Design, Synthesis, and Pharmacological Evaluation of Haloperidol Derivatives as Novel Potent Calcium Channel Blockers with Vasodilator Activity

Several haloperidol derivatives with a piperidine scaffold that was decorated at the nitrogen atom with different alkyl, benzyl, or substituted benzyl moieties were synthesized at our laboratory to establish a library of compounds with vasodilator activity. Compounds were screened for vasodilatory activity on isolated thoracic aorta rings from rats, and their quantitative structure–activity relationships (QSAR) were examined. Based on the result of QSAR, N-4-tert-butyl benzyl haloperidol chloride (16c) was synthesized and showed the most potent vasodilatory activity of all designed compounds. 16c dose-dependently inhibited the contraction caused by the influx of extracellular Ca2+ in isolated thoracic aorta rings from rats. It concentration-dependently attenuated the calcium channel current and extracellular Ca2+ influx, without affecting the intracellular Ca2+ mobilization, in vascular smooth muscle cells from rats. 16c, possessing the N-4-tert-butyl benzyl piperidine structure, as a novel calcium antagonist, may be effective as a calcium channel blocker in cardiovascular disease

18F-FDG PET/CT findings in a patient with blastic plasmacytoid dendritic cell neoplasm and post-transplant lymphoproliferative disorder after hematopoietic stem cell transplantation: a case report

BackgroundBlastic plasmacytoid dendritic cell neoplasm (BPDCN) is an extremely rare hematopoietic malignancy, which originating from precursors of plasmacytoid dendritic cells. Allogeneic hematopoietic stem cell transplantation (HSCT) is normally considered in the treatment of BPDCN patients to acquire sustained remission. Post-transplant lymphoproliferative disorder (PTLD) is a group of conditions involving abnormal lymphoid cells proliferation in the context of extrinsic immunosuppression after solid organ transplantation (SOT) or HSCT. Herein, we report a patient with BPDCN, who suffered from PTLD after allogeneic HSCT.Case presentationA 66-year-old man was diagnosed with BPDCN, confirmed by pathologic examination after splenectomy. The post-surgery 18F-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (18F-FDG PET/CT) showed multifocal 18F-FDG avidity in the left cheek, lymph nodes and bone marrow. The patient started chemotherapy, followed by allogeneic HSCT and immunosuppressive therapy. Four months after the HSCT, the patient developed intermittent fever and recurrent lymphadenopathy, accompanied with progressively elevated Epstein–Barr virus (EBV)-DNA both in serum and lymphocytes. 18F-FDG PET/CT was performed again and found multiple new enlarged 18F-FDG-avid lymph nodes, while the previous hypermetabolic lesions all disappeared. The pathology of mesenteric lymph node indicated a monomorphic PTLD (diffuse large B-cell lymphoma). Then the immunosuppressive medications were stopped and two cycles of Rituximab were given, and the follow-up CT scan indicated a complete response.ConclusionWhen patients with BPDCN recurred new enlarged lymph nodes after allogeneic HSCT and immunosuppressive therapy, PTLD should be taken into consideration. 18F-FDG PET/CT may provide additional evidence for supporting or refuting the suspicion of PTLD, and suggest lesions accessible for biopsy

Targeting Radioresistant Breast Cancer Cells by Single Agent CHK1 Inhibitor via Enhancing Replication Stress

Radiotherapy (RT) remains a standard therapeutic modality for breast cancer patients. However, intrinsic or acquired resistance limits the efficacy of RT. Here, we demonstrate that CHK1 inhibitor AZD7762 alone significantly inhibited the growth of radioresistant breast cancer cells (RBCC). Given the critical role of ATR/CHK1 signaling in suppressing oncogene-induced replication stress (RS), we hypothesize that CHK1 inhibition leads to the specific killing for RBCC due to its abrogation in the suppression of RS induced by oncogenes. In agreement, the expression of oncogenes c-Myc/CDC25A/c-Src/H-ras/E2F1 and DNA damage response (DDR) proteins ATR/CHK1/BRCA1/CtIP were elevated in RBCC. AZD7762 exposure led to significantly higher levels of RS in RBCC, compared to the parental cells. The mechanisms by which CHK1 inhibition led to specific increase of RS in RBCC were related to the interruptions in the replication fork dynamics and the homologous recombination (HR). In summary, RBCC activate oncogenic pathways and thus depend upon mechanisms controlled by CHK1 signaling to maintain RS under control for survival. Our study provided the first example where upregulating RS by CHK1 inhibitor contributes to the specific killing of RBCC, and highlight the importance of the CHK1 as a potential target for treatment of radioresistant cancer cells

Targeting Radioresistant Breast Cancer Cells by Single Agent CHK1 Inhibitor via Enhancing Replication Stress

Radiotherapy (RT) remains a standard therapeutic modality for breast cancer patients. However, intrinsic or acquired resistance limits the efficacy of RT. Here, we demonstrate that CHK1 inhibitor AZD7762 alone significantly inhibited the growth of radioresistant breast cancer cells (RBCC). Given the critical role of ATR/CHK1 signaling in suppressing oncogene-induced replication stress (RS), we hypothesize that CHK1 inhibition leads to the specific killing for RBCC due to its abrogation in the suppression of RS induced by oncogenes. In agreement, the expression of oncogenes c-Myc/CDC25A/c-Src/H-ras/E2F1 and DNA damage response (DDR) proteins ATR/CHK1/BRCA1/CtIP were elevated in RBCC. AZD7762 exposure led to significantly higher levels of RS in RBCC, compared to the parental cells. The mechanisms by which CHK1 inhibition led to specific increase of RS in RBCC were related to the interruptions in the replication fork dynamics and the homologous recombination (HR). In summary, RBCC activate oncogenic pathways and thus depend upon mechanisms controlled by CHK1 signaling to maintain RS under control for survival. Our study provided the first example where upregulating RS by CHK1 inhibitor contributes to the specific killing of RBCC, and highlight the importance of the CHK1 as a potential target for treatment of radioresistant cancer cells

Hierarchical Control Strategy for Active Hydropneumatic Suspension Vehicles Based on Genetic Algorithms

A new hierarchical control strategy for active hydropneumatic suspension systems is proposed. This strategy considers the dynamic characteristics of the actuator. The top hierarchy controller uses a combined control scheme: a genetic algorithm- (GA-) based self-tuning proportional-integral-derivative controller and a fuzzy logic controller. For practical implementations of the proposed control scheme, a GA-based self-learning process is initiated only when the defined performance index of vehicle dynamics exceeds a certain debounce time threshold. The designed control algorithm is implemented on a virtual prototype and cosimulations are performed with different road disturbance inputs. Cosimulation results show that the active hydropneumatic suspension system designed in this study significantly improves riding comfort characteristics of vehicles. The robustness and adaptability of the proposed controller are also examined when the control system is subjected to extremely rough road conditions

Partial integrated missile guidance and control with output feedback

A novel output feedback controller is presented in this paper for a class of nonlinear systems with disturbances. Firstly, a dynamic compensator is introduced and combined with the plant to form an extended system for which an estimator is constructed. Using the norm bound of estimation error vector, the controller is proposed to drive the output to zero in finite time. Then the proposed result is applied to partial integrated guidance and control design of missile to achieve hit-to-kill interception. Finally, a simulation example is presented to illustrate effectiveness of the proposed method. ? 2014 TCCT, CAA.EI

Possible intrauterine SARS-CoV-2 infection: Positive nucleic acid testing results and consecutive positive SARS-CoV-2-specific antibody levels within 50 days after birth

Whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects the fetus in utero is important to the well-being of the mother and neonate. We report the case of a full-term neonate born to a mother who developed symptoms of coronavirus disease 2019 (COVID-19) at 32 weeks of gestation. The placental pathology showed slight local inflammation. Serial quantitative antibody measurements in the neonate showed elevated levels of IgM on the day of birth and a gradual decline to negative levels within 28 days of life; the levels of IgG declined gradually, but IgG was still positive on day 50 of life. The sequential dynamic changes in antibody levels in the neonate were consistent with those in his mother. One-step reverse transcriptase droplet digital PCR testing for SARS-CoV-2 nucleic acid in throat and anal swabs showed positive results (750 and 892 copies/ml) on day 7 of life and negative results on day 14 of life. The neonate had no symptoms of COVID-19. This report enables us to re-evaluate the significance of IgM detection in intrauterine SARS-CoV-2 infection and presents a favorable prognosis for the neonate with long-term exposure to maternal COVID-19, despite a high possibility of intrauterine infection

Hierarchical Control Strategy for Active Hydropneumatic Suspension Vehicles Based on Genetic Algorithms

A new hierarchical control strategy for active hydropneumatic suspension systems is proposed. This strategy considers the dynamic characteristics of the actuator. The top hierarchy controller uses a combined control scheme: a genetic algorithm- (GA-) based self-tuning proportional-integral-derivative controller and a fuzzy logic controller. For practical implementations of the proposed control scheme, a GA-based self-learning process is initiated only when the defined performance index of vehicle dynamics exceeds a certain debounce time threshold. The designed control algorithm is implemented on a virtual prototype and cosimulations are performed with different road disturbance inputs. Cosimulation results show that the active hydropneumatic suspension system designed in this study significantly improves riding comfort characteristics of vehicles. The robustness and adaptability of the proposed controller are also examined when the control system is subjected to extremely rough road conditions