Background

Reactome aims to provide bioinformatics tools for visualisation, interpretation and analysis of pathway knowledge to support basic research, genome analysis, modelling, systems biology and education. Pathway analysis methods have a broad range of applications in physiological and biomedical research; one of the main problems, from the analysis methods performance point of view, is the constantly increasing size of the data samples.

Results

Here, we present a new high-performance in-memory implementation of the well-established over-representation analysis method. To achieve the target, the over-representation analysis method is divided in four different steps and, for each of them, specific data structures are used to improve performance and minimise the memory footprint. The first step, finding out whether an identifier in the user’s sample corresponds to an entity in Reactome, is addressed using a radix tree as a lookup table. The second step, modelling the proteins, chemicals, their orthologous in other species and their composition in complexes and sets, is addressed with a graph. The third and fourth steps, that aggregate the results and calculate the statistics, are solved with a double-linked tree.

Conclusion

Through the use of highly optimised, in-memory data structures and algorithms, Reactome has achieved a stable, high performance pathway analysis service, enabling the analysis of genome-wide datasets within seconds, allowing interactive exploration and analysis of high throughput data. The proposed pathway analysis approach is available in the Reactome production web site either via the AnalysisService for programmatic access or the user submission interface integrated into the PathwayBrowser. Reactome is an open data and open source project and all of its source code, including the one described here, is available in the AnalysisTools repository in the Reactome GitHub ( https://github.com/reactome/ ).

The effectiveness of mental health interventions in post-disaster settings is a controversial topic. A hierarchy of needs is an important consideration. After the devastating 2010 earthquake in Haiti, a partnership formed between American academic psychiatrists, human rights attorneys, and Haitian non-governmental organizations to challenge the immigration process for earthquake survivors with need for mental health interventions. The concept of humanitarian parole, usually reserved for medical conditions, was successfully challenged for survivors suffering with trauma-related mental health diagnoses. Provisions of mental health treatment in a host country, where a survivor could be safe from the post-disaster circumstances, would optimize the likelihood of successful treatment. No resources for mental health were available in Haiti. The partnership of psychiatrists and attorneys worked with Haitian non-governmental organizations to prepare parole applications for the most egregious cases of earthquake trauma and post-earthquake sexual violence. The partnership led to more than 60 successful evacuations on the basis of psychiatric diagnosis and dire need. It also led to a new model of considering humanitarian parole as a legal option for survivors of violence internationally.

▴ Desvenlafaxine extended release (ER) is a once-daily selective serotonin-noradrenaline (norepinephrine) reuptake inhibitor approved in the US for the treatment of major depressive disorder in adult patients.

▴ In two of three well designed, 8-week clinical trials, desvenlafaxine ER 50 mg/day (the recommended dosage) significantly improved depression at study end, as assessed by the 17-item Hamilton Rating Scale for Depression (primary endpoint), compared with placebo.

▴ A significant difference between desvenlafaxine ER 50 mg/day and placebo treatment groups was achieved in some, but not all, secondary measures of depression or anxiety in two of three trials, including the Clinical Global Impression-Improvement and -Severity scales, the Montgomery-Asberg Depression Rating Scale and the Covi Anxiety Scale.

▴ In two of three trials, patients receiving desvenlafaxine ER 50 mg/day for 8 weeks experienced greater improvements in health-related quality of life (as assessed by the Sheehan Disability Scale and the WHO 5-item Well-Being Index) than those receiving placebo.

▴ Desvenlafaxine ER 50 mg/day was generally well tolerated by patients in 8-week trials. Most cases of nausea, the most common adverse event, were of mild to moderate severity.

Subcutaneous immunoglobulin (SCIG) treatment provides stable serum immunoglobulin G (IgG) levels, is associated with fewer systemic adverse events than intravenous immunoglobulin (IVIG) treatment, and offers the convenience of home therapy. In clinical practice, IVIG is still used preferentially for initiation of treatment in newly diagnosed patients with primary immunodeficiency (PI) and for immunomodulatory therapy, such as treatment of peripheral neuropathies, when high doses are believed to be necessary. The authors discuss recent experience in using SCIG in place of IVIG in these settings. SCIG has been successfully used for initiation of therapy in previously untreated PI patients. Seventeen of 18 PI patients achieved serum IgG levels ≥5 g/L after the loading phase. Daily treatment was well tolerated and provided opportunities for patient/parent training in self-infusion. SCIG has been used for maintenance therapy in multifocal motor neuropathy (MMN) in three recent clinical trials, with good efficacy and tolerability results. Seven of eight MMN patients maintained serum IgG levels of 14–22 g/L with a mean dose of 272 mg/kg/week, had stable muscle strength, and felt comfortable with self-administration. Four patients with polymyositis or dermatomyositis achieved improvement in serum creatine kinase levels and muscle strength with SCIG therapy. Recent experience with SCIG suggests that traditional concepts of immunoglobulin therapy may be challenged to increase available therapy options. SCIG can be used to achieve high IgG levels within several days in untreated PI patients and to maintain high serum levels, as shown in patients with MMN.

Key Points

Considerable evidence supports the crucial roles of the signal transducer and activator of transcription (STAT) family of proteins in human diseases, particularly in immune and inflammatory disorders, infection and cancer

Increasing emphasis is being placed on developing direct STAT inhibitors for clinical application, mainly through the discovery of small molecules, oligonucleotides and natural product derivatives.

A large part of the ongoing STATs drug discovery research for therapeutics is focused on targeting STAT3, of which the efforts to develop small-molecule STAT3 inhibitors is extensive. While research into oligodeoxynucleotide (ODN) decoys and antisense oligonucleotides (ASOs) as STAT-inhibitory approaches is not as widespread, these efforts appear to be advancing as a STAT3 ODN has progressed to clinical trials (Phase 0).

Tyrosine kinase inhibitors (TKIs) as therapeutic modalities are widely explored, and this approach is highly established. TKI agents may be therapeutic considerations in STAT-associated diseases in so far as a causal link could be established between the target tyrosine kinase and dysregulated STAT signalling that is prevalent in the disease.

The precedence of natural product-based therapeutics for many diseases and the number of reports on natural product inhibitors of STAT3 signalling together highlight the potential of this resource as an important source of leads for developing STAT inhibitors.

There is a clinical trial to evaluate ISIS-STAT3Rx ASO against advanced cancers. Other clinical trials are focusing on therapeutic modalities that can affect STAT function and STAT-associated diseases, including the evaluation of curcumin for pancreatic cancer, resveratrol for colorectal cancer and 3,3′-diindolylmethane for breast cancer, and TKIs against many cancer types.

At least 2.2 million people in the USA have epilepsy – 0.7% of the population by the 2014 US Census. Most often, epilepsy presents during the first decade of life, with up to 50% of the cases occurring before the age of 5 years. Of these, 60% have focal epilepsy, and approximately 20% become drug resistant or refractory. Early onset of intractable seizures, particularly in children less than 3 years old, has a very poor prognosis. Epilepsy is considered refractory if seizures continue after 2 years of pharmacological treatment with 2–3 appropriately selected drugs with good patient compliance. Typically, the frequency or severity of seizures in this situation prevents normal function and development. Moreover, patients with refractory epilepsy commonly suffer from the side effects and complications of high-dose anti-epileptic drugs. Indeed, even in the therapeutic range, anti-epileptic medications can significantly influence the developing brain. In addition to the risk of cognitive dysfunction, physical issues are also associated with medically intractable seizures. These patients have higher rates of accidental death or sudden death, ranging from 2% to 18%, as compared to cause of death in all people with epilepsy. Only half of the patients with medically intractable seizures or refractory epilepsy are able to become self-supporting on reaching adulthood. Therefore, early surgical intervention increases the chances of significantly reducing or eliminating seizures, improving quality of life; reducing the risk of cognitive, behavioral, and motor developmental damage; and decreasing the risk for permanent brain injury in infants and young children. Common causes of pediatric refractory epilepsy that are amenable to surgery include tumors, cortical malformations, vascular abnormalities, and certain epileptic syndromes.

BACKGROUND:

Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive disorder caused by mutations in SMARCAL1. A frequent complication is arteriosclerosis associated with reduced elastin expression; however, the mechanism underlying the reduced elastin expression remains unknown.

METHODS:

Expression of transcriptional regulators of elastin (ELN) and microRNA (miRNA) regulators of ELN messenger RNA (mRNA), ELN promoter methylation, and ELN mRNA poly(A) tail length were assessed by quantitative RT-PCR, bisulfite Sanger sequencing, and the Poly(A) Tail Length Assay Kit, respectively, in unaffected developing human aortae and in an SIOD aorta.

RESULTS:

Comparing unaffected fetal and adult aortae, ELN precursor mRNA (pre-mRNA) levels remained nearly constant, whereas mRNA levels declined by ~10²-fold. This corresponded with a reduction in poly(A) tail length but not with changes in the other parameters. In contrast, compared to the unaffected fetal aortae, the SIOD aorta had 18-fold less ELN pre-mRNA and 10⁴-fold less mRNA. This corresponded with increased expression of miRNA regulators and shorter ELN mRNA poly(A) tail lengths but not with altered expression of ELN transcriptional regulators or ELN promoter methylation.

CONCLUSION:

Posttranscriptional mechanisms account for the reduction in ELN mRNA levels in unaffected aortae, whereas transcriptional and posttranscriptional mechanisms reduce elastin expression in SIOD aorta and predispose to arteriosclerosis.

Fibromyalgia syndrome (FM) is a highly prevalent musculoskeletal disorder that is often accompanied by somatic hyperalgesia (enhanced pain from noxious stimuli). Neural mechanisms of somatic hyperalgesia have been analyzed via quantitative sensory testing of FM patients. Results of these studies suggest that FM pain is associated with widespread primary and secondary cutaneous hyperalgesia, which are dynamically maintained by tonic impulse input from deep tissues and likely by brain-to-spinal cord facilitation. Enhanced somatic pains are accompanied by mechanical hyperalgesia and allodynia in FM patients as compared with healthy controls. FM pain is likely to be at least partially maintained by peripheral impulse input from deep tissues. This conclusion is supported by results of several studies showing that injection of local anesthetics into painful muscles normalizes somatic hyperalgesia in FM patients.

Background

The aim of this study was to explore the need for a new disease-specific patient reported outcome (PRO) measure for use in clinical trials of drugs designed to target the underlying causes of polycystic ovary syndrome (PCOS), and in the process contribute to our understanding of the symptoms and impacts that define the patient experience with PCOS.

Methods

Semi-structured interviews were conducted in 20 women diagnosed with PCOS according to the Rotterdam criteria who had not menstruated in the previous month. The relative importance of PCOS symptoms and impact concepts to patients was determined by analyzing the frequency of their expression in the interview transcripts. These insights were compared to clinicians’ perceptions of PCOS.

Results

Pain- and discomfort-related symptoms accounted for the highest proportion (27.6%) of the 735 patient expressions, although clinicians did not consider pain to be important to patients with PCOS. The most frequently expressed individual symptoms were cramping (70% of patients; 14.7% of concepts), irregular menstruation (95% of patients; 12.2% of concepts), facial hair growth (75% of patients; 10.6% of concepts), heavy bleeding (70% of patients; 8.8% of concepts), infertility (70% of patients; 5.4% of concepts), and bloating (60% of patients; 5.2% of concepts). Cramping, heavy bleeding, and bloating were not identified by clinicians as being important to patients with PCOS. The impacts most frequently reported by patients with PCOS related to emotional well-being (e.g. anxiety/stress) and coping behaviors (e.g. acne medication, hair removal).

Conclusions

The only validated PCOS-specific PRO, the PCOSQ, does not capture some key PCOS symptoms and impacts expressed by patients with PCOS, most notably those related to pain and discomfort, bleeding intensity and coping behaviours. Furthermore, some key PCOS symptoms may be under-recognized in the clinic.

Whether you feel dissociated from the rest of the world or from yourself, you feel some kind of mental dissociations. Each form of mental dissociations varies in symptomatology and associated deficits. Nevertheless, psychiatrists, neurologists, and neuroscientists have discussed, for decades, the possibility of a holistic neural mechanism underlying the core feature of mental dissociations, i.e., disruption of a unified sense of self and a failure to accurately integrate multisensory information between self and social environment. Recently, functional and electrical neuroimaging studies shed light on this question by pointing to a correlation between the core symptomatology of mental dissociations and temporo-parietal junction (TPJ)—an area involved in sense of self, agency, perspective taking, and multimodal integration of somatosensory information. Interestingly, results also suggest that each specific aspect of each form of mental dissociation is associated with brain areas that are specific to that domain.