Substance P autocrine signaling contributes to persistent HER2 activation that drives malignant progression and drug resistance in breast cancer.

ERBB receptor transmodulation by heterologous G-protein-coupled receptors (GPCR) generates functional diversity in signal transduction. Tachykinins are neuropeptides and proinflammatory cytokines that promote cell survival and cancer progression by activating several GPCRs. In this work, we found that the pain-associated tachykinin Substance P (SP) contributes to persistent transmodulation of the ERBB receptors, EGFR and HER2, in breast cancer, acting to enhance malignancy and therapeutic resistance. SP and its high-affinity receptor NK-1R were highly expressed in HER2(+) primary breast tumors (relative to the luminal and triple-negative subtypes) and were overall correlated with poor prognosis factors. In breast cancer cell lines and primary cultures derived from breast cancer samples, we found that SP could activate HER2. Conversely, RNA interference-mediated attenuation of NK-1R, or its chemical inhibition, or suppression of overall GPCR-mediated signaling, all strongly decreased steady-state expression of EGFR and HER2, establishing that their basal activity relied upon transdirectional activation by GPCR. Thus, SP exposure affected cellular responses to anti-ERBB therapies. Our work reveals an important oncogenic cooperation between NK-1R and HER2, thereby adding a novel link between inflammation and cancer progression that may be targetable by SP antagonists that have been clinically explored

Protein profiling in hepatocellular carcinoma by label-free quantitative proteomics in two west african populations.

Background Hepatocellular Carcinoma is the third most common cause of cancer related death worldwide, often diagnosed by measuring serum AFP; a poor performance stand-alone biomarker. With the aim of improving on this, our study focuses on plasma proteins identified by Mass Spectrometry in order to investigate and validate differences seen in the respective proteomes of controls and subjects with LC and HCC. Methods Mass Spectrometry analysis using liquid chromatography electro spray ionization quadrupole time-of-flight was conducted on 339 subjects using a pooled expression profiling approach. ELISA assays were performed on four significantly differentially expressed proteins to validate their expression profiles in subjects from the Gambia and a pilot group from Nigeria. Results from this were collated for statistical multiplexing using logistic regression analysis. Results Twenty-six proteins were identified as differentially expressed between the three subject groups. Direct measurements of four; hemopexin, alpha-1-antitrypsin, apolipoprotein A1 and complement component 3 confirmed their change in abundance in LC and HCC versus control patients. These trends were independently replicated in the pilot validation subjects from Nigeria. The statistical multiplexing of these proteins demonstrated performance comparable to or greater than ALT in identifying liver cirrhosis or carcinogenesis. This exercise also proposed preliminary cut offs with achievable sensitivity, specificity and AUC statistics greater than reported AFP averages. Conclusions The validated changes of expression in these proteins have the potential for development into high-performance tests usable in the diagnosis and or monitoring of HCC and LC patients. The identification of sustained expression trends strengthens the suggestion of these four proteins as worthy candidates for further investigation in the context of liver disease. The statistical combinations also provide a novel inroad of analyses able to propose definitive cut-offs and combinations for evaluation of performance

Effect of Metabolic Syndrome on Parkinson’s Disease: A Systematic Review

Evidence shows that metabolic syndrome (MS) is associated with a greater risk of developing Parkinson’s disease (PD) because of the increase in oxidative stress levels along with other factors such as neuroinflammation and mitochondrial dysfunction. However, because some studies have reported that MS is associated with a lower risk of PD, the relationship between MS and PD should be investigated. This study aimed to investigate the effect of MS on PD. Two authors searched five electronic databases, namely, MEDLINE, PubMed, Scopus, PsycINFO, Web of Science, and Science Direct, for relevant articles between September and October 2020. After screening the title and abstract of all articles, 34 articles were selected for full-text review. Finally, 11 articles meeting the eligibility criteria were included in the study. The quality of articles was critically evaluated using the Joanna Briggs Institute. Overall, we evaluated data from 23,586,349 individuals (including healthy individuals, with MS and PD) aged 30 years or more. In cohort studies, the follow-up period varied between 2 and 30 years. MS contributed considerably to the increase in the incidence of PD. In addition, obesity, a component of MS, alone can increase the probability of developing neurodegenerative diseases. However, despite few studies on MS and PD, changes in cognitive function and more rapid progression of PD disease has been documented in patients with MS using methods commonly used in research

Are the distributions of variations of circle of Willis different in different populations? – Results of an anatomical study and review of literature

BACKGROUND: Previous studies have proposed correlation between variants of the cerebral arterial circle (also known as circle of Willis) and some cerebrovascular diseases. Differences in the incidence of these diseases in different populations have also been investigated. The study of variations in the anatomy of the cerebral arterial circle may partially explain differences in the incidence of some of the cerebrovascular diseases in different ethnic or racial groups. While many studies have investigated the variations in the anatomy of each segment of the cerebral arterial circle, few have addressed the variants of the cerebral arterial circle as a whole. Similarly, the frequency of occurrence of such variants in different ethnic or racial groups has not been compared. METHODS: 102 brains of recently deceased Iranian males were dissected, in order to observe variations in the anatomy of the cerebral arterial circle. The dissection process was recorded on film and digitized. One resized picture from each dissection, showing complete circle has been made available online. The variations of the circle as whole and segmental variations were compared with previous studies. RESULTS: On the whole, the frequencies of the different variants of the entire cerebral arterial circle and segmental variations were comparable with previous studies. More specifically variants with uni- and bilateral hypoplasia of posterior communicating arteries were the most common in our study, similar to the previous works. No hypoplasia of the precommunicating part of the left anterior cerebral artery (A1), aplasia of A1 or the precommunicating part of the posterior cerebral artery (P1) was seen. In 3% both right and left posterior communcating arteries were absent. CONCLUSION: The anatomical variations found in the cerebral arterial circle of the Iranian males in the current study were not significantly different to those of more diverse populations reported in the literature. While taking into account potential confounding factors, the authors conclude that based on available studies, there is no evidence suggesting that the distributions of the variations of cerebral arterial circle differ in different populations

Dengue Infection and Miscarriage: A Prospective Case Control Study

Dengue is the most prevalent mosquito-borne infection with two billion of the world's population at risk and 100 million infections every year. Dengue is increasingly important due to expansion in the vector's range, increased population density in endemic areas from urbanisation, social and environment change. Miscarriage and stillbirth is associated with dengue when the illness is severe. Dengue can also be transmitted directly from the ill mother through the placenta to the fetus in later pregnancy with variable effect to the fetus. However, dengue infection is asymptomatic to mild only in almost 90% of cases and up to 20% of pregnancies miscarry. Little is known if dengue infection in early pregnancy particularly when it is asymptomatic or mild has an effect on miscarriage. Our study explored the relationship between dengue and miscarriage by looking at recent infection rates amongst women who had miscarried and those whose pregnancies were healthy in an area were dengue is common. Our study finds a positive association between recent dengue infection and miscarriage. This finding may be important in explaining some of the miscarriages in areas where dengue is common. It is also relevant to newly pregnant women from non-dengue travelling to dengue endemic areas

DNA Vaccines against Dengue Virus Type 2 Based on Truncate Envelope Protein or Its Domain III

Two DNA vaccines were constructed encoding the ectodomain (domains I, II and III) of the DENV2 envelope protein (pE1D2) or only its domain III (pE2D2), fused to the human tissue plasminogen activator signal peptide (t-PA). The expression and secretion of recombinant proteins was confirmed in vitro in BHK cells transfected with the two plasmids, detected by immunofluorescence or immunoprecipitation of metabolically labeled gene products, using polyclonal and monoclonal antibodies against DENV2. Besides, results reveal that the ectodomain of the E protein can be efficiently expressed in vivo, in a mammalian system, without the prM protein that is hypothesized to act as a chaperonin during dengue infection. Balb/c mice were immunized with the DNA vaccines and challenged with a lethal dose of DENV2. All pE1D2-vaccinated mice survived challenge, while 45% of animals immunized with the pE2D2 died after infection. Furthermore, only 10% of pE1D2-immunized mice presented some clinical signs of infection after challenge, whereas most of animals inoculated with the pE2D2 showed effects of the disease with high morbidity degrees. Levels of neutralizing antibodies were significantly higher in pE1D2-vaccinated mice than in pE2D2-immunized animals, also suggesting that the pE1D2 vaccine was more protective than the pE2D2