Combination of SAHA and bortezomib up-regulates CDKN2A and CDKN1A and induces apoptosis of Epstein-Barr virus-positive Wp-restricted Burkitt lymphoma and lymphoblastoid cell lines

Epstein-Barr virus (EBV) latent proteins exert anti-apoptotic effects on EBV-transformed lymphoid cells by down-regulating BCL2L11 (BIM), CDKN2A (p16(INK4A) ) and CDKN1A (p21(WAF1) ). However, the potential therapeutic effects of targeting these anti-apoptotic mechanisms remain unexplored. Here, we tested both in vitro and in vivo effects of the combination of histone deacetylase (HDAC) and proteasome inhibitors on the apoptosis of six endemic Burkitt lymphoma (BL) lines of different latency patterns (types I and III and Wp-restricted) and three lymphoblastoid cell lines (LCLs). We found that the combination of HDAC and proteasome inhibitors (e.g. SAHA/bortezomib) synergistically induced the killing of Wp-restricted and latency III BL and LCLs but not latency I BL cells. The synergistic killing was due to apoptosis, as evidenced by the high percentage of annexin V positivity and strong cleavage of PARP1 (PARP) and CASP3 (caspase-3). Concomitantly, SAHA/bortezomib up-regulated the expression of CDKN2A and CDKN1A but did not affect the level of BCL2L11 or BHRF1 (viral homologue of BCL2). The apoptotic effects were dependent on reactive oxygen species generation. Furthermore, SAHA/bortezomib suppressed the growth of Wp-restricted BL xenografts in nude mice. This study provides the rationale to test the novel application of SAHA/bortezomib on the treatment of EBV-associated Wp-restricted BL and post-transplant lymphoproliferative disorder.postprin

Inhibition of class I histone deacetylases by romidepsin potently induces Epstein-Barr virus lytic cycle and mediates enhanced cell death with ganciclovir

Pan-histone deacetylase (HDAC) inhibitors, which inhibit 11 HDAC isoforms, are widely used to induce Epstein-Barr virus (EBV) lytic cycle in EBV-associated cancers in vitro and in clinical trials. Here, we hypothesized that inhibition of one or several specific HDAC isoforms by selective HDAC inhibitors could potently induce EBV lytic cycle in EBV-associated malignancies such as nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC). We found that inhibition of class I HDACs, particularly HDAC-1, -2 and -3, was sufficient to induce EBV lytic cycle in NPC and GC cells in vitro and in vivo. Among a panel of selective HDAC inhibitors, the FDA-approved HDAC inhibitor romidepsin was found to be the most potent lytic inducer, which could activate EBV lytic cycle at ∼0.5 to 5 nM (versus ∼800 nM achievable concentration in patients' plasma) in more than 75% of cells. Upregulation of p21WAF1 , which is negatively regulated by class I HDACs, was observed before the induction of EBV lytic cycle. The upregulation of p21WAF1 and induction of lytic cycle were abrogated by a specific inhibitor of PKC-δ but not the inhibitors of PI3K, MEK, p38 MAPK, JNK or ATM pathways. Interestingly, inhibition of HDAC-1, -2 and -3 by romidepsin or shRNA knockdown could confer susceptibility of EBV-positive epithelial cells to the treatment with ganciclovir (GCV). In conclusion, we demonstrated that inhibition of class I HDACs by romidepsin could potently induce EBV lytic cycle and mediate enhanced cell death with GCV, suggesting potential application of romidepsin for the treatment of EBV-associated cancers.postprin

Melaena with Peutz-Jeghers syndrome: a case report

Introduction: Peutz-Jeghers syndrome (PJS) is a rare familial disorder characterised by mucocutaneous pigmentation, gastrointestinal and extragastrointestinal hamartomatous polyps and an increased risk of malignancy. Peutz-Jeghers polyps in the bowel may result in intussusception. This complication usually manifests with abdominal pain and signs of intestinal obstruction. Case Presentation: We report the case of a 24-year-old Caucasian male who presented with melaena. Pigmentation of the buccal mucosa was noted but he was pain-free and examination of the abdomen was unremarkable. Upper gastrointestinal endoscopy revealed multiple polyps. An urgent abdominal computed tomography (CT) scan revealed multiple small bowel intussusceptions. Laparotomy was undertaken on our patient, reducing the intussusceptions and removing the polyps by enterotomies. Bowel resection was not needed. Conclusion: Melaena in PJS needs to be urgently investigated through a CT scan even in the absence of abdominal pain and when clinical examination of the abdomen shows normal findings. Although rare, the underlying cause could be intussusception, which if missed could result in grave consequences

The RN/CFT Correspondence Revisited

We reconsidered the quantum gravity description of the near horizon extremal Reissner-Nordstr{\o}m black hole in the viewpoint of the AdS$_2$/CFT$_1$ correspondence. We found that, for pure electric case, the right moving central charge of dual 1D CFT is $6 Q^2$ which is different from the previous result $6 Q^3$ of left moving sector obtained by warped AdS$_3$/CFT$_2$ description. We discussed the discrepancy in these two approaches and examined novel properties of our result.Comment: revtex4, 16 pages, sign mistakes corrected, references include

Characterizing the non-linear growth of large-scale structure in the Universe

The local Universe displays a rich hierarchical pattern of galaxy clusters and superclusters. The early Universe, however, was almost smooth, with only slight 'ripples' seen in the cosmic microwave background radiation. Models of the evolution of structure link these observations through the effect of gravity, because the small initially overdense fluctuations attract additional mass as the Universe expands. During the early stages, the ripples evolve independently, like linear waves on the surface of deep water. As the structures grow in mass, they interact with other in non-linear ways, more like waves breaking in shallow water. We have recently shown how cosmic structure can be characterized by phase correlations associated with these non-linear interactions, but hitherto there was no way to use that information to reach quantitative insights into the growth of structures. Here we report a method of revealing phase information, and quantify how this relates to the formation of a filaments, sheets and clusters of galaxies by non-linear collapse. We use a new statistic based on information entropy to separate linear from non-linear effects and thereby are able to disentangle those aspects of galaxy clustering that arise from initial conditions (the ripples) from the subsequent dynamical evolution.Comment: Accepted for publication in Nature. For high-resolution Figure 3, please see http://www.nottingham.ac.uk/~ppzpc/phases/n0colorphase.html, For the animations and the idea of this paper please see http://www.nottingham.ac.uk/~ppzpc/phases/index.htm

Holographic Duals of Near-extremal Reissner-Nordstrom Black Holes

We consider the $\mathrm{AdS}_3/\mathrm{CFT}_2$ description of Reissner-Nordstr{\o}m black holes by studying their uplifted counterparts in five dimensions. Assuming a natural size of the extra dimension, the near horizon geometries for the extremal limit are exactly $\mathrm{AdS}_3 \times \mathrm{S}^2$. We compute the scattering amplitude of a scalar field, with a mode near threshold of frequency and extra dimensional momentum, by a near extremal uplifted black hole. The absorption cross section agrees with the two point function of the CFT dual to the scalar field.Comment: reference added, improper statements corrected, 17 pages, no figure

Gender-dependent differences in plasma matrix metalloproteinase-8 elevated in pulmonary tuberculosis.

Tuberculosis (TB) remains a global health pandemic and greater understanding of underlying pathogenesis is required to develop novel therapeutic and diagnostic approaches. Matrix metalloproteinases (MMPs) are emerging as key effectors of tissue destruction in TB but have not been comprehensively studied in plasma, nor have gender differences been investigated. We measured the plasma concentrations of MMPs in a carefully characterised, prospectively recruited clinical cohort of 380 individuals. The collagenases, MMP-1 and MMP-8, were elevated in plasma of patients with pulmonary TB relative to healthy controls, and MMP-7 (matrilysin) and MMP-9 (gelatinase B) were also increased. MMP-8 was TB-specific (p<0.001), not being elevated in symptomatic controls (symptoms suspicious of TB but active disease excluded). Plasma MMP-8 concentrations inversely correlated with body mass index. Plasma MMP-8 concentration was 1.51-fold higher in males than females with TB (p<0.05) and this difference was not due to greater disease severity in men. Gender-specific analysis of MMPs demonstrated consistent increase in MMP-1 and -8 in TB, but MMP-8 was a better discriminator for TB in men. Plasma collagenases are elevated in pulmonary TB and differ between men and women. Gender must be considered in investigation of TB immunopathology and development of novel diagnostic markers

Years off Your Life? The Effects of Homicide on Life Expectancy by Neighborhood and Race/Ethnicity in Los Angeles County

Homicide is one of the leading causes of death in Los Angeles County and is known to be elevated in low-income urban neighborhoods and in black males. However, because homicide occurs primarily among young adults, mortality rate statistics may underrepresent its importance. We estimated the impact of homicide on life expectancy by demographic group and geographic area in Los Angeles County, 2001–2006. Life expectancy estimates were calculated using mortality records and population estimates for Los Angeles County. Cause elimination techniques were used to estimate the impact of homicide on life expectancy. Homicide was estimated to reduce life expectancy by 0.4 years for Los Angeles County residents and by 2.1 years for black males. The impact of homicide on life expectancy was higher in low-income neighborhoods. In some low-income urban neighborhoods, homicide was estimated to decrease life expectancy in black males by nearly 5 years. Homicide causes substantial reductions in life expectancy in Los Angeles County. Its impact is magnified among black males and in low-income urban areas, underscoring the need for homicide reduction in urban centers

The Thermal Design, Characterization, and Performance of the SPIDER Long-Duration Balloon Cryostat

We describe the SPIDER flight cryostat, which is designed to cool six millimeter-wavelength telescopes during an Antarctic long-duration balloon flight. The cryostat, one of the largest to have flown on a stratospheric payload, uses liquid helium-4 to deliver cooling power to stages at 4.2 and 1.6 K. Stainless steel capillaries facilitate a high flow impedance connection between the main liquid helium tank and a smaller superfluid tank, allowing the latter to operate at 1.6 K as long as there is liquid in the 4.2 K main tank. Each telescope houses a closed cycle helium-3 adsorption refrigerator that further cools the focal planes down to 300 mK. Liquid helium vapor from the main tank is routed through heat exchangers that cool radiation shields, providing negative thermal feedback. The system performed successfully during a 17 day flight in the 2014-2015 Antarctic summer. The cryostat had a total hold time of 16.8 days, with 15.9 days occurring during flight.Comment: 15 pgs, 17 fig