Publications by authors named "Yihong Wang"

128 Publications

Energy features in spontaneous up and down oscillations.

Cogn Neurodyn 2021 Feb 29;15(1):65-75. Epub 2020 May 29.

Institute for Cognitive Neurodynamics, East China University of Science and Technology, 130 Meilong Road, Shanghai, China.

Spontaneous brain activities consume most of the brain's energy. So if we want to understand how the brain operates, we must take into account these spontaneous activities. Up and down transitions of membrane potentials are considered to be one of significant spontaneous activities. This kind of oscillation always shows bistable and bimodal distribution of membrane potentials. Our previous theoretical studies on up and down oscillations mainly looked at the ion channel dynamics. In this paper, we focus on energy feature of spontaneous up and down transitions based on a network model and its simulation. The simulated results indicate that the energy is a robust index and distinguishable of excitatory and inhibitory neurons. Meanwhile, one the whole, energy consumption of neurons shows bistable feature and bimodal distribution as well as the membrane potential, which turns out that the indicator of energy consumption encodes up and down states in this spontaneous activity. In detail, energy consumption mainly occurs during up states temporally, and mostly concentrates inside neurons rather than synapses spatially. The stimulation related energy is small, indicating that energy consumption is not driven by external stimulus, but internal spontaneous activity. This point of view is also consistent with brain imaging results. Through the observation and analysis of the findings, we prove the validity of the model again, and we can further explore the energy mechanism of more spontaneous activities.
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http://dx.doi.org/10.1007/s11571-020-09597-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947106PMC
February 2021

Risk factors for breast cancer development by tumor characteristics among women with benign breast disease.

Breast Cancer Res 2021 Mar 18;23(1):34. Epub 2021 Mar 18.

Albert Einstein College of Medicine, Jack and Pearl Resnick Campus, 1300 Morris Park Avenue, Belfer Building, Room 1301, Bronx, NY, 10461, USA.

Background: Among women diagnosed with invasive breast cancer, 30% have a prior diagnosis of benign breast disease (BBD). Thus, it is important to identify factors among BBD patients that elevate invasive cancer risk. In the general population, risk factors differ in their associations by clinical pathologic features; however, whether women with BBD show etiologic heterogeneity in the types of breast cancers they develop remains unknown.

Methods: Using a nested case-control study of BBD and breast cancer risk conducted in a community healthcare plan (Kaiser Permanente Northwest), we assessed relationships of histologic features in BBD biopsies and patient characteristics with subsequent breast cancer risk and tested for heterogeneity of associations by estrogen receptor (ER) status, tumor grade, and size. The study included 514 invasive breast cancer cases (median follow-up of 9 years post-BBD diagnosis) and 514 matched controls, diagnosed with proliferative or non-proliferative BBD between 1971 and 2006, with follow-up through mid-2015. Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained using multivariable polytomous logistic regression models.

Results: Breast cancers were predominantly ER-positive (86%), well or moderately differentiated (73%), small (74% < 20 mm), and stage I/II (91%). Compared to patients with non-proliferative BBD, proliferative BBD with atypia conferred increased risk for ER-positive cancer (OR = 5.48, 95% CI = 2.14-14.01) with only one ER-negative case, P-heterogeneity = 0.45. The presence of columnar cell lesions (CCLs) at BBD diagnosis was associated with a 1.5-fold increase in the risk of both ER-positive and ER-negative tumors, with a 2-fold increase (95% CI = 1.21-3.58) observed among postmenopausal women (56%), independent of proliferative BBD status with and without atypia. We did not identify statistically significant differences in risk factor associations by tumor grade or size.

Conclusion: Most tumors that developed after a BBD diagnosis in this cohort were highly treatable low-stage ER-positive tumors. CCL in BBD biopsies may be associated with moderately increased risk, independent of BBD histology, and irrespective of ER status.
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http://dx.doi.org/10.1186/s13058-021-01410-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977564PMC
March 2021

Immunohistochemical HER2 score correlates with response to neoadjuvant chemotherapy in HER2-positive primary breast cancer.

Breast Cancer Res Treat 2021 Apr 17;186(3):667-676. Epub 2021 Feb 17.

Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, 593 Eddy St, APC 12, Providence, RI, 02903, USA.

Purpose: The accuracy of biomarker assessment in breast cancer (BC) is paramount for therapy decisions and informs prognosis. We investigated neoadjuvant chemotherapy (NAC) response in HER2-positive BC with respect to immunohistochemistry (IHC) and in situ hybridization (ISH) results. We aimed to determine the role of HER2 protein expression in predicting NAC response and long-term outcome in two HER2-positive groups: IHC 3 + versus IHC 2 + ISH amplified groups.

Methods: This retrospective study included 192 consecutive HER2 + primary BCs diagnosed from 2007 to 2019 treated with NAC and HER2-targeted agent (NACH). There were 158 HER2 3 + and 34 HER2 2 + ISH + cases. Clinicopathological parameters and long-term outcomes were analyzed.

Results: The Pathological Complete Response (pCR) rate was 85.7% (72/84) in ER-/HER2 + BCs and was lower in ER + /HER2 + BCs (42.6%, 46/108). The pCR was 55.1% (86/156) in the HER2 3 + group and was only 17.6% in HER2 2 + ISH + group (p < 0.001). Patients who achieved pCR in HER2 2 + ISH + group did not show a significantly higher HER2/CEP17 ratio or HER2 copy number. The overall survival (OS) and progression-free survival (PFS) were significantly higher in pCR compared to non-pCR cases (p = 0.011 and p = 0.015, respectively).

Conclusions: There is significant heterogeneity in response to the NACH regimens in HER2 + cases. Our findings indicate that HER2 IHC score and ER expression determine NACH response in HER2 + BC. We recommend considering HER2 protein expression and ISH value to better select patients and assess the response for HER2-targeted therapy.
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http://dx.doi.org/10.1007/s10549-021-06124-8DOI Listing
April 2021

Apocrine ductal carcinoma in situ associated with testosterone therapy in a transgender individual.

Breast J 2021 Feb 5. Epub 2021 Feb 5.

Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.

We report the first case of apocrine ductal carcinoma in situ (DCIS) in a female-to-male transgender individual on testosterone therapy (TT). The gender confirmation total mastectomy revealed 2 cm DCIS with apocrine cytology, high nuclear grade with associated calcification, and necrosis. Immunohistochemistry revealed the DCIS was negative for ER, positive for AR with HER2/neu overexpression (3+). This patient with negative screening mammography developed apocrine DCIS on TT, suggesting that gender-affirming hormone therapy may have advanced malignant transformation of atypical apocrine cells. This may have implications for increased surveillance within the transgender population.
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http://dx.doi.org/10.1111/tbj.14187DOI Listing
February 2021

Effect of the heme oxygenase gene on mycelial growth and polysaccharide synthesis in Ganoderma lucidum.

J Basic Microbiol 2021 Mar 5;61(3):253-264. Epub 2021 Feb 5.

Microbiology Department, College of Life Sciences, Nanjing Agricultural University, Key Laboratory of Agricultural Environmental MicrobiologM, yinistry of Agriculture, Nanjing, Jiangsu, China.

The heme oxygenase gene has antioxidant and cytoprotective effects in organisms, but no related research has been conducted in Ganoderma lucidum. For the first time, we cloned the HMX1 gene in G. lucidum. The CDS is 1092 bp in length and encodes 363 amino acids. The HMX1 protein was prokaryotically expressed and purified, and the enzyme activity of the purified protein was measured. The value of K was 0.699 μM, and V was 81.9 nmol BV h  nmol protein. By constructing the silencing vector pAN7-dual-HMX1i, the transformants HMX1i1 and HMX1i2 were obtained. Compared with the wild-type (WT), the average growth rate of HMX1i1 and HMX1i2 decreased by 31% and 23%, respectively, and the mycelium biomass decreased by 53% and 48%, respectively. Compared with the WT, the extracellular polysaccharide content of HMX1i1 and HMX1i2 increased by 59% and 51%, and the intracellular polysaccharide content increased by 24% and 22%, respectively. These results indicate that the HMX1 gene affects mycelial growth and polysaccharide synthesis in G. lucidum.
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http://dx.doi.org/10.1002/jobm.202000622DOI Listing
March 2021

Infiltrating immune cells in benign breast disease and risk of subsequent invasive breast cancer.

Breast Cancer Res 2021 Jan 30;23(1):15. Epub 2021 Jan 30.

Division of Research, Peter MacCallum Cancer Centre, Melbourne, Australia.

Background: It is well established that tumors are antigenic and can induce an immune response by the host, entailing lymphocytic infiltration of the tumor and surrounding stroma. The extent and composition of the immune response to the tumor, assessed through evaluation of tumor-infiltrating lymphocyte counts, has been shown in many studies to have prognostic and predictive value for invasive breast cancer, but currently, there is little evidence regarding the association between infiltrating immune cell counts (IICCs) in women with benign breast disease (BBD) and risk of subsequent invasive breast cancer.

Methods: Using a cohort of 15,395 women biopsied for BBD at Kaiser Permanente Northwest, we conducted a nested case-control study in which cases were women who developed a subsequent invasive breast cancer during follow-up and controls were individually matched to cases on age at BBD diagnosis. We assessed IICCs in normal tissue and in the BBD lesions, and we used unconditional logistic regression to estimate the multivariable odds ratios (OR) and 95% confidence intervals (CI) for the associations between IICCs and breast cancer risk.

Results: There was no association between the IICC in normal tissue (multivariable OR per 5% increase in IICC = 1.05, 95% CI = 0.96-1.16) or in the BBD lesion (OR per 5% increase in IICC = 1.06, 95% CI = 0.96-1.18) and risk of subsequent invasive breast cancer. Also, there were no associations within subgroups defined by menopausal status, BBD histology, BMI, and history of smoking.

Conclusion: The results of this study suggest that IICCs in BBD tissue are not associated with altered risk of subsequent invasive breast cancer.
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http://dx.doi.org/10.1186/s13058-021-01395-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846992PMC
January 2021

Cancer patient management strategy in a Cancer Center of Zhejiang, China during the COVID-19 pandemic.

BMC Cancer 2020 Dec 7;20(1):1194. Epub 2020 Dec 7.

Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, China.

Background: Due to the increased risk of viral infection and the severe shortage of medical resources during the pandemic of COVID-19, most hospitals in the epidemic areas significantly reduced non-emergency admissions and services, if not closed. As a result, it has been difficult to treat cancer patients on time, which adversely affects their prognosis. To address this problem, cancer centers must develop a strategic plan to manage both inpatients and outpatients during the pandemic, provide them with the necessary treatment, and at the same time prevent the spread of the virus among patients, visitors and medical staff.

Methods: Based upon the epidemic situation in Zhejiang Province, China, the number of running non-emergency medical wards in the Zhejiang Cancer Hospital was gradually increased in a controlled manner. All staff of the hospital received COVID-19 preventive training and was provided with three different levels of protection according to the risks of their services. Only patients without a known history of SARS-CoV-2 contact were eligible to schedule an appointment. Body temperature was measured on all patients upon their arrival at the hospital. Chest CT image, blood cell counting and travel/contact history were investigated in patients with fever. Respiratory tract samples, such as sputum and throat swabs, from all patients, including those clinically suspected of SARS-CoV-2 infection, were collected for nucleic acid detection of SARS-CoV-2 before treatment.

Results: A total of 3697 inpatients and 416 outpatients seeking cancer treatment were enrolled from February 1 to April 3, 2020, in compliance with the hospital's infection-control interventions. The clinicopathological parameters of the patients were summarized herein. 4237 samples from 4101 patients produced negative RNA testing results. Four clinically suspected patients all presented negative RNA test results and were excluded from the SARS-CoV-2 infection through follow-up retesting and monitoring. Seven patients with only N-gene positive results were retested, followed by CT scan and SARS-CoV-2 contact history investigation. All of them were finally diagnosed as non-infected patients. There was one outpatient who was confirmed positive by virus RNA test and then followed up. She might be an asymptomatic laboratory-confirmed case. During the study period, there was no SARS-CoV-2 infection among staff, patients and escorts of patients in the Zhejiang Cancer Hospital.

Conclusion: This study suggested our infection-control interventions, including viral nucleic acid test, could be used as a reliable method to screen cancer patients in the area with moderate COVID-19 prevalence. Cancer may not be a high-risk factor of SARS-CoV-2 infection.
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http://dx.doi.org/10.1186/s12885-020-07577-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719731PMC
December 2020

Coexpress of GATA-3 and ER in Anorectal and Head and Neck Squamous Cell Carcinoma Mimicking Metastatic Breast Cancer.

Appl Immunohistochem Mol Morphol 2020 Dec 1. Epub 2020 Dec 1.

Department of Pathology and Lab Medicine, Alpert Medical School of Brown University, Providence, RI.

GATA binding protein 3 (GATA-3) is a sensitive marker for breast and urothelial carcinomas. In combination with the estrogen receptor (ER), it is often used for differential diagnosis of metastatic carcinomas of breast origin. In this study, we sought to characterize GATA-3 and ER expression in squamous cell carcinoma (SqCC) of various origins to compare with breast carcinoma. Sixty-four SqCC of anorectum (35), head and neck (15), lung (11), and breast (3) as well as urothelial carcinoma (31) were included. In anorectal and head and neck SqCC, GATA-3, and ER was observed in 23/50 (46.0%) and 18/50 (36.0%) of the cases, respectively. The expression of GATA-3 and ER were present in both male and female patients without significant sex predominance. In 2 metastatic SqCC, the GATA-3 and ER expressed similar immunoreactivity compatible with their anorectal primary. Progesterone receptor was only expressed in 2 anorectal SqCC and none of head and neck SqCC or urothelial carcinomas. None of the lung SqCC expressed GATA-3 or ER (0/11). p16 was expressed in the majority of head and neck (6/12) and anorectal SqCC (26/27). Our study demonstrated that the combination of GATA-3 and ER positivity is not entirely specific for breast carcinomas, since both stains are expressed in SqCC from anorectal and head and neck origins. Clinical workup for metastatic carcinoma of suspicious breast origin should be cognizant of other tumors with a similar immunohistochemical profile (ie, SqCC).
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http://dx.doi.org/10.1097/PAI.0000000000000887DOI Listing
December 2020

PAX8 Expression in Breast Cancer.

Appl Immunohistochem Mol Morphol 2021 Apr;29(4):293-298

Department of Pathology and Laboratory Medicine, Lifespan Medical Center and Brown University Alpert School of Medicine, Providence, RI.

PAX8 expression is frequently detected in renal, thyroidal, and Müllerian carcinomas, and PAX8 immunohistochemistry is often used to confirm the origin of these tumors. Tumors metastatic to the breast may masquerade as primary breast lesions. PAX8 is strongly expressed in tumors of Müllerian origin and largely negative in breast primaries, but an immunohistochemical expression of PAX8 in breast cancer has not been systematically evaluated in a large series. We analyzed 266 cases of invasive carcinoma of the breast on tissue microarrays and whole tissue sections with a PAX8 monoclonal antibody. Both the extent (focal or diffuse) and intensity (weak, moderate, or strong) of nuclear staining were assessed in the tumor cells. In total, 16 cases (6.02%) were positive for PAX8 (12 with weak and 4 with moderate staining). Expression was diffuse in 7 cases and focal in 9 cases. All 16 PAX8-positive tumors were histologic grade III invasive ductal carcinomas, 13 of these were triple-negative, 2 were HER2-positive, only and 1 was progesterone receptor-positive only. Strong PAX8 nuclear expression was not seen in any of the cases. PAX8 was negative in breast tumors with neuroendocrine features. Our study demonstrated a low rate of PAX8 expression in breast cancer. When present, PAX8 expression was only seen in high-grade invasive ductal carcinomas, mostly triple-negative. The presence of PAX8 immunoreactivity alone cannot exclude mammary origin, especially when only weak to moderate staining is observed, so the correlation with available clinical and pathologic data helps to ensure an accurate diagnosis.
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http://dx.doi.org/10.1097/PAI.0000000000000883DOI Listing
April 2021

Ratiometric Dual Signal-Enhancing-Based Electrochemical Biosensor for Ultrasensitive Kanamycin Detection.

ACS Appl Mater Interfaces 2020 Nov 10;12(47):52713-52720. Epub 2020 Nov 10.

School of Environmental Science and Engineering, Hebei University of Science and Technology, Shijiazhuang, Hebei 050018, P. R. China.

Based on the signal amplification elements of planar VS/AuNPs nanocomposites and CoFeO nanozyme, we herein developed an electrochemical biosensor for sensitive kanamycin (Kana) quantification. A ratiometric sensing platform was presented by incorporating VS/AuNPs nanocomposites as a support material with excellent conductivity and high specific surface area, as well as hairpin DNA (hDNA) with complementary hybridization of biotinylated Kana-aptamer. In addition, streptavidin-functionalized CoFeO nanozyme with superior peroxidase-like catalytic activity were immobilized onto the aptasensor, hence the peroxidase-like catalytic reaction could yield amplified electrochemical signals. With the presence of Kana, the aptamer-biorecognition resulted in a quantitative decrease of nanozyme accumulation and an increase of methylene blue response. Under optimal conditions, the electrochemical signal ratio of the aptasensor revealed a linear relation along with the logarithmic concentration of Kana from 1 pM to 1 μM, with the limit of detection reaching to 0.5 pM. Moreover, this aptasensor exhibited excellent precision, as well as high repeatability, hence possessing potentials in real samples and for diverse targets detection by easy replacement of the matched aptamer.
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http://dx.doi.org/10.1021/acsami.0c15898DOI Listing
November 2020

Elastin in the Tumor Microenvironment.

Adv Exp Med Biol 2020 ;1272:1-16

Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA.

Elastic fibers are found in the extracellular matrix (ECM) of tissues requiring resilience and depend on elasticity. Elastin and its degradation products have multiple roles in the oncologic process. In many malignancies, the remodeled ECM expresses high levels of the elastin protein which may have either positive or negative effects on tumor growth. Elastin cross-linking with other ECM components and the enzymes governing this process all have effects on tumorigenesis. Elastases, and specifically neutrophil elastase, are key drivers of invasion and metastasis and therefore are important targets for inhibition. Elastin degradation leads to the generation of bioactive fragments and elastin-derived peptides that further modulate tumor growth and spread. Interestingly, elastin-like peptides (ELP) and elastin-derived peptides (EDP) may also be utilized as nano-carriers to combat tumor growth. EDPs drive tumor development in a variety of ways, and specifically targeting EDPs and their binding proteins are major objectives for ongoing and future anti-cancer therapies. Research on both the direct anti-cancer activity and the drug delivery capabilities of ELPs is another area likely to result in novel therapeutic agents in the near future.
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http://dx.doi.org/10.1007/978-3-030-48457-6_1DOI Listing
October 2020

Dietary Fermented Soy Extract and Oligo-Lactic Acid Alleviate Chronic Kidney Disease in Mice via Inhibition of Inflammation and Modulation of Gut Microbiota.

Nutrients 2020 Aug 8;12(8). Epub 2020 Aug 8.

Nutrition/Metabolism Laboratory, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

Chronic kidney disease (CKD) is a global epidemic with an increasing prevalence worldwide. Effective preventive strategies are urgently needed. This study aimed to investigate the effect of nutraceutical components, a fermented soybean product (ImmuBalance, IMB) and an oligo-lactic acid product (LAP), on the prevention of adenine-induced CKD in mice. Female C57BL/6 mice were randomly assigned into following experimental groups: negative control; model control; and models treated with IMB at 250 or 1000 mg/kg body weight (BW), LAP at 1000 or 2000 mg/kg BW, and IMB/LAP combinations. The CKD model was established by intraperitoneal injection of adenine daily for 4 weeks, and treatments started 2 weeks before adenine injection and ended after 10 weeks. Compared with the model control, the treatments did not significantly alter the body weight or food intake. Both IMB and LAP, especially their combination, significantly inhibited tubular dilation, tubulointerstitial degeneration or atrophy, interstitial chronic inflammation and acute inflammation in the kidneys of CKD mice, and significantly decreased serum cystatin C levels. IMB or LAP significantly reversed CKD-associated increases of circulating and kidney levels of inflammatory cytokines, circulating levels of kidney injury biomarkers, and kidney levels of stem cell biomarkers, and significantly reversed CKD-associated reduction of cecum group. Our results suggest that dietary supplementation of IMB or LAP may significantly delay the development and/or progression of CKD.
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http://dx.doi.org/10.3390/nu12082376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468970PMC
August 2020

Clinicopathologic update of calcium oxalate in breast: A 15-year retrospective review.

Breast J 2020 09 21;26(9):1736-1741. Epub 2020 Jun 21.

Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA.

Mammary malignancies are radiologically detected by presence of masses, architectural distortions or microcalcifications. Unlike calcium hydroxyapatite, calcium oxalate (CaOx) deposits have been almost exclusively associated with benign mammary processes. The etiology and mechanism of mammary CaOx deposition remains poorly understood, and the original studies elucidating its histopathologic correlation are dated several decades ago. We reviewed radiopathologic findings of breast biopsies and excisions to re-examine the clinicopathologic significance of CaOx deposits and to ascertain potential radiologic characteristics for their identification. Fifty patients from 2004 to 2019 with reported "calcium oxalate" were retrospectively reviewed. CaOx was invariably detected with histopathologic changes of nonproliferative ducts/cysts (90%, 45 of 50), and less commonly, ducts/cysts with usual ductal hyperplasia (10%, 5 of 50). CaOx was missed on one biopsy with a subsequent excision showing apocrine cyst with CaOx. Despite the benign pathological findings, mammographic findings corresponding to CaOx ranged from benign to highly suspicious with 20% categorized as benign (round or punctuate), 22% as intermediate amorphous, 14% as suspicious (coarse/heterogeneous), and 18% as highly suspicious/pleomorphic, respectively. Lobular carcinoma in situ (LCIS) was present in separate fields from CaOx containing benign ducts in two cases which were radiologically characterized as "grouped heterogeneous" and "localized linear." On imaging, more than half of the cases (52.5%) had a corresponding BI-RADS score of 4 and the calcifications were associated with variable distributions and appearances. In conclusion, this is one of the largest studies of CaOx in breast with radiology and pathology correlation. The radiologic appearances of CaOx are nonspecific from benign to highly suspicious. Identification of CaOx on the biopsy is reassuring for a benign diagnosis. Incidental atypical lesions can occur that are often not directly associated with CaOx. CaOx may be overlooked on pathologic evaluation which results in unnecessary surgery. Our findings support close radiologic-pathologic correlation for clinical decision-making pertaining to breast calcifications.
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http://dx.doi.org/10.1111/tbj.13952DOI Listing
September 2020

MicroRNA-30b-5p functions as a metastasis suppressor in colorectal cancer by targeting Rap1b.

Cancer Lett 2020 05 27;477:144-156. Epub 2020 Feb 27.

Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, China. Electronic address:

Colorectal liver metastasis (CRLM) is the leading cause of death in patients with colorectal cancer (CRC). MiR-30b-5p can function as an oncogene or tumor suppressor in cancers, but its role in CRLM is still unknown. Here, we found that miR-30b-5p overexpression suppressed the invasion, migration, adhesion, and motility of HCT116 and LoVo cells. The expression of EMT (Zeb1, Snail, and vimentin) and adhesion-related proteins (p-paxillin and p-Src) was decreased. We validated Rap1b, a Ras family small GTPase that regulates cell adhesion and mobility, as the direct and functional target of miR-30b-5p. Rap1b overexpression rescued the aggressive characteristics of CRC cells that were inhibited by miR-30b-5p. Rap1b knockdown suppressed invasion and migration and decreased CRC cell-matrix adhesion and spreading, which was consistent with the results of miR-30b-5p overexpression. Further in vivo experiments demonstrated that miR-30b-5p overexpression inhibited CRLM, but Rap1b rescue attenuated the inhibitory effect of miR-30b-5p. In addition, miR-30b-5p was downregulated in CRC specimens, and Rap1b showed a negative correlation with miR-30b-5p expression in primary CRC and LM tissues. These results indicate that miR-30b-5p functions as a metastasis suppressor by targeting Rap1b and may provide a new target for the treatment of CRLM.
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http://dx.doi.org/10.1016/j.canlet.2020.02.021DOI Listing
May 2020

Wnt/β-catenin signaling regulates pathogenesis of human middle ear cholesteatoma.

Int J Clin Exp Pathol 2019 1;12(4):1154-1162. Epub 2019 Apr 1.

Department of Laboratory, Fujian Provincial Hospital, Provincial Clinical Medical College of Fujian Medical University No. 134 East Street, Fuzhou 350001, Fujian Province, China.

Cholesteatoma is characterized by the presence of a squamous epithelium invading the middle ear altering its growth properties. Wnt/β-catenin signaling controls cell proliferation and differentiation by regulating expressions of target genes. Elevated levels of β-catenin are related to tissue pathogenesis and tumor progression. Nevertheless, the mechanisms through which β-catenin contributes to middle ear cholesteatoma development remain to be elucidated. We used proliferation assay, qRT-PCR assay, and western blotting to measure levels of the Wnt/β-catenin signaling pathway. β-Catenin expression evidently increased in middle ear cholesteatoma cells when compared with normal epithelial cells. Next, we found that treatment of Wnt inhibitor dickkopf1 (Dkk1) decreased β-catenin expression, as well as the expression levels of cytokeratin 16 (CK16), CK18, Ki67 and PCNA. Overexpression of Wnt3a or β-catenin induced the expression levels of CK16, CK18, Ki67 and PCNA. Furthermore, Dkk1 treatment significantly inhibited proliferation activity of middle ear cholesteatoma cells, whereas forced expression of Wnt3a or β-catenin promoted proliferation activity of middle ear cholesteatoma cells. Wnt/β-catenin signaling induced cell proliferation and up-regulated expressions of targeted genes in human middle ear cholesteatoma.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947047PMC
April 2019

Tuning the near infrared II emitting wavelength of small molecule dyes by single atom alteration.

Chem Commun (Camb) 2020 Jan 10;56(4):523-526. Epub 2019 Dec 10.

Molecular Imaging Program at Stanford (MIPS), Bio-X Program, and Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University, California, 94305-5344, USA.

A series of small molecule dyes demonstrate the feasibility of manipulating Near Infrared II emission by simply altering the donors' heteroatoms, which involved both electronegativity and intramolecular steric effects. Furthermore, these dyes show high resolution and stability for in vivo imaging after being complexed with human serum albumin.
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http://dx.doi.org/10.1039/c9cc08434gDOI Listing
January 2020

Electrochemical detection of microRNAs based on AuNPs/CNNS nanocomposite with Duplex-specific nuclease assisted target recycling to improve the sensitivity.

Talanta 2020 Feb 4;208:120441. Epub 2019 Oct 4.

School of Chemistry and Chemical Engineering, Southeast University, Nanjing, 211189, PR China. Electronic address:

MicroRNAs (miRNAs) are important biomarkers in early diagnosis of disease. In this work, we developed a simple and effective electrochemical biosensor based on Au nanoparticles (AuNPs)/Carbon nitride nanosheet (CNNS) nanocomposite for the miRNAs detection. Duplex-specific nuclease (DSN) and hairpin structure probe were utilized to improve the sensitivity and selectivity respectively. In the presence of miRNA-21, the signal molecule could be released from the surface of the electrode and decrease the current peak in square wave voltammetry (SWV) test. Under the optimal conditions, the reported biosensor showed that the detection range of miRNA-21 is from 10 fM to 1 nM and detection limit is as low as 2.9 fM. Furthermore, the detection of miRNA-21 added in serum samples indicates the developed biosensor with good selectivity, stability and reproducibility which verify its potential to be used in the early diagnosis of diseases.
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http://dx.doi.org/10.1016/j.talanta.2019.120441DOI Listing
February 2020

Cytokeratin 7-negative and GATA binding protein 3-negative breast cancers: Clinicopathological features and prognostic significance.

BMC Cancer 2019 Nov 12;19(1):1085. Epub 2019 Nov 12.

Department of Pathology and Laboratory Medicine, Alpert Medical School of Brown University, 593 Eddy St; APC 12, Providence, RI, 02903, USA.

Background: Cytokeratin 7 (CK7) and GATA binding protein 3 (GATA3) are considered as immunohistochemical hallmarks of breast cancers; however, there are breast tumors lacking these markers. Clinicopathological characterization of CK7 negative breast cancer has not been addressed previously and similar studies on GATA3 negative tumors are limited.

Methods: This study included 196 consecutive cases of Nottingham Grade 3 breast cancers with 159 cases of Grade 1 and Grade 2 tumors for comparison. CK7 and GATA3 expression was correlated with patient's age, histological type, pathological grade and stage, hormone receptor status, molecular subtype and overall survival.

Results: CK7 negativity was seen in 13% of Grade 3, 9% of Grade 2, and 2% of Grade 1 cases (P = 0.0457). Similarly, 28% of Grade 3, 5% of Grade 2 and 2% of Grade 1 cases were GATA3 negative (P < 0.0001). CK7 negative tumors did not show association with other clinicopathological parameters. GATA3 negative tumors were enriched in the basal-like molecular subgroup and were associated with negative estrogen receptor (ER) and negative progesterone receptor (PR) statuses. Both CK7 and GATA3 expression showed no association with overall survival in patients with Grade 3 tumor.

Conclusions: This is the first study to characterize CK7 negative breast tumors in the context of clinicopathology. Profiling the CK7 negative and GATA3 negative breast cancers helps to understand the biology of these specific tumor subgroups and may aid in their diagnosis.
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http://dx.doi.org/10.1186/s12885-019-6295-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849242PMC
November 2019

Two types of primary mucinous ovarian tumors can be distinguished based on their origin.

Mod Pathol 2020 04 6;33(4):722-733. Epub 2019 Nov 6.

Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.

The origin of primary mucinous ovarian tumors is unknown. We explore the hypothesis that they originate from either Brenner tumors or teratomas and examine differences between the tumors that arise in these settings. A total of 104 Brenner tumor-associated mucinous tumors and 58 teratoma-associated mucinous tumors were analyzed. Immunohistochemistry for 21 antigens and fluorescence in situ hybridization for ERBB2 and MYC were performed. Genome-wide copy number analysis and mutation analysis for 56 cancer-related genes was carried out on a subset of mucinous ovarian tumors and their complementary Brenner tumor or teratoma. Patients with teratoma-associated mucinous tumors were significantly younger than patients with Brenner tumor-associated mucinous tumors (43 vs. 61 years). During progression from cystadenoma to atypical proliferative mucinous (borderline) tumor to carcinoma expression of typical gastrointestinal markers was increased in both Brenner tumor-associated and teratoma-associated mucinous tumors. Brenner tumor-associated mucinous tumors showed more frequently calcifications and Walthard cell nests, rarely expressed SATB2 and showed more often co-deletion of CDKN2A and MTAP. Teratoma-associated mucinous tumors were characterized by mucinous stromal dissection, SATB2 expression and RNF43 mutations. Other frequent mutations in both Brenner tumor-associated and teratoma-associated mucinous tumors were TP53 and KRAS mutations. Based on identical mutations or copy number profiles clonal relationships were indicated in two mucinous tumors and their associated Brenner tumor. Teratomas and Brenner tumors give rise to different subtypes of mucinous ovarian tumors. Subsequent progression pathways are comparable since both Brenner tumor-associated and teratoma-associated mucinous tumors develop a gastrointestinal immunophenotype during progression and show early mutations in KRAS and TP53. Teratoma-associated mucinous tumors may more closely resemble true gastrointestinal tumors, indicated by their expression of SATB2 and the presence of RNF43 mutations.
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http://dx.doi.org/10.1038/s41379-019-0401-yDOI Listing
April 2020

Stromal ColXα1 expression correlates with tumor-infiltrating lymphocytes and predicts adjuvant therapy outcome in ER-positive/HER2-positive breast cancer.

BMC Cancer 2019 Nov 1;19(1):1036. Epub 2019 Nov 1.

Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, 593 Eddy St, APC 12, Providence, RI, 02903, USA.

Background: The breast cancer microenvironment contributes to tumor progression and response to chemotherapy. Previously, we reported that increased stromal Type X collagen α1 (ColXα1) and low TILs correlated with poor pathologic response to neoadjuvant therapy in estrogen receptor and HER2-positive (ER+/HER2+) breast cancer. Here, we investigate the relationship of ColXα1 and long-term outcome of ER+/HER2+ breast cancer patients in an adjuvant setting.

Methods: A total of 164 cases with at least 5-year follow-up were included. Immunohistochemistry for ColXα1 was performed on whole tumor sections. Associations between ColXα1expression, clinical pathological features, and outcomes were analyzed.

Results: ColXα1 expression was directly proportional to the amount of tumor associated stroma (p = 0.024) and inversely proportional to TILs. Increased ColXα1 was significantly associated with shorter disease free survival and overall survival by univariate analysis. In multivariate analysis, OS was lower in ColXα1 expressing (HR = 2.1; 95% CI = 1.2-3.9) tumors of older patients (> = 58 years) (HR = 5.3; 95% CI = 1.7-17) with higher stage (HR = 2.6; 95% CI = 1.3-5.2). Similarly, DFS was lower in ColXα1 expressing (HR = 1.8; 95% CI = 1.6-5.7) tumors of older patients (HR = 3.2; 95% CI = 1.3-7.8) with higher stage (HR = 2.7; 95% CI = 1.6-5.7) and low TILs. In low PR+ tumors, higher ColXα1 expression was associated with poorer prognosis.

Conclusion: ColXα1 expression is associated with poor disease free survival and overall survival in ER+/HER2+ breast cancer. This study provides further support for the prognostic utility of ColXα1 as a breast cancer associated stromal factor that predicts response to chemotherapy.
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http://dx.doi.org/10.1186/s12885-019-6134-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825361PMC
November 2019

Symptomatic Fibroadenoma Resolves Status Post Cryoablation.

R I Med J (2013) 2019 Oct 1;102(8):49-52. Epub 2019 Oct 1.

Rhode Island Hospital, Department of Diagnostic Imaging, Providence, RI.

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October 2019

Mitochondria-targeted delocalized lipophilic cation complexed with human serum albumin for tumor cell imaging and treatment.

Nanomedicine 2020 01 24;23:102087. Epub 2019 Aug 24.

Molecular Imaging Program at Stanford (MIPS), Bio-X Program, and Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University, California, USA. Electronic address:

Small molecule 5BMF is a novel mitochondria-targeted delocalized lipophilic cation (DLC) with good anti-tumor activity and fluorescence emission suitable for bioimaging. In this study, human serum albumin (HSA) complexed with 5BMF (5BMF@HSA) has been developed to further improve its solubility (from 1.61 to 5.41 mg/mL), and the fluorescent intensity of 5BMF@HSA was improved over 2 times. Nearly 10-fold 5BMF was released from 5BMF@HSA complex in acidic condition when compared with neutral/basic environment. Intracellular distribution of 5BMF was altered by HSA as its signals were observed in lysosomes where free 5BMF barely localized. Both 5BMF@HSA and 5BMF showed selective toxicity toward tumor cells in μM and nM range and effectively inhibited tumor growth in mice model. In summary, 5BMF@HSA shows improved solubility in aqueous buffer and enhanced fluorescence emission, and maintains tumor inhibition capability. It is a promising protein complex for tumor cell imaging and tumor treatment.
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http://dx.doi.org/10.1016/j.nano.2019.102087DOI Listing
January 2020

Cholesteroloma of the breast: A 10 year retrospective review of 79 cases with radiology correlation.

Breast J 2019 11 6;25(6):1177-1181. Epub 2019 Jul 6.

Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.

A cholesteroloma or cholesterol granuloma of the breast is an uncommon lesion representing an inflammatory/reactive process with unclear etiology. In this study, we reviewed our 10-year experience with cholesteroloma of the breast with clinical, radiologic, and histopathological correlation. Seventy-nine cases were selected. The mean patient age was 57.7 (range 25-90) years old. Patients had hypercholesterolemia with mean blood cholesterol level of 201 mg/dL (P < 0.001). The mean body mass index (BMI) was 26.7 kg/m (P = 0.1976). The indications for the breast biopsies were mass lesion on radiology (85.5%, n = 65) and microcalcifications (10.5%, n = 8). Of the 65 cases of the mass lesions, 52 presented as solid masses and 13 were cystic. On the diagnostic mammogram or ultrasound, 81.9% were BI-RADS 4% and 6.9% were BI-RADS 5. Macrocysts were the most common pathological finding associated with cholesteroloma suggesting the etiology of cholesteroloma may be the result of repair process from obstruction and rupture of the macrocysts. Six cases (9.2%) of cholesterolomas had persistent masses during follow-up. The recognition of this lesion and radio-pathological correlation can help us better understand this entity and distinguish it from its mimickers.
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http://dx.doi.org/10.1111/tbj.13441DOI Listing
November 2019

Pilomatricoma of the male breast.

Breast J 2019 09 6;25(5):1012-1013. Epub 2019 Jun 6.

Department of Pathology and Laboratory Medicine, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island.

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http://dx.doi.org/10.1111/tbj.13406DOI Listing
September 2019

The place cell activity is information-efficient constrained by energy.

Neural Netw 2019 Aug 5;116:110-118. Epub 2019 Apr 5.

School of Computer Science, Hangzhou Dianzi University, Hangzhou, China. Electronic address:

Spatial representation is a crucial function of animal's brain. However, there is still no uniform explanation of how the spatial code is formed in different dimensional spaces to date. The main reason why place cell exhibits unique activity pattern is that the animal needs to retrieve and process spatial information. In this paper, we constructed a constrained optimization model based on information theory to explain the place field formation across species in different dimensional spaces. We proposed the following question that, using only limited amount of neural energy, how to organize the spiking locations (place field) in the available environment to obtain the most efficient spatial information representation? We solved this conditional functional extremum problem by variational techniques. The results showed that on the condition of limited neural energy, the place field will comply with a Gaussian-form distribution automatically to convey the largest amount information per spike. We also found that the animal's natural habitat property and locomotion experience statistics affected the symmetry of spatial representation in different dimensions. These findings not only reconcile the argument of whether the spatial codes of place cell are isotropic, but also provide an explanation of place field formation by an information-theoretic approach. Furtherly, this research revealed the energy economical and information efficient properties underlie the spatial representation system of the brain.
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http://dx.doi.org/10.1016/j.neunet.2019.04.001DOI Listing
August 2019

Dihydroartemisinin inhibits prostate cancer via JARID2/miR-7/miR-34a-dependent downregulation of Axl.

Oncogenesis 2019 Feb 19;8(3):14. Epub 2019 Feb 19.

International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town, South Africa.

Axl expression is deregulated in several cancer types, predicts poor overall patient survival and is linked to resistance to drug therapy. Here, we evaluated a library of natural compounds for inhibitors of Axl and identified dihydroartemisinin, the active principle of the anti-malarial drug artemisinin, as an Axl-inhibitor in prostate cancer. Dihydroartemisinin blocks Axl expression leading to apoptosis, decrease in cell proliferation, migration, and tumor development of prostate cancer cells. Dihydroartemisinin treatment synergizes with docetaxel, a standard of care in metastatic prostate cancer increasing overall survival of mice with human xenografts. Dihydroartemisinin control of miR-34a and miR-7 expression leads to inhibition of Axl expression in a process at least partially dependent on regulation of chromatin via methylation of histone H3 lysine 27 residues by Jumonji, AT-rich interaction domain containing 2 (JARID2), and the enhancer of zeste homolog 2. Our discovery of a previously unidentified miR-34a/miR-7/JARID2 pathway controlling dihydroartemisinin effects on Axl expression and inhibition of cancer cell proliferation, migration, invasion, and tumor formation provides new molecular mechanistic insights into dihydroartemisinin anticancer effect on prostate cancer with potential therapeutic implications.
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http://dx.doi.org/10.1038/s41389-019-0122-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381097PMC
February 2019

A miRNA Expression Signature in Breast Tumor Tissue Is Associated with Risk of Distant Metastasis.

Cancer Res 2019 04 13;79(7):1705-1713. Epub 2019 Feb 13.

Hackensack University Medical Center, Hackensack, New Jersey.

Dysregulation of miRNA expression may influence breast cancer progression, and experimental evidence suggests that miRNA silencing might suppress breast cancer metastasis. However, the relationship between miRNA and metastasis must be confirmed before this approach can be applied in the clinic. To this end, we conducted a two-stage study in a cohort of 3,760 patients with breast cancer to first identify and then validate the association between miRNA expression and risk of distant metastasis. The first stage (discovery) entailed miRNA sequencing of 126 case-control pairs; qPCR was used to validate the findings in a separate set of 80 case-control pairs. The 13 miRNAs most differentially expressed between cases and controls were combined into an miRNA score that was significantly associated with risk of distant metastasis in a logistic regression model that also included clinical variables (tumor size and number of positive lymph nodes) (OR = 1.30; 95% confidence interval, 1.03-1.66). The results of this study suggest that in women with invasive breast cancer, a miRNA score that incorporates both clinical variables and miRNA expression levels in breast tumor tissue is moderately predictive of risk of subsequent distant metastasis. SIGNIFICANCE: A novel predictive scoring system for patients with breast cancer includes clinical variables and the expression levels of 13 miRNAs and may help to identify those at increased risk of distant metastasis.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-2779DOI Listing
April 2019

Synthesis, anticancer activity and mechanism of iron chelator derived from 2,6-diacetylpyridine bis(acylhydrazones).

J Inorg Biochem 2019 04 10;193:1-8. Epub 2019 Jan 10.

School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China. Electronic address:

We synthesized five iron chelator derived from 2,6-diacetylpyridine bis(acylhydrazones) and proved their iron complexes structure by X-ray single crystal diffraction. These ligands have a significant anticancer proliferative activity and low cytotoxicity against normal cells. The Fe(III) complexes show reduced cytotoxic activity compared to the metal-free ligands. Anticancer mechanism studies indicate that ligands with a potential anticancer proliferation activity by inhibiting the activity of ribonucleotide reductase. Ligand rather than iron complexes regulate the expression of cell cycle associated proteins and inhibit cell cycle arrest in S phase. Apoptosis mechanism results showed that both ligand and iron complexes did not significantly promote apoptosis.
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http://dx.doi.org/10.1016/j.jinorgbio.2019.01.003DOI Listing
April 2019

Computer-Aided Diagnosis of Label-Free 3-D Optical Coherence Microscopy Images of Human Cervical Tissue.

IEEE Trans Biomed Eng 2019 09 1;66(9):2447-2456. Epub 2019 Jan 1.

Objective: Ultrahigh-resolution optical coherence microscopy (OCM) has recently demonstrated its potential for accurate diagnosis of human cervical diseases. One major challenge for clinical adoption, however, is the steep learning curve clinicians need to overcome to interpret OCM images. Developing an intelligent technique for computer-aided diagnosis (CADx) to accurately interpret OCM images will facilitate clinical adoption of the technology and improve patient care.

Methods: 497 high-resolution three-dimensional (3-D) OCM volumes (600 cross-sectional images each) were collected from 159 ex vivo specimens of 92 female patients. OCM image features were extracted using a convolutional neural network (CNN) model, concatenated with patient information [e.g., age and human papillomavirus (HPV) results], and classified using a support vector machine classifier. Ten-fold cross-validations were utilized to test the performance of the CADx method in a five-class classification task and a binary classification task.

Results: An 88.3 ± 4.9% classification accuracy was achieved for five fine-grained classes of cervical tissue, namely normal, ectropion, low-grade and high-grade squamous intraepithelial lesions (LSIL and HSIL), and cancer. In the binary classification task [low-risk (normal, ectropion, and LSIL) versus high-risk (HSIL and cancer)], the CADx method achieved an area-under-the-curve value of 0.959 with an 86.7 ± 11.4% sensitivity and 93.5 ± 3.8% specificity.

Conclusion: The proposed deep-learning-based CADx method outperformed four human experts. It was also able to identify morphological characteristics in OCM images that were consistent with histopathological interpretations.

Significance: Label-free OCM imaging, combined with deep-learning-based CADx methods, holds a great promise to be used in clinical settings for the effective screening and diagnosis of cervical diseases.
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http://dx.doi.org/10.1109/TBME.2018.2890167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724217PMC
September 2019

Structure-activity relationships of 2‑quinolinecarboxaldehyde thiosemicarbazone gallium(III) complexes with potent and selective anticancer activity.

J Inorg Biochem 2019 02 28;191:174-182. Epub 2018 Nov 28.

School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China. Electronic address:

Six gallium(III) complexes (Ga1-Ga6) with 2‑quinolinecarboxaldehyde thiosemicarbazone analogues were synthesized and characterized. These gallium(III) complexes exhibited potent anticancer activity and exceeded that of the corresponding metal free ligands. Importantly, these gallium(III) complexes have a strong selectivity for tumor cells. Through the study of cellular mechanisms, we have found that the lipophilicity of ligands is closely linked to the antitumor activity of gallium(III) complexes. Additionally, we have chosen Ga6 with the best anti-tumor activity to study the mechanism of apoptosis. Caspase-3 and 9 activation and Annexin V-FITC/Propidium iodide (PI) dual-staining studies revealed that Ga6 promote apoptosis in A549 cells lines. Ga6 induces intracellular reactive oxygen species (ROS) and disrupts mitochondrial membrane potential.
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http://dx.doi.org/10.1016/j.jinorgbio.2018.11.017DOI Listing
February 2019