Murine cytomegalovirus regulation of NKG2D ligands

Human cytomegalovirus (HCMV) is a ubiquitous pathogen that causes morbidity risk in immunologically suppressed and immunodeficient patients including congenital infections. Approaches to curb the consequences of HCMV infections are restricted by a lack of complete understanding of viral pathogenesis. The infection of mice with murine cytomegalovirus (MCMV) as a model of HCMV infection has been particularly useful in elucidating the role of innate and adaptive immune response mechanisms. A large number of cytomegalovirus genes modulate the innate and the adaptive host immune response. The products of several MCMV genes are involved in subverting the natural killer (NK) cell response by down-modulating cellular ligands for the NKG2D receptor expressed on NK cells and CD8⁺ T cells. Mutant viruses lacking these immunoevasion genes are attenuated with respect to virus growth in vivo. Given the importance of the NKG2D receptor in controlling both NK- and T cell-mediated immunity, it is of tremendous importance to understand the molecular mechanisms and consequences of viral regulation of the NKG2D ligands.     

Engineering of cytomegalovirus genomes for recombinant live herpesvirus vaccines

The advances of sequence knowledge and genetic engineering hold a great promise for a rational approach to vaccine development. Herpesviruses are important pathogens of all vertebrates. They cause acute and chronic infections and persist in their hosts for life. In man there are eight herpesviruses known and most of them can be linked to diseases. To date only one licensed vaccine against a human herpesvirus exists and there is no proven successful concept on rational design for herpesvirus vaccines available. Here, we use new reverse genetic systems, based on the 230-kb mouse cytomegalovirus genome to explore new methods of vaccine delivery and of virus attenuation. With regard to virus delivery, we show that the bacterial transfer of the infectious DNA in vivo is theoretically possible but not yet a practical option. With regard to a rational approach of virus attenuation, we consider a selective deletion of viral genes that modulate the immune response of the host.     

JAK–STAT inhibition impairs K-RAS-driven lung adenocarcinoma progression

Oncogenic K-RAS has been difficult to target and currently there is no K-RAS-based targeted therapy available for patients suffering from K-RAS-driven lung adenocarcinoma (AC). Alternatively, targeting K-RAS-downstream effectors, K-RAS-cooperating signaling pathways or cancer hallmarks, such as tumor-promoting inflammation, has been shown to be a promising therapeutic strategy. Since the JAK–STAT pathway is considered to be a central player in inflammation-mediated tumorigenesis, we investigated here the implication of JAK–STAT signaling and the therapeutic potential of JAK1/2 inhibition in K-RAS-driven lung AC. Our data showed that JAK1 and JAK2 are activated in human lung AC and that increased activation of JAK–STAT signaling correlated with disease progression and K-RAS activity in human lung AC. Accordingly, administration of the JAK1/2 selective tyrosine kinase inhibitor ruxolitinib reduced proliferation of tumor cells and effectively reduced tumor progression in immunodeficient and immunocompetent mouse models of K-RAS-driven lung AC. Notably, JAK1/2 inhibition led to the establishment of an antitumorigenic tumor microenvironment, characterized by decreased levels of tumor-promoting chemokines and cytokines and reduced numbers of infiltrating myeloid derived suppressor cells, thereby impairing tumor growth. Taken together, we identified JAK1/2 inhibition as promising therapy for K-RAS-driven lung AC.     

Performance of the COMPASS-31 questionnaire with regard to autonomic nervous system testing results and medication use: a prospective study in a real-life setting

The aim of this study was to investigate the performance of the Composite Autonomic System Score-31 (COMPASS-31) questionnaire in a real-life setting in consecutive patients referred to the laboratory for objective testing of the autonomic nervous system (ANS), with the hypothesis that COMPASS-31 results differ depending on medications and findings of the tilt table test results. One hundred seventy-one consecutive patients (125 females, mean age 41.5?±?19.3) referred for testing of the ANS were enrolled. Before testing, all patients completed the recently validated Croatian version of COMPASS-31. The following data were systematically collected for all patients: age, sex, diagnoses, and medications. Results of COMPASS-31 were significantly higher in patients taking medications with a known influence on the ANS (p?<?0.001). Patients with postural orthostatic tachycardia had significantly higher orthostatic intolerance and vasomotor domains of COMPASS-31 (p?=?0.048 and p?=?0.022, respectively). Patients with a cardiovagal score?≥?1 had a significantly higher vasomotor domain of COMPASS-31 compared to patients with normal results of ANS tests (p?=?0.030). These findings suggest the COMPASS-31 might be a valuable screening tool for autonomic dysfunctions, as it is associated with impaired ANS tests, but usage of medications that modify the ANS should always be taken into account.     

孟鲁司特对儿童过敏性紫癜Toll样受体表达的影响及临床疗效观察

目的:探讨孟鲁司特对儿童过敏性紫癜Toll样受体表达的影响及临床疗效。方法:将86例过敏性紫癜(HSP)患儿,按照随机数字法分为治疗组和对照组各43例。对照组采用常规综合治疗,治疗组在对照组治疗基础上加用孟鲁司特,2~6岁4 mg/d,>6岁~14岁5 mg/d,每日一次,睡前服用。比较两组患儿的临床疗效并观察皮疹消退、腹痛缓解及关节肿痛缓解时间;实时荧光定量PCR技术检测外周血单核细胞中TLR2、TLR5及TLR9 mRNA的基因相对表达量,ELISA检测患者血清中IL-6和IL-8浓度。结果:(1)治疗组总有效率97.7%,明显高于对照组的81.4%(P<0.05),治疗组患儿的皮疹消退、腹痛缓解及关节肿痛缓解时间均显著短于对照组(P<0.05);(2)治疗组和对照组治疗后与治疗前比较,外周血单核细胞TLR2、TLR5及TLR9mRNA相对表达量均显著降低(P<0.05),且治疗后观察组外周血单核细胞TLR2、TLR5及TLR9 mRNA相对表达量均明显低于对照组(P<0.05);(3)两组过敏性紫癜患儿治疗后血清中IL-6和IL-8的表达均明显低于治疗前(P<0.05),且治疗后观察组血清中IL-6和IL-8的表达明显低于对照组(P<0.05)。结论:孟鲁司特治疗儿童HSP临床疗效显著,TLR2、TLR5及TLR9活化可能参与了HSP的免疫发病机制,孟鲁司特能影响Toll样受体(TLR2、TLR5及TLR9)以及IL-6和IL-8的蛋白表达,对儿童HSP的治疗发挥积极作用。     

Innovative Calcium Carbonate-Based Products to Repair Cracked Cement Mortars

The durability of Portland cement mortars is often affected by environmental factors, which can cause physicochemical and mechanical degradation processes. In this study, the performance of three products, calcium acetoacetate and calcium tetrahydrofurfuryloxide dissolved in two different solvents developed and tested as stone consolidants, was evaluated in terms of crack filling or sealing and consolidation. Realistic cracks were induced in quasibrittle cement mortar prisms using a custom-designed test rig. The effectiveness and the performance of the considered treatments, investigated on specimens, were evaluated by optical and scanning electron microscopy, colourimetry, water absorption rate, ultrasonic pulse velocity, and surface hardness measurements. Results revealed that, in the examined conditions, the products were more suitable as surface consolidants than as crack fillers.     

Reconstructing the Temporal Origin and the Transmission Dynamics of the HIV Subtype B Epidemic in St. Petersburg,Russia

The HIV/AIDS epidemic in Russia is among the fastest growing in the world. HIV epidemic burden is non-uniform in different Russian regions and diverse key populations. An explosive epidemic has been documented among people who inject drugs (PWID) starting from the mid-1990s, whereas presently, the majority of new infections are linked to sexual transmission. Nationwide, HIV sub-subtype A6 (previously called A_FSU) predominates, with the increasing presence of other subtypes, namely subtype B and CRF063_02A. This study explores HIV subtype B sequences from St. Petersburg, collected from 2006 to 2020, in order to phylogenetically investigate and characterize transmission clusters, focusing on their evolutionary dynamics and potential for further growth, along with a socio-demographic analysis of the available metadata. In total, 54% (107/198) of analyzed subtype B sequences were found grouped in 17 clusters, with four transmission clusters with the number of sequences above 10. Using Bayesian MCMC inference, tMRCA of HIV-1 subtype B was estimated to be around 1986 (95% HPD 1984–1991), whereas the estimated temporal origin for the four large clusters was found to be more recent, between 2001 and 2005. The results of our study imply a complex pattern of the epidemic spread of HIV subtype B in St. Petersburg, Russia, still in the exponential growth phase, and in connection to the men who have sex with men (MSM) transmission, providing a useful insight needed for the design of public health priorities and interventions.     

Association between prenatal provision of lipid‐based nutrient supplements and caesarean delivery: Findings from a randomised controlled trial in Malawi

In populations with a high prevalence of childhood and adolescent undernutrition, supplementation during pregnancy aiming at improving maternal nutritional status and preventing fetal growth restriction might theoretically lead to cephalopelvic disproportion and delivery complications. We investigated whether the prenatal provision of small‐quantity lipid‐based nutrient supplements (SQ‐LNS) was associated with an increased risk of caesarean section (CS) or other delivery complications. Pregnant Malawian women were randomised to receive daily i) iron–folic acid (IFA) capsule (control), ii) multiple micronutrient (MMN) capsule of 18 micronutrients (second control), or iii) SQ‐LNS with similar micronutrients as MMN, plus four minerals and macronutrients contributing 118 kcal. We analysed the associations of SQ‐LNS, CS, and other delivery complications using log‐binomial regressions. Among 1391 women enrolled, 1255 had delivery information available. The incidence of CS and delivery complications was 6.3% and 8.2%, respectively. The incidence of CS was 4.0%, 6.0%, and 8.9% (p = 0.017) in the IFA, MMN, and LNS groups, respectively. Compared to the IFA group, the relative risk (95% confidence interval) of CS was 2.2 (1.3–3.8) (p = 0.006) in the LNS group and 1.5 (0.8–2.7) (p = 0.200) in the MMN group. We found no significant differences for other delivery complications. Provision of SQ‐LNS to pregnant women may have increased the incidence of CS. The baseline rate was, however, lower than recommended. It is unclear if the higher CS incidence in the SQ‐LNS group resulted from increased obstetric needs or more active health seeking and a better supply of services. Trial registered at clinicaltrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT01239693","term_id":"NCT01239693"}}NCT01239693.     

Detection and Localization of Hyperfunctioning Parathyroid Glands on [18F]fluorocholine PET/ CT Using Deep Learning – Model Performance and Comparison to Human Experts

BackgroundIn the setting of primary hyperparathyroidism (PHPT), [¹⁸F]fluorocholine PET/CT (FCH-PET) has excellent diagnostic performance, with experienced practitioners achieving 97.7% accuracy in localising hyperfunctioning parathyroid tissue (HPTT). Due to the relative triviality of the task for human readers, we explored the performance of deep learning (DL) methods for HPTT detection and localisation on FCH-PET images in the setting of PHPT.Patients and methodsWe used a dataset of 93 subjects with PHPT imaged using FCH-PET, of which 74 subjects had visible HPTT while 19 controls had no visible HPTT on FCH-PET. A conventional Resnet10 as well as a novel mPETResnet10 DL model were trained and tested to detect (present, not present) and localise (upper left, lower left, upper right or lower right) HPTT. Our mPETResnet10 architecture also contained a region-of-interest masking algorithm that we evaluated qualitatively in order to try to explain the model’s decision process.ResultsThe models detected the presence of HPTT with an accuracy of 83% and determined the quadrant of HPTT with an accuracy of 74%. The DL methods performed statistically worse (p < 0.001) in both tasks compared to human readers, who localise HPTT with the accuracy of 97.7%. The produced region-of-interest mask, while not showing a consistent added value in the qualitative evaluation of model’s decision process, had correctly identified the foreground PET signal.ConclusionsOur experiment is the first reported use of DL analysis of FCH-PET in PHPT. We have shown that it is possible to utilize DL methods with FCH-PET to detect and localize HPTT. Given our small dataset of 93 subjects, results are nevertheless promising for further research.Key words: primary hyperparathyroidism, deep learning, nuclear medicine, fluorocholine, PET/CT