B and T lymphocyte attenuator (BTLA) is an inhibitory immune checkpoint, which typically interacts with herpesvirus entry mediator (HVEM) and plays a crucial role in regulating immune balance. BTLA interacts with its ligand HVEM in a cis manner on the surface of the same immune cell to maintain immune tolerance, while trans interactions on the surface of different immune cells mediate immunosuppressive effects. Dysregulation of the BTLA/HVEM axis can impair the functions of immune cells, particularly T lymphocytes, promoting immune escape of tumor cells and ultimately leading to tumor progression. Researchers have found that BTLA and HVEM are abnormally expressed in various tumors and are associated with prognosis, suggesting that they may be potential targets for tumor immunotherapy. This review summarizes the molecular structures of BTLA and HVEM, immunomodulatory mechanisms, recent advances in hematologic malignancies, potential inhibitors of BTLA/HVEM interaction, and their applications in immunotherapy for hematologic malignancies.
Humans ; Receptors, Tumor Necrosis Factor, Member 14/chemistry* ; Receptors, Immunologic/immunology* ; Hematologic Neoplasms/genetics* ; Immunotherapy/methods* ; Animals

The innate immune response is the first line of defense for the host against viral infections. Targeted degradation of pathogenic microorganisms through autophagy, in conjunction with pattern recognition receptors synergistically inducing the production of interferon (IFN), constitutes an important pathway for the body to resist viral infections. Rubicon, a Run domain Beclin 1-interacting and cysteine-rich domain protein, has an inhibitory effect on autophagy and IFN production. On the one hand, Rubicon, as a component of the phosphoinositide 3-kinase (PI3K) complex, interacts with different domains of vacuolar protein sorting 34 (Vps34), ultraviolet radiation resistance associated gene (UVRAG), guanosine triphosphate (GTP) kinase, and RAS oncogene family member 7 (Rab7) to mediate the inhibition of autophagy maturation; on the other hand, Rubicon inhibits the ubiquitination of nuclear factor κB essential modulator (NEMO) and the dimerization of interferon regulatory factor 3 (IRF3), thereby blocking the signal transduction related to IFN production. Research has revealed that various viruses, such as Kaposi's sarcoma-associated herpesvirus (KSHV), hepatitis B virus (HBV), Sendai virus (SeV), and hepatitis C virus (HCV), achieve innate immune evasion by regulating the expression or function of Rubicon. Rubicon is expected to be a new target for antiviral therapy.
Humans ; Autophagy/immunology* ; Immunity, Innate ; Interferons/immunology* ; Immune Evasion ; Animals ; Virus Diseases/virology* ; Signal Transduction ; Viruses/immunology* ; Intracellular Signaling Peptides and Proteins/immunology* ; Autophagy-Related Proteins

OBJECTIVE: To establish an intestinal organoid model that mimic acute graft versus host disease (aGVHD) caused intestinal injuries by using aGVHD murine model serum and organoid culture system, and explore the changes of aGVHD intestine in vitro by advantage of organoid technology. METHODS: 20-22 g female C57BL/6 mice and 20-22 g female BALB/c mice were used as donors and recipients for bone marrow transplantation, respectively. Within 4-6 h after receiving a lethal dose (8.0 Gy) of γ ray total body irradiation, a total of 0.25 ml of murine derived bone marrow cells (1×10⁷/mice, n=20) and spleen nucleated cells (5×10⁶/mice, n=20) was infused to establish a mouse model of aGVHD (n=20). The aGVHD mice were anesthetized at the 7th day after transplantation, and the veinal blood was harvested by removing the eyeballs, and the serum was collected by centrifugation. The small intestinal crypts of healthy C57BL/6 mice were harvested and cultivated in 3D culture system that maintaining the growth and proliferation of intestinal stem cells in vitro. In our experiment, 5%, 10%, 20% proportions of aGVHD serum were respectively added into the organoid culture system for 3 days. The formation of small intestinal organoids were observed under an inverted microscope and the morphological characteristics of intestinal organoids in each groups were analyzed. For further evaluation, the aGVHD intestinal organoids were harvested and their pathological changes were observed. Combined with HE staining, intestinal organ morphology evaluation was performed. Combined with Alcian Blue staining, the secretion function of aGVHD intestinal organoids was observed. The distribution and changes of Lgr5⁺ and Clu⁺ intestinal stem cells in intestinal organoids were analyzed under the conditions of 5%, 10% and 20% serum concentrations by immunohistochemical stainings. RESULTS: The results of HE staining showed that the integrity of intestinal organoids in the 5% concentration serum group was better than that in the 10% and 20% groups. The 5% concentration serum group showed the highest number of organoids, the highest germination rate and the lowest pathological score among experimental groups, while the 20% group exhibited severe morphological destruction and almost no germination was observed, and the pathological score was the highest among all groups(t=3.668, 4.334,5.309,P<0.05). The results of Alican blue staining showed that the secretion function of intestinal organoids in serum culture of aGVHD in the 20% group was weaker than that of the 5% group and 10% of the organoids, and there was almost no goblet cells, and mucus was stainned in the 20% aGVHD serum group. The immunohistochemical results showed that the number of Lgr5⁺ cells of intestinal organoids in the 5% group was more than that of the intestinal organoids in the 10% aGVHD serum group and 20% aGVHD serum group. Almost no Clu⁺ cells were observed in the 5% group. The Lgr5⁺ cells in the 20% group were seriously injuried and can not be observed. The proportion of Clu⁺ cells in the 20% group significantly increased. CONCLUSION The concentration of aGVHD serum in the culture system can affect the number and secretion function of intestinal organoids as well as the number of intestinal stem cells in organoids. The higher the serum concentration, the greater the risk of organoid injury, which reveal the characteristics of the formation and functional change of aGVHD intestinal organoids, and provide a novel tool for the study of intestinal injury in aGVHD.
Mice ; Female ; Animals ; Mice, Inbred C57BL ; Bone Marrow Transplantation ; Graft vs Host Disease ; Stem Cells ; Organoids

OBJECTIVE: To investigate the clinical characteristics, diagnosis, and treatment of one patient with primary adrenal natural killer/T-cell lymphoma (PANKTCL), and to strengthen the understanding of this rare type of lymphoma. METHODS: The clinical manifestations, diagnosis and treatment process, and prognosis of the patient admitted in our hospital were retrospectively analyzed. RESULTS: Combined with pathology, imaging, bone marrow examination， etc, the patient was diagnosed with PANKTCL (CA stage, stage II; PINK-E score 3, high-risk group). Six cycles of "P-GemOx+VP-16" regimen（gemcitabine 1 g/m² d1 + oxaliplatin 100 mg/m² d 1 + etoposide 60 mg/m² d 2-4 + polyethylene glycol conjugated asparaginase 3 750 IU d 5） was performed, and complete response was assessed in 4 cycles. Maintenance therapy with sintilimab was administered after the completion of chemotherapy. Eight months after the complete response, the patient experienced disease recurrence and underwent a total of four courses of chemotherapy, during which hemophagocytic syndrome occurred. The patient died of disease progression 1 month later. CONCLUSION PANKTCL is rare, relapses easily, and has a worse prognosis. The choice of the "P-GemOx+VP-16" regimen combined with sintilimab help to improve the survival prognosis of patient with non-upper aerodigestive tract natural killer /T-cell lymphoma.
Humans ; Treatment Outcome ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Retrospective Studies ; Etoposide ; Neoplasm Recurrence, Local/drug therapy* ; Asparaginase ; Deoxycytidine ; Lymphoma, T-Cell, Peripheral/drug therapy* ; Lymphoma, Extranodal NK-T-Cell/therapy* ; Oxaliplatin/therapeutic use*

Objective:To assess the feasibility of the designed dual-isocenter IMRT plans based on Halcyon 3.0 linear accelerator in postoperative radiotherapy of radical mastectomy for left side of breast cancer.Methods:A total of sixteen patients received the postoperative radiotherapy of radical mastectomy for left side of breast cancer at Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine from December 2022 to June 2023 were retrospectively selected.The dual-isocenter plans based respectively on Halcyon 3.0 linear accelerator and Truebeam linear accelerator were designed,and the dosimetric parameters included conformity index(CI)values of target region,homogeneity index(HI)values and doses to organs at risk(OAR)of the two plans were calculated as statistic method.And then,the dosimetric performance of Halcyon 3.0 dual-isocenter plan was compared and analyzed.Utilizing two dose verification tools,ArcCHECK and Portal Dosimetry,to assess the precision of beam delivery of Halcyon 3.0 dual-isocenter plan.Results:The Halcyon dual-isocenter plan and the Truebeam single-isocenter plan had similar plan quality.There were not statistically significant differences(P>0.05)in dosimetric parameters such as CI,HI,exposure dose to 2%of the target volume(D2%)and exposure dose to 98%of the target volume(D98%).Compared to the average monitor unit(MU)of Truebeam single-isocenter plan,the MU values of Halcyon 3.0 dual-isocenter plan increased by 366 MU,while the difference was not statistically significant(P>0.05).The Halcyon 3.0 dual-isocenter plan provided comprehensive protection for OAR,which was better than that of the Truebeam single-isocenter plan.The values of the left side of lung volume(V20)that were covered by 20 Gy dose of the Halcyon 3.0 dual-isocenter plan and the Truebeam single-isocenter plan were respectively 20.41%±1.56%and 24.88%±2.95%,and the difference was statistically significant(t=6.413,P<0.05).There were not significant differences in other OAR dosimetric parameters between the two kinds of plans(P>0.05).The verification pass rates of the Halcyon 3.0 dual-isocenter plans on the ArcCHECK and Portal Dosimetry platforms were respectively 97.6%-98.9%and 98.1%-100%when the ratio of dose tolerance(DT)to distance to agreement(DTA)was set at 2%/2 mm.The verification pass rates of the Halcyon 3.0 dual-isocenter plans on the ArcCHECK and Portal Dosimetry platforms were respectively 99.1%-100%and 99.7%-100%when DT/DTA was set at 3%/3 mm.The beam delivery precision of the Halcyon 3.0 dual-isocenter plan could meet verification standards of clinical treatments.Conclusion:The Halcyon 3.0 dual-isocenter IMRT plan demonstrates a higher feasibility in the postoperative radiotherapy of radical mastectomy for left side of breast cancer.The precision of dose delivery of plan is high,and the dose of target area is sufficient,uniform and favorable conformability.It can effectively limit the OAR exposure dose at the same time.

Objective:To evaluate the dosimetric effects of different aperture shape controller (ASC) parameters based on the Halcyon 3.0 accelerator in the hippocampal avoidance-whole brain radiotherapy (HA-WBRT) plans.Methods:This study enrolled 13 patients treated with WBRT using a Halcyon 3.0 accelerator at the Department of Radiotherapy of the Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine. According to different aperture shape controller (ASC) parameters, the HA-WBRT plans were divided into six groups, namely non, very low, low, moderate, high, and very high ASC settings, marked by AO, AVL, AL, AM, AH, and AVH, respectively. This study presented a statistical evaluation of the effects of different ASC parameters on conformity index (CI), homogeneity index (HI), radiation doses to the hippocampus and other organs at risk, and the plans’ execution efficiency. Furthermore, using two dose verification tools, namely ArcCHECK and Portal Dosimetry, this study delivered a comprehensive analysis of the differences in beam delivery precision of the plans with different ASC parameters.Results:The six groups all met the requirements for clinical treatment. They had similar CI and HI values, with no statistically significant differences ( P > 0.05). The AVH group showed better protection effects on organs at risk. Compared to the control group, the AVL group showed lower Dmax of brainstems but higher Dmax of chiasma opticum ( F = 6.26, 8.04, P < 0.05). Compared to the control group, the AH group showed lower Dmax of eyeballs but higher Dmax of optic nerves ( F = 2.04, 1.37, P < 0.05). In contrast, the AVH group exhibited lower Dmax of brainstems, eyeballs, and lens than the control group ( F = 6.26, 2.04, 2.02, P < 0.05). No statistically significant differences were observed in dosimetric indices of other organs at risk ( P > 0.05). As verified using ArcCHECK and Portal Dosimetry, the γ passing rates of the six groups were over 98% at 2%/2 mm and 100% at 3%/3 mm. The overall γ passing rates verified using ArcCHECK were lower than those verified using Portal Dosimetry. The maximum difference in the monitor unit among the six groups was less than 15, and these groups did not show significant differences in terms of execution efficiency. Conclusions:The HA-WBRT plans based on the Halcyon 3.0 accelerator can meet the requirements for clinical treatment. Different ASC parameters can significantly optimize the dosimetric parameters. Among them, the AVH parameters can highly reduce the radiation dose to organs at risk. Furthermore, different ASC parameters show insignificant effects on beam delivery precision and plan execution efficiency, meeting the verification standards for clinical therapeutic doses.

B-Lymphocytes ; Graft vs Host Disease ; Humans ; Immunoglobulin D ; T Follicular Helper Cells ; T-Lymphocytes, Helper-Inducer

Traditional Chinese medicine （TCM） and western medicine have their respective advantages and limitations in the diagnosis and treatment of common otorhinolaryngology head and neck diseases. Although the integrated TCM and western medicine exhibits definite curative effects， there is no consensus on the otorhinolaryngology head and neck diseases responding specifically to TCM or integrated TCM and western medicine， as well as the diagnosis and treatment schemes. The China Association of Chinese Medicine （CACM） thus organized the otorhinolaryngology head and neck specialists of both TCM and western medicine to discuss the etiology， pathogenesis， and clinical diagnosis and treatment methods of common otorhinolaryngology head and neck diseases with the results of multiple clinical trials taken into account. The acute pharyngitis， chronic pharyngolaryngitis， paraesthesia pharyngis， hysterical aphasia， allergic rhinitis， subjective tinnitus， and otogenic vertigo were confirmed to respond specifically to TCM or integrated TCM and western medicine. Then a mutually agreed diagnosis and treatment scheme and recommendation with integrated TCM and western medicine was formulated as a reference for clinical practice， thus benefiting more patients.

OBJECTIVE: To investigate the effect of EBV-DNA copy number on the prognosis of patients with EBV positive lymphoma. METHODS: Clinical data of 109 patients diagnosed as EBV positive lymphoma in Tianjin Medical University Cancer Institute and Hospital from January 2010 to January 2020 were enrolled and analyzed retrospectively. Kaplan-Meier analysis was used for survival analysis, Log-rank was used to compare the clinical characteristics between the patients in different groups, and Cox regression was used for multivariate analysis. RESULTS: Among the 109 patients with EBV-positive lymphoma, the medium age were 56 (range 15 to 83) years old. 29 patients at Ann Arbor stage I-II while 80 patients at stage III-IV. The average value of EBV-DNA was 1 023 510 IU/ml, 7 patients were higher than the average value, while 102 patients were lower. KM survival analysis showed that OS and PFS in patients with EBV-DNA above average level were shorter than those in patients with EBV-DNA below average level (OS: P=0.048, PFS: P=0.001), EBV-DNA copy number was a factor affecting the prognosis of patients. In addition, LDH level showed positive correlation with EBV-DNA copy number (r=0.650), which was also one of the factors affecting OS (P=0.053). CONCLUSION EBV-DNA copy number and LDH level can influence the prognosis of EBV positive lymphoma patients. Therefore, detection of EBV-DNA copy number in peripheral blood is important for evaluate the prognosis the patients.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; DNA Copy Number Variations ; DNA, Viral ; Herpesvirus 4, Human ; Humans ; Lymphoma ; Middle Aged ; Retrospective Studies ; Young Adult

OBJECTIVE: To detect the relationship between CTGF in the bone marrow of MM patients and osteolytic lesion of myeloma, moreover, to investigate the clinical significance of CTGF in MM. METHODS: Fifity-four MM patients treated in our hospital from March 2019 to April 2020 were enrolled, and 28 healthy volunteers were selected as the control group. The plasma in bone marrow of the patients was collected, and the ELISA was used to detect the level of CTGF in bone marrow plasma and the relationship between its and clinical characteristics were statistically analyzed. RESULTS: The CTGF level of MM patients was significantly higher than those in the healthy control group (P<0.001); the CTGF level in male patients was higher than that in female patients (P=0.007); the CTGF level in MM patients with osteolytic lesions was significantly higher than patients without osteolytic lesions and controls (P=0.007, P=0.001). The CTGF level in MM patients was positively correlated with the number of bone lesions (P<0.001, r=0.52). CTGF levels in patients with ≥3 bone lesions were significantly higher than those with <3 bone lesions and without bone lesions (P=0.014, P=0.002). ROC curve result showed that CTGF expression level shows a significant diagnostic value for MM bone disease (P<0.001). CONCLUSION The abnormally high expression of CTGF level in MM patients is related to the degree of myelomas osteolytic lesions and can reflect the progress of MM.
Bone Marrow ; Connective Tissue Growth Factor ; Female ; Humans ; Male ; Multiple Myeloma ; Osteolysis ; Patients ; ROC Curve