Análise de impacto orçamentário dos inibidores da PARP no tratamento do carcinoma de ovário avançado a partir de evidências de mundo real sob a perspectiva de um hospital federal referência em oncologia / Budget impact analysis of PARP inhibitors in the treatment of advanced ovarian cancer from on real-world evidence the perspective of a federal hospital reference in oncology

Objetivo: Avaliar o impacto orçamentário do tratamento com iPARP como primeira linha de manutenção, comparado ao tratamento-padrão a partir de evidências de mundo real sob a perspectiva de um hospital público referência em oncologia no Rio de Janeiro. Métodos: Foi aplicada uma análise de impacto orçamentário para estimar a introdução das tecnologias iPARP, olaparibe e niraparibe, em comparação com o cenário referência, utilizando dados de eficácia e evidências de mundo real, e considerando os custos globais de tratamento da doença em cinco anos. Este estudo foi aprovado pelo Comitê de Ética em Pesquisa, CAAE: 95157018.9.0000.5274. Resultados: A análise demonstrou que o cenário referência apresentou um impacto orçamentário no valor de R$ 3.578.768,04 em cinco anos. No cenário alternativo, o custo incremental do olaparibe chegou a ser 23,8% maior, comparado ao niraparibe, atingindo um custo de R$ 23.736.459,20 versus R$ 18.076.951,81, respectivamente. Os parâmetros que apresentaram maior impacto nas análises para a tecnologia olaparibe foram a difusão da tecnologia e o preço do medicamento. Contudo, para o niraparibe, os parâmetros de maior impacto foram a duração do tratamento, a difusão da tecnologia e a dose utilizada, demonstrando maior suscetibilidade de variação. Conclusão: Os iPARP no tratamento de pacientes com carcinoma de ovário avançado, apesar de apresentarem custo incremental de aproximadamente R$ 23 milhões em cinco anos, apontam para uma potencial redução de custos associados à progressão da doença.

Objective: Assess the budgetary impact of treatment with iPARP as a first line of maintenance, compared to standard treatment based on real-world evidence from the perspective of a public hospital reference in oncology at Rio de Janeiro. Methods: A budget impact analysis was applied to estimate the introduction of iPARP, olaparib and niraparib technologies, compared to the reference scenario, using efficacy data and real-world evidence, and considering the global costs of treating the disease in five years. This study was approved by the Research Ethics Committee, CAAE: 95157018.9.0000.5274. Results: The analysis showed that the reference scenario presented a budgetary impact of R$ 3,578,768.04 in five years. In the alternative scenario, the incremental cost of olaparib reached 23.8% higher compared to niraparib, reaching a cost of R$ 23,736,459.20 versus R$ 18,076,951.81, respectively. The parameters that had the greatest impact on the analyzes for the olaparib technology were technology diffusion and drug price. However, for niraparib, the parameters with the greatest impact were the duration of treatment, the diffusion of the technology and the dose used, demonstrating greater susceptibility to variation. Conclusion: iPARP in the treatment of patients with advanced ovarian carcinoma, despite having an incremental cost of approximately R$ 23 million in five years, point to a potential reduction in costs associated with disease progression.

Progress of PARP inhibitors in targeted therapy of small cell lung cancer / 国际肿瘤学杂志

Small cell lung cancer (SCLC) is a rapidly developing malignant tumor, which is highly heterogeneous and prone to drug resistance, and the prognosis is usually poor. Poly ADP-ribose polymerase (PARP) inhibitors target the DNA damage response pathway, preventing DNA repair, thereby exerting anti-tumor effects. Currently, PARP inhibitors are used as monotherapy or in combination with DNA-damaging agents or immune checkpoint inhibitors in the treatment of SCLC. Although the current research results are limited, it can be seen that PARP inhibitors may be a breakthrough in the targeted therapy of SCLC.

Guidance on the management of adverse reactions induced by poly(ADP-ribose) polymerase inhibitors / 浙江大学学报·医学版

The common adverse reactions caused by poly (ADP-ribose) polymerase (PARP) inhibitors include hematological toxicity, gastrointestinal toxicity and fatigue. The main prevention and treatment of hematological toxicity include: regular blood tests, referral to hematology department when routine treatment is ineffective, and being alert of myelodysplastic syndrome/acute myeloid leukemia. The key points to deal with gastrointestinal toxicity include: taking medicine at the right time, light diet, appropriate amount of drinking water, timely symptomatic treatment, prevention of expected nausea and vomiting, and so on. For fatigue, full assessment should be completed before treatment because the causes of fatigue are various; the management includes massage therapy, psychosocial interventions and drugs such as methylphenidate and Panax quinquefolius according to the severity. In addition, niraparib and fluzoparib can cause hypertension, hypertensive crisis and palpitation. Blood pressure and heart rate monitoring, timely symptomatic treatment, and multidisciplinary consultation should be taken if necessary. When cough and dyspnea occur, high resolution CT and bronchoscopy should be performed to exclude pneumonia. If necessary, PARP inhibitors should be stopped, and glucocorticoid and antimicrobial therapy should be given. Finally, more attention should be paid to drug interaction management, patient self-management and regular monitoring to minimize the risk and harm of adverse reactions of PARP inhibitors.

Chinese expert consensus on drug interaction management of poly ADP-ribose polymerase inhibitors / 中华肿瘤杂志

Poly ADP-ribose polymerase inhibitors (PARPi), which approved in recent years, are recommended for ovarian cancer, breast cancer, pancreatic cancer, prostate cancer and other cancers by The National Comprehensive Cancer Network (NCCN) and Chinese Society of Clinical Oncology (CSCO) guidelines. Because most of PARPi are metabolized by cytochrome P450 enzyme system, there are extensive interactions with other drugs commonly used in cancer patients. By setting up a consensus working group including pharmaceutical experts, clinical experts and methodology experts, this paper forms a consensus according to the following steps: determine clinical problems, data retrieval and evaluation, Delphi method to form recommendations, finally formation expert opinion on PARPi interaction management. This paper will provide practical reference for clinical medical staff.

Research progress on treatment strategies for related diseases based on Parthanatos / 中国生物制品学杂志

@#Parthanatos is a form of programmed cell death,which is also known as poly(ADP-ribose)polymerase 1(PARP1)-mediated apoptosis-inducing factor(AIF)and macrophage migration inhibitory factor(MIF)-dependent cell death according to its molecular mechanism. Parthanatos is the main cause of a variety of neurodegenerative diseases,such as Parkinson's disease(PD),Alzheimer's disease(AD),motor neuron disease,and is also involved in the pathogenesis of some tumors,such as lung cancer and breast cancer. Therefore,a thorough understanding of the molecular mechanism of Parthanatos is crucial for the therapeutic strategies of related diseases. In recent years,studies have found that effective regulation of the occurrence of Parthanatos by regulating the key proteins PARP1,AIF and MIF is expected to become a therapeutic target for many diseases. Based on the specific molecular mechanism of Parthanatos,this paper reviewed the research progress of therapeutic strategies for related diseases from the aspects of inhibiting and promoting Parthanatos.

Progress of poly (ADP-ribose) polymerase inhibitor in advanced ovarian cancer / 肿瘤研究与临床

At present, ovarian cancer is one of the main diseases threatening women's life and health. The mortality ranks first among female reproductive system malignant tumors. Due to the hidden onset, more than 75% of them are at advanced stage once diagnosed. Advanced ovarian cancer is characterized with the Federation International of Gynecology and Obstetrics (FIGO) stage Ⅲ-Ⅳ, very poor prognosis and the 5-year survival rate less than 50%. In recent years, the exploration of maintenance treatment of ovarian cancer is in full swing. A large number of studies show that poly (ADP-ribose) polymerase (PARP) inhibitors are effective in patients with advanced ovarian cancer. Therefore, PARP inhibitors have gradually become an important part for treatment of ovarian cancer, and the indications have also been concerned by clinicians. This paper reviews the application of PARP inhibitors in advanced ovarian cancer.

Research progress on the efficacy and safety of PARP inhibitors in mCRPC / 中华泌尿外科杂志

Poly ADP-ribose polymerase (PARP) inhibitors are novel agents for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in recent years, and a variety of PARP inhibitors have been reported with clinical evidence for the beneficial. Although these drugs are actually of attributes with pharmacological similarities, due to the discrepancies in the molecular structure and pharmacodynamics, the respective efficacy and safety from clinical circumstances are quite varied. While it comes to the best clinical determination, the optimization for regimen is important on the basis of clinical exhaustiveness for the reports, in addition the laboratory examination for mCRPC, and either the tumorous genetic benchmark are necessarily being calculated.

Effects of niraparib on the radiosensitivity of human esophageal cancer cells and its mechanism / 中华放射肿瘤学杂志

Objective:To evaluate the effect of niraparib, the poly (ADP-ribose) polymerase (PARP) inhibitor, on the radiosensitivity of esophageal squamous cell carcinoma (ESCC) and to preliminarily investigate its mechanism.Methods:Human esophageal squamous cell carcinoma cells ECA-109 and KYSE-150 were divided into the control, niraparib, single irradiation, combined (niraparib+irradiation) groups. Cell proliferation was measured by CCK-8 assay. The changes of cell survival rate were detected by colony formation assay. The changes of cell cycle and apoptosis were analyzed by flow cytometry. The number of γH2AX foci was detected by immunofluorescence, and the expression levels of PARP-1, cleaved-PARP, RAD51, mitogen-activated protein kinase (MAPK) [extracellular signal-regulated kinase 1 and 2 (ERK1/2) ] and p-MAPK (ERK1/2) proteins were determined by Western blot. All data were expressed as Mean±SD. Data between two groups conforming to normal distribution through the normality test were subject to independent sample t-test and multiple groups were analyzed using one-way ANOVA. Results:In human ESCC cells ECA-109 and KYSE-150, the proliferation of ESCC cells was significantly inhibited by niraparib combined with irradiation, and the values of average lethal dose (D 0), quasi-threshould dose(D q), survival fraction after 2 Gy irradiation (SF 2) in the combined group were decreased compared with those in the single irradiation group. The effect of irradiation alone on apoptosis of ECA-109 and KYSE-150 cells was limited. Compared to single irradiation group, irradiation combined with niraparib further increased the apoptosis rate in ESCC cells ( P=0.015, P=0.006). In ECA-109 cells, G 2/M phase arrest was significantly increased in combined group compared with irradiation alone group ( P<0.001). In ECA-109 cells, the number of γH2AX foci in combined group was higher than that in the single irradiation group after 2 h, and showed a significantly slower decay of γH2AX foci ( P<0.001). Moreover, niraparib combined with irradiation enhanced the radiation-induced cleavage of PARP-1 and down-regulated the expression of Rad51 and p-MAPK(ERK1/2). Conclusion:Niraparib can increase the radiosensitivity of esophageal cancer cells by inhibiting cell proliferation, promoting cell apoptosis, inhibiting the repair of DNA damage and regulating the MARK-ERK signaling pathway.

Research progress on the involvement of poly (ADP-ribose) polymerase-1-dependent cell death in ischemia-reperfusion injury / 中国医师杂志

Ischemia reperfusion injury (IRI) of organs is a major challenge for clinicians, but the mechanism is still not elucidated, and the clinical treatment effect is still unsatisfactory. PARP-1-dependent cell death (parthanatos) is a non-apototic programmed cell death pathway involved in the development of the occurrence of IRI of organs. At the same time, parthanatos is also a multi-step pathway. There are many molecules in the parthanatos cascade that can be exploited to create therapeutic interventions for IRI, including PARP1, apoptosis inducing factor (AIF), and macrophage migration inhibitory factor (MIF). These critical molecules are involved in DNA damage, energy depletion and homeostasis imbalance. Therefore, these molecular signals in the parthanatos cascade represent promising therapeutic targets for the treatment of IRI. In the following, we will elaborate on the mechanisms and molecular characteristics of the parthanatos pathway and the relation between parthanatos pathway and IRI of vital organs. It aims to explore the posibility of IRI mechanism research and clinical treatment and to provide new ideas for clinicians and researchers.

Real-world clinical data analysis of PARPi as first-line maintenance therapy in newly diagnosed epithelial ovarian cancer patients / 中华妇产科杂志

Objective:The real-world clinical data of patients with newly diagnosed ovarian cancer (including fallopian tube cancer and primary peritoneal cancer) who received first-line maintenance therapy with poly adenosine diphosphate ribose polymerase inhibitor (PARPi) were retrospectively analyzed, and the prognostic factors were preliminarily explored.Methods:(1) The clinicopathological data and follow-up data of ovarian cancer patients treated with PARPi first-line maintenance therapy from August 2018 (PARPi was launched in China) to December 31, 2021 in Sichuan Cancer Hospital were collected (real-world clinical data). (2) According to the different types of PARPi, real-world clinical data were divided into olaparib group and niraparib group, which were respectively compared with the inclusion and exclusion criteria of representative domestic and foreign phase Ⅲ randomized controlled trials (RCT), including olaparib as first-line maintenance therapy for advanced ovarian cancer patients with BRCA1/2 gene mutation (SOLO-1 study), niraparib as first-line maintenance therapy (PRIMA study), and niraparib as first-line maintenance therapy for Chinese advanced ovarian cancer patients (PRIME study). (3) The prognosis of the two groups and the prognostic factors were analyzed.Results:(1) A total of 83 patients were included in this study, with a median age of 51 years (47-57 years), including 75 cases of ovarian cancer, 5 cases of fallopian tube cancer, and 3 cases of primary peritoneal cancer; 5 cases of stage Ⅰ, 9 cases of stage Ⅱ, 55 cases of stage Ⅲ, 12 cases of stage Ⅳ, and 2 cases of unknown stage; neoadjuvant chemotherapy (NACT) was performed in 40 cases and non-NACT in 43 cases; 62 cases had no visible residual lesion after surgery (R0), 9 cases had residual disease lesions <1 cm (R1), 8 cases had residual disease lesions ≥1 cm (R2), and 4 cases with unknown postoperative residual disease. Thirty-two cases had PARPi treatment interruption, 40 cases had PARPi reduction, and 1 case terminated treatment due to acute leukemia. Of the 83 patients, 35 were in the olaparib group and 48 were in the niraparib group. The proportion of patients with high-grade serous carcinoma (100% and 75%, respectively) and the proportion of BRCA mutant patients (91% and 10%, respectively) in the olaparib group were higher than those in the niraparib group (all P<0.01). (2) Compared with the inclusion and exclusion criteria of the SOLO-1 study, the olaparib group had only 60% (21/35) coincidence rate; compared with the inclusion and exclusion criteria of PRIMA and PRIME studies, the coincidence rates of niraparib group were only 31% (15/48) and 69% (33/48). The most common reasons for non-compliance were number of chemotherapy courses, histopathological type, and surgical pathological stage. (3) Of the 83 cases received first-line maintenance therapy with PARPi, the median follow-up was 15.9 months (11.3-22.9 months), the median progression-free survival (PFS) was 29.7 months (95% CI: 25.9-33.6 months), and the median overall survival was 49.8 months (95% CI: 47.4-52.2 months). Univariate analysis showed that unilateral or bilateral ovarian cancer, efficacy after platinum-containing chemotherapy, presence or absence of measurable lesions at the end of chemotherapy, and total number of chemotherapy courses were significantly associated with PFS (all P<0.05). Multivariate analysis showed that unilateral or bilateral ovarian cancer, total number of chemotherapy courses, and efficacy after platinum-containing chemotherapy were independent factors affecting PFS in stage Ⅱ-Ⅳ patients with PARPi first-line maintenance therapy (all P<0.05). Conclusions:Unilateral ovarian cancer, the total number of chemotherapy courses no more than 9, and achieving complete response after platinum-containing chemotherapy before maintenance therapy are independent influencing factors of PFS benefit in patients with PARPi first-line maintenance therapy. Due to the large differences between the patients in real clinical practice and the research subjects of phase Ⅲ RCT, the results of representative retrospective studies still have important clinical reference significance.

Expression level and clinical significance of PARP14 in thyroid carcinoma / 国际生物医学工程杂志

Objective:To investigate the expression level of poly ADP ribose polymerase 14(PARP14) in thyroid cancer and its relationship with the clinicopathologic characteristics of the patient with thyroid cancer and evaluate the role of PARP14 in the progression of thyroid cancer.Methods:The gene expression interaction analysis (GEPIA) database was used to analyze the expression of PARP14 in normal thyroid tissue and thyroid cancer tissue and its relationship with disease-free survival of patients. The expression of PARP14 in thyroid cancer tissue and adjacent tissues of the patient with thyroid cancer was evaluated by immunohistochemistry. According to the staining intensity, the patients were divided into the high expression group and the low expression group, and the correlation between the expression of PARP14 and clinical pathological characteristics was analyzed. The effect of PARP14 on the proliferation of thyroid cancer cells was investigated by clone formation testing and MTT testing.Results:The results of bioinformatics analysis and immunohistochemistry showed that PARP14 was overexpressed in thyroid cancer tissue, and the disease-free survival rate of the patient with high expression was lower. The expression level of PARP14 was correlated with tumor stage and intrathyroidal spread (all P<0.05). The results of the clonogenic assay and the MTT assay showed that the expression of KIF4A could promote the proliferation of thyroid cancer cells ( P<0.05). Conclusions:PARP14 is highly expressed in thyroid cancer and is related to the clinicopathological characteristics of patients, suggesting that it may be a therapeutic target for thyroid cancer.

Review of 2022 ASCO-GU prostate cancer milestone studies / 中华泌尿外科杂志

Prostate cancer is one of the most common malignancies in older men. Prostate cancer patients with distant metastasis often have a poor prognosis, and more than half of Chinese prostate cancer patients have developed distant metastasis at the time of initial diagnosis. In recent years, with the disclosure of the results of a number of global multi-center clinical trials, combination therapy and precision therapy have become two major themes in the treatment of metastatic prostate cancer (mPCa). The American Society of Clinical Oncology Genitourinary (ASCO-GU) Cancers Symposium is a grand meeting of the urologic oncology community. Several research advances reported at the meeting will help to update the treatment strategy of mPCa. This article interprets and comments on a number of milestone studies on mPCa treatment at the ASCO-GU 2022 annual meeting, with a view to providing help for the clinical treatment decisions of mPCa patients.

The progress on sensitivity of PARPi and platinum in mCRPC with DNA damage repair gene mutation / 中华泌尿外科杂志

DNA damage repair (DDR) defects occurred in 8%-16% of metastatic castration resistant prostate cancer (mCRPC). DDR gene mutation was related to poorer prognosis. Patients with DDR gene mutation, especially BRCA1/2 mutation, showed high sensitivity to poly ADP-ribose polymerase inhibitor (PARPi) and platinum.

Expression of DNA damage-binding protein 1 in hepatocellular carcinoma tissues and its effect on homologous recombination repair and targeted killing in SMMC-7721 cells / 肿瘤研究与临床

Objective:To investigate the expression of DNA damage repair factor DNA damage-binding protein 1 (DDB1) in hepatocellular carcinoma tissues, and the effect of DDB1 gene silencing on DNA repair and targeted killing in human hepatocellular carcinoma SMMC-7721 cells.Methods:The UALCAN platform was used to perform bioinformatics analysis on the expression of DDB1 in hepatocellular carcinoma tissues (371 cases) and paracancerous tissues (50 cases) in The Cancer Genome Atlas (TCGA) database and the correlation of DDB1 expression with the overall survival of liver cancer patients were analyzed by bioinformatics using the UALCAN platform. SMMC-7721 cells were transfected with small interfering RNA (siRNA) targeting DDB1 and negative control siRNA, which were DDB1 silencing group and negative control group, respectively. X-ray irradiation induced exogenous DNA double strand break (DSB) damage in the two groups of cells. Immunofluorescence staining (γH2AX was used for assessing cellular DSB damage, RPA32s33 and Rad51 were used for assessing homologous recombination repair) and Western blotting (were used to detect the level of RPA32s33 protein) were used to analyze the effect of DDB1 gene silencing on DSB damage repair. Sister chromosome exchange (SCE) experiment was used to analyze the frequency of SCE of homologous recombination of cells in DDB1 silencing group and negative control group. Tetramethylazozolium salt (MTT) method was used to analyze the killing effect of PARP inhibitor olapani (10 μmol/L), cisplatin (1 μg/ml) and olapani combined with cisplatin on SMMC-7721 cells in DDB1 silencing group and negative control group.Results:Bioinformatics analysis showed that the level of DDB1 mRNA in liver cancer tissues was higher than that in paracancerous tissues ( P < 0.001), and the overall survival of patients with high expression of DDB1 was worse than that of patients with low expression of DDB1 ( P = 0.029). When cultured for 4 hours after X-ray irradiation, the number of γH2AX foci in cells of the negative control group had mostly disappeared, and there were still more cells in DDB1 silencing group [(5.1±2.0) per cell vs. (13.4±2.0) per cell, t = -5.08, P = 0.007]. When cultured for 4 hours after X-ray irradiation, the number of RPA32s33 foci in the negative control group [(30.8±5.0) per cell vs. (13.2±1.6) per cell] and the number of Rad51 foci [(19.5±1.8) per cell vs. (8.3±3.3) per cell] were higher than those in the DDB1 silencing group, and the differences between the two groups were statistically significant (both P < 0.01). The frequency of SCE in the negative control group was higher than that in the DDB1 silencing group [(21.2±3.0)% vs. (11.2±1.6)%, t = 5.07, P = 0.007]. MTT assay showed that after olaparib treatment, the survival rate of cells in the DDB1 silencing group was lower than that in the negative control group [(40.3±3.6)% vs. (79.8±1.3)%, t = 17.94, P < 0.001]. When treated with olapani combined with cisplatin, the survival rate of cells in the two groups further decreased, and the survival rate of cells in the DDB1 silencing group was lower than that in the negative control group [(10.2±2.8)% vs. (29.6±3.4)%, t = 7.72, P = 0.002]. When treated with cisplatin alone, there was no significant difference in cell survival between DDB1 silencing group and negative control group [(41.9±5.1)% vs. (49.8±3.3)%, t = 2.71, P = 0.054]. Conclusions:The high expression of DDB1 in hepatocellular carcinoma tissues may be an important factor in the treatment resistance and poor prognosis of hepatocellular carcinoma. Knockdown of DDB1 gene expression can promote the sensitivity of SMMC-7721 cells to PARP inhibitors, and its mechanism may be related to the homologous recombination repair defect of SMMC-7721 cells caused by DDB1 silencing.

Progress in preclinical study of combination of PARP inhibitors against tumor / 中国药房

Poly（ADP-ribose）polymerase（PARP）is a kind of DNA damage repair enzyme. PARP inhibitors include Olaparib （AZD2281），Niraparib（MK-4827），Rucaparib，Veliparib（ABT-888），Fluzoparib and Talazoparib （BMN-673），etc. This article reviews the preclinical research on the combined application of PARP inhibitors against tumor by searching the relevant literatures. Through the synthetic lethal mode ，PARP inhibitors have a strong killing effect on tumor cells with homologous recombination repair defects. However ，for tumor cells with intact DNA damage repair function ，PARP inhibitors often need to be combined with radiotherapy or other drugs to play a role. Combined application drugs include antiangiogenic drugs ，heat shock protein 90 inhibitors，cyclin-dependent kinase 12 inhibitors，immune checkpoint inhibitors ，histone deacetylase inhibitors ，etc. The combined application of PARP inhibitors is expected to enhance the efficacy of anti-tumor drugs and achieve the goals of sensitization ， synergism and reversal of drug resistance ，which is worthy of further in-depth research and exploration of new combined treatment schemes.

Analysis of PARP inhibitors induced anemia in advanced and relapsed epithelial ovarian cancer / 中华妇产科杂志

Objective:To explore the clinical features of poly ADP-ribose polymerase (PARP) inhibitor-related anemia in advanced and relapsed epithelial ovarian cancer (EOC).Methods:Patients diagnosed with advanced or relapsed EOC and treated with PARP inhibitor at National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between January 2015 to October 2020 were accrued. The data included PARP inhibitors, treatment details, and lab tests before treatment and during treatment were collected and the clinical characteristics of PARP inhibitor-related anemia were analyzed.Results:(1) A total of 98 patients with a median age of 56.5 years old (30-82 years old) were enrolled in this study. All patients were treated with PARP inhibitor (65 cases of olaparib, 17 cases of niraparib, and 16 cases of fluzoparib). The median treatment duration was 37.5 weeks (4-119 weeks). (2) The anemia rate was 40% (39/98), including 5% (5/98) of grade Ⅰ, 14% (14/98) of grade Ⅱ, 11% (11/98) of grade Ⅲ, and 9% (9/98) of grade Ⅳ. Fourteen patients with pre-treatment grade Ⅰ anemia had a higher rate of anemia events than the 80 patients without pre-treatment anemia, 7/14 vs 35% (28/80; χ2=4.281, P=0.039). (3) The median anemia occurrence time was 7.0 weeks (1-52 weeks), including 41% (16/39) of anemia cases occurred in 1-4 weeks, 26% (10/39) occurred in 5-8 weeks, 13% (5/39) occurred in 9-12 weeks, 3% (1/39) occurred in 13-16 weeks, 10% (4/39) occurred in 17-20 weeks, 8% (3/39) occurred ≥21 weeks. At the time of the lowest hemoglobulin tested, the median value of mean corpuscular volume (MCV) was 106 fl,which was higher than the up limit of normal range (100 fl), 74% (29/39) of anemia patients had an elevated MCV level; the median value of mean corpuscular hemoglobin (MCH) was 36 pg, 54% (21/39) of anemia patients had an elevated MCH level; the median value of mean corpuscular hemoglobin concentration (MCHC) was 320 g/L, 69% (27/39) of anemia patients had a higher MCHC level; 92% (36/39) of anemia patients had a normal level of serum iron; 79% (31/39) of anemia patients had a normal level of transferrin. 74% (29/39) of the anemia patients were macrocytic orthochromatic anemia. (4) Among the 39 patients with anemia, 20 patients (51%, 20/39) withhold the treatment of PARP inhibitor due to grade Ⅲ or Ⅳ anemia, including 10 patients (50%, 10/20) who resumed the PARP inhibitor treatment by suppling iron, folate, and vitamin B 12. The median stopping time of PARP inhibitor was 5.5 weeks (2-10 weeks), while the other 10 patients terminated the PARP inhibitor treatment for not recovering from severe anemia. Conclusions:One of the common adverse effects of PARP inhibitors is anemia, which mostly happened in the first 3 months of treatment. In the treatment of EOC, PARP inhibitor-related anemia mainly manifest as macrocytic orthochromatic anemia, and most patients with normal serum iron and transferrin.

Standardized application of poly ADP-ribose polymerase inhibitors in maintenance therapy of ovarian cancer / 中国医师杂志

Ovarian cancer is a common gynecological malignancy and the most common cause of cancer death. Ovarian cancer is usually treated with surgery combined with chemotherapy as the preferred treatment. In recent years, with the continuous development of medical technology and the in-depth research on ovarian cancer at home and abroad, the molecular targeted therapy of ovarian cancer has received extensive attention. Among them, the poly ADP-ribose polymerase (PARP) inhibitors have made great breakthroughs and advances in the precise and standardized treatment of ovarian cancer. This paper discusses the study of PARP inhibitors in sensitivity biomarkers of ovarian cancer, and reviews the standardized treatment of PARP inhibitors in maintenance therapy of ovarian cancer.

Regulation of DNA double-strand break repair pathway choice: a new focus on 53BP1 / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Maintenance of cellular homeostasis and genome integrity is a critical responsibility of DNA double-strand break (DSB) signaling. P53-binding protein 1 (53BP1) plays a critical role in coordinating the DSB repair pathway choice and promotes the non-homologous end-joining (NHEJ)-mediated DSB repair pathway that rejoins DSB ends. New insights have been gained into a basic molecular mechanism that is involved in 53BP1 recruitment to the DNA lesion and how 53BP1 then recruits the DNA break-responsive effectors that promote NHEJ-mediated DSB repair while inhibiting homologous recombination (HR) signaling. This review focuses on the up- and downstream pathways of 53BP1 and how 53BP1 promotes NHEJ-mediated DSB repair, which in turn promotes the sensitivity of poly(ADP-ribose) polymerase inhibitor (PARPi) in BRCA1-deficient cancers and consequently provides an avenue for improving cancer therapy strategies.

Research progress in targeting homologous recombination repair for tumor therapy / 药学学报

Applying poly(ADP-ribose) polymerase inhibitors (PARPi) to the treatment of cancers with homologous recombination deficiency (HRDness) has been a great advance in the field of molecular therapeutics. However, in the clinic patients lacking the specific mutations or developing reverse mutations in the process of PARPi treatment may not benefit from PARPi monotherapy. Therefore, targeting homologous recombination (HR) repair with molecularly targeted agents is becoming an attractive research focus and is raising the concept of "chemical HRDness". HR repair is an evolutionarily conserved and extensively regulated process that employs sister chromatids as the template to repair DNA double-strand breaks with high fidelity. In addition to directly targeting HR components, modulation of regulatory pathways controlling HR repair is effective in achieving the "HRDness" phenotype; this includes modulation of the cell cycle checkpoint regulatory pathway, the phosphatidylinositol 3-kinase (PI3K) signaling pathway, the chromatin remodeling pathway, etc. Targeting HR repair can not only result in "synthetic lethality" when combined with PARPi, but also sensitizes cancers to traditional radio/chemotherapy and novel immunotherapy. In this review we describe the HR repair pathway and its regulatory pathways, summarize the preclinical and clinical outcomes of targeting HR repair, discuss the remaining problems in this field and provide a prospective on its application in tumor therapy.

Effect of acupuncture on neurological function, cerebral infarction volume, thrombolysis time window and cerebral cell apoptosis signaling pathway in cerebral infarction rats / 针刺研究

OBJECTIVE: To observe the effect of acupuncture (Acupunct) on cerebral infarction volume and expression of poly ADP ribose polymerase 1 (PARP1), apoptosis-inducing factor (AIF) and endonuclease G (Endo-G) in the cerebral cortex tissue at different time-points after cerebral ischemia (CI) in acute cerebral infarction rats, so as to explore its underlying mechanisms in prolonging time window of thrombolysis. METHODS: Forty-eight SD rats were randomly divided into sham operation, model, intravenous thrombolysis (IVT)-4.5 h, IVT-6 h, IVT-9 h, Acupunct＋IVT-4.5 h, Acupunct ＋IVT-6 h, Acupunct＋IVT-9 h groups (n＝6 in each group). The CI model was established by using modified autologous thromboembolism via the right common carotid artery. Two hours after modeling, rats of the Acupunct groups received Acupunct stimulation of "Shuigou" (GV26) and bilateral "Neiguan" (PC6) for 30 min. Thrombolysis was conducted by injection of recombinant human tissue-type plasminogen activator (rt-PA, 10 mg/kg) via caudal vein. The neurological deficit was assessed with reference to Bederson's methods. 2，3，5-triphenyltetrazolium chloride (TTC) staining was used to assess the cerebral infarction volume, and the expression of cerebral PARP1, AIF and Endo-G proteins detected by Western blot. RESULTS: Compared with the sham operation group, the neurological score and percentage of cerebral infarction volume, expression levels of PARP1, AIF and Endo-G proteins were significantly increased in the model group (P0.05). The levels of neurological score, percentage of cerebral infarction volume, and AIF expression were significantly lower in both the Acupunct＋IVT 4.5 h and Acupunct＋IVT-6 h groups than in the simple IVT-4.5 h and simple IVT-6 h groups, respectively (P<0.05), and the expression levels of PARP1 and Endo-G proteins were obviously lower in the Acupunct＋IVT-4.5 h group than in the IVT-4.5 h group (P<0.05). Endo-G proteins were obviously lower in the Acupunct＋IVT-9 h group than in the IVT-9 h group (P<0.05). CONCLUSION: Acupuncture may improve neurological function, reduce cerebral infarction volume and prolong the time window of thrombolysis in CI rats, which may be associated with its effect in suppressing AIF/PARP1/ Endo-G signaling.