Functional and pharmacological evaluation of novel GLA variants in Fabry disease identifies six (two de novo) causative mutations and two amenable variants to the chaperone DGJ

Abstract Background Allelic heterogeneity is an important feature of the GLA gene for which almost 900 known genetic variants have been discovered so far. Pathogenetic GLA variants cause alpha-galactosidase A (α-Gal A) enzyme deficiency leading to the X-linked lysosomal storage disorder Fabry disease (FD). Benign GLA intronic and exonic variants ( e.g. pseudodeficient p.Asp313Tyr) have also been described. Some GLA missense variants, previously deemed to be pathogenetic ( e.g. p.Glu66Gln and p.Arg118Cys), they have been reclassified as benign after re-evaluation by functional and population studies. Hence, the functional role of novel GLA variants should be investigated to assess their clinical relevance. Results We identified six GLA variants in 4 males and 2 females who exhibited symptoms of FD: c.159C>G p.(Asn53Lys), c.400T>C p.(Tyr134His), c.680G>C (p.Arg227Pro), c.815A>T p.(Asn272Ile), c.907A>T p.(Ile303Phe) and c.1163_1165delTCC (p.Leu388del). We evaluated their impact on the α-Gal A protein by bioinformatic analysis and homology modelling, by analysis of the GLA mRNA, and by site-directed mutagenesis and in vitro expression studies. We also measured their responsiveness to the pharmacological chaperone DGJ. Conclusions The six detected GLA variants cause deficient α-Gal A activity and impairment or loss of the protein wild-type structure. We found p.Asn53Lys and p.Ile303Phe variants to be susceptible to DGJ

An unusual presentation of multiple cavitated lung metastases from colon carcinoma

<p>Abstract</p> <p>Background</p> <p>Consolidation with or without ground-glass opacity is the typical radiologic finding of lung metastases of adenocarcinoma from the gastrointestinal tract. Lung excavated metastases from gastrointestinal carcinoma are very rare.</p> <p>Case presentation</p> <p>The authors describe an unusual presentation of multiple cavitated lung metastases from colon adenocarcinoma and discuss the outcome of a patient. The absence both of symptoms and other disease localizations, the investigations related to different diagnostic hypotheses and the empirical treatments caused a delay in correct diagnosis. Only a transparietal biopsy revealed the neoplastic origin of nodules.</p> <p>Conclusions</p> <p>This report demonstrates that although lung excavated metastases are described in literature, initial failure to reach a diagnosis is common. We would like to alert clinicians and radiologists to the possibility of unusual atypical features of pulmonary metastases from colon adenocarcinoma.</p

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)

Cancer Chemotherapy and Cardiovascular Risks: Is Capecitabine-Induced Hypertriglyceridemia a Rare Adverse Effect?

Capecitabine is an oral fluoropyrimidine which is transformed to 5-Fluorouracil inside tumor cells, where it achieves high drug concentrations. Capecitabine is an active drug diffusely utilized in the treatment of various types of tumors, such as breast, colorectal, gastric, head and neck carcinoma. In our experience, capecitabine-induced hypertriglyceridemia does not seem to be a rare adverse effect as it is observed in 10% of treated patients. It is necessary to monitor the lipidic profile of patients treated with capecitabine also in consideration of the frequent presence of comorbidities in cancer populations, the concomitant toxicity related to other drugs used in combination regimens, and cardiovascular effects characteristic of biological target therapy. Copyright (C) 2010 S. Karger AG, Base

Long-term disease free survival (DFS) in patients with small breast cancer: clinical relevance of traditional and new prognostic factors in a retrospective study

Long-term disease free survival (DFS) in patients wth small breast cancer: clinical relevance of traditional and new prognostic factors in a retrospective study Type: Abstract Category: Breast Cancer, early stage Authors: A. Emiliani, L. Filomeno, A. Iannace, T. Losanno, G. Manna, E. Franzese, F.S. Di Lisa, P. Seminara; Rome/IT Aim The incidence rate of small-size (T1) early-stage breast cancer (EBC) has increased. The risk of relapse is low, but there is a growing interest in identifying traditional and new prognostic factors to optimize therapeutic management. Patients with T1 EBC, especially if node-negative (N0), are excluded from tumor gene expression profiling due to the cost of this procedure. Immunohistochemistry (IHC)-based classification of breast cancer subtypes with confirmed prognostic and therapeutic implication is therefore recommended. Methods We reviewed the records of 511 patients diagnosed with T1 EBC referred to our oncology unit for adjuvant therapy. This retrospective study evaluated the different long-term clinical outcomes over 15 years and correlated with traditional (T, N, ER and PgR, Ki-67, HER) and surrogate molecular subtype classification of the tumors using IHC prognostic factors. Results Patient characteristics were: median age 58.5 years (range 27-86). Tumor stage: T1a 74 (14.5%), T1b 120 (23.5%), T1c 317 (62.0%). Node status: N0 327 (64.0%), N1 184 (36.0%). Tumor grade: G1 144 (28.2%), G2 216 (42.3%), G3 151(29.5%). Ki-67 index: 20% 184 (36.0%). HER overexpression: absent 378 (73.9%), present 80 (15.6%). IHC molecular subtype was: Luminal A 199 (38.9%), Luminal B HER-negative 70 (13.7%), Luminal B HER-positive 65 (12.7%), HER overexpression 14 (2.7%), Basal-like 41 (8.0%). In the overall population, the significant prognostic factors at 5 years were N0 vs. N1 (p= 0.05), PgR 20% (p= 0.03), Ki-67 index 20% (p= 0.04) and Luminal A vs. Luminal B HER-negative (p= 0.05). At the 15-years follow-up, only Ki67 index confirmed its prognostic value (p= 0.04). In the N0 subgroup of patients DFS curves were significantly different for Ki-67 index 20% both at 5years (p= 0.01) and at 15 years (p= 0.03). Conclusion The DFS curves of T1 EBC patients at 5 years underline the prognostic relevance of the cut-off of 20%, both for PgR expression and Ki-67 index as well as IHC-based molecular subtypes Luminal A vs. Luminal B HER-negative. With regard to long-term outcome, only Ki67-index seems to be useful for identifying different prognostic tumor subgroups. These results were particularly important for improve current management of N0 EBC patients with prognostic risk factors