Immune checkpoint inhibitor related tuberculosis:a case report and literature analysis / 复旦学报（医学版）

With the increasing application of immune checkpoint inhibitors(ICI)in anti-tumor therapy,ICI related infections are often neglected.Mycobacterium tuberculosis(MTB)is also a common pathogen.We reported a case of ICI related pulmonary tuberculosis from Zhongshan Hospital,Fudan University.Meanwhile,18 cases of ICI related tuberculosis infection were collected through literature search,and the characteristics of ICI related tuberculosis were analyzed to improve the understanding in clinic practice.All the cases were confirmed TB including 15 cases of pulmonary tuberculosis(1 case with complication of intestinal tuberculosis)and 4 cases of extra-pulmonary tuberculosis(1 case of disseminated tuberculosis,bone tuberculosis,tuberculous pericarditis and tuberculous pleurisy,respectively).The chest CT characteristics of pulmonary tuberculosis mainly included centrilobular nodules,ground glass nodules,empty lesions,patchy shadows,consolidation and large infiltration.Eighteen cases started anti-tuberculosis treatment,while 4 cases continued ICI treatment.Three cases suspended ICI(2 cases had remission after reuse)and 11 cases stopped ICI,and 1 case was not mentioned.ICI related tuberculosis may be a direct complication of tumor immunotherapy.It is necessary to screen tuberculosis infection and exclude active tuberculosis before immunotherapy.If there are suspected symptoms such as fever,cough and sputum during ICI treatment,active tuberculosis should be taken into account.

Efficacy of intravaginal fractional superpulse CO2 laser in the treatment of mild to moderate female stress urinary incontinence / 现代泌尿外科杂志

【Objective】 To evaluate the efficacy and safety of intravaginal fractional superpulse CO2 laser in the treatment of mild to moderate female stress urinary incontinence (SUI), so as to provide reference for the treatment options for female SUI. 【Methods】 A total of 41 female mild-to-moderate SUI patients confirmed at the Department of Urology, The First Affiliated Hospital, Air Force Medical University, during Aug.2019 and Nov.2020 were involved.All patients received 3 intravaginal fractional superpulse CO2 laser treatments (1/month).The improvement of urinary incontinence symptoms after treatment was evaluated with International Consultation on Incontinent Questionnaire Short Form (ICI-Q-SF).The motion of bladder neck and rotation angle of bladder and urethra were measured with pelvic ultrasound before and after treatment.The therapeutic effects, pain and patients’ satisfaction were evaluated, and adverse reactions such as bleeding, infection and scar were observed. 【Results】 Three months after treatment, urinary incontinence symptoms improved to varying degrees, the ICI-Q-SF score decreased, the motion of bladder neck [ (28.70±3.11) mm vs.(19.10±4.54) mm] and the vesicourethral rotation angle [(52.78°±15.79°) vs.(41.56°±13.24°)] significantly decreased (P<0.05).The total effective rate was 100.0%.No patients complained severe pain during treatment.All patients were satisfied with the treatment.No adverse reactions such as bleeding, infection or scar occurred. 【Conclusion】 Intravaginal fractional superpulse CO2 laser is effective and safe in the treatment of mild to moderate female SUI, but the long-term efficacy still needs further observation.

Immune-related ureteritis/cystitis caused by lung adenocarcinoma treated with combination of sintilimab and bevacizumab: a case report and literature review / 中国肿瘤生物治疗杂志

@#[摘 要] 免疫检查点抑制剂（ICI）延长了晚期癌症患者的生存期，然而随着ICI在抗癌治疗中的广泛应用，却涌现出新的、罕见的免疫相关不良反应（irAE）。本文报道1例由程序性死亡受体-1（PD-1）抑制剂信迪利单抗所致的罕见irAE—免疫性输尿管炎/膀胱炎。患者为55岁肺腺癌（T4N3M1，Ⅳ期），女性，在给予“贝伐珠单抗”联合“信迪利单抗”治疗4个疗程后，出现尿频、尿急、尿痛及肉眼血尿等症状治疗。尿常规显示红细胞和白细胞明显增多，尿液培养和细胞学检查均为阴性，泌尿系统彩超及全程CT显示双侧输尿管全程扩张、管壁增厚、周围多发渗出、膀胱壁增厚、周围多发渗出。经多学科会诊（MDT）及文献检索后，患者被诊断为免疫性输尿管炎/膀胱炎。本文还回顾了文献报道的病例，以阐明其临床特征，为免疫性输尿管炎/膀胱炎的临床早诊断、适当处理及治疗提供有益的帮助。

USH2A mutation and specific driver mutation subtypes are associated with clinical efficacy of immune checkpoint inhibitors in lung cancer / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

This study aimed to identify subtypes of genomic variants associated with the efficacy of immune checkpoint inhibitors (ICIs) by conducting systematic literature search in electronic databases up to May 31, 2021. The main outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and durable clinical benefit (DCB) were correlated with tumor genomic features. A total of 1546 lung cancer patients with available genomic variation data were included from 14 studies. The Kirsten rat sarcoma viral oncogene homolog G12C (KRASG12C) mutation combined with tumor protein P53 (TP53) mutation revealed the promising efficacy of ICI therapy in these patients. Furthermore, patients with epidermal growth factor receptor (EGFR) classical activating mutations (including EGFRL858R and EGFRΔ19) exhibited worse outcomes to ICIs in OS (adjusted hazard ratio (HR), 1.40; 95% confidence interval (CI), 1.01‍‒‍1.95; P=0.0411) and PFS (adjusted HR, 1.98; 95% CI, 1.49‍‒‍2.63; P<0.0001), while classical activating mutations with EGFRT790M showed no difference compared to classical activating mutations without EGFRT790M in OS (adjusted HR, 0.96; 95% CI, 0.48‍‒‍1.94; P=0.9157) or PFS (adjusted HR, 0.72; 95% CI, 0.39‍‒‍1.35; P=0.3050). Of note, for patients harboring the Usher syndrome type-2A(USH2A) missense mutation, correspondingly better outcomes were observed in OS (adjusted HR, 0.52; 95% CI, 0.32‍‒‍0.82; P=0.0077), PFS (adjusted HR, 0.51; 95% CI, 0.38‍‒‍0.69; P<0.0001), DCB (adjusted odds ratio (OR), 4.74; 95% CI, 2.75‍‒‍8.17; P<0.0001), and ORR (adjusted OR, 3.45; 95% CI, 1.88‍‒‍6.33; P<0.0001). Our findings indicated that, USH2A missense mutations and the KRASG12Cmutation combined with TP53 mutation were associated with better efficacy and survival outcomes, but EGFR classical mutations irrespective of combination with EGFRT790M showed the opposite role in the ICI therapy among lung cancer patients. Our findings might guide the selection of precise targets for effective immunotherapy in the clinic.

Discussion on the indications and timing of targeted therapy and immunotherapy before and after liver transplantation for hepatocellular carcinoma / 器官移植

Liver transplantation is one of the main treatments of early hepatocellular carcinoma (HCC). The recurrence of HCC after liver transplantation severely affects the long-term survival rate of the recipients. Targeted therapy and immunotherapy play a critical role in HCC downstaging, preventing disease progression, reducing recurrence rate, prolonging the survival and improving the quality of life. However, no consensus has been reached on the application of targeted therapy and immunotherapy in recipients undergoing liver transplantation for HCC, including indications, timing and dosage. In this article, clinical research progresses on the indications and timing of targeted therapy and immunotherapy before and after liver transplantation for HCC were reviewed, aiming to provide reference for prolonging the survival of recipients after liver transplantation for HCC.

Advance of synergism of immune checkpoint blockade and anti-angiogenesis in cancer treatment / 中国药理学通报

Immune checkpoint inhibitor ( ICI) activates the host' s anti-tumor immune response by blocking negative regulatory immune signals. A series of clinical trials showed that ICI could effectively induce tumor regression in a subset of advanced cancer patients. Anti-angiogenesis drugs commonly used to block tumor angiogenesis can inhibit the growth of tumors, but they cannot improve the survival of patients with limitations in application such as drug resistance. Tumor immune response is closely related to angiogenesis. In turn, tumor angiogenesis highly depends on immunosuppressive microenvironment. Recent studies have indicated that ICI resistance could be alleviated by combination therapy with anti-angiogenesis treatment, and the efficacy of combination therapy was superior to that of monotherapy. The reciprocal regulation between tumor vascular normalization and immune reprogramming forms a reinforcing loop that reconditions the tumor immune microenvironment to induce durable antitumor immunity. This review clarifies the latest understanding of ICI combined anti-angiogenesis therapy and provides ideas for subsequent research.

Immunotherapy of recurrence and metastasis after liver transplantation for liver cancer / 器官移植

Primary liver cancer (liver cancer) is one of the main indications of liver transplantation in China. Nevertheless, the 5-year survival rate of liver transplant recipients is lower than 50%. Recurrence and metastasis after operation are the main causes affecting the long-term survival of the recipients. At present, immunotherapy, represented by programmed cell death protein 1(PD-1)/programmed cell death protein-ligand 1(PD-L1) immune checkpoint inhibitor, has achieved remarkable clinical efficacy in the treatment of middle-stage and advanced liver cancer. However, whether it can be applied in recipients with recurrence and metastasis after liver transplantation for liver cancer remains controversial. The main reason is that it may cause acute rejection at the same time. In this article, the research progresses on the application of immunotherapy in recipients with recurrence and metastasis after liver transplantation for liver cancer were reviewed, aiming to improve the survival rate of recipients undergoing liver transplantation forliver cancer.

Immunotherapy for lung cancer: immunosuppressive cells and intrapulmonary immunity / 上海交通大学学报（医学版）

Immunotherapy is one of the most rapidly developed tumor treatment strategies. Immune checkpoint inhibitors (ICIs) enhance the anti-tumor immune response by inhibiting the inhibitory effect of tumor cells on T cells. At present, antibodies against cytotoxic T-lymphocyte associated protein 4 (CTLA-4), programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) have been approved for clinical therapies. However, those treatments are only effective in the minority of patients. This may be related to the deeper immunosuppression mediated by myeloid-derived suppressor cells (MDSCs) and regulatory cells (Tregs). The microenvironment of the lung affects tumor immunity with its unique physiological function, which can quickly resist pathogens to maintain immune balance in the lung, but also can promote tumor progression. In this paper, the effects of immunosuppressive cells in the treatment of ICIs and the role of them in the lung immune environment are analyzed to explore the strategies to improve the effect of immunotherapy in patients with lung cancer.

Evaluation of I-JS001 for hPD1 immuno-PET imaging using sarcoma cell homografts in humanized mice

JS001 (toripalimab) is a humanized IgG monoclonal antibody which strongly inhibits programmed cell death protein 1 (PD1). In this study, we used a different iodine isotype (I) to label JS001 probes to target the human PD1 (hPD1) antigen. , the half maximal effective concentration (EC) value of I-JS001 did not significantly differ from that of JS001. The uptake of I-JS001 by activated T cells was 5.63 times higher than that by nonactivated T cells after 2 h of incubation. The binding affinity of I-JS001 to T cells of different lineages after phytohemagglutinin (PHA) stimulation reached 4.26 nmol/L. Humanized C57BL/6 mice bearing mouse sarcoma S180 cell tumors were validated for immuno-positron emission tomography (immuno-PET) imaging. Pathological staining was used to assess the expression of PD1 in tumor tissues. The homologous Ihuman IgG (IhIgG) group or blocking group was used as a control group. Immuno-PET imaging showed that the uptake in the tumor area of the I-JS001 group at different time points was significantly higher than that of the blocking group or the I-hIgG group in the humanized mouse model. Taken together, these results suggest that this radiotracer has potential for noninvasive monitoring and directing tumor-specific personalized immunotherapy in PD1-positive tumors.

Effects of estrogen receptor antagonist on the expressions of Erα, Erβ and p57kip2 in JEC cells of human endometrial carcinoma / 临床与实验病理学杂志

Purpose To explore the effects of estrogen receptor antagonist on the expression of estrogen receptor subtype (ERα, ERβ), and p57kip2 protein in human endometrioid carcinoma cells named JEC. Methods The JEC cells (moderately differentiated EC cells) cultured in vitro were treated with β-Estradiol (E2) (10～6 mol/L) and two types of estrogen receptor antagonists, tamoxifen (TAM) and fulvestrant (ICI182780) (10-6 mol/L). After 24, 48, 72 h, MTT was used to detect the growth condition of JEC cells, and the light microscopy and electron microscopy were used to observe the growth condition and morphological changes of cells, Western blot was used to detect the expression of ERα, ERβ, PR-A, PR-B and P57kip2 protein in JEC cells. Results MTT results: Compared with the control group, E2 could promote the proliferation of JEC cells significantly (P＜0.05), and ICI182780 could inhibit the proliferation of JEC cells obviously (P＜0.05). Compared with the E2 group, the proliferation ability of JEC cells in E2 + ICI182780 group were lower(P＜0.05). Morphological change: Compared with the control group, the cells density of E2 group increased obviously, and the pathologic mitosis was easy to seen in some cells. The cells density decreased obviously in ICI182780 group. Compared with E2 group, the cells density of E2 + TAM group and E2 + ICI182780 group were decreased, and pathological mitotic figures were difficult to seen. Western blot results: Compared with the control group, the expression of ERβ protein increased, and the expression of p57kip2 protein decreased in E2 group (P＜0.05). The expression of ERβ protein decreased, and the expression of p57kip2 protein increased in ICI182780 group and TAM group, and the difference was statistically significant between ICI182780 group and control group (P＜0.05). Compared with the E2 group, the expression of ERβ protein decreased, and the expression of p57kip2 protein increased in E2 + ICI182780 group and E2 + TAM group, and the difference was statistically significant between E2 + ICI182780 group and E2 group (P＜0.05). ERa protein of JEC cells did not expressed in experimental group or control group. Conclusion ERa protein are not expressed in JEC cells. ICI182780 have a stronger role in antagonizing estrogen, and may induce the expression of p57kip2 protein by down-regulating the expression of ERβ protein in JEC cells, block the cell cycle progression and inhibit the growth of tumor cells. TAM has a weaker estrogen like effect on the growth of JEC cells. It is possible that combined detection of the expression of ERa and p57kip2 protein in EC has an important reference value for individualized selection of endocrine therapy for EC patients.

Experimental study on the pancreatic cancer G1/S phase arrest byβ2-adrenergic antagonist / 西安交通大学学报(医学版)

Objective To investigate the effects of β2-adrenergic antagonist ICI118 ,551 on pancreatic cancer cell G1/S phase arrest and its action mechanism .Methods The cell cycle indexes were determined by the flow cytometry assay ;the expressions of Cyclin D1 and Cyclin E were analyzed by Western blot ;the activation of NF-κB was measured by electrophoretic mobility shift assay ;the proliferation of PanCa cells was determined by BALB/c athymic nude mice subrenal capsular assay .Results β2-adrenergic antagonist ICI118 ,551 significantly induced G1/S phase arrest compared with β1-adrenergic antagonist metoprolol in MIA PaCa-2 and BxPC-3 cell lines .ICI118 ,551 inhibited the expressions of Cyclin D1 and Cyclin E and reduced the activation of NF-κB .The proliferation of PanCa cells was strongly suppressed in the renal capsule xenografts in mice after ICI 118 ,551 treatment .Conclusion The blockage ofβ2-adrenoceptor markedly induces PanCa cells to arrest at G1/S phase and inhibits the proliferation of pancreatic cancer cells .

Evaluation of the estrogenic effects of Rehmannia glutinosa Libosch / 中国药学杂志

OBJECTIVE: To screen the estrogenic effects of fresh Radix Rehmanniae, dried Radix Rehmanniae, Radix Rehmanniae Praeparata and the leaves of Rehmannia glutinosa Libosch. METHODS: Mouse uterine weight test and MCF-7 cell proliferation assay were used to evaluate the estrogenic effects of the four kinds of Chinese traditional herbs. ICI182, 780 antagonnist assay and reporter gene assay were adopted to explore the mechanism of action of fresh and dried Radix Rehmanniae. In reporter gene assay, HEK293 cells were cotranfected with pERE-TAL-luc, pβgal-Control, pCXN2-hERα or pCXN2-hERβ, and the expression of reportr gene luc was controlled by ERE. RESULTS: Mouse uterine weight test showed that compared with the control group, fresh and dried Radix Rehmanniae could increase the uterus index of premature female mice, and both of them could promote the proliferation of MCF-7 cells. Co-incubation of MCF-7 cells with estrogen receptor blocker ICI182, 780 abolished the inductive effect of the proliferation. The reporter gene controlled by ERE technology showed that when mediated by ERβ, the normalized luciferase activity of the two groups were significantly higher than the activity of the control group. CONCLUSION: Fresh and dried Radix Rehmanniae have estrogenic activities which are mainly mediated by ERβ. Fresh Radix Rehmanniae has higher estrogenic activity than dried Radix Rehmanniae. Radix Rehmanniae Praeparata does not have estrogenic activity. The estrogenic activity may change during the processing process of Rehmannia glutinosa Libosch.

Effect of estrogen on proliferation and migration of human skin fibroblast / 中华医学美学美容杂志

Objective To explore the biological effects of estrogen (17β-E2) on the proliferation and migration of human skin fibroblast (HSFB).Methods HSFBs were isolated and cultured by enzyme digestion.The fourth generation of HSFBs were adopted; (1) the proliferating effect of diverse concentrations of 17β-E2 and 17β-E2+ ICI-182780 on HSFBs was determined with MTT method at 24,48,72,96 h; (2) the influence of 17β-E2 and ICI-182780 to HSFBs cycle distribution were determined with flow cytometry; (3) the migration effect of diverse concentrations of 17β-E2 and 17β-E2+ICI-182780 on HSFBs was determined at 24,48,and 72 hours after the creation of the scratch-wound in vitro.Results (1) The proliferating speed of HSFBs in 10-10mol/L 17β-E2 group (group A)was the highest of all at 48,72,96 h,which was higher than that in ICI-182780+10-10mol/L 17β-E2 group (group B) and control group (group C) (P＜0.01) ;(2) the HSFBs during the S phase in group A was more than that in groups B and C (P＜0.01),while the HSFBs during the G0/G1 phase was less than that in groups B and C (P＜0.01); (3) the migrating effect of HSFBs in 10-8mol/L 17β-E2 group (group D) was the highest of all at 48 h,which was higher than that in ICI-182780+10-10mol/L control group (group E)and control group (group F) (P＜0.01).Conclusions The concentration of 10-10mol/L estrogen has the strongest effect of promoting proliferation and that of 10-8mol/L has the strongest chemotaxis; ICI-182780 can abate the above effect effectively.

Effect of Neutrophil Elastase inhibitor, ICI 200,355, on Interleukin-1 Induced acute lung injury in rats / 영남의대학술지

BACKGROUND: Interleukin-1 (IL-1) and neutrophil appear to contribute to the pathogenesis of acute respiratory distress syndrome (ARDS). Elastase, as well as reactive oxygen species released from activated neutrophil, are thought to play pivotal roles in the experimental models of acute lung leak. This study investigated whether ICI 200,355, a synthetic elastase inhibitor, can attenuate acute lung injury induced by IL-1 in rats. MATERIALS AND METHODS: We intratracheally instilled either saline or IL-1 with and without treatment of ICI 200,355 in rats. Lung lavage neutrophils, lung lavage cytokine-induced neutrophil chemoattractant(CINC) concentration, lung lavage protein concentration, lung myeloperoxidase(MPO) activity and lung leak index were measured at 5 hours of intratracheal treatment. RESULTS: In rats given IL-1 intratracheally, lung lavage neutrophils, lung lavage CINC concentration, lung lavage protein concentration, lung MPO activity and lung leak index were higher. Intratracheal ICI 200,355 administration decreased lung lavage neutrophils, lung MPO activity and lung leak index, respectively, but did not decreased lung lavage CINC concentration. CONCLUSION: These results suggest that ICI 200,355 decreases lung inflammation and leak without decreasing lung lavage CINC concentration in rats given IL-1 intratracheally.

Effect of Neutrophil Elastase inhibitor, ICI 200,355, on Interleukin-1 Induced acute lung injury in rats / 영남의대학술지

BACKGROUND: Interleukin-1 (IL-1) and neutrophil appear to contribute to the pathogenesis of acute respiratory distress syndrome (ARDS). Elastase, as well as reactive oxygen species released from activated neutrophil, are thought to play pivotal roles in the experimental models of acute lung leak. This study investigated whether ICI 200,355, a synthetic elastase inhibitor, can attenuate acute lung injury induced by IL-1 in rats. MATERIALS AND METHODS: We intratracheally instilled either saline or IL-1 with and without treatment of ICI 200,355 in rats. Lung lavage neutrophils, lung lavage cytokine-induced neutrophil chemoattractant(CINC) concentration, lung lavage protein concentration, lung myeloperoxidase(MPO) activity and lung leak index were measured at 5 hours of intratracheal treatment. RESULTS: In rats given IL-1 intratracheally, lung lavage neutrophils, lung lavage CINC concentration, lung lavage protein concentration, lung MPO activity and lung leak index were higher. Intratracheal ICI 200,355 administration decreased lung lavage neutrophils, lung MPO activity and lung leak index, respectively, but did not decreased lung lavage CINC concentration. CONCLUSION: These results suggest that ICI 200,355 decreases lung inflammation and leak without decreasing lung lavage CINC concentration in rats given IL-1 intratracheally.

COMPARISON OF EFFECTS OF DIFFERENT OPIOID ANTAGONISTS ON SCALD SHOCK IN RATS / 中国药理学通报

Indexes of cardiovascular function and survival time were obser-vedin rats given the following antagonists respectively after scald injury: anti-p-endorphin serum at 10?l, Naloxone at 2mg, ICI174864 at 0.2mg, or TRH at 2 mg, and half of the doses were administered at 1, 2, 3h after scald. The results showed that the cardiac indexes (dP/dtmax, -dP/dtmax and LVSP)were improved, the decrease of mean arterial pressure ( MAP ) and heart rate ( HR ) were delayed after the injections of anti-p-endorphin serum, naloxone or ICIi748e4, and survival time was significantly prolonged in anti ? - endorphin serum group. TRH had little effect on cardiac indexes, MAP and HR were maintained at high level at earlier period, but sharply sloped down in about 210 min after burn. The result suggests that intraventri-cular administration of anti-?-endorphin, naloxone or ICI174864 had much benefit on scald shock, but TRH was uncertain at least in the treatment of scald shock.