Use of electroporation and reverse iontophoresis for extraction of transdermal multibiomarkers

Congo Tak-Shing Ching1,2, Lin-Shien Fu3-5, Tai-Ping Sun1, Tzu-Hsiang Hsu1, Kang-Ming Chang21Department of Electrical Engineering, National Chi Nan University, Puli, Nantou County, 2Department of Photonics and Communication Engineering, Asia University, Wufeng, Taichung, 3Department of Pediatrics, National Yang Ming University, Taipei, 4Institute of Technology, National Chi Nan University, Puli, 5Department of Pediatrics, Taichung Veterans General Hospital, Taichung City, TaiwanBackground: Monitoring of biomarkers, like urea, prostate-specific antigen (PSA), and osteopontin, is very important because they are related to kidney disease, prostate cancer, and ovarian cancer, respectively. It is well known that reverse iontophoresis can enhance transdermal extraction of small molecules, and even large molecules if reverse iontophoresis is used together with electroporation. Electroporation is the use of a high-voltage electrical pulse to create nanochannels within the stratum corneum, temporarily and reversibly. Reverse iontophoresis is the use of a small current to facilitate both charged and uncharged molecule transportation across the skin. The objectives of this in vitro study were to determine whether PSA and osteopontin are extractable transdermally and noninvasively and whether urea, PSA, and osteopontin can be extracted simultaneously by electroporation and reverse iontophoresis.Methods: All in vitro experiments were conducted using a diffusion cell assembled with the stratum corneum of porcine skin. Three different symmetrical biphasic direct currents (SBdc), five various electroporations, and a combination of the two techniques were applied to the diffusion cell via Ag/AgCl electrodes. The three different SBdc had the same current density of 0.3 mA/cm2, but different phase durations of 0 (ie, no current, control group), 30, and 180 seconds. The five different electroporations had the same pulse width of 1 msec and number of pulses per second of 10, but different electric field strengths of 0 (ie, no voltage, control group), 74, 148, 296, and 592 V/cm. Before and after each extraction experiment, skin impedance was measured at 20 Hz.Results: It was found that urea could be extracted transdermally using reverse iontophoresis alone, and further enhancement of extraction could be achieved by combined use of electroporation and reverse iontophoresis. Conversely, PSA and osteopontin were found to be extracted transdermally only by use of reverse iontophoresis and electroporation with a high electrical field strength (>296 V/cm). After application of reverse iontophoresis, electroporation, or a combination of the two techniques, a reduction in skin impedance was observed.Conclusion: Simultaneous transdermal extraction of urea, PSA, and osteopontin is possible only for the condition of applying reverse iontophoresis in conjunction with high electroporation.Keywords: electroporation, reverse iontophoresis, nanochannels, noninvasive, urea, prostate-specific antigen, osteoponti

The nucleolar protein NIFK promotes cancer progression via CK1α/β-catenin in metastasis and Ki-67-dependent cell proliferation.

Nucleolar protein interacting with the FHA domain of pKi-67 (NIFK) is a Ki-67-interacting protein. However, its precise function in cancer remains largely uninvestigated. Here we show the clinical significance and metastatic mechanism of NIFK in lung cancer. NIFK expression is clinically associated with poor prognosis and metastasis. Furthermore, NIFK enhances Ki-67-dependent proliferation, and promotes migration, invasion in vitro and metastasis in vivo via downregulation of casein kinase 1α (CK1α), a suppressor of pro-metastatic TCF4/β-catenin signaling. Inversely, CK1α is upregulated upon NIFK knockdown. The silencing of CK1α expression in NIFK-silenced cells restores TCF4/β-catenin transcriptional activity, cell migration, and metastasis. Furthermore, RUNX1 is identified as a transcription factor of CSNK1A1 (CK1α) that is negatively regulated by NIFK. Our results demonstrate the prognostic value of NIFK, and suggest that NIFK is required for lung cancer progression via the RUNX1-dependent CK1α repression, which activates TCF4/β-catenin signaling in metastasis and the Ki-67-dependent regulation in cell proliferation

Fossil Seed from the Miocene Shihti Formation of Taiwan

A compressed fossil seed, described as Carpolithes sp., is found in the coal-bearing Miocene Shihti Formation from the Lifeng coal mine, Sanshia District of the New Taipei City. The fossil is generally rounded with a diameter of ca. 10 mm in lateral view. The anatomical features of the testa epidermal cells were observed using anatomical analysis. The anatomical features of the megafossil organ from the Formation are reported for the first time

BCL-W is dispensable for the sustained survival of select Burkitt lymphoma and diffuse large B-cell lymphoma cell lines

Dysregulated expression of BCL-2 family proteins allows cancer cells to escape apoptosis. To counter this, BH3-mimetic drugs that target and inhibit select BCL-2 prosurvival proteins to induce apoptosis have been developed for cancer therapy. Venetoclax, which targets BCL-2, has been effective as therapy for patients with chronic lymphocytic leukemia, and MCL-1-targeting BH3-mimetic drugs have been extensively evaluated in preclinical studies for a range of blood cancers. Recently, BCL-W, a relatively understudied prosurvival member of the BCL-2 protein family, has been reported to be abnormally upregulated in Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), and Hodgkin lymphoma patient samples. Therefore, to determine if BCL-W would be a promising therapeutic target for B-cell lymphomas, we have examined the role of BCL-W in the sustained growth of human BL- and DLBCL-derived cell lines. We found that CRISPR/CAS9-mediated loss or short hairpin RNA-mediated knockdown of BCL-W expression in selected BL and DLBCL cell lines did not lead to spontaneous apoptosis and had no effect on their sensitivity to a range of BH3-mimetic drugs targeting other BCL-2 prosurvival proteins. Our results suggest that BCL-W is not universally required for the sustained growth and survival of human BL and DLBCL cell lines. Thus, targeting BCL-W in this subset of B-cell lymphomas may not be of broad therapeutic benefit

Toxicity risk of non-target organs at risk receiving low-dose radiation: case report

The spine is the most common site for bone metastases. Radiation therapy is a common treatment for palliation of pain and for prevention or treatment of spinal cord compression. Helical tomotherapy (HT), a new image-guided intensity modulated radiotherapy (IMRT), delivers highly conformal dose distributions and provides an impressive ability to spare adjacent organs at risk, thus increasing the local control of spinal column metastases and decreasing the potential risk of critical organs under treatment. However, there are a lot of non-target organs at risk (OARs) occupied by low dose with underestimate in this modern rotational IMRT treatment. Herein, we report a case of a pathologic compression fracture of the T9 vertebra in a 55-year-old patient with cholangiocarcinoma. The patient underwent HT at a dose of 30 Gy/10 fractions delivered to T8-T10 for symptom relief. Two weeks after the radiotherapy had been completed, the first course of chemotherapy comprising gemcitabine, fluorouracil, and leucovorin was administered. After two weeks of chemotherapy, however, the patient developed progressive dyspnea. A computed tomography scan of the chest revealed an interstitial pattern with traction bronchiectasis, diffuse ground-glass opacities, and cystic change with fibrosis. Acute radiation pneumonitis was diagnosed. Oncologists should be alert to the potential risk of radiation toxicities caused by low dose off-targets and abscopal effects even with highly conformal radiotherapy

Epinephrine administration via a laryngeal mask airway: what is the optimal dose?

Background. The aim of this animal study was to clarify the effects of laryngeal mask airway (LMA)-administrated epinephrine and to assess the optimal dose. Methods. Thirty pigs were anesthetized and intubated with a cuffed tracheal tube (TT) and an LMA. Then they were assigned to one of five groups. The control group received distilled water 10 mL via the TT; the TT group received epinephrine 50 μg/kg via the TT; and the other three groups received two, four or six times the TT dose of epinephrine via the LMA. Heart rate (HR) and arterial pressure were monitored before and after drug administration for 15 minutes. Results. After epinephrine administration, the LMA-6 and TT groups had elevated systolic, diastolic and mean arterial pressures at 1 min and there was no significant difference between the two groups. In the TT group, these parameters peaked at 2 min then declined rapidly. In the LMA-6 group, they increased more slowly, and then maintained a plateau. The control, LMA-2 and LMA-4 groups failed to display significant persistent (>2 min) hemodynamic changes. Conclusions. We could not identify an optimal LMA-administrated epinephrine dose. The TT route is suitable when a high peak drug effect is required and the LMA route may be preferable if a persistent plateau effect is desired. Effective LMA administration of drugs may require larger doses than those given via TT

Multidrug Resistant Acinetobacter baumannii: Risk Factors for Appearance of Imipenem Resistant Strains on Patients Formerly with Susceptible Strains

BACKGROUND: Multidrug resistant Acinetobacter baumannii (MDRAB) is an important nosocomial pathogen usually susceptible to carbapenems; however, growing number of imipenem resistant MDRAB (IR-MDRAB) poses further clinical challenge. The study was designed to identify the risk factors for appearance of IR-MDRAB on patients formerly with imipenem susceptible MDRAB (IS-MDRAB) and the impact on clinical outcomes. METHODOLOGY/PRINCIPAL FINDINGS: A retrospective case control study was carried out for 209 consecutive episodes of IS-MDRAB infection or colonization from August 2001 to March 2005. Forty-nine (23.4%) episodes with succeeding clinical isolates of IR-MDRAB were defined as the cases and 160 (76.6%) with all subsequent clinical isolates of IS-MDRAB were defined as the controls. Quantified antimicrobial selective pressure, "time at risk", severity of illness, comorbidity, and demographic data were incorporated for multivariate analysis, which revealed imipenem or meropenem as the only significant independent risk factor for the appearance of IR-MDRAB (adjusted OR, 1.18; 95% CI, 1.09 to 1.27). With selected cases and controls matched to exclude exogenous source of IR-MDRAB, multivariate analysis still identified carbapenem as the only independent risk factor (adjusted OR, 1.48; 95% CI, 1.14 to 1.92). Case patients had a higher crude mortality rate compared to control patients (57.1% vs. 31.3%, p = 0.001), and the mortality of case patients was associated with shorter duration of "time at risk", i.e., faster appearance of IR-MDRAB (adjusted OR, 0.9; 95% CI, 0.83 to 0.98). CONCLUSIONS/SIGNIFICANCE: Judicious use of carbapenem with deployment of antibiotics stewardship measures is critical for reducing IR-MDRAB and the associated unfavorable outcome

Brain Network Changes in Fatigued Drivers: A Longitudinal Study in a Real-World Environment Based on the Effective Connectivity Analysis and Actigraphy Data

The analysis of neurophysiological changes during driving can clarify the mechanisms of fatigue, considered an important cause of vehicle accidents. The fluctuations in alertness can be investigated as changes in the brain network connections, reflected in the direction and magnitude of the information transferred. Those changes are induced not only by the time on task but also by the quality of sleep. In an unprecedented 5-month longitudinal study, daily sampling actigraphy and EEG data were collected during a sustained-attention driving task within a near-real-world environment. Using a performance index associated with the subjects' reaction times and a predictive score related to the sleep quality, we identify fatigue levels in drivers and investigate the shifts in their effective connectivity in different frequency bands, through the analysis of the dynamical coupling between brain areas. Study results support the hypothesis that combining EEG, behavioral and actigraphy data can reveal new features of the decline in alertness. In addition, the use of directed measures such as the Convergent Cross Mapping can contribute to the development of fatigue countermeasure devices