bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relevance of immune tumor microenvironment and its interaction with HABP4 and SERBP1 proteins in bladder cancer.
Authors: Fávaro Wagner José , Camargo Gabriela Cardoso de Arruda , Oliveira Gabriela , Roberto Isadora Manzato , Ávila Monaliza , Santos André Da Silva , Freitas Leandro Luiz Lopes de , Billis Athanase , Alonso João Carlos Cardoso 
Published: June 2024

e15187 Background: This study characterized and compared the immunohistochemical signatures associated with the cytotoxic inflammatory response (IFN-γ, CX3CR1+CD8+ T cells, iNOS+ M1 macrophages), immune checkpoints (PD-L1, CTLA-4), and the presence of immunosuppressive cells (CD163+M2 macrophages, Foxp3+regulatory T (Treg) cells) within bladder cancer samples. Furthermore, it aimed to correlate these immune signatures with the functional dynamics of Hyaluronic Acid Binding Protein 4 (HABP4) and Serpin mRNA Binding Protein 1 (SERBP1), proposing a novel perspective on the immunobiology of bladder cancer and its implications for targeted therapeutic strategies. Methods: A total of 30 formalin-fixed, paraffin-embedded bladder samples were obtained from patients aged 34 to 96 years (average 65 years) diagnosed with bladder cancer at the Municipal Hospital of Paulínia, Brazil. The samples were divided into three groups (n = 10 samples per group): Group 1 - Initial Non-Muscle Invasive Bladder Cancer (NMIBC); Group 2 - Bacillus Calmette-Guerin (BCG)-unresponsive NMIBC; and Group 3 - Muscle Invasive Bladder Cancer. Subsequently, the samples were submitted to immunohistochemical analyses. The retrospective anonymous study was approved by the local ethics committee (Clinical Trial: RBR-6swqd2). Results: Our results demonstrated that total immunoreactivities for IFN-γ, iNOS and CX3CR1 were significantly higher (p < 0.01) in Group 1 compared to Groups 2 and 3. CTLA-4 and PD-L1 immunoreactivities were significantly higher (p < 0.01) in Group 1 compared to Groups 2 and 3. Conversely, immunoreactivities for CD163 and Foxp3 were significantly higher (p < 0.01) in Groups 2 and 3 compared to Group 1. This study marks the first elucidation of HABP4 and SERBP1 immunoreactivities in the context of bladder cancer. We observed that immunoreactivity for SERBP1 was significantly higher (p < 0.01) in Groups 2 and 3 than in Group 1, implicating its overexpression in the facilitation of tumor progression. In a contrasting manner, HABP4 demonstrated significantly greater immunoreactivity (p < 0.01) in Group 1 compared to Groups 2 and 3, indicating a potential inhibitory effect on cellular proliferation. Conclusions: The augmented presence of Foxp3+Treg cells and CD163+M2 macrophages, concomitant with SERBP1 overexpression and the decrease of immune checkpoints, likely compromises the therapeutic efficacy of BCG. This immunosuppressive milieu hinders the activation, proliferation, and effector functions of CD8+ T cells, thereby promoting tumor progression. Conversely, a heightened infiltration of CX3CR1+CD8+ T cells and iNOS+M1 macrophages promotes a cytotoxic microenvironment, rendering it more amenable to immunotherapeutic interventions.
AURKA blockage as a strategy to overcome resistance to olaparib and platinum in high-grade ovarian cancer (HGOC).
Authors: Martínez-Pretel Juan José , Heredia Victoria , Ruiz Linuesa Miriam , Sanchez Serrano Paloma , Gonzalez Villena Lidia , Mendiola Marta , Redondo Andres , Pineda Begoña , Perez-Fidalgo Jose Alejandro 
Published: June 2024

e15198 Background: PARP inhibitors (PARPi) as olaparib (OLA) have become the new standard in maintenance treatment in high grade ovarian carcinoma (HGOC). Thus, there is an important need to identify the mechanisms for PARPi resistance and the strategies to overcome them. Our aim is to assess if in vitro inhibition of AURKA, a protein that plays a relevant role in centrosome spindle formation and mitotic regulation, might overcome olaparib resistance mechanisms in HGOC. Methods: Three HGOC cell lines (PEO1, Kuramochi and SKOV3) were selected, and isogenic resistant pairs generated in vitro, by pulsed exposure to OLA (PEO1-R) or by exposure to growing concentrations of OLA (Kuramochi-R and SKOV-R). AURKA expression was assessed by PCR and Western blot (WB). Cells were OLA-treated before and after the downregulation of AURKA expression by a specific small inhibitor RNA (siRNA) and by pharmacologic inhibition with alisertib. Cell viability was assessed by MTT assay and DNA damage by the evaluation of markers by WB. Combination index of the combo OLA+alisertib was assessed by Chou-Talalay method. Results: AURKA expression was lower at gene and protein levels in resistant cell lines compared to parental. Upon AURKA silencing (Si) of parental (OLA-sensitive) cell lines, no differences in the OLA IC50 values between AURKA-Si and control cells were seen. However AURKA-Si of the OLA-resistant cell lines was associated with a decreased in OLA IC50 as follows: 1) In PEO1R control scramble siRNA (sc) was 226 mM vs SI 128 mM, p < 0.0001; 2) In Kuramochi-R scRNA 268.4 mM vs si 130.2 mM p < 0.0001 and 3) in SKOV3-R scRNA 187 mM vs si 74.7 mM, p < 0.0001 suggesting a role of AURKA-si in overcoming OLA-resistance. Pharmacologic AURKA targeting with the inhibitor alisertib in all 3 sensitive and resistant cell lines showed an increase of DNA damage measured by the expression of H2AX protein by WB. Combination index of the OLA+alisertib in all resistant cell lines showed a synergistic effect of the combination with PEO1-R FA50 = 0.25 (FA25-75 0.2-0.31), Kuramochi-R FA50 = 0.29 (0.19-9.36) and SKOV3-R FA50 = 0.24 (0.19-0.36). Conclusions: AURKA targeting either by silencing or pharmacologic inhibition increased OLA-induced apoptosis or had a synergistic effect in OLA-resistant cell lines suggesting AURKA as a potential target for overcoming OLA resistance.
Exploring CK2 transcriptional regulation and signaling pathways in cancer.
Authors: Wilson Nicholas , Figueroa Cristián , Kreber Isabelle , Dominguez Isabel M. 
Published: June 2024

e15199 Background: CK2 genes have been implicated in oncogenic processes in different cancer types, and their expression is known to be increased in many cancers relative to their normal tissue types. However the regulation of the three CK2 alpha transcripts and beta transcript is not well understood. Studies investigating the alpha gene ( CSNK2A1) and beta gene ( CSNK2B) found NFκB, ETS1, and SP1 as likely transcription factor regulators in lymphoid and fibroblast cell lines. Our study seeks to explore correlations between CK2 gene expression and the expression of these transcription factors in cancer. Since CK2 also regulates intracellular signaling through pathways such as PI3K-Akt, Jak-Stat, NFkB, Wnt, IL-6, TGF-β, Ras and Notch, this study also seeks to explore the correlation between CK2 expression and gene expression of known downstream signaling pathways across a variety of cancers. Methods: 32 non-overlapping cancer datasets were obtained from the The Cancer Genome Atlas (TCGA) and Broad GDAC Firehose projects which were obtained via cBioPortal.org and analyzed using a combination of cBioportal and RStudio statistical analysis packages. For each cancer type, mRNA expression of each of the four CK2 genes in cancer was compared to expression of transcription factors both previously identified in the literature and predicted generated by TFBIND analysis (via the transcription factor database TRANSFAC R3.4) of the CK2 minimal promoter regions. CK2 gene expression was also compared to expression of genes in known CK2 signaling pathways. Results: Our analysis found CSNK2A1 and CSNK2A3 expression to have a significant, strong positive correlation in nearly all cancer types studied, except pancreatic adenocarcinoma. CSNK2A1 demonstrated significant positive correlation with expression of the transcription factors NFKB1 and c-Rel in lymphoma, thymoma, and other cancers. CSNK2B demonstrated a significant, strong positive correlation with the transcription factors NELFE in every cancer examined. CK2 transcripts also showed significant correlations with other transcription factors and genes involved in IL-6, TGF-β, MAPK, and several other CK2 signaling pathways in many different cancer types. Conclusions: Overall this study demonstrates significant correlations between CK2 gene expression and previously proposed transcriptional regulation mechanisms as well as known CK2 signaling pathways in cancer.
A new prognostic tool for metastatic colorectal cancer patients receiving anti-angiogenic treatment, the PALM score: A single-center experience.
Authors: Lai Eleonora , Palmas Enrico , Loi Francesco , Ziranu Pina , Mariani Stefano , Pretta Andrea , D'Agata Alessandra Pia , Dell'Utri Veronica , Papalexis Giulia , Deias Giulia , Rizzo Daiana , Spanu Dario , Sanna Giorgia , Moledda Giusy , Cadoni Andrea , Cucca Mattia , Donisi Clelia , Pusceddu Valeria , Puzzoni Marco , Scartozzi Mario 
Published: June 2024

e15575 Background: Even if anti-angiogenic agents are crucial for metastatic colorectal cancer (mCRC) patients (pts) treatment, to date, no validated prognostic biomarkers are available. We conducted at our Centre a retrospective research to identify a prognostic tool to be applied in clinical practice in this population. Methods: We retrospectively collected laboratory, radiological and clinical data of mCRC pts treated with anti-angiogenic agents at the Medical Oncology Unit of Cagliari University Hospital (2018- 02/2024) in order to identify a potential prognostic tool. Statistical analysis was performed with MedCalc (survival distribution: Kaplan-Meier; survival comparison: log-rank test; cut-off: ROC curves; differences among variables: Chi-square test). Results: Globally, 33 mCRC pts were evaluated in our study (19 male, 14 female; 13 RAS wild-type, 22 left-sided primary). 10 were treated with anti-angiogenic drugs in the 1st-line, 13 in the 2nd-line (bevacizumab and aflibercept) and 10 in 1st-2nd line. Median OS was 39.5 months (m) (95%CI:28.2-41.3), median Progression Free Survival (PFS) was 14.9 m (95%CI:9.5-18.5). Pts with lower platelet to lymphocyte ratio (P; ≤253; p < 0.0001, HR = 0,00000048; 95%CI 24.7-39.5 versus [vs] 95% CI 8.2-10.5), alkaline phosphatase (A; < 136 U/l; p = 0.0001, HR = 0.0001; 95%CI 12-39.5 vs 95% CI 8.2-10.5) and lactate dehydrogenasis (L; < 365 U/l; p < 0.0001, HR = 0.0000004; 95%CI 24.7-39.5 vs 95% CI 8.2-10.5) and higher monocyte count (M; > 0.3x103/μL; p = 0.0093, HR 0.01; 95%CI 26.5-39.5 vs 95%CI 8.2-24.7), showed a statistically improved OS. We created the “PALM score” and separated pts in two prognostic groups: good prognostic group (0 unfavorable variables: PALM = 0) and poor prognostic group (≥1 unfavorable variable, PALM = 1). OS was significantly improved in the good prognostic group (PALM = 0): 31.5 m (95%CI:24.7-39.5) vs 10.5 m (PALM = 1) (p = 0.0031, HR = 0.00006). Chi-square test revealed also a statistically significant correlation of upfront resection of primary tumor with the PALM score (73.9% of patients belonging to the PALM = 0 group had undergone surgery for primary tumor and all patients with resected primary belonged to the PALM = 0 group (p = 0.0352). Conclusions: Our research showed a promising prognostic role of easy-to-use PALM score tool in mCRC patients treated with anti-angiogenic drugs in a limited population at our center. Further prospective studies with larger sample size are needed to confirm our findings.
Prediction models of locally advanced rectal cancer prognosis incorporating perioperative longitudinal clinical data: A retrospective longitudinal cohort study.
Authors: WU Jeng You , Su Chia-Yu 
Published: June 2024

e15624 Background: For locally advanced rectal cancer, neoadjuvant chemoradiation(CCRT) followed by surgery is a standard treatment. Clinical T/N stage, whether pathological complete remission (pCR) after neoadjuvant CCRT or not are well recognized tumor features that predict disease prognosis. Although the parameters that determine pathologic stage are the strongest predictors of postoperative outcome, other clinical, molecular, and histologic features may influence prognosis independent of stage. The aim is to compare the predictive efficiency, between different models for overall survival in rectal cancer patients. Methods: This retrospective study is approved by TMU-JIRB(Protocol Number: N201809032).This is also a single institute study. 175 newly-diagnosed patients with locally advanced rectal cancer were retrospectively enrolled between Jan.2011 and Dec.2016. Basic information include sex, age, body weight, body height, previous medical history were recorded. CEA level, chemotherapy regimen, type of surgery, and distance between tumor and anal verge were also collected. Chemotherapy regimen of CCRT including 5FU+LV, capecitabine (Xeloda), FOLFOX, and FOLFIRI are recorded. Surgical resection was then followed 4-8 weeks after completion of CCRT. The 2010 AJCC tumor response grading (TRG) system was used to report treatment response of proctectomy samples. The progression free survival (PFS) and overall survival (OS) are then calculated. PFS is defined as survival without any recurrence or distant metastasis before Dec 31st, 2023. A comprehensive evaluation was conducted by incorporating all these machine learning models together. The aim was to compare their predictive efficiency, with models such as Random Forest, Naïve Bayes, KNeighbor, SVM, Decision Tree, Logistic Regression, XGBoost, and LightGBM. Results: 175 patients (104 men and 71 women) were enrolled in this study. The median follow up time was 7.1 yrs. The BMI was 24.05 ± 0.03 for men and 24.20 ± 0.07 for women. 32 (17.3%) patients achieved pCR, TRG 0. Clinical staging cT3 (78.8%) and nodal positive (78.8%) are the most common tumor feature in this study group. The median age of male and female patient is 58.6 and 56.1 respectively. Upon applying various machine learning models, different predictive accuracies emerged. The Random Forest, KNeighbor, and SVM models all achieved an accuracy of 0.9250. Naïve Bayes had an accuracy of 0.8620, while the SVC model registered at 0.9310, and XGBoost was slightly behind at 0.9286. SVC model is marking the best-performing model in this evaluation. Conclusions: This multicenter retrospective data-driven deep learning prediction model informed that SVC model yielded the best predictive results. Further prospective clinical trials and external validation of this prediction model are needed to further reinforce our findings.
Digital droplet PCR-based detection of KRAS, NRAS, and BRAF mutation in plasma samples from patients with colorectal cancer.
Authors: Kim Jin-Soo , Kim Mi Young , Lee Donghwa , Shin Rumi , Park Jin Hyun , Ko Jun Ho , Choi In Sil , Heo Seung Chul , Kang Mi Ran 
Published: June 2024

e15626 Background: Digital droplet PCR (ddPCR) is known for high sensitivity to detect mutated DNA in plasma. The aim of this study was to investigate the concordance of KRAS, NRAS and BRAF mutation detection in patients with colorectal cancers (CRCs) between plasma samples (PSs) and tissue samples (TSs) in pair. Methods: We prospectively collected paired PS and TS from patients with CRC (N = 200) who underwent surgery or biopsy for metastasis at Seoul National University Boramae Medical Center from Mar 2017 to January 2020. The ddPCR was performed using QX200™ Droplet Digital PCR System (Bio-Rad, USA) according to the manufacturer's recommended protocol with PCR kits developed for each gene (Gencurix, South Korea). Results: A total of 187 TSs and PSs were valid for ddPCR. Among these, 111 had results for KRAS, 51 had results for NRAS and 21 had results for BRAF, which were tested through routine clinical practice (RCP) using the pyrosequencing or Sanger sequencing method. The experiment's outcomes were analyzed for KRAS, NRAS, and BRAF, respectively. The analysis initially compared the results of RCP TS and ddPCR TS, and subsequently, intended to compare the mutation detection rates between TS and PS by comparing the results of ddPCR TS and ddPCR PS for FFPE/PS paired specimens. For KRAS, compared to RCP TS, the sensitivity of ddPCR TS was 100%, specificity was 66.7%, and the overall concordance rate was 79.3%. In TS/PS paired specimens, the sensitivity of ddPCR PS for ddPCR TS results was 38.5%, specificity was 97.6%, and the overall concordance rate was 64.7%. For NRAS, compared to RCP TS, the sensitivity of ddPCR TS was 100%, specificity was 98.0%, and the overall concordance rate was 98.0%. In TS/PS paired specimens, the sensitivity of ddPCR PS for ddPCR TS results was 33.3%, specificity was 100%, and the overall concordance rate was 97.4%. For BRAF, sensitivity of ddPCR TS was not available (no RCP positive sample), specificity was 85.7% compared to RCP, corresponded to a concordance rate of 97.0%. The sensitivity of ddPCR PS for ddPCR TS results was 71.4%, specificity was 100%, and the overall concordance rate was 97.4%. The sensitivity of ddPCR PS for ddPCR TS results was 71.4%, specificity was 100%, and the overall concordance rate was 97.4%. Conclusions: The present study showed that ddPCR has high accuracy in detecting KRAS, NRAS and BRAF mutation in plasma samples from patients with CRC. Analysis of PS could be useful in early response assessment and longitudinal disease monitoring for patient with metastatic CRC with specific mutation.
Efficacy of chemotherapy followed by chemoradiation versus initial chemoradiation as part of the total neoadjuvant therapy for patients with locally advanced rectal cancer: An NCDB analysis.
Authors: Dhahri Amina , Alnimer Yanal Mufeed , Selene Insija Ilyas , Patel Reema Anil , Hao Zhonglin 
Published: June 2024

e15629 Background: Results from multiple trials lead to modern management for locally advanced rectal cancer, with total neoadjuvant therapy (TNT) followed by surgery. However, the best sequence of different treatment modalities is unclear. Methods: We used the National Cancer Database (NCDB) to identify patients with locally advanced rectal adenocarcinoma. We divided patients into different categories based on the timing of chemo and radiation therapy relative to surgery. We used chi-square and Wilcoxon rank test for unadjusted comparison. To compare treatment efficacy with initial chemotherapy to concurrent chemoradiation in downstaging (clinical to pathological stage), we used a linear mixed effect model (LME) with adjustments on age, sex, race, facility type, and year of diagnosis. Also, we evaluated the probability of having positive lymph nodes in the pathological specimen (N+) in the multivariable logistic regression model with adjustment on the clinical stage in addition to the previously mentioned variables. All analyses were done using R 4.6.2. Results: A total of 100509 patients were identified. Only 695 patients received six cycles of neoadjuvant chemotherapy before concurrent chemoradiation (TNT chemotherapy), and 8677 patients received upfront radiation therapy with neoadjuvant chemotherapy administered within 12 weeks of neoadjuvant radiation therapy (TNT radiation). Patients whose start date of chemotherapy or radiation after surgery were excluded. The median age of participants was 63 (IQR = 54-63), and 83% were white. Patients who had TNT chemotherapy were younger (56.4 VS 59.5, P-value < 0.01), had clinically and pathologically advanced stage (IIIB, IIIC) compared to TNT radiation (64%VS 37% and 33%VS 29%, P-value < 0.01). Patients who received TNT radiation had an upgrade in their pathological stage compared to their clinical stage by 0.67 points in the LME (P value < 0.01). In multivariable logistic regression. TNT chemotherapy had a 17% lower risk of (N+) with an OR of 0.83 (0.95 CI 0.59-1.16). However, it was not statistically significant. The two groups had no difference in OS, with a median OS of 137 months (0.95 CI 110 -NR) and 143 (0.95 CI 137-151), respectively. Conclusions: Upfront chemotherapy before starting chemoradiation could be associated with more significant downstaging. Future trials to validate our finding is warranted. [Table: see text] [Table: see text]
Antibiotic exposure and colon carcinogenesis: In-depth profiling of a 492-patient cohort, with a focus on antibiotic classifications and subtypes.
Authors: Chudy-Onwugaje Dilichukwu , Salem Ahmed Elsayed , Roland Bani 
Published: June 2024

e15643 Background: To investigate whether the use of specific antibiotics is associated with an increased risk of colon cancer incidence. Methods: We conducted a retrospective cohort study comprising 492 patients diagnosed with colon cancer between 2012 and 2022, with no prior malignancies and a minimum 5-year follow-up period. We collected demographic data, medical histories, and records of antibiotic exposure, categorizing antibiotics systematically based on the Anatomical Therapeutic Chemical (ATC) classification system. Patient antibiotic histories, including drug names, dosages, durations, and therapeutic indications, were included. Antibiotics were classified as broad-spectrum, narrow-spectrum, or extended-course. We performed univariate and multivariate logistic regression models and used propensity score matching to control for potential confounding variables, such as age, gender, co-morbidities, and concurrent medications. Subgroup analyses were conducted to identify specific antibiotic classes associated with an increased risk of colon cancer. Results: The mean age of the cohort was 65.7 years (SD ± 8.3), with an equal gender distribution. Adenocarcinoma was the predominant histological subtype (429 cases, 87%), with rare subtypes accounting for the remaining cases. Common co-morbidities included hypertension (226 cases, 46%), diabetes mellitus (108 cases, 22%), and hyperlipidemia (88 cases, 18%). The most frequently prescribed antibiotics were fluoroquinolones (158 cases, 32%), followed by cephalosporins (108 cases, 22%), and macrolides (88 cases, 18%). Extended-course antibiotics were administered in 138 cases (28%). Preliminary analysis revealed a statistically significant correlation between the use of extended-course antibiotics and the risk of colon cancer (Odds Ratio = 1.89, 95% Confidence Interval: 1.32-2.71, p < 0.05). No substantial association was observed with broad-spectrum or narrow-spectrum antibiotics. Subgroup analysis identified specific agents within the extended-course antibiotics, such as fluoroquinolones and clindamycin, with an elevated risk profile. Conclusions: This study suggests a potential association between the use of extended-course antibiotics and the development of colon cancer. Further validation through larger-scale, prospective studies is strongly recommended to confirm these findings. Further in-depth mechanistic inquiries, particularly in cellular signaling pathways and microbial interactions within the gut microbiome, are warranted to elucidate the underlying biological mechanisms driving this association.