DNA repair deficiencies and cellular senescence are unrelated in xeroderma pigmentosum cell lines

Senescence of skin fibroblast cultures from normal individuals occurred after 23.9 +/- 6.3 (S.D.) passages; senescence in DNA repair-deficient cell lines from xeroderma pigmentosum patients occurred at 22.9 +/- 5.5 passages. Cells from xeroderma pigmentosum variant and Cockayne syndrome patients reached senescence at similar passage numbers. Xeroderma pigmentosum patients contract skin cancer as a consequence of their repair deficiencies but show no symptoms of premature ageing; neither do their cells age prematurely in vitro. The clinical spectrum and the life-span of fibroblasts in culture therefore lend no support for a correlation between ageing and the DNA repair or DNA replication deficiencies found in xeroderma pigmentosum and Cockayne syndrome cells.     

Connecting chaperone-mediated autophagy dysfunction to cellular senescence

Chaperone-mediated autophagy (CMA) is one of the main pathways of the lysosome-autophagy proteolytic system. It regulates different cellular process through the selective degradation of cytosolic proteins. In ageing, the function of CMA is impaired causing an inefficient stress response and the accumulation of damaged, oxidized or misfolded proteins, which is associated with numerous age-related diseases. Deficient protein degradation alters cellular proteostasis and activates signaling pathways that culminate in the induction of cellular senescence, whose accumulation is a typical feature of ageing. However, the relationship between CMA activity and cellular senescence has been poorly studied. Here, we review and integrate evidence showing that CMA dysfunction correlates with the acquisition of many hallmarks of cellular senescence and propose that loss of CMA function during aging promotes cellular senescence.     

A therapeutic approach to treat cardiovascular dysfunction of diabetes

Diabetes greatly increases risk of cardiovascular dysfunction and interruptions of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) have been shown to reduce the risk by alteration in extracellular matrix. We hypothesized that minocycline induced MMP-2 and MMP-9 inhibition can be enhanced by aspirin (through its COX and tPA inhibitory action) and this combination can reduce cardiovascular dysfunction of diabetes. Four weeks after diabetes induction (streptozotocin, 55 mg/kg, i.p.), rats were treated with minocycline (50 mg/kg, p.o.), aspirin (50 mg/kg, p.o.), or minocycline (50 mg/kg, p.o.) plus aspirin (50 mg/kg, p.o.) for a period of next four weeks. At the end of eighth week arterial pressure, heart rate and left ventricular pressure were recorded. Contractile response to phenylephrine (10^?5 M) and relaxation responses to acetylcholine (10^?9–10^?4 M) were obtained from aortic rings of diabetic rats. Gel zymography was performed to evaluate MMP-2 and MMP-9 levels. Heart rate, mean arterial pressure, dp/dt_max and dp/dt_min were found significantly decreased in STZ diabetic rats when compared with normoglycemic group. Treatment with combination of minocycline and aspirin significantly ameliorate these compared to vehicle treated diabetic group. Endothelium-dependent relaxation responses induced by acetylcholine were decreased in diabetic rats and significantly higher in combination treated group. Collagen, MMP-2 and MMP-9 levels were significantly decreased in combined treated group when compared with diabetic control. Present study revealed that aspirin potentate minocycline induced MMP-2 and MMP-9 inhibition to ameliorate cardiovascular dysfunction of diabetes and this combination can be an approach for the treatment.     

Lymphocyte dysfunction caused by deficiencies in purine metabolism

Two inborn errors of purine metabolism have been associated with autosomally inherited human immunodeficiency diseases. A lack of adenosine deaminase (ADA) produces severe lymphopenia and a combined immunodeficiency syndrome. A deficiency of purine nucleoside phosphorylase (PNP) is associated with a selective cellular immune depth. This article discusses the probable biochemical basis for lymphocyte-specific toxicity in these disorders.     

Human natural killer cell deficiencies

PURPOSE OF REVIEW: Human natural killer cell deficiencies are a relevant clinical entity that provides insight into the role of natural killer cells in host defense, as well as the basic biology of natural killer cells. Since previously reviewing these disorders, significant developments warrant their reconsideration. RECENT FINDINGS: Human natural killer cell deficiencies can occur as part of a more pervasive immunodeficiency syndrome or, rarely, in isolation. The most informative examples of the former are in the context of a known genetic defect, because the deficiency of natural killer cell development or activity can be attributed to the specific gene function. Since last reviewed, there are five human gene mutations that are now appreciated to affect natural killer cells, and additional new insights into natural killer cell biology have been obtained through seven others. Six new reports of isolated natural killer cell deficiencies, as well as a suggested classification scheme, are also reviewed. SUMMARY: Appreciation of human genetic syndromes that include natural killer cell deficiencies, as well as new cases of isolated natural killer cell deficiencies, continue to advance the understanding of natural killer cell biology and solidify the role of natural killer cells in defense against human herpesviral infection.     

带监测皮岛的腓骨头移植修复肱骨头缺损重建肩关节

目的 :探讨带监测皮岛的腓骨头移植修复肱骨头缺损重建肩关节的可行性与临床价值。方法 :对 13例因肿瘤或创伤致肱骨头缺损病例 ,用带监测皮岛的腓骨头移植修复肱骨头缺损并重建肩关节。结果 :3～ 10年随访 ,13例监测皮岛存活 ,移植腓骨头增大塑形 ,形似受区肱骨头 ,移植腓骨与肱骨的口径相当 ,肩关节活动度 :前屈 64 .6°± 8.3° ,后伸 2 7.7°± 5 .3° ,外展 72 .3°± 7.8° ,内收 17.3°± 4.4° ,上举 13 8.8°± 12 .8°。结论 :带监测皮岛腓骨头移植修复肱骨缺损重建肩关节疗效可靠。     

Engineering dendritic cell grafts for clinical trials in cellular immunotherapy of cancer: example of chronic myelogenous leukemia

Dendritic cells are pivotal regulators of immune reactivity and immune tolerance. The observation that dendritic cells can recruit naive T-cells has invigorated cancer immunology and stimulated clinical trials of dendritic cells in immunotherapy. However, variables inherent in preparation and use of dendritic cell grafts remain to be tested. Here we discuss the role of ex vivo dendritic cell processing for in vivo antigen presentation in clinical trials. As an example of the complexity in a clinical trial of dendritic cell vaccines, we present our ongoing trial in immunotherapy of chronic myelogenous leukemia.     

Autoimmune myocarditis: cellular mediators of cardiac dysfunction

Immune mediators play a critical role in the pathogenesis and outcomes of a number of cardiac diseases. This review summarizes recent findings on the composition of the inflammatory infiltrate and the role of different types and subtypes of immune cells and their products in mediating cardiac dysfunction in experimental autoimmune myocarditis (EAM). CD4+ T cells are required for initiation of myocarditis and their numbers in the heart infiltrate correlate with systolic dysfunction during disease progression. Other immune cells, including CD8+ T cells, granulocytes, and mast cells, can directly affect cardiomyocyte function. When regulatory mechanisms fail, the local damage leads to cardiomyocyte death, replacement fibrosis and overall cardiac dysfunction. EAM provides insights into the role of the immune system in the development of dilated cardiomyopathy (DCM) and heart failure and may serve as a general paradigm for autoimmune organ-specific tissue damage.     

Cord blood stem cell transplantation in primary immune deficiencies

PURPOSE OF REVIEW: Umbilical cord haematopoietic stem cell transplantation for primary immunodeficiencies is examined with other developments in treatment. Cord blood biology is reviewed, and advantages and disadvantages of umbilical cord blood stem cell transplantation for primary immunodeficiencies discussed. Clinical outcome data and future developments are reviewed. RECENT FINDINGS: Cord blood T lymphocytes become tolerant to host human leukocyte antigen antigens, but retain alloreactivity to other antigens, in part due to immaturity of cord blood T lymphocytes and dendritic cells. Although na?ve T lymphocytes can generate herpes virus specificity after transplantation, the risk of viral death is increased within the first 100 days. The clinical success of umbilical cord blood stem cell transplantation for primary immunodeficiencies is reviewed and new methods for expanding the stem cell number or encouraging engraftment with the use of third-party haematopoietic or mesenchymal stem cells examined. SUMMARY: Many advantages make umbilical cord blood an attractive source of stem cells; over 100 umbilical cord blood stem cell transplantations have been performed for primary immunodeficiencies, with low rates of significant graft vs. host disease, despite significant human leukocyte antigen mismatch. Immune reconstitution is as good as for other stem cell sources: use of nascent stem cells in young recipients may have long-term advantages. Stem cell engineering to improve engraftment will expand potential beneficiaries of umbilical cord blood stem cell transplantation to older patients.     

Inflammation-mediated dysfunction and apoptosis in pancreatic islet transplantation: implications for intrahepatic grafts

Recent advances in clinical protocols have improved the outcomes of pancreatic islet transplantation (PIT), yet PIT recipients typically require pancreatic islet grafts derived from multiple donors to achieve insulin independence. This along with experimental models of syngeneic PIT, showing that up to 60% of pancreatic islet tissue undergoes apoptosis within the first several days post-transplantation, strongly suggest the involvement of nonalloantigen-specific, inflammatory events in partial destruction of the graft following PIT. Interleukin-1beta appears to be among the most important inflammatory mediators, causing pancreatic islet dysfunction and apoptosis through the up-regulation of inducible nitric oxide (NO) synthase and cyclooxygenase-2. Kupffer cells secrete many molecules, including cytokines, NO, and free radicals, which are known to be directly toxic to the pancreatic islets, and depletion or inhibition of Kupffer cells improves outcomes following experimental PIT. Immediately after transplantation, the pancreatic islets are perfused only by portal vein blood until the process of angiogenesis restores arterial blood flow some 7-10 days later. This delayed vascularization may have implications for the expression of leukocyte adhesion molecules, the effects of free radicals, and the role of ischemia-reperfusion injury. Finally, in the immediate post-transplant period, hepatocytes may contribute to pancreatic islet injury through the production of NO. This paper reviews literature regarding the inflammatory events that follow PIT as well as the pathogenesis of diabetes and the pathophysiology of hepatic ischemia-reperfusion and their relation to the survival and function of intrahepatic pancreatic islet grafts.     

Endothelial cell attachment to the gamma irradiated small diameter polyurethane vascular grafts

Previously we have fabricated the small diameter polyurethane (Pellethane 2363-80A, abbreviated PU) vascular grafts that were modified by epoxy-crosslinked gelatin (abbreviated gelatin) and an RGD-containing protein (abbreviated CBD-RGD) to facilitate the endothelial cell (EC) seeding on the surface. In this study, the biocompatibility of such surface after freeze-drying and gamma irradiation was evaluated. The contact angle of the irradiated PU dropped a little and the ESCA spectra revealed oxygen bonding. The increases in the amount of extractables as well as in the molecular weight distribution were observed. The mechanical properties decreased only slightly. The irradiated PU surface showed enhanced EC affinity that persisted after several months of storage. Gelatin, CBD-RGD (used with either gelatin or PU), and PU modified by gelatin and CBD-RGD all demonstrated higher EC affinity after freeze-drying and gamma irradiation (2.5 Mrad). The positive cellular effect remained after storage. Based on these results, freeze-drying followed by gamma irradiation at 2.5 Mrad is a proper way to process and store these vascular grafts.     

Dendritic cell deficiencies persist seven months after SARS-CoV-2 infection

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection induces an exacerbated inflammation driven by innate immunity components. Dendritic cells (DCs) play a key role in the defense against viral infections, for instance plasmacytoid DCs (pDCs), have the capacity to produce vast amounts of interferon-alpha (IFN-α). In COVID-19 there is a deficit in DC numbers and IFN-α production, which has been associated with disease severity. In this work, we described that in addition to the DC deficiency, several DC activation and homing markers were altered in acute COVID-19 patients, which were associated with multiple inflammatory markers. Remarkably, previously hospitalized and nonhospitalized patients remained with decreased numbers of CD1c+ myeloid DCs and pDCs seven months after SARS-CoV-2 infection. Moreover, the expression of DC markers such as CD86 and CD4 were only restored in previously nonhospitalized patients, while no restoration of integrin β7 and indoleamine 2,3-dyoxigenase (IDO) levels were observed. These findings contribute to a better understanding of the immunological sequelae of COVID-19.     

Current strategies exploiting NK‐cell therapy to treat haematologic malignancies

Natural killer (NK) cells recognize targets that have been changed via malignant transformation or infection. Previously, NK cells were thought to be short‐lived, but we now know that NK cells can be long‐lived and remember past exposures in response to CMV. NK cells use a plethora of activating and inhibitory receptors to recognize these changes and attack targets, but tumour cells often evade NK cells. Therefore, major efforts are being made to hone in on NK cell antitumour properties in immunotherapy. In the clinical setting, haploidentical NK cells can be adoptively transferred to help treat cancer. To expand NK cells in vivo and enhance tumour targeting, IL‐15 is being tested in combination with a glycogen synthase kinase (GSK) 3 inhibitor (CHIR99021), an inhibitor that has been shown to expand mature, highly functional NK cells capable of killing multiple tumour targets. One major limitation to NK cell therapy is lack of specificity. To address this concern, bispecific or trispecific engagers that target NK cells to the tumour and an ADAM17 inhibitor that prevents CD16 shedding after NK cell activation are being tested. Additionally, monoclonal antibodies are being designed to redirect the inhibitory signals that limit NK cell functionality. Further understanding of the biology of NK cells will inform strategies to exploit NK cells for therapeutic purposes.     

Vaccination with BLP25 liposome vaccine to treat non-small cell lung and prostate cancers

The identification of tumor-associated/-specific antigens and an increased understanding of the ways in which antigens are processed and presented has led to a revived interest in cancer vaccines as a therapeutic strategy. BLP25 liposome (L-BLP25) vaccine is a cancer vaccine that targets the exposed core peptide of the MUC1 tumor-associated antigen. Studies in advanced-stage non-small cell lung cancer demonstrate that L-BLP25 vaccine has the potential to extend the survival of patients with Stage IIIB locoregional non-small cell lung cancer and maintain quality of life for longer. L-BLP25 vaccine also shows promise for prostate cancer patients, having the potential to prolong prostate-specific antigen doubling time in men with biochemical failure post prostatectomy. These clinically meaningful results with a relatively nontoxic therapeutic vaccine are very encouraging and suggest potential for L-BLP25 to fulfill an unmet medical need.     

Adoptive immunotherapy to treat leukemic relapse following allogeneic hematopoietic stem cell transplantation

Acute leukemia patients who relapse after haematopoetic stem cell transplantation (HSCT) have poor prognosis with few therapeutic options. An immunotherapeutic approach that specifically targets the leukemia to treat and prevent these relapses could improve survival rates for these patients. Recently a number of potential antigenic targets for leukemia have been described. These include over-expressed normal antigens such as survivin, leukemia-specific targets resulting from translocations and mutations and hematopoietic-restricted minor histocompatibility antigens such as HA-1 and HA-2. Considerable experimental data indicates that cytotoxic T cells targeting these antigens can be generated in vitro. Further improvements in the efficacy of antigen presentation and T cell activation and expansion will facilitate the clinical application of these T cells as a therapeutic strategy for patients who are likely to relapse after HSCT.     

粒细胞集落刺激因子动员骨髓干细胞治疗大鼠缺血性脑梗死

目的: 探讨粒细胞集落刺激因子(G-CSF)对大鼠缺血性脑梗死的治疗作用。方法:采用线栓法制作大鼠缺血性脑梗死模型,1 h后腹腔注射G-CSF 60 μg/kg 。TTC、HE染色及免疫组化检测脑梗死灶体积、病理改变及CD34阳性细胞浸润情况。结果:G-CSF治疗组大鼠脑梗死灶体积明显小于对照组(P<0.01);其病理损伤程度较对照组轻;脑梗死部位出现CD34阳性单个核细胞浸润,并有CD34阳性呈锥状并且带有突起的神经样细胞生长,对照组未发现CD34阳性细胞。结论: G-CSF可减轻大鼠缺血性脑梗死程度,减少脑梗死体积,其机理可能是G-CSF对缺血神经元具有保护作用,并动员自体骨髓干细胞,促进脑组织的再生与修复。