TWEAK/Fn14 signalling driven super-enhancer reprogramming promotes pro-metastatic metabolic rewiring in triple-negative breast cancer.

Triple Negative Breast Cancer (TNBC) is the most aggressive breast cancer subtype suffering from limited targeted treatment options. Following recent reports correlating Fibroblast growth factor-inducible 14 (Fn14) receptor overexpression in Estrogen Receptor (ER)-negative breast cancers with metastatic events, we show that Fn14 is specifically overexpressed in TNBC patients and associated with poor survival. We demonstrate that constitutive Fn14 signalling rewires the transcriptomic and epigenomic landscape of TNBC, leading to enhanced tumour growth and metastasis. We further illustrate that such mechanisms activate TNBC-specific super enhancers (SE) to drive the transcriptional activation of cancer dependency genes via chromatin looping. In particular, we uncover the SE-driven upregulation of Nicotinamide phosphoribosyltransferase (NAMPT), which promotes NAD+ and ATP metabolic reprogramming critical for filopodia formation and metastasis. Collectively, our study details the complex mechanistic link between TWEAK/Fn14 signalling and TNBC metastasis, which reveals several vulnerabilities which could be pursued for the targeted treatment of TNBC patients.

NF-κB/p52 augments ETS1 binding genome-wide to promote glioma progression.

Gliomas are highly invasive and chemoresistant cancers, making them challenging to treat. Chronic inflammation is a key driver of glioma progression as it promotes aberrant activation of inflammatory pathways such as NF-κB signalling, which drives cancer cell invasion and angiogenesis. NF-κB factors typically dimerise with its own family members, but emerging evidence of their promiscuous interactions with other oncogenic factors has been reported to promote transcription of new target genes and function. Here, we show that non-canonical NF-κB activation directly regulates p52 at the ETS1 promoter, activating its expression. This impacts the genomic and transcriptional landscape of ETS1 in a glioma-specific manner. We further show that enhanced non-canonical NF-κB signalling promotes the co-localisation of p52 and ETS1, resulting in transcriptional activation of non-κB and/or non-ETS glioma-promoting genes. We conclude that p52-induced ETS1 overexpression in glioma cells remodels the genome-wide regulatory network of p52 and ETS1 to transcriptionally drive cancer progression.

Tolosa-Hunt syndrome presenting with features of a trigeminal autonomic cephalalgias and pituitary enlargement.

Tolosa-Hunt syndrome is understood as a steroid-responsive, relapsing-remitting, unilateral headache disorder associated with ipsilateral cranial neuropathies, of a probable granulomatous aetiology. The diagnosis is made clinically from the history and examination, supported by appropriate imaging. Here the authors report a case of Tolosa-Hunt syndrome with a headache phenotype mimicking a trigeminal autonomic cephalalgias (hemicrania continua), and serial MRI studies showing a stable enlarged pituitary. Due to her initial lack of clinical signs, she was diagnosed with chronic migraine, revised to hemicrania continua based on indomethacin response, then revised back to chronic migraine. Her final diagnosis was achieved after she developed a left cavernous sinus syndrome 4 years into her disease course. This case shows that Tolosa-Hunt syndrome may present with a non-side-locked headache and delayed development of clinical signs. Clinicians should also maintain a high degree of suspicion when faced with incidental MRI findings.

Adalimumab-induced sensory vasculitic neuropathy.

Vasculitis and other autoimmune conditions are known complications of tumour necrosis factor alpha (TNF-α) inhibitor use. By definition, TNF-α inhibitor induced vasculitis is a secondary systemic vasculitis. However, its phenotype is varied and can present as an isolated vasculitic neuropathy. This presents a diagnostic challenge as the gold standard for diagnosis of a vasculitic neuropathy is a peripheral nerve biopsy that meets predefined histopathological criteria. Given the poor sensitivity of the peripheral nerve biopsy, it is important that clinicians take a good history and maintain a high index of suspicion, as this is a treatable iatrogenic condition. Here we present a case of adalimumab-induced sensory vasculitic neuropathy, treated according to the Peripheral Nerve Society guideline for non-systemic vasculitic neuropathy, given her disease phenotype.

Effect of a patient-centered hypertension delivery strategy on all-cause mortality: Secondary analysis of SEARCH, a community-randomized trial in rural Kenya and Uganda.

BACKGROUND: Hypertension treatment reduces morbidity and mortality yet has not been broadly implemented in many low-resource settings, including sub-Saharan Africa (SSA). We hypothesized that a patient-centered integrated chronic disease model that included hypertension treatment and leveraged the HIV care system would reduce mortality among adults with uncontrolled hypertension in rural Kenya and Uganda. METHODS AND FINDINGS: This is a secondary analysis of the SEARCH trial (NCT:01864603), in which 32 communities underwent baseline population-based multidisease testing, including hypertension screening, and were randomized to standard country-guided treatment or to a patient-centered integrated chronic care model including treatment for hypertension, diabetes, and HIV. Patient-centered care included on-site introduction to clinic staff at screening, nursing triage to expedite visits, reduced visit frequency, flexible clinic hours, and a welcoming clinic environment. The analytic population included nonpregnant adults (≥18 years) with baseline uncontrolled hypertension (blood pressure ≥140/90 mm Hg). The primary outcome was 3-year all-cause mortality with comprehensive population-level assessment. Secondary outcomes included hypertension control assessed at a population level at year 3 (defined per country guidelines as at least 1 blood pressure measure <140/90 mm Hg on 3 repeated measures). Between-arm comparisons used cluster-level targeted maximum likelihood estimation. Among 86,078 adults screened at study baseline (June 2013 to July 2014), 10,928 (13%) had uncontrolled hypertension. Median age was 53 years (25th to 75th percentile 40 to 66); 6,058 (55%) were female; 677 (6%) were HIV infected; and 477 (4%) had diabetes mellitus. Overall, 174 participants (3.2%) in the intervention group and 225 participants (4.1%) in the control group died during 3 years of follow-up (adjusted relative risk (aRR) 0.79, 95% confidence interval (CI) 0.64 to 0.97, p = 0.028). Among those with baseline grade 3 hypertension (≥180/110 mm Hg), 22 (4.9%) in the intervention group and 42 (7.9%) in the control group died during 3 years of follow-up (aRR 0.62, 95% CI 0.39 to 0.97, p = 0.038). Estimated population-level hypertension control at year 3 was 53% in intervention and 44% in control communities (aRR 1.22, 95% CI 1.12 to 1.33, p < 0.001). Study limitations include inability to identify specific causes of death and control conditions that exceeded current standard hypertension care. CONCLUSIONS: In this cluster randomized comparison where both arms received population-level hypertension screening, implementation of a patient-centered hypertension care model was associated with a 21% reduction in all-cause mortality and a 22% improvement in hypertension control compared to standard care among adults with baseline uncontrolled hypertension. Patient-centered chronic care programs for HIV can be leveraged to reduce the overall burden of cardiovascular mortality in SSA. TRIAL REGISTRATION: ClinicalTrials.gov NCT01864603.

Approaches to Identify and Characterise the Post-Transcriptional Roles of lncRNAs in Cancer.

It is becoming increasingly evident that the non-coding genome and transcriptome exert great influence over their coding counterparts through complex molecular interactions. Among non-coding RNAs (ncRNA), long non-coding RNAs (lncRNAs) in particular present increased potential to participate in dysregulation of post-transcriptional processes through both RNA and protein interactions. Since such processes can play key roles in contributing to cancer progression, it is desirable to continue expanding the search for lncRNAs impacting cancer through post-transcriptional mechanisms. The sheer diversity of mechanisms requires diverse resources and methods that have been developed and refined over the past decade. We provide an overview of computational resources as well as proven low-to-high throughput techniques to enable identification and characterisation of lncRNAs in their complex interactive contexts. As more cancer research strategies evolve to explore the non-coding genome and transcriptome, we anticipate this will provide a valuable primer and perspective of how these technologies have matured and will continue to evolve to assist researchers in elucidating post-transcriptional roles of lncRNAs in cancer.

Post-traumatic (and postsurgical) Guillain-Barré Syndrome: a rare, but treatable entity.

Guillain-Barré syndrome (GBS) is an acute, monophasic, polyradiculoneuropathy usually provoked by a preceding infection. The cardinal features are progressive weakness in the upper and lower limbs accompanied by loss of deep tendon reflexes. The diagnosis is made on the basis of the clinical history and examination findings, supported by typical cerebrospinal fluid and electrophysiology findings. Trauma and surgery are well understood but rare precipitants of GBS, which clinicians should be aware of, in order not to miss an opportunity to use immunomodulatory therapies. Furthermore, the presence of postsurgical or post-traumatic GBS should prompt careful assessment for underlying malignancy or autoimmune disease associated with an acute demyelinating polyradiculoneuropathy. Here, we present a case of post-traumatic GBS and discuss the potential mechanisms that might underlie this, as well as the investigations and treatment that should be considered.

Analysis of hospital cost outcome of DHA-rich fish-oil supplementation in pregnancy: Evidence from a randomized controlled trial.

OBJECTIVE: Recent research emphasized the nutritional benefits of omega-3 long chain polyunsaturated fatty acids (LCPUFAs) during pregnancy. Based on a double-blind randomised controlled trial named "DHA to Optimize Mother and Infant Outcome" (DOMInO), we examined how omega 3 DHA supplementation during pregnancy may affect pregnancy related in-patient hospital costs. METHOD: We conducted an econometric analysis based on ordinary least square and quantile regressions with bootstrapped standard errors. Using these approaches, we also examined whether smoking, drinking, maternal age and BMI could influence the effect of DHA supplementation during pregnancy on hospital costs. RESULTS: Our regressions showed that in-patient hospital costs could decrease by AUD92 (P<0.05) on average per singleton pregnancy when DHA supplements were consumed during pregnancy. Our regression results also showed that the cost savings to the Australian public hospital system could be between AUD15 - AUD51 million / year. CONCLUSION: Given that a simple intervention like DHA-rich fish-oil supplementation could generate savings to the public, it may be worthwhile from a policy perspective to encourage DHA supplementation among pregnant women.