Peptide-drug conjugates (PDCs) have emerged as a promising modality in precision oncology, enabling targeted delivery of cytotoxic payloads while minimizing off-target toxicity. The integration of covalent warheads, such as those based on sulfur(VI) fluoride exchange (SuFEx) chemistry, enhances drug-target residence time and tumor accumulation. However, existing screening methods for covalent peptide (CP) libraries require post-translational warhead conjugation, limiting throughput. Here, we present an integrated mRNA display platform that incorporates covalent warheads during ribosomal synthesis, enabling efficient screening of ultra-diverse covalent macrocyclic peptide libraries (>10¹³ variants). This approach, using site-specific incorporation of N-chloroacetyl-d-phenylalanine and fluorosulfate-l-tyrosine, accelerated the discovery of irreversibly binding (K _i = 3.58 μmol/L) Nectin-4-targeting peptide CP-N1-N₃ via proximity-triggered SuFEx. The peptide was further conjugated to cytotoxic payloads, yielding the covalent PDC CP-N1-MMAE with potent cytotoxicity (IC₅₀ ≈ 43 nmol/L) against MDA-MB-468 cells. This platform establishes a new paradigm for precision covalent drug discovery.

OBJECTIVE: Varied acupoint selections represent a potential cause of the uncertainty surrounding the efficacy of acupuncture for knee osteoarthritis (OA). Skin temperature, a guiding factor for acupoint selection, may help to address this issue. This study explored thermal sensitization of acupoints used for the treatment of knee OA. METHODS: This cross-sectional case-control study enrolled cases aged 45-75 years with symptomatic knee OA and age- and gender-matched non-knee OA controls in a 1:1 ratio. All participants underwent infrared thermographic imaging. The primary outcome was the relative skin temperature of acupoint (STA), and the secondary outcome was the absolute STA of 11 acupoints. The Z test was used to compare the relative and absolute STAs between the groups. Principal component analysis was used to extract the common factors (CFs, acupoint cluster) in the STAs. A general linear model was used to identify factors affecting the STA in the knee OA cases. For the group comparisons of relative STA, P < 0.0045 (adjusted for 11 acupoints through Bonferroni correction) was considered to indicate statistical significance. For other analyses, P < 0.05 was used as the threshold for statistical significance. RESULTS: The analysis included 308 participants, consisting of 151 cases (mean age: [64.58 ± 6.67] years; male: 25.83%; mean body mass index: [25.70 ± 3.16] kg/m²) and 157 controls (mean age: [63.37 ± 5.96] years; male: 26.11%; mean body mass index: [24.47 ± 2.84] kg/m²). The relative STAs of ST34 (P = 0.0001), EX-LE2 (P < 0.0001), EX-LE5 (P = 0.0006), SP10 (P < 0.0001), BL40 (P = 0.0012) and GB39 (P = 0.0037) were higher in the knee OA group. No difference was found in the STAs of ST35, ST36, SP9, GB33 and GB34. Four CFs were identified for relative STA in both groups. The acupoints within each CF were consistent between the groups. The mean values of the relative STAs across each CF were higher in the knee OA group. In the knee OA cases, no factors were observed to affect the relative STA, while age and gender were found to affect the absolute STA. CONCLUSION Among patients with knee OA, thermal sensitization occurs in the acupoints of the lower extremity, exhibiting localized and regional thermal consistencies. The thermally sensitized acupoints that we identified in this study, ST34, SP10, EX-LE2, EX-LE5, GB39 and BL40, may be good choices for the acupuncture treatment of knee OA. Please cite this article as: Tu JF, Wang XZ, Yan SY, Wang YR, Yang JW, Shi GX, Zhang WZ, Jing LN, Yang LS, Liu DH, Wang LQ, Mi BH. Thermal sensitization of acupoints in patients with knee osteoarthritis: A cross-sectional case-control study. J Integr Med. 2025; 23(3): 289-296.
Humans ; Osteoarthritis, Knee/physiopathology* ; Male ; Cross-Sectional Studies ; Middle Aged ; Female ; Acupuncture Points ; Case-Control Studies ; Aged ; Skin Temperature ; Acupuncture Therapy

Objective To evaluates the impact of early application of neuromuscular electrical stimulation(NMES)on muscle strength,clinical outcomes,and long-term quality of life improvements in patients with severe acute pancreatitis(SAP)complicated with acute respiratory distress syndrome(ARDS).Methods A total of 75 patients diagnosed with SAP and ARDS admitted in Department of Critical Care Medicine of our hospital from September 2022 to August 2023 were recruited and then randomly divided into NMES group(n=37)and control group(n=38).After 16 patients were excluded,including 8 died during treatment,3 discharged and 5 received palliative care,there were finally 29 patients in the NMES group and 30 in the control group.Within 48 h after ICU admission,the NMES group received NMES 1 h per day,for 7 d in addition to standard rehabilitation intervention.While,the control group were given conventional interventions for rehabilitation.Assessments at baseline and post-treatment included the incidence of ICU-acquired weakness(ICU-AW),Medical Research Council(MRC)score,duration of mechanical ventilation,lengths of ICU and total hospital stays,and activity,thickness and thickening fraction of the diaphragm.Mortality rates and Barthel index(BI)for self-care ability in 1,3 and 6 months after discharge were recorded for follow-up assessments.Results The NMES group had significantly lower incidence of ICU-AW(P＜0.05),higher upper and lower limb MRC scores and overall MRC score at ICU discharge(P＜0.05),shorter durations of mechanical ventilation,ICU stay,and total hospital stay when compared with the control group(P＜0.05).There was no statistical difference in the BI at 1 month post-discharge between the 2 groups,but the indexes at 3 and 6 months were notably higher in the NMES group than the control group(P＜0.05).No obvious differences were observed between the 2 groups in terms of diaphragm activity,thickness,or thickening scores at enrollment,ICU discharge,or hospital discharge,nor in mortality rates at 1,3,and 6 months after discharge.Conclusion Combined NMES and early rehabilitation therapy can improve muscle strength and reduce length of hospital stay in SAP patients complicated with ARDS,and may enhance long-term quality of life.However,it does not significantly affect diaphragm function or mortality rates.

Objective To investigate the regulatory effect of Mahuang Dingchuan Decoction on airway inflammation,airway remodeling and imbalance of helper T cell 1(Th1)/helper T cell 2(Th2)in children with allergic asthma.Methods A total of 126 children with allergic asthma of phlegm-heat obstructing the lung type at acute attack stage were randomly divided into observation group and control group,with 63 cases in each group.The control group was treated with conventional western medicine,and the observation group was treated with Mahuang Dingchuan Decoction on the basis of treatment for the control group.The total course of treatment for the two groups covered 14 days.Before and after treatment,the two groups were observed in the changes of lung function indicators of forced expiratory volume in one second(FEV1)and peak expiratory flow(PEF),airway inflammation indicators of neutrophil count,lymphocyte count,eosinophil count,monocyte percentage and levels of interleukin-6(IL-6)and tumor necrosis factor-α(TNF-α)in the sputum,airway remodeling indicators of airway wall area(WA),airway lumen area(LA)and airway total area(TA),and levels of Th1/Th2 cytokines of gamma-interferon(IFN-γ)and interleukin 4(IL-4).After treatment,the clinical efficacy and safety of the two groups were evaluated.Results(1)After 14 days of treatment,the total effective rate of the observation group was 93.65％(59/63),and that of the control group was 80.95％(51/63).The intergroup comparison(tested by chi-square test)showed that the efficacy of the observation group was significantly superior to that of the control group(P＜0.05).(2)After treatment,the values of pulmonary function indicators of FEV1 and PEF in the two groups were significantly higher than those before treatment(P＜0.01),and the increase in the observation group was significantly superior to that in the control group(P＜0.05).(3)The analysis of airway inflammation indicators showed that the percentages of neutrophils,eosinophils and monocytes and the levels of IL-6 and TNF-α in the sputum of the two groups after treatment were significantly lower than those before treatment(P＜0.05),and the percentage of lymphocytes was significantly higher than that before treatment(P＜0.05).The decrease of the percentages of neutrophils,eosinophils and monocytes and the levels of IL-6 and TNF-α in the sputum as well as the increase of the percentage of lymphocytes in the observation group was significantly superior to that in the control group(P＜0.05).(4)After treatment,the value of airway remodeling indicator of WA in the two groups was lower(P＜0.05)and the values of LA and TA were higher than those before treatment(P＜0.05).The decrease of WA value and the increase of LA and TA values in the observation group were significantly superior to those in the control group(P＜0.05).(5)The observation of Th1/Th2 cytokines showed that the serum IFN-γ level and IFN-γ/IL-4 ratio in the two groups after treatment were significantly higher than those before treatment(P＜0.05),and the serum IL-4 level was significantly lower than that before treatment(P＜0.05).The increase of serum IFN-γ level and IFN-γ/IL-4 ratio and the decrease of serum IL-4 level in the observation group were significantly superior to those in the control group(P＜0.05).(6)No serious adverse reactions were found in the two groups during the treatment,or no obvious abnormalities were found in the safety indicators such as electrocardiogram,blood routine test,liver function examination,heart rate and blood pressure.Conclusion Mahuang Dingchuan Decoction is beneficial to alleviating airway inflammation and airway remodeling in children with allergic asthma,regulating Th1/Th2 imbalance,and improving lung function in children,with definite effective and high safe.

G protein-coupled receptor (GPR) 40, as one of GPRs family, plays a potential role in regulating glucose and lipid metabolism. To study the effect of GPR40 novel agonist SZZ15-11 on hyperglycemia and hyperlipidemia and its potential mechanism, spontaneous type 2 diabetic KKA^y mice, human hepatocellular carcinoma HepG2 cells and murine mature adipocyte 3T3-L1 cells were used. KKA^y mice were divided into four groups, vehicle group, TAK group, SZZ (50 mg·kg^-1) group and SZZ (100 mg·kg^-1) group, with oral gavage of 0.5% sodium carboxymethylcellulose (CMC), 50 mg·kg^-1 TAK875, 50 and 100 mg·kg^-1 SZZ15-11 respectively for 45 days. Fasting blood glucose, blood triglyceride (TG) and total cholesterol (TC), non-fasting blood glucose were tested. Oral glucose tolerance test and insulin tolerance test were executed. Blood insulin and glucagon were measured via enzyme-linked immunosorbent assay (ELISA). After mice′s execution, liver tissue was harvested to test TG and TC content. Then pathological morphology of liver was observed through hematoxylin-eosin (HE) staining, and the lipid metabolism relative signal pathway was analyzed by Western blot and RT-PCR. The experiments were approved by the Institutional Animal Care and Use Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College. At the same time, Akt phosphorylation level in HepG2 cells and adiponectin in 3T3-L1 cells treated with TNFα were measured with Western blot. The results show that SZZ15-11 not only decreased blood glucose and lipid, improved insulin sensitivity, but also increased fasting blood glucagon and promoted insulin secretion after glucose loading in KKA^y mice. Additionally, SZZ15-11 alleviated hepatic steatosis and liver dysfunction in KKA^y mice. In liver tissue, SZZ15-11 increased AMPKα phosphorylation level and cholesterol metabolism relative gene Abcg8 transcription. In HepG2 cells, SZZ15-11 increased Akt phosphorylation level. In adipocyte 3T3-L1, SZZ15-11 recovered the decreased adiponectin expression by TNFα. This study proved that GPR40 agonist SZZ15-11 could be a candidate compound for regulating glucolipid metabolic disorder.

Objective:To investigate the clinical efficacy and safety of ixazomib-containing regimens in the treatment of patients with multiple myeloma(MM).Methods:A retrospective analysis was performed on the clinical efficacy and adverse reactions of 32 MM patients treated with a combined regimen containing ixazomib in the Hematology Department of the First People's Hospital of Lianyungang from January 2020 to February 2022.Among the 32 patients,15 patients were relapsed and refractory multiple myeloma(R/RMM)(R/RMM group),17 patients who responded to bortezomib induction therapy but converted to ixazomib-containing regimen due to adverse events(AE)or other reasons(conversion treatment group).The treatment included IPD regimen(ixazomib+pomalidomide+dexamethasone),IRD regimen(ixazomib+lenalidomide+dexamethasone),ICD regimen(ixazomib+cyclophosphamide+dexamethasone),ID regimen(ixazomib+dexamethasone).Results:Of 15 R/RMM patients,overall response rate(ORR)was 53.3％(8/15),among them,1 achieved complete response(CR),2 achieved very good partial response(VGPR)and 5 achieved partial response(PR).The ORR of the IPD,IRD,ICD and ID regimen group were 100％(3/3),42.9％(3/7),33.3％(1/3),50％(1/2),respectively,there was no statistically significant difference in ORR between four groups(x2=3.375,P=0.452).The ORR of patients was 50％after first-line therapy,42.9％after second line therapy,60％after third line therapy or more,with no statistically significant difference among them(x2=2.164,P=0.730).In conversion treatment group,ORR was 88.2％(15/17),among them,6 patients achieved CR,5 patients achieved VGPR and 4 patients achieved PR.There was no statistically significant difference in ORR between the IPD(100％,3/3),IRD(100％,6/6),ICD(100％,3/3)and ID(60％,3/5)regimen groups(x2=3.737,P=0.184).The median progression-free survival(PFS)time of R/RMM patients was 9 months(95％CI:6.6-11.4 months),the median overall survival(OS)time was 18 months(95％CI:11.8-24.4 months).The median PFS time of conversion treatment group was 15 months(95％CI:7.3-22.7 months),the median OS time not reached.A total of 10 patients suffered grade 3-4 adverse event(AE).The common hematological toxicities were leukocytopenia,anemia,thrombocytopenia.The common non-hematological toxicities were gastrointestinal symptoms(diarrhea,nausea and vomit),peripheral neuropathy,fatigue and infections.Grade 1-2 peripheral neurotoxicity occurred in 7 patients.Conclusion:The ixazomib-based chemotherapy regimens are safe and effective in R/RMM therapy,particularly for conversion patients who are effective for bortezomib therapy.The AE was manageable and safe.

Objective To explore the correlation between systemic family dynamics characteristics and adolescent depressive symptoms,and the mediating role of negative life events between them.Methods A cross-sectional study was conducted on 124 adolescent patients diagnosed with depressive disorder according to the international classification of diseases(ICD)-10 criteria at the Psychosomatic Medicine Department of Shanghai East Hospital Affiliated to Tongji University from September 2021 to February 2023.The second edition of the Scale of Systematic Family Dynamics(SSFD),Children's Depression Inventory(CDI),and Adolescent Self-Rating Life Events Checklist(ASLEC)were utilized to evaluate the family dynamics characteristics,depressive symptoms,and negative life events.Canonical correlation analysis was performed to explore the relationships between 4 dimensions of SSFD[family atmosphere(FA),individuation(IN),system logic(SL),illness concept(IC)]and 5 factors of CDI(low self-esteem,negative emotion,anhedonia,inefficiency,interpersonal problem).A mediation effect analysis using Bootstrap test was conducted to analyze the mediating role of negative life events between family dynamics and adolescent depressive symptoms.Results The scores for FA,SL,and IN in SSFD were negatively correlated with the total score of CDI(r=-0.359,-0.256,-0.291,P<0.01),and negatively correlated with the total score of ASLEC too(r=-0.318,-0.371,-0.406,P<0.01).However,a positive correlation was observed between the total scores of ASLEC and CDI(r=0.633,P<0.01).Canonical correlation analysis between the 4 dimensions of SSFD and the 5 factors of CDI revealed one pair of statistically significant canonical variables(U1,V1)with a canonical correlation coefficient of 0.483(P<0.05).This indicates that the canonical variable U1 of SSFD was primarily influenced by FA,while the canonical variable V1 of CDI was mainly affected by low self-esteem and interpersonal problems.The mediating analysis showed that the effects of FA,IN,and SL scores on CDI total score were all weak(-0.147,-0.117,-0.102,respectively)but statistically significant(P<0.05).The direct effect of IN and SL scores on CDI total score was not statistically significant(P>0.05),while the direct effect of FA score on CDI total score was statistically significant(-0.076,P<0.05).Additionally,the mediating effect of ASLEC between the scores of FA,IN,SL and CDI total score were all significant(-0.071,-0.095,-0.087,respectively)(P<0.05).Conclusions Adolescent depressive symptoms may be influenced by systemic family dynamics characteristics and negative life events.Negative life events mediate the influence of FA,IN,and SL on depressive symptoms.However,the IC is not related to depressive symptoms in adolescents.

ObjectiveTo investigate the analgesic action and mechanism of intrathecal 2R， 6R-hydroxynorketamine （2R， 6R-HNK） on spared nerve injury （SNI）-induced chronic neuropathic pain （CNP） in female mice. MethodsSNI was used to establish acute and chronic CNP models in female mice. The mice were randomly divided into different groups with administration of vehicle， 2R， 6R-HNK or S-ketamine （10 mg/kg intraperitoneal injection/i.p. or 7， 21 μmol/L intrathecal injection/i.t.） at 3 weeks after or 30 min/1 d before operation （n = 3 - 7 mice/group）. The curative or preventive effect of 2R， 6R-HNK was evaluated by mechanical paw withdrawal threshold （PWT） and the analgesic efficiency. Finally， immunofluorescence and RT-PCR of dorsal root ganglion （DRG） and spinal dorsal horn （SDH） were used to explore the possible mechanisms. ResultsCompared with vehicle， intrathecal injection of 2R， 6R-HNK largely reversed SNI-induced bilateral mechanical allodynia in a delayed-and-dose-dependent way. Among them， 21 μmol/L 2R， 6R-HNK reached its maximum analgesic efficiency （75.32±7.69） % at 2 d. Pre-intrathecal delivery of 2R， 6R-HNK also delayed the development of bilateral mechanical hypersensitivity 2 - 3 d induced by SNI. Mechanically， 2R， 6R-HNK reversed not only the abnormal excitability of neurons in bilateral DRG and superficial SDH， but also the upregulation of calcitonin gene-related peptide （CGRP） and brain-derived nerve growth factor （BDNF） in DRG. ConclusionIntrathecal administration of 2R， 6R-HNK exerts an analgesic effect against CNP， probably via suppressing abnormal neuronal excitability in ascending pain pathway as well as down-regulating CGRP and BDNF expression in DRG neurons.

In reference with the systematic review of the thought of deqi (arrival of qi) put forward in Huangdi Neijing (Internal Classic of Yellow Emperor) and other classic books of traditional Chinese medicine, in view of detecting qi and identifying qi before treatment, as well as the prerequisites of deqi in tuina, meaning the accurate syndrome differentiation and manipulations, the importance of deqi in treatment with tuina is expounded. In association with clinical experience, the specific manifestations of deqi in patients during tuina are summarized, e.g. soreness, distention, pain, numbness, warm feeling and slight sweating, local changes in intestinal sound and skin color, as well as mind regulation. It is anticipated that deqi of tuina may be drawn the attention in clinical practice, and the relevant study be expanded.
Books ; Emotions ; Humans ; Medicine, Chinese Traditional ; Pain ; Qi

Objective: To evaluate the safety and efficacy of transcatheter aortic valve implantation (TAVI) with the novel Prizvalve^® system in treating severe aortic stenosis. Methods: This is a single-center, prospective, single-arm, observational study. A total of 11 patients with severe aortic stenosis with high risk or inappropriate for conventional surgical aortic valve replacement (SAVR) were included, and TAVI was achieved with the Prizvalve^® system between March 2021 and May 2021 in West China Hospital. Transthoracic echocardiography (TTE) was performed immediately after prosthesis implantation to evaluate mean transaortic gradient and maximal transaortic velocity. The device success rate was calculated, which was defined as (1) the device being delivered via the access, deployed, implanted and withdrawn, (2) mean transaortic gradient<20 mmHg (1 mmHg=0.133 kPa) or a maximal transaortic velocity<3 m/s post TAVI, and without severe aortic regurgitation or paravalvular leak post TAVI. TTE was performed at 30 days after the surgery, and all-cause mortality as well as the major cardiovascular adverse events (including acute myocardial infarction, disabling hemorrhagic or ischemic stroke) up to 30 days post TAVI were analyzed. Results: The age of 11 included patients were (78.1±6.3) years, with 8 males. A total of 10 patients were with NYHA functional class Ⅲ or Ⅳ. Devices were delivered via the access, deployed, implanted and withdrawn successfully in all patients. Post-implant mean transaortic gradient was (7.55±4.08) mmHg and maximal transaortic velocity was (1.78±0.44) m/s, and both decreased significantly as compared to baseline levels (both P<0.05). No severe aortic regurgitation or paravalvular leak was observed post TAVI. Device success was achieved in all the 11 patients. No patient died or experienced major cardiovascular adverse events up to 30 days post TAVI. Mean transaortic gradient was (9.45±5.07) mmHg and maximal transaortic velocity was (2.05±0.42) m/s at 30 days post TAVI, which were similar as the values measured immediately post TAVI (both P>0.05). Conclusions: TAVI with the Prizvalve^® system is a feasible and relatively safe procedure for patients with severe aortic stenosis and at high risk or inappropriate for SAVR. Further clinical studies could be launched to obtain more clinical experience with Prizvalve^® system.
Aged ; Aged, 80 and over ; Aortic Valve ; Aortic Valve Stenosis/surgery* ; Heart Valve Prosthesis ; Heart Valve Prosthesis Implantation ; Humans ; Male ; Prospective Studies ; Transcatheter Aortic Valve Replacement/methods* ; Treatment Outcome