The dysregulation of cyclin-dependent kinase 12 (CDK12), which may result from genomic alterations or modulation by upstream effectors, is implicated in cancer oncogenesis and progression. CDK12 overexpression or activation is sufficient to induce tumor initiation, recurrence, and therapeutic resistance. However, CDK12 may also exert tumor-suppressive functions in a context-dependent manner. Therefore, caution is warranted when targeting CDK12 in future clinical trials. A comprehensive elucidation of the dual roles and underlying mechanisms of CDK12 in carcinogenesis is urgently needed to advance precision oncology. This review provides an overview of the current understanding of the dysregulation and biological roles of CDK12 in cancer. Subsequently, we systematically summarize the functions and mechanisms of the oncogenic and tumor-suppressive roles of CDK12 in different contexts. Finally, we discuss the potential of CDK12 as a novel therapeutic target and its implications in clinical oncology, offering insights into future directions for innovative cancer treatment strategies.

The dysregulation of cyclin-dependent kinase 12(CDK12),which may result from genomic alterations or modulation by upstream effectors,is implicated in cancer oncogenesis and progression.CDK12 over-expression or activation is sufficient to induce tumor initiation,recurrence,and therapeutic resistance.However,CDK12 may also exert tumor-suppressive functions in a context-dependent manner.Therefore,caution is warranted when targeting CDK12 in future clinical trials.A comprehensive elucidation of the dual roles and underlying mechanisms of CDK12 in carcinogenesis is urgently needed to advance pre-cision oncology.This review provides an overview of the current understanding of the dysregulation and biological roles of CDK12 in cancer.Subsequently,we systematically summarize the functions and mechanisms of the oncogenic and tumor-suppressive roles of CDK12 in different contexts.Finally,we discuss the potential of CDK12 as a novel therapeutic target and its implications in clinical oncology,offering insights into future directions for innovative cancer treatment strategies.

Objective:To investigate the cognition of the diagnosis and management of bronchiectasis among respiratory specialists.Methods:Between May and June 2020, a questionnaire survey based on expert consensus and guidelines was conducted among respiratory specialists from 50 hospitals from Sichuan and Yunnan provinces. Total 691 questionnaires were distributed and 641 were received. 601 valid questionnaires were chosen for further analysis with an effective recovery rate of 87.0%. The respondents were required to finish the e-questionnaires independently in terms of cognition of diagnosing, severity assessment, treatments and Chinese medicines of bronchiectasis. The responses were collected online and the cognitive levels were evaluated by calculating the correct rates of corresponding questions.Results:540 (89.9%) of the respondents agreed that high-resolution computed tomography (HRCT) was the gold standard for diagnosing of bronchiectasis, but 318 (52.9%) had an incomplete understanding of common radiographic manifestations of bronchiectasis, and different cognitive degrees of common radiographic manifestations of bronchiectasis existed among respondents with different qualifications or working in different levels of hospitals ( P<0.05). Only 118 (19.6%) of the respondents were familiar with severity assessments of bronchiectasis, but 65 (55.1%) of the 118 respondents said they won′t apply these severity assessments to patient during their clinical works. For the treatment of patients with stable bronchiectasis, airway clearance techniques were most recommended by specialists surveyed [410 (68.2%)], among which, postural drainage was the most known method [559 (93.0%)]. For patients undergoing an acute exacerbation, most respondents recommended antibiotics [600 (99.8%)] as the primary treatment, and examinations such as sputum culture [544 (90.5%)], inflammatory markers [523 (87.0%)] should be performed as well. 504 (83.9%) thought that pseudomonas aeruginosa was the most common conditioned pathogen for bronchiectasis. For patients with frequent exacerbations (≥3 per year), 385 (64.1%) of the respondents supported the therapeutic effect of long-term antibiotics, however, among the 385 respondents supporting long-term antibiotics, only [113 (29.4%)] were willing to recommend long-term antibiotic treatment actively during their clinical practice. Besides, 304 (50.6%) respondents held a positive attitude to the clinical effect of traditional Chinese medicine therapies. Among 304 respondents holds the point of supporting, only 86 (28.3%) were willing to recommend traditional Chinese medicine to patients actively, differences about the attitude and clinical behaviors were found between respondents working in different levels of hospitals ( P<0.05). Conclusions:Respiratory specialists′ cognition on diagnosis and treatments of bronchiectasis remains inadequate, and cognitive levels differ among respondents working in different levels of hospitals. There is a gap between respondents′ cognition and clinical practice. Further education and trainings are necessary for improving respiratory specialists′ knowledge for timely diagnosis and standard treatment of bronchiectasis.

Myoclonus dystonia syndrome (MDS) is an inherited movement disorder, and most MDS-related mutations have so far been found in the ε-sarcoglycan (SGCE) coding gene. By generating SGCE-knockout (KO) and human 237 C > T mutation knock-in (KI) mice, we showed here that both KO and KI mice exerted typical movement defects similar to those of MDS patients. SGCE promoted filopodia development in vitro and inhibited excitatory synapse formation both in vivo and in vitro. Loss of function of SGCE leading to excessive excitatory synapses that may ultimately contribute to MDS pathology. Indeed, using a zebrafish MDS model, we found that among 1700 screened chemical compounds, Vigabatrin was the most potent in readily reversing MDS symptoms of mouse disease models. Our study strengthens the notion that mutations of SGCE lead to MDS and most likely, SGCE functions to brake synaptogenesis in the CNS.

Objective To investigate the efficacy of rosuvastatin combined with silibinin capsule in treatment of hyperlipidemic patients with nonalcoholic fatty liver disease.Methods One hundred and nineteen hyperlipidemic patients with non-alcoholic fatty liver disease admitted in hospital from January 2016 to March 2017 were randomly assigned into two groups:60 patients received rosuvastatin(10 mg,q.d) and silibinin capsules(70 mg,t.i.d.,study group) and 59 patients received starch tablets(10 mg,q.d) and silibinin capsules(70 mg,t.i.d.,control group).The blood lipid,liver function,inflammatory factors,liver CT value,the specific CT value of liver and spleen were compared at baseline and 6 months after intervention.Results Compared to baseline values,the levels of total cholesterol (TC),triglyceride (TG),alanine aminotransferase (ALT),γ-glutamyltranspeptidase (GGT),TNF-α,IL-6,and CRP were decreased (t=2.44,2.04,2.48,6.95,2.38,2.78,3.97,all P＜0.05);and the levels of HDL-C,liver CT value,liver/spleen CT value ratio were increased (t=5.44,2.26,2.08,all P＜0.05) after treatment in study group.The improvement of TG,LDL-C,ALT,GGT,TNF-α,CRP,liver CT value,liver/spleen CT value ratio were more marked than those of the control group (P＜0.05) (t=1.92,2.65,2.02,5.62,2.11,2.20,2.22,2.08,all P＜0.05).The effective rate of study group was higher than that of the control group[98.2％(55/56) vs.85.7％(48/56),x2=2.05,P=0.04];the adverse reactions were similar in two groups.Conclusion Compared with silibinin alone,rosuvastatin combined with silibinin capsules is more effective in treatment of hyperlipidemic patients with nonalcoholic fatty liver disease,which can significantly improve the blood lipids,liver function,inflammatory response and aliphatic degree without increase of adverse reaction.

Objective To evaluate intraoperative placement of bile duct decompression drainage tube in CBD primary suture after laparoscopic choledocholithotomy.Methods 152 patients undergoing laparoscopic choledocholithotomy were divided into group A (placement of bile duct decompression drainage tube during operation,82 cases) and group B (no decompression drainage tube placement,70 casas).Results There was no significant difference in operative time and intraoperative bleeding between the two groups (P ＞ 0.05).In group B patients the abdominal drainage tube indwelling time,abdominal drainage volume,peritoneal drainage fluid bilirubin value,postoperative hospitalization time were significantly longer than group A,the difference was statistically significant (P ＜ 0.05).No recurrence of choledocholithiasis and biliary stricture were found in either groups.Conclusions Placement of bile duct decompression drainage tube in laparoscopic choledocholithotomy and CBD primary suture after laparoscopic choledochotomy can significantly reduce the incidence of biliary leakage and shorten the postoperative hospital stay.

Objective To investigate the clinical value and safety of cedilanid, esmolol in the treatment of atrial fibrillation. Methods From August 2014 to August 2016 our Hospital from 117 patients with atrial fibrillation clinical data, according to the random number distribution principle, the patients were divided into observation group 59 cases and control group of 58 cases, all patients were given the treatment of primary disease, the clinical symptoms, the patients in the observation group were given oxygen, has given furosemide, cedilanid, after micro injection pump intravenous nitroglycerin, 5-20 g/min. Start after the injection of nitroglycerin, establish another vein channel, every 30 min to 0.2 mg patients, the treatment group were treated with intravenous injection of small dose esmolol. The clinical efficacy, ventricular rate, systolic blood pressure, diastolic blood pressure and adverse reactions were observed in two groups. Results The early and late effective rates of the two groups were not significantly different. The observation showed that after treatment, the ventricular rate, systolic pressure and diastolic pressure in the observation group were significantly higher than those in the control group (P<0.05), and the incidence of adverse reactions in the two groups was significantly different (P<0.05). Conclusion High dose cedilanid combined with small dose esmolol in treatment of atrial fibrillation, obvious curative effect, high safety, can choose the appropriate application.

Objective To investigate the clinical effect of amlodipine combined with Telmisartan Capsules in the treatment of hypertension.MethodsThe patients with primary hypertension in 87 cases in the second hospital affiliated to Tianjin Medical University were divided into two groups.43 patients in control group were treated with amlodipine 2.5~5mg/d orally, 44 patients in the experimental group on the basis of combined with Telmisartan Capsules 40~80mg/d orally, the total course of treatment was eight weeks.The changes of blood pressure levels were compared before and after treatment, the effective rate of the treatment and adverse reactions after treatment, to evaluate the clinical efficacy of amlodipine combined with Telmisartan Capsules in the treatment of hypertension.ResultsAfter treatment, two groups of three blood pressure index were significantly decreased (P<0.05), compared with the control group, the experimental group of patients with treatment After treatment the blood pressure level is low(P<0.05).After eight weeks of treatment, the total efficiency of control group was 72.09%, the total efficiency of experimental group was 95.45%, the experimental group was higher than that in the control group (P<0.05) after treatment, patients in the control group with two cases of headache (4.65%), two cases of lower extremity edema (4.65%);the experimental group of two cases of vertigo (4.55%), three cases of joint pain (6.82%), there was no significant difference in total adverse reaction rate between the two groups.Conclusion Amlodipine combined with Telmisartan Capsules in the treatment of hypertension has good clinical effect.

Objective To evaluate the feasibility and clinical effect of stage Ⅰ posterior vertebral corpectomy filled with titanium mesh cages plus long-segmental instrumentation for treatment of Denis type D and E severe unstable thoracolumbar burst fracture.Methods A retrospectively review was made on 14 patients with Denis type D and E severe unstable thoracolumbar burst fracture,having had posterior vertebral corpectomy,titanium mesh bone grafting and long-segmental pedicle screw fixation.Parameters recorded were operation time,amount of bleeding,bone fusion and reduction,postoperative complications,low back pain,neurological performance,restoration and loss of anterior vertebral height,correction and loss of kyphosis,and intraspinal space occupying lesion.Results Mean operation time was 207.1 min (range,148-306 min) and blood loss was 585 ml (range,300-1,500 ml).Intraoperative fracture reduction was satisfactory.Follow-up ranged from 18 to 54 months (mean,28 months),which showed no complications of infection,screw-rod breakage,loosening or shifting of the internal fixation device,titanium mesh subsidence and pseudarthrosis,and no signs of adjacent segment degeneration.Six months after operation,CT scan showed bony fusion of the bone-implant interface.At the final follow-up,the Denis pain scale improved significantly including 12 patients with completely relieve of pain (P1) and 2 ache slightly but no need of taking painkiller (P2).Neurological functions were improved by 1-3 degree in all patients.Percentage of anterior vertebral height was (41.2 ± 8.9)％ before operation,significantly reduced to (8.3 ± 4.8) ％ one week after operation and to (8.9 ± 5.1) ％ at the final follow-up (P ＜0.01).Mean loss of anterior vertebral height was 0.6％.Sagittal kyphotic angle was (36.9 ± 4.9) °before operation,significantly reduced to (8.1 ± 3.4) ° one week after operation and (8.5 ± 3.8) °at the final follow-up (P ＜0.01).Mean loss of kyphotic angle was 0.9°.Ratio of intraspinal space occupancy was (74.9 ± 11.3) ％ before operation but recovered to (4.1 ± 1.6) ％ one week after operation and (1.8 ± 1.4) ％ at the final follow-up,with significant differences in pair comparison (P ＜ 0.01).Conclusion The use of posterior vertebral corpectomy and fusion with titanium mesh cage fusion in conjunction with long-segment instrumentation are effective for spinal canal decompression,fracture reduction,three-column reconstruction as well as rigid fusion at one stage,lumbar pain relief,neurological function recovery,prevention of correction loss and vertebral height restoration.

BACKGROUNDCigarette smoke induced airway inflammation plays a role in pathogenesis of airway inflammation. Resolvin-D1 derived from omega-3 polyunsaturated fatty acids is an endogenous anti-inflammatory and proresolving lipid mediator. Resolvin-D1 ameliorated inflammatory responses in lung injury, asthma, peritonitis and atherosclerosis. We investigated whether resolvin-D1 suppressed the productions of chemokines and oxidative stress induced by cigarette smoke extract (CSE) in vitro and its possible mechanism.

METHODSWe examined the proinflammatory chemokine interleukin-8 and hydrogen peroxide (H2O2) productions induced by CSE in 16 human bronchial epithelial (16HBE) cells after resolvin-D1 treatment and their mechanisms. 16HBE cells were treated with resolvin-D1 at up to 10 nmol/L, for 30 minutes before CSE up to 16% (v/v) exposure. Release of interlukin-8 proteins was assessed by enzyme linked immunosort assay (ELISA) and its mRNA level by RT-PCR. We evaluated extracellular H2O2 expression in the supernatant. Phosphorylation of NF-κB/p65 and degradation of I-κB in 16HBE cells were determined by Western blotting analysis and NF-κB DNA binding activity by electrophoretic mobility shift assay (EMSA).

RESULTS16HBE cells treated with 8% CSE showed significantly higher interlukin-8 production. Resolvin-D1 pretreatment inhibited CSE induced interlukin-8 production (mRNA and protein) in a dose and time dependent manner. Extracellular H2O2 level decreased after resolvin-D1 treatment. Resolvin-D1 attenuated CSE triggered I-κB degradation and NF-κB/p65 activation dose dependently and inhibited NF-κB DNA binding activity.

CONCLUSIONResolvin-D1 inhibits CSE induced interlukin-8 and H2O2 production in 16HBE cells by modulating NF-κB activation and has therapeutic potential for pulmonary inflammation.

Blotting, Western ; Cell Line ; Cell Survival ; drug effects ; Docosahexaenoic Acids ; pharmacology ; Electrophoretic Mobility Shift Assay ; Enzyme-Linked Immunosorbent Assay ; Humans ; Hydrogen Peroxide ; metabolism ; Interleukin-8 ; metabolism ; NF-kappa B ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Smoking ; adverse effects