bluuebunny/crossref_metadata_2025 huggingface dataset:
MicroRNAs targeted mTOR as therapeutic agents to improve radiotherapy outcome
Authors: Taeb Shahram , Rostamzadeh Davoud , Amini Seyed Mohammad , Rahmati Mohammad , Eftekhari Mohammad , Safari Arash , Najafi Masoud
Published: July 2024

MicroRNAs (miRNAs) are small RNA molecules that regulate genes and are involved in various biological processes, including cancer development. Researchers have been exploring the potential of miRNAs as therapeutic agents in cancer treatment. Specifically, targeting the mammalian target of the rapamycin (mTOR) pathway with miRNAs has shown promise in improving the effectiveness of radiotherapy (RT), a common cancer treatment. This review provides an overview of the current understanding of miRNAs targeting mTOR as therapeutic agents to enhance RT outcomes in cancer patients. It emphasizes the importance of understanding the specific miRNAs that target mTOR and their impact on radiosensitivity for personalized cancer treatment approaches. The review also discusses the role of mTOR in cell homeostasis, cell proliferation, and immune response, as well as its association with oncogenesis. It highlights the different ways in which miRNAs can potentially affect the mTOR pathway and their implications in immune-related diseases. Preclinical findings suggest that combining mTOR modulators with RT can inhibit tumor growth through anti-angiogenic and anti-vascular effects, but further research and clinical trials are needed to validate the efficacy and safety of using miRNAs targeting mTOR as therapeutic agents in combination with RT. Overall, this review provides a comprehensive understanding of the potential of miRNAs targeting mTOR to enhance RT efficacy in cancer treatment and emphasizes the need for further research to translate these findings into improved clinical outcomes.
Polyamine and EIF5A hypusination downstream of c-Myc confers targeted therapy resistance in BRAF mutant melanoma
Authors: Park Byung-Sun , Jeon Heeju , Kim Yeonseo , Kwon Haejin , Choi Ga-Eun , Chi Sung-Gil , Park Hyun-Mee , Lee Hyunbeom , Kim Tackhoon
Published: July 2024

Background

BRAF inhibitors are widely employed in the treatment of melanoma with the BRAF V600E mutation. However, the development of resistance compromises their therapeutic efficacy. Diverse genomic and transcriptomic alterations are found in BRAF inhibitor resistant melanoma, posing a pressing need for convergent, druggable target that reverse therapy resistant tumor with different resistance mechanisms.

Methods

CRISPR-Cas9 screens were performed to identify novel target gene whose inhibition selectively targets A375VR, a BRAF V600E mutant cell line with acquired resistance to vemurafenib. Various in vitro and in vivo assays, including cell competition assay, water soluble tetrazolium (WST) assay, live-dead assay and xenograft assay were performed to confirm synergistic cell death. Liquid Chromatography-Mass Spectrometry analyses quantified polyamine biosynthesis and changes in proteome in vemurafenib resistant melanoma. EIF5A hypusination dependent protein translation and subsequent changes in mitochondrial biogenesis and activity were assayed by O-propargyl-puromycin labeling assay, mitotracker, mitoSOX labeling and seahorse assay. Bioinformatics analyses were used to identify the association of polyamine biosynthesis with BRAF inhibitor resistance and poor prognosis in melanoma patient cohorts.

Results

We elucidate the role of polyamine biosynthesis and its regulatory mechanisms in promoting BRAF inhibitor resistance. Leveraging CRISPR-Cas9 screens, we identify AMD1 (S-adenosylmethionine decarboxylase 1), a critical enzyme for polyamine biosynthesis, as a druggable target whose inhibition reduces vemurafenib resistance. Metabolomic and proteomic analyses reveal that polyamine biosynthesis is upregulated in vemurafenib-resistant cancer, resulting in enhanced EIF5A hypusination, translation of mitochondrial proteins and oxidative phosphorylation. We also identify that sustained c-Myc levels in vemurafenib-resistant cancer are responsible for elevated polyamine biosynthesis. Inhibition of polyamine biosynthesis or c-Myc reversed vemurafenib resistance both in vitro cell line models and in vivo in a xenograft model. Polyamine biosynthesis signature is associated with poor prognosis and shorter progression free survival after BRAF/MAPK inhibitor treatment in melanoma cohorts, highlighting the clinical relevance of our findings.

Conclusions

Our findings delineate the molecular mechanisms involving polyamine-EIF5A hypusination-mitochondrial respiration pathway conferring BRAF inhibitor resistance in melanoma. These targets will serve as effective therapeutic targets that can maximize the therapeutic efficacy of existing BRAF inhibitors.
Exosome for mRNA delivery: strategies and therapeutic applications
Authors: Iqbal Zoya , Rehman Khurrum , Mahmood Ayesha , Shabbir Maryam , Liang Yujie , Duan Li , Zeng Hui
Published: July 2024

Messenger RNA (mRNA) has emerged as a promising therapeutic molecule with numerous clinical applications in treating central nervous system disorders, tumors, COVID-19, and other diseases. mRNA therapies must be encapsulated into safe, stable, and effective delivery vehicles to preserve the cargo from degradation and prevent immunogenicity. Exosomes have gained growing attention in mRNA delivery because of their good biocompatibility, low immunogenicity, small size, unique capacity to traverse physiological barriers, and cell-specific tropism. Moreover, these exosomes can be engineered to utilize the natural carriers to target specific cells or tissues. This targeted approach will enhance the efficacy and reduce the side effects of mRNAs. However, difficulties such as a lack of consistent and reliable methods for exosome purification and the efficient encapsulation of large mRNAs into exosomes must be addressed. This article outlines current breakthroughs in cell-derived vesicle-mediated mRNA delivery and its biomedical applications.

Graphical Abstract
Chikusetsu Saponin IVa liposomes modified with a retro-enantio peptide penetrating the blood-brain barrier to suppress pyroptosis in acute ischemic stroke rats
Authors: Liang Yitong , Fan Tingting , Bai Min , Cui Na , Li Wangting , Wang Jingwen , Guan Yue
Published: July 2024

Background

The therapeutic strategies for acute ischemic stroke were faced with substantial constraints, emphasizing the necessity to safeguard neuronal cells during cerebral ischemia to reduce neurological impairments and enhance recovery outcomes. Despite its potential as a neuroprotective agent in stroke treatment, Chikusetsu saponin IVa encounters numerous challenges in clinical application.

Result

Brain-targeted liposomes modified with THRre peptides showed substantial uptake by bEnd. 3 and PC-12 cells and demonstrated the ability to cross an in vitro blood-brain barrier model, subsequently accumulating in PC-12 cells. In vivo, they could significantly accumulate in rat brain. Treatment with C-IVa-LPs-THRre notably reduced the expression of proteins in the P2RX7/NLRP3/Caspase-1 pathway and inflammatory factors. This was evidenced by decreased cerebral infarct size and improved neurological function in MCAO rats.

Conclusion

The findings indicate that C-IVa-LPs-THRre could serve as a promising strategy for targeting cerebral ischemia. This approach enhances drug concentration in the brain, mitigates pyroptosis, and improves the neuroinflammatory response associated with stroke.
A black phosphorus nanosheet-based RNA delivery system for prostate cancer therapy by increasing the expression level of tumor suppressor gene PTEN via CeRNA mechanism
Authors: Su Shunye , Liu Leyi , Fu Qingfeng , Ma Minghao , Yang Na , Pan Ting , Geng Shengyong , Yu Xue-Feng , Zhu Jianqiang
Published: July 2024

Background

Prostate cancer (PCa) has a high incidence in men worldwide, and almost all PCa patients progress to the androgen-independent stage which lacks effective treatment measures. PTENP1, a long non-coding RNA, has been shown to suppress tumor growth through the rescuing of PTEN expression via a competitive endogenous RNA (ceRNA) mechanism. However, PTENP1 was limited to be applied in the treatment of PCa for the reason of rapid enzymatic degradation, poor intracellular uptake, and excessively long base sequence to be synthesized. Considering the unique advantages of artificial nanomaterials in drug loading and transport, black phosphorus (BP) nanosheet was employed as a gene-drug carrier in this study.

Results

The sequence of PTENP1 was adopted as a template which was randomly divided into four segments with a length of about 1000 nucleotide bases to synthesize four different RNA fragments as gene drugs, and loaded onto polyethyleneimine (PEI)-modified BP nanosheets to construct BP-PEI@RNA delivery platforms. The RNAs could be effectively delivered into PC3 cells by BP-PEI nanosheets and elevating PTEN expression by competitive binding microRNAs (miRNAs) which target PTEN mRNA, ultimately exerting anti-tumor effects.

Conclusions

Therefore, this study demonstrated that BP-PEI@RNAs is a promising gene therapeutic platform for PCa treatment.

Graphical Abstract
Liver-specific delivery of spherical DNA frameworks for alleviation of hepatic ischemic reperfusion injury
Authors: Wang Hao , Wen Li , Wei Hao , Song Yangmeihui , Song Wenyu , Li Mengting , Lan Xiaoli , Cai Weibo , Jiang Dawei
Published: July 2024

DNA nanostructures have long been developed for biomedical purposes, but their controlled delivery in vivo proposes a major challenge for disease theranostics. We previously reported that DNA nanostructures on the scales of tens and hundreds nanometers showed preferential renal excretion or kidney retention, allowing for sensitive evaluation and effective protection of kidney function, in response to events such as unilateral ureter obstruction or acute kidney injury. Encouraged by the positive results, we redirected our focus to the liver, specifically targeting organs noticeably lacking DNA materials, to explore the interaction between DNA nanostructures and the liver. Through PET imaging, we identified SDF and M13 as DNA nanostructures exhibiting significant accumulation in the liver among numerous candidates. Initially, we investigated and assessed their biodistribution, toxicity, and immunogenicity in healthy mice, establishing the structure-function relationship of DNA nanostructures in the normal murine. Subsequently, we employed a mouse model of liver ischemia-reperfusion injury (IRI) to validate the nano-bio interactions of SDF and M13 under more challenging pathological conditions. M13 not only exacerbated hepatic oxidative injury but also elevated local apoptosis levels. In contrast, SDF demonstrated remarkable ability to scavenge oxidative responses in the liver, thereby mitigating hepatocyte injury. These compelling results underscore the potential of SDF as a promising therapeutic agent for liver-related conditions. This aimed to elucidate their roles and mechanisms in liver injury, providing a new perspective for the biomedical applications of DNA nanostructures.

Graphical Abstract
Targeted delivery of CEBPA-saRNA for the treatment of pancreatic ductal adenocarcinoma by transferrin receptor aptamer decorated tetrahedral framework nucleic acid
Authors: Wang Li , Yao Qunyan , Guo Xuerui , Wang Bingmei , Si Jingyi , Wang Xingye , Jing Shisong , Yan Ming , Shi Yan , Song Guangqi , Shen Xizhong , Guan Jiyu , Zhao Yicheng , Zhu Changfeng
Published: July 2024

Pancreatic cancer, predominantly pancreatic ductal adenocarcinoma (PDAC), remains a highly lethal malignancy with limited therapeutic options and a dismal prognosis. By targeting the underlying molecular abnormalities responsible for PDAC development and progression, gene therapy offers a promising strategy to overcome the challenges posed by conventional radiotherapy and chemotherapy. This study sought to explore the therapeutic potential of small activating RNAs (saRNAs) specifically targeting the CCAAT/enhancer-binding protein alpha (CEBPA) gene in PDAC. To overcome the challenges associated with saRNA delivery, tetrahedral framework nucleic acids (tFNAs) were rationally engineered as nanocarriers. These tFNAs were further functionalized with a truncated transferrin receptor aptamer (tTR14) to enhance targeting specificity for PDAC cells. The constructed tFNA-based saRNA formulation demonstrated exceptional stability, efficient saRNA release ability, substantial cellular uptake, biocompatibility, and nontoxicity. In vitro experiments revealed successful intracellular delivery of CEBPA-saRNA utilizing tTR14-decorated tFNA nanocarriers, resulting in significant activation of tumor suppressor genes, namely, CEBPA and its downstream effector P21, leading to notable inhibition of PDAC cell proliferation. Moreover, in a mouse model of PDAC, the tTR14-decorated tFNA-mediated delivery of CEBPA-saRNA effectively upregulated the expression of the CEBPA and P21 genes, consequently suppressing tumor growth. These compelling findings highlight the potential utility of saRNA delivered via a designed tFNA nanocarrier to induce the activation of tumor suppressor genes as an innovative therapeutic approach for PDAC.
Management strategy for children with ovarian immature teratoma: results from a tertiary pediatric oncology center
Authors: Ahmed Gehad , Khalil Sahar Ahmed , Elshafiey Maged , Abdelfattah Nihal , Eid Mohamed , Zakaria Al-Shaimaa , Elwakeel Madeeha , Elgendy Ahmed
Published: July 2024

Objectives

We present an Egyptian study on pediatric ovarian immature teratomas (ITs), aiming to clarify our treatment strategy selection.

Methods

A retrospective review of all children with pure ovarian ITs who were treated at our institution between 2008 and 2023. The analysis included clinical characteristics, tumor staging according to Children’s Oncology Group (COG), grading based on the Norris system, management, and outcomes.

Results

Thirty-two patients were included, with a median age of 9 years. All patients underwent primary surgery. Unilateral salpingo-oophorectomy was performed in 31 patients. Surgical staging was completed in all patients. Based on COG staging, there were 28 patients (87.5%) stage I, 1 (3%) stage II, and 3 (9.5%) stage III. According to Norris classification, 16 patients (50%) were classified as grade I, 9 (28%) grade II, and 7 (22%) grade III. All patients in stage I were treated using surgery-alone approach, whereas the remaining four (12.5%) received adjuvant chemotherapy. Five patients in stage I had gliomatosis peritonei (GP), and none of them underwent extensive surgery. At a median follow-up of 86 months, two patients had events. The first patient (stage III/grade I) developed IT relapse on the operative bed, and the second (stage I/grade I) had a metachronous IT on the contralateral ovary. Both patients were successfully managed with surgery followed by second-line chemotherapy. Five-year overall survival and event-free survival for all patients were 100% and 93.4%, respectively.

Conclusions

Surgery-alone strategy with close follow-up achieves excellent outcomes for localized ovarian ITs in children, irrespective of the Norris grading or the presence of GP. However, adjuvant chemotherapy is questionable for patients with incompletely resected or locally advanced tumors, and its role requires further evaluation through prospective multicentric studies with a larger sample size.
SARS-CoV-2-associated lymphopenia: possible mechanisms and the role of CD147
Authors: Shouman Shaimaa , El-Kholy Nada , Hussien Alaa E. , El-Derby Azza M. , Magdy Shireen , Abou-Shanab Ahmed M. , Elmehrath Ahmed O. , Abdelwaly Ahmad , Helal Mohamed , El-Badri Nagwa
Published: July 2024

T lymphocytes play a primary role in the adaptive antiviral immunity. Both lymphocytosis and lymphopenia were found to be associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While lymphocytosis indicates an active anti-viral response, lymphopenia is a sign of poor prognosis. T-cells, in essence, rarely express ACE2 receptors, making the cause of cell depletion enigmatic. Moreover, emerging strains posed an immunological challenge, potentially alarming for the next pandemic. Herein, we review how possible indirect and direct key mechanisms could contribute to SARS-CoV-2-associated-lymphopenia. The fundamental mechanism is the inflammatory cytokine storm elicited by viral infection, which alters the host cell metabolism into a more acidic state. This “hyperlactic acidemia” together with the cytokine storm suppresses T-cell proliferation and triggers intrinsic/extrinsic apoptosis. SARS-CoV-2 infection also results in a shift from steady-state hematopoiesis to stress hematopoiesis. Even with low ACE2 expression, the presence of cholesterol-rich lipid rafts on activated T-cells may enhance viral entry and syncytia formation. Finally, direct viral infection of lymphocytes may indicate the participation of other receptors or auxiliary proteins on T-cells, that can work alone or in concert with other mechanisms. Therefore, we address the role of CD147―a novel route―for SARS-CoV-2 and its new variants. CD147 is not only expressed on T-cells, but it also interacts with other co-partners to orchestrate various biological processes. Given these features, CD147 is an appealing candidate for viral pathogenicity. Understanding the molecular and cellular mechanisms behind SARS-CoV-2-associated-lymphopenia will aid in the discovery of potential therapeutic targets to improve the resilience of our immune system against this rapidly evolving virus.

Graphical Abstract
Relative validity of an intelligent ordering system to estimate dietary intake among university students from a medical school in Shanghai, China
Authors: Zhang Yimeng , Gu Dantong , Luo Mengyun , Liu Shaojie , Peng Hong , Jia Yingnan
Published: July 2024

Background

Dietary assessment methods have limitations in capturing real-time eating behaviour accurately. Equipped with automated dietary-data-collection capabilities, the “intelligent ordering system” (IOS) has potential applicability in obtaining long-term consecutive, relatively detailed on-campus dietary records among university students with little resource consumption. We investigated (1) the relative validity of IOS-derived nutrient/food intakes compared to those from the 7-day food diary (7DFD); (2) whether including a supplemental food frequency questionnaire (SFFQ) improves IOS accuracy; and (3) sex differences in IOS dietary intake estimation.

Methods

Medical students (n = 221; age = 22.2 ± 2.4 years; 38.5% male and 61.5% female) completed the 7DFD and SFFQ. During the consecutive 7-day survey period, students weighed and photographed each meal before and after consumption. Then, students reviewed their 3-month diet and completed the SFFQ, which includes eight underprovided school-canteen food items (e.g., dairy, fruits, nuts). Meanwhile, 9385 IOS dietary data entries were collected. We used Spearman coefficients and linear regression models to estimate the associations among the different dietary intake assessment methods. Individual- and group-level agreement was assessed using the Wilcoxon signed-rank test, cross-classification, and Bland‒Altman analysis.

Results

IOS mean daily energy, protein, fat, and carbohydrate intake estimations were significantly lower (-15-20%) than those of the 7DFD. The correlation coefficients varied from 0.52 (for added sugar) to 0.88 (for soybeans and nuts), with fruits (0.37) and dairy products (0.29) showing weaker correlations. Sixty-two (milk and dairy products) to 97% (soybeans and nuts) of participants were classified into the same or adjacent dietary intake distribution quartile using both methods. The energy and macronutrient intake differences between the IOS + SFFQ and 7DFD groups decreased substantially. The separate fruit intake measurements from each assessment method did not significantly differ from each other (p > 0.05). IOS and IOS + SFFQ regression models generally yielded higher R2 values for males than for females.

Conclusion

Despite estimation differences, the IOS can be reliable for medical student dietary habit assessment. The SFFQ is useful for measuring consumption of foods that are typically unavailable in school cafeterias, improving the overall dietary evaluation accuracy. The IOS assessment was more accurate for males than for females.
Increased secretion of adipocyte-derived extracellular vesicles is associated with adipose tissue inflammation and the mobilization of excess lipid in human obesity
Authors: Matilainen Johanna , Berg Viivi , Vaittinen Maija , Impola Ulla , Mustonen Anne-Mari , Männistö Ville , Malinen Marjo , Luukkonen Veera , Rosso Natalia , Turunen Tanja , Käkelä Pirjo , Palmisano Silvia , Arasu Uma Thanigai , Sihvo Sanna P. , Aaltonen Niina , Härkönen Kai , Caddeo Andrea , Kaminska Dorota , Pajukanta Päivi , Kaikkonen Minna U. , Tiribelli Claudio , Käkelä Reijo , Laitinen Saara , Pihlajamäki Jussi , Nieminen Petteri , Rilla Kirsi
Published: July 2024

Background

Obesity is a worldwide epidemic characterized by adipose tissue (AT) inflammation. AT is also a source of extracellular vesicles (EVs) that have recently been implicated in disorders related to metabolic syndrome. However, our understanding of mechanistic aspect of obesity’s impact on EV secretion from human AT remains limited.

Methods

We investigated EVs from human Simpson Golabi Behmel Syndrome (SGBS) adipocytes, and from AT as well as plasma of subjects undergoing bariatric surgery. SGBS cells were treated with TNFα, palmitic acid, and eicosapentaenoic acid. Various analyses, including nanoparticle tracking analysis, electron microscopy, high-resolution confocal microscopy, and gas chromatography–mass spectrometry, were utilized to study EVs. Plasma EVs were analyzed with imaging flow cytometry.

Results

EVs from mature SGBS cells differed significantly in size and quantity compared to preadipocytes, disagreeing with previous findings in mouse adipocytes and indicating that adipogenesis promotes EV secretion in human adipocytes. Inflammatory stimuli also induced EV secretion, and altered EV fatty acid (FA) profiles more than those of cells, suggesting the role of EVs as rapid responders to metabolic shifts. Visceral AT (VAT) exhibited higher EV secretion compared to subcutaneous AT (SAT), with VAT EV counts positively correlating with plasma triacylglycerol (TAG) levels. Notably, the plasma EVs of subjects with obesity contained a higher number of adiponectin-positive EVs than those of lean subjects, further demonstrating higher AT EV secretion in obesity. Moreover, plasma EV counts of people with obesity positively correlated with body mass index and TNF expression in SAT, connecting increased EV secretion with AT expansion and inflammation. Finally, EVs from SGBS adipocytes and AT contained TAGs, and EV secretion increased despite signs of less active lipolytic pathways, indicating that AT EVs could be involved in the mobilization of excess lipids into circulation.

Conclusions

We are the first to provide detailed FA profiles of human AT EVs. We report that AT EV secretion increases in human obesity, implicating their role in TAG transport and association with adverse metabolic parameters, thereby emphasizing their role in metabolic disorders. These findings promote our understanding of the roles that EVs play in human AT biology and metabolic disorders.
Dysregulated proteasome activity and steroid hormone biosynthesis are associated with mortality among patients with acute COVID-19
Authors: Liu Fengjiao , Yang Huqin , Yang Tingyu , Zhang Zhijin , Guan Lujia , Gao Leyi , Ma Haomiao , Zhang Haifan , Song Nan , Tong Zhaohui , Li Jieqiong
Published: July 2024

The persistence of coronavirus disease 2019 (COVID-19)-related hospitalization severely threatens medical systems worldwide and has increased the need for reliable detection of acute status and prediction of mortality. We applied a systems biology approach to discover acute-stage biomarkers that could predict mortality. A total 247 plasma samples were collected from 103 COVID-19 (52 surviving COVID-19 patients and 51 COVID-19 patients with mortality), 51 patients with other infectious diseases (IDCs) and 41 healthy controls (HCs). Paired plasma samples were obtained from survival COVID-19 patients within 1 day after hospital admission and 1–3 days before discharge. There were clear differences between COVID-19 patients and controls, as well as substantial differences between the acute and recovery phases of COVID-19. Samples from patients in the acute phase showed suppressed immunity and decreased steroid hormone biosynthesis, as well as elevated inflammation and proteasome activation. These findings were validated by enzyme-linked immunosorbent assays and metabolomic analyses in a larger cohort. Moreover, excessive proteasome activity was a prominent signature in the acute phase among patients with mortality, indicating that it may be a key cause of poor prognosis. Based on these features, we constructed a machine learning panel, including four proteins [C-reactive protein (CRP), proteasome subunit alpha type (PSMA)1, PSMA7, and proteasome subunit beta type (PSMB)1)] and one metabolite (urocortisone), to predict mortality among COVID-19 patients (area under the receiver operating characteristic curve: 0.976) on the first day of hospitalization. Our systematic analysis provides a novel method for the early prediction of mortality in hospitalized COVID-19 patients.
Impact of therapeutic inhibition of oncogenic cell signaling tyrosine kinase on cell metabolism: in vivo-detectable metabolic biomarkers of inhibition
Authors: Nath Kavindra , Gupta Pradeep K. , Basappa Johnvesly , Wang Shengchun , Sen Neil , Lobello Cosimo , Tomar Jyoti S. , Shestov Alexander A. , Orlovskiy Stepan , Arias-Mendoza Fernando , Rauert-Wunderlich Hilka , Nelson David S. , Glickson Jerry D. , Wasik Mariusz A.
Published: July 2024

Background

Inhibition of kinases is the ever-expanding therapeutic approach to various types of cancer. Typically, assessment of the treatment response is accomplished by standard, volumetric imaging procedures, performed weeks to months after the onset of treatment, given the predominantly cytostatic nature of the kinase inhibitors, at least when used as single agents. Therefore, there is a great clinical need to develop new monitoring approaches to detect the response to kinase inhibition much more promptly. Noninvasive 1H magnetic resonance spectroscopy (MRS) can measure in vitro and in vivo concentration of key metabolites which may potentially serve as biomarkers of response to kinase inhibition.

Methods

We employed mantle cell lymphoma (MCL) cell lines demonstrating markedly diverse sensitivity of inhibition of Bruton’s tyrosine kinase (BTK) regarding their growth and studied in-depth effects of the inhibition on various aspects of cell metabolism including metabolite synthesis using metabolomics, glucose and oxidative metabolism by Seahorse XF technology, and concentration of index metabolites lactate, alanine, total choline and taurine by 1H MRS.

Results

Effective BTK inhibition profoundly suppressed key cell metabolic pathways, foremost pyrimidine and purine synthesis, the citrate (TCA) cycle, glycolysis, and pyruvate and glutamine/alanine metabolism. It also inhibited glycolysis and amino acid-related oxidative metabolism. Finally, it profoundly and quickly decreased concentration of lactate (a product of mainly glycolysis) and alanine (an indicator of amino acid metabolism) and, less universally total choline both in vitro and in vivo, in the MCL xenotransplant model. The decrease correlated directly with the degree of inhibition of lymphoma cell expansion and tumor growth.

Conclusions

Our results indicate that BTK inhibition exerts a broad and profound suppressive effect on cell metabolism and that the affected index metabolites such as lactate, alanine may serve as early, sensitive, and reliable biomarkers of inhibition in lymphoma patients detectable by noninvasive MRS-based imaging method. This kind of imaging-based detection may also be applicable to other kinase inhibitors, as well as diverse lymphoid and non-lymphoid malignancies.
Designing a Midwife-Led Birth Center Program Based on the MAP-IT Model: A Sequential Explanatory Mixed-Methods Study
Authors: Bakhshi Mohaddeseh , Mollazadeh Sanaz , Khadivzadeh Talat , Moghri Javad , Saki Azadeh , Firoozi Mahboobeh
Published: July 2024

Background

In recent decades, medical supervision of the labor and delivery process has expanded beyond its boundaries to the extent that in many settings, childbirth has become a medical event. This situation has influenced midwifery care. One of the significant barriers to midwives providing care to pregnant women is the medicalization of childbirth. So far, the policies and programs of the Ministry of Health to reduce medical interventions and cesarean section rates have not been successful. Therefore, the current study aims to be conducted with the purpose of “Designing a Midwife-Led Birth Center Program Based on the MAP-IT Model”.

Methods/design

The current study is a mixed-methods sequential explanatory design by using the MAP-IT model includes 5 steps: Mobilize, Assess, Plan, Implement, and Track, providing a framework for planning and evaluating public health interventions in a community. It will be implemented in three stages: The first phase of the research will be a cross-sectional descriptive study to determine the attitudes and preferences towards establishing a midwifery-led birthing center focusing on midwives and women of childbearing age by using two researcher-made questionnaires to assess the participants’ attitudes and preferences toward establishing a midwifery-led birthing center. Subsequently, extreme cases will be selected based on the participants’ average attitude scores toward establishing a midwifery-led birthing center in the quantitative section. In the second stage of the study, qualitative in-depth interviews will be conducted with the identified extreme cases from the first quantitative phase and other stakeholders (the first and second steps of the MAP-IT model, namely identifying and forming a stakeholder coalition, and assessing community resources and real needs). In this stage, the conventional qualitative content analysis approach will be used. Subsequently, based on the quantitative and qualitative data obtained up to this stage, a midwifery-led birthing center program based on the third step of the MAP-IT model, namely Plan, will be developed and validated using the Delphi method.

Discussion

This is the first study that uses a mixed-method approach for designing a midwife-led maternity care program based on the MAP-IT model. This study will fill the research gap in the field of improving midwife-led maternity care and designing a program based on the needs of a large group of pregnant mothers. We hope this program facilitates improved eligibility of midwifery to continue care to manage and improve their health easily and affordably.

Ethical code

IR.MUMS.NURSE.REC. 1403. 014.
The effect of matrine and glycyrrhizic acid on porcine reproductive and respiratory syndrome virus in Vitro and in vivo
Authors: Zhang Zhilong , Wu Wenyi , Li Qiannan , Du Fangfang , Wang Xuebing , Yang Mingfan , Zhang Hongying
Published: July 2024

Porcine reproductive and respiratory syndrome (PRRS) is endemic worldwide, seriously affecting the development of the pig industry, but vaccines have limited protective effects against PRRSV transmission. The aim of this study was to identify potential anti-PRRSV drugs. We examined the cytotoxicity of seven compounds formulated based on the mass ratio of glycyrrhizic acid to matrine and calculated their inhibition rates against PRRSV in vitro. The results showed that the seven compounds all had direct killing and therapeutic effects on PRRSV, and the compounds inhibited PRRSV replication in a time- and dose-dependent manner. The compound with the strongest anti-PRRSV effect was selected for subsequent in vivo experiments. Pigs were divided into a control group and a medication group for the in vivo evaluation. The results showed that pigs treated with the 4:1 compound had 100% morbidity after PRRSV challenge, and the mortality rate reached 75% on the 8th day of the virus challenge. These results suggest that this compound has no practical anti-PRRSV effect in vivo and can actually accelerate the death of infected pigs. Next, we further analyzed the pigs that exhibited semiprotective effects following vaccination with the compound to determine whether the compound can synergize with the vaccine in vivo. The results indicated that pigs treated with the compound had higher mortality rates and more severe clinical reactions after PRRSV infection (p < 0.05). The levels of proinflammatory cytokines (IL-6, IL-8, IL-1β, IFN-γ, and TNF-α) were significantly greater in the compound-treated pigs than in the positive control-treated pigs (p < 0.05), and there was no synergistic enhancement with the live attenuated PRRSV vaccine (p < 0.05). The compound enhanced the inflammatory response, prompted the body to produce excessive levels of inflammatory cytokines and caused body damage, preventing a therapeutic effect. In conclusion, the present study revealed that the in vitro effectiveness of these agents does not indicate that they are effective in vivo or useful for developing anti-PRRSV drugs. Our findings also showed that, to identify effective anti-PRRSV drugs, comprehensive drug screening is needed, for compounds with solid anti-inflammatory effects both in vitro and in vivo. Our study may aid in the development of new anti-PRRSV drugs.
Predictors of the sustainability for an evidence-based eating disorder prevention program delivered by college peer educators
Authors: Bearman Sarah Kate , Rohde Paul , Pauling Sydney , Gau Jeff M. , Shaw Heather , Stice Eric
Published: July 2024

Background

Despite ongoing efforts to introduce evidence-based interventions (EBIs) into mental health care settings, little research has focused on the sustainability of EBIs in these settings. College campuses are a natural place to intervene with young adults who are at high risk for mental health disorders, including eating disorders. The current study tested the effect of three levels of implementation support on the sustainability of an evidence-based group eating disorder prevention program, the Body Project, delivered by peer educators. We also tested whether intervention, contextual, or implementation process factors predicted sustainability.

Methods

We recruited 63 colleges with peer educator programs and randomly assigned them to (a) receive a 2-day Train-the-Trainer (TTT) training in which peer educators were trained to implement the Body Project and supervisors were taught how to train future peer educators (TTT), (b) TTT training plus a technical assistance (TA) workshop (TTT + TA), or (c) TTT plus the TA workshop and quality assurance (QA) consultations over 1-year (TTT + TA + QA). We tested whether implementation support strategies, perceived characteristics of the intervention and attitudes towards evidence-based interventions at baseline and the proportion of completed implementation activities during the implementation year predicted three school-level dichotomous sustainability outcomes (offering Body Project groups, training peer educators, training supervisors) over the subsequent two-year sustainability period using logistic regression models.

Results

Implementation support strategies did not significantly predict any sustainability outcomes, although a trend suggested that colleges randomized to the TTT + TA + QA strategy were more likely to train new supervisors (OR = 5.46, 95% CI [0.89–33.38]). Colleges that completed a greater proportion of implementation activities were more likely to offer Body Project groups (OR = 1.53, 95% CI [1.19–1.98]) and train new peer educators during the sustainability phase (OR = 1.39, 95% CI [1.10–1.74]). Perceived positive characteristics of the Body Project predicted training new peer educators (OR = 18.42, 95% CI [1.48–299.66]), which may be critical for sustainability in routine settings with high provider turnover.

Conclusions

Helping schools complete more implementation activities and increasing the perceived positive characteristics of a prevention program may result in greater sustainment of prevention program implementation.

Trial Registration

This study was preregistered on 12/07/17 with ClinicalTrials.gov, ID NCT03409809, https://clinicaltrials.gov/ct2/show/NCT03409809.
Durvalumab supplementation for non-small-cell lung cancer: a meta-analysis study
Authors: Wang Chengchen , Fu Hongyi , Wang Feng
Published: July 2024

Background

Durvalumab supplementation may have some potential in improving the efficacy in patients with non-small-cell lung cancer (NSCLC), and this meta-analysis aims to explore the impact of durvalumab supplementation on efficacy for NSCLC.

Methods

PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases were systematically searched, and we included randomized controlled trials (RCTs) assessing the effect of durvalumab supplementation on efficacy in patients with NSCLC. Overall survival and progression-free survival were included for this meta-analysis.

Results

Four RCTs were finally included in the meta-analysis. Overall, compared with control group for NSCLC, durvalumab supplementation showed significantly improved survival rate (odd ratio [OR] = 1.64; 95% confidence interval [CI] = 1.31 to 2.06; P < 0.0001), overall survival ( hazard ratio [HR] = 0.73; 95% CI = 0.61 to 0.87; P = 0.0003), progression-free survival rate (OR = 2.31; 95% CI = 1.78 to 3.01; P < 0.00001) and progression-free survival (HR = 0.71; 95% CI = 0.54 to 0.95; P = 0.02), and had the capability to reduce the incidence of grade ≥ 3 adverse events (OR = 0.26; 95% CI = 0.16 to 0.42; P < 0.00001).

Conclusions

Durvalumab supplementation is effective to improve the efficacy for NSCLC.
Measuring health related quality of life (HRQoL) in Lysosomal Storage Disorders (LSDs): a rapid scoping review of available tools and domains
Authors: McDool Emily , Powell Philip , Carlton Jill
Published: July 2024

Background

Lysosomal storage diseases (LSDs) are a group of rare inherited metabolic disorders, consisting of over 70 diseases that are characterised by lysosomal dysfunction. Due to their varied and progressive symptoms, LSDs have a continual impact on patients’ health-related quality of life (HRQoL). Several recently published studies have provided insight into the HRQoL of individuals with LSDs. However, it is challenging to meaningfully synthesise this evidence, since studies often focus upon a particular type of LSD and / or utilise different self-report questionnaires or patient-reported outcome measures (PROMs) to assess HRQoL.

Aims

The aim of this study was to review the published literature in LSDs, to identify the PROMs which have been used to assess HRQoL and generate a conceptual map of HRQoL domains measured in individuals diagnosed with LSDs.

Methods

Three electronic databases were searched in March 2022. Primary studies of any design which utilised multi-item PROMs to assess at least one aspect of HRQoL in individuals with LSDs since 2017 were identified. Data were extracted to assess both the characteristics of each study and of the PROMs utilised within each study. The extraction of HRQoL domains and synthesis were informed by an a priori framework, inductively modified to reflect data emerging from the identified literature. Selection and extraction was undertaken independently by two reviewers; discrepancies were ratified by a third reviewer.

Results

Sixty nine studies were identified which were published 2017-2022, with a combined total of 52 PROMs (71 variants) used to assess HRQoL in individuals with LSDs. The final extracted HRQoL framework included 7 domains (Activities; Physical sensations; Autonomy; Cognition; Feelings and emotions; Self-identity; Relationships), characterised by 37 sub-domains.

Conclusions

This review highlights the breadth and variety of HRQoL domains assessed in individuals with LSDs, across three broad domains of physical, psychological and social functioning. The resultant framework and mapped PROMs will aid researchers and clinicians in the selection of PROMs to assess aspects of HRQoL in people living with LSDs, based on their conceptual coverage.
Harnessing health information technology to promote equitable care for patients with limited English proficiency and complex care needs
Authors: Strechen Inna , Wilson Patrick , Eltalhi Targ , Piche Kimberly , Tschida-Reuter Dan , Howard Diane , Sutor Bruce , Tiong Ing , Herasevich Svetlana , Pickering Brian , Barwise Amelia
Published: July 2024

Background

Patients with language barriers encounter healthcare disparities, which may be alleviated by leveraging interpreter skills to reduce cultural, language, and literacy barriers through improved bidirectional communication. Evidence supports the use of in-person interpreters, especially for interactions involving patients with complex care needs. Unfortunately, due to interpreter shortages and clinician underuse of interpreters, patients with language barriers frequently do not get the language services they need or are entitled to. Health information technologies (HIT), including artificial intelligence (AI), have the potential to streamline processes, prompt clinicians to utilize in-person interpreters, and support prioritization.

Methods

From May 1, 2023, to June 21, 2024, a single-center stepped wedge cluster randomized trial will be conducted within 35 units of Saint Marys Hospital & Methodist Hospital at Mayo Clinic in Rochester, Minnesota. The units include medical, surgical, trauma, and mixed ICUs and hospital floors that admit acute medical and surgical care patients as well as the emergency department (ED). The transitions between study phases will be initiated at 60-day intervals resulting in a 12-month study period. Units in the control group will receive standard care and rely on clinician initiative to request interpreter services. In the intervention group, the study team will generate a daily list of adult inpatients with language barriers, order the list based on their complexity scores (from highest to lowest), and share it with interpreter services, who will send a secure chat message to the bedside nurse. This engagement will be triggered by a predictive machine-learning algorithm based on a palliative care score, supplemented by other predictors of complexity including length of stay and level of care as well as procedures, events, and clinical notes.

Discussion

This pragmatic clinical trial approach will integrate a predictive machine-learning algorithm into a workflow process and evaluate the effectiveness of the intervention. We will compare the use of in-person interpreters and time to first interpreter use between the control and intervention groups.

Trial registration

NCT05860777. May 16, 2023.
Coerced consent in clinical research: study protocol for a randomized controlled trial
Authors: Brenna Connor T. A. , Walton Nancy , Cohn Melanie , Siddiqui Urooj , Huszti Ella , Brull Richard
Published: July 2024

Background

Despite the low-risk nature of participation in most clinical anesthesia trials, subject recruitment on the same day as surgery is often restricted due to the concerns of researchers and local research ethics boards that same-day consent may not afford adequate time and opportunity for patients to weigh and make decisions, as well as perceptions of patient vulnerability immediately prior to surgery that could impact the voluntary nature and the rigor of the informed consent process. However, specialties such as anesthesiology, critical care, interventional radiology, and emergency medicine have a varied pattern of practice and patient acquaintance that does not typically afford the luxury of time or, in many cases, advance consent for participation in research. Indeed, the initial encounter between anesthesiologists and patients undergoing elective procedures routinely occurs on the day of surgery. Concerns of coercion related to same-day consent for clinical anesthesia research trials have not been borne out in the literature, and represent a significant obstacle to clinical researchers, as well as to the patients who are denied opportunities for potential benefit through participation in research studies.

Methods

We describe the protocol for a prospective randomized controlled trial examining the voluntariness of patient consent, solicited either in advance of surgery or on the same day, to participate in an anesthesia research study at Women’s College Hospital. One hundred fourteen patients scheduled to undergo ambulatory anterior cruciate ligament repair facilitated by general anesthesia with an adductor canal block will be randomized for recruitment either (a) in the pre-operative assessment clinic before the day of surgery or (b) on the day of surgery, to be approached for consent to participate in a fabricated research study of adjunct medications in adductor canal blocks. Regardless of allocation, patients in both groups will receive the same routine standard of care and will complete a post-operative questionnaire to signal perceptions of undue influence in the process of providing informed consent for the fabricated trial.

Discussion

This study will inform trial design and practice guidelines surrounding the amount of time patients ought to be afforded in order to make durable decisions to participate (or not) in clinical research studies. This is expected to impact trial recruitment in a variety of clinical settings where researchers have only brief opportunities to interface with patients.

Trial registration

The trial was registered prospectively on the Open Science Framework (OSF), registration #46twc, on 2023-Mar-17.
Clinical value of 68Ga-pentixafor PET/CT in patients with primary aldosteronism and bilateral lesions: preliminary results of a single-centre study
Authors: Zuo Rui , Liu Shuang , Li Wenbo , Xia Zhu , Xu Lu , Pang Hua
Published: July 2024

Background

Subtype diagnosis of primary aldosteronism (PA) is used to determine treatment, and the potential utility of 68Ga-pentixafor PET/CT for investigation of PA has long been recognized. The study aimed to evaluate the clinical value of 68Ga-pentixafor PET/CT in the diagnosis and prognosis of patients with bilateral lesions identified by CT.

Methods

In total, 25 patients with PA and bilateral lesions on CT were retrospectively evaluated. All patients underwent 68Ga-Pentixafor PET/CT and adrenal vein sampling. The analysis focused on establishing the relationship between bilateral adrenal lesions SUVmax and the ratio of bilateral adrenal lesions SUVmax (CON) and clinical diagnosis, treatment outcomes, and KCNJ5 gene status.

Results

The concordance rate between 68Ga-Pentixafor PET/CT and adrenal venous sampling was 65.2% (15/23). The lateralization results of 68Ga-pentixafor PET/CT supported the clinical decisions of 20 patients with PA, 90% of whom showed effectiveness in treatment. The SUVmax on the dominant side of the surgically treated patients was higher than that of patients treated with drugs. The SUVmax of the KCNJ5 mutant group was higher than that of the KCNJ5 wild group, and 68Ga-Pentixafor uptake was correlated with KCNJ5 gene status.

Conclusions

68Ga-Pentixafor PET/CT proves beneficial for patients with PA with bilateral lesions on CT. The treatment is generally effective based on the results of PET lateralization. Simultaneously, a certain relationship exists between 68Ga-Pentixafor PET/CT and KCNJ5 gene status, warranting further analysis.