M6A methylation of FKFB3 reduced pyroptosis of gastric cancer by NLRP3.

Gastric cancer is a kind of malignant tumor that seriously endangers human life and health. Its incidence rate and mortality rate are among the highest in the global malignant tumors. Therefore, this study explored the role of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in the progression of gastric cancer and its underlying mechanism. Patients with gastric cancer were collected, and human GC cell lines (stomach gastric carcinoma 7901, stomach gastric carcinoma 823 , human gastric carcinoma cell line 803 and adenocarcinoma gastric stomach) were used in this study. We utilized glucose consumption, cell migration, and ELISA assay kits to investigate the function of GC. To understand its mechanism, we employed quantitative PCR (qPCR), western blot, and m6A methylated RNA immunoprecipitation assay. FKFB3 protein expression levels in patients with gastric cancer were increased. The induction of PFKFB3 mRNA expression levels in patients with gastric cancer or gastric cancer cell lines. Gastric cancer patients with high PFKFB3 expression had a lower survival rate. PFKFB3 high expression possessed the probability of pathological stage, lymph node metastasis or distant metastasis in patients with gastric cancer. PFKFB3 upregulation promoted cancer progression and Warburg effect progression of gastric cancer. PFKFB3 upregulation reduced pyroptosis and suppressed nucleotidebinding domain, leucinerich repeat containing protein 3-induced pyroptosis of gastric cancer. M6A-forming enzyme methyltransferase-like 3 increased PFKFB3 stability. Taken together, the M6A-forming enzyme methyltransferase-like 3 increased PFKFB3 stability and reduced pyroptosis in the model of gastric cancer through the Warburg effect. The PFKFB3 gene represents a potential therapeutic strategy for the treatment of gastric cancer.

Combination of 308-nm excimer laser and piperine promotes melanocyte proliferation, migration, and melanin content production via the miR-328/SFRP1 axis.

OBJECTIVE: Both piperine and a 308-nm excimer laser have significant curative effects on vitiligo. This study mainly explored the molecular mechanism of a 308-nm excimer combined with piperine in regulating melanocyte proliferation. METHODS: Epidermal melanocytes were cultured in piperine solution, and the cells were irradiated by an XTRAC excimer laser treatment system at 308-nm output monochromatic light. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were for detecting the expression levels of genes or proteins. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and Transwell method was for assessing cell viability and migration capacity. The content of melanin was also detected. RESULTS: The combination of the 308-nm excimer laser and piperine enhanced the cell proliferation, migration, and melanin production of melanocytes and upregulated the level of miR-328, and restraint of miR-328 reversed the influence of the 308-nm excimer laser and piperine. Secreted frizzled-related protein 1 (SFRP1) is a direct target gene of miR-328, and miR-328 can inhibit the expression of SFRP1 and elevate the protein level of the Wnt/ß-catenin signaling pathway. CONCLUSION: The 308-nm excimer laser combined with piperine may be more efficient than piperine alone in the remedy of vitiligo, and the miR-328/SFRP1 and Wnt/ß-catenin pathways are participated in the proliferation, migration, and melanin synthesis of melanocytes.

Applied anatomy of female pelvic plexus for nerve-sparing radical hysterectomy(NSRH).

BACKGROUND: Nerve-sparing radical hysterectomy(NSRH)has the advantage of reducing postoperative complications and improving postoperative quality of life. The separation and protection of the pelvic plexus in NSRH is extremely important and challenging. METHODS: 24 female cadaveric hemipelves were dissected. Morphologic patterns and compositions of pelvic plexus as well as relationship of pelvic plexus to the surrounding structures were observed and documented. RESULTS: Two patterns of superior hypogastric plexus were observed, including fenestrated and cord-like shape. The origin of bilateral hypogastric nerves were inferiorly to upper margin of promontory about 1.6 ± 0.1 cm and parallel to the ureter in front of the sacrum. Pelvic splanchnic nerves(PSN)from the second sacral nerve, the third sacral nerve and the forth sacral nerve were observed combing with the hypogastric nerves within the lateral rectal ligament. The sacral sympathetic trunk can be identified anteriorly or medially to the anterior sacral foramen. We identified the boundaries of pelvic plexus as following: the upper margin is formed by the PSNs from the third sacral nerve, posterior margin by inferior rectal artery, and anteriorly by vesical venous plexus. The uterine branches from pelvic plexus were observed accompanying with uterine artery, while other branches were inferiorly to the artery. The PSNs were located beneath the deep uterine veins within the cardinal ligament. The upper margin of pelvic plexus was observed directly approach to urinary bladder within the vesico-vaginal ligament as a single trunk accompanying with ureter, between the middle and inferior vesical veins. CONCLUSIONS: Our study clarified the intricate arrangement, distribution and relationship of female pelvic plexus and the related structures to provide reference index for NSRH application. The innervation patterns of bladder and uterine were clarified, and by tracing these visceral branches of pelvic plexus, we suggest several new important land markers for NSRH.

MG53 alleviates hypoxia/reoxygenation-induced cardiomyocyte injury by succinylation and ubiquitination modification.

BACKGROUND: Mitsugumin 53 (MG53) is a membrane repair factor that is associated with acute myocardial infarction. This study aimed to investigate the effects of MG53 on cardiomyocyte injury and the posttranslational modification of MG53. METHODS: Cardiomyocyte injury was evaluated by enzyme-linked immunosorbent assay and flow cytometry. The succinylation and ubiquitination levels of MG53 were examined by immunoprecipitation (IP) and western blot. The relationship between MG53 and KAT3B or SIRT7 was assessed by co-IP and immunofluorescence. RESULTS: The results showed that overexpression of MG53 inhibited inflammation response and apoptosis of cardiomyocytes induced by hypoxia/reoxygenation (H/R). Succinylation and protein levels of MG53 were downregulated in H/R-induced cells, which was inhibited by SIRT7 and promoted by KAT3B. SIRT7 aggravated and KAT3B alleviated MG53-mediated cardiomyocyte injury. Moreover, MG53 was succinylated and ubiquitinated at K130. CONCLUSION: SIRT7 inhibited/KAT3B promoted succinylation of MG53 at K130 sites, which suppressed ubiquitination of MG53 and upregulated its protein levels, thereby alleviating H/R-induced cardiomyocyte injury. The findings suggested that MG53 may be a potential therapy for myocardial infarction.

A Meta-Analysis of the Relationship between Tumor Necrosis Factor-α Polymorphisms and Psoriasis.

BACKGROUND: Some previous studies already explored associations between tumor necrosis factor-α (TNF-α) polymorphisms and psoriasis, with conflicting findings. Here, we aimed to better analyze the relationship between TNF-α polymorphisms and psoriasis in a larger pooled population by performing a meta-analysis. METHODS: We searched Pubmed, Embase, Web of Science and CNKI for related articles. We calculated OR and 95% CI to estimate whether there are genetic associations between TNF-α polymorphisms and psoriasis. RESULTS: Twenty-nine studies were included for this meta-analysis. TNF-α-238 G/A (dominant comparison: OR 0.44, 95% CI 0.34-0.59; recessive comparison: OR 1.63, 95% CI 1.03-2.57; overdominant comparison: OR 2.21, 95% CI 1.71-2.85; allele comparison: OR 0.48, 95% CI 0.36-0.62) and -857 C/T (dominant comparison: OR 0.58, 95% CI 0.41-0.80; overdominant comparison: OR 1.58, 95% CI 1.12-2.23; allele comparison: OR 0.62, 95% CI 0. 0.47-0.82) polymorphisms were found to be significantly associated with psoriasis in the general population. Subgroup analyses indicated that the -238 G/A polymorphism was significantly associated with psoriasis in Caucasians and East Asians, the -308 G/A polymorphism was significantly associated with psoriasis in East Asians, and the -857 C/T polymorphism was significantly associated with psoriasis in Caucasians. CONCLUSIONS: TNF-α -238 G/A, -308 G/A and -857 C/T polymorphisms could be used to identity individuals with elevated susceptibility to psoriasis in certain populations.

Increased ABCC2 expression predicts cisplatin resistance in non-small cell lung cancer.

Long-term use of platinum-based drugs can cause non-small cell lung cancer (NSCLC) to develop extremely strong drug resistance. Increasing the drug dosage does not have better treatment effects and could lead to serious complications. High levels of drug resistance are considered to be characteristic of human tumours and are usually mediated by genes related to multidrug resistance. Multidrug resistance-associated protein 2 (ABCC2), an ATP-binding cassette multidrug resistance transporter, was found to be overexpressed in various human cancers. In this study, we found that ABCC2 was also upregulated in cisplatin (DDP)-resistant A549 cells (A549/DDP). Functional studies demonstrated that ABCC2 knockdown reversed DDP resistance and promoted G1 phase arrest in A549/DDP cells, and PARP and caspase-3 were activated in A549/DDP cells following ABCC2 knockdown. In vivo, ABCC2 knockdown enhanced the cytotoxicity of DDP to subcutaneous A549 tumours. Together, these results suggest that ABCC2 may be a potential therapeutic strategy for overcoming DDP resistance in NSCLC patients. SIGNIFICANCE OF THE STUDY: In this study, we investigated the role of ABCC2 in cisplatin resistance of NSCLC cells. Our data show that ABCC2 expression was associated with resistance to cisplatin and that knockdown ABCC2 could reverse cisplatin resistance in NSCLC cells. Taken together, our study suggests that reducing the expression of ABCC2 could become an important strategy for enhancing the sensitivity of NSCLC cells to cisplatin.

Brain dysfunction of methamphetamine-associated psychosis in resting state: Approaching schizophrenia and critical role of right superior temporal deficit.

Methamphetamine (MA)-associated psychosis (MAP) is highly debilitating and common among individuals who use the drug, yet the underlying neural mechanism is not clear. This study compared brain functions between patients with MAP and those with schizophrenia during resting state and investigated the effect of brain alteration on the association between MA use and psychosis in patients with MAP. Three groups, including 24 patients with MAP, 17 with schizophrenia in first-episode (SCZ) and 31 healthy controls (HCs), were included after receiving a resting-state functional MRI scan. The severity of psychosis was assessed with Positive and Negative Syndrome Scale (PANSS). Imaging data were analysed using regional homogeneity (ReHo) to measure individual's brain function. Compared with the HC subjects, the MAP and SCZ groups had significantly lower ReHo in the cortical regions including left postcentral cortex, right superior temporal gyrus and right rolandic operculum, while had higher ReHo in the left putamen, with brain dysfunctions being more pronounced in the SCZ group. Among the MAP subjects, a mediating effect of ReHo in the right superior temporal gyrus was found on the association between MA use frequency and PANSS positive score. MAP and schizophrenia had a common trend of brain alteration, with the dysfunction being more pronounced in schizophrenia. This finding implicated that MAP might be a condition with neuropathology approaching schizophrenia. The observed critical role of right superior temporal deficit between MA use and psychosis proposed a potential target for interventions.

The structural basis of human Spt16 N-terminal domain interaction with histone (H3-H4)2 tetramer.

FACT (Facilitates Chromatin Transactions) is a heterodimeric protein complex involved in RNA polymerase II transcription elongation, playing essential roles in chromatin remodeling during transcription, replication, and DNA damage repair. The FACT subunit hSpt16 is essential for nucleosome reorganization. The N-terminal domain of hSpt16 (hSpt16-NTD) was recently described as a histone (H3-H4)2-binding domain; however, its mode of interaction remains unknown. In this study, we solved the structure of hSpt16-NTD437 at 2.19 Šand found that a long-disordered region (hSpt16-LDR), after the main body of hSpt16-NTD, is a novel histone-binding motif. Furthermore, hSpt16-LDR interaction with (H3-H4)2 is H3 N-terminal tail-independent. Therefore, Spt16-NTD is a histone H3-H4-specific binding domain with a distinct mechanism of interaction between histones and histone chaperones.

Pyrimethamine exerts significant antitumor effects on human ovarian cancer cells both in vitro and in vivo.

Pyrimethamine has been used principally to treat infections from protozoan parasites. Although previous studies have shown that pyrimethamine exhibited anticancer activity by inducing cellular apoptosis, there are none that show that pyrimethamine possesses anticancer activity with respect to ovarian cancer. We examined the roles of pyrimethamine on apoptosis and proliferation, DNA damage, and cell cycle distribution of human ovarian cancer cell lines in vitro. To investigate the antitumor efficacy of pyrimethamine in vivo, we established two intraperitoneal ovarian carcinoma models in nude mice. Pyrimethamine significantly induced apoptosis of ovarian cancer cells via growth inhibition, cell cycle arrest, and nuclear DNA damage in vitro and manifested antitumor activity by inhibiting tumor growth, thereby prolonging the survival time of tumor-bearing mice. We also demonstrated that pyrimethamine increased the expression of caspase-9 and decreased the expression of X-linked inhibitor of apoptosis protein. In conclusion, the antitumor effects of pyrimethamine were associated with enhanced apoptosis of tumor cells and inhibition of the growth of intratumoral microvessels. Our results indicate that pyrimethamine may provide an effective approach toward inhibiting the growth of ovarian cancer with minimal adverse effects.

Perineal midline vertical incision verses inverted-U incision in the urethroplasty: which is better?

OBJECTIVE: To compare postoperative outcomes between the perineal inverted-U and the vertical midline incision approaches of the urethroplasty and clarify them via gross anatomy. PATIENTS AND METHODS: A total of 461 male patients, from Jan. 2006 to Jun. 2014, who underwent the urethroplasty via perineal midline vertical or inverted-U incision approach were recruited retrospectively. By match pairing for etiology and stricture length, 410 patients from two groups (205 for each group) were selected. Anatomy experiments were also performed. Outcome measurements and statistical analysis: the Chi-square, Student's t and binary logistic regression analyses were performed to compare the operative and postoperative data on the two groups. RESULTS: With regard to patients with bulbar urethral stricture, the rate of surgical site infection (SSI) in perineal inverted-U group was 18.6% while 1.9% in the midline vertical group (p < 0.001). As for patients with posterior urethral stricture, the rate of SSI in the perineal inverted-U group was 16.4% while 3.1% in the midline vertical group (p = 0.001). Mean hospital stay between both groups were 15.8 ± 9.0 vs. 12.7 ± 3.8 days (p < 0.001). Anatomy experiments showed the number of damaged vessels and nerves involved in the inverted-U incision were approximately 1.6 to 2.0 folds more than the vertical midline, but the visual operation fields are similar between two approaches. CONCLUSIONS: The perineal midline vertical incision is a safer approach with fewer SSI and shorter hospital stay than the perineal inverted-U incision for bulbar and posterior urethroplasty.

Long non-coding RNA CASC2 inhibits tumorigenesis via the miR-181a/PLXNC1 axis in melanoma.

Melanoma is the most malignant and aggressive form of skin carcinoma originating in the pigment-producing melanocytes. In this study, to further investigate the molecular mechanisms of the development and progression of melanoma, we explored the impacts of long non-coding RNA (lncRNA) CASC2 on melanoma cell functions. Microarray analysis was carried out to identify the expression of lncRNA CASC2 in melanoma cells. MiR-181a was predicted as a sponging target of CASC2 by miRcode, while the 3'-UTR of Plexin C1 (PLXNC1) was a potential target of miR-181a according to the TargetScan database. The correlation among CASC2, miR-181a, and PLXNC1 was verified by dual luciferase reporter assay and qRT-PCR. After manipulation of CASC2, miR-181a and PLXNC1 expression with transfection in A375 and M14 cells, cell viability, apoptosis, and invasive ability were evaluated using CCK-8, flow cytometry and Transwell assays, respectively. A low expression of CASC2 was detected in melanoma tissues and cells. Dual luciferase reporting assay confirmed that miR-181a targeted the 3'-UTR of PLXNC1. Furthermore, CASC2 could efficiently sponge miR-181a, thereby facilitating the expression of PLXNC1. Up-regulation of CASC2 suppressed the cell proliferation and invasion, but induced the apoptosis of melanoma cells. Our results demonstrated that lncRNA CASC2 can promote PLXNC1 expression by sponging miR-181a, thereby inhibiting the proliferation and invasion of melanoma cells, indicating that lncRNA CASC2 functions via the miR-181a/PLXNC1 axis in melanoma.

Synthesis and Biological Evaluation of Novel 8-Morpholinoimidazo[1,2-a]pyrazine Derivatives Bearing Phenylpyridine/Phenylpyrimidine-Carboxamides.

Herein we designed and synthesized three series of novel 8-morpholinoimidazo[1,2-a]pyrazine derivatives bearing phenylpyridine/phenylpyrimidine-carboxamides (compounds 12a-g, 13a-g and 14a-g). All the compounds were evaluated for their IC50 values against three cancer cell lines (A549, PC-3 and MCF-7). Most of the target compounds exhibited moderate cytotoxicity against the three cancer cell lines. Two selected compounds 14b, 14c were further tested for their activity against PI3Kα kinase, and the results indicated that compound 14c showed inhibitory activity against PI3Kα kinase with an IC50 value of 1.25 µM. Structure-activity relationships (SARs) and pharmacological results indicated that the replacement of the thiopyranopyrimidine with an imidazopyrazine was beneficial for the activity and the position of aryl group has a significant influence to the activity of these compounds. The compounds 13a-g in which an aryl group substituted at the C-4 position of the pyridine ring were more active than 12a-g substituted at the C-5 position. Moreover, the cytotoxicity of compounds 14a-g bearing phenylpyrimidine-carboxamides was better than that of the compounds 12a-g, 13a-g bearing phenylpyridine-carboxamides. Furthermore, the substituents on the benzene ring also had a significant impact on the cytotoxicity and the pharmacological results showed that electron donating groups were beneficial to the cytotoxicity.

Alcaligenes faecalis ZD02, a Novel Nematicidal Bacterium with an Extracellular Serine Protease Virulence Factor.

Root knot nematodes (RKNs) are the world's most damaging plant-parasitic nematodes (PPNs), and they can infect almost all crops. At present, harmful chemical nematicides are applied to control RKNs. Using microbial nematicides has been proposed as a better management strategy than chemical control. In this study, we describe a novel nematicidal bacterium named Alcaligenes faecalis ZD02. A. faecalis ZD02 was isolated from Caenorhabditis elegans cadavers and has nematostatic and nematicidal activity, as confirmed by C. elegans growth assay and life span assay. In addition, A. faecalis ZD02 fermentation broth showed toxicity against C. elegans and Meloidogyne incognita. To identify the nematicidal virulence factor, the genome of strain ZD02 was sequenced. By comparing all of the predicted proteins of strain ZD02 to reported nematicidal virulence factors, we determined that an extracellular serine protease (Esp) has potential to be a nematicidal virulence factor, which was confirmed by bioassay on C. elegans and M. incognita. Using C. elegans as the target model, we found that both A. faecalis ZD02 and the virulence factor Esp can damage the intestines of C. elegans. The discovery that A. faecalis ZD02 has nematicidal activity provides a novel bacterial resource for the control of RKNs.

[Expression and clinical significance of bone morphogenetic protein 6 in human breast cancer].

OBJECTIVE: To investigate the expression pattern and clinical significance of bone morphogenetic protein 6 (BMP6) in breast tissues. METHODS: The tumor and adjacent noncancerous tissues were harvested from 36 cases of breast cancer, the expression level of BMP6 mRNA of each sample was measured by quantitative RT-PCR. Immunohistochemistry study was used to examine BMP6 protein expression in 80 cases of breast cancer, then the relationship between the expression of BMP6 and relevant clinical and pathological parameters was analyzed. RESULTS: BMP6 mRNA expression in breast cancer was significantly reduced when compared with normal breast tissues (P< 0.01), BMP6 mRNA level in estrogen receptor-positive (ER) breast cancer was distinctly higher than that in ER breast cancer. The expression of BMP6 mRNA was correlated to tumor grade (P < 0.01). The expression level of BMP6 protein in breast cancer was associated to ER and PR status, histological grade and Ki-67 status (P < 0.05), but not correlated to age, tumor size, human epidermal factor receptor 2 (Her2) status and molecular subtypes of breast cancer (P > 0.05). CONCLUSION: The ectopic expression of BMP6 may play an important role in the development and progression of breast cancer.

Integrated Fault-Tolerant Control Design With Sampled-Output Measurements for Interval Type-2 Takagi-Sugeno Fuzzy Systems.

This article is concerned with the integrated design of fault estimation (FE) and fault-tolerant control (FTC) for uncertain nonlinear systems suffering from actuator faults and external disturbance. The uncertain nonlinear systems are characterized as the interval type-2 (IT2) Takagi-Sugeno (T-S) fuzzy model, and IT2 membership functions are employed to effectively handle uncertainties. A fuzzy observer, utilizing only sampled-output measurements, is applied to simultaneously estimate actuator faults and system states. Based on the estimation, the fault-tolerant controller is designed to ensure the system stability under a predefined H∞ performance. The sampling behavior complicates the system dynamics and makes the integrated FTC design more challenging. To confront this issue, the discontinuous Lyapunov functional technique is exploited to enhance stability results by considering the sampling characteristic, upon which FE and FTC units are co-designed in the linear matrix inequality (LMI) framework. To further relax stability criteria, the analysis process incorporates the bound information of membership functions through the membership-function-dependent (MFD) method. Additionally, the relationship of mismatched premise variables resulting from the sampling scheme is also taken into account. Moreover, considering the imperfect premise matching (IPM) framework, the proposed fault-tolerant controller provides greater flexibility in selecting the shapes of membership functions and number of fuzzy rules that can vary from the counterpart of the fuzzy system. Finally, the efficacy of the proposed FTC technique is validated through a detailed numerical example.

KCND2: A prognostic biomarker and regulator of immune function in gastric cancer.

BACKGROUND: Gastric cancer is a highly heterogeneous disease, which makes it challenging to develop effective targeted therapies. Although the potassium voltage-gated channel subfamily D (KCND) channels, particularly KCND2 (also known as Kv4.2), have found evidence of involvement in the occurrence and development of various cancers, there are still some limitations in our understanding of KCND2's roles in gastric cancer. METHODS: We analyzed the correlation between KCND2 expression and clinical features as well as immune infiltration using the Cancer Genome Atlas (TCGA) database. Functional assays of KCND2 were conducted using Cell counting Kit-8 (CCK8), clone formation assay and cell cycle analysis. Additionally, immunofluorescence, flow cytometry and quantitative real-time polymerase chain reaction (qRT-PCR) techniques were used to investigate tumor proliferation and immune cell infiltration at different levels of KCND2 expression in vivo. RESULTS: KCND2 was markedly elevated in gastric cancer and its expression appeared to link to different grades, T stages, and N stages. In addition, KCND2 was an independent predictor of prognosis, and its elevated levels in TCGA database revealed a more unfavorable prognosis for patients with gastric cancer. KCND2 strengthened the viability at the cellular level by boosting the proliferation of gastric cancer cells and reducing their death rate. Additionally, it also highlights that KCND2 the abilities of proliferating of gastric cancer cells by stimulating NF-κB both in cell and animal levels. In addition, the findings provided proof that in animal levels, KCND2 might regulate the immune system by associating with promoting M2 macrophages, which are known to play critical roles in cancer progression. Mechanistically, KCND2 was found to lead to the infiltration of M2 macrophages through activation of NF-κB, ultimately promoting the advancement of gastric cancer. CONCLUSION: Overall, these findings suggest that KCND2 is likely to be available as an underlying therapeutic target for gastric cancer.

Characterization of volatiles in flowers from four Rosa chinensis cultivars by HS-SPME-GC × GC-QTOFMS.

Rosa chinensis cultivars with volatile aromas are important resources in the perfume industry. The four rose cultivars introduced to Guizhou province are rich in volatile substances. In this study, volatiles from four Rosa chinensis cultivars were extracted using headspace-solid phase microextraction (HS-SPME), and analyzed with two-dimensional gas chromatography quadrupole time of flight mass spectrometry (GC × GC-QTOFMS). A total of 122 volatiles were identified; the main compounds in these samples were benzyl alcohol, phenylethyl alcohol, citronellol, beta-myrcene and limonene. A total of 68, 78, 71, and 56 volatile compounds were identified in Rosa 'Blue River' (RBR), Rosa 'Crimson Glory' (RCG), Rosa 'Pink Panther' (RPP), and Rosa 'Funkuhr' (RF) samples, respectively. The total volatile contents were in the following order: RBR > RCG > RPP > RF. Four cultivars exhibited similar volatility profiles, with alcohols, alkanes, and esters as the major chemical groups, followed by aldehydes, aromatic hydrocarbons, ketones, benzene, and other compounds. Alcohols and aldehydes were quantitatively the two most abundant chemical groups that included the highest number and highest content of compounds. Different cultivars have different aromas, and RCG had high contents of phenyl acetate, rose oxide, trans-rose oxide, phenylethyl alcohol and 1,3,5-trimethoxybenzene, characterized by floral and rose descriptors. RBR contained a high content of phenylethyl alcohol, and RF contained a high content of 3,5-dimethoxytoluene. Hierarchical cluster analysis (HCA) of all volatiles showed that the three cultivars (RCG, RPP, and RF) had similar volatile characteristics and were significantly different from RBR. Differential metabolites among cultivars were screened based on the OPLS-DA model, and there were six main enriched pathways of differential metabolites: biosynthesis of secondary metabolites, monoterpenoid biosynthesis, metabolic pathways, limonene and pinene degradation, sesquiterpenoid and triterpenoid biosynthesis, and alpha-linolenic acid metabolism. The biosynthesis of secondary metabolites is the most differential metabolic pathway.

Tislelizumab immunotherapy combined with chemotherapy in the treatment of a patient with primary anterior mediastinal undifferentiated pleomorphic sarcoma with high PD-L1 expression: A case report and literature review.

Undifferentiated pleomorphic sarcoma (UPS) is a rare and aggressive soft tissue tumor with a high degree of malignancy and rapid progression, usually occurring in the extremities, retroperitoneum, and abdomen, whereas it rarely arises in the mediastinum, and is treated mainly by surgical resection. The prognosis of patients with advanced sarcoma is poor, and doxorubicin monotherapy is the standard first-line chemotherapy for most advanced soft tissue sarcomas (STS), but the prognosis is generally unsatisfactory. Immune checkpoint inhibitors (ICIs) have been established as therapies for many solid cancers in recent years; however, evidence on the efficacy of ICIs in undifferentiated sarcoma is scarce, mostly consisting of small studies, and no ICIs are currently approved for use in sarcomas. We report a case of a middle-aged man with primary mediastinal UPS with high PD-L1 expression (TPS was approximately 80%) and TLS positive. The patient was treated with sequential tislelizumab monotherapy maintenance after 6 cycles of tislelizumab combined with epirubicin, efficacy evaluation was partial remission (PR), progression-free survival (PFS) was 8.5 months, and grade 1 fatigue was identified as an adverse event.

Comparative study of pancreatic vessels and mesopancreas of rhesus monkeys and humans.

Introduction: With the introduction of the concept of mesopancreas defining the perineural structures that includes neurovascular bundle and lymph nodes extending from the posterior surface of the pancreatic head to behind the mesenteric vessels,Total Mesopancreas Excision (TMpE) based on this theory has facilitated the development of pancreatic cancer surgery in clinical practice in recent years. However, the existence of so called mesopancreas in the human body is still in debate and the comparative study of mesopancreas of rhesus monkey and human have not been well investigated. Purpose: The aim of our study is to compare the pancreatic vessels and fascia of human and rhesus monkeys in anatomical and embryological perspectives and to support the utilization of rhesus monkey as animal model. Methods: In this study, 20 rhesus monkey cadavers were dissected and their mesopancreas location, relationships and arterial distribution were analyzed. We compared the location and developmental patterns of mesopancreas in macaques and humans. Results: The results showed that the distribution of pancreatic arteries in rhesus monkeys was the same as that in humans, which is consistent with phylogenetic similarities. However, the morphological features of the mesopancreas and greater omentum is anatomically different from that of humans, including (1) the greater omentum is not connected to the transverse colon in monkeys. (2) The presence of the dorsal mesopancreas of the rhesus monkey suggests that it be an intraperitoneal organ. Comparative anatomical studies of mesopancreas and arteries in macaques and humans showed characteristic patterns of mesopancreas and similarities in pancreatic artery development in nonhuman primates, consistent with phylogenetic differentiation.

Effects of the CYP3A inhibitors, voriconazole, itraconazole, and fluconazole on the pharmacokinetics of osimertinib in rats.

Background: Osimertinib, as third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is the first-line treatment approved to treat advanced T790M mutation-positive tumors. Triazole antifungals are therapeutic drugs for cancer patients to reduce the risk of opportunistic fungal infections. Our objective was to investigate whether three triazole antifungals (voriconazole, itraconazole, and fluconazole) could change the pharmacokinetics of osimertinib in rats. Methods: The adult male Sprague-Dawley rats were randomly divided into four groups (n = 6): control (0.3% CMC-Na), and voriconazole (20 mg/kg), itraconazole (20 mg/kg), or fluconazole (20 mg/kg) combined with osimertinib (10 mg/kg) group. Tail vein blood samples were collected into heparin tubes at various time points within 0-48 h after osimertinib administration. Osimrtinib's plasma concentration was detected using HPLC-MS/MS system equipped with a Waters XBridge C18 column, with the mobile phase consisting of acetonitrile and 0.2% formic acid water at a flow rate of 0.5 mL/min. Results: Co-administration with voriconazole or fluconazole increased the Cmax of osimertinib by 58.04% and 53.45%, respectively; the AUC0-t increased by 62.56% and 100.98%, respectively. However, when co-administered with itraconazole, the Cmax and AUC0-t of osimertinib only increased by 13.91% and 34.80%, respectively. Conclusions: Our results revealed that the pharmacokinetics of osimertinib were significantly changed by voriconazole and fluconazole in rats, whereas it was slightly affected by itraconazole. This work will contribute to a more comprehensive understanding of the pharmacokinetic properties of osimertinib when co-administered with triazole antifungals.