Noncanonical effector functions of the T-memory-like T-PLL cell are shaped by cooperative TCL1A and TCR signaling.

T-cell prolymphocytic leukemia (T-PLL) is a poor-prognostic neoplasm. Differentiation stage and immune-effector functions of the underlying tumor cell are insufficiently characterized. Constitutive activation of the T-cell leukemia 1A (TCL1A) oncogene distinguishes the (pre)leukemic cell from regular postthymic T cells. We assessed activation-response patterns of the T-PLL lymphocyte and interrogated the modulatory impact by TCL1A. Immunophenotypic and gene expression profiles revealed a unique spectrum of memory-type differentiation of T-PLL with predominant central-memory stages and frequent noncanonical patterns. Virtually all T-PLL expressed a T-cell receptor (TCR) and/or CD28-coreceptor without overrepresentation of specific TCR clonotypes. The highly activated leukemic cells also revealed losses of negative-regulatory TCR coreceptors (eg, CTLA4). TCR stimulation of T-PLL cells evoked higher-than-normal cell-cycle transition and profiles of cytokine release that resembled those of normal memory T cells. More activated phenotypes and higher TCL1A correlated with inferior clinical outcomes. TCL1A was linked to the marked resistance of T-PLL to activation- and FAS-induced cell death. Enforced TCL1A enhanced phospho-activation of TCR kinases, second-messenger generation, and JAK/STAT or NFAT transcriptional responses. This reduced the input thresholds for IL-2 secretion in a sensitizer-like fashion. Mice of TCL1A-initiated protracted T-PLL development resembled such features. When equipped with epitope-defined TCRs or chimeric antigen receptors, these Lckpr-hTCL1Atg T cells gained a leukemogenic growth advantage in scenarios of receptor stimulation. Overall, we propose a model of T-PLL pathogenesis in which TCL1A enhances TCR signals and drives the accumulation of death-resistant memory-type cells that use amplified low-level stimulatory input, and whose loss of negative coregulators additionally maintains their activated state. Treatment rationales are provided by combined interception in TCR and survival signaling.

The structure of schizotypal personality traits: a cross-national study.

BACKGROUND: Schizotypal traits are considered a phenotypic-indicator of schizotypy, a latent personality organization reflecting a putative liability for psychosis. To date, no previous study has examined the comparability of factorial structures across samples originating from different countries and cultures. The main goal was to evaluate the factorial structure and reliability of the Schizotypal Personality Questionnaire (SPQ) scores by amalgamating data from studies conducted in 12 countries and across 21 sites. METHOD: The overall sample consisted of 27 001 participants (37.5% males, n = 4251 drawn from the general population). The mean age was 22.12 years (s.d. = 6.28, range 16-55 years). The SPQ was used. Confirmatory factor analysis (CFA) and Multilevel CFA (ML-CFA) were used to evaluate the factor structure underlying the SPQ scores. RESULTS: At the SPQ item level, the nine factor and second-order factor models showed adequate goodness-of-fit. At the SPQ subscale level, three- and four-factor models displayed better goodness-of-fit indices than other CFA models. ML-CFA showed that the intraclass correlation coefficients values were lower than 0.106. The three-factor model showed adequate goodness of fit indices in multilevel analysis. The ordinal α coefficients were high, ranging from 0.73 to 0.94 across individual samples, and from 0.84 to 0.91 for the combined sample. CONCLUSIONS: The results are consistent with the conceptual notion that schizotypal personality is a multifaceted construct and support the validity and utility of SPQ in cross-cultural research. We discuss theoretical and clinical implications of our results for diagnostic systems, psychosis models and cross-national mental health strategies.

T cells redirected by a CD3ζ chimeric antigen receptor can establish self-antigen-specific tumour protection in the long term.

A majority of cancer deaths are because of an uncontrolled relapse of the disease despite initial remission after therapy, asking for strategies to control tumour cells in the long term. Adoptive therapy with chimeric antigen receptor (CAR)-redirected T cells showed promising success in primary tumour elimination; the capacity of such engineered T cells to establish enduring tumour protection is currently a matter of discussion, in particular as most targeted 'tumour-associated antigens' are self-antigens. To address the issue in a clinically relevant model that closely mimics the human situation, we recorded rejection of carcinoembryonic antigen (CEA)-positive pancreatic tumours in the CEA transgenic mouse that expressed CEA as self-antigen in healthy cells of the gastrointestinal tract. Adoptive therapy with CD8(+) T cells, which were redirected by a CEA-specific, low-affinity CAR with CD3ζ endodomain, eliminated CEA(+) tumours in a primary response; cured mice produced an efficient recall response in the long term towards CEA(+) tumour cells upon rechallenge. Secondary tumour rejection was CEA specific, mediated by engineered T cells and did not require host T cells. No toxicity towards healthy tissues with CEA expression was recorded. Data indicate that adoptive therapy with engineered T cells can establish self-antigen-specific tumour protection in the long term without autoimmunity.

CD28 cosignalling does not affect the activation threshold in a chimeric antigen receptor-redirected T-cell attack.

Adoptive immunotherapy of cancer using chimeric antigen receptor (CAR)-engineered T cells with redirected specificity showed efficacy in recent trials. In preclinical models, 'second-generation' CARs with CD28 costimulatory domain in addition to CD3ζ performed superior in redirecting T-cell effector functions and survival. Whereas CD28 costimulation sustains physiological T-cell receptor (TCR)-CD3 activation of naïve T cells, the impact of CD28 cosignalling on the threshold of CAR-mediated activation of pre-stimulated T cells without B7-CD28 recruitment remained unclear. Using CARs of different binding affinities, but same epitope specificity, we demonstrate that CD28 cosignalling neither lowered the antigen threshold nor the binding affinity for redirected T-cell activation. 'Affinity ceiling' above which increase in affinity does not increase T-cell activation was not altered. Accordingly, redirected tumor cell killing depended on the binding affinity but was likewise effective for CD3ζ and CD28-CD3ζ CARs. In contrast to CD3ζ, CD28-CD3ζ CAR-driven activation was not increased further by CD28-B7 engagement. However, CD28 cosignalling, which is required for interleukin-2 induction could not be replaced by high-affinity CD3ζ CAR binding or high-density antigen engagement. We conclude that CD28 CAR cosignalling does not alter the activation threshold but redirects T-cell effector functions.

Temporal discrepancies in the association between the apoB/apoA-I ratio and mortality in incident dialysis patients.

BACKGROUND: In the general population, a high apoB/apoA-I ratio is a strong risk factor for cardiovascular disease and mortality. However, whether this is the case in chronic kidney disease (CKD) patients is currently unknown. STUDY DESIGN: The apoB/apoA-I ratio was evaluated in 391 incident CKD stage 5 patients examined close to dialysis initiation, and again after 1 year of dialysis in a subgroup of 182 patients, subsequently followed for up to 3 years. RESULTS: Baseline values of the apoB/apoA-I ratio as well as changes in the ratio during the first year of dialysis correlated with body mass index (BMI) and fat mass. The baseline apoB/apoA-I ratio showed no association with 4-year mortality. However, after adjustment for confounders, a high apoB/apoA-I ratio (>0.9) predicted short-term (first year) survival [hazard ratio (HR): 0.35; 95% confidence interval (CI): 0.13-0.85)] and long-term (next 3 years) mortality (HR: 1.72; 95% CI: 1.01-2.96). An increase in the apoB/apoA-I ratio during the first year of dialysis was linked to a survival advantage thereafter (HR: 0.48; 95% CI: 0.22-0.98). However, this association lost its significance (HR: 0.62; 95% CI: 0.26-1.36) after adjustment for indices of protein-energy wasting. CONCLUSIONS: A high apoB/apoA-I ratio and an increase in this ratio during the first year on dialysis were associated with short-term survival advantage in CKD patients. This paradoxical relationship represents an example of the so-called reverse epidemiology phenomenon in CKD patients and suggests that the apoB/apoA-I ratio should always be interpreted with caution in this patient population.

[Robotic surgery program in gynecology: Lessons from the first 100 procedures]. / Implantation d'un programme de chirurgie robotique gynécologique : leçons à retenir des 100 premières procédures.

INTRODUCTION: The objective of this work is to report the first 6 months of a robotic program in a surgical gynecological team, trained in advanced laparoscopy, in terms of operating times, complication rate, analgesic consumption and average duration of hospitalization. METHODS: This is a prospective observational study, intended to treat. RESULTS: During the study period, 98 women underwent laparoscopic robot assisted surgery. The average BMI was 27.2kg/m2 (±7). Malignant diseases accounted for 41% of operative indications. Comparing the first 30 procedures to the last 30 procedures, there is a significant decrease in docking times: 14.7min (±7.0) vs 8.9min (±5.0), P=0.009. There is also a trend towards a decrease in operative times for hysterectomy: 151.9min (±56.2) vs 113min (±51.4), P=0.08. The rates of complications were not significantly different at the beginning and end of inclusion during the study (10.0% vs 16.7%). CONCLUSION: The implementation of a robotic surgery program in a gynecological surgery department does not lead to an increase in complications for the patients, including for the first procedures. The learning curve mainly allows a reduction in the robot's installation time.

Benchmarking an 11-qubit quantum computer.

The field of quantum computing has grown from concept to demonstration devices over the past 20 years. Universal quantum computing offers efficiency in approaching problems of scientific and commercial interest, such as factoring large numbers, searching databases, simulating intractable models from quantum physics, and optimizing complex cost functions. Here, we present an 11-qubit fully-connected, programmable quantum computer in a trapped ion system composed of 13 171Yb+ ions. We demonstrate average single-qubit gate fidelities of 99.5[Formula: see text], average two-qubit-gate fidelities of 97.5[Formula: see text], and SPAM errors of 0.7[Formula: see text]. To illustrate the capabilities of this universal platform and provide a basis for comparison with similarly-sized devices, we compile the Bernstein-Vazirani and Hidden Shift algorithms into our native gates and execute them on the hardware with average success rates of 78[Formula: see text] and 35[Formula: see text], respectively. These algorithms serve as excellent benchmarks for any type of quantum hardware, and show that our system outperforms all other currently available hardware.

Intra-tumoral production of IL18, but not IL12, by TCR-engineered T cells is non-toxic and counteracts immune evasion of solid tumors.

Adoptive therapy with engineered T cells shows promising results in treating patients with malignant disease, but is challenged by incomplete responses and tumor recurrences. Here, we aimed to direct the tumor microenvironment in favor of a successful immune response by local secretion of interleukin (IL-) 12 and IL-18 by sadministered T cells. To this end, we engineered T cells with a melanoma-specific T cell receptor (TCR) and murine IL-12 and/or IL-18 under the control of a nuclear-factor of activated T-cell (NFAT)-sensitive promoter. These T cells produced IL-12 or IL-18, and consequently enhanced levels of IFNγ, following exposure to antigen-positive but not negative tumor cells. Adoptive transfer of T cells with a TCR and inducible (i)IL-12 to melanoma-bearing mice resulted in severe, edema-like toxicity that was accompanied by enhanced levels of IFNγ and TNFα in blood, and reduced numbers of peripheral TCR transgene-positive T cells. In contrast, transfer of T cells expressing a TCR and iIL-18 was without side effects, enhanced the presence of therapeutic CD8+ T cells within tumors, reduced tumor burden and prolonged survival. Notably, treatment with TCR+iIL-12 but not iIL-18 T cells resulted in enhanced intra-tumoral accumulation of macrophages, which was accompanied by a decreased frequency of therapeutic T cells, in particular of the CD8 subset. In addition, when administered to mice, iIL-18 but not iIL-12 demonstrated a favorable profile of T cell co-stimulatory and inhibitory receptors. In conclusion, we observed that treatment with T cells engineered with a TCR and iIL18 T cells is safe and able to skew the tumor microenvironment in favor of an improved anti-tumor T cell response.

Percutaneous transluminal coronary angioplasty for acute myocardial infarction: the impact on sexual function in men.

The aim of this study was to evaluate changes in men's sexual function after percutaneous transluminal coronary angioplasty (PTCA) treatment for acute myocardial infarction (MI). Sixty men aged 18-70 years old were included in the study. All patients had acute MI and underwent PTCA. They underwent two post PCTA visits: 3 days and between 4 and 6 months after PTCA. During the first and second visit a standard medical interview was carried out and sexual function data collected using Changes in Sexual Functioning Questionnaire and International Index of Erectile Function (IIEF-15). The results showed no statistical differences in IIEF and CSQF scores before and after PTCA. However, when cutoff points were used, a significant decrease in severe erectile dysfunction (ED) prevalence according to IIEF (25.0% vs 16.7%; P=0.02) was observed. Based on the results, we concluded that sexual function significantly improved in the subset of men with severe ED who underwent PTCA as a treatment for acute MI, 4-6 months after the procedure.

Towards multifunctional MOFs--transforming a side reaction into a post-synthetic protection/deprotection method.

The contaminant commonly found in the important amino-substituted metal-organic framework UiO-66-NH2 has been shown to arise from partial formylation during the synthesis in DMF. Mild conditions have now been developed for both post-synthetic deformylation and near-complete formylation, offering a new post-synthetic protection-deprotection method for the synthesis of multifunctional MOFs.

Stereoselective Solid-Phase Synthesis of ß-Lactams-A Novel Cyclization/Cleavage Step towards 1-Oxacephams.

Despite the antibiotic activity and the attractiveness of ß-lactams, the solid-phase synthesis of this class of compounds has been barely reported. Now the diastereoselective synthesis of the 1-oxacepham 2 from the resin-bound ß-lactam derivative 1 has been achieved in five steps. The synthesis of 2 and other 1-oxacephams is attractive because all the reaction steps proceed in high yield, the purity of the product is high, and the reaction sequence is simple.

The 2-(N-formyl-N-methyl)aminoethyl group as a potential phosphate/thiophosphate protecting group in solid-phase oligodeoxyribonucleotide synthesis.

[reaction in text] The 2-(N-formyl-N-methyl)aminoethyl deoxyribonucleoside phosphoramidite 1 has been synthesized and used in the solid-phase synthesis of an octadecathymidylic acid as a cost-efficient monomer for potential application in the preparation of therapeutic oligonucleotides. The 2-(N-formyl-N-methyl)aminoethyl group can be cleaved from oligonucleotides according to a unique thermolytic cyclodeesterification process at pH 7.0. In addition to being cost-effective, the use of 1 simplifies oligonucleotide postsynthesis processing by eliminating the utilization of concentrated ammonium hydroxide in oligonucleotide deprotection.

Conceptual "Heat-Driven" approach to the synthesis of DNA oligonucleotides on microarrays.

The discovery of deoxyribonucleoside cyclic N-acylphosphoramidites, a novel class of phosphoramidite monomers for solid-phase oligonucleotide synthesis, has led to the development of a number of phosphate protecting groups that can be cleaved from DNA oligonucleotides under thermolytic neutral conditions. These include the 2-(N-formyl-N-methyl)aminoethyl, 4-oxopentyl, 3-(N-tert-butyl)carboxamido-1-propyl, 3-(2-pyridyl)-1-propyl, 2-[N-methyl-N-(2-pyridyl)]aminoethyl, and 4-methythiobutyl groups. When used for 5'-hydroxyl protection of nucleosides, the analogous 1-phenyl-2-[N-methyl-N-(2-pyridyl)]aminoethyloxycarbonyl group exhibited excellent thermolytic properties, which may permit an iterative "heat-driven" synthesis of DNA oligonucleotides on microarrays. In this regard, progress has been made toward the use of deoxyribonucleoside cyclic N-acylphosphoramidites in solid-phase oligonucleotide syntheses without nucleobase protection. Given that deoxyribonucleoside cyclic N-acylphosphoramidites produce oligonucleotides with heat-sensitive phosphate protecting groups, blocking the 5'-hydroxyl of these monomers with, for example, the thermolabile 1-phenyl-2-[N-methyl-N-(2-pyridyl)]aminoethyloxycarbonyl group may provide a convenient thermo-controlled method for the synthesis of oligonucleotides on microarrays.

Formation of endogenous glutamatergic receptors antagonist kynurenic acid--differences between cortical and spinal cord slices.

Rat spinal cord slices produced kynurenic acid (KYNA) upon exposure to L-kynurenine. Aminooxyacetic acid, non-selective aminotransferase inhibitor, and L-glutamate, but neither N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-metyloisoxazolo-4-propionate (AMPA), nor kainate, diminished synthesis of KYNA. L-Glutamate action was less potent in spinal than in cortical slices. Metabotropic agonists, L-(+)-2-amino-4-phosphonobutyrate (L-AP4) and (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (t-ACPD), used in concentrations inhibiting cortical KYNA synthesis, were ineffective in spinal cord. Spinal KYNA production seems less susceptible to inhibitory modulation.

Synthesis of polyhydroxyindolizidines from 5,6-dihydro-2H-pyran-2-one.

(1aR,5aR,5bS,6S,7S)-6,7-Di-tert-butoxy-5-oxo-pyrrolidino[1,2-b]isoxazolidino[4,5-c]tetrahydropyran (8) prepared by (1,3)-dipolar cycloaddition of the cyclic nitrone 6 derived from tartaric acid to 5,6-dihydro-2H-pyran-2-one (7) was transformed into indolizidine 11 via a sequence of reactions involving methanolysis of the lactone ring, intramolecular alkylation of the nitrogen atom promoted by a carbontetrabromide-triphenylphosphine mixture and hydrogenolysis of the N single bond O bond. Decarboxylation of 11 provided known 7-hydroxylentiginosine derivative 14, whereas oxidative decarboxylation gave indolizidine 15 structurally related to castanospermine.

[Efficacy of mononitrate retard therapy in patients with advanced congestive heart failure]. / Skutecznosc monoazotanu retard u chorych z zaawansowana niewydolnoscia krazenia.

To determine the efficacy of mononitrate retard therapy in congestive heart failure 54 pts (42 males and 12 females, aged 67.2 +/- 8.7 yrs.) with NYHA functional class 1-3 and left ventricular ejection fraction less than 40% were investigated. Clinical examination, exercise treadmill test (ETT), ecg holter monitoring and echocardiography (echo-2D) were performed before and after 4 weeks of therapy with Olicard 40 mg Retard. 4 weeks treatment with mononitrate improved clinical parameters. The shift to lower functional NYHA class was observed in 12 cases (p < 0.01). Number of anginal pains per week was reduced from average 3.15 to 1.55 (p < 0.01). Mononitrate therapy improved exercise tolerance during ETT. Exercise time increased from 424 +/- 168 to 568 +/- 143 sec. (p < 0.001) as well as total workload in METS (3.6 +/- 1.4 vs. 4.9 +/- 1.9, p < 0.001). The time to 0.1 mV ischemic ST segment depression was extended from 215 +/- 149 to 357 +/- 173 sec. (p < 0.01). Holter monitoring revealed moderate increase in heart rate and significant reduction of ventricular arrhythmia (p < 0.05). No changes in systolic and diastolic echo-2D parameters were observed.

[Examination of ocular lesions in drug abusers in Poland]. / Badania zmian ocznych wystepujacych po narkotykach uzywanych w Polsce.

The authors present ocular symptoms in 116 drug abusers. They have observed optic atrophy and defects in visual field in 9 cases, reduced convergence in 8 cases, slow pupillary reaction in 9 cases, ptosis in 3 cases, nystagmus in 2 cases, retinal haemorrhages in the nerve fibre layer in 2 cases, myopia in 45 cases and blepharoconjunctivitis in most of cases. The authors want to indicate the principal ocular signs in drug abusers in our country.

The role of epigenetics in kidney diseases.

Epigenetics is the study of changes in gene expression that occur without changes in DNA sequence. These reversible modifications include DNA methylation, histone acetylation and RNA interference. Epigenetic changes are fundamental for the regulatory physiological processes that regulate gene activity; therefore, these changes are altered in response to environmental factors or disease states, but, in many circumstances, they are also believed to contribute to disease occurrence and progression. So far, studies of the epigenome have been scarce in nephrology. However, there is evidence that in the uremic milieu, several features such as inflammation, dyslipidaemia, hyperhomocysteinaema, oxidative stress as well as vitamin and nutritional deficiencies may affect the epigenome, and impact patient outcome. The present review describes the current knowledge on epigenetic alterations in the course of various kidney disease states. Although the science of epigenetics is still in its infancy, it seems that it may help elucidate the pathogenic mechanisms in uraemia, and allow novel treatment strategies to be developed.