Triple-negative breast cancer (TNBC) is a highly aggressive malignancy predominantly managed via chemotherapy. Our clinical sample analysis revealed a significant correlation between elevated CD24 expression in TNBC tumor cells and patient survival rates. We developed a novel antibody-drug conjugate (ADC), named HN03, consisting of an antibody with engineered cysteines for site-specific conjugation with a low toxic nitric oxide (NO) precursor as its payload through a novel Pt(IV)-mediated bioorthogonal self-cleavable linker. HN03 specifically targets tumor cells expressing high levels of CD24, concurrently generating cisplatin and releasing NO upon activation. HN03 also exhibited potent in vitro and in vivo antitumor activity. It significantly reduced tumor growth at various doses, prevented tumor metastasis, with markedly lower toxicity than traditional chemotherapy agents. We found that a key mechanism of its action involved inducing apoptosis and endoplasmic reticulum stress, substantially decreasing the number of M2-type macrophages. Overall, HN03 stands out as a promising therapeutic option for TNBC, offering a targeted treatment with reduced side effects and the potential for improved outcomes. Furthermore, using Pt(IV) in the linker and an NO precursor as the payload enhances the versatility of the Antibody-NO donor Conjugate (ANC), offering new avenues for the design of the next generation of ADCs.

Objective:To evaluate the efficacy and safety of intensity modulated radiotherapy (IMRT) and programmed death-1 (PD-1) immunotherapy combined with single-agent chemotherapy for patients with local failure of esophageal cancer after initial radical chemoradiotherapy.Methods:Clinical data of 80 patients with local failure of esophageal cancer after initial radical chemoradiotherapy treated with IMRT or PD-1 immunotherapy combined with single-agent chemotherapy in People's Hospital of Xinghua between June 2014 and June 2023 were retrospectively analyzed. IMRT was delivered at 1.8-2.0 Gy per fraction, 5 fractions per week, with a total dose of 45.0-60.0 Gy in 40 patients (IMRT group). The other 40 patients received PD-1 immunotherapy combined with single-agent chemotherapy (PD-1 immunotherapy combined with single-agent chemotherapy group). Kaplan-Meier method was used for univariate analysis and the cumulative survival probability. Log-rank test was used for survival significance test. Cox proportional hazards model was used for multivariate analysis of related factors affecting overall survival (OS), progression-free survival (PFS) and local control (LC).Results:By December 2023, the follow-up rate was 100%. The 1- and 2-year OS rates in the IMRT group were 66.1% and 18.9%, with a median OS time of 10.1 months. In the PD-1 immunotherapy combined with single-agent chemotherapy group, the 1- and 2-year OS rates were 72.3% and 36.9%, with a median OS time of 12.4 months. There was a significant difference in OS rates between two groups ( χ2=3.89, P=0.049). The 1- and 2-year PFS rates in the IMRT group were 47.4% and 31.6%, with a median PFS time of 8.5 months. In the PD-1 immunotherapy combined with single-agent chemotherapy group, the 1- and 2-year PFS rates were 70.0% and 64.2%, with a median PFS time of 11.9 months. There was no significant difference in the PFS rates between two groups ( χ2=2.66, P=0.103). The 1- and 2-year LC rates in the IMRT group were 68.6% and 62.3%, with a median LC time of 8.9 months. In the PD-1 immunotherapy combined with single-agent chemotherapy group, the 1- and 2-year LC rates were 72.8% and 66.7%, with a median LC time of 12.0 months. There was no significant difference in LC rates between two groups ( χ2=0.18, P=0.672). Grade 2 radiation esophagitis and radiation pneumonitis developed in 82.5% (33/40) and 32.5% (13/40) in the IMRT group, respectively. The incidence of grade 1-2 peripheral blood leukopenia was 40.0% (16/40), 50.0% (20/40) for grade 1-2 peripheral blood thrombocytopenia, 27.5% (11/40) for moderate to severe anemia, and 20.0% (8/40) for grade 1-2 thyroid dysfunction in the PD-1 immunotherapy combined with single-agent chemotherapy, respectively. Single- and multi-factor analysis showed that the failure site ( χ2=9.01, P=0.011) and short-term efficacy ( χ2=7.78, P=0.005) were the independent prognostic factors affecting OS. The short-term efficacy was the independent prognostic factor for PFS ( χ2=31.63, P<0.001). The short-term efficacy was the independent prognostic factors affecting LCS ( χ2=17.64, P=0.001) too. Conclusion:For the patients with local failure of esophageal cancer after initial radical chemoradiotherapy, the combination of PD-1 immunotherapy with single-agent chemotherapy yields better survival prognosis than re-irradiation alone, but it is still necessary to pay attention to the related drug toxicities.

Objective:In order to scientifically promote the selection of appropriate technology of traditional non-pharmacologi-cal,the value evaluation index system of traditional non-pharmacological technology was constructed in line with the characteristics of TCM based on the theory of health technology assessment and multi-criteria decision analysis.Methods:The evaluation index pool was initially formed through literature research,and then those indicators were further improved through semi-structured inter-views and Delphi method.Results:The value evaluation index was constructed with seven dimensions,including quality standard,safety,effectiveness,economy,inheritance and innovation,suitability and accessibility,which were subordinated by 17 second-level indicators and 33 third-level indicators.The questionnaire response rate was 100%.The group authority coefficient of 17 experts was 0.87,and the concentration and coordination degree of expert opinions of the first-level indicators were high.Conclusion:The index pool constructed in this study has high expert authority,good concentration and coordination of expert opinions,which needs to be verified by practical experience,which is of great significance for the value evaluation of traditional non-pharmacological technology.

Isolated pontine infarction (IPI) is the main type of acute brainstem infarction. Due to the application of high-resolution MRI, the research on the etiology of IPI has gradually increased in recent years. This article reviews the latest research progress on the characteristics of basilar artery plaques and disease progression mechanisms of IPI, aiming to provide reference for the etiology research of IPI.

Objective:To investigate the clinical, genetic, and pathological features of nemaline myopathy type 8 (NEM8) caused by KLHL40 gene variation. Methods:The clinical data, gene sequencing results, and musculoskeletal pathophysiology of two cases (a pair of twins) with NEM8 admitted to our hospital in July 2022 were collected. CNKI, VIP, Wanfang, Yiigle, PubMed, Embase, and Web of Science Database were searched with the English and Chinese terms "nemaline myopathy type 8", "nemaline body myopathy type 8", and " KLHL40" from January 2007 to February 2023. The clinical, genetic, and musculoskeletal characteristics of the NEM8 cases were summarized using the descriptive statistical analysis method. Results:(1) Case report: The mother (G2P2) of the twins (Ⅳ-2 and Ⅳ-3) was conceived by IVF-embryo transfer and delivered at 37 +1 gestational weeks. The two cases were dizygotic twins whose maternal grandmother had lip and palate cleft. The first baby (Ⅳ-1) of the woman exhibited absent left pinna, contracture at the end of both fingers, talipes equinovarus in both feet and died of respiratory failure two hours after birth. Fetal edema and fetal movement delay in the twins and varus right foot in one twin were found during pregnancy. Both cases developed intrapartum asphyxia with the clinical manifestations of generalized muscle weakness, respiratory failure, dysphagia, multiple joint contractures, and fractures. The families withdrew the treatment and the twins died after maintaining life with ventilators for 53 days after birth. Whole exome sequencing of the pedigree found c.1779G>T (p.W593C) homozygous variants of the KLHL40 gene in the twins and c.1779G>T (p.W593C) heterozygous variants of the KLHL40 gene in the parents, both were de novo. Musculoskeletal pathophysiology indicated that muscle fibers are thin and round with a fetal shape and absent rod. (2) Literature review: Among the 29 cases of NEM8, including two current cases and 27 cases retrieved from 15 papers, eight cases terminated the pregnancies, and 21 were live births; seven cases (24.1%) with positive family history; 19 cases (65.5%) were found with abnormalities during pregnancy, including abnormal fetal movements, polyhydramnios, joint contracture, and fetal edema. Of the 21 live births, 20 cases had intrapartum asphyxia, 21 had postnatal respiratory failure, 20 had generalized muscle weakness, and 19 had dysphagia. Among the 29 cases, 17 cases (58.6%) were homozygous variants of the KLHL40 gene, and 12 cases (41.4%) were compound heterozygous variants. The detection rate of c.1516A>C(p.Thr506Pro) was the highest [72.4% (21/29)], followed by c.602G>A(p.Trp201*) [17.2% (5/29)]. Out of the 15 cases who underwent musculoskeletal pathological examination, all had abnormal muscle fiber size and morphology; 10 cases had rods. Conclusions:NEM8 should be considered for those with abnormal fetal movements, polyhydramnios, joint malformation, fetal edema during the fetal period and failure to establish respiration at birth as well as postnatal generalized muscle weakness, respiratory failure, dysphagia, multiple joint contractures, and fracture. Moreover, genetic detection should be performed as soon as possible. NEM8 can be diagnosed in ones with KLHL40 gene homozygous or compound heterozygous variants and musculoskeletal pathological results of abnormal size and shape of muscle fibers, regardless of the presence of rods.

OBJECTIVE: To observe the effects of catgut embedding and polyglycolic acid/poly-lactic acid (PGLA) embedding at "Zusanli" (ST 36) on the activation of local skin mast cells (MC), and expression of substance P (SP) and histamine (HA), and to explore the mechanism of the temporal stimulation effect of acupoint catgut embedding and provide a foundation for further research on the initiation mechanism of acupoint catgut embedding. METHODS: One hundred and sixty male SPF-grade SD rats were randomly divided into a blank group (10 rats), a sham-embedding group (50 rats), a catgut group (50 rats), and a PGLA group (50 rats). Each intervention group was further randomly divided into five subgroups according to the time points after intervention: 8 hours, 3 days, 7 days, 14 days, and 21 days, with 10 rats in each subgroup. One-time sham-embedding, catgut embedding and PGLA embedding was given at left "Zusanli" (ST 36) in each intervention group, respectively. The skin and subcutaneous connective tissue of the left "Zusanli" (ST 36) were collected at the corresponding time points after intervention, except for the blank group (only one day before intervention). Toluidine blue staining was used to detect MC count and degranulation, and immunohistochemical staining was used to detect the expression of SP and HA positive cells. RESULTS: There was no significant difference in MC count between the subgroups of each intervention group and the blank group (P>0.05). There was no significant difference in MC count between the subgroups of the catgut group and the PGLA group (P>0.05). The MC count in the 8-hour subgroup of PGLA group was higher than that in the 8-hour subgroup of catgut group (P<0.05), while the MC count in the 21-day subgroup of PGLA group was lower than that in the 21-day subgroup of catgut group (P<0.05). Compared with the blank group, the degranulation rates of MC were increased in the 8-hour and 3-day subgroups of sham-embedding group, 8-hour, 3-day, and 7-day subgroups of catgut group, and 8-hour, 3-day, 7-day, and 14-day subgroups of PGLA group (P<0.01, P<0.05, P<0.001). There was no significant difference in the degranulation rate of MC between the subgroups of the catgut group and the PGLA group (P>0.05), and no significant difference in the degranulation rate of MC between the two embedding groups at the same time point (P>0.05). Compared with the blank group, the expression of SP positive cells was increased in the 8-hour subgroup of sham-embedding group, 8-hour, 3-day, 7-day, and 14-day subgroups of catgut group, and 3-day, 7-day, and 14-day subgroups of PGLA group (P<0.001, P<0.05). The expression of SP positive cells in the 7-day subgroup of catgut group was higher than that in the 8-hour subgroup of catgut group (P<0.05), while the expression of SP positive cells in the 14-day subgroup of catgut group was lower than that in the 7-day subgroup of catgut group (P<0.001). The expression of SP positive cells in the 7-day subgroup of PGLA group was higher than that in the 3-day subgroup of PGLA group (P<0.05), while the expression of SP positive cells in the 14-day subgroup of PGLA group was lower than that in the 7-day subgroup of PGLA group (P<0.01). There was no significant difference in the expression of SP positive cells between the subgroups of the two embedding groups at the same time point (P>0.05). Compared with the blank group, the expression of HA positive cells was increased in the 8-hour, 3-day subgroups of sham-embedding group, 8-hour, 3-day, 7-day, and 14-day subgroups of catgut group, and 8-hour, 3-day, 7-day, 14-day, and 21-day subgroups of PGLA group (P<0.001, P<0.01, P<0.05). The expression of HA positive cells in the 14-day subgroup of catgut group was lower than that in the 7-day subgroup of catgut group (P<0.05), while the expression of HA positive cells in the 3-day subgroup of PGLA group was higher than that in the 8-hour subgroup of PGLA group (P<0.05), and the expression of HA positive cells in the 14-day subgroup of PGLA group was lower than that in the 7-day subgroup of PGLA group (P<0.05). The expression of HA positive cells in the 3-day subgroup of PGLA group was higher than that in the 3-day subgroup of catgut group (P<0.05). CONCLUSION Catgut and PGLA embedding at "Zusanli" (ST 36) in healthy rats could induce changes in local skin MC, SP, and HA, which may be one of the mechanisms of the temporal stimulation effect after acupoint embedding. There are certain differences between different suture materials. A moderate inflammatory response in the acupoint area, mediated by MC and involving SP and HA, may be one of the initiating factors for the effect of acupoint catgut embedding.
Rats ; Male ; Animals ; Rats, Sprague-Dawley ; Mast Cells ; Histamine ; Substance P/genetics* ; Catgut ; Acupuncture Points

Objective: To evaluate the protective effect of jailed balloon technique on side branch (SB) ostium using three-dimensional optical coherence tomography(OCT). Methods: This is a retrospective study. Consecutive coronary disease patients with coronary artery bifurcation lesions who underwent percutaneous coronary intervention (PCI) and completed pre-and post-procedural OCT examinations at the Chinese People's Liberation Army General Hospital from September 2019 to March 2022 were enrolled. Patients were divided into the jailed balloon technique group and the unprotected group according to the options applied for the SB. The SB ostium area difference was calculated from OCT images (SB ostium area difference=post-PCI SB ostium area-pre-PCI SB ostium area). The SB ostium area differences were compared between the two groups and compared further in the subgroup of true bifurcation lesions and non-true bifurcation lesions. In the jailed balloon group, the SB ostium area difference was compared between the active jailed balloon technique and the conventional jailed balloon technique, between the jailed balloon>2.0 mm diameter and the jailed balloon≤2.0 mm diameter, and between the higher balloon pressure (>4 atm, 1 atm=101.325 kPa) and the lower balloon pressure (≤4 atm). Multivariate linear regression analysis was used to explore the correlation between the technical parameters of the jailed balloon technique and the SB protection effect. Results: A total of 176 patients with 236 bifurcation lesions were enrolled, aged (60.7±9.3) years, and there were 128 male patients (72.7%). There were 67 patients in the jailed balloon technique group with 71 bifurcation lesions and 123 patients in the unprotected group with 165 bifurcation lesions. Fourteen patients had 2 to 3 lesions, which were treated in different ways, so they appeared in the unprotected group and the jailed balloon technique group at the same time. The area difference in SB ostium was greater in the jailed balloon group than in the unprotected group (0.07 (-0.43, 1.05)mm² vs.-0.33 (-0.83, 0.26)mm², P<0.001), and the results were consistent in the true bifurcation lesion subgroup (0.29 (-0.35, 0.96)mm² vs.-0.26 (-0.64, 0.29)mm², P=0.004), while the difference between the two groups in the non-true bifurcation lesion subgroup was not statistically significant (P=0.136). In the jailed balloon technique group, the SB ostium area difference was greater in patients treated with the active jailed balloon technique than in those treated with the conventional jailed balloon technique ((0.43±1.36)mm² vs. (-0.22±0.52)mm², P=0.013). The difference in SB ostium area was greater in those using>2.0 mm diameter jailed balloons than in those using≤2.0 mm diameter jailed balloons (0.25 (-0.51, 1.31) mm² vs.-0.01 (-0.45, 0.63) mm², P=0.020), while SB ostium area difference was similar between those endowed with higher balloon pressure (>4 atm) compared to those with lower balloon pressure (≤4 atm) (P=0.731). Multivariate linear regression analysis showed that there was a positive correlation between jailed balloon diameter and SB ostium area difference (r=0.344, P=0.019). Conclusions: The jailed balloon technique significantly protects SB ostium, especially in patients with true bifurcation lesions. The active jailed balloon technique and larger diameter balloons may provide more protection to the SB.
Humans ; Male ; Angioplasty, Balloon, Coronary/methods* ; Percutaneous Coronary Intervention ; Tomography, Optical Coherence/methods* ; Retrospective Studies ; Treatment Outcome ; Stents ; Coronary Artery Disease/therapy* ; Coronary Vessels/pathology* ; Coronary Angiography

Aim To study the effect of gender differences in C57BL / 6J mice on antigen induced Sjogren's syndrome(SS)model. Methods The submandibular gland protein of C57BL/6J female and male mice was extracted and mixed with the same amount of Freund's complete adjuvant(FCA)for the first three times, the antigen concentration was adjusted to 2.5 g·L-1, mixed with Freund's incomplete adjuvant(FIA)for the fourth time, and the same-sex mouse antigen was injected into the back of mice for a total of four times to induce the mouse SS model. The mouse SS model was induced by multi-point intradermal injection of antigen on the back of mice for four times,the body weight of female and male mice was measured every week, the general condition was observed, the saliva volume of mice was measured at the sixth week of modeling. After the mice were sacrificed, the pathological changes of submandibular gland and the changes of T and B lymphocyte subsets in spleen were detected, and the differences in SS model preparation between female and male mice were compared. Results The SS model of male and female mice was successfully established, and there was no significant difference in general condition, saliva volume, submandibular gland pathology, plasma cells and memory B cells between male and female SS mice. The success rate of SS model was 75% in female mice and 60% in male mice. Compared with normal mice of the same sex, the weight loss of female SS mice was earlier and more obvious than that of male SS mice; the submandibular gland index of male mice was significantly higher than that of female mice. Compared with normal mice of the same sex, the proportion of Th17 and Treg cells in spleen of female SS mice was more statistically significant than that of male SS mice. Conclusions The success rate of SS modeling in female mice is higher than that in male mice. Compared with male SS mice, female SS mice have more significant SS like manifestations and pathological manifestations, which can provide a reference basis for the selection of gender when establishing SS model.

Objective: To explore the differences in the biological effects of different expansion systems on natural killer (NK) cells, as well as the safety and preliminary clinical efficacy in the treatment of patients with recurrence after allogeneic hematopoietic stem cell transplantation (allo-HSCT) . Methods: Peripheral blood cells from healthy donors were stimulated with either CD3 combined with CD52 or K562 feeder cells loaded with IL-21/4-1BB to induce NK cell expansion. Changes in the NK cell phenotype, cytokine secretion, and cytotoxicity before and after expansion were detected. We also evaluated the safety and clinical efficacy of two different expansion strategies for patients received NK infusion. Results: Compared with the CD3/CD52 monoclonal antibody amplification system, the feeder cell expansion group had a higher purity of NK cells and higher expression ratios of NK cell surface activation receptors such as DNAM-1 and NKp30, while inhibitory receptor CTLA-4 expression was low and NKG2D/CD25/CD69/ Trail/PD-1/TIM-3/TIGIT had no statistically significant differences between the groups. Further functional results showed that the expression level of KI67 in NK cells after expansion in the two groups increased significantly, especially in the feeder cell expansion group. Simultaneously, the perforin and granzyme B levels of NK cells in the feeder cell expansion group were significantly higher than in the CD3/CD52 expansion group. A retrospective analysis of eight patients who received monoclonal antibody-expanded NK cell reinfusion and nine patients with trophoblast cell-expanded NK cell reinfusion was done. The disease characteristics of the two groups were comparable, NK cell reinfusion was safe, and there were no obvious adverse reactions. Clinical prognostic results showed that in the CD3/CD52 monoclonal antibody amplification group, the MRD conversion rate was 50% (2/4) , and the feeder cell expansion group was 50% (3/6) . After 5 years of follow-up from allo-HSCT, three patients in the monoclonal antibody expansion group had long-term survival without leukemia, and the remaining five patients had died; two patients died in the feeder cell expansion group, and the other six patients had long-term survival. Six cases had GVHD before NK cell reinfusion, and GVHD did not aggravate or even relieved after NK cell reinfusion. Conclusions: Preliminary results show that the biological characteristics of NK cells with diverse expansion strategies are significantly different, which may affect the clinical prognosis of patients with recurrence or persistent minimal residual disease after HSCT. The two groups of patients treated with NK cells from different expansion strategies had no obvious adverse reactions after NK cell infusion, but efficacy still needs to be further confirmed.
Antibodies, Monoclonal/pharmacology* ; Graft vs Host Disease/metabolism* ; Hematopoietic Stem Cell Transplantation ; Humans ; Killer Cells, Natural ; Retrospective Studies ; Treatment Outcome