Spontaneous xenogeneic GvHD in Wilms' tumor Patient‐Derived xenograft models and potential solutions

Severely immunocompromised NOD.Cg‐Prkdc ^scid Il2rg ^tm1Sug (NOG) mice are among the ideal animal recipients for generation of human cancer models. Transplantation of human solid tumors having abundant tumor‐infiltrating lymphocytes (TILs) can induce xenogeneic graft‐versus‐host disease (xGvHD) following engraftment and expansion of the TILs inside the animal body. Wilms'' tumor (WT) has not been recognized as a lymphocyte‐predominant tumor. However, 3 consecutive generations of NOG mice bearing WT patient‐derived xenografts (PDX) xenotransplanted from a single donor showed different degrees of inflammatory symptoms after transplantation before any therapeutic intervention. In the initial generation, dermatitis, auto‐amputation of digits, weight loss, lymphadenopathy, hepatitis, and interstitial pneumonitis were observed. Despite antibiotic treatment, no response was noticed, and thus the animals were prematurely euthanized (day 47 posttransplantation). Laboratory and histopathologic evaluations revealed lymphoid infiltrates positively immunostained with anti‐human CD3 and CD8 antibodies in the xenografts and primary tumor, whereas no microbial infection or lymphoproliferative disorder was found. Mice of the next generation that lived longer (91 days) developed sclerotic skin changes and more severe pneumonitis. Cutaneous symptoms were milder in the last generation. The xenografts of the last 2 generations also contained TILs, and lacked lymphoproliferative transformation. The systemic immunoinflammatory syndrome in the absence of microbial infection and posttransplant lymphoproliferative disorder was suggestive of xGvHD. While there are few reports of xGvHD in severely immunodeficient mice xenotransplanted from lymphodominant tumor xenografts, this report for the first time documented serial xGvHD in consecutive passages of WT PDX‐bearing models and discussed potential solutions to prevent such an undesired complication.     

On the Morphological Deviation in Additive Manufacturing of Porous Ti6Al4V Scaffold: A Design Consideration

Additively manufactured Ti scaffolds have been used for bone replacement and orthopaedic applications. In these applications, both morphological and mechanical properties are important for their in vivo performance. Additively manufactured Ti6Al4V triply periodic minimal surface (TPMS) scaffolds with diamond and gyroid structures are known to have high stiffness and high osseointegration properties, respectively. However, morphological deviations between the as-designed and as-built types of these scaffolds have not been studied before. In this study, the morphological and mechanical properties of diamond and gyroid scaffolds at macro and microscales were examined. The results demonstrated that the mean printed strut thickness was greater than the designed target value. For diamond scaffolds, the deviation increased from 7.5 μm (2.5% excess) for vertical struts to 105.4 μm (35.1% excess) for horizontal struts. For the gyroid design, the corresponding deviations were larger, ranging from 12.6 μm (4.2% excess) to 198.6 μm (66.2% excess). The mean printed pore size was less than the designed target value. For diamonds, the deviation of the mean pore size from the designed value increased from 33.1 μm (−3.0% excess) for vertical struts to 92.8 μm (−8.4% excess) for horizontal struts. The corresponding deviation for gyroids was larger, ranging from 23.8 μm (−3.0% excess) to 168.7 μm (−21.1% excess). Compressive Young’s modulus of the bulk sample, gyroid and diamond scaffolds was calculated to be 35.8 GPa, 6.81 GPa and 7.59 GPa, respectively, via the global compression method. The corresponding yield strength of the samples was measured to be 1012, 108 and 134 MPa. Average microhardness and Young’s modulus from α and β phases of Ti6Al4V from scaffold struts were calculated to be 4.1 GPa and 131 GPa, respectively. The extracted morphology and mechanical properties in this study could help understand the deviation between the as-design and as-built matrices, which could help develop a design compensation strategy before the fabrication of the scaffolds.     

Evaluation of Moisture Damage Potential in Hot Mix Asphalt Using Polymeric Aggregate Treatment

To enhance the moisture damage performance of hot mix asphalt (HMA), treating the aggregate surface with a suitable additive was a more convenient approach. In this research, two types of aggregate modifiers were used to study the effect of moisture damage on HMA. Three different aggregate sources were selected based on their abundance of use in HMA. To study the impact of these aggregate modifiers on moisture susceptibility of HMA, the indirect tensile strength test and indirect tensile modulus test were used as the performance tests. Moisture conditioning of specimens was carried out to simulate the effect of moisture on HMA. The prepared samples’ tensile strength ratio (TSR) and stiffness modulus (Sm) results indicated a decrease in the strength of the HMA after moisture conditioning. After treating the aggregate surface with additives, an improvement was seen in dry and wet strength and stiffness. Moreover, an increasing trend was observed for both additives. The correlation between TSR and strength loss reveals a strong correlation (R² = 0.7219). Also, the two additives indicate increased wettability of asphalt binder over aggregate, thus improving the adhesion between aggregate and asphalt binder.     

CHADS2 and CHA2DS2-VASc scores as predictors of platelet reactivity in acute coronary syndrome

BackgroundPlatelet function testing (PFT) in patients treated with P2Y₁₂ inhibitors has been widely evaluated for the prediction of stent thrombosis, myocardial infarction, and bleeding events following percutaneous coronary intervention (PCI) in acute coronary syndrome (ACS). Thus, PFT-guided treatment could positively affect patient outcomes. Data regarding clinical parameters for predicting platelet reactivity in ACS patients are limited. Therefore, our study aims to evaluate CHADS2 and CHA2DS2-VASc scores as predictors for platelet reactivity in ACS patients.MethodsTwo hundred and ninety-one consecutive patients who underwent PCI and were treated with aspirin and clopidogrel due to ACS were tested for their CHADS2, CHA2DS2-VASc scores and platelet reactivity using adenosine diphosphate (ADP)-induced aggregation (conventional aggregometry). Patients were classified into groups according to their CHADS2 and CHA2DS2-VASc scores. Low-risk group (0–1 score) for CHADS2 and CHA2DS2-VASc scores and high-risk group (2–6, 2–9) for CHADS2 and CHA2DS2-VASc scores, respectively. Furthermore, platelet reactivity in each group were compared (low CHADS2 group vs high CHADS2 group, and low CHA2DS2-VASc vs high CHA2DS2-VASc). Platelet reactivity was defined as low platelet reactivity (<19 U), optimal platelet reactivity [(OPR); 19–46 U], and high on-treatment platelet reactivity [(HPR); >46 U]. Thereafter receiver operating characteristic curve analysis was conducted to verify whether CHADS2 and CHA2DS2-VASc scores could predict platelet reactivity.ResultsLow CHADS2 and CHA2DS2-VASc scores were significantly correlated with lower mean platelet ADP-induced aggregation as compared with high CHADS2 and CHA2DS2-VASc scores [45.5 U (± 16) vs. 54.8 U (±15) and 44.2 U (±16) vs. 51.0 U (±17), respectively, p = 0.01 for both].ConclusionIn ACS patients treated with clopidogrel following PCI, high CHADS2 and CHA2DS2-VASc scores correlated with HPR and lower scores correlated with OPR. Further studies are needed to evaluate our findings’ clinical implications.     

Association of left ventricular hypertrophy with high-sensitive C-reactive protein in hemodialysis patients

Background

Micro inflammation and cardiovascular disease such as left ventricular hypertrophy (LVH) are common in hemodialysis (HD) patients. Hence, we have evaluated the relationship between high-sensitive C-reactive protein (hs-CRP), as an inflammation marker, and left ventricular mass index (LVMi) and left ventricular mass (LVM) in HD patients.

Methods

An analytical cross-sectional study was performed in 104 HD patients. Serum hs-CRP, LVMi, LVM, and blood pressure were evaluated; demographic data and duration of HD were also recorded. Finally, results were analyzed by using Student’s t test, Pearson’s correlation coefficient, one-way ANOVA and multiple regression to determine the relationship between LVMi and other variables.

Results

A total of 66 male patients (63.46 %) and 38 female patients, with a mean age of 51.75 ± 15.98 years-old, participated in this study. Hypertension was the most common underlying disease (65.4 %). The mean LVMi was 366.98 ± 120.89 g/m² and the mean hs-CRP was 8.55 mg/l. Eighty-nine percent of patients had LVH. The hs-CRP level was significantly associated with age and with LVM (P = 0.0001, P = 0.039, respectively). On multivariate analysis, hs-CRP and systolic blood pressure were found to be independent predictors of LVM and LVMi.

Conclusions

This study shows that hs-CRP and systolic BP are independent predictors of LVH in HD patients.