Search

This work investigates the production of hydrogen (H 2 ) and formic acid (HCOOH) through a photoelectrochemical (PEC) approach. Nickel oxide nanofilms prepared by sputtering capped on n-GaN photoelectrodes were employed to achieve simultaneous water photoelectrolysis and CO 2 reduction. The study delves into the role of the nickel oxide layer, examining its potential as a catalyst and/or a protective layer. Furthermore, the influence of nickel oxide layer thickness on the performance of the photoelectrodes is explored. In essence, appropriate nickel oxide thickness is beneficial in increasing the photocurrent of the PEC reaction. The observed improvements in photocurrents and, hence, the production rates can be attributed to the functionality of the nickel oxide nanofilm: mitigating the negative influence of surface defects on n-GaN and facilitating the separation of photogenerated electron-hole pairs at the electrolyte/n-GaN interface. Specifically, PEC cells utilizing the 4 nm-thick nickel oxide nanofilms deposited on n-gallium nitride (n-GaN) electrodes demonstrate a significant enhancement in hydrogen and formic acid production rates. These rates were at least 45% higher compared to PECs using bare n-GaN electrodes., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Background: Originator drug manufacturers use several strategies to delay generic competition in the USA, but it remains unclear whether this results in longer market exclusivity compared to other countries., Objectives: We sought to understand how drug market exclusivity lengths vary between the USA and two comparable countries., Methods: We focused on drugs approved within 2 years of each other in the USA, France, and Australia from 1995 to 2005, and we compared the lengths of exclusivity from marketing approval through first generic competition or June 2023 using Kaplan-Meier analyses., Results: Among 165 drugs in common between the USA and France, the median length of exclusivity was slightly longer in France (15.0 years, interquartile range [IQR]: 13.0-19.6) than the USA (14.5 years, IQR: 11.7-17.6). Among 100 drugs in common between the USA and Australia, the median length of exclusivity was longer in Australia (16.3 years, IQR: 13.9-22.4) than in the USA (14.4 years, IQR: 12.0-17.1)., Conclusions: Market exclusivity lengths in the USA are not longer than in France and Australia. Potential reasons include the larger US market and incentives that offer transient high generic drug prices in the USA for manufacturers that successfully challenge originator market exclusivity., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Importance: Brand-name drugs are sold at high prices in the US during market exclusivity periods protected by patents. Multiple overlapping patents protecting a drug are known as patent thickets and can effectively delay the emergence of price-lowering generic competition for many years., Objective: To evaluate the composition of patent thickets of 10 top-selling prescription drugs in the US and compare the characteristics of drug patents filed during development with those filed on these products after US Food and Drug Administration (FDA) approval., Design and Setting: This cross-sectional study examined US patent thickets of the 10 prescription drugs with the highest US net sales revenue in 2021 using information on issued patents and patent applications as of June 30, 2022, obtained from a public database by the Initiative for Medicines, Access, and Knowledge. Data were analyzed from September 2022 to June 2023., Main Outcomes and Measures: Prevalence of patents filed before and after FDA approval; types of claims present in issued patents (ie, chemical composition, method of use, process or synthesis, formulation, and delivery device); and patent thicket density (number of active patents at a given time)., Results: The 10 top-selling prescription drugs in the US for 2021 included 4 small-molecule drugs and 6 biologics. These 10 drugs were linked to 1429 patents and patent applications: 742 (52%) issued patents, 218 (15%) pending applications, and 469 (33%) abandoned applications. Almost three-quarters of patent applications (1028 [72%]) were filed after FDA approval. The postapproval proportion was higher for biologics (80%) than for small-molecule drugs (58%). Postapproval filing of patent applications peaked in the first 5 years after FDA approval for small-molecule drugs and 12 years after FDA approval for biologics. Of 465 patents issued for applications filed after FDA approval, 189 (41%) had method of use claims, 127 (27%) had formulation claims, and 103 (22%) had process or synthesis claims, while 86 (19%) had chemical composition claims and 46 (10%) had device claims. Patent thicket density peaked 13 years after FDA approval, at which time these 10 drugs were protected by a median (IQR) of 42 (18-83) active patents, 66% of which were filed after FDA approval., Conclusions and Relevance: This study found that among the 10 top-selling prescription drugs in the US in 2021, patents filed after FDA approval and containing claims covering aspects other than the active ingredient of the drug contributed to patent thickets. Scrutiny of patent applications and of patents filed after FDA approval is needed to facilitate timely generic or biosimilar competition.

Patents prevent generic drug entry. Brand firms file new "method of use" patents for old drugs to prevent generic entry. Congress addressed this issue by creating the "skinny label" pathway, which allows generic firms to use the drug label to indicate that the old drug can only be used for non-patented uses. This pathway is now in jeopardy due to a recent court case. This paper outlines the issues and suggests possible legislative solutions., (© 2023 The Authors. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)

Background: Insulin is the primary treatment for type 1 and some type 2 diabetes but remains costly in the United States, even though it was discovered more than a century ago. High prices can lead to nonadherence and are often sustained by patents and regulatory exclusivities that limit competition on brand-name products. We sought to examine how manufacturers have used patents and regulatory exclusivities on insulin products approved from 1986 to 2019 to extend periods of market exclusivity., Methods and Findings: We used the publicly available Food and Drug Administration (FDA) Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) to identify all approved biosynthetic insulin products. Individual products approved under the same New Drug Application (NDA)-e.g., a vial and pen-were considered as separate products for the purposes of analysis. We recorded all patents and regulatory exclusivities listed in the Orange Book on each product and used Google Patents to extract the timing of patent application and whether patents were obtained on delivery devices or others aspects of the product. The primary outcome was the duration of expected protection, which was determined by subtracting the FDA approval date for each product from its last-to-expire patent or regulatory exclusivity (whichever occurred later). We performed a secondary analysis that considered overall protection on insulin lines-defined as groups of products approved under the same NDA with the same active ingredients manufactured by the same company. We also examined competition from follow-on insulin products-defined as products approved with the same active ingredients as originators but manufactured by different companies (approved via a specific drug approval pathway under section 505(b)(2) of the Food, Drug, and Cosmetic Act). During the study period, the FDA approved 56 individual products across 25 different insulin lines and 5 follow-ons across 3 different insulin lines. Thirty-three (59%) of the 56 products were drug-device combinations. Manufacturers of 9 products approved during the study period obtained patents filed after FDA approval that extended their duration of expected protection (by a median of 6 years). Approximately 63% of all patents on drug-device combinations approved during the study period were related to delivery devices. The median duration of expected protection on insulin products was 16.0 years, and the median protection on insulin lines was 17.6 years. An important limitation of our analysis is that manufacturers may continue to add patents on existing insulin products while competitors may challenge patents; therefore, periods of protection may change over time., Conclusions: Among several strategies that insulin manufacturers have employed to extend periods of market exclusivity on brand-name insulin products are filing patents after FDA approval and obtaining a large number of patents on delivery devices. Policy reforms are needed to promote timely competition in the pharmaceutical market and ensure that patients have access to low-cost drugs., Competing Interests: AO serves as a fellow in the Office of the Assistant Secretary for Planning and Evaluation. ASK is a member of the PLOS Medicine Editorial Board and has served as an expert witness in litigation against Gilead relating to tenofovir-containing products. Outside the scope of the work, WBF serves as a consultant for the non-profit Alosa Health and as an expert witness in litigation against inhaler manufacturers. WBF also served as a consultant to Aetion., (Copyright: © 2023 Olsen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Importance: Glucagon-like peptide 1 (GLP-1) receptor agonists were first approved for the treatment of type 2 diabetes in 2005. Demand for these drugs has increased rapidly in recent years, as indications have expanded, but they remain expensive., Objective: To analyze how manufacturers of brand-name GLP-1 receptor agonists have used the patent and regulatory systems to extend periods of market exclusivity., Evidence Review: The annual US Food and Drug Administration's (FDA) Approved Drug Products With Therapeutic Equivalence Evaluations was used to identify GLP-1 receptor agonists approved from 2005 to 2021 and to record patents and nonpatent statutory exclusivities listed for each product. Google Patents was used to extract additional data on patents, including whether each was obtained on the delivery device or another aspect of the product. The primary outcome was the duration of expected protection from generic competition, defined as the time elapsed from FDA approval until expiration of the last-to-expire patent or regulatory exclusivity., Findings: On the 10 GLP-1 receptor agonists included in the cohort, drug manufacturers listed with the FDA a median of 19.5 patents (IQR, 9.0-25.8) per product, including a median of 17 patents (IQR, 8.3-22.8) filed before FDA approval and 1.5 (IQR, 0-2.8) filed after FDA approval. Fifty-four percent of all patents listed on GLP-1 receptor agonists were on the delivery devices rather than active ingredients. Manufacturers augmented patent protection with a median of 2 regulatory exclusivities (IQR, 0-3) obtained at approval and 1 (IQR, 0.3-4.3) added after approval. The median total duration of expected protection after FDA approval, when accounting for both preapproval and postapproval patents and regulatory exclusivities, was 18.3 years (IQR, 16.0-19.4). No generic firm has successfully challenged patents on GLP-1 receptor agonists to gain FDA approval., Conclusions and Relevance: Patent and regulatory reform is needed to ensure timely generic entry of GLP-1 receptor agonists to the market.

Background: Patients with asthma and COPD rely on inhalers to control symptoms. Yet, these products remain expensive, in part because brand-name manufacturers have obtained numerous patents on inhalers, including on their delivery devices. Recent antitrust litigation has raised questions about the boundaries of listing device patents with the US Food and Drug Administration (FDA), particularly when patents do not claim any active ingredients., Research Question: How have manufacturers relied on device patents to preserve market exclusivity on brand-name inhalers?, Study Design and Methods: We identified patents on brand-name inhalers approved for asthma and COPD between 1986 and 2020 using the FDA's Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book). We extracted information about patents from LexisNexis TotalPatent One and Google Patents and searched device patents for mention of active ingredients or other prespecified features linking the patent to the relevant drug. For each inhaler, we determined the duration of protection added by device patents., Results: The FDA approved 53 brand-name inhalers for asthma and COPD from 1986 through 2020, 39 of which had at least one device patent. One hundred thirty-seven distinct device patents were in the final cohort, representing 49% of all patents listed on inhalers. Seventy-seven percent of device patents made no mention of active ingredients or their molecular structures, and 72% made no mention of any relevant prespecified feature connecting the device patent to the drug product. For the 39 brand-name inhalers with one or more device patents listed in the Orange Book, device patents extended the duration of market protection by a median of 5.5 years (interquartile range, 0.0-10.5 years) beyond the last-to-expire nondevice patent., Interpretation: Patent and regulatory reform is needed to promote generic competition and to ensure that patients with asthma and COPD have access to affordable medications., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

In Brief: Impaired spermatogenesis resulting from disturbed cholesterol metabolism due to intake of high-fat diet (HFD) has been widely recognized, however, the role of preprotein invertase subtilin 9 (PCSK9), which is a negative regulator of cholesterol metabolism, has never been reported. This study aims to reveal the role of PCSK9 on spermatogenesis induced by HFD in mice., Abstract: Long-term consumption of a high-fat diet (HFD) is an important factor that leads to impaired spermatogenesis exhibiting poor sperm quantity and quality. However, the mechanism of this is yet to be elucidated. Disrupted cholesterol homeostasis is one of many crucial pathological factors which could contribute to impaired spermatogenesis. As a negative regulator of cholesterol metabolism, preprotein invertase subtilin 9 (PCSK9) mediates low density lipoprotein receptor (LDLR) degradation to the lysosome, thereby reducing the expression of LDLR on the cell membrane and increasing serum low-density lipoprotein cholesterol level, resulting in lipid metabolism disorders. Here, we aim to study whether PCSK9 is a pathological factor for impaired spermatogenesis induced by HFD and the underlying mechanism. To meet the purpose of our study, we utilized wild-type C57BL/6 male mice and PCSK9 knockout mice with same background as experimental subjects and alirocumab, a PCSK9 inhibitor, was used for treatment. Results indicated that HFD induced higher PCSK9 expression in serum, liver, and testes, and serum PCSK9 is negatively correlated with spermatogenesis, while both PCSK9 inhibitor treatment and PCSK9 knockout methodologies ameliorated impaired lipid metabolism and spermatogenesis in mice fed a HFD. This could be due to the overexpression of PCSK9 induced by HFD leading to dyslipidemia, resulting in testicular lipotoxicity, thus activating the Bcl-2-Bax-Caspase3 apoptosis signaling pathway in testes, particularly in Leydig cells. Our study demonstrates that PCSK9 is an important pathological factor in the dysfunction of spermatogenesis in mice induced by HFD. This finding could provide innovative ideas for the diagnosis and treatment of male infertility.

Between 1986 and 2020 the Food and Drug Administration (FDA) approved fifty-three brand-name inhalers for asthma and chronic obstructive pulmonary disease (COPD), but by the end of 2022 only three of those inhalers faced independent generic competition. Manufacturers of brand-name inhalers have created long periods of market exclusivity by obtaining multiple patents, many on the delivery devices rather than the active ingredients, and by introducing new devices that contain old active ingredients. Limited generic competition for inhalers has raised questions about whether the Drug Price Competition and Patent Term Restoration Act of 1984, also known as the Hatch-Waxman Act, for challenging patents is adequately facilitating the entry of complex generic drug-device combinations. For the fifty-three brand-name inhalers approved during the period 1986-2020, generic manufacturers filed challenges authorized by the Hatch-Waxman Act, which are known as paragraph IV certifications, on only seven products (13 percent). The median time from FDA approval to first paragraph IV certification was fourteen years. Paragraph IV certifications resulted in approved generics for only two products, each of which experienced fifteen years of market exclusivity before generic approval. Reform of the generic drug approval system is critical to ensuring the timely availability of competitive markets for generic drug-device combinations such as inhalers.

Background: Traumatic aortic dissection with traumatic diaphragmatic hernia is a rare traumatic disease. The purpose of this article is to investigate the imaging characteristics and treatment strategies for traumatic diaphragmatic hernia with aortic dissection., Case Presentation: The imaging and clinical data of 3 patients with traumatic diaphragmatic hernia combined with aortic dissection were analyzed retrospectively. Of the three cases, two were males, and one was female; their mean age was 52.7 years (range, 47-62 years). Plain chest CT scans revealed diaphragmatic hernia in 2 patients, but no traumatic aortic dissection was found. Diaphragmatic hernia repair was performed in all patients. Aortic dilatation was found during intraoperative exploration, and aortic dissection was confirmed by postoperative enhanced CT. One patient underwent stent implantation and recovered smoothly (Case 1). The other patient refused stent implantation and died of thoracic hemorrhage (Case 2). The third patient underwent preoperative enhanced CT to identify traumatic diaphragmatic hernia with aortic dissection (Case 3). Aortic covered stent implantation was performed immediately, and diaphragmatic hernia repair was performed at a selected time. The patient's postoperative recovery was good., Conclusion: A preoperative plain chest CT scan indicated diaphragmatic hernia in major blunt thoracic trauma patients with a history of trauma and blurred periaortic spaces accompanied by hematocele and other imaging manifestations. Chest-enhanced CT should be performed to improve the diagnostic accuracy of aortic dissection., (© 2023. The Author(s).)

Aims: Polycystic ovary syndrome (PCOS) is a common endocrine disorder in the women of childbearing age. It is characterized by hyperandrogenism and abnormal follicular growth and ovulation. The polyol pathway is a glucose metabolism bypass pathway initiated by aldose reductase (ADR). Androgen induces the expression of ADR in the male reproductive tract, which has a general physiological significance for male reproductive function. Here we investigate whether hyperandrogenemia in PCOS leads to increased flux of the polyol pathway in ovarian tissue, which in turn affects follicular maturation and ovulation through oxidative stress., Main Methods: We used clinical epidemiological methods to collect serum and granulosa cells from clinical subjects for a clinical case-control study. At the same time, cell biology and molecular biology techniques were used to conduct animal and cell experiments to further explore the mechanism of hyperandrogen-induced ovarian polyol pathway hyperactivity and damage to ovarian function., Key Findings: Here, we find that hyperandrogenism of PCOS can induce the expression of ovarian aldose reductase, which leads to the increase of the polyol pathway flux, and affects ovarian function through excessive oxidative stress., Significance: Our research has enriched the pathological mechanism of PCOS and may provide a new clue for the clinical treatment of PCOS., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2022. Published by Elsevier Inc.)

Bioprinting is an additive manufacturing process used to create architectures that mimic natural living tissues in form and function [1]. It involves the deposition of bioink, which can include a mixture of living cells, nutrients, and extracellular matrix. The bioink is then deposited onto a scaffold to generate 3-D structures that imitate natural tissues and organs. This process has already been used to generate a diverse range of products, including bioprinted human ears for transplant, and 3-D printed bioceramic and modified biopolymer bone implants that received U.S. Food and Drug Administration (FDA) marketing approval [2] Researchers are working on bioprinted versions of a wide range of organs, including liver, kidney, lung, and heart.

The production of antibodies for therapeutic use in clinical medicine has become a focus of the biotechnology industry. In 2021, four of the top six selling prescription drugs were monoclonal antibodies, leading to a reported revenue of over US $ 67 billion dollars. Thus, it is no surprise that the otherwise arcane rules around antibody patents have become increasingly important to drug companies, health care providers, and consumers alike.

Context: While medical end-of-life planning has been well characterized, less is known about non-medical planning to prepare for the end of life., Objectives: To determine the prevalence of engagement in non-medical end-of-life (EOL) planning and its relationship to medical EOL planning., Methods: Three hundred and four persons age 65 and older recruited from physician offices and a senior center were administered an in-person interview asking about participation in the following non-medical EOL planning behaviors: moving to a location with more help, teaching someone to do things around the house, purchasing long-term care insurance, telling someone the location of important documents, preparing a financial will, conveying wishes for funeral arrangements, purchasing a cemetery plot, and prepaying for a funeral., Results: Prevalence of participation in the different non-medical EOL planning activities varied widely, from 8% for prepaying for a funeral to 84% for telling someone the location of important documents. There was little overlap in the factors associated with participation in each activity. Conveying wishes for funeral arrangements and completing a financial will were associated with completing a living will (OR 2.69, 95% CI 1.51, 4.78; OR 6.70, 95% CI 3.18, 14.15) and communication about quality versus quantity of life (OR 4.52, 95% CI 2.54, 8.04; OR 2.47, 95% CI 1.25, 4.86)., Conclusion: There is variability in both the prevalence of and factors associated with engagement in non-medical EOL planning activities. The association of non-medical with medical planning activities supports the utility of programs assisting individuals with broad engagement in EOL planning., (Published by Elsevier Inc.)

Background: The therapeutic evidence collected from well-designed studies is needed to help manage the global pandemic of the coronavirus disease 2019 (COVID-19). Evaluating the quality of therapeutic data collected during this most recent pandemic is important for improving future clinical research under similar circumstances., Objective: To assess the methodological quality and variability in implementation of randomized controlled trials (RCTs) for treating COVID-19, and to analyze the support that should be provided to improve data collected during an urgent pandemic situation., Search Strategy: PubMed, Excerpta Medica Database, China National Knowledge Infrastructure, Wanfang, and Chongqing VIP, and the preprint repositories including Social Science Research Network and MedRxiv were systematically searched, up to September 30, 2020, using the keywords "coronavirus disease 2019 (COVID-19)," "2019 novel coronavirus (2019-nCoV)," "severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2)," "novel coronavirus pneumonia (NCP)," "randomized controlled trial (RCT)" and "random.", Inclusion Criteria: RCTs studying the treatment of COVID-19 were eligible for inclusion., Data Extraction and Analysis: Screening of published RCTs for inclusion and data extraction were each conducted by two researchers. Analysis of general information on COVID-19 RCTs was done using descriptive statistics. Methodological quality was assessed using the risk-of-bias tools in the Cochrane Handbook for Systematic Reviews of Interventions (Version 5.1.0). Variability in implementation was assessed by comparing consistency between RCT reports and registration information., Results: A total of 5886 COVID-19 RCTs were identified. Eighty-one RCTs were finally included, of which, 45 had registration information. Methodological quality of the RTCs was not optimal due to deficiencies in five main domains: allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective reporting. Comparisons of consistency between published protocols and registration information showed that the 45 RCTs with registration information had common deviations in seven items: inclusion and exclusion criteria, sample size, outcomes, research sites of recruitment, interventions, and blinding., Conclusion: The methodological quality of COVID-19 RCTs conducted in early to mid 2020 was consistently low and variability in implementation was common. More support for implementing high-quality methodology is needed to obtain the quality of therapeutic evidence needed to provide positive guidance for clinical care. We make an urgent appeal for accelerating the construction of a collaborative sharing platform and preparing multidisciplinary talent and professional teams to conduct excellent clinical research when faced with epidemic diseases of the future. Further, variability in RCT implementation should be clearly reported and interpreted to improve the utility of data resulting from those trials., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier B.V.)

Despite broad appreciation of their clinical utility, it has been unclear how vitamin B12 and folic acid (FA) function at the molecular level to directly prevent their hallmark symptoms of deficiency like anemia or birth defects. To this point, B12 and FA have largely been studied as cofactors for enzymes in the one-carbon (1C) cycle in facilitating the de novo generation of nucleotides and methylation of DNA and protein. Here, we report that B12 and FA function as natural antagonists of aryl hydrocarbon receptor (AhR). Our studies indicate that B12 and FA bind AhR directly as competitive antagonists, blocking AhR nuclear localization, XRE binding, and target gene induction mediated by AhR agonists like 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and 6-formylindolo[3,2-b]carbazole (FICZ). In mice, TCDD treatment replicated many of the hallmark symptoms of B12/FA deficiency and cotreatment with aryl hydrocarbon portions of B12/FA rescued mice from these toxic effects. Moreover, we found that B12/FA deficiency in mice induces AhR transcriptional activity and accumulation of erythroid progenitors and that it may do so in an AhR-dependent fashion. Consistent with these results, we observed that human cancer samples with deficient B12/FA uptake demonstrated higher transcription of AhR target genes and lower transcription of pathways implicated in birth defects. In contrast, there was no significant difference observed between samples with mutated and intact 1C cycle proteins. Thus, we propose a model in which B12 and FA blunt the effect of natural AhR agonists at baseline to prevent the symptoms that arise with AhR overactivation., Competing Interests: The authors declare no competing interest.

CXCR4 has been shown to play a key role in the metastasis of non-small cell lung cancer (NSCLC). And CXCR may be associated with the Hippo-Yes kinase-associated protein (YAP) pathway, thus involving in the occurrence and progression of NSCLC. This study aims to investigate the effect of CXCR4 inhibition on epithelial-mesenchymal transition (EMT), invasion and migration of NSCLC cells via the Hippo-YAP pathway. QRT-PCR and Western blot were employed to detect CXCR4 expression in NSCLC cell lines. A549 and H1299 cells were treated with WZ811 (0, 10, 30, and 50 µM), and A549 cells were also divided into the Control, WZ811, YAP siRNA, and WZ811 + YAP groups. Wound-healing, Transwell assay, immunofluorescent staining, and a luciferase reporter gene assay were performed in this experiment. Compared with human bronchial epithelial (HBE) cells, CXCR4 expression was up-regulated in NSCLC cell lines. WZ811 increased E-cadherin; decreased expression of Twist, vimentin, Snail, p-YAP, CTGF, and BIRC5; blocked GTIIC reporter activity; and reduced migration and invasion of A549 cells, all in a dose-dependent manner. YAP siRNA had a similar effect to WZ811 by inhibiting EMT, invasion and migration of A549 cells. However, compared with A549 cells in the YAP siRNA and WZ811 groups, cells in the WZ811 + YAP group showed a dramatically enhanced EMT phenotype as well as invasion and migration abilities. Inhibition of CXCR4 may reduce EMT, invasion and migration of NSCLC cells, thereby providing a new therapeutic target for NSCLC., (© 2018 International Federation for Cell Biology.)

The incorporation of nonacetate starter units during type II polyketide biosynthesis helps diversify natural products. Currently, there are few enzymatic strategies for the incorporation of nonacetate starter units in type II polyketide synthase (PKS) pathways. Here we report the crystal structure of AuaEII, the anthranilate:CoA ligase responsible for the generation of anthraniloyl-CoA, which is used as a starter unit by a type II PKS in aurachin biosynthesis. We present structural and protein sequence comparisons to other aryl:CoA ligases. We also compare the AuaEII crystal structure to a model of a CoA ligase homologue, AuaE, which is present in the same gene cluster. AuaE is predicted to have the same fold as AuaEII, but instead of CoA ligation, AuaE catalyzes acyl transfer of anthranilate from anthraniloyl-CoA to the acyl carrier protein (ACP). Together, this work provides insight into the molecular basis for starter unit selection of anthranilate in type II PKS biosynthesis.

Aim: To retrospectively evaluate our experience with the diagnosis and surgical resection of esophageal gastrointestinal stromal tumors (GISTs)., Methods: Between January 2003 and August 2014, five esophageal GIST cases were admitted to our hospital. In this study, the hospital records, surgery outcomes, tumor recurrence and survival of these patients were retrospectively reviewed., Results: The median age of the patients was 45.6 years (range: 12-62 years). Three patients presented with dysphagia, and one patient presented with chest discomfort. The remaining patient was asymptomatic. Four patients were diagnosed with esophageal GISTs by a preoperative endoscopic biopsy. Three patients underwent esophagectomy, and two patients underwent video-assisted thoracoscopic surgery. The mean operating time was 116 min (range: 95-148 min), and the mean blood loss was 176 mL (range: 30-300 mL). All tumors were completely resected. The mean length of postoperative hospital stay was 8.4 d (range: 6-12 d). All patients recovered and were discharged successfully. The median postoperative follow-up duration was 48 mo (range: 29-72 mo). One patient was diagnosed with recurrence, one patient was lost to follow-up, and three patients were asymptomatic and are currently being managed with close radiologic and clinical follow-up., Conclusion: Surgery is the standard, effective and successful treatment for esophageal GISTs. Long-term follow-up is required to monitor recurrence and metastasis.

Adefovir dipivoxil, a nucleotide analog of adenosine monophosphate, is an antiviral agent that suppresses hepatitis B virus (HBV) replication through inhibition of DNA polymerase and by chain termination. To determine the effectiveness of adefovir, three populations of patients with chronic hepatitis B patients were studied: hepatitis B e antigen (HBeAg)-positive patients, HBeAg-negative patients, and patients with lamivudine-resistant tyrosine-methionine-asparate-aspartate (YMDD) mutants. All three groups of patients were treated for 48 weeks with adefovir 10 mg/d, and significant reduction in serum HBV DNA and normalization of serum alanine aminotransferase (ALT) were noted. Significant improvement in liver histology was noted in HBeAg-positive and in HBeAg-negative patients. Significant HBeAg loss and HBeAg seroconversion rates were noted in HBeAg-positive patients and in lamivudine-resistant patients. No major drug-related side effects were noted. Adefovir 10 mg/d orally is safe and effective for treatment of chronic hepatitis B.

Cdc42 is a small GTP-binding protein which has been implicated in a number of cellular activities, including cell morphology, motility, cell-cycle progression, and malignant transformation. While GTPase-defective forms of Cdc42 inhibit cell growth, a mutation [Cdc42(F28L)] that allows the constitutive exchange of GDP for GTP and is GTPase-competent induces cellular transformation. These results suggest that Cdc42 must cycle between its GTP- and GDP-bound states to stimulate cell growth. In attempting to design Cdc42 molecules with more potent transforming activity, we set out to generate other types of Cdc42 mutants capable of constitutive GDP-GTP exchange. Here, we describe one such mutant, generated by changing a conserved aspartic acid residue at position 118 to an asparagine. The Cdc42(D118N) protein exchanges GDP for GTP more rapidly than wild-type Cdc42, but significantly more slowly than the Cdc42(F28L) mutant. Despite its slower rate of activation, the Cdc42(D118N) mutant is more potent at inducing cellular transformation than the Cdc42(F28L) protein, and causes a significant loss in actin stress fibers, reminiscent of what is observed with fibroblasts transformed by oncogenic Ras mutants. Effector-loop mutations made within the D118N background inhibit Cdc42-induced transformation and Cdc42-mediated antiapoptotic (survival) activity to similar extents. In addition, mutating aspartic acid 121 (to asparagine), which forms part of a caspase cleavage site (DLRD, residues 118-121 of Cdc42), in combination with the F28L mutation generates a Cdc42 molecule [Cdc42(F28L/D121N)] with transforming activity significantly stronger than that of Cdc42(F28L). Thus, mutations that combine some capacity for cycling between the GTP- and GDP-bound states with increased survival against apoptotic signals yield Cdc42 molecules with the maximum capability for inducing cellular transformation.