Objective:To discuss the clinical manifestations and laboratory examination results of agranulocytosis and reactive plasmacytosis(RP)in the patient with Graves'disease(GD)after treated with methimazole(MMI),and to provide the basis for the clinicians to differentiate RP from multiple myeloma(MM).Methods:The clinical manifestations,laboratory examinations,diagnosis and treatment processes of one patient with GD agranulocytosis complicated with RP were analyzed,and the related literatures were reviewed.Results:The patient had a history of GD and abdominal infection.Upon admission,a complete blood count revealed a significant decrease in white blood cell count accompanied by neutropenia,and a smear re-examination showed suspicious plasma cells.The bone marrow cytology examination results showed the percentage of bone marrow plasma cells was 33％,and the percentage of plasma cells in peripheral blood was 4％;the serum immunoglobulin results showed polyclonal hyperplasia;the serum immunofixation electrophoresis results were negative;the flow cytometry analysis results indicated the immunophenotype of the plasma cells was normal.Based on the medical history and laboratory results,MM was largely excluded,supporting the diagnosis of RP.Neutropenia was considered to be related to medication,so MMI was discontinued,granulocyte colony-stimulating factor was administered to increase the number of white blood cells,and specialized GD treatment was conducted after controlling the abdominal infection.The patient had a good prognosis,and his blood count was normal upon re-examination 6 months later.Conclusion:Agranulocytosis complicated with RP in the GD patients is clinically rare.Serum immunofixation electrophoresis,blood cell morphology,and cell immunophenotype analysis are helpful for the accurate diagnosis.After actively treating the primary disease causing RP,the patient's prognosis is favorable.

Objective To investigate the early diagnostic value of serum double cortin-like kinase 1(DCLK1),latent transforming growth factor binding protein 2(LTBP2)combined with transvaginal real-time shear wave elastography(SWE)for cervical cancer.Methods A total of 155 patients with cervical lesions treated in our hospital from August 2021 to December 2022 were selected as the research objects.Seventy-five patients with cervical cancer(the cervical cancer group)and 80 patients with cervical intraepithelial neoplasia(the CIN group)were diagnosed by surgical pathology,another 80 volunteers without cervical related diseases who participated in physical examinations at our hospital during the same period were selected as the control group.All subjects of each groups underwent serum DCLK1 and LTBP2 levels detection and transvaginal SWE examination.Receiver operating characteristic(ROC)curve was used to analyze the diagnostic value of serum DCLK1 and LTBP2 for cervical cancer;the diagnostic value of serum DCLK1 and LTBP2 combined with transvaginal SWE for cervical cancer was analyzed by fourfold table analysis.Results The serum levels of DCLK1 and LTBP2 of patients in the cervical cancer group were obviously higher than those in the CIN group and the control group(P<0.05).Compared with before surgery,the serum levels of DCLK1 and LTBP2 1,3,and 6 months after surgery in cervical cancer patients gradually decreased,and there were statistical differences in pairwise comparisons at each time point(P<0.05).The area under the curve of serum DCLK1 and LTBP2 for diagnosing cervical cancer were 0.868 and 0.754,respectively,with sensitivity of 86.67% and 78.67%,specificity of 81.25% and 60.00%,and optimal cutoff values of 1.49 ng/mL and 19.02 μg/mL.The maximum and average elastic modulus of lesion tissue in the cervical cancer group were obviously higher than those in the CIN group(P<0.05).The positive rates of serum DCLK1,serum LTBP2,and transvaginal SWE in the diagnosis of cervical cance were 86.67%,78.67%,and 82.67%,respectively,which were consistent with the gold standard(Kappa=0.624,0.501,0.673,P<0.001),and the positive rate of the combination of them in the diagnosis of cervical cancer was 97.33%,which was highly consistent with the gold standard(Kappa=0.846,P<0.001).The sensitivity and accuracy of the three combined diagnosis were obviously higher than those of the single indicator diagnosis of serum DCLK1,LTBP2,and transvaginal SWE,the specificity of the three combined diagnosis was obviously higher than that of the single indicator diagnosis of serum DCLK1 and LTBP2,the misdiagnosis rate of the three combined diagnosis was obviously lower than that of the single indicator diagnosis of serum DCLK1 and LTBP2,and the differences were all statistically significant(P<0.05).Conclusion Serum DCLK1 and LTBP2 combined with transvaginal SWE has high application value in the diagnosis of cervical cancer,which can further improve the sensitivity and accuracy of diagnosis,and reduce the misdiagnosis rate.

Objective To explore the mechanism of inhibiting a disintegrin and metalloprotease 8(ADAM8)expression on inflammatory damage in alcoholic liver fibrosis mice.Methods C57BL/6N male mice were randomly divided into the control group,the alcohol group,and the plasmid group,with 10 mice in each group.The alcohol group and plasmid group were fed alcohol liquid feed on a daily basis and gavaged with 31.5％ethanol(5 g/kg,twice a week);The control group was fed control liquid feed and gavaged with an equal amount of saline.The plasmid group was injected with the effective plasmid ADAM8-small guide RNA3(sgRNA3)(2 g/kg,twice a week)to inhibit the ADAM8 gene through the tail vein,while the alcohol group was injected with an equal amount of saline through the tail vein for 8 weeks to induce alcoholic liver fibrosis.After eyeball blood collection,the mice were euthanized,and their liver was separated and extracted.Sirius red and HE staining were employed to assess liver fibrosis and damage;Western blotting was used to determine the expression of α-smooth muscle actin(α-SMA),collagen Ⅰ,and ADAM8;Real-time PCR was used to measure the expression of ADAM8 mRNA;the expression of ADAM8,transforming growth factor-β1(TGF-β1),p-p38 MAPK and heat shock protein 27(HSP27)proteins was detected by Western blotting,Biochemical detection were used to detect alanine aminotransferase(ALT)and aspartate transaminase(AST)activity;tumor necrosis factor-α(TNF-α)and interleukin-1(IL-1)levels were determined by ELISA.Results The alcohol group had increased collagen fiber volume fraction,liver injury scores,and positive area rates of α-SMA and collagen Ⅰ;the expression of ADAM8 mRNA and ADAM8 protein increased,with increased positive area rate;and levels of AST,ALT,TNF-α,and IL-1 were higher,along with increased expression of TGF-β1,p-p38MAPK,and HSP27 proteins.In the plasmid group,the collagen fiber volume fraction,liver injury scores,and positive area rates of α-SMA and collagen Ⅰ was reduced;the expression of ADAM8 mRNA and protein was reduced,with decreased positive area rate,and levels of AST,ALT,TNF-α,and IL-1 were lower,along with reduced expression of TGF-β1,p-p38MAPK,and HSP27 proteins.Conclusion Downregulation of ADAM8 expression can alleviate inflammatory damage by inhibiting TGF-β1/p38MAPK signaling pathway to improve alcoholic liver fibrosis in mice.

Objective To construct a mouse model of alcoholic liver fibrosis and explore the effect of supplementing exogenous thyroid hormone T3 on oxidative stress in liver.Methods Eighty mice were randomly divided into 6 groups,normal control group,alcoholic liver fibrosis(ALF)model group,and low concentration T3 intervention group(25 μg/kg),medium concentration T3 intervention group(50 μg/kg),high concentration T3 intervention group(100 μg/kg)and T3 control group(the concentration of T3 is 100 μg/kg).A model of mice alcoholic liver fibrosis was established by using alcoholic liquid feed combined with 31.5％ethanol gavage.From the sixth week,mice in the T3 intervention and T3 control group were injected with corresponding concentrations of T3 intraperitoneally for three weeks.Mice in the control and T3 control groups were fed with control liquid feed.The degree of mice liver injury and fibrosis was evaluated through the sirius red staining,Western blotting,and serum biochemical testing.The activity of superoxide dismutase(SOD),the content of glutathione(GSH)and malondialdehyde(MDA)in liver tissue were detected by ELISA,and the protein expressions of microtubule-associated protein light chain 3-Ⅱ(LC3-Ⅱ)and p62 were detected by immunohistochemistry and Western blotting.Results The liver structure and function in the ALF group were severely damaged,autophagy was inhibited,and the oxidative stress response was significantly enhanced compared with the control group.Compared with the ALF group,the recovery of liver functional and structure and autophagy were showed in the T3 intervention group,and SOD activity and GSH content in the liver increased in the low and medium concentrations of T3 intervention groups,while MDA content significantly decreased.In the high concentration T3 intervention group,it showed the same increase in SOD activity,a significant decrease in MDA content,while the content of GSH was lower than that in the control group,which was not different with the ALF group.Conclusion Appropriate supplementation of T3 could affect the occurrence and development of alcoholic liver fibrosis by restoring the liver autophagy to inhibit the oxidative stress response.

Animals ; Rats ; Explosions ; Proteomics ; Autophagy

Humans ; Renal Artery ; Constriction, Pathologic ; Hypertension, Renovascular/therapy* ; Vascular Diseases ; Renal Artery Obstruction/therapy* ; Embolization, Therapeutic

Objective: Total neoadjuvant therapy has been used to improve tumor responses and prevent distant metastases in patients with locally advanced rectal cancer (LARC). Patients with complete clinical responses (cCR) then have the option of choosing a watch and wait (W&W) strategy and organ preservation. It has recently been shown that hypofractionated radiotherapy has better synergistic effects with PD-1/PD-L1 inhibitors than does conventionally fractionated radiotherapy, increasing the sensitivity of microsatellite stable (MSS) colorectal cancer to immunotherapy. Thus, in this trial we aimed to determine whether total neoadjuvant therapy comprising short-course radiotherapy (SCRT) combined with a PD-1 inhibitor improves the degree of tumor regression in patients with LARC. Methods: TORCH is a prospective, multicenter, randomized, phase II trial (TORCH Registration No. NCT04518280). Patients with LARC (T3-4/N+M0, distance from anus ≤10 cm) are eligible and are randomly assigned to consolidation or induction arms. Those in the consolidation arm receive SCRT (25Gy/5 Fx), followed by six cycles of toripalimab plus capecitabine and oxaliplatin (ToriCAPOX). Those in the induction arm receive two cycles of ToriCAPOX, then undergo SCRT, followed by four cycles of ToriCAPOX. Patients in both groups undergo total mesorectal excision (TME) or can choose a W&W strategy if cCR has been achieved. The primary endpoint is the complete response rate (CR, pathological complete response [pCR] plus continuous cCR for more than 1 year). The secondary endpoints include rates of Grade 3-4 acute adverse effects (AEs) etc. Results: Up to 30 September 2022, 62 patients attending our center were enrolled (Consolidation arm: 34, Induction arm:28). Their median age was 53 (27-69) years. Fifty-nine of them had MSS/pMMR type cancer (95.2%), and only three MSI-H/dMMR. Additionally, 55 patients (88.7%) had Stage III disease. The following important characteristics were distributed as follows: lower location (≤5 cm from anus, 48/62, 77.4%), deeper invasion by primary lesion (cT4 7/62, 11.3%; mesorectal fascia involved 17/62, 27.4%), and high risk of distant metastasis (cN2 26/62, 41.9%; EMVI+ 11/62, 17.7%). All 62 patients completed the SCRT and at least five cycles of ToriCAPOX, 52/62 (83.9%) completing six cycles of ToriCAPOX. Finally, 29 patients achieved cCR (46.8%, 29/62), 18 of whom decided to adopt a W&W strategy. TME was performed on 32 patients. Pathological examination showed 18 had achieved pCR, four TRG 1, and 10 TRG 2-3. The three patients with MSI-H disease all achieved cCR. One of these patients was found to have pCR after surgery whereas the other two adopted a W&W strategy. Thus, the pCR and CR rates were 56.2% (18/32) and 58.1% (36/62), respectively. The TRG 0-1 rate was 68.8% (22/32). The most common non-hematologic AEs were poor appetite (49/60, 81.7%), numbness (49/60, 81.7%), nausea (47/60, 78.3%) and asthenia (43/60, 71.7%); two patients did not complete this survey. The most common hematologic AEs were thrombocytopenia (48/62, 77.4%), anemia (47/62, 75.8%), leukopenia/neutropenia (44/62, 71.0%) and high transaminase (39/62, 62.9%). The main Grade III-IV AE was thrombocytopenia (22/62, 35.5%), with three patients (3/62, 4.8%) having Grade IV thrombocytopenia. No Grade V AEs were noted. Conclusions: SCRT-based total neoadjuvant therapy combined with toripalimab can achieve a surprisingly good CR rate in patients with LARC and thus has the potential to offer new treatment options for organ preservation in patients with MSS and lower-location rectal cancer. Meanwhile, the preliminary findings of a single center show good tolerability, the main Grade III-IV AE being thrombocytopenia. The significant efficacy and long-term prognostic benefit need to be determined by further follow-up.
Humans ; Middle Aged ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Chemoradiotherapy ; Immune Checkpoint Inhibitors/therapeutic use* ; Neoadjuvant Therapy ; Prospective Studies ; Rectal Neoplasms/pathology* ; Thrombocytopenia/drug therapy* ; Treatment Outcome ; Adult ; Aged

Glioblastoma(GBM)is a lethal cancer with limited therapeutic options.Dendritic cell(DC)-based cancer vaccines provide a promising approach for GBM treatment.Clinical studies suggest that other immu-notherapeutic agents may be combined with DC vaccines to further enhance antitumor activity.Here,we report a GBM case with combination immunotherapy consisting of DC vaccines,anti-programmed death-1(anti-PD-1)and poly I:C as well as the chemotherapeutic agent cyclophosphamide that was integrated with standard chemoradiation therapy,and the patient remained disease-free for 69 months.The patient received DC vaccines loaded with multiple forms of tumor antigens,including mRNA-tumor associated antigens(TAA),mRNA-neoantigens,and hypochlorous acid(HOCl)-oxidized tumor lysates.Furthermore,mRNA-TAAAs were modified with a novel TriVac technology that fuses TAAs with a destabilization domain and inserts TAAs into full-length lysosomal associated membrane protein-1 to enhance major histo-compatibility complex(MHC)class Ⅰ and Ⅱ antigen presentation.The treatment consisted of 42 DC cancer vaccine infusions,26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC infusions.The patient also received 28 doses of cyclophosphamide for depletion of regulatory T cells.No immunotherapy-related adverse events were observed during the treatment.Robust antitumor CD4+and CD8+T-cell responses were detected.The patient remains free of disease progression.This is the first case report on the combination of the above three agents to treat glioblastoma patients.Our results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment in this patient.A large-scale trial to validate these findings is warranted.

OBJECTIVE: To evaluate the efficacy and safety of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with decitabine (Dec)-conditioning regimen in the treatment of myelodysplastic syndrome (MDS) and MDS transformed acute myeloid leukemia (MDS-AML). METHODS: The characteristics and efficacy data of 93 patients with MDS and MDS-AML who received allo-HSCT in our center from April 2013 to November 2021 were retrospectively analyzed. All patients were administered by myeloablative conditioning regimen containing Dec (25 mg/m² /d×3 d). RESULTS: Among the 93 patients, 63 males and 30 females, were diagnosed as MDS（n ＝77）, MDS-AML（n ＝16）. The incidence of I/II grade regimen-related toxicity (RRT) was 39.8%, and III grade RRT was only found in 1 patient (1%). Neutrophil engraftment was successful in 91 (97.8%) patients after a median neutrophil engraftment time of 14 (9-27) days; Successful platelet engraftment was achieved in 87 (93.5%) patients, with a median engraftment time of 18 (9-290) days. The incidence of acute graft versus host disease（aGVHD） and grade III-IV aGVHD was 44.2% and 16.2%, respectively. The incidence of chronic graft versus host disease（cGVHD） and moderate-to-severe cGVHD was 59.5% and 37.1%, respectively. Of the 93 patients, 54 (58%) developed posttransplant infections, among which lung infection (32.3%) and bloodstream infection (12.9%) were the most common. The median follow-up after transplantation was 45 (0.1-108) months. The 5-year overall survival (OS) rate, disease-free survival (DFS) rate, treatment-related mortality, and cumulative incidence of relapse were 72.7%, 68.4%, 25.1%, and 6.5%, respectively. And the 1-year graft-versus-host disease/relapse-free survival rate was 49.3%. The patients in different group of relative high-risk prognostic scoring or low-risk prognostic scoring, with or without poor-risk mutation(s), with mutations number ≥3 or <3 had similar 5-year OS rate (more than 70%). Multivariate analysis showed that the incidence of grade III-IV aGVHD was the independent risk factor affecting OS（P =0.008）and DFS (P =0.019). CONCLUSION Allo-HSCT with Dec-conditioning regimen is feasible and effective in the treatment of patients with MDS and MDS-AML, especially those in high prognostic risk and with poor-risk mutations.
Male ; Female ; Humans ; Decitabine ; Retrospective Studies ; Transplantation, Homologous/adverse effects* ; Transplantation Conditioning/adverse effects* ; Myelodysplastic Syndromes/complications* ; Leukemia, Myeloid, Acute/therapy* ; Hematopoietic Stem Cell Transplantation/adverse effects* ; Chronic Disease ; Graft vs Host Disease/therapy* ; Recurrence

Age-dependent loss of skeletal muscle mass and function is a feature of sarcopenia, and increases the risk of many aging-related metabolic diseases. Here, we report phenotypic and single-nucleus transcriptomic analyses of non-human primate skeletal muscle aging. A higher transcriptional fluctuation was observed in myonuclei relative to other interstitial cell types, indicating a higher susceptibility of skeletal muscle fiber to aging. We found a downregulation of FOXO3 in aged primate skeletal muscle, and identified FOXO3 as a hub transcription factor maintaining skeletal muscle homeostasis. Through the establishment of a complementary experimental pipeline based on a human pluripotent stem cell-derived myotube model, we revealed that silence of FOXO3 accelerates human myotube senescence, whereas genetic activation of endogenous FOXO3 alleviates human myotube aging. Altogether, based on a combination of monkey skeletal muscle and human myotube aging research models, we unraveled the pivotal role of the FOXO3 in safeguarding primate skeletal muscle from aging, providing a comprehensive resource for the development of clinical diagnosis and targeted therapeutic interventions against human skeletal muscle aging and the onset of sarcopenia along with aging-related disorders.
Animals ; Humans ; Sarcopenia/metabolism* ; Forkhead Box Protein O3/metabolism* ; Muscle, Skeletal/metabolism* ; Aging/metabolism* ; Primates/metabolism*