scholarly journals Molecular genetics of PKU in Poland and potential impact of mutations on BH4 responsiveness.

2013 ◽  
Vol 60 (4) ◽  
Author(s):  
Miroslaw Bik-Multanowski ◽  
Lukasz Kaluzny ◽  
Renata Mozrzymas ◽  
Mariusz Oltarzewski ◽  
Ewa Starostecka ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Continuous Treatment ◽  
Published Data ◽  
Complementary Approach ◽  
Trial Treatment ◽  
Potential Impact ◽  
Classical Phenylketonuria ◽  
Pah Gene ◽  
Selection Of Patients ◽  
Selection Of

Tetrahydrobiopterin (BH4) has been recently approved as a treatment of patients with phenylketonuria. However, as a confirmation of BH4-responsiveness, it might require a very expensive trial treatment with BH4 or prolonged BH4-loading procedures. The selection of patients eligible for BH4-therapy by means of genotyping of the PAH gene mutations may be recommended as a complementary approach. A population-wide genotyping study was carried out in 1286 Polish phenyloketonuria-patients. The aim was to estimate the BH4 demand and to cover prospectively the treatment by a National Health Fund. A total of 95 types of mutations were identified. Genetic variants corresponding with probable BH4-responsiveness were found in 28.2% of cases. However, patients with mild or classical phenylketonuria who require continuous treatment accounted for 11.4% of the studied population only. Analysis of the published data shows similar percentage of the "BH4-responsive" variants of a PAH gene in patients from other countries of Eastern Europe. Therefore, it can be concluded, that the proportion of phenylketonuria-patients who could benefit from the use of BH4 reaches approximately 10% in the entire region.

scholarly journals Immunotherapy in Biliary Tract Cancer: Worthy of a Second Look

2020 ◽  
Vol 27 (3) ◽  
pp. 107327482094804 ◽  
Author(s):  
Angela Dalia Ricci ◽  
Alessandro Rizzo ◽  
Giovanni Brandi
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Published Data ◽  
Tract Cancer ◽  
Selection Of Patients ◽  
Selection Of

Although immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape of several malignancies, the role of immunotherapy in biliary tract cancer (BTC) is currently under investigation and ICIs are still looking for their niche in this setting. In this Editorial, we discuss recently published data regarding ICIs in BTC, with a particular focus in terms of selection of patients and biomarker-driven trials.

scholarly journals SARS-CoV-2 Spike Protein Mutations and Escape from Antibodies: a Computational Model of Epitope Loss in Variants of Concern

2021 ◽  
Author(s):  
Alice Triveri ◽  
Stefano A. Serapian ◽  
Filippo Marchetti ◽  
Filippo Doria ◽  
Silvia Pavoni ◽  
...  
Keyword(s):  
Epitope Prediction ◽  
Antibody Binding ◽  
Published Data ◽  
S Protein ◽  
Potential Impact ◽  
Protein Mutations ◽  
Protein Variants ◽  
Viral Surface ◽  
Selection Of ◽  
Prediction Strategy

The SARS-CoV-2 spike (S) protein is exposed on the viral surface and is the first point of contact between the virus and the host. For these reasons it represents the prime target for Covid-19 vaccines. In recent months, variants of this protein have started to emerge. Their ability to reduce or evade recognition by S-targeting antibodies poses a threat to immunological treatments and raises concerns for their consequences on vaccine efficacy. To develop a model able to predict the potential impact of S-protein mutations on antibody binding sites, we performed unbiased multi-microsecond molecular dynamics of several glycosylated S-protein variants and applied a straightforward structure-dynamics-energy based strategy to predict potential changes in immunogenic regions on each variant. We recover known epitopes on the reference D614G sequence. By comparing our results, obtained on isolated S-proteins in solution, to recently published data on antibody binding and reactivity in new S variants, we directly show that modifications in the S-protein consistently translate into the loss of potentially immunoreactive regions. Our findings can thus be qualitatively reconnected to the experimentally characterized decreased ability of some of the Abs elicited against the dominant S-sequence to recognize variants. While based on the study of SARS-CoV-2 Spike variants, our computational epitope-prediction strategy is portable and could be applied to study immunoreactivity in mutants of proteins of interest whose structures have been characterized, helping the development/selection of vaccines and antibodies able to control emerging variants.

Selection of patients for portal-systemic shunts

JAMA ◽  
1966 ◽  
Vol 196 (12) ◽  
pp. 1039-1044 ◽  
Author(s):  
R. E. Hermann
Keyword(s):  
Selection Of Patients ◽  
Selection Of

Perioperative acute internal carotid thrombosis after general surgery

2020 ◽  
Vol 99 (3) ◽  
pp. 136-140
Keyword(s):  
Cardiac Surgery ◽  
Internal Carotid ◽  
Right Hemicolectomy ◽  
Diagnostic Assessment ◽  
Left Carotid Artery ◽  
Perioperative Stroke ◽  
Internal Carotid Occlusion ◽  
Acute Brain Ischemia ◽  
Selection Of Patients ◽  
Selection Of

Introduction: The average incidence of perioperative stroke during major non-cardiac surgery is less than 1%, suggesting that it is rarely a major problem for the vast majority of patients. Methods: In our paper we present a 46-year-old patient undergoing acute right hemicolectomy who developed right-sided hemiparesis in the perioperative setting. Immediate CTAg examination showed an ischemic stroke in the left hemisphere as a result of left internal carotid thrombosis. A surgical procedure to recanalize the left carotid artery was performed 14 hours from the onset of neurological symptomatology and the neurological deficit gradually recovered fully. Conclusion: Our case report supports studies showing that a thorough diagnostic assessment allows the selection of patients who may benefit from urgent revascularization of acute internal carotid occlusion during the phase of acute brain ischemia.

A Melanocortin-4 Receptor Agonist Induces Skin and Hair Pigmentation in Patients with Monogenic Mutations in the Leptin-Melanocortin Pathway

2021 ◽  
pp. 1-10
Author(s):  
Varvara Kanti ◽  
Lia Puder ◽  
Irina Jahnke ◽  
Philipp Maximilian Krabusch ◽  
Jan Kottner ◽  
...  
Keyword(s):  
Leptin Receptor ◽  
Skin Pigmentation ◽  
Gene Mutations ◽  
Continuous Treatment ◽  
Whole Body ◽  
Hair Color ◽  
Phase 2 ◽  
Loss Of Function ◽  
The Impact ◽  
Over Time

<b><i>Background and Objectives:</i></b> Gene mutations within the leptin-melanocortin signaling pathway lead to severe early-onset obesity. Recently, a phase 2 trial evaluated new pharmacological treatment options with the MC4R agonist <i>setmelanotide</i> in patients with mutations in the genes encoding proopiomelanocortin (POMC) and leptin receptor (LEPR). During treatment with <i>setmelanotide,</i> changes in skin pigmentation were observed, probably due to off-target effects on the closely related melanocortin 1 receptor (MC1R). Here, we describe in detail the findings of dermatological examinations and measurements of skin pigmentation during this treatment over time and discuss the impact of these changes on patient safety. <b><i>Methods:</i></b> In an investigator-initiated, phase 2, open-label pilot study, 2 patients with loss-of-function POMC gene mutations and 3 patients with loss-of-function variants in LEPR were treated with the MC4R agonist <i>setmelanotide</i>. Dermatological examination, dermoscopy, whole body photographic documentation, and spectrophotometric measurements were performed at screening visit and approximately every 3 months during the course of the study. <b><i>Results:</i></b> We report the results of a maximum treatment duration of 46 months. Skin pigmentation increased in all treated patients, as confirmed by spectrophotometry. During continuous treatment, the current results indicate that elevated tanning intensity levels may stabilize over time. Lips and nevi also darkened. In red-haired study participants, hair color changed to brown after initiation of <i>setmelanotide</i> treatment. <b><i>Discussion:</i></b> <i>Setmelanotide</i> treatment leads to skin tanning and occasionally hair color darkening in both POMC- and LEPR-deficient patients. No malignant skin changes were observed in the patients of this study. However, the results highlight the importance of regular skin examinations before and during MC4R agonist treatment.

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