bluuebunny/crossref_metadata_2025 huggingface dataset:
Model of the external force field for the protein folding process—the role of prefoldin
Authors: Roterman Irena , Stapor Katarzyna , Konieczny Leszek
Published: March 2024

Introduction: The protein folding process is very sensitive to environmental conditions. Many possibilities in the form of numerous pathways for this process can—if an incorrect one is chosen—lead to the creation of forms described as misfolded. The aqueous environment is the natural one for the protein folding process. Nonetheless, other factors such as the cell membrane and the presence of specific molecules (chaperones) affect this process, ensuring the correct expected structural form to guarantee biological activity. All these factors can be considered components of the external force field for this process.

Methods: The fuzzy oil drop-modified (FOD-M) model makes possible the quantitative evaluation of the modification of the external field, treating the aqueous environment as a reference. The FOD-M model (tested on membrane proteins) includes the component modifying the water environment, allowing the assessment of the external force field generated by prefoldin.

Results: In this work, prefoldin was treated as the provider of a specific external force field for actin and tubulin. The discussed model can be applied to any folding process simulation, taking into account the changed external conditions. Hence, it can help simulate the in silico protein folding process under defined external conditions determined by the respective external force field. In this work, the structures of prefoldin and protein folded with the participation of prefoldin were analyzed.

Discussion: Thus, the role of prefoldin can be treated as a provider of an external field comparable to other environmental factors affecting the protein folding process.
Providing evidence for a well-worn stereotype: Italians and Swedes do gesture differently
Authors: Graziano Maria , Gullberg Marianne
Published: March 2024

Across cultures and languages spontaneous speech is often accompanied by gestures. It is a popular belief that people in Italy gesture more than people in Northern Europe, such as in Sweden. Despite this general assumption few studies empirically investigate cultural differences in gesture frequency and gesture function under similar circumstances. This study compares the spoken and gestural behaviours of Italian and Swedish speakers, assumed to represent gesture-rich vs. gesture-sparse cultures. We examine the groups' gestural behaviour for frequency, and in terms of possible differences in rhetorical style probing the distribution of gestural functions (referential vs. pragmatic) across narrative levels (narrative, metanarrative, and paranarrative). The results show that (1) Italians overall do gesture more than Swedes; (2) Italians produce more pragmatic gestures than Swedes who produce more referential gestures; (3) both groups show sensitivity to narrative level: referential gestures mainly occur with narrative clauses, and pragmatic gestures with meta- and paranarrative clauses. However, the overall group preferences for different functions still lead to different styles. These findings indicate that the two groups differ in gesture rate and, more interestingly, in rhetorical styles, one focused on events and actions in speech and gesture (Swedish), the other alternating between events in speech and gesture, and the highlighting of the presentation of new pieces of information in gesture only (Italian). We propose that the findings suggest that the two groups conceptualise narrative production in different ways reflected in two different rhetorical styles revealed by gesture production more than by speech.
Effects of forest type on carbon storage in the hilly region of Loess Plateau, China
Authors: Song Zhihua , Shi Peng , Li Peng , Li Zhanbin , Niu Hongbo , Zu Pengju , Cao Manhong , Jia Yili
Published: March 2024

The hilly region of the Loess Plateau has lush vegetation and high carbon sequestration potential. However, previous studies have not focused on differences in carbon storage of different forest types and their causes. This study aimed to explore the carbon storage of forest and identify the main influencing factors of carbon storage to provide basis for improving the carbon fixation capacity of planted forest in the region. Broad-leaved, coniferous, and mixed forests at different altitudes were selected from the Ziwuling Mountains in the Loess hilly region. The carbon storage as well as physical and chemical characteristics of the vegetation and soil samples from different soil layers were measured. The vegetation factor, terrain factor, and soil factor of the sample plot were evaluated by Mantel test and redundancy analysis (RDA). The carbon storage of the mixed forest (138.87 MgC hm−2) showed the highest carbon storage compared to broad-leaved forest (131.97 MgC hm−2) and coniferous forest (113.62 MgC hm−2) in the loess hilly region. The carbon storage of different components followed the order of soil carbon storage, vegetation carbon storage, and litter carbon storage. The soil organic carbon content and forest type had the highest explanations for total carbon storage, accounting for 57 and 26.9% of the variance, respectively. This indicates that forest type is an important factor affecting carbon storage, and selecting mixed forests can achieve better results when creating and transforming carbon sink forests.
The complex landscape of DMD mutations: moving towards personalized medicine
Authors: Gatto Francesca , Benemei Silvia , Piluso Giulio , Bello Luca
Published: March 2024

Duchenne muscular dystrophy (DMD) is a severe genetic disorder characterized by progressive muscle degeneration, with respiratory and cardiac complications, caused by mutations in the DMD gene, encoding the protein dystrophin. Various DMD mutations result in different phenotypes and disease severity. Understanding genotype/phenotype correlations is essential to optimize clinical care, as mutation-specific therapies and innovative therapeutic approaches are becoming available. Disease modifier genes, trans-active variants influencing disease severity and phenotypic expressivity, may modulate the response to therapy, and become new therapeutic targets. Uncovering more disease modifier genes via extensive genomic mapping studies offers the potential to fine-tune prognostic assessments for individuals with DMD. This review provides insights into genotype/phenotype correlations and the influence of modifier genes in DMD.
Targeting PRAME for acute myeloid leukemia therapy
Authors: Yang Jinjun , Chen Mengran , Ye Jing , Ma Hongbing
Published: March 2024

Despite significant progress in targeted therapy for acute myeloid leukemia (AML), clinical outcomes are disappointing for elderly patients, patients with less fit disease characteristics, and patients with adverse disease risk characteristics. Over the past 10 years, adaptive T-cell immunotherapy has been recognized as a strategy for treating various malignant tumors. However, it has faced significant challenges in AML, primarily because myeloid blasts do not contain unique surface antigens. The preferentially expressed antigen in melanoma (PRAME), a cancer-testis antigen, is abnormally expressed in AML and does not exist in normal hematopoietic cells. Accumulating evidence has demonstrated that PRAME is a useful target for treating AML. This paper reviews the structure and function of PRAME, its effects on normal cells and AML blasts, its implications in prognosis and follow-up, and its use in antigen-specific immunotherapy for AML.
Effects of Bacillus coagulans TBC169 on gut microbiota and metabolites in gynecological laparoscopy patients
Authors: Gao Weiqi , Yan Ya , Guan Zhaobo , Zhang Jingmin , Chen Weihong
Published: March 2024

Objective

The primary objective of this study is to investigate the mechanism by which Bacillus coagulans TBC169 accelerates intestinal function recovery in patients who have undergone gynecological laparoscopic surgery, using metabolomics and gut microbiota analysis.

Methods

A total of 20 subjects were selected and randomly divided into two groups: the intervention group (n = 10) receiving Bacillus coagulans TBC169 Tablets (6 pills, 1.05 × 108 CFU), and the control group (n = 10) receiving placebos (6 pills). After the initial postoperative defecation, fecal samples were collected from each subject to analyze their gut microbiota and metabolic profiles by high-throughput 16S rRNA gene sequencing analysis and untargeted metabonomic.

Results

There were no statistically significant differences observed in the α-diversity and β-diversity between the two groups; however, in the intervention group, there was a significant reduction in the relative abundance of unclassified_Enterobacteriaceae at the genus level. Furthermore, the control group showed increased levels of Holdemanella and Enterobacter, whereas the intervention group exhibited elevated levels of Intestinimonas. And administration of Bacillus coagulans TBC169 led to variations in 2 metabolic pathways: D-glutamine and D-glutamate metabolism, and arginine biosynthesis.

Conclusion

This study demonstrated that consuming Bacillus coagulans TBC169 after gynecological laparoscopic surgery might inhibit the proliferation of harmful Enterobacteriaceae; mainly influence 2 pathways including D-glutamine and D-glutamate metabolism, and arginine biosynthesis; and regulate metabolites related to immunity and intestinal motility; which can help regulate immune function, maintain intestinal balance, promote intestinal peristalsis, and thus accelerate the recovery of intestinal function.
SOS genes are rapidly induced while translesion synthesis polymerase activity is temporally regulated
Authors: Bergum Olaug Elisabeth Torheim , Singleton Amanda Holstad , Røst Lisa Marie , Bodein Antoine , Scott-Boyer Marie-Pier , Rye Morten Beck , Droit Arnaud , Bruheim Per , Otterlei Marit
Published: March 2024

The DNA damage inducible SOS response in bacteria serves to increase survival of the species at the cost of mutagenesis. The SOS response first initiates error-free repair followed by error-prone repair. Here, we have employed a multi-omics approach to elucidate the temporal coordination of the SOS response. Escherichia coli was grown in batch cultivation in bioreactors to ensure highly controlled conditions, and a low dose of the antibiotic ciprofloxacin was used to activate the SOS response while avoiding extensive cell death. Our results show that expression of genes involved in error-free and error-prone repair were both induced shortly after DNA damage, thus, challenging the established perception that the expression of error-prone repair genes is delayed. By combining transcriptomics and a sub-proteomics approach termed signalomics, we found that the temporal segregation of error-free and error-prone repair is primarily regulated after transcription, supporting the current literature. Furthermore, the heterology index (i.e., the binding affinity of LexA to the SOS box) was correlated to the maximum increase in gene expression and not to the time of induction of SOS genes. Finally, quantification of metabolites revealed increasing pyrimidine pools as a late feature of the SOS response. Our results elucidate how the SOS response is coordinated, showing a rapid transcriptional response and temporal regulation of mutagenesis on the protein and metabolite levels.
Therapeutic potential of tyrosine-protein kinase MET in osteosarcoma
Authors: Zeng Ming , Liu Can , Gong Haoli , Tang Zhongwen , Wen Jie , Wang Sisi , Xiao Sheng
Published: March 2024

Osteosarcoma, the most prevalent primary bone tumor in children and young adults, can often be successfully treated with standard chemotherapy and surgery when diagnosed at an early stage. However, patients presenting with metastases face significant challenges in achieving a cure. Despite advancements in classical therapies over the past few decades, clinical outcomes for osteosarcoma have not substantially improved. Recently, there has been increased understanding of the biology of osteosarcoma, leading to the identification of new therapeutic targets. One such target is MET, a tyrosine kinase receptor for Hepatocyte Growth Factor (HGF) encoded by the MET gene. In vitro and in vivo studies have demonstrated that the HGF/MET pathway plays a crucial role in cancer growth, invasion, metastasis, and drug resistance across various cancers. Clinical trials targeting this pathway are already underway for lung cancer and hepatocellular carcinoma. Moreover, MET has also been implicated in promoting osteosarcoma progression. This review summarizes 3 decades’ worth of research on MET’s involvement in osteosarcoma and further explores its potential as a therapeutic target for patients with this disease.
suMRak: a multi-tool solution for preclinical brain MRI data analysis
Authors: Ister Rok , Sternak Marko , Škokić Siniša , Gajović Srećko
Published: March 2024

Introduction

Magnetic resonance imaging (MRI) is invaluable for understanding brain disorders, but data complexity poses a challenge in experimental research. In this study, we introduce suMRak, a MATLAB application designed for efficient preclinical brain MRI analysis. SuMRak integrates brain segmentation, volumetry, image registration, and parameter map generation into a unified interface, thereby reducing the number of separate tools that researchers may require for straightforward data handling.

Methods and implementation

All functionalities of suMRak are implemented using the MATLAB App Designer and the MATLAB-integrated Python engine. A total of six helper applications were developed alongside the main suMRak interface to allow for a cohesive and streamlined workflow. The brain segmentation strategy was validated by comparing suMRak against manual segmentation and ITK-SNAP, a popular open-source application for biomedical image segmentation.

Results

When compared with the manual segmentation of coronal mouse brain slices, suMRak achieved a high Sørensen–Dice similarity coefficient (0.98 ± 0.01), approaching manual accuracy. Additionally, suMRak exhibited significant improvement (p = 0.03) when compared to ITK-SNAP, particularly for caudally located brain slices. Furthermore, suMRak was capable of effectively analyzing preclinical MRI data obtained in our own studies. Most notably, the results of brain perfusion map registration to T2-weighted images were shown, improving the topographic connection to anatomical areas and enabling further data analysis to better account for the inherent spatial distortions of echoplanar imaging.

Discussion

SuMRak offers efficient MRI data processing of preclinical brain images, enabling researchers' consistency and precision. Notably, the accelerated brain segmentation, achieved through K-means clustering and morphological operations, significantly reduces processing time and allows for easier handling of larger datasets.
The usage and advantages of several common amyotrophic lateral sclerosis animal models
Authors: Zhou Lijun , Xie Meng , Wang Xinxin , Xu Renshi
Published: March 2024

Amyotrophic lateral sclerosis is a fatal, multigenic, multifactorial neurodegenerative disease characterized by upper and lower motor neuron loss. Animal models are essential for investigating pathogenesis and reflecting clinical manifestations, particularly in developing reasonable prevention and therapeutic methods for human diseases. Over the decades, researchers have established a host of different animal models in order to dissect amyotrophic lateral sclerosis (ALS), such as yeast, worms, flies, zebrafish, mice, rats, pigs, dogs, and more recently, non-human primates. Although these models show different peculiarities, they are all useful and complementary to dissect the pathological mechanisms of motor neuron degeneration in ALS, contributing to the development of new promising therapeutics. In this review, we describe several common animal models in ALS, classified by the naturally occurring and experimentally induced, pointing out their features in modeling, the onset and progression of the pathology, and their specific pathological hallmarks. Moreover, we highlight the pros and cons aimed at helping the researcher select the most appropriate among those common experimental animal models when designing a preclinical ALS study.
U-NTCA: nnUNet and nested transformer with channel attention for corneal cell segmentation
Authors: Zhang Dan , Zhang Jing , Li Saiqing , Dong Zhixin , Zheng Qinxiang , Zhang Jiong
Published: March 2024

Background

Automatic segmentation of corneal stromal cells can assist ophthalmologists to detect abnormal morphology in confocal microscopy images, thereby assessing the virus infection or conical mutation of corneas, and avoiding irreversible pathological damage. However, the corneal stromal cells often suffer from uneven illumination and disordered vascular occlusion, resulting in inaccurate segmentation.

Methods

In response to these challenges, this study proposes a novel approach: a nnUNet and nested Transformer-based network integrated with dual high-order channel attention, named U-NTCA. Unlike nnUNet, this architecture allows for the recursive transmission of crucial contextual features and direct interaction of features across layers to improve the accuracy of cell recognition in low-quality regions. The proposed methodology involves multiple steps. Firstly, three underlying features with the same channel number are sent into an attention channel named gnConv to facilitate higher-order interaction of local context. Secondly, we leverage different layers in U-Net to integrate Transformer nested with gnConv, and concatenate multiple Transformers to transmit multi-scale features in a bottom-up manner. We encode the downsampling features, corresponding upsampling features, and low-level feature information transmitted from lower layers to model potential correlations between features of varying sizes and resolutions. These multi-scale features play a pivotal role in refining the position information and morphological details of the current layer through recursive transmission.

Results

Experimental results on a clinical dataset including 136 images show that the proposed method achieves competitive performance with a Dice score of 82.72% and an AUC (Area Under Curve) of 90.92%, which are higher than the performance of nnUNet.

Conclusion

The experimental results indicate that our model provides a cost-effective and high-precision segmentation solution for corneal stromal cells, particularly in challenging image scenarios.
Deficiency of the paternally-expressed imprinted Peg3 gene in mice has sexually dimorphic consequences for offspring communication and social behaviour
Authors: Tyson Hannah R. , Harrison David J. , Higgs Mathew J. , Isles Anthony R. , John Rosalind M.
Published: March 2024

Introduction

Imprinted genes are expressed from one parental allele as a consequence of epigenetic processes initiated in the germline. Consequently, their ability to influence phenotype depends on their parent-of-origin. Recent research suggests that the sex of the individual expressing the imprinted gene is also important. We have previously reported that genetically wildtype (WT) dams carrying and caring for pups mutant for PEG3 exhibit anxiety-like behaviours and their mutant pups show a reduction in ultrasonic vocalisation when separated from their mothers. Sex-specificity was not examined.

Methods

WT female mice were mated with WT, heterozygous Peg3−/+ or homozygous Peg3−/− studs to generate all WT (control), 50:50 mixed or 100% mutant litters, respectively, followed by behavioural assessment of both dams and their pups.

Results

We reproduced our original finding that WT dams carrying and caring for 100% mutant litters exhibit postpartum anxiety-like symptoms and delayed pup retrieval. Additionally, these WT dams were found to allocate less time to pup-directed care behaviours relative to controls. Male Peg3-deficient pups demonstrated significantly reduced vocalisation with a more subtle communication deficit in females. Postweaning, male mutants exhibited deficits across a number of key social behaviours as did WT males sharing their environment with mutants. Only modest variations in social behaviour were detected in experimental females.

Discussion

We have experimentally demonstrated that Peg3 deficiency confined to the offspring causes anxiety in mouse mothers and atypical behaviour including deficits in communication in their male offspring. A male-specific reduction in expression PEG3 in the fetally-derived placenta has previously been associated with maternal depression in human pregnancy. Maternal mood disorders such as depression and anxiety are associated with delays in language development and neuroatypical behaviour more common in sons. Peg3 deficiency could drive the association of maternal and offspring behavioural disorders reported in humans.
Acupuncture for radicular pain: a review of analgesic mechanism
Authors: Li Hong-Lin , Zhang Yi , Zhou Jian-Wei
Published: March 2024

Radicular pain, a common and complex form of neuropathic pain, presents significant challenges in treatment. Acupuncture, a therapy originating from ancient traditional Chinese medicine and widely utilized for various pain types, including radicular pain, has shown promising outcomes in the management of lumbar radicular pain, cervical radicular pain, and radicular pain due to spinal stenosis. Despite its efficacy, the exact mechanisms through which acupuncture achieves analgesia are not fully elucidated and are the subject of ongoing research. This review sheds light on the current understanding of the analgesic mechanisms of acupuncture for radicular pain, offering valuable perspectives for both clinical application and basic scientific research. Acupuncture is postulated to relieve radicular pain by several mechanisms: peripherally, it reduces muscle spasms, lessens mechanical pressure on nerve roots, and improves microcirculation; at the molecular level, it inhibits the HMGB1/RAGE and TLR4/NF-κB signaling pathways, thereby decreasing the release of pro-inflammatory cytokines; within the spinal cord, it influences synaptic plasticity; and centrally, it modulates brain function, particularly affecting the medial prefrontal cortex, anterior cingulate cortex, and thalamus within the default mode network. By acting across these diverse biological domains, acupuncture presents an effective treatment modality for radicular pain, and deepening our understanding of the underlying mechanisms regarding analgesia for radicular pain is crucial for enhancing its clinical efficacy and advancement in pain management.
Prostate cancer research: tools, cell types, and molecular targets
Authors: Liu Alvin Y.
Published: March 2024

Multiple cancer cell types are found in prostate tumors. They are either luminal-like adenocarcinoma or less luminal-like and more stem-like non-adenocarcinoma and small cell carcinoma. These types are lineage related through differentiation. Loss of cancer differentiation from luminal-like to stem-like is mediated by the activation of stem cell transcription factors (scTF) such as LIN28A, NANOG, POU5F1 and SOX2. scTF expression leads to down-regulation of β2-microglobulin (B2M). Thus, cancer cells can change from the scTF˜B2Mhi phenotype of differentiated to that of scTF˙B2Mlo of dedifferentiated in the disease course. In development, epithelial cell differentiation is induced by stromal signaling and cell contact. One of the stromal factors specific to prostate encodes proenkephalin (PENK). PENK can down-regulate scTF and up-regulate B2M in stem-like small cell carcinoma LuCaP 145.1 cells indicative of exit from the stem state and differentiation. In fact, prostate cancer cells can be made to undergo dedifferentiation or reprogramming by scTF transfection and then to differentiate by PENK transfection. Therapies need to be designed for treating the different cancer cell types. Extracellular anterior gradient 2 (eAGR2) is an adenocarcinoma antigen associated with cancer differentiation that can be targeted by antibodies to lyse tumor cells with immune system components. eAGR2 is specific to cancer as normal cells express only the intracellular form (iAGR2). For AGR2-negative stem-like cancer cells, factors like PENK that can target scTF could be effective in differentiation therapy.
Case report: Urachal perivascular epithelioid cell tumor
Authors: Liu Mengru , Liang Pan , Lyu Dongbo , Zhu Bingbing , Gao Jianbo
Published: March 2024

Background

Urachal tumors are rare in clinical practice, among which urachal adenocarcinoma is the most common. In this study, we report a rare case of urachal perivascular epithelioid cell tumor to improve our understanding of the disease.

Case presentation

A 26-year-old male patient was hospitalized for lower abdominal pain. The US showed a hypoechoic mass measuring 26mm × 18mm in the superior aspect of the bladder. MRI showed an irregular mass located anterior to the bladder roof, near the midline. The tumor exhibited hypointense on T1WI and heterogeneous hyperintense on T2WI. Additionally, contrast-enhanced T1-weighted imaging revealed obvious ring enhancement of the tumor. The patient underwent surgical resection of the urachal tumor, with subsequent pathological examination revealing a diagnosis of urachal PEComa. Following surgery, the patient underwent regular follow-up assessments, with no evidence of recurrence or metastasis observed after three and a half years.

Conclusions

Urachal PEComa is a rare mesenchymal tumor that presents challenges in diagnosis through imaging and clinical symptoms. Definitive diagnosis relies on pathological and immunohistochemical analysis. Due to the rarity of urachal PEComa, prognosis assessment necessitates long-term follow-up and evaluation of more cases.
Venetoclax combined chemotherapy versus chemotherapy alone for acute myeloid leukemia: a systematic review and meta-analysis
Authors: Zhu Jingkui , Fan Jixin , Xie Tiantian , Zhao Haiqiu , Lu Runqing , Zhang Yinyin , Li Yingmei , Xie Xinsheng , Wan Dingming , Jiang Zhongxing , He Fei , Guo Rong
Published: March 2024

Objective

To compare the efficacy and safety of venetoclax (VEN) in combination with chemotherapy (chemo) versus chemo alone in the treatment of acute myeloid leukemia (AML).

Method

To compare the efficacy and/or safety of VEN+chemo versus chemotherapy alone for AML, PubMed, Embase, Web of Science, and the Cochrane Library were used to searching up to June 2023. Comparisons included complete remission (CR), CR with incomplete hematologic recovery (CRi), morphologic leukemia-free state (MLFS), overall response rate (ORR), and adverse events (AEs).

Result

A total of 9 articles were included, including 3124 patients. The baseline characteristics between two patient groups were similar. The combined analysis showed that compared with the group receiving chemo alone, the VEN+chemo group exhibited higher rates of CR, CRi, MLFS and ORR. Additionally, the VEN+chemo group had longer event-free survival (EFS) and overall survival (OS) durations. The incidence rates of AEs and serious AEs (SAEs) were similar between the two groups, but the early 30-day mortality rate was lower in the VEN+chemo group than in the chemo alone group.

Conclusion

The VEN+chemo therapy demonstrates significant efficacy and safety profile in AML patients. However, more prospective studies are needed in the future to provide more accurate and robust evidence for treatment selection in patients.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023439288, identifier CRD42023439288.
Sacituzumab Govitecan for the treatment of advanced triple negative breast cancer patients: a multi-center real-world analysis
Authors: Caputo Roberta , Buono Giuseppe , Piezzo Michela , Martinelli Claudia , Cianniello Daniela , Rizzo Alessandro , Pantano Francesco , Staropoli Nicoletta , Cangiano Rodolfo , Turano Salvatore , Paris Ida , Nuzzo Francesco , Fabi Alessandra , De Laurentiis Michelino
Published: March 2024

Objective

The objective of this multicenter, observational, retrospective analysis was to evaluate the safety and efficacy of sacituzumab govitecan in metastatic triple-negative breast cancer (mTNBC) patients managed according to common clinical practice in Italy.

Methods

Data were retrieved by 7 sites. Triple-negative BC was defined by the lack of expression of estrogen receptor (ER <1%), progesterone receptor (PgR <1%) and human-epidermal growth factor receptor-2 (HER2 0, 1+, 2+ ISH-not amplified) according to standard ASCO-CAP criteria. Demographic and clinical characteristics were collected. Premedication, dose modifications and treatment schedule were based on the approved label of the product. Adverse events (AEs) were assessed according to NCI-CTCAE v5.0.

Results

Fifty-seven eligible patients who received sacituzumab govitecan for mTNBC were included. Median age was 53 years (range 25-75). Approximately 70% of patients had an initial diagnosis of TNBC. Median time from the diagnosis of metastatic BC to start of sacituzumab govitecan was 17 months (range 0-97) and median number of previous therapies was 3 (range 1-7). The most common sites of metastasis were lymph nodes (63.1% of patients), lung (57.9%), bone (50.8%) and liver (38.6%). Eight (14.0%) patients had a disease-free interval ≤12 months. A total of 32 (56.1%) deaths were observed and the median overall survival (OS) was 12.43 months (95% CI, 7.97 months-not reached). At a median follow-up of 10.6 months, 45 patients (78.9%) had progression and the median progression-free survival (PFS) was 4.9 months (95% CI, 3.7-7.1 months). Partial tumour response was observed in 19 patients (33.3%), stable disease in 16 (28.1%) and disease progression in 22 patients (38.6%). The most common treatment-related AEs were anemia (66.6% of patients), alopecia (66.6%), neutropenia (59.6%), nausea (42.1%) and diarrhea (38.6%). Neutropenia was the most common serious treatment-related AE: 21.0% and 8.7% of patients experienced grade 3 or 4 neutropenia, respectively. Twenty-two patients (38.6%) reduced the dose and 5.3% permanently discontinued treatment.

Conclusion

The results of this real-world analysis showed that both safety and efficacy of sacituzumab govitecan in mTNBC patients are consistent with that previously reported in regulatory trials. The use of premedication and supportive measures was associated with a satisfactory toxicity profile.
Phytocompounds targeting epigenetic modulations: an assessment in cancer
Authors: Khan Aqsa , Khan Asifa , Khan Mohammad Aasif , Malik Zoya , Massey Sheersh , Parveen Rabea , Mustafa Saad , Shamsi Anas , Husain Syed A.
Published: March 2024

For centuries, plants have been serving as sources of potential therapeutic agents. In recent years, there has been a growing interest in investigating the effects of plant-derived compounds on epigenetic processes, a novel and captivating Frontier in the field of epigenetics research. Epigenetic changes encompass modifications to DNA, histones, and microRNAs that can influence gene expression. Aberrant epigenetic changes can perturb key cellular processes, including cell cycle control, intercellular communication, DNA repair, inflammation, stress response, and apoptosis. Such disruptions can contribute to cancer development by altering the expression of genes involved in tumorigenesis. However, these modifications are reversible, offering a unique avenue for therapeutic intervention. Plant secondary compounds, including terpenes, phenolics, terpenoids, and sulfur-containing compounds are widely found in grains, vegetables, spices, fruits, and medicinal plants. Numerous plant-derived compounds have demonstrated the potential to target these abnormal epigenetic modifications, including apigenin (histone acetylation), berberine (DNA methylation), curcumin (histone acetylation and epi-miRs), genistein (histone acetylation and DNA methylation), lycopene (epi-miRs), quercetin (DNA methylation and epi-miRs), etc. This comprehensive review highlights these abnormal epigenetic alterations and discusses the promising efficacy of plant-derived compounds in mitigating these deleterious epigenetic signatures in human cancer. Furthermore, it addresses ongoing clinical investigations to evaluate the therapeutic potential of these phytocompounds in cancer treatment, along with their limitations and challenges.
Dosing optimization of rituximab for primary membranous nephropathy by population pharmacokinetic and pharmacodynamic study
Authors: Liang Hao , Deng Zhenling , Niu Shu , Kong Weijie , Liu Yang , Wang Song , Li Haiyan , Wang Yue , Zheng Danxia , Liu Dongyang
Published: March 2024

Primary membranous nephropathy (PMN) is the most common cause for adult nephrotic syndrome. Rituximab has demonstrated promising clinical efficacy by random controlled trials and the off-label use is widely adopted in PMN. However, the standard dosage is borrowed from B cell lymphoma treatment with far more antigens and is oversaturated for PMN treatment, accompanied with additional safety risk and unnecessary medical cost. More than 15% serious adverse events were observed under standard dosage and low dose therapies were explored recently. Dose optimization by clinical trials is extremely time- and cost-consuming and can be significantly accelerated with the aid of model-informed drug development. Here, we aim to establish the first population pharmacokinetic and pharmacodynamic (PPK/PD) model for rituximab in PMN to guide its dosage optimization. Rituximab pharmacokinetic and pharmacodynamic data from 41 PMN patients in a retrospective study under a newly proposed monthly mini-dose were used to construct quantitative dose-exposure-response relationship via mechanistic target-mediated drug disposition (TMDD) model followed by regression between the reduction of anti-PLA2R titer and time after the treatment. The final model, validated by goodness-of-fit plots, visual predictive checks and bootstrap, was used to recommend the optimized dosing regimen by simulations. The model was well validated for PK/PD prediction. The systemic clearance and half-life are 0.54 L/h and 14.7 days, respectively. Simulation of a novel regimen (6 monthly doses of 100 mg) indicated the comparable ability and superior duration time of CD20+ B cell depletion compared with standard dosage, while the cumulative dosage and safety risk was significantly decreased. We established the first PPK/PD model and provide evidence to support the dosage optimization based on monthly mini-dose. Our study can also efficiently accelerate dosage optimization of novel anti-CD20 antibodies in PMN and other indications.
Design and synthesis of novel dihydropyridine- and benzylideneimine-based tyrosinase inhibitors
Authors: Ahmad Ifraz , Parveen Warda , Noor Shah , Udin Zahoor , Ali Amjad , Ali Ijaz , Ullah Riaz , Ali Hamid
Published: March 2024

Tyrosinase (TYR) inhibitors are very significant as they inhibit enzyme tyrosinase activity, and its inhibition is vital for skin care, anticancer medication, and antibrowning of fruits and vegetables. This work presents a novel and economical route for the preparation of new synthetic tyrosinase inhibitors using amlodipine (4). The novel conjugates 6 (a–o) were designed, synthesized, and characterized by spectroscopic analyses, including Fourier transform infrared and low- and high-resolution mass spectroscopy. The purified compound 4 was refluxed with various aldehydes and ketones 5 (a–o) for 5–8 h in methanol at 60°C–90°C. This research modified the drug in a step-by-step manner to develop therapeutic properties as a tyrosinase inhibitor. The structures of synthesized ligands 6 (a–o) were established based on spectral and analytical data. The synthesized compounds 6 (a–o) were screened against tyrosinase enzyme. Kojic acid was taken as standard. All the prepared compounds 6 (a–o) have good inhibition potential against the enzyme tyrosinase. Compounds 6o, 6b, 6f, and 6k depicted excellent antityrosinase activity. Compound 6k, with an IC50 value of 5.34 ± 0.58 µM, is as potent as the standard kojic acid (IC50 6.04 ± 0.11 µM), standing out among all synthesized compounds 6 (a–o). The in silico studies of the conjugates 6 (a–o) were evaluated via PatchDock. Compound 6k showed a binding affinity score of 8,999 and an atomic contact energy (ACE) value of −219.66 kcal/mol. The structure–activity relationship illustrated that the presence of dihydropyridine nuclei and some activating groups at the ortho and para positions of the benzylideneimine moiety is the main factor for good tyrosinase activity. The compound 6k could be used as a lead compound for drug modification as a tyrosinase inhibitor for skin care, anticancer medication, and antibrowning for fruits and vegetables.
Inhibition of ACOX1 enhances the therapeutic efficacy of obeticholic acid in treating non-alcoholic fatty liver disease and mitigates its lipotoxicity
Authors: Yang Yuping , Yuan Weinan , He Kun , Lin Chuangzhen , Du Shenshen , Kou Yanqi , Nie Biao
Published: March 2024

Background and aims:

High-dose Obeticholic acid exhibits promise for non-alcoholic fatty liver disease (NAFLD) treatment but can induce lipotoxicity. Our study sought to understand this mechanism and propose a solution.

Approach and Results:

In a non-alcoholic fatty liver disease (NAFLD) model induced by a high-fat diet in FXR−/− mice, we pinpointed that FXR regulated the expression of ACOX1 through RNA-Seq analysis. In the livers of FXR−/− mice, both ACOX1 mRNA and protein expression notably decreased. In both HL-7702 and HEP-G2 cells, the silencing of FXR through shRNA plasmids decreased ACOX1 expression, while FXR activation with GW4064 increased it. These effects were reversible with the ACOX1-specific inhibitor, 10,12-Tricosadiynoic acid. In the NAFLD model of FXR−/− mice, The activation of ACOX1 is correlated with elevated serum LDL, triglycerides, and aggravated hepatic steatosis. However, the combination of 10,12-Tricosadiynoic acid with low-dose obeticholic acid effectively treated hepatic steatosis, reducing LDL levels in the NAFLD model of wild-type mice. This combination therapy demonstrated efficacy comparable to high-dose obeticholic acid alone. Notably, the combined drug regimen treats hepatic steatosis by inhibiting the IL-1β and α-SMA pathways in NAFLD.

Conclusion:

Combining ACOX1-specific inhibitors with low-dose obeticholic acid effectively treats high-fat diet-induced hepatic steatosis and reduces serum LDL. This approach enhances the therapeutic effects of obeticholic acid and mitigates its lipotoxicity by inhibiting the IL-1β and α-SMA pathways.
The importance of core strength for change of direction speed
Authors: Horníková Henrieta , Zemková Erika
Published: March 2024

Change of direction speed (CODS) is determined by several physical aspects, such as linear sprint speed, reactive strength and power of leg muscles. It appears that core strength may also play a role in CODS, however, its relationship to CODS remains unclear. The aim of this narrative review was to analyze the literature addressing a) the relationship between core strength and CODS and b) the effect of core strength training on CODS. This analysis revealed a significant relationship between the parameters of core strength and stability (the pressure of the activated core muscles during lower limb movement and the greatest mean force output of maximum volunteered contraction) and the time in the Agility T-Test. However, this parameter was not significantly related to the strength endurance of core muscles (total time in the plank test). Core training provides a sufficient stimulus for the development of CODS in less-skilled middle-adolescent athletes, while its effectiveness decreases in higher-skilled adult athletes. These findings indicate that core muscle strength contributes significantly to the change of direction speed. Core training is therefore useful for improving CODS.
Genome-wide identification and expression analysis of the HAK/KUP/KT gene family in Moso bamboo
Authors: Guo Hui , Tan Jiaqi , Jiao Yang , Huang Bing , Ma Ruifang , Ramakrishnan Muthusamy , Qi Guoning , Zhang Zhijun
Published: March 2024

The K+ uptake permease/high-affinity K+/K+ transporter (KUP/HAK/KT) family is the most prominent group of potassium (K+) transporters, playing a key role in K+ uptake, transport, plant growth and development, and stress tolerance. However, the presence and functions of the KUP/HAK/KT family in Moso bamboo (Phyllostachys edulis (Carriere) J. Houzeau), the fastest-growing plant, have not been studied. In this study, we identified 41 KUP/HAK/KT genes (PeHAKs) distributed across 18 chromosomal scaffolds of the Moso bamboo genome. PeHAK is a typical membrane protein with a conserved structural domain and motifs. Phylogenetic tree analysis classified PeHAKs into four distinct clusters, while collinearity analysis revealed gene duplications resulting from purifying selection, including both tandem and segmental duplications. Enrichment analysis of promoter cis-acting elements suggested their plausible role in abiotic stress response and hormone induction. Transcriptomic data and STEM analyses indicated that PeHAKs were involved in tissue and organ development, rapid growth, and responded to different abiotic stress conditions. Subcellular localization analysis demonstrated that PeHAKs are predominantly expressed at the cell membrane. In-situ PCR experiments confirmed that PeHAK was mainly expressed in the lateral root primordia. Furthermore, the involvement of PeHAKs in potassium ion transport was confirmed by studying the potassium ion transport properties of a yeast mutant. Additionally, through homology modeling, we revealed the structural properties of HAK as a transmembrane protein associated with potassium ion transport. This research provides a solid basis for understanding the classification, characterization, and functional analysis of the PeHAK family in Moso bamboo.
Short-term, manualized schema-focused group therapy for patients with CBT-resistant disorders within primary care: a pilot study with a naturalistic pre-treatment and post-treatment design
Authors: Kiers Ingeborg L. , de Haan Hein A.
Published: March 2024

The aim of this study was to explore the feasibility and preliminary effectiveness of a short-term, manualized schema therapy group for 77 patients with CBT-resistant mood and/or anxiety and/or personality disorders (PDs) in primary care. The primary focus was on the effects of this treatment on Early Maladaptive Schemas (EMS), schema modes, and psychological well-being. These aspects were assessed pre-and post-treatment treatment using the Young Schema Questionnaire (YSQ), the Schema Mode Inventory version 1.1 (SMI), and the Symptom Questionnaire-48 (SQ-48). The treatment consisted of 16 sessions, incorporating cognitive, behavioral, and experiential techniques. EMS significantly decreased from pre-treatment to post-treatment, as along with maladaptive schema modes. Adaptive modes increased, as did psychological wellbeing. There were no significant differences between the DSM-5 classifications regarding changes in the aforementioned measures, except for the maladaptive modes, where the value of the corrected within-subject effect indicated a significant interaction. Post hoc comparisons were therefore conducted which showed that patients with a mood disorder experienced more positive changes in maladaptive modes compared to patients with anxiety disorders and PDs (p < 0.001). There was no significant difference between those with PDs and those with Anxiety Disorders. Our findings provide preliminary evidence that short-term, manualized schema therapy might be an effective treatment for patients with CBT-resistant mood and/or anxiety and/or PDs in primary care.
The fairness of human resource management practices: an assessment by the justice sensitive
Authors: Haines Victor Y. , Patient David , Guerrero Sylvie
Published: March 2024

Introduction

Although fairness is a pervasive and ongoing concern in organizations, the fairness of human resource management practices is often overlooked. This study examines how individual differences in justice sensitivity influence the extent to which human resource management practices are perceived to convey principles of organizational justice.

Methods

Analysis was performed on a matching sample of 283 university students from three academic units in two countries having responded at two time points. Justice sensitivity was measured with the 40-item inventory developed and validated by Schmitt et al. (2010). Respondents were instructed to indicate to what extent each of 61 human resource management practices generally conveys principles of organizational justice.

Results

Justice sensitivity was positively associated with subsequent assessments of the justice contents of human resource management practices. The distinction between self-oriented and other-oriented justice sensitivities was helpful in determining perceptions of these human resource management practices and of a subset of pay-for-performance practices.

Discussion

The findings inform current research about the meanings borne by human resource management practices, and also increase understanding of entity judgment formation as an important aspect of systemic justice.
“FREED instils a bit of hope in the eating disorder community… that things can change.”: an investigation of clinician views on implementation facilitators and challenges from the rapid scaling of the First Episode Rapid Early Intervention for Eating Disorders programme
Authors: Hyam Lucy , Yeadon-Ray Olivia , Richards Katie , Semple Amy , Allen Karina , Owens Jill , Jackson Aileen , Semple Laura , Glennon Danielle , Di Clemente Giulia , Griffiths Jess , Mills Regan , Schmidt Ulrike
Published: March 2024

Introduction

First Episode Rapid Early Intervention for Eating Disorders (FREED) is the leading eating disorder (ED) early intervention model for young people. Research has shown that it reduces the duration of untreated illness, improves clinical outcomes, and has cost savings. However, less is known about the experience of implementing FREED. This study aimed to investigate the views and experiences of adopting, implementing, and sustaining FREED from the perspective of clinical staff.

Methods

Seven focus groups were conducted involving 26 clinicians. Thematic analysis was used, with the Non-Adoption, Abandonment and Challenges to Scale-up, Spread and Sustainability (The NASSS framework) framework being applied to organise subthemes and determine facilitators and barriers. The NASSS framework was also used to rate the complexity of themes as either simple (straightforward, predictable, few components), complicated (multiple interrelating components), or complex (dynamic, unpredictable, not easily divisible into constituent components).

Results

There were 16 subthemes identified under seven broader themes representing each domain of the NASSS framework. Key barriers and areas of complexity included factors related to EDs as an illness (e.g., high acuity and prevalence), and organisational complexity (e.g., staffing shortages, lack of managerial/team support). Key facilitators included positive clinician/adopter attitudes, a supportive national network, and the ability for FREED to be flexible/adaptable over time.

Conclusion

The FREED model appears to be desirable to clinical staff. Wider team and managerial support was perceived to be particularly important to its successful implementation, as were the national network and supervision. Key areas of complexity include staffing issues and high ED acuity/prevalence. These barriers to implementation need to be managed and investment continued to expand and improve early intervention for EDs further.