Mechanisms of MHC class I-restricted antigen presentation

The vertebrate immune system monitors whether an organism is invaded by pathogens. Therefore, each cell has to prove itself as healthy. This is achieved by presenting fragments of intracellular protein degradation products on the surface, i.e., each cell displays peptides on specialised proteins known as major histocompatibility complex (MHC) class I proteins. A displayed peptide has to pass certain constraints before its presentation: It has to be excised out of a protein, translocated into the endoplasmic reticulum (ER) and fit into the binding groove of a MHC molecule. In theory, alteration of the cellular protein profile by mutation or infection should force pathogen-specific T-cells to take action via recognition of foreign peptide bound to MHC class I molecules on the cell surface. Unfortunately, pathogens and tumours have evolved many ways to affect antigen presentation and to escape from immune response. Understanding the exact mechanisms of antigen presentation, i.e., protein cleavage and peptide binding by MHC molecules, would allow their manipulation by drugs and lead to the re-establishment of the correct antigen presentation pathway. This review will summarise current knowledge of the mechanisms of antigen presentation and discuss putative targets for therapeutic treatment as well as for vaccination strategies.     

Challenges of Childhood TB/HIV Management in Malawi

The diagnosis and management of childhood tuberculosis (TB) are major challenges in countries such as Malawi with high incidence of TB and human immunodeficiency virus (HIV) infection. Diagnosis of TB in children often relies only on clinical features but clinical overlap with the presentation of HIV and other HIV-related lung disease is common. The tuberculin skin test (TST), the standard marker of M. tuberculosis infection in immune competent children, has poor sensitivity in HIV-infected children and is not usually available in Malawi. HIV test should be routine in children with suspected TB as it improves clinical management. HIV-infected children are at increased risk of developing active disease following TB exposure which justifies the use of isoniazid preventive therapy (IPT) once active disease has been excluded but this is difficult to implement and appropriate duration of IPT is unknown. HIV-infected children with active TB experience higher mortality and relapse rates on standard TB treatment compared to HIV-uninfected children, highlighting the need for further research to define optimal treatment regimens. HIV-infected children should also receive appropriate supportive care including cotrimoxazole prophylaxis and anti-retroviral treatment (ART) if indicated. There are concerns about concurrent use of some anti-TB drugs such as rifampicin with some ARTs.     

Stereotactic radiosurgery, X: clinical isodosimetry of gamma knife versus linear accelerator X-knife for pituitary and acoustic tumours

Several review articles have compared gamma unit versus linear accelerator (linac)-based radiosurgery systems, concluding that the dose gradient 'fall-off' at the margin of the target (expressed as the distance between isodoses) is very similar for both techniques as far as single isocentre treatment volumes up to 1.5 cm diameter are concerned, and that the two radiosurgical systems are, in general, comparable. 'Fine tuning' of the gamma unit can be carried out by using multiple isocentre plans, the differential use of small collimator sizes (down to 4 mm) and field weightings, and adroit use of the gamma angle, and selective beam blocking. Multiple isocentre plans, beam modification, restriction of gantry angles and arc lengths, and microcollimation can similarly improve the isodose gradients from linac units. In both instances, the dosimetric advantages occur along selected aspects of the target perimeter border. However, the more frequent use of multiple isocentred 'shots' on the gamma unit achieves greater conformity indices for more complex target volumes, but at the expense of steeper internal dose gradients. We studied two patients with tumours close to or arising from radiosensitive special sensory nerves (optic and cochlear) to compare and contrast fine tuning of the two technologies. In a previously irradiated patient with a pituitary adenoma, the dose gradient achieved at the rostral margin, adjacent to the optic chiasma, was steeper on the gamma unit (due to the concentration of small collimator shots rostrally and beam blocking), which was therefore the dosimetrically preferred technique. In contrast, the vastly smaller internal dose gradient (11% for linac/X-knife versus 100% for Gamma Knife) and the ability to fractionate on the X-knife system, gave a large dosimetric advantage to the X-knife plan in the treatment of an acoustic neuroma, where the intracanalicular component of the cochlear nerve traversed the target volume. This advantage also pertains to the cochlear ramus of the internal auditory (labyrinthine) artery and the facial nerve. Our published work on X-knife radiosurgery of acoustic neuroma has documented improvement of hearing after therapy and may be relevant in this regard. That there are advantages in physical dose distribution and fractionation, producing a reduction in the biological dose in normal tissue, argues for the use of linac technology in acoustic neuromas. Craniopharyngiomas enveloping the optic nerve/chiasma will similarly be better treated by the linac X-knife system. It is apparent that different radiosurgery systems may be indicated in particular neuro-oncological situations.     

The eye in acute leukaemia. 2. The management of solitary anterior chamber relapse

Solitary relapse of acute lymphoblastic leukaemia (ALL) was diagnosed in the anterior chamber of the eye in five children. In all these cases, pathological confirmation of the diagnosis was obtained and there was no other evidence of relapse including cerebrospinal fluid (CSF) and bone marrow examinations. Each child had one adverse prognostic sign at the initial presentation (high white blood cell count, age or sex). Relapse always occurred soon after completion of maintenance chemotherapy (between one and 4 months), supporting the hypothesis that the eye is a pharmacological sanctuary to cytotoxic chemotherapeutic drugs. Radiotherapy to the involved orbit was given with an immediate response in all patients. The details of this treatment are discussed. Four of the five patients later relapsed, one locally and three in bone marrow; the prognosis of solitary ocular relapse therefore appears grave.     

Paediatric brachytherapy. I. The role of brachytherapy in the multidisciplinary therapy of localized cancers

Paediatric brachytherapy is rarely practised but has definite benefit in certain situations. Case reports illustrate the role of current brachytherapy strategies both as radical and salvage procedures and in the multidisciplinary management of childhood cancers.     

镁对镍、钴、锌、镉离子致蟾蜍胚胎毒性的影响

[目的 ]用FETAX设计 ,研究Mg2 对Ni2 、Co2 、Zn2 和Cd2 致Xenopus胚胎的胚胎毒性与致畸作用的影响。 [方法 ]在 7次检测中 ,分别于含Mg2 5个等级浓度 (0、6 2、62、62 0、62 0 0 μmol/L)的FETAX培养液中 ,设空白对照与加入NiCl2 (5 6μmol/L)、CoCl2 (180 0 μmol/L)、ZnCl2 (3 0 0 μmol/L)和CdCl2 (18μmol/L)的 2 5个组 ,每个组内的受精卵均经 5～10 1h孵育。在该检测中限定Mg2 (62 0 μmol/L)为标准浓度。在该浓度时Ni2 、Co2 、Zn2 和Cd2 组胚胎死亡率 <10 % ,畸形率 >95 %。 [结果 ]对照组于标准浓度时平均畸形率为 (5 4± 1 3 ) % ,低于该等级的 62 μmol/L为 (3 2± 7) % ,≤ 6 2μmol/L为 10 0 %。表明Mg2 不足与补加可极显著地增强与降低胚胎畸形率及其严重程度与胚胎毒性 (P <0 0 0 0 1,ANO VA分析 )。 [结论 ]对此 ,推测这可能与涉及在两价金属离子转运之间的金属吸收、细胞通道或对关键性分子靶 (即DNA聚合酶 )结合的竞争有关。     

First Quinquennial Review of Intensity-modulated Radiotherapy at St Bartholomew’s Hospital,London

Intensity-modulated radiotherapy (IMRT) is a relatively new technique of delivering external beam radiotherapy that is becoming increasingly available in the UK. This paper summarises the introduction and initial clinical work in IMRT over the period 2004–2009. Physics aspects of commissioning are described, including the development of a robust method of quality control using a sweeping gap test. Details of the organisational changes necessary to introduce IMRT are given. The clinical selection and practice in head and neck sites are described, together with promising early results on the maintenance of salivary flow after IMRT. A summary of research into optimal planning for pelvic cancer follows. The controversial areas of breast and paediatric IMRT are discussed with recommendations on practice. The potential for concomitant boost therapy is exemplified in the treatment of brain metastatic disease.