1.Expert consensus on neoadjuvant PD-1 inhibitors for locally advanced oral squamous cell carcinoma (2026)
LI Jinsong ; LIAO Guiqing ; LI Longjiang ; ZHANG Chenping ; SHANG Chenping ; ZHANG Jie ; ZHONG Laiping ; LIU Bing ; CHEN Gang ; WEI Jianhua ; JI Tong ; LI Chunjie ; LIN Lisong ; REN Guoxin ; LI Yi ; SHANG Wei ; HAN Bing ; JIANG Canhua ; ZHANG Sheng ; SONG Ming ; LIU Xuekui ; WANG Anxun ; LIU Shuguang ; CHEN Zhanhong ; WANG Youyuan ; LIN Zhaoyu ; LI Haigang ; DUAN Xiaohui ; YE Ling ; ZHENG Jun ; WANG Jun ; LV Xiaozhi ; ZHU Lijun ; CAO Haotian
Journal of Prevention and Treatment for Stomatological Diseases 2026;34(2):105-118
Oral squamous cell carcinoma (OSCC) is a common head and neck malignancy. Approximately 50% to 60% of patients with OSCC are diagnosed at a locally advanced stage (clinical staging III-IVa). Even with comprehensive and sequential treatment primarily based on surgery, the 5-year overall survival rate remains below 50%, and patients often suffer from postoperative functional impairments such as difficulties with speaking and swallowing. Programmed death receptor-1 (PD-1) inhibitors are increasingly used in the neoadjuvant treatment of locally advanced OSCC and have shown encouraging efficacy. However, clinical practice still faces key challenges, including the definition of indications, optimization of combination regimens, and standards for efficacy evaluation. Based on the latest research advances worldwide and the clinical experience of the expert group, this expert consensus systematically evaluates the application of PD-1 inhibitors in the neoadjuvant treatment of locally advanced OSCC, covering combination strategies, treatment cycles and surgical timing, efficacy assessment, use of biomarkers, management of special populations and immune related adverse events, principles for immunotherapy rechallenge, and function preservation strategies. After multiple rounds of panel discussion and through anonymous voting using the Delphi method, the following consensus statements have been formulated: 1) Neoadjuvant therapy with PD-1 inhibitors can be used preoperatively in patients with locally advanced OSCC. The preferred regimen is a PD-1 inhibitor combined with platinum based chemotherapy, administered for 2-3 cycles. 2) During the efficacy evaluation of neoadjuvant therapy, radiographic assessment should follow the dual criteria of Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and immune RECIST (iRECIST). After surgery, systematic pathological evaluation of both the primary lesion and regional lymph nodes is required. For combination chemotherapy regimens, PD-L1 expression and combined positive score need not be used as mandatory inclusion or exclusion criteria. 3) For special populations such as the elderly (≥ 70 years), individuals with stable HIV viral load, and carriers of chronic HBV/HCV, PD-1 inhibitors may be used cautiously under the guidance of a multidisciplinary team (MDT), with close monitoring for adverse events. 4) For patients with a poor response to neoadjuvant therapy, continuation of the original treatment regimen is not recommended; the subsequent treatment plan should be adjusted promptly after MDT assessment. Organ transplant recipients and patients with active autoimmune diseases are not recommended to receive neoadjuvant PD-1 inhibitor therapy due to the high risk of immune related activation. Rechallenge is generally not advised for patients who have experienced high risk immune related adverse events such as immune mediated myocarditis, neurotoxicity, or pneumonitis. 5) For patients with a good pathological response, individualized de escalation surgery and function preservation strategies can be explored. This consensus aims to promote the standardized, safe, and precise application of neoadjuvant PD-1 inhibitor strategies in the management of locally advanced OSCC patients.
2.Evaluation system for standardized surgery in elderly patients with lung cancer
Xingqi MI ; Nan CHEN ; Jiandong MEI ; Hecheng LI ; Shuguang ZHANG ; Huanwen CHEN ; Peng JIAO ; Jun WANG ; Chunfang ZHANG ; Guangjian ZHANG ; Xin LI ; Qiang PU ; Peng LIN ; Lunxu LIU
Chinese Journal of Clinical Thoracic and Cardiovascular Surgery 2026;33(06):866-873
To address the growing challenge of an increasing number of elderly lung cancer patients amidst China's aging population and to fill the gap in quality control standards for surgical treatment in this special population, this study aimed to develop a standardized surgical evaluation system for elderly lung cancer patients tailored to China's national conditions. The system was established through a literature review, integrated the pathophysiological characteristics of elderly patients, and was constructed following review, feedback, and revision by experts from multiple thoracic surgery centers. Employing a 100-point scoring system, it comprises three primary domains: physical infrastructure and geriatric adaptability foundational conditions (10 points); management level and perioperative care models (20 points); and technical proficiency and clinical outcomes (70 points). The system places a strong emphasis on geriatric adaptability, proposing specific, quantifiable indicators for age-friendly facility modifications, control of elderly-specific complications, multidisciplinary collaboration, and standardized perioperative management. It provides a convenient and measurable assessment tool for quality control in the surgical treatment of elderly lung cancer in China, which is expected to promote the standardization and homogenization of diagnosis and treatment.
3.Evaluation of anticancer activity of marine microbial secondary metabolites based on intrahepatic cholangiocarcinoma organoid models and study on its induction of cancer cell apoptosis
Xiaoting FAN ; Zhifan MAO ; Jian LIU ; Fan YANG ; Houwen LIN
Journal of Pharmaceutical Practice and Service 2026;44(6):280-288
Objective To investigate the anti-intrahepatic cholangiocarcinoma (ICC) activity and mechanism of 2-heptyl-3-hydroxy-4(1H)-quinolone (PQS), a secondary metabolite of polar marine microorganisms. Methods Patient-derived organoid (PDO) models were established using intrahepatic cholangiocarcinoma (ICC) tumor tissues obtained from Renji Hospital, Shanghai Jiao Tong University School of Medicine. Hematoxylin and eosin (HE) staining was performed to assess the histomorphological characteristics of both patient ICC tissues and corresponding PDOs. Immunohistochemistry (IHC) was employed to evaluate CYP3a expression in patient ICC tissues and PDOs. The antiproliferative activity of PQS against stably passaged PDOs was determined using an adenosine triphosphate (ATP)-based bioluminescence assay, and dose-response curves were fitted to calculate the half-maximal inhibitory concentration (IC50) for assessing the anti-ICC efficacy of PQS. In the human intrahepatic cholangiocarcinoma RBE cell model, the effects of PQS on RBE cell proliferation were evaluated by the cell counting kit-8 (CCK-8) assay; colony formation capacity was assessed by the plate colony formation assay; cell cycle distribution and apoptosis were analyzed by flow cytometry; and the protein expression levels of cyclin-dependent kinase 2(CDK2), CDK4, RelA(p65), and nuclear factor-κB1(p50) were detected by Western blotting. Results Two ICC PDO models were successfully established. Histomorphological observation revealed that the PDO tissues after serial passaging exhibited morphological features essentially consistent with the corresponding patient ICC tissues, both presenting as cystic vesicle-like structures. Immunohistochemical analysis demonstrated that CYP3a was expressed in both PDO tissues and patient ICC tissues. ATP-based bioluminescence assay results indicated that PQS effectively suppressed ATP content in PDO tissues, with a fitted dose-response curve yielding an IC50 value of 2.49 µmol/L. In the RBE cell model, PQS inhibited RBE cell viability in a concentration-dependent manner, and the fitted dose-response curve yielded an IC50 value of 1.05 µmol/L. Furthermore, PQS at concentrations of 1, 2, and 4 µmol/L significantly suppressed colony formation of RBE cells, arrested the cell cycle at the S phase, induced apoptosis, and downregulated the expression of proteins associated with the NF-κB signaling pathway. Conclusion ICC PDO models were successfully established, confirming the anti-ICC activity of PQS. PQS inhibited RBE cell proliferation, potentially via the NF-κB signaling pathway, by arresting the cell cycle at the S phase and inducing apoptosis of RBE cells
4.Evaluation of anticancer activity of marine microbial secondary metabolites based on intrahepatic cholangiocarcinoma organoid models and study on its induction of cancer cell apoptosis
Xiaoting FAN ; Zhifan MAO ; Jian LIU ; Fan YANG ; Houwen LIN
Journal of Pharmaceutical Practice and Service 2026;44(6):280-288
Objective To investigate the anti-intrahepatic cholangiocarcinoma (ICC) activity and mechanism of 2-heptyl-3-hydroxy-4(1H)-quinolone (PQS), a secondary metabolite of polar marine microorganisms. Methods Patient-derived organoid (PDO) models were established using intrahepatic cholangiocarcinoma (ICC) tumor tissues obtained from Renji Hospital, Shanghai Jiao Tong University School of Medicine. Hematoxylin and eosin (HE) staining was performed to assess the histomorphological characteristics of both patient ICC tissues and corresponding PDOs. Immunohistochemistry (IHC) was employed to evaluate CYP3a expression in patient ICC tissues and PDOs. The antiproliferative activity of PQS against stably passaged PDOs was determined using an adenosine triphosphate (ATP)-based bioluminescence assay, and dose-response curves were fitted to calculate the half-maximal inhibitory concentration (IC50) for assessing the anti-ICC efficacy of PQS. In the human intrahepatic cholangiocarcinoma RBE cell model, the effects of PQS on RBE cell proliferation were evaluated by the cell counting kit-8 (CCK-8) assay; colony formation capacity was assessed by the plate colony formation assay; cell cycle distribution and apoptosis were analyzed by flow cytometry; and the protein expression levels of cyclin-dependent kinase 2(CDK2), CDK4, RelA(p65), and nuclear factor-κB1(p50) were detected by Western blotting. Results Two ICC PDO models were successfully established. Histomorphological observation revealed that the PDO tissues after serial passaging exhibited morphological features essentially consistent with the corresponding patient ICC tissues, both presenting as cystic vesicle-like structures. Immunohistochemical analysis demonstrated that CYP3a was expressed in both PDO tissues and patient ICC tissues. ATP-based bioluminescence assay results indicated that PQS effectively suppressed ATP content in PDO tissues, with a fitted dose-response curve yielding an IC50 value of 2.49 µmol/L. In the RBE cell model, PQS inhibited RBE cell viability in a concentration-dependent manner, and the fitted dose-response curve yielded an IC50 value of 1.05 µmol/L. Furthermore, PQS at concentrations of 1, 2, and 4 µmol/L significantly suppressed colony formation of RBE cells, arrested the cell cycle at the S phase, induced apoptosis, and downregulated the expression of proteins associated with the NF-κB signaling pathway. Conclusion ICC PDO models were successfully established, confirming the anti-ICC activity of PQS. PQS inhibited RBE cell proliferation, potentially via the NF-κB signaling pathway, by arresting the cell cycle at the S phase and inducing apoptosis of RBE cells
5.Analysis of tick monitoring and Bandavirus dabieense carrying status in Tai'an City from 2021 to 2023
Ya-nan WEI ; Tong XU ; Su MI ; Rong-qiang ZHANG ; Fu-rong LIU ; Hao-lin XIN ; Yi-yue FU ; De-zhen MA
Acta Parasitologica et Medica Entomologica Sinica 2026;33(3):198-203
Objective To understand the distribution, species composition, seasonal fluctuations, and presence of Dabie bandavirus in ticks in Tai'an City, providing a basis for assessing tick-borne disease risks and formulating prevention strategies. Methods Free-living ticks were monitored using the flagging method, whereas parasitic ticks were monitored through host surface examination. Reverse transcription-polymerase chain reaction (RT-qPCR) was used to detect the presence of Bandavirus dabieense in tick specimens. Results The density of free-living ticks in Tai'an City showed a continuous decreasing trend over the 3 years from 2021 to 2023, with an average tick density of 0.43 ticks/(flag·100 m). The dominant habitats were scenic areas and forests, and the seasonal fluctuations exhibited a bimodal pattern, peaking in March and August. The only free-living tick species captured was Haemaphysalis longicornis. Over the 3 years, the average tick index for parasitic ticks was 1.85, with sheep as the primary host. Seasonal fluctuations also followed a bimodal pattern, peaking in March and August. The primary parasitic tick species captured were H. longicornis and Rhipicephalus sanguineus. No Dabie bandavirus was detected in the tick specimens. Conclusions Tick density in Tai'an City remains relatively high, necessitating continued efforts to enhance tick surveillance and implement targeted prevention measures in rural environments to further reduce the health risks posed by tick-borne diseases.
6.Chinese expert consensus on the application of jejunal interposition for esophageal reconstruction in complex esophageal cancer surgery (2026 edition)
Wenshu CHEN ; Lilan ZHAO ; Zhaoxian LIN ; Debin OU ; Zhigang LI ; Chengchu ZHU ; Longqi CHEN ; Shuoyan LIU ; Xiangnan LI ; Chao CHENG ; Ni ZHANG ; Songping XIE ; Xufeng GUO ; Xu LI ; Xinyu MEI ; Xuefeng LENG ; Jianqun MA ; Zhijun HUANG ; Guojun GENG ; Lin ZHANG ; Hongyan WANG ; Yi ZHANG ; Weijie WANG ; Jiangbo LIN ; Jinbiao XIE ; Jun GUAN ; Rongqi HE ; Xing LIN ; Xiuhua TU ; Yong LI ; Lijie TAN ; Xiaojie PAN
Chinese Journal of Clinical Thoracic and Cardiovascular Surgery 2026;33(10):1527-1543
Objective Jejunal interposition is an important option for restoring gastrointestinal continuity in patients with complex esophageal cancer in whom the stomach is unavailable for reconstruction due to previous gastrectomy, tumor involvement, failed gastric conduit, or other constraints. Although the jejunum offers a caliber similar to the esophagus, a rich blood supply, and preserved peristaltic function, anatomical variations in mesenteric length and vascular arcades render long-segment and high-level reconstruction susceptible to excessive tension, mesenteric torsion, venous congestion, and inadequate distal perfusion. This consensus aims to provide standardized recommendations for the application of jejunal interposition in this specific patient population. Methods This consensus was developed in accordance with the WHO Handbook for Guideline Development and Chinese national guideline development standards, with reference to the Appraisal of Guidelines for Research & Evaluation Ⅱ(AGREE Ⅱ), Reporting Items for Practice Guidelines in Healthcare (RIGHT), and Scientific, Transparent and Applicable Rankings (STAR) checklists. The project was registered on the international practice guidelines registry platform (PREPARE-2026CN1384). The working group systematically searched Chinese and English evidence addressing 12 clinical questions. Evidence was graded using the Oxford Centre for Evidence-Based Medicine (OCEBM) 2009 system, with structured appraisal of risk of bias, inconsistency, indirectness, and imprecision. Recommendations were formulated through two rounds of Delphi surveys and a face-to-face consensus meeting, with an agreement threshold of ≥75%. Results The consensus generated 12 recommendations covering indications, selection between jejunum and colon, preoperative assessment, surgical approach and reconstruction route, pedicled jejunal interposition (PJI), supercharged pedicled jejunal interposition (SPJ), indocyanine green (ICG) perfusion assessment, perioperative nutrition, management of anastomotic leakage, long-term follow-up, and special treatment scenarios. Given that the available direct evidence is predominantly derived from single-center retrospective cohorts and case series, recommendations extrapolated from general esophagectomy or other gastrointestinal surgical evidence are deliberately phrased with caution. Conclusion Jejunal interposition is a safe and effective approach for digestive tract reconstruction in patients with complex esophageal cancer in whom the stomach is unavailable. This consensus emphasizes that clinical decision-making should be individualized based on the patient's prior treatment history, reconstruction height, vascular anatomy, technical availability, and institutional experience in the Chinese context.
7.Chinese expert consensus on the clinical application of recombinant human thyroid-stimulating hormone (2025 edition)
Chentian SHEN ; Yushen GU ; Hui TAN ; Anren KUANG ; Sijin LI ; Yaming LI ; Jing WANG ; Ningyi JIANG ; Jian TAN ; Zhuoying WANG ; Shaoyan LIU ; Xiaoyi LI ; Jugao FANG ; Dingcun LUO ; Youben FAN ; Hui WANG ; Yuetao WANG ; Xuemei WANG ; Feng WANG ; Wei FU ; Feng SHI ; Xuegong LIU ; Zhongwei LÜ ; Yan XING ; Lin LI ; Hui YANG ; Jun XIN ; Yifan ZHANG ; Yue CHEN ; Yansong LIN ; Wei OUYANG ; Shuzhan YAO ; Changjiu ZHAO ; Xinming ZHAO ; Zairong GAO ; Dingde HUANG ; Qiang WEN ; Xingmin HAN ; Cen LOU ; Weibing MIAO ; Wei FAN ; Quanyong LUO ; Hongcheng SHI
Chinese Journal of Clinical Medicine 2026;33(5):932-944
The recombinant human thyroid-stimulating hormone (rhTSH) can be used for differentiated thyroid cancer (DTC) preparation before 131I therapy, and follow-up. Since its approval by the American Food and Drug Administration (FDA) in 1998, rhTSH has been clinically used in European countries, the United States, and other countries for nearly 30 years. In April 2024, China’s first independently developed rhTSH agent was approved. Based on clinical experience and evidence from domestic and international studies, an expert consensus on the application of rhTSH has been developed following thorough consultations among experts. The consensus offers evidence-based recommendations to guide the appropriate use of rhTSH in clinical practice.
8.Regulation of skin pigmentation by miR-25-5p via targeting RAB11B: a mechanistic study
Wenzhu WANG ; Hedan YANG ; Yunyao LIU ; Xiaojie SUN ; Xiaoli ZHANG ; Xiuzhen LI ; Siqi TAN ; Haoxiang XU ; Yin YANG ; Tong LIN
Chinese Journal of Dermatology 2025;58(9):816-824
Objective:To investigate the role of microRNA-25-5p (miR-25-5p) in melanogenesis, and to explore its underlying mechanisms.Methods:Target genes of miR-25-5p were predicted using the TargetScan database. The interaction between miR-25-5p and the 3' untranslated region (3' UTR) of the RAB11B gene (a member of RAS oncogene family) was validated through a dual-luciferase reporter assay. Post-inflammatory hyperpigmentation (PIH) models were established in female C57BL/6J mice (6 - 8 weeks old) and female brown guinea pigs (4 - 6 weeks old) through daily broadband ultraviolet B (UVB) irradiation on the dorsal skin of the mouse ear or shaved dorsal skin of guinea pigs, while untreated mice and untreated dorsal skin areas of guinea pigs served as control groups. During modeling, these experimental animals received intradermal injections of a miR-25-5p agomir or a miR control agomir. Changes in skin pigmentation were observed, and skin tissue samples were harvested for further analysis after modeling. Melanin content in skin tissues was evaluated using Masson-Fontana staining. Expression of RAB11B and tyrosinase (TYR) in skin tissues was determined using immunohistochemical staining and quantitative real-time PCR (qPCR). Primary human melanocytes were isolated from discarded normal foreskin tissues of healthy males after circumcision. Both primary human melanocytes and human MNT1 melanoma cells were transfected with miR-25-5p mimics or miR control mimics. Relative expression levels of miR-25-5p and RAB11B mRNA were quantified by qPCR using the 2 -ΔΔCt calculation method. In MNT1 cells, miR-25-5p and RAB11B were co-overexpressed to assess their effect on the mRNA expression of RAB11B and TYR. Statistical analysis was conducted using t test or one-way analysis of variance followed by Tukey's post hoc test for multiple comparisons. Results:The bioinformatic prediction and dual-luciferase reporter assay confirmed a binding site for miR-25-5p in the 3′ UTR of the RAB11B gene. In both animal models, the treatment with the miR-25-5p agomir significantly reduced local skin pigmentation compared to the control groups; Masson-Fontana staining showed a marked decrease in the density of melanin granules in the epidermis and dermis in the miR-25-5p agomir groups compared with the miR control agomir groups (mice: 0.050 ± 0.005 vs. 0.087 ± 0.008; guinea pigs: 0.067 ± 0.015 vs. 0.110 ± 0.013; both P < 0.05). Immunohistochemical staining revealed significantly lower expression of RAB11B in mouse skin tissues in the miR-25-5p agomir group than in those in the miR control agomir group (both P < 0.05). qPCR revealed significantly lower mRNA expression of RAB11B and TYR in skin tissues of guinea pigs in the miR-25-5p agomir group than in those in the miR control agomir group (both P < 0.05). Similarly, RAB11B mRNA expression significantly decreased in the miR-25-5p mimics group compared with the miR control mimics group in primary human melanocytes and MNT1 cells (both P < 0.05). In human MNT1 melanoma cells, miR-25-5p overexpression could suppress TYR mRNA expression, whereas co-overexpression of miR-25-5p and RAB11B could reverse this suppression. Conclusion:Overexpression of miR-25-5p could alleviate UVB-induced post-inflammatory hyperpigmentation and inhibit melanogenesis, likely by targeted suppression of RAB11B expression.
9.Effects of Wenyang Jiedu Tongluo Recipe on a mouse model of diabetic nephropathy based on macrophage recruitment and polarization
Fan LI ; Jie WANG ; Cheng-ji CUI ; Hong-bao ZHANG ; Hong-kai LIU ; Xu HUANG ; Yu-tong LIU ; Shou-lin ZHANG
Chinese Traditional Patent Medicine 2025;47(5):1494-1501
AIM To investigate the effects of Wenyang Jiedu Tongluo Recipe(WYJDTLR)on macrophage recruitment and polarization function in a mouse model of diabetic kidney disease(DKD).METHODS 50 db/db mice were randomly divided into the model group,the valsartan group(10.29 mg/kg)and the high-dose,medium-dose and low-dose WYJDTLR groups(26.52,13.26 and 6.63 g/kg),with 10 mice in each group,in contrast to another 10 db/m mice of the blank group.After 8 weeks of administration,the mice had their levels of fasting blood glucose,24-hour urinary protein quantity(24h-UTP),serum creatinine(Scr)and blood urea nitrogen(BUN)observed;their morphological changes of renal tissues observed by HE staining;their degree of renal glycogen deposition observed by PAS staining;their degree of renal fibrosis observed by Masson staining;their levels of MCP-1 and MCF-1 in serum and TNF-α and IL-1 β in renal tissue detected by ELISA;their renal protein expressions of VCAM-1 and ICAM-1 detected by IHC and Western blot;and their renal expressions of CD86 and CD206 detected by IF.RESULTS Compared with the model group,the WYJDTLR groups displayed decreased levels of fasting blood glucose,24h-UTP,Scr and BUN(P<0.05,P<0.01);improved degree of glomerular hypertrophy,mild proliferation of mesangial cells,dilatation of renal tubular,vacuolar degeneration of renal tubular epithelial cells,deposition of glomerular glycogen,and fibrosis of renal tissues(P<0.01);decreased levels of MCP-1 and MCF-1 in serum and TNF-α and IL-1β in renal tissue(P<0.05,P<0.01);decreased renal protein expressions of VCAM-1 and ICAM-1(P<0.05,P<0.01),thus reduced the recruitment of macrophages to the kidney;decreased renal CD86 protein expression(P<0.01);and increased CD206 protein expression(P<0.01),thus inhibited M1-type polarization of macrophages and promoted M2-type polarization of macrophages.CONCLUSION WYJDTLR can delay the DKD progression in mice by reducing the occurrence of inflammatory reactions through reducing the level of macrophage recruitment factor,inhibiting the M1-type polarization,and promoting the M2-type polarization.
10.Simultaneous content determination of eleven constituents in Tongxuan Lifei Pills by UPLC and their chemometric investigation
Wan-jun JIN ; Wen-ting HAO ; Jing LIU ; Ming-tong ZHANG ; Lin NI
Chinese Traditional Patent Medicine 2025;47(9):2840-2848
AIM To establish a UPLC method for the simultaneous content determination of liquiritin,ammonium glycyrrhizate,naringin,neohesperidin,hesperidin,rosmarinic acid,baicalin,wogonoside,baicalein,wogonin and praeruptorin A in Tongxuan Lifei Pills,and to make chemometric investigation.METHODS The analysis was performed on a 30 ℃ thermostatic SVEA C18 column(2.1 mm×150 mm,2.5 μm),with the mobile phase comprising of acetonitrile-0.1%phosphoric acid flowing at 0.5 mL/min in a gradient elution manner,and the detection wavelength was set at 250 nm.Subsequently,cluster analysis,principal component analysis and partial least square discriminant analysis were performed.RESULTS Eleven constituents showed good linear relationships within their own ranges(R2>0.990 0),whose average recoveries were 90.00%-98.32%with the RSDs of 0.35%-1.89%.Forty batches of samples were clustered into 3 types.Baicalein,baicalin,liquiritin,wogonin,wogonoside and neohesperidin were taken as quality differential markers.CONCLUSION This simple and reproducible method can provide the basis for quality control and evaluation of Tongxuan Lifei Pills.


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