Evaluation of Efficacy of Curcumin and Caffeic Acid Phenethyl Ester in Breast Cancer by Preclinical Studies.

ims: The aim of this study was to evaluate the combined and comparative efficacy of Caffeic acid phenethyl ester (CAPE) and curcumin in breast cancer. BACKGROUND: CAPE and curcumin are a class of phenolics. While curcumin is obtained from turmeric, CAPE is found in Baccharis sarothroides and Populus deltoides. Both agents are reported to produce activities in some cancer types. The combined and comparative effects of the two agents in breast cancer have not yet reported. OBJECTIVE: We evaluated the potential of CAPE and curcumin in both in vitro and in vivo breast cancer models. METHODS: Human breast cancer cell lines, MDA-MB-231 and MCF-7, were exposed to CAPE and curcumin, followed by functional assays such as cell cytotoxicity, cell proliferation and colony formation, cell cycle, mitochondrial membrane potential, apoptosis, and monodansylcadaverine (MDC) staining for autophagy. Computational analyses and mouse models were also used. RESULTS: Employing computational analyses, both agents were found to exhibit drug-like properties. Both molecules interacted with the key molecules of the NF-κB pathway. CAPE and curcumin inhibited cell proliferation, colony formation, and invasion, triggering apoptosis in breast cancer cells. CAPE was found to be more effective than curcumin. Two agents working together were more effective than each agent working alone. Both agents suppressed the expression of survivin, Bcl-xL and GLUT-1. The level of cleaved PARP was increased by both agents. Both phenolics observed an induction in ROS generation. Further, both molecules triggered a dissipation in mitochondrial membrane potential. In mice models implanted with Ehrlich-Lettre ascites carcinoma (EAC) cells, both drugs inhibited the growth of the tumour. The phenolics also modulated the metabolic parameters in tumour-bearing mice. CONCLUSION: The observations suggest that the combination of curcumin plus CAPE may be better in comparison to individual molecules. Other: The study opens a window for analysing the efficacy of the combination of CAPE and curcumin in animal studies. This will provide a basis for examining the combined efficacy of two agents in a clinical trial.

Semecarpus anacardium L.f. leaf extract exhibits activities against breast cancer and prolongs the survival of tumor-bearing mice.

Semecarpus anacardium L.f. has been commonly used in various traditional medicines from ancient times. The nuts have been described in Ayurveda medication systems to treat numerous clinical ailments. However, isolating phytochemical constituents from nuts remain challenging and exhibits cytotoxic effects on other cells. In this study, we have standardized procedures for isolating phytochemicals from the leaf extract. The ethyl acetate leaf extract selectively affects cancer cells in a dose-dependent manner (IC50: 0.57 µg/ml in MCF-7 cells) in various cancer cell lines and induces apoptosis in cancer cells. However, the non-malignant cells were relatively insensitive to the extract. Next, the incubation of the leaf extract induces cell cycle arrest and suppresses cancer cell migration in the cell culture model. Moreover, oral administration of extract significantly restored tumor growth in mice. Together, these observations suggest the anti-cancer activities of S. anacardium L.f. leaf potential for both in vitro and in vivo models.

A colorimetric and 'OFF-ON' fluorometric chemosensor based on a rhodamine-pyrazole derivative for the detection of Al3+, Fe3+and Cr3+metal ions, and its intracellular application.

The colorimetric and fluorescence responses of a new rhodamine-functionalized probe (E)-2-(((5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)methylene)amino)-3',6'-bis(diethylamino)spiro[isoindoline-1,9'-xanthen]-3-one (RMP) are investigated. RMP has been thoroughly characterized using various spectroscopic tools and single crystal X-ray diffraction. Among different competing cations, it shows highly sensitive colorimetric and "OFF-ON" fluorescence responses towards Al3+, Fe3+and Cr3+metal ions. The spectral shifts are clearly noticeable in the visible region of the absorption spectrum and can be observed with the naked eye. Fluorescence quantum yield, stoichiometric ratio, binding constant and detection limit of RMP towards Al3+, Fe3+and Cr3+metal ions have been calculated. Furthermore, RMP-M3+ complexes are reversible and sensitive to EDTA, which effectively mimics a molecular logic gate. Al3+, Fe3+and Cr3+metal ions have been further applied in intracellular application in model human cells.

Therapeutic potential of low dose ionizing radiation against cancer, dementia, and diabetes: evidences from epidemiological, clinical, and preclinical studies.

The growing use of ionizing radiation (IR)-based diagnostic and treatment methods has been linked to increasing chronic diseases among patients and healthcare professionals. However, multiple factors such as IR dose, dose-rate, and duration of exposure influence the IR-induced chronic effects. The predicted links between low-dose ionizing radiation (LDIR) and health risks are controversial due to the non-availability of direct human studies. The studies pertaining to LDIR effects have importance in public health as exposure to background LDIR is routine. It has been anticipated that data from epidemiological and clinical reports and results of preclinical studies can resolve this controversy and help to clarify the notion of LDIR-associated health risks. Accumulating scientific literature shows reduced cancer risk, cancer-related deaths, curtailed neuro-impairments, improved neural functions, and reduced diabetes-related complications after LDIR exposure. In addition, it was found to alter evolutionarily conserved stress response pathways. However, the picture of molecular signaling pathways in LDIR responses is unclear. Besides, there is limited/no information on biomarkers of epidemiological LDIR exposure. Therefore, the present review discusses epidemiological, clinical, and preclinical studies on LDIR-induced positive effects in three chronic diseases (cancer, dementia, and diabetes) and their associated molecular mechanisms. The knowledge of LDIR response mechanisms may help to devise LDIR-based therapeutic modalities to stop disease progression. Modulation of these pathways may be helpful in developing radiation resistance among humans. However, more clinical evidence with additional biochemical, cellular, and molecular data and exploring the side effects of LDIR are the major areas of future research.

Association of altered metabolic profiles and long non-coding RNAs expression with disease severity in breast cancer patients: analysis by 1H NMR spectroscopy and RT-q-PCR.

INTRODUCTION: Globally, one of the major causes of cancer related deaths in women is breast cancer. Although metabolic pattern is altered in cancer patients, robust metabolic biomarkers with a potential to improve the screening and disease monitoring are lacking. A complete metabolome profiling of breast cancer patients may lead to the identification of diagnostic/prognostic markers and potential targets. OBJECTIVES: The aim of this study was to analyze the metabolic profile in the serum from 43 breast cancer patients and 13 healthy individuals. MATERIALS & METHODS: We used 1H NMR spectroscopy for the identification and quantification of metabolites. q-RT-PCR was used to examine the relative expression of lncRNAs. RESULTS: Metabolites such as amino acids, lipids, membrane metabolites, lipoproteins, and energy metabolites were observed in the serum from both patients and healthy individuals. Using unsupervised PCA, supervised PLS-DA, supervised OPLS-DA, and random forest classification, we observed that more than 25 metabolites were altered in the breast cancer patients. Metabolites with AUC value > 0.9 were selected for further analysis that revealed significant elevation of lactate, LPR and glycerol, while the level of glucose, succinate, and isobutyrate was reduced in breast cancer patients in comparison to healthy control. The level of these metabolites (except LPR) was altered in advanced-stage breast cancer patients in comparison to early-stage breast cancer patients. The altered metabolites were also associated with over 25 signaling pathways related to metabolism. Further, lncRNAs such as H19, MEG3 and GAS5 were dysregulated in the breast tumor tissue in comparison to normal adjacent tissue. CONCLUSION: The study provides insights into metabolic alteration in breast cancer patients. It also provides an avenue to examine the association of lncRNAs with metabolic patterns in patients.

Potential of Cytochrome P450, a Family of Xenobiotic Metabolizing Enzymes, in Cancer Therapy.

Significance: Targeted cancer therapy with minimal off-target consequences has shown promise for some cancer types. Although cytochrome P450 (CYP) consists of 18 families, CYP1-4 families play key role in metabolizing xenobiotics and cancer drugs. This eventually affects the process of carcinogenesis, treatment outcomes, and cancer drug resistance. Differential overexpression of CYPs in transformed cells, together with phenotypic alterations in tumors, presents a potential for therapeutic intervention. Recent Advances: Recent advances in molecular tools and information technology have helped utilize CYPs as cancer targets. The precise expression in various tumors, X-ray crystal structures, improved understanding of the structure-activity relationship, and new approaches in the development of prodrugs have supported the ongoing efforts to develop CYP-based drugs with a better therapeutic index. Critical Issues: Narrow therapeutic index, off-target effects, drug resistance, and tumor heterogeneity limit the benefits of CYP-based conventional cancer therapies. In this review, we address the CYP1-4 families as druggable targets in cancer. An emphasis is given to the CYP expression, function, and the possible mechanisms that drive expression and activity in normal and transformed tissues. The strategies that inhibit or activate CYPs for therapeutic benefits are also discussed. Future Directions: Efforts are needed to develop more selective tools that will help comprehend molecular and metabolic alterations in tumor tissues with biological end-points in relation to CYPs. This will eventually translate to developing more specific CYP inhibitors/inducers. Antioxid. Redox Signal. 38, 853-876.

Efficacy of Cannabis and its Constituents in Disease Management: Insights from Clinical Studies.

There is a long history of informal use of Cannabis sativa (commonly called cannabis) for many purposes, including treating various ailments worldwide. However, the legalization of cannabis in multiple countries, specifically for medical purposes, has grabbed the researchers' attention to discover the scientific evidence regarding cannabis's beneficial effects. Among over 500 identified compounds (cannabinoids), Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are two major active cannabinoids derived from cannabis. Cannabinoids exert their effects through cannabinoid receptors (CB1R and CB2R). In the recent past, clinical trials have shown the efficacy of cannabis and cannabinoids for various human ailments, such as cancer, neurological disorders, inflammatory bowel disease, chronic pain, and metabolic disorders. The commonly used constituents and derivatives of cannabis include CBD, THC, THCV, dronabinol, nabilone, and nabiximol. The cannabis constituents have also been used in combination with other agents, such as megestrol acetate, in some clinical trials. The common routes for the administration of cannabis are oral, sublingual, or topical. Cannabis has also been consumed through smoking, inhalation, or with food and tea. A maximum of 572 patients and a minimum of nine patients have participated in a single clinical trial. Cannabis is legalized in some countries with restrictions, such as Belize, Canada, Colombia, Costa Rica, The Czech Republic, Jamaica, Netherlands, South Africa, Spain, and Uruguay. This article provides a compilation of published studies focusing on clinal trials on the therapeutic effects of cannabis. The adverse effects of cannabis and its constituents are also discussed.

The Effect of Varied Time Interval and Micro-Current (Direct) on the Level of Biomarker (IL-6) and Rate of Tooth Movement: An Animal Study.

INTRODUCTION: Exogenous application of direct current (DC) on piezoelectric biopolymers results in biochemical modifications in the intracellular/extracellular regions which profoundly affects the pace of bone turnover. A qualitative examination of DC (waveform and frequency) provides ideal qualities of current. MATERIAL AND METHOD: 20 female Wistar rats (Rattus norvegicus) were randomly selected and divided into control (group 1-4 rats) with orthodontic appliance (OA) and experimental groups (OA + Micro-current (MC). Experimental groups were subdivided into four groups (group 2-20 µA/5 sec, 3-20 µA/10 sec, 4-15 µA/5 sec, 5-15 µA/10 sec with four rats in each). The tooth movement was recorded every 24th hours for 7 days. Gingival crevicular fluid (GCF) was collected 6 hr, 12 hr, 24 hr, 3rd day and 168 hrs with the absorbent paper points at specific location around the tooth in control and experiment groups. Histopathological analysis was done on 168 hrs to assess the osteoclastic activity around the root. Interleukin-6 (IL-6) concentration was accessed using enzyme-linked immunosorbent assay (ELISA). The data were subjected to one-way ANOVA and Tukey's posthoc test. RESULTS: There was a statistically significant difference in tooth movement, group 3 (20 µA/10 sec) showed an increased rate of tooth movement on the 168 hrs. The level of IL-6 was maximum on 72 hrs in experimental group 3. CONCLUSION: The study showed time interval/frequency, the waveform, and the amount of current play a significant role in determining bone turnover and rate of tooth movement.

Reprogramming of glycolysis by chemical carcinogens during tumor development.

Indiscriminate usage and mismanagement of chemicals in the agricultural and industrial sectors have contaminated different environmental compartments. Exposure to these persistent and hazardous pollutants like heavy metals, endocrine disruptors, aromatic hydrocarbons, and pesticides can result in various health adversities, including cancer. Chemical carcinogens follow a similar pattern of carcinogenesis, like oxidative stress, chromosomal aberration, DNA double-strand break, mismatch repair, and misregulation of oncogenic and/or tumor suppressors. Out of several cancer-associated endpoints, cellular metabolic homeostasis is the commonest to be deregulated upon chemical exposure. Chemical carcinogens hamper glycolytic reprogramming to fuel the malignant transformation of the cells and/or promote cancer progression. Several regulators like Akt, ERK, Ras, c-Myc, HIF-1α, and p53 regulate glycolysis in chemical-induced carcinogenesis. However, the deregulation of the anabolic biochemistry of glucose during chemical-induced carcinogenesis remains to be uncovered. This review comprehensively covers the environmental chemical-induced glycolytic shift during carcinogenesis and its mechanism. The focus is also to fill the major gaps associated with understanding the fairy tale between environmental carcinogens and metabolic reprogramming. Although evidence from studies regarding glycolytic reprogramming in chemical carcinogenesis provides valuable insights into cancer therapy, exposure to a mixture of toxicants and their mechanism of inducing carcinogenesis still needs to be studied.

Transcription factor 4 expression and correlation with tumor progression in gallbladder cancer.

Background: Dysregulation in Wnt/ß-catenin signaling has been associated with the initiation and metastasis of cancer cells. Transcription factor 4 (TCF4) (also named as transcription factor 7-like 2) is a key transcriptional factor of the Wnt signaling pathway, which, when interact with ß-catenin activates Wnt genes which plays an essential role in tumor development. The expression pattern and clinical significance of TCF4 in gallbladder cancer (GBC) are not yet established. Aims: This study was performed to assess the expression pattern of TCF4 in GBC tissue and attempted to correlate its expression with different clinicopathological parameters. Materials and Methods: The study was conducted on 33 surgically resected specimens of gallbladder carcinoma (GBC) and 12 cases of chronic cholecystitis (CC) as control, which had been confirmed from histology. The expression of TCF4 was performed by the reverse transcription polymerase chain reaction and immunohistochemistry. Results: Relative mRNA expression levels of ß-catenin and TCF4 in GBC tissues were significantly (P < 0.05) higher than in CC samples. TCF4 protein expression was observed in 81.82% (27/33) GBC cases. Specifically, among GBC samples, 21.21% (7/33) was graded as strongly positive, 60.61% (20/33) graded as moderately positive, whereas 18.18% (6/33) graded as negative. All 12 CC samples graded as negative. Overall, TCF4 expression in GBC tissues was statistically significant over CC samples (P < 0.05). Moreover, we observed that TCF4 expression was significantly higher (P < 0.05) in high tumor grades than low grade, higher (P < 0.05) in Stage 2 and Stage 3 than Stage 1. Conclusion: The present study suggests that TCF4 may exert an oncogenic role in the progression of GBC and may serve as a new potential candidate biomarker for tumor progression, and it might be a potential therapeutic target against GBC.

A multifunctional basic pH indicator probe for distinguishable detection of Co2+, Cu2+ and Zn2+ with its utility in mitotracking and monitoring cytoplasmic viscosity in apoptotic cells.

Metal ions such as Co2+, Cu2+ and Zn2+ have extensive applications in biological and industrial realms, but the toxicity caused by these ions poses a serious threat to mankind. However, there is no report in the literature on the development of a chemosensor for distinguishable detection of these toxic ions. Addressing this challenge, a multifunctional probe as a basic pH indicator with both colorimetric and fluorescence turn-on responses has been reported. The probe selectively discriminates Co2+, Cu2+ and Zn2+ ions with brown, dark yellow and greenish yellow colors, respectively, in DMF : water (9 : 1 v/v, HEPES 10 mM). Additionally, a fluorescence turn-on response specific to Zn2+ has also been observed. The sensing mechanism has been explored using UV-Vis, fluorescence spectroscopy and 1H NMR titration and confirmed with computational results. The inhibition of CN isomerization and excited state intramolecular proton transfer (ESIPT) along with chelation enhanced fluorescence emission (CHEF) result in fluorescence enhancement with Zn2+. Job's plot and HRMS spectra confirm a 1 : 1 (L : M) stoichiometry between the probe and metal ions. The probe is able to exhibit excellent viscochromism in DMF : glycerol medium. Live cell imaging on SiHa cells has been successfully performed for intra-cellular detection of Zn2+ at basic pH. Furthermore, the probe displays its utility in mitotracking and monitoring cytoplasmic viscosity changes in SiHa cells. It is efficiently used to recognize the apoptosis process by displaying an enhancement in fluorescence intensity from cancerous SiHa cells to apoptotic cells.

Melatonin induces apoptosis and cell cycle arrest in cervical cancer cells via inhibition of NF-κB pathway.

Cervical cancer is the most prevalent cancer in females. Melatonin, a neurohormone has been documented as a promising therapeutic molecule for cervical cancer. However, the underlying molecular mechanism is not known. We explored the dose-dependent anti-tumor response of melatonin against cervical cancer cell lines, HeLa (HPV-18 positive) and SiHa (HPV-16 positive). The anti-cancer effect of melatonin was evaluated by MTT assay, cell imaging, colony formation, DAPI, AO/PI, LDH, Flow cytometry, scratch assay, western blot analysis and real-time PCR. Results of DAPI, AO/PI, LDH, and Annexin/PI staining revealed that melatonin induces apoptosis. The results of cell cycle analysis revealed that melatonin arrests the HeLa and SiHa cells in sub-G1 and G1 phases, respectively. Western blot analysis revealed that melatonin downregulated the expression of pro-inflammatory transcription factor, NF-κB and the expression of COX-2 protein, a key mediator in cell proliferation. In addition, melatonin downregulated the expression of an invasive marker, MMP-9, an antiapoptotic protein, Bcl-2, and upregulated the expression of pro-apoptotic protein, Bax at both transcriptional and translational levels. Overall, the results suggest that melatonin exhibited strong anti-cancer therapeutic potential against human cervical cancer cell line progression possibly through inhibition of NF-κB signalling pathway.

Biogenic synthesis and characterization of selenium nanoparticles and their applications with special reference to antibacterial, antioxidant, anticancer and photocatalytic activity.

Oxyanions of selenium, selenite (SeO3)2- and selenate (SeO4)2- are toxic to terrestrial and aquatic biota but few microorganisms including cyanobacteria are resistant to high levels of selenite. Cyanobacteria evade selenite toxicity through bioreduction and synthesis of selenium nanoparticles (SeNPs). In this study, extracellular biosynthesis of SeNPs (Se0) using cyanobacterium, Anabaena sp. PCC 7120 on exposure to sodium selenite and characterization was done by using UV-visible spectroscopy, SEM-EDX, TEM and FTIR analyses which confirmed spherical shape with size range of 5-50 nm diameter. These biogenic SeNPs demonstrated significant antibacterial and anti-biofilm activity against bacterial pathogens. Furthermore, these SeNPs showed high antioxidant activity at minimum concentration of 50 µg/mL and significant anti-proliferative activity against HeLa cell line with IC50 value of 5.5 µg/mL. The SeNPs also induced accumulation of cancer cells in the sub-G1 phase which was clearly observed in cellular and nuclear morphology. These biofabricated SeNPs also reduced and decolorized toxic methylene blue dye significantly through photocatalytic degradation. Therefore Anabaena sp. PCC 7120 may be employed as a green bioresource to synthesize SeNPs with potential applications in medicine and environmental bioremediation.

Genes involved in phosphatidylcholine biosynthesis correlate with nuclear factor-κB in biliary tract cancer patients: Evidence from 1H NMR and computational analyses.

Gallbladder cancer (GBC) is an aggressive malignancy of gastrointestinal tract. Due to uncontrolled growth, GBC cells rapidly synthesize biomolecules including lipids. The lipids are integral component of cell membrane with a wide range of cellular functions. In this study, we measured the clinicopathological features in 40 cases of histologically confirmed GBC and 16 cases of chronic cholecystitis (CC). The female to male ratio in the GBC and CC groups were 3.44:1 and 2.2:1, respectively. The GBC patients exhibited well to poorly differentiated tumor. In the CC group, all patients showed cholecystitis with no evidence of dysplasia or malignancy. The majority of GBC and CC patients reported pain. Using 1H NMR spectroscopy, we observed 4-folds increase in the level of choline containing phospholipids (CCPLs) in the gallbladder of GBC patients as compared to CC patients. Other lipid metabolites such as cholesterol ester, C18-cholesterol and saturated fatty acids were insignificantly changed between GBC and CC patients. Moreover, the level of CCPLs in the GBC patients with BMI <25 kg/m2 was significantly higher as compared to CC patients. Further, a significant increase in the CCPLs level was observed in GBC female patients in comparison to CC patients. From the computational analyses, we observed that the genes involved in the biosynthesis of phosphatidylcholine (PtdCho) indirectly interact with the RELA, which encodes the NF-κB p65 subunit. The genes involved in the PtdCho biosynthesis were also correlated with the overall and disease-free survival of cholangiocarcinoma patients. The study opens new window for exploring the diagnostic and therapeutic potential of CCPLs in GBC patients.

Diagnostic, prognostic, and therapeutic significance of long non-coding RNA MALAT1 in cancer.

Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) is a widely studied lncRNA in cancer. Although dispensable for normal physiology, MALAT1 is important for cancer-related pathways regulation. It is localized in the nuclear speckles periphery along with centrally located pre-RNA splicing factors. MALAT1 associated cancer signaling pathways include MAPK/ERK, PI3K/AKT, ß-catenin/Wnt, Hippo, VEGF, YAP, etc. Molecular tools such as immunoprecipitation, RNA pull-down, reporter assay, Northern blotting, microarray, and q-RT-PCR has been used to elucidate MALAT1's function in cancer pathogenesis. MALAT1 can regulate multiple steps in the development of tumours. The diagnostic and prognostic significance of MALAT1 has been demonstrated in cancers of the breast, cervix, colorectum, gallbladder, lung, ovary, pancreas, prostate, glioma, hepatocellular carcinoma, and multiple myeloma. MALAT1 has also emerged as a novel therapeutic target for solid as well as hematological malignancies. In experimental models, siRNA and antisense oligonucleotide (ASO) based strategy has been used for targeting MALAT1. The lncRNA has also been targeted for the chemosensitization and radiosensitization of cancer cells. However, most studies have been performed in preclinical models. How the cross-talk of MALAT1 with other signaling pathways affect cancer pathogenesis is the focus of this article. The diagnostic, prognostic, and therapeutic significance of MALAT1 in multiple cancer types are discussed.

Drug repurposing for breast cancer therapy: Old weapon for new battle.

Despite tremendous resources being invested in prevention and treatment, breast cancer remains a leading cause of cancer deaths in women globally. The available treatment modalities are very costly and produces severe side effects. Drug repurposing that relate to new uses for old drugs has emerged as a novel approach for drug development. Repositioning of old, clinically approved, off patent non-cancer drugs with known targets, into newer indication is like using old weapons for new battle. The advances in genomics, proteomics and information computational biology has facilitated the process of drug repurposing. Repositioning approach not only fastens the process of drug development but also offers more effective, cheaper, safer drugs with lesser/known side effects. During the last decade, drugs such as alkylating agents, anthracyclins, antimetabolite, CDK4/6 inhibitor, aromatase inhibitor, mTOR inhibitor and mitotic inhibitors has been repositioned for breast cancer treatment. The repositioned drugs have been successfully used for the treatment of most aggressive triple negative breast cancer. The literature review suggest that serendipity plays a major role in the drug development. This article describes the comprehensive overview of the current scenario of drug repurposing for the breast cancer treatment. The strategies as well as several examples of repurposed drugs are provided. The challenges associated with drug repurposing are discussed.

Clinico-pathological peculiarities of human papilloma virus driven head and neck squamous cell carcinoma: A comprehensive update.

AIMS: The current article provides a detailed account of the current understanding of molecular and clinico-pathological aspects of Human papilloma virus (HPV) driven head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: The literature review included most of the landmark trials and clinical studies related to the HPV driven HNSCC. KEY FINDINGS: HPV positive HNSCC differ distinctly from HPV negative tobacco-related HNSCC, especially in oropharyngeal region. Therefore, the American joint committee on cancer`s latest manual for classification and staging of cancer suggests a separate staging system for HPV positive oropharyngeal cancers. Despite the younger patients being affected and the high propensity for cervical metastasis, the HPV positive oropharyngeal cancers respond much better to the treatment. The association with wild type TP53 and low EGFR expression confers the favorable prognosis in HPV driven HNSCC. Since the association is not universal, we suggest checking for p53 and EGFR expression status before considering de-intensification of therapy. In addition, the presence of matted lymph nodes and five or more nodes could mean relatively poorer prognosis, and are not suitable for de-intensification of therapy. The same is also true probably with higher T stage and co-existing tobacco use. The methods for the detection of p16, HPV DNA, HPV E6/E7 mRNA, anti-E6/E7 antibodies, in tissue, in serum and in saliva of patients, along with their clinical implications are also discussed. SIGNIFICANCE: This article provides latest developments on the HPV driven HNSCC. 'Diagnosis of transcriptionally active HPV infection,' 'Modalities for surveillance,' 'Implication of de-escalation of therapy' are some of the critical issues that could serve the medical, the research as well as the patient communities.

Oxidative Stress and Cancer Development: Are Noncoding RNAs the Missing Links?

Significance: It is now clear that genetic changes underlie the basis of cancer, and alterations in functions of multiple genes are responsible for the process of tumorigenesis. Besides the classical genes that are usually implicated in cancer, the role of noncoding RNAs (ncRNAs) and reactive oxygen species (ROS) as independent entitites has also been investigated. Recent Advances: The microRNAs and long noncoding RNAs (lncRNAs), two main classes of ncRNAs, are known to regulate many aspects of tumor development. ROS, generated during oxidative stress and pathological conditions, are known to regulate every step of tumor development. Conversely, oxidative stress and ROS producing agents can suppress tumor development. The malignant cells normally produce high levels of ROS compared with normal cells. The interaction between ROS and ncRNAs regulates the expression of multiple genes and pathways implicated in cancer, suggesting a unique mechanistic relationship among ncRNA-ROS-cancer. The mechanistic relationship has been reported in hepatocellular carcinoma, glioma, and malignancies of blood, breast, colorectum, esophagus, kidney, lung, mouth, ovary, pancreas, prostate, and stomach. The ncRNA-ROS regulate several cancer-related cell signaling pathways, namely, protein kinase B (AKT), epidermal growth factor receptor (EGFR), forkhead box O3 (FOXO3), kelch-like ECH-associated protein 1 (Keap1), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), p53, phosphatase and tensin homologue (PTEN), and wingless-related integration site (Wnt)/glycogen synthase kinase-3 beta (GSK3ß). Critical Issues: To date, most of the reports about ncRNA-oxidative stress-carcinogenesis relationships are based on cell lines. The mechanistic basis for this relationship has not been completely elucidated. Future Directions: Attempts should be made to explore the association of lncRNAs with ROS. The significance of the ncRNA-oxidative stress-carcinogenesis interplay should also be explored through studies in animal models.

Health benefits of resveratrol: Evidence from clinical studies.

Resveratrol is a polyphenolic nutraceutical that exhibits pleiotropic activities in human subjects. The efficacy, safety, and pharmacokinetics of resveratrol have been documented in over 244 clinical trials, with an additional 27 clinical trials currently ongoing. Resveretrol is reported to potentially improve the therapeutic outcome in patients suffering from diabetes mellitus, obesity, colorectal cancer, breast cancer, multiple myeloma, metabolic syndrome, hypertension, Alzheimer's disease, stroke, cardiovascular diseases, kidney diseases, inflammatory diseases, and rhinopharyngitis. The polyphenol is reported to be safe at doses up to 5 g/d, when used either alone or as a combination therapy. The molecular basis for the pleiotropic activities of resveratrol are based on its ability to modulate multiple cell signaling molecules such as cytokines, caspases, matrix metalloproteinases, Wnt, nuclear factor-κB, Notch, 5'-AMP-activated protein kinase, intercellular adhesion molecule, vascular cell adhesion molecule, sirtuin type 1, peroxisome proliferator-activated receptor-γ coactivator 1α, insulin-like growth factor 1, insulin-like growth factor-binding protein 3, Ras association domain family 1α, pAkt, vascular endothelial growth factor, cyclooxygenase 2, nuclear factor erythroid 2 like 2, and Kelch-like ECH-associated protein 1. Although the clinical utility of resveratrol is well documented, the rapid metabolism and poor bioavailability have limited its therapeutic use. In this regard, the recently produced micronized resveratrol formulation called SRT501, shows promise. This review discusses the currently available clinical data on resveratrol in the prevention, management, and treatment of various diseases and disorders. Based on the current evidence, the potential utility of this molecule in the clinic is discussed.

Inflammation, a Double-Edge Sword for Cancer and Other Age-Related Diseases.

Increasing evidence from diverse sources during the past several years has indicated that long-term, low level, chronic inflammation mediates several chronic diseases including cancer, arthritis, obesity, diabetes, cardiovascular diseases, and neurological diseases. The inflammatory molecules and transcription factors, adhesion molecules, AP-1, chemokines, C-reactive protein (CRP), cyclooxygenase (COX)-2, interleukins (ILs), 5-lipooxygenase (5-LOX), matrix metalloproteinases (MMPs), nuclear factor (NF)-kB, signal transducer and activator of transcription 3 (STAT3), tumor necrosis factor (TNF), and vascular endothelial growth factor (VEGF) are molecular links between inflammation and chronic diseases. Thus, suppression of inflammatory molecules could be potential strategy for the prevention and therapy of chronic diseases. The currently available drugs against chronic diseases are highly expensive, minimally effective and produce several side effects when taken for long period of time. The focus of this review is to discuss the potential of nutraceuticals derived from "Mother Nature" such as apigenin, catechins, curcumin, ellagic acid, emodin, epigallocatechin gallate, escin, fisetin, flavopiridol, genistein, isoliquiritigenin, kaempferol, mangostin, morin, myricetin, naringenin, resveratrol, silymarin, vitexin, and xanthohumol in suppression of these inflammatory pathways. Thus, these nutraceuticals offer potential in preventing or delaying the onset of chronic diseases. We provide evidence for the potential of these nutraceuticals from pre-clinical and clinical studies.