AdHu5Ag85A Respiratory Mucosal Boost Immunization Enhances Protection against Pulmonary Tuberculosis in BCG-Primed Non-Human Primates

Persisting high global tuberculosis (TB) morbidity and mortality and poor efficacy of BCG vaccine emphasizes an urgent need for developing effective novel boost vaccination strategies following parenteral BCG priming in humans. Most of the current lead TB vaccine candidates in the global pipeline were developed for parenteral route of immunization. Compelling evidence indicates respiratory mucosal delivery of vaccine to be the most effective way to induce robust local mucosal protective immunity against pulmonary TB. However, despite ample supporting evidence from various animal models, there has been a lack of evidence supporting the safety and protective efficacy of respiratory mucosal TB vaccination in non-human primates (NHP) and humans. By using a rhesus macaque TB model we have evaluated the safety and protective efficacy of a recombinant human serotype 5 adenovirus-based TB vaccine (AdHu5Ag85A) delivered via the respiratory mucosal route. We show that mucosal AdHu5Ag85A boost immunization was safe and well tolerated in parenteral BCG-primed rhesus macaques. A single AdHu5Ag85A mucosal boost immunization in BCG-primed rhesus macaques enhanced the antigen–specific T cell responses. Boost immunization significantly improved the survival and bacterial control following M.tb challenge. Furthermore, TB-related lung pathology and clinical outcomes were lessened in BCG-primed, mucosally boosted animals compared to control animals. Thus, for the first time we show that a single respiratory mucosal boost immunization with a novel TB vaccine enhances protection against pulmonary TB in parenteral BCG-primed NHP. Our study provides the evidence for the protective potential of AdHu5Ag85A as a respiratory mucosal boost TB vaccine for human application.     

Aggravated Cardiac Remodeling post Aortocaval Fistula in Unilateral Nephrectomized Rats

Background

Aortocaval fistula (AV) in rat is a unique model of volume-overload congestive heart failure and cardiac hypertrophy. Living donor kidney transplantation is regarded as beneficial to allograft recipients and not particularly detrimental to the donors. Impact of AV on animals with mild renal dysfunction is not fully understood. In this study, we explored the effects of AV in unilateral nephrectomized (UNX) rats.

Methods

Adult male Sprague-Dawley (SD) rats were divided into Sham (n = 10), UNX (right kidney remove, n = 10), AV (AV established between the levels of renal arteries and iliac bifurcation, n = 18) and UNX+AV (AV at one week after UNX, n = 22), respectively. Renal outcome was measured by glomerular filtration rate, effective renal plasma flow, fractional excretion of sodium, albuminuria, plasma creatinine, and cystatin C. Focal glomerulosclerosis (FGS) incidence was evaluated by renal histology. Cardiac function was measured by echocardiography and hemodynamic measurements.

Results

UNX alone induced compensatory left kidney enlargement, increased plasma creatinine and cystatin C levels, and slightly reduced glomerular filtration rate and increased FGS. AV induced significant cardiac enlargement and hypertrophy and reduced cardiac function and increased FGS, these changes were aggravated in UNX+AV rats.

Conclusions

Although UNX only induces minor renal dysfunction, additional chronic volume overload placement during the adaptation phase of the remaining kidney is associated with aggravated cardiac dysfunction and remodeling in UNX rats, suggesting special medical care is required for UNX or congenital monokidney subjects in case of chronic volume overload as in the case of pregnancy and hyperthyroidism to prevent further adverse cardiorenal events in these individuals.     

PFTK1 Promotes Gastric Cancer Progression by Regulating Proliferation,Migration and Invasion

PFTK1, also known as PFTAIRE1, CDK14, is a novel member of Cdc2-related serine/threonine protein kinases. Recent studies show that PFTK1 is highly expressed in several malignant tumors such as hepatocellular carcinoma, esophageal cancer, breast cancer, and involved in regulation of cell cycle, tumors proliferation, migration, and invasion that further influence the prognosis of tumors. However, the expression and physiological significance of PFTK1 in gastric cancer remain unclear. In this study, we analyzed the expression and clinical significance of PFTK1 by Western blot in 8 paired fresh gastric cancer tissues, nontumorous gastric mucosal tissues and immunohistochemistry on 161 paraffinembedded slices. High PFTK1 expression was correlated with the tumor grade, lymph node invasion as well as Ki-67. Through Cell Counting Kit (CCK)-8 assay, flow cytometry, colony formation, wound healing and transwell assays, the vitro studies demonstrated that PFTK1 overexpression promoted proliferation, migration and invasion of gastric cancer cells, while PFTK1 knockdown led to the opposite results. Our findings for the first time supported that PFTK1 might play an important role in the regulation of gastric cancer proliferation, migration and would provide a novel promising therapeutic strategy against human gastric cancer.     

Prophylactic Use of Macrolide Antibiotics for the Prevention of Chronic Obstructive Pulmonary Disease Exacerbation: A Meta-Analysis

Background

Acute exacerbations of chronic obstructive pulmonary disease (AECOPDs) can lead to high frequencies and rates of hospitalization and mortality. Macrolides are a class of antibiotics that possess both antimicrobial and anti-inflammatory properties. Since the occurrence of AECOPDs is associated with aggravation of airway inflammation and bacterial infections, prophylactic macrolide treatment may be an effective approach towards the prevention of AECOPDs.

Methods

We systemically searched the PubMed, Embase and Cochrane Library databases to identify randomized controlled trials (RCTs) that evaluated the effect of prophylactic macrolide therapy on the prevention of AECOPDs. The primary outcomes were the total number of patients with one or more exacerbations as well as the rate of exacerbations per patient per year.

Results

Nine RCTs comprising 1666 patients met the inclusion criteria. Pooled evidence showed macrolides could reduce the frequency of exacerbations in patients with COPD by both unweighted (RR = 0.70; 95% CI: 0.56–0.87; P < 0.01) and weighted approaches (RR = 0.58, 95% CI: 0.43–0.78, P < 0.01). Subgroup analysis showed only 6–12 months of erythromycin or azithromycin therapy could be effective. Moreover, among studies with 6–12 months of azithromycin therapy, both the daily dosing regimen and the intermittent regimen significantly reduced exacerbation rates. The overall number of hospitalizations and the all-cause rate of death were not significantly different between the treatment and control groups. A tendency for more adverse events was found in the treatment groups (OR = 1.55, 95%CI: 1.003–2.39, P = 0.049).

Conclusions

Our results suggest 6-12 months erythromycin or azithromycin therapy could effectively reduce the frequency of exacerbations in patients with COPD. However, Long-term treatment may bring increased adverse events and the emergence of macrolide-resistance. A recommendation for the prophylactic use of macrolide therapy should weigh both the advantages and disadvantages.     

Cloning and Functional Characterization of SAD Genes in Potato

Stearoyl-acyl carrier protein desaturase (SAD), locating in the plastid stroma, is an important fatty acid biosynthetic enzyme in higher plants. SAD catalyzes desaturation of stearoyl-ACP to oleyl-ACP and plays a key role in determining the homeostasis between saturated fatty acids and unsaturated fatty acids, which is an important player in cold acclimation in plants. Here, four new full-length cDNA of SADs (ScoSAD, SaSAD, ScaSAD and StSAD) were cloned from four Solanum species, Solanum commersonii, S. acaule, S. cardiophyllum and S. tuberosum, respectively. The ORF of the four SADs were 1182 bp in length, encoding 393 amino acids. A sequence alignment indicated 13 amino acids varied among the SADs of three wild species. Further analysis showed that the freezing tolerance and cold acclimation capacity of S. commersonii are similar to S. acaule and their SAD amino acid sequences were identical but differed from that of S. cardiophyllum, which is sensitive to freezing. Furthermore, the sequence alignments between StSAD and ScoSAD indicated that only 7 different amino acids at residues were found in SAD of S. tuberosum (Zhongshu8) against the protein sequence of ScoSAD. A phylogenetic analysis showed the three wild potato species had the closest genetic relationship with the SAD of S. lycopersicum and Nicotiana tomentosiformis but not S. tuberosum. The SAD gene from S. commersonii (ScoSAD) was cloned into multiple sites of the pBI121 plant binary vector and transformed into the cultivated potato variety Zhongshu 8. A freeze tolerance analysis showed overexpression of the ScoSAD gene in transgenic plants significantly enhanced freeze tolerance in cv. Zhongshu 8 and increased their linoleic acid content, suggesting that linoleic acid likely plays a key role in improving freeze tolerance in potato plants. This study provided some new insights into how SAD regulates in the freezing tolerance and cold acclimation in potato.     

MicroRNA Expression Profile during Aphid Feeding in Chrysanthemum (Chrysanthemum morifolium)

MicroRNAs (miRNAs) are important regulators of gene expression, affecting many biological processes. As yet, their roles in the response of chrysanthemum to aphid feeding have not been explored. Here, the identity and abundance of miRNAs induced by aphid infestation have been obtained using high-throughput Illumina sequencing platform. Three leaf small RNA libraries were generated, one from plants infested with the aphid Macrosiphoniella sanbourni (library A), one from plants with mock puncture treatment (library M), and the third from untreated control plants (library CK). A total of 7,944,797, 7,605,251 and 9,244,002 clean unique reads, ranging from 18 to 30 nucleotides (nt) in length, were obtained from library CK, A and M, respectively. As a result, 303 conserved miRNAs belonging to 276 miRNAs families and 234 potential novel miRNAs were detected in chrysanthemum leaf, out of which 80, 100 and 79 significantly differentially expressed miRNAs were identified in the comparison of CK-VS-A, CK-VS-M and M-VS-A, respectively. Several of the differentially abundant miRNAs (in particular miR159a, miR160a, miR393a) may be associated with the plant''s response to aphid infestation.     

NMDA Receptor Antagonist Attenuates Bleomycin-Induced Acute Lung Injury

Background

Glutamate is a major neurotransmitter in the central nervous system (CNS). Large amount of glutamate can overstimulate N-methyl-D-aspartate receptor (NMDAR), causing neuronal injury and death. Recently, NMDAR has been reported to be found in the lungs. The aim of this study is to examine the effects of memantine, a NMDAR channel blocker, on bleomycin-induced lung injury mice.

Methods

C57BL/6 mice were intratracheally injected with bleomycin (BLM) to induce lung injury. Mice were randomized to receive saline, memantine (Me), BLM, BLM plus Me. Lungs and BALF were harvested on day 3 or 7 for further evaluation.

Results

BLM caused leukocyte infiltration, pulmonary edema and increase in cytokines, and imposed significant oxidative stress (MDA as a marker) in lungs. Memantine significantly mitigated the oxidative stress, lung inflammatory response and acute lung injury caused by BLM. Moreover, activation of NMDAR enhances CD11b expression on neutrophils.

Conclusions

Memantine mitigates oxidative stress, lung inflammatory response and acute lung injury in BLM challenged mice.     

Surgical Management for Early-Stage Bilateral Breast Cancer Patients in China

Background

The aim of this study was to investigate the current surgical management strategy for bilateral breast cancer (BBC) patients and to assess the changes in this strategy in China.

Methods

This is a retrospective review of all patients with early-stage BBC who underwent surgical treatment at the Fudan University Shanghai Cancer Center between June 2007 and June 2014.

Results

A total of 15,337 patients with primary breast cancer were identified. Of these patients, 218 (1.5%) suffered from synchronous bilateral breast cancer (sBBC), and 296 (2.0%) suffered from metachronous bilateral breast cancer (mBBC). Patients with a lobular carcinoma component, those with estrogen receptor-positive cancer, and those with an accompanying sclerosing adenosis in the affected breast tended to develop BBC. The rates of bilateral mastectomy, breast conserving therapy, reconstruction, and combined surgeries were 86.2%, 6.4%, 3.7%, and 3.7%, respectively, for patients with sBBC and 81.1%, 4.4%, 3.0%, and 11.5%, respectively, for patients with mBBC. The interval between bilateral cancers, age at first diagnosis of breast cancer, histopathological type, and stage have significant impacts on the choice of surgery for patients with BBC.

Conclusions

Bilateral mastectomy was the dominant surgical management for patients with BBC in China, despite the increased application of breast reconstruction surgery observed in recent years. Bilateral prosthetic breast reconstruction was the ideal choice for patients with sBBC. Chinese surgeons should take responsibility for patient education and inform their patients about their surgical options.