Comparison of clinical characteristics between ACOSOG Z0011-eligible cohort and sentinel lymph node-positive breast cancer patients in Hong Kong.

INTRODUCTION: The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial resulted in de-escalation of axillary surgery among early-stage breast cancer patients with low-volume sentinel lymph node (SLN) disease undergoing breast-conserving surgery and radiation therapy. Nevertheless, the mastectomy rate in the Chinese population remains high. This study compared the clinical characteristics of the ACOSOG Z0011-eligible cohort with SLN-positive breast cancer patients in Hong Kong. METHODS: This retrospective analysis of a prospectively maintained database at a university-affiliated breast cancer centre in Hong Kong was performed from June 2014 to May 2019. The database included all patients with clinical tumour (T) stage T1 or T2 invasive breast carcinoma, no palpable adenopathy, one or two positive SLNs on histological examination, and no prior neoadjuvant systemic treatment. Comparisons were made between the mastectomy and breast-conserving treatment groups in our cohort, along with the sentinel-alone arm in the ACOSOG Z0011 trial. RESULTS: One hundred and seventy-one patients met the inclusion criteria: 112 underwent mastectomy and 59 underwent breast-conserving treatment. Our mastectomy group had higher prevalences of T2 tumours (P<0.001), lymphovascular invasion (P<0.001), and SLN macrometastases (P=0.004) compared with the ACOSOG Z0011 cohort. However, in our patient population, mean pathological size slightly differed between the mastectomy and breast-conserving treatment groups (2.2 cm vs 1.8 cm; P=0.005). Other histopathological features were similar. CONCLUSION: This study demonstrated that clinicopathological features were comparable between SLN-positive breast cancer patients undergoing mastectomy and those undergoing breast-conserving treatment. Low-risk SLN-positive mastectomy patients may safely avoid completion axillary lymph node dissection.

Influence of ZIF-9 and ZIF-12 structure on the formation of a series of new Co/N-doped porous carbon composites as anode electrodes for high-performance lithium-ion batteries.

A series of new Co/N-doped porous carbon composites, denoted as Co/CZIF-9 and Co/CZIF-12, containing Co nanoparticles encapsulated in nitrogen-doped carbon matrices were prepared by annealing Co-based zeolite imidazolate framework materials, ZIF-9 and ZIF-12, as the efficient precursors at different temperatures. The structural features of the as-synthesized composites at 900 °C were determined by analytical methods with high reliability. Consequently, Co/CZIF-12_900 exhibits a high first specific discharge capacity of 971.0 mA h g-1 at a current density of 0.1 A g-1. Notably, the specific discharge/charge capacity of Co/CZIF-12_900 reaches about 508.8 mA h g-1 at 0.1 A g-1 after 100 cycles. The outstanding behaviors can be accounted for by the efficient incorporation of hetero-nitrogen doping and the Co nanoparticles within the layered structure of porous carbon, enhancing electrical conductivity and structural stability and limiting volume change during the intercalation/deintercalation of Li+ ions. These findings suggest that the Co/CZIF-12_900 material could be employed as a promising anode electrode for energy storage products.

A confinement of N-heterocyclic molecules in a metal-organic framework for enhancing significant proton conductivity.

A series of N-heterocyclic⊂VNU-23 materials have been prepared via the impregnation procedure of N-heterocyclic molecules into VNU-23. Their structural characterizations, PXRD, FT-IR, Raman, TGA, 1H-NMR, SEM-EDX, and EA, confirmed that N-heterocyclic molecules presented within the pores of parent VNU-23, leading to a remarkable enhancement in proton conductivity. Accordingly, the composite with the highest loading of imidazole, Im13.5⊂VNU-23, displays a maximum proton conductivity value of 1.58 × 10-2 S cm-1 (85% RH and 70 °C), which is ∼4476-fold higher than H+⊂VNU-23 under the same conditions. Remarkably, the proton conductivity of Im13.5⊂VNU-23 exceeds the values at 85% RH for several of the reported high-performing MOF materials. Furthermore, Im13.5⊂VNU-23 can retain a stable proton conductivity for more than 96 h, as evidenced by FT-IR and PXRD analyses. These results prove that this hybrid material possesses potential applications as a commercial proton exchange membrane fuel cell.

Deep Eutectic Solvent Based on Lithium Bis[(trifluoromethyl)sulfonyl] Imide (LiTFSI) and 2,2,2-Trifluoroacetamide (TFA) as a Promising Electrolyte for a High Voltage Lithium-Ion Battery with a LiMn2O4 Cathode.

To design safe and electrochemically stable electrolytes for lithium-ion batteries, this study describes the synthesis and the utilization of new deep eutectic solvents (DESs) based on the mixture of 2,2,2-trifluoroacetamide (TFA) with a lithium salt (LiTFSI, lithium bis[(trifluoromethane)sulfonyl]imide). These prepared DESs were characterized in terms of thermal properties, ionic conductivity, viscosity, and electrochemical properties. Based on the appearance of the product and DSC measurements, it appears that this system is liquid at room temperature for LiTFSI mole fraction ranging from 0.25 to 0.5. At χLiTFSI = 0.25, DESs exhibited favorable electrolyte properties, such as thermal stability (up to 148 °C), relatively low viscosity (42.2 mPa.s at 30 °C), high ionic conductivity (1.5 mS.cm-1 at 30 °C), and quite large electrochemical stability window up to 4.9-5.3 V. With these interesting properties, selected DES was diluted with slight amount of ethylene carbonate (EC). Different amounts of EC (x = 0-30 %wt) were used to form hybrid electrolytes for battery testing with high voltage LiMn2O4 cathode and Li anode. The addition of the EC solvent into DES expectedly aims at enhancing the battery cycling performance at room temperature due to reducing the viscosity. Preliminary results tests clearly show that LiTFSI-based DES can be successfully introduced as an electrolyte in the lithium-ion batteries cell with a LiMn2O4 cathode material. Among all of the studied electrolytes, DES (LiTFSI: TFA = 4:1 + 10 %wt EC) is the most promising. The EC-based system exhibited a good specific capacity of 102 mAh.g-1 at C/10 with the theoretical capacity of 148 mAh.g-1 and a good cycling behavior maintaining at 84% after 50 cycles.

Impact of isotropic constitutive descriptions on the predicted peak wall stress in abdominal aortic aneurysms.

Biomechanics-based assessment of Abdominal Aortic Aneurysm (AAA) rupture risk has gained considerable scientific and clinical momentum. However, computation of peak wall stress (PWS) using state-of-the-art finite element models is time demanding. This study investigates which features of the constitutive description of AAA wall are decisive for achieving acceptable stress predictions in it. Influence of five different isotropic constitutive descriptions of AAA wall is tested; models reflect realistic non-linear, artificially stiff non-linear, or artificially stiff pseudo-linear constitutive descriptions of AAA wall. Influence of the AAA wall model is tested on idealized (n=4) and patient-specific (n=16) AAA geometries. Wall stress computations consider a (hypothetical) load-free configuration and include residual stresses homogenizing the stresses across the wall. Wall stress differences amongst the different descriptions were statistically analyzed. When the qualitatively similar non-linear response of the AAA wall with low initial stiffness and subsequent strain stiffening was taken into consideration, wall stress (and PWS) predictions did not change significantly. Keeping this non-linear feature when using an artificially stiff wall can save up to 30% of the computational time, without significant change in PWS. In contrast, a stiff pseudo-linear elastic model may underestimate the PWS and is not reliable for AAA wall stress computations.

Neoadjuvant chemotherapy increases rates of breast-conserving surgery in early operable breast cancer.

INTRODUCTION: Neoadjuvant chemotherapy is commonly used in stage III breast cancer for disease down-staging. Its use has now been extended to early breast cancer to increase the rate of breast-conserving surgery. This study aimed to evaluate the effectiveness of neoadjuvant chemotherapy in early operable cancers. METHODS: A retrospective study was carried out at the Hong Kong Sanatorium & Hospital of 102 patients with stage I to III primary breast cancer. All patients who underwent neoadjuvant chemotherapy followed by definitive breast surgery between January 2004 and July 2013 were included. Their pathological complete response and rate of breast-conserving surgery were studied. Data were compared using Chi squared test and Student's t test. RESULTS: After neoadjuvant chemotherapy, 23% of patients achieved a pathological complete response, of whom 80% had human epidermal growth factor receptor 2 (HER2)-positive disease or triple-negative disease. Hormonal receptor negativity was associated with a higher pathological complete response rate (P<0.05) that was in turn associated with a higher likelihood of breast-conserving surgery (P=0.028). Patients with stage II disease were more likely to convert from mastectomy to breast-conserving surgery following neoadjuvant chemotherapy. CONCLUSIONS: Neoadjuvant chemotherapy is a useful treatment to downsize tumour in early breast cancer, thereby increasing the rate of breast-conserving surgery. It is especially effective in patients with HER2-positive/oestrogen receptor-negative disease or triple-negative disease.

Intraocular pressure measurement after DSAEK by iCare, Goldmann applanation and dynamic contour tonometry: A comparative study.

PURPOSE: Corneal thickness inevitably increases following Descemet's stripping automated endothelial keratoplasty (DSAEK), owing to the addition of a donor graft. The current study compares different devices in assessing post-DSAEK intraocular pressure (IOP). METHODS: We compared IOP values measured by the Goldmann tonometry (GAT), iCare rebound tonometry (iCare) and Pascal dynamic contour tonometry (PDCT) in eyes following DSAEK. Agreement between measurements was calculated with correlation analysis and Bland-Altman plots. Effects of keratometry, central, thickness (CCT), endothelial cell density (ECD) and axial length on IOP measurements were assessed with Pearson's correlation. RESULTS: Twenty eyes of 20 patients (mean age 74.3±14.4, 14 females) post-DSAEK were included in this study. There was a high concordance between the IOP readings obtained by the three devices: a strong and significant correlation was found between GAT and PDCT (r=0.94, P<0.001) GAT and iCare (r=0.86, P<0.001) and iCare with PDCT (r=0.81, P<0.001). However, the iCare measurements were significantly and consistently lower than that obtained with GAT (ΔIOP=1.68±2.0, P=0.002, 95% CI: 0.7-2.6) and with PDCT (ΔIOP=1.61±2.5, P=0.01, 95% CI: 0.4-2.8). CCT, ECD, CCT, AXL, corneal curvature or astigmatism did not influence IOP measurement by any instrument. CONCLUSIONS: IOP measurement with three different techniques (applanation, rebound and dynamic contour) showed good correlations, despite an increased corneal thickness following DSAEK. However, the iCare, which is based on a rebound tonometry showed significant lower IOP then the two other methods. This should be taken into account when evaluating patients post DSAEK.

Mice with mutant Inf2 show impaired podocyte and slit diaphragm integrity in response to protamine-induced kidney injury.

Mutations in the INF2 (inverted formin 2) gene, encoding a diaphanous formin family protein that regulates actin cytoskeleton dynamics, cause human focal segmental glomerulosclerosis (FSGS). INF2 interacts directly with certain other mammalian diaphanous formin proteins (mDia) that function as RhoA effector molecules. FSGS-causing INF2 mutations impair these interactions and disrupt the ability of INF2 to regulate Rho/Dia-mediated actin dynamics in vitro. However, the precise mechanisms by which INF2 regulates and INF2 mutations impair glomerular structure and function remain unknown. Here, we characterize an Inf2 R218Q point-mutant (knockin) mouse to help answer these questions. Knockin mice have no significant renal pathology or proteinuria at baseline despite diminished INF2 protein levels. INF2 mutant podocytes do show impaired reversal of protamine sulfate-induced foot process effacement by heparin sulfate perfusion. This is associated with persistent podocyte cytoplasmic aggregation, nephrin phosphorylation, and nephrin and podocin mislocalization, as well as impaired recovery of mDia membrane localization. These changes were partially mimicked in podocyte outgrowth cultures, in which podocytes from knockin mice show altered cellular protrusions compared to those from wild-type mice. Thus, in mice, normal INF2 function is not required for glomerular development but normal INF2 is required for regulation of the actin-based behaviors necessary for response to and/or recovery from injury.

Inactivating Variants in ANGPTL4 and Risk of Coronary Artery Disease.

BACKGROUND: Higher-than-normal levels of circulating triglycerides are a risk factor for ischemic cardiovascular disease. Activation of lipoprotein lipase, an enzyme that is inhibited by angiopoietin-like 4 (ANGPTL4), has been shown to reduce levels of circulating triglycerides. METHODS: We sequenced the exons of ANGPTL4 in samples obtain from 42,930 participants of predominantly European ancestry in the DiscovEHR human genetics study. We performed tests of association between lipid levels and the missense E40K variant (which has been associated with reduced plasma triglyceride levels) and other inactivating mutations. We then tested for associations between coronary artery disease and the E40K variant and other inactivating mutations in 10,552 participants with coronary artery disease and 29,223 controls. We also tested the effect of a human monoclonal antibody against ANGPTL4 on lipid levels in mice and monkeys. RESULTS: We identified 1661 heterozygotes and 17 homozygotes for the E40K variant and 75 participants who had 13 other monoallelic inactivating mutations in ANGPTL4. The levels of triglycerides were 13% lower and the levels of high-density lipoprotein (HDL) cholesterol were 7% higher among carriers of the E40K variant than among noncarriers. Carriers of the E40K variant were also significantly less likely than noncarriers to have coronary artery disease (odds ratio, 0.81; 95% confidence interval, 0.70 to 0.92; P=0.002). K40 homozygotes had markedly lower levels of triglycerides and higher levels of HDL cholesterol than did heterozygotes. Carriers of other inactivating mutations also had lower triglyceride levels and higher HDL cholesterol levels and were less likely to have coronary artery disease than were noncarriers. Monoclonal antibody inhibition of Angptl4 in mice and monkeys reduced triglyceride levels. CONCLUSIONS: Carriers of E40K and other inactivating mutations in ANGPTL4 had lower levels of triglycerides and a lower risk of coronary artery disease than did noncarriers. The inhibition of Angptl4 in mice and monkeys also resulted in corresponding reductions in these values. (Funded by Regeneron Pharmaceuticals.).

Pre- and postexposure efficacy of fully human antibodies against Spike protein in a novel humanized mouse model of MERS-CoV infection.

Traditional approaches to antimicrobial drug development are poorly suited to combatting the emergence of novel pathogens. Additionally, the lack of small animal models for these infections hinders the in vivo testing of potential therapeutics. Here we demonstrate the use of the VelocImmune technology (a mouse that expresses human antibody-variable heavy chains and κ light chains) alongside the VelociGene technology (which allows for rapid engineering of the mouse genome) to quickly develop and evaluate antibodies against an emerging viral disease. Specifically, we show the rapid generation of fully human neutralizing antibodies against the recently emerged Middle East Respiratory Syndrome coronavirus (MERS-CoV) and development of a humanized mouse model for MERS-CoV infection, which was used to demonstrate the therapeutic efficacy of the isolated antibodies. The VelocImmune and VelociGene technologies are powerful platforms that can be used to rapidly respond to emerging epidemics.

[Modern surgical tactics in Crohn's disease].

Surgical tactics of Crohn's disease (CD) treatment was elaborated on base of modern information analysis, concerning pathogenesis, peculiarities of clinical course, possibilities of diagnosis, experience in the disease treatment. The tactics provides a timely diagnosis of the disease, prognostication for the recurrence occurrence and postoperative complications, the indications and the method of surgery optimization. Application of the elaborated surgical tactics in CD in 121 patients have permitted to improve the objective estimation of the disease severity, to prognosticate complications, to optimize surgical indications, as well as a choice of the method of a conditionally-radical, restorational, reconstructive-restorational stages of operative intervention, to reduce the disease recurrences rate, postoperative complications, postoperative lethality.

Structure-based constitutive model can accurately predict planar biaxial properties of aortic wall tissue.

Structure-based constitutive models might help in exploring mechanisms by which arterial wall histology is linked to wall mechanics. This study aims to validate a recently proposed structure-based constitutive model. Specifically, the model's ability to predict mechanical biaxial response of porcine aortic tissue with predefined collagen structure was tested. Histological slices from porcine thoracic aorta wall (n=9) were automatically processed to quantify the collagen fiber organization, and mechanical testing identified the non-linear properties of the wall samples (n=18) over a wide range of biaxial stretches. Histological and mechanical experimental data were used to identify the model parameters of a recently proposed multi-scale constitutive description for arterial layers. The model predictive capability was tested with respect to interpolation and extrapolation. Collagen in the media was predominantly aligned in circumferential direction (planar von Mises distribution with concentration parameter bM=1.03 ± 0.23), and its coherence decreased gradually from the luminal to the abluminal tissue layers (inner media, b=1.54 ± 0.40; outer media, b=0.72 ± 0.20). In contrast, the collagen in the adventitia was aligned almost isotropically (bA=0.27 ± 0.11), and no features, such as families of coherent fibers, were identified. The applied constitutive model captured the aorta biaxial properties accurately (coefficient of determination R(2)=0.95 ± 0.03) over the entire range of biaxial deformations and with physically meaningful model parameters. Good predictive properties, well outside the parameter identification space, were observed (R(2)=0.92 ± 0.04). Multi-scale constitutive models equipped with realistic micro-histological data can predict macroscopic non-linear aorta wall properties. Collagen largely defines already low strain properties of media, which explains the origin of wall anisotropy seen at this strain level. The structure and mechanical properties of adventitia are well designed to protect the media from axial and circumferential overloads.

Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis.

UNLABELLED: A sequence polymorphism (rs738409, I148M) in patatin-like phospholipid domain containing protein 3 (PNPLA3) is strongly associated with nonalcoholic fatty liver disease (NAFLD), but the mechanistic basis for this association remains enigmatic. Neither ablation nor overexpression of wild-type PNPLA3 affects liver fat content in mice, whereas hepatic overexpression of the human 148M transgene causes steatosis. To determine whether the 148M allele causes fat accumulation in the liver when expressed at physiological levels, we introduced a methionine codon at position 148 of the mouse Pnpla3 gene. Knockin mice had normal levels of hepatic fat on a chow diet, but when challenged with a high-sucrose diet their liver fat levels increased 2 to 3-fold compared to wild-type littermates without any associated changes in glucose homeostasis. The increased liver fat in the knockin mice was accompanied by a 40-fold increase in PNPLA3 on hepatic lipid droplets, with no increase in hepatic PNPLA3 messenger RNA (mRNA). Similar results were obtained when the catalytic dyad of PNPLA3 was inactivated by substituting the catalytic serine with alanine (S47A). CONCLUSION: These data provide the first direct evidence that physiological expression of PNPLA3 148M variant causes NAFLD, and that the accumulation of catalytically inactive PNPLA3 on the surfaces of lipid droplets is associated with the accumulation of TG in the liver.

[Genetic predictors of myocardial infarction in subjects of young age].

AIM OF THE STUDY: to investigate associations of single nucleotide polymorphisms (SNP) rs499818 (6p24.1), rs619203 of ROS1 gene (6q22), rs10757278 rs1333049 (9p21.3), rs2549513 (16q23.1), rs4804611 of ZNF627 gene (19p13.2) with myocardial infarction in subjects of young age. The group of patients with MI (n=99) aged less than 45 years and the control group (n=111) did not differ significantly by sex (=0,617), age (=0.291), arterial hypertension (=0.766), diabetes mellitus (=0.395), hypercholestolemia (=0.696), excessive body mass and obesity (=0.361), abdominal obesity (=0.831) and history of smoking (=0.400). There was significant difference between groups by burdened heredity (<0.001). Genomic DNA was obtained from venous blood by phenol-chloroform extraction. Genetic testing was performed by real time polymerase chain reaction using 7900HT Fast Real-Time PCR System according to manufacturers protocol. We found significant association between rs1333049 and rs10757278 and myocardial infarction (MI). Odds ratio (OR) of development of MI in carriers of risk allele rs1333049 was 2.4 (95% confidence interval [CI] 1.24 to 4.65), in carriers of G rs10757278 allele - 2.00 (95%CI 1.05 to 3.80). Association of risk alleles rs 1333049 and G rs10757278 with MI remained significant after adjustment for burdened family history (OR 4.25, 95%CI 1.39 to 12.99, and OR 3.04, 95%CI 1.09 to 8.52, respectively). Presence in the genotype of both risk alleles rs1333049 and G rs10757278 was associated with OR of MI development 2.40 (95%CI 1.20 to 4.82) which was not different from that associated with carriage of allele rs1333049 only. Possibly in our population both SNPs belong to one linkage block and correspondingly it is sufficient to genotype one SNP. No significant associations with MI were found for variants rs4804611, rs2549513, rs499818, rs619203. SNPs rs1333049 and rs10757278 of 9p21.3 locus are predictors of MI in young individuals not dependent on both traditional risk factors and presence of burdened family history.

[Interrelationship between polymorphic markers of methylenetetrahydrofolate reductase gene and development of acute disturbance of brain circulation in families of patients with atrial fibrillation].

In the present work we for the first time on the clinic-genetic material revealed genetic predictors of development of acute disturbance of brain circulation (ADBC) in families of patients with atrial fibrillation (AF) namely polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene. Genotype CC was significantly more often found among patients with AF and ADBC compared with controls (58.1 and 35.2%, respectively, p=0.02) as well as in relatives of probands compared with the control group (59.3 and 35.2%, respectively, p=0.008). With this in relatives with revealed paroxysmal AF and ADBC we also noted presence of CC genotype. Taking into consideration the relationship obtained between polymorphysms of MTHFR gene and AF it was possible to assume that polymorphic marker CC appeared to be a predictor of ADBC in these families.

[Perception features of emotional intonation of short pseudowords].

Reaction time and recognition accuracy of speech emotional intonations in short meaningless words that differed only in one phoneme with background noise and without it were studied in 49 adults of 20-79 years old. The results were compared with the same parameters of emotional intonations in intelligent speech utterances under similar conditions. Perception of emotional intonations at different linguistic levels (phonological and lexico-semantic) was found to have both common features and certain peculiarities. Recognition characteristics of emotional intonations depending on gender and age of listeners appeared to be invariant with regard to linguistic levels of speech stimuli. Phonemic composition of pseudowords was found to influence the emotional perception, especially against the background noise. The most significant stimuli acoustic characteristic responsible for the perception of speech emotional prosody in short meaningless words under the two experimental conditions, i.e. with and without background noise, was the fundamental frequency variation.

[Association of 2B-adrenergic receptor gene polymorphism with disturbances of cardiac conduction].

In this work we for the first time revealed on clinical - genetic material association between hereditary disturbances of cardiac conduction and polymorphism of 2-adrenergic receptor gene.

[Polymorphisms of 2B-adrenergic receptor and endothelial NO-Synthase genes in genesis of the hereditary sick sinus node syndrome].

In this work we have demonstrated for the first time on the clinico-genetic material association between hereditary sick sinus node syndrome (SSNS) ADRA2B and eNOS genes polymorphisms. We have established predominance of homozygote genotype of more rare DD allele in patients with SSNS (28%) compared with subjects of control group (8.99%). We have found predominance of heterozygote genotype 4a/4b in patients with SSNS compared with subjects of control group (41.8 and 25.39%, respectively). The data obtained allow to suggest that eNOS gene polymorphism might be associated with SSNS.

[Perception of emotional intonation of noisy speech signal with different acoustic parameters by adults of different age and gender].

The listener-distinctive features of recognition of different emotional intonations (positive, negative and neutral) of male and female speakers in the presence or absence of background noise were studied in 49 adults aged 20-79 years. In all the listeners noise produced the most pronounced decrease in recognition accuracy for positive emotional intonation ("joy") as compared to other intonations, whereas it did not influence the recognition accuracy of "anger" in 65-79-year-old listeners. The higher emotion recognition rates of a noisy signal were observed for speech emotional intonations expressed by female speakers. Acoustic characteristics of noisy and clear speech signals underlying perception of speech emotional prosody were found for adult listeners of different age and gender.