Gambogic acid triggers vacuolization-associated cell death in cancer cells via disruption of thiol proteostasis
Gambogic acid triggers vacuolization-associated cell death in cancer cells via disruption of thiol proteostasis, Published online: 22 February 2019; doi:10.1038/s41419-019-1360-4
Gambogic acid triggers vacuolization-associated cell death in cancer cells via disruption of thiol proteostasisCircular RNA circBACH2 plays a role in papillary thyroid carcinoma by sponging miR-139-5p and regulating LMO4 expression
Circular RNA circBACH2 plays a role in papillary thyroid carcinoma by sponging miR-139-5p and regulating LMO4 expression, Published online: 22 February 2019; doi:10.1038/s41419-019-1439-y
Circular RNA circBACH2 plays a role in papillary thyroid carcinoma by sponging miR-139-5p and regulating LMO4 expressionType 3 inositol 1,4,5-trisphosphate receptor has antiapoptotic and proliferative role in cancer cells
Type 3 inositol 1,4,5-trisphosphate receptor has antiapoptotic and proliferative role in cancer cells, Published online: 22 February 2019; doi:10.1038/s41419-019-1433-4
Type 3 inositol 1,4,5-trisphosphate receptor has antiapoptotic and proliferative role in cancer cellsMiR-15b and miR-322 inhibit SETD3 expression to repress muscle cell differentiation
MiR-15b and miR-322 inhibit <i>SETD3</i> expression to repress muscle cell differentiation, Published online: 22 February 2019; doi:10.1038/s41419-019-1432-5
MiR-15b and miR-322 inhibit SETD3 expression to repress muscle cell differentiationConfounding off-target effects of BH3 mimetics at commonly used concentrations: MIM1, UMI-77, and A-1210477
Confounding off-target effects of BH3 mimetics at commonly used concentrations: MIM1, UMI-77, and A-1210477, Published online: 22 February 2019; doi:10.1038/s41419-019-1426-3
Confounding off-target effects of BH3 mimetics at commonly used concentrations: MIM1, UMI-77, and A-1210477circHIPK3 regulates lung fibroblast-to-myofibroblast transition by functioning as a competing endogenous RNA
circHIPK3 regulates lung fibroblast-to-myofibroblast transition by functioning as a competing endogenous RNA, Published online: 22 February 2019; doi:10.1038/s41419-019-1430-7
circHIPK3 regulates lung fibroblast-to-myofibroblast transition by functioning as a competing endogenous RNAInflammatory bowel diseases (IBD) affect working-age patients. Data was lacking concerning the impact on working life.
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Anti-tumor necrosis factor-α agents are important for managing refractory intestinal Behçet's disease. Few studies have reported the efficacy of anti-tumor necrosis factor-α monoclonal antibodies for intestinal Behçet's disease due to its rarity.
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The first infliximab biosimilar for the treatment of inflammatory bowel disease (IBD) was introduced in 2013, and today eight anti-TNF alpha biosimilars (three for infliximab and five for adalimumab) have been approved and licensed by the European Medicines Agency. Biosimilars present great potential in terms of cost saving and possible consequential reinvestment in the health care system. The increasing knowledge about the process of biosimilar development and use in IBD and the publication of many prospective clinical studies and real-life clinical experiences have progressively changed the point of view of IBD physicians.
https://ift.tt/2tA0Usd
Adequate tissue acquisition is important in making treatment decisions for patients with upper gastrointestinal subepithelial tumors (SETs). This study aimed to compare the outcomes of endoscopic ultrasonography-guided fine-needle biopsy (EUS-FNB) with those of the unroofing biopsy technique.
https://ift.tt/2GWMkTy
Neuroendocrine tumors (NETs) are rare, but their incidence is rising. Alkylating agents (ALKY), temozolomide and streptozotocin, are the main chemotherapies used for advanced pancreatic NETs. According to retrospective data, O6-methylguanine-DNA methyltransferase (MGMT) status appears to be a predictive factor of the response to ALKY.
https://ift.tt/2tCTCUO
Transjugular liver biopsy (TJLB) represents an alternative to percutaneous liver biopsy especially in patients with impaired coagulation and ascites.
https://ift.tt/2BPpyJM
Anaemia is a common pathologic condition, present in almost 5% of the adult population. Iron deficiency is the most common cause; other mechanisms can be involved, making anaemia a multi-factorial disorder in most cases. Anaemia being a frequent manifestation in the diseases of the gastrointestinal tract, patients are often referred to gastroenterologists. Furthermore, upper and lower endoscopy and enteroscopy are pivotal to the diagnostic roadmap of anaemia. In spite of its relevance in the daily clinical practice, there is a limited number of gastroenterological guidelines dedicated to the diagnosis of anaemia.
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Hot snare (HS) is widely used for the resection of adenomas >5 mm. The cold snare (CS) has a better safety profile and is more cost- effective. The aims of this study were to evaluate effectiveness and safety of CS polypectomy (CSP) compared to HS polypectomy (HSP) for adenomas sized 5–10 mm and 11–20 mm.
https://ift.tt/2U56lv0
Epidemiological studies of autoimmune hepatitis are scarce and often based on single centre registries.
https://ift.tt/2U7oMPC
Nasopharyngeal carcinoma (NPC) is a highly invasive and metastatic head and neck cancer. Distant metastasis becomes the predominant mode of treatment failure in NPC patients. Ginsenoside Rg3 (Rg3), an active pharmaceutical component extracted from traditional Chinese medicine ginseng, shows antitumor effects in various cancers. In this study, we aimed to determine whether Rg3 inhibits the migration and invasion activity of NPC cells and to explore the possible mechanisms. Our results revealed that Rg3 hampers cell migration and invasion in both HNE1 and CNE2 cell lines. A reduced level of matrix metalloproteinase-2 (MMP-2) and MMP-9 was induced by Rg3 treatment. In addition, Rg3 significantly altered the expression of epithelial mesenchymal transition (EMT) markers with increased E-cadherin but decreased Vimentin and N-cadherin expression. Transforming growth factor β- (TGF-β-) induced morphological transition and marker proteins change of EMT were reversed by Rg3. What is more, Rg3 suppressed the expression of EMT-related transcription factors, especially the Zinc Finger E-Box Binding Homeobox 1 (ZEB1). In summary, our data suggested that Rg3 could inhibit migration and invasion of NPC cells. This effect of Rg3 might be mediated through regulating MMP-2 and MMP-9 expressions and suppressing EMT. Thus, Rg3 may be a potentially effective agent for the treatment of NPC.
https://ift.tt/2GYwk3u
Read about the latest research published in Psychological Science:
When the Muses Strike: Creative Ideas of Physicists and Writers Routinely Occur During Mind Wandering
Shelly L. Gable, Elizabeth A. Hopper, and Jonathan W. Schooler
Mind wandering, which involves thoughts that are both independent from the task at hand and different from one's previous thoughts on the matter, can generate creative ideas experienced as "aha" moments, this study suggests. Every day for 1 or 2 weeks, physicists and writers listed their most important creative idea of the day, described what they were thinking and doing when the idea occurred, and rated the importance of the idea and whether it felt like an "aha" moment or not. Participants reported that about 20% of their most important ideas occurred when their minds were wandering, and these ideas were rated as being equally important and creative as the ideas formed while working on task. After 3 or 6 months, they rated all these previous ideas as slightly more creative but less important. Overall, ideas generated during mind wandering were more likely to be rated as "aha" moments, compared with ideas generated while working. Hence, profession-related ideas that occur outside of work when people are not thinking about the topic can be inventive and create sudden insights, showing a positive side of mind wandering.
Conceptually Rich, Perceptually Sparse: Object Representations in 6-Month-Old Infants' Working Memory
Melissa M. Kibbe and Alan M. Leslie
Do infants remember conceptual information about an object (e.g., the object is a ball) even when they do not remember perceptual information (e.g., the object is round and green)? This study indicates that they do. Six-month-old infants were familiarized with a yellow and red striped ball and a doll's head with brown skin and eyes. The two objects were then hidden one at a time in separate locations. One of the objects then reappeared at the location where the first object was hidden; critically, this object could be the same one that had been hidden there or the other object. The experimenters measured the time that infants spent looking at this object. Infants looked longer when the object had been swapped, indicating that they remembered the hidden object's conceptual information. This effect did not occur when the doll's head was inverted and therefore not processed as a face. It also did not occur when the ball was swapped for a green ball with red polka dots or when the doll's head was swapped for a doll's head with pink skin and blue eyes, indicating that infants' memory for the first object hidden relied on conceptual details (e.g., is the object a ball or a head?) but not on perceptual details (e.g., does the object have brown or blue eyes?). These results suggest that infants may encode the conceptual category of a hidden object, even when perceptual features are lost.
A Tight Spot: How Personality Moderates the Impact of Social Norms on Sojourner Adaptation
Nicolas Geeraert, Ren Li, Colleen Ward, Michele Gelfand, and Kali A. Demes
How do contextual factors and personality traits affect how individuals adapt to a new culture when they temporarily move to a different country? To answer this question, Geeraert and colleagues analyzed data from a longitudinal acculturation project that measured young adults' personality and cultural adaptation during and after a temporary move to a different country. These measures were collected on three occasions: 3 months before departure as well as 2 weeks and 5 months after arrival to the host country. Overall, participants who moved to a tight culture (i.e., one with strong norms and little tolerance for deviance) showed less adaptation than those who moved to a loose culture (i.e., one with less rigid norms), but participants originally from a tight culture showed more adaptation than those from a loose culture. Participants who scored higher on agreeableness and honesty-humility were less likely to feel the negative effects of cultural tightness or to return early to their home country. These results may help ensure a good fit between individuals' personalities and their destination culture, which will increase the benefits of the rapid increase in international mobility.
Read about research recently published in Clinical Psychological Science:
Genetic and Environmental Associations Among Executive Functions, Trait Anxiety, and Depression Symptoms in Middle Age
Daniel E. Gustavson, Carol E. Franz, Matthew S. Panizzon, Chandra A. Reynolds, Hong Xian, Kristen C. Jacobson, Rosemary Toomey, Michael J. Lyons, and William S. Kremen
To determine whether anxiety and depression symptoms are associated with a decreased ability to control and modify one's own behavior in response to a goal (i.e., executive functioning), and to discern the role of genetic influences on this association, Gustavson and colleagues tested more than 500 middle-aged twin pairs. They measured participants' anxiety and depression symptoms and their executive functioning — general cognitive ability, working memory, ability to inhibit responses, and ability to shift task goals. More anxiety/depression symptoms were associated with poorer executive functioning, and this relationship was mostly explained by genetic influences. However, environmental influences also affected the relationship between depression and executive functioning but not the relationship between cognitive functioning and anxiety. These associations were observed in late middle age, when cognitive abilities begin to decline, suggesting the importance of considering executive functioning when examining the relationship between anxiety, depression, and cognitive decline. Moreover, decline in executive functioning may underlie age-related decline in other cognitive abilities. Psychological interventions for individuals with anxiety or depression may be more successful when they include training in executive-functioning tasks.
Motivations to Experience Happiness or Sadness in Depression: Temporal Stability and Implications for Coping With Stress
Yael Millgram, Jutta Joormann, Jonathan D. Huppert, Avital Lampert, and Maya Tamir
Individuals experiencing various levels of depression rated their motivations to experience sadness and happiness, their current emotions and stress, and their attempts to regulate or change their emotional reactions. They were assessed three times: before an exam period, during the academic semester, and 1 to 3 months later during an exam period. In all of the assessments, individuals experiencing more depression were less likely to be motivated to experience happiness and more motivated to experience sadness compared with individuals experiencing less depression. Thus, higher motivation to experience sadness and lower motivation to experience happiness seem to be stable predispositions associated with depression. Individuals experiencing more depression and who were less motivated to experience happiness were less likely to sustain happiness when exposed to happy stimuli and to downplay their negative emotions during real-life stressful events (i.e., exams) compared with individuals not experiencing depression. These findings suggest that helping individuals with depression enhance their motivation to experience happiness may promote better adjustment to stress in daily life.
Thoughts as Unexpected Intruders: Context, Obsessive-Compulsive Symptoms, and the Sense of Agency Over Thoughts
Isaac Fradkin, Baruch Eitam, Asher Y. Strauss, and Jonathan D. Huppert
To examine the relationship between sense of agency (SoA) over thoughts (i.e., the experience of being the source of one's own thoughts) and obsessive-compulsive (OC) symptoms, Fradkin et al. told participants that an imperceptible and nonaudible auditory message (sham) could insert thoughts in their minds and measured whether they reported having experienced inserted thoughts. Participants were informed about the message that they would supposedly randomly hear (e.g., a negative word, such as death, or a neutral word, such as chair) and were instructed to click the mouse whenever they thought they heard it. Participants also completed an OC Inventory. Participants with high OC symptoms were more likely to falsely hear the sham message than were participants with low OC symptoms, showing less SoA over their thoughts. This tendency was not altered by the valence of the thoughts. Low SoA seemed related to surprise (i.e., the extent to which a thought seems out of context, given one's other thoughts), and participants who reported experiencing out-of-context or surprising thoughts in daily life were more likely to hear the sham message. Thus, context and experience of violated expectations seem to accompany low SoA. These findings suggest that besides the content and appraisals of intrusive thoughts, researchers and practitioners should also focus on the contextual and phenomenological characteristics of intrusive thoughts.
It's mid-February, around the time that most people waver in their commitment to the resolutions they've made for the new year. Many of these resolutions – whether it's to spend less time looking at screens, eat more vegetables, or save money for retirement – require us to forego a behavior we want to engage in for the one we think we should engage in. In a new report, leading researchers in behavioral science propose a new framework that outlines different types of self-control strategies and emphasizes that self-control entails more than sheer willpower to be effective.
The report comes at a time when environmental pressures and societal problems are making strategies for boosting self-control more important than ever, says Angela Duckworth, a University of Pennsylvania psychology professor and one of report's authors.
"Temptations are arguably more readily available, more creatively engineered, and cheaper than any time in history," Duckworth says. "Junk food gets tastier and cheaper every year. And then there's video games, social media, the list goes on. In parallel, there are public policy issues such as obesity, educational underachievement, and undersaving that result, in part, from failures of self-control."
Duckworth's coauthors on the report— published in Psychological Science in the Public Interest, a journal of the Association for Psychological Science—are Katherine L. Milkman (The Wharton School of the University of Pennsylvania) and David Laibson (Harvard University). George Loewenstein (Carnegie Mellon University), a leading researcher in the science of decision making, is author of an accompanying commentary.
Based on their comprehensive review of available research, Duckworth, Milkman, and Laibson propose a framework that organizes evidence-based self-control strategies along two dimensions based on how the strategies are implemented and who is initiating them.
They observe that in some cases the best self-control strategy involves us changing the situation to create incentives or obstacles that help us exercise self-control, such as using apps that restrict our phone usage or keeping junk food out of the house. In other cases it's more effective to change how we think about the situation — for example, by making an if-then plan to anticipate how we'll deal with treats in the office — so that exercising self-control becomes more appealing or easier to accomplish.
Other strategies work better when someone else implements them for us. For example, our electricity company might use social norms to prompt a change in our thinking, showing us how our energy usage compares with that of our neighbors. And policymakers often use situational constraints to prompt behavior focused on the long-term. Examples range from incentives (e.g., tax rebates for eco-friendly building materials) to penalties (e.g., raising taxes on cigarettes and alcohol). Employers are increasingly using another type of situational constraint, defaults, to encourage employees to save for retirement; many are requiring people to opt out of an employer-provided retirement plan if they don't want to participate.
The strategies, drawing from insights in psychological science and economics, can inform the efforts of policymakers, employers, healthcare professionals, educators, and other practitioners to address pressing issues that stem, at least in part, from failures in self-control, the authors write.
Identifying four types of self-control strategies that go beyond willpower sends an important message, Loewenstein writes in his commentary, given that people often believe willpower is sufficient despite its high failure rate. One of the reasons people tend to fail in their New Year's resolutions is "naivety about the limitations of the brute-force approach and ignorance of the far more effective strategies enumerated in the review," he writes.
But Loewenstein notes some important caveats to keep in mind when interpreting the research, which the researchers also acknowledge in the report. Many studies have examined self-control strategies in small groups of participants over brief periods of time, which raises questions about whether they will remain effective if implemented at a broader scale and how long the effects will last.
Duckworth, Milkman, and Laibson hope that their review helps to integrate existing research on self-control from several disciplines into a comprehensive whole.
"There is an urgent need for a cumulative and applied science of self-control—one that incorporates insights from theoretical traditions in both psychological science and economics," the researchers write. "We hope this review is a step in that direction."
The full report and commentary are available to the public online.
Beyond Willpower: Strategies for Reducing Failures of Self-Control
Angela L. Duckworth, Katherine L. Milkman, David Laibson
Self-Control and Its Discontents: A Commentary on Duckworth, Milkman, and Laibson
George Loewenstein
Whether at the supermarket, in the doctor's office, or in bed at night, it can be tempting to pick up the device and start scrolling through social media or text messages at any moment. But anyone who has done so in the presence of a close friend, family member, or romantic partner may have left that person feeling ignored, annoyed, or even pushed away. That's according to a growing body of research on "technoference," or the potential interference smartphones and other technologies can have in our face-to-face social interactions.
In a review paper forthcoming in Perspectives on Psychological Science, a journal of the Association for Psychological Science, University of Arizona psychology professor David Sbarra and his collaborators at Wayne State University in Detroit examine existing research on technoference. They propose an explanation for why humans are so drawn to their smartphones, even when the devices take us out of the moment in our close relationships. It's because of our evolutionary history, they say.
Humans are hard-wired to connect with others, Sbarra and his colleagues argue. In the course of evolutionary history, we have relied on close relationships with small networks of family and friends for survival as individuals and as a species. These relationships were based on trust and cooperation, which is built when people disclose personal information about themselves and are responsive to others.
Smartphones, and the constant access they provide to text messaging and social media, make it easier than ever for people to disclose personal information and respond to others in their social networks. And these networks are much larger and more far-flung than those of our ancestors.
"The draw or pull of a smartphone is connected to very old modules in the brain that were critical to our survival, and central to the ways we connect with others are self-disclosure and responsiveness," Sbarra said. "Evolution shaped self-disclosure and responsiveness in the context of small kin networks, and we now see these behaviors being cued more or less constantly by social networking sites and through our phones. We now have the outer-most edges of our social network cue us for responsiveness. Look no further than the next person you see scrolling through Facebook and mindlessly hitting the 'like' button while his kid is trying to tell him a story."
In their paper, Sbarra and his coauthors go beyond the idea that technology is simply attention-grabbing to suggest that there may be an evolutionary mismatch between smartphones and the social behaviors that help form and maintain close social relationships.
"Smartphones and their affordances create new contexts for disclosing information about who we are and for being responsive to others, and these virtual connections may have downstream unwanted effects on our current relationships," Sbarra said. "When you are distracted into or by the device, then your attention is divided, and being responsive to our partners – an essential ingredient for building intimacy – requires attention in the here and now."
Divided attention, Sbarra and his colleagues say, may lead to relationship conflict. For example, the review paper cites a study of 143 married women, more than 70 percent of whom reported that mobile phones frequently interfere in their relationships.
Sbarra doesn't believe smartphones are all bad. In fact, he and his coauthors acknowledge that the devices offer several benefits for health and well-being, and texting provides many couples a route for connecting in a meaningful way. But they say more research is needed to fully understand the impact that virtual connections may have on our real-world relationships and the ways in which the pull of our phones may diminish immediate interactions and lead to conflict.
"We stay away from the question of whether social networking sites and smartphone use are good or bad, per se," Sbarra said. "Technology is everywhere, and it's not going away, nor should it. In this paper, we are interested in answering two basic questions: Why do the devices seem to have such a powerful pull on us? And, what is the state of the science on the effects of being pulled away from our in-person interactions and into the virtual world?"
From there, the authors outline a research agenda they hope can guide future studies. Those studies will be increasingly important as new technologies evolve and become more integrated in our daily lives, Sbarra said.
"Between 2000 and 2018, we've seen the largest technological advances, arguably, at any point in the last 100 years," he said. "We are interested in understanding the role of social relationships in human well-being. We can understand this from the level of what individuals do in relationships, but we can also understand it at the level of societal changes and societal forces that may push on relationships."
The 2012 American Society for Colposcopy and Cervical Pathology Consensus Guidelines provide information for managing abnormal cervical cancer screening tests and cancer precursors. According to these guidelines for Pap smear diagnosis of Atypical squamous cells of undetermined significance, reflex high risk (HR) human papilloma virus (HPV) genotyping is required among women 21 years of age or older. Whereas, in women of 30 to 65 years of age, HR‐HPV can be ordered by the clinicians as part of co‐testing with any diagnosis and every 5 years with a negative Cervico‐Vaginal Pap test (CVPT).
A retrospective review of the CoPath database of the Pathology Department at the University of Florida, College of Medicine Jacksonville, FL, was performed to identify North Florida (NF) women who underwent CVPT and HR‐HPV testing between 2006 and 2014. The women were stratified by race and age, respectively.
The study included 19,933 CVPTs. Significant differences in the outcomes' distributions were found among age and race groups, respectively. Highest prevalence of HPV positivity was found in African American women, and in 14‐ to 20‐year‐old women, respectively. Twenty‐ to 30‐year‐old women had the highest percentage (59%) of epithelial abnormality. The most common HR‐HPV genotypic distribution was other HR‐HPV.
This study underscores the importance of using both HR‐HPV and CVPT for screening for cervical cancer, and confirms the need for special focus on managing high‐risk populations subgroups, such as African American women, and women of ages 14 to 20 years especially in high‐risk populations.
Journal Name: Biological Chemistry
Issue: Ahead of print
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STAT1 gain‐of‐function (GOF) variants lead to defective Th17 cell development and chronic mucocutaneous candidiasis (CMC), but frequently also to autoimmunity. Stimulation of cells with STAT1 inducing cytokines like interferons (IFN) result in hyperphosphorylation and delayed dephosphorylation of GOF STAT1. However, the mechanism how the delayed dephosphorylation exactly causes the increased expression of STAT1‐dependent genes, and how the intracellular signal transduction from cytokine receptors is affected, remains unknown. In this study we show that the circulating levels of IFN‐α were not persistently elevated in STAT1 GOF patients. Nevertheless, the expression of interferon signature genes was evident even in the patient with low or undetectable serum IFN‐α levels. Chromatin immunoprecipitation (ChIP) experiments revealed that the active chromatin mark trimethylation of lysine 4 of histone 3 (H3K4me3), was significantly enriched in areas associated with interferon‐stimulated genes in STAT1 GOF cells in comparison to cells from healthy donors. This suggests that the chromatin binding of GOF STAT1 variant promotes epigenetic changes compatible with higher gene expression and elevated reactivity to type I interferons, and possibly predisposes for interferon‐related autoimmunity. The results also suggest that epigenetic rewiring may be responsible for treatment failure of Janus kinase 1/2 (JAK1/2) inhibitors in certain patients.
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A secondary analysis of data from a phase III trial demonstrated no difference in relapse and inferior survival of patients receiving the lung dose ≥800cGy as part of their TBI regimen. TBI techniques, including the methods of lung dose calculation, were heterogeneous across the institutions participating in this study. These findings led to recommendations of lung-shielding above 800cGy for COG TBI protocols and triggered phantom-based dosimetry investigation of TBI techniques across the institutions.
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We conducted a prospective observational cohort study of physician compliance to early peer review recommendations. All patient cases are discussed twice at an early (pre-planning) and late (chart rounds, 1st week of treatment) peer review conferences. Compliance to early peer review recommendations was 59% (determined at the time of late peer review), with compliance varying amongst physicians. Compliance declined with the magnitude of the recommendation, suggesting reluctance to accept major changes in planned therapy.
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Secretory carcinoma (previously known as mammary analog secretory carcinoma) is characterized by ETV6 rearrangements, most often ETV6‐NTRK3 fusion. Given its histologic overlap with other salivary gland tumors, secretory carcinoma can be difficult to diagnose without genetic confirmation. A recently developed pan‐TRK antibody shows promise for identifying tumors with NTRK fusions. This study evaluated the utility of pan‐TRK immunohistochemistry in distinguishing secretory carcinoma from mimics.
We examined whole‐tissue sections from 86 tumors including 14 secretory carcinomas (12 parotid and 1 buccal primary, 1 metastasis; 5 with ETV6 rearrangement confirmed by fluorescence in situ hybridization, 1 ETV6‐NTRK3 and 1 ETV6‐RET fusion detected by targeted sequencing), 14 acinic cell carcinomas, 18 polymorphous adenocarcinomas, 20 low‐grade mucoepidermoid carcinomas, and 20 pleomorphic adenomas. Immunohistochemistry was performed using a pan‐TRK rabbit monoclonal antibody. Pan‐TRK staining was detected in 9 (64%) secretory carcinomas, all with nuclear pattern and 4 with diffuse staining (>50% of cells). Of other tumor types, pan‐TRK immunoreactivity was observed in all (100%) pleomorphic adenomas (particularly myoepithelial cell‐rich, myxoid areas), 15 (83%) polymorphous adenocarcinomas, and 4 (20%) low‐grade mucoepidermoid carcinomas, all with predominantly membranous/cytoplasmic immunoreactivity; only 6 cases showed focal (<10%) nuclear staining. All acinic cell carcinomas were entirely negative.
While pan‐TRK expression is not entirely sensitive or specific for secretory carcinoma, nuclear staining distinguishes secretory carcinoma from mimics. Acinic cell carcinomas are negative for pan‐TRK, though membranous expression of TRK is common in other salivary gland neoplasms. The lack of pan‐TRK immunoreactivity in a subset of secretory carcinomas may suggest non‐NTRK fusion partners.
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In addition to their critical role in allergic disorders, mast cells (MCs) are well recognized for their protective effector functions during bacteria and parasite infections. This review describes recent advancements of our understanding of the complex role of MCs in fungal infections. Specifically, we outline key features of the contribution of MCs to infections with six fungal pathogens, namelySporothrix, Paracoccidioides, Aspergillus, Malassezia,Candida andDermatophytes. Evidence from studies of these pathogens suggests that MCs can function as positive regulators that detect and contain fungi at the site of infection. However, it appears that the inflammation induced by MCs following fungal infections may not always and only be beneficial to the host. MC responses during fungal infections may primarily benefit the pathogen by facilitating its spreading and contributing to a greater severity of fungal infections.This review also highlights key drivers of MCs activation and effector mechanisms that have been identified for the multidimensional function of MCs in fungal diseases and in allergic diseases combined with fungal infection.
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Disease‐associated proteins are thought to propagate along neuronal processes in neurodegenerative diseases. To detect disease‐associated prion protein (PrPSc) in the vagus nerve in different forms and molecular subtypes of Creutzfeldt‐Jakob disease (CJD) we applied three different anti‐PrP antibodies. We screened the vagus nerve in 162 sporadic and 30 genetic CJD cases. 4/31 VV‐2 type sporadic CJD and 7/30 genetic CJD cases showed vagal PrPSc immunodeposits with distinct morphology. Thus PrPSc in CJD affects the vagus nerve analogously to α‐synuclein in Parkinson's disease. The morphologically diverse deposition of PrPSc in genetic and sporadic CJD argues against uniform mechanisms of propagation of PrPSc.
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A reliable biomarker is needed for accurate and early differentiation between Parkinson's disease (PD) and the various forms of atypical parkinsonism (AP). We used a novel real‐time quaking‐induced conversion (RT‐QuIC) assay to detect alpha‐synuclein (α‐syn) aggregates in cerebrospinal fluid (CSF) of 118 patients with parkinsonism of uncertain clinical etiology and 52 controls. Diagnostic accuracy to distinguish α‐synucleinopathies from non‐α‐synucleinopathies and controls was 84% (sensitivity 75%, specificity 94% (AUC 0.84, 95% CI 0.78‐0.91, p<0.0001), PPV 93%). CSF α‐syn RT‐QuIC could be a useful diagnostic tool to help clinicians differentiate α‐synucleinopathies from other forms of parkinsonism when the clinical picture is uncertain.
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Increasing evidence suggests that human epidermal melanocytes play an important role in the skin immune system, however, a role of their pigmentation in immune and inflammatory responses is poorly examined. In the study expression of Toll‐like receptor 4 (TLR4) and inflammatory cytokines and chemokines by cultured normal melanocytes derived from lightly and darkly pigmented skin was investigated after cell stimulation with lipopolysaccharide (LPS). The basal TLR4 mRNA level in heavily pigmented cells was higher as compared to their lightly pigmented counterparts. Melanocyte exposure to LPS upregulated the expression of TLR4 mRNA and enhanced the DNA‐binding activity of NF‐κB p50 and p65. We found substantial differences in the LPS‐stimulated expression of numerous genes encoding inflammatory cytokines and chemokines between the cells with various melanin contents. In lightly pigmented melanocytes the most significantly upregulated genes were nicotinamide phosphoribosyltransferase (NAMPT/visfatin), the chemokines CCL2 and CCL20, and IL6, while the genes for CXCL12, IL‐16 and the chemokine receptor CCR4 were the most significantly upregulated in heavily pigmented cells. Moreover, the lightly pigmented melanocytes secreted much more NAMPT, CCL2 and IL‐6. The results of our study suggest modulatory effect of melanogenesis on the immune properties of normal epidermal melanocytes.
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Following injury, skin activates a complex wound healing program. While cellular and signaling mechanisms of wound repair have been extensively studied, the principles of epidermal‐dermal interactions and their effects on wound healing outcomes are only partially understood. To gain new insight into the effects of epidermal‐dermal interactions, we developed a multiscale, hybrid mathematical model of skin wound healing. The model takes into consideration interactions between epidermis and dermis across the basement membrane via diffusible signals, defined as activator and inhibitor. Simulations revealed that epidermal‐dermal interactions are critical for proper extracellular matrix deposition in the dermis, suggesting these signals may influence how wound scars form. Our model makes several theoretical predictions. First, basal levels of epidermal activator and inhibitor help to maintain dermis in a steady‐state, whereas their absence results in a raised, scar‐like dermal phenotype. Second, wound‐triggered increase in activator and inhibitor production by basal epidermal cells, coupled with fast re‐epithelialization kinetics reduce dermal scar size. Third, high density fibrin clot leads to a raised, hypertrophic scar phenotype, whereas low density fibrin clot leads to a hypotrophic phenotype. Fourth, shallow wounds, compared to deep wounds, result in overall reduced scarring. Taken together, our model predicts the important role of signaling across dermal‐epidermal interface and the effect of fibrin clot density and wound geometry on scar formation. This hybrid modeling approach may be also applicable to other complex tissue systems, enabling the simulation of dynamic processes, otherwise computationally prohibitive with fully discrete models due to a large number of variables.
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What is the central question of this study?
High‐intensity interval exercise (HIIE) is recommended to be avoided within 4 h of bedtime due to potential sleep disruptions which may affect appetite‐related hormone interactions and subsequent energy intake. Yet, the interactions between sleep and appetite following early evening HIIE has not been previously explored.
What is the main finding and its importance?
We show that HIIE can be performed in the early evening without subsequent sleep disruptions and may favourably alter appetite‐related hormone concentrations. Nonetheless, perceived appetite and energy intake do not change with acute HIIE regardless of time‐of‐day.
Many adults remain inactive, despite exercise benefits for sleep and appetite, due to increased time‐restraints. Methods to improve exercise compliance include preferential time‐of‐day or engaging in short‐duration, high‐intensity interval exercise (HIIE). Hence, this study aimed to compare effects of HIIE time‐of‐day on sleep and appetite. Eleven inactive men undertook sleep monitoring to determine baseline (BASE) sleep stages and exclude sleep disorders. On separate days, participants completed 30 min HIIE (60 s work at 100% V̇O2peak: 240 s rest at 50% V̇O2peak) in the 1) morning (MORN; 0600–0700 h), 2) afternoon (AFT; 1400–1600 h) and 3) early evening (EVEN: 1900–2000 h). Measures included appetite‐related hormones (acylated ghrelin, leptin, peptide tyrosine tyrosine), and glucose pre‐exercise, 30 min post‐exercise, and next morning; overnight polysomnography (PSG; sleep stages); and actigraphy, self‐reported sleep and food diaries for 48 h post‐exercise. There were no between‐trial differences for total sleep time (p = 0.46). Greater stage N3 sleep was recorded for MORN (23 ± 7%) compared to BASE (18 ± 7%; p = 0.02); however, no between‐trial differences existed (p > 0.05). Rapid eye movement (REM) sleep was lower and non‐REM sleep was higher for EVEN compared to BASE (p ≤ 0.05). At 30 min post‐exercise, ghrelin was higher for AFT compared to MORN and EVEN (p = 0.01); while glucose was higher for MORN compared to AFT and EVEN (p ≤ 0.02). No between‐trial differences were found for perceived appetite (p ≥ 0.21) or energy intake (p = 0.57). Early evening HIIE can be performed without subsequent sleep disruptions and reduces acylated ghrelin. However, perceived appetite and energy intake appear to be unaffected by HIIE time‐of‐day.
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Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox), comprise 7 family members (Nox1‐5, duox1/2) and are major producers of reactive oxygen species (ROS) in mammalian cells. ROS are critically involved in cell signalling and function. While all Noxs share structural homology comprising six transmembrane domains with two heme‐binding regions and a NADPH‐binding region on the intracellular C‐terminus, their regulatory systems, mechanisms of activation and tissue distribution differ. This explains the diverse function of Noxs. Of the Noxs, Nox5 is unique in that rodents lack the gene, it is regulated by Ca2+, it does not require NADPH oxidase subunits for its activation and it is not glycosylated. Nox5 localises in the perinuclear and ER regions of cells and traffics to the cell membrane upon activation. It is tightly regulated through numerous post‐translational modifications and is activated by vasoactive agents, growth factors and pro‐inflammatory cytokines. The exact pathophysiological significance of Nox5 remains unclear but it seems to be important in the physiological regulation of sperm motility, vascular contraction and lymphocyte differentiation and Nox5 hyperactivation has been implicated in cardiovascular disease, kidney injury and cancer. The field of Nox5 biology is still in its infancy, but with new insights into its biochemistry and cellular regulation, discovery of the Nox5 crystal structure and GWAS studies implicating Nox5 in disease, the time is now ripe to advance Nox5 research. This review provides a comprehensive overview of our current understanding of Nox5, from basic biology to human disease, and highlights the unique characteristics of this enigmatic Nox isoform.
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TREAT‐ME‐1, a Phase 1/2 open‐label multicenter, first‐in‐human, first‐in‐class trial, evaluated the safety, tolerability and efficacy of treatment with genetically modified autologous mesenchymal stromal cells (MSC), MSC_ apceth_101, in combination with ganciclovir in patients with advanced gastrointestinal adenocarcinoma. Immunological and inflammatory markers were also assessed. All patients (3 in Phase 1; 7 in Phase 2) received three treatment cycles of MSC_apceth_101 at one dose level on Day 0, 7, and 14 followed by ganciclovir administration according to the manufacturer's instructions for 48─72 hours after MSC_apceth_101 injection. Ten patients were treated with a total dose of 3.0 x 106 cells/kg MSC_apceth_101. 36 adverse events and six serious adverse events were reported. Five patients achieved stable disease (change in target lesions of ‐2 to +28%). For all patients, the median time to progression was 1.8 months (95% CI: 0.5, 3.9 months). Median overall survival could not be estimated as 8/10 patients were still alive at the end of the study (one year) and therefore censored. Post‐study observation of patients showed a median overall survival of 15.6 months (ranging from 2.2─27.0 months). Treatment with MSC_apceth_101 and ganciclovir did not induce a consistent increase or decrease in levels of any of the tumor markers analyzed. No clear trends in the immunological markers assessed were observed. MSC_apceth_101 in combination with ganciclovir was safe and tolerable in patients with advanced gastrointestinal adenocarcinoma, with preliminary signs of efficacy in terms of clinical stabilization of disease.
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Melanoma of unknown primary (MUP) may have a different biology to melanoma of known primary, but clinical trials of novel therapies (e.g., immune checkpoint or BRAF/MEK inhibitors) have not reported the outcomes in this population. We therefore evaluated the overall survival (OS) among patients with MUP in the era of novel therapy. Data for stage III or IV MUP were extracted from a nationwide database for the period 2003–2016, with classification based on the eighth edition of the American Joint Committee on Cancer criteria. The population was divided into pre‐ (2003–2010) and post‐ (2011–2016) novel therapy eras. Also, OS in the post‐novel era was compared between patients with stage IV MUP by whether they received novel therapy. In total, 2028 of 65,110 patients (3.1%) were diagnosed with MUP. Metastatic sites were known in 1919 of 2028 patients, and most had stage IV disease (53.8%). For patients with stage III MUP, the 5‐year OS rates were 48.5% and 50.2% in the pre‐ and post‐novel eras, respectively (P = 0.948). For those with stage IV MUP, the median OS durations were unchanged in the pre‐novel era and post‐novel era when novel therapy was not used (both 4 months); however, OS improved to 11 months when novel therapy was used in the post‐novel era (P < 0.001). In conclusion, more than half of the patients with MUP are diagnosed with stage IV and the introduction of novel therapy appears to have significantly improved the OS of these patients.
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Genetic alterations are the starting point leading to numerous changes in clinical and pathologic features (phenotypes) of individual cancers; however, their inter‐relationships in gastric cancers (GC) are unclear. We performed massive parallel sequencing of 381 cancer‐related genes and compared the results with clinical and pathologic findings in 330 GC. High tumor mutation burden (TMB) accounted for 11% of GC (n=37) and all 19 MSI‐H GCs were high TMB. High TMB was significantly more frequent in intestinal‐type by Lauren, tumor with higher host cellular immune response, earlier AJCC stage, and favorable prognosis. The most significantly mutated genes were TP53 (54%), ARID1A (23%), CDH1 (22%), PIK3CA (12%), RNF43 (10%), and KRAS (9%). For receptor tyrosine kinases, amplifications detected by immunohistochemistry were higher than sequencing (HER2, 9.1% vs. 5.8%; EGFR, 11.2% vs. 6.1%; FGFR2, 4.6% vs. 3.9%, c‐MET, 3.4% vs. 0.9%). PTEN protein loss (22%) correlated well with underlying PTEN alterations while ATM loss (27%) was not significantly correlated with genetic alterations of ATM. p53 protein expression predicted alterations of TP53 with high sensitivity (97.8%) and low (15.9%) specificity. The poorly cohesive histology/CDH1‐mutant GC subgroup showed the worst survival (P<.001). PD‐L1 expression was significantly associated with MSI‐H, MLH1 loss, ATM loss, MET positivity, higher host immune response, and genetic alterations of ARID1A, BRD3, PIK3CA, KRAS, MAP3K13, CDH2, PTEN, and ESR1. The merged clinical, pathology and genomics of GC provide a better understanding of GC and new insights into the treatment of GC.
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Resistance of pancreatic ductal adenocarcinoma (PDAC) to radiotherapy and chemotherapy represents a significant clinical issue. Although the mechanisms of resistance are multi‐faceted, client proteins of heat shock protein 90 (HSP90) such as hypoxia induced factor‐1α (HIF‐1α) have a central role in this process. The purpose of this investigation was to evaluate inhibition of HSP90 as a therapeutic strategy for radiosensitization in pancreatic cancer. Ganetespib, a selective inhibitor of HSP90, was evaluated as a radio‐sensitizer in setting of PDAC. Inhibition of HSP90 by ganetespib potentiated the ability of radiation therapy to limit cell proliferation and colony formation in vitro. HIF‐1α expression was upregulated by irradiation and HIF‐1α‐overexpressing stable cell lines were resistant to radiation. Inhibition of HSP90 with ganetespib reversed the effects of HIF‐1α overexpression, by reducing signaling via proliferative, angiogenic and anti‐apoptotic pathways. The potentiation of the antitumor effects of chemoradiotherapy by ganetespib and modulation of key pathways (e.g. HIF‐1α, STAT3, and AKT) was confirmed in vivo in nude mice bearing HPAC xenograft tumors. These novel data highlight HIF‐1α‐mediated mechanisms of HSP90 inhibition that sensitize PDAC cells to chemoradiotherapy. This pathway and its pleiotropic effects warrant further evaluation in concert with conventional therapy in pancreatic cancer clinical trials.
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The authors thank Dr. XYZ and colleagues for an insightful response to our recent meta‐analysis on the prognostic accuracy of the HEART score for prediction of major adverse cardiac events (MACE) in patients presenting with chest pain [1]. The authors make excellent points related to the evaluation of prognostic scores, particularly as it relates to clinical decision‐making. We feel that their editorial does highlight important complementary discussion points to our article.
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In this issue, Fernando et al present a systematic review and meta‐analysis assessing the prognostic accuracy of the HEART score for prediction of major adverse cardiac events (MACE) in adult patients presenting with chest pain at the emergency department (ED).1 The authors conclude that the HEART score has excellent performance for prediction of MACE (particularly mortality and myocardial infarction) in chest pain patients and should be the primary clinical decision instrument used for risk‐stratification of this patient population.
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Mitochondrial respiration is critical for organismal survival; therefore, oxygen consumption rate is an excellent indicator of mitochondrial health. In this protocol, we describe the use of a commercially available respirometer to measure basal and maximal oxygen consumption rates in live, intact, and freely-motile Caenorhabditis elegans.
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This study focuses on an in vitro model of wound healing (scratch assay) as a mechanism for determining how environmental contaminants such as arsenic influence cellular migration. The results demonstrate that this in vitro assay provides rapid and early indications of changes to cellular migration prior to in vivo experimentation.
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Ultrasound (US) therapy may improve osteoarthritis symptoms. We investigated the effects of US on the synovial fluid (SF) proteome in a rabbit knee osteoarthritis (KOA) model to explore its therapeutic mechani...
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Hand hygiene (HH) compliance remains low in many intensive care units (ICU). Technology has been suggested to improve HH compliance.
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OqxAB efflux pump has been found to mediate multidrug resistance (MDR) in various bacteria over the past decades. The updates on the nature and epidemiology of OqxAB efflux pump need to be fully reviewed to br...
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The prognostic value of sentinel lymph node (SLN) metastases may be minimized by the limited disease burden of lymph node metastases and tailoring adjuvant therapy based on breast cancer biology. The aim of this study is to assess the prognostic significance of SLN metastasis in patients with cT1–2N0M0 breast cancer.
Between January 2006 and December 2015, 582 patients underwent SLN biopsy for cT1–2N0M0 breast cancers. cN0 was essentially diagnosed by ultrasound sonography. The prognostic values of SLN metastases were retrospectively evaluated.
Among 582 patients with cT1–2N0M0 breast cancer, 111 patients (19.1%) were positive for SLN metastasis, including 39 cases (6.7%) of micrometastasis and 72 cases (12.4%) of macrometastases. The median size of SLN metastasis was 3.0 mm (range 0.2–16 mm, mean 4.1 mm). In log-rank test, presence of SLN metastasis was not associated with breast cancer recurrence (p = 0.21); 5-year and 10-year recurrence-free survival (RFS) were 93.0% and 96.5%, and 93.0% and 90.4% in the SLN-positive and SLN-negative groups, respectively. In the propensity score matching cohort (n = 178), there was no significant difference in RFS between the SLN-positive and SLN-negative groups (p = 0.90). In Cox regression analysis, a continuous value of Ki67 expression was a significant prognostic factor (HR 1.03; 95% CI 1.01–1.05, p = 0.017).
SLN metastasis has a minimal impact on RFS for patients with cT1–2N0M0 breast cancer in the modern medical era. A proliferation marker is a better factor for poor prognosis than the presence of SLN metastases in this population.
Chest computed tomography (CTC) has now replaced chest X-ray (CXR) as the first choice of investigation to stage breast cancers in most centers in Australia. Routine staging is not recommended in early breast cancers (EBCs). This recommendation is based largely on the use of conventional tests like CXR as staging investigations (SIs). We looked at our experience with CTC in detecting asymptomatic synchronous distant metastasis (ASM) in new and recurrent breast cancers (RBCs).
Breast cancer patients from Eastern Health Breast Unit during the period from January 2012 to March 2016 were included in the study. Cases were grouped into early, advanced, and recurrent breast cancers, and outcome of CTC was assessed in each group. Relative risk of potential risk factors (tumor size, axillary nodal status, presence of lymphovascular invasion and estrogen, and HER2 receptor status) with a positive result in CTC was determined.
Fourteen ASMs were detected from 335 CTCs giving an overall yield of 4% (95% CI 1.89–6.47). The overall false-positive rate was 10% due to 35 indeterminate findings that were found not to be metastases after further tests or observation. Even with selective use, CTCs have a low yield of 2% (95% CI − 0.19–4.19) in EBCs. Advanced breast cancers have a 9% incidence of ASMs. None of the clinically isolated locoregionally recurrent diseases were associated with detectable distant metastasis in CTC. The most common cause of indeterminate findings was small pulmonary nodules.
Even with selective use, CTC has a very low yield in EBCs. Advanced breast cancers can benefit from CTC in their initial evaluation due to the higher yield. Locoregional RBCs were not usually associated with detectable metastasis on CTC. The usefulness of CTC in all stages of breast cancer is further reduced by its high rate of false-positive results.
Management of pain by different therapeutic agents has always been one of the most important components in clinical veterinary care. Concerns about various side effects of analgesics drugs have lead the pain relief to combination drug therapy. The present study was performed to evaluate the effect of combined tramadol and meloxicam on oxidative stress status in dogs. Twenty clinically healthy dogs were randomly divided into four groups and administered with placebo, tramadol, meloxicam, and combined meloxicam with tramadol for 10 days. The antioxidant enzymes (superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), total antioxidant capacity (TAC), and malondialdehyde (MDA) were assayed in blood samples which were collected in days 0, 5, 10, 15, and 20. In dogs administrated with tramadol, the antioxidant enzymes and TAC were significantly decreased and MDA level was significantly increased. However, meloxicam group showed no alteration in the levels of GPx, CAT, TAC, and MDA. Moreover, administration of meloxicam with tramadol improved oxidative stress status through inhibiting lipid peroxidation, increasing antioxidant enzymes, and TAC. These results indicate that meloxicam is effective in reducing oxidative stress induced by tramadol. Therefore, combination of tramadol and meloxicam is desired due to their potential analgesic result and ameliorating effect on oxidative stress status.
Survival in Ewing's sarcoma (ES) has increased with the use of chemotherapy. Surgical techniques such as limb salvage (LS) have been developed. Survival and adverse events have been widely studied in general series of ES, but there are few specific series of ES cases treated by LS, despite this being the most commonly used (surgical) approach. The aim of this study was to determine survival and prognostic factors in ES patients undergoing LS.
We analysed all ES patients treated between January 1984 and May 2008 and selected all those treated by systemic multimodal therapy and LS. We assessed the influence of patient characteristics, tumour parameters and therapeutic results in event-free survival (EFS).
Ninety patients were included. Fifty of them were treated by systemic multimodal therapy and locally by LS. ean age was 20 years. Overall survival (OS) was 68.8% and EFS was 60.6% at years. In the univariate analysis, pelvic location, age and response to chemotherapy were associated with poor prognosis. After multivariate analysis, poor response to treatment, pelvis location and age between 12 and 17 years were found to be independent prognostic factors. Dissemination at diagnosis was not a prognostic factor.
OS and EFS in ES treated by LS were similar to findings in previous ES studies. factors are no different, except for the presence of metastasis at diagnosis.
The direct effectiveness of infant rotavirus vaccination implemented in 2006 in the United States has been evaluated extensively, however, understanding of population-level vaccine effectiveness (VE) is still ...
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Mucormycosis is a group of rare but life threatening angioinvasive infections caused by fungi of the order Mucorales that often occurs in immunocompromised patients and individuals with poorly controlled diabetes...
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Following publication of the original article [1], the authors reported that they have provided the wrong caption.
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Guangdong Province is one of the most developed and populous provinces in southern China, with frequent foreign exchanges and large transient population. The annual number of cases of HIV/AIDS reported in Guan...
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A 64‐year‐old female presented with a slightly elevated 50‐mm lesion in the cecum, which was spread into the appendiceal orifice. The lesion was endoscopically diagnosed to be a sessile serrated adenoma/polyp without dysplasia. Endoscopic submucosal dissection (ESD) was performed using a therapeutic colonoscope (PCF‐Q260JI, Olympus) and a small‐caliber‐tip transparent hood (ST‐hood DH‐29CR, Fujifilm). First, hyaluronic acid and glycerol solution were submucosally injected into the normal mucosa of the appendiceal canal.
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Ischemic stroke is a leading cause of mortality and morbidity worldwide. Stenosis or blockage of an artery from atherosclerosis can cause insufficient cerebral blood supply, which leads to ischemic stroke. It ...
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Publication date: Available online 22 February 2019
Source: Injury
Author(s): T.H. Rainer, K.K.C. Hung, J.H.H. Yeung, S.K.C. Cheung, Y.K. Leung, L.Y. Leung, W.B. Goggins, H.F. Ho, C.W. Kam, N.K. Cheung, C.A. Graham
Trauma care systems in Asia have been developing in recent years, but there has been little long-term outcome data from injured survivors. This study aims to evaluate the trajectory of functional outcome and health status up to five years after moderate to major trauma in Hong Kong.
We report the five year follow up results of a multicentre, prospective cohort from the trauma registries of three regional trauma centres in Hong Kong. The original cohort recruited 400 adult trauma patients with ISS ≥ 9. Telephone follow up was conducted longitudinally at seven time points, and the extended Glasgow Outcome Scale (GOSE) and Short-Form 36 (SF36) were tracked.
119 out of 309 surviving patients (39%) completed follow up after 5 years. The trajectory of GOSE, PCS and MCS showed gradual improvements over the seven time points. 56/119 (47.1%) patients reported a GOSE = 8 (upper good recovery), and the mean PCS and MCS was 47.8 (95% CI 45.8, 49.9) and 55.8 (95% CI 54.1, 57.5) respectively at five years. Univariate logistic regression showed change in PCS - baseline to 1 year and 1 year to 2 years, and change in MCS - baseline to 1 year were associated with GOSE = 8 at 5 years. Linear mixed effects model showed differences in PCS and MCS were greatest between 1-month and 6-month follow up.
After injury, the most rapid improvement in PCS and MCS occurred in the first six to 12 months, but further recovery was still evident for MCS in patients aged under 65 years for up to five years.
Publication date: Available online 22 February 2019
Source: Injury
Author(s): Emir Battaloglu, Marisol Figuero, Christopher Moran, Fiona Lecky, Keith Porter
Urethral injury in major trauma is infrequent, with complex problems of diagnosis and treatment. The aims of this study are to determine the incidence and epidemiological factors relating to urethral injury in major trauma, as well as determine if any additional prognostic factors are evident within this cohort of patients. A retrospective review of patients sustaining urethral injury following major trauma was made over a 6-year period, from 2010 to 2015. Quantitative analysis was made using the national trauma registry for England and Wales, the Trauma Audit and Research Network (TARN) database, identifying all patients with injury codes for urethral injury. 165 patients with urethral injuries were identified, over 90% were male, most commonly injured during road traffic accidents and with an associated overall mortality of 12 %. Urethral injury in association with pelvic fracture occurred in 136 patients (82%), representing 0.6% of all pelvic fractures, and was associated with double the rate of mortality. Urethral injury was associated with unstable pelvic fractures (LC2, LC3, APC3, VS, CM) but not with a specific pelvic fracture type. This study confirms the rare incidence of this injury in major trauma at 1 per 2 million population per year.
In albinism of all species, perturbed melanin biosynthesis in the eye leads to foveal hypoplasia, retinal ganglion cell misrouting, and, consequently, altered binocular vision. Here, written before he died, Ray Guillery chronicles his discovery of the aberrant circuitry from eye to brain in the Siamese cat. Ray's characterization of visual pathway anomalies in this temperature sensitive mutation of tyrosinase and thus melanin synthesis in domestic cats opened the exploration of albinism and simultaneously, a genetic approach to the organization of neural circuitry. I follow this account with a remembrance of Ray's influence on my work. Beginning with my postdoc research with Ray on the cat visual pathways, through my own work on the mechanisms of retinal axon guidance in the developing mouse, Ray and I had a continuous and rich dialogue about the albino visual pathway. I will present the questions Ray posed and clues we have to date on the still‐elusive link between eye pigment and the proper balance of ipsilateral and contralateral retinal ganglion cell projections to the brain.
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Nomograms have been developed for the prediction of progression-free survival (PFS) and liver toxicity in patients with advanced renal cell carcinoma (RCC) who are treated with pazopanib. The objectives of this study were to review clinical outcomes, to perform an external validation of these nomograms and to develop a new nomogram in Japanese patients.
A retrospective chart review of 150 Japanese patients with advanced RCC who received pazopanib at Kobe University Hospital and affiliated hospitals from March 2014 to June 2017 was performed. We evaluated the clinical efficacy and safety of pazopanib using logistic regression analysis to analyze the prognostic factors for overall survival (OS) and PFS. For nomogram validation, concordance index (C-index) and calibration were used.
The median PFS and OS in this study was 13.1 and 37.4 months, respectively. Multivariate analyses identified prognostic factors for OS (number of metastasis, white blood cell (WBC) count and lactate dehydrogenase) and PFS (number of metastasis, WBC count). The C-index of nomograms for 12-month PFS was 0.598. The C-index of nomograms for liver toxicity was 0.558. A new Nomogram for predicting 12-month PFS for patients who received pazopanib was developed and performed internal validation. The C-index of the nomogram was 0.768.
The clinical effect and safety of pazopanib reported in this study was similar to previous studies. This study suggests careful application of nomograms to Japanese patients treated with pazopanib. We have developed a new nomogram for predicting 12-month PFS with pazopanib therapy from Japanese patients.
α-Synuclein is a soluble protein that is present in abundance in the brain, though its normal function in the healthy brain is poorly defined. Intraneuronal inclusions of α-synuclein, commonly referred to as Lewy pathology, are pathological hallmarks of a spectrum of neurodegenerative disorders referred to as α-synucleinopathies. Though α-synuclein is expressed predominantly in neurons, α-synuclein aggregates in astrocytes are a common feature in these neurodegenerative diseases. How and why α-synuclein ends up in the astrocytes and the consequences of this dysfunctional proteostasis in immune cells is a major area of research that can have far-reaching implications for future immunobiotherapies in α-synucleinopathies. Accumulation of aggregated α-synuclein can disrupt astrocyte function in general and, more importantly, can contribute to neurodegeneration in α-synucleinopathies through various pathways. Here, we summarize our current knowledge on how astrocytic α-synucleinopathy affects CNS function in health and disease and propose a model of neuroglial connectome altered by α-synuclein proteostasis that might be amenable to immune-based therapies.
Cancers, Vol. 11, Pages 265: MicroRNA in Lung Cancer Metastasis
Cancers doi: 10.3390/cancers11020265
Authors: Shang-Gin Wu Tzu-Hua Chang Yi-Nan Liu Jin-Yuan Shih
Tumor metastasis is a hallmark of cancer, with distant metastasis frequently developing in lung cancer, even at initial diagnosis, resulting in poor prognosis and high mortality. However, available biomarkers cannot reliably predict cancer spreading sites. The metastatic cascade involves highly complicated processes including invasion, migration, angiogenesis, and epithelial-to-mesenchymal transition that are tightly controlled by various genetic expression modalities along with interaction between cancer cells and the extracellular matrix. In particular, microRNAs (miRNAs), a group of small non-coding RNAs, can influence the transcriptional and post-transcriptional processes, with dysregulation of miRNA expression contributing to the regulation of cancer metastasis. Nevertheless, although miRNA-targeted therapy is widely studied in vitro and in vivo, this strategy currently affords limited feasibility and a few miRNA-targeted therapies for lung cancer have entered into clinical trials to date. Advances in understanding the molecular mechanism of metastasis will thus provide additional potential targets for lung cancer treatment. This review discusses the current research related to the role of miRNAs in lung cancer invasion and metastasis, with a particular focus on the different metastatic lesions and potential miRNA-targeted treatments for lung cancer with the expectation that further exploration of miRNA-targeted therapy may establish a new spectrum of lung cancer treatments.
Major BCR-ABL1 mRNA in patients with chronic myeloid leukemia (CML) has generally been analysed by real-time polymerase chain reaction (PCR). Application of the international scale (IS) for the quantification of major BCR-ABL1 mRNA has been recommended in several sets of guidelines, including those of the European LeukemiaNet. The aim of this study was to clarify the efficacy of digital PCR technology for the IS of BCR-ABL1 mRNA in the patients with CML by comparing with real-time PCR.
The analysis of BCR-ABL1 mRNA was carried out by the Ipsogen® BCR-ABL1 Mbcr IS-MMR DX Kit (Qiagen), and the QuantStudio 3D Digital PCR System (Thermo Fisher Scientific) using 20 peripheral blood samples obtained from the 9 patients with CML at Sapporo Medical University Hospital.
The correlation between the data obtained by digital PCR and by real-time PCR was really high at R = 0.96. The detection limit of digital PCR was up to 0.003% and was equal to IS with 0.01% or less in comparison with real-time PCR.
Digital PCR technology is promising for predicting the IS value with similar efficacy to real-time PCR and should be useful for simple monitoring of the effects of tyrosine kinase inhibitor (TKI) treatments.
A particularly longstanding, prevalent, and well-documented stereotype is the belief that men possess higher-level cognitive abilities than women do. This brilliance = male stereotype has been shown to be endorsed even by children as young as 6-years-old and is believed to be a factor driving the underrepresentation of women in STEM fields. Motivated by the fact that cultural products serve as a source for acquiring individual values and behaviors, we study the presence of this stereotype in a large collection of movie transcripts covering half a century of Western-world film history (n = 11,550). Concretely, we use natural language processing techniques to quantify associations between gender pronouns and high-level cognitive ability-related words. Overall, our estimates suggest that, at an aggregate level, the brilliance = male stereotype is effectively present in films and that movies specifically targeted at children contain this stereotypical association. Moreover, this pattern seems to have been quite persistent for the last 50 years.
The conflict of interest declaration was published incorrectly in the original version.
Patients with recurrent glioblastoma (rGBM) have a poor prognosis, with survival ranging from 25 to 40 weeks. Antiangiogenic agents are widely used, showing a variable response. In this study, we explored the efficacy of carmustine plus bevacizumab (BCNU/Bev) for treating rGBM.
In this study, we assessed 59 adult patients with histologically confirmed rGBM who were treated with BCNU/Bev as second-line regimen. The response rate (RR), progression-free survival (PFS) and overall survival (OS) were evaluated according to their molecular expression profile, including CD133 mRNA expression, MGMT methylation (pMGMT), PDGFR amplification, YKL40 mRNA expression, IDH1/2 condition, p53 and EGFRvIII mutation status.
Median follow-up was 18.6 months, overall RR to the combination was 56.3%, and median PFS was 9.0 months (95% CI 8.0–9.9). OS from time of diagnosis was 21.0 months (95% CI 13.2–28.7) and from starting BCNU/Bev it was 10.7 months (95% CI 9.5–11.8). IDH1/2 mutations were found in 30.5% of the patients, pMGMT in 55.9% and high CD133 mRNA expression in 57.6%. Factors which positively affected PFS included performance status (p = 0.015), IDH+ (p = 0.05), CD133 mRNA expression (p = 0.009) and pMGMT+ (p = 0.007). OS was positively affected by pMGMT+ (p = 0.05). Meanwhile, YKL40 negatively affected PFS (p = 0.01) and OS (p = 0.0001). Grade ≥ 3 toxicities included hypertension (22%) and fatigue (12%).
BCNU/Bev is a safe and tolerable treatment for rGBM. Patients with MGMT+/IDH+ derive the greatest benefit from the treatment combination in the second-line setting. Nonetheless, high YKL40 expression discourages the use of antiangiogenic therapy.
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy typically with poor prognosis. This review aims to summarize the current knowledge regarding the clinical management of ACC.
Surgery remains the cornerstone for localized ACC management. In more advanced cases, debulking surgery when feasible can help with hormonal control and may allow the initiation of systemic therapy. Over the last few years, our understanding of ACC molecular pathogenesis has expanded with no significant change in treatment options. Platinum-based chemotherapy is the gold standard in metastatic ACC despite suboptimal efficacy. Tyrosine kinase inhibitor use did not result in meaningful benefit in ACC patients. Multiple clinical trials are currently exploring the role of immunotherapy in ACC.
Despite the remarkable improvement in our understanding of the molecular signature and pathways in ACC, this knowledge did not yield a major breakthrough in management of advanced ACC. Multi-institutional and international collaborations are needed to identify promising treatments and new therapeutic targets to improve the care of ACC patients.
To compare the efficacy and safety of the ketogenic diet (KD) with standard adrenocorticotropic hormone (ACTH) treatment in infants with West syndrome.
In this parallel‐cohort (PC) randomized controlled trial (RCT), infants were randomly allocated to KD or high‐dose ACTH. Those who could not be randomized were followed in a PC. Primary end point was electroclinical remission at day 28. Secondary end points were time to electroclinical remission, relapse after initial response, seizure freedom at last follow‐up, adverse effects, and developmental progress.
One hundred one infants were included: 32 in the RCT (16 KD; 16 ACTH) and 69 in the PC (37 KD; 32 ACTH). Electroclinical remission at day 28 was similar between KD and ACTH (RCT: 62% vs 69%; PC: 41% vs 38%; combined cohort: 47% vs 48%; KD vs ACTH, respectively). In the combined cohort, time to electroclinical remission was similar between both treatments (14 days for KD, 16 days for ACTH). However, relapse rates were 16% (KD) and 43% (ACTH, P = 0.09), and seizure freedom at last follow‐up was 40% (KD) and 27% (ACTH, P = 0.18). Adverse effects needing acute medical intervention occurred more often with ACTH (30% with KD, 94% with ACTH, P < 0.001). Age‐appropriate psychomotor development and adaptive behavior were similar.
Without prior vigabatrin (VGB) treatment, remission at day 28 was 47% (KD) and 80% (ACTH, P = 0.02); relapse rates were 29% (KD) and 56% (ACTH, P = 0.13). Consequently, seizure freedom at last follow‐up was similar. In infants with prior VGB, seizure freedom at last follow‐up was 48% (KD) and 21% (ACTH, P = 0.05).
The study is underpowered; therefore, its results should be interpreted with caution. KD is as effective as ACTH in the long term but is better tolerated. Without prior VGB treatment, ACTH remains the first choice to achieve short‐term remission. However, with prior VGB, KD was at least as effective as ACTH in the short term and was associated with lower relapse rates in the long term; therefore, it represents an appropriate second‐line treatment after VGB.
Invasive lobular carcinoma (ILC) is a histological subtype of breast cancer that is predominantly estrogen receptor alpha (ER)-positive (+) and is thus treated with endocrine therapies. Herein, we sought to understand the molecular underpinnings of the 4-hydroxytamoxifen (4OHT) resistance in ILC by assessing the potential role of the epithelial-to-mesenchymal transition transcription factor (EMT-TF) SNAIL (SNAI1).
Using a series of breast cancer cell lines, we measured the basal, estrogen and 4OHT-induced expression of SNAIL and other EMT-TF family members by quantitative reverse transcription-polymerase chain reaction and immunoblotting. Chromatin immunoprecipitation experiments were performed to assess ER binding to the SNAIL promoter. Cell proliferation, cell cycle and apoptosis were assessed in 2D cultures. 3D growth was assessed in Matrigel and Collagen I cultures.
Estrogen and 4OHT induced SNAIL expression, but not that of the other EMT-TF family members SLUG (SNAI2) and SMUC (SNAI3), with the 4OHT effect being specific to the lobular but not the ductal subtype. We observed estrogen and 4OHT-induced ER recruitment to the SNAI1 promoter and high endogenous basal levels of SNAIL and several EMT-TFs in ILC cell lines. While SNAIL knockdown had a minor impact on the 4OHT partial agonism in estrogen-depleted conditions, it led to a surprising increase in cell proliferation in full serum. In complementary experiments, inducible SNAI1 overexpression caused decreased proliferation, associated with a cell cycle arrest in G0/G1. Additionally, apoptosis was observed in BCK4 cells.
These data suggest a previously unrecognized role for SNAIL in ILC, substantiating a context-dependent behavior for this EMT-TF.
The mission of the Society for Craniofacial Genetics and Developmental Biology (SCGDB) is to promote education, research, and communication about normal and abnormal development of the tissues and organs of the head. The SCGDB welcomes as members undergraduate students, graduate students, postdoctoral researchers, medical and dental practitioners, scientists, and academicians who possess an interest in craniofacial biology. Each year our members come together to share their novel findings, build upon, and challenge current knowledge of craniofacial biology.
Patients with mCRPC have a significantly (1.8‐fold) lower docetaxel AUC compared to patients with other solid tumors, determined by our meta‐analysis. This could explain the lower incidence of neutropenia reported for this patient population, and confirmed by analysis of our clinical cohorts.
The incidence of neutropenia in metastatic castration‐resistant prostate cancer (mCRPC) patients treated with docetaxel has been reported to be lower compared to patients with other solid tumors treated with a similar dose. It is suggested that this is due to increased clearance of docetaxel in mCRPC patients, resulting in decreased exposure. The aims of this study were to (1) determine if exposure in mCRPC patients is lower vs patients with other solid tumors by conducting a meta‐analysis, (2) evaluate the incidence of neutropenia in patients with mCRPC vs other solid tumors in a clinical cohort, and (3) discuss potential clinical consequences. A meta‐analysis was conducted of studies which reported areas under the plasma concentration‐time curves (AUCs) of docetaxel and variability. In addition, grade 3/4 neutropenia was evaluated using logistic regression in a cohort of patients treated with docetaxel. The meta‐analysis included 36 cohorts from 26 trials (n = 1150 patients), and showed that patients with mCRPC had a significantly lower mean AUC vs patients with other solid tumors (fold change [95% confidence interval (CI)]: 1.8 [1.5‐2.2]), with corresponding AUCs of 1.82 and 3.30 mg∙h/L, respectively. Logistic regression, including 812 patient, demonstrated that patients with mCRPC had a 2.2‐fold lower odds of developing grade 3/4 neutropenia compared to patients with other solid tumors (odds ratio [95%CI]: 0.46 [0.31‐0.90]). These findings indicate that mCRPC patients have a lower risk of experiencing severe neutropenia, possibly attributable to lower systemic exposure to docetaxel.
The cytodiagnosis of melanoma in effusions can be challenging. Although immunohistochemical (IHC) stains such as HMB45, Melan A, and S‐100 are often utilized; the role of Sry‐related HMG‐box gene 10 (SOX10) in the diagnosis of melanoma in effusions has not been previously reported.
A total of 14 confirmed melanoma cases diagnosed on effusion cytology (nine pleural and five peritoneal) were collected from 2000 to 2016. IHC stain for SOX10 was performed and compared with HMB45, Melan A, and S‐100. To evaluate the specificity of SOX10, we stained 47 previously diagnosed nonmelanocytic malignant effusions. A cut‐off of >1 positively staining cells was considered positive. The intensity of staining was graded as weak, moderate, and strong.
All 14 melanoma cases were positive for SOX10 and HMB45 (100%), compared to 12 cases (86%) using Melan A and S‐100. Among 47 previously diagnosed nonmelanocytic malignant effusions (4 malignant mesotheliomas, 12 müllerian tumors, 9 breast carcinomas, 9 lung adenocarcinomas, and 13 hematologic tumors), SOX10 and HMB45 showed a specificity of 98%, whereas Melan A and S100 had a specificity of 100%.
The sensitivity of SOX10 for melanoma in effusions is comparable with HMB45 with a 100% sensitivity. In terms of staining intensity, HMB45 appeared to be superior as it showed 100% moderate to strong intensity compared to 72% for SOX10. All four markers showed near‐100% specificity in differentiating melanoma from nonmelanocytic malignant effusions. A combination of HMB45 and SOX10 might be useful as the initial stains of choice in diagnosing melanoma in effusion cytology.
Follicular thyroid carcinoma, spindle cell variant is extremely rare. The tumor is predominantly composed of spindle cells with a fusiform appearance that are arranged in intersecting fascicles. Fine‐needle aspiration biopsy of this entity has not been previously described. We report a case of a 58‐year‐old woman who presented with metastasis to a left neck lymph node 15 years after the original diagnosis. Fine‐needle aspiration cytology showed numerous bland, spindled to epithelioid cells with thin, elongated, and plump nuclei with finely granular chromatin and inconspicuous nucleoli. The tumor cells had a moderate amount of cytoplasm with occasional elongated cytoplasmic tails. The cells were arranged in irregular aggregates with a fascicular pattern or singly dispersed. The tumor cells demonstrated positive staining for pan‐keratin, PAX8, thyroid transcription factor‐1, and thyroglobulin, which confirmed thyroid primary origin.
Fine‐needle aspiration (FNA) is frequently utilized in the diagnostic workup of lymphadenopathy. We evaluated the correlation of cytopathology with flow cytometry and tissue biopsy results and assessed the prevalence of specific malignancies in young adults presenting with cervical lymphadenopathy.
Database was searched for cervical lymph node FNA performed by a cytopathologist in patients aged 18‐30 years from 2005 to 2017.
Cervical lymph node FNA was performed on 48 patients without prior history of malignancy. Nineteen patients had cytology results only, of which all were interpreted as benign reactive lymph node. None developed subsequent malignancies. The remaining 29 patients had cytology with flow cytometry and/or tissue biopsy results. A benign reactive cytology diagnosis was rendered in 18 (62%) cases, of which 11 had concordant diagnosis on flow cytometry, 2 had tissue biopsy, and 3 had both. Eleven (38%) patients had cytology results concerning for a hematologic malignancy, of which 7 were confirmed by flow cytometry and 3 by both flow cytometry and tissue biopsy. Cervical lymph node FNA has 94.1% sensitivity, 83.3% specificity, 88.9% positive predictive value, and 90.9% negative predictive value. The most common hematologic malignancy in our young adult population presenting with cervical lymphadenopathy was Hodgkin lymphoma.
FNA is a useful first‐line diagnostic procedure for assessing cervical lymphadenopathy in young adults to allow for better triage of specimens for flow cytometry and/or tissue biopsy concerning for a hematologic malignancy and potentially avoid invasive excisional biopsy in a proportion of cases.
Cancers, Vol. 11, Pages 262: Circulating Tumor Cell Detection in Lung Cancer: But to What End?
Cancers doi: 10.3390/cancers11020262
Authors: Véronique Hofman Simon Heeke Charles-Hugo Marquette Marius Ilié Paul Hofman
The understanding of the natural history and biology of lung cancer has been enhanced by studies into circulating tumor cells (CTCs). Fundamental and translational research, as well as clinical trials in the characterization and behavior of these cells, have constantly contributed to improving understanding within the domain of thoracic oncology. However, the use of these CTCs as prognostic and predictive biomarkers has not been adopted to the same extent as circulating free DNA (cf-DNA) in plasma, in the daily practice of thoracic oncologists. However, recent technological advances have firmly put the detection and characterization of CTCs in thoracic oncology back on the agenda, and have opened up perspectives for their routine clinical use. This review discusses the major advances of using CTCs in the domain of thoracic oncology, as well as the envisaged short- and long-term prospects.
Cancers, Vol. 11, Pages 264: Deciphering the Mechanism of Action Involved in Enhanced Suicide Gene Colon Cancer Cell Killer Effect Mediated by Gef and Apoptin
Cancers doi: 10.3390/cancers11020264
Authors: Blanca Cáceres Alberto Ramirez Esmeralda Carrillo Gema Jimenez Carmen Griñán-Lisón Elena López-Ruiz Yaiza Jiménez-Martínez Juan A. Marchal Houria Boulaiz
Despite the great advances in cancer treatment, colorectal cancer has emerged as the second highest cause of death from cancer worldwide. For this type of tumor, the use of suicide gene therapy could represent a novel therapy. We recently demonstrated that co-expression of gef and apoptin dramatically inhibits proliferation of the DLD-1 colon cell line. In the present manuscript, we try to establish the mechanism underlying the enhanced induction of apoptosis by triggering both gef and apoptin expression in colon tumor cells. Scanning microscopy reveals that simultaneous expression of gef and apoptin induces the apparition of many “pores” in the cytoplasmic membrane not detected in control cell lines. The formation of pores induced by the gef gene and accentuated by apoptin results in cell death by necrosis. Moreover, we observed the presence of apoptotic cells. Performing protein expression analysis using western blot, we revealed an activation of mitochondrial apoptosis (increased expression of Pp53, cytochrome c, Bax, and caspase 9) and also the involvement of the extrinsic pathway through caspase 8activation. In conclusion, in this manuscript we demonstrate for the first time that the extrinsic pathway of apoptosis and pore formation is also involved in the cell death caused by the co-expression of the gef and apoptin genes. Our results suggest that co-expression of gef and apoptin genes induces an increase in post-apoptotic necrotic cell death and could be a valuable tool in the design of new antitumor strategies focused on the enhancement of the immune response against cancer cell death.
Cancers, Vol. 11, Pages 263: Integrative Omic Profiling Reveals Unique Hypoxia Induced Signatures in Gastric Cancer Associated Myofibroblasts
Cancers doi: 10.3390/cancers11020263
Authors: Hanna Najgebauer Andrew F. Jarnuczak Andrea Varro Christopher M. Sanderson
Although hypoxia is known to contribute to several aspects of tumour progression, relatively little is known about the effects of hypoxia on cancer-associated myofibroblasts (CAMs), or the consequences that conditional changes in CAM function may have on tumour development and metastasis. To investigate this issue in the context of gastric cancer, a comparative multiomic analysis was performed on populations of patient-derived myofibroblasts, cultured under normoxic or hypoxic conditions. Data from this study reveal a novel set of CAM-specific hypoxia-induced changes in gene expression and secreted proteins. Significantly, these signatures are not observed in either patient matched adjacent tissue myofibroblasts (ATMs) or non-cancer associated normal tissue myofibroblasts (NTMs). Functional characterisation of different myofibroblast populations shows that hypoxia-induced changes in gene expression not only enhance the ability of CAMs to induce cancer cell migration, but also confer pro-tumorigenic (CAM-like) properties in NTMs. This study provides the first global mechanistic insight into the molecular changes that contribute to hypoxia-induced pro-tumorigenic changes in gastric stromal myofibroblasts.
