Mayra Pacheco Pachado

We hardly comprehend any disease mechanistically, meaning most disease definitions are organ- and symptom-based and fail to represent the underlying mechanism of the disease. Current therapies can thus only treat symptoms chronically yielding unprecise and low patient-relevant outcomes ( 1, 2). Symptom-based disease definitions also have the risk of agglutinating different molecular mechanisms that cause similar symptoms under umbrella disease terms. As a result, they are combined into a single common and complex disease entity that is impossible to untangle with present diagnostic methods. Contrarily, apparently unrelated disease phenotypes co-occur in the same patient beyond chance, which may indicate shared causal mechanisms ( 3). Thus, in order to reach precision medicine and to achieve treatment accuracy, we must first determine the underlying disease mechanism and endotype patients based on the cause of the disease. This approach will redefine diseases, shifting the focus from symptoms and affected organs to the underlying mechanisms and causes ( 4). Here, we investigate one of the best studied diseasome clusters of fourteen heterogeneous cardiovascular, neuro-psychiatric, metabolic and pulmonary comorbid disease phenotypes of unmet medical need, defined - at least in part - by reactive oxygen species ( ROS)-induced dysfunction of and cGMP signaling (ROCG) ( 5, 6). Previously, we have shown that NADPH oxidase 5 (NOX5) levels in endothelial microparticles were able to identify the ROCG endotype in hypertensive patients ( 7). Here, we used a high-throughput screening plasma antibody assay to measure NOX5 plasma levels and analyze over 1,000 human samples of the ROCG cluster in collaboration with the Estonian biobank to identify the prevalence of the ROCG endotype. Stratifying patients according to both phenotype and endotype will allow for high precision, i.e., low number needed to treat therapeutic interventions. These data show that even for supposedly complex diseases, endotyping for precision medicine and mechanistic disease re-definition is possible.

In Europe about 1% of people over the age of 60 are diagnosed with Parkinson’s disease (PD) with a tendency to increase, representing a major socioeconomic challenge ( 1, 2). PD is characterized by impaired movement control and progressively degenerating neurons in the substantia nigra of the brain. As a result, the amount of dopamine in the corpus striatum is lowered. Treatment options mainly center around substituting dopamine, a principle introduced in the 1960’s. Since then, no innovation has occurred. We question whether PD is a single disease. We hypothesize that PD’s comorbidities such as cognitive impairment, neuropsychiatric and autonomic symptoms and other comorbidities may lead towards a much better understanding of the presumably different underlying causal mechanisms. Histologically, PD is correlates with the accumulation of alpha-synuclein aggregates called Lewy Bodies that may spread in a characteristic fashion within the brain ( 5). Lewy Bodies are thought to contribute to the loss of dopaminergic neurons in the substantia nigra. However, whether this is a uniform and causal mechanism, its origin and role in disease progression are unclear ( 6, 7). Not knowing the underlying causality makes both early-stage diagnosis of PD and curative treatments impossible ( 8). Here we propose to define so-called disease modules ( 9) causally involved in different phenotypes of PD. Beginning with identified risk or PD associated genes, the resulting protein-protein interaction modules within the interactome, different signaling modules are constructed ( 10-12). The crucial point for building those disease modules is to identify the right set of seeds to begin with. This appears to be quite challenging due to the arbitrariness of different disease definitions and differences in genetic databases even for uniform disease ontologies. Even when using the same disease term, different databases including the Comparative Toxicogenomics Database (CTD), DisGeNET, OMIM, GWAS catalog, Open Target Genetics or Platform (OTG, OTP), the Catalogue of Somatic Mutations in Cancer (COSMIC) and the Cancer Genome Atlas Program (TCGA), yield different results, and thus suggesting entirely different starting points to define the disease modules. Using the PD term, six of these databases contain different number of genes: 129 (OTG), 386 (GWAS catalog), 435 (OTP), 474 (OMIM), 2,185 (DisGeNET) and 28,574 (CTD). Intersecting them shows generally low overlap between different databases and only 5 genes are shared across all databases. However, we know from other examples that even the consensus among different databases is misleading when compared to the gold standard, a systematic review followed by quantitative meta-analysis (SR/MA). Therefore, we propose to use a SR/MA of the entire literature also for PD to identify and rank disease genes, that can be further utilized for network analyses. In addition, the SR/MA can be further used to evaluate different databases.

Age-related loss of cognitive capacity and neurodegeneration have a great socioeconomical impact on our rapidly aging population. Despite numerous hypotheses, the causes for phenotypes currently termed as vascular dementia (vaD) and Alzheimer’s disease (AD) remain largely unknown. Currently approved drugs for dementias do not target causative mechanisms and only offer symptomatic relief with mild efficacy. Therefore, the identification of dementia causal mechanisms and the development of mechanism-based curative strategies are urgently needed. One common causal disease mechanism recently identified among dementias, cardiovascular, metabolic, respiratory, and other neurological conditions is related to reactive oxygen species (ROS) and cyclic GMP signaling (ROCG) dysfunction [1,2]. In patients with both vaD and AD, the impairment of this signaling pathway plays a crucial role in endothelial dysfunction, leading to reduced cerebral blood flow (CBF), impaired blood brain barrier (BBB), vascular lesions, and to AD-associated pathology amyloid-beta plaques and hyperphosphorylation of tau [3-6]. Here, our aim is to validate the efficacy of a network pharmacology approach, using repurposed drugs targeting the ROCG signaling module, to treat cerebrovascular dysfunction and cognitive impairment in a clinically relevant animal model Specifically, we will use the transgenic NADPH oxidase 5 (NOX5) KI/ apolipoprotein E (ApoE) KO mouse fed with a sodium-rich diet. Rodents lack the NOX5 gene, thus its insertion in the mouse is key due to its major role in the ROCG signaling and its association with disrupted BBB integrity and memory loss [7,8]. ApoE is a positive modulator of endothelial nitric oxide (NO) production and, functionally, loss of ApoE in mice results in attenuation of NO-cGMP dependent endothelial relaxation and reduction of CBF [9-11]. The inclusion of a diet rich in sodium, which in humans is a life-style factor shown to negatively impact cognition, is relevant as this diet impacts endothelial function via increased NOX-derived ROS and decreased endothelial NO synthase activity, leading to attenuated NO-dependent vasodilation [12-14]. By combining the genetic insertion of NOX5, deletion of ApoE and a specific diet, we aim to model ROCG dysfunction and its associated dementia-relevant pathophysiological features. Our purpose is to set the basis for a subsequent phase IIa clinical trial based on this first-in-class mechanism-based treatment for a mechanism-based subgroup of MCI and dementia. Through this proof-of-concept pre-clinical study we aim to acquire the necessary scientific data for the delivery of an innovative drug repurposing strategy with strong potential for clinical application and rapid translation. If demonstrated to be effective, this approach could benefit a subset of patients with ROCG signaling dysfunction, most likely with symptoms beyond cognitive impairment and in other organs, to improve with high precision their quality of life.

Genomic profiling has shown that not all cancer patients who share similar macro- and microscopical features harbour the same underlying molecular mechanism. This suggests the urge for matching patients to mechanism-based cancer therapies, independent of their primary tumour location and histology (Bashraheel et al. 2020). Currently, precision oncology trials provide personalised treatments based on the druggable variants found in a patient genetic makeup. Typically, those trials target single genetic variants (Schmidt et al. 2016; Murciano-Goroff et al. 2020) or provide combination therapies targeting single, mechanistically unrelated proteins which have been proven to be ineffective and or insufficient (Choobdar et al. 2019; Lazareva et al. 2021). In parallel, these variants are allocated to so-called canonical signalling pathways, e.g., KEGG pathways, Wiki Pathways. However, these are rather curated mind maps only combining similar signalling proteins or messengers. They do not represent true cellular signalling entities. Alternatively, signalling modules can be constructed in an unbiased manner from the interactome using validated seed proteins, also termed cancer driver genes, resulting in fragments and often mixtures of the above curated pathways (Nogales et al. 2022). These modules likely represent the true cancer mechanism and concerted network modulation with multiple mechanistically related drugs all acting on the same module i.e., network pharmacology, promise to be much more effective than targeting single unrelated variants (Cheng et al. 2019). As complex tumours will require multiple drugs targeting several modules (Sanchez-Vega et al. 2018), we start with low complexity tumours with a low mutational burden, e.g., thyroid cancer and diffuse intrinsic pontine gliomas (DIPG) (Vogelstein et al. 2013). Here, we (i) construct de-novo disease modules to identify drug targets and repurposable drugs, (ii) apply diagnostic assays to detect the patient-specific perturbed modules and (iii) decide on the therapeutic strategy to correct the modules using network pharmacology. Repurposable drugs are ranked based on clinical feasibility and other parameters. This allows a fundamentally new approach to cancer therapy often using low-side effect drugs acting in concert to improve patient survival and quality of life by implementing biology-informed drug interventions.

This study aimed to investigate the association between exposure to different types of child maltreatment (CM) and the development of substance use disorders (SUDs) later in life. A systematic review was conducted: the PubMed, EMBASE and PsycINFO databases were searched for relevant papers and ten studies were identified for further analysis. Random effects meta‐analyses were performed for each type of maltreatment in order to estimate the odds ratio (OR) for SUD incidence, and meta‐regressions were performed to explore potential moderators. Individuals with a history of physical abuse during childhood had a 74 per cent increased risk for drug abuse later in life (OR = 1.74, 95% confidence interval (CI) = 1.362.18). The risk for drug abuse was also 73 per cent higher in individuals with a history of sexual abuse during childhood (OR = 1.73, 95% CI = 1.242.41). A meta‐regression found that gender has a moderating effect, with women at a greater risk of SUD incidence compared to men. Exposure to CM, such as physical and sexual abuse in childhood, increases the risk of further substance abuse. Understanding the interplay between the different factors associated with violence and abuse of psychoactive substances is of fundamental importance in designing prevention approaches and interventions for drug users. ‘Investigate[s] the association between exposure to different types of child maltreatment and the development of substance use disorders later in life ’ Key Practitioner Messages: Child exposure to violence was associated with the development of substance use disorder. Exposure to violence affects men and women in a gender‐dependent manner, with females being at a higher risk. Understanding the interplay between the different factors associated with violence and drug abuse is of fundamental importance to design prevention approaches and interventions. Drug users have higher rates of child maltreatment and psychological suffering compared to the general population.

Crack cocaine users frequently report difficulties regarding having healthy and rewarding relationships. Factors other than the use of crack cocaine itself may be at play when it comes to being able to develop healthier connections with partners, adult relatives and close friends. To verify which factors, including demographics, substance abuse related factors and psychiatric comorbidities could be markers for a higher severity of problems in interpersonal relationships of crack cocaine users seeking for treatment. This was a cross-sectional study, conducted between April 2011 and November 2012. Participants were 407 crack cocaine users seeking treatment in specialized public facilities of six Brazilian capitals. The relationship of severity of problems in the family/social area and the prevalence of psychiatric disorders, exposure to stressful events, substance use related factors and practice of illicit activities were explored through multivariate analyses. Number of days using crack cocaine in the last 30 days, age of first time using alcohol and feeling its effects, a diagnosis of alcohol abuse, posttraumatic stress disorder, antisocial personality disorder and attention-deficit/hyperactivity disorder were significantly associated with a higher severity of problems in interpersonal relationships with partners, adult relatives and friends. Problems in interpersonal relationships are strongly related to specific psychiatric comorbidities and the frequency of crack cocaine use. Factors identified by this study can make the paths to recovery more challenging. These results support psychosocial interventions that focus in the improvement of interpersonal relationships of crack cocaine users.

Key words: Substance-related disorders; occupational health; mental health services; mental health personnel