bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor-targeted superantigens produce curative tumor immunity with induction of memory and demonstrated antigen spreading
Authors: Azulay Meir , Shahar Michal , Shany Eitan , Elbaz Eti , Lifshits Sveta , Törngren Marie , Friedmann Adam , Kramer Robert , Hedlund Gunnar 
Published: March 2023

Abstract
Background
Despite remarkable progress, the immunotherapies currently used in the clinic, such as immune checkpoint blockade (ICB) therapy, still have limited efficacy against many types of solid tumors. One major barrier to effective treatment is the lack of a durable long-term response. Tumor-targeted superantigen (TTS) therapy may overcome this barrier to enhance therapeutic efficacy. TTS proteins, such as the clinical-stage molecule naptumomab estafenatox (NAP), increase tumor recognition and killing by both coating tumor cells with bacterial-derived superantigens (SAgs) and selectively expanding T-cell lineages that can recognize them. The present study investigated the efficacy and mechanism of action of repeated TTS (C215Fab-SEA) treatments leading to a long-term antitumor immune response as monotherapy or in combination with PD-1/PD-L1 inhibitors in murine tumor models.

Methods
We used syngeneic murine tumor models expressing the human EpCAM target (C215 antigen) to assess the efficacy and mechanism of action of repeated treatment with TTS C215Fab-SEA alone or with anti-PD-1/PD-L1 monoclonal antibodies. Tumor draining lymph nodes (TDLNs) and tumor tissues were processed and analyzed by immunophenotyping and immunohistochemistry. Isolated RNA from tumors was used to analyze gene expression and the TCR repertoire. Tumor rechallenge and T-cell transfer studies were conducted to test the long-term antitumor memory response.

Results
TTS therapy inhibited tumor growth and achieved complete tumor rejection, leading to a T-cell-dependent long-term memory response against the tumor. The antitumor effect was derived from inflammatory responses converting the immunosuppressive TME into a proinflammatory state with an increase in T-cell infiltration, activation and high T-cell diversity. The combination of TTS with ICB therapy was significantly more effective than the monotherapies and resulted in higher tumor-free rates.

Conclusions
These new results indicate that TTSs not only can turn a “cold” tumor into a “hot” tumor but also can enable epitope spreading and memory response, which makes TTSs ideal candidates for combination with ICB agents and other anticancer agents.
Helicobacter pylori outer membrane vesicles induce astrocyte reactivity through nuclear factor-κappa B activation and cause neuronal damage in vivo in a murine model
Authors: Palacios Esteban , Lobos-González Lorena , Guerrero Simón , Kogan Marcelo J. , Shao Baohai , Heinecke Jay W. , Quest Andrew F. G. , Leyton Lisette , Valenzuela-Valderrama Manuel 
Published: March 2023

Abstract
Background
Helicobacter pylori (Hp) infects the stomach of 50% of the world’s population. Importantly, chronic infection by this bacterium correlates with the appearance of several extra-gastric pathologies, including neurodegenerative diseases. In such conditions, brain astrocytes become reactive and neurotoxic. However, it is still unclear whether this highly prevalent bacterium or the nanosized outer membrane vesicles (OMVs) they produce, can reach the brain, thus affecting neurons/astrocytes. Here, we evaluated the effects of Hp OMVs on astrocytes and neurons in vivo and in vitro.

Methods
Purified OMVs were characterized by mass spectrometry (MS/MS). Labeled OMVs were administered orally or injected into the mouse tail vein to study OMV-brain distribution. By immunofluorescence of tissue samples, we evaluated: GFAP (astrocytes), βIII tubulin (neurons), and urease (OMVs). The in vitro effect of OMVs in astrocytes was assessed by monitoring NF-κB activation, expression of reactivity markers, cytokines in astrocyte-conditioned medium (ACM), and neuronal cell viability.

Results
Urease and GroEL were prominent proteins in OMVs. Urease (OMVs) was present in the mouse brain and its detection coincided with astrocyte reactivity and neuronal damage. In vitro, OMVs induced astrocyte reactivity by increasing the intermediate filament proteins GFAP and vimentin, the plasma membrane αVβ3 integrin, and the hemichannel connexin 43. OMVs also produced neurotoxic factors and promoted the release of IFNγ in a manner dependent on the activation of the transcription factor NF-κB. Surface antigens on reactive astrocytes, as well as secreted factors in response to OMVs, were shown to inhibit neurite outgrowth and damage neurons.

Conclusions
OMVs administered orally or injected into the mouse bloodstream reach the brain, altering astrocyte function and promoting neuronal damage in vivo. The effects of OMVs on astrocytes were confirmed in vitro and shown to be NF-κB-dependent. These findings suggest that Hp could trigger systemic effects by releasing nanosized vesicles that cross epithelial barriers and access the CNS, thus altering brain cells.
Decrease in naturally occurring antibodies against epitopes of Alzheimer’s disease (AD) risk gene products is associated with cognitive decline in AD
Authors: Gu Dongmei , Wang Luchun , Zhang Nan , Wang Huali , Yu Xin 
Published: March 2023

Abstract
Background
Naturally occurring antibodies (NAbs) are germline-encoded immunoglobulins that can bind to and clear out self-neo-epitopes as well as apoptotic and necrotic cells. However, NAbs pathological relevance in Alzheimer’s disease (AD) is not well-understood.

Methods
Twenty-eight candidate proteins encoded by AD-associated genes were selected for this study based on a number of selection criteria, including preferential expression in the brain and B-lymphocyte cells. The levels of NAbs in plasma were analyzed according to their epitopes in age- and gender-matched cognitively normal subjects (CN, n = 56), subjects with mild cognitive impairment (MCI, n = 16) and subjects with AD (n = 56). We aimed to study the levels of their NAbs in plasma and their associations with cognitive decline in individuals with AD.

Results
Of the 28 antigens tested, 17 showed decreased NAbs in individuals with AD; in particular, NAb-TREM2 had an area under the ROC curve of 0.806, with the highest sensitivity (0.370) at 95% specificity among all 28 tests. Further protein–protein interaction networks and functional enrichment analysis suggested that target genes were enriched in AD-related pathological processes classified under “Alzheimer’s disease”, “neurodegenerative disease” and “amyloidosis”. The “Alzheimer’s disease” and “neurodegenerative disease” clusters, which converged on the initial “recognition” step of microglial phagocytosis, showed the best diagnostic performance for AD.

Conclusions
This study suggests a decline in the function of the adaptive immune system in AD, and the levels of circulating NAbs are likely to serve as biomarkers for surveilling the progression of AD.
Reproductive health service utilization and associated factors among secondary school students in Harari regional state, eastern Ethiopia, 2022: a multicenter study
Authors: Sertsu Addisu , Eyeberu Addis , Bete Tilahun , Yadeta Elias , Lami Magarsa , Balcha Tegenu , Berhanu Bekelu , Alemu Ayichew , Meseret Fentahun , Mohammed Hanan , Alemu Addisu , Husen Ahmed Mohammed , Ahemed Fila , Birhanu Abdi , Gemechu Kabtamu , Debella Adera , Getachew Tamirat , Nigussie Kabtamu , Nigussie Shambel , Negash Abraham 
Published: March 2023

Abstract
Introduction
Reproductive health encompasses all conditions relating to the reproductive system and goes beyond simply being free from disease or infirmity. Several socioeconomic and socio-cultural factors affect reproductive health service utilization.

Objectives
To assess reproductive health service utilization and its associated factors among government secondary school students in Harari regional state, Eastern Ethiopia 2022.

Methods
A school-based cross-sectional study design was conducted among 1275 secondary school students in six randomly selected secondary schools in Harari Regional state, in eastern Ethiopia. The study participants were chosen using a simple random sampling method. Data was gathered using self-administered questionnaires, entered into Epi Data version 3.1, and exported to SPSS version 25 for cleaning and analysis. Descriptive statistics, bivariable, and multivariable logistic regression analyses were carried out to compute the frequency of each independent variable and the magnitude of the outcome variables, then to identify factors associated with the outcome variable, respectively. To declare a significant association, an adjusted odd ratio (AOR) with a 95% confidence interval and a p-value of 0.05 were used.

Results
Our finding indicated that 25.3% (95% CI:22.9, 27.7) of the secondary school students utilized reproductive health services. Being in grade 11–12 (AOR = 1.67, 95% CI: 1.18, 2.38), having a history of sexually transmitted infection (AOR = 6.11, 95% CI: 2.20, 16.99), presence of a health facility nearby (AOR = 1.49, 95% CI: 1.12, 1.99), discuss voluntary counseling and testing with family (AOR = 2.73, 95% CI: 1.90, 3.94), and discussing about contraceptive with friends (AOR = 1.22, 95% CI: 0.91, 1.65) were the elements that had a strong correlation with reproductive health service utilization.

Conclusion
In this study, only one-fourth of secondary school students utilized RH service during the past year. The student's educational level, having a history of STI, the presence of a health facility nearby, and discussing RH service with family/friends were the factors significantly associated with reproductive service utilization among secondary school students.
Nab-paclitaxel and gemcitabine plus camrelizumab and radiotherapy versus nab-paclitaxel and gemcitabine alone for locally advanced pancreatic adenocarcinoma: a prospective cohort study
Authors: Chen Shuling , Li Jiaxin , Dong Aoran , Liu Zelong , Zhu Meiyan , Jin Meng , Wei Guangyan , Wu Shuang , Wang Yan , Chen Yong , Peng Zhenwei 
Published: March 2023

AbstractTreatment options specifically for patients with locally advanced pancreatic adenocarcinoma (LAPC) are scare and chemotherapy alone delivers limited efficacy. Immunotherapy and radiotherapy are potential effective treatments for LAPC, and both of them may synergize with chemotherapy. Therefore, in this prospective cohort study, we compared the efficacy and safety of nab-paclitaxel plus gemcitabine combined with anti-programmed cell death (PD-1) immunotherapy and radiotherapy (hereafter, combination treatment) versus nab-paclitaxel plus gemcitabine (chemotherapy alone) in the treatment of LAPC. In the combination group, participants received conventional fractionated radiotherapy with doses ranging from 54 to 63 Gy in 28 fractions, intravenous camrelizumab 200 mg once every 3 weeks, and intravenous nab-paclitaxel plus gemcitabine on day 1 and 8 of a 21-day cycle for eight cycles until disease progression, death or unacceptable toxicity. In the chemotherapy group, participants received intravenous nab-paclitaxel plus gemcitabine on day 1 and 8 of a 21-day cycle for eight cycles. From April, 2020 to December, 2021, 96 participants with LAPC were prospectively enrolled with 32 received combination treatment and 64 received chemotherapy alone at a single center. The combination treatment yielded significantly longer median overall-survival (22.3 months vs. 18.6 months, P = 0.031) and progression-free survival (12.0 months vs. 10.5 months, P = 0.043) than chemotherapy alone did. And the incidence of severe adverse events was not significantly different between the combination group and chemotherapy group (P = 0.856). In conclusion, nab-paclitaxel plus gemcitabine combined with anti-PD-1 immunotherapy and radiotherapy was effective and safe for LAPC patients, and it warrants further investigation in larger randomized trials.
Validation of a modified South African triage scale in a high-resource setting: a retrospective cohort study
Authors: Markussen Dagfinn Lunde , Brevik Heidi Synnøve , Bjørneklett Rune Oskar , Engan Mette 
Published: March 2023

Abstract
Background
Triage systems are widely used in emergency departments, but are not always validated. The South African Triage Scale (SATS) has mainly been studied in resource-limited settings. The aim of this study was to determine the validity of a modified version of the SATS for the general population of patients admitted to an ED at a tertiary hospital in a high-income country. The secondary objective was to study the triage performance according to age and patient categories.

Methods
We conducted a retrospective cohort study of patients presenting to the Emergency Department of Haukeland University Hospital in Norway during a four-year period. We used short-term mortality, ICU admission, and the need for immediate surgery and other interventions as the primary endpoints.

Results
A total of 162,034 emergency department visits were included in the analysis. The negative predictive value of a low triage level to exclude severe illness was 99.1% (95% confidence interval: 99.0–99.2%). The level of overtriage, defined as the proportion of patients assigned to a high triage level who were not admitted to the hospital, was 4.1% (3.9–4.2%). Receiver operating characteristic (ROC) curves showed an area under the ROC for the detection of severe illness of 0.874 (95% confidence interval: 0.870–0.879) for all patients and 0.856 (0.837–0.875), 0.884 (0.878–0.890) and 0.869 (0.862–0.876) for children, adults and elderly individuals respectively.

Conclusion
We found that the modified SATS had a good sensitivity to identify short-term mortality, ICU admission, and the need for rapid surgery and other interventions. The sensitivity was higher in adults than in children and higher in medical patients than in surgical patients. The over- and undertriage rates were acceptable.
The use of pediatric short-stay observation in Italy
Authors: Pinto Luciano , Bianchini Sonia , Barbieri Maria Antonietta , Cherchi Gabriella , Miceli Andrea , Mirauda Maria Pia , Russotto Valeria Spica , Raffaldi Irene , Zangardi Tiziana , Perri Domenico , Agostiniani Rino , Rugolotto Simone , Cardinale Fabio , Zampogna Stefania , Staiano Annamaria 
Published: March 2023

Abstract
Background
In Italy, the State Regions Conference on 1st August 2019 approved the Guidelines for Short-Stay Observation (SSO). At the beginning of 2022, the main Scientific Societies of the pediatric hospital emergency-urgency area launched a national survey to identify the extent to which these national guidelines had been adopted in the emergency rooms and pediatric wards of the Italian Regions.

Methods
A survey has been widespread, among Pediatric Wards and Pediatric Emergency Departments (EDs), using both a paper questionnaire and a link to a database on Google Drive, for those who preferred to fill it directly online. Those who did not spontaneously answer, where directly contacted, via email and/or through a phone call and invited to participate. The data collected have been: age of managed children, presence of triage, presence of Sub-intensive Care Unit and Intensive Care Unit and special questions about Pediatric SSO, availability of training courses for workers, number of ED access in the last 4 years.

Results
This survey is still ongoing, without a definite deadline, so we presented the preliminary data.
Currently, 8/20 Regions have not yet adopted the Guidelines. Till 02 January 2023, data from 253 hospitals were collected. There are currently 180/253 active Pediatric SSO (71.03% of the Hospitals). There are not active SSO in 33.27% of first level ED, in 19.35% of second level ED and in 33.66% of General Hospitals with Pediatric Wards. Active SSO are located mainly (75.97%) within Pediatric Wards. At the moment, the survey has been completed in 16 Regions: in the 8 Regions which are using guidelines, pediatric SSOs are active in all the second level ED (compared to 60.87% of the other 8 regions), in the 91.66% of first level ED (compared to the 33.3%), and in the 97.1% of General Hospitals (compared to 33.3%), with a statistically significance (p < 0.0001).
The territorial analysis of these 16 regions highlighted geographical differences in the percentage of SSOs active: 35.22% are active in hospitals in Southern Italy, 88.64% in Central Italy and 91.67% in those of the North.

Conclusions
The delay in adopting specific guidelines negatively influences activation of pediatric SSOs in hospital system and prevents the adjustment of welfare level to new needs. To facilitate the activation of SSOs in hospitals, it is also necessary to guarantee adequate economic recognition. It is essential to implement public interventions to overcome the current inequalities in the interest of children and their families: the current delay seriously penalizes emergency pediatric hospital care, especially in the southern Italian Regions.
A structured diagnostic algorithm for patients with ARDS
Authors: Bos Lieuwe Durk Jacobus , de Grooth Harm Jan , Tuinman Pieter Roel 
Published: March 2023

AbstractThis article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2023. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2023. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from https://link.springer.com/bookseries/8901.
Effect of total cholesterol and statin therapy on mortality in ARDS patients: a secondary analysis of the SAILS and HARP-2 trials
Authors: Pienkos Shaun M. , Moore Andrew R. , Guan Jiazhen , Levitt Joseph E. , Matthay Michael A. , Baron Rebecca M. , Conlon John , McAuley Daniel F. , O’Kane Cecilia M. , Rogers Angela J. 
Published: March 2023

Abstract
Background
Two acute respiratory distress syndrome (ARDS) trials showed no benefit for statin therapy, though secondary analyses suggest inflammatory subphenotypes may have a differential response to simvastatin. Statin medications decrease cholesterol levels, and low cholesterol has been associated with increased mortality in critical illness. We hypothesized that patients with ARDS and sepsis with low cholesterol could be harmed by statins.

Methods
Secondary analysis of patients with ARDS and sepsis from two multicenter trials. We measured total cholesterol from frozen plasma samples obtained at enrollment in Statins for Acutely Injured Lungs from Sepsis (SAILS) and Simvastatin in the Acute Respiratory Distress Syndrome (HARP-2) trials, which randomized subjects with ARDS to rosuvastatin versus placebo and simvastatin versus placebo, respectively, for up to 28 days. We compared the lowest cholesterol quartile (< 69 mg/dL in SAILS, < 44 mg/dL in HARP-2) versus all other quartiles for association with 60-day mortality and medication effect. Fisher’s exact test, logistic regression, and Cox Proportional Hazards were used to assess mortality.

Results
There were 678 subjects with cholesterol measured in SAILS and 509 subjects in HARP-2, of whom 384 had sepsis. Median cholesterol at enrollment was 97 mg/dL in both SAILS and HARP-2. Low cholesterol was associated with higher APACHE III and shock prevalence in SAILS, and higher Sequential Organ Failure Assessment score and vasopressor use in HARP-2. Importantly, the effect of statins differed in these trials. In SAILS, patients with low cholesterol who received rosuvastatin were more likely to die (odds ratio (OR) 2.23, 95% confidence interval (95% CI) 1.06–4.77, p = 0.02; interaction p = 0.02). In contrast, in HARP-2, low cholesterol patients had lower mortality if randomized to simvastatin, though this did not reach statistical significance in the smaller cohort (OR 0.44, 95% CI 0.17–1.07, p = 0.06; interaction p = 0.22).

Conclusions
Cholesterol levels are low in two cohorts with sepsis-related ARDS, and those in the lowest cholesterol quartile are sicker. Despite the very low levels of cholesterol, simvastatin therapy seems safe and may reduce mortality in this group, though rosuvastatin was associated with harm.

Graphical abstract
The effect of denosumab on disseminated tumor cells (DTCs) of breast cancer patients with neoadjuvant treatment: a GeparX translational substudy
Authors: Wimberger Pauline , Blohmer Jens-Uwe , Krabisch Petra , Link Theresa , Just Marianne , Sinn Bruno Valentin , Simon Eike , Solbach Christine , Fehm Tanja , Denkert Carsten , Kühn Cristin , Rhiem Kerstin , Tesch Hans , Kümmel Sherko , Petzold Andrea , Stötzer Oliver , Meisel Cornelia , Kuhlmann Jan Dominik , Nekljudova Valentina , Loibl Sibylle 
Published: March 2023

Abstract
Background
Disseminated tumor cells (DTCs) in the bone marrow are observed in about 40% at primary diagnosis of breast cancer and predict poor survival. While anti-resorptive therapy with bisphosphonates was shown to eradicate minimal residue disease in the bone marrow, the effect of denosumab on DTCs, particularly in the neoadjuvant setting, is largely unknown. The recent GeparX clinical trial reported that denosumab, applied as an add-on treatment to nab-paclitaxel based neoadjuvant chemotherapy (NACT), did not improve the patient’s pathologic complete response (pCR) rate. Herein, we analyzed the predictive value of DTCs for the response to NACT and interrogated whether neoadjuvant denosumab treatment may eradicate DTCs in the bone marrow.

Methods
A total of 167 patients from the GeparX trial were analyzed for DTCs at baseline by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3. Initially DTC-positive patients were re-analyzed for DTCs after NACT ± denosumab.

Results
At baseline, DTCs were observed in 43/167 patients (25.7%) in the total cohort, however their presence did not predict response to nab-paclitaxel based NACT (pCR rates: 37.1% in DTC-negative vs. 32.6% DTC-positive; p = 0.713). Regarding breast cancer subtypes, the presence of DTCs at baseline was numerically associated with response to NACT in TNBC patients (pCR rates: 40.0% in DTC-positive vs. 66.7% in DTC-negative patients; p = 0.16). Overall, denosumab treatment did not significantly increase the given DTC-eradication rate of NACT (NACT: 69.6% DTC-eradication vs. NACT + denosumab: 77.8% DTC-eradication; p = 0.726). In TNBC patients with pCR, a numerical but statistically non-significant increase of DTC-eradication after NACT + denosumab was observed (NACT: 75% DTC-eradication vs. NACT + denosumab: 100% DTC-eradication; p = 1.00).

Conclusion
This is the first study worldwide, demonstrating that neoadjuvant add-on denosumab over a short-term period of 24 months does not increase the DTC-eradication rate in breast cancer patients treated with NACT.
HiCAT: a tool for automatic annotation of centromere structure
Authors: Gao Shenghan , Yang Xiaofei , Guo Hongtao , Zhao Xixi , Wang Bo , Ye Kai 
Published: March 2023

AbstractSignificant improvements in long-read sequencing technologies have unlocked complex genomic areas, such as centromeres, in the genome and introduced the centromere annotation problem. Currently, centromeres are annotated in a semi-manual way. Here, we propose HiCAT, a generalizable automatic centromere annotation tool, based on hierarchical tandem repeat mining to facilitate decoding of centromere architecture. We apply HiCAT to simulated datasets, human CHM13-T2T and gapless Arabidopsis thaliana genomes. Our results are generally consistent with previous inferences but also greatly improve annotation continuity and reveal additional fine structures, demonstrating HiCAT’s performance and general applicability.