A distinct pre-existing inflammatory tumour microenvironment is associated with chemotherapy resistance in high-grade serous epithelial ovarian cancer.

BACKGROUND: Chemotherapy resistance is a major determinant of poor overall survival rates in high-grade serous ovarian cancer (HGSC). We have previously shown that gene expression alterations affecting the NF-κB pathway characterise chemotherapy resistance in HGSC, suggesting that the regulation of an immune response may be associated with this phenotype. METHODS: Given that intrinsic drug resistance pre-exists and is governed by both tumour and host factors, the current study was performed to examine the cross-talk between tumour inflammatory microenvironment and cancer cells, and their roles in mediating differential chemotherapy response in HGSC patients. Expression profiling of a panel of 184 inflammation-related genes was performed in 15 chemoresistant and 19 chemosensitive HGSC tumours using the NanoString nCounter platform. RESULTS: A total of 11 significantly differentially expressed genes were found to distinguish the two groups. As STAT1 was the most significantly differentially expressed gene (P=0.003), we validated the expression of STAT1 protein by immunohistochemistry using an independent cohort of 183 (52 resistant and 131 sensitive) HGSC cases on a primary tumour tissue microarray. Relative expression levels were subjected to Kaplan-Meier survival analysis and Cox proportional hazard regression models. CONCLUSIONS: This study confirms that higher STAT1 expression is significantly associated with increased progression-free survival and that this protein together with other mediators of tumour-host microenvironment can be applied as a novel response predictive biomarker in HGSC. Furthermore, an overall underactive immune microenvironment suggests that the pre-existing state of the tumour immune microenvironment could determine response to chemotherapy in HGSC.

Somatic hypermutations and isotype restricted exceptionally long CDR3H contribute to antibody diversification in cattle.

Antibody diversification in IgM and IgG antibodies was analyzed in an 18-month old bovine (Bos taurus) suffering from naturally occurring chronic and recurrent infections due to bovine leukocyte adhesion deficiency (BLAD). The BLAD, involving impaired leukocyte beta2 integrin expression on leukocytes, develops due to a single point mutation in conserved region of the CD18 gene resulting in substitution of aspartic acid128 with glycine (D128G). Twenty four VDJCmu and 25 VDJCgamma recombinations from randomly constructed cDNA libraries, originating from peripheral blood lymphocytes, were examined for the variable-region structural characteristics in IgM and IgG antibody isotypes. These analyses led to conclude that: (a) expression of exceptionally long CDR3H is isotype restricted to cattle IgM antibody; (b) VDJ recombinations encoding IgM with exceptionally long CDR3H undergo clonal selection and affinity maturation via somatic mutations similar to conventional antibodies; (c) somatic mutations contribute significantly to both IgM and IgG antibody diversification but significant differences exist in the patterns of 'hot spot' in the FR1, FR3 and CDR1H and, also, position-dependant amino acid diversity; and (d) transition nucleotide substitutions predominate over transversions in both VDJCmu and VDJCgamma recombinations consistent with the evolutionary conservation of somatic mutation machinery. Overall, these studies suggest that both somatic mutations and exceptional CDR3H size generation contribute to IgM and IgG antibody diversification in cattle during the development of immune response to naturally occurring chronic and multiple microbial infections.

Organization of D(H)-gene locus is distinct in cattle.

Some cattle antibodies are amongst the largest known to exist, in a species where CDR3 of the heavy-chain variable region (CDR3H) is of exceptional size as it may extend up to 61 amino acids. The origin of such an exceptionally long CDR3H in cattle antibodies is not yet understood. For these reasons, we have completely characterized DH gene locus in a Holstein cow. In contrast to other species, such as mice and humans, the DH gene locus in cattle, extending over 68 kb, is organized in subclusters comprising two to four DH gene segments. Analysis of DH genes reveals the presence of characteristic repetitive GGT and TAT codons. No evidence for a DH gene segment longer than 148 base pairs has been noted. Therefore, mechanistic factors contribute significantly to CDR3H size generation. Such comparative genomics perspectives of bovine D gene loci have revealed the complexity of evolution, across animal phyla, of functional significance in the generation of antibody diversity.

Bunionette.

The bunionette, or tailor's bunion, is a painful osseous prominence on the lateral aspect of the head of the fifth metatarsal. This prominence occurs in many individuals but seldom causes symptoms. Orthotic devices may be useful if a symptomatic bunionette results from excessive pronation of the subtalar joint. Operative management to decrease the width of the foot and the osseous prominence is indicated when nonoperative treatment can no longer control symptoms and when the patient has special demands, particularly in sports. A proximal osteotomy is able to correct most deformities. A distal osteotomy is recommended if medial translation of the head for one-third of the width of the metatarsal shaft produces a normal fourth-fifth intermetatarsal angle.

Detection of egg drop syndrome 1976 virus by polymerase chain reaction and study of its persistence in experimentally infected layer birds.

Polymerase chain reaction (PCR) assay was developed for the detection of Egg drop syndrome 1976 (EDS-76) virus in tissues, namely in the uterus, spleen and buffy coat. It was also used to study the persistence of the virus in tissues of experimentally infected layer birds. The PCR assay could detect as little as 10 fg of purified EDS-76 viral DNA. It also amplified the DNA of Fowl adenovirus serotypes 4 (FAV-4) and 8 (FAV-8). The virus persisted in the uterus up to day 21 post infection (p.i.). Detection of EDS-76 viral DNA in the buffy coat could be useful for studying the occurrence of the respective disease in layer bird flocks.

Restriction enzyme analysis of Indian isolates of egg drop syndrome 1976 virus recovered from chicken, duck and quail.

Egg drop syndrome 1976 (EDS-76) is caused by a haemagglutinating adenovirus belonging to group III of the genus Aviadenovirus in the family Adenoviridae. All isolates are serologically identical, but have been divided into three groups based on restriction endonuclease (RE) analysis. In this study the viral DNA of various Indian EDS-76 viral isolates (CEDS-A, CEDS-B, EDS-M, EDS-ML, EDS-1/AD/86, EDS-KC and QEDS) obtained from different avian species and different geographical regions were digested with restriction endonucleases viz., EcoRI, BamHI, HindIII and PstI. The results showed that one Indian isolate obtained from duck (DEDS-KC) was different from all other chicken and quail counterparts. All other isolates were identical to the reference viral strain BC-14, which belong to group I of EDS-76 viruses. The duck isolate EDS-KC could not be placed in any of the three groups reported earlier.

Subungual glomus tumor of the hallux. A case report.

The authors report a rare case of subungual glomus tumor in the right hallux, which was excised with complete relief of symptoms. They provide a brief description of histological features and review the literature.

Diagnosis of lumbosacral nerve root anomalies by magnetic resonance imaging.

This study evaluates the use of magnetic resonance imaging (MRI) in the diagnosis of lumbosacral nerve root anomalies. Prevalence of anomalous nerve roots has been based on anatomic dissection or preoperative neuroradiologic investigations. Three hundred seventy-six patients with low back pain and/or radicular pain who underwent MRI of the lumbar spine were reviewed. Sixty-five cases of nerve root anomalies were found (an incidence of 17.3%) of which 1 case of cranial origin, 5 cases of caudal origin, 2 cases of conjoined nerve root, and 57 cases of furcal nerve roots (15.1%) were identified. Furcal nerve roots were most commonly found at L3 and L4 levels and were classified, according to their division, into intra-and extraforaminal. MRI provided accurate information on lumbosacral nerve root anomalies.