bluuebunny/crossref_metadata_2025 huggingface dataset:
TET2 regulates early and late transitions in exhausted CD8
+
T cell differentiation and limits CAR T cell function
Authors: Dimitri Alexander J. , Baxter Amy E. , Chen Gregory M. , Hopkins Caitlin R. , Rouin Geoffrey T. , Huang Hua , Kong Weimin , Holliday Christopher H. , Wiebking Volker , Bartoszek Robert , Drury Sydney , Dalton Katherine , Koucky Owen M. , Chen Zeyu , Giles Josephine R. , Dils Alexander T. , Jung In-Young , O’Connor Roddy , Collins Sierra , Everett John K. , Amses Kevin , Sherrill-Mix Scott , Chandra Aditi , Goldman Naomi , Vahedi Golnaz , Jadlowsky Julie K. , Young Regina M. , Melenhorst Jan Joseph , Maude Shannon L. , Levine Bruce L. , Frey Noelle V. , Berger Shelley L. , Grupp Stephan A. , Porter David L. , Herbst Friederike , Porteus Matthew H. , Carty Shannon A. , Bushman Frederic D. , Weber Evan W. , Wherry E. John , Jordan Martha S. , Fraietta Joseph A.
Published: November 2024

CD8
+
T cell exhaustion hampers control of cancer and chronic infections and limits chimeric antigen receptor (CAR) T cell efficacy. Targeting
TET2
in CAR T cells provides therapeutic benefit; however, TET2’s role in exhausted T cell (T
EX
) development is unclear. In chronic lymphocytic choriomeningitis virus (LCMV) infection, TET2 drove conversion from stem cell–like T
EX
progenitors toward terminally differentiated and effector (T
EFF
)–like T
EX
. TET2 also enforced a terminally differentiated state in the early bifurcation between T
EFF
and T
EX
, indicating broad roles for TET2 in acquisition of effector biology. To exploit the therapeutic potential of TET2, we developed clinically actionable
TET2-
targeted CAR T cells by disrupting
TET2
via knock-in of a safety switch alongside CAR knock-in at the
TRAC
locus.
TET2
-targeted CAR T cells exhibited restrained terminal exhaustion in vitro and enhanced antitumor responses in vivo. Thus, TET2 regulates fate transitions in T
EX
differentiation and can be targeted with a safety mechanism in CAR T cells for improved tumor control.
Frailty or resilience? Hazard-based and cumulative phenotype approaches to discerning signals of health inequality in medieval London
Authors: Yaussy Samantha L. , Marklein Kathryn E. , DeWitte Sharon N. , Crews Douglas E.
Published: November 2024

Bioarchaeology uses human skeletal remains to reconstruct varied experiences of individuals and populations in the past, including patterns of health across time periods and cultural contexts. In the past three decades, bioarchaeological studies have highlighted the concept of “frailty,” operationalizing it as increased risk of mortality or cumulative phenotypes. Using data from medieval London cemeteries, we integrate these two approaches to frailty in past populations. First, we estimate the risks of mortality and survivorship (hazard and survival analyses) associated with 10 biomarkers and use these results to construct population-specific frailty and resilience indices. Then, we apply the indices to adult individuals to explore frailty and resilience differentials between males and females in medieval London. Findings suggest that the male-female morbidity-mortality paradox observed in modern populations may not have existed in this context, which may be explained by preferential cultural buffering of men in this patriarchal, urban setting.
Toxic small alarmone synthetase FaRel2 inhibits translation by pyrophosphorylating tRNA
Gly
and tRNA
Thr
Authors: Kurata Tatsuaki , Takegawa Masaki , Ohira Takayuki , Syroegin Egor A. , Atkinson Gemma C. , Johansson Marcus J.O. , Polikanov Yury S. , Garcia-Pino Abel , Suzuki Tsutomu , Hauryliuk Vasili
Published: November 2024

Translation-targeting toxic small alarmone synthetases (toxSAS) are effectors of bacterial toxin-antitoxin systems that pyrophosphorylate the 3′-CCA end of transfer RNA (tRNA) to prevent aminoacylation. toxSAS are implicated in antiphage immunity: Phage detection triggers the toxSAS activity to shut down viral production. We show that the toxSAS FaRel2 inspects the tRNA acceptor stem to specifically select tRNA
Gly
and tRNA
Thr
. The first, second, fourth, and fifth base pairs of the stem act as the specificity determinants. We show that the toxSASs PhRel2 and CapRel
SJ46
differ in tRNA specificity from FaRel2 and rationalize this through structural modeling: While the universal 3′-CCA end slots into a highly conserved CCA recognition groove, the acceptor stem recognition region is variable across toxSAS diversity. As phages use tRNA isoacceptors to overcome tRNA-targeting defenses, we hypothesize that highly evolvable modular tRNA recognition allows for the escape of viral countermeasures through tRNA substrate specificity switching.
NeuralFeels with neural fields: Visuotactile perception for in-hand manipulation
Authors: Suresh Sudharshan , Qi Haozhi , Wu Tingfan , Fan Taosha , Pineda Luis , Lambeta Mike , Malik Jitendra , Kalakrishnan Mrinal , Calandra Roberto , Kaess Michael , Ortiz Joseph , Mukadam Mustafa
Published: November 2024

To achieve human-level dexterity, robots must infer spatial awareness from multimodal sensing to reason over contact interactions. During in-hand manipulation of novel objects, such spatial awareness involves estimating the object’s pose and shape. The status quo for in-hand perception primarily uses vision and is restricted to tracking a priori known objects. Moreover, visual occlusion of objects in hand is imminent during manipulation, preventing current systems from pushing beyond tasks without occlusion. We combined vision and touch sensing on a multifingered hand to estimate an object’s pose and shape during in-hand manipulation. Our method, NeuralFeels, encodes object geometry by learning a neural field online and jointly tracks it by optimizing a pose graph problem. We studied multimodal in-hand perception in simulation and the real world, interacting with different objects via a proprioception-driven policy. Our experiments showed final reconstruction
F
scores of 81% and average pose drifts of 4.7 millimeters, which was further reduced to 2.3 millimeters with known object models. In addition, we observed that, under heavy visual occlusion, we could achieve improvements in tracking up to 94% compared with vision-only methods. Our results demonstrate that touch, at the very least, refines and, at the very best, disambiguates visual estimates during in-hand manipulation. We release our evaluation dataset of 70 experiments, FeelSight, as a step toward benchmarking in this domain. Our neural representation driven by multimodal sensing can serve as a perception backbone toward advancing robot dexterity.
Consequences beyond acute SARS-CoV-2 infection in children
Authors: Saydah Sharon H. , Campbell Angela P. , Randolph Adrienne G.
Published: November 2024

Although most children are spared from developing complications from SARS-CoV-2 infection, some may suffer consequences including Long Covid and multisystem inflammatory syndrome in children (MIS-C). Although the occurrence of these conditions has decreased over time, they can still occur, and recognition of symptoms and prompt diagnosis is imperative for early intervention.
Sex differences in postacute infection syndromes
Authors: Silva Julio , Iwasaki Akiko
Published: November 2024

Postacute infection syndromes like Long Covid disproportionately affect females, differing in prevalence, symptoms, and potential causes from males. This Viewpoint highlights these sex differences, gaps in current understanding, and the critical need for sex-based research.
Animal models of Long Covid: A hit-and-run disease
Authors: Schäfer Alexandra , Leist Sarah R. , Powers John M. , Baric Ralph S.
Published: November 2024

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2) pandemic has caused more than 7 million deaths globally. Despite the presence of infection- and vaccine-induced immunity, SARS-CoV-2 infections remain a major global health concern because of the emergence of SARS-CoV-2 variants that can cause severe acute coronavirus disease 2019 (COVID-19) or enhance Long Covid disease phenotypes. About 5 to 10% of SARS-CoV-2–infected individuals develop Long Covid, which, similar to acute COVID 19, often affects the lung. However, Long Covid can also affect other peripheral organs, especially the brain. The causal relationships between acute disease phenotypes, long-term symptoms, and involvement of multiple organ systems remain elusive, and animal model systems mimicking both acute and post-acute phases are imperative. Here, we review the current state of Long Covid animal models, including current and possible future applications.
Draft genome sequences of multi-drug-resistant
Escherichia coli
strains isolated from ulcerative colitis patients
Authors: Yadav Asha , Shinde Pratik Balwant , Dhar Mahesh S. , Ponnusamy Kalaiarasan , Marwal Robin , VS RadhaKrishnan , Kedia Saurabh , Ahuja Vineet , Sharma Krishna Kant
Published: November 2024

The whole-genome sequences of four multi-drug-resistant
Escherichia coli
strains, namely, DAK02, DAK03, DAK05, and DAK10, are reported here. The
E. coli
strains were isolated from fecal samples of ulcerative colitis patients from Northern India. The size of the draft genome sequence ranged from 4,809 to 5,000 kb.
Draft genome sequences of six multidrug-resistant
Escherichia coli
isolates from pigeons in Bangladesh
Authors: Gupta Mukta Das , Shaha Mishuk , Das Ashutosh
Published: November 2024

Household pigeons are a potential source of multidrug-resistant (
Escherichia coli
(
E. coli
) and act as a transmission vehicle of this bacterium to humans. Here, we characterized the antimicrobial resistance profile and molecular properties of the whole genome sequences of six
E. coli
strains from household pigeons.
Exploring the genomic basis of Mpox virus-host transmission and pathogenesis
Authors: Young Brayden , Seifert Stephanie N. , Lawson Crystal , Koehler Heather
Published: November 2024

Mpox disease, caused by the monkeypox virus (MPXV), was recently classified as a public health emergency of international concern due to its high lethality and pandemic potential. MPXV is a zoonotic disease that emerged and is primarily spread by small rodents. Historically, it was considered mainly zoonotic and not likely to sustain human-to-human transmission. However, the worldwide outbreak of Clade IIb MPXV from 2020 to 2022 and ongoing Clade I MPXV epidemics in the Democratic Republic of the Congo and surrounding areas are a warning that human-adapted MPXVs will continually arise. Understanding the viral genetic determinants of host range, pathogenesis, and immune evasion is imperative for developing control strategies and predicting the future of Mpox. Here, we delve into the MPXV genome to detail genes involved in host immune evasion strategies for this zoonotic rodent-borne and human-circulating virus. We compare MPXV gene content to related Orthopoxviruses, which have narrow host ranges, to identify potential genes involved in species-specific pathogenesis and host tropism. In addition, we cover the key virulence factor differences that distinguish the MPXV clade lineages. Finally, we dissect how genomic reduction of Orthopoxviruses, through various molecular mechanisms, is contributing to the generation of novel MPXV lineages with increased human adaptation. This review aims to highlight gene content that defines the MPXV species, MPXV clades, and novel MPXV lineages that have culminated in this virus being elevated to a public health emergency of national concern.
Functional insights of novel Bathyarchaeia reveal metabolic versatility in their role in peatlands of the Peruvian Amazon
Authors: Pavia Michael J. , Garber Arkadiy I. , Avalle Sarah , Macedo-Tafur Franco , Tello-Espinoza Rodil , Cadillo-Quiroz Hinsby
Published: November 2024

The decomposition of soil organic carbon within tropical peatlands is influenced by the functional composition of the microbial community. In this study, building upon our previous work, we recovered a total of 28 metagenome-assembled genomes (MAGs) classified as Bathyarchaeia from the tropical peatlands of the Pastaza-Marañón Foreland Basin (PMFB) in the Amazon. Using phylogenomic analyses, we identified nine genus-level clades to have representatives from the PMFB, with four forming a putative novel family (“
Candidatus
Paludivitaceae”) endemic to peatlands. We focus on the
Ca
. Paludivitaceae MAGs due to the novelty of this group and the limited understanding of their role within tropical peatlands. Functional analysis of these MAGs reveals that this putative family comprises facultative anaerobes, possessing the genetic potential for oxygen, sulfide, or nitrogen oxidation. This metabolic versatility can be coupled to the fermentation of acetoin, propanol, or proline. The other clades outside
Ca
. Paludivitaceae are putatively capable of acetogenesis and
de novo
amino acid biosynthesis and encode a high amount of Fe
3+
transporters. Crucially, the
Ca
. Paludivitaceae are predicted to be carboxydotrophic, capable of utilizing CO for energy generation or biomass production. Through this metabolism, they could detoxify the environment from CO, a byproduct of methanogenesis, or produce methanogenic substrates like CO
2
and H
2
. Overall, our results show the complex metabolism and various lineages of Bathyarchaeia within tropical peatlands pointing to the need to further evaluate their role in these ecosystems.

IMPORTANCE

With the expansion of the
Candidatus
Paludivitaceae family by the assembly of 28 new metagenome assembled genomes, this study provides novel insights into their metabolic diversity and ecological significance in peatland ecosystems. From a comprehensive phylogenic and functional analysis, we have elucidated their putative unique facultative anaerobic capabilities and CO detoxification potential. This research highlights their crucial role in carbon cycling and greenhouse gas regulation. These findings are essential for resolving the microbial processes affecting peat soil stability, offering new perspectives on the ecological roles of previously underexplored and underrepresented archaeal populations.
Quantitative MODS-Wayne assay for rapid detection of pyrazinamide resistance in
Mycobacterium tuberculosis
from sputum samples
Authors: Toscano-Guerra Emily , Alcántara Roberto , Untiveros Katherine Lozano , Gilman Robert , Grandjean Louis , Zimic Mirko , Sheen Patricia
Published: November 2024

Tuberculosis (TB) remains a significant global health challenge, exacerbated by the emergence of drug-resistant strains, such as those resistant to pyrazinamide (PZA). The current scarcity of affordable and precise quantitative diagnostic tests for PZA resistance underscores the urgent need for more accessible diagnostic tools. We evaluated PZA susceptibility in 264 TB-positive samples by quantifying pyrazinoic acid (POA) production, using both the MODS-Wayne qualitative assay and our newly developed quantitative approach (MODS-WQ). The MODS-WQ was assessed in 7H9 medium (MODS-WQ
7H9
) or citrate buffer (MODS-WQ
CB
), with POA levels measured via spectrophotometry against a calibration curve. PZA susceptibility determinations were based on a composite reference standard. Associations between POA levels and pyrazinamidase mutations were explored. The composite standard detected PZA resistance in 23.5% of the samples, which accounts for 62.8% of the multidrug-resistant (MDR) samples. The MODS-WQ established specific POA cutoffs of 123.25 µM for MODS-WQ
7H9
and 664.7 µM for MODS-WQ
CB
, with sensitivities of 81.3% and 92.3% and specificities of 77.2% and 95.9%, respectively. Notably, samples with mutations in the pyrazinamidase metal-binding site exhibited significantly lower POA levels compared with mutations in the enzyme periphery. Furthermore, a significant correlation was found between POA production and PZA resistance, Bactec Growth Index, and minimum inhibitory concentration (MIC) values. This study presents a novel, direct, and accessible susceptibility test for PZA resistance that quantifies POA, enhancing the detection capabilities for this condition. The citrate-buffered MODS-WQ assay demonstrated high sensitivity and specificity for quantifying POA, confirming that POA production is a reliable indicator of PZA resistance.

IMPORTANCE

PZA susceptibility testing continues to be a challenge, particularly in countries with high TB incidence. In response to this pressing need, we have developed a quantitative MODS-Wayne (MODS-WQ) assay. This approach offers a direct and cost-effective solution representing a significant advancement in TB diagnostics, particularly benefiting resource-limited laboratories, primarily in developing regions. The MODS-WQ assay stands out for its ability to quantify pyrazinoic acid (POA) production, as a reliable indicator of PZA resistance. Unlike traditional qualitative assays, MODS-WQ eliminates the inherent subjectivity in interpretation, providing more accurate and actionable results. Moreover, the MODS-WQ approach accounts for critical factors influencing PZA resistance, including enzymatic efficiency and efflux pump activity. By integrating these factors into the detection process, our methodology offers a comprehensive understanding of PZA resistance levels, enabling tailored treatment strategies for patients.
Throw distribution across the Dabbahu–Manda Hararo dike-induced fault array: Implications for rifting and faulting
Authors: Hofmann Barbara , Magee Craig , Wright Tim J.
Published: November 2024

Dike intrusion and formation of overlying dike-induced normal faults facilitate plate extension. The kinematics of these dike-induced normal faults provide an accessible record of subsurface diking. Here, we use high-resolution light detection and ranging (LiDAR) and interferometric synthetic aperture radar (InSAR) data to explore how strain was distributed across a preexisting dike-induced fault array during diking events in the Dabbahu–Manda Hararo magmatic segment (Afar, Ethiopia) in 2008 and 2010. By analyzing throw of the dike-induced normal faults, we show that only a small number of faults were reactivated during each diking event; the distribution of this reactivation likely reflects dike depth, opening, and inclination, as well as fault orientation. We also show fault throw favorably accrued toward fault centers, away from areas of soft- or hard-linkage. Our high-resolution data sets demonstrate the importance of reactivation to rifting, as it means extension can occur at lower extensional forces, and that fault slip (and seismic hazard) may not localize at sites of fault linkage.
Ex utero intrapartum treatment (EXIT) procedure for the second twin with neck mass in a twin pregnancy with vertex/breech presentation
Authors: Tan Ilka , Bhatia Anju , Tan June Vic Khi
Published: November 2024

We report a case of a dichorionic diamniotic twin pregnancy where twin B was diagnosed with a large multi-loculated exophytic cystic neck mass arising from the right side with involvement of the right proximal upper limb and significant mass effect on the trachea diagnosed during antenatal MRI. After multidisciplinary discussion, an ex utero intrapartum treatment (EXIT) procedure was planned given concerns about airway obstruction in twin B. Successful EXIT was performed with the delivery of twin A first, followed by an intraoperative external cephalic version of twin B and subsequent delivery of the fetal head and intubation on maternal circulation.
Simulation with Monte Carlo methods to focus quality improvement efforts on interventions with the greatest potential for reducing PACU length of stay: a cross-sectional observational study
Authors: Jones James Harvey , Fleming Neal
Published: November 2024

Background

Time and money are limited resources to pursue quality improvement (QI) goals. Computer simulation using Monte Carlo methods may help focus resources towards the most efficacious interventions to pursue.

Methods

This observational, cross-sectional study analysed the length of stay (LOS) for adult American Society of Anesthesiologists (ASA) 1–3 patients in the postanaesthesia care unit (PACU) at a major academic medical centre. Data were collected retrospectively from 1 April 2023 to 31 March 2024. Statistical analysis with Monte Carlo methods simulated the per cent reduction in PACU LOS following the elimination of postoperative nausea and vomiting (PONV), hypothermia (initial temperature<36°C), severe pain (pain score≥7) or moderate opioid use (≥ 50 mcg fentanyl or≥0.4 mg hydromorphone).

Results

The PACU LOS of 7345 patients were included in this study. PONV was experienced by 10.29% of patients and was associated with a mean PACU LOS of 96.64 min (±33.98 min). Hypothermia was the least frequent complication, experienced by 8.93% of patients and was associated with a mean PACU LOS of 83.55 min (±35.99 min). Severe pain and moderate opioid use were seen in 34.05% and 40.83% of patients, respectively and were associated with PACU LOS that were shorter than those experienced by patients with PONV. Monte Carlo simulations demonstrated that the greatest impact on PACU LOS (12.5% (95% CI 12.0% to 13.0%)) would result from the elimination of moderate opioid use.

Discussion

Although PONV was associated with the longest PACU LOS, statistical simulation with Monte Carlo methods demonstrated the greatest per cent reduction in PACU LOS would result from the elimination of moderate opioid use, thus indicating the most efficacious project to pursue.

Conclusion

Statistical simulation with Monte Carlo methods can help guide QI teams to the most efficacious project or intervention to pursue.
Hearing loss in newborn infants with hypoxic ischaemic encephalopathy: protocol for a case–control study
Authors: Pereira Sujith , D'costa Milton , Aladangady Narendra
Published: November 2024

Introduction

Hypoxic ischaemic encephalopathy (HIE), a condition where the brain does not receive enough oxygen and/or blood flow around the time of birth, is associated with significant morbidity and mortality. Systemic circulation may be affected due to poor myocardial function. The cochlear hair cells are vulnerable to changes in microcirculation, which may occur in HIE predisposing to hearing loss. Therefore, all infants with HIE undergo neurodevelopmental surveillance after discharge to monitor for adverse neurodevelopment including speech and hearing problems. This study will examine the incidence of confirmed hearing loss in newborn infants with any stage of HIE (cases) and compare them with controls.

Methods and analysis

All infants diagnosed with any stage of HIE (cases) over a 12-year period (January 2010 to December 2021) will be examined. Controls were newborn infants without HIE who were admitted to the neonatal unit and received intensive care including antibiotics (control group 1) and stable infants in the postnatal ward who received antibiotics (eg, gentamicin) (control group 2). Controls matched for gestation, gender and birth weight will be selected from a similar time period. Infant details and hearing screening data will be gathered from prospectively entered BadgerNet and S4H system databases, respectively. Categorical data will be analysed using the χ2test. Predictors for hearing loss will be performed using binary logistic regression analysis.

Ethics and dissemination

The study is approved by the Health and Care Research Wales (HCRW) Research Ethics Committee and the Health Research Authority (HRA) (reference 21/HRA/4506). The study findings will be presented at national/international conferences and published in peer-reviewed scientific journals.
Investigating awareness and implementation of adrenaline auto-injectors (AAI) via the ‘Spare Pens in Schools’ scheme in Wales: a cross-sectional pilot study
Authors: Panayiotou Eliana , Hassoulas Athanasios , Tuthill David , Miles Elizabeth , Holloway Judith
Published: November 2024

Objective

To investigate awareness and implementation of the Spare Pens (ie, adrenaline auto-injectors (AAIs)) scheme in primary and secondary schools in two regions in Wales.

Design

A cross-sectional pilot study employing a mixed research methods approach was carried out.

Setting and participants

State primary and secondary schools within Swansea and Pembrokeshire regional authorities were invited to take part. For geographical context, Swansea is the second largest city in Wales and is situated in the southwest of the country. Pembrokeshire is located in West Wales, with a large rural population outside of its main towns.

Main outcome measures

Awareness and implementation of the Spare Pens in Schools scheme. Additionally, compliance with national guidance was measured by administering a questionnaire capturing data on registers, procedures, storage and training in the use of AAIs.

Results

35 schools (30 primary, 5 secondary) participated, with 11% and 6% reporting awareness and implementation of the scheme, respectively. No significant differences in awareness or implementation of the scheme were revealed for school type or region. Secondary schools reportedly stored more AAI devices compared with primary schools. The location of stored AAIs varied by school type, with 46.7% of primary schools storing AAIs in the classroom while 80% of secondary schools stored AAIs in the school office. Procedures for accessing AAI training differed, with 83% of primary schools receiving training by school nurses and 60% of secondary schools accessing training via an allergy team.

Conclusions

The overall poor awareness of the Spare Pens in Schools scheme has resulted in a worrying lack of implementation of generic AAI devices. An urgent review of information dissemination regarding the scheme is required.
Industry marketing payments to physicians and prescription patterns for sacubitril/valsartan in the USA
Authors: Murayama Anju
Published: November 2024

Objectives

Although financial interactions between physicians and pharmaceutical and medical device companies could be potential conflicts of interest, in certain instances, industry promotion targeted at physicians may facilitate the early adoption of effective, novel care for patients such as sacubitril/valsartan in the USA. This study aims to evaluate associations between industry-sponsored meal payments to physicians and their prescribing patterns for sacubitril/valsartan in the USA.

Methods

Using the publicly accessible Centers for Medicare and Medicaid Services Medicare Part D database and the Open Payments Database, this study assessed associations between industry-sponsored meal payments to physician prescribers and total amounts of Medicare claims and spending for sacubitril/valsartan between 2015 and 2021.

Results

Among 220 147 eligible physician prescribers, 60 568 (27.5%) received at least one meal payment related to sacubitril/valsartan from the manufacturer, totaling US$13.9 million. The receipt of meal payments was significantly associated with a higher proportion of sacubitril/valsartan prescriptions to all sacubitril/valsartan, angiotensin receptor blocker and angiotensin-converting enzyme inhibitor prescriptions, with an OR of 2.04 (95% CI: 1.98 to 2.10, p<0.001). Moreover, a 10% increase in the annual number of meal payments was associated with a 2.6% (95% CI: 2.5% to 2.6%, p<0.001) increase in the annual number of Medicare claims and a 7.3% (95% CI: 7.1% to 7.5%, p<0.001) increase in annual Medicare spending per physician.

Conclusions

Given the underprescription of sacubitril/valsartan in the USA, the positive associations between meal payments and physicians' prescribing patterns suggest that industry-sponsored meals may contribute to the early adoption of this cost-effective, novel heart failure drug among US Medicare beneficiaries.
Systemic chemokine-modulatory regimen combined with neoadjuvant chemotherapy in patients with triple-negative breast cancer
Authors: Gandhi Shipra , Slomba Ronald T , Janes Cayla , Fitzpatrick Victoria , Miller Janine , Attwood Kristopher , Ioannou Giorgio , Ozbey Sinem , De Souza Igor , Roudko Vladimir , Kumar Prasanna , Kalathil Suresh , Kokolus Kathleen M , Wang Jianming , Cortes Gomez Eduardo , Takabe Kazuaki , Edge Stephen , Young Jessica , Cappuccino Helen , Opyrchal Mateusz , O’Connor Tracey , Levine Ellis G , Gnjatic Sacha , Kalinski Pawel
Published: November 2024

Background

Higher cytotoxic T lymphocyte (CTL) numbers in the tumor microenvironment (TME) predict pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) and positive long-term outcomes in triple-negative breast cancer (TNBC). pCR to NAC is achieved only in 30–40% of patients. The combination of NAC with pembrolizumab increases the pCR rate but at the cost of immune-related adverse events (irAEs). Based on these considerations, we tested if systemic infusion of the chemokine modulatory regimen (CKM; selective toll-like receptor 3 (TLR3) agonist rintatolimod, interferon (IFN)-α2b, and cyclooxygenase-2 (COX-2) inhibitor celecoxib) regimen can be safely combined with NAC to enhance intratumoral CTL numbers and NAC effectiveness.

Methods

Phase I studyNCT04081389evaluated nine patients with early-stage TNBC who received 3 weeks of paclitaxel with CKM (dose-escalation of IFN-α2b), followed by 9 weeks of paclitaxel alone, dose-dense doxorubicin and cyclophosphamide, and surgery. Primary and secondary endpoints were safety and clinical efficacy, respectively.

Results

The combination treatment was well-tolerated with no dose-limiting toxicities or irAEs. 5/9 patients achieved pCR and one patient had microinvasive disease (ypTmic). We observed elevated IFN signature and uniform decreases in CTL numbers (average 8.3-fold) in the blood of all treated patients. This was accompanied by reciprocal uniform increases in CD8β (overall 5.9-fold), CD8α/FoxP3 (2.11-fold), and CCL5 (4.73-fold) transcripts in TME, particularly pronounced in patients with pCR. Multiplex immunohistochemistry revealed selectively increased numbers of CTL (but not regulatory T cells) in both the epithelial and stromal tumor compartments and early decreases in the numbers of αSMA+vascular/stromal cells in the tumors of all pCR patients.

Conclusions

Combined paclitaxel/CKM regimen was safe, with desirable TME changes and preliminary indications of promising pCR+ypTmic of 66%, comparable to the combination of NAC with pembrolizumab.
FOXA1 enhances antitumor immunity via repressing interferon-induced PD-L1 expression in nasopharyngeal carcinoma
Authors: Ge Junshang , Liu Ying , Chen Pan , Zeng Zhaoyang , Li Guiyuan , Xiong Wei , Yi Mei , Xiang Bo
Published: November 2024

Background

Nasopharyngeal carcinoma (NPC) is a distinct subtype of head and neck cancer which is prevalent in south of China and southeastern of Asia. Consistent activation of interferon (IFN) signaling, and impairment of T cell mediated antitumor immunity is frequent in NPC. Forkhead box A1 (FOXA1) is one of the earliest discovered pioneer factors, which can open up compact chromatin structures to facilitate the binding of other proteins to chromatin.

Methods

By using RNA sequencing, it was discovered that FOXA1 suppresses the activation of the interferon signaling pathway and the expression of the related interferon-responsive genes in NPC cells. The effect of FOXA1 on programmed death-ligand 1 (PD-L1) expression in C666-1 and HK1 cells under conditions with or without IFN-γ was detected through quantitative PCR (qPCR), western blot, and flow cytometry. After co-culturing T cells with IFN-γ-treated NPC cells in vitro, apoptosis of CD8+T cells and the expression of cytotoxic cytokines were assessed by flow cytometry. The cytotoxic effects of T cells on tumor cells in nude mice were measured by tumorigenesis in nude mice and adoptive T cell therapy. The effects of IFN-γ on the expression and nuclear localization of STAT1, as well as the colocalization of FOXA1 with STAT1 were detected by immunofluorescence, qPCR, western blot, and co-immunoprecipitation experiments.

Results

In this study, we reported that loss of FOXA1, a pioneer factor downregulated in NPC, results in activation of IFN signaling in NPC cells. Repression of FOXA1 facilitates IFN-γ induced PD-L1 expression, whereas overexpression of FOXA1 exerts the opposite effect. Mechanistically, FOXA1 interacts with STAT1 and inhibits IRF1 expression and binding to PD-L1 promoter on IFN-γ treatment. Co-culture with FOXA1-silenced NPC cells promotes apoptosis of in vitro activated tumor-specific CD8+T cells and reduces the expression of cytotoxic effector molecules. Furthermore, overexpression of FOXA1 increases the therapeutic efficacy of PD-L1 antibody (atezolizumab) against NPC in nude mice receiving adoptive T-cell therapy.

Conclusions

We demonstrated that FOXA1 prevents tumor immune evasion by inhibiting IFN-γ induced PD-L1 expression in NPC cells. Our research findings provide new insights into the immunotherapeutic biomarkers and targets for NPC, which is important for the clinical application of programmed cell death protein-1/PD-L1 antibodies in NPC.
Therapeutic serum level for adalimumab in rheumatoid arthritis: explorative analyses of data from a randomised phase III trial
Authors: Gehin Johanna Elin , Klaasen Rolf Anton , Klami Kristianslund Eirik , Jyssum Ingrid , Sexton Joseph , Warren David John , Aletaha Daniel , Haavardsholm Espen Andre , Syversen Silje Watterdal , Goll Guro Løvik , Bolstad Nils
Published: November 2024

Objectives

The objectives of this study are to identify a therapeutic serum level for adalimumab associated with remission and low disease activity in patients with rheumatoid arthritis.

Methods

Associations between serum adalimumab trough levels and disease activity were examined using longitudinal data from a 48-week randomised phase III trial including patients with tumour necrosis factor inhibitor-naïve rheumatoid arthritis with active disease starting adalimumab treatment. Disease activity was classified according to 28-joint Disease Activity Score (DAS28)-erythrocyte sedimentation rate and C reactive protein (CRP) levels.

Results

Adalimumab trough levels were recorded longitudinally for 336, 330 and 302 patients at weeks 12, 24 and 48, respectively. All patients received concomitant methotrexate. Median adalimumab trough levels were 6.4 mg/L (IQR 3.4–9.5) at week 12, 7.5 mg/L (IQR 3.5–10.9) at week 24 and 7.6 mg/L (IQR 3.6–12.0) at week 48. In serial serum samples from weeks 12, 24 and 48, trough levels ≥3.9 mg/L were associated with DAS28 remission (OR 3.88 (95% CI 1.80, 8.38), p<0.001) and lower CRP levels (p<0.001). Week 12 trough levels ≥3.5 mg/L were associated with DAS28 low disease activity at week 24 (OR 2.62 (1.50, 4.56), p<0.001) and remission at week 48 (OR 1.99 (1.02, 3.88), p=0.04), as well as lower CRP levels at both time points (p<0.001).

Conclusion

Adalimumab trough levels above 4.0 mg/L were associated with remission/low disease activity throughout the first year of adalimumab therapy and can be considered a lower target level for therapeutic drug monitoring of adalimumab therapy.
Numerical FE three-phasic simulation to predict the effect of air voids on the dynamic modulus of bituminous composites
Authors: Fakhari Tehrani Fateh , Hajikarimi Pouria , Hosseini Alireza Sadat , Absi Joseph , Petit Christophe
Published: November 2024

In this study, the mechanical performance of bituminous composites was predicted using an upscaling methodology that integrated both finite element analysis and analytical modeling. The FE approach was employed to incorporate intricate geometries, and material characteristics. The dynamic modulus of the matrix and the elastic properties of aggregates served as inputs for the numerical models at various scales. This approach considers the distinctive attributes of the granular framework at each level. Furthermore, the investigation involved the influence of air void proportions on the composite’s modulus. The numerical models encompassed the random incorporation of air voids within the matrix at varying levels. Notably, it was observed that at low frequencies, air voids reduced the dynamic modulus of asphalt more than at high frequencies due to its effect on viscoelastic nature of the bituminous composite. Moreover, heightened temperatures intensified the impact of air void on the dynamic modulus of the asphalt mixture.
Improved adaptive genetic algorithm for dynamic multi-specification one-dimensional cutting problem
Authors: Liu Li , Liu Zijin , Qian Xuefei
Published: November 2024

Rebar is an essential material in the construction of bridges and houses. Rebar cutting is an important link in rebar processing, but it is usually completed by manual experience, which is not only time-consuming, but also causes serious waste and reduces the economic benefits. As the country vigorously promotes the green construction method, the traditional rebar cutting method is difficult to meet the development requirements. So dynamic multi-specification one-dimensional cutting problem is studied in this paper. A mathematical model aiming at the maximum utilization rate of raw material is established, and an improved adaptive genetic algorithm is proposed. Large-scale, small-scale, single-specification masterbatch and multi-specification masterbatch are selected for simulation experiments, respectively. The results show that the proposed algorithm can deal with both large- and small-scale multi-specification or single-specification masterbatch cutting problems. Moreover, the algorithm has good performance in solving accuracy and convergence speed, which verifies its feasibility, effectiveness, and stability. Finally, aiming at the problem of dynamic insertion of orders, one-dimensional cutting software is developed, rapid and real-time cutting of rebars is realized, and the utilization rate of building rebars is improved, which plays a positive role in promoting the high-quality development of construction industries such as bridges.
Based on the Principle Component Analysis of the Level of Cultural and Tourism Integration in a Place and Obstacles Analysis
Authors: Zhang Haitao , Wu Tongyong
Published: November 2024

China’s culture is one of the oldest and most complex in the world, with a history that spans thousands of years. Rooted in Confucianism, Taoism, and Buddhism, Chinese culture emphasizes harmony, respect for tradition, and the importance of family. These philosophies have profoundly influenced the social values, customs, and daily life of the Chinese people. This study aimed to identify 10 different dimensions and the perception of quality amongst tourists based on the rural tourism experience. Perceived value and tourism satisfaction are seen as two constructs that bridge the gulf between these quality perceptions and the tourists’ future behavior — that is, the intent of tourists to revisit, spread positive word-of-mouth, and their propensity to splurge on unique rural products. Furthermore, we also examined the respondents’ areas where they lived in urban or rural areas which would affect their perceptions and behaviors. The analysis was identified using data from 650 respondents’ four key quality dimensions: tourism environment and transportation, companionship and learning, culture and local items, and rural environment as perceived by the tourists. Indeed, the findings lend considerable empirical support to the relationship of perceived quality with perceived value, satisfaction, and the dimensions of the behavioral intentions of tourists. Interestingly, the study showed residents — the urban and rural residents of tourists — as a very important moderator of these relationships. These are important insights that would be invaluable in explaining the driving factors of tourists’ intentions and the imperative for the sustainable growth of rural tourism in China.
Design of Travel Route Planning Model Based on Deep Learning
Authors: Xu Xiaoyan , Zhang Li
Published: November 2024

Tourism route planning is affected by the factors such as tourism destination and tourists’ preference, which leads to poor automatic matching of routes. A mathematical model of tourism route planning based on deep learning is proposed. Under the condition of total route constraints, according to the historical tourism preference information and prior information of tourists, a big data model for the distribution of personalized characteristics of tourists is established, spatial constraints and time constraints parameters are input, and the feature matching of geographic location information and tourist interest parameter information is carried out by using the deep learning method, and the statistical feature quantity of the parameters of the tourism route planning model is extracted. Under the control of the deep learning and geographic information data set, Carry out multi-constraint and multi-objective hierarchical analysis of tourists and tourism destinations, and realize the optimization design of tourism route planning algorithm. The simulation results show that the accuracy of this method is high and the deviation is small. It improves the satisfaction level of tourists and helps users complete a series of visual analysis tasks such as route mining, route planning and destination analysis.
An analytic study of a novel algebraic public key encryption scheme based on polynomials over noncommutative matrix ring
Authors: Kanwal Shamsa , Inam Saba , Ali Rashid
Published: November 2024

Different public key exchange protocols can be employed to design a cryptosystem. The most famous example is the ElGamal cryptosystem which is based on the Diffie–Hellman key establishment to do encryption and decryption. In the same fashion, we propose a public key cryptosystem using a public key exchange protocol. This variant uses the polynomials over noncommutative matrix ring as underlying work structure. The useful feature of the proposed cryptosystem is that it provides favorable security because of use of the generalized decomposition problem over the noncommutative ring of matrices. The issues regarding the choice of parameters and platform are discussed. Further, a brief note on security analysis of the proposed cryptosystem is also presented.
Global well-posedness and large-time behavior for a special 21 2D full compressible viscous non-resistive MHD system
Authors: Zhai Xiaoping , Zhang Shunhang
Published: November 2024

In this paper, we consider the full compressible, viscous, non-resistive MHD system under the assumption that the fluids move on a plane while the magnetic field is oriented vertically. Within the framework of Besov spaces, by introducing several new unknown quantities and exploiting the intrinsic structure of the system, we prove the global well-posedness of strong solutions for initial data close to a constant equilibrium state. Furthermore, under some suitable additional conditions involving only the low-frequency part of the initial perturbation, we develop a Lyapunov-type energy argument, which yields the optimal time-decay rates of the global solution. To the best of our knowledge, our result is the first one on global-in-time solvability to the full compressible, viscous, non-resistive MHD system in multi-dimensional whole space.
Characteristics Associated with Genetic Progress in Grain Yield in Wheat (Triticum aestivum L.)
Authors: Ledesma-Ramirez Lourdes , Solis-Moya Ernesto , Gonzalez-Figueroa Sarahyt Santamaria , Mariscal-Amaro Luis Antonio , Buenrostro-Rodriguez Juan Francisco , de la Cruz Gonzalez Maria de Lourdes
Published: November 2024

Increasing the yield potential of cultivars can contribute to solving the problems of climate change and the increase in world population. The objectives of this study were to study the variation of 60 wheat (Triticum aestivum L.) genotypes and to estimate the genetic progress in agronomic characters of varieties released in Mexico in the period from 1966 to 2015. The hypothesis was that the increases in yield of the genotypes are the result of the increase in the number of grains per surface unit and biomass. The study was established in six experimental stations of the National Institute of Agricultural Forestry and Livestock Research in the states of Guanajuato, Sonora, Chihuahua, Jalisco, Sinaloa, and Baja California, Mexico. Phenology, yield, and its components were measured. The treatment design was alpha lattice with two replications. The location and genotype that showed the highest yield (P ≤ 0.01) were Baja California and COLIBRI/MONARCA, with 7309 and 5966 kg·ha−1. The average genetic gain in yield was 23.8 kg·ha−1·year−1. The grain weight increase rate was 0.21 g per year. During the period, there was no genetic progress in plant height, heading days, harvest index, grains per square meter, and ears per square meter. The increases in yield of the recent lines are due to increases in ears per square meter, grains per square meter, and biomass.
Morphological Characterization and Genotyping of Acanthamoeba Isolates From Oral and Nasal Samples of Cancer Patients in Kashan, Iran
Authors: Rasti Sima , Taghipour Tayebeh , Delavari Mahdi , Hooshyar Hossein , Moosavi Gholam Abbas , Arbabi Mohsen
Published: November 2024

Background: Acanthamoeba​ species are recognized as the most prevalent free‐living amoebae (FLA). They can cause granulomatous amebic encephalitis (GAE) and pulmonary and ocular infections. The present study aimed to isolate and identify Acanthamoeba genotypes in cancer patients referred to Kashan’s hospitals in Central Iran.

Methods: This cross‐sectional study was conducted with oral and nasal swab samples collected from a hundred cancer patients referred to Kashan’s Beheshti and Yasrebi hospitals during 2019–2020. The samples were cultured in 1.5% non‐nutrient agar (NNA) with heat‐killed Escherichia coli and examined for “FLA.” A polymerase chain reaction (PCR) assay amplifying the 18S rRNA gene was performed, and Acanthamoeba‐positive isolates were subjected to nucleotide sequencing to identify their genotypes.

Results: The prevalence of Acanthamoeba infection was 51% in the oral cavity and 38% in the nasal samples of cancer patients. The most frequent Acanthamoeba cysts were (51.3%) wrinkled polygonal and sized 9.55‐11.5 μm (Group II). Acanthamoeba genotypes T4, T11, and T5 were identified in the oral cavity samples, whereas T4 and T11 were detected in the nasal samples.

Conclusion: The prevalence of Acanthamoeba infection in oral and nasal cancer patients was higher in Kashan, Iran, compared to other countries. Due to the high rate of oral Acanthamoeba contamination, oral sampling is recommended for better detection of this protozoan. Since T4 is the predominant genotype that can cause serious diseases in high‐risk groups, increasing physicians’ awareness of infections associated with Acanthamoeba and preventive and control measures are strongly suggested.
Understanding Parental Emotions
Authors: Odeh Ruba , Brigi Carel , Walia Tarun , Hashim Raghad
Published: November 2024

Objectives: The presence of parents during dental treatment in children is a controversial concern in dental practice. This is because of conflicting views and practices regarding the presence of parents. Therefore, the objective of this study was to evaluate parental response to their presence/absence during their child’s dental treatment and to determine the factors that would influence their decision.

Methods: A cross‐sectional survey questionnaire was administered to United Arab Emirates (UAE) parents. A total of 240 parents participated in the survey, which contained 15 questions that analyzed the participants’ demographic details, dental procedures influencing parental separation, and factors influencing their desire to be present during their child’s dental treatment.

Results: Data were analyzed using descriptive statistics and chi‐square tests (p  < 0.05). The majority (78%) of the parents chose to stay with their children during dental treatment, with a higher prevalence of female parents. The results showed that more parents opted to be with their children during invasive procedures. Younger parents are more likely to stay with their children during dental treatment. The factors influencing parental presence/absence in the dental treatment room depended on the age and nationality of the parent and the type of dental procedure (p  < 0.05).

Conclusions: Dental practitioners must provide parents with sufficient opportunities to be present during their children’s dental procedures. The factors influencing parental presence/absence should be considered before deciding whether to include or exclude parents in the dental treatment room.