Quantum circuits with many photons on a programmable nanophotonic chip.

Growing interest in quantum computing for practical applications has led to a surge in the availability of programmable machines for executing quantum algorithms1,2. Present-day photonic quantum computers3-7 have been limited either to non-deterministic operation, low photon numbers and rates, or fixed random gate sequences. Here we introduce a full-stack hardware-software system for executing many-photon quantum circuit operations using integrated nanophotonics: a programmable chip, operating at room temperature and interfaced with a fully automated control system. The system enables remote users to execute quantum algorithms that require up to eight modes of strongly squeezed vacuum initialized as two-mode squeezed states in single temporal modes, a fully general and programmable four-mode interferometer, and photon number-resolving readout on all outputs. Detection of multi-photon events with photon numbers and rates exceeding any previous programmable quantum optical demonstration is made possible by strong squeezing and high sampling rates. We verify the non-classicality of the device output, and use the platform to carry out proof-of-principle demonstrations of three quantum algorithms: Gaussian boson sampling, molecular vibronic spectra and graph similarity8. These demonstrations validate the platform as a launchpad for scaling photonic technologies for quantum information processing.

Intimate Partner Violence (IPV) and Associated Factors in HPTN 071 (PopART) Study Communities in Zambia and South Africa-A Comparison by HIV Status.

The HPTN 071(PopART) study was a community-randomised trial in Zambia and South Africa, examining the impact of combination-prevention including universal testing and treatment (UTT), on HIV-incidence. This sub-study evaluated factors associated with IPV (physical and/or sexual) to identify differences by HIV status. During 2015-16, a random subset of adults who participated in the first year of the PopART intervention were recruited and standardised questionnaires were administered. Logistic regression was performed to estimate odds ratios of factors associated with IPV. Among > 700 women studied (300 HIV-negative;400 HIV-positive), ~ 20% reported experiencing physical and/or sexual violence in the last 12-months. Sexual violence was similar by HIV status, but physical violence and reporting both physical/sexual violence was more common among HIV-positive women. Spending nights away from the community in the last 12-months was associated with higher odds of IPV among both HIV-negative (aOR 3.17, 95% CI 1.02-9.81) and HIV-positive women (aOR 1.79, 95% CI 0.99-3.24). Among HIV-positive women, financial autonomy was associated with reduced IPV (aOR:0.41,95%CI:0.23-0.75) while pregnancy in the last 12-months (aOR 2.25, 95% CI 1.07-4.74), risk of alcohol dependence (aOR 2.75, 95% CI 1.51-5.00) and risk of mental distress (aOR 2.62, 95% CI 1.33-5.16) were associated with increased IPV. Among HIV-negative women reporting sex in the last 12-months, transactional sex (aOR 3.97, 95% CI 1.02-15.37) and not knowing partner's HIV status (aOR 3.01, 95% CI 1.24-7.29) were associated with IPV. IPV was commonly reported in the study population and factors associated with IPV differed by HIV status. The association of mobility with IPV warrants further research. The high prevalence of harmful alcohol use and mental distress, and their association with IPV among HIV-positive women require urgent attention.

RESUMEN: El estudio HPTN 071 (PopART) fue un ensayo aleatorio-comunitario realizado en Zambia y Sudáfrica, que examinó el impacto de la prevención combinada, incluyendo las pruebas y tratamiento universal (UTT), en la incidencia del VIH. Este subestudio evaluó los factores asociados con la IPV (físicos y / o sexuales) para identificar diferencias en el estado del VIH. Durante 2015-16, un subconjunto aleatorio de adultos fueron reclutados para participar en el primer año de intervención de PopART, donde se administraron cuestionarios estandarizados. Se realizó una regresión logística para estimar las ratios de probabilidad de los factores asociados con la VPI. Entre las > 700 mujeres estudiadas (300 VIH negativas; 400 VIH positivas), ~ 20% informó haber experimentado violencia física y / o sexual en los últimos 12 meses. La violencia sexual fue similar en cuanto al estado del VIH. La denuncia de violencia física y sexual fue más común entre las mujeres VIH positivas. Pasar noches fuera de la comunidad en los últimos 12 meses, se asoció con mayores probabilidades de VPI entre las mujeres VIH negativas (ORa 3,17, 95% IC 1,02­9,81) y las mujeres VIH positivas (ORa 1,79, 95% IC 0,99­3,24). Entre las mujeres VIH positivas, la autonomía financiera se asoció con una reducción de la VPI (ORa 0,41; IC del 95% 0,23-0,75) mientras que en el embarazo en los últimos 12 meses (ORa 2,25; IC del 95% 1,07­4,74), riesgo a la dependencia del alcohol (ORa 2,75% IC 1,51­5,00) y el riesgo de angustia mental (ORa 2,62% IC del 95% 1,33­5,16) se asociaron con un aumento de la VPI. Entre las mujeres VIH negativas que informaron haber tenido relaciones sexuales en los últimos 12 meses, el sexo transaccional (ORa 3.97, 95% CI 1.02­15.37) y el desconocimiento del estado de VIH de la pareja (ORa 3.01, 95% CI 1.24­7.29) se asociaron con IPV. La IPV fue notificada mayoritariamente en la población de estudio y los factores asociados con la IPV diferían según el estado del VIH. La asociación de la movilidad con la IPV justifica una mayor investigación. La alta prevalencia de l consumo nocivo de alcohol y la angustia mental, y su asociación con la VPI entre las mujeres seropositivas, requieren atención urgente.

Achieving the UNAIDS 90-90-90 targets: a comparative analysis of four large community randomised trials delivering universal testing and treatment to reduce HIV transmission in sub-Saharan Africa.

BACKGROUND: Four large community-randomized trials examining universal testing and treatment (UTT) to reduce HIV transmission were conducted between 2012-2018 in Botswana, Kenya, Uganda, Zambia and South Africa. In 2014, the UNAIDS 90-90-90 targets were adopted as a useful metric to monitor coverage. We systematically review the approaches used by the trials to measure intervention delivery, and estimate coverage against the 90-90-90 targets. We aim to provide in-depth understanding of the background contexts and complexities that affect estimation of population-level coverage related to the 90-90-90 targets. METHODS: Estimates were based predominantly on "process" data obtained during delivery of the interventions which included a combination of home-based and community-based services. Cascade coverage data included routine electronic health records, self-reported data, survey data, and active ascertainment of HIV viral load measurements in the field. RESULTS: The estimated total adult populations of trial intervention communities included in this study ranged from 4,290 (TasP) to 142,250 (Zambian PopART Arm-B). The estimated total numbers of PLHIV ranged from 1,283 (TasP) to 20,541 (Zambian PopART Arm-B). By the end of intervention delivery, the first-90 target (knowledge of HIV status among all PLHIV) was met by all the trials (89.2%-94.0%). Three of the four trials also achieved the second- and third-90 targets, and viral suppression in BCPP and SEARCH exceeded the UNAIDS target of 73%, while viral suppression in the Zambian PopART Arm-A and B communities was within a small margin (~ 3%) of the target. CONCLUSIONS: All four UTT trials aimed to implement wide-scale testing and treatment for HIV prevention at population level and showed substantial increases in testing and treatment for HIV in the intervention communities. This study has not uncovered any one estimation approach which is superior, rather that several approaches are available and researchers or policy makers seeking to measure coverage should reflect on background contexts and complexities that affect estimation of population-level coverage in their specific settings. All four trials surpassed UNAIDS targets for universal testing in their intervention communities ahead of the 2020 milestone. All but one of the trials also achieved the 90-90 targets for treatment and viral suppression. UTT is a realistic option to achieve 95-95-95 by 2030 and fast-track the end of the HIV epidemic.

Hospital-based routine HIV testing in high-income countries: a systematic literature review.

OBJECTIVES: To produce a summary of the published evidence of the barriers and facilitators for hospital-based routine HIV testing in high-income countries. METHODS: Electronic databases were searched for studies, which described the offer of HIV testing to adults attending emergency departments (EDs) and acute medical units (AMUs) in the UK and US, published between 2006 and 2015. Other high-income countries were not included, as their guidelines do not recommend routine testing for HIV. The main outcomes of interest were HIV testing uptake, HIV testing coverage, factors facilitating HIV screening and barriers to HIV testing. Fourteen studies met the pre-defined inclusion criteria and critically appraised using mixed methods appraisal tool (MMAT). RESULTS: HIV testing coverage ranged from 9.7% to 38.3% and 18.7% to 26% while uptake levels were high (70.1-84% and 53-75.4%) in the UK and US, respectively. Operational barriers such as lack of time, the need for training and concerns about giving results and follow-up of HIV positive results, were reported. Patient-specific factors including female sex, old age and low risk perception correlated with refusal of HIV testing. Factors that facilitated the offer of HIV testing were venous sampling (vs. point-of-care tests), commitment of medical staff to HIV testing policy and support from local HIV specialist providers. CONCLUSIONS: There are several barriers to routine HIV testing in EDs and AMUs. Many of these stem from staff fears about offering HIV testing due to the perceived lack of knowledge about HIV. Our systematic review highlights areas which can be targeted to increase coverage of routine HIV testing.

Is home-based HIV testing universally acceptable? Findings from a case-control study nested within the HPTN 071 (PopART) trial.

OBJECTIVE: The HPTN 071 (PopART) trial is examining the impact of a package including universal testing and treatment on community-level HIV incidence in Zambia and South Africa. We conducted a nested case-control study to examine factors associated with acceptance of home-based HIV testing and counselling (HB-HTC) delivered by community HIV-care providers (CHiPs) in PopART intervention communities. METHODS: Of 295 447 individuals who were offered testing, random samples of individuals who declined HB-HTC (cases) and accepted HB-HTC (controls), stratified by gender and community, were selected. Odds ratios comparing cases and controls were estimated using multivariable logistic regression. RESULTS: Data from 642 participants (313 cases, 329 controls) were analysed. There were no differences between cases and controls by demographic or behavioural characteristics including age, marital or socio-economic position. Participants who felt they could be open with CHiPs (AOR: 0.46, 95% CI: 0.30-0.71, P < 0.001); self-reported as not previously tested (AOR: 0.64; 95% CI: 0.43-0.95, P = 0.03); considered HTC at home to be convenient (AOR: 0.38, 95% CI: 0.27-0.54, P = 0.001); knowing others who had accepted HB-HTC from the CHiPs (AOR: 0.49, 95% CI: 0.31-0.77, P = 0.002); or were motivated to get treatment without delay (AOR: 0.60, 95% CI: 0.43-0.85, P = 0.004) were less likely to decline the offer of HB-HCT. Those who self-reported high-risk sexual behaviour were also less likely to decline HB-HCT (AOR: 0.61, 95% CI: 0.39-0.93, P = 0.02). Having stigmatising attitudes about HB-HTC was not an important barrier to HB-HCT uptake. Men who reported fear of HIV were more likely to decline HB-HCT (AOR: 2.68, 95% CI: 1.33-5.38, P = 0.005). CONCLUSION: Acceptance of HB-HTC was associated with lack of previous HIV testing, positive attitudes about HIV services/treatment and perception of high sexual risk. Uptake of HB-HCT among those offered it was similar across a range of demographic and behavioural subgroups suggesting it was 'universally' acceptable.

Community-based health workers implementing universal access to HIV testing and treatment: lessons from South Africa and Zambia-HPTN 071 (PopART).

The global expansion of HIV testing, prevention and treatment services is necessary to achieve HIV epidemic control and promote individual and population health benefits for people living with HIV (PLHIV) in sub-Saharan Africa. Community-based health workers (CHWs) could play a key role in supporting implementation at scale. In the HPTN 071 (PopART) trial in Zambia and South Africa, a cadre of 737 study-specific CHWs, working closely with government-employed CHW, were deployed to deliver a 'universal' door-to-door HIV prevention package, including an annual offer of HIV testing and referral services for all households in 14 study communities. We conducted a process evaluation using qualitative and quantitative data collected during the trial (2013-2018) to document the implementation of the CHW intervention in practice. We focused on the recruitment, retention, training and support of CHWs, as they delivered study-specific services. We then used these descriptions to: (i) analyse the fidelity to design of the delivery of the intervention package, and (ii) suggest key insights for the transferability of the intervention to other settings. The data included baseline quantitative data collected with the study-specific CHWs (2014-2018); and qualitative data from key informant interviews with study management (n = 91), observations of CHW training events (n = 12) and annual observations of and group discussions (GD) with intervention staff (n = 68). We show that it was feasible for newly recruited CHWs to implement the PopART intervention with good fidelity, supporting the interpretation of the trial outcome findings. This was despite some challenges in managing service quality and CHW retention in the early years of the programme. We suggest that by prioritizing the adoption of key elements of the in-home HIV services delivery intervention model-including training, emotional support to workers, monitoring and appropriate remuneration for CHWs-these services could be successfully transferred to new settings.

c-Jun NH2-terminal kinase (JNK)1 and JNK2 have similar and stage-dependent roles in regulating T cell apoptosis and proliferation.

Apoptotic and mitogenic stimuli activate c-Jun NH2-terminal kinases (JNKs) in T cells. Although T cells express both JNK1 and JNK2 isozymes, the absence of JNK2 alone can result in resistance to anti-CD3-induced thymocyte apoptosis and defective mature T cell proliferation. Similar defects in thymocyte apoptosis and mature T cell proliferation, the latter due to reduced interleukin 2 production, are also caused by JNK1 deficiency. Importantly, T cell function was compromised in Jnk1(+/-)Jnk2(+/-) double heterozygous mice, indicating that JNK1 and JNK2 play similar roles in regulating T cell function. The reduced JNK dose results in defective c-Jun NH2-terminal phosphorylation in thymocytes but not in peripheral T cells, in which nuclear factors of activated T cells (NK-ATs)-DNA binding activity is affected. Thus, JNK1 and JNK2 control similar functions during T cell maturation through differential targeting of distinct substrates.

Defective MHC class I antigen surface expression promotes cellular survival through elevated ER stress and modulation of p53 function.

Defects in Major Histocompatibility class I cell surface expression is thought to allow escape of tumor cells from immune surveillance. Hitherto, it is unclear whether this deficiency confers immune-independent survival advantage. We show here that class I cell surface expression deficiency due to defects in beta2 microglobulin or the transporter-associated with antigen processing (TAP) results in resistance to apoptosis in response to various cytotoxic signals. Reduced apoptosis correlated with altered p53 activation, which was due to compromised nuclear translocation of p53. Binding of p53 to glycogen synthase kinase-3beta (GSK3beta), which is known to phosphorylate and lead to cytoplasmic sequestration of p53, was enhanced in these cells. Consistently, endoplasmic reticulum (ER) stress, which promotes binding of p53 to GSK3beta was constitutively elevated in the absence of class I cell surface expression. Taken together, the results suggest a non-immunological causal role for defective class I cell surface expression in regulating cellular survival in a p53-dependent manner, through the upregulation of ER stress, which could be another mechanism leading to carcinogenesis.

Polyoma middle T-induced vascular tumor formation: the role of the plasminogen activator/plasmin system.

The middle T antigen of murine Polyomavirus (PymT) rapidly transforms endothelial cells, leading to the formation of vascular tumors in newborn mice. Transformed endothelial (End.) cell lines established from such tumors exhibit altered proteolytic activity as a result of increased expression of urokinase-type plasminogen activator (uPA) and are capable of inducing vascular tumors efficiently when injected into adult mice. In this study we have used mice lacking components of the PA/plasmin system to analyze the role of this system in the transformation process and in tumor growth. We found that the proteolytic status of the host is not a critical determinant for PymT-induced vascular tumor formation. In addition, the lack of either uPA or tissue-type PA (tPA) activity is not limiting for the establishment and proliferation of End. cells in vitro, although the combined loss of both PA activities leads to a marked reduction in proliferation rates. Furthermore, the in vitro morphogenetic properties of mutant End. cells in fibrin gels could only be correlated with an altered proteolytic status in cells lacking both uPA and tPA. However, in contrast with tumors induced by PymT itself, the tumorigenic potential of mutant and wild-type End. cell lines was found to be highly dependent on the proteolytic status of both the tumor cells and the host. Thus, genetic alterations in the PA/plasmin system affect vascular tumor development, indicating that this system is a causal component in PymTmediated oncogenesis.

The codon 72 polymorphism-specific effects of human p53 are absent in mouse cells: implications on generation of mouse models.

Human p53, unlike mouse p53, contains a polymorphic site at codon 72 in exon 4 encoding either an arginine amino acid (72R) or a proline residue (72P). The 72R form was shown to induce apoptosis better than the 72P form, partly owing to its ability to efficiently bind to the nuclear-export protein CRM1 and localize to the mitochondria. This polymorphism has also been associated with cancer predisposition and chemo-sensitivity. Further understanding of the in vivo significance of this polymorphism in carcinogenesis requires the generation of mouse models. We have thus evaluated if the polymorphism-specific effects of human p53 are retained in mouse cells. Though being transcriptionally active, both the human polymorphs were found to have lost their ability to differentially suppress growth and bind to CRM1 or MDM2 in mouse cells. Moreover, chimaeric proteins containing mouse exons 2-3 and human exons 4-11 have also lost the polymorphism-specific effects in human cells, suggesting that human exons 2-3 are important in regulating the polymorphism-specific effects. Furthermore, human p53 and the various chimaeric proteins were generally less effective in inhibiting growth of mouse cells compared to mouse p53, suggesting that mouse p53 is more potent than human p53 in suppressing growth, partly due to enhanced binding of MDM2 to human p53. The data together suggest that mouse cells may not provide an appropriate environment for the manifestation of the polymorphism-specific functional differences of human p53, and hence, cautions against the expression of full-length or chimaeric p53 proteins in mice to study the effects of the polymorphism.

c-Jun promotes cellular survival by suppression of PTEN.

Activation of c-Jun, a component of the AP-1 family of transcription factors, leads to either promotion or prevention of apoptosis. However, the molecular determinants of c-Jun-mediated cell survival are still unclear. We show here that inducible expression of c-Jun promotes cellular survival by negatively regulating the expression of the tumor-suppressor PTEN, resulting in the concomitant activation of the Akt survival pathway. Consistently, c-jun-/- fibroblasts, which are sensitive to nutrient deprivation, and human cell lines in which c-Jun expression is silenced, express elevated levels of PTEN. siRNA-mediated silencing of PTEN resulted in the reduction of cell-death owing to c-Jun deficiency. c-Jun was found to suppress PTEN expression by binding to a variant AP-1 site found in the 5' upstream sequences of PTEN promoter. Finally, an inverse correlation between c-Jun and PTEN levels was apparent in a panel of human tumor cell lines, independent of their p53 status. Together, the data demonstrate that c-Jun contributes to the promotion of cellular survival by regulating the expression of PTEN.

Trp53-dependent DNA-repair is affected by the codon 72 polymorphism.

Trp53 is arguably the most critical tumour suppressor gene product that inhibits malignant transformation. Besides mutations that inactivate Trp53 functions, genetic polymorphisms have been suggested to be risk factors for cancer. A polymorphic site at codon 72 in exon 4 encodes either an arginine amino acid (Trp53(72R)) or a proline residue (Trp53(72P)). Previous studies have shown that the Trp53(72R) form is more efficient in apoptosis induction, whereas the Trp53(72P) form was suggested to induce G1 arrest better. Here we report that Trp53(72P) is more efficient than Trp53(72R) in specifically activating several Trp53-dependent DNA-repair target genes in several cellular systems. Moreover, using isogenic cell lines and several DNA-repair assays, we show that Trp53(72P) cells have a significantly higher DNA-repair capacity than the Trp53(72R) cells. Furthermore, Trp53(72P)-expressing cells exhibit reduced micronuclei formation compared to Trp53(72R)-expressing cells, suggesting that genomic instability is reduced in these cells. Together, the data highlight the functional differences between the Trp53 polymorphic variants, and suggest that their expression status may influence cancer risk.

JNK2 is required for efficient T-cell activation and apoptosis but not for normal lymphocyte development.

BACKGROUND: The Jun N-terminal kinase (JNK) signaling pathway has been implicated in cell proliferation and apoptosis, but its function seems to depend on the cell type and inducing signal. In T cells, JNK has been implicated in both antigen-induced activation and apoptosis. RESULTS: We generated mice lacking the JNK2 isozymes. The mutant mice were healthy and fertile but defective in peripheral T-cell activation induced by antibody to the CD3 component of the T-cell receptor (TCR) complex - proliferation and production of interleukin-2 (IL-2), IL-4 and interferon-gamma (IFN-gamma) were reduced. The proliferation defect was restored by exogenous IL-2. B-cell activation was normal in the absence of JNK2. Activation-induced peripheral T-cell apoptosis was comparable between mutant and wild-type mice, but immature (CD4(+) CD8(+)) thymocytes lacking JNK2 were resistant to apoptosis induced by administration of anti-CD3 antibody in vivo. The lack of JNK2 also resulted in partial resistance of thymocytes to anti-CD3 antibody in vitro, but had little or no effect on apoptosis induced by anti-Fas antibody, dexamethasone or ultraviolet-C (UVC) radiation. CONCLUSIONS: JNK2 is essential for efficient activation of peripheral T cells but not B cells. Peripheral T-cell activation is probably required indirectly for induction of thymocyte apoptosis resulting from administration of anti-CD3 antibody in vivo. JNK2 functions in a cell-type-specific and stimulus-dependent manner, being required for apoptosis of immature thymocytes induced by anti-CD3 antibody but not for apoptosis induced by anti-Fas antibody, UVC or dexamethasone. JNK2 is not required for activation-induced cell death of mature T cells.

Role of the ATFa/JNK2 complex in Jun activation.

The ATFa proteins, which are members of the CREB/ATF family of transcription factors, display quite versatile properties. We have previously shown that they interact with the adenovirus E1a oncoprotein, mediating part of its transcriptional activity and heterodimerize with the Jun, Fos or related transcription factors, thereby modulating their DNA-binding specificity. In the present study, we report the sequence requirement of the N-terminal activation domain of ATFa and demonstrate the importance of specific threonine residues (Thr51 and Thr53) in addition to that of the metal-binding domain, in transcriptional activation processes. We also show that the N-terminal domain of ATFa which stably binds the Jun N-terminal kinase-2 (JNK2) (Bocco et al., 1996), is not a substrate for this kinase in vivo but, instead, serves as a JNK2-docking site for ATFa-associated partners like JunD, allowing them to be phosphorylated by the bound kinase.

Defective neural tube morphogenesis and altered apoptosis in the absence of both JNK1 and JNK2.

Mice lacking both c-Jun-NH(2)-terminal kinases (JNK1 and JNK2) were generated to define their roles in development. Jnk1/jnk2 double mutant fetuses die around embryonic day 11 (E11) and were found to display an open neural tube (exencephaly) at the hindbrain level with reduced apoptosis in the hindbrain neuroepithelium at E9.25. In contrast, a dramatic increase in cell death was observed one day later at E10.5 in both the hindbrain and forebrain regions. Moreover, about 25% of jnk1-/-jnk2+/- fetuses display exencephaly probably due to reduced levels of JNK proteins, whereas jnk1+/-jnk2-/- mice are viable. These results assign both pro- and anti-apoptotic functions for JNK1 and JNK2 in the development of the fetal brain.

Oxy5, a novel protein from Arabidopsis thaliana, protects mammalian cells from oxidative stress.

The use of molecular oxygen in various cellular processes results in the generation of toxic intracellular by-products termed reactive oxygen species (ROS). In Escherichia coli the oxyR gene product is a transcriptional regulator of the oxyR regulon that is induced in response to hydrogen peroxide-induced oxidative stress (OS). We have previously shown that an annexin-like protein from Arabidopsis thaliana, termed Oxy5, can replace the obligatory role of OxyR in E. coli. Here, we have investigated as to whether oxy5 can function across evolutionary boundaries to protect mammalian cells from OS. Overexpression of the oxyR gene in mammalian tumor cell lines protects them from hydrogen peroxide-induced cell death, and these cells are also highly resistant to the superoxide ion producing compound paraquat. Oxy5 appears to be involved in the detection of calcium flux, as it binds to Ca2+ ions during hydrogen peroxide stress. Moreover, overexpression of Oxy5 leads to lowered protein kinase C activity. Thus, Oxy5 probably functions to sense and initiate protective responses to OS. In addition, Oxy5-overexpressing cells exhibit a reduction in endogenous superoxide ion levels, which concomitantly results in a dramatic decrease in their tumorigenic potential. Taken together, the results demonstrate an antioxidant role for plant oxy5 gene in mammalian cells, which can be potentially utilized in gene therapy programs aimed at reducing the deleterious effects of ROS.

Role of splenectomy in chronic idiopathic thrombocytopenic purpura.

AIM OF THE STUDY: To evaluate the usefulness of splenectomy and factors which predict long term remission in chronic idiopathic thrombocytopenic purpura (ITP). METHODS: We reviewed the data of 364 patients diagnosed as chronic ITP between January 1983 to December 1996 of whom 71 patients underwent splenectomy. The patients were followed up for an average period of 58 months and the short and long term response to splenectomy were analyzed at the end of one month and 60 months, respectively. RESULTS: At the end of one month after splenectomy, 82% had complete response, 7% partial response and 11% had no response. At the end of 60 months, 42% maintained complete response, 7% partial response, 34% had no response and 17% were lost to follow up. The results were statistically evaluated by using non-parametric test (Chi-square test) to age, sex, platelet count prior to treatment, initial response to steroids, time interval between diagnosis and splenectomy and post-operative platelet count. Of these factors only preoperative response to steroids (p value = 0.018303) and postoperative platelet count (p value = 0.013536) were found to be significant, statistically to predict long term remission. Age, sex, initial platelet count and time interval between diagnosis and splenectomy didn't seem to be statistically significant. CONCLUSION: This study suggests, that patients with an initial complete response to steroids and a post-operative platelet count > 300 x 10(9)/L at the time of discharge were associated with a long term remission. Splenectomy in ITP is a safe procedure with minimal morbidity and mortality and gives a good long term remission in steroid- failure patients with chronic ITP.

Suppression of acetylpolyamine oxidase by selected AP-1 members regulates DNp73 abundance: mechanistic insights for overcoming DNp73-mediated resistance to chemotherapeutic drugs.

Enhanced resistance to chemotherapy has been correlated with high levels of Delta-Np73 (DNp73), an anti-apoptotic protein of the p53 tumor-suppressor family which inhibits the pro-apoptotic members such as p53 and TAp73. Although genotoxic drugs have been shown to induce DNp73 degradation, lack of mechanistic understanding of this process precludes strategies to enhance the targeting of DNp73 and improve treatment outcomes. Antizyme (Az) is a mediator of ubiquitin-independent protein degradation regulated by the polyamine biosynthesis pathway. We show here that acetylpolyamine oxidase (PAOX), a catabolic enzyme of this pathway, upregulates DNp73 levels by suppressing its degradation via the Az pathway. Conversely, downregulation of PAOX activity by siRNA-mediated knockdown or chemical inhibition leads to DNp73 degradation in an Az-dependent manner. PAOX expression is suppressed by several genotoxic drugs, via selected members of the activator protein-1 (AP-1) transcription factors, namely c-Jun, JunB and FosB, which are required for stress-mediated DNp73 degradation. Finally, chemical- and siRNA-mediated inhibition of PAOX significantly reversed the resistant phenotype of DNp73-overexpressing cancer cells to genotoxic drugs. Together, these data define a critical mechanism for the regulation of DNp73 abundance, and reveal that inhibition of PAOX could widen the therapeutic index of cytotoxic drugs and overcome DNp73-mediated chemoresistance in tumors.

p53 promotes cellular survival in a context-dependent manner by directly inducing the expression of haeme-oxygenase-1.

A variety of cellular insults activate the tumour suppressor p53, leading generally to cell-cycle arrest or apoptosis. However, it is not inconceivable that cellular protective mechanisms may be required to keep cells alive while cell-fate decisions are made. In this respect, p53 has been suggested to perform functions that allow cells to survive, by halting of the cell-cycle, and thus preventing immediate cell death. Nonetheless, the existence of direct pro-survival p53 target genes regulating cellular survival is lacking. We show here evidence for p53-dependent cellular survival in a context-dependent manner. Both mouse and human cells lacking p53 are hypersensitive to hydrogen peroxide (H(2)O(2))-induced cell death compared with their isogenic wild-type counterparts. By contrast, p53(-/-) cells are expectedly resistant to cell death upon exposure to DNA-damaging agents such as cisplatin (CDDP) and etoposide. Although p53 and its classical targets such as p21 and Mdm2 are activated by both H(2)O(2) and CDDP, we found that the expression of haeme-oxygenase-1 (HO-1)-an antioxidant and antiapoptotic protein-was directly induced only upon H(2)O(2) treatment in a p53-dependent manner. Consistently, p53, but not its homologue p73, activated HO-1 expression and was bound to the HO-1 promoter specifically only upon H(2)O(2) treatment. Moreover, silencing HO-1 expression enhanced cell death upon H(2)O(2) treatment only in p53-proficient cells. Finally, H(2)O(2)-mediated cell death was rescued significantly in p53-deficient cells by antioxidant treatment, as well as by bilirubin, a by-product of HO-1 metabolism. Taken together, these data demonstrate a direct role for p53 in promoting cellular survival in a context-specific manner through the activation of a direct transcriptional target, HO-1.