Association of complete blood count parameters with the risk of incident pulmonary heart disease in pneumoconiosis: a retrospective cohort study.

BACKGROUND: Pneumoconiosis mostly combines pulmonary and cardiovascular diseases, among which pulmonary heart disease (PHD) is of major concern due to its significant impact on the survival of pneumoconiosis patients. White cell count (WCC), red cell distribution width (RDW) and platelet parameters are thought to affect inflammatory responses and may be predictors of various cardiovascular diseases. However, very few studies have focused on PHD. OBJECTIVES: To examine the relationship between baseline complete blood count parameters (WCC, RDW, platelet parameters) and the risk of incident PHD in pneumoconiosis patients. DESIGN: A retrospective cohort study. SETTING: This was a single-centre, retrospective cohort study that used data from an Occupational Disease Hospital, Chengdu, Sichuan. PARTICIPANTS: A total of 946 pneumoconiosis patients from January 2012 to November 2021 were included in the study. Female patients and patients who had PHD, coronary heart disease, hypertensive heart disease, cardiomyopathy, heart failure, oncological disease, multiple organ dysfunction, AIDS at baseline and follow-up time of less than 6 months were also excluded. OUTCOME MEASURES: We identified PHD according to the patient's discharge diagnosis. We constructed Cox proportional hazard regression models to assess the HR of incident PHD in pneumoconiosis, as well as 95% CIs. RESULTS: In the multiple Cox proportional hazard regression analysis, platelet count (PLT) and plateletcrit (PCT) above the median at baseline were associated with an increased risk of PHD in pneumoconiosis with adjusted HR of 1.52 (95% CI 1.09 to 2.12) and 1.42 (95% CI 1.02 to 1.99), respectively. CONCLUSION: Higher baseline PLT and PCT are associated with a higher risk of PHD in pneumoconiosis.

Calorie restriction activates a gastric Notch-FOXO1 pathway to expand ghrelin cells.

Calorie restriction increases lifespan. Among the tissue-specific protective effects of calorie restriction, the impact on the gastrointestinal tract remains unclear. We report increased numbers of chromogranin A-positive (+), including orexigenic ghrelin+ cells, in the stomach of calorie-restricted mice. This effect was accompanied by increased Notch target Hes1 and Notch ligand Jag1 and was reversed by blocking Notch with DAPT, a gamma-secretase inhibitor. Primary cultures and genetically modified reporter mice show that increased endocrine cell abundance is due to altered Lgr5+ stem and Neurog3+ endocrine progenitor cell proliferation. Different from the intestine, calorie restriction decreased gastric Lgr5+ stem cells, while increasing a FOXO1/Neurog3+ subpopulation of endocrine progenitors in a Notch-dependent manner. Further, activation of FOXO1 was sufficient to promote endocrine cell differentiation independent of Notch. The Notch inhibitor PF-03084014 or ghrelin receptor antagonist GHRP-6 reversed the phenotypic effects of calorie restriction in mice. Tirzepatide additionally expanded ghrelin+ cells in mice. In summary, calorie restriction promotes Notch-dependent, FOXO1-regulated gastric endocrine cell differentiation.

Anti-angiogenesis and anti-immunosuppression gene therapy through targeting COUP-TFII in an in situ glioblastoma mouse model.

Glioblastoma (GBM) is the most common and aggressive primary brain cancer; angiogenesis and immunosuppression exacerbate GBM progression. COUP-TFII demonstrates pro-angiogenesis activity; however, its role in glioma progression remains unclear. This study revealed that COUP-TFII promotes angiogenesis in gliomas by inducing transdifferentiation of glioma cells into endothelial-like cells. Mechanistic investigation suggested that COUP-TFII as a transcription factor exerts its function via binding to the promoter of TXNIP. Interestingly, COUP-TFII knockdown attenuated tumorigenesis and tumor progression in an immunocompetent mouse model but promoted tumor progression in an immuno-deficient mouse model. As an explanation, repression of COUP-TFII induces cellular senescence and activates immune surveillance in glioma cells in vitro and in vivo. In addition, we used heparin-polyethyleneimine (HPEI) nanoparticles to deliver COUP-TFII shRNA, which regulated tumor angiogenesis and immunosuppression in an in situ GBM mouse model. This study provides a novel strategy and potential therapeutic targets to treat GBM.

Myosin II mediates Shh signals to shape dental epithelia via control of cell adhesion and movement.

The development of ectodermal organs begins with the formation of a stratified epithelial placode that progressively invaginates into the underlying mesenchyme as the organ takes its shape. Signaling by secreted molecules is critical for epithelial morphogenesis, but how that information leads to cell rearrangement and tissue shape changes remains an open question. Using the mouse dentition as a model, we first establish that non-muscle myosin II is essential for dental epithelial invagination and show that it functions by promoting cell-cell adhesion and persistent convergent cell movements in the suprabasal layer. Shh signaling controls these processes by inducing myosin II activation via AKT. Pharmacological induction of AKT and myosin II can also rescue defects caused by the inhibition of Shh. Together, our results support a model in which the Shh signal is transmitted through myosin II to power effective cellular rearrangement for proper dental epithelial invagination.

Flow field analysis of cigarette filter through micro-CT-based geometries and CFD simulation.

The cigarette filter is an essential component of modern cigarettes and studying the flow distribution within the cigarette filter is of great significance in reducing the harm of cigarettes and optimizing smoking sensations. As the object of numerical simulation research, a three-dimensional model of the cigarette was accurately constructed through micro-CT reverse engineering, achieving a scanning accuracy of 4.05 µm. An overall porous media model of the cigarette filter was established to characterize the pressure distribution inside the filter. Based on the three-dimensional reconstruction, a local simulation model of the cavity-filtered filter was created by extracting a 1/36 geometric model. The simulation results of the overall porous media model of the cigarette filter were used as the pressure boundary conditions for the local simulation model of the cavity-filtered filter, and the effects of the wrapped paper and cavity on the flow field were analyzed. The results show that the simulated pressure drop in the overall porous media model of the cigarette filter had a deviation of less than 3.5% compared to the experimental results. This suggests that the porous media model can effectively predict the changes in pressure drop within the filter. When both wrapped paper and cavity were present, the velocity at the interface between acetate fiber and wrapped paper increased by 141.54%, while the pressure approached 0 Pa. Similarly, at the interface between acetate fiber and cavity, the velocity increased by 130.77%. It indicates that both wrapped paper and cavity significantly influenced the flow field characteristics within the cigarette filter. Additionally, as the porosity of the wrapped paper gradually increased from 0.69 to 0.99 in the radial direction, the fluid velocity increased by 14.46%, while the fluid pressure decreased by 29.09%. These changes were particularly evident when the porosity was below 0.87.

Diabetes treatment by conversion of gut epithelial cells to insulin-producing cells.

Insulin-deficient (type 1) diabetes is treated by providing insulin to maintain euglycemia. The current standard of care is a quasi-closed loop integrating automated insulin delivery with a continuous glucose monitoring sensor. Cell replacement technologies are advancing as an alternative treatment and have been tested as surrogates to cadaveric islets in transplants. In addition, immunomodulatory treatments to delay the onset of type 1 diabetes in high-risk (stage 2) individuals have gained regulatory approval. We have pioneered a cell conversion approach to restore insulin production through pharmacological conversion of intestinal epithelial cells into insulin-producing cells. We have advanced this approach along a translational trajectory through the discovery of small molecule forkhead box protein O1 inhibitors. When administered to different rodent models of insulin-deficient diabetes, these inhibitors have resulted in robust glucose-lowering responses and generation of insulin-producing cells in the gut epithelium. We review past work and delineate a path to human clinical trials.

Machine learning-based decision support system for orthognathic diagnosis and treatment planning.

BACKGROUND: Dento-maxillofacial deformities are common problems. Orthodontic-orthognathic surgery is the primary treatment but accurate diagnosis and careful surgical planning are essential for optimum outcomes. This study aimed to establish and verify a machine learning-based decision support system for treatment of dento-maxillofacial malformations. METHODS: Patients (n = 574) with dento-maxillofacial deformities undergoing spiral CT during January 2015 to August 2020 were enrolled to train diagnostic models based on five different machine learning algorithms; the diagnostic performances were compared with expert diagnoses. Accuracy, sensitivity, specificity, and area under the curve (AUC) were calculated. The adaptive artificial bee colony algorithm was employed to formulate the orthognathic surgical plan, and subsequently evaluated by maxillofacial surgeons in a cohort of 50 patients. The objective evaluation included the difference in bone position between the artificial intelligence (AI) generated and actual surgical plans for the patient, along with discrepancies in postoperative cephalometric analysis outcomes. RESULTS: The binary relevance extreme gradient boosting model performed best, with diagnostic success rates > 90% for six different kinds of dento-maxillofacial deformities; the exception was maxillary overdevelopment (89.27%). AUC was > 0.88 for all diagnostic types. Median score for the surgical plans was 9, and was improved after human-computer interaction. There was no statistically significant difference between the actual and AI- groups. CONCLUSIONS: Machine learning algorithms are effective for diagnosis and surgical planning of dento-maxillofacial deformities and help improve diagnostic efficiency, especially in lower medical centers.

Targeting progranulin alleviated silica particles-induced pulmonary inflammation and fibrosis via decreasing Il-6 and Tgf-ß1/Smad.

Long term exposure to silica particles leads to various diseases, among which silicosis is of great concern. Silicosis is an interstitial lung disease caused by inhalation of silica particles in production environments. However, the mechanisms underlying silicosis remains unclear. Our previous studies revealed that progranulin (Pgrn) promoted the expression of pro-inflammatory factors in alveolar macrophages treated with silica particles and the secretion of extracellular matrix of pulmonary fibroblasts. Nevertheless, the role of Pgrn in silica particles-induced silicosis in vivo was unknown. This study found that silica particles increased Pgrn expression in silicosis patients. Pgrn deficiency reduced lung inflammation and fibrosis in silica particles-induced silicosis mouse models. Subsequently, based on transcriptional sequencing and interleukin (Il) -6 knockout mouse models, results demonstrated that Pgrn deficiency might decrease silicosis inflammation by reducing the production of Il-6, thereby modulating pulmonary fibrosis in the early stage of silicosis mouse models. Furthermore, another mechanism through which Pgrn deficiency reduced fibrosis in silicosis mouse models was the regulation of the transforming growth factor (Tgf) -ß1/Smad signaling pathway. Conclusively, Pgrn contributed to silicosis inflammation and fibrosis induced by silica particles, indicating that Pgrn could be a promising therapeutic target.

Oral glucocorticoids with intravenous cyclophosphamide or oral glucocorticoids alone in the treatment of IgA nephropathy present with nephrotic syndrome and mesangioproliferative glomerulonephritis.

Background: Few studies have evaluated the treatment of immunoglobulin A nephropathy (IgAN) patients with nephrotic syndrome (NS) and mesangioproliferative glomerulonephritis (MPGN). The aim of this study was to compare the therapeutic effects of oral glucocorticoids (GCS) combined with intravenous cyclophosphamide (CTX) and oral GCS alone in the treatment of the MPGN-IgAN patients with NS. Methods: Biopsy-proven primary IgAN patients who were aged ≥14 years at diagnosis, had coexistent NS and MPGN and estimated glomerular filtration rate (eGFR) ≥15 mL/min/1.73 m2, and were treated by oral GCS combined with intravenous CTX or oral GCS alone for 6-12 months were retrospectively included. The patients in the GCS + CTX (prednisone 0.6-0.8 mg/kg/day and intravenous CTX 0.6-1.0 g monthly) or GCS (prednisone 0.8-1 mg/kg/day) group were rather matched at a 1:1 ratio on key characteristics by propensity score matching. The primary outcome was defined as either complete remission or partial remission at Month 24. The secondary outcome was a composite renal endpoint defined as a 50% decline in eGFR, doubling of serum creatinine or progression to end-stage kidney disease. Results: Among the 146 IgAN patients who met the inclusion criteria, 42 patients were enrolled in the GCS + CTX group, and 42 patients were enrolled in the GCS group after propensity score matching. The clinical and histological parameters were similar between the two groups. Remission occurred more frequently in the GCS + CTX group at Month 6 (88.1% vs 52.4%, P < 0.001), Month 12 (88.1% vs 56.1%, P = 0.001) and Month 24 (85.0% vs 47.5%, P < 0.001) than in the GCS group. Moreover, subgroup analysis revealed that the higher response rate at Month 24 in the GCS + CTX group than in the GCS group was also present in different subgroups defined by sex, age, eGFR or Oxford MEST-C. Notably, we found that eGFR decreased at a lower rate in patients from the GCS + CTX group than in patients from the GCS group [eGFR slope: 0.05(-3.09, 3.67) vs -2.56 (-11.30, 0.86) mL/min/1.73 m2/year, P = 0.03]. Based on multivariate Cox regression analysis, GCS + CTX treatment was found to be independently associated with a decrease in risk for the composite endpoint after adjusted by the International Risk Prediction Score with race (hazard ratio = 0.17, 95% confidence interval 0.04-0.83, P = .03). There was no significant difference in adverse events (50.0% vs 42.9%, P = 0.51) or serious adverse events (7.1% vs 11.9%, P = .71) between the two groups. Conclusions: Oral GCS combined with intravenous CTX is superior to GCS alone in treating MPGN-IgAN patients combined with NS. As the retrospective design and small sample size, our findings need to be validated by a prospective study.

Activation of GPER1 in macrophages ameliorates UUO-induced renal fibrosis.

Numerous studies have proven the critical role of macrophages in the renal fibrosis process. Notably, G Protein-coupled Estrogen Receptor 1 (GPER1), a novel estrogen receptor, has been shown to play a ubiquitous role in regulating macrophage activities and proinflammatory pathways. However, the precise role of GPER1 in macrophage-mediated renal fibrosis is unknown. In this study, we aimed to investigate the function of macrophage GPER1 in the UUO-induced renal fibrosis model. Compared to vehicle-treated ovariectomized (OVX) female and male unilateral ureteral obstruction (UUO) models, we observed that G-1 (GPER1 agonist)-treated OVX female and male UUO mice had fewer renal fibrotic lesions and less M1 and M2 macrophage infiltration in the kidney tissues. Conversely, Gper1 deletion in male UUO mice accelerated renal fibrosis and increased inflammation. In vitro studies also revealed that GPER1 activation reduced M0 macrophage polarization towards M1 or M2 phenotypes. The RNA-sequencing analysis and immunoblotting indicated that GPER1 activation was primarily involved in downregulating immune pathways activation and inactivating MAPK pathways. Tubular epithelial cells co-cultured with G-1-pretreated M1 macrophages exhibited fewer injuries and immune activation. In addition, fibroblasts co-cultured with G-1-pretreated M2 macrophages showed downregulated extracellular matrix expression. Overall, this is the first study to demonstrate the effect of GPER1 on macrophage-mediated renal fibrosis via inhibition of M1 and M2 macrophage activation. These findings indicate that GPER1 may be a promising therapeutic target for treating renal fibrosis.

A deep learning and radiomics fusion model based on contrast-enhanced computer tomography improves preoperative identification of cervical lymph node metastasis of oral squamous cell carcinoma.

OBJECTIVES: In this study, we constructed and validated models based on deep learning and radiomics to facilitate preoperative diagnosis of cervical lymph node metastasis (LNM) using contrast-enhanced computed tomography (CECT). MATERIALS AND METHODS: CECT scans of 100 patients with OSCC (217 metastatic and 1973 non-metastatic cervical lymph nodes: development set, 76 patients; internally independent test set, 24 patients) who received treatment at the Peking University School and Hospital of Stomatology between 2012 and 2016 were retrospectively collected. Clinical diagnoses and pathological findings were used to establish the gold standard for metastatic cervical LNs. A reader study with two clinicians was also performed to evaluate the lymph node status in the test set. The performance of the proposed models and the clinicians was evaluated and compared by measuring using the area under the receiver operating characteristic curve (AUC), accuracy (ACC), sensitivity (SEN), and specificity (SPE). RESULTS: A fusion model combining deep learning with radiomics showed the best performance (ACC, 89.2%; SEN, 92.0%; SPE, 88.9%; and AUC, 0.950 [95% confidence interval: 0.908-0.993, P < 0.001]) in the test set. In comparison with the clinicians, the fusion model showed higher sensitivity (92.0 vs. 72.0% and 60.0%) but lower specificity (88.9 vs. 97.5% and 98.8%). CONCLUSION: A fusion model combining radiomics and deep learning approaches outperformed other single-technique models and showed great potential to accurately predict cervical LNM in patients with OSCC. CLINICAL RELEVANCE: The fusion model can complement the preoperative identification of LNM of OSCC performed by the clinicians.

Mechanical Signaling in Dental Pulp Stem Cells.

Dental pulp stem cells (DPSCs) are a type of mesenchymal stem cells derived from dental pulp that serves as an important model for investigating biological regeneration. DPSCs have a multipotent differentiation capacity and can promote different biological processes, including osteogenesis, odontogenesis, chondrogenesis, and angiogenesis. These biological processes are regulated by an extensive range of intra- and extra-cellular factors. Further, biomechanical cues, such as substrate stiffness, physical stress, and cell spreading, have been highlighted as particularly important modulators of DPSC function. This review sought to discuss various related signaling components involved in biomechanical cues and their respective roles in cellular and tissue responses in DPSCs, summarize current findings, and provide an outlook on the potential applications of biomechanics in regenerative medicine and tissue engineering.

Toxic Epidermal Necrolysis Induced by Sintilimab: A Case Report.

Sintilimab is an anti-programmed cell death receptor-1 antibody. The phase III clinical trial ORIENT-12 confirmed the safety of sintilimab combined with pemetrexed/platinum in the treatment of advanced squamous non-small cell lung cancer. Skin reactions are the most commonly reported adverse events of immune checkpoint inhibitors and are rarely severe. We describe a case of toxic epidermal necrolysis related to sintilimab in an elderly oncologic patient. 3 weeks after immunotherapy, the patient developed an extensive rash and diffuse itching, rapidly evolving into macules, blisters, bullae and erosions. Causal evaluation was performed based on the algorithm of drug causality for epidermal necrolysis and national Food and Drug Administration qualitative analysis. The patient responded to high-dose glucocorticosteroid and supportive therapy, alongside with local wound care. If immune checkpoint inhibitors need to be extrapolated clinically, strictly following evidence-based research, promptly detecting and treating adverse reactions is crucial.

Risk factors and their interactive effects on severe acute pancreatitis complicated with acute gastrointestinal injury.

BACKGROUND: There are many risk factors for severe acute pancreatitis (SAP) complicated with acute gastrointestinal injury (AGI), but few reports on the interaction between these risk factors. AIM: To analyze the risk factors for SAP complicated with AGI and their interactive effects. METHODS: We selected 168 SAP patients admitted to our hospital between December 2019 and June 2022. They were divided into AGI group and non-AGI group according to whether AGI was present. Demographic data and laboratory test data were compared between the two groups. The risk factors for SAP with concomitant AGI were analyzed using multifactorial logistic regression, and an analysis of the interaction of the risk factors was performed. RESULTS: The percentage of patients with multiple organ dysfunction syndrome, acute physiological and chronic health scoring system II (APACHE II) score, white blood cell count and creatinine (CRE) level was higher in the AGI group than in the non-AGI group. There was a statistically significant difference between the two groups (P < 0.05). Logistic regression analysis indicated that an APACHE II score > 15 and CRE > 100 µmol/L were risk factors for SAP complicating AGI. The interaction index of APACHE II score and CRE level was 3.123. CONCLUSION: An APACHE II score > 15 and CRE level > 100 µmol/L are independent risk factors for SAP complicated with AGI, and there is a positive interaction between them.

HPV E7-drived ALKBH5 promotes cervical cancer progression by modulating m6A modification of PAK5.

Human papillomavirus (HPV) infection is a causative agent of cervical cancer (CC). N6-methyladenosine (m6A) modification is implicated in carcinogenesis and tumor progression. However, the involvement of m6A modification in HPV-involved CC remains unclear. Here we showed that HPV E6/7 oncoproteins affected the global m6A modification and E7 specifically promoted the expression of ALKBH5. We found that ALKBH5 was significantly upregulated in CC and might serve as a valuable prognostic marker. Forced expression of ALKBH5 enhanced the malignant phenotypes of CC cells. Mechanistically, we discovered that E7 increased ALKBH5 expression through E2F1-mediated activation of the H3K27Ac and H3K4Me3 histone modifications, as well as post-translational modification mediated by DDX3. ALKBH5-mediated m6A demethylation enhanced the expression of PAK5. The m6A reader YTHDF2 bound to PAK5 mRNA and regulated its stability in an m6A-dependent manner. Moreover, ALKBH5 promoted tumorigenesis and metastasis of CC by regulating PAK5. Overall, our findings herein demonstrate a significant role of ALKBH5 in CC progression in HPV-positive cells. Thus, we propose that ALKBH5 may serve as a prognostic biomarker and therapeutic target for CC patients.

ESM-1 Mediates Cell Progression in Clear Cell Renal Cell Carcinoma by Affecting Wnt/ß-Catenin Signalling Pathway.

BACKGROUND: Overexpressed endothelial cell specific molecule-1 (ESM-1) has been identified in various human malignancies, but its expression and function in clear cell renal cell carcinoma (ccRCC) progression are still uncovered. This study explored the critical roles as well as molecular mechanism of ESM-1 in ccRCC progression. METHODS: The ESM-1 expression in ccRCC tissues and cells was measured using Western blot assay. The function of ESM-1 knockdown in ccRCC cell viability, invasion as well as migration was analysed. Changes in specific proteins were also detected by Western blot analysis. RESULTS: The ESM-1 expression increased in ccRCC tissue samples and cells, which indicated poor prognosis. Moreover, ESM-1 silencing considerably inhibited ccRCC cell growth, invasion and migration in vitro. ESM-1 partially promoted ccRCC development through wingless-type mouse mammary tumour integration site family/beta-catenin (Wnt/ß-catenin signalling). CONCLUSIONS: ESM-1 acted as an oncogene by influencing the Wnt/ß-catenin pathway in ccRCC.

COPS6 promotes tumor progression and reduces CD8+ T cell infiltration by repressing IL-6 production to facilitate tumor immune evasion in breast cancer.

Due to poor T cell infiltration, tumors evade immune surveillance. Increased CD8+ T cell infiltration in breast cancer suggests a satisfactory response to immunotherapy. COPS6 has been identified as an oncogene, but its role in regulating antitumor immune responses has not been defined. In this study, we investigated the impact of COPS6 on tumor immune evasion in vivo. Tumor transplantation models were established in C57BL/6 J mice and BALB/c nude mice. Flow cytometry was conducted to identify the role of COPS6 on tumor-infiltrating CD8+ T cells. By analyzing the TCGA and GTEx cohort, we found that COPS6 expression was significantly up-regulated in a variety of cancers. In human osteosarcoma cell line U2OS and non-small cell lung cancer cell line H1299, we showed that p53 negatively regulated COPS6 promoter activity. In human breast cancer MCF-7 cells, COPS6 overexpression stimulated p-AKT expression as well as the proliferation and malignant transformation of tumor cells, whereas knockdown of COPS6 caused opposite effects. Knockdown of COPS6 also significantly suppressed the growth of mouse mammary cancer EMT6 xenografts in BALB/c nude mice. Bioinformatics analysis suggested that COPS6 was a mediator of IL-6 production in the tumor microenvironment and a negative regulator of CD8+ T cell tumor infiltration in breast cancer. In C57BL6 mice bearing EMT6 xenografts, COPS6 knockdown in the EMT6 cells increased the number of tumor-infiltrating CD8+ T cells, while knockdown of IL-6 in COPS6KD EMT6 cells diminished tumor infiltrating CD8+ T cells. We conclude that COPS6 promotes breast cancer progression by reducing CD8+ T cell infiltration and function via the regulation of IL-6 secretion. This study clarifies the role of p53/COPS6/IL-6/CD8+ tumor infiltrating lymphocytes signaling in breast cancer progression and immune evasion, opening a new path for development of COPS6-targeting therapies to enhance tumor immunogenicity and treat immunologically "cold" breast cancer.

Application of a linear interpolation algorithm in radiation therapy dosimetry for 3D dose point acquisition.

Air-vented ion chambers are generally used in radiation therapy dosimetry to determine the absorbed radiation dose with superior precision. However, in ion chamber detector arrays, the number of array elements and their spacing do not provide sufficient spatial sampling, which can be overcome by interpolating measured data. Herein, we investigated the potential principle of the linear interpolation algorithm in volumetric dose reconstruction based on computed tomography images in the volumetric modulated arc therapy (VMAT) technique and evaluated how the ion chamber spacing and anatomical mass density affect the accuracy of interpolating new data points. Plane measurement doses on 83 VMAT treatment plans at different anatomical sites were acquired using Octavius 729, Octavius1500, and MatriXX ion chamber detector arrays, followed by the linear interpolation to reconstruct volumetric doses. Dosimetric differences in planning target volumes (PTVs) and organs at risk (OARs) between treatment planning system and reconstruction were evaluated by dose volume histogram metrics. The average percentage dose deviations in the mean dose (Dmean) of PTVs reconstructed by 729 and 1500 arrays ranged from 4.7 to 7.3% and from 1.5 to 2.3%, while the maximum dose (Dmax) counterparts ranged from 2.3 to 5.5% and from 1.6 to 7.6%, respectively. The average percentage dose/volume deviations of mixed PTVs and OARs in the abdomen/gastric and pelvic sites were 7.6%, 3.5%, and 7.2%, while mediastinum and lung plans showed slightly larger values of 8.7%, 5.1%, and 8.9% for 729, 1500, and MatriXX detector arrays, respectively. Our findings indicated that the smaller the spacing between neighbouring detectors and the more ion chambers present, the smaller the error in interpolating new data points. Anatomical regions with small local mass density inhomogeneity were associated with superior dose reconstruction. Given a large mass density difference in the various human anatomical structures and the characteristics of the linear interpolation algorithm, we suggest that an alternative data interpolation method should be used in radiotherapy dosimetry.

Effect of Porcine- and Bovine-Derived Xenografts with Hydroxypropyl Methylcellulose for Bone Formation in Rabbit Calvaria Defects.

In this study, hydroxypropyl methylcellulose (HPMC) was mixed with particle-type xenografts, derived from two different species (bovine and porcine), to increase the manipulability of bone grafts and compare the bone regeneration ability. Four circular defects with a diameter of 6 mm were formed on each rabbit calvaria, and the defects were randomly divided into three groups: no treatment (control group), HPMC-mixed bovine xenograft (Bo-Hy group), and HPMC-mixed porcine xenograft (Po-Hy group). At eight weeks, micro-computed tomography (µCT) scanning and histomorphometric analyses were performed to evaluate new bone formation within the defects. The results revealed that the defects treated with the Bo-Hy and the Po-Hy showed higher bone regeneration than the control group (p < 0.05), while there was no significant difference between the two xenograft groups (p > 0.05). Within the limitations of the present study, there was no difference in new bone formation between porcine and bovine xenografts with HPMC, and bone graft material was easily moldable with the desired shape during surgery. Therefore, the moldable porcine-derived xenograft with HPMC used in this study could be a promising substitute for the currently used bone grafts as it exhibits good bone regeneration ability for bony defects.

Genetic and pharmacologic inhibition of ALDH1A3 as a treatment of ß-cell failure.

Type 2 diabetes (T2D) is associated with ß-cell dedifferentiation. Aldehyde dehydrogenase 1 isoform A3 (ALHD1A3) is a marker of ß-cell dedifferentiation and correlates with T2D progression. However, it is unknown whether ALDH1A3 activity contributes to ß-cell failure, and whether the decrease of ALDH1A3-positive ß-cells (A+) following pair-feeding of diabetic animals is due to ß-cell restoration. To tackle these questions, we (i) investigated the fate of A+ cells during pair-feeding by lineage-tracing, (ii) somatically ablated ALDH1A3 in diabetic ß-cells, and (iii) used a novel selective ALDH1A3 inhibitor to treat diabetes. Lineage tracing and functional characterization show that A+ cells can be reconverted to functional, mature ß-cells. Genetic or pharmacological inhibition of ALDH1A3 in diabetic mice lowers glycemia and increases insulin secretion. Characterization of ß-cells following ALDH1A3 inhibition shows reactivation of differentiation as well as regeneration pathways. We conclude that ALDH1A3 inhibition offers a therapeutic strategy against ß-cell dysfunction in diabetes.