Genomic characterisation of breast fibroepithelial lesions in an international cohort

Fibroepithelial lesions (FELs) are a heterogeneous group of tumours comprising fibroadenomas (FAs) and phyllodes tumours (PTs). Here we used a 16-gene panel that was previously discovered to be implicated in pathogenesis and progression, to characterise a large international cohort of FELs via targeted sequencing. The study comprised 303 (38%) FAs and 493 (62%) PTs which were contributed by the International Fibroepithelial Consortium. There were 659 (83%) Asian and 109 (14%) non-Asian FELs, while the ethnicity of the rest was unknown. Genetic aberrations were significantly associated with increasing grade of PTs, and were detected more in PTs than FAs for MED12, TERT promoter, RARA, FLNA, SETD2, TP53, RB1, EGFR, and IGF1R. Most borderline and malignant PTs possessed ≥ 2 mutations, while there were more cases of FAs with ≤ 1 mutation compared to PTs. FELs with MED12 mutations had significantly higher rates of TERT promoter, RARA, SETD2, EGFR, ERBB4, MAP3K1, and IGF1R aberrations. However, FELs with wild-type MED12 were more likely to express TP53 and PIK3CA mutations. There were no significant differences observed between the mutational profiles of recurrent FAs, FAs with a history of subsequent ipsilateral recurrence or contralateral occurrence, and FAs without a history of subsequent events. We identified recurrent mutations which were more frequent in PTs than FAs, with borderline and malignant PTs harbouring cancer driver gene and multiple mutations. This study affirms the role of a set of genes in FELs, including its potential utility in classification based on mutational profiles. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Gastroprotective activity of chloroform extract of Muntingia calabura and Melastoma malabathricum leaves

Context: Muntingia calabura L. (family Muntingiaceae) and Melastoma malabathricum L. (family Melastomaceae) are traditionally used to treat gastric ulcer.

Objective: The present study determines the mechanisms of gastroprotective activity of the chloroform extract of leaves obtained from both the plants using several in vitro and in vivo assays.

Materials and methods: Phytochemical screening, HPLC analysis, and antioxidant activity of the respective extract were carried out. Gastroprotective activity was determined using ethanol-induced gastric ulcer assay while the mechanisms of gastroprotection were determined using the pyloric ligation assay. The test solutions [8% Tween-80 (vehicle), 20?mg/kg omeprazole, and different doses of extracts (50, 250, or 500?mg/kg] were administered orally once daily for 7 consecutive days before the animals were subjected to ethanol induced gastric ulcers.

Results: The chloroform-extracted M. calabura (CEMC) contains tannins, polyphenolics, triterpenes, and steroids while the chloroform-extracted M. malabathricum (CEMM) contains only triterpenes and steroids. CEMC, but not CEMM, exerted remarkably strong antioxidant activity in the 2,2-diphenyl-1-picrylhydrazyl (DPPH)- (86% versus 16%) and superoxide- (73% versus 36%) radical scavenging assays. Both extracts demonstrated significant (p?<?0.05) gastroprotection with the EC₅₀ value recorded at 192.3 or 297.7?mg/kg, respectively. In the pylorus ligation assay, CEMC and CEMM significantly (p?<?0.05) reduced the total and free acidity and volume; while increased the pH of gastric juice as well as the gastric wall mucus content in comparison with the vehicle-treated group.

Discussion and conclusion: CEMC and CEMM exert gastroprotective effects in animals with ethanol-induced gastric ulcers via antioxidant and anti-secretory effects.     

Effect of Mn Doping on the Optical and Electrical Properties of Double Perovskite Sr2TiCoO6

A new series of Sr₂TiCo_1−xMn_xO₆ (0.0 ≤ x ≤ 0.7) materials has been synthesized using the conventional solid-state method. In this research, X-ray diffraction (XRD) results showed that Mn was successfully doped at the Co site in a cubic structure with monoclinic P2₁/n space group. The effect of Mn cation substitution on the structural, optical and electrical performance of Sr₂TiCo_1−xMn_xO₆ double perovskite was investigated. The optical study revealed a nonlinearity pattern of the band gap that is referred to as the band gap bowing trend. Results from optical and Rietveld refinement supports that the band gap bowing trend is correlated with the charge distribution that produces unique effects on structural and size changes due to the Co-Mn compositions. The morphological scanning electron microscopy studies also showed that larger crystallite sizes were developed when dopant was added. Furthermore, increases in the conductivities support the lowering band gap of Mn-doped samples. Here, the intermixing of the atomic orbitals of Co-Mn provides an efficient interlink electrical pathway to improve conductivity and exhibits a high dielectric property at room temperature. These values are strong evidence that STCM material will be suitable for applications in the semiconductor industry.     

Different sensitivities of senescent breast cancer cells to immune cell‐mediated cytotoxicity

Senescence is a state of growth arrest induced not only in normal cells but also in cancer cells by aging or stress, which triggers DNA damage. Despite growth suppression, senescent cancer cells promote tumor formation and recurrence by producing cytokines and growth factors; this state is designated as the senescence‐associated secretory phenotype. In this study, we examined the susceptibility of senescent human breast cancer cells to immune cell‐mediated cytotoxicity. Doxorubicin (DXR) treatment induced senescence in 2 human breast cancer cell lines, MDA‐MB‐231 and BT‐549, with the induction of γH2AX expression and increased expression of p21 or p16. Treatment with DXR also induced the expression of senescence‐associated β‐galactosidase and promoted the production of pro‐inflammatory cytokines. Importantly, DXR‐treated senescent MDA‐MB‐231 cells showed increased sensitivity to 2 types of immune cell‐mediated cytotoxicity: cytotoxicity of activated CD4⁺ T cells and Ab‐dependent cellular cytotoxicity by natural killer cells. This increased sensitivity to cytotoxicity was partially dependent on tumor necrosis factor‐related apoptosis‐inducing ligand and perforin, respectively. This increased sensitivity was not observed following treatment with the senescence‐inducing cyclin‐dependent kinase‐4/6 inhibitor, abemaciclib. In addition, treatment with DXR, but not abemaciclib, decreased the expression of antiapoptotic proteins in cancer cells. These results indicated that DXR and abemaciclib induced senescence in breast cancer cells, but that they differed in their sensitivity to immune cell‐mediated cytotoxicity. These findings could provide an indication for combining anticancer immunotherapy with chemotherapeutic drugs or molecular targeting drugs.     

Do Temporal Eating Patterns Differ in Healthy versus Unhealthy Overweight/Obese Individuals?

This study examined whether the temporal patterns of energy and macronutrient intake in early and late eating windows were associated with metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO) among non-shift workers. A total of 299 overweight/obese non-shift workers (Age: 40.3 ± 6.9 years; 73.6% women; BMI: 31.7 ± 5.0 kg/m²) were recruited in the Klang Valley area of Malaysia. The biochemical parameters were determined from fasting blood samples, whereas information on dietary intake and timing was obtained from a 7-day diet history questionnaire. The midpoint of eating was used to determine the early and late windows. Compared to MHO non-shift workers (n = 173), MUO non-shift workers (n = 126) had lower energy intake from carbohydrates and protein during the early window. In contrast, MUO participants had greater energy intake from carbohydrates and fat during the late window. Participants with unhealthy metabolic status (regardless of their chronotypes) had similar temporal patterns of energy intake characterized by smaller energy intake during the early window and greater energy intake during the late window compared with participants with healthier metabolic status. Overall, the lowest percentile of energy intake during the early window was associated with an increased risk of MUO, after adjustment for potential confounders [odds ratio (OR) = 4.30, 95% confidence interval (CI) 1.41–13.11]. The greater the energy intake during the late window, the greater the risk of MUO (OR = 2.38, 95% CI 1.11–5.13) (OR = 2.33, 95% CI 1.03–5.32) (OR = 4.45, 95% CI 1.71–11.56). In summary, consuming less energy earlier in the day and more energy and carbohydrate later in the day was associated with a greater risk of MUO. Thus, a prospective study is needed to explore the potential role of chrono-nutrition practices in modifying risk factors to delay the transition of MHO to MUO.     

Geometrical Investigation of Piezoelectric Patches for Broadband Energy Harvesting in Non-Deterministic Composite Plates

Mechanical energy is the most ubiquitous form of energy that can be harvested and converted into useful electrical power. For this reason, the piezoelectric energy harvesters (PEHs), with their inherent electromechanical coupling and high-power density, have been widely incorporated in many applications to generate power from ambient mechanical vibrations. However, one of the main challenges to the wider adoption of PEHs is how to optimize their design for maximum energy harvesting. In this paper, an investigation was conducted on the energy harvesting from seven piezoelectric patch shapes (differing in the number of edges) when attached to a non-deterministic laminated composite (single/double lamina) plate subjected to change in fiber orientation. The performance of the PEHs was examined through a coupled-field finite element (FE) model. The plate was simply supported, and its dynamics were randomized by attaching randomly distributed point masses on the plate surface in addition to applying randomly located time-harmonic point forces. The randomization of point masses and point force location on a thin plate produce non-deterministic response. The design optimization was performed by employing the ensemble-responses of the electrical potential developed across the electrodes of the piezoelectric patches. The results present the optimal fiber orientation and patch shape for maximum energy harvesting in the case of single and double lamina composite plates. The results show that the performance is optimal at 0° or 90° fiber orientation for single-lamina, and at 0°/0° and 0°/90° fiber orientations for double-lamina composites. For frequencies below 25 Hz, patches with a low number of edges exhibited a higher harvesting performance (triangular for single-lamina/quadrilateral for double-lamina). As for the broadband frequencies (above 25 Hz), the performance was optimal for the patches with a higher number of edges (dodecagonal for single-lamina/octagonal for double-lamina).     

Prevalence and characteristics of left ventricular noncompaction in a community hospital cohort of patients with systolic dysfunction

BACKGROUND: Left ventricular noncompaction (LVNC) is felt to be a rare form of cardiomyopathy, although its prevalence in a nonreferred population is unknown. We examined the prevalence and clinical characteristics of LVNC in a community hospital cohort of adult patients with echocardiographic evidence of left ventricular (LV) systolic dysfunction. METHODS: All adult echocardiograms with global LV dysfunction and an LVEF < or = 45% over a 1-year period were reviewed for signs of LV noncompaction. Its presence was confirmed by the consensus of at least 2/3 readers specifically searching for this using standard criteria for noncompaction. RESULTS: A 3.7% prevalence of definite or probable LVNC was found in those with LVEF < or = 45% and a 0.26% prevalence for all patients referred for echocardiography during this period. This is appreciably higher than prior reports from tertiary centers. CONCLUSION: Noncompaction may not be a rare phenomenon and is comparable to other more widely recognized but less common causes of heart failure such as peripartum myopathy, connective tissue diseases, chronic substance abuse and HIV disease.     

An assimilatory sulfite reductase,CysI, negatively regulates the dormancy of Microbulbifer aggregans CCB-MM1T

Sulfur is one of the common and essential elements of all life. Sulfate, which is a major source of sulfur, plays an important role in synthesizing sulfur-containing amino acids, such as cysteine and methionine, organic compounds essential to all living organisms. Some investigations reported that the assimilatory sulfate reduction pathway (ASRP) involved in cysteine synthesis is crucial to entering bacterial dormancy in pathogens. Our previous investigation reported that the halophilic marine bacterium, Microbulbifer aggregans CCB-MM1^T, possesses an ASRP and the dissimilatory sulfate reduction pathway (DSRP). The bacterium might use DSRP to generate energy required for entering its dormant. However, the role of the ASRP in the dormancy of M. aggregans CCB-MM1^T was so far unknown. In this study, we found that genes involved in ASRP were downregulated in the dormancy. The disruption of the gene encoding an assimilatory sulfite reductase, cysI, suppressed a completely dormant state under low nutrient conditions. In addition, the cysI mutant showed cell aggregation at the middle-exponential phase under high nutrient conditions, indicating that the mutation might be stimulated to enter the dormancy. The wild-type phenotype of the bacterium was recovered by the addition of cysteine. These results suggested that cysteine concentration may play an important role in inducing the dormancy of M. aggregans.     

Plasmodium cynomolgi: An emerging threat of zoonotic malaria species in Malaysia?

Malaria remains a public health problem in many parts of the world. It is a disease that can endanger human life if left untreated, especially among young child...