A review of recent advances in the use of complex metal nanostructures for biomedical applications from diagnosis to treatment.

Complex metal nanostructures represent an exceptional category of materials characterized by distinct morphologies and physicochemical properties. Nanostructures with shape anisotropies, such as nanorods, nanostars, nanocages, and nanoprisms, are particularly appealing due to their tunable surface plasmon resonances, controllable surface chemistries, and effective targeting capabilities. These complex nanostructures can absorb light in the near-infrared, enabling noteworthy applications in nanomedicine, molecular imaging, and biology. The engineering of targeting abilities through surface modifications involving ligands, antibodies, peptides, and other agents potentiates their effects. Recent years have witnessed the development of innovative structures with diverse compositions, expanding their applications in biomedicine. These applications encompass targeted imaging, surface-enhanced Raman spectroscopy, near-infrared II imaging, catalytic therapy, photothermal therapy, and cancer treatment. This review seeks to provide the nanomedicine community with a thorough and informative overview of the evolving landscape of complex metal nanoparticle research, with a specific emphasis on their roles in imaging, cancer therapy, infectious diseases, and biofilm treatment. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Diagnostic Tools > Diagnostic Nanodevices.

Directing Boron-Phosphorus Bonds in Crystalline Solid: Oxidative Polymerization of P═B═P Monomers into 1D Chains.

Over 20 years after the last inorganic ternary B-P compound was reported, Na2BP2, a new compound containing one-dimensional B-P polyanionic chains has been synthesized. Common high-temperature synthetic methods required for the direct reaction of boron and phosphorus negate the possible formation of metastable or low temperature phases. In this study, oxidative elimination was used to successfully condense 0D BP23- anionic monomers found in a Na3BP2 precursor into unique 1D BP22- chains consisting of five-member B2P3 rings connected by bridging P atoms in the crystal structure of Na2BP2. The synthesis was guided by in situ X-ray powder diffraction studies, which revealed the metastable nature of the products of oxidative elimination reactions. Na2BP2 is predicted to be an electron balanced semiconductor which was confirmed by UV-vis spectroscopy with the experimentally determined band gap of 1.1 eV.

Critical Role of an MHC Class I-Like/Innate-Like T Cell Immune Surveillance System in Host Defense against Ranavirus (Frog Virus 3) Infection.

Besides the central role of classical Major Histocompatibility Complex (MHC) class Ia-restricted conventional Cluster of Differentiation 8 (CD8) T cells in antiviral host immune response, the amphibian Xenopuslaevis critically rely on MHC class I-like (mhc1b10.1.L or XNC10)-restricted innate-like (i)T cells (iVα6 T cells) to control infection by the ranavirus Frog virus 3 (FV3). To complement and extend our previous reverse genetic studies showing that iVα6 T cells are required for tadpole survival, as well as for timely and effective adult viral clearance, we examined the conditions and kinetics of iVα6 T cell response against FV3. Using a FV3 knock-out (KO) growth-defective mutant, we found that upregulation of the XNC10 restricting class I-like gene and the rapid recruitment of iVα6 T cells depend on detectable viral replication and productive FV3 infection. In addition, by in vivo depletion with XNC10 tetramers, we demonstrated the direct antiviral effector function of iVα6 T cells. Notably, the transitory iV6 T cell defect delayed innate interferon and cytokine gene response, resulting in long-lasting negative inability to control FV3 infection. These findings suggest that in Xenopus and likely other amphibians, an immune surveillance system based on the early activation of iT cells by non-polymorphic MHC class-I like molecules is important for efficient antiviral immune response.

Superseding van der Waals with Electrostatic Interactions: Intercalation of Cs into the Interlayer Space of SiAs2.

Cs yM xSi1- xAs2 (M = Cu, Zn, or Ga; y = 0.15-0.19; x depends on M) represents a new group of pseudo-two-dimensional compounds that allow property tuning with various metal substituents without alteration of the main Si-As two-dimensional framework. Their crystal structure is built from M xSi1- xAs2 layers separated by disordered chains of Cs cations. These compounds are synthesized using a CsCl flux as a source of Cs, circumventing the need for an expensive and air-sensitive Cs metal reagent. M-Si substitution is required to compensate for the excess electrons donated by Cs cations. Alternatively, the charge compensation can be achieved by the formation of As vacancies. Resistivity measurements confirm the electron-balanced nature of the compounds that exhibit semiconducting behavior with small bandgaps.

Chemical and Electrochemical Lithiation of van der Waals Tetrel-Arsenides.

Lithiation of van der Waals tetrel-arsenides, GeAs and SiAs, has been investigated. Electrochemical lithiation demonstrated large initial capacities of over 950 mAh g-1 accompanied by rapid fading over successive cycling in the voltage range 0.01-2 V. Limiting the voltage range to 0.5-2 V achieved more stable cycling, which was attributed to the intercalation process with lower capacities. Ex situ powder X-ray diffraction confirmed complete amorphization of the samples after lithiation, as well as recrystallization of the binary tetrel-arsenide phases after full delithiation in the voltage range 0.5-2 V. Solid-state synthetic methods produce layered phases, in which Si-As or Ge-As layers are separated by Li cations. The first layered compounds in the corresponding ternary systems were discovered, Li0.9 Ge2.9 As3.1 and Li3 Si7 As8 , which crystallize in the Pbam (No. 55) and P2/m (No. 10) space groups, respectively. Semiconducting layered GeAs and SiAs accommodate the extra charge from Li cations through structural rearrangement in the Si-As or Ge-As layers and eventually by replacement of the tetrel dumbbells with sets of Li atoms. Ge and Si monoarsenides demonstrated high structural flexibility and a mild ability for reversible lithiation.

Identification of nonalcoholic fatty liver disease following pancreatectomy for noninvasive intraductal papillary mucinous neoplasm.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) following pancreatectomy is a potential cause of long term morbidity in patients undergoing pancreatic resection with curative intent. Prior studies have reported an incidence of NAFLD up to 30% following pancreatectomy but the investigated cohorts were typically a mix of benign and malignant disease. Here we examined the incidence of NAFLD in a homogenous cohort of patients following pancreatectomy for benign intraductal papillary mucinous neoplasm (IPMN). METHODS: A retrospective review of patients who underwent pancreatic resection for IPMN from 2000 to 2016 was performed. Post pancreatectomy CT/MRI scans were obtained as standard surveillance. We investigated changes in the liver parenchymal density on post surgical imaging to estimate the frequency with which NAFLD occurred. Radiographic criteria for NAFLD included Hounsfield units less than 40 on CT or liver:spleen ratio <0.9 on CT or MRI. Fischer's exact test, Kruskal-Wallis test, and logistic regression were performed. RESULTS: Our study cohort included 109 patients who underwent pancreatectomy for nonmalignant intraductal papillary mucinous neoplasm with no evidence of NAFLD preoperatively and at least 6 months follow-up. Mean follow-up was 52 months (range 8-130/months). The incidence of postoperative NAFLD was 17/109 (15.6%). Most cases occurred within 12 months of pancreatectomy. On multivariate analysis, proximal pancreatectomy (pancreaticoduodenectomy) and development of atrophy of the pancreas remnant were significant risk factors for development of hepatic steatosis (p < 0.05). CONCLUSION: Patients undergoing pancreatectomy for benign disease have a significant risk of developing NAFLD but the frequency is lower than previously reported in cohorts that included individuals with malignant disease. Highest risk was observed in individuals who underwent pancreaticoduodenectomy or developed pancreatic atrophy. Further investigations to define the mechanisms that promote steatosis and interventions to prevent subsequent morbidity from NAFLD are warranted.

DIA's Adaptive Design Scientific Working Group (ADSWG): Best Practices Case Studies for "Less Well-understood" Adaptive Designs.

Adaptive design (AD) clinical trials use accumulating subject data to modify the parameters of the design of an ongoing study, without compromising the validity and integrity of the study. The 2010 US Food and Drug Administration (FDA) Draft Guidance on Adaptive Design Clinical Trials described a subset of 7 primary design types as "less well-understood." FDA defined these designs as those with limited regulatory experience. To better understand the properties of these less well-understood ADs and to promote their use when applicable, the Best Practices Subteam for DIA's Adaptive Design Scientific Working Group conducted an extensive nonsystematic search and reviewed trials from multiple sponsors who had employed these designs. Here, we review 10 specific case studies for which less well-understood ADs were employed and share feedback about their challenges and successes, as well as details about the regulatory interactions from these trials. We learned that these designs and associated statistical methodologies can make difficult research situations more amenable for study and, therefore, are needed in our toolbox. While they can be used to study many diseases, they are particularly valuable for rare diseases, small populations, studies involving terminal illnesses, and vaccine trials, in which it is important to find efficient ways to bring effective treatments to market more rapidly. It is imperative, however, that these methodologies be utilized appropriately, which requires careful planning and precise operational execution.

Does histology really influence gastric cancer prognosis?

BACKGROUND: Gastric cancer (GC) is associated with poor survival despite curative-intent surgical resection and systemic therapy. Our objective is to examine the impact of histology on prognosis as well as the impact of linitis plastica (LP) on survival. METHODS: The GC database at a single institution was evaluated for patients who underwent resection from 2000 to 2015. Clinicopathologic characteristics were examined and descriptive statistics was used to analyze four groups of patients based on Lauren classification: intestinal (n=93), diffuse (n=20), diffuse with signet-ring cell features (n=57), and LP (n=40). LP patients had diffuse GC but also presented with circumferential infiltration of the gastric wall for at least a third of the stomach length on endoscopy or imaging. Fisher's exact test was used to compare groups; Cox regression was used for multivariate analysis and Kaplan-Meier method for survival. RESULTS: Of 210 patients who underwent gastric resection, 112 (53%) were male with mean age 65.3 years (SD ±14.6 years). Intestinal GC patients were older at diagnosis but other patient demographics were similar between all groups. LP patients had a higher rate of R1 resection despite higher rates of total gastrectomy (P<0.01). Rates of perineural invasion (PNI) and nodal metastasis were higher in LP (P<0.001). The majority of intestinal GC patients (79%) had stage I/II disease compared to 70% of LP patients with stage III disease. Median overall survival (OS) was 13.7 months for LP, 79 months for intestinal, 97 months for signet-ring cell, and not reached for diffuse GC (P<0.001). When stratified by stage, there were no significant differences in survival by histology for stage II and stage III patients. However, by Cox regression analysis, factors associated with worse survival included lymphovascular invasion (LVI), nodal disease, and presence of LP. Neutrophil-lymphocyte ratio (NLR), neoadjuvant and adjuvant therapy, and tumor regression grade did not influence survival on multivariate analysis. CONCLUSIONS: Intestinal GC is thought to have a better prognosis. Interestingly, this study demonstrates similar outcomes in patients with intestinal, diffuse, and signet-ring cell GC. However, a subset of diffuse GC-LP was associated with an infiltrative pattern of disease characterized by PNI and LVI. Despite controlling for poor prognostic markers, LP was independently associated with a worse prognosis. More research is needed to identify methods of earlier diagnosis and effective systemic therapy to treat this aggressive disease.

A pair of dopamine neurons target the D1-like dopamine receptor DopR in the central complex to promote ethanol-stimulated locomotion in Drosophila.

Dopamine is a mediator of the stimulant properties of drugs of abuse, including ethanol, in mammals and in the fruit fly Drosophila. The neural substrates for the stimulant actions of ethanol in flies are not known. We show that a subset of dopamine neurons and their targets, through the action of the D1-like dopamine receptor DopR, promote locomotor activation in response to acute ethanol exposure. A bilateral pair of dopaminergic neurons in the fly brain mediates the enhanced locomotor activity induced by ethanol exposure, and promotes locomotion when directly activated. These neurons project to the central complex ellipsoid body, a structure implicated in regulating motor behaviors. Ellipsoid body neurons are required for ethanol-induced locomotor activity and they express DopR. Elimination of DopR blunts the locomotor activating effects of ethanol, and this behavior can be restored by selective expression of DopR in the ellipsoid body. These data tie the activity of defined dopamine neurons to D1-like DopR-expressing neurons to form a neural circuit that governs acute responding to ethanol.

Unresolved issues in anthelmintic pharmacology for helminthiases of humans.

Helminth infections are an important constraint on the health and development of poor children and adults. Anthelmintic treatment programmes provide a safe and effective response, and increasing numbers of people are benefitting from these public health initiatives. Despite decades of clinical experience with anthelmintics for the treatment of human infections, relatively little is known about their clinical pharmacology. All of the drugs were developed initially in response to the considerable market for veterinary anthelmintics in high- and middle-income countries. In contrast, the greatest burden caused by these infections in humans is in resource-poor settings and as a result there has been insufficient commercial incentive to support studies on how these drugs work in humans, and how they should best be used in control programmes. The advent of mass drug administration programmes for the control of schistosomiasis, lymphatic filariasis, onchocerciasis and soil-transmitted helminthiases in humans increases the urgency to better understand and better monitor drug resistance, and to broaden the currently very narrow range of available anthelmintics. This provides fresh impetus for developing a comprehensive research platform designed to improve our understanding of these important drugs, in order to bring the scientific knowledge base supporting their use to a standard equivalent to that of drugs commonly used in developed countries. Furthermore, a better understanding of their clinical pharmacology will enable improved therapy and could contribute to the discovery of new products.

Enteric vaccines for pediatric use. Workshop summary.

Diarrheal diseases remain a major cause of death in children under 5 in less developed countries (LDCs). Vaccine development and implementation offers the best near-term approach to alleviating this problem. For this reason, a workshop to examine the possibilities for making enteric vaccines available to meet the specific needs of children in LDCs was convened in Virginia on April 24-26, 2004. Discussants considered research and development needs, regulatory and business issues, and previous experiences with enteric vaccine development and implementation. No insurmountable roadblocks to progress in this area were noted, and the possibility currently exists that properly supported efforts will enable the realization of enteric vaccines for pediatric use.

Oxymoron no more: the potential of nonprofit drug companies to deliver on the promise of medicines for the developing world.

Although some pharmaceutical company efforts to develop and distribute drugs in developing countries have been successful, many fall short of meeting needs in resource-poor nations. In the context of public-private partnerships, we discuss the concept of a nonprofit pharmaceutical company dedicated to developing and distributing drugs for diseases endemic in developing countries. Using the experience of the Institute for OneWorld Health, we present the vision, core elements of the product development model, and challenges confronting this model. Despite limitations, early successes raise hopes that a nonprofit drug company can exist successfully both as a global health organization and as a business.

Rough eye is a gain-of-function allele of amos that disrupts regulation of the proneural gene atonal during Drosophila retinal differentiation.

The regular organization of the ommatidial lattice in the Drosophila eye originates in the precise regulation of the proneural gene atonal (ato), which is responsible for the specification of the ommatidial founder cells R8. Here we show that Rough eye (Roi), a dominant mutation manifested by severe roughening of the adult eye surface, causes defects in ommatidial assembly and ommatidial spacing. The ommatidial spacing defect can be ascribed to the irregular distribution of R8 cells caused by a disruption of the patterning of ato expression. Disruptions in the recruitment of other photoreceptors and excess Hedgehog production in differentiating cells may further contribute to the defects in ommatidial assembly. Our molecular characterization of the Roi locus demonstrates that it is a gain-of-function mutation of the bHLH gene amos that results from a chromosomal inversion. We show that Roi can rescue the retinal developmental defect of ato1 mutants and speculate that amos substitutes for some of ato's function in the eye or activates a residual function of the ato1 allele.