Refractoriness of acute myeloid leukemia (AML) cells to chemotherapeutics represents a major clinical barrier. Suicide gene therapy for cancer has been attractive but with limited clinical efficacy. In this study, we investigated the potential application of herpes simplex virus thymidine kinase/ganciclovir (HSV-TK/GCV) based system to inhibit chemoresistant AML cells. We first generated Ara-C resistant K562 cells and doxorubicin-resistant THP-1 cells. We found that the HSV-TK/GCV anticancer system suppressed drug resistant leukemic cells in culture. Chemoresistant AML cell lines displayed similar sensitivity to HSV-TK/GCV. Moreover, HSV-TK/GCV killing of leukemic cells was augmented to a mild but significant extent by all-trans retinoic acid (ATRA) with concomitant upregulation of Connexin 43, a major component of gap junctions. Interestingly, HSV-TK/GCV killing was enhanced by expression of vesicular stomatitis virus G glycoprotein (VSV-G), a fusogenic membrane protein, which also increased leukemic cell fusion. Co-culture resistant cells expressing HSV-TK and cells stably transduced with VSV-G showed that expression of VSV-G could promote the bystander killing effect of HSV-TK/GCV. Furthermore, combination of HSV-TK/GCV with VSV-G plus ATRA produced more pronounced antileukemia effect. These results suggest that the HSV-TK/GCV system in combination with fusogenic membrane proteins and/or ATRA could provide a strategy to mitigate the chemoresistance of AML.
Cell Fusion ; Cell Line ; Coculture Techniques ; Connexin 43 ; Cytarabine ; Gap Junctions ; Genetic Therapy ; Glycoproteins* ; Homicide* ; K562 Cells ; Leukemia, Myeloid, Acute ; Membrane Proteins ; Simplexvirus* ; Suicide ; Thymidine* ; Tretinoin ; Up-Regulation ; Vesicular Stomatitis*

Objective:To explore the clinical application value of pre-breathing mode in double-low imaging of 320-slices computed tomography(CT)for pulmonary artery.Methods:A total of 100 patients who underwent CT pulmonary angiography(CTPA)for suspected pulmonary embolism(PE)in Liuzhou People's Hospital from July 2021 to September 2022 were prospectively selected as the research subjects and they were randomly divided into observation group and control group,with 50 cases in each group.The patients of the control group adopted conventional breathing mode(the breathing password was activated after reaching the threshold,and the scan was triggered after 6 s),while the patients of the observation group adopted the pre-breathing mode(the breathing password was activated after 1 or 2 seconds,and the scan was triggered after reaching the threshold).Both two groups adopted double low-technique scan of 320 slices CT.The differences in delay time,radiation dose,the points of subjective and objective image quality,and other indicators were compared between the two groups.Results:The volume CT dose index(CTDIvol),dose length product(DLP),effective dose(ED)and delay time of the observation group were significantly lower than those of the control group(t=76.230,30.225,12.282,7.088,P<0.05),respectively.The comparison of the subjective points of image qualities between the two groups indicated that there were 25 cases with 5 points,23 cases with 4 points and 2 cases with 3 points in the observation group,and there were 21 cases with 5 points,26 cases with 4 points and 3 cases with 3 points in the control group.There was no significant difference in the averagely subjective points of image qualities between two groups(P>0.05).The signal-to-noise ratio(SNR)and signal to noise ratio(CNR)of the observation group were significantly lower than those of the control group,and the noise level(SD)of the observation group was significantly higher than that of the control group(t=25.441,23.886、11.426,P<0.05),respectively.The CT values of the artery trunk of right pulmonary,artery branch of right pulmonary,artery trunk of left pulmonary and artery branch of left pulmonary in the observation group were significantly higher than those in the control group(t=2.256,2.225,2.042,2.277,P<0.05),respectively.Conclusion:The pre-breathing mode can effectively improve CTPA image quality,and reduce radiation dose and the dosage of contrast agent,which clinical application effect is significant.It is worth learning.

Objective:To explore the efficacy and compliance of e-aid cognitive behavioral therapy (eCBTI) in patients with situational insomnia among different age groups.Methods:A total of 194 patients with situational insomnia were recruited via a campaign of the " Prevention and Protection Handbook Against Epidemic" from March to April 2020 in Guangzhou, China.Participants were divided into two groups according to age: under 35 years old ( n=87) and 35 years old and above ( n=107). They all received one-week eCBTI intervention.Insomnia severity index (ISI), Pre-sleep arousal scale (PSAS) and Hospital anxiety and depression scale (HADS) were used to evaluate the severity of insomnia for all participants pre- and post-intervention.The change of each scale within the group and the reduction rate of each scale between groups were compared using t test and one-way ANOVA. Results:(1) Intervention efficacy: in the <35-year-old group, compared with baseline, the scores of ISI scale ((9.2±4.1), (14.8±5.1)), PSAS cognitive arousal subscale ((18.5±8.4), (23.5±6.6)), PSAS((34.3±15.8), (40.3±10.7)), HADS depression subscale ((5.8±3.6), (8.5±4.6)) and HADS anxiety subscale((7.1±3.9), (9.5±4.5) )were statistically significant after eCBTI intervention ( t= 2.88-8.80, all P<0.01), but there was no significant difference in score of PSAS body subscale ((15.8±7.8), (16.8±5.7)). In ≥35-year-old group, compared with baseline, the scores of ISI scale ((9.7±4.2), (14.4±4.3)), HADS depression subscale ((4.6±2.2), (6.6±3.5))and PSAS cognitive arousal subscale ((16.9 ±8.5), (20.0±5.8))were significantly different after intervention ( t= 2.90-6.86, all P<0.01), meanwhile the scores of PSAS body subscale ((14.3±8.0), (13.9±5.2)), PSAS((32.2±16.5), (33.9±9.2)), HADS anxiety subscale((6.1±3.2), (7.0±3.5)) were not statistically significant (all P>0.05). There was no significant difference in the score reduction rate between the two groups before and after intervention (all P>0.05). (2) Compliance: 86 cases dropped out, and the dropout rate was 61.3%.Totally 75 cases (38.7%) completed the 7-day treatment, and 119 cases (61.3%) completed the treatment within 1-6 days.Further study found that there was statistically significant difference in the reduction rate of ISI total score among the three groups with excellent, good and poor compliance ( F=5.655, P=0.004). Conclusion:eCBTI has a good effect on situational insomnia in different age groups, and there is no difference in treatment compliance.

Hypoxia is a common feature of solid tumors. As transcription factors, hypoxia-inducible factors (HIFs) are the master regulators of the hypoxic microenvironment; their target genes function in tumorigenesis and tumor development. Intriguingly, both yes-associated protein (YAP) and its paralog transcriptional coactivator with a PDZ-binding motif (TAZ) play fundamental roles in the malignant progression of hypoxic tumors. As downstream effectors of the mammalian Hippo pathway, YAP and/or TAZ (YAP/TAZ) are phosphorylated and sequestered in the cytoplasm by the large tumor suppressor kinase 1/2 (LATS1/2)-MOB kinase activator 1 (MOB1) complex, which restricts the transcriptional activity of YAP/TAZ. However, dephosphorylated YAP/TAZ have the ability to translocate to the nucleus where they induce transcription of target genes, most of which are closely related to cancer. Herein we review the tumor-related signaling crosstalk between YAP/TAZ and hypoxia, describe current agents and therapeutic strategies targeting the hypoxia-YAP/TAZ axis, and highlight questions that might have a potential impact in the future.