bluuebunny/crossref_metadata_2025_split huggingface dataset:
Splanchnic sympathetic nerve denervation improves bacterial clearance and clinical recovery in established ovine Gram-negative bacteremia
Authors: Peiris Rachel M. , May Clive N. , Booth Lindsea C. , McAllen Robin M. , McKinley Michael J. , Hood Sally , Martelli Davide , Bellomo Rinaldo , Lankadeva Yugeesh R. 
Published: August 2023

Abstract
Background
The autonomic nervous system can modulate the innate immune responses to bacterial infections via the splanchnic sympathetic nerves. Here, we aimed to determine the effects of bilateral splanchnic sympathetic nerve denervation on blood pressure, plasma cytokines, blood bacterial counts and the clinical state in sheep with established bacteremia.

Methods
Conscious Merino ewes received an intravenous infusion of Escherichia coli for 30 h (1 × 109 colony forming units/mL/h) to induce bacteremia. At 24 h, sheep were randomized to have bilaterally surgically implanted snares pulled to induce splanchnic denervation (N = 10), or not pulled (sham; N = 9).

Results
Splanchnic denervation did not affect mean arterial pressure (84 ± 3 vs. 84 ± 4 mmHg, mean ± SEM; PGroup = 0.7) compared with sham treatment at 30-h of bacteremia. Splanchnic denervation increased the plasma levels of the pro-inflammatory cytokine interleukin-6 (9.2 ± 2.5 vs. 3.8 ± 0.3 ng/mL, PGroup = 0.031) at 25-h and reduced blood bacterial counts (2.31 ± 0.45 vs. 3.45 ± 0.11 log10 [CFU/mL + 1], PGroup = 0.027) at 26-h compared with sham treatment. Plasma interleukin-6 and blood bacterial counts returned to sham levels by 30-h. There were no differences in the number of bacteria present within the liver (PGroup = 0.3). However, there was a sustained improvement in clinical status, characterized by reduced respiratory rate (PGroup = 0.024) and increased cumulative water consumption (PGroup = 0.008) in splanchnic denervation compared with sham treatment.

Conclusion
In experimental Gram-negative bacteremia, interrupting splanchnic sympathetic nerve activity increased plasma interleukin-6, accelerated bacterial clearance, and improved clinical state without inducing hypotension. These findings suggest that splanchnic neural manipulation is a potential target for pharmacological or non-pharmacological interventions.
Does the use of pharmacotherapy interact with the effects of psychotherapy? A meta-analytic review
Authors: Cuijpers Pim , Miguel Clara , Harrer Mathias , Ciharova Marketa , Karyotaki Eirini 
Published: August 2023

Abstract

Background
It is not clear if there is an interaction between psychotherapy and pharmacotherapy. First, there may be no interaction at all, meaning that the effects of both are independent of each other. Second, antidepressants may reduce the effects of psychotherapy, and third, antidepressants may increase the effects of psychotherapy. We examined which of the three is correct.

Methods
We conducted random effects meta-analyses of randomized trials comparing psychotherapies for adult depression with control conditions. The proportion of users of antidepressants was used as a predictor of the effect size in a series of meta-regression analyses, while adjusting for relevant moderators, such as type of control group and baseline severity.

Results
We included 300 randomized controlled trials (353 comparisons between treatment and control; 32,852 participants). The main effect size of psychotherapy was g = 0.71 (95% CI: 0.64; 0.79) with high heterogeneity (I2 = 82; 95% CI: 80; 84). We found no significant association between the proportion of antidepressants users and effect size (p = .07). We did find a significant association with some other predictors, including the type of control group and risk of bias. The use of antidepressants was associated with higher response rates within the control conditions, but not with the relative effects of the treatments compared to the control groups.

Discussion
We found support for the independent effects of psychotherapy and pharmacotherapy, which is good news from a clinical perspective. Apparently, patients can start with psychotherapy and do not have to be afraid that this will reduce the effects of the therapy.
Diversity data in oncology electronic data capture and database design: A global overview, gap analysis and recommendations for industry from the imCORE network, a worldwide research network designed to connect members in an open environment of shared information, expertise, and decisions.
Authors: Helou Sarah , Vidhyarkorn Tanya , Russell Janice , Churchill Sarah 
Published: August 2023

101 Background: The importance of enrolling diverse and inclusive patient populations in clinical trials has never been more critical however the implementation of measures to ensure inclusive clinical trials remains inconsistent and challenging industry wide. One key mechanism for tracking diversity in clinical trials is the database design of patient demographic classifications. Methods: In this paper we utilize the global reach of the imCORE network to explore the current trends in clinical trial database design for demographic data. We collect and review data on the design of electronic database systems from a diversity of sources including Roche Genentech clinical trial database frameworks and databases at our imCORE sites. We then provide a global electronic database demographic data classification overview and gap analysis. Results: Findings related to electronic database design, demographic data collection process, barriers to capturing diversity and demographic data are presented. Conclusions: Based on our findings we make recommendations from the site and sponsor perspective for an improved future state of electronic demographic diversity data collection in clinical trials with the goal of ultimately leading to meaningful change toward fully inclusive and equitable clinical trials.
Preclinical evaluation of JAK2 specific investigational oligonucleotide for the treatment of MDS/PV.
Authors: Przychodzen Bartlomiej , Smieszek Sandra Paulina 
Published: August 2023

122 Background: Myeloproliferative disorders (MPD) are clonal hematopoietic stem cell malignancies with cytokine independency or hypersensitivity. Polycythemia vera (PV), an acquired MPD characterized by increased blood cell mass and hematocrit and leukocyte count, is associated with incidental myelofibrosis (MF). MDS is characterized by cytopenia and the presence of morphological dysplasia of precursor and mature bone marrow blood cells. PV and MDS leave patients at risk for progression to acute myeloid leukemia. Abnormal cytokine signaling due to an aberrant JAK2-STAT pathway has a vital role in PV and MDS pathogenesis. JAK2 mutations can result in hematologic malignancies, where hyperactive signaling of the JAK2-STAT pathway promotes tumor cell proliferation, invasion, and angiogenesis. Increased JAK2 kinase activity is observed in hematologic malignancies; somatic JAK2 V617F gain-of-function mutations are found in at least 95% of PV patients and is implicated in MDS cases. We hypothesize that preventing JAK2 transcription by antisense oligonucleotide (ASO) mediated exon masking of the JAK2 intron-exon junction will result in reduced JAK2 mRNA, and thus JAK2 protein, by providing nonsense mediated decay (NMD) in the reading frame. This may alleviate disease manifestations of hematologic malignancies like PV and MDS. Methods: This study utilized a HEL cell line harboring the V617F JAK2 gain-of-function mutation. We designed a series 19mer ASO targeting JAK2 exon-intron junctions ( JAK2 intron-exon junction providing NMD in the reading frame, steric, non-RNAse H1) and tested these at a range of concentrations. The ASOs were designed with a phosphorothioate 2’-O-methoxyethyl backbone and prioritized based on in silico binding affinity and limited off-target binding. HEL cells underwent ASO treatment (1µM) and 72-hour incubation. Results: We observed significant JAK2 protein decrease (~50%) in ASO-treated samples compared to untreated samples. JAK2 qPCR results confirmed 40-60% of target transcript. STAT5 phosphorylation status further confirmed this effect, and we report a 35% pSTAT5 reduction. Furthermore, this ASO showed limited off-target effects in silico. siRNA and CRISPR knockout lysate were used as controls. Our preclinical data support this ASO as a highly specific JAK2 agent, affecting direct levels of JAK2 as well as downstream STAT signaling. Conclusions: Around 50-60% of primary MF patients harbor the JAK2 V617F gain-of-function mutation. ASOs offer the capability to directly target JAK2 mutations with high precision and effectively reduce JAK2 protein production, without off-target kinase effects. The ability to reduce JAK2 protein may alleviate the disease burden that patients with hematologic malignancies face, resulting in a higher quality of life through prevention and treatment.
Survival benefit of maintenance therapy in AML patients after complete remission in northeast Iran oncology centers with limited access to oral azacitidine.
Authors: Shariatmaghani Somayeh Sadat , Moeini Nodeh Mohammad , Emadzadeh Maryam , Allahyari Abollghasem , Rahimi Hossein , Mozaheb Zahra , Seddigh Shamsi Mohsen , ataei Azimi Sajad , Bary Alireza , Mohaddes Tahereh , Nazar Eisa , Davoudi Farnoush , Rezaei Borojerdi Zahra 
Published: August 2023

123 Background: Acute myeloid leukemia (AML) is associated with high relapse rates even in patients who achieve a complete remission with initial treatment. Maintenance therapy with cytotoxic agents has been considered a strategy to prolong disease-free survival (DFS) and overall survival (OS). The lack of availability of oral Azacitidine in some countries limits its use. This study aimed to compare the DFS and OS rates of AML patients with and without maintenance therapy using subcutaneous cytarabine or oral thioguanine. Methods: This retrospective cohort study reviewed the charts of non-m3 AML patients treated in oncology centers in northeast Iran from February 2015 to February 2021. The study included patients aged 15-60 who experienced complete remission following induction and then consolidation chemotherapy and did not receive Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT). Patients were categorized based on receiving maintenance therapy (MT) after the first-line treatment and those who were only followed up (FU). Patients’ demographic information, pathology and lab findings, date of relapse and/or death, and first-line and maintenance treatments regimens were extracted. For each of the MT and FU groups, the frequency of main outcomes (death and/or relapse) was calculated, and the Median (95%CI) of DFS and OS was estimated. The log-rank test was used to compare the DFS and OS between groups. Results: A total of 100 patients (50 MT and 50 FU) met the study inclusion criteria. There were no significant differences between the two groups regarding patients’ demographic characteristics, pathology and lab findings, and ELN’s risk category. The relapse rate in the FU and MT groups was 76% (n=38) and 60% (n=30) respectively (p=0.09). 39 individuals (78%) in the FU group and 26 individuals (54.2%) in the MT group died between complete remission and Feb 2022(p=0.01). The Median (95% CI) of DFS in FU and MT groups were 11 (8.6-13.3) and 18 (7.3 -28.6) months respectively (P=0.03). The median OS (95% CI) was 16 (10.8 - 21.1) months in the FU group and 23 (10.8 - 35) months in the MT group (P=0.04). Further comparisons between patients who received subcutaneous cytarabine and oral thioguanine revealed no significant differences regarding DFS and OS. Conclusions: The study results suggest that maintenance therapy with subcutaneous cytarabine or oral thioguanine after complete remission in non-m3 AML patients is associated with improved DFS and OS. Further randomized controlled trials and cost-utility studies are recommended to consider these available cytotoxic agents as maintenance therapy alternatives in regions where Azacitidine is not available.
Global public health implications of social media engagement from a virtual education platform to combat oncology misinformation.
Authors: Wilkerson William B. , Pawar Shubhadarshini , Leyfman Yan , Menon Gayathri P. , Joshi Muskan , Balasubramanian Maduri , Van de Kieft Alexandra , Park Chandler H. 
Published: August 2023

139 Background: While the popularity of social media has grown as a source of healthcare news, studies have shown that one third of social media posts contain misinformation with 76.9% of them containing harmful information leading to adverse outcomes. As a result, MedNews Week (MNW), a digital platform dedicated to combating misinformation, was developed to contribute to global oncology education through its free programming. In its first year, MNW has connected 193,000 live viewers from 57 countries with opportunities to learn from and engage live with oncology’s global leaders during their Keynote Lectures. The goal of this study was to assess whether Twitter Impressions, LinkedIn Impressions and Speaker H-Index significantly predicted the number of live attendees at Keynote Lectures as a marker for the utilization of medical information resources by a global network of patients and patient advocates. Methods: In 2022, MNW hosted 32 distinguished physician-researchers as Keynote Speakers for live streamed virtual lectures of which 25 spoke on oncology topics. Twitter and LinkedIn promotional posts for each Keynote Lecture began one week before every event and the number of impressions were collected. The number of virtual attendees at each live lecture and speaker h-index (a common metric of scholarly impact) were recorded for each lecturer for statistical testing. Multiple linear regression was performed using R. Results: Results showed that the overall regression was statistically significant (R2 = 0.9977, F(3, 18) = 2650, p-value < 0.001). Twitter and LinkedIn Impressions significantly predicted the number of live attendees at Keynote Lectures (p-value < 0.001). However, the speaker H-index did not significantly predict the number of live Keynote attendees (p-value = 0.258 > 0.05). Conclusions: There is very strong evidence to support social media engagement as a predictor of health resource utilization as evident by Keynote Lecture attendance. However, a speaker’s H-index was not found to be a good predictor of health resource utilization by patients and patient advocates. The results of this analysis highlight the importance of traditional resources of medical knowledge adapting to the current digital climate, as platforms like MNW and COSMO demonstrate the growing impact of social media as an outlet for patient education and outreach – particularly in underserved regions globally.[Table: see text]
Impact of a digital education platform to combat global inequity in oncology education amongst healthcare professionals in lower socioeconomic areas.
Authors: Leyfman Yan , Pawar Shubhadarshini , Joshi Muskan , Van de Kieft Alexandra , Menon Gayathri P. , Wilkerson William B. , Balasubramanian Maduri , Jackewicz Sean , Azeez Ahmed , Chorya Harshal , Pai Pallavi , Coloma Helena S , Wilson Steven , Park Chandler H. 
Published: August 2023

140 Background: Studies have shown that lower socioeconomic (LS) status contributes to heavier disease burden. While finances and infrastructural challenges have contributed to these inequities, access to the latest medical information has been cited as an equally important contributor. To address this, MedNews Week (MNW), a free, digital education platform was developed to provide global oncology education through its programming featuring Keynote presentations from oncology’s global leaders. To reach healthcare professionals (HCP), MNW has partnered with VuMedi, a global video education platform for physicians. The aim of this study was to assess the impact of MNW’s oncology programming on VuMedi’s education platform for HCP. Methods: From September 2022 to February 2023, MNW hosted 37 global oncology leaders and their Keynote Presentations were showcased on VuMedi. Data including viewership, global reach, page views, tumor subtype views, unique visits, and audience occupation demographics. In collaboration with VuMedi, descriptive analysis was performed, and a mixed-methods approach was employed to assess engagement. Results: During this 6-month period, the MNW channel on VuMedi demonstrated increased linear growth. Programming generated 4,387,213 total page views and 206 channel views with viewership from 22 countries— 12 of which are from LS areas, including Nigeria, Sudan, Georgia, and Bangladesh. Viewers were largely surgeons compared to Allied HCP (11:2). Solid tumors had high viewership [706 (0.012%) page views and 9717 (7%) impressions] compared with heme malignancies [689 (0.001%) page views and 1688 (1.22%) impressions]. Within solid tumors, GI oncology presentations were the most viewed— generating 3755 (0.06%) page views and 28067 (20%) impressions, and the highest number of registrations recorded for this category. During this period, the channel had 1,750,161 total visits with 44,982 new registrants. Conclusions: MNW has demonstrated an ability to attract and sustain a diverse, global, growing physician audience— especially within LE areas. While previous studies have identified internet access, cost, and infrastructural challenges as barriers to high-quality medical information, MNW has experienced steady growth and reachability especially within these limited areas. The platform’s ability to showcase global leaders to HCP offers an effective and practical approach to combat educational inequity, while positively impacting oncology education globally.[Table: see text]
Association of Claudin-1 overexpression with immune exclusion in nasopharyngeal carcinoma and its potential as a novel therapeutic target.
Authors: Yeo Eugenia Li Ling , Ong Enya , Neo Jialing , Chow Wen Min , Tan Kah Min , Tan Janice Ser Huey , Yeong Joe Poh Sheng , Lim Tony Kiat Hon , Hwang Jacqueline Siok Gek , Ng Quan Sing , Soong Yoke Lim , Ang Mei-Kim , Tan Sze Huey , Chua Melvin Lee Kiang , Lim Darren Wan-Teck 
Published: August 2023

151 Background: Claudin-1 (CLDN1) is a tight junction protein overexpressed in several cancers, where it is involved in the tumor microenvironment remodeling and stiffening of the tumor-stroma interface. This potentially prevents penetration of tumor infiltrating immune cells, in turn hindering the efficacy of immune checkpoint inhibitors (ICI). Given recent evidence supporting ICI efficacy in nasopharyngeal carcinoma (NPC), we investigated whether CLDN1 is overexpressed in NPC and its association with the tumor immune microenvironment (TME). Methods: 131 NPC patients treated at a single institution were prospectively recruited. TME profiling was performed using deconvolutional methods (CIBERSORT, quanTIseq) on tumor transcriptomes to estimate proportions of immune cell subsets, and expression of immune-related genes and pathways. Transcriptome profiling was performed on tumors with >70% cellularity and normal controls using Illumina Truseq (CA). We stratified tumors by their median CLDN1 expression and compared the immune profile of CLDN1high versus CLDN1low tumors. Cox regression model was used to analyze disease-free survival (DFS) as the primary clinical endpoint. Results: We observed CLDN1 overexpression in NPC versus normal tissues ( P=0.0046) that was independent of known prognostic clinical parameters e.g., TNM-stage and EBV DNA levels. Consistent with our hypothesis, CLDN1 expression was negatively correlated with total immune cell fraction in the tumor ( P<0.001). We observed reduced abundance of most immune subsets in CLDN1high tumors, notably CD8 T cells ( P<0.001), activated CD4 memory T cells ( P<0.001), and M1 and M2 macrophages ( P=0.048 and P<0.001). There was an overall downregulation of both stimulatory and suppressive GO immune-related gene-sets and genes in CLDN1high versus CLDN1low tumors, thereby corroborating our preceding observation of reduced immune infiltration in the TME in CLDN1 overexpressing NPC. Our findings were validated in a published dataset of 113 NPC tumors (Zhang et al., 2017). Of clinical relevance, reduced immune infiltration in the TME was prognostic for DFS; HR of CLDN1high, CD8 T celllow (stratified by median) NPC was 2.1 (95% CI:0.9-5.0) when compared with CLDN1low, CD8 T cellhigh NPC. Conclusions: Here, we report the overexpression of CLDN1 in NPC that is ubiquitous across disease stages and associated with an immune-low TME. This influence on the TME is associated with an inferior outcome of NPC patients. Given the role of the tumor TME in ICI response, our findings provide a rationale for future trials investigating combination of CLDN1 targeting with ICI to reverse this immune exclusion effect, potentially leading to improved outcomes.
Characteristics and prognosis of adolescent and young adult breast cancer.
Authors: Tokumaru Yoshihisa , Okawa Mai , Ando Saki , Niwa Yoshimi , Mori Ryutaro , Matsuhashi Nobuhisa , Futamura Manabu 
Published: August 2023

16 Background: Adolescent and young adult (AYA)-generation breast cancer has characteristics of high clinicopathological malignancy and poor prognosis compared to cancers of other age groups. In recent advances in cancer research, the tumor microenvironment is involved in cancer invasion. In this study, we investigated the biology of AYA-generation breast cancer and the prognostic effects of the cancer microenvironment in breast cancer patients. Methods: In the current study, we analyzed 2042 breast cancer patients with clinical and intratumoral gene expression data from the open public databases TCGA and METABRIC. Patients aged 15-39 were defined as AYA-generation breast cancer, and patients aged 40-65 as middle-aged breast cancer. Tumor biology and cancer microenvironment were assessed using gene set enrichment analysis (GSEA) and the xCell algorithm. Disease-specific survival (DSS) and disease-free survival (DFS) were used to evaluate the prognosis of AYA-generation breast cancer compared to that of middle-aged and elderly breast cancer. Results: In METABRIC, the proportion of advanced stages was higher in AYA generation breast cancer than in middle-aged and elderly breast cancer (p<0.01). However, this was not the case with TCGA cohort. In the prognostic analysis, AYA-generation breast cancer showed shortened DSS and DFS compared with middle-aged breast cancer only in METABRIC. To clarify the association between prognosis and cancer biology, we performed GSEA. AYA-generation breast cancer enriched cell proliferation-related gene sets such as E2F Targets, G2M Checkpoints, and MYC Targets V1 in METABRIC. The analysis of TCGA also confirmed this result. Interestingly, the infiltration of macrophage M1 (p<0.001) and helper T cell Th1 (p=0.007), which act as tumor suppressors, was significantly higher in AYA generation breast cancer in METABRIC cohort. In TCGA, there was only a tendency for Th1 infiltration to be high in AYA generation breast cancer. Conclusions: AYA-generation breast cancer enriched gene sets associated with cell proliferation which might explain the worse prognosis of AYA-generation breast cancer.