Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over the past few decades, significant progress has been made in the development of targeted epigenetic modulators (e.g., inhibitors). However, epigenetic inhibitors have faced multiple challenges, including limited clinical efficacy, toxicities, lack of subtype selectivity, and drug resistance. As a result, the design of new epigenetic modulators (e.g., degraders) such as PROTACs, molecular glue, and hydrophobic tagging (HyT) degraders has garnered significant attention from both academia and pharmaceutical industry, and numerous epigenetic degraders have been discovered in the past decade. In this review, we aim to provide an in-depth illustration of new degrading strategies (2017-2023) targeting epigenetic proteins for cancer therapy, focusing on the rational design, pharmacodynamics, pharmacokinetics, clinical status, and crystal structure information of these degraders. Importantly, we also provide deep insights into the potential challenges and corresponding remedies of this approach to drug design and development. Overall, we hope this review will offer a better mechanistic understanding and serve as a useful guide for the development of emerging epigenetic-targeting degraders.

Objective:To compare the diagnostic efficacy of 22 G fine needle aspiration (FNA) needles and 22 G end-cutting fine needle biopsy (FNB) needles for solid pancreatic lesion using both cytological and histological examination.Methods:Clinical data of 116 patients who underwent endoscopic ultrasound-guided fine needle aspiration/biopsy (EUS-FNA/FNB) at the Digestive Endoscopy Center of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine from June 2022 to March 2023 were retrospectively analyzed. Sixty-three patients sampled with 22 G FNA needles were the FNA group, and 53 sampled with 22 G FNB needles were the FNB group. The diagnostic accuracy, sensitivity, specificity, positive predictive value, negative predictive value, and cytological and histological diagnostic yield of FNA needles and FNB needles for solid pancreatic lesions were compared.Results:There were no significant differences in age, gender, lesion location, lesion size, or the number of passes between the FNA group and the FNB group ( P>0.05). There were no significant differences in the diagnostic accuracy [93.7% (59/63) VS 90.6% (48/53), P=0.730], sensitivity [93.0% (53/57) VS 90.2% (46/51), P=0.732], specificity [100.0% (6/6) VS 100.0% (2/2), P=1.000], positive predictive value [100.0% (53/53) VS 100.0% (46/46), P=1.000] and negative predictive value [60.0% (6/10) VS 28.6% (2/7), P=0.335] of combined cytology and histology in distinguishing benign and malignant lesions between the two groups. In the FNA group, the diagnostic accuracy of combined cytology and histology was higher than cytology alone [93.7% (59/63) VS 81.0% (51/63), P=0.008], and was higher than histology alone without statistical significance [93.7% (59/63) VS 87.3% (55/63), P=0.125]. In the FNB group, the diagnostic accuracy of combined cytology and histology was higher than cytology alone [90.6% (48/53) VS 69.8% (37/53), P=0.001], but not than histology alone [90.6% (48/53) VS 90.6% (48/53)， P=1.000]. For solid masses located in pancreatic body/tail, the diagnostic accuracy for malignancy by histology using FNB needles tended to be higher than that of FNA needles [100.0% (17/17) VS 81.3% (26/32), P=0.080]. Conclusion:Both FNA needles and FNB needles exhibit adequate diagnostic yield for solid pancreatic masses when combining cytology and histology. FNB needles may offer a higher histological diagnostic yield.

Tremor is an involuntary and repetitive swinging movement of limb, which can be regarded as a periodic disturbance in tremor suppression system based on functional electrical stimulation (FES). Therefore, using repetitive controller to adjust the level and timing of FES applied to the corresponding muscles, so as to generate the muscle torque opposite to the tremor motion, is a feasible means of tremor suppression. At present, most repetitive control systems based on FES assume that tremor is a fixed single frequency signal, but in fact, tremor may be a multi-frequency signal and the tremor frequency also varies with time. In this paper, the tremor data of intention tremor patients are analyzed from the perspective of frequency, and an adaptive repetitive controller with internal model switching is proposed to suppress tremor signals with different frequencies. Simulation and experimental results show that the proposed adaptive repetitive controller based on parallel multiple internal models and series high-order internal model switching can suppress tremor by up to 84.98% on average, which is a significant improvement compared to the traditional single internal model repetitive controller and filter based feedback controller. Therefore, the adaptive repetitive control method based on FES proposed in this paper can effectively address the issue of wrist intention tremor in patients, and can offer valuable technical support for the rehabilitation of patients with subsequent motor dysfunction.
Humans ; Wrist ; Tremor/therapy* ; Movement ; Computer Simulation ; Electric Stimulation

Suffering is prevalent in the palliative care population and is an important factor affecting the quality of life of palliative care patients and their family caregivers. In this paper, we review the assessment content, measurement methods, current application status and advantages and disadvantages of suffering assessment tools for palliative care patients, analyze the problems of current suffering assessment tools for palliative care patients and make suggestions, aiming to provide reference for palliative suffering treatment in China.

Objective:To evaluate and quantify the degree of language impairment by obtaining the cerebral blood flow in the main language functional areas of aphasia patients after stroke with arterial spin labeling sequence, so as to make aphasia evaluation more objectively, accurately and effectively.Methods:From May 2016 to October 2019, 22 patients with aphasia after stroke and 22 healthy controls were collected from the Department of Neurology, the First Affiliated Hospital of Zhejiang University, for multimode MR scanning, and the patients were evaluated by aphasia scale during hospitalization. The classic language related brain area and potential language related brain area were selected as the regions of interest to extract the local mean cerebral blood flow. The differences of cerebral blood flow between the two groups were compared, and the correlation between the cerebral blood flow of each region of interest and the sub items of multiple language scales was analyzed.Results:Compared with the control group, the cerebral blood flow of the inferior parietal gyrus （AAL-11，(39.18±3.85) ml·100 g -1·min -1vs (50.41±1.93) ml·100 g -1·min -1， t=2.605）, angular gyrus （AAL-13，(39.90±3.29) ml·100 g -1·min -1vs (47.86±1.93) ml·100 g -1·min -1, t=2.087） in the patients was obviously decreased; In the relevant brain areas of listening comprehension, the cerebral blood flow of the inferior parietal gyrus (AAL-61, (33.86±4.15) ml·100 g -1·min -1vs (44.31±2.39) ml·100 g -1·min -1, t=2.179), superior marginal gyrus (AAL-63, (36.49±4.40) ml·100 g -1·min -1vs（50.17±2.26） ml·100 g -1·min -1, t=2.765), and angular gyrus (AAL-65, (35.56±4.24) ml·100 g -1·min -1vs(48.98±2.32) ml·100 g -1·min -1, t=2.777), Heschl gyrus (AAL-79, (47.30±5.11) ml·100 g -1·min -1vs（62.54±2.45） ml·100 g -1·min -1, t=2.689) and superior temporal gyrus (AAL-81, (43.56±4.82) ml·100 g -1·min -1vs (56.29±2.06) ml·100 g -1·min -1, t=2.429) of the patients was also decreased to different degrees ( P<0.05). In addition, the cerebral blood flow of the left insula (AAL-29, (46.59±3.76) ml·100 g -1·min -1vs (55.74±2.12) ml·100 g -1·min -1, t=2.120) and the rolandic island (AAL-17, (39.71±3.81) ml·100 g -1·min -1vs (52.48±2.01) ml·100 g -1·min -1, t=2.968)cover in the patients was also lower than that in the control group significantly ( P<0.05). The results of correlation analysis showed that there was a significant positive correlation ( P<0.05) between the brain blood flow of the left inferior frontal gyrus, the triangle of inferior frontal gyrus, the insular lobe, the inferior parietal lobe, the bilateral superior marginal gyrus and the sub item scores of the language scale in the patients. Conclusions:The decrease of cerebral blood flow is the potential cause of the decrease of language function in aphasia patients after stroke. The decrease of cerebral blood flow in six brain regions, including the frontal inferior gyrus, the frontal inferior gyrus triangle, the insular lobe, the left and right superior marginal gyrus and the inferior parietal lobe, can be used as an objective quantitative index to reflect the level of naming function.

Objective: To evaluate the efficacy and safety of Oryz-Aspergillus enzyme and pancreatin tablets (Combizym^®) in the treatment of postprandial distress syndrome (PDS) in the elderly, compared with gastrointestinal motility drugs. Methods: A prospective randomized controlled trial was designed and registered in the China Clinical Trials Registry (ChiCTR-IPR-16008185). The elderly patients with PDS were randomly divided into three groups, including Mosapride group with Mosapride citrate tablets 5 mg 3 times per day for 2 weeks; Combizym^® group with Combizym tablets 244 mg 3 times per day for 2 weeks; combined treatment group with both drugs and same doses for 2 weeks. The modified Nepean dyspepsia index (NDSI) score, discomfort intensity score and PDS score were calculated on patients before treatment, at the end of first and second week of treatment, as well as 4 weeks after treatment finished, respectively. Adverse effects were evaluated. Results: A total of 323 patients from 16 tertiary hospitals in China were enrolled in this study. Among them, 105 patients were in Mosapride group, 109 in Combizym^® group and 109 in combined treatment group. There were 148 males (45.8%) and 175 females (54.2%) with median age 71.4±9.0 years (60-100 years). Baseline characteristics of three groups were comparable. After treatment, the NDSI scores in three groups all decreased significantly (P<0.001), while they were similar between groups (P>0.05). The discomfort intensity score and PDS score in three groups showed a significant reduction after treatment (P<0.001), especially in the combined treatment group. Compared with Mosapride group, the scores in Combizym^® group decreased significantly after one or two weeks [discomfort intensity score: after one week, 4.0(2.5, 8.0) vs. 6.0(3.0, 10.0); after two weeks, 3.0(0.0, 5.0) vs. 4.0(2.0, 6.0); all P<0.05. PDS score: after one week, 6.0(3.0, 9.0) vs. 7.0(3.5, 10.5); after two weeks, 3.0(0.0, 5.0) vs. 4.0(2.0, 7.0); all P<0.05]. The efficacy rate in all patients after first week of treatment was over 15.0%. The efficacy rates after two weeks were 55.2%, 68.8% and 73.4% in Mosapride group, Combizym^® group and combined treatment group, respectively. After two week treatment, the efficacy rates in Combizym^® group (P=0.041) and combined group (P=0.006) were higher than that of Mosapride group. The recurrence rate of Mosapride group was 9.5%, which was significantly higher than that of Combizym^® group (1.8%, P<0.05) and combined treatment group (1.8%, P<0.05). There were no serious adverse effects in the three groups. Conclusions The efficacy of Oryz-Aspergillus enzyme and pancreatin tablets is comparable with that of Mosapride in elderly PDS patients, with fewer adverse effects and low recurrence rate. Combination regimen indicates better efficacy than that of Oryz-Aspergillus enzyme and pancreatin tablets or Mosapride alone.

Arterial spin labeling (ASL) technology is a popular technique for evaluating and studying cerebral perfusion in recent years. It can sensitively detect the abnormal cerebral perfusion and effectively avoid the potential risks caused by exogenous contrast agents in other tests. Detection of the abnormal cerebral blood flow perfusion by ASL technology can early predict cognitive decline in normal elderly, explore the pathogeneses of mild cognitive dysfunction and Alzheimer's disease, and evaluate the cerebral blood flow around the ischemic focus and the establishment of collateral circulation in patients with aphasia after stroke. At the same time, it is verified that the decrease of cerebral blood flow perfusion is another precipitating factor of primary progressive aphasia except cortex atrophy. Although there are still some limitations, the ASL technology has a good prospect in the application of cognitive disorders.

Objective To investigate the disease types incurring poverty, patient population layout, and cost burden by poor households due to illness. Methods During the time August 17-24,2017, App questionnaires were used onsite for data survey at 2 824 poor hourseholds in Nanyang city of Henan province, in order to learn the impacts of the poverty-causing diseases on the labor capacity of the patients and the cost burdens. Such methods as descriptive analysis, rank sum test and correlation analysis were used for data analysis. Results The survey found that 61.79 percent(1 745 households) of the poor households turned poor by illness, most of them aged 40 to 60 years old. The ten disease categories, namely cerebrovascular diseases, malignant tumor, ischemic heart diseases and mental diseases, constitute top disease causes of poverty. These diseases significantly damage their labor capacity, up to 37.67% of them totally disabled. The self-paid expenses of the patients per year accounted for 57.22% of the total annual expenses. Conclusions Medical insurance policies need to elevate the scope and efforts of medical compensation;public health services need to improve health promotion and health education; government supervision needs to be enhanced to keep minimizing patients′disease burdens.

Objective To investigate the relationship between the level of serum cystatin C (CysC) and cognitive function in patients with acute cerebral lacunar infarction caused by small vessel disease . Methods One hundred twen-ty-three patients with acute cerebral lacunar infarction were divided into 3 groups according to serum cystatin C level. Patients were further divided into normal group (n=64), vascular mild cognitive impairment (VaMCI) group(n=36),and vascular dementia( VaD) group (n=23). The CysC, estimated glomerular filtration rate (eGFR), serum creatinine (Scr), TC, TG, HDL, LDL, fast glucose, HbA1C, NIHSS, MMSE, ADAS-cog score were compared between the 3 groups. Multivari-able logistic regression analysis was used to examine the association of serum CysC with cognitive function. Results Sub-jects with higher CysC levels tended to have lower MMSE score(21.98 ± 6.08 vs. 25.02 ± 4.69 vs. 25.10 ± 3.95 )and higher ADAS-cog score(17.73±14.23 vs. 12.51±10.39 vs. 10.67±7.53). The higher CysC was, the higher SCr and lower eGFR were. Subjects with severer cognition impairment tended to have higher CysC(0.93 ± 0.21 vs. 1.10 ± 0.45 vs. 1.34 ± 0.58). Multivariable logistic regression showed the regression coefficient was 7.06(P<0.05). Conclusion Elevated Serum CysC is one of the risk factors of cognitive dysfunction and associated with the severity in patients with small vessel disease-re-lated acute lacunar cerebral infarction.

Objective To prospectively explore the impact of hypocalcemia on the prognostic value of intracerebral hemorrhage.Methods A total of 410 patients consecutively admitted within 12 hours after intracerebral hemorrhage onset were divided into 3 groups based on admission serum calcium:low serum calcium group,normal serum calcium group and high serum calcium group.Baseline characteristics of patients including age,gender,Glasgow coma score(GCS),hematoma volume,etc were collected and analyzed.A follow-up was performed after 6 months.Final outcome was assessed using Glasgow outcome scale(GOS)with a score＞3 regarded as favourable prognosis,a score≤3 as unfavourable prognosis.Results Patients with low serum calcium had lower GOS,bigger hematoma volume,higher rate of operation,higher re-bleeding rate,more unfavourable prognosis than did the other 2 serum calcium groups.Multivariable Logistic regression analysis showed that patients with low serum calcium had poorer prognosis than patients with normal serum calcium after adjusting for other potential confounders(Odds ratio:3.01,95％ confidence interval:1.06-6.12,P＜0.05).Conclusions Hypocalcemia is an independent risk factor for the prognosis of patients with intracerebral hemorrhage.