bluuebunny/crossref_metadata_2025 huggingface dataset:
Change in attitudes after a suicide prevention media campaign in the Mid-Norway region
Authors: Mohn Christine , Haga Egil , Nilsson Hanne Sofie Wernoe , Pirkis Jane , Mehlum Lars
Published: June 2024

Background

Suicide prevention media campaigns are one way of reaching people at increased suicide risk who would otherwise not seek help. This is the first study of a Norwegian campaign directed both at individuals at risk for suicide and at their social network.

Methods

We evaluated a media campaign consisting of outdoor posters, feature articles, film clips, and online banners in print, digital, and social media spread across the Mid-Norway region in late autumn 2022. This campaign material consisted of information about how to seek help for suicide thoughts and mental health problems and how to help a friend in similar situations. Before and after this campaign, 1149 adult individuals living in Mid-Norway participated in a survey on attitudes to suicide, mental ill health, and help-seeking.

Results

There were only marginal changes in attitudes and help-seeking literacy after the campaign. This result was sustained when controlling for age, sex, and campaign visibility. For males, there were a few changes in the negative direction, i.e. lack of willingness to seek help from family and friends, after the campaign.

Conclusion

We conclude that the campaign did not seem to have the desired effect and suggest ways of improving future regional Norwegian media campaigns.
Characteristics of drug overdose suicide attempts presenting to the psychiatric emergency department of Beijing Anding Hospital
Authors: Tu Lihui , Liu Yi , Zhu Hui , Zhang Qinge , Ji Xiao
Published: June 2024

Background

Overdose-related suicide attempts represent a significant portion of self-harm presentations in the psychiatric emergency department (ED). Identifying specific patient characteristics associated with these attempts holds promise for pinpointing drug classes with elevated risk and paving the way for tailored suicide prevention interventions. This study aims to examine the demographic profiles of ED patients who had experienced overdose-related suicide attempts.

Methods

This retrospective study was conducted at Beijing Anding Hospital, Capital Medical University, from January 2020 to December 2021. Patients with psychiatric drug overdose suicide attempts presenting to the psychiatric ED were included. Sociodemographic characteristics and the specific classes of drugs involved were collected, and analysed descriptively.

Results

This study examined 252 overdose patients, excluding 51 patients treated with alcohol or nonpsychiatric drugs, and a total 201 cases were included. The mean age of the patients was 28 ± 16 years (median 23, range 12–78), and 82% (n = 165) of the sample were females. Notably, nearly half (45%) of the patients were aged ≤ 20 years. While the number of cases decreased with increasing age, a significant increase was observed in 2021 compared to 2020. Benzodiazepines (BZDs) were the most frequently implicated substance class (n = 126, 63%), followed by antidepressants (n = 96, 48%), antipsychotics (n = 44, 22%), Z-drugs (n = 43, 21%), and mood stabilizers (n = 36, 18%). For adolescents, antidepressants (n = 52, 71%) overtook BZDs (n = 38, 52%) as the most common drug. The monthly distribution of cases revealed peaks in April and November. Furthermore, 21% (n = 42) of patients ingested more than two psychotropic medications concurrently. Finally, approximately half (n = 92) of the patients required inpatient admission for further treatment. Comparisons between hospitalized and nonhospitalized patients did not reveal any significant differences.

Conclusions

The present study revealed a greater prevalence of suicide overdose attempts among young females receiving prescriptions for antidepressants and/or BZDs. This finding suggests a potential need for enhanced monitoring of suicidal behaviour in this specific population when prescribing psychotropic medications. These findings contribute to the growing body of knowledge regarding drug overdose suicide attempts in psychiatric emergency settings and underscore the importance of further research to develop targeted prevention interventions.
Effectiveness of fentanyl buccal soluble film in cancer patients with inadequate breakthrough pain control
Authors: Chiang Yi-Hao , Lien Ching-Ting , Su Wen-Hao , Yen Tsung-Yu , Chen Yu-Jen , Lai Yuen-Liang , Lim Ken-Hong , Dai Kun-Yao , Chung Hsin-Pei , Hung Chia-Yen , Leu Yi-Shing
Published: June 2024

Background

Clinical evidence for the rapidity and effectiveness of fentanyl buccal soluble film (FBSF) in reducing pain intensity of breakthrough cancer pain (BTcP) remains inadequate. This study aimed to evaluate the efficacy of FBSF proportional to the around-the‐clock (ATC) opioid regimens in rapidly relieving the intensity of BTcP episodes by determining the percentage of patients requiring further dose titration.

Methods

The study procedure included a dose-finding period followed by a 14-day observation period. Pain intensity was recorded with a Numeric Rating Scale (NRS) at onset and 5, 10, 15, and 30 min after FBSF self-administration. Meaningful pain relief was defined as the final NRS score ≤ 3. Satisfaction survey was conducted for each patient after treatment using the Global Satisfaction Scale.

Results

A total of 63 BTcP episodes occurred in 30 cancer patients. Only one patient required rescue medication at first BTcP episode and then achieved meaningful pain relief after titrating FBSF by 200 µg. Most BTcP episodes relieved within 10 min. Of 63 BTcP episodes, 30 (47.6%), 46 (73.0%), and 53 (84.1%) relieved within 5, 10, and 15 min after FBSF administration. Only grade 1/2 adverse events were reported, including somnolence, malaise, and dizziness. Of the 63 BTcP episodes, 82.6% were rated as excellent/good satisfaction with FBSF.

Conclusion

FBSF can be administrated “on demand” by cancer patients at the onset of BTcP, providing rapid analgesia by achieving meaningful pain relief within 10 min.

Trial registration

This study was retrospectively registered 24 December, 2021 at Clinicaltrial.gov (NCT05209906): https://clinicaltrials.gov/study/NCT05209906.
The advanced lung cancer inflammation index (ALI) predicted the postoperative survival rate of patients with non-small cell lung cancer and the construction of a nomogram model
Authors: Ma Shixin , Li Zongqi , Wang Lunqing
Published: June 2024

Objective

To investigate the prognostic significance of the advanced lung cancer inflammation index (ALI) in patients with operable non-small-cell lung carcinoma (NSCLC). By constructing the nomogram model, it can provide a reference for clinical work.

Methods

A total of 899 patients with non-small cell lung cancer who underwent surgery in our hospital between January 2017 and June 2021 were retrospectively included. ALI was calculated by body mass index (BMI) × serum albumin/neutrophil to lymphocyte ratio (NLR). The optimal truncation value of ALI was obtained using the receiver operating characteristic (ROC) curve and divided into two groups. Survival analysis was represented by the Kaplan-Meier curve. The predictors of Overall survival (OS) were evaluated by the Cox proportional risk model using single factor and stepwise regression multifactor analysis. Based on the results of multi-factor Cox proportional risk regression analysis, a nomogram model was established using the R survival package. The bootstrap method (repeated sampling 1 000 times) was used for internal verification of the nomogram model. The concordance index (C-index) was used to represent the prediction performance of the nomogram model, and the calibration graph method was used to visually represent its prediction conformity. The application value of the model was evaluated by decision curve analysis (DCA).

Results

The optimal cut-off value of ALI was 70.06, and the low ALI group (ALI < 70.06) showed a poor survival prognosis. In multivariate analyses, tumor location, pathological stage, neuroaggression, and ALI were independently associated with operable NSCLC-specific survival. The C index of OS predicted by the nomogram model was 0.928 (95% CI: 0.904–0.952). The bootstrap self-sampling method (B = 1000) was used for internal validation of the prediction model, and the calibration curve showed good agreement between the prediction and observation results of 1-year, 2-year, and 3-year OS. The ROC curves for 1-year, 2-year, and 3-year survival were plotted according to independent factors, and the AUC was 0.952 (95% CI: 0.925–0.979), 0.951 (95% CI: 0.916–0.985), and 0.939 (95% CI: 0.913–0.965), respectively. DCA shows that this model has good clinical application value.

Conclusion

ALI can be used as a reliable indicator to evaluate the prognosis of patients with operable NSCLC, and through the construction of a nomogram model, it can facilitate better individualized treatment and prognosis assessment.
Haemoglobin values, transfusion practices, and long-term outcomes in critically ill patients with traumatic brain injury: a secondary analysis of CENTER-TBI
Authors: Guglielmi Angelo , Graziano Francesca , Bogossian Elisa Gouvêa , Turgeon Alexis F. , Taccone Fabio Silvio , Citerio Giuseppe ,   the CENTER-TBI Participants and Investigators
Published: June 2024

Haemoglobin (Hb) thresholds and red blood cells (RBC) transfusion strategies in traumatic brain injury (TBI) are controversial. Our objective was to assess the association of Hb values with long-term outcomes in critically ill TBI patients. We conducted a secondary analysis of CENTER-TBI, a large multicentre, prospective, observational study of European TBI patients. All patients admitted to the Intensive Care Unit (ICU) with available haemoglobin data on admission and during the first week were included. During the first seven days, daily lowest haemoglobin values were considered either a continous variable or categorised as < 7.5 g/dL, between 7.5–9.5 and > 9.5 g/dL. Anaemia was defined as haemoglobin value < 9.5 g/dL. Transfusion practices were described as “restrictive” or “liberal” based on haemoglobin values before transfusion (e.g. < 7.5 g/dL or 7.5–9.5 g/dL). Our primary outcome was the Glasgow outcome scale extended (GOSE) at six months, defined as being unfavourable when < 5. Of 1590 included, 1231 had haemoglobin values available on admission. A mean Injury Severity Score (ISS) of 33 (SD 16), isolated TBI in 502 (40.7%) and a mean Hb value at ICU admission of 12.6 (SD 2.2) g/dL was observed. 121 (9.8%) patients had Hb < 9.5 g/dL, of whom 15 (1.2%) had Hb < 7.5 g/dL. 292 (18.4%) received at least one RBC transfusion with a median haemoglobin value before transfusion of 8.4 (IQR 7.7–8.5) g/dL. Considerable heterogeneity regarding threshold transfusion was observed among centres. In the multivariable logistic regression analysis, the increase of haemoglobin value was independently associated with the decrease in the occurrence of unfavourable neurological outcomes (OR 0.78; 95% CI 0.70–0.87). Congruous results were observed in patients with the lowest haemoglobin values within the first 7 days < 7.5 g/dL (OR 2.09; 95% CI 1.15–3.81) and those between 7.5 and 9.5 g/dL (OR 1.61; 95% CI 1.07–2.42) compared to haemoglobin values > 9.5 g/dL. Results were consistent when considering mortality at 6 months as an outcome. The increase of hemoglobin value was associated with the decrease of mortality (OR 0.88; 95% CI 0.76–1.00); haemoglobin values less than 7.5 g/dL was associated with an increase of mortality (OR 3.21; 95% CI 1.59–6.49). Anaemia was independently associated with long-term unfavourable neurological outcomes and mortality in critically ill TBI patients.

Trial registration: CENTER-TBI is registered at ClinicalTrials.gov, NCT02210221, last update 2022–11–07.
Brain age as a biomarker for pathological versus healthy ageing – a REMEMBER study
Authors: Wittens Mandy M.J. , Denissen Stijn , Sima Diana M. , Fransen Erik , Niemantsverdriet Ellis , Bastin Christine , Benoit Florence , Bergmans Bruno , Bier Jean-Christophe , de Deyn Peter Paul , Deryck Olivier , Hanseeuw Bernard , Ivanoiu Adrian , Picard Gaëtane , Ribbens Annemie , Salmon Eric , Segers Kurt , Sieben Anne , Struyfs Hanne , Thiery Evert , Tournoy Jos , van Binst Anne-Marie , Versijpt Jan , Smeets Dirk , Bjerke Maria , Nagels Guy , Engelborghs Sebastiaan
Published: June 2024

Objectives

This study aimed to evaluate the potential clinical value of a new brain age prediction model as a single interpretable variable representing the condition of our brain. Among many clinical use cases, brain age could be a novel outcome measure to assess the preventive effect of life-style interventions.

Methods

The REMEMBER study population (N = 742) consisted of cognitively healthy (HC,N = 91), subjective cognitive decline (SCD,N = 65), mild cognitive impairment (MCI,N = 319) and AD dementia (ADD,N = 267) subjects. Automated brain volumetry of global, cortical, and subcortical brain structures computed by the CE-labeled and FDA-cleared software icobrain dm (dementia) was retrospectively extracted from T1-weighted MRI sequences that were acquired during clinical routine at participating memory clinics from the Belgian Dementia Council. The volumetric features, along with sex, were combined into a weighted sum using a linear model, and were used to predict ‘brain age’ and ‘brain predicted age difference’ (BPAD = brain age–chronological age) for every subject.

Results

MCI and ADD patients showed an increased brain age compared to their chronological age. Overall, brain age outperformed BPAD and chronological age in terms of classification accuracy across the AD spectrum. There was a weak-to-moderate correlation between total MMSE score and both brain age (r = -0.38,p < .001) and BPAD (r = -0.26,p < .001). Noticeable trends, but no significant correlations, were found between BPAD and incidence of conversion from MCI to ADD, nor between BPAD and conversion time from MCI to ADD. BPAD was increased in heavy alcohol drinkers compared to non-/sporadic (p = .014) and moderate (p = .040) drinkers.

Conclusions

Brain age and associated BPAD have the potential to serve as indicators for, and to evaluate the impact of lifestyle modifications or interventions on, brain health.
A new suction feeder and miniature teleosteomorph, Marcopoloichthys mirigioliensis, from the lower Besano Formation (late Anisian) of Monte San Giorgio
Authors: Arratia Gloria , Bürgin Toni , Furrer Heinz
Published: June 2024

A new species (Marcopoloichthys mirigioliensis) of the stem teleosteomorph genus Marcopoloichthys is described from the lower Besano Formation (late Anisian at Monte San Giorgio, southern Switzerland), making this new species distinct from Marcopoloichthys furreri from the Prosanto Formation (early Ladinian at Ducanfurgga, southeastern Switzerland). Marcopoloichthys mirigioliensis n. sp. is smaller (ca. 32 mm standard length) than M. furreri (ca. 40 mm standard length), and in addition, the two species have some important differences in the caudal endoskeleton and fin, e.g., number of epaxial and hypaxial basal fulcra, uroneural structure, size of hypurals, and presence versus absence of urodermals. Marcopoloichthys mirigioliensis n. sp. is the smallest member of Marcopoloichthyidae which is currently known from at least five species living in the Triassic of China (one species), Italy (two and others that remain undescribed), and Switzerland and according to current information, with its ca. 32 mm standard length is candidate to be considered a miniature fish. Additionally, this size makes it the smallest known stem teleost. As in other marcopoloichthyids, the buccal and suspensorium anatomy of M. mirigiolensis n. sp. corresponds to that of suction-feeder fishes.
Exploring a novel GH13_5 α-amylase from Jeotgalibacillus malaysiensis D5T for raw starch hydrolysis
Authors: Radzlin Nurfatini , Mohamad Ali Mohd Shukuri , Goh Kian Mau , Yaakop Amira Suriaty , Zakaria Iffah Izzati , Kahar Ummirul Mukminin
Published: June 2024

α-Amylase plays a crucial role in the industrial degradation of starch. The genus Jeotgalibacillus of the underexplored marine bacteria family Caryophanaceae has not been investigated in terms of α-amylase production. Herein, we report the comprehensive analysis of an α-amylase (AmyJM) from Jeotgalibacillus malaysiensis D5T (= DSM28777T = KCTC33550T). Protein phylogenetic analysis indicated that AmyJM belongs to glycoside hydrolase family 13 subfamily 5 (GH13_5) and exhibits low sequence identity with known α-amylases, with its closest counterpart being the GH13_5 α-amylase from Bacillus sp. KSM-K38 (51.05% identity). Purified AmyJM (molecular mass of 70 kDa) is stable at a pH range of 5.5–9.0 and optimally active at pH 7.5. The optimum temperature for AmyJM is 40 °C, where the enzyme is reasonably stable at this temperature. Similar to other α-amylases, the presence of CaCl2 enhanced both the activity and stability of AmyJM. AmyJM exhibited activity toward raw and gelatinized forms of starches and related α-glucans, generating a mixture of reducing sugars, such as glucose, maltose, maltotriose, maltotetraose, and maltopentaose. In raw starch hydrolysis, AmyJM exhibited its highest efficiency (51.10% degradation) in hydrolyzing raw wheat starch after 3-h incubation at 40 °C. Under the same conditions, AmyJM also hydrolyzed tapioca, sago, potato, rice, and corn raw starches, yielding 16.01–30.05%. These findings highlight the potential of AmyJM as a biocatalyst for the saccharification of raw starches, particularly those derived from wheat.
Fourth order Hankel determinants for certain subclasses of modified sigmoid-activated analytic functions involving the trigonometric sine function
Authors: Srivastava Hari M. , Khan Nazar , Bah Muhtarr A. , Alahmade Ayman , Tawfiq Ferdous M. O. , Syed Zainab
Published: June 2024

The aim of this paper is to introduce two new subclasses $\mathcal{R}_{\sin }^{m}(\Im )$

R
sin
m

(
ℑ
)
and $\mathcal{R}_{\sin }(\Im )$

R
sin

(
ℑ
)
of analytic functions by making use of subordination involving the sine function and the modified sigmoid activation function $\Im (v)=\frac{2}{1+e^{-v}}$
ℑ
(
v
)
=

2

1
+

e

−
v

, $v\geq 0$
v
≥
0
in the open unit disc E. Our purpose is to obtain some initial coefficients, Fekete–Szego problems, and upper bounds for the third- and fourth-order Hankel determinants for the functions belonging to these two classes. All the bounds that we will find here are sharp. We also highlight some known consequences of our main results.
Nano-modifications of edible materials using ionizing radiation for potential application in active food safety
Authors: Aboulfotouh Maysara E. , Ali Hussein El-shahat , Mohamed Maha R.
Published: June 2024

Active food packaging films from Carboxy methyl cellulose and starch (CMC-g-Starch) reinforced with Magnesium-oxide (MgO) NPs are created and characterized. The effect of different particle sizes, MgO NPs concentrations and different gamma irradiation doses on the preparation of (CMC-g-Starch-MgO) edible nanocomposite films were investigated to determine their properties. Several analytical methods, such as swelling behavior, FT-IR, TEM, TGA, and mechanical characteristics, are represented to investigate different characteristics of the prepared (CMC-g-Starch-MgO) edible nanocomposite films. Also, the prepared (CMC-g-Starch-MgO) edible nanocomposite films and their coating were subjected to the fresh Peaches fruits. Their effect on the Peach fruits' lifespan was evaluated. The anti-microbial property of the edible (CMC-g-Starch-MgO) nanocomposite films of gram (+ve) and gram (–ve) bacteria was reported. Results represented the thermal and mechanical characteristics of (CMC-g-Starch-MgO) edible nanocomposite films, which were enhanced by γ irradiation. Also, the irradiated (CMC-g-Starch-MgO) edible nanocomposite films and their coating extend the lifespan of Peaches fruits and exhibit resistance to pathogenic microorganisms. In conclusion, (CMC-g-Starch-MgO) edible nanocomposite films fulfilled the required behaviors for the application in the nanofood packaging era.
Organ-specific immune-related adverse events and survival in patients with cancer with immune checkpoint inhibitors.
Authors: Wang Jun , Han Xinyue , Chen Yingcui , Xie Hong , Zhang Yuekai , Cui Yu , Guan Yaping
Published: June 2024

12124

Background: Immunotherapy with immune checkpoint inhibitors (ICIs) can lead to immune-related adverse events (irAEs). This study was designed to assess whether the occurrence of irAEs or different irAE characteristics correlates with survival outcomes in advanced cancer patients treated with ICIs. Methods: This cohort study included a panel of patients with advanced cancer who received ICI therapy at a single institute. Kaplan‒Meier curves were generated to describe progression-free survival (PFS) and overall survival (OS) in patients with irAEs or specific irAE characteristics. Results: A total of 238 patients were enrolled, and 83 (34.9%) patients developed at least one irAE. The irAE development was associated with prolonged OS (not reached vs 17.8 months, HR: 0.48, p < 0.001), PFS (8.7 vs 4.8 months, HR: 0.63, p = 0.003), and an improved objective response rate (24.1% vs 10.3%, p = 0.005). However, irAE characteristics, including severity, number of organs or systems affected, and timing of onset, were not associated with OS. Furthermore, we observed that only skin and endocrine toxicities independently protected against OS and PFS. Based on the results from organ-specific irAEs, the first development of skin or endocrine toxicities as protective irAEs rather than other irAEs was an independent indicator for predicting OS (HR: 0.24, p < 0.001) and PFS (HR: 0.43, p< 0.001). A prognostic irAE score based on organ-specific irAEs was developed to show the effect of total protective irAEs on patient outcomes. Conclusions: Not all irAEs are associated with prolonged survival. Identification of organ-specific irAEs but not other irAE characteristics is useful for stratifying patients who actually respond to and benefit from ICIs across different cancer types.
Zotiraciclib for newly diagnosed or recurrent glioblastoma: Updated outcome and biomarker analysis.
Authors: Weller Michael , Gorlia Thierry , Felsberg Joerg , Jongen Joost , Maurage Claude-Alain , Ducray Francois , Gramatzki Dorothee , Hau Peter , Chinot Olivier L. , Preusser Matthias , Cartalat Stephanie , Roth Patrick , Van Den Bent Martin J. , Furtner Julia , Collienne Maike , Reifenberger Guido , Weiss Tobias , Le Rhun Emilie
Published: June 2024

2058

Background: There has been little progress in the treatment of newly diagnosed glioblastoma in decades and standards of care for recurrent glioblastoma remain poorly defined. The multi-cyclin dependent kinase inhibitor Zotiraciclib (TG02) depletes short-lived survival proteins such as c-MYC and MCL-1 which are overexpressed in glioblastoma. The mode of action is thought to be specific inhibition of cyclin-dependent kinase (CDK) 9. Methods: EORTC 1608 was a three parallel group (A,B,C) phase Ib, non-randomized, multicenter study in isocitrate dehydrogenase wildtype newly diagnosed glioblastoma or anaplastic astrocytoma. In groups A and B, the maximum tolerated dose (MTD) of Zotiraciclib in elderly patients, in combination with radiotherapy alone (group A) or temozolomide alone (group B), stratified by O6-methylguanine DNA methyltransferase promoter methylation status, were determined. In group C, we explored single agent activity of TG02 at first relapse with a primary endpoint of progression-free survival at 6 months (PFS-6). Tumor expression of CDK-9, c-MYC and MCL-1 was determined by immunohistochemistry. Tumor-related extracellular vesicles were quantified according to the minimal information for studies of extracellular vesicles 2018 (MISEV2018) guidelines. Results: Main toxicities of zotiraciclib were neutropenia, gastrointestinal disorders and hepatotoxicity. The MTD was 150 mg twice weekly in group A (weekly) or twice weekly in alternating weeks in group B. PFS-6 in group C was 6.7%. The tumor expression of c-MYC and MCL-1 was moderately cross-correlated. High protein levels of MCL-1 were associated with inferior survival. The levels of tumor-related extracellular vesicles in the blood correlated with tumor volumes determined by MRI and increased from baseline to recurrence. Conclusions: Zotiraciclib exhibits overlapping toxicity with alkylating agents which are the cornerstone of medical treatment for glioblastoma. Its single agent clinical activity in the recurrent setting was low. The role of c-MYC and MCL-1 as therapeutic targets and the diagnostic value of extracellular vesicles in peripheral blood in glioblastoma warrant further study.
Identification of molecular subtypes for integrated multi-omics analysis for use in guiding precision medicine in hepatocellular carcinoma.
Authors: Chen Yihong , Han Ying , Cai Changjing , Peng Yinghui , Ma Jiayao , Shen Hong , Zeng Shan
Published: June 2024

2576

Background: Tumor microenvironment (TME) heterogeneity leads to the discrepancy of survival prognosis and clinical treatment response for HCC patients. Although the documented molecular subtypes moderately describe the TME heterogeneity and characteristics, their clinical application is constrained by several issues. Methods: We integrated three single-cell datasets from 39 HCC patients to describe the TME landscape and identified prognosis-related cell subclusters. Unsupervised clustering of subcluster-specific markers (SSMs) was performed to generate transcriptomic subtypes. The predictive value of these molecular subtypes for prognosis and treatment response was explored in multiple external HCC cohorts and Xiangya real-world HCC cohort with patients who received immune checkpoint blockade (ICB) therapy. Cancer stemness was estimated using bioinformatic methods and in vivo and in vitro experiments. The features of TME were further validated using single-cell RNA-seq and immune repertoire sequencing, mass cytometry (CyTOF) and multiplex immunofluorescence (mIF). Ultimately, we constructed prognosis-related score (PRS)based on machine learning algorithm, and identified the potential therapeutic targets and agents for high-PRS patients. Results: The comprehensive single-cell analysis provided a high-resolution depiction of TME heterogeneity in HCC and confirmed 6 cell subclusters of prognostic relevance. Five transcriptomic subtypes were constructed using SSMs, which possessed different clinical prognosis, stemness characteristics, immune landscape and therapeutic responses. Class 1 indicated an inflamed phenotype with better clinical outcomes, while Class 2 and class 4 demonstrated immune-deserted phenotypes lacking T cells infiltration. Class 5 and class 3 indicated inhibitory tumor immune microenvironment enriched regulatory T cells and suppressive immune checkpoints. Multiple therapeutic cohorts suggested that Class 5 and class 3 were sensitive to ICB and targeted therapy, while Class 1 and Class 2 were more responsive to transcatheter arterial chemoembolization treatment (TACE). Class 4 displayed resistant to all conventional HCC therapies. The PRS performed well in prognostic prediction in multiple HCC cohorts. Four potential therapeutic agents and four targets were further identified for high-PRS HCC patients. Conclusions: Our study generated a clinically valid molecular classification, thereby providing guidance for precision medicine in HCC patients.
SH2B3 mutation as a potential resistance mechanism to oncolytic virus therapy.
Authors: Costa Philippos Apolinario , Ishizuka Jeffrey Joseph , Olino Kelly , Frey Alexander , Lee Daniel
Published: June 2024

2578

Background: Oncolytic viruses (OV) are viruses that preferentially destroy cancer cells while sparing healthy cells. Currently, talimogene laherparepvec (TVEC) is the sole FDA-approved OV product; however, resistance to therapy often emerges. To further understand OV resistance mechanisms, we performed transcriptome and mutational analysis on patient samples using a discordant lesion approach. Methods: An 80-year-old woman was diagnosed with Merkel cell carcinoma of the right lower extremity and underwent wide local excision. Her disease recurred, and she developed multiple metastatic lesions over three years. During that time, she was further treated with radiation, immunotherapy, and intralesional TVEC. Despite the different treatments, her disease eventually progressed, leading to her death. We analyzed the primary lesion and four discordant lesions that either persisted or recurred following treatment. Treatment data were extracted from medical records, and lesions were classified based on their resistance to therapies. DNA and RNA were extracted from tissue, and whole exome sequencing and bulk RNA sequencing were performed. Whole exome data was compared between specimens to determine mutation enrichment over time. Gene Set Enrichment Analysis was used to interpret bulk RNA sequencing data and compare transcriptional states of lesions. Results: Lesions four and five recurred following TVEC treatment and were, therefore, classified as TVEC resistant. Whole exome sequencing of all five lesions identified a heterozygous point mutation (P521L) in the SH2B3 gene in lesions four and five only. Additionally, the variant allelic fraction of this point mutation increased from 33% in lesion four to 44% in lesion five, where it was the highest frequency variant. When comparing lesion five to lesion one, Gene Set Enrichment Analysis showed an increase in both the hallmark inflammatory response gene signature and the hallmark interferon alpha response gene signature. SH2B3 is a gene that encodes the LNK protein, which functions as a negative regulator of the JAK-STAT signaling pathway and is, therefore, a negative regulator of interferon signaling. A mutation leading to a loss of function in SH2B3 would conceptually lead to upregulation of interferon signaling, which has previously been shown to promote an antiviral state within the tumor microenvironment and limit the effectiveness of OV treatment. Conclusions: Sequencing of discordant MCC lesions revealed enrichment in the mutational fraction of SH2B3 associated with an increase in interferon alpha and inflammatory signaling among lesions that were resistant to TVEC treatment. This is the first study to report a possible genetic driver for OV resistance. We introduced using CRISPR-HDR P521L SH2B3 in MCC cell lines to investigate its impact on LNK expression and its role as a mechanism of OV treatment resistance, with results to be presented.
AI based PD-L1 CPS quantifier software to identify more patients for checkpoint therapy in gastric cancer at pathologist-level interobserver concordance.
Authors: Badve Sunil S , Kumar George Louis , Lang Tobias , Mulder David , Calvopiña Diego , Frey Patrick , Karasarides Maria
Published: June 2024

2633

Background: To determine whether gastric cancer (GC) patients are eligible for immunotherapy, PD-L1 expression is analyzed by immunohistochemistry (IHC) using the “Combined Positive Score” (CPS). This requires quantification of PD-L1 stained tumor and tumor-associated immune cells as well as all viable tumor cells. However, manual CPS scoring on whole-slide images (WSIs) is time-consuming and prone to error as evidenced by low interobserver concordance. While the use of artificial intelligence (AI) holds the promise to ameliorate this key challenge in clinical practice, AI models have not yet met the required accuracy thresholds for PD-L1 CPS scoring on GC biopsies. Methods: We investigated the use of an AI-based PD-L1 CPS quantifier software to support pathologists in standardized PD-L1 IHC assessment on GC biopsies.An AI software for automated PD-L1 CPS scoring was deployed on WSIs from GC biopsies (n = 97) stained for PD-L1 with the 28-8 pharmDx assay and scanned on a 3DHistech P1000 scanner. Manual CPS scores from 12 pathologists on all 97 slides were available for comparison. Pairwise correlation was calculated for continuous values using Lin’s concordance correlation coefficient (CCC). Pairwise concordance was measured for scores binarized at the clinically relevant positivity cutoff of CPS ≥ 5 using unweighted Cohen’s kappa. Results: For continuous CPS scores, the CCC between AI scores and pathologists’ scores was higher (0.59) than the mean correlation among pathologists (0.56). In the majority of cases, the AI scores were found to be within the range of all pathologists, but slightly above the pathologist median. At a cutoff of CPS≥5, the concordance between AI scores and pathologists’ manual scores (κ=0.45) was higher than the mean concordance among pathologists’ manual scores (κ=0.39) (p<0.05). Substantial variability is seen among pathologists when categorizing patients as positive (CPS≥5), with approximately 30.3 ±5.0 patients classified as positive on average by manual scoring and 46 patients (>50% more) categorized as positive by the AI model. Conclusions: An AI model for the assessment of PD-L1 expression in GC using CPS was applied successfully without human intervention. The correlation in continuous CPS scores as well as the concordance in clinical categories with all pathologists was higher for the AI model than for individual pathologists on average, while at the same time, the AI model found more positive patients. This shows that by using AI more positive patients eligible for PD-L1 targeted treatment might be identified while simultaneously ensuring a level of concordance that is non-inferior to pathologists.
Effect of continued immunotherapy on survival of extensive-stage small cell lung cancer: A retrospective analysis.
Authors: Sun Zhuoran , Tian Yaru , Lu Shuangqing , Zhu Hui
Published: June 2024

e20114

Background: Immunotherapy has shown significant survival advantages in the first-line treatment of extensive-stage small cell lung cancer (ES-SCLC),and the second-line treatment options for ES-SCLC are gradually attracting wider attention. The aim of this study was to evaluate the clinical efficacy of continued immunotherapy as the second-line treatment for ES-SCLC. Methods: Between September 2020 and August 2023, the study included 207 patients diagnosed with ES-SCLC, all of whom progressed after first-line immunotherapy plus chemotherapy. The primary endpoints was progression-free survival (PFS) from the first disease progression to the second progression or date cutoff. And the second endpoints were overall survival(OS) from diagnosis to death or date cutoff and adverse events (AEs).OS and PFS were calculated using the Kaplan-Meier method, and compared using the log-rank test. Results: Overall, 124 patients were included in the continued immunotherapy group, and 83 patients in the control immunotherapy group. The basic characteristics of patients included age: 62.3% below 65 years old and 37.7% over or equal 65 years old; Most patients had KPS scores≥80 (85%),138 patients (66.7%) had baseline liver metastases, and 146 patients(70.5%) had baseline brain metastases.The continued second-line immunotherapy (including PD-L1 inhibitors and PD-1 inhibitors) did not prolong OS (median:18.03 vs. 21.34 months, HR=1.15,p=0.47) and PFS (median:4.30 vs. 4.43 months,HR=1.29,p=0.19) compared with the control. In the subgroup analysis, there were no significant differences in PFS among patients with partial response (PR, median:4.46 vs 4.43 months, HR=1.35,p=0.10) and stable disease (SD, median:4.75 vs 3.08 months HR=0.81, p=0.56), as well as in OS among patients with partial response (PR, median:18.43 vs 21.34 months, HR=1.15,p=0.53) and stable disease (SD, median:14.98 vs 17.80 months HR=0.95,p=0.90).I n the continued immunotherapy group, PFS was not significantly different between continued PD-L1 inhibitor group and PD-1 inhibitor group (median: 4.26 vs 4.59 months HR=1.04,p=0.17). There was no significant difference in adverse effects between the groups. Conclusions: Continued immunotherapy did not prove survival of ES-SCLC patients progressed after the standard first-line immunotherapy plus chemotherapy, neither efficacy nor type of immune checkpoint inhibitors produces benefit after progression in ES-SCLC patients.
Efficacy and safety of anti-angiogenic therapy plus immunotherapy as later-line treatment for small cell lung cancer: A real-world study.
Authors: Chen Tong , Wang Mingzhao , Chen Yanchao , Cao Yang , Liu Yutao
Published: June 2024

e20125

Background: Small cell lung cancer (SCLC) is an highly aggressive malignancy with a poor prognosis, and current therapeutic options for relapsed SCLC are limited. This study aims to evaluate the efficacy and safety of immune checkpoint inhibitors (ICIs) combined with antiangiogenic agents in patients (pts) with previously treated SCLC, and to initially explore biomarkers for the response prediction of combination therapy. Methods: In this single-center study, medical records and follow-up data of pts with SCLC who received antiangiogenic therapy plus immunotherapy (combination therapy) or antiangiogenic monotherapy as second or later-line treatment were retrospectively analyzed. The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Additionally, plasma was collected from pts in the combination therapy cohort before and after two cycles of treatment. The samples were tested for extracellular vesicles (EVs) membrane protein expression profiles. Potential biomarkers for the therapeutic effect were screened and then evaluated for their predictive performance. Results: A total of 61 pts were enrolled, including the combination therapy group (n = 40) and the antiangiogenic monotherapy group (n = 21). Baseline characteristics of the two groups were comparable. Kaplan-Meier (K-M) curve demonstrated superior PFS in combination therapy group than in monotherapy group (mPFS: 4.0 vs.2.7 months, P = 0.029). Both univariate (HR 0.634, 95%CI: 0.420-0.959, P = 0.031) and multivariate Cox regression (HR 0.554, 95%CI: 0.345-0.888, P = 0.014) proved that combination therapy, compared to antiangiogenic monotherapy, was correlated with markedly improved PFS. The combination group had higher DCR than the monotherapy group (77.5% vs. 52.4%, P = 0.044). No significant difference in the incidence of AEs between the two groups was observed. Plasma EV membrane protein detection and differential expression analysis suggested that IL-12 served as a prognostic marker for adverse outcomes in combination therapy. The Receiver Operating Characteristic (ROC) curve and K-M curve showed that IL-12 possessed favorable efficacy prediction performance (Area Under Curve, AUC = 0.85), and pts with high IL-12 expression exhibited significantly shorter PFS in contrast to those with low expression (P < 0.0001). In pts experiencing progression within 3 months, higher levels of IL-12 were detected compared to those who did not (P = 0.002). Conclusions: ICIs plus antiangiogenic therapy has demonstrated superior efficacy in disease control and delayed progression over antiangiogenic monotherapy as later-line treatment in pts with SCLC. Serum EV membrane proteins showed promising predictive value for the efficacy of combination therapy.
A real-world study of anlotinib in combination with PD-L1 inhibitors plus chemotherapy as first-line therapy for extensive-stage small cell lung cancer.
Authors: Chen Size , Lin Yiguang , Song Minghan , Dong Jiayi , Lijuan Shao
Published: June 2024

e20135

Background: Current first-line treatment options for extensive stage small cell lung cancer (ES-SCLC) are the PD-L1 inhibitor in combination with chemotherapy. Although these regimens have improved outcomes, most patients experience disease progression (PD), and median survival remains approximately 12 months. Anlotinib represents a tyrosine kinase inhibitor targeting multiple receptor tyrosine kinases, achieved good efficacy in third-line therapy in ES-SCLC. We conducted a real-world study to explore the safety and efficacy of adding anlotinib to the current first-line therapy in ES-SCLC. Methods: This real-world study included 16 patients with ES-SCLC treated with antirotinib in combination with the PD-L1 inhibitor and etoposide and cisplatin chemotherapy at our hospital between Oct 2020 and Nov 2023. Patients received six cycles of a standard dose of the PD-L1 inhibitor (Atezolizumab; Adebrelimab; Envafolimab; Nivolumab; Pembrolizumab; Tirelizumab or Sugemalimab) in combination with cisplatin (25 mg/m2, day 1-3 of each cycle) and etoposide (100 mg/m2, day 1-3 of each cycle), and anlotinib was taken orally (4-6mg, day 1-14 of each cycle). Maintenance PD-L1 inhibitor plus anlotinib was followed in a 21-day cycle until disease progression, intolerant toxicity, or longer than 2 years of treatment. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Secondary outcomes were disease control rate (DCR), objective response rate (ORR), and adverse reactions. Treatment response and adverse events (AEs) were assessed using the RECIST 1.1 and CTCAE 5.0, respectively. Results: A total of 16 patients were recruited. The median age was 72 years (66-76). Four patients (25%) had brain metastases at baseline, and seven patients (43.8%) had liver metastases. Median PFS was 10.8 months (95% CI, 8.3-13.3 months) and the median OS was 16.4 months (95% CI, 9.6-23.2 months). Totally 15 and 1 participants showed PR and SD, respectively. ORR and DCR were 93.8% and 100%. All patients had treatment-related AEs, of which grade 3-4 AE occurred in 50% (8/16). No serious infection or treatment-related death occurred. Myelosuppression was the most common AE, such as anemia (100%), leukocytopenia (100%), lymphocytopenia (100%), neutropenia (87.5%), and thrombocytopenia (50%). Other common AEs included hypoproteinemia (68.8%); hyponatremia (62.5%); creatinine elevation (56.3%), proteinuria (43.8%); hypertension (37.5%) and hypertriglyceridemia (37.5%). No unexpected AEs were found in this study. No patient stopped treatment due to intolerable toxicity. Conclusions: The addition of anlotinib to first-line immunotherapy in combination with chemotherapy results in extended PFS and OS in patients with ES-SCLC without additional AEs. The preliminary results warrant further investigation of this treatment modality in ES-SCLC.
They Took the Best Farms
Authors: Mueser Anna Lehr
Published: June 2024

This article explores collective memories about lost farms in New York City's watershed. It argues that farms taken by eminent domain for two water supply reservoirs came to symbolize lost rural and agricultural lifeways in the twentieth century. In the 1950s and 1960s, New York City condemned over two hundred farms in Delaware County, New York, flooding two valleys for reservoirs, contributing to a pattern of farm closure, and dramatically changing social and economic life. Nonetheless, farms declined in this region more slowly than across the state and nation, suggesting that it was not the loss of farms but the specific way these agricultural valleys were flooded that became important for collective memories about this local history. Using transcripts from eminent domain proceedings and local newspapers, this article explores the making and mobilization of collective memories that blamed New York City for the loss of the county's “best” farms. Reading historical documents as cultural texts, this article brings together the insights of science and technology studies and memory studies to show how residents in the watershed localized a more general politics of rural-urban division by linking anxieties about changes in the region to New York City's water supply development history.
Farming for the Overseas Market under the Maoist State
Authors: Hu Guangji
Published: June 2024

Drawing on county-level foreign trade archival documents, this article explores export production in the rural Pearl River delta during the 1960s and 1970s, focusing on the relationship between local foreign trade agencies and grassroots collectives in three counties. The study contends that, instead of the state having complete control of the entire production and procurement process, rural export production in the Pearl River delta demonstrates remarkable diversity and responsiveness to fluctuating overseas market conditions, whose adaptability, however, was significantly constrained by the grain-first policy during the Maoist era. This research further posits that the interplay between control and autonomy mechanisms shaped the institutional context in which rational, calculating Chinese peasants navigated the Maoist state. Notably, the state was not a monolithic entity, and its boundaries with the peasants were permeable and dynamic.
Estimating dengue disease and economic burden to inform municipal-level policymakers: Method for a pragmatic city-level observational cohort study
Authors: Wilastonegoro Nandyan N. , Andriani Sri , Sebong Perigrinus H. , Agarwal-Harding Priya , Shepard Donald S.
Published: June 2024

Background Recent trials have confirmed the effectiveness of promising dengue control technologies – two vaccines, and Wolbachia. These would generally be applied at the municipal level. To help local officials to decide which, if any, control strategy to implement, these officials need affordable, timely, and accurate data on dengue burden. Building on our previous work in Mexico, Indonesia, and Thailand, we developed a streamlined prospective method to estimate dengue burden at the municipal level quickly, accurately, and efficiently. Method The method entails enrolling and repeatedly interviewing 100 patients with laboratory-confirmed dengue. They will be selected after screening and testing about 1,000 patients with clinical dengue. The method will capture both acute and chronic effects relating to disease, economic burden, and psychological impacts (presenteeism). The total time requirements are 1.5 years, comprised of 0.25 years for planning and approvals, 1 year for data collection (a full dengue cycle), and 0 .25 years for data cleaning and analysis. A collaboration with municipal and academic colleagues in the city of Semarang, Central Java, Indonesia shows how the method could be readily applied in Indonesia’s eighth largest city (population 1.8 million). Conclusions Many surveillance studies gather only information on numbers of cases. This proposed method will provide a comprehensive picture of the dengue burden to the health system, payers, and households at the local level.
A TEORIA DA REPRODUÇÃO SOCIAL E A ARTE: DIALOGANDO SOBRE REALIDADES FEMININAS
Authors: Teles Cardoso Gleiciane , Vieira Soares Cunha Niágara
Published: June 2024

O objetivo deste estudo é elucidar a percepção das mulheres participantes do Projeto Cine-Poesia sobre a Teoria da Reprodução Social. Usamos o materialismo histórico-dialético como referencial teórico-metodológico da pesquisa e o tipo de análise categorial qualitativa. O estudo foi formado por mulheres que tiveram acesso à pesquisa através das redes sociais. Concluiu-se que elas assimilaram que a Teoria da Reprodução Social debate o que é instituído como papel da mulher na sociabilidade capitalista e discute a reprodução da força de trabalho, que é colocada sobre a responsabilidade da mulher, gerando um processo de opressão e exploração feminina.