bluuebunny/crossref_metadata_2025_split huggingface dataset:
3D Jones-maxtrix scanning of polycrystalline films of blood plasma in the diagnosis of pathological conditions of human organs.
Authors: Tryfonyuk Liliya , Dubolazov Alexandr , Ushenko Yuriy , Soltys Irina , Pavlukovich Natalia , Ushenko Oleksandr 
Published: June 2022

e15053 Background: This work is devoted to the development and experimental verification of a new method of three-dimensional matrix mapping of anisotropic properties of optically thin layers of polycrystalline films of blood plasma of biological tissues for express diagnostics and differentiation of histological sections of a prostate tumor. Methods: Biological samples. Three representative groups of polycrystalline blood plasma films were formed: 1 group consisted of blood plasma samples of polycrystalline adenoma; Group 2 consisted ofpolycrystalline adenocarcinoma, blood plasma samples are moderately differentiated (3+3 on the Gleason scale); Group 3 consisted ofpolycrystalline adenocarcinoma, blood plasma samples are poorly differentiated (4+4 on the Gleason scale). Results: The results obtained can be associated with changes in the ratio between the concentrations of albumin and globulin proteins in the blood plasma from patients with prostate tumors. It is known that malignant processes are accompanied by an increase in the concentration of optically active globulin molecules. Due to this, there is an increase in the magnitude and range of scatter in the magnitude of circular birefringence of samples of polycrystalline blood plasma films from patients with adenocarcinoma (3 + 3) and adenocarcinoma (4 + 4) in comparison with similar maps of blood plasma from patients with benign adenoma. On the contrary, due to a decrease in the concentration of albumin molecules, the values of linear birefringence of blood plasma films from patients with malignant prostate tumors decrease. Conclusions: The method of 3D Jones matrix mapping of blood plasma layers with digital holographic reconstruction of layered maps of linear and circular birefringence is analytically substantiated. The operational characteristics (sensitivity, specificity and balanced accuracy) that demonstrate the diagnostic power of 3D Jones matrix mapping of biological layers. The use of the algorithm for tomographic reproduction of linear birefringence maps provided high accuracy in differentiating benign and malignant conditions of the prostate tissue.[Table: see text]
Anticancer effects of PARP1 hyperactivation by a decoy oligodeoxynucleotide in vitro and in vivo.
Authors: Jdey Wael , Doizelet Chloe , Galassi Claudia , Zandanel Christelle , Trochon-Joseph Veronique , Hayes Vincent , Lienafa Marie-Christine , Petroni Giulia , Galluzzi Lorenzo 
Published: June 2022

e15060 Background: Poly (ADP-ribose) polymerase (PARP) inhibitors mediate significant anticancer effects against homologous recombination defective (HRD) tumors but have limited efficacy against homologous recombination proficient (HRP) neoplasms. Moreover, HRD tumors often become resistant to PARP inhibitors during treatment, constituting a major limitation to the clinical use of these agents. Here, we describe the metabolic, antineoplastic and immunomodulatory effects of a first-in-class oligodeoxynucleotide that operates as a PARP1 decoy (OX413), resulting in constitutive hyperactivation of PARP1 and consequent exhaustion of the DNA damage response. Methods: OX413-induced PARP trapping and hyperactivation, NAD+ consumption and cell cytotoxicity were monitored using (HRP and HRD) breast, ovarian or prostate cancer cells as well as normal fibroblasts and leukocytes. DNA repair abrogation was monitored by analyzing repair protein recruitment to damage sites. Accumulation of cytoplasmic DNA fragments was monitored after DNA staining and microscopy analysis. Effects on the innate immune response was assessed by following STING pathway activation and T-cell mediated anti-tumor cytotoxicity. In a mouse xenograft model of breast cancer, OX413-induced PARP activation and tumor infiltration by immune cells were analyzed ex-vivo by flow cytometry. Antitumor efficacy of OX413 alone or combined to a PD1 blocker was assessed in MPA/DMBA-driven HR+ HER2- mouse mammary carcinomas. Results: At odds with conventional PARP inhibitors, OX413 bound to and hyperactivated PARP1 with high affinity and in a dose-dependent manner, resulting in elevated cytotoxicity in multiple cancer (but not normal) cells irrespective of HR status. OX413 impaired DNA repair due to PARP trapping and rapid NAD+ consumption, leading to the accumulation of cytoplasmic chromatin fragments (CCFs). Consistent with this, OX413 triggered activation of the CGAS/STING pathway, CCL5 secretion and potentiation of tumor-targeting T cell responses. PARP1 engagement and STING activation were corroborated in vivo in EMT6 mouse mammary carcinomas, correlating with anticancer effects coupled to tumor infiltration by innate and adaptive immune cells. In MPA/DMBA-driven tumors, OX413 mediated considerable anticancer effects that could be exacerbated by PD1 inhibition. Conclusions: Our results provide preclinical rationale for using OX413 to trigger metabolic exhaustion in cancer cells and initiate inflammatory responses that can be actioned by immune checkpoint inhibitors in patients bearing HRD as well as HRP tumors.
Translational modeling for patients with RAS mutant tumors: Profiling the dual-MEK inhibitor IMM-1-104 in a humanized 3D assay.
Authors: Hall Brett , Nair Praveen , Fowler Kevin , Axel Amy , Kolitz Sarah , Funt Jason , Barrett Scott , Zeskind Benjamin , King Peter J. 
Published: June 2022

e15084 Background: Elevated RAS-RAF-MEK-ERK (MAPK pathway) signaling is observed in over half of all solid human tumors, and mutations in RAS or RAF account for a large fraction. Given MEK’s unique position in the MAPK cascade, it remains an attractive target in cancer. However, FDA-registered MEK inhibitors are susceptible to pathway reactivation events that limit their use to RAF mutant disease and cause on-target toxicities stemming from chronic target engagement. IMM-1-104 is a novel, allosteric dual-MEK inhibitor designed for better applicability to RAS mutant tumors by preventing MEK reactivation. Endowed with a short plasma half-life, IMM-1-104 promotes deep cyclic inhibition with a near-zero drug trough, affording normal cells a chance to recover between doses. Methods: We characterized IMM-1-104’s pharmacologic activity across 52 tumor cell lines that spanned 11 distinct tumor types in a humanized, ECM-based 3D tumor growth assay (3D-TGA). The 3D-TGA has better predicted in vivo tumor responses versus 2D culture and more accurately reflects human tumor biology. Tumor models were categorized based on in vivo drug PK limits as sensitive to IMM-1-104 (EC50 < 1uM), intermediate (1uM≤EC50≤10uM and ≥25% inhibition at 10uM) or resistant otherwise. Models were evaluated by whole exome sequencing, along with RNA sequencing in the 3D context, to profile determinants of sensitivity and resistance and to prioritize patient populations most likely to respond to IMM-1-104. Results: Models sensitive to IMM-1-104 were enriched for MAPK driver mutations, consistent with pathway addiction. We reasoned that activation of parallel compensatory pathways that can reduce reliance on MAPK signaling may increase the likelihood of resistance to IMM-1-104. Pathways and genes suspected of contributing to resistance helped refine signatures based on 3D-TGA outcome data. Models with a MAPK driver mutation and compensatory mutations such as PIK3CA or PTEN deletion were more likely to show intermediate response than those with a greater addiction to MAPK drivers. Models lacking a clear MAPK driver mutation but harboring other putative resistance alterations were more likely to be resistant in the 3D-TGA. Conclusions: To better understand the relevance of tumor model responses in the 3D-TGA relative to RAS mutant patient populations, we computationally compared tumor model data to patient somatic alterations, identified in the public resource GENIE, which has cataloged the molecular profiles of over 100,000 cancer patients. Based on model-to-patient molecular mapping, we identified biomarker-defined subsets of sensitive KRAS mutant lung and colorectal models. The most broadly sensitive patient-aligned models in the 3D assay were KRAS mutant pancreatic cancer and NRAS mutant melanoma patients, supporting the inclusion of such patients in planned clinical studies of IMM-1-104.
Drugging the undruggable-targeting P53: A comparative analysis of APR-246 and coti-2 in human tumor primary culture explants.
Authors: Nagourney Adam Jeremiah , Evans Steven Scott , Duesberg Max Serge , D'Amora Paulo , Bernard Paula J. , Francisco Eric , Nagourney Robert Alan 
Published: June 2022

e15092 Background: The TP53 tumor suppressor is the most commonly mutated gene in human cancer. P53 protein comprised of 393 amino acids functions as a tetramer with the loss of function mutations concentrated in “hotspots” that often affect DNA binding domains. APR-246 and COTI-2 are novel small molecules that are under clinical investigation for the treatment of P53 mutated cancers. APR, a quinuclidine binds to P53 cysteine residues altering the functional conformation while COTI is a thio-semicarbazone, found active in P53 mutant tumors using a novel computational platform. As the mechanisms of action may differ we undertook a comparative analysis of these compounds in 3D human tumor explants derived from surgical specimens. Methods: Ex Vivo Analyses of Programmed Cell Death (EVA/PCD) (D’Amora, P et al Gyn. Oncol. 2021) was applied to 236 human tumor primary culture explants isolated from surgical specimens. After disaggregation, micro-spheroids, isolated by precise density centrifugation were exposed to APR, COTI and other agents for 72-96 hours. Drug-induced cell death was measured by delayed-loss-of-membrane integrity and ATP content (luciferase). Dose response curves were interpolated to LC50 values. Synergy analysis used the method of Chou & Talalay. Correlation coefficients used Pearson moment. Results: APR and COTI reveal the highest activity in hematologic neoplasms. Solid tumor activity patterns diverged with COTI active in gynecologic malignancies and NSCLC and moderately active in breast and colorectal while APR is active in colorectal but less active in breast and NSCLC. Pearson moments for COTI vs APR revealed an R value = 0.146 (NS). COTI activity correlated with Nitrogen Mustard and Alpelisib (PIK3CA) while APR activity correlated with Doxorubicin and Everolimus. COTI combinations focused upon ovarian cancers identified synergy in 25% and antagonism in 18%. Conclusions: P53’s function as the “guardian of the genome” is consistent with our findings that many cytotoxic and targeted agents that induce cell death reveal correlations with APR and COTI. While APR affects the structural conformation of P53, COTI may function downstream via oxidative, metabolic or other stress responses. The correlation coefficient for APR vs COTI at 0.146 (NS) suggests distinct mechanisms of action. This is supported by different disease-specific-profiles and correlations with other drugs. COTI synergy in ovarian cancers, the target of current clinical trials at 25% is below expectations. With differing disease specificities, selecting between these and related agents to optimize clinical outcomes may require a more granular examination of cellular mechanisms of response and resistance. Primary culture analyses offer insights into drug mechanisms of action, combinatorial potential and have the capacity to improve patient selection.
Antitumor activity of KIN-2787, a next-generation pan-RAF inhibitor, in combination with MEK inhibition in preclinical models of human NRAS mutant melanoma.
Authors: Miller Nichol , Wang Tim Sen , Lee Catherine , Severson Paul , Ke Eugene , Kobayashi Ken , Williams Richard Thomas 
Published: June 2022

e15099 Background: NRAS mutations which activate MAPK signaling represent oncogenic driver alterations in approximately 20% melanoma cases in the US. NRAS mutant melanomas are uniquely dependent upon CRAF rather than BRAF for activation of downstream MEK/ERK signaling. In BRAF mutant melanoma, approved RAF-targeted therapies are commonly used in combination with a MEK inhibitor which provides clinical benefit by inhibition of two targets within the oncogenic MAPK signaling pathway. Emerging data with pan-RAF inhibitors in early clinical development suggests benefit with and without combined MEK inhibition, yet no approved targeted therapy exists for NRAS mutant melanoma patients. KIN-2787 is a novel, orally available pan-RAF inhibitor designed to be effective in RAF-dependent cancers, regardless of isoform. Methods: Kinome profiling was evaluated by radiometric enzyme assay at Reaction Biology across 688 kinases (including wild type, atypical, and mutant). Cellular activity was assessed by suppression of downstream MAPK pathway signaling and cell growth inhibition in human tumor cell lines. Combination cell growth inhibition studies were performed in 9x5 dose matrices with KIN-2787 and binimetinib, respectively. Extended cell growth inhibition effects were assessed by Incucyte imaging. In vivo KIN-2787 and combination efficacy was evaluated in NRAS mutant xenograft models. Results: Kinome profiling of KIN-2787 revealed exquisite selectivity with only 2 of 669 non-RAF family kinases inhibited > 75% at 1 M KIN-2787 and retained ̃10x and 70x selectivity window against those two kinases, DDR1 and p38b, respectively, relative to RAF kinases. We previously reported KIN-2787 activity across BRAF, NRAS, and KRAS mutant tumor cell lines with greatest sensitivity in Class II and III dimer-driven BRAF models. Here, we evaluated NRAS mutant, BRAF WT melanoma for combination potential with binimetinib. Melanoma tumor cell lines bearing NRAS hotspot mutations demonstrated synergistic benefit with KIN-2787 combined with binimetinib. Daily KIN-2787 plus binimetinib treatment in NRAS mutant melanoma xenograft models resulted in significant tumor growth inhibition benefit relative to either agent alone and was associated with added MAPK pathway biomarker suppression. Conclusions: KIN-2787 is a highly selective, potent, next-generation, pan-RAF inhibitor with activity across BRAF and RAS mutant human tumor cell models. Preclinical in vitro and in vivo studies using KIN-2787 in combination with binimetinib demonstrated significant combination benefit in NRAS mutant melanoma models. Taken together with its unique selectively, these data support use of KIN-2787 in combination therapy in this patient segment. A Phase 1/1b dose escalation and expansion clinical trial evaluating the safety and efficacy of KIN-2787 is ongoing (NCT04913285).
The landscape of KDM5A mutations and hotspots in Chinese patients with solid tumors.
Authors: Li Ke , He Zhe 
Published: June 2022

e15115 Background: As a kind of histone modification enzyme, Lysine-specific demethylase can eliminate di- and tri-methyl groups from lysine 4 of histone. A growing number of shreds of evidence demonstrate that the disfunction of KDM5A relates closely to the initiation and progression of various diseases, particularly cancers, including but not limited to breast cancer, prostate cancer, glioblastoma, etc. However, research on the mutation spectrum of KDM5A in Chinese cancer patients is lacking. Methods: Ranging from Jan 14, 2020, to Oct 25, 2021, genomic DNA extracted from 5419 blood or tissue samples involving more than 22 solid tumors types were analyzed by NGS assay to investigate the landscape of KDM5A mutations and hotspots. Results: KDM5A somatic mutations existed in approximately 6.50% of all samples and almost all kinds of screened cancer types, among which, endometrial cancer comes first with the highest mutational frequency up to 21.05%, followed by the esophagus and esophagogastric junction cancer (18.18%) and bladder cancer (12.50%). Further analysis was conducted to explore mutational hotspots in KDM5A. Although almost 150 mutation sites existing in KDM5A had been identified in our research, the most prominent mutational hotspots are G1200, T30, M766, occupying 19.63%, 17.51%, and 6.37% of all SNV and Indel KDM5A mutations, respectively. Conclusions: Our study partially disclosed the panorama of the KDM5A mutational landscape in Chinese patients with solid tumors for the first time. Further studies with larger samples and populations are much needed to enhance our understanding of this enzyme in cancer biology.
Tissue-based next generation sequencing (NGS) testing in solid tumors: A single-center experience in Malaysia.
Authors: Ahmad Azura Rozila , Toh Yi Long , Tan William , Wahid Mohamed Ibrahim A. 
Published: June 2022

e15121 Background: There is an increased appreciation for precision oncology in which clinicians are utilizing NGS testing to guide treatment selection and to identify resistance mutations. This study aims to identify clinically significant biomarkers in prospectively collected FFPE tumor tissue specimens. Genomic testing of molecular alterations was conducted using an in-house 50-gene hotspot APEX panel (MiRXES). Herein, we report a single center experience with targeted NGS panel testing in solid tumors. Methods: The analyzed cohort consisted of 75 clinical samples submitted for molecular testing over a 3-month period from Beacon Hospital, Malaysia (October to December 2021). The identified variants were tiered according to AMP/ASCO/CAP guidelines, in which actionable targets are defined as being able to be matched with existing FDA-approved drugs, including off-label prescriptions. Results: Among the samples received, 85.3% of samples passed quality control requirements for SNV/Indels and amplifications. Majority of the tumor types were categorized under colorectal cancer (20.3%), NSCLC (18.7%), followed by breast cancer (13.6%). Of the samples successfully sequenced, actionable targets were identified in 76.2% of patients, with Tier I variants [such as EGFR exon19del (6), EGFR exon20insertion (1), ERBB2 amp (5), KRAS G12C (3), KRAS G12D (1), KRAS G12V(1), KRAS G12F (1) KRAS G13D (1), PIK3CA H1047R (1), MET exon 14 skipping (1) and NRAS Q61H (1)) being identified in 20 patients. When stratified across tumor types, actionability rates were found to differ, with 100.0%, 83.3% and 81.8%, of tested tissues samples yielding results informing treatment selection or resistance mutations for breast, colorectal and NSCLC respectively. Based on APEX-tissue testing, the median number of actionable genes identified was 2 (IQR: 0 – 3) while the mean time from sampling to report was 4.7 days. Conclusions: This study shows the clinical utility and feasibility of targeted panel testing in cancer types of breast, colorectal and NSCLC. With fast turnaround time of 4 working days, this ensures timely access to treatment for patients.
Analysis of ROS1 fusions in nonlung solid tumors.
Authors: Yan Dong , Xu Mengxiang , Wang Weiran , Han Yushuai , Zhu Jianhua , Ma Tonghui 
Published: June 2022

e15124 Background: Somatic chromosomal fusions involving ROS1 produce chimeric proteins that drive tumorigenesis and progression. Currently, ROS1-directed tyrosine kinase inhibitors (TKIs) are effective treatments for advanced non-small cell lung cancer (NSCLC) patients (pts) with ROS1 fusions. Except for NSCLC, Glioblastoma and spitzoid neoplasms, ROS1 fusions have been rarely reported in other cancers. Therefore, clarifying the patterns and frequency of ROS1 fusions in multi-cancer may help pts benefit from ROS1 inhibit therapy. Methods: To characterize the ROS1-fusion patterns in Chinese pts, we retrospectively analyzed the next-generation sequencing (NGS) data of 11,740 pts from 2017 to 2021. Results: In this study, a total of 12 ROS1 fusions were identified in this Chinese nonlung solid tumors cohort (12/11,740). Among them, the ROS1-fusion positive rate is 0.037% in colonrectal cancer pts (2/5,467), 0.13% in stomach cancer pts (3/2,268), 0.11% in liver cancer pts (2/1,774), 0.19% in kidney cancer pts (1/540), 0.21% in pancreatic cancer pts (2/966) and 0.28% in sarcoma pts (2/725). Particularly, we observed the coexistence of CD80- ROS1 and Intergenic- ROS1 in the same kidney cancer pt. Among ROS1 fusions described in this cohort, the frequency of known partners was 16.67%, and the frequency of unreported partners was 83.33%. Compared with NSCLC (1%̃2%), the ROS1 fusions are less frequent in the nonlung solid tumors (≤0.3%), and fusion partners are mostly unreported, which means that the efficacy of ROS1 TKIs in these solid tumor pts may be different from that in lung cancer. Therefore, more attention and in-depth research are needed in ROS1 fusion positive nonlung solid tumors, which have a low incidence and few cases, so as to bring clinical benefits to more pts. Conclusions: Through NGS, we identified ROS1 fusion patterns in non-lung solid tumors, most of which fusion partners are unreported, expanding the range of ROS1 fusions documented in tumors and providing potential for ROS1 TKIs in multiple tumors.[Table: see text]
Features of chromosome instability in Chinese early-onset colorectal cancers.
Authors: Zhou Xiangwu , Chen Guijin , Zhuo Jinchun , Liu Xinyi , Gao Haixin , Yi Quanwang , Huang Mengli 
Published: June 2022

e15519 Background: In recent years, the etiology and molecular mechanism of early-onset colorectal cancers (EOCRC) has evoking more and more attention. Previous studies suggested that EOCRC had unique somatic mutational characteristics, such as frequent mutations in genes of WNT signaling pathway. However, the features of chromosome instability in this particular subgroup of colorectal cancer remain unclear. Somatic copy number alteration (SCNA) is the main manifestation of chromosome instability. We performed a systematic analysis in regard to SCNAs in a large cohort of Chinese colorectal. Since the microsatellite instable (MSI-H) cancers rarely occurred SCNAs, only microsatellite stable (MSS) patients were included. Methods: A total of 1696 Chinese MSS CRC patients diagnosed in 2018-2020 were included. Early-onset were defined as patients diagnosed under 50 year-olds and the others were late-onset (LO). Genomic alterations and SCNAs were elucidated in all patients’ tumor specimen using next-generation sequencing (NGS) testing. Results: All patients were stratified as EOCRC (n = 439) and LOCRC (n = 1214). 3.87% EOCRC harbored germline cancer susceptibility genes (mainly APC and ATM) mutations while in the LOCRC counterpart the proportion was only 2.06% (mainly MUTYH and BRCA2). Of note, MYC amplification was detected in 71.43% EOCRC with copy-number gain and presented a trend to correlated with APC germline mutations (Fisher’s exact test, p-value = 0.07). In the other CRC (n = 1654) with no germline cancer susceptibility genes, genomic amplifications were detected in 831 (50.2%) cases. The frequency of 8q and 13q amplification were equal in EOCRC and LOCRC. However, EOCRC had higher proportion of 8p and 17q amplification, lower proportion of 20q amplification than LOCRC. Moreover, a higher ratio of EOCRC had high-level amplifications, mainly concentrated in 17q ( ERBB2, CDK12 and RARA) and 13q ( FLT3, CDK8 and FLT1), than LOCRC (23.7% vs 19.1%). Other high-level amplified genes include MYC, CCND2 and EGFR. EGFR high-level amplifications occurred more in EOCRC than LOCRC (13.5 % 2.6%), while CCND2 high-level amplifications were only detected in LOCRC. Gene copy number losses were detected in 195 (11.8%) cases. Loss of SMAD4, CDKN2A, CDKN2B, MAP2K4, PTEN and AMER1 genes were most recurrent. The incidence of SMAD4 (43.1% vs 22.9%), CDKN2B (11.8% vs 6.2%), MAP2K4 (7.8% vs 4.2%) gene losses were higher in EOCRC while the incidence of PTEN (13.9% vs 7.8%) and SMAD3 (6.9% vs 1.9%) gene losses were higher in LOCRC. Conclusions: EOCRC present different SCNA characteristics from LOCRC, including unique focal amplifications, distinct recurrent genes with copy number losses, and more high-level amplifications events mainly distributed in 17q and 13q. It can be reasonably speculated that MYC gene gain was a critical event correlated with familial mutations in EOCRC.