Cerebrospinal fluid and ophthalmic disease.

PURPOSE OF REVIEW: The purpose of this review is to discuss the contemporary body of literature examining the relationship between cerebrospinal fluid (CSF) and ophthalmic disease. This review focuses on diseases that have a pathogenesis related to the translaminar pressure difference, defined as the pressure difference between the orbital subarachnoid space (OSAS) and the intraocular pressure. The diseases discussed include glaucoma, idiopathic intracranial hypertension, and spaceflight associated neuro-ocular syndrome. RECENT FINDINGS: The relationship between cerebrospinal and ophthalmic disease has been investigated for over 100 years. Recent research provides insight into the mechanisms that dictate CSF circulation in the OSAS and how alterations in these mechanism lead to disease. This review discusses these recent findings and their relationship to major ophthalmic diseases. SUMMARY: The recent findings provide insight into diseases that have pathogenic mechanisms that are not fully understood. This information will help physicians gain a clearer understanding of the relationship between CSF and ophthalmic disease and guide future research.

Bottom trawl fishing footprints on the world's continental shelves.

Bottom trawlers land around 19 million tons of fish and invertebrates annually, almost one-quarter of wild marine landings. The extent of bottom trawling footprint (seabed area trawled at least once in a specified region and time period) is often contested but poorly described. We quantify footprints using high-resolution satellite vessel monitoring system (VMS) and logbook data on 24 continental shelves and slopes to 1,000-m depth over at least 2 years. Trawling footprint varied markedly among regions: from <10% of seabed area in Australian and New Zealand waters, the Aleutian Islands, East Bering Sea, South Chile, and Gulf of Alaska to >50% in some European seas. Overall, 14% of the 7.8 million-km2 study area was trawled, and 86% was not trawled. Trawling activity was aggregated; the most intensively trawled areas accounting for 90% of activity comprised 77% of footprint on average. Regional swept area ratio (SAR; ratio of total swept area trawled annually to total area of region, a metric of trawling intensity) and footprint area were related, providing an approach to estimate regional trawling footprints when high-resolution spatial data are unavailable. If SAR was ≤0.1, as in 8 of 24 regions, there was >95% probability that >90% of seabed was not trawled. If SAR was 7.9, equal to the highest SAR recorded, there was >95% probability that >70% of seabed was trawled. Footprints were smaller and SAR was ≤0.25 in regions where fishing rates consistently met international sustainability benchmarks for fish stocks, implying collateral environmental benefits from sustainable fishing.

B-cell receptor-mediated NFATc1 activation induces IL-10/STAT3/PD-L1 signaling in diffuse large B-cell lymphoma.

Knowledge of programmed death ligand 1 (PD-L1) expression and its regulation in B-cell lymphoma cells is limited. Investigating mechanisms that control PD-L1 expression in B-cell lymphoma cells might identify biomarkers that predict the efficacy of immunotherapy with anti-programmed death-1/PD-L1 antibodies. In addition, identification of mechanisms that regulate PD-L1 may identify molecules that can be targeted to improve the clinical efficacy of immune checkpoint inhibitors. In this study, we used proteomic approaches and patient-derived B-cell lymphoma cell lines to investigate mechanisms that regulate PD-L1 expression. We found that PD-L1 expression, particularly in nongerminal center B cell-derived diffuse large B-cell lymphoma (DLBCL), is controlled and regulated by several interactive signaling pathways, including the B-cell receptor (BCR) and JAK2/STAT3 signaling pathways. We found that that BCR-mediated NFATc1 activation upregulates IL-10 chemokine expression in PD-L1+ B-cell lymphoma cells. Released IL-10 activates the JAK2/STAT3 pathway, leading to STAT3-induced PD-L1 expression. IL-10 antagonist antibody abrogates IL-10/STAT3 signaling and PD-L1 protein expression. We also found that BCR pathway inhibition by BTK inhibitors (ibrutinib, acalabrutinib, and BGB-3111) blocks NFATc1 and STAT3 activation, thereby inhibiting IL-10 and PD-L1 expression. Finally, we validated the PD-L1 signaling network in 2 primary DLBCL cohorts consisting of 428 and 350 cases and showed significant correlations among IL-10, STAT3, and PD-L1. Thus, our findings reveal a complex signaling network regulating PD-L1 expression in B-cell lymphoma cells and suggest that PD-L1 expression can be modulated by small molecule inhibitors to potentiate immunotherapies.

Analysis of a volumetric-modulated arc therapy (VMAT) single phase prostate template as a class solution.

AIM: To assess a class solution template for volumetric-modulated arc therapy (VMAT) for prostate cancer using plan analysis software. BACKGROUND: VMAT is a development of intensity-modulated radiotherapy (IMRT) with potential advantages for the delivery of radiotherapy (RT) in prostate cancer. Class solutions are increasingly used for facilitating RT planning. Plan analysis software provides an objective tool for evaluating class solutions. MATERIALS AND METHODS: The class solution for VMAT was based on the current static field IMRT template. The plans of 77 prostate cancer patients were evaluated using a set of in-house plan quality metrics (scores) (PlanIQ™, Sun Nuclear Corporation). The metrics compared the class solution for VMAT planning with the IMRT template and the delivered clinical plan (CP). Eight metrics were associated with target coverage and ten with organs-at-risk (OAR). Individual metrics were summed and the combined scores were subjected to non-parametric analysis. The low-dose wash for both static IMRT and VMAT plans were evaluated using 40 Gy and 25 Gy isodose volumes. RESULTS: VMAT plans were of equal or better quality than the IMRT template and CP for target coverage (combined score) and OAR combined score. The 40 Gy isodose volume was marginally higher with VMAT than IMRT (4.9%) but lower than CP (-6.6%)(P = 0.0074). The 25 Gy volume was significantly lower with VMAT than both IMRT (-32.7%) and CP (-34.4%)(P < 0.00001). CONCLUSIONS: Automated VMAT planning for prostate cancer is feasible and the plans are equal to or better than the current IMRT class solution and the delivered clinical plan.

The Significance of Hypothermia in Abdominal Aortic Aneurysm Repair.

BACKGROUND: The aim of this study was to review the literature on the association between hypothermia and outcomes in open and endovascular abdominal aortic aneurysm (AAA) repair. The secondary aim was to determine whether there is a difference in body temperature in patients undergoing either transperitoneal (TP), retroperitoneal (RP), or endovascular surgical repair of the abdominal aorta (EVAR). METHODS: MEDLINE, Web of Science, and Trip searched for all studies on temperature in the context of aortic surgery or endovascular aortic interventions. To be included in the review, the papers had to be related to intraoperative or postoperative hypothermia and/or normothermia, with regards to either open or endovascular repair of the abdominal aorta. Thoracic or thoracoabdominal aortic repairs were not included for review. RESULTS: Eight studies involving 765 patients were eligible. Of these, 6 studies looked at open elective AAA repair involving 605 patients. Only 2 studies investigated emergency AAA repair and consisted of 160 patients where only 35 of those patients underwent emergency EVAR. Normothermic patients had a shorter length of stay in the intensive care unit (P = 0.0008), while hypothermia was independently associated with higher rates of organ dysfunction, in-hospital mortality, and prolonged hospital length of stay. In ruptured AAAs, the lowest average intraoperative temperature was recorded in open repair compared with EVAR (P = 0.02). There was no statistically significant difference in postoperative temperature between patients undergoing elective RP repair and those having TP surgery. CONCLUSIONS: The studies identified in this review have shown that hypothermia has numerous deleterious effects on outcomes in AAA repair - whether or not these adverse outcomes are those such as higher rates of organ dysfunction, mortality or prolonged hospital length of stay, can only be done at the single paper level and not at a literature review level, due to multiple confounding variables. Despite these limitations, the benefits of this review are numerous. This article highlights the importance of core body temperature and outcomes of AAA repair. Furthermore, it brings forth the need to standardize the method of core body temperature measurement and method of rewarming. Given the body of evidence so far, these standardized data collection points will be important for national vascular quality improvement initiatives. Only through rigorous analysis of standardized dataset can firm recommendation regarding peri- and postoperative temperature management be made.

Constitutive BR3 receptor signaling in diffuse, large B-cell lymphomas stabilizes nuclear factor-κB-inducing kinase while activating both canonical and alternative nuclear factor-κB pathways.

Aberrant nuclear factor κB (NF-κB) signaling has been found to be of particular importance in diffuse, large B-cell lymphoma (DLBCL) cell survival and proliferation. Although the canonical NF-κB signaling pathway has been studied in some detail, activation of the alternative NF-κB pathway in DLBCL is not well characterized. Important insights into the regulation of the alternative NF-κB pathway in B lymphocytes has recently revealed the regulatory importance of the survival kinase NIK (NF-κB-inducing kinase) in genetically engineered murine models. Our studies demonstrate that both the canonical and alternative NF-κB pathways are constitutively activated in DLBCL. We also demonstrate that NIK kinase aberrantly accumulates in DLBCL cells due to constitutive activation of B-cell activation factor (BAFF)-R (BR3) through interaction with autochthonous B-lymphocyte stimulator (BLyS) ligand in DLBCL cells. Activation of BR3 in DLBCL induces recruitment and degradation of tumor necrosis factor receptor-associated factor 3, which results in NIK kinase accumulation, IκBα phosphorylation, and NF-κB p100 processing, thereby resulting in continuous activation of both NF-κB pathways in DLBCL cells, leading to autonomous lymphoma cell growth and survival. These results further elucidate mechanisms involved in abnormal NF-κB activation in DLBCL, and should contribute to better future therapeutic approaches for patients with DLBCL.

The microenvironment in mantle cell lymphoma: cellular and molecular pathways and emerging targeted therapies.

There is growing evidence suggesting that cross talk between mantle cell lymphoma (MCL) cells and stromal cells in tissue microenvironments, such as the bone marrow and secondary lymphoid organs, causes disease progression by promoting lymphoma cell survival, growth, and drug resistance. Conceivably, while conventional treatment eliminates the bulk of MCL cells, residual lymphoma cells may lurk in protective tissue niches, where they receive signals from accessory cells that promote survival and drug-resistance, thereby paving the way for residual disease and relapses. Based on this concept, the lymphoma microenvironment has become a growing area of current research, and initial clinical trials targeting cross talk between MCL cells and their microenvironment are showing promising early results. In this review, we summarize key cellular and molecular interactions between MCL cells and their microenvironment, and update new clinical developments in this area.

An epigenetic chromatin remodeling role for NFATc1 in transcriptional regulation of growth and survival genes in diffuse large B-cell lymphomas.

The nuclear factor of activated T cells (NFAT) family of transcription factors functions as integrators of multiple signaling pathways by binding to chromatin in combination with other transcription factors and coactivators to regulate genes central for cell growth and survival in hematopoietic cells. Recent experimental evidence has implicated the calcineurin/NFAT signaling pathway in the pathogenesis of various malignancies, including diffuse large B-cell lymphoma (DLBCL). However, the molecular mechanism(s) underlying NFATc1 regulation of genes controlling lymphoma cell growth and survival is still unclear. In this study, we demonstrate that the transcription factor NFATc1 regulates gene expression in DLBCL cells through a chromatin remodeling mechanism that involves recruitment of the SWItch/Sucrose NonFermentable chromatin remodeling complex ATPase enzyme SMARCA4 (also known as Brahma-related gene 1) to NFATc1 targeted gene promoters. The NFATc1/Brahma-related gene 1 complex induces promoter DNase I hypersensitive sites and recruits other transcription factors to the active chromatin site to regulate gene transcription. Targeting NFATc1 with specific small hairpin RNA inhibits DNase I hypersensitive site formation and down-regulates target gene expression. Our data support a novel epigenetic control mechanism for the transcriptional regulation of growth and survival genes by NFATc1 in the pathophysiology of DLBCL and suggests that targeting NFATc1 could potentially have therapeutic value.

Lenalidomide treatment promotes CD154 expression on CLL cells and enhances production of antibodies by normal B cells through a PI3-kinase-dependent pathway.

Chronic lymphocytic leukemia (CLL) involves a profound humoral immune defect and tumor-specific humoral tolerance that directly contribute to disease morbidity and mortality. CD154 gene therapy can reverse this immune defect, but attempts to do this pharmacologically have been unsuccessful. The immune-modulatory agent lenalidomide shows clinical activity in CLL, but its mechanism is poorly understood. Here, we demonstrate that lenalidomide induces expression of functional CD154 antigen on CLL cells both in vitro and in vivo. This occurs via enhanced CD154 transcription mediated by a Nuclear Factor of Activated T cells c1 (NFATc1)/Nuclear Factor-kappaB (NF-kappaB) complex and also through phosphoinositide-3 (PI3)-kinase pathway-dependent stabilization of CD154 mRNA. Importantly, CD154-positive CLL cells up-regulate BID, DR5, and p73, become sensitized to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis, and promote costimulatory activation of normal B cells to produce antibodies. In CLL patients receiving lenalidomide, similar evidence of CD154 activation is observed including BID, DR5, and p73 induction and also development of anti-ROR1 tumor-directed antibodies. Our data demonstrate that lenalidomide promotes CD154 expression on CLL cells with subsequent activation phenotype, and may therefore reverse the humoral immune defect observed in this disease. This study is registered at http://clinicaltrials.gov as NCT00466895.

One-Year Front Versus Central and Paracentral Corneal Changes After Bowman Layer Transplantation for Keratoconus.

PURPOSE: To report the front corneal versus central and paracentral corneal changes after Bowman layer transplantation for keratoconus in a tertiary hospital in the United Kingdom. METHODS: Five eyes of 5 patients receiving Bowman layer transplant for advanced keratoconus in Royal Gwent Hospital (Newport, United Kingdom) were included. Preoperative and postoperative visual acuity; Kmax; Kmean, and corneal cylinder in the front cornea, 4.5 mm central, and 6 mm central; and corneal thickness were analyzed. RESULTS: Corneal flattening and reduction in corneal astigmatism was observed, more marked in the central and paracentral zone, allowing for improvement in best-corrected visual acuity with the aid of visual correction in 4 eyes. CONCLUSIONS: These results support previous data reporting Bowman layer transplantation as a useful strategy in the treatment of advanced keratoconus and suggest greater attention may be focused on central or paracentral corneal changes.

A Pilot Study Assessing Treatment Outcomes in Neovascular Glaucoma Using Ahmed Glaucoma Valve with and without Cyclophotocoagulation.

Purpose: The purpose of this retrospective pilot study was to examine the short-term effect of simultaneous Ahmed Glaucoma Valve implantation and cyclophotocoagulation on postoperative outcomes in patients with neovascular glaucoma. Methods and materials: Patient charts were selected for inclusion in this study if they carried a diagnosis of neovascular glaucoma and underwent Ahmed glaucoma valve implantation only, Ahmed glaucoma valve implantation with cyclophotocoagulation, or cyclophotocoagulation only. A total of 55 eyes of 54 patients were selected for data collection and analysis. Main outcome measures included 1-, 3-, and 6-month intraocular pressure and occurrence of the hypertensive phase. Other outcomes included visual acuity, surgical complication rate, and a number of 6-month postoperative ophthalmic medications. Results: A significantly lower intraocular pressure was seen in the group that received Ahmed glaucoma valve implantation + cyclophotocoagulation compared to the Ahmed glaucoma valve-only group at 3 and 6 months (p = 0.03 and <0.001, respectively). The difference in the occurrence of the hypertensive phase between the Ahmed glaucoma valve-only group and the Ahmed glaucoma valve + cyclophotocoagulation group approached but did not reach significance (p = 0.052). A significantly lower intraocular pressure was also seen in the cyclophotocoagulation-only group compared to the Ahmed glaucoma valve-only group at 3 months (p = 0.006). Conclusion: Simultaneous Ahmed glaucoma valve implantation and cyclophotocoagulation significantly lowered intraocular pressure at 3 and 6 months compared to Ahmed glaucoma valve implantation alone in patients with neovascular glaucoma. Clinical significance: Neovascular glaucoma is difficult to manage medically and surgically. When surgery is performed, intraocular pressure often remains elevated postoperatively despite aggressive medical management. This study examines a novel method to lower intraocular pressure after Ahmed glaucoma valve implantation in patients with neovascular glaucoma. How to cite this article: Ford RL, Knight ORJ, Klifto MR, et al. A Pilot Study Assessing Treatment Outcomes in Neovascular Glaucoma Using Ahmed Glaucoma Valve with and without Cyclophotocoagulation. J Curr Glaucoma Pract 2022;16(1):4-10.

Mantle cell lymphoma cells express high levels of CXCR4, CXCR5, and VLA-4 (CD49d): importance for interactions with the stromal microenvironment and specific targeting.

Mantle cell lymphoma (MCL) is characterized by an early, widespread dissemination and residual disease after conventional treatment, but the mechanisms responsible for lymphoma cell motility and drug resistance are largely unknown. There is growing evidence suggesting that chemokine receptors and adhesion molecules are critical for malignant B-cell trafficking and homing to supportive tissue microenvironments, where they receive survival and drug resistance signals. Therefore, we examined chemokine receptor and adhesion molecule expression and function in MCL cells and their importance for migration and adhesion to marrow stromal cells (MSCs). We found that MCL cells display high levels of functional CXCR4 and CXCR5 chemokine receptors and VLA-4 adhesion molecules. We also report that MCL cells adhere and spontaneously migrate beneath MSCs in a CXCR4- and VLA-4-dependent fashion (pseudoemperipolesis). Moreover, we demonstrate that MSCs confer drug resistance to MCL cells, particularly to MCL cells that migrate beneath MSC. To target MCL-MSC interactions, we tested Plerixafor, a CXCR4 antagonist, and natalizumab, a VLA-4 antibody. Both agents blocked functional responses to the respective ligands and inhibited adhesive interactions between MCL cells and MSCs. These findings provide a rationale to further investigate the therapeutic potential of these drugs in MCL.

BAFF-R promotes cell proliferation and survival through interaction with IKKbeta and NF-kappaB/c-Rel in the nucleus of normal and neoplastic B-lymphoid cells.

BLyS and its major receptor BAFF-R have been shown to be critical for development and homeostasis of normal B lymphocytes, and for cell growth and survival of neoplastic B lymphocytes, but the biologic mechanisms of this ligand/receptor-derived intracellular signaling pathway(s) have not been completely defined. We have discovered that the BAFF-R protein was present in the cell nucleus, in addition to its integral presence in the plasma membrane and cytoplasm, in both normal and neoplastic B cells. BAFF-R interacted with histone H3 and IKKbeta in the cell nucleus, enhancing histone H3 phosphorylation through IKKbeta. Nuclear BAFF-R was also associated with NF-kappaB/c-Rel and bound to NF-kappaB targeted promoters including BLyS, CD154, Bcl-xL, IL-8, and Bfl-1/A1, promoting the transcription of these genes. These observations suggested that in addition to activating NF-kappaB pathways in the plasma membrane, BAFF-R also promotes normal B-cell and B-cell non-Hodgkin lymphoma (NHL-B) survival and proliferation by functioning as a transcriptional regulator through a chromatin remodeling mechanism(s) and NF-kappaB association. Our studies provide an expanded conceptual view of the BAFF-R signaling, which should contribute a better understanding of the physiologic mechanisms involved in normal B-cell survival and growth, as well as in the pathophysiology of aggressive B-cell malignancies and autoimmune diseases.

IGF-IR tyrosine kinase interacts with NPM-ALK oncogene to induce survival of T-cell ALK+ anaplastic large-cell lymphoma cells.

Type I insulin-like growth factor receptor (IGF-IR) tyrosine kinase plays important roles in the pathogenesis of several malignancies. Although it promotes the growth of stimulated hematopoietic cells, a direct role of IGF-IR in malignant lymphoma has not been identified. Anaplastic lymphoma kinase-positive anaplastic large-cell lymphoma (ALK(+) ALCL) is a unique type of T-cell lymphoma. Approximately 85% of ALK(+) ALCL cases harbor the translocation t(2;5)(p23;q35), which generates the chimeric oncogene NPM-ALK. In the present study, we explored a possible role of IGF-IR in ALK(+) ALCL. Our results demonstrate that IGF-IR and IGF-I are widely expressed in ALK(+) ALCL cell lines and primary tumors. Importantly, we identified novel reciprocal functional interactions between IGF-IR and NPM-ALK. Antagonism of IGF-IR decreased the viability, induced apoptosis and cell-cycle arrest, and decreased proliferation and colony formation of ALK(+) ALCL cell lines. These effects could be explained by alterations of cell survival regulatory proteins downstream of IGF-IR signaling. Our findings improve current understanding of the biology of IGF-IR and NPM-ALK and have significant therapeutic implications as they identify IGF-IR signaling as a potential therapeutic target in ALK(+) ALCL and possibly other types of malignant lymphoma.

Determining the Value-Efficiency of Respiratory Care.

In order to determine, document, and communicate the value of respiratory therapists performing respiratory care procedures, the respiratory care profession needs to position itself to capture and report both time and value standards that can be applied in allocating respiratory care resources. To do this, we propose a new metric called value-efficiency. If we wish to use value-efficiency as a metric to justify respiratory care activities and support labor budgets, there are three key considerations: (1) What value does respiratory care add to the health care organization? (2) Are the interventions provided necessary and of clinical value? (3) What is the value of the respiratory therapist in the delivery of these services? Significant challenges are facing the respiratory care profession and a focus on value-efficiency is a direction the profession must pursue. This approach is a practical response to the increasing demands of payers, administrators, consultants, and patients.

Chronic Kidney Disease as a Predictor of Postoperative Choroidal Effusions After Glaucoma Surgery.

PRCIS: Patients with chronic kidney disease (CKD) are at increased risk for choroidal effusion development following glaucoma surgery. PURPOSE: Choroidal effusion is a postoperative complication of glaucoma surgery that results from a transudative fluid collection in the suprachoroidal space. Kidney disease alters bodily fluid dynamics through a variety of mechanisms. The relationship between CKD and choroidal effusion following glaucoma surgery has not previously been studied. The purpose of this study was to determine the relationship between CKD and choroidal effusion development after glaucoma surgery. PATIENTS AND METHODS: This retrospective cohort study consisted of 86 eyes from 86 patients who received glaucoma filtering surgery or transscleral cyclophotocoagulation within the study timeframe. Forty-three patients had CKD, and 43 patients did not have kidney disease. The main outcome of this study was the development of choroidal effusion measured by the Pearson χ2 test and multivariate analysis using a binomial regression with a log link. RESULTS: Ten patients (23.3%) in the CKD group developed choroidal effusion, while 2 patients (4.7%) in the no-kidney disease group developed choroidal effusion (relative risk, 5.0; 95% confidence interval: 1.16-21.5; P=0.013). The association between CKD and choroidal effusion showed mixed results in the multivariate analysis, with some analyses showing a significant association and others showing no significant association. CONCLUSIONS: In both the univariate and multivariate analyses, CKD was found to be significantly associated with choroidal effusion after glaucoma surgery.

Thyroid Disruptors: Extrathyroidal Sites of Chemical Action and Neurodevelopmental Outcome-An Examination Using Triclosan and Perfluorohexane Sulfonate.

Many xenobiotics are identified as potential thyroid disruptors due to their action to reduce circulating levels of thyroid hormone, most notably thyroxine (T4). Developmental neurotoxicity is a primary concern for thyroid disrupting chemicals yet correlating the impact of chemically induced changes in serum T4 to perturbed brain development remains elusive. A number of thyroid-specific neurodevelopmental assays have been proposed, based largely on the model thyroid hormone synthesis inhibitor propylthiouracil (PTU). This study examined whether thyroid disrupting chemicals acting distinct from synthesis inhibition would result in the same alterations in brain as expected with PTU. The perfluoroalkyl substance perfluorohexane sulfonate (50 mg/kg/day) and the antimicrobial Triclosan (300 mg/kg/day) were administered to pregnant rats from gestational day 6 to postnatal day (PN) 21, and a number of PTU-defined assays for neurotoxicity evaluated. Both chemicals reduced serum T4 but did not increase thyroid stimulating hormone. Both chemicals increased expression of hepatic metabolism genes, while thyroid hormone-responsive genes in the liver, thyroid gland, and brain were largely unchanged. Brain tissue T4 was reduced in newborns, but despite persistent T4 reductions in serum, had recovered in the PN6 pup brain. Neither treatment resulted in a low dose PTU-like phenotype in either brain morphology or neurobehavior, raising questions for the interpretation of serum biomarkers in regulatory toxicology. They further suggest that reliance on serum hormones as prescriptive of specific neurodevelopmental outcomes may be too simplistic and to understand thyroid-mediated neurotoxicity we must expand our thinking beyond that which follows thyroid hormone synthesis inhibition.

Side population of a murine mantle cell lymphoma model contains tumour-initiating cells responsible for lymphoma maintenance and dissemination.

'Cancer stem cells' or 'tumour initiating cells' in B-cell non-Hodgkin lymphomas have not been demonstrated, although some studies focused on other cancer types suggest that such populations exist and represent tumour cells resistant to therapy and involved in relapse. These cells may also represent a putative neoplastic 'cell of origin' in lymphomas, but there is little substantive data to support this suggestion. Using cell lines derived from a recently established murine IL-14alphax c-Myc double transgenic/mantle cell lymphoma-blastoid variant model, heretofore referred to as DTG cell lines, we identified a subset of cells within the side population (SP) with features of 'tumour-initiating cells'. These features include higher expression of ABCG2 and BCL-2, longer telomere length, greater self-renewal ability and higher in vitro clonogenic and in vivo tumorigenic capacities compared with non-SP. In addition, in vitro viability studies demonstrated that the non-SP lymphoma subpopulation has a limited lifespan in comparison with the SP fraction. Syngenic transplant studies showed that non-SP derived tumours, in comparison to the SP-derived tumours, exhibit greater necrosis/apoptosis and less systemic dissemination capability. In conclusion, our data support the interpretation that the DTG SP fraction contains a cell population highly capable of tumour maintenance and systemic dissemination and lends support to the concept that 'tumour-initiating cells' occur in lymphomas.

A transient window of hypothyroidism alters neural progenitor cells and results in abnormal brain development.

Cortical heterotopias are clusters of ectopic neurons in the brain and are associated with neurodevelopmental disorders like epilepsy and learning disabilities. We have previously characterized the robust penetrance of a heterotopia in a rat model, induced by thyroid hormone (TH) disruption during gestation. However, the specific mechanism by which maternal TH insufficiency results in this birth defect remains unknown. Here we first determined the developmental window susceptible to endocrine disruption and describe a cellular mechanism responsible for heterotopia formation. We show that five days of maternal goitrogen treatment (10 ppm propylthiouracil) during the perinatal period (GD19-PN2) induces a periventricular heterotopia in 100% of the offspring. Beginning in the early postnatal brain, neurons begin to aggregate near the ventricles of treated animals. In parallel, transcriptional and architectural changes of this region were observed including decreased Sonic hedgehog (Shh) expression, abnormal cell adhesion, and altered radial glia morphology. As the ventricular epithelium is juxtaposed to two sources of brain THs, the cerebrospinal fluid and vasculature, this progenitor niche may be especially susceptible to TH disruption. This work highlights the spatiotemporal vulnerabilities of the developing brain and demonstrates that a transient period of TH perturbation is sufficient to induce a congenital abnormality.

Creating metal-spiked bed sediments: a case study from Orewa estuary, New Zealand.

Spiking sediments to achieve target concentrations of heavy metal pollutants is a key step in sediment toxicity tests. It is difficult, however, to ensure that metals in an artificially spiked sediment will behave naturally. A method has been developed in the present study to create Cu-, Pb-, and Zn-spiked sediments in which naturally occurring adsorption onto sediment surfaces is the dominant process binding the metals and in which precipitation of readily redissolved minerals and other metal-bearing phases (artifacts of the spiking procedure) are avoided. Uncontaminated bed sediment from an intertidal mudflat in the Orewa estuary, New Zealand, was characterized in terms of existing metal content, optimal adsorption pH, and adsorption capacity. Competitive adsorption between Cu and Pb as well as complexation by seawater anions only slightly affected metal adsorption from seawater. Surface complexation modeling indicated that iron oxide surfaces in the sediment likely were dominating metal adsorption processes. Spiking experiments were designed using these established adsorption characteristics but with significantly higher (>100-fold) concentrations of sediments and dissolved metals and a liquid to solid (L:S) ratio of approximately 5.5. An equilibration time of at least 36 h was required to achieve a reproducible target metal concentration, which could be reliably predicted from the L:S ratio and the initial metal concentration in the spiking solution. Adsorption equilibrium remained the process governing metal binding to the sediment, and no indication was observed that the adsorption capacity of the sediment had been exceeded or that additional metal-bearing phases had been formed.