Effects of physical activity levels on characteristic pain in temporomandibular dysfunctions: a cross-sectional study.

BACKGROUND: Physical activity is known to influence the symptoms of a variety of pain disorders including fibromyalgia and osteoarthritis although the underlying mechanism is not fully understood. In spite of the high prevalence of temporomandibular disorders (TMD), no previous study has objectively evaluated the relationship between TMD and general physical activity. This study aims to investigate the influence of physical activity on pain and disability from TMD, considering various confounders including sleep, systemic inflammation, psychosocial disturbances, and widespread pain. METHODS: This observational cross-sectional study is based on consecutive samples of 100 TMD patients (22 with high pain disability and 78 with low pain disability level). Physical activity levels were assessed with actigraph. Level of pain and disability were evaluated using the Graded Chronic Pain Scale. Hematologic examinations including inflammatory biomarkers were assessed and comorbidities were investigated with validated questionnaires. Differences were analyzed according to disability level. RESULTS: Patients with high disability level spent significantly more time doing both moderate (p = 0.033) and vigorous (p = 0.039) level physical activity. Light physical activity, on the other hand, was associated with low disability but the difference did not reach statistical significance. Time spent in light physical activity was significantly associated with high levels of pain and disability (p = 0.026, ß = -0.001) and time spent in vigorous physical activity had significant predictive power (cutoff value 2.5 min per week, AUC 0.643, p = 0.041). Scores of the Jaw Function Limitation Score-20 (p = 0.001), present McGill Pain Score (p = 0.010), and number of people potentially diagnosed with fibromyalgia (p = 0.033) were significantly higher in the high disability group. CONCLUSIONS: Moderate or vigorous physical activity is associated with worse TMD symptoms while light physical activity may be beneficial. Further research related to the amount and frequency of physical activity is necessary to establish clinical guidelines for TMD. TRIAL REGISTRATION: clinical trial registration of the Clinical Research Information Service of Republic of Korea (number KCT0007107).

Correlates of jaw functional limitation, somatization and psychological distress among different temporomandibular disorder diagnostic subtypes.

OBJECTIVES: This study investigated the jaw functional status and severity of somatic/psychological symptoms in different Diagnostic Criteria for temporomandibular disorders (DC/TMD) diagnostic subtypes and established the correlates between jaw functional limitation, somatization, depression and anxiety. METHODS: Data were accrued from consecutive 'first-visit' patients seeking TMD treatment at a university-based oral medicine/diagnosis clinic. Axis I physical TMD diagnoses were derived using the DC/TMD methodology and patients were categorized into pain-related (PT), intra-articular (IT) and combined (CT) TMD groups. Axis II measures were also administered and included the Jaw Functional Limitation Scale-20 (JFLS-20), Patient Health Questionnaire-15 and 9 (PHQ-15 and PHQ-9) and General Anxiety Disorder Scale-7 (GAD-7). Chi-square/Kruskal-Wallis tests and Spearman's correlation were employed for statistical evaluations (α = .05). RESULTS: The final dataset consisted of 772 TMD patients (mean age of 37.7 ± 15.9 years; 70.2% females). The prevalence of PT, IT and CT was 11.9%, 15.7% and 72.4%, respectively. Significant differences in functional jaw limitations, somatization, depression (CT, PT > IT) and anxiety (CT > PT, IT) were observed. Moderate-to-severe somatization, depression and anxiety were detected in 12.6%-15.7% of patients. For all three TMD groups, JFLS global scale/subscale scores were weakly associated with somatization, depression and anxiety scores (rs < 0.4). Moderate-to-strong correlations were noted between somatization, depression and anxiety (rs = 0.50-0.74). CONCLUSIONS: Functional jaw limitations were associated with painful TMDs but appear to be unrelated to somatization and psychological distress. Somatization and depression/anxiety were moderately correlated, underscoring the importance of somatic symptom screening when managing TMD patients.

Geniohyoid Muscle: Anatomy and Clinical Implications in Dentistry / Músculo Geniohioideo: Anatomía e Implicaciones Clínicas en Odontología

SUMMARY: The geniohyoid muscle is one of the suprahyoid muslces, and arises from the inferior mental spine and inserts into the hyoid bone. The muscle is a narrow paired one and its main action is pulling the hyoid upward and forward. Its function is very important in deglutition as well as respiration. Therefore, this muscle has been extensively researched, especially in the context of dysphagia and sleep apnea. This review deals with the general anatomic features, main functions, and abnormal states of the geniohyoid muscle, and the clinical implications of these.

El músculo geniohioideo es uno de los músculos suprahioideos que surge de la espina mental inferior y se inserta en el hueso hioides. Son un par de músculo delgados y su acción principal es elevar y estirar el hueso hioides hacia arriba y hacia adelante. Su función es importante tanto en la deglución como en la respiración. Por lo tanto, este músculo ha sido ampliamente investigado, especialmente en el contexto de la disfagia y la apnea del sueño. Esta revisión trata de las características anatómicas generales, funciones principales y estados anormales del músculo geniohioideo, y las implicaciones clínicas de estos.

Sleep duration and inflammatory mediator levels associated with long-term prognosis in temporomandibular disorders.

BACKGROUND: Sleep disturbance is a systemic symptom and at the same time a major modulating factor of temporomandibular disorders (TMD). Inflammation is known as a underlying mechanism involved in both poor sleep and increased pain. OBJECTIVE: The relationship between long-term clinical characteristics and hematologic biomarkers of hypothalamic-pituitary-adrenal axis activity and inflammation in TMD patients according to sleep duration was investigated to verify the possible role of sleep disturbance and systemic inflammation in TMD. MATERIALS AND METHODS: Inflammatory and stress mediator levels of venous blood samples were investigated in 63 female TMD patients along with comorbidity levels including stress, somatization, autonomic symptoms and sleep quality based on structured questionnaires. Differences in long-term clinical characteristics and hematologic variables following conservative treatment were analysed according to total sleep time as normal, short and long sleep groups. Also, clinical and hematologic indices related to favourable treatment response were sought out. RESULTS: Significantly less patients in the long sleep group reported pain on voluntary mandibular movement (p = .042) while depression (p = .043) and somatization levels (p = .002) were significantly higher in the short sleep group. Norepinephrine levels of the long sleep group were significantly lower than other groups. Decrease in pain intensity with treatment was smallest in the short sleep group. Erythrocyte sedimentation rate was associated with significant pain improvement at 3 months post-treatment and interleukin-1ß, -4, and -8 levels could predict favourable treatment response. CONCLUSION: Short sleep is associated with more comorbidities and unfavourable long-term treatment response in TMD which may be mediated by systemic inflammation. Effective management of sleep is necessary for successful TMD management.

Temporomandibular disorders-related videos on YouTube are unreliable sources of medical information: A cross-sectional analysis of quality and content.

Objective: The amount of online medical information available is rapidly growing and YouTube is considered as the most popular source of healthcare information nowadays. However, no study has been conducted to comprehensively evaluate YouTube videos related to temporomandibular disorders (TMD). So this study aimed to evaluate the content and quality of YouTube videos as a source of medical information on TMD. Method: A total of 237 YouTube videos that were systematically searched using five keywords (temporomandibular disorders, tmd, temporomandibular joint, tmj, and jaw joint) were included. Included videos were categorized by purpose and source for analysis. The quality (DISCERN, Health on the Net (HON), Ensuring Quality Information for Patients (EQIP), and Global Quality Scale (GQS)) and scientific accuracy of video contents were evaluated. Results: Total content, DISCERN, HON, EQIP, and GQS scores were 7.5%, 38.9%, 35.2%, 53.0%, and 48.6% of the maximum possible score, respectively. Only 69 videos (29.1%) were considered as "useful" for patients. News media, physician, and medical source videos showed higher evaluation scores than others. Quality evaluation scores were not significantly correlated or negatively correlated with public preference indices. In the ROC curve analysis, content and DISCERN score showed above excellent discrimination ability for high-quality videos based on GQS (P < 0.001) and total score (P < 0.001). Conclusions: YouTube videos related to TMD contained low quality and scientifically inaccurate information that could negatively influence patients with TMD.

Does physical activity level have an impact on long-term treatment response in temporomandibular disorders: protocol for a prospective study.

BACKGROUND: Temporomandibular disorders (TMD) is a disease characterized by pain and dysfunction of the masticatory muscles and temporomandibular joint. Many factors have been found to be related to the disease however, the underlying mechanism is yet to be fully elucidated. Physical activity is widely known to modulate pain intensity in various pain disorders. However, literature suggesting the association between physical activity and signs and symptoms of TMD are limited. METHODS AND DESIGN: The "Physical Activity in TMD (PAT)" is a prospective study on TMD patients that aims to determine how daily physical activity and sleep duration affect long-term TMD prognosis following conventional treatment. To analyze such effects, objective data on daily physical activity levels will be collected along with clinical indices including mouth opening ranges and masticatory muscle palpation responses from adult Koreans diagnosed with TMD following standardized diagnostic procedures. Well-known comorbidities of TMD will be extensively evaluated based on validated structured questionnaires on sleep quality, fatigue level, widespread pain, psychological status including depression and anxiety, autonomic symptoms, and health-related quality of life. The collected data will be analyzed according to TMD pain severity and physical activity level, and correlations among physical activity indices and long-term TMD prognosis will be investigated. DISCUSSION: In this longitudinal prospective study of adult Koreans diagnosed with TMD following standardized diagnostic procedures, primary outcomes include physical activity levels and long-term TMD clinical outcomes and secondary outcomes include disability from pain and related comorbidity levels. Results and analysis are ongoing. The results of this study will provide reliable data for future research and establish clinical guidelines that will allow cause-related, patient-tailored personalized medicine for TMD. TRIAL REGISTRATION: Clinical Research Information Service (Registration number: KCT0007107). Registered March 22 2022 https://cris.nih.go.kr/cris/search/detailSearch.do?search_lang=E&focus=reset_12&search_page=M&pageSize=10&page=undefined&seq=21420&status=5&seq_group=21420 .

Hyoid bone position as an indicator of severe obstructive sleep apnea.

BACKGROUND: The objective of this study was to evaluate the relationship between hyoid bone position and severity of obstructive sleep apnea (OSA), and to investigate its value as a complementary diagnostic method. METHODS: A total of 133 patients who were diagnosed as OSA with an apnea-hypopnea index ≥ 5 were included. Clinical examination, level I polysomnography (PSG) and lateral cephalographic analysis were done. Comprehensive PSG characteristics were compared according to hyoid bone position and the predictive power of the distance between the mandible and hyoid was assessed. RESULTS: The distance between the hyoid bone and mandibular plane was significantly longer in the severe OSA group (p = 0.013). The distance from hyoid bone to third vertebrae (C3) and hyoid bone to mentum were also longer in the severe OSA group but the difference did not reach statistical significance. The distance between hyoid bone and mandibular plane was effective in predicting severe OSA, with a cut-off value of 19.45 mm (AUC = 0.623, p = 0.040). When grouped according to a distance cut-off value of 19.45 mm, those with a longer distance between the hyoid bone and mandibular plane showed more respiratory disturbance, lower oxygen saturation levels, less deep slow wave sleep, and more fragmented sleep with arousals. CONCLUSIONS: The distance between the hyoid bone and mandibular plane derived from cephalometric analysis can be a valuable diagnostic parameter that can be easily applied in differentiating severe OSA patients.

The multisystemic effects of oral appliance therapy for obstructive sleep apnea: A narrative review.

Obstructive sleep apnea (OSA) is a chronic condition accompanied by repeated obstruction of the upper airway during sleep despite respiratory efforts, resulting in intermittent hypoxemia, altered sleep structure, and sympathetic activation. Previous studies have shown a significant association between OSA and general health issues such as cardiovascular diseases, endocrine disorders, neurocognitive function decline, and poor quality of life. Continuous positive airway pressure (CPAP) has been considered as the first line treatment for OSA. However, accumulating evidence supports the role of oral appliance (OA) therapy, including mandibular advancement devices, as an alternative option for snoring and OSA patients who do not comply with or refuse CPAP usage. Despite a generally favorable outcome of OA therapy for OSA related respiratory indices, studies focusing on the impact of systemic effects of OA therapy in OSA patients are relatively scarce compared with the extensive literature focusing on the systemic effects of CPAP. Therefore, this article aimed to provide an overview of the current evidence regarding the multisystemic effects of OA therapy for OSA.

Hematological biomarkers of systemic inflammation in genuine (physiologic and pathologic) halitosis.

Halitosis is an unpleasant odor discharged through the oral cavity with a prevalence as high as 30%-50% of the general population. Conventional diagnostic methods have been focused on mouth air analysis measuring the amount of sulfur compounds which does not directly reflect the cause of halitosis. Also, the possible role of halitosis as an indicator of general health status has been steadily suggested and inflammation has been constantly associated with aversive body odor. Therefore, this study aimed to search for inter-relationships between hematologic indicators, clinical characteristics, and halitosis measurement that can predict the presence of pathologic halitosis and its intensity. Furthermore, the tentative relationship between halitosis and the presence of systemic inflammation was investigated. A total of 125 patients were divided into 103 patients in the genuine halitosis group (value ⩾80 ppb) and 22 patients in the pseudo halitosis group (value <80 ppb) based on portable sulfide monitor measurements. Clinical examination and hematological indices including inflammatory prognostic factors and halitosis measurements including organoleptic testing, portable sulfide monitor, and gas chromatography were evaluated. The genuine halitosis group showed a significantly higher white blood cell (WBC) count (p< 0.01) compared to the pseudo halitosis group. Erythrocyte sedimentation rate (ESR,ß= 0.341,p< 0.05) values and duration of halitosis (ß= 0.353,p< 0.05) showed a significant association with halitosis intensity and neutrophil to lymphocyte ratio (NLR) values (ß= 3.859,p< 0.05) were significantly related to genuine halitosis diagnosis. A new WBC cut-off value of 5575µl-1showed near to fair discriminative power in predicting genuine halitosis (area under the curve 0.661,p< 0.05). The results of this study showing an increased WBC count in genuine halitosis and its strong association with hematologic indices of subclinical inflammation including ESR and NLR suggest inflammatory hematologic markers as potential diagnostic tools in the diagnosis of genuine halitosis.

Comparison of polysomnographic and cephalometric parameters based on positional and rapid eye movement sleep dependency in obstructive sleep apnea.

The aim of this study is to investigate the differences in polysomnographic and cephalometric features according to positional and rapid eye movement (REM) sleep dependencies in obstructive sleep apnea patients. Standard polysomnography and cephalometric analyses were performed on 133 OSA patients. The subjects were categorized into positional and non-positional, and REM-related and not-REM-related OSA groups according to positional and REM sleep dependency on severity of sleep apnea. Polysomnographic and cephalometric parameters were compared between groups. Positional and REM-related OSA patients showed significantly lower non-supine apnea-hypopnea index (AHI), non-REM (NREM) AHI and overall AHI and higher NREM oxygen saturation (SpO2) and mean SpO2 compared to non-positional and not-REM-related OSA patients, respectively. Cephalometric features between positional and non-positional OSA patients did not show any significant differences. However, REM-related OSA patients showed significantly larger inferior oral airway space and shorter perpendicular distance between mandibular plane and anterior hyoid bone and the distance between uvula and posterior nasal spine, and narrower maximum width of soft palate than not-REM-related OSA patients. Positional and REM-related OSA patients have lower severity of sleep apnea, suggesting the possibility of lower collapsibility of the upper airway. REM sleep dependency was associated with anatomical factors, while positional dependency did not show such a tendency.

Comparative analysis of the oral microbiome of burning mouth syndrome patients.

Burning mouth syndrome (BMS) is a chronic pain condition accompanied by unpleasant burning sensations of the oral mucosa. While multiple factors were proposed for the etiology, evidence suggested a neuropathic pain origin while others suspected the use of antibiotics as the underlying cause. Interestingly, several reports demonstrated the intimate interaction of the nervous system and the microbiome. The current study aims to elucidate the correlation of the oral microbiome with the pathophysiology of the primary BMS. Microbiome samples obtained from the unstimulated whole saliva of 19 primary BMS patients and 22 healthy controls were sequenced and analyzed of the V3-V4 region of 16S rRNA gene. There was a distinct difference in the microbial composition between the BMS and the control groups at all taxonomic levels. Alpha diversity indexes of the oral microbiome were significantly lower in the BMS group. The samples were readily distinguished by multidimensional scaling analysis and linear discriminant analysis effect size. Streptococcus, Rothia, Bergeyella, and Granulicatella genus were dominant in the BMS group, while Prevotella, Haemophilus, Fusobacterium, Campylobacter, and Allorevotella genus were more abundant in the healthy group. Distinct microbiome signatures of BMS patients suggested a diagnostic value and a potential role in the pathogenesis of BMS.

Various painful oral adverse reactions following COVID-19 vaccination: a case series.

BACKGROUND: Adverse events are increasingly being reported with the growing COVID-19 vaccination rate. However, the current literature on orofacial adverse effects following COVID-19 vaccination are severely limited. With the continuation of the global vaccination campaign the incidence of oral adverse effects will inevitably increase. CASE PRESENTATION: Clinical characteristics and treatment results of nine patients who complained of pain and discomfort of the oral cavity following SARS-CoV-2 vaccination were analyzed. Swelling and pain of the posterior palatal area, pain on palatal area of the central incisor, pain on the mucosa of the lip and lower gingiva, right preauricular region and right posterior lower gingiva, the buccal mucosa, tongue, and the right lower second molar area were the reported symptoms. Ulceration and swelling of the oral mucosa were found in certain cases. The symptoms were generally mild and responded well to medication within a relatively short period of time. CONCLUSION: Oral adverse reactions following COVID-19 vaccination were manageable with treatment. Clinicians should understand the true nature of orofacial adverse reactions following COVID-19 vaccines and guide patients in decision-making.

Presence of widespread pain predicts comorbidities and treatment response in temporomandibular disorders patients.

OBJECTIVES: Investigate the presence of widespread pain in a well-defined TMD group and analyze its interrelationship with various comorbidities. Also, longitudinally seek the difference in treatment response according to the presence of widespread pain. SUBJECTS AND METHODS: The observational study involved 45 female TMD patients in their 20s. Patients were grouped into localized and widespread pain groups based on the widespread pain index (WPI ≥ 4). Clinical characteristics and levels of comorbidities were analyzed through physical examination and validated questionnaires. Differences between the groups and the power of pre-treatment WPI in predicting pre-treatment comorbidities and post-treatment pain level improvement were statistically analyzed. RESULTS: Patients with widespread pain showed higher somatization and anxiety levels. SF-36 scores were significantly lower and more patients complained of gastrointestinal symptoms. Conventional treatment significantly reduced pain intensity in both groups but less in the widespread pain group. WPI showed significant chances to predict patients showing improvement in pain levels with treatment with a cutoff value of 4. WPI was also effective in differentiating patients that showed a higher level of somatization. CONCLUSION: Widespread pain index could be effectively applied in differentiating those with a higher level of psychological distress and predicting TMD treatment response with further investigations into its reliability.

Long-term efficacy and patient satisfaction of pulsed radiofrequency therapy in temporomandibular disorders: A randomized controlled trial.

BACKGROUND: Pulse radiofrequency (PRF) therapy is one of effective physical therapy modalities for treat temporomandibular disorders (TMD). This prospective randomized controlled trial aimed to evaluate the long-term treatment efficacy and patient satisfaction with PRF therapy in TMD. METHODS: Eighty-six female patients with TMD were randomly assigned to either pulsed radiofrequency or placebo therapy in combination with other conventional treatments once a week for 12 weeks. A final analysis was performed 12 weeks after the completion of treatment. Clinical parameters and patient satisfaction were analyzed at baseline, 4, 8, and 12 weeks of intervention and at 24 weeks from baseline. RESULTS: Pain intensity, comfortable and maximum mouth opening, and pain on capsule and masticatory muscle palpation were significantly improved after treatment in both groups. Notably, the pulsed radiofrequency group showed a significantly lower pain intensity at the final evaluation performed 3 months after the completion of treatment. Significantly more patients reported subjective pain improvement and satisfaction with treatment following intervention at baseline in the PRF group. Most patients did not report any discomfort following treatment in either group. However, significantly more patients in the PRF group reported a burning sensation with intervention. CONCLUSION: Long-term regular pulsed radiofrequency therapy was effective in significantly reducing TMD pain, and the effect was long-lasting following treatment completion. Pulsed radiofrequency therapy should be considered as a supportive physical therapy modality for TMD.

Limited implication of initial bone scintigraphy on long-term condylar bone change in temporomandibular disorders-Comparison with cone beam computed tomography at 1 year.

BACKGROUND: The current diagnostic criteria for temporomandibular disorders (TMD) do not require imaging for the diagnosis of degenerative joint disease (DJD) of the temporomandibular joint (TMJ) condyle, and there is a lack of data investigating the effectiveness of imaging modalities in predicting long-term TMJ DJD prognosis. OBJECTIVES: To verify the association between initial bone scintigraphy results and long-term DJD bone changes occurring in the TMJ condyle on cone beam computed tomography (CBCT). METHODS: Initial bone scintigraphy, panoramic radiography and CBCT results were analysed in relation to long-term (12 months) TMJ DJD bone change on CBCTs in 55 TMD patients (110 joints). Clinical and radiographic indices were statistically analysed among three groups (improved, no change, and worsened) based on long-term TMJ DJD prognosis calculated by destructive change index (DCI). RESULTS: Neither the uptake ratio nor visual assessment results from initial bone scintigraphy showed a significant difference according to long-term condylar bone change groups. The cut-off value of bone scintigraphy uptake ratio was 2.53 for long-term worsening of TMJ DJD. Worsening of TMJ DJD was significantly associated with the diagnosis based on panoramic radiography (p = .011) and CBCT (p < .001). Initial DCI (ß = -.291, p = .046) had a significant association with long-term worsening of TMJ DJD. CONCLUSION: Initial bone scintigraphy results did not show sufficiently close associations with long-term TMJ DJD prognosis. This should be considered in the selection process of imaging modalities for TMJ DJD patients. Future studies are needed to develop prognostic indices that comprise both clinical and imaging contents for improved predictive ability.

Upper cervical spine abnormalities as a radiographic index in the diagnosis and treatment of temporomandibular disorders.

OBJECTIVE: The aim of this study was to investigate the clinical characteristics and treatment outcomes of patients with temporomandibular disorders (TMD) according to the presence of upper cervical spine abnormalities and craniofacial morphology. STUDY DESIGN: Clinical examinations were conducted on 43 patients with TMD. Upper cervical spine characteristics (fusion, posterior arch deficiency [PAD], and craniofacial morphology) reflecting head-and-neck posture were evaluated on lateral cephalograms. Condylar bone changes in the temporomandibular joint were evaluated by using cone beam computed tomography. Clinical characteristics and treatment outcomes after 1 year of conservative therapy were statistically analyzed between groups, according to the presence of upper cervical spine abnormalities. RESULTS: Pain on neck muscle palpation was more frequent in patients with cervical fusion (P = .019) and with either fusion or PAD (P = .004) before treatment. Patients with PAD had smaller comfortable mouth opening ranges compared with those without the deficiency (P = .044) before treatment and smaller comfortable (P = .020) and maximum (P = .021) mouth opening ranges after treatment. Patients with PAD also had mouth opening limitation (P = .028) and pain on masticatory muscle palpation (P = .014) more frequently after treatment compared with patients without the deficiency. CONCLUSIONS: Associations exist between upper cervical spine characteristics and treatment outcomes in patients with TMD, suggesting such parameters as a possible radiographic index in TMD diagnosis and treatment.

Quality and readability of online information on dental treatment for snoring and obstructive sleep apnea.

PURPOSE: To evaluate quality and readability of online information on dental treatment for snoring and obstructive sleep apnea. METHODS: An Internet search was done using three engines (Bing, Google, and Yahoo) with the combination of terms, "snoring sleep apnea dental treatment". The first 100 sites from the search of each engine were screened. Subject sites were evaluated with Health on the Net(HON) criteria, Journal of American Medical Association(JAMA) benchmarks, DISCERN, Ensuring Quality Information for Patients(EQIP), Flesch-Kincaid Grade level and Flesch Reading Ease(FRE) score. RESULTS: One hundred and thirty websites were evaluated. The HON, DISCERN, EQIP, and FRE score were each 39.4%, 47.3%, 49.7%, and 51.6% of the maximum possible score, respectively. According to JAMA benchmarks fewer than 50% of the sites displayed attribution and currency. There was only one site displaying the HON seal. HON score, DISCERN score and EQIP score showed significant inter-correlation. CONCLUSION: Based on this study, the current quality and readability of searchable websites on dental treatment for snoring and sleep apnea are low and poorly maintained on average. Clinicians should be able to evaluate and give accurate online information on this issue to patients.

Secreted protein acidic and rich in cysteine mediates active targeting of human serum albumin in U87MG xenograft mouse models.

Human serum albumin (HSA) is the most abundant plasma protein. The main reason for using HSA as a versatile tool for drug delivery is based on its ability to accumulate in tumors. However, the mechanism of albumin accumulation in tumors is not yet clear. Many researchers using HSA as a drug-carrier have focused on the passive tumor targeting by enhanced permeability and retention (EPR) effect, while other investigators proposed that albumin binding proteins mediate albumin accumulation in tumors. We investigated whether HSA accumulation in tumors is mediated by the EPR effect or by secreted protein acidic and rich in cysteine (SPARC), which is known to be an albumin-binding protein. Methods: To investigate the role of SPARC on HSA accumulation in tumors, we compared HSA uptake in U87MG glioblastoma cells with different SPARC expression. U87MG cells generally express high levels of SPARC and were, therefore, used as SPARC-rich cells. SPARC-less U87MG (U87MG-shSPARC) cells were established by viral-shSPARC transduction. We detected cellular uptake of fluorescence-labeled HSA by confocal microscopy in U87MG and U87MG-shSPARC cells. To demonstrate the mechanism of HSA accumulation in tumors, we injected FNR648-labeled HSA and FITC-labeled dextran in U87MG and U87MG-shSPARC tumor-bearing mice and observed their micro-distribution in tumor tissues. Results: HSA was internalized in cells by binding with SPARC in vitro. HSA accumulation in U87MG glioma was associated with SPARC expression in vivo. FITC-dextran was distributed in U87MG tumors in the vicinity of blood vessels. The distribution of HSA, on the other hand, was observed in the regions remote from blood vessels of U87MG tumor tissues but not in U87MG-shSPARC tumor tissues. Conclusion: Our results demonstrate that the tumor-distribution of HSA is affected not only by the EPR-effect but also by SPARC expression. SPARC enhances HSA accumulation in U87MG glioma and mediates active targeting of HSA in tumors.

Expanding therapeutic utility of carfilzomib for breast cancer therapy by novel albumin-coated nanocrystal formulation.

Carfilzomib (CFZ) is the second-in-class proteasome inhibitor with much improved efficacy and safety profiles over bortezomib in multiple myeloma patients. In expanding the utility of CFZ to solid cancer therapy, the poor aqueous solubility and in vivo instability of CFZ are considered major drawbacks. We investigated whether a nanocrystal (NC) formulation can address these issues and enhance anticancer efficacy of CFZ against breast cancer. The surface of NC was coated with albumin in order to enhance the formulation stability and drug delivery to tumors via interactions with albumin-binding proteins located in and near cancer cells. The novel albumin-coated NC formulation of CFZ (CFZ-alb NC) displayed improved metabolic stability and enhanced cellular interactions, uptake and cytotoxic effects in breast cancer cells in vitro. Consistently, CFZ-alb NC showed greater anticancer efficacy in a murine 4T1 orthotopic breast cancer model than the currently used cyclodextrin-based formulation. Overall, our results demonstrate the potential of CFZ-alb NC as a viable formulation for breast cancer therapy.