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This review focuses on mature T cells, natural killer (NK) cells, and stroma-derived neoplasms in the fifth edition of the World Health Organization classification of hematolymphoid tumors, including changes from the revised fourth edition. Overall, information has expanded, primarily due to advancements in genomic understanding. The updated classification adopts a hierarchical format. The updated classification relies on a multidisciplinary approach, incorporating insights from a diverse group of pathologists, clinicians, and geneticists. Indolent NK-cell lymphoproliferative disorder of the gastrointestinal tract, Epstein-Barr virus-positive nodal T- and NK-cell lymphoma, and several stroma-derived neoplasms of lymphoid tissues have been newly introduced or included. The review also provides guidance on how the fifth edition of the World Health Organization classification of hematolymphoid tumors can be applied in routine clinical practice., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Background: No oral systemic treatments are approved for pediatric patients with psoriasis., Objective: To evaluate the pharmacokinetics and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in pediatric patients with psoriasis., Methods: This phase 2, multicenter, open-label study enrolled pediatric patients with moderate to severe plaque psoriasis. Patients received apremilast twice daily without titration for 2 weeks (group 1 [age, 12-17 years; weight, ≥35 kg]: apremilast 20 or 30 mg; group 2 [age, 6-11 years; weight, ≥15 kg]: apremilast 20 mg), followed by a 48-week extension. Primary endpoints were pharmacokinetics and safety. Other endpoints were taste/acceptability and change from baseline in score on the Psoriasis Area and Severity Index., Results: A total of 42 enrolled patients (21 adolescents [age, 12-17 years] and 21 children [age, 6-11 years]) received apremilast. Pharmacokinetics modeling and noncompartmental analyses showed that weight-based dosing with apremilast 20 mg twice daily in children or apremilast 20 or 30 mg twice daily in adolescents provides exposure (area under the concentration-time curve from time 0 to 12 hours after the dose) that is comparable to that achieved with apremilast 30 mg twice daily in adults. The safety profile was generally similar to that in adults. Most study participants liked the taste of the tablet. Improvements from baseline in mean Psoriasis Area and Severity Index score were 68% for adolescents (overall) and 79% for children., Limitations: No children weighing less than 20 kg were enrolled., Conclusions: This first-time-in-children phase 2 study supports weight-based apremilast dosing for future phase 3 studies of pediatric plaque psoriasis., (Copyright © 2019 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Pathologic reorganization of spinal networks and activity-dependent plasticity are common neuronal adaptations after spinal cord injury (SCI) in humans. In this work, we examined changes of reciprocal Ia and nonreciprocal Ib inhibition after locomotor training in 16 people with chronic SCI. The soleus H-reflex depression following common peroneal nerve (CPN) and medial gastrocnemius (MG) nerve stimulation at short conditioning-test (C-T) intervals was assessed before and after training in the seated position and during stepping. The conditioned H reflexes were normalized to the unconditioned H reflex recorded during seated. During stepping, both H reflexes were normalized to the maximal M wave evoked at each bin of the step cycle. In the seated position, locomotor training replaced reciprocal facilitation with reciprocal inhibition in all subjects, and Ib facilitation was replaced by Ib inhibition in 13 out of 14 subjects. During stepping, reciprocal inhibition was decreased at early stance and increased at midswing in American Spinal Injury Association Impairment Scale C (AIS C) and was decreased at midstance and midswing phases in AIS D after training. Ib inhibition was decreased at early swing and increased at late swing in AIS C and was decreased at early stance phase in AIS D after training. The results of this study support that locomotor training alters postsynaptic actions of Ia and Ib inhibitory interneurons on soleus motoneurons at rest and during stepping and that such changes occur in cases with limited or absent supraspinal inputs., (Copyright © 2015 the American Physiological Society.)

In humans, a chronic spinal cord injury (SCI) impairs the excitability of pathways mediating early flexor reflexes and increases the excitability of late, long-lasting flexor reflexes. We hypothesized that in individuals with SCI, locomotor training will alter the behavior of these spinally mediated reflexes. Nine individuals who had either chronic clinically motor complete or incomplete SCI received an average of 44 locomotor training sessions. Flexor reflexes, elicited via sural nerve stimulation of the right or left leg, were recorded from the ipsilateral tibialis anterior (TA) muscle before and after body weight support (BWS)-assisted treadmill training. The modulation pattern of the ipsilateral TA responses following innocuous stimulation of the right foot was also recorded in 10 healthy subjects while they stepped at 25% BWS to investigate whether body unloading during walking affects the behavior of these responses. Healthy subjects did not receive treadmill training. We observed a phase-dependent modulation of early TA flexor reflexes in healthy subjects with reduced body weight during walking. The early TA flexor reflexes were increased at heel contact, progressively decreased during the stance phase, and then increased throughout the swing phase. In individuals with SCI, locomotor training induced the reappearance of early TA flexor reflexes and changed the amplitude of late TA flexor reflexes during walking. Both early and late TA flexor reflexes were modulated in a phase-dependent pattern after training. These new findings support the adaptive capability of the injured nervous system to return to a prelesion excitability and integration state., (Copyright © 2014 the American Physiological Society.)

Spinal inhibition is significantly reduced after spinal cord injury (SCI) in humans. In this work, we examined if locomotor training can improve spinal inhibition exerted at a presynaptic level. Sixteen people with chronic SCI received an average of 45 training sessions, 5 days/wk, 1 h/day. The soleus H-reflex depression in response to low-frequency stimulation, presynaptic inhibition of soleus Ia afferent terminals following stimulation of the common peroneal nerve, and bilateral EMG recovery patterns were assessed before and after locomotor training. The soleus H reflexes evoked at 1.0, 0.33, 0.20, 0.14, and 0.11 Hz were normalized to the H reflex evoked at 0.09 Hz. Conditioned H reflexes were normalized to the associated unconditioned H reflex evoked with subjects seated, while during stepping both H reflexes were normalized to the maximal M wave evoked after the test H reflex at each bin of the step cycle. Locomotor training potentiated homosynaptic depression in all participants regardless the type of the SCI. Presynaptic facilitation of soleus Ia afferents remained unaltered in motor complete SCI patients. In motor incomplete SCIs, locomotor training either reduced presynaptic facilitation or replaced presynaptic facilitation with presynaptic inhibition at rest. During stepping, presynaptic inhibition was modulated in a phase-dependent manner. Locomotor training changed the amplitude of locomotor EMG excitability, promoted intralimb and interlimb coordination, and altered cocontraction between knee and ankle antagonistic muscles differently in the more impaired leg compared with the less impaired leg. The results provide strong evidence that locomotor training improves premotoneuronal control after SCI in humans at rest and during walking., (Copyright © 2014 the American Physiological Society.)

Heterotopic ossification (HO) is a disabling condition associated with neurologic injury, inflammation, and overactive bone morphogenetic protein (BMP) signaling. The inductive factors involved in lesion formation are unknown. We found that the expression of the neuro-inflammatory factor Substance P (SP) is dramatically increased in early lesional tissue in patients who have either fibrodysplasia ossificans progressiva (FOP) or acquired HO, and in three independent mouse models of HO. In Nse-BMP4, a mouse model of HO, robust HO forms in response to tissue injury; however, null mutations of the preprotachykinin (PPT) gene encoding SP prevent HO. Importantly, ablation of SP(+) sensory neurons, treatment with an antagonist of SP receptor NK1r, deletion of NK1r gene, or genetic down-regulation of NK1r-expressing mast cells also profoundly inhibit injury-induced HO. These observations establish a potent neuro-inflammatory induction and amplification circuit for BMP-dependent HO lesion formation, and identify novel molecular targets for prevention of HO., (Copyright © 2011 Wiley-Liss, Inc.)

Purpose: High-motility group AT-hook gene 1 (HMGA1) is a non-histone nuclear binding protein that is developmentally regulated. HMGA1 is significantly overexpressed in and associated with high grade and advance stage of prostate cancer (PC). The oncogenic role of HMGA1 is at least mediated through chromosomal instability and structural aberrations. However, regulation of HMGA1 expression is not well understood. Identification of microRNA-mediated HMGA1 regulation will provide a promising therapeutic target in treating PC., Experimental Design: In this study, we examined the functional relation between miR-296 and HMGA1 expression in several PC cell lines and a large PC cohort. We further examined the oncogenic property of HMGA1 regulated by miR-296., Results: Here we report that miR-296, a microRNA predicted to target HMGA1, specifically represses HMGA1 expression by promoting degradation and inhibiting HMGA1translation. Repression of HMGA1 by miR-296 is direct and sequence specific. Importantly, ectopic miR-296 expression significantly reduced PC cell proliferation and invasion, in part through the downregulation of HMGA1. Examining PC patient samples, we found an inverse correlation between HMGA1 and miR-296 expression: high levels of HMGA1 were associated with low miR-296 expression and strongly linked to more advanced tumor grade and stage., Conclusions: Our results indicate that miR-296 regulates HMGA1 expression and is associated with PC growth and invasion., (©2010 AACR.)

Background: Ciliary neurotrophic factor (CNTF), a member of the interleukin-6 cytokine family, has been implicated in the development, differentiation and survival of retinal neurons. The mechanisms of CNTF action as well as its cellular targets in the retina are poorly understood. It has been postulated that some of the biological effects of CNTF are mediated through its action via retinal glial cells; however, molecular changes in retinal glia induced by CNTF have not been elucidated. We have, therefore, examined gene expression dynamics of purified Müller (glial) cells exposed to CNTF in vivo., Methodology/principal Findings: Müller cells were flow-sorted from mgfap-egfp transgenic mice one or three days after intravitreal injection of CNTF. Microarray analysis using RNA from purified Müller cells showed differential expression of almost 1,000 transcripts with two- to seventeen-fold change in response to CNTF. A comparison of transcriptional profiles from Müller cells at one or three days after CNTF treatment showed an increase in the number of transcribed genes as well as a change in the expression pattern. Ingenuity Pathway Analysis showed that the differentially regulated genes belong to distinct functional types such as cytokines, growth factors, G-protein coupled receptors, transporters and ion channels. Interestingly, many genes induced by CNTF were also highly expressed in reactive Müller cells from mice with inherited or experimentally induced retinal degeneration. Further analysis of gene profiles revealed 20-30% overlap in the transcription pattern among Müller cells, astrocytes and the RPE., Conclusions/significance: Our studies provide novel molecular insights into biological functions of Müller glial cells in mediating cytokine response. We suggest that CNTF remodels the gene expression profile of Müller cells leading to induction of networks associated with transcription, cell cycle regulation and inflammatory response. CNTF also appears to function as an inducer of gliosis in the retina.

Oral squamous cell carcinoma (OSCC) has 50% 5-year survival rate, highlighting our limited understanding of the molecular events that contribute to disease progression. Microarray analyses of primary oral tumors have identified urinary-type plasminogen activator (uPA) and its receptor (uPAR) as key genes associated with human OSCC progression. The uPAR functions as both a proteinase receptor and an integrin ligand, modifying proteolysis, migration, integrin signaling, and cellular transcription. In the current study, uPAR expression levels were modified in OSCC cells followed by analysis of tumor growth in an in vivo orthotopic xenograft model and by transcriptional profiling. Overexpression of uPAR resulted in more infiltrative and less differentiated tumors, with ill-defined borders, cytologic atypia, and enhanced vascularity. Analysis of serial sections of both murine experimental tumors and microarrayed human OSCC showed a statistically significant association between uPAR and alpha(3) integrin colocalization in areas exhibiting extracellular signal-regulated kinase phosphorylation, suggesting that uPAR/alpha(3) integrin interaction potentiates extracellular signal-regulated kinase signaling in vivo. This is supported by cDNA microarray analysis, which showed differential expression of 148 genes (113 upregulated and 35 downregulated). Validation of gene expression changes in human OSCC using immunohistochemistry and quantitative real-time PCR showed increased growth factors, proteinases/inhibitors, and matrix components in uPAR-overexpressing tumors. Together, these results support a model wherein increased uPAR expression promotes alpha(3)beta(1) integrin association, resulting in increased mitogen-activated protein kinase signaling and transcriptional activation, leading to the formation of more aggressive tongue tumors. This combined approach has efficacy to identify additional biomarkers and/or prognostic indicators associated with aggressive human OSCC.

We elaborate on the diagnosis of CD30 positive cutaneous lymphoproliferative conditions including the various clinical and pathological presentations, our understanding of its pathomechanisms and prognostic implications. The most common reactive conditions that can simulate CD30 lymphoproliferative conditions, including arthropod bite reactions, various viral infections, pityriasis lichenoides and lymphocytic papules in myelodysplastic syndrome, are discussed in detail.

Increasing evidence suggests that the cytoplasmic tail of membrane type 1 matrix metalloproteinase (MT1-MMP) is subject to phosphorylation and that this modification may influence its enzymatic activity at the cell surface. In this study, phosphorylated MT1-MMP is detected using a phospho-specific antibody recognizing a protein kinase C consensus sequence (phospho-TXR), and a MT1-MMP tail peptide is phosphorylated by exogenous protein kinase C. To characterize the potential role of cytoplasmic residue Thr(567) in these processes, mutants that mimic a state of either constitutive (T567E) or defective phosphorylation (T567A) were expressed and analyzed for their functional effects on MT1-MMP activity and cellular behavior. Phospho-mimetic mutants of Thr(567) exhibit enhanced matrix invasion as well as more extensive growth within a three-dimensional type I collagen matrix. Together, these findings suggest that MT1-MMP surface action is regulated by phosphorylation at cytoplasmic tail residue Thr(567) and that this modification plays a critical role in processes that are linked to tumor progression.

Heterotopic ossification (HO), the abnormal formation of true marrow-containing bone within extraskeletal soft tissues, is a serious bony disorder that may be either acquired or hereditary. We utilized an animal model of the genetic disorder fibrodysplasia ossificans progressiva to examine the cellular mechanisms underlying HO. We found that HO in these animals was triggered by soft tissue injuries and that the effects were mediated by macrophages. Spreading of HO beyond the initial injury site was mediated by an abnormal adaptive immune system. These observations suggest that dysregulation of local stem/progenitor cells could be a common cellular mechanism for typical HO irrespective of the signal initiating the bone formation.

Objectives: To evaluate the safety, outcomes, and complications of percutaneous liver biopsies (PLB) in infants aged 0 to 3 months., Methods: We retrospectively reviewed the hospital records of all infants less than 3 months old who underwent PLB at Children's Memorial Hospital between July 1, 1997 and June 30, 2004 for complications surrounding the procedure and risk factors that might lead to complications., Results: Sixty-six PLBs were performed in 63 infants. Most patients tolerated the procedure without complications. Twelve complications were recorded, for an overall complication rate of 18%. Of these, five were directly related to the procedure, and seven were sedation related. Three patients experienced a drop in hemoglobin greater than 2 gm/dL, one patient developed a bile leak, and one developed a skin hematoma. Seven patients had respiratory difficulty related to sedation, which manifested as increased work of breathing or decreased respiratory rate with depression in pulse oximetry., Conclusion: We conclude that PLB in young infants is associated with a somewhat higher risk of complications than in older children, particularly complications related to sedation.

This article reviews safety, efficacy, and complications of intracervical osmotic devices and discusses diagnostic, therapeutic, and preventative measures for managing them. Osmotic dilators have been used to ripen the cervix in gynecologic and obstetric procedures for centuries. Their gradual effect in softening and dilating the cervix reduces the chance of stretch injury or perforation and could enhance completeness of evacuation of the uterine cavity. Natural and synthetic devices are available, each with unique properties. Notwithstanding major advances in prostaglandin analogs as cervical ripeners, these mechanical devices continue to play a vital role in cervical preparation. In the event of an unfavorable cervix, they are adjuncts for accelerating inductions of labor and for safe uterine entry during hysteroscopy and diagnostic dilation and curettage. For inducing pregnancy, they are routinely used as cervical ripeners from the late first trimester onward. The English-language literature was surveyed. The author used citations from a MEDLINE search, 2 unpublished case reports, and personal experience. Laminaria and Dilapan dilators can get trapped and fragment with the potential for serious adverse clinical and legal consequences. Lamicel devices do not share this feature. Serious infection is uncommon and anaphylaxis is rare. Timely, well-selected imaging techniques can aid diagnosis. Preventative measures could reduce the number and severity of osmotic dilator-associated complications. Measures suggested by some include predilating with metal dilators, incorporating laminaria or Lamicel devices with Dilapan, adding misoprostol, and using sonohysterography. However, these measures, singly and in combination, are unlikely to eliminate all complications.

This "Part II morphology and cytoarchitecture" study is based on paraffin-embedded specimens in which the extracellular and intracellular matrix are preserved; single parallel, perpendicular, and transverse serial sections of the entire atrioventricular (AV) junction region (AVJR) and their correlation with photographs of the tissue blocks. As in Part I, the same major new findings are: 1) a coronary sinus fossa is formed by the superoposterior right medial atria wall (MAW), the left atrium, and the coronary sinus roof; 2) the posterior MAW forms two myocardial bridges and is isolated from the sinus venarum by the floor of the inferior vena cava; 3) the tendon of Todaro terminates in the superior lip of the coronary sinus ostium; 4) only ordinary myocardium contacts the annulus fibrosus, and there is little to no collagen separating its myofibers and tissues; 5) the ventricular septum shoulder is humped shaped, completely overlaid by annular myocardium, and joined by struts of papillary muscle; 6) the membranous septum joining the ventricular septum shoulder to the crista supraventricularis forms part of the aortic valve sinus walls; and 7) myocardium of the atrionodal bundles is aggregated into numerous small fascicles encased by collagen and is outside of the MAW as are the other specialized tissues. The proximal AV bundle and medial atrionodal bundle are aligned to the medial leg of Koch's triangle and the tendon of Todaro. These data show, therefore, that the AVJR contains two overlapping atrial circuits. In the MAW, acivation of the posterior region is delayed because of the two myocardial bridges. Puncture of the AVJR can produce communication with an extracardiac space, posteriorly and medially, and with the aorta, anteriorly.

Infection with different picornaviruses can cause meningitis/encephalitis in humans and experimental animals. To investigate the mechanisms of such inflammatory diseases, potential chemokine gene activation in human astrocytes was investigated following infection with Theiler's murine encephalomyelitis virus (TMEV), coxsackievirus B3 (CVB3), or coxsackievirus B4 (CVB4). We report that all these viruses are potent inducers for the expression of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) genes in primary human astrocytes, as well as in an established astrocyte cell line (U-373MG). Further studies indicated that both activator protein-1 (AP-1) and NF-kappaB transcription factors are required in the activation of chemokine genes in human astrocytes infected with various picornaviruses. Interestingly, the pattern of activated chemokine genes in human astrocytes is quite restricted compared to that in mouse astrocytes infected with the same viruses, suggesting species differences in gene activation. This may result in potential differences in the pathogenic outcome in each species., (Copyright 2003 Wiley-Liss, Inc.)