Chang Wei Qing Decoction enhances the anti-tumor effect of PD-1 inhibitor therapy by regulating the immune microenvironment and gut microbiota in colorectal cancer / 中国天然药物

The anti-tumor effect of anti-PD-1 antibody has long been shown to be strongly related to the tumor immune microenvironment (TIME). This study aimed to mechanistically assess whether Chang Wei Qing (CWQ) Decoction can enhance the anti-tumor effect of PD-1 inhibitor therapy. PD-1 inhibitor therapy showed the significant anti-tumor effect in patients with mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) colorectal cancer (CRC), rather than those with mismatch repair-proficient/microsatellite stable (pMMR/MSS) CRC. Hence, immunofluorescence double-label staining was utilized to explore the difference in the TIME between dMMR/MSI-H and pMMR/MSS CRC patients. Flow cytometry was used to analyze T-lymphocytes in tumors from mice. Western blot was used to measure the expression of PD-L1 protein in mouse tumors. The intestinal mucosal barrier of mice was evaluated by hematoxylin-eosin staining and immunohistochemistry. 16S rRNA-gene sequencing was used to examine the structure of the gut microbiota in mice. Subsequently, Spearmanapos;s correlation analysis was used to analyze the relationship between the gut microbiota and tumor-infiltrating T-lymphocytes. The results showed that dMMR/MSI-H CRC patients had more CD8+T cells and higher expression of PD-1 and PD-L1 proteins. In vivo, CWQ enhanced the anti-tumor effect of anti-PD-1 antibody and increased the infiltration of CD8+ and PD-1+CD8+ T cells in tumors. Additionally, the combination of CWQ with anti-PD-1 antibody resulted in lower inflammation in the intestinal mucosa than that induced by anti-PD-1 antibody alone. CWQ and anti-PD-1 antibody co-treatment upregulated PD-L1 protein and reduced the abundance of Bacteroides in the gut microbiota but increased the abundance of Akkermansia,Firmicutes, andActinobacteria. Additionally, the proportion of infiltrated CD8+PD-1+, CD8+, and CD3+ T cells were found to be positively correlated with the abundance of Akkermansia. Accordingly, CWQ may modulate the TIME by modifying the gut microbiota and consequently enhance the anti-tumor effect of PD-1 inhibitor therapy.

Analysis of the characteristics of sarcopenia in elderly patients of different age groups / 中华老年医学杂志

Objective:To compare clinical characteristics and results on parameters for muscle measurement in elderly sarcopenia patients of different age groups.Methods:This was a cross-sectional study, and 404 outpatients aged 60 years and over were enrolled and received a long-term follow-up.According to the World Health Organization classification of the elderly, the subjects were divided into a youngest-old group, a middle old group and an oldest-old group; and according to the diagnostic criteria of the Asian Working Group for Sarcopenia in 2019, elderly people of all ages were divided into a sarcopenia group and a non-sarcopenia group.General clinical data were recorded, and the upper arm circumference, leg circumference, skeletal muscle index, grip strength and walking speed, the Short Physical Performance Battery and timed up and go were conducted.At the same time, the body composition was measured by multifrequency bioelectrical impedance analysis.Results:The subjects had a mean age of(85.24 ± 8.23)years, including 90(22.28%)youngest-old, 165(40.84%)middle old and 149(36.88%)oldest-old.123 patients(30.45%)were diagnosed with sarcopenia, with a prevalence of 27.78%(25)in the youngest-old group, 28.48%(47)in the middle old group and 34.23%(51)in the oldest-old group.Compared with those without sarcopenia, the basal metabolic rate in sarcopenia patients of all age groups decreased significantly, the levels of hemoglobin and albumin in youngest-oldsarcopenia patients decreased, the waist circumference and body mass index in middle old and oldest-old sarcopenia patients decreased, and the body fat rate in middle old sarcopenia patients increased.In the subjects with sarcopenia, the proportion of men in the oldest-old group was higher than in the other two groups.Compared with the youngest-old group, the levels of alanine aminotransferase and prealbumin decreased, serum creatinine increased, and skeletal muscle index values did not change in the middle old and longest-old groups, but handgrip strength(27.7±5.9 vs.23.2±6.9 vs.21.4±5.8, F=5.81, P=0.004), gait speed(0.8±0.2 vs.0.7±0.2 vs.0.5±0.2, F=11.88, P=0.000)and calf circumference(33.4±3.3 vs.15.9± 8.4 vs.31.5±3.1 vs.30.9±3.3, F=3.58, P=0.031)significantly decreased, and time up and go values(10.0±2.1 vs.15.9±8.4 vs.20.8±12.8, F=6.98, P=0.001)increased in the middle old and longest-old groups.Partial correlation analysis showed that age had a significant negative correlation with handgrip( r=-0.374, P=0.001), daily gait speed( r=-0.441, P=0.000), and calf circumference( r=-0.223, P=0.017), but a significant positive correlation with timed up and go( r=0.319, P=0.009). Conclusions:Compared with youngest-old sarcopenia patients, middle old patients show significant decline in muscle function, muscle strength and muscle mass in the lower limb.With increasing age, the impact of changes in muscle function, muscle strength and regional muscle mass on adverse events should receive heightened attention.

Si Junzitang Regulates NKG2A Expression to Improve Anti-colon Cancer Function of NK Cells / 中国实验方剂学杂志

ObjectiveTo explore the mechanism of Si Junzitang in regulating the expression of NKG2A to affect the anti-colon cancer function of natural killer （NK） cells. MethodNK cells isolated from healthy honors were cultured and used to construct the three incubation models of NK cells， human colon cancer HCT116 cells， and NK cells + HCT116 cells （co-incubation）. real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was conducted to determine the mRNA levels of natural killer group 2 member A （NKG2A） and interleukin （IL）-15 in NK cells， as well as the mRNA level of histocompatibility leucocyte antigen E （HLA-E） in HCT116 cells. The secretion of IL-15 was detected by enzyme-linked immunosorbent assay （ELISA）. Methyl thiazolyl tetrazolium （MTT） assay was employed to determine the applicable concentration of IL-15 and test the effects of Si Junzitang and IL-15 on the activities of NK cells and the HCT116 cells in the co-incubation model. The effects of Si Junzitang and IL-15 on the mRNA levels of NKG2A in NK cells and HLA-E in HCT116 cells were detected by Real-time PCR. Monalizumab （M， anti-NKG2A mab） was used to block the NKG2A-HLA-E pathway in co-incubation model， and then the proliferation of HCT116 cells was detected by MTT assay. ResultThe interaction of NK cells and HCT116 cells up-regulated the mRNA levels of NKG2A in NK cells and HLA-E in HCT116 cells （P<0.05）， as well as the expression level and secretion of IL-15 （P<0.05）. Compared with the blank group， Si Junzitang and Si Junzitang + IL-15 promoted the proliferation and improved the anti-colon cancer function of NK cells （P<0.01）. Furthermore， they down-regulated the mRNA levels of NKG2A in NK cells and HLA-E in the HCT116 cells co-incubated with NK cells （P<0.01）. M and IL-15 + M inhibited the proliferation of HCT116 cells compared with the groups without M （P<0.01）. ConclusionThe interaction of NK cells and HCT116 cells can induce activation of NKG2A-HLA-E pathway to impair NK cell function. Si Junzitang can inhibit the activation of NKG2A-HLA-E pathway to restore the anti-colon cancer function of NK cells.

Allogeneic CAR-T for treatment of relapsed and/or refractory multiple myeloma: four cases report and literatures review / 中华血液学杂志

Objective@#To investigate the safety and efficacy of allogeneic CAR-T cells in the treatment of relapsed/refractory multiple myeloma (RRMM) .@*Methods@#CAR-T cells were prepared from peripheral blood lymphocytes of HLA mismatch healthy donors. Median age was 55 (48-60) . Allogeneic cells were derived from 3 HLA haploidentical donors and 1 HLA completely mismatch unrelated donor. Four patients with RRMM were conditioned with FC regimen followed by CAR-T cell transfusion. They were infused into CART-19 (1×107/kg on day 0) and (4.0-6.8) ×107/kg CART-BCMA cells as split-dose infusions (40% on day 1 and 60% on day 2) . The adverse reactions and clinical efficacy were observed during follow-up after infusion, and the amplification and duration of CAR-T cells in vivo were monitored by PCR technique.@*Results@#CAR-T cells were successfully infused in 3 of the 4 RRMM patients according to the study plan, and the infusion in one patient was delayed by 1 day due to high fever and elevated creatinine levels on day 3. The side effects included hematological and non-hematological toxicity, grade 3 hematological toxicity in 2 patients, grade 3 CRS in 1 one, grade 1 CRES in 1 one, prolonged APTT in 3 ones, tumor lysis syndrome in 1 one, mixed chimerism detected STR and clinical GVHD manifestation in 1 one. According to the efficacy criterias of IMWG, 2 patients acquired PR, 1 MR, and 1 SD respectively. Progression-free survival was 4 (3-5) weeks and overall survival was 63 (3-81) weeks. CAR T cells were amplified 2.2 (2-14) times in the patients with a median survival time of 10 (8-36) days.@*Conclusions@#Small sample studies suggested that GVHD may be present in the treatment of RRMM with allogeneic CAR-T cells. There were early clinical transient events after transfusion. Low amplification and short duration of CAR-T cells in vivo may be the main factors affecting the efficacy.

Primary testicular NK/T cell lymphoma: a clinicopathologic analysis of six cases / 中华病理学杂志

Objective@#To evaluate the clinicopathological features, diagnosis and management of primary testicular NK/T cell lymphoma (NKTCL).@*Methods@#Six cases of primary testicular NKTCL at Beijing Friendship Hospital, Capital Medical University from January 2007 to December 2016 were retrospectively analyzed for the morphology, immunephenotype and outcome, and relevant literature was reviewed.@*Results@#The median age of patients at diagnosis was 45 years(range 32-65 years). All patients presented with testicular masses as initial symptoms (6/6), five cases (5/6) were on the right. The lesions were confined to the testis. All patients were classified as Ann Arbor stage Ⅰ but the tumors exhibited aggressive clinical behavior. Two patients died of the disease within two months, three (3/6) had clinical remission, and one (1/6) was lost to follow-up. Morphologically, the lymphoma cells showed a diffuse growth pattern that largely effaced the interstitial tissues, and surrounded seminiferous tubules in all cases. There was also a prominent angioinvasive pattern, with focal necrosis and karyorrhexis(4/6). Cytologically, the medium-sized neoplastic cells showed scanty to moderate amount of cytoplasm and irregular folded nuclei. The immunophenotype was similar to that of nasal NKTCL: the neoplastic cells were positive for cytoplasmic CD3, CD56, cytotoxic molecules and EBV-encoded small RNA, the loss of CD5 antigen was seen in all cases.@*Conclusions@#Primary testicular NKTCL is extremely rare, highly aggressive and is associated with a poor prognosis. There is no unified standard of treatment. Thus, at the time of diagnosis of testicular lymphoma, NKTCL should be included in the differential diagnosis.

Research Progress of Measurement and Evaluation System of Physician Professionalism / 中国医学伦理学

This paper analyzed the foreign measurement and evaluation system of physician professionalism,from the perspectives of the evaluation of occupation behavior,the multi sources of evaluation,the evaluation of empathy,and the cross-cultural background.It also discussed the basic condition of the development of domestic evaluation and evaluation system,and analyzed it from the diversity and comprehensiveness of evaluation perspectives,the specific and objectivity of evaluation items,the clarity and quantitative feature of evaluation indexes,as well as the openness and feedback of evaluation system.In addition,this paper reviewed the domestic and foreign measurement and evaluation methods of physician professionalism in recent years and pointed out that the construction of good measurement and evaluation system is the only way to deepen the research of physician professionalism.

Piperine inhibits Ang Ⅱ-induced cellproliferation and migration of rat airway smooth muscle cells / 基础医学与临床

Objective To explore the effects of piperine on cell proliferation and migration in angiotensin Ⅱ (Ang Ⅱ)-treated rat airway smooth muscle cells (ASMCs).Methods The primary ASMCs of rats were cultured by improved tissue-piece digestion inoculation and trypsin digestion.MTT assay was used to detect the effects of Ang Ⅱ and Ang Ⅱ receptor antagonist losartan on cell proliferation activity.After treatment with Ang Ⅱ and piperine, the cell proliferation activity, the cell cycle distribution and the cell migration were detected by MTT, flow cytometry and Transwell assay respectively.ERK1/2 inhibitor PD98059 and losartan were then applied to determine the expression of cyclin D1, MMP-9, p-ERK1/2, ERK1/2, and β-actin proteins by Western blot assay.Results After 24 h culture, Ang Ⅱ treatment promoted the cell proliferative activity in rat ASMCs (P<0.05), and the promotive effect of 10-7 mol/L Ang Ⅱ was the most significant.Additionally, losartan blocked the Ang Ⅱ-induced cell proliferative activity in rat ASMCs (P<0.05).10-7 mol/L Ang Ⅱ treatment resulted in the elevated cell proliferative activity, higher S phase fraction, increased migrated cell number, and enhanced expression of cyclin D1, MMP-9and p-ERK1/2 proteins (P<0.05);these effects were dose-dependently reversed by piperine.Both PD98059 and losartan blocked Ang Ⅱ-induced expression of p-ERK1/2, cyclin D1 and MMP-9 proteins in rat ASMCs.Conclusions Piperine may inhibit Ang Ⅱ-induced cell proliferation and cell migration via ERK1/2 signaling pathway in rat ASMCs.

Clinical Observation of Electroacupuncture for Peri-menopausal Depression / 上海针灸杂志

Objective To observe the clinical efficacy of electroacupuncture in treating peri-menopausal depression. Method Patients diagnosed with peri-menopausal depression were randomized into a Guanyuan (CV4) group (n=30) and a Neiguan (PC6) group (n=30). After 1-month treatment, Hamilton Depression Scale (HAMD), modified Kupperman index, plasm ACTH and serum CORT levels were observed and compared. Result After intervention, the observed indexes were decreased to different extents, and the between-group differences were statistically significant (P<0.05). Conclusion Electroacupuncture can effectively regulate the endocrine function of peri-menopausal depression patients, improve symptoms, and thus enhance the compensatory function and the quality of life, and the Guanyuan group shows a more significant effect.

PI3K/Akt/NF-κB regulate ABCB1/P-glycoprotein-mediated multidrug resistance in colon carcinoma cells / 中国癌症杂志

Background and purpose: Multidrug resistance (MDR) is the dominating obstacle to the chemotherapy. There is strong evidence that the phosphoinositide 3-kinases (PI3Ks) signaling pathway is involved in MDR phenotype, however, the mechanism of MDR occurrence is still unknown. This study tended to investigate the regulating effect of PI3K/Akt signaling pathway and its downstream target genes in P-glycoprotein (P-gp) (ABCB1 gene encoding)-mediated MDR in human colon carcinoma HCT-116/L-OHP cells. Methods:Pretreatment with PI3K selective inhibitor LY294002 (20μmol/L) for 2 h, the sensitivity of L-OHP was evaluated by the CCK-8 (cell counting kit-8) assay in HCT-116/L-OHP cells, and the expressions of P-gp, LRP, MRP-2, Akt, p-Akt, IκB and p-IκB were evaluated by Western blot. The activity of ABCB1 promoter was evaluated by chromatin immunoprecipitation analysis (CHIP). Results: After inhibiting the activity of PI3K/Akt signaling pathway, the IC50 value of L-OHP decreased from(157.48±16.73)μg/mL to (53.68±3.18)μg/mL in HCT-116/L-OHP cells, and the reversal index was 2.93 (P<0.01). The expressions of P-gp, p-Akt and p-IκB were down-regulation compared with the concrol group (P<0.01), but the expressions of LRP, MRP-2, Akt and IκB didn't change signiifcantly. CHIP result has conifrmed that NF-κB protein could bind to the region of ABCB1 gene promoter in HCT116/L-OHP cells. Conclusion:Blocking of PI3K/Akt/NF-kB signal pathway could increase the drug sensitivity to MDR cells, inhibit the phosphorylation of p-Akt and p-IκB, and reversing ABCB1/P-glycoprotein-mediated multidrug resistance in colon carcinoma cells.

Clinical application of percutaneous implantation of ~(125)I seeds for treating malignant tumor / 介入放射学杂志

Objective To investigate the therapeutic mechanism of ~(125)I seeds based on physical properties, the significance of therapeutic planning system (TPS), the therapeutic means and the clinical efficacy. Methods Eighteen cases with advanced carcinoma were treated through percutaneous implantation of 125 I for interstitial radiotherapy. Results No serious complications occurred in the patients after radiotherapy associated with apparent improved living quality. Two months after therapy, the tumors had shrunk in different degrees with conspicuous decrease in 12, of which 5 tumors disappeared. Conclusions Short-term efficacy demonstrates that intra-tissue radiotherapy of ~(125)I had significant efficacy for advanced tumors.