scholarly journals Ossifications in Albright Hereditary Osteodystrophy: Role of Genotype, Inheritance, Sex, Age, Hormonal Status, and BMI

2017 ◽  
Vol 103 (1) ◽  
pp. 158-168 ◽  
Author(s):  
Parissa Salemi ◽  
Julie M Skalamera Olson ◽  
Lauren E Dickson ◽  
Emily L Germain-Lee
Keyword(s):  
Medical Center ◽  
Johns Hopkins Hospital ◽  
Parental Origin ◽  
Hormonal Status ◽  
Missense Mutations ◽  
Nonsense Mutations ◽  
Albright Hereditary Osteodystrophy ◽  
Hormonal Resistance ◽  
Kennedy Krieger Institute

Abstract Context Albright hereditary osteodystrophy (AHO) is caused by heterozygous inactivating mutations in GNAS. Depending on the parental origin of the mutated allele, patients develop either pseudohypoparathyroidism type 1A (PHP1A), with multihormone resistance and severe obesity, or pseudopseudohypoparathyroidism (PPHP), without hormonal abnormalities or marked obesity. Subcutaneous ossifications (SCOs) are a source of substantial morbidity in both PHP1A and PPHP. Objective This study investigated the previously undetermined prevalence of SCO formation in PHP1A vs PPHP as well as possible correlations with genotype, sex, age, hormonal resistance, and body mass index (BMI). Design This study evaluated patients with AHO for SCOs by physical examination performed by one consistent physician over 16 years. Setting Albright Clinic, Kennedy Krieger Institute; Institute for Clinical and Translational Research, Johns Hopkins Hospital; Albright Center, Connecticut Children’s Medical Center. Patients We evaluated 67 patients with AHO (49 with PHP1A, 18 with PPHP) with documented mutations in GNAS. Main Outcome Measures Relationships of SCOs to genotype, sex, age, hormonal resistance, and BMI. Results Forty-seven of 67 participants (70.1%) had SCOs. Patients with PHP1A and PPHP had similar prevalences and degrees of ossification formation. Patients with frameshift and nonsense mutations had much more extensive SCOs than those with missense mutations. Males were affected more than females. There was no correlation with hormonal status or BMI. Conclusions There is a similar prevalence of SCOs in PHP1A and PPHP, and the extent of SCO formation correlates with the severity of the mutation. Males are affected more extensively than females, and the SCOs tend to worsen with age.

scholarly journals Parental origin of Gsα inactivation differentially affects bone remodeling in a mouse model of Albright hereditary osteodystrophy

2021 ◽  
Author(s):  
Patrick McMullan ◽  
Qingfen Yang ◽  
Peter Maye ◽  
David Rowe ◽  
Emily Germain-Lee
Keyword(s):  
Bone Resorption ◽  
Mouse Model ◽  
Bone Remodeling ◽  
Parental Origin ◽  
Mineral Density ◽  
Bone Parameters ◽  
Albright Hereditary Osteodystrophy ◽  
Osteoblast Activity ◽  
Hormonal Resistance ◽  
Serum Pth

Albright hereditary osteodystrophy (AHO) is caused by heterozygous inactivation of GNAS, a complex locus that encodes the alpha-stimulatory subunit of GPCRs (Gsα) in addition to NESP55 and XLαs due to alternative first exons. AHO skeletal manifestations include brachydactyly, brachymetacarpia, compromised adult stature, and subcutaneous ossifications. AHO patients with maternally-inherited GNAS mutations develop pseudohypoparathyroidism type 1A (PHP1A) with resistance to multiple hormones that mediate their actions through GPCRs requiring Gsα (eg., PTH, TSH, GHRH, calcitonin) and severe obesity. Paternally-inherited GNAS mutations cause pseudopseudohypoparathyroidism (PPHP), in which patients have AHO skeletal features but do not develop hormonal resistance or marked obesity. These differences between PHP1A and PPHP are caused by tissue-specific reduction of paternal Gsα expression. Previous reports in mice have shown loss of Gsα causes osteopenia due to impaired osteoblast number and function and suggest AHO patients could display evidence of reduced bone mineral density (BMD). However, we previously demonstrated PHP1A patients display normal-increased BMD measurements without any correlation to body mass index or serum PTH. Due to these observed differences between PHP1A and PPHP, we utilized an AHO mouse model generated in our laboratory to address whether Gsα heterozygous inactivation by the targeted disruption of exon 1 of Gnas differentially affects bone remodeling based on the parental inheritance of the mutation. Mice with paternally-inherited (Gnas E1+/-p) and maternally-inherited (Gnas E1+/-m) mutations displayed reductions in osteoblasts along the bone surface compared to wildtype. Gnas E1+/-p mice displayed reduced cortical and trabecular bone parameters due to impaired bone formation and excessive bone resorption. Gnas E1+/-m mice however displayed enhanced bone parameters due to increased osteoblast activity and normal bone resorption. These distinctions in bone remodeling between Gnas E1+/-p and Gnas E1+/-m mice appear to be secondary to changes in the bone microenvironment driven by calcitonin-resistance within Gnas E1+/-m osteoclasts and therefore warrant further studies into understanding how Gsα influences osteoblast-osteoclast coupling interactions.

Anti-Myelin Oligodendrocyte Glycoprotein Encephalomyelitis and Extensive Longitudinal Transverse Myelitis Associated with Compound Heterozygous NLRP3 Missense Mutations in a Young Child

2020 ◽  
Author(s):  
Deirdre O'Sullivan ◽  
Michael Moore ◽  
Susan Byrne ◽  
Andreas O. Reiff ◽  
Susanna Felsenstein
Keyword(s):  
Young Child ◽  
Genetic Basis ◽  
Transverse Myelitis ◽  
Acute Disseminated Encephalomyelitis ◽  
Myelin Oligodendrocyte Glycoprotein ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
Childhood Onset

AbstractAcute disseminated encephalomyelitis in association with extensive longitudinal transverse myelitis is reported in a young child with positive anti-myelin oligodendrocyte glycoprotein (MOG) antibody with heterozygous NLRP3 missense mutations; p.(Arg488Lys) and p.(Ser159Ile). This case may well present an exceptional coincidence, but may describe a yet unrecognized feature of the spectrum of childhood onset cryopyrinopathies that contribute to the understanding of the genetic basis for anti-MOG antibody positive encephalomyelitis. Based on this observation, a larger scale study investigating the role of NLRP3 and other inflammasomes in this entity would provide important pathophysiological insights and potentially novel avenues for treatment.

scholarly journals Mutated p53 in HGSC—From a Common Mutation to a Target for Therapy

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3465
Author(s):  
Aya Saleh ◽  
Ruth Perets
Keyword(s):  
Cancer Progression ◽  
Target Genes ◽  
P53 Protein ◽  
Genetic Alterations ◽  
Common Mutation ◽  
Missense Mutations ◽  
P53 Expression ◽  
Histologic Subtype ◽  
Tp53 Mutations

Mutations in tumor suppressor gene TP53, encoding for the p53 protein, are the most ubiquitous genetic variation in human ovarian HGSC, the most prevalent and lethal histologic subtype of epithelial ovarian cancer (EOC). The majority of TP53 mutations are missense mutations, leading to loss of tumor suppressive function of p53 and gain of new oncogenic functions. This review presents the clinical relevance of TP53 mutations in HGSC, elaborating on several recently identified upstream regulators of mutant p53 that control its expression and downstream target genes that mediate its roles in the disease. TP53 mutations are the earliest genetic alterations during HGSC pathogenesis, and we summarize current information related to p53 function in the pathogenesis of HGSC. The role of p53 is cell autonomous, and in the interaction between cancer cells and its microenvironment. We discuss the reduction in p53 expression levels in tumor associated fibroblasts that promotes cancer progression, and the role of mutated p53 in the interaction between the tumor and its microenvironment. Lastly, we discuss the potential of TP53 mutations to serve as diagnostic biomarkers and detail some more advanced efforts to use mutated p53 as a therapeutic target in HGSC.

542 Objective Sleep Duration, Sleep Timing and Completion of In Vitro Fertilization Cycles; a Prospective Cohort Study

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A214-A214
Author(s):  
Chawanont Pimolsri ◽  
Xiru Lyu ◽  
Cathy Goldstein ◽  
Chelsea Fortin ◽  
Sunni Mumford ◽  
...  
Keyword(s):  
Embryo Transfer ◽  
Sleep Duration ◽  
Medical Center ◽  
Working Women ◽  
Vitro Fertilization ◽  
Circadian Misalignment ◽  
Logistic Regression Models ◽  
Sleep Timing

Abstract Introduction Sleep duration and circadian misalignment have been linked to fertility and fecundability. However, sleep in women undergoing IVF has rarely been examined. This study investigated the role of sleep duration and timing with completion of an IVF cycle. Methods Prospective study of women undergoing IVF at a tertiary medical center between 2015 and 2017. Sleep was assessed by wrist-worn actigraphy 1–2 weeks prior to the initiation of their IVF cycle. Reproductive profile, IVF cycle details, demographic and health information were obtained from medical charts. Sleep duration, midpoint and bedtime were examined in relation to IVF cycle completion using logistic regression models, adjusted for age and anti-Müllerian hormone levels. A sub-analysis excluded women who worked non-day shifts to control for circadian misalignment. Results A total of 48 women were studied. Median age was 33y (range 25–42), with 29% of women older than 35 years. Ten women had an IVF cycle cancellation prior to embryo transfer. These women had shorter sleep duration, more nocturnal awakenings, lower sleep efficiency, and later sleep timing in comparison to those who completed their cycle. Twenty-minute increases in sleep duration were associated with lower odds of an uncompleted IVF cycle (OR = 0.88; 95% CI 0.78, 1.00). Women with later sleep midpoints and later bedtime had higher odds of an uncompleted cycle relative to those with earlier midpoints and earlier bedtime; OR=1.24; 95% CI 1.09, 1.40 and OR=1.33; 95% CI 1.17, 1.53 respectively, per 20-minute increments. These results were independent of age, levels of anti-Müllerian hormone, or sleep duration, and remained unchanged after exclusion of shift-working women. Conclusion This study demonstrated the influence of sleep duration and sleep timing on the odds of an uncompleted IVF cycle prior to embryo transfer. Sleep is a modifiable behavior that may contribute to IVF cycle success. Support (if any):

Extrapulmonary Small Cell Cancer: A New Insight into a Rare Disease

Oncology ◽  
2021 ◽  
pp. 1-7
Author(s):  
Leora Brazg Ferro ◽  
Ido Wolf ◽  
Shira Peleg Hasson ◽  
Inbal Golomb ◽  
Ester Osher ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Response Rate ◽  
Medical Center ◽  
Cell Cancer ◽  
Small Cell ◽  
Ki 67 ◽  
Small Cell Cancer ◽  
Pathological Characteristics ◽  
Results Of Treatment

<b><i>Introduction:</i></b> Extrapulmonary small-cell cancer (EPSCC) is a relatively rare malignancy. The management of EPSCC is usually extrapolated from small-cell lung cancer (SCLC). In spite of the morphological similarity of the 2 malignancies, there are many differences in clinical features, prognosis, and recommendations of treatment of these disorders. The data on the correlation of clinical-pathological characteristics of EPSCC and treatment results is scarce. <b><i>Materials and Methods:</i></b> This retrospective analysis of 41 consecutively treated patients diagnosed with EPSCC in 2015–2018 was performed in a tertiary medical center. The correlation between the clinical and pathological characteristics and the treatment outcome (response rate, disease-free interval, and overall medial survival) was done using the standard statistics, Kaplan-Meier method, and multivariate analyses. The stratification was done on the stage of the disease, Ki-67 proliferative index, the location of the tumor, and smoking. <b><i>Results:</i></b> Forty-one patients were included with a median age of 66.3 years. The most common primary site was the gastrointestinal tract (28, 68.3%) including the pancreas. The most common distant metastasis site was the liver (23, 56.1%). Only 2 patients (4.9%) had brain metastases. Unlike in SCLC, most patients did not have any history of smoking (23, 56.1%). Nineteen patients with metastatic disease received systemic treatment, mostly cisplatin-based chemotherapy, with a response rate of 57.9%. The results of treatment were significantly better in patients with disseminated EPSCC with Ki-67 &#x3c;55%, while its role in limited disease was nonsignificant. <b><i>Discussion:</i></b> The results of our study show the unique entity of EPSCC. The rarity of brain metastases proves that prophylactic brain irradiation should not be recommended in practice. The provocative idea of prophylactic liver irradiation in limited-stage EPSCC of gastrointestinal origin can be evaluated in future studies. The predictive role of Ki-67 is important in metastatic EPSCC. There is probably no role of smoking in developing EPSCC.

scholarly journals Mutation-specific non-canonical pathway of PTEN as a distinct therapeutic target for glioblastoma

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Seung Won Choi ◽  
Yeri Lee ◽  
Kayoung Shin ◽  
Harim Koo ◽  
Donggeon Kim ◽  
...  
Keyword(s):  
Functional Properties ◽  
Therapeutic Target ◽  
Medical Center ◽  
Dominant Negative ◽  
The Cancer Genome Atlas ◽  
Dominant Negative Effect ◽  
Cell Periphery ◽  
Missense Mutations ◽  
Phosphatase Domain ◽  
Mutant Proteins

AbstractPTEN is one of the most frequently altered tumor suppressor genes in malignant tumors. The dominant-negative effect of PTEN alteration suggests that the aberrant function of PTEN mutation might be more disastrous than deletion, the most frequent genomic event in glioblastoma (GBM). This study aimed to understand the functional properties of various PTEN missense mutations and to investigate their clinical relevance. The genomic landscape of PTEN alteration was analyzed using the Samsung Medical Center GBM cohort and validated via The Cancer Genome Atlas dataset. Several hotspot mutations were identified, and their subcellular distributions and phenotypes were evaluated. We established a library of cancer cell lines that overexpress these mutant proteins using the U87MG and patient-derived cell models lacking functional PTEN. PTEN mutations were categorized into two major subsets: missense mutations in the phosphatase domain and truncal mutations in the C2 domain. We determined the subcellular compartmentalization of four mutant proteins (H93Y, C124S, R130Q, and R173C) from the former group and found that they had distinct localizations; those associated with invasive phenotypes (‘edge mutations’) localized to the cell periphery, while the R173C mutant localized to the nucleus. Invasive phenotypes derived from edge substitutions were unaffected by an anti-PI3K/Akt agent but were disrupted by microtubule inhibitors. PTEN mutations exhibit distinct functional properties regarding their subcellular localization. Further, some missense mutations (‘edge mutations’) in the phosphatase domain caused enhanced invasiveness associated with dysfunctional cytoskeletal assembly, thus suggesting it to be a potent therapeutic target.

scholarly journals Prediction of Functional Consequences of Missense Mutations in ANO4 Gene

2021 ◽  
Vol 22 (5) ◽  
pp. 2732
Author(s):  
Nadine Reichhart ◽  
Vladimir M. Milenkovic ◽  
Christian H. Wetzel ◽  
Olaf Strauß
Keyword(s):  
Transmembrane Protein ◽  
Functional Characterization ◽  
Missense Mutations ◽  
Mutant Proteins ◽  
Functional Consequences ◽  
New Perspective ◽  
The Stability ◽  
Dynamics Simulations ◽  
And Function

The anoctamin (TMEM16) family of transmembrane protein consists of ten members in vertebrates, which act as Ca2+-dependent ion channels and/or Ca2+-dependent scramblases. ANO4 which is primarily expressed in the CNS and certain endocrine glands, has been associated with various neuronal disorders. Therefore, we focused our study on prioritizing missense mutations that are assumed to alter the structure and stability of ANO4 protein. We employed a wide array of evolution and structure based in silico prediction methods to identify potentially deleterious missense mutations in the ANO4 gene. Identified pathogenic mutations were then mapped to the modeled human ANO4 structure and the effects of missense mutations were studied on the atomic level using molecular dynamics simulations. Our data show that the G80A and A500T mutations significantly alter the stability of the mutant proteins, thus providing new perspective on the role of missense mutations in ANO4 gene. Results obtained in this study may help to identify disease associated mutations which affect ANO4 protein structure and function and might facilitate future functional characterization of ANO4.

Role of postgraduate year 2 pharmacy residents in providing weekend antimicrobial stewardship coverage in an academic medical center

2017 ◽  
Vol 74 (6) ◽  
pp. 417-423 ◽  
Author(s):  
Justin Siegfried ◽  
Cristian Merchan ◽  
Marco R. Scipione ◽  
John Papadopoulos ◽  
Arash Dabestani ◽  
...  
Keyword(s):  
Antimicrobial Stewardship ◽  
Medical Center ◽  
Academic Medical Center ◽  
Academic Medical

scholarly journals The specific distribution pattern of IKZF1 mutation in acute myeloid leukemia

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Xiang Zhang ◽  
Xuewu Zhang ◽  
Xia Li ◽  
Yunfei Lv ◽  
Yanan Zhu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Genetic Alteration ◽  
Missense Mutations ◽  
Nonsense Mutations ◽  
Specific Distribution ◽  
Aggressive Clinical Course ◽  
Acute Myeloid

Abstract IKZF1 belongs to the IKAROS family of transcription factors, and its deletion/mutation frequently affects acute lymphoblastic leukemia. In acute myeloid leukemia, IKZF1 deletion has been demonstrated recurrent, but whether IKZF1 mutation also exists in AML remained largely unknown. Herein, we analyzed the IKZF1 mutation in AML. In our cohort, the frequency of IKZF1 mutation was 2.6% (5/193), and 5 frameshift/nonsense mutations as well as 2 missense mutations were identified in total. Molecularly, IKZF1 mutation was absent in fusion gene-positive AML, but it was demonstrated as the significant concomitant genetic alteration with SF3B1 or bi-alleleCEBPA mutation in AML. Clinically, two IKZF1, PTPN11 and SF3B1-mutated AML patients exhibited one aggressive clinical course and showed primary resistant to chemotherapy. Furthermore, we confirmed the recurrent IKZF1 mutation in AML with cBioPortal tool from OHSU, TCGA and TARGET studies. Interestingly, OHSU study also showed that SF3B1 mutation was the significant concomitant genetic alteration with IKZF1 mutation, indicating their strong synergy in leukemogenesis. In conclusion, IKZF1 mutation recurrently affected AML.

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