Development of PET Radioisotope Copper-64-Labeled Theranostic Immunoliposomes for EGFR Overexpressing Cancer-Targeted Therapy and Imaging.

Combining standard surgical procedures with personalized chemotherapy and the continuous monitoring of cancer progression is necessary for effective NSCLC treatment. In this study, we developed liposomal nanoparticles as theranostic agents capable of simultaneous therapy for and imaging of target cancer cells. Copper-64 (64Cu), with a clinically practical half-life (t1/2 = 12.7 h) and decay properties, was selected as the radioisotope for molecular PET imaging. An anti-epidermal growth factor receptor (anti-EGFR) antibody was used to achieve target-specific delivery. Simultaneously, the chemotherapeutic agent doxorubicin (Dox) was encapsulated within the liposomes using a pH-gradient method. The conjugates of 64Cu-labeled and anti-EGFR antibody-conjugated micelles were inserted into the doxorubicin-encapsulating liposomes via a post-insertion procedure (64Cu-Dox-immunoliposomes). We evaluated the size and zeta-potential of the liposomes and analyzed target-specific cell binding and cytotoxicity in EGFR-positive cell lines. Then, we analyzed the specific therapeutic effect and PET imaging of the 64Cu-Dox-immunoliposomes with the A549 xenograft mouse model. In vivo therapeutic experiments on the mouse models demonstrated that the doxorubicin-containing 64Cu-immunoliposomes effectively inhibited tumor growth. Moreover, the 64Cu-immunoliposomes provided superior in vivo PET images of the tumors compared to the untargeted liposomes. We suggest that nanoparticles will be the potential platform for cancer treatment as a widely applicable theranostic system.

E3 ligase SOCS3 regulates NOD2 expression by ubiquitin proteasome system in lung cancer progression.

PURPOSE: Despite lung cancer is one of the leading causes of cancer-related deaths, it remains hard to discover effective diagnostic and therapeutic approaches. Moreover, the five-year survival rate is relatively lower than other tumors. So urgent needs for finding a new theranostic target to treat lung cancer effectively. This study aims to present SOCS3 and NOD2 proteins as novel targets for diagnosis and therapy. METHODS: We first confirmed SOCS3 expression level in patients' tissues. Then, we applied knockdown and overexpression of SOCS3 on lung cancer cell lines and performed proliferation, migration, and invasion assay. After that, we found NOD2 is a target of SOCS3 and introduced overexpression of NOD2 to A549 for verifying reduced tumorigenicity of lung cancer cells. RESULTS: We identified protein expression level of SOCS3 was frequently higher in tumor tissues than adjacent normal tissues. Truly, overexpression of SOCS3 promoted proliferation, migration, and invasion capacity of lung cancer cells. We found that SOCS3 interacts with NOD2 and SOCS3 ubiquitinates NOD2 directly. Furthermore, lung cancer tissues with higher SOCS3 expression showed lower NOD2 expression. We confirmed overexpression of NOD2 leads to suppressed tumorigenicity of lung cancer cells, and these effects occurred through MAPK pathway. CONCLUSION: Collectively, our work reveals novel roles of SOCS3 in lung tumorigenesis and proposes SOCS3 as a promising biomarker candidate for therapeutic and diagnostic target for lung cancer.

Microcurvature Controllable Metal-Organic Framework Nanoagents Capable of Ice-Lattice Matching for Cellular Cryopreservation.

Ice-binding proteins (IBPs) produced by psychrophilic organisms to adapt for the survival of psychrophiles in subzero conditions have received illustrious interest as a cryopreservation agent required for cells and tissues to completely recover after freezing/thawing. Depressing water-freezing point and avoiding ice-crystal growth affect their activities which are closely related to the presence of ice crystal well-matched binding moiety. The interaction of IBPs with ice and water is critical in enhancing their freeze avoidance against cell or tissue damage. Metal-organic frameworks (MOFs) with a controllable lattice at the molecular level and a size at the nanometer scale can offer periodically ordered ice-binding sites by modifying organic linkers and controlling microcurvature at the ice surface. Herein, zirconium (Zr)-based MOF-801 nanoparticles (NPs) with good biocompatibility were used as a cryoprotectant that is well dispersed and colloidal-stable in an aqueous solution. The MOF NP size was precisely controlled, and 10, 35, 100, and 250 nm NPs were prepared. The specific IBPs-mimicking pendants (valine and threonine) were simply introduced into the MOF NP-surface through the acrylate-based functionalization to endow with hydrophilic and hydrophobic dualities. When small-sized MOF-801 NPs were attached to ice, they confined ice growth in high curvature between the adsorption sites because of the decreased radius of the convex area of the growth region, leading to highly enhanced ice recrystallization inhibition (IRI). Surface-functionalized MOF NPs could increase the number of anchored clathrate water molecules with hydrophilic/hydrophobic balance of the ice-binding moiety, effectively inhibiting ice growth. The MOF-801 NPs were biocompatible with various cell lines regardless of concentration or NP surface-functionalization, whereas the smaller-sized surface-functionalized NPs showed a good cell recovery rate after freezing/thawing by induction of IRI. This study provides a strategy for the fabrication of low-cost, high-volume antifreeze nanoagents that can extend useful applications to organ transplantation, cord blood storage, and vaccines/drugs.

Suppression of Lung Cancer Malignancy by Micellized siRNA through Cell Cycle Arrest.

UBA6-specific E2 conjugation enzyme 1 (USE1) is frequently overexpressed in lung cancer patients. Moreover, the critical role of USE1 in the progression of human lung cancer is also indicated. As the next step, the authors aim to develop USE1-targeted therapeutic agents based on RNA interference (RNAi). In this study, a lipid-modified DNA carrier, namely U4T, which consists of four consecutive dodec-1-ynyluracil (U) nucleobases to increase the cell permeability of siRNA targeting of USE1 is introduced. The U4Ts aggregate to form micelles, and the USE1-silencing siRNA-incorporated soft spherical nucleic acid aggregate (siSNA) can be created simply through base-pairing with siRNA. Treatment with siSNA is effective in suppressing tumor growth in vivo as well as cell proliferation, migration, and invasion of lung cancer cells. Furthermore, siSNA inhibited tumor cell growth by inducing cell cycle arrest in the G1 phase and apoptosis. Thus, the anti-tumor efficacy of siSNA in lung cancer cell lines and that siSNA possesses effective cell-penetrating ability without using cationic transfection moieties are confirmed. Collectively, these results suggest that siSNA can be applied to the clinical application of RNAi-based therapeutics for lung cancer treatment.

Tailoring the Electrical Characteristics of MoS2 FETs through Controllable Surface Charge Transfer Doping Using Selective Inkjet Printing.

Surface charge transfer doping (SCTD) has been regarded as an effective approach to tailor the electrical characteristics of atomically thin transition metal dichalcogenides (TMDs) in a nondestructive manner due to their two-dimensional nature. However, the difficulty of achieving rationally controlled SCTD on TMDs via conventional doping methods, such as solution immersion and dopant vaporization, has impeded the realization of practical optoelectronic and electronic devices. Here, we demonstrate controllable SCTD of molybdenum disulfide (MoS2) field-effect transistors using inkjet-printed benzyl viologen (BV) as an n-type dopant. By adjusting the BV concentration and the areal coverage of inkjet-printed BV dopants, controllable SCTD results in BV-doped MoS2 FETs with elaborately tailored electrical performance. Specifically, the suggested solvent system creates well-defined droplets of BV ink having a volume of ∼2 pL, which allows the high spatial selectivity of SCTD onto the MoS2 channels by depositing the BV dopant on demand. Our inkjet-printed SCTD method provides a feasible solution for achieving controllable doping to modulate the electrical and optical performances of TMD-based devices.

Individual Differences in Colour Perception: The Role of Low-Saturated and Complementary Colours in Ambiguous Images.

Individual differences in colour perception, as evidenced by the popular debate of "The Dress" picture, have garnered additional interest with the popularisation of additional, similar photographs. We investigated which colorimetric characteristics were responsible for individual differences in colour perception. All objects of the controversial photographs are composed of two representative colours, which are low in saturation and are either complementary to each other or reminiscent of complementary colours. Due to these colorimetric characteristics, we suggest that one of the two complementary pixel clusters should be estimated as the illuminant hue depending on assumed brightness. Thus, people perceive the object's colours as being biased toward complementarily different colour directions and perceive different pixel clusters as chromatic and achromatic. Even though the distance between colours that people perceive differently is small in colour space, people perceive the object's colour as differently categorized colours in these ambiguous photographs, thereby causing debate. We suggest that people perceive the object's colours using different "modes of colour appearance" between surface-colour and self-luminous modes.

Enhanced Output Performance of All-Solution-Processed Organic Thermoelectrics: Spray Printing and Interface Engineering.

We report two organocompatible strategies to enhance the output performance of all-solution-processed poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) thermoelectric generators (TEGs): introducing an additive spray printing process and functionalized polymer interlayers to reduce the module resistance. The spray printing enabled the deposition of 1-µm-thick PEDOT:PSS layers with a high degree of design freedom, resulting in a significantly reduced sheet resistance of 16 Ω sq-1 that is closely related to the thermoelectric output performance. Also, by inserting an ultrathin silane-terminated polystyrene (PS) interlayer between the PEDOT:PSS thermoelectric layers and inkjet-printed Ag interconnects selectively, the contact resistivity extracted by the transmission line method was reduced from 6.02 × 10-2 to 2.77 × 10-2 Ω cm2. We found that the PS interlayers behaved as a thin tunneling layer, which facilitated the carrier injection from the inkjet-printed Ag electrodes into the PEDOT:PSS films by field emission with an effectively lowered energy barrier. The activation energy was also extracted using the Richardson equation, resulting in a reduction of 2.59 ± 0.04 meV after the PS treatment. Scalable plastic-compatible processability and selective interface engineering enabled to demonstrate the flexible 74-leg PEDOT:PSS TEGs exhibiting the open-circuit voltage of 9.21 mV and the output power of 2.23 nW at a temperature difference of 10 K.

Surface Engineered Colloidal Quantum Dots for Complete Green Process.

The rising demand for eradicating hazardous substances in the workplace has motivated vigorous researches on environmentally sustainable manufacturing processes of colloidal quantum dots (QDs) for their optoelectronic applications. Despite remarkable achievements witnessed in QD materials (e.g., Pb- or Cd-free QDs), the progress in the eco-friendly process is far falling behind and thus the practical use of QDs. Herein, a complete "green" process of QDs, which excludes environmentally unfriendly elements from QDs, ligands, or solvents, is presented. The implant of mono-2-(methacryloyloxy)ethyl succinate (MMES) ligands renders InP/ZnSexS1-x QDs dispersed in eco-friendly polar solvents that are widely accepted in the industry while keeping the photophysical properties of QDs unchanged. The MMES-capped QDs show exceptional colloidal stabilities in a range of green polar solvents that permit uniform inkjet printing of QD dispersion. In addition, MMES-capped QDs are also compatible with commercially available photo-patternable resins, and the cross-linkable moiety within MMES further facilitates the achievement in the formation of well-defined, micrometer-scale patterning of QD optical films. The presented materials, all composed of simple, scalable, and environmentally safe compounds, promise low environmental impact during the processing of QDs and thus will catalyze the practicable use of QDs in a variety of optoelectronic devices.

BRC-mediated RNAi targeting of USE1 inhibits tumor growth in vitro and in vivo.

USE1 has been demonstrated to play crucial roles in the development and progression of human lung cancer. However, the antitumor efficacy of RNA interference (RNAi) targeting of USE1 has not yet been evaluated as a possible clinical application. We here synthesized USE1 targeting bubbled RNA-based cargo (BRC) composed of densely packed multimeric pre-siRNAs with specific Dicer cleavage sites to enable efficient siRNA release upon entry to target cells. The physical entanglement and continuous networking of RNAs via hybridization during enzymatic replication serve as a driving force for the self-assembly of BRCs. These molecules effectively suppressed the transcription of their target genes, leading to tumor growth suppression in vitro and in vivo. Moreover, their repeated intravenous administration efficiently inhibited the growth of A549 tumor xenografts. Based on these findings of a reduced cancer cell viability following a USE1 knockdown, we further explored cell cycle arrest and apoptosis pathways. The observed tumor cell growth suppression was found to be controlled by cell cycle arrest and apoptosis signals induced by the USE1 reduction. These results suggest that USE1 BRCs may have future clinical applications as an RNAi-based cancer therapy.

USP14 Inhibition Regulates Tumorigenesis by Inducing Autophagy in Lung Cancer In Vitro.

The ubiquitin-proteasome system is an essential regulator of several cellular pathways involving oncogenes. Deubiquitination negatively regulates target proteins or substrates linked to both hereditary and sporadic forms of cancer. The deubiquitinating enzyme ubiquitin-specific protease 14 (USP14) is associated with proteasomes where it trims the ubiquitin chain on the substrate. Here, we found that USP14 is highly expressed in patients with lung cancer. We also demonstrated that USP14 inhibitors (IU1-47 and siRNA-USP14) significantly decreased cell proliferation, migration, and invasion in lung cancer. Remarkably, we found that USP14 negatively regulates lung tumorigenesis not only through apoptosis but also through the autophagy pathway. Our findings suggest that USP14 plays a crucial role in lung tumorigenesis and that USP14 inhibitors are potent drugs in lung cancer treatment.

Charge Transport Characteristics of the PEDOT:PSS Interlayer Electrode/Molecule Physisorbed Contact in Large-Area Molecular Junctions.

Here we studied the effect of electrical contact between the PEDOT:PSS conducting polymer and the prototype benzenethiol molecules on the charge transport through the PEDOT:PSS-electrode molecular junctions. For this study, two different benzenethiol molecules were incorporated into the molecular junctions: 4-methylbenzenethiol (MBT) and 1,4-benzenedithiol (BDT). They have the same backbone structure but different top end-group. By investigating the MBT and BDT junctions with the PEDOT:PSS electrode, we demonstrated that the charge transport characteristics were dominated by distinct electrical contact properties at the PEDOT:PSS/molecule interface.

Electrical characterization of benzenedithiolate molecular electronic devices with graphene electrodes on rigid and flexible substrates.

We investigated the electrical characteristics of molecular electronic devices consisting of benzenedithiolate self-assembled monolayers and a graphene electrode. We used the multilayer graphene electrode as a protective interlayer to prevent filamentary path formation during the evaporation of the top electrode in the vertical metal-molecule-metal junction structure. The devices were fabricated both on a rigid SiO2/Si substrate and on a flexible poly(ethylene terephthalate) substrate. Using these devices, we investigated the basic charge transport characteristics of benzenedithiolate molecular junctions in length- and temperature-dependent analyses. Additionally, the reliability of the electrical characteristics of the flexible benzenedithiolate molecular devices was investigated under various mechanical bending conditions, such as different bending radii, repeated bending cycles, and a retention test under bending. We also observed the inelastic electron tunneling spectra of our fabricated graphene-electrode molecular devices. Based on the results, we verified that benzenedithiolate molecules participate in charge transport, serving as an active tunneling barrier in solid-state graphene-electrode molecular junctions.

Post-traumatic intradiploic leptomeningeal cyst of the posterior fossa in an adult.

Intradiploic cysts in the posterior fossa are rare. We report a post-traumatic intradiploic leptomeningeal cyst in an adult and review the diagnosis and pathogenesis of this lesion. A 28-year-old woman presented with a headache and a hard mass in the occipital region. She had a history of head injury as she had fallen from a height at the age of 18 months. CT scans and MRI revealed an expanding intradiploic cyst with the density of cerebrospinal fluid (CSF) and thinning of the inner and outer tables. A bony defect of the inner table connecting to the cisterna magna was also visualized. At surgery, we detected free communication of the CSF between the cystic cavity and the subarachnoid space of the posterior fossa via a defect in the dura and inner table. The dural defect was sutured primarily and covered with the autogenous outer table. An intradiploic cyst of the occipital bone can be detected in adults and might be caused by remote head injuries during childhood. Prompt surgical repair of the dural and bony defect in an adult patient has an excellent prognosis.

Contralateral pedicular fracture with unilateral spondylolysis.

Although most authors regard contralateral pedicular fracture with unilateral spondylolysis as an unstable condition and recommend surgical management when immobilization fails in promoting bony healing of the fracture, few researchers have investigated the natural history of pedicle fracture or the causal relationship between symptoms and the fracture. In addition, there are no detailed guidelines that address the management of this disease. We report a rare case of contralateral pedicular fracture associated with unilateral spondylolysis at the L5 level which was successfully treated by rehabilitation with activity modification.

Iatrogenic intraspinal epidermoid tumor: case report.

Iatrogenic spinal epidermoid tumors are extremely rare and may be caused by skin fragments which were implanted in the spine as a result of a trauma or lumbar puncture. Due to the time lag between the lumbar puncture and the development of a symptomatic tumor, this relationship is often overlooked and can cause a delay in the proper diagnosis. Here, we report a rare case of an intraspinal epidermoid tumor, which developed 7 years after a lumbar puncture in a 12-year-old boy, who presented with back pain and radiating pain to the posterior of both thighs. A total excision of the tumor via L3-L4 hemilaminectomy yielded a good functional recovery.

Ectopic recurrence of craniopharyngioma: a case report and review of the literature.

The ectopic recurrence of craniopharyngioma is a rare postoperative complication, for which there are fifteen reported cases that have been surgically verified. The authors present a rare case of ectopic recurrence along the tract of the surgical route. A 12-year-old girl, who had undergone total removal of a suprasellar craniopharyngioma 4 years previously, presented with a generalized tonic-clonic seizure. Magnetic resonance imaging revealed a strongly enhancing cystic tumor in the right frontal lobe, under the bone flap used for the previous craniotomy. Gross total resection was achieved by revision of previous craniotomy. The intraoperative findings revealed that the recurrent tumor was anatomically related to the previous surgical tract, suggesting dissemination along the operative tract. The histopathological features of the mass were the same as those of the previous suprasellar craniopharyngioma. The case presented here and a review of the reports on the previous instances of ectopic recurrence of craniopharyngioma suggest that meticulous protection of the surgical field and careful handling of the tumor during the operation are required. It should be emphasized that long-term follow-up is mandatory, even in patients who underwent a gross total removal.

Metastatic liver cancer: a rare case.

Hemangiopericytoma is a rare tumor especially when it rises in the peritoneal cavity. We present a case of a 60-year-old woman with an isolated recurrent hemangiopericytoma of the liver. The patient presented with a palpable right upper quadrant abdominal mass, which occurred 7 years after undergoing resection of a malignant hemangiopericytoma arising from the greater omentum. She had not followed up 6 mo after surgery. Various imaging studies showed a single large, well-capsulated liver tumor with central necrosis, accompanied by hypervascularity typical of a vascular tumor. Preoperative laboratory HBsAg and anti-HCV workup were both negative. Under the impression of recurrent malignant hemangiopericytoma, right trisegmentectomy was performed to completely resect the tumor. Pathological examination confirmed the diagnosis of recurrent hemangiopericytoma. Even though the incidence of the hemangiopericytoma is relatively low, malignant hemangiopericytoma has a tendency to recur frequently after a long-term disease-free interval. Also, the recurrent hemangiopericytoma is not easily detected early during follow-up until it becomes symptomatic because there are no specific tumor markers, and because of the diversity with regard to site of recurrence. The authors suggest that Positron Emission Tomogram (PET) may be a useful tool for the detection of recurrent hemangiopericytoma. We describe herein some characteristics and behaviors of malignant hemangiopericytoma, particularly after surgical resection.

Amylase level in extrahepatic bile duct in adult patients with choledochal cyst plus anomalous pancreatico-biliary ductal union.

AIM: To investigate the relationship between pancreatic amylase in bile duct and the clinico-pathological features in adult patients with choledochal cyst and anomalous pancreatico-biliary ductal union (APBDU). METHODS: From 39 patients who underwent surgery for choledochal cyst between March 1995 and March 2003, we selected 15 adult patients who had some symptoms and were radiologically diagnosed as APBDU, and their clinico-pathological features were subsequently evaluated retrospectively. However, we could not obtain biliary amylase in all the patients because of the surgeon's slip. Therefore, we measured the amylase level in gall bladder of 10 patients and in common bile duct of 11 patients. RESULTS: Levels of amylase in common bile duct and gall bladder ranged from 11,500 to 212,000 IU/L, and the younger the patients, the higher the biliary amylase level (r = -0.982, P<0.01). Pathologically, significant correlation was found between the size of choledochal cyst and the grade of inflammation (r = 0.798, P<0.01). And, significant correlation was found between the level of amylase in gall bladder and the grade of hyperplasia. On the other hand, there was no correlation to the age of symptomatic onset or inflammatory grade (r = 0.743, P<0.05). Level of lipase was elevated from 6,000 to 159,000 IU/L in bile duct and from 14,400 to 117,000 IU/L in the gall bladder; however, there was no significant correlation with age or clinico-pathological features. CONCLUSION: The results support the notion that amylase has a particular role in the onset of symptoms, and suggest that a large amount of biliary amylase induces early onset of symptom, thereby making early diagnosis possible.