CPT Treatment Research Articles

Splanchnic and cerebral oxygenation during cyclic phototherapy in preterm infants with hyperbilirubinemia

Cyclic phototherapy (cPT) can achieve a reduction in total serum bilirubin comparable to that achieved with standard continuous PT in preterm infants. Our aim was to assess the effect of cPT on splanchnic (rSO2S) and cerebral (rSO2C) oxygenation measured by near-infrared spectroscopy (NIRS). We prospectively studied 16 infants with a gestational age of 25–34 weeks with hyperbilirubinemia requiring PT. Splanchnic regional oxygenation (rSO2S), oxygen extraction fraction (FOES), and cerebro-splanchnic oxygenation ratio (CSOR) were recorded before, during, and after cPT discontinuation. We found that rSO2S, FOES, and CSOR did not change during the study period. The overall duration of single or multiple courses of PT was 6.5 (6.0–13.5) h, but by cycling PT, the actual exposure was 3.0 (1.5–4.9) h. Twelve patients (75%) required 15 min/h cPT, and four (25%) required prolonging cPT to 30 min/h. None of the patients developed enteral feeding intolerance.Conclusions: cPT treatment of hyperbilirubinemia in preterm infants does not affect splanchnic oxygenation or intestinal oxygen blood extraction, likely due to the short exposure to PT light, and it could contribute to decreasing the risk of feeding intolerance.What is Known:• The assumption that phototherapy (PT) is innocuous with no serious adverse effects has been questioned.• Cyclic phototherapy (cPT) can achieve a reduction in total serum bilirubin comparable to that achieved with standard continuous PT in preterm infants.What is New:• Splanchnic and cerebral oxygenation measured by near-infrared spectroscopy did not change during KMC.• cPT can contribute to decrease the risk of feeding intolerance likely due to the short exposure to PT light.

Creative puppet therapy reduces hallucinations in patients diagnosed with schizophrenia: Preliminary findings

Anomalous experiences and hallucinations characterize schizophrenia. This study aimed at determining the efficacy of creative puppet therapy (CPT; creation of a puppet with malleable DAS) to reduce severe anomalous experiences and hallucinations among patients diagnosed with schizophrenia. Double-blinded, controlled trials were performed on a convenience sample of 24 patients from a mental health center. The intervention group of 12 patients (who created puppets) and the pseudo-treatment group of 12 patients (who were involved in outdoor leisure trips) were compared to the control group of 12 control participants (who created puppets). Cardiff Anomalous Perceptions Scale (CAPS) assessed hallucinations; Emotional Expression Inventory (EEXI) assessed the emotional expression of one's own puppet. Puppet facial features were measured. Results showed that CPT effectively reduced (d = –4.00) hallucination frequency in patients. Hallucination reduction occurred across all sensory modalities, but touch and bodily interoception. Exteroceptive vs. interoceptive hallucinations was the most valuable classification in patients. Compared to controls, puppets created by patients expressed more negative emotions and had larger eye diameters, shorter noses, and larger whole face width. Eye diameter was correlated with fear, sadness, anger, and disgust, and whole face width with boredom. Fragmented-self integration of schizophrenia through CPT treatment might exploit aggregative dominance of the patient's own body.

Functional correlation between WRN and SAMHD1 in DNA end-resection.

Double-strand breaks (DSBs) can cause chromosome rearrangements, leading to cancer and some genetic diseases. WRN and SAMHD1 are proteins implicated in DSB processing and form a complex. Our study shows that SAMHD1 influences the nuclear recruitment of WRN in response to CPT-induced DSBs. Silencing SAMHD1 restores single-stranded DNA formation in WRN-deficient cells. However, DSB accumulation from CPT treatment is not recovered in WRN S1133A or WS cells when SAMHD1 is silenced. This suggests SAMHD1 cooperates with WRN in DNA damage repair and may have additional protective roles when WRN function in DSBs processing is impaired.

A phase II trial of gemcitabine and erlotinib followed by ChemoProton therapy plus capecitabine and oxaliplatin for locally advanced pancreatic cancer.

BackgroundEpidermal growth factor receptor (EGFR) is overexpressed in pancreatic cancer. EGFR expression plays a potentially important role in modulation of tumor sensitivity to either chemotherapy or radiotherapy. Erlotinib is a receptor tyrosine kinase inhibitor with specificity for EGFR/HER1. A phase II trial was conducted to explore the efficacy of a regimen utilizing erlotinib and proton therapy.MethodsPatients with unresectable or borderline resectable non-metastatic adenocarcinoma of the pancreas were included. Patients received 8-week systemic treatment with gemcitabine 1,000 mg/m2 and erlotinib 100 mg (GE). If there was no evidence of metastatic disease after GE, then patients preceded with proton therapy to 50.4 Gy in 28 fractions with concurrent capecitabine 825 mg/m2 (CPT). This was followed with oxaliplatin 130 mg/m2 and capecitabine 1,000 mg/m2 (CapOx) for 4 cycles. The primary study objective was 1-year overall survival (OS). The benchmark was 43% 1-year survival as demonstrated in RTOG/NRG 98-12. The Kaplan-Meier method was used to estimate the one-year OS and the median OS and progression-free survival (PFS).ResultsThe study enrolled 9 patients ages 47–81 years old (median 62) between January 2013 and March 2016, when the trial was closed due to low patient accrual. The 1-year OS rate was 55.6% (95% CI: 31% to 99%). The median OS was 14.1 months (95% CI: 11.4–NE) and the median PFS was 10.8 months (95% CI: 7.44–NE). A majority of patients completed CPT and GE, but only 33.3% completed the four cycles of CapOx. A third of patients experienced grade 3 toxicities, which were all hepatic along with one patient who also had grade 3 diarrhea. There were no grade 4 or 5 toxicities. Four patients were enrolled with borderline resectable disease, three of which were eligible for pancreaticoduodenectomy after GE and CPT treatment. One of two patients who underwent resection had a negative margin.ConclusionsThis regimen for locally advanced pancreatic cancer (LAPC) exceeded the pre-specified benchmark and was safe and well tolerated. Additional investigations utilizing more current systemic treatment regimens with proton therapy are warranted.Trial RegistrationClinicalTrials.gov identifier (NCTNCT01683422).

Cyclocarya paliurus triterpenoids suppress hepatic gluconeogenesis via AMPK-mediated cAMP/PKA/CREB pathway

BackgroundAbnormal enhancement of hepatic gluconeogenesis is a vital mechanism of the pathogenesis of Type 2 diabetes mellitus (T2DM); thus, its suppression may present an efficient therapeutic strategy for T2DM. Cyclocarya paliurus (CP), a plant species native to China, has been reported to have anti-hyperglycemia activity. Our previous studies have revealed that Cyclocarya paliurus triterpenic acids (CPT) exert the favorable glucose-lowering activity, but the regulatory effect of CPT on hepatic gluconeogenesis is still unclarified. PurposeThis study aimed to investigate the potential role and mechanism of CPT in gluconeogenesis. Study designIn this study, the ameliorative effect and underlying mechanism of CPT on gluconeogenesis were investigated: high-fat diet and streptozotocin-induced T2DM mice and glucagon-challenged mouse primary hepatocytes. MethodsT2DM model mice with or without oral administration of CPT for 4 weeks were monitored for body weight, glucose and lipid metabolism. Hematoxylin and eosin staining was used to observe liver lipid deposition. Real-time PCR assays were performed to examine the mRNA expression of glucose-6-phosphate (G6Pase), and phosphoenolpyruvate carboxykinase (PEPCK), two key enzymes involved in liver gluconeogenesis. Western blotting was used to determine AMP-dependent protein kinase (AMPK) expression and induction of the glucagon signaling pathway. The possible mechanism of CPT on liver gluconeogenesis was further explored in glucagon-induced mouse primary hepatocytes. ResultsIn vivo and in vitro experiments revealed that CPT treatment significantly reduced fasting blood glucose, total cholesterol and triglyceride levels, and improved insulin resistance. Furthermore, CPT could obviously decreased the mRNA and protein expression of G6Pase and PEPCK, the cyclic AMP content, the phosphorylation level of protein kinase A and cyclic AMP response element-binding protein. But CPT promoted the phosphorylation of AMP-dependent protein kinase (AMPK) and activation of phosphodiesterase 4B. Mechanistically, intervention with Compound C (an AMPK inhibitor) partially blocked the suppressive effect of CPT on hepatic gluconeogenesis. ConclusionThese findings suggested that CPT may inhibit hepatic gluconeogenesis against T2DM by activating AMPK.

Cryptotanshinone ameliorates CUS-induced depressive-like behaviors in mice

ObjectivesCryptotanshinone (CPT), a natural quinoid diterpene, isolated from Salvia miltiorrhiza, has shown various pharmacological properties. However, its effect on chronic unpredictable stress (CUS)-induced depression phenotypes and the underlying mechanism remain unclear. Therefore, the aim of this study was to investigate whether CPT could exert an antidepressant effect.MethodsWe investigated the effects of CPT in a CUS-induced depression model and explored whether these effects were related to the anti-inflammatory and neurogenesis promoting properties by investigating the expression levels of various signaling molecules at the mRNA and protein levels.ResultsAdministration of CPT improved depression-like behaviors in CUS-induced mice. CPT administration increased the levels of doublecortin-positive cells and reversed the decrease in the expression levels of brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) signaling transduction, as well as the downstream functional proteins, phosphorylated extracellular regulated protein kinases (p-ERK), and cyclic adenosine monophosphate (cAMP)-response element-binding protein levels (p-CREB) in hippocampus. CPT treatment also inhibited the activation of microglia and suppressed M1 microglial polarization, while promoting M2 microglial polarization by monitoring the expression levels of arginase 1 (Arg-1) and inducible nitric oxide synthase (iNOS), and further inhibited the expression of proinflammatory cytokines, including interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNF-α), and increased the expression of the anti-inflammatory cytokine IL-10 by regulating nuclear factor-κB (NF-κB) activation.ConclusionsCPT relieves the depressive-like state in CUS-induced mice by enhancing neurogenesis and inhibiting inflammation through the BDNF/TrkB and NF-κB pathways and could therefore serve as a promising candidate for the treatment of depression.

Potential anticancer effects of cyclo(-Pro-Tyr) against N-diethyl nitrosamine induced hepatocellular carcinoma in mouse through PI3K/AKT signaling.

The oceans are considered as magnificent source of bioactive metabolites, of which marine sponges associated organisms are being the most effective producers of various bioactive molecules. We previously reported that cyclo(-Pro-Tyr) (CPT), a dipeptide from marine sponge Callyspongia fistularis associated Bacillus pumilus AMK1 bacteria for its anti-proliferative activity through down regulating PI3K signaling and inducing mitochondrial mediated apoptosis in HepG2 cells. Further we emphasize to study the role of CPT against hepatocellular carcinoma (HCC) induced by N-diethylnitrosamine (DEN) in male swiss albino mice in vivo. In this study, HCC was induced by the administration of DEN (75 mg/kg b.wt) dissolved in saline once/week for 3 weeks, then 100 mg/kg b.wt for another successive 3 weeks and observed for 18 weeks. CPT (100 mg/kg b.wt) treatment was started after 14 weeks of DEN induction. The obtained results demonstrated that CPT altered DEN induced oxidative stress by decreasing serum SGOT and SGPT followed increment in the antioxidants such as superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase. This was accompanied by decreased accumulation of glycoconjugates and argyophilic nucleolar organizing regions in the treatment groups. Further, CPT significantly reduced the levels of phospho-PI3Kinase p85 and phospho-AKT and upregulation of PTEN compared with DEN induced group. Besides this, decreased expression of Bcl-2 and increased expression of Bax, Caspase 3, and p53 was observed in CPT treated mice. Therefore, the anticancer mechanism of CPT against DEN induced HCC may be associated with the regulation of the PI3K/AKT signaling pathway, which ultimately stimulates apoptosis.

The Role of Convalescent Plasma and Tocilizumab in the Management of COVID-19 Infection: A Cohort of 110 Patients from a Tertiary Care Hospital in Oman

AimAs Coronavirus Disease-2019 (COVID-19) pandemic continues to evolve, the search for safe and effective therapeutic interventions remain essential.MethodsWe conducted a retrospective cohort study on patients hospitalized with laboratory confirmed severe acute respiratory syndrome coronavirus-2 infection, comparing standard of care along with Convalescent Plasma with or without Tocilizumab (CP vs. CPT).ResultsA total of 110 patients were enrolled with an overall mean age of 50 ± 16 years. Patients on CPT were more likely to have had acute respiratory distress syndrome (77% vs. 42%; p < 0.001), sepsis (9.7% vs. 0; p = 0.036), chest X-ray abnormalities (71% vs. 44%; p = 0.004), intensive care unit admission (84% vs. 56%; p = 0.001) as well as being on mechanical ventilation (79% vs. 48%; p = 0.001). After CPT treatment, all measured inflammatory markers, except interleukine-6, showed an overall steady decline over time (all p-values <0.05) and the ventilatory parameters showed significant improvement of PaO2/FiO2 ratio from 127 to 188 within 7 days (p < 0.001). Additionally, 52% (32/62) of the patients had favorable outcome, either as improvement of ventilatory parameters or extubation within 14 days of hospitalization. However, mortality rate in those on CPT was higher than those who received CP alone (24% vs. 8.3%; p = 0.041).ConclusionIn patients with severe COVID-19 infection, using tocilizumab with convalescent plasma is associated with improvement in inflammatory and ventilatory parameters but no effect on mortality. These findings require validation from randomized clinical trials.

Cryptotanshinone reverses the epithelial-mesenchymal transformation process and attenuates bleomycin-induced pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fibrotic interstitial pneumonia that causes pulmonary tissue damage and functional impairment. To investigate the effects of cryptotanshinone on pulmonary fibrosis, the expression of NIH/3T3, HPF, and rat primary pulmonary fibroblasts was measured and found to be inhibited by CPT in a time- and concentration-dependent manner, and the upregulation of α-SMA expression in NIH/3T3 and HPF cells, which had been stimulated by TGFβ-1, was decreased after CPT administration. We observed that CPT could reverse the increase in α-SMA expression and vimentin and the decrease in E-cad expression in A549 cells, which had been induced by 5 ng/mL TGFβ-1, indicating that CPT has inhibitory effects in the EMT process. A BLM-induced pulmonary fibrosis model was established in C57BL/6 mice. The lung coefficient and hydroxyproline content increased significantly in the BLM-induced group and were decreased in the CPT-treated group. The expression levels of collagen-I and α-SMA and the phosphorylation level of Stat3 were significantly increased, and CPT treatment decreased these levels. Furthermore, the results from the flow cytometry analysis indicated that, in lung tissues, the frequencies of MDSCs, macrophages, DCs and T cells were considerably increased in the BLM-induced group, while CPT treatment reduced these immunocyte populations.

Cryptotanshinone from Salvia miltiorrhiza Bunge (Danshen) inhibited inflammatory responses via TLR4/MyD88 signaling pathway

BackgroundCryptotanshinone (CPT), as a major component of Salvia miltiorrhiza Bunge (Danshen), displays many pharmacological activities including anti-inflammatory effects. However, the exact cellular and molecular mechanisms of the anti-inflammatory activities of CPT remain to be elucidated. The present study was aimed to clarify its mechanisms on lipopolysaccharide (LPS)-induced inflammatory responses in mouse macrophages, RAW264.7 cells.MethodsIn the current study, the anti-inflammatory properties of CPT were evaluated using LPS-stimulated RAW264.7 cell model. MTT assay was used to determine the viability of RAW264.7 cells. The anti-inflammatory effects of CPT were measured based on the detection of nitric oxide (NO) production (Griess and flow cytometry assay), and tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) release (ELISA). Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) enzyme expressions were also determined by western blotting. Besides, by using flow cytometry, we also evaluated the effect of CPT on LPS-induced calcium influx. Finally, the underlying anti-inflammatory mechanisms of CPT were investigated using western blotting to assess the protein levels of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), phosphatidylinositol 3-kinase (PI3K)/AKT, nuclear factor erythroid 2 related factor 2 (Nrf2), mitogen-activated protein kinase (MAPK), and nuclear factor-kappa B (NF-κB) pathways.ResultsOur data showed that CPT inhibited LPS-induced pro-inflammatory cytokine release like IL-6, and TNF-α, as well as NO production. It displayed a significant inhibitory effect on the protein expressions such as iNOS, COX-2, NF-κB pathway like inhibitor of kappa B kinase (IKK)α/β, inhibitor of kappa B (IκB)-α and NF-κB/p65, PI3K/AKT pathway like PI3K and AKT, and MAPK pathway like c-Jun N-terminal kinase (JNK)1/2, extracellular signal-regulated kinase (ERK)1/2, and p38, in LPS-stimulated RAW264.7 macrophages. Moreover, the immunofluorescence results indicated that CPT suppressed NF-κB/p65 translocation from the cytoplasm into the nucleus. Further investigations showed that CPT treatment increased NAD(P)H quinone oxidoreductase-1 (NQO1) and heme oxygenase-1 (HO-1) expressions together with its upstream mediator, Nrf2. In addition, CPT inhibited LPS-induced toll-like receptor 4 (TLR4) and MyD88 expressions in RAW264.7 macrophages.ConclusionsCollectively, we suggested that CPT exerted significant anti-inflammatory effects via modulating TLR4-MyD88/PI3K/Nrf2 and TLR4-MyD88/NF-κB/MAPK pathways.

Cyclocarya paliurus Triterpenoids Improve Diabetes-Induced Hepatic Inflammation via the Rho-Kinase-Dependent Pathway.

This study aimed to assess the effects of triterpene extract of Cyclocarya paliurus (Batal.) Iljinskaja (CPT) on diabetes-induced hepatic inflammation and to unveil the underlying mechanisms. Diabetes in db/db mice was alleviated after CPT administration, as assessed by the oral glucose tolerance test. In addition, treatment with CPT dramatically reduced serum insulin, aspartate amino-transaminase, alanine aminotransferase, triglyceride, and total cholesterol amounts. Besides, serum levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α were also reduced after CPT administration. Western blot analysis revealed that CPT treatment significantly reversed the protein expression levels of Rho, ROCK1, ROCK2, p-P65, p-IκBα, p-IKKα, and p-IKKβ in liver samples obtained from db/db mice. Upon palmitic acid stimulation, the protective effects of CPT on the liver were further assessed in HepG2 and LO2 cells, and no appreciable cytotoxic effects were found. Therefore, these findings indicate that CPT alleviates liver inflammation via Rho-kinase signaling. Chemical compounds evaluated in this report: Metformin (PubChem CID: 4091); Fasudil (PubChem CID: 3547); Palmitic acid (PubChem CID: 985).

Vimentin activation in early apoptotic cancer cells errands survival pathways during DNA damage inducer CPT treatment in colon carcinoma model

Epithelial to mesenchymal transitions (EMT) is a preparatory process for cancer cells to attain motility and further metastasis to distant sites. Majority of DNA damaging drugs have shown to develop EMT as one of the major mechanisms to attain drug resistance. Here we sought to understand the resistance/survival instincts of cancer cells during initial phase of drug treatment. We provide a tangible evidence of stimulation of EMT factors in Apc knockout colorectal carcinoma model. Our results implied that CPT-treated Apc knockout cohorts depicted increased pro-invasive and pro-survival factors (Vimentin/pser38Vimentin & NFκB). Moreover, by cell sorting experiment, we have observed the expression of Vimentin in early apoptotic cells (AnnexinV positive) from 36 to 48 h of CPT treatment. We also observed the expression of chimeric Sec-AnnexinV-mvenus protein in migrated cells on transwell membrane recapitulating signatures of early apoptosis. Notably, induction of Vimentin-mediated signaling (by CPT) delayed apoptosis progression in cells conferring survival responses by modulating the promoter activity of NFκB. Furthermore, our results unveiled a novel link between Vimentin and ATM signaling, orchestrated via binding interaction between Vimentin and ATM kinase. Finally, we observed a significant alteration of crypt-villus morphology upon combination of DIM (EMT inhibitor) with CPT nullified the background EMT signals thus improving the efficacy of the DNA damaging agent. Thus, our findings revealed a resistance strategy of cancer cells within a very initial period of drug treatment by activating EMT program, which hinders the cancer cells to achieve later phases of apoptosis thus increasing the chances of early migration.

RAD51 regulates REV1 recruitment to DNA double-strand break sites

REV1 is one of the major Y-family DNA polymerases. It not only functions as a scaffold protein to mediate other specialized DNA polymerases to sites of lesions, but also inserts deoxycytidine across the lesion strand during translesion DNA synthesis (TLS). Meanwhile, REV1 has been reported to be involved in homologous recombination (HR) repair. Here we further explore the roles of REV1-interacting proteins RAD51 and RAD51C in REV1-mediated DNA double-strand break (DSB) repair. We found that RAD51 but not RAD51C regulates REV1 recruitment to DSB sites via pulsed laser microirradiation. Interestingly, immunofluorescence staining exhibits that REV1 also regulates RAD51 focus formation in response to CPT treatment. These results suggest that REV1 and RAD51 might be mutually dependent on each other in the REV1-related HR pathway.

Efficacy of Ceftaroline against Methicillin-Susceptible Staphylococcus aureus Exhibiting the Cefazolin High-Inoculum Effect in a Rat Model of Endocarditis.

Certain Staphylococcus aureus strains exhibit an inoculum effect (InE) with cefazolin (CFZ) that has been associated with therapeutic failures in high-inoculum infections. We assessed the in vitro activities of ceftaroline (CPT), CFZ, and nafcillin (NAF) against 17 type A β-lactamase (βla)-producing, methicillin-susceptible S. aureus (MSSA) strains, including the previously reported TX0117, which exhibits the CFZ InE, and its βla-cured derivative, TX0117c. Additionally, we determined the pharmacokinetics of CPT in rats after single intramuscular doses of 20 and 40 mg/kg of body weight and evaluated the activities of CPT (40 mg/kg every 8 h [q8h]), CFZ, and NAF against TX0117 and TX0117c in a rat model of infective endocarditis. No InE was observed for CPT or NAF, whereas a marked InE was detected for CFZ (MIC, 8 to ≥128 μg/ml). CPT and NAF treatment against TX0117 resulted in mean bacterial counts of 2.3 and 2.1 log10 CFU/g in vegetations, respectively, compared to a mean of 5.9 log10 CFU/g in the CFZ-treated group (CPT and NAF versus CFZ, P = 0.001; CPT versus NAF, P = 0.9830). Both CFZ and CPT were efficacious against the βla-cured derivative, TX0117c, compared to time zero (t0) (P = <0.0001 and 0.0015, respectively). Our data reiterate the in vivo consequences of the CFZ InE and show that CPT is not affected by this phenomenon. CPT might be considered for high-inoculum infections caused by MSSA exhibiting the CFZ InE.

Fidelity to the Cognitive Processing Therapy Protocol: Evaluation of Critical Elements

The contributions of individual therapy elements to the overall efficacy of evidence-based practices for the treatment of posttraumatic stress disorder (PTSD) are not well-understood. This study first examined the extent to which theoretically important treatment components of Cognitive Processing Therapy (CPT; i.e., skill in Socratic questioning; prioritizing assimilation; attention to practice assignments; emphasis on expression of natural affect) were successfully administered across the course of therapy for 68 PTSD-positive survivors of interpersonal trauma. Therapist fidelity in the administration of these four elements was evaluated in 533 taped CPT sessions of study participants included in one of two randomized controlled CPT treatment trials. Second, we examined therapist fidelity to these components as a predictor of session-to-session PTSD and depression symptom change. Third, follow-up analyses examined the influence of high therapist competence for these four components across an entire course of therapy on symptom change from pre- to posttreatment. Results showed consistently high adherence and more variable competence for these four treatment components. There were no significant effects of therapist fidelity on session-to-session symptom change. However, results showed that overall high therapist competence for “skill in Socratic questioning” and “prioritizing assimilation before overaccommodation” were related to greater client improvement in PTSD severity, but “attention to practice assignments” and “emphasis on expression of natural affect” were not. Overall competence ratings for the four components were not significantly associated with improvement in depressive symptoms. Findings contribute to increased understanding of the relationship between the key treatment components of CPT and symptom change.

Abstract TP92: Prevalence of Aortic Aneurysms in Patients With Intracranial Aneurysms: A Retrospective Analysis

Introduction: Intracranial (IA) and aortic aneurysms (AA) share genetic and environmental risks. In a retrospective review of clinical data, we identified those presenting with IA (+/- subarachnoid hemorrhage), who also had abdominal or thoracic imaging. Method: In the University of Virginia (UVA) Clinical Data Repository we searched for patients with IA by ICD-9 diagnosis codes and CPT treatment codes. We used three strategies to identify those with aortic imaging: 1) ICD-9 diagnosis codes for AA, 2) CPT and billing codes for abdominal or thoracic imaging (aortogram, ultrasound, angiography, magnetic resonance, and computerized tomography), and 3) CPT and billing codes for AA treatment (endovascular, stent, graft, wrap, or screening). We reviewed all charts to identify those with confirmed IA and imaging. We performed a multivariable logistic regression analysis accounting for sex, age, hypertension, diabetes mellitus, smoking status, and IA size, multiplicity, and location to look for associations with AA. Results: Among individuals seen at UVA hospital from 2004 to 2015, we identified 13245 cases with a possible IA, of whom 1017 potential aortic imaging. Our review of charts revealed that 720 did not having an IA. Of the remaining 287 cases, 51 lacked appropriate aortic imaging. We recorded information from the remaining 236 cases - 94/236 (39.8%) had an AA identified. In our multivariable analysis, only female sex was significantly associated with a co-prevalent AA (Odds Ratio: 0.20, 95% confidence interval 0.09 - 0.45). In the table, we provide descriptive statistics for those with and without AA as well as the subsets with thoracic aortic aneurysms (TAA) and abdominal aortic aneurysms (AAA). Conclusion: The co-prevalence of AA in a clinical population known to have IA and with aortic imaging was 39.8%. Men had higher risk for AA. This indicates a shared risk for aneurismal disease in the aorta and brain warranting prospective investigation on the mechanisms of risk.

An Acetamide Derivative as a Camptothecin Sensitizer for Human Non-Small-Cell Lung Cancer Cells through Increased Oxidative Stress and JNK Activation.

In recent years, combination chemotherapy is a primary strategy for treating lung cancer; however, the issues of antagonism and side effects still limit its applications. The development of chemosensitizer aims to sensitize chemoresistant cancer cells to anticancer drugs and therefore improve the efficacy of chemotherapy. In this study, we examined whether N-[2-(morpholin-4-yl)phenyl]-2-{8-oxatricyclo[7.4.0.0,2,7]trideca-1(9),2(7),3,5,10,12-hexaen-4-yloxy}acetamide (NPOA), an acetamide derivative, sensitizes human non-small-cell lung cancer (NSCLC) H1299 cells towards camptothecin- (CPT-) induced apoptosis effects. Our results demonstrate that the combination of CPT and NPOA enhances anti-lung-cancer effect. The cytometer-based Annexin V/propidium iodide (PI) staining showed that CPT and NPOA cotreatment causes an increased population of apoptotic cells compared to CPT treatment alone. Moreover, Western blotting assay showed an enhancement of Bax expression and caspase cascade leading to cell death of H1299 cells. Besides, CPT and NPOA cotreatment-mediated disruption of mitochondrial membrane potential (MMP) in H1299 cells may function through increasing the activation of the stressed-associated c-Jun N-terminal kinase (JNK). These results showed that NPOA treatment sensitizes H1299 cells towards CPT-induced accumulation of cell cycle S phase and mitochondrial-mediated apoptosis through regulating endogenous ROS and JNK activation. Accordingly, NPOA could be a candidate chemosensitizer of CPT derivative agents such as irinotecan or topotecan in the future.

FBH1 Catalyzes Regression of Stalled Replication Forks.

DNA replication fork perturbation is a major challenge to the maintenance of genome integrity. It has been suggested that processing of stalled forks might involve fork regression, in which the fork reverses and the two nascent DNA strands anneal. Here, we show that FBH1 catalyzes regression of a model replication fork invitro and promotes fork regression invivo in response to replication perturbation. Cells respond to fork stalling by activating checkpoint responses requiring signaling through stress-activated protein kinases. Importantly, we show that FBH1, through its helicase activity, is required for early phosphorylation of ATM substrates such as CHK2 and CtIP as well as hyperphosphorylation of RPA. These phosphorylations occur prior to apparent DNA double-strand break formation. Furthermore, FBH1-dependent signaling promotes checkpoint control and preserves genome integrity. We propose a model whereby FBH1 promotes early checkpoint signaling by remodeling of stalled DNA replication forks.

Group psychotherapy's impact on trust in veterans with PTSD: a pilot study.

Interpersonal trust is fundamental for the recovery of trauma survivors and the effectiveness of group psychotherapy. Yet there is limited research on the relationship between interpersonal trust and group psychotherapy. Twenty-one male Vietnam combat veterans with posttraumatic stress disorder (PTSD) (6 in a long-term process group [LTP], 10 in a short-term cognitive processing therapy group [CPT], and 5 treatment-as-usual controls) were evaluated before and after group psychotherapy using the Posttraumatic Stress Disorder Checklist-Military Version (PCL-M) and an in-vivo measure of interpersonal trust, the Iterated Trust Game. Three (14.3%) of the veterans were African American, 9 were Caucasian (42.9%), and 9 were Hispanic (42.9%); they averaged 61.9 years of age (SD = 1.8 years). Change in PCL-M scores differed by group (controls: -1.0 ± 3.7; CPT: -15.5 ± 6.8; LTP: -1.3 ± 12.2; p = .003). CPT group subjects improved more than controls (p < .001) and trended toward more improvement than the LTP group (p = .081). Members of the LTP group, compared to nonprocess group participants, showed greater initial (p = .042), and posttherapy trust (p = .003). Posttreatment, interpersonal trust was significantly higher in the LTP than the CPT group (p < .001). These results suggest that CPT treatment may be better than LTP treatment for improving PTSD symptoms, but LTP therapy may be better than CPT therapy for improving interpersonal trust in veterans with PTSD. They suggest important roles for both group treatments and point to the value of interpersonal trust in successful recovery from PTSD.

Angiotensin II–Converting Enzyme Inhibition Improves Survival, Ventricular Remodeling, and Myocardial Energetics in Experimental Aortic Regurgitation

Aortic valve regurgitation (AR) is a volume-overload disease causing severe eccentric left ventricular (LV) hypertrophy and eventually heart failure. There is currently no approved drug to treat patients with AR. Many vasodilators including angiotensin-converting enzyme inhibitors have been evaluated in clinical trials, but although some results were promising, others were inconclusive. Overall, no drug has yet been able to improve clinical outcome in AR and the controversy remains. We have previously shown in an animal model that captopril (Cpt) reduced LV hypertrophy and protected LV systolic function, but we had not evaluated the clinical outcome. This protocol was designed to evaluate the effects of a long-term Cpt treatment on survival in the same animal model of severe aortic valve regurgitation. Forty Wistar rats with AR were treated or untreated with Cpt (1 g/L in drinking water) for a period of 7 months to evaluate survival, myocardial remodeling, and function by echocardiography as well as myocardial metabolism by µ positron emission tomography scan. Survival was significantly improved in Cpt-treated animals with a survival benefit visible as soon as after 4 months of treatment. Cpt reduced LV dilatation and LV hypertrophy. It also significantly improved the myocardial metabolic profile by restoring the level of fatty acids metabolic enzymes and use. In a controlled animal model of pure severe aortic valve regurgitation, Cpt treatment reduced LV remodeling and LV hypertrophy and improved myocardial metabolic profile and survival. These results support the need to reevaluate the role of angiotensin-converting enzyme inhibitors in humans with AR in a large, carefully designed prospective clinical trial.