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Background: Hypoparathyroidism (HP) is a rare disease that is characterized by insufficient levels of parathyroid hormone, resulting in hypocalcemia, hyperphosphatemia and hypercalciuria. Standard of care (SoC) consists of calcium and active vitamin D supplementation. Some patients may suffer from “calcium crashes”, sudden hypocalcemia symptoms that can be severe enough to require a visit to the emergency room (ER) or urgent care. Conversely, chronic use of SoC supplements can also increase risk of hypercalciuria and renal failure. The HypoPARAthyroidism Association (HPA), a nonprofit organization dedicated to improving the lives of hypoparathyroid patients, developed the “Voices of Hypopara” survey to capture the journey of patients with HP in the US. Methods: The online survey was distributed to all HPA members (approximately 1,000) in May 2020. Questions focused on evaluating patients’ experiences including diagnosis, treatment, quality of care, and impact on daily living. Results: The survey was completed by 146 HPA members (89% female; mean age 51). Most participants reported they are currently taking SoC (calcium 91%; active vitamin D 77%). However, over half felt that this did not optimally address their disease and 29% were extremely concerned about hypocalcemia despite supplementation. Many (69%) felt that taking SoC was moderately to extremely burdensome. More than two-thirds (69%) of respondents reported a “calcium crash” in the past year; of these, 43% reported calcium crashes monthly or weekly. Almost half (42%) of all participants required a visit to an ER/urgent care in the last year as a result of HP symptoms; of these, 56% believed that the staff was inexperienced with management of a calcium crash. More than 60% of participants checked serum calcium levels at least every couple of months at a physician’s office or lab in the past year, with 36% checking monthly or more frequently; the majority of respondents (70%) said the reason was due to symptoms of hypocalcemia. Participants viewed an at-home device for measuring serum calcium, phosphate, and magnesium levels as one key approach to manage their HP symptoms (47% ranked as “most preferred”), followed by more effective medications as the second most preferred option (23%). Almost all (99%) responded that they would use an at-home monitoring device and would test frequently. Conclusions: Results from this survey underscore the high disease burden of patients with HP, highlighting sudden hypocalcemic episodes as a key morbidity despite treatment with calcium and active vitamin D supplementation, and sub-optimal management by clinicians as an impediment to optimal treatment. These findings reinforce the need for more frequent, easily accessible, and real-time serum calcium level monitoring device, more efficacious therapies, and greater disease understanding among health care workers to best manage patients with HP.

We demonstrate a novel scheme for a full-field optical coherence tomography (FF-OCT) system using a tunable-path-difference source (TPDS). Recently, the comb-spacing-swept source (CSWS) method, including TPDS, has been successfully applied to improve the stability of three-dimensional (3D) time-domain (TD)-FF-OCT imaging by eliminating the mechanical scanning of the reference path, which has been the main source of undesirable noise in general TD-OCT. However, CSWS-OCT has the drawback of a degraded signal-to-noise ratio (SNR) from a duplicated interferometer structure. In this study, we improve the configuration of the TPDS so that it can be connected directly to the measurement interferometer, including the sample and reference paths of the OCT system. In our novel TPDS-OCT, a propagating optical path through only a single interferometer was critically helpful in enhancing the SNR while retaining the benefits of CSWS-OCT, and a free-space full-field interferometer of dual-input Mach–Zehnder type also has an even higher imaging performance owing to the simultaneous exposure of optical intensity into the camera and the short image acquisition time laterally. We theoretically and experimentally demonstrated the benefits of TPDS-OCT compared with CSWS-OCT in terms of SNR. We also demonstrated 3D multi-layered imaging, which CSWS-OCT cannot achieve owing to its limited SNR.

SummaryDespite nearly four decades of effort, broad inhibition of oncogenic RAS using small molecule approaches has proven to be a major challenge. Here we describe the development of a novel pan-RAS biologic inhibitor comprised of the RAS-RAP1-specific endopeptidase fused to the protein delivery machinery of diphtheria toxin. We show that this engineered chimeric toxin irreversibly cleaves and inactivates intracellular RAS at low picomolar concentrations terminating downstream signaling in receptor-bearing cells. Further, we demonstrate in vivo target engagement and reduction of tumor burden in three mouse xenograft models driven by either wild-type or mutant RAS. Intracellular delivery of a potent anti-RAS biologic through a receptor-mediated mechanism represents a promising new approach to developing RAS therapeutics against a broad array of cancers.SignificanceRAS oncoproteins have long been considered among the most elusive drug targets in cancer research. At issue is the lack of accessible drug binding sites and the extreme affinity for its GTP substrate. Covalent inhibitors against the KRAS G12C mutant have shown early clinical promise, however, targeting the other oncogenic RAS mutants across three RAS isoforms has proven challenging. Inhibition of activated wild-type RAS in the absence of canonical RAS mutations is also highly desirable in certain tumors. Here, we demonstrate delivery of an extremely potent pan-RAS and RAP1 cleaving enzyme in therapeutic quantities to specific receptor-bearing cells in vitro and in vivo. We aim to advance this approach to engineer the first targeted pan-RAS inhibitor for cancer therapy.One Sentence SummaryEngineered chimeric toxin halts tumor growth in vivo via RAS cleavage

Objective The aim of this study was to evaluate obstetric outcomes of external cephalic version (ECV) performed at or near term. Methods Single pregnant woman with breech presentation at or near term (n=145), who experienced ECV by one obstetrician from November 2009 to July 2014 in our institution were included in the study. Maternal baseline characteristic and fetal ultrasonographic variables were checked before the procedure. After ECV, the delivery outcomes of the women were gathered. Variables affecting the success or failure of ECV were evaluated. Results Success rate of ECV was 71.0% (n=103). Four variables (parity, amniotic fluid index, fetal spine position and rotational direction) were observed to be in correlation with success or failure of ECV. In contactable 83 individuals experienced successful ECV, cesarean delivery rates were 18.1%, 28.9%, and 5.3% in total, nulliparas, and multiparas, respectively. Conclusion Based on the results, ECV is proposed to be safe for both mother and her fetus. In addition, it is a valuable procedure that increases probability of vaginal delivery for women with breech presentation.

Ras GTPases are critical molecular hubs regulating cell proliferation and survival and are among the most frequently mutated oncogenes in human cancers. In recent years, significant efforts have been made to develop Ras-targeting anticancer strategies. Although promising preclinical results were reported for approaches directed against specific KRas mutant variants (e.g., G12C), more effective tools for inhibiting the spectrum of common KRas mutants and/or aberrantly activated wild-type Ras oncoproteins are required to bring Ras-blocking strategies from the bench to the bedside. We discovered the Ras-Rap1-Specific Protease (RRSP) from bacterium Vibrio vulnificus. RRSP site-specifically cleaves the major Ras isoforms (H, N and K) and the most common mutated Ras oncoproteins (G12V, G13D and Q61R) within the Switch I region. In order to bring RRSP into cancer cells, the Melnyk’s group fused RRSP with diphtheria toxin binding subunit B (DTB). DTB is a novel tool for delivery of cargo proteins into the cytosol of target cells via binding to its receptor hHB-EGF (human heparin-binding epidermal growth factor-like growth factor), which is expressed on most human cell types. Successful RRSP intracellular delivery was assessed via Western blot as indicated by Ras cleavage and pERK1/2 dephosphorylation. In MDA-MB-436 (triple-negative breast cancer, KRAS WT) cells with hyperactive Ras signaling, RRSP-DTB efficiently cleaved Ras at concentrations as low as 1 pM. As a consequence of Ras cleavage, we observed pERK1/2 dephosphorylation and decrease in cell viability as shown by crystal violet assay. Similar results were observed in MDA-MB-231 (triple-negative breast cancer, KRAS G13D) cells. A catalytically dead mutant of RRSP carrying an amino acid substitution in its active site (H451A RRSP-DTB) did not show Ras clipping nor decrease in pERK1/2 expression. We also found that RRSP-DTB reduced viability and proliferation of HCT-116 (colorectal, KRAS G13D) cells in 2-dimensional monolayers and 3-dimensional (3D) spheroids in a time- and dose-dependent manner. Notably, 3D spheroids from HCT-116 cells showed a significant reduction in size following RRSP-DTB but not H451A RRSP-DTB treatment. Also, in vivo experiments are currently ongoing to corroborate our in vitro findings. All together our results revealed that, by physically clipping Ras, bacterial toxin RRSP strongly reduces viability and proliferation of Ras-dependent human cancer cell lines bearing either wild-type or mutant KRAS. This work supports further development of RRSP as a potential anticancer therapeutic for a wide variety of Ras-driven tumors. Citation Format: Vania Vidimar, Minyoung Park, Roman A. Melnyk, Karla J.F. Satchell. Ras clipping by bacterial toxin RRSP reduces viability and proliferation of Ras-dependent cancer cell lines in 2D and 3D in vitro models [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr B38.

A 31-year-old multigravida woman at 27 weeks' gestation was admitted with vaginal bleeding and a hypervascular mass near the cervix on ultrasonography. After discharge with improvement, she was readmitted the next day for uncontrolled, heavy vaginal bleeding and underwent emergency cesarean section at 29 weeks' gestation. A 3-cm friable mass found near the cervix was removed surgically; this lesion was shown to be primary cervical choriocarcinoma. On the 17th postoperative day the patient underwent total abdominal hysterectomy with preservation of both ovaries and biopsy was performed on the right ovary. The International Federation of Gynecology and Obstetrics (FIGO) stage was I and her World Health Organization prognostic score was 9, representing high risk. The patient received three rounds of chemotherapy until achieving three consecutive normal human chorionic gonadotropin levels with two additional courses to address risk of relapse. DNA genotyping on short tandem repeat polymorphism confirmed the gestational choriocarcinoma.

Aim We determined to investigate the effect of plasma hemodilution on tumor marker concentration in obese women. Methods We collected the data for tumor markers (cancer-associated antigen 125 [CA125], carbohydrate antigen 19-9 [CA19-9], carcinoembryonic antigen [CEA] and α-fetoprotein) from 6917 healthy women who visited the health promotion center at the Chung-Ang University Hospital from 2003 to 2011. We used multivariate linear regression analysis and χ2-test for linear-by-linear association adjusting for age, alanine aminotransferase and creatinine to determine the association between the serum tumor marker concentrations, plasma volume, tumor marker mass, and body mass index (BMI). Results Higher BMI was significantly associated with higher plasma volume (P

INTRODUCTION Mibyeongbogam (MBBG) is a mobile application developed for subhealth status self-management in the Republic of Korea. It aims to assess a user's subhealth status, and then to recommend relevant traditional Korean medicine (TKM)-based health-promoting strategies. The purpose of this study is to evaluate the feasibility and effectiveness of MBBG's employment for the subhealth management of general healthy adults. METHODS This is a prospective, open-label, parallel group, randomized controlled trial that will seek to enroll 150 healthy adults, aged 30 to 49 years old, from 2 hospitals in the Republic of Korea. The eligible participants will then be randomly allocated to either the MBBG or control group, at a 1:1 allocation ratio. The MBBG group will use the application for 12 weeks, while the control group will undergo no intervention. The awareness of subhealth status will be primarily assessed. Health promoting behaviors, quality of life, TKM-based health questionnaires, and physical examination results will be assessed as secondary outcomes. DISCUSSION The primary endpoint will be tested with a 2-sample t test, or a Wilcoxon rank sum test. Any other continuous variables will be tested via an analysis of covariance, while categorical variables will be tested by a Chi-squared or Fisher exact test. Repeated measure analysis of variance will be performed to explore any in-group differences. The results will be addressed with a 95% confidence interval. We expect that MBBG will be the 1st TKM-based mobile application to be feasible for primary care in subhealth management. TRIAL REGISTRATION CRIS (Clinical Research Information Service), KCT0003488, February 11, 2019.

Alcoholic and nonalcoholic liver steatosis have an indistinguishable spectrum of histological features and liver enzyme elevations. In this study, we investigated the potential of the ethanolic extract of Acanthopanax koreanum Nakai (AK) to protect against experimental alcoholic liver disease in a mouse model that couples diet and daily ethanol bolus gavage. Fifty-six C57BL/6J mice were randomly divided into seven groups: normal control (NC), alcohol control (AC), alcohol/HFD control (AH), low-dose (1%) AK in alcohol group (ACL), high-dose (3%) AK in alcohol group (ACH), low-dose AK in alcohol/HFD group (AHL), and high-dose AK in alcohol/HFD group (AHH). The AH group showed more severe damage than the AC group in terms of biochemical and molecular data that were observed in this study. The administration of AK exerted remarkable effects in: plasma ALT (p < 0.0001), total lipid (p = 0.014), TG (p = 0.0037) levels; CPT-1α (p = 0.0197), TLR4 (p < 0.0001), CD14 (p = 0.0002), IL-6 (p = 0.0264) and MCP-1 (p = 0.0045) gene expressions; and ALDH (p < 0.0001) and CAT (p = 0.0076) activities. The data suggested that at least the high dose AK might confer protection against alcoholic liver damage combined with an HFD by accelerating lipid oxidation and alcohol metabolism and by suppressing the inflammatory response, including the TLR pathway.

Despite the well-established role of the human serotonin transporter (hSERT) in the treatment of depression, the molecular details of antidepressant drug binding are still not fully understood. Here we utilize amber codon suppression in a membrane-bound transporter protein to encode photocrosslinking unnatural amino acids (UAAs) into 75 different positions in hSERT. UAAs are incorporated with high specificity, and functionally active transporters have similar transport properties and pharmacological profiles compared with wild-type transporters. We employ ultraviolet-induced crosslinking with p-azido-L-phenylalanine (azF) at selected positions in hSERT to map the binding site of imipramine, a prototypical tricyclic antidepressant, and vortioxetine, a novel multimodal antidepressant. We find that the two antidepressants crosslink with azF incorporated at different positions within the central substrate-binding site of hSERT, while no crosslinking is observed at the vestibular-binding site. Taken together, our data provide direct evidence for defining the high-affinity antidepressant binding site in hSERT., Molecular details of how antidepressant drugs bind to the human serotonin transporter are not currently clear. Here, the authors introduce photo-cross-linkers into the protein and map the binding site of several antidepressants.

This paper presents a case study examining the emissions impacts of a modal shift from on-road trucks to rail for goods movement through the Southern California ports region, one of the severest non-attainment areas in terms of national air quality standards. Recent completion of the Alameda Corridor, a 20-mile rail expressway that connects the Ports of Long Beach and Los Angeles with rail mainlines near downtown Los Angeles, provides substantial reserve capacity for port traffic to be diverted from the severely congested road network to the rail line. On-road vehicles emissions were estimated using California mobile-source emissions model, ‘EMFAC’ that incorporates a set of emissions factors for each vehicle type and an estimate of vehicle activity. These emissions were then compared with the emissions generated from trains increased to carry freight volume diverted from truck traffic. On the basis of year 2000 traffic level, it was estimated that for a 20 percent modal shift of port traffic, mobile-source emissions can be reduced up to 0.86 tons for nitrogen oxides and 16 kg for particulate matter per day. The analysis results indicate that encouraging the modal shift for port-related freight traffic should be an integral part of overall air quality improvement initiatives for the study area.

The aim of this study was to identify smoking cessation failure subgroups among Korean adolescents. Participants were 379 smoking adolescents who joined a smoking cessation program. A questionnaire and a cotinine urine test were administered before the program began. Three months after the program ended, the cotinine urine test was repeated. A decision-tree model identified seven subgroups with low or high smoking cessation rates. The predictors of smoking cessation were intention to stop smoking, initiation of smoking, amount of cigarette use, self-efficacy, and paternal smoking status. The subgroup with the lowest smoking cessation rate included adolescents who did not have any intention to stop smoking and who had started smoking after eighth grade, and none of the participants in this group stopped smoking. The results of this study provide crucial information for tailored smoking cessation programs.

Pharmacopuncture, or herbal acupuncture, is a new form of therapy derived from combinations of two traditional therapeutic methods, herbal medicine and acupuncture therapy. To compare the efficacy between dexamethasone-pharmacopuncture (DP) and dexamethasone-oral administration (DO), the effect of DP was investigated in murine models. Anti-anaphylactic effects of dexamethasone treatments were investigated in compound 48/80-induced systemic anaphylactic reaction, ear swelling response, and passive cutaneous anaphylaxis (PCA). DP treatment significantly inhibited the compound 48/80-induced systemic anaphylactic reaction, ear swelling response, and PCA. The effects between DP and DO were on a similar level. These results indicate that DP can be used as an alternative method for DO in case of emergency.