Inhibitors of Fumarylacetoacetate Hydrolase Domain Containing Protein 1 (FAHD1).

FAH domain containing protein 1 (FAHD1) acts as oxaloacetate decarboxylase in mitochondria, contributing to the regulation of the tricarboxylic acid cycle. Guided by a high-resolution X-ray structure of FAHD1 liganded by oxalate, the enzymatic mechanism of substrate processing is analyzed in detail. Taking the chemical features of the FAHD1 substrate oxaloacetate into account, the potential inhibitor structures are deduced. The synthesis of drug-like scaffolds afforded first-generation FAHD1-inhibitors with activities in the low micromolar IC50 range. The investigations disclosed structures competing with the substrate for binding to the metal cofactor, as well as scaffolds, which may have a novel binding mode to FAHD1.

Can Oncotype DX testing be omitted in invasive breast cancer patients with clinicopathologic factors predicting very high pretest probability of a concordant result?

OBJECTIVE: To determine if clinicopathologic (CP) factors could identify patients at "very low" and/or "very high" pretest probability of a high Oncotype DX (ODX) score. METHODS: A retrospective analysis of all patients that had ODX testing 2008-2018 at a single institution. RESULTS: Of 215 patients, all 16 (7.4%) with "all high" risk CP factors had high ODX scores, and all 45 (20.9%) over age 50 with "all low" risk CP factors had ODX recommendations for no chemotherapy. CONCLUSIONS: Oncotype DX results did not change chemotherapy recommendations in those with "very low" or "very high" pretest probability of high ODX scores.

The fumarylacetoacetate hydrolase (FAH) superfamily of enzymes: multifunctional enzymes from microbes to mitochondria.

Prokaryotic and eukaryotic fumarylacetoacetate hydrolase (FAH) superfamily members, sharing conserved regions that form the so-called FAH-domain, catalyze a remarkable variety of reactions. These enzymes are essential in the metabolic pathways to degrade aromatic compounds in prokaryotes and eukaryotes. It appears that prokaryotic FAH superfamily members evolved mainly to allow microbes to generate energy and useful metabolites from complex carbon sources. We review recent findings, indicating that both prokaryotic and eukaryotic members of the FAH superfamily also display oxaloacetate decarboxylase (ODx) activity. The identification of human FAH domain-containing protein 1 as mitochondrial ODx regulating mitochondrial function supports the new concept that, during evolution, eukaryotic FAH superfamily members have acquired important regulatory functions beyond catabolism of complex carbon sources. Molecular studies on the evolution and function of FAH superfamily members are expected to provide new mechanistic insights in their physiological roles.

The added value of ultrasound imaging biomarkers to clinicopathological factors for the prediction of high-risk Oncotype DX recurrence scores in patients with breast cancer.

Background: The Oncotype DX (ODX) recurrence score (RS), a 21-gene assay, has been proven to recognize patients at high risk of recurrence (RS ≥26) who would benefit from chemotherapy. However, it has limited availability and high costs. Our study thus aimed to identify ultrasound (US) imaging biomarkers and develop a prediction model for identifying patients with a high ODX RS. Methods: In this retrospective study, consecutive patients with T1-3N0-1M0 breast cancer who were hormone receptor positive and human epidermal growth factor receptor 2 (HER2) negative who had an available ODX RS were reviewed. Patients treated from May 2012 and December 2015 were placed into a training cohort, and those treated from January 2016 to January 2017 were placed in a validation cohort. Clinicopathologic data were collected, and preoperative US scans were analyzed. Univariable and multivariable regression analyses were performed to evaluate the independent predictors for a high-risk of breast cancer in the training cohort, and a nomogram was developed and evaluated with the area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA). Results: A total of 363 patients were in the training cohort and 160 in the validation cohort, with the proportion with a high RS (RS 26-100) being 14% and 13.1%, respectively. Echogenic halo, enhanced posterior echo, low level of progesterone receptor (PR), and high Ki-67 index were identified as independent risk factors for high RS (all P values <0.05). The nomogram was constructed based on the combined model, which showed a better discrimination ability than did the clinicopathological model [combined model: AUC =0.95, 95% confidence interval (CI): 0.93-0.97; clinicopathological model: AUC =0.89, 95% CI: 0.86-0.92; P=0.001] and greater clinical benefit according to DCA. Furthermore, the nomogram was found to be effective in the validation cohort (AUC =0.90, 95% CI: 0.84-0.94), especially in patients with stage T1N0M0 disease (AUC =0.91, 95% CI: 0.84-0.95). Conclusions: US features may serve as valuable imaging biomarkers for the prediction of high recurrence risk in patients with T1-3N0-1M0 breast cancer and hormone receptor (HR)-positive and HER2-negative status. A nomogram incorporating PR status, Ki-67 index, and US imaging biomarkers showed a good discrimination ability in the early selection of patients at high risk of recurrence, especially in those with stage T1N0M0 disease.

A randomised, double-blind, dose-finding, phase II multicentre study of ODX in the treatment of patients with castration-resistant prostate cancer and skeletal metastases.

AIMS: This study aimed to assess the efficacy and safety of ODX, a novel, cytotoxic, bone-targeting drug candidate, in castration-resistant prostate cancer bone metastatic disease. METHODS: Patients with progressive disease were randomised to ten cycles of ODX, intravenous infusion Q2W (3, 6, and 9 mg/kg, respectively). The primary objective was to assess the relative change from baseline in bone alkaline phosphatase (B-ALP) and serum-aminoterminal-propeptide of Type I procollagen (S-P1NP) at 12 weeks. The inclusion criteria selected were broad, and a double-blind design was used to ensure objective recruitment of patients for the assessment of efficacy. None of the patients received bone-protecting agents during the ODX treatment period. RESULTS: Fifty-five 21,20 and 14) patients were randomised to ODX (3, 6 and 9 mg/kg), respectively. The lower number of patients in arm 3 was due to too low a recruitment rate towards the end of the study. The median treatment time were 14, 13 and 14 weeks, respectively. The decrease in B-ALP at 12 weeks in study arms 3, 6 and 9 mg/kg was seen in 6/15 (40%), 8/12 (67%) and 5/12 (42%) patients, respectively, whereas the corresponding numbers for P1NP were 8/15 (53%), 8/12 (67%), and 4/12 (33%), respectively. The median decrease in B-ALP and P1NP at 12 weeks for study arms 3, 6 and 9 mg/kg were 37%, 14% and 43%, respectively, and 51%, 40% and 64%, respectively. The decrease in serum C-terminal telopeptide at 12 weeks was seen in the vast majority of patients and in about one-third of patients in bone scan index. ODX was well tolerated, and no drug-related serious adverse events occurred. There were no significant differences between study arms regarding efficacy and safety. CONCLUSIONS: ODX was well tolerated and demonstrated inhibitory effects on markers related to the vicious cycle in bone at all three doses. The reduction in metastatic burden, assessed with bone scan index, supports this finding. Studies with continued ODX treatment until disease progression are being planned (ClinicalTrials.gov Identifier: NCT02825628).

Burden of Acute-Care Hospitalization for Community-Acquired Pneumonia in Canadian Adults Aged 50 Years or Older: Focusing on Most Responsible Diagnosis Tells Only Part of the Story.

The burden of all-cause community-acquired pneumonia (CAP), including pneumococcal pneumonia, is typically estimated using ICD codes where pneumonia is coded as the most responsible diagnosis (MRDx). Pneumonia may also be coded as other than most responsible diagnosis (ODx) based on administrative and reimbursement criteria. Analyses including pneumonia as MRDx only likely underestimate hospitalized CAP incidence. The aim of this study was to estimate the burden of hospitalized all-cause CAP in Canada and to assess the contribution of ODx-coded cases to the overall disease burden. This longitudinal retrospective study obtained data from the Canadian Institutes of Health Information (CIHI) for adults 50+ years hospitalized for CAP between 1 April 2009 and 31 March 2019. Cases were identified as those where pneumonia was either diagnosis code type M (MRDx) or pre-admit comorbidity type 1 (ODx). Reported outcomes include pneumonia incidence rate, in-hospital mortality, hospital length of stay, and cost. Outcomes were stratified by age group, case coding, and comorbidity. Between 2009-2010 and 2018-2019, CAP incidence increased from 805.66 to 896.94 per 100,000. During this time, 55-58% of cases had pneumonia coded as ODx. Importantly, these cases had longer hospital stays, higher in-hospital mortality, and higher cost of hospitalization. The burden of CAP remains substantial and is significantly greater than that estimated by solely focusing on MRDx-coded cases. Our findings have implications for policy decision making related to current and future immunization programs.

Oxaloacetate decarboxylase FAHD1 - a new regulator of mitochondrial function and senescence.

FAHD1, a member of the FAH superfamily of enzymes, was identified in a proteomic screen for mitochondrial proteins with differential expression in young versus senescent human endothelial cells. FAHD1 acts as oxaloacetate decarboxylase, and recent observations suggest that FAHD1 plays an important role in regulating mitochondrial function. Thus, mutation of the nematode homolog, fahd-1, impairs mitochondrial function in Caenorhabditis elegans. When FAHD1 gene expression was silenced in human cells, activity of the mitochondrial electron transport (ETC) system was reduced and the cells entered premature senescence-like growth arrest. These findings suggest a model where FAHD1 regulates mitochondrial function and in consequence senescence. These findings are discussed here in the context of a new concept where senescence is divided into deep senescence and less severe forms of senescence. We propose that genetic inactivation of FAHD1 in human cells induces a specific form of cellular senescence, which we term senescence light and discuss it in the context of mitochondrial dysfunction associated senescence (MiDAS) described by others. Together these findings suggest the existence of a continuum of cellular senescence phenotypes, which may be at least in part reversible.