NPPC increased sperm motility and intracellular Ca2+ levels, and induced sperm release from oviduct isthmic cell aggregates. These actions of NPPC were blocked by the cyclic guanosine monophosphate (cGMP)-sensitive cyclic nucleotide-gated (CNG) channel inhibitor l-cis-Diltiazem. Moreover, porcine COCs acquired the ability to promote NPPC expression in the ampullary epithelial cells when the immature COCs were induced to maturation by epidermal growth factor (EGF). Simultaneously, transforming growth factor-β ligand 1 (TGFB1) levels were dramatically increased in the cumulus cells of the mature COCs. The addition of TGFB1 promoted NPPC expression in the ampullary epithelial cells, and the mature COC-induced NPPC was blocked by the transforming growth factor-β type 1 receptor (TGFBR1) inhibitor SD208. Taken together, the mature COCs promote NPPC expression in the ampullae via TGF-β signaling, and NPPC is required for the release of porcine spermatozoa from the oviduct isthmic cells.

Currently, research on toxic effects of PCP Na is greatly insufficient. The aim of this study is to explore the toxic effects of PCP-Na for better conducting future work on PCP-Na toxicology. For this purpose, S. constricta adults were exposed to PCP-Na for toxicity testing. The results showed that PCP-Na could easily bioaccumulate in S. constricta and significantly affected both phrase I and II metabolism enzymes. Meanwhile, PCP-Na strongly activated antioxidant system and caused PC, LPO and DNA damage. In addition, neurotoxicity and immunotoxicity of PCP-Na was demonstrated in this study. Interestingly, we observed that PCP-Na significantly affected the expression of genes of electron transport chain and induced key enzymes of glycolysis, indicating that PCP-Na may act as an uncoupler of oxidative phosphorylation, interfering with energy supply and causing energy compensation. This study is the first to fully analyze and provide a new perspective on the toxicity of PCP-Na.

We examined a modified encoder-decoder architecture-based fully convolutional neural network, OrganNet, for simultaneous auto-segmentation of 24 organs at risk (OARs) in the head and neck, followed by validation tests and evaluation of clinical application.Computed tomography (CT) images from 310 radiotherapy plans were used as the experimental data set, of which 260 and 50 were used as the training and test sets, respectively. An improved U-Net architecture was established by introducing a batch normalization layer, residual squeeze-and-excitation layer, and unique organ-specific loss function for deep learning training. The performance of the trained network model was evaluated by comparing the manual-delineation and the STAPLE contour of 10 physicians from different centers.Our model achieved good segmentation in all 24 OARs in nasopharyngeal cancer radiotherapy plan CT images, with an average Dice similarity coefficient of 83.75%. Specifically, the mean Dice coefficients in large-volume organs (brainstem, spinal cord, left/right parotid glands, left/right temporal lobes, and left/right mandibles) were 84.97% - 95.00%, and in small-volume organs (pituitary, lens, optic nerve, and optic chiasma) were 55.46% - 91.56%. respectively. Using the STAPLE contours as standard contour, the OrganNet achieved comparable or better DICE in organ segmentation then that of the manual-delineation as well.The established OrganNet enables simultaneous automatic segmentation of multiple targets on CT images of the head and neck radiotherapy plans, effectively improves the accuracy of U-Net based segmentation for OARs, especially for small-volume organs.

To compare the incidence of xerostomia in nasopharyngeal carcinoma (NPC) patients treated with superficial parotid lobe-sparing intensity-modulated radiation therapy (SPLS-IMRT) and conventional IMRT (C-IMRT).Patients with histologically confirmed NPC who met the eligibility criteria were randomly assigned to receive either SPLS-IMRT or C-IMRT. The primary endpoint was the incidence of xerostomia at 12 months post-IMRT. The secondary endpoints included the xerostomia questionnaire (XQ) score, unstimulated salivary flow rate (USFR), stimulated salivary flow rate (SSFR), and survival outcomes.Ninety patients were enrolled. Eighty-two patients were included for xerostomia analysis (42 in the SPLS-IMRT group and 40 in the C-IMRT group). At 12 months post-IMRT, the incidence of xerostomia in the SPLS-IMRT group was significantly lower than that in the C-IMRT group (83.4% vs 95.0%; P = 0.007), especially the grade 3 xerostomia (0% vs 12.5%; P 0.001). The median change in XQ score was similar between the two groups (11.9 points vs 14.1 points; P = 0.194). There was a significantly higher median fractional USFR (0.67 vs 0.35; P = 0.024) and SSFR (0.66 vs 0.32; P = 0.021) in the SPLS-IMRT group than the C-IMRT group. The 3-year LRRFS, DMFS, and OS in the SPLS-IMRT and C-IMRT groups were 92.5% vs 90.9%, 83.8% vs 81.7%, and 88.9% vs 88.2% (all P 0.05).SPLS-IMRT significantly reduced the incidence of xerostomia at 12 months post-IMRT in NPC by recovering parotid gland function earlier than C-IMRT, without compromising survivals. Phase III clinical trials are warranted. (ClinicalTrials.gov, number NCT05020067).

As a common pollutant in marine environment, benzo[a]pyrene (B[a]P) has high toxicity to economic shellfish. In order to explore the mechanism of oxidative stress and apoptosis, the effects of 0, 2, 4, 8 μg/mL B[a]P on gill cells of C. farreri at 12 and 24 h were studied. The results showed that B[a]P decreased the activity of gill cells, increased the content of reactive oxygen species (ROS) and the expression of antioxidant defense genes. Besides, B[a]P could induce oxidative damage to nucleus and mitochondria. The gene expression and enzyme activity of apoptosis pathway related factors were changed. In conclusion, these results showed that B[a]P could cause oxidative stress and oxidative damage in gill cells of C. farreri, and mediate gill cell apoptosis through mitochondrial pathway and death receptor pathway. This article provides a theoretical basis for clarifying the molecular mechanism of PAHs-included oxidative stress and apoptosis in bivalves.

We conducted a single-arm phase II trial to evaluate the efficacy and adverse effects (AEs) of an anti-epidermal growth factor receptor monoclonal antibody, nimotuzumab, combined with cisplatin and 5-fluorouracil (PF) as first-line treatment in recurrent metastatic nasopharyngeal carcinoma after radical radiotherapy.Patients who met the eligibility criteria were recruited from ten institutions (ClinicalTrials.gov; NCT01616849). A Simon optimal two-stage design was used to calculate the sample size. All patients received weekly nimotuzumab (200 mg) added to cisplatin (100 mg/m2 D1) and 5-fluorouracil (4 g/m2 continuous infusion D1-4) every 3-weekly for a maximum of six cycles. Primary end point was objective response rate (ORR). Secondary end points included disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and AEs.A total of 35 patients were enrolled (13 in stage 1 and 22 in stage 2). Overall ORR and DCR were 71.4% (25/35) and 85.7% (30/35), respectively. Median PFS and OS were 7.0 (95% CI 5.8-8.2) months and 16.3 (95% CI 11.4-21.3) months, respectively. Unplanned exploratory analyses suggest that patients who received ≥2400 mg nimotuzumab and ≥4 cycles of PF had superior ORR, PFS and OS than those who did not (88.9% versus 12.5%, P 0.001; 7.4 versus 2.7 months, P = 0.081; 17.0 versus 8.0 months, P = 0.202). Favourable subgroups included patients with lung metastasis [HROS 0.324 (95% CI 0.146-0.717), P = 0.008] and disease-free interval of12 months [HROS 0.307 (95% CI 0.131-0.724), P = 0.004], but no difference was observed for metastatic burden. The only major grade 3/4 AE was leukopenia (62.9%).Combination nimotuzumab-PF chemotherapy demonstrates potential efficacy, and is well tolerated as first-line chemotherapy regimen in recurrent metastatic nasopharyngeal carcinoma.

ImportanceInduction or adjuvant chemotherapy with concurrent chemoradiotherapy (CCRT) are first-line treatment options for treatment of locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Adjuvant platinum regimens are, however, poorly tolerated, highlighting the unmet need for an efficacious, tolerable adjuvant regimen.ObjectiveTo investigate the efficacy and safety of adjuvant capecitabine with CCRT for the treatment of patients with LA-NPC.Design, Setting, and ParticipantsThis open-label randomized clinical trial recruited patients from March 31, 2014, to July 27, 2018, at 3 institutions in China, with at least 3 years of follow-up. The data collection cutoff date was February 9, 2022. Eligibility included stage III-IVb nasopharyngeal carcinoma and at least 1 of the following: T3-4N2 or T1-4N3; plasma Epstein-Barr virus DNA titer higher than 20 000 copies/mL; primary gross tumor volume larger than 30.0 cm3; fluorodeoxyglucose F 18 positron emission tomography/computed tomography maximum standard uptake value of the primary gross tumor volume larger than 10.0; or multiple nodal metastases and any larger than 4.0 cm.InterventionsPatients were randomly assigned 1:1 to receive either capecitabine (1000 mg/m2 twice daily for 14 days every 3 weeks for 8 cycles) or observation following CCRT (100 mg/m2 cisplatin every 3 weeks for 2 to 3 cycles, depending on duration of radiotherapy).Main Outcomes and MeasuresFailure-free survival in the intention-to-treat cohort was assessed using Kaplan-Meier survival curves compared with the log-rank test. Unstratified Cox proportional hazards regression models were used to estimate hazard ratios, with corresponding 95% CIs based on the Wald test.ResultsThere were 180 patients enrolled (median [IQR] age, 47 [40-55] years; 143 [79.4%] men). Among 90 patients in the capecitabine group, 76 (84.4%) had at least 2 high-risk factors; among 90 patients in the control group, 80 (88.9%) had at least 2 high-risk factors. All patients completed CCRT, except 1 patient in the capecitabine group who received 1 cycle of cisplatin. Of the 90 patients in the capecitabine group, 85 (94.4%) received capecitabine, with 71 (78.9%) completing 8 cycles. With a median (IQR) follow-up of 58.0 (49.5-80.1) months, 18 events were recorded in the capecitabine group vs 31 events in the control group. Failure-free survival was improved with adjuvant capecitabine (3 years, 83.3% vs 72.2%; 5 years, 78.5% vs 65.9%; hazard ratio, 0.53 [95% CI, 0.30-0.94]; P = .03). The incidence of grade 3 treatment-related adverse events (TRAEs) was higher in the capecitabine group than in the control group (54 of 90 patients [60.0%] vs 46 of 90 patients [51.1%]). Treatment-related adverse events included xerostomia (17 [18.9%] vs 9 [10.0%] patients), mucositis (21 [23.3%] vs 15 [16.7%] patients), and anorexia (8 [8.9%] vs 4 [4.4%] patients). The incidence of grade 3 delayed treatment-related adverse events was comparable in both groups (9 of 83 [10.8%] vs 7 of 81 [8.6%] patients).Conclusions and RelevanceIn this randomized clinical trial, adjuvant capecitabine at the full dose following CCRT was well tolerated and improved failure-free survival among patients with LA-NPC and high-risk factors. Further investigations assessing optimal dose and duration are warranted.Trial RegistrationClinicalTrials.gov Identifier: NCT02143388

As a hazardous chemical, p-chloroaniline (PCA) shows intensive adsorption and accumulation after entering the aquatic ecosystem, which can be enriched in organisms and cause damage. With the objective of achieving an integrated and mechanistic view of the toxic effects of PCA in the marine sentinel organism

Reproductive toxicity induced by benzo[a]pyrene (B[a]P) exposure has received great ecotoxicological concerns. However, huge gaps on the molecular mechanism still exist in bivalves. In this study, reproduction-related indicators were investigated in female scallops Chlamys farreri during life cycle of proliferative, growth, mature, and spawn stages, under gradient concentrations of B[a]P at 0, 0.04, 0.4, and 4 μg/L. Meanwhile, a multi-stage ovarian transcriptome analysis under 4 μg/L B[a]P exposure was also conducted to elucidate the potential molecular mechanisms. The results indicated that life-cycle exposure to 0.4 and 4 μg/L B[a]P significantly decreased GSI and sex steroid levels. Even 0.04 μg/L B[a]P could play the adverse role in DNA integrity at the mature and spawn stages. Ovarian histological sections showed that B[a]P inhibited the maturation and release of oocytes. Through the functional enrichment analysis of differentially expressed genes (DEGs) from transcriptome data, 18 genes involved in endocrine disruption effects, DNA damage and repair, and oogenesis were selected and further determined by qRT-PCR. The downregulation of genes involved in steroidogenic and estrogen signaling pathways indicated that B[a]P could cause endocrine disruption through both receptor-dependent and receptor-independent pathways. The variations of gene expressions involved in DNA single-strand break and repair implied the presence of toxic mechanisms similar with vertebrates. Additionally, the changes of gene expressions of cell cycle, apoptosis, and cell adhesion suggested that exposure to B[a]P possibly caused the reproductive toxicity effects by affecting oogenesis. Taken together, this study was a pioneer in combining genome-wide transcriptomic analysis with its corresponding reproductive indicators (GSI, sex steroid levels, DNA single-strand break, and histological sections) to explore the bivalves' toxic mechanisms under B[a]P exposure. Meanwhile, some genes involved in estrogen signaling pathway and DNA damage were firstly analyzed in bivalves, and the expression data might be useful in establishing new hypotheses and discovering new biomarkers for marine biomonitoring.

The gut tissue interacts with nutrients and pollutants which can impact gut health. Gut microbiota is essential to the host health, but is also easily affected by external environment. However, little is known about the toxicological assessment of environmental contaminants on gut health and microbiota, especially in marine invertebrates. In this study, we first explored the effect of benzo(a)pyrene (BaP) on the gut health and gut microbiota of scallops (Chlamys farreri). The scallops were exposed to different concentrations (0, 0.4, 2 and 10 μg/L) of BaP for 21 days. The histological morphology, immune- and oxidative enzyme-related gene expression, and lipid peroxidation of the scallops were analyzed at 7, 14 and 21 days. The results revealed that BaP could impair intestinal barrier function, increasing the intestinal permeability of scallops. Moreover, immune and antioxidant responses were induced in the gut tissue. After a 21-day exposure to different concentrations of BaP, the intestinal microbial community was analyzed based on 16S rRNA sequencing. Our results suggested that BaP exposure altered the gut microbial diversity and composition in scallops. Many beneficial genera declined after BaP treatment, while the potential pathogens were increased, such as Mycoplasma and Tenacibaculum. A series of hydrocarbon-degrading bacteria were recognized in BaP-treated groups, such as Pseudomonas, Polaribacter, Amphritea and Kordiimonas. Interestingly, the degrading bacteria present varied after exposure to different concentrations of BaP. Overall, this study provides new insights into gut health and gut microbiota in marine invertebrates following exposure to persistent organic pollutants.

Butyl acrylate is a hazardous and noxious substance (HNS) listed in the top 50 chemicals that is most likely to be involved in HNS spilling incident. At present, information about toxicity effect of butyl acrylate on marine organisms was insufficient, especially on marine microalgae. Phaeodactylum tricornutum (P. tricornutum) and Platymonas subcordiformis (P. subcordiformis) were used as test organism to evaluate the toxic effect of butyl acrylate on their photosynthetic system. Results showed that chlorophyll a (Chl-a) content, the net photosynthetic oxygen evolution rate (NOR), and chlorophyll fluorescence parameters including maximal photochemical efficiency (Fv/Fm), electron transfer rate (ETR), photochemical quenching (qP), and non-photochemical quenching (NPQ) were all stimulated in the toxic dose of 5,10, and 25 mg/L while those were significantly inhibited in the highest concentration of 25 mg/L groups after 96 h. Meanwhile, it was also found that Fv/Fm would be a suitable indicator for evaluating the toxicity of butyl acrylate on the photosynthetic system of two marine microalgae according to the analysis of Pearson correlation coefficient and integrated biomarker response (IBR). Once butyl acrylate enters the marine ecosystem, the toxicity data obtained in this study could be used as a reference for evaluating the effect of butyl acrylate on the photosynthetic capacity of marine microalgae.

Objectives We aimed to build a survival system by combining a highly-accurate machine learning (ML) model with explainable artificial intelligence (AI) techniques to predict distant metastasis in locoregionally advanced nasopharyngeal carcinoma (NPC) patients using magnetic resonance imaging (MRI)-based tumor burden features. Materials and methods 1643 patients from three hospitals were enrolled according to set criteria. We employed ML to develop a survival model based on tumor burden signatures and all clinical factors. Shapley Additive exPlanations (SHAP) was utilized to explain prediction results and interpret the complex non-linear relationship among features and distant metastasis. We also constructed other models based on routinely used cancer stages, Epstein-Barr virus (EBV) DNA, or other clinical features for comparison. Concordance index (C-index), receiver operating curve (ROC) analysis and decision curve analysis (DCA) were executed to assess the effectiveness of the models. Results Our proposed system consistently demonstrated promising performance across independent cohorts. The concordance indexes were 0.773, 0.766 and 0.760 in the training, internal validation and external validation sets. SHAP provided personalized protective and risk factors for each NPC patient and uncovered some novel non-linear relationships between features and distant metastasis. Furthermore, high-risk patients who received induction chemotherapy (ICT) and concurrent chemoradiotherapy (CCRT) had better 5-year distant metastasis-free survival (DMFS) than those who only received CCRT, whereas ICT + CCRT and CCRT had similar DMFS in low-risk patients. Conclusions The interpretable machine learning system demonstrated superior performance in predicting metastasis in locoregionally advanced NPC. High-risk patients might benefit from ICT.

Purpose: Previous studies suggest that a cumulative cisplatin dose of 200 mg/m2 might be adequate in the intensity-modulated radiation therapy (IMRT) era for locoregionally advanced nasopharyngeal carcinoma (LANPC). However, two cycles of once-every-3-weeks cisplatin at 100 mg/m2 has never been prospectively compared with standard once-a-week cisplatin regimen. Patients and Methods: This trial was conducted at three hospitals from 2011 to 2016. Patients who met the eligibility criteria were recruited (ChiCTR-TRC-12001979) and randomly assigned (1:1) via a computer-generated sequence to receive once-every-3-weeks cisplatin at 100 mg/m2 for two cycles or once-a-week cisplatin at 40 mg/m2 for six cycles concurrently with IMRT. Primary endpoint was failure-free survival and between-group absolute difference of 10% as the noninferiority margin. Results: A total of 510 patients were enrolled. Median follow-up time was 58.3 months with 85.4% of 3-year failure-free survival in the once-every-3-weeks group and 85.6% in the once-a-week group. An absolute difference of −0.2% (95% confidence interval, −6.3 to 5.9; Pnoninferiority = 0.0016). Acute toxicities of grade 3 or higher occurred in 55.8% in the once-every-3-weeks group and 66.3% in the once-a-week group (P = 0.015). The most common acute toxicities were hematologic abnormalities, including leukopenia (16% vs. 27%; P = 0.0022) and thrombocytopenia (1% vs. 5%; P = 0.015). The late grade 3–4 auditory loss rate was significantly lower in the once-every-3-weeks group than the once-a-week group (6% vs. 13%; P = 0.0039). Conclusions: Once-every-3-weeks cisplatin as concurrent chemoradiotherapy is noninferior to once-a-week cisplatin in the treatment efficacy in the LANPC. Although both regimens are well tolerated, severe acute toxicities and late-onset auditory loss are higher in the once-a-week group.

Summary 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/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1–5 and 22–26 for two cycles) or cisplatin-based (cisplatin 100 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1–5 and 22–26 for two cycles) induction chemotherapy, followed by concurrent lobaplatin-based (two cycles of intravenous lobaplatin 30 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) or cisplatin-based (two cycles of intravenous cisplatin 100 mg/m2 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; pnon-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; pnon-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.

Purpose: To explore the efficacy of concomitant chemotherapy in intensity-modulated radiotherapy (IMRT) to treat stage II nasopharyngeal carcinoma (NPC). Methods and Materials: In this randomized phase 2 study [registered with ClinicalTrials.gov (NCT01187238)], eligible patients with stage II (2010 UICC/AJCC) NPC were randomly assigned to either IMRT alone (RT group) or IMRT combined with concurrent cisplatin (40 mg/m2, weekly) (CCRT group). The primary endpoint was overall survival (OS). The second endpoints included local failure-free survival (LFFS), regional failure-free survival (RFFS), disease-free survival (DFS), distant metastasis-free survival (DMFS), and acute toxicities. Results: Between May 2010 to July 2012, 84 patients who met the criteria were randomized to the RT group (n = 43) or the CCRT group (n = 41). The median follow-up time was 75 months. The OS, LFFS, RFFS, DFS, and DMFS for the RT group and CCRT group were 100% vs. 94.0% (p = 0.25), 93.0% vs. 89.3% (p = 0.79), 97.7% vs. 95.1% (p = 0.54), 90.4% vs. 86.6% (p = 0.72), and 95.2% vs. 94.5% (p = 0.77), respectively. A total of 14 patients experienced disease failure, 7 patients in each group. The incidence of grade 2 to 4 leukopenia was higher in the CCRT group (p = 0.022). No significant differences in liver, renal, skin, or mucosal toxicity was observed between the two groups. Conclusion: For patients with stage II NPC, concomitant chemotherapy with IMRT did not improve survival or disease control but had a detrimental effect on bone marrow function.

Background To analyse the survival and late toxicities of elderly nasopharyngeal carcinoma (NPC) patients treated by intensity-modulated radiotherapy (IMRT) with the high-total- and fractionated-dose simultaneous modulated accelerated radiation therapy (SMART) boost technique and to identify the effect of concurrent chemotherapy for these patients. Methods Two hundred and fifty-four elderly patients (age ≥ 60.0) with newly diagnosed non-metastatic NPC were retrospectively analysed. Statistical analyses were performed using the SPSS software program. Results The actual mean total and fractionated doses delivered to the gross tumour volume of the nasopharynx (GTVnx) were 74.55 Gy and 2.49 Gy, respectively. The 5-year locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), disease-specific survival (DSS) and overall survival (OS) of the whole cohort were 93.0%, 85.7%, 83.2% and 74.1%, respectively. No grade 4 acute or late radiotherapy-induced toxicities were observed. Of 247 patients with stage II–IVb disease, 89 patients received radiotherapy (RT) alone, and 158 patients received concurrent chemoradiotherapy (CCRT), and the 5-year LRRFS, DMFS, DSS and OS of the RT-alone group vs. the CCRT group were 94.0% vs. 92.2%, 83.5% vs. 86.2%, 81.8% vs. 83.1% and 74.0% vs. 72.8% (all P > 0.05), respectively. Multivariate analyses showed that CCRT was not an independent predictor for LRRFS, DMFS, DSS and OS (all P > 0.05). Conclusion High-total- and fractionated-dose SMART boost IMRT could obtain a satisfactory long-term outcome with mild late toxicity in elderly NPC patients. The role of CCRT needs to be further studied to optimize the treatment strategy and improve the overall survival.