The association between autoantibody types and salivary gland hypofunction in patients with primary Sjögren's syndrome.

BACKGROUND: This study analyzed the association between autoantibody types and salivary gland hypofunction in patients with primary Sjögren's syndrome (pSS). METHODS: A retrospective analysis was performed on patients who visited the Department of Orofacial Pain and Oral Medicine at Yonsei University Dental Hospital from January 1, 2010 to May 31, 2021, and who were diagnosed with pSS. Out of 191 patients who fulfilled the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria, 50 were positive for both anti-Ro/SSA and anti-La/SSB, whereas 97 had anti-Ro/SSA but not anti-La/SSB antibodies. Forty-four patients for whom neither anti-Ro/SSA nor anti-La/SSB antibodies were found were diagnosed with Sjögren's syndrome by minor salivary gland biopsy. RESULTS: The anti-Ro/SSA antibody-positive group showed higher rheumatoid factor (RF) levels than the anti-Ro/SSA antibody-negative group. The anti-La/SSB antibody-positive group showed lower unstimulated whole saliva (UWS), stimulated whole saliva (SWS), higher erythrocyte sedimentation rate and RF level than the anti-La/SSB antibody-negative group. In addition, the group with both anti-Ro/SSA and anti-La/SSB antibodies showed lower UWS than the group with only anti-Ro/SSA antibodies. However, there were no significant differences in UWS or SWS after taking pilocarpine, and C-reactive protein. CONCLUSIONS: UWS and SWS were lower when a patient was positive for anti-La/SSB, showing that anti-La/SSB is more likely to be involved in salivary gland hypofunction than anti-Ro/SSA in patients with pSS. Therefore, performing laboratory tests, including anti-La/SSB, helps predict the prognosis of salivary gland function in patients with suspected pSS.

Microfluidic confinement enhances phenotype and function of hepatocyte spheroids.

A number of cell culture approaches have been described for maintenance of primary hepatocytes. Forming hepatocytes into three-dimensional (3-D) spheroids is one well-accepted method for extending epithelial phenotype of these cells. Our laboratory has previously observed enhanced function of two-dimensional (2-D, monolayer) hepatocyte cultures in microfluidic devices due to increased production of several hepato-inductive growth factors, including hepatocyte growth factor (HGF). In the present study, we wanted to test a hypothesis that culturing hepatocyte spheroids (3-D) in microfluidic devices will also result in enhanced phenotype and function. To test this hypothesis, we fabricated devices with small and large volumes. Both types of devices included a microstructured floor containing arrays of pyramidal wells to promote assembly of hepatocytes into spheroids with individual diameters of ~100 µm. The hepatocyte spheroids were found to be more functional, as evidenced by higher level of albumin synthesis, bile acid production, and hepatic enzyme expression, in low-volume compared with large-volume devices. Importantly, high functionality of spheroid cultures correlated with elevated levels of HGF secretion. Although decay of hepatic function (albumin secretion) was observed over the course 3 wk, this behavior could be abrogated by inhibiting TGF-ß1 signaling. With TGF-ß1 inhibitor, microfluidic hepatocyte spheroid cultures maintained high and stable levels of albumin synthesis over the course of 4 wk. To further highlight utility of this culture platform for liver disease modeling, we carried out alcohol injury experiments in microfluidic devices and tested protective effects of interleukin-22: a potential therapy for alcoholic hepatitis.

Ca(2+) is a Regulator of the WNK/OSR1/NKCC Pathway in a Human Salivary Gland Cell Line.

Wnk kinase maintains cell volume, regulating various transporters such as sodium-chloride cotransporter, potassium-chloride cotransporter, and sodium-potassium-chloride cotransporter 1 (NKCC1) through the phosphorylation of oxidative stress responsive kinase 1 (OSR1) and STE20/SPS1-related proline/alanine-rich kinase (SPAK). However, the activating mechanism of Wnk kinase in specific tissues and specific conditions is broadly unclear. In the present study, we used a human salivary gland (HSG) cell line as a model and showed that Ca(2+) may have a role in regulating Wnk kinase in the HSG cell line. Through this study, we found that the HSG cell line expressed molecules participating in the WNK-OSR1-NKCC pathway, such as Wnk1, Wnk4, OSR1, SPAK, and NKCC1. The HSG cell line showed an intracellular Ca(2+) concentration ([Ca(2+)]i) increase in response to hypotonic stimulation, and the response was synchronized with the phosphorylation of OSR1. Interestingly, when we inhibited the hypotonically induced [Ca(2+)]i increase with nonspecific Ca(2+) channel blockers such as 2-aminoethoxydiphenyl borate, gadolinium, and lanthanum, the phosphorylated OSR1 level was also diminished. Moreover, a cyclopiazonic acid-induced passive [Ca(2+)]i elevation was evoked by the phosphorylation of OSR1, and the amount of phosphorylated OSR1 decreased when the cells were treated with BAPTA, a Ca(2+) chelator. Finally, through that process, NKCC1 activity also decreased to maintain the cell volume in the HSG cell line. These results indicate that Ca(2+) may regulate the WNK-OSR1 pathway and NKCC1 activity in the HSG cell line. This is the first demonstration that indicates upstream Ca(2+) regulation of the WNK-OSR1 pathway in intact cells.

Macro/Nano-gel composite as an injectable and bioactive bulking material for the treatment of urinary incontinence.

Many women around the world are suffering from urinary incontinence, defined as the unintentional leakage of urine by external abnormal pressure. Although various kinds of materials have been utilized to treat this disease, therapies that are more effective are still needed for the treatment of urinary incontinence. Here, we present a macro/nanogel composed of in situ forming gelatin-based macrogels and self-assembled heparin-based nanogels, which can serve as an injectable and bioactive bulking material for the treatment of urinary incontinence. The hybrid hydrogels were prepared via enzymatic reaction in the presence of horseradish peroxidase and hydrogen peroxide. Incorporating a growth factor (GF)-loaded heparin nanogel into a gelatin gel matrix enabled the hybrid gel matrix to release GF continuously up to 28 days. Moreover, we demonstrated that the hydrogel composites stimulated the regeneration of the urethral muscle tissue surrounding the urethral wall and promoted the recovery of their biological function when injected in vivo. Thus, the macro/nanohydrogels may provide an advanced therapeutic technique for the treatment of urinary incontinence as well as an application for regenerative medicine.

Molecular Prevalence of Blastocystis sp. from Patients with Diarrhea in the Republic of Korea.

Blastocystis sp. is the most common intestinal protozoan affecting human health worldwide. Several studies have reported the prevalence of Blastocystis sp. in various regions of the Republic of Korea. However, limited data are available on the prevalence and subtype (ST) distribution of this parasite among regions. Therefore, we investigated the prevalence and ST distributions of this parasite in the Republic of Korea. For this purpose, 894 stool specimens were collected from patients with diarrhea and tested for the presence of Blastocystis sp. using PCR analysis. The isolates were subsequently subtyped. The overall prevalence was 11.6%. Of the 104 isolates, ST3 was the most prevalent, followed by ST1. Additionally, a single case of the rare subtype ST8 was identified, representing the first reported case in the Republic of Korea. The results suggested that the predominance of ST3 observed in this study reflects human-to-human transmission with low genetic diversity within the ST, while ST1 transmission is likely correlated with animals. In the future, to better understand Blastocystis sp. transmission dynamics, human, animal, and environmental factors should be studied from a "One Health" perspective.

Heparin-conjugated pluronic nanogels as multi-drug nanocarriers for combination chemotherapy.

Combination chemotherapy using more than two therapeutic agents with different modes of action is a promising strategy that can be used to enhance the therapeutic efficacy of cancer treatment, even though it is a complicated treatment modality. The aim of this study was to investigate how a novel multidrug nanocarrier is effective for combination chemotherapy in vitro and, more specifically, whether combined agents with different modes of action and physicochemical properties show synergistic cytotoxicity with the use of this nanocarrier. A heparin-Pluronic (Hep-Pr) nanogel encapsulating both paclitaxel and DNase was shown to be efficient for intracellular delivery with respect to size, encapsulation efficiency, and intracellular uptake/fates. As a result of these properties, a Hep-Pr nanogel combined with paclitaxel and DNase exhibited a dose-dependent synergistic cytotoxicity compared to single drug and free-drug treatments, whose combination indices were 0.93 and 0.45 at higher concentrations (250 and 500 µg/mL). Therefore, Hep-Pr nanogels have the potential to deliver multitherapeutic agents with different characteristics and thereby enhance the therapeutic efficacy of combination cancer chemotherapy.

Three-dimensional courses of zygomaticofacial and zygomaticotemporal canals using micro-computed tomography in Korean.

The zygomatic nerve (ZN), which originates from the maxillary nerve at the pterygopalatine fossa, enters the orbit through the inferior orbital fissure. Within the lateral region of the orbit, the ZN divides into the zygomaticofacial (ZF) and zygomaticotemporal (ZT) nerves. The ZF and ZT nerves then pass on to the face and temporal region through the zygomaticoorbital foramen and enter their own bony canals within the zygomatic bone. However, multiple zygomaticofacial and zygomaticotemporal canals (ZFCs and ZTCs, respectively) can be observed, and their detailed intrabony courses are unknown. The aim of this study was clarify the three-dimensional intrabony courses and running patterns of the ZFCs and ZTCs, both to obtain a detailed anatomical description and for clinical purposes. Fourteen sides of the zygomatic bones were scanned as two-dimensional images using a micro-computed tomography (CT), with 32-µm slice thickness. Intrabony structures of each canals were three-dimensionally reconstructed and analyzed using Mimics computer software (Version 10.01; Materialise, Leuven, Belgium). We found that some ZTC was originated from ZFC. In 71.4% of the specimens, the ZTC(s) divided from the intrabony canal along the course of the ZFC(s). In other cases, 28.6% of ZTCs were opened through each corresponding ZT foramen. Zygomaticofacial canal originates from zygomaticoorbital foramen, divided into some of ZTCs, and is finally opened as ZF foramen. This new anatomical description of the intrabony structures of the ZFC(s) and ZTC(s) within the zygomatic bone by micro-CT technology provided helpful information to surgeons performing clinical procedures such as Le Fort osteotomy and reconstructive surgeries in the midface region.

Guiding Hepatic Differentiation of Pluripotent Stem Cells Using 3D Microfluidic Co-Cultures with Human Hepatocytes.

Human pluripotent stem cells (hPSCs) are capable of unlimited proliferation and can undergo differentiation to give rise to cells and tissues of the three primary germ layers. While directing lineage selection of hPSCs has been an active area of research, improving the efficiency of differentiation remains an important objective. In this study, we describe a two-compartment microfluidic device for co-cultivation of adult human hepatocytes and stem cells. Both cell types were cultured in a 3D or spheroid format. Adult hepatocytes remained highly functional in the microfluidic device over the course of 4 weeks and served as a source of instructive paracrine cues to drive hepatic differentiation of stem cells cultured in the neighboring compartment. The differentiation of stem cells was more pronounced in microfluidic co-cultures compared to a standard hepatic differentiation protocol. In addition to improving stem cell differentiation outcomes, the microfluidic co-culture system described here may be used for parsing signals and mechanisms controlling hepatic cell fate.

Effects of the Washing Time and Washing Solution on the Biocompatibility and Mechanical Properties of 3D Printed Dental Resin Materials.

Three-dimensional (3D) printing technology is highly regarded in the field of dentistry. Three-dimensional printed resin restorations must undergo a washing process to remove residual resin on the surface after they have been manufactured. However, the effect of the use of different washing solutions and washing times on the biocompatibility of the resulting resin restorations is unclear. Therefore, we prepared 3D-printed denture teeth and crown and bridge resin, and then washed them with two washing solutions (isopropyl alcohol and tripropylene glycol monomethyl ether) using different time points (3, 5, 10, 15, 30, 60, and 90 min). After this, the cell viability, cytotoxicity, and status of human gingival fibroblasts were evaluated using confocal laser scanning. We also analyzed the flexural strength, flexural modulus, and surface SEM imaging. Increasing the washing time increased the cell viability and decreased the cytotoxicity (p < 0.001). Confocal laser scanning showed distinct differences in the morphology and number of fibroblasts. Increasing the washing time did not significantly affect the flexural strength and surface, but the flexural modulus of the 90 min washing group was 1.01 ± 0.21 GPa (mean ± standard deviation), which was lower than that of all the other groups and decreased as the washing time increased. This study confirmed that the washing time affected the biocompatibility and mechanical properties of 3D printed dental resins.

Sestrin2 Regulates Osteoclastogenesis via the p62-TRAF6 Interaction.

The receptor activator of nuclear factor-kappa B ligand (RANKL) mediates osteoclast differentiation and functions by inducing Ca2+ oscillations, activating mitogen-activated protein kinases (MAPKs), and activating nuclear factor of activated T-cells type c1 (NFATc1) via the RANK and tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) interaction. Reactive oxygen species (ROS) also plays an important role during osteoclastogenesis and Sestrin2, an antioxidant, maintains cellular homeostasis upon stress injury via regulation of ROS, autophagy, and inflammation. However, the role of Sestrin2 in osteoclastogenesis remains unknown. In this study, we investigated the role of Sestrin2 in the RANKL-RANK-TRAF6 signaling pathway during osteoclast differentiation. Deletion of Sestrin2 (Sesn2) increased bone mass and reduced the number of multinucleated osteoclasts on bone surfaces. RANKL-induced osteoclast differentiation and function decreased in Sesn2 knockout (KO) bone marrow-derived monocytes/macrophages (BMMs) due to inhibition of NFATc1 expression, but osteoblastogenesis was not affected. mRNA expression of RANKL-induced specific osteoclastogenic genes and MAPK protein expression were lower in Sesn2 KO BMMs than wild-type (WT) BMMs after RANKL treatment. However, the Sesn2 deletion did not affect ROS generation or intracellular Ca2+ oscillations during osteoclastogenesis. In contrast, the interaction between TRAF6 and p62 was reduced during osteoclasts differentiation in Sesn2 KO BMMs. The reduction in the TRAF6/p62 interaction and TRAP activity in osteoclastogenesis in Sesn2 KO BMMs was recovered to the WT level upon expression of Flag-Sesn2 in Sesn2 KO BMMs. These results suggest that Sestrin2 has a novel role in bone homeostasis and osteoclasts differentiation through regulation of NFATc1 and the TRAF6/p62 interaction.

Anti-inflammatory effects of licorice and roasted licorice extracts on TPA-induced acute inflammation and collagen-induced arthritis in mice.

The anti-inflammatory activity of licorice (LE) and roasted licorice (rLE) extracts determined in the murine phorbol ester-induced acute inflammation model and collagen-induced arthritis (CIA) model of human rheumatoid arthritis. rLE possessed greater activity than LE in inhibiting phorbol ester-induced ear edema. Oral administration of LE or rLE reduced clinical arthritis score, paw swelling, and histopathological changes in a murine CIA. LE and rLE decreased the levels of proinflammatory cytokines in serum and matrix metalloproteinase-3 expression in the joints. Cell proliferation and cytokine secretion in response to type II collagen or lipopolysaccharide stimulation were suppressed in spleen cells from LE or rLE-treated CIA mice. Furthermore, LE and rLE treatment prevented oxidative damages in liver and kidney tissues of CIA mice. Taken together, LE and rLE have benefits in protecting against both acute inflammation and chronic inflammatory conditions including rheumatoid arthritis. rLE may inhibit the acute inflammation more potently than LE.

The chronology of second and third molar development in Koreans and its application to forensic age estimation.

The accuracy of forensic age estimation based on the chronology of second (M2) and third molar (M3) development was investigated using 2,087 orthopantomograms of Korean men and women aged between 3 and 23 years. The developmental stages of M2s and M3s in these subjects were classified using the criteria of Demirjian. Inter-observer reliability and statistical data on each stage of mineralization of M2s and M3s were evaluated. The left-right symmetries of the maturation degrees in the M2s and M3s were observed in both sexes, between which no arch differences were found, but statistically significant sex-specific differences were observed in some stages of M2 and M3 development. In multiple regression analysis, a strong positive relationship was observed between age and mineralization of M2s and M3s. The regression formulas for estimating the age of Koreans were presented based on sex and combination of teeth. These results suggest that the developments of second and third molars can be considered as valuable age indicators in Korean adolescents and young adults.

Use of botulinum toxin type A injection for neuropathic pain after trigeminal nerve injury.

OBJECTIVE: To present a case that neuropathic pain following traumatic injury of the inferior alveolar nerve, which was relieved by the injection of BTX-A. DESIGN: Case report. SETTING: Tertiary care University hospital. SUBJECT: A 62-year-old female was referred by her general dentist to our clinic due to numbness and pain over the left side of her lower lip and chin region. INTERVENTION: Botulinum toxin type A injected into the middle of chin area subcutaneously. RESULTS: At 1 month after BTX-A injection, the affected area had decreased in size. And at 2 months, the patient reported a slight decreased in pain, and CPT differences being sustained at a reduced level. CONCLUSIONS: This case report suggests an effective new modality for treating neuropathic pain after trigeminal nerve injury. A further randomized controlled study involving a large number of patients is needed.

Red ginseng saponin extract attenuates murine collagen-induced arthritis by reducing pro-inflammatory responses and matrix metalloproteinase-3 expression.

Ginseng, the root of Panax ginseng C. A. MEYER, has been used as a food product and medicinal ingredient. In this study, we assessed the anti-arthritic effects of red ginseng saponin extract (RGSE), including ginsenosides Rg3, Rk1 and Rg5 as major components, on a murine type II collagen (CII)-induced arthritis (CIA), which is a valid animal model of human arthritis. Oral administration of RGSE at 10 mg/kg reduced the clinical arthritis score and paw swelling in the CIA mice, and inhibited joint space narrowing and histological arthritis, illustrating the severity of synovial hyperplasia, inflammatory cell infiltration, pannus formation, and erosion of cartilage. RGSE inhibited the expression of matrix metalloproteinase-3 and nitrotyrosine formation, and recovered the expression of superoxide dismutase in the joints of the CIA mice. Orally administered RGSE also reduced the levels of serum tumor necrosis factor-alpha and interleukin-1beta in the CIA mice. CII- or lipopolysaccharide-stimulated cytokine production, in addition to CII-specific proliferation, was reduced in the spleen cells of the RGSE-treated CIA mice, as compared with those from vehicle-treated CIA mice. Furthermore, RGSE administration protected against CIA-induced oxidative tissue damage by restoring the increased malondialdehyde levels and the decreased glutathione levels and catalase activities almost to control levels. Therefore, RGSE may be a beneficial supplement which can improve human arthritis.

Intramuscular nerve distribution of the masseter muscle as a basis for botulinum toxin injection.

The aim of this study was to determine intramuscular distribution pattern of the masseteric nerve, thus providing information regarding the most efficient and safe site for botulinum toxin (BTX) injection for conventional BTX intervention therapy in the treatment of masseteric hypertrophy.Twelve masseter muscles were dissected, and the pattern of innervation of the masseteric nerve was observed in the superficial, middle, and deep layers. We also analyzed 10 muscles that had been stained using Sihler's staining technique.The nerve branches from the posterosuperior and posteroinferior groups innervating the deep and middle layers of the masseter muscle, respectively. Among the nerve twigs originating from the anteroinferior nerve group, 2 or 3 perforated the superficial layer of the muscle. Observation of stained specimens revealed that all perforating branches innervating the superficial layer were mainly confined to and distributed within areas V or VI.Between 2 and 4 perforating branches supply the superficial layer of the masseter muscle. In addition, the richest arborization of the perforating masseteric nerve branches is confined mostly to area V, approximately in accordance with the BTX injection point that is currently used clinically. Area V is thus strongly recommended as the most efficient and safe BTX injection area for the treatment of masseteric hypertrophy.

CT-like MRI using the zero-TE technique for osseous changes of the TMJ.

OBJECTIVE: This study was conducted to assess the clinical usability of the zero-echo time (ZTE) technique of MRI for evaluating bone changes of the temporomandibular joint (TMJ) in comparison with CBCT. METHODS: Twenty patients with TMJ disorder who underwent both CBCT and MRI were randomly selected. CBCT images were obtained with an Alphard 3030 device (Asahi Roentgen Ind., Co. Ltd, Kyoto, Japan). MRIs were obtained using a 3.0 T scanner (Pioneer; GE Healthcare, Waukesha, WI, USA) and a 21-channel head coil. An isotropic three-dimensional proton-density-weighted ZTE sequence was acquired. Two radiologists evaluated 40 joints of 20 patients for the presence of the following osseous changes: flattening, erosion, osteophyte and sclerosis of the condyle; and flattening, erosion and sclerosis of the articular fossa. CBCT and ZTE-MRI assessments were performed at a 2-month interval. The prevalence-adjusted and bias-adjusted κ statistic was used to analyse interexaminer and intraexaminer agreement and the agreement between ZTE-MRI and CBCT. RESULTS: Intraexaminer and interexaminer agreement analyses of ZTE-MRI showed high reproducibility (κ>0.80), which was comparable to that of CBCT. Flattening, osteophyte and sclerosis of the condyle and all types of bone changes in the mandibular fossa showed nearly perfect agreement between CBCT and ZTE-MRI (κ = 0.80-0.90). Erosion of the condyle showed substantial agreement between both sets of images (κ = 0.65-0.70). CONCLUSIONS: It is suggested that ZTE-MRI provides clinically reliable images for bone assessment in TMJ disorder. MRI may become a beneficial diagnostic tool for patients with both TMJ disc and bone pathology, with advantages involving medical costs and radiation dose.

Assessment of tooth wear based on autofluorescence properties measured using the QLF technology in vitro.

BACKGROUND: The difference in autofluorescence between enamel and dentine layer has prompted recommendations to use the quantitative light-induced fluorescence (QLF) method for quantifying tooth wear (TW). This study investigated the potential of QLF for distinguishing the severity of occlusal TW based on differences in the autofluorescence intensity. METHODS: In total, 106 extracted permanent molars and premolars having suspected wear without pulp exposure were used. The severity of wear was determined by visually examining all teeth using the tooth wear index (TWI) of Smith and Knight. QLF images were captured and converted into 8-bit grayscale images. The difference in the fluorescence intensity (ΔG) was calculated by comparing mean grayscale levels between sound and worn areas. Finally, histological examination was conducted by stereomicroscope to confirm the presence of dentine exposure. RESULTS: 100 teeth were included in the final analysis without six teeth having enamel cracks around worn area. The ΔG values increased with the severity of TW as quantified using conventional TWI codes, and differed significantly between the sound and enamel- and dentine-wear teeth (P < 0.001). The histology indicated that enamel remained on 57 teeth, while 43 teeth had dentine-exposed wear and showed significant differences in ΔG compared with enamel-remained teeth. CONCLUSIONS: The fluorescence intensity differed significantly depending on the presence of dentine exposure. ΔG could be used to distinguish between sound and enamel- and dentine-wear teeth with a significant correlation. These findings indicate that QLF could be useful for determining the severity of TW of occlusal surfaces noninvasively.

Hyper-branched poly(poly(ethylene glycol)methacrylate)-grafted surfaces by photo-polymerization with iniferter for bioactive interfaces.

A new hyper-branched surface in which three species of architectures were constructed as stem chain, branched stem and twig chain-grafted branched chain of poly(poly(ethylene glycol)methacrylate) (poly(PEGMA)) by photo-polymerization using dithiocarbamyl group (DC) as iniferter was prepared and characterized. For these surfaces, radical copolymerization of styrene and an iniferter-activated chain that was previously synthesized was performed for using as base materials for surface coating. On a DC-activated surface, hyper-branched poly(PEGMA) was introduced by photo-polymerization and dithiocarbamylation. All modified surfaces were analyzed by X-ray photoelectron spectroscopy (XPS) and water contact angle measurements. Our results demonstrated that a highly hyper-branched graft architecture of poly(PEGMA) can be constructed on PU surface by photo-polymerization using dithiocarbamyl group as iniferter, in which first, second and third generation gave stem chain, branched chain and twig chain of poly(PEGMA), respectively. Our hyper-branched surfaces could be regulated by photo-irradiation time and might be controlled by feed amounts or other reaction conditions. This highly dense architecture of PEG chain with hydrophilicity and chain mobility, grafted on surface, is expected to be effectively utilized in bio-implantable substrates or micro- or nano-patterned surfaces for immobilization of bioactive molecules in biomedical fields.

Alteration of expression of Ca2+ signaling proteins and adaptation of Ca2+ signaling in SERCA2+/- mouse parotid acini.

PURPOSE: The sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), encoded by ATP2A2, is an essential component for G-protein coupled receptor (GPCR)-dependent Ca2+ signaling. However, whether the changes in Ca2+ signaling and Ca2+ signaling proteins in parotid acinar cells are affected by a partial loss of SERCA2 are not known. MATERIALS AND METHODS: In SERCA2+/- mouse parotid gland acinar cells, Ca2+ signaling, expression levels of Ca2+ signaling proteins, and amylase secretion were investigated. RESULTS: SERCA2+/- mice showed decreased SERCA2 expression and an upregulation of the plasma membrane Ca2+ ATPase. A partial loss of SERCA2 changed the expression level of 1, 4, 5-tris-inositolphosphate receptors (IP3Rs), but the localization and activities of IP3Rs were not altered. In SERCA2+/- mice, muscarinic stimulation resulted in greater amylase release, and the expression of synaptotagmin was increased compared to wild type mice. CONCLUSION: These results suggest that a partial loss of SERCA2 affects the expression and activity of Ca2+ signaling proteins in the parotid gland acini, however, overall Ca2+ signaling is unchanged.

Particle-in-Particle Platform for Nanoconfinement-Induced Oncothermia.

Oncothermia, a special form of hyperthermia for oncological purposes, has been widely shown to be an effective mode of cancer therapy. However, its adoption among standard therapeutic practices has been limited by constraints in delivering sufficient thermal energy to tumor targets. To overcome these unique challenges in delivery presented by oncothermic therapeutics, we engineered a novel universal platform for hyperthermia cancer therapy utilizing versatile biocompatible materials. Herein, we show that Gold particle-in-particle (PIP), in which gold nanoparticles are physically confined within PLGA-PEG nanoparticles, significantly enhances thermal energy production by red-shifting the gold nanoparticle's absorption spectra via a mechanism in which we call nanoconfinement-induced therapeutic enhancement (NITE). NITE mediated Gold PIPs significantly suppress breast, skin, and multidrug resistant tumors and result in a multifold increase of heat shock protein expressed by cancer cells in vivo. Cotreatment of Gold PIP with doxorubicin shows a synergistic advantage. By using tumor-bearing mice, significant suppression of tumor growth by Gold PIPs shows the advantage of NITE mediated hyperthermia. Thus, we conclude that NITE mediated Gold PIP can be a strong anticancer therapy because of its sufficient amount of heat generation.