Testicular seminoma – unusual histology and staging with sub epithelial spread of seminoma along the vas deferans

BACKGROUND: The route of local and metastatic spread of testicular seminoma is well recognised and accepted. The spread is via lymphatics to the paraaortic nodes. CASE PRESENTATION: We present a case report of testicular seminoma in a 56 year old man with previously unreported histological findings. In this case seminoma tumour cells did not appear to have spread by the expected lymphatic route. There was no involvement of retro-peritoneal para-aortic lymph nodes. The tumour appeared to have spread directly along the vas deferans in the sub epithelial plane to the mesenteric lymph nodes. CONCLUSION: This type of seminoma tumour spread has not previously been described and it is not a recognised route for metastasis by seminoma tumour. In this case the macroscopic clinical appearance was of a stage I tumour with normal tumour markers. However, the pathological stage of the tumour was surprisingly increased to stage III on the basis of histology and CT radiological findings. We present the unusual histological findings. In view of this unusual histological finding we reinforce the need for accurate staging and for resection of the spermatic cord close to the deep inguinal ring. Accurate staging is crucial in planning the treatment and follow up of seminoma and determines the prognosis

A global characterization of the translational and transcriptional programs induced by methionine restriction through ribosome profiling and RNA-seq

Background: Among twenty amino acids, methionine has a special role as it is coded by the translation initiation codon and methionyl-tRNAi (Met-tRNAi) is required for the assembly of the translation initiation complex. Thus methionine may play a special role in global gene regulation. Methionine has also been known to play important roles in cell growth, development, cancer, and aging. In this work, we characterize the translational and transcriptional programs induced by methionine restriction (MetR) and investigate the potential mechanisms through which methionine regulates gene expression, using the budding yeast S. cerevisiae as the model organism. Results: Using ribosomal profiling and RNA-seq, we observed a broad spectrum of gene expression changes in response to MetR and identified hundreds of genes whose transcript level and/or translational efficiency changed significantly. These genes show clear functional themes, suggesting that cell slows down its growth and cell cycle progression and increases its stress resistance and maintenance in response to MetR. Interestingly, under MetR cell also decreases glycolysis and increases respiration, and increased respiration was linked to lifespan extension caused by caloric restriction. Analysis of genes whose translational efficiency changed significantly under MetR revealed different modes of translational regulation: 1) Ribosome loading patterns in the 5'UTR and coding regions of genes with increased translational efficiency suggested mechanisms both similar and different from that for the translational regulation of Gcn4 under general amino acid starvation condition; 2) Genes with decreased translational efficiency showed strong enrichment of lysine, glutamine, and glutamate codons, supporting the model that methionine can regulate translation by controlling tRNA thiolation. Conclusions: MetR induced a broad spectrum of gene expression changes at both the transcriptional and translational levels, with clear functional themes indicative of the physiological state of the cell under MetR. Different modes of translational regulation were induced by MetR, including the regulation of the ribosome loading at 5'UTR and regulation by tRNA thiolation. Since MetR extends the lifespan of many species, the list of genes we identified in this study can be good candidates for studying the mechanisms of lifespan extension.National Institutes of Health [AG043080]SCI(E)ARTICLE1

Small but crucial : the novel small heat shock protein Hsp21 mediates stress adaptation and virulence in Candida albicans

Peer reviewedPublisher PD

Direct comparison of methionine restriction with leucine restriction on the metabolic health of C57BL/6J mice

EKL was the recipient of a BBSRC postgraduate studentship. This work was funded by Tenovus Scotland project grant to MD and NM (G13/07) and BBSRC DTG. MD is also supported by the British Heart Foundation (PG/09/048/27675, PG/11/8/28703 and PG/14/43/30889) and Diabetes UK (14/0004853). NM is funded by British Heart Foundation (PG/16/90/32518).Peer reviewedPublisher PD

Comprehensive profiling of DNA methylation in colorectal cancer reveals subgroups with distinct clinicopathological and molecular features

<p>Abstract</p> <p>Background</p> <p>Most previous studies of the CpG island methylator phenotype (CIMP) in colorectal cancer (CRC) have been conducted on a relatively small numbers of CpG sites. In the present study we performed comprehensive DNA methylation profiling of CRC with the aim of characterizing CIMP subgroups.</p> <p>Methods</p> <p>DNA methylation at 1,505 CpG sites in 807 cancer-related genes was evaluated using the Illumina GoldenGate^®methylation array in 28 normal colonic mucosa and 91 consecutive CRC samples. Methylation data was analyzed using unsupervised hierarchical clustering. CIMP subgroups were compared for various clinicopathological and molecular features including patient age, tumor site, microsatellite instability (MSI), methylation at a consensus panel of CpG islands and mutations in <it>BRAF </it>and <it>KRAS</it>.</p> <p>Results</p> <p>A total of 202 CpG sites were differentially methylated between tumor and normal tissue. Unsupervised hierarchical clustering of methylation data from these sites revealed the existence of three CRC subgroups referred to as CIMP-low (CIMP-L, 21% of cases), CIMP-mid (CIMP-M, 14%) and CIMP-high (CIMP-H, 65%). In comparison to CIMP-L tumors, CIMP-H tumors were more often located in the proximal colon and showed more frequent mutation of <it>KRAS </it>and <it>BRAF </it>(<it>P </it>< 0.001).</p> <p>Conclusions</p> <p>Comprehensive DNA methylation profiling identified three CRC subgroups with distinctive clinicopathological and molecular features. This study suggests that both <it>KRAS </it>and <it>BRAF </it>mutations are involved with the CIMP-H pathway of CRC rather than with distinct CIMP subgroups.</p

HacA-Independent Functions of the ER Stress Sensor IreA Synergize with the Canonical UPR to Influence Virulence Traits in Aspergillus fumigatus

Endoplasmic reticulum (ER) stress is a condition in which the protein folding capacity of the ER becomes overwhelmed by an increased demand for secretion or by exposure to compounds that disrupt ER homeostasis. In yeast and other fungi, the accumulation of unfolded proteins is detected by the ER-transmembrane sensor IreA/Ire1, which responds by cleaving an intron from the downstream cytoplasmic mRNA HacA/Hac1, allowing for the translation of a transcription factor that coordinates a series of adaptive responses that are collectively known as the unfolded protein response (UPR). Here, we examined the contribution of IreA to growth and virulence in the human fungal pathogen Aspergillus fumigatus. Gene expression profiling revealed that A. fumigatus IreA signals predominantly through the canonical IreA-HacA pathway under conditions of severe ER stress. However, in the absence of ER stress IreA controls dual signaling circuits that are both HacA-dependent and HacA-independent. We found that a ΔireA mutant was avirulent in a mouse model of invasive aspergillosis, which contrasts the partial virulence of a ΔhacA mutant, suggesting that IreA contributes to pathogenesis independently of HacA. In support of this conclusion, we found that the ΔireA mutant had more severe defects in the expression of multiple virulence-related traits relative to ΔhacA, including reduced thermotolerance, decreased nutritional versatility, impaired growth under hypoxia, altered cell wall and membrane composition, and increased susceptibility to azole antifungals. In addition, full or partial virulence could be restored to the ΔireA mutant by complementation with either the induced form of the hacA mRNA, hacAi, or an ireA deletion mutant that was incapable of processing the hacA mRNA, ireAΔ10. Together, these findings demonstrate that IreA has both HacA-dependent and HacA-independent functions that contribute to the expression of traits that are essential for virulence in A. fumigatus

DNA methylation subgroups and the CpG island methylator phenotype in gastric cancer: A comprehensive profiling approach

10.1186/1471-230X-14-55BMC Gastroenterology141-BGMA

Impact of caloric and dietary restriction regimens on markers of health and longevity in humans and animals: a summary of available findings

Considerable interest has been shown in the ability of caloric restriction (CR) to improve multiple parameters of health and to extend lifespan. CR is the reduction of caloric intake - typically by 20 - 40% of ad libitum consumption - while maintaining adequate nutrient intake. Several alternatives to CR exist. CR combined with exercise (CE) consists of both decreased caloric intake and increased caloric expenditure. Alternate-day fasting (ADF) consists of two interchanging days; one day, subjects may consume food ad libitum (sometimes equaling twice the normal intake); on the other day, food is reduced or withheld altogether. Dietary restriction (DR) - restriction of one or more components of intake (typically macronutrients) with minimal to no reduction in total caloric intake - is another alternative to CR. Many religions incorporate one or more forms of food restriction. The following religious fasting periods are featured in this review: 1) Islamic Ramadan; 2) the three principal fasting periods of Greek Orthodox Christianity (Nativity, Lent, and the Assumption); and 3) the Biblical-based Daniel Fast. This review provides a summary of the current state of knowledge related to CR and DR. A specific section is provided that illustrates related work pertaining to religious forms of food restriction. Where available, studies involving both humans and animals are presented. The review includes suggestions for future research pertaining to the topics of discussion

A Role for the Unfolded Protein Response (UPR) in Virulence and Antifungal Susceptibility in Aspergillus fumigatus

Filamentous fungi rely heavily on the secretory pathway, both for the delivery of cell wall components to the hyphal tip and the production and secretion of extracellular hydrolytic enzymes needed to support growth on polymeric substrates. Increased demand on the secretory system exerts stress on the endoplasmic reticulum (ER), which is countered by the activation of a coordinated stress response pathway termed the unfolded protein response (UPR). To determine the contribution of the UPR to the growth and virulence of the filamentous fungal pathogen Aspergillus fumigatus, we disrupted the hacA gene, encoding the major transcriptional regulator of the UPR. The ΔhacA mutant was unable to activate the UPR in response to ER stress and was hypersensitive to agents that disrupt ER homeostasis or the cell wall. Failure to induce the UPR did not affect radial growth on rich medium at 37°C, but cell wall integrity was disrupted at 45°C, resulting in a dramatic loss in viability. The ΔhacA mutant displayed a reduced capacity for protease secretion and was growth-impaired when challenged to assimilate nutrients from complex substrates. In addition, the ΔhacA mutant exhibited increased susceptibility to current antifungal agents that disrupt the membrane or cell wall and had attenuated virulence in multiple mouse models of invasive aspergillosis. These results demonstrate the importance of ER homeostasis to the growth and virulence of A. fumigatus and suggest that targeting the UPR, either alone or in combination with other antifungal drugs, would be an effective antifungal strategy