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The aim of the present study was to investigate the biomechanical behaviors of the pre-shaped titanium (PS-Ti) cranial mesh implants with different pore structures and thicknesses as well as the surface characteristics of the three-dimensional printed Ti (3DP-Ti) cranial mesh implant. The biomechanical behaviors of the PS-Ti cranial mesh implants with different pore structures (square, circular and triangular) and thicknesses (0.2, 0.6 and 1 mm) were simulated using finite element analysis. Surface properties of the 3DP-Ti cranial mesh implant were performed by means of scanning electron microscopy, X-ray diffraction and static contact angle goniometer. It was found that the stress distribution and peak Von Mises stress of the PS-Ti cranial mesh implants significantly decreased at the thickness of 1 mm. The PS-Ti mesh implant with the circular pore structure created a relatively lower Von Mises stress on the bone defect area as compared to the PS-Ti mesh implant with the triangular pore structure and square pore structure. Moreover, the spherical-like Ti particle structures were formed on the surface of the 3DP-Ti cranial mesh implant. The microstructure of the 3DP-Ti mesh implant was composed of α and rutile-TiO2 phases. For wettability evaluation, the 3DP-Ti cranial mesh implant possessed a good hydrophilicity surface. Therefore, the 3DP-Ti cranial mesh implant with the thickness of 1 mm and circular pore structure is a promising biomaterial for cranioplasty surgery applications.

Actively acquired tolerance occurs when foreign antigens come into contact with the immature fetal immune system.Armed with the knowledge of actively acquired tolerance, we attempted to prenatally abolish or diminish allergic responses.In utero injection of adjuvant-free ovalbumin (OVA) was conducted in Gestational Day 14 FVB/N mouse fetuses. Postnatally, mice were evaluated for their resistance to intraperitoneal OVA sensitization and oral or aerosolized OVA challenge, and then they were examined for humoral and cellular immunological profiles, airway hyperresponsiveness to bronchospastic stimuli, and lung histology. Fluorescent conjugates of OVA were used for further studies of mechanisms.This presumed tolerogenic action turned out to be a sensitization process with the development of anaphylaxis or heightened recall, T-helper cell type 2-skewed responses to postnatal encounter with OVA. Further postnatal aerosolized OVA stress triggered allergic lungs with functional and structural alterations of airways. The unintended consequence resulted from macrophage-like fetal phagocytes that took up OVA and differentiated toward dendritic cells. These fetal dendritic cell progenitors attenuated proteolysis of endocytosed OVA for delayed presentation in postnatal life. This specialty of fetal phagocytes effectively retains the memory of antigens internalized early before full development of the immune system, leading to an event of in utero sensitization.Our results have mechanical implications for prenatal imprinting of atopy and shed light on the importance of fetal phagocytes in shaping the developing immune system and initiating allergic airway diseases.

Allergic airway inflammation driven by T helper 2 (Th2)-type immunity is characterized by airway hyperresponsiveness, eosinophilic infiltration, and elevated IgE production. Various novel strategies for managing asthma have been explored, such as DNA vaccines, T-cell peptides, and allergen-specific immunotherapy. A principal goal of most immunotherapeutic approaches is active and long-term allergen-specific tolerance. Liver-specific gene transfer using adeno-associated virus (AAV) has been shown to favorably induce tolerogenic responses to therapeutic products in various experimental models. AAV8 has strong liver tropism and induces immune tolerance in mice. The present study aimed to determine whether hepatocyte-specific allergen expression by pseudotyped AAV2/8 alleviates asthmatic symptoms in ovalbumin (OVA)-sensitized mice. Mice were intravenously injected with AAV2/8 vector carrying membrane-bound OVA transgene under transcriptional control of a hepatocyte-specific alpha 1 antitrypsin promoter (AAV2/8-OVA) and then sensitized with OVA. AAV2/8-OVA specifically transduced the OVA transgene in the liver. Airway hyperresponsiveness, eosinophilia, mucus hypersecretion, and Th2 cytokines were significantly suppressed in both the lungs and secondary lymphoid organs of asthmatic mice infected with AAV2/8-OVA. Significant reduction of OVA-specific antibodies was detected in the bronchoalveolar lavage fluid from AAV2/8-OVA-treated mice. Moreover, AAV2/8-OVA treatment prominently promoted the expression of Foxp3, IL-10, and TGF-β in the liver. Enhanced Foxp3 expression was also detected in the lungs of asthmatic mice after AAV2/8-OVA treatment. Taken together, these results suggest that the induction of immune tolerance by hepatic AAV gene transfer may be beneficial for modulating allergic asthma.

The surface characteristics, microstructures, and biocompatibility of the metal titanium oxide (TiO) film cross-linked with different self-assembled monolayers (SAMs) of phosphonate were elucidated through scanning electron microscopy, atomic force microscopy, X-ray diffractometry, transmission electron microscopy, and in vitro cell culturing assay in the present study. It was found that a relatively uniform and flat SAM with a roughness of 3.09 ± 0.32 nm can be formed on the specimen surface after cross-linking with 11-phosphonoundecanoic acid solution (PUA-SAM/TiO). The microstructures of the investigated SAMs were composed of amorphous structure. Moreover, analytical results from the biocompatibility assay and cell adhesion response also demonstrated that the PUA-SAM/TiO specimen possesses better osteoblast-like MG-63 cell adhesion and proliferation ability at the early time point of culturing (24 h). Thus, these findings reveal that the formation of SAM of phosphonate as the targeted biomimetic surface could potentially promote early-stage osseointegration for biomedical Ti implants.

Asthma is the result of chronic inflammation of the airways which subsequently results in airway hyper-responsiveness and airflow obstruction. It has been shown that an elicited expression of acidic mammalian chitinase (AMCase) may be involved in the pathogenesis of asthma. Our recent study has demonstrated that the specific suppression of elevated AMCase leads to reduced eosinophilia and Th2-mediated immune responses in an ovalbumin (OVA)-sensitized mouse model of allergic asthma. In the current study, we show that the elicited expression of AMCase in the lung tissues of both ovalbumin- and Der P2-induced allergic asthma mouse models. The effects of allergic mediated molecules on AMCase expression were evaluated by utilizing promoter assay in the lung cells. In fact, the exposure of chitin, a polymerized sugar and the fundamental component of the major allergen mite and several of the inflammatory mediators, showed significant enhancement on AMCase expression. Such obtained results contribute to the basis of developing a promising therapeutic strategy for asthma by silencing AMCase expression.

Immunotherapies have shown promising results in certain cancer patients. For hepatocellular carcinoma (HCC), the multiplicity of an immunotolerant microenvironment within both the tumor, and the liver per se may limit the efficacy of cancer immunotherapies. Since radiation induces immunogenic cell death and inflammatory reactions within the tumor microenvironment, we hypothesized that a combination therapy of radiation and lasting local immunostimulating agents, achieved by intratumoral injection of an adenoviral vector encoding interleukin 12, may reverse the immunotolerant microenvironment within a well-established orthotopic HCC toward a state favorable for inducing antitumor immunities. Our data showed that radiation and IL-12 combination therapy (RT/IL-12) led to dramatic tumor regression in animals bearing large subcutaneous or orthotopic HCC, induced systemic effect against distant tumor, and significantly prolonged survival. Radiation monotherapy induced tumor regression at early times but afterwards most tumors regained exponential growth, while IL-12 monotherapy only delayed tumor growth. Mechanistic studies revealed that RT/IL-12 increased expression of MHC class II and co-stimulatory molecules CD40 and CD86 on tumor-infiltrating dendritic cells, suggesting an improvement of their antigen presentation activity. RT/IL-12 also significantly reduced accumulation of tumor-infiltrating myeloid-derived suppressor cells (MDSCs) and impaired their suppressive functions by reducing production of reactive oxygen species. Accordingly, tumor-infiltrating CD8+ T cells and NK cells were significantly activated toward the antitumor phenotype, as revealed by increased expression of CD107a and TNF-α. Together, our data showed that RT/IL-12 treatment could reset the intratumoral immunotolerant state and stimulate activation of antitumor cellular immunity that is capable of eliminating large established HCC tumors.

Objective: Using a population-based nationwide database, we describe the changing surgical trends for laparoscopy or laparotomy for benign ovarian tumors among hospitals of different accreditation levels in Taiwan (medical centers, regional hospitals, and local hospitals). Materials and methods: Women who had National Health Insurance and received either laparoscopy or laparotomy as the primary surgery for benign ovarian tumors in Taiwan during 1999–2009 were identified for analysis. Results: In total, 135,793 women who received either laparotomic (39,779) or laparoscopic surgery (96,014) for benign ovarian pathology were identified. The increase in annual laparoscopy number from 7176 in 1999 to 11,046 in 2009 was significant according to a log-linear regression test (p

The goal of cancer immunotherapy is to elicit robust tumor-specific immune responses that can generate durable tumor regression and/or eradication. Recent clinical trials using immune checkpoint blockades specific to programmed cell death-1/ligand-1 (PD-1/PD-L1) have shown durable clinical responses in various cancer types but benefit only a small portion of patients. We previously demonstrated that combination of radiation and immunotherapy of interleukin 12 (IL-12) and granulocyte macrophage colony-stimulator factor (GM-CSF) greatly improved the therapeutic efficacy than either single therapy alone. In analysis of the tumor-infiltrating leukocytes post combination therapy, we found that the number of CD11b+F4/80-/Ly6G+ neutrophils were greatly increased. In this study, we characterized these tumor-associated neutrophils (TANs) before and after treatment and investigated their role in mediating the antitumor activity of the combination therapy. We isolated TANs from the regressing tumors and demonstrated that these TANs were impaired in their immunosuppressive activities. Flowcytometric analysis revealed that several co-stimulatory molecules, including class II major histocompatibility complex, CD40 and CD86, were increased on these TANs. Accordingly, these TANs gained the ability to stimulate T cell proliferation. Antibody-depletion experiments showed that TANs were required for tumor regression in RT/12GM combination therapy. Together, our data demonstrate that combination of radiotherapy and IL-12/GM-CSF improved antitumor immunity through enhancing antigen presentation activity and reduced immunosuppressive functions of TANs. Citation Format: Mi-Hua Tao, Chia-Jen Wu, Yi-Ting Tsai, Ping-Yi Wu. Neutrophils play a critical role in mediating antitumor activity of a combination therapy of radiation and immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 609.

Carotid blow-out syndrome (CBS) is a life-threatening complication of head and neck cancer (HNC). One of the various methods used for emergency management of CBS is covered stent placement (CSP). Our initial experience in CSP is evaluated and compared with reports in the literature.This study analysed 17 patients with HNC who had received CSP for CBS at Kaohsiung Medical University Chung-Ho Memorial Hospital from May 2005 to December 2013. The medical records and images for these patients were retrospectively reviewed to evaluate the causes of CBS, treatment success rates and complications.The initial angiography success rate was 100%. Procedural or periprocedural complications were noted in two (12%) cases, both suffering from cerebral vascular accident (CVA). Short-term complications were noted in eight (47%) cases, including four rebleeding cases and four CVA cases. Medium- to long-term complications were noted in nine cases, which included two asymptomatic in-stent thrombosis cases, one symptomatic CVA case, two abscess formation cases and four rebleeding cases. Overall, eight (47%) cases of rebleeding occurred during follow-up. Three of the eight cases were fatal, accounting for 27% of the all-cause mortality.Although CSP is considered effective for achieving haemostasis in patients with HNC with CBS, the medium- to long-term outcomes are unfavourable owing to high risks of rebleeding, CVA and other complications. Therefore, CSP should be considered a temporary life-saving technique rather than a definitive treatment.Analysis of the relatively large series of patients with HNC in this study suggests that CSP is a useful temporary treatment for CBS.

Cancer immunotherapy can elicit robust tumor-specific immune responses that can generate durable tumor regression or eradication. Immune checkpoint blockade specific to programmed death-1/ligand-1 (PD1/PDL1) have shown durable clinical responses in various cancer types but benefit only a small portion of patients. Interleukin 12 (IL-12) and granulocyte macrophage colony-stimulator factor (GM-CSF) have shown potent antitumor activities through activating innate and adaptive immunities, and reprogramming tumor-promoting myeloid cells from immune-suppressive to immune-active phenotypes. In this study, we showed the effect of radiation, which increased release of tumor antigens so that augment the efficacy of immunotherapy, in combination with IL-12/GM-CSF (RT/12GM) or anti-PDL1 antibody (RT/PDL1) on TAN in advanced 14-day-CT26 colorectoral cancer. We found that both combination treatment significantly suppressed tumor growth, only RT/12GM but not RT/PDL1 can cure mice; radiation or immunotherapy alone single therapies were much less effective. Mechanistic analysis showed that RT/12GM, but not RT/PDL1, greatly increased accumulation of TAN. These TANs were not only impaired in their suppressive activities, but also able to induce T cell proliferation, in accordance with their increased expressions of MHC class I and II, CD40 and CD86, indicating they presented in a status with higher Ag presentation ability. Antibody depletion experiments showed that TAN was required for tumor regression in RT/12GM therapy. Together, our data demonstrate that combination of radiotherapy and IL-12/GM-CSF improved antitumor immunity through enhancing Ag presentation activity and reducing immunosuppressive functions of TAN.

Immune checkpoint blockade antibodies specific to programed death-1/ligand-1 (PD-1/PD-L1) shows durable clinical responses in various cancers but benefit only to a small portion of patients. The failure of immunotherapy is likely due to the complex network of immunosuppressive mechanisms present in advanced tumors. Radiation (RT) modifies tumor microenvironment and causes tumor antigen release, and thus augment efficacy of immunotherapy. Interleukin 12 (IL-12) and granulocyte macrophage colony-stimulator factor (GM-CSF) have shown potent antitumor activities through activating innate and adaptive immunities, as well as reprogramming myeloid cells to a phenotype that favors immune activation. The aim of this project is to compare the therapeutic efficacy of two types of combination therapy: RT combined with IL-12/GM-CSF (RT/12GM) versus RT combined with anti-PD-L1 antibody (RT/PD-L1), and to dissect the molecular mechanisms of the antitumor responses. Our data showed that RT/12GM led to tumor regression in a majority of mice with large established tumors and suppressed liver metastasis, while RT/PD-L1 could only suppress primary tumors but not metastatic tumor. Mechanistic analysis showed that RT/12GM was superior to RT/PD-L1 in inducing accumulation of CD8+ T cells in tumor and in augmenting both NK and CD8+ T cells cytotoxicity in tumor and liver. Interestingly, RT/12GM also induced infiltration of tumor-associated neutrophils (TAN) and impaired their immunosuppressive functions. Depletion experiments showed that both CD8+ T cell and TAN were required for tumor regression in RT/12GM. Together, our results demonstrate that RT/12GM represent a powerful alternative therapy against both primary and metastatic tumors.

Tamoxifen has been used to treat patients in all stages of breast cancer. However, the drawback of its estrogenmimicking effects on endometrium raises the risk of endometrial cancer for chronic users as it has been shown to stimulate growth of some endometrial adenocarcinoma cell lines by estrogen receptor-independent mechanisms in vitro [3]. For long-term Tamoxifen use for breast cancer patients, development of secretory endometrial adenocarcinoma without estrogen receptors occurs rarely. According to the keyword searches for “secretory endometrial adenocarcinoma,” “Tamoxifen,” and “breast cancer” on MEDLINE of the reports in English language between 1970s and the end of 2005, our case is the second one to describe secretory endometrial adenocarcinoma associated with Tamoxifen use for breast cancer. A 71-year-old woman, multigravida, complained of postmenopausal vaginal bleeding for 2 to 3 months. She had undergone right mastectomy for stage II breast cancer 15 years prior to this admission. Thereafter, she had received chemotherapy and had been taking oral 10 mg Tamoxifen twice a day for 10 years. Current medical diseases include hypertension and diabetes mellitus for 10 years and 2 months, respectively. She denied any history of estrogen replacement therapy after menopause at the age of 50 years. Under vaginal echography, unusual endometrial contour was detected as thick as 21 mm. Her pelvic examination results revealed no senile changes but a large uterus as if in 3-months’ gestation. Coupled with atypical glandular cells on her Papanicolaou smear, fractional endometrial dilatation and curettage (D&C) revealed endometrial carcinoma with secretory changes. She underwent staging laparotomy including total hysterectomy, bilateral salpingoophorectomy, partial omentectomy, sampling of pelvic and paraaortic lymph nodes, and peritoneal cytology. Grossly, the uterus showed no apparent myometrial invasion or generalized thickness of endometrium with multiple polypoid lesions. On paraffin sections, the tumor measured 1 cm at the greatest dimension and was estimated at only 5 mm downward invasion into the 3-cm thick myometrium. The histological morphology revealed a well-differentiated adenocarcinoma with dominant papillary and glandular patterns, consisting of columnar epithelial cells and containing intracytoplasmic basal vacuoles (Figure 1), which was similar to secretory endometrium arising from atypical complex secretory hyperplasia. Using immunohistochemical stains, we found exclusively strong positive results for progesterone receptors

The purpose of our study was to describe the surgical trends for female stress urinary incontinence (SUI) during 2006–2010, and a time-frame comparison with 1997–2005, based upon the National Health Insurance (NHI) claims data in Taiwan. Women who underwent various primary surgeries for SUI during 2006–2010 were identified, with a total of 15,099 inpatients. The variables included surgical types, patient age, surgeon age and gender, specialty, and hospital accreditation levels. Chi-squared tests and SAS version 9.3.1 were used for statistical analysis. During the follow-up study, midurethral sling (MUS) application increased significantly from 53.09 % in 2006 to 78.74 % in 2010. It was associated concomitantly with a decrease in retropubic urethropexy (RPU) from 29.68 % to 12.99 %, and pubovaginal sling treatment (PVS) from 9.33 % to 3.46 %. MUS was most commonly used among all patients’ and surgeons’ age groups, and different accreditation hospital levels. MUS was more commonly used by gynecologists (71.38 %) than urologists (57.91 %); while PVS and periurethral injection were more commonly performed by urologists than gynecologists. Similar surgical trends were found during time-frame comparison, 2006–2010 vs 1997–2005. SUI surgeries increased in patients aged ≥60, surgeons aged ≥ 50, and in regional hospitals. This follow-up study depicts the increase in popularity of MUS and offers evidence of surgical trends and a paradigm shift for female SUI surgery. More older women were willing to seek healthcare and undergo surgery. The surgical skills and knowledge spread from medical centers into regional hospitals. The time-frame shift may have a profound impact on patients, as well as the healthcare providers.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide with few therapeutic options. Radiation is wildly used for cancer treatment, but local relapse often occurs. Interleukin 12 (IL-12) has potent antitumor activities by activating natural killer cells (NK) and CD8+ T cells, reprogramming myeloid cells to an immune active phenotype, and inhibiting new blood vessel formation. We hypothesized that combined radiation and IL-12 treatment may change tumor suppressive microenvironment and induce antitumor immune responses. Our data showed that only combination of radiation and intratumoral injection of adenovirus encoding IL-12 (Ad/IL-12) led to tumor regression in mice with large subcutaneous or orthotopic HCC, and significantly prolonged their survival. Mechanistic studies revealed that combination therapy enhanced antigen (Ag) presentation ability of DCs by increasing MHC class II, CD40 and CD86 expression. Combination therapy also significantly reduced numbers of tumor-infiltrating myeloid-derived suppressor cells (MDSCs) and impaired their suppressive functions by reducing reactive oxygen species (ROS) production. Accordingly, combination therapy significantly increased the cell numbers of tumor-infiltrating CD8+ T cells and their expressions of CD107a and TNF-α. The cell numbers of tumor-infiltrating NK cells was not affected, but the expression of activation markers was significantly increased after treatment. Together, our results demonstrate that combination therapy effectively against advanced HCC through activating tumor-infiltrating NK cells and tumor-specific CD8+ T cells, enhancing Ag presentation ability of DCs while reducing the suppressive functions of MDSCs.

Objective The purpose of this study was to evaluate the efficacy and feasibility of concomitant trocar-guided transvaginal mesh (TVM) surgery with a midurethral sling (MUS) for treating women with advanced pelvic organ prolapse (POP) and stress urinary incontinence (SUI) or occult SUI (OSUI). Materials and methods Eighty-nine women with advanced POP and SUI or OSUI were retrospectively enrolled. The Total Prolift and Tension-free Vaginal Tape-Obturator Systems were used for trocar-guided TVM surgery and MUS. Patients received regular follow-up at 1 week, and 1 month, 3 months, 6 months, and 12 months postoperatively, and then annually thereafter. The endpoints were the success rate for POP, and perioperative and postoperative complications. Functional outcomes were the presence of voiding difficulty, persistent or de novo overactive bladder symptoms, postoperative SUI, and paresthesia. Results The median follow-up period was 35 months (range, 12–50 months). Within the follow-up period, 84 patients (94.4%) were objectively cured, five patients (5.6%) had vaginal apical mesh exposure, 29 individuals (32.6%) had persistent or de novo overactive bladder symptoms, six individuals (22.5%) had de novo SUI (two were found by urodynamics), and nine individuals (10.1%) had voiding difficulties (two were found by urodynamics). In addition, the vaginal hysterectomy group had greater blood loss, longer operation times, and a higher mesh erosion rate compared to the uterine suspension group. Conclusion Concomitant trocar-guided TVM surgery and MUS with the use of total Prolift and Tension-free Vaginal Tape-Obturator offer good efficacy in treating women with advanced POP and SUI or OSUI. The vaginal hysterectomy group had more perioperative complications.

Asthma is a chronic airway inflammatory disease characterized by eosinophilic infiltration and airway hyperresponsiveness. The over-activated Th2 and lung epithelium cells express many different cytokines, and chemokines mainly contribute to the severity of lung inflammation. Clara cell 10 kD protein (CC10) is highly expressed in airway epithelium cells and exhibits anti-inflammatory and immunomodulatory effects. Adeno-associated virus (AAV) 2/9 vector, composed of AAV2 rep and AAV9 cap genes, can efficiently and specifically target lung epithelium cells. Thus, AAV2/9 vector might carry therapeutic potential gene sequences for the treatment of asthma. This study tested whether AAV2/9 vector carrying CC10 could reduce inflammatory and asthmatic responses in OVA-induced asthmatic mouse model. The results showed that AAV2/9-CC10 vector virus significantly reduced airway hyperresponsiveness, CCL11, interleukin (IL)-4, IL-5, IL-6, IL-13, and eosinophilia in the lungs of sensitized mice. CC10 level in OVA-sensitized mice was rescued with the administration of AAV2/9-CC10 vector virus. Lung tissue remodeling, including collagen deposition and goblet cell hyperplasia, was also alleviated. However, serum levels of OVA-specific IgG1 and IgE as well as Th2 cytokine levels in OVA-stimulated splenocyte culture supernatants were at the comparable levels to the sensitized control group. The results demonstrate that AAV2/9-CC10 vector virus relieved local inflammatory and asthmatic responses in lung. Therefore, we propose that AAV2/9-CC10 vector virus guaranteed sufficient CC10 expression and had an anti-inflammatory effect in asthmatic mice. It might be applied as a novel therapeutic approach for asthma.

Airway infiltration by eosinophils is a major characteristic of chronic asthma. CCL11 (eotaxin-1) is secreted by lung epithelial cells and functions as the major chemokine for eosinophil recruitment. Pseudotyped adeno-associated virus (AAV) 2/9, composed by the AAV2 rep and AAV9 cap genes, can efficiently target lung epithelial cells and might carry gene sequences with therapeutic potential for asthma. This study aimed to determine whether pseudotyped AAV2/9 virus carrying the small hairpin RNA targeting CCL11 and expressed by CMV/U6 promoter could reduce eosinophilia and asthmatic responses in mite allergen-sensitized mice. Mice were sensitized by intraperitoneal and challenged by intratracheal injection with recombinant Dermatophagoides pteronyssinus group 2 allergen (rDp2). AAV2/9 viral vectors were intratracheally injected three days before the first challenge. AAV2/9 sh47 virus significantly reduced airway hyperresponsiveness, airway resistance, CCL11 levels, and eosinophilia in the lungs of sensitized mice. Th2 cytokines, including interleukins (IL)-4, IL-5, and IL-10, were also significantly reduced in the bronchoalveolar lavage fluid of AAV2/9 sh47 virus-treated mice. Th2 cytokine levels were also reduced in rDp2-stimulated mediastinal lymphocytes in treated mice. However, serum levels of rDp2-specific IgG1 and IgE, as well as Th2 cytokine levels in rDp2-stimulated splenocyte culture supernatants, were comparable to the sensitized control group. The results suggest that AAV2/9 sh47 virus relieved local instead of systemic inflammatory responses. Therefore, the CMV/U6 promoter with AAV2/9 viral vector, which is preferable to target lung epithelia cells, might be applied as a novel therapeutic approach for asthma.

The gene (SCGB1A1) encoding Clara cell 10-kDa protein (CC10), a steroid-inducible immune modulator, is a candidate gene for asthma, but the evidence is equivocal. The potential influence of a common variant on asthma severity and serum CC10 levels during acute exacerbation and after corticosteroid treatment in Chinese case-control children and its functional relevance was investigated.Genotyping of a non-coding variant G+38A was performed in 489 children, of whom 277 had asthma with varying severity, and 212 healthy controls. Associations were tested for asthma, asthma severity, and responsiveness to steroid treatment. The transcriptional activity of this variant was examined in a Clara-like cell line (H358) using transient transfection assays.Significant association was observed for the combined GA and AA genotypes of the CC10 G+38A variant and an increased risk of asthma [odds ratio (OR), 2.62, p.001]. This association was correlated with asthma severity (moderate: OR, 2.85, p.001; near-fatal: OR, 4.81, p.001). Also, patients with the GA and AA genotypes showed significantly lower serum CC10 (p.01) and provocation concentration causing a 20% fall (PC(20)) in forced expiratory volume in 1 s (FEV(1)) (p.0001) when compared with those with the GG. After glucocorticoid treatment, the CC10 levels were significantly increased in asthmatic patients with GG (p.0001), but not those with the GA and AA genotypes. Moreover, a lower dexamethasone-induced reporter (luciferase) activity was observed for H358 cells transiently transfected with the G38A risk allele (A) compared with wild-type allele (G).These findings suggest that the CC10 G+38A variant may contribute to the severity of asthma and lower level of steroid responsiveness.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide with few therapeutic options. Radiation is one of the mainstay cancer therapies. We hypothesize that combination of radiation and local interleukin 12 (IL-12) immunotherapy may change the suppressive tumor microenvironment to a proinflammatory condition favorable in induction of antitumor immune responses. IL-12 has potent antitumor activities through activation of CD8+ T cells and natural killer cells, reprogramming several types of myeloid-derived suppressor cells to a phenotype that favors immune activation, and inhibiting new blood vessel formation within tumors. Our data showed that combination of radiation and intratumoral injection of an adenoviral vector encoding IL-12 (Ad/IL-12) led to tumor regression in the majority of animals bearing large orthotopic hepatocellular carcinoma and significantly prolonged their survival. Single treatment of radiation or Ad/IL-12 delayed tumor growth but did not result in tumor regression. Mechanistic studies revealed that combination therapy greatly increased the cell numbers and activities of tumor-infiltrating CD8+ T cells, while the cell numbers and suppressive functions of MDSC and tumor-associated macrophages (TAM) were significantly decreased. Our results strongly suggest that a combinatorial treatment of radiation and IL-12 may represent an alternative therapy for advanced HCC.

An analytical model for super low-noise InAlAs/InGaAs/InAlAs/InP HEMTs is presented. The carriers are well confined in the quantum well formed in InGaAs due to the large conduction band discontinuities (/spl Delta/EC) at the InAlAs/InGaAs and InGaAs/InAlAs heterointerfaces. Moreover, a smaller electron effective mass in InGaAs results in a higher device transconductance g/sub m/ and lower noise figure NF. The noise figure of InP based HEMTs is much lower than that of GaAs based pseudomorphic or normal HEMTs. The present model is based on a self-consistent solution of Schroedinger and Poisson's equations to calculate the properties of the quantum well formed in InGaAs, namely the average distance of two-dimensional electron gas (2DEG), x/sub av/, and the position of Fermi level, E/sub F/, as a function of 2DEG concentration n/sub s/. Instead of using a two-line or an exponential approximation, an improved velocity electric field (v/sub d/-E) characteristic is used to calculate the current-voltage (I-V) characteristics, small-signal parameters and noise performance analytically. Based on the model developed by Liu and Anwar et al., g/sub m/ is calculated and the result shows an excellent agreement with experimental data. The present model yields a minimum noise figure, F/sub min/, of 0.8 and 1.2 dB at 60 and 94 GHz, respectively, which well fit to the experimental data. The noise performance of this class of devices with different gate lengths is studied in the present model.

Data-over-cable service interface specifications v1.1 (DOCSIS v1.1) defines five upstream services for supporting per-flow quality of service (QoS). The cable modem termination system (CMTS) must periodically grant upstream transmission opportunities to the QoS flows based on their QoS parameters. This study proposes a two-phase minislot scheduling algorithm to reduce the QoS violation rate. In the scheduling sequence determination phase, the flow whose packets are most unlikely to violate QoS is scheduled first. In the minislot assignment phase, the scheduler allocates to a flow the available interval where the likelihood of packet violation is minimum. Simulation results demonstrate that our scheduling algorithm can reduce the QoS violation rate by 80% - 35% over that of the first-come-first-serve-random-selection algorithm and increase the utilization by 25% as well.

stabilization and with laboratory data trending toward normal values. She was healthy at follow-up 16 days after the initial admission. There are 2 previous reports of acute misoprostol toxicity during the first trimester of pregnancy [1,2]. One report described mild adverse gastrointestinal symptoms after the ingestion of 8.4 mg of misoprostol [1] and the other describedmultiorgan failure, gastric and esophageal necrosis, and the death of the woman after the ingestion of 12 mg of misoprostol [2]. The present report describes a hospital admission for misoprostol overdose after an attempted abortion without medical supervision, despite the fact that, in Portugal, voluntary abortion is legal and offered by the Servico Nacional de Saude (National Health Service) for women whoareup to10 weekspregnant. It is necessary, therefore, to emphasize the need for careful monitoring of voluntary abortion, in addition to highlighting the risks involved, as part of public education efforts. Clinicians must be prepared to deal with similar situations, especially because they may require early and prompt intervention with support measures, as illustrated by the present case.

Asthma is considered as a chronic pulmonary inflammatory disease, characterized by eosinophilia. Lung epithelium cells secrete CCL11, the major chemokine for the recruitment of eosinophils. Hybrid adeno-associated virus serotype 2/9 might achieve long-term gene delivery specifically to lung epithelium cells. Thus, this study tested whether hybrid AAV2/9 virus carrying shRNA specific for CCL11, sh47 and sh137, could reduce eosinophilia in a mite allergen-sensitized mouse model. Both sh47 and sh137 viruses significantly reduced CCL11 level in CCL11-transformed NIH 3T3 cells, compared with others. Both viruses were delivered into Dp2 (group 2 allergen of Dermatophagoides pteronyssinus) sensitized mice before first challenge. The results showed that sh47 virus significantly reduced airway resistance, airway hyperresponsiveness, CCL11 levels and eosinophilia in the lungs of Dp2-sensitized mice. Th2 cytokines were also significantly reduced in the bronchoalveolar lavage fluid and Dp2-stimulated mediastinal lymphocytes of sh47 virus-treated mice. However, serum levels of Dp2-specific IgG1 and IgE as well as Th2 cytokine levels in Dp2-stimulated splenocytes culture supernatants were at the comparable levels to the untreated group. The results suggest that sh47 virus relieved local instead of systemic inflammatory responses. Therefore, the hybrid AAV2/9 viral vector, which is preferable to target lung epithelia cells, might be applied as a novel therapeutic approach for asthma.

Les caracteristiques specifiques de la gravure en solution des transistors a mobilite d'electrons elevee avec heterostructures (AL, Ga) As/GaAs permettent de fabriquer une structure de grille etroite en retrait pour des longueurs de canal inferieures a la longueur de grille. Les resultats electriques montrent que les principaux effets parasites dus au materiau, comme la limitation du courant dans le canal par suite de l'appauvrissement en surface et la suppression de la caracteristique courant-tension a basse temperature a l'obscurite, sont supprimees

A large number of (Hg.8Cd.2)Te films, about ten microns thick, were prepared on low-cost Si substrates by r.f..triode-sputtering in a Hg atmosphere. The sensitivity of the film conduction properties to small changes in snutter-deposition parameters (particularly Hg sputtering gas pressure and substrate dc bias and temnerature) and to post deposition annealina parameters was studied by Vanderpauw Hall effect measurements variable tempera-ture and magnetic field. Wavelength dispersive electron-probe microanalysis and optical absorption analysis were used to measure the film composition which under the proper souttering conditions matched the nominal composition value of the pressed-powder target in the 0.2-0.27 x value range. Substrate bias to remove impurities depositing during the sputter-ing process was found to be effective for obtaining n-type films with carrier concentrations as low as 1015 cm-3 at 1000oK. Although the electron mobilities were only about 10% of bulk values, the experimental results indicate that considerable improvement can be obtained by further fine tuning of the deposiiton and annealing parameters.© (1983) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.