bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of six commercial and in-house phenotypic tests for detection of AmpC β-lactamases: is routine detection possible?
Authors: Al Mamari Azza Mohammed Khalifa , Al Jabri Zaaima , Sami Hiba , Rizvi Syed Gauhar A , Chan Moon Fai , Al Siyabi Turkiya , Al Muharrmi Zakariya , Rizvi Meher
Published: September 2023

Background

Phenotypic characterization of the prevalent AmpC β-lactamases in clinical isolates is essential for making informed empirical decisions and critical for strengthening antimicrobial stewardship programmes. This study focused on assessing six assays, two in-house and four commercial phenotypic tests for detection of AmpC, to study the feasibility of making its detection a routine diagnostic microbiology laboratory activity.

Methods

A total of 116 non-duplicate Gram-negative bacteria that were resistant to third-generation cephalosporins and amoxicillin/clavulanic acid, and resistant or susceptible to piperacillin/tazobactam and carbapenems, were screened by cefoxitin discs for AmpC. These isolates were subjected to two in-house (AmpC Tris-EDTA and disc approximation) methods and four commercial tests: D69C AmpC Detection Set; D72C ESBL, AmpC & Carbapenemase Detection Set; combination disc test: ESBL + AmpC Screen Disc Kit; and AmpC MIC Test Strip for confirmation of AmpC production. Ten whole-genome-sequenced AmpC-confirmed Gram-negative isolates were used as positive controls and one as a negative control.

Results

The prevalence of AmpC β-lactamases was 16%. Escherichia coli was a major carrier of plasmid-mediated AmpC (26.5%), followed by Klebsiella pneumoniae (23.4%). Phenotypically, 61% of AmpCs were detected by Tris-EDTA (accuracy: 73.8%), 76% by disc approximation (accuracy: 89.2%), 75% by the D69C AmpC Detection Set (accuracy: 95.4%), 74% by the D72C AmpC, ESBL & Carbapenemase Detection Set (accuracy: 95.4%), 76% by the combination disc test (accuracy: 95.4%) and 63% by AmpC MIC Test Strip (accuracy: 87.7%). The sensitivity and specificity of D69C were 97.9% and 88.2%, respectively, and 95.9% and 93.8% for the combination disc test, while for the disc approximation test and D72C they were 93.9% and 75%, and 93.9% and 100%, respectively. Screening by cefoxitin screening was less sensitive (75%) and specific (25%). Disc approximation and the combination disc test detect AmpC in Enterobacterales and also Pseudomonas aeruginosa and Acinetobacter species.

Conclusions

We recommend the in-house disc approximation test and the commercial D69C, as well as the combination disc test, as excellent tools for detection of AmpC. The cefoxitin test overcalls AmpC and cannot be considered a good stand-alone test for AmpC detection.
Choosing Therapies in Ulcerative Colitis
Authors: Das Ronit , Steinhart A Hillary
Published: September 2023

Those managing ulcerative colitis (UC) must be aware of new treatments. Mesalamine (5-ASA) is the first treatment for mild UC. Steroids have been the first therapy for patients with more severe UC but these are not effective or safe long term. This means that other medicines are needed. Newer advanced therapies are now frequently used. There are several types of advanced therapies. These are the anti-TNF, anti-integrin and anti-IL12/23 agents as well as the JAK inhibitors and sphingosine1-phosphate receptor modulators. All of these are effective in treating UC. Choosing among treatments is complicated. There are multiple factors to think about when choosing a treatment for UC. Without research studies that directly compare the different treatments, the use of any one treatment should be based on effectiveness and safety. Other considerations include specific disease features, patient factors and the preference of patients.
From Canadian Surgeon to Chinese Martyr: Dr. Norman Bethune and the Making of a Medical Folk Hero
Authors: Ross Brendan , Del Maestro Rolando F
Published: September 2023

This paper reexamines the public memory of Canadian surgeon Norman Bethune. In 1938, Bethune traveled to China to serve at the communist front and to treat soldiers fighting against the invading Japanese army. Throughout China, Bethune is a household name and a communist icon. Back in Canada, however, his name does not evoke the same ubiquity. While Canadians remembered Bethune through biographies, a film, statues, and a small museum, his story in the Anglophone world is confined primarily to the telling of distant history. To explain Bethune’s greater notoriety and public presence in China, this essay first turns our attention to Chinese sources that mythologized Bethune’s death in 1939. The essay then revisits Chinese propaganda that established Bethune as a lasting political symbol during the Cultural Revolution in the 1960s and 1970s. These national efforts show how a volunteer surgeon such as Bethune became such an important figure in a remote foreign country. China’s Communist Party turned Bethune’s death into a political event to rally support for their war of resistance against Japan. Later, during the tumultuous period of the Cultural Revolution, Mao Zedong used Bethune to symbolize unwavering service and loyalty to leader and party. This essay utilizes primary materials in McGill’s Osler Library and commentary from the field of memory studies to contextualize Bethune and to situate him within the broader narrative of political education that arose in China during the Cultural Revolution. A layered interpretation of Bethune — as doctor, martyr, and symbolic hero — slowly emerges. Political forces in China transformed his memory into legacy and carry this complicated figure into the present day.
Land use supervision and environmental pollution: multitasking bureaucrats and spillovers across regulations
Authors: Fan Haichao , Liu Guanchun , Wang Huanhuan , Zhao Xiaoxue
Published: September 2023

This article provides evidence on the strong spillover effects of land use regulations on environmental regulation enforcement in China. We find that the establishment of China’s Land Supervision Bureaus, which effectively reduced land use violations, led to a significant relaxation of environmental regulations by local officials and an increase in cities’ pollution intensity and overall pollution. In addition, the detrimental environmental effects of land use supervision are particularly strong among cities governed by officials with stronger promotion incentives. The results are consistent with a model in which multitasking local officials loosen environmental regulations to meet GDP growth targets in response to reduced industrial land supply. We further support the model by documenting land use supervision’s negative effect on new firm entries but significantly positive effect on incumbent firms’ outputs. (JEL D73, H77, P26, Q53, R52)
Blockade of Arf1-mediated lipid metabolism in cancers promotes tumor infiltration of cytotoxic T cells via the LPE-PPARγ-NF-κB-CCL5 pathway
Authors: Wang Na , Yao Tiange , Luo Chenfei , Sun Ling , Wang Yuetong , Hou Steven X
Published: September 2023

Tumor immunotherapy has achieved breakthroughs in a variety of tumors. However, the systemic absence of T cells in tumors and immunosuppressive tumor microenvironment so far limits the efficacy of immunotherapy to a small population of patients. Therefore, novel agents to increase T-cell tumor infiltration are urgently needed in the clinic. We recently found that inhibition of the ADP-ribosylation factor 1 (Arf1)-mediated lipid metabolism not only kills cancer stem cells (CSCs) but also elicits an anti-tumor immune response. In this study, we revealed a mechanism that targeting Arf1 promotes the infiltration of cytotoxic T lymphocytes (CTLs) into tumors through the C-C chemokine ligand 5 (CCL5)- C-C chemokine receptor type 5 (CCR5) pathway. We found that blockage of Arf1 induces the production of the unsaturated fatty acid (PE 18:1) that binds and sequestrates peroxisome proliferator-­activated receptor-γ (PPARγ) from the PPARγ-nuclear factor-κB (NF-κB) cytoplasmic complex. The released NF-κB was then phosphorylated and translocated into the nucleus to regulate the transcription of chemokine CCL5. CCL5 promoted infiltration of CTLs for tumor regression. Furthermore, the combination of the Arf1 inhibitor and programmed cell death protein 1 (PD-1) blockade induced an even stronger anti-tumor immunity. Therefore, targeting Arf1 represents a novel anti-tumor immune approach by provoking T-cell tumor infiltration and may provide a new strategy for tumor immunotherapy.
Total Force Fitness: Making Holistic, Integrated Whole-Person Research a DoD Priority
Authors: Deuster Patricia A , Meyer Vanessa M , Langevin Helene M
Published: September 2023

Total Force Fitness (TFF) was conceived as a holistic framework for building and sustaining Human Performance Optimization for Warfighters and their families. As such, TFF research must also be holistic in nature. During the research breakout, group barriers and challenges to TFF research were discussed, and critical research focus areas were prioritized. The top approaches discussed were (1) using big data to identify best practices and health trajectories; (2) applying community-based participatory research principles to military units; (3) focusing on “Whole-Person,” integrative research (physical, behavioral, spiritual, and biological) across the Department of Defense; and, finally, (4) prioritizing key opportunities to advance TFF across the active duty and Reserve/Guard enterprises and their families. The research group noted that coordinated action would be needed to move the prioritized agenda forward. Finally, translating research into action is essential because TFF is a way of honoring our service members as whole persons with careers, goals, and families.
Towards a History of the Eccentric Artist: Beethoven’s Bad Manners and the Lure of the Anecdote
Authors: Fine Abigail
Published: September 2023

Since the late nineteenth century, Beethoven’s bad manners have been framed as a political act of resistance against the stilted affect of the nobility. Yet this posthumous view does not fully account for how Beethoven’s contemporaries understood his (mis)behaviour. This article situates reactions to Beethoven’s bad manners that originated during his lifetime, alongside anecdotes published shortly after his death, to show how the eccentric artist persona interfaced with a history of etiquette. The very act of noticing behavioural minutiae took part in a celebrity culture poised on the cusp of novelty and conformity, entertainment and moral instruction. In a period dominated by conduct books, Beethoven’s friends sought to reconcile his gaffes with sensibility and (mannered) naturalness, reframing him as an ideal bourgeois subject. The case of Beethoven not only sheds light on the formation of the eccentric artist, but on the lure of the anecdote as an imaginative form of re-enactment.
The linear response of stellar systems does not diverge at marginal stability
Authors: Hamilton Chris , Heinemann Tobias
Published: September 2023

The linear response of a stellar system’s gravitational potential to a perturbing mass comprises two distinct contributions. Most famously, the system will respond by forming a polarization ‘wake’ around the perturber. At the same time, the perturber may also excite one or more ‘Landau modes’, i.e. coherent oscillations of the entire stellar system which are either stable or unstable depending on the system parameters. The amplitude of the first (wake) contribution is known to diverge as a system approaches marginal stability. In this paper, we consider the linear response of a homogeneous stellar system to a point mass moving on a straight line orbit. We prove analytically that the divergence of the wake response is in fact cancelled by a corresponding divergence in the Landau mode response, rendering the total response finite. We demonstrate this cancellation explicitly for a box of stars with Maxwellian velocity distribution. Our results imply that polarization wakes may be much less efficient drivers of secular evolution than previously thought. More generally, any prior calculation that accounted for wakes but ignored modes – such as those based on the Balescu-Lenard equation – may need to be revised.
A transient ultraviolet outflow in the short-period X-ray binary UW CrB
Authors: Fijma S , Castro Segura N , Degenaar N , Knigge C , Higginbottom N , Hernández Santisteban J V , Maccarone T J
Published: September 2023

Accreting low-mass X-ray binaries (LMXBs) are capable of launching powerful outflows such as accretion disc winds. In disc winds, vast amounts of material can be carried away, potentially greatly impacting the binary and its environment. Previous studies have uncovered signatures of disc winds in the X-ray, optical, near-infrared, and recently even the ultraviolet (UV) band, predominantly in LMXBs with large discs (Porb ≥ 20 h). Here, we present the discovery of transient UV outflow features in UW CrB, a high-inclination (i ≥ 77°) neutron star LMXB (NS-LMXB) with an orbital period of only Porb ≈ 111 min. We present P-Cygni profiles identified for Si iv 1400 Å and tentatively for N v 1240 Å in one 15 min exposure, which is the only exposure covering orbital phase ϕ ≈ 0.7–0.8, with a velocity of ≈1500 km s−1. We show that due to the presence of blackbody emission from the neutron star surface and/or boundary layer, a thermal disc wind can be driven despite the short Porb, but explore alternative scenarios as well. The discovery that thermal disc winds may occur in NS-LMXBs with Porb as small as ≈111 min, and can potentially be transient on time-scales as short as ≈15 min, warrants further observational and theoretical work.
Novobiocin blocks nucleic acid binding to Polθ and inhibits stimulation of its ATPase activity
Authors: Syed Aleem , Filandr Frantisek , Patterson-Fortin Jeffrey , Bacolla Albino , Ravindranathan Ramya , Zhou Jia , McDonald Drew T , Albuhluli Mohammed E , Verway-Cohen Amy , Newman Joseph A , Tsai Miaw-Sheue , Jones Darin E , Schriemer David C , D’Andrea Alan D , Tainer John A
Published: September 2023

Polymerase theta (Polθ) acts in DNA replication and repair, and its inhibition is synthetic lethal in BRCA1 and BRCA2-deficient tumor cells. Novobiocin (NVB) is a first-in-class inhibitor of the Polθ ATPase activity, and it is currently being tested in clinical trials as an anti-cancer drug. Here, we investigated the molecular mechanism of NVB-mediated Polθ inhibition. Using hydrogen deuterium exchange-mass spectrometry (HX-MS), biophysical, biochemical, computational and cellular assays, we found NVB is a non-competitive inhibitor of ATP hydrolysis. NVB sugar group deletion resulted in decreased potency and reduced HX-MS interactions, supporting a specific NVB binding orientation. Collective results revealed that NVB binds to an allosteric site to block DNA binding, both in vitro and in cells. Comparisons of The Cancer Genome Atlas (TCGA) tumors and matched controls implied that POLQ upregulation in tumors stems from its role in replication stress responses to increased cell proliferation: this can now be tested in fifteen tumor types by NVB blocking ssDNA-stimulation of ATPase activity, required for Polθ function at replication forks and DNA damage sites. Structural and functional insights provided in this study suggest a path for developing NVB derivatives with improved potency for Polθ inhibition by targeting ssDNA binding with entropically constrained small molecules.
Surgical management and outcome of newly diagnosed glioblastoma without contrast enhancement (low-grade appearance): a report of the RANO resect group
Authors: Karschnia Philipp , Dietrich Jorg , Bruno Francesco , Dono Antonio , Juenger Stephanie T , Teske Nico , Young Jacob S , Sciortino Tommaso , Häni Levin , van den Bent Martin , Weller Michael , Vogelbaum Michael A , Morshed Ramin A , Haddad Alexander F , Molinaro Annette M , Tandon Nitin , Beck Juergen , Schnell Oliver , Bello Lorenzo , Hervey-Jumper Shawn , Thon Niklas , Grau Stefan J , Esquenazi Yoshua , Rudà Roberta , Chang Susan M , Berger Mitchel S , Cahill Daniel P , Tonn Joerg-Christian
Published: September 2023

Background

Resection of the contrast-enhancing (CE) tumor represents the standard of care in newly diagnosed glioblastoma. However, some tumors ultimately diagnosed as glioblastoma lack contrast enhancement and have a ‘low-grade appearance’ on imaging (non-CE glioblastoma). We aimed to (a) volumetrically define the value of non-CE tumor resection in the absence of contrast enhancement, and to (b) delineate outcome differences between glioblastoma patients with and without contrast enhancement.

Methods

The RANO resect group retrospectively compiled a global, eight-center cohort of patients with newly diagnosed glioblastoma per WHO 2021 classification. The associations between postoperative tumor volumes and outcome were analyzed. Propensity score-matched analyses were constructed to compare glioblastomas with and without contrast enhancement.

Results

Among 1323 newly diagnosed IDH-wildtype glioblastomas, we identified 98 patients (7.4%) without contrast enhancement. In such patients, smaller postoperative tumor volumes were associated with more favorable outcome. There was an exponential increase in risk for death with larger residual non-CE tumor. Accordingly, extensive resection was associated with improved survival compared to lesion biopsy. These findings were retained on a multivariable analysis adjusting for demographic and clinical markers. Compared to CE glioblastoma, patients with non-CE glioblastoma had a more favorable clinical profile and superior outcome as confirmed in propensity score analyses by matching the patients with non-CE glioblastoma to patients with CE glioblastoma using a large set of clinical variables.

Conclusions

The absence of contrast enhancement characterizes a less aggressive clinical phenotype of IDH-wildtype glioblastomas. Maximal resection of non-CE tumors has prognostic implications and translates into favorable outcome.
Longitudinal analysis of serum-derived extracellular vesicle RNA to monitor dacomitinib treatment response in EGFR-amplified recurrent glioblastoma patients
Authors: Yekula Anudeep , Hsia Tiffaney , Kitchen Robert R , Chakrabortty Sudipto K , Yu Wei , Batool Syeda M , Lewis Brian , Szeglowski Antoni J , Weissleder Ralph , Lee Hakho , Chi Andrew S , Batchelor Tracy , Carter Bob S , Breakefield Xandra O , Skog Johan , Balaj Leonora
Published: September 2023

Background

Glioblastoma (GBM) is a highly aggressive and invasive brain tumor associated with high patient mortality. A large fraction of GBM tumors have been identified as epidermal growth factor receptor (EGFR) amplified and ~50% also are EGFRvIII mutant positive. In a previously reported multicenter phase II study, we have described the response of recurrent GBM (rGBM) patients to dacomitinib, an EGFR tyrosine kinase inhibitor (TKI). As a continuation of that report, we leverage the tumor cargo-encapsulating extracellular vesicles (EVs) and explore their genetic composition as carriers of tumor biomarker.

Methods

Serum samples were longitudinally collected from EGFR-amplified rGBM patients who clinically benefitted from dacomitinib therapy (responders) and those who did not (nonresponders), as well as from a healthy cohort of individuals. The serum EV transcriptome was evaluated to map the RNA biotype distribution and distinguish GBM disease.

Results

Using long RNA sequencing, we show enriched detection of over 10 000 coding RNAs from serum EVs. The EV transcriptome yielded a unique signature that facilitates differentiation of GBM patients from healthy donors. Further analysis revealed genetic enrichment that enables stratification of responders from nonresponders prior to dacomitinib treatment as well as following administration.

Conclusion

This study demonstrates that genetic composition analysis of serum EVs may aid in therapeutic stratification to identify patients with dacomitinib-responsive GBM.
Are we providing best-available care to newly diagnosed glioblastoma patients? Systematic review of phase III trials in newly diagnosed glioblastoma 2005–2022
Authors: Oster Christoph , Schmidt Teresa , Agkatsev Sarina , Lazaridis Lazaros , Kleinschnitz Christoph , Sure Ulrich , Scheffler Björn , Kebir Sied , Glas Martin
Published: September 2023

Background

Glioblastoma is the most aggressive primary brain cancer with a poor prognosis. Despite numerous studies in the past 17 years, effective treatment options for glioblastoma remain limited. In this study, we aimed to identify and compare phase III clinical trials for glioblastoma in terms of efficacy and baseline characteristics.

Methods

A systematic literature search was conducted using PubMed and ClinicalTrials.gov to identify phase III clinical trials for glioblastoma in adult patients. The target population included adult patients aged 18 years and above (younger cohort) and patients ≥60 years of age (elderly cohort). The search results were screened based on predefined inclusion criteria, and the included trials were analyzed for their study design, baseline characteristics, and survival results.

Results

Eleven trials met the inclusion criteria in the younger cohort. Of these, three reported a statistically significant improvement in overall survival (OS), including the EORTC/NCIC study (NCT00006353), EF-14 (NCT00916409), and CeTeG (NCT01149109). Of the 11 trials, eight were open-label randomized trials, including all of the positive ones, while three negative trials employed treatment blinding and a placebo control. The baseline characteristics of the trials [such as extent of resection, age, gender, and O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status] did not significantly differ between positive and negative trials. Isocitrate dehydrogenase (IDH) mutation status was analyzed in only two trials, with a small percentage of IDH-mutated tumors in each. Additionally, three more trials in the elderly cohort showed a statistically significant improvement of OS, the NOA-08 trial, the ISRCTN81470623-trial by Malmström et al. and NCT00482677-trial by Perry et al. Their baseline characteristics and implications are also analyzed.

Conclusion

This analysis of phase III clinical trials for glioblastoma conducted since 2005 showed that the majority of trials did not result in a significant improvement in OS. Among the trials included in this analysis, only the EORTC/NCIC, EF-14, and CeTeG studies demonstrated a positive OS outcome in the younger cohort.
Prognostic impact of malnutrition in patients with coronary artery disease: a systematic review and meta-analysis
Authors: He Fengling , Huang Haoxiang , Xu Wenlong , Cui Kai , Ruan Yifei , Guo Yuetong , Wang Junfen , Bin Jianping , Wang Yuegang , Chen Yanmei
Published: September 2023

Context

Conflicting predictions of malnutrition for the long-term prognosis of coronary artery disease (CAD) exist.

Objective

This study aimed to investigate the relationship between malnutrition and long-term prognosis of patients with CAD.

Data Sources

Four databases were searched for articles from February 11, 1936, to September 10, 2022.

Data Extraction

Cohort studies adjusting for multiple cardiovascular risk factors with data on CAD and malnutrition were included. Malnutrition was measured and defined by different nutritional evaluation tools. The hazard ratios (HRs) and confidence intervals (CIs) for all-cause mortality and major adverse cardiovascular events (MACEs) were synthesized. Subgroup analyses were performed based on study design, assessment tools, ethnicity/race, follow-up, sample size, and types of CAD. Meta-regression was used to compare whether the effect sizes of the 2 subgroups were statistically significant.

Data Analysis

A total of 30 cohort studies were included, totaling 81 361 participants with CAD. Nutritional evaluation tools, including the Geriatric Nutritional Risk Index (GNRI), Controlling Nutritional Status (CONUT), Nutritional Risk Screening 2002, Mini-Nutritional Assessment, and Prognostic Nutritional Index, were used. Malnutrition increased all-cause mortality (HR = 1.72; 95% CI: 1.53, 1.93) and MACEs (HR = 1.47; 95% CI: 1.35, 1.60) in patients with CAD. Subgroup analysis revealed the results were consistent across study design, ethnicity/race, follow-up, sample size, and types of CAD. Subgroup analyses and meta-regression revealed that malnutrition was associated with a higher risk of all-cause mortality (HR = 2.26; 95% CI: 1.91, 2.68) and MACEs (HR = 2.28; 95% CI: 1.69, 3.08) in patients with stable CAD than those with other types of CAD. Meta-regression revealed that the GNRI (HR = 2.20; 95% CI: 1.65, 2.93) was more effective than CONUT (HR = 1.47; 95% CI: 1.21, 1.78) in predicting all-cause mortality.

Conclusion

Malnutrition independently increased all-cause mortality by 72% and MACEs by 47% in patients with CAD, especially with stable CAD. The GNRI is a more effective nutritional evaluation tool than CONUT in predicting all-cause mortality.
Microorganisms Detected in Intussusception Cases and Controls in Children <3 Years in South Africa From 2013 to 2017
Authors: Page Nicola Anne , Netshikweta Rembuluwani , Tate Jacqueline E , Madhi Shabir A , Parashar Umesh D , Groome Michelle J ,   the South African Intussusception Surveillance Group, Arnold Marion , Chitnis Milind , Cox Sharon , de Vos Corné , Kirsten Mari , le Grange Susanna M , Loveland Jerome , Machaea Sello , Maharaj Ashwini , Withers Aletha
Published: September 2023

A matched case-control evaluated infectious etiologies in children <3 years in post-rotavirus vaccine intussusception surveillance. Adenovirus and adenovirus types C, A, and B were detected more frequently in cases versus controls at statistically significant values. Wild-type rotavirus, rotavirus vaccine strains, and human herpesvirus were not associated with intussusception.
Oryza glumaepatula: A wild relative to improve drought tolerance in cultivated rice
Authors: Thathapalli Prakash Parthiban , Chebotarov Dmytro , Zhang Jianwei , Kudrna David A , Torres Rolando O , Natividad Mignon A , Quintana Marinell R , Song Jiaming , Maldonado Carlos E , Hechanova Sherry Lou , Jena Kshirod , Wing Rod A , Henry Amelia
Published: September 2023

Developing drought-resistant rice (Oryza sativa, L.) is essential for improving field productivity, especially in rain-fed areas affected by climate change. Wild relatives of rice are potential sources for drought-resistant traits. Therefore, we compared root growth and drought response among 22 wild Oryza species, from which Oryza glumaepatula was selected as a promising source for further exploration. A geographically diverse panel of 69 O. glumaepatula accessions was then screened for drought stress-related traits, and 6 of these accessions showed lower shoot dry weight (SDW) reduction, greater percentage of deep roots, and lower stomatal density (STO) under drought than the drought tolerant O. sativa variety, Sahbhagi dhan. Based on whole-genome resequencing of all 69 O. glumaepatula accessions and variant calling to a high-quality O. glumaepatula reference genome, we detected multiple genomic loci colocating for SDW, root dry weight at 30 to 45 cm depth, and STO in consecutive drought trials. Geo-referencing indicated that the potential drought donors originated in flood-prone locations, corroborating previous hypotheses about the coexistence of flood and drought tolerance within individual Oryza genomes. These findings present potential donor accessions, traits, and genomic loci from an AA genome wild relative of rice that, together with the recently developed reference genome, may be useful for further introgression of drought tolerance into the O. sativa backgrounds.
Abstract 1 Clinical and Imaging Outcomes After Allogenic Umbilical Cord Blood Transfusions in a Young Adult with Cerebral Palsy
Authors: Tseng Sung Hui , Lu Long-Sheng , Kuo Chen-Yuan , Lin Ching Po , Yeh Tu-Hsueh
Published: September 2023

Introduction

Umbilical cord blood transplant is an emerging promising therapy for cerebral palsy. Here we report a case of a 23-year-old spastic quadriplegic young adult whose motor and cognitive function improved after allogenic umbilical cord blood transfusion.

Methods

The patient received three times of cord blood transfusion intravenously (2022/2/15, 2022/05/16, 2022/8/15). Each cord blood was 4/6 HLA-matched and contained 10 × 107 total nucleated cells (TNC)/kg.

Results

The young man was born preterm. Due to motor developmental delay, he began rehabilitation when 1-year-old. His best mobility function was GMFCS III. At the age of 18, there was a rapid decline of his mobility. EEG showed seizure like waves and TRODAT brain scan on 2018/9/28 revealed symmetric mild striatal dopaminergic neuron loss. He was totally ADL dependent and mobility and communication severely restricted due to strong spasticity and rigidity. 3 days after 1st cord blood transfusion, he walked 500 steps (1 km/h) on LOKOMAT with 100% guidance force and 50% body weight supported. In the 16th session (when he also completed the 3rd cord blood transfusion), he walked1000 steps (1.5 km/h) on LOKOMAT with 90% guidance force and 50% body weight supported. Afterward, he regained sufficient motor function to maintain daily training with traditional physiotherapy. There was no adverse event during all the transplant procedures. Brain images taken before and after cord blood transfusion were compared with a brain-age predicting model to obtain differences in predicted and chronological age in 3 sets of brain images. The result showed reduced differences between predicted and chronological brain age (Figure 1). His mother reported that he became more alert and more responsive during interaction.

Discussio

This case highlights the therapeutic effect of allogenic umbilical cord blood transfusion to benefit adult CP manifest deterioration in physical activity and cognitive function. The specific mechanisms involved in this process are not yet fully understood. Therefore, any use of stem cell transplantation for the treatment of cerebral palsy should be done under the guidance of good clinical practice to accumulate robust real-world data, and more research is needed to fully understand its mechanisms of action.
Abstract 3 Efficacy of Foscarnet in Preventing HHV6 Encephalitis in Adult Single Cord Blood Transplantation
Authors: Suzuki Kotaro , Kanda Junya , Iemura Tomoki , Arai Yasuyuki , Watanabe Mizuki , Shimazu Yutaka , Kitawaki Toshio , Mizumoto Chisaki , Yamashita Kouhei , Takaori-Kondo Akifumi
Published: September 2023

Introduction

The risk of HHV-6 encephalitis is high in cord blood transplantation (CBT) and the prognosis after encephalitis is poor, but there is no clarity regarding effective prevention methods for HHV-6 encephalitis.

Objectives

We retrospectively evaluated the effect of foscarnet (FCN) in preventing HHV-6 encephalitis in CBT.

Methods

We included 184 patients who underwent single CBT at Kyoto University Hospital from 2005 to 2022. For those who developed HHV-6 encephalitis, we calculated cumulative steroid doses from transplantation to the date of encephalitis onset, and for those who did not develop encephalitis, we calculated them to 25 days (the median encephalitis onset).

Results

Median (range) age was 49 years (18-70 years); 82% used tacrolimus and MMF for GVHD prophylaxis; FCN was used prophylactically or preemptively in 141 patients (77%) to prevent HHV6 encephalitis. FCN was used in 35% of patients from day 7 post-transplant, 20% from the time of HHV-6 reactivation, and 8% after the start of steroid administration. HHV-6 encephalitis occurred in 18 (10%) of 184 patients.

The median cumulative steroid dose for those receiving steroids was 4.0 mg/kg. Steroid dose (mg/kg) had a significant effect on the development of encephalitis (HR 1.09, P=0.003); pre-engraftment immune reaction had no significant effect. The ROC curve showed that the cutoff for cumulative steroid dose that best predicted the development of encephalitis was 6.5 mg/kg. FCN prophylaxis showed no significant effect in preventing HHV6 encephalitis in the high-steroid group. However, FCN prophylaxis reduced the incidence of HHV6 encephalitis in the low-steroid group with marginal significance (HR 0.22, P=0.070). Patients who developed encephalitis without HHV6 prophylaxis had a significantly lower survival rate than those who did not develop encephalitis (1yr-OS, 25% vs. 69%). However, those who developed encephalitis during HHV6 prophylaxis did not differ significantly from those who did not develop encephalitis (1yr-OS, 59% vs. 69%) (Figure).

Discussion

FCN prophylaxis significantly reduced the incidence of encephalitis in the low-dose steroid group, whereas prophylaxis was not effective in the high-dose steroid group. However, prophylactic administration may improve the prognosis after the onset of encephalitis.
Abstract 14 Omidubicel-Onlv: Robustness of the Manufacturing Process
Authors: Landau Efrat , Goudsmid-Rosenheimer Noga , Hasson Nira , Bengaiev Roman , Guttman Miri , Yaacobov Liat , Nuriel Yonatan , Geffen Yona
Published: September 2023

Introduction

Omidubicel-onlv is a nicotinamide (NAM) -modified allogeneic hematopoietic progenitor cell therapy derived from cord blood. NAM expansion increases the number of stem and progenitor cells, inhibits differentiation, and potentiates migration, bone marrow homing, and engraftment efficiency. A global phase 3 trial demonstrated faster hematopoietic recovery, reduced rates of infection, and shorter hospitalizations for patients randomized to omidubicel-onlv compared to standard umbilical cord blood (UCB). Omidubicel-onlv is manufactured for each patient from a single, appropriately matched cord blood unit (CBU). The inherent donor variability as well as the different processing and testing methods used by different Cord Blood Banks (CBBs) present challenges in maintaining a consistent product.

Objectives

This extensive study was conducted to confirm the robustness of the manufacturing process and the proven acceptable range for the critical and key process parameters.

Methods

Seven process parameters were evaluated in total. Of these, three parameters were related to the CD34+ expansion phase: CD34+ seeding concentration, incubation temperature, and CO2 levels. Four additional parameters were related to final product formulation and cryopreservation: hold times during harvest and formulation, cell concentration in the drug product, DMSO concentration, and storage temperature. The impact of each process parameter on product performance was assessed by a side-by-side comparison of its target value (control) versus the tested range. Each parameter was evaluated using at least three batches derived from three CBUs. Statistical analysis of the coefficient of variation or recovery against the control was applied to the data sets.

Results

Statistical analyses demonstrated an overall variability of ≤30% in critical attributes including fold expansion, viability, phenotyping, and recovery of cells post-cryopreservation and stability.

Discussion

The omidubicel-onlv manufacturing process is robust, overcoming the variability of batches derived from different donors, different processing and testing methods at CBBs, and manufacturing process parameters.
Abstract 15 A State-Run Public Cord Blood Collection Program
Authors: Wilt Kristen , Ober Charis , Garcia John
Published: September 2023

Introduction

The Arizona Public Cord Blood Program was created in 2011 by the Arizona Biomedical Research Centre, a sub-section of the Arizona Department of Health Services, to advance the collection and increase the number of racially and ethnically diverse cord blood units available for transplantation, as well as promote awareness of the benefits of cord blood stem cells through our educational partner, Save the Cord Foundation (STCF).

Objectives

Create a sustainable program for women of all racial and ethnic backgrounds to have the opportunity to donate cord blood, with the primary goal of transplantation, and secondary goal of providing non-transplantable cord blood units for research. A second objective was to educate the residents of the state of Arizona about cord blood stem cells and the need for their preservation.

Methods

A portion of state lottery funds supports the program monetarily. Those funds are provided to four collection hospitals who employ "cord blood consenters" whose responsibility it is to consent patients, assist delivery providers with collections, and package and ship cord blood units to our partner cord blood bank at MD Anderson Cancer Center. There are also two clinical coordinators who educate and train hospital staff on quality collection practices, with special emphasis on the importance of high volume, sterile collections.

STCF provides education across the state to expectant parents, healthcare providers, schools, and the public about the need for cord blood stem cell donation for transplant and research.

Results

Since 2011, the Arizona Public Cord Blood Program has banked hundreds of racially and ethnically diverse cord blood units with the National Marrow Donor Program, and has had 86 life-saving cord blood units matched with patients in need around the globe. This innovative program has not only expanded cord blood awareness and promoted the preservation of cord blood; it has resulted in the creation of an economic engine for the state of Arizona that is an attractant for STEM based businesses and careers.

Discussion

A decade later, the Arizona Public Cord Blood Program has proven to be a sustainable model for collecting and providing suitable cord blood units for transplant to diverse patient populations.
Abstract 17 Umbilical Cord Blood Collection. How Do Different Factors Affect CD45 Cell Viability in Our Experience?
Authors: Gonel Lorena , Gonzalez Lihue
Published: September 2023

Introduction

Umbilical cord blood (UCB) is an important source of hematopoietic stem cells for transplantation in some hematological diseases. One of the main factors influencing sample quality and transplantation success, in addition to histocompatibility, is the number of viable CD34+ cells. Over the years, different factors that could directly affect viability have been studied and evaluated. It is important to be able to define favorable ranges for obtaining high viabilities and optimal samples for their use.

Objectives

The aim of our study is to evaluate the incidence of three factors temperature during transport, volume and time between collection and process of UCB over cellular viability previous to cryopreservation.

Methods

We analyzed 10483 UCB samples collected between 2018 and 2022. Cell viability values were analyzed in total CD45 using flow cytometry with 7-AAD and Annexin V. We evaluated the relationship between cell viability with the three factors mentioned above.

Results

We observed a tendency for viability to decrease as the blood volume collected decreases, and as the temperature and elapsed hours increase. In concordance, we found that viability is dependent on the 3 factors analyzed (p <<0.001), observing that its variability can be explained in 4% by the variation of elapsed hours as well as the collection volume, while temperature explains this variation in 1%.

Discussion

With our samples we can assume that the variations in the ranges analyzed would not affect them to a great extent, since they are not determinant for obtaining an average viability lower than that established as acceptable in our bank (75%). On the other hand, we also conclude that viability cannot be explained from the variation of a single factor, so it would be important to analyze the interactions between them. For the time being, and in order to improve the quality of the samples, we consider it necessary to emphasize the collection of a good volume of blood and the rapid transport of the samples for processing.
Abstract 18 Leveraging the BMDI Cord Blood Bank to Create a GMP-Compliant Cord Blood (CB)–Derived Induced Pluripotent Stem Cell (iPSC) Master Cell Bank (MCB) for Potential Allogeneic Therapies
Authors: Tian Pei , Whish-Wilson Junann , Choi Kawa , Tsoutras Denise , McDonald Trish , Abberton Keren , Elwood Ngaire
Published: September 2023

Introduction

The BMDI Cord Blood Bank (CBB) in Melbourne is a public cord blood bank that operates under a Good Manufacturing Practice (GMP) cell-manufacturing licence from the Therapeutic Goods Administration (TGA) and is internationally accredited by the Foundation for the Accreditation of Cellular Therapy (FACT). An iPSC MCB derived from cord blood (CB) could form the basis of future cell-based therapies. Banked CB is an ideal source of starting material for the creation of iPSCs, with a host of advantages not afforded by other cell sources.

Objectives

We have previously described the technical aspects of creating “GMP-like” iPSCs from banked CB (https://www.frontiersin.org/articles/10.3389/fcell.2022.835321/full). Our objective is to leverage the CBB to transition our “GMP-like” protocols, developed in the research lab, into a fully GMP-compliant environment.

Methods

A small lab within the CBB was seconded for the purpose of establishing an Institutional Biosafety Committee (IBC) – approved PC2 laboratory to create GMP-compliant iPSC lines from banked cord blood. CB donors have been re-consented to use a portion of their banked HLA homozygous CB to create iPSC lines (https://doi.org/10.1093/stcltm/szac060). The CBB Quality Framework was replicated as a side module, mimicking all key components.

Results

* Established an IBC-approved PC2 laboratory within the GMP-compliant CBB facility.

* Developed a Quality Systems framework in-line with the FACT Common Standards for Cellular Therapy, leveraging off that in place for the CBB.

* Tested and validated the process in its entirety, including robustness of the Quality Systems, by the creation of new CB-derived “GMP-mock” iPSC lines.

* Established collaborations for pre-clinical studies to use our CB-derived iPSC lines for therapies directed towards retinal and neurological repair, NK and CAR-NK immunotherapies.

Discussion

A PC2 GMP-compliant laboratory has been established. Challenges, and solutions, will be discussed. Quality systems have been developed that mimic those in place for the CBB. The robustness of the Quality framework and GMP manufacturing have been confirmed by a full mock-run to create new CB-derived iPSC lines. Lower grade reagents used for the mock-run have now been swapped out for more expensive, fully GMP-certified (CTS) reagents and creation of our first fully GMP CB-derived iPSC line is underway.
Abstract 28 A Novel Chemically Defined Culturing System to Support Hematopoietic Stem Cell Expansion
Authors: Uchiyama Asako , Ishihara Haruna , Nakayama Akiko , Watanabe Motoo , Arakawa Nobuyuki
Published: September 2023

Introduction

Hematopoietic stem cells (HSCs) are known to be multipotent and can reconstitute the entire blood and immune system following HSC transplantation (HSCT). However, the current HSCTs have many unresolved issues including difficulties in finding donors for bone marrow transplantation, preparing a sufficient HSC dose in cord blood transplantation, and the risk of graft-versus-host disease (GvHD) for all allogeneic HSCTs. In recent years, there have been substantial efforts to research and understand the biology of HSCs to develop cell therapy products that meet these challenges and provide an alternative to traditional HSCTs. Several culturing methods have been developed to stimulate HSC expansion ex vivo, but the use of biological materials, such as albumin, has not been ideal for pharmaceutical manufacturing, and it has been difficult inhibiting differentiation of HSCs into lineage-committed cells while culturing in a cytokine-filled medium. We have developed a novel albumin-free culturing system that supports proliferation of long-term HSCs ex vivo by replacing cytokines and albumin with chemical agonists and a caprolactam-based polymer.

Objectives

The objective of this study is to characterize our expanded cell population as part of an analysis to determine whether the population reconstitutes bone marrow and is therefore suitable for development of a cell therapy product.

Methods

Here we report the in vitro and in vivo characterization of proliferated HSCs using our novel culturing system compared with a nicotinamide system which is known to support HSC proliferation ex vivo. A colony forming assay, cell surface marker analysis using a flow cytometer, and in vivo repopulating analysis using the NOD/Shi-scid IL-2Rγnull (NOG) mouse were conducted.

Results

Surface marker analysis of the proliferated population shows more than 70% remaining as undifferentiated CD34+. Of which, a higher number of CD201+CD90+CD45RA- exists compared with the nicotinamide-cultured population. Colony forming unit assays indicate that our proliferated cell population contains a higher number of multipotent progenitors. The repopulating cell assay also shows that the proliferated cells have bone marrow reconstitution capability in bone marrow-ablated NOG mice.

Discussion

We believe that our chemically defined culturing system can selectively proliferate HSCs while restraining their differentiation and will contribute to the development of novel HSC therapy products.
Do epiphytic lichens negatively impact their hosts through allelopathy? The effect of Evernia esorediosa on growth and biochemical processes of Larix gmelinii
Authors: Vitalievich Sleptsov Igor , Mikhailovna Rozhina Sakhaiana , Andreevich Prokopiev Ilya , Vasilievich Mikhailov Vladislav , Vasilievich Alekseev Kirill
Published: September 2023

The question of the nature of the interaction between epiphytic lichens and their host trees remains highly debated. Some authors showed cases of allelopathy, but this needs further investigation. Our study covers the effects caused by the epiphytic lichen Evernia esorediosa (Müll. Arg.) Du Rietz on growth and biochemical processes in Larix gmelinii (Rupr.) Rupr. ex Kuzen trees in cryolithozone boreal forests. Usnic acid (UA) is shown to migrate from the thalli of E. esorediosa in the bark and phloem of L. gmelinii, from which it is transported to the root system of the tree, and then UA is moved upward through the xylem into tree needles. Accumulation of UA in L. gmelinii needles causes the following effects: inhibition of photosynthesis, cellular respiration and oxidative phosphorylation. These disruptions could reflect on the tree growth processes. The L. gmelinii trees inhabited by the epiphytic lichen E. esorediosa were found to show lower radial and apical growth parameters. Our results show that E. esorediosa exhibits an allelopathic effect toward L. gmelinii through the migration of UA from the lichen thalli to the tissues of the tree, which led to inhibition of energetic processes in cells. This caused the tree growth to slow down and could ultimately lead to its death.
Damage-Associated Molecular Patterns and Systemic Signaling
Authors: Harris Fiona M. , Mou Zhonglin
Published: September 2023

Cellular damage inflicted by wounding, pathogen infection, and herbivory releases a variety of host-derived metabolites, degraded structural components, and peptides into the extracellular space that act as alarm signals when perceived by adjacent cells. These so-called damage-associated molecular patterns (DAMPs) function through plasma membrane localized pattern recognition receptors to regulate wound and immune responses. In plants, DAMPs act as elicitors themselves, often inducing immune outputs such as calcium influx, reactive oxygen species generation, defense gene expression, and phytohormone signaling. Consequently, DAMP perception results in a priming effect that enhances resistance against subsequent pathogen infections. Alongside their established function in local tissues, recent evidence supports a critical role of DAMP signaling in generation and/or amplification of mobile signals that induce systemic immune priming. Here, we summarize the identity, signaling, and synergy of proposed and established plant DAMPs, with a focus on those with published roles in systemic signaling.