Biophysical perspectives to understanding cancer-associated fibroblasts.

The understanding of cancer has evolved significantly, with the tumor microenvironment (TME) now recognized as a critical factor influencing the onset and progression of the disease. This broader perspective challenges the traditional view that cancer is primarily caused by mutations, instead emphasizing the dynamic interaction between different cell types and physicochemical factors within the TME. Among these factors, cancer-associated fibroblasts (CAFs) command attention for their profound influence on tumor behavior and patient prognoses. Despite their recognized importance, the biophysical and mechanical interactions of CAFs within the TME remain elusive. This review examines the distinctive physical characteristics of CAFs, their morphological attributes, and mechanical interactions within the TME. We discuss the impact of mechanotransduction on CAF function and highlight how these cells communicate mechanically with neighboring cancer cells, thereby shaping the path of tumor development and progression. By concentrating on the biomechanical regulation of CAFs, this review aims to deepen our understanding of their role in the TME and to illuminate new biomechanical-based therapeutic strategies.

Corrigendum: Intrahepatic infiltration of activated CD8+ T cells and mononuclear phagocyte is associated with idiosyncratic drug-induced liver injury.

[This corrects the article DOI: 10.3389/fimmu.2023.1138112.].

The effect of shoulder muscle succinylcholine injection on the foreleg raising power: Sion's local paralysis.

Objective: We examined the change in foreleg raising power after Sion's local paralysis (SLP) with succinylcholine in the shoulder muscle. Methods: A randomized, double blind, placebo-controlled, porcine study was designed and performed at a research institution. Ten male Korean native pigs were randomized into an intervention group (n = 5) and a control group (n = 5). The injection points were in the middle of the left trapezius muscle and the middle of the left deltoid muscle. The control group received 2 ml normal saline (NS), 1 ml injected in each point. The intervention group received 0.4 mg/kg succinylcholine diluted to 2 ml in NS, and 1 ml was injected in each point. To represent the foreleg raising power, the height of the left forelegs from baseline (experiment table) was measured. We measured the foreleg height and oxygen saturation at -4, -2, 0, +2, +4, +6, +8, +10, +20, +30, and +60 min. Results: After SLP, foreleg height immediately declined in the intervention group. It recovered slightly for a few minutes and declined from 4 to 8 min. In the control group, foreleg height was relatively similar throughout the study period. A repeated-measure analysis of variance revealed a significant group × time interaction (F10,80 = 2.37, P = 0.017), a significant main effect for group (F1,8 = 6.25, P = 0.037), and a significant main effect for time (F10,80 = 4.41, P < 0.001). Post hoc analysis demonstrated that the intervention group showed significantly less foreleg raising power than the control group at 0, 4, 6, 8, 20, and 30 min (P < 0.05). Conclusions: Compared with the control group, the foreleg raising power in the intervention group immediately decreased significantly and persisted for a period after SLP, without hypoxia, in a pig model.

Impact of intravesical administration of tranexamic acid on gross hematuria in the emergency department: A before-and-after study.

INTRODUCTION: Local applications of tranexamic acid (TXA) have been effective in treating various hemorrhagic conditions. In patients with gross hematuria, the main treatment in the emergency department (ED) is continuous bladder irrigation (CBI). However, CBI has no pharmacological effects except blood clot removal from dilution. The aim of this study was to evaluate the impact of the intravesical TXA injection before CBI. METHODS: This study was a before-and-after, retrospective, and single-center study. The target population was hematuria patients who received CBI via a 3-way Foley catheter. As the intervention procedure, 1000 mg of TXA was injected through the Foley catheter and after 15 min, the Foley catheter was declamped and CBI started. Since the intervention started in March 2022, the patients from March 2022 to August 2022 were assigned to the after group and the patients from March 2021 to August 2021 were assigned to the before group. The primary outcomes were the length of stay in the ED and duration of Foley catheter placement. The secondary outcomes were the admissions and the revisits for CBI within 48 h after discharge. RESULTS: The numbers of patients in the before group and after group were 73 and 86, respectively. The median length of stay in the ED was shorter in the intervention group than in the group not treated with TXA (274 min vs. 411 mins, P < 0.001). The median duration of Foley catheter placement was also shorter in the intervention group than not treated with TXA (145 min vs. 308 mins, P < 0.001). The revisits after ED discharge were lower in the after group than in the before group (2.3% vs. 12.3%, P = 0.031). There was a trend for lower admissions in the TXA treatment group than before group (29.1% vs. 45.2%, P = 0.052). CONCLUSION: After the TXA intervention, reduction in the length of stay in the ED, the duration of Foley catheter placement, and the revisits after ED discharge was observed.

Intrahepatic infiltration of activated CD8+ T cells and mononuclear phagocyte is associated with idiosyncratic drug-induced liver injury.

Background: Idiosyncratic drug-induced liver injury (DILI) is caused by the interplay among drugs, their metabolites, and the host immune response. The characterization of infiltrated immune cells in the liver may improve the understanding of the pathogenesis of idiosyncratic DILI. This study investigated the phenotypes and clinical implications of liver-infiltrating immune cells in idiosyncratic DILI. Methods: From January 2017 to June 2021, 53 patients with idiosyncratic DILI who underwent liver biopsy were prospectively enrolled in this study. Immunohistochemical staining and flow cytometry analyses were performed on the biopsy specimens. Serum levels of CXC chemokine ligand 10 (CXCL10) and soluble CD163 were measured. A multivariate cox proportional hazards model was used to evaluate predictors of DILI resolution within 30 days. Results: The numbers of intrahepatic T cells and mononuclear phagocytes were positively correlated with serum levels of total bilirubin, alanine aminotransferase (ALT), and the model of end-stage liver disease score. The frequency of activated CD8+ T cells among liver-infiltrating CD8+ T cells in DILI livers was higher than that in healthy livers. Notably, the percentages of activated intrahepatic CD8+ T cells and mononuclear phagocytes in DILI livers showed a positive correlation with ALT. Additionally, serum CXCL10 level was positively correlated with intrahepatic T cell infiltration and ALT, and soluble CD163 level was positively correlated with intrahepatic mononuclear phagocyte infiltration and ALT. Thirty-six patients (70.6%) were treated with steroids. In multivariate analysis, total bilirubin and steroid use independently influenced DILI resolution within 30 days. Conclusions: Activated CD8+ T cells and mononuclear phagocyte are associated with liver injury caused by drugs. Therefore, we suggest that steroids are a potential treatment option for idiosyncratic DILI.

Influence of Transforming Growth Factors beta 1 and beta 3 in the Scar Formation Process.

BACKGROUND: Transforming growth factor-beta (TGF-ß) plays an instrumental role in forming scars and keloids. TGF-ß isoforms exhibit differential expression, indicating distinct wound healing and scar formation functions. However, the role of TGF-ß1 and TGF-ß3 in wound healing and scar formation remains unclear. This study aimed to compare the specific roles of TGF-ß1 and TGF-ß3 in wound healing and scar formation by biomolecular analysis. MATERIALS AND METHODS: The study was conducted by cell isolation and culture cells from a total of 20 human samples. Normal human fibroblasts (NHF) were isolated from normal human samples and myofibroblasts from the different scar types, namely hypertrophic (HT) and keloid (K) scars. NHF and cells from the HT, and K scar, each of which were divided into 3 sample groups: the untreated control, TGF-ß1 (10 µg/mL)-treated group, and TGF-ß3 (10 µg/mL)-treated group. The results of confocal microscopy and fluorescence-activated cell sorting experiments were compared. RESULTS: Both the HT and K groups had higher α-smooth muscle actin (α-SMA) expression than the NHF group in the untreated control group. In comparison with the untreated group, NHFs showed a significant increase in α-SMA expression in the TGF-ß1-treated group. HT showed a high α-SMA level, which was statistically significant compared with the normal fibroblasts. In the TGF-ß3-treated group, α-SMA expression was slightly increased in NHF as compared with the untreated group. TGF-ß3 treated HT exhibited a greater reduction in α-SMA expression than in the TGF-ß1 treated HT. K, on the other hand, had only a minimal effect on the treatment of TGF-ß1 and TGF-ß3. CONCLUSIONS: The findings suggest that TGF-ß3 may play a regulatory role in the wound repair process, which could be useful in the development of scar-reducing therapies for patients with scar-related cosmetic concerns.

The Risk of Major Depressive Disorder Due to Cataracts among the Korean Elderly Population: Results from the Korea National Health and Nutrition Examination Survey (KNHANES) in 2016 and 2018.

Cataracts and major depressive disorder (MDD) both have high prevalence, representing for major health burdens globally. In this study, we examined the risk of MDD due to cataracts. Data from the 2016 to 2018 Korea National Health and Nutrition Examination Survey (KNHANES) were used, including 4122 participants. Logistic regression analysis was performed to evaluate the odds ratio for MDD in association with cataracts. Controlled variables were age, gender, smoking, dyslipidemia and mobility. Subgroup analysis was performed with stratification by gender. The results reveal that cataracts are significantly correlated with MDD. Elderly people with cataracts were found to be more likely to develop MDD compared to those without cataracts (adjusted odds ratio: 1.654; 95% CI = 1.197-2.286). In subgroup analysis, men (adjusted odds ratio: 2.631; 95% CI = 1.247-5.551) were found to be more likely to develop MDD than women (adjusted odds ratio: 1.510; 95% CI = 1.061-2.150). Cataracts may be a risk factor for MDD in the elderly, especially among the male population.

Fibrous Matrix Architecture-Dependent Activation of Fibroblasts with a Cancer-Associated Fibroblast-like Phenotype.

Cancer-associated fibroblasts (CAFs) are one of the most prevalent cell types within the tumor microenvironment (TME). While several physicochemical cues from the TME, including growth factors, cytokines, and ECM specificity, have been identified as essential factors for CAF activation, the precise mechanism of how the ECM architecture regulates CAF initiation remains elusive. Using a gelatin-based electrospun fiber mesh, we examined the effect of matrix fiber density on CAF activation induced by MCF-7 conditioned media (CM). A less dense (3D) gelatin mesh matrix facilitated better activation of dermal fibroblasts into a CAF-like phenotype in the CM than a highly dense (3D) gelatin mesh matrix. In addition, it was discovered that CAF activation on the less dense (LD) matrix is dependent on the cell size-related AKT/mTOR signaling cascade, accompanied by an increase in intracellular tension within the well-spread fibroblasts.

Genotype-Phenotype Association in ABCC2 Exon 18 Missense Mutation Leading to Dubin-Johnson Syndrome: A Case Report.

We report a case of a patient with Dubin-Johnson syndrome confirmed by a genetic study. A 50-year-old woman who had symptoms of intermittent right upper quadrant abdominal pain was diagnosed with calculous cholecystitis at another institute and was presented to our hospital for a cholecystectomy. She had no history of liver disease, and her physical examination was normal. Abdominal computed tomography showed a gallbladder stone with chronic cholecystitis. During a laparoscopic cholecystectomy for cholecystitis, a smooth, black-colored liver was noted, and a liver biopsy was performed. The biopsy specimen showed coarse, dark brown granules in centrilobular hepatocytes via hematoxylin and eosin staining. We performed a genetic study using the blood samples of the patient. In the adenosine triphosphate-binding cassette subfamily C member 2 (ABCC2) mutation study, a missense mutation in exon 18 was noted. Based on the black-colored liver without nodularity, conjugated hyperbilirubinemia, the liver biopsy results of the coarse pigment in centrilobular hepatocytes, and the ABCC2 mutation, Dubin-Johnson syndrome was diagnosed. The patient was managed with conservative care using hepatotonics. One month after follow-up, total bilirubin and direct bilirubin remained in a similar range. Another follow-up was planned a month later, and the patient maintained her use of hepatotonics.

Therapeutic Response Monitoring with 89Zr-DFO-Pertuzumab in HER2-Positive and Trastuzumab-Resistant Breast Cancer Models.

Immuno-positron emission tomography (PET) has great potential to evaluate the target expression level and therapeutic response for targeted cancer therapy. Immuno-PET imaging with pertuzumab, due to specific recognition in different binding sites of HER2, could be useful for the determination of the therapeutic efficacy of HER2-targeted therapy, trastuzumab, and heat shock protein 90 (HSP90) inhibitor, in HER2-expressing breast cancer. The aim of this study is to evaluate the feasibility of monitoring therapeutic response with 89Zr-DFO-pertuzumab for the treatment of HER2-targeted therapeutics, trastuzumab, or the HSP90 inhibitor 17-DMAG, in trastuzumab-resistant JIMT-1 breast cancer models. We prepared an immuno-PET imaging agent using desferoxamine (DFO)-pertuzumab labeled with 89Zr and performed the biodistribution and PET imaging in breast cancer xenograft models for monitoring therapeutic response to HER2-targeted therapy. 89Zr-DFO-pertuzumab was successfully prepared and showed specific binding to HER2 in vitro and clearly visualized HER2 expressing JIMT-1 tumors. 89Zr-DFO-pertuzumab had prominent tumor uptake in HER2 expressing JIMT-1 tumors. JIMT-1 tumors showed trastuzumab-resistant and HSP90 inhibitor sensitive characterization. In immuno-PET imaging, isotype antibody-treated JIMT-1 tumors had similar uptake in trastuzumab-treated JIMT-1 tumors, but 17-DMAG-treated JIMT-1 tumors showed greatly reduced uptake compared to vehicle-treated tumors. Additionally, HER2 downregulation evaluated by immuno-PET imaging was verified by western blot analysis and immunofluorescence staining which resulted in a significant reduction in the tumor's HER2 level in 17-DMAG-treated JIMT-1 tumors. 89Zr-DFO-pertuzumab immuno-PET may be clinically translated to select pertinent patients for HER2-targeted therapy and to monitor the therapeutic response in HER2-positive cancer patients under various HER2-targeted therapeutics treatments.

Causal Effects of Serum Levels of n-3 or n-6 Polyunsaturated Fatty Acids on Coronary Artery Disease: Mendelian Randomization Study.

We aimed to investigate the causal effects of n-3 and n-6 polyunsaturated fatty acids (PUFAs) on the risk of coronary artery disease (CAD) through Mendelian randomization (MR) analysis. This MR study utilized a genetic instrument developed from previous genome-wide association studies for various serum n-3 and n-6 PUFA levels. First, we calculated the allele scores for genetic predisposition of PUFAs in individuals of European ancestry in the UK Biobank data (N = 337,129). The allele score-based MR was obtained by regressing the allele scores to CAD risks. Second, summary-level MR was performed with the CARDIoGRAMplusC4D data for CAD (N = 184,305). Higher genetically predicted eicosapentaenoic acid and dihomo-gamma-linolenic acid levels were significantly associated with a lower risk of CAD both in the allele-score-based and summary-level MR analyses. Higher allele scores for linoleic acid level were significantly associated with lower CAD risks, and in the summary-level MR, the causal estimates by the pleiotropy-robust MR methods also indicated that higher linoleic acid levels cause a lower risk of CAD. Arachidonic acid showed significant causal estimates for a higher risk of CAD. This study supports the causal effects of certain n-3 and n-6 PUFA types on the risk of CAD.

Removal of pharmaceuticals and personal care products using native fungal enzymes extracted during the ligninolytic process.

Significant concentrations of pharmaceuticals and personal care products (PPCPs) have been detected in aquatic environment. Fungal enzymatic processes can oxidize these persistent PPCPs; thus, these processes have attracted considerable attention from the scientific community. Here, we evaluated the efficacy of the removal of PPCPs using native fungal enzymes derived from Bjerkandera spp. TBB-03 under various conditions. Among the eight lignocellulosic substrates, ash, which showed the highest laccase production, was selected as the sole enzyme inducer. TBB-03 laccase was found to exhibit remarkable stability under varied pH and temperature conditions. Acetaminophen and bisphenol A were effectively removed by TBB-03 laccase under various conditions, except at pH 8. Although TBB-03 laccase could not efficiently remove single-state sulfamethoxazole directly, a 22% of improvement in sulfamethoxazole removal was observed in the presence of acetaminophen. Overall, our proposed approach showed that Bjerkandera adusta TBB-03 can be potentially applied for further research regarding PPCP remediation.

Chest radiography for simplified evaluation of central venous catheter tip positioning for safe and accurate haemodynamic monitoring: a retrospective observational study.

OBJECTIVES: The tip-to-carina (TC) distance on a simple chest X-ray (CXR) has proven value in the determination of correct central venous catheter (CVC) positioning. However, previous studies have mostly focused on preventing the atrial insertion of the CVC tip, and not on appropriate positioning for accurate haemodynamic monitoring. We aimed to assess whether the TC distance could detect the passage of the CVC tip into the superior vena cava (SVC) and the right atrium (RA), and to accordingly suggest cut-off reference values for these two aspects. DESIGN: Retrospective observational cohort study. SETTING: Single urban tertiary level academic hospital. PARTICIPANTS: 479 patients who underwent CXR and chest CT scan after the insertion of a CVC with a 24-hour interval during the study period. INTERVENTION: The TC distance was measured on CXR, and the position of the CVC tip was assessed on the chest CT images. The TC distance was described as a negative or positive number if the CVC tip was above or below the carina, respectively. Receiver-operating characteristics curve analyses were conducted to ascertain the TC distance to detect SVC entrance and RA insertion of CVC tip. RESULTS: The TC distance could significantly detect both SVC entrance and RA insertion (p<0.001 for both; area under curve 0.987 and 0.965, respectively), with a reference range of -6.69 to 15.61 mm. CONCLUSION: The TC distance in CXR is a simple and precise method to confirm not only the safe placement of the CVC tip but also its optimal positioning for accurate haemodynamic monitoring.

Vanillic Acid Improves Comorbidity of Cancer and Obesity through STAT3 Regulation in High-Fat-Diet-Induced Obese and B16BL6 Melanoma-Injected Mice.

Obesity is known to be associated with risk and aggressiveness of cancer. Melanoma, the most lethal type of skin cancer, is also closely related to the prevalence of obesity. In this study, we established a cancer-obesity comorbidity (COC) model to investigate the effects of vanillic acid (VA). After a five-week administration with a high-fat diet (HFD) to induce obesity, subcutaneous allograft of B16BL6 cells were followed, and VA was orally administrated for an additional two weeks. VA-fed mice showed significantly decreased body weight and white adipose tissue (WAT) weight, which were due to increased thermogenesis and AMPK activation in WATs. Growth of cancer was also suppressed. Mechanistic studies revealed increased apoptosis and autophagy markers by VA; however, caspase 3 was not involved. Since signal transducer and activator of transcription 3 (STAT3) is suggested as an important pathway linking obesity and cancer, we further investigated to find out if STAT3 phosphorylation was repressed by VA treatment, and this was again confirmed in a COC cell model of adipocyte conditioned medium-treated B16BL6 melanoma cells. Overall, our results show VA induces STAT3-mediated autophagy to inhibit cancer growth and thermogenesis to ameliorate obesity in COC. Based on these findings, we suggest VA as a candidate therapeutic agent for COC treatment.

Albiflorin ameliorates obesity by inducing thermogenic genes via AMPK and PI3K/AKT in vivo and in vitro.

OBJECTIVE: Brown adipose tissue (BAT) activation has been identified as a possible target to treat obesity and to protect against metabolic diseases by increasing energy consumption. We explored whether albiflorin (AF), a natural compound, could contribute to lowering the high risk of obesity with BAT and primary brown preadipocytes in vivo and in vitro. MATERIALS/METHODS: Human adipose tissue-derived mesenchymal stem cells (hAMSCs) were cultured with adipogenic differentiation media with or without AF. Male C57BL/6J mice (n=5 per group) were fed a high-fat diet (HFD) for six weeks with or without AF. Brown preadipocytes from the interscapular BAT of mice were cultured with or without AF. RESULTS: In white adipogenic differentiation of hAMSCs, AF treatment significantly reduced the formation of lipid droplets and the expression of adipogenesis-related genes. In HFD-induced obese C57BL/6J mice, AF treatment significantly reduced body weight gain as well as the weights of the white adipose tissue, liver and spleen. Furthermore, AF induced the expression of genes involved in thermogenic function in BAT. In primary brown adipocytes, AF effectively stimulated the expressions of thermogenic genes and markedly up-regulated the AMP-activated protein kinase (AMPK) signaling pathway. Pretreatment with phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 nullified the induction of the thermogenic genes by AF in primary brown adipocytes. Moreover, AF activated beige cell marker genes induced by the pharmacological activation of peroxisome proliferator-activated receptor γ in hAMSCs. CONCLUSION: This study shows that AF prevents the development of obesity in hAMSCs and mice fed an HFD and that it is also capable of stimulating the differentiation of brown adipocytes through the modulation of thermogenic genes by AMPK and PI3K/AKT.