Paclitaxel， a highly effective natural antitumor drug， has been demonstrated to be efficacious in the treatment of a variety of cancers， including breast cancer， ovarian cancer， and lung cancer. The traditional paclitaxel injections have been observed to present certain issues， including overt adverse reactions and a decline in the quality of life of patients following treatment. This ultimately leads to an inability to meet the comprehensive needs of patients， thereby limiting the clinical applications of the drugs. Compared with injectable administration， the oral administration can avoid the risk of infection present in the invasive route， is conducive to improving patient compliance and quality of life， and reduces healthcare costs， and has a good application prospect. However， paclitaxel has low solubility， poor permeability， and is susceptible to the exocytosis of P-glycoprotein， which presents a significant challenge in the development of its oral preparations. Novel drug delivery technologies can enhance the solubility of paclitaxel and facilitate its controlled release， which is beneficial for the oral absorption and efficacy. The paper reviews the development history of oral preparations of paclitaxel， and summarizes the delivery technologies such as polymer micelles， nanoparticles， nanoemulsions and nanocrystals， and discusses the application mechanisms， advantages and limitations of these technologies and their adaptability in different cancer treatments. Finally， the challenges faced in the development of oral preparations of paclitaxel are summarized， and future research directions are proposed in order to provide new ideas for the development of oral delivery of paclitaxel.

Paclitaxel， a highly effective natural antitumor drug， has been demonstrated to be efficacious in the treatment of a variety of cancers， including breast cancer， ovarian cancer， and lung cancer. The traditional paclitaxel injections have been observed to present certain issues， including overt adverse reactions and a decline in the quality of life of patients following treatment. This ultimately leads to an inability to meet the comprehensive needs of patients， thereby limiting the clinical applications of the drugs. Compared with injectable administration， the oral administration can avoid the risk of infection present in the invasive route， is conducive to improving patient compliance and quality of life， and reduces healthcare costs， and has a good application prospect. However， paclitaxel has low solubility， poor permeability， and is susceptible to the exocytosis of P-glycoprotein， which presents a significant challenge in the development of its oral preparations. Novel drug delivery technologies can enhance the solubility of paclitaxel and facilitate its controlled release， which is beneficial for the oral absorption and efficacy. The paper reviews the development history of oral preparations of paclitaxel， and summarizes the delivery technologies such as polymer micelles， nanoparticles， nanoemulsions and nanocrystals， and discusses the application mechanisms， advantages and limitations of these technologies and their adaptability in different cancer treatments. Finally， the challenges faced in the development of oral preparations of paclitaxel are summarized， and future research directions are proposed in order to provide new ideas for the development of oral delivery of paclitaxel.

OBJECTIVE To standardize the main processes and related technical links of the clinical comprehensive evaluation of drugs， and provide guidance and reference for improving the quality of comprehensive evaluation evidence and its transformation and application value. METHODS The construction of Guideline for the Workflow of Clinical Comprehensive Evaluation of Drugs was based on the standard guideline formulation method of the World Health Organization （WHO）， strictly followed the latest definition of guidelines by the Institute of Medicine of the National Academy of Sciences of the United States， and conformed to the six major areas of the Guideline Research and Evaluation Tool Ⅱ. Delphi method was adopted to construct the research questions； research evidence was established by applying the research methods of evidence-based medicine. The evidence quality classification system of the Chinese Evidence-Based Medicine Center was adopted for evidence classification and evaluation. The recommendation strength was determined by the recommendation strength classification standard formulated by the Oxford University Evidence-Based Medicine Center， and the recommendation opinions were formed through the expert consensus method. RESULTS & CONCLUSIONS The Guideline for the Workflow of Clinical Comprehensive Evaluation of Drugs covers 4 major categories of research questions， including topic selection， evaluation implementation， evidence evaluation， and application and transformation of results. The formulation of this guideline has standardized the technical links of the entire process of clinical comprehensive evaluation of drugs， which can effectively guide the high-quality and high-efficient development of this work， enhance the standardized output and transformation application value of evaluation evidence， and provide high-quality evidence support for the scientific decision-making of health and the rationalization of clinical medication.

Mycophenolic acid (MPA), the active moiety of both mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS), serves as a primary immunosuppressant for maintaining solid organ transplants. Therapeutic drug monitoring (TDM) enhances treatment outcomes through tailored approaches. This study aimed to develop an evidence-based guideline for MPA TDM, facilitating its rational application in clinical settings. The guideline plan was drawn from the Institute of Medicine and World Health Organization (WHO) guidelines. Using the Delphi method, clinical questions and outcome indicators were generated. Systematic reviews, Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evidence quality evaluations, expert opinions, and patient values guided evidence-based suggestions for the guideline. External reviews further refined the recommendations. The guideline for the TDM of MPA (IPGRP-2020CN099) consists of four sections and 16 recommendations encompassing target populations, monitoring strategies, dosage regimens, and influencing factors. High-risk populations, timing of TDM, area under the curve (AUC) versus trough concentration (C₀), target concentration ranges, monitoring frequency, and analytical methods are addressed. Formulation-specific recommendations, initial dosage regimens, populations with unique considerations, pharmacokinetic-informed dosing, body weight factors, pharmacogenetics, and drug‍-‍drug interactions are covered. The evidence-based guideline offers a comprehensive recommendation for solid organ transplant recipients undergoing MPA therapy, promoting standardization of MPA TDM, and enhancing treatment efficacy and safety.
Mycophenolic Acid/administration & dosage* ; Drug Monitoring/methods* ; Humans ; Organ Transplantation ; Immunosuppressive Agents/administration & dosage* ; Delphi Technique

OBJECTIVE To investigate the preferences of patients who underwent solid organ transplantation regarding therapeutic drug monitoring （TDM） of mycophenolic acid （MPA） and explore the factors influencing patients’ decision-making process， so as to provide support for the development of individualized medication guidelines for MPA and improvement of clinical decision-making. METHODS The cross-sectional study was used to design the questionnaire on the patients’ preferences to accept MPA TDM， and involved patients who underwent solid organ transplantation and received MPA treatment at two tertiary hospitals in Beijing from April 14， 2022， to June 27， 2022. The Likert 5-level scoring method was used to score the patients’ preferences to accept MPA TDM， the influencing factors and their correlation of the patients’ preferences to accept MPA TDM were analyzed by Pearson correlation analysis and binary Logistic regression analysis， and the nonparametric test and chi-square test were used to rank and analyze the consistency of the factors affecting patients’ preference decision. RESULTS A total of 140 questionnaires were collected， and the effective recovery rate was 77.35%. The average preference score of 140 patients to receive MPA TDM was （4.01±0.65）， and the overall preference value was high. There were 116 （82.86%） patients agreed or strongly agreed with MPA TDM. Significant differences were observed in preference scores between patients who had previously undergone MPA TDM and those who had never undergone it （[ 4.30±0.53） scores vs. （3.80±0.65） scores， P＜0.001]. Additionally， patients’ preference scores were significantly influenced by their understanding level and attention level （P＜0.001）. The ranking of factors contributing to decision-making exhibited consistency （P＜0.001）. The factors were ranked in descending order of clinical efficacy， safety， comfortability， economy and time cost. CONCLUSIONS The patients who underwent solid organ transplantation hold high preferences towards MPA TDM. The primary factors influencing their decisions are their prior experience， understanding level， and attention level.

Objective To investigate the efficacy of entecavir (ETV) versus tenofovir disoproxil fumarate (TDF) and the treatment measures for poor response in previously untreated chronic hepatitis B (CHB) patients with high viral load. Methods A total of 165 CHB patients who received antiviral therapy and met the inclusion criteria in Department of Infectious Diseases, The First Affiliated Hospital of Guangxi Medical University, from June 2016 to July 2021 were enrolled. The patients enrolled had a baseline HBV DNA level of > 6lg copies/ml and were previously untreated CHB patients who had used ETV or TDF for 48 weeks, and quantitative real-time PCR was used to measure HBV DNA. Virologic response rate was calculated after 48 weeks of treatment; a logistic regression analysis was used to investigate the influencing factors for the response of HBV DNA < 500 copies/mL and HBV DNA < 100 copies /mL at 48 weeks; a stratified analysis was performed to compare the virologic response rate of HBV DNA < 500 copies /ml and HBV DNA < 100 copies/ml after 48 weeks between the patients with different ages, sexes, baseline HBV DNA levels, baseline alanine aminotransferase (ALT) levels, types of first-line medication, and HBeAg statuses. The Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups, the chi-square test or the Fisher's exact test was used for comparison of categorical data between two groups, and the binary logistic regression model was used for multivariate analysis. Results After 48 weeks of treatment, 85.5% (141/165) of the patients achieved an HBV DNA load of < 500 copies/mL, and 66.1% (109/165) of the patients achieved an HBV DNA load of < 100 copies /mL, with no significant difference in treatment outcome between the ETV group and the TDF group. The multivariate logistic regression analysis showed that sex( OR =2.793, 95% CI : 1.197-6.517), baseline HBV DNA( OR =0.369, 95% CI : 0.142-0.959), baseline ALT( OR =4.556, 95% CI : 1.770-11.732), and baseline HBeAg( OR =0.120, 95% CI : 0.033-0.429) were influencing factors for complete virologic response(all P < 0.05). For the patients with normal ALT (≤40 U/L) at baseline, 75.6% (34/45) achieved an HBV DNA load of < 500 copies/mL after 48 weeks of treatment, and 53.3% (24/45) achieved an HBV DNA load of < 100 copies/mL, with no significant difference in treatment outcome between the ETV group and the TDF group. For the patients with abnormal ALT (> 40 U/L) at baseline, 89.2% (107/120) achieved an HBV DNA load of < 500 copies/mL after 48 weeks of treatment, and the proportion of such patients in the TDF group was significantly higher than that in the ETV group (96.1% vs 84.1%, χ 2 =4.386, P =0.036); 70.8% (85/120) achieved an HBV DNA load of < 100 copies/mL, the proportion of such patients was no significant difference between the TDF group and the ETV group (78.4% vs 65.2%). The response of HBV DNA < 100 copies/ml of the normal baseline ALT group and the abnormal baseline ALT group, there were no significant differences between the patients aged≤30 years and aged > 30 years (77.8% vs 47.2%, 85.2% vs 66.7%). For the patients who did not achieve complete virologic response (HBV DNA ≥100 copies/mL) after 48 weeks of treatment, 87.9% (29/33) achieved complete virologic response after the original treatment regimen was prolonged for 48 weeks, and 100% (9/9) of the patients achieved complete virologic response after switching to or adding the first-line nucleos(t)ide analogues (NUCs) without cross-resistance sites with the original regimen for another 48 weeks. Conclusion The patients aged > 30 years should receive antiviral therapy as early as possible, regardless of viral load and ALT level, especially those with a family history of liver cirrhosis or hepatocellular carcinoma; the patients aged ≤30 years who have a normal ALT level and a high viral load should consider initiating antiviral therapy after providing informed consent. For the patients with poor response after 48 weeks of treatment, first-line NUCs without cross-resistance sites with the original regimen should be switched to or added in time.

Objective:To observe the efficacy and safety of teriprizumab combined with bevacizumab in above the second line treatment of high-level microsatellite instability (MSI-H) type metastatic colorectal cancer (mCRC) patients.Methods:From February 2019 to September 2019, 56 patients with MSI-H mCRC admitted to the Third Affiliated Hospital of Guangdong Medical University were selected and divided into control group and test group by random number table method, with 28 cases in each group. The control group was treated with bevacizumab, and the test group was treated with teriprizumab combined with bevacizumab. The objective response rate (ORR), disease control rate (DCR), progression-free survival, overall survival and incidence of adverse reactions were compared between the two groups.Results:The ORR and DCR of the test group were 60.71% (17/28) and 75.00% (21/28) respectively, higher than 28.57% (8/28) and 46.63% (13/28) of the control group, with statistically significant differences ( χ2=5.85, P=0.016; χ2=4.79, P=0.029). The median progression-free survival of patients in the control group and the test group were 3.5 months and 5.8 months respectively, with a statistically significant difference ( χ2=9.83, P=0.003). The median overall survival of patients in the control group and the test group were 12.1 months and 16.2 months respectively, with a statistically significant difference ( χ2=6.13, P=0.007). There were no significant diffe-rences in the incidences of hematological reaction (17.86% vs. 14.29%, χ2=0.13, P=0.716), cardiovascular injury (10.71% vs. 14.29%, χ2=0.16, P=0.686), liver and kidney function injury (25.00% vs. 21.43%, χ2=0.10, P=0.752), gastrointestinal reaction (28.57% vs. 35.71%, χ2=0.33, P=0.567), skin and mucosal injury (7.14% vs. 10.71%, χ2=0.35, P=0.553), nervous system disease (3.57% vs. 14.29%, χ2=2.25, P=0.134), endocrine reaction (3.57% vs. 10.71%, χ2=1.29, P=0.256), alopecia (14.29% vs. 17.86%, χ2=0.13, P=0.716) and fatigue (25.00% vs. 28.57%, χ2=0.27, P=0.605) between the control group and the test group. Conclusion:The combination of teriprizumab and bevacizumab can improve the short-term and medium-long-term efficacy of patients with MSI-H mCRC, which is safe and reliable.

Objective:To identify the key genes related to rheumatoid arthritis (RA) by to the weighted gene co-expression network analysis (WGCNA) and experimental verification to find key genes related to RA.Methods:The microarray data of RA were downloaded from the Gene Expression Omnibus (GEO) database. Gene network was constructed, and the genes were classified into different modules using WGCNA. HUB genes in modules related to RA clinical symptoms were analyzed by gene ontology. Subsequently, different data sets of GEO were used to verify the expression profile and diagnostic capacity of the HUB gene [receiver operating characteristic curve (ROC)]. In addition, the expression of HUB gene in RA was verified by real time polymerase chain reaction (RT-PCR) and Western blot, and the relationship between key genes and disease activity score 28 joints (DAS28) was analyzed. Paired-sample t-test and Pearson's correlation analysis was used for statistical analysis. Results:A total of 5 413 differentially expressed genes were filtered. Weighted gene coexpression network was constructed and genes were classified into 23 modules. Among them, the black module is closely related to the clinical symptoms of RA, which contained 346 genes. Enrichment analysis and Kyoto encyclopedia of genes and genomes (KEGG) signal pathway analysis showed that it was to be enriched in the positive regulation of interleukin 6, interleukin 1 beta secretion, osteoclast differentiation, NOD-like receptor signaling pathway, T helper cell 17 (Th17) cell differentiation and many other pathways closely related to RA. Motile sperm domain-containing protein 2 (MOSPD2) was significantly correlated with clinical symptoms. It was highly expressed in blood monocytes and bone marrow monocytes ( t=2.238, P=0.032; t=3.153, P=0.006), and positively correlated with blood expression in RA joint synovial fluid ( r=0.683, P=0.03). ROC curve analysis determined that MOSPD2 could distinguish RA from the control group (the area under the curve was 0.855 and 0.726) respectively. RT-PCR and Western blotting results showed that MOSPD2 was up-regulated in RA patients ( t=-3.96, P=0.02). MOSPD2 expression levels in blood were positively correlated with DAS28 in RA patients ( r=0.884 6, P=0.046 2). Conclusion:MOSDP2 is closely related to the clinical symptoms of RA patients, and may be one of the targets for the diagnosis and treatment of RA.

Objective:In general, patients with seropositive rheumatoid arthritis (RA) are considered to show an aggressive disease course. However, the relationship between the two subgroups in disease severity is controversial. Our study is aimed to compare the clinical characteristics and prognosis of double-seropositive and seronegative RA in China through a real-world large scale study.Methods:RA patients who met the 1987 American College of Rheumatology (ACR) classification criteria or the 2010 ACR/European Anti-Rheumatism Alliance RA classification criteria, and who attended the 10 hospitals across the country from September 2015 to January 2020, were enrolled. According to the serological status, patients were divided into 4 subgroups [rheumatoid factor (RF)(-) anti-cyclic citrullinated peptide (CCP) antibody (-), RF(+), RF(+) anti-CCP antibody(+), anti-CCP antibody(+)] and compared the disease characteristics and treatment response. One-way analysis of variance was used for measurement data that conformed to normal distribution, Kruskal-Wallis H test was used for measurement data that did not conform to normal distribution; paired t test was used for comparison before and after treatment within the group if the data was normally distributed else paired rank sum test was used; χ2 test was used for count data. Results:① A total of 2 461 patients were included, including 1 813 RF(+) anti-CCP antibody(+) patients (73.67%), 129 RF(+) patients (5.24%), 245 RF(-) anti-CCP antibody(-) patients (9.96%), 74 anti-CCP antibody(+) patients (11.13%). ② Regardless of the CCP status, RF(+) patients had an early age of onset [RF(-) anti-CCP antibody(-) (51±14) years old, anti-CCP antibody(+) (50±15) years old, RF(+) anti-CCP antibody(+) (48±14) years old, RF(+)(48±13) years old, F=3.003, P=0.029], longer disease duration [RF(-) anti-CCP antibody(-) 50 (20, 126) months, anti-CCP antibody(+) 60(24, 150) months, RF(+) anti-CCP antibody(+) 89(35, 179) months, RF(+) 83(25, 160) months, H=22.001, P<0.01], more joint swelling counts (SJC) [RF(-) anti-CCP antibody(-) 2(0, 6), Anti-CCP antibody(+) 2(0, 5), RF(+) anti-CCP antibody(+) 2(0, 7), RF(+) 2(0, 6), H=8.939, P=0.03] and tender joint counts (TJC) [RF(-) anti-CCP antibody(-) 3(0, 8), anti-CCP antibody(+) 2(0, 6), RF(+) anti-CCP antibody(+) 3(1, 9), RF(+) 2(0, 8), H=11.341, P=0.01] and the morning stiff time was longer [RF(-) anti-CCP antibody(-) 30(0, 60) min, anti-CCP antibody(+) 20(0, 60) min, RF(+) anti-CCP antibody(+) 30(10, 60) min, RF(+) 30(10, 60) min, H=13.32, P<0.01]; ESR [RF(-) anti-CCP antibody(-) 17(9, 38) mm/1 h, anti-CCP antibody(+) 20(10, 35) mm/1 h, RF(+) anti-CCP antibody(+) 26(14, 45) mm/1 h, RF(+) 28(14, 50) mm/1 h, H=37.084, P<0.01] and CRP [RF(-) anti-CCP antibody(-) 2.3 (0.8, 15.9) mm/L, Anti-CCP antibody(+) 2.7(0.7, 12.1) mm/L, RF(+) anti-CCP antibody(+) 5.2(1.3, 17.2) mm/L, RF (+) 5.2(0.9, 16.2) mm/L, H=22.141, P<0.01] of the RF(+)patients were significantly higher than RF(-) patients, and RF(+) patients had higher disease severity(DAS28-ESR) [RF(-) anti-CCP antibody(-) (4.0±1.8), anti-CCP antibody(+) (3.8±1.6), RF(+) anti-CCP antibody(+) (4.3±1.8), RF(+) (4.1±1.7), F=7.269, P<0.01]. ③ The RF(+) anti-CCP antibody(+) patients were divided into 4 subgroups, and it was found that RF-H anti-CCP antibody-L patients had higher disease severity [RF-H anti-CCP antibody-H 4.3(2.9, 5.6), RF-L anti-CCP antibody-L 4.5(3.0, 5.7), RF-H anti-CCP antibody-L 4.9(3.1, 6.2), RF-L anti-CCP antibody-H 2.8(1.8, 3.9), H=20.374, P<0.01]. ④ After 3-month follow up, the clinical characteristics of the four groups were improved, but there was no significant difference in the improvement of the four groups, indicating that the RF and anti-CCP antibody status did not affect the remission within 3 months. Conclusion:Among RA patients, the disease activity of RA patients is closely related to RF and the RF(+) patients have more severe disease than RF(-) patients. Patients with higher RF titer also have more severe disease than that of patients with low RF titer. After 3 months of medication treatment, the antibody status does not affect the disease remission rate.

Objective:To retrospectively analyze the serological, virological, biochemical, liver histological status and clinical outcomes in HBeAg-negative chronic hepatitis B (CHB) patients with low HBV viral load, and to explore the necessity of antiviral therapy for these patients.Methods:A total of 99 HBeAg-negative CHB patients with HBV DNA level < 4 lg copies/ml who performed liver biopsy at the baseline were enrolled from the follow-up cohort. Among them, 23 cases received the second liver biopsy during follow-up. The relationships among the degree of inflammation and fibrosis of liver tissues, the status of HBsAg and HBcAg, age, gender, family history, HBV DNA load, serological markers and other indicators were analyzed. The pathological differences between two liver biopsy examinations were compared. The effect of nucleos(t)ide analogues (NAs) treatment on patient’s clinical outcomes were analyzed. For multivariate analysis, a binary logistic regression model was performed. Log-rank test was used to compare the cumulative incidence of hepatocellular carcinoma (HCC) in NAs-treated and non-NA streated patients.Results:Baseline liver histology status showed that 58.6% (58/99) patients had obvious liver tissue damage in their baseline liver tissue pathology (G≥2 and /or S≥2). Univariate logistic regression analysis showed that a liver cirrhosis (LC) family history, a HBsAg-positive family history, baseline alanine aminotransferase and aspartate aminotransferase levels were positively correlated factors for liver tissue damage. Multivariate logistic regression analysis showed that a LC family history was the main risk factor for liver tissue damage. Twenty-three cases had received a second liver biopsy after an interval of 4.5 years. In 10 untreated cases, the second liver biopsy results showed the rate of obvious liver tissue damage (G≥2 and/ or S≥2) increased from 50.0% to 90.0%. In the other 13 cases who received NAs treatment, the second liver biopsy showed improvement in liver histology, and the rate of obvious liver tissue damage decreased from 61.5% to 46.2%. The 5-year HCC cumulative incidence in non-NAs-treated patients was significantly higher than that of in NAs-treated patients (17.7% vs. 3.8%, P = 0.046). Conclusion:For most HBeAg-negative CHB patients with low viral load, liver tissue pathology result suggests that it meets the indications for antiviral therapy, especially in patients with a LC familial history. Without antiviral therapy, liver tissue damage for these patients will progressively worse with the high incidence of HCC. Therefore, it is suggested that antiviral therapy should be started as soon as possible for the HBeAg-negative CHB patients with low viral load regardless of the alanine aminotransferase level, especially in patients over 30 years-old with a LC or HCC family history.