Antibody-mediated blockade for galectin-3 binding protein in tumor secretome abrogates PDAC metastasis.

The major challenges in pancreatic ductal adenocarcinoma (PDAC) management are local or distant metastasis and limited targeted therapeutics to prevent it. To identify a druggable target in tumor secretome and to explore its therapeutic intervention, we performed a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomic analysis of tumors obtained from a patient-derived xenograft model of PDAC. Galectin-3 binding protein (Gal-3BP) is identified as a highly secreted protein, and its overexpression is further validated in multiple PDAC tumors and primary cells. Knockdown and exogenous treatment of Gal-3BP showed that it is required for PDAC cell proliferation, migration, and invasion. Mechanistically, we revealed that Gal-3BP enhances galectin-3-mediated epidermal growth factor receptor signaling, leading to increased cMyc and epithelial-mesenchymal transition. To explore the clinical impact of these findings, two antibody clones were developed, and they profoundly abrogated the metastasis of PDAC cells in vivo. Altogether, our data demonstrate that Gal-3BP is an important therapeutic target in PDAC, and we propose its blockade by antibody as a therapeutic option for suppressing PDAC metastasis.

Spatial transcriptomic brain imaging reveals the effects of immunomodulation therapy on specific regional brain cells in a mouse dementia model.

Increasing evidence of brain-immune crosstalk raises expectations for the efficacy of novel immunotherapies in Alzheimer's disease (AD), but the lack of methods to examine brain tissues makes it difficult to evaluate therapeutics. Here, we investigated the changes in spatial transcriptomic signatures and brain cell types using the 10x Genomics Visium platform in immune-modulated AD models after various treatments. To proceed with an analysis suitable for barcode-based spatial transcriptomics, we first organized a workflow for segmentation of neuroanatomical regions, establishment of appropriate gene combinations, and comprehensive review of altered brain cell signatures. Ultimately, we investigated spatial transcriptomic changes following administration of immunomodulators, NK cell supplements and an anti-CD4 antibody, which ameliorated behavior impairment, and designated brain cells and regions showing probable associations with behavior changes. We provided the customized analytic pipeline into an application named STquantool. Thus, we anticipate that our approach can help researchers interpret the real action of drug candidates by simultaneously investigating the dynamics of all transcripts for the development of novel AD therapeutics.

Influence of Oxygen Vacancies Introduced via Acceptor (Gadolinium) Doping to the Pseudocapacitive Properties of Nano-Sized Cerium Oxide.

The voluntary introduction of defects can be considered an effective strategy for enhancing the electrochemical properties of metal oxide electrodes. In this study, the enhanced pseudocapacitive properties of an acceptor (Gd) doped cerium oxide nanoparticle-a sustainable metal oxide with low environmental and human toxicity-are investigated in depth using ex situ X-ray photoemission spectroscopy (XPS) and electrochemical impedance spectroscopy (EIS). Interestingly, with 15 at% Gd doping (15GDC), the specific capacitance of the nanoparticles measured at 1 A g-1 enhanced to 547.8 F g-1, which is fivefold higher than undoped CeO2 (98.7 F g-1 at 1 A g-1). The rate-dependent capacitance is also improved for 15GDC, which showed a 31.0% decrease in the specific capacitance upon a tenfold increase in the current density, while CeO2 showed a 49.9% decrease. The enhanced electrochemical properties are studied in depth via ex situ XPS and EIS analysis, which revealed that the oxygen vacancies at the surface of the nanoparticles played important roles in enhancing both the specific capacitance and the high-rate performance of 15GDC by acting as the active site for pseudocapacitive redox reaction and allowing fast diffusion of oxygen ions at the surface of 15GDC nanoparticles.

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.

Current updates relating to treatment for interstitial cystitis/bladder pain syndrome: systematic review and network meta-analysis.

BACKGROUND: Despite the publication of several meta-analyses regarding the efficacy of certain therapies in helping individuals with interstitial cystitis (IC) / bladder pain syndrome (BPS), these have not provided a comprehensive review of therapeutic strategies. The study aimed to determine the efficacy of various therapies for IC/BPS and identify potential moderating factors using randomized controlled trials (RCTs). METHODS: We queried the PubMed, Cochrane, and Embase databases to identify prospective RCTs using inclusion criteria: 1) patients diagnosed with IC, 2) interventions included relevant treatments, 3) comparisons were a specified control or placebo, 4) outcomes were mean differences for individual symptoms and structured questionnaires. The pairwise meta-analysis and network meta-analysis (NMA) were performed to compare the treatments used in IC/BPS. Hedges' g standardized mean differences (SMDs) were used for improvement in all outcomes using random-effects models. Efficacy outcomes included individual symptoms such as pain, frequency, urgency, and nocturia, as well as structured questionnaires measuring IC/BPS symptoms. RESULTS: A comprehensive literature search was conducted which identified 70 RCTs with 3,651 patients. The analysis revealed that certain treatments, such as instillation and intravesical injection, showed statistically significant improvements in pain and urgency compared to control or placebo groups in traditional pairwise meta-analysis. However, no specific treatment demonstrated significant improvement in all outcomes measured in the NMA. The results of moderator analyses to explore influential variables indicated that increasing age was associated with increased nocturia, while longer follow-up periods were associated with decreased frequency. CONCLUSION: This systematic review and meta-analysis provide insights into the efficacy of various treatments for IC. Current research suggests that a combination of therapies may have a positive clinical outcome for patients with IC, despite the fact that treatment for this condition is not straightforward. TRIAL REGISTRATION: PROSPERO CRD42022384024.

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.

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.

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.

Development of a Normal Porcine Cell Line Growing in a Heme-Supplemented, Serum-Free Condition for Cultured Meat.

A key element for the cost-effective development of cultured meat is a cell line culturable in serum-free conditions to reduce production costs. Heme supplementation in cultured meat mimics the original meat flavor and color. This study introduced a bacterial extract generated from Corynebacterium that was selected for high-heme expression by directed evolution. A normal porcine cell line, PK15, was used to apply the bacterial heme extract as a supplement. Consistent with prior research, we observed the cytotoxicity of PK15 to the heme extract at 10 mM or higher. However, after long-term exposure, PK15 adapted to tolerate up to 40 mM of heme. An RNA-seq analysis of these heme-adapted PK15 cells (PK15H) revealed a set of altered genes, mainly involved in cell proliferation, metabolism, and inflammation. We found that cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1), lactoperoxidase (LPO), and glutathione peroxidase 5 (GPX5) were upregulated in the PK15H heme dose dependently. When we reduced serum serially from 2% to serum free, we derived the PK15H subpopulation that was transiently maintained with 5-10 mM heme extract. Altogether, our study reports a porcine cell culturable in high-heme media that can be maintained in serum-free conditions and proposes a marker gene that plays a critical role in this adaptation process.

Utility of accelerated T2-weighted turbo spin-echo imaging with deep learning reconstruction in female pelvic MRI: a multi-reader study.

OBJECTIVES: To determine the clinical feasibility of T2-weighted turbo spin-echo (T2-TSE) imaging with deep learning reconstruction (DLR) in female pelvic MRI compared with conventional T2 TSE in terms of image quality and scan time. METHODS: Between May 2021 and September 2021, 52 women (mean age, 44 years ± 12) who underwent 3-T pelvic MRI with additional T2-TSE using a DLR algorithm were included in this single-center prospective study with patient's informed consents. Conventional, DLR, and DLR T2-TSE images with reduced scan times were independently assessed and compared by four radiologists. The overall image quality, differentiation of anatomic details, lesion conspicuity, and artifacts were evaluated using a 5-point scale. Inter-observer agreement of the qualitative scores was compared and reader protocol preferences were then evaluated. RESULTS: In the qualitative analysis of all readers, fast DLR T2-TSE showed significantly better overall image quality, differentiation of anatomic regions, lesion conspicuity, and lesser artifacts than conventional T2-TSE and DLR T2-TSE, despite approximately 50% reduction in scan time (all p < 0.05). The inter-reader agreement for the qualitative analysis was moderate to good. All readers preferred DLR over conventional T2-TSE regardless of scan time and preferred fast DLR T2-TSE (57.7-78.8%), except for one who preferred DLR over fast DLR T2-TSE (53.8% vs. 46.1%). CONCLUSION: In female pelvic MRI, image quality and accelerated image acquisition for T2-TSE can be significantly improved by using DLR compared to conventional T2-TSE. Fast DLR T2-TSE was non-inferior to DLR T2-TSE in terms of reader preference and image quality. CLINICAL RELEVANCE STATEMENT: DLR of T2-TSE in female pelvic MRI enables fast imaging along with maintaining optimal image quality compared with parallel imaging-based conventional T2-TSE. KEY POINTS: • Conventional T2 turbo spin-echo based on parallel imaging has limitations for accelerated image acquisition while maintaining good image quality. • Deep learning image reconstruction showed better image quality in both images obtained using the same or accelerated image acquisition parameters compared with conventional T2 turbo spin-echo in female pelvic MRI. • Deep learning image reconstruction enables accelerated image acquisition while maintaining good image quality in the T2-TSE of female pelvic MRI.