DEK expression in Merkel cell carcinoma and small cell carcinoma

Background The chromatin architectural factor DEK maps to chromosome 6p and is frequently overexpressed in several neoplasms, including small cell lung carcinoma, where it is associated with poor prognosis, tumor initiation activity and chemoresistance. DEK expression has not been studied in cutaneous Merkel cell carcinoma. Methods We applied a DEK monoclonal antibody to 15 cases of Merkel cell carcinoma and 12 cases of small cell carcinoma. DEK nuclear immunoreactivity was scored based on percentage (0, negative; 1+, 50%) and intensity (weak, moderate or strong). Results All 15 Merkel cell carcinoma cases (100%) showed diffuse (3+) nuclear positivity (14 strong, 1 weak). Six of 12 small cell carcinoma cases (50%) showed diffuse (3+) and strong nuclear positivity, while one case exhibited focal (1+) weak nuclear positivity. The remaining five cases were negative for DEK expression. Conclusions Our results suggest that DEK may be involved in the pathogenesis of Merkel cell carcinoma and therefore may provide therapeutic implications for Merkel cell carcinomas. In addition, the difference in DEK expression between Merkel cell carcinoma and small cell carcinoma suggests possible separate tumorigenesis pathways for the two tumors.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/92401/1/cup1941.pd

Oncoprotein DEK as a tissue and urinary biomarker for bladder cancer

<p>Abstract</p> <p>Background</p> <p>Bladder cancer is a significant healthcare problem in the United States of America with a high recurrence rate. Early detection of bladder cancer is essential for removing the tumor with preservation of the bladder, avoiding metastasis and hence improving prognosis and long-term survival. The objective of this study was to analyze the presence of DEK protein in voided urine of bladder cancer patients as a urine-based bladder cancer diagnostic test.</p> <p>Methods</p> <p>We examined the expression of DEK protein by western blot in 38 paired transitional cell carcinoma (TCC) bladder tumor tissues and adjacent normal tissue. The presence of DEK protein in voided urine was analyzed by western blot in 42 urine samples collected from patients with active TCC, other malignant urogenital disease and healthy individuals.</p> <p>Results</p> <p>The DEK protein is expressed in 33 of 38 bladder tumor tissues with no expression in adjacent normal tissue. Based on our sample size, DEK protein is expressed in 100% of tumors of low malignant potential, 92% of tumors of low grade and in 71% of tumors of high grade. Next, we analyzed 42 urine samples from patients with active TCC, other malignant urogenital disease, non-malignant urogenital disease and healthy individuals for DEK protein expression by western blot analysis. We are the first to show that the DEK protein is present in the urine of bladder cancer patients. Approximately 84% of TCC patient urine specimens were positive for urine DEK.</p> <p>Conclusion</p> <p>Based on our pilot study of 38 bladder tumor tissue and 42 urine samples from patients with active TCC, other malignant urogenital disease, non-malignant urogenital disease and healthy individuals; DEK protein is expressed in bladder tumor tissue and voided urine of bladder cancer patients. The presence of DEK protein in voided urine is potentially a suitable biomarker for bladder cancer and that the screening for the presence of DEK protein in urine can be explored as a noninvasive diagnostic test for bladder cancer.</p

The human DEK oncogene regulates DNA damage response signaling and repair

The human DEK gene is frequently overexpressed and sometimes amplified in human cancer. Consistent with oncogenic functions, Dek knockout mice are partially resistant to chemically induced papilloma formation. Additionally, DEK knockdown in vitro sensitizes cancer cells to DNA damaging agents and induces cell death via p53-dependent and -independent mechanisms. Here we report that DEK is important for DNA double-strand break repair. DEK depletion in human cancer cell lines and xenografts was sufficient to induce a DNA damage response as assessed by detection of γH2AX and FANCD2. Phosphorylation of H2AX was accompanied by contrasting activation and suppression, respectively, of the ATM and DNA-PK pathways. Similar DNA damage responses were observed in primary Dek knockout mouse embryonic fibroblasts (MEFs), along with increased levels of DNA damage and exaggerated induction of senescence in response to genotoxic stress. Importantly, Dek knockout MEFs exhibited distinct defects in non-homologous end joining (NHEJ) when compared to their wild-type counterparts. Taken together, the data demonstrate new molecular links between DEK and DNA damage response signaling pathways, and suggest that DEK contributes to DNA repair

Application of chiral perturbation theory to K→2π decays

Chiral perturbation theory is applied to the decay K→2π. It is shown that, to quadratic order in meson masses, the amplitude for K→2π can be written in terms of the unphysical amplitudes K→π and K→0, where 0 is the vacuum. One may then hope to calculate these two simpler amplitudes with lattice Monte Carlo techniques, and thereby gain understanding of the ΔI=1/2 rule in K decay. The reason for the presence of the K→0 amplitude is explained: it serves to cancel off unwanted renormalization contributions to K→π. We make a rough test of the practicability of these ideas in Monte Carlo studies. We also describe a method for evaluating meson decay constants which does not require a determination of the quark masses

Differential expression and prognostic value of long nonâ coding RNA in HPVâ negative head and neck squamous cell carcinoma

BackgroundLong nonâ coding RNA (lncRNA) has emerged as a new avenue of interest due to its various biological functions in cancer. Abnormal expression of lncRNA has been reported in other malignancies but has been understudied in head and neck squamous cell carcinoma (HNSCC).MethodsThe lncRNA expression was interrogated via quantitative realâ time polymerase chain reaction (qRTâ PCR) array for 19 human papillomavirus (HPV)â negative HNSCC tumorâ normal pairs. The Cancer Genome Atlas (TCGA) was used to validate these results. The association between differentially expressed lncRNA and survival outcomes was analyzed.ResultsDifferential expression was validated for 5 lncRNA (SPRY4â IT1, HEIH, LUCAT1, LINC00152, and HAND2â AS1). There was also an inverse association between MEG3 expression (not significantly differentially expressed in TCGA tumors but highly variable expression) and 3â year recurrenceâ free survival (RFS).ConclusionWe identified and validated differential expression of 5 lncRNA in HPVâ negative HNSCC. Low MEG3 expression was associated with favorable 3â year RFS, although the significance of this finding remains unclear.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144638/1/hed25136_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144638/2/hed25136.pd

Phase 1 doseâ finding study of metformin in combination with concurrent cisplatin and radiotherapy in patients with locally advanced head and neck squamous cell cancer

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153201/1/cncr32539.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153201/2/cncr32539_am.pd

Working in disadvantaged communities: What additional competencies do we need?

Background: Residents of socioeconomically disadvantaged locations are more likely to have poor health than residents of socioeconomically advantaged locations and this has been comprehensively mapped in Australian cities. These inequalities present a challenge for the public health workers based in or responsible for improving the health of people living in disadvantaged localities. The purpose of this study was to develop a generic workforce needs assessment tool and to use it to identify the competencies needed by the public health workforce to work effectively in disadvantaged communities. Methods: A two-step mixed method process was used to identify the workforce needs. In step 1 a generic workforce needs assessment tool was developed and applied in three NSW Area Health Services using focus groups, key stakeholder interviews and a staff survey. In step 2 the findings of this needs assessment process were mapped against the existing National Health Training Package (HLT07) competencies, gaps were identified, additional competencies described and modules of training developed to fill identified gaps. Results: There was a high level of agreement among the AHS staff on the nature of the problems to be addressed but less confidence indentifying the work to be done. Processes for needs assessments, community consultations and adapting mainstream programs to local needs were frequently mentioned as points of intervention. Recruiting and retaining experienced staff to work in these communities and ensuring their safety were major concerns. Workforce skill development needs were seen in two ways: higher order planning/epidemiological skills and more effective working relationships with communities and other sectors. Organisational barriers to effective practice were high levels of annual compulsory training, balancing state and national priorities with local needs and giving equal attention to the population groups that are easy to reach and to those that are difficult to engage. A number of additional competency areas were identified and three training modules developed. Conclusion: The generic workforce needs assessment tool was easy to use and interpret. It appears that the public health workforce involved in this study has a high level of understanding of the relationship between the social determinants and health. However there is a skill gap in identifying and undertaking effective intervention

Association of immunotherapy and immunosuppression with severe COVID-19 disease in patients with cancer

Background: Cytokine storm due to COVID-19 can cause high morbidity and mortality. Patients with cancer treated with immunotherapy (IO) and those with immunosuppression may have higher rates of cytokine storm due to immune dysregulation. We sought to evaluate the association of IO and immunosuppression with COVID-19 outcomes and cytokine storm occurrence among patients with cancer and COVID-19, based on data from the COVID-19 and Cancer Consortium (CCC19). Methods: A registry-based retrospective cohort study was conducted on patients reported to the CCC19 registry from March 2020 to September 2021. The primary outcome was defined as an ordinal scale of COVID-19 severity. The secondary outcome was the occurrence of a cytokine storm using CCC19 variables, defined as biological and clinical evidence of severe inflammation, with end-organ dysfunction (Fajgenbaum D.C. et al., N Engl J Med., 2020). The association of IO or immunosuppression with the outcomes of interest were evaluated using a multivariable logistic regression balanced for covariate distributions through inverse probability of treatment weighting (IPTW). Results: A total of 10,214 patients were included, among which 482 (4.7%) received IO, 3,715 (36.4%) received non-IO systemic therapies, and 6,017 (58.9%) were untreated in the 3 months prior to COVID-19 diagnosis. No difference in COVID-19 severity or the development of a cytokine storm was found in the IO group compared to the untreated group (aOR: 0.77; 95%CI:0.45-1.32, and aOR: 1.06; 95%CI:0.42-2.67, respectively). On multivariable analysis, baseline immunosuppression was associated with worse outcomes both in relation to COVID-19 severity (aOR: 1.89; 95%CI:1.51-2.35) and the presence of a cytokine storm (aOR: 1.75; 95%CI:1.30-2.35). Conclusions: Administration of IO was not associated with severe outcomes in patients with cancer and COVID-19, whereas pre-existing baseline immunosuppression appears to be independently associated with worse clinical outcomes including cytokine storm

A prognostic model of all-cause mortality at 30 days in patients with cancer and COVID-19

Background: Patients with cancer are at higher risk of dying of COVID-19. Known risk factors for 30-day all-cause mortality (ACM-30) in patients with cancer are older age, sex, smoking status, performance status, obesity, and co-morbidities. We hypothesized that common clinical and laboratory parameters would be predictive of a higher risk of 30-day ACM, and that a machine learning approach (random forest) could produce high accuracy. Methods: In this multi-institutional COVID-19 and Cancer Consortium (CCC19) registry study, 12,661 patients enrolled between March 17, 2020 and December 31, 2021 were utilized to develop and validate a model of ACM-30. ACM-30 was defined as death from any cause within 30 days of COVID-19 diagnosis. Pre-specified variables were: age, sex, race, smoking status, ECOG performance status (PS), timing of cancer treatment relative to COVID19 diagnosis, severity of COVID19, type of cancer, and other laboratory measurements. Missing variables were imputed using random forest proximity. Random forest was utilized to model ACM-30. The area under the curve (AUC) was computed as a measure of predictive accuracy with out-of-bag prediction. One hundred bootstrapped samples were used to obtain the standard error of the AUC. Results: The median age at COVID-19 diagnosis was 65 years, 53% were female, 18% were Hispanic, and 16.7% were Black. Over half were never smokers and the median body mass index was 28.2. Random forest with under sampling selected 20 factors prognostic of ACM-30. The AUC was 88.9 (95% CI 88.5-89.2). Highly informative parameters included: COVID-19 severity at presentation, cancer status, age, troponin level, ECOG PS and body mass index. Conclusions: This prognostic model based on readily available clinical and laboratory values can be used to estimate individual survival probability within 30-days for COVID-19. In addition, this model can be used to select or classify patients with cancer and COVID-19 into risk groups based on validated cut points, for treatment selection, prophylaxis prioritization, and/or enrollment in clinical trials. Future work includes external validation using other large datasets of patients with COVID-19 and cancer