BACKGROUND: Several studies have demonstrated the occurrence of secondary tumors as a rare but significant complication of chimeric antigen receptor T (CAR-T) cell therapy, underscoring the need for a detailed investigation. Given the limited variety of secondary tumor types reported to date, a comprehensive characterization of the various secondary tumors arising after CAR-T therapy is essential to understand the associated risks and to define the role of the immune microenvironment in malignant transformation. This study aims to characterize the immune microenvironment of a newly identified secondary tumor post-CAR-T therapy, to clarify its pathogenesis and potential therapeutic targets. METHODS: In this study, the bone marrow (BM) samples were collected by aspiration from the primary and secondary tumors before and after CD19 CAR-T treatment. The CD45 + BM cells were enriched with human CD45 microbeads. The CD45 + cells were then sent for 10× genomics single-cell RNA sequencing (scRNA-seq) to identify cell populations. The Cell Ranger pipeline and CellChat were used for detailed analysis. RESULTS: In this study, a rare type of secondary chronic myelomonocytic leukemia (CMML) were reported in a patient with diffuse large B-cell lymphoma (DLBCL) who had previously received CD19 CAR-T therapy. The scRNA-seq analysis revealed increased inflammatory cytokines, chemokines, and an immunosuppressive state of monocytes/macrophages, which may impair cytotoxic activity in both T and natural killer (NK) cells in secondary CMML before treatment. In contrast, their cytotoxicity was restored in secondary CMML after treatment. CONCLUSIONS This finding delineates a previously unrecognized type of secondary tumor, CMML, after CAR-T therapy and provide a framework for defining the immune microenvironment of secondary tumor occurrence after CAR-T therapy. In addition, the results provide a rationale for targeting macrophages to improve treatment strategies for CMML treatment.
Humans ; Lymphoma, Large B-Cell, Diffuse/therapy* ; Tumor Microenvironment/genetics* ; Antigens, CD19/metabolism* ; Leukemia, Myelomonocytic, Chronic/genetics* ; Immunotherapy, Adoptive/adverse effects* ; Male ; Single-Cell Analysis/methods* ; Female ; Sequence Analysis, RNA/methods* ; Receptors, Chimeric Antigen ; Middle Aged

Traumatic brain injury(TBI)is mostly caused by motor vehicle traffic accidents or competitive sports,with high mortality and disability.TBI mainly includes primary injury and secondary injury.Primary injuries were caused directly by external forces.Secondary injuries include brain edema,excitotoxic effect of neuron cells,oxidative stress and neuroinflammation,etc.Effective intervention of secondary injury not only helps to improve the prognosis of patients with TBI,but also reduces the risk of Parkinson's disease and other neurodegenerative diseases related to TBI.Autophagy is one of approaches to regulate homeostasis in cells,and autophagy dysfunction has been found in several neurodegenerative diseases and TBI.It is speculated that autophagy dysfunction may play an important role in TBI and explain why patients with TBI have higher risk of neurodegenerative disease.Discovering the role of autophagy in the pathological mechanism of TBI may provide new targets for TBI clinical treatment and cognitive impairment prevention in patients with TBI.

Objective To explore the value of inflammatory markers in predicting paroxysmal sympathetic hyperactivity(PSH)after traumatic brain injury(TBI).Methods A total of 84 TBI patients who were admitted to The Second Affiliated Hospital of Naval Medical University(Second Military Medical University)from Dec.2016 to Nov.2020 were retrospectively analyzed.They were classified into PSH group(n=41)and non-PSH group(n=43)according to whether PSH occurred during hospitalization.The baseline data and laboratory results of the 2 groups were collected and compared.Kendall correlation analysis was used to analyze the correlation between inflammatory markers and the occurrence of PSH after TBI,and receiver operating characteristic(ROC)curve was used to analyze the predictive value of inflammatory markers to PSH.Results There were no significant differences in baseline data,including age,gender,or Glasgow coma scale score,between the 2 groups(all P＞0.05).Compared with patients in the non-PSH group,the neutrophil to lymphocyte ratio(NLR),platelet to lymphocyte ratio(PLR),systemic immune-inflammation index(SII),neutrophils and leukocytes in the PSH group were significantly increased(all P＜0.05).NLR,SII and neutrophil were positively correlated with PSH(r=0.360,0.308,0.289;all P＜0.01),with the corresponding ROC area under curve values being 0.752,0.716 and 0.702,respectively.Conclusion NLR,SII and neutrophils have a value in predicting the occurrence of PSH after TBI.

Craniocerebral injury with seawater immersion is a special kind of compound injury, with low temperature, high permeability, high alkali, high salt content, and bacterial infection being the main causes. The injury is also characterized with complex damage mechanisms, difficulty to treat, and poor prognosis. At present, the damage mechanisms of craniocerebral injury with seawater immersion are mainly studied by establishing the experimental animal models at the levels of tissue, cell, organelle, molecule, etc. However, the craniocerebral injury with seawater immersion is more complex than the simple onshore craniocerebral injury, therefore, a stable disease model is not easy to construct. Most researches on the specific injury mechanisms are relatively single and one-sided, with many different views in existence, and the damage mechanisms of craniocerebral injury with seawater immersion have hitherto not been clear. The authors reviewed the research progress in the damage mechanisms of craniocerebral injury with seawater immersion, in order to promote the in-depth study of the mechanism of craniocerebral injury with seawater immersion and provide reference for its clinical treatment.

Posttraumatic stress disorder (PTSD), the most common mental illness after patients suffer physically or emotionally from traumatic events, can cause persistently strong, painful and terrible avoidance symptoms, emotional and cognitive changes, causing psychologically strong stimulation and heavy burden to patients and even leading to some extreme behavioral reactions. Traumatic brain injury (TBI) is an important factor in the occurrence of PTSD, both of which shares many similar pathological overlaps, and may coexist and interact with each other. The hippocampus and amygdala play a central role in the pathogenesis of PTSD, but the specific cellular and molecular and neural circuit mechanisms are still unclear. About two-thirds of the patients still meet the diagnostic criteria for PTSD after psychotherapy. However, the current treatment methods are complicated and not unified, and patients treated with medications may have adverse drug reactions, poor treatment outcomes and recurrence. Therefore, it is of great significance to further clarify the occurrence and development of PTSD in TBI patients. The authors reviewed the research progress of the pathogenesis and treatment of PTSD in TBI patients, so as to provide reference for the related research and treatment of PTSD in TBI patients.

Chronic superficial gastritis(CSG)is a common disease of the digestive system that possesses a serious pathogenesis.Jinhong tablet(JHT),a traditional Chinese medicine(TCM)prescription,exerts therapeutic effects against CSG.However,the molecular basis of its therapeutic effect has not been clarified.Herein,we employed ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry(UPLC-Q/TOF-MS)based chemical profile identification to determine the chemical components in JHT.Further,we applied network pharmacology to illustrate its molecular mechanisms.A total of 96 chemical constituents were identified in JHT,31 of which were confirmed using reference standards.Based on the bioinformatics analysis using the symptom-guided pharmacological networks of"chi,""blood,""pain,"and"inflammation,"and target screening through the interaction probabilities between compounds and targets,matrix metalloproteinase 2(MMP2),dopamine d2 receptor(DRD2),and Aldo-keto reductase family 1 member B1(AKR1B1)were identified as key targets in the therapeutic effect exhibited by JHT against CSG.Moreover,according to the inhibitory activities presented in the literature and binding mode analysis,the structural types of alkaloids,flavonoids,organic acids,including chlorogenic acid(10),caffeic acid(13),(-)-corydalmine(33),(-)-isocorypalmine(36),isochlorogenic acid C(38),isochlorogenic acid A(41),quercetin-3-O-α-L-rhamnoside(42),isochlorogenic acid B(47),quercetin(63),and kaempferol(70)tended to show remarkable activities against CSG.Owing to the above findings,we systematically identified the chemical components of JHT and revealed its molecular mechanisms based on the symptoms associated with CSG.

This study was aimed to design the first dual-target small-molecule inhibitor co-targeting poly (ADP-ribose) polymerase-1 (PARP1) and bromodomain containing protein 4 (BRD4), which had important cross relation in the global network of breast cancer, reflecting the synthetic lethal effect. A series of new BRD4 and PARP1 dual-target inhibitors were discovered and synthesized by fragment-based combinatorial screening and activity assays that together led to the chemical optimization. Among these compounds, 19d was selected and exhibited micromole enzymatic potencies against BRD4 and PARP1, respectively. Compound 19d was further shown to efficiently modulate the expression of BRD4 and PARP1. Subsequently, compound 19d was found to induce breast cancer cell apoptosis and stimulate cell cycle arrest at G1 phase. Following pharmacokinetic studies, compound 19d showed its antitumor activity in breast cancer susceptibility gene 1/2 (BRCA1/2) wild-type MDA-MB-468 and MCF-7 xenograft models without apparent toxicity and loss of body weight. These results together demonstrated that a highly potent dual-targeted inhibitor was successfully synthesized and indicated that co-targeting of BRD4 and PARP1 based on the concept of synthetic lethality would be a promising therapeutic strategy for breast cancer.

Objective To observe the effect of oral massage combined with trial feeding on dysphagia in neonates with hypoxic- ischemic encephalopathy (HIE). Methods We enrolled 30 hospitalized newborns who were diagnosed moderate to severe HIE with dysphagia in the NICU of our hospital from January 2016 to December 2017. According to the random number table method, these newborns was divided into control group and study group. Oral massage combined with trial feeding were given in the study group, nasogastric feeding in the control group and family participatory care and the treatment of nutritional neurodrugs were also given in two groups. To campare the oral milk remnant, feeding time and sucking action after the flow of milk and swallowing, oral feeding time, gastric tube indwelling time and length of stay in two groups. Results After 5 days intervention, the clinical manifestations of dysphagia in two groups were compared, and there were 6 cases, (8.50 ± 1.05)ml, (36.40 ± 2.87)min and 10 cases of oral milk remnant, feeding time and sucking action after the flow of milk and swallowing respectively in the study group, and 15 cases were 15 cases, (10.80 ± 0.39 )ml, (42.29 ± 1.60) min, 3 cases in the control group, respectively. The difference between the two groups was statistically significant ( χ2=12.86, t=7.52, 6.93, χ2=6.66, P<0.05). The oral feeding time, gastric tube indwelling time and hospitalization time of the study group were (15.60±1.35) d, (11.73±1.39) d, and (21.47±2.03)d, and the control group were (17.00±0.65) d , (14.13±0.99) d, (23.27 ± 1.16) d, respectively. The difference between the two groups was statistically significant (t=3.61, 5.45, 2.98, P<0.05). Conclusions For children with dysphagia, oral massage and combined feeding before each feeding can promote the improvement of oral motor nerves in children, and improve feeding effect, and promote rehabilitation of children.

Objective To observe the effects of seawater immersion at different temperatures on survival time and mortality and physiological state of non-anesthetized rats.Methods Totally 100 SD male rats(The abdominal cavity was implanted with a temperature sensor in advance)were randomly divided into five groups which were immersed in 20 ℃,17 ℃,15 ℃,13 ℃ and 10 ℃ seawater,respectively.Each group contains 20 rats.The changes of respiration,heart rate and muscle fibrillation within 2 hours were observed and the survival time and mortality of each group were counted in 24 hours.The decrease trend of intraperitoneal temperature in rats was analyzed retrospectively within 2 hours.Results Soaking for 10 minutes,the respiratory and heart rate of each group were significantly increased,but there was no significant difference among groups(P>0.05).The respiratory and heart rate decreased rapidly between 10 and 40 minutes,and the decline was slower relatively between 40 and 80 minutes.Soaking for 80 minutes,the respiration rate of rats among groups had significant difference(P<0.05).Immersing for 100 minutes,the heart rates of rats in each group were significantly different(P<0.05).Soaking for 20 minutes,the muscle fibrillation of 15 ℃,13 ℃ and 10 ℃ group reached the peak,and there were significant differences among groups(P<0.05),then disappeared.However the rats in 20 ℃ and 17 ℃ group reached the peak at 30 minutes,but there was no significant difference between two groups(P>0.05),hereafter the muscle fibrillation was maintained at a certain level.The mean survival time of 20 ℃ group,17 ℃ group,15 ℃ group,13 ℃ group and 10 ℃ group in 24 hours were(23.6±1.23)hours,(15.0±4.16)hours,(7.7±3.21)hours,(2.4±0.91)hours and (1.1±0.39)hours,respectively,and the survival curve of each group was statistically significant(P<0.05).The intraperitoneal temperature of rats showed a decline in the cliff,the lower the water temperature,the faster the descending.Soaking for 40 minutes,the difference of intraperitoneal temperature of each group was statistically significant(P<0.05).Conclusion The effects of seawater immersion at different temperatures on the physiological state and survival time and mortality of rats are significantly different.With the decrease of water temperature,the physiological state changes more obviously,the survival time is shorter and the mortality rate is higher.

Objective To explore the expression and localization of aquaporin 11(AQP11) in human term pregnancies with oligihydramnios, and its role in amniotic fluid balance.Methods We studied 55 patients who underwent elective cesarean sections, consisting of 25 patients with isolated oligohydramnios and 30 with normal amniotic fluid volume.Immunohistochemistry and reverse transcription polymerase chain reaction were employed to determine the expression and localization of AQP11 in the amnion, chorion and placenta.Results AQP11 protein was detected in expressed in the full-term pregnant women`s amnion, chorion and placenta.The expression in the amnion was positively correlated with amniotic fluid amount;the expression in the placenta was negatively correlated with amniotic fluid amount.The expression increased in the chorion with different amniotic fluid amount.Conclusion AQP11 plays an important role in regulating amniotic fluid balance.