bluuebunny/crossref_metadata_2025 huggingface dataset:
T. gondii excretory proteins promote the osteogenic differentiation of human bone mesenchymal stem cells via the BMP/Smad signaling pathway
Authors: Deng Mingzhu , Gao Feifei , Liu Tianfeng , Zhan Weiqiang , Quan Juanhua , Zhao Ziquan , Wu Xuyang , Zhong Zhuolan , Zheng Hong , Chu Jiaqi
Published: July 2024

Background

Bone defects, resulting from substantial bone loss that exceeds the natural self-healing capacity, pose significant challenges to current therapeutic approaches due to various limitations. In the quest for alternative therapeutic strategies, bone tissue engineering has emerged as a promising avenue. Notably, excretory proteins from Toxoplasma gondii (TgEP), recognized for their immunogenicity and broad spectrum of biological activities secreted or excreted during the parasite’s lifecycle, have been identified as potential facilitators of osteogenic differentiation in human bone marrow mesenchymal stem cells (hBMSCs). Building on our previous findings that TgEP can enhance osteogenic differentiation, this study investigated the molecular mechanisms underlying this effect and assessed its therapeutic potential in vivo.

Methods

We determined the optimum concentration of TgEP through cell cytotoxicity and cell proliferation assays. Subsequently, hBMSCs were treated with the appropriate concentration of TgEP. We assessed osteogenic protein markers, including alkaline phosphatase (ALP), Runx2, and Osx, as well as components of the BMP/Smad signaling pathway using quantitative real-time PCR (qRT-PCR), siRNA interference of hBMSCs, Western blot analysis, and other methods. Furthermore, we created a bone defect model in Sprague-Dawley (SD) male rats and filled the defect areas with the GelMa hydrogel, with or without TgEP. Microcomputed tomography (micro-CT) was employed to analyze the bone parameters of defect sites. H&E, Masson and immunohistochemical staining were used to assess the repair conditions of the defect area.

Results

Our results indicate that TgEP promotes the expression of key osteogenic markers, including ALP, Runx2, and Osx, as well as the activation of Smad1, BMP2, and phosphorylated Smad1/5—crucial elements of the BMP/Smad signaling pathway. Furthermore, in vivo experiments using a bone defect model in rats demonstrated that TgEP markedly promoted bone defect repair.

Conclusion

Our results provide compelling evidence that TgEP facilitates hBMSC osteogenic differentiation through the BMP/Smad signaling pathway, highlighting its potential as a therapeutic approach for bone tissue engineering for bone defect healing.
The effect of a split-dose intravenous dexamethasone and a single high-dose on postoperative blood glucose after total joint arthroplasty: a randomized double-blind placebo-controlled trial
Authors: Liu Xiao-yang , Mou Ping , Cao Jian , Chen Xu-ming , Wang Hao-Yang , Zeng Wei-Nan , Zhou Zong-Ke
Published: July 2024

Background

In patients undergoing total joint arthroplasty (TJA), the administration of dexamethasone may contribute to perioperative blood glucose (BG) disturbances, potentially resulting in complications, even in patients without diabetes. This study aimed to demonstrate the impact of different administration regimens of dexamethasone in postoperative BG levels.

Methods

In this randomized, controlled, double-blind trial, 136 patients without diabetes scheduled for TJA were randomly assigned to three groups: two perioperative saline injections (Group A, placebo); a single preoperative injection of 20 mg dexamethasone and a postoperative saline injection (Group B), and two perioperative injections of 10 mg dexamethasone (Group C). Primary outcomes were the postoperative fasting blood glucose (FBG) levels. Secondary outcome parameters were the postoperative postprandial blood glucose (PBG) levels. Postoperative complications within 90 days were also recorded. Risk factors for FBG ≥ 140 mg/dl and PBG ≥ 180 mg/dl were investigated.

Results

Compared to Group A, there were transient increases in FBG and PBG on postoperative days (PODs) 0 and 1 in Groups B and C. Statistical differences in FBG and PBG among the three groups were nearly absent from POD 1 onward. Both dexamethasone regimens did not increase the risk for postoperative FBG ≥ 140 mg/dl or PBG ≥ 180 mg/dl. Elevated preoperative HbA1c levels may increase the risk of postoperative FBG ≥ 140 mg/dl or PBG ≥ 180 mg/dl, respectively.

Conclusion

Perioperative intravenous high-dose dexamethasone to patients without diabetes has transient effects on increasing BG levels after TJA. However, no differences were found between the split-dose and single high-dose regimens. The elevated preoperative HbA1c, but not the dexamethasone regimens were the risk factor for FBG ≥ 140 mg/dl and PBG ≥ 180 mg/dl.

Trial registration

Chinese Clinical Trail Registry, ChiCTR2300069473. Registered 17 March 2023, https://www.chictr.org.cn/showproj.html?proj=186760.
Hodgkin lymphoma and liquid biopsy: a story to be told
Authors: Velasco-Suelto Jesús , Gálvez-Carvajal Laura , Comino-Méndez Iñaki , Rueda-Domínguez Antonio
Published: July 2024

Hodgkin lymphoma (HL) represents a neoplasm primarily affecting adolescents and young adults, necessitating the development of precise diagnostic and monitoring tools. Specifically, classical Hodgkin lymphoma (cHL), comprising 90% of cases, necessitating tailored treatments to minimize late toxicities. Although positron emission tomography/computed tomography (PET/CT) has enhanced response assessment, its limitations underscore the urgency for more reliable progression predictive tools. Genomic characterisation of rare Hodgkin Reed-Sternberg (HRS) cells is challenging but essential. Recent studies employ single-cell molecular analyses, mass cytometry, and Next-Generation Sequencing (NGS) to unveil mutational landscapes. The integration of liquid biopsies, particularly circulating tumor DNA (ctDNA), extracellular vesicles (EVs), miRNAs and cytokines, emerge as groundbreaking approaches. Recent studies demonstrate ctDNA's potential in assessing therapy responses and predicting relapses in HL. Despite cHL-specific ctDNA applications being relatively unexplored, studies emphasize its value in monitoring treatment outcomes. Overall, this review underscores the imperative role of liquid biopsies in advancing HL diagnosis and monitoring.
LILRB4 on multiple myeloma cells promotes bone lesion by p-SHP2/NF-κB/RELT signal pathway
Authors: Wang Hongying , Wang Lei , Luan Huiwen , Xiao Jing , Zhao Zhiling , Yu Pengfei , Deng Mi , Liu Yifan , Ji Shuhao , Ma Junjie , Zhou Yan , Zhang Jiashen , Meng Xianhui , Zhang Juan , Zhao Xinyu , Li Chunling , Li Fangmin , Wang Dapeng , Wei Shujuan , Hui Lijun , Nie Siman , Jin Changzhu , An Zhiqiang , Zhang Ningyan , Wang Yaopeng , Zhang Cheng Cheng , Li Zunling
Published: July 2024

Background

Leukocyte Ig-like receptor B family 4 (LILRB4) as an immune checkpoint on myeloid cells is a potential target for tumor therapy. Extensive osteolytic bone lesion is the most characteristic feature of multiple myeloma. It is unclear whether ectopic LILRB4 on multiple myeloma regulates bone lesion.

Methods

The conditioned medium (CM) from LILRB4-WT and -KO cells was used to analyze the effects of LILRB4 on osteoclasts and osteoblasts. Xenograft, syngeneic and patient derived xenograft models were constructed, and micro-CT, H&E staining were used to observe the bone lesion. RNA-seq, cytokine array, qPCR, the activity of luciferase, Co-IP and western blotting were used to clarify the mechanism by which LILRB4 mediated bone damage in multiple myeloma.

Results

We comprehensively analyzed the expression of LILRB4 in various tumor tissue arrays, and found that LILRB4 was highly expressed in multiple myeloma samples. The patient’s imaging data showed that the higher the expression level of LILRB4, the more serious the bone lesion in patients with multiple myeloma. The conditioned medium from LILRB4-WT not -KO cells could significantly promote the differentiation and maturation of osteoclasts. Xenograft, syngeneic and patient derived xenograft models furtherly confirmed that LILRB4 could mediate bone lesion of multiple myeloma. Next, cytokine array was performed to identify the differentially expressed cytokines, and RELT was identified and regulated by LILRB4. The overexpression or exogenous RELT could regenerate the bone damage in LILRB4-KO cells in vitro and in vivo. The deletion of LILRB4, anti-LILRB4 alone or in combination with bortezomib could significantly delay the progression of bone lesion of multiple myeloma.

Conclusions

Our findings indicated that LILRB4 promoted the bone lesion by promoting the differentiation and mature of osteoclasts through secreting RELT, and blocking LILRB4 singling pathway could inhibit the bone lesion.
Enhancement of protein production in Aspergillus niger by engineering the antioxidant defense metabolism
Authors: Chen Xin , Pan Baoxiang , Yu Leyi , Wang Bin , Pan Li
Published: July 2024

Background

Research on protein production holds significant importance in the advancement of food technology, agriculture, pharmaceuticals, and bioenergy. Aspergillus niger stands out as an ideal microbial cell factory for the production of food-grade proteins, owing to its robust protein secretion capacity and excellent safety profile. However, the extensive oxidative folding of proteins within the endoplasmic reticulum (ER) triggers ER stress, consequently leading to protein misfolding reactions. This stressful phenomenon results in the accelerated generation of reactive oxygen species (ROS), thereby inducing oxidative stress. The accumulation of ROS can adversely affect intracellular DNA, proteins, and lipids.

Result

In this study, we enhanced the detoxification of ROS in A. niger (SH-1) by integrating multiple modules, including the NADPH regeneration engineering module, the glutaredoxin system, the GSH synthesis engineering module, and the transcription factor module. We assessed the intracellular ROS levels, growth under stress conditions, protein production levels, and intracellular GSH content. Our findings revealed that the overexpression of Glr1 in the glutaredoxin system exhibited significant efficacy across various parameters. Specifically, it reduced the intracellular ROS levels in A. niger by 50%, boosted glucoamylase enzyme activity by 243%, and increased total protein secretion by 88%.

Conclusion

The results indicate that moderate modulation of intracellular redox conditions can enhance overall protein output. In conclusion, we present a strategy for augmenting protein production in A. niger and propose a potential approach for optimizing microbial protein production system.
Mesenchymal stem cells ameliorate inflammation and pyroptosis in diabetic cardiomyopathy via the miRNA-223-3p/NLRP3 pathway
Authors: Yang Qu , Chen Qi , Li Sihui , Luo Jun
Published: July 2024

Background

Diabetic cardiomyopathy (DCM) stands as the primary cause of heart failure and mortality among patients with diabetes. Nevertheless, conventional treatment approaches are limited in their ability to effectively prevent myocardial tissue damage itself. Mesenchymal stem cell (MSC) therapy exhibits immense potential for treating DCM; however, the precise mechanisms involved in regulating inflammatory responses and pyroptosis processes, an emerging form of cellular death, within myocardial cells remain elusive. Hence, it is imperative to further elucidate the precise underlying mechanisms to facilitate the clinical implementation of MSC therapy.

Methods

In vivo, we established a DCM mouse model by administering streptozotocin and fed the mice a high-glucose and high-fat diet, followed by MSC therapy. Cardiac function and myocardial injury were evaluated through echocardiography and histological analysis. Furthermore, the levels of inflammation and pyroptosis were assessed using ELISA, Western blotting, and qRT-PCR. In vitro experiments involved inducing H9C2 myocardial cell damage with high glucose treatment, followed by coculture with MSCs to investigate their role in modulating inflammation and pyroptosis mechanisms.

Results

MSCs can maintain cardiac function and alleviate myocardial injury in mice with DCM. Moreover, they effectively suppress the activation of NLRP3 and reduce the release of inflammatory factors (such as IL-1β and ROS), thereby further downregulating the expression of pyroptosis-related proteins including NLRP3, Caspase-1, and GSDMD. Additionally, we experimentally validated that MSCs exert their therapeutic effects by promoting the expression of miR-223-3p in cardiac myocytes; however, this effect can be reversed by an miR-223-3p inhibitor.

Conclusion

MSCs effectively mitigate the release of inflammatory factors and cell lysis caused by pyroptosis through the regulation of the miR-223-3p/NLRP3 pathway, thereby safeguarding cardiomyocytes against damage in DCM. This mechanism establishes a novel theoretical foundation for the clinical treatment of cardiac conditions utilizing MSCs.
Hypoimmunogenic human iPSCs expressing HLA-G, PD-L1, and PD-L2 evade innate and adaptive immunity
Authors: Tsuneyoshi Norihiro , Hosoya Tomonori , Takeno Yuriko , Saitoh Kodai , Murai Hidetaka , Amimoto Naoki , Tatsumi Rie , Watanabe Sono , Hasegawa Yudai , Kikkawa Eri , Goto Kumiko , Nishigaki Fusako , Tamura Kouichi , Kimura Hironobu
Published: July 2024

Background

The human induced pluripotent stem cells (hiPSCs) can generate all the cells composing the human body, theoretically. Therefore, hiPSCs are thought to be a candidate source of stem cells for regenerative medicine. The major challenge of allogeneic hiPSC-derived cell products is their immunogenicity. The hypoimmunogenic cell strategy is allogenic cell therapy without using immune suppressants. Advances in gene engineering technology now permit the generation of hypoimmunogenic cells to avoid allogeneic immune rejection. In this study, we generated a hypoimmunogenic hiPSC (HyPSC) clone that had diminished expression of human leukocyte antigen (HLA) class Ia and class II and expressed immune checkpoint molecules and a safety switch.

Methods

First, we generated HLA class Ia and class II double knockout (HLA class Ia/II DKO) hiPSCs. Then, a HyPSC clone was generated by introducing exogenous β-2-microglobulin (B2M), HLA-G, PD-L1, and PD-L2 genes, and the Rapamycin-activated Caspase 9 (RapaCasp9)-based suicide gene as a safety switch into the HLA class Ia/II DKO hiPSCs. The characteristics and immunogenicity of the HyPSCs and their derivatives were analyzed.

Results

We found that the expression of HLA-G on the cell surface can be enhanced by introducing the exogenous HLA-G gene along with B2M gene into HLA class Ia/II DKO hiPSCs. The HyPSCs retained a normal karyotype and had the characteristics of pluripotent stem cells. Moreover, the HyPSCs could differentiate into cells of all three germ layer lineages including CD45+ hematopoietic progenitor cells (HPCs), functional endothelial cells, and hepatocytes. The HyPSCs-derived HPCs exhibited the ability to evade innate and adaptive immunity. Further, we demonstrated that RapaCasp9 could be used as a safety switch in vitro and in vivo.

Conclusion

The HLA class Ia/II DKO hiPSCs armed with HLA-G, PD-L1, PD-L2, and RapaCasp9 molecules are a potential source of stem cells for allogeneic transplantation.
Rising socioeconomic disparities in childhood overweight and obesity in Belgium
Authors: Drieskens Sabine , Charafeddine Rana , Vandevijvere Stefanie , De Pauw Robby , Demarest Stefaan
Published: July 2024

Background

Childhood overweight, especially obesity, significantly impacts children’s health and poses an increased risk of adult-onset diseases. This study aims to analyse the evolution of childhood overweight and obesity in Belgium from 1997 to 2018 and assess its variation across parental socioeconomic status (SES).

Methods

The Health Interview Survey, a cross-sectional survey representative of the Belgian population, has been conducted since 1997, with the latest survey conducted in 2018. This study focuses on children aged 2–17 years. Body Mass Index (BMI, kg/m²) was derived from self-reported data, supplemented with proxy reports for children under 15 years old. Overweight and obesity were classified using age/sex-specific cut-off points. Highest parental educational level served as the indicator of SES. In addition to reporting the overall prevalence and the 95% confidence interval (95%CI) of childhood overweight and obesity by year, this study examines the absolute difference in prevalence between SES groups (low minus high) and calculates the Odds Ratio (OR, adjusted for age and sex) to evaluate the relative difference.

Results

The overall prevalence of childhood overweight rose from 13.6% (95%CI = 11.2-16.1%) in 1997 to 18.9% (95%CI = 16.3-21.5%) in 2018; while it remained stable for obesity, fluctuating between 5.4% and 6.3% over the same period. This increase was more pronounced among children with low SES compared to those with high SES. Consequently, the absolute difference between children with low and high SES increased over time from 8.0% points (pp) in 1997 to 14.9 pp in 2018 for overweight, and from 3.1 pp to 6.8 pp for obesity. In terms of relative inequalities, overall, children with low SES exhibited significantly higher odds of overweight and of obesity than those with high SES (OR varying between 2 à 3 for overweight and between 2 and 4 for obesity).

Conclusions

The escalating disparities over time highlight SES as a significant risk factor for childhood overweight and obesity. Addressing these inequalities requires interventions such as providing healthy meals and increasing sports opportunities at school. Additionally, it is recommended to regulate fast food outlets near schools and limit unhealthy food marketing, particularly because children with low SES are more exposed to such influences.
A stony track towards innovation in remote highland regions: agricultural intensification in the apricot sector of Northern Pakistan
Authors: Köster Mareike , Alam Iftikhar , Rana Jai , Wiehle Martin , Buerkert Andreas
Published: July 2024

Background

Traditional farming practices of remote highland regions are usually well adapted to the local agro-ecological and social conditions. There, introduced agricultural innovation geared towards sustainable intensification as a response to changing environments often faces multiple barriers. These may comprise limited market incentives for enhanced production, narrow pathways of knowledge transmission, and infrastructural hurdles. To quantify effects of innovation and sustainable intensification in enhancing smallholders’ livelihoods in the Karakoram Mountains of Northern Pakistan, the present study was conducted with 86 small-holder farmers. We chose interviewees who are involved in the cultivation, processing and/or trading of apricot (Prunus armeniaca L.), a traditionally important currently eroding fruit crop of the Central Asian highlands. By investigating the status quo of apricot production and producers’ innovative farming practices, we generated an intensification index based on simple agronomic indicators. Explanatory farm and framers’ characteristics, production characteristics, knowledge, and apricot management were tested for their predictive power.

Results

Although the data show low average profits of 3.8 US$ tree−1, we found that intensified apricot production can contribute to the provision of nutritious food and increased household income. Age and training of farmers were key factors fostering innovation, while lacking awareness of innovative practices was attributed to slow communication. Rejection of intensification was either due to low-value attribution towards apricot farming or risk aversion. Commonly adopted innovations, particularly sulfur drying, were either well integrated with traditional practices or characterized by low up-front costs and high returns on investment.

Conclusions

Management intensification may increase farmers’ incomes and retard abandonment of apricot farming and the consecutive loss of associated benefits, such as diversified farm output and improved ecosystem services.

Graphical Abstract
Psychometric properties of the arabic translation of the Physical Appearance Comparison Scale-Revised (PACS-R) in adults
Authors: El Khoury Marie Anne , Malaeb Diana , Fawaz Mirna , Chammas Nancy , Soufia Michel , Fekih-Romdhane Feten , Obeid Sahar , Hallit Souheil
Published: July 2024

Background

Physical comparison may be a factor in body dissatisfaction and related issues, like eating disorders and depression. The Physical Appearance Comparison Scale-Revised (PACS-R) is a scale developed to assess the frequency of physical comparison. Because there is no validated scale for body comparison in Arabic, this study aims to address this gap by validating the PACS-R in the Arabic language.

Methods

The PACS-R was translated to Arabic following a conventional forward-backward translation procedure, and was administered to a sample of 359 Lebanese adults along with The Depression Anxiety Stress Scale, and the Rosenberg self-esteem scale (RSES) for convergent validity. The factor structure was studied by confirmatory factor analysis (CFA), and composite reliability was assessed using McDonald’s omega and Cronbach’s alpha.

Results

Results suggested a one-factor structure of the Arabic PACS-R, with good internal consistency (McDonald’s ω = 0.97 / Cronbach α = 0.97). Measurement invariance was established across sex groups, with no significant difference being reported between males and females in terms of PACS-R scores (15.42 ± 10.64 vs. 13.16 ± 11.88; t(357) = 1.84; p = .066). Finally, adequate convergent validity was tested and found to be adequate, with PACS-R scores found to be correlated negatively with self-esteem and positively with psychological distress.

Conclusion

The present findings preliminarily establish the Arabic PACS-R as an effective instrument for researchers and practitioners aiming to explore the physical comparison among Arabic-speaking populations, thus contributing to research and clinical work in the Arabic community.
Accuracy of the national violent death reporting system in identifying unintentional firearm deaths to children by children
Authors: Fischer Samuel , Miller Matthew , Barber Catherine , Azrael Deborah
Published: July 2024

Background

In assigning manner of death (MOD) for inclusion on death certificates, medical examiners and coroners do not always apply uniform criteria. Previous research indicates surveillance statistics based on death certificates, such as the National Vital Statistics System, grossly miscount unintentional firearm deaths. The National Violent Death Reporting System (NVDRS) has taken steps to reduce variability in manner of death coding by providing uniform criteria for assigning an “abstractor manner of death” (AMD). AMD has five categories: unintentional, suicide, homicide, undetermined, and legal intervention homicide. A previous study found good accuracy of AMD coding for unintentional firearm deaths, all ages, 2003–2006, but a more recent study reported that the NVDRS undercounted self- and other-inflicted unintentional firearm deaths in which both the victim and shooter (for other-inflicted injuries) were under age 15 (2009–2018).

Findings

We replicated the recent study’s sample population, identifying 924 NVDRS incidents from 2009 to 2018 in which both victim and, for other-inflicted injuries, shooter age was under 15 and AMD was homicide, suicide, unintentional or undetermined (there were no legal intervention deaths to children). We assigned a researcher-adjudicated MOD (RMD) by reviewing incident narratives. RMD was compared with AMD and with manner recorded on the death certificate. Based on RMD as the gold standard, the sensitivity, specificity, and predictive values positive and negative of the AMD for unintentional childhood firearm deaths were, respectively, 90%, 99%, 98% and 96%; 86% (24/28) of false negatives were coded by abstractors as homicides. By contrast, death certificate manner had relatively poor sensitivity (63%).

Conclusions

In our sample of 924 deaths, the abstractor manner of death generally agreed with researcher-adjudicated manner of death, though not perfectly, missing 10% of researcher-adjudicated unintentional deaths, mostly because abstractors coded these unintentional deaths as homicides. A sizable minority of false negatives were unintentional deaths where the narrative explicitly noted that adult negligence contributed to a child’s unintentional shooting death. While AMD coding in NVDRS is good, it could be improved if NVDRS coding guidelines explicitly affirmed that potential prosecution for negligent manslaughter is not a contraindication to an AMD of unintentional, provided the firearm was not used to intentionally harm, threaten, or coerce.
Hepatopancreatoduodenectomy with delayed division of the pancreatic parenchyma when utilizing a right lateral approach to the superior mesenteric artery
Authors: Hayasaki Aoi , Kuriyama Naohisa , Kaluba Benson , Sakamoto Tatsuya , Komatsubara Haruna , Maeda Koki , Shinkai Toru , Noguchi Daisuke , Ito Takahiro , Gyoten Kazuyuki , Fujii Takehiro , Iizawa Yusuke , Tanemura Akihiro , Murata Yasuhiro , Kishiwada Masashi , Narushima Mitsunaga , Mizuno Shugo
Published: July 2024

Background

Hepatopancreatoduodenectomy (HPD) is a high-risk surgical procedure. Delayed division of the pancreatic parenchyma (DDPP) was reported as a novel technique in HPD for reducing postoperative pancreatic fistula. However, it is often difficult to dissect the pancreatic head nerve plexus while leaving the pancreatic parenchyma intact, particularly in patients with a bulky tumor with vascular invasion. Of the various reported approaches to the superior mesenteric artery, the right lateral approach can provide a useful surgical field to conduct DDPP in HPD.

Case presentation

A 78-year-old man visited a local clinic with itching and jaundice. Laboratory tests revealed elevated hepatobiliary enzyme, total bilirubin, and tumor markers. Enhanced computed tomography, endoscopic retrograde cholangiopancreatography, and intraductal ultrasonography of the bile duct were performed, and he was diagnosed with perihilar cholangiocarcinoma with invasion to the right hepatic artery (40 × 15 mm, Bismuth IIIa, cT3N0M0 cStage III). After neoadjuvant chemotherapy, he underwent left hepatectomy with caudate lobectomy, pancreatoduodenectomy, and combined resection of right hepatic artery using DDPP with a right lateral approach to the superior mesenteric artery. The pathological diagnosis was perihilar cholangiocarcinoma ypT3N1M0 ypStage IIIC, R0 resection. He was discharged on postoperative day 57 in good health and has been doing well for 6 months since the surgery.

Conclusions

We present an effective application of the right lateral approach to the superior mesenteric artery in DDPP during HPD. This procedure can provide a clear surgical field to easily divide the pancreatic head nerve plexus before transection of the pancreatic parenchyma.
3D printed ventilation tubes and their effect on biological models
Authors: Govea-Camacho Luis Humberto , Castillo-López Irma Yolanda , Carbajal-Castillo Sergio Alejandro , Gonzalez-Ojeda Alejandro , Cervantes-Guevara Gabino , Cervantes-Pérez Enrique , Ramírez-Ochoa Sol , Vázquez-Sánchez Sergio Jiram , Delgado-Hernández Gonzalo , Tavares-Ortega Jaime Alberto , González-Muñoz Samantha Emily , Fuentes-Orozco Clotilde
Published: July 2024

Background

Acute otitis media (AOM) causes inflammation and hearing loss. Ventilation tubes are key in treatment. 3D printing improves prostheses in otorhinolaryngology, offering precision and greater adaptability.

Materials and methods

An experimental study was conducted with Wistar rats from July to December 2020. 3D tympanostomy tube models were designed, with technical specifications and tests performed on inexpensive 3D printers. The tympanostomy tube was inserted endoscopically.

Results

Procedures were performed on five rats with implants in both ears. Pre-intervention pathologies, such as atical retraction and glue ear, were found. The PLA-printed tympanostomy tube showed improvement after adjustments. Histopathological results revealed significant middle and inner ear damage.

Conclusion

In our study, the design and 3D printing of implants fulfilled the desired functions when modified, with a height of 5 mm. Complications included PLA degradation and ear damage. There were no adverse events during observation, highlighting the need for further research on 3D-printed implants.
Intraoperative fluid management is not predictive of AKI in major pancreatic surgery: a retrospective cohort study
Authors: Lydon Kerri , Shah Saurin , Mongan Kai L. , Mongan Paul D. , Cantrell Michael Calvin , Awad Ziad
Published: July 2024

Background

Pancreatic surgery is associated with a significant risk for acute kidney injury (AKI) and clinically relevant postoperative pancreatic fistula (CR-POPF). This investigation evaluated the impact of intraoperative volume administration, vasopressor therapy, and blood pressure management on the primary outcome of AKI and the secondary outcome of a CR-POPF after pancreatic surgery.

Methods

This retrospective single-center cohort investigated 200 consecutive pancreatic surgeries (January 2018–December 2021). Patients were categorized for the presence/absence of AKI (Kidney Disease Improving Global Outcomes) and CR-POPF. After univariate analysis, multivariable models were constructed to control for the univariate cofactor differences in the primary and secondary outcomes.

Results

AKI was identified in 20 patients (10%) with significant univariate differences in demographics (body mass index and gender), comorbidities, indices of chronic renal insufficiency, and an increased AKI Risk score. Surgical characteristics, intraoperative fluid, vasopressor, and blood pressure management were similar in patients with and without AKI. Patients with AKI had increased blood loss, lower urine output, and packed red blood cell administration. After multivariate analysis, male gender (OR = 7.9, 95% C.I. 1.8–35.1) and the AKI Risk score (OR = 6.3, 95% C.I. 2.4–16.4) were associated with the development of AKI (p < 0.001). Intraoperative and postoperative volume, vasopressor administration, and intraoperative hypotension had no significant impact in the multivariate analysis. CR-POPF occurred in 23 patients (11.9%) with no significant contributing factors in the multivariate analysis. Patients who developed AKI or a CR-POPF had an increase in surgical complications, length of stay, discharge to a skilled nursing facility, and mortality.

Conclusion

In this analysis, intraoperative volume administration, vasopressor therapy, and a blood pressure < 55 mmHg for more than 10 min were not associated with an increased risk of AKI. After multivariate analysis, male gender and an elevated AKI Risk score were associated with an increased likelihood of AKI.
Identification of common genetic factors and immune-related pathways associating more than two autoimmune disorders: implications on risk, diagnosis, and treatment
Authors: Rajalingam Aruna , Ganjiwale Anjali
Published: July 2024

Autoimmune disorders (ADs) are chronic conditions resulting from failure or breakdown of immunological tolerance, resulting in the host immune system attacking its cells or tissues. Recent studies report shared effects, mechanisms, and evolutionary origins among ADs; however, the possible factors connecting them are unknown. This study attempts to identify gene signatures commonly shared between different autoimmune disorders and elucidate their molecular pathways linking the pathogenesis of these ADs using an integrated gene expression approach. We employed differential gene expression analysis across 19 datasets of whole blood/peripheral blood cell samples with five different autoimmune disorders (rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, Crohn’s disease, and type 1 diabetes) to get nine key genes—EGR1, RUNX3, SMAD7, NAMPT, S100A9, S100A8, CYBB, GATA2, and MCEMP1 that were primarily involved in cell and leukocyte activation, leukocyte mediated immunity, IL-17, AGE-RAGE signaling in diabetic complications, prion disease, and NOD-like receptor signaling confirming its role in immune-related pathways. Combined with biological interpretations such as gene ontology (GO), pathway enrichment, and protein–protein interaction (PPI) network, our current study sheds light on the in-depth research on early detection, diagnosis, and prognosis of different ADs.
Enrichment of somatic mosaic states involving DNA damage response and repair genes in patients treated with 177Lutetium.
Authors: Kusne Yael , Mosalem Osama M , Lasho Terra L. , Pritzl Stephanie L , Finke Christy , Hobday Timothy J. , Starr Jason S. , Bekaii-Saab Tanios S. , Halfdanarson Thorvardur Ragnar , Sonbol Mohamad B. , Orme Jacob , Childs Daniel S , Sartor Oliver , Patnaik Mrinal
Published: July 2024

3020

Background: Radioligand therapy (RLT) use has been increasing with the approval of 177Lu-Dotatate for metastatic neuroendocrine tumors (NET) & 177Lu-PSMA-617 for metastatic castration resistant prostate cancer (mCRPC). Therapy-related myeloid neoplasms [tMN, including myelodysplastic syndrome (MDS) & acute myeloid leukemia, (AML)] have been reported after 177Lutetium (177Lu) for NET with rates of 2-20% & median time from first 177Lu to tMN of 2.8yrs [4-12]. Clonal hematopoiesis (CH) is a risk factor for tMN, with the spectrum of CH depending on selection pressures. To describe the prevalence of therapy selected CH & tMN, we performed a retrospective analysis of patients (pts) who had a bone marrow biopsy (BMB) post-177Lu. Methods: After IRB approval, we queried the electronic health record for pts with BMB post-177Lu. Pt demographics, treatment history, labs & BMB results were collected. Results: Fifty-seven pts met criteria, 41 (72%) with NET & 16 (28%) with mCRPC. . Median age at BMB was 68yrs (range, 28-85). Of the 57pts, prior treatments included: radiation (RT) in 21 (37%), temozolomide in 14 (25%), taxane in 15 (26%), & platinum agents in 10 (18%). The median number of 177Lu cycles was 4 (range, 1-11).Cytogenetics were available in 84% (n = 48) & were normal in 60% (n = 29). Of those with abnormal cytogenetics (n = 18, 38%), the most common abnormalities involved chromosome (chr) 7 (n = 12, 26%), chr 5 (n = 7, 15%), chr 20 (n = 5, 11%) and complex karyotypes in 7 (15%), with 3 (17%) of these patients having no mutations. Diagnoses were assessable in 49 (86%) pts: 15 (31%) with undefined cytopeniasand 16 (33%) with tMDS. Metastatic carcinoma was identified in 17 Fifty-one percent (n = 29), at a median of 0.5yrs (range, 0.04-2.6) after hematologic diagnosis. Conclusions: The enrichment of CH involving the DDR pathway in recipients of 177Lu underscores the impact of RLT on bone marrow progenitors.
Multicentric retrospective study on the treatment characteristics, efficacy and safety of eribulin in Slovenian patients with breast cancer.
Authors: Dobovisek Luka , Borstnar Simona , Ravnik Maja , Privsek Nina
Published: July 2024

e13123

Background: Eribulin mesylate (eribulin) is a microtubule inhibitor and a synthetic analog of halichondrin B, a natural product isolated from the marine sponge Halichondria okadai. Eribulin was approved based on the randomized Phase 3 EMBRACE clinical trial, which showed an improvement in survival compared to chemotherapy (CT) of the physician's choice. The efficacy and safety of eribulin treatment in real-world settings has been reported in several studies: Korean and Chinese multicenter retrospective studies and a meta-analysis from 2020. Methods: We included all patients treated with eribulin between January 24, 2013 and September 14, 2022 at the Institute of Oncology Ljubljana (85.4% of patients) and University Medical Centre Maribor (14.6%). Clinical data were collected retrospectively from paper and electronic patient records. The primary endpoints were median progression-free survival (PFS), overall survival (OS), response rates and safety. We performed a descriptive statistical analysis and a survival analysis using the Kaplan-Meier method. Results: 205 patients, whose average age was 58.6 (29-88) years, were included in the study. The majority (79%) had a hormone receptor (HR+) positive tumor, 12.2% were HER2 positive and 16.6% were triple negative. 32/205 (15.6%) were primary metastatic. Of the remaining 173 patients, 160/173 (92.4%) received adjuvant therapy, of which 15% received hormone therapy, 23.1% received CT and 61.9% received both. At the start of treatment with eribulin, 84.9% had visceral tumors and 14.6% had tumors in the CNS. The median number of all treatment lines was 6 (range 2–15) and the median number of CT lines was 4 (0–13). The ECOG performance status was: 0 in 4.9%, 1 in 53.2%, 2 in 35.1% and 3 in 4.9% and 4 in 0.5% of patients. The objective response rate was 7.3% and clinical benefit was achieved in 27.3%. The median CT line in which eribulin was used was the fourth (1–10). Eribulin was used as the last CT line in half of the patients. The median PFS was 3.01 months (95% confidence interval 2.56–3.47) and the median OS was 6.68 months (95% confidence interval 5.60–7.77). Patients who received eribulin in the first 3 lines of treatment had a better OS than those who received eribulin in later lines. Adverse events (AEs) occurred in 52.7%. Eribulin therapy was discontinued due to AEs in 18.5% of patients. The most common AE was fatigue (25.9%), followed by neuropathy and neutropenia (22.9% and 18%). Conclusions: In our retrospective analysis, we found significantly worse results of treatment with eribulin than in previous studies. In our population, eribulin was used in the late stages of treatment and in older patients with poorer performance status. The proportion of patients with visceral and CNS tumors was higher. The side effects were comparable.
First-line TQB2450 plus anlotinib combined with paclitaxel and cisplatin for advanced esophageal squamous cell carcinoma (ESCC): Update results of a multicenter phase II trial.
Authors: Wang Junsheng , Li Ning , Guo Yanzhen , Cheng Yufeng , Li Baosheng , Luo Suxia
Published: July 2024

e16011

Background: PD-1 inhibitor combined with chemotherapy are the standard first-line treatment for advanced ESCC. Anlotinib, a multitargeted tyrosine kinase inhibitor (TKI), has been demonstrated favorable efficacy and manageable toxicity as both first-line treatment when combined with TP and second-line monotherapy in advanced ESCC. TQB2450 is a novel humanized anti-PD-L1 monoclonal antibody. We conducted a phase II trial to evaluate the efficacy and safety of alotinib combined with TQB2450, cisplatin, and paclitaxel as first-line treatment for advanced ESCC. Here is the update results. Methods: Eligible patients (pts) with previously untreated unresectable locally advanced or metastatic ESCC received TQB2450 (1200mg, iv, d1, q3w) plus anlotinib (10mg, po, d1~14, q3w) combined with paclitaxel (135mg/m2, iv, d1, q3w) and cisplatin (60~75mg/m2, iv, d1~3, q3w) for 4 - 6 cycles as initial therapy. Patients without progressive disease (PD) continued to receive same dose of anlotinib plus TQB2450 as maintenance therapy until PD or unacceptable toxicity. The primary endpoint was PFS (RECIST version 1.1). Secondary endpoints included iPFS (iRECIST), ORR (RECIST version 1.1), DCR, DOR and safety. Results: At the data cutoff date of November 14, 2023, 50 pts were enrolled with a median age of 64 years (range 41-74), male (39/50, 78%) and ECOG PS 1 (38/50, 76%). Among 43 tumor response evaluable pts , 4 achieved complete response, 32 had partial response and 8 had stable disease. The ORR was 72.00% (95% CI: 57.51, 83.77) and the DCR was 84.0% (95% CI: 70.89, 92.83). The 12-month PFS rate was 66.84% (95% CI: 48.73, 79.79) and the 12-month OS rate was 74.22% (95% CI: 59.06, 84.46), but the median PFS and OS was not reached. The incidence of ≥G3 treatment emergent adverse events was 78%, mainly included neutropenia (44%, 22/50), leukopenia (24%, 12/50) and hypertension (20%, 10/50). 20 pts (48%, 24/50) occurred serious AEs. Conclusions: The combination of TQB2450 plus anlotinib, paclitaxel and cisplatin, demonstrated encouraging efficacy and manageable toxicity in patients with advanced ESCC when used as first-line treatment. Clinical trial information: NCT05013697 .
Intratumoral and fecal microbiota to reveal microbial markers associated with gastric carcinogenesis.
Authors: Wang Yiwen , Han Wenjie , Wang Yue , Sun Tao , Xu Junnan , Han Li , Liu Xiaolin
Published: July 2024

e16014

Background: The relationship between dysbiosis of the gastrointestinal microbiota and gastric cancer (GC) has been extensively studied. However, microbiota alterations in GC patients vary widely across studies, and there are still no diagnostic biomarkers for early GC that can be replicated in multiple populations. Therefore, this study aimed to characterize the gastrointestinal microbial communities associated with gastric carcinogenesis. The diversity results showed significant differences in GC patients' intratumoral microbiota compared with the non-GC population. Methods: 1,642 gastric tissue samples and 394 fecal samples were tested using 16s rRNA amplicon sequencing. After identifying taxa with differential biomarkers, we built a random forest model to distinguish gastric cancer from normal controls. We validated the generalizability and specificity of the model using an external cohort. In addition, we used the KEGG database for predictive analysis of colony correlation functions. Results: The positive correlation between GC-enriched bacteria increased, and the positive correlation between GC-depleted bacteria decreased compared to healthy individuals. Functional analysis revealed that carbohydrate and iron metabolism pathways significantly enriched in the GC phase. In addition, we explored non- Helicobacter pylori ( HP) commensals, which play an essential role in HP-negative and HP-positive GC. Finally, random forest models were constructed using the specific taxa associated with GC obtained from the Lefse analysis, and it was found that the combination of Lactobacillus and Streptococcus included alone could well discriminate between GC patients and healthy individuals in fecal samples (area under the curve (AUC) = 0.7949). We also validated it in an independent cohort (AUC = 0.7712). Conclusions: This study demonstrates the validity of GC-specific microbial markers across multiple populations, which may contribute to early non-invasive diagnosis of GC.
Triple combination treatment of trastuzumab, chemotherapy and immune checkpoint inhibitor in HER2 positive unresectable, locally advanced, metastatic gastric and esophageal adenocarcinoma: A systematic review and meta-analysis.
Authors: Revillas Lorenz Fort Estrada , Dy Carlos , Lalusis John Kelvin
Published: July 2024

e16071

Background: The current standard of care for unresectable, locally advanced or metastatic HER2 positive gastric, esophageal and gastroesophageal junction adenocarcinomas is the combination of the anti HER 2 antibody trastuzumab and cytotoxic chemotherapy. In recent years, the addition of immune checkpoint inhibitors to this combination has been studied to determine if it can improve clinical outcomes for this disease. This systematic review and meta-analysis evaluated high-quality data from clinical trials to determine the role and efficacy of this triple combination treatment. Methods: A systematic search of English-language articles on PubMed, Cochrane and Google scholar was done to identify randomized trials (RCTs) investigating the use of triple combination treatment of anti-Her 2 antibody, chemotherapy and immune checkpoint inhibitor in the treatment of unresectable, locally advanced, or metastatic HER2 overexpression positive gastric, esophageal and gastroesophageal junction adenocarcinoma. Quality of the studies was assessed using the Revised Cochrane risk-of-bias tool for randomized trials (RoB 2). Inverse variance was the statistical method used with random effects as the analysis model in the production of the Forest plot and calculation of risk ratio (RR) at 95% confidence intervals (CI). Results: Four (4) RCTs (N = 866) were included for quality assessment and data extraction. Two (2) of these RCTs (N = 80) were single arm studies which both showed favorable outcomes in terms of objective response rate and progression free survival. The two (2) other RCTS (N = 786), each had two arms (triple regimen versus comparator) and were used in the meta-analysis. Risk of bias was low and heterogeneity was low (I2 below 50%). Pooled results showed that in patients given triple combination regimen, there is statistically significant improvement in progression free survival (RR 1.55 95% CI 1.20-2.00, p 0.0007). There is also an increase in overall response rate in favor of the triple combination regimen, albeit not statistically significant (RR 1.31 95% CI 0.99-1.74, p = 0.06). Conclusions: The addition of an immune checkpoint inhibitor to the current standard of care of anti Her 2 antibody and chemotherapy provides meaningful results in terms of tumor response and progression free survival in Her 2 positive locally advanced or metastatic gastric and esophageal adenocarcinomas. More robust trials, and data on overall survival supporting the use of this triple regimen may help re-shape the current standard of care for this disease.
Combining nimotuzumab with PD-L1 inhibitors and chemotherapy to treat esophageal cancer: A retrospective study.
Authors: Chen Size , Lin Yiguang , Dong Jiayi , Song Minghan , Lijuan Shao
Published: July 2024

e16072

Background: Combining immunotherapy with targeted therapy and/or chemotherapy has been shown to have superior clinical benefits in cancer treatment. The combination of immunotherapy, targeted therapy, and chemotherapy may be an option for esophageal cancer. This study assessed retrospectively the efficacy and safety of nimotuzumab combined with the PD-L 1 inhibitor and chemotherapy in the treatment of patients with esophageal cancer. Methods: All enrolled patients were from the First Affiliated Hospital of Guangdong Pharmaceutical University between September 2021 and August 2023. All patients received intravenous nimotuzumab (200 mg/w) combining with PD-L1 inhibitors (Tirelizumab; Caralizumab; Sintilimab; Pembrolizumab; Nivolumab and Penpulimab, 6 cycles in total) and chemotherapy (albumin paclitaxel 150mg/m2, cisplatin 25mg/m2, for 1-3 days per cycle, for a total of 6 cycles). The primary endpoint was overall survival (OS). Secondary endpoints consisted of the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and safety. Efficacy was assessed according to the criteria of RECIST 1.1 and while adverse events (AEs) were graded according to CTCAE 5.0. Following treatment, patients’ general condition, levels of lymphocytes, IL-6, hs-CRP, PCT, CYFRA21, NSE(E), and SCC were monitored regularly. Results: A total of18 patients diagnosed with EC were enrolled in the study. The majority of the patients were male (16/18), 17 (94.4%) patients diagnosed with esophageal squamous cell carcinoma. Lymphatic metastasis occurred in 13 (72.2%) patients and 5 (27.8%) patients experienced distant metastases. Six (33.3%) patients received radical surgery and five (27.8%) patients did not receive systematic antitumor therapy in the past. 17 (94.4%) patients diagnosed with esophageal squamous cell carcinoma (ESCC). No patient achieved complete response (CR) and 6 (33.3%) patients achieved partial response (PR). The ORR and DCR were 33.3% and 83.3%, respectively. The median OS was not achieved, the 12-month OS rate was 84.8%, 24-month OS rate was 74.2%. The median PFS was 7.9 months, the 12- and 24-month PFS rates were 44.0% and 36.7%, respectively. The incidence of Grade ≥ 3 AEs was 43.85%, including anemia (18.8%), lymphopenia (18.8%) and rash (6.3%). Conclusions: This combinational treatment regimen results in a significant improvement in OS compared to the combination of PD-L1 inhibitors and chemotherapy without increased AEs. Compared to other combinations of targeted drugs with PD-L1 inhibitors and chemotherapy, the use of nituzumab significantly prolonged mPFS and increased OS rates at 12 and 24 months.