Fluorescent protein tagging promotes phase separation and alters the aggregation pathway of huntingtin exon-1.

Fluorescent protein tags are convenient tools for tracking the aggregation states of amyloidogenic or phase separating proteins, but the effect of the tags is often not well understood. Here, we investigated the impact of a C-terminal red fluorescent protein (RFP) tag on the phase separation of huntingtin exon-1 (Httex1), an N-terminal portion of the huntingtin protein that aggregates in Huntington's disease. We found that the RFP-tagged Httex1 rapidly formed micron-sized, phase separated states in the presence of a crowding agent. The formed structures had a rounded appearance and were highly dynamic according to electron paramagnetic resonance and fluorescence recovery after photobleaching, suggesting that the phase separated state was largely liquid in nature. Remarkably, the untagged protein did not undergo any detectable liquid condensate formation under the same conditions. In addition to strongly promoting liquid-liquid phase separation, the RFP tag also facilitated fibril formation, as the tag-dependent liquid condensates rapidly underwent a liquid-to-solid transition. The rate of fibril formation under these conditions was significantly faster than that of the untagged protein. When expressed in cells, the RFP-tagged Httex1 formed larger aggregates with different antibody staining patterns compared to untagged Httex1. Collectively, these data reveal that the addition of a fluorescent protein tag significantly impacts liquid and solid phase separations of Httex1 in vitro and leads to altered aggregation in cells. Considering that the tagged Httex1 is commonly used to study the mechanisms of Httex1 misfolding and toxicity, our findings highlight the importance to validate the conclusions with untagged protein.

Real World Data Studies of Antineoplastic Drugs: How Can They Be Improved to Steer Everyday Use in the Clinic?

There is a growing interest in real world evidence when developing antineoplastic drugs owing to the shorter length of time and low costs compared to randomised controlled trials. External validity of studies in the regulatory phase can be enhanced by complementing randomised controlled trials with real world evidence. Furthermore, the use of real world evidence ensures the inclusion of patients often excluded from randomised controlled trials such as the elderly, certain ethnicities or those from certain geographical areas. This review explores approaches in which real world data may be integrated with randomised controlled trials. One approach is by using big data, especially when investigating drugs in the antineoplastic setting. This can even inform artificial intelligence thus ensuring faster and more precise diagnosis and treatment decisions. Pragmatic trials also offer an approach to examine the effectiveness of novel antineoplastic drugs without evading the benefits of randomised controlled trials. A well-designed pragmatic trial would yield results with high external validity by employing a simple study design with a large sample size and diverse settings. Although randomised controlled trials can determine efficacy of antineoplastic drugs, effectiveness in the real world may differ. The need for pragmatic trials to help guide healthcare decision-making led to the development of trials within cohorts (TWICs). TWICs make use of cohorts to conduct multiple randomised controlled trials while maintaining characteristics of real world data in routine clinical practice. Although real world data is often affected by incomplete data and biases such as selection and unmeasured biases, the use of big data and pragmatic approaches can improve the use of real world data in the development of antineoplastic drugs that can in turn steer decision-making in clinical practice.

Use of Antiepileptic Drugs and Risk of Prostate Cancer: A Nationwide Case-Control Study in Prostate Cancer Data Base Sweden.

An inverse association between use of antiepileptic drugs (AEDs) and prostate cancer (PCa) has been suggested, putatively due to the histone deacetylases inhibitory (HDACi) properties of the AEDs. In a case-control study in Prostate Cancer data Base Sweden (PCBaSe), PCa cases diagnosed between 2014 and 2016 were matched to five controls by year of birth and county of residence. AED prescriptions were identified in the Prescribed Drug Registry. Odds ratios (ORs) and 95% confidence intervals for risk of PCa were estimated using multivariable conditional logistic regression, adjusted for civil status, education level, Charlson comorbidity index, number of outpatient visits, and cumulative duration of hospital stay. Dose responses in different PCa risk categories and HDACi properties of specific AED substances were further explored. 1738/31591 (5.5%) cases and 9674/156802 (6.2%) controls had been exposed to AED. Overall, users of any AED had a reduced risk of PCa as compared to nonusers (OR: 0.92; 95% CI: 0.87-0.97) which was attenuated by adjustment to healthcare utilisation. A reduced risk was also observed in all models for high-risk or metastatic PCa in AED users compared to nonusers (OR: 0.89; 95% CI: 0.81-0.97). No significant findings were observed for dose response or HDACi analyses. Our findings suggest a weak inverse association between AED use and PCa risk, which was attenuated by adjustment for healthcare utilisation. Moreover, our study showed no consistent dose-response pattern and no support for a stronger reduction related to HDAC inhibition. Further studies focusing on advanced PCa and PCa treatments are needed to better analyse the association between use of AED and risk of PCa.

Incidence and survival of neuroendocrine neoplasia in England 1995-2018: A retrospective, population-based study.

Background: Neuroendocrine neoplasia (NEN) incidence is rising internationally. We aimed to evaluate the epidemiology of NEN in England and examine changes in survival over time. Methods: A retrospective, population-based study using nationally representative data between 1995 and 2018 from the National Cancer Registry and Analysis Service (NCRAS) in England was conducted on 63,949 tumours. Age-standardized incidence was calculated using Office for National Statistics (ONS) data. Overall survival (OS) was calculated using the Kaplan-Meier estimator. Multivariable analysis was performed using an accelerated failure time model. Findings: Of 63,949 cases, 50.5% (32,309) were female. Age-adjusted incidence increased 3.7-fold between 1995 and 2018 from 2.35 to 8.61 per 100,000. In 2018, highest incidence occurred in lung (1.47 per 100,000), small intestine (1.46 per 100,000), pancreas (1.00 per 100,000) and appendix (0.95 per 100,000). In multivariable analysis, age, sex, morphology, stage, site and deprivation were independent predictors of survival (p < 0.001). Survival of the entire cohort, and by primary site, is improving over time. Interpretation: NEN incidence continues to rise in England with survival improving over time. Relatively high survival compared to other cancers is an issue for long-term outcomes and funding of care. Funding: Data were extracted and transferred using a grant from Neuroendocrine cancer UK.

Qualitative Analysis of Interviews and Focus Groups Exploring Factors Contributing to Adherence to GnRH Agonists in Men with Prostate Cancer.

OBJECTIVES: Side effects from the prolonged use of gonadotropin-releasing hormone (GnRH) agonists may lead to nonadherence to the treatment in men with advanced prostate cancer (PCa). We investigated the reasons contributing to nonadherence to GnRH agonists through interviews with men with PCa and focus groups with their health care professionals. DATA SOURCES: The three stages of the study were validation of themes, interviews with men on GnRH agonists, and focus groups with oncology specialists and clinical nurse specialists. An experienced oncologist validated factors contributing to nonadherence identified from the literature. A total of 10 men with PCa were recruited from a large teaching hospital and were interviewed on a one-to-one basis using a topic guide. In stage three, two separate focus groups were held with oncology specialists and clinical nurse specialists treating men with PCa. The interviews and focus groups were audio recorded and transcribed verbatim. Initial codes identified from stage three were grouped into themes and thematically analyzed. CONCLUSION: Themes identified from the interviews and focus groups influencing adherence to treatment were side effects of treatment, patient belief system, benefits outweigh harm, quality of life over quantity of life, social support, and patient-clinician relationship. Although side effects such as hot flushes and loss of libido were sometimes overwhelming for many, these men felt that treatment benefits outweighed harm. IMPLICATIONS FOR NURSING PRACTICE: Reasons leading to nonadherence can be multifactorial and unique to each patient. Employing different strategies by health care professionals may lead to the eventual acceptance of treatment, while also acknowledging their reasons for nonadherence.

Predicting response to neoadjuvant chemotherapy in patients with oesophageal adenocarcinoma.

BACKGROUND: Neoadjuvant chemotherapy is often used prior to surgical resection for oesophageal adenocarcinoma but remains ineffective in a high proportion of patients. The histological Mandard tumour regression grade is used to determine chemoresponse but is not available at the time of treatment decision-making. The aim of this cohort study was to identify factors that predict chemotherapy response prior to surgery. METHODS: A prospectively collected database of patients undergoing surgical resection for oesophageal adenocarcinoma from a high-volume UK institution was used. Patients were subcategorised using pathological tumour response into 'responders' (Mandard grade 1-3) and 'non-responders' (Mandard grade 4 and 5). Multivariable logistic regression analysis was performed to calculate crude and adjusted odds ratios (OR) with 95% confidence intervals (CI) for responder status adjusting for a variety of parameters. Receiver operating characteristic (ROC) curves were calculated. RESULTS: Among 315 patients included, 102 (32%) were responders and 213 (68%) non-responders. A decrease in radiological tumour volume (OR 1.92 95%CI 1.02-3.62; p = 0.05), a 'partial response' RECIST score (OR 7.16 95%CI 1.49-34.36; p = 0.01), a clinically improved dysphagia score (OR 2.79 95%CI 1.05-7.04; p = 0.04) and lymphovascular invasion (OR 0.06 95%CI 0.02-0.13; p = 0.000) influenced responder status. ROC curve analysis for responder status utilising all available parameters had an area under the curve (AUC) of 0.86. CONCLUSION: This study has highlighted the potential for using pre-defined factors to identify those patients who have responded to neoadjuvant chemotherapy, prior to surgical resection, potentially facilitating a more individualised therapeutic approach.

Is there a role for physical activity when treating patients with cancer with immune checkpoint inhibitors? Protocol for a scoping review.

INTRODUCTION: For patients with cancer, immune checkpoint inhibitors (ICIs) produce superior long-term responses compared with alternative treatments, although at the cost of manifesting adverse immune-related events. There are many hypotheses of the impacts of physical activities in immunotherapy, but little is known about the oncological outcomes and the underlying mechanisms. This scoping review aims to identify possible physical activity interventions, their efficacy and feasibility and the potential underlying biological mechanisms responsible for their effects. METHOD AND ANALYSIS: The Levac methodology framework was used along with guidance from the Joanna Briggs Institute Manual for Evidence Synthesis to inform development of this protocol. Abstracts and titles followed by full-text screening will be performed by two independent reviewers for inclusion. All studies describing the impact of physical activities and exercise interventions on cancer ICIs, with particular focus on oncological outcomes, quality of life or underling biological mechanisms, will be included. After extracting qualitative and quantitative data, they will be evaluated and summarised, respectively. Subsequently, a further consultation step with other scientists and healthcare professionals will be performed. ETHICS AND DISSEMINATION: The research findings will be published through an open-access peer-reviewed journal. The results of this scoping review will be used to inform further studies on physical impacts on immunotherapy. All data included will be from open resources, therefore, no ethical clearances are required.

Real-world outcomes associated with new cancer medicines approved by the Food and Drug Administration and European Medicines Agency: A retrospective cohort study.

PURPOSE: Real-World Data (RWD) studies are increasingly used to support regulatory approvals, reimbursement decisions, and changes in clinical practice for novel cancer drugs. However, few studies have systematically appraised their quality or compared outcomes to pivotal trials. METHODS: All RWD studies (2010-2019) for drugs approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) from 2010 to 2015 for solid organ tumours in the non-curative setting were identified. Quality assessment was undertaken using the Newcastle Ottawa Scale. Survival differences between each RWD study and the pivotal trial were determined using a related sample Wilcoxon signed-rank test. RESULTS: 293 RWD studies for 45 of the 57 drug indications approved by the FDA/EMA were identified. The most common tumour types were prostate cancer (29%, n = 86) and melanoma (15%, n = 43). A quarter of the studies had industry funding. No high-quality studies were identified, and 78% were low quality. Comparative survival analysis between RWD and pivotal trials was possible for 224 studies (37 drug indications). Differences in median survival between the RWD studies and their corresponding trial ranged from -32 months to 21 months (IQR -4·2 months to 1·6 months). Low-quality studies were more likely to report superior survival outcomes (23%) compared to higher quality studies (8%) (p = 0.02). CONCLUSION: RWD study quality for novel cancer drugs is low and of insufficient rigour to inform reimbursement decisions and clinical practice. RWD studies seeking publication should provide a completed quality assessment tool on submission. Greater investment in properly designed RWD studies is required.

Risk of COVID-19 death in cancer patients: an analysis from Guy's Cancer Centre and King's College Hospital in London.

BACKGROUND: Using an updated dataset with more patients and extended follow-up, we further established cancer patient characteristics associated with COVID-19 death. METHODS: Data on all cancer patients with a positive reverse transcription-polymerase chain reaction swab for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) at Guy's Cancer Centre and King's College Hospital between 29 February and 31 July 2020 was used. Cox proportional hazards regression was performed to identify which factors were associated with COVID-19 mortality. RESULTS: Three hundred and six SARS-CoV-2-positive cancer patients were included. Seventy-one had mild/moderate and 29% had severe COVID-19. Seventy-two patients died of COVID-19 (24%), of whom 35 died <7 days. Male sex [hazard ratio (HR): 1.97 (95% confidence interval (CI): 1.15-3.38)], Asian ethnicity [3.42 (1. 59-7.35)], haematological cancer [2.03 (1.16-3.56)] and a cancer diagnosis for >2-5 years [2.81 (1.41-5.59)] or ≥5 years were associated with an increased mortality. Age >60 years and raised C-reactive protein (CRP) were also associated with COVID-19 death. Haematological cancer, a longer-established cancer diagnosis, dyspnoea at diagnosis and raised CRP were indicative of early COVID-19-related death in cancer patients (<7 days from diagnosis). CONCLUSIONS: Findings further substantiate evidence for increased risk of COVID-19 mortality for male and Asian cancer patients, and those with haematological malignancies or a cancer diagnosis >2 years. These factors should be accounted for when making clinical decisions for cancer patients.

The incidence and prevalence of upper tract urothelial carcinoma: a systematic review.

BACKGROUND: Upper tract urothelial carcinoma (UTUC) is a rare urological cancer that is still an important public health concern in many areas around the world. Although UTUC has been linked to a number of risk factors, to our knowledge no systematic review has been published on the overall incidence and prevalence of de-novo UTUC. This review aimed to examine the global epidemiology of UTUC to provide clinicians and public health specialists a better understanding of UTUC. METHODS: A systematic search was conducted on MEDLINE, Embase, and the Web of Science using a detailed search strategy. Observational epidemiological studies describing the incidence and prevalence of de-novo UTUC in adults were included, and the Joanna Briggs Institute checklist was used for critical appraisal and data extraction of the studies selected. RESULTS: The systematic search identified 3506 papers, of which 59 papers were included for qualitative synthesis. The studies selected included data ranging from the years 1943 to 2018. A comprehensive qualitative synthesis of the data was performed. UTUC incidence generally varied according to age (higher with increasing age), sex (unclear), race (unclear), calendar time (increased, stable, or decreased according to region), geographical region (higher in Asian countries), occupation (higher in seamen and printers), and other population characteristics. Prevalence was only reported by one study, which showed UTUC to have the highest incidence of the rare urogenital cancers in Europe. CONCLUSION: This systematic review highlights an increased incidence of UTUC in certain groups, including increasing age and certain occupations such as seamen. The incidence of UTUC also varies between certain geographical regions. The trend of UTUC incidence for sex, race, and calendar time is less clear due to a wide variety of metrics used by the studies identified. More studies are also required on the prevalence of UTUC to understand its disease burden. Trial registration This review was registered on PROSPERO (registration number CRD42019134255).

Erectile Function Following Surgery for Benign Prostatic Obstruction: A Systematic Review and Network Meta-analysis of Randomised Controlled Trials.

CONTEXT: Benign prostatic obstruction (BPO) is associated with sexual dysfunction. Furthermore, numerous BPO interventions may themselves impact sexual function. OBJECTIVE: To perform a systematic review with network meta-analysis to evaluate how BPO interventions affect erectile function. EVIDENCE ACQUISITION: Three databases were searched for randomised controlled trials (RCTs) comparing surgical interventions for BPO. The primary outcome was postoperative International Index of Erectile Function-5 (IIEF-5) score at ten time points up to 72 mo. A random-effects Bayesian network meta-analysis with meta-regression was performed. In comparison to monopolar transurethral resection (mTURP), the mean difference (MD) with 95% credible interval (CrI) and rank probability (rank p) were calculated for interventions. The mean baseline score was studied in meta-regression. τ2 values were used to quantify heterogeneity. EVIDENCE SYNTHESIS: A total of 48 papers (33 RCTs, 5159 patients, 16 interventions) were included. Prostatic urethral lift (PUL) ranked highest at 1 mo (MD 3.88, 95% CrI -0.47 to 8.25; rank p = 0.742), 6 mo (MD 2.43, 95% CrI -0.72 to 5.62; rank p = 0.581), 12 mo (MD 2.94, 95% CrI -0.26 to 6.12, rank p = 0.782), and 24 mo (MD 3.63, 95% CrI 0.14 to 7.11; rank p = 0.948), at which point statistical significance was reached. At time points up to 60 mo, there were no statistically significant comparisons for other interventions. Analyses were not possible at 18, 48, or 72 mo. ß did not reach statistical significance in meta-regression. τ2 was highest at 1 mo (0.56) and 60 mo (0.55). CONCLUSIONS: PUL ranked highly and resulted in erectile function improvement at 24 mo compared to mTURP, but direct evidence is lacking. We did not observe significant differences in erectile function following other interventions up to 60 mo. Owing to heterogeneity, our conclusions are weakest at 1 and 60 mo. Further RCTs comparing sexual function outcomes are recommended, such as PUL versus holmium laser or bipolar enucleation. PATIENT SUMMARY: Different surgical treatments can be used to treat benign enlargement of the prostate causing urinary problems. We compared the effects of various treatments on erectile function at time points up to 5 years after surgery. Compared to surgical removal of some of the prostate gland (transurethral resection of the prostate, TURP), a technique called prostatic urethral lift resulted in better erectile function scores at 24 months. However, other treatments did not differ in their effect on erectile function.

Risk of cardiovascular events in men on abiraterone or enzalutamide combined with GnRH agonists: nation-wide, population-based cohort study in Sweden.

BACKGROUND: Men with prostate cancer (PCa) on gonadotropin-releasing hormone agonists (GnRH) have an increased risk of cardiovascular disease (CVD) compared to men with PCa not on GnRH as well as compared with PCa-free men. Whether the addition of androgen receptor targeted (ART) drugs to GnRH further increases CVD risk, remains to be fully elucidated. MATERIAL AND METHODS: We investigated risk of CVD for men with castration resistant PCa (CRPC) on GnRH plus ART; abiraterone or enzalutamide vs 5,127 and 12,079 respective matched comparator men on GnRH in Prostate Cancer data Base Sweden (PCBaSeTraject) 4.1 between 1 June 2015 and 31 December 2018. PCBaSeTraject links National Prostate Cancer Register of Sweden to other healthcare registries and demographic databases. We conducted multivariable Cox proportional hazard models adjusting for PCa risk category, Charlson comorbidity index (CCI), insulin or statin use, civil status, level of education, history of CVD events and number of CVD drugs, with any incident or fatal CVD as the outcome. RESULTS AND CONCLUSION: 1,310 men were treated with abiraterone and 3,579 with enzalutamide. In multivariable analysis, CVD risk was increased in men on abiraterone (hazard ratio (HR): 1.19; 95% confidence interval (CI): 1.03-1.38) and in men on enzalutamide (HR: 1.10; 95% CI: 1.01-1.20). Men with a recent CVD (<12 months) including both men on ART as well as comparators had a much higher probability of a new CVD vs men with no prior CVD. CVD risk was mildly increased in men with PCa on GnRH plus abiraterone or enzalutamide vs comparator men on GnRH. Residual confounding and detection bias may at least partly explain this association.

Depression, anxiety, and suicidality in patients with prostate cancer: a systematic review and meta-analysis of observational studies.

BACKGROUND: Psychiatric implications of prostate cancer are increasingly recognised, having important effects on oncological and functional outcomes. However, findings for co-occurring depression, anxiety, and suicidality remain variable. Therefore, this review of observational studies aimed to establish best estimates of the prevalence and rates of these outcomes in prostate cancer patients. METHODS: A systematic literature search was conducted using MEDLINE, Scopus, PsycInfo, and Cochrane Library databases from inception up to 26 May 2020. Observational studies using validated methods for evaluating prevalences of depression, anxiety and suicidal ideation, or suicide mortality rates post prostate cancer diagnosis were included. Random effect models were used to calculate pooled prevalences of depressive and anxiety symptoms or disorders, and suicidal ideation post diagnosis. Additionally, pooled crude suicide mortality rates per 100,000 person years were calculated. Heterogeneity was explored using a stratified analysis. RESULTS: Of 3537 articles screened, 117 were included. Pooled prevalence for depressive disorders was 5.81% (95% CI 4.36-7.46) in 11 studies, representing 655,149 patients. Significant depressive symptoms were identified in 17.07% (15.14-19.09) across 32,339 patients and 76 studies. In total, 16.86% (14.92-18.89) had significant anxiety symptoms in 56 studies combining 24,526 patients. In 6,173 patients and eight studies, recent suicidal ideation was present in 9.85% (7.31-12.70). Crude suicide mortality rate after diagnosis was 47.1 (39.85-54.96) per 100,000 person years in 12 studies. Significant heterogeneity was seen with potential sources identified through our sensitivity analysis including diagnostic method utilised, study size and location of study. CONCLUSIONS: The mental health impact in patients with prostate cancer is significant. Depressive, anxiety, and suicidal symptoms were common. Additionally, a high suicide mortality rate was identified when compared to general population estimates. Screening of patients and integration of physical and mental health care should be evaluated further to improve quality of life and functional outcomes.

Risk of cardiovascular disease following gonadotropin-releasing hormone agonists vs antagonists in prostate cancer: Real-world evidence from five databases.

Observational studies in prostate cancer (PCa) have shown an increased risk of cardiovascular disease (CVD) following gonadotropin-releasing hormone (GnRH) agonists, whereas randomised-controlled trials have shown no associations. Compared to GnRH agonists, GnRH antagonists have shown less atherosclerotic effects in preclinical models. We used real-world data from five countries to investigate CVD risk following GnRH agonists and antagonists in PCa men. Data sources included cancer registries, primary and secondary healthcare databases. CVD event was defined as an incident or fatal CVD. Multivariable Cox proportional hazard models estimated hazard ratios (HRs) and 95% confidence intervals (CIs), which were pooled using random-effects meta-analysis. Stratified analyses were conducted by history of CVD and age (75 years). A total of 48 757 men were on GnRH agonists and 2144 on GnRH antagonists. There was no difference in risk of any CVD for men on GnRH antagonists and agonists (HR: 1.25; 95% CI: 0.96-1.61; I2 : 64%). Men on GnRH antagonists showed increased risk of acute myocardial infarction (HR: 1.62; 95% CI: 1.11-2.35; I2 : 0%) and arrhythmia (HR: 1.55; 95% CI: 1.11-2.15, I2 : 17%) compared to GnRH agonists. Having a history of CVD was found to be an effect modifier for the associations with some CVD subtypes. Overall, we did not observe a difference in risk of overall CVD when comparing GnRH antagonists with agonists-though for some subtypes of CVD we noted an increased risk with antagonists. Further studies are required to address potential confounding caused by unadjusted variables such as severity of CVD history and PCa stage.

An Amphipathic Alpha-Helix Domain from Poliovirus 2C Protein Tubulate Lipid Vesicles.

Positive-strand RNA viruses universally remodel host intracellular membranes to form membrane-bound viral replication complexes, where viral offspring RNAs are synthesized. In the majority of cases, viral replication proteins are targeted to and play critical roles in the modulation of the designated organelle membranes. Many viral replication proteins do not have transmembrane domains, but contain single or multiple amphipathic alpha-helices. It has been conventionally recognized that these helices serve as an anchor for viral replication protein to be associated with membranes. We report here that a peptide representing the amphipathic α-helix at the N-terminus of the poliovirus 2C protein not only binds to liposomes, but also remodels spherical liposomes into tubules. The membrane remodeling ability of this amphipathic alpha-helix is similar to that recognized in other amphipathic alpha-helices from cellular proteins involved in membrane remodeling, such as BAR domain proteins. Mutations affecting the hydrophobic face of the amphipathic alpha-helix severely compromised membrane remodeling of vesicles with physiologically relevant phospholipid composition. These mutations also affected the ability of poliovirus to form plaques indicative of reduced viral replication, further underscoring the importance of membrane remodeling by the amphipathic alpha-helix in possible relation to the formation of viral replication complexes.

Associations between immune-suppressive and stimulating drugs and novel COVID-19-a systematic review of current evidence.

BACKGROUND: Cancer and transplant patients with COVID-19 have a higher risk of developing severe and even fatal respiratory diseases, especially as they may be treated with immune-suppressive or immune-stimulating drugs. This review focuses on the effects of these drugs on host immunity against COVID-19. METHODS: Using Ovid MEDLINE, we reviewed current evidence for immune-suppressing or -stimulating drugs: cytotoxic chemotherapy, low-dose steroids, tumour necrosis factorα (TNFα) blockers, interlukin-6 (IL-6) blockade, Janus kinase (JAK) inhibitors, IL-1 blockade, mycophenolate, tacrolimus, anti-CD20 and CTLA4-Ig. RESULTS: 89 studies were included. Cytotoxic chemotherapy has been shown to be a specific inhibitor for severe acute respiratory syndrome coronavirus in in vitro studies, but no specific studies exist as of yet for COVID-19. No conclusive evidence for or against the use of non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of COVID-19 patients is available, nor is there evidence indicating that TNFα blockade is harmful to patients in the context of COVID-19. COVID-19 has been observed to induce a pro-inflammatory cytokine generation and secretion of cytokines, such as IL-6, but there is no evidence of the beneficial impact of IL-6 inhibitors on the modulation of COVID-19. Although there are potential targets in the JAK-STAT pathway that can be manipulated in treatment for coronaviruses and it is evident that IL-1 is elevated in patients with a coronavirus, there is currently no evidence for a role of these drugs in treatment of COVID-19. CONCLUSION: The COVID-19 pandemic has led to challenging decision-making about treatment of critically unwell patients. Low-dose prednisolone and tacrolimus may have beneficial impacts on COVID-19. The mycophenolate mofetil picture is less clear, with conflicting data from pre-clinical studies. There is no definitive evidence that specific cytotoxic drugs, low-dose methotrexate for auto-immune disease, NSAIDs, JAK kinase inhibitors or anti-TNFα agents are contraindicated. There is clear evidence that IL-6 peak levels are associated with severity of pulmonary complications.

Association of Serum Immunoglobulin Levels with Solid Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: The nature of humoral immunity in carcinogenesis remains poorly understood. In this systematic review and meta-analysis, we aimed to evaluate the association of serum immunoglobulin classes with solid cancer and test our hypothesis that the immune escape of tumors is accompanied by dysregulated systemic immunoglobulin class-switching. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we systematically searched the Cochrane Library, Embase, and MEDLINE/PubMed databases for observational studies investigating the association between serum immunoglobulins (IgA, IgG, and IgM) and histologically confirmed diagnosis of solid cancer in adults. We selected case-control studies, including more than 20 cases, and those explicitly stating that no form of anticancer treatment was administered prior to immunoglobulin measurement. No eligible cohort studies were identified. The primary summary measure was the standardized mean difference (SMD) with 95% confidence intervals (CI) calculated using a random effects model. RESULTS: Pooling 11 eligible studies comparing serum IgA levels in 1,351 patients and 560 control subjects revealed a statistically significant SMD (1.50; 95% CI, 0.96-2.04). Nonsignificant SMDs were observed for the 14 selected studies investigating serum IgG [SMD, -0.02 (95% CI, -0.22 to 0.18)] and for the 10 studies reporting serum IgM [SMD, 0.11 (95% CI, -0.10 to 0.32)]. Substantial heterogeneity between studies was observed despite sensitivity analysis by immunoglobulin measurement method, control matching, type of cancer, stage of disease, and sequential study exclusion. CONCLUSIONS: Serum immunoglobulin levels in patients diagnosed with solid cancer might be skewed toward class-switching to IgA, possibly reflecting Th2-polarized immunity. IMPACT: Further combinatorial analyses of serum immunoglobulin isotypes alongside other immune parameters in databases and observational studies are warranted.

Long-term adherence to GnRH agonists in men with prostate cancer. A nation-wide population-based study in prostate cancer data base Sweden.

Aim: Gonadotropin-releasing hormone (GnRH) agonists are used to treat men with prostate cancer (PCa). To date, no study has fully assessed patterns of adherence to GnRH agonists. We investigated patterns of adherence to GnRH agonists using data from Prostate Cancer data Base Sweden (PCBaSe).Methods: PCBaSe links the National Prostate Cancer Register (NPCR) Sweden to other healthcare registers and demographic databases. Men on primary or secondary GnRH agonists between 2006-2013 entered the study 45 days after GnRH agonists' initiation (run-in period) and exited at 3 years. Medication possession ratio quantified adherents (≥80%). Multivariable logistic regression models included age, injection interval, PCa risk categories, Charlson Comorbidity Index, prior PCa treatment, civil status and year of GnRH initiation. Odds ratios (OR) and 95% confidence intervals (CI) expressed odds of adherence.Results: Men on primary GnRH agonists (n = 8,105) were more adherent with increasing age (75-84 years compared to ≤65 years OR: 1.49; 95% CI: 1.23-1.81), longer injection intervals (365 days compared to 90 days OR: 3.29; 95% CI: 2.52-4.30) and higher PCa risk categories at diagnosis (distant metastasis compared to low risk PCa OR: 3.56; 95% CI: 2.54-5.00). Men on secondary GnRH agonists (n = 4,738) were more adherent with increasing age (≥85 years compared to ≤65 years OR: 1.65; 95% CI: 1.23-2.22) and prior PCa treatment (anti-androgens compared to deferred treatment OR: 1.50; 95% CI: 1.23-1.82), (radiotherapy compared to deferred treatment OR: 1.35; 95% CI: 1.11-1.64).Conclusions: Longer injection intervals could be addressed in the clinical setting to improve adherence.

Real-world insights into risk of developing cardiovascular disease following GnRH agonists versus antagonists for prostate cancer: a methodological protocol to a study using five European databases.

One of the more recently investigated adverse long-term side effects of gonadotropin-releasing hormone (GnRH) agonists for prostate cancer (PCa) is cardiovascular disease (CVD). Studies suggest lower risk of CVD following GnRH antagonists (degarelix) than GnRH agonists. This protocol describes precise codes used to extract variables from five European databases for a study that compares risk of CVD following GnRH agonists and antagonists for PCa. PCa men on primary GnRH agonists or antagonists were identified from the UK THIN (The Health Improvement Network) database, National Health Service (NHS) Scotland, Belgian Cancer Registry (BCR), Dutch PHARMO Database Network and French National Database (SNIIRAM). Cohort entry was defined as date of treatment initiation. CVD event was defined as any first incident or fatal CVD after cohort entry. Readcodes in THIN and ICD codes in NHS Scotland, BCR, PHARMO and SNIIRAM were used to extract variables. Risk of Bias in Non-randomised studies of Interventions (ROBINS-I) tool was used to assess the potential risk of biases in this study. 51 572 men with a median follow-up time of 2 years started on GnRH agonists and 2 417 men with a median follow-up time of 1 year started on GnRH antagonists between 2010 and 2017 in the UK, Scotland, Belgium, the Netherlands and France. Data from five countries improved the study power and internal validity required to compare risk of CVD between GnRH agonists and antagonists, the latter being a fairly new drug with limited data in individual countries.

Construction of Parkinson's disease marker-based weighted protein-protein interaction network for prioritization of co-expressed genes.

BACKGROUND: Parkinson's disease (PD) is a complex neurodegenerative movement disorder that primarily results due to the loss of dopaminergic neurons in the substantia nigra region. Studying gene expression in the substantia nigra region would potentially unravel disease-relevant protein-protein interactions. METHODS: In this study we have used network science approach to prioritize candidate genes by focussing on differentially expressed genes (DEGs) that interact with established PD associated-genes (PDAG). Prioritizing genes that interact with already established PDAG would reduce the probability of spurious protein-protein associations. The dataset GSE54282 with Parkinson's disease affected substantia nigra samples was extracted from Gene Expression Omnibus (GEO) database. Protein-Protein Interaction Network (PPIN) was constructed by retrieving all possible interactions between DEGs from high-throughput experiments and literature data using Bisogenet. This complex PPIN was decomposed to construct a subnetwork of Parkinson's Disease-Protein Interaction Map (PD-PIM) by including PDAG and following well-established concepts of network biology such as degree and betweenness centrality. We then implemented a "two-way analysis" where we selected genes belonging to PDPIM subnetwork with their primary interacting partners and highly coexpressed genes on the basis of Pearson score. RESULTS: A complex PPIN comprised of 5340 nodes (genes) and 39,199 edges (interactions) was obtained. A list of 205 genes (123 PDAGs, 69 hub genes and 13 bottleneck genes) with their respective first level interacting partners were extracted from PPIN interactome to build a PD-specific subnetwork, PD-PIM. This subnetwork PD-PIM comprised of 5078 nodes and 38,357 edges. We then employed a "two-way" gene prioritization method that delineated 267 genes of which 16 genes were found to intersect in the two networks of the "two-way analysis". Of the 16 genes, we narrowed down to 7 novel candidate genes (VCAM1, BACH1, CALM3, EGR1, IKBKE, MYC and YWHAG) displaying significant changes in their network interactions between control and disease samples. Interestingly, these genes were associated with neuroinflammation signaling pathway, MAPK signaling apoptosis pathway, movement disorders and development of neurons that are linked with development of PD. CONCLUSION: We propose that VCAM1, BACH1, CALM3, EGR1, IKBKE, MYC and YWHAG genes might play important roles in PD pathogenesis, as well as facilitate the development of effective targeted therapies. Our integrative and network based approach for finding therapeutic targets in genomic data could accelerate the identification of novel drug targets for Parkinson's disease.