ABSTRACT
T lymphocytes and B lymphocytes integrate activating signals to control the size of their proliferative response. Here we report that such control was achieved by timed changes in the production rate of cell-cycle-regulating proto-oncoprotein Myc, with division cessation occurring when Myc levels fell below a critical threshold. The changing pattern of the level of Myc was not affected by cell division, which identified the regulating mechanism as a cell-intrinsic, heritable temporal controller. Overexpression of Myc in stimulated T cells and B cells did not sustain cell proliferation indefinitely, as a separate 'time-to-die' mechanism, also heritable, was programmed after lymphocyte activation and led to eventual cell loss. Together the two competing cell-intrinsic timed fates created the canonical T cell and B cell immune-response pattern of rapid growth followed by loss of most cells. Furthermore, small changes in these timed processes by regulatory signals, or by oncogenic transformation, acted in synergy to greatly enhance cell numbers over time.
Subject(s)
B-Lymphocytes/physiology , CD8-Positive T-Lymphocytes/physiology , Cell Division , Cell Proliferation/genetics , Immunity, Cellular , Proto-Oncogene Proteins c-myc/metabolism , Animals , Cell Death/genetics , Cell Division/genetics , Cells, Cultured , Gene Expression Regulation , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Mice, Transgenic , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-myc/genetics , Signal Transduction , Transgenes/geneticsABSTRACT
INTRODUCTION: The goal of this study was to compare the results of LPD with those of open pancreaticoduodenectomy (OPD). METHOD: Data were retrospectively collected from a database of patients who underwent PD from January 2010 to May 2020. Intraoperative, postoperative, and follow-up assessment studies were conducted. RESULTS: A total of 149 patients were selected. Compared with OPD, LPD was fewer intraoperative blood transfusions (p = 0.015), a longer median operative time (p < 0.001), hospital stay (p = 0.034), a higher rate of bile leakage (p = 0.02), overall morbidity (p = 0.045), and re-operation (p = 0.044). There was no difference between the two groups in severe pancreatic fistula, postoperative bleeding, delayed gastric emptying, Clavien-Dindo classification ≥ III, or 30-day mortality. LPD had a similar number of excised lymph nodes, R0 resection rate, and long-term survival cases involving malignant tumors, ampulla of Vater cancer, and pancreatic ductal adenocarcinoma. CONCLUSION: In the early period, the benefit of LPD has not been found as there was a high rate of conversion to laparotomy, morbidity, and re-operation. Despite that, LPD is a feasible oncological approach with long-term survival comparable to OPD.
Subject(s)
Laparoscopy , Pancreatic Neoplasms , Humans , Pancreaticoduodenectomy/methods , Retrospective Studies , Vietnam , Pancreatic Neoplasms/surgery , Postoperative Complications/epidemiology , Postoperative Complications/surgery , Laparoscopy/methods , Length of StayABSTRACT
Background: Predominantly antibody deficiencies (PADs) are the most common type of primary immunodeficiency in adults. PADs frequently pass undetected leading to delayed diagnosis, delayed treatment, and the potential for end-organ damage including bronchiectasis. In addition, PADs are frequently accompanied by comorbid autoimmune disease, and an increased risk of malignancy. Objectives: To characterize the diagnostic and clinical features of adult PAD patients in Victoria, Australia. Methods: We identified adult patients receiving, or having previously received immunoglobulin replacement therapy for a PAD at four hospitals in metropolitan Melbourne, and retrospectively characterized their clinical and diagnostic features. Results: 179 patients from The Royal Melbourne, Alfred and Austin Hospitals, and Monash Medical Centre were included in the study with a median age of 49.7 years (range: 16-87 years), of whom 98 (54.7%) were female. The majority of patients (116; 64.8%) met diagnostic criteria for common variable immunodeficiency (CVID), and 21 (11.7%) were diagnosed with X-linked agammaglobulinemia (XLA). Unclassified hypogammaglobulinemia (HGG) was described in 22 patients (12.3%), IgG subclass deficiency (IGSCD) in 12 (6.7%), and specific antibody deficiency (SpAD) in 4 individuals (2.2%). The remaining four patients had a diagnosis of Good syndrome (thymoma with immunodeficiency). There was no significant difference between the age at diagnosis of the disorders, with the exception of XLA, with a median age at diagnosis of less than 1 year. The median age of reported symptom onset was 20 years for those with a diagnosis of CVID, with a median age at diagnosis of 35 years. CVID patients experienced significantly more non-infectious complications, such as autoimmune cytopenias and lymphoproliferative disease, than the other antibody deficiency disorders. The presence of non-infectious complications was associated with significantly reduced survival in the cohort. Conclusion: Our data are largely consistent with the experience of other centers internationally, with clear areas for improvement, including reducing diagnostic delay for patients with PADs. It is likely that these challenges will be in part overcome by continued advances in implementation of genomic sequencing for diagnosis of PADs, and with that opportunities for targeted treatment of non-infectious complications.