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Abstract To evaluate the dosimetric benefits and clinical feasibility of deep inspiratory breath-hold (DIBH) combined with volumetric modulated arc therapy (VMAT) in left-sided postmastectomy radiotherapy (PMRT). Eligible patients with left-sided breast cancer undergoing DIBH-based PMRT were prospectively included. Chest wall, supra/infraclavicular fossa, and/or internal mammary node irradiation (IMNI) were planned with a prescription dose of 43.5 Gy in 15 fractions. VMAT plans were designed on free breathing (FB)—and DIBH-CT to compare dosimetric parameters in heart, left anterior descending artery (LAD) and lung. Cone-beam computed tomography (CBCT) was performed before and after treatment to evaluate inter- and intra-fractional setup errors. Heart position and dose variations during treatment were estimated by fusing CBCT with DIBH-CT scans.Twenty patients were included with 10 receiving IMNI. In total, 193 pre-treatment and 39 pairs pre- and post-treatment CBCT scans were analyzed. The Dmean, Dmax, and V5−40 of the heart, LAD, and left lung were significantly lower in DIBH than FB (p

To evaluate a novel technique for six-point scleral fixation of a three-looped haptics posterior chamber intraocular lens (PCIOL) by a single suture. Nine eyes of nine patients were studied from September 2021 to March 2023. All patients had undergone vitrectomy. Only a single 9-0 polypropylene suture was used for scleral fixation. The three looped haptics were fixed at 12, 4, and 8 o'clock with six-point scleral fixation. The entire procedure took about 30 min. Among the nine patients, eight (88.8%) eyes had a significant improvement in best-corrected visual acuity, whereas one (11.2%) eye showed no change. No intraoperative or postoperative complications were observed. By ultrasonic biomicroscopy examination, intraocular lenses were well positioned and stable with no tilt in the horizontal and vertical axis. The method of six-point scleral fixation of a three-looped haptics PCIOL by a single suture is safe and effective.

This paper introduces a hybrid readout system for a cross-strip position-sensitive anode detector that combines a lookup table and weighted averaging. The lookup table approach is used to identify event channels and select appropriate weights based on the corresponding index code for calculating the centroid of the electron cloud. This effectively enhances the readout system’s processing speed while preserving the high-resolution advantage of the cross-strip position-sensitive anode. Simulations were performed to evaluate the performance of the system. Experimental results demonstrate that this readout method achieves an event processing speed exceeding 10 MHz while maintaining a resolution of 17.96 lp/mm.

Fe–TiB2 composite shows great potential in lightweight materials for automotive parts due to its lightweight, high strength and high specific modulus etc. However, challenges remain with regard to establishing a fine hot working process of Fe–TiB2 composites. Here, a series of isothermal hot compression tests was conducted to systematically investigate the microstructure evolution and the dynamic recrystallization (DRX) mechanisms of as-cast Fe–TiB2 composites at different sets of hot deformation parameters. The results indicate the true stress drops more significantly after reaching its peak at low temperatures compared to high temperatures, since low temperatures favors the DRX through particle stimulated nucleation (PSN) in Fe–TiB2 composites, as featured by layers of DRXed grains surrounding TiB2 particles. Continuous dynamic recrystallization (CDRX) process gradually dominates as strain rate increase from 0.01 s−1 to 1 s−1 in Fe–TiB2 composites hot compressed to the true strain of 0.69 at 900 °C, as evidenced by the presence of DRXed grains with larger size and uniform distribution in matrix. DRX through PSN is the primary DRX mechanism at low temperature and low strain rate, while CDRX dominates the DRX mechanism at high temperature and high strain rate. Both DRX behaviors deepen with the increase of the strain. Different hot deformation parameters favor different DRX mechanisms. The increase in temperature and strain rate leads to a transition of the dominant recrystallization mechanism from the DRX through PSN to CDRX which is attributed to the competition for stored energy between the DRX through PSN and CDRX process.

Objectives: To investigate the prognostic capacity of baseline 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) metabolic parameters in extranodal natural killer/T-cell lymphoma (ENKTCL), and the influence of relative thresholds (RT) and absolute thresholds (AT) selection on prognostic capacity. Materials and methods: Metabolic tumor volume (MTV)-based parameters were defined using RTs (41 % or 25 % of maximum standardized uptake value [SUVmax]), ATs (SUV 2.5, 3.0, 4.0, or mean liver uptake) in 133 patients. Metabolic parameters were classified into avidity-related parameters (SUVmax, mean SUV [SUVmean], standard deviation of SUV [SUVsd]), volume-related parameters (RT-MTV), and avidity- and volume-related parameters (total lesion glycolysis [TLG] and AT-MTV). The prognostic capacity of the metabolic parameters and the effects of different threshold types (RT vs. AT) were evaluated. Results: All metabolic parameters were moderately associated with prognosis. However, the area under the receiver operating characteristic curve of MTV and TLG was slightly higher than that of avidity-related parameters for predicting 5-year progression-free survival (PFS) (0.614–0.705 vs. 0.563–0.609) and overall survival (OS) (0.670–0.748 vs. 0.562–0.593). Correlations of MTV and avidity-related parameters differed between RTs (r

Abstract This study aimed to predict the 5‐year overall survival (OS) benefit of pola‐R‐CHP versus R‐CHOP in the POLARIX trial based on the 2‐year event‐free survival (EFS) and progression‐free survival (PFS) rates in diffuse large B‐cell lymphoma (DLBCL). We identified randomized controlled trials (RCT) published before 31 May 2023. The correlation between the logarithmic (log) hazard ratio (HR) for EFS (HREFS) or PFS (HRPFS) and the HR for OS (HROS) was estimated at the trial‐level. Correlation analysis was performed between 2‐year PFS or EFS and 5‐year OS rates at the treatment arm‐level. Linear regression models were used to calculate the 5‐year OS of pola‐R‐CHP and R‐CHOP. In the included 20 RCTs, a linear correlation between HREFS (r = 0.765) or HRPFS (r = 0.534) and HROS was observed at the trial‐ level. Two‐year EFS (r = 0.918) or 2‐year PFS (r = 0.865) correlated linearly with 5‐year OS. Linear regression analysis between 2‐year EFS/PFS and 5‐year OS gave estimated 5‐year OS rates between pola‐R‐CHP and R‐CHOP of 6.4% and 6.3%, respectively. Two‐year EFS and PFS are feasible early endpoints in patients with DLBCL treated primarily with immunochemotherapy. The pola‐R‐CHP regimen is expected to improve 5‐year OS.

Background Recently, with the rapid development of the perinatal medical system and related life-saving techniques, both the short-term and long-term prognoses of extremely preterm infants (EPIs) have improved significantly. In rapidly industrialising countries like China, the survival rates of EPIs have notably increased due to the swift socioeconomic development. However, there is still a reasonably lower positive response towards the treatment of EPIs than we expected, and the current situation of withdrawing care is an urgent task for perinatal medical practitioners.Objective To develop and validate a model that is practicable for EPIs as soon as possible after birth by regression analysis, to assess the risk of mortality and chance of survival.Methods This multicentre prospective cohort study used datasets from the Sino-Northern Neonatal Network, including 46 neonatal intensive care units (NICUs). Risk factors including maternal and neonatal variables were collected within 1 hour post-childbirth. The training set consisted of data from 41 NICUs located within the Shandong Province of China, while the validation set included data from 5 NICUs outside Shandong Province. A total of 1363 neonates were included in the study.Results Gestational age, birth weight, pH and lactic acid in blood gas analysis within the first hour of birth, moderate-to-severe hypothermia on admission and adequate antenatal corticosteroids were influencing factors for EPIs’ mortality with important predictive ability. The area under the curve values for internal validation of our prediction model and Clinical Risk Index for Babies-II scores were 0.81 and 0.76, and for external validation, 0.80 and 0.51, respectively. Moreover, the Hosmer-Lemeshow test showed that our model has a constant degree of calibration.Conclusions There was good predictive accuracy for mortality of EPIs based on influencing factors prenatally and within 1 hour after delivery. Predicting the risk of mortality of EPIs as soon as possible after birth can effectively guide parents to be proactive in treating more EPIs with life-saving value.Trial registration number ChiCTR1900025234.

ObjectiveTo investigate the impact of optimized thrombus aspiration on myocardial perfusion, prognosis, and safety in patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention(primary PCI).MethodsA total of 129 patients with STEMI were randomly allocated into control group (Subgroup A and B) and experimental group(Subgroup C and D). Control group received percutaneous transluminal coronary angioplasty (PTCA),thrombus aspiration and primary PCI. Experimental group received optimized thrombus aspiration and primary PCI. The number of thrombus aspiration was less than 4 times in Subgroup A and C. The number of thrombus aspiration was performed more than 4 times in Subgroups B and D. The classification of thrombi extracted, the TIMI flow grade, the incidence of no-reflow and slow flow, cTFC, TPI and CK-MB at 12 h and 24 h after stenting, ST segment resolution of ECG after stenting, NT-proBNP, LVEFat 24 h, 30 days and 180 days after stenting were compared between groups. The incidence of intraoperative and postoperative bleeding complications, stroke events and major cardiovascular events (MACE) were recorded and compared between groups.ResultsThe classification of thrombi extracted in the experimental group was higher than that in the control group. The TIMI flow grade of the experimental group was better than the control group after thrombus aspiration. After stenting, the advantage still existed, but the difference was not statistically significant. On cTFC, the experimental group was lower than the control group, but the difference was not statistically significant; After stenting the experimental group was significantly lower than the control group. The CK-MB at 12 h and 24 h of the experimental group was lower than the control group. After thrombus aspiration the incidence of no-reflow in the experimental group was significantly lower than that in the control group; after stenting the incidence of no-reflow in the experimental group was still lower than the control group, but no statistically difference. After thrombus aspiration and stenting the incidence of slow flow in the experimental group were lower than that in the control group. After stenting, NT-proBNP at 24 h was lower in the experimental group than that in the control group, However, there was no statistical difference; after stenting, The NT-proBNP in the experimental group was lower than that in the control group at 30 days and 180 days. After stenting, LVEF of the experimental group was significantly higher than the control group at 24 h and 30 days; superiority remained after 180 days but no statistical difference. There was no statistical difference between two groups for intraoperative and postoperative bleeding complications, stroke events, and MACE events. In Subgroup analysis,there was no significant difference in the classification of thrombi extracted, TIMI flow grade, cTFC, CK-MB,NT-proBNP and LVEF between group C and D, but group A was better than group B. Analysis of variance showed that the optimal number of suction was 4–5 times.ConclusionsOptimized thrombus aspiration can significantly improve myocardial perfusion and short-term and medium-term prognosis of STEMI patients after PCI, and reduce the incidence of slow flow and no-reflow. The optimal suction times were 4–5 times. Traditional aspiration method with more aspiration times is harmful to cardiac prognosis. Thrombus aspiration does not increase the incidence of stroke events and is safe.Clinical Trial Registration: identifier, ChiCTR2300073410.

AIM: To observe the long-term clinical efficacy of intravitreal injections of conbercept, a novel vascular growth factor inhibitor, for the treatment of pathological myopia choroidal neovascularization (PM-CNV). METHODS: A total of 67 eyes (from 67 patients; mean age, 54.90±12.7y) with PM-CNV were retrospectively researched. Based on the different schemes used for the administration of the drug, the patients were divided into two groups: group A (n=35; average age, 53.31±13.6y; average diopter, 9.25±1.72 D), which received only one injection of pro re nata (PRN; 1+PRN regimen), and group B (n=32; average age, 56.49±11.8y; average diopter, 9.63±2.24 D), which received one injection per month for 3mo (3+PRN regimen). Best-corrected visual acuity (BCVA) analysis, intraocular pressure (IOP) examination, slit-lamp microscopy, fundus examination and optical coherence tomography were performed at each follow-up. The recurrence and treatment times of CNV were recorded. The patients were followed up for at least 12mo. RESULTS: The BCVA was increased in 29 eyes (82.9%) in group A and 30 eyes (93.75%) in group B; no increase or decrease was observed in 6 (17.1%) and 2 (6.25%) eyes in groups A and B, respectively. The BCVA (logMAR) values before treatment (0.67±0.48 and 0.71±0.56) were significantly higher than those 12mo after treatment (0.31±0.26 and 0.33±0.17) in groups A and B, respectively (P

Low carbon transition strategies of power plants are crucial to meet China’s ‘Dual Carbon’ targets. While the Beijing–Tianjin–Hebei (BTH) region, the ‘capital economic circles’ of China, is suffering from serious air pollution, air quality co-benefits of low carbon transition policies in electricity system in BTH area remain unclear. Here, we estimate the impacts of low carbon transition policies, including one BAU, six single and five combined scenarios, in electricity system in BTH area on installed power capacity, CO _2 emissions, air quality and human health through 2060 based on open source energy modeling system and extend response surface model ERSM models. Results show that the total installed capacity under single and combined scenarios (except RE and Tech single scenarios) fluctuates around the BAU level of 310.5 GW in 2060. While all single and combined scenarios would generally achieve ‘carbon peak’ in BTH electricity system before 2030, only S4 (combining technological progress, renewable energy development and CCUS) and S5 (in additional to S4, including gas-fired power generation instead of coal-fired power generation) scenarios have the potential to realize carbon neutrality by 2060. The magnitude of reductions in air pollutant emissions and improvement in air quality in BTH area from the BAU level in 2060 under combined scenarios, especially S4 and S5, generally exceed that of six single scenarios. Importantly, S5 in 2060 contributes to about 8528 avoided premature mortalities in BTH area, which are more effective than any other scenarios. The results suggest that S5 is a promising low carbon transition policy to achieve environmental improvement and produce health benefits.

The radiation impedance is an essential parameter in analyzing the vibroacoustic response of the planar source. In order to calculate the acoustic radiation impedance of the rectangular plate with arbitrary boundary conditions, a unified approximate approach is proposed in this study. The displacement function of the plate is expressed in the form of a supplemented two-dimensional Fourier cosine series, which can be solved by the Rayleigh–Ritz method. The radiated acoustic field from the plate is further determined by the Rayleigh integrals. The coordinate transformation is performed twice to convert the quadruple integrals into simple integrals, significantly reducing the computational effort of the acoustic calculation. Regardless of the wavenumber or frequency, the proposed approach is theoretically accurate because no assumptions or approximations are involved in the mathematical process. Furthermore, the correctness of the formulas is validated by the results obtained from previous studies. Several numerical examples are performed using this approach, and the effects of boundary conditions on the modal radiation impedance are discussed.

Abstract Background The role of skeletal muscle index (SMI) and systemic inflammation index (SII) for patients with lymph node-positive breast cancer remain controversial. This retrospective study aims to evaluate the individual and synergistic value of SMI and SII in outcomes prediction in this population. Methods Lymph node-positive breast cancer patients who received mastectomy between January 2011 and February 2013 were included in this retrospective study. We used abdominal computed tomography (CT) to measure skeletal muscle mass at the third lumbar (L3) level. The optimal cut-off values of SMI and SII were determined through maximizing the Youden index on the receiver operating characteristic (ROC) curves. Kaplan–Meier method was used to assess the correlation between SMI, SII, and overall survival (OS). The prognostic value of SMI and SII were analyzed with the multivariable Cox proportional hazards model. Results Of 97 patients included in our study (mean age: 46 [range: 27–73] years; median follow-up: 62.5 months), 71 had low SMI (sarcopenia), 59 had low SII, and 56 had low SMI + SII. Kaplan–Meier survival curves showed that both high SMI (P = 0.021, 5-year OS: 84.0% vs. 94.1%) and high SII (P = 0.043, 5-year OS: 81.0% vs. 97.3%) were associated with worse OS. Additionally, patients with either low SMI or low SII had significantly better OS (P = 0.0059, 5-year OS: 100.0% vs. 84.6%) than those with high SMI + SII. Multivariable analysis confirmed the predictive values of high SMI (P = 0.024, hazard ratio [HR]: 9.87) and high SII (P = 0.048, HR: 6.87) for poor OS. Moreover, high SMI + SII was significantly associated with poor survival (P = 0.016, HR: 16.36). Conclusions In this retrospective analysis, both SMI and SII independently predicted the prognosis of patients with lymph node-positive breast cancer. SMI + SII might be a stronger prognostic factor than either alone based on our findings, but should be further verified in a larger study.

The synthesis of 2-aminoquinazoline derivatives is achieved by using hydrochloric acid as a mediator in the [4+2] annulation reaction between N-benzyl cyanamides and 2-amino aryl ketones. In addition, 2-amino-4-iminoquinazolines are synthesized by the reaction of 2-aminobenzonitriles, instead of 2-amino aryl ketones, with N-benzyl cyanamides. A wide range of substrates can be used and high yields are obtained, demonstrating the practicality of this method for the synthesis of 2-aminoquinazoline derivatives.

The coexistence of chronic pain and anxiety is a common clinical phenomenon. Here, the role of tachykinin receptor 3 (NK3R) in the lateral habenula (LHb) in trigeminal neuralgia and in pain-associated anxiety was systematically investigated. First, electrophysiological recording showed that bilateral LHb neurons are hyperactive in a mouse model of trigeminal neuralgia made by partial transection of the infraorbital nerve (pT-ION). Chemicogenetic activation of bilateral LHb glutamatergic neurons in naive mice induced orofacial allodynia and anxiety-like behaviors, and pharmacological activation of NK3R in the LHb attenuated allodynia and anxiety-like behaviors induced by pT-ION. Electrophysiological recording showed that pharmacological activation of NK3R suppressed the abnormal excitation of LHb neurons. In parallel, pharmacological inhibition of NK3R induced orofacial allodynia and anxiety-like behavior in naive mice. The electrophysiological recording showed that pharmacological inhibition of NK3R activates LHb neurons. Neurokinin B (NKB) is an endogenous high-affinity ligand of NK3R, which binds NK3R and activates it to perform physiological functions, and further neuron projection tracing showed that the front section of the periaqueductal gray (fPAG) projects NKB-positive nerve fibers to the LHb. Optogenetics combined with electrophysiology recordings characterize the functional connections in this fPAG NKB → LHb pathway. In addition, electrophysiological recording showed that NKB-positive neurons in the fPAG were more active than NKB-negative neurons in pT-ION mice. Finally, inhibition of NKB release from the fPAG reversed the analgesic and anxiolytic effects of LHb Tacr3 overexpression in pT-ION mice, indicating that fPAG NKB → LHb regulates orofacial allodynia and pain-induced anxious behaviors. These findings for NK3R suggest the cellular mechanism behind pT-ION in the LHb and suggest that the fPAG NKB → LHb circuit is involved in pain and anxiety comorbidity. This previously unrecognized pathway might provide a potential approach for relieving the pain and anxiety associated with trigeminal neuralgia by targeting NK3R.

Abstract Background Malignant melanoma of the female genital tract is relatively uncommon and accounts for 3–7% of all melanoma localizations. This study aimed to identify driver genes in melanoma of the female genital tract with the purpose of enhancing understanding of disease pathogenesis and identifying potential new therapeutic targets to develop effective therapies. Methods KIT (CD117) and BRAF expression were detected immunohistochemically. Polymerase Chain Reaction (PCR) and Sanger sequencing techniques were performed to identify the mutational status of BRAF, NRAS, KRAS, NF1, KIT, PDGFRA and SF3B1 on 19 melanomas of the female genital tract, paired with 25 cutaneous melanomas, 18 acral melanomas and 11 melanomas of nasal cavity. Results Somatic variant analysis identified KRAS (6/19; 32%) as the most commonly mutated gene, followed by KIT (4/19; 21%), SF3B1 (3/19; 16%) and NRAS (1/19; 5%). None of the cases were found to harbor BRAF, NF1 and PDGFRA mutations in melanomas of the female genital tract. However, none of the cases were found to harbor SF3B1 and KIT mutations in cutaneous melanomas, acral melanomas and melanomas of nasal cavity. Recurrent KIT mutations, as well as mutations in the less frequently mutated genes NRAS and SF3B1, were exclusively detected in vulvovaginal melanomas, but not in tumors arising in the cervix. However, recurrent KRAS mutations were detected in similar frequencies in tumors of the vulva, vagina, and cervix. Additionally, recurrent KRAS and KIT mutations occurred predominantly in polygonal and epithelioid cell types of melanoma in the female genital tract. Immunohistochemistry revealed moderate or strong cytoplasmic CD117 expression in 6 of the 19 cases (31.6%). Conclusions We observed that gynecologic melanoma harbored distinct mutation rates in the KIT, BRAF, SF3B1, KRAS, and NRAS genes. Our findings support the notion that gynecologic melanoma is a distinct entity from non-gynecologic melanoma, and these findings offer insights into future therapeutic options for these patients.

When primary angle-closure glaucoma occurs during an acute attack, routine phacoemulsification is challenging because of the high intra-ocular pressure (IOP) and shallow anterior chamber (AC). To reduce IOP and deepen the AC before phacoemulsification, a portion of the vitreous body is often removed. In this report, we introduce an extended trocar/cannula system with lateral micropores to drain the liquid vitreous before routine phacoemulsification to solve this problem. A modified trocar was used to drain the liquefied vitreous before routine phacoemulsification. We demonstrated that this novel trocar/cannula system is safe and effective for draining liquefied vitreous before routine phacoemulsification. It also facilitates the transition to smooth phacoemulsification.

Abstract Background Ocular toxoplasmosis caused by Toxoplasma gondii is an infectious disease which is widely distributed around the world and can present with various clinic manifestations. We are here reporting an unusual case presented with epiretinal membrane (ERM), i.e., macular pucker. Case presentation A 16-year old male patient visited our outpatient clinic complaining of decreased vision for about 8 years in his left eye. The best-corrected visual acuity (BCVA) was 20/20 OD and 20/400 OS. There was sensory exotropia in his left eye. No inflammatory cells or flare were found in his anterior chamber or vitreous cavity OU. An ERM involving his left macular area was found on his dilated fundus exam, which was confirmed by Optical Coherence Tomography (OCT). The ERM was found to involve his left macular area with his foveal ellipsoid zone absent. The right eye was found to be within normal limit. After a thorough discussion with the patient and his parents about treatment options and surgical benefits, risks and alternatives, we performed vitrectomy, peeled off the ERM and collected the vitreous sample for parasite testing during the procedure. Patient’s blood also was drawn for serological testing. Vitreous sample analysis and serological tests confirmed ocular toxoplasmosis OS as his final diagnosis. Unfortunately, the BCVA of this patient was not improved after the surgery, but the exotropia disappeared. Conclusion ERM is an unusual clinical presentation of ocular toxoplasmosis. We may add Toxoplasma gondii infection as a differential diagnosis when encountering ERM cases.

Purpose: To evaluate the effect of the 21-gene recurrence score (RS) assay in breast cancer-specific mortality (BCSM) and decision-making for chemotherapy in older (aged ≥65 years) breast cancer. Methods: We retrospectively included older patients with T1-2N0 and estrogen receptor-positive breast cancer in the Surveillance, Epidemiology, and End Results database. Cox regression model and competing-risks model were used for data analysis. Results: This study included 8524 patients, 1987 (23.3%) had low RS, 5059 (59.4%) had intermediate RS, and 1478 (17.3%) had high RS. Chemotherapy was administrated in 2.0%, 8.6%, and 51.2% for low, intermediate, and high RS cohorts, respectively (P

Abstract The management of metaplastic breast carcinoma (MBC) has largely paralleled the paradigms used for invasive ductal carcinoma (IDC) in the current National Comprehensive Cancer Network guidelines of breast cancer. However, patients with IDC and MBC have been shown to have a different prognosis, and there are significant differences in risk and failure patterns after treatment. The purpose of this study was to compare breast cancer specific survival (BCSS) and hazard function between IDC and MBC. We included patients from the Surveillance, Epidemiology, and End Results program with stage I-III IDC and MBC between 2000 and 2012. Statistical analyses were including chi-square analysis, life-table methods, multivariate Cox proportional hazards models, and propensity score matching (PSM). We identified 294,719 patients; 293,199 patients with IDC and 1520 patients with MBC. Multivariate analyses showed that the MBC subtype had significantly lower BCSS than the IDC subtype before and after PSM (p

Abstract Trigeminal neuralgia (TN) is debilitating and is usually accompanied by mood disorders. The lateral habenula (LHb) is considered to be involved in the modulation of pain and mood disorders, and the present study aimed to determine if and how the LHb participates in the development of pain and anxiety in TN. To address this issue, a mouse model of partial transection of the infraorbital nerve (pT-ION) was established. pT-ION induced stable and long-lasting primary and secondary orofacial allodynia and anxiety-like behaviors that correlated with the increased excitability of LHb neurons. Adeno-associated virus (AAV)-mediated expression of hM4D(Gi) in glutamatergic neurons of the unilateral LHb followed by clozapine-N-oxide application relieved pT-ION-induced anxiety-like behaviors but not allodynia. Immunofluorescence validated the successful infection of AAV in the LHb, and microarray analysis showed changes in gene expression in the LHb of mice showing allodynia and anxiety-like behaviors after pT-ION. Among these differentially expressed genes was Tacr3, the downregulation of which was validated by RT-qPCR. Rescuing the downregulation of Tacr3 by AAV-mediated Tacr3 overexpression in the unilateral LHb significantly reversed pT-ION-induced anxiety-like behaviors but not allodynia. Whole-cell patch clamp recording showed that Tacr3 overexpression suppressed nerve injury-induced hyperexcitation of LHb neurons, and western blotting showed that the pT-ION-induced upregulation of p-CaMKII was reversed by AAV-mediated Tacr3 overexpression or chemicogenetic inhibition of glutamatergic neurons in the LHb. Moreover, not only anxiety-like behaviors, but also allodynia after pT-ION were significantly alleviated by chemicogenetic inhibition of bilateral LHb neurons or by bilateral Tacr3 overexpression in the LHb. In conclusion, Tacr3 in the LHb plays a protective role in treating trigeminal nerve injury-induced allodynia and anxiety-like behaviors by suppressing the hyperexcitability of LHb neurons. These findings provide a rationale for suppressing unilateral or bilateral LHb activity by targeting Tacr3 in treating the anxiety and pain associated with TN.

Ca2+/calmodulin-stimulated group I adenylyl cyclase (AC) isoforms AC1 and AC8 have been involved in nociceptive processing and morphine responses. However, whether AC3, another member of group I ACs, is involved in nociceptive transmission and regulates opioid receptor signaling remains elusive. Here, we report that conditional KO of AC3 (AC3 CKO) in L3 and L4 DRGs robustly facilitated the mouse nociceptive responses, decreased voltage-gated potassium (Kv) channel currents, and increased neuronal excitability. Furthermore, we report AC3 CKO eliminated the analgesic effect of κ-opioid receptor (KOR) agonist and its inhibition on Kv channel by classical Gαi/o signaling or nonclassical direct interaction of KOR and AC3 proteins. Interestingly, significantly upregulated AC1 level and cAMP concentration were detected in AC3-deficient DRGs. Inhibition of AC1 completely reversed cAMP upregulation, neuronal excitability enhancement, and nociceptive behavioral hypersensitivity in AC3-CKO mice. Our findings suggest a crucial role of peripheral AC3 in nociceptive modulation and KOR opioid analgesia.

Naringenin (5,7,4′-trihydroxyflavanone), belonging to the flavanone subclass, is associated with beneficial effects such as anti-oxidation, anticancer, anti-inflammatory, and anti-diabetic effects. Drug metabolism plays an essential role in drug discovery and clinical safety. However, due to the interference of numerous endogenous substances in metabolic samples, the identification and efficient characterization of drug metabolites are difficult. Here, ultra-high-performance liquid chromatography (UHPLC) coupled with high-resolution mass spectrometry was used to obtain mass spectral information of plasma (processed by three methods), urine, feces, liver tissue, and liver microsome samples. Moreover, a novel analytical strategy named “ion induction and deduction” was proposed to systematically screen and identify naringenin metabolites in vivo and in vitro. The analysis strategy was accomplished by the establishment of multiple “net-hubs” and the induction and deduction of fragmentation behavior. Finally, 78 naringenin metabolites were detected and identified from samples of rat plasma, urine, feces, liver tissue, and liver microsomes, of which 67 were detected in vivo and 13 were detected in vitro. Naringenin primarily underwent glucuronidation, sulfation, oxidation, methylation, ring fission, and conversion into phenolic acid and their composite reactions. The current study provides significant help in extracting target information from complex samples and sets the foundation for other pharmacology and toxicology research.

Abstract. Background:. MicroRNAs (miRNAs) have played important roles in the regulation of gene expression in many cancers, but their roles in esophageal squamous cell carcinoma (ESCC) are still unclear. The aim of this study was to determine the potential ESCC-specific key miRNAs from a large sample dataset in The Cancer Genome Atlas (TCGA). Methods:. Integrative bioinformatics analysis was used to identify key ESCC-specific miRNAs related to the ESCC patients’ tumor histological grade and lymphatic metastasis from TCGA. Next, these key miRNA potential gene regulatory functions and relationships with ESCC patients’ clinical characteristics and overall survival were analyzed. Finally, three key miRNAs were selected randomly and quantificational real-time polymerase chain reaction (qRT-PCR) was used to validate in 51 newly diagnosed ESCC patients’ tissues samples (collected from Nov. 2017 to Feb. 2019, in Wuwei, China) whether the bioinformatics analyses results were reliable and valid. Two-tailed Student's t test, Pearson Chi-squared test and Kaplan-Meier survival analysis were used in this study. Results:. Thirty-five ESCC-specific miRNAs from TCGA database were investigated (fold-change > 2.0, P

Saline area is an important reserve resource of arable land, however, the effects of soil microorganisms on the soil fertility in saline coastal ecosystems remain poorly understood. The salinity effects on soil microorganisms, nutrient availabilities and their relationships were studied in soils along a salinity gradient. A total of 80 soil samples were collected from 16 sites at four salinity levels (non-saline soil, salt content4 g kg−1). The results showed that the salinity increased soil pH and exchangeable Na percent, but decreased soil organic matter, soil exchangeable K, and soil microbial biomass. Both the abundance and community composition of soil bacteria and fungi were significantly different between the non-saline and the saline soils. The predominant genera of soil bacteria (Planctomyces and Archangium, positive for carbon fixation) and fungi (Hydropisphaera, efficient in lignin degradation) changed with the increasing soil salinity and the decreasing soil organic matter. In summary, soil salinity changed the abundances of soil bacterial, fungal, and arbuscular mycorrhizal communities and, subsequently, affected their function in saline coastal ecosystems.

Background: IQ motif-containing GTPase activating protein 3 (IQGAP3), the latest identified member of the IQGAP family, may act as a crucial factor in cancer development and progression; however, its clinical value in breast cancer remains unestablished. We explored the correlation between IQGAP3 expression profile and the clinicopathological features in breast cancer.Methods: IQGAP3 mRNA and protein levels were detected in breast cancer cell lines and tumor tissues by real-time PCR and western blotting and compared to the normal control groups. Protein expression of IQGAP3 was also evaluated immunohistochemically in archived paraffin-embedded specimens from 257 breast cancer patients, and the associations between IQGAP3 expression level, clinical characteristics, and prognosis were analyzed. We assessed the relationship between IQGAP3 expression and sensitivity to radiation therapy which was determined by subgroup analysis.Results: IQGAP3 was significantly upregulated in breast cancer cell lines and human tumor tissues at both the mRNA and protein level compared to controls. Additionally, high levels of IQGAP3 expression were detected in 110/257 (42.8%) of archived paraffin-embedded breast cancer specimens. High IQGAP3 expression level was significantly related to clinical stage (p = 0.001), T category (p = 0.002), N category (p = 0.001), locoregional recurrence (p = 0.002), distant metastasis (p = 0.001), and vital status (p = 0.001). Univariate and multivariate statistical analysis showed that IQGAP3 expression was an independent prognostic factor among all 257 breast cancer patients in our cohort (p = 0.003, p = 0.001). Subgroup analysis revealed IQGAP3 expression correlated with radioresistance and was also an independent predictor of radiotherapy outcome.Conclusion: Our findings suggest that high IQGAP3 expression predicts poor prognosis and radioresistance in breast cancer. Therefore, IQGAP3 may be a reliable prognostic biomarker in breast cancer and could be used to identify patients who may benefit from radiotherapy.

Purpose: It was reported that the novel preoperative systemic immune-inflammation index (SII) can predict survival in cases of many malignant tumors. However, the prognostic significance of preoperative SII in breast cancer remains unclear. The purpose of this study was to investigate the relationship between SII and survival in breast cancer patients.Methods: Breast cancer patients (1,026) who underwent a mastectomy at Sun Yat-sen University Cancer Center were retrospectively studied. The SII was determined using the following formula: neutrophil count × platelet count/lymphocyte count. The receiver operating characteristic (ROC) curve was used to determine the optimal cut-off value for SII. Propensity score matching (PSM) was applied to develop comparable cohorts of high SII group and low SII group.Results: A total of 1,026 patients were included as the primary cohort, and 894 patients were matched and regarded as the matched cohort. Patients were divided into two groups based on SII value: SII 601.7. In the primary cohort, the 5-years overall survival (OS), recurrence-free survival (RFS), and distant metastasis-free survival (DMFS) rates for high SII group and low SII group were (85.6% vs. 91.3%, P = 0.016), (95.8% vs. 96.4%, P = 0.684), and (83.5% vs. 90.6%, P = 0.007), respectively. Univariate analysis showed that histological type, T stage, N stage, PR, HER2, Ki67, and SII all showed significant associations with OS; and histological type, T stage, N stage, and SII all showed significant associations with DMFS. Multivariate survival analysis revealed that SII can independently predict OS (P = 0.017) and DMFS (P = 0.007). Similar results were found in PSM cohort.Conclusions: Preoperative SII may be a reliable predictor of OS and DMFS in patients with operable breast cancer to provide personalized prognostication and assist in formulation of the clinical treatment strategy.

The ultimate goal of cataract surgery is to restore the accommodation while restoring distance visual acuity. Different kinds of accommodative intraocular lens (IOLs) and surgical techniques have been suggested to apply during the surgery, but they showed poor postoperative accommodation. It is possible to achieve this goal by refilling the lens with an injectable polymer. We present a summary of the existing materials, methods, results, and some obstacles in clinical application that remain of lens refilling for restoration of accommodation. Two main problems have restricted the clinical application of this technique. One was the formation of postoperative secondary capsule opacification and the other was the different accommodative power after surgery.

Background: To investigate the significance of the prognostic nutrition index (PNI) as a predictor of survival and guide for treating T1-2N1 breast cancer.Methods: Patients with T1-2N1 breast cancer (N = 380) who underwent a mastectomy at our center were studied. PNI was calculated as 10 × serum albumin (g/dl) + 0.005 × total lymphocyte count (per mm3). The cutoff for the PNI was calculated using the time-dependent receiver operating characteristic (ROC) curve analysis by overall survival (OS) prediction. The associations between the PNI and the clinicopathologic characteristics were analyzed using Pearson's χ2 test. Survival curves were calculated using the Kaplan–Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazards model.Results: Subgroup analyses of patients with low PNI value (≤52.0) and high PNI value (>52.0) showed that a high PNI was significantly associated with HER2 status, the neutrophil–lymphocyte ratio (NLR), the monocyte–lymphocyte ratio (MLR), and KI 67 status. The OS of patients with a high PNI was significantly better than that of patients with a low PNI. We then conducted subgroup analyses based on PNI and radiotherapy. Among patients who received radiotherapy, the OS of those with a high PNI was significantly better than that of patients with a low PNI. Among patients with a high PNI, the OS of those who received radiotherapy was better than that of the patients who did not receive radiotherapy. However, among the patients with a low PNI, the OS of those who received radiation was worse than that of patients who did not receive radiotherapy. The Kaplan–Meier survival analysis and the multivariate analysis of patients with T1-2N1 breast cancer who received radiotherapy showed PNI independently predicted OS.Conclusions: The preoperative PNI may be a reliable predictor of OS of patients with operable T1-2N1 breast cancer, with the capacity to provide a personalized prognosis and facilitate the development of clinical treatment strategies. However, radiotherapy did not achieve satisfactory outcomes in patients with PNI ≤52.0; thus, further studies on treatment optimization are needed.

Background: Nasopharyngeal carcinoma (NPC) patients receiving concurrent chemoradiotherapy (CCRT) frequently develop low skeletal muscle mass (SMM), but, little is known about the impacts of low SMM on health-related quality of life (QOL).Methods: We retrospectively assessed 56 patients with locoregionally advanced NPC enrolled in a prospective trial. Low SMM was determined on routine computed tomography simulation (CT-sim) scans taken before radiotherapy, at the third cervical (C3) vertebral level with validated sex-specific cutoffs. QOL was assessed using the World Health Organization Quality of Life Questionnaire-100 at baseline and after 3 weeks. Pain was scored every 24 h using a numerical rating scale (NRS). Characteristics related to low SMM were identified by logistic regression. The chi-square test was used to examine the association of low SMM with QOL and pain.Results: Of the 56 participants (mean age 44.20 ± 10.93 years), over half (60.71%) developed low SMM. Patients with low SMM were more likely to be older (P = 0.035), male (P = 0.066), have a lower body-mass index (BMI; P = 0.091), and have a higher pain score (P = 0.001). Older age (hazard ratio [HR] = 1.788, P = 0.016), being male (HR = 3.145, P = 0.010), lower BMI (HR = 0.761, P = 0.033), and lower prognostic nutritional index (HR = 0.186, P = 0.034) were associated with higher risk of low SMM. Low SMM was associated with poorer baseline QOL scores (P = 0.072), especially in the physical domain (P = 0.002) and its three facets: pain (P = 0.003), energy (P = 0.021), and sleep (P = 0.007). Low SMM was also associated with significantly worse QOL scores (P = 0.006) at 3 weeks, especially in the physical (P = 0.002), psychological (P = 0.046), independence (P = 0.003), social domains (P = 0.023), and in general health condition (P = 0.043). For pain score, low SMM group had worse overall changes from baseline to week 3 (P = 0.011).Conclusions: The incidence of low SMM, as evaluated using routine CT-sim scans, is high in patients receiving CCRT for locoregionally advanced NPC. Low SMM results in poorer QOL and higher pain scores, which underscores the requirement for nutritional and functional interventions to address low SMM early in the treatment course.

Abstract Background The value of postoperative radiotherapy in tubular breast carcinoma patients under 65 years is uncertain. Methods Data on patients with estrogen receptor positive T1N0M0 tubular breast carcinoma who were younger than 65 years and who received breast-conserving surgery between 2000 and 2013 were retrieved from the Surveillance, Epidemiology and End Results database. Demographic, clinicopathologic features, and receipt of postoperative radiotherapy were analyzed to investigate effects on survival. Results Data from 2442 patients were analyzed, of whom 2020 (82.7%) received postoperative radiotherapy and 422 (17.3%) did not. The number of patients treated with or without postoperative radiotherapy showed no differences during the study period (p = 0.184). Radiotherapy was more likely to be administered in patients with well differentiated tumors. Multivariate Cox analysis showed that postoperative radiotherapy delivery was significantly correlated with better breast cancer-specific survival (BCSS) (hazard ratio [HR] 0.297, 95% confidence interval [CI] 0.105–0.836, p = 0.022) and overall survival (OS) (HR 0.656, 95% CI 0.441–0.978, p = 0.038). Ten 10-year BCSS was 99.3% in patients who received postoperative radiotherapy and 98.1% in those who did not (p = 0.020), and 10-year OS was 93.4 and 91.0%, respectively (p = 0.029). Postoperative radiotherapy increased BCSS and OS in the subgroups of age

Abstract Tumor local invasion is the first step of metastasis cascade which remains the key obstacle for cancer therapy. Collective cell migration plays a critical role in tumor invading into surrounding tissues. In vitro assays fail to assess collective invasion in a real time manner. Herein we aim to develop a three-dimensional (3D) microfluidic cell invasion model to determine the dynamic process. In this model, collective invasion of breast cancer cells is induced by the concentration gradient of fetal bovine serum. We find that breast cancer cells adopt a collective movement rather than a random manner when the cells invade into extracellular matrix. The leading cells in the collective movement exhibit an increased expression of an Aurora kinase family protein - AURKA compared with the follower cells. Inhibition of AURKA kinase activity by VX680 or AKI603 significantly reduces the phosphorylation of ERK1/2 (Thr202/Tyr204) and collective cohort formation. Together, our study illustrates that AURKA acts as a potential therapeutic target for suppressing the process of tumor collective invasion. The 3D microfluidic cell invasion model is a reliable, measurable and dynamic platform for exploring potential drugs to inhibit tumor collective invasion.

Summary: The proinflammatory cytokine interleukin-17 (IL-17) is implicated in pain regulation. However, the synaptic mechanisms by which IL-17 regulates pain transmission are unknown. Here, we report that glia-produced IL-17 suppresses inhibitory synaptic transmission in the spinal cord pain circuit and drives chemotherapy-induced neuropathic pain. We find that IL-17 not only enhances excitatory postsynaptic currents (EPSCs) but also suppresses inhibitory postsynaptic synaptic currents (IPSCs) and GABA-induced currents in lamina IIo somatostatin-expressing neurons in mouse spinal cord slices. IL-17 mainly expresses in spinal cord astrocytes, and its receptor IL-17R is detected in somatostatin-expressing neurons. Selective knockdown of IL-17R in spinal somatostatin-expressing interneurons reduces paclitaxel-induced hypersensitivity. Overexpression of IL-17 in spinal astrocytes is sufficient to induce mechanical allodynia in naive animals. In dorsal root ganglia, IL-17R expression in nociceptive sensory neurons is sufficient and required for inducing neuronal hyperexcitability after paclitaxel. Together, our data show that IL-17/IL-17R mediate neuron-glial interactions and neuronal hyperexcitability in chemotherapy-induced peripheral neuropathy. : Luo et al. find that glia-produced IL-17 regulates synaptic transmission and excitability of spinal SOM+ neurons and DRG small neurons by IL-17R in the DRG and spinal pain circuit. These results suggest that IL-17/IL-17R mediate neuron-glial interactions and drives chemotherapy-induced neuropathic pain. Keywords: interleukin-17, chemotherapy-induced peripheral neuropathy, excitatory postsynaptic currents (EPSCs), inhibitory postsynaptic synaptic currents (IPSCs), somatostatin-expressing neurons, Cre-recombinase-dependent adeno-associated virus (AAV), astrocytes, allodynia, spinal cord, neuron-glial interaction

Introduction: Metaplastic breast cancer (MBC) is a rare and aggressive form of breast cancer. The present study aimed to assess the effect of post-mastectomy radiotherapy (PMRT) in MBC patients with intermediate-risk (T1-2N1M0 and T3N0M0) and high-risk (T1-4N2-3M0 and T4N0-1M0) disease.Methods: The Surveillance, Epidemiology and End Results database was used to analyze patients with MBC between 2000 and 2014. Kaplan–Meier analysis, log-rank tests, and the multivariate Cox proportional model were used for statistical analysis.Results: We identified 460 patients with a median follow-up time of 31 months (range, 2–178 months). Five-year breast cancer specific survival (BCSS) for all patients was 57.5%. In the entire group, multivariate analysis showed that PMRT was associated with better BCSS (hazard ratio (HR) 0.500, 95% confidence interval (CI) 0.366–0.683, P < 0.001). The 5-year BCSS in PMRT and non-PMRT groups were 62.3 and 50.3%, respectively (P = 0.001). When stratified the patients into intermediate-risk and high-risk groups, PMRT could improve BCSS compared with that in non-PMRT patients in both the intermediate- and high-risk groups. For the intermediate-risk group, the 5-year BCSS was 74.3 and 64.7% in PMRT and non-PMRT groups (P = 0.042), respectively, and was 52.1 and 28.8% in high-risk patients treated with PMRT and non-PMRT, respectively (P < 0.001).Conclusion: PMRT could improve the BCSS of MBC patients with intermediate- and high-risk disease.

Introduction: Although advances in surgical and chemotherapeutic approaches have improved management of epithelial ovarian cancer (EOC) in recent decades. The mortality of EOC over time remains controversial. The aim of this study was to assess the survival trends of EOC according to period of diagnosis using real-world data.Methods: Patients with EOC diagnosed from 1990 to 2014 were included from the Surveillance, Epidemiology, and End Results database. The Kaplan-Meier method and multivariate Cox regression models were used to evaluate the trends in survival over time.Results: We identified 59,763 patients diagnosed with EOC as follows: 6,586 (11.0%) in 1990–1994, 7,408 (12.4%) in 1995–1999, 15,348 (25.7%) in 2000–2004, 14,908 (24.9%) in 2005–2009, and 15,513 (26.0%) in 2010–2014. In the distant stage, the use of surgery decreased from 92.0% in 1990–1994 to 88.9% in 2010–2014. The use of chemotherapy increased from 67.4% in 1990–1994 to 75.0% in 2010–2014. The 5-year cause-specific survival (CSS) increased from 48.6% in 1990–1994 to 57.4% in 2010–2014 (P < 0.001). The 5-year overall survival (OS) increased from 42.7% in 1990–1994 to 51.7% in 2010–2014 (P < 0.001). The 5-year CSS and OS showed slight improvement in the localized stage (CSS, 91.9 vs. 93.1%; OS, 85.6 vs. 88.5%), and largely improved in the distant stage (CSS, 31.4 vs. 42.7%; OS, 26.7 vs. 37.4%) between 1990–1994 and 2010–2014. The multivariate analysis indicated that being diagnosed in the later years was related to better CSS and OS of EOC.Conclusion: The trends in survival of EOC have improved over time, but net survival remains poor overall in distant-stage EOC.

Introduction: It is still controversial whether post-mastectomy radiotherapy (PMRT) is necessary for women with T1-2 N1mic ER-positive HER2-negative breast cancer. The 21-gene recurrence score (RS) assay has been validated in T1-2 N1 breast cancer to be prognostic of locoregional recurrence (LRR) and overall survival (OS). This study aims to evaluate the predict value of 21-gene recurrence score assay for the benefit of PMRT in T1-2 N1mic ER-positive HER2-negative breast cancer.Methods: A population-based cohort study was performed on women with T1-2 N1mic ER-positive HER2-negative breast cancer who underwent mastectomy and were evaluated using the 21-gene RS in the Surveillance, Epidemiology, and End Results (SEER) registry between 2004 and 2015. Clinical characteristics as well as OS and breast cancer-specific survival (BCSS) were compared between patients with and without PMRT in patients with a Low-, Intermediate-, and High-RS. Multivariate COX regression analysis was performed to investigate if the 21-gene RS assay could predict benefit of PMRT in this group of breast cancer patients.Results: A total of 1571 patients met the criteria of our study and were enrolled, including 970 patients in the Low-Risk group (score 30). In the High-Risk group, there were more patients with age ≥50 (87.0 vs. 64.3%, P = 0.040) and received chemotherapy with a borderline significance (91.3 vs. 72.9%, P = 0.066) in the PMRT subgroup than in the no PMRT subgroup. In all three groups, OS was comparable between the PMRT subgroup and the no PMRT subgroup. Furthermore, multivariate analysis did not show any OS benefit for PMRT based on the 21-gene recurrence score.Conclusion: This study showed that the 21-gene RS assay was not able to predict the benefit of PMRT for OS in women with T1-2 N1mic ER-positive HER2-negative breast cancer. However, further prospective larger sample-size trials are warranted to determine if a benefit exists.

Introduction: We conducted a non-inferiority analysis using real-world data to compare the survival outcomes of stage T1-2N2-3 (tumor size ≤5 cm and four or more node metastases) breast cancer after breast-conserving surgery (BCS) and mastectomy (MAST).Methods: The study included patients with stage T1-2N2-3 invasive breast carcinoma from the Surveillance, Epidemiology, and End Results program, who underwent BCS or MAST between 2004 and 2012, along with both radiotherapy and chemotherapy. The statistical analyses used included the chi-squared test, multivariate Cox proportional hazards models, and propensity score matching (PSM).Results: The study population comprised 13,263 patients, including 4,787 (36.1%) and 8,476 (63.9%) patients who were treated with BCS and MAST, respectively. Patients with younger age and advanced stage were more likely to have received MAST. The probability of receiving MAST increased over the years, while the probability of BCS decreased (p < 0.001). The 5-year breast cancer-specific survival (BCSS) was 86.1% in the BCS cohort compared to 83.1% in the MAST cohort (p < 0.001). Surgical procedure was an independent prognostic factor for BCSS. Patients who received MAST had worse BCSS than those treated with BCS (hazard ratio = 1.179, 95% confidence interval = 1.087–1.278, p < 0.001). These results remained significant after stratification by age, tumor grade, T stage, N stage as well as marital status. Similar results were obtained after PSM.Conclusions: BCS resulted in noninferior outcome than MAST in patients with T1-2/N2-3 invasive breast carcinoma. BCS may therefore be an optimal treatment option when both treatment options are feasible and appropriate.

Introduction: To assess the role of the 21-gene recurrence score (RS) assay on decision-making of postoperative radiotherapy (RT) following breast-conserving surgery (BCS) in elderly women with early-stage breast cancer.Methods: The 21-gene RS for elderly (≥65 years) women with stage T1–2N0M0 estrogen receptor-positive breast cancer who underwent BCS from 2004 to 2015 was obtained from the Surveillance, Epidemiology, and End Results program. We estimated the association of 21-gene RS and adjuvant RT related to breast cancer-specific survival (BCSS) using propensity score matching (PSM).Results: We identified 18,456 patients, of which 15,326 (83.0%) received postoperative RT. Of identified patients, 58.9, 34.0, and 7.1% of patients had a low-, intermediate-, and high-risk RS, respectively. Receipt of postoperative RT was not related to the year of diagnosis according to the 21-gene RS groups. Multivariate analysis suggested that receipt of postoperative RT was an independent predictor of better BCSS before (hazard ratio [HR] 0.587, 95% confidence interval [CI] 0.426–0.809, P = 0.001) and after (HR 0.613, 95%CI 0.390–0.963, P = 0.034) PSM. However, subgroups analyses indicated that receipt of postoperative RT was related to better BCSS in women with intermediate-risk RS before (HR 0.467, 95%CI 0.283–0.772, P = 0.003) and after (HR 0.389, 95%CI 0.179–0.846, P = 0.017) PSM, but not in women with low- and high-risk RS groups before and after PSM.Conclusions: Although causation cannot be implied, adjuvant RT in elderly women was associated with a greater effect size in patients with an intermediate-risk RS.

Background: The clinical value of 21-gene recurrence score (RS) in various breast cancer histologic subtypes is not well established.Aims: To assess the distribution and outcomes of the 21-gene RS among various T1-T2N0 estrogen receptor-positive breast cancer histologic subtypes.Methods: Using the Surveillance, Epidemiology and End Results database, we investigated the distribution and outcomes of the 21-gene RS among various breast cancer histologic subtypes between 2004 and 2015. The histologic subtypes with 200 or more cases were further analyzed.Results: We identified 83,665 patients including eight histologic subtypes. The most common subtype was invasive ductal carcinoma not otherwise specified (IDC NOS) (77.9%), followed by lobular carcinoma NOS, mixed infiltrating duct and lobular carcinoma (IDC-L), mucinous adenocarcinoma, tubular adenocarcinoma, micropapillary ductal carcinoma, cribriform carcinoma NOS, and intraductal papillary adenocarcinoma with invasion with 10.8, 7.7, 2.1, 0.6, 0.3, 0.2, and 0.2%, respectively. The 5-years breast cancer specific survival (BCSS) was 98.8, 98.8, 98.9, 99.6, 100, 100, 100, and 100%, respectively (P = 0.011). Patients with IDC NOS (8.9%), micropapillary ductal carcinoma (8.8%), and intraductal papillary adenocarcinoma with invasion (8.2%) had significantly higher percentage of high-risk RS compared to other histologic subtypes (1.0–3.8%) (P < 0.001). The mean RS was higher in IDC NOS, lobular carcinoma NOS, and IDC-L compared to other subtypes. In multivariate analysis, 21-gene RS was the independent prognostic factor in patients with IDC NOS (P < 0.001), lobular carcinoma NOS (P < 0.001), and IDC-L (P < 0.001), patients with a higher RS was associated with poor BCSS.Conclusion: Our results demonstrate that there is a significant difference in distribution of 21-gene RS in T1-T2N0 estrogen receptor-positive breast cancer with different histologic subtypes. Long-term studies with larger series are needed to confirm the role of the 21-gene RS array in prognosis assessment and chemotherapy decision-making in special histologic subtypes with favorable prognosis.

Introduction: To examined survival outcome by histological subtypes in de novo stage IV epithelial ovarian cancer (EOC).Methods: Between 2004 and 2015, patients with stage IV EOC were included using the Surveillance, Epidemiology, and End Results program. The effects of histological subtypes on overall survival (OS) were assessed using Kaplan–Meier and multivariable Cox regression analyses.Results: We identified 5,953 patients including 5,351 (89.9%), 249 (4.2%), 145 (2.4%), and 208 (3.4%) patients with high-grade serous, endometrioid, mucinous, and clear cell subtypes, respectively. The 5-year OS rates were 28.1, 38.6, 14.2, and 18.8% in patients with high-grade serous, endometrioid, mucinous, and 18.8% clear cell subtypes, respectively, (p < 0.001). Multivariate analyses indicated that histological subtype was an independent predictor of OS. Using the high-grade serous subtype as a reference, OS was comparable for the endometrioid subtype (hazard ratio (HR) 0.915, 95% confidence interval) (CI 0.772–1.085, p = 0.305), but significantly lower for mucinous (HR 3.292, 95% CI 2.701–4.011, p < 0.001) and clear cell subtypes (HR 1.820, 95% CI 1.546–2.141, p < 0.001). Patients with no residual tumor had better OS in the high-grade serous and endometrioid subtypes compared to patients with residual tumors. However, the residual tumor size was not a prognostic factor for OS in mucinous and clear cell carcinoma.Conclusions: Our study suggest a markedly mortality rate in patients with stage IV mucinous and clear cell carcinoma, but better survival in patients with high-grade serous and endometrioid subtypes. Aggressive radical surgery to leave no residual disease would improve survival for high-grade serous and endometrioid carcinoma. More studies are needed to assess the value of aggressive radical surgery in patients with mucinous and clear cell subtypes.

Abstract Background Natural killer/T-cell lymphoma (NKTCL) is an Epstein–Barr virus (EBV)-associated, highly aggressive lymphoma. Treatment outcome remains sub-optimal, especially for advanced-stage or relapsed diseases. Programmed cell death receptor 1 (PD-1) and PD ligand 1 (PD-L1) have become promising therapeutic targets for various malignancies, but their role in the pathogenesis and their interactions with EBV in NKTCL remains to be investigated. Methods Expression of PD-L1 was measured in NK-92 (EBV-negative) and SNK-6 (EBV-positive) cells by western blot, quantitative real-time PCR and enzyme-linked immunosorbent assay, and flow cytometry, respectively. Latent membrane protein 1 (LMP1)-harboring lentiviral vectors were transfected into NK-92 cells to examine the correlation between LMP1 and PD-L1 expression. Proteins in the downstream pathways of LMP1 signaling were measured in NK-92 cells transfected with LMP1-harboring or negative control vectors as well as in SNK-6 cells. PD-L1 expression on tumor specimens and serum concentration of soluble PD-L1 were collected in a retrospective cohort of patients with Ann Arbor stage I~II NKTCL, and their prognostic significance were analyzed. Results Expression of PD-L1 was significantly higher in SNK-6 cells than in NK-92 cells, at both protein and mRNA levels. Expression of PD-L1 was remarkably upregulated in NK-92 cells transfected with LMP1-harboring lentiviral vectors compared with those transfected with negative control vectors. Proteins in the MAPK/NF-κB pathway were upregulated in LMP1-expressing NK-92 cells compared with the negative control. Selective inhibitors of those proteins induced significant downregulation of PD-L1 expression in LMP1-expressing NK-92 cells as well as in SNK-6 cells. Patients with a high concentration of serum soluble PD-L1 (≥3.4 ng/ml) or with a high percentage of PD-L1 expression in tumor specimens (≥38 %) exhibited significantly lower response rate to treatment and remarkably worse survival, compared with their counterparts. A high concentration of serum soluble PD-L1 and a high percentage of PD-L1 expression in tumor specimens were independent adverse prognostic factors among patients with stage I~II NKTCL. Conclusions PD-L1 expression positively correlated LMP1 expression in NKTCL, which was probably mediated by the MAPK/NF-κB pathway. PD-L1 expression in serum and tumor tissues has significant prognostic value for early-stage NKTCL.

Safflower honey is a unique type of monofloral honey collected from the nectar of Carthamus tinctorius L. in the Apis mellifera colonies of northwestern China. Scant information is available regarding its chemical composition and biological activities. Here, for the first time, we investigated this honey’s chemical composition and evaluated its in vitro antioxidant and anti-inflammatory activities. Basic physicochemical parameters of the safflower honey samples in comparison to established quality standards suggested that safflower honeys presented a good level of quality. The in vitro antioxidant tests showed that extract from Carthamus tinctorius L. honey (ECH) effectively scavenged DPPH and ABTS+ free radicals. In lipopolysaccharides (LPS) activated murine macrophages inflammatory model, ECH treatment to the cells inhibited the release of nitric oxide and down-regulated the expressions of inflammatory-relating genes (iNOS, IL-1β, TNF-α and MCP-1). The expressions of the antioxidant genes TXNRD, HO-1, and NQO-1, were significantly boosted in a concentration-dependent manner. ECH decreased the phosphorylation of IκBα and inhibited the nuclear entry of the NF-κB-p65 protein, in LPS-stimulated Raw 264.7 cells, accompany with the increased expressions of Nrf-2 and HO-1, suggesting that ECH achieved the anti-inflammatory effects by inhibiting NF-κB signal transduction and boosting the antioxidant system via activating Nrf-2/HO-1 signaling. These results, taken together, indicated that safflower honey has great potential into developing as a high-quality agriproduct.

There are increasing concerns regarding the impact of agrochemical pesticides on non-target organisms. Pesticides could cause honeybee abnormal development in response to neurotoxins such as neonicotinoid. However, knowledge of carbendazim, a widespread fungicide in beekeeping practice, influencing on honeybee (Apis mellifera L.) brain development is lacking. Large-scale transcriptome approaches were applied to determine the changes in global gene expression in the brains of newly emerged honeybees after carbendazim exposure during the larval stage. To further understand the effects of carbendazim on the brain development of honeybees, the functions of differentially expressed genes were compared between the treatment and control groups. We found that neuroregulatory genes were down-regulated after carbendazim exposure, which suggest the neurotoxic effects of this fungicide on honeybee nervous system. Carbendazim exposure also altered the expression of genes implicated in metabolism, transport, sensor, and hormone. Notably, larvae in the carbendazim-treated group observed longer time to shift into the dormant pupal state than the control group. Moreover, a low juvenile hormone and high ecdysone titers were found in the treatment group compared to control group. The data is the first report of neurotoxic effects on honeybee caused by carbendazim, and the sublethal carbendazim may disturb honeybee development and is a potential chemical threating the honeybee colonies.

Introduction: Distant metastasis remains the major cause of treatment failure in esophageal cancer, though there have been few large-scale studies of the patterns of distant metastasis in different histological types. We investigated the patterns of distant metastasis in esophageal adenocarcinoma (AC) and squamous cell carcinoma (SCC) using a population-based approach.Methods: Patients with de novo stage IV esophageal cancer at diagnosis were identified using the Surveillance, Epidemiology, and End Results database. Multivariable logistic regression was performed to identify potential risk factors for site-specific distant metastasis to the distant lymph nodes, bone, liver, brain, and lung at diagnosis.Results: We identified 1,470 patients with complete data for analysis including 1,096 (74.6%) patients with AC and 374 (25.4%) patients with SCC. A total of 2,243 sites of distant metastasis were observed, the liver was the most common site of distant metastasis (727, 32.4%), followed by the distant lymph nodes (637, 28.4%), lung (459, 20.5%), bone (344, 15.3%), and brain (76, 3.4%). Multivariable logistic regression showed that compared to patients with SCC, patients with AC were more likely to have metastasis to the brain (odds ratio [OR] 3.026, 95% confidence interval [CI] 1.441-6.357, p = 0.003) and liver (OR 1.848, 95% CI 1.394–2.451, p < 0.001), and less likely to have metastasis to the lung (OR 0.404, 95% CI 0.316–0.516, p < 0.001). Histological type had no effect on metastasis to the distant lymph nodes or bone.Conclusions: Patients with esophageal AC are more likely to present with liver and brain metastases, and less likely to present with lung metastasis than patients with esophageal SCC.

IntroductionTo investigate the effect of the number of removed lymph nodes (RLNs) on outcomes in patients with node-positive vulvar squamous cell carcinoma (SCC).MethodsThis population-based retrospective study included vulvar SCC patients recorded on the surveillance, epidemiology, and end results database, who received surgery and lymphadenectomy. Cox regression proportional hazards were used for multivariate analysis. The number of RLNs was examined as a 4-level categorical variable based on quartiles.ResultsIn total, 703 patients were identified. Patients with a higher RLN count had a significantly higher number of positive lymph nodes. The 3-year cause-specific survival (CSS) rates were 48.9, 65.9, 73.1, and 67.3% in patients with 1–6, 7–10, 11–16, and 17–45 RLNs, respectively (p 6 RLNs.ConclusionThe removal of more than six lymph nodes improves vulvar SCC outcomes in patients with node-positive disease.

IntroductionTo investigate the temporal trends of postoperative radiotherapy (RT) administration and the effects of omitting postoperative RT on breast cancer-specific survival (BCSS) in women aged ≥65 years with tubular carcinoma (TC) of the breast who received breast-conserving surgery (BCS).MethodsWe included women aged ≥65 years with non-metastatic TC of the breast who underwent BCS between 2000 and 2013 using the Surveillance, Epidemiology, and End Results database. Statistical analyses were performed using chi-square tests, Kaplan–Meier analyses, Cox proportional hazards models, and a 1:1 propensity score matching (PSM).ResultsBefore PSM, a total of 1,475 patients with tumor size ≤2 cm, node-negative disease, and estrogen receptor-positive disease were identified, including 927 (62.8%) underwent postoperative RT and 548 (37.2%) had postoperative omission of RT. The administration of postoperative RT steadily declined over the study period. Patients with younger age, larger tumor size, and other race/ethnicity were more likely to receive postoperative RT. The median follow-up duration was 85.0 months, the 5- and 10-year BCSS rates were 98.7 and 97.9%, respectively. The median BCSS was 161.9 and 165.0 months for patients with and without postoperative RT, respectively, and the corresponding 5-year BCSS rates were 98.5 and 98.8%, respectively (p = 0.134). Prognostic analysis indicated that postoperative RT was not associated with improved BCSS rates compared with RT omission (p = 0.134). After PSM, a total of 431 complete pairs were generated. In the matched population, the 5-year BCSS rates were 98.6 and 98.4% in non-postoperative RT and postoperative RT groups, respectively (p = 0.858). The univariate analyses also confirmed that the administration of postoperative RT was not associated with better BCSS (p = 0.858).ConclusionThe incidence of breast cancer-related death is probably sufficiently low to avoid postoperative RT in women aged ≥65 years with TC of the breast after BCS.

The aim of this work was to assess the effect of applying three different doses of fluxapyroxad on microbial activity, community structure and functional diversity as measured by respiration, microbial biomass C, phospholipid fatty acid (PLFA) and community-level physiological profiles (CLPPs). Our results demonstrated that substrate-induced respiration (on day 15) and microbial biomass C (on days 7 and 15) were inhibited by fluxapyroxad, but stimulation was observed thereafter. In contrast, fluxapyroxad addition increased the basal respiration and metabolic quotients (qCO2) and respiratory quotients (QR). Analysis of the PLFA profiles revealed that the total and bacterial biomass (both Gram-positive bacteria (GP) and Gram-negative bacteria (GN)) were decreased within the initial 15 days, whereas those as well as the GN/GP ratio were increased at days 30 and 60. Fluxapyroxad input decreased the fungi biomass but increased the bacteria/fungi ratio at all incubation time. Moreover, high fluxapyroxad input (75 mg fluxapyroxad kg−1 soil dry weight) increased the microbial stress level. A principal component analysis (PCA) of the PLFAs revealed that fluxapyroxad treatment significantly shifted the microbial community structure, but all of the observed effects were transient. Biolog results showed that average well color development (AWCD) and functional diversity index (H') were increased only on day 60. In addition, the dissipation of fluxapyroxad was slow in soil, and the degradation half-lives varied from 158 to 385 days depending on the concentration tested.

Background: Surgical resection is generally considered the main curative treatment for intrahepatic biliary cystadenocarcinoma (IBCA) or suspected IBCAs, but controversy exists regarding the prognosis for IBCAs. This study aimed to describe the clinicopathological characteristics of IBCA and identify prognostic factors that may influence the survival of patients treated with surgical procedures. Methods: Thirty-four patients with histologically confirmed IBCA treated between January 2000 and June 2014 were included. The clinical characteristics of patients with IBCA were compared with those of 41 patients with intrahepatic biliary cystadenoma (IBC); factors that significant difference were analyzed for prognosis analysis of IBCA using multivariate/univariate Cox proportional hazards regression models. Survival curves were constructed using the Kaplan-Meier method and compared using the log-rank test. Results: IBCAs had a strong female predominance, and the most common presenting symptoms were abdominal pain or discomfort. Compared with IBCs, IBCAs occurred in older patients, in more male patients, and were associated statistically significant abnormal increase in alanine aminotransferase (P = 0.01) and total bilirubin (P = 0.04). Mural nodules were more frequently seen with IBCAs and may associate with malignancy. It was difficult to differentiate between IBC and IBCA based on laboratory examination and imaging findings. Although complete resection is recommended, enucleation with negative margins also achieved good outcomes. Median overall patient survival was 76.2 months; survival at 1, 3, and 5 years was 88.0%, 68.7%, and 45.8%, respectively. Radical resection and noninvasive tumor type were independent prognostic factors for overall survival. Conclusions: It remains difficult to distinguish between cystadenomas and cystadenocarcinomas based on laboratory examination and image findings. Complete resection is recommended for curative treatment, and patients should be closely followed postoperatively, particularly those with invasive tumors.

To investigate the effect of distant metastases sites on survival in patients with de novo stage-IV breast cancer. From 2010 to 2013, patients with a diagnosis of de novo stage-IV breast cancer were identified using the Surveillance, Epidemiology, and End Results database. Univariate and multivariate Cox regression analyses were performed to analyze the effect of distant metastases sites on breast cancer–specific survival and overall survival. A total of 7575 patients were identified. The most common metastatic sites were bone, followed by lung, liver, and brain. Patients with hormone receptor+/human epidermal growth factor receptor 2− and hormone receptor+/human epidermal growth factor receptor 2+ status were more prone to bone metastases. Lung and brain metastases were common in hormone receptor−/human epidermal growth factor receptor 2+ and hormone receptor−/human epidermal growth factor receptor 2− subtypes, and patients with hormone receptor+/ human epidermal growth factor receptor 2+ and hormone receptor−/human epidermal growth factor receptor 2+ subtypes were more prone to liver metastases. Patients with liver and brain metastases had unfavorable prognosis for breast cancer–specific survival and overall survival, whereas bone and lung metastases had no effect on patient survival in multivariate analyses. The hormone receptor−/human epidermal growth factor receptor 2− subtype conferred a significantly poorer outcome in terms of breast cancer–specific survival and overall survival. hormone receptor+/human epidermal growth factor receptor 2+ disease was associated with the best prognosis in terms of breast cancer–specific survival and overall survival. Patients with liver and brain metastases were more likely to experience poor prognosis for breast cancer–specific survival and overall survival by various breast cancer subtypes. Distant metastases sites have differential impact on clinical outcomes in stage-IV breast cancer. Follow-up screening for brain and liver metastases might be effective in improving breast cancer–specific survival and overall survival.

Microbial production of polyhydroxyalkanoic acid (PHA) with customized features has been attempted by humans through metabolic engineering. However, few studies have explored the green chemical synthesis of customized PHA using hydroxy fatty acids. In the present study, new mcl-PHA having C _16 - co -C _16 , blocked by esterification of hydroxy groups in the side chain, was synthesized by melt polycondensation using aleuritic acid (9, 10, 16-trihydroxyhexadecanoic acid) and lactic acid as long-chain fatty acid monomers and active blocking molecule, respectively. The results showed that when the two monomers reacted at 150 °C for 24 h, the properties of PHA were largely retained, along with free hydroxyl groups as much as possible. Comparison of the effect of different ratios of active small molecule (lactic acid) on the properties of new mcl-PHA revealed that copolymerization mainly happened between the long-chain monomers, and lactic acid served as a blocker by esterification in the side chain on the hydroxy groups of mcl-PHA. Further, the properties of side chain-esterified mcl-PHA (SCE-mcl-PHA) changed from rigid to soft with increasing ratio of active lactic acid monomer. The tensile strength of mcl-PHA was similar to that of commercially available products PLA and PHBV. The mechanical properties of SCE-mcl-PHA significantly changed by adding only 5 wt% lactic acid monomer. Besides, the cell proliferation analysis showed that the new PHA had minimum cytotoxicity, which was close to PLA and PHBV. Therefore, these new mcl-PHA and SCE-mcl-PHA have great potential for application in food, medicine, cosmetics, and other fields, and hence require further investigation.

Background. The pretreatment albumin to globulin ratio (AGR) has been reported to be a predictor of survival in several types of cancer. The aim of this study was to evaluate the prognostic impact of AGR in patients with natural killer/T-cell lymphoma (NKTCL). Methods. We retrospectively reviewed the available serum biochemistry results for 331 NKTCL patients before treatment. AGR was calculated as albumin/(total protein—albumin), and a cut-off value of 1.3 was used to define AGR as low or high. Survival analysis was used to assess the prognostic value of AGR. Results. A low AGR (