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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated symptoms, named coronavirus disease 2019 (COVID-19), have rapidly spread worldwide, resulting in the declaration of a pandemic. When several countries began enacting quarantine and lockdown policies, the pandemic as it is now known truly began. While most patients have minimal symptoms, approximately 20% of verified subjects are suffering from serious medical consequences. Co-existing diseases, such as cardiovascular disease, cancer, diabetes, and others, have been shown to make patients more vulnerable to severe outcomes from COVID-19 by modulating host–viral interactions and immune responses, causing severe infection and mortality. In this review, we outline the putative signaling pathways at the interface of COVID-19 and several diseases, emphasizing the clinical and molecular implications of concurring diseases in COVID-19 clinical outcomes. As evidence is limited on co-existing diseases and COVID-19, most findings are preliminary, and further research is required for optimal management of patients with comorbidities.

Fibroblast-like synoviocytes (FLS) are important components of the synovial membrane. They can contribute to joint damage through crosstalk with inflammatory cells and direct actions on tissue damage pathways in rheumatoid arthritis (RA). Recent evidence suggests that, compared with FLS in normal synovial tissue, FLS in RA synovial tissue exhibits significant differences in metabolism. Recent metabolomic studies have demonstrated that metabolic changes, including those in glucose, lipid, and amino acid metabolism, exist before synovitis onset. These changes may be a result of increased biosynthesis and energy requirements during the early phases of the disease. Activated T cells and some cytokines contribute to the conversion of FLS into cells with metabolic abnormalities and pro-inflammatory phenotypes. This conversion may be one of the potential mechanisms behind altered FLS metabolism. Targeting metabolism can inhibit FLS proliferation, providing relief to patients with RA. In this review, we aimed to summarize the evidence of metabolic changes in FLS in RA, analyze the mechanisms of these metabolic alterations, and assess their effect on RA phenotype. Finally, we aimed to summarize the advances and challenges faced in targeting FLS metabolism as a promising therapeutic strategy for RA in the future.

Childhood obesity rates have risen dramatically over the past few decades. Although obesity has been linked to poorer neurocognitive functioning in adults, much less is known about this relationship in children and adolescents. Therefore, we conducted a systematic review to examine the relationship between obesity and obesity-related behaviors with neurocognitive functioning in youth. We reviewed articles from 1976 to 2013 using PsycInfo, PubMed, Medline and Google Scholar. Search terms included cognitive function, neurocognitive function/performance, executive function, impulsivity, self-regulation, effortful control, cognitive control, inhibition, delayed gratification, memory, attention, language, motor, visuo-spatial, academic achievement, obesity, overweight, body mass index, waist-hip ratio, adiposity and body fat. Articles were excluded if participants had health problems known to affect cognitive functioning, the study used imaging as the only outcome measure, they were non-peer-reviewed dissertations, theses, review papers, commentaries, or they were non-English articles. Sixty-seven studies met inclusion criteria for this review. Overall, we found data that support a negative relationship between obesity and various aspects of neurocognitive functioning, such as executive functioning, attention, visuo-spatial performance, and motor skill. The existing literature is mixed on the effects among obesity, general cognitive functioning, language, learning, memory, and academic achievement. Executive dysfunction is associated with obesity-related behaviors, such as increased intake, disinhibited eating, and less physical activity. Physical activity is positively linked with motor skill. More longitudinal research is needed to determine the directionality of such relationships, to point towards crucial intervention time periods in the development of children, and to inform effective treatment programs.

The outbreak of the novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as a serious public health concern. Patients with cancer have been disproportionately affected by this pandemic. Increasing evidence has documented that patients with malignancies are highly susceptible to severe infections and mortality from COVID-19. Recent studies have also elucidated the molecular relationship between the two diseases, which may not only help optimize cancer care during the pandemic but also expand the treatment for COVID-19. In this review, we highlight the clinical and molecular similarities between cancer and COVID-19 and summarize the four major signaling pathways at the intersection of COVID-19 and cancer, namely, cytokine, type I interferon (IFN-I), androgen receptor (AR), and immune checkpoint signaling. In addition, we discuss the advantages and disadvantages of repurposing anticancer treatment for the treatment of COVID-19.

Background Mansonella perstans is a vector-borne filarial parasite widely endemic in sub-Saharan Africa, with sporadic cases in Latin America. Infection is often overlooked; treatment is not standardized, and effectiveness of common regimes is difficult to ascertain. Anti- Wolbachia macrofilaricidal treatment with doxycycline has been applied, but there are scant and contrasting reports about the presence of Wolbachia in M. perstans isolates from different geographical locations. Taking advantage of a network of European centres expert in traveller and migrant health, we aimed to expand the knowledge concerning the distribution of Wolbachia in M. perstans to contribute to the design of optimal treatment approaches. Methods We analysed 19 samples of concentrated microfilariae or whole blood from M. perstans -infected patients who reported having resided or travelled in one or more of 10 West African countries. Wolbachia was detected by PCR targeting 16S and ftsZ genes and phylogenetic analysis of M. perstans was performed based on COX1 gene sequencing. Results Wolbachia was identified in 14/19 (74%) samples. With the possible inaccuracy deriving from potential origin of infection being identified retrospectively from routine clinical visit’s documents, this study identified Wolbachia in M. perstans from Burkina Faso, Equatorial Guinea, Republic of Guinea and Senegal for the first time to our knowledge. Furthermore, Wolbachia might also be present in M. perstans from Democratic Republic of the Congo, Mali, Niger and Nigeria. Conclusions The retrieval of Wolbachia -positive and Wolbachia -negative M. perstans samples can either be explained by technical limitations or reflect the real existence of Wolbachia -positive and Wolbachia -negative M. perstans populations. However, this latter hypothesis was not supported by our phylogenetic analysis. Our results suggest that doxycycline could be used for the treatment of M. perstans infection upfront or, if possible, after ascertaining the presence of Wolbachia by PCR performed on concentrated microfilariae using two targets to avoid false-negative results. Graphical Abstract

Non-small cell lung cancer(NSCLC) accounts for 85% of all lung cancer cases and is often associated with mutations in hepatocyte growth factor(HGF) and epidermal growth factor(EGF) expression. Tunneling nanotubes(TNTs) are thin cytoplasmic connections shown to be involved in long-distance intercellular communication and have an important role in cancer progression. We investigated the role of EGF/HGF signalling pathway crosstalk in TNT formation, in addition to defining key characteristics of TNTs in A549 cells. For TNT quantification, A549 cells were cultured and treated with 100ng/mL EGF/HGF/EGF+HGF for 24h and analysis of phase-light images was undertaken using ImageJ. Pharmacological inhibition of MEK,PI3K,c-Met,EGFR,Rac1,Cdc42, and the Arp2/3 complex and siRNA-mediated knockdown of Paxillin was performed to assess signalling pathways. EGF,HGF and EGF+HGF induced TNTs in 42%,39% and 46% of cells respectively. EGF+HGF yielded effects consistent with individual EGF and HGF treatments, indicating convergence of EGF/HGF signalling pathways at receptor level. We also found the Ras/MAPK/MEK, PI3K/Akt and the Arp2/3 complex pathways regulated EGF/HGF-induced TNTs. While singular inhibition of MEK or PI3K diminished HGF or EGF-induced TNTs, this was not sufficient to inhibit EGF+HGF-induced TNTs, and simultaneous MEK+PI3K inhibition was required for TNT suppression to basal levels. This suggests the MAPK/MEK and PI3K/Akt pathways, traditionally thought to be independent, may be participating in compensatory signalling to overcome pathway inhibition. Furthermore, knockdown of Paxillin inhibited EGF+HGF-induced TNTs, marking it as an important scaffolding protein in TNT formation. The structure of observed TNTs was examined by scanning electron microscopy, wherein TNTs demonstrated non-adherence to the substrate and presence of vesicles, which was confirmed later by trafficking of DiO lipid vesicles and mitochondria between cells via TNTs. Finally, immunofluorescent labelling of EGF+HGF-induced TNTs showed localisation of the novel proteins EGFR, c-Met and β1-integrin, in addition to expressing the classical TNT markers F-actin and α-tubulin. The findings of this study serve a wider implication in understanding the mechanisms of NSCLC progression and chemoresistance via TNTs in the tumour microenvironment. Future work will explore the functional consequences of mitochondria/organelle transfer via TNTs, and eventually stratify NSCLC patient samples for HGF/EGF dual expression to determine the contribution of TNTs to treatment resistance.

Translating research to behavioral healthcare practice is vital for improving treatment impact but can be challenging. Current and lifetime histories of trauma need to be considered in behavioral healthcare provision as they can significantly affect an individual’s treatment experience. This article provides guidance on how to utilize research findings regarding trauma prevalence and experiences of women who have substance use disorder and who are homeless or near homeless to help guide responsive healthcare and treatment in practice.

BackgroundLung adenocarcinomas (LUADs) usually show one predominant morphological pattern (either lepidic, papillary, acinar, cribriform, micropapillary or solid) that predicts patient’s survival. In addition, LUADs may be classified according to their predominant subtype (either mucinous, non-mucinous or mixed). Genomic differences that may influence patterns have been minimally studied. Our aim was to identify genetic alterations with pathogenic relevance related to LUAD morphology.MethodsWe genomically profiled 89 LUAD tumour samples (13 lepidic, 13 papillary, 37 acinar, 7 cribriform, 7 micropapillary and 12 solid, sub-typed as 48 non-mucinous, 20 mucinous and 19 mixed) by Affymetrix microarrays, single nucleotide polymorphism genotyping and whole-exome or targeted capture sequencing.Results TP53 mutations were the most frequent abnormalities overall (41%) but were notably absent in cribriform tumours, where CDKN2A alterations were most frequent. EGFR mutations were more common in never-smokers, were mutually exclusive to KRAS in all subjects and not detected in solid, papillary or cribriform patterns. KRAS mutations in the acinar subtype were the only predictor for patient survival.The solid tumours (mostly of the non-mucinous subtype [83.3%]) had a high tumour mutation burden (TMB). Solid tumours also exhibited high levels of expression for VEGFA and CD274 (PD-L1) transcripts level and the highest CD8 T-cell abundance, shown by CIBERSORT analysis, suggesting potential response to checkpoint inhibitors for this pattern.Network analysis discovered 92 modules of co-expressed genes in LUAD tumours. The greatest number of co-expression modules were found in solid and lepidic patterns (11 and 10 networks respectively). These associations were almost entirely opposing in directionality, indicating strongly contrasting mechanisms underlying these two histotypes. The largest co-expression module ME1 (chromosome organization, containing 1,007 genes, with TPX2 as hub gene) showed the strongest associations: Cor 0.53, P 8.92x10-08 [% solid]/-0.52, P 1.38x10-07 [% lepidic]). The ME1 module was also linked to with γδ T cells (strength: 1.00, direction: 0.95).ConclusionsOur study has highlighted existence of genomic heterogeneity in LUAD patterns. Assessing key molecular changes in combination with standard histology in LUAD might have direct impact in classifying responders to targeted therapies, in particular solid pattern patients to immune checkpoint inhibitors.

BackgroundPleural mesothelioma is a rare, aggressive cancer. It is characterised by intra-tumour genomic heterogeneity (ITH) that has a direct impact on a patient’s clinical outcome including selection and response to therapy.MethodsTo gain insight into spatial ITH, we have conducted target gene sequencing of 26 tumour samples and matched blood samples from four mesothelioma patients. For each patient tumour samples were taken from multiple affected regions including lateral, diaphragmatic, and mediastinal sites. Histology and immunohistochemistry were conducted on all samples.ResultsWe observed quite marked genetic heterogeneity across tumours for three patients. In the remaining patient NF2 mutations was detected in all tumour samples with high variant allele frequencies (≥50% in three samples and >30% in the other three) pointing to an early clonal origin.Immunohistochemistry showed focal or total loss of protein BAP1 in all patients but mutations or single copy number aberrations (sCNA) were only seen in two patients. Aberrations of SETD2, on chromosome 3, were detected in single samples from two patients.Mutations in the SWI/SNF chromatin remodelling member ARID1A, and its homolog ARID1B, were also identified heterogeneously in three patients: ARID1B was present in 4/6 samples in one patient and in 1/7 samples for a second patient, ARID1A in 1/7 samples in a third patient. ARID1A mutated tumours may be targeted in vitro with EZH2 inhibitors thus it may be considered as a potential therapeutic target for a subset of pleural mesothelioma patients.Mutations in MET, TSC1 and SF3B1 were detected in single samples from two patients. sCNA of the cytobands containing SUFU (Hedgehog pathway) on chromosome 10q24.32 was detected in two samples from one patient, and RBFOX1 on chromosome 16p13.13 was detected in two different samples from the same patient. RBFOX1 is within a chromosomal region that has been implicated in autoimmunity.ConclusionsSpatial profiling of pleural mesothelioma revealed marked inter and intra- patient heterogeneity, with only one patient showing an apparent founder mutation in NF2. Although alterations affecting Hippo, Hedgehog or SWI/SNF pathways may define subsets of responders to therapies, it is possible that underlying heterogeneity will result in poor response.

IntroductionCOPD is an independent risk factor for lung carcinoma and lung cancer more likely to occur in smokers with airflow obstruction than those with normal lung function.1 IL-22 is produced by innate lymphoid cells and mediates its cellular effects via a heterodimer receptor complex composed of two different subunits (IL-22 receptor subunit 1 (IL-22R1) and IL-10R2). IL-22 signaling regulates pro-survival, cell migration, mitogenic and anti-apoptotic effects, leading to enhancement of tumor growth and metastasis. IL-22 is overexpressed in lung cancer tissues, malignant pleural effusions, and serum of NSCLC patients.2 AimWe attempted to determine lung tissue IL-22 levels in patients with early-stage NSCLC with and without COPD.MethodThe expression of IL-22 was studied with immunohistochemistry.Results85 patients were recruited 12 of which with coexistent COPD confirmed by spirometry. Expression of IL-22 (%) in lung cancer tissue was significantly higher in men (n=64) compared to women (n=21), (p=0,005). A negative correlation between% percentage levels of IL-22 tissue expression and BMI was found (p=0,017). The% expression of IL-22 was marginally not different between lung cancer patients with COPD vs. lung cancer patients without COPD. (49,06% vs 43,53%, p=0,059). No significant difference was detected in immunohistochemical staining of IL-22 in lung cancer tissues according to age, gender and BMI. On the other hand, immunohistochemical expression of tissue IL-22 was higher in lung adenocarcinoma, with 62,9% of cytoplasmic expression vs. 2,9% in the other histological subtypes (p=0,039). Furthermore, cytoplasmic expression of IL-22 was significantly higher in current smokers vs ex-smokers (69,7% vs 18,2%, p=0,019).ConclusionsIL-22 expression in lung cancer tissue of early-stage NSCLC was significantly higher in men, lung adenocarcinoma, current smokers and showed a trend to be higher in NSCLC patients with concomitant COPD compared to NSCLC without COPD. Our findings indicate that IL-22 may represent a promising therapeutic target for NSCLC.ReferencesDurham AL, Adcock IM. The relationship between COPD and lung cancer. Lung Cancer. 2015 Nov;90(2):121–7.Guillon A, Gueugnon F, et al. Interleukin-22 receptor is overexpressed in non small cell lung cancer and portends a poor prognosis. Eur Respir J. 2016 Apr;47(4):1277–80.