Analysis of Lymphocyfic Infiltration in Uveal Melanoma

Among 27 uveal melanomas, five were found to contain tumor infiltrating lymphocytes (TILs). Four had high levels of lymphocytes, and the fifth had comparatively low levels but adequate numbers for comprehensive analysis. The TILs were analyzed by flow cytometry to determine the relative proportions of lymphocyte subsets and markers of lymphocyte activation. The results show the predominance of T-suppressor/cytotoxic lymphocytes and insignificant levels of B-cells present in the infiltrate. The T-suppressor/cytotoxic cells were generally activated to a higher degree than the T-helper cells when assayed for levels of the histocompatibility antigen, HLA-DR. T-helper cells expressed more interleukin (IL-2) receptor (Tac) than T-suppressor/cytotoxic cells. Invest Ophthalmol Vis Sci 31: [2106][2107][2108][2109][2110]1990 Uveal melanomas, like their cutaneous counterpart, are considered to be relatively susceptible to immunologic influences because of reports of spontaneous regression, 1 -2 of the development of vitiligo and halo nevi, 5 Such intraocular transplantation can be prevented by prior adoptive transfer of humoral or cellular immunity to the recipient. " 14 Some investigators report the predominance of the T-cytotoxic/suppressor cell subpopulation; 1213 others found a majority of T-helper/inducer cells. 10 " 14 There is, however, no convincing evidence that a more favorable prognosis is associated with lymphocytic infiltration in uveal melanomas, 715 and it remains uncertain whether tumor infiltrating lymphocytes (TILs) play a significant role in tumor immunity. The availability of precisely defined monoclonal-antibody markers and flow-cytometric techniques makes it From the *Department of Biochemistry and the fTennent Institute of Ophthalmology, University of Glasgow, Glasgow, Scotland. Reprint requests: Fiona H. Durie, Department of Biochemistry, University of Glasgow, Glasgow G12 8QQ, UK. possible to do a detailed objective analysis of a large number of lymphocytes in any tumour. We characterized the phenotype of the TILs and studied the expression of the histocompatibility antigen, HLA-DR, and interleukin (IL-2) receptor (Tac), which are markers of activation, on the surface of T-helper and T-suppressor/cytotoxic lymphocytes in ocular melanoma. Materials and Methods Preparation of Cells Tissue was obtained from five choroidal melanomas which were removed either by local resection or by enucleation. Slices were cut from the apical part of the fresh specimen after preliminary examination, and these were transferred to RPMI-1640 medium (Gibco, Grand Island, NY). Spilled cells were teased out using a sterile needle. The cells were then harvested, washed by centrifugation at 1000 rpm for 15 min, counted, and adjusted to 1X10 6 cells/ml. The remaining cell suspensions of TILs and tumor cells were cryopreserved in medium containing 90% fetal calf serum and 10% dimethylsulfoxide and stored in liquid nitrogen until use. Four of the five patients consented to venipuncture, and peripheral blood lymphocytes were separated on a discontinuous ficoll density gradient. 1617 Preparation of Samples Cell suspensions of TILs and tumor cells were washed and resuspended in 1 ml of phosphate-buffered saline. Cells (50 ii\) were incubated on ice with appropriate fluorescein isothiocyanate (FITC)-conjugated leu series monoclonal antibody and phycoerythrin (PE) conjugated antibody (Becton-Dickinson, 2106 Downloaded from iovs.arvojournals.org on 06/28/201

hnRNPA1 couples nuclear export and translation of specific mRNAs downstream of FGF-2/S6K2 signalling

The increased cap-independent translation of anti-apoptotic proteins is involved in the development of drug resistance in lung cancer but signalling events regulating this are poorly understood. Fibroblast growth factor 2 (FGF-2) signalling-induced S6 kinase 2 (S6K2) activation is necessary, but the downstream mediator(s) coupling this kinase to the translational response is unknown. Here, we show that S6K2 binds and phosphorylates hnRNPA1 on novel Ser4/6 sites, increasing its association with BCL-XL and XIAP mRNAs to promote their nuclear export. In the cytoplasm, phosphoS4/6-hnRNPA1 dissociates from these mRNAs de-repressing their IRES-mediated translation. This correlates with the phosphorylation-dependent association of hnRNPA1 with 14-3-3 leading to hnRNPA1 sumoylation on K183 and its re-import into the nucleus. A non-phosphorylatible, S4/6A mutant prevented these processes, hindering the pro-survival activity of FGF-2/S6K2 signalling. Interestingly, immunohistochemical staining of lung and breast cancer tissue samples demonstrated that increased S6K2 expression correlates with decreased cytoplasmic hnRNPA1 and increased BCL-XL expression. In short, phosphorylation on novel N-term sites of hnRNPA1 promotes translation of anti-apoptotic proteins and is indispensable for the pro-survival effects of FGF-2

Non-Born-Oppenheimer calculations of the lowest vibrational energy of HD including relativistic corrections

In this work we report variational calculations of the two lowest vibrational states of the HD molecule within the framework that does not assume the Born-Oppenheimer BO approximation. The nonrelativistic energies of the states were corrected for the relativistic effects of the order of 2 where = 1 c , calculated as expectation values of the operators representing these effects with the nonrelativistic non-BO wave functions. The non-BO wave functions were expanded in terms of the one-center explicitly correlated Gaussian functions multiplied by even powers of the internuclear distance. The v=0→1 transition energy obtained in the calculations is compared with the previous calculations, as well as with the transition frequency obtained from the experimental spectra. The comparison shows the need to include corrections higher than second order in to further improve the agreement between the theory and the experimen

Monocyte Subsets and Serum Inflammatory and Bone-Associated Markers in Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma

© 2021 by the authors.Monocyte/macrophages have been shown to be altered in monoclonal gammopathy of undetermined significance (MGUS), smoldering (SMM) and active multiple myeloma (MM), with an impact on the disruption of the homeostasis of the normal bone marrow (BM) microenvironment.This research was funded by the Biomedical Research Networking Center Consortium CIBER-CIBERONC (CB16/12/00400, CB16/12/00369 and CB16/12/00233-FEDER), PI13/01412- FEDER, from the Instituto de Salud Carlos III (ISCIII), Ministerio de Economía y Competitividad, Madrid, Spain; the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (grant agreement ERC-2015-AdG 695655 (TiMaScan); and the Black Swan Research Initiative of the International Myeloma Foundation (Los Angeles, CA, USA), (grant IMF13/IMF16

Clinical predictors of long-term survival in newly diagnosed transplant eligible multiple myeloma - an IMWG Research Project

Purpose: multiple myeloma is considered an incurable hematologic cancer but a subset of patients can achieve long-term remissions and survival. The present study examines the clinical features of long-term survival as it correlates to depth of disease response. Patients & Methods: this was a multi-institutional, international, retrospective analysis of high-dose melphalan-autologous stem cell transplant (HDM-ASCT) eligible MM patients included in clinical trials. Clinical variable and survival data were collected from 7291 MM patients from Czech Republic, France, Germany, Italy, Korea, Spain, the Nordic Myeloma Study Group and the United States. Kaplan–Meier curves were used to assess progression-free survival (PFS) and overall survival (OS). Relative survival (RS) and statistical cure fractions (CF) were computed for all patients with available data. Results: achieving CR at 1 year was associated with superior PFS (median PFS 3.3 years vs. 2.6 years, p < 0.0001) as well as OS (median OS 8.5 years vs. 6.3 years, p < 0.0001). Clinical variables at diagnosis associated with 5-year survival and 10-year survival were compared with those associated with 2-year death. In multivariate analysis, age over 65 years (OR 1.87, p = 0.002), IgA Isotype (OR 1.53, p = 0.004), low albumin < 3.5 g/dL (OR = 1.36, p = 0.023), elevated beta 2 microglobulin ≥ 3.5 mg/dL (OR 1.86, p < 0.001), serum creatinine levels ≥ 2 mg/dL (OR 1.77, p = 0.005), hemoglobin levels < 10 g/dL (OR 1.55, p = 0.003), and platelet count < 150k/μL (OR 2.26, p < 0.001) appeared to be negatively associated with 10-year survival. The relative survival for the cohort was ~0.9, and the statistical cure fraction was 14.3%. Conclusions: these data identify CR as an important predictor of long-term survival for HDM-ASCT eligible MM patients. They also identify clinical variables reflective of higher disease burden as poor prognostic markers for long-term survival

Recommendations for acquisition, interpretation and reporting of whole body low dose CT in patients with multiple myeloma and other plasma cell disorders: a report of the IMWG Bone Working Group

Whole Body Low Dose CT (WBLDCT) has important advantages as a first-line imaging modality for bone disease assessment in patients with plasma cell disorders and has been included in the 2014 International Myeloma Working Group (IMWG) criteria for multiple myeloma (MM) definition. Nevertheless, standardization guidelines for the optimal use of WBLDCT in MM patients are still lacking, preventing its more widespread use, both in daily practice and clinical trials. The aim of this report by the Bone Group of the IMWG is to provide practical recommendations for the acquisition, interpretation and reporting of WBLDCT in patients with multiple myeloma and other plasma cell disorders

Second malignancies in the context of lenalidomide treatment: an analysis of 2732 myeloma patients enrolled to the Myeloma XI trial.

We have carried out the largest randomised trial to date of newly diagnosed myeloma patients, in which lenalidomide has been used as an induction and maintenance treatment option and here report its impact on second primary malignancy (SPM) incidence and pathology. After review, 104 SPMs were confirmed in 96 of 2732 trial patients. The cumulative incidence of SPM was 0.7% (95% confidence interval (CI) 0.4-1.0%), 2.3% (95% CI 1.6-2.7%) and 3.8% (95% CI 2.9-4.6%) at 1, 2 and 3 years, respectively. Patients receiving maintenance lenalidomide had a significantly higher SPM incidence overall (P=0.011). Age is a risk factor with the highest SPM incidence observed in transplant non-eligible patients aged >74 years receiving lenalidomide maintenance. The 3-year cumulative incidence in this group was 17.3% (95% CI 8.2-26.4%), compared with 6.5% (95% CI 0.2-12.9%) in observation only patients (P=0.049). There was a low overall incidence of haematological SPM (0.5%). The higher SPM incidence in patients receiving lenalidomide maintenance therapy, especially in advanced age, warrants ongoing monitoring although the benefit on survival is likely to outweigh risk

Guidelines for Diagnosis of Cystic Fibrosis in Newborns through Older Adults: Cystic Fibrosis Foundation Consensus Report

Newborn screening (NBS) for cystic fibrosis (CF) is increasingly being implemented and is soon likely to be in use throughout the United States, because early detection permits access to specialized medical care and improves outcomes. The diagnosis of CF is not always straightforward, however. The sweat chloride test remains the gold standard for CF diagnosis but does not always give a clear answer. Genotype analysis also does not always provide clarity; more than 1500 mutations have been identified in the CF transmembrane conductance regulator (CFTR) gene, not all of which result in CF. Harmful mutations in the gene can present as a spectrum of pathology ranging from sinusitis in adulthood to severe lung, pancreatic, or liver disease in infancy. Thus, CF identified postnatally must remain a clinical diagnosis. To provide guidance for the diagnosis of both infants with positive NBS results and older patients presenting with an indistinct clinical picture, the Cystic Fibrosis Foundation convened a meeting of experts in the field of CF diagnosis. Their recommendations, presented herein, involve a combination of clinical presentation, laboratory testing, and genetics to confirm a diagnosis of CF