Novel insights into regulators and functional modulators of adipogenesis.

Adipogenesis is a process that differentiates new adipocytes from precursor cells and is tightly regulated by several factors, including many transcription factors and various post-translational modifications. Recently, new roles of adipogenesis have been suggested in various diseases. However, the molecular mechanisms and functional modulation of these adipogenic genes remain poorly understood. This review summarizes the regulatory factors and modulators of adipogenesis and discusses future research directions to identify novel mechanisms regulating adipogenesis and the effects of adipogenic regulators in pathological conditions. The master adipogenic transcriptional factors PPARγ and C/EBPα were identified along with other crucial regulatory factors such as SREBP, Kroxs, STAT5, Wnt, FOXO1, SWI/SNF, KLFs, and PARPs. These transcriptional factors regulate adipogenesis through specific mechanisms, depending on the adipogenic stage. However, further studies related to the in vivo role of newly discovered adipogenic regulators and their function in various diseases are needed to develop new potent therapeutic strategies for metabolic diseases and cancer.

The Efficacy and Tolerability of Radiosurgery in Treating Benign Meningiomas: A Dose Comparison Study from a Single-Center Analysis.

This retrospective study aimed to evaluate the impact of radiation dose on the outcomes of stereotactic radiosurgery (SRS) for benign meningiomas and determine an optimal dosing strategy for balancing tumor control and treatment-related toxicity. Clinical data of 147 patients with 164 lesions treated between 2014 and 2022 were reviewed. Primary outcomes included progression-free survival (PFS), local control rate (LCR), and radiation-induced toxicity, with secondary outcomes focusing on LCR and radiation-induced peritumoral edema (PTE) in two dose groups (≥14 Gy and <14 Gy). The results revealed a median follow-up duration of 47 months, with 1-year, 2-year, and 5-year PFS rates of 99.3%, 96.7%, and 93.8%, respectively, and an overall LCR of 95.1%. Radiation-induced toxicity was observed in 24.5% of patients, primarily presenting mild symptoms. Notably, no significant difference in LCR was found between the two dose groups (p = 0.628), while Group 2 (<14 Gy) exhibited significantly lower PTE (p = 0.039). This study concludes that SRS with a radiation dose < 14 Gy demonstrates comparable tumor control with reduced toxicity, advocating consideration of such dosing to achieve a balance between therapeutic efficacy and safety.

Survival and Risk Factors for Mortality in Infants With Congenital Heart Disease in South Korea.

BACKGROUND/AIM: The survival of patients with congenital heart disease (CHD) has dramatically improved over recent decades. However, a disparity exists depending on the country and medical system. This study aimed to analyze the survival of infants with CHD until the age of 18 years using large-scale population data in South Korea and investigate the effect of neonatal conditions at birth. PATIENTS AND METHODS: We retrospectively extracted the Korean National Health Insurance Service claims data from January 2002 to December 2020. We included patients diagnosed with CHD who were less than one year of age. The follow-up duration was until their death or until they were censored before the age of 18 years. The CHD lesions were classified hierarchically (conotruncal, severe non-conotruncal, coarctation of the aorta, ventricular septal defect, atrial septal defect, and others). Several neonatal conditions were adopted as risk factors. RESULTS: Overall, 127,958 infants had been diagnosed with CHD and 2,275 died before the age of 18 years. The survival rate of infants with CHD during childhood was 97.9%. The highest childhood mortality rate was associated with non-conotruncal defects (19.7%), followed by conotruncal defects (10.2%). The significant risk factors for childhood mortality were complex CHD, pulmonary hypertension, birth asphyxia, small for gestational age, respiratory distress, pulmonary hemorrhage, bronchopulmonary dysplasia, and convulsions. CONCLUSION: The survival of infants with CHD has been favorable in South Korea. Several neonatal conditions are risk factors for childhood mortality. Individualized risk assessment and optimal treatment strategies may help improve their survival rate.

Comparison between Nivolumab and Regorafenib as Second-line Systemic Therapies after Sorafenib Failure in Patients with Hepatocellular Carcinoma.

PURPOSE: Nivolumab and regorafenib are second-line therapies for patients with advanced hepatocellular carcinoma (HCC). We aimed to compare the effectiveness of nivolumab and regorafenib. MATERIALS AND METHODS: We retrospectively reviewed patients with HCC treated with nivolumab or regorafenib after sorafenib failure. Progression-free survival (PFS) and overall survival (OS) were analyzed. An inverse probability of treatment weighting using the propensity score (PS) was performed to reduce treatment selection bias. RESULTS: Among the 189 patients recruited, 137 and 52 patients received regorafenib and nivolumab after sorafenib failure, respectively. Nivolumab users showed higher Child-Pugh B patients (42.3% vs. 24.1%) and shorter median sorafenib maintenance (2.2 months vs. 3.5 months) compared to regorafenib users. Nivolumab users showed shorter median OS (4.2 months vs. 7.4 months, p=0.045) than regorafenib users and similar median PFS (1.8 months vs. 2.7 months, p=0.070). However, the median overall and PFS did not differ between the two treatment groups after the 1:1 PS matching (log-rank p=0.810 and 0.810, respectively) and after the stabilized inverse probability of treatment weighting (log-rank p=0.445 and 0.878, respectively). In addition, covariate-adjusted Cox regression analyses showed that overall and PFS did not significantly differ between nivolumab and regorafenib users after 1:1 PS matching and stabilized inverse probability of treatment weighting (all p>0.05). CONCLUSION: Clinical outcomes of patients treated with nivolumab and regorafenib after sorafenib treatment failure did not differ significantly.

Double entrapment neuropathy of the ulnar nerve at the elbow and the wrist : double crush syndrome?

BACKGROUND: Double crush syndrome refers to a nerve in the proximal region being compressed, affecting its proximal segment. Instances of this syndrome involving ulnar and cubital canals during ulnar neuropathy are rare. Diagnosis solely through clinical examination is challenging. Although electromyography (EMG) and nerve conduction studies (NCS) can confirm neuropathy, they do not incorporate inching tests at the wrist, hindering diagnosis confirmation. We recently encountered eight cases of suspected double compression of ulnar nerve, reporting these cases along with a literature review. METHODS: The study included 5 males and 2 females, averaging 45.6 years old. Among them, 4 had trauma history, and preoperative McGowan stages varied. Ulnar neuropathy was confirmed in 7 cases at both cubital and ulnar canal locations. Surgery was performed for 4 cases, while conservative treatment continued for 3 cases. RESULTS: In 4 cases with wrist involvement, 2 showed ulnar nerve compression by a fibrous band, and 1 had nodular hyperplasia. Another case displayed ulnar nerve swelling with muscle covering. Among the 4 surgery cases, 2 improved from preoperative McGowan stage IIB to postoperative stage 0, with significant improvement in subjective satisfaction. The remaining 2 cases improved from stage IIB to IIA, respectively, with moderate improvement in subjective satisfaction. In the 3 cases receiving conservative treatment, satisfaction was significant in 1 case and moderate in 2 cases. Overall, there was improvement in hand function across all 7 cases. CONCLUSION: Typical outpatient examinations make it difficult to clearly differentiate the two sites, and EMG tests may not confirm diagnosis. Therefore, if a surgeon lacks suspicion of this condition, diagnosis becomes even more challenging. In cases with less than expected postoperative improvement in clinical symptoms of cubital tunnel syndrome, consideration of double crush syndrome is warranted. Additional tests and detailed EMG tests, including inching tests at the wrist, may be necessary. We aim to raise awareness double crush syndrome with ulnar nerve, reporting a total of 7 cases to support this concept.

MB2033, an anti-PD-L1 × IL-2 variant fusion protein, demonstrates robust anti-tumor efficacy with minimal peripheral toxicity.

Interleukin-2 (IL-2), a cytokine with pleiotropic immune effects, was the first approved cancer immunotherapy agent. However, IL-2 is associated with systemic toxicity due to binding with its ligand IL-2Rα, such as vascular leakage syndrome, limiting its clinical applications. Despite efforts to extend the half-life of IL-2 and abolish IL-2Rα interactions, the risk of toxicity remains unresolved. In this study, we developed the bispecific fusion protein MB2033, comprising a novel IL-2 variant (IL-2v) connected to anti-programmed death ligand 1 (PD-L1) via a silenced Fc domain. The IL-2v of MB2033 exhibits attenuated affinity for IL-2Rßγ without binding to IL-2Rα. The binding affinity of MB2033 for PD-L1 is greater than that for IL-2Rßγ, indicating its preferential targeting of PD-L1+ tumor cells to induce tumor-specific immune activation. Accordingly, MB2033 exhibited significantly reduced regulatory T cell activation, while inducing comparable CD8+ T cell activation to recombinant human IL-2 (rhIL-2). MB2033 induced lower immune cell expansion and reduced cytokine levels compared with rhIL-2 in human peripheral blood mononuclear cells, indicating a decreased risk of peripheral toxicity. MB2033 exhibited superior anti-tumor efficacy, including tumor growth inhibition and complete responses, compared with avelumab monotherapy in an MC38 syngeneic mouse model. In normal mice, MB2033 was safer than non-α IL-2v and tolerable up to 30 mg/kg. These preclinical results provide evidence of the dual advantages of MB2033 with an enhanced safety and potent clinical efficacy for cancer treatment.

In Vivo Evaluation of 68Ga-Labeled NOTA-EGFRvIII Aptamer in EGFRvIII-Positive Glioblastoma Xenografted Model.

EGFRvIII is expressed only in tumor cells and strongly in glioblastoma and is considered a promising target in cancer diagnosis and therapy. Aptamers are synthetic single-stranded oligonucleotides that bind to biochemical target molecules with high binding affinity and specificity. This study examined the potential of the 68Ga-NOTA-EGFRvIII aptamer as a nuclear imaging probe for visualizing EGFRvIII-expressing glioblastoma by positron emission tomography (PET). EGFRvIII aptamer was selected using the SELEX technology, and flow cytometry and fluorescence microscopy verified the high binding affinity to EGFRvIII positive U87MG vIII 4.12 glioma cells but not to EGFRvIII negative U87MG cells. The EGFRvIII aptamer was conjugated with a chelator (1,4,7-triazanonane-1,4,7-triyl)triacetic acid (NOTA) for 68Ga-labeling. The 68Ga-NOTA-EGFRvIII aptamer was prepared using the preconcentration-based labeling method with a high radiolabeling yield at room temperature. Ex vivo biodistribution analyses confirmed the significantly higher tumor uptake of the 68Ga-NOTA-EGFRvIII aptamer in EGFRvIII-expressing xenograft tumors than that in EGFRvIII negative tumors, confirming the specific tumor uptake of the 68Ga-NOTA-EGFRvIII aptamer in vivo. PET imaging studies revealed a high retention rate of the 68Ga-NOTA-EGFRvIII aptamer in U87MG vIII 4.12 tumors but only low uptake levels in U87-MG tumors, suggesting that the 68Ga-NOTA-EGFRvIII aptamer may be used as a PET imaging agent for EGFRvIII-expressing glioblastoma.

Biomarkers of Cellular Senescence and Aging: Current State-of-the-Art, Challenges and Future Perspectives.

Population aging has increased the global prevalence of aging-related diseases, including cancer, sarcopenia, neurological disease, arthritis, and heart disease. Understanding aging, a fundamental biological process, has led to breakthroughs in several fields. Cellular senescence, evinced by flattened cell bodies, vacuole formation, and cytoplasmic granules, ubiquitously plays crucial roles in tissue remodeling, embryogenesis, and wound repair as well as in cancer therapy and aging. The lack of universal biomarkers for detecting and quantifying senescent cells, in vitro and in vivo, constitutes a major limitation. The applications and limitations of major senescence biomarkers, including senescence-associated ß-galactosidase staining, telomere shortening, cell-cycle arrest, DNA methylation, and senescence-associated secreted phenotypes are discussed. Furthermore, explore senotherapeutic approaches for aging-associated diseases and cancer. In addition to the conventional biomarkers, this review highlighted the in vitro, in vivo, and disease models used for aging studies. Further, technologies from the current decade including multi-omics and computational methods used in the fields of senescence and aging are also discussed in this review. Understanding aging-associated biological processes by using cellular senescence biomarkers can enable therapeutic innovation and interventions to improve the quality of life of older adults.

Systemic Inflammatory Response Following Preoperative Chemoradiotherapy Can Affect Oncologic Outcomes in MSI-H/dMMR Rectal Cancer.

Systemic inflammatory response (SIR) is a crucial determinant of disease progression and survival in patients with colorectal cancer. This study investigated the prognostic relevance of changes in the platelet count on survival and the predictive value of changes in the platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) on the pathological tumor response to preoperative chemoradiotherapy (CRT) in patients with microsatellite instability-high (MSI-H) rectal cancer. From 2011 to 2022, data of 46 consecutive patients with MSI-H rectal cancer who were treated with preoperative CRT followed by curative surgery at Kyungpook National University Chilgok Hospital (Daegu, South Korea) were retrospectively analyzed. A 235 cut-off value was used to define whether PLR was high or low. Any change in the PLR or NLR was calculated on the basis of subtracting the pre-CRT PLR or NLR from the post-CRT values. Both pre-CRT and post-CRT values of the NLR and PLR were not significantly associated with clinical outcomes. Simple logistic regression analysis showed that a change in the PLR following CRT was not significantly associated with survival outcomes; however, patients who maintained a high change in the PLR following CRT showed significantly better pathologic T-stage. No statistically significant association was noted between changes in the platelet count and clinical outcomes of patients. The results suggested that changes in the PLR following CRT are associated with pathologic T-stage of the group. However, the SIR markers showed no prognostic values on the survival outcomes of the patients with MSI-H/mismatch repair-deficient (dMMR) locally advanced rectal cancer (LARC).

ESR1 and p53 interactome alteration defines mechanisms of tamoxifen response in luminal breast cancer.

The canonical mechanism behind tamoxifen's therapeutic effect on estrogen receptor α/ESR1+ breast cancers is inhibition of ESR1-dependent estrogen signaling. Although ESR1+ tumors expressing wild-type p53 were reported to be more responsive to tamoxifen (Tam) therapy, p53 has not been factored into choice of this therapy and the mechanism underlying the role of p53 in Tam response remains unclear. In a window-of-opportunity trial on patients with newly diagnosed stage I-III ESR1+/HER2/wild-type p53 breast cancer who were randomized to arms with or without Tam prior to surgery, we reveal that the ESR1-p53 interaction in tumors was inhibited by Tam. This resulted in functional reactivation of p53 leading to transcriptional reprogramming that favors tumor-suppressive signaling, as well as downregulation of oncogenic pathways. These findings illustrating the convergence of ESR1 and p53 signaling during Tam therapy enrich mechanistic understanding of the impact of p53 on the response to Tam therapy.

The effect of preoperative botulinum toxin a injection on traction force during hernia repair: a prospective, single-blind study, intra-patient comparison using contralateral side as a control.

PURPOSE: Ventral hernias are a common complication of laparotomy, posing challenges particularly when primary fascial closure is unattainable. Although chemical component separation using preoperative botulinum toxin A (BTX) injections has emerged as a promising adjunct, objective evidence of its efficacy remains limited. This study aimed to objectively assess the effect of preoperative BTX on traction force during ventral hernia repair. METHODS: A prospective, single-blind study was conducted on patients with midline incisional hernias following liver transplantation. BTX was administered unilaterally, and the traction force required to medially advance the anterior rectus sheath was measured intraoperatively. Pre- and post-injection CT scans were analyzed for changes in hernia size and LAW muscle measurements. Statistical analyses were performed to evaluate traction force differences between BTX-injected and uninjected sides. RESULTS: Ten patients underwent hernia repair with primary fascial closure achieved in all cases. Comparison of pre- and post-injection CT scans showed no significant changes in hernia size. LAW muscle length increased by 1.8 cm, while thickness decreased by 0.2 cm. Intraoperative traction force measurements revealed a significant reduction on the BTX-injected side compared to the uninjected side (p < 0.0001). The traction force ratio on the BTX-injected to the uninjected side averaged 57%, indicating the efficacy of BTX in reducing tension. CONCLUSION: Preoperative BTX significantly reduces traction force during ventral hernia repair, highlighting its potential as an adjunctive therapy in complex cases. While challenges remain in patient selection and outcome assessment, BTX offers a promising avenue for enhancing abdominal wall reconstruction outcomes and reducing surgical complications.

The Influence of Tacrolimus on Cellular Morphology, Cellular Viability, Osteogenic Differentiation, and mRNA Expression within Stem Cell Spheroids.

Background and Objectives: Tacrolimus is a macrolide lactone compound derived from the bacterium Streptomyces tsukubensis, widely known as an immunosuppressant. In basic research, the effects of tacrolimus on osteogenic differentiation have been tested using mesenchymal stem cells. In this study, tacrolimus's effects on the cellular survival and osteogenic differentiation of stem cell spheroids were investigated. Materials and Methods: Concave microwells were used to form stem cell spheroids in the presence of tacrolimus at final concentrations of 0 µg/mL, 0.1 µg/mL, 1 µg/mL, 10 µg/mL, and 100 µg/mL. A microscope was used to test cellular vitality qualitatively, and an assay kit based on water-soluble tetrazolium salt was used to measure cellular viability quantitatively. Alkaline phosphatase activity and an anthraquinone dye test for measuring calcium deposits were used to assess osteogenic differentiation. To assess the expression of osteogenic differentiation, a quantitative polymerase chain reaction, Western blot, and RNA sequencing were performed. Results: Spheroids across all concentrations maintained a relatively uniform and spherical shape. Cell viability assay indicated that tacrolimus, up to a concentration of 100 µg/mL, did not significantly impair cell viability within spheroids cultured in osteogenic media. The increase in calcium deposition, particularly at lower concentrations of tacrolimus, points toward an enhancement in osteogenic differentiation. There was an increase in COL1A1 expression across all tacrolimus concentrations, as evidenced by the elevated mean and median values, which may indicate enhanced osteogenic activity. Conclusions: This study showed that tacrolimus does not significantly impact the viability of stem cell spheroids in osteogenic media, even at high concentrations. It also suggests that tacrolimus may enhance osteogenic differentiation, as indicated by increased calcium deposition and COL1A1 expression. These findings advance our understanding of tacrolimus's potential roles in tissue repair, regeneration, and stem cell-based therapeutic applications.

Single-cell and spatial transcriptomics analysis of non-small cell lung cancer.

Lung cancer is the second most frequently diagnosed cancer and the leading cause of cancer-related mortality worldwide. Tumour ecosystems feature diverse immune cell types. Myeloid cells, in particular, are prevalent and have a well-established role in promoting the disease. In our study, we profile approximately 900,000 cells from 25 treatment-naive patients with adenocarcinoma and squamous-cell carcinoma by single-cell and spatial transcriptomics. We note an inverse relationship between anti-inflammatory macrophages and NK cells/T cells, and with reduced NK cell cytotoxicity within the tumour. While we observe a similar cell type composition in both adenocarcinoma and squamous-cell carcinoma, we detect significant differences in the co-expression of various immune checkpoint inhibitors. Moreover, we reveal evidence of a transcriptional "reprogramming" of macrophages in tumours, shifting them towards cholesterol export and adopting a foetal-like transcriptional signature which promotes iron efflux. Our multi-omic resource offers a high-resolution molecular map of tumour-associated macrophages, enhancing our understanding of their role within the tumour microenvironment.

Pediatric Eosinophilic Granuloma Associated With Delayed Epidural Hematoma Following on Seizure: A Case Report.

Eosinophilic granuloma (EG), a subtype of Langerhans cell histiocytosis (LCH), the monostotic form, is a rare condition characterized by a solitary bone lesion. It is even more unusual for this condition to be accompanied by an epidural hematoma (EDH). This case is unique in that it is the first to involve delayed EDH following a seizure. We describe a remarkable example of EG accompanied by an EDH and consider the rarity of this comorbidity. A 32-month-old boy developed a rapidly growing skull mass following a minor head injury. During surgical preparation for a biopsy, the patient experienced a single convulsion. Imaging following the seizure revealed an EDH in the vicinity of the mass. The mass was excised and confirmed to be an EG, but with positive margins. The patient underwent chemotherapy after systemic skeletal evaluation, in accordance with the LCH III protocol established by the Histiocytosis Society. EG is a rare neoplasm that typically presents as a painless growth on the skull that gradually enlarges over time. The correlation between EG and EDH is exceedingly uncommon, with only a few documented cases. This case study underscores the significance of considering EG in the differential diagnosis of an expanding cranium mass, even when associated with EDH. Prompt diagnosis and treatment can prevent serious complications and improve patient outcomes.

Deep-learning-based pelvic automatic segmentation in pelvic fractures.

With the recent increase in traffic accidents, pelvic fractures are increasing, second only to skull fractures, in terms of mortality and risk of complications. Research is actively being conducted on the treatment of intra-abdominal bleeding, the primary cause of death related to pelvic fractures. Considerable preliminary research has also been performed on segmenting tumors and organs. However, studies on clinically useful algorithms for bone and pelvic segmentation, based on developed models, are limited. In this study, we explored the potential of deep-learning models presented in previous studies to accurately segment pelvic regions in X-ray images. Data were collected from X-ray images of 940 patients aged 18 or older at Gachon University Gil Hospital from January 2015 to December 2022. To segment the pelvis, Attention U-Net, Swin U-Net, and U-Net were trained, thereby comparing and analyzing the results using five-fold cross-validation. The Swin U-Net model displayed relatively high performance compared to Attention U-Net and U-Net models, achieving an average sensitivity, specificity, accuracy, and dice similarity coefficient of 96.77%, of 98.50%, 98.03%, and 96.32%, respectively.

Anatomical study to determine a new approach to treat benign masses located in the anterior condyle region: a case report.

A 22-year-old male patient presented to the clinic with severe pain in the preauricular area with an inability to completely occlude the jaw. Facial computed tomography and magnetic resonance imaging revealed a well-defined lesion that was tentatively diagnosed as a benign tumor or cystic mass. Surgical approach of a lesion in the condyle is delicate and problematic as many vulnerable anatomical structures are present. There are several methods for surgery in this area. Typically, an extraoral approach is dangerous because of potential injuries to nerves and arteries. The intraoral approach also presents difficulties due to the lack of visibility and accessibility. On occasion, coronoidectomy may be performed. The goal here was to determine an easier and safer new surgical approach to the condyle. We reached the anterior part of the pterygoid plate in the same method as in Le Fort I surgery. From this point, through the external pterygoid muscle, approaching the anterior aspect of the condyle is relatively easy and safe, with minimal damage to the surrounding tissues. Pus was drained at the site, and the lesion was diagnosed as an abscess. Pain and inability to close the mouth resolved without recurrence.

Literature review of non-pharmacological treatment for patients with axial spondyloarthritis.

Axial spondyloarthritis (axSpA) is a chronic inflammatory disorder affecting the sacroiliac joints and axial spine. Along with pharmacotherapy, non-pharmacological interventions for axSpA are crucial and constitute the cornerstone of treatment. Here, we review the evidence for non-pharmacological treatment of axSpA as a basis for the 2023 Korean treatment recommendations for patients with axSpA. The effectiveness of the core non-pharmacological approaches, such as education, smoking cessation, and exercise, has been reaffirmed. High-quality research on surgical treatment is limited. However, total hip replacement is advised in patients with ongoing pain or disability and visible structural damage to the hip on imaging. Urgent spinal intervention should be considered in cases of acute spinal pain with neurological deficiency or concurrent unstable fractures. Evidence for complementary therapies, including spas and acupuncture, remains insufficient.

Polyhexamethylene guanidine phosphate induces pyroptosis via reactive oxygen species-regulated mitochondrial dysfunction in bronchial epithelial cells.

Pyroptosis is a form of programmed cell death characterized by gasdermin (GSDM)-mediated pore formation in the cell membrane, resulting in the release of pro-inflammatory cytokines and cellular lysis. Increasing evidence has shown that pyroptosis is responsible for the progression of various pulmonary disorders. The inhalation of polyhexamethylene guanidine (PHMG) causes severe lung inflammation and pulmonary toxicity; however, the underlying mechanisms are unknown. Therefore, in this study, we investigate the role of pyroptosis in PHMG-induced pulmonary toxicity. We exposed bronchial epithelial cells, BEAS-2B, to PHMG phosphate (PHMG-p) and evaluated cell death type, reactive oxygen species (ROS) levels, and relative expression levels of pyroptosis-related proteins. Our data revealed that PHMG-p reduced viability and induced morphological alterations in BEAS-2B cells. Exposure to PHMG-p induced excessive accumulation of mitochondrial ROS (mtROS) in BEAS-2B cells. PHMG-p activated caspase-dependent apoptosis as well as NLRP3/caspase-1/GSDMD-mediated- and caspase-3/GSDME-mediated pyroptosis through mitochondrial oxidative stress in BEAS-2B cells. Notably, PHMG-p reduced mitochondrial respiratory function and induced the translocation of Bax and cleaved GSDM into the mitochondria, leading to mitochondrial dysfunction. Our results enhanced our understanding of PHMG-p-induced lung toxicity by demonstrating that PHMG-p induces pyroptosis via mtROS-induced mitochondrial dysfunction in bronchial epithelial cells.

α-Klotho levels in girls with central precocious puberty: potential as a diagnostic and monitoring marker.

Background: Recent studies suggest a link between the Klotho protein, sex hormones, and insulin-like growth factor-1 (IGF-1), indicating that α-Klotho levels may rise during puberty, including in central precocious puberty (CPP) cases. This study aimed to explore α-Klotho levels in girls with CPP to assess its potential as a diagnostic and monitoring tool for this condition. Methods: In total, 139 girls, comprising 82 patients diagnosed with CPP and 57 healthy prepubertal controls, were enrolled in this study. From March 2020 to May 2023, we assessed both α-Klotho levels and clinical parameters. α-Klotho concentrations were measured using an α-Klotho ELISA kit. For the girls with CPP, we additionally analyzed samples taken 6 months after GnRH agonist treatment. Results: α-Klotho levels were higher in the CPP group compared with the control (CPP group: 2529 ± 999 ng/mL; control group: 1802 ± 675 pg/mL) (P < 0.001), and its level modest decreased after 6 months of GnRH agonist treatment (2147± 789 pg/mL) (P < 0.001). The association between α-Klotho and IGF-1 SDS, follicular stimulating hormone and baseline luteinizing hormone was assessed by partial correlation after adjusting for age, BMI SDS (r= 0.416, p= <0.001; r= 0.261, p= 0.005; r= 0.278, p= 0.002), respectively. Receiver operating characteristic curve analysis identified an α-Klotho cut-off differentiating CPP from controls, with a cut-off of 1914 pg/mL distinguishing girls with CPP from controls with a sensitivity of 69.5% and specificity of 70.2%; the area under the curve was 0.723. Conclusion: The findings of our study are the first step towards deciphering the role of α-Klotho in puberty induction. With additional data and further research, α-Klotho could potentially be utilized as a significant diagnostic and monitoring tool for CPP.

Human ST3Gal II and ST6GalNAc IV genes increase human serum-mediated cytotoxicity to xenogeneic cells.

Carbohydrate-antigens widely existed on glycoproteins and glycosphingolipids of all mammalian cells play a crucial role in self-defense and immunity. Xeno-reactive antibodies included in natural human sera play a protecting role in an acute phase-rejection of xenotransplantation. In this study, we investigated the effect of an alteration of glycosylation-pattern, caused by human sialyltransferases such as hST3Gal II or hST6GalNAc IV, on human serum mediated cytotoxicity in pig kidney PK15 cells. From LDH cytotoxicity assay, cytotoxicity to human serum was significantly increased in hST3Gal II and hST6GalNAc IV-transfected PK15 cells, as compared to the control. In the hST6Gal I-carrying cells, the cytotoxicity to human serum was rather decreased. Moreover, flow cytometry analysis revealed that an alteration of pig glycosylation-pattern by hST3Gal II or hST6GalNAc IV influences on a binding of human IgM or IgG, respectively, in pig kidney cells, regardless of Gal antigen alteration. Finally, we found that hST6GalNAc IV contributed to increase of terminal disialylated tetrasaccharide structure, disialyl T antigen, as evidenced by increase of the MAL II lectin binding capacity in the hST6GalNAc IV-transfected PK15 cells, compared with control. Therefore, our results suggest that carbohydrate antigens, such as disialyl T antigen, newly synthesized by the ST3Gal II- and ST6GalNAc IV are potentially believed to be new xeno-reactive elements.