bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety, Efficacy, and Pharmacokinetics of Unecritinib (TQ-B3101) in Pediatric Patients with Relapsed/Refractory Anaplastic Lymphoma Kinase Positive Anaplastic Large Cell Lymphoma: A Phase I Study
Authors: Lu Suying , Huang Junting , Cai Ruiqing , Gao Yan , Zhu Jia , Wang Juan , Que Yi , Zhen Zi-Jun , Sun Feifei , Huang Huiqiang , Zhang Yizhuo
Published: December 2024

Background

Over several decades, despite multiple treatment strategies for pediatric patients with anaplastic large-cell lymphoma (ALCL), approximately 30% of pediatric patients with ALCL experience relapse. This study investigated the safety and efficacy of unecritinib (TQ-B3101), a novel inhibitor of ROS1, ALK, and c-MET kinases, for the first time, in pediatric patients with relapsed/refractory (R/R) ALK+ ALCL.

Methods

This was an open-label, single-arm, phase I study. Eligible patients were aged 10-18 years. A 3+3 design was employed to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). The dose levels investigated were 200, 250, and 300 mg twice daily (BID). The primary end points were safety and drug pharmacokinetics. Secondary endpoints included the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).

Results

Nine patients were screened, enrolled, and evaluated for toxicity and responses. No dose-limiting toxicities occurred, and the MTD was not reached. The most frequently reported treatment-related adverse events were neutropenia, leukopenia, vomiting, and nausea, predominantly of grade 1 or 2. Most of the administered unecritinib was hydrolyzed by carboxylesterase in the body to form unecritinib M, with Tmax of approximately 3 h. The ORR was 100%, with six complete and three partial responses. The median PFS and OS have not been reached, with all patients still alive. Six patients who underwent targeted gene panel sequencing had alterations in other genes, including TP53, MYC, KMT2D, and MYCL1, indicating poor prognosis.

Conclusion

Unecritinib showed a good safety profile and promising efficacy in pediatric patients with R/R ALK+ ALCL. The RP2D of unecritinib is 300 mg BID for pediatric patients older than 10 years.
Kinetics of Blast Clearance in Cerebrospinal Fluid (CSF) Detected on Flow Cytometric Immunophenotyping (FCM), but Negative By Cytopathology in Newly Diagnosed Acute Lymphoblastic Leukemia Patients
Authors: Seth Tulika , Keerthana Kavya , Dass Jasmita , Agarwal Mukul , Pushpam Deepam , Mallick Saumyaranjan
Published: December 2024

Background: Flow cytometric immunophenotyping (FCM) detects two-fold higher CSF disease. Limited data on kinetics of CNS disease detected in this manner. Our study aimed to identify and follow course of CSF FCM+ in newly diagnosed ALL. Serial CSF FCM examinations performed to detect and see persistence of blasts. Identify risk factors for CSF involvement any correlation with post-induction measurable residual disease (PI-MRD).

Methods: Enrolled 125 patients newly diagnosed treatment naïve ALL patients from April 2022 to December 2023, Ethics approval and informed consent. CNS status assessed CSF cytopathology and FCM. Patients categorized as CNS1, CNS2, and CNS3 based on St Jude's criteria. CNS1 patients further divided into Cyto-FCM+ and Cyto-FCM - groups. Additional CSF FCM samples collected D+15 and D+28. All FCM analysis performed on BD FACS Canto II flow cytometer and BD FACS Diva v8.0.3 used for analysis. Patients received augmented BFM or adult protocol. Intrathecal Mtx given after baseline CSF and administered on D+15 and D+28 of induction.

Statistical analysis- Qualitative variables assessed using Chi-square test or Fisher's exact test. Quantitative variables assessed using ANOVA with post-hoc Bonferroni or Kruskal-Wallis test, p-value<0.05 was considered statistically significant.

Results: total 125 patients, 104 B-ALL, 16 T-ALL, and 5 MPAL, male-to-female ratio 3:1. Median age 16 years (1-57). CNS signs or symptoms present in 17 patients (13.6%) they had CNS2 or CNS3 status. Of remaining 108 patients, 22 (20.4%) were Cyto-FCM+, and 86 (79.6%) were Cyto-FCM-

Three patients in Cyto-FCM+ group died before D+15. Of remaining 19 patients repeat CSF, FCM detected persistent blasts in 2 (10.5%) while 17 (89.5%) showed blast clearance. The 2 patients with persistent CNS blasts cleared blasts D+15 and D+28.

Cyto-FCM- group vs CNS2/3 group significantly lower number of NCI high-risk patients (69.8% vs 100%). Cyto-FCM+ group significant hepatomegaly compared to Cyto-FCM- group (72.7% vs 46.5%). CNS2/3 and Cyto-FCM+ group higher median total leucocyte counts (TLC ) compared to Cyto-FCM-- and Higher LDH (589 vs 651 vs 349.5 IU/L, p-0.012 and 0.02). Receiver operator characteristic curve analysis showed TLC >6.3X10^9/L and LDH more than 314IU/L could predict Cyto-FCM+ with a sensitivity of 84.6% and 87.2% (p=0.0005 and 0.0006) respectively. Lowest end-of-induction MRD positivity was seen in Cyto-FCM- group.

Conclusions: FCM detects CSF higher involvement in newly diagnosed ALL patients. However, ~90% patients cleared CSF by standard intrathecal methotrexate by D+15 and all patients cleared disease by D+28 without extra intrathecal therapy. Longterm effect impacts needs evaluation.
Dietary Sucrose Exacerbates Antibiotic-Induced Microbiome Injury in Allo-HCT
Authors: Rangesa Madhumitha , Dai Anqi , Adintori Peter , Jogia William , Fei Teng , Waters Nicholas , Baichoo Mirae , Ballweg Annamaria , Sahu Sukanya , Schluter Jonas , van den Brink Marcel R.M. , Peled Jonathan U. , Perales Miguel-Angel
Published: December 2024

Patients with blood cancers who undergo allogeneic hematopoietic cell transplantation (allo-HCT) are typically hospitalized for several weeks while they receive chemotherapy, sometimes irradiation, and antibiotics. Nutrition influences the composition of the gut microbiome, yet its contribution to microbiome disruption during cancer treatment remains poorly understood. We profiled fecal microbiome composition and detailed dietary intake in 158 allo-HCT patients. Intake of sugar-enriched foods during antibiotic exposure predicted low fecal microbiome α-diversity and expansion of Enterococcus, two patterns of microbiome we previously identified as predictors of mortality in this population.

To validate this finding, we developed a simple mouse model of antibiotic-induced expansion of Enterococci endogenous to the mouse gut microbiome by administering a single subcutaneous dose of the carbapenem antibiotic biapenem to C57BL/6 mice induced a moderate bloom of Enterococci, as assessed by dilution plating on selective agar. In line with our observations in human patients, supplementation of the disaccharide sucrose to the diet intensified the Enterococcus expansion, leading to a 51.8-fold median increase at day 3 (p = 0.002) and a 42.4-fold median increase at day 6 (p = 0.030). Importantly, sucrose alone, without antibiotics, did not influence the abundance of Enterococcus.

The monosaccharide components of sucrose, fructose and glucose, were each sufficient to exacerbate the antibiotic-induced Enterococcus bloom (fructose median fold change on day 3: 104.7, p = 0.002; glucose median fold change on day 3: 105.1, p = 0.003), although the effect was not as sustained as that of sucrose, as by day 6, no significant differences were observed in colony counts between fructose- and glucose-treated samples and diet vehicle-treated samples. A similar pattern was observed in mice that were irradiated and allografted with T-cell-depleted grafts to model the early post-transplant period: a bloom of Enterococcus induced rapidly by the carbapenem that resolved 5 days later, and sucrose prolonged the relative expansion. These findings underscore the influence of diet on gut microbiota diversity and composition in HCT patients receiving antibiotics, highlighting the need for targeted nutritional interventions to mitigate adverse microbiome-related outcomes in this vulnerable population. Avoiding sugar-enriched foods while taking antibiotics may also have relevance outside the setting of cancer treatment. The general recommendation to limit consumption of sweets for cardiovascular health might, with further study, be tailored to abbreviated periods of avoidance to mitigate microbiome disruption during antimicrobial therapy.
Universal Cloaking of Allogeneic T Cell Therapies Against Natural Killer Cells Via CD300a Agonism
Authors: Welstead G. Grant , Zhang Shuqi , Fang Justin , Thomas Faith , Lebid Andriana , Miller Mike , Perry Daniel , Whitney Dustin , Carton Jill , Kurtz Jonathan , Cowan Chad
Published: December 2024

Immunogenicity limits the persistence of off-the-shelf, allogeneic cell therapies and transplants. While ablation of human leukocyte antigen (HLA) removes most T cell and humoral alloreactivity, no solution has enabled universal protection against the resulting natural killer (NK) cell response. Here, we engineered Trans Antigen Signaling Receptors (TASR) as a new class of NK inhibitory ligands and discovered CD300a, a previously inaccessible receptor, as a functional target. CD300a TASR outperformed leading alternative strategies in focused screens, including CD47 and HLA-E, and was solely capable of universally protecting allogeneic T cells against a large human cohort (45/45 donors), spanning diverse demographics and NK cell phenotypes. When combined with an anti-CD19 Chimeric Antigen Receptor (CAR) using multiplexed non-viral integration, allogeneic primary T cells exhibited enhanced B cell killing potency under allogeneic immune pressure. Additionally, the expression of CD300a TASR on iPSC-derived T cells provided protection against alloreactive NK cells. CD300 TASR represents a universal solution to NK alloreactivity, broadening the population that could be effectively treated by next-generation allogeneic cell therapies, including iPSC-derived CAR T cells.
Role and Mechanisms Exploration of Histamine and Its Receptors in the Progression of Peripheral T-Cell Lymphoma
Authors: Jin Hui , Wang Ling , Ren Yimin , Wu Zijuan , Shi Wenyu , Li Jianyong
Published: December 2024

Introduction: Peripheral T-cell lymphoma (PTCL) is a group of malignant lymphomas originating from mature T cells, characterized by clinical aggressiveness, rapid progression, and dismal survival outcomes. Elevated levels of inflammatory reactants are closely associated with poor prognosis. The incidence of PTCL in China is much higher than that in European and American countries, while basic and clinical research is relatively lagging behind. Hence, there is an urgent need for a comprehensive and systematic analysis of the tumor microenvironment of PTCL and discover new effective targets as well as reliable prognostic indicators.

Objectives: This study intends to progressively analyze the spatial characteristics of PTCL tumors and the inflammatory microenvironment at the genomic, cellular, and animal levels, using single-cell RNA sequencing combined with image mass cytometry and other multi-omics methods. On this basis, it focuses on the role and molecular mechanism of the Histamine-HRH2 axis in PTCL disease progression and drug resistance, verifying it at the cellular and animal levels. The project aims to fully explore potential therapeutic targets, providing new ideas for optimizing treatment schemes and overcoming drug resistance in PTCL patients.

Methods: By conducting single-cell RNA sequencing (scRNA-seq) and imaging mass cytometry (IMC), we conducted a comprehensive investigation of the complexity of inflammatory microenvironmen in PTCL. We unveiled the role and molecular mechanism of the Histamine-HRH2 axis in the progression of PTCL as well as the potential drug resistance regulatory mechanisms. Immunohistochemistry, immunofluorescence, and publicly available microarray datasets were used to validate these findings.

Results: The present study highlighted histamine, an inflammatory mediator, was abundant in the microenvironment of PTCL and was associated with poor prognosis of patients. Histamine, upon interaction with the HRH2 receptor on tumor cell surfaces, triggers the secretion of CSF1, consequently inducing M2 macrophage polarization and mediates immune suppression. The expression of p-CREB and CEBPB were upregulated after the treatment of histamine, which mediated the transcriptional activation of CSF1. In addition, we uncovered that histamine and CSF1 played important roles in remodeling the tumor microenvironment of PTCL, and combination therapy with antihistamines and CSF1R inhibitors may effectively enhance tumor cell killing effect of HDAC inhibitor.

Conclusions: In this study, we constructed comprehensive single-cell atlas of PTCL tumors and inflammatory microenvironment, using single-cell RNA sequencing combined with image mass spectrometry. On this basis, for the first time, we elucidated the role and molecular mechanism of histamine/HRH2 receptor axis in the progression of PTCL, explored potential therapeutic targets to provide new strategies for optimizing clinical treatment of PTCL patients.
Genetic disruption of Blimp-1 drastically augments the antitumor efficacy of BCMA-targeting CAR T cells
Authors: Battram Anthony M. , Mañé-Pujol Joan , Moreno David F. , Oliver-Caldés Aina , Carpio Judit , Cardus Oriol , Rodríguez-Lobato Luis Gerardo , Urbano-Ispizua Álvaro , Fernández de Larrea Carlos
Published: December 2024

Chimeric antigen receptor (CAR) T cells directed against B-cell maturation antigen (BCMA) are an effective treatment for multiple myeloma (MM), but short persistence and frequent relapses are challenges for this immunotherapy. This lack of durability has been attributed to the premature terminal differentiation of CAR T cells, which prevents the formation of long-lived memory cells that maintain antitumor responses. To improve long-term efficacy, we used CRISPR/CRISPR-associated protein 9-mediated gene editing to ablate the expression of the transcription factor Blimp-1. Blimp-1 knockout (KO) CAR T cells displayed a memory-like phenotype compared with control (Mock) CAR T cells, but had reduced effector function, with a striking loss of granzyme B. However, in a murine model of advanced MM, Blimp-1 KO CAR T cells effectively slowed or even prevented disease progression, significantly outperforming Mock CAR T cells in improving survival (P = .006). To understand this enhanced in vivo effectiveness, Blimp-1 KO CAR T cells were characterized after being repeatedly challenged with tumor cells in vitro. In this setting, Blimp-1 KO CAR T cells maintained a highly active state with high expression of memory markers, but, crucially, demonstrated enhanced effector function and increased energetic capacity. RNA-sequencing analysis of tumor-exposed Blimp-1 KO CAR T cells confirmed the presence of a memory-like transcriptomic signature and, additionally, revealed enhanced ribosome biogenesis and repressed CAR T-cell dysfunction as mechanisms that could contribute to improved antitumor activity. Put together, our findings show that dampening Blimp-1 expression altered the phenotype and function of anti-BCMA CAR T cells, leading to augmented therapeutic efficacy in MM.
Agent-based modelling of Mycobacterium tuberculosis transmission: a systematic review
Authors: Bui Viet Long , Hughes Angus E. , Ragonnet Romain , Meehan Michael T. , Henderson Alec , McBryde Emma S. , Trauer James M.
Published: December 2024

Background

Traditional epidemiological models tend to oversimplify the transmission dynamics of Mycobacterium tuberculosis (M.tb) to replicate observed tuberculosis (TB) epidemic patterns. This has led to growing interest in advanced methodologies like agent-based modelling (ABM), which can more accurately represent the complex heterogeneity of TB transmission.

Objectives

To better understand the use of agent-based models (ABMs) in this context, we conducted a systematic review with two main objectives: (1) to examine how ABMs have been employed to model the intricate heterogeneity of M.tb transmission, and (2) to identify the challenges and opportunities associated with implementing ABMs for M.tb.

Search methods

We conducted a systematic search following PRISMA guidelines across four databases (MEDLINE, EMBASE, Global Health, and Scopus), limiting our review to peer-reviewed articles published in English up to December 2022. Data were extracted by two investigators using a standardized extraction tool. Prospero registration: CRD42022380580.

Selection criteria

Our review included peer-reviewed articles in English that implement agent-based, individual-based, or microsimulation models of M.tb transmission. Models focusing solely on in-vitro or within-host dynamics were excluded. Data extraction targeted the methodological, epidemiological, and computational characteristics of ABMs used for TB transmission. A risk of bias assessment was not conducted as the review synthesized modelling studies without pooling epidemiological data.

Results

Our search initially identified 5,077 studies, from which we ultimately included 26 in our final review after exclusions. These studies varied in population settings, time horizons, and model complexity. While many incorporated population heterogeneity and household structures, some lacked essential features like spatial structures or economic evaluations. Only eight studies provided publicly accessible code, highlighting the need for improved transparency.

Authors’ conclusions

ABMs are a versatile approach for representing complex disease dynamics, particularly in cases like TB, where they address heterogeneous mixing and household transmission often overlooked by traditional models. However, their advanced capabilities come with challenges, including those arising from their stochastic nature, such as parameter tuning and high computational expense. To improve transparency and reproducibility, open-source code sharing, and standardised reporting are recommended to enhance ABM reliability in studying epidemiologically complex diseases like TB.
Knowledge, attitudes, and self-perceived skills regarding ultrahigh risk (UHR) for psychosis and schizophrenia in primary care physicians: new insights from Tunisia
Authors: Fekih-Romdhane Feten , Jaoua Amira , Homri Wided , Hakiri Abir , Cheour Majda , Loch Alexandre Andrade , Hallit Souheil
Published: December 2024

Background

There is evidence indicating that an important proportion of young people at ultrahigh risk (UHR) for psychosis do consult in primary care, but their identification may be hindered by multiple factors, such as primary care physicians (PCPs)’ limited skills and perceived stigma toward the condition. This study aimed to investigate attitudes/beliefs toward both UHR and schizophrenia and perceived self-efficacy in screening for, diagnosing, and managing these conditions among PCPs. The secondary objective was to determine the potential effects of psychosis level (UHR vs. schizophrenia) on PCP’s views.

Methods

A cross-sectional survey was carried out among Tunisian PCPs working in primary care setting in Tunisia (N = 232, 66.4% females, mean age of 47.5 ± 9.9 years). An anonymous paper-and-pencil self-administered questionnaire was adopted to collect data. PCPs were asked to read vignettes describing individuals with UHR and schizophrenia and answer a series of questions that followed.

Results

The schizophrenia vignette aroused significantly more feelings of “need to help the person” than the UHR vignette (87.8% vs. 88%, p = .022). The perceptions that the person depicted in the vignette is “strange” and “not intelligent” were more frequently endorsed for UHR than schizophrenia (18.7% vs. 16%, p = 0.028, and 8.4% vs. 5.6%, p = 0.043, respectively), whereas the person with schizophrenia was perceived are more dangerous than the UHR person (38.4% vs. 25.2%, p = 0.033). Only 28.9% and 14% of participants agreed that they have the necessary skills to make the diagnosis and manage the condition depicted in the UHR vignette, respectively.

Conclusion

Findings indicated that a high proportion of our Tunisian PCPs show a deficit in identifying both UHR and schizophrenia diagnoses. Given that PCPs can be key sources of referral of at-risk young help-seekers to specialized early intervention services, urgent interventions are needed to help PCPs enhance their knowledge and reduce stigma associated with psychosis.
Comparison of Survivorship Care Guidelines for Patients With Lymphoma: Recommendations for Harmonization and Future Research Agenda
Authors: Valcarcel Bryan , Savage Kerry J. , Link Brian K. , Leonard John P. , Kelly Kara M. , Thanarajasingam Gita , Cerhan James R. , Pro Barbara , Gordon Leo I. , Thompson Carrie A. , Smith Sonali M. , Morton Lindsay M.
Published: December 2024

PURPOSE

Lymphomas are a heterogeneous group of diseases that develop in individuals of all ages and have variable prognoses. Improved survival resulting from therapy advances has led to the emergence of diverse late effects. Although several (US)–based organizations have developed survivorship guidelines, the distinct features of lymphoma subtypes and diverse therapies used raise concerns regarding their applicability to lymphoma survivors. We compared survivorship recommendations (outside primary disease monitoring) between US clinical guidelines.

METHODS

We extracted information from 17 guidelines from five US-based organizations: ASCO (n = 11), American Cancer Society (n = 1), Children's Oncology Group (n = 1), Center for International Blood and Marrow Transplant Research (n = 1), and the National Comprehensive Cancer Network (n = 3). Guidelines were evaluated to determine whether they offer recommendations on
physical effects
,
psychosocial and quality of life
(
QOL
), and
health promotion and prevention
. Comparisons were focused on second primary malignancy, cardiovascular complications, and vaccination.

RESULTS

Survivorship recommendations on
physical effects
and
psychosocial and QOL
mainly differ in the timing and approaches for screening. Vaccination recommendations were primarily derived from other cancer populations. Identified research gaps were a lack of understanding of the risk of late effects across lymphoma subtypes, the role of social determinants of health in survivorship, and the lack of a survivorship care model that integrates lymphoma subtypes and treatment exposures.

CONCLUSION

This study raises awareness about the complexity and challenges of managing survivors under the umbrella diagnosis of lymphoma. The inconsistency and incompleteness of existing guidelines may lead to suboptimal survivorship care. We propose expert-based research priorities to address gaps and unmet needs to help develop risk-based follow-up recommendations to optimize survivorship care for lymphoma survivors.
Cancer-Control Outcomes of Patients With Metastatic Castration-Resistant Prostate Cancer With
BRCA
Gene or Tumor Suppressor Mutations Undergoing 177-Lutetium Prostate-Specific Membrane Antigen Radioligand Therapy
Authors: Wenzel Mike , Koll Florestan , Hoeh Benedikt , Humke Clara , Reis Henning , Wild Peter , Steuber Thomas , Graefen Markus , Tilki Derya , Sabet Amir , Gröner Daniel , Chun Felix K.H. , Mandel Philipp
Published: December 2024

PURPOSE

Several tumor gene mutations are known for metastatic castration-resistant prostate cancer (mCRPC). The individual response to 177-lutetium prostate specific membrane antigen radioligand therapy (Lu-PSMA) is under current investigation regarding the genomic profile of patients with mCRPC.

MATERIALS AND METHODS

We relied on the FRAMCAP database and compared progression-free survival (PFS) and overall survival (OS) rates of patients with mCRPC with breast cancer–related antigen (
BRCA
) or tumor suppressor gene mutations (
TP53
,
PTEN
,
RB1
). Specifically, subgroup analyses were performed for patients with Lu-PSMA–treated mCRPC.

RESULTS

Of 194 patients with mCRPC, 22% was
BRCA1/2
versus 14%
PTEN/TP53/RB1
versus 63% without one of these mutations. Patients with no mutation harbored a significantly lower Gleason score of 8-10, relative to
BRCA
and
PTEN/TP53/RB1
patients. In PFS analyses of first-line mCRPC, no difference between all three groups was observed, whereas the median OS differed significantly with 46.3 versus 48.7 versus 95.4 months for
BRCA
versus
PTEN/TP53/RB1
versus no mutated patients (
P
< .05). In univariable Cox regression models, BRCA-mutated patients were at higher risk of death (hazard ratio, 2.57;
P
< .01), whereas
PTEN/TP53/RB1
patients were not (
P
= .4). Of 87 patients with Lu-PSMA–treated mCRPC, significant differences in PFS and OS were observed (both
P
≤ .02). In univariable and multivariable Cox regression models, BRCA-mutated Lu-PSMA patients were at higher risk of death, whereas
PTEN/TP53/RB1
patients had similar outcomes as no mutated patients.

CONCLUSION

In real-world setting, substantially lower OS in mCRPC is observed for
BRCA
- and
PTEN/TP53/RB1
-mutated patients, whereas no difference in first-line PFS could be computed. In Lu-PSMA–treated patients, worst outcomes were observed for
BRCA
patients.
Influence of Epithelial-Mesenchymal Transition on Risk of Relapse and Outcome to Eribulin or Cyclin-Dependent Kinase Inhibitors in Metastatic Breast Cancer
Authors: Chan Arlene , Gill Jespal , Chih HuiJun , Wright Sarah Christine Elisabeth , Vasilevski Natali , Eichhorn Pieter Johan Adam
Published: December 2024

PURPOSE

The presence of epithelial-mesenchymal transition (EMT) in breast cancer (BC) cells has been linked to worse prognosis and may influence response to systemic treatment. We explored the effect of EMT in tumor samples of patients with metastatic BC on disease-free interval and overall survival in those patients receiving eribulin or cyclin-dependent kinase 4/6 inhibitors (CDK4/6i).

MATERIALS AND METHODS

Key inclusion criteria included available archived primary BC tissue and, where available, matched metastatic biopsy. Patients received eribulin and/or a CDK4/6i in the metastatic setting. Specimens were assessed for biomarkers by immunohistochemistry (CDH1, AE1/3, VIM, CDH2, ZEB1, pSMAD2, and SMAD4) and gene expression by droplet digital polymerase chain reaction (
CDH1
,
CDH2
,
SNAI1
&
2
,
TWIST1
,
VIM
,
PTEN
, and
ZEB1
&
2
).

RESULTS

Between 2002 and 2020, 127 patients were included (95 early-stage disease at diagnosis with metastatic relapse, 32 de novo metastatic disease). In metastatic samples, presence of ZEB1 overexpression was associated with shorter time to recurrence (48.1 months shorter;
P
= .003), with pSMAD2 overexpression suggesting clinical significance of 52.0 months shorter;
P
= .01. High gene expression levels for SNAIL1,
TWIST1
, and
PTEN
in the primary BC were associated with significantly longer survival in patients who received eribulin (
P
< .05); high
VIM
was associated with a clinically relevant trend toward shorter survival after a CDK4/6i (
P
= .013).

CONCLUSION

We demonstrate in our exploratory study that biomarkers involved in the process of EMT could have a prognostic impact in a cohort of patients with BC uniformly treated and with long-term follow-up. Genes known to be involved in EMT were associated with improved eribulin efficacy, while suggesting a poorer outcome with CDK4/6i.
Picking Your Professor: Bridging Scholarly and Popular Bookish Publics in the Digital Age
Authors: Murray Simone
Published: December 2024

The study of literature is currently imperiled by political attacks, defunding, and casualization within universities, yet simultaneously thrives beyond them in an online world of author-reader interaction, amateur reviewing, and social-media book talk. This article traces the relationship between literary studies and lay book-reading communities in the past, present, and future. How was the professional/amateur distinction a precondition for the discipline's institutionalization? How do digital technologies now enable us to bridge this divide between the academy and the broader world of booklovers online? Looking forward, what best practices aid professional literary scholars to engage constructively with amateur online bookish communities?
Ultrapassando as barreiras da inovação radical
Authors: Gomes Leonardo Augusto Vasconcelos , Borini Felipe Mendes
Published: December 2024

Objetivo: propor o estabelecimento de governança da falha na empresa e no ecossistema para implantar projetos de inovação radical.
Estado da arte: no processo de inovação radical, as empresas inevitavelmente falham, pois esses projetos enfrentam uma série de incertezas. No entanto, pesquisas mostram um viés antifalhas nas empresas, o que dificulta a criação ou finalização de projetos disruptivos. Isso ocorre porque falhas são tratadas como erros - esses sim previsíveis, comuns em projetos de inovação incremental.
Originalidade: o artigo propõe quatro passos para a implementação de uma governança da falha, de modo que as empresas possam estabelecer, com sucesso, projetos de inovação radical.
Impactos: o modelo de governança da falha proposto no artigo pode ser implementado por organizações que estão iniciando ou já trabalharam com inovação radical, assim como por gestores e demais atores de ecossistemas de inovação.
Some Questions to Transformations of the Accounting Intangible Asset
Authors: Polenova S.
Published: December 2024

The article considers questions of categorizations and identifications object intangible asset, characterizes types property, presenting intangible assets, considers signs asset, identifies as of little value intangible assets, as well as possible variants of their reflection on count of the accounting.
New Developments in the Development of Financial Technologies
Authors: Smirnov E.
Published: December 2024

Last summer, the Russian Parliament adopted federal laws No. 221-FZ and 223-FZ aimed at regulating issues related to the issuance and circulation of digital currencies in order to develop new financial technologies.
Features of the development of special economic zones in Russia in English
Authors: Baublis Yuriy
Published: December 2024

The article considers the main vectors of development of special economic zones in Russia in the context of tightening sanctions policy and transformation of the global economy. The role of SEZ for the national economy, the structure of Russian SEZ, key areas of support for SEZ by the state are studied, and problems that have hindered more active development of SEZ in recent years are identified. Among these problems, political, economic, industrial and infrastructural ones were especially highlighted. It was proposed to focus, first of all, on such measures as: strengthening the system of control over the expenditure of budget funds, including in a number of Russian regions; reducing administrative barriers not only for Russian resident companies, but also for foreign companies; expanding the areas for stimulating the development of the PPP mechanism within the framework of the functioning of Russian SEZ. It is concluded that the implementation of these measures will attract new residents to the SEZ mechanism, including from friendly countries, which will further contribute to the achievement of the main goals set for Russian SEZ.
Chińska wojna domowa 1946–1949 w zachodniej historiografii
Authors: Polit Jakub
Published: December 2024

Chińska wojna domowa 1946–1949 była długo uważana za wojnę, w której komunistyczna partyzantka chłopska pokonała armię wspieraną przez USA. Począwszy od lat osiemdziesiątych XX w. staje się coraz bardziej jasne, że wojska Mao Zedonga były profesjonalną armią wyposażoną przez Związek Sowiecki.
Między tożsamością pokoleniową a narzuconą. Losy przedstawicieli generacji „urwanego lotu” na przykładzie Barbary Otwinowskiej (1924–2018). Próba rekonstrukcji biograficznej
Authors: Wiśniewska Monika
Published: December 2024

Celem artykułu jest próba rekonstrukcji biograficznej przedstawicielki pokolenia „urwanego lotu” – Barbary Otwinowskiej: uczestniczki powstania warszawskiego, studentki polonistyki Uniwersytetu Warszawskiego, więźniarki politycznej, pracownika naukowego Instytutu Badań Literackich Polskiej Akademii Nauk, profesora doktora habilitowanego nauk humanistycznych w zakresie filologii polskiej, językoznawczyni, specjalistki od literatury staropolskiej, poetki, kustoszki pamięci narodowej.
Miejsca napięć pamięci Zagłady w Polsce w kontekście tendencji we współczesnej Europie
Authors: Ambrosewicz-Jacobs Jolanta
Published: December 2024

SITES OF TENSION OF MEMORY OF THE HOLOCAUST IN POLAND IN THE CONTEXT OF TENDENCIES IN CONTEMPORARY EUROPE
Many researchers, among them Jacques Le Goff, have stressed the significance of memory of the past as a determinant in the struggle for power and in creating collective identities. This text evolved on the basis of qualitative studies undertaken in 2019‒2022 within the framework of the international research project “Sites of Tension: Shifts in Holocaust Memory in Relation to Antisemitism and Political Contestation in Europe” carried out by the University of Haifa in cooperation with five research teams from Germany, the United Kingdom, Spain, Hungary, and Poland. The aim of the study, in which the author participated, was to examine contemporary tensions and conflicts related to memory of the Holocaust on the basis of analysis of political discourse, social media, and interviews with teachers. The text seeks answers to research questions about affinities and divergences between selected states, about recently emerging patterns in teaching about the Holocaust in the context of increasing historical politics in Poland, and about resistance to education programmes imposed by the authorities. The cases from the five selected European countries indicate how memory of the Holocaust serves expression of political attitudes and social identities.
Program UE dla zdrowia w europejskiej debacie parlamentarnej
Authors: Marcinkowski Tomasz
Published: December 2024

EU HEALTH PROGRAMME IN THE EUROPEAN PARLIAMENTARY DEBATEThe weakness of the response to the pandemic that was visible in many EU Member States, especially in the first period of the crisis, resulted in increased expectations for action at the European level. This was reflected in the EU4Health programme prepared in the same period. The analysis carried out in this article concerns parliamentary debates on the new EU health program and, indirectly, discussions on the further direction of changes in European health policy. The author put forward two hypotheses: 1. In the parliamentary debate on the EU health programme, positive opinions (regardless of party differences) towards the proposed actions, resulting from the experience of the pandemic crisis, will prevail. 2. The analysed debate will highlight differences regarding the further deepening of the integration process in the area of health – supporters of deepening integration (‘towards a real health union’) versus supporters of cooperation based on the current state-centric approach to health in the EU. As the analysis of the strategy and speeches during the plenary debates shows, the pandemic context has become an important point of reference for these activities. It allows us to confirm the hypothesis indicating the dominance of MEPs’ positive assessment of the solutions proposed by the strategies. The second hypothesis was also confirmed. The analysed speeches presented varied assessments of further integration leading to the creation of the European Health Union. Right-wing parties emphasised the need to maintain the status quo in the field of health (health policy in the hands of the state). MEPs from the EPP, S&D and Renew Europe presented a position more open to change. Taking into account that member states are responsible for health policy and for any changes in this area (specific treaty changes), the results of the debate should be treated as a presentation of political possibilities rather than a forecast of actions for the near future.
Wdrażanie koncepcji Mission Command i Versatile Leadership w kontekście kulturowych wymiarów zaprogramowania umysłowego
Authors: Milczanowski Maciej
Published: December 2024

INTRODUCING OF THE MISSION COMMAND AND VERSATILE LEADERSHIP CONCEPTS IN THE CONTEXT OF CULTURAL DIMENSIONS OF MIND PROGRAMMING
The concepts of Mission Command and Versatile Leadership are very similar in many ways, regardless the fact that they develop in ‘parallel’ realities – military and civilian. Both concepts require the use of a culture dependent methods of introducing into the military or civilian organisations. The cultural dimension of mind programming creates the set of specific conditions for introducing the MC and VL – some of those aspects can be positive and some negative toward those two concepts. But without researching and without awareness of those conditions there will be a lot of chaos and misinterpretations in the organisations where MC and VL concepts appear.
The Price of Fairness of Scheduling a Scarce Resource
Authors: Vardi Shai , Haskell William
Published: December 2024

Balancing Fairness and Efficiency: The Price of Fairness in Scheduling Scarce Resources

“The Price of Fairness of Scheduling a Scarce Resource” investigates the trade-offs between fairness and utility when scheduling scarce resources among multiple stakeholders. The research focuses on envy-freeness, a widely recognized fairness criterion, and explores how fairness constraints impact overall utility, quantified by the price of fairness—the ratio of attainable utility with and without fairness considerations. By analyzing various factors, including the number of agents, time horizon, discount factors, and switching costs, the authors derive tight bounds on the price of fairness. Interestingly, they discover that, whereas fairness often increases utility loss, certain parameters—such as reducing the time horizon or increasing the number of agents—can counterintuitively reduce this loss. These findings offer strategic insights for decision makers facing fairness constraints in scheduling, helping them navigate complex trade-offs between equitable resource allocation and maximizing efficiency.
The ‘5 Moments for Hand Hygiene’: casting a critical eye on the implications for practice
Authors: Cole Mark
Published: December 2024

The ‘5 Moments’ approach is a time–space framework that delineates when hand hygiene should be performed and provides a resource for educators and auditors. It has become the dominant paradigm for organisations, practice, policy, and research in relation to hand hygiene. It is a concept that adopts the ‘precautionary principle’ that if the relative risk of a specific care task is unknown, a safe system must be to treat them on an equal level. However, a literal interpretation will frequently result in an extraordinary, implausible number of hand-hygiene opportunities and if this then becomes the standard to audit practice, within a policy document that espouses zero tolerance, it is likely to generate inauthentic data. If used effectively the 5 Moments concept provides an opportunity to enhance practice and reduce healthcare-associated infections but the healthcare provider organisation must embody a ‘just culture’ and collect the data in a climate of openness, transparency, and learning.
A novel approach to prehospital continuing professional development
Authors: Bloch Mathew , Watson Daniel , Willis Sebastian
Published: December 2024

Introduction:

Prehospital practice is wide-ranging and busy. Staying up-to-date through continuing professional development (CPD) can be a challenge. Prehospital clinician SHORTs is a WhatsApp-based discussion group where interesting cases are presented and discussed.

Methods:

Cases with valuable learning points are identified and a moderated discussion is facilitated by an emergency medicine registrar. An automated CPD recording function is available that provides curriculum-mapped reflective learning records for participants.

Results:

Over 80 cases have been discussed with 200 prehospital staff signed up via word-of-mouth. A total of 130 CPD records have been provided and are monitored by faculty to ensure correct transfer of key learning. Messages are read from 0–72 hours after posting, demonstrating asynchronous learning, with two-thirds of people engaging with the material after the live discussion.

Conclusion:

There is demand among ambulance service staff for flexible, novel approaches to CPD, which incorporate interprofessional learning.
An A to Z of enhancements: U is for Under the Sea
Authors: Jackson Amy
Published: December 2024

Water trays, books, small-world toys and real-world objects can all be part of a sealife enhancement, explains Amy Jackson
transport Trains
Authors: Rawstrone Annette
Published: December 2024

In the first of a new six-part series, Annette Rawstrone delves into the popular topic of vehicles, starting with activities featuring trains
In other words
Authors: Hart Karen
Published: December 2024

From play-based approaches to books and music, Karen Hart discovers how early years settings are supporting all children's communication and language development
Scandi sustainability on display
Authors: McClean Andrew
Published: December 2024

Andrew McClean reports from independent eyewear show Copenhagen Specs
CONTACT LENSES: Water gradient technology – applied science and future applications
Authors: Guillon Michel , Bauman Erich
Published: December 2024

In the second of two articles looking at the performance of the contact lens material delefilcon A, Professor Michel Guillon and Dr Erich Baumann focus on the published literature relating to clinical performance and in vivo studies
Taking care of mother
Authors: Thethi Neha
Published: December 2024

Neha Thethi gives the lowdown on new mothers’ rights in the workplace
Enter the titan
Authors: Harvey Bill
Published: December 2024

Bill Harvey is excited to learn of the launch of a new slit-lamp system that can be operated remotely
Far from the madding crowd phenomenon
Authors: Harvey Bill
Published: December 2024

Bill Harvey takes a new near acuity test chart system out on the road and finds it both easy-to-use and flexible enough to adapt to a range of patients
Planning for the unthinkable
Authors: Bernstein Adam
Published: December 2024

Adam Bernstein extols the virtues of disaster planning
Keeping up with changing times
Authors: Harvey Bill
Published: December 2024

Bill Harvey finds much to be impressed by among the myriad of new technology on display at this year's 100% Optical show
CPD: The impact of harmful substances on eye health
Authors: Patel Sunni
Published: December 2024

In the first of a short new series looking at the impact of lifestyles on eye health, we invited Dr Sunni Patel to evaluate how harmful substances can impact the eye
Diary of a Spectacle Designer
Authors: Davies Tom
Published: December 2024

Tom Davies hits upon a new marketing strategy to drive eyewear sales
The visual benefits of blue-violet light filtering
Authors: Bishop Meredith , Martin Patricia , Buch John , Ruston David
Published: December 2024

Meredith Bishop, David Ruston, Patricia Martin and John Buch look at the operation and effects of blue light
New approach for glaucoma pitched in Scotland
Authors: McCarthy-McClean Andrew
Published: December 2024

Andrew McCarthy-McClean explores findings into how surgical innovations could improve patient outcomes
Flexor Tendon Rupture After a Cat Bite – A Case Report of An Uncommon Sequela
Authors:   Department of Orthopaedics, Orlando Health Level One Orthopaedics, Orlando, Florida, United States., Lewellyn Brett , Young Matthew ,   Department of Orthopaedics, Orlando Health Level One Orthopaedics, Orlando, Florida, United States., Blanco Paula ,   Department of Orthopaedics, Orlando Health Level One Orthopaedics, Orlando, Florida, United States.
Published: December 2024

Introduction: Cat bites are a remarkably common injury seen in the emergency department )setting . Due to the morphology of feline teeth and anatomy of the human hand, seemingly innocuous surface bites can seed infections in deeper structures of the hand that can result in adverse outcomes. We report on a case of a rare complication of a flexor tendon rupture that occurred well after the initial treatment of a superficial infection.

Case Report: A healthy 61 year old male presented to the emergency department with concerns for possible infection after sustaining a cat bite to the proximal phalanx of his left long finger 48 hoursh earlier. The patient was treated for suspected cellulitis and underwent irrigation and debridement within 36 hoursh. Five months after presentation, it was determined that the patient had suffered a spontaneous rupture of the flexor digitorum profundus tendon of the left long finger. The patient underwent surgical debridement, flexor tendon tenolysis, and tendon reconstruction. Postoperatively, the patient returned to normal activities with good function of his left hand after a course of occupational therapy.

Conclusion: The purpose of this case report is to describe the clinical course of a patient with the rare complication of a flexor tendon rupture after being bitten by a cat, as well as to review the current literature and treatment for feline bite-related hand injuries. We recommend patients who have sustained a cat bite with a suspected infection to present as early as possible for an evaluation by a medical professional, early appropriate empiric antibiotic administration, and early surgical debridement when warranted to help prevent complications.

Keywords: Cat bite, flexor tendon rupture, infection.
Tuberculous Tenosynovitis of the Wrist: A Rare Case Report
Authors:   Department of Orthopaedics, Maharishi Markandeshwar Institute of Medical Sciences and Research (MMIMSR), Ambala, Haryana, India,, Chahal Jashandeep Singh , Gupta Palak ,   Department of Medicine, Maharishi Markandeshwar Institute of Medical Sciences and Research (MMIMSR), Ambala, Haryana, India., Aggarwal Nipun ,   Department of Orthopaedics, Maharishi Markandeshwar Institute of Medical Sciences and Research (MMIMSR), Ambala, Haryana, India,, Gupta Aniket ,   Department of Orthopaedics, Maharishi Markandeshwar Institute of Medical Sciences and Research (MMIMSR), Ambala, Haryana, India,, Vats Amanpreet ,   Department of Orthopaedics, Maharishi Markandeshwar Institute of Medical Sciences and Research (MMIMSR), Ambala, Haryana, India,
Published: December 2024

Introduction: Tuberculosis (TB) of the wrist joint is a rare presentation of extrapulmonary TB, accounting for about 1% of musculoskeletal TB cases. We present a case of wrist joint TB in a 15-year-old immunocompetent male patient.

Case Report: A 15-year-old boy presented with 6- month history of left wrist swelling and pain along with constitutional symptoms for 2 months. Examination showed swelling, tenderness, and reduced range of wrist motion. Investigations revealed elevated inflammatory markers, lytic lesions on wrist X-ray, and positive polymerase chain reaction ( ) for Mycobacterium tuberculosis in synovial fluid. Histopathology of synovial biopsy demonstrated caseating granulomas, confirming the diagnosis- treatment with 6 months of anti-tubercular therapy led to complete resolution.

Conclusion: Though rare, wrist joint TB should be a diagnostic consideration in patients with chronic wrist symptoms. A high index of suspicion and early diagnosis using microbiological, radiological, and histopathological investigations prevents morbidity.

Keywords: Tuberculosis, extrapulmonary, wrist joint, case report.