Tunable optical bistability of two-dimensional tilted Dirac system.

We study the phenomenon of controlling the light by light known as the optical bistability for the two-dimensional tilted Dirac system. Using the Boltzmann approach under relaxation time approximation, we find that the optical bistability can be controlled by the nonlinear response of the system. For the prototype, we consider an inversion symmetry broken system. We find that the optical bistability associated with the nonlinear response is tunable with the strength of the tilt, gap and chemical potential. The resulting features suggest the inputs for the development of future-generation optical devices.

Resonant Second-Harmonic Generation as a Probe of Quantum Geometry.

Nonlinear responses are actively studied as probes of topology and band geometric properties of solids. Here, we show that second harmonic generation serves as a probe of the Berry curvature, quantum metric, and quantum geometric connection. We generalize the theory of second harmonic generation to include Fermi surface effects in metallic systems, and finite scattering timescale. In doped materials the Fermi surface and Fermi sea cause all second harmonic terms to exhibit resonances, and we identify two novel contributions to the second harmonic signal: a double resonance due to the Fermi surface and a higher-order pole due to the Fermi sea. We discuss experimental observation in the monolayer of time reversal symmetric Weyl semimetal WTe_{2} and the parity-time reversal symmetric topological antiferromagnet CuMnAs.

Therapeutic Targeting of EZH2 and BET BRD4 in Pediatric Rhabdoid Tumors.

Aberrant activity of the H3K27 modifiers EZH2 and BRD4 is an important oncogenic driver for atypical teratoid/rhabdoid tumor (AT/RT), and each is potentially a possible therapeutic target for treating AT/RT. We, therefore, determined whether targeting distinct histone modifier activities was an effective approach for treating AT/RT. The effects of EZH2 and BRD4 inhibition on histone modification, cell proliferation, and cell invasion were analyzed by immunoblotting, MTS assay, colony formation assay, and cell invasion assay. RNA- and chromatin immunoprecipitation-sequencing were used to determine transcriptional and epigenetic changes in AT/RT cells treated with EZH2 and BRD4 inhibitors. We treated mice bearing human AT/RT xenografts with EZH2 and BRD4 inhibitors. Intracranial tumor growth was monitored by bioluminescence imaging, and the therapeutic response was evaluated by animal survival. AT/RT cells showed elevated levels of H3K27 trimethylation (H3K27me3) and H3K27 acetylation (H3K27ac), with expression of EZH2 and BRD4, and lack of SMARCB1 proteins. Targeted inhibition of EZH2 and BRD4 activities reduced cell proliferation and invasiveness of AT/RT in association with decreasing H3K27me3 and H3K27ac. Differential genomic occupancy of H3K27me3 and H3K27ac regulated specific gene expression in response to EZH2 and BRD4 inhibitions. A combination of EZH2 and BRD4 inhibition increased the therapeutic benefit in vitro and in vivo, outperforming either monotherapy. Overall, histones H3K27me3 and H3K27ac were elevated in AT/RT cells and distributed in distinct chromatin regions to regulate specific gene expression and to promote AT/RT growth. Targeting EZH2 and BRD4 activity is, therefore, a potential combination therapy for AT/RT.

Nonlinear Ballistic Response of Quantum Spin Hall Edge States.

Topological edge states (TES) exhibit dissipationless transport, yet their dispersion has never been probed. Here we show that the nonlinear electrical response of ballistic TES ascertains the presence of symmetry breaking terms, such as deviations from nonlinearity and tilted spin quantization axes. The nonlinear response stems from discontinuities in the band occupation on either side of a Zeeman gap, and its direction is set by the spin orientation with respect to the Zeeman field. We determine the edge dispersion for several classes of TES and discuss experimental measurement.

Generating a Topological Anomalous Hall Effect in a Nonmagnetic Conductor: An In-Plane Magnetic Field as a Direct Probe of the Berry Curvature.

We demonstrate that the Berry curvature monopole of nonmagnetic two-dimensional spin-3/2 holes leads to a novel Hall effect linear in an applied in-plane magnetic field B_{∥}. Remarkably, all scalar and spin-dependent disorder contributions vanish to leading order in B_{∥}, while there is no Lorentz force and hence no ordinary Hall effect. This purely intrinsic phenomenon, which we term the anomalous planar Hall effect (APHE), provides a direct transport probe of the Berry curvature accessible in all p-type semiconductors. We discuss experimental setups for its measurement.

Optical phonon contribution to the thermal conductivity of a quantum paraelectric.

Motivated by recent experimental findings, we study the contribution of a quantum critical optical phonon branch to the thermal conductivity of a paraelectric system. We consider the proximity of the optical phonon branch to transverse acoustic phonon branch and calculate its contribution to the thermal conductivity within the Kubo formalism. We find a low temperature power law dependence of the thermal conductivity asTα, with 1 <α< 2, (lower thanT3behavior) due to optical phonons near the quantum critical point. This result is in accord with the experimental findings and indicates the importance of quantum fluctuations in the thermal conduction in these materials.

Resonant Photovoltaic Effect in Doped Magnetic Semiconductors.

The rectified nonlinear response of a clean, time-reversal symmetric, undoped semiconductor to an ac electric field includes a well known intrinsic shift current. We show that when Kramers degeneracy is broken, a distinct second order rectified response appears due to Bloch state anomalous velocities in a system with an oscillating Fermi surface. This effect, which we refer to as the resonant photovoltaic effect, produces a resonant galvanic current peak at the interband absorption threshold in doped semiconductors or semimetals with approximate particle-hole symmetry. We evaluate the resonant photovoltaic effect for a model of the surface states of a magnetized topological insulator.

Deletion of the glucocorticoid receptor chaperone FKBP51 prevents glucocorticoid-induced skin atrophy.

FKBP51 (FK506-binding protein 51) is a known co-chaperone and regulator of the glucocorticoid receptor (GR), which usually attenuates its activity. FKBP51 is one of the major GR target genes in skin, but its role in clinical effects of glucocorticoids is not known. Here, we used FKBP51 knockout (KO) mice to determine FKBP51's role in the major adverse effect of topical glucocorticoids, skin atrophy. Unexpectedly, we found that all skin compartments (epidermis, dermis, dermal adipose and CD34+ stem cells) in FKBP51 KO animals were much more resistant to glucocorticoid-induced hypoplasia. Furthermore, despite the absence of inhibitory FKBP51, the basal level of expression and glucocorticoid activation of GR target genes were not increased in FKBP51 KO skin or CRISPR/Cas9-edited FKBP51 KO HaCaT human keratinocytes. FKBP51 is known to negatively regulate Akt and mTOR. We found a significant increase in AktSer473 and mTORSer2448 phosphorylation and downstream pro-growth signaling in FKBP51-deficient keratinocytes in vivo and in vitro. As Akt/mTOR-GR crosstalk is usually negative in skin, our results suggest that Akt/mTOR activation could be responsible for the lack of increased GR function and resistance of FKBP51 KO mice to the steroid-induced skin atrophy.

Rapamycin Modulates Glucocorticoid Receptor Function, Blocks Atrophogene REDD1, and Protects Skin from Steroid Atrophy.

Glucocorticoids have excellent therapeutic properties; however, they cause significant adverse atrophogenic effects. The mTORC1 inhibitor REDD1 has been recently identified as a key mediator of glucocorticoid-induced atrophy. We performed computational screening of a connectivity map database to identify putative REDD1 inhibitors. The top selected candidates included rapamycin, which was unexpected because it inhibits pro-proliferative mTOR signaling. Indeed, rapamycin inhibited REDD1 induction by glucocorticoids dexamethasone, clobetasol propionate, and fluocinolone acetonide in keratinocytes, lymphoid cells, and mouse skin. We also showed blunting of glucocorticoid-induced REDD1 induction by either catalytic inhibitor of mTORC1/2 (OSI-027) or genetic inhibition of mTORC1, highlighting role of mTOR in glucocorticoid receptor signaling. Moreover, rapamycin inhibited glucocorticoid receptor phosphorylation, nuclear translocation, and loading on glucocorticoid-responsive elements in REDD1 promoter. Using microarrays, we quantified a global effect of rapamycin on gene expression regulation by fluocinolone acetonide in human keratinocytes. Rapamycin inhibited activation of glucocorticoid receptor target genes yet enhanced the repression of pro-proliferative and proinflammatory genes. Remarkably, rapamycin protected skin against glucocorticoid-induced atrophy but had no effect on the glucocorticoid anti-inflammatory activity in different in vivo models, suggesting the clinical potential of combining rapamycin with glucocorticoids for the treatment of inflammatory diseases.

Important role of kallikrein 6 for the development of keratinocyte proliferative resistance to topical glucocorticoids.

One of the major adverse effects of topical glucocorticoids is cutaneous atrophy often followed by development of resistance to steroids (tachyphylaxis). Previously we showed that after two weeks, interfollicular mouse keratinocytes acquired resistance to anti-proliferative effects of glucocorticoid fluocinolone acetonide (FA). One of the top genes activated by FA during tachyphylaxis was Klk6 encoding kallikrein-related peptidase 6, known to enhance keratinocyte proliferation. KLK6 was also strongly induced by chronic glucocorticoids in human skin. Double immunostaining showed that KLK6+ keratinocytes, localized in suprabasal layer of mouse skin, were frequently adjacent to proliferating 5-bromo-2'-deoxyuridine-positive basal keratinocytes. We used KLK6 knockout (KO) mice to evaluate KLK6 role in skin regeneration after steroid-induced atrophy. KLK6 KOs had thinner epidermis and decreased keratinocyte proliferation. The keratinocytes in wild type and KLK6 KO epidermis were equally sensitive to acute anti-proliferative effect of FA. However, the development of proliferative resistance during chronic treatment was reduced in KO epidermis. This was not due to the changes in glucocorticoid receptor (GR) expression or function as GR protein level and induction of GR-target genes were similar in wild type and KLK6 KO skin. Overall, these results suggest a novel mechanism of epidermal regeneration after glucocorticoid-induced atrophy via KLK6 activation.

REDD1 functions at the crossroads between the therapeutic and adverse effects of topical glucocorticoids.

Cutaneous atrophy is the major adverse effect of topical glucocorticoids; however, its molecular mechanisms are poorly understood. Here, we identify stress-inducible mTOR inhibitor REDD1 (regulated in development and DNA damage response 1) as a major molecular target of glucocorticoids, which mediates cutaneous atrophy. In REDD1 knockout (KO) mice, all skin compartments (epidermis, dermis, subcutaneous fat), epidermal stem, and progenitor cells were protected from atrophic effects of glucocorticoids. Moreover, REDD1 knockdown resulted in similar consequences in organotypic raft cultures of primary human keratinocytes. Expression profiling revealed that gene activation by glucocorticoids was strongly altered in REDD1 KO epidermis. In contrast, the down-regulation of genes involved in anti-inflammatory glucocorticoid response was strikingly similar in wild-type and REDD1 KO mice. Integrative bioinformatics analysis of our and published gene array data revealed similar changes of gene expression in epidermis and in muscle undergoing glucocorticoid-dependent and glucocorticoid-independent atrophy. Importantly, the lack of REDD1 did not diminish the anti-inflammatory effects of glucocorticoids in preclinical model. Our findings suggest that combining steroids with REDD1 inhibitors may yield a novel, safer glucocorticoid-based therapies.

Selective Activator of the Glucocorticoid Receptor Compound A Dissociates Therapeutic and Atrophogenic Effects of Glucocorticoid Receptor Signaling in Skin.

BACKGROUND: Glucocorticoids are effective anti-inflammatory drugs widely used in dermatology and for the treatment of blood cancer patients. Unfortunately, chronic treatment with glucocorticoids results in serious metabolic and atrophogenic adverse effects including skin atrophy. Glucocorticoids act via the glucocorticoid receptor (GR), a transcription factor that causes either gene transactivation (TA) or transrepression (TR). Compound A (CpdA), a novel non-steroidal GR ligand, does not promote GR dimerization and TA, retains anti-inflammatory potential but induces fewer metabolic side effects compared to classical glucocorticoids when used systemically. As topical effects of CpdA have not been well studied, this work goal was to compare the anti-inflammatory and side effects of topical CpdA and glucocorticoids and to assess their effect on GR TA and TR in keratinocytes. METHODS: We used murine immortalized keratinocytes and F1 C57BlxDBA mice. Effect of glucocorticoid fluocinolone acetonide (FA) and CpdA on gene expression in keratinocytes in vitro and in vivo was evaluated by reverse transcription-PCR. The anti-inflammatory effects were assessed in the model of tumor promoter 12-O-tertradecanoyl-acetate (TPA)-induced dermatitis and in croton oil-induced ear edema test. Skin atrophy was assessed by analysis of epidermal thickness, keratinocyte proliferation, subcutaneous adipose hypoplasia, and dermal changes after chronic treatment with FA and CpdA. RESULTS: In mouse keratinocytes in vitro and in vivo, CpdA did not activate GR-dependent genes but mimicked closely the inhibitory effect of glucocorticoid FA on the expression of inflammatory cytokines and matrix metalloproteinases. When applied topically, CpdA inhibited TPA-induced skin inflammation and hyperplasia. Unlike glucocorticoids, CpdA itself did not induce skin atrophy which correlated with lack of induction of atrophogene regulated in development and DNA damage response 1 (REDD1) causatively involved in skin and muscle steroid-induced atrophy. CONCLUSIONS: Overall, our results suggest that CpdA and its derivatives represent novel promising class of anti-inflammatory compounds with reduced topical side effects.

Synchronous hepatocellular carcinoma with renal cell carcinoma: a case report and review of literature of multiple synchronous primary malignancies.

Multiple synchronous primary malignancies have been reported since the 19th century. A number of proposed theories as to the predisposing factors have been discussed. The criteria to diagnose multiple primary malignancies have been revised by Warren and Gates. We hereby present a case of an asymptomatic individual detected with a synchronous hepatocellular carcinoma and a renal cell carcinoma, its presentation, diagnosis, and the management. The occurrence of synchronous hepatocellular carcinoma with renal cell carcinoma is very rare and only a few cases have been reported. Synchronous extrahepatic primary malignancies have been reported in a few studies across the world though with a varied incidence rate. The occurrence seems to be in the older age group without gender differentiation. The extrahepatic malignancies were more common in cirrhotic livers though the overall survival does not differ between patients with hepatocellular carcinoma alone and hepatocellular carcinoma with synchronous extrahepatic malignancies.

Neuroendocrine tumor of common hepatic duct.

Extrahepatic bile ducts (EHBD) remain one of the rarest primary sites for neuroendocrine tumors (NETs) accounting for 0.1 % to 0.2 % of all NETs of the gastrointestinal tract. We present one such case, a 28-year-old female with vague abdominal symptoms and periportal lymph node enlargement on radiological examination. Endoscopic retrograde cholangiopancreaticography revealed 1.5 cms long common hepatic duct stricture and brush cytology showed no malignant cells. Endoscopic ultrasound guided fine needle aspiration cytology from the lymph nodes reported malignant cells. Roux-en-Y hepaticojejunostomy with excision of the extrahepatic biliary tree and radical lymphadenectomy was done. The diagnosis of well-differentiated neuroendocrine carcinoma was confirmed on histological and immunohistochemical studies. NETs of biliary tract are difficult to diagnose preoperatively. The aggressive use of curative and cytoreductive surgery is the frontline of treatment. But the rare alternative diagnosis of NETs should be kept in mind by the surgeon for proper timely management.

Differential targeting of androgen and glucocorticoid receptors induces ER stress and apoptosis in prostate cancer cells: a novel therapeutic modality.

Androgen (AR) and glucocorticoid (GR) receptor signaling play opposing roles in prostate tumorigenesis: in prostate, AR acts as an oncogene, and GR is a tumor suppressor. Recently, we found that non-steroidal phyto-chemical Compound A (CpdA) is AR/GR modulator acting as anti-inflammatory anti-androgen. CpdA inhibits AR and prevents GR transactivation while enhancing GR transrepression. GR and AR are controlled by proteasomal degradation. We found that prolonged exposure of LNCaP, LNCaP-GR, DU145 and PC3 prostate carcinoma (PCa) cells to proteasome inhibitor Bortezomib (BZ) caused AR degradation and GR accumulation. BZ enhanced CpdA ability to inhibit AR and to augment GR transrepression. We also found that CpdA+BZ differentially regulated GR/AR to cooperatively suppress PCa cell growth and survival and to induce endoplasmic reticulum stress (ERS). Importantly, CpdA+BZ differentially regulated GR-responsive genes. CpdA+BZ blocked activation of glucocorticoid-responsive pro-survival genes, including SGK1, but activated BZ-induced ERS-related genes BIP/HSPA5 and CHOP /GADD153. Using ChIP, we showed that SGK1, BIP/HSPA5 and CHOP regulation was due to effects of CpdA and CpdA+BZ on GR loading on their promoters. We also found that AR and GR are abundant in advanced PCa from patients treated by androgen ablation and/or chemotherapy: 56% of carcinomas from treated patients expressed both receptors, and the other 27% expressed either GR or AR. Overall, our data validate the concept of dual AR/GR targeting in prostate cancer (PC) and suggest that BZ combination with dual-target steroid receptor modulator CpdA has high potential for PC therapy.

Molecular cloning and tissue distribution of mRNA encoding porcine 5-HT7 receptor and its comparison with the structure of other species.

The effects of 5-hydroxytriptamine (5-HT, serotonin) are mediated via five main receptor types of which the 5-HT7 receptor is the most recently characterised member. The 5-HT7 receptor has been shown to participate in mediating cranial blood vessels dilatation that may result in migraine headache. We report here the cDNA cloning, sequencing and tissue distribution of porcine 5-HT7 receptor and illustrate its comparison with corresponding receptor of known species. Employing a combination of reverse transcriptase and inverse polymerase chain reaction we amplified and sequenced a full length cDNA from the porcine cerebral cortex. The deduced amino acid sequence comparison confirmed that the cloned porcine receptor belongs to 5-HT7 receptor as described for human and other species and showing overall homology of 92-96%. The expression of 5-HT7 receptor mRNA was observed in porcine central (cerebral cortex, trigeminal ganglion and cerebellum) as well as in peripheral (pulmonary and coronary arteries, superior vena cava and saphenous vein) tissues. The established cDNA sequence and tissue distribution of porcine 5-HT7 receptor will be helpful in exploring the role of this receptor in pathophysiological processes and to predict as a potential therapeutic target for antimigraine drug development.

Molecular cloning and expression of the porcine trigeminal ganglion cDNA encoding a 5-ht(1F) receptor.

Using a combination of reverse transcription polymerase chain reaction (RT-PCR) and inverse-PCR techniques, we amplified, cloned and sequenced a full-length porcine 5-hydroxytryptamine 1F (5-ht(1F)) receptor complementary DNA (cDNA) derived from porcine trigeminal ganglion. Sequence analysis revealed 1101 base pairs (bp) encoding an open reading frame of 366 amino acids showing a high similarity (>90%) with the 5-ht(1F) receptor sequences from other species, including human. The recombinant porcine 5-ht(1F) receptor was expressed in African green monkey kidney cell lines (COS-7 cells) and its ligand binding profile was determined using [3H]5-HT. The affinities of several agonists (LY334370 (5-(4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole fumarate)>CP122638 (N-methyl-3 [pyrrolidin 2(R)-yl methyl]-1H-indol-5-ylmethyl sulphonamide)=naratriptan =5HT>eletriptan>sumatriptan>frovatriptan =avitriptan>dihydroergotamine>zolmitriptan>5-carboxamidotryptamine>rizatriptan>alniditan=donitriptan>L694247 (2-[5-[3-(4-methylsulphonylamino)benzyl-1,2,4-oxadiazol-5-yl]-1H-indole-3-yl] ethylamine) and putative antagonists (methiothepin>GR127935 (N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl 4'-(5-methyl-1,2,4-oxadiazol-3-yl) [1,1-biphenyl]-4-carboxamide hydrochloride)>ritanserin>SB224289 (2,3,6,7-tetrahydro-1'-methyl-5-[2'-methyl-4'(5-methyl-1,2,4-oxadiazol-3-yl) biphenyl-4-carbonyl] furo [2,3-f] indole-3-spiro-4'-piperidine hydrochloride)>BRL155572 ([1-(3-chlorophenyl)-4-[3,3-diphenyl (2-(S,R) hydroxypropanyl)piperazine] hydrochloride)>ketanserin=pindolol) correlated highly with those described for the recombinant human 5-ht(1F) receptor (Spearman correlation coefficient; r(s)=0.942). Nevertheless, as compared to the human homologue, some triptans (i.e. sumatriptan, zolmitriptan and rizatriptan) displayed a 10- to 15-fold lower affinity for the porcine 5-ht(1F) receptor. Using RT-PCR technique, the expression of porcine 5-ht(1F) receptor mRNA was observed in cerebral cortex, trigeminal ganglion and several blood vessels, but not in skeletal muscles. In conclusion, we have cloned and established the amino acid sequence and ligand binding profile of the porcine 5-ht(1F) receptor as well as the distribution of its mRNA. This information may be helpful in exploring the role of 5-ht(1F) receptor in physiological processes and diseases, such as migraine.