Humans ; Immune Checkpoint Inhibitors/therapeutic use* ; Prospective Studies ; HIV Infections/drug therapy* ; Anti-HIV Agents/therapeutic use* ; Comorbidity

The proteolysis targeting chimeras (PROTACs) technology has been rapidly developed since its birth in 2001, attracting rapidly growing attention of scientific institutes and pharmaceutical companies. At present, a variety of small molecule PROTACs have entered the clinical trial. However, as small molecule PROTACs flourish, non-small molecule PROTACs (NSM-PROTACs) such as peptide PROTACs, nucleic acid PROTACs and antibody PROTACs have also advanced considerably over recent years, exhibiting the unique characters beyond the small molecule PROTACs. Here, we briefly introduce the types of NSM-PROTACs, describe the advantages of NSM-PROTACs, and summarize the development of NSM-PROTACs so far in detail. We hope this article could not only provide useful insights into NSM-PROTACs, but also expand the research interest of NSM-PROTACs.

Rearranged during transfection (RET) fusions are found in 0.7% to 2% of non-small cell lung cancer (NSCLC). Fusions between RET gene and other domains represent the distinct biological and clinicopathological subtypes of NSCLC. Recent years have witnessed the remarkable advancement of RET fusion-positive advanced NSCLC therapy. Conventional chemotherapy produced moderate clinical benefits. Prior to the introduction of targeted therapy or in the context of unavailability, platinum-based systemic regimens are initial therapy options. Immunotherapy predicted minimal response in the presence of RET fusions while currently available data have been scarce, and the single-agent immunotherapy or in combination with chemotherapy regimens are not recommended as initial systemic therapy in this population. The repurpose of multi-target kinase inhibitors in patients with RET fusion-positive NSCLC showed encouraging therapeutic activity, with only cabozantinib and vandetanib being recommended as initial or subsequent options under certain circumstances. However, there are still unmet clinical needs. Pralsetinib and selpercatinib have been developed as tyrosine kinase inhibitors (TKI) selectively targeting RET variation of fusions or mutations, and both agents significantly improved the prognosis of patients with RET fusion-positive NSCLC. Pralsetinib and selpercatinib have been established as preferred first-line therapy or subsequent therapy options. As observed with other TKIs treatment, resistance has also been associated with RET targeted inhibition, and the acquired resistance eventually affect the long-term therapeutic effectiveness, leading to limited subsequent treatment options. Therefore, it is essential to identify resistance mechanisms to TKI in RET fusion-positive advanced NSCLC to help reveal and establish new strategies to overcome resistance. Here, we review the advances in the treatment of RET fusion-positive advanced NSCLC.
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Carcinoma, Non-Small-Cell Lung/genetics* ; Humans ; Lung Neoplasms/genetics* ; Mutation ; Protein Kinase Inhibitors/therapeutic use* ; Proto-Oncogene Proteins c-ret/genetics*

Objective: To study the effect of low-to-moderate dose glucocorticoid therapy on viral clearance time in patients with COVID-19. Methods: A total of 72 patients diagnosed with COVID-19 from January 19 to February 17, 2020 at the First Affiliated Hospital, School of Medicine, Zhejiang University were recruited. All patients received oral abidol and/or combined lopinavir/ritonavir, darunavir antiviral, and symptomatic supportive care. Among them, 51 patients received methylprednisolone (0.75-1.50 mg·kg^-1·d^-1) (glucocorticoid treatment group), and 21 patients who did not use glucocorticoid were the control group. The time of stable virologic conversion insputumand the time of radiologic recovery in lungsince onset were compared between the two groups and among the normal patients.The Kruskal-Wallis test or Fisher exact test was used to compare the difference between groups. Results: The median ages of the glucocorticoid group and the control group were 52 [interquartile range (IQR):45, 62] years and 46 (IQR: 32, 56)years, and the differences were significant (P<0.05). The clinical conditions at hospital admission were different between the two groups (P<0.01). There were 52.0% critical ill patients in the glucocorticoid treatment group, compared to that of 71.4% normal patients in the control group. The median times from the onset tostable virologic conversion to negative in the two groups were 15 (IQR:13,20) days and 14 (IQR:12,20) days (P>0.05), and the difference was no statistically significant. The median times from onset to radiologic recovery were 13 (IQR: 11,15) days and 13 (IQR:12,17) days in the two groups, and there was no difference (P>0.05). In ordinary patients, the median timesfrom the onset tostable virologic conversion insputum were no difference (P>0.05), with 13 (IQR:11,18) days in the glucocorticoid group and 13 (IQR:12,15) days in the control group; The median times from onset to radiologic recovery in lungwere also no difference (P>0.05), with 12 (IQR: 10,15)days in the glucocorticoid group and 13 (IQR: 12,17) days inthe control group. Conclusions Low-to-moderate glucocorticoid treatment has no effect on the time of virus clearance in patients with different clinical types of COVID-19. The glucocorticoid is not recommended since no effectiveness on accelerating the improvement of radiologic recovery in lung has been observed.

Objective:To study the effect of low-to-moderate dose glucocorticoid therapy on viral clearance in patients with COVID-19.Methods:A total of 72 patients diagnosed with COVID-19 from January 19 to February 17, 2020 at the First Affiliated Hospital, Zhejiang University School of Medicine were recruited. All patients received oral arbidol and combination of lopinavir/ritonavir or darunavir/cobistitat for antiviral therapy, and symptomatic supportive care. Among them, 51 patients received methylprednisolone (0.75-1.50 mg·kg -1·d -1) (glucocorticoid treatment group), and 21 patients did not use glucocorticoid (control group). The time of virologic negative conversion in sputum and the time of radiologic recovery in lung since onset were compared between the two groups. The Kruskal-Wallis test or Fisher exact test was used to compare the difference between groups. Results:The median ages of the glucocorticoid group and the control group were 52 (45, 62) and 46 (32, 56) years ( χ2=4.365, P<0.05). The clinical conditions at hospital admission were different between the two groups ( P<0.01). The severe cases accounted for 52.0%, while moderate cases in the control group accounted for 71.4%. The median times from the onset to virologic negative conversion in the two groups were 15 (13, 20) and 14 (12, 20) days ( P>0.05). The median times from onset to radiologic recovery were 13 (11, 15) and 13 (12, 17) days in the two groups ( P>0.05). In moderate cases, the median times from the onset to virologic conversion in sputum were 13 (11, 18) days in the glucocorticoid group and 13 (12, 15) days in the control group ( P>0.05). The median times from onset to radiologic recovery in lung were 12 (10, 15) and 13 (12, 17) days, respectively ( P>0.05). Conclusions:Low-to-moderate glucocorticoid treatment has no effect on the time of virus clearance in patients with different clinical types of COVID-19, and also no effect on accelerating radiologic recovery in lung, so it is not recommended.

Four hundred and four male patients with primary gout were enrolled. According to the degree of nonalcoholic fatty liver diseases (NAFLD), the patients were divided into simple gout ( n=121), gout combined with mild NAFLD ( n=149) and gout combined with moderate-severe NAFLD ( n=134). The height, weight, waist, hip, blood pressure and blood biochemistry parameters of patients were measured. The degree of NAFLD was negatively correlated with the age of patients in three groups. The BMI, ratio of waist/hip, count of red cells, hemoglobin, hematocrit, red blood cell distribution width ( SD and CV), triglyceride, alanine aminotransferase and HOMA-IR were increased with the increasing of NAFLD severity (all P<0.05). Red blood cell count, hemoglobin, alanine aminotransferase, serum uric acid increased with the increasing of NAFLD severity (all P<0.05). Platelet, serum urea nitrogen and serum creatinine were decreased with the increase of NAFLD severity. Logistic regression showed that BMI, hemoglobin and HOMA-IR were independent risk factors for NAFLD. The prevalence and the severity of NAFLD was increased with increasing quadrates of hemoglobin. Taking group Q1 as a control, OR of NAFLD in group Q2 was 1.166(95 %CI:0.638-2.133), OR in group Q3 was 2.011(95 %CI:1.122-3.605)and OR in group Q4 was 3.120(95 %CI:1.613-6.034). The result indicates that hemoglobin levels are associated with the development and the severity of NAFLD in male patients with primary gout.

Objective To study the serum level of 25 (OH)D in children aged 0-12 years in Quanzhou,Fujian Province.Methods The clinical data at serum levels of 25(OH) D in children aged 0-12 years old in Quanzhou Women and Children's Hospital were analyzed retrospectively from January 1,2016 to May 31,2017.The nutritional status of vitamin D in children at different genders,age and seasons were analyzed.All the subjects were divided into ＜1 year old group,1-3 years old group,＞ 3-6 years old group,and ＞ 6 years old group.Results A total of 5 830 children aged 0-12 years were included in this study.The serum 25 (OH) D level was (68.85 ± 22.53) nmol/L,and among them there were 4 682 cases (80.31％) of vitamin D abundant,723 cases (12.40％) of vitamin D insufficient,425 cases (7.29％) of vitamin D deficiency,and 0 case of both vitamin D overdose and poisoning.The levels of vitamin D in children in different seasons were different,and the levels of serum 25 (OH) D in summer[(76.20 ± 22.25)nmol/L] were significantly higher than those in other 3 seasons [vitamin D in spring,autumn and winter was (68.35 ±22.08) nmol/L,(62.35 ± 21.88) nmol/L,(66.13 ± 21.78) nmol/L,respectively],and the differences were all statistically significant (all P ＜ 0.01).There was no significant difference in the serum levels of 25 (OH)D in children of different genders in both ＜ 1 year old group and 1-3 year old group [(88.45 ± 28.20) nmol/L vs.(82.60 ± 20.33)nmol/L,(79.28 ± 18.98) nmol/L vs.(78.68 ± 21.80) umol/L] (all P ＞ 0.05),while the levels of which were higher in boys in both ＞ 3-6 years old group and ＞ 6 years old group than those in girls [(64.63 ± 19.53) nmol/L vs.(59.78 ± 17.88) nmol/L,(57.63 ± 16.65) nmol/L vs.(51.00 ± 15.58) nmol/L],and the differences were all statistically significant (all P ＜ 0.01).The levels of serum 25 (OH) D decreased gradually with age [vitamin D in ＜ 1 year old group,1-3 year old group,＞ 3-6 years old group,＞ 6-years old group were (84.08 ± 26.93) nmol/L,(78.43 ± 22.50) nmol/L,(64.43 ± 19.55) nmol/L,(59.20 ± 19.00) nmol/L],and the differences were all statistically significant (all P ＜ 0.01).Conclusions The serum levels of 25 (OH) D in children aged 0-12 years in Quanzhou area are comparatively fine.Vitamin D supplementation in children over 3 years old should not be ignored.

Objective To investigate the effect of bilateral internal iliac artery balloon occlusion in cesarean section for dangerous placenta previa and placenta implantation.Methods From January 2011 to December 2016,The clinical data of 15 cases of dangerous placenta previa and placenta implantation were retrospectively analyzed in the General Hospital of Huainan Oriental Hospital Group.All patients underwent internal iliac arterial intubation prior to cesarean section and into the balloon,placed the balloon in the bilateral internal iliac artery,and filled the balloon to temporarily block internal iliac arterial blood flow.The number of hysterectomy cases of cesarean sections were recorded.Results The amount of intraoperative hemorrhage was about 200-4 000mL,average 1 500mL.Intraoperative,postoperative red blood cell was 0-3 000mL,average 1 000mL,there were no maternal and fetal death and serious complications,2 cases in hysterectomy,the resection rate was 10.8％.Conclusion Bilateral internal iliac arterial balloon occlusion can effectively control the bleeding of the dangerous placenta previa during cesarean section and reduce the hysterectomy.The radiation dose is safe for the fetus.

Autonomic dysreflexia (AD) is an emergency commonly happened in patients with spinal cord injury (SCI) above T6 and especially in chronic SCI patients. AD is usually triggered by stimuli below the injury level. Sudden elevated blood pressure is the main clinical symptom and cardiovascular and/or cerebral complication even death if effective treatments are not provided. Mechanisms contributed to AD possibly are dysfunction of supra spinal control, plastic changes of neurons and receptors. Preventive measures and managements such as removal of risk factor, adjustment of body position, and pharmacological treatment are now in use.

Objective To investigate the distribution of occupations and traditional Chinese medical syndromes of the patients with hypokalemic periodic paralysis in Foshan area. Methods A multicenter retrospective investigation was carried out to analyze the characteristics of occupations and syndrome types of hypokalemic periodic paralysis in Foshan area, and the correlation of occupations with syndrome types was also explored. Results (1) The workers engaged in agriculture, forestry, animal-breeding and fishing, and the workers engaged in production & transportation were most likely to suffering from hypokalemic periodic paralysis, with the incidence being 36.8%, 34.7% respectively. (2) The damp-heat syndrome was the most commonly-seen syndrome type, accounting for 53.1%, and then followed by Qi deficiency syndrome (20.3%) and Qi-Yin deficiency syndrome(15.7%).(3) The syndromes of heavy manual labor workers such as agriculture, forestry, animal-breeding and fishing workers, production & transportation workers, and soldiers were characterized by damp-heat type, accounting for 62.5%, 69.4%, 47.0% respectively. Professionals & technicians were most likely to suffering from Qi-Yin deficiency syndrome, accounting for 44.4%; business service personnel were most likely to suffering from Qi-Yin deficiency syndrome (32.5%) and Qi deficiency syndrome (31.3%). The syndrome distribution of heavy manual labor workers differed from that of light manual labor workers and brain workers(P < 0.001). Conclusion The high-risk groups of hypokalemic periodic paralysis in Foshan area are the heavy manual labor workers who are manifested with the damp-heat syndrome. The dominated syndrome types of light manual labor workers and brain workers are Qi deficiency and Qi-Yin deficiency.