TOR1B: a predictor of bone metastasis in breast cancer patients.

Recent therapeutic advances in breast cancer (BC) have improved survival outcomes; however, the prognosis for patients with bone metastasis (BM) remains poor. Hence, novel clinical biomarkers are needed to accurately predict BC BM as well as to promote personalized medicine. Here, we discovered a novel biomarker, TOR1B, for BM in BC patients via analysis of BC gene expression data and clinical information downloaded from open public databases. In cancer cells, we found high expression levels of TOR1B in the nucleus and endoplasmic reticulum. Regarding gene expression, the level of TOR1B was significantly upregulated in BC patients with BM (p < 0.05), and the result was externally validated. In addition, gene expression clearly demonstrated two distinct types of prognoses in ER- and PR-positive patients. In multivariate regression, the gene could be an independent predictor of BM in BC patients, i.e., a low expression level of TOR1B was associated with delayed metastasis to bone in BC patients (HR, 0.28; 95% CI 0.094-0.84). Conclusively, TOR1B might be a useful biomarker for predicting BM; specifically, patients with ER- and PR-positive subtypes would benefit from the clinical use of this promising prognostic biomarker.

Dietary carbohydrates: Pathogenesis and potential therapeutic targets to obesity-associated metabolic syndrome.

Metabolic syndrome (MetS) is a common feature in obesity, comprising a cluster of abnormalities including abdominal fat accumulation, hyperglycemia, hyperinsulinemia, dyslipidemia, and hypertension, leading to diabetes and cardiovascular diseases (CVD). Intake of carbohydrates (CHO), particularly a sugary diet that rapidly increases blood glucose, triglycerides, and blood pressure levels is the predominant determining factor of MetS. Complex CHO, on the other hand, are a stable source of energy taking a longer time to digest. In particular, resistant starch (RS) or soluble fiber is an excellent source of prebiotics, which alter the gut microbial composition, which in turn improves metabolic control. Altering maternal CHO intake during pregnancy may result in the child developing MetS. Furthermore, lifestyle factors such as physical inactivity in combination with dietary habits may synergistically influence gene expression by modulating genetic and epigenetic regulators transforming childhood obesity into adolescent metabolic disorders. This review summarizes the common pathophysiology of MetS in connection with the nature of CHO, intrauterine nutrition, genetic predisposition, lifestyle factors, and advanced treatment approaches; it also emphasizes how dietary CHO may act as a key element in the pathogenesis and future therapeutic targets of obesity and MetS.

Recent Advances in Ovarian Cancer: Therapeutic Strategies, Potential Biomarkers, and Technological Improvements.

Aggressive and recurrent gynecological cancers are associated with worse prognosis and a lack of effective therapeutic response. Ovarian cancer (OC) patients are often diagnosed in advanced stages, when drug resistance, angiogenesis, relapse, and metastasis impact survival outcomes. Currently, surgical debulking, radiotherapy, and/or chemotherapy remain the mainstream treatment modalities; however, patients suffer unwanted side effects and drug resistance in the absence of targeted therapies. Hence, it is urgent to decipher the complex disease biology and identify potential biomarkers, which could greatly contribute to making an early diagnosis or predicting the response to specific therapies. This review aims to critically discuss the current therapeutic strategies for OC, novel drug-delivery systems, and potential biomarkers in the context of genetics and molecular research. It emphasizes how the understanding of disease biology is related to the advancement of technology, enabling the exploration of novel biomarkers that may be able to provide more accurate diagnosis and prognosis, which would effectively translate into targeted therapies, ultimately improving patients' overall survival and quality of life.

Diagnosis by Volatile Organic Compounds in Exhaled Breath in Exhaled Breath from Patients with Gastric and Colorectal Cancers.

One in three cancer deaths worldwide are caused by gastric and colorectal cancer malignancies. Although the incidence and fatality rates differ significantly from country to country, the rates of these cancers in East Asian nations such as South Korea and Japan have been increasing each year. Above all, the biggest danger of this disease is how challenging it is to recognize in its early stages. Moreover, most patients with these cancers do not present with any disease symptoms before receiving a definitive diagnosis. Currently, volatile organic compounds (VOCs) are being used for the early prediction of several other diseases, and research has been carried out on these applications. Exhaled VOCs from patients possess remarkable potential as novel biomarkers, and their analysis could be transformative in the prevention and early diagnosis of colon and stomach cancers. VOCs have been spotlighted in recent studies due to their ease of use. Diagnosis on the basis of patient VOC analysis takes less time than methods using gas chromatography, and results in the literature demonstrate that it is possible to determine whether a patient has certain diseases by using organic compounds in their breath as indicators. This study describes how VOCs can be used to precisely detect cancers; as more data are accumulated, the accuracy of this method will increase, and it can be applied in more fields.

Correlation between Oxidative Stress and Transforming Growth Factor-Beta in Cancers.

The downregulation of reactive oxygen species (ROS) facilitates precancerous tumor development, even though increasing the level of ROS can promote metastasis. The transforming growth factor-beta (TGF-ß) signaling pathway plays an anti-tumorigenic role in the initial stages of cancer development but a pro-tumorigenic role in later stages that fosters cancer metastasis. TGF-ß can regulate the production of ROS unambiguously or downregulate antioxidant systems. ROS can influence TGF-ß signaling by enhancing its expression and activation. Thus, TGF-ß signaling and ROS might significantly coordinate cellular processes that cancer cells employ to expedite their malignancy. In cancer cells, interplay between oxidative stress and TGF-ß is critical for tumorigenesis and cancer progression. Thus, both TGF-ß and ROS can develop a robust relationship in cancer cells to augment their malignancy. This review focuses on the appropriate interpretation of this crosstalk between TGF-ß and oxidative stress in cancer, exposing new potential approaches in cancer biology.

Glucose and lipid lowering effects of Enhydra fluctuans extract in cadmium treated normal and type-2 diabetic model rats.

BACKGROUND: Recent epidemiological and experimental studies suggest that cadmium and diabetes-related hyperglycemia may act synergistically to worsen metabolic regulation. The present study aims to evaluate the potential effects of Enhydra fluctuans extract in diabetes and dyslipidemia in cadmium (CdCl2) induced- normal and type 2 diabetic model rats. METHOD: Forty-eight Long-Evans rats were divided equally into the following six groups: Normal Control (N-C), Normal treated with CdCl2 (N-Cd), Normal treated with plant extract (N-P), Normal treated with both plant extract and CdCl2 (N-PCd), Diabetic treated with plant extract (DM-P) and Diabetic treated with both plant extract and CdCl2 (DM-PCd). Blood glucose and other biochemical parameters were estimated by the enzymatic colorimetric method. Histological analysis of liver and heart was done by the hematoxylin-eosin (H & E) method. RESULTS: Twenty-one days treatment of E. fluctuans extracts at a dose of 200 mg/kg significantly reduced blood glucose level in N-PCd and DM-PCd (p < 0.05), and DM-P (p < 0.01) group. The plant extract had no direct effects on total blood lipids but, it had beneficial effects on TG/HDL-C ratio in N-P and DM-PCd groups (p < 0.05). Cd induction significantly reduced body weight [(N-Cd, N-PCd, DM-PCd) (p < 0.01)], and induced liver [N-Cd (p < 0.05), N-PCd, p < 0.001] and renal impairment [N-Cd (p < 0.05)]. In bi-variate association, a significant positive correlation between serum glucose and SGPT (p < 0.05) as well as SGPT and TG/HDL ratio (p = 0.019) was found in DM-P and in the merged group. The histology of liver and heart showed severe damages including inflammation, nuclear pyknosis, loss of myocardial fibers, necrosis and fibrosis in the Cd treated groups compared to plant treated groups. CONCLUSION: E. fluctuans seems to have potent antihyperglycemic effects in diabetes and Cd toxicity along with partial antidyslipidemic properties in euglycemic and diabetic rats. Our study suggests a novel oral antihyperglycemic agent in the present environmental context.

The Prognostic 97 Chemoresponse Gene Signature in Ovarian Cancer.

Patient diagnosis and care would be significantly improved by understanding the mechanisms underlying platinum and taxane resistance in ovarian cancer. Here, we aim to establish a gene signature that can identify molecular pathways/transcription factors involved in ovarian cancer progression, poor clinical outcome, and chemotherapy resistance. To validate the robustness of the gene signature, a meta-analysis approach was applied to 1,020 patients from 7 datasets. A 97-gene signature was identified as an independent predictor of patient survival in association with other clinicopathological factors in univariate [hazard ratio (HR): 3.0, 95% Confidence Interval (CI) 1.66-5.44, p = 2.7E-4] and multivariate [HR: 2.88, 95% CI 1.57-5.2, p = 0.001] analyses. Subset analyses demonstrated that the signature could predict patients who would attain complete or partial remission or no-response to first-line chemotherapy. Pathway analyses revealed that the signature was regulated by HIF1α and TP53 and included nine HIF1α-regulated genes, which were highly expressed in non-responders and partial remission patients than in complete remission patients. We present the 97-gene signature as an accurate prognostic predictor of overall survival and chemoresponse. Our signature also provides information on potential candidate target genes for future treatment efforts in ovarian cancer.

Inhibition of Carbonyl Reductase 1 Safely Improves the Efficacy of Doxorubicin in Breast Cancer Treatment.

AIMS: Doxorubicin (DOX) is a chemotherapeutic drug that is used to treat many cancers, but its use is limited by cardiotoxic side effect. Carbonyl reductase 1 (CBR1) is an NADPH-dependent oxidoreductase that reduces DOX to doxorubicinol (DOXOL), a less potent derivative that is responsible for DOX cardiotoxicity. Thus, we aimed to demonstrate that inhibition of CBR1 enhances the chemotherapeutic efficacy of DOX and attenuates cardiotoxicity. RESULTS: Pharmacological or genetic inhibition of CBR1 improved the anticancer effects of DOX in preclinical models of breast cancer. RNA interference or chemical inhibition of CBR1 improved the anticancer effect of DOX in breast cancer. Moreover, CBR1 overexpression enabled breast cancer cells to obtain chemotherapeutic resistance to DOX treatment. Intriguingly, inhibition of CBR1 decreased DOX-induced cardiotoxicity in animal model. Innovation and Conclusions: Inhibition of CBR1 increases chemotherapeutic efficacy of DOX and reduces cardiotoxicity by blocking DOX reduction to DOXOL. Therefore, we offer preclinical proof-of-concept for a combination strategy to safely leverage the efficacy of doxorubicin by blunting its cardiotoxic effects that limit use of this cytotoxic agent used widely in the oncology clinic. Antioxid. Redox Signal. 26, 70-83.

An 8-gene signature for prediction of prognosis and chemoresponse in non-small cell lung cancer.

Identification of a potential gene signature for improved diagnosis in non-small cell lung cancer (NSCLC) patient is necessary. Here, we aim to establish and validate the prognostic efficacy of a gene set that can predict prognosis and benefits of adjuvant chemotherapy (ACT) in NSCLC patients from various ethnicities. An 8-gene signature was calculated from the gene expression of 181 patients using univariate Cox proportional hazard regression analysis. The prognostic value of the signature was robustly validated in 1,477 patients from five microarray independent data sets and one RNA-seq data set. The 8-gene signature was identified as an independent predictor of patient survival in the presence of clinical parameters in univariate and multivariate analyses [hazard ratio (HR): 2.84, 95% confidence interval CI (1.74-4.65), p=3.06e-05, [HR] 2.62, 95% CI (1.51-4.53), p=0.001], respectively. Subset analysis demonstrated that the 8-gene signature could identify high-risk patients in stage II-III with improved survival from ACT [(HR) 1.47, 95% CI (1.01-2.14), p=0.044]. The 8-gene signature also stratified risk groups in EGFR-mutated and wild-type patients. In conclusion, the 8-gene signature is a strong and independent predictor that can significantly stratify patients into low- and high-risk groups. Our gene signature also has the potential to predict patients in stage II-III that are likely to benefit from ACT.

Subclinical inflammation in relation to insulin resistance in prediabetic subjects with nonalcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a metabolic disease commonly associated with obesity, type 2 diabetes, and inflammation-all features of insulin resistant syndrome. However, very limited data are available regarding the association of subclinical inflammation and insulin resistance with NAFLD in a prediabetic state. We, therefore, conducted the study to assess this relationship among this population. METHODS: We studied a cross-sectional analytical design of 140 [male/female, 77/63; age in years (ranges), 45 (25-68)] prediabetic subjects after confirming with 75 g oral glucose tolerance test. The diagnosis of NAFLD was made by ultrasonic examination of the liver and divided into groups of without NAFLD (n = 63) and NAFLD (n = 77). All individuals underwent anthropometric and clinical examinations. Among laboratory investigations, serum glucose was estimated by glucose oxidase method, serum lipid profile and liver enzymes were measured by the enzymatic colorimetric method and glycated hemoglobin was measured by high performance liquid chromatography technique. Serum insulin and high sensitivity C reactive protein (hsCRP) were measured by enzyme immunoassay technique. Insulin resistance (HOMA-IR) was calculated by homeostasis model assessment (HOMA). RESULTS: There was significantly higher levels of hsCRP (2.82 ± 1.60 vs. 1.39 ± 0.66 mg/l, P < 0.001) and HOMA-IR (4.03 ± 1.39 vs. 1.98 ± 1.04, P < 0.001) in NAFLD subjects compared to their without NAFLD counterparts. hsCRP [odds ratio (OR) = 5.888, 95 % confidence interval (CI) 2.673-12.970, P < 0.001] and HOMA-IR (OR = 4.618, 95 % CI 2.657-8.024, P < 0.001) showed significant determinants of NAFLD after potential confounders of body mass index and triglyceride were adjusted. CONCLUSIONS: Subclinical chronic inflammation and insulin resistance seem to be independent mediators of the association between NAFLD and prediabetes. The data also indicate that the inflammatory condition and insulin resistance are associated with each other and these, in turn, are affected by adiposity and dyslipidemia in prediabetic subjects.

Gender Specific Association of Serum Leptin and Insulinemic Indices with Nonalcoholic Fatty Liver Disease in Prediabetic Subjects.

Adipose tissue-derived hormone leptin plays a functional role in glucose tolerance through its effects on insulin secretion and insulin sensitivity which also represent the risk factors for nonalcoholic fatty liver disease (NAFLD). The present study explored the gender specific association of serum leptin and insulinemic indices with NAFLD in Bangladeshi prediabetic subjects. Under a cross-sectional analytical design a total of 110 ultrasound examined prediabetic subjects, aged 25-68 years consisting of 57.3% male (55.6% non NAFLD and 44.4% NAFLD) and 42.7% female (57.4% non NAFLD and 42.6% NAFLD), were investigated. Insulin secretory function (HOMA%B) and insulin sensitivity (HOMA%S) were calculated from homeostasis model assessment (HOMA). Serum leptin showed significant positive correlation with fasting insulin (r = 0.530, P = 0.004), postprandial insulin (r = 0.384, P = 0.042) and HOMA-IR (r = 0.541, P = 0.003) as well as significant negative correlation with HOMA%S (r = -0.388, P = 0.046) and HOMA%B (r = -0.356, P = 0.039) in male prediabetic subjects with NAFLD. In multiple linear regression analysis, log transformed leptin showed significant positive association with HOMA-IR (ß = 0.706, P <0.001) after adjusting the effects of body mass index (BMI), triglyceride (TG) and HOMA%B in male subjects with NAFLD. In binary logistic regression analysis, only log leptin [OR 1.29 95% (C.I) (1.11-1.51), P = 0.001] in male subjects as well as HOMA%B [OR 0.94 95% (C.I) (0.89-0.98), P = 0.012], HOMA-IR [OR 3.30 95% (C.I) (0.99-10.95), P = 0.049] and log leptin [OR 1.10 95% (C.I) (1.01-1.20), P = 0.026] in female subjects were found to be independent determinants of NAFLD after adjusting the BMI and TG. Serum leptin seems to have an association with NAFLD both in male and female prediabetic subjects and this association in turn, is mediated by insulin secretory dysfunction and insulin resistance among these subjects.

Structure-Based Discovery of Novel Cyclophilin A Inhibitors for the Treatment of Hepatitis C Virus Infections.

Hepatitis C virus (HCV) is a major cause of end-stage liver disease. Direct-acting antivirals (DAAs), including inhibitors of nonstructural proteins (NS3/4A protease, NS5A, and NS5B polymerase), represent key components of anti-HCV treatment, but these are associated with increased drug resistance and toxicity. Thus, the development of host-targeted antiviral agents, such as cyclophilin A inhibitors, is an alternative approach for more effective, selective, and safer treatment. Starting with the discovery of a bis-amide derivative 5 through virtual screening, the lead compound 25 was developed using molecular modeling-based design and systematic exploration of the structure-activity relationship. The lead 25 lacked cytotoxicity, had potent anti-HCV activity, and showed selective and high binding affinity for CypA. Unlike cyclosporin A, 25 lacked immunosuppressive effects, successfully inhibited the HCV replication, restored host immune responses without acute toxicity in vitro and in vivo, and exhibited a high synergistic effect in combination with other drugs. These findings suggest that the bis-amides have significant potential to extend the arsenal of HCV therapeutics.

CRC-113 gene expression signature for predicting prognosis in patients with colorectal cancer.

Colorectal cancer (CRC) is the third leading cause of global cancer mortality. Recent studies have proposed several gene signatures to predict CRC prognosis, but none of those have proven reliable for predicting prognosis in clinical practice yet due to poor reproducibility and molecular heterogeneity. Here, we have established a prognostic signature of 113 probe sets (CRC-113) that include potential biomarkers and reflect the biological and clinical characteristics. Robustness and accuracy were significantly validated in external data sets from 19 centers in five countries. In multivariate analysis, CRC-113 gene signature showed a stronger prognostic value for survival and disease recurrence in CRC patients than current clinicopathological risk factors and molecular alterations. We also demonstrated that the CRC-113 gene signature reflected both genetic and epigenetic molecular heterogeneity in CRC patients. Furthermore, incorporation of the CRC-113 gene signature into a clinical context and molecular markers further refined the selection of the CRC patients who might benefit from postoperative chemotherapy. Conclusively, CRC-113 gene signature provides new possibilities for improving prognostic models and personalized therapeutic strategies.

Prognostic value of a 92-probe signature in breast cancer.

Clinical applications of gene expression signatures in breast cancer prognosis still remain limited due to poor predictive strength of single training datasets and appropriate invariable platforms. We proposed a gene expression signature by reducing baseline differences and analyzing common probes among three recent Affymetrix U133 plus 2 microarray data sets. Using a newly developed supervised method, a 92-probe signature found in this study was associated with overall survival. It was robustly validated in four independent data sets and then repeated on three subgroups by incorporating 17 breast cancer microarray datasets. The signature was an independent predictor of patients' survival in univariate analysis [(HR) 1.927, 95% CI (1.237-3.002); p < 0.01] as well as multivariate analysis after adjustment of clinical variables [(HR) 7.125, 95% CI (2.462-20.618); p < 0.001]. Consistent predictive performance was found in different multivariate models in increased patient population (p = 0.002). The survival signature predicted a late metastatic feature through 5-year disease free survival (p = 0.006). We identified subtypes within the lymph node positive (p < 0.001) and ER positive (p = 0.01) patients that best reflected the invasive breast cancer biology. In conclusion using the Common Probe Approach, we present a novel prognostic signature as a predictor in breast cancer late recurrences.

Liver-targeted cyclosporine A-encapsulated poly (lactic-co-glycolic) acid nanoparticles inhibit hepatitis C virus replication.

Therapeutic options for hepatitis C virus (HCV) infection have been limited by drug resistance and adverse side effects. Targeting the host factor cyclophilin A (CypA), which is essential for HCV replication, offers a promising strategy for antiviral therapy. However, due to its immunosuppressive activity and severe side effects, clinical application of cyclosporine A (CsA) has been limited as an antiviral agent. To overcome these drawbacks, we have successfully developed a liver-specific, sustained drug delivery system by conjugating the liver-targeting peptide (LTP) to PEGylated CsA-encapsulated poly (lactic-co-glycolic) acid (PLGA) nanoparticles. Furthermore, our delivery system exhibited high specificity to liver, thus contributing to the reduced immunosuppressive effect and toxicity profile of CsA. Finally, targeted nanoparticles were able to effectively inhibit viral replication in vitro and in an HCV mouse model. As a proof of principle, we herein show that our delivery system is able to negate the adverse effects of CsA and produce therapeutic effects in an HCV mouse model.

Cost-effectiveness analysis of medical intervention in patients with early detection of diabetic foot in a tertiary care hospital in Bangladesh.

The economic burden resulting from diabetic foot consumes a major portion of resources. The study was undertaken to assess the cost-effectiveness of medical intervention in patients with diabetic foot. At baseline 906 patients were analyzed. Then 200 patients with diabetic foot were purposively selected from a tertiary diabetes care hospital. Of these, 100 were late in detection and poorly managed (late diabetic foot or LDF) and 100 were detected early and properly managed (early diabetic foot or EDF). Among 906 patients, 2.8% (25 patients) were found to develop diabetic foot. Total cost of treatment was US$13,308.16 with an average of US$443.60 per patient. Comparing the cost of patients who underwent amputation with the patients who are not yet amputated, cost difference was US$6657.74. The result showed that cost of amputation was 5.54 times higher than the usual treatment. The average cost of care was US$134 per patient. Among the average annual cost, LDF consumed US$18,918. Fifty percent of the costs were attributable to drugs for both groups of which 77% was for LDF and 29% to hospitalizations. The regression equation showed that medical cost is significantly related to complications. Proper management can substantially reduce the cost of care of patients with diabetic foot.