Potential utility of telomere length assessment in breast cancer in a diagnostic histopathology setting.

INTRODUCTION: Telomeres shorten with cell cycling but are restored above mortality threshold in many cancers making them potentially exploitable for differentiating malignant from benign tissues, and for cancer evaluation. MATERIALS AND METHODS: We assessed telomeres in a diagnostic histopathology setting using quantitative fluorescence in situ hybridisation on 33 fibroadenoma (FA) and 73 invasive breast carcinoma of no special type (IBC-NST) (prototypes of benign and malignant breast tumours, respectively) with paired benign, non-lesional breast tissues (BNL). Telomere lengths were expressed as telomere/chromosome-2-centromere ratio (TCR). The telomere length cut-off for malignancy was also determined. RESULTS: Mean TCR of IBC-NST was significantly shorter than FA and BNL (p<0.001). Mean TCR of FA was shorter than BNL but not significantly (p>0.05). TCR cut-off for IBC-NST based on FA was ≤0.29 (sensitivity=75.3%; specificity=78.8%), and ≤0.30 based on BNL (sensitivity=76.7%; specificity=89.0%). TCR of IBC-NST did not differ in relation to histological grade, nodal and hormonal status (p>0.05) but was significantly shorter in HER2-overexpressing cancers (p<0.05). CONCLUSION: We have demonstrated a first-step to the development of methodologybased cut-off values of mean telomere length for distinguishing benign from malignant breast tissues. Telomere length may not value-add to the standard prognostic and predictive parameters, but has potential in relation to HER2.

Universal diamond edge Raman scale to 0.5 terapascal and implications for the metallization of hydrogen.

The recent progress in generating static pressures up to terapascal values opens opportunities for studying novel materials with unusual properties, such as metallization of hydrogen and high-temperature superconductivity. However, an evaluation of pressure above ~0.3 terapascal is a challenge. We report a universal high-pressure scale up to ~0.5 terapascal, which is based on the shift of the Raman edge of stressed diamond anvils correlated with the equation of state of Au and does not require an additional pressure sensor. According to the new scale, the pressure values are substantially lower by 20% at ~0.5 terapascal compared to the extrapolation of the existing scales. We compare the available data of H2 at the highest static pressures. We show that the onset of the proposed metallization of molecular hydrogen reported by different groups is consistent when corrected with the new scale and can be compared with various theoretical predictions.

Blends of palm kernel oil, soybean oil and palm stearin as an alternative to milk fat for frozen dessert application.

In this study, the ternary blends of palm kernel oil (PKO), soybean oil (SBO) and two types of palm stearin (PS) (PS33 and PS38) were systematically prepared and evaluated for their application as an alternative to milk fat in frozen dessert. The physicochemical characteristics namely fatty acids constituent, triacylglycerols (TAGs) composition, melting behavior, solid fat content (SFC) and microstructure were studied. All ternary blends of PKO/SBO/PS33 and PKO/SBO/PS38 had comparable microstructure to that of milk fat. However, 80/15/5 (PKO/SBO/PS33) and 80/15/5 to 80/5/15 (PKO/SBO/PS38) mixtures were found to have similar SFC as milk fat at temperature above 20 °C, allowing these ternary blends to be completely melted at body temperature. With this, 80/15/5 (PKO/SBO/PS33) and 80/15/5 to 80/5/15 (PKO/SBO/PS38) mixtures were able to provide similar meltdown and mouth feel as milk fat at room temperature. Nonetheless, fatty acids constituent, TAGs composition and melting behavior of the blends were different from milk fat. This study showed that ternary blends of PKO, SBO and PS at ratios 80/15/5 (PKO/SBO/PS33) and 80/15/5 to 80/5/15 (PKO/SBO/PS38) can be potentially used as a milk fat alternative for frozen dessert application based on its similar microstructure and SFC profile as the milk fat. Supplementary Information: The online version contains supplementary material available at 10.1007/s13197-022-05507-z.

Influence of combat boot types on in-shoe forces and perceived comfort during unloaded and loaded walking.

INTRODUCTION: Combat boots are essential protective gear for military personnel. The purposes of the present study were to examine (1) the influence of combat boot type on ground reaction force (GRF) variables and perceived comfort during unloaded and loaded walking and (2) the relationship between comfort and biomechanical measurements. METHODS: Four types of combat boots with different physical features (eg, mass, thickness) and mechanical properties (eg, cushioning, rigidity) were compared across 61 male participants with experience in military marching while carrying heavy loads. In each boot type, participants completed a 10-m walk under an unloaded and a 20-kg loaded conditions at their preferred speeds. Peak force and loading rate during walking were measured using the loadsol wireless in-shoe sensor system. Comfort level was assessed using a 7-point Likert scale. Difference between loaded and unloaded walking, and across boot types were statistically compared. Correlation analyses were performed between comfort and GRF variables. RESULTS: On average across all boot types, participants walked 2.1% slower when carrying 20-kg loads while experiencing 24.3% higher peak force and 20.8% higher loading rate. Boot D was perceived as most comfortable, followed by boots C, B and A (χ2(2)=115.4, p<0.001). Participants walked slightly faster (p=0.022, ηp 2 = 0.052) and displayed higher loading rates (p<0.001, ηp 2=0.194) in the two more comfortable boots (C and D) than the less comfortable boots (A and B). No significant correlations were found between perceived comfort and any GRF variables. CONCLUSIONS: Combat boot features can influence perceived comfort ratings substantially during walking, whereas biomechanical differences among boot types are more subtle regardless of load conditions. The lack of relationship between comfort and force variables suggests that both subjective and objective measurements should be considered for comprehensive evaluation of combat boots.

Structural defects of monolayer wet particles during melting under vertical vibration.

The evolution of structural defects during phase transition is of great significance to the understanding of the mechanism of solid-liquid transition. However, the current research on topological defects still uses the pair-correlation function and the orientational order correlation function, so it is difficult to quantify the detailed changes of structural defects locally. In this paper, the local volume fraction is proposed as a key parameter to accurately quantify the variation of structural defects. The experimental results indicate that the evolution of structural defects in the particle system is caused by the decrease of local volume fraction, so the critical value of phase transition could be determined by the minimum local volume fraction ϕ_{min}. Furthermore, according to the evolution law of structural defects, it can be deduced that the phase transition is continuous, which is consistent with the Kosterlitz-Thouless-Halperin-Nelson-Young theory. Therefore, the quantitative analysis of structural defects by using local volume fraction can help make the mechanism of solid-liquid phase transformation clearer.

Regression model for predicting knee flexion angles using ankle plantar flexion angles, body mass index and generalised joint laxity.

Increased knee flexion angles are associated with reduced non-contact anterior cruciate ligament (ACL) injury risks. Ankle plantar flexion angles and internal risk factors could influence knee flexion angles, but their correlations are unknown. This study aimed to establish and validate a regression model to predict knee flexion angles using ankle plantar flexion angles, body mass index (BMI) and generalised joint laxity (GJL) at initial contact of single-leg drop landings. Thirty-two participants performed single-leg drop landings from a 30-cm-high platform. Kinematics and vertical ground reaction forces were measured using a motion capture system and force plate. A multiple regression was performed, and it was validated using a separate data set. The prediction model explained 38% (adjusted R2) of the change in knee flexion angles at initial contact (p = 0.001, large effect size). However, only the ankle plantar flexion angle (p < 0.001) was found to be a significant predictor of knee flexion angles. External validation further showed that the model explained 26% of knee flexion angles (large effect size). The inverse relationship between ankle plantar flexion and knee flexion angles suggests that foot landing strategies could be used to increase knee flexion angles, thereby reducing non-contact ACL injury risks.

HIF-1α repairs degenerative chondrocyte glycolytic metabolism by the transcriptional regulation of Runx2.

OBJECTIVE: HIF-1α and Runx2 expression usually increase in chondrocytes (CHs) during osteoarthritis (OA), which involves the changes in glycolytic metabolism. However, the molecular regulation of HIF-1α related to the CHs glycolytic metabolism is still unclear. In this study, we aimed to reveal the mediation of HIF-1α by Runx2 and its effect on the glycolytic metabolism of degenerative CHs. PATIENTS AND METHODS: The expression of HIF-1α, Runx2, and the degenerative markers of CHs in both natural conditions from the OA patients and IL-1ß treated in vitro model was analyzed by a Western blot or real-time polymerase chain reaction (RT-PCR). The glycolytic metabolism was determined by the intracellular glucose uptake and adenosine triphosphate (ATP) generation. Transfection of siRNA coding HIF-1α or Runx2 was used to clear the function between HIF-1α and Runx2 in the glycolytic metabolism of degenerated CHs caused by IL-1ß. Chromatin immunoprecipitation (ChIP) and Luciferase reporter gene assay were used to verify the Runx2 protein binds to the promoter of HIF-1α and promote its expression. RESULTS: HIF-1α and Runx2 were increased, and glucose uptake and ATP generation were decreased in the degenerative CHs from both OA and IL-1ß conditions. Under the stimulation of IL-1ß, Runx2 silencing rejected the upregulation of HIF-1α and further aggravated the glycolytic metabolism. When HIF-1α was silenced, the glycolytic metabolism of CHs was also suppressed. Besides, Runx2 protein could regulate HIF-1α expression in the transcriptional level by binding to its promoter. CONCLUSIONS: OHIF-1α plays a role in the self-repair of the glycolytic metabolism of degenerative CHs via the transcriptional regulation of Runx2.

FISHing for 1p19q codel in oligodendroglioma.

Together with isocitrate dehydrogenase (IDH) mutation, co-deletion of 1p19q (1p19q codel) is a prerequisite for diagnosis of oligodendroglioma, making it imperative that histopathology laboratories introduce testing for 1p19q codel. To date there is still no consensus reference range and cut-offs that confirm deletion of 1p or 19q. We embarked on determining our reference range in 11 formalinfixed, paraffin-embedded non-neoplastic brain tissue using fluorescence in situ hybridisation (FISH) with the Vysis 1p36/1q25 and 19q13/19p13 FISH Probe Kit (Abbott Molecular Inc., USA). At same time we attempted to validate our methodology in 13 histologically-confirmed IDH-mutant oligodendrogliomas. For 1p, percentage cells with deletion (range=8-23%; mean±SD = 15.73±5.50%) and target: control (1p36:1q25) ratio (range = 0.89-0.96; mean±SD = 0.92±0.03) in non-neoplastic brain, differed significantly (p<0.000) from oligodendroglioma (percentage cells with deletion: range = 49-100%; mean±SD = 82.46±15.21%; target:control ratio range:0.50-0.76; mean±SD = 0.59±0.08). For 19q, percentage cells with deletion (range = 7-20%; mean±SD = 12.00±3.49%) and target:control (19q13/19p13) ratio (range:0.90-0.97; mean±SD = 0.94±0.02) in non-neoplastic brain also differed significantly from oligodendroglioma (percentage cells with deletion: range = 45-100%; mean±SD = 82.62±18.13%; target:control ratio range:0.50-0.78; mean±SD = 0.59±0.09). Using recommended calculation method, for diagnosis of 1p deletion, percentage of cells showing deletion should be >32-33% and/or target:control ratio <0.83. For 19q, percentage of cells showing deletion should be >22% and target:control ratio <0.88. Using these cut-offs all 13 oligodendroglioma demonstrated 1p19q codel.

[The clinical observation of sirolimus combined with calcineurin inhibitors for steroid-resistant/steroid-dependent extensive cGVHD].

Objective: To observe the efficacy and safety of sirolimus combined with calcineurin inhibitor (CNI) in the treatment of glucocorticoid resistant/dependent extensive chronic graft-versus-host disease (cGVHD) . Methods: A total of 27 patients with steroid-resistant/steroid-dependent extensive cGVHD from November 2015 to January 2019 were enrolled and given sirolimus capsules combined with cyclosporine or tacrolimus to observe the clinical efficacy and adverse events. Results: The median duration of medication was 14.2 months and the mean duration was 16.7 months. The median follow-up time was 20.1 months (12.9-46.1 months) . Following the 6-month follow-up, 3 cases achieved complete response (CR) and 12 cases partial response (PR) . The overall response rate (ORR) was 55.6% ; for progression-free survival (PFS) , PFS-6 reached 88.9% (24/27) , and for overall survival (OS) , OS-6 was 100% . At the 1-year follow-up, there were 5 cases of CR and 11 cases of PR, ORR was 59.3% , PFS-12 reached 62.9% (17/27) , and OS-12 was 100% . The subgroup analysis found that the program was more effective for cGVHD in male donors and the target organ analysis had an advantage in the treatment of oral cavity, skin, and liver rejection. Adverse events were observed: hyperlipidemia 11.1% , oral ulcer 7.4% , fungal infection 11.1% , liver injury 3.7% , renal insufficiency 0, and no new CMV and EB viremia. Conclusion: Sirolimus combined with calcineurin inhibitors is effective in treating steroid-resistant/steroid-dependent extensive cGVHD, especially because adverse reactions (renal toxicity, CMV, EBV infection) are low in number, which is suitable for long-term treatment of cGVHD.

[The clinical observation of serum specific biomarkers in patients with chronic graft-versus-host disease].

Objective: Chronic graft-versus-host disease (cGVHD) is a major long-term complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) . It is important to study the changes of serum biomarkers expression in patients for early diagnosis and treatment. Methods: The expression levels of five serum protein markers (IL-1b, IL-16, CXCL9, CCL19, CCL17) in patients with or without cGVHD after allo-HSCT were detected by liquid suspension microarray. Results: Compared with the control group without cGVHD, the expression levels of CXCL9 and CCL17 in serum of patients with cGVHD were significantly increased (P<0.05) . CCL17 was correlated with the severity of cGVHD (P<0.001) . CXCL9 was significantly increased in the serum of patients with skin lesion (P<0.01) , and CCL17 was significantly expressed in cGVHD patients with liver as the target organ (P<0.01) . Conclusion: The combination of CXCL9 and CCL17 can be used as serum biomarkers of cGVHD, which has certain reference value in assisting the diagnosis and evaluation of cGVHD severity.

Superconductivity at 250 K in lanthanum hydride under high pressures.

With the discovery1 of superconductivity at 203 kelvin in H3S, attention returned to conventional superconductors with properties that can be described by the Bardeen-Cooper-Schrieffer and the Migdal-Eliashberg theories. Although these theories predict the possibility of room-temperature superconductivity in metals that have certain favourable properties-such as lattice vibrations at high frequencies-they are not sufficient to guide the design or predict the properties of new superconducting materials. First-principles calculations based on density functional theory have enabled such predictions, and have suggested a new family of superconducting hydrides that possess a clathrate-like structure in which the host atom (calcium, yttrium, lanthanum) is at the centre of a cage formed by hydrogen atoms2-4. For LaH10 and YH10, the onset of superconductivity is predicted to occur at critical temperatures between 240 and 320 kelvin at megabar pressures3-6. Here we report superconductivity with a critical temperature of around 250 kelvin within the [Formula: see text] structure of LaH10 at a pressure of about 170 gigapascals. This is, to our knowledge, the highest critical temperature that has been confirmed so far in a superconducting material. Superconductivity was evidenced by the observation of zero resistance, an isotope effect, and a decrease in critical temperature under an external magnetic field, which suggested an upper critical magnetic field of about 136 tesla at zero temperature. The increase of around 50 kelvin compared with the previous highest critical temperature1 is an encouraging step towards the goal of achieving room-temperature superconductivity in the near future.

Preventing Soil Inoculum of Calonectria pseudonaviculata from Splashing onto Healthy Boxwood Foliage by Mulching.

Boxwood blight, caused by Calonectria pseudonaviculata, is an emerging disease of great concern to horticulturists in the United States and other affected countries. The objective of this study was to evaluate the efficacy of mulching as a physical barrier to prevent soil inoculum from splashing onto healthy boxwood foliage. A field trial consisting of two treatments, mulched and nonmulched, was conducted under field conditions in Lowgap, North Carolina, and in a residential landscape setting near Richmond, Virginia, for 2 years at each site. Mulching efficacy was assessed by monitoring and comparing boxwood blight development on detector plants: containerized 'Justin Brouwers' boxwood, which were rotated through mulched and nonmulched plots at 1- and 2-week intervals in the Lowgap and Richmond sites, respectively. Boxwood blight was observed on detector plants in a combined 55 of the 88 monitoring periods during this study at the two sites. Mulching provided complete protection of Justin Brouwers boxwood from infection by C. pseudonaviculata soil inoculum during 33 of the 55 positive monitoring periods (60%) and good to excellent protection during 13 monitoring periods (24%). The potential applications of mulching for boxwood blight mitigation are discussed.

Microwave ablation combined with doxorubicin enhances cell death via promoting reactive oxygen species generation in breast cancer cells.

PURPOSE: To evaluate the mechanism for enhancing cell death induced by microwave ablation (MWA) combined with doxorubicin treatment in breast cancer cells. MATERIALS AND METHODS: Different temperatures of heat treatment were used to mimic the tumor affected by sublethal heat during MWA in vitro. Breast cancer cells were treated at 43°C and 45°C, with or without doxorubicin. Cell viability, apoptosis, and intracellular reactive oxygen species (ROS) were evaluated in MDA-MB-231 and SUM-1315 cells. Nude mice breast cancer models were randomly divided into control, MWA, doxorubicin, and combined treatment groups. Tumor apoptosis and DNA damage were evaluated in these groups. RESULTS: The combined group had lower cell viability than the heat or doxorubicin group (all P<0.05), and enhanced apoptosis rate was observed in the combined group compared to others (all P<0.01) in MDA-MB-231 and SUM-1315. Increased capase3 (all P<0.01) and decreased Bcl-Xl (all P<0.01) were detected after combined therapy compared to single treated group in vitro. The raisedCaspase3 and DNA damage marker histone H2A.X induced by combined treatment were also approved in the nude mice models. Combined treatment promoted ROS generation compared to doxorubicin or MWA treatment (all P < 0.01). NF-κB expression in the combined group was higher than that of the single treatment group (all P<0.05). N-acetylcysteine (NAC), a ROS scavenger, partly restrained the combined treatment induced cell proliferation inhibition, Caspase3 and NF-κB compared to doxorubicin treatment (all P<0.05). CONCLUSION: MWA combined with doxorubicin promote cell death via ROS induced cell apoptosis and DNA damage. Increasing ROS has potential for improving the efficiency of combined treatment.

Autoantibody against integrin αv ß3 contributes to thrombocytopenia by blocking the migration and adhesion of megakaryocytes.

Essentials The pathogenesis of immune thrombocytopenia (ITP) has not been fully clarified. We analyzed the role of anti-αvß3 autoantibody in the pathogenesis of ITP in patients. Anti-αvß3 autoantibody impeded megakaryocyte migration and adhesion to the vascular niche. Anti-αv ß3 autoantibody potentially contributes to the pathogenesis of refractory ITP. SUMMARY: Background The pathogenesis of immune thrombocytopenia (ITP) has not been fully clarified. Anti-αvß3 integrin autoantibody is detected in chronic ITP patients, but its contribution to ITP is still unclear. Objectives To clarify the potential role of anti-αvß3 integrin autoantibody in chronic ITP and the related mechanism. Methods Relationship between levels of anti-αvß3 autoantibody and platelets in chronic ITP patients was evaluated. The influence of anti-αvß3 antibody on megakaryocyte (MK) survival, differentiation, migration and adhesion was assessed, and the associated signal pathways were investigated. Platelet recovery and MKs' distribution were observed in an ITP mouse model pretreated with different antibodies. Result In this study, we showed that the anti-αvß3 autoantibody usually coexists with anti-αIIbß3 autoantibody in chronic ITP patients, and patients with both autoantibodies have lower platelets. In in vitro studies, we showed that the anti-αvß3 antibody had no significant effect on the survival and proliferation of MKs, whereas it decreased formations of proplatelet significantly. Anti-αvß3 antibody impeded stromal cell derived facor-1 alpha (SDF-1α)- mediated migration and inhibited the phosphorylation of protein kinase B. Anti-αvß3 antibody significantly inhibited MKs' adhesion to endothelial cells and Fibrogen. The phosphorylation of focal adhesion kinase and proto-oncogene tyrosine-protein kinase Src induced by adhesion was inhibited when MKs were pretreated with anti-αvß3 antibody. In in vivo studies, we showed that injection with anti-αv antibody delayed platelet recovery in a mouse model of ITP. Conclusions These findings demonstrate that the autoantibody against integrin αv ß3 may aggravate thrombocytopenia in ITP patients by impeding MK migration and adhesion to the vascular niche, which provides new insights into the pathogenesis of ITP.

Increased expression of miR-330-3p: a novel independent indicator of poor prognosis in human breast cancer.

OBJECTIVE: Previous study has reported that miR-330-3p was highly expressed in breast cancer (BC) patients. However, the effect of miR-330-3p in BC progression remains largely unclear. The purpose of this study was to investigate the clinical significance of miR-330-3p expression in BC. PATIENTS AND METHODS: The expression of miR-330-3p was detected by quantitative Real-time PCR in BC tissues and matched normal breast tissues. The association of miR-330-3p expression with clinicopathological factors of BC patients was also analyzed by x2-test. Prognosis value of patients with BC was assessed by Kaplan-Meier method and Cox proportional hazards model, respectively. RESULTS: Quantitative real-time PCR analysis showed that the expression level of miR-330-3p was significantly higher in BC specimens than that in corresponding noncancerous tissues (p < 0.01). The levels of miR-330-3p were positively correlated with the status of TNM stage (p = 0.011) and lymph node metastasis (p = 0.006). Kaplan-Meier analysis revealed that 5-year overall survival of BC patients with high miR-330-3p expression was shorter compared to those patients with low miR-330-3p expression (p < 0.0001). Moreover, univariate and multivariate regression analysis demonstrated that miR-330-3p was an independent prognostic factor in BC. CONCLUSIONS: Our data suggest that miR-330-3p upregulation maybe concurrently associated with prognosis in patients with BC, suggesting that miR-330-3p may be a potential prognostic biomarker and therapeutic target for patients with BC.