A Practical and Modular Method for Direct C-H Functionalization of the BODIPY Core via Thianthrenium Salts.

Direct structural modification of small-molecule fluorophores represents a straightforward and appealing strategy for accessing new fluorescent dyes with desired functionalities. We report herein a general and efficient visible-light-mediated method for the direct C-H functionalization of BODIPY, an important fluorescent chromophore, using readily accessible and bench-stable aryl and alkenylthianthrenium salts. This practical approach operates at room temperature with extraordinary site-selectivity, providing a step-economical means to construct various valuable aryl- and alkenyl-substituted BODIPY dyes. Remarkably, this protocol encompasses a broad substrate scope and excellent functional-group tolerance, and allows for the modular synthesis of sophisticated symmetrical and asymmetrical disubstituted BODIPYs by simply employing different combinations of thianthrenium salts. Moreover, the late-stage BODIPY modification of complex drug molecules further highlights the potential of this novel methodology in the synthesis of fluorophore-drug conjugates.

Identification of Anticancer Enzymes and Biomarkers for Hepatocellular Carcinoma through Constraint-Based Modeling.

Hepatocellular carcinoma (HCC) results in the abnormal regulation of cellular metabolic pathways. Constraint-based modeling approaches can be utilized to dissect metabolic reprogramming, enabling the identification of biomarkers and anticancer targets for diagnosis and treatment. In this study, two genome-scale metabolic models (GSMMs) were reconstructed by employing RNA sequencing expression patterns of hepatocellular carcinoma (HCC) and their healthy counterparts. An anticancer target discovery (ACTD) framework was integrated with the two models to identify HCC targets for anticancer treatment. The ACTD framework encompassed four fuzzy objectives to assess both the suppression of cancer cell growth and the minimization of side effects during treatment. The composition of a nutrient may significantly affect target identification. Within the ACTD framework, ten distinct nutrient media were utilized to assess nutrient uptake for identifying potential anticancer enzymes. The findings revealed the successful identification of target enzymes within the cholesterol biosynthetic pathway using a cholesterol-free cell culture medium. Conversely, target enzymes in the cholesterol biosynthetic pathway were not identified when the nutrient uptake included a cholesterol component. Moreover, the enzymes PGS1 and CRL1 were detected in all ten nutrient media. Additionally, the ACTD framework comprises dual-group representations of target combinations, pairing a single-target enzyme with an additional nutrient uptake reaction. Additionally, the enzymes PGS1 and CRL1 were identified across the ten-nutrient media. Furthermore, the ACTD framework encompasses two-group representations of target combinations involving the pairing of a single-target enzyme with an additional nutrient uptake reaction. Computational analysis unveiled that cell viability for all dual-target combinations exceeded that of their respective single-target enzymes. Consequently, integrating a target enzyme while adjusting an additional exchange reaction could efficiently mitigate cell proliferation rates and ATP production in the treated cancer cells. Nevertheless, most dual-target combinations led to lower side effects in contrast to their single-target counterparts. Additionally, differential expression of metabolites between cancer cells and their healthy counterparts were assessed via parsimonious flux variability analysis employing the GSMMs to pinpoint potential biomarkers. The variabilities of the fluxes and metabolite flow rates in cancer and healthy cells were classified into seven categories. Accordingly, two secretions and thirteen uptakes (including eight essential amino acids and two conditionally essential amino acids) were identified as potential biomarkers. The findings of this study indicated that cancer cells exhibit a higher uptake of amino acids compared with their healthy counterparts.

[Pharmacoeconomic evaluation of Suhuang Zhike Capsules using Markov model for inpatients with acute exacerbation of chronic obstructive pulmonary disease].

To evaluate the economics of Suhuang Zhike Capsules in the treatment of acute exacerbation of chronic obstructive pulmonary disease(AECOPD) for inpatients. Based on the published clinical research data, cost-utility analysis was used in this study to evaluate the pharmacoeconomics of Suhuang Zhike Capsules in treatment of AECOPD inpatients from the perspective of medical insu-rance. The test group was treated with Suhuang Zhike Capsules combined with conventional Western medicine, and the control group was treated with conventional Western medicine alone. Treeage software was used to construct a pharmacoeconomic model and perform simulation analysis. The results showed that the cost and output of Suhuang Zhike Capsules combined with the conventional Western medicine were 60 010.18 yuan and 1.92 quality adjusted life year(QALYs), respectively in the simulated 3 years of disease treatment. The cost and output of the conventional Western medicine were 96 730.60 yuan and 1.90 QALYs respectively. Suhuang Zhike Capsules combined with conventional Western medicine required lower cost but achieved higher output, showing cost-utility advantages, so this drug combination was a plan with pharmacoeconomic advantages. The sensitivity analysis results showed that the conclusion was relatively stable. Based on the above results, it is believed that as compared with the conventional Western medicine, Suhuang Zhike Capsules combined with conventional Western medicine have lower cost and higher output for the treatment of AECOPD inpatients, and it is a treatment plan with pharmacoeconomic advantages.

[Genetic association of MKL1 gene polymorphisms with the high-altitude adaptation].

Genetic factors are closely related to the high-altitude adaptation. Several candidate genes have been reported to be significantly associated with high-altitude adaptation. Megakaryocytic leukemia 1 (MKL1) is a transcriptional regulator, which plays crucial roles in the phenotypic modulation of smooth muscle cells. To explore whether MKL1 gene is involved in high-altitude adaptation, we performed genetic association study between MKL1 gene polymorphisms and high-altitude adaptation. We recruited 595 Tibetans from the Qinghai-Tibet plateau and 442 Hans living at low altitude. The SNP rs59098711 locus in the MKL1 gene was genotyped using the MassARRAY assays. We compared the genotypes and allele frequency distributions of rs59098711 between the Hans and Tibetans. The results showed that the genotypes of rs59098711 are significantly different between these two populations (P<0.05). We further compared the genotypes of rs59098711 between Tibetans and other ethnic groups using data from various public databases. We also observed that the genotypes of rs59098711 are significantly different between Tibetans and these other populations (P<0.05). Bioinformatics analyses suggested that rs59098711 could be located at the enhancer region and regulate the expression of the MKL1 gene. Additional study of gene expression data from available public datasets showed that MKL1 gene was up-regulated in a hypobaric hypoxic environment. Our results suggested that the genetic polymorphism rs59098711 locus of the MKL1 gene is associated with high-altitude adaption.

[Efficacy, safety and cost of Qianlieshutong Capsules in the treatment of chronic prostatitis].

OBJECTIVE: To comprehensively evaluate the clinical effect, safety and cost of Qianlieshutong Capsules (QC) in the treatment of chronic prostatitis. METHODS: We searched Cochrane Library, PubMed, Springer, ProQuest, CNKI, Wanfang Data and VIP for randomized controlled trials (RCT) on the treatment of chorionic prostatitis with QC published from January 2000 to May 2018. According to the inclusion and exclusion criteria, two researchers independently completed the screening and evaluation of the articles, extraction of information, and meta-analysis of the included RCTs using the RevMan 5.3 software. RESULTS: Totally 10 RCTs involving 1 796 cases were included in this study, in which the chronic prostatitis patients treated by the combination of QC and quinolones all showed a significantly better response than the controls (P < 0.05). QC combined with quinolones cost an average of ¥23 more than quinolones alone with a 1% increase of therapeutic effectiveness, ¥38.39 more with a 1-unit reduction of WBCs, and ¥38.84 more with a 1-point decrease in the NIH-CPSI score. CONCLUSIONS: The combination of QC with quinolones has a better therapeutic efficacy but a higher cost than quinolones alone in the treatment of chronic prostatitis.

The safety, feasibility, and oncological outcomes of laparoscopic completion total gastrectomy for remnant gastric cancer: a prospective study with 3-year follow-up (FUGES-004 study).

BACKGROUND: The efficacy of laparoscopic completion total gastrectomy (LCTG) for remnant gastric cancer (RGC) remains controversial. METHODS: The primary outcome was postoperative morbidity within 30 days after surgery. Secondary outcomes included 3-year disease-free survival (DFS), 3-year overall survival (OS), and recurrence. Inverse probability treatment weighted (IPTW) was used to balance the baseline between LCTG and OCTG. RESULTS: Final analysis included 46 patients with RGC who underwent LCTG at the FJMUUH between June 2016 and June 2020. The historical control group comprised of 160 patients who underwent open completion total gastrectomy (OCTG) in the six tertiary teaching hospitals from CRGC-01 study. After IPTW, no significant difference was observed between the LCTG and OCTG groups in terms of incidence (LCTG vs. OCTG: 28.0 vs. 35.0%, P =0.379) or severity of complications within 30 days after surgery. Compared with OCTG, LCTG resulted in better short-term outcomes and faster postoperative recovery. However, the textbook outcome rate was comparable between the two groups (45.9 vs. 32.8%, P =0.107). Additionally, the 3-year DFS and 3-year OS of LCTG were comparable to those of OCTG (DFS: log-rank P =0.173; OS: log-rank P =0.319). No significant differences in recurrence type, mean recurrence time, or 3-year cumulative hazard of recurrence were observed between the two groups (all P >0.05). Subgroup analyses and concurrent comparisons demonstrated similar trends. CONCLUSIONS: This prospective study suggested that LCTG was noninferior to OCTG in both short-term and long-term outcomes. In experienced centers, LCTG may be considered as a viable treatment option for RGC.

Accuracy of computer-assisted dynamic navigation when performing coronectomy of the mandibular third molar: A pilot study.

OBJECTIVES: The study represents a preliminary evaluation of the accuracy of the dynamic navigation system (DNS) in coronectomy of the mandibular third molar (M3M). METHODS: The study included participants with an impacted M3M near the inferior alveolar canal. The coronectomy planes were designed before the surgery using cone-beam computed tomography (CBCT) imaging data and then loaded into the DNS program. Intraoperatively, the navigation system was used to guide the complete removal of the target crown. Postoperative CBCT imaging was used to assess any three-dimensional deviations of the actual postoperative from the planned preoperative section planes for each patient. RESULTS: A total of 12 patients (13 teeth) were included. The root mean square (RMS) deviation of the preoperatively designed plane from the actual postoperative surface was 0.69 ± 0.21 mm, with a maximum of 1.45 ± 0.83/-1.87 ± 0.63 mm deviation. The areas with distance deviations < 1 mm, 1-2 mm, and 2-3 mm were 71.97 ± 5.72 %, 22.96 ± 6.57 %, and 4.52 ± 2.28 %, respectively. Most patients showed extremely high convexity of the surface area located in the mesial region adjacent to the base of the extraction socket. There was no observable evidence of scratching of the buccolingual bone plate at the base of the extraction socket by the handpiece drill. CONCLUSIONS: These results provide preliminary support for the use of DNS-based techniques when extracting M3M using a buccal approach. This would improve the accuracy of coronectomy and reduce the potiential damage to the surrounding tissue. CLINICAL SIGNIFICANCE: DNS is effective for guiding coronectomy.

Precise determination of major and trace elements in micrometer-scale ilmenite lamellae in titanomagnetite using LA-ICP-MS technique: application of regression analysis to time-resolved signals.

Laser ablation ICP-MS (LA-ICP-MS) is a powerful microbeam technique capable of rapid and precise determination for a large spectrum of trace elements at ppm or sub-ppm levels. Micrometer-scale minerals and inclusions are very common in geological materials, for which direct measurement is restricted by the spot size using LA-ICP-MS (generally 20-50 µm). In this study, ilmenite lamellae intergrown with magnetite were selected as an example to describe a practical algorithm that applies regression analysis to extract the chemical compositions of binary phases from mixed LA-ICP-MS signals. The method accuracy is confirmed by the agreement between the regressed value for various trace elements in ilmenite exsolutions and their reference values (direct analyses using EPMA and LA-ICP-MS). Results were obtained for most detectable components (Mg, Mn, V, Nb, Ta, Sc, Zr, Hf, Sn, et c.) and their relative deviations are within ±10%, even for those <10 ppm (such as Hf and W). Relative standard errors on the regressed value were calculated to evaluate the precision of the method, which is mostly within 10%, and the worst up to 25%. Therefore, the algorithm described in this contribution provides a solution for precise determination of trace element compositions for micrometer-scale ilmenite lamellae in titanomagnetite using LA-ICP-MS, and is potentially practical for other geological materials.

Fuzzy optimization for identifying anti-cancer targets with few side effects in constraint-based models of head and neck cancer.

Computer-aided methods can be used to screen potential candidate targets and to reduce the time and cost of drug development. In most of these methods, synthetic lethality is used as a therapeutic criterion to identify drug targets. However, these methods do not consider the side effects during the identification stage. This study developed a fuzzy multi-objective optimization for identifying anti-cancer targets that not only evaluated cancer cell mortality, but also minimized side effects due to treatment. We identified potential anti-cancer enzymes and antimetabolites for the treatment of head and neck cancer (HNC). The identified one- and two-target enzymes were primarily involved in six major pathways, namely, purine and pyrimidine metabolism and the pentose phosphate pathway. Most of the identified targets can be regulated by approved drugs; thus, these drugs are potential candidates for drug repurposing as a treatment for HNC. Furthermore, we identified antimetabolites involved in pathways similar to those identified using a gene-centric approach. Moreover, HMGCR knockdown could not block the growth of HNC cells. However, the two-target combinations of (UMPS, HMGCR) and (CAD, HMGCR) could achieve cell mortality and improve metabolic deviation grades over 22% without reducing the cell viability grade.

Renoprotective effects of pirfenidone on chronic renal allograft dysfunction by reducing renal interstitial fibrosis in a rat model.

AIM: Pirfenidone (PFD) has been used as medication for idiopathic pulmonary fibrosis due to its ability in reducing lung fibrosis. However, the underlying mode of action in renal fibrosis during chronic renal allograft dysfunction (CRAD) requires further investigation. Therefore, the present study was conducted to explore the effects of PFD on renal injury induced by CRAD. MAIN METHODS: Initially, the CRAD rat model was established, followed by the intragastric administration of PFD to the rats. Urine and blood samples were collected and tested against indicators of renal functions. The renal tissues were microscopically observed to determine the changes in pathological morphology. The anti-inflammatory, anti-fibrotic and anti-oxidant properties of PFD were explored in the setting of CRAD. KEY FINDINGS: The success rate of model establishment was 92.31%, which was reflected by weight loss, appetite loss, faded fur, and retarded reaction, with the symptoms found to exacerbate with time. PFD treatment could improve renal function, ameliorate inflammation and renal fibrosis as well as promote the anti-oxidant ability of renal allograft, indicating its potential role as an effective therapeutic agent for CRAD. SIGNIFICANCE: In conclusion, PFD was found to have renoprotective effects on renal injury induced by CRAD, which resulted in the alleviation of inflammation and renal fibrosis, providing novelty for CRAD clinical treatment.