Imaging applications of nanotechnology in cancer

Consider a single agent capable of diagnosing cancer, treating it simultaneously and monitoring response to treatment. Particles of this agent would seek cancer cells accurately and destroy them without harming normal surrounding cells. Science fiction or reality? Nanotechnology and nanomedicine are rapidly growing fields that encompass the creation of materials and devices at atomic, molecular and supramolecular level, for potential clinical use. Advances in nanotechnology are bringing us closer to the development of dual and multi-functional nanoparticles that are challenging the traditional distinction between diagnostic and treatment agents. Examples include contrast agents capable of delivering targeted drugs to specific epithelial receptors. This opens the way for targeted chemotherapy which could minimise systemic side-effects, avoid damage to benign tissues and also reduce the therapeutic treatment dose of a drug required. Most of the current research is still at the pre-clinical stage, with very few instances of bench to bedside research. In order to encourage more translational research, a fundamental change is required to consider the current clinical challenges and then look at ways in which nanotechnology can address these.     

Isolation of viable antigen-specific CD8+ T cells based on membrane-bound tumor necrosis factor (TNF)-α expression

Current technology to isolate viable cytokine-producing antigen-specific primary human T cells is limited to bi-specific antibody capture systems, which suffer from limited sensitivity and high background. Here, we describe a novel procedure for isolating antigen-specific human T cells based on their ability to produce tumor necrosis factor (TNF)-α. Unlike many cytokines, TNF-α is initially produced in a biologically active membrane-bound form that is subsequently cleaved by TNF-α converting enzyme (TACE) to release the soluble form of TNF-α. By preventing this cleavage event, we show that TNF-α can be 'trapped' on the surface of the T cells from which it originates and directly labeled for viable isolation of these antigen-specific T cells. Together with other existing sorting procedures to isolate activated T cells, this new technique should permit the direct isolation of multi-functional T lymphocytes for further protein and gene expression analyses, as well as a detailed functional assessment of the potential role that TNF-α producing T cells play in the adaptive immune system.     

Determinants of protection among HIV‐exposed seronegative persons: an overview

Both clinical experience and a growing medical literature indicate that some persons who have been exposed to human immunodeficiency virus (HIV) infection remain uninfected. Although in some instances this may represent good fortune, cohorts of uninfected persons have been reported who are considered at high risk for infection. In these cohorts a variety of characteristics have been proposed as mediating protection, but to date only the 32–base pair deletion in the chemokine (C‐C motif) receptor 5 gene, which results in complete failure of cell surface expression of this coreceptor, has been associated with high‐level protection from HIV infection. With this in mind, there are probably many other factors that may individually or in combination provide some level of protection from acquisition of HIV infection. Because some of these factors are probably incompletely protective or inconsistently active, identifying them with confidence will be difficult. Nonetheless, clarifying the determinants of protection against HIV infection is a high priority that will require careful selection of high‐risk uninfected cohorts, who should undergo targeted studies of plausible mediators and broad screening for unexpected determinants of protection.     

'Nipped in the Budd': hepatic venous outflow obstruction in evolution

Hepatic venous thrombosis (Budd-Chiari) in evolution is a rare phenomenon and carries a high morbidity and mortality. We describe the case of a 39-year-old Bangladeshi lady who presented with severe abdominal pain secondary to a perforated duodenal ulcer and during her hospital admission developed an asymptomatic Budd-Chiari syndrome (BCS). Our report highlights the important role of an inflammatory focus, and how this process with an associated reactive thrombocytosis may act as a trigger for the development of BCS in an individual with predisposing risk factors. Our patient had been on the contraceptive pill, and was homozygous for the C677T mutation of 5,10-methylenetetrahydrofolate reductase, which results in hyperhomocysteinaemia. These pro-thrombotic risk factors were compounded by the thrombogenic potential of subsequent laparoscopic surgery, and resulted in an evolving thrombus that progressed into the inferior vena cava causing hepatic infarction. A particular feature of this case was the radiological demonstration of complete regression of the thrombus and the hepatic parenchymal changes, upon resolution of the inflammation and normalization of the platelet count. These changes occurred with oral anticoagulation as the only treatment modality, since our patient declined systemic thrombolysis. The demonstration of complete radiological resolution raises the question of how long one should continue oral anticoagulants and, indeed, whether in some instances a conservative approach may be the best management strategy for evolving BCS.     

Vaccination preserves CD4 memory T cells during acute simian immunodeficiency virus challenge

Acute simian immunodeficiency virus (SIV)/human immunodeficiency virus infection is accompanied by a massive destruction of CD4 memory T cells across all the tissue compartments. These early events set the course toward disease progression and immunodeficiency. Here, we demonstrate that prior vaccination reduces this destruction during acute SIV Mac251 infection, leading to better survival and long-term outcome. Systemic vaccination with a DNA-prime recombinant adenovirus boost regimen preserved memory CD4 T cells throughout the body. The vaccine regimen induced broad CD4 and CD8 T cell responses in all tissues examined and, importantly, induced antibodies that neutralized the primary isolate of SIV used for challenge. Finally, we demonstrate that the extent of preservation of the CD4 memory compartment during the acute phase provides a strong predictor for subsequent progression to death. Our data provide a mechanism to explain clinical observations that acute-phase viral loads predict long-term disease progression and underscore the need for interventions that protect against early destruction of CD4 memory T cells during acute infection.     

Pregnancy after bariatric surgery: Consensus recommendations for periconception,antenatal and postnatal care

The objective of the study is to provide evidence‐based guidance on nutritional management and optimal care for pregnancy after bariatric surgery. A consensus meeting of international and multidisciplinary experts was held to identify relevant research questions in relation to pregnancy after bariatric surgery. A systematic search of available literature was performed, and the ADAPTE protocol for guideline development followed. All available evidence was graded and further discussed during group meetings to formulate recommendations. Where evidence of sufficient quality was lacking, the group made consensus recommendations based on expert clinical experience. The main outcome measures are timing of pregnancy, contraceptive choice, nutritional advice and supplementation, clinical follow‐up of pregnancy, and breastfeeding. We provide recommendations for periconception, antenatal, and postnatal care for women following surgery. These recommendations are summarized in a table and print‐friendly format. Women of reproductive age with a history of bariatric surgery should receive specialized care regarding their reproductive health. Many recommendations are not supported by high‐quality evidence and warrant further research. These areas are highlighted in the paper.     

IL-7 therapy dramatically alters peripheral T-cell homeostasis in normal and SIV-infected nonhuman primates

Interleukin-7 (IL-7) is important for thymopoiesis in mice and humans because IL-7 receptor alpha (IL-7Ralpha) mutations result in a severe combined immunodeficiency phenotype with severe thymic hypoplasia. Recent evidence has indicated that IL-7 also plays an important role as a regulator of T-cell homeostasis. Here we report the immunologic effects of recombinant human IL-7 (rhIL-7) therapy in normal and simian immunodeficiency virus (SIV)-infected nonhuman primates. Cynomolgus monkeys receiving 10 days of rhIL-7 showed substantial, reversible increases in T-cell numbers involving a dramatic expansion of both naive and nonnaive phenotype CD4(+) and CD8(+) subsets. Although IL-7 is known to have thymopoietic effects in mice, we observed marked declines in the frequency and absolute number of T-cell receptor excision circle-positive (TREC(+)) cells in the peripheral blood and dramatic increases in the percentage of cycling T cells in the peripheral blood as measured by Ki-67 expression (baseline less than 5% to approximately 50% after 6 days of therapy) and ex vivo bromodeoxyuridine (BrdU) incorporation. Similarly, moderately CD4- depleted SIV-infected macaques treated with rhIL-7 also had significant increases in peripheral blood CD4(+) and CD8(+) T cells following rhIL-7 therapy. Thus, rhIL-7 induces dramatic alterations in peripheral T-cell homeostasis in both T-cell-replete and T-cell-depleted nonhuman primates. These results further implicate IL-7 as a promising immunorestorative agent but illustrate that a major component of its immunorestorative capacity reflects effects on mature cells. These results also raise the possibility that IL-7 therapy could be used to temporarily modulate T-cell cycling in vivo in the context of immunotherapies such as vaccination.     

Early reconstitution of the T-cell repertoire after non-myeloablative peripheral blood stem cell transplantation is from post-thymic T-cell expansion and is unaffected by graft-versus-host disease or mixed chimaerism

To study immune recovery after non-myeloablative, reduced-intensity stem cell allografts (NST) and T-cell-depleted myeloablative transplants (TCD), we measured T-cell subset recovery by flow cytometry, T-cell repertoire by spectratyping and thymic T-cell output using a T-cell receptor excision circle (TREC) assay. We found a rapid and comparable increase in lymphocyte numbers in both NST and TCD, supporting the presence of a powerful drive for lymphocyte recovery after transplant. Spectratyping on d 45 and 100 revealed almost complete normalization of the T-cell repertoire in NST patients by d 45, whereas TCD patients demonstrated marked skewing of the repertoire, persisting to d 100. After NST, there was a significantly higher number of TREC-positive CD4+ and CD8+ cells (P = 0.02 and P = 0.01 respectively). However, in both NST and TCD, early T-cell recovery after transplant appeared to result entirely from post-thymic T cells, the expansion pattern of which is most influenced by the starting T-cell dose, but not markedly by graft-versus-host disease (GVHD) or mixed chimaerism. These results define important qualitative differences in the T-cell repertoire according to the type of transplant schedule used.