Comparative analysis of breast and lung cancer survival rates and clinical trial enrollments among rural and urban patients in Georgia

Objectives:Rural patients have poor cancer outcomes and clinical trial(CT)enrollment compared to urban patients due to attitudinal,awareness,and healthcare access differential.Knowledge of cancer survival disparities and CT enrollment is important for designing interventions and innovative approaches to address the stated barriers.The study explores the potential disparities in cancer survival rates and clinical trial enrollments in rural and urban breast and lung cancer patients.Our hypotheses are that for both cancer types,urban cancer patients will have longer 5-year survival rates and higher enrollment rates in clinical trials than those in rural counties.Methods:We compared breast and lung cancer patients’survival rates and enrollment ratios in clinical trials between rural(RUCC 4-9)and urban counties in Georgia at a Comprehensive Cancer Center(CCC).To assess these differences,we carried out a series of independent samples t-tests and Chi-Square tests.Results:The outcomes indicate comparable 5-year survival rates across rural and urban counties for breast and lung cancer patients,failing to substantiate our hypothesis.While clinical trial enrollment rates demonstrated a significant difference between breast and lung cancer patients at CCC,no significant variation was observed based on rural or urban classification.Conclusion:These findings underscore the need for further research into the representation of rural patients with diverse cancer types at CCC and other cancer centers.Further,the findings have considerable implications for the initiation of positive social change to improve CT participation and reduce cancer survival disparities.

Role of endoscopic-ultrasound-guided biliary drainage with electrocautery-enhanced lumen-apposing metal stent for palliation of malignant biliary obstruction

In this editorial,we discuss the article by Peng et al in the recent issue of the World Journal of Gastrointestinal Surgery,focusing on the evolving role of endoscopicultrasound-guided biliary drainage(EUS-BD)with electrocautery lumen apposing metal stent(LAMS)for distal malignant biliary obstruction.Therapeutic endoscopy has rapidly advanced in decompression techniques,with growing evidence of its safety and efficacy surpassing percutaneous and surgical approaches.While endoscopic retrograde cholangiopancreatography(ERCP)has been the gold standard for biliary decompression,its failure rate approaches 10.0%,prompting the exploration of alternatives like EUS-BD.This random-effects meta-analysis demonstrated high technical and clinical success of over 90.0% and an adverse event rate of 17.5%,mainly in the form of stent dysfunction.Outcomes based on stent size were not reported but the majority used 6 mm and 8 mm stents.As the body of literature continues to demonstrate the effectiveness of this technique,the challenges of stent dysfunction need to be addressed in future studies.One strategy that has shown promise is placement of double-pigtail stents,only 18% received the prophylactic intervention in this study.We expect this to improve with time as the technique continues to be refined and standardized.The results above establish EUS-BD with LAMS as a reliable alternative after failed ERCP and considering EUS to ERCP upfront in the same session is an effective strategy.Given the promising results,studies must explore the role of EUS-BD as first-line therapy for biliary decompression.

Science and the practice of cardiovascular medicine in the geriatric population

1 Why is the demograpy important? In the half century 2000-2050,there will be a virtual tsunami of aging in the United States.The anticipated increase in the population older than age 65 is 140%,and for the population older than age 85,389%.More than half of the current U.S.population can anticipate living to age 80,with a contemporary life expectancy at age 75 of 11 years,and at age 85 of 6 years.

Acute and chronic excitotoxicity in ischemic stroke and late-onset Alzheimer's disease

Stroke and Alzheimer's disease are common neurological disorders and often occur in the same individuals.The comorbidity of the two neurological disorders represents a grave health threat to older populations.This review presents a brief background of the development of novel concepts and their clinical potentials.The activity of glutamatergic N-methyl-D-aspartate receptors and N-methyl-D-aspartate receptor-mediated Ca^(2+)influx is critical for neuronal function.An ischemic insult induces prompt and excessive glutamate release and drastic increases of intracellular Ca^(2+)mainly via N-methyl-D-aspartate receptors,particularly of those at the extrasynaptic site.This Ca^(2+)-evoked neuronal cell death in the ischemic core is dominated by necrosis within a few hours and days known as acute excitotoxicity.Furthermore,mild but sustained Ca^(2+)increases under neurodegenerative conditions such as in the distant penumbra of the ischemic brain and early stages of Alzheimer's disease are not immediately toxic,but gradually set off deteriorating Ca^(2+)-dependent signals and neuronal cell loss mostly because of activation of programmed cell death pathways.Based on the Ca^(2+)hypothesis of Alzheimer's disease and recent advances,this Ca^(2+)-activated“silent”degenerative excitotoxicity evolves from years to decades and is recognized as a unique slow and chronic neuropathogenesis.The N-methyl-D-aspartate receptor subunit GluN3A,primarily at the extrasynaptic site,serves as a gatekeeper for the N-methyl-D-aspartate receptor activity and is neuroprotective against both acute and chronic excitotoxicity.Ischemic stroke and Alzheimer's disease,therefore,share an N-methyl-D-aspartate receptor-and Ca^(2+)-mediated mechanism,although with much different time courses.It is thus proposed that early interventions to control Ca^(2+)homeostasis at the preclinical stage are pivotal for individuals who are susceptible to sporadic late-onset Alzheimer's disease and Alzheimer's disease-related dementia.This early treatment simultaneously serves as a preconditioning therapy against ischemic stroke that often attacks the same individuals during abnormal aging.

Complement-dependent neuroinflammation in spinal cord injury:from pathology to therapeutic implications

Spinal cord injury remains a major cause of disability in young adults,and beyond acute decompression and rehabilitation,there are no pharmacological treatments to limit the progression of injury and optimize recovery in this population.Following the thorough investigation of the complement system in triggering and propagating cerebral neuroinflammation,a similar role for complement in spinal neuroinflammation is a focus of ongoing research.In this work,we survey the current literature investigating the role of complement in spinal cord injury including the sources of complement proteins,triggers of complement activation,and role of effector functions in the pathology.We study relevant data demonstrating the different triggers of complement activation after spinal cord injury including direct binding to cellular debris,and or activation via antibody binding to damage-associated molecular patterns.Several effector functions of complement have been implicated in spinal cord injury,and we critically evaluate recent studies on the dual role of complement anaphylatoxins in spinal cord injury while emphasizing the lack of pathophysiological understanding of the role of opsonins in spinal cord injury.Following this pathophysiological review,we systematically review the different translational approaches used in preclinical models of spinal cord injury and discuss the challenges for future translation into human subjects.This review emphasizes the need for future studies to dissect the roles of different complement pathways in the pathology of spinal cord injury,to evaluate the phases of involvement of opsonins and anaphylatoxins,and to study the role of complement in white matter degeneration and regeneration using translational strategies to supplement genetic models.

Advances in Wireless,Batteryless,Implantable Electronics for Real‑Time,Continuous Physiological Monitoring

This review summarizes recent progress in developing wireless,batteryless,fully implantable biomedical devices for real-time continuous physiological signal monitoring,focusing on advancing human health care.Design considerations,such as biological constraints,energy sourcing,and wireless communication,are discussed in achieving the desired performance of the devices and enhanced interface with human tissues.In addition,we review the recent achievements in materials used for developing implantable systems,emphasizing their importance in achieving multi-functionalities,biocompatibility,and hemocompatibility.The wireless,batteryless devices offer minimally invasive device insertion to the body,enabling portable health monitoring and advanced disease diagnosis.Lastly,we summarize the most recent practical applications of advanced implantable devices for human health care,highlighting their potential for immediate commercialization and clinical uses.

Optimizing care for gastric cancer with overt bleeding:Is systemic therapy a valid option?

Gastric cancer(GC)and gastroesophageal junction cancer(GEJC)represent a significant burden globally,with complications such as overt bleeding(OB)further exacerbating patient outcomes.A recent study by Yao et al evaluated the effectiveness and safety of systematic treatment in GC/GEJC patients presenting with OB.Using propensity score matching,the study balanced the comparison groups to investigate overall survival and treatment-related adverse events.The study's findings emphasize that systematic therapy can be safe and effective and contribute to the ongoing debate about the management of advanced GC/GEJC with OB,highlighting the complexities of treatment decisions in these high-risk patients.

Krüppel-like factors 4 and 5:the yin and yang regulators of cellular proliferation

Krüppel-like factors (KLFs) are evolutionarily conserved zinc finger-containing transcription factors with diverseregulatory functions in cell growth, proliferation, differentiation, and embryogenesis. KLF4 and KLF5 are two closelyrelated members of the KLF family that have a similar tissue distribution in embryos and adults. However, the two KLFsoften exhibit opposite effects on regulation of gene transcription, despite binding to similar, if not identical, cis-actingDNA sequences. In addition, KLF4 and 5 exert contrasting effects on cell proliferation in many instances; while KLF4is an inhibitor of cell growth, KLF5 stimulates proliferation. Here we review the biological properties and biochemicalmechanisms of action of the two KLFs in the context of growth regulation.

Neuroprotective mechanisms and translational potential of therapeutic hypothermia in the treatment of ischemic stroke

Stroke is a leading cause of disability and death,yet effective treatments for acute stroke has been very limited.Thus far,tissue plasminogen activator has been the only FDA-approved drug for thrombolytic treatment of ischemic stroke patients,yet its application is only applicable to less than 4–5% of stroke patients due to the narrow therapeutic window（〈 4.5 hours after the onset of stroke） and the high risk of hemorrhagic transformation.Emerging evidence from basic and clinical studies has shown that therapeutic hypothermia,also known as targeted temperature management,can be a promising therapy for patients with different types of stroke.Moreover,the success in animal models using pharmacologically induced hypothermia（PIH） has gained increasing momentum for clinical translation of hypothermic therapy.This review provides an updated overview of the mechanisms and protective effects of therapeutic hypothermia,as well as the recent development and findings behind PIH treatment.It is expected that a safe and effective hypothermic therapy has a high translational potential for clinical treatment of patients with stroke and other CNS injuries.

Urokinase-type plasminogen activator is a modulator of synaptic plasticity in the central nervous system:implications for neurorepair in the ischemic brain

The last two decades have witnessed a rapid decrease in mortality due to acute cerebral ischemia that paradoxically has led to a rapid increase in the number of patients that survive an acute ischemic stroke with various degrees of disability.Unfortunately,the lack of an effective therapeutic strategy to promote neurological recovery among stroke survivors has led to a rapidly growing population of disabled patients.Thus,understanding the mechanisms of neurorepair in the ischemic brain is a priority with wide scientific,social and economic implications.Cerebral ischemia has a harmful effect on synaptic structure associated with the development of functional impairment.In agreement with these observations,experimental evidence indicates that synaptic repair underlies the recovery of neurological function following an ischemic stroke.Furthermore,it has become evident that synaptic plasticity is crucial not only during development and learning,but also for synaptic repair after an ischemic insult.The plasminogen activating system is assembled by a cascade of enzymes and their inhibitors initially thought to be solely involved in the generation of plasmin.However,recent work has shown that in the brain this system has an important function regulating the development of synaptic plasticity via mechanisms that not always require plasmin generation.Urokinase-type plasminogen activator(uPA)is a serine proteinase and one of the plasminogen activators,that upon binding to its receptor(uPAR)not only catalyzes the conversion of plasminogen into plasmin on the cell surface,but also activates cell signaling pathways that promote cell migration,proliferation and survival.The role of uPA is the brain is not fully understood.However,it has been reported while uPA and uPAR are abundantly found in the developing central nervous system,in the mature brain their expression is restricted to a limited group of cells.Remarkably,following an ischemic injury to the mature brain the expression of uPA and uPAR increases to levels comparable to those observed during development.More specifically,neurons release uPA during the recovery phase from an ischemic injury,and astrocytes,axonal boutons and dendritic spines recruit uPAR to their plasma membrane.Here we will review recent evidence indicating that binding of uPA to uPAR promotes the repair of synapses damaged by an ischemic injury,with the resultant recovery of neurological function.Furthermore,we will discuss data indicating that treatment with recombinant uPA is a potential therapeutic strategy to promote neurological recovery among ischemic stroke survivors.

Outcomes of per oral endoscopic pyloromyotomy in gastroparesis worldwide

Per oral endoscopic pyloromyotomy(POP),also known as gastric per-oral endoscopic myotomy(GPOEM),is a novel procedure with promising potential for the treatment of gastroparesis.As more data emerge and the procedure is becoming more recognized in clinical practice,its safety and efficacy need to be carefully evaluated.Appropriate patient selection for favorable clinical success prediction after GPOEM also needs additional research.This review aims to systemically summarize the existing data on clinical outcomes of POP.Symptomatologic responses to the procedure,its adverse effects,procedural techniques,and predictive factors of clinical success are also discussed.

Clinical significance of main pancreatic duct dilation on computed tomography: Single and double duct dilation

AIM: To study the patients with main pancreatic duct dilation on computed tomography (CT) and thereby to provide the predictive criteria to identify patients at high risk of significant diseases, such as pancreatic cancer, and to avoid unnecessary work up for patients at low risk of such diseases. METHODS: Patients with dilation of the main pancreatic duct on CT at Emory University Hospital in 2002 were identified by computer search. Clinical course and ultimate diagnosis were obtained in all the identified patients by abstraction of their computer database records. RESULTS: Seventy-seven patients were identified in this study. Chronic pancreatitis and pancreatic cancer were the most common causes of the main pancreatic duct dilation on CT. Although the majority of patients with isolated dilation of the main pancreatic duct (single duct dilation) had chronic pancreatitis, one-third of patients with single duct dilation but without chronic pancreatitis had pancreatic malignancies, whereas most of patients with concomitant biliary duct dilation (double duct dilation) had pancreatic cancer. CONCLUSION: Patients with pancreatic double duct dilation need extensive work up and careful followup since a majority of these patients are ultimately diagnosed with pancreatic cancer. Patients with single duct dilation, especially such patients without any evidence of chronic pancreatitis, also need careful follow-up since the possibility of pancreatic malignancy, including adenocarcinoma and intraductal papillary mucinous tumors, is still high.

Receptor activator of NF-κB Ligand （RANKL） expression is associated with epithelial to mesenchymal transition in human prostate cancer cells

Epithelial-mesenchymal transition （EMT） in cancer describes the phenotypic and behavioral changes of cancer cells from indolent to virulent forms with increased migratory, invasive and metastatic potential. EMT can be induced by soluble proteins like transforming growth factor β1 （TGFβ1） and transcription factors including Snail and Slug. We utilized theARCaPE/ARCaPM prostate cancer progression model and LNCaP clones stably overexpressing Snail to identify novel markers associated with EMT. Compared to ARCaPE cells, the highly tumorigenic mesenchymal ARCaPM and ARCaPM1 variant cells displayed a higher incidence of bone metastasis after intracardiac administration in SCID mice. ARCaPM and ARCaPM1 expressed mesenchymal stromal markers of vimentin and N-cadherin in addition to elevated levels of Receptor Activator of NF-κB Ligand （RANKL）. We observed that both epidermal growth factor （EGF） plus TGFβ1 treatment and Snail overexpression induced EMT in ARCaPE and LNCaP cells, and EMT was associated with increased expression of RANKL protein. Finally, we determined that the RANKL protein was functionally active, promoting osteoclastogenesis in vitro. Our results indicate that RANKL is a novel marker for EMT during prostate cancer progression. RANKL may function as a link between EMT, bone turnover, and prostate cancer skeletal metastasis.

Are bone marrow regenerative cells ideal seed cells for the treatment of cerebral ischemia?

Bone marrow cells for the treatment of ischemic brain injury may depend on the secretion of a large number of neurotrophic factors. Bone marrow regenerative cells are capable of increasing the secretion of neurotrophic factors. In this study, after tail vein injection of 5-fluorouracil for 7 days, bone marrow cells and bone marrow regenerative cells were isolated from the tibias and femurs of rats, and then administered intravenously via the tail vein after focal cerebral ischemia. Immunohistological staining and reverse transcription-PCR detection showed that transplanted bone marrow cells and bone marrow regenerative cells could migrate and survive in the ischemic regions, such as the cortical and striatal infarction zone. These cells promote vascular endothelial cell growth factor mRNA expression in the ischemic marginal zone surrounding the ischemic penumbra of the cortical and striatal infarction zone, and have great advantages in promoting the recovery of neurological function, reducing infarct size and promoting angiogenesis. Bone marrow regenerative cells exhibited stronger neuroprotective effects than bone marrow cells. Our experimental findings indicate that bone marrow regenerative cells are preferable over bone marrow cells for cell therapy for neural regeneration after cerebral ischemia. Their neuroprotective effect is largely due to their ability to induce the secretion of factors that promote vascular regeneration, such as vascular endothelial growth factor.

Dysregulation of mTOR activity through LKB1 inactivation

Mammalian target of rapamycin (mTOR) is aberrantly activated in many cancer types, and two rapamycin derivatives are currently approved by the Food and Drug Administration (FDA) of the United States for treating renal cell carcinoma. Mechanistically, mTOR is hyperactivated in human cancers either due to the genetic activation of its upstream activating signaling pathways or the genetic inactivation of its negative regulators. The tumor suppressor liver kinase B1 (LKB1), also known as serine/threonine kinase 11 (STK11), is involved in cell polarity, cell detachment and adhesion, tumor metastasis, and energetic stress response. A key role of LKB1 is to negatively regulate the activity of mTOR complex 1 (mTORC1). This review summarizes the molecular basis of this negative interaction and recent research progress in this area.

Effects of congenital ptosis on the refractive development of eye and vision in children

AIM:To investigate the influence of unilateral congenital ptosis on the development of the eye and vision in children.METHODS:In this prospective observational study,41 patients with unilateral congenital ptosis were enrolled(age range 3-15y).The blepharoptosis was divided into 3 subgroups according to the margin reflex distance-1(MRD-1),including mild group(MRD-1>2 mm),moderate group(0<MRD-1<2 mm),and severe group(MRD-1<0 mm).The fellow eyes served as controls.All subjects underwent ocular examinations,including axial length,keratometry,and refractive error.RESULTS:The incidence of astigmatism(ptotic eyes:58.5%vs fellow eyes:24.4%,P=0.002)and magnitude of cylindrical power(ptotic eyes:-0.86±0.79 D vs fellow eyes:-0.43±0.63 D,P=0.003)differed significantly between the ptotic eyes and the fellow eyes.The spherical equivalent refraction(P=0.006),spherical power(P=0.01),cylindrical power(P=0.011),axial length-corneal radius(AL/CR)ratio(P=0.009),frequency of hyperopia(P=0.002)and astigmatism(P=0.004)were significantly different among the ptotic eye subgroups and the fellow eye group.In addition,in patients with congenital ptosis,the incidence of amblyopia is 43.9%and the incidence of anisometropia is 24.4%.More importantly,the ratio of AL/CR showed significantly positive correlation with the severity of ptosis(P=0.002).CONCLUSION:Congenital ptosis may lead to a delayed eyeball development in the aspect of AL/CR.The risk of amblyopia is also increased due to visual deprivation and aggravated anisometropia,particularly in severe ptosis case.

Genomic profiling of lower-grade gliomas uncovers cohesive disease groups:implications for diagnosis and treatment

Lower-grade gliomas(including low-and intermediate-grade gliomas,World Health Organization grades II and III)are diffusely infiltrative neoplasms that arise most often in the cerebral hemispheres of adults and have traditionally been classified based on their presumed histogenesis as astrocytomas,oligodendrogliomas,or oligoastrocytomas.Although the histopathologic classification of lower-grade glioma has been the accepted standard for nearly a century,it suffers from high intra-and inter-observer variability and does not adequately predict clinical outcomes.Based on integrated analysis of multiplatform genomic data from The Cancer Genome Atlas,lower-grade gliomas have been found to segregate into three cohesive,clinically relevant molecular classes.Molecular classes were closely aligned with the status of isocitrate dehydrogenase(IDH)mutations,tumor protein 53 mutations and the co-deletion of chromosome arms 1 p and 19q,but were not closely aligned with histologic classes.These findings emphasize the potential for improved definition of clinically relevant disease subsets using integrated molecular approaches and highlight the importance of biomarkers for brain tumor classification.

Impact of genetic alterations on mTOR-targeted cancer therapy

Rapamycin and its derivatives (rapalogs) , a group of allosteric inhibitors of mammalian target of rapamycin (mTOR), have been actively tested in a variety of cancer clinical trials, and some have been approved by the Food and Drug Administration for the treatment of certain types of cancers. However, the single agent activity of these compounds in many tumor types remains modest. The mTOR axis is regulated by multiple upstream signaling pathways. Because the genes (e.g., PIK3CA, KRAS, PTEN, and LKB1) that encode key components in these signaling pathways are frequently mutated in human cancers, a subset of cancer types may be addicted to a given mutation, leading to hyperactivation of the mTOR axis. Thus, efforts have been made to demonstrate the potential impact of genetic alterations on rapalogbased or mTOR-targeted cancer therapy. This review will primarily summarize research advances in this direction.

The plasminogen activating system in the pathogenesis of Alzheimer’s disease

Dementia is a clinical syndrome that affects approximately 47 million people worldwide and is characterized by progressive and irreversible decline of cognitive,behavioral and sesorimotor functions.Alzheimer’s disease(AD)accounts for approximately 60–80%of all cases of dementia,and neuropathologically is characterized by extracellular deposits of insoluble amyloid-β(Aβ)and intracellular aggregates of hyperphosphorylated tau.Significantly,although for a long time it was believed that the extracellular accumulation of Aβwas the culprit of the symptoms observed in these patients,more recent studies have shown that cognitive decline in people suffering this disease is associated with soluble Aβ-induced synaptic dysfunction instead of the formation of insoluble Aβ-containing extracellular plaques.These observations are translationally relevant because soluble Aβ-induced synaptic dysfunction is an early event in AD that precedes neuronal death,and thus is amenable to therapeutic interventions to prevent cognitive decline before the progression to irreversible brain damage.The plasminogen activating(PA)system is an enzymatic cascade that triggers the degradation of fibrin by catalyzing the conversion of plasminogen into plasmin via two serine proteinases:tissue-type plasminogen activator(tPA)and urokinase-type plasminogen activator(uPA).Experimental evidence reported over the last three decades has shown that tPA and uPA play a role in the pathogenesis of AD.However,these studies have focused on the ability of these plasminogen activators to trigger plasmin-induced cleavage of insoluble Aβ-containing extracellular plaques.In contrast,recent evidence indicates that activity-dependent release of uPA from the presynaptic terminal of cerebral cortical neurons protects the synapse from the deleterious effects of soluble Aβvia a mechanism that does not require plasmin generation or the cleavage of Aβfibrils.Below we discuss the role of the PA system in the pathogenesis of AD and the translational relevance of data published to this date.

Memory CD8+ T cell differentiation in viral infection: A cell for all seasons

Chronic viral infections such as hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are major global health problems affecting more than 500 million people worldwide. Virus-specific CD8+ T cells play an important role in the course and outcome of these viral infections and it is hypothesized that altered or impaired differentiation of virus- specific CD8+ T cells contributes to the development of persistence and/or disease progression. A deeper understanding of the mechanisms responsible for functional differentiation of CD8+ T cells is essential for the generation of successful therapies aiming to strengthen the adaptive component of the immune system.