Drug repositioning by merging active subnetworks validated in cancer and COVID-19.

Computational drug repositioning aims at ranking and selecting existing drugs for novel diseases or novel use in old diseases. In silico drug screening has the potential for speeding up considerably the shortlisting of promising candidates in response to outbreaks of diseases such as COVID-19 for which no satisfactory cure has yet been found. We describe DrugMerge as a methodology for preclinical computational drug repositioning based on merging multiple drug rankings obtained with an ensemble of disease active subnetworks. DrugMerge uses differential transcriptomic data on drugs and diseases in the context of a large gene co-expression network. Experiments with four benchmark diseases demonstrate that our method detects in first position drugs in clinical use for the specified disease, in all four cases. Application of DrugMerge to COVID-19 found rankings with many drugs currently in clinical trials for COVID-19 in top positions, thus showing that DrugMerge can mimic human expert judgment.

Finding disease modules for cancer and COVID-19 in gene co-expression networks with the Core&Peel method.

Genes are organized in functional modules (or pathways), thus their action and their dysregulation in diseases may be better understood by the identification of the modules most affected by the disease (aka disease modules, or active subnetworks). We describe how an algorithm based on the Core&Peel method is used to detect disease modules in co-expression networks of genes. We first validate Core&Peel for the general task of functional module detection by comparison with 42 methods participating in the Disease Module Identification DREAM challenge. Next, we use four specific disease test cases (colorectal cancer, prostate cancer, asthma, and rheumatoid arthritis), four state-of-the-art algorithms (ModuleDiscoverer, Degas, KeyPathwayMiner, and ClustEx), and several pathway databases to validate the proposed algorithm. Core&Peel is the only method able to find significant associations of the predicted disease module with known validated relevant pathways for all four diseases. Moreover, for the two cancer datasets, Core&Peel detects further eight relevant pathways not discovered by the other methods used in the comparative analysis. Finally, we apply Core&Peel and other methods to explore the transcriptional response of human cells to SARS-CoV-2 infection, finding supporting evidence for drug repositioning efforts at a pre-clinical level.

Distinct signatures of lung cancer types: aberrant mucin O-glycosylation and compromised immune response.

BACKGROUND: Genomic initiatives such as The Cancer Genome Atlas (TCGA) contain data from -omics profiling of thousands of tumor samples, which may be used to decipher cancer signaling, and related alterations. Managing and analyzing data from large-scale projects, such as TCGA, is a demanding task. It is difficult to dissect the high complexity hidden in genomic data and to account for inter-tumor heterogeneity adequately. METHODS: In this study, we used a robust statistical framework along with the integration of diverse bioinformatic tools to analyze next-generation sequencing data from more than 1000 patients from two different lung cancer subtypes, i.e., the lung adenocarcinoma (LUAD) and the squamous cell carcinoma (LUSC). RESULTS: We used the gene expression data to identify co-expression modules and differentially expressed genes to discriminate between LUAD and LUSC. We identified a group of genes which could act as specific oncogenes or tumor suppressor genes in one of the two lung cancer types, along with two dual role genes. Our results have been validated against other transcriptomics data of lung cancer patients. CONCLUSIONS: Our integrative approach allowed us to identify two key features: a substantial up-regulation of genes involved in O-glycosylation of mucins in LUAD, and a compromised immune response in LUSC. The immune-profile associated with LUSC might be linked to the activation of three oncogenic pathways, which promote the evasion of the antitumor immune response. Collectively, our results provide new future directions for the design of target therapies in lung cancer.

New functionalities in the TCGAbiolinks package for the study and integration of cancer data from GDC and GTEx.

The advent of Next-Generation Sequencing (NGS) technologies has opened new perspectives in deciphering the genetic mechanisms underlying complex diseases. Nowadays, the amount of genomic data is massive and substantial efforts and new tools are required to unveil the information hidden in the data. The Genomic Data Commons (GDC) Data Portal is a platform that contains different genomic studies including the ones from The Cancer Genome Atlas (TCGA) and the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiatives, accounting for more than 40 tumor types originating from nearly 30000 patients. Such platforms, although very attractive, must make sure the stored data are easily accessible and adequately harmonized. Moreover, they have the primary focus on the data storage in a unique place, and they do not provide a comprehensive toolkit for analyses and interpretation of the data. To fulfill this urgent need, comprehensive but easily accessible computational methods for integrative analyses of genomic data that do not renounce a robust statistical and theoretical framework are required. In this context, the R/Bioconductor package TCGAbiolinks was developed, offering a variety of bioinformatics functionalities. Here we introduce new features and enhancements of TCGAbiolinks in terms of i) more accurate and flexible pipelines for differential expression analyses, ii) different methods for tumor purity estimation and filtering, iii) integration of normal samples from other platforms iv) support for other genomics datasets, exemplified here by the TARGET data. Evidence has shown that accounting for tumor purity is essential in the study of tumorigenesis, as these factors promote confounding behavior regarding differential expression analysis. With this in mind, we implemented these filtering procedures in TCGAbiolinks. Moreover, a limitation of some of the TCGA datasets is the unavailability or paucity of corresponding normal samples. We thus integrated into TCGAbiolinks the possibility to use normal samples from the Genotype-Tissue Expression (GTEx) project, which is another large-scale repository cataloging gene expression from healthy individuals. The new functionalities are available in the TCGAbiolinks version 2.8 and higher released in Bioconductor version 3.7.

Computational Structural Biology of S-nitrosylation of Cancer Targets.

Nitric oxide (NO) plays an essential role in redox signaling in normal and pathological cellular conditions. In particular, it is well known to react in vivo with cysteines by the so-called S-nitrosylation reaction. S-nitrosylation is a selective and reversible post-translational modification that exerts a myriad of different effects, such as the modulation of protein conformation, activity, stability, and biological interaction networks. We have appreciated, over the last years, the role of S-nitrosylation in normal and disease conditions. In this context, structural and computational studies can help to dissect the complex and multifaceted role of this redox post-translational modification. In this review article, we summarized the current state-of-the-art on the mechanism of S-nitrosylation, along with the structural and computational studies that have helped to unveil its effects and biological roles. We also discussed the need to move new steps forward especially in the direction of employing computational structural biology to address the molecular and atomistic details of S-nitrosylation. Indeed, this redox modification has been so far an underappreciated redox post-translational modification by the computational biochemistry community. In our review, we primarily focus on S-nitrosylated proteins that are attractive cancer targets due to the emerging relevance of this redox modification in a cancer setting.

Natural history of optic pathway gliomas in a cohort of unselected patients affected by Neurofibromatosis 1.

Optic pathway glioma (OPG) represents the most common central nervous system tumor in children with Neurofibromatosis type-1 (NF1). Although overall survival is usually good, no clear prognostic factors have been identified so far. We assessed the natural history of OPG in a cohort of unselected patients affected by NF1. We retrospectively evaluated 414 consecutive patients affected by NF1 and referred to our NF1 clinic before age 6. Average follow-up was 11.9 years: 52 out of 414 patients had OPG with a total cumulative incidence of 15.4% at age 15 (Kaplan-Meier estimate) and a statistically significant difference according to sex. Brain and orbit MRI was performed in 44.7% of patients: 34.6% for screening purposes and 65.4% because of the presence of neurological, ocular or other symptoms. OPG was diagnosed in 12.5% of cases in the first group, whereas in 36.4% in the latter group (p = 0.001). Clinical management was conservative in most patients, while 8 of them underwent therapy mainly because of visual deterioration. OPG was diagnosed earlier in treated patients, but the difference was not statistically significant. Conversely, all patients who underwent screening MRI had normal visual outcome. In conclusion, OPG location does not correlate with need for treatment; female patients were more frequently affected by OPG but not more frequently treated. OPG diagnosis by screening MRI does not affect the natural history of the tumor.

Lenalidomide long-term neurotoxicity: Clinical and neurophysiologic prospective study.

OBJECTIVE: To evaluate long-term lenalidomide neurotoxicity and correlation with cumulative dose and hematologic response. METHODS: Nineteen myeloma patients (7 men, mean age 63.2 years) underwent clinical and neurophysiologic assessment at baseline and at 2 (8 patients, group A) or 5 years (11 patients, group B) after starting lenalidomide therapy for relapsed/refractory multiple myeloma. Neuropathy was scored with Total Neuropathy Score clinical version (TNSc). Lenalidomide cumulative dose was correlated with severity of neuropathy and hematologic response. RESULTS: At enrollment, 7/19 patients (3 in group A, 4 in group B) had neurophysiologic signs of neuropathy secondary to previous chemotherapy, in 2 of them subclinical. Neurophysiologic evidence of sensory axonal neuropathy occurred in 4/8 patients at 2 years follow-up (group A) and in 3/11 patients at 5 years follow-up (group B). Dorsal sural nerve sensory action potential amplitude was the earliest neurophysiologic abnormality. No relevant (≥4) clinical changes were found in TNSc score. Hematologic overall response was 62% in group A and 100% in group B. No correlation was found between lenalidomide cumulative dose and neuropathy or between neuropathy and hematologic response. CONCLUSIONS: In our study, up to 50% of myeloma patients on long-term lenalidomide therapy developed sensory axonal neuropathy. Reduced dorsal sural nerve sensory action potential amplitude was the first neurophysiologic alteration. Neuropathy was usually subclinical or mild, however. Neurotoxicity was independent of lenalidomide cumulative dose and hematologic response.

Regression of gadolinium-enhanced lesions in patients affected by neurofibromatosis type 1.

Neurofibromatosis type I is a genetic condition with an autosomal dominant transmission characterized by neurocutaneous involvement and a predisposition to tumor development. Central nervous system manifestations include benign areas of dysmyelination and possibly hazardous glial tumors whose clinical management may result challenging. Here, we report on three patients diagnosed with Neurofibromatosis type I whose brain MRI follow-up showed the presence of gadolinium-enhancing lesions which spontaneously regressed. In none of the three cases, the lesions showed any clinical correlate and eventually presented a striking reduction in size while gadolinium enhancement disappeared despite no specific therapy administration during the follow-up. Although their nature remains undetermined, these lesions presented a benign evolution. However, they might be misdiagnosed as potentially life-threatening tumors. Hitherto, a similar behavior has been described only in scattered cases and we believe these findings may be of particular interest for the clinical management of patients affected by neurofibromatosis type I.

Pentraxin-3 and VEGF in POEMS syndrome: a 2-year longitudinal study.

Circulating Pentraxin 3 (PTX3) and vascular endothelial growth factor (VEGF) levels were measured longitudinally (mean follow-up 2 years) by ELISA in 6 patients with polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes (POEMS) syndrome and 16 controls. Expression of PTX3 was also assessed (immunohistochemistry) on sural nerve biopsies from POEMS and vasculitic neuropathy patients. No correlation was found between PTX3 and VEGF levels in POEMS or controls. Sural nerve biopsies from vasculitic neuropathy patients, but not those from POEMS syndrome, showed strong PTX3 staining. PTX3, expression of vessel inflammation/remodeling, and VEGF, crucial pro-angiogenic cytokine, appear to be independently regulated in POEMS syndrome.

Lenalidomide in patients with chemotherapy-induced polyneuropathy and relapsed or refractory multiple myeloma: results from a single-centre prospective study.

Lenalidomide, an immunomodulatory drug used in myeloma therapy, has been claimed to be less neurotoxic than thalidomide, but evidence is still weak. We prospectively assessed lenalidomide safety in myeloma patients to evaluate whether it would induce or modify a previously ensued chemotherapy-induced peripheral neuropathy (CIPN). Thirty consecutive patients (17 men, mean age 63.7 ± 9.4) previously treated with bortezomib and/or thalidomide and starting on lenalidomide (25 mg/day for 21-day cycles) for relapsed or refractory myeloma were assessed at baseline, 6, and 12 months from the beginning of lenalidomide with Total Neuropathy Score clinical version (TNSc), Eastern Cooperative Oncology Group (ECOG) performance status, and numeric rating scale (NRS) for pain. TNSc >2 was considered significant for CIPN. TNSc changes of at least 4 points from baseline value were considered clinically relevant. At baseline 16 of the 30 patients (53.3%) had CIPN (mean TNSc 5.8, range 3-15). After 6 months, 13 patients were unchanged, 1 improved, and 2 worsened. After 12 months the patient who had improved persisted stable, and the two who had worsened returned to TNSc baseline value. The 14 patients without CIPN at baseline did not develop neuropathy. NRS and ECOG performance status persisted unchanged. Our results demonstrate lenalidomide safety and very low neurotoxicity also in patients with pre-existing CIPN treated for 1 year.

Incidence of atypical acute nerve hyperexcitability symptoms in oxaliplatin-treated patients with colorectal cancer.

CONTEXT: Peripheral, acute or chronic, neurotoxicity is one of the main dose-limiting adverse effects of oxaliplatin (OXA). Acute neurotoxicity is typically characterized by distal and perioral cold-induced paresthesias and dysesthesias, but other uncommon symptoms might also be present. OBJECTIVES: The aim of this post hoc analysis of data extracted from a prospective, multicenter study was to assess the incidence of uncommon acute OXA neurotoxicity symptoms in patients undergoing OXA-based chemotherapy. METHODS: One hundred chemotherapy-naïve patients (62 males, 38 females, aged 64.7 ± 8.7 years) with colorectal cancer scheduled to receive OXA-based therapy (FOLFOX-4, FOLFOX-6, and XELOX) underwent neurologic evaluation after the 1st infusion and then after 3 and 6 months of OXA-based chemotherapy (after 6th or 4th and 12th or 8th cycles, respectively, according to regimen). At evaluation, patients were asked to report the presence and characteristics of acute hyperexcitability symptoms. RESULTS: Eighty-two patients presented typical symptoms of acute OXA neurotoxicity in the form of cold-induced paresthesias and dysesthesias. In 45/82 (54.9 %) of patients, uncommon symptoms were also present; shortness of breath (32 %), jaw spasm (26 %), fasciculations (25 %), cramps (20 %), and difficulty in swallowing (18 %) were more frequently reported, while voice (4 %) and visual changes, ptosis and pseudolaryngospasm (1 %) occurred rarely. No significant correlation was disclosed between acute OXA neurotoxicity and chemotherapy regimen, cumulative dose of OXA or patients' age. CONCLUSIONS: A high percentage of patients treated with OXA-based chemotherapy develop acute neurotoxicity also with uncommon manifestations. Since OXA acute neurotoxicity might be related to the onset of chronic neurotoxicity, these patients should be closely monitored to avoid this dose-limiting adverse effect.

Pachymeningeal involvement in POEMS syndrome: MRI and histopathological study.

Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS) syndrome is a rare plasma cell disease. Vascular endothelial growth factor (VEGF) seems to play a pathogenic role. Peripheral neuropathy is the main neurological feature. Cranial pachymeningitis has occasionally been reported, but no histopathological studies have been performed. The authors extensively evaluated the central nervous system MRI in 11 patients (seven men, four women; mean age at diagnosis 54.45 years) with POEMS syndrome. In two patients, meningeal histopathology with staining for VEGF and VEGF receptor was performed, and pachymeningeal involvement characterised at histopathological, immunohistochemical and confocal microscopy levels. Nine patients presented with cranial pachymeningitis. One patient suffered from migraine, and none complained of cranial nerve palsies or visual loss. None showed any MRI signs of spinal pachymeningitis. No correlation was found with disease duration and VEGF serum level. Histopathology showed hyperplasia of meningothelial cells, neovascularisation and obstructive vessel remodelling, without inflammation. VEGF and VEGF receptor were strongly coexpressed on endothelium, smooth-muscle cells of arterioles and meningothelial cells. In conclusion, POEMS patients present a high prevalence of meningeal involvement. The histological changes, different from those present in chronic pachymeningitis of other aetiology, suggest a possible VEGF role in the pathogenesis of the meningeal remodelling.

Ultrasound diagnosis of peroneal nerve variant in a child with compressive mononeuropathy.

We report on a 6-year-old child presenting with subacute foot drop. Neurophysiologic and radiologic studies revealed a peroneal nerve compression secondary to fibular exostosis. Before undergoing surgical removal of the exostosis, the patient underwent further neurophysiologic and ultrasonographic evaluation that showed the presence of an accessory peroneal nerve branch that caused gastrocnemius involvement. Findings at surgery confirmed the supposed anatomical variant. Both nerve components were carefully preserved during the operative procedure. The association of ultrasonographic and neurophysiologic studies was crucial in identifying the etiopathologic mechanism and anatomical picture and provided clinicians and surgeons with important information in planning the procedure.

Syringomyelia associated with Chiari I malformation.

An 18-year-old man with progressive paraparesis, thermal hypoesthesia, sweating abnormalities, bladder dysfunction, severe orthostatic hypotension, bilateral Babinski sign, underwent a brain MRI scan that showed downward displacement of cerebellar tonsils through the foramen magnum, consistent with Chiari I malformation, compression of the brainstem-spinal cord junction, and C1-D11 syringomyelia (6.5 mm diameter at C2 level) consistent with Chiari I syndrome. Suboccipital craniectomy and duraplasty were performed. A C2 partial laminectomy and ablation of posterior arch of the atlas was performed. MRI scans 4 days and 1 month after surgery showed a dramatic syringomyelia reabsorption (2.5 and 1 mm, respectively) associated with complete clinical recovery.

Antibodies to muscle and ganglionic acetylcholine receptors (AchR) in celiac disease.

BACKGROUND: About 2.5% of patients with idiopathic peripheral neuropathy or idiopathic dysautonomia have underlying celiac disease (CD). Antibodies to ganglioside have been reported in CD patients with neuropathy. No data are so far available on the presence in CD of acetylcholine receptor (AChR) antibodies. Muscle AChR antibodies are found in patients with myasthenia gravis, and ganglionic AChR antibodies in patients with autoimmune autonomic neuropathy. OBJECTIVE: To determine the frequency of AChR antibodies in CD patients and assess possible correlations with neurological manifestations. METHODS: Seventy CD patients (16 M, 54 F, mean age 36 years) underwent neurological and electrophysiological evaluation. AChR antibodies were detected with radioimmunoprecipitation assay. Sera from 15 age-matched patients with systemic lupus erythematosus (SLE) and 10 with Sjogren syndrome were studied as controls. RESULTS: None of our CD patients complained of autonomic symptoms or fatigable weakness. Borderline titres (0.03-0.05 nmol/l) of ganglionic AChR antibodies were present in 4 patients, one affected with type I diabetes and one with subclinical neuropathy. Three of the 4 patients underwent cardiovascular autonomic function tests, which showed no abnormalities. Low levels of ganglionic AChR antibodies (0.05-0.10 nmol/l) were found in 2 SLE control patients, one of whom had a severe sicca complex. Muscle AChR antibodies (>1.0 nmol/l) were found in two CD patient and one control patient with SLE. Neither had symptoms or signs of myasthenia gravis. DISCUSSION AND CONCLUSIONS: CD is occasionally associated with neurologic disease, and with antibody reactivity to neuronal antigens. None of our CD patients had autonomic failure or significant levels of ganglionic AChR antibodies. Two CD patient and one control with SLE had muscle AChR antibodies without clinical evidence of myasthenia. The presence of antibodies in CD and in SLE patients may reflect a non-specific autoimmune response in these patients or may indicate subclinical autoimmune autonomic and neuromuscular involvement.