bluuebunny/crossref_metadata_2025_split huggingface dataset:
Type 1 Familial Hypocalciuric Hypercalcemia Caused by p.M74L Variant in the Calcium Sensing Receptor (CASR) Gene
Authors: Antony McAnto , Maliakal Alvin , Burdette Jameson , Verma Vipin , Kant Ravi 
Published: May 2021

Abstract
Background: Familial hypocalciuric hypercalcemia (FHH) is a rare cause of hypercalcemia caused by inactivating mutations in specific regions of chromosome 3 and 19. Most cases are due to inactivating mutations in the Calcium sensing receptor (CASR) which is encoded by the gene located on the long arm of chromosome 3 (3q 21.1). FHH is characterized by hypercalcemia, an inappropriately normal to elevated serum PTH level, hypocalciuria, and a family history of hypercalcemia. Several mutations in the CASR gene have been described in literature. However, the p.M74L variant in the CASR gene has an extremely low frequency of occurrence in population databases such as the genome aggregation database (gnomAD)1.
Clinical Case: A 67 years old woman with a past medical history of hypertension, dyslipidemia, type 2 diabetes mellitus, and chronic kidney disease presented for an evaluation of a long standing history of hypercalcemia. Patient reported non-specific symptoms including chronic fatigue and arthralgias. She denied a history of renal stone or chronic use of lithium. She distinctly recalled that her mother and maternal grandmother had high blood calcium levels. Review of old records showed an elevated corrected calcium level of 11.3 mg/dl, which was elevated since at least October 2013 (no medical records prior to October 2013 were available) which persisted to-date. Patient underwent work-up which revealed a high corrected serum calcium of 10.4 (8.6–10.0mg/dl), high serum PTH of 101 (15–65 pg/ml), an extremely low 24hr urine calcium of &lt;9.2 (100–300 mg/24hr) with corresponding urine volume of 1150 cc and urine creatinine of 1392 (740–1570 mg/24hr), low 25-OH vitamin D of 20.6 (30–100 ng/ml), and a low eGFR of 47 ml/m/1.73. SPECT parathyroid gland was negative. FHH was suspected and subsequent CASR gene analysis panel showed a heterogenous DNA sequence change at nucleotide position c.220 in exon 3 of the CASR gene (c.220A&gt;C). This nucleotide change results in an amino acid change from methionine (M) to leucine (L) at position 74 in the CASR protein (p.M74L).
Conclusion: We report a case of a p.M74L variant in the CASR gene which is an extremely uncommon mutation in the CASR gene1. Our case supports the current limited evidence that p.M74L variant in the CASR gene can cause FHH.
References: 1) Genome Aggregation Database: https://gnomad.broadinstitute.org/
Chronic Stimulation of Arcuate Kiss1 Neurons Decreases Bone Mass in Female Mice
Authors: Rodriguez Ruben , Herber Candice B , Krause William C , Ingraham Holly A 
Published: May 2021

Abstract
Loss of peripheral estrogen in postmenopausal women is often associated with decreased physical activity and loss of bone mass, leading to an increased risk of metabolic diseases, osteoporosis, and skeletal fragility. While it is well-established that loss of peripheral estrogen signaling results in bone loss, we previously found that eliminating central estrogen signaling paradoxically results in an unexpected massive increase in bone mass only in female mice. Specifically, deletion of estrogen receptor alpha (ERα) signaling in kisspeptin 1 (Kiss1) expressing neurons of the arcuate nucleus (ARCKiss1) increases bone mass at the expense of reproduction in female mice. Currently, the mechanisms and the neurocircuits that modulate these unexpected responses are unknown. Here, to begin addressing these questions, we asked if changing the neuronal output of ARCKiss1 neurons using chemogenetic manipulation of ARCKiss1 neurons might also alter bone mass and locomotion in female mice. To do this, we delivered stimulatory (AAV2-hM3Dq-mCherry) designer receptors exclusively activated by designer drugs (DREADDs) to the ARC of wild type and Kiss1-Cre+ (Kiss1-CrehM3q-DREADDs) female mice and asked if chronic activation of ARCKiss1 neurons might alter bone mass as analyzed by standard ex-vivo µCT imaging. Clozapine N-oxide (CNO) was delivered for 22 days (0.1 mg/mL). We also leveraged the ANY-Maze system to assess home cage activity over an extensive 96-hour period. Acute activation of ARCKiss1 tended to decrease home cage activity by nearly 40% in Kiss1-CrehM3q-DREADDs mice during the dark period compared to WT females. Interestingly, chronic activation of ARCKiss1 neurons significantly lowered trabecular bone volume by nearly 30%. Current studies are underway to ask if inhibiting ARCKiss1 neurons results in increased bone mass. Our findings collectively suggest that the neuronal activity of ARCKiss1 neurons is sufficient to shift energy allocation away from locomotion and bone-building to maximize reproductive capacity. We speculate that the widely used SERM in breast cancer treatment, Tamoxifen, might exert its bone sparing effect by silencing ARCKiss1 neurons.
Comparative Transcriptomic Profiling Revealed Distinctive Patterns in Differentially Expressed Genes Related to Clinicopathologic Features of Parathyroid Carcinoma and Adenoma
Authors: Hong Namki , Lee Seunghyun , Kim Kyoungjin , Jeong Jong Joo , Kim Sang Kyum , Jo Se-Young , Kim Sangwoo , Rhee Yumie 
Published: May 2021

Abstract
Parathyroid carcinoma is a rare malignancy which remains as a clinical unmet need lacking effective therapeutic intervention. (1) In this study, we compared mutational profile of parathyroid carcinoma, adenoma, and normal parathyroid tissue using RNA-Seq based transcriptomics analysis and whole exome sequencing. A total of 40 parathyroid specimens [parathyroid carcinoma (n=8), adenoma (n=24), and normal tissue incidentally obtained from thyroidectomy for various reasons (n=8)] from 39 individuals (women n=34, 87%; mean age 51 year) were analyzed. Compared to adenoma and normal parathyroid groups, parathyroid carcinoma group had younger age (carcinoma 35 ± 12 vs. other 56 ± 16 year, p=0.001) and higher serum parathyroid hormone (PTH; 231 [145–474] vs. 114 [88–196] vs. 34 [29–41] pg/mL, p=0.001) prior to surgery. CDC73 mutation was found in 7 of 8 carcinoma specimens, which harbored germline mutation in 6 of them. Among top feature gene mutations for classifying adenoma and carcinoma, carcinoma-specific genes showed high specificity, whereas adenoma-related key features were largely overlapped with normal tissues. Transcriptional profiling revealed 546 carcinoma-specific differentially expressed genes (DEGs), 135 adenoma-specific DEGs, and 323 common DEGs. Hierarchical clustering with 546 carcinoma-specific DEGs detected four clusters with distinctive clinicopathologic characteristics (cluster 1 [n=12]: 7 normal tissues and 5 adenomas; cluster 2 and 3 [n=22]: all adenomas except one normal tissue; cluster 4 [n=9]: all parathyroid carcinomas except one adenoma). Carcinoma-specific DEGs include upregulation of GRIN2A, LYPD1, and SOX2 and downregulation of ENTPPL, MYO3B, and PIK3C2G. Gene ontology enrichment revealed that these DEGs were mainly involved in the binding of cell adhesion molecule, actin, and Rho GTPase, and extracellular matrix structural constituent. Two adenoma clusters significantly differed in urinary calcium excretion level (403 [312–488] vs. 205 [150–327], p=0.037) without significant differences in median PTH (102 [86–138] vs. 125 [92–229] pg/mL) and calcium level (11.1 ± 1.0 vs. 11.0 ± 0.9 mg/dL; P&gt;0.05 for all). In summary, parathyroid carcinoma had distinctive transcriptional profiles which might improve the early detection of parathyroid carcinoma. Parathyroid adenomas were clustered into two groups with regard to urinary calcium excretion level based on transcriptional profiles, which merits further investigation. Reference: (1) Pandya C et al., JCI Insight. 2017 Mar 23; 2(6): e92061. Sources of Research Support: This study was supported by Severance Hospital Research Fund for Clinical Excellence (SHRC C-2019-0032; C-2020-0035).
Importance of Extra-Renal CYP24A1 Expression for Maintaining Mineral Homeostasis
Authors: Shi Melody , Grabner Alexander , Wolf Myles 
Published: May 2021

Abstract
Calcium homeostasis involves a complex interplay between kidneys, parathyroid glands, intestine and bone. Specifically, 1,25(OH)2D3 is a key calciotropic hormone which stimulates intestinal calcium absorption. A growing body of evidence suggests that circulating levels of 1,25(OH)2D3 depend not only on its synthesis under the action of PTH in the kidneys, but also its catabolism by 24-hydroxylase, herein referred to as CYP24A1. The clinical importance of CYP24A1 has been demonstrated by human loss-of-function mutations, which lead to severe hypercalcemia due to exaggerated levels of 1,25(OH)2D3. Despite its growing importance, little is known about its tissue-specific contributions to normal vitamin D metabolism. To explore the physiology of CYP24A1 and delineate renal-specific effects of CYP24A1 in calcium metabolism, we generated a mouse with constitutive kidney-specific deletion of Cyp24a1 (Six2Cre-Cyp24flox). Six2 marks the nephron progenitor population throughout nephrogenesis. We hypothesized that hypercalcemia as seen in CYP24A1 inactivating mutations is related to lack of both renal and extrarenal expression, and that renal deletion does not lead to severe hypercalcemia. To confirm Cyp24a1 deletion, we measured mRNA expression in the kidney using qPCR and RNA in situ hybridization. All mice were fed a standard commercial rodent diet and followed longitudinally for five months with interval calcium measurements. At time of termination, serum PTH levels were measured along with vitamin D-dependent calcium transporters as a functional measure of 1,25(OH)2D3 action. Cyp24a1 expression was significantly knocked down in total kidneys from Six2Cre-Cyp24flox mice as compared to intestinal expression suggesting successful gene deletion. Compared to age-matched wildtype controls, Six2Cre-Cyp24flox mice were mildly but persistently hypercalcemic (diff between means= 0.46 mg/dL, p-value: 0.03, n=8 per group). As expected, 1,25D-dependent calcium transporters in the kidney (Calb1, Trpv5, Slc8a1, Atp2b1) and intestine (Trpv6, s100g) were all increased, consistent with increased systemic 1,25(OH)2D3 activity. PTH levels were appropriately suppressed in the Six2Cre-Cyp24flox mice (diff between means=83 pg/mL, p-value 0.2, n=9 control, n=3 exp) as were renal cyp27b1 mRNA expression. These data suggest that renal CYP24A1 is important for systemic 1,25(OH)2D3 regulation, but the lack of severe hypercalcemia supports critical contributions of extra-renal CYP24A1.
In Vivo Effects of Osteoblast-Specific Overexpression of Gα s and Gα q/11 on Bone Formation and Bone Remodeling During Fracture Healing
Authors: Lee Kathy Kyungeun , Mitchell Jane 
Published: May 2021

Abstract
Although the regenerative potential of bone is high, fracture healing is sometimes compromised resulting in fracture non-union. Successful prevention and treatment of non-union rely on accurate prognosis of fracture and treatment assignment but are often impeded by a high degree of heterogeneity in fracture pathogenesis and treatment response. Burgeoning evidence that indicates differential levels of G proteins among healthy populations offers a plausible explanation, since G protein signaling plays regulatory roles in bone development and remodeling. We previously demonstrated the in vivo effects of G protein level variation on bone development by characterizing the skeletal phenotypes of two transgenic mouse lines that overexpress normal Gα s (Gs-Tg) or Gα 11 (G11-Tg) in osteoblast lineage cells under the control of the 3.6-kb Col1a1 promoter. Gs-Tg mice showed high bone mass but diminished bone quality due to increased formation of woven bone and cortical porosity. Conversely, G11-Tg mice displayed a low bone mass phenotype with reduced bone strength primarily due to increased bone resorption. It still remains unclear, however, how variation in G protein signaling in osteoblasts affects the rate and quality of bone repair. To characterize bone healing in Gs-Tg and G11-Tg mice, we induced a stabilized transverse osteotomy in the tibia of wild-type, Gs-Tg or G11-Tg at 8 weeks of age and assessed the progression of bone healing at the tissue and molecular levels by Micro-CT, histomorphometry, and quantitative gene expression analysis at 1, 2, 3, and 4 weeks post-fracture. The effects of increased G protein signaling during repair on Wnt and Hh signaling, the two signaling pathways essential in osteogenesis, were also examined by assessing mRNA levels of key components of each pathway. Persistent upregulation of Wnt and Hh signaling in Gs-Tg fractures led to enhanced callus mineralization and new woven bone formation at the expense of cartilaginous callus formation and defective bone remodeling. G11-Tg fractures, in contrast, showed minimal changes in Wnt and Hh pathways and consequently led to only subtle changes in the healing response with a transient increase in callus mineralization followed by its rapid resorption. Our results indicate that G protein signaling in osteoblasts regulates bone formation and remodeling during fracture repair in part by tightly controlling the strength and duration of Wnt and Hh signaling pathways.
Modeling COVID 19: The Value of Practice
Authors: Fredericks Robert S 
Published: May 2021

Abstract
The necessity of developing models that effectively organize data for the purpose of translating basic science to clinical care is being increasingly recognized. Reliance upon digital computational methods restricts the value of natural experience reportable by patients, often considered subjective. In the course of modeling phosphate metabolism in the context of clinical practice it has become evident that use of categories based on normality, as definition of health, is inconsistent with the experience of patients. Given the opportunity, patients can provide detailed observations upon their experience of heat as the principle component of metabolism. It seems logical that heat should also be the foundational principal component of models developed for the translation of data to clinical care. This strategy has been applied to modeling the role of ACE2 in the expression of variable phenotypes of COVID 19. Attempts to engage massive data and super-computing to the modeling of COVID 19 supported the assumption that ACE2 is a critical component causing disease. The finding is attributed to an influence, not on heat, but instead suggested bradykinin that has long been a proposed explanation for ACE inhibition on chronic cough. Our modeling would posit that the ACE system engages aldosterone and subsequent influence on heat and acid/base balance as the mediators of variance in the expression of individual phenotypes. This clarification has been useful for addressing complexity in the presentation of metabolic disorders including thyroid disease, Diabetes, bone health, sleep disorders, vascular disease and Chronic Fatigue Syndrome. It appears that the risk of developing ARDS shares a predisposition to chronic kidney disease mediated by excessive FGF23 effects, while the asymptomatic spreaders are more Klotho dependent. The vitamin D system is also complex and involved in the modulation of heat and phosphate. These and other components can be extended to understanding bone and the hematopoietic marrow niche governing immune responses and includes a role for modulation of the microbiome influences by ACE2.
It is concluded that SARS-CoV-2 has helped to clarify the complexity of biology and has exposed the limitations of modeling strategies that do not include the application of case-based practice that can be described as “model-dependent realism” 1 as a means to discover the principle components of nature. The models are the valued product of the research that is mandated by the Helsinki accords when outcomes do not meet expectations. These models can facilitate the organization of all data in the appropriate translation to clinical care.
1 Hawking S., Mlodinow L. The Grand Design p 39–59, Bantom Books NY, 2010
Therapeutic Potentials of Dimeric Cys25PTH(1–34) Peptide for Osteoporosis and Fracture Healing of the Bones- Buy One, Get One Free
Authors: Park Doori , Kitaura Yoshiaki , Dean Thomas , Ohba Shinsuke , Gardella Thomas James , Chung Ung-il , Lee Soo Young , Lee Sihoon 
Published: May 2021

Abstract
Objective: The extraordinarily high bone densities identified in the hypoparathyroidism patients originating from PTH R25C mutation suggested the possibility that this modified protein has unique biologic effects and contributes to the gain of bone volume. Interestingly, western blot of cell lysates stably transfected with PTH R25C construct revealed that Cys25PTH(1–84) formed a dimer, presumably due to disulfide bonding of the cysteine residues. This study aims to study the characteristics of Cys25PTH(1–34) dimeric peptide (Dimer) both in vitro and in vivo for potential therapeutic application of Dimer as a novel anabolic agent. Methods: Identity of the chemically synthesized Dimer was confirmed by its molecular weight and purity using MS and HPLC, respectively. Basic characteristics, for example, ability to bind to PTHR and cAMP production were investigated using a variety of cells. In addition, the ligand-receptor internalization was investigated using TMR tagged Dimer. In vivo characteristics, such as calcemic and phosphatemic responses, pharmacokinetics and pharmacodynamics, were assessed in CD1 mice. The osteoanabolic effects of Dimer were assessed using a fracture-healing model, a calvarial-injection model and an OVX mouse model. Results:In vivo study showed that Dimer has similar calcemic and phosphatemic responses to PTH(1–34; WT). In cell assays, Dimer showed a similar cAMP production but slightly lower binding affinity compared to WT. Dimer-receptor complex was internalized into the cells. Surprisingly, Dimer showed a potent anabolic effect in the fracture-healing model in mice measured as the callus volume fraction by microCT. We also observed a comparable anabolic effect of Dimer in calvarial-injection model and OVX model. Conclusions: Dimeric Cys25PTH(1–84) peptide might play a substantial role in the high bone mass in hypoparathyroidism patients, originating from the PTH R25C mutation. This may be translated into the development of potential therapeutic modality for the treatment of osteoporosis and fracture healing using Dimer.
Efficacy of Low Dose Denosumab in Maintaining Bone Mineral Density in Postmenopausal Women With Osteoporosis Switching From 60mg to 30mg 6 Monthly: A Real World, Prospective Observational Study
Authors: Khan Aliya , Alrob Hajar Abu , Said Hosay , Iqbal Salman , Hweija Ismail , Hussain Sharjil 
Published: May 2021

Abstract
Introduction: Denosumab, a fully human monoclonal antibody to RANK-ligand, has been shown to increase bone mineral density (BMD) and reduce the risk of fracture in postmenopausal women with osteoporosis. Cessation of denosumab is associated with rises in bone remodelling, reductions in BMD and an increased risk of fracture. The primary objective of this study is to evaluate the efficacy of low dose denosumab (30mg/6 months) in preventing bone loss in postmenopausal women with osteoporosis switching from 60mg to 30mg every 6 months. We report the effects of low dose denosumab for upto 2years in patients previously treated with denosumab for &gt;=3 years as well as &lt; 3years. Methods: Following informed consent, postmenopausal women with osteoporosis who had been on denosumab 60mg every 6 months were switched to receive 30mg of denosumab every 6 months.. Patients with an additional skeletal disorder, prior fragility fracture, or on oral steroids (daily in the past 12 months) were excluded. The primary endpoint was the percent change in BMD at the lumbar spine (LS), total hip (HP), femoral neck (FN) and 1/3 radius (1/3R) at 12 and 24 months. Secondary outcomes were adverse effects and fracture Results: 127 patients were included in the study. 44 patients had received 60 mg for 3 years or longer before transitioning to 30mg and 83 patients switched before completing 3 years on full dose therapy. Patients on less than 3yrs of 60mg therapy before the switch showed a significant improvement in BMD at LS (+2.00%, 95% CI 0.49% to 3.51%, n = 55, p-value = 0.01) 1 year post transition. There were no significant changes at the FN, TH or 1/3 radial sites 1 year post transition compared to baseline. At 2 years post transition (n=35) significant changes were noticed at LS (+4.65%, 95% CI 2.29% to 7.01%, p value &lt;0.001), FN (+ 4.87%, 95% CI 1.46% to 8.28%, p value = 0.006) and 1/3 radial sites (+4.95%, 95% CI 0.73% to 9.17%, p value = 0.02). No significant changes were noted at TH. Similar results were seen with prior denosumab therapy for &lt;3years No fractures were observed in this observational study. Conclusions: Switching from 60mg of denosumab to 30 mg every 6 months was not associated with reductions in BMD and may be a valuable treatment option in patients who have completed long term denosumab therapy.
Effect of Statin Use on the Risk of Osteoporotic Fracture in Patients With Metabolic Syndrome: A Nested Case-Control Study
Authors: Kim Kyoung Jin , Choi Jimi , Kim Ji Yoon , Bae Jae Hyun , Kim Kyeong Jin , Kim Hee Young , Yoo Hye Jin , Seo Ji A , Kim Nan Hee , Choi Kyung Mook , Baik Sei Hyun , Kim Sin Gon , Kim Nam Hoon 
Published: May 2021

Abstract
Statins may have advantageous pleiotropic effects on bone metabolism, however, the clinical evidence about the association is still unclear. Although many studies have already evaluated this association, they have performed mostly in a general population with limitation of between-study heterogeneity. Statin may not be equally effective for bone metabolism to every patient, but it can give some benefits for some patients especially with metabolic syndrome (MetS). However, no recent study assessing this relationship, to best our knowledge, has evaluated specifically on patients with MetS. It is also unclear whether the association between statin and osteoporotic fracture differ by statin intensity, dose (cumulative defined daily dose), and duration. This study aimed to investigate the association of statin use with the risk of major osteoporotic fracture in MetS patients from a population-based cohort (NHIS-HEALS, 2002–2015). A nested case-control study was performed in patients with MetS (≥50 years) who had no history of previous osteoporotic fracture. This study included 17,041 cases diagnosed as new-onset osteoporotic fractures and controls matched in a 1:1 ratio by age, sex, body mass index, cohort entry date, and follow-up duration. Conditional logistic regression analysis was used to evaluate covariate-adjusted odds ratio (OR) and 95% confidence interval (CI). During the 4-year follow up period, statin users had a significantly lower risk of major osteoporotic fractures by 9% (OR, 0.91; 95% CI, 0.85 to 0.97) compared with non-users. Among subtypes of major osteoporotic fracture, a risk reduction of vertebral fracture was significant (OR, 0.86; 95% CI, 0.79 to 0.94), but not non-vertebral fracture (OR, 0.97; 95% CI, 0.88 to 1.06) with statin use. Longer duration (OR, 0.97 per 1 year) and cumulative dose (OR, 0.97 per 365 defined daily dose) of statin was negatively associated with the risk of major osteoporotic fracture. There was no difference in risk of major osteoporotic fractures among groups according to statin intensity. In conclusion, this study supports the hypothesis that statin treatment has a beneficial effect on major osteoporotic fracture, especially for vertebral fracture, in patients with MetS with a possibly dose-effect relationship.