Epidemiology of cranial infections in battlefield-related penetrating and open cranial injuries.

BACKGROUND: Penetrating brain injuries are a potentially lethal injury associated with substantial morbidity and mortality. We examined characteristics and outcomes among military personnel who sustained battlefield-related open and penetrating cranial injuries during military conflicts in Iraq and Afghanistan. METHODS: Military personnel wounded during deployment (2009-2014) were included if they sustained an open or penetrating cranial injury and were admitted to participating hospitals in the United States. Injury characteristics, treatment course, neurosurgical interventions, antibiotic use, and infection profiles were examined. RESULTS: The study population included 106 wounded personnel, of whom 12 (11.3%) had an intracranial infection. Posttrauma prophylactic antibiotics were prescribed in more than 98% of patients. Patients who developed central nervous system (CNS) infections were more likely to have undergone a ventriculostomy ( p = 0.003), had a ventriculostomy in place for a longer period (17 vs. 11 days; p = 0.007), had more neurosurgical procedures ( p < 0.001), and have lower presenting Glasgow Coma Scale ( p = 0.01) and higher Sequential Organ Failure Assessment scores ( p = 0.018). Time to diagnosis of CNS infection was a median of 12 days postinjury (interquartile range, 7-22 days) with differences in timing by injury severity (critical head injury had median of 6 days, while maximal [currently untreatable] head injury had a median of 13.5 days), presence of other injury profiles in addition to head/face/neck (median, 22 days), and the presence of other infections in addition to CNS infections (median, 13.5 days). The overall length of hospitalization was a median of 50 days, and two patients died. CONCLUSION: Approximately 11% of wounded military personnel with open and penetrating cranial injuries developed CNS infections. These patients were more critically injured (e.g., lower Glasgow Coma Scale and higher Sequential Organ Failure Assessment scores) and required more invasive neurosurgical procedures. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level IV.

Novel Dihydropyrimidinone Derivatives as Potential P-Glycoprotein Modulators.

P-glycoprotein (Pgp), an ATP binding cassette (ABC) transporter, is an ATP-dependent efflux pump responsible for cancer multidrug resistance. As part of efforts to identify human Pgp (hPgp) inhibitors, we prepared a series of novel triazole-conjugated dihydropyrimidinones using a synthetic approach that is well suited for obtaining compound libraries. Several of these dihydropyrimidinone derivatives modulate human P-glycoprotein (hPgp) activity with low micromolar EC50 values. Molecular docking studies suggest that these compounds bind to the M-site of the transporter.

Risk factors for abdominal surgical site infection after exploratory laparotomy among combat casualties.

BACKGROUND: Surgical site infections (SSIs) are well-recognized complications after exploratory laparotomy for abdominal trauma; however, little is known about SSI development after exploration for battlefield abdominal trauma. We examined SSI risk factors after exploratory laparotomy among combat casualties. METHODS: Military personnel with combat injuries sustained in Iraq and Afghanistan (June 2009 to May 2014) who underwent laparotomy and were evacuated to participating US military hospitals were included. Log-binominal regression was used to identify SSI risk factors. RESULTS: Of 4,304 combat casualties, 341 patients underwent a total of 1,053 laparotomies. Abdominal SSIs were diagnosed in 49 patients (14.4%): 8% with organ space SSI, 4% with deep incisional SSI, and 4% with superficial SSIs (4 patients had multiple SSIs). Patients with SSIs had more colorectal (p < 0.001), small bowel (p = 0.010), duodenum (p = 0.006), pancreas (p = 0.032), and abdominal vascular injuries (p = 0.040), as well as prolonged open abdomen (p = 0.004) and more infections diagnosed before the SSI (or final exploratory laparotomy) versus non-SSI patients (p < 0.001). Sustaining colorectal injuries (risk ratio [RR], 3.20; 95% confidence interval [CI], 1.58-6.45), duodenum injuries (RR, 6.71; 95% CI, 1.73-25.58), and being diagnosed with prior infections (RR, 10.34; 95% CI, 5.05-21.10) were independently associated with any SSI development. For either organ space or deep incisional SSIs, non-intra-abdominal infections, fecal diversion, and duodenum injuries were independently associated, while being injured via an improvised explosive device was associated with reduced likelihood compared with penetrating nonblast (e.g., gunshot wounds) injuries. Non-intra-abdominal infections and hypotension were independently associated with organ space SSIs development alone, while sustaining blast injuries were associated with reduced likelihood. CONCLUSION: Despite severity of injuries and the battlefield environment, the combat casualty laparotomy SSI rate is relatively low at 14%, with similar risk factors and rates reported following severe civilian trauma. LEVEL OF EVIDENCE: Epidemiological, level III.

TNF Receptor Type II as an Emerging Drug Target for the Treatment of Cancer, Autoimmune Diseases, and Graft-Versus-Host Disease: Current Perspectives and In Silico Search for Small Molecule Binders.

There is now compelling evidence that TNF receptor type II (TNFR2) is predominantly expressed on CD4+Foxp3+ regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and plays a major role in the expansion and function of Tregs and MDSCs. Consequently, targeting of TNFR2 by either antagonists or agonists may represent a novel strategy in the treatment of cancer and autoimmune diseases, by downregulating or upregulating suppressor cell activity. The advance in the understanding of complex structure of TNFR2 and its binding with TNF at molecular levels offers opportunity for structure-guided drug discovery. This article reviews the current evidences regarding the decisive role of TNFR2 in immunosuppressive function of Tregs and MDSCs, and the current effort to develop novel TNFR2-targeting therapeutic agents in the treatment of cancer, autoimmune diseases, and graft-versus-host disease. To shed light on the potential TNFR2-targeting small molecules, we for the first time performed virtual screening of 400,000 natural compounds against the two TNF-binding sites, regions 3 and 4, of TNFR2. Our result showed that the top hits at region 4 had slightly higher docking energies than those at region 3. Nevertheless, free energy calculation from the TNF-TNFR2 molecular dynamics simulation revealed that the binding strength of TNF in region 3 is only one-tenth of that in region 4. This suggests that region 3 is a potentially more viable binding site to be targeted by small molecules than region 4. Therefore, the effectiveness in targeting region 3 of TNFR2 deserves further investigation.

Early infectious outcomes after addition of fluoroquinolone or aminoglycoside to posttrauma antibiotic prophylaxis in combat-related open fracture injuries.

BACKGROUND: We examined combat-related open extremity fracture infections as a function of whether posttrauma antimicrobial prophylaxis included expanded Gram-negative (EGN) coverage. METHODS: Military personnel with open extremity fractures sustained in Iraq and Afghanistan (2009-2014) who transferred to participating hospitals in the United States were assessed. The analysis was restricted to patients with a U.S. hospitalization period of ≥7 days. Prophylaxis was classified as narrow (e.g., IV cefazolin, clindamycin, and/or amoxicillin-clavulanate) or EGN, if the prophylactic regimen included fluoroquinolones and/or aminoglycosides. RESULTS: The study population included 1,044 patients, of which 585 (56%) and 459 (44%) received narrow and EGN coverage, respectively (p < 0.001). Skin and soft-tissue infections (SSTIs) were more common among patients who received narrow prophylaxis compared to EGN coverage (28% vs. 22%; p = 0.029), whereas osteomyelitis rates were comparable between regimens (8%). Similar findings were noted when endpoints were measured at 2 and 4 weeks postinjury. There was no significant difference related to length of hospitalization between narrow and EGN regimens (median: 34 and 32 days, respectively) or operating room visits (median: 5 and 4). A higher proportion of EGN coverage patients had Gram-negative organisms isolated that were not susceptible to fluoroquinolones and/or aminoglycosides (49% vs. 40%; p < 0.001). In a Cox proportional model, narrow prophylaxis was independently associated with an increased risk of extremity SSTIs (hazard ratio: 1.41; 95% confidence interval: 1.09-1.83). DISCUSSION: Despite seeing a small benefit with EGN coverage related to a reduction of SSTIs, it does not decrease the risk of osteomyelitis, and there seems to be a cost of increased antibiotic resistance associated with use. Overall, our findings support the current post-combat trauma antibiotic prophylaxis guidelines, which recommend the use of cefazolin or clindamycin with open fractures. LEVEL OF EVIDENCE: Prognostic/Epidemiological, Level II; Therapy, level IV.

Insights into the structural perturbations of spliced variants of CD44: a modeling and simulation approach.

Transient interactions between cancer stem cells and components of the tumor microenvironment initiate various signaling pathways crucial for carcinogenesis. Predominant hyaluronan (HA) receptor, CD44 is structurally and functionally one of the most variable cell surface receptors having the potential to generate a diverse repertory of CD44 isoforms by alternative splicing of variant exons and post-translational modifications. A structurally distinctive variant of CD44, CD44v10, has an inevitable role in malignant progression, invasion, and metastasis. This can be attributed to the binding of HA with CD44v10, which demonstrates a completely different behavioral pattern as compared to the other spliced variants of CD44 molecule. Absence of a comprehensively predicted crystal structure of human CD44s and CD44v10 is an impediment in understanding the resultant structural alterations caused by the binding of HA. Thus, in this study, we aim to predict the CD44s and CD44v10 structures to their closest native confirmation and study the HA binding-induced structural perturbations using homology modeling, molecular docking, and MD simulation approach. The results depicted that modeled 3D structures of CD44s and CD44v10 isoforms were found to be stable throughout MD simulations; however, a substantial decrease was observed in the binding affinity of HA with CD44v10 (-5.355 kcal/mol) as compared to CD44s. Furthermore, loss and gain of several H-bonds and hydrophobic interactions in CD44v10-HA complex during the simulation process not only elucidated the reason for decreased binding affinity for HA but also prompted toward the plausible role of HA-induced structural perturbations in occurrence and progression of carcinogenesis.

Design and Synthesis of 1,4-dihydropyridine Derivatives as Anti-cancer Agent.

AIMS: A series of 1,4-dihydropyridine based compounds bearing benzylpyridinium moiety have been designed and evaluated for in vitro anticancer activity against glioblastoma U87MG, lung cancer A549 and colorectal adenocarcinoma Caco-2 cell lines using the MTT assay. METHOD: Among these compounds, 7b, 7d, 7e, and 7f exhibited potent anticancer activity against the cell lines tested. The cytotoxicity of the synthesized derivatives was compared to standard drugs (carboplatin, gemcitabine, and daunorubicin). RESULT: Thus, synthesized 1,4-dihydropyridines can be considered as the encouraging molecules for further drug development as anticancer agents.

Clinical relevance of mold culture positivity with and without recurrent wound necrosis following combat-related injuries.

BACKGROUND: Invasive fungal wound infections (IFIs) are a recognized threat for personnel who sustain combat-related blast trauma in Afghanistan. Blast trauma, particularly when dismounted, has wounds contaminated with organic debris and potential for mold infection. Trauma-associated IFI is characterized by recurrent wound necrosis on serial debridement with histologic evidence of invasive molds and/or fungal culture growth. Wounds with mold growth but lacking corresponding recurrent necrosis present a clinical dilemma of whether to initiate antifungal treatment. Our objective was to assess the clinical significance of fungal culture growth without recurrent wound necrosis. METHODS: US military personnel wounded during combat in Afghanistan (June 2009 to August 2011) were assessed for growth of mold from wound cultures and/or histopathologic evidence of IFI. Identified patients were stratified based on clinical wound appearance (with/without recurrent necrosis), and the resultant groups were compared for injury characteristics, clinical management, and outcomes. RESULTS: A total of 96 patients were identified: 77 with fungal elements on histopathology and/or fungal growth plus recurrent wound necrosis and 19 with fungal growth on culture but no wound necrosis after initial debridements. Injury patterns and severity were similar between the groups. Patients with recurrent necrosis had more frequent fevers and leukocytosis during the first 2 weeks after injury, and the majority received antifungal therapy compared with only three patients (16%) without recurrently necrotic wounds. Overall, patients without recurrent wound necrosis had significantly less operative procedures (p = 0.02), shorter stay in the intensive care unit (p < 0.01), and lower rates of high-level amputations (5% vs. 20%) and deaths (none vs. 8%) despite no or infrequent antifungal use. CONCLUSION: The finding of molds on wound culture among patients with blast trauma in the absence of recurrently necrotic wounds on serial debridement does not require systemic antifungal chemotherapy. LEVEL OF EVIDENCE: Therapeutic study, level IV. Prognosti/epidemiologic study, level III.

Combining the pan-aurora kinase inhibitor AMG 900 with histone deacetylase inhibitors enhances antitumor activity in prostate cancer.

Histone deacetylase inhibitors (HDACIs) are being tested in clinical trials for the treatment of solid tumors. While most studies have focused on the reexpression of silenced tumor suppressor genes, a number of genes/pathways are downregulated by HDACIs. This provides opportunities for combination therapy: agents that further disable these pathways through inhibition of residual gene function are speculated to enhance cell death in combination with HDACIs. A previous study from our group indicated that mitotic checkpoint kinases such as PLK1 and Aurora A are downregulated by HDACIs. We used in vitro and in vivo xenograft models of prostate cancer (PCA) to test whether combination of HDACIs with the pan-aurora kinase inhibitor AMG 900 can synergistically or additively kill PCA cells. AMG 900 and HDACIs synergistically decreased cell proliferation activity and clonogenic survival in DU-145, LNCaP, and PC3 PCA cell lines compared to single-agent treatment. Cellular senescence, polyploidy, and apoptosis was significantly increased in all cell lines after combination treatment. In vivo xenograft studies indicated decreased tumor growth and decreased aurora B kinase activity in mice treated with low-dose AMG 900 and vorinostat compared to either agent alone. Pharmacodynamics was assessed by scoring for phosphorylated histone H3 through immunofluorescence. Our results indicate that combination treatment with low doses of AMG 900 and HDACIs could be a promising therapy for future clinical trials against PCA.

Identification & Characterization of lactobacillus salavarius bacteriocins and its relevance in cancer therapeutics.

UNLABELLED: Therapeutic agents with a goal to eradicate cancer needs to capable of inhibiting the growth and kill, any preformed tumor and should also inhibit oncogenic transformation of normal cells to cancer cells. Bacteriocins are bacterial proteins produced to prevent the growth of competing microorganisms in a particular biological niche and have been proved to possess antineoplastic activity. The entire genome of Lactobacillus salavarius was scanned for putative bacteriocins and subsequently these bacteriocins were characterized by subjecting them as functional annotation algorithms. Azurin is a well characterized bacteriocins with proven cytostatic and apoptotic effect against human cancer cell and was taken as control. Functional characterization revealed that the three bacteriocins Lsl_003, Lsl_0510, Lsl_0554 possessed functional properties very similar to that of Azurin. Molecular screening of these bacteriocins against the common cancer targets p53, Rb1 and AR revealed that Lsl_0510 possessed highest binding affinity towards the all the three receptors making it to ideal candidate for future cancer therapeutics. ABBREVIATIONS: P53 - Protein 53, Rb1 - Retinoblastoma 1, AR - Androgen Receptor, Lsl - Lactobacillus salavarius.

Molecular screening of compounds to the predicted Protein-Protein Interaction site of Rb1-E7 with p53- E6 in HPV.

UNLABELLED: Cervical cancer is malignant neoplasm of the cervix uteri or cervical area. Human Papillomaviruses (HPVs) which are heterogeneous groups of small double stranded DNA viruses are considered as the primary cause of cervical cancer, involved in 90% of all Cervical Cancers. Two early HPV genes, E6 and E7, are known to play crucial role in tumor formation. E6 binds with p53 and prevents its translocation and thereby inhibit the ability of p53 to activate or repress target genes. E7 binds to hypophosphorylated Rb and thereby induces cells to enter into premature S-phase by disrupting Rb-E2F complexes. The strategy of the research work was to target the site of interaction of Rb1 -E7 & p53-E6. A total of 88 compounds were selected for molecular screening, based on comprehensive literature survey for natural compounds with anti-cancer activity. Molecular docking analysis was carried out with Molegro Virtual Docker, to screen the 88 chosen compounds and rank them according to their binding affinity towards the site of interaction of the viral oncoproteins and human tumor suppressor proteins. The docking result revealed that Nicandrenone a member of Withanolides family of chemical compounds as the most likely molecule that can be used as a candidate drug against HPV induced cervical cancer. ABBREVIATIONS: HPV - Human Papiloma Virus, HTSP - Human Tumor Suppressor Proteins, VOP - Viral oncoproteins.