BSHI guideline: HLA matching and donor selection for haematopoietic progenitor cell transplantation.

A review of the British Society for Histocompatibility and Immunogenetics (BSHI) Guideline 'HLA matching and donor selection for haematopoietic progenitor cell transplantation' published in 2016 was undertaken by a BSHI appointed writing committee. Literature searches were performed and the data extracted were presented as recommendations according to the GRADE nomenclature.

Anti-N-methyl-d-aspartate receptor encephalitis in Maori and Pacific Island children in New Zealand.

AIM: To investigate the incidence and severity of anti-N-methyl-d-aspartate (anti-NMDA) receptor encephalitis in children from New Zealand. METHOD: A retrospective case series was undertaken of all children (≤18y) diagnosed with anti-NMDA receptor encephalitis from January 2008 to October 2015. RESULTS: Sixteen patients were identified with anti-NMDA receptor antibodies in the cerebrospinal fluid, three of whom had an associated teratoma. Fifteen children had Maori and/or Pacific Island ancestry. The incidence of anti-NMDA receptor encephalitis in Maori children was 3.4 per million children per year (95% confidence interval [CI] 1.4-7.0) and the incidence in Pacific children was 10.0 per million children per year (95% CI 4.3-19.8) compared with 0.2 per million children per year (95% CI 0.0-1.0) in children without Maori or Pacific Island ancestry. Sixty-seven per cent of children had a good outcome (modified Rankin Score ≤2) at 2 years' follow-up. This compares unfavourably with other cohorts despite a shorter median time to first-line immunotherapy (13d; range 4-89) and a higher proportion of children being treated with second-line therapy (50%). INTERPRETATION: Maori and Pacific Island children have a higher incidence of anti-NMDA receptor encephalitis and possibly a more severe phenotype. These data suggest a genetic predisposition to anti-NMDA receptor encephalitis in these populations.

Restoration of tumor suppression in prostate cancer by targeting the E3 ligase E6AP.

Restoration of tumor suppression is an attractive onco-therapeutic approach. It is particularly relevant when a tumor suppressor is excessively degraded by an overactive oncogenic E3 ligase. We previously discovered that the E6-associated protein (E6AP; as classified in the human papilloma virus context) is an E3 ligase that has an important role in the cellular stress response, and it directly targets the tumor-suppressor promyelocytic leukemia protein (PML) for proteasomal degradation. In this study, we have examined the role of the E6AP-PML axis in prostate cancer (PC). We show that knockdown (KD) of E6AP expression attenuates growth of PC cell lines in vitro. We validated this finding in vivo using cell line xenografts, patient-derived xenografts and mouse genetics. We found that KD of E6AP attenuates cancer cell growth by promoting cellular senescence in vivo, which correlates with restoration of tumor suppression by PML. In addition, we show that KD of E6AP sensitizes cells to radiation-induced death. Overall, our findings demonstrate a role for E6AP in the promotion of PC and support E6AP targeting as a novel approach for PC treatment, either alone or in combination with radiation.

Diversity in exon 5 of HLA-C(∗)04:01:01G is significant in anthropological studies.

Polymorphisms in Human Leukocyte Antigen (HLA) class I genes are generally considered to be relevant only if they reside in exons 2 and 3 or if they affect the expression of the allele. HLA-C(∗)04:82 differs from the common HLA-C(∗)04:01:01 by having a 9 nucleotide, or 3 amino acid duplication, in exon 5. Having observed HLA-C(∗)04:82 in a New Zealand Maori stem cell patient, we have attempted to examine the prevalence of this allele in different ethnicities. Although our studies are in a limited number of patients and donors, they have revealed that, in the Pacific region, HLA-C(∗)04:82 appears to be the most common allele of the HLA-C(∗)04:01:01G group of alleles, notably in Filippinos and in Maori/Polynesians. In these populations this allele has characteristic HLA-ABCDRB1 haplotypes. Thus, our studies have shown that polymorphisms outside of the clinically important exons can be considered to be relevant in anthropological studies.

Targeting Mdmx to treat breast cancers with wild-type p53.

The function of the tumor suppressor p53 is universally compromised in cancers. It is the most frequently mutated gene in human cancers (reviewed). In cases where p53 is not mutated, alternative regulatory pathways inactivate its tumor suppressive functions. This is primarily achieved through elevation in the expression of the key inhibitors of p53: Mdm2 or Mdmx (also called Mdm4) (reviewed). In breast cancer (BrCa), the frequency of p53 mutations varies markedly between the different subtypes, with basal-like BrCas bearing a high frequency of p53 mutations, whereas luminal BrCas generally express wild-type (wt) p53. Here we show that Mdmx is unexpectedly highly expressed in normal breast epithelial cells and its expression is further elevated in most luminal BrCas, whereas p53 expression is generally low, consistent with wt p53 status. Inducible knockdown (KD) of Mdmx in luminal BrCa MCF-7 cells impedes the growth of these cells in culture, in a p53-dependent manner. Importantly, KD of Mdmx in orthotopic xenograft transplants resulted in growth inhibition associated with prolonged survival, both in a preventative model and also in a treatment model. Growth impediment in response to Mdmx KD was associated with cellular senescence. The growth inhibitory capacity of Mdmx KD was recapitulated in an additional luminal BrCa cell line MPE600, which expresses wt p53. Further, the growth inhibitory capacity of Mdmx KD was also demonstrated in the wt p53 basal-like cell line SKBR7 line. These results identify Mdmx growth dependency in wt p53 expressing BrCas, across a range of subtypes. Based on our findings, we propose that Mdmx targeting is an attractive strategy for treating BrCas harboring wt p53.

Preoperative physical therapy for elective cardiac surgery patients.

BACKGROUND: After cardiac surgery, physical therapy is a routine procedure delivered with the aim of preventing postoperative pulmonary complications. OBJECTIVES: To determine if preoperative physical therapy with an exercise component can prevent postoperative pulmonary complications in cardiac surgery patients, and to evaluate which type of patient benefits and which type of physical therapy is most effective. SEARCH METHODS: Searches were run on the Cochrane Central Register of Controlled Trials (CENTRAL) on the Cochrane Library (2011, Issue 12 ); MEDLINE (1966 to 12 December 2011); EMBASE (1980 to week 49, 2011); the Physical Therapy Evidence Database (PEDro) (to 12 December 2011) and CINAHL (1982 to 12 December 2011). SELECTION CRITERIA: Randomised controlled trials or quasi-randomised trials comparing preoperative physical therapy with no preoperative physical therapy or sham therapy in adult patients undergoing elective cardiac surgery. DATA COLLECTION AND ANALYSIS: Data were collected on the type of study, participants, treatments used, primary outcomes (postoperative pulmonary complications grade 2 to 4: atelectasis, pneumonia, pneumothorax, mechanical ventilation > 48 hours, all-cause death, adverse events) and secondary outcomes (length of hospital stay, physical function measures, health-related quality of life, respiratory death, costs). Data were extracted by one review author and checked by a second review author. Review Manager 5.1 software was used for the analysis. MAIN RESULTS: Eight randomised controlled trials with 856 patients were included. Three studies used a mixed intervention (including either aerobic exercises or breathing exercises); five studies used inspiratory muscle training. Only one study used sham training in the controls. Patients that received preoperative physical therapy had a reduced risk of postoperative atelectasis (four studies including 379 participants, relative risk (RR) 0.52; 95% CI 0.32 to 0.87; P = 0.01) and pneumonia (five studies including 448 participants, RR 0.45; 95% CI 0.24 to 0.83; P = 0.01) but not of pneumothorax (one study with 45 participants, RR 0.12; 95% CI 0.01 to 2.11; P = 0.15) or mechanical ventilation for > 48 hours after surgery (two studies with 306 participants, RR 0.55; 95% CI 0.03 to 9.20; P = 0.68). Postoperative death from all causes did not differ between groups (three studies with 552 participants, RR 0.66; 95% CI 0.02 to 18.48; P = 0.81). Adverse events were not detected in the three studies that reported on them. The length of postoperative hospital stay was significantly shorter in experimental patients versus controls (three studies with 347 participants, mean difference -3.21 days; 95% CI -5.73 to -0.69; P = 0.01). One study reported a reduced physical function measure on the six-minute walking test in experimental patients compared to controls. One other study reported a better health-related quality of life in experimental patients compared to controls. Postoperative death from respiratory causes did not differ between groups (one study with 276 participants, RR 0.14; 95% CI 0.01 to 2.70; P = 0.19). Cost data were not reported on. AUTHORS' CONCLUSIONS: Evidence derived from small trials suggests that preoperative physical therapy reduces postoperative pulmonary complications (atelectasis and pneumonia) and length of hospital stay in patients undergoing elective cardiac surgery. There is a lack of evidence that preoperative physical therapy reduces postoperative pneumothorax, prolonged mechanical ventilation or all-cause deaths.

A "silent" nucleotide substitution in exon 4 is responsible for the "alternative expression" of HLA-A*01:01:38L through aberrant splicing.

A Welsh Bone Marrow Donor Registry donor was serologically typed, using both alloantisera and monoclonal antibodies, as human leukocyte antigen (HLA)-A2, A-, but typed by polymerase chain reaction sequence-specific priming as HLA-A*01, A*02. Full gene sequencing of the A*01 separated allele indicated an apparently normal A*01:01:01:01 apart from a silent change at nucleotide 705 in exon 4, codon 211 (alanine: normally GCG but GCA in this donor). Sequence analysis of the amplified A*01 allele in cDNA synthesized from RNA indicated that exons 1, 2, 3, and 5 had typical A*01:01 sequences. However, exon 4 was truncated in this allele (87 nucleotides shorter), beginning just after the single nucleotide polymorphism (SNP) identified in genomic DNA sequencing. The nucleotide sequence up to, and 1 nucleotide after, the SNP is homologous with the 3' end of human leukocyte antigen (HLA)-A intron 3 and thus resembles a splice site. However, a small amount of "normal" HLA-A1 was detected on the surface of cells from an Epstein-Barr virus transformed B-cell line (BCL), but not on peripheral blood mononuclear cells, by flow cytometry. Additionally, a trace amount of "normal sized" A*01 was amplified from cDNA. We suggest that in this A*01 variant allele (A*01:01:38L) intron 3 is largely spliced out with a part of exon 4; exon 4 is still in-frame but the protein is smaller than the wild type. This is likely to affect folding and assembly of the "wild type" mature protein on the cell surface, thus explaining the apparent null phenotype when assayed by conventional serology. However, a small amount of A1 protein is made from correctly spliced A*01 mRNA and is detectable on BCLs using flow cytometry.

On the identifiability of pharmacokinetic parameters in dynamic contrast-enhanced imaging.

The so-called "Kety model" is a two-compartment pharmacokinetic model describing tumor perfusion kinetics. Its parameters, the transendothelial transfer constant (K(trans)), extravascular extracellular volume fraction (upsilon(e)), and microvascular plasma volume fraction (upsilon(p)), can be estimated with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). However, the results obtained by current methods show large variation in predictability and reliability. Here, the aim was to examine which experimental conditions have to be fulfilled to avoid large uncertainties and mutual dependencies of the parameters. Using frequency response analysis and simulation, the identifiability of the model was examined. The requirements and influence of contrast enhancement measurements, such as temporal resolution, signal to noise ratio, and contrast injection rate, on the accuracy of the parameters were analyzed. Tissue response characteristics revealed a low-frequency system with a cutoff frequency equal to K(trans)/upsilon(e), which confines the required temporal resolution. For malignant tissue with hyperpermeable vasculature (high K(trans)) a higher sampling frequency is required to accurately estimate K(trans) than for normal tissue. Too low sampling rates or too low injection rates resulted in inaccurate K(trans) values and hereby unreliable classification of malignant tissue.