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Precise modulation of transcription factor levels identifies features underlying dosage sensitivity.Nature Genetics May 2023Transcriptional regulation exhibits extensive robustness, but human genetics indicates sensitivity to transcription factor (TF) dosage. Reconciling such observations...
Transcriptional regulation exhibits extensive robustness, but human genetics indicates sensitivity to transcription factor (TF) dosage. Reconciling such observations requires quantitative studies of TF dosage effects at trait-relevant ranges, largely lacking so far. TFs play central roles in both normal-range and disease-associated variation in craniofacial morphology; we therefore developed an approach to precisely modulate TF levels in human facial progenitor cells and applied it to SOX9, a TF associated with craniofacial variation and disease (Pierre Robin sequence (PRS)). Most SOX9-dependent regulatory elements (REs) are buffered against small decreases in SOX9 dosage, but REs directly and primarily regulated by SOX9 show heightened sensitivity to SOX9 dosage; these RE responses partially predict gene expression responses. Sensitive REs and genes preferentially affect functional chondrogenesis and PRS-like craniofacial shape variation. We propose that such REs and genes underlie the sensitivity of specific phenotypes to TF dosage, while buffering of other genes leads to robust, nonlinear dosage-to-phenotype relationships.
Topics: Humans; SOX9 Transcription Factor; Pierre Robin Syndrome; Gene Expression Regulation; Regulatory Sequences, Nucleic Acid; Phenotype
PubMed: 37024583
DOI: 10.1038/s41588-023-01366-2 -
Molecular Cell May 2023Enhancer clusters overlapping disease-associated mutations in Pierre Robin sequence (PRS) patients regulate SOX9 expression at genomic distances over 1.25 Mb. We applied...
Enhancer clusters overlapping disease-associated mutations in Pierre Robin sequence (PRS) patients regulate SOX9 expression at genomic distances over 1.25 Mb. We applied optical reconstruction of chromatin architecture (ORCA) imaging to trace 3D locus topology during PRS-enhancer activation. We observed pronounced changes in locus topology between cell types. Subsequent analysis of single-chromatin fiber traces revealed that these ensemble-average differences arise through changes in the frequency of commonly sampled topologies. We further identified two CTCF-bound elements, internal to the SOX9 topologically associating domain, which promote stripe formation, are positioned near the domain's 3D geometric center, and bridge enhancer-promoter contacts in a series of chromatin loops. Ablation of these elements results in diminished SOX9 expression and altered domain-wide contacts. Polymer models with uniform loading across the domain and frequent cohesin collisions recapitulate this multi-loop, centrally clustered geometry. Together, we provide mechanistic insights into architectural stripe formation and gene regulation over ultra-long genomic ranges.
Topics: Humans; Chromatin; Regulatory Sequences, Nucleic Acid; Promoter Regions, Genetic; Gene Expression Regulation; Genome; Cell Cycle Proteins; Enhancer Elements, Genetic; CCCTC-Binding Factor
PubMed: 36996812
DOI: 10.1016/j.molcel.2023.03.009 -
Rare syndromes in dentistry Part 1: The Pierre Robin sequence: a focus on a rare congenital anomaly.European Journal of Paediatric Dentistry Feb 2023The aim of this paper was to enlighten the peculiar findings of the Pierre Robin sequence, a rare congenital anomaly with important afterbirth comorbidities. The...
The aim of this paper was to enlighten the peculiar findings of the Pierre Robin sequence, a rare congenital anomaly with important afterbirth comorbidities. The management of this pathology requires highly specialised centers and highly qualified specialists in order to offer the best therapeutic strategy to the affected child. Early diagnosis and parental counseling play a key role in the managing of PRS: an earlier activation of the treatment path helps to yield better outcomes and to prevent complications. A case of a newborn affected by PRS is presented, showing the steps of the treatment strategy and the final outcome.
Topics: Child; Infant, Newborn; Humans; Pierre Robin Syndrome; Parents; Dentistry
PubMed: 36853208
DOI: 10.23804/ejpd.2023.24.01.14 -
Plastic Surgery (Oakville, Ont.) Feb 2023Timing of extubation on post-mandibular distraction osteogenesis (MDO) surgery is critical, given that at baseline these infants have difficult airways and failed...
Timing of extubation on post-mandibular distraction osteogenesis (MDO) surgery is critical, given that at baseline these infants have difficult airways and failed extubation requires either re-intubation of an already complex airway with a fragile, recently osteotomized mandible, or adjunctive airway measures such as CPAP that may apply unwanted pressure to the surgical site. Thus, the goal is to plan extubation when the risk of failure is minimal. Currently, there is a void in the literature addressing the timing of extubation post-MDO and no objective sign of extubation readiness has been elucidated. This study describes a simple clinical pearl to assist in the evaluation of extubation readiness in these patients. Postoperatively, we obtain weekly radiographs to assess distractor stability and advancement, and to assess for the "Air Sign". The Air Sign describes a radiolucent space (air) visualized in the oropharynx on lateral radiographs, likely indicating that the tongue based airway obstruction has been relieved by mandibular advancement.
PubMed: 36755816
DOI: 10.1177/22925503211048529 -
Indian Journal of Otolaryngology and... Dec 2022Carotid Anomalies are with significant surgical implication to an Otorhinolaryngologist. The authors discuss the evaluation and management of a child with Pierre Robin...
Carotid Anomalies are with significant surgical implication to an Otorhinolaryngologist. The authors discuss the evaluation and management of a child with Pierre Robin Syndrome who presented with severe OSA, secondary to bilateral midline carotids that compromised the airway, and an adult with cervical bolus and dysphagia who presented similar to chronic tonsillitis but found to have Retropharyngeal Carotids. This case study emphasizes the need for awareness and a high index of suspicion to identify the variation of the carotid artery in nasopharyngeal and oropharyngeal surgery that has a propensity to result in catastrophic consequences if operated upon.
PubMed: 36742624
DOI: 10.1007/s12070-021-02501-3 -
Oxford Medical Case Reports Dec 2022Pierre Robin syndrome (PRS) neonates are one of the most difficult cases to intubate even for an experienced paediatric anaesthesiologist. We describe a case of a...
Pierre Robin syndrome (PRS) neonates are one of the most difficult cases to intubate even for an experienced paediatric anaesthesiologist. We describe a case of a PRS-related anatomical anomaly that hindered attempts to manage the airway and the final approach that made it possible to insert an endotracheal tube (ETT). We describe the novel use of a video ureteroscope (Olympus URF-V2) as an airway endoscope. A 7-day-old, 2-kg boy was referred to our tertiary care hospital with diagnosed PRS. He was planned for correction of the mandible with mandibular distraction osteogenesis under general anaesthesia. Fibreoptic scope (Olympus, Japan) revealed the epiglottis lying on the posterior pharynx, which could not be manoeuvred. Due to repeated attempts, the patient developed laryngospasm, and his pulse arterial oxygen saturation (SpO2) was reduced to 70%. Following jaw thrust and slight pulling of the tongue with Magill's Forceps, a 150-cm long and 0.035-inch diameter atraumatic, Roadrunner® hydrophilic polyurethane-coated guidewire was introduced through the working channel of the video ureteroscope into the trachea under the vision (and a 3.5-mm ID ETT was railroaded over it and a definitive airway was established). A flexible fibreoptic ureteroscope may be useful in the management of a difficult airway and may become an important tool in the armoury of an anaesthesiologist. At our institute, which is a tertiary care centre, we are now training and utilising video-ureteroscope as an airway endoscope. To our knowledge, there is no documentary evidence of the use of a video ureteroscope for difficult airway management of a neonate.
PubMed: 36579079
DOI: 10.1093/omcr/omac132 -
Journal of Clinical Oncology : Official... Apr 2023Epcoritamab is a subcutaneously administered CD3xCD20 T-cell-engaging, bispecific antibody that activates T cells, directing them to kill malignant CD20 B cells....
PURPOSE
Epcoritamab is a subcutaneously administered CD3xCD20 T-cell-engaging, bispecific antibody that activates T cells, directing them to kill malignant CD20 B cells. Single-agent epcoritamab previously demonstrated potent antitumor activity in dose escalation across B-cell non-Hodgkin lymphoma subtypes.
PATIENTS AND METHODS
In the dose-expansion cohort of a phase I/II study (ClinicalTrials.gov identifier: NCT03625037), adults with relapsed or refractory CD20 large B-cell lymphoma and at least two prior therapy lines (including anti-CD20 therapies) received subcutaneous epcoritamab in 28-day cycles (once weekly step-up doses in weeks 1-3 of cycle 1, then full doses once weekly through cycle 3, once every 2 weeks in cycles 4-9, and once every 4 weeks in cycle 10 and thereafter) until disease progression or unacceptable toxicity. The primary end point was overall response rate by the independent review committee.
RESULTS
As of January 31, 2022, 157 patients were treated (median age, 64 years [range, 20-83]; median of three [range, 2-11] prior therapy lines; primary refractory disease: 61.1%; prior chimeric antigen receptor (CAR) T-cell exposure: 38.9%). At a median follow-up of 10.7 months, the overall response rate was 63.1% (95% CI, 55.0 to 70.6) and the complete response rate was 38.9% (95% CI, 31.2 to 46.9). The median duration of response was 12.0 months (among complete responders: not reached). Overall and complete response rates were similar across key prespecified subgroups. The most common treatment-emergent adverse events were cytokine release syndrome (49.7%; grade 1 or 2: 47.1%; grade 3: 2.5%), pyrexia (23.6%), and fatigue (22.9%). Immune effector cell-associated neurotoxicity syndrome occurred in 6.4% of patients with one fatal event.
CONCLUSION
Subcutaneous epcoritamab resulted in deep and durable responses and manageable safety in highly refractory patients with large B-cell lymphoma, including those with prior CAR T-cell exposure.
Topics: Adult; Humans; Middle Aged; Neoplasm Recurrence, Local; Lymphoma, Large B-Cell, Diffuse; Antineoplastic Agents; T-Lymphocytes; Receptors, Chimeric Antigen
PubMed: 36548927
DOI: 10.1200/JCO.22.01725 -
Genes Nov 2022TARP syndrome (Talipes equinovarus, Atrial septal defect, Robin sequence, and Persistence of the left superior vena cava) is a rare genetic condition, caused by...
TARP syndrome (Talipes equinovarus, Atrial septal defect, Robin sequence, and Persistence of the left superior vena cava) is a rare genetic condition, caused by developmental defects during embryogenesis. The phenotypic spectrum of TARP shows high clinical variability with patients either missing cardinal features or having additional clinical traits. Initially, TARP was considered a lethal syndrome, but patients with milder symptoms were recently described. The TARP-locus was mapped to the gene RNA-binding motif protein 10 () on the human X-chromosome. We clinically and genetically described a six-year-old boy with a TARP-phenotype. Clinical heterogeneity of symptoms prompted us to sequence the entire exome of this patient. We identified a novel splice variant (NM_005676: c.17+1G>C, p.?) in . A patient-derived cell line was used to verify the pathogenicity of the splice variant by RNA analyses, Western blotting, and immunofluorescence staining. Our molecular genetic findings together with the analyses of progressing clinical symptoms confirmed the diagnosis of TARP. It seems essential to analyze correlations between genotype, phenotype, and molecular/cellular data to better understand -associated pathomechanisms, assist genetic counseling, and support development of therapeutic approaches.
Topics: Male; Humans; Child; Pierre Robin Syndrome; Clubfoot; Vena Cava, Superior; Phenotype; Rare Diseases; RNA-Binding Proteins
PubMed: 36421828
DOI: 10.3390/genes13112154