Design, synthesis, and biological evaluation of N-(pyridin-3-yl)pyrimidin-4-amine analogues as novel cyclin-dependent kinase 2 inhibitors for cancer therapy.

The discovery and development of CDK2 inhibitors has currently been validated as a hot topic in cancer therapy. Herein, a series of novel N-(pyridin-3-yl)pyrimidin-4-amine derivatives were designed and synthesized as potent CDK2 inhibitors. Among them, the most promising compound 7l presented a broad antiproliferative efficacy toward diverse cancer cells MV4-11, HT-29, MCF-7, and HeLa with IC50 values of 0.83, 2.12, 3.12, and 8.61 µM, respectively, which were comparable to that of Palbociclib and AZD5438. Interestingly, these compounds were less toxic on normal embryonic kidney cells HEK293 with high selectivity index. Further mechanistic studies indicated 7l caused cell cycle arrest and apoptosis on HeLa cells in a concentration-dependent manner. Moreover, 7l manifested potent and similar CDK2/cyclin A2 nhibitory activity to AZD5438 with an IC50 of 64.42 nM. These findings revealed that 7l could serve as ahighly promisingscaffoldfor CDK2 inhibitors as potential anticancer agents and functional probes.

Association of biopsy core number and location with pain in patients undergoing a transperineal prostate biopsy under local anaesthesia: a secondary analysis of the APROPOS trial.

BACKGROUND: APROPOS was a multicentre, randomized, blinded trial focus on investigating the perineal nerve block versus the periprostatic block in pain control for men undergoing a transperineal prostate biopsy. In the analysis reported here, the authors aimed to evaluate the association of biopsy core count and location with pain outcomes in patients undergoing a transperineal prostate biopsy under local anesthesia. METHODS: APROPOS was performed at six medical centers in China. Patients with suspected prostate cancer were randomized to receive either a perineal nerve block or a periprostatic block (1:1), followed by a transperineal prostate biopsy. The secondary analysis outcomes were the worst pain experienced during the prostate biopsy and postbiopsy pain at 1,6, and 24 h. RESULTS: Between 12 August 2020 and 20 July 2022, a total of 192 patients were randomized in the original trial, and 188 were involved in this analysis, with 94 patients per group. Participants had a median (IQR) age of 68 (63-72) and a median (IQR) prostate volume of 42.51 (30.04-62.84). The patient population had a median (IQR) number of biopsy cores of 15 (12-17.50), and 26.06% of patients had a biopsy cores count of more than 15. After adjusting the baseline characteristics, the number of biopsy cores was associated with the worst pain during the biopsy procedure in both the perineal nerve block group ( ß 0.19, 95% CI: 0.12-0.26, P <0.001) and the periprostatic block group ( ß 0.16, 95% CI: 0.07-0.24, P <0.001). A similar association was also evident for the postbiopsy pain at 1, 6, and 24 h. A lesser degree of pain in both groups at any time (r range -0.57 to -0.01 for both groups) was associated with biopsy cores from the peripheral zone of the middle gland, while other locations were associated with a higher degree of pain. In addition, the location of the biopsy core had less of an effect on pain during the biopsy (r range -0.01-0.25 for both groups) than it did on postbiopsy pain (r range -0.57-0.60 for both groups). CONCLUSIONS: In this secondary analysis of a randomized trial, biopsy core count and location were associated with pain in patients undergoing a transperineal prostate biopsy under local anesthesia. These results may be helpful for making clinical decisions about the anesthetic approach for scheduled transperineal prostate biopsies.

Perineal nerve block versus periprostatic block for patients undergoing transperineal prostate biopsy (APROPOS): a prospective, multicentre, randomised controlled study.

Background: We aimed to investigate perineal nerve block versus periprostatic block in pain control for men undergoing a transperineal prostate biopsy. Methods: In this prospective, randomised, blinded and parallel-group trial, men in six Chinese hospitals with suspected prostate cancer were randomly assigned (1:1) at the point of local anaesthesia to receive a perineal nerve block or periprostatic block and followed by a transperineal prostate biopsy. Centres used their usual biopsy procedure. Operators who performed anaesthesia were trained in both techniques before the trial and were masked to the randomised allocation until the time of anaesthesia and were not involved in the subsequent biopsy procedure and any assessment or analysis. Other investigators and the patients were masked until trial completion. The primary outcome was the level of the worst pain experienced during the prostate biopsy procedure. Secondary outcomes included pain (post-biopsy at 1, 6 and 24 h), changes in blood pressure, heart rate and breathing rate during the biopsy procedure, external manifestations of pain during biopsy, anaesthesia satisfaction, the detection rate of PCa and clinically significant PCa. This trial is registered on ClinicalTrials.gov, NCT04501055. Findings: Between August 13, 2020, and July 20, 2022, 192 men were randomly assigned to perineal nerve block or periprostatic block, 96 per study group. Perineal nerve block was superior for the relief of pain during the biopsy procedure (mean 2.80 for perineal nerve block and 3.98 for periprostatic block; adjusted difference in means -1.17, P < 0.001). Although the perineal nerve block had a lower mean pain score at 1 h post-biopsy compared with the periprostatic block (0.23 vs 0.43, P = 0.042), they were equivalent at 6 h (0.16 vs 0.25, P = 0.389) and 24 h (0.10 vs 0.26, P = 0.184) respectively. For the change in vital signs during biopsy procedure, perineal nerve block was significantly superior to periprostatic block in terms of maximum value of systolic blood pressure, maximum value of mean arterial pressure and maximum value of heart rate. There are no statistical differences in average value of systolic blood pressure, average value of mean, average value of heart rate, diastolic blood pressure and breathing rate. Perineal nerve block was also superior to periprostatic block in external manifestations of pain (1.88 vs 3.00, P < 0.001) and anaesthesia satisfaction (8.93 vs 11.90, P < 0.001). Equivalence was shown for the detection rate of PCa (31.25% for perineal nerve block and 29.17% for periprostatic block, P = 0.753) or csPCa (23.96% for perineal nerve block and 20.83% for periprostatic block, P = 0.604). 33 (34.8%) of 96 patients in the perineal nerve block group and 40 (41.67%) of 96 patients in the periprostatic block group had at least one complication. Interpretation: Perineal nerve block was superior to periprostatic block in pain control for men undergoing a transperineal prostate biopsy. Funding: Grant 2019YFC0119100 from the National Key Research and Development Program of China.

Rational design, synthesis and biological evaluation of novel 2-(substituted amino)-[1,2,4]triazolo[1,5-a]pyrimidines as novel tubulin polymerization inhibitors.

Following our previously reported compound 3, we designed and synthesized a series of new 2-(substituted amino)- [1,2,4]triazolo[1,5-a]pyrimidines as potential tubulin polymerization inhibitors. Among them, analogue 4k, having a 3-hydroxy-4-methoxyphenylamino group, was observed to display excellent antiproliferative activity toward HeLa, HCT116, A549, and T47D with the IC50 values of 0.31, 1.28, 3.99 and 10.32 µM, respectively, which were approximately 32, 48, 4, and 5-fold improvement compared with 3. Importantly, 4k possessed significant selectivity in inhibiting cancer cell lines over the normal HEK293 cells. Moreover, futher mechanism analysis demonstrated that 4k caused G2/M arrest, induced cells apoptosis in HeLa cells, and manifested significant tubulin polymerization inhibitory activity with the IC50 value of 4.9 µM, which is comparable to CA-4 (IC50 = 4.2 µM). The observations performed in this study reveal that 2-arylamino- [1,2,4]triazolo[1,5-a]pyrimidines represent a novel class of tubulin polymerization inhibitors with potent antiproliferative efficacy.

Efficient synthesis and evaluation of novel 6-arylamino-[1,2,4]triazolo[4,3-a]pyridine derivatives as antiproliferative agents.

Based on our previous work, a series of novel 6-arylamino-[1,2,4]triazolo[4,3-a]pyridine derivatives were synthesized, and evaluated for antiproliferative activities. SAR studies revealed that inserting an amino linkage between 6­aryl group and [1,2,4]triazolo[4,3-a]pyridine core led to amuch broaderantitumorspectrum, and the most promising compound 8 l exerted potent andbroad-spectrum antiproliferative activity toward HeLa, HCT116, MCF-7, and A549 cell lines, with IC50 values in the micromolar range of 5.98-12.58 µM, which were more active than the positive control 5-FU. The mechanism investigation illustrated that 8 l dose-dependently caused cell cycle arrest at the G2/M phase, and induced cell apoptosis in HeLa cells. Consequently, these findings suggest the 6-arylamino-[1,2,4]triazolo[4,3-a]pyridines afford significant potential for the discovery of a new highly efficient anticancer agents.

Anti-Allergic Rhinitis Mechanism of Bikangfu via Regulation of IL-35/STAT3， Inhibition of Eosinophil Activation and Improvement of Immune Function / 中国实验方剂学杂志

ObjectiveTo investigate the mechanism of interleukin-35（IL-35）/signal transducer and activator of transcription 3（STAT3）inhibition of eosinophil activation against allergic rhinitis（AR） by Bifukang. MethodOne hundred patients were randomly divided into a control group and a treatment group，50 cases in each group. The control group was given mometasone furoate nasal spray，and the treatment group was given Bifukang by nasal packing. The course of treatment was 28 days. The clinical efficacy，nasal classification and visual analogue scale（VAS） score of the two groups were observed before and after treatment. Enzyme linked immunosorbent assay（ELISA） was used to detect the expression levels of inflammatory factors ［interleukin（IL）-4，IL-10，IL-17，IL-35］ and Eotaxin and CC chemokine receptor-3（CCR3）in serum and nasal secretion of the two groups. The expression levels of STAT1，STAT3 and STAT4 were detected by real-time polymerase chain reaction（Real-time PCR）.The content of immunoglobulin G（IgG） and the ratio of CD4+/CD8+were detected by ELISA and flow cytometry. ResultAfter treatment， compared with before treatment， the levels of IL-4 and IL-17 in serum and nasal secretion in 2 groups were decreased， while the levels of IL-10 and IL-35 were increased （P<0.05， P<0.01）. The expression of STAT1， STAT2 and STAT3 in nasal secretions were significantly decreased （P<0.05）. IgG and CD4+/CD8+ were decreased， and the differences were statistically significant （P<0.05， P<0.01）.After treatment，compared with the control group，the levels of IL-4 and IL-17 in serum and nasal secretions of the treatment group were decreased，while the levels of IL-10 and IL-35 were increased （P<0.05）. The expression of STAT1，STAT3 and STAT4 in the treatment group was significantly inhibited compared with the control group after treatment （P<0.05）. In addition， the post-treatment serum CD4+/CD8+ and immunoglobulin G （IgG） levels were reduced in the treatment group compared with those of the control group （P<0.05， P<0.01）. During the treatment，there were no abnormal changes in heart，liver，kidney function and routine blood and urine tests in the two groups. ConclusionBifukang has a good effect on allergic rhinitis，and its mechanism may be related to the regulation of IL-35/STAT3 pathway，the inhibition of eosinophil activation and the improvement of related immune function.

Short-Term Effect of Modified Kaijie Huatantang on Chronic Rhinosinusitis with Nasal Polyp Due to Qi Stagnation Phlegm Syndrome / 中国实验方剂学杂志

Objective:To observe the short-term effect of modified Kaijie Huatantang on chronic rhinosinusitis with nasal polyp due to qi stagnation phlegm syndrome. Method:A total of 90 cases were divided into control group and observation group，with 45 cases in each group. The control group was given mometasone furoate，and the observation group was given modified Kaijie Huatantang after nasal endoscopy surgery for 4 weeks. After treatment and follow-up for 1 years，the sino-nasal outcome test-20（SNOT-20），Lund-Kennedy and traditional Chinese medicine（TCM） syndrome were observed. The serum and nasal secretions tumor necrosis factor-alpha（TNF-<italic>α</italic>），interleukin（IL）-1<italic>β</italic>，IL-8，IL-17，eosinophilic cationic protein（ECP） and immunoglobulin E（IgE） were detected before and after treatment. The safety，clinical efficacy after treatment and follow-up for 1 years were compared between two groups. Result:After treatment and follow-up for 1 years，the total control rates were 97.7%，93.0% in observation group， which were higher than 87.8%，75.6% in control group（<italic>P</italic><0.05）. Compared with the control group after treatment and follow-up for 1 years，SNOT-20，Lund-Kennedy and TCM syndrome scores in the observation group decreased in the same period（<italic>P</italic><0.05）. Compared with the control group after treatment，the serum and nasal secretions TNF-<italic>α</italic>，IL-1<italic>β</italic>，IL-8，IL-17，ECP and IgE in the observation group were significantly decreased（<italic>P</italic><0.05）. The incidence of postoperative complications was 2.3% in the observation group， which was lower than 17.1% in the control group（<italic>P</italic><0.05）. The incidence of adverse reactions was 4.7% in the observation group， which was lower than 41.5% in the control group（<italic>P</italic><0.05）. Conclusion:Modified Kaijie Huatantang can significantly improve the short-term clinical efficacy of patients with chronic rhinosinusitis and nasal polyp due to Qi stagnation phlegm obstruction，with a low incidence of adverse reactions.

Effect of Modified Shuzhong Huatantang Replace Hormone on Children with Chronic Rhinosinusitis and Adenoid Hypertrophy due to Spleen Deficiency and Phlegm Obstruction After Operation / 中国实验方剂学杂志

Objective:To observe the effect of modified Shuzhong Huatantang replace hormone on children with rhinosinusitis and adenoid hypertrophy due to spleen deficiency and phlegm obstruction after operation. Method:Eighty cases were randomly divided into control group and observation group，40 cases in each group. After nasal endoscopy，the control group was given mometasone furoate，and the observation group was given modified Shuzhong Huatantang for 6 week. The nasal situation Lund-Kennedy assessment scal（Lund-Kennedy），adenoid thickness /nasopharyngeal cavity width （A/N），TCM syndrome were observed for before treatment，6，24，and 48 weeks after operation. The contents of immunoglobulin E（IgE），eosinophilic cationic protein（ECP），eosinophilic granulocyte（EOS），tumor necrosis factor-alpha（TNF-<italic>α</italic>），interleukin-1<italic>β</italic>（IL-1<italic>β</italic>），interleukin-17（IL-17） in serum and nasal secretions were detected before and 48 weeks after operation. The clinical efficacy，complications，recurrence 48 weeks after operation were compared between the two groups. Result:Three cases of abscission in the control group and one case in the observation group during the study period. The total control rate was 94.9% in the observation group higher than that 75.7% in the control group six weeks after the operation（<italic>χ</italic>²=6.972，<italic>P</italic><0.05）. The recurrence rate was 2.6% in the observation group lower than that 18.9% in the control group 48 weeks after operation（<italic>χ</italic>²=4.137，<italic>P</italic><0.05）. To compared with the control group at 6，24 and 48 weeks after operation，Lund-Kennedy，A/N，TCM syndromes in the observation group decrease in the same period （<italic>P</italic><0.05）. To compared with the control group 48 weeks after operation，The TNF-<italic>α</italic>，IL-1<italic>β，</italic>IL-17，IgE，ECP，EOS in serum and nasal secretions in the observation group were reduced （<italic>P</italic><0.05）. The incidence of adverse reactions was 2.7% in the observation group lower than that 29.7% in the control group. Conclusion:Modified Shuzhong Huatantang can significantly improve the postoperative clinical symptoms with chronic rhinosinusitis and adenoid hypertrophy due to spleen deficiency and phlegm obstruction，and the recurrence rate is lower.

Next-Generation Sequencing Reveals That Oxidative Phosphorylation Might Be a Key Pathway Differently Expressed in the Third and Fourth Stages Larvae of Angiostrongylus cantonensis.

BACKGROUND: When Angiostrongylus cantonensis develops from the third and fourth stage, it needs to change its host from the middle host, snail to the final host, rat. However, the mechanism involved in this change remains unclear. METHODS: The transcriptome differences of the third and fourth stages of A. cantonensis were explored by next-generation Illumina Hiseq/Miseq sequencing in China, in 2018. RESULTS: Overall, 137 956 488 clean reads and 20 406 213 373 clean bases of the two stages larvae were produced. Based on the queries against the Gene Ontology (GO), NCBI non-redundant protein sequences (Nr), Swissprot, and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, 14 204 differentially expressed genes (DEGs) were predicted. GO enrichment analysis revealed 5660 DEGs with the top s categories as followings: biological process (GO:0008150, related to 5345 DEGs), cellular component (GO:0005575, related to 5297 DEGs), molecular function (GO:0003674, related to 5290 DEGs). In KEGG enrichment analysis, 116 genes were related to oxidative phosphorylation and 49 genes involved in the glycolytic process. CONCLUSION: Metabolism changes, especially oxidative phosphorylation and glycolysis, might play a key role in A. cantonensis infection of its final rat host. Many other pathways might also contribute to the transcriptome changes between these two life stages. Overall, additional studies are needed for further details.

Effect of Modified Huading Loulutang on Postoperative Recovery of Chronic Rhinosinusitis with Secretory Otitis Media Due to Toxic Heat Syndromes / 中国实验方剂学杂志

Objective:To observe the efficacy of modified Huading Loulutang on postoperative recovery of chronic rhinosinusitis with secretory otitis media due to toxic heat syndromes and the effect of eosinophil cationic protein (ECP), immunoglobulin E (IgE) and intercellular adhesion molecule-1 (ICAM-1) in serum, nasal secretion and otitis media. Method:According to the random number table method, 90 cases were divided into control group and observation group, with 45 cases in each group. All patients were given ceftriaxone sodium + hydroxymezoline after nasal endoscopy. In addition, control group was given Biyuan Tongqiao granule, while observation group was given modified Huading Loulutang for 6 weeks. Lund-Kennedy nasal assessment scale, traditional Chinese medicine symptoms and threshold of hearing at different frequencies were observed in two groups before and after treatment and during 6-week and 18-week follow-up visits. The levels of ECP, IgE and ICAM-1 in serum, nasal and ear secretions were detected before and after treatment. Clinical symptoms, adverse reactions and 12-month recurrence rate were compared. Result:Total control rate was 97.7% (43/44, 95%CI [95.6，98.6]) in observation group, which was higher than 78.6% (33/42, 95%CI [72.4，83.5]) in control group (χ2=6.946, P<0.05). During the 12-month follow-up visit, the recurrence rate was 4.5% (2/44, 95%CI [3.7，5.8]) in observation group, which was lower than 19.0% (8/42, 95%CI[16.8，21.3]) in control group (P<0.05). After treatment, Lund-Kennedy and traditional Chinese medicine symptoms score during 6-week and 18-week follow-up visits in observation group were significantly lower than those in control group (P<0.05). Hearing threshold in observation group at different frequencies was significantly lower than that in control group (P<0.05). ECP, IgE and ICAM-1 levels in serum, nasal and auricular secretions in observation group were significantly lower than those in control group (P<0.05). The incidence of adverse reactions was 6.8% (3/44, 95%CI [5.3，8.1]) in observation group, which was lower than 28.6% (12/42,95%CI [25.3，30.2]) in control group (P<0.05). Conclusion:Modified Huading Loulutang can significantly improve postoperative clinical symptoms of chronic rhinosinusitis and otitis media due to toxic heat syndromes with secretion, with a low recurrence rate and fewer complications.

Practice and exploration of the tuition-free medical students' in rural areas of Sichuan province / 中国卫生政策研究

Objective:This paper summarizes the practical problems encountered in the implementation of the tuition-free medical students' policyin rural areas of Sichuan Province, and provides a reference for the implementation of this policy across the province. Methods :Semi-structured interviews were conducted with the principals of the orientation management policies of the health administrative departments and county level and primary health care in-stitutionsin Sichuan, and the focus group interviews were used to understand the dynamics of directed students. Results :The survey results showed that there were limited channels for students to understand the policy ; students' barren understanding of the work of grass-roots doctors ; credit and integrity files played a relatively low role in retaining medical talent students;the willingness of orientation students is higher, but there is a contradiction between applying for graduate students and retaining grassroots in rural areas ; and the relevant departments lacked a rational and efficient management mode for students. Conclusions :In order to ameliorate the construction of rural health human resources,policy administrators should place their emphasis on cultivating the sense of honor and responsibility in the rural-oriented tuition-free medical students'policy, improve the reward and punishment mechanism in policies, optimize the management and assessment process, and promote the orientation of the work among the various policy-participating departments in a more harmonious and orderly manner.

Calcaneal varus angle change in normal calcaneus: a three-dimensional finite element analysis.

The objective of the study was to investigate the stress changes in the posterior articular surface of the calcaneus following alternation of the calcaneal varus angle in normal calcaneus and discuss the clinical significance of the calcaneal varus angle. Axial view radiographs of 165 volunteers were obtained to measure the calcaneal varus angle of normal calcaneus. A calcaneal model with different varus angle changes (including +2°, +4°, +6°, -2°, -4°, and -6°) was established using Creo 2.0 software. Stress changes at different calcaneal varus angles in the posterior articular surface of the calcaneus under a load of 100 N were measured. Stressed areas in posterior articular facets were slightly fewer following +2°, +4°, and +6° changes in varus angle than in normal varus angles with stress concentering regions moving to the anteromedial aspect of the posterior calcaneal facet. However, stress concentering areas in posterior calcaneal facets following -4° and -6° changes in varus angle obviously moved to the anterior and posterior medial side of posterior calcaneal facets. Stress distribution in the posterior articular surface of the calcaneus varies with the calcaneal varus angle. The decrease in calcaneal varus angle following operative treatment of calcaneal fractures should be controlled within 2°.

Design and application of performance salary allocation scheme in operating room / 中华护理杂志

Objective To realize long-term effective mechanism of performance salary allocation scheme in operating room based on fair and transparent with more pay for more work,excellent pay for excellent work.Methods Based on resource based relative value scale (RBRVS),a performance salary allocation scheme was designed and implemented,taking workload accounting as basis,involving multidimensional comprehensive evaluation.Results After implementation,proportion of surgery time was increased from 57.63％ to 71.22％ (P＜0.05),while proportion of non-surgical worktime was decreased from 42.37％ to 28.78％(P＜0.05).Conclusion The improved performance salary allocation scheme can mobilize nurses' work enthusiasm and improve work efficiency;it can realize objective data collection,reduce second distribution and ensure openness and transparency;it can reflect overtime labor value with scientific index design.

[Study on preparations and fluorescent properties of rare earth complex with property of fluorescence sensor].

Europium chloride, 2-thienylformyltrifluoroacetone and sodium silicate were used to synthesize new-style rare earth complex (Eu-TNS). By adding into dichloromethane solution containing Eu-TNS, the fluorescent intensities were enhanced gradually and regularly. High-resolution mass spectrometry was used to detect the formula of Eu-TNS, which belongs to multi-core rare-earth complex. Polarity of solution increasing by adding absolute ethanol will cause Eu-TNS to dissociate, which enhances the fluoresceot intensities of Eu-TNS solution. This rare earth complex Eu-TNS can be employed as fluorescence sensor to detect the content of ethanol in organic solvent.

Analysis of TCR V? repertoire and clonality of CD4~+ and CD8~+ T cells in patients with CML / 中国免疫学杂志

Objective:To investigate the gene expression of TCR V? subfamily T cells and clonality in peripheral blood CD4+ and CD8+ cells from patients with chronic myelogenous leukemia-chronic phase(CML-CP).Methods:The complementarity determining region 3(CDR3)of TCR V? subfamily genes in peripheral blood mononuclear cells(PBMCs),sorted CD4+ and CD8+ cells from 19 CML-CP patients were amplified using RT-PCR,the products were further by genescan analysis to identify the clonality of T cells.Results:Only 1 to 21 V? subfamilies were detected in peripheral blood CD4+ and CD8+ cells from patients with CML.The most frequent expression of V? subfamily was V?13 followed by V?9.Clonal expanded T cells in some V? subfamilies could be identified in both CD4+ and CD8+ cells,especially in CD8+ cells.The clonal expanded of V?21 subfamily in CD4+ cells and V?11 subfamily in CD8+ cells were identified most frequently.Conclusion:The restricted distribution of TCR V? repertoire has been found in CD4+ and CD8+ cells in patients with CML.Clonal expanded CD4+ cells and CD8+ cells have been identified which may relate to host immune response to CML antigen and may play a important role in anti-CML effect.