Circulating microRNA as a Potential Biomarker for Skeletal Disease in Primary Hyperparathyroidism: A Case-control Study.

OBJECTIVE: The goal of this study was to characterize the microRNA (miRNA) expression signatures in patients with PHPT and identify miRNA biomarkers of bone homeostasis. SUMMARY BACKGROUND DATA: Primary hyperparathyroidism (PHPT) is associated with increased bone turnover and decreased bone mass. miRNA are markers of bone remodeling. METHODS: We performed a prospective case-control study of post-menopausal females with PHPT and control subjects matched for race, age, and BMD. We collected clinical and biochemical data, assessed BMD by dual-energy X-ray absorptiometry, and measured 27 serum miRNAs related to bone remodeling. We used linear regression to assess the correlation between miRNA levels, conventional biochemical markers and BMD. RESULTS: A total of 135 subjects were evaluated, including 49 with PHPT (discovery group), 47 control patients without PHPT, and an independent validation cohort of 39 PHPT patients. Of 27 miRNAs evaluated, nine (miR-335-5p, miR-130b-3p, miR-125b-5p, miR-23a-3p, miR-152-3p, miR-582-5p, miR-144-5p, miR-320a and miR-19b-3p) were differentially expressed in PHPT compared to matched control subjects. All nine differentially expressed miRNAs significantly correlated with levels of serum parathyroid hormone (PTH), and eight of the nine correlated with calcium levels. No differentially expressed miRNAs were consistently correlated with markers of BMD. Subjects with PHPT segregate from controls based on the signature of these nine miRNAs on principle component analysis. CONCLUSIONS: These data suggest that PHPT is characterized by a unique miRNA signature that is distinct from postmenopausal and idiopathic osteoporosis. Levels of specific miRNAs significantly correlate with PTH, suggesting that bone remodeling in PHPT may be mediated in part by PTH-induced changes in miRNA.

Temporal variability in the relationship between line height absorption and chlorophyll concentration: a case study from the Northern Gulf of Alaska.

The Line Height Absorption (LHA) method uses absorption of light to estimate chlorophyll-a. While most users consider regional variability and apply corrections, the effect of temporal variability is typically not explored. The Northern Gulf of Alaska (NGA) was selected for this study because there was no published regional value and its large swings in temporal productivity would make it a good candidate to evaluate the effect of temporal variability on the relationship. The mean NGA value of 0.0114 obtained here should be treated with caution, as variation in the slope of the relationship (aLH*), and thus chlorophyll-a estimates, in the NGA region varied by ∼25% between spring (aLH* = 0.0109) and summer (aLH* = 0.0137). Results suggest that this change is driven by a shift in pigment packaging and cell size associated with changes in mixed layer depth and stratification. Consideration of how temporal variability may affect the accuracy of the LHA method in other regions is thus recommended.

Transient gas-induced differential refractive index effects in as-drawn hollow core optical fibers.

When a hollow core fiber is drawn, the core and cladding holes within the internal cane geometry are pressurized with an inert gas to enable precise control over the internal microstructure of the fiber and counteract surface tension forces. Primarily by considering the temperature drop as the fiber passes through the furnace and the geometrical transformation of the internal microstructure from preform-to-fiber, we recently established that the gas pressure within the final 'as-drawn' fiber is substantially below atmospheric pressure. We have also established that slight changes in the gas refractive index within the core and surrounding cladding holes induced by changes in gas pressure are sufficient to significantly affect both the modality and loss of the fiber. Here we demonstrate, through both simulations and experimental measurements, that the combination of these effects leads to transient changes in the fiber's attenuation when the fibers are opened to atmosphere post-fabrication. It is important to account for this phenomenon for accurate fiber characterization, particularly when long lengths of fiber are drawn where it could take many weeks for every part of the internal microstructure to reach atmospheric pressure.

Randomness of optical turbulence generated by Rayleigh-Bénard convection using intensity statistics.

The experimental study of optical turbulence proves difficult due to challenges in generating controllable conditions in a laboratory environment. Confined water tanks that produce Rayleigh-Bénard (RB) convection are one method to generate optical turbulence using a controllable temperature gradient. It is of utmost concern to quantify the properties of the optical turbulence generated for characterization of other optical applications such as imaging, sensing, or communications. In this experimental study a Gaussian beam is propagated through a RB water tank where two intensity measurements are made at the receiver's pupil and focal plane. The pupil and focal plane results include quantification of the intensity fluctuation distribution, scintillation distribution, and refractive index structure constant at various values of the temperature gradient. The angle of arrival fluctuations is also calculated at the focal plane to obtain a second estimate of C n2. The pupil plane estimate for C n2 using scintillation index and focal plane angle of arrival fluctuations is compared to preliminary predictions of C n2 as a function of RB temperature gradient showing C n2âˆ¼Δ T 4/3. The outcomes of the study confirm that the RB process produces intensity fluctuations that follow gamma-gamma and log-normal probability density functions. Estimates of the refractive index structure constant C n2 produce the same trends with different magnitudes when measured from the pupil and focal plane.

Prevalence of weakness and factors mediating discrepancy between reported and observed leg weakness in people with sciatica.

PURPOSE: To establish the prevalence and agreement between reported and observed leg weakness in people with sciatica. To establish which factors mediate any identified difference between reported and observed leg weakness in people with sciatica. METHODS: 68 people with a clinical diagnosis of sciatica, records from spinal service, secondary care NHS Hospital, England, UK reviewed. Primary outcome measures were the sciatica bothersome index for reported leg weakness and the Medical Research Council scale for observed weakness. Agreement was established with Cohen's Kappa and intraclass correlation coefficient. Potential factors that may mediate a difference between reported and observed weakness included leg pain, sciatica bothersome index sensory subscale, age, hospital anxiety and depression subscale for anxiety. RESULTS: 85% of patients reported weakness but only 34% had observed weakness. Cohen's Kappa (0.066, 95% CI - 0.53, 0.186; p = 0.317)] and ICC 0.213 (95% CI - 0.26, 0.428, p = 0.040) both showed poor agreement between reported and observed weakness. The difference between reported and observed measures of weakness was mediated by the severity of leg pain (b = 0.281, p = 0.024) and age (b = 0.253, p = 0.042). CONCLUSION: There is a high prevalence of reported leg weakness in people with sciatica, which is not reflected in observed clinical measures of weakness. Differences between reported and observed weakness may be driven by the severity of leg pain and age. Further work needs to establish whether other objective measures can detect patient reported weakness.

Management of Pediatric Cavum Cysts: A Scoping Review and a Single Institution Case Series.

INTRODUCTION: Pediatric cavum cysts are a rare yet complicated pathology to manage. The literature is scarce, primarily consisting of case series, and lacking a consensus regarding clear management. In this scoping review, we aimed to compile existing information in the literature regarding the management of pediatric cavum cysts across the last 10 years. We also present our management of 19 patients, the largest case series to date, highlighting knowledge gaps surrounding the management of this salient pathology. METHODS: A literature search using PubMed and SCOPUS was conducted using the following search terms: (pediatric) AND (Cavum septum pellucidum) OR (cavum vergae) OR (cavum velum interpositum) AND (management). Eligibility criteria included peer-reviewed publication published in the last 10 years, pediatric population, cavum cyst, and English language. A retrospective search was conducted for all pediatric cavum cysts between 2013 and 2023 at our institution. Clinical and radiographic characteristics as well as intervention and outcome data were collected for both the scoping review and our cases. RESULTS: 330 total articles were populated using our search. 12 articles met our inclusion criteria. 41.7% (n = 5) of the articles were case series, 33.3% (n = 4) were case reports, 8.3% (n = 1) was a technical article, 8.3% (n = 1) was a systematic review, and 8.3% (n = 1) was a case questionnaire. Resolution of symptoms was noted in all articles of our scoping review, regardless of treatment modality. The average age in our case series was 9.84 years old and average age at diagnosis was 5.53 years old. 6 patients (31.6%) were female and 13 patients (68.4%) were male. 2 out of the 19 patients (10.5%) were surgically treated. CONCLUSION: There is no clear consensus on the management of cavum cysts. A prospective, multicenter study is needed to create standardized pediatric cyst management guidelines. The current thought is that surgical intervention should be saved for those patients with obstructive hydrocephalus and signs of intracranial hypertension.

The Tumor Microenvironment and Immune Response in Breast Cancer.

The complex interactions between cancer cells and their surrounding microenvironment are fundamental in determining tumor progression, response to therapy, and, ultimately, patient prognosis [...].

NR3C2 microdeletions-an underrecognized cause of pseudohypoaldosteronism type 1A: a case report and literature review.

OBJECTIVES: Pseudohypoaldosteronism type 1A (PHA1A) is caused by haploinsufficiency of the mineralocorticoid receptor (MR). Heterozygous small insertions/deletions, transitions, and/or transversions within NR3C2 comprise the majority (85%-90%) of pathogenic copy number variants. Structural chromosomal abnormalities, contiguous gene deletion syndromes, and microdeletions are infrequent. We describe a neonate with PHA1A due to a novel NR3C2 microdeletion involving exons 1-2. METHODS: Literature review identified 39 individuals with PHA1A due to NR3C2 microdeletions. Transmission modality, variant description(s), testing method(s), exon(s) deleted, and affected functional domain(s) were characterized. RESULTS: In total, 40 individuals with NR3C2 microdeletions were described: 19 involved contiguous exons encoding a single MR domain; 21 involved contiguous exons encoding multiple MR domains. Transmission modality frequency was familial (65%), de novo (20%), or unknown (15%). Sequencing (Sanger or short-read next-generation) failed to detect microdeletions in 100% of tested individuals (n = 38). All were detected using deletion/duplication testing modalities. In 2 individuals, only microarray-based testing was performed; microdeletions were detected in both cases. CONCLUSION: Initial testing for PHA1A should rely on sequencing to detect the most common genetic alterations. Deletion/duplication analysis should be performed when initial testing is nondiagnostic. Most NR3C2 microdeletions are parentally transmitted, thus highlighting the importance of familial genetic testing and counseling.

Development and validation of a rapid multicompartment body composition model using 3-dimensional optical imaging and bioelectrical impedance analysis.

BACKGROUND & AIMS: The multicompartment approach to body composition modeling provides a more precise quantification of body compartments in healthy and clinical populations. We sought to develop and validate a simplified and accessible multicompartment body composition model using 3-dimensional optical (3DO) imaging and bioelectrical impedance analysis (BIA). METHODS: Samples of adults and collegiate-aged student-athletes were recruited for model calibration. For the criterion multicompartment model (Wang-5C), participants received measures of scale weight, body volume (BV) via air displacement, total body water (TBW) via deuterium dilution, and bone mineral content (BMC) via dual energy x-ray absorptiometry. The candidate model (3DO-5C) used stepwise linear regression to derive surrogate measures of BV using 3DO, TBW using BIA, and BMC using demographics. Test-retest precision of the candidate model was assessed via root mean square error (RMSE). The 3DO-5C model was compared to criterion via mean difference, concordance correlation coefficient (CCC), and Bland-Altman analysis. This model was then validated using a separate dataset of 20 adults. RESULTS: 67 (31 female) participants were used to build the 3DO-5C model. Fat-free mass (FFM) estimates from Wang-5C (60.1 ± 13.4 kg) and 3DO-5C (60.3 ± 13.4 kg) showed no significant mean difference (-0.2 ± 2.0 kg; 95 % limits of agreement [LOA] -4.3 to +3.8) and the CCC was 0.99 with a similar effect in fat mass that reflected the difference in FFM measures. In the validation dataset, the 3DO-5C model showed no significant mean difference (0.0 ± 2.5 kg; 95 % LOA -3.6 to +3.7) for FFM with almost perfect equivalence (CCC = 0.99) compared to the criterion Wang-5C. Test-retest precision (RMSE = 0.73 kg FFM) supports the use of this model for more frequent testing in order to monitor body composition change over time. CONCLUSIONS: Body composition estimates provided by the 3DO-5C model are precise and accurate to criterion methods when correcting for field calibrations. The 3DO-5C approach offers a rapid, cost-effective, and accessible method of body composition assessment that can be used broadly to guide nutrition and exercise recommendations in athletic settings and clinical practice.

Identification of new microtubule small-molecule inhibitors and microtubule-associated genes against triple negative breast cancer.

Breast cancer represents the leading cancer type and leading cause of cancer-related death among women in the world. Triple-negative breast cancer (TNBC) is a subset of breast cancer with the poorest prognosis and still lacking of effective therapeutic options. We recently screened a natural product library and identified 3 new hit compounds with selective and prominent anti-TNBC activities on different subtype of TNBC cell lines. Interestingly, all of these 3 hit compounds belong to "cytoskeletal drugs" that target tubulin and microtubule function. Our data also showed that these hit compounds showed consistently effective on TNBC cells which are resistant to those currently used antimicrotubule agents such as Paclitaxel. RNA-Sequencing analyses revealed the anti-TNBC mechanisms of these hit compounds and identified a subset of new cellular factors commonly affected by hit compounds in different subtypes of TNBC cells. Among them, we demonstrated AHCYL1 and SPG21 as new microtubule-associated proteins, which were required for TNBC cell survival with clinical implication through tissue array analysis. Our studies provide new insights into the mechanisms of TNBC pathogenesis and offer promising therapeutic directions for this aggressive breast cancer.

Gastric Cancer Survivorship: Multidisciplinary Management, Best Practices and Opportunities.

PURPOSE: Gastric cancer is the 5th most common malignancy worldwide. As early detection increases and treatments for gastric cancer improve, the number of gastric cancer survivors grows. METHODS: Here, we review the diagnosis and management of gastric cancer and discuss important considerations for gastric cancer survivorship including cancer surveillance, weight loss, malnutrition, fatigue, specific complications related to surgery and radiation, quality of life in gastric cancer survivorship, health behavior, and models of survivorship. RESULTS: Multimodality therapy with chemotherapy and surgery can result in chronic toxicities in multiple organ systems. This emphasizes the need for a multidisciplinary survivorship care model including cancer surveillance, management of chronic toxicities, and optimization of modifiable risk factors with long-term involvement of appropriate providers. CONCLUSION: Adequately caring for gastric cancer survivors requires a coordinated, multidisciplinary approach.

When will we have a clone? An industry perspective on the typical CLD timeline.

Cell line development (CLD) represents a complex but highly critical process during the development of a biological drug. To shed light on this crucial workflow, a team of BioPhorum members (authors) has developed and executed surveys focused on the activities and effort involved in a typical CLD campaign. An average of 27 members from different companies that participate in the BioPhorum CLD working group answered surveys covering three distinguishable stages of a standard CLD process: (1) Pre-transfection, including vector design and construction; (2) Transfection, spanning the initial introduction of vector into cells and subsequent selection and analysis of the pools; and (3) Single Cell Cloning and Lead Clone Selection, comprising methods of isolating single cells and confirming clonal origin, subsequent expansion and screening processes, and methods for identifying and banking lead clones. The surveys were very extensive, including a total of 341 questions split between antibody and complex molecule CLD processes. In this survey review, the authors interpret and highlight responses for antibody development and, where relevant, contrast complex molecule development challenges to provide a comprehensive industry perspective on the typical time and effort required to develop a CHO production cell line.

E3 ubiquitin ligase CBLB regulates innate immune responses and bacterial dissemination during nontuberculous mycobacteria infection.

Nontuberculous mycobacteria (NTM) are emerging opportunistic pathogens causing pulmonary infection to fatal disseminated disease. NTM infections are steadily increasing in children and adults, and immune-compromised individuals are at a greater risk of fatal infections. The NTM disease's adverse pathology and resistance to antibiotics have further worsened the therapeutic measures. Innate immune regulators are potential targets for therapeutics to NTM, especially in a T cell-suppressed population, and many ubiquitin ligases modulate pathogenesis and innate immunity during infections, including mycobacterial infections. Here, we investigated the role of an E3 ubiquitin ligase, Casitas B-lineage lymphoma proto-oncogene B (CBLB), in immunocompromised mouse models of NTM infection. We found that CBLB is essential to prevent bacterial growth and dissemination. Cblb deficiency debilitated natural killer cells, inflammatory monocytes, and macrophages in vivo. However, Cblb deficiency in macrophages did not wane its ability to inhibit bacterial growth or production of reactive oxygen species or interferon γ production by natural killer cells in vitro. CBLB restricted NTM growth and dissemination by promoting early granuloma formation in vivo. Our study shows that CBLB bolsters innate immune responses and helps prevent the dissemination of NTM during compromised T cell immunity.

Accuracy and precision of multiple body composition methods and associations with muscle strength in athletes of varying hydration: The Da Kine Study.

BACKGROUND: Athletes vary in hydration status due to ongoing training regimes, diet demands, and extreme exertion. With water being one of the largest body composition compartments, its variation can cause misinterpretation of body composition assessments meant to monitor strength and training progress. In this study, we asked what accessible body composition approach could best quantify body composition in athletes with a variety of hydration levels. METHODS: The Da Kine Study recruited collegiate and intramural athletes to undergo a variety of body composition assessments including air-displacement plethysmography (ADP), deuterium-oxide dilution (D2O), dual-energy X-ray absorptiometry (DXA), underwater-weighing (UWW), 3D-optical (3DO) imaging, and bioelectrical impedance (BIA). Each of these methods generated 2- or 3-compartment body composition estimates of fat mass (FM) and fat-free mass (FFM) and was compared to equivalent measures of the criterion 6-compartment model (6CM) that accounts for variance in hydration. Body composition by each method was used to predict abdominal and thigh strength, assessed by isokinetic/isometric dynamometry. RESULTS: In total, 70 (35 female) athletes with a mean age of 21.8 ± 4.2 years were recruited. Percent hydration (Body Water6CM/FFM6CM) had substantial variation in both males (63-73 %) and females (58-78 %). ADP and DXA FM and FF M had moderate to substantial agreement with the 6C model (Lin's Concordance Coefficient [CCC] = 0.90-0.95) whereas the other measures had lesser agreement (CCC <0.90) with one exception of 3DO FFM in females (CCC = 0.91). All measures of FFM produced excellent precision with %CV < 1.0 %. However, FM measures in general had worse precision (% CV < 2.0 %). Increasing quartiles (significant p < 0.001 trend) of 6CM FFM resulted in increasing strength measures in males and females. Moreover, the stronger the agreement between the alternative methods to the 6CM, the more robust their correlation with strength, irrespective of hydration status. CONCLUSION: The criterion 6CM showed the best association to strength regardless of the hydration status of the athletes for both males and females. Simpler methods showed high precision for both FM and FFM and those with the strongest agreement to the 6CM had the highest strength associations. SUMMARY BOX: This study compared various body composition analysis methods in 70 athletes with varying states of hydration to the criterion 6-compartment model and assessed their relationship to muscle strength. The results showed that accurate and precise estimates of body composition can be determined in athletes, and a more accurate body composition measurement produces better strength estimates. The best laboratory-based techniques were air displacement plethysmography and dual-energy x-ray absorptiometry, while the commercial methods had moderate-poor agreement. Prioritizing accurate body composition assessment ensures better strength estimates in athletes.

Enhancing Neoadjuvant Virotherapy's Effectiveness by Targeting Stroma to Improve Resectability in Pancreatic Cancer.

About one-fourth of patients with pancreatic ductal adenocarcinoma (PDAC) are categorized as borderline resectable (BR) or locally advanced (LA). Chemotherapy and radiation therapy have not yielded the anticipated outcomes in curing patients with BR/LA PDAC. The surgical resection of these tumors presents challenges owing to the unpredictability of the resection margin, involvement of vasculature with the tumor, the likelihood of occult metastasis, a higher ratio of positive lymph nodes, and the relatively larger size of tumor nodules. Oncolytic virotherapy has shown promising activity in preclinical PDAC models. Unfortunately, the desmoplastic stroma within the PDAC tumor microenvironment establishes a barrier, hindering the infiltration of oncolytic viruses and various therapeutic drugs-such as antibodies, adoptive cell therapy agents, and chemotherapeutic agents-in reaching the tumor site. Recently, a growing emphasis has been placed on targeting major acellular components of tumor stroma, such as hyaluronic acid and collagen, to enhance drug penetration. Oncolytic viruses can be engineered to express proteolytic enzymes that cleave hyaluronic acid and collagen into smaller polypeptides, thereby softening the desmoplastic stroma, ultimately leading to increased viral distribution along with increased oncolysis and subsequent tumor size regression. This approach may offer new possibilities to improve the resectability of patients diagnosed with BR and LA PDAC.

A Pilot Feasibility Trial of an Upper Extremity Assistive System.

Objective: To develop and clinically evaluate a customizable active upper extremity (UE) assistive system with integrated functional electrical stimulation (FES) that improves function and independence of individuals during activities of daily living (ADLs). Design: Single-arm, prospective, open-label cohort feasibility trial. Setting: An academic research institution. Participants: Subjects were 5 adults with a medical history of stroke resulting in distal UE impairment (N=5). The subjects volunteered from recruitment materials that detailed information about the study. Interventions: A novel, wearable, lightweight, low-profile, and patient-tailored UE assistive system. It comprises a splint component and FES unit that may each be controlled by electromyography (EMG) signals, inertial measurement units (IMUs), manual control source (joystick), and/or voice control. Main Outcome Measures: Several occupational therapy outcome measures were used, including the Canadian Occupational Performance Measure (COPM), Action Research Arm Test (ARAT), The Box and Blocks Test (BBT), the ABILHAND-Manual Ability Measure, and Patient Reported Outcomes Measurement Information System (PROMIS) UE Short Form. Results: All participants learned to use our UE assistive system to perform ADLs and were able to use it independently at home. Most participants experienced a clinically meaningful improvement in both performance and satisfaction for the majority of their COPM goals while using the system. All participants experienced improvement in hand grip and release as shown by their baseline and post assessment scores for hand function (BBT, ARAT) and patient-reported outcomes (ABILHAND, PROMIS). Conclusions: The clinical outcomes suggest that our UE assistive system improves functional performance in patients with UE impairment, allowing them to engage more actively in ADLs. Further innovation including elbow and shoulder components will allow users to have more degrees of freedom during tasks.