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

Objective To investigate the biomechanical differences in plantar pressure,postural stability,and plantar Visual Analogue Scale(VAS)scores between normal feet and unilateral/bilat-eral pes cavus,reveal their unique neuromechanical compensation mechanisms,and construct a sta-bility early warning model based on the minimum center of pressure(COP)trajectory classification.Methods A total of 70 patients with pes cavus from December 2023 to October 2024 were selected as study subjects,including 33 patients in the unilateral pes cavus group and 37 patients in the bilat-eral pes cavus group.During the same period,32 normal feet were included as normal foot group.A flat-panel plantar pressure testing system was used to collect dynamic plantar pressure data and COP trajectories from three groups at a self-selected walking speed.There were no statistically significant differences in baseline data such as age,gender,and body mass index among the three groups(P＞0.05).One-way analysis of variance and the Wilcoxon rank-sum test were used to compare the differences in maximum pressure,contact area,VAS scores,and the 95％confidence ellipse area of the COP among the three groups in 10 plantar regions.Results Patients with pes cavus exhibited lower peak pressure in the MF region compared to normal feet,while higher peak pressure in the M2,M3,and MH regions.Patients with bilateral pes cavus showed lower peak pressure in the T1 region compared to normal feet,and patients with unilateral pes cavus had lower peak pressure in the LH region compared to the normal group(P＜0.05).The plantar contact area in patients with pes cavus was reduced in the T1,M2,M3,M4,MF,and MH regions compared to normal feet(P＜0.05).The 95％confidence ellipse area of the COP was larger in both the bilateral and uni-lateral pes cavus groups compared to the normal foot group(P＜0.001).Unilateral pes cavus pres-ented a specific lateral COP drift(amplitude of 3 to 4 cm),which is a biomechanical manifestation of compensatory eversion of the unaffected foot.Patients with bilateral pes cavus exhibited a"bimod-al oscillation"trajectory(amplitude of 6 to 8 cm),suggesting possible vestibular-spinal regulatory dysfunction and the poorest postural stability.In the pes cavus group,there was a significant in-crease in pressure in the M2,M3,and MH regions,with peak pressures exceeding 190 kPa in pa-tients with bilateral pes cavus,which was highly correlated with plantar pain and could serve as a pain early warning threshold.Conclusion Unilateral and bilateral pes cavus exhibit significantly different neuromechanical compensation patterns.The classification based on the"lateral drift"and"bimodal oscillation"characteristics of the COP trajectory can serve as a stability early warning indi-cator for assessing fall risk.Decompression interventions targeting the key pressure regions of M2,M3,and MH(such as customized orthotic insoles)are the core strategies for alleviating pain and optimizing dynamic gait stability.

Myeloid cell leukemia-1 (MCL-1) is an anti-apoptotic protein that plays a key role in promoting cell survival in multiple myeloma, acute myeloid leukemia and non-Hodgkin lymphoma. MCL-1 is highly expressed in a variety of hematological malignancies, which is one of the important factors leading to poor prognosis and chemoresistance in patients with hematological malignancies. Therefore, MCL-1 is an important therapeutic target for hematological malignancies. Several MCL-1 inhibitors have entered clinical trials, including S63845, AZD5991, S64315, AMG-176, and AMG-397. The treatment plans used for hematological malignancies include monotherapy with MCL-1 inhibitors, as well as combination therapy with B cell lymphoma 2 inhibitors or immunomodulatory drugs, all indicating that MCL-1 inhibitors may be a breakthrough point for targeted treatment of hematological malignancies.

[摘 要] 目的：探究伴有肾损害（RI）的多发性骨髓瘤（MM）患者与无RI患者间是否存在免疫学指标差异。方法：用2017年1月至2023年8月在兰州大学第二医院收治的134例首次确诊为MM的患者相关信息进行回顾性分析，研究对比RI组和非RI组及Durie⁃Salmon（DS）分期和危险分层两个亚组的10种免疫学指标和6个常规血液学参数的差异。结果：RI组外周血中性粒细胞/淋巴细胞比值（NLR）、外周血单核细胞/淋巴细胞比值（MLR）、CD8+ T细胞比例、IL-10均较非RI组高（均P<0.05），淋巴细胞绝对值、CD4/CD8比值均较非RI组低（均P<0.05）。DS-Ⅲ分期患者中，RI组NLR、MLR、CD8+ T细胞比例、IL-8、IL-10均较非RI组升高（均P<0.05），而DS-Ⅰ和DS-Ⅱ患者中，RI组和非RI组患者免疫指标无明显差异。高危MM患者RI组淋巴细胞数、NLR、IL-10均较非RI有明显差异（均P<0.05）。结论：伴RI的MM患者免疫相关指标异常更为明显，DS-Ⅲ分期和高危险度分层表现出明显的免疫指标异常，本研究结果对进一步阐明MM伴有RI患者预后较差的原因及个体化治疗提供参考依据。

Multiple myeloma(MM)is a malignant proliferative disease of plasma cells,ranking as the second most common hematologic tu-mor.Although the use of proteasome inhibitors and immunotherapeutic regimens has improved the prognosis of patients with MM,it re-mains incurable in most patients,mainly because of the eventual development of drug resistance in MM cells.Myeloid-derived suppressor cells(MDSCs)are a heterogeneous group of cells causing significant suppression of the T-cell immune response.They arise from bone mar-row myeloid progenitor cells that are blocked from differentiation and promote MM development by resisting immune destruction.Recent studies indicate that MDSCs stimulate MM cell proliferation,inducing drug resistance and metastasis.In this paper,we review multiple mechanisms exhibited by MDSCs in MM pathogenesis and discuss the feasibility and challenges of current therapeutic strategies targeting MDSCs,aiming to provide pertinent references regarding MM treatment.

Objective To clarify the characteristics of shock wave sources generated at different medium interfaces.Methods The experiment used an in vitro adjustable impact pressure shock wave generation and signal acquisition system combined with a flexible PVDF sensor.The waveform of the shock wave generated by the applicator at the interface of different media(soft tissue-mimicking phantom,water and air)was explored.The characteristics of the shock wave source in the time and frequency domains were analyzed.Results When the same impact pressure was applied,shock waveforms generated at the interfaces of the phantom and water exhibited similar characteristics from a time-domain perspective.At the same time,both differed significantly from those generated at the air interface,where the absolute values of the positive and negative pressures were noticeably reduced.The characteristics of the shockwave spectra in various media revealed three distinct peak frequencies,with the modulation frequencies varying in the phantom(12.2 kHz),water(8.5 kHz),and air(7.2 kHz).In contrast,the carrier frequency remained relatively constant(between 82 and 83 kHz).When different impact pressures were applied,there was little influence on the waveform at the same medium interface,indicating that the impact pressure affected only the shockwave amplitude and not the peak frequency.As the impact pressure increases,the absolute values of the positive and negative pressures at the medium interface increase linearly.Conclusions Shockwave sources can be effectively measured using a flexible PVDF sensor.Shock waves generated at different medium interfaces exhibit temporal and spectral differences,indicating that the characteristics of shock wave propagation in air or water cannot be substituted for those in biological soft tissues.These findings provide crucial information for evaluating shockwave devices and formulating treatment protocols in the clinic.

Multiple myeloma bone disease(MBD)is a common clinical complication in patients with multiple myeloma(MM),and the occurrence of bone-related events seriously affects the quality of survival and prognosis of patients.The pathogenesis of MBD involves an imbalance in physiologic bone remodeling:overactivation of osteoclasts,suppression of osteoblasts,and multiple cell-cytokine interactions in the microenvironment,including osteoblasts,bone marrow stromal cells,and immune cells.The current treatment of MBD is based on standard antimyeloma therapy to control tumor progression,along with the use of bone-related drugs act-ing on bone remodeling within the indications.To prevent bone destruction.In order to prevent bone destruction,it is essential to in-duce new bone formation to repair the existing lesions while resisting bone resorption,and a variety of novel bone-targeting drugs are currently demonstrating anti-osteopathic effects in preclinical and clinical trials.This article summarizes new advances in the mecha-nisms of bone remodeling and treatment of MBD.

Multiple myeloma(MM)is a highly heterogeneous and refractory plasma cell tumor.It is similar to most solid tumors in the hyp-oxic tumor microenvironment(TME)it is exposed to,promoting hypoxia inducible factor-1(HIF-1)activation and related transcription factors of the corresponding downstream signaling pathways,affecting tumor angiogenesis,myeloma cell dissemination and metastasis,anti-tumor immunity,tumor immune escape promotion as well as altering the cellular energy metabolism and participating in therapeutic resistance in-duction.In this study,based on the above-described mechanisms,we aim at reviewing the current research status of hypoxic microenviron-ment-targeting therapies in MM treatment,focusing on the direct inhibition of HIF factors or signaling pathway targeting;metabolism im-provement and oxygenation increase;effective tumor immunity restoration by targeting immune checkpoints;anti-angiogenesis.Precise hypoxia targeting combined with standardized therapy offers a promising strategy and research hotspot in MM therapy.

Objective To investigate the effect of exposure to lead oxide nanoparticles (PbO NPs) on the polarization of microglia in mouse hippocampus. Methods i) Specific pathogen-free male C57 mice were randomly divided into control group, low-, medium- and high-dose groups, with 10 mice in each group. Mice in these three dose groups were intraperitoneally injected with PbO NPs suspension at doses of 5, 10 and 20 mg/kg per day, respectively, and mice in the control group were intraperitoneally injected with the same volume of 0.9% sodium chloride solution, five days per week for four weeks. ii) BV-2 cells were treated with PbO NPs at doses of 0.0, 2.5, 5.0 and 10.0 mg/L for 24 hours. iii) BV-2 cells were randomly divided into control group, PbO NPs group and triggering receptor expressed on myeloid cells 2 (TREM2) high expression + PbO NPs group. The cells in the control group received no treatment. The cells in PbO NPs group were exposed to 10.0 mg/L PbO NPs suspension for 24 hours. Cells in TREM2 high expression + PbO NPs group were transfected with Trem2 high expression plasmid, and then exposed to 10.0 mg/L PbO NPs suspension for 24 hours. iv) The mRNA expression of M1 markers ［nitric oxide synthase (iNos), cyclooxygenase 2 (Cox2), chemokine receptor 7 (Ccr7)］, M2 markers ［arginin-1 (Arg-1), transforming growth factor-β (Tgf-β), chemokine receptor 2 (Ccr2)］ and Trem2 of microglia was detected by real-time fluorescent quantitative polymerase chain reaction. The protein expression of iNOS, ARG-1 and TREM2 was detected by Western blotting. Results i) During the experiment, there was no significant difference in body weight of mice among these four groups (P>0.05). The relative expression of Cox2 and Ccr7 mRNA in the hippocampus of the mice increased in the low-dose group and the iNos, Cox2 and Ccr7 mRNA increased in the medium- and high-dose groups, compared with the control group (all P<0.05). The relative mRNA expression of Tgf-β in the hippocampus of the mice of low-dose group and Arg-1, Tgf-β and Ccr2 in the medium- and high-dose groups was decreased compared with the control group (all P<0.05). The mRNA relative expression of iNos, Cox2 and Ccr7 was increased (all P<0.05), while the mRNA relative expression of Arg-1, Tgf-β and Ccr2 was decreased (all P<0.05) in the hippocampus of the mice of high-dose group compared with the low-dose group. The relative expression of Trem2 mRNA and TREM2 protein in the hippocampus of mice of the medium- and high-dose groups was lower than those in the control group (all P<0.05). The relative expression of Trem2 mRNA and TREM2 protein in the hippocampus of mice of the high dose group was lower than those in the low- and the medium-dose groups (all P<0.05). With the increase of PbO NPs exposure dose, the relative expression of iNOS protein in hippocampus tissues of mice increased (P<0.01), and the relative expression of ARG-1 protein decreased (P<0.01). ii) With the increase of PbO NPs exposure dose, the relative expression of iNOS protein increased (P<0.01), and the relative expression of ARG-1 protein decreased (P<0.01) in BV-2 cells. The relative expression of iNOS protein in BV-2 cells of PbO NPs group and TREM2 high expression + PbO NPs group was increased (all P<0.05), and the relative expression of ARG-1 protein decreased (all P<0.05) compared with the control group. The relative expression of iNOS protein decreased (P<0.05), and the relative expression of ARG-1 protein increased (P<0.05) in BV-2 cells of TREM2 high expression + PbO NPs group compared with the PbO NPs group. Conclusion Exposure to PbO NPs could increase the M1 polarization and decrease the M2 polarization of microglia, with a dose-effect relationship. The M1 polarization of microglia decreased and M2 polarization increased after overexpression of Trem2 gene. The regulation of microglia polarization by TREM2 may be involved in the neurotoxic effects of PbO NPs.

T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is a new immune checkpoint protein. Studies have shown that TIGIT can cause dysfunction of immune cells, weaken the anti-tumor effect, thus leading to tumor immune tolerance and immune escape. Blocking TIGIT can reverse immune cell failure and exert anti-tumor effect, which is expected to become a new therapeutic target for multiple myeloma.