Hypermodification and Immune Escape of an Internally Deleted Middle-Envelope (M) Protein of Frequent and Predominant Hepatitis B Virus Variants

AbstractNaturally occurring deletions within the human hepatitis B virus (HBV) preS2 region have frequently been identified in patients with hepatocellular carcinoma (HCC), while chronic carriers without cirrhosis and HCC contain no detectable preS2 deletion variants. We have characterized two different preS2 internal deletion variants from two patients. In addition to several weak phenotypes, our study revealed three unexpected strong phenotypes: (1) a paradoxical “hypermodification” phenomenon was observed with significantly increased size heterogeneity and molecular weights of the secreted middle (M) envelope proteins containing a preS2 internal deletion. This phenomenon was observed in transient transfection with a human hepatoma Huh7 cell line as well as in stable transfection with a rodent hepatoma cell line 7777. (2) A significantly increased intracellular accumulation of all three envelope proteins (large, middle, and small) was detected by both Western blot analysis and immunofluorescence microscopy. (3) The middle envelope proteins with a preS2 internal deletion were not recognized in vitro by a putative neutralizing antiserum, suggesting that these variants can evade immune recognition in vivo. To our knowledge, this is the first identification and characterization of the M deletion variant protein in HBV natural infection

The Relationship between Brown Adipose Tissue Activity and Neoplastic Status: an 18F-FDG PET/CT Study in the Tropics

<p>Abstract</p> <p>Background</p> <p>Brown adipose tissue (BAT) has thermogenic potential. For its activation, cold exposure is considered a critical factor though other determinants have also been reported. The purpose of this study was to assess the relationship between neoplastic status and BAT activity by 2-deoxy-2-[18F]fluoro-D-glucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT) in people living in the tropics, where the influence of outdoor temperature was low.</p> <p>Methods</p> <p>¹⁸F-FDG PET/CT scans were reviewed and the total metabolic activity (TMA) of identified activated BAT quantified. The distribution and TMA of activated BAT were compared between patients with and without a cancer history. The neoplastic status of patients was scored according to their cancer history and ¹⁸F-FDG PET/CT findings. We evaluated the relationships between the TMA of BAT and neoplastic status along with other factors: age, body mass index, fasting blood sugar, gender, and outdoor temperature.</p> <p>Results</p> <p>Thirty of 1740 patients had activated BAT. Those with a cancer history had wider BAT distribution (<it>p </it>= 0.043) and a higher TMA (<it>p </it>= 0.028) than those without. A higher neoplastic status score was associated with a higher average TMA. Multivariate analyses showed that neoplastic status was the only factor significantly associated with the TMA of activated BAT (<it>p </it>= 0.016).</p> <p>Conclusions</p> <p>Neoplastic status is a critical determinant of BAT activity in patients living in the tropics. More active neoplastic status was associated with more vigorous TMA of BAT.</p

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

Safety assessment of poly-ε-caprolactone in the treatment of primary spontaneous pneumothorax

Background/purposeBiomaterial-based implants are gaining traction as an option for pleurodesis treatment, yet the search for the best biomaterial or the most suitable shape to handle spontaneous pneumothorax continues. This forward-looking research assessed the use of a poly-ε-caprolactone membrane for its safety when applied as a sclerosant in pleurodesis procedures in human patients.MethodsFrom July 2017 to February 2018, we conducted a Phase I trial in which 10 patients with primary spontaneous pneumothorax were treated using video-assisted thoracoscopic surgery with a poly-ε-caprolactone membrane. These procedures encompassed bleb resection and mechanical pleurodesis through parietal pleura scrubbing. After resection, a 150 × 150 mm poly-ε-caprolactone membrane was applied to the apex. The primary outcome measures were the adverse events and laboratory outcomes.ResultsAfter surgery, we observed no cardiopulmonary-related adverse events or indications of systemic inflammation. Furthermore, no episodes of hypothermia or hyperthermia occurred. Chest radiographs showed no evident pneumonitis or effusion associated with tissue reactions. The average follow-up duration was 31.7 ± 17.7 months, during which two patients exhibited recurrence.ConclusionThis study is the first to show the biocompatibility of poly-ε-caprolactone in humans, suggesting its potential as a treatment option for patients with primary spontaneous pneumothorax. Despite the relatively small number of patients, we maintain confidence in the reliability and safety profile of the PCL membrane, bolstered by its previously established efficacy in applications involving other organs. Phase II and phase III clinical studies are needed to support these observations

THE USE OF MANDAMUS TO COMPEL EDUCATIONAL INSTITUTIONS TO CONFER DEGREES

Hispolon is an active phenolic compound of <i>Phellinus igniarius</i>, a mushroom that was recently shown to have antioxidant and anticancer activities in various solid tumors. Here, the molecular mechanisms by which hispolon exerts anticancer effects in acute myeloid leukemia (AML) cells was investigated. The results showed that hispolon suppressed cell proliferation in the various AML cell lines. Furthermore, hispolon effectively induced apoptosis of HL-60 AML cells through caspases-8, -9, and -3 activations and PARP cleavage. Moreover, treatment of HL-60 cells with hispolon induced sustained activation of JNK1/2, and inhibition of JNK by JNK1/2 inhibitor or JNK1/2-specific siRNA significantly abolished the hispolon-induced activation of the caspase-8/-9/-3. In vivo, hispolon significantly reduced tumor growth in mice with HL-60 tumor xenografts. In hispolon-treated tumors, activation of caspase-3 and a decrease in Ki67-positive cells were observed. Our results indicated that hispolon may have the potential to serve as a therapeutic tool to treat AML

Serotonin receptor HTR6-mediated mTORC1 signaling regulates dietary restriction-induced memory enhancement

Dietary restriction (DR; sometimes called calorie restriction) has profound beneficial effects on physiological, psychological, and behavioral outcomes in animals and in humans. We have explored the molecular mechanism of DR-induced memory enhancement and demonstrate that dietary tryptophan-a precursor amino acid for serotonin biosynthesis in the brain-and serotonin receptor 5-hydroxytryptamine receptor 6 (HTR6) are crucial in mediating this process. We show that HTR6 inactivation diminishes DR-induced neurological alterations, including reduced dendritic complexity, increased spine density, and enhanced long-term potentiation (LTP) in hippocampal neurons. Moreover, we find that HTR6-mediated mechanistic target of rapamycin complex 1 (mTORC1) signaling is involved in DR-induced memory improvement. Our results suggest that the HTR6-mediated mTORC1 pathway may function as a nutrient sensor in hippocampal neurons to couple memory performance to dietary intake

Comparison of coplanar and noncoplanar intensity-modulated radiation therapy and helical tomotherapy for hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>To compare the differences in dose-volume data among coplanar intensity modulated radiotherapy (IMRT), noncoplanar IMRT, and helical tomotherapy (HT) among patients with hepatocellular carcinoma (HCC) and portal vein thrombosis (PVT).</p> <p>Methods</p> <p>Nine patients with unresectable HCC and PVT underwent step and shoot coplanar IMRT with intent to deliver 46 - 54 Gy to the tumor and portal vein. The volume of liver received 30Gy was set to keep less than 30% of whole normal liver (V30 < 30%). The mean dose to at least one side of kidney was kept below 23 Gy, and 50 Gy as for stomach. The maximum dose was kept below 47 Gy for spinal cord. Several parameters including mean hepatic dose, percent volume of normal liver with radiation dose at X Gy (Vx), uniformity index, conformal index, and doses to organs at risk were evaluated from the dose-volume histogram.</p> <p>Results</p> <p>HT provided better uniformity for the planning-target volume dose coverage than both IMRT techniques. The noncoplanar IMRT technique reduces the V10 to normal liver with a statistically significant level as compared to HT. The constraints for the liver in the V30 for coplanar IMRT vs. noncoplanar IMRT vs. HT could be reconsidered as 21% vs. 17% vs. 17%, respectively. When delivering 50 Gy and 60-66 Gy to the tumor bed, the constraints of mean dose to the normal liver could be less than 20 Gy and 25 Gy, respectively.</p> <p>Conclusion</p> <p>Noncoplanar IMRT and HT are potential techniques of radiation therapy for HCC patients with PVT. Constraints for the liver in IMRT and HT could be stricter than for 3DCRT.</p

Task-Switching Performance Improvements After Tai Chi Chuan Training Are Associated With Greater Prefrontal Activation in Older Adults

Studies have shown that Tai Chi Chuan (TCC) training has benefits on task-switching ability. However, the neural correlates underlying the effects of TCC training on task-switching ability remain unclear. Using task-related functional magnetic resonance imaging (fMRI) with a numerical Stroop paradigm, we investigated changes of prefrontal brain activation and behavioral performance during task-switching before and after TCC training and examined the relationships between changes in brain activation and task-switching behavioral performance. Cognitively normal older adults were randomly assigned to either the TCC or control (CON) group. Over a 12-week period, the TCC group received three 60-min sessions of Yang-style TCC training weekly, whereas the CON group only received one telephone consultation biweekly and did not alter their life style. All participants underwent assessments of physical functions and neuropsychological functions of task-switching, and fMRI scans, before and after the intervention. Twenty-six (TCC, N = 16; CON, N = 10) participants completed the entire experimental procedure. We found significant group by time interaction effects on behavioral and brain activation measures. Specifically, the TCC group showed improved physical function, decreased errors on task-switching performance, and increased left superior frontal activation for Switch &gt; Non-switch contrast from pre- to post-intervention, that were not seen in the CON group. Intriguingly, TCC participants with greater prefrontal activation increases in the switch condition from pre- to post-intervention presented greater reductions in task-switching errors. These findings suggest that TCC training could potentially provide benefits to some, although not all, older adults to enhance the function of their prefrontal activations during task-switching

Detection of SARS-associated Coronavirus in Throat Wash and Saliva in Early Diagnosis

Early detection of SARS-CoV in throat wash and saliva suggests that these specimens are ideal for SARS diagnosis