bluuebunny/crossref_metadata_2025 huggingface dataset:
A versatile method to profile hepatitis B virus DNA integration
Authors: Fukano Kento , Wakae Kousho , Nao Naganori , Saito Masumichi , Tsubota Akihito , Toyoshima Takae , Aizaki Hideki , Iijima Hiroko , Matsudaira Takahiro , Kimura Moto , Watashi Koichi , Sugiura Wataru , Muramatsu Masamichi
Published: December 2023

Background:

HBV DNA integration into the host genome is frequently found in HBV-associated HCC tissues and is associated with hepatocarcinogenesis. Multiple detection methods, including hybrid capture-sequencing, have identified integration sites and provided clinical implications; however, each has advantages and disadvantages concerning sensitivity, cost, and throughput. Therefore, methods that can comprehensively and cost-effectively detect integration sites with high sensitivity are required. Here, we investigated the efficiency of RAISING (Rapid Amplification of Integration Site without Interference by Genomic DNA contamination) as a simple and inexpensive method to detect viral integration by amplifying HBV-integrated fragments using virus-specific primers covering the entire HBV genome.

Methods and Results:

Illumina sequencing of RAISING products from HCC-derived cell lines (PLC/PRF/5 and Hep3B cells) identified HBV-human junction sequences as well as their frequencies. The HBV-human junction profiles identified using RAISING were consistent with those determined using hybrid capture-sequencing, and the representative junctions could be validated by junction-specific nested PCR. The comparison of these detection methods revealed that RAISING-sequencing outperforms hybrid capture-sequencing in concentrating junction sequences. RAISING-sequencing was also demonstrated to determine the sites of de novo integration in HBV-infected HepG2-NTCP cells, primary human hepatocytes, liver-humanized mice, and clinical specimens. Furthermore, we made use of xenograft mice subcutaneously engrafted with PLC/PRF/5 or Hep3B cells, and HBV-human junctions determined by RAISING-sequencing were detectable in the plasma cell-free DNA using droplet digital PCR.

Conclusions:

RAISING successfully profiles HBV-human junction sequences with smaller amounts of sequencing data and at a lower cost than hybrid capture-sequencing. This method is expected to aid basic HBV integration and clinical diagnosis research.
A genetic variant in the CD40 gene is related to HBV infection in the Chinese Han population
Authors: Wu Wennan , Xu Siyi , Zeng Yongbin , Yu Luoli , Chen Tianbin , Shang Hongyan , Liu Can , Yang Bin , Ou Qishui
Published: December 2023

Background:

CD40 is an important immune costimulatory molecule that has recently been found to be associated with chronic hepatitis B. This study aims to explore the association between CD40 polymorphisms and HBV infection, as well as to investigate the impact of different rs1883832 genotypes on CD40 expression and its effect on the progression of chronic HBV infection.

Methods:

We genotyped rs1883832 in 3433 individuals using MassARRAY, and quantified the CD40 expression, including CD40 mRNA, sCD40, and mCD40. The CD40 and HBV infection indicators were assessed to investigate the potential function of rs1883832 in suppressing HBV replication in HepG2.2.15 and HepAD38, CD40L in cytotoxic t lymphocytes (CTLs) and interferon-γ, TNF-α, granzyme B, and perforin were measured to elucidate the mechanism by which CD40 inhibits HBV replication.

Results:

Our study revealed that the frequencies of CC genotype and C allele of rs1883832 were significantly higher in immune recovery compared to chronic hepatitis B. Individuals with CC genotype exhibited significantly elevated CD40 in serum and B cells compared to TT genotypes in chronic hepatitis B. Additionally, CD40 is capable of inhibiting HBV replication and transcription in hepatocytes by means of interaction with CD40L. A significant negative correlation was found between HBV DNA, HBeAg, and mCD40. Conversely, the expressions of ALT and mCD40 showed a positive correlation, which aligns with the trend of CD40L.

Conclusions:

rs1883832 C allele may have a protective role in HBV immune recovery. This protective effect could potentially be attributed to the regulation of CD40 expression. The activation of the anti-HBV immune response, which occurs through binding CD40L on CTL, can suppress HBV DNA replication and potentially facilitate immune recovery in HBV infection.
Atorvastatin for patients with cirrhosis. A randomized, placebo-controlled trial
Authors: Kronborg Thit M. , Schierwagen Robert , Trošt Kajetan , Gao Qian , Moritz Thomas , Bendtsen Flemming , Gantzel Rasmus H. , Andersen Mette L. , Teisner Ane S. , Grønbæk Henning , Hobolth Lise , Møller Søren , Trebicka Jonel , Kimer Nina
Published: December 2023

Background:

Patients with cirrhosis and portal hypertension face a high risk of complications. Besides their anti-inflammatory and antifibrotic effects, statins may reduce portal pressure and thus the risk of complications and mortality. We aimed to investigate the effects of atorvastatin on hospital admissions, mortality, inflammation, and lipidomics in cirrhosis with portal hypertension.

Methods:

We performed a double-blinded, randomized, placebo-controlled clinical trial among patients with cirrhosis and portal hypertension. Atorvastatin (10–20 mg/d) was administered for 6 months. We measured splanchnic hemodynamics, analyzed inflammatory markers, and performed lipidomics at baseline and after 6 months.

Results:

Seventy-eight patients were randomized, with 38 patients allocated to atorvastatin and 40 patients to placebo. Fifty-nine patients completed 6 months of intervention. Comparisons between changes in each group were calculated. Liver-related complications and mortality were similar between the groups. The HVPG and Model for End-stage Liver Disease score did not change between groups (p=0.95 and 0.87, respectively). Atorvastatin decreased 3 of 42 inflammatory markers, CD62-L-selectin, matrix metalloproteinases-2, and TNF-α (p-values: 0.005, 0.011, and 0.023, respectively), while lipidomics was not significantly changed.

Conclusions:

In patients with cirrhosis, atorvastatin was safe to use, but did not reduce mortality, the risk of liver-related complications, or the HVPG. Atorvastatin induced minor anti-inflammatory effects and minor effects on lipids during a 6-month treatment period.
Role and Value of the Corporate Medical Director
Authors: Stave Gregg M. , Burton Wayne N. , Heron Richard J.L. , Hudson T. Warner , Pawlecki J. Brent , Roomes David , Sepulveda Martin J. , Rendel Michael , Hymel Pamela A.
Published: December 2023

The role of the Corporate Medical Director (CMD) has received increased attention during the COVID-19 pandemic and has continued to evolve. This updated guidance addresses the role and value of the CMD in: health policy, strategy, and leadership; fostering a culture of health and well-being; supporting worker health and productivity/performance; addressing mental health; collaborating on employer benefits design; developing programs for global health, travel medicine, and remote/extreme environments; overseeing on- and near-site clinics; incorporating digital technology, artificial intelligence, and telehealth in health programs; supporting critical incident preparedness and business continuity planning; addressing workplace hazards; and overseeing periodic executive health examinations.
Is Oxytocin Administration During Childbirth Associated With Increased Risk for Postpartum Posttraumatic Stress Symptoms?
Authors: Tenne Yaara , Kahalon Rotem , Daari Laura , Preis Heidi , Eisner Michal , Chen Rony , Mor Pnina , Grisaru Granovsky Sorina , Samueloff Arnon , Benyamini Yael
Published: December 2023

Introduction:

Synthetic oxytocin is one of the most regularly administered medications to facilitate labor induction and augmentation. The present study examined the associations between oxytocin administration during childbirth and postpartum posttraumatic stress symptoms (PTSS).

Materials and Methods:

In a multicenter longitudinal study, women completed questionnaires during pregnancy and at 2 months postpartum (N = 386). PTSS were assessed with the Impact of Event Scale. Logistic regression was used to examine the difference in PTSS at Time 2 between women who received oxytocin and women who did not.

Results:

In comparison with women who did not receive oxytocin, women who received oxytocin induction were 3.20 times as likely to report substantial PTSS (P = .036, 95% confidence interval: 1.08-9.52), and women who received oxytocin augmentation were 3.29 times as likely to report substantial PTSS (P = .036, 95% confidence interval: 1.08-10.03), after controlling for being primiparous, preeclampsia, prior mental health diagnosis, mode of birth, postpartum hemorrhage, and satisfaction with staff.

Discussion:

Oxytocin administration was associated with a 3-fold increased risk of PTSS. The findings may reflect biological and psychological mechanisms related to postpartum mental health and call for future research to establish the causation of this relationship.
Racial Disparities in Surgical Outcomes after Mastectomy in 223,000 Female Breast Cancer Patients – A Retrospective Cohort Study
Authors: Knoedler Samuel , Kauke-Navarro Martin , Knoedler Leonard , Friedrich Sarah , Matar Dany Y. , Diatta Fortunay , Mookerjee Vikram G. , Ayyala Haripriya , Wu Mengfan , Kim Bong-Sung , Machens Hans-Guenther , Pomahac Bohdan , Orgill Dennis P. , Broer P. Niclas , Panayi Adriana C.
Published: December 2023

Background:

Breast cancer mortality and treatment differ across racial groups. It remains unclear whether such disparities are also reflected in perioperative outcomes of breast cancer patients undergoing mastectomy.

Study Design:

We reviewed the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database (2008-2021) to identify female patients who underwent mastectomy for oncological purposes. The outcomes were stratified by five racial groups (white, Black/African American, Asian, American Indian/Alaska Native, and Native Hawaiian/Pacific Islander) and included 30-day mortality, reoperation, readmission, surgical and medical complications, and non-home discharge.

Results:

The study population included 222,947 patients, 68% (n=151,522) of whom were white, 11% (n=23,987) Black/African American, 5% (n=11,217) Asian, 0.5% (n=1,198) American Indian/Alaska Native, and 0.5% (n=1,018) Native Hawaiian/Pacific Islander. While 136,690 (61%) patients underwent partial mastectomy, 54,490 (24%) and 31,767 (14%) women received simple and radical mastectomy, respectively. Overall, adverse events occurred in 17, 222 (7.7%) patients, the largest portion of which were surgical complications (n=7,246; 3.3%). Multivariable analysis revealed that being of Asian race was protective against perioperative complications (OR=0.71;P<0.001), whereas American Indian/Alaska Native women were most vulnerable to the complication occurrence (OR=1.41;P<0.001). Black/African American patients had a significantly lower risk of medical (OR=0.59;P<0.001) and surgical complications (OR=0.60;P<0.001) after partial and radical mastectomy, respectively, their likelihood of readmission (OR=1.14;P=0.045) following partial mastectomy was significantly increased.

Conclusion:

We identified American Indian/Alaska Native women as particularly vulnerable to complications following mastectomy. Asian patients experienced the lowest rate of complications in the perioperative period. Our analyses revealed comparable confounder-adjusted outcomes following partial and complete mastectomy between Black and white races. Our findings call for care equalization in the field of breast cancer surgery.
Carbon dioxide gas-induced pneumothorax versus one-lung ventilation in minimally invasive esophagectomy: a multicenter propensity score matching cohort study
Authors: Chen Junying , Heng Jiao , Zheng Bin , Zeng Taidui , Wang Hao , Wang Peizong , Lin Yaobin , Gao Wuyou , Chen Chun , Tan Lijie , Fu Jianhua
Published: December 2023

Background:

Carbon dioxide gas-induced pneumoperitoneum might be the reason for the shorter postoperative survival of patients with malignant tumors. Whether CO2 gas-induced pneumothorax has unfavorable impacts on the surgical and oncological outcomes of minimally invasive esophagectomy remains unclear.

Methods:

Between 2010 and 2016, a total of 998 patients with squamous cell carcinoma of the esophagus who received video-assisted surgery were registered from three large-volume medical centers. The overall survival (OS) and disease-free survival (DFS) were compared after using propensity score-matched and inverse probability-weighted methods. In addition, the tumor-relapse state was evaluated, and the relapse pattern was compared.

Results:

A total of 422 and 576 minimally invasive esophagectomies with intraoperative one-lung ventilation and CO2-induced pneumothorax were enrolled, respectively. The 5-year OS and DFS were similar between the CO2-induced pneumothorax (64.2% and 64.7%) and one-lung ventilation (65.3% and 62.4%) groups following propensity matching. The inverse probability weighting revealed similarly equal survival results in the two groups. The 5-year relapse rates were 35.1% and 30.6% in the one-lung ventilation and CO2-induced pneumothorax groups, respectively. Moreover, the relapse patterns were not significantly different between the two groups.

Conclusion:

The results of this study suggested that the use of intraoperative one-lung ventilation and CO2-induced pneumothorax have similar oncological outcomes; therefore, the two methods are both viable options in esophagectomy.
Neoadjuvant camrelizumab combined with paclitaxel and nedaplatin for locally advanced esophageal squamous cell carcinoma: a single-arm phase 2 study (cohort study)
Authors: Yang Yingnan , Zhang Jinfeng , Meng Hongxue , Ling Xiaodong , Wang Xiaoyuan , Xin Yanzhong , Jiang Hao , Zhang Luquan , Fang Chengyuan , Liang Hao , Ma Jianqun , Zhu Jinhong
Published: December 2023

Background:

Neoadjuvant administration of immune checkpoint inhibitors (ICIs) combined with chemotherapy demonstrated promising efficacy and manageable safety in locally advanced esophageal squamous cell carcinoma (ESCC). This prospective, single-arm, phase 2 study evaluated the efficacy and safety of neoadjuvant therapy with camrelizumab plus paclitaxel and nedaplatin for 2–4 cycles in ESCC.

Methods:

Patients with locally advanced stage IIa–IIIb ESCC were enrolled in the study and received camrelizumab (200 mg), paclitaxel (155 mg/m2), and nedaplatin (80 mg/m2) intravenously on day one every 3 weeks. Patients underwent surgery after 2–4 cycles of treatment. The primary endpoint was the pathological complete response (pCR) rate. Secondary endpoints included the major pathological response (MPR) rate, R0 resection rate, tumor regression, objective response rate (ORR), and disease-free survival (DFS). Programmed cell death 1 ligand 1 (PD-L1) expression in tumor tissues was measured and quantified using immunohistochemistry staining and combined positive score (CPS), respectively.

Results:

In total, 75 patients were enrolled and received neoadjuvant treatment. Of them, 45 (60%) received two cycles, 18 (24%) received three cycles, and 10 patients (13.3%) received four cycles of neoadjuvant therapy. Ultimately, 62 patients (82.7%) underwent surgery. The patients achieved a pCR of 27.4% (95% CI: 16.9–40.2), an MPR of 45.2% (95% CI: 33.1–59.2), and an ORR of 48.4% (95% CI: 35.5–61.4); all patients had an R0 resection. T and N downstaging occurred in 39 (62.9%) and 19 (30.6%) patients Moreover, patients with CPS ≥10 tended to have enhanced ORR, pCR, and MPR compared to those with CPS <10. Treatment-related adverse events (TRAEs) of grade 1–2 occurred in 59 (78.7%) patients, grade 3 TRAEs in four (5.3%), and one patient (1.3%) experienced a grade 4 TRAE.

Conclusions:

Neoadjuvant camrelizumab combined with chemotherapy showed promising efficacy in locally advanced ESCC, with a manageable safety profile, when administered flexibly in two to four cycles.
A comparative analysis of perioperative complications and biochemical recurrence between standard and extended pelvic lymph node dissection in prostate cancer patients undergoing radical prostatectomy: a systematic review and meta-analysis
Authors: Ding Guixin , Tang Gonglin , Wang Tianqi , Zou Qingsong , Cui Yuanshan , Wu Jitao
Published: December 2023

Introduction:

Pelvic lymph node dissection (PLND) is commonly performed during radical prostatectomy (RP) for prostate cancer staging. This study aimed to comprehensively analyze existing evidence compare perioperative complications associated with standard (sPLND) versus extended PLND templates (ePLND) in RP patients.

Methods:

A meta-analysis of prospective studies on PLND complications was conducted. Systematic searches were performed on Web of Science, Pubmed, Embase, and the Cochrane Library until May 2023. Risk ratios (RRs) were estimated using random-effects models in the meta-analysis. The statistical analysis of the data was carried out using Review Manager software.

Results:

Nine studies, including three randomized clinical trial and six prospective studies, with a total of 4962 patients were analyzed. The meta-analysis revealed that patients undergoing ePLND had a higher risk of partial perioperative complications, such as lymphedema (I
2=28%; RR 0.05; 95% CI: 0.01–0.27; P<0.001) and urinary retention (I
2=0%; RR 0.30; 95% CI: 0.09–0.94; P=0.04) compared to those undergoing sPLND. However, there were no significant difference was observed in pelvic hematoma (I
2=0%; RR 1.65; 95% CI: 0.44–6.17; P=0.46), thromboembolic (I
2=57%; RR 0.91; 95% CI: 0.35–2.38; P=0.85), ureteral injury (I
2=33%; RR 0.28; 95% CI: 0.05–1.52; P=0.14), intraoperative bowel injury (I
2=0%; RR 0.87; 95% CI: 0.14–5.27; P=0.88), and lymphocele (I
2=0%; RR 1.58; 95% CI: 0.54–4.60; P=0.40) between sPLND and ePLND. Additionally, no significant difference was observed in overall perioperative complications (I
2=85%; RR 0.68; 95% CI: 0.40–1.16; P=0.16). Furthermore, ePLND did not significantly reduce biochemical recurrence (I
2=68%; RR 0.59; 95% CI: 0.28–1.24; P=0.16) of prostate cancer.

Conclusion:

This analysis found no significant differences in overall perioperative complications or biochemical recurrence between sPLND and ePLND, but ePLND may offer enhanced diagnostic advantages by increasing the detection rate of lymph node metastasis.
Uropathogenic Dysbiosis Pattern is Associated With Urethral Fibrosis
Authors: Witthaus Michael , Chawla Saager , Puri Dhruvi , Sakamoto Kyoko , Buckley Jill , Miller Aaron , Rajasekaran Mahadevan
Published: December 2023

Purpose:

Cellular mechanisms of stricture progression after repeated transurethral interventions are unclear. We hypothesize that urethral injury and mechanical stretch cause tears on the urethral epithelial cell lining leading to leaking epithelium and urine extravasation. Urinary bacteria traverse the epithelial lining and may promote fibrogenesis through inflammation due to microbial activity. Our objective was to perform a case-control study of the urobiome from patients with urethral stricture disease or healthy controls using 16S rRNA and shotgun metagenomic sequencing profiling to elucidate the clinical relevance of the urobiome in urinary stricture progression.

Materials and Methods:

First catch urine samples from patients and healthy volunteers were collected and pelleted urine was used for DNA extraction, followed by high throughput 16S rRNA and shotgun metagenomic sequencing. Sequencing data were used to determine microbial taxa and functions associated with urethral stricture disease.

Results:

Sequencing results revealed that the lower urinary tract urobiome was significantly different between urethral stricture disease cases and healthy controls. In particular, taxonomic and metabolic profiles point toward anaerobic biofilm formation by antibiotic-resistant species of Klebsiella, which is a known uropathogen. Importantly, no patients in the study exhibited signs or symptoms of clinical infection.

Conclusions:

Our findings suggest a role for biofilm formation by uropathogens such as Klebsiella spp. in developing an inflammatory environment and consequent fibrosis progression. Future studies will elucidate specific mechanisms of Klebsiella-induced fibrosis. Our data suggest that targeting specific bacteria or biofilm formation may be beneficial for urethral stricture disease detection and prevention of progression.
Neuromonitoring of Pediatric and Adult Extracorporeal Membrane Oxygenation Patients: The Importance of Continuous Bedside Tools in Driving Neuroprotective Clinical Care
Authors: Tabet Margherita , Custer Chasity , Khan Imad R. , Sanford Ethan , Sharma Jayesh , Choe Regine , Singh Sumit , Sirsi Deepa , Olson DaiWai M. , Morriss Michael Craig , Raman Lakshmi , Busch David R.
Published: December 2023

Extracorporeal membrane oxygenation (ECMO) is a form of temporary cardiopulmonary bypass for patients with acute respiratory or cardiac failure refractory to conventional therapy. Its usage has become increasingly widespread and while reported survival after ECMO has increased in the past 25 years, the incidence of neurological injury has not declined, leading to the pressing question of how to improve time-to-detection and diagnosis of neurological injury. The neurological status of patients on ECMO is clinically difficult to evaluate due to multiple factors including illness, sedation, and pharmacological paralysis. Thus, increasing attention has been focused on developing tools and techniques to measure and monitor the brain of ECMO patients to identify dynamic risk factors and monitor patients’ neurophysiological state as a function in time. Such tools may guide neuroprotective interventions and thus prevent or mitigate brain injury. Current means to continuously monitor and prevent neurological injury in ECMO patients are rather limited; most techniques provide indirect or postinsult recognition of irreversible brain injury. This review will explore the indications, advantages, and disadvantages of standard-of-care, emerging, and investigational technologies for neurological monitoring on ECMO, focusing on bedside techniques that provide continuous assessment of neurological health.
Increased contact activated endogenous thrombin potential in pregnant women with preeclampsia
Authors: Godtfredsen Anne Cathrine , Palarasah Yaseelan , Dolleris Britta Blume , Jørgensen Jan Stener , Sidelmann Johannes Jakobsen , Gram Jørgen Brodersen
Published: December 2023

Preeclampsia is a worldwide contributor to maternal and fetal morbidity and mortality. Women with preeclampsia are in a hyper-coagulable state with increased risk of thromboembolic disease later in life compared with normal pregnant women. The contact system (CAS) in plasma can mediate thrombin generation and is an important contributor to thrombus growth, but the activation of CAS during pregnancy complicated by preeclampsia is not yet elucidated, and CAS may play a role in the pathophysiology of preeclampsia. Therefore, the aim of the study is to address thrombin generation, and in particular, the capacity of the CAS-mediated pathway in patients with preeclampsia compared with pregnant controls. One hundred and seventeen women with preeclampsia and matched controls were included. The project was registered at www.clinicaltrials.gov as NCT04825145. CAS and tissue factor induced thrombin generation, proteins C and S, antithrombin, and histidine-rich glycoprotein (HRG) were assessed. Women with preeclampsia had significantly increased CAS and tissue factor-induced endogenous thrombin potential (ETP), and HRG compared with controls, P = 0.022, P = 0.024, and P = 0.02, respectively. The concentrations of protein C and antithrombin were significantly reduced in the preeclampsia group, P = 0.024 and P < 0.0001, respectively. No significant difference in the concentration of protein S was detected, P = 0.06. This study demonstrates a significant increased CAS-induced ETP and an overall decrease of important regulators of coagulation in women with preeclampsia compared with controls. These aspects can contribute to the hyper-coagulable state characterizing preeclampsia.
The association between anticholinergic/sedative burden and physical frailty in people aging with HIV
Authors: Michael Henry Ukachukwu , Brouillette Marie-Josée , Tamblyn Robyn , Fellows Lesley K. , Mayo Nancy E.
Published: December 2023

Objective:

This study aimed to estimate the strength of the association between anticholinergic/sedative burden and concurrent physical frailty in people aging with HIV.

Design:

This cross-sectional analysis examined baseline data from 824 adults with a mean age of 53 enrolled in the Positive Brain Health Now study.

Methods:

Anticholinergic medications were identified using four methods: Anticholinergic Cognitive Burden (ACB) Scale, Anticholinergic Risk Scale (ARS), Anticholinergic Drug Scale (ADS), and the anticholinergic list of the Anticholinergic and Sedative Burden Catalog (ACSBC). Sedatives were identified using the Sedative Load Model (SLM) and the sedative list of the ACSBC. Physical frailty was assessed using a modified Fried Frailty Phenotype (FFP) based on self-report items. Multivariable logistic regression models, adjusted for sociodemographic factors, lifestyle considerations, HIV-related variables, comorbidities, and co-medication use, were used to estimate odds ratios (ORs).

Results:

Anticholinergic burden demonstrated associations with frailty across various methods: total anticholinergic burden (OR range: 1.22–1.32; 95% confidence interval (CI) range: 1.03–1.66), sedative burden (OR range: 1.18–1.24; 95% CI range: 1.02–1.45), high anticholinergic burden (OR range: 2.12–2.74; 95% CI range: 1.03–6.19), and high sedative burden (OR range: 1.94–2.18; 95% CI: 1.01–4.34).

Conclusion:

The anticholinergic and sedative burdens may represent modifiable risk factors for frailty in people aging with HIV. Future studies should evaluate the effects of reducing anticholinergic and sedative burdens on frailty outcomes and explore the prognostic value of diverse scoring methods.
18F-FDG PET/CT Imaging of Prostatic Epithelioid Hemangioendothelioma
Authors: Deng Yan , Deng Yujiao , He Limeng , Zhang Wei , Lei Xiaoping
Published: December 2023

Epithelioid hemangioendothelioma of the prostate is a rare malignant vasogenic tumor. We report a case of epithelioid hemangioendothelioma of the prostate in a 65-year-old man with lymph nodes and lung metastases on 18F-FDG PET/CT imaging. The patient presented with symptoms of frequent and urgent urination. On 18F-FDG PET/CT, intense FDG uptake was observed in the prostate mass along with multiple FDG-avid lesions involving the lung and lymph nodes. Histopathological examination confirmed epithelioid hemangioendothelioma in both the prostate mass and lung nodule.
Evaluation of a STAT MRI Protocol for Patients with Optic Disc Edema
Authors: Gibbons Alison B. , Huang Peng , Sklar Matthew , Kim Philip , Henderson Amanda D.
Published: December 2023

Background:

Evaluating patients with potentially sight-threatening conditions frequently involves urgent neuroimaging, and some providers recommend expediting emergency department (ED) evaluation. However, several factors may limit the practicality of ED evaluation. This pilot study assessed the feasibility and safety of a STAT magnetic resonance imaging (MRI) protocol, designed to facilitate outpatient MRI within 48 hours of referral, compared with ED evaluation for patients with optic disc edema.

Methods:

A retrospective chart review was performed. Demographics, clinical data, and baseline ophthalmic measures were compared between patients in STAT and ED groups using the t test or Fisher exact test. Multivariate analyses compared changes in visual acuity (VA), visual field mean deviation (VF MD), retinal nerve fiber layer thickness, and edema grade between presentation and follow-up using a mixed-effects model adjusting for age, sex, and baseline measures.

Results:

A total of 70 patients met the study criteria—24 (34.3%) in the STAT MRI cohort and 46 (65.7%) in the ED cohort. Demographic variables were similar between groups. Patients referred to the ED had worse VA (P < 0.001), larger VF MD (P < 0.001), and higher edema grade (P = 0.002) at presentation. Four patients in the ED group and none in the STAT group were found to have space-occupying lesions. Multivariate analyses showed that follow-up measures were significantly associated with their baseline values (all P < 0.001) but not with referral protocol (all P > 0.099). The STAT MRI protocol was associated with lower average patient charges and hospital costs.

Conclusions:

The STAT MRI protocol did not result in inferior visual outcomes or delay in life-threatening diagnoses. Urgent outpatient evaluation, rather than ED referral, seems safe for some patients with optic disc edema. These findings support continued utilization of the protocol and ongoing improvement efforts.
In-depth analyses of lncRNA and circRNA expression in the hippocampus of LPS-induced AD mice by Byu d Mar 25
Authors: Zhang Yongcang , Tang Liang , Wang Yan , Zhu Xiaoyan , Liu Lan
Published: December 2023

Byu d Mar 25 (BM25) has been verified to have neuroprotective effects in Alzheimer’s disease (AD) mice. However, the molecular mechanism remains unclear. We aimed to investigate the expression profiling of lncRNAs and circRNAs by microarray analysis. Six hippocampus from LPS-mediated AD mice model treated with (normal saline (NS) (n = 3) and AD mice model treated with BM25 (n = 3) were selected. Microarray analysis was performed to detect the expression profiles of lncRNAs and circRNAs in hippocampus. Differentially expressed (DE) lncRNAs, mRNAs and circRNAs were identified through scatter plot and volcano plot filtering with a threshold of fold-change ≥2 and P ≤ 0.05. Co-expression network is analyzed by Circos software. Cis- and Trans- regulation were analyzed using RIsearch-2.0 and FEELNC softwares. LncRNA-transcription factors (TFs) and LncRNA-Target-TFs network were analyzed by Clusterprofiler software. The prediction of miRNAs bind to circRNAs were performed with miRNAbase. A total of 113 DElncRNAs, 117 DEmRNAs, and 4 DEcircRNAs were detected. The pathway analysis showed the mRNAs that correlated with lncRNAs were involved in apoptosis, inflammatory mediator regulation of TRP channels, NF-kappa B and PI3K-Akt signaling pathway. The lncRNA-TFs network analysis suggested the lncRNAs were mostly regulated by Ncoa1, Phf5a, Klf6, Lmx1b, and Pax3. Additionally, lncRNA-target-TFs network analysis indicated the GATA6, Junb, Smad1, Twist1, and Mafb mostly regulate the same lncRNAs: XR_001783430.1 and NR_051982.1. Furthermore, 480 miRNAs were predicted binding to 4 identified circRNAs. The BM25 may affect AD by regulating the expression of lncRNAs and circRNAs, which could regulate the expressions of mRNAs or miRNAs by LncRNA-Target-TFs network.
The Effects of Preeclamptic Milieu on Cord Blood Derived Endothelial Colony-Forming Cells
Authors: Hall Eva , Alderfer Laura , Neu Erin , Saha Sanjoy , Johandes Ellie , Haas David M. , Haneline Laura S. , Hanjaya-Putra Donny
Published: December 2023

Preeclampsia is one of the leading causes of infant and maternal mortality worldwide. Many infants born from preeclamptic pregnancies are born prematurely with higher risk of developing cardiovascular later in their life. A key mechanism by which these complications occur is through stress-induced dysfunction of endothelial progenitor cells (EPCs), including endothelial colony-forming cells (ECFCs). To gain insight into this, cord blood derived ECFCs isolated from preeclamptic pregnancies (PRECs) were analyzed and compared to their healthy counterparts. While PRECs preserve key endothelial markers, they upregulate several markers associated with oxidative stress and inflammatory response. Compared to ECFCs, PRECs also exhibit lower migratory behaviors and impaired angiogenic potential. Interestingly, treatment of neuropilin-1 can improve tube formationin vitro. Collectively, this study reports that preeclamptic milieu influence phenotypes and functionality of PRECs, which can be rejuvenated using exogenous molecules. Promising results from this study warrant future investigations on the prospect of the rejuvenated PRECs to improve lung function of infants born from preeclamptic pregnancies.
MARK1 regulates dendritic spine morphogenesis and cognitive functionsin vivo
Authors: Kelly-Castro Emily C. , Shear Rebecca , Dindigal Ankitha H. , Bhagwat Maitreyee , Zhang Huaye
Published: December 2023

Dendritic spines play a pivotal role in synaptic communication and are crucial for learning and memory processes. Abnormalities in spine morphology and plasticity are observed in neurodevelopmental and neuropsychiatric disorders, yet the underlying signaling mechanisms remain poorly understood. The microtubule affinity regulating kinase 1 (MARK1) has been implicated in neurodevelopmental disorders, and theMARK1gene shows accelerated evolution in the human lineage suggesting a role in cognition. However, thein vivorole of MARK1 in synaptogenesis and cognitive functions remains unknown. Here we show that forebrain-specific conditional knockout (cKO) ofMark1causes defects in dendritic spine morphogenesis in hippocampal CA1 pyramidal neurons with a significant reduction in spine density. In addition, we found that MARK1 cKO mice show defects in spatial learning in the Morris Water Maze and reduced anxiety-like behaviors in the Elevated Plus Maze. Furthermore, we found loss of MARK1 causes synaptic accumulation of GKAP and GluR2. Taken together, our data show a novel role for MARK1 in regulating dendritic spine morphogenesis and cognitive functionsin vivo.
Advancing childhood cancer research through young investigator and advocate collaboration
Authors: Weiner Amber K. , Palmer Antonia , Moll Melanie Frost , Lindberg Gavin , Reidy Kevin , Diskin Sharon J. , Mackall Crystal L. , Maris John M. , Sullivan Patrick J.
Published: December 2023

Cancer advocates and researchers share the same goal of driving science forward to create new therapies to cure more patients. The power of combining cancer researchers and advocates has become of increased importance due to their complementary expertise. Therefore, advocacy is a critical component of grant structures and has become embedded into the Stand Up 2 Cancer (SU2C) applications. To date, the optimal way to combine these skillsets and experiences to benefit the cancer community is currently unknown. The Saint Baldrick’s Foundation (SBF)–SU2C now called St. Baldrick’s Empowering Pediatric Immunotherapies for Childhood Cancer (EPICC) Team is comprised of a collaborative network across nine institutions in the United States and Canada. Since SU2C encourages incorporating advocacy into the team structure, we have assembled a diverse team of advocates and scientists by nominating a young investigator (YI) and advocate from each site. In order to further bridge this interaction beyond virtual monthly and yearly in person meetings, we have developed a questionnaire and conducted interviews. The questionnaire is focused on understanding each member’s experience at the intersection between science/advocacy, comparing to previous experiences, providing advice on incorporating advocacy into team science and discussing how we can build on our work. Through creating a YI and advocate infrastructure, we have cultivated a supportive environment for meaningful conversation that impacts the entire research team. We see this as a model for team science by combining expertise to drive innovation forward and positively impact pediatric cancer patients, and perhaps those with adult malignancies.

Significance

Questionnaire results show both advocates and YI’s see this structure to be valuable and beneficial. YI’s communicated their research to a non-scientific audience and learned advocate’s experience. This was their first advocacy experience for most YIs. Advocates learned more about the research being conducted to provide hope. They can also aid with fundraising, publicity and lobbying. This collaboration improves science communication, designing patient-friendly clinical trials and sharing experience across institutions.
Evolutionary analysis reveals the origin of sodium coupling in glutamate transporters
Authors: Reddy Krishna D. , Rasool Burha , Akher Farideh Badichi , Kutlešić Nemanja , Pant Swati , Boudker Olga
Published: December 2023

Secondary active membrane transporters harness the energy of ion gradients to concentrate their substrates. Homologous transporters evolved to couple transport to different ions in response to changing environments and needs. The bases of such diversification, and thus principles of ion coupling, are unexplored. Employing phylogenetics and ancestral protein reconstruction, we investigated sodium-coupled transport in prokaryotic glutamate transporters, a mechanism ubiquitous across life domains and critical to neurotransmitter recycling in humans. We found that the evolutionary transition from sodium-dependent to independent substrate binding to the transporter preceded changes in the coupling mechanism. Structural and functional experiments suggest that the transition entailed allosteric mutations, making sodium binding dispensable without affecting ion-binding sites. Allosteric tuning of transporters’ energy landscapes might be a widespread route of their functional diversification.
BayesAge: A Maximum Likelihood Algorithm To Predict Epigenetic Age
Authors: Mboning Lajoyce , Rubbi Liudmilla , Thompson Michael , Bouchard Louis-S. , Pellegrini Matteo
Published: December 2023

DNA methylation is a reaction that results in the formation of 5-methylcytosine when a methyl group is added to the cytosine’s C5 position. As organisms age, DNA methylation patterns change in a reproducible fashion. This phenomenon has established DNA methylation as a valuable biomarker in aging studies. Epigenetic clocks based on weighted combinations of methylation sites have been developed to accurately predict the age of an individual from their methylome. However, many epigenetic clocks, particularly those that utilize penalized regression, model the changes in methylation linearly with age. Moreover, these models, which use methylation levels as features, are not robust to missing data and do not account the count-based nature of bisulfite sequence data. Additionally, the models are generally not interpretable. To overcome these challenges, we present BayesAge, an extension of the previously developed scAge approach that was developed for the analysis of single cell DNA methylation datasets. BayesAge utilizes maximum likelihood estimation (MLE) to infer ages, models count data using binomial distributions, and uses LOWESS smoothing to capture the non-linear dynamics between methylation and age. Our approach is designed for use with bulk bisulfite sequencing datasets. BayesAge outperforms scAge in several respects. Specifically, BayesAge’s age residuals are not age associated, thus providing a less biased representation of epigenetic age variation across populations. Moreover, BayesAge enables the estimation of error bounds on age inference and, when run on down-sampled data, its coefficient of determination between predicted and actual ages surpasses both scAge and penalized regression.
Increased susceptibility for pathogenesis of post-traumatic epilepsy in offspring exposed to deltamethrin during gestation and ameliorative effects of dietary curcumin
Authors: Kumar Prince , Kumar Kamendra , Sharma Deepak
Published: December 2023

Deltamethrin (DLT) is a most potent and widely used pesticide that does not cross Blood Brain Barrier (BBB) in adults. While it considered as safe, its lipophilic properties makes it a neurotoxic substance specially in early stages of brain development. It has shown neurotoxic effects on the brain by hyper-excitation of neurons. Epilepsy is a neurological disorder with recurring seizures where epileptogenesis occurs due to hyperexcitation of neurons. In various kinds of epilepsy, post-traumatic epilepsy (PTE) is a common epilepsy in children due to traumatic brain injury (TBI). PTE, however reportedly alleviated by curcumin in rats. Therefore, in the current study, we assessed the effect of gestational DLT exposure on the severity of PTE. The pregnant rats were injected with 0.75mg/kg-b/w of DLT dissolved in 1% DMSO each day of gestation between days 7-15. Epilepsy was induced four months postnatally, and curcumin was orally administered by oral gavage. ECoG, behavioral tests, Golgi Staining, immunofluorescence, and immunohistochemistry was performed to assess the pathogenesis, severity of epilepsy, and mitigating effects of curcumin. The results indicated the neurotoxic effects of DLT by raising the severity of seizures in an electrophysiological and behavioral manner. PTE decreased the dendritic branching and arborization. Sodium channel overexpression is an important reason for the hyperexcitation of neurons during the pathogenesis of epilepsy. DLT enhanced the increase in expression of both sodium channel subunits NaV1.1 and NaV1.6 during epileptogenesis. Similarly, synaptic markers PSD95 and SYP decreased. Astrocytic and microglial activation increased during pathogenesis of PTE. The antiepileptic effects of curcumin alleviated the effects on electrobehavioral response, neuronal arborization, and levels of NaVs, PSD95, SYP, GFAP and Iba1 in epilepsy. However, DLT raised the severity and susceptibility of epilepsy and decreased the antiepileptic effects on gestationally DLT-exposed epileptic animals. Our result demonstrates the gestational neurotoxic exposure of DLT increased the severity and susceptibility for PTE while decreasing the antiepileptic effects of curcumin.
Saturation resistance profiling of EGFR variants against tyrosine kinase inhibitors using prime editing
Authors: Kim Younggwang , Oh Hyeong-Cheol , Lee Seungho , Kim Hyongbum Henry
Published: December 2023

Variants of uncertain significance (VUS) hamper the clinical application of genetic information. For example, in treating lung cancer with tyrosine kinase inhibitors (TKIs), many epidermal growth factor receptor (EGFR) variants remain classified as VUS with respect to TKI sensitivity1,2. Such incomplete resistance profiles hinder clinicians from selecting optimal therapeutic agents3,4. A high-throughput approach that can evaluate the functional effects of single nucleotide variants (SNVs) could reduce the number of VUS. Here we introduce SynPrime, a method based on prime editing that enabled the generation and functional evaluation of 2,476 SNVs in theEGFRgene, including 99% of all possible variants in the canonical tyrosine kinase domain (exons 18 to 21). We determined resistance profiles of 95% (= 1,726/1,817) of all possible EGFR protein variants encoded in the whole tyrosine kinase domain (exons 18 to 24) against afatinib, osimertinib, and osimertinib in the presence of the co-occurring mutation T790M, in PC-9 cells. SynPrime, which uses direct sequencing of endogenous regions to identify SNVs, provided more accurate functional evaluations than a guide RNA abundance-based approach. Our study has the potential to substantially improve the precision of therapeutic choices in clinical settings and contribute to addressing the issue of VUS by being applied to other genes.
A Whole-Cell Screening Platform to Discover Cell Adhesion Molecules that Enable Programmable Bacterial Cell-Cell Adhesion
Authors: Chen Po-Yin , Chen Yung-Chih , Chen Po-Pang , Lin Kuan-Ting , Wang Wei-Le , Hsia Kuo-Chiang , Ting See-Yeun
Published: December 2023

Developing programmable bacterial cell-cell adhesion is of significant interest due to its versatile applications. Current methods that rely on presenting cell adhesion molecules (CAMs) on bacterial surfaces are limited by the lack of a generalizable strategy to identify such molecules targeting bacterial membrane proteins in their natural states. Here, we introduce a whole-cell screening platform designed to discover CAMs targeting bacterial membrane proteins within a synthetic bacteria-displayed nanobody library. Leveraging the potency of the bacterial type IV secretion system—a contact-dependent DNA delivery nanomachine—we have established a positive feedback mechanism to selectively enrich for bacteria displaying nanobodies that target antigen-expressing cells. Our platform successfully identified functional CAMs capable of recognizing three distinct outer membrane proteins (TraN, OmpA, OmpC), demonstrating its efficacy in CAM discovery. This approach holds promise for engineering bacterial cell-cell adhesion, such as targeted antimicrobial interventions in the microbiome by deploying programmed inhibitor cells.
Genomic and immune determinants of resistance to anti-CD38 monoclonal antibody-based therapy in relapsed refractory multiple myeloma
Authors: Ziccheddu Bachisio , Giannotta Claudia , D’Agostino Mattia , Bertuglia Giuseppe , Saraci Elona , Oliva Stefania , Genuardi Elisa , Papadimitriou Marios , Diamond Benjamin , Corradini Paolo , Coffey David , Landgren Ola , Bolli Niccolò , Bruno Benedetto , Boccadoro Mario , Massaia Massimo , Maura Francesco , Larocca Alessandra
Published: December 2023

Anti-CD38 antibody therapies have transformed multiple myeloma (MM) treatment. However, a large fraction of patients inevitably relapses. To understand this, we investigated 32 relapsed MM patients treated with daratumumab, lenalidomide, and dexamethasone (Dara-Rd;NCT03848676). Whole genome sequencing (WGS) before and after treatment pinpointed genomic drivers associated with early progression, includingRPL5loss and APOBEC mutagenesis. Flow cytometry on 202 blood samples, collected every three months until progression for 31 patients, revealed distinct immune changes significantly impacting clinical outcomes. Progressing patients exhibited significant depletion of CD38+ NK cells, persistence of T cell exhaustion, and reduced depletion of T-reg cells over time. These findings underscore the influence of immune composition and daratumumab-induced immune changes in promoting MM resistance. Integrating genomics and flow cytometry unveiled associations between adverse genomic features and immune patterns. Overall, this study sheds light on the intricate interplay between genomic complexity and the immune microenvironment driving resistance to Dara-Rd.