Protein arginine methyltransferase 5 (PRMT5) exhibits elevated expression levels in a variety of cancers and has emerged as a critical target for cancer therapy in recent years. However, first-generation PRMT5 inhibitors have exhibited inadequate selectivity, leading to significant hematological toxicity, thus limiting their clinical utility. The second-generation PRMT5 inhibitors have shown marked improvement in safety and efficacy by selectively targeting MTAP-null tumor cells without impacting normal cells. This review systematically summarizes the biological and functional roles of PRMT5 in MTAP-deficient tumor cells, and comprehensively analyzes the research and development process, molecular binding mechanisms, and the latest advancements in clinical trials of the five second-generation PRMT5 inhibitors currently under investigation, aiming to provide valuable insights for further in-depth studies in this field.

Objective:To explore the effects of Yishen Tonglong Granules (YSTLG) on cell proliferation and apoptosis in a nude mouse model of androgen independent prostate cancer subcutaneous transplantation based on non classical Wnt signaling pathway.Methods:The tumor-bearing nude mouse model was established using the human prostate cancer bone metastatic cell line PC-3. After successful modeling, the mice were equally divided into six groups using the random number table method: model group, Western medicine group, Chinese materia medica low-, medium-, and high-dosage groups, and Chinese materia medica-Western medicine combination group. Corresponding drug interventions were administered to each group. Following 28 consecutive days of drug administration, the nude mice were euthanized. Tumor tissues were harvested for pathological observation via HE staining. Cell proliferation was assessed by immunohistochemistry; apoptosis was detected using TUNEL assay; the expressions of non-canonical Wnt signaling pathway-related proteins (Wnt5a, Rac1, RhoA, NFATc1) were analyzed through Western blot and immunohistochemical methods.Results:THE staining results demonstrated that YSTLG could effectively ameliorate pathological alterations in tumor tissues. Compared with the model group, the Chinese materia medica low-, medium-, and high-dosage groups, as well as the Chinese materia medica-Western medicine combination group, exhibited reduced proliferation indices ( P<0.01), elevated apoptosis indices ( P<0.01), down-regulated protein expressions of Wnt5a, Rac1, RhoA, and NFATc1 ( P<0.01), and decreased optical density values of Wnt5a, Rac1, RhoA, and NFATc1 ( P<0.01). These effects displayed a dosage-dependent trend. The Chinese materia medica-Western medicine combination group achieved the most pronounced therapeutic outcomes. Conclusions:YSTLG may exert inhibitory effects on the proliferation of androgen-independent prostate cancer cells and promote apoptosis, possibly through suppression of the non-canonical Wnt signaling pathway. Furthermore, its combination with Wnt signaling inhibitors may exhibit synergistic therapeutic effects.

Phosphatidylinositol-3-kinase (PI3K) inhibitors can increase the sensitivity of tumor cells to Poly ADP-ribose polymerase-1 (PARP-1) inhibitors. Therefore, the simultaneous inhibition of the PARP-1 and PI3K activities are expected to overcome the drug resistance of PARP-1 inhibitors.In our previous work, two compounds XW-1 and WZ-1 with excellent activities against PARP-1 and PI3K were obtained with the limitation to further study due to their poor water solubility.Therefore, XW-1 and WZ-1 were chosen as lead compounds to optimize their solubility by introducing a salt-forming site via a urea group, and 11 novel compounds were designed and synthesized. The structure of all target compounds was confirmed by 1H NMR, 13C NMR, and HRMS.The enzyme activities of the compounds against PARP-1 and PI3K were measured, and the results showed that most of the compounds demonstrated good inhibitory activities against PARP-1 and PI3K.Based on the above result, the inhibitory activities of compounds 8b, 8e, and 8f against MDA-MB-231, MDA-MB-468, HCC1937, HCT116, and olaparib-resistant HCT116R were determined by MTT, respectively.Additionally, the structure-activity relationship was discussed. The results showed that these compounds displayed excellent antiproliferation activity.Among them, compound 8f demonstrated antiproliferation remarkably against all five tumor cells, which was more potent than that of olaparib, and was comparable to that of BKM120.Furthermore, the solubility of hydrochloride salts of compound 8b and 8f was significantly improved compared to the lead compounds.The results of this study will provide a theoretical basis for the further development of PARP-1 and PI3K dual-target inhibitors with good pharmaceutical properties and strong inhibitory activities.

Poly(ADP-ribose)polymerase-1(PARP-1)plays a vital role in the regulation of DNA repair and apoptosis. Breakthrough has been made in the treatment of cancer with PARP-1 inhibitors, but the emergence of drug resistance has limited its further application in clinic. This paper reviews advances in the research on PARP-1 inhibitors combined with other drugs to overcome drug resistance, highlights and evaluates the existing drug combination strategies and their therapeutic effects in clinical practice. It is proposed that the development of dual-target or multi-target drugs will become a promising approach to overcome the resistance of PARP-1 inhibitors and broaden their indications.

Phosphoinositide 3-kindase,an important signal transduction molecule in cells,plays a key role in the process of cell survival,proliferation and differentiation.Significant progress has been made in the treatment of cancer with PI3K inhibitors,yet the drug resistance of PI3K inhibitors affects their long-term efficacy in clinical treatment.In order to overcome the drug resistance,a variety of rational combined therapies have been developed.In this paper,the research progress of phosphoinositide-3 kinase inhibitors in combination with other drugs to overcome the drug resistance were reviewed.

Objective To study the clinical significance of thromboelastography (TEG) for determining the presence of coagulation disorders in septic children.Methods A total of 100 patients suffering from sepsis or severe sepsis in pediatric intensive care unit (PICU) of Shanghai Children's Medical Center from February 2014 to January 2015 were recruited.TEG tests and conventional coagulation laboratory tests (CCTs) including platelet count,fibrinogen,prothrombin time (PT),activated partial thromboplastin time,D-dimers,and international normalized ratio (INR) were carried out in all patients at the primary diagnosis of sepsis.Another 25 healthy children taking physical examination were enrolled as control group.Rank Sum Test was used to detect the differences in coagulation markers and TEG between the groups and there was statistical significance when P ＜ 0.05.Receiver operating characteristic (ROC) curves were used to evaluate the roles of TEG and CCTs tests in this study.Results Of them,there were 56 patients with sepsis and 44 with severe sepsis.The male to female ratio was 63∶ 37,the median age was 11.5 (3.3-48) months,and 71％ patients suffered from underlying disease.According to TEG,72 patients had coagulation disorders,including 28 with hypercoagulation and 44 with hypocoagulation.CCTs tests showed 50 patients had coagulation disorders,including 29 with non-overt DIC and 21 with overt DIC.The rate of hypercoagulability was significantly higher in non-DIC group than in non-overt DIC group (46％vs.17.2％,P =0.016).The rate of hypocoagulability was significantly higher in overt DIC group than in non-overt DIC group (100％ vs.44.8％,P ＜ 0.01).Patients with hypercoagulation disorders had significantly shorter R (coagulation reaction time) and K (coagulation formation time) and greater α (angle α),MA (maximal amplitude) and CI (comprehensive coagulation index) compared with control group (P ＜ 0.01).According to CCTs results,patients with hypercoagulation had significantly prolonged PT compared with control group (P =0.002).Compared with sepsis group,severe sepsis group had significantly prolonged R and K and lower α,MA and CI (P ＜ 0.01).ROC analysis demonstrated that area under the curve (AUC) of TEG and CCTs variables for diagnosis of severe sepsis were significantly greater than 0.5.Both variables of α (P =0.000 2) and K (P =0.004 1) had significantly greater AUCs compared with Fib.Conclusions There were 72％ septic patients with coagulation disorders.The hypercoagulability occurred earlier in patients with sepsis and the hypocoagulability occurred later in patients with severe sepsis.The TEG may provide important information for clinicians to deal with coagulation disorders in septic children.

Objective To compare the clinical manifestations,renal histological lesions,and the levels of urinary protein markers between the children with IgA nephropathy (IgAN) and those with IgM nephropathy (IgMN), and to determine whether urinary protein markers could predict the severity of renal histological lesions in children with IgAN and IgMN.Methods Seventy-four children with renal biopsy-proven IgAN and IgMN from January 2002 to October 2014 were enrolled in the study.The levels of IgG, albumin (Alb), transferrin (TRF), α1-microglobulin (α1-MG) ,β2-microglobulin (β2-MG) and N-acetyl-β-glucosaminidase (NAG) in morning urine samples before biopsy were measured.The semi-quantitative scores of mesangial hypercellularity (MC), glomerulosclerosis (GS), and tubule-interstitial damage (TID) were used to assess renal histological lesions.Multivariate Logistic regression analysis was used to determine whether urinary protein levels were independently associated with renal histological lesions.The area under the receiver-operating-characteristic curve (AUC) was calculated to assess the predictive ability of urinary protein markers.Results Seventy-four children (44 cases with IgAN,30 cases with IgMN) were included.The urinary levels of α1-MG and Alb were significantly higher in children with IgAN as compared to those with IgMN.The differences, however, did not remain significant after adjustment for age.The urine protein, as an independent factor associated with severe MC(＞ 5 mesangial cells per mesangial area) was TRF(B =0.010), and severe GS (≥ 10％ glomeruli showing segmental adhesion or sclerosis) was significantly correlated with Alb(B =0.001) ,and severe TID (focal or diffuse tubular and interstitial lesions) was significantly correlated with NAG(B =0.038).Urinary β2-MG was not significantly associated with severe MC, GS and TID.Urinary TRF, Alb and NAG achieved the best AUC of 0.85 (P ＜ 0.001) ,0.78 (P =0.002), and 0.78 (P =0.003), respectively, for predicting severe MC, GS, and TID.Conclusions Urinary proteins are useful to predict the severity of renal histological lesions in children with IgAN and IgMN.Urinary TRF, Alb and NAG have better predictive value.

BACKGROUND AND OBJECTIVEEpidemiology of lung cancer will be changed along with time and region. The aim of this study is to acknowledge the tendency of primary lung cancer in hunan province in recent years by comparing and analyzing the distribution of gender, age, area, smoking and pathology of patients who were initial diagnosed lung cancer and ancestral or permanent residence of hunan province in 1997 and 2007.

METHODSClinical data of 908 patients with primary lung cancer hospitalized in Xiangya hospital were collected and evaluated.

RESULTSCompared patients in 2007 with those in 1997, ratio between male and female dropped from 3.8:1 to 2.98:1, while the proportion of young patients who were under 40 years old raised from 4.4% to 8.6% (chi2 = 4.465, P = 0.035), patients living in the county raised from 19.9% to 40.1% (chi2 = 30.670, P < 0.001), smoking rate of patients from county raised from 16.9% to 39.9% (chi2 = 24.939, P < 0.01). In addition, the proportion of rare histological types of lung cancer were also increased from 1.3% to 4.5% (chi2 = 5.142, P = 0.023).

CONCLUSIONFemale patients, young patients, rural patients and rare histological types of lung cancer may have a tendency of increase in hunan province in recent years, whereas smoking cessation education should be strengthened.

Adult ; Age Factors ; Aged ; China ; Female ; Humans ; Lung Neoplasms ; epidemiology ; Male ; Middle Aged ; Risk Factors ; Sex Factors ; Smoking ; epidemiology ; Young Adult

OBJECTIVETo prepare ginkgo biloba extract (GBE) sustained-release tablets and observe its in vitro release profile.

METHODGBE sustained-release tablets were prepared by direct compression method using sodium carboxymethylcellulose (CMC-Na) and hydroxypropyl methylcellulose HPMC) as matrix excipients. Based on the result of single-factor selecting experiment, the formulations and preparation process were optimized through orthogonal design, and release difference of tablets was evaluated with similarity factor (f2).

RESULTThe ratio of HPMC and CMC-Na, the viscosity of HPMC and the different types of the diluents had pronounced effect on the release of GBE sustained release tablets, although the hardness and weight difference of tablets did not show notable influences.

CONCLUSIONGBE sustained-release tablets that prepared by using the mixture of HPMC and CMC-Na display constant release profile in 12 h.

Delayed-Action Preparations ; chemistry ; Drug Compounding ; methods ; Drug Stability ; Ginkgo biloba ; chemistry ; Plant Extracts ; chemistry ; Tablets ; chemistry

By taking the 《Inorganic Chemistry》of the national standard textbook for the pharmaceutical speciality as a chief source (chief editonHou Xinchu), adopting the softwares of powerpoint, ISIS/ Draw, formula edit tool...etc., and combining the download from the internet, video and refering to the related coursewares in other colleges ...etc., we have and manufactured the multimedia courseware of 《Inorganic Chemistry 》,composed perfectly of various means such as writing, picture, showbiz, animation, voice...etc. This courseware has already been applied in 2001 class,2002 class of the pharmaceutical specialty in our college and has achieved a good result.