Drugging SUMOylation for neuroprotection and oncotherapy

Recently there have been exciting research advances in neuroprotective therapies for ischemic stroke. In the past, the search for neu- roprotective agents has been fraught with failure at the clinical trials stage due to numerous factors, including subject heterogeneity and improper therapeutic windows （Tymianski, 2017）. Moreover, it is becoming clearer that the complex and evolving pathobiology of stroke requires multimodal therapeutic approaches capable of modulating the numerous axes that contribute to ischemia/reperfusion damage, rather than targeting a single axis （Bernstock et al., 2018a）. With the success of recent endovascular thrombectomy （EVT） trials, it has been suggested that clinical trials of EVT with adjunct neuroprotection can overcome past difficulties and maximize the effect size by using imaging to reduce patient heterogeneity （i. e., selecting those with large vessel occlusions, small ischemic cores, and good collateral circulation）, restoring perfusion using better EVT devices, and enrolling patients in the correct therapeutic window （i.e., when they still have salvageable brain tissue） （Tymianski, 2017）. Considering the opportunity that this represents for new, better clinical trials of neuroprotective agents, the search is on for high-potential compounds that may be investigated in these future studies.

Pathologic etiology and predictors of malignancy in children with cervical lymphadenopathy

Cervical lymphadenopathy in children is a common disease entity that is accompanied by a variety of processes,ranging from benign disease to malignancy.Although the cause of cer-vical lymphadenopathy in children is often benign[1-4],the presence of enlarged lymph nodes can cause anxiety to parents because of its association with malignancy.Biopsy should be considered for the histologic diagnosis of persistent or unex-plained cervical lymphadenopathy in children.However,biopsy is an invasive examination method,and it is difficult to clinically determine whether biopsy is needed in children with unexplained cervical lymphadenopathy.Therefore,clini-cians should be aware of the differential diagnosis of lymph node enlargement in children and should identify situations in which malignancy may be suspected.In this study,we aimed to identify the etiology of pediatric cervical lymphadenopathy using biopsy and to analyze the risk factors associated with malignancy in children with cervical lymphadenopathy.

组织因子表达下调影响阿霉素诱导人胶质母细胞瘤细胞凋亡的研究

目的研究组织因子(TF)对阿霉素诱导人胶质母细胞瘤细胞凋亡的影响。方法以免疫印迹法检测TF表达。分子生物学方法构建TFsiRNA-pSUPER表达载体,以脂质体介导进行基因转染。以水溶性四唑盐法检测阿霉素的细胞毒性。以印迹法检测阿霉素诱导的Caspase-3、PARP的裂解。以Hochest33342染色荧光显微镜检测凋亡细胞。结果人胶质母细胞瘤细胞系U373MG高表达TF。转染TFsiRNA-pSUPER表达载体的U373MG细胞及对照细胞分别以阿霉素处理,可见转染细胞较对照细胞Caspase-3、PARP的裂解增强。以不同浓度阿霉素处理48h后,可见转染后的U373MG细胞的存活数较对照细胞明显减少(P<0.05)。以Hochest33342染色检测到转染后的U373MG细胞经阿霉素处理后的凋亡细胞数显著增多(P<0.05)。结论人胶质母细胞瘤U373MG中TF异常高表达的下调,可增强阿霉素诱导的细胞凋亡。肿瘤细胞中TF的异常高表达可能影响肿瘤细胞对化疗药物的耐受性。

Recurrent lymphoma presenting as painless, chronic intussusception: A case report

BACKGROUND The clinical presentation of acute lymphoblastic lymphoma is highly varied.While prognosis is good, recurrence of disease can occur. Gastrointestinal relapse, including intussusception, is well-described but the absence of abdominal pain in this setting is rare.CASE SUMMARY We report a 13-year-old male with B-cell precursor acute lymphoblastic leukemia in remission presenting with anemia and weight loss. Examination was significant for absence of abdominal pain, but a stool sample was positive for occult blood. Pan-endoscopy was performed with colonoscopy revealing a mass filling the colonic lumen. Biopsy of the mass confirmed recurrence of recurrent Bcell lymphoma. Computed tomography scan revealed ileocolic intussusception resulting from the tumor. This case is unusual in that the patient had no abdominal pain despite the presence of intussusception.CONCLUSION While intestinal involvement with lymphoma has been well described in the literature, presentation as painless intussusception has not been reported. This case report highlights the wide spectrum of clinical manifestations of recurrent Bcell lymphoma involving the gastrointestinal tract, in particular the near absence of symptoms despite the finding of intussusception.

Chemotherapy-induced small extracellular vesicles prime the pre-metastatic niche to accelerate neuroblastoma metastasis

Neuroblastoma is the most common extracranial solid tumor in children,accounting for more than 10%of cancerrelated deaths in this population.The standard of care for patients diagnosed with medium-to high-risk neuroblastoma,including those who present with metastatic disease,is preoperative inductionchemotherapy.

Inhibition of Mcl-1 enhances cell death induced by the Bcl-2-selective inhibitor ABT-199 in acute myeloid leukemia cells

Acute myeloid leukemia(AML)is a serious disease.The 5-year survival rates remain frustratingly low(65%for children and 26%for adults).Resistance to frontline chemotherapy(usually cytarabine)often develops;therefore a new treatment modality is needed.Bcl-2 family proteins play an important role in balancing cell survival and apoptosis.The antiapoptotic Bcl-2 family proteins have been found to be dysregulated in AML.ABT-199,a BH3 mimetic,was developed to target antiapoptotic protein Bcl-2.Although ABT-199 has demonstrated promising results,resistance occurs.Previous studies in AML show that ABT-199 alone decreases the association of proapoptotic protein Bim with Bcl-2,but this is compensated by increased association of Bim with prosurvival protein Mcl-1,stabilizing Mcl-1,resulting in resistance to ABT-199.In this study,we investigated the antileukemic activity of the Mcl-1-selective inhibitor A-1210477 in combination with ABT-199 in AML cells.We found that A-1210477 synergistically induced apoptosis with ABT-199 in AML cell lines and primary patient samples.The synergistic induction of apoptosis was decreased upon Bak,Bax and Bim knockdown.While A-1210477 treatment alone also increased Mcl-1 protein levels,combination with ABT-199 reduced binding of Bim to Mcl-1.Our results demonstrate that sequestration of Bim by Mcl-1,a mechanism of ABT-199 resistance,can be abrogated by combined treatment with the Mcl-1 inhibitor A-1201477.

Inhibition of CDK9 by voruciclib synergistically enhances cell death induced by the Bcl-2 selective inhibitor venetoclax in preclinical models of acute myeloid leukemia

Venetoclax,an FDA-approved Bcl-2 selective inhibitor for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia(AML),is tolerated well in elderly patients with AML and has good overall response rates;however,resistance remains a concern.In this study,we show that targeting CDK9 with voruciclib in combination with venetoclax results in synergistic antileukemic activity against AML cell lines and primary patient samples.CDK9 inhibition enhances venetoclax activity through downregulation of Mcl-1 and c-Myc.However,downregulation of Mcl-1 is transient,which necessitates an intermittent treatment schedule to allow for repeated downregulation of Mcl-1.Accordingly,an every other day schedule of the CDK9 inhibitor is effective in vitro and in vivo in enhancing the efficacy of venetoclax.Our preclinical data provide a rationale for an intermittent drug administration schedule for the clinical evaluation of the combination treatment for AML.

Kaposiform hemangioendothelioma in children: a benign vascular tumor with multiple treatment options

Background Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor affecting infants and young children. Although benign, it can be associated with an aggressive locally growing tumor and/or a life-threatening Kasabach–Merritt phenomenon (KMP). To date, only reviews of limited cases have been performed. We, therefore, conducted a comprehensive literature search to collect relevant data and make recommendations for future treatment trials. Methods Review of the available literature between 1993 and 2017 revealed a total of 105 publications involving 215 patients of less than 21 years of age. To this, we added 12 from our department and 4 from the Cooperative Weichteilsarkomstudie database. Results We found that KMP was present in 79% of the infants, in 47% of the 1–5-year olds, in 43% of the 6–12-year olds, and in 10% of the 13–21-year-old patients. KMP was present in nearly all (94%) patients with retroperitoneal tumors and in all patients with extra-regional tumors. The median size of a KHE without KMP was 12 cm2 as compared to 49 cm2 when associated with a KMP. With complete (not further classifiable if R0 or R1) resection, all patients were cured. If inoperable, response regarding KMP/regression of tumor size was seen in 29/28% with steroid-, 47/39% with vincristine-, 44/43% with interferon alpha-, 65/61% with anti-platelet agents-, and in 97/100% with sirolimus-containing therapies. Conclusions Patients with progressive KHE should undergo resection whenever it is considered a safe option. If inoperable, sirolimus should be the first choice for treating KMP and reducing tumor size.

The septin complex links the catenin complex to the actin cytoskeleton for establishing epithelial cell polarity

Cell polarity is essential for spatially regulating of physiological processes in metazoans by which hormonal stimulation‒secretion coupling is precisely coupled for tissue homeostasis and organ communications.However,the molecular mechanisms underlying epithelial cell polarity establishment remain elusive.Here,we show that septin cytoskeleton interacts with catenin complex to organize a functional domain to separate apical from basal membranes in polarized epithelial cells.Using polarized epithelial cell monolayer as a model system with transepithelial electrical resistance as functional readout,our studies show that septins are essential for epithelial cell polarization.Our proteomic analyses discovered a novel septin‒catenin complex during epithelial cell polarization.The functional relevance of septin‒catenin complex was then examined in three-dimensional(3D)culture in which suppression of septins resulted in deformation of apical lumen in cysts,a hallmark seen in polarity-deficient 3D cultures and animals.Mechanistically,septin cytoskeleton stabilizes the association of adherens catenin complex with actin cytoskeleton,and depletion or disruption of septin cytoskeleton liberates adherens junction and polarity complexes into the cytoplasm.Together,these findings reveal a previously unrecognized role for septin cytoskeleton in the polarization of the apical‒basal axis and lumen formation in polarized epithelial cells.