bluuebunny/crossref_metadata_2025 huggingface dataset:
Effectiveness of IVIG on Non–Length-Dependent Skin Biopsies in Small Fiber Neuropathy With Plexin D1, Trisulfated Heparin Disaccharide, and Fibroblast Growth Factor Receptor 3 Autoantibodies
Authors: Zeidman Lawrence A.
Published: May 2024

Objectives:

To demonstrate treatment efficacy on composite and non–length-dependent (NLD) punch biopsy specimens from intravenous immunoglobulin (IVIG) in pure small-fiber neuropathy (SFN) with trisulfated heparin disaccharide (TS-HDS), fibroblast growth factor-3 (FGFR-3), or Plexin D1 antibodies. SFN has an increasing prevalence, and over 30% of cases may be immune-mediated. TS-HDS, FGFR-3, and Plexin D1 autoantibodies have been shown to be present in 44%–55% of cryptogenic SFN cases, suggesting an immune mechanism. Reports have shown IVIG to be effective for this condition, but some controversy exists based on length-dependent (LD) post-IVIG treatment data in a recent trial.

Methods:

In a retrospective review, all pure SFN cases tested for the 3 antibodies from January 2021 to May 2022 were tabulated, and patients who underwent IVIG treatment were separated and analyzed for changes in epidermal nerve fiber density (ENFD) on skin biopsy, as well as SFN-specific questionnaire and pain scores.

Results:

Ninety-one patients with pure SFN had antibody testing. Sixty of these (66%) were seropositive, and 31 (34%) were seronegative. Seventeen seropositive patients (13 female patients, 4 male patients, 6 FGFR-3, 2 TS-HDS, 4 Plexin D1, 2 with all 3 antibodies, 1 with FGFR-3 and Plexin D1, 1 with FGFR-3 and TS-HDS, and 1 with TS-HDS and Plexin D1) underwent IVIG treatment. Of these, 2 patients stopped treatment due to side effects, and the remaining 15 completed at least 6 months of IVIG. Of these, 12 had a post-IVIG skin biopsy, and of these, 11 (92%) had a 55.1% improved mean composite ENFD (P = 0.01). NLD-ENFD specimens improved by 42.3% (P = 0.02), and LD-ENFD specimens improved by 99.7% (P = 0.01). Composite ENFD in Plexin D1-SFN patients improved by 139% (P = 0.04). In addition, 14 patients had questionnaires pre-IVIG/post-IVIG, and average pain decreased by 2.7 (P = 0.002).

Conclusions:

IVIG shows disease-modifying effect in immune SFN with novel antibodies, especially Plexin D1-SFN, as well as significantly improved pain. NLD-ENFD should be examined as well as LD-ENFD to see this effect. Further randomized controlled trials looking at NLD-ENFD as well as LD-ENFD improvement, along with pain and SFN-specific questionnaires, are needed to confirm these findings.
Survival outcomes of radium-223 therapy for metastatic castration-resistant prostate cancer following national health insurance reimbursement in Taiwan
Authors: Yao Shan-Fan , Huang William J. , Wei Tzu-Chun , Wang Yuh-Feng , Lin Ko-Han , Hu Lien-Hsin , Ting Chien-Hsin , Lee Tse-Hao , Yeh Skye Hsin-Hsien , Peng Nan-Jing
Published: May 2024

Background:

Radium-223 dichloride (Ra-223) prolongs overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) with symptomatic bone metastases. However, there is considerable variation in outcomes among individuals. We aimed to evaluate the prognostic determinants associated with patient survival following National Health Insurance (NHI) reimbursement for Ra-223 therapy in Taiwan.

Methods:

Patients with mCRPC who underwent Ra-223 treatment at Taipei Veterans General Hospital were retrospectively enrolled. Each intravenous Ra-223 dose was administered at 55 kBq/kg at 4-week intervals. Clinical outcomes were obtained from medical records; potential prognostic factors for survival were assessed. Kaplan-Meier analysis was used to generate cumulative survival curves; between-group differences were evaluated using the Chi-squared test. Statistical significance was set at p < 0.05.

Results:

Seventy-six patients underwent Ra-223 therapy; 62 patients received NHI reimbursement and the remainder self-paid. Fifty patients (65.8%) completed six cycles of treatment; 26 (34.2%) received 1 to 5 cycles. Mortality occurred in 47 patients. Factors significantly associated with survival included ≤five bone metastases (p = 0.0018), baseline prostate-specific antigen (PSA) ≤36 ng/mL (p = 0.0004), baseline alkaline phosphate (ALP) <115 U/L (p = 0.0007), and baseline hemoglobin (Hb) >12 g/dL (p = 0.0029). Patients who completed six cycles of treatment achieved significantly higher OS compared to those who did not (p < 0.0001). There has been a 4.4-fold increase in the number of patients since reimbursement began; there was no significant difference in OS between patients who received NHI reimbursement and those who self-paid.

Conclusion:

Administration of Ra-223 demonstrates considerable potential to extend the survival of patients with mCRPC. Survival outcomes may be influenced by various prognostic factors. However, no significant difference in OS was observed subsequent to reimbursement of Ra-223 therapy for mCRPC through the NHI system in Taiwan.
Diagnostic ability of macular nerve fiber layer thickness measured by swept-source optical coherence tomography in preperimetric glaucoma
Authors: Yeh Shih-Jung , Su Yi-Wen , Chen Mei-Ju
Published: May 2024

Background:

We evaluated the diagnostic ability of macula retinal nerve fiber layer (mRNFL) thickness in preperimetric glaucoma (PPG) patients.

Methods:

This prospective study included 83 patients with PPG and 83 age- and refractive error-matched normal control subjects. PPG was defined as a localized RNFL defect corresponding to glaucomatous optic disc changes with a normal visual field test. We used spectral-domain (SD) optical coherence tomography (OCT) to measure the circumpapillary RNFL (cpRNFL) thickness and macular ganglion cell-inner plexiform layer (GCIPL) thickness. Swept-source (SS) OCT was used to measure cpRNFL thickness, macular ganglion cell layer + inner plexiform layer (IPL) thickness (GCL+), and macular ganglion cell layer + IPL+ mRNFL thickness (GCL++). The mRNFL thickness was defined as GCL++ minus GCL+. To evaluate the diagnostic power of each parameter, the area under the receiver operating characteristics curve (AUROC) was analyzed to differentiate PPG from the normal groups.

Results:

Using SD-OCT, all GCIPL parameters and most cpRNFL parameters, except at the nasal and temporal quadrant, were significantly lower in PPG versus normal controls. PPG eyes had significantly smaller values than normal controls for all cpRNFL and GCL parameters measured by SS-OCT, except mRNFL at the superonasal area. The inferotemporal GCL++ had the largest AUROC value (0.904), followed by inferotemporal GCL+ (0.882), inferotemporal GCIPL thickness (0.871), inferior GCL++ (0.866), inferior cpRNFL thickness by SS-OCT (0.846), inferior cpRNFL thickness by SD-OCT (0.841), and inferotemporal mRNFL thickness (0.840). The diagnostic performance was comparable between inferotemporal mRNFL thickness and the best measures of GCL (inferotemporal GCL++, p = 0.098) and cpRNFL (inferior cpRNFL thickness by SS-OCT, p = 0.546).

Conclusion:

The diagnostic ability of mRNFL thickness was comparable to that of the best measures of cpRNFL and GCL analysis for eyes with PPG. Therefore, mRNFL thickness could be a new parameter to detect early structural changes in PPG.
People-Oriented Culture and Its Association With Burnout, Depressive Symptoms, and Sleep Problems During COVID-19 Pandemic Among EMS Providers in Korea
Authors: Kim Ji-Hwan , Yoon Jaehong , Kim Soo Jin , Kim Ja Young , Kim Seung-Sup
Published: May 2024

Objective

This study examined how perceived people-oriented culture (POC) was associated with burnout, depressive symptoms, and sleep problems during the COVID-19 pandemic among emergency medical service (EMS) providers in Korea.

Methods

We conducted a cross-sectional survey among 693 EMS providers in 2021.

Results

Overall, prevalence of personal burnout, work-related burnout, and citizen-related burnout were 61.5%, 60.0%, and 60.6%, respectively. Prevalence of depressive symptoms was 25.1%. Prevalence of poor sleep quality, unrestful sleep, and sleep disturbance were 46.5%, 58.2%, and 52.2%, respectively. Compared to high POC group, higher prevalence of depressive symptoms was observed among medium (prevalence ratio: 1.57, 95% CI: 1.06, 2.32) and low (prevalence ratio: 2.70, 95% CI: 1.92, 3.79) POC group. Similar trends were observed in the analysis of burnout and sleep problems.

Conclusions

Our findings underscore that low POC could play a critical role in worsening burnout, depressive symptoms, and sleep problems among EMS providers.
Anatomical Analysis of the Eustachian Tube in the Temporal Bone Through the Middle Fossa Window
Authors: Talas Derya Ümit , Güven Onurhan , Taghipour Pourya , Acar Funda , Beger Orhan , Işık Ecenur , Bal Kemal Koray , Yeşilova Mesut , Vayısoğlu Yusuf
Published: May 2024

Purpose

This cadaveric anatomical study aimed to explore precise morphometric measurements of the eustachian tube (ET) and adjacent structures in the middle cranial fossa, focusing on identifying reliable surgical landmarks when traditional markers are compromised due to tumors or trauma.

Methods

Twenty-two temporal bones from 11 adult cadavers (mean age: 75.70 ± 13.75 yr, range: 40–90 yr; sex: 5 females and 6 males) were dissected bilaterally. Surgical tools, including an operation microscope, endoscope, and digital caliper, were used for meticulous measurements. Parameters such as ET dimensions, distances between key points, and relevant angles were quantified, ensuring precise anatomical data.

Results

ET width at the foramen spinosum (FS) level, the midline level, and the eustachian orifice level were measured as 2.18 ± 0.68, 2.42 ± 0.70, and 2.30 ± 0.74 mm, respectively. The distances from the zygomatic root (ZR) to FS, ET, superior semicircular canal (SSC), and internal carotid artery (ICA) were 29.61 ± 2.56, 23.28 ± 2.61, 26.53 ± 2.56, and 32.61 ± 3.69 mm, respectively. The angles between SSC-ZR-ICA and FS-ZR-ICA were measured as 36.57 ± 10.32 and 13.63 ± 3.72 degrees, respectively. No statistical difference was found between right–left or male–female measurements (p > 0.05).

Conclusion

The present study offers invaluable insights for neurotological surgeons performing middle fossa approaches. ET and ZR may serve as crucial reference points, enhancing surgical orientation and minimizing risks during complex procedures. These precise anatomical data may empower surgeons, ensuring safer and more confident middle cranial fossa operations, even in challenging clinical scenarios.
Prediction of Cochlear Implant Fitting by Machine Learning Techniques
Authors: Koyama Hajime , Kashio Akinori , Yamasoba Tatsuya
Published: May 2024

Objective

This study aimed to evaluate the differences in electrically evoked compound action potential (ECAP) thresholds and postoperative mapping current (T) levels between electrode types after cochlear implantation, the correlation between ECAP thresholds and T levels, and the performance of machine learning techniques in predicting postoperative T levels.

Study Design

Retrospective case review.

Setting

Tertiary hospital.

Patients

We reviewed the charts of 124 ears of children with severe-to-profound hearing loss who had undergone cochlear implantation.

Interventions

We compared ECAP thresholds and T levels from different electrodes, calculated correlations between ECAP thresholds and T levels, and created five prediction models of T levels at switch-on and 6 months after surgery.

Main Outcome Measures

The accuracy of prediction in postoperative mapping current (T) levels.

Results

The ECAP thresholds of the slim modiolar electrodes were significantly lower than those of the straight electrodes on the apical side. However, there was no significant difference in the neural response telemetry thresholds between the two electrodes on the basal side. Lasso regression achieved the most accurate prediction of T levels at switch-on, and the random forest algorithm achieved the most accurate prediction of T levels 6 months after surgery in this dataset.

Conclusion

Machine learning techniques could be useful for accurately predicting postoperative T levels after cochlear implantation in children.
Cochlear Implant Outcomes in Patients With TMTC2-Associated Sensorineural Hearing Loss and Auditory Neuropathy/Auditory Dys-Synchrony
Authors: North Lauren , Olivier Michael , Runge Christina L.
Published: May 2024

Objective

To investigate the outcomes of cochlear implantation in patients with TMTC2-associated sensorineural hearing loss and auditory neuropathy/auditory dys-synchrony.

Patients

Adult and pediatric cochlear implant (CI) patients followed in an academic center who tested positive for TMTC2 genetic variant rs35725509.

Intervention

Cochlear implantation.

Main Outcome Measures

Speech perception scores in quiet.

Results

Ten CI patients were identified with TMTC2 variant rs35725509 out of 157 patients who underwent genetic testing (i.e., 6.3% of patients tested). All demonstrated progressive, bilateral hearing loss with severe-to-profound audiometric thresholds preoperatively. Pre-CI and 1-year post-CI speech recognition percent correct scores were compared. Post-CI speech perception (mean 61.0%, standard deviation 31.4%) was significantly higher than pre-CI speech perception (mean 21.0%, standard deviation 27.0%) (p = 0.002). Individually, 9 of the 10 subjects experienced significant improvements in speech perception pre- to post-CI (p < 0.05). Electrically evoked compound action potential measures were available for five patients, and all showed normal electrically evoked compound action potential thresholds.

Conclusion

Patients with TMTC2-associated sensorineural hearing loss and auditory neuropathy/auditory dys-synchrony have significantly improved speech perception outcomes with cochlear implantation and should be considered candidates for this intervention if there are no other contraindications.
Features of Ugly but Capable Women of Ancient China
Authors: Jung Sung Gyun , Hwang Kun , Hwang Young Joong
Published: May 2024

The aim of this study was to analyze the appearance of women viewed as “ugly but capable” in ancient China. A Google search was conducted for the “Four Great Ugly Women.” Information on 3 women was collected from Lienüzhuana, a collection of biographies of eminent women compiled by the Former Han period. With the addition of 1 (Huang Yueying), 7 “ugly but capable” women were analyzed. The manifestations of their ugliness in the texts were recorded. Among the 7 women, 5 exhibited physical manifestations, whereas the remaining 2 were simply described as “ugly” without specific characteristics. Among the discernible body characteristics of the 5 women deemed unattractive, the most common feature was dark skin (80%), followed by body shape (60%). Other frequently observed traits included sparse or yellow hair, an upturned or overly large nose, a convex forehead, and an unattractive neck (each at 40%), with the latter potentially exhibiting a protruding Adam’s apple, a thick neck, or a neck mass. Less common features were sunken eyes, a large head, and a masculine skeleton, each occurring in 20% of cases. Based on the depiction of women considered unattractive, the authors can infer that dark skin, a fat body, a large or upturned nose, sparse hair, a protruding forehead, a thick neck, deep-set eyes, and a large head were elements associated with ugliness. Through the description of the ugly woman, authors can infer the standards of ugliness in ancient China.
Extracellular Vesicle - MDM2-DNA as a Potential Liquid Biopsy Biomarker for Disease Identification in Retroperitoneal Liposarcoma
Authors: Calore Federica , Casadei Lucia , Sarchet Patricia D. , Fadda Paolo , Nigita Giovanni , Coombes Kevin R. , Cascione Luciano , Costas C. de Faria Fernanda , Tahara Sayumi , Iwenofu O Hans , Pollock Raphael E. , Grignol Valerie P.
Published: May 2024

Objective:

We aimed to assess the levels of MDM2-DNA within extracellular vesicles (EVs) isolated from the serum of retroperitoneal liposarcoma (RLS) patients versus healthy donors, as well as within the same patients at the time of surgery versus post-operative surveillance visits. To determine whether EV-MDM2 may serve as a possible first-ever biomarker of liposarcoma recurrence.

Background:

A hallmark of well-differentiated and de-differentiated (WD/DD) retroperitoneal liposarcoma is elevated MDM2 due to genome amplification, with recurrence rates of >50% even after complete resection. Imaging technologies frequently cannot resolve recurrent WD/DD-RLS versus postoperative scarring. Early detection of recurrent lesions, for which biomarkers are lacking, would guide surveillance and treatment decisions.

Methods:

WD/DD-RLS serum samples were collected both at the time of surgery and during follow-up visits from 42 patients, along with sera from healthy donors (n=14). EVs were isolated, DNA purified and MDM2-DNA levels determined through q-PCR analysis. Non-parametric tests were employed to compare EV-MDM2 DNA levels from patients versus control group, as well as the time of surgery versus post-surgery conditions.

Results:

EV-MDM2 levels were significantly higher in WD/DD-RLS than controls (P= 0.00085). Moreover, EV-MDM2 levels were remarkably decreased in WD/DD-RLS patients after resection (P=0.00036), reaching values comparable to control group (P=0.124). During post-operative surveillance, significant increases of EV-MDM2 was observed in some patients, correlating with CT scan evidence of recurrent or persistent post-resection disease.

Conclusions:

Serum EV-MDM2 may serve as a potential biomarker of early recurrent or post-operatively persistent WD/DD-RLS, a disease currently lacking such determinants.
Outcomes of Visceral Arterial Interposition Graft Reconstruction for Locally Advanced Pancreatic Cancer
Authors: Yonkus Jennifer A. , Alva-Ruiz Roberto , Colglazier Jill J. , Kendrick Michael L. , Kalra Manju , Rasmussen Todd E. , Demartino Randall D. , Bower Thomas C. , Truty Mark J. , Mendes Bernardo C.
Published: May 2024

Objective:

The aim of this study is to determine perioperative outcomes and the patency of interposition conduits for visceral arterial reconstruction in this setting.

Summary Background Data:

Visceral arterial encasement in locally advanced pancreatic cancer was historically a contraindication for surgery. With modern effective neoadjuvant strategies, our recent experience has made advanced vascular resection and reconstruction feasible in selected patients.

Methods:

A retrospective review was performed of patients undergoing pancreatic tumor resection with en bloc arterial resection and interposition revascularization between 6/2002-10/2022. Endpoints included graft patency, vascular-related complications, reinterventions, morbidity, and mortality.

Results:

Visceral arterial reconstruction with interposition grafting was performed in 111 patients undergoing en bloc arterial resections for pancreatic cancer. Graft types included autologous arterial conduits (n=66, 58 superficial femoral artery (SFA) and 8 splenic artery), cryopreserved arterial allografts (n=24), autologous saphenous veins (n=12), synthetic conduits (n=8), and composite autologous artery and synthetic (n=1). Perioperative 90-day mortality decreased significantly over time to 5% in the last six years. Vascular complications related to arterial reconstruction occurred in 11% (n=12) and included pseudoaneurysm (n=6), graft thrombus (n=2), stenosis requiring reintervention (n=2), hepatic failure (n=1), and hepatic and intestinal ischemia (n=1). Nine (8%) patients underwent vascular-related reinterventions. After median follow-up of 17-months, primary patency was 81% for the entire cohort and was highest in the SFA group (95%). The donor limb/harvest site complication rate was 8% with 100% primary patency.

Conclusion:

Visceral arterial resection with interposition reconstruction for locally advanced pancreatic cancer can be performed with acceptable vascular morbidity and durable patency. Autologous SFA was the most suitable conduit for reconstructions in our experience, with highest primary patency.
Percent Thrombus Predicts Popliteal Artery Aneurysm Related Limb Threatening Events
Authors: Bellomo Tiffany R. , Goudot Guillaume , Lella Srihari K. , Gaston Brandon , Sumetsky Natalie , Patel Shiv , Zacharias Nikolaos , Dua Anahita
Published: May 2024

Objective:

The objective of this study was to identify clinical and anatomic characteristics of Popliteal artery aneurysms (PAAs) associated with acutely limb threatening events.

Summary Background Data:

Popliteal artery aneurysms (PAAs) are associated with high morbidity and mortality. Current guidelines recommend operative repair for PAAs with a diameter greater than 20 mm based on very limited evidence.

Methods:

This retrospective cross-sectional cohort was derived from a multi-institutional database queried for all patients with a PAA from 2008 to 2022. Duplex ultrasound (DUS) characteristics of PAAs were abstracted by registered physicians in vascular interpretation. Symptom status at the time of DUS was divided into three categories: asymptomatic PAA, symptomatic PAA with claudication or chronic limb ischemia, and acutely limb threatening PAAs with a thromboembolic event, acute limb ischemia, or rupture.

Results:

There were 470 PAAs identified in 331 patients. The mean age was 74 years at diagnosis, 94% of patients were white, and 97% of patients were male. In a univariate analysis, patient comorbidities and medications were not associated with symptom status. In a multivariate analysis including age, higher percent thrombus was significantly associated with symptomatic PAAs (RRR 15.2; CI 2.69-72.3; P<0.01) and PAAs with an acutely limb threatening event (RRR 17.9; CI 3.76-85.0; P<0.01). All other anatomic characteristics were not associated with symptom status.

Conclusion:

Percent thrombus was significantly associated with symptomatic PAAs and acutely limb threatening events, whereas diameter was not significantly associated with any symptom group. This analysis supports the use of percent thrombus in identifying high risk PAAs that warrant repair.
Infectious bronchitis virus: an overview of the “chicken coronavirus”
Authors: Falchieri Marco , Coward Vivien J. , Reid Scott M. , Lewis Tom , Banyard Ashley C.
Published: May 2024

Graphical Abstract

IBV transmission pathway and viral electron microscopy image. The virus can spread between commercial farm either directly or indirectly through fomites, personnel or wild birds.
Effects of storage temperature on quality characteristics of texturized vegetable protein
Authors: Lee Seul , Jung Sun Young , Seo Mi Sook , Park Chan Soon
Published: May 2024

This study evaluated the impact of storage temperature on the quality characteristics of texturized vegetable protein (TVP). TVP was prepared by mixing defatted Daewon soybean flour at 80°C, gluten, and corn starch in a 5:3:2 ratio, which was then extruded at a screw speed of 250 rpm and a barrel temperature of 190°C with moisture addition at 9 rpm. Subsequently, the extruded TVP was vacuum-sealed in polyethylene packaging and stored at −20°C, 0°C, and 4°C for 9 days. Texture analysis revealed that the curing rate followed 4°C > 0°C > −20°C sequence. No significant color variation was observed across the storage conditions, although water content increased at all temperatures. Notable changes were detected in moisture absorption capacity (%) and solid leaching (%), following the order of −20°C > 0°C > 4°C. The turbidity of the solution released during cooking varied, with the highest to the lowest sequence being −20°C > 4°C > 0°C, while pH levels remained neutral. Regarding free amino acids, sweetness and textural quality improved with storage across all temperatures, whereas bitterness components diminished at 4°C. The study suggests that refrigerated storage at 4°C is a viable method for distributing TVP, which was previously distributed only in a frozen and dry state.
Quality comparison of non-thermal sterilized raw apple vinegar and commercial apple vinegar products
Authors: Kim Sun Hwa , Seo Ji-Hyung , Jeong Yong-Jin
Published: May 2024

A nonthermally sterilized raw apple vinegar was manufactured using an ultra-fine filtration process (0.2 μm membrane filter) and its quality was comparable to commercially available vinegar products. First, using apple concentrate as a raw material, it was possible to produce non-thermal sterilized Using a two-stage fermentation process of alcohol and acetic acid fermentations, a non-thermally sterilized raw apple vinegar with pH 2.94 and an acidity of 6.20% was produced from an apple concentrate. The fermentation process increased the browning index significantly. However, the fundamental quality parameters of the non-thermal sterilized raw apple vinegar (A) with sterilized apple vinegar (B) did not differ significantly. The pH (2.92-2.95) of apple vinegar (A and B) was higher than that (pH 2.65-2.70) of commercial vinegar (C and D), and the total acidity, which is in the range of 6.20-6.21% and 6.53-6.90%, respectively, was higher in samples C and D than in samples A and B. However, four kinds of organic acids were detected in non-thermal sterilized raw apple vinegar (A), and its total organic acid content (6,245.00 mg%) was significantly higher than that of other samples (B, C, D) (p<0.05). In particular, malic acid content, as a main organic acid in apples, was very high in sample (A) (244.83 mg%) and sample (B) (210.21 mg%), compared to commercial products C (125.78 mg%) and D (86.90 mg%). The total polyphenol content and antioxidant activity of fermented apple vinegar (A, B) were more than twice as high as those of commercial products (C, D). Vinegar A had higher total polyphenol content than vinegar B. The above results suggest it is possible to manufacture and commercialize non-thermal sterilized raw apple vinegar with higher organic acid content and antioxidant properties using ultra-fine filtration.
Anti-inflammatory effect in macrophages according to the mixing
ratio of acemannan and aloesin
Authors: Kim Hyo-Min , Kim Jeong-Hwan , Yoo Dan-Hee , Jeon Se-Yeong , Kim Hyun-Jin , Do Seon-Gil , Lee In-Chul , Kang Jung-Wook
Published: May 2024

This study aims to confirm the anti-inflammatory activities of acemannan and
aloesin, which have been studied for various efficacies at various mixed sample
ratios. The mixed samples were mixed at a ratio of 1:1 (AA-1), 1:2 (AA-2), 1:3
(AA-3), 2:1 (AA-4), and 3:1 (AA-5). Seven samples were evaluated for their
cytotoxic ability on macrophages, and the results showed that all cell viability
was over 90% at a concentration of 100 μg/mL. First, due to the NO
production inhibitory activity, a better inhibitory effect was achieved when
using a mixed sample rather than a single material. Afterward, the activity of
inhibiting the production of PGE2, TNF-α, and IL-6 was
confirmed using a mixed sample. It was confirmed that AA-2 had the best
inhibitory activity on producing PGE2, TNF-α, and IL-6 rather
than AA-1, AA-3, AA-4, and AA-5. For this reason, experiments were conducted
using AA-2 to determine the protein expression levels of iNOS and COX-2, which
are inflammation-related proteins. It was confirmed that AA-2 inhibited iNOS and
COX-2 protein expression by 25.01% and 27.27%, respectively,
compared to the LPS-alone treatment group. In conclusion, the mixed sample of
acemannan and aloesin is judged to have anti-inflammatory activity and can
potentially to be used as a functional material.
iSeq: An integrated tool to fetch public sequencing data
Authors: Chao Haoyu , Li Zhuojin , Chen Dijun , Chen Ming
Published: May 2024

High-throughput sequencing technologies (Next Generation Sequencing; NGS) are increasingly utilized by researchers to tackle a diverse array of biological inquiries. Leveraging the remarkable scale and efficiency of modern sequencing, significant advancements are made across various fields, spanning from genome analysis to the intricate dynamics of protein-nucleic acid interactions. Recognizing that NGS data harbors rich biological information, the International Nucleotide Sequence Database Collaboration (INSDC) was established nearly 40 years ago to collect and disseminate public nucleotide sequence data and associated metadata. The National Genomics Data Center (NGDC) has also provided open access to vast amounts of raw sequence data. These databases have greatly enhanced the capacity for reanalyzing NGS data. In recent years, amid the rise of large language models, biological sequences and data have emerged as inputs for training models to address biological challenges. However, methods for programmatically accessing this public sequencing data remain limited. To address this gap, we have developed iSeq, an integrated tool that allows for quick and straightforward retrieval of metadata and NGS data via the command-line interface. iSeq is currently the only tool that supports simultaneous retrieval from multiple databases (GSA, SRA, ENA, DDBJ, and GEO). Additionally, iSeq supports a wide range of accession formats as input and features parallel downloads, multi-threaded processes, and FASTQ file merging. It is freely available on Bioconda (https://anaconda.org/bioconda/iseq) and GitHub (https://github.com/BioOmics/iSeq).

Highlights

iSeq supports multiple databases for accessing a wide range of raw sequencing data and metadata.

iSeq supports at least 25 different accession formats as input.

iSeq supports parallel downloads, multi-threaded processes, FASTQ file merging, and integrity verification.
Overcoming Hemophilia A Gene Therapy Limitations with an Enhanced Function Factor VIII Variant
Authors: Sternberg Anna R. , Martos-Rus Cristina , Davidson Robert , Liu Xueyuan , George Lindsey
Published: May 2024

Durable factor VIII (FVIII) expression that normalizes hemostasis is an unrealized goal of hemophilia A adeno-associated virus (AAV)-mediated gene therapy. Trials with initial normal FVIII activity observed unexplained year-over-year declines in expression while others reported low-level, stable FVIII expression inadequate to restore normal hemostasis. Here we demonstrate that mice recapitulate FVIII expression-level-dependent loss of plasma FVIII levels due to declines in vector copy number. We show that an enhanced function FVIII variant (FVIII-R336Q/R562Q; FVIII-QQ), resistant to inactivation by protein C, normalizes hemostasis at below-normal expression levels without evidence of prothrombotic risk in hemophilia A mice. These data support that FVIII-QQ may restore normal FVIII function at low-levels of expression to permit durability using low AAV vector doses to minimize dose-dependent AAV toxicities. This work informs the mechanism of FVIII durability after AAV gene transfer and supports that incorporating the FVIII-QQ transgene may safely overcome current hemophilia A gene therapy limitations.
Targeting mitochondrial metabolism with CPI-613 in chemoresistant ovarian tumors
Authors: Udumula Mary P , Rashid Faraz , Singh Harshit , Pardee Tim , Luther Sanjeev , Bhardwaj Tanya , Anjaly Km , Piloni Sofia , Hijaz Miriana , Gogoi Radhika , Philip Philip A , Munkarah Adnan R , Giri Shailendra , Rattan Ramandeep
Published: May 2024

Background

There is evidence indicating that chemoresistance in tumor cells is mediated by the reconfiguration of the tricarboxylic acid cycle, leading to heightened mitochondrial activity and oxidative phosphorylation (OXPHOS). Previously, we have shown that ovarian cancer cells that are resistant to chemotherapy display increased OXPHOS, mitochondrial function, and metabolic flexibility. To exploit this weakness in chemoresistant ovarian cancer cells, we examined the effectiveness of the mitochondrial inhibitor CPI-613 in treating preclinical ovarian cancer.

Methods

Chemosensitive OVCAR3, and chemoresistant CAOV3 and F2 ovarian cancer cells lines and their xenografts in nude mice were used. Functional metabolic studies were performed using Seahorse instrument. Metabolite quantification was performed using LC/MS/MS.

Results

Mice treated with CPI-613 exhibited a notable increase in overall survival and a reduction in tumor development and burden in OVCAR3, F2, and CAOV3 xenografts. CPI-613 suppressed the activity of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase complex, which are two of its targets. This led to a reduction in OXPHOS and tricarboxylic acid cycle activity in all 3 xenografts. The addition of CPI-613 enhanced the responsiveness of chemotherapy in the chemoresistant F2 and CAOV3 tumors, resulting in a notable improvement in survival rates and a reduction in tumor size as compared to using chemotherapy alone. CPI-613 reduced the chemotherapy-induced OXPHOS in chemoresistant tumors. The study revealed that the mechanism by which CPI-613 inhibits tumor growth is through mitochondrial collapse. This is evidenced by an increase in superoxide production within the mitochondria, a decrease in ATP generation, and the release of cytochrome C, which triggers mitochondria-induced apoptosis. Our study demonstrates the translational potential of CPI-613 against chemoresistant ovarian tumors.
Spatial Transcriptomics Reveals Spatially Diverse Cancer-Associated Fibroblast in Lung Squamous Cell Carcinoma Linked to Tumor Progression
Authors: Choi Hongyoon , Na Kwon Joong , Jung Yeonjae , Lim Myunghyun , Lee Dongjoo , Lee Jae Eun , Im Hyung-Jun , Lee Daeseung , Koh Jaemoon , Kim Young Tae
Published: May 2024

While cancer-associated fibroblasts (CAFs) are crucial in influencing tumor growth and immune responses in lung cancer, we still lack a comprehensive understanding of their spatial organization associated with tumor progression and clinical outcomes. This gap highlights the need to elucidate how the intricate spatial arrangement of CAFs affects their interactions within the tumor microenvironment, ultimately shaping cancer progression and patient prognosis. Here, we unveil the spatial diversity of CAFs in lung squamous cell carcinoma (LUSC), a prevalent and aggressive lung cancer type, elucidating their impact on tumor progression and patient outcomes using spatial transcriptomics (ST). Image-based ST data from 33 LUSC patients demonstrated a significant association of spatial interactions of tumor epithelium and CAFs with tumor size and metabolic activity measured by [18F]fluorodeoxyglucose PET. Furthermore, the proximity of fibroblasts to tumor epithelial cells was linked to recurrence-free survival in LUSC patients. By characterizing CAFs based on their spatial relationship, we identified distinct molecular signatures related to spatially distinct fibroblast subpopulations. In addition, barcode-based ST data from 8 LUSC patients revealed spatially overlapping fibroblast regions characterized by upregulated glycolysis pathways. Our study underscores the importance of the complex spatial dynamics of the tumor microenvironment revealed by ST and its implications for patient outcomes in LUSC.
FoodAtlas: Automated Knowledge Extraction of Food and Chemicals from Literature
Authors: Youn Jason , Li Fangzhou , Simmons Gabriel , Kim Shanghyeon , Tagkopoulos Ilias
Published: May 2024

Automated generation of knowledge graphs that accurately capture published information can help with knowledge organization and access, which have the potential to accelerate discovery and innovation. Here, we present an integrated pipeline to construct a large-scale knowledge graph using large language models in an active learning setting. We apply our pipeline to the association of raw food, ingredients, and chemicals, a domain that lacks such knowledge resources. By using an iterative active learning approach of 4,120 manually curated premise-hypothesis pairs as training data for ten consecutive cycles, the entailment model extracted 230,848 food-chemical composition relationships from 155,260 scientific papers, with 106,082 (46.0%) of them never been reported in any published database. To augment the knowledge incorporated in the knowledge graph, we further incorporated information from 5 external databases and ontology sources. We then applied a link prediction model to identify putative food-chemical relationships that were not part of the constructed knowledge graph. Validation of the 443 hypotheses generated by the link prediction model resulted in 355 new food-chemical relationships, while results show that the model score correlates well (R2= 0.70) with the probability of a novel finding. This work demonstrates how automated learning from literature at scale can accelerate discovery and support practical applications through reproducible, evidence-based capture of latent interactions of diverse entities, such as food and chemicals.
iLipidome: enhancing statistical power and interpretability using hidden biosynthetic interdependencies in the lipidome
Authors: Lin Wen-Jen , Chiang Austin W.T. , Zhou Evanston H. , Liang Chenguang , Liu Chia-Hsin , Ma Wen-Lung , Cheng Wei-Chung , Lewis Nathan E.
Published: May 2024

Numerous biological processes and diseases are influenced by lipid composition. Advances in lipidomics are elucidating their roles, but analyzing and interpreting lipidomics data at the systems level remain challenging. To address this, we present iLipidome, a method for analyzing lipidomics data in the context of the lipid biosynthetic network, thus accounting for the interdependence of measured lipids. iLipidome enhances statistical power, enables reliable clustering and lipid enrichment analysis, and links lipidomic changes to their genetic origins. We applied iLipidome to investigate mechanisms driving changes in cellular lipidomes following supplementation of docosahexaenoic acid (DHA) and successfully identified the genetic causes of alterations. We further demonstrated how iLipidome can disclose enzyme-substrate specificity and pinpoint prospective glioblastoma therapeutic targets. Finally, iLipidome enabled us to explore underlying mechanisms of cardiovascular disease and could guide the discovery of early lipid biomarkers. Thus, iLipidome can assist researchers studying the essence of lipidomic data and advance the field of lipid biology.
Zinc finger transcription factorsBnaSTOP2sregulate sulfur metabolism and confer resistance toSclerotinia sclerotioruminBrassica napus
Authors: Dai Lihong , Xie Zhaoqi , Ai Tianxu , Jiao Yushun , Lian Xiaoyi , Long Angchen , Zhang Jinyun , Yang Guangsheng , Hong Dengfeng
Published: May 2024

Rapeseed (Brassica napusL.) has a high sulfur requirement for optimal growth, development, and pathogen resistance. In this study, we identified zinc finger transcription factors,BnaSTOP2s, that play key roles in sulfur metabolism andSclerotinia sclerotiorumresistance. First, our results suggested thatBnaSTOP2sare involved in sulfur as evidenced from extensive protein interaction screening. Knockout ofBnaSTOP2sreduced the response sensitivity in both sulfur-deficient and sulfur-excessive conditions by promoting the elongation of primary roots of seedlings. Furthermore, the content of essential sulfur-containing metabolites, including glucosinolate and glutathione, were substantially down-regulated in roots and leaves ofBnastop2mutants, which is consistent with the significantly lowered transcriptional levels of key players of GSL synthesis and transportation,BnaMYB28sandBnaGTR2s, respectively. Through comprehensive RNA-seq analysis, we revealed the substantial effect ofBnaSTOP2son sulfur metabolism from source to sink. Additionally, we observed a significant decrease while increase in leaf lesion sizes of theBnaSTOP2-OE andBnastop2mutants, respectively, when compared to the wild type duringSclerotinia sclerotioruminfection, suggesting the vital role ofBnaSTOP2in plant defense response. Overall, our findings highlight thatBnaSTOP2sseems to be global regulators of sulfur metabolism and confer resistance toSclerotinia sclerotioruminfection inB. napus.
Small but mitey: long-read assembly of a streamlined mite genome from contaminated host plant sequencing data
Authors: Chen Stephanie H , Jones Ashley , Lu-Irving Patricia , Yap Jia-Yee S , van der Merwe Marlien , Bragg Jason G , Edwards Richard J
Published: May 2024

Technological advances have propelled DNA sequencing of non-model organisms, making sequencing more accessible and cost effective, which has also increased the availability of raw data in public repositories. However, contamination is a significant concern, and the use and reuse of sequencing data requires quality control and curation. A reference genome for the Australian native rainforest treeRhodamnia argenteaBenth. (malletwood) was assembled from Oxford Nanopore Technologies (ONT) long-reads, 10x Genomics Chromium linked-reads, and Hi-C data (N50 = 32.3 Mbp and BUSCO completeness 98.0%) with 99.0% of the 347 Mbp assembly anchored to 11 chromosomes (2n= 22). TheR.argenteagenome will inform conservation efforts for Myrtaceae species threatened by the global spread of the fungal disease myrtle rust. We observed contamination in the sequencing data and further investigation revealed an arthropod source. Here, we demonstrate the feasibility of assembling a high-quality gapless telomere-to-telomere mite genome using contaminated host plant sequencing data. The mite exhibits genome streamlining and has a 35 Mbp genome (68.6% BUSCO completeness) on two chromosomes, capped with a novel TTTGG telomere sequence. Phylogenomic analysis suggests that it is a previously unsequenced eriophyoid mite. Despite its unknown identity, this complete nuclear genome provides a valuable resource to investigate invertebrate genome reduction. This study emphasises the importance of checking sequencing data for contamination, especially when working with non-model organisms. It also enhances our understanding of two species, including a tree that faces substantial conservation challenges, contributing to broader biodiversity initiatives.

Significance

The genomes ofRhodamnia argenteaand an associated eriophyoid mite, which contaminated the tree raw sequencing data, were assembled for the first time. We generated valuable chromosome-level genomic resources for the conservation of myrtle rust impacted tree species, pest genomics, and understanding genome streamlining. The research underscores the growing prevalence of sequencing experiments in non-model organisms while emphasising the importance of quality control and curation of sequencing data.
Protein Structure Inspired Drug Discovery
Authors: Qiao Fangfang , Binknowski T. Andrew , Broughan Irene , Chen Weining , Natarajan Amarnath , Schiltz Gary E. , Scheidt Karl A. , Anderson Wayne F. , Bergan Raymond
Published: May 2024

Drug discovery starts with known function, either of a compound or a protein, in-turn prompting investigations to probe 3D structure of the compound-protein interface. As protein structure determines function, we hypothesized that unique 3D structural motifs represent primary information denoting unique function that can drive discovery of novel agents. Using a physics-based protein structure analysis platform developed by us, designed to conduct computationally intensive analysis at supercomputing speeds, we probed a high-resolution protein x-ray crystallographic library developed by us. We selected 3D structural motifs whose function was not otherwise established, that offered environments supporting binding of drug-like chemicals and were present on proteins that were not established therapeutic targets. For each of eight potential binding pockets on six different proteins we accessed a 60 million compound library and used our analysis platform to evaluate binding. Using eight-day colony formation assays acquired compounds were screened for efficacy against human breast, prostate, colon and lung cancer cells and toxicity against human bone marrow stem cells. Compounds selectively inhibiting cancer growth segregated to two pockets on separate proteins. The compound, Dxr2-017, exhibited selective activity against human melanoma cells in the NCI-60 cell line screen, had an IC50 of 19 nM against human melanoma M14 cells in our eight-day assay, while over 2100-fold higher concentrations inhibited stem cells by less than 30%. We show that Dxr2-017 induces anoikis, a unique form of programmed cell death in need of targeted therapeutics. The predicted target protein for Dxr2-017 is expressed in bacteria, not in humans. This supports our strategy of focusing on unique 3D structural motifs. It is known that functionally important 3D structures are evolutionarily conserved. Here we demonstrate proof-of-concept that protein structure represents high value primary data to support discovery of novel therapeutics. This approach is widely applicable.

Author summary

We introduce the concept that protein 3D structure represents primary information which can support downstream investigations, in this instance leading to the discovery of novel anticancer therapeutics.
Direct detection of 8-oxo-dG using nanopore sequencing
Authors: Pagès-Gallego Marc , van Soest Daan M. K. , Besselink Nicolle J. M. , Straver Roy , Keijer Janneke P. , Vermeulen Carlo , Marcozzi Alessio , van Roosmalen Markus J. , van Boxtel Ruben , Burgering Boudewijn M. T. , Dansen Tobias B. , de Ridder Jeroen
Published: May 2024

Genomic DNA is constantly subjected to oxidative damage, which is thought to be one of the major drivers of cancer and age-dependent decline. The most prominent consequence is the modification of guanine into 8-hydroxyguanine (8-oxo-dG), which has important mutagenic potential and plays a role in methylation-mediated gene regulation. Methods to simultaneously detect and quantify 8-oxo-dG within its genomic context have been lacking; mainly because these methods rely on indirect detection or are based on hydrolysis of the DNA. Nanopore sequencing has been deployed for the direct detection of base-modifications like cytosine methylation during sequencing. However, currently there is no model to detect 8-oxo-dG by nanopore sequencing due to the lack of training data. Here, we developed a strategy based on synthetic oligos to create long DNA molecules with context variability for effective deep learning and nanopore sequencing. Moreover, we showcase a training approach suitable to deal with the extreme scarceness of 8-oxo-dG compared to canonical G to enable specific 8-oxo-dG detection. Applied to an inducible tissue culture system for oxidative DNA damage, our approach reveals variable 8-oxo-dG distribution across the genome, a dissimilar context pattern to C>A mutations, and concurrent 5-mC depletion within a 2-kilobase window surrounding 8-oxo-dG sites. These findings not only underscore the potential of nanopore sequencing in epigenetic research, but also shed light on 8-oxo-dG’s role in genomic regulation. By simultaneously measuring 5-mC and 8-oxo-dG at single molecule resolution, our study provides insights into the functional interplay between these DNA modifications. Moreover, our approach using synthetic oligos to generate a ground truth from machine learning modification calling could be applied to any other DNA modification. Overall, our work contributes to advancing the field of epigenetics and highlights nanopore sequencing as a powerful tool for studying DNA modifications.