CDKs proteins are a kind of cell cycle protein-dependent kinases, which serve as important roles in controlling cell division and transcriptional stages. Among them, CDK9, as a key regulator responsible for the transcriptional elongation of cells, drives the development of various malignant cells and is considered as an important target in the field of anti-tumor drug development. However, the CDK family proteins feature high conservativeness and similarity in structure, leading to the poor selectivity and severe side effects for traditional small-molecular CDK9 inhibitors, which has limited their clinical applications. In view of this, there is an urgent need to investigate CDK9 targets through a novel strategy. The PROTAC is an emerging drug discovery strategy that the degrader could specifically recognize the target protein through indirect linkage with ubiquitin ligases and ultimately eliminate the target protein through the ubiquitination degradation system. This paper provides a brief overview of the structure and function of CDK9 protein, its relationship with the poor prognosis of clinical diseases, as well as the currently reported small molecular inhibitors. The latest research progress on the targeted degradation of CDK9 protein based on PROTAC technology is highlighted. Finally, the development prospects of this target protein in this novel technology field are summarized and prospected, aiming to provide a reference for the development of antitumor drugs in this direction.

Objective To observe the influence of ATP protection after brachial plexus injuries. Methods A total of 80 female Wistar rats,weighting 280～300 g,were randomly divided into ATP and con- trol groups.The right C_5～T_1 nerve roots were transected and then the intraperitoneal injection of 4m[ of ATP or normal saline was given immediately and once daily to the rats,respectively.The rats were sacrificed on postoperative days 14,28 and 42 respectively.The C_5-T_1 segments of the spinal cord were harvested.NT-3 activity was measured by enzymo-histochemistry method.Four weeks and 6 weeks postoperatively,ultrastruc- ture of the denervated skeletal muscles was observed.Results Compared to the control group,the expres- sions of NT-3 was increased in the treated groups with ATP injection (P

A 68?year?old female patient was admitted to the hospital for multiple masses in the mouth and lungs as well as on dorsal hands for more than 20 days without obvious subjective symptoms. No abnormalities were found by physical examination. Dermatological examination showed two bean?sized dark?red nodules on the upper jaw as well as one pigeon egg?sized dark?red nodule on the left dorsal hand, and all the nodules were hard with smooth surfaces and limited mobility. Positron emission tomography?computed tomography (PetCT) revealed multiple metastases to the brain, lymph nodes, lungs, gastrointestinal tract, both kidneys, multiple bones and intermuscular tissues. Pathology of nodules from the upper jaw showed lowly differentiated tumor cells with osteoid matrix, chondroid structures and tumor bone in local areas, and immunohistochemical examination of tumor cells found positive staining for S100(focally), vimentin, CD99, P63 and Ki?67(60%), but negative staining for keratin. A diagnosis of osteosarcoma of the right side of the upper jaw was considered. Pathology of nodules from the dorsal hand revealed no obvious abnormalities in the epidermis, while there was a diffuse infiltration of medium?to large?sized histiocyte?like cells in the whole dermis with cell atypia and irregularly red?stained bone matrix and tumor bone in some regions. Immunopathology showed positive staining for Ki67(60%), and negative staining for CD3, CD10, CD20, Bcl?2, and Bcl?6. A diagnosis of cutaneous metastasis of osteosarcoma was made. The patient refused further treatment and died 6 months after the onset of lesions.

A Kinase Anchor Proteins ; Cardiomegaly ; metabolism ; Humans

Streptozotocin-induced diabetic model was prepared in Wistar rats and the blood glucose levels were controlled at 3 levels of＜10,10-14 mmol/L or＞16.7 mmol/L by insulin,and changes of glucose transporter(GLUT)1 and 3 protein expressions of brain were observed in control rats and diabetic rats with different blood glucose levels by immunohistochemistry.The results showed that chronic hyperglycemia could decrease the protein expressions of GLUT 1 and GLUT3.

Objective To establish a mouse model of prostate cancer expressing human PSCA for the development of new anti-tumor drugs or vaccines. Methods The total RNA of DU145 cells,a human prostate cancer cell line,was isolated by using TRIzol reagent according to the (RT-PCR),the first-strand cDNA was synthesized using the SuperScript First-Strand synthesis system. The human PSCA gene was amplified with the primers and cloned into the plasmid pcDNA3.1 to generate pcDNA-PSCA. DNA sequencing was used to confirm the constructs. The mouse prostate tumor cell line RM-1 cells,syngeneic to C57BL/6,were transfected with pcDNA-PSCA plasmids followed by selection using G418. RT-PCR analysis was performed to examine the validity of the constructs. Expression of PSCA on the cell surface was determined by staining with anti-PSCA antibody,and the anti-PSCA antibody was detected using an FITC-conjugated goat anti-rabbit IgG antibody,and analyzed by flow cytometry. 4-6-week-old male C57BL/6 mice purchased from the Laboratory Animals Center were inoculated with different amounts of RM-PSCA cells to search for suitable cell population which can form tumor in mouse,and the mice were monitored twice a week. The growth and the survival time of mice were measured,respectively. The tumor volume was measured by vernier caliper according to the formula:V=0.5a×b~2,where a and b are the long and short diameters of the tumor,respectively. Results The plasmid pcDNA-PSCA was successfully constructed and the PSCA was successfully expressed in RM-PSCA 7~# and RM-PSCA 28~# cells by RT-PCR and confirmed by flow cytometry. 1×10~5 RM-PSCA cells were sufficient to get tumor growth in 100% of inoculated mice. The tumor grew quickly and the volume of the tumor reached 12000 mm~3 within 34 days. All the mice died within 40 days and their mean survival time was 37 days. Conclusion A PSCA-expressing tumor model in mice has been successfully established. It can be used to evaluate the activities of drugs or vaccines.

Objective To explore the diagnosis and treatment of altitude sickness combined with urinary retention. Methods 30 cases of altitude sickness combined with urinary retention were treated from April 16th to 26th,2010.They were all male,The average age of them was 24 years (range,19 -38).All were the first time entering the high altitude area (3600 -5000 m) from low altitude area (600 - 1800 m ).The urinary frequency of 25 patients reduced from 8 to 10 times/d to 2 to 4 times/d,the urine output reduced from the 1500- 2400 ml/d to 600- 800 ml/d; the other 5 patients had no urine in 12 -18 h,even had no sense to urinate.26 patients also combined with altitude pulmonary edema and 4 combined with altitude cerebral edema.30 patients had double renal columns enlarged,21 cases had urinary protein ( + ～ ++ ). Results 30 patients were exported urine 300 -600 ml within 10 min,leaded to urine 1800 -2300ml in 12 h,returned to normal voiding after catheter removal in 18 -24 h. After comprehensive treatment such as oxygen,dehydration,diuretic,sedative,antispasmodic and anti-infection,22 cases who with chest tightness,shortness of breath,dyspnea,hemoptysis foam sputum,headache,vomiting and other symptoms of jet-like improved apparently after hospital admission within 1 hour.Their heart rate downed from 90 - 145beats/min to 68 -92 beats/min,respiration from 28 -45 times/min to 18 - 28 times/min,oxygen saturation from 48％ - 84％ to 92％ - 100％ ; 8 cases who with shortness of breath,palpitation and headache improved not obviously.After the antihypertensive treatment,their blood pressure was still high (systolic blood pressure 150 - 180 mm Hg,diastolic blood pressure 90 -110 mm Hg),oxygen saturation between 78％ to 87％,so they were carried to rear area for further treatment.30 cases were all cured no death. Conclusions The high altitude urinary retention is reversible disease,which is often associated with high altitude pulmonary edema,altitude cerebral edema,acute subclinical renal dysfunction and gastrointestinal disorders.They are easily being induced by elements such as gastroenteritis,lung infection,tonsillitis,periodontitis,tiredness and so on; low atmospheric pressure,hypoxia and high altitude is the possible cause; the ratio of missed diagnosis is high; the treatment of oxygen and indwelling catheterization is better; The best method of prevention is to wear pressurized suits and adapt the environment in a ladder-step gradual way.

Objective To figure out the effect of resveratrol (Res) in skin and lung pathology of systemic sclerosis (SSc) animal model and find a new target of anti-fibrosis therapy in SSc.Methods First, we establish ed SSc animal model by daily subcutaneous injection of bleomycin (BLM) for 4 weeks in BALB/c mice.Then we fed the mice with Res.We observed the pathological changes in skin and lung and the expression of the deacetylase SIRT1.We observed the following parametrs.The pathologicalchanges in injected skin and lung which shown by hematoxylin-eosin (HE) staining, the expression of α-smooth muscle actin (α-SMA) in injected skin and lung which measured by immunohistochemistry, the expression of SIRT1 and pro-collagen Ⅲ mRNA which assessed by Real Time polymerase chain reaction (PCR).For the homosce dasticity data.We used one-way analysis of variance (ANOVA) and LSD-t test to compare between the groups.Results Daily subcutaneous injection of BLM for 4 weeks in Balb/c mice could successfully establish a mouse model of SSc.The thickening of skin and alveolar septum, the infiltration of inflammatory cells in lung, and even fibrosis insome area of lung could be observed.The number of α-SMA positive cells and the expression of pro-collagen Ⅲ mRNA were increased (P＜0.05).Meanwhile, the expression of SIRT1 mRNA was decreased [the number of α-SMA positive cell: skin 26.4±5.9 vs 4.4±2.2, lung 14.6±4.6 vs 2.4±1.1, cells per view, P＜0.01;the expression of pro-collagen Ⅲ mRNA: 1.06±0.24 vs 0.45±0.14, relative to glyceraldehyde phosphate dehydrogenase (GAPDH), P＜0.05].Meanwhile, the expression of SIRT1 mRNA was decreased (1.01±0.51 vs 5.03±1.59, relative to GAPDH, P＜0.05).Treated with Res, the pathological changes in skin and lung were alleviated and the number of α-SMA positive cells in lung and skin was decreased [skin 26.4±5.9 vs 10.0±3.5 (high dosage group), 26.4±5.9 vs 13.4±4.4 (medium dosage group);lung 14.6±4.6 vs 8.8±3.5 (high dosage group), cells per view, P＜0.05].There was were no significant differences in the expression of SIRT1 and pro-collagen Ⅲ mRNA in lung after treated by Res.Conclusion Daily subcutaneous injection of BLM for 4 weeks could successfully establish a mouse model of SSc.Res could be a new medicine for the treatment of SSc.

This study was aimed to determine the solubility an d oil-water partition coefficient of main active com-ponents in Ge-Gen Qin-Lian (GGQL) Tablets (puerarin, baicalin and berberine hydrochloride) in phosphate buffer solution of different pH values and under the background of many components. Solubility of puerarin, baicalin and berberine hydrochloride in different medium pH, and oil-water partition coefficient of the octanol-water and oc-tanol-buffer system were determined by HPLC method. The results showed that the solubility and oil-water partition coefficient of puerarin, baicalin and berberine hydrochloride were varied with the change of pH, and varied under the background of components. At pH 7.4, the solubility was the biggest;puerarin was 7.56 mg·mL-1;baicalin was 17.07 mg·mL-1; berberine hydrochloride was 3.57 mg·mL-1. Oil-water partition coefficient P of these components at pH 1.0 was bigger;puerarin was 0.420 (lgP=-0.38);baicalin was 10.783 (lgP=1.03);berberine hydrochloride was 0.267 (lgP=-0.57). It was concluded that lipid solubility of puerarin, baicalin and berberine hydrochloride at pH 1.0 was better. It was speculated that better absorption in the stomach, and low lipid solubility under other pH. It was speculated that lipid solubility may be one of the reasons affecting the intestinal absorption.

Adolescent ; Adult ; Antigens, CD34 ; metabolism ; Antineoplastic Agents ; therapeutic use ; Benzamides ; Chondroma ; drug therapy ; metabolism ; pathology ; surgery ; Female ; Follow-Up Studies ; Gastrectomy ; Gastrointestinal Stromal Tumors ; drug therapy ; metabolism ; pathology ; surgery ; Humans ; Imatinib Mesylate ; Lung Neoplasms ; drug therapy ; metabolism ; pathology ; surgery ; Neoplasm Recurrence, Local ; Neoplasms, Multiple Primary ; drug therapy ; metabolism ; pathology ; surgery ; Piperazines ; therapeutic use ; Pneumonectomy ; Proto-Oncogene Proteins c-kit ; metabolism ; Pyrimidines ; therapeutic use