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Antidepressants, while effective in treating depression and anxiety disorders, also induce deficits in sensory (particularly auditory) processing, which in turn may exacerbate psychiatric symptoms. How antidepressants cause auditory signature deficits remains largely unknown. Here, we found that fluoxetine-treated adult female rats were significantly less accurate when performing a tone-frequency discrimination task compared with age-matched control rats. Their cortical neurons also responded less selectively to sound frequencies. The degraded behavioral and cortical processing was accompanied by decreased cortical perineuronal nets, particularly those wrapped around parvalbumin-expressing inhibitory interneurons. Furthermore, fluoxetine induced critical period-like plasticity in their already mature auditory cortices; therefore, a brief rearing of these drug-treated rats under an enriched acoustic environment renormalized auditory processing degraded by fluoxetine. The altered cortical expression of perineuronal nets was also reversed as a result of enriched sound exposure. These findings suggest that the adverse effects of antidepressants on auditory processing, possibly because of a reduction in intracortical inhibition, can be substantially alleviated by simply pairing drug treatment with passive, enriched sound exposure. They have important implications for understanding the neurobiological basis of antidepressant effects on hearing and for designing novel pharmacological treatment strategies for psychiatric disorders.SIGNIFICANCE STATEMENTClinical experience suggests that antidepressants adversely affect sensory (particularly auditory) processing, which can exacerbate patients' psychiatric symptoms. Here, we show that the antidepressant fluoxetine reduces cortical inhibition in adult rats, leading to degraded behavioral and cortical spectral processing of sound. Importantly, fluoxetine induces a critical period-like state of plasticity in the mature cortex; therefore, a brief rearing under an enriched acoustic environment is sufficient to reverse the changes in auditory processing caused by the administration of fluoxetine. These results provide a putative neurobiological basis for the effects of antidepressants on hearing and indicate that antidepressant treatment combined with enriched sensory experiences could optimize clinical outcomes.

Objective: Long intergenic noncoding RNA 00632 (LINC00632) regulates nasal inflammation and CD4+ T cell differentiation into T helper (Th) 2 cells in allergic rhinitis (AR). This study aimed to explore the relationship between LINC00632 and Th1/Th2 balance, and the clinical value of LINC00632 in AR patients. Methods: In total, 120 AR patients, 20 non-atopic obstructive snoring patients as disease controls (DCs), and 20 healthy controls (HCs) were recruited. Their LINC00632 expressions in peripheral blood mononuclear cells were detected by RT-qPCR. Results: LINC00632 expression was declined in AR patients compared with DCs and HCs (both P ˂ 0.001). Moreover, LINC00632 could distinguish AR patients from DCs with an area under curve (AUC) of 0.795 (95% confidence interval [CI]: 0.701–0.889), and from HCs with an AUC of 0.895 (95%CI: 0.831–0.960). LINC00632 was positively related to Th1 cells (P = 0.037) and Th1/Th2 axis (P ˂ 0.001) in AR patients. In addition, LINC00632 was inversely associated with Th2 cells (P ˂ 0.001) and interleukin (IL)-4 (P = 0.010) in AR patients. Besides, LINC00632 was negatively related to rhinorrhea score (P = 0.019), itching score (P = 0.008), sneezing score (P = 0.004), and total nasal symptom score (TNSS) (P ˂ 0.001), but no correlation between LINC00632 and congestion score was observed (P = 0.093). During treatment, LINC00632 was elevated, while TNSS score was reduced (both P ˂ 0.001). Furthermore, LINC00632 increment was associated with the reduction of TNSS score during the therapy (P = 0.005). Conclusion: LINC00632 relates to milder Th1/Th2 imbalance, attenuated nasal symptoms, and better response during 4-week therapy in AR patients.

Background: The genetic transformation of indicarice (Oryza sativa ssp. indica) is limited by its poor in vitro tissue culturability, especially callus browning. Elucidating the common wild rice (Oryza rufipogon Griff.) genes controlling callus browning is a literally fundamental method for improving the tissue culturability of indica rice varieties. Methods and results: In the present study, we used a population of 129 O. rufipogon (Dongxiang common wild rice; DXCWR) introgression lines in the elite cultivar GC2 (Oryza sativa ssp. indica) background and 159 simple sequence repeat (SSR) markers to identify quantitative trait loci (QTLs) associated with callus browning in rice. The callus browning phenotype was evaluated using the indices of the callus browning rate (CBR), callus browning index (CBI), and standard callus browning index (SCBI). Conclusions: We detected 30 QTLs associated with callus browning across the genotypes, which were located on chromosomes 1, 2, 3, 4, 8, 9, and 12. These were repeatedly associated with differences in CBR, CBI, and SCBI. The alleles from DXCWR had an additive effect in reducing callus browning. Especially, we identified new QTLs near RM247 an RM7003 on chromosome 12, indicating the QTLs were unique in DXCWR. Furthermore, we identified six introgression lines with significantly reduced callus browning, which is expected that these lines will be useful materials for the genetic transformation and fine mapping of the culturability trait.

Original end-to-end smart diagnosis framework of systematic critical quality attributes for green manufacturing of phytomedicine.

There is increasing recognition that pathogenic germ line variants drive the development of hematopoietic cancers in many individuals. Currently, patients with hereditary hematologic malignancies (HHMs) receive similar standard therapies and hematopoietic stem cell transplant (HSCT) approaches as those with sporadic disease. We hypothesize that patients with myeloid malignancies and deleterious germ line predisposition variants have different posttransplant outcomes than those without such alleles. We studied 472 patients with myeloid neoplasms, of whom 26% had deleterious germ line variants and 34% underwent HSCT. Deleterious germ line variants in CHEK2 and DDX41 were most commonly seen in American and Australian cohorts, respectively. Patients with deleterious germ line DDX41 variants had a higher incidence of severe (stage 3-4) acute graft-versus-host disease (GVHD) (38%) than recipients with deleterious CHEK2 variants (0%), other HHM variants (12%), or patients without such germ line variants (9%) (P = .002). Importantly, the use of posttransplant cyclophosphamide reduced the risk of severe acute GVHD in patients receiving HSCT for deleterious germ line DDX41-associated myeloid neoplasms (0% vs 53%, P = .03). Based on these results, we advocate the use of posttransplant cyclophosphamide when individuals with deleterious germ line DDX41 variants undergo allogeneic HSCT for myeloid malignancies, even when transplantation has been performed using wild-type donors.

Developing effective bacterial autolytic systems for fast release of intracellular bioproducts could simplify purification procedures and help with the high throughput screening of mutant libraries in protein engineering. Here, we developed a fast and tightly regulated

Gefitinib (GEF) is an anti-tumor oral solid formulation with a superior advantage for lung tumors. However, it has poor aqueous solubility which limits its utility in vivo. Herein, a novel cocrystal (GEF-RES) assembled by GEF and RES (Resveratrol) has been successfully prepared and comprehensively characterized by differential scanning calorimetry, thermogravimetric analysis, Raman spectroscopy and powder X-ray diffraction. A single-crystal structure of the GEF-RES cocrystal was solved and illustrated in detail. In aqueous hydrochloric acid, the GEF-RES cocrystal showed that the maximum concentration of GEF was slightly higher than that of raw GEF. Furthermore, the thermal and physical stability of the GEF-RES cocrystal were also evaluated in this paper. The enhanced solubility and excellent solid-state stability results may provide new potential to the application of key GEF in clinical.

During pandemics, effective interventions require monitoring the problem at different scales and understanding the various tradeoffs between efficacy, privacy, and economic burden. To address these challenges, we propose a framework where we perform Bayesian change-point analysis on aggregate behavior markers extracted from mobile sensing data collected during the COVID-19 pandemic. Results generated by 598 participants for up to four months reveal rich insights: We observe an increase in smartphone usage around February 10th, followed by an increase in email usage around February 27th and, finally, a large reduction in participant’s mobility around March 13th. These behavior changes overlapped with important news events and government directives such as the naming of COVID-19, a spike in the number of reported cases in Europe, and the declaration of national emergency by President Trump. We also show that our detected change points align with changes in large scale external sources, including number of COVID-19 tweets, COVID-19 search traffic, and a large-scale foot traffic data collected by SafeGraph, providing further validation of our method. Our results show promise towards the feasibility of using mobile sensing to understand communities’ responses to public health interventions.

Introduction: Cervical cancer (CC) is the main malignant tumor of gynecology with high mortality. This study aimed to explore the changes of T lymphocyte subsets in the peripheral blood of patients with intermediate and advanced CC (IACC) treated with nimotuzumab (Nimo) combined with chemoradiotherapy (CRT). Methods: Peripheral blood was extracted before and after treatment, and patients were randomly divided into the CRT group (N = 68) or the Nimo + CRT group (N = 68). The levels of tumor markers squamous cell carcinoma antigen (SCCA), carbohydrate antigen 125 (CA125), and carcinoembryonic antigen (CEA), tumor indexes leptin and insulin-like growth factor-2 (IGF2), and key secretory factors (interferon γ/tumor necrosis factor α/interleukin (IL)-4/IL-13) of Th1 and Th2 cells in the serum were detected. The levels of T lymphocyte subsets CD3+, CD4+, CD8+, and CD4+/CD8+ and the levels of Th1/Th2 and Th17/Treg in CD4+ cell subsets were determined by flow cytometry. The objective remission rate, progression-free survival (PFS), and overall survival (OS) of patients were analyzed, and Kaplan-Meier curves were drawn to show the prognosis of patients. Results: After treatment, the levels of SCCA, CA125, CEA, leptin, and IGF2 in the serum of patients with IACC were decreased, the level of Th1/Th2 was increased, and the Th17/Treg level was decreased. The treatment effect of Nimo + CRT was more significant than that of CRT alone. Survival curve analysis showed that Nimo + CRT could prolong PFS and OS in patients with IACC. In addition, the follow-up results of patients showed that Nimo did not increase the incidence and severity of adverse reactions caused by CRT. Conclusion: Nimo combined with CRT can protect the immune function of patients, improve the effective rate, and prolong the survival rate of patients with IACC.

In the current study, we assessed the relationship between mutations and the blood cell counts and early progression of patients with diffuse large-B cell lymphoma (DLBCL). A total of 109 patients with newly diagnosed DLBCL were included in this study.

This paper examines how network structure and coordinating mechanisms in the US power transmission system affect the integration of wind energy through comparative case studies. The two transmission network cases represent two major transmission network governance models in the US power sector. Using archival data from all network participants and interviews with key stakeholders, we find that a centralized transmission network coordinated by an independent network administrative organization (NAO) is more effective in integrating wind power than a less centralized structure. Particularly, the concentration of decision-making authorities is a more substantial determinant than the structural centrality of the core agency. The two cases also highlight that hierarchy, collaboration, and market mechanisms coexist in a transmission network to manage the tension between stability and flexibility. When the network operates in a turbulent environment with great uncertainties, different coordinating mechanisms complement each other to improve system resilience.

In the procedure from composing English, it is inevitable to face the phenomenon of word writing errors. In recent years, English composition automatic correcting system has attracted much attention. However, the precision of the existing word errors correcting system is vague generalization. So as to move forward the accuracy of checking and correcting word errors, this paper designs a word errors correction model based on natural language processing technology. This model designs phoneme matching method based on an improved IDM algorithm, and combined with a non-word input errors correction method based on character distance. The accuracy of correcting non-word errors in this model reached 86.5%. The study also proposes a real-word errors correction method, which is implemented basing on the real-word confusion set and combining the binary statistical model and the GloVe word vector model, improving the real-word errors correction method based on feature annotation of the real-word confusion set, with an accuracy of 77.9%. &nbsp

With the reform of English examination in China in recent years, the automatic evaluation of English essays as subjective questions has always been the focus and difficulty of research. The existing automatic essay evaluation system (AEE) has obtained good feedback on the vocabulary, syntactic and other features of English essays, but there is still a problem of low accuracy in the analysis of potential topic in English essay. In order to solve this problem, this paper takes relational triples as the carrier to analyze the potential topics of English essays. By constructing the hierarchical topic trees hybrid semantic spaces to carry out topic clustering, distributed representation of topic relational triples and topic set extension in English essays. Then, based on the improved on-topic analysis algorithm in this paper, the paper analyzes the topic of English essay in multiple dimensions to obtain more abundant potential on-topic semantic information. The experiment results show that the proposed model can reduce the noise caused by non-topic words effectively, and improve the fine-grained topic semantic space in English essays, and the proposed model has better performance than the current methods of on-topic analysis in English esssays. &nbsp

Higher activity and alkaline α-amylases are desired for textile desizing and detergent additive. Here, rational design was used to improve the specific activity and thermostability of the α-amylase BLA from Bacillus licheniformis. Seventeen mutants of BLA were designed based on sequence consensus analysis and folding free energy calculation, and characterized by measuring their respective activity and thermostability at pH 8.5. Among them, mutant Q360C exhibited nearly threefold improved activity than that of wild-type and retained a higher residual activity (75% vs 59% for wild-type) after preincubation at 70 ℃ for 30 min. The modeled structures and molecular dynamics simulations analysis demonstrated that the enhanced hydrophobic interaction near residue 360 and reduced disturbance to the conformation of catalytic residues are the possible reasons for the improved thermostability and activity of Q360C. The results suggest that 360th of BLA may act as a hotspot for engineering other enzymes in the GH13 superfamily.

Morroniside is the main ingredient of Cornus officinalis and has a variety of biological activities including antioxidative effects. Ovarian granulosa cells (GCs) are responsible for regulating the development and atresia of follicles, which are susceptible to oxidative stress. In this study, we determined whether morroniside can inhibit the oxidative stress of GCs induced by hydrogen peroxide (H2O2), leading to improved oocyte quality. The oxidative damage and apoptosis of ovarian GCs cultured in vitro were induced by the addition of H2O2. After pretreatment with morroniside, the levels of ROS, MDA, and 8-OHdG in ovarian GCs were significantly decreased. Morroniside significantly upregulated p-Nrf2 and promoted the nuclear translocation of Nrf2, which transcriptionally activated antioxidant SOD and NQO1. In addition, morroniside significantly regulated the levels of apoptosis-related proteins Bax, Bcl-2, cleaved caspase-9, and cleaved caspase-3 via the p38 and JNK pathways. These results suggest that morroniside can reduce the oxidative damage and apoptosis of ovarian GCs induced by H2O2.

Hongbao Liang,1– 3,&ast; Chenghong Sun,2,3,&ast; Zhong Feng,2– 4 Xianzhen Wang,2 Lingpeng Kong,2,3 Feng Zhu,2,3 Jingchun Yao,2,3 Xiaomei Yuan,3 Zhong Liu,2,3 Guimin Zhang,2,3 Feng Li1 1School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China; 2Center for Drug Safety Evaluation, Shandong New Time Pharmaceutical Co., Ltd., Linyi, People’s Republic of China; 3State Key Laboratory of Generic Manufacture Technology of Chinese Traditional Medicine, Lunan Pharmaceutical Group Co., Ltd., Linyi, People’s Republic of China; 4School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Feng Li, Shandong University of Traditional Chinese Medicine, No. 4655 Daxue Road, Jinan, 250355, People’s Republic of China, Tel +86 139 6914 1796, Email 13969141796@163.com Guimin Zhang, Lunan Pharmaceutical Group Co., Ltd., State Key Laboratory of Generic Manufacture Technology of Chinese Traditional Medicine, No. 209 Hongqi Road, Linyi, 276006, People’s Republic of China, Tel +86 539-5019206, Email lunanzhangguimin@yeah.netBackground: To improve the dissolution and bioavailability of the component-based Chinese medicine of Ginkgo biloba leaves (GBCCM), a novel nanocrystalline solid dispersion of GBCCM (GBCCM NC-SD) was first prepared.Methods: GBCCM mainly containing high pure flavonoid aglycones (FAs) and terpenoid lactones (TLs) was used as the model drug. PVP K30 and SDS were used as solubilizers, combined stabilizers and carriers, and GBCCM NC-SD was prepared by high-pressure homogenization combined with freeze-dryer. Morphology and crystal characteristic of GBCCM NC-SD were analyzed. The dissolution and bioavailability evaluation were performed to investigate the feasibility of GBCCM NC-SD by in vitro dissolution and in vivo integrated pharmacokinetic models.Results: After homogenizing for 30 cycles under the pressure of 650 bar and freeze-drying, GBCCM NC-SD with uniform quality would be obtained. The particle size, PDI and zeta potential were found to be 335.9 ± 32.8 nm, 0.29 ± 0.02 and − 28.4 ± 0.7 mV respectively. Based on charged aerosol detector (CAD) technology, a new chromatographic method for simultaneous detection of eight components in GBCCM was developed. In vitro drug release study showed that the cumulative dissolution of FAs and TLs in GBCCM NC-SD increased from 12.77% to 52.92% (P < 0.01) and 90.91% to 99.21% (P < 0.05) respectively. In comparison with physical mixture of GBCCM and stabilizer (PM), the integrated pharmacokinetics AUC0-t of FAs and TLs in GBCCM NC-SD were significantly increased (P < 0.05), and the T1/2 of TLs was also significantly prolonged (P < 0.05).Conclusion: This study demonstrated that novel GBCCM NC-SD was prepared using Polyvinylpyrrolidone K30 (PVP K30) and Sodium dodecyl sulfate (SDS) as a synergetic stabilizer and also provided a feasible way to improve the dissolution and oral bioavailability of poorly soluble candidate antihypertensive drugs.Keywords: Ginkgo biloba, flavonoid aglycones, terpenoid lactones, nanocrystalline solid dispersion, integrated pharmacokinetics, charged aerosol detector

Parecoxib sodium is a widely used parenteral cyclooxygenase 2 selective inhibitor to relieve acute postoperative pain following gynecologic laparotomy surgery. To ensure the quality of the drug, a detailed quality specification is indispensable. Nevertheless, it is unavoidable to introduce inorganic impurities during the drug preparation process and how to assess and control them matters. This study proposed an analytical procedure for the determination of elemental impurities (Cd, Pb, As, Hg, Co, V, Ni, Li, Sb, and Cu) in parecoxib sodium, where an easier and safer digestion protocol, graphite digestion, combined with an inductively coupled plasma-mass spectrometer (ICP-MS) was adopted when compared with microwave digestion. Moreover, the study also discussed whether should they be listed in specification to comply with ICH Q3D guidelines after test of process validation batches. Limit of quantitation (LOQ) of the above elemental impurities reached to 0.05, 0.125, 0.375, 0.075, 0.125, 0.25, 0.5, 6.25, 2.25 and 7.5 ppm, respectively, and recovery in accuracy item ranged from 90.2% to 129.9%, reflecting a sensitive and accurate method.

Previous studies on resting-state electroencephalographic responses in patients with depressive disorders have identified electroencephalogram (EEG) parameters as potential biomarkers for the early detection and diagnosis of depressive disorders. However, these studies did not investigate the relationship between resting-state EEG microstates and the early detection of depressive symptoms in preclinical individuals. To explore the possible association between resting-state EEG microstate temporal dynamics and depressive symptoms among college students, EEG microstate analysis was performed on eyes-closed resting-state EEG data for approximately 5 min from 34 undergraduates with high intensity of depressive symptoms and 34 age- and sex-matched controls with low intensity of depressive symptoms. Five microstate classes (A-E) were identified to best explain the datasets of both groups. Compared to controls, the mean duration, occurrence, and coverage of microstate class B increased significantly, whereas the occurrence and coverage of microstate classes D and E decreased significantly in individuals with high intensity of depressive symptoms. Additionally, the presence of microstate class B was positively correlated with participants' Beck Depression Inventory-II (BDI-II) scores, and the presence of microstate classes D and E were negatively correlated with their BDI-II scores. Further, individuals with high intensity of depressive symptoms had higher transition probabilities of A→B, B→A, B→C, B→D, and C→B, with lower transition probabilities of A→D, A→E, D→A, D→E, E→A, E→C, and E→D than controls. These results highlight resting-state EEG microstate temporal dynamics as potential biomarkers for the early detection and timely treatment of depression in college students.

Newcastle disease (ND) and infectious bursal disease (IBD) are two key infectious diseases that significantly threaten the health of the poultry industry. Although existing vaccinations can effectively prevent and treat these two diseases through multiple immunizations, frequent immunization stresses significantly impact chicken growth. In this study, three recombinant adenoviruses, rAd5-F expressing the NDV (genotype VII) F protein, rAd5-VP2 expressing the IBDV VP2 protein, and rAd5-VP2-F2A-F co-expressing F and VP2 proteins, were constructed using the AdEasy system. The F and VP2 genes of the recombinant adenoviruses could be transcribed and expressed normally in HEK293A cells as verified by RT-PCR and Western blot. The three recombinant viruses were shown to have similar growth kinetics as rAd5-EGFP. Compared with the PBS and rAd5-EGFP groups, SPF chickens immunized with recombinant adenoviruses produced higher antibody levels, more significant lymphocyte proliferation, and significantly higher CD4+/CD3+ and CD8+/CD3+ cells in peripheral blood. The survival rate of SPF chickens immunized with rAd5-F and rAd5-VP2-F2A-F after the challenge with DHN3 was 100%, and 86% of SPF chickens showed no viral shedding at 7 dpc. The survival rate of SPF chickens immunized with rAd5-VP2 and rAd5-VP2-F2A-F after the challenge with BC6/85 was 86%. rAd5-VP2 and rAd5-VP2-F2A-F significantly inhibited bursal atrophy and pathological changes compared to the rAd5-EGFP and PBS groups. This study provides evidence that these recombinant adenoviruses have the potential to be developed into safe and effective vaccine candidates for the prevention and control of ND and IBD.

Immunotherapy is effective in the treatment of melanoma due to its immunogenicity. In recent years, researchers have identified LTP is rich in active substances that can induce apoptosis in tumor cells and trigger an immune response. However, it is unclear how LTP works to antitumor by enhancing immune cell function. Therefore, the purpose of this study is to investigate the effects of direct and indirect LTP treatments on the quantity and function of Treg cells and CD8+ T cells in B16-F10 melanoma-bearing mice and their associated mechanisms. The results revealed that both direct and indirect LTP treatments were effective at inhibiting tumor growth and extending the survival of B16-F10 melanoma-bearing mice. In addition, both direct and indirect LTP treatments reduced the number of Treg cells and improved the immune function of CD8+ T cells in the spleen and tumor. Nevertheless, the indirect LTP treatment proved to be more effective than the LTP direct treatment. Mechanistic studies demonstrated that direct LTP treatment might affect the quantity and function of Treg cells and CD8+ T cells by modulating cytokine level changes. However, indirect LTP treatment might have a greater tumor immunotherapeutic potential by inhibiting the activation of key protein molecules in the IL-6/STAT3 signaling pathway and regulating cytokine level changes. In conclusion, this study reveals that LTP exerts an anti-melanoma effect by regulating the level and function of Treg cells and CD8+ T cells. This study is expected to provide new ideas for LTP anti-tumor immunotherapy.

Field experiments were carried out in Western Liaoning Province to investigate the effects of biochar on peanut nitrogen accumulation (NA) and soil properties in aeolian sandy soil and the relationship between NA parameters regulated by biochar and peanut quality. A split-plot design was adopted. Drip irrigation and mulched drip irrigation were used in the main plot, and three biochar application rates of B0 (0 t/ha), B1 (24 t/ha), and B2 (48t/ha) were used in the sub-plots. The results showed that different irrigation methods and biochar application significantly increased NA of peanuts, and NA of peanuts was in line with a logistic growth function (R2༞0.97). In 2020 and 2021, the pod NA of MB1 compared with MB0 treatment increased by 52.28% and 32.58% at pod filling stage, respectively. B2 treatment increased soil organic matter by 109.66%, cation exchange capacity by75.94%, total N content by 5% (P༞0.05), and pH by 15.24% compared with no biochar. The correlation coefficient between soil total N and protein content was 0.73, and that between soil pH and oil was 0.83. Compared with MB2 and DB0, MB1 treatment increased yield by 62.50% and 38.30%, respectively. In conclusion, applying biochar (B1) to a peanut cultivation system in aeolian sandy soil area increased peanut NA, improved soil properties related to peanut quality, broke through environmental barriers and improved peanut quality, which is important for peanut N fixation and improving quality in the semi-arid aeolian sandy soil area of western Liaoning Province.

Elagolix sodium is a gonadotropin-releasing hormone (GnRH) receptor antagonist that inhibits endogenous GnRH signaling by competitively binding to GnRH receptors in the pituitary gland to treat moderate to severe pain associated with endometriosis. To keep the safety and quality of the drug, a fast quantitative method by reversed-phase ultrahigh-performance liquid chromatography coupled with tandem mass spectrometry has been developed and validated for the identification, assay and estimation of potential genotoxic impurities trimethyl phosphate and triisopropyl phosphate in commercial batches of this active pharmaceutical ingredient in accordance with International Conference on Harmonization guidelines Q2 and M7. The method was validated by assessing specificity, sensitivity, linearity, the limit of quantification and detection, accuracy, precision and robustness for above analytes at a very low concentration, whose quantification and detection limits reached to 24 and 4.8 pg/ml, respectively, and the total run time for a single injection was 6 min.

Objectives Mesothelioma is a lethal disease that arises from the serosal lining of organ cavities. Several recurrent alterations have been observed in pleural and peritoneal ­mesotheliomas, including in BAP1, NF2, and CDKN2A. Although specific histopathologic parameters have been correlated with prognosis, it is not as well known whether genetic alterations correlate with histologic findings. Methods We reviewed 131 mesotheliomas that had undergone next-generation sequencing (NGS) at our institutions after pathologic diagnosis. There were 109 epithelioid mesotheliomas, 18 biphasic mesotheliomas, and 4 sarcomatoid mesotheliomas. All our biphasic and sarcomatoid cases arose in the pleura. Of the epithelioid mesotheliomas, 73 were from the pleura and 36 were from the peritoneum. On average, patients were 66 years of age (range, 26-90 years) and predominantly male (92 men, 39 women). Results The most common alterations identified were in BAP1, CDKN2A, NF2, and TP53. Twelve mesotheliomas did not show a pathogenic alteration on NGS. For epithelioid mesotheliomas in the pleura, the presence of an alteration in BAP1 correlated with low nuclear grade (P = .04), but no correlation was found in the peritoneum (P = .62). Similarly, there was no correlation between the amount of solid architecture in epithelioid mesotheliomas and any alterations in the pleura (P = .55) or peritoneum (P = .13). For biphasic mesotheliomas, cases with either no alteration detected or with an alteration in BAP1 were more likely to be epithelioid predominant (>50% of the tumor, P = .0001), and biphasic mesotheliomas with other alterations detected and no alteration in BAP1 were more likely to be sarcomatoid predominant (>50% of the tumor, P = .0001). Conclusions This study demonstrates a significant association between morphologic features associated with a better prognosis and an alteration in BAP1.