Search

Simple Summary: Prostatic adenocarcinoma (PRAD) and prostatic transitional cell carcinoma (P-TCC) are the most common subtypes of prostate cancer (PCa) in dogs, and differentiating them often requires an invasive tissue biopsy with histopathology. Routine laboratory data from blood work and minimally invasive tests, such as fine-needle aspiration cytology, have been overlooked as a tool for discerning between these tumors. This is the first study to utilize clinicopathologic and cytologic data to differentiate PRAD and P-TCC in dogs. Clinicopathologic data in dogs with prostate cancer (PCa) may aid in the differentiation between tumor types and subsequent treatment decisions; however, these data are often unreported. Demographic, clinicopathologic, cytologic, histologic and survival data from dogs with primary prostatic adenocarcinoma (PRAD) (n = 56) and primary prostatic transitional cell carcinoma (P-TCC) (n = 74) were acquired from a tertiary veterinary teaching hospital from 1992 to 2022. Red blood cell distribution width (RDW) to albumin ratio (RAR) was evaluated for diagnostic utility in differentiating between PRAD and P-TCC. Sections from PRAD tumors (n = 50) were stained for androgen receptor (AR) expression, and laboratory data were compared between AR positive (AR+) and AR negative (AR−) groups. RDW was increased in PRAD, while albumin was decreased (p < 0.05). P-TCC was associated with Melamed-Wolinska bodies (MWB) and necrosis on cytology (p < 0.05). RAR had acceptable diagnostic utility in the differentiation of PCa tumors (AUC = 0.7; p < 0.05). Survival rates and metastases were equivocal. AR+ and AR− PRAD tumors did not differ in clinicopathologic data or survival (p > 0.05). In conclusion, hypoalbuminemia was significantly associated with PRAD and decreased survival, while MWB and necrosis were significantly associated with P-TCC on cytology. These clinicopathologic data may help clinicians differentiate between these tumors ante mortem to guide appropriate treatment and intervention. [ABSTRACT FROM AUTHOR]

A new palladium(II) complex, [Pd(LSEt)Cl] (C1) with benzothiazole based ONS donor pincer ligand (HLSEt) was synthesized (where, HLSEt = 2-(benzothiazol-2-yl)-6-(((2-(ethylthio)phenyl)imino)methyl)phenol). Interaction of C1 with CT DNA was investigated, and its binding constant was found to be 4.0×105 M−1. The proficiency of ethidium bromide (EB) displacement from its EB-CTDNA complex by C1 was performed by the fluorescence quenching method, and Stern-Volmer quenching constant (Ksv) was found to be 4.3×105 M−1. Similarly, the interaction of C1 with BSA protein was investigated by UV-Vis and fluorescence methods. The apparent association constant (Ka) and Ksv were determined (Ka = 2.8×104 M−1 and Ksv = 5.5×104 M−1). In vitro cytotoxicity of the complex, [Pd(LSEt)Cl] (C1), towards human gastric cancer cell lines (AGS) was assessed by the MTT assay method. The half maximal inhibitory concentration (IC50) of C1 (9.55 ± 1.23 µM) towards AGS cancer lines was found to be lower than cisplatin (23.13 ± 1.03 µM). Herein, new palladium(II) complex, [Pd(LSEt)Cl] (C1) with benzothiazole-based ONS donor pincer ligand (HLSEt) was synthesized and characterized by several spectroscopic techniques. Interaction of C1 with CT DNA and BSA protein was investigated by UV-Vis and fluorescence methods. In vitro cytotoxicity of the complex toward human gastric cancer cell lines (AGS) was evaluated by the MTT assay method. The half maximal inhibitory concentration (IC50) of the palladium(II) complex (9.55±1.23 µM) was found to be less compared to cisplatin (23.13±1.03 µM) towards AGS cancer lines. [ABSTRACT FROM AUTHOR]

In this issue of Endocrine-Related Cancer, we are celebrating the 80th anniversary of hormone ablation as treatment for metastatic prostate cancer. Our understanding has evolved from the observation that androgen withdrawal, either surgical or pharmacological, resulted in prostatic atrophy in animal models, to its application in patients, to investigation of the mysterious way in which pr ostate cancer escapes androgen dependence. We are now in an era of novel AR pathway i nhibitors, the combination of androgen ablation with chemotherapy, PARP inhibitors, immunotherapies, guided radiotherapy, and novel drug application based upon genetic testing of individual tumors. In this special issue, we bring t ogether a collection of eight reviews that cover not only the history of 80 years of pr ogress after the initial identification of androgen ablation as an effective treatment of prostate cancer, but subsequent improvements in the understanding of the biology of the disease, development of novel treatment paradigms, resistance to those treatments and disease progression following that resistance. [ABSTRACT FROM AUTHOR]

Piper capense belongs to Piperaceae family and has long been used as a traditional medicine to treat various diseases in several parts of Africa. The present study aims to investigate the effect of Piper capense fruit extract (PCFE) alone and in combination with dacarbazine on metastatic melanoma cell line B16-F10 and in vivo in C57BL/6J mice. Cytotoxic effects of PCFE alone and in association with dacarbazine on B16-F10 cells were studied by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay and colony formation assay. Wound healing assay, immunofluorescence staining, and western blot analysis were performed to evaluate the individual and combined effect of PCFE and dacarbazine on epithelial-mesenchymal transition (EMT). For in vivo studies, C57BL/6J mice were subcutaneously injected with B16-F10 cells (5 × 105 cells/mL), and the effect of PCFE and dacarbazine was studied on tumor development. The alteration of EMT was evaluated by targeting E-cadherin, vimentin, and CD133 in PCFE alone and in combination with dacarbazine-treated tumor tissues by western blot analysis. Phytochemical screening of PCFE reveals the presence of certain secondary metabolites. Our results showed that PCFE alone and in association with dacarbazine has a good activity in preventing B16-F10 melanoma cell progression and clonogenicity. This extract also regulated EMT. In vivo results showed that PCFE (100 mg/kg body weight) reduced tumor size in C57BL/6J mice along with the decrease in the expression of vasculogenic mimicry (VM) tubes as well as an improvement in the qualitative and quantitative expression of markers involved in EMT. Our study suggests that PCFE may be useful for managing the growth and metastasis of melanoma. [ABSTRACT FROM AUTHOR]

Aims The cytotoxic response of an intermediate metabolite glyoxylate (Glx) on colon carcinoma has been evaluated in vitro . Main methods The anti-proliferative effect of Glx was assessed on HT-29 and HCT-116 cells by performing MTT assay as well as beta-hexosaminidase assay. Evaluation of apoptotic event of Glx treated cells was measured by flow cytometry using annexin-V/PI staining. The mitochondrial membrane potential and level of ROS were estimated using DiOC 6 (3)/CCCP and DCFH-DA method, respectively. The assessment of catalase, LDH and IDH were performed. Key findings The results of MTT assay indicated that treatment with Glx significantly inhibited the proliferation of HT-29 and HCT-116 cells. Beta-hexosaminidase assay also confirmed the inhibition of cellular viability. The dose-dependent Glx treatment indicated lowering the colony forming ability of HT-29 and HCT-116 cells. Flow cytometric data demonstrated the significant increment of late apoptotic event after Glx treatment. In addition, substantial LDH activity was noticed in both the colon cancer cells whereas the IDH activity was unaltered after extra-cellular addition of Glx. Further, dissipation of mitochondrial membrane potential and subsequently elevated ROS generation was also detected in the Glx treated colon cancer cells. However, gradual elevation of catalase activities indicated that Glx treatment on colon cancer cells exhibit oxidative stress. Significance This study depicts that supra-physiological concentration of Glx inhibits the proliferation of colon cancer cells due to oxidative stress. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) progression involves a shift from endocrine to paracrine and eventually autocrine control resulting from alterations inmolecular mechanisms in the cells. Deregulation of RNA translation is crucial for tumor cells to grow and proliferate; therefore, overactivation of the translationmachinery is often observed in cancer. The twomost important signal transduction pathways regulating PCa progression are PI3K/Akt/mTOR and Ras/MAPK. These two pathways converge on the eukaryotic translation initiation factor 4E (eIF4E) which binds to the protein scaffold eIF4G upon mechanistic target of rapamycin (mTOR) activation and is phosphorylated by the mitogen-activated protein kinase (MAPK) interacting protein kinases (Mnk1/2). This review describes the role of eIF4E in mRNA translation initiation mediated by its binding to the methylated 5' terminal structure (m7G-cap) of many mRNAs, and the ability ofmany tumor cells to bypass this mechanism. Hormonal therapy and chemotherapy are two of the most prevalent therapies used in patients with advanced PCa, and studies have implicated a role for eIF4E phosphorylation in promoting resistance to both these therapies. It appears that eIF4E phosphorylation enhances the rate of translation of oncogene mRNAs to increase tumorigenicity. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) progression involves a shift from endocrine to paracrine and eventually autocrine control resulting from alterations inmolecular mechanisms in the cells. Deregulation of RNA translation is crucial for tumor cells to grow and proliferate; therefore, overactivation of the translationmachinery is often observed in cancer. The twomost important signal transduction pathways regulating PCa progression are PI3K/Akt/mTOR and Ras/MAPK. These two pathways converge on the eukaryotic translation initiation factor 4E (eIF4E) which binds to the protein scaffold eIF4G upon mechanistic target of rapamycin (mTOR) activation and is phosphorylated by the mitogen-activated protein kinase (MAPK) interacting protein kinases (Mnk1/2). This review describes the role of eIF4E in mRNA translation initiation mediated by its binding to the methylated 5' terminal structure (m7G-cap) of many mRNAs, and the ability ofmany tumor cells to bypass this mechanism. Hormonal therapy and chemotherapy are two of the most prevalent therapies used in patients with advanced PCa, and studies have implicated a role for eIF4E phosphorylation in promoting resistance to both these therapies. It appears that eIF4E phosphorylation enhances the rate of translation of oncogene mRNAs to increase tumorigenicity. [ABSTRACT FROM AUTHOR]

A highly sensitive and selective coumarin based chemosensor H 2 L for the efficient detection of Al 3+ has been developed. The synthesized chemosensor H 2 L is efficient in detecting Al 3+ over other metal ions which are commonly obtained in various physiological and environmental samples. H 2 L shows fluorescence ‘turn-on’ response at 610 nm in presence of Al 3+ , without the interference of other metal ions. The resulting H 2 L-Al 3+ complex behave as a sequential chemosensor for F − , by showing quenching of emission intensity upon addition of F − to it. This quenching of emission intensity is only specific for F − and is not hampered due to the presence of other anions that commonly coexist with F − in various environmental solutions. Theoretical calculations using DFT/B3LYP method has been used to get insight into the sensing mechanism as well as electronic structure of the synthesized chemosensor H 2 L. H 2 L is efficient in detecting Al 3+ in the intracellular region of human A549 cell and also exhibits an INHIBIT logic gate with Al 3+ and F − as chemical inputs by monitoring the emission mode at 610 nm. [ABSTRACT FROM AUTHOR]

We develop a modified solid-on-solid model for studying heteroepitaxial growth of Ge on a 2 × 1 reconstructed Si(001) surface. The model is implemented using lattice-based kinetic Monte Carlo simulations using an atomistic model of elasticity. Our simulations show that the films are grown via Stranski–Krastanov mode with about 2 film layers wetting the substrate below three-dimensional islands. The island shapes evolve from rectangular-based at low coverage(thin films) to square-based at higher coverage. Their size distribution changes from bimodal to unimodal at higher coverage, and subsequently the surface is covered by uniform-sized islands. For simulations performed at lower deposition flux, the shape transition is observed for lower coverage. Our results are consistent with experiments and emphasize the role of the 2 × 1 reconstruction of the underlying Si(001) surface on the observed behavior. This is the only atomistic model that has been shown to reproduce features of both submonolayer growth and the Stranski–Krastanov growth transition at higher coverage. [ABSTRACT FROM AUTHOR]

The androgen receptor (AR) plays a key role in the development and progression of prostate cancer (CaP). Since the mid-1990s, reports in the literature pointed out higher incidences of CaP in some select groups, such as airline pilots and night shift workers in comparison with those working regular hours. The common finding in these ‘high-risk’ groups was that they all experienced a deregulation of the body’s internal circadian rhythm. Here, we discuss how the circadian rhythm affects androgen levels and modulates CaP development and progression. Circadian rhythmicity of androgen production is lost in CaP patients, with the clock genes Per1 and Per2 decreasing, and Bmal1 increasing, in these individuals. Periodic expression of the clock genes was restored upon administration of the neurohormone melatonin, thereby suppressing CaP progression. Activation of the melatonin receptors and the AR antagonized each other, and therefore the tumour-suppressive effects of melatonin and the clock genes were most clearly observed in the absence of androgens, that is, in conjunction with androgen deprivation therapy (ADT). In addition, a large-scale study found that high-dose radiation was more effective in CaP patients when it was delivered before 17:00 h, compared with those delivered after 17:00 h, suggesting that the therapy was more effective when delivered in synchrony with the patient’s circadian clock. As CaP patients are shown to become easily resistant to new therapies, perhaps circadian delivery of these therapeutic agents or delivery in conjunction with melatonin and its novel analogs should be tested to see if they prevent this resistance. [ABSTRACT FROM AUTHOR]

Background: The mammalian target of rapamycin (mTOR) pathway is up-regulated in castration-resistant prostate cancer (CRPC). Nevertheless, inhibition of mTOR is ineffective in inducing apoptosis in prostate cancer cells, likely because of the compensatory up-regulation of the androgen receptor (AR) pathway.Methods: Patients who were eligible for this study had to have progressive CRPC with serum testosterone levels <50 ng/dL. No prior bicalutamide (except to prevent flare) or everolimus was allowed. Treatment included oral bicalutamide 50 mg and oral everolimus 10 mg, both once daily, with a cycle defined as 4 weeks. The primary endpoint was the prostate-specific antigen (PSA) response (≥30% reduction) from baseline. A sample size of 23 patients would have power of 0.8 and an α error of .05 (1-sided) if the combination had a PSA response rate of 50% versus a historic rate of 25% with bicalutamide alone.Results: Twenty-four patients were enrolled. The mean age was 71.1 years (range, 53.0-87.0 years), the mean PSA level at study entry was 43.4 ng/dL (range, 2.5-556.9 ng/dL), and the mean length of treatment was 8 cycles (range, 1.0-23.0 cycles). Of 24 patients, 18 had a PSA response (75%; 95% confidence interval [CI], 0.53-0.90), whereas 15 (62.5%; 95% CI, 0.41-0.81) had a PSA decrease ≥50%. The median overall survival was 28 months (95% CI, 14.1-42.7 months). Fourteen patients (54%; 95% CI, 0.37-0.78) developed grade 3 (13 patients) or grade 4 (1 patient with sepsis) adverse events that were attributable to treatment.Conclusions: The combination of bicalutamide and everolimus has encouraging efficacy in men with bicalutamide-naive CRPC, thus warranting further investigation. A substantial number of patients experienced everolimus-related toxicity. Cancer 2016;122:1897-904. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

A modified lattice model is developed to study the growth of Ge on Si(001). In addition to the usual bond energies, surface reconstruction and elastic strain are explicitly taken into account in this study. We introduce an additional rebonding energy for formation of vacancies in the dimer chains. Kinetic Monte Carlo simulations of growth and annealing successfully reproduce several important features in the range of growth from a small fraction of a monolayer to about one monolayer thick. These include the formation of dimer chains, formation and alignment of vacancies in the dimer chains and the peak in the dimer chain length distribution. We carefully analyze separately the role of mismatch strain and surface reconstruction on this behavior. Through this work, we show a significantly simplified, but nevertheless quantitatively accurate model for the early stages of growth of Ge on Si(001). [ABSTRACT FROM AUTHOR]

New palladium(II) complexes, [Pd(L)Cl] (C1) and [Pd(L)PPh 3 ](ClO 4) (C2), with ONS donor thioether containing ligand (HL) were synthesized and characterized. Distorted square planar geometries of the complexes were determined unambiguously by single crystal X-ray diffraction analysis. Cytotoxicity of the complexes was evaluated in vitro using MTT assay on human gastric cancer cell lines (AGS). Activity results showed that, the palladium(II) complexes (C1 / C2) have higher anti-cancer activity (IC 50 = 13.4 µM for C1 and 16.0 µM for C2) compare to HL against AGS cell lines (67.1 µM). [Display omitted] • New palladium(II) complexes are synthesized with ONS donor thioether ligand. • Square planar geometries of the complexes are confirmed by X-ray crystallography. • Electronic structure and redox properties are interpreted by DFT calculations. • The palladium(II) complexes exhibit potential anti-cancer activity towards AGS cancer cell lines. • Pd(II) complexes inhibit the cell viability of AGS cells at its low dose as compared to HL. Synthesis of new palladium(II) complexes, [Pd(L)Cl] (C1) and [Pd(L)PPh 3 ](ClO 4) (C2), with ONS donor thioether ligand (HL) is reported. All the complexes were thoroughly characterized by using numerous spectroscopic techniques like FT-IR, NMR and UV–visible spectroscopy and so forth. Distorted square planar geometries of the complexes were confirmed unambiguously by means of single crystal X–ray diffraction analysis. Moreover, DFT and TDDFT calculations were performed to interpret the electronic structure, redox and spectral properties of the complexes. Cytotoxicity of the complexes was evaluated in vitro using MTT assay on human gastric cancer cell lines (AGS). The anti-cancer effects of HL and palladium(II) complexes (C1 / C2) on AGS cell lines were determined by comparing the half maximal inhibitory concentration (IC 50) values. The results revealed that synthesized palladium(II) complexes (C1 / C2) showed higher anti-cancer activity (IC 50 = 13.4 µM for C1 and 16.0 µM for C2) compare to HL against AGS cell lines (67.1 µM). [ABSTRACT FROM AUTHOR]

We have developed a simple cubic solid-on-solid (SOS) model of growth that captures many of the features of 2 × 1 reconstructed surfaces. Energetics in the model is based on bond-counting and the tendency to form dimer rows is controlled by a reconstruction energy parameter δ . We examine the dependence of the shapes and sizes of islands formed at submonolayer coverage on the parameter δ . The aspect ratio distribution of islands indicates a transition from two-dimensional to one-dimensional growth as δ is increased. At coverages below 0.2 ML, the islands are mostly made of dimer chains with aspect ratios as large as 14. On annealing the system, the islands coalesce into larger islands with a much smaller aspect ratio of approximately 3. Through extensive simulations, we have found a set of parameters that reproduces the known experimental results on submonolayer growth on Si(001) in Molecular Beam Epitaxy(MBE). These results include island size and shape distribution and their dependence on temperature. This model can be used to study heteroepitaxial thin film growth on reconstructed surfaces. [ABSTRACT FROM AUTHOR]

Androgen deprivation therapy (ADT) is known to cause bone loss in a majority of patients with castration-resistant prostate cancer (CRPC). A study published in this issue of Endocrine-Related Cancer by Ottewell and colleagues shows that ADT increased bone resorption and triggered growth of disseminated prostate cancer (CaP) cells to form bone metastasis using an in vivo model. However, prevention of bone decay by weekly administration of zoledronic acid (ZOL) at the time of castration prevented ADT-induced tumor growth in bone. Recently, two publications from Japan have demonstrated that ZOL combined with ADT improved outcomes for patients with treatment-naïve CaP with bone metastasis. The mechanistic cause for these patients having an improved overall survival compared with those who were treated with ZOL after ADT initiation or before metastasis development was never explained. Ottewell and colleague's study now suggests that it is the bone loss caused by ADT that promoted bone metastasis, and if ZOL is administered at the time of ADT initiation, it would prevent this bone loss and prolong skeletal-related event-free survival. [ABSTRACT FROM AUTHOR]

Filamin A (FlnA) has been associated with actin as cytoskeleton regulator. Recently its role in the cell has come under scrutiny for FlnA's involvement in cancer development. FlnA was originally revealed as a cancer-promoting protein, involved in invasion and metastasis. However, recent studies have also found that under certain conditions, it prevented tumor formation or progression, confusing the precise function of FlnA in cancer development. Here, we try to decipher the role of FlnA in cancer and the implications for its dual role. We propose that differences in subcellular localization of FlnA dictate its role in cancer development. In the cytoplasm, FlnA functions in various growth signaling pathways, such as vascular endothelial growth factor, in addition to being involved in cell migration and adhesion pathways, such as R-Ras and integrin signaling. Involvement in these pathways and various others has shown a correlation between high cytoplasmic FlnA levels and invasive cancers. However, an active cleaved form of FlnA can localize to the nucleus rather than the cytoplasm and its interaction with transcription factors has been linked to a decrease in invasiveness of cancers. Therefore, overexpression of FlnA has a tumor-promoting effect, only when it is localized to the cytoplasm, whereas if FlnA undergoes proteolysis and the resulting C-terminal fragment localizes to the nucleus, it acts to suppress tumor growth and inhibit metastasis. Development of drugs to target FlnA and cause cleavage and subsequent localization to the nucleus could be a new and potent field of research in treating cancer. [ABSTRACT FROM AUTHOR]

Contribution of genes in attention deficit hyperactivity disorder (ADHD) has been explored in various populations, and several genes were speculated to contribute small but additive effects. We have assessed variants in four genes, DDC (rs3837091 and rs3735273), DRD2 (rs1800496, rs1801028, and rs1799732), DRD4 (rs4646984 and rs4646983), and COMT (rs165599 and rs740603) in Indian ADHD subjects with comorbid attributes. Cases were recruited following the Diagnostic and Statistical Manual for Mental Disorders-IV-TR after obtaining informed written consent. DNA isolated from peripheral blood leukocytes of ADHD probands (N = 170), their parents (N = 310), and ethnically matched controls (n = 180) was used for genotyping followed by populationand family-based analyses by the UNPHASED program. DRD4 sites showed significant difference in allelic frequencies by casecontrol analysis, while DDC and COMT exhibited bias in familial transmission (P < 0.05). rs3837091 "AGAG," rs3735273 "A," rs1799732 "C," rs740603 "G," rs165599 "G" and single repeat alleles of rs4646984/rs4646983 showed positive correlation with comorbid characteristics (P < 0.05). Multi dimensionality reduction analysis of case-control data revealed significant interactive effects of all four genes (P < 0.001), whilefamily-baseddatashowedinteractionbetweenDDCandDRD2(_P = 0.04). This first study on these gene variants in Indo-Caucasoid ADHD probands and associated co-morbid conditions indicates altered dopaminergic neurotransmission in ADHD. [ABSTRACT FROM AUTHOR]

Excessive fat accumulation in liver (hepatic steatosis) predisposes to hepatic functional and structural impairment and overall metabolic risk. Previous studies noted an association between hepatic steatosis and age in humans and rodents. However, the mechanisms leading to age-associated hepatic fat accumulation remain unknown. Earlier work from our group showed that b-adrenergic receptor (&bgr;-AR) levels and &bgr;-AR-stimulated adenylyl cyclase activity increase in rat liver during aging. Herewe investigated whether age-associated increases in &bgr;-AR signaling play a role in augmenting hepatic lipid accumulation. We demonstrate an increase in hepatic lipid content during senescence and a significant correlation between hepatic fat content and stimulation of adenylyl cyclase activity by the &bgr;-AR agonist isoproterenol in rat liver. Isoproterenol administration to young and old rodents in vivo increased hepatic lipid accumulation. Furthermore, in vitro overexpression of &bgr;1- and &bgr;2-AR subtypes in hepatocytes from young rodents increased cellular lipid content, whereas inhibition of &bgr;-ARs by receptor subtype-specific inhibitors reduced lipid levels in hepatocytes from senescent animals. Isoproterenol-induced hepatic lipid accumulation in vivo was prevented by the &bgr;-AR nonselective blocker propranolol, suggesting a novel therapeutic effect of this class of drugs in hepatic steatosis. Acipimox, which inhibits adipose tissue lipolysis, did not alter isoproterenolmediated hepatic fat accumulation; thus &bgr;-AR responsive hepatic lipid accumulation does not appear to be related primarily to altered lipolysis. These findings suggest that augmented hepatic &bgr;-AR signaling during aging may increase lipid accumulation in liver and advocate a possible role for &bgr;-adrenergic blockers in preventing or retarding the development of hepatic steatosis. [ABSTRACT FROM AUTHOR]

Methicillin-resistant Staphylococcus aureus (MRSA) cultures were obtained from 288 mother-infant pairs. A questionnaire given to mothers and medical record review assessed risk factors for colonization. Only 2.1% of mothers and 0.7% of infants carried MRSA. There were no identical MRSA mother-newborn pairs. MRSA colonization by expectant mothers is uncommon and transmission to newborns from vaginal delivery did not occur. [ABSTRACT FROM AUTHOR]

Proliferative responsiveness of hepatocytes to epidermal growth factor (EGF) declines during aging. The role of EGF receptors in mediating age-dependent changes of EGF-induced mitogenic signaling in liver remains incompletely understood. We assessed EGF receptor expression levels in whole liver specimens as well as in freshly isolated and cultured hepatocytes from young adult and senescent Fischer 344 male rats. Hepatic EGF receptor messenger RNA and protein levels, and the number of high- and low-affinity receptor binding sites, decreased with aging. Ligand-induced EGF receptor activation, determined by receptor dimerization and tyrosine phosphorylation, was reduced in old animals in parallel with the age-related decline in receptor expression. Stimulation of the extracellular signal-regulated kinase pathway by EGF was also attenuated in hepatocytes from old animals. Our results implicate decreased expression of EGF receptors as a key determinant of reduced mitogenic signaling responsive to EGF stimulation of liver during aging. [ABSTRACT FROM AUTHOR]

Abstract: The effect of phosphorylation on the gating of rat liver gap junction hemichannels (Cx 32) has been investigated. It has been shown that self-phosphorylation of rat liver Cx 32 protein reduces the permeability of proteoliposomes as well the current flowing through multichannels in lipid bilayer membrane (BLM). The low frequency power spectral density analyses of nonstationary noise evolved due to the gating of Cx 32 multichannels demonstrated that self-phosphorylation modulated the channel functioning. A clear change in the power spectrum slopes (α) of the nonstationary noise profiles confirmed the modulation of the channel dynamics due to self-regulation. [Copyright &y& Elsevier]

Abstract: Gap junction provides low resistance pathways for cell-to-cell passive diffusion of ions, metabolites, second messengers etc. and thus, controls development, differentiation in embryonic tissues, and communication in adult tissues. It has been pointed out in our previous work that these passive diffusion channels behave cooperatively which in turn depends on the structural parameters and also membrane potentials. In the present paper, we have analyzed the multichannel bilayer electrophysiological data of rat liver gap junction Connexin 32 (Cx32) hemichannels. Through the measurements of relaxation time it has been demonstrated that one of the relaxation time constants follows a decay pattern with the number of channels open at various potentials applied across the bilayer membrane. This leads to the conclusion that the collective behaviour of rat liver gap junction hemichannels is cooperative in multichannel ensembles. [Copyright &y& Elsevier]

The β-adrenergic receptor agonist isoproterenol exerts growth-promoting effects on salivary glands. in this study, activation of ERKs, members of the mitogen-activated protein kinase family, by isoproterenol was examined in a human salivary gland cell line (HSY). Immunoblot analysis indicated that isoproterenol (10-5 M) induced transient activation of ERK1/2 (4.4-fold relative to basal at 10 min) similar to that caused by EGF (6.7 fold). Isoproterenol, like EGF, also induced phosphorylation of the EGF receptor. However, inhibition of EGF receptor phosphorylation by the tyrphostin AG-1478 only partially attenuated isoproterenol-induced ERK phosphorylation, whereas EGF-responsive ERK activation was completely blocked. The Gi inhibitor pertussis toxin also caused partial inhibition of isoproterenol-stimulated ERK activation. The cAMP analog 8-(4-chlorophenylthio)adenosine 3′,5′-cyclic monophosphate (CPT-cAMP) and the cAMP-elevating agents IBMX and cholera toxin produced transient ERK1/2 activation, similar to the effect of isoproterenol, in HSY cells. The stimulatory effects of isoproterenol and cAMP on ERK phosphorylation were not reduced by the PKA inhibitor H-89, whereas the Src family inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidase (PP2) and transfection of a dominant-negative Src construct diminished isoproterenol-induced ERK activation. Isoproterenol induced marked overexpression of the cell growth-related adhesion molecule CD44, and this effect of isoproterenol was abolished by the ERK pathway inhibitor PD-98059. In summary, we show a dual, mechanism of isoproterenol-induced ERK phosphorylation in HSY cells—one pathway mediated by EGF receptor transactivation and the other by an EGF receptor-independent pathway possibly mediated by cAMP. Our results also suggest that isoproterenol-induced growth of salivary tissue may involve ERK-mediated CD44 expression. [ABSTRACT FROM AUTHOR]

We have studied the functioning of rat liver Connexin 32 (Cx32) at the single channel level in presence of ATP. It was observed that ATP regulates the functioning of the channel by running down the junctional conductance. A non-specific exogenous protein phosphatase (alkaline phosphatase) reversed the rundown of junctional activity to its normal functioning state. Autoradiograhic studies demonstrate autophosphorylation of rat liver Cx32. These findings indicate a self-regulatory mechanism of the channel. [Copyright &y& Elsevier]

Focuses on a study which discussed the stimulation of the mesangial cell proliferation by arginine vasopressin through activation of the epidermal growth factor receptor. Implications of excessive mesangial cell proliferation in maintaining the microcirculation of the glomerulus; Materials and methods used; Results; Conclusions.

• New cyclometalated bimetallic palladium(II) complexes are synthesized via C H bond activation. • Square planar geometries of the complexes are confirmed by X-ray crystallography. • Electronic structure and UV–vis spectra are interpreted by DFT and TDDFT calculations. • Interaction with CT DNA are studied by UV–vis and fluorescence method. • Palladium(II) complexes exhibit potential anti-cancer activity towards AGS cancer cell lines. Herein, we report the synthesis, characterization and in vitro anticancer activity of two μ -Cl and μ -O bridged dimeric cyclometalated palladium(II) complexes having general formula [Pd 2 (L1)Cl 2 ] (1) and [Pd 2 (L2)Cl 2 ] (2). The complexes are synthesized via palladium assisted aromatic C H bond activation of coordinating ligands (HL1/HL2) and thoroughly characterized by spectroscopic techniques. X-ray crystal structure analysis has confirmed the square planar geometry of the complexes. DFT and TDDFT results have interpreted the electronic structure and solution spectra of the complexes. Cytotoxicity of the complexes was studied by in vitro model with human gastric cancer cell lines (AGS). Cytotoxicity investigation reveals that the complexes have promising anti-cancer activity, with IC 50 values of 13.03 µM and 17.86 µM for 1 and 2 , respectively. UV–vis and fluorescence techniques are used to examine how the complexes interact with CT DNA. Fluorescence-based competitive binding analysis with ethidium bromide (EB) indicates that the complexes effectively displace EB from the EB-DNA complex. Herein, we report the synthesis of two μ -Cl and μ -O bridged dimeric palladium(II) complexes (1 / 2) via metal assisted aromatic C H bond activation. Geometries of the complexes are confirmed by single crystal X-ray diffraction method. Electronic structure and solution spectra of the complexes are interpreted by DFT and TDDFT calculations. In vitro cytotoxic activity of the complexes against human AGS gastric cancer cell lines by MTT colorimetric assay exhibit promising anti-cancer activities with IC 50 values of 13.03 µM and 17.86 µM for palladium(II) complexes 1 and 2 respectively. The interaction of the complexes with CT DNA are investigated by UV–vis and fluorescence methods. [Display omitted] [ABSTRACT FROM AUTHOR]

Prostate cancer cells derived from transgenic mice with adenocarcinoma of the prostate (TRAMP cells) were treated with the HMG-CoA reductase inhibitor, lovastatin. This caused inactivation of the small GTPase RhoA, actin stress fiber disassembly, cell rounding, growth arrest in the G1 phase of the cell cycle, cell detachment and apoptosis. Addition of geranylgeraniol (GGOL) in the presence of lovastatin, to stimulate protein geranylgeranylation, prevented lovastatin's effects. That is, RhoA was activated, actin stress fibers were assembled, the cells assumed a flat morphology and cell growth resumed. The following observations support an essential role for RhoA in TRAMP cell growth: (1) TRAMP cells expressing dominant-negative RhoA (T19N) mutant protein displayed few actin stress fibers and grew at a slower rate than controls (35 h doubling time for cells expressing RhoA (T19N) vs 20 h for untransfected cells); (2) TRAMP cells expressing constitutively active RhoA (Q63L) mutant protein displayed a contractile phenotype and grew faster than controls (13 h doubling time). Interestingly, addition of farnesol (FOL) with lovastatin, to stimulate protein farnesylation, prevented lovastatin-induced cell rounding, cell detachment and apoptosis, and stimulated cell spreading to a spindle shaped morphology. However, RhoA remained inactive and growth arrest persisted. The morphological effects of FOL addition were prevented in TRAMP cells expressing dominant-negative H-Ras (T17N) mutant protein. Thus, it appears that H-Ras is capable of inducing cell spreading, but incapable of supporting cell proliferation, in the absence of geranylgeranylated proteins like RhoA. [ABSTRACT FROM AUTHOR]

Estrogens were once used for the treatment of prostate cancer (PC). They may still be used in various parts of the world to that effect. Recent developments in the understanding of a role for estrogen receptor β (ERβ) in the development and progression of this disease resurrect the discussion on the intertwined roles of ERb and the androgen receptor (AR) in promoting PC. A new article by Zellweger et al. in Endocrine-Related Cancer investigates the expression and assesses the activity of ERa and ERb as well as the AR, in addition to a phosphorylated form of AR in hormone-naıve and castration-resistant PC. [ABSTRACT FROM AUTHOR]

Herein, we have designed and synthesized an effective fluorogenic chemosensor, BTCP for the sensing of DCP, a very low toxic simulant of sarin both in the vapour and solution phases. The poor emission property (λ max = 470 nm, quantum yield (φ) = 0.051) of BTCP is significantly increased in the presence of DCP with a red shift of the emission wavelength (λ max = 542 nm, quantum yield (φ) = 0.241) in CH 3 CN/H 2 O (1/1, v/v, pH = 7.2) medium. The limit of detection is found to be as low as 15.8 nM for the detection of DCP. Moreover, the fluorescent probe (BTCP) is very useful for the visualization of DCP within human lung cancer cell lines (A549). • We have designed and synthesized an effective fluorogenic chemosensor for DCP. • Structure of the probe (BTCP) is confirmed by single crystal X-ray diffraction method. • The limit of detection is found to be as low as 15.8 nM for the detection of DCP. • The fluorescent probe (BTCP) is very useful for the visualization of DCP within human lung cancer cell lines (A549). • DFT and TDDFT computational techniques are used to interpret the electronic structure and Uv–vis spectra Herein, we have designed and synthesized an effective fluorogenic chemosensor, BTCP for the sensing of DCP, a very low toxic simulant of sarin both in the vapour and solution phases. The poor emission property (λ max = 470 nm, quantum yield (φ) = 0.051) of BTCP is significantly increased in the presence of DCP with a red shift of the emission wavelength (λ max = 542 nm, quantum yield (φ) = 0.241) in CH 3 CN/H 2 O (1/1, v/v, pH = 7.2) medium. The limit of detection is found to be as low as 15.8 nM for the detection of DCP. Moreover, the fluorescent probe (BTCP) is very useful for the visualization of DCP within human lung cancer cell lines (A549). Sensing of the probe is based on the formation of a new adduct, BTCP-DCP and inhibition of photo-induced electron transfer (PET) process present in the free BTCP. The structure of the probe (BTCP) is confirmed by single crystal X-ray crystallography. Density functional theory (DFT) and time dependent density functional theory (TDDFT) computational techniques are used to interpret the electronic structure and Uv–vis spectra of both BTCP and BTCP-DCP adduct. [ABSTRACT FROM AUTHOR]

A new fluorescent "on–off–on" probe (BIPQ) is designed and developed which selectively binds with Hg2+; its emission intensity is quenched almost 40-fold at 455 nm without interference from other metal cations. On gradual addition of I− to the solution of BIPQ-Hg2+, the emission reverts to its original intensity. The limits of detection of BIPQ for Hg2+ and I− are found to be on the order of 3.12 × 10−9 and 5.48 × 10−8 M, respectively, which shows clearly that BIPQ can sense Hg2+ at a very minute level. DFT and TDDFT studies are conducted with the probe to establish similarity between theoretical and experimental outcomes. Finally, to demonstrate its practical benefit in biological fields, live cell imaging experiments with BIPQ are carried out to detect Hg2+ in human AGS gastric cancer cell lines. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is an increasingly prevalent health problem in the developed world. Effective treatment options exist for localized PCa, but metastatic PCa has fewer treatment options and shorter patient survival. PCa and bone health are strongly entwined, as PCa commonly metastasizes to the skeleton. Since androgen receptor signaling drives PCa growth, androgen-deprivation therapy whose sequelae reduce bone strength constitutes the foundation of advanced PCa treatment. The homeostatic process of bone remodeling -- produced by concerted actions of bone-building osteoblasts, bone-resorbing osteoclasts, and regulatory osteocytes -- may also be subverted by PCa to promote metastatic growth. Mechanisms driving skeletal development and homeostasis, such as regional hypoxia or matrix-embedded growth factors, may be subjugated by bone metastatic PCa. In this way, the biology that sustains bone is integrated into adaptive mechanisms for the growth and survival of PCa in bone. Skeletally metastatic PCa is difficult to investigate due to the entwined nature of bone biology and cancer biology. Herein, we survey PCa from origin, presentation, and clinical treatment to bone composition and structure and molecular mediators of PCa metastasis to bone. Our intent is to quickly yet effectively reduce barriers to team science across multiple disciplines that focuses on PCa and metastatic bone disease. We also introduce concepts of tissue engineering as a novel perspective to model, capture, and study complex cancer-microenvironment interactions. [ABSTRACT FROM AUTHOR]

Prostate cancer is initially regulated by the androgen receptor (AR), a ligand-activated, transcription factor, and is in a hormone-dependent state (hormone-sensitive prostate cancer (HSPC)), but eventually becomes androgen-refractory (castration- resistant prostate cancer (CRPC)) because of mechanisms that bypass the AR, including by activation of ErbB3, a member of the epidermal growth factor receptor family. ErbB3 is synthesized in the cytoplasm and transported to the plasma membrane for ligand binding and dimerization, where it regulates downstream signaling, but nuclear forms are reported. Here, we demonstrate in prostatectomy samples that ErbB3 nuclear localization is observed in malignant, but not benign prostate, and that cytoplasmic (but not nuclear) ErbB3 correlated positively with AR expression but negatively with AR transcriptional activity. In support of the latter, androgen depletion upregulated cytoplasmic, but not nuclear ErbB3, while in vivo studies showed that castration suppressed ErbB3 nuclear localization in HSPC, but not CRPC tumors. In vitro treatment with the ErbB3 ligand heregulin-1β (HRG) induced ErbB3 nuclear localization, which was androgen-regulated in HSPC but not in CRPC. In turn, HRG upregulated AR transcriptional activity in CRPC but not in HSPC cells. Positive correlation between ErbB3 and AR expression was demonstrated in AR-null PC-3 cells where stable transfection of AR restored HRG-induced ErbB3 nuclear transport, while AR knockdown in LNCaP reduced cytoplasmic ErbB3. Mutations of ErbB3’s kinase domain did not affect its localization but was responsible for cell viability in CRPC cells. Taken together, we conclude that AR expression regulated ErbB3 expression, its transcriptional activity suppressed ErbB3 nuclear translocation, and HRG binding to ErbB3 promoted it. [ABSTRACT FROM AUTHOR]

Graphical abstract A new fluorescent rhenium(I) carbonyl complex 1 , bearing {Re(CO) 3 }+ core with ONS donor thioether containing redox noninnocent azo-phenol ligand has been synthesized and characterized. The distorted octahedral geometry of the complex is confirmed by X-ray structure. The complex exhibits low energy emission band at 525 nm with high emission quantum yield (ϕ = 0.115). Cytotoxicity of the complex is studied by MTT method with human breast cancer cell lines (MCF-7) and IC 50 value is found to be 23.6 μM. In presence of the complex (10 μM) a bright green fluorescence image of MCF-7 cell lines is observed under fluorescence microscope. Abstract Herein, we have synthesized a new fluorescent rhenium(I) carbonyl complex 1 , bearing {Re(CO) 3 }+ core with ONS donor thioether containing azo-phenol redox noninnocent ligand. The distorted octahedral geometry of the complex is confirmed by single crystal X-ray diffraction method. Cyclic voltammogram in acetonitrile exhibits irreversible oxidation peak (E pa = 1.36 V) along with quasi-reversible reduction peak at E 1/2 = −0.92 V (Δ E = 210 mV). The complex exhibits low energy emission band at 525 nm with high emission quantum yield (ϕ = 0.115). Cytotoxicity of the complex is studied by MTT method with human breast cancer cell lines (MCF-7) and IC 50 value is found to be 23.6 μM. In presence of the complex (10 μM) a bright green fluorescence image of MCF-7 cell lines is observed under fluorescence microscope. [ABSTRACT FROM AUTHOR]

Multiple risk factors have been associated with bladder cancer. This review focuses on pesticide exposure, as it is not currently known whether agricultural products have a direct or indirect effect on bladder cancer, despite recent reports demonstrating a strong correlation. While it is known that pesticide exposure is associated with an increased risk of bladder cancer in humans and dogs, the mechanism(s) by which specific pesticides cause bladder cancer initiation or progression is unknown. In this narrative review, we discuss what is currently known about pesticide exposure and the link to bladder cancer. This review highlights multiple pathways modulated by pesticide exposure with direct links to bladder cancer oncogenesis/metastasis (MMP-2, TGF-β, STAT3) and chemoresistance (drug efflux, DNA repair, and apoptosis resistance) and potential therapeutic tactics to counter these pesticide-induced affects. [ABSTRACT FROM AUTHOR]

Cisplatin-based combination chemotherapy is the foundation for treatment of advanced bladder cancer (BlCa), but many patients develop chemoresistance mediated by increased Akt and ERK phosphorylation. However, the mechanism by which cisplatin induces this increase has not been elucidated. Among six patient-derived xenograft (PDX) models of BlCa, we observed that the cisplatin-resistant BL0269 express high epidermal growth factor receptor, ErbB2/HER2 and ErbB3/HER3. Cisplatin treatment transiently increased phospho-ErbB3 (Y1328), phospho-ERK (T202/Y204) and phospho-Akt (S473), and analysis of radical cystectomy tissues from patients with BlCa showed correlation between ErbB3 and ERK phosphorylation, likely due to the activation of ERK via the ErbB3 pathway. In vitro analysis revealed a role for the ErbB3 ligand heregulin1-β1 (HRG1/NRG1), which is higher in chemoresistant lines compared to cisplatin-sensitive cells. Additionally, cisplatin treatment, both in PDX and cell models, increased HRG1 levels. The monoclonal antibody seribantumab, that obstructs ErbB3 ligand-binding, suppressed HRG1-induced ErbB3, Akt and ERK phosphorylation. Seribantumab also prevented tumor growth in both the chemosensitive BL0440 and chemoresistant BL0269 models. Our data demonstrate that cisplatin-associated increases in Akt and ERK phosphorylation is mediated by an elevation in HRG1, suggesting that inhibition of ErbB3 phosphorylation may be a useful therapeutic strategy in BlCa with high phospho-ErbB3 and HRG1 levels. [ABSTRACT FROM AUTHOR]

Contribution of genes in attention deficit hyperactivity disorder (ADHD) has been explored in various populations, and several genes were speculated to contribute small but additive effects. We have assessed variants in four genes, DDC (rs3837091 and rs3735273), DRD2 (rs1800496, rs1801028, and rs1799732), DRD4 (rs4646984 and rs4646983), and COMT (rs165599 and rs740603) in Indian ADHD subjects with comorbid attributes. Cases were recruited following the Diagnostic and Statistical Manual for Mental Disorders-IV-TR after obtaining informed written consent. DNA isolated from peripheral blood leukocytes of ADHD probands (N = 170), their parents (N = 310), and ethnically matched controls (n = 180) was used for genotyping followed by populationand family-based analyses by the UNPHASED program. DRD4 sites showed significant difference in allelic frequencies by casecontrol analysis, while DDC and COMT exhibited bias in familial transmission (P < 0.05). rs3837091 "AGAG," rs3735273 "A," rs1799732 "C," rs740603 "G," rs165599 "G" and single repeat alleles of rs4646984/rs4646983 showed positive correlation with comorbid characteristics (P < 0.05). Multi dimensionality reduction analysis of case-control data revealed significant interactive effects of all four genes (P < 0.001), whilefamily-baseddatashowedinteractionbetweenDDCandDRD2(_P = 0.04). This first study on these gene variants in Indo-Caucasoid ADHD probands and associated co-morbid conditions indicates altered dopaminergic neurotransmission in ADHD. [ABSTRACT FROM AUTHOR]

The observed sex disparity in bladder cancer (BlCa) argues that androgen receptor (AR) signaling has a role in these malignancies. BlCas express full-length AR (FL-AR), constitutively active AR splice variants, including AR-v19, or both, and their depletion limits BlCa viability. However, the mechanistic basis of AR-dependence is unknown. Here, we depleted FL-AR, AR-v19, or all AR forms (T-AR), and performed RNA-seq studies to uncover that different AR forms govern distinct but partially overlapping transcriptional programs. Overlapping alterations include a decrease in mTOR and an increase of hypoxia regulated transcripts accompanied by a decline in oxygen consumption rate (OCR). Queries of BlCa databases revealed a significant negative correlation between AR expression and multiple hypoxia-associated transcripts arguing that this regulatory mechanism is a feature of high-grade malignancies. Our analysis of a 1600-compound library identified niclosamide as a strong ATPase inhibitor that reduces OCR in BlCa cells, decreased cell viability and induced apoptosis in a dose and time dependent manner. These results suggest that BlCa cells hijack AR signaling to enhance metabolic activity, promoting cell proliferation and survival; hence targeting this AR downstream vulnerability presents an attractive strategy to limit BlCa. [ABSTRACT FROM AUTHOR]

Association of dopaminergic genes, mainly receptors and transporters, with Attention Deficit Hyperactivity Disorder (ADHD) has been investigated throughout the world due to the importance of dopamine (DA) in various physiological functions including attention, cognition and motor activity, traits. However, till date, etiology of ADHD remains unknown. We explored association of functional variants in the DA receptor 2 (rs1799732 and rs6278), receptor 4 (exon 3 VNTR and rs914655), and transporter (rs28363170 and rs3836790) with hyperactivity, cognitive deficit, and co-morbid disorders in eastern Indian probands. Diagnostic and Statistical Manual for Mental Disorders-IV was followed for recruitment of nuclear families with ADHD probands ( N = 160) and ethnically matched controls ( N = 160). Cognitive deficit and hyperactive traits were measured using Conner's parents/teachers rating scale. Peripheral blood was collected after obtaining informed written consent and used for genomic DNA isolation. Genetic polymorphisms were analyzed by PCR-based methods followed by population- as well as family-based statistical analyses. Association between genotypes and cognitive/hyperactivity traits and co-morbidities was analyzed by the Multifactor dimensionality reduction (MDR) software. Case-control analysis showed statistically significant difference for rs6278 and rs28363170 ( P = 0.004 and 1.332e−007 respectively) while family-based analysis exhibited preferential paternal transmission of rs28363170 '9R' allele ( P = 0.04). MDR analyses revealed independent effects of rs1799732, rs6278, rs914655, and rs3836790 in ADHD. Significant independent effects of different sites on cognitive/hyperactivity traits and co-morbid disorders were also noticed. It can be summarized from the present investigation that these gene variants may influence cognitive/hyperactive traits, thereby affecting the disease etiology and associated co-morbid features. [ABSTRACT FROM AUTHOR]

Synaptosomal-associated protein 25 (SNAP25) is an essential component for synaptic vesicle mediated release of neurotransmitters. Deficiencies or abnormal structure or function of SNAP25 protein, possibly arising through genetic variations in the relevant DNA code, has been suggested to play role in the pathology of several neurobehavioural disorders including Attention deficit Hyperactivity Disorder (ADHD) and a number of polymorphisms in the SNAP25 gene has been studied for association with the disorder. In the present investigation, for the first time association between ADHD and six SNAP25 polymorphisms, rs1889189, rs362569, rs362988, rs3746544, rs1051312, and rs8636 was explored in eastern Indian population. Subjects were recruited following the Diagnostic and Statistical Manual for Mental Disorders-IV. Genomic DNA isolated from peripheral blood leukocytes of ADHD probands (n = 150), their parents (n = 272) and ethnically matched controls (n = 100) was used for amplifying target sites. Data obtained were subjected to population- as well as family-based analyses. While case-control analysis revealed lack of any significant difference for alleles, family-based studies revealed a mild over transmission rs3746544 'T' and rs8636 'C' alleles ( P = 0.05 and 0.03 respectively). Haplotypes formed between rs362569 'T', 362988 'G', rs3746544 'T', rs1051312 'T' and rs8636 'C' in different combinations showed statistically significant transmission to ADHD probands. Excepting rs3746544 and rs8636, all the tested sites showed very low linkage disequilibrium between them. Data obtained in this preliminary study indicates that rs3746544 'T' allele may have some role in the disease etiology in the studied Indian population. [ABSTRACT FROM AUTHOR]

Extracellular nano vesicles and exosomes hold compelling evidence in intercellular communication. Exosomal intracellular signal transduction is mediated by the transfer of cargo proteins, lipids, micro (mi)RNAs, long noncoding (lnc)RNAs, small interfering (si)RNAs, DNA, and other functional molecules that play a pivotal role in regulating tumor growth and metastasis. However, emerging research trends indicate that exosomes may be used as a promising tool in anticancer treatment. This review features a majority of the bioengineering applications of fabricated exosomal cargoes. It also encompasses how the manipulation and delivery of specific cargoes--noncoding RNAs (ncRNAs), recombinant proteins, immune-modulators, chemotherapeutic drugs, and other small molecules--may serve as a precise therapeutic approach in cancer management. [ABSTRACT FROM AUTHOR]

Collective behaviour of a crown ether channel, bis[(benzo-15-crown-5)-15-yl methyl] pimelate, in a planar lipid bilayer membrane has been studied through electrophysiological methods. A characteristic feature of these channels is their sequential opening, indicated by a uniform stepwise increase in the multi-channel current. The experimental results show that there are three modes of relaxation, of which the slowest one is attributed to the channel–channel interaction. The latter varies with the number of channels incorporated in the bilayer membrane, leading to the interpretation that crown channels behave cooperatively. [ABSTRACT FROM AUTHOR]

Bladder cancer (BlCa) exhibits a gender disparity where men are three times more likely to develop the malignancy than women suggesting a role for the androgen receptor (AR). Here we report that BlCa cells express low molecular weight (LMW) AR isoforms that are missing the ligand binding domain (LBD). Isoform expression was detected in most BlCa cells, while a few express the full-length AR. Immunofluorescence studies detect AR in the nucleus and cytoplasm, and localization is cell dependent. Cells with nuclear AR expression exhibit reduced viability and increased apoptosis on total AR depletion. A novel AR-LMW variant, AR-v19, that is missing the LBD and contains 15 additional amino acids encoded by intron 3 sequences was detected in most BlCa malignancies. AR-v19 localizes to the nucleus and can transactivate AR-dependent transcription in a dose dependent manner. AR-v19 depletion impairs cell viability and promotes apoptosis in cells that express this variant. Thus, AR splice variant expression is common in BlCa and instrumental in ensuring cell survival. This suggests that targeting AR or AR downstream effectors may be a therapeutic strategy for the treatment of this malignancy. [ABSTRACT FROM AUTHOR]

A new fluorescent Rh(III) cyclometalated complex, [Rh(PPh 3) 2 (L)Cl] (1) is synthesized via sp2(C)–S bond activation of a thioether containing azo-phenol ligand (L-SCH 2 CH 3). The pseudo octahedral geometry around rhodium is confirmed by single crystal X-ray diffraction method. Cyclic voltammogram of the complex exhibits a quasi-reversible oxidation couple with E 1/2 of 0.74 V (ΔE = 100 mV) along with a quasi-reversible reduction couple (E 1/2 = −1.18 V, ΔE = 130 mV) in acetonitrile. The complex exhibits low energy emission band at 682 nm with emission quantum yield (ϕ = 0.103) upon excitation at 583 nm. Cytotoxicity of the complex is studied by MTT method with human breast cancer cell lines and IC 50 value is found to 18.5 μM. In presence of the complex (10 μ M) a bright red fluorescence image of MCF-7 cell lines is observed under fluorescence microscope. Moreover, the complex acts as effective catalyst towards transfer hydrogenation of ketones. A new fluorescent Rh(III) cyclometalated complex, [Rh(PPh 3) 2 (L)Cl] (1) has been synthesized via sp2(C)–S bond activation of a thioether containing azo-phenol ligand (L-SCH 2 CH 3). The complex exhibits low energy emission band at 682 nm with high emission quantum yield (ϕ = 0.103). In presence of the complex a bright red fluorescence image of MCF-7 cell lines is observed under fluorescence microscope. Catalytic activity of complex 1 towards transfer hydrogenation of ketones is studied. Image 1050165 • New Rh(III) cyclometalated complex, [Rh(PPh 3) 2 (L)Cl] (1) is synthesized via sp2(C)–S bond activation. • The complex exhibits low energy emission band at 682 nm with emission quantum yield, ϕ = 0.103 upon excitation at 583 nm. • Cytotoxicity of the complex is studied by MTT method with MCF-7 cell lines and IC 50 value is found to 18.5 μM. • In presence of the complex, a bright red fluorescence image of MCF-7 cell lines is observed under fluorescence microscope. • The catalytic activity towards transfer hydrogenation of ketones is studied. [ABSTRACT FROM AUTHOR]

• Herein, we report the synthesis and cation sensing properties of a new fluorescence reversible "turn-on" probe (HCBP). • HCBP selectively detects Al3+ in aqueous methanol medium at physiological pH with the enhancement of emission intensity. • Limit of detection (LOD) of the probe towards Al3+ is found to be in the order of 10-9 M. • Electronic structure and sensing mechanism of the probe is interpreted by DFT calculations. • The fluorescence imaging is performed using gastric cancer cells (AGS). A new coumarin based fluorescent switch (HCBP) has been fabricated which displays high selective sensing towards Al3+ among other metal cations at physiological pH. On gradual addition of Al3+ specifically, HCBP shows a brilliant "turn-on" emission enhancement of about ∼13-fold with about 50 nm red shift at 481 nm in MeOH/H 2 O (1/1, v/v) solution. The fluorescent switch is proven to be a reversible probe by addition of EDTA gradually into the HCBP-Al3+ solution. Detection limit as well as Binding constant values have been calculated and found to be in the order of 10−9 M and 103 M-1 respectively. DFT and TDDFT studies are conducted with the probe to establish a similarity between theoretical and experimental outcomes. We can also use this new fluorescent switch as a biomarker kit as it has shown a brilliant potential in the application of live cell imaging using gastric cancer cell (AGS cell). [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is characterized by a unique dependence on optimal androgen receptor (AR) activity where physiological androgen concentrations induce proliferation but castrate and supraphysiological levels suppress growth. This feature has been exploited in bipolar androgen therapy (BAT) for castrate resistant malignancies. Here, we investigated the role of the tumor suppressor protein p14ARF in maintaining optimal AR activity and the function of the AR itself in regulating p14ARF levels. We used a tumor tissue array of differing stages and grades to define the relationships between these components and identified a strong positive correlation between p14ARF and AR expression. Mechanistic studies utilizing CWR22 xenograft and cell culture models revealed that a decrease in AR reduced p14ARF expression and deregulated E2F factors, which are linked to p14ARF and AR regulation. Chromatin immunoprecipitation studies identified AR binding sites upstream of p14ARF. p14ARF depletion enhanced AR-dependent PSA and TMPRSS2 transcription, hence p14ARF constrains AR activity. However, p14ARF depletion ultimately results in apoptosis. In PCa cells, AR co-ops p14ARF as part of a feedback mechanism to ensure optimal AR activity for maximal prostate cancer cell survival and proliferation. [ABSTRACT FROM AUTHOR]

Background: Despite overexpression of the ErbB (EGFR/HER2/ErbB3/ErbB4) family in castration-resistant prostate cancer (CRPC), some inhibitors of this family, including the dual EGFR/HER2 inhibitor lapatinib, failed in Phase II clinical trials. Hence, we investigated mechanisms of lapatinib resistance to determine whether alternate ErbB inhibitors can succeed.Methods: The CWR22 human tumour xenograft and its CRPC subline 22Rv1 and sera from lapatinib-treated CRPC patients from a previously reported Phase II trial were used to study lapatinib resistance. Mechanistic studies were conducted in LNCaP, C4-2 and 22Rv1 cell lines.Results: Lapatinib increased intratumoral HER2 protein, which encouraged resistance to this treatment in mouse models. Sera from CRPC patients following lapatinib treatment demonstrated increased HER2 levels. Investigation of the mechanism of lapatinib-induced HER2 increase revealed that lapatinib promotes HER2 protein stability, leading to membrane localisation, EGFR/HER2 heterodimerisation and signalling, elevating cell viability. Knockdown of HER2 and ErbB3, but not EGFR, sensitised CRPC cells to lapatinib. At equimolar concentrations, the recently FDA-approved pan-ErbB inhibitor dacomitinib decreased HER2 protein stability, prevented ErbB membrane localisation (despite continued membrane integrity) and EGFR/HER2 heterodimerisation, thereby decreasing downstream signalling and increasing apoptosis.Conclusions: Targeting the EGFR axis using the irreversible pan-ErbB inhibitor dacomitinib is a viable therapeutic option for CRPC. [ABSTRACT FROM AUTHOR]

A new ESIPT based fluorescent probe has been introduced for selective detection of Zn2+ in human breast cancer cells. The designed probe exhibits a prominent ratiometric fluorescence change along with a sharp blue shift of ∼71 nm which can be attributed to the hampering of the ESIPT process. The probe is efficient enough to detect Zn2+ solely in the presence of other biologically relevant cations with a limit of detection value of 1.6 × 10−7 M. The experimentally observed changes in the structure and absorption properties of the probe after complete addition of Zn2+ were further studied by density functional theory (DFT) and time dependent density functional theory (TDDFT) calculations. Moreover, the dip-stick experiment with this probe displays both absorption and fluorescence color changes after exposure to Zn2+ which also turns out to be a potential application for the probe. Live cell imaging studies have been carried out using human breast cancer cells (MCF-7) and tissues. [ABSTRACT FROM AUTHOR]

Increased β-adrenergic receptor (β-AR)-mediated activation of adenylyl cyclase (AC) in rat liver during aging has been linked to age-related increases in hepatic glucose output and hepatosteatosis. In this study, we investigated the expression of β-ARs, individual receptor subtypes, and G protein-coupled receptor (GPCR) regulatory proteins in livers from aging rats. Radioligand-binding studies demonstrated that β-AR density increased by greater than threefold in hepatocyte membranes from senescent (24-mo-old) compared with young adult (7-mo-old) rats and that this phenomenon was blocked by food restriction, which is known to retard aging processes in rodents. Competition-binding studies revealed a mixed population of β1- and β2-AR subtypes in liver membranes over the adult life span, with a trend for greater β2-AR density with age. Expression of both β-AR subtype mRNAs in rat liver increased with age, whereas β2- but not β1-AR protein levels declined in livers of old animals. Immunoreactive β2- but not β1-ARs were preferentially distributed in pericentral hepatic regions. Levels of GRK2/3 and β-arrestin 2 proteins, which are involved in downregulation of agonist-activated GPCRs, including β-ARs, increased during aging. Insofar as sympathetic tone increases with age, our findings suggest that, despite enhanced agonist-mediated downregulation of hepatic β-ARs preferentially affecting the β2-AR subtype, increased generation of both receptor subtypes during aging augments the pool of plasma membrane-bound β-ARs coupled to AC in hepatocytes. This study thus identifies one or both β-AR subtypes as possible therapeutic targets involved in aberrant hepatic processes of glucose and lipid metabolism during aging. [ABSTRACT FROM AUTHOR]

A novel coumarin based azo-phenol ligand (H 2 L) has been synthesized and characterized by several spectroscopic techniques. An almost 16 fold enhancement of emission intensity has been observed upon gradual addition of Mg 2+ to H 2 L in DMSO:H 2 O (1:5 v/v) medium while it has no significant effect in emission intensity even in presence of other metal ions. The emission intensity of L-Mg 2+ complex has almost quenched on gradual addition of F − to it. The limit of detection for both Mg 2+ and F − are of 10 −8 M order, hence the newly developed chemosensor is highly efficient in detecting Mg 2+ and F − in very minute levels. The chemosensor can even detect Mg 2+ in the intracellular region of human lung cancer cells (A549 cells). [ABSTRACT FROM AUTHOR]