The relationship of race, ethnicity, gender identity, sex assigned at birth, sexual orientation, parental education, financial hardship and comorbid mental disorders with quality of life in college students with anxiety, depression or eating disorders.

BACKGROUND: Previous studies showed that comorbidity and demographic factors added to burden on health-related quality of life (HRQoL). Only one study explored the relationship between HRQoL and comorbidity in college students with mental disorders, leaving generalizability of findings uncertain. Less is known about the association of demographics on HRQoL. This study investigated HRQoL based on demographics and comorbidity among college students with mental disorders. METHODS: Participants were students (N = 5535) across 26 U.S. colleges and universities who met criteria for depression, generalized anxiety, panic, social anxiety, post-traumatic stress, or eating disorders based on self-report measures. ANOVA and linear regressions were conducted. RESULTS: Overall, female, minoritized (gender, sexual orientation, race, or ethnicity), and lower socioeconomic status students reported lower HRQoL than male, heterosexual, White, non-Hispanic, and higher socioeconomic status peers. After accounting for comorbidity, differences in physical HRQoL based on sex assigned at birth and gender were no longer significant. For mental HRQoL, only gender and sexual orientation remained significant. A greater number of comorbidities was associated with lower HRQoL regardless of demographic group. LIMITATIONS: The non-experimental design limits causal inference. The study focused on univariable associations without examining potential interactions between demographic factors. Future research should explore structural factors like discrimination. CONCLUSION: Results suggested that increased comorbidities placed an additional burden on HRQoL and that certain demographic groups were more vulnerable to HRQoL impairment among students with mental disorders. Findings suggest the need for prevention of disorders and their comorbidity and implementing tailored interventions for specific student subgroups with increased vulnerability.

Orai3 Calcium Channel Contributes to Oral/Oropharyngeal Cancer Stemness through the Elevation of ID1 Expression.

Emerging evidence indicates that intracellular calcium (Ca2+) levels and their regulatory proteins play essential roles in normal stem cell proliferation and differentiation. Cancer stem-like cells (CSCs) are subpopulations of cancer cells that retain characteristics similar to stem cells and play an essential role in cancer progression. Recent studies have reported that the Orai3 calcium channel plays an oncogenic role in human cancer. However, its role in CSCs remains underexplored. In this study, we explored the effects of Orai3 in the progression and stemness of oral/oropharyngeal squamous cell carcinoma (OSCC). During the course of OSCC progression, the expression of Orai3 exhibited a stepwise augmentation. Notably, Orai3 was highly enriched in CSC populations of OSCC. Ectopic Orai3 expression in non-tumorigenic immortalized oral epithelial cells increased the intracellular Ca2+ levels, acquiring malignant growth and CSC properties. Conversely, silencing of the endogenous Orai3 in OSCC cells suppressed the CSC phenotype, indicating a pivotal role of Orai3 in CSC regulation. Moreover, Orai3 markedly increased the expression of inhibitor of DNA binding 1 (ID1), a stemness transcription factor. Orai3 and ID1 exhibited elevated expression within CSCs compared to their non-CSC counterparts, implying the functional importance of the Orai3/ID1 axis in CSC regulation. Furthermore, suppression of ID1 abrogated the CSC phenotype in the cell with ectopic Orai3 overexpression and OSCC. Our study reveals that Orai3 is a novel functional CSC regulator in OSCC and further suggests that Orai3 plays an oncogenic role in OSCC by promoting cancer stemness via ID1 upregulation.

Potential Inflammatory Biomarkers for Major Depressive Disorder Related to Suicidal Behaviors: A Systematic Review.

Major depressive disorder (MDD) is a highly prevalent psychiatric condition affecting an estimated 280 million individuals globally. Despite the occurrence of suicidal behaviors across various psychiatric conditions, MDD is distinctly associated with the highest risk of suicide attempts and death within this population. In this study, we focused on MDD to identify potential inflammatory biomarkers associated with suicidal risk, given the relationship between depressive states and suicidal ideation. Articles published before June 2023 were searched in PubMed, Embase, Web of Science, and the Cochrane Library to identify all relevant studies reporting blood inflammatory biomarkers in patients with MDD with suicide-related behaviors. Of 571 articles, 24 were included in this study. Overall, 43 significant biomarkers associated with MDD and suicide-related behaviors were identified. Our study provided compelling evidence of significant alterations in peripheral inflammatory factors in MDD patients with suicide-related behaviors, demonstrating the potential roles of interleukin (IL)-1ß, IL-6, C-reactive protein, C-C motif chemokine ligand 2, and tumor necrosis factor-α as biomarkers. These findings underscore the intricate relationship between the inflammatory processes of these biomarkers and their interactions in MDD with suicidal risk.

Frequency, Characteristics, and Risk Factors for Falls at an Inpatient Cancer Rehabilitation Unit.

PURPOSE: Falls in the hospital can lead to adverse events, including injuries. Studies have shown that patients with cancer and those undergoing inpatient rehabilitation (IPR) are at higher risk for falls. Therefore, we measured the frequency, degree of harm, and characteristics of patients who fell in an inpatient cancer rehabilitation unit. METHODS: A retrospective review was conducted on inpatient cancer rehabilitation patients admitted from January 2012 to February 2016. Fall frequency, degree of harm, fall circumstances, cancer type, patient's fall risk score on the basis of the MD Anderson Cancer Center Adult Inpatient Fall Risk Assessment Tool (MAIFRAT), length of stay, and risk factors were evaluated for patients. RESULTS: There were 72 out of 1,571 unique individual falls (4.6%), with a falls incidence of 3.76 falls per 1,000 patient-days. Most fallers (86%) suffered no harm. Risk factors for falls included presence of patient-controlled analgesia pump (P = .03), pump such as insulin or wound vacuum-assisted closure (P < .01), nasogastric, gastric, or chest tube (P = .05), and higher MAIFRAT score (P < .01). The fallers were younger (62 v 66; P = .04), had a longer IPR stay (13 v 9; P = .03), and had a lower Charlson comorbidity index (6 v 8; P < .01). CONCLUSION: The frequency and degree of harm for falls in the IPR unit were less than previous studies, which suggests that mobilization for these patients with cancer is safe. The presence of certain medical devices may contribute to fall risk, and more research is needed to better prevent falls in this higher-risk subgroup.

Current Status of Genetically Engineered Pig to Monkey Kidney Xenotransplantation in Korea.

BACKGROUND: In South Korea, pig-to-nonhuman primate trials of solid organs have only been performed recently, and the results are not sufficiently satisfactory to initiate clinical trials. Since November 2011, we have performed 30 kidney pig-to-nonhuman primate xenotransplantations at Konkuk University Hospital. METHODS: Donor αGal-knockout-based transgenic pigs were obtained from 3 institutes. The knock-in genes were CD39, CD46, CD55, CD73, and thrombomodulin, and 2-4 transgenic modifications with GTKO were done. The recipient animal was the cynomolgus monkey. We used the immunosuppressants anti-CD154, rituximab, anti-thymocyte globulin, tacrolimus, mycophenolate mofetil, and steroids. RESULTS: The mean survival duration of the recipients was 39 days. Except for a few cases for which survival durations were <2 days because of technical failure, 24 grafts survived for >7 days, with an average survival duration of 50 days. Long-term survival was observed 115 days after the removal of the contralateral kidney, which is currently the longest-recorded graft survival in Korea. We confirmed functioning grafts for the surviving transplanted kidneys after the second-look operation, and no signs of hyperacute rejection were observed. CONCLUSIONS: Although our survival results are relatively poor, they are the best-recorded results in South Korea, and the ongoing results are improving. With the support of government funds and the volunteering activities of clinical experts, we aim to further improve our experiments and contribute to the commencement of clinical trials of kidney xenotransplantation in Korea.

Primary well differentiated hepatic liposarcoma in a meerkat (Suricata suricatta).

A 9-year-old female meerkat (Suricata suricatta) succumbed to progressive abdominal distension, anorexia, and depression. Necropsy revealed an extensively distended abdomen with ascites and markedly enlarged liver. The liver had multiple yellowish masses and displaced the thoracic cavity and abdominal organs. There was no evidence of metastatic lesions based on the gross and microscopic findings. Histologically, the liver mass was composed of locally invasive well-differentiated neoplastic adipocytes with Oil Red O-positive lipid vacuoles. Immunohistochemistry revealed positive immunoreactivity to vimentin, S-100 and negative to pancytokeratin, desmin, smooth muscle actin (SMA), ionized calcium-binding adapter molecule 1 (IBA-1). Thus, the primary well differentiated hepatic liposarcoma was diagnosed based on gross, histological and immunohistochemistry results.

Solubilized curcuminoid complex prevents extensive immunosuppression through immune restoration and antioxidant activity: Therapeutic potential against SARS-CoV-2 (COVID-19).

The therapeutic benefits of curcuminoids in various diseases have been extensively reported. However, little is known regarding their preventive effects on extensive immunosuppression. We investigated the immunoregulatory effects of a curcuminoid complex (CS/M), solubilized with stevioside, using a microwave-assisted method in a cyclophosphamide (CTX)-induced immunosuppressive mouse model and identified its new pharmacological benefits. CTX-treated mice showed a decreased number of innate cells, such as dendritic cells (DCs), neutrophils, and natural killer (NK) cells, and adaptive immune cells (CD4 and CD8 T cells) in the spleen. In addition, CTX administration decreased T cell activation, especially that of Th1 and CD8 T cells, whereas it increased Th2 and regulatory T (Treg) cell activations. Pre-exposure of CS/M to CTX-induced immunosuppressed mice restored the number of innate cells (DCs, neutrophils, and NK cells) and increased their activity (including the activity of macrophages). Exposure to CS/M also led to the superior restoration of T cell numbers, including Th1, activated CD8 T cells, and multifunctional T cells, suppressed by CTX, along with a decrease in Th2 and Treg cells. Furthermore,CTX-injected mice pre-exposed to CS/M were accompanied by an increase in the levels of antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase), which play an essential role against oxidative stress. Importantly, CS/M treatment significantly reduced viral loads in severe acute respiratory syndrome coronavirus2-infected hamsters and attenuated the gross pathology in the lungs. These results provide new insights into the immunological properties of CS/M in preventing extensive immunosuppression and offer new therapeutic opportunities against various cancers and infectious diseases caused by viruses and intracellular bacteria.

Chronic Alcohol Exposure Promotes Cancer Stemness and Glycolysis in Oral/Oropharyngeal Squamous Cell Carcinoma Cell Lines by Activating NFAT Signaling.

Alcohol consumption is associated with an increased risk of several cancers, including oral/oropharyngeal squamous cell carcinoma (OSCC). Alcohol also enhances the progression and aggressiveness of existing cancers; however, its underlying molecular mechanism remains elusive. Especially, the local carcinogenic effects of alcohol on OSCC in closest contact with ingestion of alcohol are poorly understood. We demonstrated that chronic ethanol exposure to OSCC increased cancer stem cell (CSC) populations and their stemness features, including self-renewal capacity, expression of stem cell markers, ALDH activity, and migration ability. The ethanol exposure also led to a significant increase in aerobic glycolysis. Moreover, increased aerobic glycolytic activity was required to support the stemness phenotype of ethanol-exposed OSCC, suggesting a molecular coupling between cancer stemness and metabolic reprogramming. We further demonstrated that chronic ethanol exposure activated NFAT (nuclear factor of activated T cells) signaling in OSCC. Functional studies revealed that pharmacological and genetic inhibition of NFAT suppressed CSC phenotype and aerobic glycolysis in ethanol-exposed OSCC. Collectively, chronic ethanol exposure promotes cancer stemness and aerobic glycolysis via activation of NFAT signaling. Our study provides a novel insight into the roles of cancer stemness and metabolic reprogramming in the molecular mechanism of alcohol-mediated carcinogenesis.

TRAF2 regulates the protein stability of HIPK2.

A nuclear serine/threonine kinase homeodomain-interacting protein kinase 2 (HIPK2) is a critical regulator of development and DNA damage response. HIPK2 can induce apoptosis under cellular stress conditions and thus its protein level is maintained low by constant proteasomal degradation. In the present study, we present evidence that TNF receptor-associated factor 2 (TRAF2) regulates the protein stability of HIPK2. Overexpression of TRAF2 decreased while its knockdown increased the HIPK2 protein level. The TRAF2-mediated decrease in HIPK2 protein expression was blocked by proteasomal inhibitor. In addition, TRAF2 decreased the protein half-life of HIPK2. We found that HIPK2 and TRAF2 co-immunoprecipitated. Interestingly, the co-immunoprecipitation was reduced while HIPK2 protein level increased following TNFα treatment, suggesting TNFα induced dissociation of TRAF2 from HIPK2 to accumulate HIPK2. Inhibition of HIPK2 partially suppressed TNFα-induced cell death, indicating that the accumulated HIPK2 may contribute to the TNFα-induced cell death. Our results suggest that TRAF2 can regulate proapoptotic function of HIPK2 by promoting proteasomal degradation.

Therapeutic Singing as a Swallowing Intervention in Head and Neck Cancer Patients With Dysphagia.

BACKGROUND: Head and neck cancer patients often suffer from dysphagia after surgery and radiotherapy. A singing-enhanced swallowing protocol was established to improve their swallowing function. This study aimed to evaluate the beneficial effects of therapeutic singing on dysphagia in head and neck cancer (HNC) patients. METHODS: Patients who participated in this study were allocated to the intervention group (15 patients) and the control group (13 patients). Patients assigned to the intervention group received therapeutic singing 3 times per week for 4 weeks. Each group was divided into 2 subgroups, including the oral cavity cancer group and the pharyngeal cancer group. The patients' vocal functions were evaluated in maximum phonation time, pitch, intensity, jitter, shimmer, harmonics to noise ratio, and laryngeal diadochokinesis (L-DDK). To evaluate swallowing function, videofluoroscopic swallowing study was done, and the results were analyzed by videofluoroscopic dysphagia scale (VDS) and dynamic imaging grade of swallowing toxicity (DIGEST). RESULTS: Among the voice parameters, L-DDK of the intervention group significantly increased compared to that of the control group. Swallowing functions of the intervention group were significantly improved in VDS and DIGEST after the intervention. Detailed items of VDS and DIGEST showed improvements especially in the pharyngeal phase score of VDS, such as laryngeal elevation, pharyngeal transit time, and aspiration. In addition, the pharyngeal cancer group showed significant improvements in VDS and DIGEST scores after the intervention. CONCLUSIONS: Our outcomes highlight the beneficial effects of singing for HNC patients with dysphagia. The notable improvements in the pharyngeal phase suggest that therapeutic singing would be more appropriate for HNC patients who need to improve their intrinsic muscle movements of vocal fold and laryngeal elevation.

Effect of Regular Taekwondo Self-Defense Training on Oxidative Stress and Inflammation Markers in Postmenopausal Women.

We aimed to investigate the effect of a 12-week Taekwondo self-defense training course on oxidative stress and inflammation in postmenopausal women. Sixteen middle-aged women participated and were randomized into two groups: a control group (CG, n = 8) and a Taekwondo self-defense training group (TSDG, n = 8). The TSDG was trained for 60 min, four times per week, for 12 weeks. Following the Taekwondo training intervention, side-step was significantly higher in the TSDG than in the CG (p < 0.001). Malondialdehyde levels were significantly lower after the intervention than before in the TSDG (p < 0.01). Superoxide dismutase (SOD) levels were also significantly higher after the intervention than before in the TSDG (p < 0.001). After the Taekwondo training intervention, SOD levels were significantly higher in the TSDG than in the CG (p < 0.01). Tumor necrosis factor α (TNF-α) levels were significantly lower after the intervention than before in the TSDG (p < 0.05). After the Taekwondo training intervention, TNF-α levels were significantly lower in the TSDG than in the CG (p < 0.05). The results of this study suggest that Taekwondo self-defense training is an effective exercise that improves agility, oxidative stress, and inflammatory responses in postmenopausal women.

Medical X-band linear accelerator for high-precision radiotherapy.

PURPOSE: Recently, high-precision radiotherapy systems have been developed by integrating computerized tomography or magnetic resonance imaging to enhance the precision of radiotherapy. For integration with additional imaging systems in a limited space, miniaturization and weight reduction of the linear accelerator (linac) system have become important. The aim of this work is to develop a compact medical linac based on 9.3 GHz X-band RF technology instead of the S-band RF technology typically used in the radiotherapy field. METHODS: The accelerating tube was designed by 3D finite-difference time-domain and particle-in-cell simulations because the frequency variation resulting from the structural parameters and processing errors is relatively sensitive to the operating performance of the X-band linac. Through the 3D simulation of the electric field distribution and beam dynamics process, we designed an accelerating tube to efficiently accelerate the electron beam and used a magnetron as the RF source to miniaturize the entire linac. In addition, a side-coupled structure was adopted to design a compact linac to reduce the RF power loss. To verify the performance of the linac, we developed a beam diagnostic system to analyze the electron beam characteristics and a quality assurance (QA) experimental environment including 3D lateral water phantoms to analyze the primary performance parameters (energy, dose rate, flatness, symmetry, and penumbra) The QA process was based on the standard protocols AAPM TG-51, 106, 142 and IAEA TRS-398. RESULTS: The X-band linac has high shunt impedance and electric field strength. Therefore, even though the length of the accelerating tube is 37 cm, the linac could accelerate an electron beam to more than 6 MeV and produce a beam current of more than 90 mA. The transmission ratio is measured to be approximately 30% ~ 40% when the electron gun operates in the constant emission region. The percent depth dose ratio at the measured depths of 10 and 20 cm was approximately 0.572, so we verified that the photon beam energy was matched to approximately 6 MV. The maximum dose rate was measured as 820 cGy/min when the source-to-skin distance was 80 cm. The symmetry was smaller than the QA standard and the flatness had a higher than standard value due to the flattening filter-free beam characteristics. In the case of the penumbra, it was not sufficiently steep compared to commercial equipment, but it could be compensated by improving additional devices such as multileaf collimator and jaw. CONCLUSIONS: A 9.3 GHz X-band medical linac was developed for high-precision radiotherapy. Since a more precise design and machining process are required for X-band RF technology, this linac was developed by performing a 3D simulation and ultraprecision machining. The X-band linac has a short length and a compact volume, but it can generate a validated therapeutic beam. Therefore, it has more flexibility to be coupled with imaging systems such as CT or MRI and can reduce the bore size of the gantry. In addition, the weight reduction can improve the mechanical stiffness of the unit and reduce the mechanical load.

DYRK1A is required for maintenance of cancer stemness, contributing to tumorigenic potential in oral/oropharyngeal squamous cell carcinoma.

DYRK1A, one of the dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs), plays an important role in various biological processes by regulating downstream targets via kinase-dependent and independent mechanisms. Here, we report a novel role of DYRK1A in maintaining tumor growth and stemness of oral/oropharyngeal squamous cell carcinoma (OSCC) cells. Deletion of DYRK1A from OSCC cells abrogated their in vivo tumorigenicity and self-renewal capacity, the key features of cancer stem-like cells (CSCs; also referred to as tumor-initiating cells). The DYRK1A deletion also induced the suppression of CSC populations and properties, such as migration ability and chemoresistance. Conversely, ectopic expression of DYRK1A in OSCC cells augmented their CSC phenotype. Among five DYRK members (DYRK1A, 1B, 2, 3, and 4), DYRK1A is the most dominantly expressed kinase, and its expression is upregulated in OSCC compared to normal oral epithelial cells. More importantly, DYRK1A was highly enriched in various CSC-enriched OSCC populations compared to their corresponding non-CSC populations, indicating its pivotal role in cancer progression and stemness. Further, our study revealed that fibroblast growth factor 2 (FGF2) is a key regulator in the DYRK1A-mediated CSC regulation. Functional studies demonstrated that the loss of DYRK1A inhibits CSC phenotype via reduction of FGF2. Overexpression of DYRK1A promotes CSC phenotype via upregulation of FGF2. Our study delineates a novel mechanism of cancer stemness regulation by DYRK1A-FGF2 axis in OSCC. Thus, inhibition of DYRK1A would lead to a potential novel therapeutic option for targeting CSCs in OSCC.

Frequency of Sarcopenia, Sarcopenic Obesity, and Changes in Physical Function in Surgical Oncology Patients Referred for Prehabilitation.

PURPOSE: Sarcopenia and suboptimal performance status are associated with postoperative complications and morbidity in cancer patients. Prehabilitation has emerged as an approach to improve fitness and muscle strength in patients preoperatively. We sought to describe the frequency of sarcopenia and sarcopenic obesity (SO) in a cohort of cancer patients referred for prehabilitation and the association between body composition and physical function. METHODS: In this retrospective review of 99 consecutive cancer patients referred for prehabilitation prior to intended oncologic surgery, prehabilitation included physical medicine and rehabilitation (PM&R) physician evaluation of function and physical therapy for individualized home-based exercise. Sarcopenic A was defined using sex-adjusted norms of skeletal muscle (SKM), measured using the sliceOmatic software (TomoVision, 2012) on computed tomography images at baseline. Sarcopenic B was defined by abnormal SKM and physical function. SO was defined as sarcopenia with BMI ≥ 25. Six-minute walk test (6MWT), 5 times sit-to-stand (5×STS), and grip strength were obtained at consultation (baseline) and at preoperative follow-up (if available). RESULTS: Forty-nine patients (49%) were Sarcopenic A, 28 (28%) SO, and 38 (38%) Sarcopenic B. Age was negatively correlated with SKM (P = .0436). There were no significant associations between Sarcopenic A/B or SO with baseline or changes in physical function. Assessed by sex, Sarcopenic A females had low 5×STS (P = .04) and Sarcopenic B females had low GS (P = .037). Sarcopenic B males had low preoperative GS (P = .026). 6MWT and grip strength at baseline were lower than age- and sex-related norms (both P < .001). Preoperatively, 6MWT distance and 5×STS time improved (both P < .001). Functional improvement in the sarcopenic and nonsarcopenic patients did not differ according to sex. CONCLUSIONS: In this cohort of prehabilitation surgical oncology patients, frequencies of sarcopenia and SO were high, and baseline physical function was abnormal but improved significantly regardless of body composition. These findings suggest that patients have considerable prehabilitation needs and are capable of improving with comprehensive care.

Development of a compact X-band linear accelerator system mounted on an O-arm rotating gantry for radiation therapy.

A compact X-band linear accelerator (LINAC) system equipped with a small and lightweight magnetron was constructed to develop a high-precision image-guided radiotherapy system. The developed LINAC system was installed in an O-ring gantry where cone-beam computed tomography (CBCT) was embedded. When the O-arm gantry is rotated, an x-ray beam is stably generated, which resulted from the stable transmission of radio frequency power into the X-band LINAC system. Quality assurance (QA) tests, including mechanical and dosimetry checks, were carried out to ensure safety and operation performance according to the American Association of Physicists in Medicine's TG-51, 142, an international standard protocol established by accredited institutions. In addition, delivery QA of the radiotherapy planning system was conducted to verify intensity-modulated radiotherapy techniques. Therefore, it was demonstrated that the developed X-band LINAC system mounted on the O-arm gantry proved to be valid and reliable for potential use in CBCT image-guided radiation therapy.

Zoledronic acid impairs oral cancer stem cells by reducing CCL3.

Cancer stem­like cells (CSCs; also referred to as tumor­initiating cells) play crucial roles in tumor progression and aggressiveness. Recent studies have demonstrated the antitumor activity of zoledronic acid (ZA), a third­generation bisphosphonate, in various types of human cancer. However, its effect on oral CSCs and the underlying mechanism remain obscure. The present study demonstrated that ZA suppresses the growth and stemness properties of oral/oropharyngeal squamous cell carcinoma (OSCC) cells. ZA inhibited the malignant characteristics of OSCC cells, such as anchorage­independent growth and epithelial thickening in organotypic raft cultures. Moreover, ZA treatment resulted in suppression of self­renewal capacity, a key feature of CSCs. ZA also inhibited important CSC properties, such as migration and chemo­radioresistance. Mechanistically, ZA exposure significantly decreased chemokine (C­C motif) ligand 3 (CCL3) expression in OSCC cells. It was further demonstrated that CCL3 signaling via its receptor is crucial for supporting the CSC phenotype in OSCC cells. Moreover, an antagonist of the CCL3 receptor reversed the effect of CCL3 on CSC properties, and exogenous CCL3 rescued the suppressaed CSC phenotype in ZA­treated OSCC cells. These results demonstrated that ZA suppresses the CSC phenotype in OSCC cells by reducing CCL3 expression, suggesting that ZA may be an effective therapeutic agent for oral cancer by targeting CSCs.

Molecular consequences of fetal alcohol exposure on amniotic exosomal miRNAs with functional implications for stem cell potency and differentiation.

Alcohol (ethanol, EtOH) consumption during pregnancy can result in fetal alcohol spectrum disorders (FASDs), which are characterized by prenatal and postnatal growth restriction and craniofacial dysmorphology. Recently, cell-derived extracellular vesicles, including exosomes and microvesicles containing several species of RNAs (exRNAs), have emerged as a mechanism of cell-to-cell communication. However, EtOH's effects on the biogenesis and function of non-coding exRNAs during fetal development have not been explored. Therefore, we studied the effects of maternal EtOH exposure on the composition of exosomal RNAs in the amniotic fluid (AF) using rat fetal alcohol exposure (FAE) model. Through RNA-Seq analysis we identified and verified AF exosomal miRNAs with differential expression levels specifically associated with maternal EtOH exposure. Uptake of purified FAE AF exosomes by rBMSCs resulted in significant alteration of molecular markers associated with osteogenic differentiation of rBMSCs. We also determined putative functional roles for AF exosomal miRNAs (miR-199a-3p, miR-214-3p and let-7g) that are dysregulated by FAE in osteogenic differentiation of rBMSCs. Our results demonstrate that FAE alters AF exosomal miRNAs and that exosomal transfer of dysregulated miRNAs has significant molecular effects on stem cell regulation and differentiation. Our results further suggest the usefulness of assessing molecular alterations in AF exRNAs to study the mechanisms of FAE teratogenesis that should be further investigated by using an in vivo model.

Proinflammatory cytokine TNFα promotes HPV-associated oral carcinogenesis by increasing cancer stemness.

High-risk human papillomaviruses (HPVs) are involved in the development of several human cancers, including oropharyngeal squamous cell carcinomas. However, many studies have demonstrated that HPV alone is not sufficient for the oncogenic transformation of normal human epithelial cells, indicating that additional cofactors are required for the oncogenic conversion of HPV-infected cells. Inasmuch as chronic inflammation is also closely associated with carcinogenesis, we investigated the effect of chronic exposure to tumor necrosis factor α (TNFα), the major proinflammatory cytokine, on oncogenesis in two immortalized oral keratinocyte cell lines, namely, HPV16-immortalized and human telomerase reverse transcriptase (hTERT)-immortalized cells. TNFα treatment led to the acquisition of malignant growth properties in HPV16-immortalized cells, such as (1) calcium resistance, (2) anchorage independence, and (3) increased cell proliferation in vivo. Moreover, TNFα increased the cancer stem cell-like population and stemness phenotype in HPV16-immortalized cells. However, such transforming effects were not observed in hTERT-immortalized cells, suggesting an HPV-specific role in TNFα-promoted oncogenesis. We also generated hTERT-immortalized cells that express HPV16 E6 and E7. Chronic TNFα exposure successfully induced the malignant growth and stemness phenotype in the E6-expressing cells but not in the control and E7-expressing cells. We further demonstrated that HPV16 E6 played a key role in TNFα-induced cancer stemness via suppression of the stemness-inhibiting microRNAs miR-203 and miR-200c. Overexpression of miR-203 and miR-200c suppressed cancer stemness in TNFα-treated HPV16-immortalized cells. Overall, our study suggests that chronic inflammation promotes cancer stemness in HPV-infected cells, thereby promoting HPV-associated oral carcinogenesis.

Effects of Applied Voltages on the Charge Transport Properties in a ZnO Nanowire Field Effect Transistor.

We investigate the effect of applied gate and drain voltages on the charge transport properties in a zinc oxide (ZnO) nanowire field effect transistor (FET) through temperature- and voltage-dependent measurements. Since the FET based on nanowires is one of the fundamental building blocks in potential nanoelectronic applications, it is important to understand the transport properties relevant to the variation in electrically applied parameters for devices based on nanowires with a large surface-to-volume ratio. In this work, the threshold voltage shift due to a drain-induced barrier-lowering (DIBL) effect was observed using a Y-function method. From temperature-dependent current-voltage (I-V) analyses of the fabricated ZnO nanowire FET, it is found that space charge-limited conduction (SCLC) mechanism is dominant at low temperatures and low voltages; in particular, variable-range hopping dominates the conduction in the temperature regime from 4 to 100 K, whereas in the high-temperature regime (150-300 K), the thermal activation transport is dominant, diminishing the SCLC effect. These results are discussed and explained in terms of the exponential distribution and applied voltage-induced variation in the charge trap states at the band edge.

Investigation of Hot Spot Region in XIAP Inhibitor Binding Site by Fragment Molecular Orbital Method.

X-linked inhibitor of apoptosis protein (XIAP) is an important regulator of cancer cell survival whose BIR3 domain (XIAP-BIR3) recognizes the Smac N-terminal tetrapeptide sequence (AVPI), making it an attractive protein-protein interaction (PPI) target for cancer therapies. We used the fragment molecular orbital (FMO) method to study the binding modes and affinities between XIAP-BIR3 and a series of its inhibitors (1-8) that mimic the AVPI binding motif; the inhibitors had common interactions with key residues in a hot spot region of XIAP-BIR3 (P1-P4 subpockets) with increased binding affinity mainly attributed to specific interactions with the P1 and P4 subpockets. Based on the structural information from FMO results, we proposed a novel XIAP natural product inhibitor, neoeriocitrin 10, which was derived from our preciously reported XIAP-BIR3 inhibitor 9, can be used as a highly potent candidate for XIAP-BIR3 inhibition. We also performed pair interaction energy decomposition analysis to investigate the binding energies between specific binding residues and individual ligands, showing that the novel natural product neoeriocitrin 10 had a higher binding affinity than epicatechin gallate 9. Molecular docking and dynamics simulations were performed to explore the mode of binding between 10 and XIAP-BIR3, demonstrating that 10 binds more strongly to the P1 and P4 pockets than 9. Overall, we present a novel natural product, neoeriocitrin 10, and demonstrate that the FMO method can be used to identify hot spots in PPIs and design new compounds for XIAP inhibition.