Poly(ADP-ribose) polymerase 1 (PARP1) is a multifunctional protein involved in diverse cellular functions, notably DNA damage repair. Pharmacological inhibition of PARP1 has therapeutic benefits for various pathologies. Despite the increased use of PARP inhibitors, challenges persist in achieving PARP1 selectivity and effective blood-brain barrier (BBB) penetration. The development of a PARP1-specific positron emission tomography (PET) radioligand is crucial for understanding disease biology and performing target occupancy studies, which may aid in the development of PARP1-specific inhibitors. In this study, we leverage the recently identified PARP1 inhibitor, AZD9574, to introduce the design and development of its ¹⁸F-isotopologue ([¹⁸F]AZD9574). Our comprehensive approach, encompassing pharmacological, cellular, autoradiographic, and in vivo PET imaging evaluations in non-human primates, demonstrates the capacity of [¹⁸F]AZD9574 to specifically bind to PARP1 and to successfully penetrate the BBB. These findings position [¹⁸F]AZD9574 as a viable molecular imaging tool, poised to facilitate the exploration of pathophysiological changes in PARP1 tissue abundance across various diseases.

Objective·To investigate the therapeutic effect of telomerase gene therapy(JV001)on heart failure induced by transverse aortic constriction(TAC)in mice.Methods·Male C57BL/6J mice were randomly divided into sham operation group(Sham group),model group(TAC group),and JV001 treatment group(TAC+JV001 group).An adeno-associated virus 9(AAV9)vector containing the catalytic inactivation(D868A)and nuclear export phosphorylation(Y707F)mutations in the human telomerase reverse transcriptase(hTERT)gene(AAV9-modhTERT,named JV001)was intravenously administered to TAC animals at a single dose of 4×1012 gc/kg.The Sham group and the TAC group received equivalent volumes of saline via tail vein injection.Six weeks after administration,the expression of JV001 in the heart was determined by real-time quantitative PCR(RT-qPCR).Murine cardiac functions were assessed using echocardiography.Physiological indexes of mice were recorded for calculating heart weight/body weight ratio(HW/BW)and heart weight/tibial length ratio(HW/TL).Cardiac hypertrophy was assessed using hematoxylin-eosin(HE)staining and wheat germ agglutinin(WGA)staining.Cardiac collagen deposition was observed by Masson staining.The expressions of myocardial hypertrophy-related genes(Nppa,Nppb,Myh7,Myh6)and myocardial fibrosis-related genes(Col1a1,Col3a1,Ctgf)were detected by RT-qPCR.Results·High levels of modhTERT mRNA were expressed in the hearts of mice at 6 weeks post-injection.Compared with sham-operated mice,TAC mice exhibited significantly reduced left ventricular ejection fraction(LVEF)and left ventricular fractional shortening(LVFS).Compared to TAC mice,TAC+JV001 mice exhibited a significant improvement in LVEF and LVFS.Concurrently,there was a downregulation in the HW/BW and HW/TL in TAC+JV001 mice compared to TAC mice.Furthermore,JV001 treatment reduced the mean cardiomyocyte cross-sectional area and improved the expression levels of myocardial hypertrophy-related genes,including Nppa,Nppb,Myh7 and Myh6.Additionally,JV001 treatment ameliorated the TAC-induced increase in myocardial interstitial fibrosis and reduced the elevated expression levels of myocardial fibrosis-related genes,including Col1a1,Col3a1,and Ctgf.Conclusion·AAV9-modhTERT treatment can alleviate TAC-induced cardiac dysfunction,cardiac hypertrophy,and fibrosis in mice.

Objective·To investigate the therapeutic effect of telomerase gene therapy(JV001)on heart failure induced by transverse aortic constriction(TAC)in mice.Methods·Male C57BL/6J mice were randomly divided into sham operation group(Sham group),model group(TAC group),and JV001 treatment group(TAC+JV001 group).An adeno-associated virus 9(AAV9)vector containing the catalytic inactivation(D868A)and nuclear export phosphorylation(Y707F)mutations in the human telomerase reverse transcriptase(hTERT)gene(AAV9-modhTERT,named JV001)was intravenously administered to TAC animals at a single dose of 4×1012 gc/kg.The Sham group and the TAC group received equivalent volumes of saline via tail vein injection.Six weeks after administration,the expression of JV001 in the heart was determined by real-time quantitative PCR(RT-qPCR).Murine cardiac functions were assessed using echocardiography.Physiological indexes of mice were recorded for calculating heart weight/body weight ratio(HW/BW)and heart weight/tibial length ratio(HW/TL).Cardiac hypertrophy was assessed using hematoxylin-eosin(HE)staining and wheat germ agglutinin(WGA)staining.Cardiac collagen deposition was observed by Masson staining.The expressions of myocardial hypertrophy-related genes(Nppa,Nppb,Myh7,Myh6)and myocardial fibrosis-related genes(Col1a1,Col3a1,Ctgf)were detected by RT-qPCR.Results·High levels of modhTERT mRNA were expressed in the hearts of mice at 6 weeks post-injection.Compared with sham-operated mice,TAC mice exhibited significantly reduced left ventricular ejection fraction(LVEF)and left ventricular fractional shortening(LVFS).Compared to TAC mice,TAC+JV001 mice exhibited a significant improvement in LVEF and LVFS.Concurrently,there was a downregulation in the HW/BW and HW/TL in TAC+JV001 mice compared to TAC mice.Furthermore,JV001 treatment reduced the mean cardiomyocyte cross-sectional area and improved the expression levels of myocardial hypertrophy-related genes,including Nppa,Nppb,Myh7 and Myh6.Additionally,JV001 treatment ameliorated the TAC-induced increase in myocardial interstitial fibrosis and reduced the elevated expression levels of myocardial fibrosis-related genes,including Col1a1,Col3a1,and Ctgf.Conclusion·AAV9-modhTERT treatment can alleviate TAC-induced cardiac dysfunction,cardiac hypertrophy,and fibrosis in mice.

OBJECTIVE To provide ideas for clinical diagnosis， treatment and pharmaceutical care of rhino-orbito-cerebral mucormycosis （ROCM）. METHODS The diagnosis and treatment of 1 case of ROCM in which clinical pharmacists participated were analyzed. Combined with treatment guidelines， the actual situation of drug accessibility and economy， clinical pharmacists recommend amphotericin B colloidal dispersion in combination with posaconazole to treat fungal infections. The clinical efficacy， liver and kidney function and electrolytes were monitored. To increase the local concentration of amphotericin B deoxycholate （AmB-D）， clinical pharmacists assisted physicians in determining the dosage and formulation of AmB-D for intrathecal injection， intranasal and eye drops based on the results of blood and cerebrospinal fluid examinations. In response to the situation that the plasma trough concentration of posaconazole had not reached the target， clinical pharmacists recommended that Posaconazole oral suspension was replaced with Posaconazole enteric-coated tablets， and provided the patient with therapeutic drug monitoring （TDM）， individualized medication guidance， and long-term follow-up after discharge. RESULTS The clinician adopted the advice of the clinical pharmacists. After treatment， the patient was discharged from the hospital with medicine after her condition improved. CONCLUSIONS Clinical pharmacists develop individualized treatment protocols for ROCM patients by adjusting dose and dosage forms， providing medication monitoring and TDM to ensure the safety of drug use for patients.

There is an accumulating body of evidence implicating the muscarinic acetylcholine receptor 4 (M₄) in schizophrenia and dementia with Lewy bodies, however, a clinically validated M₄ positron emission tomography (PET) radioligand is currently lacking. As such, the aim of this study was to develop a suitable M₄ PET ligand that allows the non-invasive visualization of M₄ in the brain. Structure-activity relationship studies of pyrazol-4-yl-pyridine derivates led to the discovery of target compound 12 - a subtype-selective positive allosteric modulator (PAM). The radiofluorinated analogue, [¹⁸F] 12, was synthesized in 28 ± 10% radiochemical yield, >37 GBq/μmol and an excellent radiochemical purity >99%. Initial in vitro autoradiograms on rodent brain sections were performed in the absence of carbachol and showed moderate specificity as well as a low selectivity of [¹⁸F] 12 for the M₄-rich striatum. However, in the presence of carbachol, a significant increase in tracer binding was observed in the rat striatum, which was reduced by >60% under blocking conditions, thus indicating that orthosteric ligand interaction is required for efficient binding of [¹⁸F] 12 to the allosteric site. Remarkably, however, the presence of carbachol was not required for high specific binding in the non-human primate (NHP) and human striatum, and did not further improve the specificity and selectivity of [¹⁸F] 12 in higher species. These results pointed towards significant species-differences and paved the way for a preliminary PET study in NHP, where peak brain uptake of [¹⁸F] 12 was found in the putamen and temporal cortex. In conclusion, we report on the identification and preclinical development of the first radiofluorinated M₄ PET radioligand with promising attributes. The availability of a clinically validated M₄ PET radioligand harbors potential to facilitate drug development and provide a useful diagnostic tool for non-invasive imaging.

Thyroid cancer is the most common malignant tumor of the endocrine system, and the incidence is increasing year by year, which seriously threatens people's health. Autophagy is a programmed mode of death that can be used as a potential target for anti-tumor therapy and plays an important regulatory role. Leucine-rich repeat kinase 2 (LRRK2) is a protein kinase encoded by PARK8 gene. The recent studies have confirmed that autophagy is closely related to thyroid cancer. This paper analyzes the possible regulatory mechanism of LRRK2 affecting thyroid cancer through autophagy, providing new ideas for basic research and clinical diagnosis and treatment of thyroid cancer.

Thyroid cancer is the most common head and neck malignant tumor, and its incidence is increasing year by year. Therefore, it is of great significance to explore the mechanism of the occurrence and development of thyroid cancer, and develop the diagnostic markers and therapeutic targets of thyroid cancer, so as to improve the curative effect of thyroid cancer and prolong the survival time of patients. The previous study has found that long non-coding RNA (lncRNA) DANCR has abnormal high expression in thyroid cancer, which could promote the expression of leucine-rich repeat kinase 2 (LRRK2) by affecting miRNA-185-5p and transcription factor SMARCB1, and indirectly participate in autophagy and regulate the development of thyroid cancer. LncRNA DANCR is expected to become a new target for diagnosis and treatment of thyroid cancer. This paper introduces the possible regulatory mechanism of lncRNA DANCR in thyroid cancer, and provides new ideas for the basic research and clinical diagnosis and treatment of thyroid cancer.

Objective:To investigate the detection rate and related factors of thyroid nodules in people with abnormal lipid metabolism.Methods:From September 4, 2016 to February 1, 2017, community residents living in Lanzhou City, Longnan City, Dingxi City and Linxia City of Gansu Province for more than 5 years were selected as the respondents. General data were recorded, venous blood was collected, blood lipid related biochemical indexes were detected, and thyroid ultrasound was performed. By comparing the general data and biochemical indexes, the detection of abnormal lipid metabolism and thyroid nodules were analyzed, and the risk factors of thyroid nodules in people with abnormal lipid metabolism were analyzed by logistic regression.Results:Two thousand and fifty-nine residents were included in this study (1 049 males and 1 010 females). The total detection rate of thyroid nodules was 23.17% (477/2 059). The detection rate of thyroid nodules in people with abnormal lipid metabolism [34.16%(151/442)] was significantly higher than that in people with normal lipid metabolism [20.16% (326/1 617) , P < 0.01], and the detection rate of thyroid nodules of women [43.37% (85/196) ] was higher than that of men [26.83% (66/246) , P < 0.01]. Among the people with abnormal lipid metabolism, the highest detection rate of thyroid nodules was in mixed hyperlipidemia [57.14% (16/28)], followed by hypertriglyceridemia [34.59% (92/266)]. The detection rates of thyroid nodules in the groups with elevated total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels [35.16% (32/91), 34.85% (23/66)] were higher than those in the marginal elevated group [27.04%(86/318), 30.42% (73/240)] and the normal groups [21.76% (359/1 650), 21.73% (381/1 753), P < 0.05]. The results of logistic regression analysis showed that the risk factors of thyroid nodules in people with abnormal lipid metabolism were increased age, elevated fasting blood glucose (FPG), elevated blood glucose 2 hours (2 h PG) after oral glucose tolerance test (OGTT) load and elevated glycosylated hemoglobin [HbA1c, odds ratio ( OR)=1.065, 1.387, 1.866, 1.384, P < 0.05]. Conclusions:The prevalence of TN is higher in populations with abnormal lipid metabolism. The control of blood sugar and blood lipid levels may play a role in the prevention of thyroid nodules.

Ferroptosis is a newly discovered form of cell death in recent years. Its essence is the cell peroxidation death caused by the accumulation of intracellular lipid reactive oxygen species (L-ROS) in a iron-dependent manner. As a highly efficient ferroptosis inducer, Erastin mediates ferroptosis through multiple molecules, such as cystine-glutamate transport receptor, voltage-dependent anion channel and p53. More importantly, Erastin can enhance the sensitivity of cancer cells to chemotherapy and radiotherapy, so it can be used as a new type of anticancer drug. This article reviews the discovery of Erastin, the pathways of ferroptosis, the pathways of Erastin-induced ferroptosis, the anti-tumor characteristics of Erastin, and the latest domestic and international research results.

The occurrence of thyroid gland is easily affected by iodine deficiency, the enzyme defect, drugs, autoimmune and other factors. The increased incidence of thyroid cancer year by year has threatened the health of the human, which requires to study thyroid gland cancer invasion and metastasis, investigate the molecular mechanism of cancer metastasis, search the differential molecular expression gene, predict the metastatic biomarkers and the intervening treatment target molecule, in order to improve the cure rate and the survival rate. This paper reviews the possible role of long chain non-coding RP11-23J9.4-miRNA-15a-axis inhibiting factor 2-Wnt pathway in the occurrence, development and dedifferentiation of thyroid cancer.