Whole mount of adult ear skin as a model to study vascular malformations

Background:Genetic analysis in human patients has linked mutations in PIK3CA,the catalytic subunit of PI-3′Kinase,to sporadic incidences of vascular malformations.Methods:We have developed a mouse model with inducible and endothelial-specific expression of PIK3CA H1047R,resulting in the development of vascular malformations.Systemic induction of this mutation in adult mice results in rapid lethality,limiting our ability to track and study these lesions;therefore,we developed a topical and local induction protocol using the active metabolite of tamoxifen,4OH-T,on the ear skin of adults.Results:This approach allows us to successfully model the human disease in a mature and established vascular bed and track the development of vascular malformations.To validate the utility of this model,we applied a topical rapamycin ointment,as rapamycin is therapeutically beneficial to patients in clinical trials.We found that the induced ear lesions showed significant attenuation after treatment,which was easily quantified.Conclusions:These data collectively provide evidence of a new model to study vascular malformations in adult tissues,which should be particularly useful in environments lacking specialized small-animal imaging facilities.

Update on hepatocellular carcinoma: Pathologists' review

Histopathologic diversity and several distinct histologic subtypes of hepatocellular carcinoma(HCC) are well-recognized. Recent advances in molecular pathology and growing knowledge about the biology associated with distinct histologic features and immuno-profile in HCC allowed pathologists to update classifications. Improving sub-classification will allow for more clinically relevant diagnoses and may allow for stratification into biologically meaningful subgroups. Therefore, immuno-histochemical and molecular testing are not only diagnostically useful, but also are being incorporated as crucial components in predicting prognosis of the patients with HCC. Possibilities of targeted therapy are being explored in HCC, and it will be important for pathologists to provide any data that may be valuable from a theranostic perspective. Herein, we review and provide updates regarding the pathologic sub-classification of HCC.Pathologic diagnostic approach and the role of biomarkers as prognosticators are reviewed. Further, the histopathology of four particular subtypes of HCC:Steatohepatitic, clear cell, fibrolamellar and scirrhous-and their clinical relevance, and the recent consensus on combined HCC-cholangiocarcinoma is summarized. Finally, emerging novel biomarkers and new approaches to HCC stratification are reviewed.

A unique sequence in the N-terminal regulatory region controls the nuclear localization of KLF8 by cooperating with the C-terminal zinc-fingers

Kr 眉 p 像像素的因素 8 (KLF8 ) 抄写因素在房间周期前进起一个关键作用， oncogenic 转变，对间充质的转变和侵略上皮。然而，它的原子本地化信号(NLS ) 没被识别。有另外的 KLF monopartite NLS (mNLS ) 和 C2H2 锌手指(ZF ) 的 KLF8 份额，哪个被显示了是为一些另外的 KLF 的 NLS。在这份报告，用指导 PCR 的 mutagenesis 和 immunofluorescent 显微镜学，我们显示出 mNLSs，任何单个 ZF 的删除，或变化的那混乱 Zn2+ 有约束力或联系 DNA 主题没影响 KLF8 的原子本地化。删除 > 然而，从 C 终点的 1.5 ZF 引起了 KLF8 的细胞质的累积。令人惊讶地，氨基酸(aa ) 的删除 151-200 区域几乎从原子核消除了 KLF8。有 PKC 禁止者的 S165A， K171E 或 K171R 变化，或处理导致了部分细胞质的累积。Co-immunoprecipitation 证明 KLF8 与 importin- 交往了，这个相互作用要求了 ZF 主题。aa 1-150 或 201-261 区域的删除独自没改变原子本地化。BrdU 加入和 cyclin D1 倡导者酶试金作为野类型的 KLF8 证明在原子本地化的 KLF8 异种有缺陷者不能支持 DNA 合成或 cyclin D1 倡导者激活。一起拿，这些结果建议 KLF8 有二 NLS，一包围 S165 和 K171 并且另外的是二双人脚踏车 ZF，它为 KLF8 原子本地化和它的细胞的功能的规定是批评的。

New insight in expression, transport, and secretion of brain-derived neurotrophic factor: Implications in brainrelated diseases

Brain-derived neurotrophic factor(BDNF) attracts increasing attention from both research and clinical fields because of its important functions in the central nervous system. An adequate amount of BDNF is critical to develop and maintain normal neuronal circuits in the brain. Given that loss of BDNF function has beenreported in the brains of patients with neurodegenerative or psychiatric diseases, understanding basic properties of BDNF and associated intracellular processes is imperative. In this review, we revisit the gene structure, transcription, translation, transport and secretion mechanisms of BDNF. We also introduce implications of BDNF in several brain-related diseases including Alzheimer's disease, Huntington's disease, depression and schizophrenia.

Functional interactions between steroid hormones and neurotrophin BDNF

Brain-derived neurotrophic factor(BDNF),a critical neurotrophin,regulates many neuronal aspects including cell differentiation,cell survival,neurotransmission,and synaptic plasticity in the central nervous system(CNS) .Though BDNF has two types of receptors,high affinity tropomyosin-related kinase(Trk) B and low affinity p75 receptors,BDNF positively exerts its biological effects on neurons via activation of TrkB and of resultant intracellular signaling cascades including mitogenactivated protein kinase/extracellular signal-regulated protein kinase,phospholipase Cγ,and phosphoinositide 3-kinase pathways.Notably,it is possible that alteration in the expression and/or function of BDNF in the CNS is involved in the pathophysiology of various brain diseases such as stroke,Parkinson's disease,Alzheimer's disease,and mental disorders.On the other hand,glucocorticoids,stress-induced steroid hormones,also putatively contribute to the pathophysiology of depression.Interestingly,in addition to the reduction in BDNF levels due to increased glucocorticoid exposure,current reports demonstrate possible interactions between glucocorticoids and BDNF-mediated neuronal functions. Other steroid hormones,such as estrogen,are involved in not only sexual differentiation in the brain,but also numerous neuronal events including cell survival and synaptic plasticity.Furthermore,it is well known that estrogen plays a role in the pathophysiology of Parkinson's disease,Alzheimer's disease,and mental illness,while serving to regulate BDNF expression and/or function.Here,we present a broad overview of the current knowledge concerning the association between BDNF expression/function and steroid hormones(glucocorticoids and estrogen).

Serrated lesions:A challenging enemy

The serrated pathway accounts for 30%-35%of colorectal cancer(CRC).Unlike hyperplastic polyps,both sessile serrated lesions(SSLs)and traditional serrated adenomas are premalignant lesions,yet SSLs are considered to be the principal serrated precursor of CRCs.Serrated lesions represent a challenge in detection,classification,and removal–contributing to post-colonoscopy cancer.Therefore,it is of the utmost importance to characterize these lesions properly to ensure complete removal.A retrospective cohort study developed a diagnostic scoring system for SSLs to facilitate their detection endoscopically and subsequent removal.From the study,it can be ascertained that both indistinct border and mucus cap are essential in both recognizing and diagnosing serrated lesions.The proximal colon poses technical challenges for some endoscopists,which is why high-quality colonoscopy plays such an important role.The indistinct border of some SSLs poses another challenge due to difficult complete resection.Overall,it is imperative that gastroenterologists use the key features of mucus cap,indistinct borders,and size of at least five millimeters along with a high-quality colonoscopy and a good bowel preparation to improve the SSL detection rate.

Generation of dynamically perfused functional vascular network system within hydrogel using3D bio-printing technology

Introduction:3D bio-printing technology[1-3]（Figure 1）capable of dispensing live cells,soluble factors,and phase-changing hydrogel in a desired pattern,has great potential in creating 3D tissue.However,maintaining the viability of a thick tissue structure during tissue growth and maturation is challenging due to lack of adequate vascular perfusion.In a simple tissue model with

Preoperative physiological esophageal assessment for anti-reflux surgery:A guide for surgeons on high-resolution manometry and pH testing

Gastroesophageal reflux disease (GERD) is one of the most commonlyencountered digestive diseases in the world, with the prevalence continuing toincrease. Many patients are successfully treated with lifestyle modifications andproton pump inhibitor therapy, but a subset of patients require more aggressiveintervention for control of their symptoms. Surgical treatment with fundoplicationis a viable option for patients with GERD, as it attempts to improve the integrityof the lower esophageal sphincter (LES). While surgery can be as effective asmedical treatment, it can also be associated with side effects such as dysphagia,bloating, and abdominal pain. Therefore, a thorough pre-operative assessment iscrucial to select appropriate surgical candidates. Newer technologies arebecoming increasingly available to help clinicians identify patients with true LESdysfunction, such as pH-impedance studies and high-resolution manometry(HRM). Pre-operative evaluation should be aimed at confirming the diagnosis ofGERD, ruling out any major motility disorders, and selecting appropriate surgicalcandidates. HRM and pH testing are key tests to consider for patients with GERDlike symptoms, and the addition of provocative measures such as straight legraises and multiple rapid swallows to HRM protocol can assess the presence ofunderlying hiatal hernias and to test a patient’s peristaltic reserve prior tosurgery.

Colorectal cancer screening in the COVID-19 era

Colorectal cancer(CRC)is the third most diagnosed form of cancer and second most deadly cancer worldwide.Introduction of better screening has improved both incidence and mortality.However,as the coronavirus disease 2019(COVID-19)pandemic began,healthcare resources were shunted away from cancer screening services resulting in a sharp decrease in CRC screening and a backlog of patients awaiting screening tests.This may have significant effects on CRC cancer mortality,as delayed screening may lead to advanced cancer at diagnosis.Strategies to overcome COVID-19 related disruption include utilizing stool-based cancer tests,developing screening protocols based on individual risk factors,expanding telehealth,and increasing open access colonoscopies.In this review,we will summarize the effects of COVID-19 on CRC screening,the potential longoutcomes,and ways to adapt CRC screening during this global pandemic.

Rebuilding trust in proton pump inhibitor therapy

Introduction of proton pump inhibitor(PPI)therapy into clinical practice has revolutionized treatment approach to acid-related diseases.With its clinical success came a widespread use of PPI therapy.Subsequently,several studies found that PPIs were oftentimes overprescribed in primary care and emergency setting,likely attributed to seemingly low side-effect profile and physicians having low threshold to initiate therapy.However,now there is a growing concern over PPI side-effect profile among both patients and providers.We would like to bring more awareness to the currently available guidelines on PPI use,discuss clinical indications for PPIs and the evidence behind the reported sideeffects.We hope that increased awareness of proper PPI use will make the initiation or continuation of therapy a well informed and an evidence-based decision between patient and physician.We also hope that discussing evidence behind the reported side-effect profile will help clarify the growing concerns over PPI therapy.

Dendroaspis natriuretic peptide relaxes gastric antral circular smooth muscle of guinea-pig through thecGMP/cGMP-dependent protein kinase pathway

AIM: To systematically investigate if cGMP/cGMP- dependent protein kinase G (PKG) signaling pathway may participate in dendroaspis natriuretic peptide (DNP)-induced relaxation of gastric circular smooth muscle. METHODS: The content of cGMP in guinea pig gastric antral smooth muscle tissue and perfusion solution were measured using radioimmunoassay; spontaneous contraction of gastric antral circular muscles recorded using a 4-channel physiograph; and Ca2+-activated K+ currents (IK(Ca)) and spontaneous transient outward currents (STOCs) in isolated gastric antral myocytes were recorded using the whole-cell patch clamp technique. RESULTS: DNP markedly enhanced cGMP levels in gastric antral smooth muscle tissue and in the perfusion medium. DNP induced relaxation in gastricantral circular smooth muscle, which was inhibited by KT5823, a cGMP-dependent PKG inhibitor. DNP increased IK(Ca). This effect was almost completely blocked by KT5823, and partially blocked by LY83583, an inhibitor of guanylate cyclase to change the production of cGMP. DNP also increased STOCs. The effect of DNP on STOCs was abolished in the presence of KT5823, but not affected by KT-5720, a PKA-specific inhibitor. CONCLUSION: DNP activates IK(Ca) and relaxes guinea-pig gastric antral circular smooth muscle via the cGMP/PKG-dependent singling axis instead of cAMP/ PKA pathway.

Ventricular Arrhythmia-Free Survival Following Therapeutic Hypothermia in Patients with Sudden Cardiac Death Due to Ventricular Tachycardia or Fibrillation

Background: The potential benefits of implantable cardioverter-defibrillator (ICD) therapy in patients with sudden cardiac death (SCD) treated with therapeutic hypothermia (TH) have not been well studied. Methods: Incidence of recurrent non-sustained ventricular arrhythmia, ICD therapy, and death were ascertained in 64 consecutive survivors of SCD due to ventricular fibrillation or tachycardia, who were treated with TH. Follow-up was 31.5 +/- 3.3 months in 41 ICD recipients and 36.3 +/- 3.9 months in 23 patients who did not receive an ICD due to the presence of a reversible cause of cardiac arrest, an acute myocardial infarction in 87%. Results: Combined incidence of ventricular arrhythmia, ICD therapy, or death in patients who underwent ICD placement (21.9%) were similar to overall mortality in the patients who did not receive an ICD (21.7%, p = 0.752). ICD placement was associated with a significant mortality benefit;95.1% survival in ICD recipients vs. 78.3% in the no-ICD group (p = 0.038). Electrocardiographic findings of ST segment elevation on admission were associated with increased event rate in ICD recipients (p = 0.039) and increased mortality in SCD patients who did not receive an ICD (p Conclusions: SCD survivors treated with TH are at increased risk for recurrent arrhythmic events and derive significant mortality benefit from ICD implantation. Increased mortality in revascularized SCD patients with acute coronary syndrome, thought to have a reversible cause of cardiac arrest, calls for prospective trials investigating utility of ICD in this vulnerable patient population.

儿童扩张型心肌病的发病率、病因及预后

背景：扩张型心肌病（dilated cardiomyopathy，DCM）是儿童心肌病最常见的类型，也是小儿心脏移植最常见的原因。但是，目前尚不清楚儿童DCM的流行病学特点和临床过程。 目的：详细描述儿童DCM的发病率、病因、预后及相关危险因素。 设计及地点：本项以人群为基础的前瞻性纵向队列研究入选1996年1月至2003年2月在89个儿科心脏中心诊断为DCM的儿童以及1990年1月至1995年12月在北美大型三级治疗中心诊断的患儿。 参试者：共入选1426例来自美国和加拿大的18岁以下DCM患儿。通过严格的超声心动图和／或病理学标准来诊断原发性DCM。因内分泌、免疫、药物中毒及其他原因患病者除外。 主要观测指标：每年每10万儿童的发病率、死亡率和心脏移植率。 结果：18岁以下儿童DCM每年的总发病率为0．57／10万，男孩的年发病率高于女孩（分别为0．66／10万和0．47／10万；P〈0．001），黑人的年发病率高于白人（分别为0．98／10万和0．46／10万；P〈0．001），婴儿（〈1岁）的年发病率高于儿童（分别为4．40／10万和0．34／10万；P〈0．001）。绝大部分属特发性，最常见的病因为心肌炎（46％）和神经肌肉性疾病（26％）。1年和5年死亡／移植率分别为31％和46％。死亡／移植的独立危险因素包括患儿诊断DCM时年龄较大、伴有充血性心力衰竭、左室收缩期Z评分较低以及DCM的病因（P均〈0．001）。 结论：儿童DCM有其多样性。患儿预后主要取决于病因、年龄和心力衰竭状况。人种、性别和年龄对发病率有一定影响。大部分患儿无明确病因，限制了特异性治疗。

Practical considerations for colorectal cancer screening in older adults

Recent guidelines recommend that colorectal cancer(CRC)screening after age 75 be considered on an individualized basis,and discourage screening for people over 85 due to competing causes of mortality.Given the heterogeneity in the health of older individuals,and lack of data within current guidelines for personalized CRC screening approaches,there remains a need for a clearer framework to inform clinical decision-making.A revision of the current approach to CRC screening in older adults is even more compelling given the improvements in CRC treatment,post-treatment survival,and increasing life expectancy in the population.In this review,we aim to examine the personalization of CRC screening cessation based on specific factors influencing life and health expectancy such as comorbidity,frailty,and cognitive status.We will also review screening modalities and endoscopic technique for minimizing risk,the risks of screening unique to older adults,and CRC treatment outcomes in older patients,in order to provide important information to aid CRC screening decisions for this age group.This review article offers a unique approach to this topic from both the gastroenterologist and geriatrician perspective by reviewing the use of specific clinical assessment tools,and addressing technical aspects of screening colonoscopy and periprocedural management to mitigate screening-related complications.

Dysphagia,reflux and related sequelae due to altered physiology in scleroderma

Systemic sclerosis is a connective tissue disease that presents with significant gastrointestinal involvement,commonly in the esophagus.Dysphagia is a common clinical manifestation of systemic sclerosis and is strongly related to esophageal dysmotility.However,there are multiple other contributing factors in each step in the physiology of swallowing that may contribute to development of severe dysphagia.The oral phase of swallowing may be disrupted by poor mastication due to microstomia and poor dentition,as well as by xerostomia.In the pharyngeal phase of swallowing,pharyngeal muscle weakness due to concurrent myositis or cricopharyngeal muscle tightening due to acid reflux can cause disturbance.The esophageal phase of swallowing is most commonly disturbed by decreased peristalsis and esophageal dysmotility.However,it can also be affected by obstruction from chronic reflux changes,pill-induced esophagitis,or Candida esophagitis.Other contributing factors to dysphagia include difficulties in food preparation and gastroparesis.Understanding the anatomy and physiology of swallowing and evaluating systemic sclerosis patients presenting with dysphagia for disturbances in each step can allow for development of better treatment plans to improve dysphagia and overall quality of life.

Ethical dilemma of colorectal screening: What age should a screening colonoscopy start and stop?

Many advanced age patients who are diagnosed with colorectal cancer are often not offered surgical treatment due to presumed high risks of the procedure.While there is data to support surgical treatment of colorectal cancer in advanced age patients,screening colonoscopy is not currently recommended for patients older than 85 years.Moreover,recent studies concluded that the incidence of colorectal cancer in patients 80 years and older is increasing.This raises the concern that the current guidelines are withholding screening colonoscopy for healthy elderly patients.Another concern contrary to this would be the new trend of growing incidence of advanced colorectal cancer in the younger patient population.Together they raise the ethical dilemma of how to best utilize colonoscopies as well as surgical intervention,as they are limited resources.

Lessons learned:Preventable misses and near-misses of endoscopic procedures

Endoscopy is a complex procedure that requires advanced training and a highly skilled practitioner.The advances in the field of endoscopy have made it an invaluable diagnostic tool,but the procedure remains provider dependent.The quality of endoscopy may vary from provider to provider and,as a result,is not perfect.Consequently,11.3%of upper gastrointestinal neoplasms are missed on the initial upper endoscopy and 2.1%-5.9%of colorectal polyps or cancers are missed on colonoscopy.Pathology is overlooked if endoscopic exam is not done carefully,bypassing proper visualization of the scope’s entry and exit points or,if exam is not taken to completion,not visualizing the most distal bowel segments.We hope to shed light on this issue,establish areas of weakness,and propose possible solutions and preventative measures.

Atypical Cutaneous Lymphoproliferative Disorder: A Fatal Mimic of Cutaneous T-Cell Lymphoma in a Patient with HIV Infection

Atypical cutaneous lymphoproliferative disorder (ACLD) is a rare condition that has been associated with HIV infection. Patients with ACLD present with diffuse, erythematous and pruritic skin lesions accompanied by generalized lymphadenopathy. The clinical characteristics of ACLD overlap most notably with several other conditions including Mycosis Fungoides/Sézary Syndrome (MF/SS), a cutaneous lymphoma of T-cell lineage. Unlike Mycosis Fungoides, the noxious infiltrates of ACLD are not monoclonal but polyclonal and consist of cytotoxic CD8+ T-cells instead of CD4+ T-cells or B-cells. Highly active antiretroviral therapy (HAART) has been reported to improve ACLD. We describe the case of a Caucasian man with longstanding HIV infection who presented with severe erythroderma. Skin and lymph node biopsies showed polyclonal CD8+ T-cell infiltrates. Gene rearrangement studies did not reveal an obvious clonal disorder. Hallmark peripheral blood findings consisting of a severe depletion of CD4+ T-lymphocytes and markedly elevated CD8+ cells provided an important diagnostic clue. Despite the purported benefits of HAART in ameliorating this disorder, erythroderma and extreme pruritus improved only after the patient began taking mycophenolate mofetil and hydroxyurea. Unfortunately, he succumbed to complications of methicillin-resistant Staphylococcus aureus septicemia. We alert readers to this rare HIV-associated condition which may mimic other benign and malignant skin conditions and briefly discuss diagnostic and therapeutic options.

Interaction between Antihypertensive Therapy Class and Pulse Pressure on Outcomes Following Acute Ischemic Stroke

Goal: The effect of pulse pressure and interactions with type of antihypertensive therapy on mortality after acute ischemic stroke has not been previously evaluated. Materials and Methods: A retrospective cohort study was conducted to evaluate the independent and interactive effects of pulse pressure and antihypertensive class (specifically angiotensin converting enzyme inhibitor/angiotensin type 1 receptor blocker, or beta blocker) on mortality following acute ischemic stroke. Findings/Conclusions: 343 patients were identified with 49 months of follow-up. Baseline pulse pressure was 64 mmHg and age was 66.5 years. Patients were divided at a pulse pressure of 70. Patients with pulse pressure ≥ 70 were older (p < 0.001) and had higher comorbid vascular burden (p = 0.031) than those with pulse pressure < 70. Pulse pressure did not remain a significant predictor of follow-up mortality after adjustment for baseline comorbidities. Angiotensin converting enzyme inhibitor/angiotensin type 1 receptor blocker based therapy was associated with lower follow-up mortality when beta blocker was not used in pulse pressure < 70 group (odds ratio 0.07, 95% confidence interval 0.01 - 0.48). Prospective analysis will be needed to confirm the protective effect of angiotensin converting enzyme inhibitor/angiotensin type 1 receptor blocker based on pulse pressure in acute ischemic stroke.

Cautious optimism in anticipation of hepatitis B curative therapies

Despite relative effectiveness of current hepatitis B therapies,there is still no curative agents available.The new emerging approaches hold promise to achieve cure and loss of hepatitis B surface antigen.Studies or clinical trials investigating new therapies remain small and either focus on patients with low viral load and without hepatotoxic injury or patients with hepatitis D co-infection,which makes it challenging to assess their effectiveness and side effect profile in hepatitis B population.