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Vertical and torsional ocular misalignment can occur from mild traumatic brain injury or inner ear pathology, which may vary depending on head position. Here, we evaluate differences in a behavioral measure of binocular alignment in both upright and supine head position. Ocular perception of vertical and torsional alignment was measured using the torsional and vertical alignment nulling (TAN, VAN) task in N = 52 veterans with dizziness (N = 38 with traumatic brain injury), N = 41 civilians with vestibular schwannoma resection (UVD), and N = 33 healthy controls for both positions. The interquartile range within each group, regardless of head position, was greater for torsional compared to vertical misalignment. We use generalized estimating equations to compare average TAN (torsional) scores and VAN (vertical) scores between groups and test position. Compared to the healthy controls, TAN was significantly increased by + 0.4186° in veterans (P = 0.030) and by + 0.5747° in UVD (P = 0.010), but there was no difference with head position. For VAN, no difference was found between the three groups, but the misalignment did worsen by 0.0888° (P = 0.0070) as the head position moved from upright to supine. Head position had negligible effects on this behavioral measure of vertical and torsional binocular misalignment, and torsional misalignments were worse than controls in both veterans with dizziness and patients with vestibular nerve resection although neither reported torsional diplopia. Our data suggests that the tolerance for roll misalignment may be abnormally large in patients with dizziness. Alternatively, perceptual roll misalignments may be a manifest cause for dizziness, and therefore a useful proxy for distinguishing differences in putative otolith function in veterans with dizziness.

Extended list of genes (overall FDR p-value

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Mechanisms underlying the propensity of latent lung adenocarcinoma (LUAD) to relapse are poorly understood. In this study, we show how differential expression of a network of extracellular matrix (ECM) molecules and their interacting proteins contributes to risk of relapse in distinct LUAD subtypes. Overexpression of the hyaluronan receptor HMMR in primary LUAD was associated with an inflammatory molecular signature and poor prognosis. Attenuating HMMR in LUAD cells diminished their ability to initiate lung tumors and distant metastases. HMMR upregulation was not required for dissemination in vivo, but enhanced ECM-mediated signaling, LUAD cell survival, and micrometastasis expansion in hyaluronan-rich microenvironments in the lung and brain metastatic niches. Our findings reveal an important mechanism by which disseminated cancer cells can coopt the inflammatory ECM to persist, leading to brain metastatic outgrowths. Cancer Res; 77(8); 1905–17. ©2017 AACR.

Physiologic and genetic analyses implicate hyperandrogenemia (HA) as a core causal pathway in PCOS. Both daughters of women with PCOS (PCOS-d) and overweight/obese girls (OW-g) have HA beginning in childhood suggesting that they are at increased risk for PCOS. Accordingly, we performed a prospective study of girls in the early postmenarchal transition until the diagnosis of PCOS can be established according to clinical guidelines at 2 or more yrs after menarche. | PCOS-d, OW-g and lean control girls (LC), ages 11-16 yrs at baseline, were studied within 0.2-1.2 yrs of menarche and returned after 1-3 years. Two PCOS-d, 2 OW-g, and 4 LC could not be assessed at follow up because they were taking hormonal contraception, which was most often prescribed for irregular menses. Baseline and follow up sample sizes were: PCOS-d 16, 12; OW-g 13, 9; LC 18, 14. A fasting morning blood sample was obtained. | Age was similar but BMI differed by design. The change in BMI from baseline to follow up did not differ between the groups. At baseline, DHEAS levels were increased (P=0. 009) and SHBG levels decreased (P LC mean + 1 SD) was increased (χ2 P=0. 04) in PCOS-d (69%) compared to OW-g (62%) and LC (28%). The prevalence of ovulatory dysfunction (OD, menses >45 d or Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Primary hyperparathyroidism (PHPT) is a common endocrine disorder characterized by dysregulation of parathyroid hormone release. The large majority of PHPT cases are attributable to sporadic, single-gland parathyroid adenoma, in which MEN1 and CCND1/cyclin D1 are the most well-established drivers of tumorigenesis. Sporadic parathyroid carcinoma, which appears to mostly arise through molecular pathways distinct from those causing benign parathyroid tumors, is rare and is most frequently driven by mutational inactivation of the CDC73 (HRPT2) tumor suppressor gene. Targeted investigation of suspected tumor driver genes, as well as unbiased whole-genome or exome sequencing of small cohorts, have revealed additional novel candidate tumor genes in sporadic parathyroid neoplasia, generally at modest or low mutational frequencies consistent with marked molecular genetic heterogeneity from tumor to tumor. The ability of these additional candidates to participate in the pathogenic process of driving parathyroid tumorigenesis in vivo largely remains to be demonstrated experimentally. This review will summarize the molecular genetic abnormalities identified to date in sporadic PHPT and discuss the strength of evidence for their proposed roles in parathyroid tumor formation.

Objective Primary hyperparathyroidism is most often caused by a sporadic single-gland parathyroid adenoma (PTA), a tumor type for which cyclin D1 is the only known and experimentally validated oncoprotein. However, the molecular origins of its frequent overexpression have remained mostly elusive. In this study, we explored a potential tumorigenic mechanism that could increase cyclin D1 stability through a defect in molecules responsible for its degradation. Methods We examined two tumor suppressor genes known to modulate cyclin D1 ubiquitination, PRKN and FBXO4 (FBX4), for evidence of classic two-hit tumor suppressor inactivation within a cohort of 82 PTA cases. We examined the cohort for intragenic inactivating and splice site mutations by Sanger sequencing and for locus-associated loss of heterozygosity (LOH) by microsatellite analysis. Results We identified no evidence of bi-allelic tumor suppressor inactivation of PRKN or FBXO4 via inactivating mutation or splice site perturbation, neither in combination with nor independent of LOH. Among the 82 cases, we encountered previously documented benign single nucleotide polymorphisms (SNPs) in 35 tumors at frequencies similar to those reported in the germlines of the general population. Eight cases exhibited intragenic LOH at the PRKN locus, in some cases extending to cover at least an additional 1.7 Mb of chromosome 6q25-26. FBXO4 was not affected by LOH. Conclusion: The absence of evidence for specific bi-allelic inactivation in PRKN and FBXO4 in this sizeable cohort suggests that these genes only rarely, if ever, serve as classic driver tumor suppressors responsible for the growth of PTAs.

Background: Deficits in vestibular function increase the risk for fall while turning. However, the clinical assessment of turning in patients with vestibular dysfunction is lacking, and evidence is limited that identifies how effective vestibular physical therapy (VPT) is for improving turning performance. Objective: To quantify and compare walking and turning performance during the instrumented timed up and go (TUG) test using inertial measurement units (IMUs) for clinical settings. We investigate novel instrumented TUG parameters for ability to distinguish patients with unilateral vestibular deafferentation (UVD) from control groups, and discriminate the differences in turning parameters of UVD patients following a VPT program. Methods: We recruited 38 patients following UVD surgery, 26 age-matched Veteran patient (VA) controls with reports of non-vestibular dizziness, and 12 age-matched healthy controls. Individuals were donned with body-worn IMUs and given verbal instructions to complete the TUG test as fast as safely possible. The IMU-instrumented and automated assessment of the TUG test provided component-based TUG parameters, including the novel walking:turning ratio. Among the UVD patients, 19 patients completed an additional instrumented TUG testing after VPT. Results: The walking:turning time ratio showed that turning performance in pre VPT UVD patients are significantly more impaired than VA patients and healthy controls (p < 0.001). Vestibular rehabilitation significantly improved turning performance and “normalized” their walking:turning time ratio compared to healthy controls (p < 0.001). However, the duration of the straight walking component in UVD patients before VPT was not significantly different as to that after VPT as well as healthy controls. Conclusions: Our data showed that the IMU-instrumented TUG test can distinguish patients with vestibular deafferentation and objectively quantify the change in their turning performance after surgery. The IMU-based instrumented TUG parameters have potential to quantify the efficacy of VPT and be adopted in the clinic.

Objective Deficits in vestibular function increase the risk for falls while turning. However, the clinical assessment of turning in patients with vestibular dysfunction is lacking, and evidence is limited that identifies the effectiveness of vestibular physical therapy in improving turning performance. The purpose of this study was to quantify walking and turning performance during the instrumented Timed “Up & Go” (TUG) test using body-worn inertial measurement units (IMUs). Novel instrumented TUG parameters were investigated for ability to distinguish patients with unilateral vestibular deafferentation (UVD) from control groups and discriminate the differences in turning parameters of patients with UVD following vestibular physical therapy. Methods Thirty-eight individuals were recruited following UVD surgery: 26 age-matched veteran controls with reports of dizziness not from a peripheral vestibular origin, and 12 age-matched healthy controls. Participants were donned with IMUs and given verbal instructions to complete the TUG test as fast as safely possible. The IMU-instrumented and automated assessment of the TUG test provided component-based TUG parameters, including the novel walk:turn ratio. Among the participants with UVD, 19 completed an additional instrumented TUG testing after vestibular physical therapy. Results The walk:turn time ratio showed that turning performance in patients with UVD before rehabilitation is significantly more impaired than both the individuals with nonperipheral conditions and healthy controls. Vestibular rehabilitation significantly improved turning performance and “normalized” their walk:turn time ratio compared with healthy controls. The duration of the straight walking component in individuals with UVD before vestibular physical therapy, however, was not significantly different compared with that component in people after vestibular physical therapy and in healthy controls. Conclusion The IMU-instrumented TUG test can be used to distinguish individuals with vestibular deafferentation and to objectively quantify the change in their turning performance after vestibular physical therapy. Impact The IMU-based instrumented TUG parameters have the potential to quantify the efficacy of vestibular physical therapy and be adopted in the clinic.

Mechanisms underlying the propensity of latent lung adenocarcinoma (LUAD) to relapse are poorly understood. In this study, we show how differential expression of a network of extracellular matrix (ECM) molecules and their interacting proteins contributes to risk of relapse in distinct LUAD subtypes. Overexpression of the hyaluronan receptor HMMR in primary LUAD was associated with an inflammatory molecular signature and poor prognosis. Attenuating HMMR in LUAD cells diminished their ability to initiate lung tumors and distant metastases. HMMR upregulation was not required for dissemination in vivo, but enhanced ECM-mediated signaling, LUAD cell survival, and micrometastasis expansion in hyaluronan-rich microenvironments in the lung and brain metastatic niches. Our findings reveal an important mechanism by which disseminated cancer cells can coopt the inflammatory ECM to persist, leading to brain metastatic outgrowths. Cancer Res; 77(8); 1905–17. ©2017 AACR.

The purpose of our study was to obtain a clear understanding of the various diagnoses within the closed neural tube defect (NTD) groups included in the large database of clients in our Spina Bifida Clinic and a clear picture of the outcomes for the various NTD groups.One hundred and four clients with closed NTD were categorized using a classification system devised by Tortori-Donati et al. Various clinical markers were investigated, including ambulation and the need for orthoses and wheelchairs.Most clients are ambulatory, requiring an orthoses, but not a wheelchair, despite the high incidence of ankle/foot abnormalities.This classification system has enhanced our knowledge of this group of clients, provided a greater understanding of the varied outcomes of these children and clinical management required.

The molecular mechanisms underlying the pathogenesis of sporadic parathyroid adenomas are incompletely understood. The oncoprotein cyclin D1 is overexpressed in 20-40% of sporadic parathyroid adenomas; however, known aberrations in the gene that encodes cyclin D1, CCND1, account for less than half of these cases. Genetic alterations of PARK2, which encodes the E3 ubiquitin ligase responsible for targeting cyclin D1 for degradation, have been identified as a frequent finding in a variety of human tumors. Interestingly, genetic abnormalities of PARK2 were mutually exclusive of cyclin D1 gene alterations, suggesting a common pathway in tumorigenesis. We postulate that inactivating mutations in PARK2 lead to increased stability of cyclin D1 and thereby may contribute to the development of sporadic parathyroid adenoma. We therefore sought to identify PARK2 coding region mutations in a series of sporadic parathyroid adenomas by direct DNA sequencing. The entire coding region and intron-exon boundaries of PARK2 were examined in a cohort of eighty typically presenting, sporadic parathyroid adenomas. Six known polymorphisms were identified in several of the adenomas in this series; however, none of the polymorphisms are associated with cancer, and no other cancer-associated mutations were found. The absence of intragenic mutations in PARK2 suggests that such mutations do not commonly contribute to the development of sporadic parathyroid adenoma. However, because such intragenic mutations could be rare and limited to only those samples in which overexpression of cyclin D1 cannot be explained by genetic abnormalities in the CCND1 gene, a significant role for cyclin D1 accumulation in parathyroid tumor formation due intragenic inactivating mutations of PARK2 cannot be ruled out. Further research must be conducted in order to elucidate the mechanism(s) of cyclin D1 accumulation in parathyroid adenomas in which CCND1 aberrations are not present. . Citation Format: Kelly Brewer, Jessica Costa-Guda, Andrew Arnold. Mutational analysis of PARK2, a regulator of cyclin D1 stability, in sporadic parathyroid adenoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3653.

The membranes of healthy lymphocytes normally resist hydrolysis by secretory phospholipase A2. However, they become susceptible during the process of apoptosis. Previous experiments have demonstrated the importance of certain physical changes to the membrane during cell death such as a reduction in membrane lipid order and exposure of phosphatidylserine on the membrane surface. Nevertheless, those investigations also showed that at least one additional factor was required for rapid hydrolysis by the human group IIa phospholipase isozyme. This study was designed to test the possibility that oxidation of membrane lipids is the additional factor. Flow cytometry and confocal microscopy with a fluorescent probe of oxidative potential suggested that oxidation of the plasma membrane occurs during apoptosis stimulated by thapsigargin. When oxidative potential was high, the activity of human group IIa secretory phospholipase A2 was enhanced 30- to 100-fold compared to that observed with conditions sufficient for maximal hydrolysis by other secretory phospholipase A2 isoforms. Direct oxidation of cell membranes with either of two oxidizing agents also stimulated hydrolysis by secretory phospholipase A2. Both oxidizers caused externalization of phosphatidylserine, but a change in lipid order did not always occur. These results demonstrated that membrane oxidation strongly stimulates human group IIa secretory phospholipase A2 activity toward apoptotic cells. Interestingly, the change in membrane order, previously thought to be imperative for high rates of hydrolysis, was not required when membrane lipids were oxidized. Whether phosphatidylserine exposure is still necessary with oxidation remains unresolved since the two events could not be deconvoluted.