bluuebunny/crossref_metadata_2025_split huggingface dataset:
Colorectal adenocarcinoma in Uganda: are right-sided and left-sided colon cancers two distinct disease entities?
Authors: Wismayer Richard , Kiwanuka Julius , Wabinga Henry , Odida Michael 
Published: July 2023

Abstract
Introduction
In Western countries, right-sided colon cancers (RSCC) present at an older age and advanced stage. Researchers believe that there is a difference between left-sided colon cancer (LSCC) and RSCC. In Uganda, however, it is unknown whether differences exist in the pathological profile between RSCC and LSCC. The aim of this study was to determine the differences in clinicopathological characteristics between RSCC and LSCC in Ugandan patients.

Methodology
A cross-sectional study was conducted in which colorectal adenocarcinoma formalin-fixed paraffin-embedded tissue (FFPE) blocks were obtained from 2008 to 2021. Colorectal specimens were obtained from prospectively recruited patients. In the retrospective study arm, FFPE blocks and data were obtained from the archives of pathology laboratory repositories. Parameters studied included age, sex, location of the tumour, grade, stage, lymphovascular (LVI) status, and histopathological subtype between LSCC and RSCC.

Results
Patients with RSCC were not older than those with LSCC (mean age, 56.3 years vs 53.5 years; p = 0.170). There was no difference in the stage between RSCC and LSCC. Poorly differentiated tumours were more commonly found in RSCC than in LSCC (18.7% vs 10.1%; p = 0.038). Moderately and poorly differentiated colonic tumours were more common with RSCC (89.3%) than with LSCC (75.1%) (p = 0.007). Younger patients had more poorly differentiated tumours than older patients (19.6% versus 8.6%; p = 0.002). LVI was more common with RSCC than with LSCC (96.8% vs 85.3%; p = 0.014). Mucinous adenocarcinoma (MAC) was more common with RSCC (15.8%) compared with LSCC (8.5%) (p = 0.056) although statistical significance was borderline.

Conclusions
Clinicopathological features of RSCCs tend to be different from those of LSCCs. RSCCs tend to be associated with MAC, a higher grade and LVI status compared to LSCC. LSCC and RSCC present predominantly with an advanced stage; therefore, national screening programmes for the early detection of CRC are necessary to reduce mortality in our Ugandan population.
Socioeconomic position as a predictor of youth's movement trajectory profiles between ages 10 and 14 years
Authors: Wilhite Katrina , del Pozo Cruz Borja , Noetel Michael , Lonsdale Chris , Ridgers Nicola D. , Maher Carol , Bradshaw Emma , Sanders Taren 
Published: July 2023

Abstract
Background
Combinations of movement behaviors (i.e., physical activity, sedentary behavior, sleep) are associated with health and developmental outcomes in youth. Youth vary in how they accumulate these behaviors, both in volume and specific domains (e.g., sedentary time spent on recreational screen activities vs homework). The aim of this study was to examine how youth’s combined general and domain-specific movement trajectories differ by socioeconomic position.

Methods
We conducted a longitudinal, group-based multi-trajectory analysis to identify general and domain-specific movement trajectory profiles for 2457 youth from age 10 to 14 years from the Longitudinal Study of Australian Children from 2014–2018. We used multinomial logistic regression to test if socioeconomic position predicted profile membership.

Results
We identified three general movement trajectory profiles for both sexes, four domain-specific profiles for males, and five for females. For general movement trajectories, females from lower socioeconomic positions were more likely to be a combination of less active and more sedentary than females from higher socioeconomic positions. Males across socioeconomic positions spend similar amounts of time in physical activity, sedentary time, and sleep. For domain-specific movement trajectories, youth from lower socioeconomic positions were likely to spend a combination of less time in education-based sedentary behavior and more time in recreational screen activities than their higher socioeconomic position peers.

Conclusion
Our results indicate that socioeconomic position predicted in which domains youth accumulate their movements. Future observational research and interventions targeting different socioeconomic groups should therefore consider domain-specific movement trajectories.
SIRT3 ameliorates diabetes-associated cognitive dysfunction via regulating mitochondria-associated ER membranes
Authors: Chang Yanmin , Wang Cailin , Zhu Jiahui , Zheng Siyi , Sun Shangqi , Wu Yanqing , Jiang Xingjun , Li Lulu , Ma Rong , Li Gang 
Published: July 2023

Abstract
Background
Diabetes is associated with an increased risk of cognitive decline and dementia. These diseases are linked with mitochondrial dysfunction, most likely as a consequence of excessive formation of mitochondria-associated membranes (MAMs). Sirtuin3 (SIRT3), a key mitochondrial NAD+-dependent deacetylase, is critical responsible for mitochondrial functional homeostasis and is highly associated with neuropathology. However, the role of SIRT3 in regulating MAM coupling remains unknown.

Methods
Streptozotocin-injected diabetic mice and high glucose-treated SH-SY5Y cells were established as the animal and cellular models, respectively. SIRT3 expression was up-regulated in vivo using an adeno-associated virus in mouse hippocampus and in vitro using a recombinant lentivirus vector. Cognitive function was evaluated using behavioural tests. Hippocampus injury was assessed using Golgi and Nissl staining. Apoptosis was analysed using western blotting and TUNEL assay. Mitochondrial function was detected using flow cytometry and confocal fluorescence microscopy. The mechanisms were investigated using co-immunoprecipitation of VDAC1–GRP75–IP3R complex, fluorescence imaging of ER and mitochondrial co-localisation and transmission electron microscopy of structural analysis of MAMs.

Results
Our results demonstrated that SIRT3 expression was significantly reduced in high glucose-treated SH-SY5Y cells and hippocampal tissues from diabetic mice. Further, up-regulating SIRT3 alleviated hippocampus injuries and cognitive impairment in diabetic mice and mitigated mitochondrial Ca2+ overload-induced mitochondrial dysfunction and apoptosis. Mechanistically, MAM formation was enhanced under high glucose conditions, which was reversed by genetic up-regulation of SIRT3 via reduced interaction of the VDAC1–GRP75–IP3R complex in vitro and in vivo. Furthermore, we investigated the therapeutic effects of pharmacological activation of SIRT3 in diabetic mice via honokiol treatment, which exhibited similar effects to our genetic interventions.

Conclusions
In summary, our findings suggest that SIRT3 ameliorates cognitive impairment in diabetic mice by limiting aberrant MAM formation. Furthermore, targeting the activation of SIRT3 by honokiol provides a promising therapeutic candidate for diabetes-associated cognitive dysfunction. Overall, our study suggests a novel role of SIRT3 in regulating MAM coupling and indicates that SIRT3-targeted therapies are promising for diabetic dementia patients.
Chimeric antigen receptor T cells targeting cell surface GRP78 efficiently kill glioblastoma and cancer stem cells
Authors: Wang Shijie , Wei Wenwen , Yuan Yuncang , Sun Bin , Yang Dong , Liu Nan , Zhao Xudong 
Published: July 2023

Abstract
Background
Glioblastoma (GBM) is recognized as among the most aggressive forms of brain tumor. Patients typically present with a five-year survival rate of less than 6% with traditional surgery and chemoradiotherapy, which calls for novel immunotherapies like chimeric antigen receptor T (CAR-T) cells therapy. In response to endoplasmic reticulum (ER) stress in multiple tumor cells including GBM, the glucose-regulated protein 78 (GRP78) expression increases and the protein is partially translocated to the cell surface, while it is restricted to the cytoplasm and the nucleus in normal cells.

Methods
In this study, to target the cell surface GRP78 (csGRP78), CAR-T cells based on its binding peptide were generated. In vitro two GBM cell lines and glioma stem cells (GSCs) were used to confirm the localization of csGRP78 and the cytotoxicity of the CAR-T cells. In vivo a GBM xenograft model was used to assess the killing activity and the safety of the CAR-T cells.

Results
We confirmed the localization of csGRP78 at the cell surface of two GBM cell lines (U-251MG and U-87MG) and in GSCs. Co-culture experiments revealed that the CAR-T cells could specifically kill the GBM tumor cells and GSCs with specific IFN-γ release. Furthermore, in the tumor xenograft model, the CAR-T cells could decrease the number of GSCs and significantly suppress tumor cell growth. Importantly, we found no obvious off-target effects or T cell infiltration in major organs following systemic administration of these cells.

Conclusions
The csGRP78 targeted CAR-T cells efficiently kill GBM tumor cells and GSCs both in vitro and in vivo, and ultimately suppress the xenograft tumors growth without obvious tissue injuries. Therefore, our study demonstrates that csGRP78 represents a valuable target and the csGRP78-targeted CAR-T cells strategy is an effective immunotherapy against GBM.
Elevated blood and cerebrospinal fluid biomarkers of microglial activation and blood‒brain barrier disruption in anti-NMDA receptor encephalitis
Authors: Chang Haoxiao , Ma Jia , Feng Kai , Feng Ning , Wang Xinxin , Sun Jiali , Guo Tianshu , Wei Yuzhen , Xu Yun , Wang Huabing , Yin Linlin , Zhang Xinghu 
Published: July 2023

Abstract
Background
Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune disease characterized by complex neuropsychiatric syndrome and cerebrospinal fluid (CSF) NMDAR antibodies. Triggering receptor expressed on myeloid cells 2 (TREM2) has been reported to be associated with inflammation of the central nervous system (CNS). Matrix metalloproteinase-9 (MMP9) and cluster of differentiation (CD44) were measured to evaluate blood‒brain barrier (BBB) permeability in anti-NMDAR encephalitis. The roles of microglial activation and BBB disruption in anti-NMDAR encephalitis are not well known.

Findings
In this work, we detected increased expression levels of CSF sTREM2, CSF and serum CD44, and serum MMP9 in anti-NMDAR encephalitis patients compared with controls. CSF sTREM2 levels were positively related to both CSF CD44 levels (r = 0.702, p < 0.0001) and serum MMP9 levels (r = 0.428, p = 0.021). In addition, CSF sTREM2 levels were related to clinical parameters (modified Rankin Scale scores, r = 0.422, p = 0.023, and Glasgow Coma Scale scores, r = − 0.401, p = 0.031).

Conclusion
Increased sTREM2 levels in CSF as well as increased CD44 and MMP9 in serum and CSF reflected activation of microglia and disruption of the BBB in anti-NMDAR encephalitis, expanding the understanding of neuroinflammation in this disease. The factors mentioned above may have potential as novel targets for intervention or novel diagnostic biomarkers.
Iron induces B cell pyroptosis through Tom20–Bax–caspase–gasdermin E signaling to promote inflammation post-spinal cord injury
Authors: Wu Chengjie , Wang Lining , Chen Sixian , Shi Lei , Liu Mengmin , Tu Pengcheng , Sun Jie , Zhao Ruihua , Zhang Yafeng , Wang Jianwei , Pan Yalan , Ma Yong , Guo Yang 
Published: July 2023

Abstract
Background
Immune inflammatory responses play an important role in spinal cord injury (SCI); however, the beneficial and detrimental effects remain controversial. Many studies have described the role of neutrophils, macrophages, and T lymphocytes in immune inflammatory responses after SCI, although little is known about the role of B lymphocytes, and immunosuppression can easily occur after SCI.

Methods
A mouse model of SCI was established, and HE staining and Nissl staining were performed to observe the pathological changes. The size and morphology of the spleen were examined, and the effects of SCI on spleen function and B cell levels were detected by flow cytometry and ELISA. To explore the specific mechanism of immunosuppression after SCI, B cells from the spleens of SCI model mice were isolated using magnetic beads and analyzed by 4D label-free quantitative proteomics. The level of inflammatory cytokines and iron ions were measured, and the expression of proteins related to the Tom20 pathway was quantified by western blotting. To clarify the relationship between iron ions and B cell pyroptosis after SCI, we used FeSO4 and CCCP, which induce oxidative stress to stimulate SCI, to interfere with B cell processes. siRNA transfection to knock down Tom20 (Tom20-KD) in B cells and human B lymphocytoma cell was used to verify the key role of Tom20. To further explore the effect of iron ions on SCI, we used deferoxamine (DFO) and iron dextran (ID) to interfere with SCI processes in mice. The level of iron ions in splenic B cells and the expression of proteins related to the Tom20–Bax–caspase–gasdermin E (GSDME) pathway were analyzed.

Results
SCI could damage spleen function and lead to a decrease in B cell levels; SCI upregulated the expression of Tom20 protein in the mitochondria of B cells; SCI could regulate the concentration of iron ions and activate the Tom20–Bax–caspase–GSDME pathway to induce B cell pyroptosis. Iron ions aggravated CCCP-induced B cell pyroptosis and human B lymphocytoma pyroptosis by activating the Tom20–Bax–caspase–GSDME pathway. DFO could reduce inflammation and promote repair after SCI by inhibiting Tom20–Bax–caspase–GSDME-induced B cell pyroptosis.

Conclusions
Iron overload activates the Tom20–Bax–caspase–GSDME pathway after SCI, induces B cell pyroptosis, promotes inflammation, and aggravates the changes caused by SCI. This may represent a novel mechanism through which the immune inflammatory response is induced after SCI and may provide a new key target for the treatment of SCI.
Contextual factors influencing the roles of patent medicine vendors in the provision of injectable contraception services in Nigeria
Authors: Adebayo Ayodeji Matthew , Oluwasanu Mojisola Morenike , Okunade Faizah Tosin , Ajayi Olayinka Olufunke , Akindele Akinwumi Oyewole , Ajuwon Ademola Johnson 
Published: July 2023

AbstractBackgroundPatent medicine vendors (PMVs) play vital roles in the delivery of family planning services in Nigeria and other developing countries. There is a growing recognition of the need to integrate them into the formal health care system as a strategy to increase the contraceptive prevalence rate and achieve universal health coverage. Though promising, the success of this proposition is largely dependent on a critical analysis of the factors which influence their operations. This study was designed to identify the contextual factors influencing the provision of injectable contraceptive services by PMVs and the broader effects of their activities on the health system to inform similar interventions in Nigeria.MethodsThis was a qualitative study guided by the UK Medical Research Council’s Framework for Complex Interventions. Twenty-seven in-depth interviews were conducted among officials of the association of PMVs, health workers, government regulatory officers and programme implementers who participated in a phased 3-year (2015–2018) intervention designed to enhance the capacity of PMVs to deliver injectable contraceptive services. The data were transcribed and analyzed thematically using NVIVO software.ResultsThe contextual factors which had implications on the roles of PMVs were socio-cultural and religious, the failing Nigerian health system coupled with government regulatory policies. Other factors were interprofessional tensions and rivalry between the PMVs and some categories of health care workers and increasing donors’ interest in exploring the potentials of PMVs for expanded healthcare service provision. According to the respondents, the PMVs bridged the Nigerian health system service delivery gaps serving as the first point of contact for injectable contraceptive services and this increased contraceptive uptake in the study sites. A negative effect of their operation is the tendency to exceed their service provision limits, which has spurred a planned tiered PMV accreditation system.ConclusionsThis study has highlighted the contextual factors which define the roles and scope of practice of PMVs involved in injectable contraceptive service provision. Strategies and interventions aimed at expanding the healthcare delivery roles of PMVs must be encompassing to address the broader contextual factors which underpin their capacities and functions.
Assessment of emerging pretraining strategies in interpretable multimodal deep learning for cancer prognostication
Authors: Azher Zarif L. , Suvarna Anish , Chen Ji-Qing , Zhang Ze , Christensen Brock C. , Salas Lucas A. , Vaickus Louis J. , Levy Joshua J. 
Published: July 2023

AbstractBackgroundDeep learning models can infer cancer patient prognosis from molecular and anatomic pathology information. Recent studies that leveraged information from complementary multimodal data improved prognostication, further illustrating the potential utility of such methods. However, current approaches: 1) do not comprehensively leverage biological and histomorphological relationships and 2) make use of emerging strategies to “pretrain” models (i.e., train models on a slightly orthogonal dataset/modeling objective) which may aid prognostication by reducing the amount of information required for achieving optimal performance. In addition, model interpretation is crucial for facilitating the clinical adoption of deep learning methods by fostering practitioner understanding and trust in the technology.MethodsHere, we develop an interpretable multimodal modeling framework that combines DNA methylation, gene expression, and histopathology (i.e., tissue slides) data, and we compare performance of crossmodal pretraining, contrastive learning, and transfer learning versus the standard procedure.ResultsOur models outperform the existing state-of-the-art method (average 11.54% C-index increase), and baseline clinically driven models (average 11.7% C-index increase). Model interpretations elucidate consideration of biologically meaningful factors in making prognosis predictions.DiscussionOur results demonstrate that the selection of pretraining strategies is crucial for obtaining highly accurate prognostication models, even more so than devising an innovative model architecture, and further emphasize the all-important role of the tumor microenvironment on disease progression.
Treatment of adult ALL patients with third-generation CD19-directed CAR T cells: results of a pivotal trial
Authors: Schubert Maria-Luisa , Schmitt Anita , Hückelhoven-Krauss Angela , Neuber Brigitte , Kunz Alexander , Waldhoff Philip , Vonficht Dominik , Yousefian Schayan , Jopp-Saile Lea , Wang Lei , Korell Felix , Keib Anna , Michels Birgit , Haas Dominik , Sauer Tim , Derigs Patrick , Kulozik Andreas , Kunz Joachim , Pavel Petra , Laier Sascha , Wuchter Patrick , Schmier Johann , Bug Gesine , Lang Fabian , Gökbuget Nicola , Casper Jochen , Görner Martin , Finke Jürgen , Neubauer Andreas , Ringhoffer Mark , Wolleschak Denise , Brüggemann Monika , Haas Simon , Ho Anthony D. , Müller-Tidow Carsten , Dreger Peter , Schmitt Michael 
Published: July 2023

AbstractBackgroundThird-generation chimeric antigen receptor (CAR)-engineered T cells (CARTs) might improve clinical outcome of patients with B cell malignancies. This is the first report on a third-generation CART dose-escalating, phase-1/2 investigator-initiated trial treating adult patients with refractory and/or relapsed (r/r) acute lymphoblastic leukemia (ALL).MethodsThirteen patients were treated with escalating doses of CD19-directed CARTs between 1 × 106and 50 × 106CARTs/m2. Leukapheresis, manufacturing and administration of CARTs were performed in-house.ResultsFor all patients, CART manufacturing was feasible. None of the patients developed any grade of Immune effector cell-associated neurotoxicity syndrome (ICANS) or a higher-grade (≥ grade III) catokine release syndrome (CRS). CART expansion and long-term CART persistence were evident in the peripheral blood (PB) of evaluable patients. At end of study on day 90 after CARTs, ten patients were evaluable for response: Eight patients (80%) achieved a complete remission (CR), including five patients (50%) with minimal residual disease (MRD)-negative CR. Response and outcome were associated with the administered CART dose. At 1-year follow-up, median overall survival was not reached and progression-free survival (PFS) was 38%. Median PFS was reached on day 120. Lack of CD39-expression on memory-like T cells was more frequent in CART products of responders when compared to CART products of non-responders. After CART administration, higher CD8 + and γδ-T cell frequencies, a physiological pattern of immune cells and lower monocyte counts in the PB were associated with response.ConclusionIn conclusion, third-generation CARTs were associated with promising clinical efficacy and remarkably low procedure-specific toxicity, thereby opening new therapeutic perspectives for patients with r/r ALL.Trial registrationThis trial was registered atwww.clinicaltrials.govas NCT03676504.
Novel target and treatment agents for natural killer/T-cell lymphoma
Authors: Tian Xiao-Peng , Cao Yi , Cai Jun , Zhang Yu-Chen , Zou Qi-Hua , Wang Jin-Ni , Fang Yu , Wang Jia-Hui , Guo Song-Bin , Cai Qing-Qing 
Published: July 2023

AbstractThe rapidly increasing use of high-throughput screening had produced a plethora of expanding knowledge on the molecular basis of natural killer/T-cell lymphoma (NKTCL), which in turn has revolutionized the treatment. Specifically, the use of asparaginase-containing regimens has led to substantial improvement in survival outcomes in NKTCL patients. Novel treatment strategies that are currently under development include cell-surface-targeted antibodies, immune checkpoint inhibitors, Epstein-Barr virus targeted cytotoxic T lymphocyte, immunomodulatory agents, chimeric antigen receptor T cells, signaling pathway inhibitors and epigenetic targeted agents. In almost all cases, initial clinical studies of newly developed treatment are conducted in patients relapsed, and refractory NKTCL due to very limited treatment options. This review summarizes the results of these novel treatments for NKTCL and discusses their potential for likely use in NKTCL in a wider setting in the future.