Use of the esophageal balloon in the diagnosis of carcinomas of the head, neck and upper gastrointestinal tract

A study was undertaken to demonstrate the safety, efficacy and value of esophageal balloon cytology in the diagnosis of esophageal lesions and as a tool in screening a high-risk patient population. The sampling was performed 110 times on 96 patients, 11 with known obstructive carcinoma of the esophagus and 85 thought to be at risk for esophageal cancer: 74 with treated or untreated cancer of the head and neck area and 11 with dysphagia or other findings requiring clarification. The method was well tolerated by the patients, and the cytologic smears were of excellent quality. Malignant or suspicious cells were found in smears from 7 to 11 patients with documented esophageal cancer and in 7 of 85 patients believed to be at risk. In the latter group there were three unsuspected recurrent cancers of the oropharyngeal region and one unsuspected carcinoma in situ of the esophagus. There were no false-suspicious or false-positive results. This noninvasive technique of esophageal cytology obviously deserves additional trials as an adjunct in the diagnosis of carcinoma of the head and neck and upper gastrointestinal tract, especially in high-risk patients.     

Genetic diversity and climatic determinants of tree frogs in Israel

Summary Allozymic variation in proteins encoded by 27 loci was analyzed electrophoretically in 218 adult specimens, mostly males, representing 8 populations, 5 central and 3 marginal, of lemon yellow treefrogs, Hyla arborea savignyi, in Israel along two transects of increasing aridity: (a) north to south and (b) west to east. The results indicate that (a) Of the 27 loci examined, 5 are monomorphic in all 8 populations; 9 are locally and weakly polymorphic; 6 are regionally and weakly polymorphic; and 7 are regionally and strongly polymorphic; (b) In the populations studied, no alternative fixations were found in any of the 27 loci, except in the Wasit population. The commonest allele predominates across all populations, except Wasit, central as well as marginal; (c) Clinal patterns associated with increasing aridity southwards and eastwards occur in polymorphism, P, heterozygosity, H, and in allele frequencies of Ldh-1, Fum, Got-1, and Sdh; (d) For habitat generalists, treefrogs have above average number of alleles per locus, A, and polymorphism, P, while the heterozygosity, H, is average. All three estimates A, P, and H exhibit wide geographic variation decreasing progressively southwards and eastwards; (e) Central populations harbor more genic variation then marginal populations; (f) Genic similarity between populations is high; (g) Significant gametic phase disequilibria were found in several tests in 2 populations; (h) P, H, and allozymic variation in several gene loci are significantly correlated and predictable by environmental variables, primarily those related to water; (i) Morphological and allozymic variations are uncorrelated.The spatial patterns and environmental correlates and predictors of genic variation in Hyla arborea savignyi in Israel suggest that (i) protein polymorphisms are largely adaptive and are molded primarily by climatic selection rather than by stochastic processes or neutrality, and (ii) the environmental variation model seems to be the best predictor of genic variation in treefrogs.     

Effector phenotype and immunologic specificity of T-cell-mediated adoptive therapy for a murine tumor that lacks intrinsic immunogenicity

The MCA 102 sarcoma has been defined by a variety of immunologic studies as a tumor lacking intrinsic immunogenicity. Nevertheless, we have recently demonstrated the feasibility of generating therapeutically effective lymphocytes for adoptive immunotherapy of this tumor. Procedures to achieve this required in vivo priming of syngeneic mice to elicit preeffector cells followed by in vitro sensitization (IVS) with tumor cells in the presence of IL-2. By selective depletion of T cell subsets in vivo, we identified the involvement of both CD4+ (L3T4+) and CD8+ (Lyt-2+) T cells in mediating tumor regression. The CD4+ cells exerted their helper function via the secretion of IL-2 because antitumor effects abrogated by depletion of CD4+ cells could be reconstituted by exogenous IL-2. In order to elicit preeffector cells with reactivity against the MCA 102 tumor, we found that in vivo sensitization could be accomplished with either the MCA 102 or MCA 106 tumor but not with the MCA 101 or MCA 105 tumor. Analysis of specificity of tumor stimulation during IVS of MCA 102 tumor-primed preeffector cells demonstrated cross-reactivity between not only the MCA 102 and MCA 106 tumors but also the MCA 105 tumor whereas the MCA 101 tumor was ineffective. In adoptive immunotherapy, transfer of IVS cells generated from MCA 102 tumor-primed and stimulated lymph node cells was able to mediate reductions of pulmonary metastases established from the MCA 102, MCA 105, and MCA 106 tumors but not from the MCA 101 tumor. We conclude that regression of the MCA 102 tumor is probably mediated through T cell recognition of a set of common tumor-associated Ag shared by several other syngeneic tumors. Immunologically, the tumor-associated Ag are characteristically different from classical tumor-specific transplantation Ag (TSTA) because immunity to TSTA on the MCA 105 or MCA 106 tumor does not cross-react with the MCA 102 tumor. Thus, this study demonstrates that Ag other than TSTA on chemically induced tumors can serve as target molecules for T cell-mediated adoptive immunotherapy.     

Adenosine deaminase polymorphism among the Semai, Temuan, Semelai, and Jakun groups of West Malaysian Orang Asli

812 West Malaysian Orang Asli belonging to four ethnic groups were surveyed for adenosine deaminase (ADA; EC 3.5.4.4) using starch gel electrophoresis. Only the common ADA1 and ADA2 alleles were found, with the frequencies of the latter being 0.025, 0.103, 0.115 and 0.028 in the Semai, Semelai, Temuan, and Jakun groups, respectively. A new 'breeding genetic distance' was applied to these gene frequencies and the Semelai and Temuan were found to be more closely related to each other, and to have considerably more evolutionary flexibility on this scale of 'micro-evolution' than the other two groups. The Semai and Jakun were more similar to each other on the basis of these ADA gene frequencies.     

基于EMA-qPCR的茄科青枯菌活体检测技术的建立

【目的】利用特异性核酸染料叠氮溴乙锭(Ethidium monoazide bromide, EMA)与实时荧光定量PCR技术相结合, 建立一种能有效区分青枯菌死活细胞的检测方法。【方法】样品DNA制备前经EMA渗透预处理, 再进行实时荧光定量PCR特异扩增菌体DNA。【结果】终浓度为2.0 mg/L的EMA能有效排除1.0×107 CFU/mL灭活青枯菌细胞DNA的扩增, 对活细胞和不可培养状态(Viable but non-culturable, VBNC)活菌的DNA扩增均没有影响。当每个定量PCR反应体系中的活细胞在5.0×100?5.0×104 CFU范围内时, 扩增Ct值与定量PCR反应体系中活细胞CFU对数值呈良好的负相关性(R2=0.992 5)。比较EMA-qPCR法和平板计数法对经过不同温度短期保存的青枯菌检测结果发现, 待检样品可在24 °C与4 °C冷藏条件下短期保存。【结论】本研究建立的EMA-qPCR方法能有效检测青枯菌VBNC细胞和有效区分死活菌, 避免或减少青枯菌PCR检测的假阳性和假阴性。     

Paradoxical role of β8 integrin on angiogenesis and vasculogenic mimicry in glioblastoma

Glioblastoma multiforme (GBM) is the most aggressive and highly vascularized brain tumor with poor prognosis. Endothelial cell-dependent angiogenesis and tumor cell-dependent Vasculogenic mimicry (VM) synergistically contribute to glioma vascularization and progression. However, the mechanism underlying GBM vascularization remains unclear. In this study, GBM stem cells (GSCs) were divided into high and low β8 integrin (ITGB8) subpopulations. Co-culture assays followed by Cell Counting Kit-8 (CCK-8), migration, Matrigel tube formation, and sprouting assays were conducted to assess the proliferative, migratory and angiogenic capacity of GBM cells and human brain microvascular endothelial cells (hBMECs). An intracranial glioma model was constructed to assess the effect of ITGB8 on tumor vascularization in vivo. Our results indicated that ITGB8 expression was elevated in GSCs and positively associated with stem cell markers in glioma tissues, and could be induced by hypoxia and p38 activation. ITGB8 in GSCs inhibited the angiogenesis of hBMECs in vitro, while it promoted the ability of network formation and expression of VM-related proteins. The orthotopic GBM model showed that ITGB8 contributed to decreased angiogenesis, meanwhile enhanced invasiveness and VM formation. Mechanistic studies indicated that ITGB8-TGFβ1 axis modulates VM and epithelial-mesenchymal transition (EMT) process via Smad2/3-RhoA signaling. Together, our findings demonstrated a differential role for ITGB8 in the regulation of angiogenesis and VM formation in GBM, and suggest that pharmacological inhibition of ITGB8 may represent a promising therapeutic strategy for treatment of GBM.Subject terms: Cancer stem cells, CNS cancer     

Genome-wide CRISPR screen identifies synthetic lethality between DOCK1 inhibition and metformin in liver cancer

Metformin is currently a strong candidate anti-tumor agent in multiple cancers. However, its anti-tumor effectiveness varies among different cancers or subpopulations, potentially due to tumor heterogeneity. It thus remains unclear which hepatocellular carcinoma (HCC) patient subpopulation(s) can benefit from metformin treatment. Here, through a genome-wide CRISPR-Cas9-based knockout screen, we find that DOCK1 levels determine the anti-tumor effects of metformin and that DOCK1 is a synthetic lethal target of metformin in HCC. Mechanistically, metformin promotes DOCK1 phosphorylation, which activates RAC1 to facilitate cell survival, leading to metformin resistance. The DOCK1-selective inhibitor, TBOPP, potentiates anti-tumor activity by metformin in vitro in liver cancer cell lines and patient-derived HCC organoids, and in vivo in xenografted liver cancer cells and immunocompetent mouse liver cancer models. Notably, metformin improves overall survival of HCC patients with low DOCK1 levels but not among patients with high DOCK1 expression. This study shows that metformin effectiveness depends on DOCK1 levels and that combining metformin with DOCK1 inhibition may provide a promising personalized therapeutic strategy for metformin-resistant HCC patients.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13238-022-00906-6.     

界面发酵红曲霉的图像解析*

利用计算机视觉技术研究了红曲霉界面发酵过程中菌体形态变化与菌体生长的关系。在界面培养中通过检测前期菌落面积,后期隆起部分的表征体积——基于颜色变化的生长点分布,可以有效表示菌体生长状况。基于此建立了含有相应形态参数的动力学模型,该模型与常规动力学模型具有相似的表达形式。