Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis

Oesophageal adenocarcinoma (EAC) incidence is rapidly increasing in Western countries. A better understanding of EAC underpins efforts to improve early detection and treatment outcomes. While large EAC exome sequencing efforts to date have found recurrent loss-offunction mutations, oncogenic driving events have been underrepresented. Here we use a combination of whole-genome sequencing (WGS) and single-nucleotide polymorphism-array profiling to show that genomic catastrophes are frequent in EAC, with almost a third (32%, n¼40/123) undergoing chromothriptic events. WGS of 22 EAC cases show that catastrophes may lead to oncogene amplification through chromothripsis-derived double-minute chromosome formation (MYC and MDM2) or breakage-fusion-bridge (KRAS, MDM2 and RFC3). Telomere shortening is more prominent in EACs bearing localized complex rearrangements. Mutational signature analysis also confirms that extreme genomic instability in EAC can be driven by somatic BRCA2 mutations. These findings suggest that genomic catastrophes have a significant role in the malignant transformation of EAC

Selective impact of CDK4/6 suppression on patient-derived models of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDA) harbors an exceedingly poor prognosis, and is generally considered a therapy-recalcitrant disease due to poor response to conventional chemotherapy coupled with non-actionable genetic drivers (e.g. KRAS mutations). However, PDA frequently loses p16ink4a, thereby leading to deregulation of CDK4/6. Surprisingly, in established cell models and xenografts, CDK4/6 inhibition has a modest effect on proliferation and resistance develops rapidly. To determine if such weak response was an intrinsic feature of PDA, we developed primary tumor explants that maintain the tumor environment and recapitulate feuture of primary PDA. The CDK4/6 inhibitor PD-0332991 was highly efficient at suppressing proliferation in 14 of the 15 explants. In the single resistant explant, we identified the rare loss of the RB tumor suppressor as the basis for resistance. Patient-derived xenografts (PDXs) were developed in parallel, and unlike the xenografts emerging from established cell lines, the PDXs maintained the histoarchitecture of the primary tumor. These PDXs were highly sensitive to CDK4/6 inhibition, yielding a complete suppression of PDA proliferation. Together, these data indicate that primary PDA is sensitive to CDK4/6 inhibition, that specific biomarkers can delineate intrinsic resistance, and that established cell line models may not represent an adequate means for evaluating therapeutic sensitivities

Voronovskaja type theorem for the Lupaş q-analogue of the Bernstein operators

In this paper, we estimate the third and the fourth order central moments for the difference of the Lupaş q-analogue of the Bernstein operator and the limit q-Lupaş operator. We also prove a quantitative variant of Voronovskaja\u27s theorem for $R_{n,q}$

Somatic point mutation calling in low cellularity tumors

Somatic mutation calling from next-generation sequencing data remains a challenge due to the difficulties of distinguishing true somatic events from artifacts arising from PCR, sequencing errors or mis-mapping. Tumor cellularity or purity, sub-clonality and copy number changes also confound the identification of true somatic events against a background of germline variants. We have developed a heuristic strategy and software (http://www.qcmg.org/bioinformatics/qsnp/) for somatic mutation calling in samples with low tumor content and we show the superior sensitivity and precision of our approach using a previously sequenced cell line, a series of tumor/normal admixtures, and 3,253 putative somatic SNVs verified on an orthogonal platform.Karin S. Kassahn, Oliver Holmes, Katia Nones, Ann-Marie Patch, David K. Miller, Angelika N. Christ, Ivon Harliwong, Timothy J. Bruxner, Qinying Xu, Matthew Anderson, Scott Wood, Conrad Leonard, Darrin Taylor, Felicity Newell, Sarah Song, Senel Idrisoglu, Craig Nourse, Ehsan Nourbakhsh, Suzanne Manning, Shivangi Wani, Anita Steptoe, Marina Pajic, Mark J. Cowley, Mark Pinese, David K. Chang, Anthony J. Gill, Amber L. Johns, Jianmin Wu, Peter J. Wilson, Lynn Fink, Andrew V. Biankin, Nicola Waddell, Sean M. Grimmond, John V. Pearso

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Wireless Sensor System for Monitoring Sportsmen Exposed to Hazardous Concussions

Sport-related Traumatic Brain injuries (TBI) are a major problem in ice hockey. Reports show that it occurs 160 concussion per 1000 hours of play time and 4.6% of head injuries leads to a concussion in Sweden. A system that can monitor the players in real time and indicate an impact can contribute to better understanding the biomechanical etiology of a concussion. Purpose of this project is to test the ability of a wireless sensor network for monitoring the g-Forces that affect the head of the ice hockey players in real-time. We build a wireless sensor network system called g-Force Monitoring System (GFMS) by implementing a Web Socket connection between the sensor nodes and the server. The sensor measures and transmits the data over the Web Socket protocol to the server and the server registers and allows monitoring of the g-Force values in real-time. We achieved a 6 ms sampling rate by using the g-Force Monitoring System. The system was able to operate during one hour play time without any significant problem. The stored data shows that the GFMS has an ability to indicate impact and its duration over a predefined threshold. The user of the system can monitor the g-Force data in real time or can do analyzes on stored values. The GFMS can deliver valuable indications. If the system can come to existence and be implemented into the ice hockey helmets, by letting medical experts to look at and analyze the g-Force data, it can decrease the diagnosis and recovery time of a concussion. It can help to make the Ice hockey arena to a safer place without having to change the rhythm of the game

Wireless Sensor System for Monitoring Sportsmen Exposed to Hazardous Concussions

Sport-related Traumatic Brain injuries (TBI) are a major problem in ice hockey. Reports show that it occurs 160 concussion per 1000 hours of play time and 4.6% of head injuries leads to a concussion in Sweden. A system that can monitor the players in real time and indicate an impact can contribute to better understanding the biomechanical etiology of a concussion. Purpose of this project is to test the ability of a wireless sensor network for monitoring the g-Forces that affect the head of the ice hockey players in real-time. We build a wireless sensor network system called g-Force Monitoring System (GFMS) by implementing a Web Socket connection between the sensor nodes and the server. The sensor measures and transmits the data over the Web Socket protocol to the server and the server registers and allows monitoring of the g-Force values in real-time. We achieved a 6 ms sampling rate by using the g-Force Monitoring System. The system was able to operate during one hour play time without any significant problem. The stored data shows that the GFMS has an ability to indicate impact and its duration over a predefined threshold. The user of the system can monitor the g-Force data in real time or can do analyzes on stored values. The GFMS can deliver valuable indications. If the system can come to existence and be implemented into the ice hockey helmets, by letting medical experts to look at and analyze the g-Force data, it can decrease the diagnosis and recovery time of a concussion. It can help to make the Ice hockey arena to a safer place without having to change the rhythm of the game