PRO-03 / Prothix - LARVOL DELTA

Two Novel Mutations at the CD36 Gene Splicing Sites and Their Molecular Basis for the CD36 Deficiency (PubMed, Zhongguo Shi Yan Xue Ye Xue Za Zhi) - "This study identifies two novel CD36 mutations at CD36 splicing site, and preliminary clarified their molecular basis for the CD36 deficiency and the distribution characteristics in Guangxi population as well. It provides an experimental and theoretical basis for studying the molecular mechanism and characteristics of CD36 deficiency in Chinese population."

Journal • CD36

[VIRTUAL] PRO 03 - Head and Neck Cancer: Case Based Discussion (ASTRO 2020) - "Analyze current clinical data and understand the evolving approaches to care in the difficult head and neck cancers. Better participate in multidisciplinary discussions for patients with head and neck cancer."

Clinical • Head and Neck Cancer • Laryngeal Cancer • Oncology • Oropharyngeal Cancer • Palliative care • Solid Tumor • Xerostomia

Profiling the Structural Determinants of Aryl Benzamide Derivatives as Negative Allosteric Modulators of mGluR5 by In Silico Study. (PubMed, Molecules) - "Moreover, we found that aryl benzamide series molecules bind as mGluR5 NAMs at Site 1, which consists of amino acids Pro655, Tyr659, Ile625, Ile651, Ile944, Ser658, Ser654, Ser969, Ser965, Ala970, Ala973, Trp945, Phe948, Pro903, Asn907, Val966, Leu904, and Met962. This site is the same as that of other types of NAMs; mGluR5 NAMs are stabilized in the "linear" and "arc" configurations mainly through the H-bonds interactions, π-π stacking interaction with Trp945, and hydrophobic contacts. We hope that the models and information obtained will help understand the interaction mechanism of NAMs and design and optimize NAMs as new types of antidepressants."

Journal • CNS Disorders • Depression

A novel RUNX1 mutation with ANKRD26 dysregulation is related to thrombocytopenia in a sporadic form of myelodysplastic syndrome. (PubMed, Aging Clin Exp Res) - "Functional studies of the variant p.Pro103Arg showed no changes in RUNX1 expression, but the variant was associated with deregulated high transcriptional activity of ANKRD26 in MEG-01 cells...Our findings are consistent with dysregulation of ANKRD26 in RUNX1 haploinsufficiency. Lack of repression of ANKRD26 expression may contribute to thrombocytopenia of subjects with sporadic myelodysplastic syndromes."

Journal • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Neutropenia • Oncology • Thrombocytopenia • ETV6 • RUNX1

Presentation of a rare case of hereditary hearing loss with X-linked recessive inheritance associated with the POU3F4 gene (PubMed, Vestn Otorinolaringol) - "NGS analysis identified a pathogenic variant c.907C>T (p.Pro303Ser) in the POU3F4 gene mapped to the Xq21.1 locus...Their father had no variant c.907C>T. Molecular genetic analysis showed that the genetic variant c.907C>T was not detected in the control sample of healthy female from the Nogai population, which suggests its low frequency in the population."

Clinical • Journal • Otorhinolaryngology

Effects of Pro1266Leu mutation on structure and function of glycoprotein Ib binding domain of von Willebrand factor. (PubMed, J Cell Biochem) - "MD simulations have provided atomic-level details of intermolecular motions as a function of time to understand the dynamic behavior of A1 domain of vWF. Comparative analysis of the trajectories obtained from MD simulations of both the wild type and Pro503Leu mutant suggesting appreciable conformational changes in the structure of mutant which might provide a basis for assuming the "gain of function" effects of these mutations on the A1 domain of vWF, resulting in the constitutive binding with GpIbα."

Journal • Cardiovascular • Hematological Disorders • Thrombosis

DEPDC5 Variants Associated Malformations of Cortical Development and Focal Epilepsy With Febrile Seizure Plus/Febrile Seizures: The Role of Molecular Sub-Regional Effect. (PubMed, Front Neurosci) - "We identified a homozygous DEPDC5 mutation (p.Pro1031His) in a case with focal cortical dysplasia and eight heterozygous mutations in 11 families with mild focal epilepsies, including 13 patients in eight families with focal epilepsy with febrile seizures plus/febrile seizures (FEFS + /FS)...Heterozygous DEPDC5 mutations are generally less pathogenic and commonly associated with mild phenotypes. Bi-allelic mutations and second hit of somatic mutations, together with the genotype-phenotype correlation and sub-regional implication of DEPDC5 variants, explain severe phenotypes."

Journal • CNS Disorders • Epilepsy

[VIRTUAL] Examining the Relationship Between ACGME Internal Medicine Residency Milestones and Subsequent Pulmonary and Critical Care Fellowship Milestones (ATS-I 2020) - "Similar associations were noted in PROF2 ("accepts responsibility and follows through on tasks," β-0.450, p 0.018) and PROF03 ("responds to each patient's unique characteristics," β-0.573, p 0.007)... Our study revealed an association between IM milestone ratings and low milestone ratings during PCCM fellowship. We found that IM trainees with low ratings in several professionalism and ICS subcompetencies were more likely to be rated at or below 2.5 during their first year in PCCM fellowship. This highlights a potential use of longitudinal milestones to target educational gaps and develop individualized learning plans in PCCM fellowship education."

Critical care

[VIRTUAL] Digenic Inheritance of PCSK1 and CHD7 Mutations in PAX4 Homozygous Diabetic Male with Normosmic Hypogonadotropic Hypogonadism (ENDO-I 2020) - "WES of the proband revealed the presence of heterozygote missense mutations of the CHD7 gene (c.6107C>T, p.Pro2036Leu, rs369543203) and PCSK1 gene (c.239G>A, p.Arg80Gln, rs1799904)... This is the first case demonstrating digenic inheritance of mutations in PCSK1 and CHD7 as a potential cause of normosmic hypogonadotrophic hypogonadism, interestingly in PAX4 homozygous diabetic male."

Diabetes • Metabolic Disorders • MRI

Exploring biological efficacy of coumarin clubbed thiazolo[3,2-b][1,2,4]triazoles as efficient inhibitors of urease: A biochemical and in silico approach. (PubMed, Int J Biol Macromol) - "Moreover, this amino group also interacts with the carbonyl oxygen of Ala366 at a distance of 2.75Å. The chromenone moiety of compound 6o is stabilized by the side chains of various amino acid residues including Ala279, Thr301, Pro303, Thr304, His315 and Met367."

Clinical • Journal

Examining the Relationship Between ACGME Internal Medicine Residency Milestones and Subsequent Pulmonary and Critical Care Fellowship Milestones (ATS 2020) - "Similar associations were noted in PROF2 (“accepts responsibility and follows through on tasks,” β-0.450, p0.018) and PROF03 (“responds to each patient’s unique characteristics,” β-0.573, p0.007)... Our study revealed an association between IM milestone ratings and low milestone ratings during PCCM fellowship. We found that IM trainees with low ratings in several professionalism and ICS subcompetencies were more likely to be rated at or below 2.5 during their first year in PCCM fellowship. This highlights a potential use of longitudinal milestones to target educational gaps and develop individualized learning plans in PCCM fellowship education."

Defining metrics for whole-genome sequence analysis of MRSA in clinical practice. (PubMed, Microb Genom) - "We use MRSA MPROS0386 to control for base calling accuracy by the sequencer, and used multiple repeat sequences of the control to define a permitted range of SNPs different to the mapping reference for this control (equating to 3 standard deviations from the mean)...Sequencing from bacteria harvested from clinical plates runs an increased risk of contamination with the same or different species, and we defined a cut-off of 30 heterozygous sites >50 bp apart to identify same-species contamination for MRSA. These metrics were combined into a quality-control (QC) flowchart to determine whether sequence runs and individual clinical isolates passed QC, which could be adapted by future automated analysis systems to enable rapid hands-off sequence analysis by clinical laboratories."

Clinical • Journal

Digenic Inheritance of PCSK1 and CHD7 Mutations in PAX4 Homozygous Diabetic Male with Normosmic Hypogonadotropic Hypogonadism (ENDO 2020) - "WES of the proband revealed the presence of heterozygote missense mutations of the CHD7 gene (c.6107C>T, p.Pro2036Leu, rs369543203) and PCSK1 gene (c.239G>A, p.Arg80Gln, rs1799904)... This is the first case demonstrating digenic inheritance of mutations in PCSK1 and CHD7 as a potential cause of normosmic hypogonadotrophic hypogonadism, interestingly in PAX4 homozygous diabetic male."

MRI

Novel RHD-CE-D Hybrid Allele Associated with D- C+ Phenotype (AABB 2019) - "Results/Findings: The PreciseTypeTM HEA Molecular BeadChip panel predicted the donor to be C negative due to the absence of the RHCE c.307C>T (Pro103Ser) and RHCE 109bp insertion... This donor was found to express two hybrid RHD alleles. The previously reported RHD*D-CE(2-9)-D allele (RHD*01N.03) is associated with a D negative phenotype but has not been reported to encode an altered C antigen. The novel RHD*DIIIa-CE(4-9)-D allele is similar to the RHD*DIIIa-CE(4-7)-D allele (RHD*03N.01), which contains RHD markers c.186G>T, c.410C>T, c.455A>C, RHCE exons 4-7, and RHCE markers c. 733C>G and 1006G>T."

PRO 03 - (INTERACTIVE) Practical Radiation Oncology- Breast Cancer Session (ASTRO 2019) - "Time will be reserved for questions and answers by the expert panelists. Learning Objectives: Discuss the methods used to treat the axilla in various scenarios depending on the surgical results from lymph node sampling.Discuss the condierations for radiotherapy planning after neoadjuvant chemotherapy, and how radiotherapy is applied depending on the results of treatment"

De novo KCNA1 variants in the PVP motif cause infantile epileptic encephalopathy and cognitive impairment similar to recurrent KCNA2 variants. (PubMed, Am J Med Genet A) - "...The first two patients have KCNA1 variants resulting in (p.Pro405Ser) and (p.Pro405Leu), respectively, and a set of identical twins has a variant affecting a nearby residue (p.Pro403Ser). Notably, recurrent de novo variants in the paralogous PVP motif of KCNA2 have previously been shown to abolish channel function and also cause early-onset epileptic encephalopathy. Importantly, this report extends the range of phenotypes associated with KCNA1 variants to include epileptic encephalopathy when the PVP motif is involved."

Journal

Initiation of prolyl cis-trans isomerisation in the CDR-H3 loop of an antibody in response to antigen binding. (PubMed, Sci Rep) - "As a result, we were able to describe the process by which cis-trans isomerisation is initiated, and suggest a catalysis mechanism for cis-trans isomerization in this antigen-antibody system. We found that Asp102, which is immediately adjacent to Pro103, rotates while changing its interacting partner residues in the light chain of 9E5, and at the same time EPR polar residues help to stabilise the intermediate states in the isomerisation process by interacting strongly with Asp102."

Journal

Diagnosis Challenge in Type 4 Familial Partial Lipodystrophic Syndrome (ENDO 2019) - "...Our team had already described the p.Val398Glyfs*167 variant, and 2 new variants p.Gly362Glyfs*63 and p.Pro403Argfs*164 were identified... The clinical phenotype of FPLD4 is quite homogeneous, but the clinical diagnosis requires a careful clinical examination and/or an expert advice. An early genetic diagnosis is recommended to confirm the disease and prevent metabolic complications.*Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins."

Diagnosis Challenge in Type 4 Familial Partial Lipodystrophic Syndrome (ENDO 2019) - "...Our team had already described the p.Val398Glyfs*167 variant, and 2 new variants p.Gly362Glyfs*63 and p.Pro403Argfs*164 were identified... The clinical phenotype of FPLD4 is quite homogeneous, but the clinical diagnosis requires a careful clinical examination and/or an expert advice. An early genetic diagnosis is recommended to confirm the disease and prevent metabolic complications.*Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins."

Diagnosis Challenge in Type 4 Familial Partial Lipodystrophic Syndrome (ENDO 2019) - "...Our team had already described the p.Val398Glyfs*167 variant, and 2 new variants p.Gly362Glyfs*63 and p.Pro403Argfs*164 were identified... The clinical phenotype of FPLD4 is quite homogeneous, but the clinical diagnosis requires a careful clinical examination and/or an expert advice. An early genetic diagnosis is recommended to confirm the disease and prevent metabolic complications."