OBJECTIVE To evaluate the efficacy and safety of rituximab （RTX） in the treatment of primary Sjögren syndrome （pSS）. METHODS Randomized controlled trials （RCTs） on the effects of RTX （trial group） versus placebo （control group） in the treatment of pSS were searched from the Cochran Library， PubMed， Embase， Medline， Web of Science， VIP， CNKI， Wanfang， and other databases during the inception to February 2024. After literature screening and quality evaluation， meta-analysis was performed by using RevMan 5.3 software. RESULTS Seven RCTs were finally included， involving a total of 518 patients. Results of meta-analysis showed that European League Against Rheumatism Sjögren syndrome disease activity index （ESSDAI） score [MD＝－1.17， 95%CI（－1.52， －0.82）， P＜0.000 01] and oral dryness visual analogue scale （VAS） score [MD＝－3.97， 95%CI （－5.08， －2.86）， P＜0.000 01] in the trial group were significantly lower than the control group； unstimulated salivary flow rate [SMD＝0.64， 95%CI（0.41， 0.87）， P＜0.000 01] and Schirmer score [MD＝0.19， 95%CI（0.18， 0.20）， P＜0.000 01] were significantly higher than the control group. There was no statistical significance in response rate [RD＝0.10， 95%CI（－0.04， 0.23）， P＝0.16]， fatigue VAS score [MD＝－12.50， 95%CI（－35.14， 10.15）， P＝0.28]， European League Against Rheumatism Sjögren syndrome patient reported index （ESSPRI） score [MD＝0.33， 95%CI（－0.53， 1.18）， P＝0.46]， Short-form 36 health survey physical component summary （SF36-PCS） score [MD＝0.90， 95%CI（－2.97， 4.78）， P＝0.65]， SF-36 mental component summary （SF36-MCS） score [MD＝0.11， 95%CI（－0.41， 0.63）， P＝0.68]， total salivary gland ultrasound score [SMD＝－1.91， 95%CI（－4.01， 0.19）， P＝0.07] or the incidence of adverse drug reactions [OR＝1.15，95%CI（0.62，2.13），P＝0.66] between 2 groups. CONCLUSIONS RTX has advantages in the improvement of ESSDAI score， unstimulated salivary flow rate， Schirmer score and oral dryness VAS score in pSS patients， and has a good safety profile. However， it did not exhibit significant improvement in fatigue VAS score， ESSPRI score， SF36-PCS score， SF36-MCS score or response rates.

The Kirsten rat sarcoma viral oncogene homolog ( KRAS ) mutation is one of the most prevalent activating alterations in cancer. It indicates a poor overall prognosis due to its highly invasive nature. Although several KRAS inhibitors have been developed in recent years, a significant clinical challenge has emerged as a substantial proportion of patients eventually develop resistance to these therapies. Therefore, identifying determinants of drug resistance is critical for guiding treatment strategies. This review provides a comprehensive overview of the mutation landscape and molecular mechanisms of KRAS activity in various cancers. Meanwhile, it summaries the progress and prospects of small molecule KRAS inhibitors undergoing clinical trials. Furthemore, this review explores potential strategies to overcome drug resistance, with the ultimate goal of steering toward patient-centric precision oncology in the foreseeable future.
Humans ; Drug Resistance, Neoplasm/drug effects* ; Proto-Oncogene Proteins p21(ras)/metabolism* ; Mutation/genetics* ; Neoplasms/genetics* ; Antineoplastic Agents/therapeutic use*

The liver performs multiple life-sustaining functions. Hepatic diseases, including hepatitis, cirrhosis, and hepatoma, pose significant health and economic burdens globally. Along with the advances in nanotechnology, mesoporous silica nanoparticles (MSNs) exhibiting diversiform size and shape, distinct morphological properties, and favorable physico-chemical features have become an ideal choice for drug delivery systems and inspire alternative thinking for the management of hepatic diseases. Initially, we introduce the physiological structure of the liver and highlight its intrinsic cell types and correlative functions. Next, we detail the synthesis methods and physicochemical properties of MSNs and their capacity for controlled drug loading and release. Particularly, we discuss the interactions between liver and MSNs with respect to the passive targeting mechanisms of MSNs within the liver by adjusting their particle size, pore diameter, surface charge, hydrophobicity/hydrophilicity, and surface functionalization. Subsequently, we emphasize the role of MSNs in regulating liver pathophysiology, exploring their value in addressing liver pathological states, such as tumors and inflammation, combined with multi-functional designs and intelligent modes to enhance drug targeting and minimize side effects. Lastly, we put forward the problems, challenges, opportunities, as well as clinical translational issues faced by MSNs in the management of liver diseases.

Objective:To evaluate the efficacy and safety of febuxostat in the treatment of hyperuricemia with hypertension.Methods:Randomized controlled trials (RCT) on the treatment of hyperuricemia with hypertension using febuxostat were retrieved from Medline, Web of Science, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), Wanfang Database, and VIP Database from January 2013 to July 2023, according to the retrieval strategy. Two trained researchers completed the literature screening, quality evaluation, and data extraction. Meta-analysis was performed using RevMan 5.3. The fixed-effect model or random-effects model was used to analyze the research data, and subgroup analysis was conducted to identify the source of heterogeneity.Results:A total of 5 RCTs involving 456 patients (228 in the experimental group and 228 in the control group) were included in the meta-analysis, all of which were English-language literatures and foreign studies. In the treatment of hyperuricemia with hypertension, febuxostat showed a statistically significant difference in reducing serum uric acid (sUA) levels compared to control drugs [MD(95% CI)=-1.31(-2.55, -0.07), P=0.040]; there was no statistically significant difference in reducing systolic blood pressure (SBP) [SMD(95% CI)=-0.12(-0.51, 0.27), P=0.540] or diastolic blood pressure (DBP) [SMD(95% CI)=-0.15(-0.40, 0.09), P=0.220]. Subgroup analysis showed that the difference in intervention drugs in the control group may be the cause of heterogeneity in sUA levels, and the difference in intervention time may be the cause of heterogeneity in SBP levels among different studies. There was no statistically significant difference in the incidence of adverse reactions between the febuxostat group and the control group [RD (95% CI) =-0.01(-0.08, 0.06), P=0.770]. Conclusion:Febuxostat has a significant advantage in improving sUA levels and is relatively safe in the treatment of hyperuricemia with hypertension, but it does not show significant advantages in blood pressure control.

Objective To establish and validate a Nomogram model for predicting the overall survival(OS)of the patients with intrahepatic cholangiocarcinoma(ICC)based on domestic multicenter data,and screen the beneficiaries of adjuvant chemotherapy based on the prediction model.Methods From December 2011 to December 2017,the data of 278 patients with postoperative pathological diagnosis of ICC from 4 medical centers in our country were collected retrospectively COX regression model was used to screen the independent risk factors of OS and constructed a Nomogram model.This model was used to stratify the risk of OS for all patients and to screen the beneficiaries of adjuvant chemotherapy.Results A total of 278 patients were enrolled,and 23 cases(8.3%)received adjuvant chemotherapy.COX multivariate analysis showed that drinking history,ECOG score,method of hepatectomy,lymph node status,number of tumors,and tumor differentiation were independent risk factors for postoperative OS.The Nomogram model had a C-index of 0.690(95%CI:0.646-0.734)in the training cohort and 0.740(95%CI:0.863-0.617)in the validation cohort.According to risk stratification by Nomogram model,in the high-risk group there was a statistically significant difference in survival between adjuvant chemotherapy and non-adjuvant chemotherapy(P=0.033),whereas in the low-risk group,there was no significant difference in survival(P=0.59).Conclusions Nomogram model based on independent risk factors of OS demonstrated excellent predictive capability for survival and could be used to screen,and identify the patients with ICC who benefit from adjuvant chemotherapy.

Objective:To analyze the impact of lymph node dissection on textbook outcomes (TO) and the prognosis of intrahepatic cholangiocarcinoma (ICC).Methods:The retrospective cohort study was conducted. The clinicopathological data of 376 ICC patients who underwent hepatectomy in 4 medical centers, including Mengchao Hepatobiliary Hospital of Fujian Medical University et al, from December 2011 to December 2017 were collected. There were 242 males and 134 females, aged 57(range, 48-63)years. According to the criteria of TO, patients were classified as two cate-gories, including patients achieving TO and not achieving TO. Measurement data with normal distri-bution were represented as Mean± SD, and comparison between groups was conducted using the independent sample t test. Measurement data with skewed distribution were represented as M(range) or M( Q1, Q3), and comparison between groups was conducted using the Mann-Whitney U test. Count data were represented as absolute numbers, and comparison between groups was conducted using the chi-square test, Yates adjusted chi-square test or Fisher exact probability. Comparison of ordinal data was conducted using the non-parameter rank sum test. Univariate and multivariate analyses were conducted using the Logistic regression model. The Kaplan-Meier method was used to draw survival curve. Survival analysis was conducted using the Log-rank test. Results:(1) TO situations. Of the 376 ICC patients who underwent hepatectomy, 199 cases achieved TO, including 40 cases with lymph node dissection and 159 cases without lymph node dissection, 177 cases did not achieve TO, including 76 cases with lymph node dissection and 101 cases without lymph node dissection. (2) Influencing factors for TO after hepatectomy of ICC patients. Results of multivariate analysis showed that lymph node dissection, microvascular invasion, nerve invasion and the volume of intraoperative blood loss >800 mL were independent risk factors for achieving TO after hepatec-tomy of ICC patients ( odds ratio=2.22, 2.95, 3.58, 4.09,95% confidence interval as 1.34-3.69, 1.43-6.07, 1.40-9.17, 1.35-12.43, P<0.05). Of the 116 patients with lymph node dissection, 40 cases achieved TO, 103 cases achieved R 0 resection, 38 cases had postoperative complications, 67 cases had delayed hospital stay. The above indicators were 159, 255, 41, 65 of 260 patients without lymph node dissection. There were significant differences in the above indicators between patients with and without lymph node dissection ( χ2=22.90, 15.16, 13.95, 37.78, P<0.05). (3) Follow-up. All the 376 patients were followed up for 19(range, 1-74)months. Of 199 patients achieving TO, the 1-, 2-and 3-year survival rates of 40 patients with lymph node dissection were 54.0%, 36.6% and 26.1%, respectively, versus 67.7%, 42.7% and 34.4% of 159 patients without lymph node dissection, showing no significant difference between them ( χ2=1.89, P>0.05). Of 177 patients not achieving TO, the 1-, 2-and 3-year survival rates of 76 cases with lymph node dissection were 58.9%, 25.7% and 10.3%, respectively, versus 53.0%, 28.5% and 17.2% of 101 cases without lymph node dissection, showing no significant difference between them ( χ2=0.25, P>0.05). Conclusions:Lymph node dissec-tion, microvascular invasion, nerve invasion and the volume of intraoperative blood loss >800 mL are independent risk factors for achieving TO after hepatectomy of ICC patients. Lymph node dissec-tion may increase the postoperative complication rate, prolong the hospital stay and decrease the rate of achieving TO. However, it does not affect the prognosis of patients.

In February 2023, the National Health Commission, together with the Ministry of Science and Technology, the Ministry of Education, and the State Administration of Traditional Chinese Medicine issued the Ethical Review Measures for Life Science and Medical Research Involving Humans, which emphasizes that research participants involving vulnerable groups such as children, intellectual disabilities, and mental disabilities should be given special protection. This paper expounded the current situation of protecting vulnerable groups from six aspects: inadequate protection of vulnerable groups by relevant laws and regulations, unclear definition of vulnerable groups, insufficient supervision by relevant departments, insufficient review ability of ethics committee to satisfy the protection of vulnerable groups, difficulty in fair inclusion of vulnerable groups, and the need to improve the ethical awareness of researchers and vulnerable groups. This paper also analyzed the new requirements for the protection of vulnerable groups in the Ethical Review Measures for Life Science and Medical Research Involving Humans from the following three aspects: expanding attention to potentially vulnerable research participants, paying more attention to the consent of research participants without or with limited capacity for civil conduct, and re-informed consent after the improvement of civil capacity level. Finally, suggestions on strengthening the protection of vulnerable groups were put forward from six aspects: improving the relevant legal system, clarifying the category of vulnerable groups, strengthening the implementation by regulatory departments, establishing a research participant protection system by research institutions, improving the ethical review capacity of ethics committees, formulating review guidelines by industry associations, and strengthening the education and training of all parties, so as to minimize the risk of vulnerable groups participating in clinical research and boost the quality and speed of clinical research in China.

Background Air pollution is a major public health concern. Air Quality Health Index (AQHI) is a very important air quality risk communication tool. However, AQHI is usually constructed by single-pollutant model, which has obvious disadvantages. Objective To construct an AQHI based on the joint effects of multiple air pollutants (J-AQHI), and to provide a scientific tool for health risk warning and risk communication of air pollution. Methods Data on non-accidental deaths in Yunnan, Guangdong, Hunan, Zhejiang, and Jilin provinces from January 1, 2013 to December 31, 2018 were obtained from the corresponding provincial disease surveillance points systems (DSPS), including date of death, age, gender, and cause of death. Daily meteorological (temperature and relative humidity) and air pollution data (SO₂, NO₂, CO, PM_2.5, PM₁₀, and maximum 8 h O₃ concentrations) at the same period were respectively derived from China Meteorological Data Sharing Service System and National Urban Air Quality Real-time Publishing Platform. Lasso regression was first applied to select air pollutants, then a time-stratified case-crossover design was applied. Each case was matched to 3 or 4 control days which were selected on the same days of the week in the same calendar month. Then a distributed lag nonlinear model (DLNM) was used to estimate the exposure-response relationship between selected air pollutants and mortality, which was used to construct the AQHI. Finally, AQHI was classified into four levels according to the air pollutant guidance limit values from World Health Organization Global Air Quality Guidelines (AQG 2021), and the excess risks (ERs) were calculated to compare the AQHI based on single-pollutant model and the J-AQHI based on multi-pollutant model. Results PM_2.5, NO₂, SO₂, and O₃ were selected by Lasso regression to establish DLNM model. The ERs for an interquartile range (IQR) increase and 95% confidence intervals (CI) for PM_2.5, NO₂, SO₂ and O₃ were 0.71% (0.34%–1.09%), 2.46% (1.78%–3.15%), 1.25% (0.9%–1.6%), and 0.27% (−0.11%–0.65%) respectively. The distribution of J-AQHI was right-skewed, and it was divided into four levels, with ranges of 0-1 for low risk, 2-3 for moderate risk, 4-5 for high health risk, and ≥6 for severe risk, and the corresponding proportions were 11.25%, 64.61%, 19.33%, and 4.81%, respectively. The ER (95%CI) of mortality risk increased by 3.61% (2.93–4.29) for each IQR increase of the multi-pollutant based J-AQHI , while it was 3.39% (2.68–4.11) for the single-pollutant based AQHI . Conclusion The J-AQHI generated by multi-pollutant model demonstrates the actual exposure health risk of air pollution in the population and provides new ideas for further improvement of AQHI calculation methods.

Background It is projected that the frequency, density, and duration of compound hot extreme may increase in the 21st century in the context of global warming. Objective To explore the association between compound hot extreme and blood pressure, and identify sensitive populations. Methods This was a cross-sectional study. The study subjects were from six Guangdong Province Chronic Disease and Nutrition Surveys during 2002 through 2015. A questionnaire was administered to the participants with questions about demographic information, drinking and smoking status, and measurements on their height, weight, and blood pressure were also collected. We chose the data of May, September, and October to explore the association between compound hot extreme and blood pressure. Compound hot extreme means a hot day with a proceeding hot night. Daily meteorological data were obtained from China Meteorological Data Service Centre. We employed inverse distance weighting to interpolate the temperature and relative humidity values for each participant. A distributed lag non-linear model was used to estimate the association between compound hot extreme and blood pressure. Stratified analyses by sex, age, area, body mass index (BMI), smoking status, and drinking status were also performed to identify sensitive populations. A sensitivity analysis was conducted by adjusting the degrees of freedom for lag spline and removing relative humidity. Result A total of 10967 participants without history of hypertension were included in this study. The average systolic blood pressure (SBP) was 120.8 mmHg and the average diastolic blood pressure (DBP) was 74.5 mmHg. The proportion of participants who experienced hot day, hot night, or compound hot extreme were 9.34%, 17.95% and 2.90%, respectively. Compared to hot day, hot night and compound hot extreme were related with decreased blood pressure, and the effect of compound hot extreme was stronger: the changes and 95%CI for SBP was −6.2 (−10.3-−2.1) mmHg, and for DBP was −2.7 (−5.2-−0.2) mmHg. Compound hot extreme induced decreased SBP among male, population ≥ 65 years, and those whose BMI < 24 kg·m^-2, and their ORs (95%CIs) were −6.2 (−10.7-−1.6). −19.1 (−33.0-−5.1), and −6.7 (−11.8~−1.6) mmHg, respectively, and also decreased DBP among population ≥ 65 years, and its OR (95%CI) was −8.4 (−15.6-−1.1) mmHg. During compound hot extremes, participants living in rural areas showed decreased SBP and DBP, and the ORs (95%CIs) were −10.5 (−16.6-−4.5) and −4.4 (−7.7-−1.1) mmHg respectively, while those living in urban areas showed increased SBP, and the OR (95%CI) was 9.7 (2.9-16.5) mmHg. A significant decrease in blood pressure [OR (95%CI)] was also found in non-smokers [DBP, −3.7 (−6.6-−0.8) mmHg] and non-drinkers [SBP, −4.8 (−9.4-−0.2) mmHg; DBP, −3.4 (−6.0-−0.9) mmHg]. Conclusion Compound hot extreme is negatively associated with SBP, and being male, aged 65 years and over, and having BMI < 24 kg·m⁻² may be more sensitive to compound hot extreme.

Objective:To investigate the effect of six degree of freedom (6-DOF) bed combined with cone beam computed tomography (CBCT) in the on-line correction of setup errors in patients with primary rectal cancer.Methods:The clinicopathological data of 17 patients with primary rectal cancer in Department of Radiotherapy, Third Hospital of Peking University from July 2013 to January 2014 were collected. There were 14 males and 3 females, a median age of 65 years. The difference of CBCT and 6-DOF bed combined with CBCT online correction of patients with positioning error were retrospectively analyzed.Results:Before position correction, the first CBCT verification of setup errors in the three translation directions including X (left and right), Y (in and out) and Z (up and down) directions were (0.06±0.25) cm, (0.13±0.40) cm and (-0.28±0.31) cm, respectively. The setup errors of RX (rotation pitch), RY(rolling) and RZ (left and right rotation) directions were (0.62±1.15)°, (-0.19±0.99)°, and (-0.34 ± 0.84)°, respectively . After correction of IGRT combined with six freedom of bed, the setup errors of translation X, Y and Z were (0.01±0.09) cm, (-0.01±0.05) cm and (-0.03±0.08) cm, respectively, and the setup errors of rotation RX, RY and RZ directions were (-0.16±0.40)°, (0.36±0.31)°and (-0.01±0.25)°, respectively. There were significant differences in translation direction (X, Y and Z direction) and rotation direction (Rx, RY and RZ) before and after 6-DOF bed combined with CBCT correction (all P<0.05). In the translation direction, the higher frequency range of Z-direction error value was 0.20-0.79 cm. In the rotation direction, the frequency range of error in Rx direction was 0.20°-2.99°. There was no significant difference between bone mode and gray scale model registration ( P>0.05). With the progress of radiotherapy, the setup errors of X, Z, Rx, RY and RZ directions increased except Y direction. Conclusions:In radiotherapy, six freedom bed combined with CBCT is helpful to correct the setup errors of patients with primary rectal cancer. Six freedom bed may be used to correct the setup errors of patients with primary rectal cancer online. Image-guided radiation therapy (IGRT) is recommended for bone pattern registration in patients with rectal cancer.