bluuebunny/crossref_metadata_2025 huggingface dataset:
Notch signaling regulates mineralization via microRNA modulation in dental pulp stem cells
Authors: Kulthanaamondhita Promphakkon , Kornsuthisopon Chatvadee , Chansaenroj Ajjima , Suwittayarak Ravipha , Trachoo Voraphat , Manokawinchoke Jeeranan , Lee Seung‐Cheol , Egusa Hiroshi , Kim Jin Man , Osathanon Thanaphum
Published: January 2024

Objectives

This study investigated the miRNA expression profile in Notch‐activated human dental stem pulp stem cells (DPSCs) and validated the functions of miRNAs in modulating the odonto/osteogenic properties of DPSCs.

Methods

DPSCs were treated with indirect immobilized Jagged1. The miRNA expression profile was examined using NanoString analysis. Bioinformatic analysis was performed, and miRNA expression was validated. Odonto/osteogenic differentiation was examined using alkaline phosphatase staining, Alizarin Red S staining, as well as odonto/osteogenic‐related gene and protein expression.

Results

Fourteen miRNAs were differentially expressed in Jagged1‐treated DPSCs. Pathway analysis revealed that altered miRNAs were associated with TGF‐β, Hippo, ErbB signalling pathways, FoxO and Ras signalling. Target prediction analysis demonstrated that 7604 genes were predicted to be targets for these altered miRNAs. Enrichment analysis revealed relationships to various DNA bindings. Among differentially expressed miRNA, miR‐296‐3p and miR‐450b‐5p were upregulated under Jagged1‐treated conditions. Overexpression of miR‐296‐3p and miR‐450b‐5p enhanced mineralization and upregulation of odonto/osteogenic‐related genes, whereas inhibition of these miRNAs revealed opposing results. The miR‐296‐3p and miR‐450b‐5p inhibitors attenuated the effects of Jagged1‐induced mineralization in DPSCs.

Conclusions

Jagged‐1 promotes mineralization in DPSCs that are partially regulated by miRNA. The novel understanding of these miRNAs could lead to innovative controlled mechanisms that can be applied to modulate biology‐targeted dental materials.
Editing VvDXS1 for the creation of muscat flavour in Vitis vinifera cv. Scarlet Royal
Authors: Yang Yingzhen , Wheatley Matthew , Meakem Victoria , Galarneau Erin , Gutierrez Benjamin , Zhong Gan‐Yuan
Published: January 2024

Muscat flavour represents a group of unique aromatic attributes in some grape varieties. Biochemically, grape berries with muscat flavour produce high levels of monoterpenes. Monoterpene biosynthesis is mainly through the DOXP/MEP pathway, and VvDXS1 encodes the first enzyme in this plastidial pathway of terpene biosynthesis in grapevine. A single‐point mutation resulting in the substitution of a lysine with an asparagine at position 284 in the VvDXS1 protein has previously been identified as the major cause for producing muscat flavour in grapes. In this study, the same substitution in the VvDXS1 protein was successfully created through prime editing in the table grape Vitis vinifera cv. ‘Scarlet Royal’. The targeted point mutation was detected in most of the transgenic vines, with varying editing efficiencies. No unintended mutations were detected in the edited alleles, either by PCR Sanger sequencing or by amplicon sequencing. More than a dozen edited vines were identified with an editing efficiency of more than 50%, indicating that these vines were likely derived from single cells in which one allele was edited. These vines had much higher levels of monoterpenes in their leaves than the control, similar to what was found in leaf samples between field‐grown muscat and non‐muscat grapes.
A solitary scalp mass as the presenting feature of clear cell sarcoma of the kidney in a pediatric patient
Authors: Pascual Micah G. , Bruckner Anna L. , Torres‐Zegarra Carla
Published: January 2024

Clear cell sarcoma of the kidney is a rare renal malignancy, accounting for 2%–4% of all pediatric renal tumors. In this case report, we describe a 9‐year‐old boy with an asymptomatic, solitary mass on the scalp, ultimately found to be metastatic clear cell sarcoma of the kidney. This report reviews indications for imaging scalp masses to facilitate making an accurate diagnosis and treatment planning.
Nucleus accumbens degeneration in spinocerebellar ataxia type 2: a preliminary study
Authors: Nakayama Kenjiro , Nemoto Kiyotaka , Arai Tetsuaki
Published: January 2024

Background

Spinocerebellar ataxia type 2 (SCA2) exhibits mainly cerebellar and oculomotor dysfunctions but also, frequently, cognitive impairment and neuropsychological symptoms. The mechanism of the progression of SCA2 remains unclear. This study aimed to evaluate longitudinal structural changes in the brains of SCA2 patients based on atrophy rate.

Methods

The OpenNeuro Dataset ds001378 was used. It comprises the demographic data and two magnetic resonance images each of nine SCA2 patients and 16 healthy controls. All structural images were preprocessed using FreeSurfer software, and each region's bilateral volume was summed. Atrophy rates were calculated based on the concept of symmetrised percent change and compared between SCA2 patients and healthy controls using non‐parametric statistics. As post hoc analysis, correlation analysis was performed between infratentorial volume ratio and the accumbens area atrophy rates in SCA2 patients.

Results

There were no significant differences between groups for age, gender, and the time between scans. Statistical analysis indicated a significantly larger atrophy rate of the accumbens area in SCA2 patients than in controls. Additionally, the infratentorial volume ratio and accumbens area atrophy rates showed moderate negative correlation.

Conclusions

This study found that nucleus accumbens (NAc) atrophy was significantly accelerated in SCA2 patients. Anatomically, the NAc is densely connected with infratentorial brain regions, so it is reasonable to posit that degeneration propagates from the cerebellum and brainstem to the NAc and other supratentorial areas. Functionally, the NAc is essential for appropriate behaviour, so NAc degeneration might contribute to neuropsychological symptoms in SCA2 patients.
Unlocking PD‐1 antibody resistance: The MUC1 DNA vaccine augments CD8+ T cell infiltration and attenuates tumour suppression
Authors: Wang Xiaoqin , Miao Yinsha , Shen Jinghui , Li Dandan , Deng Xinyue , Yang Chengcheng , Ji Yanhong , Dai ZhiJun , Ma Yunfeng
Published: January 2024

In light of increasing resistance to PD1 antibody therapy among certain patient populations, there is a critical need for in‐depth research. Our study assesses the synergistic effects of a MUC1 DNA vaccine and PD1 antibody for surmounting PD1 resistance, employing a murine CT26/MUC1 colon carcinoma model for this purpose. When given as a standalone treatment, PD1 antibodies showed no impact on tumour growth. Additionally, there was no change observed in the intra‐tumoural T‐cell ratios or in the functionality of T‐cells. In contrast, the sole administration of a MUC1 DNA vaccine markedly boosted the cytotoxicity of CD8+ T cells by elevating IFN‐γ and granzyme B production. Our compelling evidence highlights that combination therapy more effectively inhibited tumour growth and prolonged survival compared to either monotherapy, thus mitigating the limitations intrinsic to single‐agent therapies. This enhanced efficacy was driven by a significant alteration in the tumour microenvironment, skewing it towards pro‐immunogenic conditions. This assertion is backed by a raised CD8+/CD4+ T‐cell ratio and a decrease in immunosuppressive MDSC and Treg cell populations. On the mechanistic front, the synergistic therapy amplified expression levels of CXCL13 in tumours, subsequently facilitating T‐cell ingress into the tumour setting. In summary, our findings advocate for integrated therapy as a potent mechanism for surmounting PD1 antibody resistance, capitalizing on improved T‐cell functionality and infiltration. This investigation affords critical perspectives on enhancing anti‐tumour immunity through the application of innovative therapeutic strategies.
Emergency medical services (EMS) clinicians' views on EMS‐delivered interventions to promote secure firearm storage practices
Authors: Stanley Ian H. , Hom Melanie A. , Wright Angela
Published: January 2024

Introduction

Lethal means safety counseling (LMSC) to promote secure firearm storage may reduce the risk of firearm‐involved deaths, including suicide. We examined if emergency medical services (EMS) clinicians, including emergency medical technicians and paramedics, may be suitable LMSC messengers.

Method

We conducted a web‐based survey of 229 US EMS clinicians.

Results

While few EMS clinicians supported EMS‐delivered LMSC to all patients (17.0%), most supported EMS‐delivered LMSC to patients in an acute suicidal crisis (64.2%) or with a known suicide attempt history (55.9%). Barriers to EMS‐delivered LMSC included lack of training (73.4%), perceptions that LMSC is outside EMS clinicians' scope of practice (58.1%), and lack of standard operating procedures (56.3%). Most reported at least some interest in receiving training on EMS‐delivered LMSC (67.7%). Participants holding more accurate beliefs about the link between firearm storage practices and suicide risk, as well as the efficacy of LMSC, were more likely to support EMS‐delivered LMSC across patient scenarios (ORs = 2.18–5.21, ps <0.01) and express interest in receiving LMSC training (ORs = 3.78–5.43, ps <0.001).

Conclusion

Given that many EMS clinicians interface with patients at elevated suicide risk, targeted LMSC training may be strategic; however, research is needed to determine if and how EMS clinicians might be viable LMSC messengers.
Innocent Comrades or Blameworthy Foreigners: Transborder Ethnic Boundary Formation by South Korean Newspapers and Readers Amidst Anti‐Asian Racism in the US
Authors: Lee Ji‐won , Jo Hyerim
Published: January 2024

Drawing on ethnic boundary‐making literature, this study investigates how Korean newspapers and readers adjusted their ethnic boundaries towards Asian migrants in response to the evolving phases of the COVID‐19 pandemic. We analyzed the extent and nature of coverage in five major newspapers on anti‐Asian racism in the US published between January 1 and May 24, 2020, along with associated reader comments. During the maintenance phase, marked by persistent concerns about the resurgence of infections, we observed the highest number of articles and the most significant disparities between the media's portrayal and reader reactions. Contrary to the newspapers, readers perceived the racist threat faced by Asian migrants differently depending on the pandemic circumstances, displaying a more flexible boundary‐making. Despite the general description of Asian diasporas as “innocent comrades” in newspapers, readers viewed the Chinese and Korean diasporas as “blameworthy foreigners,” regarding them as potential threats to the nation. We discuss factors and conditions that might have influenced the formation of transborder ethnic boundaries among Korean newspapers and the public.
Atypical disseminated histiocytic sarcoma in a 7‐month‐old dog
Authors: Garcia‐Torres Maria , Muñoz Bárbara Serrano , Segalés Joaquim , Mallol Clàudia , Sanz Alba , López María C. , Roura Xavier
Published: January 2024

A 7‐month‐old intact female bearded collie dog was admitted after a 2‐week history of progressive cough, inappetence, and lethargy, with no response to previous treatment with doxycycline and steroids. Mild attenuation of lung sounds in the right middle hemithorax was the only abnormality detected on physical examination. Abdominal ultrasound and thoracic radiographs were performed and revealed multifocally distributed nodules and masses, well‐circumscribed and of variable size in the kidneys and pulmonary parenchyma. Ultrasound‐guided fine needle aspirates of the renal and pulmonary masses were taken. A cytologic evaluation of these lesions pointed towards a malignant mesenchymal neoplasia. Euthanasia was elected due to the poor prognosis and rapid progression. The post‐mortem histopathology, a positive result to IBA1 immunoperoxidase staining, and a lack of detection of infectious agents, and negative E‐cadherin immunostaining enabled the final diagnosis of a disseminated histiocytic sarcoma. We report an atypical form, both in breed and age, of canine disseminated histiocytic sarcoma. While all breeds can be affected, there is a clear predisposition in some, and no cases have been previously described in bearded collies. Moreover, to the authors' knowledge, this is the youngest dog with this histiocytic disorder described to date. Disseminated histiocytic sarcoma should be considered as a differential diagnosis of multinodular tumors in dogs, regardless of the anatomic location and age of the dogs, even in puppies.
The effects of TGF‐β1 and IFN‐α2b on decorin, decorin isoforms and type I collagen in hypertrophic scar dermal fibroblasts
Authors: Eremenko Elizabeth E. , Kwan Peter O. , Ding Jie , Ghosh Sunita , Tredget Edward E.
Published: January 2024

Hypertrophic scars (HTS) develop from an excessive synthesis of structural proteins like collagen and a decreased expression of proteoglycans such as decorin. Previous research has demonstrated that decorin expression is significantly down‐regulated in HTS, deep dermal tissue, and thermally injured tissue, reducing its ability to regulate pro‐fibrotic transforming growth factor‐beta 1 (TGF‐β1) and normal fibrillogenesis. However, treatment of HTS fibroblasts with interferon‐alpha 2b (IFN‐α2b) has been shown to reduce excessive collagen synthesis and improve HTS by reducing serum TGF‐β1 levels. The expression of decorin isoforms in HTS is currently unknown and the effects of TGF‐β1 and IFN‐α2b on decorin, decorin isoform expression and type 1 collagen are of great interest to our group. Dermal fibroblasts were treated with TGF‐β1 and/or IFN‐α2b, for 48 h. The expression and secretion of decorin, decorin isoforms and type 1 collagen were quantified with reverse transcription‐quantitative polymerase chain reaction, immunofluorescence staining and enzyme‐linked immunosorbent assays. The mRNA expression of decorin and each isoform was significantly reduced in HTS fibroblasts relative to normal skin. TGF‐β1 decreased the mRNA expression of decorin and decorin isoforms, whereas IFN‐α2b showed the opposite effect. IFN‐α2b significantly inhibited TGF‐β1's effect on the mRNA expression of type I collagen alpha 1 in papillary dermal fibroblasts and overall showed relative effects of inhibiting TGF‐β1. These data support that a further investigation into the structural and functional roles of decorin isoforms in HTS pathogenesis is warranted and that IFN‐α2b is an important agent in reducing fibrotic outcomes.
Comments on and illustrations of the WFUMB CEUS liver guidelines: Rare malignant neuroendocrine and predominant epithelioid liver lesions
Authors: Zadeh Ehsan Safai , Huber Katharina Paulina , Görg Christian , Möller Kathleen , Jenssen Christian , Lim Adrian , Taut Heike , Dong Yi , Cui Xin Wu , Dietrich Christoph F
Published: January 2024

The diagnosis or rare, non-hematologic malignant lesions of the liver may be a challenge owing to the rarity of the disease, and is usually made by histological confirmation. Ultrasound with color Doppler and contrast-enhanced, if required, taking into account the clinical background of the patient, may help to focus the differential diagnosis. In this review, we describe the pathological and ultrasound features of rare malignant neuroendocrine and predominantly epithelioid liver lesions including primary neuroendocrine tumor of the liver, Invasive mucinous cystic neoplasm of the liver, and also hepatoblastoma.
Biphasic synovial sarcoma with epithelial predominance reminiscent of adenocarcinoma: a diagnostic challenge
Authors: Rani Hephzibah , Rao Ravikala Vittal , Badiger Suresh , Holla Sukesh
Published: January 2024

Synovial sarcoma (SS) is a rare tumour of unknown origin with peak incidence between 10 and 35 years. Although it arises in juxta-articular location, SS is a misnomer and has no true relationship with synovium. In this case report, we present an elderly female patient with a long-standing history of thigh mass which was initially misdiagnosed as metastatic adenocarcinoma deposits on fine needle aspiration cytology, and again misdiagnosed as malignant adnexal skin tumour on core needle biopsy and referred for further management. Here, we discuss the challenges faced in the diagnosis of SS on a small biopsy and ways to differentiate it from other morphological mimickers. Therefore, we aim to increase the awareness of soft tissue tumours that microscopically appear like adenocarcinoma, which is a potential diagnostic pitfall. We also highlight the importance of morphological diagnosis and the utility of molecular testing using fluorescence in situ hybridisation, to arrive at the correct diagnosis of SS.
Thoracentesis to alleviate pleural effusion in acute heart failure: study protocol for the multicentre, open-label, randomised controlled TAP-IT trial
Authors: Glargaard Signe , Thomsen Jakob Hartvig , Løgstrup Brian Bridal , Schou Morten , Iversen Kasper Karmark , Tuxen Christian , Nielsen Olav W , Bang Christian Axel , Lindholm Matias Greve , Seven Ekim , Barasa Anders , Stride Nis , Vraa Søren , Tofterup Marlene , Rasmussen Rasmus Vedby , Høfsten Dan Eik , Rossing Kasper , Køber Lars , Gustafsson Finn , Thune Jens Jakob
Published: January 2024

Introduction

Pleural effusion is present in half of the patients hospitalised with acute heart failure. The condition is treated with diuretics and/or therapeutic thoracentesis for larger effusions. No evidence from randomised trials or guidelines supports thoracentesis to alleviate pleural effusion due to acute heart failure. The Thoracentesis to Alleviate cardiac Pleural effusion Interventional Trial (TAP-IT) will investigate if a strategy of referring patients with acute heart failure and pleural effusion to up-front thoracentesis by pleural pigtail catheter insertion in addition to pharmacological therapy compared with pharmacological therapy alone can increase the number of days the participants are alive and not hospitalised during the 90 days following randomisation.

Methods and analysis

TAP-IT is a pragmatic, multicentre, open-label, randomised controlled trial aiming to include 126 adult patients with left ventricular ejection fraction ≤45% and a non-negligible pleural effusion due to heart failure. Participants will be randomised 1:1, stratified according to site and anticoagulant treatment, and assigned to referral to up-front ultrasound-guided pleural pigtail catheter thoracentesis in addition to standard pharmacological therapy or to standard pharmacological therapy only. Thoracentesis is performed according to local guidelines and can be performed in participants in the pharmacological treatment arm if their condition deteriorates or if no significant improvement is observed within 5 days. The primary endpoint is how many days participants are alive and not hospitalised within 90 days from randomisation and will be analysed in the intention-to-treat population. Key secondary outcomes include 90-day mortality, complications, readmissions, and quality of life.

Ethics and dissemination

The study has been approved by the Capital Region of Denmark Scientific Ethical Committee (H-20060817) and Knowledge Center for Data Reviews (P-2021–149). All participants will sign an informed consent form. Enrolment began in August 2021. Regardless of the nature, results will be published in a peer-reviewed medical journal.

Trial registration number

NCT05017753.
Patient preferences for the treatment of chronic cough: a discrete choice experiment
Authors: Swaminathan Aparna C , Yang Jui-Chen , Ding Helen , Grover Kiran , Coles Theresa , Schelfhout Jonathan , Johnson F Reed
Published: January 2024

Background

Chronic cough is common, negatively affects quality of life and has limited treatment options. Inhibition of purinergic signalling is a promising therapeutic approach but is associated with taste-related adverse effects. Little is known about treatment preferences from the perspective of patients with chronic cough, such as trade-offs between efficacy and side effect.

Methods

Patients with chronic cough completed an online discrete choice experiment survey in which they answered a series of questions requiring a choice between two constructed treatment options characterised by varying attribute levels. Selection of cough and taste-related attributes was informed by qualitative interviews and clinical trial data. Logit-based models were used to analyse resulting choice data.

Results

The discrete choice experiment survey was completed by 472 participants with chronic cough. Among study attributes, frequency of intense cough attacks was the most important to participants, followed by taste change, frequency of night-time coughing and frequency of daytime coughing. To accept the least preferred taste disturbance of a bitter, metallic, chalky or oily taste change, participants required either: (1) elimination of night-time cough along with a slight reduction in daytime cough; (2) elimination of daytime cough along with a pronounced reduction in night-time or (3) reduction in intense cough attacks from 7 to 2 times per week. Two distinct preference patterns were identified, each placing different importance on efficacy versus side effect trade-offs.

Conclusions

Participants with chronic cough were willing to accept some taste disturbances in exchange for improved efficacy of chronic cough treatments. Knowledge of patient preferences can facilitate shared decision-making.
The burden of depression, anxiety and schizophrenia among the older population in ageing and aged countries: an analysis of the Global Burden of Disease Study 2019
Authors: Cheng Ying , Fang Yu , Zheng Jinxin , Guan Shiyang , Wang Meiti , Hong Wu
Published: January 2024

Background

Depression, anxiety and schizophrenia among older persons have become global public health challenges. However, the burden of these disorders in ageing and aged countries has not been analysed.

Aims

To investigate the burden of depression, anxiety and schizophrenia among older adults in ageing and aged countries.

Methods

Using data from the Global Burden of Disease Study 2019, we calculated the estimated annual percentage change (EAPC) in the age-standardised incidence rates (ASIR) and age-standardised disability-adjusted life years (DALYs) rates (ASDR) for depression, anxiety and schizophrenia of older people in ageing countries (China, India, Indonesia) and aged countries (Japan, Italy, Portugal) between 1990 and 2019. Trends in incidence and DALYs were analysed by gender and age.

Results

In 2019, the highest incidence of depression, anxiety and schizophrenia in the older population in aged countries was in Japan (927 271.3 (752 552.3–1 125 796.5), 51 498.2 (37 625.7–70 487.3) and 126.0 (61.0–223.2), respectively), while the highest incidence in ageing countries was in China (5 797 556.9 (4 599 403.4–7 133 006.5), 330 256.1 (246 448.9–445 987.4) and 1067.7 (556.2–1775.9), respectively). DALYs for these disorders were similar, with the highest in Japan and China. From 1990 to 2019, the ASIR for depressive disorders decreased in aged countries but increased in ageing countries; the ASIR for anxiety disorders and schizophrenia declined in both ageing and aged countries. The ASDR for depressive disorders was consistent with the ASIR but not for anxiety disorders and schizophrenia. The ASIR for depressive disorders was higher in older women, while the opposite was observed in anxiety disorders and schizophrenia. Notably, the conditions of burden of depressive disorders, anxiety disorders and schizophrenia in the 65–70-year-old age group were the most burdensome.

Conclusions

The incidence and DALYs of these three mental disorders increased while exhibiting differences between ageing and aged countries. Raising awareness about formulating health policies for preventing and treating mental disorders in the older population is necessary to reduce the future burden posed by the ageing challenge.
Evaluation of potential biomarkers for lenvatinib plus pembrolizumab among patients with advanced endometrial cancer: results from Study 111/KEYNOTE-146
Authors: Makker Vicky , Taylor Matthew H , Aghajanian Carol , Cohn Allen L , Brose Marcia S , Simone Christopher Di , Cao Zhu Alexander , Suttner Leah , Loboda Andrey , Cristescu Razvan , Jelinic Petar , Orlowski Robert , Dutta Lea , Matsui Junji , Dutcus Corina E , Minoshima Yukinori , Messing Mark J
Published: January 2024

Background

Lenvatinib plus pembrolizumab demonstrated clinically meaningful benefit in patients with previously treated advanced endometrial carcinoma in Study 111/KEYNOTE-146 (NCT02501096). In these exploratory analyses from this study, we evaluated the associations between clinical outcomes and gene expression signature scores and descriptively summarized response in biomarker subpopulations defined by tumor mutational burden (TMB) and DNA variants for individual genes of interest.

Methods

Patients with histologically confirmed metastatic endometrial carcinoma received oral lenvatinib 20 mg once daily plus intravenous pembrolizumab 200 mg every 3 weeks for 35 cycles. Archived formalin-fixed paraffin-embedded tissue was obtained from all patients. T-cell–inflamed gene expression profile (TcellinfGEP) and 11 other gene signatures were evaluated by RNA sequencing. TMB, hotspot mutations inPIK3CA(oncogene), and deleterious mutations inPTENandTP53(tumor suppressor genes) were evaluated by whole-exome sequencing (WES).

Results

93 and 79 patients were included in the RNA-sequencing-evaluable and WES-evaluable populations, respectively. No statistically significant associations were observed between any of the RNA-sequencing signature scores and objective response rate or progression-free survival. Area under the receiver operating characteristic curve values for response ranged from 0.39 to 0.54; all 95% CIs included 0.50. Responses were seen regardless of TMB (≥175 or <175 mutations/exome) and mutation status. There were no correlations between TcellinfGEP and TMB, TcellinfGEP and microvessel density (MVD), or MVD and TMB.

Conclusions

This analysis demonstrated efficacy for lenvatinib plus pembrolizumab regardless of biomarker status. Results from this study do not support clinical utility of the evaluated biomarkers. Further investigation of biomarkers for this regimen is warranted.

Trial registration number

NCT02501096.
Ipilimumab and nivolumab combined with anthracycline-based chemotherapy in metastatic hormone receptor-positive breast cancer: a randomized phase 2b trial
Authors: Andresen Nikolai Kragøe , Røssevold Andreas Hagen , Quaghebeur Claire , Gilje Bjørnar , Boge Beate , Gombos Andrea , Falk Ragnhild Sørum , Mathiesen Randi R. , Julsrud Lars , Garred Øystein , Russnes Hege G. , Lereim Ragnhild Reehorst , Chauhan Sudhir Kumar , Lingjærde Ole Christian , Dunn Claire , Naume Bjørn , Kyte Jon Amund
Published: January 2024

Background

Immune checkpoint inhibitors have shown minimal clinical activity in hormone receptor-positive metastatic breast cancer (HR+mBC). Doxorubicin and low-dose cyclophosphamide are reported to induce immune responses and counter regulatory T cells (Tregs). Here, we report the efficacy and safety of combined programmed cell death protein-1/cytotoxic T-lymphocyte-associated protein 4 blockade concomitant with or after immunomodulatory chemotherapy for HR+mBC.

Methods

Patients with HR+mBC starting first-/second- line chemotherapy (chemo) were randomized 2:3 to chemotherapy (pegylated liposomal doxorubicin 20 mg/m2every second week plus cyclophosphamide 50 mg by mouth/day in every other 2-week cycle) with or without concomitant ipilimumab (ipi; 1 mg/kg every sixth week) and nivolumab (nivo; 240 mg every second week). Patients in the chemo-only arm were offered cross-over to ipi/nivo without chemotherapy. Co-primary endpoints were safety in all patients starting therapy and progression-free survival (PFS) in the per-protocol (PP) population, defined as all patients evaluated for response and receiving at least two treatment cycles. Secondary endpoints included objective response rate, clinical benefit rate, Treg changes during therapy and assessment of programmed death-ligand 1 (PD-L1), mutational burden and immune gene signatures as biomarkers.

Results

Eighty-two patients were randomized and received immune-chemo (N=49) or chemo-only (N=33), 16 patients continued to the ipi/nivo-only cross-over arm. Median follow-up was 41.4 months. Serious adverse events occurred in 63% in the immune-chemo arm, 39% in the chemo-only arm and 31% in the cross-over-arm. In the PP population (N=78) median PFS in the immune-chemo arm was 5.1 months, compared with 3.6 months in the chemo-only arm, with HR 0.94 (95% CI 0.59 to 1.51). Clinical benefit rates were 55% (26/47) and 48% (15/31) in the immune-chemo and chemo-only arms, respectively. In the cross-over-arm (ipi/nivo-only), objective responses were observed in 19% of patients (3/16) and clinical benefit in 25% (4/16). Treg levels in blood decreased after study chemotherapy. High-grade immune-related adverse events were associated with prolonged PFS. PD-L1 status and mutational burden were not associated with ipi/nivo benefit, whereas a numerical PFS advantage was observed for patients with a high Treg gene signature in tumor.

Conclusion

The addition of ipi/nivo to chemotherapy increased toxicity without improving efficacy. Ipi/nivo administered sequentially to chemotherapy was tolerable and induced clinical responses.

Trial registration number

ClinicalTrials.gov Identifier:NCT03409198.
Tumor-draining lymph nodes: opportunities, challenges, and future directions in colorectal cancer immunotherapy
Authors: Wang Yao , Zhu Tingting , Shi Qi , Zhu Guanghui , Zhu Siwei , Hou Fenggang
Published: January 2024

Tumor-draining lymph nodes (TDLNs) are potential immunotherapy targets that could expand the population of patients with colorectal cancer (CRC) who may benefit from immunotherapy. Currently, pathological detection of tumor cell infiltration limits the acquisition of immune information related to the resected lymph nodes. Understanding the immune function and metastatic risk of specific stages of lymph nodes can facilitate better discussions on the removal or preservation of lymph nodes, as well as the timing of immunotherapy. This review summarized the contribution of TDLNs to CRC responses to immune checkpoint blockade therapy, local immunotherapy, adoptive cell therapy, and cancer vaccines, and discussed the significance of these findings for the development of diagnostics based on TDLNs and the potential implications for guiding immunotherapy after a definitive diagnosis. Molecular pathology and immune spectrum diagnosis of TDLNs will promote significant advances in the selection of immunotherapy options and predicting treatment efficacy.
Rituximab as an effective add-on maintenance therapy for disease activities in childhood-onset systemic lupus erythematosus
Authors: Lin Ting-Wei , Lin Yu-Tsan , Hu Ya-Chiao , Yu Hsin-Hui , Chiang Bor-Luen
Published: January 2024

Objectives

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that can result in high morbidity if not treated. This retrospective study aimed to evaluate the outcomes of rituximab treatment in a paediatric SLE cohort in Taiwan.

Methods

The medical records of paediatric patients diagnosed with SLE at the National Taiwan University Hospital between January 1992 and August 2022 who received rituximab as maintenance therapy between January 2015 and August 2022 were retrospectively reviewed. To enhance our analysis, we included a contemporary comparison group, matching in case number and demographic characteristics. This study aimed to describe the indications, efficacy and safety of rituximab in the treatment of paediatric SLE and to analyse the factors associated with disease outcomes.

Results

The study included 40 rituximab-treated patients with a median age of 14.3 years at the time of disease diagnosis. In the rituximab-treated cohort, the median score on the Systemic Lupus Erythematosus Disease Activity Index 2000 decreased from 8 before rituximab administration to 4 after 2 years. The levels of C3 and C4 increased and anti-double stranded DNA (anti-dsDNA) levels decreased significantly within 6 months. The equivalent oral prednisolone dose halved after 6 months. Finally, 8 (20%) patients achieved disease control and 35 (87.5%) patients had no flare-ups during the follow-up period (median, 2 years). Those patients who achieved disease control had a significantly shorter interval between diagnosis and rituximab administration. In terms of adverse effects, only one patient developed hypogammaglobulinaemia that required intravenous immunoglobulin (IVIG) replacement. Compared with the comparison group (n=53), the rituximab-treated cohort exhibited superior disease outcomes and a reduced incidence of flare-ups.

Conclusions

This study provides real-world data and illuminates rituximab’s role in maintaining disease stability among patients with paediatric-onset SLE who are serologically active without major clinical deterioration. Most importantly, no mortality or development of end-stage renal disease was observed in the rituximab-treated cohort.
Quantum gravity induced entanglement of masses with extra dimensions
Authors: Feng Shuai , Gu Bao-Min , Shu Fu-Wen
Published: January 2024

It is believed that gravity can be considered as a quantum coherent mediator. In this study, we propose a plan to test the existence of extra dimensions using the quantum gravity induced entanglement of masses (QGEM) experiment. This experiment involves two freely falling test masses passing through a Stern–Gerlach-like device. We investigate the entanglement witness between these masses within the framework of the Randall–Sundrum II model (RS-II). Our findings indicate that the system reaches entanglement more rapidly in the presence of extra dimensions, particularly when the radius of the extra dimension is large.
Multimodal Covariance Network Reflects Individual Cognitive Flexibility
Authors: Jiang Lin , Eickhoff Simon B. , Genon Sarah , Wang Guangying , Yi Chanlin , He Runyang , Huang Xunan , Yao Dezhong , Dong Debo , Li Fali , Xu Peng
Published: January 2024

Cognitive flexibility refers to the capacity to shift between patterns of mental function and relies on functional activity supported by anatomical structures. However, how the brain’s structural–functional covarying is preconfigured in the resting state to facilitate cognitive flexibility under tasks remains unrevealed. Herein, we investigated the potential relationship between individual cognitive flexibility performance during the trail-making test (TMT) and structural–functional covariation of the large-scale multimodal covariance network (MCN) using magnetic resonance imaging (MRI) and electroencephalograph (EEG) datasets of 182 healthy participants. Results show that cognitive flexibility correlated significantly with the intra-subnetwork covariation of the visual network (VN) and somatomotor network (SMN) of MCN. Meanwhile, inter-subnetwork interactions across SMN and VN/default mode network/frontoparietal network (FPN), as well as across VN and ventral attention network (VAN)/dorsal attention network (DAN) were also found to be closely related to individual cognitive flexibility. After using resting-state MCN connectivity as representative features to train a multi-layer perceptron prediction model, we achieved a reliable prediction of individual cognitive flexibility performance. Collectively, this work offers new perspectives on the structural–functional coordination of cognitive flexibility and also provides neurobiological markers to predict individual cognitive flexibility.
Robust Federated Learning for Heterogeneous Model and Data
Authors: Madni Hussain Ahmad , Umer Rao Muhammad , Foresti Gian Luca
Published: January 2024

Data privacy and security is an essential challenge in medical clinical settings, where individual hospital has its own sensitive patients data. Due to recent advances in decentralized machine learning in Federated Learning (FL), each hospital has its own private data and learning models to collaborate with other trusted participating hospitals. Heterogeneous data and models among different hospitals raise major challenges in robust FL, such as gradient leakage, where participants can exploit model weights to infer data. Here, we proposed a robust FL method to efficiently tackle data and model heterogeneity, where we train our model using knowledge distillation and a novel weighted client confidence score on hematological cytomorphology data in clinical settings. In the knowledge distillation, each participant learns from other participants by a weighted confidence score so that knowledge from clean models is distributed other than the noisy clients possessing noisy data. Moreover, we use symmetric loss to reduce the negative impact of data heterogeneity and label diversity by reducing overfitting the model to noisy labels. In comparison to the current approaches, our proposed method performs the best, and this is the first demonstration of addressing both data and model heterogeneity in end-to-end FL that lays the foundation for robust FL in laboratories and clinical applications.
Numerical study of the influence of amplitudes on heat transfer in a tube bundle
Authors: Foual Mohammed , Chaib Khaled , Chemloul Nordeddine Sad , Becheffar Youcef
Published: January 2024

The objective of this study is to investigate the impact of different surface roughness levels on a staggered arrangement of tubes in a cross-flow configuration, with water as the fluid being used. The focus lies in comparing the data obtained from the rough surface configuration with that of a smooth cylinder reference point. To assist this comparison, a comprehensive two-dimensional computational fluid dynamics (CFD) model is created, which accurately represents the distinctive characteristics of each surface shape. This study also included modifying the Remax within a range of 10 000–16 000 and analyzing the outcomes of using four different tube types, each with different supernatant thicknesses labeled as [Formula: see text], [Formula: see text], [Formula: see text] and [Formula: see text] accordingly. Surprisingly, the tube with a 0.4 wave surface had significantly higher average Nusselt numbers (Nu) compared to the other tubes, indicating superior performance. The ideal tube design was found based on three main metrics: The performance evaluation criterion (PEC), the global performance criterion (GPC) and the average Nu. The performance metrics encompassed the PEC, GPC and the Colburn factor [Formula: see text]. The average Nu of the wavy_0.4 tube was higher than that of the SM by 31.66–32.54%, higher than that of the wavy_0.2 tube by 19.76–20.74%, and higher than that of the wavy_0.1 tube by 9.38–16.58%. According to the statistics, a heat exchanger that cools and has a wave with an amplitude of 0 is the most efficient choice for offshore energy systems. The smooth bundle tube (SBT) demonstrated the most significant increase in GPC, with values of 9.3–12.7% and 20.3–28.3% higher than those of wavy tubes with amplitudes of 0.1 and 0.2, respectively. In addition, correlations for the Nu are given, with results verified using empirical data from Balabani et al.
A NARRATIVE ON OVERSEAS LISTINGS BY CHINESE FIRMS
Authors: FENG QU , WEI SHANG-JIN , WU GUIYING LAURA , YUAN MENGYING
Published: January 2024

Overseas listings by domestic firms are one of the ways for a country to attract foreign capital. China leads the world in the number and value of overseas listings. This paper documents the evolution of Chinese firms’ initial public offerings outside mainland China. We pay special attention to the role of the listing criteria of various exchanges in this evolution. We discuss important reforms of the listing requirements in both mainland and Hong Kong and their effects on the listing location choices by Chinese firms. Finally, we examine the delisting pressure on Chinese stocks from the US exchanges from both the Chinese and US authorities.
THE EFFECT OF PARENTAL EDUCATION ON CHILDREN’S EDUCATION AND SKILLS IN THAILAND
Authors: PAWEENAWAT SASIWIMON WARUNSIRI
Published: January 2024

This study proposes evidence of the effect of parental education on children’s education and skills in Thailand, using data from the Thailand Labor Force Survey of 1985–2017. Employing the instrumental variable (IV) approach using Thailand’s compulsory educational reform of 1978 as the IV to minimize the bias caused by the endogeneity of parental education, this study reaffirms the conventional positive link between parental education and children’s education. New and intriguing evidence is put forth on the negative link between parental education and the child’s brawn skill, based on industry and occupation used in the labor market. The influence of paternal education outweighs maternal education, in contrast to the evidence found in developed countries. The high intergenerational educational persistence indicates unequal opportunities in the country, as individual welfare is primarily tied to parental background. Therefore, weakening this linkage is a policy recommendation for the government to improve equality in the country.
Mole Fraction and Device Reliability Analysis of Vertical-Tunneling-Attributed Dual-Material Double-Gate Heterojunction-TFET with Si0.7Ge0.3 Source Region at Device and Circuit Level
Authors: Singh Km. Sucheta , Kumar Satyendra
Published: January 2024

This paper puts forward a new vertical-tunneling-attributed dual-material double-gate heterojunction-TFET (VTDMDG-HTFET). The device structure of VTDMDG-HTFET includes Si[Formula: see text]Ge[Formula: see text] material for the designing of source region. The mechanism of vertical tunneling in VTDMDG-HTFET provides superior electric field at tunneling interface and leads to improved transfer characteristics. VTDMDG-HTFET also includes metal gate work-function engineering approach to facilitate high ON-current and small OFF-current. Application of high-[Formula: see text] dielectric material [Formula: see text] in the form of gate oxide enhances the capacitive-coupling at channel-source interface. Moreover, the work includes the comparison of proposed VTDMDG-HTFET with the conventional vertical-tunneling based dual-material double-gate-TFET (VTDMDG-TFET). It has been observed from the simulation results that SiGe source-based VTDMDG-HTFET offers better DC characteristics in terms of superior ON-current, smaller OFF-current, steeper subthreshold-slope, lower threshold voltage, higher transconductance along with smaller drain-induced barrier-lowering (DIBL) effects as compared to its counterpart silicon-source-based VTDMDG-TFET. In this work, reliability of VTDMDG-HTFET has also been examined and compared with VTDMDG-TFET in terms of temperature sensitivity and effect of different interface trap charges. The device simulation and investigations have been carried out using technology computer aided design (TCAD) tool. Moreover, device circuit mixed-mode simulation analysis is carried out for conventional and proposed device based resistive load inverters. A comparison is performed between both the inverters in terms of prorogation delay and switching threshold voltages. Further, the mixed mode simulation analysis is also performed for the proposed device based inverter under the influence of different interface trap charges (ITCs). Study shows that reliability performance of the proposed device is better as compared to its counterpart conventional device. Hence, vertical tunneling and SiGe source-based VTDMDG-HTFET can be a better choice for various applications such as analog/RF, analog and digital electronic circuits, energy harvesting, gas-sensing and memory devices.
Global solvability of a two-species chemotaxis–fluid system with Lotka–Volterra type competitive kinetics
Authors: Ren Guoqiang , Liu Bin
Published: January 2024

In this paper, we study a two-species chemotaxis–fluid system with Lotka–Volterra type competitive kinetics in a bounded and smooth domain [Formula: see text] with no-flux/Dirichlet boundary conditions. We present the global existence of weak energy solution to a two-species chemotaxis Navier–Stokes system, and then the global weak energy solution which coincides with a smooth function throughout [Formula: see text], where [Formula: see text] represents a countable union of open intervals which is such that [Formula: see text]. In such two-species chemotaxis–fluid setting, our existence improves known blow-up prevention by logistic source to blow-up prevention by sub-logistic source, indicating standard logistic source is not the weakest damping source to prevent blow-up. This finding significantly extends previously known ones.
Inf–sup stabilized Scott–Vogelius pairs on general shape-regular simplicial grids by Raviart–Thomas enrichment
Authors: John Volker , Li Xu , Merdon Christian , Rui Hongxing
Published: January 2024

This paper considers the discretization of the Stokes equations with Scott–Vogelius pairs of finite element spaces on arbitrary shape-regular simplicial grids. A novel way of stabilizing these pairs with respect to the discrete inf–sup condition is proposed and analyzed. The key idea consists in enriching the continuous polynomials of order [Formula: see text] of the Scott–Vogelius velocity space with appropriately chosen and explicitly given Raviart–Thomas bubbles. This approach is inspired by [X. Li and H. Rui, A low-order divergence-free [Formula: see text]-conforming finite element method for Stokes flows, IMA J. Numer. Anal. 42 (2022) 3711–3734], where the case [Formula: see text] was studied. The proposed method is pressure-robust, with optimally converging [Formula: see text]-conforming velocity and a small [Formula: see text]-conforming correction rendering the full velocity divergence-free. For [Formula: see text], with [Formula: see text] being the dimension, the method is parameter-free. Furthermore, it is shown that the additional degrees of freedom for the Raviart–Thomas enrichment and also all non-constant pressure degrees of freedom can be eliminated, effectively leading to a pressure-robust, inf–sup stable, optimally convergent [Formula: see text] scheme. Aspects of the implementation are discussed and numerical studies confirm the analytic results.
Magnetic fields in inhomogeneous axion stars
Authors: Akhmetiev Petr , Dvornikov Maxim
Published: January 2024

We study the time evolution of magnetic fields in various configurations of spatially inhomogeneous pseudoscalar fields, which are the coherent superposition of axions. The new induction equation for the magnetic field, which accounts for this inhomogeneity, is derived for such systems. Based on this equation, we study, first, the evolution of two Chern–Simons (CS) waves interacting with a linearly decreasing pseudoscalar field. The nonzero gradient of the pseudoscalar field results in the mixing between these CS waves. Then, we consider the problem in a compact domain, when an initial CS wave is mirror symmetric. In this situation, the inhomogeneity of a pseudoscalar field acts as the effective modification of the [Formula: see text]-dynamo parameter. Thus, we conclude that the influence of a spatially inhomogeneous pseudoscalar field on the magnetic field evolution strongly depends on the geometry of the system.