Loss of hepatic Sirt7 accelerates diethylnitrosamine (DEN)-induced formation of hepatocellular carcinoma by impairing DNA damage repair.

The mammalian sirtuin family (SIRT1-SIRT7) has shown diverse biological roles in the regulation and maintenance of genome stability under genotoxic stress. SIRT7, one of the least studied sirtuin, has been demonstrated to be a key factor for DNA damage response (DDR). However, conflicting results have proposed that Sirt7 is an oncogenic factor to promote transformation in cancer cells. To address this inconsistency, we investigated properties of SIRT7 in hepatocellular carcinoma (HCC) regulation under DNA damage and found that loss of hepatic Sirt7 accelerated HCC progression. Specifically, the number, size, and volume of hepatic tumor colonies in diethylnitrosamine (DEN) injected Sirt7-deficient liver were markedly enhanced. Further, levels of HCC progression markers and pro-inflammatory cytokines were significantly elevated in the absence of hepatic Sirt7, unlike those in the control. In chromatin, SIRT7 was stabilized and colocalized to damage site by inhibiting the induction of γH2AX under DNA damage. Together, our findings suggest that SIRT7 is a crucial factor for DNA damage repair and that hepatic loss-of-Sirt7 can promote genomic instability and accelerate HCC development, unlike early studies describing that Sirt7 is an oncogenic factor [BMB Reports 2024; 57(2): 98-103].

Soluble receptors in cancer: mechanisms, clinical significance, and therapeutic strategies.

Soluble receptors are soluble forms of receptors found in the extracellular space. They have emerged as pivotal regulators of cellular signaling and disease pathogenesis. This review emphasizes their significance in cancer as diagnostic/prognostic markers and potential therapeutic targets. We provide an overview of the mechanisms by which soluble receptors are generated along with their functions. By exploring their involvement in cancer progression, metastasis, and immune evasion, we highlight the importance of soluble receptors, particularly soluble cytokine receptors and immune checkpoints, in the tumor microenvironment. Although current research has illustrated the emerging clinical relevance of soluble receptors, their therapeutic applications remain underexplored. As the landscape of cancer treatment evolves, understanding and targeting soluble receptors might pave the way for novel strategies for cancer diagnosis, prognosis, and therapy.

Inhibition of SIRT7 overcomes sorafenib acquired resistance by suppressing ERK1/2 phosphorylation via the DDX3X-mediated NLRP3 inflammasome in hepatocellular carcinoma.

AIMS: Sirtuin 7 (SIRT7) plays an important role in tumor development, and has been characterized as a potent regulator of cellular stress. However, the effect of SIRT7 on sorafenib acquired resistance remains unclear and a possible anti-tumor mechanism beyond this process in HCC has not been clarified. We examined the therapeutic potential of SIRT7 and determined whether it functions synergistically with sorafenib to overcome chemoresistance. METHODS: Cancer Genome Atlas-liver HCC data and unbiased gene set enrichment analyses were used to identify SIRT7 as a potential effector molecule in sorafenib acquired resistance. Two types of SIRT7 chemical inhibitors were developed to evaluate its therapeutic properties when synergized with sorafenib. Mass spectrometry was performed to discover a direct target of SIRT7, DDX3X, and DDX3X deacetylation levels and protein stability were explored. Moreover, an in vivo xenograft model was used to confirm anti-tumor effect of SIRT7 and DDX3X chemical inhibitors combined with sorafenib. RESULTS: SIRT7 inhibition mediated DDX3X depletion can re-sensitize acquired sorafenib resistance by disrupting NLRP3 inflammasome assembly, finally suppressing hyperactive ERK1/2 signaling in response to NLRP3 inflammasome-mediated IL-1ß inhibition. CONCLUSIONS: SIRT7 is responsible for sorafenib acquired resistance, and its inhibition would be beneficial when combined with sorafenib by suppressing hyperactive pro-cell survival ERK1/2 signaling.

Tumoural Pellino-1 expression and Pellino-1-expressive cytotoxic T-cells are associated with poor prognosis in diffuse large B-cell lymphoma.

Pellino-1 plays a role in regulating inflammation and immune responses, and its effects on tumours are complex, with different outcomes reported in various studies. Additionally, the role of Pellino-1 in diffuse large B-cell lymphoma (DLBCL) has not been thoroughly investigated. We aimed to examine the expression of Pellino-1 in tumour cells and tumour-infiltrating lymphocytes (TILs) separately and identify the clinicopathological significance of Pellino-1 expression in DLBCL. We evaluated Pellino-1 expression in 104 patients with DLBCL. The density of specific cell types was quantitatively analysed using digital image analysis after a multiplex immunofluorescence staining with Pellino-1, CD20, CD8, FOXP3, and PD-1. Pellino-1 expression was mostly observed in CD20+ tumour cells and CD8+ TILs. The high CD8+/Pellino-1+ group was significantly associated with the non-GCB subtype and higher numbers of Foxp3+ T-cells. Patients with high CD20+/Pellino-1+ and high CD8+/Pellino-1+ cell densities had significantly shorter event-free survival (EFS) rates. The multivariate Cox-regression analysis showed that CD20+/Pellino-1+ cell density and CD8+/Pellino-1+ cell density were independent poor prognostic factors for EFS. Furthermore, patients with low densities of both CD20+/Pellino-1+ and CD8+/Pellino-1+ cells demonstrated a prognosis superior to that of patients with high Pellino-1+ cell densities, either alone or in combination. Additionally, the multivariate analysis demonstrated that the combination of CD20+/Pellino-1+ and CD8+/Pellino-1+ cell densities was an independent prognostic factor for EFS and overall survival. Pellino-1 expression was observed in both tumour cells and TILs, particularly in cytotoxic T-cells, and was correlated with poor outcomes in DLBCL. Thus, Pellino-1 might have an oncogenic effect on DLBCL and might be a potential target for improving cytotoxic T-cell activity.

Structural conservation in the glutathione binding in Sphingomonas sp. glutaredoxin Grx3 and variations for cold adaptation.

Glutaredoxin 3 (Grx3), a redox protein with a thioredoxin-fold structure, maintains structural integrity and glutathione (GSH) binding capabilities across varying habitat temperatures. The cis-Pro loop, essential for GSH binding, relies on the Arg-Asp salt bridge (α2-α3) and Gln-His hydrogen bond (ß3-ß4) for its conformation. In some psychrophilic Grx3 variants, Arg in α2 is replaced with Tyr, and His in ß4 is replaced with Phe. This study examines the roles of these bonds in Grx3's structure, function, and cold adaptation, using SpGrx3 from the Arctic bacterium Sphingomonas sp. Despite its cold habitat, SpGrx3 maintains the Arg51-Asp69 salt bridge and Gln56-His63 hydrogen bond. The R51Y substitution disrupts the α2-α3 salt bridge, while the H63F and H63Y substitutions hinder the salt bridge through cation-π interactions with Arg51, involving Phe63/Tyr63, thereby enhancing flexibility. Conversely, mutations that disrupt the hydrogen bond (Q56A, H63A, and H63F) reduce thermal stability. In the psychrophilic Grx3 configuration A48T/R51Y/H63F, a Thr48-Gln56 hydrogen bond stabilizes the cis-Pro loop, enhancing flexibility by disrupting both bonds. Furthermore, all mutants exhibit reduced α-helical content and catalytic efficiency. In summary, the highly conserved Arg51-Asp69 salt bridge and Gln56-His63 hydrogen bond are crucial for stabilizing the cis-Pro loop and catalytic activity in SpGrx3. His63 is favored as it avoids cation-π interactions with Arg51, unlike Phe63/Tyr63. Psychrophilic Grx3 variants have adapted to cold environments by reducing GSH binding and increasing structural flexibility. These findings deepen our understanding of the structural conservation in Grx3 for GSH binding and the critical alterations required for cold adaptation.

Machine learning-based prediction model for emergency department visits using prescription information in community-dwelling non-cancer older adults.

Older adults are more likely to require emergency department (ED) visits than others, which might be attributed to their medication use. Being able to predict the likelihood of an ED visit using prescription information and readily available data would be useful for primary care. This study aimed to predict the likelihood of ED visits using extensive medication variables generated according to explicit clinical criteria for elderly people and high-risk medication categories by applying machine learning (ML) methods. Patients aged ≥ 65 years were included, and ED visits were predicted with 146 variables, including demographic and comprehensive medication-related factors, using nationwide claims data. Among the eight ML models, the final model was developed using LightGBM, which showed the best performance. The final model incorporated 93 predictors, including six sociodemographic, 28 comorbidity, and 59 medication-related variables. The final model had an area under the receiver operating characteristic curve of 0.689 in the validation cohort. Approximately half of the top 20 strong predictors were medication-related variables. Here, an ED visit risk prediction model for older people was developed and validated using administrative data that can be easily applied in clinical settings to screen patients who are likely to visit an ED.

A comparative analysis on the publicness of medical services in public health institutions: With an empirical analysis of the national health insurance database.

The purpose of this study is to analyze the publicness of medical services in public and private medical institutions, with a focus on treatment performance using National Health Insurance data. Data from the National Health Insurance Service were used to compare the publicness of medical services in public and private medical institutions. Beta regression analysis was conducted after adjusting for the relevant characteristics to identify the impact on the public treatment performance of medical institutions. The public case rate of public health institutions was higher than that of private medical institutions. According to the type of medical care institution, the public case rate was higher in general hospitals and tertiary hospitals than in hospitals. Recently, it has often highlighted that increasing emphasis of profitability in the evaluation of public health institutions is damaging the publicness of medical services. Even in this study, it can be evaluated that the public case rate of public health institutions is not higher than that of private medical institutions.

Pellino-1 expression is associated with epidermal proliferation and enhanced Th17 cell infiltration in psoriatic lesions.

Pellino-1 plays a crucial role in cellular proliferation and regulates inflammatory processes. This study investigated Pellino-1 expression patterns and their relationship with CD4+ T-cell subsets in psoriasis patients. Group 1 comprised primarily biopsied psoriasis lesions from 378 patients, multiplex-immunostained for Pellino-1, CD4 and representative T helper (Th) cells (T-bet [Th1], GATA3 [Th2], and RORγt [Th17] and regulatory T cell [FoxP3] markers). Ki-67 labeling was evaluated in the epidermis. Group 2 comprised 43 Pellino-1-positive cases immunostained for Pellino-1 in both lesion and non-lesion skin biopsy samples. Five normal skin biopsies served as controls. Among 378 psoriasis cases, 293 (77.5%) were positive for Pellino-1 in the epidermis. Pellino-1-positivity was higher in psoriasis lesions than in non-lesions and normal skin (52.55% vs. 40.43% vs. 3.48%, p < 0.001; H-score, 72.08 vs. 47.55 vs. 4.40, p < 0.001, respectively). Pellino-1-positive cases also had a significantly higher Ki-67 labeling index (p < 0.001). Epidermal Pellino1-positivity was significantly associated with higher RORγt+ (p = 0.001) and FoxP3+ (p < 0.001) CD4+ T cell ratios but not T-bet+ and GATA3+ CD4+ T cell ratios. Among the CD4+ Pellino-1+ T-cell subsets, the CD4+ Pellino-1+ RORγt+ ratio was significantly associated with epidermal Pellinio-1 expression (p < 0.001). Pellino-1 expression is thus increased in psoriasis lesions and associated with increased epidermal proliferation and CD4+ T-cell subset infiltration, especially Th17 cells. This suggests that Pellino-1 could be a therapeutic target that simultaneously regulates psoriasis epidermal proliferation and immune interactions.

Ubiquitination Links DNA Damage and Repair Signaling to Cancer Metabolism.

Changes in the DNA damage response (DDR) and cellular metabolism are two important factors that allow cancer cells to proliferate. DDR is a set of events in which DNA damage is recognized, DNA repair factors are recruited to the site of damage, the lesion is repaired, and cellular responses associated with the damage are processed. In cancer, DDR is commonly dysregulated, and the enzymes associated with DDR are prone to changes in ubiquitination. Additionally, cellular metabolism, especially glycolysis, is upregulated in cancer cells, and enzymes in this metabolic pathway are modulated by ubiquitination. The ubiquitin-proteasome system (UPS), particularly E3 ligases, act as a bridge between cellular metabolism and DDR since they regulate the enzymes associated with the two processes. Hence, the E3 ligases with high substrate specificity are considered potential therapeutic targets for treating cancer. A number of small molecule inhibitors designed to target different components of the UPS have been developed, and several have been tested in clinical trials for human use. In this review, we discuss the role of ubiquitination on overall cellular metabolism and DDR and confirm the link between them through the E3 ligases NEDD4, APC/CCDH1, FBXW7, and Pellino1. In addition, we present an overview of the clinically important small molecule inhibitors and implications for their practical use.

Protein phosphatases regulate the liver microenvironment in the development of hepatocellular carcinoma.

The liver is a complicated heterogeneous organ composed of different cells. Parenchymal cells called hepatocytes and various nonparenchymal cells, including immune cells and stromal cells, are distributed in liver lobules with hepatic architecture. They interact with each other to compose the liver microenvironment and determine its characteristics. Although the liver microenvironment maintains liver homeostasis and function under healthy conditions, it also shows proinflammatory and profibrogenic characteristics that can induce the progression of hepatitis and hepatic fibrosis, eventually changing to a protumoral microenvironment that contributes to the development of hepatocellular carcinoma (HCC). According to recent studies, phosphatases are involved in liver diseases and HCC development by regulating protein phosphorylation in intracellular signaling pathways and changing the activities and characteristics of liver cells. Therefore, this review aims to highlight the importance of protein phosphatases in HCC development and in the regulation of the cellular components in the liver microenvironment and to show their significance as therapeutic targets.

Effect of optical blurring of X-ray source on breast tomosynthesis image quality: Modulation transfer function, anatomical noise power spectrum, and signal detectability perspectives.

We investigated the effect of the optical blurring of X-ray source on digital breast tomosynthesis (DBT) image quality using well-designed DBT simulator and table-top experimental systems. To measure the in-plane modulation transfer function (MTF), we used simulated sphere phantom and Teflon sphere phantom and generated their projection data using two acquisition modes (i.e., step-and-shoot mode and continuous mode). After reconstruction, we measured the in-plane MTF using reconstructed sphere phantom images. In addition, we measured the anatomical noise power spectrum (aNPS) and signal detectability. We constructed simulated breast phantoms with a 50% volume glandular fraction (VGF) of breast anatomy using the power law spectrum and inserted spherical objects with 1 mm, 2 mm, and 5 mm diameters as breast masses. Projection data were acquired using two acquisition modes, and in-plane breast images were reconstructed using the Feldkamp-Davis-Kress (FDK) algorithm. For the experimental study, we used BR3D breast phantom with 50% VGF and obtained projection data using a table-top experimental system. To compare the detection performance of the two acquisition modes, we calculated the signal detectability using the channelized Hotelling observer (CHO) with Laguerre-Gauss (LG) channels. Our results show that spatial resolution of in-plane image in continuous mode was degraded due to the optical blurring of X-ray source. This blurring effect was reflected in aNPS, resulting in large ß values. From a signal detectability perspective, the signal detectability in step-and-shoot mode is higher than that in continuous mode for small spherical signals but not large spherical signals. Although the step-and-shoot mode has disadvantage in terms of scan time compared to the continuous mode, scanning in step-and-shoot mode is better for detecting small signals, indicating that there is a tradeoff between scan time and image quality.

Are high medical costs incurred by people with disabilities excessive?: An empirical analysis of Korean National Health Insurance Data.

A crude comparison of medical costs between people with disabilities (PWD) and without disabilities (PWoD) shows a much higher expenditure among PWD and such results have been a cause for further stigmatization. This study aims to empirically analyze whether the medical costs for PWD are actually high when characteristics related to medical costs are adjusted. Ten percent of the total population was randomly selected from the Korean National Health Insurance (NHI) Database in 2016. A crude comparative analysis was performed to calculate the medical cost of PWD and PWoD. A subsequent multiple regression analysis was conducted to adjust factors affecting the medical costs such as socioeconomic status, disease, and health behavior-related characteristics. The medical cost for PWD was 3.6 times higher than that for PWoD by crude comparison. However, after multiple regression analysis, margin of difference decreased to 1.5 times although the cost for PWD remained higher. Substantial decrease in higher medical costs for PWD after multiple analyses compared to crude analysis implies that additional adjustment using variables such as disease severity, not available in the NHI database, may predict a further reduction in differences. Thus, it is difficult to determine that the medical expenditure for PWD is excessive.

The Pellino1-PKCθ Signaling Axis Is an Essential Target for Improving Antitumor CD8+ T-lymphocyte Function.

CD8+ T cells play an important role in the elimination of tumors. However, the underlying mechanisms involved in eliciting and maintaining effector responses in CD8+ T cells remain to be elucidated. Pellino1 (Peli1) is a receptor signal-responsive ubiquitin E3 ligase, which acts as a critical mediator for innate immunity. Here, we found that the risk of developing tumors was dependent on Peli1 expression. Peli1 was upregulated in CD8+ T cells among tumor-infiltrating lymphocytes (TIL). In contrast, a deficit of Peli1 enhanced the maintenance and effector function of CD8+ TILs. The development of Peli1-deficient CD8+ TILs prevented T-cell exhaustion and retained the hyperactivated states of T cells to eliminate tumors. We also found that Peli1 directly interacted with protein kinase C-theta (PKCθ), a central kinase in T-cell receptor downstream signal transduction, but whose role in tumor immunology remains unknown. Peli1 inhibited the PKCθ pathway by lysine 48-mediated ubiquitination degradation in CD8+ TILs. In summary, the Peli1-PKCθ signaling axis is a common inhibitory mechanism that prevents antitumor CD8+ T-cell function, and thus targeting Peli1 may be a useful therapeutic strategy for improving cytotoxic T-cell activity.

Mammalian Ssu72 phosphatase preferentially considers tissue-specific actively transcribed gene expression by regulating RNA Pol II transcription.

Reversible phosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) is essential for gene expression control. How altering the phosphorylation of the CTD contributes to gene expression in mammalian systems remains poorly understood. Methods: Primary mouse embryonic fibroblasts, hepatocytes, and embryonic stem cells were isolated from conditional Ssu72f/f mice. To knockout the mouse Ssu72 gene, we infected the cells with adenoviruses of incorporated luciferase and Cre recombinase, respectively. RNA sequencing, ChIP sequencing, ChIP assay, immunoblot analyses, qRT-PCR assay, and immunostaining were performed to gain insights into the functional mechanisms of Ssu72 loss in Pol II dynamics. Results: Using primary cells isolated from Ssu72 conditional knockout and transgenic mice, we found that mammalian Ssu72-mediated transcriptional elongation rather than polyadenylation or RNA processing contributed to the transcriptional regulation of various genes. Depletion of Ssu72 resulted in aberrant Pol II pausing and elongation defects. Reduced transcriptional elongation efficiency tended to preferentially affect expression levels of actively transcribed genes in a tissue-specific manner. Furthermore, Ssu72 CTD phosphatase seemed to regulate the phosphorylation levels of CTD Ser2 and Thr4 through accurate modulation of P-TEFb activity and recruitment. Conclusions: Our findings demonstrate that mammalian Ssu72 contributes to the transcription of tissue-specific actively transcribed gene expression by regulating reciprocal phosphorylation of Pol II CTD.

Ssu72-HNF4α signaling axis classify the transition from steatohepatitis to hepatocellular carcinoma.

Growing evidence suggests a mechanistic link between steatohepatitis and hepatocellular carcinoma (HCC). However, the lack of representative animal models hampers efforts to understand pathophysiological mechanisms underlying steatohepatitis-related HCC. We found that liver-specific deletion of Ssu72 phosphatase in mice, leads to a high incidence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, but not HCC. However, loss of Ssu72 drastically increased the probability of HCC developing, as well as the population of hepatic progenitors, in various chemical and metabolic syndrome-induced HCC models. Importantly, hepatic Ssu72 loss resulted in the induction of mature hepatocyte-to-progenitor cell conversion, by dedifferentiation orchestrated by Ssu72-mediated hypo-phosphorylation of hepatocyte nuclear factor 4α (HNF4α), a master regulator of hepatocyte function. Our findings suggest that Ssu72-mediated HNF4α transcription contributes to the progression of steatohepatitis-associated HCC by regulating the dedifferentiation potential of hepatocytes. Thus, targeting the Ssu72-mediated HNF4α signaling that underlies the pathogenesis of steatohepatitis-associated HCC development could be a novel therapeutic intervention for steatohepatitis-associated HCC.

A novel function of HRP-3 in regulating cell cycle progression via the HDAC-E2F1-Cyclin E pathway in lung cancer.

To improve the poor survival rate of lung cancer patients, we investigated the role of HDGF-related protein 3 (HRP-3) as a potential biomarker for lung cancer. The expression of endogenous HRP-3 in human lung cancer tissues and xenograft tumor models is indicative of its clinical relevance in lung cancer. Additionally, we demonstrated that HRP-3 directly binds to the E2F1 promoter on chromatin. Interestingly, HRP-3 depletion in A549 cells impedes the binding of HRP-3 to the E2F1 promoter; this in turn hampers the interaction between Histone H3/H4 and HDAC1/2 on the E2F1 promoter, while concomitantly inducing Histone H3/H4 acetylation around the E2F1 promoter. The enhanced Histone H3/H4 acetylation on the E2F1 promoter through HRP-3 depletion increases the transcription level of E2F1. Furthermore, the increased E2F1 transcription levels lead to the enhanced transcription of Cyclin E, known as the E2F1-responsive gene, thus inducing S-phase accumulation. Therefore, our study provides evidence for the utility of HRP-3 as a biomarker for the prognosis and treatment of lung cancer. Furthermore, we delineated the capacity of HRP-3 to regulate the E2F1 transcription level via histone deacetylation.

Immunological distinctions between nonalcoholic steatohepatitis and hepatocellular carcinoma.

Nonalcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease, ranges from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), which is a more aggressive form characterized by hepatocyte injury, inflammation, and fibrosis. Increasing evidence suggests that NASH is a risk factor for hepatocellular carcinoma (HCC), which is the fifth most common cancer worldwide and the second most common cause of cancer-related death. Recent studies support a strong mechanistic link between the NASH microenvironment and HCC development. The liver has a large capacity to remove circulating pathogens and gut-derived microbial compounds. Thus, the liver is a central player in immunoregulation. Altered immune responses are tightly associated with the development of NASH and HCC. The objective of this study was to differentiate the roles of specific immune cell subsets in NASH and HCC pathogenesis.

Dysregulation of cancer genes by recurrent intergenic fusions.

BACKGROUND: Gene fusions have been studied extensively, as frequent drivers of tumorigenesis as well as potential therapeutic targets. In many well-known cases, breakpoints occur at two intragenic positions, leading to in-frame gene-gene fusions that generate chimeric mRNAs. However, fusions often occur with intergenic breakpoints, and the role of such fusions has not been carefully examined. RESULTS: We analyze whole-genome sequencing data from 268 patients to catalog gene-intergenic and intergenic-intergenic fusions and characterize their impact. First, we discover that, in contrast to the common assumption, chimeric oncogenic transcripts-such as those involving ETV4, ERG, RSPO3, and PIK3CA-can be generated by gene-intergenic fusions through splicing of the intervening region. Second, we find that over-expression of an upstream or downstream gene by a fusion-mediated repositioning of a regulatory sequence is much more common than previously suspected, with enhancers sometimes located megabases away. We detect a number of recurrent fusions, such as those involving ANO3, RGS9, FUT5, CHI3L1, OR1D4, and LIPG in breast; IGF2 in colon; ETV1 in prostate; and IGF2BP3 and SIX2 in thyroid cancers. CONCLUSION: Our findings elucidate the potential oncogenic function of intergenic fusions and highlight the wide-ranging consequences of structural rearrangements in cancer genomes.

Kinesin light chain 4 as a new target for lung cancer chemoresistance via targeted inhibition of checkpoint kinases in the DNA repair network.

The poor therapeutic efficacy of non-small cell lung cancer (NSCLC) is partly attributed to the acquisition of chemoresistance. To investigate the mechanism underlying this resistance, we examined the potential link between kinesin light chain 4 (KLC4), which we have previously reported to be associated with radioresistance in NSCLC, and sensitivity to chemotherapy in human lung cancer cell lines. KLC4 protein levels in lung cancer cells correlated with the degree of chemoresistance to cisplatin treatment. Furthermore, KLC4 silencing enhanced the cytotoxic effect of cisplatin by promoting DNA double-strand breaks and apoptosis. These effects were mediated by interaction with the checkpoint kinase CHK2, as KLC4 knockdown increased CHK2 activation, which was further enhanced in combination with cisplatin treatment. In addition, KLC4 and CHEK2 expression levels showed negative correlation in lung tumor samples from patients, and KLC4 overexpression correlated negatively with survival. Our results indicate a novel link between the KLC4 and CHK2 pathways regulating DNA damage response in chemoresistance, and highlight KLC4 as a candidate for developing lung cancer-specific drugs and customized targeted molecular therapy.

Human observer performance on in-plane digital breast tomosynthesis images: Effects of reconstruction filters and data acquisition angles on signal detection.

For digital breast tomosynthesis (DBT) systems, we investigate the effects of the reconstruction filters for different data acquisition angles on signal detection. We simulated a breast phantom with a 30% volume glandular fraction (VGF) of breast anatomy using the power law spectrum and modeled the breast mass as a spherical object with a 1 mm diameter. Projection data were acquired using two different data acquisition angles and numbers of projection view pairs, and in-plane breast images were reconstructed using the Feldkamp-Davis-Kress (FDK) algorithm with three different reconstruction filter schemes. To measure the ability to detect a signal, we conducted the human observer study with a binary detection task and compared the signal detectability of human to that of channelized Hotelling observer (CHO) with Laguerre-Gauss (LG) channels and dense difference-of-Gaussian (D-DOG) channels. We also measured the contrast-to-noise ratio (CNR), signal power spectrum (SPS), and ß values of the anatomical noise power spectrum (NPS) to show the association between human observer performance and these traditional metrics. Our results show that using a slice thickness (ST) filter degraded the signal detection performance of human observers at the same data acquisition angle. This could be predicted by D-DOG CHO with internal noise, but the correlation between the traditional metrics and signal detectability was not observed in this work.