Gastric Cancer and Viruses: A Fine Line between Friend or Foe.

Gastric cancer (GC) is a significant health concern worldwide, with a GLOBOCAN estimate of 1.08 million novel cases in 2020. It is the leading cause of disability-adjusted life years lost to cancer, with the fourth most common cancer in males and the fifth most common cancer in females. Strategies are pursued across the globe to prevent gastric cancer progression as a significant fraction of gastric cancers have been linked to various pathogenic (bacterial and viral) infections. Early diagnosis (in Asian countries), and non-invasive and surgical treatments have helped manage this disease with 5-year survival for stage IA and IB tumors ranging between 60% and 80%. However, the most prevalent aggressive stage III gastric tumors undergoing surgery have a lower 5-year survival rate between 18% and 50%. These figures point to a need for more efficient diagnostic and treatment strategies, for which the oncolytic viruses (OVs) appear to have some promise. OVs form a new therapeutic agent class that induces anti-tumor immune responses by selectively killing tumor cells and inducing systemic anti-tumor immunity. On the contrary, several oncogenic viruses have been shown to play significant roles in malignancy progression in the case of gastric cancer. Therefore, this review evaluates the current state of research and advances in understanding the dual role of viruses in gastric cancer.

Interaction Analysis of MRP1 with Anticancer Drugs Used in Ovarian Cancer: In Silico Approach.

Multidrug resistance (MDR) is one of the major therapeutic challenges that limits the efficacy of chemotherapeutic response resulting in poor prognosis of ovarian cancer (OC). The multidrug resistance protein 1 (MRP1) is a membrane-bound ABC transporter involved in cross resistance to many structurally and functionally diverse classes of anticancer drugs including doxorubicin, taxane, and platinum. In this study, we utilize homology modelling and molecular docking analysis to determine the binding affinity and the potential interaction sites of MRP1 with Carboplatin, Gemcitabine, Doxorubicin, Paclitaxel, and Topotecan. We used AutoDock Vina scores to compare the binding affinities of the anticancer drugs against MRP1. Our results depicted Carboplatin < Gemcitabine < Topotecan < Doxorubicin < Paclitaxel as the order of binding affinities. Paclitaxel has shown the highest binding affinity whereas Carboplatin displayed the lowest affinity to MRP1. Interestingly, our data showed that Carboplatin, Paclitaxel, and Topotecan bind specifically to Asn510 residue in the transmembrane domains 1 of the MRP1. Our results suggest that Carboplatin could be an appropriate therapeutic choice against MRP1 in OC as it couples weakly with Carboplatin. Further, our findings also recommend opting Carboplatin with Gemcitabine as a combinatorial chemotherapeutic approach to overcome MDR phenotype associated with recurrent OC.

Incidence and risk factors for secondary pulmonary infections in patients hospitalized with coronavirus disease 2019 pneumonia.

BACKGROUND: Secondary pulmonary infections (SPI) have not been well described in COVID-19 patients. Our study aims to examine the incidence and risk factors of SPI in hospitalized COVID-19 patients with pneumonia. METHODS: This was a retrospective, single-center study of adult COVID-19 patients with radiographic evidence of pneumonia admitted to a regional tertiary care hospital. SPI was defined as microorganisms identified on the respiratory tract with or without concurrent positive blood culture results for the same microorganism obtained at least 48 h after admission. RESULTS: Thirteen out of 244 (5%) had developed SPI during hospitalization. The median of the nadir lymphocyte count during hospitalization was significantly lower in patients with SPI as compared to those without SPI [0.4 K/uL (IQR 0.3-0.5) versus 0.6 K/uL (IQR 0.3-0.9)]. Patients with lower nadir lymphocyte had an increased risk of developing SPI with odds ratio (OR) of 1.21 (95% CI: 1.00 to 1.47, p = 0.04) per 0.1 K/uL decrement in nadir lymphocyte. The baseline median inflammatory markers of CRP [166.4 mg/L vs. 100.0 mg/L, p = 0.01] and d-dimer (18.5 mg/L vs. 1.4 mg/L, p<0.01), and peak procalcitonin (1.4 ng/mL vs. 0.3 ng/mL, p<0.01) and CRP (273.5 mg/L vs. 153.7 mg/L, p<0.01) during hospitalization were significantly higher in SPI group. CONCLUSIONS: The incidence of SPI in hospitalized COVID-19 patients was 5%. Lower nadir median lymphocyte count during hospitalization was associated with an increased OR of developing SPI. The CRP and d-dimer levels on admission, and peak procalcitonin and CRP levels during hospitalization were higher in patients with SPI.

Incidental Discovery of Embryonal Rhabdomyosarcoma on CT Imaging.

Rhabdomyosarcoma is an uncommon soft tissue sarcoma that rarely presents in adults. Clinical presentation is dependent on site and size. We present the case of a woman who presented with acute-onset dyspnoea and whose pathology report confirmed embryonal rhabdomyosarcoma (ERMS) seen as an incidental finding on chest computed tomography. We also describe the clinical, laboratory and radiological work-up conducted to diagnose and manage ERMS in the critical care setting. LEARNING POINTS: Rhabdomyosarcoma is a rare malignancy with a poor prognosis in adults compared with children, especially if it presents in an unfavourable primary site and has an unfavourable histological diagnosis.Immunohistochemical diagnosis remains the gold standard for embryonal rhabdomyosarcoma diagnosis and differentiation from similar malignancies on initial imaging studies.Management of adult rhabdomyosarcoma is usually multimodal with surgical resection and a combination of chemo and radiotherapy.

Hodgkin's Lymphoma Presenting as Multiple Cavitary Lung Lesions.

Hodgkin Lymphoma (HL) typically presents similarly to an infectious etiology, thus awareness of its atypical presentations is essential. We present a case of an adult woman who was found to have HL after presenting with a dry, non-productive cough and showing cavitary lesions on chest computed tomography (CT). We also describe the clinical, laboratory, and radiological workup done leading to the diagnosis and management of HL in a critical care setting. LEARNING POINTS: Cavitary lung lesions, particularly multiloculated, are often caused by mycobacterium tuberculosis (TB), aspergillosis, granulomatosis with polyangiitis, sarcoidosis, and rheumatic nodules.Pulmonary infiltration is a rare disorder of an extra-nodal site in Hodgkin's Lymphoma. The mediastinum and head and neck regions remain the most common sites affected by HL.Radiologically, primary pulmonary HL may mimic pneumonia, carcinoma making the diagnosis unclear.

Structure prediction of transferrin receptor protein 1 (TfR1) by homology modelling, docking, and molecular dynamics simulation studies.

Transferrin receptor protein 1 (TfR1) is an important molecule in anti-cancer therapy. Targeted delivery of such therapeutic compounds improves their cellular uptake and circulation time, thereby enhancing therapeutic efficacy. Drug designing is therefore used to engineer molecules with structures that facilitate specific interactions. However, this process requires a thorough knowledge of all the interactions, including the three-dimensional (3D) and quaternary structures (QS) of the interacting molecules. Since structural information is available for only a part of the full TfR1 sequence, in the present study, we predicted the whole structure of TfR1 using homology modelling, docking, and molecular dynamics simulations. Homology modelling is used to generate 3D structures of TfR1 using MODELLER, I-TASSER, and RaptorX programs. Verify3D and Rampage server evaluated the quality of the resultant models. According to this evaluation, the model built by the RaptorX server and validated by Verify3D (compatibility: 83.82%) had the highest number of residues (95.5%) within the favoured regions of the Ramachandran plot, making it the most reliable 3D protein structure for TfR1 compared with others. The QS of TfR1 was built using HADDOCK and SymmDock docking software, and the results were evaluated by the ligand root mean square deviation (l-RMSD) value computed using the ProFit software. This showed that both HADDOCK and SymmDock gave acceptable results. However, the HADDOCK result was more stable and closest to the native complex structure with disulfide bonds. Therefore, the HADDOCK complex was further refined using both SymmRef and GalaxyRefineComplex until the medium l-RMSD rank was reached. This QS was successfully verified using nanoscale molecular dynamics (NAMD) energy minimization. This model could pave the way for further functional, structural, and therapeutic studies on TfR1.

Identification and analysis of pathogenic nsSNPs in human LSP1 gene.

LSP1 (Lymphocyte-specific protein 1) protein plays an important role in neutrophil motility, fibrinogen matrix proteins adhesion, and trans-endothelial migration. Variation in the LSP1 gene is associated with leukemia and lymphomas in tumor cells of Hodgkin's disease and breast cancer. Despite extensive study on the human LSP1, a comprehensive analysis on the Single Nucleotide Polymorphism (SNPs) of the gene is not available. Therefore, it is of interest to identify, collect, store and analyze the SNPs of the LSP1 gene in relation to several known diseases. Hence, the SNP data (398 rsids) from dbSNP database was downloaded and mapped to the genomic coordinate of "NM_002339.2" transcript expressed by LSP1 (P33241). There were 300 nsSNPs with missense mutation in the dataset. Tools such as SIFT, PROVEAN, Condel, and PolyPhen-2 were further used to identify 29 highly deleterious or damaging on synonymous SNP (nsSNPs) for LSP1. These high confident damaging nsSNPs were further analyzed for disease association using SNPs and GO tool. SNPs of the gene such as nsSNPs C283R, G234R, Y328D and H325P showed disease association with high prevalence.

Antiplatelet therapy in the primary prevention of cardiovascular disease in patients with chronic obstructive pulmonary disease: a randomised controlled proof-of-concept trial.

The APPLE COPD-ICON2 trial is a prospective 2×2 factorial, double-blinded proof-of-concept randomised controlled trial targeting patients with chronic obstructive pulmonary disease (COPD) without prior history of cardiovascular disease. The primary goal of this trial is to investigate if treatment with antiplatelet therapy will produce the predefined cut-off of platelet inhibition measured using the Multiplate test in COPD patients. Eligible patients were randomised to aspirin plus placebo, ticagrelor plus placebo, aspirin plus ticagrelor or placebo only for 6 months. The primary outcome comprises inhibition (binary response) of arachidonic acid- (ASPI test, cut-off <40) and adenosine diphosphate- (ADP test, cut-off <46) induced platelet aggregation at 6 months. 543 patients were screened and 120 patients were recruited with mean age of 67.5 years; 47.5% patients were male. The per-protocol ASPI test response rate to aspirin was 68.3% (95% CI 52.3-80.9%). The per-protocol ADP test response rate to ticagrelaor was 68.8% (95% CI 50.4-82.6%). Platelet response to antiplatelet therapy with aspirin and ticagrelor was not observed in nearly one-third of COPD patients without prior history of cardiovascular disease. These findings support the high pro-thrombotic milieu and the need for further research to determine the effect of antiplatelet/antithrombotic therapy on cardiovascular morbidity and mortality in COPD patients.

Variables predictive of the intensity of postoperative pain following mandibular third molar surgery: a prospective study.

BACKGROUND: The aim of this paper was to identify the most important variables that predict the intensity of postoperative pain following lower third molar surgery. METHODS: A unilateral 100 impacted lower third molar teeth were surgically removed under local anesthesia. Preoperative predictor variables were categorized as demographic, anatomic and radiographic, and operative variables. Evaluation of these variables was performed through personal data, extra and intra oral examination, and radiological examination, while the postoperative pain was recorded by the patient using a visual analogue scale. Statistical analysis was conducted for all the variables to assess their effect on the intensity of postoperative pain. RESULTS: This study composed of one hundred patients;58 males (58%) and 42 females (42%) having 100 mandibular third molar removed surgically. The mean age of patients was 29.4±5.2. Results displayed an increase in postoperative pain related to increase of the patient's age, poor oral hygiene, unfavorable tooth morphology, proximity to the inferior alveolar canal, three sided flap design and increasing the operative time. CONCLUSIONS: Age, oral hygiene, anatomical and operative variables increase the risk of aggravating postoperative pain intensity following mandibular third molar surgery.

Selenite and methylseleninic acid epigenetically affects distinct gene sets in myeloid leukemia: A genome wide epigenetic analysis.

Selenium compounds have emerged as promising chemotherapeutic agents with proposed epigenetic effects, however the mechanisms and downstream effects are yet to be studied. Here we assessed the effects of the inorganic selenium compound selenite and the organic form methylseleninic acid (MSA) in a leukemic cell line K562, on active (histone H3 lysine 9 acetylation, H3K9ac and histone H3 lysine 4 tri-methylation, H3K4me3) and repressive (histone H3 lysine 9 tri-methylation, H3K9me3) histone marks by Chromatin immunoprecipitation followed by DNA sequencing (ChIP-Seq). Both selenite and MSA had major effects on histone marks but the effects of MSA were more pronounced. Gene ontology analysis revealed that selenite affected genes involved in response to oxygen and hypoxia, whereas MSA affected distinct gene sets associated with cell adhesion and glucocorticoid receptors, also apparent by global gene expression analysis using RNA sequencing. The correlation to adhesion was functionally confirmed by a significantly weakened ability of MSA treated cells to attach to fibronectin and linked to decreased expression of integrin beta 1. A striking loss of cellular adhesion was also confirmed in primary patient AML cells. Recent strategies to enhance the cytotoxicity of chemotherapeutic drugs by disrupting the interaction between leukemic and stromal cells in the bone marrow are of increasing interest; and organic selenium compounds like MSA might be promising candidates. In conclusion, these results provide new insight on the mechanism of action of selenium compounds, and will be of value for the understanding, usage, and development of new selenium compounds as anticancer agents.

Histone deacetylase inhibitor SAHA mediates mast cell death and epigenetic silencing of constitutively active D816V KIT in systemic mastocytosis.

Systemic mastocytosis (SM) is a clonal bone marrow disorder, where therapeutical options are limited. Over 90% of the patients carry the D816V point mutation in the KIT receptor that renders this receptor constitutively active. We assessed the sensitivity of primary mast cells (MC) and mast cell lines HMC1.2 (D816V mutated), ROSA (KIT WT) and ROSA (KIT D816V) cells to histone deacetylase inhibitor (HDACi) treatment. We found that of four HDACi, suberoyl anilide hydroxamic acid (SAHA) was the most effective in killing mutated MC. SAHA downregulated KIT, followed by major MC apoptosis. Primary SM patient MC cultured ex vivo were even more sensitive to SAHA than HMC1.2 cells, whereas primary MC from healthy subjects were less affected. There was a correlation between cell death and SM disease severity, where cell death was more pronounced in the case of aggressive SM, with almost 100% cell death among MC from the mast cell leukemia patient. Additionally, ROSA (KIT D816V) was more affected by HDACi than ROSA (KIT WT) cells. Using ChIP qPCR, we found that the level of active chromatin mark H3K18ac/H3 decreased significantly in the KIT region. This epigenetic silencing was seen only in the KIT region and not in control genes upstream and downstream of KIT, indicating that the downregulation of KIT is exerted by specific epigenetic silencing. In conclusion, KIT D816V mutation sensitized MC to HDACi mediated killing, and SAHA may be of value as specific treatment for SM, although the specific mechanism of action requires further investigation.

Ethylene responsive transcription factor ERF109 retards PCD and improves salt tolerance in plant.

BACKGROUND: The ultimate goal of this work was to detect the role of transcription factors (TFs) concordantly expressed with genes related to programmed cell death (PCD) during PCD and salt stress. This work was based on the hypothesis that TFs and their driven genes likely co-express under different stimuli. The conserved superfamily ethylene responsive factor (AP2/ERF) draw attention of the present study as it participates in the response to biotic and abiotic stimuli as well as to program cell death (PCD). RESULTS: RNA-Seq analysis was done for tobacco (N. benthamiana) leaves exposed to oxalic acid (OA) at 20 mM for 0, 2, 6, 12 and 24 h to induce PCD. Genes up-regulated after 2 h of OA treatment with known function during PCD were utilized as landmarks to select TFs with concordant expression. Knockdown mutants of these TFs were generated in tobacco via virus induced gene silencing (VIGS) in order to detect their roles during PCD. Based on the results of PCD assay, knockout (KO) T-DNA insertion mutants of Arabidopsis as well as over-expression lines of two selected TFs, namely ERF109 and TFIID5, analogs to those in tobacco, were tested under salt stress (0, 100, 150 and 200 mM NaCl). CONCLUSIONS: Results of knockdown mutant tobacco cells confirmed the influence of these two TFs during PCD. Knockout insertion mutants and over-expression lines indicated the role of ERF109 in conferring salt tolerance in Arabidopsis.

Novel therapies for constipation.

Constipation is a common medical problem and when standard laxatives fail it can be difficult to treat. Different aetiologies require tailored therapeutic approaches. Simple constipation may only require dietary manipulation while severe neurological or slow transit constipation may need pharmacologic intervention. Recently new drug therapies have been introduced. PubMed and Ovid were searched for reviews, systematic reviews and meta-analysis published since 2003 using the terms: constipation, prucalopride, linaclotide and lubiprostone. This review summarizes potential novel therapies identified as effective in the management of chronic constipation. Prucalopride is a selective 5-hydroxytryptamine receptor agonist. The prucalopride study was in patients, largely women with idiopathic constipation showed improved spontaneous complete bowel movement (SCBM) at a dose of 2 mg a day with few adverse events reported. Linaclotide is a 14-amino acid peptide guanylate cyclase-C agonist. The linaclotide study was carried out in patients with irritable bowel syndrome, constipation group (IBS-C). There was significant improvement of bowel evacuation and symptom resolution in patients on the active treatment arm. Lubiprostone activates type-2 chloride channels, increasing intestinal fluid secretion. In the trials of this drug, the lubiprostone arms had a greater mean number of SCBM. The novel therapies, prucalopride, lubiprostone, and linaclotide had very different modes of action yet, all three have been shown to be efficacious and safe in the treatment dose for constipation.

Nanosecond pulse electrical fields used in conjunction with multi-wall carbon nanotubes as a potential tumor treatment.

The objectives of this communication were to fabricate pure samples of multi-walled carbon nanotubes (MWCNTs) and to determine their toxicity in tumor cell lines. MWCNTs were dispersed in a concentration of the surfactant T80 that was minimally toxic. Cell-type variation in toxicity to MWCNTs was observed but was not significantly different to unexposed controls. Additionally, we investigated the increased cell killing of the pancreatic cancer cell line PANC1 when exposed to ultrashort (nanosecond) pulsed electrical fields (nsPEF) in the presence of MWCNTs as a potential form of cancer therapy. We hypothesized that the unique electronic properties of MWCNTs disrupt cell function, leading to cell death, when cells are exposed to nsPEF. We observed a 2.3-fold reduction in cell survival in cells pulsed in the presence of MWCNTs compared to pulsed controls. This study demonstrates that ultrashort pulse electrical field applications have enhanced killing effects when cells are previously grown in the presence of MWCNTs, suggesting that the electrical properties of MWCNTs play a vital role in this process and is suggestive of a synergistic interaction between these nanomaterials and electrical fields.

From upfront nephrectomy to preoperative chemotherapy and back: a single institution experience in the treatment of Wilms tumor.

BACKGROUND: Over the past decades, 2 different approaches for the treatment of Wilms tumor have emerged: upfront nephrectomy (UN) and preoperative chemotherapy (PC), with adjuvant treatment adjusted to stage, histology, and chemotherapy response. METHODS: In July 2005, we switched our strategy from UN to PC. This study is a retrospective review of patients treated at our institution between January 2003 and October 2007. RESULTS: Thirty-six children (20 males) with Wilms tumor were studied. Median age was 3.45 years (range: 0.3 to 15.8 y). Nineteen patients (53%) were treated according to the International Society of Paediatric Oncology 93-01/German Pediatric Oncology Hematology, Group protocol (PC group) and 17 (47%) according to the National Wilms' Tumor Study-5 (UN group). UN group received more radiation dose and less cumulative doses of doxorubicin. The 3-year event-free survival and overall survival estimates for the whole group were 86% and 89%, respectively. Survival estimates were similar in both groups. CONCLUSIONS: The use of PC reduced the use of radiation; however, patients treated using the SIOP 93-01/German Pediatric Oncology Hematology Group protocol received higher cumulative doses of doxorubicin; these doses were believed to be high in this young group of patients with potential for long-term toxicity. Although selecting a specific protocol for Wilms tumor is important, the development of surgical expertise and referral to specialized centers takes priority.

Pediatric Burkitt's lymphoma: CT findings.

PURPOSE: To review and analyze all CT scans of the cases of Burkitt's lymphoma (BL) in children diagnosed in our institution. MATERIALS AND METHODS: A retrospective analysis of 33 children with BL between the years 2003 and 2005 seen in our institution was undertaken. Twenty-nine male and four female patients from age 3 to 16 years (with a mean age 5.9 years) were reviewed. RESULTS: The gastrointestinal tract was involved in 19 patients (57.5%), kidneys in 9 (27.2%), peritoneum in 8 (24.2%), liver in 4 (12.1%), spleen in 3 (9%), adrenals in 3 (9%), and pancreas in 1 patient (3%). Extra-nodal head and neck involvement was seen in eight patients (24.2%). Bone involvement in four (12.1%), lung in three (9%), heart in two (6%), skin in two (6%), and testis in one (3%) of these patients. Abdominal lymph nodes were enlarged in 21 children (63.6%), while cervical lymph nodes were enlarged in 8 (24.2%). CONCLUSION: CT proved to be an invaluable tool in the characterization of the disease processes in these children. In addition, it provided us with useful information about the anatomical distribution, patterns of involvement, as well as complications of BL.