Application of Machine Learning Algorithms to Metadynamics for the Elucidation of the Binding Modes and Free Energy Landscape of Drug/Target Interactions: a Case Study.

In the context of drug discovery, computational methods were able to accelerate the challenging process of designing and optimizing a new drug candidate. Amongst the possible atomistic simulation approaches, metadynamics (metaD) has proven very powerful. However, the choice of collective variables (CVs) is not trivial for complex systems. To automate the process of CVs identification, two different machine learning algorithms were applied in this study, namely DeepLDA and Autoencoder, to the metaD simulation of a well-researched drug/target complex, consisting in a pharmacologically relevant non-canonical DNA secondary structure (G-quadruplex) and a metallodrug acting as its stabilizer, as well as solvent molecules.

Prodromal depression and anxiety are associated with worse treatment compliance and survival among patients with pancreatic cancer.

OBJECTIVE: To determine the frequency of depression or anxiety preceding a diagnosis of pancreatic cancer (PC). Further, to examine the association of PC-associated depression or anxiety with treatment compliance and survival. METHODS: 856 patients with PC from a single institution were identified using International Classification of Diseases (ICD) codes. For each case, two non-cancer age- and sex-matched controls were included. Dates of depression or anxiety diagnosis identified using ICD codes were compared to the date of PC diagnosis. The medical record was queried to further explore psychiatric symptoms. Multivariable analyses were performed to examine if prediagnosis depression or anxiety was associated with receipt of treatment or survival. RESULTS: A greater proportion of patients with PC experienced depression or anxiety in the year preceding diagnosis than the overall frequency in controls (4.6% vs. 2.6%, p = 0.005) based on ICD codes. Patients with PC exhibited signs of prodromal depression or anxiety based on ICD codes, clinical documentation of psychiatric symptoms, or initiation of new psychiatric medications more often than controls (20.7% vs. 6.7%, p < 0.001). Prediagnosis depression or anxiety was associated with a reduced likelihood of receiving chemotherapy (OR = 0.58, p = 0.04). There was an associated decrease in overall survival among patients with metastatic disease who experienced depression or anxiety before PC diagnosis (HR = 1.32, p = 0.04). CONCLUSIONS: The frequency of depression or anxiety among patients with PC was higher than the general population. Prediagnosis psychiatric symptoms were associated with reduced chemotherapy utilization and worse overall survival. Thus, timely identification and treatment of these symptoms may improve outcomes.

Disseminated strongyloidiasis in an immunocompetent male: A Case Report.

Strongyloidiasis is a human parasitic disease caused by infection of Strongyloidesstercoralis. It can manifest from asymptomatic eosinophilia in an immunocompetent host and disseminate the disease in the immunocompromised ones. The inconsistency of eosinophilia and low sensitivity of a standard microscopic stool examination makes it difficult to diagnose the disease. We report a case of chronic strongyloidiasis who, despite being immunocompetent, developed dissemination. The patient was a 30-years-old male who presented with diarrhoea, vomiting, high-grade fever and dyspnoea. On examination, he was pale, oedematous and had ascites with systolic murmurs in tricuspid area. After a fullworkup for differentials, biopsy confirmed the diagnosis of strongyloidiasis. Echocardiogram revealed vegetations on mitral and tricuspid valves and regurgitation through the valves, which confirmed dissemination to endocardium. A course of Ivermectin 9 mg daily for two weeks eradicated the infection in time. In conclusion, awareness for physicians and the use of various diagnostic methods like serology, endoscopy and biopsy should be considered for high risk patients.

IDH1 inhibition potentiates chemotherapy efficacy in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is associated with a five-year overall survival rate of just 13%, and development of chemotherapy resistance is nearly universal. PDAC cells overexpress wild-type IDH1 that can enable them to overcome metabolic stress, suggesting it could represent a therapeutic target in PDAC. Here, we found that anti-IDH1 therapy enhanced the efficacy of conventional chemotherapeutics. Chemotherapy treatment induced ROS and increased TCA cycle activity in PDAC cells, along with the induction of wild-type IDH1 expression as a key resistance factor. IDH1 facilitated PDAC survival following chemotherapy treatment by supporting mitochondrial function and antioxidant defense to neutralize reactive oxygen species through the generation of alpha-ketoglutarate and NADPH, respectively. Pharmacologic inhibition of wild-type IDH1 with ivosidenib synergized with conventional chemotherapeutics in vitro and potentiated the efficacy of sub-therapeutic doses of these drugs in vivo in murine PDAC models. This promising treatment approach is translatable through available and safe oral inhibitors and provides the basis of an open and accruing clinical trial testing this combination (NCT05209074).

Giant Meckel's Diverticulum as a Cause of Post-traumatic Hemoperitoneum in a 25-Year-Old Male: An Extremely Rare Phenomenon.

Following the "rule of 2", Meckel's Diverticulum (MD) is 2 inches or 5cm long. However, we report the case of an extremely large MD. To the best of our elucidated literature search, it is the first case of Giant Meckel's Diverticulum (GMD) from Pakistan presenting with post-traumatic hemoperitoneum. A 25-year-old Pakistani male presented to a surgical emergency with a two-hour history of generalized abdominal pain after blunt abdominal trauma. An exploratory laparotomy was carried out due to the deranged hemodynamic parameters and free fluid in the abdominopelvic cavity, revealing a 35 centimeters long MD with a bleeding vessel on its tip. Diverticulectomy with the repair of a small intestinal defect was performed after the evacuation of 2.5 liters of clotted blood. Histologic evaluation revealed ectopic gastric tissue. He had an uneventful post-operative stay and was discharged home. The current English scientific literature has adequate case reports documenting the complications of perforation, intestinal obstruction, and diverticulitis of Meckel's Diverticulum (MD) of normal length. However, this case report highlights the significance of an MD with an abnormal length which put the patient's life at risk of death in the setting of normal intra-operative anatomy of all other abdominal organs.

Cliniciopathological Spectrum of Skin and Soft Tissue Swellings at a Tertiary Care Hospital of Lahore, Pakistan.

Background Skin and soft tissue swellings (SSTS) frequently present in dermatology, plastic surgery, and general surgery departments. While a general surgeon can take care of excisable lesions, people typically seek plastic surgery for cosmetic reasons. According to the signs and symptoms, soft tissue and skin lesions must be removed, and it is crucial to maintain cosmesis following their removal. Objective The aim of this article is to describe the clinical and histopathological types, sites, laterality, and postoperative complications of SSTS. Material and methods This retrospective study was conducted at the Department of Plastic and Reconstructive Surgery, Lahore General Hospital, Lahore, Pakistan in November 2022. We studied admitted patients from July 1, 2020 to June 30, 2022 for SSTS excision. Data on patients' demographics, associated features of SSTS, and their postoperative complications was gathered using Google Docs-generated proforma and sent to a statistician for the computation of results via a Microsoft Excel-generated spreadsheet. Results Out of the total 60 patients, 66.7% of the lesions were found in women. The mean age at presentation came out to be 34.16±17.42 years. Nevi with 16.7% were the most common SSTS in our study. The most common site of presentation of SSTS was the scalp and face in 63.3% of cases. Fever was the most frequently encountered post-excision complication in 40% of patients. Conclusion A comprehensive history, clinical examination, signs and symptoms, and the histology of the lesion, all play a crucial role in the management of such swellings. Surgery was the definitive treatment option for SSTS. There were very few major complications in a handful of patients.

Increased glucose availability sensitizes pancreatic cancer to chemotherapy.

Pancreatic Ductal Adenocarcinoma (PDAC) is highly resistant to chemotherapy. Effective alternative therapies have yet to emerge, as chemotherapy remains the best available systemic treatment. However, the discovery of safe and available adjuncts to enhance chemotherapeutic efficacy can still improve survival outcomes. We show that a hyperglycemic state substantially enhances the efficacy of conventional single- and multi-agent chemotherapy regimens against PDAC. Molecular analyses of tumors exposed to high glucose levels reveal that the expression of GCLC (glutamate-cysteine ligase catalytic subunit), a key component of glutathione biosynthesis, is diminished, which in turn augments oxidative anti-tumor damage by chemotherapy. Inhibition of GCLC phenocopies the suppressive effect of forced hyperglycemia in mouse models of PDAC, while rescuing this pathway mitigates anti-tumor effects observed with chemotherapy and high glucose.

Estimating the energy consumption function: evidence from across the globe.

The motivation for the current study stem from the United Nations Sustainable Development Goals (UN-SDGs) such as access to clean (SDG-7) and responsible energy consumption (SDG-12) and climate change mitigation (SDG-12). This chase for these goals is pertinent for sustainable economic growth and environmental sustainability. This becomes necessary given the global demand for energy which comes has it environmental consequences given anthropogenic effect. To this end, the present study seeks to identify the factors determining the energy consumption function for 79 economies across the globe. For empirical investigation, 44 years data of five regions, namely Asia and Pacific, Europe, Africa, Latin America, and the Middle East and Arab States, is analyzed. A multivariate regression model and the method of least squares are employed to achieve set of objectives. The least squares result of the regions and single country of the regions are not significantly different from each other. Every region exhibits a common narrative that economic growth, carbon emissions, and urbanization are the key factors determining the consumption function in most of the sample economies. The empirical findings revealed that energy consumption function is determined by economic growth, urbanization, and carbon emissions. In the light of these findings, it is recommended that energy policy needs to be designed considering the significance of economic growth and environmental quality, and consequently it leads toward the achievement of the sustainable development goals.

The prevalence, risk factors analysis and evaluation of two diagnostic techniques for the detection of Cryptosporidium infection in diarrheic sheep from Pakistan.

BACKGROUND: Cryptosporidium spp. is recognized as an opportunistic zoonotic parasite that infects humans as well as wild and domestic animals. This enteric protozoan is a major cause of diarrhea in humans and animals and often result in death due to severe dehydration. The present study was designed to investigate the prevalence, identification of various risk factors and evaluation of sensitivity of the two diagnostic techniques for rapid and correct detection of Cryptosporidium infection in diarrheic sheep in Pakistan. METHODS: A total of 360 fecal samples were collected and processed for detection of Cryptosporidium infection after proper preservation. These samples were properly stained with modified Ziehl-Neelsen acid staining and then examined under simple microscope at 100x magnification for confirmation of Cryptosporidium oocysts. The same samples were again processed through simple PCR for confirmation of the Cryptosporidium spp. RESULTS: The age wise prevalence was detected through simple microscopy and PCR. We found highest prevalence at the age of ≤1 year followed by 1-2 years of age while the lowest prevalence was recorded at the age of ≥ 2-3 years of sheep and found significant difference between different ages (P<0.05). The sex wise prevalence showed the highest prevalence in male (♂) animals detected compared to female (♀). The overall prevalence was detected 27.08% and 18.80% through PCR and simple microscopy, respectively, and significant difference between two diagnostic techniques were observed (P<0.05). Considering the seasonality, the highest prevalence was recorded through simple microscopy in autumn, summer, and spring, while the lowest in winter. These results were confirmed through PCR. CONCLUSION: It was concluded that molecular detection is the most efficient, specific and sensitive technique for detection of Cryptosporidium infection than simple microscopy. Moreover sheep is the major potential source of infection to other wild and domestic animals including humans.

Liver Endothelium Promotes HER3-Mediated Cell Survival in Colorectal Cancer with Wild-Type and Mutant KRAS.

We previously identified that human epidermal growth factor receptor 3 (HER3, also known as ERBB3) is a key mediator in liver endothelial cell (EC) promoting colorectal cancer growth and chemoresistance, and suggested HER3-targeted therapy as a strategy for treating patients with metastatic colorectal cancer in the liver. Meanwhile, KRAS mutations occur in 40%-50% of metastatic colorectal cancer and render colorectal cancer resistant to therapies targeting the other HER family protein epidermal growth factor receptor (EGFR). It is necessary to elucidate the roles of KRAS mutation status in HER3-mediated cell survival and colorectal cancer response to HER3 inhibition. In the present study, we used primary ECs isolated from non-neoplastic liver tissues to recapitulate the liver EC microenvironment. We demonstrated that liver EC-secreted factors activated colorectal cancer-associated HER3, and increased colorectal cancer cell survival in vitro and promoted colorectal cancer patient-derived xenograft tumor growth in vivo. Moreover, we determined that blocking HER3, either by siRNA knockdown or the humanized antibody seribantumab, blocked EC-induced colorectal cancer survival in vitro in both KRAS wild-type and mutant colorectal cancer cells, and the HER3 antibody seribantumab significantly decreased colorectal cancer tumor growth and sensitized tumors to chemotherapy in an orthotopic xenograft model with colorectal cancer tumors developed in the liver. In summary, our findings demonstrated that blocking HER3 had significant effects on attenuating liver EC-induced colorectal cancer cell survival independent of the KRAS mutation status. IMPLICATIONS: This body of work highlighted a potential strategy of using HER3 antibodies in combination with standard chemotherapy agents for treating patients with either KRAS wild-type or KRAS mutant metastatic colorectal cancer.

Clinical development of IDH1 inhibitors for cancer therapy.

Isocitrate dehydrogenase 1 (IDH1) has been investigated as a promising therapeutic target in select cancers with a mutated version of the enzyme (mtIDH1). With only one phase III trial published to date and two indications approved for routine clinical use by the FDA, we reviewed the entire clinical trial portfolio to broadly understand mtIDH1 inhibitor activity in patients. We queried PubMed.gov and ClinicalTrials.gov to identify published and ongoing clinical trials related to IDH1 and cancer. Progression-free survival (PFS), overall survival (OS), 2-hydroxyglutarate levels, and adverse events were summarized. To date, ten clinical trials investigating mtIDH1 inhibitors among patients with diverse malignancies (cholangiocarcinoma, acute myeloid leukemia, chondrosarcoma, glioma) have been published. Almost every trial (80%) has investigated ivosidenib. In multiple phase I trials, ivosidenib treatment resulted in promising radiographic and biochemical responses with improved survival outcomes (relative to historic data) among patients with both solid and hematologic mtIDH1 malignancies. Among patients enrolled in a phase III trial with advanced cholangiocarcinoma, ivosidenib resulted in a PFS rate of 32% at 6 months, as compared to 0% with placebo. There was a 5.2 month increase in OS with ivosidenib relative to placebo, after considering crossover. The treatment-specific grade ≥3 adverse event rate of ivosidenib was 2%-26% among all patients, and was just 3.6% among 284 patients who had a solid tumor across four trials. Although <1% of malignancies harbor IDH1 mutations, small molecule mtIDH1 inhibitors, namely ivosidenib, appear to be biologically active and well tolerated in patients with solid and hematologic mtIDH1 malignancies.

IDO1 Is a Therapeutic Target for Pancreatic Cancer-Associated Depression.

Metabolites of tryptophan degradation are known to alter mood. Their effects have only been superficially examined in the context of pancreatic cancer. Herein, we study the role of indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme important in the conversion of tryptophan to kynurenine, in a murine model of pancreatic cancer-associated depression. Behavioral tests (open field, forced swim, tail suspension, and elevated plus maze) and biochemical assays (LC-MS metabolomics) were used to characterize a depressive-phenotype in tumor-bearing mice (relative to non-tumor-bearing mice). In addition, we determine whether pharmacologic blockade of IDO1 affects mood in tumor-bearing mice. Immunocompetent mice bearing orthotopic pancreatic tumors exhibit depressive-like behavior relative to non-tumor-bearing mice. Pancreatic tumors strongly express IDO1. Consequently, serum kynurenine levels in tumor-bearing mice are elevated relative to non-tumor-bearing mice. Tumor-bearing mice treated with epacadostat, an IDO1 inhibitor, exhibited improved mood relative to mice receiving vehicle. There was a 95% reduction in serum kynurenine levels in mice receiving epacadostat relative to mice treated with vehicle. As confirmatory evidence of on-target activity, tumors of mice treated with epacadostat exhibited a compensatory increase in IDO1 protein levels. Escitalopram, an approved antidepressant, was ineffective at improving mood in tumor-bearing mice as measured by behavioral assays and did not affect kynurenine levels. Neither epacadostat, nor escitalopram, affected overall survival relative to vehicle. Mice with pancreatic cancer exhibit depressive-like behavior. Epacadostat was effective as an antidepressant for pancreatic cancer-associated depression in mice. These data offer a rationale to consider IDO1 inhibition as a therapeutic strategy to mitigate depressive symptoms in patients with pancreatic cancer.

Wild-type IDH1 inhibition enhances chemotherapy response in melanoma.

BACKGROUND: Alternative treatment strategies in melanoma beyond immunotherapy and mutation-targeted therapy are urgently needed. Wild-type isocitrate dehydrogenase 1 (wtIDH1) has recently been implicated as a metabolic dependency in cancer. The enzyme protects cancer cells under metabolic stress, including nutrient limited conditions in the tumor microenvironment. Specifically, IDH1 generates NADPH to maintain redox homeostasis and produces α-ketoglutarate to support mitochondrial function through anaplerosis. Herein, the role of wtIDH1 in melanoma is further explored. METHODS: The expression of wtIDH1 was determined by qRT-PCR, and Western blot in melanoma cell lines and the effect of wtIDH1 on metabolic reprogramming in melanoma was interrogated by LC-MS. The impact of wtIDH1 inhibition alone and in combination with chemotherapy was determined in cell culture and mouse melanoma models. RESULTS: Melanoma patients express higher levels of the wtIDH1 enzyme compared to normal skin tissue, and elevated wtIDH1 expression portends poor patient survival. Knockdown of IDH1 by RNA interference inhibited cell proliferation and migration under low nutrient levels. Suppression of IDH1 expression in melanoma also decreased NADPH and glutathione levels, resulting in increased reactive oxygen species. An FDA-approved inhibitor of mutant IDH1, ivosidenib (AG-120), exhibited potent anti-wtIDH1 properties under low magnesium and nutrient levels, reflective of the tumor microenvironment in natura. Thus, similar findings were replicated in murine models of melanoma. In light of the impact of wtIDH1 inhibition on oxidative stress, enzyme blockade was synergistic with conventional anti-melanoma chemotherapy in pre-clinical models. CONCLUSIONS: These results demonstrate the clinical potential of wtIDH1 inhibition as a novel and readily available combination treatment strategy for patients with advanced and refractory melanoma. Schematic shows increased wild-type IDH1 expression and activity as an adaptive response to metabolic stress induced by chemotherapy.

Liver Endothelium Microenvironment Promotes HER3-mediated Cell Growth in Pancreatic Ductal Adenocarcinoma.

~90% metastatic pancreatic ductal adenocarcinoma (mPDAC) occurs in the liver, and the 5-year survival rate for patients with mPDAC is only at 3%. The liver has a unique endothelial cell (EC)-rich microenvironment, and preclinical studies showed that ECs promote cancer cell survival pathways by secreting soluble factors in a paracrine fashion in other types of cancer. However, the effects of liver ECs on mPDAC have not been elucidated. In this study, we used primary liver ECs and determined that liver EC-secreted factors containing conditioned medium (CM) increased PDAC cell growth, compared to control CM from PDAC cells. Using an unbiased receptor tyrosine kinase array, we identified human epidermal growth factor receptor 3 (HER3, also known as ErbB3) as a key mediator of liver EC-induced growth in PDAC cells with HER3 expression (HER3 +ve). We found that EC-secreted neuregulins activated the HER3-AKT signaling axis, and that depleting neuregulins from EC CM or blocking HER3 with an antibody, seribantumab, attenuated EC-induced functions in HER3 +ve PDAC cells, but not in cells without HER3 expression. Furthermore, we determined that EC CM increased PDAC xenograft growth in vivo, and that seribantumab blocked EC-induced growth in xenografts with HER3 expression. These findings elucidated a paracrine role of liver ECs in promoting PDAC cell growth, and identified the HER3-AKT axis as a key mediator in EC-induced functions in HER3 +ve PDAC cells. As over 70% mPDAC express HER3, this study highlights the potential of using HER3-targeted therapies for treating patients with HER3 +ve mPDAC.

Limited nutrient availability in the tumor microenvironment renders pancreatic tumors sensitive to allosteric IDH1 inhibitors.

Nutrient-deprived conditions in the tumor microenvironment (TME) restrain cancer cell viability due to increased free radicals and reduced energy production. In pancreatic cancer cells a cytosolic metabolic enzyme, wild-type isocitrate dehydrogenase 1 (wtIDH1), enables adaptation to these conditions. Under nutrient starvation, wtIDH1 oxidizes isocitrate to generate α-ketoglutarate (αKG) for anaplerosis and NADPH to support antioxidant defense. In this study, we show that allosteric inhibitors of mutant IDH1 (mIDH1) are potent wtIDH1 inhibitors under conditions present in the TME. We demonstrate that low magnesium levels facilitate allosteric inhibition of wtIDH1, which is lethal to cancer cells when nutrients are limited. Furthermore, the Food & Drug Administration (FDA)-approved mIDH1 inhibitor ivosidenib (AG-120) dramatically inhibited tumor growth in preclinical models of pancreatic cancer, highlighting this approach as a potential therapeutic strategy against wild-type IDH1 cancers.

Nuclear Receptor 4A2 (NR4A2/NURR1) Regulates Autophagy and Chemoresistance in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor prognosis and chemotherapy with gemcitabine has limited effects and is associated with development of drug resistance. Treatment of Panc1 and MiaPaca2 pancreatic cancer cells with gemcitabine induced expression of the orphan nuclear receptor 4A2 (NURR1) and analysis of the cancer genome atlas indicated the NURR1 is overexpressed in pancreatic tumors and is a negative prognostic factor for patient survival. Results of NURR1 knockdown or treatment with the NURR1 antagonist 1,1-bis(3΄-indolyl)-1-(p-chlorophenyl)methane (C-DIM 12) demonstrated that NURR1 was pro-oncogenic in pancreatic cancer cells and regulated cancer cell and tumor growth and survival. NURR1 is induced by gemcitabine and serves as a key drug-resistance factor and is also required for gemcitabine-induced cytoprotective autophagy. NURR1 regulated genes were determined by RNA sequencing of mRNAs expressed in MiaPaCa2 cells expressing NURR1 and in CRISPR/Cas9 gene edited cells for NURR1 knockdown and KEGG enrichment analysis of the differentially expressed genes showed that autophagy was the major pathway regulated by NURR1. Moreover, NURR1 regulated expression of two major autophagic genes ATG7 and ATG12 which are also overexpressed in pancreatic tumors and like NURR1 are negative prognostic factors for patient survival. Thus, gemcitabine-induced cytoprotective autophagy is due to the NURR1 - ATG7/ATG12 axis and this can be targeted and disrupted by NURR1 antagonist C-DIM12 demonstrating the potential clinical applications for combination therapies with gemcitabine and NURR1 antagonists.

RNA-Binding Protein HuR Regulates Both Mutant and Wild-Type IDH1 in IDH1-Mutated Cancer.

Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated metabolic enzyme in human malignancy. A heterozygous genetic alteration, arginine 132, promotes the conversion of α-ketoglutarate to D-2-hydroxyglutarate (2-HG). Although pharmacologic inhibitors of mutant IDH1 are promising, resistance mechanisms to targeted therapy are not understood. Additionally, the role of wild-type IDH1 (WT.IDH1) in cancer requires further study. Recently, it was observed that the regulatory RNA-binding protein, HuR (ELAVL1), protects nutrient-deprived cancer cells without IDH1 mutations, by stabilizing WT.IDH1 transcripts. In the present study, a similar regulatory effect on both mutant (Mut.IDH1) and WT.IDH1 transcripts in heterozygous IDH1-mutant tumors is observed. In ribonucleoprotein immunoprecipitation assays of IDH1-mutant cell lines, wild-type and mutant IDH1 mRNAs each bound to HuR. Both isoforms were profoundly downregulated at the mRNA and protein levels after genetic suppression of HuR (siRNAs or CRISPR deletion) in HT1080 (R132C IDH1 mutation) and BT054 cells (R132H). Proliferation and invasion were adversely affected after HuR suppression and metabolomic studies revealed a reduction in Pentose Phosphate Pathway metabolites, nucleotide precursors, and 2-HG levels. HuR-deficient cells were especially sensitive to stress, including low glucose conditions or a mutant IDH1 inhibitor (AGI-5198). IDH1-mutant cancer cells were rescued by WT.IDH1 overexpression to a greater extent than Mut.IDH1 overexpression under these conditions. This study reveals the importance of HuR's regulation of both mutant and wild-type IDH1 in tumors harboring a heterozygous IDH1 mutation with implications for therapy. IMPLICATIONS: This study highlights the HuR-IDH1 (mutant and wild-type IDH1) regulatory axis as a critical, actionable therapeutic target in IDH1-mutated cancer, and incomplete blockade of the entire HuR-IDH1 survival axis would likely diminish the efficacy of drugs that selectively target only the mutant isoenzyme.

Large mediastinal mass in a 15-year-old boy.

Hyperimmunoglobulin E syndrome is a rare multisystem inherited disorder characterised by high serum IgE levels, skin disorder causing eczema, dermatitis, recurrent staphylococcal infections and pulmonary infections and various skeletal and connective tissue abnormalities. Common presentation is with recurrent skin and sinopulmonary infections. Several features unrelated to immune system such as characteristic facial features, hyperextensibility of joints, multiple bone fractures and craniosynostosis have been described in the literature. We describe a rare presentation of this disease with invasive aspergillosis presenting as mediastinal mass with extension to mediastinal structures and pulmonary vasculature.

Corrigendum: Metabolic Dependencies in Pancreatic Cancer.

[This corrects the article DOI: 10.3389/fonc.2018.00617.].

Metabolic Dependencies in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDA) is a highly lethal cancer with a long-term survival rate under 10%. Available cytotoxic chemotherapies have significant side effects, and only marginal therapeutic efficacy. FDA approved drugs currently used against PDA target DNA metabolism and DNA integrity. However, alternative metabolic targets beyond DNA may prove to be much more effective. PDA cells are forced to live within a particularly severe microenvironment characterized by relative hypovascularity, hypoxia, and nutrient deprivation. Thus, PDA cells must possess biochemical flexibility in order to adapt to austere conditions. A better understanding of the metabolic dependencies required by PDA to survive and thrive within a harsh metabolic milieu could reveal specific metabolic vulnerabilities. These molecular requirements can then be targeted therapeutically, and would likely be associated with a clinically significant therapeutic window since the normal tissue is so well-perfused with an abundant nutrient supply. Recent work has uncovered a number of promising therapeutic targets in the metabolic domain, and clinicians are already translating some of these discoveries to the clinic. In this review, we highlight mitochondria metabolism, non-canonical nutrient acquisition pathways (macropinocytosis and use of pancreatic stellate cell-derived alanine), and redox homeostasis as compelling therapeutic opportunities in the metabolic domain.