A pancreatic player in dementia:pathological role for islet amyloid polypeptide accumulation in the brain

Type 2 diabetes mellitus patients have a markedly higher risk of developing dementia.While multiple factors contribute to this predisposition,one of these involves the increased secretion of amylin,or islet amyloid polypeptide,that accompanies the pathophysiology of type 2 diabetes mellitus.Islet amyloid polypeptide accumulation has undoubtedly been implicated in various forms of dementia,including Alzheimer’s disease and vascular dementia,but the exact mechanisms underlying islet amyloid polypeptide’s causative role in dementia are unclear.In this review,we have summarized the literature supporting the various mechanisms by which islet amyloid polypeptide accumulation may cause neuronal damage,ultimately leading to the clinical symptoms of dementia.We discuss the evidence for islet amyloid polypeptide deposition in the brain,islet amyloid polypeptide interaction with other amyloids implicated in neurodegeneration,neuroinflammation caused by islet amyloid polypeptide deposition,vascular damage induced by islet amyloid polypeptide accumulation,and islet amyloid polypeptide-induced cytotoxicity.There are very few therapies approved for the treatment of dementia,and of these,clinical responses have been controversial at best.Therefore,investigating new,targetable pathways is vital for identifying novel therapeutic strategies for treating dementia.As such,we conclude this review by discussing islet amyloid polypeptide accumulation as a potential therapeutic target not only in treating type 2 diabetes mellitus but as a future target in treating or even preventing dementia associated with type 2 diabetes mellitus.

Brain stem cells as the cell of origin in glioma

Glioma incidence rates in the United States are near 20000 new cases per year, with a median survival time of 14.6 mo for high-grade gliomas due to limited therapeutic options. The origins of these tumors and their many subtypes remain a matter of investigation. Evidence from mouse models of glioma and human clinical data have provided clues about the cell types and initiating oncogenic mutations that drive gliomagenesis, a topic we review here. There has been mixed evidence as to whether or not the cells of origin are neural stem cells, progenitor cells or differentiated progeny. Many of the existing murine models target cell populations defined by lineage-specific promoters or employ lineagetracing methods to track the potential cells of origin. Our ability to target specific cell populations will likely increase concurrently with the knowledge gleaned from an understanding of neurogenesis in the adult brain. The cell of origin is one variable in tumorigenesis, as oncogenes or tumor suppressor genes may differentially transform the neuroglial cell types. Knowledge of key driver mutations and susceptible cell types will allow us to understand cancer biology from a developmental standpoint and enable early interventional strategies and biomarker discovery.

An update on the diagnosis of gastroenteropancreatic neuroendocrine neoplasms

Gastroenteropancreatic neuroendocrine neoplasms(GEP-NENs)arise from neuroendocrine cells found throughout the gastrointestinal tract and islet cells of the pancreas.The incidence and prevalence of GEP-NENs have been increasing each year due to higher awareness,improved diagnostic modalities,and increased incidental detection on cross-sectional imaging and endoscopy for cancer screening and other conditions and symptoms.GEP-NENs are a heterogeneous group of tumors and have a wide range in clinical presentation,histopathologic features,and molecular biology.Clinical presentation most commonly depends on whether the GEP-NEN secretes an active hormone.The World Health Organization recently updated the classification of GEP-NENs to introduce a distinction between high-grade neuroendocrine tumors and neuroendocrine carcinomas,which can be identified using histology and molecular studies and are more aggressive with a worse prognosis compared to high-grade neuroendocrine tumors.As our understanding of the biology of GEP-NENs has grown,new and improved diagnostic modalities can be developed and optimized.Here,we discuss clinical features and updates in diagnosis,including histopathological analysis,biomarkers,molecular techniques,and radiology of GEP-NENs.We review established diagnostic tests and discuss promising novel diagnostic tests that are currently in development or require further investigation and validation prior to broad utilization in patient care.

Glioblastoma stem cells:Molecular characteristics and therapeutic implications

Glioblastoma Multiforme(GBM)is a grade IV astrocytoma,with a median survival of 14.6 mo.Within GBM,stem-like cells,namely glioblastoma stem cells(GSCs),have the ability to self-renew,differentiate into distinct lineages within the tumor and initiate tumor xenografts in immunocompromised animal models.More importantly,GSCs utilize cell-autonomous and tumor microenvironment-mediated mechanisms to overcome current therapeutic approaches.They are,therefore,very important therapeutic targets.Although the functional criteria defining GSCs are well defined,their molecular characteristics,the mechanisms whereby they establish the cellular hierarchy within tumors,and their contribution to tumor heterogeneity are not well understood.This review is aimed at summarizing current findings about GSCs and their therapeutic importance from a molecular and cellular point of view.A better characterization of GSCs is crucial for designing effective GSCtargeted therapies.

Rapid improvement in post-infectious gastroparesis symptoms with mirtazapine

We report the case of a 34-year-old woman with severe post-infectious gastroparesis who was transferred from an outside medical facility for a second opinion regarding management.This patient had no prior history of gastrointestinal symptoms.However,in the aftermath of a viral illness,she developed two months of intractable nausea,vomiting,and oral intake intolerance that resulted in numerous hospitalizations for dehydration and electrolyte disturbances.A solid-phase gastric emptying scan had confirmed delayed emptying,confirming gastroparesis.Unfortunately,conventional pro-kinetic agents and numerous anti-emetic drugs provided little or no relief of the patient’s symptoms.At our institution,the patient experienced a cessation of vomiting,reported a significant reduction in nausea,and toler-ated oral intake shortly after taking mirtazapine.Based on mirtazapine’s primary action as a serotonin(5-HT)1a receptor agonist,we infer that this receptor system mediated the clinical improvement through a combination of peripheral and central neural mechanisms.This report highlights the potential utility of 5-HT1a agonists in the management of nausea and vomiting.We conclude that mirtazapine may be effective in treating symptoms associated with non-diabetic gastroparesis that are refractory to conventional therapies.

Genetic targeting of astrocytes to combat neurodegenerative disease

Astrocytes, glial cells that interact extensively with neurons and other support cells throughout the central nervous system, have recently come under the spotlight for their potential contribution to, or potential regenerative role in a host of neurodegenerative disorders. It is becoming increasingly clear that astrocytes, in concert with microglial cells, activate intrinsic immunological pathways in the setting of neurodegenerative injury, although the direct and indirect consequences of such activation are still largely unknown. We review the current literature on the astrocyte’s role in several neurodegenerative diseases, as well as highlighting recent advances in genetic manipulation of astrocytes that may prove critical to modulating their response to neurological injury, potentially combatting neurodegenerative damage.

Primary cilia as a novel horizon between neuron and environment

The primary cilium, a hair-like sensory organelle found on most mammalian cells, has gained recent attention within the field of neuroscience. Although neural primary cilia have been known to play a role in embryonic central nervous system patterning, we are just beginning to appreciate their importance in the mature organism. After several decades of investigation and controversy, the neural primary cilium is emerging as an important regulator of neuroplasticity in the healthy adult central nervous system. Further, primary cilia have recently been implicated in disease states such as cancer and epilepsy. Intriguingly, while primary cilia are expressed throughout the central nervous system, their structure, receptors, and signaling pathways vary by anatomical region and neural cell type. These differences likely bear relevance to both their homeostatic and neuropathological functions, although much remains to be uncovered. In this review, we provide a brief historical overview of neural primary cilia and highlight several key advances in the field over the past few decades. We then set forth a proposed research agenda to fill in the gaps in our knowledge regarding how the primary cilium functions and malfunctions in nervous tissue, with the ultimate goal of targeting this sensory structure for neural repair following injury.

Peripheral vestibular system: Age-related vestibular loss and associated deficits

Given the interdependence of multiple factors in age-related vestibular loss (e.g., balance, vision,cognition), it is important to examine the individual contributions of these factors with ARVL. While therelationship between the vestibular and visual systems has been well studied (Bronstein et al., 2015),little is known about the association of the peripheral vestibular system with neurodegenerative disorders (Cronin et al., 2017). Further, emerging research developments implicate the vestibular system asan opportunity for examining brain function beyond balance, and into other areas, such as cognition andpsychological functioning. Additionally, the bidirectional impact of psychological functioning is understudied in ARVL. Recognition of ARVL as part of a multifaceted aging process will help guide thedevelopment of integrated interventions for patients who remain at risk for decline. In this review, wewill discuss a wide variety of characteristics of the peripheral vestibular system and ARVL, how it relatesto neurodegenerative diseases, and correlations between ARVL and balance, vision, cognitive, and psychological dysfunction. We also discuss clinical implications as well as future directions for research, withan emphasis on improving care for patients with ARVL.

Optical coherence tomography and T cell gene expression analysis in patients with benign multiple sclerosis

Benign multiple sclerosis is a retrospective diagnosis based primarily on a lack of motor symptom progression. Recent findings that suggest patients with benign multiple sclerosis experience non-motor symptoms highlight the need for a more prospective means to diagnose benign multiple sclerosis early in order to help direct patient care. In this study, we present optical coherence tomography and T cell neurotrophin gene analysis findings in a small number of patients with benign multiple sclerosis. Our results demonstrated that retinal nerve fiber layer was mildly thinned, and T cells had a distinct gene expression profile that included upregulation of interleukin 10 and leukemia inhibitory factor, downregulation of interleukin 6 and neurotensin high affinity receptor 1（a novel neurotrophin receptor）. These findings add evidence for further investigation into optical coherence tomography and m RNA profiling in larger cohorts as a potential means to diagnose benign multiple sclerosis in a more prospective manner.

Adult hippocampal neurogenesis and its impairment in Alzheimer's disease

Adult neurogenesis is the creation of new neurons which integrate into the existing neural circuit of the adult brain.Recent evidence suggests that adult hippocampal neurogenesis(AHN)persists throughout life in mammals,including humans.These newborn neurons have been implicated to have a crucial role in brain functions such as learning and memory.Importantly,studies have also found that hippocampal neurogenesis is impaired in neurodegenerative and neuropsychiatric diseases.Alzheimer’s disease(AD)is one of the most common forms of dementia affecting millions of people.Cognitive dysfunction is a common symptom of AD patients and progressive memory loss has been attributed to the degeneration of the hippocampus.Therefore,there has been growing interest in identifying how hippocampal neurogenesis is affected in AD.However,the link between cognitive decline and changes in hippocampal neurogenesis in AD is poorly understood.In this review,we summarized the recent literature on AHN and its impairments in AD.

ADAM10 facilitates rapid neural stem cell cycling and proper positioning within the subventricular zone niche via JAMC/RAP1Gap signaling

The mechanisms that regulate neural stem cell(NSC)lineage progression and maintain NSCs within diffe rent domains of the adult neural stem cell niche,the subventricular zone are not well defined.Quiescent NSCs are arranged at the apical ventricular wall,while mitotically activated NSCs are found in the basal,vascular region of the subventricular zone.Here,we found that ADAM 10(a disintegrin and metalloproteinase 10)is essential in NSC association with the ventricular wall,and via this adhesion to the apical domain,ADAM10 regulates the switch from quiescent and undiffe rentiated NSC to an actively prolife rative and differentiating cell state.Processing of JAMC(junctional adhesion molecule C)by ADAM 10 increases Rap1 GAP activity.This molecular machinery promotes NSC transit from the apical to the basal compartment and subsequent lineage progression.Understanding the molecular mechanisms responsible for regulating the proper positioning of NSCs within the subventricular zone niche and lineage progression of NSCs could provide new targets for drug development to enhance the regenerative prope rties of neural tissue.

Long noncoding RNA(lncRNA)H19:An essential developmental regulator with expanding roles in cancer,stem cell differentiation,and metabolic diseases

Recent advances in deep sequencing technologies have revealed that,while less than 2%of the human genome is transcribed into mRNA for protein synthesis,over 80%of the genome is transcribed,leading to the production of large amounts of noncoding RNAs(ncRNAs).It has been shown that ncRNAs,especially long non-coding RNAs(lncRNAs),may play crucial regulatory roles in gene expression.As one of the first isolated and reported lncRNAs,H19 has gained much attention due to its essential roles in regulating many physiological and/or pathological processes including embryogenesis,development,tumorigenesis,osteogen-esis,and metabolism.Mechanistically,H19 mediates diverse regulatory functions by serving as competing endogenous RNAs(CeRNAs),Igf2/H19 imprinted tandem gene,modular scaffold,cooperating with H19 antisense,and acting directly with other mRNAs or lncRNAs.Here,we summarized the current understanding of H19 in embryogenesis and development,cancer development and progression,mesenchymal stem cell lineage-specific differentiation,and metabolic diseases.We discussed the potential regulatory mechanisms underlying H19’s func-tions in those processes although more in-depth studies are warranted to delineate the exact molecular,cellular,epigenetic,and genomic regulatory mechanisms underlying the physiolog-ical and pathological roles of H19.Ultimately,these lines of investigation may lead to the development of novel therapeutics for human diseases by exploiting H19 functions.

Ryanodine受体的功能结构和调节因子

Ryanodine受体(ryanodine receptor,Ry R)是位于细胞内内质网/肌浆网膜上的钙离子释放通道蛋白。Ry R是由四个足状结构的亚单位组成的同源四聚体,每个亚单位大于550 k Da,四聚体的总分子量超过2 MDa,是迄今发现的内质网/肌浆网膜上最大的离子通道。哺乳动物有三种类型的Ry R,其中Ry R1主要分布在骨骼肌中,Ry R2首先发现于心肌,Ry R3主要在脑中有较多分布。Ry R钙离子释放通道在肌肉收缩、突触传递、激素分泌、蛋白折叠和程控性凋亡以及坏死等一系列以细胞功能为基础的生理过程中起着极其重要的作用,因而近些年在医学生物学和药学应用上都有极大的进展。该文就Ry R在机体中的分布、功能结构和调节因子等进行了介绍,其蛋白调节因子二氢吡啶受体(dihydropyridine receptor,DHPR)、钙调蛋白(Calmodulin)、隐钙素(calsequestrin)、FKBP(FK506-binding protein)家族蛋白和小分子调节因子咖啡因、离子等都是Ry R复合体行使细胞生理功能必不可少的因素。

Melanoma:Molecular genetics,metastasis,targeted therapies,immunotherapies,and therapeutic resistance

Cutaneous melanoma is a common cancer and cases have steadily increased since the mid 70s.For some patients,early diagnosis and surgical removal of melanomas is lifesaving,while other patients typically turn to molecular targeted therapies and immunotherapies as treatment options.Easy sampling of melanomas allows the scientific community to identify the most prevalent mutations that initiate melanoma such as the BRAF,NRAS,and TERT genes,some of which can be therapeutically targeted.Though initially effective,many tumors acquire resistance to the targeted therapies demonstrating the need to investigate compensatory pathways.Immunotherapies represent an alternative to molecular targeted therapies.However,inter-tumoral immune cell populations dictate initial therapeutic response and even tumors that responded to treatment develop resistance in the long term.As the protocol for combination therapies develop,so will our scientific understanding of the many pathways at play in the progression of melanoma.The future direction of the field may be to find a molecule that connects all of the pathways.Meanwhile,noncoding RNAs have been shown to play important roles in melanoma development and progression.Studying noncoding RNAs may help us to understand how resistance e both primary and acquired e develops;ultimately allow us to harness the true potential of current therapies.This review will cover the basic structure of the skin,the mutations and pathways responsible for transforming melanocytes into melanomas,the process by which melanomas metastasize,targeted therapeutics,and the potential that noncoding RNAs have as a prognostic and treatment tool.

Analytical strategies for studying stem cell metabolism

Owing to their capacity for self-renewal and pluripotency, stem cells possess untold potential for revolutionizing the field of regenerative medicine through the development of novel therapeutic strategies for treating cancer, diabetes, cardiovascular and neurodegenerative diseases. Central to developing these strategies is improving our understanding of biological mechanisms responsible for governing stem cell fate and self-renewal. Increasing attention is being given to the significance of metabolism, through the production of energy and generation of small molecules, as a critical regulator of stem cell functioning. Rapid advances in the field of metabolomics now allow for in-depth profiling of stem cells both in vitro and in vivo, providing a systems perspective on key metabolic and molecular pathways which influence stem cell biology. Understanding the analytical platforms and techniques that are currently used to study stem cell metabolomics, as well as how new insights can be derived from this knowledge, will accelerate new research in the field and improve future efforts to expand our understanding of the interplay between metabolism and stem cell biology.

The radial organization of neuronal primary cilia is acutely disrupted by seizure and ischemic brain injury

BACKGROUND： Neuronal primary cilia are sensory organelles that are critically involved in the proper growth, development, and function of the central nervous system （CNS）. Recent work also suggests that they signal in the context of CNS injury, and that abnormal ciliary signaling may be implicated in neurological diseases. METHODS： We quantified the distribution of neuronal primary cilia alignment throughout the normal adult mouse brain by immunohistochemical staining for the primary cilia marker adenylyl cyclase Ⅲ （ACⅢ） and measuring the angles of primary cilia with respect to global and local coordinate planes. We then introduced two different models of acute brain insult--temporal lobe seizure and cerebral ischemia, and re-examined neuronal primary cilia distribution, as well as ciliary lengths and the proportion of neurons harboring cilia. RESULTS： Under basal conditions, cortical cilia align themselves radially with respect to the cortical surface, while cilia in the dentate gyms align themselves radially with respect to the granule cell layer. Cilia of neurons in the striatum and thalamus, by contrast, exhibit a wide distribution of ciliary arrangements. In both cases of acute brain insult, primary cilia alignment was significantly disrupted in a region-specific manner, with areas affected by the insult preferentially disrupted. Further, the two models promoted differential effects on ciliary lengths, while only the ischemia model decreased the proportion of ciliated cells. CONCLUSIONS： These findings provide evidence for the regional anatomical organization of neuronal primary cilia in the adult brain and suggest that various brain insults may disrupt this organization.

The exploration of N6-deoxyadenosine methylation in mammalian genomes

N^(6)-methyladenine(N^(6)-mA,m^(6)dA,or 6mA),a prevalent DNA modification in prokaryotes,has recently been identified in higher eukaryotes,including mammals.Although 6mA has been well-studied in prokaryotes,the function and regulatory mechanism of 6mA in eukaryotes are still poorly understood.Recent studies indicate that 6mA can serve as an epigenetic mark and play critical roles in various biological processes,from transposable-element suppression to environmental stress response.Here,we review the significant advances in methodology for 6mA detection and major progress in understanding the regulation and function of this non-canonical DNA methylation in eukaryotes,predominantly mammals.

Targeted tumor coating with antigenic, CTL-recognizable peptides via Annexin A5 chimeric constructs following chemotherapy redirects adaptive CD8+ T cell immunity for tumor clearance

A common drawback of many cancer immunotherapies,including immune checkpoint blockade,is their reliance on the expression of immunogenic tumor antigens by cancer cells for immune recognition and clearance,which limits their efficacy against cancers with weak antigenicity.1 To overcome this obstacle,we and others have explored strategies to harness the immune responses against nontumor antigens and redirect those immune responses to target tumor cells.2,3,4,5 In particular,we have pioneered a therapeutic strategy fusing tumor-targeting proteins with known antigenic peptide epitopes not naturally expressed by tumor cells,which are flanked by peptide sequences that can be recognized and cleaved by proteases overexpressed in most cancers.2,3 This strategy facilitates the targeted delivery of immunogenic peptides into tumor foci,the release of immunogenic peptides into the tumor microenvironment(TME)via tumor protease cleavage,and subsequent loading of these peptides onto major histocompatibility complex class 1(MHC-I)on the tumor cell surface,allowing the recognition of coated tumor cells by the respective peptide-specific cytotoxic CD8+T lymphocytes(CTLs)for elimination.

Cancer Cell:利用脑瘤对胆固醇的需求或可开发出癌症治疗的新方法

最近路德维希癌症研究所的研究人员发表了一项研究进展，他们发现了成胶质细胞瘤的一个代谢弱点，并在研究中揭示了如何利用这个弱点开发潜在治疗方法。成胶质细胞瘤是一种侵袭性强并且不可治愈的脑癌类型。研究人员发现成胶质细胞瘤细胞向细胞内转入大量胆固醇以维持细胞存活。可以利用处于临床开发阶段的药物分子特异且有效地削弱这一维持癌细胞存活的机制。相关研究结果发表在国际学术期刊Cancer Cell上。

Paradox-driven adventures in the development of cancer immunology and immunotherapy

After more than one hundred years of documented trials,immunotherapy has become a standard of care in the treatment of human cancer.Much of the knowledge that led to recent breakthroughs seems quite logical from today’s point of view.However,what we now cite as facts were originally considered paradoxes,meaning something contrary to expectations or perceived opinion at the time.In order to make gains in the field of immunotherapy,one had to be willing to confront ideas and concepts that seemed to contradict one another,and reconcile how each could be true.This is what led to new knowledge and advances.Here,we highlight some of these paradoxes and the milestone discoveries that followed,each one critical for our understanding of immune checkpoint pathways.By outlining some of the steps that we took and the challenges that we overcame,we hope to inspire and encourage future generations of researchers to confront the paradoxes that still permeate the field.