DNA damage response (DDR) is critical to ensure genome stability, and defects in this signaling pathway are highly associated with carcinogenesis and tumor progression. Nevertheless, this also ...provides therapeutic opportunities, as cells with defective DDR signaling are directed to rely on compensatory survival pathways, and these vulnerabilities have been exploited for anticancer treatments. Following the impressive success of PARP inhibitors in the treatment of
-mutated breast and ovarian cancers, extensive research has been conducted toward the development of pharmacologic inhibitors of the key components of the DDR signaling pathway. In this review, we discuss the key elements of the DDR pathway and how these molecular components may serve as anticancer treatment targets. We also summarize the recent promising developments in the field of DDR pathway inhibitors, focusing on novel agents beyond PARP inhibitors. Furthermore, we discuss biomarker studies to identify target patients expected to derive maximal clinical benefits as well as combination strategies with other classes of anticancer agents to synergize and optimize the clinical benefits.
The recurrence score based on the 21-gene breast-cancer assay has been clinically useful in predicting a chemotherapy benefit in hormone-receptor-positive, human epidermal growth factor receptor 2 ...(HER2)-negative, axillary lymph-node-negative breast cancer. In women with positive lymph-node disease, the role of the recurrence score with respect to predicting a benefit of adjuvant chemotherapy is unclear.
In a prospective trial, we randomly assigned women with hormone-receptor-positive, HER2-negative breast cancer, one to three positive axillary lymph nodes, and a recurrence score of 25 or lower (scores range from 0 to 100, with higher scores indicating a worse prognosis) to endocrine therapy only or to chemotherapy plus endocrine (chemoendocrine) therapy. The primary objective was to determine the effect of chemotherapy on invasive disease-free survival and whether the effect was influenced by the recurrence score. Secondary end points included distant relapse-free survival.
A total of 5083 women (33.2% premenopausal and 66.8% postmenopausal) underwent randomization, and 5018 participated in the trial. At the prespecified third interim analysis, the chemotherapy benefit with respect to increasing invasive disease-free survival differed according to menopausal status (P = 0.008 for the comparison of chemotherapy benefit in premenopausal and postmenopausal participants), and separate prespecified analyses were conducted. Among postmenopausal women, invasive disease-free survival at 5 years was 91.9% in the endocrine-only group and 91.3% in the chemoendocrine group, with no chemotherapy benefit (hazard ratio for invasive disease recurrence, new primary cancer breast cancer or another type, or death, 1.02; 95% confidence interval CI, 0.82 to 1.26; P = 0.89). Among premenopausal women, invasive disease-free survival at 5 years was 89.0% with endocrine-only therapy and 93.9% with chemoendocrine therapy (hazard ratio, 0.60; 95% CI, 0.43 to 0.83; P = 0.002), with a similar increase in distant relapse-free survival (hazard ratio, 0.58; 95% CI, 0.39 to 0.87; P = 0.009). The relative chemotherapy benefit did not increase as the recurrence score increased.
Among premenopausal women with one to three positive lymph nodes and a recurrence score of 25 or lower, those who received chemoendocrine therapy had longer invasive disease-free survival and distant relapse-free survival than those who received endocrine-only therapy, whereas postmenopausal women with similar characteristics did not benefit from adjuvant chemotherapy. (Funded by the National Cancer Institute and others; RxPONDER ClinicalTrials.gov number, NCT01272037.).
In pathophysiology, reactive oxygen species oxidize biomolecules that contribute to disease phenotypes
. One such modification, 8-oxoguanine
(o
G), is abundant in RNA
but its epitranscriptional role ...has not been investigated for microRNAs (miRNAs). Here we specifically sequence oxidized miRNAs in a rat model of the redox-associated condition cardiac hypertrophy
. We find that position-specific o
G modifications are generated in seed regions (positions 2-8) of selective miRNAs, and function to regulate other mRNAs through o
G•A base pairing. o
G is induced predominantly at position 7 of miR-1 (7o
G-miR-1) by treatment with an adrenergic agonist. Introducing 7o
G-miR-1 or 7U-miR-1 (in which G at position 7 is substituted with U) alone is sufficient to cause cardiac hypertrophy in mice, and the mRNA targets of o
G-miR-1 function in affected phenotypes; the specific inhibition of 7o
G-miR-1 in mouse cardiomyocytes was found to attenuate cardiac hypertrophy. o
G-miR-1 is also implicated in patients with cardiomyopathy. Our findings show that the position-specific oxidation of miRNAs could serve as an epitranscriptional mechanism to coordinate pathophysiological redox-mediated gene expression.
The effects of nitrogen and oxygen atomic co-functionalization of graphite felt (GF) by ammoxidation reactions for the positive and negative electrodes of vanadium redox flow battery (VRFB) are ...investigated. Ammoxidative surface reactions of the pristine-GF with NH3/O2 results in effective N and O co-doping dominantly with kinetically relevant N and O functional groups; pyrrolic-N, pyridinic-N, and hydroxyl with high site densities. The intrinsic rate measurements reveal that the N and O co-functionalized GF electrodes (referred to as N-GF) afford one to several orders magnitude higher VO2+/VO2+ and V2+/V3+ redox kinetics than the pristine-GF. Notably, the N and O co-functionalization gives rise to 2–3 folds greater reaction kinetics for both half-cell reactions than the conventional electrodes doped only with O functional groups (O-GF) at similar atomic contents. The high electrocatalytic properties of N-GF afford 4–6% greater voltage and energy efficiencies in VRFB than the conventional O-GF electrode at high current density (110 mA cm−2) with ∼38% higher initial charge-discharge capability owing to the significantly reduced overpotential. These results suggest the marked synergetic contributions of N and O co-functionalization of carbon electrode for facilitation of vanadium redox kinetics and the high effectiveness of the simple and scalable ammoxidation-based functionalization protocol.
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Renal renin-angiotensin system (RAS) activation is one of the important pathogenic mechanisms in the development of diabetic nephropathy in type 2 diabetes. The aim of this study was to investigate ...the effects of a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, dapagliflozin, on renal RAS in an animal model with type 2 diabetes.
Dapagliflozin (1.0 mg/kg, OL-DA) or voglibose (0.6 mg/kg, OL-VO, diabetic control) (n = 10 each) was administered to Otsuka Long-Evans Tokushima Fatty (OLETF) rats for 12 weeks. We used voglibose, an alpha-glucosidase inhibitor, as a comparable counterpart to SGLT2 inhibitor because of its postprandial glucose-lowering effect without proven renoprotective effects. Control Long-Evans Tokushima Otsuka (LT) and OLETF (OL-C) rats received saline (n = 10, each). Changes in blood glucose, urine albumin, creatinine clearance, and oxidative stress were measured. Inflammatory cell infiltration, mesangial widening, and interstitial fibrosis in the kidney were evaluated by histological analysis. The effects of dapagliflozin on renal expression of the RAS components were evaluated by quantitative RT-PCR in renal tissue.
After treatment, hyperglycemia and urine microalbumin levels were attenuated in both OL-DA and OL-VO rather than in the OL-C group (P < 0.05). The urine angiotensin II (Ang II) and angiotensinogen levels were significantly decreased following treatment with dapagliflozin or voglibose, but suppression of urine Ang II level was more prominent in the OL-DA than the OL-VO group (P < 0.05). The expressions of angiotensin type 1 receptor and tissue oxidative stress markers were markedly increased in OL-C rats, which were reversed by dapagliflozin or voglibose (P < 0.05, both). Inflammatory cell infiltration, mesangial widening, interstitial fibrosis, and total collagen content were significantly increased in OL-C rats, which were attenuated in OL-DA group (P < 0.05).
Dapagliflozin treatment showed beneficial effects on diabetic nephropathy, which might be via suppression of renal RAS component expression, oxidative stress and interstitial fibrosis in OLETF rats. We suggest that, in addition to control of hyperglycemia, partial suppression of renal RAS with an SGLT2 inhibitor would be a promising strategy for the prevention of treatment of diabetic nephropathy.
Clusterin (CLU) is a heterodimeric glycoprotein involved in a range of biological processes. We investigated the function of CLU as a novel regulator of adipogenesis. CLU expression increased during ...3T3‐L1 preadipocyte differentiation. CLU overexpression promoted adipogenic differentiation of preadipocytes and increased the mRNA levels of adipogenic markers including peroxisome proliferator‐activated receptor γ (Pparg) and CCAAT enhancer‐binding protein α (Cebpa). Conversely, knockdown of CLU attenuated adipogenesis and reduced transcript levels of Pparg and Cebpa. However, the promoter activities of both the Pparg and the Cebpa gene were not affected by alteration of CLU expression on its own. Additionally, the protein level of Krüppel‐like factor 5 (KLF5), an upstream transcription factor of Pparg and Cebpa involved in adipogenic differentiation, was upregulated by CLU overexpression, although the mRNA level of Klf5 was not altered by changes in the expression level of CLU. Cycloheximide chase assay showed that the increased level of KLF5 by CLU overexpression was due to decreased degradation of KLF5 protein. Interestingly, CLU increased the stability of KLF5 by decreasing KLF5 ubiquitination. CLU inhibited the interaction between KLF5 and F‐box/WD repeat‐containing protein 7, which is an E3 ubiquitin ligase that targets KLF5. The adipogenic role of CLU was also addressed in mesenchymal stem cells (MSCs) and Clu−/− mouse embryonic fibroblasts (MEFs). Furthermore, CLU enhanced KLF5‐mediated transcriptional activation of both the Cebpa and the Pparg promoter. Taken together, these results suggest that CLU is a novel regulator of adipocyte differentiation by modulating the protein stability of the adipogenic transcription factor KLF5.
RNA interference (RNAi) has been widely adopted to repress specific gene expression and is easily achieved by designing small interfering RNAs (siRNAs) with perfect sequence complementarity to the ...intended target mRNAs. Although siRNAs direct Argonaute (Ago), a core component of the RNA-induced silencing complex (RISC), to recognize and silence target mRNAs, they also inevitably function as microRNAs (miRNAs) and suppress hundreds of off-targets. Such miRNA-like off-target repression is potentially detrimental, resulting in unwanted toxicity and phenotypes. Despite early recognition of the severity of miRNA-like off-target repression, this effect has often been overlooked because of difficulties in recognizing and avoiding off-targets. However, recent advances in genome-wide methods and knowledge of Ago–miRNA target interactions have set the stage for properly evaluating and controlling miRNA-like off-target repression. Here, we describe the intrinsic problems of miRNA-like off-target effects caused by canonical and noncanonical interactions. We particularly focus on various genome-wide approaches and chemical modifications for the evaluation and prevention of off-target repression to facilitate the use of RNAi with secured specificity.
Probiotics are the most useful tools for balancing the gut microbiota and thereby influencing human health and disease. Probiotics have a range of effects, from those on nutritional status to medical ...conditions throughout the body from the gut to non-intestinal body sites such as the brain and skin. Research interest in probiotics with nutritive claims (categorized as nutribiotics) has evolved into interest in therapeutic and pharmacological probiotics with health claims (pharmabiotics). The concept of pharmabiotics emerged only two decades ago, and the new categorization of probiotics to nutribiotics and pharmabiotics was recently suggested, which are under the different regulation depending on that they are food or drug. Information of the gut microbiome has been continuously accumulating, which will make possible the gut microbiome-based healthcare in the future, when nutribiotics show potential for maintaining health while pharmabiotics are effective therapeutic tools for human diseases. This review describes the current understanding in the conceptualization and classification of probiotics. Here, we reviewed probiotics as nutribiotics with nutritional functions and pharmabiotics with pharmaceutic functions in different diseases.
The use of multigene panel testing for patients with a predisposition to breast/ovarian cancer is increasing as the identification of variants is useful for diagnosis and disease management. We ...identified pathogenic and likely pathogenic (P/LP) variants of high‐and moderate‐risk genes using a 23‐gene germline cancer panel in 518 patients with hereditary breast and ovarian cancers (HBOC). The frequency of P/LP variants was 12.4% (64/518) for high‐ and moderate‐penetrant genes, namely, BRCA2 (5.6%), BRCA1 (3.3%), CHEK2 (1.2%), MUTYH (0.8%), PALB2 (0.8%), MLH1 (0.4%), ATM (0.4%), BRIP1 (0.4%), TP53 (0.2%), and PMS2 (0.2%). Five patients possessed two P/LP variants in BRCA1/2 and other genes. We also compared the results from in silico splicing predictive tools and exon splicing patterns from patient samples by analyzing RT‐PCR product sequences in six P/LP intronic variants and two intronic variants of unknown significance (VUS). Altered transcriptional fragments were detected for P/LP intronic variants in BRCA1, BRIP1, CHEK2, PARB2, and PMS2. Notably, we identified an in‐frame deletion of the BRCA1 C‐terminal (BRCT) domain by exon skipping in BRCA1 c.5152+6T>C—as known VUS—indicating a risk for HBOC. Thus, exon splicing analysis can improve the identification of veiled intronic variants that would aid decision making and determination of hereditary cancer risk.
This study identified 12.4% (64/518) pathogenic or likely pathogenic (P/LP) variants using a comprehensive multi‐gene panel including 23 cancer susceptibility genes and analyzed the pathogenic effects in the intronic variants identified by analyzing exon splicing patterns. These analyses would help further identify the uncharacterized variants that are expected to increase hereditary breast/ovarian cancer risk.
We investigated the relationship of changes in Metabolic syndrome (MetS) and its components with the risk of type 2 diabetes (T2D) in South Korea. Records of 10,806,716 adults aged ≥ 20 years without ...a history of T2D between 2009 and 2015 were retrieved from database of the South Korean National Health Insurance Service and analyzed. Changes in metabolic components were monitored over a two-year period with follow-up occurring at an average of 4.087 years. During the follow-up period, 848,859 individuals were diagnosed with T2D. The risk of diabetes was lowered with a decrease in the number of MetS components at baseline and the second visit (p for trend <0.0001). Multivariable-adjusted HRs for incident diabetes were 0.645 among individuals with reduced number of MetS components, 0.54 for those with improvement in elevated fasting glucose, 0.735 for those with improvement in elevated triglycerides, 0.746 for those with improvement in elevated blood pressure, 0.763 for those with improvement in reduced HDL-cholesterol, and 0.92 for those with improvement in abdominal obesity compared with those manifesting them at both time points. In conclusion, changes in metabolic syndrome and its components were significantly associated with the development of T2D. Improvement in MetS and its components attenuated the risk of diabetes.
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