A novel therapeutic bispecific format based on synthetic orthogonal heterodimers enables T cell activity against Acute myeloid leukemia.

Many therapeutic bispecific T-cell engagers (BiTEs) are in clinical trials. A modular and efficient process to create BiTEs would accelerate their development and clinical applicability. In this study, we present the design, production, and functional activity of a novel bispecific format utilizing synthetic orthogonal heterodimers to form a multichain modular design. Further addition of an immunoglobulin hinge region allowed a stable covalent linkage between the heterodimers. As proof-of-concept, we utilized CD33 and CD3 binding scFvs to engage leukemia cells and T-cells respectively. We provide evidence that this novel bispecific T-cell engager (termed IgGlue-BiTE) could bind both CD3+ and CD33+ cells and facilitates robust T-cell mediated cytotoxicity on AML cells in vitro. In a mouse model of minimal residual disease, we showed that the novel IgGlue-BiTE greatly extended survival, and mice of this treatment group were free of leukemia in the bone marrow. These findings suggest that the IgGlue-BiTE allows for robust simultaneous engagement with both antigens of interest in a manner conducive to T cell cytotoxicity against AML. These results suggest a compelling modular system for bispecific antibodies, as the CD3- and CD33-binding domains can be readily swapped with domains binding to other cancer- or immune cell-specific antigens.

Use of α-cyclodextrin to Promote Clean and Environmentally Friendly Disinfection of Phenolic Substrates via Chlorine Dioxide Treatment.

The use of chlorine dioxide to disinfect drinking water and ameliorate toxic components of wastewater has significant advantages in terms of providing safe water. Nonetheless, significant drawbacks toward such usage remain. These drawbacks include the fact that toxic byproducts of the disinfection agents are often formed, and the complete removal of such agents can be challenging. Reported herein is one approach to solving this problem: the use of α-cyclodextrin to affect the product distribution in chlorine dioxide-mediated decomposition of organic pollutants. The presence of α-cyclodextrin leads to markedly more oxidation and less aromatic chlorination, in a manner that is highly dependent on analyte structure and other reaction conditions. Mechanistic hypotheses are advanced to explain the cyclodextrin effect, and the potential for use of α-cyclodextrin for practical wastewater treatment is also discussed.

Redescription of the holotype of Bostrichoclerus bicornus Van Dyke, 1938, a rare species of the New World Tillinae Fauna (Coleoptera: Cleridae), with some taxonomic notes.

Bostrichoclerus bicornus Van Dyke is known from southwest United States and northwest Mexico. To date, only two specimens have been captured: the holotype, collected on Isla Angel de la Guarda, in the Gulf of California, Mexico, and a second individual collected in San Bernardino County, California, United States. The original description of B. bicornus is brief and lacks any images. Considering its rarity, we present the redescription of this species based on the examination of the holotype and compare this taxon to similar genera of New World Tillinae. Images of the holotype and the Bostrichoclerus specimen collected in southern California are given. We conclude that B. bicornus is undoubtedly a member of the subfamily Tillinae with unclear intergeneric relations in the group.

Five new species of Cymatodera Gray, 1832 (Coleoptera: Cleridae: Tillinae) from Mexico and Central America.

Five new species of Cymatodera from Mexico, Guatemala, Honduras, Costa Rica and Panama are described here based on adult male and female specimens: Cymatodera humeralis sp. n; Cymatodera lorenae sp. n.; Cymatodera crassa sp. n.; Cymatodera depressa sp. n; and Cymatodera nigrofasciata sp. n. Male genitalia and other characters of taxonomic value are used for diagnostic purposes.

A taxonomic revision of the subfamily Tillinae Leach sensu lato (Coleoptera, Cleridae) in the New World.

The subfamily Tillinae Leach is represented by 12 genera in the New World. In this study, eight of these genera are revised. A diagnosis and redescription of the species of Araeodontia Barr, Barrotillus Rifkind, Bogcia Barr, Cylidrus Latreille, Cymatoderella Barr, Lecontella Wolcott & Chapin, Monophylla Spinola, and Onychotillus Chapin are presented. Bogcia oaxacae Barr is designated as a junior synonym of Bogcia disjuncta Barr. One species, Cymatodera striatopunctata Chevrolat, is transferred to Lecontella. The following species are redescribed: Araeodontia isabellae (Wolcott), A. marginalis Barr, A. peninsularis (Schaeffer), Barrotillus kropotkini Rifkind, Bogcia disjuncta Barr, Cylidrus abdominalis Klug, Cymatoderella collaris (Spinola), C. morula Rifkind, C. patagoniae (Knull), Lecontella brunnea (Spinola), L. gnara Wolcott, L. striatopunctata (Chevrolat), Monophylla californica (Fall), M. pallipes Schaeffer, M. terminata (Say), Onychotillus vittatus Chapin, and O. cubana De Zayas. Transcriptions of the original descriptions of Araeodontia picipennis Barr, Bostrichoclerus bicornis Van Dyke and Monophylla cinctipennis (Chevrolat) are given. Cymatodera Gray, with approximately 130 described species, is excluded from this study due to the number of species involved. The genera Neocallotillus Burke and Callotillus Wolcott are also excluded here since these groups have been recently revised elsewhere. Collection data are provided for all species revised. Updated distribution maps are presented. Keys to New World genera and species are given and taxonomic characters of relevant importance are provided and discussed.

Improving performance of nanoscale ultrasound contrast agents using N,N-diethylacrylamide stabilization.

The design of nanoscale yet highly echogenic agents for imaging outside of the vasculature and for ultrasound-mediated drug delivery remains a formidable challenge. We have previously reported on formulation of echogenic perfluoropropane gas nanobubbles stabilized by a lipid-pluronic surfactant shell. In the current work we describe the development of a new generation of these nanoparticles which consist of perfluoropropane gas stabilized by a surfactant and lipid membrane and a crosslinked network of N,N-diethylacrylamide. The resulting crosslinked nanobubbles (CL-PEG-NB) were 95.2±25.2nm in diameter and showed significant improvement in stability and retention of echogenic signal over 24h. In vivo analysis via ultrasound and fluorescence mediated tomography showed greater tumor extravasation and accumulation with CL-PEG-NB compared to microbubbles. Together these results demonstrate the capabilities and advantages of a new, more stable, nanometer-scale ultrasound contrast agent that can be utilized in future work for diagnostic scans and molecular imaging.

Taxonomic revision of the New World genus Callotillus Wolcott (Cleridae, Tillinae), with the description of the new genus Neocallotillus, and an illustrated key of identification to species.

The New World checkered beetle genus Callotillus Wolcott, 1911 is revised and the new genus Neocallotillus established. The subspecies Callotillus elegans vafer Wolcott is synonymized with the nominal subspecies, Callotillus elegans elegans (Erichson), which is transferred to, and designated as the type species of Neocallotillus gen. n. as Neocallotillus elegans (Erichson, 1847), comb. n. Two additional species are transferred from Callotillus to the new genus: Neocallotillus intricatus (Wolcott & Dybas, 1947), comb. n. and Neocallotillus crusoe (Wolcott, 1923), comb. n., the latter tentatively and based on Wolcott's original description. Callotillus is now composed of two species: Callotillus eburneocinctus Wolcott, 1911 and Callotillus bahamensis Vaurie, 1952. All abovementioned species except Neocallotillus crusoe are diagnosed and redescribed. In the absence of reference material of Neocallotillus crusoe, Wolcott's original description is transcribed. An illustrated key to species is provided. Characters of taxonomic relevance are illustrated and discussed. Updated distribution maps and locality data for all specimens examined are presented.

A checklist of the New World species of Tillinae (Coleoptera: Cleridae), with an illustrated key to genera and new country records.

This checklist presents the distribution of the checkered beetle subfamily Tillinae (Coleoptera: Cleridae) in the New World. Information for 164 species and 2 subspecies from 11 genera is included. The data are based on an extensive survey of material collected throughout the Americas, descriptions of new species, a number of revisionary works, data from museum specimens, as well as unpublished checklists. Cymatodera, the most speciose tilline genus in the New World, has its greatest diversity in Mexico where 100 of the 134 recognized species are known to occur. Remaining genera inhabiting the New World and corresponding species numbers are: Araeodontia, 5 species; Barrotillus, 1 species; Bogcia, 2 species; Bostrichoclerus, 1 species; Callotillus, 5 species; Cylidrus, 1 species; Cymatoderella, 3 species; Lecontella, 3 species; Monophylla, 4 species; and Onychotillus, 5 species. An illustrated key to the genera of the New World Tillinae is provided. Forty-eight new country records are given for 35 species. References are presented for all species listed. Distribution maps for all New World genera are provided and locality data is presented for selected species.

Four new species of Cymatodera Gray from central and southern Mexico (Coleoptera, Cleridae, Tillinae).

Four new species of Cymatodera are described from Mexico: Cymatoderatortuosa Burke & Rifkind, sp. n. from Hidalgo and Tamaulipas; Cymatoderaortegae Burke, sp. n. from Colima, Jalisco and Michoacan; Cymatoderagerstmeieri Burke & Rifkind, sp. n. from Chiapas; and Cymatoderamixteca Burke & Rifkind, sp. n. from Puebla and Guerrero. Male genitalia and other characters of taxonomic value are illustrated.

Ultrasound imaging beyond the vasculature with new generation contrast agents.

Current commercially available ultrasound contrast agents are gas-filled, lipid- or protein-stabilized microbubbles larger than 1 µm in diameter. Because the signal generated by these agents is highly dependent on their size, small yet highly echogenic particles have been historically difficult to produce. This has limited the molecular imaging applications of ultrasound to the blood pool. In the area of cancer imaging, microbubble applications have been constrained to imaging molecular signatures of tumor vasculature and drug delivery enabled by ultrasound-modulated bubble destruction. Recently, with the rise of sophisticated advancements in nanomedicine, ultrasound contrast agents, which are an order of magnitude smaller (100-500 nm) than their currently utilized counterparts, have been undergoing rapid development. These agents are poised to greatly expand the capabilities of ultrasound in the field of targeted cancer detection and therapy by taking advantage of the enhanced permeability and retention phenomenon of many tumors and can extravasate beyond the leaky tumor vasculature. Agent extravasation facilitates highly sensitive detection of cell surface or microenvironment biomarkers, which could advance early cancer detection. Likewise, when combined with appropriate therapeutic agents and ultrasound-mediated deployment on demand, directly at the tumor site, these nanoparticles have been shown to contribute to improved therapeutic outcomes. Ultrasound's safety profile, broad accessibility and relatively low cost make it an ideal modality for the changing face of healthcare today. Aided by the multifaceted nano-sized contrast agents and targeted theranostic moieties described herein, ultrasound can considerably broaden its reach in future applications focused on the diagnosis and staging of cancer.

Cymatodera ochlera Barr, a junior synonym of Cymatodera wolcotti Barr, with a comparison to similar species (Coleoptera: Cleridae).

Cymatodera ochlera Barr 1972 has been considered to be very similar to but distinct from C. wolcotti Barr 1950. We present evidence to show that these two species are conspecific and C. ochlera should be treated as a junior synonym of C. wolcotti. Cymatodera wolcotti is compared to C. balteata and C. undulata, two species remarkably similar to C. wolcotti. Morphological characters of significant value are presented that confirm C. balteata and C. undulata are separate species. Images of all characters discussed are provided. 

A comparison of neuroinflammation to implanted microelectrodes in rat and mouse models.

Rat models have emerged as a common tool to study neuroinflammation to intracortical microelectrodes. While a number of studies have attempted to understand the factors resulting in neuroinflammation using rat models, a complete understanding of key mechanistic pathways remains elusive. Transgenic mouse models, however, could facilitate a deeper understanding of mechanistic pathways due to an ease of genetic alteration. Therefore, the goal of the present study is to compare neuroinflammation following microelectrode implantation between the rat and the mouse model. Our study suggests that subtle differences in the classic neuroinflammatory markers exist between the animal models at both two and sixteen weeks post implantation. Most notably, neuronal densities surrounding microelectrodes were significantly lower in the rat model at two weeks, while similar densities were observed between the animal models at sixteen weeks. Physiological differences between the species and slight alterations in surgical methods are likely key contributors to the observed differences. Moving forward, we propose that differences in the time course of neuroinflammation between the animal models should be considered when trying to understand and prevent intracortical microelectrode failure.

Four new species of Cymatodera Gray from Mexico (Coleoptera, Cleridae, Tillinae).

Four new species of Cymatodera from Mexico: Cymatodera bogcioides sp. n.; Cymatodera pueblae sp. n.; Cymatodera mitae sp. n.; and Cymatodera lineata sp. n. are described based on adult male and female specimens. Male genitalia and other characters of taxonomic value are presented.

Six new species of Cymatodera from Mexico and Central America and the retention of Cymatodera obliquefasciata as a valid name (Cleridae, Tillinae).

Six new Cymatodera speciesfrom the Mexican states of Jalisco and Chiapas, and the Central American countries of El Salvador, Honduras, Costa Rica and Panamá are described: Cymatodera rosalinae sp. n., Cymatodera capax sp. n., Cymatodera sinuosa sp. n., Cymatodera vittata sp. n., Cymatodera rubida sp. n. and Cymatodera limatula sp. n. Justification for retaining Cymatodera obliquefasciata within Cymatodera instead of transferring it to Bogcia is provided. Male genitalia and other characters of taxonomic value are illustrated.

ResumenSe describen seis nuevas especies del género Cymatodera pertenecientes a los estados Mexicanos de Jalisco y Chiapas, y los países Centroamericanos de El Salvador, Honduras, Costa Rica y Panamá: Cymatodera rosalinaesp. n., Cymatodera capaxsp. n., Cymatodera sinuosasp. n., Cymatodera vittatasp. n., Cymatodera rubidasp. n. y Cymatodera limatulasp. n. Se proporciona información sobre la retención de Cymatodera obliquefasciata dentro de Cymatodera, invalidando así su transferencia a Bogcia. Se presentan ilustraciones de la genitalia masculina así como otros caracteres de valor taxonómico.

A novel advancement flap for reconstruction of massive forehead and temple soft-tissue defects.

OBJECTIVES/HYPOTHESIS: To describe the authors' experience with an extended deep-plane cervicofacial (EDPCF) advancement flap, a modification of the deep-plane cervicofacial flap, for reconstruction of large forehead and temple soft-tissue defects. STUDY DESIGN: Case series at a tertiary referral medical center. METHODS: The charts of 11 consecutive patients who underwent EDPCF flap surgery for reconstruction of forehead and temple skin cancer defects were reviewed for demographics, smoking status, defect size, length of surgery and hospitalization, American Society of Anesthesiologists Physical Status Classification (ASA) grade, and postoperative complications. RESULTS: All patients had reconstruction of large forehead and temple defects following either primary resection or Mohs micrographic surgery for skin cancer. No skin grafting was required for secondary defects. The average defect size was 52.2 cm(2) . Patient ages averaged 74 years with a median ASA grade of 3. Thirty-six percent of patients admitted to smoking. Average operative time was 100 minutes, with 82% of patients treated on an outpatient basis. There were no complications of ectropion or facial nerve injury encountered. Partial distal flap necrosis occurred in one patient who admitted to smoking and resolved with conservative management. CONCLUSIONS: The EDCPF flap is a robust flap with a dual arterial supply and both rotation and advancement components. It is ideal in frail patients with good soft-tissue laxity and provides an immediate one-stage reconstruction with ideal skin color, texture, and thickness matches for large forehead and temple defects.

The role of periadventitial fat in atherosclerosis.

CONTEXT: It has become increasingly evident that adipose tissue is a multifunctional organ that produces and secretes multiple paracrine and endocrine factors. Research into obesity, insulin resistance, and diabetes has identified a proinflammatory state associated with obesity. Substantial differences between subcutaneous and omental fat have been noted, including the fact that omental fat produces relatively more inflammatory cytokines. Periadventitial fat, as a specific adipose tissue subset, has been overlooked in the field of atherosclerosis despite its potential diagnostic and therapeutic implications. OBJECTIVE: To review (1) evidence for the role of adventitial and periadventitial fat in vessel remodeling after injury, (2) the relationship between adventitial inflammation and atherosclerosis, (3) the association between periadventitial fat and plaque inflammation, and (4) the diagnostic and therapeutic implications of these roles and relationships for the progression of atherosclerosis. DATA SOURCES: We present new data showing greater uptake of iron, administered in the form of superparamagnetic iron oxide, in the periadventitial fat of atherosclerotic mice than in control mice. In addition, macrophage density in the periadventitial fat of lipid-rich plaques is increased compared with fibrocalcific plaques. CONCLUSIONS: There is a striking paucity of data on the relationship between the periadventitial fat of coronary arteries and atherosclerosis. Greater insight into this relationship might be instrumental in making strides into the pathophysiology, diagnosis, and treatment of coronary artery disease.

Irradiated homograft rib cartilage in facial reconstruction.

OBJECTIVE: To evaluate long-term structural, functional, and cosmetic results as well as resorption with the use of irradiated homologous rib cartilage grafts (IHRGs). DESIGN: Cases in which IHRGs were used were reviewed for a long-term follow-up study for nasal and auricular reconstruction, dating back 18 years. A retrospective medical chart review was conducted in the cases in which the patients had returned for clinical examination with photographic documentation. RESULTS: A total of 118 patients who had undergone nasal reconstruction with a mean follow-up of 36 months were identified from our database. There were 12 patients who had undergone auricular reconstruction, with a mean follow-up of 82 months. Resorption with compromise in cosmesis was noted in 11% (11/102) of the grafts used in nasal reconstruction but in 71% (5/7) of those used in auricular reconstruction. Minor resorption without change in form or function was found in 29% (30/102) of the cases. Loss of support, which was related more to graft displacement rather than resorption, was identified in 19% (21/109) of the cases, and loss of support affecting cosmesis was observed in 8% (9/109) of the cases. Maintenance of form and function appeared to be unrelated to the amount of resorption noted for the nasal grafts but was significant for the auricular grafts (P < .01). CONCLUSIONS: The longevity of IHRGs has been favorable for functional, structural, and cosmetic nasal reconstruction, with low levels of resorption identified clinically. The use of IHRGs was associated with an unacceptable rate of graft failure in auricular reconstruction; therefore, they are no longer selected for use in such cases.

Total nasal reconstruction: utility of the free radial forearm fascial flap.

BACKGROUND: Total nasal defects present daunting challenges to the reconstructive surgeon. The nasal skeleton can be successfully fabricated with bone and cartilage. Reconstruction of the nasal skin with a forehead flap produces an excellent color match for nasal skin. Resurfacing of the internal lining is the most difficult of the 3 layers. Local tissue is often unsatisfactory in amount and/or vascular supply. METHODS: A patient requiring total nasal reconstruction was prospectively examined. Intraoperative technique was recorded, and postoperative function was determined. RESULTS: A paramedian forehead flap was used to resurface the external defect. Split calvarium and conchal cartilage were used to reconstruct the nasal skeleton. A fascial flap harvested from the forearm was used to replace the intranasal lining. Turbinate grafts were placed to line the flap. Postoperative breathing was excellent. CONCLUSIONS: The intranasal portion of a total nasal defect can be successfully reconstructed with a fascial forearm flap. Placement of a turbinate or mucosal graft allows for a thin mucosalized lining with an excellent functional outcome.