bluuebunny/crossref_metadata_2025 huggingface dataset:
041 Pre-hospital PEWS is not a useful predictor of the need for hospital admission from ED
Authors: Corfield Alasdair , Booth Kate , Clerihew Linda , Staines Harry , Stewart Elaine , Rooney Kevin
Published: April 2023

Objective

Physiological derangement, as measured by Paediatric Early Warning Score (PEWS) is used to try and identify children with critical illness at an early point to identify and intervene in children at risk. PEWS have shown some utility as a track and trigger system in hospital and also as a predictor of adverse outcome both and and out of hospital. We wanted to examine whether a single pre-hospital PEWS, based on observations made by ambulance staff, was associated with the need for hospital admission.

Methods

A retrospective analysis of all patients aged <16 transported to hospital by the Scottish Ambulance Survey between 2011 and 2015. Data was matched to outcome data regarding hospital admission or discharge, and length of stay.

Results

Full data was available for 21,202 paediatric patients, of whom 6340 (29.9%) were admitted to hospital, although this varied considerably by age (figure 1). Pre-hospital PEWS was associated with an odds ratio for admission of 1.173 (95% CI 1.160–1.187). Further analysis of PEWS shows Area Under ROC of 0.617 for PEWS, suggesting poor predictive ability. Gender does not significantly alter this (p=0.322) whereas addition of age increase the ROC to 0.630 (p<0.001) - see figure 2. There was no association between pre-hospital PEWS and length of hospital stay.

Abstract 041 Figure 1

Percent in-patient admission by gender and age

Abstract 041 Figure 2

ROC Curves for comparisons

Discussion

These data show that a single pre-hospital PEWS is a poor predictor of hospital admission for unselected patients in the Scottish Ambulance Service. The decision to admit a child to hospital is not only based on physiological derangement, and hence physiological based scoring systems such as PEWS cannot be used as the sole criteria for hospital admission, from an undifferentiated pre hospital population.
049 Development of a clinical decision rule for the early safe discharge of patients with mild traumatic brain injury and findings on CT brain scan: a retrospective cohort study
Authors: Marincowitz Carl , Lecky Fiona , Allgar Victoria , Hutchinson Peter , Elbeltagi Hadir , Johnson Faye , Quinn Eimhear , Tarantino Silvia , Townend Will , Kolias Angelos
Published: April 2023

Background

International guidelines recommend routine hospital admission for all patients with mild traumatic brain injury (TBI) who have injuries on CT brain scan. Only a small proportion of these patients require neurosurgical or critical care intervention. We aimed to develop an accurate clinical decision rule to identify low risk patients safe for discharge from the emergency department (ED) and facilitate earlier referral of those requiring intervention.

Method and results

A retrospective cohort study of case-notes of patients admitted with initial GCS13-15 and injuries identified by CT was completed. Data on a primary outcome measure of clinically important deterioration (indicating need for hospital admission) and secondary outcome of neurosurgery, ICU admission or intubation (indicating need for neurosurgical admission) were collected. Multivariable logistic regression was used to derive models and a risk score predicting deterioration using routinely reported candidate variables identified in a systematic review. We compared the performance of this new risk score with the Brain Injury Guideline (BIG) criteria, derived in the USA.

Abstract 049 Figure 1

Population selection

Abstract 049 Table 1

Model performance

Abstract 049 Table 2

Performance of risk score and BIG criteria

Conclusions

1699 patients were included from 3 English Major Trauma Centres. 27.7% (95% CI: 25.5% to 29.9%) met the primary, and 13.1% (95% CI: 11.6% to 14.8%) met the secondary, outcome of deterioration. The derived clinical decision rule suggests that patients with simple skull fractures or intracranial bleeding less than 5 mm in diameter who are fully conscious could be safely discharged from the Emergency Department. The decision rule achieved a sensitivity of 99.5% (95% CI: 98.1% to 99.9%) and specificity of 7.4% (95% CI: 6% to 9.1%) to the primary outcome. The BIG criteria achieved the same sensitivity but lower specificity (5%).

Our empirical models showed good predictive performance and outperformed the BIG criteria. This would potentially allow ED discharge of one in twenty patients currently admitted for observation. However prospective external validation and economic evaluation is required.
005 Rectal bleeding presenting to the paediatric emergency department
Authors: Evans Jordan , Metezai Huria , Roberts Zoe
Published: April 2023

Background

Bleeding per rectum in infants and children is often an alarming symptom for caregivers. The differential diagnosis is wide, from the benign to life-threatening. The current literature is limited on the description of this undifferentiated population in the UK. We aimed to describe the frequency of this presentation, the most common diagnoses and current management in the Paediatric Emergency Department (PED).

Method and results

Retrospective case note review of all patients presenting to a tertiary PED within a two year period from April 2017 to March 2019, with blood in stool/per rectum. Cases were identified by reviewing all presenting complaints including the words ‘blood’ or ‘bleed’. Data was collected using a standardised data collection form for the following variables; age, sex, diagnosis in PED, urgent intervention required, diagnosis on follow-up, diagnostic concordance between PED and follow-up diagnosis, investigation (stool, blood, imaging), admission, outpatient referral and reattendance during thestudy period.

Conclusions

A total of 90 cases were identified, 10 were excluded as they did not meet inclusion criteria (n=80). This made up 0.14% of all presentations to the PED within the two year period. Mean age was 5 years (3 months - 15 years) with 51% female and 49% male. Collectively constipation and gastroenteritis accounted for 76% of diagnoses. 24% of patients were admitted the same day and 38% referred for outpatient follow up. There was agreement between PED diagnosis and outpatient diagnosis in 87% of cases. 5% of cases required urgent intervention.

Bleeding per rectum is an infrequent presentation to the PED. The most common diagnoses are benign and many cases may be managed without need of admission or outpatient follow up. A high index of suspicion remains necessary to identify infrequent but serious pathology. There is currently limited evidence to guide practice and therefore further work is required.
Follow-on RifAximin for the Prevention of recurrence following standard treatment of Infection withClostridium Difficile(RAPID): a randomised placebo controlled trial
Authors: Major Giles , Bradshaw Lucy , Boota Nafisa , Sprange Kirsty , Diggle Mathew , Montgomery Alan , Jawhari Aida , Spiller Robin C
Published: April 2023

Background

Clostridium difficile infection (CDI) recurs after initial treatment in approximately one in four patients. A single-centre pilot study suggested that this could be reduced using ‘follow-on’ rifaximin treatment. We aimed to assess the efficacy of rifaximin treatment in preventing recurrence.

Methods

A multisite, parallel group, randomised, placebo controlled trial recruiting patients aged ≥18 years immediately after resolution of CDI through treatment with metronidazole or vancomycin. Participants received either rifaximin 400 mg three times a day for 2 weeks, reduced to 200 mg three times a day for a further 2 weeks or identical placebo. The primary endpoint was recurrence of CDI within 12 weeks of trial entry.

Results

Between December 2012 and March 2016, 151 participants were randomised to either rifaximin or placebo. Primary outcome data were available on 130. Mean age was 71.9 years (SD 15.3). Recurrence within 12 weeks was 29.5% (18/61) among participants allocated to placebo compared with 15.9% (11/69) among those allocated to rifaximin, a difference between groups of 13.7% (95% CI −28.1% to 0.7%, p=0.06). The risk ratio was 0.54 (95% CI 0.28 to 1.05, p=0.07). During 6-month safety follow-up, nine participants died in each group (12%). Adverse event rates were similar between groups.

Conclusion

While ‘follow-on’ rifaximin after CDI appeared to halve recurrence rate, we failed to reach our recruitment target in this group of frail elderly patients, so the estimated effect of rifaximin lacks precision. A meta-analysis including a previous trial suggests that rifaximin may be effective; however, further, larger confirmatory studies are needed.
Cancer cell genotype associated tumor immune microenvironment exhibits differential response to therapeutic STING pathway activation in high-grade serous ovarian cancer
Authors: Shakfa Noor , Li Deyang , Conseil Gwenaelle , Lightbody Elizabeth D , Wilson-Sanchez Juliette , Hamade Ali , Chenard Stephen , Jawa Natasha A. , Laight Brian J. , Afriyie-Asante Afrakoma , Tyryshkin Kathrin , Koebel Martin , Koti Madhuri
Published: April 2023

Background

High-grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy characterized by resistance to chemotherapy and high rates of recurrence. HGSC tumors display a high prevalence of tumor suppressor gene loss. Given the type 1 interferon regulatory function ofBRCA1andPTENgenes and their associated contrasting T-cell infiltrated and non-infiltrated tumor immune microenvironment (TIME) states, respectively, in this study we investigated the potential of stimulator of interferon genes (STING) pathway activation in improving overall survival via enhancing chemotherapy response, specifically in tumors with PTEN deficiency.

Methods

Expression of PTEN protein was evaluated in tissue microarrays generated using pretreatment tumors collected from a cohort of 110 patients with HGSC. Multiplex immunofluorescence staining was performed to determine spatial profiles and density of selected lymphoid and myeloid cells. In vivo studies using the syngeneic murine HGSC cell lines, ID8-Trp53–/–;Pten–/–and ID8-Trp53–/–;Brca1–/–, were conducted to characterize the TIME and response to carboplatin chemotherapy in combination with exogenous STING activation therapy.

Results

Patient tumors with absence of PTEN protein exhibited a significantly decreased disease specific survival and intraepithelial CD68+ macrophage infiltration as compared with intact PTEN expression. In vivo studies demonstrated thatPten-deficient ovarian cancer cells establish an immunosuppressed TIME characterized by increased proportions of M2-like macrophages, GR1+MDSCs in the ascites, and reduced effector CD8+ cytotoxic T-cell function compared withBrca1-deficient cells; further, tumors from mice injected withPten-deficient ID8 cells exhibited an aggressive behavior due to suppressive macrophage dominance in the malignant ascites. In combination with chemotherapy, exogenous STING activation resulted in longer overall survival in mice injected withPten-deficient ID8 cells, reprogrammed intraperitoneal M2-like macrophages derived fromPten-deficient ascites to M1-like phenotype and rescued CD8+ cytotoxic T-cell activation.

Conclusions

This study reveals the importance of considering the influence of cancer cell intrinsic genetic alterations on the TIME for therapeutic selection. We establish the rationale for the optimal incorporation of interferon activating therapies as a novel combination strategy in PTEN-deficient HGSC.
Axonal degeneration in chemotherapy-induced peripheral neurotoxicity: clinical and experimental evidence
Authors: Park Susanna B , Cetinkaya-Fisgin Aysel , Argyriou Andreas A , Höke Ahmet , Cavaletti Guido , Alberti Paola
Published: April 2023

Multiple pathological mechanisms are involved in the development of chemotherapy-induced peripheral neurotoxicity (CIPN). Recent work has provided insights into the molecular mechanisms underlying chemotherapy-induced axonal degeneration. This review integrates evidence from preclinical and clinical work on the onset, progression and outcome of axonal degeneration in CIPN. We review likely triggers of axonal degeneration in CIPN and highlight evidence of molecular pathways involved in axonal degeneration and their relevance to CIPN, including SARM1-mediated axon degeneration pathway. We identify potential clinical markers of axonal dysfunction to provide early identification of toxicity as well as present potential treatment strategies to intervene in axonal degeneration pathways. A greater understanding of axonal degeneration processes in CIPN will provide important information regarding the development and progression of axonal dysfunction more broadly and will hopefully assist in the development of successful interventions for CIPN and other neurodegenerative disorders.
Plasma phosphorylated tau 181 predicts amyloid status and conversion to dementia stage dependent on renal function
Authors: Lehmann Sylvain , Schraen-Maschke Susanna , Vidal Jean-Sébastien , Delaby Constance , Blanc Frédéric , Paquet Claire , Allinquant Bernadette , Bombois Stéphanie , Gabelle Audrey , Hanon Olivier
Published: April 2023

Objectives

Plasma P-tau181 is an increasingly established diagnostic marker for Alzheimer’s disease (AD). Further validation in prospective cohorts is still needed, as well as the study of confounding factors that could influence its blood level.

Methods

This study is ancillary to the prospective multicentre Biomarker of AmyLoid pepTide and AlZheimer’s diseAse Risk cohort that enrolled participants with mild cognitive impairment (MCI) who were examined for conversion to dementia for up to 3 years. Plasma Ptau-181 was measured using the ultrasensitive Quanterix HD-X assay.

Results

Among 476 MCI participants, 67% were amyloid positive (Aβ+) at baseline and 30% developed dementia. Plasma P-tau181 was higher in the Aβ+ population (3.9 (SD 1.4) vs 2.6 (SD 1.4) pg/mL) and in MCI that converted to dementia (3.8 (SD 1.5) vs 2.9 (SD 1.4) pg/mL). The addition of plasma P-tau181 to a logistic regression model combining age, sex, APOEε4 status and Mini Mental State Examination improved predictive performance (areas under the curve 0.691–0.744 for conversion and 0.786–0.849 for Aβ+). The Kaplan-Meier curve of conversion to dementia, according to the tertiles of plasma P-tau181, revealed a significant predictive value (Log rank p<0.0001) with an HR of 3.8 (95% CI 2.5 to 5.8). In addition, patients with plasma P-Tau(181) ≤2.32 pg/mL had a conversion rate of less than 20% over a 3-year period. Using a linear regression approach, chronic kidney disease, creatinine and estimated glomerular filtration rate were independently associated with plasma P-tau181 concentrations.

Conclusions

Plasma P-tau181 effectively detects Aβ+ status and conversion to dementia, confirming the value of this blood biomarker for the management of AD. However, renal function significantly modifies its levels and may thus induce diagnostic errors if not taken into account.
Analysis and simulation of arbitrary order shallow water and Drinfeld–Sokolov–Wilson equations: Natural transform decomposition method
Authors: Ali Nasir , Zada Laiq , Nawaz Rashid , Jamshed Wasim , Ibrahim Rabha W. , Guedri Kamel , Khalifa Hamiden Abd El-Wahed
Published: April 2023

Within the context of fractional calculus, we investigate novel mathematical possibilities. In this context, using the fractional dispersion relations for the fractional wave equation, we explore a class of the generalized fractional wave equation numerically. Some important classes of differential equations in the theory of wave studies are Drinfeld–Sokolov–Wilson and Shallow Water equations. In this effort, the natural transform decomposition technique has been implemented to investigate the explicit result of fractional-order coupled schemes of Drinfeld–Sokolov–Wilson and Shallow Water coupled systems. The proposed method is obtained by coupling the Natural transform with the Adomian decomposition process. The current technique significantly works to find the approximate solution without any discretization or constraining parameter assumptions. The obtained numerical and graphical outcomes by the devised technique are compared with the available exact result to verify the convergence of the method. For mathematical calculations, the Mathematica software package is used.
The relationship between elastin cross linking and alveolar wall rupture in human pulmonary emphysema
Authors: Fagiola Michael , Reznik Sandra , Riaz Muhammad , Qyang Yibing , Lee Seoyeon , Avella Joseph , Turino Gerard , Cantor Jerome
Published: April 2023

The current findings support the hypothesis that airspace enlargement is an emergent phenomenon in which initial proliferation of DID cross links to counteract alveolar wall distention is followed by a phase transition involving rapid acceleration of elastin breakdown, alveolar wall rupture, and progression to an active disease state that is less amenable to therapeutic intervention.
Mesenchymal Stem Cell-derived Exosomes: Novel Therapeutic Approach for Inflammatory Bowel Diseases
Authors: Tian Cheng-mei , Yang Mei-feng , Xu Hao-ming , Zhu Min-zheng , Zhang Yuan , Yao Jun , Wang Li-sheng , Liang Yu-jie , Li De-feng
Published: April 2023

As double membrane-encapsulated nanovesicles (30-150 nm), exosomes (Exos) shuttle between different cells to mediate intercellular communication and transport active cargoes of paracrine factors. The anti-inflammatory and immunomodulatory activities of mesenchymal stem cell (MSC)-derived Exos (MSC-Exos) provide a rationale for novel cell-free therapies for inflammatory bowel disease (IBD). Growing evidence has shown that MSC-Exos can be a potential candidate for treating IBD. In the present review, we summarized the most critical advances in the properties of MSC-Exos, provided the research progress of MSC-Exos in treating IBD, and discussed the molecular mechanisms underlying these effects. Collectively, MSC-Exos had great potential for cell-free therapy in IBD. However, further studies are required to understand the full dimensions of the complex Exo system and how to optimize its effects.
Removal of Natural Organic Matter (NOM) from Aqueous Solutions by Multi-Walled Carbon Nanotube Modification with Magnetic Fe3O4 Nanoparticles
Authors: Khodabakhshi Abbas , Riahi Farssani Ayoub , Sedehi Morteza , Sadeghi Mehraban
Published: April 2023

Backgroundand Aim. Natural organic matter (NOM) has become one of the most serious environmental problems due to its persistence in aqueous solutions and the risk of carcinogenesis. In this study, the removal efficiencies of real and synthetic humic acid (HA) by multi-walled carbon nanotubes (MWCNTs) coated with iron oxide were evaluated. Materials and Methods. The MWCNs were synthesized and coated with iron oxide. In addition, the effects of pH, contact time, mixing speed, and adsorbent dose on the removal efficiency of NOM by MWCNTs-Fe3O4 were studied. Then, the removal efficiency of NOM from real samples was investigated at optimal conditions. The MWCNT-Fe3O4 was characterized by scanning electron microscopy (SEM) test and X-ray diffraction (XRD), respectively. Data analysis was performed using Minitab software based on the Taguchi method. Results. The results showed that MWCNTs were coated with Fe3O4. The SEM test shows particle (MWCNTs-Fe3O4) size in the range of 48–143 nm, and the particles have uniform spherical shapes. Enix software was used to identify the phase in this sample. The conditions including

p
H
=
3

, mixing speed = 120 rpm, adsorbent dosage = 1.5 g·L−1, and contact time = 90 minutes were selected as optimal for NOM adsorption. The mean removal efficiencies of NOM in synthetic samples at 5, 10, and 20 mg·L−1 concentrations were 86.6%, 84.87%, and 95.41%, respectively. In addition, the mean removal efficiency of NOM in Choghakhor Wetland was 77%. Conclusion. Our findings demonstrated that the MWCNTs-Fe3O4 can be potentially used as an adsorbent for removing natural organic matter (HA) from aqueous solutions.
Do Residents Living in Transit-Oriented Development Station Catchment Areas Travel More Sustainably? The Impacts of Life Events
Authors: Shen Tonggaochuan , Cheng Long , Yang Yongjiang , Deng Jialin , Jin Tanhua , Cao Mengqiu
Published: April 2023

Transit-oriented development (TOD) is an urban designed model aimed at attracting more sustainable travellers. However, not all TOD projects succeed in maintaining a high rate of sustainable travel behaviour. To examine the impacts of TOD on residents’ travel behaviour, this paper applies binary logistic regression to analyse survey data for 1,298 residents living in the TOD areas in Hangzhou collected in 2020. The results show that socioeconomic characteristics, built environment factors, and travel attitudes play important roles in influencing their travel mode choices. Furthermore, the number of children in households and higher levels of car ownership significantly influence residents’ sustainable travel behaviours. However, it appears that only a limited number of factors can convince car users to shift to sustainable modes of travel, such as their workplace being accessible by metro and attitudes towards changes in accessibility. This research study contributes to the existing literature in terms of enhancing the understanding of travel mode choice behaviours, particularly with regard to people who live near public transport infrastructure, as well as formulating evidence-based TOD policies to achieve more sustainable transport systems.
A Hybrid Energy Storage System Strategy for Smoothing Photovoltaic Power Fluctuation Based on Improved HHO-VMD
Authors: Zhang Yu , Wu Yuhu , Li Lianmin , Liu Zhongxiang
Published: April 2023

To solve the problems of large fluctuation of photovoltaic output power affecting the safe operation of the power grid, a hybrid energy storage capacity configuration strategy based on the improved Harris hawks optimization algorithm optimizing variational mode decomposition (IHHO-VMD) is proposed. In this strategy, the improved Harris hawk optimization algorithm is used to adaptively select

k

and

α

in VMD parameters and decompose the photovoltaic output power and distinguish between correlated and uncorrelated modes. Similarly, the moving average method (MA) is used to extract the continuous component signal in the uncorrelated mode, and it is reconstructed with the related mode as the grid-connected power that meets the national standard. The hybrid energy storage system (HESS) is used to stabilize the fluctuation component signal. The minimum annual configuration cost of the energy storage system is established as the objective function. The simulation results show that the improved algorithm reduces the cost of the hybrid energy storage system by 6.15% compared with the original algorithm, suppresses the power fluctuation, and improves the economy and stability of the system.
Inferred Immune-Cell Activity Is an Independent Predictor of HER2-Negative Breast Cancer Prognosis and Response to Paclitaxel-Based Therapy in the GeparSepto Trial
Authors: Fasching Peter A. , Szeto Christopher , Denkert Carsten , Benz Stephen , Weber Karsten , Spilman Patricia , Budczies Jan , Schneeweiss Andreas , Stickeler Elmar , Schmatloch Sabine , Jackisch Christian , Karn Thomas , Sinn Hans Peter , Warm Mathias , van Mackelenbergh Marion , Rabizadeh Shahrooz , Schem Christian , Heinmöller Ernst , Mueller Volkmar , Marmé Frederik , Soon-Shiong Patrick , Nekljudova Valentina , Untch Michael , Loibl Sibylle
Published: April 2023

Purpose:

Tumor microenvironment (TME) immune markers have been correlated with both response to neoadjuvant therapy and prognosis in patients with breast cancer. Here, immune-cell activity of breast cancer tumors was inferred by expression-based analysis to determine if it is prognostic and/or predictive of response to neoadjuvant paclitaxel-based therapy in the GeparSepto (G7) trial (NCT01583426).

Experimental Design:

Pre-study biopsies from 279 patients with HER2-negative breast cancer in the G7 trial underwent RNA-seq-based profiling of 104 immune-cell-specific genes to assess inferred Immune Cell Activity (iICA) of 23 immune-cell types. Hierarchical clustering was used to classify tumors as iICA “hot,” “warm,” or “cold” by comparison of iICA in the G7 cohort relative to that of 1,467 samples from a tumor database established by Nantomics LLC. Correlations between iICA cluster, pathology-assessed tumor-infiltrating lymphocytes (TIL), and hormone receptor (HR) status for pathologic complete response (pCR), disease-free survival (DFS), and overall survival (OS) were determined.

Results:

iICA cluster correlated with TIL levels. The highest pCR rates were observed in hot cluster tumors, and those with relatively higher TILs. Greater inferred activity of several T-cell types was significantly associated with pCR and survival. DFS and OS were prolonged in patients with hot or warm cluster tumors, the latter particularly for HR negative tumors, even if TILs were relatively low.

Conclusions:

Overall, TIL level better predicted pCR, but iICA cluster better predicted survival. Differences in associations between TILs, cluster, pCR, and survival were observed for HR-positive tumors versus HR-negative tumors, suggesting expanded study of the implication of these findings is warranted.
The Negative Influence of Baseline Cell-free DNA on Long-term Survival in DLBCL Depends on Frontline Treatment Intensity
Authors: Desmots Fabienne , Rossille Delphine , Roussel Mikael , Pangault Céline , Louarn Laetitia , De Saint Jore Mylène , Le Gouill Steven , Bouabdallah Krimo , Delwail Vincent , Gressin Remy , Cornillon Jérôme , Damaj Gandhi , Maisonneuve Hervé , Damotte Diane , Kraeber-Bodere Françoise , Lamy Thierry , Parrens Marie-Cécile , Milpied Noël , Fest Thierry
Published: April 2023

Purpose:

This study aims to investigate the relationship between the intensity of the initial treatment given to patients with de novo diffuse large B-cell lymphoma (DLBCL) and the impact of their baseline cell-free DNA (cfDNA) levels on their long-term survival.

Experimental Design:

The GOELAMS 075 randomized clinical trial compared rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) with high-dose R-chemotherapy plus autologous stem cell transplantation (R-HDT) for patients aged ≤60. An interim PET assessment was used to refer patients for salvage therapy. With a median follow-up of more than 5.8 years, we analyzed the effects of the treatment arm, salvage therapy, and cfDNA level at diagnosis on overall survival (OS).

Results:

In a representative group of 123 patients, a high cfDNA concentration (>55 ng/mL) at diagnosis was associated with poor clinical prognostic factors and constituted a prognostic marker, independently of the age-adjusted International Prognostic Index. A cfDNA level above a threshold value of 55 ng/mL at diagnosis was associated with significantly worse OS. In an intention-to-treat analysis, high-cfDNA R-CHOP patients (but not high-cfDNA R-HDT patients) had worse OS [HR (95% confidence interval), 3.99 (1.98–10.74); P = 0.006]. In patients with high cfDNA levels, salvage therapy and transplantation were associated with a significantly higher OS rate. Among 50 patients with complete response 6 months after the end of treatment, for 11 of 24 R-CHOP patients, the cfDNA did not fall back to normal values.

Conclusions:

In this randomized clinical trial, intensive regimens mitigated the negative influence of high cfDNA levels in de novo DLBCL, relative to R-CHOP.
Data from Antitumor Activity of Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor, in ETV6-NTRK3–Positive Acute Myeloid Leukemia
Authors: Smith Kristen M. , Fagan Patrick C. , Pomari Elena , Germano Giuseppe , Frasson Chiara , Walsh Colin , Silverman Ian , Bonvini Paolo , Li Gang
Published: April 2023

Abstract
Activation of tropomyosin receptor kinase (TRK) family tyrosine kinases by chromosomal rearrangement has been shown to drive a wide range of solid tumors and hematologic malignancies. TRK fusions are actionable targets as evidenced by recent clinical trial results in solid tumors. Entrectinib (RXDX-101) is an investigational, orally available, CNS-active, highly potent, and selective kinase inhibitor against TRKA/B/C, ROS1, and ALK kinase activities. Here, we demonstrate that TRK kinase inhibition by entrectinib selectively targets preclinical models of TRK fusion–driven hematologic malignancies. In acute myelogenous leukemia (AML) cell lines with endogenous expression of the ETV6–NTRK3 fusion gene, entrectinib treatment blocked cell proliferation and induced apoptotic cell death in vitro with subnanomolar IC50 values. Phosphorylation of the ETV6–TRKC fusion protein and its downstream signaling effectors was inhibited by entrectinib treatment in a dose-dependent manner. In animal models, entrectinib treatment at clinically relevant doses resulted in tumor regression that was accompanied by elimination of residual cancer cells from the bone marrow. Our preclinical data demonstrate the potential of entrectinib as an effective treatment for patients with TRK fusion–driven AML and other hematologic malignancies. Mol Cancer Ther; 17(2); 455–63. ©2017 AACR.
Data from Anti-MET VHH Pool Overcomes MET-Targeted Cancer Therapeutic Resistance
Authors: Su Zhipeng , Han Yunchun , Sun Qichen , Wang Xiaoxiao , Xu Ting , Xie Wei , Huang Xing
Published: April 2023

Abstract
Receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) play crucial roles in many human malignancies. Numerous drugs have been developed against kinase center of MET or HGF-mediated activation; however, the outcomes in patients are not so promising. Increasing evidence show that MET has kinase-independent effects on tumorigenesis and dissemination, which explains the low efficacy in kinase inhibition-based strategy. VHH is the recombinant variable region of Camelid heavy-chain antibody. As a nanoscale antigen-binding unit, VHH has become an appealing drug candidate in cancer therapy. In our study, we choose a novel strategy to construct an anti-MET VHH pool against the whole ecto-domain of MET. Comparing to monoclonal antibody or single VHH, the anti-MET VHH pool strongly promotes MET degradation through Clathrin-dependent endo-lysosomal pathway. Thus, the anti-MET VHH pool not only blocks kinase activity of MET, but also reduces protein level of MET. As a consequence, anti-MET VHH pool dramatically suppresses cancer cell proliferation, viability, and colony formation in vitro, and inhibits tumorigenesis and growth in mice. Taken together, VHH pool-based strategy greatly improves MET-targeted therapeutic effects on cancer.
Data from Mouse Strains Influence Clearance and Efficacy of Antibody and Antibody–Drug Conjugate Via Fc–FcγR Interaction
Authors: Li Fu , Ulrich Michelle L. , Shih Vincent Feng-Sheng , Cochran Julia H. , Hunter Joshua H. , Westendorf Lori , Neale Jason , Benjamin Dennis R.
Published: April 2023

Abstract
To provide a better understanding of the pharmacokinetics–pharmacodynamics relationships of antibody-based drugs, we analyzed several chimeric and humanized monoclonal antibodies or antibody–drug conjugates (ADC) for PK and efficacy among four strains of mice. Notably, antibodies and ADCs displayed a dose-dependent drug disposition profile in the plasma of NSG mice. The increased clearance rate in NSG mice resulted in the reduction of antitumor activity of ADCs. Furthermore, we identified that the abnormal clearance was mediated by Fc–FcγR interaction by comparing antibodies that lack FcγR binding capacity. We also found a high percentage of FcγR-expressing macrophages in the bone marrow, spleen, and liver of NSG mice, which may be responsible for the abnormal distribution of antibodies. Overall, these findings suggest that preclinical evaluation of efficacy and pharmacokinetics of antibodies and ADCs need to consider mouse strain-induced variations.
Data from Sprague Dawley Rag2-Null Rats Created from Engineered Spermatogonial Stem Cells Are Immunodeficient and Permissive to Human Xenografts
Authors: Noto Fallon K. , Adjan-Steffey Valeriya , Tong Min , Ravichandran Kameswaran , Zhang Wei , Arey Angela , McClain Christopher B. , Ostertag Eric , Mazhar Sahar , Sangodkar Jaya , DiFeo Analisa , Crawford Jack , Narla Goutham , Jamling Tseten Y.
Published: April 2023

Abstract
The rat is the preferred model for toxicology studies, and it offers distinctive advantages over the mouse as a preclinical research model including larger sample size collection, lower rates of drug clearance, and relative ease of surgical manipulation. An immunodeficient rat would allow for larger tumor size development, prolonged dosing and drug efficacy studies, and preliminary toxicologic testing and pharmacokinetic/pharmacodynamic studies in the same model animal. Here, we created an immunodeficient rat with a functional deletion of the Recombination Activating Gene 2 (Rag2) gene, using genetically modified spermatogonial stem cells (SSC). We targeted the Rag2 gene in rat SSCs with TALENs and transplanted these Rag2-deficient SSCs into sterile recipients. Offspring were genotyped, and a founder with a 27 bp deletion mutation was identified and bred to homozygosity to produce the Sprague-Dawley Rag2 - Rag2tm1Hera (SDR) knockout rat. We demonstrated that SDR rat lacks mature B and T cells. Furthermore, the SDR rat model was permissive to growth of human glioblastoma cell line subcutaneously resulting in successful growth of tumors. In addition, a human KRAS-mutant non–small cell lung cancer cell line (H358), a patient-derived high-grade serous ovarian cancer cell line (OV81), and a patient-derived recurrent endometrial cancer cell line (OV185) were transplanted subcutaneously to test the ability of the SDR rat to accommodate human xenografts from multiple tissue types. All human cancer cell lines showed efficient tumor uptake and growth kinetics indicating that the SDR rat is a viable host for a range of xenograft studies. Mol Cancer Ther; 17(11); 2481–9. ©2018 AACR.
Data from G-1 Inhibits Breast Cancer Cell Growth via Targeting Colchicine-Binding Site of Tubulin to Interfere with Microtubule Assembly
Authors: Lv Xiangmin , He Chunbo , Huang Cong , Hua Guohua , Wang Zhengfeng , Remmenga Steven W. , Rodabough Kerry J. , Karpf Adam R. , Dong Jixin , Davis John S. , Wang Cheng
Published: April 2023

Abstract
G-protein–coupled estrogen receptor 1 (GPER1) has been reported to play a significant role in mediating the rapid estrogen actions in a wide range of normal and cancer cells. G-1 was initially developed as a selective agonist for GPER. However, the molecular mechanisms underlying the actions of G-1 are unknown, and recent studies report inconsistent effects of G-1 on the growth of breast cancer cells. By employing high-resolution laser scanning confocal microscopy and time-lapse imaging technology, as well as biochemical analyses, in the current study, we provide convincing in vitro and in vivo evidence that G-1 is able to suppress the growth of breast cancer cells independent of the expression status of GPERs and classic estrogen receptors. Interestingly, we found that triple-negative breast cancer cells (TNBC) are very sensitive to G-1 treatment. We found that G-1 arrested the cell cycle in the prophase of mitosis, leading to caspase activation and apoptosis of breast cancer cells. Our mechanistic studies indicated that G-1, similar to colchicine and 2-methoxyestradiol, binds to colchicine binding site on tubulin, inhibiting tubulin polymerization and subsequent assembly of normal mitotic spindle apparatus during breast cancer cell mitosis. Therefore, G-1 is a novel microtubule-targeting agent and could be a promising anti-microtubule drug for breast cancer treatment, especially for TNBC treatment. Mol Cancer Ther; 16(6); 1080–91. ©2017 AACR.
Data from Nuclear Factor-κB Promotes Urothelial Tumorigenesis and Cancer Progression via Cooperation with Androgen Receptor Signaling
Authors: Inoue Satoshi , Ide Hiroki , Mizushima Taichi , Jiang Guiyang , Netto George J. , Gotoh Momokazu , Miyamoto Hiroshi
Published: April 2023

Abstract
We investigated the role of NF-κB in the development and progression of urothelial cancer as well as cross-talk between NF-κB and androgen receptor (AR) signals in urothelial cells. Immunohistochemistry in surgical specimens showed that the expression levels of NF-κB/p65 (P = 0.015)/phospho-NF-κB/p65 (P < 0.001) were significantly elevated in bladder tumors, compared with those in nonneoplastic urothelial tissues. The rates of phospho-NF-κB/p65 positivity were also significantly higher in high-grade (P = 0.015)/muscle-invasive (P = 0.033) tumors than in lower grade/non–muscle-invasive tumors. Additionally, patients with phospho-NF-κB/p65-positive muscle-invasive bladder cancer had significantly higher risks of disease progression (P < 0.001) and cancer-specific mortality (P = 0.002). In immortalized human normal urothelial SVHUC cells stably expressing AR, NF-κB activators and inhibitors accelerated and prevented, respectively, their neoplastic transformation induced by a chemical carcinogen 3-methylcholanthrene. Bladder tumors were identified in 56% (mock), 89% (betulinic acid), and 22% (parthenolide) of N-butyl-N-(4-hydroxybutyl)nitrosamine-treated male C57BL/6 mice at 22 weeks of age. NF-κB activators and inhibitors also significantly induced and reduced, respectively, cell proliferation/migration/invasion of AR-positive bladder cancer lines, but not AR-knockdown or AR-negative lines, and their growth in xenograft-bearing mice. In both nonneoplastic and neoplastic urothelial cells, NF-κB activators/inhibitors upregulated/downregulated, respectively, AR expression, whereas AR overexpression was associated with increases in the expression levels of NF-κB/p65 and phospho-NF-κB/p65. Thus, NF-κB appeared to be activated in bladder cancer, which was associated with tumor progression. NF-κB activators/inhibitors were also found to modulate tumorigenesis and tumor outgrowth in AR-activated urothelial cells. Accordingly, NF-κB inhibition, together with AR inactivation, has the potential of being an effective chemopreventive and/or therapeutic approach for urothelial carcinoma. Mol Cancer Ther; 17(6); 1303–14. ©2018 AACR.
Data from A CRISPR/Cas9–Based Screening for Non-Homologous End Joining Inhibitors Reveals Ouabain and Penfluridol as Radiosensitizers
Authors: Du Jie , Shang Jun , Chen Fei , Zhang Yushuo , Yin Narui , Xie Ting , Zhang Haowen , Yu Jiahua , Liu Fenju
Published: April 2023

Abstract
Non-homologous end joining (NHEJ) is the major pathway responsible for the repair of ionizing radiation (IR)–induced DNA double-strand breaks (DSB), and correspondingly regulates the cellular response to IR. Identification of NHEJ inhibitors could substantially enhance the tumor radiosensitivity and improve the therapeutic efficiency of radiotherapy. In this study, we demonstrated a screening for NHEJ inhibitors using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and high-resolution melting (HRM) analysis. Because NHEJ is regarded as an error-prone mechanism, the NHEJ-mediated ligation of the site-specific DSB induced by Cas9 nuclease would eventually cause the mutation of the targeted sequence. Then, HRM analysis, a reliable and rapid assay for detecting sequence variation, was performed to evaluate the mutation efficiency of the targeted site. Validating analysis confirmed the NHEJ activities were positively correlated with the mutation frequencies. Next, an approved drug library containing 1,540 compounds was interrogated by using this screening strategy. Our results identified ouabain, a cardiotonic agent, and penfluridol, an antipsychotic agent, have the capacity to restrain NHEJ activity. Further experiments in vitro revealed the radiosensitizing effects of these compounds. Overall, we presented a cell-based screening for NHEJ inhibitors, which could promote the discovery of novel radiosensitizers. Mol Cancer Ther; 17(2); 419–31. ©2017 AACR.

See all articles in this MCT Focus section, “Developmental Therapeutics in Radiation Oncology.”
Data from Small Molecules Target the Interaction between Tissue Transglutaminase and Fibronectin
Authors: Sima Livia Elena , Yakubov Bakhtiyor , Zhang Sheng , Condello Salvatore , Grigorescu Arabela A. , Nwani Nkechiyere G. , Chen Lan , Schiltz Gary E. , Arvanitis Constandina , Zhang Zhong-Yin , Matei Daniela
Published: April 2023

Abstract
Tissue transglutaminase (TG2) is a multifunctional protein with enzymatic, GTP-ase, and scaffold properties. TG2 interacts with fibronectin (FN) through its N-terminus domain, stabilizing integrin complexes, which regulate cell adhesion to the matrix. Through this mechanism, TG2 participates in key steps involved in metastasis in ovarian and other cancers. High-throughput screening identified several small molecule inhibitors (SMI) for the TG2/FN complex. Rational medicinal chemistry optimization of the hit compound (TG53) led to second-generation analogues (MT1-6). ELISA demonstrated that these analogues blocked TG2/FN interaction, and bio-layer interferometry (BLI) showed that the SMIs bound to TG2. The compounds also potently inhibited cancer cell adhesion to FN and decreased outside-in signaling mediated through the focal adhesion kinase. Blockade of TG2/FN interaction by the small molecules caused membrane ruffling, delaying the formation of stable focal contacts and mature adhesions points and disrupted organization of the actin cytoskeleton. In an in vivo model measuring intraperitoneal dissemination, MT4 and MT6 inhibited the adhesion of ovarian cancer cells to the peritoneum. Pretreatment with MT4 also sensitized ovarian cancer cells to paclitaxel. The data support continued optimization of the new class of SMIs that block the TG2/FN complex at the interface between cancer cells and the tumor niche.
Data from Inhibition of MDM2 by a Rhein-Derived Compound AQ-101 Suppresses Cancer Development in SCID Mice
Authors: Gu Lubing , Zhang Hailong , Liu Tao , Draganov Alexander , Yi Sha , Wang Binghe , Zhou Muxiang
Published: April 2023

Abstract
A novel small-molecule anthraquinone (AQ) analogue, AQ-101, which was synthesized through chemical modification of the core structures of rhein, exhibited potent anticancer activity. In the present study, we evaluated the cancer-inhibiting mechanism of AQ-101 and tested the therapeutic potential of this compound for treating cancer in mice. We found that AQ-101 was able to induce MDM2 protein degradation through a self-ubiquitination and proteasome-mediated mechanism. This AQ-101–induced MDM2 downregulation led to activation of p53, which contributed to apoptosis of acute lymphoblastic leukemia (ALL), especially those with a wild-type p53 phenotype and MDM2 expression in vitro and in vivo. When given for a period of 2 weeks (20 mg/kg/day, 3×/week), AQ-101 inhibited development of ALL in nude or SCID mice with a human ALL xenograft and achieved cure by the end of the 5-month experiment. Importantly, AQ-101 showed minimal or no inhibitory effect on normal human hematopoiesis in vitro and was well tolerated in vivo in animal models. Given that MDM2-overexpressing cancers are commonly refractory to current treatment options, our study results suggest that further development of AQ-101 is warranted, as it represents a potentially new, safe anticancer drug with a novel strategy for targeting MDM2. Mol Cancer Ther; 17(2); 497–507. ©2017 AACR.
Data from Targeting of Hematologic Malignancies with PTC299, A Novel Potent Inhibitor of Dihydroorotate Dehydrogenase with Favorable Pharmaceutical Properties
Authors: Cao Liangxian , Weetall Marla , Trotta Christopher , Cintron Katherine , Ma Jiyuan , Kim Min Jung , Furia Bansri , Romfo Charles , Graci Jason D. , Li Wencheng , Du Joshua , Sheedy Josephine , Hedrick Jean , Risher Nicole , Yeh Shirley , Qi Hongyan , Arasu Tamil , Hwang Seongwoo , Lennox William , Kong Ronald , Petruska Janet , Moon Young-Choon , Babiak John , Davis Thomas W. , Jacobson Allan , Almstead Neil G. , Branstrom Art , Colacino Joseph M. , Peltz Stuart W.
Published: April 2023

Abstract
PTC299 was identified as an inhibitor of VEGFA mRNA translation in a phenotypic screen and evaluated in the clinic for treatment of solid tumors. To guide precision cancer treatment, we performed extensive biological characterization of the activity of PTC299 and demonstrated that inhibition of VEGF production and cell proliferation by PTC299 is linked to a decrease in uridine nucleotides by targeting dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme for de novo pyrimidine nucleotide synthesis. Unlike previously reported DHODH inhibitors that were identified using in vitro enzyme assays, PTC299 is a more potent inhibitor of DHODH in isolated mitochondria suggesting that mitochondrial membrane lipid engagement in the DHODH conformation in situ is required for its optimal activity. PTC299 has broad and potent activity against hematologic cancer cells in preclinical models, reflecting a reduced pyrimidine nucleotide salvage pathway in leukemia cells. Archived serum samples from patients treated with PTC299 demonstrated increased levels of dihydroorotate, the substrate of DHODH, indicating target engagement in patients. PTC299 has advantages over previously reported DHODH inhibitors, including greater potency, good oral bioavailability, and lack of off-target kinase inhibition and myelosuppression, and thus may be useful for the targeted treatment of hematologic malignancies.
Data from Blockade of Glutathione Metabolism in IDH1-Mutated Glioma
Authors: Tang Xiaoying , Fu Xiao , Liu Yang , Yu Di , Cai Sabrina J. , Yang Chunzhang
Published: April 2023

Abstract
Mutations in genes encoding isocitrate dehydrogenases (IDH) 1 and 2 are common cancer-related genetic abnormalities. Malignancies with mutated IDHs exhibit similar pathogenesis, metabolic pattern, and resistance signature. However, an effective therapy against IDH1-mutated solid tumor remains unavailable. In this study, we showed that acquisition of IDH1 mutation results in the disruption of NADP+/NADPH balance and an increased demand for glutathione (GSH) metabolism. Moreover, the nuclear factor erythroid 2–related factor 2 (Nrf2) plays a key protective role in IDH1-mutated cells by prompting GSH synthesis and reactive oxygen species scavenging. Pharmacologic inhibition of the Nrf2/GSH pathway via brusatol administration exhibited a potent tumor suppressive effect on IDH1-mutated cancer in vitro and in vivo. Our findings highlight a possible therapeutic strategy that could be valuable for IDH1-mutated cancer treatment.