The effect of e-cigarettes on cognitive function: a scoping review.

AIM: Much research has been conducted on the acute effects of nicotine on human cognitive performance, demonstrating both enhancing and impairing cognitive effects. With the relatively recent introduction of electronic cigarettes ('e-cigarettes') as a smoking cessation device, little is known about the cognitive effects of e-cigarettes specifically, either as a nicotine replacement device or in the absence of nicotine. The purpose of this review was to present an overview of evidence from empirical studies on the effect of e-cigarettes on cognitive function. APPROACH: Guided by Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews guidelines (PRISMA-ScR), SCOPUS, PubMed, and EBSCOhost were searched from 2006, the year e-cigarettes were introduced, to June 2023 for relevant papers, along with reference lists checked for additional papers. KEY FINDINGS: Seven experimental and four cross-sectional survey studies were identified and included. The majority of the studies only include regular and current cigarette smokers and primarily assessed the acute cognitive effect of e-cigarettes relative to nicotine. While the findings primarily suggest either no or positive effect of e-cigarettes on cognition in cigarette smokers, associations between e-cigarettes and cognitive impairments in memory, concentration and decision making were reported in both cigarette smokers and never-smokers. IMPLICATIONS AND CONCLUSIONS: The acute cognitive effect of e-cigarettes on regular cigarette smokers appears minimal. However, long-term cognitive effect and their effects on never-smokers are unclear. Given that the increased numbers of e-cigarette users are non-smokers and/or adolescents, research with those naïve to nicotine and a developmentally vulnerable adolescent population on its long-term effect is needed.

Interobserver Agreement Across Subspecialties for Diagnosis of Differentiated Vulvar Intraepithelial Neoplasia and Predictive Values of 20 Histologic Features.

CONTEXT.­: Differentiated vulvar intraepithelial neoplasia (dVIN) is a human papillomavirus-independent lesion with the potential for rapid progression to invasive squamous cell carcinoma (SCC). The histopathologic features of dVIN are diverse, have overlapping characteristics with lichen sclerosus (LS) and lichen simplex chronicus (LSC), and may be diagnosed by dermatopathologists or gynecologic pathologists because of the vulva's anatomic location. OBJECTIVES.­: To identify the salient histopathologic features of dVIN, particularly those that predict progression to SCC, and to evaluate interobserver agreement in diagnosing dVIN within the same subspecialty and across subspecialties. DESIGN.­: One general surgical pathologist, 2 pathology-trained dermatopathologists, and 1 gynecologic pathologist blinded to the final diagnoses were asked to record 20 histopathologic features and to provide their final interpretations on cases of dVIN (n = 65), LS (n = 126), LSC (n = 112), and LS with LSC (n = 6). RESULTS.­: Interobserver agreement for the 4 diagnoses and 10 histopathologic features was moderate. Logistic regression analysis indicated that keratin pearls, basal pleomorphism, and basal layer disarray were independent variables for diagnosing dVIN (coefficients 1.95, 1.97, and 0.91, respectively; P < .001) and progression to SCC (coefficients 1.96, 1.20, and 1.08, respectively; P < .001). CONCLUSIONS.­: There is no single histopathologic feature pathognomonic for dVIN; however, the presence of keratin pearls, basal pleomorphism, and basal layer disarray should raise high suspicion for dVIN and concurrent SCC. Expertise in both dermatologic and gynecologic pathology is beneficial for diagnosing dVIN.

p53/CK17 Dual Stain Improves Accuracy of Distinction Between Differentiated Vulvar Intraepithelial Neoplasia and Its Mimics.

Accurate diagnosis of differentiated vulvar intraepithelial neoplasia (dVIN) is challenging, in part due to the sometimes subtle nature of its atypia. Many dVIN lesions demonstrate aberrant p53 staining; however, staining patterns overlap between dVIN and benign/reactive entities. We evaluate a p53/CK17 dual stain in an initial cohort of dVIN (n=30), benign vulvar skin (n=5), lichen sclerosus (LS, n=10), lichen simplex chronicus (LSC, n=10), and pseudoepitheliomatous hyperplasia (PEH, n=10). In the initial cohort, aberrant p53 staining was seen only in dVIN (50%, 15/30). Equivocal p53 staining patterns were seen in dVIN (37%, 11/30), LS (50%, 5/10), LSC (40%, 4/10), and PEH (40%, 4/10). All 30 dVIN cases were positive for CK17 (strong partial-thickness or full-thickness staining), but positive CK17 staining was also seen in LS (70%, 7/10), LSC (50%, 5/10), and PEH (100%, 10/10). In the initial cohort, the combination of aberrant p53 and positive CK17 was seen only for dVIN (50%, 15/30). Forty cases of LS with known follow-up (20 with progression to dVIN, 20 without) were stained to assess prognostic value. Three LS cases showed aberrant p53 staining with CK17 positivity; all progressed to dVIN. Equivocal p53 staining and CK17 positivity were seen in cases with and without progression. The p53/CK17 dual stain is more diagnostically useful than either stain alone. Negative/focal staining for CK17 argues against a diagnosis of dVIN, while aberrant p53 staining with CK17 positivity strongly supports the diagnosis.

Expanding the Morphologic, Immunohistochemical, and HPV Genotypic Features of High-grade Squamous Intraepithelial Lesions of the Vulva With Morphology Mimicking Differentiated Vulvar Intraepithelial Neoplasia and/or Lichen Sclerosus.

Squamous cell carcinoma of the vulva can arise through 2 pathways: human papillomavirus (HPV)-dependent high-grade squamous intraepithelial lesions (previously termed usual vulvar intraepithelial neoplasia) or HPV-independent (differentiated vulvar intraepithelial neoplasia, dVIN). Distinguishing between the 2 types can be clinically and histologically difficult. A subset of high-grade squamous intraepithelial lesions with superimposed chronic inflammation mimicking dVIN has recently been reported; p53 shows characteristic mid-epithelial staining (with basal sparing) in such cases. The pathology databases of 2 academic institutions were searched for vulva specimens with corresponding p53 and p16 immunohistochemical stains, yielding 38 specimens (from 27 patients). In situ hybridization and multiplex polymerase chain reaction-MassArray for high-risk HPV were performed on at least 1 block from each patient. All cases resembled dVIN or lichen sclerosus morphologically, but with a higher degree of atypia. All but 1 case demonstrated mid-epithelial p53 staining with basal sparing by immunohistochemistry. All cases showed block positivity for p16 and at least patchy positivity by HPV in situ hybridization. Of the 23 cases with valid HPV DNA polymerase chain reaction results, 15 were positive and 8 were negative. Of the positive cases, HPV16 was identified in 10 cases, with other high-risk types in the remaining 5. To our knowledge, this is the largest cohort of high-grade squamous intraepithelial lesions mimicking dVIN reported to date. Prior studies reported positivity for HPV16 in all cases tested, however, we found HPV16 in only 67% of HPV positive cases. This case series highlights the importance of immunohistochemistry, and occasionally HPV in situ hybridization, for accurate diagnosis, and expands the spectrum of associated HPV types.

Primary Leiomyosarcoma of Bone: Review and Update.

CONTEXT.­: Leiomyosarcoma of bone is a rare primary osseous sarcoma characterized by smooth muscle differentiation and absence of malignant osteoid formation. Leiomyosarcoma of bone is diagnostically challenging; this can be improved with greater awareness of this entity and the ability to differentiate it from its histologic mimics. Because of its rarity, only a small number of studies are available in the literature. These factors contribute to our limited understanding of its pathology, prognosis, and treatment. OBJECTIVE.­: To review the clinicopathologic features of leiomyosarcoma of bone and present the most up-to-date understanding of its behavior and management in accordance with the current literature. DATA SOURCES.­: Review of pertinent literature on the major features, current knowledge thereof, and the authors' experience in the diagnosis and management of leiomyosarcoma of bone. CONCLUSIONS.­: Leiomyosarcoma of bone is a rare but well-recognized primary osseous sarcoma that may arise de novo or in association with radiation. Although it is diagnostically challenging, awareness of this rare sarcoma and knowledge of its key histomorphologic and immunohistochemical features allow for accurate diagnosis.

EWSR1-NFATC2 Translocation-associated Sarcoma Clinicopathologic Findings in a Rare Aggressive Primary Bone or Soft Tissue Tumor.

In recent years, a novel small round cell sarcoma harboring EWSR1-NFATC2 translocation with immunomorphologic overlap with Ewing sarcoma (ES), myoepithelial tumors, and extraskeletal myxoid chondrosarcoma has emerged. There has not been a case series devoted to describing its detailed clinicopathologic and immunohistochemical characteristics. Six sarcomas harboring EWSR1-NFATC2 fusion transcripts by reverse transcription polymerase chain reaction and amplification of the fusion gene by fluorescence in situ hybridization were identified. The patients were 5 adult men and 1 adult woman. Three were primary bone tumors of the radius and 3 were primary soft tissue tumors. Most tumors showed monomorphic round to epithelioid cells in anastomosing cords and abundant myxohyaline to collagenous extracellular matrix. Two tumors had large areas of a solid, matrix-poor histomorphology. All tumors stained for CD99 and NKX2.2; while EMA, dot-like cytokeratin, and focal WT-1 and SMA were present in some tumors. All but 1 tumor showed poor histologic and radiologic responses to neoadjuvant ES-specific chemotherapy. Local or distant recurrences happened in 4 cases. EWSR1-NFATC2 sarcoma is a novel translocation-associated sarcoma. It presents as either a primary bone or soft tissue tumor, usually exhibits distinctive histopathologic features, and has predilection for long bones of adult men. It consistently shows recurrent fusion gene amplification readily detectable by EWSR1 breakapart fluorescence in situ hybridization, which serves as a diagnostic surrogate. It has potential for local and distant recurrence and histologic progression, and is resistant to Ewing sarcoma-specific chemotherapy.

Dedifferentiated Liposarcoma With Myofibroblastic Differentiation.

CONTEXT.­: Liposarcoma is divided into myxoid, pleomorphic, well-differentiated, and dedifferentiated subtypes. Dedifferentiated liposarcoma displays the greatest histomorphologic diversity, including a subset with myofibroblastic differentiation that shares similarities with a spectrum of reactive, benign, and malignant soft tissue lesions. Misdiagnosis may lead to deleterious consequences, as dedifferentiated liposarcoma differs significantly in its prognosis and treatment from its mimics. OBJECTIVE.­: To review the clinicopathologic, immunohistochemical, and molecular features of the myofibroblastic variant of dedifferentiated liposarcoma as well as the key distinguishing features from its mimics. DATA SOURCES.­: Review of pertinent literature on major features and current understanding of dedifferentiated liposarcoma with myofibroblastic differentiation. CONCLUSIONS.­: The myofibroblastic variant of dedifferentiated liposarcoma is an uncommon and underrecognized sarcoma with several important differential diagnoses, and likely represents the major subset of aggressive retroperitoneal tumors that may have been misdiagnosed as desmoid-type fibromatosis, inflammatory myofibroblastic tumor, or another type of sarcoma in the past.

Interleukin-13 receptor alpha 2 cooperates with EGFRvIII signaling to promote glioblastoma multiforme.

The interleukin-13 receptor alpha2 (IL-13Rα2) is a cancer-associated receptor overexpressed in human glioblastoma multiforme (GBM). This receptor is undetectable in normal brain which makes it a highly suitable target for diagnostic and therapeutic purposes. However, the pathological role of this receptor in GBM remains to be established. Here we report that IL-13Rα2 alone induces invasiveness of human GBM cells without affecting their proliferation. In contrast, in the presence of the mutant EGFR (EGFRvIII), IL-13Rα2 promotes GBM cell proliferation in vitro and in vivo. Mechanistically, the cytoplasmic domain of IL-13Rα2 specifically binds to EGFRvIII, and this binding upregulates the tyrosine kinase activity of EGFRvIII and activates the RAS/RAF/MEK/ERK and STAT3 pathways. Our findings support the "To Go or To Grow" hypothesis whereby IL-13Rα2 serves as a molecular switch from invasion to proliferation, and suggest that targeting both receptors with STAT3 signaling inhibitor might be a therapeutic approach for the treatment of GBM.

Histologic Mimics of Basal Cell Carcinoma.

CONTEXT: - Basal cell carcinoma (BCC) is the most common human malignant neoplasm and is a frequently encountered diagnosis in dermatopathology. Although BCC may be locally destructive, it rarely metastasizes. Many diagnostic entities display morphologic and immunophenotypic overlap with BCC, including nonneoplastic processes, such as follicular induction over dermatofibroma; benign follicular tumors, such as trichoblastoma, trichoepithelioma, or basaloid follicular hamartoma; and malignant tumors, such as sebaceous carcinoma or Merkel cell carcinoma. Thus, misdiagnosis has significant potential to result in overtreatment or undertreatment. OBJECTIVE: - To review key features distinguishing BCC from histologic mimics, including current evidence regarding immunohistochemical markers useful for that distinction. DATA SOURCES: - Review of pertinent literature on BCC immunohistochemistry and differential diagnosis. CONCLUSIONS: - In most cases, BCC can be reliably diagnosed by histopathologic features. Immunohistochemistry may provide useful ancillary data in certain cases. Awareness of potential mimics is critical to avoid misdiagnosis and resulting inappropriate management.

Associations between immunological function and memory recall in healthy adults.

Studies in clinical and aging populations support associations between immunological function, cognition and mood, although these are not always in line with animal models. Moreover, very little is known about the relationship between immunological measures and cognition in healthy young adults. The present study tested associations between the state of immune system and memory recall in a group of relatively healthy adults. Immediate and delayed memory recall was assessed in 30 participants using the computerised cognitive battery. CD4, CD8 and CD69 subpopulations of lymphocytes, Interleukin-6 (IL-6) and cortisol were assessed with blood assays. Correlation analysis showed significant negative relationships between CD4 and the short and long delay memory measures. IL-6 showed a significant positive correlation with long-delay recall. Generalized linear models found associations between differences in all recall challenges and CD4. A multivariate generalized linear model including CD4 and IL-6 exhibited a stronger association. Results highlight the interactions between CD4 and IL-6 in relation to memory function. Further study is necessary to determine the underlying mechanisms of the associations between the state of immune system and cognitive performance.

Reduction in N2 amplitude in response to deviant drug-related stimuli during a two-choice oddball task in long-term heroin abstainers.

RATIONALE: Chronic heroin use can cause deficits in response inhibition, leading to a loss of control over drug use, particularly in the context of drug-related cues. Unfortunately, heightened incentive salience and motivational bias in response to drug-related cues may exist following abstinence from heroin use. OBJECTIVES: The present study aimed to examine the effect of drug-related cues on response inhibition in long-term heroin abstainers. METHODS: Sixteen long-term (8-24 months) male heroin abstainers and 16 male healthy controls completed a modified two-choice oddball paradigm, in which a neutral "chair" picture served as frequent standard stimuli; the neutral and drug-related pictures served as infrequent deviant stimuli of different conditions respectively. Event-related potentials were compared across groups and conditions. RESULTS: Our results showed that heroin abstainers exhibited smaller N2d amplitude (deviant minus standard) in the drug cue condition compared to the neutral condition, due to smaller drug-cue deviant-N2 amplitude compared to neutral deviant-N2. Moreover, heroin abstainers had smaller N2d amplitude compared with the healthy controls in the drug cue condition, due to the heroin abstainers having reduced deviant-N2 amplitude compared to standard-N2 in the drug cue condition, which reversed in the healthy controls. CONCLUSIONS: Our findings suggested that heroin addicts still show response inhibition deficits specifically for drug-related cues after longer-term abstinence. The inhibition-related N2 modulation for drug-related could be used as a novel electrophysiological index with clinical implications for assessing the risk of relapse and treatment outcome for heroin users.

Effect of drug-related cues on response inhibition through abstinence: A pilot study in male heroin abstainers.

BACKGROUND: Chronic heroin use can cause a deficit of inhibitory function, leading to a loss of control over drug use. Exposure to drug-related cues is considered as one of the contributing factors. However, it is unclear whether there are dynamic changes on the effect of drug-related cues on response inhibition following prolonged abstinence. OBJECTIVE: The present study investigated the effect of drug-related cues on response inhibition in heroin abstainers at different abstinent phases. METHODS: 26 shorter-term (2-6 months) and 26 longer-term (19-24 months) male heroin abstainers performed on a modified two-choice Oddball task, which included two conditions: in the cued condition, neutral pictures served as the background of standard stimuli (yellow frame) and heroin-related pictures served as the background of deviant stimuli (blue frame), reversed in the controlled conditions. RESULTS: Compared to longer-term abstainers, mean reaction time (RT) for drug deviants in shorter-term abstainers was significantly longer. Shorter-term abstainers also showed markedly slower response to neutral deviants relative to drug deviants, but this tendency was not observed in longer-term abstainers. Nevertheless, both groups had similar RT for standard stimuli regardless of their paired background pictures. CONCLUSION: Effect of drug-related cues on response inhibition remains at the early stage of abstinence; however, this effect may be reduced following a longer period of drug abstinence. Our findings highlight the importance of assessing and improving the ability of inhibiting drug-related cue reactivity during treatment.

Protein gene product 9.5 (PGP9.5) expression in benign cutaneous mesenchymal, histiocytic, and melanocytic lesions: comparison with cellular neurothekeoma.

Cellular neurothekeoma (CNTK) frequently enters the differential diagnosis of a benign dermal cellular proliferation. Diagnosis often relies on immunohistochemistry including the use of protein gene product 9.5 (PGP9.5). A previous study demonstrated PGP9.5 expression across a wide variety of soft tissue neoplasms. We explored the utility of this antibody in distinguishing CNTK from other benign dermal-based lesions. A cohort of CNTK (n=7) and benign cutaneous lesions of neural (n=28), fibrohistiocytic (n=23), fibroblastic (n=25), histiocytic (n=18), myofibroblastic (n=7), smooth muscle (n=14), and melanocytic (n=12) differentiations were immunostained with PGP9.5. Staining was graded by H-score and compared with CNTK. A significantly higher H-score was found in CNTK compared with the fibrohistiocytic (p=0.0001), histiocytic (p=0.0016), myofibroblastic (p=0.0003), smooth muscle (p<0.0001), and melanocytic (p=0.0004) groups, with the exceptions of plexiform fibrohistiocytic tumour, xanthoma, and xanthogranuloma. No significant difference was found when comparing CNTK with fibroblastic and neural lesions, with the exceptions of neurofibroma and perineurioma. In conclusion, PGP9.5 is helpful in distinguishing CNTK from most benign cutaneous fibrohistiocytic, histiocytic, myofibroblastic, smooth muscle, and melanocytic lesions. In addition to CNTK and neural lesions, PGP9.5 is also expressed in benign fibroblastic lesions, and therefore distinction of these lesions should not be based on PGP9.5 positivity.

PI3K-AKT signaling is a downstream effector of retinoid prevention of murine basal cell carcinogenesis.

Basal cell carcinoma (BCC) is the most common human cancer. We have demonstrated previously that topical application of the retinoid prodrug tazarotene profoundly inhibits murine BCC carcinogenesis via retinoic acid receptor γ-mediated regulation of tumor cell transcription. Because topical retinoids can cause adverse cutaneous effects and because tumors can develop resistance to retinoids, we have investigated mechanisms downstream of tazarotene's antitumor effect in this model. Specifically we have used (i) global expression profiling to identify and (ii) functional cell-based assays to validate the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway as a downstream target pathway of tazarotene's action. Crucially, we have demonstrated that pharmacologic inhibition of this downstream pathway profoundly reduces murine BCC cell proliferation and tumorigenesis both in vitro and in vivo. These data identify PI3K/AKT/mTOR signaling as a highly attractive target for BCC chemoprevention and indicate more generally that this pathway may be, in some contexts, an important mediator of retinoid anticancer effects.

Sodium oxybate reduces pain, fatigue, and sleep disturbance and improves functionality in fibromyalgia: results from a 14-week, randomized, double-blind, placebo-controlled study.

This 14-week, phase 3, double-blind, randomized, controlled trial evaluated sodium oxybate (SXB) 4.5 and 6g per night versus placebo in patients with fibromyalgia (FM). SXB is the sodium salt of γ-hydroxybutyrate (GHB). GHB is an endogenous compound, synthesized from γ-aminobutyric acid (GABA) and found broadly in the central nervous system and body. Among 548 randomized patients, a ≥30% reduction in pain was experienced by 54.2% and 58.5% of patients treated with SXB 4.5 and 6g, respectively, versus 35.2% for placebo with a 100-mm Visual Analog Scale (VAS) (P<0.001 for both comparisons). Relative to placebo, both SXB doses significantly reduced fatigue (with a 100-mm VAS; P<0.001) and sleep disturbance (with the Jenkins Sleep Scale; P<0.001), and resulted in significant improvements in function as measured by the FM Impact Questionnaire (P=0.003 and P=0.001 for 4.5 and 6 g per night, respectively). On the Short-Form 36 Health Survey, SXB-related improvement was significant on the Physical, but not the Mental, Component Scale. The proportion of patients who reported a global improvement of "much" or "very much" better on the Patient Global Impression of Change was significantly greater in both SXB groups versus placebo (P<0.001). Headache, nausea, dizziness, vomiting, diarrhea, anxiety, and sinusitis were the most commonly reported adverse events, with an incidence at least twice that of placebo. These results expand the evidence from previous clinical trials suggesting that SXB is effective and safe in FM.

An efficient and safe herpes simplex virus type 1 amplicon vector for transcriptionally targeted therapy of human hepatocellular carcinomas.

Our previous studies have shown that transgene expression could be targeted to proliferating cells when cell cycle transcriptional regulatory elements were incorporated into herpes simplex virus type 1 (HSV-1) amplicon backbone vectors. In the study reported here, we further demonstrated the transcriptional activation of transgene expression in association with the onset of cellular proliferation using the mouse partial hepatectomy model. Moreover, transcriptional regulation could be rendered specific to human hepatocellular carcinoma (HCC) cells by inserting the chimeric gene Gal4/NF-YA under the regulation of the HCC-specific hybrid promoter. The hybrid promoter, which consists of four copies of the apolipoprotein E (ApoE) enhancer element inserted upstream of the human alpha1-antitrypsin(hAAT) promoter, induced an higher level of transcription than other liver-specific promoters such as alpha-fetoprotein (AFP) and albumin (Alb) promoter. As a consequence, the enhancement of tissue-specific expression in the context of Gal4/NF-YA fusion proteins enabled the monitoring of transgene expression using a bioluminescence imaging system. Furthermore, these vectors have been shown to be non-toxic and exhibited potent infectivity for proliferating primary HCC cells and HCC cell lines. Together, these results demonstrated that the new hybrid vectors could provide options for the design of safe and efficient systemic gene therapeutic strategies for human HCC.

Engineering an improved cell cycle-regulatable herpes simplex virus type 1 amplicon vector with enhanced transgene expression in proliferating cells yet attenuated activities in resting cells.

We previously generated a herpes simplex virus type 1 (HSV-1)-based amplicon vector (denoted pC8-36) in which gene expression from the minimal cyclin A promoter is repressed by preventing the binding of a trans-activating protein, Gal4-NF-YA, to it through selective interaction with the transcriptional repressor protein CDF-1. Because CDF-1 is absent in actively dividing cells, transgene expression conferred by the pC8-36 vector is therefore cell cycle dependent. As gene therapy evolves to become a promising therapeutic modality for many human diseases, there is an increasing need to further improve the kinetics of gene regulation. In the present study, we examined whether the availability of more binding sites for CDF-1 repressor proteins could enhance transgene expression. Using an overlap extension polymerase chain reaction (PCR) method, the CDE and CHR elements within the minimum cyclin A promoter were multimerized to contain two, three, and six copies of the designated CDE/CHR sequence. Interestingly, our results demonstrated that six-copy CDE/CHR sequence motifs (pC8-6CC-Luc) conferred an approximately 20-fold increase in the ratio of cell cycle regulation compared with the previous reported construct. Further, the overall transcriptional activities mediated by pC8-6CC-Luc were stronger compared with the native human survivin promoter, which consists of three copies of the CDE element and one copy of the CHR element. pC8-6CC-Luc contained, in essence, only the synthetic six-copy CDE/CHR sequence motif (about 262 bp). In comparison with other native endogenous promoters, which usually contain many other transcription binding sites, pC8-6CC-Luc amplicon vectors should confer better regulated and consistent transgene expression and may be considered a gene delivery vector of choice to target actively proliferating tumor cells.

An Efficient and Safe Herpes Simplex Virus Type 1 Amplicon Vector for Transcriptionally Targeted Therapy of Human Hepatocellular Carcinomas.

Our previous studies have shown that transgene expression could be targeted to proliferating cells when cell cycle transcriptional regulatory elements were incorporated into herpes simplex virus type 1 (HSV-1) amplicon backbone vectors. In the study reported here, we further demonstrated the transcriptional activation of transgene expression in association with the onset of cellular proliferation using the mouse partial hepatectomy model. Moreover, transcriptional regulation could be rendered specific to human hepatocellular carcinoma (HCC) cells by inserting the chimeric gene Gal4/NF-YA under the regulation of the HCC-specific hybrid promoter. The hybrid promoter, which consists of four copies of the apolipoprotein E (ApoE) enhancer element inserted upstream of the human α1-antitrypsin(hAAT) promoter, induced an higher level of transcription than other liver-specific promoters such as alpha-fetoprotein (AFP) and albumin (Alb) promoter. As a consequence, the enhancement of tissue-specific expression in the context of Gal4/NF-YA fusion proteins enabled the monitoring of transgene expression using a bioluminescence imaging system. Furthermore, these vectors have been shown to be non-toxic and exhibited potent infectivity for proliferating primary HCC cells and HCC cell lines. Together, these results demonstrated that the new hybrid vectors could provide options for the design of safe and efficient systemic gene therapeutic strategies for human HCC.