Protein kinase C (PKC) positively modulates NMDA receptor (NMDAR) currents. In contrast to previous reports, this study determines the importance of individual exons in the mechanism underlying the ...potentiation process by examining the complete set of eight naturally occurring splice variants expressed in Xenopus oocytes both as homomers and as heteromeric NR1/NR2A or NR1/NR2B complexes. After PKC stimulation, homomeric currents demonstrated a high level of potentiation ( approximately 500% of untreated baseline currents) that reduced to a lower level ( approximately 300% of baseline) in variants containing the first C-terminal exon (C1). An ANOVA showed that only C1 and no other exon or interaction of exons determined the degree of NMDAR current modulation by PKC. When recordings were performed in solutions in which barium replaces calcium, only the lower form of potentiation was observed, regardless of the splice variant exon composition. This suggested an important role for calcium in the PKC modulation of homomeric NMDA splice variant currents in which the C1 exon also participates. The effectiveness of the C1 exon to reduce the higher form of potentiation is modulated by heteromeric assemblies with NR2A heteromers yielding smaller levels of potentiation and a larger C1 exon effect compared with NR2B heteromers. The heteromers demonstrated the higher form of potentiation even in the absence of calcium. Furthermore, calcium had different effects in the potentiation of the heteromers depending on the NR2 subunit. This study refines the region of the NR1 subunit involved in a modulation crucial to the function of NMDA receptors and provides evidence that the NR2A and NR2B subunits realize this modulation differentially.
Abstract
Chemotherapy/ targeted therapy are both known to trigger evolution of treatment resistant clones that can lead to relapse. Allogeneic stem cell transplant (alloSCT) for refractory Chronic ...Lymphocytic Leukemia (CLL) patients is associated with better outcomes. We hypothesized that allogeneic T-cell immunotherapies, including alloSCT and donor lymphocyte infusion (DLI) would impact tumor evolution through the application of selective immunologic pressure with reciprocal changes in the T-cell compartment. Here, we tested a cohort of 24 heavily pre-treated CLL patients treated. Treatments consisted of alloSCT alone, or with follow-up DLI, which are two established mediators of effective Graft versus Leukemia (GVL). Our cohort included 11 patients who relapsed (denoted as non-responder, NR) after alloSCT and 13 patients who had complete response (CR) after alloSCT, with 11/13 patients showing durable CR with a median post-transplant overall survival (OS) of 9.8 years. We mapped the evolutionary trajectories of tumor cells by whole exome sequencing (WES) of sort purified CLL in post-transplant relapsed patients. To investigate changes in immune repertoire and gene expression post-transplant, CD3 positive T-cells from peripheral blood and bone marrows of CLL patients at complete donor chimerism were analyzed both at bulk and at the single cell level. We found evidence of subclonal leukemic evolution in the majority of our CLL patient cohort after nonmyeloablative HLA-matched alloSCT. Different patterns of CLL evolution were observed, and these changes included putative CLL drivers in every case. In all of the 11 patients with longitudinal post-alloSCT samples available, we observed branched CLL evolution in 4 patients, linear evolution in 4 patients, and no evolution in 3 patients. These data suggest that differential sensitivity of leukemic subclones to allogeneic T cell killing may underlie the branched and linear evolution that we observed, and therefore can shape leukemic subclonal architecture after transplant. Of note, we found that clonal CLL was more responsive to alloSCT in comparison to CLL with subclonal disease architecture.To identify T-cells with GVL potential, we first cataloged potential neoantigens by screening mutated regions in CLL with in silico HLA binding prediction models. Neoantigen specific T-cells were then sorted from longitudinal peripheral blood samples using tetramers, followed by identification of GVL specific TCR in both bulk and single cell setting. We were able to identify T-cells that coevolved with specific tumorigenic lesions in a subset of CLL patients. Taken together, our results suggest that donor-derived antigen-specific T-cells mediate clonal selection of CLL with concurrent changes in allogeneic T-cells, and that these changes can be monitored in longitudinal patient samples.
Citation Format: Celine Kerros, John P. Miller, Xizeng Mao, Haven R. Garber, Hannah C. Beird, Jianhua Zhang, Jason Roszik, Paul Leonard, Li Zhao, Sahil Seth, Pei Lin, Huandong Sun, William G. Wierda, Issa F. Khouri, Karen Clise-Dwyer, Andrew Futreal, Shoudan Liang, Koppikar Priya, Jeffrey Molldrem. Deep profiling of T-cell repertoire and tumor heterogeneity in chronic lymphocytic leukemia patients following allogeneic T-cell therapy abstract. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1516.
Experimental autoimmune encephalomyelitis (EAE) is an inflammatory disease of the central nervous system (CNS) that can be induced in susceptible mice by the transfer of autoreactive T cells that ...recognize myelin basic protein (MBP). The onset and subsequent recovery from disease are associated with distinct patterns of cytokine and chemokine expression within the inflammatory lesions of the CNS. Given the likely importance of the local cytokine milieu in regulating the disease process, it would be preferable to administer cytokines locally to the CNS and reduce systemic delivery in order to evaluate their immunoregulatory roles in EAE. For this purpose, we have used retrovirally transduced T cells from MBP-specific T cell receptor transgenic mice in an attempt to target cytokine delivery to the CNS where MBP is primarily expressed. We have found that T cells expressing granulocyte macrophage colony-stimulating factor (GM-CSF) induce severe, chronic EAE from which mice fail to recover. Our results indicate that increased local GM-CSF expression could play an important role in inducing chronic EAE.
: Recent advances in islet transplantation have enabled physicians to cure type 1 autoimmune diabetes, but at the cost of lifelong immunosuppression with its attendant side effects and long‐term ...health risks. To eliminate the need for immunosuppression, researchers have developed methods for inducing tolerance to transplanted allografts. Tolerance‐based transplantation using costimulation blockade has proven remarkably successful in many animal model systems. The most widely used animal model system for studying islet transplantation in type 1‐like autoimmune diabetes is the NOD mouse. Unfortunately, this strain has proven resistant to costimulation blockade‐based transplantation tolerance protocols that are successful in chemically diabetic mice given islet grafts. It has been assumed that resistance to transplantation tolerance in the NOD mouse is (1) related to autoimmunity directed against its pancreatic β cells, (2) a consequence of that autoimmunity, and (3) under the control of the same genes that control autoimmunity. In this review, we provide arguments to challenge these assumptions. We describe a new animal model and a new conceptual framework based on data indicating that the mechanisms responsible for resistance to transplantation tolerance and β cell autoimmunity are not identical. We believe that the recent discoveries we describe will have important implications for the development of tolerance‐based transplantation therapies and their translation from the laboratory to the clinic.
Investigates the efficacy of iodine-131-labeled (I-131) tositumomab for patients with B-cell non-Hodgkin's lymphoma (NHL), including its use as a single agent in relapsed/refractory NHL and in ...untreated follicular NHL, in combination with chemotherapy, and as part of a conditioning regimen for autologous stem cell transplantation. Addresses toxicities. Source: National Library of New Zealand Te Puna Matauranga o Aotearoa, licensed by the Department of Internal Affairs for re-use under the Creative Commons Attribution 3.0 New Zealand Licence.
Background
In untreated FL, rituximab (R)-bendamustine leads to overall response (OR), complete response (CR), and 3-year progression-free survivals (PFS) of 91-97%, 31-40%, and 68-70%, respectively. ...The GALLIUM study demonstrated an improved PFS with obinutuzumab-chemotherapy compared to R-chemotherapy with 3-year PFS 80% and 73.3%, respectively. In relapsed FL, phase 2 trials demonstrated OR and CR of 88% and 53% with combined rituximab, bendamustine, and bortezomib. We conducted a multicenter, randomized phase 2 trial to determine the CR with ofatumumab and bendamustine and with ofatumumab, bendamustine, and bortezomib induction and maintenance in pts with untreated high risk FL.
Methods
Pts with untreated grade 1-3a FL and either a FL international prognostic index (FLIPI) of 2 with at least one lymph node > 6 cm or FLIPI 3-5 were enrolled. Pts were randomized to arm A (ofatumumab 1000 mg day (d) 1 with bendamustine 90 mg/m2 d 1 and 2 every 35 d for 6 cycles followed by maintenance ofatumumab 1000 mg d 1 every 2 months (mos) for 4 cycles) or to arm B (ofatumumab 1000 mg d 1, bendamustine 90 mg/m2 d 1 and 2, and bortezomib 1.6 mg/m2 (IV or SQ) d 1, 8, 15, and 22 every 35 d for 6 cycles followed by maintenance ofatumumab 1000 mg d 1 and bortezomib 1.6 mg/m2 d 1, 8, 15, and 22 every 2 mos for 4 cycles). Response was assessed by FDG PET/CT after cycles 2 and 6 of induction and by CT every 4 mos during maintenance and every 6 mos until progression. The primary endpoint was CR, targeting a CR of 40% in A and 60% in B. A 2-stage design was used to compare CR between treatment groups. Evaluation of PFS and toxicity were secondary endpoints.
Results
From 2011-2016, 135 pts enrolled with 127 (A=66 and B=61) eligible for response assessment. The median age was 61 (range 25-87), 73% had grade 1-2 FL, 33% were stage III, 65% were stage IV, 19% had B-symptoms, 47% had bulky disease > 6 cm, 29% had elevated LDH, 28% were FLIPI 2, and 69% FLIPI 3-5. In A, 58 (87%) pts completed induction and 38 (57%) completed maintenance. In B, 42 (65%) and 27 (42%) completed induction and maintenance. Eight pts in A and 9 in B are still receiving maintenance. Reasons for early termination included adverse events (A=12 and B=9), progression (A=2 and B=6), pt refusal (A=4 and B=7), death due to sepsis (B=1), and other (A=3 and B=6). Dose reductions or delays were required in 66% and 86% pts on A and B, respectively. Grade 3-4 events occurred in 75% A and 75% B. These events included neutropenia (A=31%, B=27%), thrombocytopenia (A=2%, B=5%), febrile neutropenia (A=1%, B=3%), infection (A=7%, B=12%) nausea/vomiting (A=0, B=8%), diarrhea (A=4%, B=9%), fatigue (A=4%, B=11%), infusion reactions or cytokine release (A=5%, B=10%), and peripheral neuropathy (A=0, B=3%).
For A, the OR was 92% (n=61, 95% CI 83-97%) with 59% CR (95% CI 46-71%) and for B, the OR was 84% (n=51, 95% CI 72-92%) with 57% CR (95% CI, 44-70%), with no significant difference in CR in A or B (p=0.65). Thirty pts have progressed (A=18 and B=12). Ten pts have died (A=3 and B=7), due to FL (5), sepsis (1), lung cancer (1), and unknown cause (3). With a median follow-up of 25 mos in A (< 1-70 mos), the 2-, 3-, and 4-year PFS are 81%, 64%, and 53%. With a median follow-up of 22 mos in B (1-69 mos), the 2-, 3-, and 4-year PFS are 77%, 71%, and 67% (see figure). The 4-year overall survival in A and B are 87% and 84%, respectively. The surrogate endpoint EFS24 is 81% in A and 75% in B. In univariable analysis, elevated LDH was significantly associated with an inferior PFS (p=0.014), while FLIPI 2 vs. 3-5, stage, and bulk > 6 cm were not associated with OR, PFS, or OS.
Conclusion
In this multicenter randomized phase 2 trial, the OR, CR, and PFS with ofatumumab and bendamustine and with ofatumumab, bendamustine, and bortezomib are similar in pts with previously untreated high risk FL, with no significant difference with intensification of therapy with bortezomib. Although grade 3-4 toxicities are similar, more pts treated with bortezomib required dose modifications and early discontinuation. While not the primary endpoint of this trial, the addition of ofatumumab to bendamustine appears to improve CR when compared to historical data with R-bendamustine in untreated FL. However, 3-year PFS rates are similar to historical data and a randomized study would be required to determine if ofatumumab improves PFS as recently observed with obinutuzumab. Support: U10CA180821, U10CA180882. ClinicalTrials.gov Identifier: NCT01286272
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Blum:Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Novartis: Research Funding; Cephalon: Research Funding; Millenium: Research Funding; Pharmacylics: Research Funding; Janssen: Research Funding. Hsi:Eli Lilly: Research Funding; Abbvie: Research Funding; Cellerant Therapeutics: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Wagner-Johnston:Novartis: Research Funding; Celgene: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; JUNO: Membership on an entity's Board of Directors or advisory committees; Regeneron: Research Funding. Cheson:Celgene: Consultancy; Roche-genentech: Consultancy, Research Funding; Pharmacyclics: Research Funding. Bartlett:Novartis: Research Funding; ImaginAB: Research Funding; Astra Zeneca: Research Funding; Millenium: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Affimed: Research Funding; Forty Seven: Research Funding; Immune Design: Research Funding; Bristol-Meyers Squibb: Research Funding; Merck & Co: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding.
Abstract
The COVID-19 pandemic presents a serious public health challenge in all countries. However, repercussions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections on future ...global health are still being investigated, including the pandemic’s potential effect on the emergence and spread of global antimicrobial resistance (AMR). Critically ill COVID-19 patients may develop severe complications, which may predispose patients to infection with nosocomial bacterial and/or fungal pathogens, requiring the extensive use of antibiotics. However, antibiotics may also be inappropriately used in milder cases of COVID-19 infection. Further, concerns such as increased biocide use, antimicrobial stewardship/infection control, AMR awareness, the need for diagnostics (including rapid and point-of-care diagnostics) and the usefulness of vaccination could all be components shaping the influence of the COVID-19 pandemic. In this publication, the authors present a brief overview of the COVID-19 pandemic and associated issues that could influence the pandemic’s effect on global AMR.
Recurrence in the pelvis after resection of a rectal or rectosigmoid cancer presents a dilemma. Resection offers the only reasonable probability for cure, but at the cost of marked perioperative ...morbidity and potential mortality. Clinical decision making remains difficult.
Patients who underwent resection with curative intent for isolated pelvic recurrences after curative colorectal surgery from 1988 through 2003 were reviewed retrospectively. Clinical and pathological factors, salvage operations, and complications were recorded. The primary measured outcome was overall survival. Univariate and multivariate analyses were conducted to identify prognostic factors of improved outcome.
Ninety patients underwent an attempt at curative resection of a pelvic recurrence; median follow-up was 31 months. Complications occurred in 53% of patients. Operative mortality occurred in 4 (4.4%) of 90 patients. Median overall survival was 38 months, and estimated 5-year survival was 40%. A total of 51 of 86 patients had known recurrences (15 local, 16 distant, 20 both). Multivariate analysis revealed that preoperative carcinoembryonic antigen level and final margin status were statistically significant predictors of outcome.
The resection of pelvic recurrences after colorectal surgery for cancer can be performed with low mortality and good long-term outcome; however, morbidity from such procedures is high. Low preoperative carcinoembryonic antigen and negative margin of resection predict improved survival.
In one third of patients who die of rectal cancer, a pelvic recurrence after resection represents isolated disease for which re-resection may provide cure. These extensive resections can carry high ...morbidity. Proper patient selection is desirable but difficult. Hydronephrosis has been documented previously to portend a poor prognosis, and some consider it a contraindication to attempted resection. It was our goal to review our experience and either confirm or refute these conclusions.
We performed a retrospective analysis of 90 patients resected with curative intent for pelvic recurrence at our center from 1988 through 2003. Seventy-one records documented the preoperative presence or absence of hydronephrosis. Clinical and pathologic data were recorded. The groups with and without hydronephrosis were compared.
There were 15 patients with hydronephrosis in this study and 56 without. Although patients with hydronephrosis had shorter overall survival, disease-free survival, and rate of local control, none of these differences was statistically significant. Patients in the hydronephrosis group were younger and had higher-stage primary tumors and larger recurrent tumors. Subsequently, they underwent more extensive resections and were more likely to be treated with adjuvant therapies. There was no difference in the rate of margin-negative resections between the groups.
Hydronephrosis correlates with younger patients with larger recurrent tumors undergoing more extensive operations and multimodality therapy but does not preclude curative (R0) resection or independently affect overall survival, disease-free survival, or local control. We believe that it should not be considered a contraindication to attempting curative resection.
Abstract Patients with indolent non-Hodgkin lymphoma (I-NHL) often receive multiple courses of cytotoxic chemotherapy over several years. Radioimmunotherapy (RIT) has become an important part of ...treatment for relapsed patients and tositumomab/lodine I-131 tositumomab is a promising regimen currently being incorporated into first-line therapy. While treatment-related myelodysplasia (tMDS) and acute myeloid leukemia (tAML) are well-known, poor-prognosis complications of conventional chemotherapy and radiation therapy, they have not been previously observed as a consequence of initial treatment with RIT-based regimens. We describe four patients with tMDS/tAML who received a sequential chemotherapy and tositumomab/lodine I-131 tositumomab program as their initial and only lymphoma treatment. Our findings suggest that the potential risk of these important complications must be considered in the development of this novel therapeutic strategy in the first-line setting.
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