More than 99% of cervical cancers have been associated with human papillomaviruses (HPVs), particularly HPV type 16. The clear association between HPV infection and cervical cancer indicates that HPV serves as an ideal target for development of preventive and therapeutic vaccines. Although the recently licensed preventive HPV vaccine, Gardasil, has been shown to be safe and capable of generating significant protection against specific HPV types, it does not have therapeutic effect against established HPV infections and HPV-associated lesions. Two HPV oncogenic proteins, E6 and E7, are consistently co-expressed in HPV-expressing cervical cancers and are important in the induction and maintenance of cellular transformation. Therefore, immunotherapy targeting E6 and/or E7 proteins may provide an opportunity to prevent and treat HPV-associated cervical malignancies. It has been established that T cell-mediated immunity is one of the most crucial components to defend against HPV infections and HPV-associated lesions. Therefore, effective therapeutic HPV vaccines should generate strong E6/E7-specific T cell-mediated immune responses. DNA vaccines have emerged as an attractive approach for antigen-specific T cell-mediated immunotherapy to combat cancers. Intradermal administration of DNA vaccines via a gene gun represents an efficient way to deliver DNA vaccines into professional antigen-presenting cells in vivo. Professional antigen-presenting cells, such as dendritic cells, are the most effective cells for priming antigen-specific T cells. Using the gene gun delivery system, we tested several DNA vaccines that employ intracellular targeting strategies for enhancing MHC class I and class II presentation of encoded model antigen HPV-16 E7. Furthermore, we have developed a strategy to prolong the life of DCs to enhance DNA vaccine potency. More recently, we have developed a strategy to generate antigen-specific CD4+ T cell immune responses to further enhance DNA vaccine potency. The impressive pre- clinical data generated from our studies have led to several HPV DNA vaccine clinical trials.
Female ; Humans ; Oncogene Proteins, Viral/genetics/immunology ; Papillomaviridae/*genetics/immunology ; Papillomavirus Infections/immunology/*prevention & control ; Papillomavirus Vaccines/*administration & dosage ; Repressor Proteins ; Uterine Cervical Neoplasms/*prevention & control ; Vaccines, DNA/*administration & dosage ; Viral Vaccines/administration & dosage

Cervical cancer is the fourth most lethal women's cancer worldwide. Current treatments against cervical cancer include surgery, radiotherapy, chemotherapy, and anti-angiogenic agents. However, despite the various treatments utilized for the treatment of cervical cancer, its disease burden remains a global issue. Persistent infection of human papillomavirus (HPV) has been identified as an essential step of pathogenesis of cervical cancer and many other cancers, and nation-wide HPV screening as well as preventative HPV vaccination program have been introduced globally. However, even though the commercially available prophylactic HPV vaccines, Gardasil (Merck) and Cervarix (GlaxoSmithKline), are effective in blocking the entry of HPV into the epithelium of cervix through generation of HPV-specific neutralizing antibodies, they cannot eliminate the pre-existing HPV infection. For these reason, other immunotherapeutic options against HPV-associated diseases, including therapeutic vaccines, have been continuously explored. Therapeutic HPV vaccines enhance cell-mediated immunity targeting HPV E6 and E7 antigens by modulating primarily dendritic cells and cytotoxic T lymphocyte. Our review will cover various therapeutic vaccines in development for the treatment of HPV-associated lesions and cancers. Furthermore, we will discuss the potential of immune checkpoint inhibitors that have recently been adopted and tested for their treatment efficacy against HPV-induced cervical cancer.
Dendritic Cells/immunology ; Female ; Genetic Vectors ; Humans ; *Immunotherapy ; Papillomavirus Infections/*complications/therapy ; Papillomavirus Vaccines/therapeutic use ; *Translational Medical Research ; Uterine Cervical Neoplasms/*therapy ; Vaccines, DNA/therapeutic use ; Vaccines, Subunit/therapeutic use

*Abnormalities, Multiple/radiography ; Basilar Artery/*abnormalities ; Basilar Artery/radiography ; Carotid Artery, Internal/radiography ; Intracranial Aneurysm/*complications ; Intracranial Aneurysm/radiography ; Vertebral Artery/radiography

Objective: This study evaluated the validity of self-reported smartphone usage data against objectively-measured smartphone usage data by directly tracking the activities in the participants’ smartphone among Chinese adolescents and young adults in Hong Kong. Methods: A total of 187 participants were recruited (mean age 19.4, 71.7% female) between 2017 and 2018. A smartphone usage tracking app was installed on all participants’ smartphone for 7 consecutive days. After the 7-day monitoring period, they completed a selfadministered questionnaire on smartphone usage habits. Results: Although the correlation between self-reported and objectively-measured total smartphone usage time was insignificant (ρ=-0.10, p=0.18), in three out of the four usage domains were positively and significantly correlated, namely social network (ρ=0.21, p=0.005), instant messaging (ρ=0.27, p<0.001), and games (ρ=0.64, p<0.001). Participants’ self-report of the total time spent on smartphones exceeded the objective data by around 760 min per week (self-reported 1,930.3 min/wk vs. objectively-measured 1,170.7 min/wk, p<0.001). Most of the over-reporting was contributed by the web browsing domain (self-reported 447.8 min/wk vs. objectively-measured 33.3 min/wk, p<0.001). Conclusion Our results showed large discrepancies between self-reported smartphone and objectively-measured smartphone usage except for self-reported usage on game apps.

Objective: Previous studies have indicated a convergent and bidirectional relationship between metabolic syndrome (MetS) and bipolar disorder (BD). As most of these studies focused mainly on adults diagnosed with BD, our study aims to investigate and characterize metabolic disturbances in child-adolescents diagnosed with BD. Methods: We retrospectively examined the medical records of psychiatric hospitalizations with admitting diagnosis of BD in child-adolescents (age ＜ 18 years). Body mass index (BMI), lipid profile, fasting blood glucose, and blood pressure were primary variables. National Cholesterol Education Program criteria were used to define MetS. Reference group data was obtained from the National Health and Nutrition Examination Survey study. Statistical analyses included t tests, chi-square tests, and Fisher’s exact tests. Results: We identified 140 child-adolescent patients with BD (mean age = 15.12 ± 1.70 years, 53% male). MetS was significantly more common in BD compared to the reference group: 14% (95% confidence interval [95% CI] 8−20) vs. 6.7% (95% CI 4.1−9.2), p = 0.001 with no significant difference by sex. MetS components were higher in the BD group, particularly BMI ≥ 95% (25% vs. 11.8%, p ＜ 0.001) and high blood pressure (17% vs. 8%, p = 0.05). Moreover, female patients had lower odds of high blood pressure (odds ratio = 0.24 [95% CI 0.08−0.69], p = 0.005). Conclusion Compared with the general child-adolescent population, the prevalence of MetS was significantly higher in patients with BD of same age. This reiterates the notion of an increased risk of MetS in patients diagnosed with BD; and thus, further exploration is warranted.

BACKGROUND/AIMS: Patients with irritable bowel syndrome (IBS) are characterized by abnormal central processing with altered brain activation in response to visceral nociceptive signals. The effect of electroacupuncture (EA) on IBS patients is unclear. The study is set to study the effect of EA on brain activation during noxious rectal distension in IBS patients using a randomized sham-controlled model. METHODS: Thirty IBS-diarrhea patients were randomized to true electroacupuncture or sham acupuncture. Functional MRI was performed to evaluate cerebral activation at the following time points: (1) baseline when there was rectal distension only, (2) rectal distension during application of EA, (3) rectal distension after cessation of EA and (4) EA alone with no rectal distension. Group comparison was made under each condition using SPM5 program. RESULTS: Rectal distension induced significant activation of the anterior cingulated cortex, prefrontal cortex, thalamus, temporal regions and cerebellum at baseline. During and immediately after EA, increased cerebral activation from baseline was observed in the anterior cingulated cortex, bilateral prefrontal cortex, thalamus, temporal regions and right insula in both groups. However, true electroacupuncture led to significantly higher activation at right insula, as well as pulvinar and medial nucleus of the thalamus when compared to sham acupuncture. CONCLUSIONS: We postulate that acupuncture might have the potential effect of pain modulation in IBS by 2 actions: (1) modulation of serotonin pathway at insula and (2) modulation of mood and affection in higher cortical center via ascending pathway at the pulvinar and medial nucleus of the thalamus.
Acupuncture ; Acupuncture Therapy ; Brain ; Cerebellum ; Electroacupuncture ; Humans ; Irritable Bowel Syndrome ; Magnetic Resonance Imaging ; Magnetic Resonance Spectroscopy ; Magnetics ; Magnets ; Neural Pathways ; Pain Perception ; Prefrontal Cortex ; Pulvinar ; Salicylamides ; Serotonin ; Thalamus

Abnormalities, Multiple ; diagnostic imaging ; Basilar Artery ; abnormalities ; diagnostic imaging ; Carotid Artery, Internal ; diagnostic imaging ; Humans ; Intracranial Aneurysm ; complications ; diagnostic imaging ; Male ; Middle Aged ; Radiography ; Vertebral Artery ; diagnostic imaging

Objective: To analyze the characteristics of super-antigen (SAg) of group A Streptococcus pyogenes (GAS), isolated from patients with scarlet fever or pharyngeal infections in Beijing between 2015-2017. Methods: Throat swab specimens from patients with scarlet fever or pharyngeal infections were collected and tested for GAS. Eleven currently known SAg genes including SpeA, speC, speG, speH, speI, speJ, speK, speL, speM, smeZ and ssa were tested by real-time PCR while M protein genes (emm genes) were amplified and sequenced by PCR. Results: A total of 377 GAS were isolated from 6 801 throat swab specimens, with the positive rate as 5.5%. There were obvious changes noticed among speC, speG, speH and speK in three years. A total of 45 SAg genes profiles were observed, according to the SAgs inclusion. There were significant differences appeared in the frequencies among two of the highest SAg genes profiles between emm1 and emm12 strains (χ(2)=38.196, P<0.001; χ(2)=72.310, P<0.001). There also appeared significant differences in the frequencies of speA, speH, speI and speJ between emm1 and emm12 strains (χ(2)=146.154, P<0.001; χ(2)=52.31, P<0.001; χ(2)=58.43, P<0.001; χ(2)=144.70, P<0.001). Conclusions: Obvious changes were noticed among SAg genes including speC, speG, speH and speK from patients with scarlet fever or pharyngeal infections in Beijing between 2015-2017. SAg genes including speA, speH, speI and speJ appeared to be associated with the emm 1 and emm 12 strains. More kinds of SAg genes profiles were isolated form GAS but with no significant differences seen in the main SAg genes profiles, during the epidemic period.
Antigens, Bacterial/genetics* ; Bacterial Outer Membrane Proteins ; Bacterial Proteins ; Beijing/epidemiology* ; China/epidemiology* ; Exotoxins ; Female ; Humans ; Membrane Proteins ; Pharyngitis/microbiology* ; Pharynx/microbiology* ; Pregnancy ; Pregnancy Complications, Infectious/microbiology* ; Real-Time Polymerase Chain Reaction ; Scarlet Fever/microbiology* ; Streptococcal Infections ; Streptococcus pyogenes/isolation & purification* ; Superantigens/genetics*

During the Coronavirus Disease 2019 (COVID-19) pandemic, practices of gastrointestinal procedures within the digestive tract require special precautions due to the risk of contraction of severe acute respiratoy syndrome coronavirus-2 (SARS-CoV-2) infection. Many procedures in the gastrointestinal motility laboratory may be considered moderate to high-risk for viral transmission. Healthcare staff working in gastrointestinal motility laboratories are frequently exposed to splashes, air droplets, mucus, or saliva during the procedures. Moreover, some are aerosol-generating and thus have a high risk of viral transmission. There are multiple guidelines on the practices of gastrointestinal endoscopy during this pandemic. However, such guidelines are still lacking and urgently needed for the practice of gastrointestinal motility laboratories. Hence, the Asian Neurogastroenterology and Motility Association had organized a group of gastrointestinal motility experts and infectious disease specialists to produce a position statement paper based-on current available evidence and consensus opinion with aims to provide a clear guidance on the practices of gastrointestinal motility laboratories during the COVID-19 pandemic. This guideline covers a wide range of topics on gastrointestinal motility activities from scheduling a motility test, the precautions at different steps of the procedure to disinfection for the safety and well-being of the patients and the healthcare workers. These practices may vary in different countries depending on the stages of the pandemic, local or institutional policy, and the availability of healthcare resources. This guideline is useful when the transmission rate of SARS-CoV-2 is high. It may change rapidly depending on the situation of the epidemic and when new evidence becomes available.

OBJECTIVETo investigate the impact of novel P2Y(12) receptor inhibitors including prasugrel or ticagrelor on platelet reactivity in patients with acute coronary syndrome (ACS) receiving percutaneous coronary intervention (PCI), and provide clinical data for novel oral P2Y(12) receptor inhibitors use among Chinese patients.

METHODSBetween October 2011 to February 2014, 174 consecutive patients (135 males; (67.8±11.8) years old) with ACS undergoing PCI in Kiang Wu Hospital, Macau were prospectively enrolled in this study. Oral aspirin and one P2Y(12) receptor inhibitor were administered for 5 days or above after PCI, patients were divided into clopidogrel, prasugrel and ticagrelor groups in accordance with the agent administered. Platelet reactivity of the patients was detected by VerifyNow P2Y(12) reaction unit (PRU); and the high on-treatment platelet reactivity (HPR) and non-HPR were defined as PRU≥208 and PRU<208 respectively. Patients with HPR during clopidogrel therapy were switched either to prasugrel or ticagrelor, or continued the same treatment; and then the platelet reactivity was monitored again.

RESULTSThere were 113 clopidogrel cases (64.9%), 20 prasugrel cases (11.5%) and 41 ticagrelor cases (23.6%). Fifty-seven cases (32.8%) were defined as HPR post P2Y(12) receptor inhibitor use, in which 55 cases (55/113, 48.7%) were treated with clopidogrel. The degree of inhibition of platelet reactivity was significantly different in patients on clopidogrel, prasugrel and ticagrelor therapy, percent inhibition assayed by the VerifyNow P2Y(12) system was 28.2%±23.5%, 61.4%±26.7% and 81.3%±19.8% respectively (P<0.05). Different degree of platelet reactivity was achieved by the 3 P2Y(12) receptor inhibitors at multiple time points. The among-group differences in platelet reactivity became apparent at the early treatment stage (P<0.05). Platelet aggregation decreased significantly in patients switched from clopidogrel to prasugrel or ticagrelor (P<0.05).

CONCLUSIONNovel oral P2Y(12) receptor inhibitors are more effective in inhibiting platelet reactivity in ACS patients, and our results show that novel oral P2Y(12) receptor inhibitors provide a new option for ACS patients with HPR post clopidogrel or high-risk features of ischemic complications, including stent thrombosis and post-PCI ischemic events.

Acute Coronary Syndrome ; Adenosine ; analogs & derivatives ; Aged ; Aspirin ; Blood Platelets ; Female ; Humans ; Male ; Percutaneous Coronary Intervention ; Platelet Aggregation ; Platelet Aggregation Inhibitors ; Platelet Function Tests ; Prasugrel Hydrochloride ; Prospective Studies ; Ticlopidine ; analogs & derivatives