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The insanity defense has been criticized with consequences for individuals with real mental illness. In the United States, several states have redefined the insanity defense by excluding antisocial personality disorder from consideration for the not guilty by reason of insanity plea. Four states have eliminated the insanity defense completely. The purpose of this article is to analyze the diagnosis of borderline personality disorder, its relevance in the courtroom setting, and how this speaks to the approach of the insanity defense in general. The history of the insanity defense, impulsive nature of borderline personality disorder, and the reasons that make personality disorders controversial are reviewed. The impulsive nature, and the association to childhood trauma, dissociation, and frontolimbic abnormalities support the continued protection of borderline personality disorder under the insanity defense. Knowledge of these facts will assist the forensic psychiatrist in effectively educating the courtroom about borderline personality disorder. [ABSTRACT FROM AUTHOR]

This paper proposes a repetitive controller with phase-lead compensation for an unfolding-type Cuk continuous conduction mode (CCM) inverter operating in the CCM. The Cuk CCM inverter features medium power capacity, step up/down ability, and low input/output current ripples, so it is well suited to distributed power generation systems. To achieve accurate tracking of the reference output current, we make the use of the repetitive controller coupled with a conventional proportional-integral controller and a nominal duty ratio. In developing the proposed controller, we use the average model of the Cuk CCM inverter in the grid-connected case. The two right-half plane (RHP) zeros in the transfer function of the Cuk CCM inverter cause phase lag of the closed-loop system; to compensate for the phase lag, we implement a phase-lead compensation algorithm in the repetitive control scheme. We also provide detailed and practical design guidelines of the control parameters to develop a stable Cuk CCM inverter. Experimental tests using a 500-W Cuk CCM inverter demonstrate the desirable performance of the proposed control approach. [ABSTRACT FROM PUBLISHER]

In this paper, we propose a Lyapunov-function-based controller for the flyback converter operating in the continuous conduction mode (CCM). The controller consists of a duty-ratio feedforward control unit and a Lyapunov-function-based feedback control unit. The duty-ratio feedforward signal is used to reduce the burden from the Lyapunov feedback controller. The control system guarantees global exponential stability of the closed-loop system and, hence, offers fast transient response under large-signal perturbations. In constructing the controller, we use the average model of the flyback CCM converter taking the parasitic components into account. Numerical simulations confirmed its superior performance, and experimental tests validated the proposed control approach. [ABSTRACT FROM PUBLISHER]

We propose a downsampled iterative learning controller (ILC) for a flyback inverter operating in continuous conduction mode (CCM). The flyback CCM inverter features step-up/-down ability, small number of circuit components, and high conversion efficiency, so it is well suited to the distributed renewable energy systems. But the conventional proportional-integral (PI) controller for the flyback CCM inverter shows poor steady-state response because the inverter itself suffers from time-varying grid-voltage disturbances and its transfer function has a right-half plane zero. The ILC itself achieves acceptable steady-state response of the flyback CCM inverter but can excite large overshoot in the iteration domain; this overshoot may destroy the solid state devices in the power circuit. To overcome this problem, we use a downsampled ILC technique that guarantees monotonic convergence of tracking error. The proposed ILC is computationally simple and easy to implement. Numerical simulations and experimental tests validate the proposed control approach. [ABSTRACT FROM PUBLISHER]

This paper presents adaptive time-delay control (TDC) with a supervising switching technique (SST) for controlling robot manipulators. Two adaptive techniques are used to enhance the TDC. The control gain of TDC is adaptively tuned using a class of Nussbaum functions. With Nussbaum functions, compared with conventional TDC using a constant gain, the proposed control using Nussbaum functions can deal with inertia parameter variations due to the movement of a robot manipulator. The SST is used to deal with discontinuous disturbances. The proposed control is model-free, highly accurate, robust and adaptive. [ABSTRACT FROM AUTHOR]

This paper proposes an iterative learning control (ILC) scheme for a dual-mode flyback inverter operating in both discontinuous conduction mode (DCM) and continuous conduction mode (CCM). In dealing with more than 200-W power applications, the dual-mode flyback inverter takes advantage of both DCM and CCM operations. However, it is difficult to control the output current because the system gain is quite low in DCM and the system transfer function has a right-half plane zero in CCM. To overcome the problems occurring in DCM and CCM operations, we propose an ILC scheme with multiple phase-lead compensation. The ILC is proposed to achieve accurate reference tracking and to reject periodic disturbances. The multiple phase-lead compensation technique is then employed to compensate for the effect of different system dynamics. As a theoretical result, we derive the asymptotic stability of the closed-loop system. We also performed the numerical simulations and experimental tests to validate the proposed control approach. [ABSTRACT FROM AUTHOR]

We propose a path-tracking algorithm that is developed using an iterative learning control (ILC) technique and use the algorithm to control an omni-directional mobile robot. The proposed algorithm can be categorized as an open-closed PD-type ILC; it generates robot velocity commands by a PD-type ILC update rule using both previous and current information. When applied to the omni-directional mobile robot, it can decrease position errors and track the desired trajectory. Under the general problem setting that includes a mobile robot, we show that the proposed algorithm guarantees that the system states, outputs and control inputs converge to within small error bounds around the desired ones even under state disturbances, measurement noises and initial state errors. By using simulation and experimental tests, we demonstrate that the proposed algorithm converges fast to the desired path, and results in small root-mean-square (r.m.s.) position error under various surface conditions. The proposed algorithm shows better path-tracking performance than the conventional PID algorithm and achieves faster convergence and lower r.m.s. error than the existing two ILC algorithms. [ABSTRACT FROM AUTHOR]

An algorithm that can compute the rotation angle between two images is proposed, independently of the translation angle by using only two‐point correspondence pairs. A parameterised solution vector can be calculated from the null‐space of a matrix constructed of two‐point correspondence pairs, and then the rotation angle is evaluated from this vector by using the relation between the elements of the essential matrix. Once the rotation angle is determined, the translation angle can be computed by using the Ackermann steering constraint, and then the translation distance can be determined. In the experiments, the proposed algorithm estimated the rotation angle and the translation distance better than did previous algorithms. [ABSTRACT FROM AUTHOR]

Mitogen-activated protein kinase (MAPK) signalling networks are important regulators of environmental responses and developmental processes in plants. To understand the role of MAPK signalling modules in the regulation of plant microtubule functions, we searched for MAPKs that interact with the dual-specificity MAPK phosphatase, PROPYZAMIDE HYPERSENSITIVE 1 ( PHS1), whose mutation has previously been reported to confer hypersensitivity to microtubule-disrupting drugs in Arabidopsis. Yeast two-hybrid assays demonstrated that PHS1 specifically interacts with two MAPKs, MPK12 and MPK18. Bimolecular fluorescence complementation (BiFC) studies confirmed that the PHS1 and MPK18 proteins are physically coupled, and that this interaction occurs in the cytoplasm. At the biochemical level, in vitro dephosphorylation assays indicated that phospho-MPK18 can be dephosphorylated by recombinant PHS1. Mutant mpk18 seedlings show defects in microtubule-related functions, and have moderately stabilized microtubules. Absence of MPK18 in the phs1-1 background partially complements the phs1-1 root growth phenotypes, providing genetic evidence for involvement of MPK18 signalling in microtubule-related functions. We propose a model whereby the PHS1–MPK18 signalling module is involved in a phosphorylation/dephosphorylation switch that regulates cortical microtubule functions. [ABSTRACT FROM AUTHOR]

This paper proposes a robust path-following control method of a kinematic mobile robot system subject to bounded angular velocity error. The angular velocity error usually arises from imperfect performance of the dynamic control system. Given a kinematic model of the mobile robot system with bounded angular velocity error, we present a stable and robust path-following controller which is based on the sliding mode control technique and prove that the path-following errors (the lateral distance and orientation error) are ultimately bounded. In addition, the safety margin of the lateral distance error is defined, which is useful for higher-level path-planning tasks. The feasibility of the proposed controller has been demonstrated through simulation tests. [ABSTRACT FROM AUTHOR]

Proposes a way of generating a state equation which is useful for analyzing token flows in a Petri Net. Replacement of transition values as used in the conventional state equation with transition variables; Overview of state equation with firing condition functions; Dreadlock analysis using the proposed state equation.

This paper presents a special hierarchical fuzzy system where the outputs of the previous layer are not used in the IF-parts, but used only in the THEN-parts of the fuzzy rules of the current layer.The proposed scheme can be shown to be a universal approximator to any continuous function on a compact set if complete fuzzy sets are used in the IF-parts of the fuzzy rules with singleton fuzzifier and center average defuzzifier.From the simulation of ball and beam control system, it is demonstrated that the proposed scheme approximates with good accuracy the model nonlinear controller with fewer fuzzy rules than the centralized fuzzy system and its control performance is comparable to that of the nonlinear controller. [Copyright &y& Elsevier]

Purpose: Clinical experience of both physicians and institutions has been shown to significantly influence the outcome of patients. We conducted this retrospective cohort study to examine its impact on the outcome of patients undergoing combined chemoradiation therapy for the treatment of locally advanced inoperable non-small-cell lung cancer.Methods and Materials: We compared the clinical data from 239 patients who were enrolled in two consecutive Radiation Therapy Oncology Group (RTOG) trials (RTOG 91-06, RTOG 92-04) according to the number of patients enrolled from each institution in either trial alone or the two trials combined.Results: Overall, patients treated at the institutions that enrolled ≥5 patients survived longer than those treated at the institutions that enrolled <5 patients (median survival 20.5 vs. 13.4 months, p = 0.0006) with a more than doubling of the 2- and 3-year survival rates (45% and 31% vs. 20% and 13%, respectively). Multivariate analyses confirmed that the number of patients enrolled from each institution was an important prognostic factor for the entire group (p = 0.001) and also for RTOG 91-06 (p = 0.05) and RTOG 92-04 (p = 0.004) when the data were analyzed separately.Conclusion: Institutional experience has a significant impact on the survival outcome of patients undergoing combined chemoradiation therapy for inoperable non-small cell lung cancer. [Copyright &y& Elsevier]

The COVID‐19 pandemic highlighted the clear risk that zoonotic viruses pose to global health and economies. The scientific community responded by developing several efficacious vaccines which were expedited by the global need for vaccines. The emergence of SARS‐CoV‐2 breakthrough infections highlights the need for additional vaccine modalities to provide stronger, long‐lived protective immunity. Here we report the design and preclinical testing of small extracellular vesicles (sEVs) as a multi‐subunit vaccine. Cell lines were engineered to produce sEVs containing either the SARS‐CoV‐2 Spike receptor‐binding domain, or an antigenic region from SARS‐CoV‐2 Nucleocapsid, or both in combination, and we tested their ability to evoke immune responses in vitro and in vivo. B cells incubated with bioengineered sEVs were potent activators of antigen‐specific T cell clones. Mice immunised with sEVs containing both sRBD and Nucleocapsid antigens generated sRBD‐specific IgGs, nucleocapsid‐specific IgGs, which neutralised SARS‐CoV‐2 infection. sEV‐based vaccines allow multiple antigens to be delivered simultaneously resulting in potent, broad immunity, and provide a quick, cheap, and reliable method to test vaccine candidates. [ABSTRACT FROM AUTHOR]

Background: Retinoids can reverse neoplastic lesions and prevent second primary tumors in the aerodigestive tract. These effects are thought to be mediated by nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs), each receptor group including three subtypes (alpha, beta, and gamma). Previously, we found that RARbeta expression was suppressed in lung cancer. In this study, we investigated whether expression of RARbeta is modulated by chemopreventive intervention.Methods: Using in situ hybridization, we analyzed RARbeta messenger RNA (mRNA) expression in bronchial biopsy specimens from heavy smokers, at baseline and after 6 months of treatment with 13-cis-retinoic acid (13-cis-RA) or placebo. Since we had previously detected RARbeta expression in 90% of bronchial specimens from nonsmokers, we considered loss of RARbeta mRNA expression in at least one of six biopsy specimens at baseline in this study to be aberrant.Results: RARbeta mRNA expression was aberrant in 30 (85.7%) of 35 subjects in the 13-cis-RA group and in 24 (72.7%) of 33 subjects in the placebo group. After 6 months of 13-cis-RA treatment, the number of subjects who were RARbeta positive in all six biopsy specimens increased from five of 35 to 13 of 35 (2.6-fold), so that the percentage of individuals with aberrant RARbeta expression decreased to 62.9% (22 of 35), which represents a statistically significant difference from baseline expression (two-sided P =.01). In the placebo group, no statistically significant difference in RARbeta expression was observed between baseline and 6 months. RARbeta expression was not related to current smoking status or reversal of squamous metaplasia.Conclusions: These results indicate that RARbeta is an independent marker of response to 13-cis-RA and may serve as an intermediate biomarker in chemoprevention trials of upper aerodigestive tract cancers. [ABSTRACT FROM AUTHOR]

Background: New methods are needed to detect precancerous lesions in lung tissue. We conducted a study to determine the utility of LIFE (laser-induced fluorescence emission) autofluorescence bronchoscopy for the detection of squamous metaplasia and dysplasia in current and former smokers.Methods: In this prospective, single-center study, 53 participants underwent standard white-light bronchoscopy and 39 underwent both white-light and LIFE bronchoscopy. Bronchial biopsy specimens were obtained from all participants at six pre-determined sites using white-light bronchoscopy and from all other sites that appeared to be abnormal in participants who underwent LIFE bronchoscopy. Relationships between LIFE imaging and histologic findings were examined for 245 biopsy specimens obtained from those participants who had undergone LIFE bronchoscopy.Results: LIFE imaging revealed abnormalities designated as either class II or class III in 89 (36.3%) and 16 (6.5%) of the 245 sites examined, respectively, and histopathologic examination showed dysplasia and metaplasia in eight (3.3%) and in 52 (21.2%) of the 245 specimens, respectively. Among the 105 biopsy specimens obtained from sites with abnormal LIFE imaging, only 26 (24.8%) exhibited squamous metaplasia and/or dysplasia, similar to the findings for sites with normal LIFE imaging (34 [24.3%] of 140). Comparison of individuals examined by LIFE imaging with those who underwent white-light bronchoscopy alone revealed no increase in the detection of dysplasia or metaplasia with LIFE bronchoscopy.Conclusion: In this population of current and former smokers, abnormalities detected by LIFE bronchoscopy did not improve the detection of squamous metaplasia or dysplasia. [ABSTRACT FROM AUTHOR]

Examines protein expression in primary tumor specimens of patients with head and neck squamous cell carcinoma to determine whether expression of p53 protein has prognostic significance or is associated with patterns of treatment failure. Clinical and pathologic characteristics of patients; Survival according to p53 expression.

Summary. Recurring land price inflation in Korea is one of the most worrisome policy issues. It frustrates people's aspirations of home-ownership, aggravates income/wealth disparities, raises business costs and requires higher costs for government of land acquisition for infrastructure. Any effort to combat this problem must consider whether this land price inflation reflects a change in fundamentals or is led by speculative bubbles. An econometric test concludes that land markets in Korea have partly been driven by speculative bubbles. Then this paper argues that bubbles are cyclically formed and are persistent due to structural differences in the rate of return between land and financial assets, which are enforced by the centrally administered economic order. Thus, to reduce the bubble element in Korean land prices, fundamental reform is necessary towards a genuine market economy. This includes financial liberalisation and land tax reform to decrease speculative demand, and reform of land-use control to increase the supply of urban land. [ABSTRACT FROM AUTHOR]

An algorithm that can compute the rotation angle between two images is proposed, independently of the translation angle by using only two-point correspondence pairs. A parameterised solution vector can be calculated from the null-space of a matrix constructed of twopoint correspondence pairs, and then the rotation angle is evaluated from this vector by using the relation between the elements of the essential matrix. Once the rotation angle is determined, the translation angle can be computed by using the Ackermann steering constraint, and then the translation distance can be determined. In the experiments, the proposed algorithm estimated the rotation angle and the translation distance better than did previous algorithms. [ABSTRACT FROM AUTHOR]

Highlights • We propose a novel two-stream ConvNet model for first person action recognition. • Our model effectively captures the temporal structure of actions. • We introduce novel long-term pooling operators for appearance and motion information. • We analyze the effect of the proposed architecture with extensive experiments. • We achieve the state-of-the-art performance for first person action recognition. Abstract First person action recognition is an active research area with increasingly popular wearable devices. Action classification for first person video (FPV) is more challenging than conventional action classification due to strong egocentric motions, frequent changes of viewpoints, and diverse global motion patterns. To tackle these challenges, we introduce a two-stream convolutional neural network that improves action recognition via long-term fusion pooling operators. The proposed method effectively captures the temporal structure of actions by leveraging a series of frame-wise features of both appearance and motion in actions. Our experiments validate the effect of the feature pooling operators, and show that the proposed method achieves state-of-the-art performance on standard action datasets. [ABSTRACT FROM AUTHOR]

Editorial. Discusses non-small-cell lung cancer, which accounts for approximately 75 percent of the cases of lung cancer in the United States. Article by Miyake, et al in the July 2, 1992 issue of the `New England Journal of Medicine'; Role of the expression of a carbohydrate antigen related to blood-group antigen H, detected with the monoclonal antibody MIA-15-5 as a prognostic factor in patients with non-small-cell lung cancer; More.

Adaptive beamforming methods for ultrasound imaging have been studied to improve image resolution and contrast. The most common approach is the minimum variance (MV) beamformer which minimizes the power of the beamformed output while maintaining the response from the direction of interest constant. The method achieves higher resolution and better contrast than the delay-and-sum (DAS) beamformer, but it suffers from high computational cost. This cost is mainly due to the computation of the spatial covariance matrix and its inverse, which requires O(L^3) computations, where L denotes the subarray size. In this study, we propose a computationally efficient MV beamformer based on QR decomposition. The idea behind our approach is to transform the spatial covariance matrix to be a scalar matrix \sigma \mathbfI and we subsequently obtain the apodization weights and the beamformed output without computing the matrix inverse. To do that, QR decomposition algorithm is used and also can be executed at low cost, and therefore, the computational complexity is reduced to O(L^2). In addition, our approach is mathematically equivalent to the conventional MV beamformer, thereby showing the equivalent performances. The simulation and experimental results support the validity of our approach. [ABSTRACT FROM PUBLISHER]

This paper presents sufficient conditions on the parameters of the Takagi–Sugeno–Kang (TSK) fuzzy system under which the output of the TSK fuzzy system becomes monotonic with respect to its input. The output of the TSK fuzzy system is first differentiated with respect to its input and the parameter conditions are derived so as to make the derivative nonnegative. The parameter conditions are developed for both single-input and multi-input TSK fuzzy systems where the involved fuzzy membership functions are differentiable everywhere or bar some finite points. The derived monotonicity conditions consist of two parts: the conditions on the consequent parts and the conditions on the fuzzy membership functions. They are further characterized for the most important types of fuzzy membership functions. [Copyright &y& Elsevier]

We propose a new duty-ratio feedforward controller for the flyback inverter with a synchronous rectifier (SR) circuit. For grid-connected photovoltaic power systems, the power factor (PF) of the output current must be high under most of the load conditions. To improve the PF of the flyback inverter even under light load, we propose a compensation method for the output capacitor current. The proposed method improves the displacement factor as well as the distortion factor, so the flyback inverter with the SR circuit has high power quality. By means of the SR circuit, the flyback inverter can operate in reverse when the negative current is required. The derivation of the proposed method is presented based on time-domain analysis. We also provide the boundary of the region where the proposed scheme should be adopted. The effectiveness of the proposed method is demonstrated in experiments with a 120-W rated power prototype. [ABSTRACT FROM AUTHOR]

We propose an improved version of a synthetic aperture focusing technique (SAFT) based on a delaymultiply- and-sum algorithm for acoustic-resolution photoacoustic microscopy (AR-PAM). In this method, the photoacoustic (PA) signals from multiple scan-lines are combinatorially coupled, multiplied, and then summed. This process can be considered a correlation operation of the PA signals in each scan-line, so the spatial coherent information between the PA signals can be efficiently extracted. By applying this method in conventional ARPAM, lateral resolution and signal-to-noise ratio in out-of-focus regions are much improved compared with those estimated from the previously developed SAFT, respectively, thereby achieving the extension of the imaging focal region. Our phantom and in vivo imaging experiments prove the validity of our proposed method. [ABSTRACT FROM AUTHOR]

This paper presents an enhanced time-delay controller (TDC) for the position control of an autonomous underwater vehicle (AUV) under disturbances. A conventional TDC performs well when the involved data acquisition rate is fast. However, in AUV control applications that use a Doppler velocity log (DVL) navigation system, we cannot keep the data acquisition rate sufficiently fast because a DVL sensor generally supplies data at a slow acquisition rate, which degrades the performance of the TDC. To overcome this problem, we propose an integral sliding-mode controller to be supplemented to the conventional TDC to improve the control precision even if the DVL navigation system is in operation. The proposed controller is computationally simple and robust to unmodeled dynamics and disturbances. We performed computer simulations and experiments with the Cyclops AUV to demonstrate the validity of the proposed controller. [ABSTRACT FROM PUBLISHER]

Time-delay control (TDC) has been widely used to control various systems thanks to its simplicity and robustness. The control distribution matrix of TDC is assumed to be constant and tuned heuristically. However, the constant TDC control gain could degrade the system control performance and even cause the closed-loop system to become unstable when the system parameters are substantially changing, resulting in the violation of the stability criterion of TDC. We propose an algorithm for automatic tuning of the TDC gain in order to guarantee stability by using a modified Nussbaum function. Thus, the closed-loop system controlled by TDC with the modified Nussbaum function is proven to be semi-globally uniformly ultimately bounded. The auto-tuned gain satisfies the stability criterion of TDC and the proposed method can widen the range of implementable dynamic systems. Simulations are conducted to verify the simplicity, robustness, and guaranteed stability by auto-tuning of the proposed method. [ABSTRACT FROM AUTHOR]

Background: The combination of chemotherapy with thoracic radiotherapy (TRT) compared with TRT alone has been shown to confer a survival advantage for good performance status patients with stage III non-small cell lung cancer. However, it is not known whether sequential or concurrent delivery of these therapies is the optimal combination strategy.Methods: A total of 610 patients were randomly assigned to two concurrent regimens and one sequential chemotherapy and TRT regimen in a three-arm phase III trial. The sequential arm included cisplatin at 100 mg/m2 on days 1 and 29 and vinblastine at 5 mg/m2 per week for 5 weeks with 63 Gy TRT delivered as once-daily fractions beginning on day 50. Arm 2 used the same chemotherapy regimen as arm 1 with 63 Gy TRT delivered as once-daily fractions beginning on day 1 [corrected]. Arm 3 used cisplatin at 50 mg/m2 on days 1, 8, 29, and 36 with oral etoposide at 50 mg twice daily for 10 weeks on days 1, 2, 5, and 6 with 69.6 Gy delivered as 1.2 Gy twice-daily fractions beginning on day 1. The primary endpoint was overall survival, and secondary endpoints included tumor response and time to tumor progression. Kaplan-Meier analyses were used to assess survival, and toxic effects were examined using the Wilcoxon rank sum test. All statistical tests were two-sided.Results: Median survival times were 14.6, 17.0, and 15.6 months for arms 1-3, respectively. Five-year survival was statistically significantly higher for patients treated with the concurrent regimen with once-daily TRT compared with the sequential treatment (5-year survival: sequential, arm 1, 10% [20 patients], 95% confidence interval [CI] = 7% to 15%; concurrent, arm 2, 16% [31 patients], 95% CI = 11% to 22%, P = .046; concurrent, arm 3, 13% [22 patients], 95% CI = 9% to 18%). With a median follow-up time of 11 years, the rates of acute grade 3-5 nonhematologic toxic effects were higher with concurrent than sequential therapy, but late toxic effects were similar.Conclusion: Concurrent delivery of cisplatin-based chemotherapy with TRT confers a long-term survival benefit compared with the sequential delivery of these therapies. [ABSTRACT FROM AUTHOR]

Background The combination of chemotherapy with thoracic radiotherapy (TRT) compared with TRT alone has been shown to confer a survival advantage for good performance status patients with stage III non–small cell lung cancer. However, it is not known whether sequential or concurrent delivery of these therapies is the optimal combination strategy. Methods A total of 610 patients were randomly assigned to two concurrent regimens and one sequential chemotherapy and TRT regimen in a three-arm phase III trial. The sequential arm included cisplatin at 100 mg/m2 on days 1 and 29 and vinblastine at 5 mg/m2 per week for 5 weeks with 60 Gy TRT beginning on day 50. Arm 2 used the same chemotherapy regimen as arm 1 with 60 Gy TRT once daily beginning on day 1. Arm 3 used cisplatin at 50 mg/m2 on days 1, 8, 29, and 36 with oral etoposide at 50 mg twice daily for 10 weeks on days 1, 2, 5, and 6 with 69.6 Gy delivered as 1.2 Gy twice-daily fractions beginning on day 1. The primary endpoint was overall survival, and secondary endpoints included tumor response and time to tumor progression. Kaplan–Meier analyses were used to assess survival, and toxic effects were examined using the Wilcoxon rank sum test. All statistical tests were two-sided. Results Median survival times were 14.6, 17.0, and 15.6 months for arms 1–3, respectively. Five-year survival was statistically significantly higher for patients treated with the concurrent regimen with once-daily TRT compared with the sequential treatment (5-year survival: sequential, arm 1, 10% [20 patients], 95% confidence interval [CI] = 7% to 15%; concurrent, arm 2, 16% [31 patients], 95% CI = 11% to 22%, P = .046; concurrent, arm 3, 13% [22 patients], 95% CI = 9% to 18%). With a median follow-up time of 11 years, the rates of acute grade 3–5 nonhematologic toxic effects were higher with concurrent than sequential therapy, but late toxic effects were similar. Conclusion Concurrent delivery of cisplatin-based chemotherapy with TRT confers a long-term survival benefit compared with the sequential delivery of these therapies. [ABSTRACT FROM PUBLISHER]

Abstract: Regulating molten steel level in continuous casting is difficult because it suffers from various disturbances, among which the bulging disturbance is the most prominent. Moreover, as the casting speed increases in continuous casting, the phase lag due to the system delay increases. To eliminate the bulging disturbance in the presence of system delay, we propose an adaptive sine estimator based disturbance observer and a phase lead adaptive fuzzy controller. We tested the proposed method using a 1:1 scale hardware simulator and confirmed that the method successfully decreased the bulging disturbance effect from the molten steel level. [Copyright &y& Elsevier]

Purpose: To evaluate the effect of q.d. or b.i.d. radiotherapy (RT) on the outcome of patients with locally advanced non-small-cell lung cancer.Methods and Materials: We retrospectively reviewed the outcome of 261 patients with medically inoperable or surgically unresectable Stage II-IIIB non-small-cell lung cancer, who were treated with combined modality cisplatin-based chemotherapy and RT. Chemotherapy was administered either sequentially or concurrently with thoracic RT. The median follow-up was 18 months (range 2–92). Treatment groups included sequential chemotherapy and q.d. RT (n = 109), concurrent chemotherapy and q.d. RT (n = 48), and concurrent chemotherapy and b.i.d. RT (n = 104). Of the 261 patients, 97% had a Karnofsky performance score ≥80, and 86.2% had ≤5% weight loss in the 3 months before diagnosis; 66.7% had nonsquamous cell histologic features. All but 8 patients had Stage IIIA-B disease.Results: The 2- and 5-year locoregional control rate was 42.4% and 25.7% for the q.d. group and 70.6% and 45.8% for the b.i.d. group, respectively (p = 0.0001). The 2- and 5-year disease-free survival rate was 26.7% and 6.5% for the q.d. group and 39.6% and 27.3% for the b.i.d. group, respectively (p = 0.0114). The corresponding overall survival rates were 35.9% and 9.4% for the q.d. group and 38.7% and 26.1% for the b.i.d. group. No difference was found in the rate of distant metastasis between the 2 groups. Multivariate analysis indicated that b.i.d. RT was a favorable prognostic factor for locoregional control and disease-free survival.Conclusion: RT b.i.d. significantly improved locoregional control and disease-free survival compared with RT q.d. in patients with Stage IIIA-B non-small-cell lung cancer. [Copyright &y& Elsevier]

The immune responses of 10 patients with advanced non-small cell lung cancer receiving monthly intratumoral injections of a recombinant adenovirus containing human wild-type p53 (Ad-p53) to adenovirus and transgene antigens were studied. The predominate cellular and humoral immune responses as measured by lymphocyte proliferation and neutralizing antibody (Ab) formation were to adenovirus serotype 5 vector antigens, with increased responses in posttreatment samples. Consistent alterations in posttreatment cellular and humoral immune responses to p53 epitopes were not observed, and cytotoxic Abs to human lung cancer cells were not generated. Patients in this study had evidence of an antitumoral effect of this treatment with prolonged tumor stability or regression; however, neither Abs to p53 protein nor increased lymphocyte proliferative responses to wild-type or mutant p53 peptides have been consistently detected. [ABSTRACT FROM AUTHOR]

Background: Preclinical studies in animal models have demonstrated tumor regression following intratumoral administration of an adenovirus vector containing wild-type p53 complementary DNA (Ad-p53). Therefore, in a phase I clinical trial, we administered Ad-p53 to 28 patients with non-small-cell lung cancer (NSCLC) whose cancers had progressed on conventional treatments.Methods: Patients received up to six, monthly intratumoral injections of Ad-p53 by use of computed tomography-guided percutaneous fine-needle injection (23 patients) or bronchoscopy (five patients). The doses ranged from 10(6) plaque-forming units (PFU) to 10(11) PFU.Results: Polymerase chain reaction (PCR) analysis showed the presence of adenovirus vector DNA in 18 (86%) of 21 patients with evaluable posttreatment biopsy specimens; vector-specific p53 messenger RNA was detected by means of reverse transcription-PCR analysis in 12 (46%) of 26 patients. Apoptosis (programmed cell death) was demonstrated by increased terminal deoxynucleotide transferase-mediated biotin uridine triphosphate nick-end labeling (TUNEL) staining in posttreatment biopsy specimens from 11 patients. Vector-related toxicity was minimal (National Cancer Institute's Common Toxicity Criteria: grade 3 = one patient; grade 4 = no patients) in 84 courses of treatment, despite repeated injections (up to six) in 23 patients. Therapeutic activity in 25 evaluable patients included partial responses in two patients (8%) and disease stabilization (range, 2-14 months) in 16 patients (64%); the remaining seven patients (28%) exhibited disease progression.Conclusions: Repeated intratumoral injections of Ad-p53 appear to be well tolerated, result in transgene expression of wild-type p53, and seem to mediate antitumor activity in a subset of patients with advanced NSCLC. [ABSTRACT FROM AUTHOR]

Cyclin D1 proto-oncogene is a key regulator of the mammalian cell-cycle acting at the restriction point in late G1. Amplification of the cyclin D1 locus, located on chromosome 11q13, as well as cyclin D1 protein overexpression have been reported in several human malignancies. The purpose of this study was to evaluate cyclin D1 gene copy status and protein expression during the multistep process of head and neck tumorigenesis, using a combination of fluorescence in situ hybridization and immunohistochemistry techniques. From 29 selected patients presenting with head and neck squamous carcinoma and whose tumor cytospins had been previously screened for presence (16 cases) or absence (13 cases) of amplification at the 11q13 band, we analysed 46 paraffin-embedded tissue specimens that demonstrated, besides the primary tumor, the presence of contiguous adjacent normal tissue and/or premalignant lesions. Of the 16 amplified cases, nine demonstrated a continuous progression from premalignant to invasive carcinoma and seven (77.7%) of these cases showed cyclin D1 gene amplification in premalignant lesions prior to development of invasive carcinoma. Increased cyclin D1 protein expression was observed in all 16 amplified tumors and five of the 13 (38.4%) non-amplified tumors. Interestingly, dysregulated cyclin D1 expression was also found in the premalignant lesions adjacent to all 16 amplified tumors, and it appeared to precede cyclin D1 gene amplification. In contrast no dysregulated expression was detected in the premalignant lesions of the non-amplified tumors. In conclusion, these findings provide strong evidence for early dysregulation of cyclin D1 expression during the tumorigenesis process and suggest that dysregulated increased expression precedes and possibly enables gene amplification. [ABSTRACT FROM AUTHOR]

Background: Retinoids are effective in the treatment and prevention of certain human cancers. Most of their actions are thought to result from changes in gene expression mediated by nuclear retinoic acid receptors and retinoid X receptors. We conducted a study to determine whether the expression of these receptors was altered in premalignant oral lesions and, if so, whether their expression could be restored by treatment with isotretinoin. Methods: We performed in situ hybridization of retinoic acid receptors and retinoid X receptors using antisense riboprobes in specimens of oral mucosa from 7 normal subjects and specimens of premalignant oral lesions from 52 patients before treatment with isotretinoin and from 39 of the 52 patients after three months of treatment. Results: All the normal specimens expressed retinoic acid receptor–β messenger RNA (mRNA). In contrast, retinoic acid receptor–β mRNA was detected in only 21 of the 52 premalignant oral lesions (P = 0.003). Thirty-five of the 39 specimens available for evaluation after treatment expressed retinoic acid receptor–β mRNA (P<0.001). All normal and premalignant specimens expressed similar levels of mRNA for retinoic acid receptor–α and retinoic acid receptor–γ and the three types of retinoid X receptors, α, β, and γ. The levels of retinoic acid receptor–β mRNA increased in the specimens from 18 of the 22 patients who had responses to isotretinoin and in 8 of the 17 specimens from the patients without responses (P = 0.04). Conclusions: The expression of retinoic acid receptor–β mRNA is selectively lost in premalignant oral lesions and can be restored by treatment with isotretinoin. Restoration of the expression of retinoic acid receptor–β mRNA is associated with a clinical response. Retinoic acid receptor–β may have a role in mediating the response to retinoids and may be a useful intermediate biologic marker in trials of these agents for the prevention of oral carcinogenesis. (N Engl J Med 1995;332:1405-10.) [ABSTRACT FROM AUTHOR]