Use of reconstruction plates prebent on three-dimensional models to reduce the complications of mandibular reconstruction.

Background/purpose: Though the gold standard method for mandible reconstruction of the defect from segmental mandibulectomy is by osseous flap or graft, using reconstruction plates is still indicated in some cases. Traditionally, the plate is bended immediately after the segmental mandibulectomy by freehand. However, it's difficult to fit well to the original position of mandible, which may result in more complications. This study therefore aimed to investigate whether using prebent plates on computer-aided 3D printing models could reduce the complication rate. Materials and methods: Patients who received mandible reconstruction by reconstruction plate from 2018 to 2022 were enrolled and evaluated in this study. The data, including demographics, indications for surgery, pre-existed preoperative and postoperative therapies, classification of defects, and postoperative outcomes were collected and analyzed. Results: A total of 52 patients were enrolled in our study. The prebent group exhibited a significantly lower complication rate than that of the immediately bent group (P = 0.012). Other risk factors of plate complications included postoperative adjuvant radiotherapy (P = 0.017) and previous surgery (P = 0.047). The complication-free survival rate was also better in the prebent group in a 3-year follow-up period (P = 0.012). Conclusion: Prebent plates on computer-aided printing models proved to be an effective approach to reduce the complications for mandibular reconstruction in segmental mandibulectomy.

Radiomic biomarkers for platinum-refractory head and neck cancer in the era of immunotherapy.

OBJECTIVE: Immune checkpoint inhibitors (ICI) are recommended as the first-line therapy for platinum-refractory head and neck squamous cell carcinoma (HNSCC), a disease with a poor prognosis. However, biomarkers in this situation are rare. The objective was to identify radiomic features-associated biomarkers to guide the prognosis and treatment opinions in the era of ICI. METHODS: A total of 31 platinum-refractory HNSCC patients were retrospectively enrolled. Of these, 65.5% (20/31) received ICI-based therapy and 35.5% (11/31) did not. Radiomic features of the primary site at the onset of recurrent metastatic (R/M) status were extracted. Prognostic and predictive radiomic biomarkers were analysed. RESULTS: The median overall survival from R/M status (R/M OS) was 9.6 months. Grey-level co-occurrence matrix-associated texture features were the most important in identifying the patients with or without 9-month R/M death. A radiomic risk-stratification model was established and equally separated the patients into high-, intermittent- and lower-risk groups (1-year R/M death rate, 100.0% vs. 70.8% vs. 27.1%, p = 0.001). Short-run high grey-level emphasis (SRHGE) was more suitable than programmed death ligand 1 (PD-L1) expression in selecting whether patients received ICI-based therapy. CONCLUSIONS: Radiomic features were effective prognostic and predictive biomarkers. Future studies are warranted.

Reversal of arterial stiffness in medically and surgically treated unilateral primary aldosteronism.

OBJECTIVE: Hyperaldosteronism has adverse effects on cardiovascular structure and function. Laparoscopic adrenalectomy is the gold standard for patients with unilateral primary aldosteronism. For unilateral primary aldosteronism patients unable or unwilling to undergo surgery, the effects of mineralocorticoid receptor antagonists (MRAs) on the reversibility of arterial stiffness and other clinical data remain unclear. We aimed to compare the reversibility of arterial stiffness using pulse wave velocity (PWV) and other clinical parameters between surgically and medically treated unilateral primary aldosteronism patients. METHODS: We prospectively enrolled 306 unilateral primary aldosteronism patients, of whom 247 received adrenalectomy and 59 received medical treatment with MRAs. Detailed medical history, basic biochemistry and PWV data were collected in both groups before treatment and 1 year after treatment. After propensity score matching (PSM) for age, sex, SBP and DBPs, 149 patients receiving adrenalectomy and 54 patients receiving MRAs were included for further analysis. RESULTS: After PSM, the patients receiving adrenalectomy had a greater reduction in blood pressure, increase in serum potassium, and change in PWV (ΔPWV, -53 ±â€Š113 vs. -10 ±â€Š140 cm/s, P  = 0.028) than those receiving MRAs 1 year after treatment. Multivariable regression analysis further identified that surgery (compared with MRA treatment), baseline PWV, baseline DBP, the change in DBP and the use of diuretics were independently correlated with ΔPWV. CONCLUSION: Adrenalectomy is superior to MRA treatment with regards to vascular remodeling when treating unilateral primary aldosteronism patients.

Anatomical and functional remodeling of left ventricle in patients with primary aldosteronism and concomitant albuminuria.

Background: Primary aldosteronism (PA) is the leading cause of secondary hypertension globally and is associated with adverse cardiovascular outcomes. However, the cardiac impact of concomitant albuminuria remains unknown. Objective: To compare anatomical and functional remodeling of left ventricle (LV) in PA patients with or without albuminuria. Design: Prospective cohort study. Methods: The cohort was separated into two arms according to the presence or absence of albuminuria (>30 mg/g of morning spot urine). Propensity score matching with age, sex, systolic blood pressure, and diabetes mellitus was performed. Multivariate analysis was conducted with adjustments for age, sex, body mass index, systolic blood pressure, duration of hypertension, smoking, diabetes mellitus, number of antihypertensive agents, and aldosterone level. A local-linear model with bandwidth of 2.07 was used to study correlations. Results: A total of 519 individuals with PA were enrolled in the study, of whom 152 had albuminuria. After matching, the albuminuria group had a higher creatinine level, at baseline. With regard to LV remodeling, albuminuria was independently associated with a significantly higher interventricular septum (1.22 > 1.17 cm, p = 0.030), LV posterior wall thickness (1.16 > 1.10 cm, p = 0.011), LV mass index (125 > 116 g/m2, p = 0.023), and medial E/e' ratio (13.61 > 12.30, p = 0.032), and a lower medial early diastolic peak velocity (5.70 < 6.36 cm/s, p = 0.016). Multivariate analysis further revealed that albuminuria was an independent risk factor for elevated LV mass index (p < 0.001) and medial E/e' ratio (p = 0.010). Non-parametric kernel regression also demonstrated that the level of albuminuria was positively correlated with LV mass index. The remodeling of LV mass and diastolic function under the presence of albuminuria distinctly improved after PA treatment. Conclusion: The presence of concomitant albuminuria in patients with PA was associated with pronounced LV hypertrophy and compromised LV diastolic function. These alterations were reversible after treatment for PA. Plain language summary: Cardiac Impact of Primary Aldosteronism and Albuminuria Primary aldosteronism and albuminuria has been, respectively, demonstrated to bring about left ventricular remodeling, but the aggregative effect was unknown. We constructed a prospective single-center cohort study in Taiwan. We proposed the presence of concomitant albuminuria was associated with left ventricular hypertrophy and compromised diastolic function. Intriguingly, management of primary aldosteronism was able to restore these alterations. Our study delineated the cardiorenal crosstalk in the setting of secondary hypertension and the role of albuminuria for left ventricular remodeling. Future interrogations toward the underlying pathophysiology as well as therapeutics will facilitate the improvement of holistic care for such population.

Is OLP potentially malignant? A clue from ZNF582 methylation.

OBJECTIVE: Whether oral lichen planus (OLP) was potentially malignant remains controversial. Here, we examined associations of ZNF582 methylation (ZNF582m ) with OLP lesions, dysplastic features and squamous cell carcinoma (OSCC). MATERIALS AND METHODS: This is a case-control study. ZNF582m was evaluated in both lesion and adjacent normal sites of 42 dysplasia, 90 OSCC and 43 OLP patients, whereas ZNF582m was evaluated only in one mucosal site of 45 normal controls. High-risk habits affecting ZNF582m such as betel nut chewing and cigarette smoking were also compared in those groups. RESULTS: OLP lesions showed significantly lower ZNF582m than those of dysplasia and OSCC. At adjacent normal mucosa, ZNF582m increased from patients of OLP, dysplasia, to OSCC. In addition, ZNF582m at adjacent normal sites in OLP patients was comparable to normal mucosa in control group. Dysplasia/OSCC patients with high-risk habits exhibited significantly higher ZNF582m than those without high-risk habits. However, ZNF582m in OLP patients was not affected by those high-risk habits. CONCLUSIONS: OLP is unlikely to be potentially malignant based on ZNF582m levels. ZNF582m may also be a potential biomarker for distinguishing OLP from true dysplastic features and OSCC, and for monitoring the malignant transformation of OLP, potentially malignant disorders with dysplastic features and OSCC.

Improving the Diagnostic Performance by Adding Methylation Marker to Conventional Visual Examination in Identifying Oral Cancer.

BACKGROUND: Visual oral examination (VOE) is a conventional oral cancer screening method. This study aimed to evaluate the value of methylation marker to assist VOE in identifying oral epithelial dysplasia and oral squamous cell carcinoma (OED/OSCC) from non-cancerous lesions in a real-world situation. METHODS: 201 patients with high-risk personal habits who self-perceived oral anomaly were VOE examined, ZNF582 methylation (ZNF582m) tested, and histologically diagnosed. RESULTS: Among them, 132 patients (65.7%) were histologically diagnosed OED/OSCC. Using VOE, 56.1% OED/OSCC patients had possible oral cancer, whereas 37.7% non-OED/OSCC patients had leukoplakia. ZNF582m-positive was detected in 90.2% OED/OSCC patients and 44.9% non-OED/OSCC patients. Various logistic regression models were postulated to evaluate the diagnostic performance of conventional VOE and new strategies using ZNF582m. ROC analysis and its corresponding C-index demonstrated that either triage or co-testing models of VOE and ZNF582m could improve diagnostic performance and discriminative abilities compared with the VOE only approach. CONCLUSIONS: In conclusion, methylation marker test shows equivalent performance to an experienced judgment by oral maxillofacial surgeons and plays a significantly supplementary role in increasing the efficacy in identifying oral malignant lesions. ZNF582m may be an especially important tool for family physicians or general dentists to properly diagnose suspicious oral lesions.

Association of dipeptidyl peptidase IV polymorphism with clinicopathological characters of oral cancer.

OBJECTIVE: To evaluate the associations between dipeptidyl peptidase IV (DPP4) single-nucleotide polymorphism (SNP) and clinicopathological characteristics of oral cancer. METHODS: Four loci of DPP4 SNPs (rs7608798 A/G, rs3788979 C/T, rs2268889 T/C, and rs6741949 G/C) were genotyped by using the TaqMan allelic discrimination in 1238 oral cancers patients and 1197 non-cancer individuals. RESULTS: The percentage of DPP4 SNP rs2268889 TC + CC was significantly higher in the oral cancer participants compared to the control group (odds ratio [OR]: 1.178, 95% confidence interval (CI): 1.004-1.382, p = 0.045). Among 1676 smokers, DPP4 polymorphisms carriers with betel quid chewing were found to have an 8.785- to 10.903-fold risk to have oral cancer compared to DPP4 wild-type carriers without betel quid chewing. Similar trend was found in individuals with alcohol consumption. Moreover, the oral cancer individuals without cigarette smoking history with at least one varied C allele of DPP4 rs2268889 had a significantly higher percentage of large tumor size with the wild-type TT homozygote (p = 0.011). CONCLUSIONS: The DPP4 SNP may correlate to the development of oral cancer in those with cigarette smoking and alcohol consumption. Besides, the DPP4 SNP rs2268889 could relate to worse clinical course of oral cancer in non-smokers.

Preoperative prediction model to evaluate salvage surgery in patients with recurrent or second primary oral cavity squamous cell carcinoma.

OBJECTIVE: In approximately 50% of patients with oral cavity squamous cell carcinoma (OCSCC), the disease progresses after curative surgery. However, the role of salvage surgery (SS) is controversial, and life expectancy after SS is unknown. METHODS: In this study, 262 patients with OCSCC with locoregional recurrence and second primary OCSCC were retrospectively enrolled and divided into a resectable (55.0%, 144/262) and unresectable (45.0%, 118/262) groups. After excluding neck recurrence only, SS had been performed 195 times in the resectable group. The corresponding preoperative clinicopathologic factors and postsurgery survival (PSS) of each SS were pooled for analysis. RESULTS: Median survival after disease progression was 64.2 and 10.4 months for the resectable and unresectable groups, respectively. In the resectable group, one-fifth (19.5%, 37/190) of the patients died within 1 year of SS (PSS < 1 year), and one-third (32.8%, 64/195) of the patients had undergone SS two or more times. The interval from the last surgery ≤ 12 months, depth of invasion of the last surgery > 1 cm, and clinical evidence of nodal disease at the preoperative evaluation were independent predictors of poor PSS. A scoring prediction model was established with 1 point for each factor. The results revealed 1-year postsurgery death rates of 10.3% in the low-risk group (score: 0-1) and 48.6% in the high-risk group (score: 2 or 3) (P < 0.001). CONCLUSIONS: In conclusion, an effective scoring model predicting life expectancy after SS for patients with OCSCC was established.

KCNJ5 Somatic Mutation Is Associated With Higher Aortic Wall Thickness and Less Calcification in Patients With Aldosterone-Producing Adenoma.

Objective: Primary aldosteronism (PA) is the most common type of secondary hypertension, and it is associated with a higher rate of cardiovascular complications. KCNJ5 somatic mutations have recently been identified in aldosterone-producing adenoma (APA), however their influence on vascular remodeling and injury is still unclear. The aim of this study was to investigate the association between KCNJ5 somatic mutation status and vascular status. Methods: We enrolled 179 APA patients who had undergone adrenalectomy from a prospectively maintained database, of whom 99 had KCNJ5 somatic mutations. Preoperative clinical, biochemical and imaging data of abdominal CT, including abdominal aortic calcification (AAC) score, aortic diameter and wall thickness at levels of superior (SMA) and inferior (IMA) mesenteric arteries were analyzed. Results: After propensity score matching for age, sex, body mass index, triglycerides and low-density lipoprotein, there were 48 patients in each KCNJ5 (+) and KCNJ5 (-) group. Mutation carriers had a lower AAC score (217.3 ± 562.2 vs. 605.6 ± 1359.1, P=0.018), higher aortic wall thickness (SMA level: 2.2 ± 0.6 mm vs. 1.8 ± 0.6 mm, P=0.006; IMA level: 2.4 ± 0.6 mm vs. 1.8 ± 0.7 mm, P<0.001) than non-carriers. In multivariate analysis, KCNJ5 mutations were independently associated with AAC score (P=0.014) and aortic wall thickness (SMA level: P<0.001; IMA level: P=0.004). After adrenalectomy, mutation carriers had less aortic wall thickness progression than non-carriers (Δthickness SMA: -0.1 ± 0.8 mm vs. 0.9 ± 0.6 mm, P=0.024; IMA: -0.1 ± 0.6 mm vs. 0.8 ± 0.7 mm, P=0.04). Conclusion: KCNJ5 mutation carriers had less calcification burden of the aorta, thickened aortic wall, and less wall thickness progression than non-carriers.

KCNJ5 Somatic Mutations in Aldosterone-Producing Adenoma Are Associated with a Greater Recovery of Arterial Stiffness.

Primary aldosteronism is the most common form of secondary hypertension and induces various cardiovascular injuries. In aldosterone-producing adenoma (APA), the impact of KCNJ5 somatic mutations on arterial stiffness excluding the influence of confounding factors is uncertain. We enrolled 213 APA patients who were scheduled to undergo adrenalectomy. KCNJ5 gene sequencing of APA was performed. After propensity score matching (PSM) for age, sex, body mass index, blood pressure, number of hypertensive medications, and hypertension duration, there were 66 patients in each group with and without KCNJ5 mutations. The mutation carriers had a higher aldosterone level and lower log transformed brachial-ankle pulse wave velocity (baPWV) than the non-carriers before PSM, but no difference in log baPWV after PSM. One year after adrenalectomy, the mutation carriers had greater decreases in log plasma aldosterone concentration, log aldosterone-renin activity ratio, and log baPWV than the non-carriers after PSM. Only the mutation carriers had a significant decrease in log baPWV after surgery both before and after PSM. KCNJ5 mutations were not correlated with baseline baPWV after PSM but were significantly correlated with ∆baPWV after surgery both before and after PSM. Conclusively, APA patients with KCNJ5 mutations had a greater regression in arterial stiffness after adrenalectomy than those without mutations.

Comparison of cystatin C-based and creatinine-based glomerular filtration rate in the prediction of postoperative residual hypertension in aldosterone-producing adenoma patients after adrenalectomy.

Renal function is associated with postoperative residual hypertension in aldosterone-producing adenoma(APA) patients. Cystatin C-based glomerular filtration rate (GFR) can more accurately estimate renal function than creatinine-based methods. However, which renal function estimation method can more accurately predict postoperative hypertension in APA patients is still unknown. We recruited 180 APA patients who underwent adrenalectomy. Preoperative creatinine and cystatin C-based GFRs were calculated. Residual hypertension was defined as persistent hypertension > 140/90 mmHg or requiring anti-hypertensive medications 1 year after surgery. Sixty-five(36.1%) of the 180 APA patients had residual hypertension. Multivariate logistic regression and receiver operating characteristic (ROC) curve analysis showed a combination of creatinine and cystatin method CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine-cystatin GFR was significantly associated with residual postoperative hypertension and had the largest area under the ROC curve, which was statistically larger than that of Cockcroft-Gault creatinine-based GFR. In both net reclassification index and integrated discrimination index models, CKD-EPI creatinine-cystatin GFR significantly improved the discriminatory power of CG-GFR. Among these renal function estimations used in the presented study, creatinine-cystatin combined GFR was a precise method to predict residual postoperative hypertension in APA patients received adrenalectomy. These finding may help identify those patients with higher risk of residual hypertension after operation.

Prediction Model of Distant Metastasis in Oral Cavity Squamous Cell Carcinoma With or Without Regional Lymphatic Metastasis.

Patients with oral cavity squamous cell carcinoma (OCSCC) who develop distant metastasis (DM) face poor outcomes, and effective prediction models of DM are rare. A total of 595 patients with OCSCC were retrospectively enrolled in this study. Because pathological N staging significantly influences the development and mechanisms of DM, the patients were divided into nodal-negative (pN-) and -positive (pN+) groups. Clinical outcomes, prognoses, and prediction models were analyzed separately for both groups. Overall, 8.9% (53/595) of these patients developed DM. Among the DM cases, 84.9% (45/53) of them developed DM within the first 3 years. The median overall survival, locoregional recurrence-free survival, time until DM development, and postmetastatic survival were 19.8, 12.7, 14.6, and 4.1 months, respectively. Distinguishing patients who only developed locoregional recurrence from those with DM according to locoregional conditions was difficult. Age, surgical margin, and early locoregional recurrence were predictors of DM that were independent of time until DM in the pN- group; the lymphocyte-to-monocyte ratio, presence of lymphovascular invasion, and early locoregional recurrence in the pN+ group were determined. If one point was scored for each factor, then two scoring systems were used to classify the patients into low- (score = 0), intermittent- (score = 1), or high- (score = 2 or 3) risk for the pN- and pN+ groups. According to this scoring system, the 3-year DM rates for the low, intermittent, and high risk subgroups were 0.0%, 5.9%, and 17.8% for the pN- group and 7.1%, 44.9%, and 82.5% for the pN+ group, respectively. These systems also effectively predicted DM, and the areas under the curve predicted DM occurring within the first 3 years were 0.744 and 0.820 for the pN- and pN+ groups, respectively. In conclusion, effective scoring models were established for predicting DM.

Oral microbial dysbiosis and its performance in predicting oral cancer.

Dysbiosis of oral microbiome may dictate the progression of oral squamous cell carcinoma (OSCC). Yet, the composition of oral microbiome fluctuates by saliva and distinct sites of oral cavity and is affected by risky behaviors (smoking, drinking and betel quid chewing) and individuals' oral health condition. To characterize the disturbances in the oral microbial population mainly due to oral tumorigenicity, we profiled the bacteria within the surface of OSCC lesion and its contralateral normal tissue from discovery (n = 74) and validation (n = 42) cohorts of male patients with cancers of the buccal mucosa. Significant alterations in the bacterial diversity and relative abundance of specific oral microbiota (most profoundly, an enrichment for genus Fusobacterium and the loss of genus Streptococcus in the tumor sites) were identified. Functional prediction of oral microbiome shown that microbial genes related to the metabolism of terpenoids and polyketides were differentially enriched between the control and tumor groups, indicating a functional role of oral microbiome in formulating a tumor microenvironment via attenuated biosynthesis of secondary metabolites with anti-cancer effects. Furthermore, the vast majority of microbial signatures detected in the discovery cohort was generalized well to the independent validation cohort, and the clinical validity of these OSCC-associated microbes was observed and successfully replicated. Overall, our analyses reveal signatures (a profusion of Fusobacterium nucleatum CTI-2 and a decrease in Streptococcus pneumoniae) and functions (decreased production of tumor-suppressive metabolites) of oral microbiota related to oral cancer.

Malignant transformation of Taiwanese patients with oral leukoplakia: A nationwide population-based retrospective cohort study.

BACKGROUND/PURPOSE: Oral leukoplakia (OL) is one of the clinically diagnosed oral potentially malignant disorders (OPMDs) with an increased risk of oral cancer development. In this study, we investigated the malignant transformation of OL in Taiwanese population. METHODS: A retrospective cohort study was analyzed from Taiwan's National Health Insurance Research Database. A comparison cohort was randomly frequency-matched with the OL cohort according to age, sex, and index year. Oral submucous fibrosis (OSF) and oral lichen planus (OLP) were further stratified to evaluate the possible synergistic effects for OL-associated malignant transformation. RESULTS: In this cohort, 102 (5.374%) of 1898 OL patients were observed to transform into oral cancer. The malignant transformation rate was 26.40-fold in the OL cohort than in the comparison cohort after adjustment (95% confidence intervals 18.46-37.77). To further stratify with OSF and OLP, OL with OSF (58.38; 95% confidence intervals 34.61-98.50) and OL with OLP (36.88; 95% confidence intervals 8.90-152.78) had higher risk of malignant transformation rate than OL alone (27.01; 95% confidence intervals 18.91-38.59). The Kaplan-Meier plot revealed the free of malignant transformation rate was significant over the 13 years follow-up period (log-rank test, p < 0.001). CONCLUSION: OL patients exhibited a significantly higher risk of malignant transformation than those without OL. In addition, both OSF and OLP could enhance malignant transformation in patients with OL. However, further studies are required to identify the histopathological and clinical parameters in the pathogenesis of malignant transformation among OPMDs.

Hinokitiol ablates myofibroblast activation in precancerous oral submucous fibrosis by targeting Snail.

Oral submucous fibrosis (OSF) is a precancerous condition with symptoms of limited mouth opening and areca nut chewing habit has been implicated in its pathogenesis. Hinokitiol, a natural tropolone derived from Chamacyparis taiwanensis, has been reported to improve oral lichen planus and inhibit various cancer cells. Here, we showed that hinokitiol reduced the myofibroblast activities in fBMFs and prevented the arecoline-induced transdifferentiation. Treatment of hinokitiol dose-dependently downregulated the myofibroblast markers as well as various EMT transcriptional factors. In particular, we identified that Snail was able to bind to the E-box in the α-SMA promoter. Our data suggested that exposure of fBMFs to hinokitiol mitigated the hallmarks of myofibroblasts, while overexpression of Snail eliminated the effect of hinokitiol. These findings revealed that the inhibitory effect of hinokitiol on myofibroblasts was mediated by repression of α-SMA via regulation of Snail and showed the anti-fibrotic potential of hinokitiol in the treatment of OSF.

Human Placenta-Derived Multipotent Cells (hPDMCs) Modulate Cardiac Injury: From Bench to Small and Large Animal Myocardial Ischemia Studies.

Cardiovascular disease is the leading cause of death globally, and stem cell therapy remains one of the most promising strategies for regeneration or repair of the damaged heart. We report that human placenta-derived multipotent cells (hPDMCs) can modulate cardiac injury in small and large animal models of myocardial ischemia (MI) and elucidate the mechanisms involved. We found that hPDMCs can undergo in vitro cardiomyogenic differentiation when cocultured with mouse neonatal cardiomyocytes. Moreover, hPDMCs exert strong proangiogenic responses in vitro toward human endothelial cells mediated by secretion of hepatocyte growth factor, growth-regulated oncogene-α, and interleukin-8. To test the in vivo relevance of these results, small and large animal models of acute MI were induced in mice and minipigs, respectively, by permanent left anterior descending (LAD) artery ligation, followed by hPDMC or culture medium-only implantation with follow-up for up to 8 weeks. Transplantation of hPDMCs into mouse heart post-acute MI induction improved left ventricular function, with significantly enhanced vascularity in the cell-treated group. Furthermore, in minipigs post-acute MI induction, hPDMC transplantation significantly improved myocardial contractility compared to the control group (p = 0.016) at 8 weeks postinjury. In addition, tissue analysis confirmed that hPDMC transplantation induced increased vascularity, cardiomyogenic differentiation, and antiapoptotic effects. Our findings offer evidence that hPDMCs can modulate cardiac injury in both small and large animal models, possibly through proangiogenesis, cardiomyogenesis, and suppression of cardiomyocyte apoptosis. Our study offers mechanistic insights and preclinical evidence on using hPDMCs as a therapeutic strategy to treat severe cardiovascular diseases.

The arrhythmogenic effect of self-assembling nanopeptide hydrogel scaffolds on neonatal mouse cardiomyocytes.

The chaotic spatial disarray due to extracellular matrix expansion disrupts cardiomyocytes interaction and causes arrhythmia. We hypothesized that disordered nanopeptide scaffolds can mimic the chaotic spatial disarray related to cardiac fibrosis and have arrhythmogenic effects on cardiomyocytes. Primary mouse cardiomyocytes were cultured in 2D traditional and 3D nanopeptide hydrogel scaffold systems. Cardiomyocytes in 3D scaffolds showed irregular spontaneous contractile activity as compared with 2D culture controls. Calcium fluorimetric imaging revealed that basal intracellular calcium level increased 1.42-fold in cardiomyocytes cultured in the 3D scaffold, in vitro. The mRNA levels of sarcoplasmic reticulum calcium transport ATPase, ryanodine 2 receptor and connexin 43 elevated 2.14-fold, 2.33-fold and 2.62-fold in 3D compared with 2D. Immunofluorescence imaging revealed lateralization of the distribution of connexin 43 in 3D group. These findings suggest that 3D hydrogel culture system provides a model for the development of cardiac dysrhythmia. These limitations should be considered during cardiac tissue engineering. FROM THE CLINICAL EDITOR: This team of scientists has established a unique 3D hydrogel culture system as a model for the development of cardiac dysrhythmia.