Caffeic acid ethanolamide induces antifibrosis, anti-inflammatory, and antioxidant effects protects against bleomycin-induced pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease; its cause is unknown, and it leads to notable health problems. Currently, only two drugs are recommended for IPF treatment. Although these drugs can mitigate lung function decline, neither can improve nor stabilize IPF or the symptoms perceived by patients. Therefore, the development of novel treatment options for pulmonary fibrosis is required. The present study investigated the effects of a novel compound, caffeic acid ethanolamide (CAEA), on human pulmonary fibroblasts and evaluated its potential to mitigate bleomycin-induced pulmonary fibrosis in mice. CAEA inhibited TGF-ß-induced α-SMA and collagen expression in human pulmonary fibroblasts, indicating that CAEA prevents fibroblasts from differentiating into myofibroblasts following TGF-ß exposure. In animal studies, CAEA treatment efficiently suppressed immune cell infiltration and the elevation of TNF-α and IL-6 in bronchoalveolar lavage fluid in mice with bleomycin-induced pulmonary fibrosis. Additionally, CAEA exerted antioxidant effects by recovering the enzymatic activities of oxidant scavengers. CAEA directly inhibited activation of TGF-ß receptors and protected against bleomycin-induced pulmonary fibrosis through inhibition of the TGF-ß/SMAD/CTGF signaling pathway. The protective effect of CAEA was comparable to that of pirfenidone, a clinically available drug. Our findings support the potential of CAEA as a viable method for preventing the progression of pulmonary fibrosis.

Technical Refinement of a Bilateral Renal Ischemia-Reperfusion Mouse Model for Acute Kidney Injury Research.

Cardiac arrest poses a large public health burden. Acute kidney injury (AKI) is an adverse marker in survivors of cardiac arrest following the return of spontaneous circulation (ROSC) after successful cardiopulmonary resuscitation. Conversely, recovery of kidney function from AKI is a predictor of favorable neurological outcomes and hospital discharge. However, an effective intervention to prevent kidney damage caused by cardiac arrest after ROSC is lacking, suggesting that additional therapeutic strategies are required. Renal hypoperfusion and reperfusion are two pathophysiological mechanisms that cause AKI after cardiac arrest. Animal models of ischemia-reperfusion-induced AKI (IR-AKI) of both kidneys are comparable with patients with AKI following ROSC in a clinical setting. However, IR-AKI of both kidneys is technically challenging to analyze because the model is associated with high mortality and wide variation in kidney damage, which may affect the analysis. Lightweight mice were chosen, placed under general anesthesia with isoflurane, subjected to surgery with a dorsolateral approach, and their body temperature maintained during operation, thereby reducing tissue damage and establishing a reproducible acute renal IR-AKI research protocol.

Soluble dipeptidyl peptidase-4 induces epithelial-mesenchymal transition through tumor growth factor-ß receptor.

BACKGROUND: Kidney fibrosis is the final manifestation of chronic kidney disease, a condition mainly caused by diabetic nephropathy. Persistent tissue damage leads to chronic inflammation and excessive deposition of extracellular matrix (ECM) proteins. Epithelial-mesenchymal transition (EMT) is involved in a variety of tissue fibrosis and is a process during which epithelial cells transform into mesenchymal-like cells and lose their epithelial functionality and characteristics Dipeptidyl peptidase-4 (DPP4) is widely expressed in tissues, especially those of the kidney and small intestine. DPP4 exists in two forms: a plasma membrane-bound and a soluble form. Serum-soluble DPP4 (sDPP4) levels are altered in many pathophysiological conditions. Elevated circulating sDPP4 is correlated with metabolic syndrome. Because the role of sDPP4 in EMT remains unclear, we examined the effect of sDPP4 on renal epithelial cells. METHODS: The influences of sDPP4 on renal epithelial cells were demonstrated by measuring the expression of EMT markers and ECM proteins. RESULTS: sDPP4 upregulated the EMT markers ACTA2 and COL1A1 and increased total collagen content. sDPP4 activated SMAD signaling in renal epithelial cells. Using genetic and pharmacological methods to target TGFBR, we observed that sDPP4 activated SMAD signaling through TGFBR in epithelial cells, whereas genetic ablation and treatment with TGFBR antagonist prevented SMAD signaling and EMT. Linagliptin, a clinically available DPP4 inhibitor, abrogated sDPP4-induced EMT. CONCLUSIONS: This study indicated that sDPP4/TGFBR/SMAD axis leads to EMT in renal epithelial cells. Elevated circulating sDPP4 levels may contribute to mediators that induce renal fibrosis.

Pelvic Neoadjuvant Radiotherapy for Stage M1a Rectal Adenocarcinoma Patients Treated With Systemic Therapy Followed by Proctectomy and Metastasectomy: A Nationwide Retrospective Cohort Study.

BACKGROUND/AIM: The effect of pelvic neoadjuvant radiotherapy (nRT) for stage M1a rectal adenocarcinoma patients treated with systemic therapy followed by proctectomy and metastasectomy was scarcely investigated in the literatures. PATIENTS AND METHODS: The eligible rectal cancer patients diagnosed between 2011-2019 were identified via the Taiwan Cancer Registry. In the primary analysis, we used propensity score weighting to balance observable potential confounders and compared the hazard ratio (HR) of death for the nRT group vs. without RT group. We also compared the incidence of rectal cancer mortality (IRCM) and performed various supplementary analyses. RESULTS: Our primary analyses included 145 patients. nRT was associated with improved OS (HR=0.51, p=0.01). The numerical trends remained similar for IRCM and in supplementary analyses. CONCLUSION: nRT was associated with improved OS in our study population.

Photoreactive Mercury-Containing Metallosupramolecular Nanoparticles with Tailorable Properties That Promote Enhanced Cellular Uptake for Effective Cancer Chemotherapy.

A new potential route to enhance the efficiency of supramolecular polymers for cancer chemotherapy was successfully demonstrated by employing a photosensitive metallosupramolecular polymer (Hg-BU-PPG) containing an oligomeric poly(propylene glycol) backbone and highly sensitive pH-responsive uracil-mercury-uracil (U-Hg-U) bridges. This route holds great promise as a multifunctional bioactive nano-object for development of more efficient and safer cancer chemotherapy. Owing to the formation of uracil photodimers induced by ultraviolet irradiation, Hg-BU-PPG can form a photo-cross-linked structure and spontaneously forms spherical nanoparticles in aqueous solution. The irradiated nanoparticles possess many unique characteristics, such as unique fluorescence behavior, highly sensitive pH-responsiveness, and intriguing phase transition behavior in aqueous solution as well as high structural stability and antihemolytic activity in biological media. More importantly, a series of cellular studies clearly confirmed that the U-Hg-U photo-cross-links in the irradiated nanoparticles substantially enhance their selective cellular uptake by cancer cells via macropinocytosis and the mercury-loaded nanoparticles subsequently induce higher levels of cytotoxicity in cancer cells (compared to non-irradiated nanoparticles), without harming normal cells. These results are mainly attributed to cancer cell microenvironment-triggered release of mercury ions from disassembled nanoparticles, which rapidly induce massive levels of apoptosis in cancer cells. Overall, the pH-sensitive U-Hg-U photo-cross-links within this newly discovered supramolecular system are an indispensable factor that offers a potential path to remarkably enhance the selective therapeutic effects of functional nanoparticles toward cancer cells.

A Pathophysiological Approach to Reduce Peritumoral Edema with Gamma Knife Radiosurgery for Large Incidental Meningiomas.

BACKGROUND: Peritumoral edema may be a prohibitive side effect in treating large incidental meningiomas with stereotactic radiosurgery. An approach that limits peritumoral edema and achieves tumor control with SRS would be an attractive management option for large incidental meningiomas. METHODS: This is a retrospective cohort study of patients with large incidental meningiomas (≥2 mL in volume and/or 2 cm in diameter) treated with gamma knife radiosurgery (GKRS) between 2000 and 2019 in Taiwan and followed up for 5 years. The outcomes of a pathophysiological approach targeting the dural feeding artery site with a higher marginal dose (18-20 Gy) to enhance vascular damage and the parenchymal margin of the tumor with a lower dose (9-11 Gy) to reduce parenchymal damage were compared with those of a conventional approach targeting the tumor center with a higher dose and tumor margin with a lower dose (12-14 Gy). RESULTS: A total of 53 incidental meningiomas were identified, of which 23 (43.4%) were treated with a pathophysiological approach (4 cases underwent a two-stage approach) and 30 (56.7%) were treated with a conventional approach. During a median follow-up of 3.5 (range 1-5) years, tumor control was achieved in 19 (100%) incidental meningiomas that underwent a single-stage pathophysiological approach compared with 29 (96.7%) incidental meningiomas that underwent a conventional approach (log-rank test: p = 0.426). Peritumoral edema developed in zero (0%) incidental meningiomas that underwent a single stage pathophysiological approach compared to seven (23.3%) incidental meningiomas that underwent a conventional approach (log-rank test: p = 0.023). CONCLUSIONS: Treatment of large incidental meningiomas with a pathophysiological approach with GKRS achieves similar rates of tumor control and reduces the risk of peritumoral edema. GKRS with a pathophysiological approach may be a reasonable management strategy for large incidental meningiomas.

Real-world use patterns of angiotensin receptor-neprilysin inhibitor (sacubitril/valsartan) among patients with heart failure within a large integrated health system.

BACKGROUND: Sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI) that is now preferred in guidelines over angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) for patients with heart failure with reduced ejection fraction (HFrEF). However, it has not been broadly adopted in clinical practice. OBJECTIVE: To characterize ARNI use within a large diverse real-world population and assess for any racial disparities. METHODS: We conducted a cross-sectional study within Kaiser Permanente Southern California. Adult patients with HFrEF who received ARNIs, ACEIs, or ARBs between January 1, 2014, and November 30, 2020, were identified. The prevalence of ARNI use among the cohort and patient characteristics by ARNIs vs ACEIs/ARBs use were described. Multivariable regression was performed to estimate odds ratios and 95% CIs of receiving ARNI by race and ethnicity. RESULTS: Among 12,250 patients with HFrEF receiving ACEIs, ARBs, or ARNIs, 556 (4.54%) patients received ARNIs. ARNI use among this cohort increased from 0.02% in 2015 to 7.48% in 2020. Patients receiving ARNIs were younger (aged 62 vs 69 years) and had a lower median ejection fraction (27% vs 32%) compared with patients receiving ACEIs/ARBs. They also had higher use of mineralocorticoid antagonists (24.1% vs 19.8%) and automatic implantable cardioverterdefibrillators (17.4% vs 13.3%). There were no significant differences in rate of ARNI use by race and ethnicity. CONCLUSIONS: Within a large diverse integrated health system in Southern California, the rate of ARNI use has risen over time. Patients given ARNIs were younger with fewer comorbidities, while having worse ejection fraction. Racial minorities were no less likely to receive ARNIs compared with White patients. DISCLOSURES: Dr Huang had stock ownership in Gilead and Pfizer. Dr Liang received support for article processing and medical writing.

Retrograde Intramedullary Kirschner Wire Fixation as an Alternative for Treating Distal Fibular Shaft Fractures Combined with Distal Tibial Pilon Fractures.

Treatment or management techniques for pilon fractures are associated with high complication rates and poor outcomes. No consensus exists regarding the optimal surgical option for pilon fractures, especially for pilon fractures combined with distal fibular fractures. Accordingly, we explored the use of fibular fixation for treating pilon fractures involving distal fibular shaft fractures. We hypothesized that retrograde intramedullary Kirschner wire (K-wire) fixation is a suitable alternative technique for distal fibular fixation. We retrospectively reviewed the data of 156 patients who underwent surgery for pilon fractures at our hospital from May 2013 to May 2021. The radiographic and functional outcomes were comparable between the fibular intramedullary nailing (Group A; n = 80) and the fibular plating (Group B; n = 76) groups. Groups A and B differed significantly in total hospitalization time (11.4 vs. 18.2 days, p = 0.024), length of postoperative admission (6.8 vs. 11.4 days, p = 0.012), and total admission cost (USD 3624 vs. USD 6145, p = 0.004). We also noted that poor Olerud and Molander ankle scores were significantly associated with age (p = 0.008), smoking (p = 0.012), and preoperative admission length (p = 0.018). Retrograde intramedullary K-wire fixation produced a comparable 12-month functional outcome to plate fixation for distal fibular shaft fractures, rendering it a viable alternative method based on soft tissue condition.

Genome-wide profiling in colorectal cancer identifies PHF19 and TBC1D16 as oncogenic super enhancers.

Colorectal cancer is one of the most common cancers in the world. Although genomic mutations and single nucleotide polymorphisms have been extensively studied, the epigenomic status in colorectal cancer patient tissues remains elusive. Here, together with genomic and transcriptomic analysis, we use ChIP-Seq to profile active enhancers at the genome wide level in colorectal cancer paired patient tissues (tumor and adjacent tissues from the same patients). In total, we sequence 73 pairs of colorectal cancer tissues and generate 147 H3K27ac ChIP-Seq, 144 RNA-Seq, 147 whole genome sequencing and 86 H3K4me3 ChIP-Seq samples. Our analysis identifies 5590 gain and 1100 lost variant enhancer loci in colorectal cancer, and 334 gain and 121 lost variant super enhancer loci. Multiple key transcription factors in colorectal cancer are predicted with motif analysis and core regulatory circuitry analysis. Further experiments verify the function of the super enhancers governing PHF19 and TBC1D16 in regulating colorectal cancer tumorigenesis, and KLF3 is identified as an oncogenic transcription factor in colorectal cancer. Taken together, our work provides an important epigenomic resource and functional factors for epigenetic studies in colorectal cancer.

A novel caffeic acid derivative prevents renal remodeling after ischemia/reperfusion injury.

Acute kidney disease due to renal ischemia/reperfusion (I/R) is a major clinical problem without effective therapies. The injured tubular epithelial cells may undergo epithelial-mesenchymal transition (EMT). It will loss epithelial phenotypes and express the mesenchymal characteristics. The formation of scar tissue in the interstitial space during renal remodeling is caused by the excessive accumulation of extracellular matrix components and induced fibrosis. This study investigated the effect of caffeic acid ethanolamide (CAEA), a novel caffeic acid derivative, on renal remodeling after injury. The inhibitory role of CAEA on EMT was determined by western blotting, real-time PCR, and immunohistochemistry staining. Treating renal epithelial cells with CAEA in TGF-ß exposed cell culture successfully maintained the content of E-cadherin and inhibited the expression of mesenchymal marker, indicating that CAEA prevented renal epithelial cells undergo EMT after TGF-ß exposure. Unilateral renal I/R were performed in mice to induce renal remodeling models. CAEA can protect against I/R-induced renal remodeling by inhibiting inflammatory reactions and consecutively inhibiting TGF-ß-induced EMT, characterized by the preserved E-cadherin expression and alleviated α-SMA and collagen expression, as well as the alleviated of renal fibrosis. We also revealed that CAEA may exhibits biological activity by targeting TGFBRI. CAEA may antagonize TGF-ß signaling by interacting with TGFBR1, thereby blocking binding between TGF-ß and TGFBR1 and reducing downstream signaling, such as Smad3 phosphorylation. Our data support the administration of CAEA after I/R as a viable method for preventing the progression of acute renal injury to renal fibrosis.

MLL3 suppresses tumorigenesis through regulating TNS3 enhancer activity.

MLL3 is a histone H3K4 methyltransferase that is frequently mutated in cancer, but the underlying molecular mechanisms remain elusive. Here, we found that MLL3 depletion by CRISPR/sgRNA significantly enhanced cell migration, but did not elevate the proliferation rate of cancer cells. Through RNA-Seq and ChIP-Seq approaches, we identified TNS3 as the potential target gene for MLL3. MLL3 depletion caused downregulation of H3K4me1 and H3K27ac on an enhancer ~ 7 kb ahead of TNS3. 3C assay indicated the identified enhancer interacts with TNS3 promoter and repression of enhancer activity by dCas9-KRAB system impaired TNS3 expression. Exogenous expression of TNS3 in MLL3 deficient cells completely blocked the enhanced cell migration phenotype. Taken together, our study revealed a novel mechanism for MLL3 in suppressing cancer, which may provide novel targets for diagnosis or drug development.

Gamma Knife radiosurgery for large vestibular schwannomas greater than 3 cm in diameter.

OBJECTIVE Stereotactic radiosurgery (SRS) is an important alternative management option for patients with small- and medium-sized vestibular schwannomas (VSs). Its use in the treatment of large tumors, however, is still being debated. The authors reviewed their recent experience to assess the potential role of SRS in larger-sized VSs. METHODS Between 2000 and 2014, 35 patients with large VSs, defined as having both a single dimension > 3 cm and a volume > 10 cm3, underwent Gamma Knife radiosurgery (GKRS). Nine patients (25.7%) had previously undergone resection. The median total volume covered in this group of patients was 14.8 cm3 (range 10.3-24.5 cm3). The median tumor margin dose was 11 Gy (range 10-12 Gy). RESULTS The median follow-up duration was 48 months (range 6-156 months). All 35 patients had regular MRI follow-up examinations. Twenty tumors (57.1%) had a volume reduction of greater than 50%, 5 (14.3%) had a volume reduction of 15%-50%, 5 (14.3%) were stable in size (volume change < 15%), and 5 (14.3%) had larger volumes (all of these lesions were eventually resected). Four patients (11.4%) underwent resection within 9 months to 6 years because of progressive symptoms. One patient (2.9%) had open surgery for new-onset intractable trigeminal neuralgia at 48 months after GKRS. Two patients (5.7%) who developed a symptomatic cyst underwent placement of a cystoperitoneal shunt. Eight (66%) of 12 patients with pre-GKRS trigeminal sensory dysfunction had hypoesthesia relief. One hemifacial spasm completely resolved 3 years after treatment. Seven patients with facial weakness experienced no deterioration after GKRS. Two of 3 patients with serviceable hearing before GKRS deteriorated while 1 patient retained the same level of hearing. Two patients improved from severe hearing loss to pure tone audiometry less than 50 dB. The authors found borderline statistical significance for post-GKRS tumor enlargement for later resection (p = 0.05, HR 9.97, CI 0.99-100.00). A tumor volume ≥ 15 cm3 was a significant factor predictive of GKRS failure (p = 0.005). No difference in outcome was observed based on indication for GKRS (p = 0.0761). CONCLUSIONS Although microsurgical resection remains the primary management choice in patients with VSs, most VSs that are defined as having both a single dimension > 3 cm and a volume > 10 cm3 and tolerable mass effect can be managed satisfactorily with GKRS. Tumor volume ≥ 15 cm3 is a significant factor predicting poor tumor control following GKRS.

Outcome of Gamma Knife radiosurgery for trigeminal neuralgia associated with neurovascular compression.

We reviewed 130 patients from 1999 to 2012 to evaluate whether neurovascular compression (NVC) has prognostic value for pain relief in idiopathic trigeminal neuralgia (TN) treated by Gamma Knife radiosurgery (GKRS). Patients were assigned to one of the following groups based on NVC identified by MRI: no NVC, small vessel NVC, and large vessel (defined as part of the vertebrobasilar arterial system) NVC. Follow-up ranged from 4 to 14years. Primary outcome was pain graded by the Barrow Neurological Institute (BNI) pain scale. Successful pain control was defined asa score within Grade I-IIIb. Among the 130 patients, 53 had no neurovascular compression (group 1), 60 had a small vessel NVC (group 2), and 17 had a large vessel NVC (group 3). Successful pain control was 85% in group 1, 75% in group 2, and 88% in group 3 (X2=2.480, p=.289). Secondary outcome was new onset facial numbness which was 21% in group 1, 28% in group 2, and 35% in group 3 (X2=1.683, p=.431). NVC did not affect pain outcome for TN patients treated by GKRS. The lack of poorer response with large vessel NVC that has been reported in literature may be explained by treatment of multiple 4mm shots (as opposed to a single shot in 11/17 patients) to cover a larger compression area of the nerve root by a tortuous vessel.

Magnesium hydroxide extracted from a magnesium-rich mineral for CO2 sequestration in a gas-solid system.

Magnesium hydroxide extracted from magnesium-bearing minerals is considered a promising agent for binding CO2 as a carbonate mineral in a gas-solid reaction. An efficient extraction route consisting of hydrothermal treatment on serpentine in HCl followed by NaOH titration for Mg(OH)2 precipitation was demonstrated. The extracted Mg(OH)2 powder had a mean crystal domain size as small as 12 nm and an apparent surface area of 54 m2/g. Under one atmosphere of 10 vol% CO2/N2, carbonation of the serpentine-derived Mg(OH)2 to 26% of the stoichiometric limit was achieved at 325 degrees C in 2 h; while carbonation of a commercially available Mg(OH)2, with a mean crystal domain size of 33 nm and an apparent surface area of 3.5 m2/g, reached only 9% of the stoichiometric limit. The amount of CO2 fixation was found to be inversely proportional to the crystal domain size of the Mg(OH)2 specimens. The experimental data strongly suggested that only a monolayer of carbonates was formed on the crystal domain boundary in the gas-solid reaction, with little penetration of the carbonates into the crystal domain.