Introduction

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68468/2/10.1177_107554708600800101.pd

Assessing deep learning reconstruction for faster prostate MRI:visual vs. diagnostic performance metrics

Objective: Deep learning (DL) MRI reconstruction enables fast scan acquisition with good visual quality, but the diagnostic impact is often not assessed because of large reader study requirements. This study used existing diagnostic DL to assess the diagnostic quality of reconstructed images. Materials and methods: A retrospective multisite study of 1535 patients assessed biparametric prostate MRI between 2016 and 2020. Likely clinically significant prostate cancer (csPCa) lesions (PI-RADS ≥ 4) were delineated by expert radiologists. T2-weighted scans were retrospectively undersampled, simulating accelerated protocols. DL reconstruction (DLRecon) and diagnostic DL detection (DLDetect) were developed. The effect on the partial area under (pAUC), the Free-Response Operating Characteristic (FROC) curve, and the structural similarity (SSIM) were compared as metrics for diagnostic and visual quality, respectively. DLDetect was validated with a reader concordance analysis. Statistical analysis included Wilcoxon, permutation, and Cohen’s kappa tests for visual quality, diagnostic performance, and reader concordance. Results: DLRecon improved visual quality at 4- and 8-fold (R4, R8) subsampling rates, with SSIM (range: −1 to 1) improved to 0.78 ± 0.02 (p &lt; 0.001) and 0.67 ± 0.03 (p &lt; 0.001) from 0.68 ± 0.03 and 0.51 ± 0.03, respectively. However, diagnostic performance at R4 showed a pAUC FROC of 1.33 (CI 1.28–1.39) for DL and 1.29 (CI 1.23–1.35) for naive reconstructions, both significantly lower than fully sampled pAUC of 1.58 (DL: p = 0.024, naïve: p = 0.02). Similar trends were noted for R8. Conclusion: DL reconstruction produces visually appealing images but may reduce diagnostic accuracy. Incorporating diagnostic AI into the assessment framework offers a clinically relevant metric essential for adopting reconstruction models into clinical practice. Clinical relevance statement: In clinical settings, caution is warranted when using DL reconstruction for MRI scans. While it recovered visual quality, it failed to match the prostate cancer detection rates observed in scans not subjected to acceleration and DL reconstruction.</p

The bmi-1 oncoprotein is differentially expressed in non-small cell lung cancer and correlates with INK4A-ARF locus expression

Genes of the polycomb group function by silencing homeotic selector genes that regulate embryogenesis. In mice, downregulation of one of the polycomb genes, bmi-1, leads to neurological alterations and severe proliferative defects in lymphoid cells, whilst bmi-1 overexpression, together with upregulation of myc-1, induces lymphoma. An oncogenic function has been further supported in primary fibroblast studies where bmi-1 overexpression induces immortalization due to repression of p16/p19ARF, and where together with H-ras, it readily transforms MEFs. It was the aim of this study to assess the expression of bmi-1 in resectable non-small cell lung cancer (NSCLC) in association with p16 and p14ARF (=human p19ARF). Tumours (48 resectable NSCLC (32 squamous, 9 adeno-, 2 large cell, 4 undifferentiated carcinomas and 1 carcinoid); stage I, 29, II, 7, III, 12; T1, 18, T2, 30; differentiation: G1 12, G2 19, G3 17) were studied by immunohistochemistry for protein expression and by comparative multiplex PCR for gene amplification analysis. In tumour-free, normal lung tissue from patients, weak – moderate bmi-1 staining was seen in some epithelial cells, lymphocytes, glandular cells and in fibroblasts, whereas blood, endothelial, chondrocytes, muscle cells and adipocytes did not exhibit any bmi-1 expression. In tumours, malignant cells were negative/weakly, moderately and strongly positive in 20, 22 and 6 cases, respectively. As assessed by multiplex PCR, bmi-1 gene amplification was not the reason for high-level bmi-1 expression. Tumours with moderate or strong bmi-1 expression were more likely to have low levels of p16 and p14ARF (P = 0.02). Similarly, tumours negative for both, p16 and p14ARF, exhibit moderate–strong bmi-1 staining. 58% of resectable NSCLC exhibit moderate–high levels of bmi-1 protein. The inverse correlation of bmi-1 and the INK4 locus proteins expression (p16/p14ARF) supports a possible role for bmi-1 misregulation in lung carcinogenesis. © 2001 Cancer Research Campaign www.bjcancer.co

Ezh2 inhibition in Kras-driven lung cancer amplifies inflammation and associated vulnerabilities

Kras-driven non–small-cell lung cancers (NSCLCs) are a leading cause of death with limited therapeutic options. Many NSCLCs exhibit high levels of Ezh2, the enzymatic subunit of polycomb repressive complex 2 (PRC2). We tested Ezh2 inhibitors as single agents or before chemotherapy in mice with orthotopic Kras-driven NSCLC grafts, which homogeneously express Ezh2. These tumors display sensitivity to EZH2 inhibition by GSK126 but also amplify an inflammatory program involving signaling through NF-κB and genes residing in PRC2-regulated chromatin. During this process, tumor cells overcome GSK126 antiproliferative effects. We identified oncogenes that may mediate progression through an in vivo RNAi screen aimed at targets of PRC2/NF-κB. An in vitro compound screening linked GSK126-driven inflammation and therapeutic vulnerability in human cells to regulation of RNA synthesis and proteostasis. Interestingly, GSK126-treated NSCLCs in vivo also showed an enhanced response to a combination of nimesulide and bortezomib. Thus, Ezh2 inhibition may restrict cell proliferation and promote defined adaptive responses. Targeting these responses potentially improves outcomes in Kras-driven NSCLCs

Using deep learning to optimize the prostate MRI protocol by assessing the diagnostic efficacy of MRI sequences

Purpose: To explore diagnostic deep learning for optimizing the prostate MRI protocol by assessing the diagnostic efficacy of MRI sequences. Method: This retrospective study included 840 patients with a biparametric prostate MRI scan. The MRI protocol included a T2-weighted image, three DWI sequences (b50, b400, and b800 s/mm2), a calculated ADC map, and a calculated b1400 sequence. Two accelerated MRI protocols were simulated, using only two acquired b-values to calculate the ADC and b1400. Deep learning models were trained to detect prostate cancer lesions on accelerated and full protocols. The diagnostic performances of the protocols were compared on the patient-level with the area under the receiver operating characteristic (AUROC), using DeLong's test, and on the lesion-level with the partial area under the free response operating characteristic (pAUFROC), using a permutation test. Validation of the results was performed among expert radiologists. Results: No significant differences in diagnostic performance were found between the accelerated protocols and the full bpMRI baseline. Omitting b800 reduced 53% DWI scan time, with a performance difference of + 0.01 AUROC (p = 0.20) and −0.03 pAUFROC (p = 0.45). Omitting b400 reduced 32% DWI scan time, with a performance difference of −0.01 AUROC (p = 0.65) and + 0.01 pAUFROC (p = 0.73). Multiple expert radiologists underlined the findings. Conclusions: This study shows that deep learning can assess the diagnostic efficacy of MRI sequences by comparing prostate MRI protocols on diagnostic accuracy. Omitting either the b400 or the b800 DWI sequence can optimize the prostate MRI protocol by reducing scan time without compromising diagnostic quality.</p

Bmi1 loss produces an increase in astroglial cells and a decrease in neural stem cell population and proliferation

The polycomb transcriptional repressor Bmi1 promotes cell cycle progression, controls cell senescence, and is implicated in brain development. Loss of Bmi1 leads to a decreased brain size and causes progressive ataxia and epilepsy. Recently, Bmi1 was shown to control neural stem cell (NSC) renewal. However, the effect of Bmi1 loss on neural cell fate in vivo and the question whether the action of Bmi1 was intrinsic to the NSCs remained to be investigated. Here, we show that Bmi1 is expressed in the germinal zone in vivo and in NSCs as well as in progenitors proliferating in vitro, but not in differentiated cells. Loss of Bmi1 led to a decrease in proliferation in zones known to contain progenitors: the newborn cortex and the newborn and adult subventricular zone. This decrease was accentuated in vitro, where we observed a drastic reduction in NSC proliferation and renewal because of NSC-intrinsic effects of Bmi1 as shown by the means of RNA interference. Bmi1(-/-) mice also presented more astrocytes at birth, and a generalized gliosis at postnatal day 30. At both stages, colocalization of bromodeoxyuridine and GFAP demonstrated that Bmi1 loss did not prevent astrocyte precursor proliferation. Supporting these observations, Bmi1(-/-) neurospheres generate preferentially astrocytes probably attributable to a different responsiveness to environmental factors. Bmi1 is therefore necessary for NSC renewal in a cell-intrinsic mode, whereas the altered cell pattern of the Bmi1(-/-) brain shows that in vivo astrocyte precursors can proliferate in the absence of Bmi1

USP15 deubiquitinase safeguards hematopoiesis and genome integrity in hematopoietic stem cells and leukemia cells

Altering ubiquitination by disruption of individual deubiquitinating enzymes (DUBs) has proven to affect hematopoietic stem cell (HSC) maintenance. However, comprehensive knowledge of DUB function during hematopoiesis in vivo is lacking. To accomplish this goal, we systematically inactivated DUBs in mouse hematopoietic progenitors using in vivo small hairpin RNAs (shRNAs) screens. We found that multiple DUBs may be individually required for hematopoiesis and that the ubiquitin-specific protease 15 (USP15) is particularly important for the maintenance of murine hematopoietic stem and progenitor cells in vitro and in vivo. Consistently, Usp15 knockout mice exhibited a reduced HSC pool. The defect was intrinsic to HSCs, as demonstrated by competitive repopulation assays. Importantly, USP15 is highly expressed in normal human hematopoietic cells and leukemias, and USP15 depletion in murine early progenitors and myeloid leukemia cells impaired in vitro expansion and increased genotoxic stress. Our study underscores the importance of DUBs in preserving normal hematopoiesis and uncovers USP15 as a critical DUB in safeguarding genome integrity in HSC and in leukemia cells

Managing Knowledge in Policymaking and Decision Making

The combined effect of increasing problem complexity and growing demand for participation in decisions has forced policymaking and decision making in organizations to become less an analytic endeavor and more a process of "knowledge management ' This requires an intermediarv to mediate among conflicting perspectives and integrate the different forms and levels of knowledge This article describes one such approach to knowledge management that utilizes a third party to create and facilitate a temporary task organization Following a brief case example, some research resultsfrom an evaluation of six past applications of the approach are presented These results provide insight into the effective structuring and conduct of knowledge management proceduresPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68626/2/10.1177_107554708600800106.pd

Tight regulation of ubiquitin-mediated DNA damage response by USP3 preserves the functional integrity of hematopoietic stem cells

Histone ubiquitination at DNA breaks is required for activation of the DNA damage response (DDR) and DNA repair. How the dynamic removal of this modification by deubiquitinating enzymes (DUBs) impacts genome maintenance in vivo is largely unknown. To address this question, we generated mice deficient for Ub-specific protease 3 (USP3; Usp3{delta}/{delta}), a histone H2A DUB which negatively regulates ubiquitin-dependent DDR signaling. Notably, USP3 deletion increased the levels of histone ubiquitination in adult tissues, reduced the hematopoietic stem cell (HSC) reserves over time, and shortened animal life span. Mechanistically, our data show that USP3 is important in HSC homeostasis, preserving HSC self-renewal, and repopulation potential in vivo and proliferation in vitro. A defective DDR and unresolved spontaneous DNA damage contribute to cell cycle restriction of Usp3{delta}/{delta} HSCs. Beyond the hematopoietic system, Usp3{delta}/{delta} animals spontaneously developed tumors, and primary Usp3{delta}/{delta} cells failed to preserve chromosomal integrity. These findings broadly support the regulation of chromatin ubiquitination as a key pathway in preserving tissue function through modulation of the response to genotoxic stress

Transgenic Expression of P1A Induced Thymic Tumor: A Role for Onco-Fetal Antigens in Tumorigenesis

P1A is the first known tumor rejection antigen. It is expressed in embryonic stem cells and multiple tumors but is silent in adult tissues except for the testis and placenta. Therefore, P1A represents a prototype for onco-fetal antigens. To test the potential function of P1A in tumorigenesis, we used a transgenic mouse expressing P1A in lymphoid cells. We observed that immunodeficient host P1A transgenic mice developed thymic tumors after 7 months of age and had shorter survival rates compared to control groups. Most of the 7 examined tumors displayed B cell lineage markers. The P1A transgenic bone marrow cells had higher proliferation ability and more potential progenitors compared to control bone marrow cells. To our knowledge, our data provided the first example that onco-fetal antigen can promote tumorigenesis