bluuebunny/crossref_metadata_2025 huggingface dataset:
IMP3 Immunohistochemical Expression Is Related with Progression and Metastases in Xenografted and Cutaneous Melanomas
Authors: Martin-Morales Natividad , Padial-Molina Miguel , Tovar Isabel , De Araujo Farias Virginea , Hernández-Cortés Pedro , Ramirez-Moreno Esperanza , Caba-Molina Mercedes , Davis Justin , Carrero Castaño Alejandro , Ruiz de Almodovar Jose Mariano , Galindo-Moreno Pablo , Oliver-Pozo Javier , O’Valle Ravassa Francisco Javier
Published: October 2023

Introduction: Insulin-like growth factor-II messenger RNA-binding protein-3 (IMP3) over-expression is a predictor of tumor recurrence and metastases in some types of human melanoma. Our objective was to evaluate the immunohistochemical expression of IMP3 and other molecules related to tumor prognosis in melanoma-xeno-tumors undergoing treatment. We test the effect of radiotherapy (RT) and mesenchymal stromal cells (MSCs) treatment, analyzing the tumorigenic and metastatsizing capacity in a mice melanoma xenograft model. Materials and Methods: We inoculated A375 and G361 human melanoma cell lines into NOD/SCID gamma mice (n = 64). We established a control group, a group treated with MSCs, a group treated with MSCs plus RT, and a group treated with RT. We assessed the immunohistochemical expression of IMP3, E-cadherin, N-cadherin, PARP1, HIF-1α, and the proliferation marker Ki-67. Additionally, we performed a retrospective study including 114 histological samples of patients diagnosed with malignant cutaneous superficial spreading melanoma (n = 104) and nodular melanoma (n = 10) with at least 5 years of follow-up. Results: Most morphological and immunohistochemical features show statistically significant differences between the 2 cell lines. The A375 cell line induced the formation of metastases, while the G361 cell line provoked tumor formation but not metastases. All three treatments reduced the cell proliferation evaluated by the Ki-67 nuclear antigen (p = 0.000, one-way ANOVA test) and reduced the number of metastases (p = 0.004, one-way ANOVA test). In addition, the tumor volumes reduced in comparison with the control groups, 31.74% for RT + MSCs in the A357 tumor cell line, and 89.84% RT + MSCs in the G361 tumor cell line. We also found that IMP3 expression is associated with greater tumor aggressiveness and was significantly correlated with cell proliferation (measured by the expression of Ki-67), the number of metastases, and reduced expression of adhesion molecules. Conclusions: The combined treatment of RT and MSCs on xenografted melanomas reduces tumor size, metastases frequency, and the epithelial to mesenchymal transition/PARP1 metastatic phenotype. This treatment also reduces the expression of molecules related to cellular proliferation (Ki-67), molecules that facilitate the metastatic process (E-cadherin), and molecules related with prognosis (IMP3).
Relationship between VO2peak, VO2 Recovery Kinetics, and Muscle Function in Older Adults
Authors: Healy Rhiannon D. , Smith Cassandra , Woessner Mary N. , Levinger Itamar
Published: October 2023

Introduction: The efficiency of the cardiovascular system to recover following an exercise bout is measured by oxygen (VO2) recovery kinetics. In older adults with a chronic disease, a higher aerobic capacity (VO2peak) and faster VO2 recovery kinetics are associated with higher muscle strength and physical capacity. Yet, this relationship in healthy older adults remains unclear. The aim of this cross-sectional study was to determine whether a higher VO2peak and faster VO2 recovery kinetics are associated with higher muscle strength and physical performance in healthy community-dwelling older adults. Methods: Thirty-five healthy older adults (female 25/male 10, mean age 73 ± 6 years) performed a graded exercise test on a cycle ergometer. VO2peak and VO2 recovery kinetics were assessed through gas exchange analysis. Muscle strength was determined by maximal leg (one-repetition maximum on leg press; 1RM) and grip strength, and physical performance was determined by the physical performance test (PPT) which assessed gait speed, stair ascent and descent, and timed up-and-go. Results: Higher VO2peak was associated with stronger leg (r = 0.59, p < 0.001) and grip strength (r = 0.39, p < 0.03), but no relationship to PPT (p > 0.05). There was also no relationship between VO2 recovery kinetics and leg and grip strength or PPT (p > 0.05). Conclusion: In healthy community-dwelling older adults, VO2peak, but not VO2 recovery kinetics, is associated with muscle strength. This suggests that muscle strength may be an important factor related to aerobic capacity that could assist in identifying older adults who should be prioritized for resistance training.
Age-Related Gene and Protein Expression in Mouse Mandibular Condyle Analyzed by Cap Analysis of Gene Expression and Immunohistochemistry
Authors: Yang Mu-Chen , Nakamura Megumi , Kageyama Yoko , Igari Yohei , Sasano Yasuyuki
Published: October 2023

Introduction: Aging, an inevitable physiological process, leads to morphological and histological degenerative changes in the mandibular condylar cartilage (MCC); however, the molecular mechanism has not yet been elucidated, and little information is available on age-related factors. Therefore, this study was designed to identify age-related factors by investigating the age-related differentially expressed genes (DEGs) and localization of their translated protein expression in the mandibular condyle. Methods: Mandibular condyles were collected from 10- and 50-week-old mice. Total RNA was extracted from the samples and then analyzed using cap analysis of gene expression (CAGE) to identify age-related DEGs. Gene ontology (GO) enrichment analysis was performed to determine which biological processes were most affected by aging in terms of gene expression using Metascape. The mandibular condyle samples were processed for histology to investigate morphological changes caused by aging and for immunohistochemistry to localize the protein expression encoded by age-related genes identified with CAGE. Semi-quantitative immunohistochemistry was performed to assess age-related extracellular matrix (ECM) protein levels in the MCC. The histological sections were also used for Alcian blue histochemistry to detect glycosaminoglycans (GAGs). Results: GO enrichment analysis revealed that the genes related to “extracellular matrix organization,” including Acan, Col1a1, Col1a2, Col2a1, Mmp3, Mmp9, and Mmp13, were most differentially expressed in the aged mandibular condyle. Among these seven genes, Mmp3 was upregulated, and the others were downregulated with aging. Histological examination showed the age-related morphological and histological changes in the MCC. Immunohistochemical investigation showed the localization of matrix metalloproteinases (MMPs)-3, -9, and -13 and their substrate proteins, aggrecan, type I collagen, and type II collagen, in the mandibular condyle at 10 and 50 weeks, indicating different localizations between the young and the aged. In the aged MCC, semi-quantitative immunohistochemistry showed a significant decrease in the aggrecan protein level, and Alcian blue histochemistry showed a decrease in GAGs. Conclusion: MMP-3, MMP-9, and MMP-13 contribute to the remodeling of the ECM of the MCC and subchondral bone during aging by degrading ECM proteins at specific times and sites under the regulation of their production and secretion.
Spatial Transcriptomics of Aging Rat Ovaries Reveals Unexplored Cell Subpopulations with Reduced Antioxidative Defense
Authors: Shen Jiayu , Liu Yuanyuan , Teng Xinyuan , Jin Ligui , Feng Lin , Sun Xiwen , Zhao Fengdong , Huang Bao , Zhong Jinjie , Chen Yingying , Wang Liquan
Published: October 2023

Introduction: Ovarian aging is characterized by a gradual decline in quantity and quality of oocytes and lower chance of fertility. Better understanding the genetic modulation during ovarian aging can further address available treatment options for aging-related ovarian diseases and fertility preservation. Methods: A novel technique spatial transcriptomics (ST) was used to investigate the spatial transcriptome features of rat ovaries. Transcriptomes from ST spots in the young and aged ovaries were clustered using differentially expressed genes. These data were analyzed to determine the spatial organization of age-induced heterogeneity and potential mechanisms underlying ovarian aging. Results: In this study, ST technology was applied to profile the comprehensive spatial imaging in young and aged rat ovary. Fifteen ovarian cell clusters with distinct gene-expression signatures were identified. The gene expression dynamics of granulosa cell clusters revealed three sub-types with sequential developmental stages. Aged ovary showed a significant decrease in the number of granulosa cells from the antral follicle. Besides, a remarkable rearrangement of interstitial gland cells was detected in aging ovary. Further analysis of aging-associated transcriptional changes revealed that the disturbance of oxidative pathway was a crucial factor in ovarian aging. Conclusions: This study firstly described an aging-related spatial transcriptome changes in ovary and identified the potential targets for prevention of ovarian aging. These data may provide the basis for further investigations of the diagnosis and treatment of aging-related ovarian disorders.
Irisin Ameliorated Skeletal Muscle Atrophy by Inhibiting Fatty Acid Oxidation and Pyroptosis Induced by Palmitic Acid in Chronic Kidney Disease
Authors: Zhou Ting , Wang Shiyuan , Pan Yajing , Dong Xingtong , Wu Leiyun , Meng Jiali , Zhang Jialing , Pang Qi , Zhang Aihua
Published: October 2023

Introduction: Protein-energy waste (PEW) is a common complication in patients with chronic kidney disease (CKD), among which skeletal muscle atrophy is one of the most important clinical features of PEW. Pyroptosis is a type of proinflammatory, programmed cell death associated with skeletal muscle disease. Irisin, as a novel myokine, has attracted extensive attention for its protective role in the complications associated with CKD, but its role in muscle atrophy in CKD is unclear. Methods: Palmitic acid (PA)-induced muscular atrophy was evaluated by a reduction in C2C12 myotube diameter. Muscle atrophy model was established in male C57BL/6J mice treated with 0.2% adenine for 4 weeks and then fed a 45% high-fat diet. Blood urea nitrogen and creatinine levels, body and muscle weight, and muscle histology were assessed. The expression of carnitine palmitoyltransferase 1A (CPT1A) and pyroptosis-related protein was analysed by Western blots or immunohistochemistry. The release of IL-1β was detected by enzyme-linked immunosorbent assay. Results: In this study, we showed that PA-induced muscular atrophy manifested as a reduction in C2C12 myotube diameter. During this process, PA can also induce pyroptosis, as shown by the upregulation of NLRP3, cleaved caspase-1 and GSDMD-N expression and the increased IL-1β release and PI-positive cell rate. Inhibition of caspase-1 or NLRP3 attenuated PA-induced pyroptosis and myotube atrophy in C2C12 cells. Importantly, irisin treatment significantly ameliorated PA-induced skeletal muscle pyroptosis and atrophy. In terms of mechanism, PA upregulated CPT1A, a key enzyme of fatty acid oxidation (FAO), and irisin attenuated this effect, which was consistent with etomoxir (CPT1A inhibitor) treatment. Moreover, irisin improved skeletal muscle atrophy and pyroptosis in adenine-induced mice by regulating FAO. Conclusion: Our study firstly verifies that pyroptosis is a novel mechanism of skeletal muscle atrophy in CKD. Irisin ameliorates skeletal muscle atrophy by inhibiting FAO and pyroptosis in CKD, and irisin may be developed as a potential therapeutic agent for the treatment of muscle wasting in CKD patients.
High-Mobility Group Box 1 Overexpression Predicts a Poor Prognosis and Promotes Epithelial-Mesenchymal Transition in Gastric Cancer by Activating TLR4/NF-κB Signaling
Authors: Ma Jichun , Da Mingxu
Published: October 2023

Introduction: The molecular mechanism of high-mobility group box 1 (HMGB1) promoting the epithelial-mesenchymal transition (EMT) of gastric cancer (GC) has not been known well. This study aimed to explore the clinical effects of HMGB1 expression levels on the clinicopathological characteristics of patients with GC and to uncover the potential molecular mechanism which promotes tumor progression. Methods: The expression levels of HMGB1 in 125 patients with GC were detected by immunohistochemistry and Western blotting. Univariate and multivariate analyses were performed to evaluate the relationship between HMGB1 expression and clinical characteristics of patients with GC. Stable overexpression (over-HMGB1) and knockdown (sh-HMGB1) GC cell lines (AGS and MKN-45) were used to determine the effects of HMGB1 on the activation of TLR4/NF-κB signaling. Differences were considered statistically significant at p < 0.05 in two sides. Results: HMGB1 is highly expressed in GC tissues and cell lines. High HMGB1 expression (HR = 1.89, 95% CI: 1.44–2.39, p = 0.001) was an independent risk factor for overall survival in patients with GC. Downregulation of HMGB1 resulted in downregulation of TLR4 and NF-κB subunit (p-p65 and p-IκBα) expression, whereas the upregulated expression of HMGB1 led to increased expression of TLR4 and NF-κB subunits. Overexpression of HMGB1 promotes the upregulation of EMT-TF expression, which enhances the proliferation and migration abilities of GC cell lines. Conclusion: HMGB1 is highly expressed in GC tissues and is associated with a poorer prognosis in patients with GC. HMGB1 activates the TLR4/NF-κB signaling pathway to promote EMT progression in GC cell lines. HMGB1 may be a critical molecule in prognosis prediction and a therapeutic target for patients with GC.
Risk Factors for Acute Kidney Injury after Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis
Authors: Cui Kai , Zhang Senlin , Li Jie
Published: October 2023

Aims: The aim of this study was to identify risk factors associated with acute kidney injury (AKI) after hematopoietic stem cell transplantation (HSCT) by systematically reviewing the relevant literature. Methods: This meta-analysis surveyed relevant articles published in PubMed, Embase, and the Cochrane Library up to December 2022 to identify the reliable risk factors for AKI after HSCT, calculating odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Results: Twenty studies with 4,378 patients were included. Umbilical cord blood transplantation (OR = 2.36; 95% CI: 1.77–3.15; p < 0.00001), calcineurin inhibitors (CNIs) (OR = 1.97; 95% CI: 1.06–3.67; p = 0.03), sinusoidal obstruction syndrome (SOS) (OR = 5.80; 95% CI: 3.96–8.51; p < 0.00001), allogeneic transplantation (OR = 4.27; 95% CI: 1.83–9.95; p = 0.0008), hypertension (OR = 2.07; 95% CI: 1.16–3.69; p = 0.01), amphotericin B (OR = 4.03; 95% CI: 2.54–6.40; p < 0.00001), vancomycin (OR = 2.19; 95% CI: 1.24–3.87; p = 0.007), and total body irradiation (TBI) (OR = 1.81; 95% CI: 1.27–2.57; p = 0.001) were risk factors for AKI. Conclusion: Umbilical cord blood transplantation, CNIs, SOS, allogeneic transplantation, hypertension, amphotericin B, vancomycin, and TBI were risk factors for AKI. It is important for clinical staff to be aware of these risk factors in their treatment planning with patients undergoing HSCT.
Global Epidemiology of Cirrhosis: Changing Etiological Basis and Comparable Burden of Nonalcoholic Steatohepatitis between Males and Females
Authors: Tan Darren , Chan Kai En , Wong Zhen Yu , Ng Cheng Han , Xiao Jieling , Lim Wen Hui , Tay Phoebe , Tang Ansel , Fu Clarissa Elysia , Muthiah Mark , Nah Benjamin , Tan Eunice X. , Teng Margaret L.P. , Siddiqui Mohammad Shadab , Dan Yock Young , Lim Seng Gee , Loomba Rohit , Huang Daniel Q.
Published: October 2023

Introduction: The etiology of liver diseases has changed significantly, but its impact on the comparative burden of cirrhosis between males and females is unclear. We estimated sex differences in the burden of cirrhosis across 204 countries and territories from 2010 to 2019. Methods: We analyzed temporal trends in the burden of cirrhosis using the methodology framework of the 2019 Global Burden of Disease study. We estimated annual frequencies and age-standardized rates (ASRs) of cirrhosis incidence, death, and disability-adjusted life-years (DALYs) by sex, region, country, and etiology. Results: In 2019, the frequency of incident cases, deaths, and DALYs due to cirrhosis was 1,206,125, 969,068, and 31,781,079 in males versus 845,429, 502,944, and 14,408,336 in females, respectively. From 2010 to 2019, the frequency of cirrhosis deaths increased by 9% in males and 12% in females. Incidence ASRs remained stable in males but increased in females, while death ASRs declined in both. Death ASRs for both sexes declined in all regions, except in the Americas where they remained stable. In 2019, alcohol was the leading cause of cirrhosis deaths in males, and hepatitis C in females. Death ASRs declined for all etiologies in both sexes, except in nonalcoholic steatohepatitis (NASH). The ratio of female-to-male incidence ASRs in 2019 was lowest in alcohol(0.5), and highest in NASH(1.3), while the ratio of female-to-male death ASRs was lowest in alcohol(0.3) and highest in NASH(0.8). Conclusion: The global burden of cirrhosis is higher in males. However, incidence and death ASRs from NASH cirrhosis in females are comparable to that of males.
Immunomodulatory Role of Mesenchymal Stem Cells in Liver Transplantation: Status and Prospects
Authors: Li Haitao , Yu Saihua , Chen Lihong , Liu Hongzhi , Shen Conglong
Published: October 2023

Background: Liver transplantation (LT) is the only effective therapy for end-stage liver diseases, but some patients usually present with serious infection and immune rejection. Those with immune rejection require long-term administration of immunosuppressants, leading to serious adverse effects. Mesenchymal stem cells (MSCs) have various advantages in immune regulation and are promising drugs most likely to replace immunosuppressants. Summary: This study summarized the application of MSCs monotherapy, its combination with immunosuppressants, MSCs genetic modification, and MSCs derivative therapy (cell-free therapy) in LT. This may deepen the understanding of immunomodulatory role of MSCs and promote the application of MSCs in immune rejection treatment after LT. Key Messages: MSCs could attenuate ischemia-reperfusion injury and immune rejection. There is no consensus on the effects of types and concentrations of immunosuppressants on MSCs. Although genetically modified MSCs have contributed to better outcomes to some extent, the best modification is still unclear. Besides, multiple clinical complications developed frequently after LT. Unfortunately, there are still few studies on the polygenic modification of MSCs for the simultaneous treatment of these complications. Therefore, more studies should be performed to investigate the potency of multi-gene modified MSCs in treating complications after LT. Additionally, MSC derivatives mainly include exosomes, extracellular vesicles, and conditioned medium. Despite therapeutic effects, these three therapies still have some limitations such as heterogeneity between generations and that they cannot be quantified accurately.
Cladribine, Cytarabine, and Etoposide-Based Regimens Are Safe and Tolerable In Relapsed and Refractory Acute Myeloid Leukemia Patients
Authors: Tinajero Jose , Ngo Dat , Salhotra Amandeep , Koller Paul
Published: October 2023

Intensive treatment regimens for relapsed/refractory (R/R) acute myeloid leukemia (AML) generally include an anthracycline, cytarabine, with or without a purine analog. In patients who cannot tolerate an anthracycline due to comorbidities, one may consider using etoposide. Given the ongoing fludarabine shortage, it has prompted the switch to other purine analogs, such as cladribine, in combination with cytarabine and etoposide in patients who may be eligible for intensive chemotherapy but not able to tolerate an anthracycline due to comorbidities or cardiotoxicity risks. Here, we present 4 patients who received a cladribine, cytarabine, and etoposide (CCE) based regimen for R/R AML. There were no significant therapy-related adverse events, dose holds, or delays. Two out of 3 evaluable patients were successfully bridged to allogeneic transplant, and one is pending another cycle of chemotherapy as a bridge to transplant. The CCE regimen offers a potential option for patients with R/R AML in need of an anthracycline-free salvage regimen during a fludarabine shortage.
Clinicoradiological Factors Predicting Lymph Node Metastasis in Patients with Nonfunctioning Pancreatic Neuroendocrine Neoplasms: A Systematic Review and Meta-Analysis
Authors: Jeong Boryeong , Heo Subin , Kim Dong Wook , Kim Kyung Won
Published: October 2023

Introduction: Lymph node metastasis of nonfunctioning pancreatic neuroendocrine neoplasms (pNENs) potentially leads to poor survival. Given the contradictory results in the literature regarding factors associated with lymph node metastasis of nonfunctioning pNENs, we conducted a systematic review and meta-analysis to determine the preoperative predictors of lymph node metastasis. Methods: Original studies reporting factors associated with lymph node metastasis in patients with nonfunctioning pNENs were identified in PubMed, EMBASE, and Cochrane Library databases, and data from eligible studies were analyzed using random-effects meta-analysis to obtain pooled estimates of odds ratios (ORs) and their 95% confidence intervals (CIs). Results: Eleven studies were included. Tumor size (>2 cm or >2.5 cm; OR, 5.80 [95% CI, 4.07–8.25]) and pancreatic head location (OR, 1.75 [95% CI, 1.05–2.94]) were significant preoperative predictors of lymph node metastasis. Old age (OR, 1.07 [95% CI, 0.68–1.68]) and male sex (OR, 1.12 [95% CI, 0.74–1.70]) were not significantly associated with lymph node metastasis. Conclusions: A large tumor size and pancreatic head location can be useful for planning optimal treatment in patients with nonfunctioning pNENs.
Association between the High-Sensitivity C-Reactive Protein/Albumin Ratio and New-Onset Chronic Kidney Disease in Chinese Individuals
Authors: Zhang Zihao , Liu Peipei , Yang Ling , Zhao Naihui , Ou Wenli , Zhang Xiaofu , Zhang Yinggen , Chen Shuohua , Wu Shouling , Yang Xiuhong
Published: October 2023

Introduction: Inflammation is associated with development of chronic kidney disease (CKD). However, the association of the high-sensitivity C-reactive protein (hs-CRP)/albumin ratio (CAR) on the risk of CKD in the general population is unknown. This study explored the relationship between the CAR and CKD and the ability of this ratio to predict CKD in the general population. Methods: A total of 47,472 participants in the Kailuan study who met the inclusion criteria in 2010 were selected and grouped using the quartile method. A Cox proportional hazard regression model was used to evaluate the association of the CAR on the risk of CKD. The C-index, net reclassification index (NRI), and overall identification index (IDI) were calculated to evaluate the ability of the CAR to predict CKD. Results: During a follow-up of 378,383 person-years, CKD events occurred in 6,249 study participants (13.16%). The Cox proportional hazard regression model showed that the hazard ratio (95% confidence interval) for CKD events was 1.18 (1.10–1.28) in the Q3 group and 1.42 (1.32–1.53) in the Q4 group when compared with the Q1 group. Compared with the single index, the C-index, NRI, and IDI values were significantly improved when the CAR was added for prediction of risk of CKD. Conclusions: A higher CAR was an independent risk factor for CKD. The ability of the CAR to predict CKD was better than that of hs-CRP or albumin. The CAR provides an important reference index for predicting the risk of CKD.
Interaction between Hexametaphosphate, Other Active Ingredients of Toothpastes, and Erosion-Abrasion in Enamel in vitro
Authors: Luka Benedikt , Duerrschnabel Andrea , Neumaier Sina , Schlueter Nadine , Vach Kirstin
Published: October 2023

Sodium hexametaphosphate (HMP) as toothpaste additive is claimed to reduce erosive tooth wear and to stabilize stannous ions. However, little is known about the impact of concentration and its interactions with fluoride (F) or stannous+fluoride ions (F/Sn) on enamel erosion and erosion-abrasion. In a 10 day cyclic in vitro erosion-abrasion model, 320 flat human enamel specimens were divided into ten groups (n = 32 each) and daily subjected to six erosive challenges (0.5% citric acid, 2 min) and two toothpaste suspension applications (2 min, 1:3 F-free toothpaste:mineral-salt solution, 0.23% sodium gluconate). Half of specimens per group were additionally brushed twice/day (200 g, 15 s) during suspension immersion. Nine suspensions contained HMP (0.25%, 1.75%, 3.25%), either on its own or combined with F (373 ppm F−) or F/Sn (800 ppm Sn2+, 373 ppm F−). One suspension contained sodium gluconate only (NegContr). After 10 days, specimens’ surfaces were analysed with profilometry, energy dispersive X-ray spectroscopy, and scanning electron microscopy. Tissue loss (µm, mean ± standard deviation) in NegContr was 10.9 ± 2.0 (erosion), 22.2 ± 1.6 (erosion-abrasion). Under erosive conditions, only 0.25% HMP in any combination and 1.75% HMP with F/Sn reduced loss significantly (−28% to −54%); 3.25% HMP without F and F/Sn increased loss significantly (+35%). With additional abrasion, no suspension reduced loss significantly compared to NegContr, instead, in groups without F and F/Sn or with 3.25% HMP loss was increased (+15% to +30%). Conclusively, at higher concentrations, HMP increased erosive tooth wear and seemed to reduce anti-erosive effects of fluoride and stannous ions.
C-Terminal PEGylation Improves SAAP-148 Peptide’s Immunomodulatory Activities
Authors: van Gent Miriam E. , Schonkeren-Ravensbergen Bep , Achkif Asma , Beentjes Daan , Dolezal Natasja , van Meijgaarden Krista E. , Drijfhout Jan Wouter , Nibbering Peter H.
Published: October 2023

Synthetic antibacterial and anti-biofilm peptide (SAAP)-148 was developed to combat bacterial infections not effectively treatable with current antibiotics. SAAP-148 is highly effective against antimicrobial-resistant bacteria without inducing resistance; however, challenges for further development of SAAP-148 include its cytotoxicity and short circulation half-life. To circumvent these drawbacks, a library of SAAP-148 linked to polyethylene glycol (PEG) groups of various lengths was synthesized and screened for in vitro antibacterial activity and hemolytic activity. Results indicated that PEGylated SAAP-148 variants combine antibacterial activities with reduced hemolysis compared to SAAP-148. Interestingly, proinflammatory immunomodulatory activities of SAAP-148 were enhanced upon C-terminal PEGylation, with SAAP-148-PEG27 showing the most effect. SAAP-148-PEG27 enhanced SAAP-148’s capacity to chemoattract human neutrophils and was able to more efficiently (re)direct M-CSF-induced monocyte-macrophage differentiation toward type 1 macrophages as opposed to SAAP-148. Furthermore, dendritic cells with a stronger mature expression profile were produced if monocytes were exposed to SAAP-148-PEG27 during monocyte-immature dendritic cell differentiation in comparison to SAAP-148. Parameters that influenced the immunomodulatory activities of the peptide-PEG conjugate include (i) the length of the PEG group, (ii) the position of PEG conjugation, and (iii) the peptide sequence. Together, these results indicate that SAAP-148-PEG27 is highly effective in redirecting monocyte-macrophage differentiation toward a proinflammatory phenotype and promoting monocyte-mature dendritic cell development. Therefore, SAAP-148-PEG27 may be a promising agent to modulate inadequate immune responses in case of tumors and chronically infected wounds.
The Shift from Individual to Organizational Health Literacy: Implications for Kidney Healthcare Leaders and Clinicians
Authors: Smith Graeme , Lui Siu-Fai , Kalantar-Zadeh Kamyar , Bonner Ann
Published: October 2023

Background: As a social determinant of health, health literacy has a vital role in the management of chronic disease management, including chronic kidney disease (CKD). Summary: To be able to manage their condition, patients with CKD need to be able to assess, comprehend, appraise, and utilize complex health-related information. Those patients are much more likely to understand and use health information appropriately, if it addresses their personal needs related to language, culture, educational background, and socioeconomic status. One aspect of health literacy, organizational health literacy (OHL), relates to the degree with which health organizations justifiably empower patients to locate, understand, and utilize health information and facilities to inform their decision-making and health behaviours. With increasing evidence-based about OHL as a way to improve healthcare, it is a new concept for kidney clinicians. Key Messages: As producers of health-related information, the multidisciplinary kidney healthcare team have a responsibility to meet the needs of those in their care, as such, priority should be given to implementation of OHL initiatives. Through enhancing the clarity of information, OHL initiatives may provide a game plan for person-centred care for those with CKD.
The Worsening Renal Perfusion Index Predicts the Prognoses of Heart Failure Patients Treated with Sacubitril/Valsartan
Authors: Hsu Wan-Tseng , Cheng Yu-Yang , Yang Tsun-Yu , Chang Chao-Kai , Lin Yi-Hsuan , Lee Chii-Ming , Huang Tao-Min
Published: October 2023

Introduction: Sacubitril/valsartan (S/V) reduces all-cause mortality in patients with heart failure with reduced ejection fraction (HFrEF), but it may decline their estimated glomerular filtration rates (eGFR). In addition to eGFR, this clinical study aimed to develop a blood urea nitrogen (BUN)-based index to evaluate the status of renal perfusion and then identify predictors of all-cause death or heart transplant in patients with HFrEF receiving S/V. Methods: From the recruited 291 patients with HFrEF who were prescribed S/V from March 2017 to March 2019, we collected demographic, drug history, laboratory, echocardiographic, and clinical data from 1 year before S/V initiation until December 2020. Regression analysis was conducted by fitting Cox’s models with time-dependent covariates for the survival time and applying the modern stepwise variable selection procedure. The smoothing spline method was used to detect nonlinearity in effect and yield optimal cut-off values for continuous covariates. Results: In the Cox’s model, decreased hemoglobin level, decreased mean left ventricular ejection fraction, declined daily dose of S/V, decreased eGFR within 3 months, and increased BUN levels within 1 month and 9 months over time were significantly associated with an increased risk of all-cause death or heart transplant in patients with HFrEF. Conclusions: Adequate maintenance of renal perfusion is crucial for the continuous use of S/V and to avoid worsening renal function in patients with HFrEF. We defined the maximum increase in BUN levels within a specified period as the Worsening Renal Perfusion Index (WRPSV Index) to capture the prognostic effect of renal hypoperfusion in patients with HFrEF.
Preterm Birth by Cesarean Section: The Gut-Brain Axis, a Key Regulator of Brain Development
Authors: Morin Cécile , Bokobza Cindy , Fleiss Bobbi , Hill-Yardin Elisa L. , Van Steenwinckel Juliette , Gressens Pierre
Published: October 2023

Understanding the long-term functional implications of gut microbial communities during the perinatal period is a bourgeoning area of research. Numerous studies have revealed the existence of a “gut-brain axis” and the impact of an alteration of gut microbiota composition in brain diseases. Recent research has highlighted how gut microbiota could affect brain development and behavior. Many factors in early life such as the mode of delivery or preterm birth could lead to disturbance in the assembly and maturation of gut microbiota. Notably, global rates of cesarean sections (C-sections) have increased in recent decades and remain important when considering premature delivery. Both preterm birth and C-sections are associated with an increased risk of neurodevelopmental disorders such as autism spectrum disorders, with neuroinflammation a major risk factor. In this review, we explore links between preterm birth by C-sections, gut microbiota alteration, and neuroinflammation. We also highlight C-sections as a risk factor for developmental disorders due to alterations in the microbiome.
Immunohistochemistry, Molecular Biology, and Clinical Scoring for the Detection of Muir-Torre Syndrome in Cutaneous Sebaceous Tumors: Which Strategy?
Authors: Sinson Hélinie , Karayan-Tapon Lucie , Godet Julie , Rivet Pierre , Alleyrat Camille , Battistella Maxime , Pierron Hugo , Morel Franck , Lecron Jean-Claude , Favot Laure , Frouin Eric
Published: October 2023

Background: Sebaceous neoplasms (SNs) always raise the possibility of an association with Muir-Torre syndrome (MTS) and permit to screen internal malignancies, colorectal and endometrial carcinomas, before they become symptomatic. Immunohistochemistry (IHC), molecular biology, and clinical examination are different approaches for detection of MTS. We conducted a retrospective analysis of non-selected SNs in order to determine the optimal tools to implement for MTS screening. Methods: Deficient MMR phenotype (dMMR) was determined by either IHC using antibodies directed to four mismatch repair (MMR) antigens on tissue microarray or molecular biology using pentaplex PCR. The Mayo Clinic risk score of MTS was calculated from medical records. Sensibility and specificity of each test for the detection of MTS were determined. Results: We included 107 patients, 8 with multiple SNs, for a total of 123 SNs (43 sebaceous adenomas, 19 sebaceomas, and 61 sebaceous carcinomas (SC)). Loss of at least one MMR protein was observed in 70.7% of tumors, while 48% had a microsatellite instable phenotype. Concordance between both techniques was 92.9%, with a 0.85 Cohen’s kappa coefficient. Nineteen patients (20.2%) had a ≥2 points Mayo Clinic risk score, one having a pMMR SC. Among the 13 patients with confirmed MTS, 2 had a low Mayo Clinic risk score (1 point). IHC had the highest sensitivity for MTS screening (100%) with a specificity of 34.1%, while a >2-point Mayo Clinic risk score had a lower sensitivity (92%) but a higher specificity (89%). Conclusion: To detect MTS in SN patients, the first-line Mayo Clinic risk score followed by IHC appears to be the most accurate strategy with lower cost for society. This strategy should be adapted to the medico-economic resources of each country.
The Safety and Efficacy of Emergency Stenting during Bridging Therapy: A Single-Center Retrospective Study
Authors: Chen Zhengwen , Ying Yaoyu , Lu Xiaojian , Sun Shuqing , Huang Qingfeng , Shao Junjie , Li Peicheng , Chen Long
Published: October 2023

Introduction: The objective of this study was to investigate the safety and efficacy of emergency stenting for patients with ischemic stroke treated with bridging therapy. Methods: Patients with onset of stroke who underwent bridging therapy were included in the two groups with emergency stenting (ESG) and without stenting (NSG). To avoid the bias due to confounding variables, subjects were further assigned in two groups using 1:1 propensity score matching (PSM). The safety outcomes include the incidence of intracranial hemorrhage (ICH), parenchymal hemorrhage type 2 (PH2), symptomatic intracranial hemorrhage (sICH), fatal hemorrhage, and mortality. The efficacy outcomes include successful recanalization, 3-month favorable outcome (modified Rankin Scale [mRS]: 0–2). Results: 175 patients treated with bridging therapy were included in this study, with 52 patients in the ES group and 123 patients in the groups without ES, and with 30 patients in each group after PSM. No significant differences in the incidences of ICH, PH2, sICH, fatal hemorrhage, and mortality were found between the two groups with ES and without ES before and after PSM (p > 0.05 for all groups). The analysis without PSM showed that the group with ES had a higher rate of successful recanalization (98.1 vs. 88.6%, p = 0.041) than the group without ES, but no significant difference was seen (96.6 vs. 93.3%, p = 0.554) between the two groups after PSM. There was no difference in favorable outcome between the two groups before and after matching as well (p > 0.05). Conclusions: It is safe and effective for patients with onset of ischemic stroke to receive emergency stenting during bridging therapy, without increasing the risk of hemorrhagic transformation and mortality.
The Skin Barrier and Moisturization: Function, Disruption, and Mechanisms of Repair
Authors: Rajkumar Jeffrey , Chandan Neha , Lio Peter , Shi Vivian
Published: October 2023

Background: The anatomic layers of the skin are well-defined, and a functional model of the skin barrier has recently been described. Barrier disruption plays a key role in several skin conditions, and moisturization is recommended as an initial treatment in conditions such as atopic dermatitis. This review aimed to analyze the skin barrier in the context of the function model, with a focus on the mechanisms by which moisturizers support each of the functional layers of the skin barrier to promote homeostasis and repair. Summary: The skin barrier is comprised of four interdependent layers – physical, chemical, microbiologic, and immunologic – which maintain barrier structure and function. Moisturizers target disruption affecting each of these four layers through several mechanisms and were shown to improve transepidermal water loss in several studies. Occlusives, humectants, and emollients occlude the surface of the stratum corneum (SC), draw water from the dermis into the epidermis, and assimilate into the SC, respectively, in order to strengthen the physical skin barrier. Acidic moisturizers bolster the chemical skin barrier by supporting optimal enzymatic function, increasing ceramide production, and facilitating ideal conditions for commensal microorganisms. Regular moisturization may strengthen the immunologic skin barrier by reducing permeability and subsequent allergen penetration and sensitization. Key Messages: The physical, chemical, microbiologic, and immunologic layers of the skin barrier are each uniquely impacted in states of skin barrier disruption. Moisturizers target each of the layers of the skin barrier to maintain homeostasis and facilitate repair.
Biomarker Phenotypes in Heart Failure with Preserved Ejection Fraction Using Hierarchical Clustering: A Pilot Study
Authors: Mitic Valentina , Stojanovic Dijana , Deljanin Ilic Marina , Petrovic Dejan , Ignjatovic Aleksandra , Milenkovic Jelena
Published: October 2023

Objectives: We hypothesized the existence of distinct phenotype-based groups within the very heterogeneous population of patients of heart failure with preserved ejection fraction (HFpEF) and using an unsupervised hierarchical clustering applied to plasma concentration of various biomarkers. We sought to characterize them as “biomarker phenotypes” and to conclude differences in their overall characteristics. Subjects and Methods: A cross-sectional study was conducted on 75 patients with HFpEF. An agglomerative hierarchical clustering was performed using the concentrations of cardiac remodeling biomarkers, BNP, and cystatin C. Results: According to the obtained heat map of this analysis, we concluded two distinctive biomarker phenotypes within the HFpEF. The “remodeled phenotype” presented with significantly higher concentrations of cardiac remodeling biomarkers and cystatin C (p < 0.001), higher prevalence of myocardial infarction (p = 0.047), STEMI (p = 0.045), atrial fibrillation (p = 0.047), and anemia: lower erythrocytes count (p = 0.037), hemoglobin concentration (p = 0.034), and hematocrit (p = 0.046), compared to “non-remodeled phenotype.” Echocardiography showed that patients within “remodeled phenotype” had significantly increased parameters of left ventricular remodeling: left ventricular mass index (p < 0.001), left ventricular mass (p = 0.001), diameters of the interventricular septum (p = 0.027), posterior wall (p = 0.003), and function alterations, intermediate pauses duration >2.0 s (p < 0.006). Conclusion: Unsupervised hierarchical clustering applied to plasma concentration of various biomarkers in patients with HFpEF enables the identification of two biomarker phenotypes, significantly different in clinical characteristics and cardiac structure and function, whereas one phenotype particularly relates to patients with reduced ejection fraction. These findings imply distinct underlying pathophysiology within a unique cohort of HFpEF.
Clinical Utility of Inflammatory and Nutritious Index as Therapeutic Prediction of Nivolumab plus Ipilimumab in Advanced Non-Small Cell Lung Cancer
Authors: Yamaguchi Ou , Kaira Kyoichi , Imai Hisao , Mouri Atsuto , Shiono Ayako , Miura Yu , Hashimoto Kosuke , Kobayashi Kunihiko , Kagamu Hiroshi
Published: October 2023

Introduction: Biomarkers for predicting the outcome of ipilimumab plus nivolumab (Nivo-Ipi) treatment in cancer patients have not been identified. Herein, we investigated the prognostic significance of inflammatory and nutritional markers in patients with advanced non-small cell lung cancer (NSCLC) receiving Nivo-Ipi. Methods: Our study retrospectively analyzed 101 patients with advanced NSCLC who received Nivo-Ipi at a single institution. Inflammatory and nutritional indices were correlated with patient outcomes and included the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), systemic immune-inflammation index (SII), prognostic nutritional index (PNI), advanced lung cancer inflammation index (ALI), and Glasgow prognostic score (GPS). Results: The NLR significantly correlated with the PLR, SII, PNI, ALI, and GPS. Regarding therapeutic efficacy, the NLR, SII, and PNI predicted a partial response, and all indices predicted progressive disease. In subgroup analyses, the SII, PNI, and ALI predicted the outcome of patients with adenocarcinoma, whereas only the PNI predicted the outcome of patients with non-adenocarcinoma. The PNI and SII were the most useful indices in patients with a programmed death ligand-1 expression level of <1% and ≥1%, respectively. Conclusion: The NLR, PLR, SII, PNI, ALI, and GPS were significantly associated with the outcome of Nivo-Ipi treatment in patients with NSCLC. The PNI was the most suitable marker regardless of histological type. The SII and PNI were the most promising markers for patients with and without PD-L1 expression, respectively.
Ocular Surface, Intraocular Pressure, and Lens Condition in Bronchodilator and Steroid-Treated Patients with Chronic Pulmonary Disease
Authors: Aydın Güçlü Özge , Sariyeva Ismayilov Ayna
Published: October 2023

Objectives: The aim of this study was to investigate the ocular surface, intraocular pressure, and lens condition in bronchodilator- and steroid-treated chronic pulmonary disease patients. Methods: In this cross-sectional clinical study, 101 patients with chronic pulmonary disease were treated with an inhaler and/or nebulized therapy for bronchodilatation. The patients were evaluated in 2 groups namely chronic obstructive pulmonary disease and asthma. We investigated the effects of patient demographic characteristics, smoking, and medications on the presence of dry eye disease (DED), intraocular pressure, and cataract. Results: Patients had a mean age of 66.4 ± 11.9 years, and 46.5% (n = 47) were female. A unit increase in the length of inhaled corticosteroids (ICS) and long-acting β-agonists (LABA) combination use was associated with a 1.02-fold increase in cataract risk (OR: 1.02, CI: 1.01–1.04, p = 0.016), and current smokers had 10.8 times as many cataracts (OR: 10.79, CI: 1.70–68.30, p = 0.011). Patients who used a nebulized corticosteroid had a 9.15 times higher risk of developing dry eyes than those who did not (OR: 9.15, CI: 2.34–35.75, p = 0.001). In patients using ICS-LABA, in comparison to formoterol beclomethasone, salmeterol fluticasone was found to increase the risk 7.49-fold for DED (OR: 7.49, CI: 1.48–35.75, p = 0.015). Conclusions: Nebulizer delivery of steroids is associated with dry eyes and cataracts. Smoking, aging, and long-term inhaled steroid use have all been linked to an increased risk of cataracts. Longitudinal and larger sample size studies are needed to explore cause-effect relationships.
Predictive Factors of Early 18F-Fluorodeoxyglucose-Positron Emission Tomography Response to [131I] Metaiodobenzylguanidine Treatment for Unresectable or Metastatic Pheochromocytomas and Paragangliomas
Authors: Takenaka Junki , Watanabe Shiro , Abe Takashige , Tsuchikawa Takahiro , Takeuchi Satoshi , Hirata Kenji , Kimura Rina , Wakabayashi Naoto , Shinohara Nobuo , Kudo Kohsuke
Published: October 2023

Introduction: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours that produce catecholamines. [131I] metaiodobenzylguanidine (MIBG)-avid unresectable or metastatic PPGLs are treated with [131I] MIBG radionuclide therapy. A high metabolic tumour volume (MTV) and total lesion glycolysis (TLG) can be poor prognostic factors. Therefore, we evaluated the metabolic responses to [131I] MIBG therapy with respect to other clinical factors. Methods: A retrospective study was performed on a series of 20 patients who underwent FDG-PET before and after [131I] MIBG therapy. We administered a single dose comprising 5.5 GBq of [131I] MIBG (usually three times; for some cases, the number was increased or decreased considering treatment efficacy and side effects). Semi-quantitative parameters (SUVmax, MTV, and TLG) were calculated using the liver SUV (mean + 3 × standard deviation) as a threshold on Metavol software. The semi-quantitative FDG-PET parameters for determining response were complete response (CR), partial remission (PR), stable disease (SD), and progressive disease (PD). We divided our study participants into the PD and non-PD groups (i.e., SD + PR + CR) and compared the overall survival (OS) between the two groups. Subsequently, we evaluated the relationships between metabolic response and age, sex, tumour type, metastatic site, chemotherapy or external radiation history, and 24-h urine catecholamine levels by univariate logistic regression analyses. Results: Both MTV-based and TLG-based criteria for PD versus non-PD were significant prognostic factors (p = 0.014). However, treatment response as evaluated based on the SUVmax was not a significant predictor. Higher urinary dopamine levels were associated with poor metabolic response as assessed by MTV and TLG (OR 1.002, p = 0.029). The other clinical parameters were non-significant. Conclusion: Poor metabolic response (measured with MTV and TLG) to [131I] MIBG therapy in unresectable or metastatic PPGLs was related to shorter OS. The poor metabolic response can be predicted using the urinary dopamine level.