Nanostructured bioactive glasses: A bird's eye view on cancer therapy.

Bioactive glasses (BGs) arewell known for their successful applications in tissue engineering and regenerative medicine. Recent experimental studies have shown their potential usability in oncology, either alone or in combination with other biocompatible materials, such as biopolymers. Direct contact with BG particles has been found to cause toxicity and death in specific cancer cells (bone-derived neoplastic stromal cells) in vitro. Nanostructured BGs (NBGs) can be doped with anticancer elements, such as gallium, to enhance their toxic effects against tumor cells. However, the molecular mechanisms and intracellular targets for anticancer compositions of NBGs require further clarification. NBGs have been successfully evaluated for use in various well-established cancer treatment strategies, including cancer hyperthermia, phototherapy, and anticancer drug delivery. Existing results indicate that NBGs not only enhance cancer cell death, but can also participate in the regeneration of lost healthy tissues. However, the application of NBGs in oncology is still in its early stages, and numerous unanswered questions must be addressed. For example, the impact of the composition, biodegradation, size, and morphology of NBGs on their anticancer efficacy should be defined for each type of cancer and treatment strategy. Moreover, it should be more clearly assessed whether NBGs can shrink tumors, slow/stop cancer progression, or cure cancer completely. In this regard, the use of computational studies (in silico methods) is highly recommended to design the most effective glass formulations for cancer therapy approaches and to predict, to some extent, the relevant properties, efficacy, and outcomes. This article is categorized under: Implantable Materials and Surgical Technologies > Nanomaterials and Implants Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Selection of patients for large mailed fecal immunochemical test colorectal cancer screening outreach programs: A systematic review.

OBJECTIVE: Digital health care offers an opportunity to scale and personalize cancer screening programs, such as mailed outreach for colorectal cancer (CRC) screening. However, studies that describe the patient selection strategy and process for CRC screening are limited. Our objective was to evaluate implementation strategies for selecting patients for CRC screening programs in large health care systems. METHODS: We conducted a systematic review of 30 studies along with key informant surveys and interviews to describe programmatic implementation strategies for selecting patients for CRC screening. PubMed and Embase were searched since inception through December 2018, and hand searches were performed of the retrieved reference lists but none were incorporated (n = 0). No language exclusions were applied. RESULTS: Common criteria for outreach exclusion included: being up-to-date with routine CRC screening (n = 22), comorbidities (n = 20), and personal history (n = 22) or family history of cancer (n = 9). Key informant surveys and interviews were performed (n = 28) to understand data sources and practices for patient outreach selection, and found that 13 studies leveraged electronic medical care records, 10 studies leveraged a population registry (national, municipal, community, health), 4 studies required patient opt-in, and 1 study required primary care provider referral. Broad ranges in fecal immunochemical test completion were observed in community clinic (n = 8, 31.0-59.6%), integrated health system (n = 5, 21.2-82.7%), and national regional CRC screening programs (n = 17, 23.0-64.7%). Six studies used technical codes, and four studies required patient self-reporting from a questionnaire to participate. CONCLUSION: This systematic review provides health systems with the diverse outreach practices and technical tools to support efforts to automate patient selection for CRC screening outreach.

Feasibility and delivery of patient-reported outcomes in clinical practice among racially diverse bladder and prostate cancer patients.

OBJECTIVE: To assess the feasibility of enrollment and collecting patient-reported outcome (PRO) data as part of routine clinical urologic care for bladder and prostate cancer patients and examine overall patterns and racial variations in PRO use and symptom reports over time. SUBJECTS/PATIENTS AND METHODS: We recruited 76 patients (n = 29 Black and n = 47 White) with prostate or bladder cancer at a single, comprehensive cancer center. The majority of prostate cancer patients had intermediate risk (57%) disease and underwent either radiation or prostatectomy. Over half (58%) of bladder cancer patients had muscle invasive disease and underwent cystectomy. Patients were asked to complete PRO symptom surveys using their preferred mode [web- or phone-based interactive voice response (IVR)]. Symptom summary reports were shared with providers during visits. Surveys were completed at 3 time points and assessed urinary, sexual, gastrointestinal, anxiety/depression, and sleep symptoms. Feasibility of enrollment and survey completion were calculated, and linear mixed effects models estimated differences in outcomes by race and time. RESULTS: Sixty three percent of study participants completed all PRO measures at all 3 time points. Black patients were more likely to select IVR as their survey mode (40% vs. 13%, P < 0.05), and less likely to complete all surveys (55% vs. 74%, P = 0.13). Patients using IVR were also less likely to complete all surveys (41% vs. 69%, P = 0.046). CONCLUSIONS: Reported preferences for survey mode and completion rates differ by race, which may influence survey completion rates and highlight potential obstacles for equitable implementation of PROs into clinical care.

The Impact of IV Electrolyte Replacement on the Fluid Balance of Critically Ill Surgical Patients.

Avoiding excess fluid administration is necessary when managing critically ill surgical patients. The aim of this study was to delineate the current practices of IV electrolyte (IVE) replacement in a surgical ICU and quantify their contribution to the fluid balance (FB) status. Patients admitted to the surgical ICU over a six-month period were reviewed. Patients undergoing dialysis and those with ICU stay <72 hours were excluded. A total of 248 patients were included. The median age was 60 years, and 57 per cent were male. Overall, 1131 patient ICU days were analyzed. The median daily FB was 672 mL. IVEs were administered in 62 per cent of ICU days. In days that IVEs were used, negative FB was significantly less likely to be achieved (62% vs 69%, P = 0.02). The most commonly administered IVE was calcium (32% of ICU days); however, the largest volume of IVE was administered in the form of phosphorus (median 225 mL). Diuretics were administered in 17 per cent of ICU days. Patients who received diuretics were significantly more likely to receive IVE (70% vs 61%, P = 0.02). Administration of IVE may contribute to the daily positive FB of surgical ICU patients. Implementation of practices that can ameliorate this effect is encouraged.

Early hyperbaric oxygen therapy improves survival in a model of severe sepsis.

Sepsis is a major clinical challenge, with therapy limited to supportive interventions. Therefore, the search for novel remedial approaches is of great importance. We addressed whether hyperbaric oxygen therapy (HBOT) could improve the outcome of sepsis using an acute experimental mouse model. Sepsis was induced in male CD-1 mice by cecal ligation and puncture (CLP) tailored to result in 80-90% mortality within 72 h of the insult. After CLP, mice were randomized into two groups receiving HBOT or not at different times after the initial insult or subjected to multiple HBOT treatments. HBOT conditions were 98% oxygen pressurized to 2.4 atmospheres for 1 h. HBOT within 1 h after CLP resulted in 52% survival in comparison with mice that did not receive the treatment (13% survival). Multiple HBOT at 1 and 6 h or 1, 6, and 21 h displayed an increase in survival of >50%, but they were not significantly different from a single treatment after 1 h of CLP. Treatments at 6 or 21 h after CLP, excluding the 1 h of treatment, did not show any protective effect. Early HBO treatment did not modify bacterial counts after CLP, but it was associated with decreased expression of TNF-α, IL-6, and IL-10 expression in the liver within 3 h after CLP. The decrease of cytokine expression was reproduced in cultured macrophages after exposure to HBOT. Early HBOT could be of benefit in the treatment of sepsis, and the protective mechanism may be related to a reduction in the systemic inflammatory response.

An evolutionary perspective on immunometabolism.

Metabolism is at the core of all biological functions. Anabolic metabolism uses building blocks that are either derived from nutrients or synthesized de novo to produce the biological infrastructure, whereas catabolic metabolism generates energy to fuel all biological processes. Distinct metabolic programs are required to support different biological functions. Thus, recent studies have revealed how signals regulating cell quiescence, proliferation, and differentiation also induce the appropriate metabolic programs. In particular, a wealth of new studies in the field of immunometabolism has unveiled many examples of the connection among metabolism, cell fate decisions, and organismal physiology. We discuss these findings under a unifying framework derived from the evolutionary and ecological principles of life history theory.

Operative treatment for intussusception: Should an incidental appendectomy be performed?

BACKGROUND/OBJECTIVES: An incidental appendectomy is performed by some surgeons during operative treatment for intussusception to eliminate future appendicitis as a diagnostic consideration. However, an appendectomy can increase the risk of infection and other noninfectious complications making an incidental appendectomy controversial. We examined outcomes for surgical intervention for intussusception with appendectomy (SWA) compared to surgical reduction alone (SRA). METHODS: The Pediatric Health Information System database, 8/2008-9/2015, was retrospectively analyzed for patients under the age of five who required an operative intervention for intussusception without bowel resection. Demographic data and postoperative outcomes were analyzed. Available data included need for postoperative enema, subsequent small bowel obstruction, recurrent intussusception, length of stay (LOS), and adjusted total cost (ATC). RESULTS: Fifty-seven percent (748/1312) of patients had appendectomy performed during surgical reduction, 564 (43%) did not. ATC ($10,594 vs. $8939, p < 0.001) and LOS (3.0 vs. 2.48, p < 0.001) are higher in the SWA group. Rates of readmission are similar, but post-operative small bowel obstruction may be higher in the SWA group (1.3% vs. 0.35%, p = 0.06). CONCLUSION: There is a higher mean LOS and ATC in the SWA group. This study suggests that appendectomy during surgery for uncomplicated intussusception should be reconsidered and requires further investigation. TYPE OF STUDY: retrospective comparative study. LEVEL OF EVIDENCE: III.

Squalene synthase as a target for Chagas disease therapeutics.

Trypanosomatid parasites are the causative agents of many neglected tropical diseases and there is currently considerable interest in targeting endogenous sterol biosynthesis in these organisms as a route to the development of novel anti-infective drugs. Here, we report the first x-ray crystallographic structures of the enzyme squalene synthase (SQS) from a trypanosomatid parasite, Trypanosoma cruzi, the causative agent of Chagas disease. We obtained five structures of T. cruzi SQS and eight structures of human SQS with four classes of inhibitors: the substrate-analog S-thiolo-farnesyl diphosphate, the quinuclidines E5700 and ER119884, several lipophilic bisphosphonates, and the thiocyanate WC-9, with the structures of the two very potent quinuclidines suggesting strategies for selective inhibitor development. We also show that the lipophilic bisphosphonates have low nM activity against T. cruzi and inhibit endogenous sterol biosynthesis and that E5700 acts synergistically with the azole drug, posaconazole. The determination of the structures of trypanosomatid and human SQS enzymes with a diverse set of inhibitors active in cells provides insights into SQS inhibition, of interest in the context of the development of drugs against Chagas disease.

Receipt of guideline-concordant treatment in elderly prostate cancer patients.

PURPOSE: To examine the proportion of elderly prostate cancer patients receiving guideline-concordant treatment, using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. METHODS AND MATERIALS: A total of 29,001 men diagnosed in 2004-2007 with localized prostate cancer, aged 66 to 79 years, were included. We characterized the proportion of men who received treatment concordant with the National Comprehensive Cancer Network guidelines, stratified by risk group and age. Logistic regression was used to examine covariates associated with receipt of guideline-concordant management. RESULTS: Guideline concordance was 79%-89% for patients with low- or intermediate-risk disease. Among high-risk patients, 66.6% of those aged 66-69 years received guideline-concordant management, compared with 51.9% of those aged 75-79 years. Discordance was mainly due to conservative management-no treatment or hormone therapy alone. Among the subgroup of patients aged ≤76 years with no measured comorbidity, findings were similar. On multivariable analysis, older age (75-79 vs 66-69 years, odds ratio 0.51, 95% confidence interval 0.50-0.57) was associated with a lower likelihood of guideline concordance for high-risk prostate cancer, but comorbidity was not. CONCLUSIONS: There is undertreatment of elderly but healthy patients with high-risk prostate cancer, the most aggressive form of this disease.

Iron oxide nanoparticles as a clinically acceptable delivery platform for a recombinant blood-stage human malaria vaccine.

This study explored the novel use of iron oxide (IO) nanoparticles (<20 nm) as a vaccine delivery platform without additional adjuvants. A recombinant malaria vaccine antigen, the merozoite surface protein 1 (rMSP1), was conjugated to IO nanoparticles (rMSP1-IO). Immunizations in outbred mice with rMSP1-IO achieved 100% responsiveness with antibody titers comparable to those obtained with rMSP1 formulated with a clinically acceptable adjuvant, Montanide ISA51 (2.7×10 vs. 1.6×10; respectively). Only rMSP1-1O could induce significant levels (80%) of parasite inhibitory antibodies. The rMSP1-IO was highly stable at 4°C and was amenable to lyophilization, maintaining its antigenicity, immunogenicity, and ability to induce inhibitory antibodies. Further testing in nonhuman primates, Aotus monkeys, also elicited 100% immune responsiveness and high levels of parasite inhibitory antibodies (55-100% inhibition). No apparent local or systemic toxicity was associated with IO immunizations. Murine macrophages and dendritic cells efficiently (>90%) internalized IO nanoparticles, but only the latter were significantly activated, with elevated expression/secretion of CD86, cytokines (IL-6, TNF-α, IL1-b, IFN-γ, and IL-12), and chemokines (CXCL1, CXCL2, CCL2, CCL3, CCL4, and CXCL10). Thus, the IO nanoparticles is a novel, safe, and effective vaccine platform, with built-in adjuvancy, that is highly stable and field deployable for cost-effective vaccine delivery.

Structure-based development of bacterial nitroreductase against nitrobenzodiazepine-induced hypnosis.

Nitrobenzodiazepine (NBDZ) is an addictive drug of the abused substances that causes severe neurological effects and even death. Bacterial type I nitroreductase NfsB (EC 1.5.1.34) has been reported to catalyze NBDZ into inactive metabolite 7-amino-benzodiazepine (7ABDZ) with promising activity, so as to become an attractive candidate for treatment of NBDZ overdose and addiction. Here, we investigate the nitroreduction of an NBDZ, flunitrazepam (FZ), by various mutants of NfsB designed from the solved crystal structure and characterize their in vitro and in vivo potency. Conformational changes occurred in the active site of N71S/F124W in contrast to the wild-type, including the flipping on the aromatic rings of W124 and F70 as well as the extension on the hydrogen bond network between flavin mononucleotide (FMN) and S71, which allow the significant enlargement in the active site pocket. In the complex structure of N71S/F124W and nicotinamide (NIA), stacking sandwich attractions of W124-FMN-NIA were also found, implying the importance of W124 in substrate accessibility. Consequently, N71S/F124W exhibited increased 7AFZ production in vitro with nearly no toxicity and reduced 50% sleeping time (hypnosis) in vivo. Taken together, we demonstrate for the first time that N71S/F124W can serve as an effective antidote for NBDZ-induced hypnosis and provide the molecular basis for designing NfsB and the like in the future.

The DNA-recognition fold of Sso7c4 suggests a new member of SpoVT-AbrB superfamily from archaea.

Organisms growing at elevated temperatures face the challenge of maintaining the integrity of their genetic materials. Archaea possess unique chromatin proteins for gene organization and information processing. We present the solution structure of Sso7c4 from Sulfolobus solfataricus, which has a homodimeric DNA-binding fold forming a swapped ß-loop-ß 'Tai-Chi' topology. The fold is reminiscent of the N-terminal DNA-binding domain of AbrB and MazE. In addition, several amide resonances in the heteronuclear single quantum coherence spectra of Sso7c4 are shifted and broadened with the addition of small amounts of duplex DNA oligomers. The locations of the corresponding amides in the Sso7c4 structure define its DNA-interacting surface. NMR spectra of DNA titrated with the protein further indicated that Sso7c4 interacts with DNA in the major groove. Taken together, a plausible model for the Sso7c4-DNA complex is presented, in which the DNA double helix is curved around the protein dimer.

Artificial modulation of the gating behavior of a K+ channel in a KvAP-DNA chimera.

We present experiments where the gating behavior of a voltage-gated ion channel is modulated by artificial ligand binding. We construct a channel-DNA chimera with the KvAP potassium channel reconstituted in an artificial membrane. The channel is functional and the single channel ion conductivity unperturbed by the presence of the DNA. However, the channel opening probability vs. bias voltage, i.e., the gating, can be shifted considerably by the electrostatic force between the charges on the DNA and the voltage sensing domain of the protein. Different hybridization states of the chimera DNA thus lead to different response curves of the channel.

Glycan array on aluminum oxide-coated glass slides through phosphonate chemistry.

A new type of glycan array covalently or noncovalently attached to aluminum oxide-coated glass (ACG) slides has been developed for studies of enzymatic reactions and protein binding. To prepare the noncovalent array, glycans with a polyfluorinated hydrocarbon (-C(8)F(17)) tail are spotted robotically onto the ACG slide surface containing a layer of polyfluorinated hydrocarbon terminated with phosphonate. After incubation and washing, the noncovalent array can be characterized by MS-TOF via ionization/desorption at a low laser energy without addition of matrix. A representative cellotetraose array was developed to study the activity and specificity of different cellulases and to differentiate the exo- and endoglucanase activities. To prepare the covalent array, glycans with a phosphonic acid tail were synthesized and spotted robotically onto the ACG slide surface. After incubation, the slides can be used directly for quantitative protein binding analysis. Compared to the preparation of glycan arrays on glass slides and other surfaces, this method of arraying using phosphonic acid reacting with ACG is more direct, convenient, and effective and represents a new platform for the high-throughput analysis of protein-glycan interactions.

Biochemical and immunological studies of nucleocapsid proteins of severe acute respiratory syndrome and 229E human coronaviruses.

Severe acute respiratory syndrome (SARS) is a serious health threat and its early diagnosis is important for infection control and potential treatment of the disease. Diagnostic tools require rapid and accurate methods, of which a capture ELISA method may be useful. Toward this goal, we have prepared and characterized soluble full-length nucleocapsid proteins (N protein) from SARS and 229E human coronaviruses. N proteins form oligomers, mostly as dimers at low concentration. These two N proteins degrade rapidly upon storage and the major degraded N protein is the C-terminal fragment of amino acid (aa) 169-422. Taken together with other data, we suggest that N protein is a two-domain protein, with the N-terminal aa 50-150 as the RNA-binding domain and the C-terminal aa 169-422 as the dimerization domain. Polyclonal antibodies against the SARS N protein have been produced and the strong binding sites of the anti-nucleocapsid protein (NP) antibodies produced were mapped to aa 1-20, aa 150-170 and aa 390-410. These sites are generally consistent with those mapped by sera obtained from SARS patients. The SARS anti-NP antibody was able to clearly detect SARS virus grown in Vero E6 cells and did not cross-react with the NP from the human coronavirus 229E. We have predicted several antigenic sites (15-20 amino acids) of S, M and N proteins and produced antibodies against those peptides, some of which could be recognized by sera obtained from SARS patients. Antibodies against the NP peptides could detect the cognate N protein clearly. Further refinement of these antibodies, particularly large-scale production of monoclonal antibodies, could lead to the development of useful diagnostic kits for diseases associated with SARS and other human coronaviruses.