ER Stress-Activated HSF1 Governs Cancer Cell Resistance to USP7 Inhibitor-Based Chemotherapy through the PERK Pathway.

Ubiquitin-specific protease 7 inhibitors (USP7i) are considered a novel class of anticancer drugs. Cancer cells occasionally become insensitive to anticancer drugs, known as chemoresistance, by acquiring multidrug resistance, resulting in poor clinical outcomes in patients with cancer. However, the chemoresistance of cancer cells to USP7i (P22077 and P5091) and mechanisms to overcome it have not yet been investigated. In the present study, we generated human cancer cells with acquired resistance to USP7i-induced cell death. Gene expression profiling showed that heat stress response (HSR)- and unfolded protein response (UPR)-related genes were largely upregulated in USP7i-resistant cancer cells. Biochemical studies showed that USP7i induced the phosphorylation and activation of heat shock transcription factor 1 (HSF1), mediated by the endoplasmic reticulum (ER) stress protein kinase R-like ER kinase (PERK) signaling pathway. Inhibition of HSF1 and PERK significantly sensitized cancer cells to USP7i-induced cytotoxicity. Our study demonstrated that the ER stress-PERK axis is responsible for chemoresistance to USP7i, and inhibiting PERK is a potential strategy for improving the anticancer efficacy of USP7i.

Effects of Fermented Polygonum cuspidatum on the Skeletal Muscle Functions.

Plant extract fermentation is widely employed to enhance the nutritional and pharmaceutical value of functional foods. Polygonum cuspidatum (Pc) contains flavonoids, anthraquinones, and stilbenes, imparting protective effects against inflammatory diseases, cancer, diabetes, and cardiovascular diseases. However, the effects of fermented Pc on skeletal muscle strength remain unexplored. In this study, we generated fermented Pc using a complex of microorganisms containing Lactobacillus spp. (McPc) and assessed its effects on muscle strength and motor function in mice. Compared to unfermented Pc water extract, elevated levels of emodin and resveratrol were noted in McPc. This was identified and quantified using UPLC-QTOF/MS and HPLC techniques. Gene expression profiling through RNA-seq and quantitative RT-PCR revealed that McPc administration upregulated the expression of genes associated with antioxidants, glycolysis, oxidative phosphorylation, fatty acid oxidation, and mitochondrial biogenesis in cultured C2C12 myotubes and the gastrocnemius muscle in mice. McPc significantly improved skeletal muscle strength, motor coordination, and traction force in mice subjected to sciatic neurectomy and high-fat diet (HFD). McPc administration exhibited more pronounced improvement of obesity, hyperglycemia, fatty liver, and hyperlipidemia in HFD mice compared to control group. These findings support the notion that emodin and resveratrol-enriched McPc may offer health benefits for addressing skeletal muscle weakness.

Erratum: Correction of Affiliations in the Article "Establishment of a Nationwide Korean Imaging Cohort of Coronavirus Disease 2019".

This corrects the article on p. e413 in vol. 35, PMID: 33258333.

Correction: Deep Learning With Chest Radiographs for Making Prognoses in Patients With COVID-19: Retrospective Cohort Study.

[This corrects the article DOI: 10.2196/42717.].

Streptonigrin Mitigates Lung Cancer-induced Cachexia by Suppressing TCF4/TWIST1-induced PTHLH Expression.

BACKGROUND/AIM: Cachexia - a wasting disorder of adipose and skeletal muscle tissue - is the most common driver of poor prognosis in patients with advanced lung cancer. Parathyroid hormone-like hormone (PTHLH) is potentially a critical factor in cancer-associated cachexia. We previously showed that streptonigrin - an aminoquinone with antitumor effects - inhibited the interaction between TCF4 and TWIST1. This study aimed to determine the anti-cachectic performance of streptonigrin in lung cancer. MATERIALS AND METHODS: We assessed the effect of streptonigrin on the interaction of TCF4 and TWIST1 using co-immunoprecipitation and a mammalian-two hybrid luciferase assay, which was confirmed by an in vitro GST pull-down assay using recombinant bHLH domain-containing TCF4 and TWIST1. We assessed the anti-cachectic effect of streptonigrin in vivo using an LLC1 cell-induced tumour-bearing mouse model. Changes in the degree of skeletal muscle and adipose tissue wasting were determined by measuring the weights of gastrocnemius and epidydimal white adipose tissue. RESULTS: Streptonigrin was found to inhibit the interaction of TCF4 with TWIST1 in a dose-dependent manner. The in vitro GST pull-down assay revealed that streptonigrin directly inhibited the interaction between TCF4 and TWIST1. The expression of PTHLH mRNA, which is transcriptionally regulated by the TCF4/TWIST1 complex in response to TGF-ß1 signalling, was decreased in streptonigrin-treated lung cancer cells. Streptonigrin significantly decreased the expression of proteolysis-related genes in skeletal muscle and browning-related genes in white adipose tissues of LLC1-induced tumour-bearing mice. CONCLUSION: Streptonigrin exerts potent therapeutic effects on lung cancer-induced cachexia by suppressing TCF4/TWIST1-mediated PTHLH expression.

Long-Term Ultrasonographic and Histologic Changes in Acellular Dermal Matrix in Implant-Based Breast Reconstructions.

BACKGROUND: Acellular dermal matrix (ADM) is composed of extracellular matrix (ECM) and is widely used in implant-based breast reconstructions. However, long-term changes in the ADM around implants have not been established. This study aimed to investigate long-term changes in the ADM covering breast implants using serial ultrasound and histologic evaluations. METHODS: The authors evaluated the ultrasound results of 145 patients who underwent implant-based breast reconstructions with ADM coverings. The ultrasound results obtained within 18 months of surgery and those obtained 5 years postoperatively were analyzed to determine the change in ADM thickness. For histologic analysis, the ADM was harvested from 30 patients who underwent secondary breast surgery. Histologic features of the ECM and cellular components within the ADM were compared at specific intervals from ADM implantation and the second operation (early ADM group, <18 months; late ADM group, >5 years postoperatively). RESULTS: The ADM thickness on ultrasound examination was significantly decreased in the late ADM group compared with that in the early ADM group ( P < 0.001). Histologic analyses revealed that the late ADM group had less thickness with lower ECM levels versus the early ADM group. Increased infiltration of host cells, such as vascular endothelial cells, myofibroblasts, and immune cells, occurred in the late ADM group. CONCLUSIONS: Implanted ADMs underwent gradual thinning over time, in addition to ECM reduction and infiltration of host cells. These findings are useful in understanding the natural course of ADMs currently used in implant-based breast reconstructions. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Deep Learning With Chest Radiographs for Making Prognoses in Patients With COVID-19: Retrospective Cohort Study.

BACKGROUND: An artificial intelligence (AI) model using chest radiography (CXR) may provide good performance in making prognoses for COVID-19. OBJECTIVE: We aimed to develop and validate a prediction model using CXR based on an AI model and clinical variables to predict clinical outcomes in patients with COVID-19. METHODS: This retrospective longitudinal study included patients hospitalized for COVID-19 at multiple COVID-19 medical centers between February 2020 and October 2020. Patients at Boramae Medical Center were randomly classified into training, validation, and internal testing sets (at a ratio of 8:1:1, respectively). An AI model using initial CXR images as input, a logistic regression model using clinical information, and a combined model using the output of the AI model (as CXR score) and clinical information were developed and trained to predict hospital length of stay (LOS) ≤2 weeks, need for oxygen supplementation, and acute respiratory distress syndrome (ARDS). The models were externally validated in the Korean Imaging Cohort of COVID-19 data set for discrimination and calibration. RESULTS: The AI model using CXR and the logistic regression model using clinical variables were suboptimal to predict hospital LOS ≤2 weeks or the need for oxygen supplementation but performed acceptably in the prediction of ARDS (AI model area under the curve [AUC] 0.782, 95% CI 0.720-0.845; logistic regression model AUC 0.878, 95% CI 0.838-0.919). The combined model performed better in predicting the need for oxygen supplementation (AUC 0.704, 95% CI 0.646-0.762) and ARDS (AUC 0.890, 95% CI 0.853-0.928) compared to the CXR score alone. Both the AI and combined models showed good calibration for predicting ARDS (P=.079 and P=.859). CONCLUSIONS: The combined prediction model, comprising the CXR score and clinical information, was externally validated as having acceptable performance in predicting severe illness and excellent performance in predicting ARDS in patients with COVID-19.

Effect of postbiotics derived from kefir lactic acid bacteria-mediated bioconversion of citrus pomace extract and whey on high-fat diet-induced obesity and gut dysbiosis.

The objective of this study was to develop a highly bioactive postbiotic for weight management by bioconversion of whey (WHE) and polyphenol-rich citrus pomace extract (CPX) using kefir lactic acid bacteria (LAB). WHE and CPX bioconverted by kefir LAB (CPB) were fed to C57BL/6J mice on high-fat diets for five weeks and compared with oral administrations of saline (CON), WHE, CPX, and kefir LAB. Hesperetin, a potential therapeutic agent for obesity, was increased in the CPB after bioconversion from an inactive precursor. Compared with the CON group, the CPB group showed significantly reduced body weight gain, adipose tissue weight/body weight ratio, hypertriglyceridemia, and adipocyte diameter along with increased gene expression related to energy expenditure in adipose tissue (p < 0.05). Interestingly, the abundance of gut microbiota related to butyrate production was significantly altered in the CPB group compared with the CON group. There was a significant correlation between obesogenic biomarkers and the abundance of butyrate-producing and obesogenic gut microbiota. In conclusion, kefir LAB-derived bioconversion of WHE and CPX may be effective in combating obesity and obesity-related diseases.

Unilateral Pulmonary Vein Atresia Initially Presenting as Interstitial Lung Disease in an Elderly Female: Serial Chest Radiograph Changes and Its Literature Review.

Unilateral pulmonary vein atresia (PVA) is a rare congenital cardiovascular anomaly occurring after the common pulmonary vein fails to incorporate into the left atrium. It is most commonly diagnosed in childhood, and diagnosis after reaching adulthood is extremely rare. Dyspnea on exertion and hemoptysis are common clinical features in adult PVA patients, whereas lung parenchymal abnormalities are indirect signs of PVA, which can manifest as interstitial lung disease. Herein, we present the case of a 62-year-old female diagnosed with unilateral PVA presenting as unilateral interstitial lung disease and report the changes in her chest radiographs over 12 years.

Fibrosing Mediastinits Causing Obstruction of Left Lower Lobar Bronchus: A Pediatric Case Report.

Fibrosing mediastinitis is a rare benign disorder characterized by the proliferation of dense fibrous tissue within the mediastinum. It typically manifests as localized or infiltrative soft-tissue masses in the middle mediastinum or hilar area, which cause compression and encasement of adjacent mediastinal structures, such as the vessels or airway. Here, we report a rare case of fibrosing mediastinitis in a 13-year-old girl that presented as a middle mediastinal mass lesion on CT scan with obliterating left lower lobar bronchus. The patient's symptoms and follow-up chest CT showed significant improvement following systemic corticosteroid treatment. As fibrosing mediastinitis can improve with systemic steroid therapy, radiologists must be aware of its radiologic findings when discriminating between infiltrating soft tissue lesions in the mediastinum.

Radiation-induced osteoradionecrosis of the ribs in a patient with breast cancer: A case report.

Osteoradionecrosis of the chest wall after radiation therapy for breast cancer is rare; however, it is one of the most severe complications of radiation treatment. Radiologically, osteoradionecrosis can manifest as a focal lucent area in bone, periostitis, sclerosis, and cortical irregularity of bones on X-ray or computed tomography; therefore, differentiation from bone metastasis can be challenging. Associated insufficiency fractures, ulceration, and skin necrosis may also occur. We encountered a patient with osteoradionecrosis in the left anterior ribs after radiation therapy for breast cancer. Chest computed tomography revealed cortical irregularity with severe sclerotic changes of the anterior arc of the left fist to the fourth ribs. The patient's skin on the left chest wall exhibited ulceration with purulent discharge. Ultrasonography of the left chest wall revealed diffuse skin thickening with hyperechoic changes in the subcutaneous fat layer of the left chest wall with calcifications. The patient underwent rib resection and chest wall reconstruction. Recognizing characteristic imaging features of osteoradionecrosis is important for radiologists to differentiate it from bone metastasis and plan appropriate treatment.

Prediction of Implant Size Based on Breast Volume Using Mammography with Fully Automated Measurements and Breast MRI.

BACKGROUND: Determination of implant size is crucial for patients with breast cancer undergoing one-stage breast reconstruction. The purpose of this study is to predict the implant size based on the breast volume measured by mammography (MG) with a fully automated method, and by breast magnetic resonance imaging (MRI) with a semi-automated method, in breast cancer patients with direct-to-implant reconstruction. PATIENTS AND METHODS: This retrospective study included 84 patients with breast cancer who underwent direct-to-implant reconstruction after nipple-sparing or skin-sparing mastectomy and preoperative MG and MRI between April 2015 and April 2019. Breast volume was measured using (a) MG with a fully automated commercial software and (b) MRI with an in-house semi-automated software program. Multivariable regression analyses including breast volume and patient weight (P < 0.05 in univariable analysis) were conducted to predict implant size. RESULTS: MG and MRI breast volume was highly correlated with both implant size (correlation coefficient 0.862 and 0.867, respectively; P values < 0.001) and specimen weight (correlation coefficient 0.802 and 0.852, respectively; P values < 0.001). Mean absolute difference between the MR breast volume and implant size was 160 cc, which was significantly higher than that between the MG breast volume and implant size of 118 cc (P < 0.001). On multivariable analyses, only breast volume measured by both MG and MRI was significantly associated with implant size in any implant type (all P values < 0.001). CONCLUSION: Breast volume measured by MG and MRI can be used to predict appropriate implant size in breast cancer patients undergoing direct-to-implant reconstruction in an efficient and objective manner.

Imaging features of volume replacement using an acellular dermal matrix in oncoplastic breast conserving surgery: A case report.

An acellular dermal matrix (ADM) is a type of allograft that can be made from human, bovine, or porcine dermis and is used to support or reconstruct soft tissue. During breast reconstructive surgeries, ADMs are widely used to partially cover breast implants following a mastectomy to correct for insufficient subcutaneous tissue. Recently, ADMs have been used as a filling material for volume replacement in oncoplastic breast conserving surgery. In this report, we present the case of a female, middle-aged patient who underwent breast conserving surgery with volume replacement using an ADM.

Tips for finding magnetic resonance imaging-detected suspicious breast lesions using second-look ultrasonography: a pictorial essay.

Second-look ultrasonography (US) is a targeted breast US examination that evaluates suspicious lesions detected on magnetic resonance imaging (MRI). It is a useful tool for determining the probability of malignancy and facilitating US-guided biopsy. Lesions detected on MRI and US should be correlated accurately, which is challenging in some cases. This article documents second-look US and MRI findings that are correlated with the pathology, and suggests helpful approaches for correlating between the two modalities.

Polygonum cuspidatum Extract (Pc-Ex) Containing Emodin Suppresses Lung Cancer-Induced Cachexia by Suppressing TCF4/TWIST1 Complex-Induced PTHrP Expression.

Cachexia, which is characterised by the wasting of fat and skeletal muscles, is the most common risk factor for increased mortality rates among patients with advanced lung cancer. PTHLH (parathyroid hormone-like hormone) is reported to be involved in the pathogenesis of cancer cachexia. However, the molecular mechanisms underlying the regulation of PTHLH expression and the inhibitors of PTHLH have not yet been identified. The PTHLH mRNA levels were measured using quantitative real-time polymerase chain reaction, while the PTHrP (parathyroid hormone-related protein) expression levels were measured using Western blotting and enzyme-linked immunosorbent assay. The interaction between TCF4 (Transcription Factor 4) and TWIST1 and the binding of the TCF4-TWIST1 complex to the PTHLH promoter were analysed using co-immunoprecipitation and chromatin immunoprecipitation. The results of the mammalian two-hybrid luciferase assay revealed that emodin inhibited TCF4-TWIST1 interaction. The effects of Polygonum cuspidatum extract (Pc-Ex), which contains emodin, on cachexia were investigated in vivo using A549 tumour-bearing mice. Ectopic expression of TCF4 upregulated PTHLH expression. Conversely, TCF4 knockdown downregulated PTHLH expression in lung cancer cells. The expression of PTHLH was upregulated in cells ectopically co-expressing TCF4 and TWIST1 when compared with that in cells expressing TCF4 or TWIST1 alone. Emodin inhibited the interaction between TCF4 and TWIST1 and consequently suppressed the TCF4/TWIST1 complex-induced upregulated mRNA and protein levels of PTHLH and PTHrP. Meanwhile, emodin-containing Pc-Ex significantly alleviated skeletal muscle atrophy and downregulated fat browning-related genes in A549 tumour-bearing mice. Emodin-containing Pc-Ex exerted therapeutic effects on lung cancer-associated cachexia by inhibiting TCF4/TWIST1 complex-induced PTHrP expression.

Abnormal Ultrasonographic Findings of Acellular Dermal Matrix in Implant-Based Breast Reconstruction: Correlations with Histopathology.

BACKGROUND: Acellular dermal matrix (ADM) in implant-based breast reconstruction can show various ultrasound (US) findings. However, there are limited reports on the US features of the ADM. The aims of this study were to evaluate US findings of the ADM in implant-based breast reconstruction and correlate them with histopathological findings. METHODS: Between January 2015 and August 2020, 250 women who underwent implant-based breast reconstruction with ADM and a breast US examination at 6 months to 1 year after reconstruction were retrospectively analyzed. Abnormal US findings were classified as type 1 (focal thickening with decreased echogenicity), 2 (diffusely hyperechoic), or 3 (bright echogenic spots). ADM biopsy was performed in 33 patients who underwent second stage or revisional surgeries. RESULTS: In total, 176 consecutive women with 207 US findings were analyzed. The US findings were normal in 52.2% of the women. The percentages of type 1, 2, and 3 patients were 13.5%, 11.1%, and 23. 2%, respectively. These patients had microscopic findings that showed patchy areas with chronic inflammatory infiltrates, dense collagen bundles without degenerative or inflammatory changes, and empty spaces or degenerated foci unaccompanied by inflammation. CONCLUSION: Knowing the various ADM presentations on US can help avoid unnecessary invasive procedures.

Ultrasonographic morphological characteristics determined using a deep learning-based computer-aided diagnostic system of breast cancer.

ABSTRACT: To investigate the correlations between ultrasonographic morphological characteristics quantitatively assessed using a deep learning-based computer-aided diagnostic system (DL-CAD) and histopathologic features of breast cancer.This retrospective study included 282 women with invasive breast cancer (<5 cm; mean age, 54.4 [range, 29-85] years) who underwent surgery between February 2016 and April 2017. The morphological characteristics of breast cancer on B-mode ultrasonography were analyzed using DL-CAD, and quantitative scores (0-1) were obtained. Associations between quantitative scores and tumor histologic type, grade, size, subtype, and lymph node status were compared.Two-hundred and thirty-six (83.7%) tumors were invasive ductal carcinoma, 18 (6.4%) invasive lobular carcinoma, and 28 (9.9%) micropapillary, apocrine, and mucinous. The mean size was 1.8 ±â€Š1.0 (standard deviation) cm, and 108 (38.3%) cases were node positive. Irregular shape score was associated with tumor size (P < .001), lymph nodes status (P = .001), and estrogen receptor status (P = .016). Not-circumscribed margin (P < .001) and hypoechogenicity (P = .003) scores correlated with tumor size, and non-parallel orientation score correlated with histologic grade (P = .024). Luminal A tumors exhibited more irregular features (P = .048) with no parallel orientation (P = .002), whereas triple-negative breast cancer showed a rounder/more oval and parallel orientation.Quantitative morphological characteristics of breast cancers determined using DL-CAD correlated with histopathologic features and could provide useful information about breast cancer phenotypes.

Association Between Imaging Features Using the BI-RADS and Tumor Subtype in Patients with Invasive Breast Cancer.

BACKGROUND: Different molecular breast cancer subtypes present different biologic features, treatment options, and clinical prognoses. The breast cancer imaging phenotype may help precisely classify breast cancer in a non-invasive manner. OBJECTIVE: To identify the association between the imaging and clinicopathologic features of invasive breast cancer according to the molecular subtype. METHODS: We retrospectively reviewed the electronic medical records of 313 consecutive women with breast cancer who underwent surgery between March 2018 and February 2019. Preoperative imaging studies were also reviewed and the association between the clinicopathologic and imaging features was evaluated according to the molecular subtype. RESULTS: On mammography, the presence of microcalcifications was correlated with the human epidermal factor receptor 2-positive subtype (67%, 14/21). Luminal A and B tumors were more likely to have a spiculated margin (57% [63/110] and 41% [34/81]), while human epidermal factor receptor 2-positive and triple-negative breast cancers were more likely to have an indistinct margin (56% [10/18] and 35% [17/48]). On ultrasonography, luminal A tumors were likely to be depicted as masses with an irregular shape (85%, 115/136) and spiculated margin (49%, 66/136). On magnetic resonance imaging, triple-negative breast cancer appeared as a mass (n=13) that frequently had an irregular shape (62%, 8/13) but was more likely to be oval or round (39%, 5/13) than other subtypes. CONCLUSION: Some imaging features on mammography, ultrasonography, and magnetic resonance imaging could be useful predictors of the molecular subtype of breast cancer and may aid precision medicine development for patients with breast cancer according to the subtype.