Systemic Therapy of Metastatic Melanoma: On the Road to Cure.

Abstract: This decade has brought significant survival improvement in patients with metastatic melanoma with targeted therapies and immunotherapies. As our understanding of the mechanisms of action of these therapeutics evolves, even more impressive therapeutic success is being achieved through various combination strategies, including combinations of different immunotherapies as well as with other modalities. This review summarizes prospectively and retrospectively generated clinical evidence on modern melanoma therapy, focusing on immunotherapy and targeted therapy with BRAF kinase inhibitors and MEK kinase inhibitors (BRAF/MEK inhibitors), including recent data presented at major conference meetings. The combination of the anti-PD-1 directed monoclonal antibody nivolumab and of the CTLA-4 antagonist ipilimumab achieves unprecedented 5-year overall survival (OS) rates above 50%; however, toxicity is high. For PD-1 monotherapy (nivolumab or pembrolizumab), toxicities are in general well manageable. Today, novel combinations of such immune checkpoint inhibitors (ICIs) are under investigation, for example with cytokines and oncolytic viruses (i.e., pegylated interleukin-2, talimogene laherparepvec). Furthermore, current studies investigate the combined or sequential use of ICIs plus BRAF/MEK inhibitors. Several studies focus particularly on poor prognosis patients, as e.g., on anti-PD-1 refractory melanoma, patients with brain metastases, or uveal melanoma. It is hoped, on the road to cure, that these new approaches further improve long term survival in patients with advanced or metastatic melanoma.

systemic therapy
melanoma
MEK inhibitors
Immune checkpoint inhibitors
BRAF inhibitors


Impact of point-of-care testing and treatment of sexually transmitted infections and bacterial vaginosis on genital tract inflammatory cytokines in a cohort of young South African women.

Abstract:
OBJECTIVES
STIs cause inflammation that is detrimental for both HIV risk and reproductive health. We assessed the impact of point-of-care (POC) STI testing, immediate treatment and expedited partner therapy (EPT) on genital tract cytokines among a cohort of young South African women.

METHODS
HIV-negative women underwent POC testing for Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG) and Trichomonas vaginalis (TV) by Xpert CT/NG and OSOM TV, and for bacterial vaginosis (BV) by microscopy. Women with STIs and/or BV received immediate treatment, EPT for STIs and retested after 6 and 12 weeks. Concentrations of 48 cytokines were measured in cervicovaginal fluid at each visit using multiplex ELISA technology. The impact of STI treatment on cytokine concentrations was assessed by multivariable linear mixed models and principal component analysis.

RESULTS
The study enrolled 251 women with median age of 23 years (IQR 21-27). The prevalence of CT, NG and TV were 14.3%, 4.4% and 4.0%, and 34.3% had BV. Women with STIs or BV at baseline (n=94) had significantly higher concentrations of pro-inflammatory cytokines (interleukin (IL)-1α, IL-1β, IL-6, tumour necrosis factor (TNF)-α, TNF-β, IL-18 and macrophage inflammatory factor (MIF)) and chemokines (IL-8, IL-16, macrophage inflammatory protein (MIP)-1α, IFN-α2, monokine induced by gamma interferon (MIG), monocyte chemoattractant protein (MCP)-3, regulated on activation normal T cell expressed and secreted and eotaxin) compared with women without (n=157). STI treatment was strongly associated with reduced concentrations of pro-inflammatory cytokines IL-6 (p=0.004), IL-1β (p=0.013), TNF-α (p=0.018) and chemokines MIG (p=0.008) and growth-related oncogene (GRO)-α (p=0.025). A lower Nugent score was associated with a reduction in pro-inflammatory cytokines IL-1α (p=0.003), TNF-related apoptosis-inducing ligand (p=0.004), MIF (p=0.010) and IL-18 (p<0.001), but an increase in chemokines MIG (p=0.020), GRO-α (p<0.001), IP-10 (p<0.001), MIP-1β (p=0.008) and MCP-1 (p=0.005). Principal component analysis showed differences in STI and BV-related inflammatory profiles, but that resolution restored a profile consistent with vaginal health.

CONCLUSIONS
A comprehensive STI intervention effectively reduced genital inflammation among young women, thereby improving vaginal health and potentially reducing HIV risk.

testing
inflammation
clinical STI care
point of care


Perceived anxiety and physical activity behaviour changes during the early stages of COVID-19 restrictions in community-dwelling adults in Canada: a cross-sectional study.

Abstract:
OBJECTIVES
The COVID-19 pandemic changed daily routines, including physical activity, which could influence physical and mental health. In our study, we describe physical activity and sedentary behaviour patterns in relation to the pandemic and estimate associations between anxiety and physical activity and sedentary behaviour in community-dwelling adults.

DESIGN
Cross-sectional study.

SETTING
Calgary, Alberta, Canada.

PARTICIPANTS
Between April and June 2020, a random sample of 1124 adults (≥18 years) completed an online questionnaire.

PRIMARY AND SECONDARY OUTCOMES
The online questionnaire captured current walking, moderate intensity, vigorous intensity and total physical activity and sedentary behaviour (ie, sitting and leisure-based screen time), perceived relative changes in physical activity, sedentary and social behaviours since the pandemic, perceived seriousness and anxiety related to COVID-19, and sociodemographic characteristics. Differences in sociodemographic characteristics, perceived relative change in behaviour and current physical activity and sedentary behaviour were compared between adults with low and high anxiety.

RESULTS
Our sample (n=1047) included more females (60.3%) and fewer older adults (19.2%). Most participants (88.4%) considered COVID-19 as extremely or very serious and one-third (32.9%) felt extremely or very anxious. We found no differences (p>0.05) in current physical activity or sedentary behaviour by anxiety level. The largest perceived change in behaviours included social distancing, driving motor vehicles, use of screen-based devices, watching television and interactions with neighbours. We found anxiety-related differences (p<0.05) in perceived changes in various behaviours.

CONCLUSIONS
Changes in physical activity, sedentary behaviour and social behaviour occurred soon after the COVID-19 pandemic was declared, and some of these changes differed among those with low and high anxiety.

COVID-19
mental health
epidemiology
public health


Peak Bone Mass and Quantitative Ultrasound Bone Properties in Young Adulthood: A Study in the PEAK-25 Cohort of Women.

Abstract: Peak bone mass is normally reached in the third decade of life. Previously, in the population-based PEAK-25 cohort (n = 1061, age 25.5 ± 0.2), we demonstrated that bone mineral density in the population-based PEAK-25 cohort is comparatively high; therefore, this study aimed to determine if the calcaneus microarchitecture mirrored this. In the process, we describe normative quantitative ultrasound (QUS) values for 25-yr-old women and the relationship between QUS values and extremes of body weight. QUS variables speed of sound (SOS), broadband ultrasound attenuation (BUA), and stiffness index were measured. Young adult values were based on the manufacturer-supplied QUS reference values. Analyses were performed in the cohort as a whole, and additionally, to understand the relationship between body weight and QUS values in young women, the variables were categorized into octiles for weight or body mass index (BMI) and the lowest and highest octiles were compared. In the cohort, SOS values, reflecting bone density, were higher (108 ± 18%), whereas BUA values, reflecting bone complexity, were lower (90 ± 14%) compared to the young adult reference population. SOS did not correlate with body weight or BMI. In the cohort, overall correlations between BUA weight, and BMI were small and positive (Pearson's r coefficients 0.261 and 0.197, respectively; p < 0.001), although in the low-weight group, r coefficients were higher (r = 0.313 and 0.268; p < 0.05). In contrast, in the high-weight group, correlation with BUA values tended to be small, negative, and nonsignificant. Correlation between QUS and dual-energy X-ray absorptiometry-measured bone mineral density was low to moderate and significant at all skeletal sites (r = 0.37-0.52). Whereas coefficients tended to be higher in the low-weight group, the reverse was apparent for the low-BMI group. In these 25-yr-old women, a comparatively high dual-energy X-ray absorptiometry-measured bone mass is offset by less complex bone structures assessed by QUS. This may have implications for later osteoporosis assessment and future fracture risk.

Sandström|Linnéa|L|
McGuigan|Fiona E A|FE|
Callréus|Mattias|M|
Akesson|Kristina E|KE|

peak bone mass
quantitative ultrasound
SOS
BUA
young adult women


Preparation of activated petroleum coke for removal of naphthenic acids model compounds: Box-Behnken design optimization of KOH activation process.

Abstract: This study employed Box-Behnken design and response surface methodology to optimize activation parameters for the production of activated petroleum coke (APC) adsorbent from petroleum coke (PC) to achieve highest adsorption capacity for three model naphthenic acids. Activated petroleum coke (APC) adsorbent with a BET surface area of 1726 m2/g and total pore volume of 0.85 cc/g was produced at the optimum activation conditions (KOH/coke mass ratio) of 3.0, activation temperature 790 °C, and activation time 3.47 h). Effects of the activation parameters on the adsorption pefromances (adsortion capaciy and kinetics) were investigated. With the APC obtained at the optimum activation condition, the maximum adsorption capacity of 451, 362, and 320 (mg/g) was achieved for 2-naphthoic acid, diphenylacetic acid and cyclohexanepentanoic acid (CP), respectively. Although, generally APC adsorbents with a higher specific surface area and pore volume provide better adsorption capacity, the textural properties (surface areas and pore volume) are not the only parameters determining the APC adsorbents' adsorption capacity. Other parameters such as surface functionalities play effective roles on the adsorption capacity of the produced APC adsorbents for NAs. The KOH activation process, in particular the acid washing step, distinctly reduced the sulfur and metals contents in the raw PC, decreasing the leaching potential of metals from APC adsorbents during adsorption.

Petroleum coke
Naphthenic acids
Optimization
KOH activation
Adsorption capacity
Leaching of metals


Parkia speciosa empty pod extract exerts anti-inflammatory properties by modulating NFκB and MAPK pathways in cardiomyocytes exposed to tumor necrosis factor-α.

Abstract: Parkia speciosa Hassk is a plant found abundantly in the Southeast Asia region. Its seeds, with or without pods, have been used in traditional medicine locally to treat cardiovascular problems. The pathogenesis of cardiovascular diseases involves inflammation and oxidative stress. Based on this information, we sought to investigate the potential protective effects of Parkia speciosa empty pod extract (PSE) on inflammation in cardiomyocytes exposed to tumor necrosis factor-α (TNF-α). H9c2 cardiomyocytes were divided into four groups; negative control, TNF-α, PSE + TNF-α and quercetin + TNF-α. Groups 3 and 4 were pretreated with PSE ethyl acetate fraction of ethanol extract (500 µg/mL) or quercetin (1000 µM, positive control) for 1 h before inflammatory induction with TNF-α (12 ng/mL) for 24 h. TNF-α increased protein expression of nuclear factor kappa B cell (NFκB) p65, p38 mitogen-activated protein kinase (p38 MAPK), inducible nitric oxide synthase, cyclooxygenase-2 and vascular cell adhesion molecule-1 when compared to the negative control (p < 0.05). It also elevated iNOS activity, nitric oxide and reactive oxygen species levels. These increases were significantly reduced with PSE and quercetin pretreatments. The effects of PSE were comparable to that of quercetin. PSE exhibited anti-inflammatory properties against TNF-α-induced inflammation in H9c2 cardiomyocytes by modulating the NFκB and p38 MAPK pathways.


Tragopogon porrifolius improves serum lipid profile and increases short-term satiety in rats.

Abstract: Tragopogon porrifolius (white salsify) is an edible plant commonly used in folk medicine in Lebanon and neighbouring countries. This study investigates the effect of the aqueous extract of the aerial part of T. porrifolius on lipemia and appetite regulation using a rat model. Food intake, abdominal fat percentage, blood lipid profile, liver weight and liver enzymes were assessed following 4 weeks of extract intake via drinking water (50, 100, or 250 mg/kg body weight) in standard high-carbohydrate and high-fat dietary conditions. In a separate study, the short term effect of a preload of T. porrifolius extract on food intake was evaluated. Results showed that consumption of the plant extract for a period of four weeks resulted in a marked improvement of the lipid profile (triglycerides, total cholesterol, LDL and HDL cholesterol). Body weight, food intake and intra-abdominal fat were also lower in animals given the plant extract (100 and 250 mg/kg). In addition, T. porrifolius extract preload produced a dose dependent decrease in food intake observed over 24h. The intake of T. porrifolius aqueous extract therefore improved lipemia and increased satiety in rats with no visible adverse effects.

Zeeni|Nadine|N|
Daher|Costantine F|CF|
Saab|Lea|L|
Mroueh|Mohamad|M|

Tragopogon porrifolius
Lipid profile
Satiety
Cholesterol
High-fat diet


Selective serotonin reuptake inhibitors and Alzheimer's disease.

Abstract: Given the failure to develop disease-modifying therapies for Alzheimer's disease (AD), strategies aiming at preventing or delaying the onset of the disease are being prioritized. While the debate regarding whether depression is an etiological risk factor or a prodrome of AD rages on, a key determining factor may be the timing of depression onset in older adults. There is increasing evidence that untreated early-onset depression is a risk factor and that late-onset depression may be a catalyst of cognitive decline. Data from animal studies have shown a beneficial impact of selective serotonin reuptake inhibitors on pathophysiological biomarkers of AD including amyloid burden, tau deposits and neurogenesis. In humans, studies focusing on subjects with a prior history of depression also showed a delay in the onset of AD in those treated with most selective serotonin reuptake inhibitors. Paroxetine, which has strong anticholinergic properties, was associated with increased mortality and mixed effects on amyloid and tau deposits in mice, as well as increased odds of developing AD in humans. Although most of the data regarding selective serotonin reuptake inhibitors is promising, findings should be interpreted cautiously because of notable methodological heterogeneity between studies. There is thus a need to conduct large scale randomized controlled trials with long follow up periods to clarify the dose-effect relationship of specific serotonergic antidepressants on AD prevention.

selective serotonin reuptake inhibitor
prevention
depression
antidepressant
Alzheimer’s disease
SSRI
amyloidogenesis
animal models
onset delay


Chemical grafting fluoropolymer on cellulose nanocrystals and its rheological modification to perfluoropolyether oil.

Abstract: Cellulose nanocrystal (CNC) is the sustainable nanoparticle derived from natural cellulose, widely used as the functional additive to tailor the properties and performances of diverse matters. This study attempted the application of CNC as the rheological modifier in fluorocarbon lubricating oil (perfluoropolyether, PFPE). To solve the incompatibility between cellulose and base oil, fluoropolymer was covalently grafted onto the surface of nanocrystals by living radical polymerization. The introduction of modified cellulose nanocrystals exhibited significant thickening effect to PFPE-based hybrid oils, with the increase on viscosity, improved thixotropy performance and enhanced storage modulus (G') and loss modulus (G″). In particular, when adding 10-15 wt% modified nanocrystals, a transition of G' > G″ from the flowable state to grease-like state appeared in hybrid oils, attributed to the formation of stable subnetwork based on the chain entanglement of the grafted fluoropolymer and PFPE oil.

Wang|Sunan|S| Li|Ke|K| Xia|Tao|T| Lan|Ping|P| Xu|Hui|H| Lin|Ning|N|

Cellulose nanocrystals
Rheology
Perfluoropolyether oil
ATRP


Can the Diagnostic Accuracy of Bone Scintigraphy Be Maintained with Half the Scanning Time?

Abstract: We aimed to show that the acquisition time of a conventional bone scan could be reduced by half without losing the diagnostic value of the scan. Methods: Fifty adult patients (37 male and 13 female; mean age, 62.5 y; SD, 8.7 y) were enrolled. The patients were injected with 925-1,110 MBq (25-30 mCi) of 99mTc-methylene diphosphonate intravenously. The standard-protocol whole-body planar images were acquired first (scan speed, 10 cm/min; acquisition time, ∼20 min) and were followed immediately by the half-time protocol whole-body planar images (scan speed, 20 cm/min; acquisition time, ∼10 min). Both sets of images were interpreted by 2 nuclear medicine physicians. Each reviewer, when reviewing the standard-protocol images, was self-masked to the result he or she had obtained when reviewing the half-time images, and vice versa. This self-masking was accomplished by allowing a minimum of 2 wk to elapse between the 2 interpretations. We used the κ-coefficient to compare agreement between the standard-protocol results and the half-time results. Results: There was no difference in clinically significant diagnostic information between the half-time and standard protocols. The diagnostic quality of half-time and standard-protocol images did not significantly differ (0.86 < κ < 1.0). Conclusion: Our data suggest that if we reduce the 99mTc-methylene diphosphonate dose by half and keep the acquisition time at its standard value, we gain the benefit of reduced dose without loss of diagnostic value.

Moncayo|Valeria M|VM|
Chimafor|Sebastine|S|
Lulaj|Elizabeth|E|
Malko|John A|JA|
Halkar|Raghuveer|R|

99mTc-MDP bone scan
Image Wisely
half-time acquisition


Functional Analysis of KIT Gene Structural Mutations Causing the Porcine Dominant White Phenotype Using Genome Edited Mouse Models.

Abstract: The dominant white phenotype in pigs is thought to be mainly due to a structural mutation in the KIT gene, a splice mutation (G > A) at the first base in intron 17 which leads to the deletion of exon 17 in the mature KIT mRNA. However, this hypothesis has not yet been validated by functional studies. Here, we created two mouse models, KIT  to mimic the splice mutation, and KIT  to partially mimic the duplication mutation of KIT gene in dominant white pigs using CRISPR/Cas9 technology. We found that the splice mutation homozygote is lethal and the heterozygous mice have a piebald coat. Slightly increased expression of KIT in KIT  mice did not confer the patched phenotype and had no obvious impact on coat color. Interestingly, the combination of these two mutations reduced the phosphorylation of PI3K and MAPK pathway associated proteins, which may be related to the impaired migration of melanoblasts observed during embryonic development that eventually leads to the dominant white phenotype.

Sun|Guanjie|G| Liang|Xinyu|X| Qin|Ke|K| Qin|Yufeng|Y| Shi|Xuan|X| Cong|Peiqing|P| Mo|Delin|D| Liu|Xiaohong|X| Chen|Yaosheng|Y| He|Zuyong|Z|

KIT
mouse model
CDS duplication
exon 17 deletion
melanocyte
porcine coat color


Increased Expression of PPAR-γ Modulates Monocytes Into a M2-Like Phenotype in SLE Patients: An Implicative Protective Mechanism and Potential Therapeutic Strategy of Systemic Lupus Erythematosus.

Abstract: Systemic lupus erythematosus (SLE) is a spectrum of autoimmune disorders characterized by continuous inflammation and the production of autoantibodies. Monocytes, as precursors of dendritic cells and macrophages, are involved in the pathogenesis of SLE, particularly in the inflammatory reactions. Previous studies have proved that Pam3CSK4, as a synthetic ligand of TLR2, could stimulate monocytes to differentiated into a M2-like phenotype which presented immunosuppressive functions. However, the underlying mechanisms remain to be further studied. Here, we reported an increased expression of PPAR-γ in the CD14+ monocytes from SLE patients, particularly in the treated group of SLE patients and the group with positive anti-dsDNA antibodies. Additionally, PPAR-γ expression decreased in the SLE patients with skin lesion. Furthermore, we demonstrated that Pam3CSK4 stimulation can decrease the expression of CCR7, CD80, IL-1β, IL-6, IL-12, and NF-κB which were related to the M1-like subset of monocytes and increased the expression of ARG1 which was related to the M2-like subset through upregulated PPAR-γ expression and consequently downregulated NF-κB expression in the CD14+ monocytes in a time-dependent manner. ChIP-qPCR results further demonstrated that Pam3CSK4 pretreatment could modulate PPAR-γ expression by regulating histone modification through the inhibition of Sirt1 binding to the PPAR-γ promoter. Taken together, our study indicated a protective role of TLR2/Sirt1/PPAR-γ pathway in the pathogenesis of SLE which provided potential therapeutic strategies.

Liu|Yu|Y| Luo|Shuangyan|S| Zhan|Yi|Y| Wang|Jiayu|J| Zhao|Rui|R| Li|Yingjie|Y| Zeng|Jinrong|J| Lu|Qianjin|Q|

PPAR-γ
monocytes
systemic lupus erythematosus
histone modification
Sirt1


Development of 'S', 'N' Heterocycles as Antimycobacterials Targeting Fatty Acid Biosynthesis.

Abstract:
BACKGROUND
Mycobacterium tuberculosis is a causative organism of tuberculosis, which is the most deadly disease after cancer in the current decade. The development of multidrug and broadly drug- resistant strains makes the tuberculosis problem more and more critical. In the last 40 years, only one molecule is added to the treatment regimen. Generally, drug design and development programs are targeted proteins whose function is known to be essential to the bacterial cell.

OBJECTIVES
Here are the development of 'S', 'N' heterocycles as antimycobacterials targeting fatty acid biosynthesis are reported.

MATERIALS AND METHODS
In the present communication, rational development of anti-mycobacterial agent's targeting fatty acid biosynthesis has been done by integrating the pocket modeling and virtual analysis.

RESULTS
The identified potential 33 lead compounds were synthesized, characterized by physicochemical and spectroscopic methods like IR, NMR spectroscopy and further screened for antimycobacterial activity using isoniazid as standard. All the designed compounds have shown profound antimycobacterial activity.

CONCLUSION
In this present communication, we found that 3c, 3f, 3l and 4k molecules had expressive desirable biological activity and specific interactions with fatty acids. Further optimization of these leads is necessary for the development of potential antimycobacterial drug candidates having fewer side effects.

Dahiwade|Lalita K|LK|
Rochlani|Sneha P|SP|
Choudhari|Prafulla B|PB|
Dhavale|Rakesh P|RP|
More|Harinath N|HN|

D000995:Antitubercular Agents
D001426:Bacterial Proteins
D003198:Computer Simulation
D015195:Drug Design
D005227:Fatty Acids
D007538:Isoniazid
D050356:Lipid Metabolism
D062105:Molecular Docking Simulation
D009169:Mycobacterium tuberculosis
D014376:Tuberculosis

heterocyclic
Mycobacterium tuberculosis
isoniazid
Antitubercular
InhA
molecular docking


Long non-coding RNA Mirt2 prevents TNF-α-triggered inflammation via the repression of microRNA-101.

Abstract: Parkinson's disease is normally accompanied by excessive inflammation. Myocardial infraction associated transcript 2 (Mirt2) has an activity to relieve inflammation in numerous cell types. Here, we aimed to investigate whether Mirt2 could elevate the resistance of SH-Sy5y cells to inflammation. Tumor necrosis factor alpha (TNF-α) was used to induce inflammation in SH-Sy5y cells. Mirt2 overexpressed or silenced cells were established. MicroRNA-101 (miR-101) mimic was used to up-regulate miR-101. Viable and apoptotic cells as well as reactive oxidative species (ROS) were detected after staining. Proteins associated with apoptosis, interleukin (IL) and signaling regulators were evaluated by Western blot. IL secretion was assessed by ELISA. Mirt2 and miR-101 were determined by qRT-PCR. We discovered that TNF-α weakened viability of SH-Sy5y cells and resulted in sensitivity to apoptosis with cleavage of PARP and caspase-3. Expression and secretion of IL-6 as well as generation of ROS were facilitated by TNF-α. However, Mirt2 overexpression moderated TNF-α-caused apoptosis associated with inflammation and oxidative stress. Mirt2 suppressed TNF-α-induced accumulation of miR-101, and based on this Mirt2 exhibited anti-inflammatory roles. Additionally, TNF-α-triggered phosphorylation of regulators was blocked by Mirt2 while restored by miR-101 mimic. In short Mirt2 overexpression exhibited anti-inflammatory properties through miR-101 suppression. Through down-regulating miR-101, Mirt2 blocked TNF-α-triggered NF-κB/p38MAPK pathway.

Han|Yingying|Y| Kang|Chunyang|C| Kang|Mingyang|M| Quan|Wei|W| Gao|Heming|H| Zhong|Zhuan|Z|


The Compositional and Functional Attributes of Commercial Flours from Tropical Fruits (Breadfruit and Banana).

Abstract: The objective of this study was to compare the compositional and functional properties of tropical flour sources (two breadfruit flours (type A and type B) and a banana flour) with a more traditional flour source (wheat flour). Macro-nutrient composition, pH, water and oil holding capacity, bulk density, particle size, solubility, swelling power, pasting properties, and thermodynamics (gelatinization and retrogradation) were determined. All flours evaluated were similar in their composition with high levels of carbohydrates (greater than 82.52 g/100 g on a dry-matter basis), with most of the carbohydrate content comprised of starch (greater than 67.02 g/100 g). The tropical fruit flours had greater (p < 0.05) water holding capacity than wheat flour. Breadfruit flour B had the lowest (p < 0.05) bulk density, while banana flour had the greatest (p < 0.05) bulk density. The swelling power of the tropical flours was greater (p < 0.05) than the wheat flour. The viscosity of the tropical flours was higher than wheat flour but decreased significantly when temperature was held at 130 °C. These results indicated that the two breadfruit flours and banana flour have great potential for application in processed food products, and have similar compositional attributes to a more traditional flour.

composition
flour
breadfruit
banana
pasting properties
thermodynamics
retrogradation


Factors for C-Kit Expression in Cardiac Outgrowth Cells and Human Heart Tissue.

Abstract: We determined the factors associated with the expression of c-kit in the heart and the proliferation of c-kit-positive (c-kitpos) cardiac stem cells among the outgrowth cells cultured from human cardiac explants.Samples of the right atrium (RA), left atrium (LA), and left ventricle obtained from patients during open-heart surgery were processed for cell culture of outgrowth cells and tissue analysis. The total number of growing cells and the population of c-kitpos cells were measured and compared with c-kit expression in native tissues and characteristics of the patients according to the region of the heart.We analyzed 452 samples from 334 patients. Atrial fibrillation (AF) in the patients reduced the number of outgrowth cells from the RA and LA, and aging was a co-factor for the LA. The c-kitpos population from the RA was associated with serum brain natriuretic peptide (BNP). C-kit expression in native tissue was also associated with BNP expression. However, we observed no relationship in expression between outgrowth cells and native tissue. In addition, the RA tissue provided the highest number of c-kitpos cells, and the left ventricle provided the lowest.C-kit was weakly expressed in response to damage. In addition, no correlation between outgrowth cells and native tissue was found for c-kit expression.

Matsushita|Satoshi|S| Minematsu|Kazuo|K| Yamamoto|Taira|T| Inaba|Hirotaka|H| Kuwaki|Kenji|K| Shimada|Akie|A| Yokoyama|Yasutaka|Y| Amano|Atsushi|A|

Cardiac stem cells
Atrial fibrillation
Aging
Brain natriuretic peptide
Heart injury
Self-repair


Novel method to evaluate the risk of tumor adhesions and post-operative hemorrhage of meningiomas using 320 row CT-DSA: A clinical research study.

Abstract:
OBJECTIVE
Meningioma is an extra-axial tumor that forms adhesions toward the brain surface in the course of its growth. Predicting adhesions between the tumor and the brain surface leads to better predictions of surgical results. There are few studies on brain-tumor adhesions or postoperative hemorrhage. This study aimed to assess tumor vascularity of the dura and cerebral surface, and predict surgical outcomes using four-dimensional computed tomography angiography (4D CTA).

PATIENTS AND METHODS
Using a dynamic contrast CT, we conducted a retrospective study of 27 patients with convexity (n = 15), falx (n = 6), and parasagittal (n = 6) meningiomas treated in our hospital from January 2016 to September 2018. We set the region of interest on the dural layer and cerebral surface side of meningiomas and calculated the mean CT value in each region. Distribution of blood flow in the tumor was classified into two groups: A, which has a higher CT value of the dural side than that of the brain surface side at every timing, and B, which meets the criteria other than those in group A. Demographic data, preoperative characteristic images, and postoperative complications were compared between the groups.

RESULTS
Twelve and 15 patients were classified into groups A and B, respectively. The extent of adhesions against the cerebral cortex in group A was significantly less severe compared with that in group B (p = 0.038). The rate of postoperative hemorrhage occurrence in group B (53%) was significantly higher than that in group A (8%) (p = 0.04). There were no significant differences in the other preoperative characteristic images or perioperative parameters between groups A and B.

CONCLUSION
A 320-row dynamic contrast CT scanner can detect meningiomas with a high probability of severe adhesion toward the brain surface and postoperative intraparenchymal hematoma.

Arai|Nobuhiko|N| Mizutani|Katsuhiro|K| Horiguchi|Takashi|T| Akiyama|Takenori|T| Takahashi|Satoshi|S| Yanagisawa|Kaoru|K| Koike|Kazunari|K| Yoshida|Kazunari|K|

Meningioma
CT-DSA
Postoperative hemorrhage
320-row CT
Brain adhesion
Pial feed


Utility and Perceived Value of a Provincial Digital Diagnostic Imaging Repository: Multimethod Study.

Abstract:
BACKGROUND
Timely and comprehensive diagnostic image sharing across institutional and regional boundaries can produce multiple benefits while supporting integrated models of care. In Ontario, Canada, the Diagnostic Imaging Common Service (DICS) was created as a centralized imaging repository to enable the sharing and viewing of diagnostic images and associated reports across hospital-based and community-based clinicians throughout the province.

OBJECTIVE
The aims of this study were as follows: (1) to explore real-world utilization and perceived clinical value of the DICS following the provision of system-wide access and (2) to identify strategies to optimize the technology platform functionality and encourage adoption.

METHODS
This multimethod study included semistructured interviews with physicians and administrative stakeholders and descriptive analysis of the current DICS usage data.

RESULTS
In this study, 41 participants were interviewed, that is, 34 physicians and 7 administrative stakeholders. The following 4 key themes emerged: (1) utilization of the DICS depended on the awareness of the technology and the preferred channels for accessing images, which varied widely, (2) clinical responsibilities and available institutional resources were the drivers of utilization (or lack thereof), (3) centralized image repositories were perceived to offer value at the patient, clinician, and health care system levels, and (4) the enabling factors to realize value included aspects of technology infrastructure (ie, available functionality) alongside policy supports. High-volume DICS usage was not evenly distributed throughout the province.

CONCLUSIONS
Suboptimal adoption of the DICS was driven by poor awareness and variations in the clinical workflow. Alignment with physician workflow, policy supports, and investment in key technological features and infrastructure would improve functionality and data comprehensiveness, thereby optimizing health system performance, patient and provider experience, population health, and health care costs.

diagnostic imaging
eHealth
health care delivery


Overexpression of Sirt1 in mesenchymal stem cells protects against bone loss in mice by FOXO3a deacetylation and oxidative stress inhibition.

Abstract:
OBJECTIVE
B cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) deficiency (Bmi-1-/-) leads to an osteoporotic phenotype with a significant downregulation of Sirt1 protein expression. Sirtuin 1 (Sirt1) haploinsufficiency results in a bone loss by decreased bone formation; however, it is unclear whether Sirt1 overexpression in mesenchymal stem cells (MSCs) plays an anti-osteoporotic role. The aim of the study is to identify whether the overexpression of Sirt1 in MSCs could restore skeletal growth retardation and osteoporosis in Bmi-1 deficient mice.

METHODS
We used our new generated transgenic mouse model that overexpresses Sirt1 in its MSCs (Sirt1TG) to cross with Bmi-1-/- mice to generate Bmi-1-/- mice with Sirt1 overexpression in MSCs, and compared their skeletal metabolism with those of their Bmi-1-/- and wild-type (WT) littermates (6 mice for each genotype) at 4 weeks of age using imaging, histopathological, immunohistochemical, histomorphometric, cellular, and molecular methods.

RESULTS
The levels of expression for Sirt1 were noticeably higher in the skeletal tissue of Sirt1TG mice than in those of WT mice. In Comparison to WT mice, the body weight and size, skeletal size, bone volume, osteoblast number, alkaline phosphatase and type I collagen positive areas, osteogenic related gene expression levels were all significantly increased in the Sirt1TG mice. Overexpression of Sirt1 in Bmi-1-/- mouse MSCs resulted in a longer lifespan, improved skeletal growth and significantly increased bone mass by stimulating osteoblastic bone formation and inhibiting osteoclastic bone resorption in the Bmi-1-/- mice, although the defects were not completely restored. Furthermore, Sirt1 overexpression in MSCs reduced the acetylation level of FOXO3a (Forkhead box O3a), increasing levels of expression for FOXO3a and SOD2 (Superoxide dismutase 2) in bony tissue, enhanced osteogenesis and reduced osteogenic cell senescence. We also demonstrated that nicotinamide, a Sirt1 inhibitor, blocks the effect of overexpression of Sirt1 in MSCs on osteogenesis and osteogenic cell senescence.

CONCLUSIONS
Taken together, these results demonstrate that Sirt1 overexpression in MSCs increased the osteoblastic bone formation and partially restores the defects in skeletal growth and osteogenesis in Bmi-1-/- mice by FOXO3a deacetylation and oxidative stress inhibition. Our data support the proposal that Sirt1 is a target for promoting bone formation as an anabolic approach for the treatment of osteoporosis.

Sun|Wen|W| Qiao|Wanxin|W| Zhou|Bin|B| Hu|Zixuan|Z| Yan|Quanquan|Q| Wu|Jun|J| Wang|Rong|R| Zhang|Qian|Q| Miao|Dengshun|D|


Long-Period Gratings and Microcavity In-Line Mach Zehnder Interferometers as Highly Sensitive Optical Fiber Platforms for Bacteria Sensing.

Abstract: Selected optical fiber sensors offer extraordinary sensitivity to changes in external refractive (RI), which make them promising for label-free biosensing. In this work the most sensitive ones, namely long-period gratings working at (DTP-LPG) and micro-cavity in-line Mach-Zehnder interferometers (µIMZI) are discussed for application in bacteria sensing. We describe their working principles and RI sensitivity when operating in water environments, which is as high as 20,000 nm/RIU (Refractive index unit) for DTP-LPGs and 27,000 nm/RIU for µIMZIs. Special attention is paid to the methods to enhance the sensitivity by etching and nano-coatings. While the DTP-LPGs offer a greater interaction length and sensitivity to changes taking place at their surface, the µIMZIs are best suited for investigations of sub-nanoliter and picoliter volumes. The capabilities of both the platforms for bacteria sensing are presented and compared for strains of Escherichia coli, lipopolysaccharide E. coli, outer membrane proteins of E. coli, and Staphylococcus aureus. While DTP-LPGs have been more explored for bacteria detection in 102-106 Colony Forming Unit (CFU)/mL for S. aureus and 103-109 CFU/mL for E. coli, the µIMZIs reached 102-108 CFU/mL for E. coli and have a potential for becoming picoliter bacteria sensors.

Eftimov|Tinko|T| Janik|Monika|M|0000-0002-8002-3055 Koba|Marcin|M|0000-0002-0295-8242 Śmietana|Mateusz|M| Mikulic|Predrag|P| Bock|Wojtek|W|

D015374:Biosensing Techniques
D004926:Escherichia coli
D055100:Optical Fibers
D012031:Refractometry
D013211:Staphylococcus aureus


Unfortunate Hand Positioning Yielding Inappropriate Defibrillator Shock: Another Paradigm of a Guilty Association Between Patient Awareness and Occupational Hazard.

Abstract: A 64-year-old patient had a cardiac resynchronization therapy defibrillator implanted 4 years ago for dilated cardiomyopathy. He recently had an inappropriate shock as a result of an electrical leak from a refrigerator causing electromagnetic interference. An analysis of the patient case and a discussion of the features of this specific paradigm of inappropriate therapy are presented.


Epidemiology of Taenia saginata taeniosis/cysticercosis: a systematic review of the distribution in East, Southeast and South Asia.

Abstract:
BACKGROUND
Taenia saginata is an important zoonotic parasite, causing taeniosis in humans and cysticercosis in bovines, the latter being a significant concern for the global beef industry. Many countries in East, Southeast and South Asia are experiencing rapid economic growth, and an increasing number of people in these countries are dependent on the livestock industry. Currently, however, an overview of the prevalence of T. saginata in this region is lacking. In this review, we analysed the available literature on T. saginata taeniosis and bovine cysticercosis for East, Southeast and South Asia.

METHODS
A systematic review was conducted, based on both published and grey literature. Articles published between 1990 and 2017 were mined for information on the occurrence, prevalence, and geographical distribution of T. saginata taeniosis and bovine cysticercosis in East, Southeast and South Asia.

RESULTS
The presence of T. saginata was described in 15 of 27 countries of the region, including Afghanistan, Cambodia, China, India, Indonesia, Japan, Lao PDR, Malaysia, Mongolia, Nepal, Pakistan, Philippines, South Korea, Thailand and Vietnam. The only country that reported an absence of T. saginata is Japan, although sporadic reports of imported cases and unconfirmed reports of autochthonous infections were identified. Nationwide surveys of taeniosis with systematic sample collection and high sample numbers were available for Cambodia, China, Lao PDR, and South Korea, although speciation of Taenia was not always performed. Regional prevalence of taeniosis and bovine cysticercosis in endemic regions ranged between 0.02-42.6%, and 0.76-46.7%, respectively. However, data for bovine cysticercosis were only available for five countries (Japan, Lao PDR, Mongolia, Pakistan and Vietnam).

CONCLUSIONS
The data indicate a widespread occurrence of T. saginata throughout East, Southeast and South Asia. Identification of Taenia spp. in human infections was frequently not performed, leading to gaps in knowledge about the distribution of human tapeworm infections, mainly in regions where different human Taenia species co-occur. A high prevalence of T. saginata taeniosis and bovine cysticercosis may reflect insufficiencies in sanitation, limited health education standards, and insufficient food safety measures. Therefore, there is a need to improve local surveillance, notification, and overall control systems.

Eichenberger|Ramon M|RM|
Thomas|Lian F|LF|
Gabriël|Sarah|S|
Bobić|Branco|B|
Devleesschauwer|Brecht|B|
Robertson|Lucy J|LJ|
Saratsis|Anastasios|A|
Torgerson|Paul R|PR|
Braae|Uffe C|UC|
Dermauw|Veronique|V|
Dorny|Pierre|P|

Taenia saginata
Taeniosis
South Asia
Bovine cysticercosis
Beef tapeworm
Cestode
East Asia
Foodborne pathogen
Southeast Asia
Zoonosis


Spatial and Temporal Variations in Nutrients During Upwelling Season Off the East Coast of Peninsular Malaysia.

Abstract: This study determines the bulk surface water (BSW) dissolved inorganic nutrients of nitrogen (DINi) and phosphate (DIP) during the upwelling season off the east coast of Peninsular Malaysia, South China Sea. BSW samples were analysed for DINi and DIP by using a standard automated colorimetric method. BSW DINi and DIP concentrations varied between 0.11 and 2.55 μM (mean 1.12 ± 0.63 μM), and below detection limit, and 0.29 μM (mean 0.11 ± 0.08 μM), respectively. The spatial distribution of higher concentrations between DINi and DIP was distinct. However, the highest concentrations of DINi and DIP were mostly recorded in the month of peak upwelling (July and August), where colder BSW temperatures were also encountered during field sampling. This study provides new evidence on the presence of BSW nutrients of DINi and DIP during upwelling season peak in July and August before their decline in September.

Upwelling
Peninsular Malaysia
Surface water
Dissolved inorganic nutrients
Physical parameter


4-Year Changes in Sex Hormones, Sexual Functioning, and Psychosocial Status in Women Who Underwent Bariatric Surgery.

Abstract:
BACKGROUND
Initial weight loss after bariatric surgery has been associated with improvements in reproductive hormones and sexual functioning in women. Few studies have investigated the durability of these changes.

OBJECTIVES
The objective of this paper is to investigate changes in sex hormones, sexual functioning, and relevant psychosocial constructs over 4 years in women who underwent bariatric surgery.

SETTING
The setting is a prospective cohort of 106 women from the Longitudinal Assessment of Bariatric Surgery consortium.

METHODS
Changes in sex hormones were assessed by blood assay. Sexual functioning, quality of life (QOL), body image, depressive symptoms, and marital adjustment were assessed by psychometric measures.

RESULTS
Women lost on average (95% confidence interval) 32.3% (30.4%, 34.3%) at postoperative year 3 and 30.6% (28.5%, 32.8%) at postoperative year 4. Compared to baseline, women experienced significant changes at 4 years in all hormones assessed, except estradiol. Women reported significant improvements in sexual functioning (i.e., arousal, desire, and satisfaction) through year 3, but these changes were not maintained through year 4. Changes in relationship quality followed a similar pattern. Improvements in physical aspects of QOL, body image, and depressive symptoms were maintained through 4 years.

CONCLUSIONS
Improvements in reproductive hormones and physical aspects of QOL, body image, and depressive symptoms were maintained 4 years after bariatric surgery. Improvements in sexual functioning, relationship satisfaction, and mental components of QOL eroded over time.

Sarwer|David B|DB|0000-0003-1033-5528
Wadden|Thomas A|TA|
Spitzer|Jacqueline C|JC|
Mitchell|James E|JE|
Lancaster|Kathy|K|
Courcoulas|Anita|A|
Gourash|William|W|
Rosen|Raymond C|RC|
Christian|Nicholas J|NJ|

D000328:Adult
D050110:Bariatric Surgery
D001828:Body Image
D003863:Depression
D005260:Female
D012739:Gonadal Steroid Hormones
D006801:Humans
D008137:Longitudinal Studies
D017533:Marital Status
D008875:Middle Aged
D009767:Obesity, Morbid
D011184:Postoperative Period
D011788:Quality of Life
D012725:Sexual Behavior
D015431:Weight Loss

Sex hormones
Sexual functioning
Psychosocial status
Bariatric surgery
Quality of life


Gender-specific linkages of parents' childhood physical abuse and neglect with children's problem behaviour: evidence from Japan.

Abstract:
BACKGROUND
Childhood abuse has far-reaching effects, not only for survivors of maltreatment but also for subsequent generations. However, the mechanism of such intergenerational linkages has not been fully explored. This study investigated this linkage with special reference to its gender-specific features.

METHODS
A dataset of parents and their children, obtained from a cross-sectional survey in the Tokyo metropolitan area of Japan, was used. The study sample consisted of 1750 children aged between 2 and 18 years (865 daughters and 885 sons) and their parents (1003 mothers and fathers). Regression models were estimated to assess the associations among 1) both parents' childhood physical abuse and neglect (childhood abuse), 2) parents' psychological distress, as measured by the Kessler Psychological Distress Scale (K6), and 3) children's problem behaviour, as measured by the clinical scales of the Child Behavior Checklist.

RESULTS
Daughters' problem behaviour was more closely associated with mothers' than fathers' childhood abuse, whereas sons' problem behaviour was more closely associated with their fathers' experience. The impact of mothers' childhood abuse on daughters' problem behaviour was mediated at a rate of around 40 % by both parents' psychological distress. The proportion of the effect mediated by parents' psychological distress was less than 20 % for the impact of fathers' childhood abuse on sons' problem behaviour.

CONCLUSION
The intergenerational impact of parental childhood abuse on children's problem behaviour is gender specific, i.e. largely characterized by the same gender linkages. Further studies that explore the mechanisms involved in the intergenerational impact of childhood abuse are needed.

Problem behaviour
Childhood abuse
Psychological distress


A comprehensive review on non-clinical methods to study transfer of medication into breast milk - A contribution from the ConcePTION project.

Abstract: Breastfeeding plays a major role in the health and wellbeing of mother and infant. However, information on the safety of maternal medication during breastfeeding is lacking for most medications. This leads to discontinuation of either breastfeeding or maternal therapy, although many medications are likely to be safe. Since human lactation studies are costly and challenging, validated non-clinical methods would offer an attractive alternative. This review gives an extensive overview of the non-clinical methods (in vitro, in vivo and in silico) to study the transfer of maternal medication into the human breast milk, and subsequent neonatal systemic exposure. Several in vitro models are available, but model characterization, including quantitative medication transport data across the in vitro blood-milk barrier, remains rather limited. Furthermore, animal in vivo models have been used successfully in the past. However, these models don't always mimic human physiology due to species-specific differences. Several efforts have been made to predict medication transfer into the milk based on physicochemical characteristics. However, the role of transporter proteins and several physiological factors (e.g., variable milk lipid content) are not accounted for by these methods. Physiologically-based pharmacokinetic (PBPK) modelling offers a mechanism-oriented strategy with bio-relevance. Recently, lactation PBPK models have been reported for some medications, showing at least the feasibility and value of PBPK modelling to predict transfer of medication into the human milk. However, reliable data as input for PBPK models is often missing. The iterative development of in vitro, animal in vivo and PBPK modelling methods seems to be a promising approach. Human in vitro models will deliver essential data on the transepithelial transport of medication, whereas the combination of animal in vitro and in vivo methods will deliver information to establish accurate in vitro/in vivo extrapolation (IVIVE) algorithms and mechanistic insights. Such a non-clinical platform will be developed and thoroughly evaluated by the Innovative Medicines Initiative ConcePTION.

Nauwelaerts|Nina|N|
Deferm|Neel|N|
Smits|Anne|A|
Bernardini|Chiara|C|
Lammens|Bart|B|
Gandia|Peggy|P|
Panchaud|Alice|A|
Nordeng|Hedvig|H|
Bacci|Maria Laura|ML|
Forni|Monica|M|
Ventrella|Domenico|D|
Van Calsteren|Kristel|K|
DeLise|Anthony|A|
Huys|Isabelle|I|
Bouisset-Leonard|Michele|M|
Allegaert|Karel|K|
Annaert|Pieter|P|

Breastfeeding
Infants
Maternal medication
Lactation
In vitro
In vivo
Neonates
Pharmacokinetics
PBPK
Medication exposure


SAS-6 Association with γ-Tubulin Ring Complex Is Required for Centriole Duplication in Human Cells.

Abstract: Centrioles are essential components of centrosome, the main microtubule-organizing center of animal cells required for robust spindle bipolarity [1, 2]. They are duplicated once during the cell cycle [3], and the duplication involves assembly of a cartwheel on the pre-existing centriole followed by assembly of triplet microtubules around the cartwheel [4, 5]. Although the molecular details of cartwheel formation are understood [6-13], the mechanisms initiating the formation of centriolar microtubules are not known. Here, we show that the central component of cartwheel, HsSAS-6 plays a crucial role in the formation of centriolar microtubules by interacting with the microtubule nucleation machinery, γ-tubulin ring complex (γ-TuRC) in human cells. The globular N terminus and the central coiled-coil domain of SAS-6 are required for formation of the cartwheel [7, 14], whereas the function of its C-terminal outer cartwheel region in centriole duplication remains unclear. We find that deletion of HsSAS-6 C terminus disrupts microtubule formation in daughter centriole, and as a result, cells fail to form the new centriole. Consequently, this results in mitotic cells having only two centrioles localized at a single site. Detailed molecular analyses showed that HsSAS-6 interacts with the γ-TuRC proteins and associates with the γ-TuRC at the centrosome, and furthermore, the C terminus is essential for this association. High-resolution microscopy revealed localization of the γ-TuRC protein, γ-tubulin as multiple lobes surrounding the HsSAS-6-containing central hub in the centriole. Together, the results indicate that HsSAS-6 regulates centriolar microtubule assembly by anchoring γ-TuRCs to the pro-centriole at the onset of daughter centriole formation.

Gupta|Hindol|H|
Rajeev|Resmi|R|
Sasmal|Ranjan|R|
Radhakrishnan|Renjith M|RM|
Anand|Ushma|U|
Chandran|Haritha|H|
Aparna|Nurni R|NR|
Agasti|Sarit|S|
Manna|Tapas K|TK|

D018797:Cell Cycle Proteins
D002502:Centrioles
D057809:HEK293 Cells
D006367:HeLa Cells
D006801:Humans
D008869:Microtubule-Associated Proteins
D001678:Organelle Biogenesis

γ-tubulin centriole microtubule HsSAS-6 mitosis


Evaluation of process performance, energy consumption and microbiota characterization in a ceramic membrane bioreactor for ex-situ biomethanation of H2 and CO2.

Abstract: The performance of a pilot ceramic membrane bioreactor for the bioconversion of H2 and CO2 to bioCH4 was evaluated in thermophilic conditions. The loading rate was between 10 and 30 m3 H2/m3reactor d and the system transformed 95% of H2 fed. The highest methane yield found was 0.22 m3 CH4/m3 H2, close to the maximum stoichiometric value (0.25 m3 CH4/m3 H2) thus indicating that archaeas employed almost all H2 transferred to produce CH4. kLa value of 268 h-1 was reached at 30 m3 H2/m3reactor d. DGGE and FISH revealed a remarkable archaeas increase related to the selection-effect of H2 on community composition over time. Methanothermobacter thermautotrophicus was the archaea found with high level of similarity. This study verified the successful application of membrane technology to efficiently transfer H2 from gas to the liquid phase, the development of a hydrogenotrophic community from a conventional thermophilic sludge and the technical feasibility of the bioconversion.

Alfaro|Natalia|N| Fdz-Polanco|María|M| Fdz-Polanco|Fernando|F| Díaz|Israel|I|

Biomethane
Methanation
Ex-situ upgrading
Hydrogenotrophic archaea
MBR


Effect of cyclosporine A versus tacrolimus on the response to antiviral therapy after hepatitis C genotype-4 recurrence post-liver transplantation: A prospective cohort trial.

Abstract:
WHAT IS KNOWN AND OBJECTIVE
The influence of immunosuppression on the response to antiviral therapy (AVT) for recurrent hepatitis C virus (HCV) infection in liver transplant (LT) recipients remains controversial, especially for the rarely investigated genotype 4. This study aims to compare the effects of the two widely used calcineurin inhibitors (CNIs) (cyclosporine A (CsA) and tacrolimus (Tac)) on the therapeutic response to different AVT regimens.

METHODS
A prospective, dual-centre, cohort study of 126 Egyptian living donor liver transplant (LDLT) recipients with recurrent HCV genotype 4 infection, who were categorized into three groups according to the AVT used. Group I received pegylated interferon (Peg-IFN-α 2a) plus ribavirin (RBV) (n = 44), group II received the direct antiviral agent (DAA) sofosbuvir plus RBV (n = 52) and group III received daclatasvir and sofosbuvir (also DAAs) plus RBV (n = 30). Each group was further subdivided according to the primary immunosuppression (CsA or Tac). The sustained virological response (SVR) and relapse rates were considered the primary therapeutic outcomes of AVT.

RESULTS
No significant intergroup differences were observed in the achievement of primary and secondary outcomes. SVR rates in the IFN-based regimen were 75% and 66.7% in CsA and Tac users and 81.2% and 83% in DAAs, respectively. Relapse rates in the IFN-based regimen were 10% and 16.7% in CsA and Tac users and 12.5% and 14.9% in DAAs, respectively.

WHAT IS NEW AND CONCLUSION
Within the limitations of a relatively small study, CsA did not offer an advantage over Tac regarding the response to AVT after HCV genotype 4 recurrence in LDLT recipients.

antiviral therapy
hepatitis C genotype-4
liver transplantation
calcineurin inhibitors
sustained virological response


Biomimetic particles as therapeutics.

Abstract: In recent years, there have been major advances in the development of novel nanoparticle- and microparticle-based therapeutics. An emerging paradigm is the incorporation of biomimetic features into these synthetic therapeutic constructs to enable them to better interface with biological systems. Through the control of size, shape, and material consistency, particle cores have been generated that better mimic natural cells and viruses. In addition, there have been significant advances in biomimetic surface functionalization of particles through the integration of bio-inspired artificial cell membranes and naturally derived cell membranes. Biomimetic technologies enable therapeutic particles to have increased potency to benefit human health.

Meyer|Randall A|RA|
Sunshine|Joel C|JC|
Green|Jordan J|JJ|

biomimetic
biomaterial
drug delivery
micro/nanoparticle


Broad targeted analysis of neurochemicals in rat serum using liquid chromatography tandem mass spectrometry with chemical derivatization.

Abstract: In this study, an efficient and sensitive assay for the detection of 42 polar neurochemicals, including neurotransmitters, amino acids, and biogenic amines, was established by combining reversed-phase liquid chromatography tandem mass spectrometry with chemical derivatization. An optimally designed benzoyl chloride derivatization was easily conducted in a one-pot reaction and stable neurochemical derivatives were obtained under mild conditions within 5 min (except for acetylcholine and melatonin). Derivatization also enabled the introduction of heavy labeling of the analytes through the use of labeled derivatization agents. Chromatography separation was performed on an HSS T3 column within 15 min by gradient elution. Multiple reaction monitoring acquisition mode enabled quantitation of neurochemicals with limits of detection of 0.05 to 11.63 nM and lower limits of quantitation of 0.09 to 46.50 nM in rat serum. The assay was well validated in terms of linearity and extraction recovery. Furthermore, the instrumental precision, specificity, matrix effect, accuracy, precision, stability, dilution effect, and carry-over effect were also validated. Finally, the overall efficacy of the assay was experimentally tested using serum from six Sprague-Dawley rats. The results demonstrated that the developed method is effective for broad targeted analysis of 42 neurochemicals in serum.

D002851:Chromatography, High Pressure Liquid

targeted analysis
neurochemicals
rat serum
chemical derivatization


Betulin Alleviates the Inflammatory Response in Mouse Chondrocytes and Ameliorates Osteoarthritis via AKT/Nrf2/HO-1/NF-κB Axis.

Abstract: Osteoarthritis (OA) is a common degenerative joint disease featuring the degeneration, destruction, and ossification of cartilage. Inflammation which may facilitate OA occurrence and development is considered as the main pathological factor. Betulin, a natural product extracted from birch bark, has been commonly used for inflammation treatment; however, its role in OA remains unclear. This study is aimed to explore whether betulin can suppress IL-1β-induced inflammation in chondrocytes and alleviate OA in vitro and in vivo. In in vitro studies, the generation of pro-inflammatory factors, such as interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), prostaglandin E2 (PGE2), and nitric oxide (NO), was assessed using the enzyme-linked immunosorbent assay (ELISA) and Griess reaction. As revealed by results, betulin inhibited the expression of pro-inflammatory mediators. In addition, the protein expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), matrix metalloproteinase (MMP-13), thrombospondin motifs 5 (ADAMTS5), Collagen II, and Aggrecan were quantified using Western blot analysis. We found that betulin could inhibit the generation of COX-2 and iNOS induced by IL-1β, indicating that betulin has anti-inflammatory effects in chondrocytes. Furthermore, betulin downregulates the expression of MMP-13 and ADAMTS-5 and upregulates the expression of Collagen II and Aggrecan, indicating that it can inhibit the degradation of the extracellular matrix. In mechanism, betulin activated the AKT/Nrf2 pathway and inhibited the phosphorylation of p65. In in vivo studies, administration of betulin in vivo could inhibit cartilage destruction and inflammatory progression. Therefore, these findings suggest that betulin may alleviate IL-1β-induced OA via the AKT/Nrf2/HO-1/NF-κB signal axis, and betulin may be a potential drug for the treatment of OA.

Ren|Chenghao|C| Jin|Jie|J| Hu|Wei|W| Chen|Qi|Q| Yang|Jian|J| Wu|Yaosen|Y| Zhou|Yifei|Y| Sun|Liaojun|L| Gao|Weiyang|W| Zhang|Xiaolei|X| Tian|Naifeng|N|

betulin
AKT
NF-κB
osteoarthritis (OA)
inflammation
NRF


Friend or foe? Mogamulizumab in allogeneic hematopoietic stem cell transplantation for adult T-cell leukemia/lymphoma.

Abstract: Adult T-cell leukemia/lymphoma (ATL/ATLL) is a peripheral T-cell neoplasm associated with human T-lymphotropic virus type-1 (HTLV-1). Even the currently most intensive chemotherapy regimen modified LSG15 (mLSG15, VCAP-AMP-VECP) results in a dismal clinical outcome, with a median overall survival of only around 1 year. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) may lead to long-term remission in a proportion of patients with aggressive ATL, the clinical outcome in patients with refractory or relapsed ATL is unsatisfactory. The anti-CCR4 antibody mogamulizumab (moga) has been recently approved for ATL in Japan, and it is effective in a significant proportion of patients with refractory or relapsed ATL. However, there are major concerns about the harmful influences of pretransplant moga on the immune reconstitution after allo-HSCT. Specifically, moga depletes regulatory T cells (Tregs) for at least a few months, which may increase the risk of graft-versus-host disease (GVHD) after allo-HSCT. A recent retrospective study from Japan clearly showed that pretransplant moga increased the risk of severe and steroid-refractory GVHD, which led to increases in non-relapse mortality and overall mortality. To improve the overall clinical outcome in patients with relapsed or refractory ATL, more studies are needed to incorporate moga without increasing adverse effects on the clinical outcome after allo-HSCT. In this review, we aim to provide an updated summary of the research related to moga and allo-HSCT.

adult T-cell leukemia/lymphoma (ATL/ATLL)


Polyadenine-mediated Immobilization of Aptamers on a Gold Substrate for the Direct Detection of Bacterial Pathogens.

Abstract: Nucleic acid aptamers have been widely used as synthetic probes for bioanalytical applications. Herein, we carried out a detailed study on the immobilization of a series of aptamers ranging from 37 to 88 bases, which are specific to either Escherichia coli (E. coli) or Staphylococcus aureus (S. aureus), on a planar gold substrate via a polyadenine-mediated immobilization method. The resultant surfaces were characterized by both surface plasmon resonance spectroscopy (SPR) and X-ray photoelectron spectroscopy. The results clearly show that the aptamer solution at a lower ionic strength gives rise to a higher lateral density of the aptamer when compared to that at a higher ionic strength. The SPR aptasensors are then employed for detecting their corresponding bacteria (i.e., E. coli and S. aureus, respectively). The data indicate that the SPR aptasensor with a higher density of aptamer exhibits a better capture of target bacteria.

D052157:Aptamers, Nucleotide
D001483:Base Sequence
D001965:Bromides
D004926:Escherichia coli
D006046:Gold
D009994:Osmolar Concentration
D011061:Poly A
D017670:Sodium Compounds
D013211:Staphylococcus aureus
D020349:Surface Plasmon Resonance

aptamer
Escherichia coli
Staphylococcus aureus
Surface plasmon resonance spectroscopy
polyadenine


Adult sex ratios and partner scarcity among hunter-gatherers: implications for dispersal patterns and the evolution of human sociality.

Abstract: Small populations are susceptible to high genetic loads and random fluctuations in birth and death rates. While these selective forces can adversely affect their viability, small populations persist across taxa. Here, we investigate the resilience of small groups to demographic uncertainty, and specifically to fluctuations in adult sex ratio (ASR), partner availability and dispersal patterns. Using 25 years of demographic data for two Savannah Pumé groups of South American hunter-gatherers, we show that in small human populations: (i) ASRs fluctuate substantially from year to year, but do not consistently trend in a sex-biased direction; (ii) the primary driver of local variation in partner availability is stochasticity in the sex ratio at maturity; and (iii) dispersal outside of the group is an important behavioural means to mediate locally constrained mating options. To then simulate conditions under which dispersal outside of the local group may have evolved, we develop two mathematical models. Model results predict that if the ASR is biased, the globally rarer sex should disperse. The model's utility is then evaluated by applying our empirical data to this central prediction. The results are consistent with the observed hunter-gatherer pattern of variation in the sex that disperses. Together, these findings offer an alternative explanation to resource provisioning for the evolution of traits central to human sociality (e.g. flexible dispersal, bilocal post-marital residence and cooperation across local groups). We argue that in small populations, looking outside of one's local group is necessary to find a mate and that, motivated by ASR imbalance, the alliances formed to facilitate the movement of partners are an important foundation for the human-typical pattern of network formation across local groups.This article is part of the themed issue 'Adult sex ratios and reproductive decisions: a critical re-examination of sex differences in human and animal societies'.

adult sex ratio
dispersal
Savannah Pumé
human evolution
hunter–gatherers
sexual selection


K+ deficiency caused defects in renal tubular cell proliferation, oxidative stress response, tissue repair and tight junction integrity, but enhanced energy production, proteasome function and cellular K+ uptake.

Abstract: Hypokalemia is a common electrolyte disorder in hospitalized patients and those with chronic diseases and is associated with renal tubular injury. Our recent expression proteomics study revealed changes in levels of several proteins in renal tubular cells during K+ deficiency. However, functional significance and mechanisms underlying such changes remained unclear. The present study, thus, aimed to investigate functional changes of renal tubular cells induced by K+ deficiency. MDCK cells were maintained in normal-K+ (ANK; [K+] = 5.0 mM), Low-K+ (ALK; [K+] = 2.5 mM), or K+-depleted (AKD; [K+] = 0 mM) medium. Cell count and cell death assay showed that ALK and AKD groups had marked decrease in cell proliferation without significant change in cell death. Other functional investigations revealed that AKD cells had significantly increased levels of carbonylated proteins (by OxyBlot assay), impaired tissue repair (by scratch assay), defective tight junction (by Western blotting, immunofluorescence staining and measuring transepithelial electrical resistance), increased intracellular ATP level (by ATP measurement), decreased levels of ubiquitinated proteins (by Western blotting), and increased level of Na+/K+-ATPase (by Western blotting), which was consistent with the increased cellular K+ uptake after K+ repletion. Our findings have shown that AKD caused defects in cell proliferation, oxidative stress response, tissue repair and tight junction integrity, but on the other hand, enhanced energy production, proteasome function and cellular K+ uptake. These findings may shed light onto cellular response to K+ deficiency and better understanding of both pathogenic and compensatory mechanisms in hypokalemic nephropathy.

oxidative stress
tight junction
proteasome
ATP
ubiquitin
ZO-1


Multigenic engineering of the chloroplast genome in the green alga Chlamydomonas reinhardtii.

Abstract: The chloroplast of microalgae such as Chlamydomonas reinhardtii represents an attractive chassis for light-driven production of novel recombinant proteins and metabolites. Methods for the introduction and expression of transgenes in the chloroplast genome (=plastome) of C. reinhardtii are well-established and over 100 different proteins have been successfully produced. However, in almost all reported cases the complexity of the genetic engineering is low, and typically involves introduction into the plastome of just a single transgene together with a selectable marker. In order to exploit fully the potential of the algal chassis it is necessary to establish methods for multigenic engineering in which many transgenes can be stably incorporated into the plastome. This would allow the synthesis of multi-subunit proteins and the introduction into the chloroplast of whole new metabolic pathways. In this short communication we report a proof-of-concept study involving both a combinatorial and serial approach, with the goal of synthesizing five different test proteins in the C. reinhardtii chloroplast. Analysis of the various transgenic lines confirmed the successful integration of the transgenes and accumulation of the gene products. However, the work also highlights an issue of genetic instability when using the same untranslated region for each of the transgenes. Our findings therefore help to define appropriate strategies for robust multigenic engineering of the algal chloroplast.

D016825:Chlamydomonas reinhardtii
D002736:Chloroplasts
D005818:Genetic Engineering
D054628:Genome, Chloroplast
D053858:Metabolic Networks and Pathways
D058086:Microalgae
D010940:Plant Proteins

chloroplast
Chlamydomonas
microalgae
plastome
genetic engineering


Experiences of Parental Suicide-Bereavement: A Longitudinal Qualitative Analysis Over Two Years.

Abstract: Limited research exists on the experiences of parents bereaved by suicide. Our earlier qualitative analysis examined the experiences of parents' suicide bereavement at 6 and 12 months after their loss. The current study aimed to extend the analysis over 24 months, outlining the key themes of parents' suicide bereavement experience. In the frames of a longitudinal study of suicide bereavement in Queensland, Australia, parents were interviewed at 6, 12, and 24 months after their loss. Thematic analysis was used to further explore new themes and three key themes identified in earlier analyses: searching for answers and sense-making, coping strategies and support, and finding meaning and purpose. Results at 24 months revealed a clearer differentiation between strategies adopted by mothers and fathers. Anger and blame had changed towards feelings of depression. A polarization was observed between parents still oscillating in brooding rumination and those who have shifted towards sense-making. The former more frequently reported depression symptoms, and the latter reported a more positive attitude towards life and acceptance of their loss. Consistent with the dual-process model, parents managed to reach acceptance after oscillating between sense-making and meaning making. Findings provide insights how suicide loss affects parents, with implications for postvention.

parents
suicide
suicide bereavement
child death
longitudinal qualitative research


Iterative and Complex Asymmetric Divisions Control Cell Volume Differences in Ciona Notochord Tapering.

Abstract: The notochord of the invertebrate chordate Ciona forms a tapered rod at tailbud stages consisting of only 40 cylindrical cells in a single-file column. This tapered shape involves differences in notochord cell volume along the anterior-posterior axis. Here, we quantify sibling cell volume asymmetry throughout the developing notochord and find that there are distinctive patterns of unequal cleavage in all 4 bilateral pairs of A-line primary notochord founder cells and also in the B-line-derived secondary notochord founder cells. A quantitative model confirms that the observed patterns of unequal cleavage are sufficient to explain all the anterior-posterior variation in notochord cell volume. Many examples are known of cells that divide asymmetrically to give daughter cells of different size and fate. Here, by contrast, a series of subtle but iterative and finely patterned asymmetric divisions controls the shape of an entire organ. Quantitative 3D analysis of cell shape and spindle positioning allows us to infer multiple cellular mechanisms driving these unequal cleavages, including polarized displacements of the mitotic spindle, contributions from the shape of the mother cell, and late changes occurring between anaphase and abscission that potentially involve differential cortical contractility. We infer differential use of these mechanisms between different notochord blastomeres and also between different rounds of cell division. These results demonstrate a new role for asymmetric division in directly shaping a developing organ and point toward complex underlying mechanisms.

Winkley|Konner|K| Ward|Spencer|S| Reeves|Wendy|W| Veeman|Michael|M|

asymmetric division
Ciona
notochord
tapering
unequal cleavage
cell shape
spindle positioning
morphogenesis


Mucosal-associated invariant T cells: new players in CF lung disease?

Abstract: The past decade has witnessed a surge in research centered around exploring the role of the enigmatic innate immune-like lymphocyte MAIT cell in human disease. Recent evidence has led to the elucidation of its role as a potent defender at mucosal surfaces including lungs due to its capacity to mount a formidable immediate response to bacterial pathogens. MAIT cells have a unique attribute of recognizing microbial ligands in conjunction with non-classical MHC-related protein MR1. Recent studies have demonstrated their contribution in the pathogenesis of chronic pulmonary disorders including asthma and chronic obstructive pulmonary disease. Several cellular players including innate immune cells are active contributors in the immune imbalance present in cystic fibrosis(CF) lung. This immune dysregulation serves as a central pivot in disease pathogenesis, responsible for causing immense structural damage in the CF lung. The present review focuses on understanding the role of MAIT cells in CF lung disease. Future studies directed at understanding the possible relationship between MAIT cells and regulatory T cells (Tregs) in CF lung disease could unravel a holistic picture where a combination of antimicrobial effects of MAIT cells and anti-inflammatory effects of Tregs could be exploited in synergy to alleviate the rapid deterioration of lung function in CF lung disease due to the underlying complex interplay between persistent infection and inflammation.

D000072336:Mucosal-Associated Invariant T Cells

MAIT cells
Cystic fibrosis
Pulmonary inflammation


Plasma high-resolution metabolomics identifies linoleic acid and linked metabolic pathways associated with bone mineral density.

Abstract:
BACKGROUND & AIMS
There is a considerable degree of variation in bone mineral density (BMD) within populations. Use of plasma metabolomics may provide insight into established and novel determinants of BMD variance, such as nutrition and gut microbiome composition, to inform future prevention and treatment strategies for loss of BMD. Using high-resolution metabolomics (HRM), we examined low-molecular weight plasma metabolites and nutrition-related metabolic pathways associated with BMD.

METHODS
This cross-sectional study included 179 adults (mean age 49.5 ± 10.3 yr, 64% female). Fasting plasma was analyzed using ultra-high-resolution mass spectrometry with liquid chromatography. Whole body and spine BMD were assessed by dual energy X-ray absorptiometry and expressed as BMD (g/cm2) or Z-scores. Multiple linear regression, pathway enrichment, and module analyses were used to determine key plasma metabolic features associated with bone density.

RESULTS
Of 10,210 total detected metabolic features, whole body BMD Z-score was associated with 710 metabolites, which were significantly enriched in seven metabolic pathways, including linoleic acid, fatty acid activation and biosynthesis, and glycerophospholipid metabolism. Spine BMD was associated with 970 metabolites, significantly enriched in pro-inflammatory pathways involved in prostaglandin formation and linoleic acid metabolism. In module analyses, tryptophan- and polyamine-derived metabolites formed a network that was significantly associated with spine BMD, supporting a link with the gut microbiome.

CONCLUSIONS
Plasma HRM provides comprehensive information relevant to nutrition and components of the microbiome that influence bone health. This data supports pro-inflammatory fatty acids and the gut microbiome as novel regulators of postnatal bone remodeling.

Bellissimo|Moriah P|MP|
Ziegler|Thomas R|TR|
Jones|Dean P|DP|
Liu|Ken H|KH|
Fernandes|Jolyn|J|
Roberts|Joseph L|JL|
Weitzmann|M Neale|MN|
Pacifici|Roberto|R|
Alvarez|Jessica A|JA|

Nutrition
Fats
Inflammation
Omega-6
PUFA
Skeletal health


Elements of an Excellent Psychiatry Clerkship Experience: A Survey Study of Graduating Medical Students.

Abstract:
OBJECTIVE
One possible factor associated with choosing psychiatry as a career is students rating their psychiatry clerkship as excellent. Although this suggests that an excellent clerkship may improve recruitment into psychiatry, to our knowledge there has never been a multi-site survey study of graduating medical students that identify what factors lead to an excellent clerkship rating. The purpose of this study was to determine factors that medical student find important for an excellent psychiatry clerkship experience.

METHODS
A total of 1457 graduating medical students at eight institutions were sent a 22-item Likert-type survey about what clinical and administrative factors they considered when rating their psychiatry clerkship via email in the fall of their last year. 357 (24.5%) responded and Z-test, t-tests, and multiple regression analyses were carried out.

RESULTS
The factors which students rated higher than the mean included planned application to psychiatry residency, clear expectations, a transparent grading process, feeling part of a team, timely feedback by faculty, and a competent clerkship coordinator and director. Lectures, active learning, and self-study were rated as less pertinent, and the overall clerkship rating did differ between students going into psychiatry versus other specialties.

CONCLUSIONS
Although the low response undermines the validity of findings, by improving the administration of the clerkship with clear expectations, grading, feedback, and by encouraging clinical teams to fully integrate students clerkship ratings might improve which could potentially improve recruitment. Future research could further quantify and qualify these parameters and compare psychiatric clerkships to other clerkships.

D002982:Clinical Clerkship
D006801:Humans
D018794:Problem-Based Learning
D011570:Psychiatry
D013337:Students, Medical
D011795:Surveys and Questionnaires

Psychiatry
Clerkship
Recruitment
Medical education


Test-Retest Reliability and Convergent Validity of Two Brief Fruit and Vegetable Intake Questionnaires among School-Aged Children.

Abstract: Reliable, valid, and easy-to-implement tools are required to assess children's fruit and vegetable intake as part of behavior change-focused nutrition education programs; however, the availability of such instruments is limited. The purpose of this study was to examine the reproducibility and accuracy of two brief fruit and vegetable intake questionnaires among 8- to 12-year-old children. A total of 109 participants from diverse racial/ethnic groups were recruited from urban afterschool programs. The results of two short questionnaires (food web and plate activity) were reproducible between two repeated measures conducted one week apart. Compared to a reference 24-h dietary recall, the food web questionnaire had acceptable convergent validity for assessing children's fruit intake (kappa: 0.51; r = 0.53, p < 0.001), but limited validity for assessing children's vegetable intake (kappa: 0.43; r = 0.33, p < 0.003). Children tended to overestimate intake when visualizing fruit and vegetable consumption via the plate activity questionnaire, indicating that this questionnaire was not a valid tool to assess children's fruit and vegetable consumption at dinner meals. Children's report of fruit intake via the food web questionnaire may be a useful indicator of program success in improving fruit intake.

D007722:Health Knowledge, Attitudes, Practice

validation
fruit
vegetable
children
assessment
survey and questionnaire


Copper complexes of the 1,3,4-thiadiazole derivatives modulate antioxidant defense responses and resistance in tomato plants against fungal and bacterial diseases.

Abstract: The metallic complexes μ-chloro-μ-[2,5-bis (2-pyridyl)-1,3,4-thiadiazole] aqua chlorocopper (II) dichlorocopper (II) (abbreviated 2PTH-Cu2-Cl4); aquabis [2,5-bis (2-pyridyl)-1,3,4-thiadiazole-κ2N2,N3] (trifluoromethane-sulfonato-κO) copper(II) trifluoro metrhanesulfonate (2PTH-Cu-tF) and bis[(2,5-bis(pyridine-2-yl)-1,3,4-thiadiazole-di-azido copper(II)] (2PTH-Cu-Az) were compared for their antimicrobial activities in vitro, and their aptitude to control Verticillium wilt and crown gall diseases development of tomato in the greenhouse. Results showed that the complex 2PTH-Cu-Az inhibited drastically the growth of V. dahliae in vitro. 2PTH-Cu2-Cl4 and 2PTH-Cu-tF did not display any noticeable antimicrobial activity in vitro against all of the pathogens tested. However, in planta evaluation revealed that the three complexes protected tomato against crown gall similarly. They also reduced Verticillium wilt disease severity, although the complex 2PTH-Cu-Az was the most efficient. When compared to other complexes, 2PTH-Cu-Az triggered only a weak oxidative burst as revealed by H2O2 measurement and the activity of ascorbate peroxidase and catalase. These results suggest that the superiority of 2PTH-Cu-Az against V. dahliae rely on its direct antifungal activity and its ability to modulate H2O2 accumulation.

Smaili|Amal|A|
Rifai|Lalla Aicha|LA|
Esserti|Siham|S|
Koussa|Tayeb|T|
Bentiss|Fouad|F|
Guesmi|Salaheddine|S|
Laachir|Abdelhakim|A|
Faize|Mohamed|M|

D016960:Agrobacterium tumefaciens
D000935:Antifungal Agents
D060387:Ascorbate Peroxidases
D002374:Catalase
D003300:Copper
D044084:Erwinia amylovora
D006861:Hydrogen Peroxide
D018551:Lycopersicon esculentum
D010935:Plant Diseases
D044224:Pseudomonas syringae
D013830:Thiadiazoles
D020172:Verticillium

Crown gall, active oxygen species, antioxidant defenses


Fighting COVID-19: A quick review of diagnoses, therapies, and vaccines.

Abstract: The coronavirus disease 2019 (COVID-19) pandemic caused by a novel coronavirus, SARS-CoV-2, has infected more than 22 million individuals and resulted in over 780,000 deaths globally. The rapid spread of the virus and the precipitously increasing numbers of cases necessitate the urgent development of accurate diagnostic methods, effective treatments, and vaccines. Here, we review the progress of developing diagnostic methods, therapies, and vaccines for SARS-CoV-2 with a focus on current clinical trials and their challenges. For diagnosis, nucleic acid amplification tests remain the mainstay diagnostics for laboratory confirmation of SARS-CoV-2 infection, while serological antibody tests are used to aid contact tracing, epidemiological, and vaccine evaluation studies. Viral isolation is not recommended for routine diagnostic procedures due to safety concerns. Currently, no single effective drug or specific vaccine is available against SARS-CoV-2. Some candidate drugs targeting different levels and stages of human responses against COVID-19 such as cell membrane fusion, RNA-dependent RNA polymerase, viral protease inhibitor, interleukin 6 blocker, and convalescent plasma may improve the clinical outcomes of critical COVID-19 patients. Other supportive care measures for critical patients are still necessary. Advances in genetic sequencing and other technological developments have sped up the establishment of a variety of vaccine platforms. Accordingly, numerous vaccines are under development. Vaccine candidates against SARS-CoV-2 are mainly based upon the viral spike protein due to its vital role in viral infectivity, and most of these candidates have recently moved into clinical trials. Before the efficacy of such vaccines in humans is demonstrated, strong international coordination and collaboration among studies, pharmaceutical companies, regulators, and governments are needed to limit further damage due the emerging SARS-CoV-2 virus.

Shih|Hsin-I|HI| Wu|Chi-Jung|CJ| Tu|Yi-Fang|YF| Chi|Chia-Yu|CY|

COVID-19
Vaccine
SARS-CoV-2
Clinical trials
Spike protein
NAATs


Advantage of HSP110 (T17) marker inclusion for microsatellite instability (MSI) detection in colorectal cancer patients.

Abstract: Colorectal cancer (CRC) is a leading cause of cancer death worldwide. Microsatellite instability (MSI) is a genetic pathway leading to CRC, associated with particular clinicopathological features, and recently a major biomarker of immunotherapy response. There is little information the frequency MSI among Brazilian CRC patients, and it is still debatable the ideal methodology for MSI screening in countries with limited resources. We proposed to evaluate MSI by molecular and immunohistochemistry (IHC) methods, to compare both methodologies and also to assess the inclusion of a novel microsatellite marker, HSP110 (T17). The molecular MSI evaluation was performed using a PCR-multiplex panel in a total of 1013 CRC patients. Mismatch repair (MMR) proteins (MLH1, MSH2, MSH6 and PMS2) expression were evaluated by IHC. HSP110 (T17) marker was analyzed by fragment analysis. Molecularly, 89.5% of cases were MSI-negative and 10.5% were MSI-positive. The IHC showed that 88.9% of cases exhibited MMR-proficient status, 10.2% were MMR-deficient and 0.9% was inconclusive. Genotyping of the HSP110 (T17) in 106 MSI-positive and 215 MSI-negative cases showed its alteration only among the MSI-positive cases. We observed agreement (0.956, Kappa Test) between both molecular and IHC methodologies, with only eight discordant results, and in this subset of cases the HSP110 (T17) corroborate the molecular findings. This study suggests the use of molecular assays over IHC for MSI analysis and proposes the inclusion HSP110 (T17) marker as a complementary analysis in discordant cases.

Berardinelli|Gustavo Noriz|GN|
Scapulatempo-Neto|Cristovam|C|
Durães|Ronílson|R|
Antônio de Oliveira|Marco|M|
Guimarães|Denise|D|
Reis|Rui Manuel|RM|

HSP110 (T17)
microsatellite instability
colorectal cancer
immunohistochemistry
molecular diagnostic


Cervical disc width index is a reliable parameter and consistent in young growing Dutch Warmblood horses.

Abstract: Intervertebral disc disease, as well as the associated alteration of the radiographic intervertebral disc space width, has been reported in horses. Disc height index (DHI) has proven to be an accurate and objective parameter in other species but data related to this parameter are lacking in horses. Therefore, the aims of this retrospective longitudinal diagnostic accuracy study were (a) to evaluate the reliability of measurements within and between observers of the equine Disc Width Index (EDWI) as a parameter for radiographic equine cervical intervertebral disc space width, and (b) to evaluate the sequential development of the EDWI over time. For this, EDWI from all intervertebral disc spaces between second cervical (C) to first thoracic (Th) vertebrae were obtained in a group of 39 Dutch Warmblood horses at 1, 5, and 18 months of age, by one European College of Veterinary Diagnostic Imaging (ECVDI) board-certified veterinary radiologist (S.V.) and two veterinary students. Bland-Altmann plots and intraclass Correlation Coefficient revealed a good intra- and interobserver agreement. A linear mixed-effect model did reveal that mean EDWI increases significantly toward the caudal cervical spine, but did not differ significantly for a certain location over time or between sexes. Spearman's rank test did show a significant correlation between the vertebral alignment angle induced by different head-neck positions and a normalized EDWI (ρ = 0.33, P < .0001). Student's t-test revealed that the presence of C6-C7 transposition of the transverse processes did not influence EDWI significantly. It was concluded that EDWI represents a reliable parameter for equine cervical radiographic intervertebral disc space width. Practical implementation of EDWI warrants monitoring in a group of adult horses while maintaining a standardized head-neck position.

disc degeneration
radiography
vertebral column


Evaluation of a highly skin permeable low-molecular-weight protamine conjugated epidermal growth factor for novel burn wound healing therapy.

Abstract: We evaluated the laser induced burn wound healing efficacy of a recombinant low-molecular-weight protamine conjugated epidermal growth factor (rLMWP-EGF). rLMWP-EGF was prepared by genetically combining LMWP with the N-terminal sequence of EGF; we obtained a homogeneous modified EGF without reduced biological activity. Because of the protein transduction domain of LMWP, rLMWP-EGF showed enhanced drug penetration across artificial skin constructs and excised mouse skin layers versus EGF and showed significantly improved burn wound healing efficacy, with accelerated wound closure and minimized eschar and scar formation, compared with EGF or no treatment. Histological examination also revealed that rLMWP-EGF permeated through the intact skin around the wound and facilitated residual epithelial cell proliferation in an integrated manner to reform an intact epidermis. Radiofrequency microwound formation was effective for reducing large hypertrophic scars formed after severe laser burning by collagen remodeling but rLMWP-EGF did not show a meaningful synergistic effect in burn scar reduction. However, rLMWP-EGF was helpful for forming skin with a more normal appearance and texture. Thus, rLMWP-EGF demonstrated therapeutic potential as a novel topical burn wound healing drug with no obvious toxic effect.

Lee|Ji Hae|JH|
Bae|Il-Hong|IH|
Choi|Jin Kyu|JK|
Park|Jin Woo|JW|

permeability
conjugation
wound healing
epithelial delivery/permeability
peptide delivery
percutaneous
permeation enhancers
protein delivery
transdermal drug delivery


Magnetic resonance imaging-guided three-dimensional real-time bile duct reconstruction and end-to-end anastomosis under laparoscopy: A case report.

Abstract: In laparoscopic cholecystectomy (LC), the anatomical variation of gallbladder canal should be noted. Bile duct injury is one of the most serious complications of LC, which might lead to serious complications. This case because of an intraoperative accidental cut to right anterior inferior lobe bile duct which joins to the cystic duct, after confirming by intraoperative magnetic resonance imaging-guided real-time three-dimensional bile duct reconstruction and performing end-to-end anastomosis of the right anterior inferior lobe bile duct and the gallbladder tube under laparoscopy, the patient was discharged 5 days after surgery, was followed up for 4 months and was disease-free.

Jie|Zhu|Z| Siming|Zheng|Z| Xuechang|Zhang|Z| Xiancheng|Wang|W|

three-dimensional
Anastomosis
laparoscopy
biliary variation
end to end


Removal of pharmaceutical compounds commonly-found in wastewater through a hybrid biological and adsorption process.

Abstract: Nowadays, alternative options to conventional wastewater treatment should be studied due to rising concerns emerged by the presence of pharmaceuticals compounds (PhCs) in the aquatic environment. In this work, a combined system including biological treatment by activated sludge plus adsorption with activated carbon is proposed to remove three selected drugs (acetaminophen (ACT), caffeine (CAF) and ibuprofen (IBU)) in a concentration of 2 mg L-1 of each one. For it three sequencing batch reactors (SBR) were operated. SBR-B treated a synthetic wastewater (SWW) without target drugs and SBR-PhC and SBR-PhC + AC operated with SWW doped with the three drugs, adding into SBR-PhC + AC 1.5 g L-1 of a mesoporous granular activated carbon. Results showed that the hybrid system SBR-activated carbon produced an effluent free of PhCs, which in addition had higher quality than that achieved in a conventional activated sludge treatment in terms of lower COD, turbidity and SMP concentrations. On the other hand, five possible routes of removal for target drugs during the biological treatment were studied. Hydrolysis, oxidation and volatilization pathways were negligible after 6 h of reaction time. Adsorption route only was significant for ACT, which was adsorbed completely after 5 h of reaction, while only 1.9% of CAF and 5.6% of IBU were adsorbed. IBU was the least biodegradable compound.

Ferrer-Polonio|Eva|E|
Fernández-Navarro|Julián|J|
Iborra-Clar|María-Isabel|MI|
Alcaina-Miranda|María-Isabel|MI|
Mendoza-Roca|José Antonio|JA|

Pharmaceutical compounds
Activated carbon
Emerging pollutants
Sequencing bath reactor


Combined radiomics-clinical model to predict malignancy of vertebral compression fractures on CT.

Abstract:
OBJECTIVES
To develop and validate a combined radiomics-clinical model to predict malignancy of vertebral compression fractures on CT.

METHODS
One hundred sixty-five patients with vertebral compression fractures were allocated to training (n = 110 [62 acute benign and 48 malignant fractures]) and validation (n = 55 [30 acute benign and 25 malignant fractures]) cohorts. Radiomics features (n = 144) were extracted from non-contrast-enhanced CT images. Radiomics score was constructed by applying least absolute shrinkage and selection operator regression to reproducible features. A combined radiomics-clinical model was constructed by integrating significant clinical parameters with radiomics score using multivariate logistic regression analysis. Model performance was quantified in terms of discrimination and calibration. The model was internally validated on the independent data set.

RESULTS
The combined radiomics-clinical model, composed of two significant clinical predictors (age and history of malignancy) and the radiomics score, showed good calibration (Hosmer-Lemeshow test, p > 0.05) and discrimination in both training (AUC, 0.970) and validation (AUC, 0.948) cohorts. Discrimination performance of the combined model was higher than that of either the radiomics score (AUC, 0.941 in training cohort and 0.852 in validation cohort) or the clinical predictor model (AUC, 0.924 in training cohort and 0.849 in validation cohort). The model stratified patients into groups with low and high risk of malignant fracture with an accuracy of 98.2% in the training cohort and 90.9% in the validation cohort.

CONCLUSIONS
The combined radiomics-clinical model integrating clinical parameters with radiomics score could predict malignancy in vertebral compression fractures on CT with high discriminatory ability.

KEY POINTS
• A combined radiomics-clinical model was constructed to predict malignancy of vertebral compression fractures on CT by combining clinical parameters and radiomics features. • The model showed good calibration and discrimination in both training and validation cohorts. • The model showed high accuracy in the stratification of patients into groups with low and high risk of malignant vertebral compression fractures.

D015331:Cohort Studies
D050815:Fractures, Compression
D006801:Humans
D008175:Lung Neoplasms
D016103:Spinal Fractures
D014057:Tomography, X-Ray Computed

compression
Fractures
Multidetector computed tomography
Spine


Synthesis, characterization and biological evaluation of dihydropyrimidine derivatives.

Abstract: A series of dihydropyrimidines containing quinoline were prepared under conventional heating and microwave irradiation. The structures of newly synthesized compounds were established based on analytical and spectral studies. Further these compounds were evaluated for their antioxidant, antifungal and antibacterial activities. Most of the compounds showed moderate to good activity when compared with standard.

Adhikari|Adithya|A|
Kalluraya|Balakrishna|B|
Sujith|K V|KV|
Gouthamchandra|||
Mahmood|Riaz|R|

Antibacterial activity
Antifungal activity
Antioxidant activity
MW assisted synthesis
Quinolinodihydropyrimidines
Three component reaction


Connectome-based functional connectivity markers of suicide attempt.

Abstract:
BACKGROUND
Functional brain markers of suicidality can help identify at-risk individuals and uncover underlying neurocognitive mechanism(s). Although some converging evidence has implicated dysfunction in several brain networks, suicide-related neuroimaging markers are inconsistent across studies, due to heterogeneity of neuroimaging approaches, clinical populations, and experimental methods.

METHODS
The current study aimed to address these limitations by examining resting-fMRI connectivity in a sample of post-9/11 veterans with a past suicide attempt (SA; n = 16) compared to a psychiatric control group (PC; n = 124) with no SA history but comparable past and present symptomatology, as well as a trauma control group (TC; n = 66) of trauma-exposed healthy controls. We used both a novel graph-analytic and seed-based approach to characterize SA-related connectivity differences across brain networks.

RESULTS
First, the graph-analytic approach identified the right amygdala and a region in the cognitive control network (right middle temporal gyrus; MTG) as regional SA-related hubs of dysfunction (HoD), or regions that exhibited a high number of SA-related connections. Aberrant SA-related connectivity between these hubs spanned multiple networks, including the cognitive control, default mode and visual networks. Second, the seed-based connectivity analysis that identifies SA-related differences in the strength of neural connections across the whole brain further implicated the right amygdala.

LIMITATIONS
Small sample size and potential underreporting of SA.

CONCLUSIONS
These two analytic approaches preliminarily suggest that the right amygdala and right MTG may be specific neural markers of SA that can be differentiated from neural markers of psychopathology more broadly.

Stumps|Anna|A|
Jagger-Rickels|Audreyana|A|
Rothlein|David|D|
Amick|Melissa|M|
Park|Hannah|H|
Evans|Travis|T|
Fortenbaugh|Francesca C|FC|
Fortier|Catherine B|CB|
Fonda|Jennifer R|JR|
Lee|Daniel|D|
Milberg|William|W|
McGlinchey|Regina|R|
DeGutis|Joseph|J|
Esterman|Michael|M|

Suicide attempt
Veterans
Biomarker
PTSD
Resting-state
fMRI