MMR Deficiency Defines Distinct Molecular Subtype of Breast Cancer with Histone Proteomic Networks.

Mismatch repair (MMR) alterations are important prognostic and predictive biomarkers in a variety of cancer subtypes, including colorectal and endometrial. However, in breast cancer (BC), the distinction and clinical significance of MMR are largely unknown. This may be due in part to the fact that genetic alterations in MMR genes are rare and only seen to occur in around 3% of BCs. In the present study, we analyzed TCGA data using a multi-sample protein-protein interaction (PPI) analysis tool, Proteinarium, and showed a distinct separation between specific MMR-deficient and -intact networks in a cohort of 994 BC patients. In the PPI networks specific to MMR deficiency, highly connected clusters of histone genes were identified. We also found the distribution of MMR-deficient BC to be more prevalent in HER2-enriched and triple-negative (TN) BC subtypes compared to luminal BCs. We recommend defining MMR-deficient BC by next-generation sequencing (NGS) when any somatic mutation is detected in one of the seven MMR genes.

Recurrent joint infection caused by a multidrug-resistant capnophilic Escherichia coli ST131 O25H4 strain.

We report a case of a native knee septic arthritis and subsequent osteomyelitis due to a CO2-dependent (capnophilic) multidrug-resistant E. coli ST131 O25:H4 strain. Capnophilic phenotype made microbiology investigation challenging; susceptibility testing could not be performed and the organism did not grow in the urine culture using standard method. The combination of unique virotype and capnophilia may have contributed to the aggressiveness of this organism and the initial unsuccessful carbapenem course, leading to recurrent infection.

Clinical features of patients with MTAP-deleted bladder cancer.

Advanced urothelial carcinoma continues to have a dismal prognosis despite several new therapies in the last 5 years. FGFR2 and FGFR3 mutations and fusions, PD-L1 expression, tumor mutational burden, and microsatellite instability are established predictive biomarkers in advanced urothelial carcinoma. Novel biomarkers can optimize the sequencing of available treatments and improve outcomes. We describe herein the clinical and pathologic features of patients with an emerging subtype of bladder cancer characterized by deletion of the gene MTAP encoding the enzyme S-Methyl-5'-thioadenosine phosphatase, a potential biomarker of response to pemetrexed. We performed a retrospective analysis of 61 patients with advanced urothelial carcinoma for whom demographics, pathologic specimens, next generation sequencing, and clinical outcomes were available. We compared the frequency of histology variants, upper tract location, pathogenic gene variants, tumor response, progression free survival (PFS) and overall survival (OS) between patients with tumors harboring MTAP deletion (MTAP-del) and wild type tumors (MTAP-WT). A propensity score matching of 5 covariates (age, gender, presence of variant histology, prior surgery, and prior non-muscle invasive bladder cancer) was calculated to compensate for disparity when comparing survival in these subgroups. Non-supervised clustering analysis of differentially expressed genes between MTAP-del and MTAP-WT urothelial carcinomas was performed. MTAP-del occurred in 19 patients (31%). Tumors with MTAP-del were characterized by higher prevalence of squamous differentiation (47.4 vs 11.9%), bone metastases (52.6 vs 23.5%) and lower frequency of upper urinary tract location (5.2% vs 26.1%). Pathway gene set enrichment analysis showed that among the genes upregulated in the MTAP-del cohort, at least 5 were linked to keratinization (FOXN1, KRT33A/B, KRT84, RPTN) possibly contributing to the higher prevalence of squamous differentiation. Alterations in the PIK3 and MAPK pathways were more frequent when MTAP was deleted. There was a trend to inferior response to chemotherapy among MTAP-del tumors, but no difference in the response to immune checkpoint inhibitors or enfortumab. Median progression free survival after first line therapy (PFS1) was 5.5 months for patients with MTAP-WT and 4.5 months for patients with MTAP-del (HR = 1.30; 95% CI, 0.64-2.63; P = 0.471). There was no difference in the time from metastatic diagnosis to death (P = 0.6346). Median OS from diagnosis of localized or de novo metastatic disease was 16 months (range 1.5-60, IQR 8-26) for patients with MTAP-del and 24.5 months (range 3-156, IQR 16-48) for patients with MTAP-WT (P = 0.0218), suggesting that time to progression to metastatic disease is shorter in MTAP-del patients. Covariates did not impact significantly overall survival on propensity score matching. In conclusion, MTAP -del occurs in approximately 30% of patients with advanced urothelial carcinoma and defines a subgroup of patients with aggressive features, such as squamous differentiation, frequent bone metastases, poor response to chemotherapy, and shorter time to progression to metastatic disease.

Assessing spatial, temporal, and analytical variation of groundwater chemistry in a large nuclear complex, USA.

Statistical analyses were applied at the Hanford Site, USA, to assess groundwater contamination problems that included (1) determining local backgrounds to ascertain whether a facility is affecting the groundwater quality and (2) determining a 'pre-Hanford' groundwater background to allow formulation of background-based cleanup standards. The primary purpose of this paper is to extend the random effects models for (1) assessing the spatial, temporal, and analytical variability of groundwater background measurements; (2) demonstrating that the usual variance estimate s2, which ignores the variance components, is a biased estimator; (3) providing formulas for calculating the amount of bias; and (4) recommending monitoring strategies to reduce the uncertainty in estimating the average background concentrations. A case study is provided. Results indicate that (1) without considering spatial and temporal variability, there is a high probability of false positives, resulting in unnecessary remediation and/or monitoring expenses; (2) the most effective way to reduce the uncertainty in estimating the average background, and enhance the power of the statistical tests in general, is to increase the number of background wells; and (3) background for a specific constituent should be considered as a statistical distribution, not as a single value or threshold. The methods and the related analysis of variance tables discussed in this paper can be used as diagnostic tools in documenting the extent of inherent spatial and/or temporal variation and to help select an appropriate statistical method for testing purposes.

Optimizing liquid effluent monitoring at a large nuclear complex.

Effluent monitoring typically requires a large number of analytes and samples during the initial or startup phase of a facility. Once a baseline is established, the analyte list and sampling frequency may be reduced. Although there is a large body of literature relevant to the initial design, few, if any, published papers exist on updating established effluent monitoring programs. This paper statistically evaluates four years of baseline data to optimize the liquid effluent monitoring efficiency of a centralized waste treatment and disposal facility at a large defense nuclear complex. Specific objectives were to: (1) assess temporal variability in analyte concentrations, (2) determine operational factors contributing to waste stream variability, (3) assess the probability of exceeding permit limits, and (4) streamline the sampling and analysis regime. Results indicated that the probability of exceeding permit limits was one in a million under normal facility operating conditions, sampling frequency could be reduced, and several analytes could be eliminated. Furthermore, indicators such as gross alpha and gross beta measurements could be used in lieu of more expensive specific isotopic analyses (radium, cesium-137, and strontium-90) for routine monitoring. Study results were used by the state regulatory agency to modify monitoring requirements for a new discharge permit, resulting in an annual cost savings of US dollars 223,000. This case study demonstrates that statistical evaluation of effluent contaminant variability coupled with process knowledge can help plant managers and regulators streamline analyte lists and sampling frequencies based on detection history and environmental risk.