Discovering a novel dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) inhibitor and its impact on tau phosphorylation and amyloid-ß formation.

Dual-specificity tyrosine-regulated kinase 1 A (DYRK1A) is crucial in neurogenesis, synaptogenesis, and neuronal functions. Its dysregulation is linked to neurodegenerative disorders like Down syndrome and Alzheimer's disease. Although the development of DYRK1A inhibitors has significantly advanced in recent years, the selectivity of these drugs remains a critical challenge, potentially impeding further progress. In this study, we utilised structure-based virtual screening (SBVS) from NCI library to discover novel DYRK1A inhibitors. The top-ranked compounds were then validated through enzymatic assays to assess their efficacy towards DYRK1A. Among them, NSC361563 emerged as a potent and selective DYRK1A inhibitor. It was shown to decrease tau phosphorylation at multiple sites, thereby enhancing tubulin stability. Moreover, NSC361563 diminished the formation of amyloid ß and offered neuroprotective benefits against amyloid ß-induced toxicity. Our research highlights the critical role of selective DYRK1A inhibitors in treating neurodegenerative diseases and presents a promising starting point for the development of targeted therapies.

Patients Engaged in Losing Weight Preoperatively Experience Improved Outcomes After Hiatal Hernia Repair.

BACKGROUND: Adherence to preoperative weight loss recommendations may serve as a surrogate for the level of engagement in hiatal hernia (HH) patients. This study aims to evaluate the relationship between achieving preoperative weight loss goals and outcomes after HH repair. METHODS: A retrospective review of 235 patients undergoing laparoscopic HH repair at a single institution was performed. Patients were grouped based on the percentage of weight loss goal achieved. Low achievement was defined as the bottom quartile of goal achievement (≤75%); high achievement was defined as the top quartile (≥140%). Baseline characteristics, clinical outcomes, and patient reported outcomes (PROMs) were compared between groups. RESULTS: 131/235 (55.7%) achieved their weight loss goal. No differences in baseline characteristics or clinical outcomes were observed between the low and high achievement groups. While both groups experienced improvements in PROMs postoperatively, patients in the high achievement group demonstrated significantly lower symptom burden at one-month postoperatively. Further, high-achievement patients were more likely to experience complete resolution of common HH symptoms at one-month postoperatively, including no difficulty swallowing food, no breathing difficulties or choking episodes, no choking when eating food, no choking when drinking liquid, and no regurgitation of food or liquid. CONCLUSIONS: In patients undergoing laparoscopic HH repair, patients achieving their preoperative weight loss goals experienced less overall symptom burden and lower prevalence of common symptoms one-month postoperatively than those with low levels of goal achievement. These results demonstrate that patients can take an active role in improving their own surgical outcomes and health status.

Bioactive Properties of Enzymatic Gelatin Hydrolysates Based on In Silico, In Vitro, and In Vivo Studies.

This current study aims to analyze the potential bioactivities possessed by the enzymatic hydrolysates of commercial bovine, porcine, and tilapia gelatins using bioinformatics in combination with in vitro and in vivo studies. The hydrolysate with superior inhibition of angiotensin converting enzyme (ACE) activity was used to treat the D-galactose (DG)-induced amnesic mice. In silico digestion of the gelatins led to the identification of peptide sequences with potential antioxidant, ACE-inhibitory, and anti-amnestic properties. The results of in vitro digestion revealed that the <1 kDa peptide fraction of porcine gelatin hydrolysate obtained after 1 h digestion with papain (PP) (PP1, <1 kDa) potently inhibited ACE, acetylcholinesterase, and prolyl endopeptidase activities at 87.42%, 21.24%, and 48.07%, respectively. Administering the PP1 to DG-induced amnesic mice ameliorated the spatial cognitive impairment and Morris water maze learning abilities. The dentate area morphology in the PP1-treated mice was relatively similar to the control group. In addition, PP1 enhanced the antioxidant capacity in the DG-induced amnesic mice. This study suggests that PP1 could serve as a potential treatment tool against oxidative stress, hypertension, and neurodegenerative diseases.

Multiplex Connectome Changes across the Alzheimer's Disease Spectrum Using Gray Matter and Amyloid Data.

The organization of the Alzheimer's disease (AD) connectome has been studied using graph theory using single neuroimaging modalities such as positron emission tomography (PET) or structural magnetic resonance imaging (MRI). Although these modalities measure distinct pathological processes that occur in different stages in AD, there is evidence that they are not independent from each other. Therefore, to capture their interaction, in this study we integrated amyloid PET and gray matter MRI data into a multiplex connectome and assessed the changes across different AD stages. We included 135 cognitively normal (CN) individuals without amyloid-ß pathology (Aß-) in addition to 67 CN, 179 patients with mild cognitive impairment (MCI) and 132 patients with AD dementia who all had Aß pathology (Aß+) from the Alzheimer's Disease Neuroimaging Initiative. We found widespread changes in the overlapping connectivity strength and the overlapping connections across Aß-positive groups. Moreover, there was a reorganization of the multiplex communities in MCI Aß + patients and changes in multiplex brain hubs in both MCI Aß + and AD Aß + groups. These findings offer a new insight into the interplay between amyloid-ß pathology and brain atrophy over the course of AD that moves beyond traditional graph theory analyses based on single brain networks.

A booster dose of Delta × Omicron hybrid mRNA vaccine produced broadly neutralizing antibody against Omicron and other SARS-CoV-2 variants.

BACKGROUND: With the continuous emergence of new SARS-CoV-2 variants that feature increased transmission and immune escape, there is an urgent demand for a better vaccine design that will provide broader neutralizing efficacy. METHODS: We report an mRNA-based vaccine using an engineered "hybrid" receptor binding domain (RBD) that contains all 16 point-mutations shown in the currently prevailing Omicron and Delta variants. RESULTS: A booster dose of hybrid vaccine in mice previously immunized with wild-type RBD vaccine induced high titers of broadly neutralizing antibodies against all tested SARS-CoV-2 variants of concern (VOCs). In naïve mice, hybrid vaccine generated strong Omicron-specific neutralizing antibodies as well as low but significant titers against other VOCs. Hybrid vaccine also elicited CD8+/IFN-γ+ T cell responses against a conserved T cell epitope present in wild type and all VOCs. CONCLUSIONS: These results demonstrate that inclusion of different antigenic mutations from various SARS-CoV-2 variants is a feasible approach to develop cross-protective vaccines.

Disclosing an In-Frame Deletion of the Titin Gene as the Possible Predisposing Factor of Anthracycline-Induced Cardiomyopathy: A Case Report.

Anthracycline-induced cardiomyopathy has been noted as a non-neglectable issue in the field of clinical oncology. Remarkable progress has been achieved in searching for inherited susceptible genetic deficits underlying anthracycline cardiotoxicity in the past several years. In this case report, we present the preliminary results of a genetic study in a young male patient who was treated with standard dose anthracycline-based chemotherapy for his acute myeloid leukemia and attacked by acute congestive heart failure after just two courses of therapy. After a survey of 76 target genes, an in-frame deletion of the titin gene was recognized as the most possible genetic defect responsible for his cardiomyopathy caused by anthracycline. This defect proved to pass down from the patient's mother and did not exist in seven unrelated chemotherapy-treated cancer patients without chemotherapy-induced cardiomyopathy and four other healthy volunteer DNA donors.

Totally extraperitoneal approach for open complex abdominal wall reconstruction.

BACKGROUND: Ventral hernia repair is typically performed via a transabdominal approach and the peritoneal cavity is opened and explored. Totally extraperitoneal ventral hernia repair (TEVHR) facilitates dissection of the hernia sac without entering the peritoneal cavity. This study evaluates our experience of TEVHR, addressing technique, decision-making, and outcomes. METHODS: This is an IRB-approved retrospective review of open TEVHR performed between January 2012 and December 2016. Medical records were reviewed for patient demographics, operative details, postoperative outcomes, hospital readmissions, and reoperations. RESULTS: One hundred sixty-six patients underwent TEVHR (84 males, 82 females) with a mean BMI range of 30-39. Eighty-six percent of patients underwent repair for primary or first-time recurrent hernia, and 89% CDC wound class I. Median hernia defect size was 135 cm2. Hernia repair techniques included Rives-Stoppa (34%) or transversus abdominis release (57%). Median operative time was 175 min, median blood loss 100 mL, and median length of stay 4 days. There were no unplanned bowel resections or enterotomies. Four cases required intraperitoneal entry to explant prior mesh. Wound complication rate was 27%: 9% seroma drainage, 18% superficial surgical site infection (SSI), and 2% deep space SSI. Five patients (3%) required reoperation for wound or mesh complications. Over the study, four patients were hospitalized for postoperative small bowel obstruction and managed non-operatively. Of the 166 patients, 96%, 54%, and 44% were seen at 3-month, 6-month, and 12-month follow-ups, respectively. Recurrences were observed in 2% of patients at 12-month follow-up. One patient developed an enterocutaneous fistula 28 months postoperatively. CONCLUSIONS: TEVHR is a safe alternative to traditional transabdominal approaches to ventral hernia repair. The extraperitoneal dissection facilitates hernia repair, avoiding peritoneal entry and adhesiolysis, resulting in decreased operative times. In our study, there was low risk for postoperative bowel obstruction and enterotomy. Future prospective studies with long-term follow-up are required to draw definitive conclusions.

Survival analysis of extramammary Paget's disease (EMPD) in a tertiary hospital in Taiwan.

BACKGROUND: This study aimed to investigate the survival analysis of extramammary Paget's disease (EMPD) in a Taiwanese population and to provide data for comparison with other studies in various locations and racial populations. METHODS: We retrospectively analyzed the medical records of 63 patients with EMPD who were surgically treated from 2002 to 2019 at a single institution. The primary endpoint was the 5-year overall survival rate of EMPD, and the secondary endpoint was recurrence-free 5-year survival. Independent variables included patients' demographic data, concurrent malignancy (i.e., non-EMPD-related cancers), tumor size, distant metastasis, and surgery and/or radiation. RESULTS: Of all the 63 patients, 8 cases were excluded. A total of 43 patients (78.18%) were male, and 12 were female, with a mean age of 72.67 years (range 44-89 years). The most common affected anatomic site was the penoscrotal region (22 patients, 40.00%), followed by the perianal and perineal regions (17 patients, 30.91%). Among the 55 patients, 41 patients (74.55%) were diagnosed with at least one underlying disease, whereas the most common underlying disease was cardiovascular disease (30 patients, 54.55%). The overall survival rate was 80.00% at 36 months and 65.45% at the end of follow-up. EMPD with deep dermal invasion was a significant poor prognostic factor of overall survival in cause-specific hazard model (sub-hazard ratio (HR) 5.167, p = 0.0015, 95% confidence interval (CI) 1.876-14.230). Patients with regional metastasis or distant metastasis had poorer prognosis of 5-year survival (sub-HR 4.513, p = 0.0028, CI 1.683-12.103). The limitations of this study include its retrospective nature and sample size. CONCLUSIONS: In our series, EMPD with metastasis and deep dermal invasion was the significant harmful factors in both overall 5-year survival and 5-year recurrence-free survival. The surgical excision is not associated with a low risk of local recurrence or overall survival, and long-term follow-up is still needed.

The win ratio: Impact of censoring and follow-up time and use with nonproportional hazards.

The win ratio has been studied methodologically and applied in data analysis and in designing clinical trials. Researchers have pointed out that the results depend on follow-up time and censoring time, which are sometimes used interchangeably. In this article, we distinguish between follow-up time and censoring time, show theoretically the impact of censoring on the win ratio, and illustrate the impact of follow-up time. We then point out that, if the treatment has long-term benefit from a more important but less frequent endpoint (eg, death), the win ratio can show that benefit by following patients longer, avoiding masking by more frequent but less important outcomes, which occurs in conventional time-to-first-event analyses. For the situation of nonproportional hazards, we demonstrate that the win ratio can be a good alternative to methods such as landmark survival rate, restricted mean survival time, and weighted log-rank tests.

Arsenic induces fibrogenic changes in human kidney epithelial cells potentially through epigenetic alterations in DNA methylation.

Arsenic contamination is a significant public health issue, and kidney is one of the target organ for arsenic-induced adverse effects. Renal fibrosis is a well-known pathological stage frequently observed in progressive chronic kidney disease (CKD). Epidemiological studies implicate arsenic exposure to CKD, but the role of arsenic in kidney fibrosis and the underlying mechanism is still unclear. It is in this context that the current study evaluated the effects of long-term arsenic exposure on the cellular response in morphology, and marker genes expression with respect to fibrosis using human kidney 2 (HK-2) epithelial cells. Results of this study revealed that in addition to increased growth, HK-2 cells underwent phenotypic, biochemical and molecular changes indicative of epithelial-mesenchymal transition (EMT) in response to the exposure to arsenic. Most importantly, the arsenic-exposed cells acquired the pathogenic features of fibrosis as supported by increased expression of markers for fibrosis, such as Collagen I, Fibronectin, transforming growth factor ß, and α-smooth muscle actin. Upregulation of fibrosis associated signaling molecules such as tissue inhibitor of metalloproteinases-3 and matrix metalloproteinase-2 as well as activation of AKT was also observed. Additionally, the expression of epigenetic genes (DNA methyltransferases 3a and 3b; methyl-CpG binding domain 4) was increased in arsenic-exposed cells. Treatment with DNA methylation inhibitor 5-Aza-2'-dC reversed the EMT properties and restored the level of phospho-AKT. Together, these data for the first time suggest that long-term exposure to arsenic can increase the risk of kidney fibrosis. Additionally, our data suggest that the arsenic-induced fibrotic changes are, at least in part, mediated by DNA methylation and therefore potentially can be reversed by epigenetic therapeutics.

Nicotine-induced oxidative stress contributes to EMT and stemness during neoplastic transformation through epigenetic modifications in human kidney epithelial cells.

Nicotine is a component of cigarette smoke and mounting evidence suggests toxicity and carcinogenicity of tobacco smoke in kidney. Carcinogenicity of nicotine itself in kidney and the underlying molecular mechanisms are not well-understood. Hence, the objective of this study was to determine the carcinogenic effects of chronic nicotine exposure in Hk-2 human kidney epithelial cells. The effects of nicotine exposure on the expression of genes for cellular reprogramming, redox status, and growth signaling pathways were also evaluated to understand the molecular mechanisms. Results revealed that chronic exposure to nicotine induced growth and neoplastic transformation in HK-2 cells. Increased levels of intracellular reactive oxygen species (ROS), acquired stem cell-like sphere formation, and epithelial-mesenchymal-transition (EMT) changes were observed in nicotine exposed cells. Treatment with antioxidant N-acetyl cysteine (NAC) resulted in abrogation of EMT and stemness in HK-2 cells, indicating the role of nicotine-induced ROS in these morphological changes. The result also suggests that ROS controls the stemness through regulation of AKT pathway during early stages of carcinogenesis. Additionally, the expression of epigenetic regulatory genes was altered in nicotine-exposed cells and the changes were reversed by NAC. The epigenetic therapeutics 5-aza-2'-deoxycytidine and Trichostatin A also abrogated the stemness. This suggests the nicotine-induced oxidative stress caused epigenetic alterations contributing to stemness during neoplastic transformation. To our knowledge, this is the first report showing the ROS-mediated epigenetic modifications as the underlying mechanism for carcinogenicity of nicotine in human kidney epithelial cells. This study further suggests the potential of epigenetic therapeutics for pharmacological intervention in nicotine-induced kidney cancer.

Arsenic-Induced Neoplastic Transformation Involves Epithelial-Mesenchymal Transition and Activation of the ß-Catenin/c-Myc Pathway in Human Kidney Epithelial Cells.

Arsenic contamination is a serious environmental and public health issue worldwide including the United States. Accumulating evidence suggests that kidney is one of the target organs for arsenic-induced carcinogenesis. However, the mechanism of arsenic-induced renal carcinogenesis is not well understood. Therefore, the objective of this study was to evaluate the carcinogenicity of chronic exposure to an environmentally relevant concentration of arsenic on kidney epithelial cells and identify the molecular mechanism underlying this process. HK-2 kidney epithelial cells were treated with arsenic for acute, long-term, and chronic durations, and cellular responses to arsenic exposure at these time points were evaluated by the changes in growth, morphology, and expression of genes. The results revealed a significant growth increase after long-term and chronic exposure to arsenic in HK-2 cells. The morphological changes of EMT and stem cell sphere formation were also observed in long-term arsenic exposed cells. The anchorage-independent growth assay for colony formation and cell maintenance in cancer stem cell medium further confirmed neoplastic transformation and the induced cancer stem cell properties of arsenic-exposed cells. Additionally, the expression of marker genes confirmed the increased growth, EMT, and stemness during arsenic-induced carcinogenesis. Moreover, the increase expression of ß-catenin and c-Myc further suggested the role of these signaling molecules during carcinogenesis in HK-2 cells. In summary, results of this study suggest that chronic exposure to arsenic even at a relatively lower concentration can induce neoplastic transformation through acquisitions of EMT, stemness, and MET phenotypes, which might be related to the ß-catenin/c-Myc signaling pathway.

Statistical considerations for rare diseases drug development.

One of the most challenges for rare disease clinical trials is probably the availability of a small patient population. It is then a great concern on how to conduct clinical trials with a small number of subjects available for obtaining substantial evidence regarding safety and effectiveness for approval of the rare disease drug product under investigation. FDA, however, does not have the intention to create a statutory standard for approval of orphan drugs that are different from the standard for approval of drugs in common conditions. Thus, it is suggested that innovative trial designs such as a complete n-of-1 trial design or an adaptive design should be used for an accurate and reliable assessment of rare disease drug products under investigation. In this article, basic considerations, innovative trial designs, and statistical methods for data analysis are discussed. In addition, some innovative thinking for the evaluation of rare disease drug products is proposed.

In Silico and In Vitro Assessment of Portuguese Oyster (Crassostrea angulata) Proteins as Precursor of Bioactive Peptides.

In this study, the potential bioactivities of Portuguese oyster (Crassostrea angulata) proteins were predicted through in silico analyses and confirmed by in vitro tests. C. angulata proteins were characterized by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and identified by proteomics techniques. Hydrolysis simulation by BIOPEP-UWM database revealed that pepsin (pH > 2) can theoretically release greatest amount of bioactive peptides from C. angulata proteins, predominantly angiotensin I-converting enzyme (ACE) and dipeptidyl peptidase IV (DPP-IV) inhibitory peptides, followed by stem bromelain and papain. Hydrolysates produced by pepsin, bromelain and papain have shown ACE and DPP-IV inhibitory activities in vitro, with pepsin hydrolysate (PEH) having the strongest activity of 78.18% and 44.34% at 2 mg/mL, respectively. Bioactivity assays of PEH fractions showed that low molecular weight (MW) fractions possessed stronger inhibitory activity than crude hydrolysate. Overall, in vitro analysis results corresponded with in silico predictions. Current findings suggest that in silico analysis is a rapid method to predict bioactive peptides in food proteins and determine suitable enzymes for hydrolysis. Moreover, C. angulata proteins can be a potential source of peptides with pharmaceutical and nutraceutical application.

Prediction of Bioactive Peptides from Chlorella sorokiniana Proteins Using Proteomic Techniques in Combination with Bioinformatics Analyses.

Chlorella is one of the most nutritionally important microalgae with high protein content and can be a good source of potential bioactive peptides. In the current study, isolated proteins from Chlorella sorokiniana were subjected to in silico analysis to predict potential peptides with biological activities. Molecular characteristics of proteins were analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and proteomics techniques. A total of eight proteins were identified by proteomics techniques from 10 protein bands of the SDS-PAGE. The predictive result by BIOPEP's profile of bioactive peptides tools suggested that proteins of C. sorokiniana have the highest number of dipeptidyl peptidase-IV (DPP IV) inhibitors, with high occurrence of other bioactive peptides such as angiotensin-I converting enzyme (ACE) inhibitor, glucose uptake stimulant, antioxidant, regulating, anti-amnestic and antithrombotic peptides. In silico analysis of enzymatic hydrolysis revealed that pepsin (pH > 2), bromelain and papain were proteases that can release relatively larger quantity of bioactive peptides. In addition, combinations of different enzymes in hydrolysis were observed to dispense higher numbers of bioactive peptides from proteins compared to using individual proteases. Results suggest the potential of protein isolated from C. sorokiniana could be a source of high value products with pharmaceutical and nutraceutical application potential.

Tellimagrandin II, A Type of Plant Polyphenol Extracted from Trapa bispinosa Inhibits Antibiotic Resistance of Drug-Resistant Staphylococcus aureus.

The emergence of methicillin-resistant Staphylococcus aureus (MRSA) has become a critical global concern. Identifying new candidates of anti-S. aureus agents is urgently required because the therapeutic strategies for infected patients are limited currently. Therefore, the present study investigated whether Tellimagrandin II (TGII), a pure compound extracted from the shells of Trapa bispinosa, exhibits antibacterial effects against MRSA. We first showed that TGII exerted potent inhibitory activity against MRSA with a minimum inhibitory concentration of 128 µg/mL. The obtained fractional inhibitory concentration suggested that TGII could alone exert antistaphylococcal activity, and TGII combined with low doses of antibiotics displayed synergistic effects against MRSA. Moreover, we found that TGII exerted bactericidal activity by reducing the expression of mecA followed by the negative regulation of the penicillin-binding protein 2a (PBP2a) of MRSA. Transmission electron microscopy (TEM) images further confirmed that TGII destroyed the integrity of the cell wall of MRSA and caused the loss of cytoplasm content. In conclusion, we evidenced the antibacterial effects of TGII against MRSA, which enables the effective dose of current antibiotics to be reduced and the predicament of drug-resistant S. aureus isolates to be overcome.

Trifluoperazine, an Antipsychotic Drug, Effectively Reduces Drug Resistance in Cisplatin-Resistant Urothelial Carcinoma Cells via Suppressing Bcl-xL: An In Vitro and In Vivo Study.

Cisplatin-based chemotherapy is the primary treatment for metastatic bladder urothelial carcinoma (UC). Most patients inevitably encounter drug resistance and resultant disease relapse. Reduced apoptosis plays a critical role in chemoresistance. Trifluoperazine (TFP), an antipsychotic agent, has demonstrated antitumor effects on various cancers. This study investigated the efficacy of TFP in inhibiting cisplatin-resistant bladder UC and explored the underlying mechanism. Our results revealed that cisplatin-resistant UC cells (T24/R) upregulated the antiapoptotic factor, B-cell lymphoma-extra large (Bcl-xL). Knockdown of Bcl-xL by siRNA resensitized cisplatin-resistant cells to the cisplatin cytotoxic effect. TFP (10-45 µM) alone elicited dose-dependent cytotoxicity, apoptosis, and G0/G1 arrest on T24/R cells. Co-treatment of TFP potentiated cisplatin-induced cytotoxicity in T24/R cells. The phenomenon that TFP alleviated cisplatin resistance to T24/R was accompanied with concurrent suppression of Bcl-xL. In vivo models confirmed that TFP alone effectively suppressed the T24/R xenograft in nude mice. TFP co-treatment enhanced the antitumor effect of cisplatin on the T24/R xenograft. Our results demonstrated that TFP effectively inhibited cisplatin-resistant UCs and circumvented cisplatin resistance with concurrent Bcl-xL downregulation. These findings provide a promising insight to develop a therapeutic strategy for chemoresistant UCs.

Duration-dependent effects of nicotine exposure on growth and AKT activation in human kidney epithelial cells.

Exposure to nicotine is known to cause adverse effects in many target organs including kidney. Epidemiological studies suggest that nicotine-induced kidney diseases are prevalent worldwide. However, the impact of duration of exposure on the nicotine-induced adverse effects in normal kidney cells and the underlying molecular mechanism is still unclear. Hence, the objective of this study was to evaluate both acute and long-term effects of nicotine in normal human kidney epithelial cells (HK-2). Cells were treated with 1 and 10 µM nicotine for acute and long-term duration. The result of cell viability showed that the acute exposure to 1 µM nicotine has no significant effect on growth. However, the 10 µM nicotine caused significant decrease in the growth of HK-2 cells. The long-term exposure resulted in significantly increased cell growth in both 1 and 10 µM nicotine-treated groups. Analysis of cell cycle and expression of marker genes related to proliferation and apoptosis further confirmed the effects of nicotine. Additionally, the analysis of growth signaling pathway revealed the decreased level of pAKT in cells with acute exposure whereas the increased level of pAKT in long-term nicotine-exposed cells. This suggests that nicotine, through modulating the AKT pathway, controls the duration-dependent effects on the growth of HK-2 cells. In summary, this is the first report showing long-duration exposure to nicotine causes increased proliferation of human kidney epithelial cells through activation of AKT pathway.

On sample size requirement for analytical similarity assessment.

For approval of biosimilar products, the U.S. Food and Drug Administration (FDA) recommends a stepwise approach for obtaining the totality-of-the-evidence for assessing biosimilarirty between a proposed biosimilar product and its corresponding innovative (reference) biologic product. The stepwise approach starts with the assessment of analytical similarity of critical quality attributes (CQAs) for structural/physicochemical and functional properties in the manufacturing process of biosimilar products. For Tier 1 CQAs which are most relevant to clinical outcomes, the FDA recommends an equivalence test be performed for similarity assessment based on an equivalence acceptance criterion (EAC). While performing the equivalence test, sample size is a critical component of the equivalence test. This article focuses on the discussion of the FDA's proposal: select an appropriate sample size by adjusting EAC margin and variability ([Formula: see text]). The article provides a thorough discussion on the FDA's proposal; sample size requirement under different scenarios are briefly described and a numerical study which compares sample size requirement under various combinations of study parameters is conducted.

A Novel Dual-Band Six-Phase Voltage-Control Oscillator.

The paper presents a novel dual-band six-phase voltage-control oscillator. The voltage-controlled oscillator (VCO) with a single-ended delay cell architecture has a lower power consumption, a smaller chip area, and a larger output swing than one with a differential delay cell architecture. However, the conventional even-phase outputs ring-type VCO cannot be implemented using single-ended delay cells. In other words, the VCO with single-ended delay cells meets most of the requirements of a sensor circuit system, except even-phase outputs function. This work presents a dual-band six-phase ring type VCO, which is implemented using the proposed single-ended delay cell. The proposed VCO both exhibits the advantages of single-ended delay cells and differential delay cells. The proposed delay cell has a band-switching function, which improves the jitter performance of a VCO in which it is used. The proposed VCO can be operated at 890⁻1080 MHz. The peak-to-peak jitter and the root mean square jitter are the 35.5 ps and 2.8 ps (at 1 GHz), respectively. The maximal power consumption is approximately 6.4 mW at a supply voltage of 1.8 V in a United Microelectronics Corporation 0.18 µm RF CMOS process. The area of the chip is 0.195 × 0.208 mm².