The secreted protein Amuc_1409 from Akkermansia muciniphila improves gut health through intestinal stem cell regulation.

Akkermansia muciniphila has received great attention because of its beneficial roles in gut health by regulating gut immunity, promoting intestinal epithelial development, and improving barrier integrity. However, A. muciniphila-derived functional molecules regulating gut health are not well understood. Microbiome-secreted proteins act as key arbitrators of host-microbiome crosstalk through interactions with host cells in the gut and are important for understanding host-microbiome relationships. Herein, we report the biological function of Amuc_1409, a previously uncharacterised A. muciniphila-secreted protein. Amuc_1409 increased intestinal stem cell (ISC) proliferation and regeneration in ex vivo intestinal organoids and in vivo models of radiation- or chemotherapeutic drug-induced intestinal injury and natural aging with male mice. Mechanistically, Amuc_1409 promoted E-cadherin/ß-catenin complex dissociation via interaction with E-cadherin, resulting in the activation of Wnt/ß-catenin signaling. Our results demonstrate that Amuc_1409 plays a crucial role in intestinal homeostasis by regulating ISC activity in an E-cadherin-dependent manner and is a promising biomolecule for improving and maintaining gut health.

Prediction of complete response after neoadjuvant chemotherapy for invasive breast cancers: The utility of shear wave elastography and superb microvascular imaging in pretreatment breast ultrasound.

PURPOSE: To investigate whether multiparametric parameters of pretreatment breast ultrasound (US) and clinicopathologic factors are associated with pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) for breast cancer. METHODS: Between November 2018 and September 2022, 88 patients who underwent NAC and subsequent surgery were included in this study (median age, 55 years; interquartile range [IQR], 45, 59.3). Multiparametric breast US including grayscale, shear wave elastography (SWE) and superb microvascular imaging (SMI) of pathologically proven invasive breast cancers were retrospectively reviewed. Clinicopathological and multiparametric parameters of breast US, including size, SWEmax, SWEratio and vascular index on SMI (SMIVI) were compared between the groups. Univariate and multivariate logistic regression analyses were performed to determine factors predicting pCR after NAC. AUROC curve analysis was performed to determine the predictors' optimal cut-off values and diagnostic performance. RESULTS: The pCR group (n = 24) showed a significantly smaller tumor size, lower SWEmax, higher Ki-67 index, higher hormone receptor negativity and negative axillary lymph node metastasis compared to the non-pCR group (n = 64). Multivariate regression analysis showed that SWEmax (adjusted odds ratio[aOR] = 0.956, 95 % confidence interval [CI] = 0.919-0.994, P = 0.025) and Ki-67 index (aOR = 1.083, 95 % CI = 1.012-1.159, P = 0.021) were independently associated with pathologically complete response. The optimal cut-off values for predicting pCR were 27.5 % for Ki-67 with an AUC of 0.743 and 134.8 kPa for SWEmax with an AUC of 0.779. A combination model including clinical factors and SWEmax showed the best diagnostic performance with an AUC of 0.876. CONCLUSION: A higher Ki-67 index and lower SWEmax measured on pretreatment breast US were independently associated with pCR in invasive breast cancer after NAC.

Lymphadenectomy in clinically early epithelial ovarian cancer and survival analysis (LILAC): a Gynecologic Oncology Research Investigators Collaboration (GORILLA-3002) retrospective study.

OBJECTIVE: This study aimed to evaluate the therapeutic role of lymphadenectomy in patients surgically treated for clinically early-stage epithelial ovarian cancer (EOC). METHODS: This retrospective, multicenter study included patients with clinically early-stage EOC based on preoperative abdominal-pelvic computed tomography or magnetic resonance imaging findings between 2007 and 2021. Oncologic outcomes and perioperative complications were compared between the lymphadenectomy and non-lymphadenectomy groups. Independent prognostic factors were determined using Cox regression analysis. Disease-free survival (DFS) was the primary outcome. Overall survival (OS) and perioperative outcomes were the secondary outcomes. RESULTS: In total, 586 patients (lymphadenectomy group, n=453 [77.3%]; non-lymphadenectomy groups, n=133 [22.7%]) were eligible. After surgical staging, upstaging was identified based on the presence of lymph node metastasis in 14 (3.1%) of 453 patients. No significant difference was found in the 5-year DFS (88.9% vs. 83.4%, p=0.203) and 5-year OS (97.2% vs. 97.7%, p=0.895) between the two groups. Using multivariable analysis, lymphadenectomy was not significantly associated with DFS or OS. However, using subgroup analysis, the lymphadenectomy group with serous histology had higher 5-year DFS rates than did the non-lymphadenectomy group (86.5% vs. 74.4%, p=0.048; adjusted hazard ratio=0.281; 95% confidence interval=0.107-0.735; p=0.010). The lymphadenectomy group had longer operating time (p<0.001), higher estimated blood loss (p<0.001), and higher perioperative complication rate (p=0.004) than did the non-lymphadenectomy group. CONCLUSION: In patients with clinically early-stage EOC with serous histology, lymphadenectomy was associated with survival benefits. Considering its potential harm, lymphadenectomy should be performed according to histologic subtype and subsequent chemotherapy in patients with clinically early-stage EOC. TRIAL REGISTRATION: Clinical Research Information Service Identifier: KCT0007309.

Effects of Extracellular Calcium Concentration on Hepatic Ischemia-Reperfusion Injury in a Rat Model.

OBJECTIVES: Hypocalcemia is frequently identified during liver transplant. However, supplementation of extracellular calcium could induce increased intracellular calcium concentration, as a potential factor for injury to the liver graft. We evaluated the effects of regulating extracellular calcium concentrations on hepatic ischemia-reperfusion injury. MATERIALS AND METHODS: We randomly divided 24 Sprague-Dawley rats into 3 groups: group C received normal saline (n = 8), group L received citrate to induce hypocalcemia (n = 8), and group L-Co received citrate followed by calcium gluconate to ameliorate hypocalcemia (n = 8). Liver enzyme levels and extracellular calcium were measured before surgery, 1 hour after ischemia, and 2 hours after reperfusion. The primary outcome was liver enzyme levels measured 2 hours after reperfusion. In addition, we evaluated intracellular calcium levels, lactate dehydrogenase activity, and histopathological results in liver tissue. RESULTS: Three groups demonstrated significant differences in extracellular calcium concentrations, but intracellular calcium concentrations in liver tissue were not significantly different. Group L showed significantly lower mean arterial pressure than other groups at 1 hour after ischemia (93.6 ± 20.8 vs 69.4 ± 14.2 vs 86.6 ± 10.4 mmHg; P = .02, for group C vs L vs L-Co, respectively). At 2 hours after reperfusion, group L showed significantly higher liver enzymes than other groups (aspartate aminotransferase 443.0 ± 353.2 vs 952.3 ± 94.8 vs 502.4 ± 327.3 U/L, P = .01; and alanine aminotransferase 407.9 ± 406.5 vs 860.6 ± 210.9 vs 333.9 ± 304.2 U/L, P = .02; for group C vs L vs L-Co, respectively). However, no significant difference was shown in lactate dehydrogenase and histological liver injury grade. CONCLUSIONS: Administering calcium to rats with hypocalcemia did not increase intracellular calcium accumulation but instead resulted in less hepatic injury compared with rats with low extracellular calcium concentrations in this rat model study.

Evaluation of stability and safety of equine mesenchymal stem cells derived from amniotic fluid for clinical application.

Amniotic fluid mesenchymal stem cells (AF-MSCs), which can be obtained from fetal tissue, reportedly have self-renewal capacity and multi-lineage differentiation potential. The aim of this study was to identify the biological characteristics of AF-MSCs and evaluate their stability and safety in long-term culture. To confirm the biological characteristics of AF-MSCs, morphology, proliferation capacity, karyotype, differentiation capacity, gene expression level, and immunophenotype were analyzed after isolating AF-MSCs from equine amniotic fluid. AF-MSCs were differentiated into adipocytes, chondrocytes, and osteocytes. Immunophenotype analyses revealed expression levels of ≥95% and ≤ 2% of cells for a positive and negative marker, respectively. Analysis of the MSCs relative gene expression levels of AF-MSCs was approximately at least twice that of the control. The endotoxin level was measured to verify the safety of AF-MSCs and was found to be less than the standard value of 0.5 EU/ml. AF-MSCs were cultured for a long time without any evidence of abnormalities in morphology, proliferation ability, and karyotype. These results suggest that amniotic fluid is a competent source for acquiring equine MSCs and that it is valuable as a cell therapy due to its high stability.

Discovery of a Novel Potent EGFR Inhibitor Against EGFR Activating Mutations and On-Target Resistance in NSCLC.

PURPOSE: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) serve as the standard first-line therapy for EGFR-mutated non-small cell lung cancer (NSCLC). Despite the sustained clinical benefits achieved through optimal EGFR-TKI treatments, including the third-generation EGFR-TKI osimertinib, resistance inevitably develops. Currently, there are no targeted therapeutic options available postprogression on osimertinib. Here, we assessed the preclinical efficacy of BI-4732, a novel fourth-generation EGFR-TKI, using patient-derived preclinical models reflecting various clinical scenarios. EXPERIMENTAL DESIGN: The antitumor activity of BI-4732 was evaluated using Ba/F3 cells and patient-derived cell/organoid/xenograft models with diverse EGFR mutations. Intracranial antitumor activity of BI-4732 was evaluated in a brain-metastasis mouse model. RESULTS: We demonstrated the remarkable antitumor efficacy of BI-4732 as a single agent in various patient-derived models with EGFR_C797S-mediated osimertinib resistance. Moreover, BI-4732 exhibited activity comparable to osimertinib in inhibiting EGFR-activating (E19del and L858R) and T790M mutations. In a combination treatment strategy with osimertinib, BI-4732 exhibited a synergistic effect at significantly lower concentrations than those used in monotherapy. Importantly, BI-4732 displayed potent antitumor activity in an intracranial model, with low efflux at the blood-brain barrier. CONCLUSIONS: Our findings highlight the potential of BI-4732, a selective EGFR-TKI with high blood-brain barrier penetration, targeting a broad range of EGFR mutations, including C797S, warranting clinical development.

Systemic immune-inflammation index as a predictor of early stroke progression/recurrence in acute atherosclerotic ischemic stroke.

OBJECTIVES: Although the systemic immune-inflammatory index (SII) has recently been correlated with stroke severity and functional outcome, the underlying pathogenesis remains largely unknown. The objective of this study was to explore whether SII could predict early neurologic deterioration (END) in different etiologies of acute ischemic stroke. MATERIALS AND METHODS: From January 2019 to December 2021, a total of 697 consecutive patients with acute ischemic stroke, admitted within 72 hours from stroke onset, were prospectively enrolled. The patients were categorized into 4 groups based on quartiles of SII, calculated as platelets multiplied by neutrophils divided by lymphocytes. END and stroke progression/recurrence were assessed during the first 7 days after stroke onset using predetermined definitions. Logistic regression analysis was conducted to evaluate the association between SII and END, while considering the variation in association across stroke etiologies. RESULTS: END occurred in 135 patients: 24 (3.4%) for Group I, 25 (3.6%) for Group II, 33 (4.7%) for Group III, and 53 (7.6%) for Group IV. Among the END subtypes, stroke progression/recurrence stroke was the most prevalent. In the logistic regression model, the adjusted odds ratios (ORs) of END and stroke progression/recurrence for group IV were 2.51 (95% CI, 1.27-4.95) and 1.98 (95% CI, 1.03-3.89), respectively. Among the stroke etiologies, group IV showed a significant increase in END (OR 4.24; 95% CI, 1.42-12.64) and stroke progression/recurrence (OR 4.13; 95% CI, 1.39-12.27) specifically in case of large artery atherosclerosis. CONCLUSIONS: SII independently predicts early stroke progression/recurrence in patients with acute atherosclerotic ischemic stroke.

Clinical Characteristics and Relevance of Dizziness in Patients with de novo Parkinson's Disease.

BACKGROUND: The purpose of this study was to determine the detailed characteristics of dizziness in patients with de novo Parkinson's disease (PD) and the clinical implications of dizziness. METHODS: Ninety-three people with de novo PD were enrolled between July 2017 and August 2022 for this retrospective study. Using each representative scale, various motor and non-motor symptoms were assessed. In addition, clinical manifestations of dizziness in those patients, including its presence, type, frequency, and duration of occurrence, were investigated. RESULTS: Thirty-nine patients with de novo PD reported dizziness, with presyncope being the most common (38%). The most common frequency was several times a week (51%). The most common duration was a few seconds (67%). Multivariable logistic regression analysis showed that dizziness was more common in women than in men {odds ratio (OR): 3.3601, 95% confidence interval (CI): 1.0820-10.4351, p = 0.0361}. Dizziness was significantly related to non-motor symptoms of low global cognition (OR: 0.8372, 95% CI: 0.7285-0.9622, p = 0.0123) and severe autonomic dysfunction (OR: 1.1112, 95% CI: 1.0297-1.1991, p = 0.0067). A post-hoc analysis revealed that dizziness was only associated with cardiovascular dysautonomia (adjusted OR: 10.2377, 95% CI: 3.3053-31.7098, p < 0.0001) among several domains of dysautonomia. CONCLUSIONS: About 42% of patients with de novo PD complained of dizziness. The occurrence of dizziness in those people was highly associated with female gender women, cognitive impairment, and cardiovascular dysautonomia. These results suggest that clinicians should pay close attention when patients with PD complain of dizziness.

Successful expansion and cryopreservation of human natural killer cell line NK-92 for clinical manufacturing.

Natural killer (NK) cells have recently shown renewed promise as therapeutic cells for use in treating hematologic cancer indications. Despite this promise, NK cell manufacturing workflows remain largely manual, open, and disconnected, and depend on feeders, as well as outdated unit operations or processes, often utilizing research-grade reagents. Successful scale-up of NK cells critically depends on the availability and performance of nutrient-rich expansion media and cryopreservation conditions that are conducive to high cell viability and recovery post-thaw. In this paper we used Cytiva hardware and media to expand the NK92 cell line in a model process that is suitable for GMP and clinical manufacturing of NK cells. We tested a range of cryopreservation factors including cooling rate, a range of DMSO-containing and DMSO-free cryoprotectants, ice nucleation, and cell density. Higher post-thaw recovery was seen in cryobags over cryovials cooled in identical conditions, and cooling rates of 1°C/min or 2°C/min optimal for cryopreservation in DMSO-containing and DMSO-free cryoprotectants respectively. Higher cell densities of 5x107 cells/ml gave higher post-thaw viability than those cryopreserved at either 1x106 or 5x106 cells/ml. This enabled us to automate, close and connect unit operations within the workflow while demonstrating superior expansion and cryopreservation of NK92 cells. Cellular outputs and performance were conducive to clinical dosing regimens, serving as a proof-of-concept for future clinical and commercial manufacturing.

Association Between Baseline Gait Parameters and Future Fall Risk in Patients With De Novo Parkinson's Disease: Forward Versus Backward Gait.

BACKGROUND AND PURPOSE: Falls are not uncommon even in patients with early stages of Parkinson's disease (PD). The aims of this study were to determine the relationships between gait parameters and falls and identify crucial gait parameters for predicting future falls in patients with de novo PD. METHODS: We prospectively recruited patients with de novo PD, and evaluated their baseline demographics, global cognitive function on the Montreal Cognitive Assessment test, and parkinsonian motor symptoms including their subtypes. Both forward gait (FG) and backward gait (BG) were measured using the GAITRite system. The history of falls in consecutive patients with de novo PD was examined along with 1 year of follow-up data. RESULTS: Among the 76 patients with de novo PD finally included in the study, 16 (21.1%) were classified as fallers. Fallers had slower gait and shorter stride for FG and BG parameters than did non-fallers, while stride-time variability was greater in fallers but only for BG. Multivariable logistic regression analysis revealed that slow gait was an independent risk factor in BG. CONCLUSIONS: Among the patients with de novo PD, gait speed and stride length were more impaired for both FG and BG in fallers than in non-fallers. It was particularly notable that slow BG was significantly associated with future fall risk, indicating that BG speed is a potential biomarker for predicting future falls in patients with early-stage PD.

Uncovering the colorectal cancer immunotherapeutic potential: Evening primrose (Oenothera biennis) root extract and its active compound oenothein B targeting the PD-1/PD-L1 blockade.

BACKGROUND: The emergence of immune checkpoint inhibitors, a novel class of immunotherapy drugs, represents a major breakthrough in cancer immunotherapy, substantially improving patient survival post-treatment. Blocking programmed death-ligand 1 (PD-L1) and programmed death protein-1 (PD-1) has demonstrated promising clinical results in various human cancer types. The US FDA has recently permitted only monoclonal antibody (mAb)-based PD-L1 or PD-1 blockers. Although these antibodies exhibit high antitumor efficacy, their size- and affinity-induced side effects limit their applicability. PURPOSE: As small-molecule-based PD-1/PD-L1 blockers capable of reducing the side effects of antibody therapies are needed, this study focuses on exploring natural ingredient-based small molecules that can target hPD-L1/PD-1 using herbal medicines and their components. METHODS: The antitumor potential of evening primrose (Oenothera biennis) root extract (EPRE), a globally utilized traditional herbal medicine, folk remedy, and functional food, was explored. A coculture system was established using human PD-L1-expressed murine MC38 cells (hPD-L1-MC38s) and CD8+ tumor-infiltrating T lymphocytes (CD8+ TILs) expressing humanized PD-1. The in vivo experiments utilized a colorectal cancer (CRC) C57BL/6 J mouse model bearing MC38 cells expressing humanized PD-L1 and PD-1 proteins. RESULTS: EPRE and its active compound oenothein B effectively hindered the molecular interaction between hPD-L1 and hPD-1. EPRE stimulated tumor-specific T lymphocytes of a hPD-L1/PD-1 CRC mice. This action resulted in the elevated infiltration of cytotoxic CD8+T lymphocytes and subsequent tumor growth reduction. Moreover, the combined therapy of oenothein B, a PD-1/PD-L1 blocker, and FOLFOX (5-fluorouracil plus oxaliplatin) cooperatively suppressed hPD-L1-MC38s growth in the ex vivo model through activated CD8+ TIL antitumor immune response. Oenothein B exhibited a high binding affinity for hPD-L1 and hPD-1. We believe that this study is the first to uncover the inhibitory effects of EPRE and its component, oenothein B, on PD-1/PD-L1 interactions. CONCLUSION: This study identified a promising small-molecule candidate from natural products that blocks the hPD-L1/PD-1 signaling pathway. These findings emphasize the potential of EPRE and oenothein B as effective anticancer drugs.

Comparison of the diagnostic performance of the Swischuk line method and the anterior atlantodental interval method in atlantodental subluxation.

BACKGROUND: Atlantodental subluxation (ADS) is a serious condition that can result in sudden death. Measuring the anterior atlantodental interval (AADI method) is the gold standard for diagnosis but the complex anatomy of this region can make diagnosis difficult, especially for beginners. Therefore, we would like to use a simpler method, the Swischuk line method, to diagnose ADS. The purpose of our study was to evaluate the diagnostic performance of the Swischuk line method for ADS on lateral cervical spine radiographs compared to the AADI method. METHODS: A retrospective study was conducted with patients who presented with ADS (ADS group, n = 32, mean age 57.78 years, age range 34-82 years, 10 men, 21 women) and an age- and sex-matched control group (n = 32). The diagnostic performance of the AADI method and the Swischuk line method for ADS was assessed using lateral cervical radiographs in both flexion and neutral postures by an experienced musculoskeletal radiologist (reader 1), a senior resident (reader 2), and a junior resident (reader 3) in the radiologic department. RESULTS: In the flexion posture, the AADI method and the Swischuk line method showed excellent diagnostic performance with AUCs > 0.9 for readers 1 2 and reader 3. In a neutral posture, the diagnostic performance of the AADI and Swischuk line methods was decreased. With a 1 mm cut-off value using the Swischuk line method in flexion posture, the sensitivity was 75% or more, the specificity was 100%, and the accuracy was 87.50% or more 90.63% for all readers. With a 2 mm cut-off value, the sensitivity was low (37.50-46.88%) but the specificity was 100% for all three readers. In a neutral posture, the sensitivity for both methods decreased, though specificity remained high (> 80%). CONCLUSIONS: The Swischuk line method was found to be reliable and showed high sensitivity and specificity with a cut-off value of 1 mm for the diagnosis of ADS in cervical lateral radiographs in flexion posture. It can be used as a complement to the AADI method.

Viral vector-mediated transgene delivery with novel recombinase systems for targeting neuronal populations defined by multiple features.

A comprehensive understanding of neuronal diversity and connectivity is essential for understanding the anatomical and cellular mechanisms that underlie functional contributions. With the advent of single-cell analysis, growing information regarding molecular profiles leads to the identification of more heterogeneous cell types. Therefore, the need for additional orthogonal recombinase systems is increasingly apparent, as heterogeneous tissues can be further partitioned into increasing numbers of specific cell types defined by multiple features. Critically, new recombinase systems should work together with pre-existing systems without cross-reactivity in vivo. Here, we introduce novel site-specific recombinase systems based on ΦC31 bacteriophage recombinase for labeling multiple cell types simultaneously and a novel viral strategy for versatile and robust intersectional expression of any transgene. Together, our system will help researchers specifically target different cell types with multiple features in the same animal.

Non-intrusive quality appraisal of differentiation-induced cardiovascular stem cells using E-Nose sensor technology.

Stem cell technology holds immense potential for revolutionizing medicine, particularly in regenerative treatment for heart disease. The unique capacity of stem cells to differentiate into diverse cell types offers promise in repairing damaged tissues and implanting organs. Ensuring the quality of differentiated cells, essential for specific functions, demands in-depth analysis. However, this process consumes time and incurs substantial costs while invasive methods may alter stem cell features during differentiation and deplete cell numbers. To address these challenges, we propose a non-invasive strategy, using cellular respiration, to assess the quality of differentiation-induced stem cells, notably cardiovascular stem cells. This evaluation employs an electronic nose (E-Nose) and neural pattern separation (NPS). Our goal is to assess differentiation-induced cardiac stem cells (DICs) quality through E-Nose data analysis and compare it with standard commercial human cells (SCHCs). Sensitivity and specificity were evaluated by interacting SCHCs and DICs with the E-Nose, achieving over 90% classification accuracy. Employing selective combinations optimized by NPS, E-Nose successfully classified all six cell types. Consequently, the relative similarity among DICs like cardiomyocytes, endothelial cells with SCHCs was established relied on comparing response data from the E-Nose sensor without resorting to complex evaluations.

Lugol's Solution Reduces Positive Margins and Residual Disease After the Large Loop Excision of Transformation Zone.

OBJECTIVE: This study aimed to examine whether the intraoperative use of Lugol's solution reduces the proportion of positive resection margins (RMs) using the data of women who underwent large loop excision of the transformation zone (LLETZ). MATERIALS AND METHODS: A total of 1,751 consecutive women with cervical intraepithelial neoplasia (CIN) who underwent LLETZ with or without Lugol's solution were retrospectively retrieved from each database of 3 university hospitals in South Korea. Outcomes included positive RMs and residual disease pathologically confirmed within 6 months after LLETZ. RESULTS: Positive RMs were noted in 345 cases (19.7%). Among 1,507 women followed up, residual disease was diagnosed in 100 cases (6.6%) (69/308 cases with positive RMs; 31/1,199 cases with negative RMs). The Lugol's solution group was less likely to have positive RMs (11.8% vs 25.5%, p < .01), to require additional surgical intervention (5.4% vs 10.2%, p < .01), and to have residual disease (4.9% vs 8.0%, p = .02). On multiple logistic regression analysis, Lugol's solution reduced the proportion of positive RMs (adjusted odds ratio [aOR], 0.31). Age (50 years or older; aOR, 1.64), preconization cervical cytology (aOR, 1.53), high-risk human papillomavirus (aOR, 1.75), and CIN 2 or 3 (aOR, 2.65) were independent risk factors for margin positivity ( p < .01 for all except high-risk human papillomavirus of p = .05). CONCLUSIONS: Lugol's solution optimizes CIN treatment by reducing the proportion of positive RMs and residual disease after LLETZ.

Influence of choroidal microvasculature dropout on progressive retinal nerve fibre layer thinning in primary open-angle glaucoma: comparison of parapapillary ß-zones and γ-zones.

BACKGROUND/AIMS: To compare the influence of choroidal microvasculature dropout (cMvD) on progressive retinal nerve fibre layer (RNFL) thinning in glaucomatous eyes with parapapillary ß-zones and γ-zones. METHODS: 294 eyes with primary open-angle glaucoma (POAG) and parapapillary atrophy (PPA) underwent optical coherence tomography (OCT) to determine the type of PPA and OCT angiography scanning of the optic nerve head to determine the presence of cMvD. Eyes were classified based on the type of PPA (ß-zones and γ-zones), and their clinical characteristics were compared. Factors associated with the rate of rapid progressive RNFL thinning were determined in each group, including the presence of cMvD as an independent variable. RESULTS: Of the 294 eyes, 186 and 108 were classified as having ß-zones and γ-zones, respectively. The rate of RNFL thinning was slower (p<0.001), axial length was longer (p<0.001) and presence of cMvD was less frequent (57.4% vs 73.1%, p=0.006) in eyes with γ-zone than those with ß-zone. Multivariate analyses showed that greater lamina cribrosa curvature (p=0.047) and the presence of cMvD (p=0.010) were associated with a faster rate of RNFL thinning in eyes with ß-zone, whereas larger intraocular pressure fluctuation (p<0.001), shorter axial length (p=0.042) and greater baseline RNFL thickness (p<0.001) were associated with a faster rate of RNFL thinning in eyes with γ-zone. CONCLUSIONS: The presence of cMvD was significantly associated with a faster rate of RNFL thinning in POAG eyes with ß-zone, but not γ-zone. The pathogenic consequences of cMvD in POAG eyes may depend on accompanying peripapillary structures.

Effect and Safety of Diluted Vasopressin Injection for Bleeding Control During Robot-assisted Laparoscopic Myomectomy in Reproductive Women With Uterine Fibroids: A Randomized Controlled Pilot Trial (VALENTINE Trial).

BACKGROUND/AIM: Vasopressin injected during myomectomy is known to effectively reduce bleeding but is sometimes associated with intraoperative vasoconstriction and hypertension due to systemic absorption. Although there is a growing preference for the use of diluted vasopressin, evidence of its effect and safety is still lacking. PATIENTS AND METHODS: We performed a randomized controlled pilot trial to evaluate the effect and safety of vasopressin diluted in a constant volume during robot-assisted laparoscopic myomectomy (RALM), where a total of 39 women with uterine fibroids were randomly assigned into the following three groups (group 1, 0.2 IU/ml; group 2, 0.1 IU/ml; group 3, 0.05 IU/ml with a total of 100 ml of normal saline). The primary endpoint was to compare estimated blood loss (EBL), and the secondary endpoints were to compare postoperative value and drop ratio of hemoglobin, operation time, transfusion, hospitalization, and complications among the three groups. RESULTS: There were no differences in the number and largest size of uterine fibroids, total weight of uterine fibroids, console time, and volumes of intravenous fluid administered during RALM among the three groups, whereas combined operation was performed more commonly in group 2 than in groups 1 and 3 (53.9% vs. 0 to 7.7%; p=0.01). The primary and secondary endpoints were also not different among the three groups. However, two patients in group 1 (15.4%) showed vasopressin-related hypertension. CONCLUSION: Vasopressin diluted in a volume of 100 ml showed an effective hemostatic effect and safety during RALM (Trial No. NCT04874246 in ClinicalTrial.gov).

GV1001 modulates neuroinflammation and improves memory and behavior through the activation of gonadotropin-releasing hormone receptors in a triple transgenic Alzheimer's disease mouse model.

GV1001 protects neural cells from amyloid-ß (Aß) toxicity and other stressors in in vitro studies and demonstrates clinically beneficial effects in patients with moderate to severe Alzheimer's disease (AD). Here, we investigated the protective effects and mechanism of action of GV1001 in triple transgenic AD (3xTg-AD) mice. We found that GV1001 improved memory and cognition in middle- and old-aged 3xTg-AD mice. Additionally, it reduced Aß oligomer and phospho-tau (Ser202 and Thr205) levels in the brain, and mitigated neuroinflammation by promoting a neuroprotective microglial and astrocyte phenotype while diminishing the neurotoxic ones. In vitro, GV1001 bound to gonadotropin releasing hormone receptors (GnRHRs) with high affinity. Levels of cyclic adenosine monophosphate, a direct downstream effector of activated GnRHRs, increased after GV1001 treatment. Furthermore, inhibition of GnRHRs blocked GV1001-induced effects. Thus, GV1001 might improve cognitive and memory functions of 3xTg-AD mice by suppressing neuroinflammation and reducing Aß oligomers levels and phospho-tau by activating GnRHRs and their downstream signaling pathways.

Comparative RNA-Seq Analysis Revealed Tissue-Specific Splicing Variations during the Generation of the PDX Model.

Tissue-specific gene expression generates fundamental differences in the function of each tissue and affects the characteristics of the tumors that are created as a result. However, it is unclear how much the tissue specificity is conserved during grafting of the primary tumor into an immune-compromised mouse model. Here, we performed a comparative RNA-seq analysis of four different primary-patient derived xenograft (PDX) tumors. The analysis revealed a conserved RNA biotype distribution of primary-PDX pairs, as revealed by previous works. Interestingly, we detected significant changes in the splicing pattern of PDX, which was mainly comprised of skipped exons. This was confirmed by splicing variant-specific RT-PCR analysis. On the other hand, the correlation analysis for the tissue-specific genes indicated overall strong positive correlations between the primary and PDX tumor pairs, with the exception of gastric cancer cases, which showed an inverse correlation. These data propose a tissue-specific change in splicing events during PDX formation as a variable factor that affects primary-PDX integrity.