A 50-year-old male patient diagnosed with extensive stage small cell lung cancer was treated with pamiparib in combination with temozolomide.Five days later,the patient developed fever with fatigue.After 10 days,the patient stopped taking the drug due to worsening symptoms and was diagnosed with chemotherapy-induced myelosuppression(grade 4).The clinicist evaluated the patient's condition and assessed the association of adverse reactions using the Naranjo's evaluation scale,and concluded that myelosuppression may be induced by the combination of pamiparib and temozolomide.After symptomatic treatment,the patient's myelosuppression recovered completely.This article discusses the correlation between myelosuppression and the combination of the two drugs,provides treatment measures for this situation,briefly describes the risk factors of myelosuppression,treatment and prevention,and guides medical personnel to adjust the treatment plan in time according to different individuals in the process of using similar programs,and strengthens the monitoring and education of adverse drug reactions,so as to provide references for safe drug use.

The treatment of bone defects caused by fractures or bone tissue lesions has always been a difficult problem in the field of orthopedics.Implantation of high-performance titanium alloy prosthesis is an effective method to treat bone defects.3D printing technology can produce low-modulus titanium alloy implants with porous structures,providing a better solution to the above problems.This technology is convenient to design and has a huge advantage in making orthopedic implants.The article used electron beam melting in 3D printing technology to create two samples of Ti-6Al-4V prosthesis,including solid structural pelvic prosthesis and porous structural pelvic prosthesis.The mechanical properties of the prosthesis showed that the yield and tensile strengths of the rod tensile specimen were 894 MPa and 956 MPa,respectively,and the compressive modulus and compressive strength of the porous pelvic prosthesis were 55 GPa and 65.2 MPa,respectively.The results of the L929 cytotoxicity assay and the MC3T3-E1 cell adhesion assay demonstrated good biocompatibility of the prosthetic samples.New Zealand white rabbits were used to prepare the femoral joint cavity defect models and two pelvic prostheses were implanted.A microscopic CT scan 4 weeks after implantation showed that the bone defect caused by the drill had healed and that the porous structure of the pelvic prosthesis formed a new trabecular structure within the hole.In conclusion,the 3D printed Ti-6Al-4V pelvic prosthesis has excellent mechanical properties,biocompatibility,and the ability to promote new bone growth.

Abdominal aortic aneurysm (AAA) is a life-threatening disease associated with chronic inflammation in the vascular wall while its specific pathogenesis is not fully understood. Recently, a growing number of studies have indicated that pyroptosis, which is a pro-inflammatory kind of programmed cell death might play a vital role in AAA. In this review, we first summarize the role of pyroptosis in AAA progression by not only providing a literature review on the expression changes of NLRP3 inflammasome components and effector mediators in clinical and experimental AAAs, but also discussing the effects of genetic defects or pharmacological inhibition of NLRP3 inflammasome components on experimental AAAs. Next, we introduce the mechanism of canonical and non-canonical pathway of pyroptosis and its activation and execution process. Finally, we discuss several pyroptosis-related drug targets for treating AAA by inhibiting the assembly of NLRP3 inflammasome and its effector mediators. In conclusion, we believe that pyroptosis might be a new treatment target of AAA.

Pancreatic cancer is a kind of digestive system tumor with insidious clinical manifestations,rapid development and very poor prognosis,and its early diagnosis and surgical treatment can significantly improve the survival rate and prognosis of patients.So far,no tumor marker with sufficient sensitivity and specificity for early pancreatic cancer has been found for tumor screening.In recent years,more and more pancreatic canc-er-related tumor markers have been discovered and studied.Liquid biopsy has shown potential utility in a range of applications,with the advantages of non-invasive,non-destructive,real-time,multiple,and has broad prospects in many aspects of tumor diagnosis and treatment.This article discusses and summarizes the screen-ing and early diagnosis of circulating tumor cells and circulating tumor DNA in liquid biopsy,so as to provide reference for early detection and early treatment of pancreatic cancer.

Metformin is currently a strong candidate anti-tumor agent in multiple cancers. However, its anti-tumor effectiveness varies among different cancers or subpopulations, potentially due to tumor heterogeneity. It thus remains unclear which hepatocellular carcinoma (HCC) patient subpopulation(s) can benefit from metformin treatment. Here, through a genome-wide CRISPR-Cas9-based knockout screen, we find that DOCK1 levels determine the anti-tumor effects of metformin and that DOCK1 is a synthetic lethal target of metformin in HCC. Mechanistically, metformin promotes DOCK1 phosphorylation, which activates RAC1 to facilitate cell survival, leading to metformin resistance. The DOCK1-selective inhibitor, TBOPP, potentiates anti-tumor activity by metformin in vitro in liver cancer cell lines and patient-derived HCC organoids, and in vivo in xenografted liver cancer cells and immunocompetent mouse liver cancer models. Notably, metformin improves overall survival of HCC patients with low DOCK1 levels but not among patients with high DOCK1 expression. This study shows that metformin effectiveness depends on DOCK1 levels and that combining metformin with DOCK1 inhibition may provide a promising personalized therapeutic strategy for metformin-resistant HCC patients.
Animals ; Antineoplastic Agents/therapeutic use* ; Carcinoma, Hepatocellular/metabolism* ; Cell Line, Tumor ; Clustered Regularly Interspaced Short Palindromic Repeats ; Genome ; Humans ; Liver Neoplasms/metabolism* ; Metformin/therapeutic use* ; Mice ; Phosphorylation ; Synthetic Lethal Mutations ; Transcription Factors/metabolism* ; rac GTP-Binding Proteins/metabolism*

Objective:To investigate the effect of IKKε on autophagy during abdominal aortic aneurysm formation in mice.Methods:We stimulated ApoE -/- mice and ApoE -/-IKKε -/- mice with AngⅡ and saline for 28 days. Metaboilic levels and aortic diameter of ApoE -/- mice and ApoE -/-IKKε -/- mice were measured. The arterial fibrosis of mice was detected by Masson staining and HE staining, mitochondrial reactive oxides were detected by fluorescence assay, the expression levels of autophagy factors LC3B and Beclin-1 were detected by immunohistochemistry, and the protein level of LC3B was detected by Western blot. Results:There was no significant difference in metaboilic levels between ApoE -/- mice and ApoE -/- IKKε -/- mice. However, the aortic diameterf ApoE -/-IKKε -/- mice was significantly less than that of ApoE -/- mice. The fibrosis level of ApoE -/-IKKε -/- mice was significantly lower than that of ApoE -/- mice. Furthermore, ROS in ApoE -/-IKKε -/- mice was lower than that in ApoE -/- mice. In addition, immunohistochemical and western blot showed that the expression levels of LC3B and Beclin-1 in ApoE -/-IKKε -/- mice were significantly lower than in ApoE -/- mice. Conclusion:IKKε -/- deficiency can significantly inhibit autophagy, thus reducing the development of abdominal aortic aneurysm in mice.

Objective:To evaluate the long-term health-related quality of life (QOL) in pediatric patients with acute leukemia after hematopoietic stem cell transplantation (HSCT) and to analyze potential influence factors.Methods:Patients with acute leukemia aging 8-18 years who received HSCT in the Hematology Oncology Center of Beijing Children′s Hospital from June 2009 to June 2012 with more than 80 months survival postoperatively were recruited.All of them were subjected to a short-term QOL survey in 2013.PedsQL? Transplantation Module 3.0 in Chinese mandarin version was completed.QOL data and influence factors were analyzed.Results:Forty-one patients completed the questionnaires, involving 32 males and 9 females with the mean age of(14.29±2.72) years.The mean scores of overall long-term QOL after HSCT were above 75 (total scores: 100), which was above the average.The age, disease status before transplantation, donor sources, post-transplant complications and the parental education level were the influential factors for the long-term QOL in pediatric patients with acute leukemia at post-HSCT, which could affect a certain dimension in QOL.Conclusions:The overall long-term QOL of pediatric patients with acute leukemia who survived for more than 80 months at post-HSCT is acceptable, which is significantly better than the short-term QOL after 4 months of HSCT.The age, disease status before transplantation, donor sources, post-transplant complications and the education level of parents could affect a certain dimension of QOL.

Objective To retrospectively analyze the clinical efficacy,safety and influencing factors of radiotherapy in children with stage Ⅳ high-risk neuroblastoma (HR-NB).Methods A total of 120 children with HR-NB who were diagnosed and treated with local radiotherapy according to the BCH-HR-NB-2007 protocol in the Oncology Department of Beijing Children's Hospital from January 2014 to December 2017 were enrolled.Among them,56 children were male and 64 female with a median age of 43 months (9 -148 months).The treatment protocol consisted of 4 cycles of CAV chemotherapy,3 cycles of CVP chemotherapy,surgical resection after 4 cycles,autologous hematopoietic stem cell transplantation after 7 cycles,local radiotherapy at a dose of 15.0-30.6 Gy for 82 cases of primary tumors and 38 cases of primary and metastatic tumors,followed by 13 cis-retinoic acid as maintenance therapy.The entire treatment protocol endured for approximately 18 months.Results The median follow-up time was 21 months.The 3-year local control rate was 84.4％.Before radiotherapy,the 3-year event-free survival rate was 78.4％ in children without metastases,significantly higher compared with 30.4％ in the residual group (P=0.003).The 3-year event-free survival rate was 66.1％ in patients who underwent radiotherapy within 6 months after surgery,significantly higher than 50.6％ in their counterparts receiving radiotherapy at 6 months or more after surgery (P=0.018).Among the children with residual metastases before radiotherapy,the progression rate in children who did not receive radiotherapy was 66.6％,significantly higher compared with 20.0％ in those receiving radiotherapy (P=0.001).All patients had no radiation-related adverse reactions in the liver,kidney and heart,etc.The incidence rate of grade Ⅲ-Ⅳ myelosupression was 24.5％ at 1 week post-radiotherapy,and 8％ at 2 weeks after radiotherapy.Conclusions Radiotherapy yields definite clinical efficacy in the local control of children with stage Ⅳ HR-NB.Early radiotherapy after surgery and radiotherapy for the metastatic lesions can improve the clinical prognosis.No vital organ injuries are observed during the short-term follow-up.At 2 weeks after radiotherapy,the myelosupression is gradually restored.

PURPOSE: Immune suppression is common in patients with advanced breast cancer but the mechanisms underlying this phenomenon have not been sufficiently studied. In this study, we aimed to identify B7 family members that were able to predict the immune status of patients, and which may serve as potential targets for the treatment of breast cancer. We also aimed to identify microRNAs that may regulate the expression of B7 family members. METHODS: The Cancer Genome Atlas data from 1,092 patients with breast cancer, including gene expression, microRNA expression and survival data, were used for statistical and survival analyses. Polymerase chain reaction and Western blot were used to measure messenger RNA and protein expression, respectively. Luciferase assay was used to investigate direct microRNA target. RESULTS: Bioinformatic analysis predicted that microRNA (miR)-93, miR-195, miR-497, and miR-340 are potential regulators of the immune evasion of breast cancer cells, and that they exert this function by targeting CD274, PDCD1LG2, and NCR3LG1. We chose CD274 for further investigations. We found that miR-195, miR-497, and CD274 expression levels were inversely correlated in MDA-MB-231 cells, and miR-195 and miR-497 expressions mimic inhibited CD274 expression in vitro. Mechanistic investigations demonstrated that miR-195 and miR-497 directly target CD274 3′ untranslated region. CONCLUSION: Our data indicated that the level of B7 family members can predict the prognosis of breast cancer patients, and miR-195/miR-497 regulate CD274 expression in triple negative breast cancer. This regulation may further influence tumor progression and the immune tolerance mechanism in breast cancer and may be able to predict the effect of immunotherapy on patients.
Antigens, CD274 ; B7 Antigens ; Blotting, Western ; Breast Neoplasms ; Computational Biology ; Gene Expression ; Genome ; Humans ; Immune Evasion ; Immune Tolerance ; Immunotherapy ; In Vitro Techniques ; Ligands* ; Luciferases ; MicroRNAs ; Polymerase Chain Reaction ; Prognosis ; RNA, Messenger ; Triple Negative Breast Neoplasms* ; Untranslated Regions

Background: Anti-programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) immunotherapy has been proved to be effective on gastric cancer in ongoing clinical trials. However, the value of PD-L1 in predicting responses of patients with gastric cancer to anti-PD-1/PD-L1 immunotherapy is controversial. Some studies suggested that intra- and inter-tumoral heterogeneity of PD-L1 expression might explain the controversy. This study aimed to analyze the expression of PD-L1, PD-L2, and PD-1 as well as CD8(+) T-cell density in primary tumors and lymph nodes from patients with stage T1-4N+M0 gastric adenocarcinoma to explore the heterogeneity of PD-1 signaling pathway molecules. Methods: In primary tumors and metastatic as well as non-metastatic lymph nodes from patients with stage T1-4N+M0 gastric adenocarcinoma, we detected PD-L1 and PD-L2 expression with immunohistochemistry. CD8(+) T-cell density in primary tumors and PD-1 expression on CD8(+) T cells were detected with immunofluorescence. Uni-variate analysis was used to determine the prognostic values of them. Cox proportional hazard regression model was used to identify independent risk factors that affect patients' overall survival and disease-free survival. Results: Among 119 eligible patients who had undergone surgical resection, the positive rate of PD-L1 was higher in metastatic lymph nodes than in primary tumors (45.4％ vs. 38.7％,P= 0.005); the positive rate of PD-1 on CD8(+) T cells was significantly higher in primary tumors and metastatic lymph nodes than in tumor-free lymph nodes (both P < 0.001). The intensity of PD-1 expression on CD8(+) T cells in primary tumors and in metastatic lymph nodes were stronger than that in tumor-free lymph nodes from the same patient. Beside, the positive rate of PD-L2 did not show any differences between primary tumors and metastatic lymph nodes. In multivariate analysis, PD-L1 expression, PD-L2 expression, a low density of CD8(+) T cells in primary tumors, and PD-1 expression on CD8(+) T cells in primary tumors were associated with poor prognosis.Conclusion: The expression of PD-L1 is heterogeneous in primary tumors and in metastatic lymph nodes from patients with stage T1-4N+M0 gastric adenocarcinoma, which might explain the inconsistent results in assessing the prognostic value of PD-L1 expression in previous studies.