Frozen Sections in Decision-Making Regarding the Axillary Procedures in Breast Conserving Surgery for Intraductal Carcinoma at Preoperative Diagnosis.

BACKGROUND: Axillary evaluation is unnecessary for pure ductal carcinoma in situ (DCIS); however, it is performed because of the risk of upstaging to invasive cancer. We assessed the role of intraoperative frozen section (IOF) biopsy in reducing invasive cancer upstaging and axillary evaluation in preoperative DCIS patients. METHODS: We reviewed patients with preoperative DCIS who underwent breast-conserving surgery (BCS) with IOF biopsy. Positive IOF biopsy findings were defined as the presence of invasive or micro-invasive cancer. The IOF biopsy and permanent pathology findings were compared. RESULTS: Seventy-eight patients underwent BCS with IOF biopsy. Six patients showed positive IOF biopsy findings; five of these patients showed concordant permanent pathology findings. Sentinel lymph node biopsy (SLNB) was positive in one patient. Thirteen patients with invasive breast cancer were missed by IOF biopsy; they underwent SLNB during the second surgery. None of them had metastatic lymph nodes. The sensitivity and specificity of IOF biopsy were 27.7% and 98.3%, respectively, with 82.1% accuracy. None of the other factors showed statistically significant relationships with the permanent pathology findings, except for the IOF biopsy findings. CONCLUSION: IOF evaluation can aid in detecting the invasiveness of tumors in patients with preoperative DCIS.

Emergence of a Metal-Insulator Transition and High-Temperature Charge-Density Waves in VSe2 at the Monolayer Limit.

Emergent phenomena driven by electronic reconstructions in oxide heterostructures have been intensively discussed. However, the role of these phenomena in shaping the electronic properties in van der Waals heterointerfaces has hitherto not been established. By reducing the material thickness and forming a heterointerface, we find two types of charge-ordering transitions in monolayer VSe2 on graphene substrates. Angle-resolved photoemission spectroscopy (ARPES) uncovers that Fermi-surface nesting becomes perfect in ML VSe2. Renormalization-group analysis confirms that imperfect nesting in three dimensions universally flows into perfect nesting in two dimensions. As a result, the charge-density wave-transition temperature is dramatically enhanced to a value of 350 K compared to the 105 K in bulk VSe2. More interestingly, ARPES and scanning tunneling microscopy measurements confirm an unexpected metal-insulator transition at 135 K that is driven by lattice distortions. The heterointerface plays an important role in driving this novel metal-insulator transition in the family of monolayer transition-metal dichalcogenides.

GOLGA2 loss causes fibrosis with autophagy in the mouse lung and liver.

Autophagy is a biological recycling process via the self-digestion of organelles, proteins, and lipids for energy-consuming differentiation and homeostasis. The Golgi serves as a donor of the double-membraned phagophore for autophagosome assembly. In addition, recent studies have demonstrated that pulmonary and hepatic fibrosis is accompanied by autophagy. However, the relationships among Golgi function, autophagy, and fibrosis are unclear. Here, we show that the deletion of GOLGA2, encoding a cis-Golgi protein, induces autophagy with Golgi disruption. The induction of autophagy leads to fibrosis along with the reduction of subcellular lipid storage (lipid droplets and lamellar bodies) by autophagy in the lung and liver. GOLGA2 knockout mice clearly demonstrated fibrosis features such as autophagy-activated cells, densely packed hepatocytes, increase of alveolar macrophages, and decrease of alveolar surfactant lipids (dipalmitoylphosphatidylcholine). Therefore, we confirmed the associations among Golgi function, fibrosis, and autophagy. Moreover, GOLGA2 knockout mice may be a potentially valuable animal model for studying autophagy-induced fibrosis.

Methylisothiazolinone may induce cell death and inflammatory response through DNA damage in human liver epithelium cells.

Methylisothiazolinone (MIT) is a powerful biocide and preservative, which is widely used alone or in a 1:3 ratio with methylchloroisothiazolinone (MCIT) under the trade name of Kathons in the manufacture of numerous personal and household products. Considering that Kathons injected intravenously is distributed in the blood and then in the liver, we explored the toxic mechanism of MIT on human liver epithelium cells. At 24 h after exposure, MIT bound to the plasma membrane and the inner wall of vacuoles in the cells, and rupture of the cell membrane and nuclear envelop, autophagosome-like vacuoles formation and mitochondrial damage were observed. Cell viability dose-dependently decreased accompanying an increase of apoptotic cells, and the level of LDH, NO, IFN-gamma, IL-10 and IL-8, but not IL-1ß, significantly increased in the culture media of cells exposed to MIT. Additionally, expression of autophagy-, membrane damage- and apoptosis-related proteins was notably enhanced, and the produced ATP level dose-dependently decreased with the reduced mitochondrial activity. Furthermore, the increased DNA damage and the decreased transcription activity were observed in MIT-treated cells. Meanwhile, the intracellular ROS level did not show dose-dependent change at the same time-point. Then we explored the role of autophagy in MIT-induced cytotoxicity by inhibiting or inducing the autophagic signal. Intriguingly, no additional cell death induced by autophagic modulation occurred when MIT was treated. Taken together, we suggest that MIT may induce multiple pathways of cell death and inflammatory response through DNA damage caused by rupture of the nuclear envelope.

Exposure to cigarette smoke disturbs adipokines secretion causing intercellular damage and insulin resistance in high fructose diet-induced metabolic disorder mice.

A large amount of fructose intake along with smoking is associated with increased incidence of diseases linked to metabolic syndrome. More research is necessary to understand the complex mechanism that ultimately results in metabolic syndrome and the effect, if any, of high fructose dietary intake and smoking on individual health. In this study, we investigated changes in ER-Golgi network and disturbance to secretion of adipokines induced by cigarette smoking (CS) and excess fructose intake and their contribution to the disruption of metabolic homeostasis. We used high fructose-induced metabolic disorder mice model by feeding them with high fructose diet for 8 weeks. For CS exposure experiment, these mice were exposed to CS for 28 days according to OECD guideline 412. Our results clearly showed that the immune system was suppressed and ER stress was induced in mice with exposure to CS and fed with high fructose. Furthermore, their concentrations of adipokines including leptin and adiponectin were aberrant. Such alteration in secretion of adipokines could cause insulin resistance which may lead to the development of type 2 diabetes.

Dihydroceramide is a key metabolite that regulates autophagy and promotes fibrosis in hepatic steatosis model.

Non-alcoholic fatty liver disease (NAFLD) is an increasingly common chronic liver disease worldwide. Sphingolipids are a family of lipids that play essential roles as critical regulators in metabolic disorders. Some sphingolipids are known key factors in metabolic dysfunction. However, the precise effect of dihydroceramide on NAFLD remains unknown. Here, we report how dihydroceramide in autophagosome accumulation activates fibrogenesis in human liver Chang cells treated with free fatty acids (FFA). According to LC/MS lipid profiling, FFA increased the levels of sphingolipids and triacylglycerol (TG). To demonstrate the potential role of dihydroceramide metabolism in autophagy, several sphingolipid synthesis inhibitors were used. Increased dihydroceramide led to impairment of autophagic flux, resulting in increased TG storage in lipid droplets (LD) and upregulated expression of fibrosis markers. Hepatic stellate cells (HSCs, LX-2 cells) were co-cultured with Chang cells to assess the potential fibrogenic response to dihydroceramide, Treatment with rapamycin recovered autophagic flux in Chang cells and fibrogenesis in the co-culture system. Our results identified a critical function of dihydroceramide metabolism in autophagy. It could play an important role in the progression of NAFLD associated with lipid over-accumulation. Therefore, preventing autophagic flux by regulating dihydroceramide could be a potential strategic approach for providing therapy for NAFLD.

Chemotherapy-induced irreversible alopecia in early breast cancer patients.

PURPOSE: The purpose of this work is to determine the prevalence of chemotherapy-induced irreversible alopecia (CIIA), which is defined as an alopecia that exists at least 6 months after completion of chemotherapy and factors affecting CIIA in early breast cancer patients. METHODS: We performed a cross-sectional study. We retrospectively identified breast cancer patients who had received AC (Adriamycin, Cyclophosphamide) or AC-T (AC followed by Taxane) as neoadjuvant or adjuvant chemotherapy. We conducted questionnaire survey regarding alopecia and measured hair density using phototrichogram. RESULTS: From February 2015 to May 2015, among 265 patients who responded properly to the questionnaire, the women who answered they had severe alopecia (alopecia > 50% of scalp) were 19 patients (7.2%). AC-only and AC-T treated patients reported severe alopecia in 2.7% and 10.5%, respectively, which were significantly different (p < 0.001). Mean hair density was 75 hair/cm2 (range 42-112) and 75.2/cm2 (range 48.3-102) on occipital area and vertex area, respectively. Hair loss was the most frequent in parietal area (42.6%). Half of total patients (46%) and 73% of CIIA patients regarded that their hair became thinner after chemotherapy CONCLUSIONS: We found that significant proportion of early breast cancer patients were suffering from severe CIIA, especially when they had been treated with AC followed by taxane regimen.

Ambient fine particulate matters induce cell death and inflammatory response by influencing mitochondria function in human corneal epithelial cells.

Ambient fine particulate matter (AFP) is a main risk factor for the cornea as ultraviolet light. However, the mechanism of corneal damage following exposure to AFP has been poorly understood. In this study, we first confirmed that AFP can penetrate the cornea of mice, considering that two-dimensional cell culture systems are limited in reflecting the situation in vivo. Then, we investigated the toxic mechanism using human corneal epithelial (HCET) cells. At 24h after exposure, AFP located within the autophagosome-like vacuoles, and cell proliferation was clearly inhibited in all the tested concentration. Production of ROS and NO and secretion of pro-inflammatory cytokines were elevated in a dose-dependent manner. Additionally, conversion of LC3B from I-type to II-type and activation of caspase cascade which show autophagic- and apoptotic cell death, respectively, were observed in cells exposed to AFP. Furthermore, AFP decreased mitochondrial volume, inhibited ATP production, and altered the expression of metabolism-related genes. Taken together, we suggest that AFP induces cell death and inflammatory response by influencing mitochondrial function in HCET cells. In addition, we recommend that stringent air quality regulations are needed for eye health.

No effect of tumor-infiltrating lymphocytes (TILs) on prognosis in patients with early triple-negative breast cancer: Validation of recommendations by the International TILs Working Group 2014.

PURPOSE: The aim of this study was to examine the International TILs Working Group 2014 (IWG) recommendations for evaluating the clinical utility of tumor-infiltrating lymphocytes (TILs) in patients with early triple-negative breast cancer (TNBC). METHODS: Records for 133 patients with early TNBC who underwent surgery between 2008 and 2010 were reviewed. A total of 121 of 133 formalin-fixed, paraffin-embedded tumor samples were available and reviewed following IWG recommendations. RESULTS: Most of the patients had node-negative T1-2 tumors and received adjuvant chemotherapy; T1-2 tumors accounted for 117 of 121 cases. Sixty-two percent (75/121) of all patients had >10% stromal TILs. Intratumoral TILs and lymphocyte-predominant breast cancer (LPBC) were observed in 72% and 19% of the patients, respectively. However, there were no significant differences according to the presence of stromal TILs, intratumoral TILs, TILs at the invasive edge, or LPBC in terms of recurrence-free and overall survival (all P > 0.05). A multivariate analysis adjusted for T and N stage, grade, and adjuvant chemotherapy revealed that no TILs parameters were associated with survival outcomes. CONCLUSIONS: TILs evaluations following the IWG recommendations may not be useful for predicting survival outcomes in patients with early TNBC. J. Surg. Oncol. 2016;114:17-21. © 2016 Wiley Periodicals, Inc.

Cigarette Smoking Condensate Disrupts Endoplasmic Reticulum-Golgi Network Homeostasis Through GOLPH3 Expression in Normal Lung Epithelial Cells.

INTRODUCTION: Cigarette smoke (CS) is associated with a broad range of diseases including lung cancer. Many researchers have suggested that cigarette smoke condensate (CSC) may be more toxic compared to cigarette smoke extract (CSE) because CSC contains the lipid-soluble faction of smoke while CSE contains the hydrophilic or gas phase. The aim of this research is to investigate the effects of CSC on the disruption of endoplasmic reticulum (ER)-Golgi homeostasis in normal lung epithelial cells. METHODS: CS was generated according to the ISO 3308 method. To ascertain the mechanistic effects of CSC on lung toxicity, normal lung epithelial cells of the cell line 16HBE14o- were treated with CSC (0.1mg/mL) for 48 hours. The toxic effects of CSC on ER-Golgi homeostasis and GOLPH3 expression were observed through diverse molecular tools including transmission electron microscope analysis. RESULTS: Our results demonstrated that CSC treatment increased reactive oxygen species generation in lung cells and led to the alteration of ER-Golgi homeostasis in conjunction with increased autophagy. In particular, GOLPH3, known as an oncogene and a marker protein for the trans-Golgi network, was upregulated in CSC-treated cells. GOLPH3 protein overexpression was also confirmed in the lungs of human lung cancer patients as well as NNK-treated mice. CONCLUSION: Our study revealed that CSC caused lung damage through the disruption of ER-Golgi homeostasis and autophagy induction. The expression level of the trans-Golgi marker protein GOLPH3 could serve as a reliable bio-indicator for CS-related lung cancer. IMPLICATIONS: CS is a harmful factor in the development of many diseases including cancer. In this research, we demonstrated that CSC treatment led to malfunction of the ER-Golgi network, with the disrupted ER and Golgi causing GOLPH3 overexpression and abnormal autophagy accumulation. In addition, although the value of GOLPH3 as a predictor remains to be fully elucidated, our data suggest that GOLPH3 levels may be a novel prognostic biomarker of tobacco related lung disease.

Serum 25-hydroxyvitamin D deficiency and increased risk of breast cancer among Korean women: a case-control study.

Despite the emerging literature supporting the beneficial role of vitamin D on various health outcomes including carcinogenesis, current evidence on the association between vitamin D and breast cancer is still largely inconsistent. Furthermore, this relationship is particularly under explored among Asian population. We conducted a large case-control study with Korean women. We obtained and compared serum 25-hydroxyvitamin D (25(OH)D) between breast cancer patients (N = 3634) and general population (N = 17,133). Moreover, we further examined the association between serum 25(OH)D and breast cancer risk stratified by menopausal status and hormone receptor (HR) status of the tumor. Adjusted odds ratio (OR) for breast cancer comparing women with deficient level of serum 25(OH)D to women with sufficient level of serum 25(OH)D was 1.27 [95 % confidence interval (CI) 1.15-1.39]. This association did not significantly vary by menopausal status [pre-menopause: 1.26 (95 % CI 1.09-1.45) vs. post-menopause: 1.25 (95 % CI 1.10-1.41)]. When stratified by HR status, the inverse association remained significant in both positive and negative statuses. However, this association was more pronounced in HR-negative breast cancer, particularly with triple-negative breast cancer patients (1.45, 95 % CI 1.15-1.82). Given the growing burden of breast cancer in Asia and dearth of studies examining the association between vitamin D and breast cancer risk in Asian women thus far, this study provides a meaningful evidence for potential preventive effect of vitamin D on breast cancer for this particular population.

Omission of axillary surgery in cN0, postmenopausal ER-positive/HER2-negative breast cancer patients undergoing breast-conserving treatment.

Background: Previous clinical trials have diminished the significance of lymph node (LN) metastasis and axillary surgery in breast cancer, particularly in cN0, postmenopausal estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative patients undergoing breast-conserving treatment (BCT). We assessed the replacement of axillary surgery with preoperative imaging modalities by analyzing the proportion of high nodal burden (HNB) patients with ≥3 LN metastases in these patients. Methods: We retrospectively identified 333 cN0, postmenopausal ER-positive/HER2-negative breast cancer patients who underwent BCT in two hospitals between January 2003 and December 2017. The proportion of LN metastasis patients and the number of metastatic LN were investigated. Risk factors of LN metastasis were analyzed and recurrence-free survival (RFS) was compared. Results: Axillary surgery confirmed LN metastasis in 81 (24.3%) of the cN0 patients. The clinical tumor size (cT) and age were factors associated with LN metastasis [cT: odds ratio (OR), 2.92, 95% confidence interval (CI): 1.69-5.05, P<0.001; age: OR, 0.33, 95% CI: 0.11-0.99, P=0.048]. However, HNB patients with ≥3 LN metastases were 15 (4.5%) of all the patients. There was statistically significant difference in the incidence of HNB between patients with cT1 tumors (3.6%) and those with cT2 tumors (7.4%) (P<0.001). Conclusions: In cN0, postmenopausal ER-positive/HER2-negative patients who underwent BCT, patients with cT1 tumors had lower rate of LN metastasis, and there were fewer instances of HNB. Therefore, in these patients, omission of axillary surgery including SLNB can be carefully considered.

Deciphering the underlying mechanism of liver diseases through utilization of multicellular hepatic spheroid models.

Hepatocellular carcinoma (HCC) is a very common form of cancer worldwide and is often fatal. Although the histopathology of HCC is characterized by metabolic pathophysiology, fibrosis, and cirrhosis, the focus of treatment has been on eliminating HCC. Recently, three-dimensional (3D) multicellular hepatic spheroid (MCHS) models have provided a) new therapeutic strategies for progressive fibrotic liver diseases, such as antifibrotic and anti-inflammatory drugs, b) molecular targets, and c) treatments for metabolic dysregulation. MCHS models provide a potent anti-cancer tool because they can mimic a) tumor complexity and heterogeneity, b) the 3D context of tumor cells, and c) the gradients of physiological parameters that are characteristic of tumors in vivo. However, the information provided by an multicelluar tumor spheroid (MCTS) model must always be considered in the context of tumors in vivo. This mini-review summarizes what is known about tumor HCC heterogeneity and complexity and the advances provided by MCHS models for innovations in drug development to combat liver diseases. [BMB Reports 2023; 56(4): 225-233].

HO-1089 and HO-1197, Novel Herbal Formulas, Have Antitumor Effects via Suppression of PLK1 (Polo-like Kinase 1) Expression in Hepatocellular Carcinoma.

The treatment for hepatocellular carcinoma (HCC), a severe cancer with a very high mortality rate, begins with the surgical resection of the primary tumor. For metastasis or for tumors that cannot be resected, sorafenib, a multi-tyrosine protein kinase inhibitor, is usually the drug of choice. However, typically, neither resection nor sorafenib provides a cure. The drug discovery strategy for HCC therapy is shifting from monotherapies to combination regimens that combine an immuno-oncology agent with an angiogenesis inhibitor. Herbal formulas can be included in the combinations used for this personalized medicine approach. In this study, we evaluated the HCC anticancer efficacy of the new herbal formula, HO-1089. Treatment with HO-1089 inhibited HCC tumor growth by inducing DNA damage-mediated apoptosis and by arresting HCC cell replication during the G2/M phase. HO-1089 also attenuated the migratory capacity of HCC cells via the inhibition of the expression of EMT-related proteins. Biological pathways involved in metabolism and the mitotic cell cycle were suppressed in HO-1089-treated HCC cells. HO-1089 attenuated expression of the G2/M phase regulatory protein, PLK1 (polo-like kinase 1), in HCC cells. HCC xenograft mouse models revealed that the daily oral administration of HO-1089 retarded tumor growth without systemic toxicity in vivo. The use of HO-1197, a novel herbal formula derived from HO-1089, resulted in statistically significant improved anticancer efficacy relative to HO-1089 in HCC. These results suggest that HO-1089 is a safe and potent integrated natural medicine for HCC therapy.

The Risk of Venous Thromboembolism in Korean Patients with Breast Cancer: A Single-Center Experience.

The relationship between cancer and venous thromboembolism (VTE) has long been described. The risk of VTE in Asian patients with breast cancer remains largely unknown. This study described the incidence and risk factors of VTE in Korean patients with breast cancer. Data were collected from a retrospective database of patients who underwent breast cancer surgery between 2011 and 2020 at a single institution. The Cox proportional-hazards model was used to identify factors associated with VTE occurrences. Among the 2246 patients with breast cancer, 48 (2.1%) developed VTE during a median follow-up period of 53 months. The average incidence of VTE was 459 per 100,000 person-years. Age ≥ 60 years, male sex, chronic kidney disease, reconstructive procedures, and stage II or higher were independent predictive factors for VTE. VTE was associated with poor disease-free survival (hazard ratio (HR), 6.140; 95% confidence interval (CI), 3.480-10.835), and overall survival (HR, 8.842; 95% CI 4.386-17.824). Most VTE events were manageable with anticoagulation; three (6.3%) patients died of VTE, despite intensive care. The incidence of VTE was significantly elevated in Korean patients with breast cancer. Since VTE has a negative effect on oncologic outcomes of breast cancer, clinicians should manage its risk throughout their lifetime.

Complete Surgical Excision Is Necessary following Vacuum-Assisted Biopsy for Breast Cancer.

Vacuum-assisted breast biopsy (VABB) has been replacing excisional biopsy in the treatment of benign breast lesions. Complete surgical excision is still needed for the lesions occasionally diagnosed with breast cancer after VABB. We aimed to characterize residual tumors after VABB and define a subset of patients who do not need surgical excision after VABB. From a retrospective database, we identified patients diagnosed with breast cancer after VABB guided with ultrasonography. Patients who underwent stereotactic biopsies were excluded. We reviewed clinicopathologic data and radiologic findings of the sample. We identified 48 patients with 49 lesions. After surgical excision, the residual tumors were identified in 40 (81.6%) lesions, and there was no residual tumor in nine (18.3%) patients. Imaging studies could not accurately locate residual tumors after VABB. A small tumor size on a VABB specimen was associated with no residual tumor on final pathology. However, residual tumors were identified in four (40%) of 10 lesions with a pathologic tumor size less than 0.5 cm. In conclusion, complete surgical excision remains the primary option for most of the patients diagnosed with breast cancer after VABB. Imaging surveillance without surgery should be carefully applied for selected low-risk patients.

Efficient gene transfection to lung cancer cells via Folate-PEI-Sorbitol gene transporter.

Lung cancer is known to be one of the fatal diseases in the world and is experiencing treatment difficulties. Many treatments have been discovered and implemented, but death rate of patients with lung cancer continues to remain high. Current treatments for cancer such as chemotherapy, immunotherapy, and radiotherapy have shown considerable results, yet they are accompanied by side effects. One effective method for reducing the cytotoxicity of these treatments is via the use of a nanoparticle-mediated siRNA delivery strategy with selective silencing effects and non-viral vectors. In this study, a folate (FA) moiety ligand-conjugated poly(sorbitol-co-PEI)-based gene transporter was designed by combining low-molecular weight polyethyleneimine (LMW PEI) and D-sorbitol with FA to form FPS. Since folate receptors are commonly overexpressed in various cancer cells, folate-conjugated nanoparticles may be more effectively delivered to selective cancer cells. Additionally, siOPA1 was used to induce apoptosis through mitochondrial fusion. The OPA1 protein stability level is important for maintaining normal mitochondrial cristae structure and function, conserving the inner membrane structure, and protecting cells from apoptosis. Consequently, when FPS/siOPA1 was used for lung cancer in-vitro and in-vivo, it improved cell viability and cellular uptake.

Chromenopyrimidinone exhibit antitumor effects through inhibition of CAP1 (Adenylyl cyclase-associated protein 1) expression in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most malignant human cancers, with a high mortality rate worldwide. Within an HCC tumor, cancer stem cells (CSCs) are responsible for tumor maintenance and progression and may contribute to resistance to standard HCC treatments. Previously, we characterized CD133+ cells as CSCs in primary HCC and identified chromenopyrimidinone (CPO) as a novel therapeutic for the effective treatment of CD133+ HCC. However, the biological function and molecular mechanism of CD133 remain unclear. Epigenetic alterations of CSCs have impacts on tumor initiation, progression, and therapeutic response. Here, we found that pharmacological and genetic depletion of CD133 in HCC attenuated the activity of DNA methyltransferases via control of DNMT3B stabilization. Genes were ranked by degree of promoter hypo/hyper methylation and significantly differential expression to create an "epigenetically activated by CPO" ranked genes list. Through this epigenetic analysis, we found that CPO treatment altered DNA methylation-mediated oncogenic signaling in HCCs. Specifically, CPO treatment inhibited Adenylyl cyclase-associated protein 1 (CAP1) expression, thereby reducing FAK/ERK activity and EMT-related proteins in HCC. Moreover, CPO improved the efficacy of sorafenib by inhibiting CAP1 expression and FAK/ERK activation in sorafenib-resistant HCC. These novel mechanistic insights may ultimately open up avenues for strategies targeting DNA methylation in liver cancer stem cells and provides novel therapeutic function of CPO for the effective treatment of sorafenib-resistant HCC.

Sorbitol dehydrogenase induction of cancer cell necroptosis and macrophage polarization in the HCC microenvironment suppresses tumor progression.

Hepatocellular carcinoma (HCC) is among the most common malignant cancers worldwide, with an increasing incidence associated with an increase in deaths due to liver cancer. HCC is typically detected at an advanced stage in patients with underlying liver dysfunction, resulting in high mortality. The identification of HCC-specific targets represents a desired but unmet need for liver cancer treatment. To identify potentially novel HCC therapeutic targets, we performed a secretome analysis using HCC spheroids. Sorbitol dehydrogenase (SORD) was identified as uniquely enriched in the secretomes and lysates derived from HCC spheroids, and high SORD expression in HCC tissues was associated with favorable effects on overall survival among patients with liver cancer. We found that the introduction of excess SORD in HCC cells inhibited tumor growth and stemness by enhancing necroptosis signal and bypassing energy-yielding pathways through regulation of lactate dehydrogenase A (LDHA) expression and mitochondrial dynamics. Treatment with human recombinant SORD (hrSORD) controlled HCC cell growth and regulated macrophage polarization in the tumor microenvironment. These results demonstrate that SORD plays critical functional roles in HCC suppression through polyol pathway-independent mechanisms, suggesting that targeting SORD expression might represent a promising therapeutic strategy for liver cancer therapy.

PIK3CA Mutation as Potential Poor Prognostic Marker in Asian Female Breast Cancer Patients Who Received Adjuvant Chemotherapy.

Background: The prognostic relevance of the PIK3CA mutation together with PD-L1, c-Met, and mismatch repair deficiency (dMMR) have not been fully investigated in Asian women with breast cancer (BC) who have undergone postoperative adjuvant chemotherapy. Methods: We analyzed PIK3CA mutations via peptide nucleic acid (PNA)-mediated real-time PCR assay, PD-L1/c-Met expression via immunohistochemistry (IHC), and microsatellite instability (MSI) status using PCR and IHC, in 191 resected BCs from 2008 to 2011. The Cancer Genome Atlas (TCGA) dataset for the involvement of the PIK3CA mutation with PD-L1/c-Met/MMR was explored. Results: The PNA clamp-mediated assay was able to detect the PIK3CA mutation in 1% of the mutant population in the cell line validation. Using this method, the PIK3CA mutation was found in 78 (49.4%) of 158 samples. c-Met and PD-L1 positivity were identified in 31.4 and 21.8% of samples, respectively, which commonly correlated with high histologic grade and triple-negative subtype. MSI/dMMR was observed in 8.4% of patients, with inconsistency between MMR IHC and the MSI PCR. The PIK3CA mutation exhibited a poor prognostic association regarding recurrence-free survival (RFS) in both overall and triple-negative BCs. In subgroup analyses, the PIK3CA-mutated tumors showed poorer RFS than the PIK3CA-wildtype within the c-Met-positive, MSS, triple-negative, or age onset <50 years subgroups, which showed a similar trend of association in TCGA data. Conclusions: PIK3CA mutation together with c-Met or dMMR/MSI status might be relevant to poor prognosis in BC subsets, especially in Asian women.