Validation of MIPAS HNO3 operational data

Nitric acid (HNO3) is one of the key products that are operationally retrieved by the European Space Agency (ESA) from the emission spectra measured by the Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) onboard ENVISAT. The product version 4.61/4.62 for the observation period between July 2002 and March 2004 is validated by comparisons with a number of independent observations from ground-based stations, aircraft/balloon campaigns, and satellites. Individual HNO3 profiles of the ESA MIPAS level-2 product show good agreement with those of MIPAS-B and MIPAS-STR (the balloon and aircraft version of MIPAS, respectively), and the balloon-borne infrared spectrometers MkIV and SPIRALE, mostly matching the reference data within the combined instrument error bars. In most cases differences between the correlative measurement pairs are less than 1 ppbv (5-10%) throughout the entire altitude range up to about 38 km (similar to 6 hPa), and below 0.5 ppbv (15-20% or more) above 30 km (similar to 17 hPa). However, differences up to 4 ppbv compared to MkIV have been found at high latitudes in December 2002 in the presence of polar stratospheric clouds. The degree of consistency is further largely affected by the temporal and spatial coincidence, and differences of 2 ppbv may be observed between 22 and 26 km (similar to 50 and 30 hPa) at high latitudes near the vortex boundary, due to large horizontal inhomogeneity of HNO3. Similar features are also observed in the mean differences of the MIPAS ESA HNO3 VMRs with respect to the ground-based FTIR measurements at five stations, aircraft-based SAFIRE-A and ASUR, and the balloon campaign IBEX. The mean relative differences between the MIPAS and FTIR HNO3 partial columns are within +/- 2%, comparable to the MIPAS systematic error of similar to 2%. For the vertical profiles, the biases between the MIPAS and FTIR data are generally below 10% in the altitudes of 10 to 30 km. The MIPAS and SAFIRE HNO3 data generally match within their total error bars for the mid and high latitude flights, despite the larger atmospheric inhomogeneities that characterize the measurement scenario at higher latitudes. The MIPAS and ASUR comparison reveals generally good agreements better than 10-13% at 20-34 km. The MIPAS and IBEX measurements agree reasonably well (mean relative differences within +/- 15%) between 17 and 32 km. Statistical comparisons of the MIPAS profiles correlated with those of Odin/SMR, ILAS-II, and ACE-FTS generally show good consistency. The mean differences averaged over individual latitude bands or all bands are within the combined instrument errors, and generally within 1, 0.5, and 0.3 ppbv between 10 and 40 km (similar to 260 and 4.5 hPa) for Odin/SMR, ILAS-II, and ACE-FTS, respectively. The standard deviations of the differences are between 1 to 2 ppbv. The standard deviations for the satellite comparisons and for almost all other comparisons are generally larger than the estimated measurement uncertainty. This is associated with the temporal and spatial coincidence error and the horizontal smoothing error which are not taken into account in our error budget. Both errors become large when the spatial variability of the target molecule is high.Peer reviewe

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

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Granular cell tumour of the pancreas: A case report and systematic review

Purpose: Granular cell tumours (GCTs) of the pancreas are mostly benign and exceptionally rare, with no unique identifying radiological features. Following a case discussion of a patient with GCT, a comprehensive review of available literature was conducted to identify the common diagnostic features associated with GCT. Methods: Following a case report identifed in our institution, a systematic review was conducted by two authors in accordance with Preferred Reporting Items for Systematic review and Meta-Analysis protocols (PRISMA) guidelines. Databases MEDLINE, EMBASE, Scopus, World of Science, and grey literature were searched on August 2021. Inclusion criteria were histopathology diagnosed granular cell tumour of the pancreas. Results: A 37-year-old male presented with 1 month of abdominal pain and an MRI demonstrating a dilated main pancreatic duct, distal parenchymal atrophy, but no focal lesion. Repeat MRI at 6 months re-demonstrated similar fndings and subsequent endoscopic ultrasound was suspicious for main duct IPMN. Following multidisciplinary team discussion, a spleenpreserving distal pancreatectomy was performed. Histopathology demonstrated granular cell tumour with cells difusely positive for S100 and no malignant transformation. 11 case reports were identifed in the literature with diagnosis confrmed on tissue histopathology based on positive immunohistochemical staining for S-100 protein. Eight patients presented with gastrointestinal symptoms with abdominal pain the main presenting complaint (50%). 10 patients underwent CT with portal venous contrast and all underwent endoscopic examination. Imaging fndings were similar in fve studies for EUS which demonstrated a hypoechoic lesion with homogenous appearance. On non-contrast CT GCT was iso-enhancing, and with portal venous contrast demonstrated hypo-enhancement that gradually enhanced on late phases. Pre-operative diagnosis of pancreatic carcinoma was described in six cases based on imaging and biopsy, resulting in progression to surgical resection. Nine patients were managed surgically and no complications identifed on follow-up (6–52 months). Conclusion: The currently proposed management pathway includes EUS with biopsy and CT, and surgical resection recommended due to malignancy risk. Improved sample collection with EUS-FNA and microscopic assessment utilising S-100 immunohistochemistry may improve pre-operative diagnosis. Limitations include rare numbers in reported literature and short follow-up not allowing an assessment of GCT’s natural history and malignancy risk. Additional cases would expand the current dataset of GCTs of the pancreas, so that surgical resection may be avoided in the future

A further investigation of combined mismatch repair and BRAFV600E mutation specific immunohistochemistry as a predictor of overall survival in colorectal carcinoma.

Mutation specific immunohistochemistry (IHC) is a promising new technique to detect the presence of the BRAFV600E mutation in colorectal carcinoma (CRC). When performed in conjunction with mismatch repair (MMR) IHC, BRAFV600E IHC can help to further triage genetic testing for Lynch Syndrome. In a cohort of 1426 patients undergoing surgery from 2004 to 2009 we recently demonstrated that the combination of MMR and BRAFV600E IHC holds promise as a prognostic marker in CRC, particularly because of its ability to identify the poor prognosis MMR proficient (MMRp) BRAFV600E mutant subgroup. We attempted to validate combined MMR and BRAFV600E IHC as a prognostic indicator in a separate cohort comprising consecutive CRC patients undergoing surgery from 1998 to 2003. IHC was performed on a tissue microarray containing tissue from 1109 patients with CRC. The 5 year survivals stratified by staining patterns were: MMRd/BRAFwt 64%, MMRd/BRAFV600E 64%, MMRp/BRAFwt 60% and MMRp/BRAFV600E 53%. Using the poor prognosis MMRp/BRAFV600E phenotype as baseline, univariate Cox regression modelling demonstrated the following hazard ratios for death: MMRd/BRAFwt HR = 0.71 (95%CI = 0.40-1.27), p = 0.31; MMRd/BRAFV600E HR = 0.74 (95%CI = 0.51-1.07), p = 0.11 and MMRp/BRAFwt HR = 0.79 (95%CI = 0.60-1.04), p = 0.09. Although the findings did not reach statistical significance, this study supports the potential role of combined MMR and BRAF IHC as prognostic markers in CRC

Multivariable Cox regression proportional hazards analysis of 1421 CRCs including myc IHC status and MMR/BRAF IHC phenotype interaction terms.

<p>MMRd – DNA mismatch repair deficient; MMRp – DNA mismatch repair proficient; BRAFwt – BRAF wild type; BRAFV600E – BRAFV600E mutant.</p