Search

Background: In order for cancers to progress, they must evade elimination by CD8 T cells or other immune mechanisms. CD8 T cells recognize and kill tumor cells that display immunogenic tumor peptides bound to MHC I molecules. One of the ways that cancers can escape such killing is by reducing expression of MHC I molecules, and loss of MHC I is frequently observed in tumors. There are multiple different mechanisms that can underly the loss of MHC I complexes on tumor and it is currently unclear whether there are particular mechanisms that occur frequently and, if so, in what types of cancers. Also of importance to know is whether the loss of MHC I is reversible and how such loss and/or its restoration would impact responses to immunotherapy. Here, we investigate these issues for loss of IRF1 and IRF2, which are transcription factors that drive expression of MHC I pathway genes and some killing mechanisms. Methods: Bioinformatics analyses of IRF2 and IRF2-dependent gene transcripts were performed for all human cancers in the TCGA RNAseq database. IRF2 protein-DNA-binding was analyzed in ChIPseq databases. CRISRPcas9 was used to knock out IRF1 and IRF2 genes in human and mouse melanoma cells and the resulting phenotypes were analyzed in vitro and in vivo. Results: Transcriptomic analysis revealed that IRF2 expression was reduced in a substantial subset of cases in almost all types of human cancers. When this occurred there was a corresponding reduction in the expression of IRF2-regulated genes that were needed for CD8 T cell recognition. To test cause and effect for these IRF2 correlations and the consequences of IRF2 loss, we gene-edited IRF2 in a patient-derived melanoma and a mouse melanoma. The IRF2 gene-edited melanomas had reduced expression of transcripts for genes in the MHC I pathway and decreased levels of MHC I complexes on the cell surface. Levels of Caspase 7, an IRF2 target gene involved in CD8 T cell killing of tumors, were also reduced. This loss of IRF2 caused both human and mouse melanomas to become resistant to immunotherapy with a checkpoint inhibitor. Importantly, these effects were reversible. Stimulation of the IRF2-deficient melanomas with interferon induced the expression of a functionally homologous transcription factor, IRF1, which then restored the MHC I pathway and responsiveness to CPI. Conclusions: Our study shows that a subset of cases within most types of cancers downregulates IRF2 and that this can allow cancers to escape immune control. This can cause resistance to checkpoint blockade immunotherapy and is reversible with currently available biologics. [ABSTRACT FROM AUTHOR]

Objective: Glioblastoma multiforme (GBM) accounts for up to 60% of all malignant primary brain tumours in adults, occurring in 2–3 cases per 100 000 in Europe and North America. In 2005, a Phase III clinical trial demonstrated a significant improvement in survival over 2, and subsequently 5, years with the addition of concurrent and adjuvant temozolomide (TMZ) to radical radiotherapy (RT). The aim of this study was to investigate if the demonstrated improved survival in the literature translated to clinical practice. Methods: This was a retrospective study including all patients with histologically proven GBM diagnosed from 1999 to 2008 and treated with adjuvant RT at our institution. A total of 273 patients were identified. Statistical analysis was carried out using SPSS® v.18 (SPSS, Chicago, IL). Results: The median survival for the whole group (n5273) over the 10-year period was 7.6 months (95% confidence interval 6.7–8.4 months). Overall, the cumulative probability of survival at 1 and 2 years was 31.5% and 9.4%, respectively. In total, 146 patients received radical RT. 103 patients were treated with radical RT and TMZ and 43 patients received radical RT alone. The median survival for patients receiving radical RT with TMZ was 13.4 months (95% CI 10.9–15.8 months) vs 8.8 months for radical RT alone (95% CI 6.9–10.7 months, p50.006). 2-year survival figures were 21.2% vs 4.7%, respectively. On multivariate analysis, independent predictors of survival included Karnofsky Performance Status, RT dose, TMZ and extent of surgery. The strongest predictors of poorer outcome based on the hazard ratio were palliative RT, followed by not receiving TMZ chemotherapy, then KPS <90 and a biopsy only surgical approach. Conclusion: This paper demonstrates improved survival outcomes consistent with those published in the literature for the addition of concurrent and adjuvant TMZ to radical RT for the treatment of GBM. Although 63% of patients seen in the clinic were suitable for a combined modality approach, the prognosis for the lower Radiation Therapy Oncology Group classes still remains poor. [ABSTRACT FROM AUTHOR]

Jiang Z, Wu C L, Woda B A, Iczkowski K A, Chu P G, Tretiakova M S, Young R H, Weiss L M, Blute R D Jr, Brendler C B, Krausz T, Xu J C, Rock K L, Amin M B & Yang X J (2004) Histopathology 45, 218–225 Alpha-methylacyl-CoA racemase: a multi-institutional study of a new prostate cancer marker : To test whether α-methylacyl-CoA racemase (AMACR) is a sensitive and specific marker of prostate cancer. : The expression levels of AMACR mRNA were measured by real-time polymerase chain reaction. A total of 807 prostatic specimens were further examined by immunohistochemistry specific for AMACR. Quantitative immunostaining analyses were carried out by using the ChromaVision Automated Cellular Imaging System and the Ariol SL-50 Imaging System, respectively. AMACR mRNA levels measured in prostatic adenocarcinoma were 55 times higher than those in benign prostate tissue. Of 454 cases of prostatic adenocarcinoma, 441 were positive for AMACR, while 254 of 277 cases of benign prostate were negative for AMACR. The sensitivity and specificity of AMACR immunodetection of prostatic adenocarcinomas were 97% and 92%, respectively. Both positive and negative predictive values were 95%. By automatic imaging analyses, the AMACR immunostaining intensity and percentage in prostatic adenocarcinomas were also significantly higher than those in benign prostatic tissue (105.9 versus 16.1 for intensity, 45.7% versus 0.02% and 35.03% versus 4.64% for percentage, respectively). : We have demonstrated the promising features of AMACR as a biomarker for prostate cancer in this large series and the potential to develop automated quantitative diagnostic tests. [ABSTRACT FROM AUTHOR]

Various instruments were used to observe the solar corona near or at the time of total eclipse, 31 July, 1981. The High Altitude Observatory (HAO) coronal eclipse camera and the MK-III K-coronameter recorded the lower portions of the corona; the distribution of white light material above 3 R was observed with the Naval Research Laboratory (NRL) satellite coronagraph on P78-1. These data sets are used to describe coronal structure and to identify coronal active regions. The polar coronal holes, as developed at this time in the solar cycle, were offset from the poles of rotation; both were seen displaced eastward on eclipse day. High latitude streamers appear in all three data sets, extending from the base of the corona outward to at least eight solar radii from Sun center. At least two transients were observed by the NRL experiment on the eclipse day, but it is likely that no transient was in progress during any observation along the eclipse path. A distribution of the white-light corona, derived from synoptic K-coronameter data, is given. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 28-year-old woman with a monochorionic diamniotic twin pregnancy and presented with discordant karyotype and anomalies. It mentions that the patient had developed Stage III twin-to-twin transfusion syndrome (TTTS) and an amniotic fluid sample was taken for chromosomal microarray to evalaute the genetics of the fetus.

An abstract of the article "Extending the window for genetic screening sonograms: needs assessment for an ultrasound-based Down's syndrome risk model up to 24 weeks gestation," by C. B. Hertenstein and collesagues is presented.

Presents correction of errors made in the article 'Not Just Research Tools -- proteasome inhibitors offer therapeutic promise,' by A.L. Goldbert and K. Rock which was previously published in volume 8 of 2002 issue of the journal 'Nature Medicine.'