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Abstract: Millimeter waves (MMW) are pervasive in society; however, studies on the biological effects of MMW exposure are usually performed in laboratory settings not reflecting global environmental diversity. We investigated the effects of a 6-min exposure to 60 GHz MMW (wavelength, 5.0 mm) at incident power densities of 200 and 300 mW cm-2 in eyes (exposed right eyes vs. unexposed left eyes) under various ambient temperature/relative humidity environments (24 °C/50%, 45 °C/20%, and 45 °C/80%) using an in vivo rabbit model. Correlations were examined with adverse ocular events, including corneal epithelial damage (assessed using fluorescein staining), corneal opacity (evaluated by slit-lamp microscopy), and corneal thickness (measured via optical coherence tomography). Our findings indicate that higher temperatures and humidity tend to exacerbate MMW-induced ocular damage, albeit not significantly in the present study. Further research with a larger sample size is warranted. Incident power density emerged as a factor that was directly linked to the ocular damage threshold. High ambient temperature and humidity tended to exacerbate ocular damage from MMW exposure, although the effect was secondary. Ocular damage in a high-temperature (45 °C), high-humidity (80%) environment was increased to the same extent as that by incident power density increased by approximately 100 mW cm-2 in an ocular damage model in a standard environment (24 °C, 50%). In a high-humidity environment, the internal ocular tissue temperature increased at a high ambient temperature of 45 °C, suggesting that the eyeball may respond differently compared to other tissues., (Copyright © 2024 Health Physics Society.)

Background : In patients with chronic kidney disease (CKD), Fibroblast Growth Factor 23 (FGF23) is markedly increased and has been proposed to interact with systemic inflammation. Methods : In this cross-sectional study, we evaluated the correlations of intact FGF23, c-terminal FGF23, and the FGF23 ratio (c-terminal to intact) with some inflammatory cytokines in 111 elderly patients with advanced CKD not yet in dialysis. Results : Estimated glomerular filtration rate (eGFR) was inversely correlated with intact FGF23 and c-terminal FGF23, as well as with interleukin 6 (IL-6), tumor necrosis factor alpha (TNFα), and monocyte chemoattractant protein-1 (MCP-1). Intact FGF23 levels were directly correlated with IL-6 (r = 0.403; p < 0.001) and TNFα (r = 0.401; p < 0.001) while c-terminal FGF23 was directly correlated with MCP-1 (r = 0.264; p = 0.005). The FGF23 ratio was, instead, inversely correlated with IL-6 (r = -0.326; p < 0.001). Multivariate analysis revealed that intact FGF23 was directly associated with TNFα [B = 0.012 (95% CI 0.006, 0.019); p = 0.003] and c-terminal FGF23 was directly associated with MCP-1 [B = 0.001 (95% CI 0.000, 0.002); p = 0.038], while the FGF23 ratio was inversely correlated with IL-6 [B = -0.028 (95% CI -0.047, -0.010); p = 0.002]. Conclusions : Our data demonstrate that, in CKD patients, intact FGF23 and the metabolites deriving from its proteolytic cleavage are differently associated with some inflammatory pathways. In particular, intact FGF23 is mainly associated with IL-6 and TNFα, c-terminal FGF23 with MCP-1, and the FGF23 ratio with IL6.

Kidney transplant (KT) candidates with donor-specific antibodies (DSA) exhibit exceedingly high antibody-mediated rejection (ABMR) and allograft loss rates. Currently, treatment of ABMR remains an unmet clinical need. We report the use of the anti-C5 eculizumab and the type-2 anti-CD20 obinutuzumab in two patients with early ABMR. Eculizumab (900 mg IV) led to complete inhibition of the terminal complement cascade (unremarkable AP50 and CH50 activity) and prompt stoppage of complement-dependent antibody-mediated allograft injury (clearance of intra-graft C4d and C5b-9 deposition). Despite complement inhibition, obinutuzumab (1000 mg IV) determined full and long-lasting peripheral B-cell depletion, with significant reduction in all DSA. Graft function improved, remaining stable up to three years of follow-up. No signs of active ABMR and rebound DSA were detected. Obinutuzumab B-cell depletion and inhibition of DSA production were not affected by complement blockage. Further studies are needed to confirm the potential benefit of obinutuzumab in association with complement inhibitors., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflicts of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Glucagon-like peptide-1 receptor (GLP-1R) is a key regulator of glucose metabolism known to be expressed by pancreatic β cells. We herein investigated the role of GLP-1R on T lymphocytes during immune response. Our data showed that a subset of T lymphocytes expresses GLP-1R, which is upregulated during alloimmune response, similarly to PD-1. When mice received islet or cardiac allotransplantation, an expansion of GLP-1R pos T cells occurred in the spleen and was found to infiltrate the graft. Additional single-cell RNA sequencing (scRNA-seq) analysis conducted on GLP-1R pos and GLP-1R neg CD3 + T cells unveiled the existence of molecular and functional dissimilarities between both subpopulations, as the GLP-1R pos are mainly composed of exhausted CD8 T cells. GLP-1R acts as a T cell-negative costimulatory molecule, and GLP-1R signaling prolongs allograft survival, mitigates alloimmune response, and reduces T lymphocyte graft infiltration. Notably, GLP-1R antagonism triggered anti-tumor immunity when tested in a preclinical mouse model of colorectal cancer., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: The dysregulation of cell fate toward osteoprecursor cells associated with most GNAS -based disorders may lead to episodic de novo extraskeletal or ectopic bone formation in subcutaneous tissues. The bony lesion distribution suggests the involvement of abnormal differentiation of mesenchymal stem cells (MSCs) and/or more committed precursor cells. Data from transgenic mice support the concept that GNAS is a crucial factor in regulating lineage switching between osteoblasts (OBs) and adipocyte fates. The mosaic nature of heterotopic bone lesions suggests that GNAS genetic defects provide a sensitized background for ectopic osteodifferentiation, but the underlying molecular mechanism remains largely unknown., Methods: The effect of GNAS silencing in the presence and/or absence of osteoblastic stimuli was evaluated in the human L88/5 MSC line during osteodifferentiation. A comparison of the data obtained with data coming from a bony lesion from a GNAS -mutated patient was also provided., Results: Our study adds some dowels to the current fragmented notions about the role of GNAS during osteoblastic differentiation, such as the premature transition of immature OBs into osteocytes and the characterization of the differences in the deposed bone matrix., Conclusion: We demonstrated that our cell model partially replicates the in vivo behavior results, resulting in an applicable human model to elucidate the pathophysiology of ectopic bone formation in GNAS -based disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Elli, Mattinzoli, Ikehata, Bagnaresi, Maffini, Del Sindaco, Pagnano, Lucca, Messa, Arosio, Castellano, Alfieri and Mantovani.)

The glomerular filtration barrier (GFB), composed of endothelial cells, glomerular basement membrane, and podocytes, is a unique structure for filtering blood while detaining plasma proteins according to size and charge selectivity. Structurally, the fenestrated endothelial cells, which align the capillary loops, are in close proximity to mesangial cells. Podocytes are connected by specialized intercellular junctions known as slit diaphragms and are separated from the endothelial compartment by the glomerular basement membrane. Podocyte-endothelial cell communication or crosstalk is required for the development and maintenance of an efficient filtration process in physiological conditions. In pathological situations, communication also has an essential role in promoting or delaying disease progression. Podocytes and endothelial cells can secrete signaling molecules, which act as crosstalk effectors and, through binding to their target receptors, can trigger bidirectional paracrine or autocrine signal transduction. Moreover, the emerging evidence of extracellular vesicles derived from various cell types engaging in cell communication has also been reported. In this review, we summarize the principal pathways involved in the development and maintenance of the GFB and the progression of kidney disease, particularly in kidney transplantation.

During chronic kidney disease (CKD) progression, an increase in fibroblast growth factor (FGF23) is present. In stage 5, a positive correlation between FGF23 and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) emerges. Hypothesizing that the rising positive correlation between monocyte chemoattractant protein 1 (MCP1) and n-6 in stage 4 could be the cause, we previously explored FGF23 and MCP1's roles in dyslipidemia and cardiovascular risk in CKD. In the present paper, we retraced the study evaluating 40 kidney transplant patients (KTx), a cohort where several factors might modify the previous relationships found. An ELISA and gas chromatography assessed the MCP1, FGF23, and PUFA levels. Despite the FGF23 increase ( p < 0.0001), low MCP1 levels were found. A decrease in the n-6/n-3 ratio ( p = 0.042 CKD stage 4 vs. 5) lowered by the increase in both n-3 αlinolenic ( p = 0.012) and docosapentaenoic acid ( p = 0.049) was observed. A negative correlation between FGF23 and the n-6/n-3 ratio in CKD stage 4 (r 2 -0.3 p = 0.043) and none with MCP1 appeared. According to our findings, different mechanisms in the relationship between FGF23, PUFAs, and MCP1 in CKD and KTx patients might be present, which is possibly related to the immunosuppressive status of the last. Future research will further clarify our hypothesis.

Calf diarrhea adversely affects growth and sometimes results in mortality, leading to severe economic losses to the cattle industry. Antibiotics are useful in the treatment against bacterial diarrhea, but not against viral, protozoan, and antibiotic-resistant bacterial diarrhea. Therefore, there are growing requirements for a novel control method for calf diarrhea. Probiotics have been considered promising candidates for preventive and supportive therapy for calf diarrhea for many years. A recent study has revealed that Lactiplantibacillus plantarum HOKKAIDO strain (Lp-HKD) reduces intestinal pathology and the severity of diarrhea in bovine rotavirus (BRV)-infected calves. Lp-HKD is known to enhance the function of human immune cells and expected to be used as probiotics for humans. Therefore, it is hypothesized that Lp-HKD modulates antiviral immune response in cattle and provide the clinical benefits in BRV-infected calves. However, the detailed mechanism of Lp-HKD-induced immunomodulation remains unknown. Thus, this study aimed to elucidate the immunomodulatory and antiviral effects of Lp-HKD in cattle. Cultivation assay of bovine peripheral blood mononuclear cells (PBMCs) showed that live and heat-killed Lp-HKD stimulates the production of interleukin-1β (IL-1β), IL-6, IL-10, and interferon-γ (IFN-γ) from PBMCs. Stimulation by heat-killed Lp-HKD yielded stronger cytokine production than stimulation by the live Lp-HKD. Additionally, CD14 + monocytes were identified as major producers of IL-1β, IL-6, and IL-10 under Lp-HKD stimulation; however, IFN-γ was mainly produced from immune cells other than CD14 + monocytes. Depletion of CD14 + monocytes from the PBMCs cultivation strongly decreased cytokine production induced by heat-killed Lp-HKD. The inhibition of toll-like receptor (TLR) 2/4 signaling decreased IL-1β and IL-6 production induced by live Lp-HKD and IL-1β, IL-6, and IFN-γ production induced by heat-killed Lp-HKD. Furthermore, live or heat-killed Lp-HKD also activated T cells and their production of IFN-γ and tumor necrosis factor-α. Then, culture supernatants of bovine PBMCs treated with heat-killed Lp-HKD demonstrated antiviral effects against BRV in vitro . In conclusion, this study demonstrated that Lp-HKD activates the functions of bovine immune cells via TLR2/4 signaling and exerts an antiviral effect against BRV through the induction of antiviral cytokines. Lp-HKD could be useful for the prevention and treatment of calf diarrhea through its immune activating effect., Competing Interests: KA, MH, and TK were employed by Snow Brand Seed Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ikehata, Konnai, Okagawa, Abe, Honma, Kitamura, Maekawa, Suzuki, Murata and Ohashi.)

Introduction: High serum levels of fibroblast growth factor 23 (FGF23) characterize chronic kidney disease (CKD) since its early stages and have been suggested to contribute to inflammation and cardiovascular disease. However, the mechanisms linking FGF23 with these pathological conditions remain still incompletely defined. The alpha-2-HS-glycoprotein (AHSG), a liver-produced anti-inflammatory cytokine, is highly modulated by inflammation itself, also through the TNFα/NFκB signaling pathway. In our previous study, we found that FGF23 modulates the production of AHSG in the liver in a bimodal way, with stimulation and inhibition at moderately and highly increased FGF23 concentrations, respectively., Methods: The present study, aiming to gain further insights into this bimodal behavior, was performed in hepatocyte human cells line (HepG2), using the following methods: immunochemistry, western blot, chromatin immunoprecipitation, fluorescence in situ hybridization (FISH), qRT-PCR, and gene SANGER sequencing., Results: We found that FGF23 at 400 pg/ml activates nuclear translocation of NFκB, possibly increasing AHSG transcription. At variance, at 1,200 pg/ml, FGF23 inactivates NFκB through the activation of two specific NFκB inhibitors (IκBα and NKIRAS2) and induces its detachment from the AHSG promoter, reducing AHSG transcription., Conclusion: These results add another piece to the puzzle of FGF23 involvement in the multifold interactions between CKD, inflammation, and cardiovascular disease, suggesting the involvement of the NFκB pathway, which might represent a potential therapeutic target in CKD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mattinzoli, Li, Castellano, Ikehata, Armelloni, Elli, Molinari, Tsugawa, Alfieri and Messa.)

Fibroblast growth factor 23 (FGF23) concentrations rise after the early stages of chronic kidney disease (CKD). FGF23 is involved in inflammatory reactions closely associated with an incremented risk of cardiovascular disease (CVD). There is growing evidence that omega-6 (n-6) and n-3 polyunsaturated fatty acids (PUFA) can modulate inflammation through several mediators producing an opposite effect on cardiovascular (CV) risks. In this study, we explore whether there is any correlation between PUFA, FGF23, and inflammation in CKD patients. We evaluated, cross-sectionally, 56 patients at different stages of CKD. Monocyte chemoattractant protein 1 (MCP1), and intact and c-terminal FGF23 (iFGF23, cFGF23) were quantified by the ELISA, and the fatty acids (FA) profile was analyzed by gas chromatography. Concurrently with an eGFR decrease (p < 0.01) and an MCP1 increase (p = 0.031), we observed an inversion of the correlation between FGF23 and the n-6/n-3 ratio. This last correlation was inversed in CKD stage 3 (r2 (−) 0.502 p = 0.029) and direct in stage 5 (r2 0.657 p = 0.020). The increase in MCP1 seems to trigger events in the inversion of the correlation between FGF23 and the n-6/n-3 PUFA ratio. This result strongly encourages future studies on basal pathways, on possible pharmacological interventions, and on managing kidney transplant patients treated with immunosuppressive therapy.

Objectives: Chorda tympani nerve (CTN) function may be damaged more by two-stage than by one-stage surgery for middle ear cholesteatoma. However, few studies have reported the relationship between two-stage cholesteatoma surgery and CTN function. This study aimed to investigate CTN function after two-stage surgery for cholesteatoma., Methods: In this prospective study, 35 patients underwent two-stage canal wall up tympanoplasty (CWUT). Perioperative CTN function was assessed using questionnaires and electrogustometry (EGM). Participants were categorized into minor, major, and section groups, based on the degree of CTN manipulation during surgery., Results: In the first-stage surgery, posterior tympanotomy with an intact canal wall reduced the degree of CTN manipulation. The incidence of taste disorder after the first-stage surgery was 71.4%. Postoperative taste disorder and the EGM threshold improved early in the minor manipulation group. In the second-stage surgery, no new CTN damage occurred, even if this surgery involved removal of residual cholesteatoma. The incidence of taste disorder after second-stage surgery was less than that after first-stage surgery, independent of CTN preservation. However, the recovery rate of the EGM threshold after second-stage surgery was significantly lower in the section group than in those with CTN preservation., Conclusion: CTN function, including symptoms and EGM threshold, can be preserved during two-stage cholesteatoma surgery if care is taken to preserve the CTN in both the first- and second-stage surgeries. A two-stage CWUT, ensuring an intact bony annulus, may be effective to facilitate CTN preservation., Level of Evidence: 2b., Competing Interests: The authors declare that they have no conflicts of interest to disclose., (© 2022 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC on behalf of The Triological Society.)

Irinotecan (CTP-11) is one of the standard therapies for colorectal cancer (CRC). CTP-11 is enzymatically converted to the hydrophobic 7-ethyl-10-hydroxycamptothecin (SN38), a one hundred-fold more active metabolite. Conjugation of hydrophobic anticancer drugs to nanomaterials is a strategy to improve their solubility, efficacy, and selectivity. Carbon dots (CDs) have garnered interest for their small sizes (<10 ​nm), low toxicity, high water solubility, and bright fluorescence. This paper describes the use of CDs to improve drug vehiculation, stability, and chemotherapeutic efficiency of SN38 through a direct intracellular uptake in CRC. The covalent conjugation of SN38 to CDs via a carbamate bond provides a CD-SN38 hybrid material for slow, sustained, and pH-responsive drug release. CD-SN38 successfully penetrates the CRC cells with a release in the nucleus affecting first the cell cycle and then the cytoskeleton. Moreover, CD-SN38 leads to a deregulation of the extracellular matrix (ECM), one of the major components of the cancer niche considered a possible target therapy for reducing the cancer progression. This work shows the combined therapeutic and imaging potential of CD-based hybrid materials for the treatment of CRC. Future efforts for targeted therapy of chronic diseases characterized by altered ECM deposition, such as chronic kidney disease and chronic allograft nephropathy in kidney transplant patients are envisaged., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Background: Gene methylation is deeply involved in epigenetics and affects both the development and maintenance of homeostasis and carcinogenesis. ALKBH4 is a member of the AlkB homolog (ALKBH) family that controls demethylation of DNA and RNA., Methods: This study enrolled 160 patients with non-small cell lung cancer (NSCLC) who underwent complete resection. The expression of ALKBH4 in cancer tissue was evaluated by immunohistochemistry. The correlation among the expression of ALKBH4, clinicopathological factors, and prognostic outcome was evaluated., Results: In the NSCLC clinical samples, the expression of ALKBH4 was identified not only in cell membranes but also in the cytoplasm of cancer cells. In 140 of 160 cases, ALKBH4 was more highly expressed in the cancerous tissue than in the surrounding normal tissue. The proportion of cancer cells expressing ALKBH4 was higher in adenocarcinoma than in other histological types. In addition, the expression intensity of ALKBH4 in each cancer cell was also stronger in adenocarcinoma than in squamous cell carcinoma. The expression of ALKBH4 was not associated with clinicopathological factors, except for histological type. In adenocarcinoma, the recurrence-free survival (RFS) and overall survival (OS) rates were significantly lower in the ALKBH4-positive group than in the ALKBH4-negative group (P=0.008, 0.031, respectively). A multivariate logistic regression analysis indicated that the ALKBH4 expression was an independent prognostic factor for RFS (P=0.003) and OS (P=0.013). The expression of ALKBH4 was observed in all four patients with adenocarcinoma in situ ., Conclusions: The ALKBH4 expression may be a useful predictor of the postoperative outcomes of lung adenocarcinoma (LUAD) patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-39/coif). The authors have no conflicts of interest to declare., (2022 Translational Cancer Research. All rights reserved.)

Mesenchymal stem cells (MSCs), which are isolated from adipose tissue (AD-MSCs), umbilical cord (UC-MSCs), or bone marrow, have therapeutic potential including anti-inflammatory and immunomodulatory activities. It was recently reported that MSCs are also effective as a therapeutic treatment for neuropathic pain, although the underlying mechanisms have yet to be resolved. Therefore, in this study, we investigated the effects of human AD- and UC-MSCs on neuropathic pain and its mechanisms using rat models of partial sciatic nerve ligation (PSNL). AD- or UC-MSCs were intravenously administered 4 days after PSNL. Antinociceptive effects were then evaluated using the von Frey and weight-bearing tests. We found that, 3-9 days after the administration of AD- or UC-MSCs to PSNL-exposed rats, both the mechanical threshold and differences in weight-bearing of the right and left hind paws were significantly improved. To reveal the potential underlying antinociceptive mechanisms of MSCs, the levels of activation transcription factor 3- and ionized calcium-binding adapter molecule 1-positive cells were measured by immunohistochemical analysis. AD- and UC-MSCs significantly decreased the levels of these proteins that were induced by PSNL in the dorsal root ganglia. Additionally, UC-MSC significantly improved the PSNL-induced decrease in the myelin basic protein level in the sciatic nerve, indicating that UC-MSC reversed demyelination of the sciatic nerve produced by PSNL. These data suggest that AD- and UC-MSCs may help in the recovery of neuropathic pain via the different regulation; AD-MSCs exhibited their effects via suppressed neuronal damage and anti-inflammatory actions, while UC-MSCs exhibited their effects via suppressed neuronal damage, anti-inflammatory actions and remyelination., Competing Interests: Yasuhito Uezono and Kanako Miyano received grant support from Biomimetics Sympathies Inc. Minori Ikehata, Yasuhiro Nose, Seiichi Yoshihara and Katsuyuki Oki are employees of Biomimetics Sympathies Inc. The other authors declare no competing interests.