In this report,we described a case of a clinical practice,in which the clinical pharmacists was involved in the treatment of a soft tissue sarcoma patient,who was diagnosed with mental disorders induced by regorafenib.The patient was complicated with hypoproteinemia,hepatic insufficiency,leukoencephalopathy and other diseases.Before the treatment,the patient's mental was normal.After continuous administration of regorafenib(40 mg,po,qd)for 5 days,the patient has a sudden loss of consciousness.Clinical pharmacists excluded the possibility of mental disorders caused by tumor brain metastases,exacerbation of leucoencephalopathy or hepatic encephalopathy and the drugs used together.They determined that mental disorders were likely to be related to the use of regorafenib through the association evaluation of adverse reactions.It was considered to be an adverse reaction induced by regorafenib.Therefore,regorafenib treatment was temporarily suspended and symptomatic treatment was given.After 5 days,the patient's mental state improved.In addition,clinical pharmacists monitored the patient for symptomatic treatment,and provided appropriate antitumor drug treatment recommendations based on evidence-based evidence.This case suggests that the clinical use of regorafenib should be vigilant against mental disorders adverse reactions,do a good job of pharmaceutical care,and timely drug analysis and symptomatic treatment after adverse reactions.

Objective:To study the current status of longitudinal extrauterine growth restriction (EUGR) in extremely preterm infants (EPIs) and to develop a prediction model based on clinical data from multiple NICUs.Methods:From January 2017 to December 2018, EPIs admitted to 32 NICUs in North China were retrospectively studied. Their general conditions, nutritional support, complications during hospitalization and weight changes were reviewed. Weight loss between birth and discharge > 1SD was defined as longitudinal EUGR. The EPIs were assigned into longitudinal EUGR group and non-EUGR group and their nutritional support and weight changes were compared. The EPIs were randomly assigned into the training dataset and the validation dataset with a ratio of 7∶3. Univariate Cox regression analysis and multiple regression analysis were used in the training dataset to select the independent predictive factors. The best-fitting Nomogram model predicting longitudinal EUGR was established based on Akaike Information Criterion. The model was evaluated for discrimination efficacy, calibration and clinical decision curve analysis.Results:A total of 436 EPIs were included in this study, with a mean gestational age of (26.9±0.9) weeks and a birth weight of (989±171) g. The incidence of longitudinal EUGR was 82.3%(359/436). Seven variables (birth weight Z-score, weight loss, weight growth velocity, the proportion of breast milk ≥75% within 3 d before discharge, invasive mechanical ventilation ≥7 d, maternal antenatal corticosteroids use and bronchopulmonary dysplasia) were selected to establish the prediction model. The area under the receiver operating characteristic curve of the training dataset and the validation dataset were 0.870 (95% CI 0.820-0.920) and 0.879 (95% CI 0.815-0.942), suggesting good discrimination efficacy. The calibration curve indicated a good fit of the model ( P>0.05). The decision curve analysis showed positive net benefits at all thresholds. Conclusions:Currently, EPIs have a high incidence of longitudinal EUGR. The prediction model is helpful for early identification and intervention for EPIs with higher risks of longitudinal EUGR. It is necessary to expand the sample size and conduct prospective studies to optimize and validate the prediction model in the future.

Periodontitis is a chronic inflammatory and destructive disease in which plaque acts as an initiator.Recruitment of host im-mune cells and production of multiple inflammatory mediators leads to periodontal tissue damage.Programmed cell death(PCD)is a self-destructive process that is actively initiated by cells under specific conditions and can be mainly categorized into apoptosis,necrop-tosis,autophagy,pyroptosis,ferroptosis,cuproptosis,etc.Different types of programmed cell death have their own distinctive roles in periodontitis.In this review,we summarizes the characteristics of different types of PCD and their role in the progression of periodonti-tis,in order to provide new research ideas on the pathogenic mechanism of periodontitis and more references for the precise treatment of periodontitis.

ObjectiveTo investigate the effect and mechanism of Nongsuo Dangguiwan in improving ovarian oxidative stress in rats with ovarian dysfunction. MethodThirty-six adult female SD rats were randomly divided into normal group， model group， positive drug group （Femoston， 0.3 mg·kg^-1）， and high-， medium-， and low-dose groups of concentrated Nongsuo Dangguiwan （2.08， 4.16， 8.32 g·kg^-1）， with six rats in each group. Rats， except for those in the normal group， were injected with 80 mg·kg^-1 vinyl cyclohexene dioxide （VCD） per day for 14 consecutive days to induce ovarian dysfunction. From the 15th day， rats were treated with corresponding drugs by gavage， while those in the model group received 2 mL·kg^-1 saline， once daily for 28 consecutive days. The ovarian index， levels of related hormones including estradiol （E₂）， follicle-stimulating hormone （FSH）， luteinizing hormone （LH）， and anti-mullerian hormone （AMH） in serum， as well as superoxide dismutase （SOD） activity and glutathione （GSH） content in serum were measured by enzyme-linked immunosorbent assay （ELISA）. The malondialdehyde （MDA） content in serum was detected by the thiobarbituric acid （TAB） method. Ovarian morphology was observed by hematoxylin-eosin （HE） staining. The expression of nuclear factor E₂-related factor 2 （Nrf2）， heme oxygenase-1 （HO-1）， SOD2， and SOD1 in ovarian tissues was detected by immunohistochemistry （IHC） and Western blot. ResultCompared with the normal group， the model group showed a significant reduction in growing follicles in the ovary， loose arrangement of granulosa cells in the follicle， decreased body weight， ovarian index， and serum AMH and E₂ levels， increased LH and FSH levels （P<0.01）， reduced levels of SOD and GSH in serum （P<0.01）， and increased MDA level （P<0.01）. Compared with the model group， the groups with drug intervention showed increased ovarian index （P<0.05， P<0.01）， increased serum E₂ level （P<0.05， P<0.01）， decreased FSH， AMH， and LH levels （P<0.05， P<0.01）， increased number of growing follicles in the ovary， potentiated SOD activity in serum， increased GSH content， decreased MDA content （P<0.05， P<0.01）， and up-regulated expression levels of Nrf2， HO-1， SOD2， and SOD1 proteins in ovarian tissues （P<0.05， P<0.01）. ConclusionNongsuo Dangguiwan can regulate serum hormone levels， increase the expression of Nrf2， HO-1， SOD2， and SOD1 in ovarian tissues， and improve ovarian antioxidant capacity to resist oxidative stress injury， thereby improving ovarian reserve function.

ObjectiveBased on ultra performance liquid chromatography-quadrupole-time-of-flight mass spectrometry（UPLC-Q-TOF-MS^E） technique， we identified qualitatively the metabolites of aristolochic acid（AAs） in rat in order to analyze the metabolic differences between water extract of Aristolochiae fructus（AFE） and Aristolochic acid Ⅰ（AAⅠ）. MethodSD rats were selected and administered AFE（110 g·kg^-1·d^-1） or AAⅠ（5 mg·kg^-1·d^-1） by oral for 5 days， respectively. Serum， urine and feces were collected after administration. Through sample pretreatment， ACQUITY UPLC BEH C₁₈ column（2.1 mm×100 mm， 1.7 μm） was used with the mobile phase of 0.01% formic acid methanol（A）-0.01% formic acid water（B， containing 5 mmol·L^-1 ammonium acetate） for gradient elution（0-1 min， 10%B； 1-7 min， 10%-75%B； 7-7.2 min， 75%-95%B； 7.2-10.2 min， 95%B； 10.2-10.3 min， 95%-10%B； 10.3-12 min， 10%B） at a flow rate of 0.3 mL·min^-1. Positive ion mode of electrospray ionization（ESI⁺） was performed in the scanning range of m/z 100-1 200. In combination with UNIFI 1.9.4.053 system， the Pathway-MS^E was used to qualitatively analyze and identify the AAs prototype and related metabolites in biological samples（serum， urine and feces）， and to compare the similarities and differences of metabolites in rats in the subacute toxicity test between AFE group and AAⅠ group. ResultCompared with AAⅠ group， 6， 10， 13 common metabolites and 14， 20， 30 unique metabolites were identified in biological samples（serum， urine and feces） of AFE group， respectively. Moreover， the main AAs components always followed the metabolic processes of demethylation， nitrate reduction and conjugation. Compared with common metabolites in AAⅠ group， prototype components of AAⅠ in serum and most metabolic derivatives of AAⅠ［AAⅠa， aristolochic lactam Ⅰ（ALⅠ）a， 7-OHALⅠ and its conjugated derivatives］ in biological samples were significantly increased in AFE group（P<0.05， P<0.01）， except that the metabolic amount of ALⅠ in feces of AFE group was remarkably lowed than that of AAⅠ group（P<0.01）. In addition， a variety of special ALⅠ efflux derivatives were also identified in the urine and feces of the AFE group. ConclusionAlthough major AAs components in AFE all show similar metabolic rules as AAⅠ components in vivo， the coexistence of multiple AAs components in Aristolochiae Fructus may affect the metabolism of AAⅠ， and achieve the attenuating effect by increasing the metabolic effection of AAⅠ and ALⅠ.

ObjectiveTo explore the mechanism of Jianpi Yishen Huazhuo prescription in the improvement of ovarian function in polycystic ovary syndrome （PCOS）. MethodSeventy female SD rats in SPF grade were randomly divided into 6 groups， 15 in the blank group and 15 in the model group， 10 in the metformin group （0.1 g·kg^-1·d^-1）， and 10 in the low （1.275 g·kg^-1·d^-1）， medium （2.55 g·kg^-1·d^-1）， and high-dose （5.10 g·kg^-1·d^-1） Jianpi Yishen Huazhuo prescription groups. The blank group was given normal saline （10 mL·kg^-1·d^-1） by gavage and ordinary feed， and the other groups were given letrozole （1 mg·kg^-1·d^-1） by gavage combined with high-fat feed for 21 days to induce the model of PCOS. After modeling， the blank group and model group were given equal volume normal saline by gavage， and each drug group was given the corresponding dose of the drug by gavage for 30 days. The changes in body mass and fasting blood glucose （FPG） of rats before and after modeling were compared. Hematoxylin eosin （HE） staining was used to observe the morphological change in the ovaries of rats in each group. The serum levels of follicle stimulating hormone （FSH）， luteinizing hormone （LH）， testosterone （T）， anti-Mullerian hormone （AMH）， and estradiol （E₂） were measured by enzyme-linked immunosorbent assay （ELISA）， and the LH/FSH ratio was calculated. Immunohistochemical staining （IHC） and Western blot were used to detect the protein expression levels of nucleoside binding oligomerization domain protein like receptor 3 （NALP3）， apoptosis-associated speck-like protein （ASC）， cysteine protease-1 （Caspase-1）， nuclear transcription factor-κB （NF-κB）， interleukin-1β （IL-1β）， interleukin-18 （IL-18）， and interleukin-6 （IL-6） in the rat ovaries. ResultAs compared with the blank group， large follicles with polycystic expansion were found in the ovaries of the model group， no dominant follicles were found， the granular layer of follicles decreased and arranged loosely， and the number of corpus luteum decreased significantly. Serum T， LH， AMH and LH/FSH increased in the model group （P<0.05， P<0.01）， while FSH and E₂ decreased （P<0.05， P<0.01）. The relative protein expression levels of NALP3， ASC， Caspase-1， NF-κB， IL-1β， IL-18， and IL-6 increased （P<0.05， P<0.01） in the ovaries of the model group. Compared with the model group， the low， medium， and high-dose Jianpi Yishen Huazhuo prescription groups and the metformin group showed growing follicles and corpus luteum at all levels， the number of cystic expanding follicles decreased， the thickness of follicular granular layer increased， the number of follicular fluid increased， mature follicles were visible， and the local morphology of oocytes was complete. Serum T， LH， AMH， and LH/FSH in these groups decreased （P<0.05， P<0.01）， while E₂ and FSH increased （P<0.05）. The relative protein expressions of NALP3， ASC， Caspase-1， NF-κB， IL-1β， IL-18， and IL-6 in the ovaries of these groups decreased （P<0.05， P<0.01）. There was no significant difference among the treatment groups. ConclusionBy inhibiting the activation of NLRP3 inflammasome， Jianpi Yishen Huazhuo prescription reduces the release of NALP3， ASC， Caspase-1， NF-κB， IL-18， IL-1β， and IL-6 inflammatory factors in ovarian tissues， regulates endocrine level， and effectively reduces PCOS inflammatory statu， so as to play a role in improving ovarian function.

[摘 要] 近年来，以T淋巴细胞为主的免疫细胞疗法在血液系统肿瘤和部分实体瘤中取得了一定的进展。然而，其对大部分实体瘤治疗的有效性和安全性仍面临着诸多挑战，如肿瘤抗原异质性和免疫逃逸、免疫细胞浸润能力差、免疫抑制微环境、代谢微环境阻碍和T细胞耗竭等，这些问题限制了免疫细胞对实体瘤治疗的疗效进一步的提升。通过寻找新抗原、设计多靶点CAR、过表达趋化因子受体及细胞因子、敲除抑制性信号分子、增强T细胞代谢能力、联合免疫检查点抑制剂，以及表观遗传修饰等手段能够有效改善免疫细胞在实体瘤治疗中的效果。本文系统性地对TIL、TCR-T细胞和CAR-T细胞为代表的免疫细胞对实体瘤治疗的研究现状、面临的挑战和解决策略进行评述。

BACKGROUND: Changes in thyroid hormone levels are commonly recognized characters among the elderly, which were reported to potentially influence incident frailty. Therefore, we examined the cross-sectional associations of thyroid hormones (THs) with frailty as well as the five components characterizing frailty (fatigue, resistance, ambulation, number of illnesses, and loss of weight) among the oldest-old. METHODS: Four hundred and eighty-seven community-dwelling oldest-old from a local community in Haidian District, Beijing, participated in our recruitment campaign between April 2019 and May 2020. The primary outcomes were a definitive diagnosis of frailty according to the FRAIL scale (Fatigue, Resistance, Ambulation, Illnesses, Loss of weight) and a positive score for each frailty subdomain. Demographic information (age, sex, marital status, and educational status), comorbidities, and details on the participants' lifestyles were recorded. Serum THs including free triiodothyronin (fT3), triiodothyronine (T3), free thyroxine (fT4), and thyroxine (T4) and thyroid stimulating hormone (TSH) levels were also measured at the beginning of our study. Logistic regressions were conducted to screen for potential risk factors for frailty and its subdomains. RESULTS: Among the total 487 subjects at enrollment, 60 (12.23%) of them were diagnosed with subclinical hypothyroidism and 110 (22.59%) of the total population scored positive for frailty. Logistic regression analyses adjusted for all potential confounders, showed that frailty was significantly associated with the serum TSH concentration (odds ratio [OR]: 1.06), fT3 concentration (OR: 0.54), and subclinical hypothyroidism score (OR: 2.18). The association between fT4 and frailty was absent in our observational study. The fT3/fT4 ratio characterizing peripheral hormone conversion was also tested to be correlated with frailty. CONCLUSION Subclinical hypothyroidism, higher TSH level, lower fT3 level, and decreased fT3/fT4 ratio were all associated with frailty assessed by the FRAIL scale among the community-dwelling oldest-old, suggesting a relevant role of thyroid function in aging. Future longitudinal studies are warranted to determine the casual relationship between thyroid dysfunction and frailty in the oldest-old.
Humans ; Aged, 80 and over ; Aged ; Thyroxine ; Cross-Sectional Studies ; Thyrotropin ; Frailty ; Independent Living ; Triiodothyronine ; Thyroid Function Tests ; Thyroid Hormones ; Hypothyroidism ; Fatigue

Objective:To evaluate the assistant role of manifestations under tracheoscopy in the diagnosis of invasive pulmonary aspergillosis (IPA) in severe patients.Methods:A retrospective study was conducted. The patients with suspected IPA admitted to intensive care unit (ICU) of Affiliated Hospital of Binzhou Medical College from January 2015 to December 2019 were enrolled. The diagnosis, clinical diagnosis and suspected diagnosis were made according to the grading criteria of Guidelines for the diagnosis and treatment of invasive fungal infection in severe patients (2007). Those who met the criteria were enrolled in the IPA group, and those who did not meet the criteria or other pathogens were enrolled in the non-IPA group. The general data of the patients were collected, and the changes of tracheal and bronchial mucosa under tracheal microscope before and after treatment were recorded, as well as the results of galactomannan (GM) test and aetiology culture of bronchoalveolar lavage fluid (BALF). The baseline, bronchoscopy and pulmonary CT manifestations and their dynamic changes were compared in each group. Results:A total of 142 patients with suspected IPA were finally enrolled. Among them, 12 were pathologically proven IPA, 77 were probable IPA, 22 were possible IPA, and 31 were undefined IPA. Of the 142 patients, 60 had typical manifestations of mucosal injury under bronchoscopy, including 7 proven IPA patients (58.3%), 52 probable IPA patients (67.5%), and 1 possible IPA patient (4.5%), but none undefined IPA patient. The patients undergoing lung CT scan were 12 proven IPA patients (100%), 73 probable IPA patients (94.8%), and 21 possible IPA patients (95.5%), respectively. Most of the Chest CT showed patchy or strip density increasing and other non-specific manifestations. There were 3 proven IPA patients (25.0%), 7 probable IPA patients (9.0%), and 0 possible IPA patient (0%) who had typical IPA CT manifestations (halo sign and cavity or crescent sign). Among the patients of proven IPA and probable IPA (89 cases), there were a total of 35 cases with endoscopic airway mucosal injury and tracheoscopy reexamination ≥ 3 times. All the 35 patients received anti-aspergillus treatment, among which 16 survived and 19 died. Among the 16 patients who survived, the microscopic appearance of mucosal injury was gradually reduced and the clinical manifestations were gradually improved. Of the 19 patients who died, 16 had deteriorated endoscopic airway mucosal injury.Conclusions:The specific manifestations of severe patients with bronchial mucosal injury are of great significance in the diagnosis of IPA. In the case of severe patients who cannot receive pathological examination or chest CT in time, dynamic observation of the changes of airway mucosal injury is a simple auxiliary method to discover the changes of patients' condition in time, evaluate the effect of antifungal therapy and the prognosis of IPA.

[摘 要] 目的：探究瑞戈非尼（regorafenib，Rego）对人肝癌SMMC-7721细胞增殖、凋亡的影响及其可能的机制。方法：将SMMC-7721细胞分为对照组及Rego组，分别用0、10 μmol/L Rego处理48 h后，流式细胞术检测各组细胞凋亡率，qPCR检测细胞中miR-122的表达。采用脂质体转染的方法将合成的hsa-miR-122-5p模拟物转染SMMC-7721细胞构建miR-122过表达的overExp-miR-122细胞，并将细胞分为对照组、Rego组、overExp-NC组、overExp-NC+Rego组、overExp-miR-122组及overExp-miR-122+Rego组，采用MTT法检测细胞活性，流式细胞术检测细胞凋亡率、WB法检测细胞中Bcl2、cleaved caspase-3、RAS、RAF1、p-ERK1蛋白表达水平。结果：与对照组相比，Rego处理后细胞凋亡率显著升高（P<0.05），且miR-122表达量显著上升（P<0.01）；与overExp-NC组比较，overExp-miR-122组细胞增殖抑制率、凋亡率和cleaved caspase-3表达均显著升高（均P<0.01），RAS蛋白表达显著下降（P<0.05），Bcl2、RAF、p-ERK1蛋白表达均显著下降（均P<0.01）；与overExp-miR-122组相比，overExp-miR-122+Rego组细胞中各检测指标变化进一步显著增加（P<0.01）。结论：Rego可抑制SMMC-7721细胞增殖、促进凋亡，其作用可能与调控miR-122、凋亡相关因子的表达和抑制RAS/RAF/ERK信号通路有关。