bluuebunny/crossref_metadata_2025_split huggingface dataset:
Flow cytometric analysis for Ki67 assessment in formalin-fixed paraffin-embedded breast cancer tissue
Authors: Sato Natsuki , Tsujimoto Masahiko , Nakatsuji Masatoshi , Tsuji Hiromi , Sugama Yuji , Shimazu Kenzo , Shimoda Masafumi , Ishihara Hideki 
Published: August 2024

Abstract
Background
Pathologists commonly employ the Ki67 immunohistochemistry labelling index (LI) when deciding appropriate therapeutic strategies for patients with breast cancer. However, despite several attempts at standardizing the Ki67 LI, inter-observer and inter-laboratory bias remain problematic. We developed a flow cytometric assay that employed tissue dissociation, enzymatic treatment and a gating process to analyse Ki67 in formalin-fixed paraffin-embedded (FFPE) breast cancer tissue.

Results
We demonstrated that mechanical homogenizations combined with thrombin treatment can be used to recover efficiently intact single-cell nuclei from FFPE breast cancer tissue. Ki67 in the recovered cell nuclei retained reactivity against the MIB-1 antibody, which has been widely used in clinical settings. Additionally, since the method did not alter the nucleoskeletal structure of tissues, the nuclei of cancer cells can be enriched in data analysis based on differences in size and complexity of nuclei of lymphocytes and normal mammary cells. In a clinical study using the developed protocol, Ki67 positivity was correlated with the Ki67 LI obtained by hot spot analysis by a pathologist in Japan (rho = 0.756, P < 0.0001). The number of cancer cell nuclei subjected to the analysis in our assay was more than twice the number routinely checked by pathologists in clinical settings.

Conclusions
The findings of this study showed the application of this new flow cytometry method could potentially be used to standardize Ki67 assessments in breast cancer.
You talkin’ to me? Functional breed selection may have fundamentally influenced dogs’ sensitivity to human verbal communicative cues
Authors: Dobos Petra , Pongrácz Péter 
Published: August 2024

Abstract
Background
The ability to learn from humans via observation was considered to be equally present across properly socialized dogs. We showed recently that cooperative working breeds learned from a human demonstrator more effectively. We hypothesized that functional breed selection could affect sensitivity to human attention-eliciting behavior. Accordingly, we ran the first ever study on dogs that compared the effect of ostensive and neutral verbal communication in a social learning scenario. We used the detour paradigm around a transparent V-shaped fence with either ostensive (addressing the receiver both with words and specific, attention-eliciting prosody) or neutral speech (monotonous reciting of a short poem) demonstration. The other features (gestures, movement) of the demonstration sequence were kept identical between the two conditions. We tested (N = 70) companion dogs from 17 cooperative and 16 independent breeds in three 1-min trials. Subjects had to obtain the reward by detouring around the fence.

Results
Detour latencies of the cooperative dogs improved after both ostensive and neutral speech demonstrations. The independent dogs did not improve their detour latency in either of the conditions. Remarkably, ostensive verbal utterances elicited longer relative looking time towards the demonstrator, cooperative dogs looked longer at the demonstrator, and longer looking time resulted in more successful detours.

Conclusions
Our study provides the first indication that functional breed selection had a significant impact on dogs’ sensitivity to ostensive human communication, which, apart from being crucially important for social learning from humans, until now was considered as a uniformly present heritage of domestication in dogs.

Graphical Abstract
The impact of a child’s inborn error of metabolism: the parents’ perspectives on restrictions, discrimination, family planning, and emergency management
Authors: Harings Tanjana , Neininger Martina P. , Eisenhofer Simone , Thiele Alena G. , Kiess Wieland , Bertsche Astrid , Bertsche Thilo , Beblo Skadi 
Published: August 2024

AbstractBackgroundTo investigate the impact of children’s inborn error of metabolism (IEMs) on the children’s and their parents’ lives from the parents’ perspective. We focused on disease-related restrictions in various issues of daily life, experienced discrimination, parental family planning, and management of metabolic emergencies.MethodsWe conducted a questionnaire-based survey with 108 parents of 119 children with IEM who attended a metabolic outpatient clinic. The children were categorized into 4 cohorts, based on increasing disease severity (cohort 1: IEMs with lowest severity, cohort 4: IEMs with highest severity), and compared by using Tobit regressions.ResultsThe severity of the child’s IEM was associated with an increase in the intensity of perceived restrictions from the parents’ perspective for themselves and their children in all aspects of life: in general, in contact with friends, in the pursuit of hobbies, in childcare/school/occupation, and due to emotional stress. The highest intensity of restrictions in all cohorts was found for the parents themselves in contact with friends (compared to cohort 1: cohort 2: c. 3.556,p = 0.002; cohort 3: c. 4.159,p = 0.003; cohort 4: c. 7.224,p < 0.001). Parents of 8% of children reported that their children were discriminated against because of IEM, with the highest proportion of affected children (43%) in cohort 4. Parental family planning decisions were influenced in 34% of parents, with fear of recurrence being a predominant aspect. Of the parents of children diagnosed with IEMs associated with metabolic emergencies, 68% stated that they felt well or very well prepared for the occurrence of a metabolic emergency, and 100% of parents were able to name the necessary action steps from memory. Nevertheless, 58% stated that they experienced an occurring emergency as rather or very stressful.ConclusionsFrom the parents’ perspective, the intensity of restrictions increased with the severity of the child’s IEM. The study shows the high impact of IEM on parents of children with IEM and the daily challenges they face. These findings emphasize the importance of comprehensive support for parents of children with IEM.
The viral origins of breast cancer
Authors: Lawson James S. , Glenn Wendy K. 
Published: August 2024

AbstractDuring the past two decades evidence has been developed that indicates a handful of viruses with known oncogenic capacity, have potential roles in breast cancer. These viruses are mouse mammary tumour virus (MMTV - the cause of breast cancer in mice), high-risk human papilloma viruses (HPV-the cause of cervical cancer), Epstein Barr virus (EBV-the cause of lymphomas and naso-pharyngeal cancer) and bovine leukemia virus (BLV - the cause of cancers in cattle). These viruses may act alone or in combination. Each of these viruses are significantly more prevalent in breast cancers than in normal and benign breast tissue controls. The odds ratios for the prevalence of these viruses in breast cancer compared to normal and benign breast controls, are based on case control studies - MMTV 13·40, HPV 5.56, EBV 4·43 and BLV 2·57. The odds ratios for MMTV are much greater compared to the other three viruses. The evidence for a causal role for mouse mammary tumour virus and high risk for cancer human papilloma viruses in human breast cancer is increasingly comprehensive. The evidence for Epstein Barr virus and bovine leukemia virus is more limited. Overall the evidence is substantial in support of a viral cause of breast cancer.
Delta-radiomics features of ADC maps as early predictors of treatment response in lung cancer
Authors: Heidt Christian M. , Bohn Jonas R. , Stollmayer Róbert , von Stackelberg Oyunbileg , Rheinheimer Stephan , Bozorgmehr Farastuk , Senghas Karsten , Schlamp Kai , Weinheimer Oliver , Giesel Frederik L. , Kauczor Hans-Ulrich , Heußel Claus Peter , Heußel Gudula 
Published: August 2024

Abstract
Objective
Investigate the feasibility of detecting early treatment-induced tumor tissue changes in patients with advanced lung adenocarcinoma using diffusion-weighted MRI-derived radiomics features.

Methods
This prospective observational study included 144 patients receiving either tyrosine kinase inhibitors (TKI, n = 64) or platinum-based chemotherapy (PBC, n = 80) for the treatment of pulmonary adenocarcinoma. Patients underwent diffusion-weighted MRI the day prior to therapy (baseline, all patients), as well as either + 1 (PBC) or + 7 and + 14 (TKI) days after treatment initiation. One hundred ninety-seven radiomics features were extracted from manually delineated tumor volumes. Feature changes over time were analyzed for correlation with treatment response (TR) according to CT-derived RECIST after 2 months and progression-free survival (PFS).

Results
Out of 14 selected delta-radiomics features, 6 showed significant correlations with PFS or TR. Most significant correlations were found after 14 days. Features quantifying ROI heterogeneity, such as short-run emphasis (p = 0.04(pfs)/0.005(tr)), gradient short-run emphasis (p = 0.06(pfs)/0.01(tr)), and zone percentage (p = 0.02(pfs)/0.01(tr)) increased in patients with overall better TR whereas patients with worse overall response showed an increase in features quantifying ROI homogeneity, such as normalized inverse difference (p = 0.01(pfs)/0.04(tr)). Clustering of these features allows stratification of patients into groups of longer and shorter survival.

Conclusion
Two weeks after initiation of treatment, diffusion MRI of lung adenocarcinoma reveals quantifiable tissue-level insights that correlate well with future treatment (non-)response. Diffusion MRI-derived radiomics thus shows promise as an early, radiation-free decision-support to predict efficacy and potentially alter the treatment course early.

Critical relevance statement
Delta-Radiomics texture features derived from diffusion-weighted MRI of lung adenocarcinoma, acquired as early as 2 weeks after initiation of treatment, are significantly correlated with RECIST TR and PFS as obtained through later morphological imaging.

Key Points

Morphological imaging takes time to detect TR in lung cancer, diffusion-weighted MRI might identify response earlier.

Several radiomics features are significantly correlated with TR and PFS.

Radiomics of diffusion-weighted MRI may facilitate patient stratification and management.

Graphical Abstract
Digital breast tomosynthesis in breast cancer screening: an ethical perspective
Authors: Rosenqvist Simon , Brännmark Johan , Dustler Magnus 
Published: August 2024

Abstract
Although digital breast tomosynthesis has higher sensitivity than digital mammography and at least as high specificity, digital mammography remains the most common method for conducting mammographic screening. At the same time, mammography systems are now delivered “DBT-ready” and can be used for either digital mammography or digital breast tomosynthesis. In this paper, we ask whether it is ethically permissible to use such equipment for digital mammography, given its lower sensitivity. We argue it is not, and that clinics are ethically required to use their DBT-ready equipment to screen with digital breast tomosynthesis whenever this is practically possible. Our argument relies on a comparison between digital breast tomosynthesis and a hypothesized improvement in the image quality of digital mammography.

Critical relevance statement
Women may lose out on the benefits of screening with digital breast tomosynthesis when DBT-ready equipment is used to screen with digital mammography; we argue that this practice is ethically problematic.

Key Points

Digital breast tomosynthesis finds more cases of breast cancer than digital mammography.

Mammography equipment can often be used to screen with both digital breast tomosynthesis and digital mammography.

When they can, clinics are ethically required to use existing equipment to screen with digital breast tomosynthesis instead of digital mammography.
Decoding MRI-informed brain age using mutual information
Authors: Li Jing , Lam Linda Chiu Wa , Lu Hanna 
Published: August 2024

Abstract
Objective
We aimed to develop a standardized method to investigate the relationship between estimated brain age and regional morphometric features, meeting the criteria for simplicity, generalization, and intuitive interpretability.

Methods
We utilized T1-weighted magnetic resonance imaging (MRI) data from the Cambridge Centre for Ageing and Neuroscience project (N = 609) and employed a support vector regression method to train a brain age model. The pre-trained brain age model was applied to the dataset of the brain development project (N = 547). Kraskov (KSG) estimator was used to compute the mutual information (MI) value between brain age and regional morphometric features, including gray matter volume (GMV), white matter volume (WMV), cerebrospinal fluid (CSF) volume, and cortical thickness (CT).

Results
Among four types of brain features, GMV had the highest MI value (8.71), peaking in the pre-central gyrus (0.69). CSF volume was ranked second (7.76), with the highest MI value in the cingulate (0.87). CT was ranked third (6.22), with the highest MI value in superior temporal gyrus (0.53). WMV had the lowest MI value (4.59), with the insula showing the highest MI value (0.53). For brain parenchyma, the volume of the superior frontal gyrus exhibited the highest MI value (0.80).

Conclusion
This is the first demonstration that MI value between estimated brain age and morphometric features may serve as a benchmark for assessing the regional contributions to estimated brain age. Our findings highlighted that both GMV and CSF are the key features that determined the estimated brain age, which may add value to existing computational models of brain age.

Critical relevance statement
Mutual information (MI) analysis reveals gray matter volume (GMV) and cerebrospinal fluid (CSF) volume as pivotal in computing individuals’ brain age.

Key Points

Mutual information (MI) interprets estimated brain age with morphometric features.

Gray matter volume in the pre-central gyrus has the highest MI value for estimated brain age.

Cerebrospinal fluid volume in the cingulate has the highest MI value.

Regarding brain parenchymal volume, the superior frontal gyrus has the highest MI value.

The value of mutual information underscores the key brain regions related to brain age.

Graphical Abstract
Successful conservative management of advanced pyogenic sternoclavicular joint arthritis with osteomyelitis and pulmonary infiltration: a case report
Authors: Sugihara Takahito , Sano Yoshifumi , Ueki Takashi , Ishimura Takao , Takeda Masashi , Kiriyama Yosuke , Mori Yu , Sakao Nobuhiko , Otani Shinji , Izutani Hironori 
Published: August 2024

Abstract
Background
Sternoclavicular joint arthritis is a rare condition that poses considerable diagnostic and therapeutic challenges, leading to severe complications and a high mortality rate. Although surgical interventions are often considered necessary for advanced cases, some reports have suggested that conservative management with antibiotic therapy can be effective in certain cases. However, to our knowledge, there are no reports of successful conservative treatment in cases exhibiting aggressive spread. This report highlights a case of advanced sternoclavicular joint arthritis with bone destruction and pulmonary infiltration, successfully treated conservatively with outpatient antibiotic therapy.

Case presentation
A 58-year-old Japanese male presented with a 1-month history of left-sided shoulder pain. Contrast-enhanced computed tomography showed abscess formation and clavicular bone destruction, with infiltrative shadows suggesting lung involvement. The diagnosis of sternoclavicular joint arthritis was made, and outpatient oral antibiotic therapy was initiated. The patient exhibited a marked reduction in inflammatory marker levels and symptoms, and antibiotic therapy was discontinued after 3 weeks, with no recurrence observed at a 4-month follow-up.

Conclusions
This case highlights that conservative management with antibiotics can be effective for treating advanced sternoclavicular joint arthritis, emphasizing the need for individualized management and further research into non-surgical treatment options.
Attracting medical school graduates to residency programs in remotely located hospitals: the challenge lies beyond financial incentives
Authors: Fried Shalev , Zloto Ofira , Doron Avia , Feldman Zeev , Belinsky Alexey , Segal Gad , Frenkel-Nir Yael , Afek Arnon 
Published: August 2024

Abstract
Background
Recruitment to residency programs in hospitals located in other than major hubs (“remotely located”) is a challenge in many countries. In 2011, the Israeli Ministry of Health launched a 10-year financial incentive to encourage physicians to enroll in residency programs in such hospitals. Nearly 1 billion New Israeli Shekels (260 million US$) were invested in that program which had only limited success. As a new physician association’s collective agreement is impending, we aimed to measure the effectiveness of selected incentives in attracting medical school graduates to residencies in remotely located hospitals.

Methods
This study included Israeli medical students in their final year of medical school. We used an online questionnaire with multiple-choice demographic questions and a 5-point Likert scale to gauge the effect of various incentives on their preference for residency location.

Results
Between July and November 2022, 522 students responded (405 studied in Israeli medical schools [out of 705 students] and 117 in foreign medical schools [out of 1936 students]). Forty-two percent had at least one clerkship in a remotely located hospital, and 24% had included at least one remotely located hospital among their top five choices for internship. Only 13% reported that they prefer a residency program in those institutions. The incentive selected by students as most persuasive was government assistance in acceptance to and financial support for a fellowship abroad, followed by a financial grant and fewer on-call hours. Only 7% of the students indicated that no incentive would influence them to choose a remotely located hospital for their residency training. Medical education in a remotely located university and the choice of at least one remotely located hospital among the top five choices for internship were significantly associated with positive incentive receptivity, whereas male sex and older age were associated with negative receptivity.

Conclusion
This study on the attitudes of Israeli medical school graduates toward incentives aimed at attracting them to residencies in remotely located institutions revealed that career development opportunities and assistance in obtaining fellowships might influence their choice.
Predicting early appropriate therapy for patients infected by carbapenem-resistant Gram-negative pathogens in intensive care units in Italy
Authors: Bassetti Matteo , Monti Gianpaola , Henriksen Anne Santerre , Longshaw Christopher 
Published: August 2024

Abstract
Background
Antibiotic resistance among Gram-negative bacteria in intensive care units (ICUs) is linked with high morbidity and mortality in patients. In this study, we estimated the therapeutic coverage of various antibiotics, focusing on cefiderocol and comparators, administered empirically against an infection of unknown origin in the ICU.

Methods
In the ARTEMIS surveillance study, susceptibilities of 624 Italian Gram-negative isolates to amikacin, aztreonam-avibactam, cefiderocol, ceftazidime-avibactam, ceftolozane-tazobactam, colistin, imipenem-relebactam, meropenem, and meropenem-vaborbactam were tested by broth microdilution, and results were interpreted by European Committee on Antimicrobial Susceptibility Testing breakpoints. The susceptibility rates from the ARTEMIS study were extrapolated to Gram-negative isolates obtained from 5,774 patients in Italian ICUs in 2021. The sum of the predicted susceptibilities of individual pathogens represented the overall likelihood of in vitro activity of each antibiotic as early targeted therapy for ICU patients.

Results
A total of 624 Italian Gram-negative isolates included 206 Pseudomonas aeruginosa, 138 Acinetobacter baumannii, 187 Klebsiella pneumoniae, and 93 Escherichia coli. Against A. baumannii, K. pneumoniae, P. aeruginosa, and E. coli, the overall susceptibility rates for cefiderocol were 87.7%, 96.8%, 99%, and 100%, respectively; and for comparator agents, 8.7–96.4%, 25.7–100%, 73.3–100%, and 89.2–100%, respectively. Among the subset of meropenem-resistant isolates, susceptibility rates of A. baumannii, K. pneumoniae, and P. aeruginosa to cefiderocol were 86.4%, 96.2% and 100%, respectively. Corresponding susceptibility rates to comparator agents were 0–96.8%, 0–100%, and 6.4–100%, respectively. There were no meropenem-resistant isolates of E. coli. The extrapolation of data to isolates from Italian ICUs showed that the highest likelihood of therapeutic coverage, both overall and among meropenem-resistant isolates, was reported for colistin (96.8% and 72.2%, respectively) and cefiderocol (95.7% and 71.4%, respectively). All other antibiotics were associated with a likelihood below 73% overall and between 0% and 41.4% for meropenem-resistant isolates.

Conclusions
Based on confirmed susceptibility rates and reported ICU prevalence of multiple Gram-negative species, cefiderocol showed a higher predicted therapeutic coverage and utility in ICUs compared with comparator beta-lactam–beta-lactamase inhibitor antibiotics. Cefiderocol may be a promising early treatment option for patients at high risk of carbapenem-resistant Gram-negative bacterial infections in the ICU.
Current status and future perspectives of platelet-derived extracellular vesicles in cancer diagnosis and treatment
Authors: Zhuang Tongtao , Wang Shenrong , Yu Xiaoqian , He Xiaoyun , Guo Hongbin , Ou Chunlin 
Published: August 2024

AbstractPlatelets are a significant component of the cell population in the tumour microenvironment (TME). Platelets influence other immune cells and perform cross-talk with tumour cells, playing an important role in tumour development. Extracellular vesicles (EVs) are small membrane vesicles released from the cells into the TME. They can transfer biological information, including proteins, nucleic acids, and metabolites, from secretory cells to target receptor cells. This process affects the progression of various human diseases, particularly cancer. In recent years, several studies have demonstrated that platelet-derived extracellular vesicles (PEVs) can help regulate the malignant biological behaviours of tumours, including malignant proliferation, resistance to cell death, invasion and metastasis, metabolic reprogramming, immunity, and angiogenesis. Consequently, PEVs have been identified as key regulators of tumour progression. Therefore, targeting PEVs is a potential strategy for tumour treatment. Furthermore, the extensive use of nanomaterials in medical research has indicated that engineered PEVs are ideal delivery systems for therapeutic drugs. Recent studies have demonstrated that PEV engineering technologies play a pivotal role in the treatment of tumours by combining photothermal therapy, immunotherapy, and chemotherapy. In addition, aberrant changes in PEVs are closely associated with the clinicopathological features of patients with tumours, which may serve as liquid biopsy markers for early diagnosis, monitoring disease progression, and the prognostic assessment of patients with tumours. A comprehensive investigation into the role and potential mechanisms of PEVs in tumourigenesis may provide novel diagnostic biomarkers and potential therapeutic strategies for treating human tumours.