bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of PARP inhibition on androgen receptor localization and activity in castration resistant prostate cancer.
Authors: Nizialek Emily , Haffner Michael , Bhamidipati Akshay , Yegnasubramanian Srinivasan 
Published: June 2022

e17037 Background: The poly(ADP-ribose) polymerase inhibitors (PARPi) olaparib and rucaparib have been approved for the treatment of metastatic castration resistant prostate cancer (mCRPC) in the setting of homologous recombination deficiency (HRD). Additionally, PARPi have been shown to modulate androgen receptor (AR) signaling, with a recent report demonstrating mono-ADP-ribosylation of cysteine residues in AR by Parp7. Here, we further evaluated the effect of PARPi on AR activity and localization. Methods: The effect of PARPi on cell growth and survival of CRPC cell lines was evaluated in vitro and in vivo. AR ribosylation was assessed in CRPC cell lines by immunoprecipitation (IP) assays and proximity ligation assays (PLA). The subcellular localization of AR was determined by quantitative immunofluorescence microscopy in CRPC cell lines and xenograft models. Changes in AR activity with PARPi treatment were evaluated by a luciferase reporter assay and AR target gene expression in a PDX model. Finally, PARPi mediated alteration in the AR protein interactome was evaluated by liquid chromatography tandem mass spectrometry (LC-MS/MS) proteomics. Results: The PARPi olaparib and talazoparib, and to a lesser extent veliparib, inhibited CRPC cell growth. Evidence of AR ribosylation was seen by IP and PLA. PARPi treatment of multiple in vitro and in vivo prostate cancer models resulted in a shift of AR subcellular localization, from predominantly nuclear to cytoplasmic compartments. In luciferase reporter assays, AR transactivation activity was decreased after PARPi treatment in a dose dependent manner. In vivo, in prostate cancer xenograft models, decreased AR target gene expression was seen upon PARPi treatment. LC-MS/MS proteomic studies revealed that PARP inhibition resulted in significant changes in the composition of AR interaction partners, in particular of proteins related to intracellular trafficking and nuclear transport. This suggests a potential link between altered AR complex assembly and the observed changes in AR subcellular localization in the context of PARPi treatment. Conclusions: We describe a novel sequela of PARPi therapy to alter AR localization and activity in CRPC. Single agent PARP inhibition can alter prostate cancer cell growth in vitro and in vivo. With PARPi treatment, AR localization is shifted to the cytoplasm, the AR interactome is altered, and AR transcriptional activity decreased. These findings implicate a collateral mechanism of PARPi in preventing prostate cancer cell growth/survival that may augment previously described mechanisms related to HDR and synthetic lethality. It is essential to understand the role of PARPi beyond synthetic lethality in the context of HRD in order to better define the spectrum of response to PARPi across patients, and for development of biology-informed combination therapies.
Changes of immune microenvironment before and after chemoradiotherapy in cervical cancer.
Authors: Liu Sihan , He Qianru , Xing Xiaodan , Sun Tingting , Qi Chuang 
Published: June 2022

e17503 Background: Cervical cancer is the fourth most common cancer in women worldwide. Metastasis and invasion of cervical cancer are closely related to the tumor microenvironment. As an effective treatment, chemoradiotherapy plays a vital role in immune-related cells and factors. However, little is known about the effect of chemoradiotherapy on the immune microenvironment in cervical cancers. Therefore, we studied the immune microenvironment alterations before and after chemoradiotherapy and analyzed their prognostic significance in cervical cancer patients. Methods: We recruited 15 patients with stage IB1-IVA cervical squamous cell carcinoma. Pelvic intensity-modulated radiotherapy (IMRT) was performed with conventional segmentation of 2Gy per irradiation (IB3 stage was treated with synchronous cisplatin for weeks), FFPE samples pre-treatment, and one-week after-chemoradiotherapy were conducted an exploratory biomarker analysis based on gene expression profiling (GEP). The panel of 289 genes was customized based on critical genes and pathways during tumor immunoregulation (e.g., tumor antigen release, T cell activation, and immune metabolism). The differential expressed genes between these two groups were then assessed. Results: Forty-two genes were found to be differentially expressed, with 21 genes having > 1.5-fold mean expression difference after chemoradiotherapy. Analysis of important GO terms and KEGG pathways indicated that the pathways enriched by different genes are located in immune-related pathways, specifically, T cell activation (GO-BP), cytokine activity (GO-MF), and cytokine-cytokine receptor interaction (KEGG). After-chemoradiotherapy, the enrichment of tumor-infiltrating lymphocytes (TILs) varied greatly, especially the macrophages. Conclusions: This study preliminarily demonstrated that chemoradiotherapy caused the release of pro-inflammatory like CCR7 and CD69 and immune cell (macrophages) infiltration alterations after chemoradiotherapy in cervical cancer patients.
Low doses of visible electromagnetic radiation activating endogenous nonspecific antitumor resistance in patients with cervical cancer.
Authors: Rodionova Olga G. , Sakun Pavel G. , Sheiko Elena A. , Karnaukhova Elena A. , Pustovalova Alla V. , Chalabova Tatiana G. , Savchenko Dmitriy A. , Kabanov Sergey N. , Adamyan Meri L. , Kruze Polina A. , Poryvaev Yuriy A. , Chernikova Natalia V. , Voshedskiy Vitaliy I. , Tolmacheva Ekaterina A. , Vasilieva Ekaterina O. , Solntseva Anna A. , Zhenilo Oksana E. , Cherkasova Anna A. , Krokhmal Julia N. 
Published: June 2022

e17506 Background: Ionizing radiation inhibits the immunological reactivity of the body and the system of nonspecific antitumor resistance in patients with cervical cancer (CC). The purpose of this study was to activate the system of nonspecific antitumor resistance using visible electromagnetic radiation in CC patients receiving chemoradiotherapy. Methods: The study included 30 patients, mean age 61 years, with stage IIIb CC (T3bNxM0). The main group (n = 15) received standard chemoradiotherapy (CRT): irradiation of the primary focus 80 Gy, lymphatic paths 55 Gy, with radiomodification with cisplatin 40mg/m2; the patients were additionally exposed to visible electromagnetic radiation: the red spectrum λ = 640 nm on the cubital vein projection (exposure time 5 minutes, dose 6.86 J/cm2), twice a week (the total of 14 sessions). The method is based on the ability of monochrome red light to induce photobioadaptive processes in the body, leading to the formation of non-specific antistress reactions, activation of reparative and regenerative tissue reactions with an increase in the synthetic, phagocytic activity of neutrophils and the growth of the immunity lymphoid indicators. The control group included 12 patients receiving only standard CRT. Parameters of nonspecific antitumor adaptation reactions were evaluated. Results: Lower abdominal pain and discomfort were managed in 20% of patients of the main group on day 8, in 30% on day 10, and in 50% on day 14. In the control group, the symptoms were managed in 40% of patients only on day 22. More rapid regression of the cervical tumor was registered in patients of the main group, as well as decreased infiltration of the parametrium and vaginal fornices, disappearance of bloody discharge, management of intoxication syndrome. Gastrointestinal toxicity (nausea, diarrhea, flatulence) was noted in 10% of patients in the main group and in 100% controls. 7 patients in the control group developed leukopenia; in the main group, it was not observed. MRI-confirmed complete tumor regression amounted to 88% in the main group and 65% in the control group. CRT was completed within 7 weeks in the main group and 8.5 weeks in the control group. Conclusions: Low doses of electromagnetic radiation of the red spectrum activate endogenous nonspecific antitumor resistance of the body by forming nonspecific antistress reactions of activation and increasing the immunity lymphoid indicators, which improves the efficacy of CRT.
Opportunistic cervical cancer screening for elderly women without standardized screening.
Authors: Li Kemin , Yin Rutie 
Published: June 2022

e17511 Background: To explore the important of the opportunistic cervical cancer screening for elderly women without standardized screening and the best opportunistic screening strategy. Methods: The participants were elderly women over the age of 65 without being undergone standardized cervical cancer screening from June 2017 to June 2021. All participants were undergone an opportunistic cervical cancer screening. High-risk HPV distribution was analyzed, and we would analysis the accuracy of different screening methods (only cytology, only HPV, HPV +cytology triage, and non-HPV 16/18 +cytology triage or HPV 16/18) for CINII+. Results: A total of 848 elderly women with high-risk HPV infection were included. There were 325 (38.3%) CINII+ patients and 145 (17.1%) invasive cancer patients. The top five HPV subtypes are HPV16, HPV52, HPV58, HPV53 and HPV56, and the infection rates are 31.4%, 21.9%, 19.7%, 11.6%, and 11.6%, respectively. The area under the ROC curve of five screening strategies was 0.715(0.681, 0.750) (ASCUS+), 0.498(0.458, 0.538), 0.623(0.584, 0.663), 0.714(0.680, 0.748) (ASCUS+), and 0.698(0.664, 0.733) (ASCUS+). Conclusions: Elderly women without being undergone standardized cervical cancer screening should be given a chance to be screened for cervical cancer, and the standardized screening program is suitable for elderly women.
Characteristics of expression of cancer stem cell markers in various approaches to cervical cancer treatment.
Authors: Menshenina Anna P. , Ulianova Elena P. , Nepomnyashchaya Evgeniya M. , Sagakyants Aleksandr B. , Verenikina Ekaterina V. , Moiseenko Tatiana I. , Frantsiyants Elena M. , Cherkasova Anna A. , Selezneva Olga G. , Rogozin Mark A. 
Published: June 2022

e17516 Background: Cancer stem cells (CSCs) are being actively studied as a possible origin of malignant neoplasms. Research of the properties of CSCs and mechanisms of their regulation holds the promise of the development of new approaches to antitumor therapy. The most frequently detected CSC markers in different tumors are CD44 and CD133. In this regard, the aim of our study was to identify characteristics of expression of CSC markers in cervical cancer treatment and their possible predictive value. Methods: The study included 237 patients with locally advanced cervical cancer T2a-2bNx-1M0. Patients were divided depending on the treatment: neoadjuvant chemotherapy with cisplatin and bleomycin (NACT, n = 84); plasmapheresis (PA) in combination with NACT (PA+NACT, n = 60); PA+NACT with nonspecific immunotherapy with an interferon inducer (PA+NACT+IT, n = 93). Immunohistochemical study was performed on sections from paraffin blocks of tumors using anti-CD44 monoclonal mouse antibodies (156-3C11, Thermo Scientific) at a dilution of 1:2500 and anti-CD133 polyclonal rabbit antibodies (AF5120, Affinity Biosciences) at a dilution of 1:400 (Thermo autostainer Scientific 480S). Membrane staining and staining intensity were evaluated: 0, 1+ weak, 2+ moderate, 3+ strong staining. Protein expression was defined as positive when staining was detected in ≥10% of all tumor cells with a staining intensity ≥2. Statistical analysis of the results was performed with the STATISTICA 13.0 program (StatSoftInc., USA) using the Mann-Whitney U-test. Results: Tumors with positive CD133 and CD44 expression were observed in all groups of patients. However, only PA+NACT+IT patients had CD133- (57%) and CD44- (43%) tumors. Median expression of CD133: in NACT - 70 [60;80]; PA+NACT - 60 [37;70], PA+NACT+IT - 25 [5;60]. Median expression of CD44: in NACT - 30 [10;40]; PA+NACT - 30 [13;65], PA+NACT+IT - 20 [2; 40]. CD133 expression in PA+NACT+IT patients was significantly lower than in PA+NACT and NACT patients by 2.4 times (*p = 0.009) and 2.8 times (*p = 0.002), respectively. CD44 expression in tumors of patients with PA+NACT+IT was 1.5 times lower (statistically non-significant). Differences in tumors of NACT and PA+NACT patients were not found. Conclusions: The immunohistochemical study revealed a decline in the expression of CSC markers (CD133 and CD44) in tumors of patients who received PA+NAPCT+IT. The results obtained for the CD133 marker show its possible value as a predictive factor in the treatment of cervical cancer.
Tumor-stroma interaction in cervical cancer: The prognostic importance of desmoplasia.
Authors: Wolf Benjamin , Horn Lars-Christian , Höckel Michael , Aktas Bahriye 
Published: June 2022

e17519 Background: During tumor growth, cancer cells can induce the formation of new extracellular matrix, mainly by activating peritumoral fibroblasts. This stromal reconfiguration has been termed desmoplasia. In pancreatic and ovarian cancer models, targeting desmoplasia therapeutically to normalize the microenvironment has recently shown promising results. We investigated the frequency and prognostic relevance of peritumoral desmoplasia, as well as its association with other prognostic factors such as lymph node involvement and parametrial tumor extension in cervical cancer patients. Methods: A retrospective cohort study based on data from the prospective monocentric observational Leipzig School Mesometrial Resection study was conducted. Cervical cancer patients staged IB1 to IVA according to the Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) who underwent primary surgery between 1999 and 2017 were included. Information regarding desmoplastic tumor reaction was retrospectively retrieved from the pathology reports. All other data had been collected prospectively during the trial period. Using non-parametric tests, we calculated the association of peritumoral desmoplasia with other common risk factors. To determine the prognostic significance of desmoplasia, we used the Kaplan-Meier estimator and performed multivariable Cox-regression modelling. Results: Overall, 355 patients were included. Desmoplasia was present in 298 cases and was associated with a significantly higher likelihood of lymphovascular space involvement (odds ratio [OR] 2.7, 95% confidence interval [CI] 1.4 – 5.1, p = 0.001) and venous infiltration (OR 5.1, 95%-CI 1.3 – 44.9, p = 0.01). Lymph node metastasis was more common in patients with desmoplasia (OR 2.4, 95%-CI 1.2 – 5.0, p = 0.01), as was parametrial involvement (OR 3.5, 95%-CI 1.7 – 7.9, p = 0.0002). Interestingly, the presence of desmoplasia was not associated with larger tumor size. Patients with desmoplastic tissue reaction were significantly older than those without desmoplasia (median 41 years [inter quartile range 34 – 51] vs. 47 years [IQR 39-56], p = 0.009). These prognostically negative parameters in patients with desmoplastic disease translated into inferior overall (94.5% vs 80.5%, OR 3.9 [95%-CI 1.2 – 12.5], p = 0.02) and recurrence-free survival (86.8% vs. 74.2%, OR 2.3 [95%-CI 1.0 – 4.9], p = 0.04). A multivariable Cox-regression model including tumor size, patient age, and nodal status indicated that desmoplasia was an independent risk factor for overall death (OR 4.2, 95%-CI 1.03 – 17.5, p = 0.04). Conclusions: Desmoplastic stromal remodeling is associated with a more aggressive phenotype of cervical cancer and inferior survival. Targeting desmoplasia, especially in advanced disease when surgical treatment is not feasible, might be a promising treatment approach in the future.
A novel predictor for the use of concurrent chemotherapy in early-stage cervical cancer with intermediate-risk factors.
Authors: Zhang Guangyu , Fu Chunli , Ma Changdong , Zhang Youzhong , Miao Li , Wang Cong 
Published: June 2022

e17521 Background: For early-stage cervical cancer patients experiencing radical surgery, postoperative radiotherapy was recommended for patients with a combination of intermediate-risk factors. However, there was no consensus on whether to administer concurrent chemotherapy. The aim of the study was to confirm the clinical value of the controlling nutritional status (COUNT) score in guiding the use of concurrent chemotherapy in patients with early-stage cervical cancers during postoperative radiotherapy. Methods: A total of 945 patients with FIGO stage IB-IIA (2009) cervical cancer were retrospectively analyzed in the study from 2009 to 2018. There were 503 patents receiving concurrent chemoradiotherapy, while another 442 patents undergone radiotherapy lonely. Radiotherapy was performed by conformal radiotherapy or intensity-modulated radiotherapy. The concurrent chemotherapy regimen included either cisplatin or paclitaxel. Pre-treatment CONUT score were calculated within 1 weeks before curative resection. Low CONUT group and high CONUT group were defined based on the cutoff value of CONUT score which was determined by the receiver operating characteristic analysis. Kaplan-Meier survival analysis was performed to compare disease-free survival (DFS) and cancer-specific survival (CSS) rates between different group. A Cox proportional hazards regression test was used to conduct multivariate analyses of DFS, local recurrence-free survival and distant metastasis-free survival (DMFS). Results: The median follow-up was 54.6 months (range: 4.8-147.5 months). The optimal cutoff value of CONUT was 3 in the study. For the patients included in the high CONUT group (≥3), the addition of concurrent chemotherapy significantly improved treatment outcomes, and had better 5-year DFS (90.37% vs 70.69%, P < 0.001) and CSS (95.02% vs 78.74%, P = 0.005) than those without it. Meanwhile, the patients with concurrent chemotherapy had less rate of distant metastasis (6.5% vs 28.1%, P < 0.001). For the patients included in low CONUT group (< 3), there was no difference in prognosis between patients receiving concurrent chemotherapy and not receiving. In the high CONUT group, the multivariate analysis showed that concurrent chemotherapy was detected to be a factor significantly associated with DFS (HR 3.077; 95% CI: 1.295-6.679, P = 0.011) and DMFS (HR 3.435; 95% CI: 1.506-7.014, P = 0.006). Conclusions: Pre-treatment CONUT score may be a predictive factor for the use of concurrent chemotherapy in early-stage cervical cancer patients with intermediate-risk factors during postoperative radiotherapy, and it can be helpful to determine the adjuvant treatment scheme.
Photodynamic therapy for early cervical cancer.
Authors: Ivanova Viktoria A. , Nikitina Vera P. , Verenikina Ekaterina V. , Zhenilo Oksana E. , Ardzha Anna Yu 
Published: June 2022

e17528 Background: Photodynamic therapy (PDT), with its high efficiency and selective impact on tumor cells without damaging healthy tissues, is an organ-sparing treatment preserving the anatomy and function of the cervix. Preservation of the reproductive function is the most significant criterion for the efficacy of an organ-sparing treatment. The purpose of this study was to evaluate the efficacy of PDT for early cervical cancer. Methods: PDT results were studied in 74 patients aged 18-40 years with early cervical cancer. The patients were divided into 3 groups depending on the type of transformation zone (TZ), the degree of invasion and the tumor site: group 1 - 36 patients with preinvasive cancer in the exocervix (TZ type I-II); group 2 - 34 patients with preinvasive cancer in the endocervix (TZ type III); group 3 - 4 patients with microinvasive cancer T1a1N0M0 with invasion of no more than 1 mm as an alternative to surgical intervention. Infection with high-risk genotypes of HPV (16, 18, 31, 33, 35, 45, 56) was detected with PCR in 62 (84%) women. All patients received PDT with the semiconductor Latus laser up to 3 W, a single-use diffusing fiber for the exocervix irradiation and a single-use cylindrical diffusing fiber for tumors in the cervical canal. Chlorin e6 was used as a photosensitizer. The efficiency criteria included the normalization of the colposcopic and morphological picture, and the HPV elimination confirmed by the PCR test. 4 to 8 procedures were required to restore the normal layer of stratified squamous epithelium. Results: PDT was followed by direct photocoagulation necrosis caused by the destruction of cellular structures, and ischemic necrosis as a result of damage and destruction of the microvasculature of the initial tumor changes in the cervical epithelium. Epithelialization of the cervix was completed by days 35-40. Normal morphological picture was observed in 96% of patients in group 1 and in 95% of patients in group 2; all patients in group 3 had a pronounced positive response. PCR 3 months after PDT showed a positive HPV reaction in 5.1% of patients. No negative changes in the cytogram were detected 6 and 12 months after PDT. The maximum follow-up period has lasted for 5.1 years. No relapses of the disease have been registered. During the follow-up period, four patients with preinvasive cancer and one patient with microinvasive cancer successfully gave birth to healthy children. Conclusions: PDT is an alternative treatment for precancerous and early malignant tumors of the cervix; it preserves the anatomical and functional integrity of the organ, which is important for the female reproductive function. The results of the study allow recommending PDT in the treatment of early cervical cancer.
BRCA variants and the risk of adverse reactions in patients with ovarian cancer: A single-center real-world study.
Authors: Li Kemin , Yin Rutie 
Published: June 2022

e17530 Background: To study the correlation between BRCA mutation status and the risk of adverse reactions in patients with ovarian cancer. Methods: A real-world study was conducted at the largest gynecological oncology center in western China, the West China Second University Hospital of Sichuan University. The research subjects were patients diagnosed with ovarian cancer who were initially treated in our hospital from January 2016 to January 2020 and had their BRCA gene status evaluated. Multivariate Cox analysis was conducted to investigate the correlation between the BRCA mutation status and adverse reactions in ovarian cancer patients during initial treatment. Results: A total of 349 ovarian cancer patients were enrolled, including 79 patients with pathogenic BRCA variants, resulting in a pathogenic mutation rate of 22.6%. Among these 79 patients, 57 had BRCA1 variants and 22 had BRCA2 variants, yielding a pathogenic mutation rate of 16.3% and 6.3%, respectively. Multivariate COX analysis revealed that pathogenic BRCA variants were not related to the risk of adverse reactions, such as myelosuppression and allergies to chemotherapy drugs, during the initial treatment of ovarian cancer. Conclusions: BRCA variants did not increase the risk of adverse reactions, such as myelosuppression and allergies to chemotherapy drugs, in ovarian cancer patients during initial treatment.