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// Katarzyna Izykowska 1 , Grzegorz K. Przybylski 1 , Claudia Gand 2 , Floriane C. Braun 2 , Piotr Grabarczyk 2 , Andreas W. Kuss 3 , Karolina Olek-Hrab 4 , Armando N. Bastidas Torres 5 , Maarten H. Vermeer 5 , Willem H. Zoutman 5 , Cornelis P. Tensen 5 , Christian A. Schmidt 2 1 Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland 2 Clinic for Internal Medicine C, University Medicine Greifswald, Greifswald, Germany 3 Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany 4 Department of Dermatology, Karol Marcinkowski University of Medical Sciences, Poznan, Poland 5 Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands Correspondence to: Grzegorz K. Przybylski, email: grzegorz.przybylski@igcz.poznan.pl Keywords: Sezary syndrome, NGS, whole genome, RNASeq, rearrangement Received: July 26, 2016 Accepted: March 27, 2017 Published: April 24, 2017 ABSTRACT Sezary syndrome (SS) is an aggressive, leukemic cutaneous T-cell lymphoma variant. Molecular pathogenesis of SS is still unclear despite many studies on genetic alterations, gene expression and epigenetic regulations. Through whole genome and transcriptome next generation sequencing nine Sezary syndrome patients were analyzed in terms of copy number variations and rearrangements affecting gene expression. Recurrent copy number variations were detected within 8q ( MYC, TOX ), 17p ( TP53, NCOR1 ), 10q ( PTEN, FAS ), 2p ( DNMT3A ), 11q ( USP28 ), 9p ( CAAP1 ), but no recurrent rearrangements were identified. However, expression of five genes involved in rearrangements ( TMEM244, EHD1, MTMR2, RNF123 and TOX) was altered in all patients. Fifteen rearrangements detected in Sezary syndrome patients and SeAx resulted in an expression of new fusion transcripts, nine of them were in frame ( EHD1-CAPN12, TMEM66-BAIAP2, MBD4-PTPRC, PTPRC-CPN2, MYB-MBNL1, TFG-GPR128, MAP4K3-FIGLA, DCP1A-CCL27, MBNL1-KIAA2018 ) and five resulted in ectopic expression of fragments of genes not expressed in normal T-cells ( BAIAP2, CPN2, GPR128, CAPN12, FIGLA). Our results not only underscored the genomic complexity of the Sezary cancer cell genome but also showed an unpreceded large variety of novel gene rearrangements resulting in fusions transcripts and ectopically expressed genes.

The 6q23-27 region, recurrently deleted in Sézary syndrome (SS), was characterized at the molecular level in 13 SS patients and SS cell line SeAx. Using fine-tiling comparative genomic hybridization, deletions within the 6q23-27 region were detected in half of the samples (six patients and SeAx). All samples with deletions were further analyzed by ligation-mediated PCR. In addition, in one patient sample and in SeAx, paired-end next-generation sequencing was performed on the HiSeq2000 Illumina platform. Using those techniques, 23 rearrangements associated with the deletions were identified. The majority of rearrangements showed enormous complexity and diversity, including eight inversions, three transpositions, and four translocations (with chromosomes 3, 17, 10, and 12). Fifteen genes were disrupted by those rearrangements, the MYB proto-oncogene three times and the interleukin-22 receptor subunit alpha-2 gene (IL22RA2) twice. All three patients with MYB alterations showed low MYB expression, whereas seven of the remaining patients showed overexpression. Most patients overexpressing MYB also presented increased expression of MYC, HSPA8, and BCL2. Five gene fusions were identified, of which two, CCDC28A-IL22RA2 and AIG1-GOSR1, both in SeAx, were in the same orientation and were expressed at the messenger RNA level.

Despite recent therapeutic improvements, the prognosis for patients suffering from Sézary syndrome (SS), a disseminated form of cutaneous T-cell lymphomas, is still poor. We identified bi- and monoallelic deletions of the tumor necrosis factor-α-induced protein 3 gene (TNFAIP3; A20) in a high proportion of SS patients as well as biallelic A20 deletion in the SS-derived cell line SeAx. Furthermore, we demonstrate that inhibition of A20 activates the NF-κB pathway thereby increasing the proliferation of normal T lymphocytes. On the other hand, the reconstitution of A20 expression slowed down the cell cycle in SeAx cells. Recently A20 inactivation has been reported in various B-cell lymphomas. In this study, we show that A20 is also a putative tumor suppressor in the T-cell malignancy-SS.

A20 is an ubiquitin-editing enzyme that ensures the transient nature of inflammatory signaling pathways induced by cytokines like TNF-α and IL-1 or pathogens via Toll-like receptor (TLR) pathways. It has been identified as a negative regulator of dendritic cell (DC) maturation and attenuator of their immunostimulatory properties. Ex vivo A20-depleted dendritic cells showed enhanced expression of pro-inflammatory cytokines and costimulatory molecules, which resulted in hyperactivation of tumor-infiltrating T lymphocytes and inhibition of regulatory T cells. In the present study, we demonstrate that a synthetic molecule consisting of a CpG oligonucleotide TLR9 agonist linked to A20-specific siRNAs silences its expression in TLR9+ mouse dendritic cells in vitro and in vivo. In the B16 mouse melanoma tumor model, silencing of A20 enhances the CpG-triggered induction of NFκB activity followed by elevated expression of IL-6, TNF-α and IL-12. This leads to potentiated antitumor immune responses manifested by increased numbers of tumor-specific cytotoxic T cells, high levels of tumor cell apoptosis and delayed tumor growth. Our findings confirm the central role of A20 in controlling the immunostimulatory potency of DCs and provide a strategy for simultaneous A20 silencing and TLR activation in vivo.

There are reports that age of broiler breeders and turkey breeders can influence offspring performance; however, there are no data to support such possibilities in the Pekin duck. The effects of breeder age (prepeak and postpeak egg production) on fertility and hatchability were evaluated. Additionally, after hatch the effects of breeder age on body weight gain, feed conversion rates, and mortality through 8 d of age were investigated. These data suggest that prepeak breeders (24 wk of age) exhibit lower levels of fertility and reduced hatch of fertile eggs. In addition, ducklings from prepeak breeders display lower body weight gains and higher mortality rates when compared to their counterpart hatched from peak or postpeak breeders.

Marked WISC-R verbal-performance discrepancy commonly leads to the assumption that such children have brain pathology or cognitive disorders. Children without brain dysfunction may also exhibit wide discrepancy, but a discrepancy score of 30 is assumed to occur in only 2% of the population. The actual investigation presents an 11-year-old child showing a 54-point discrepancy between the two scales of the WISC-R. Results of wide ranging testing and other considerations strongly suggested that this child didn't manifest any kind of brain dysfunction. It was concluded that the particular academic environment of the child, an alternative school, exerted a very strong influence on her results on the WISC-R. This conclusion is furthermore supported by the results of a follow-up evaluation, done 1 year after the child has been transferred to a traditional school, which revealed a WISC-R verbal-performance discrepancy of only 12 points.

In the wake of, and as a complement to, a recently published major meta-analytic review of empirical support of the Geschwind-Behan-Galaburda model (GBGM) of cerebral lateralization (CL) the present brief essay attempts to present a critical assessment of the theoretical approach underlying the GBGM. The GBGM is criticized for having been misguided in its representation of the cerebral basis of handedness, and of the links between testosterone and immune function. Some guidelines are presented for the development of a general theory of CL, emphasizing animal research, greater interdisciplinary communication, a hierarchical model-building approach, and the relevance of neuropharmacology and psychiatry.

Callosal agenesics and callosotomized epileptics manifest markedly increasing simple visual reaction time (SVRT) from conditions of ipsilateral to contralateral stimulus-response relation (SRR). In the contralateral SRR, a response is presumed possible because of presence of other commissures (anterior, intercollicular). The SRR effect is prolonged presumably because the remaining commissures are less efficient than the corpus callosum in relaying necessary visual or motor information. Consequently, the SRR effect is believed to correspond to callosal relay time (CRT) in the normal subject. However, both callosal agenesics and callosotomy patients manifest general slowing of SVRT in addition to a prolonged SRR effect. These patients have massive extra-callosal damage which could plausibly cause both the SVRT and the CUD prolongation. If such were the case, the CRT inference would be in jeopardy. A test of the CRT inference is therefore required where patients with massive diffuse extra-callosal brain damage and normal callosi would show marked general SVRT prolongation and a normal SRR effect. Four trisomy-21 (T21) males were compared to age and sex-matched normal controls. General SVRT was highly significantly prolonged in T21, but the CUD was nearly identical in both groups.

The purpose of this study was to investigate the effects of duck breeder age on liver lipid accumulation and yolk absorption and utilization in duck embryos (day 25 of incubation) and newly hatched ducklings. One breeder flock was monitored at 24 (young breeders), 31 (mature breeders and near peak egg production) and 47 (post peak egg production) weeks of age. Electron microscopy images of duck embryo liver slices revealed a significant change in hepatic lipid accumulation as a function of breeder age. More specifically, as breeder age increased both the relative number of liver lipid droplets as well as the size of the lipid droplets increased in duck embryos (day 25 of incubation). At hatch, however, newly hatched ducklings from 31-week-old breeders exhibited the lowest number as well as the smallest sized lipid droplets when compared to ducklings from 24 or 47-week-old breeders. The trend in yolk absorption at day 25 as a function of breeder age paralleled that in liver lipid accumulation. That is, day 25 maintained a higher percentage of unabsorbed yolk when compared to embryos from 31- or 47-week-old breeders. In contrast to breeder age, time of incubation (day 25 vs. day 28 or hatch) had little effect on yolk fatty acid profiles when compared to breeder age. Although there were no clear trends in yolk fatty acid usage among the various ages of breeders, newly hatched ducklings from 31-week-old breeders did have a significantly higher proportion of 18:2 n6 compared to those from breeders at 24 or 47 weeks of age. These data would suggest that breeder age subsequently affects the relative number and size of liver lipid droplets in embryos and newly hatched ducklings.

Simple and complex visuomotor performance of the right and left sides of the body was investigated in 37 children with left hemisphere lesions, 35 children with right hemisphere lesions, 53 developmentally dyslexic children, 29 developmentally hyperactive children, and 35 "normal" children who had endured a very mild head injury with no sequelae.Lateralized soft signs, EEG topography, metabolic brain imaging, and neuropsychological test profiles suggest a predominance of left hemisphere dysfunction in dyslexia and right hemisphere dysfunction in hyperactivity.Nine measures of lateralized performance were drawn from the Purdue pegboard, Letter cancellation, Rey complex figure, Wechsler Intelligence Scale for Children (WISC) Mazes, and WISC Picture completion tests.The children with left hemisphere lesions manifested significantly weaker performance on test components involving the right body side, relative to the normal controls, on the Purdue pegboard, Rey complex figure (delayed recall condition), and WISC Picture completion tests, and the dyslexic children on the former two. The children with right hemisphere lesions manifested significantly weaker performance on test components involving the left body side, relative to the normal controls, on the WISC Mazes test, as did the hyperactive children.We propose that (1) contralateral performance decrement results from a unilateral cortical lesion in children, and (2) developmental dyslexia may comprise a slight predominance of left hemisphere dysfunction and developmental hyperactivity of right hemisphere dysfunction.

We describe a seven year old child with a hypothalamic hamartoma. Classical symptoms of hypothalamic hamartoma include gelastic epileptic laughter, precocious puberty, aggressiveness, and progressively worsening epilepsy. After a normal first few years of life, this case presents all these symptoms except the precocious puberty. He has a markedly morbid personality disorder: he assaults strangers and relatives, bites people, spits in their faces unpredictably, is coprolalic and coprophagic, has gelastic laughter, puts pencils, erasers, and other non-comestible objects in his mouth, chews and ingests them, has tics (plays noisily with his saliva, empty chewing, compulsive spitting) and is self-injurious. None of the medications attempted to date have been of any help. Medical prognosis is somber, and this case is difficult to institutionalize, the more "congenial" institutions being insufficiently equipped to protect him and the beneficiaries and staff from his aggressive behavior. MRI showed the typical profile of hypothalamic hamartoma, and the diagnosis was confirmed with partial resection. This case illustrates that a tiny lesion, the size of a small cherry, can have extremely morbid psychological consequences. Detailed neuropsychological evaluation, certain unusual electroencephalographic traits and neurosurgical issues are discussed.

Brown and colleagues (1994) found that most evoked potential studies provide evidence of faster interhemispheric relay from the right to the left hemisphere, as determined from N160 latencies derived from parietal and occipital electrode sites. The experiment reported here was designed to complement those findings by 1) analyzing more electrode sites (several frontal, temporal, and central sites in addition to the previously investigated sites) and more waveforms (P1 and P2 waves); 3) introducing analysis of amplitude data; 4) carrying out site-specific and experiment-wise inference tests of putative interhemispheric relay asymmetry. We found that all of the conclusions of Brown and colleagues, regarding latency effects, could be extended to the ensemble of electrode sites and waveforms. However, amplitude effects were significantly compatible with stronger (though slower) relay from the left to the right hemisphere.

This consecutive multiple case study was designed to determine whether cortical lesion sites can predict occurrence of mood or psychomotor disorders in adults and children.Most of a large body of research supports the contention that left hemisphere lesions result more often than right ones in depression, and that the inverse occurs in mania. However, it is not clear how psychomotor status fits into this picture, nor whether children respond to the same lesions in a similar manner.Published (n = 88) and unpublished (n = 31) cases of school-aged child and adult patients with focal unilateral cortical lesions and psychomotor agitation or lethargy with or without corresponding mania or depression were reviewed systematically to determine whether lesion location relates systematically to any of those psychiatric conditions. No patients had symptoms prior to detection of their lesion. Manic-depressives and agitated depressives were also excluded.Patients with mania and/or psychomotor agitation had predominantly right hemisphere lesions. Postlesion hyperactivity (without mania) in children was common but was not more related to lesions in one or the other hemisphere. Adult and child patients with depression and/or psychomotor lethargy had predominantly left hemisphere lesions. The intrahemispherical site of the lesion did not significantly predict the type of mood or psychomotor disorder. Nevertheless, the nonsignificant trend was for right posterorolandic lesions to predict mania or agitation and for left frontal lesions to predict depression or psychomotor lethargy.These findings support the neuropsychiatric approach to mood and psychomotor disorder in children and adults.

Akathisia, "inability to remain seated", is a common condition in patients medicated with neuroleptics, and also occurs in other medication regimens. Only a few cases of akathisia resulting from focal lesions have been published. These cases suggest that differing lesion sites are sufficient for producing objective or subjective akathisia. The authors present a patient with akathisia who had no subjective complaints, suggesting that a combined basal ganglia and frontal lobe lesion may lead to objective akathisia (pseudoakathisia).

Sergent (1982a, 1982b, 1982c) proposed that stimuli carrying high luminous energy will be better detected in the right field (left hemisphere) and stimuli carrying low energy in the left visual field (right hemisphere). A photoreceptor-based model could explain the same effects as well as several others (eccentricity effects, retinal adaptation effects). Braun, Mailloux, and Dufresne (1995) suggested that cones might favor right field stimuli and rods might favor left field stimuli. We implemented a series of near-threshold simple detection experiments comprising stimuli varying along four dimensions (color, eccentricity, duration, and size) in dark-adapted subjects. Consistent and significant right field advantages accrued for near-meridianal foveal red stimuli, but there were no field effects for eccentric blue stimuli. An alternative to Sergent's stimulus energy model and the photoreceptor-based model, namely a parvocellular-magnocellular model, is proposed.

Acoustic analysis of unvoiced diadochokinetic respiratory cycles helped identify two kinds of impairments in ten Friedreich's ataxia patients. Four patients manifested moderate problems maintaining regularity in the repetition of unvoiced respiratory cycles, and also showed moderate articulatory dysarthric problems in a syllabic repetition task. Six patients had severe respiratory insufficiency in the inspiration/expiration repetition task, and exhibited very important amplitude and fundamental frequency disturbances and a much slower rate of syllabic utterances. This respiratory insufficiency and aggravated speech disorders were linked to presence of pontine and medullary atrophy, sites comprising the respiratory centers of the brain stem.

Electrochemistry uses current and impedance data to derive chemical rate constants and to obtain information about reaction mechanisms, usually with techniques operating below 100 kHz. By the application of time-domain spectroscopy this region can be extended to nano- or picoseconds and information about the electronic structure of cell components, e.g. electrodes, can be obtained. Fast transient faradic and nonfaradic currents of electrochemical cells can be measured conveniently by a new apparatus which combines the conventional time domain spectroscopy configuration with a potentiostat. The system is applied to semiconductor electrodes in contact with an aqueous electrolyte and multiexponential relaxation spectra are observed.