cGAS-STING pathway expression correlates with genomic instability and immune cell infiltration in breast cancer

Genomic instability, as caused by oncogene-induced replication stress, can lead to the activation of inflammatory signaling, involving the cGAS-STING and JAK-STAT pathways. Inflammatory signaling has been associated with pro-tumorigenic features, but also with favorable response to treatment, including to immune checkpoint inhibition. In this study, we aim to explore relations between inflammatory signaling, markers of replication stress, and immune cell infiltration in breast cancer. Expression levels of cGAS-STING signaling components (STING, phospho-TBK1, and phospho-STAT1), replication stress markers (γH2AX and pRPA), replication stress-related proto-oncogenes (Cyclin E1 and c-Myc) and immune cell markers (CD20, CD4, and CD57) are determined immunohistochemically on primary breast cancer samples (n = 380). RNA-sequencing data from TCGA (n = 1082) and METABRIC (n = 1904) are used to calculate cGAS-STING scores. pTBK1, pSTAT1 expression and cGAS-STING pathway scores are all increased in triple-negative breast cancers compared to other subtypes. Expression of γH2AX, pRPA, Cyclin E1, c-Myc, and immune cell infiltration positively correlate with p-STAT1 expression (P &lt; 0.001). Additionally, we observe significant positive associations between expression of pTBK1 and γH2AX, pRPA, c-Myc, and number of CD4+ cells and CD20+ cells. Also, cGAS-STING scores are correlated with genomic instability metrics, such as homologous recombination deficiency (P &lt; 0.001) and tumor mutational burden (P &lt; 0.01). Moreover, data from the I-SPY2 clinical trial (n = 71) confirms that higher cGAS-STING scores are observed in breast cancer patients who responded to immunotherapy combined with chemotherapy. In conclusion, the cGAS-STING pathway is highly expressed in TNBCs and is correlated with genomic instability and immune cell infiltration.</p

cGAS-STING pathway expression correlates with genomic instability and immune cell infiltration in breast cancer

Genomic instability, as caused by oncogene-induced replication stress, can lead to the activation of inflammatory signaling, involving the cGAS-STING and JAK-STAT pathways. Inflammatory signaling has been associated with pro-tumorigenic features, but also with favorable response to treatment, including to immune checkpoint inhibition. In this study, we aim to explore relations between inflammatory signaling, markers of replication stress, and immune cell infiltration in breast cancer. Expression levels of cGAS-STING signaling components (STING, phospho-TBK1, and phospho-STAT1), replication stress markers (γH2AX and pRPA), replication stress-related proto-oncogenes (Cyclin E1 and c-Myc) and immune cell markers (CD20, CD4, and CD57) are determined immunohistochemically on primary breast cancer samples (n = 380). RNA-sequencing data from TCGA (n = 1082) and METABRIC (n = 1904) are used to calculate cGAS-STING scores. pTBK1, pSTAT1 expression and cGAS-STING pathway scores are all increased in triple-negative breast cancers compared to other subtypes. Expression of γH2AX, pRPA, Cyclin E1, c-Myc, and immune cell infiltration positively correlate with p-STAT1 expression (P &lt; 0.001). Additionally, we observe significant positive associations between expression of pTBK1 and γH2AX, pRPA, c-Myc, and number of CD4+ cells and CD20+ cells. Also, cGAS-STING scores are correlated with genomic instability metrics, such as homologous recombination deficiency (P &lt; 0.001) and tumor mutational burden (P &lt; 0.01). Moreover, data from the I-SPY2 clinical trial (n = 71) confirms that higher cGAS-STING scores are observed in breast cancer patients who responded to immunotherapy combined with chemotherapy. In conclusion, the cGAS-STING pathway is highly expressed in TNBCs and is correlated with genomic instability and immune cell infiltration.</p

cGAS-STING pathway expression correlates with genomic instability and immune cell infiltration in breast cancer

Genomic instability, as caused by oncogene-induced replication stress, can lead to the activation of inflammatory signaling, involving the cGAS-STING and JAK-STAT pathways. Inflammatory signaling has been associated with pro-tumorigenic features, but also with favorable response to treatment, including to immune checkpoint inhibition. In this study, we aim to explore relations between inflammatory signaling, markers of replication stress, and immune cell infiltration in breast cancer. Expression levels of cGAS-STING signaling components (STING, phospho-TBK1, and phospho-STAT1), replication stress markers (γH2AX and pRPA), replication stress-related proto-oncogenes (Cyclin E1 and c-Myc) and immune cell markers (CD20, CD4, and CD57) are determined immunohistochemically on primary breast cancer samples (n = 380). RNA-sequencing data from TCGA (n = 1082) and METABRIC (n = 1904) are used to calculate cGAS-STING scores. pTBK1, pSTAT1 expression and cGAS-STING pathway scores are all increased in triple-negative breast cancers compared to other subtypes. Expression of γH2AX, pRPA, Cyclin E1, c-Myc, and immune cell infiltration positively correlate with p-STAT1 expression (P &lt; 0.001). Additionally, we observe significant positive associations between expression of pTBK1 and γH2AX, pRPA, c-Myc, and number of CD4+ cells and CD20+ cells. Also, cGAS-STING scores are correlated with genomic instability metrics, such as homologous recombination deficiency (P &lt; 0.001) and tumor mutational burden (P &lt; 0.01). Moreover, data from the I-SPY2 clinical trial (n = 71) confirms that higher cGAS-STING scores are observed in breast cancer patients who responded to immunotherapy combined with chemotherapy. In conclusion, the cGAS-STING pathway is highly expressed in TNBCs and is correlated with genomic instability and immune cell infiltration.</p

Functional independence and health-related functional status following spinal cord injury: A prospective study of the association with physical capacity

Objective: To determine changes in functional independence following spinal cord injury and to evaluate the association between functional independence and physical capacity. Design: Multi-centre prospective cohort study. Subjects: Patients with spinal cord injury admitted for initial rehabilitation. Methods: The motor Functional Independence Measure (FIMmotor) was determined at the start of rehabilitation (n=176), 3 months later (n=124), at discharge (n=160) and one year after discharge from inpatient rehabilitation (n=133). One year after discharge, physical and social dimensions of health-related functional status (Sickness Impact Profile 68; SIP68) were determined. On each occasion, physical capacity was established by measuring arm muscle strength, peak power output and peak oxygen uptake. Results: Multi-level random coefficient analyses revealed that FIMmotor improved during inpatient rehabilitation, but stabilized thereafter. Changes in FIMmotor were associated with peak power output. Multiple regression models showed that FIMmotor and peak power output at discharge were associated with FIMmotor one year after discharge (R2=0.85), and that peak power output at discharge was associated with the social dimension of the SIP68 (R2=0.18) one year after discharge. Conclusion: Functional independence improves during inpatient rehabilitation, and functional independence is positively associated with peak power output

Validating shrimp

Presentation of the progress and future outlook of the chitin valorisation project at the annual DAS Conference, Utrecht

Validating shrimp

Presentation of the progress and future outlook of the chitin valorisation project at the annual DAS Conference, Utrecht

Novel damage model for delamination in Cu/low-k IC backend structures

\u3cp\u3eFor the development of state-of-the-art Cu/low-k CMOS technologies, the integration and introduction of new low-k materials are one of the major bottlenecks due to the bad thermal and mechanical integrity of these materials and the inherited weak interfacial adhesion. Especially the forces resulting from packaging related processes such as dicing, wire bonding, bumping and molding are critical and can easily result in cracking, delamination and chipping of the IC back-end structure if no appropriate measures are taken. This paper presents a methodology for optimizing the thermo-mechanical reliability of bond pads by using a 3D multi-level Finite Element approach. An important characteristic of this methodology is the use of a novel energy-based damage model, which allows a fast qualitative comparison of different back-end structures. The usability of the methodology will be illustrated by the comparison of three different bond pad structures.\u3c/p\u3

Diastereoselective Addition of Allylzinc Bromide to Imines Derived from (R)-Phenylglycine Amide

The highly diastereoselective addition of allylzinc bromide to imines derived from (R)-phenylglycine amide is reported. Homoallylamines with high enantiomeric purity are obtained from the adducts in three steps on removal of the chiral auxiliary by means of a nonreductive protocol. Removal of the auxiliary by hydrogenation leads to the saturated amines, also in high enantiomeric purity.