Transglutaminase 6: a protein associated with central nervous system development and motor function.

Transglutaminases (TG) form a family of enzymes that catalyse various post-translational modifications of glutamine residues in proteins and peptides including intra- and intermolecular isopeptide bond formation, esterification and deamidation. We have characterized a novel member of the mammalian TG family, TG6, which is expressed in a human carcinoma cell line with neuronal characteristics and in mouse brain. Besides full-length protein, alternative splicing results in a short variant lacking the second ß-barrel domain in man and a variant with truncated ß-sandwich domain in mouse. Biochemical data show that TG6 is allosterically regulated by Ca(2+) and guanine nucleotides. Molecular modelling indicates that TG6 could have Ca(2+) and GDP-binding sites related to those of TG3 and TG2, respectively. Localization of mRNA and protein in the mouse identified abundant expression of TG6 in the central nervous system. Analysis of its temporal and spatial pattern of induction in mouse development indicates an association with neurogenesis. Neuronal expression of TG6 was confirmed by double-labelling of mouse forebrain cells with cell type-specific markers. Induction of differentiation in mouse Neuro 2a cells with NGF or dibutyryl cAMP is associated with an upregulation of TG6 expression. Familial ataxia has recently been linked to mutations in the TGM6 gene. Autoantibodies to TG6 were identified in immune-mediated ataxia in patients with gluten sensitivity. These findings suggest a critical role for TG6 in cortical and cerebellar neurons.

Treatment of Metastatic Colorectal Carcinoma with Bevacizumab in First-Line and beyond First Progression: The KORALLE Non-Interventional Cohort Study.

INTRODUCTION: The non-interventional study (NIS) KORALLE evaluated the effectiveness and safety of bevacizumab in patients with metastatic colorectal carcinoma (mCRC) treated with bevacizumab in combination with fluoropyrimidine-based chemotherapy in the first-line setting and beyond first progression in routine clinical practice. METHODS: This prospective, multicenter NIS observed adult patients with mCRC who started first-line bevacizumab therapy. The planned maximum duration of observation per patient was 21 months. The primary effectiveness variable was progression-free survival in the first-line therapy setting (PFS-1). Secondary effectiveness variables included PFS after first progression as well as overall survival and overall response rate. All analyses were carried out descriptively for the full analysis population set (FAS). Effectiveness analyses were also assessed for predefined subgroups based on therapy goals. RESULTS: Between December 2012 and July 2016, 2,429 eligible patients were observed at 314 sites in Germany. In the first-line setting in the FAS, the median PFS-1 was 10.3 months (95% CI: 9.9; 10.8), the median overall survival was 16.9 months (95% CI: 16.3; 17.5), and the overall response rate (ORR-1) was 44.2% (95% CI: 41.6%; 46.8%). Effectiveness results of all subgroups were similar to the FAS. Overall, 80.9% of patients experienced any adverse events, 36.6% of patients experienced serious adverse events, and 8.8% of patients experienced fatal adverse events. CONCLUSION: The NIS KORALLE provided broad real-world evidence on effectiveness and safety of bevacizumab. Despite different treatment intentions, the combination of bevacizumab plus fluoropyrimidine-based chemotherapy was similarly effective in all subgroups in routine clinical practice. The safety information reported in this study is consistent with the known safety profile of bevacizumab.

Partial Response and Stable Disease Correlate with Positive Outcomes in Atezolizumab-treated Patients with Advanced Urinary Tract Carcinoma.

BACKGROUND: The value of a complete response to immune checkpoint inhibitor treatment for urothelial cancer is well recognised, but less is known about long-term outcomes in patients with a partial response or the benefit of achieving disease stabilisation. OBJECTIVE: To determine clinical outcomes in patients with a partial response or stable disease on atezolizumab therapy for advanced urinary tract carcinoma (UTC). DESIGN, SETTING, AND PARTICIPANTS: Data were extracted from three prospective trials (IMvigor210 cohort 2, SAUL, and IMvigor211) evaluating single-agent atezolizumab therapy for platinum-pretreated advanced UTC. The analysis population included 604 atezolizumab-treated and 208 chemotherapy-treated patients (229 achieving a partial response and 583 achieving stable disease). INTERVENTION: Atezolizumab 1200 mg every 3 wk until progression or unacceptable toxicity or single-agent chemotherapy for patients in the control arm of IMvigor211. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Baseline characteristics, treatment exposure, overall survival, duration of disease control. Partial response and stable disease populations were analysed separately. RESULTS AND LIMITATIONS: The population of patients with a partial response included more patients with programmed cell death ligand 1 (PD-L1) expression on ≥5% of tumour-infiltrating immune cells than the stable disease population. The median time to best response was 2.1 mo across trials and treatments, regardless of the type of response. Atezolizumab-treated patients with a partial response had sustained disease control (median overall survival not reached); durations of disease control and overall survival were longer with atezolizumab than with chemotherapy. In patients with stable disease, median overall survival was numerically longer with atezolizumab (exceeding 1 yr) than with chemotherapy. Irrespective of treatment, durations of disease control and survival were shorter in patients with stable disease than in those achieving a partial response. These analyses are limited by their post hoc exploratory nature and relatively short follow-up. CONCLUSIONS: Stable disease and partial response are meaningful clinical outcomes in atezolizumab-treated patients with advanced UTC. PATIENT SUMMARY: In this report, we looked at the outcomes in patients whose tumours responded to treatment to some extent, but the tumour did not disappear completely. We aimed to understand whether a modest response to treatment was associated with meaningful long-term outcomes for patients. We found that on average, life expectancy was >1 yr in patients whose disease was stabilised and even longer in those whose tumours showed some shrinkage in response to treatment.

Understanding the role of primary tumour localisation in colorectal cancer treatment and outcomes.

Metastatic colorectal carcinoma (mCRC) is a heterogeneous disease with differing outcomes and clinical responses and poor prognosis. CRCs can be characterised by their primary tumour location within the colon. The left-sided colon, derived from the hindgut, includes the distal third of the transverse colon, splenic flexure, descending colon, sigmoid colon and rectum. The right-sided colon, derived from the midgut, includes the proximal two-thirds of the transverse colon, ascending colon and caecum. Sometimes, the rectum is described separately, despite originating from the hindgut, and in many clinical series, the left-sided colon includes only tumours within and distal to the splenic flexure. Differences in the microbiome, clinical characteristics and chromosomal and molecular characteristics have been reported between the right and left side of the colon, regardless of how this is defined. There is now strong evidence from clinical studies in patients with mCRC for the prognostic effect of primary tumour location. The impact of primary colonic tumour location on response to treatment is now under investigation in a large number of clinical studies in patients with mCRC. In this review, we summarise the microbiome, clinical, chromosomal and molecular differences associated with the primary location of CRC. We present an overview of the proven prognostic impact of primary tumour location for patients with mCRC and discuss emerging data for the predictive impact of primary tumour location on clinical outcome.

X-ray structure of glutathione S-transferase from Schistosoma japonicum in a new crystal form reveals flexibility of the substrate-binding site.

The crystal structure of the 26 kDa glutathione S-transferase from Schistosoma japonicum (SjGST) was determined at 3 A resolution in the new space group P2(1)2(1)2(1). The structure of orthorhombic SjGST reveals unique features of the ligand-binding site and dimer interface when compared with previously reported structures. SjGST is recognized as the major detoxification enzyme of S. japonicum, a pathogenic helminth causing schistosomiasis. As resistance against the established inhibitor of SjGST, praziquantel, has been reported these results might prove to be valuable for the development of novel drugs.

Epidermal transglutaminase (TGase 3) is required for proper hair development, but not the formation of the epidermal barrier.

Transglutaminases (TGase), a family of cross-linking enzymes present in most cell types, are important in events as diverse as cell-signaling and matrix stabilization. Transglutaminase 1 is crucial in developing the epidermal barrier, however the skin also contains other family members, in particular TGase 3. This isoform is highly expressed in the cornified layer, where it is believed to stabilize the epidermis and its reduction is implicated in psoriasis. To understand the importance of TGase 3 in vivo we have generated and analyzed mice lacking this protein. Surprisingly, these animals display no obvious defect in skin development, no overt changes in barrier function or ability to heal wounds. In contrast, hair lacking TGase 3 is thinner, has major alterations in the cuticle cells and hair protein cross-linking is markedly decreased. Apparently, while TGase 3 is of unique functional importance in hair, in the epidermis loss of TGase 3 can be compensated for by other family members.