An anti-CTLA-4 heavy chain-only antibody with enhanced Treg depletion shows excellent preclinical efficacy and safety profile.

The value of anti-CTLA-4 antibodies in cancer therapy is well established. However, the broad application of currently available anti-CTLA-4 therapeutic antibodies is hampered by their narrow therapeutic index. It is therefore challenging and attractive to develop the next generation of anti-CTLA-4 therapeutics with improved safety and efficacy. To this end, we generated fully human heavy chain-only antibodies (HCAbs) against CTLA-4. The hIgG1 Fc domain of the top candidate, HCAb 4003-1, was further engineered to enhance its regulatory T (Treg) cell depletion effect and to decrease its half-life, resulting in HCAb 4003-2. We tested these HCAbs in in vitro and in vivo experiments in comparison with ipilimumab and other anti-CTLA4 antibodies. The results show that human HCAb 4003-2 binds human CTLA-4 with high affinity and potently blocks the binding of B7-1 (CD80) and B7-2 (CD86) to CTLA-4. The results also show efficient tumor penetration. HCAb 4003-2 exhibits enhanced antibody-dependent cellular cytotoxicity function, lower serum exposure, and more potent anti-tumor activity than ipilimumab in murine tumor models, which is partly driven by a substantial depletion of intratumoral Tregs. Importantly, the enhanced efficacy combined with the shorter serum half-life and less systemic drug exposure in vivo potentially provides an improved therapeutic window in cynomolgus monkeys and preliminary clinical applications. With its augmented efficacy via Treg depletion and improved safety profile, HCAb 4003-2 is a promising candidate for the development of next generation anti-CTLA-4 therapy.

Design, synthesis, and evaluation of cyclic C7-bridged monocarbonyl curcumin analogs containing an o-methoxy phenyl group as potential agents against gastric cancer.

The structure-activity relationship (SAR) between toxicity and the types of linking ketones of C7 bridged monocarbonyl curcumin analogs (MCAs) was not clear yet. In the pursuit of effective and less cytotoxic chemotherapeutics, we conducted a SAR analysis using various diketene skeletons of C7-bridged MCAs, synthesized cyclic C7-bridged MCAs containing the identified low-toxicity cyclopentanone scaffold and an o-methoxy phenyl group, and assessed their anti-gastric cancer activity and safety profile. Most compounds exhibited potent cytotoxic activities against gastric cancer cells. We developed a quantitative structure-activity relationship model (R2 > 0.82) by random Forest method, providing important information for optimizing structure. An optimized compound 2 exhibited in vitro and in vivo anti-gastric cancer activity partly through inhibiting the AKT and STAT3 pathways, and displayed a favorable in vivo safety profile. In summary, this paper provided a promising class of MCAs and a potential compound for the development of chemotherapeutic drugs.

Electrophysiological Changes in the Rabbit Ventricular Wedge and Human-Induced Pluripotent Stem-Cell Derived (IPSC) Cardiomyocytes Translate to Severe Arrhythmia Observed in a Canine Toxicology Study, Not Predicted by Standard In Vitro Ion Channel Assays.

During drug discovery, small molecules are typically assayed in vitro for secondary pharmacology effects, which include ion channels relevant to cardiac electrophysiology. Compound A was an irreversible inhibitor of myeloperoxidase investigated for the treatment of peripheral artery disease. Oral doses in dogs at ≥5 mg/kg resulted in cardiac arrhythmias in a dose-dependent manner (at Cmax, free ≥1.53 µM) that progressed in severity with time. Nevertheless, a panel of 13 different cardiac ion channel (K, Na, and Ca) assays, including hERG, failed to identify pharmacologic risks of the molecule. Compound A and a related Compound B were evaluated for electrophysiological effects in the isolated rabbit ventricular wedge assay. Compounds A and B prolonged QT and Tp-e intervals at ≥1 and ≥.3 µM, respectively, and both prolonged QRS at ≥5 µM. Compound A produced early after depolarizations and premature ventricular complexes at ≥5 µM. These data indicate both compounds may be modulating hERG (Ikr) and Nav1.5 ion channels. In human IPSC cardiomyocytes, Compounds A and B prolonged field potential duration at ≥3 µM and induced cellular dysrhythmia at ≥10 and ≥3 µM, respectively. In a rat toxicology study, heart tissue: plasma concentration ratios for Compound A were ≥19X at 24 hours post-dose, indicating significant tissue distribution. In conclusion, in vitro ion channel assays may not always identify cardiovascular electrophysiological risks observed in vivo, which can be affected by tissue drug distribution. Risk for arrhythmia may increase with a "trappable" ion channel inhibitor, particularly if cardiac tissue drug levels achieve a critical threshold for pharmacologic effects.

Mexiletine: Antiarrhythmic mechanisms, emerging clinical applications and mortality.

Mexiletine, a class Ib antiarrhythmic drug, exhibits its major antiarrhythmic effect via inhibition of the fast and late Na+ currents in myocardial tissues that are dependent on the opening of Na+ channels for their excitation. Through a comprehensive examination of mexiletine's therapeutic benefits and potential risks, we aim to provide valuable insights that reinforce its role as a vital therapeutic option for patients with ventricular arrhythmias, long QT syndrome, and other heart rhythm disorders. This review will highlight the current understandings of the antiarrhythmic effects and rationales for recent off-label use and address the mortality and proarrhythmic effects of mexiletine utilizing published basic and clinical studies over the past five decades.

Design, synthesis and evaluation of monoketene compounds as novel potential Parkinson's disease agents by suppressing ER stress via AKT.

Curcumin is identified that it has the potential to treat Parkinson's disease (PD), but its instability limits its further application in clinic. The mono-carbonyl analogs of curcumin (MACs) with diketene structure can effectively improve its stability, but it is highly toxic. In the present study, a less cytotoxic and more stable monoketene MACs skeleton S2 was obtained, and a series of monoketene MACs were synthesized by combining 4-hydroxy-3­methoxy groups of curcumin. In the 6-OHDA-induced PD's model in-vitro, some compounds exhibited significant neurotherapeutic effect. The quantitative structure-activity relationship (QSAR) model established by the random forest algorithm (RF) for the cell viability rate of above compounds showed that the statistical results are good (R2 = 0.883507), with strong reliability. Among all compounds, the most active compound A4 played an important role in neuroprotection in the PD models both in vitro and in vivo by activating AKT pathway, and then inhibiting the apoptosis of cells caused by endoplasmic reticulum (ER) stress. In the PD model in-vivo, compound A4 significantly improved survival of dopaminergic neurons and the contents of neurotransmitters. It also enhanced the retention of nigrostriatal function which was better than the effect in the mice treated by Madopar, a classical clinical drug for PD. In summary, we screened out the compound A4 with high stability, less cytotoxic monoketene compounds. And these founding provide evidence that the compound A4 can protect dopaminergic neurons via activating AKT and subsequently suppressing ER stress in PD.

Ultra-Confined Catalytic Growth Integration of Sub-10 nm 3D Stacked Silicon Nanowires Via a Self-Delimited Droplet Formation Strategy.

Fabricating ultrathin silicon (Si) channels down to critical dimension (CD) <10 nm, a key capability to implementing cutting-edge microelectronics and quantum charge-qubits, has never been accomplished via an extremely low-cost catalytic growth. In this work, 3D stacked ultrathin Si nanowires (SiNWs) are demonstrated, with width and height of Wnw  = 9.9 ± 1.2 nm (down to 8 nm) and Hnw  = 18.8 ± 1.8 nm, that can be reliably grown into the ultrafine sidewall grooves, approaching to the CD of 10 nm technology node, thanks to a new self-delimited droplet control strategy. Interestingly, the cross-sections of the as-grown SiNW channels can also be easily tailored from fin-like to sheet-like geometries by tuning the groove profile, while a sharply folding guided growth indicates a unique capability to produce closely-packed multiple rows of stacked SiNWs, out of a single run growth, with the minimal use of catalyst metal. Prototype field effect transistors are also successfully fabricated, achieving Ion/off ratio and sub-threshold swing of >106 and 125 mV dec-1 , respectively. These results highlight the unexplored potential of versatile catalytic growth to compete with, or complement, the advanced top-down etching technology in the exploitation of monolithic 3D integration of logic-in-memory, neuromorphic and charge-qubit applications.

CRKL is a critical target of Hh-GLI2 pathway in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is one of the important components of non-small-cell lung cancer (NSCLC) and leads to many deaths every year. During the initiation and progression of the LUAD, the Hh-GLI2 pathway plays critical roles. Several components of this pathway have been shown to be amplified or overexpressed in LUAD, providing this pathway as an attractive target for therapeutics. However, a gap in our understanding of the Hh-GLI2 pathway is the identity of transcriptional targets of GLI2 that drive LUAD tumorigenesis. Here, we show that the oncogene CRKL is a direct target of GLI2. GLI2 turns on CRKL transcription through binding its second intron. Furthermore, CRKL is an essential mediator for GLI2-driven proliferation and migration of LUAD cells. Depletion of CRKL blunts Hh-GLI2 pathway-mediated cell proliferation and invasion. Lastly, we find that CRKL knockout cells are more sensitive to EGFR-TKI and chemotherapeutics. Taken together, our work here identifies a specific target for Hh-related malignancies and provides CRKL as a promising therapeutic target for LUAD.

Emergence of a Salmonella enterica serovar Typhimurium ST34 isolate, CFSA629, carrying a novel mcr-1.19 variant cultured from egg in China.

OBJECTIVES: This study aimed to characterize the genomic features of a Salmonella enterica serovar Typhimurium ST34 isolate, CFSA629, which carried a novel mcr-1 variant, designated as mcr-1.19, mapped to an ESBL-encoding IncHI2 plasmid. METHODS: Antimicrobial susceptibility assays as well as WGS were carried out on isolate CFSA629. The complete closed genome was obtained and then explored to obtain genomic features. Plasmid sequence comparison was performed for pCFSA629 with similar plasmids and the mcr-1 genetic environment was analysed. RESULTS: S. Typhimurium ST34 CFSA629 expressed an MDR phenotype to six classes of compound and consisted of a single circular chromosome and one plasmid. It possessed 11 resistance genes including 2 ESBL genes that mapped to the chromosome and the plasmid; an IS26-flanked composite-like transposon was identified. A novel mcr-1 variant (mcr-1.19) was identified, which had a unique SNP (G1534A) that gave rise to a novel MCR-1 protein containing a Val512Ile amino acid substitution. Plasmid pCFSA629 possessed a conjugative plasmid transfer gene cluster as well as an antimicrobial resistance-encoding gene cluster-containing region that contained two IS26 composite-like transposonal modules, but was devoid of any plasmid-mediated quinolone resistance genes. The background of mcr-1.19 consisted of an ISApl1-mcr-1-PAP2-ter module. CONCLUSIONS: We report on an MDR S. Typhimurium ST34 CFSA629 isolate cultured from egg in China, harbouring an mcr-1.19 variant mapped to an IncHI2 plasmid. This highlights the importance of surveillance to mitigate dissemination of mcr-encoding genes among foodborne Salmonella. Improved surveillance is important for tackling the dissemination of mcr genes among foodborne Salmonella around the world.

Effect of fermentation bed on bacterial growth in the fermentation mattress material and cecum of ducks.

The composition of microorganisms in the gastrointestinal tract is closely related to the intestinal microenvironments and the exterior growth environments of host. In this study, 16S rDNA sequencing technology was adopted to investigate the influence of fermentation bed on the cecum microorganisms of ducks. Two feeding density treatment groups were set up, including group A (n = 4brids/m2) and group B (n = 6brids/m2). Samples were collected from the intermediate core fermentation layer (10-20 cm) of the fermented mattress materials and from the intestinal contents of ducks at 4, 6 and 8 weeks, respectively. Results showed that Bacteroidetes (20.12-27.17%) and Ruminococcaceae UCG-014 (2.97-10.1%) were the predominant microorganisms in duck cecum, while the Truepera (5.08-6.29%), Pricia (4.44-5.44%) and Luteimonas (3.62-4.99%) were the dominant microorganisms in fermentation mattress material. The cecum bacteria exhibited great difference among different growth periods of the ducks. Increasing the stocking density of ducks had a negative effect on the beneficial bacteria in the cecum. The microbial populations in fermentation mattress material were very different from that in the cecal. In summary, our findings can provide a scientific data for the rational use of fermentation bed feeding mode in poultry production.

Delta QRS distinguishes Ito -mediated J waves from pseudo J waves produced by conduction delay on body surface electrocardiographic.

BACKGROUND: On surface electrocardiographic (ECGs), it is difficult to differentiate Ito -mediated J waves, a repolarization phenomenon seen in J wave syndromes (JWS) from terminal QRS deflections that mimic J waves (pseudo J waves) in intraventricular conduction delay (IVCD), an abnormality in depolarization. We hypothesize that the difference between the "maximum QRS duration" inclusive of J point or terminal QRS deflections and the minimum QRS duration identified across a 12-lead ECG is significantly larger in Ito -mediated J waves, and can serve as a marker to make this distinction. METHODS: A retrospective analysis was performed on adults with ECGs consisting of one of the four following manifestations: J waves associated with hypothermia and early repolarization, and pseudo J waves associated with right bundle branch block (RBBB) and non-specific intraventricular conduction delay (NS-IVCD). All ECGs were assessed individually and the maximum and minimum discrete QRS deflections on 12-lead tracings, defined as "QRSmax " and QRSmin , were identified. The difference between "QRSmax " and QRSmin , designated as ∆QRS, was calculated and compared across the studied populations. RESULTS: A total of 60 patients consisting of 15 patients in each arm were included in the study. ΔQRS was significantly larger in the hypothermia and early repolarization groups, compared to RBBB and NS-IVCD (p < .0001), with the following mean ∆QRS: hypothermia 54.3 ± 13.7 ms, early repolarization pattern 47.3 ± 15.3 ms, RBBB 19.3 ± 6.5 ms, and NS-IVCD 16.0 ± 6.6 ms. CONCLUSION: ∆QRS may serve as a reliable ECG parameter for distinguishing Ito -mediated J waves from pseudo J waves produced by delayed intraventricular conduction.

Laparoscopic radical antegrade modular pancreatosplenectomy: preliminary experience with 10 cases.

BACKGROUND: The radical antegrade modular pancreatosplenectomy (RAMPS) which is a reasonable surgical approach for left-sided pancreatic cancer is emphasis on the complete resection of regional lymph nodes and tumor-free margin resection. Laparoscopic radical antegrade modular pancreatosplenectomy (LRAMPS) has been rarely performed, with only 49 cases indexed on PubMed. In this study, we present our experience of LRAMPS. METHODS: From December 2018 to February 2020, 10 patients underwent LRAMPS for pancreatic cancer at our department. The data of the patient demographics, intraoperative variables, postoperative hospital stay, morbidity, mortality, pathologic findings and follow-up were collected. RESULTS: LRAMPS was performed successfully in all the patients. The median operative time was 235 min (range 212-270 min), with an EBL of 120 ml (range 100-200 ml). Postoperative complications occurred in 5 (50.0%) patients. Three patients developed a grade B pancreatic fistula. There was no postoperative 30-day mortality and reoperation. The median postoperative hospital stay was 14 days (range 9-24 days).The median count of retrieved lymph nodes was 15 (range 13-21), and four patients (40%) had malignant-positive lymph nodes. All cases achieved a negative tangential margin and R0 resection. Median follow-up time was 11 months (range 3-14 m). Two patients developed disease recurrence (pancreatic bed recurrence and liver metastasis) 9 months, 10 months after surgery, respectively. Others survived without tumor recurrence or metastasis. CONCLUSIONS: LRAMPS is technically safe and feasible procedure in well-selected patients with pancreatic cancer in the distal pancreas. The oncologically outcomes need to be further validated based on additional large-volume studies.

High expression of NEK2 promotes lung cancer progression and drug resistance and is regulated by mutant EGFR.

Activating mutations within the tyrosine kinase (TK) domain of epidermal growth factor receptor (EGFR) gene are observed in 10 ~ 30% of the patients diagnosed with non-small cell lung cancer (NSCLC), and are causally related to NSCLC initiation and progression. Treatments with tyrosine kinase inhibitors (TKIs) targeting EGFR significantly improve the outcome of NSCLC patients with EGFR mutation, but are often associated with drug resistance, which is the main cause of treatment failure and cancer relapse. In the present study, by screening the transcriptome of NSCLC patients, we found that EGFR activation is highly correlated with the up-regulation of mitotic regulator, never in mitosis gene A-related kinase 2 (NEK2). NEK2 overexpression is associated with the poor survival of EGFR-mutant patients but not the wild-type patients. Further functional validation revealed that EGFR mutation induces NEK2 expression by activating ERK signaling pathway. Elevated NEK2 level promotes the rapid cell cycle progression and favors the rapid proliferation of EGFR-mutant NSCLC cells. Of note, NEK2 overexpression also impairs the efficacy of TKI treatment via inhibiting apoptosis, while depleting NEK2 suppresses cell growth and restored the sensitivity of TKI in NSCLC cells. Taken together, our study revealed that NEK2 is an oncogene regulated by EGFR mutation and is involved in disease progression and treatment response in NSCLC with EGFR mutation. These findings will pave the road for optimizing personalized treatment strategies to overcome drug resistance and improve the prognosis of lung cancer patients with EGFR mutation.

A Biomimetic Model of Adaptive Contrast Vision Enhancement from Mantis Shrimp.

Mantis shrimp have complex visual sensors, and thus, they have both color vision and polarization vision, and are adept at using polarization information for visual tasks, such as finding prey. In addition, mantis shrimp, almost unique among animals, can perform three-axis eye movements, such as pitch, yaw, and roll. With this behavior, polarization contrast in their field of view can be adjusted in real time. Inspired by this, we propose a bionic model that can adaptively enhance contrast vision. In this model, a pixel array is used to simulate a compound eye array, and the angle of polarization (AoP) is used as an adjustment mechanism. The polarization information is pre-processed by adjusting the direction of the photosensitive axis point-to-point. Experiments were performed around scenes where the color of the target and the background were similar, or the visibility of the target was low. The influence of the pre-processing model on traditional feature components of polarized light was analyzed. The results show that the model can effectively improve the contrast between the object and the background in the AoP image, enhance the significance of the object, and have important research significance for applications, such as contrast-based object detection.

MiR-520b promotes the progression of non-small cell lung cancer through activating Hedgehog pathway.

Although the non-small cell lung cancer (NSCLC) is one of the most malignant tumours worldwide, the mechanisms controlling NSCLC tumourigenesis remain unclear. Here, we find that the expression of miR-520b is up-regulated in NSCLC samples. Further studies have revealed that miR-520b promotes the proliferation and metastasis of NSCLC cells. In addition, miR-520b activates Hedgehog (Hh) pathway. Inhibitor of Hh pathway could relieve the oncogenic effect of miR-520b upon NSCLC cells. Mechanistically, we demonstrate that miR-520b directly targets SPOP 3'-UTR and decreases SPOP expression, culminating in GLI2/3 stabilization and Hh pathway hyperactivation. Collectively, our findings unveil that miR-520b promotes NSCLC tumourigenesis through SPOP-GLI2/3 axis and provide miR-520b as a potential diagnostic biomarker and therapeutic target for NSCLC.

Susceptibility (re)-testing of a large collection of Listeria monocytogenes from foods in China from 2012 to 2015 and WGS characterization of resistant isolates.

OBJECTIVES: Our aim was to determine the antimicrobial susceptibilities of 2862 Listeria monocytogenes cultured from various foods in China and to use WGS to characterize the antimicrobial resistance and virulence genotypes of those expressing a resistance phenotype. METHODS: The susceptibilities of 2862 L. monocytogenes were determined by broth microdilution. Twenty-eight L. monocytogenes were found to be resistant to one to four antibiotics. All 28 resistant isolates were subsequently sequenced using short-read high accuracy protocols. The corresponding genomes were assembled and further analysis was carried out using appropriate bioinformatics pipelines. RESULTS: All 28 resistant L. monocytogenes were classified into five STs (ST3, ST8, ST9, ST155 and ST515). Both ST9 and ST155 were dominant and their genotypes correlated with their resistance phenotypes. All ST9 isolates were MDR and could be phylogenetically classified into two clusters. One was relatively close to clinical origins and one to food. Downstream analysis of the genetic contexts in which these resistance genotypes were found suggested that these may have been acquired from other bacteria by horizontal transfer or insertion into the chromosome. All isolates harboured Listeria pathogenicity island (LIPI)-1 and LIPI-2, and only two harboured LIPI-3. CONCLUSIONS: This study reported on the antimicrobial susceptibilities of 2862 foodborne L. monocytogenes along with the genomic characterization of 28 resistant isolates, 11 of which expressed an MDR phenotype. These data showed that this bacterium can acquire resistance by horizontal gene transfer in and between species. This study may necessitate a re-evaluation of risk to public health, associated with this bacterial species.

Time-to-first appropriate shock in patients implanted prophylactically with an implantable cardioverter-defibrillator: data from the Survey on Arrhythmic Events in BRUgada Syndrome (SABRUS).

AIMS: Data on predictors of time-to-first appropriate implantable cardioverter-defibrillator (ICD) therapy in patients with Brugada Syndrome (BrS) and prophylactically implanted ICD's are scarce. METHODS AND RESULTS: SABRUS (Survey on Arrhythmic Events in BRUgada Syndrome) is an international survey on 678 BrS patients who experienced arrhythmic event (AE) including 252 patients in whom AE occurred after prophylactic ICD implantation. Analysis was performed on time-to-first appropriate ICD discharge regarding patients' characteristics. Multivariate logistic regression models were utilized to identify which parameters predicted time to arrhythmia ≤5 years. The median time-to-first appropriate ICD therapy was 24.8 ± 2.8 months. A shorter time was observed in patients from Asian ethnicity (P < 0.05), those with syncope (P = 0.001), and those with Class IIa indication for ICD (P = 0.001). A longer time was associated with a positive family history of sudden cardiac death (P < 0.05). Multivariate Cox regression revealed shorter time-to-ICD therapy in patients with syncope [odds ratio (OR) 1.65, P = 0.001]. In 193 patients (76.6%), therapy was delivered during the first 5 years. Factors associated with this time were syncope (OR 0.36, P = 0.001), spontaneous Type 1 Brugada electrocardiogram (ECG) (OR 0.5, P < 0.05), and Class IIa indication (OR 0.38, P < 0.01) as opposed to Class IIb (OR 2.41, P < 0.01). A near-significant trend for female gender was also noted (OR 0.13, P = 0.052). Two score models for prediction of <5 years to shock were built. CONCLUSION: First appropriate therapy in BrS patients with prophylactic ICD's occurred during the first 5 years in 76.6% of patients. Syncope and spontaneous Type 1 Brugada ECG correlated with a shorter time to ICD therapy.

[Clinical features and outcomes of neonatal necrotizing enterocolitis].

OBJECTIVE: To study the clinical features of neonatal necrotizing enterocolitis (NEC) and risk factors for poor outcomes. METHODS: A retrospective analysis was performed for the clinical data of 121 preterm infants diagnosed with NEC. According to the treatment method, they were divided into a non-surgical group (n=66) and a surgical group (n=55). According to the outcome, they were divided into a survival group (n=76) and a death group (n=45). Clinical features were compared between these groups. Risk factors for poor outcomes were analyzed by multivariate logistic regression analysis. RESULTS: Compared with the non-surgical group, the surgical group had significantly lower corrected gestational age, minimum platelet count, and incidence rate of bloody stool at the onset of NEC (P<0.05). The maximum C-reactive protein (CRP) and mortality rate in the surgical group were significantly higher than those in the non-surgical group (P<0.05). Compared with the survival group, the death group had significantly lower gestational age at birth, birth weight, proportion of small-for-gestational-age infants, and corrected gestational age, body weight and minimum platelet count at the onset of NEC (P<0.05). The incidence of patent ductus arteriosus, rate of use of ibuprofen, maximum CRP and rate of surgical treatment in the death group were significantly higher than those in the survival group (P<0.05). The multivariate logistic regression analysis showed that ibuprofen treatment was a risk factor for death in infants with NEC (OR=9.149, P<0.05). CONCLUSIONS: Ibuprofen treatment increases the risk for death in preterm infants with NEC.

The phenomena of balanced effect between α-globin gene and of ß-globin gene.

BACKGROUND: Thalassemias (TM) are the most common autosomal recessive disorders in Southeast Asian countries. Both α- and ß-thalassemia lead to a decrease or absence of globin chains. The most serious of the thalassemia syndromes is thalassemia major which is characterized by a transfusion dependent anemia and subsequent iron overload caused by repeated blood transfusions. It is preventive by genotyping the parents. A better understanding of the laboratory data will help provide an accurate diagnosis of thalassemia major, and prevention and controlling programs in routine laboratories. CASE PRESENTATION: The patient was a one-year-old boy born to non-consanguineous parents. He was referred to our outpatient clinic for hemolytic anemia after a cold. Hematological investigations revealed severe anemia (Hb57 g/dL). The red cells displayed microcytosis, hypochromia and misshapen erythrocytes (MCV48.8 fL, MCH15.7 pg). Capillary electrophoresis (CE) electropherogram revealed normal level of HbA2 (3.2%) and elevated HbF (35.1%). The patient was diagnosed with ß-TM, based on severe microcytosis, hypochromia, normal Hb A2 and high Hb F level but no Hb H inclusion at the first visit. Later our molecular analysis revealed compound heterozygosity for codons 41-42 (-TTCT) (HBB: c.126_129delCTTT, ß0) and IVS-II-654 (C > T) (HBB: c.316-197C > T, ß+) mutation and deletional Hb H (--SEA/-α3.7). Thus, a combination of Hb H disease and a compound heterozygosity of ß+/ß0-thalassemia (ß+/ß0-thal) was finally diagnosed. CONCLUSIONS: Genotype-phenotype analysis shows that heterozygous mutations in the ß-globin gene could affect not only hematological parameters, but also elevate HbA2 levels. These effects could be ameliorated by the coinheritance of Hb H disease, which may be explained by the phenomena of the α-globin gene and of the ß-globin gene balanced effect.

A meta-analysis on the prognostic significance of inferolateral early repolarization pattern in Brugada syndrome.

Aims: The early repolarization (ER) pattern has been linked to an increased risk for arrhythmic death in various clinical settings. There are limited and conflicting data regarding the prognostic significance of ER pattern in Brugada syndrome (BS). The aim of this meta-analysis was to provide a detailed analysis of the currently available studies regarding the arrhythmic risk in patients with BS and ER pattern. Methods and results: Current databases were searched until May 2015. A random-effect meta-analysis of the effect of ER pattern on the incidence of arrhythmic events in patients with BS was performed. Five studies were included comprising a total of 1375 patients with BS. An ER pattern was reported in 177 patients (12.8%). During follow-up (44.9-93 months), 143 patients (10.4%) suffered an arrhythmic event. Overall, BS patients with ER pattern displayed an increased risk of arrhythmic events compared to patients without ER (OR 3.29, 95% CI: 2.06 to 5.26, P < 0.00001; Heterogeneity: P = 0.11, I2 = 48%). Three studies provided data regarding ER pattern location. Inferior, lateral, or inferolateral ER pattern location was observed in 20.3%, 32.2%, and 48%, respectively. An inferolateral ER location conferred the higher arrhythmic risk (OR 4.87, 95% CI: 2.64 to 9.01, P< 0.00001; Heterogeneity: P = 0.85, I2 = 0%). Conclusion: This meta-analysis suggests that the ER pattern is associated with a high risk of arrhythmic events in patients with BS. In particular, BS patients with inferolateral ER (global ER pattern) displayed the highest arrhythmic risk.

SND p102 promotes extracellular matrix accumulation and cell proliferation in rat glomerular mesangial cells via the AT1R/ERK/Smad3 pathway.

SND p102 was first described as a transcriptional co-activator, and subsequently determined to be a co-regulator of Pim-1, STAT6 and STAT5. We previously reported that SND p102 expression was increased in high glucose-treated mesangial cells (MCs) and plays a role in the extracellular matrix (ECM) accumulation of MCs by regulating the activation of RAS. In this study, we further examined the roles of SND p102 in diabetic nephropathy (DN)-induced glomerulosclerosis. Rats were injected with STZ (50 mg/kg, ip) to induce diabetes. MCs or isolated glomeruli were cultured in normal glucose (NG, 5.5 mmol/L)- or high glucose (HG, 25 mmol/L)-containing DMEM. We found that SND p102 expression was significantly increased in the diabetic kidneys, as well as in HG-treated isolated glomeruli and MCs. In addition, HG treatment induced significant fibrotic changes in MCs evidenced by enhanced protein expression of TGF-ß, fbronectin and collagen IV, and significantly increased the proliferation of MCs. We further revealed that overexpression of SND p102 significantly increased the protein expression of angiotensin II (Ang II) type 1 receptor (AT1R) in MCs by increasing its mRNA levels via directly targeting the AT1R 3'-UTR, which resulted in activation of the ERK/Smad3 signaling and subsequently promoted the up-regulation of fbronectin, collagen IV, and TGF-ß in MCs, as well as the cell proliferation. These results demonstrate that SND p102 is a key regulator of AT1R-mediating ECM synthesis and cell proliferation in MCs. Thus, small molecule inhibitors of SND p102 may be a novel therapeutic strategy for DN.