SummaryAbout half of human cancers are associated with mutations of the tumor suppressor p53. Gained oncogenic functions of the mutants have been related to aggregation behaviors of wild-type and mutant p53. The thermodynamic and kinetic mechanisms of p53 aggregation are poorly understood. Here we find that wild-type p53 forms an anomalous liquid phase. The liquid condensates exhibit several behaviors beyond the scope of classical phase transition theories: their size, ca. 100 nm, is independent of the p53 concentration and decoupled from the protein mass held in the liquid phase. Furthermore, the liquid phase lacks constant solubility. The nucleation of p53 fibrils deviates from the accepted mechanism of sequential association of single solute molecules. We find that the liquid condensates serve as pre-assembled precursors of high p53 concentration that facilitate fibril assembly. Fibril nucleation hosted by precursors represents a novel biological pathway, which opens avenues to suppress protein fibrillation in aggregation diseases.

Background: To study the predictive value of semi-quantitative pleural effusion and pulmonary consolidation for acute pancreatitis (AP) severity.Methods: Thorax-abdominal computed tomography (CT) examinations were performed on 309 consecutive AP patients in a single center. Among them, 196 were male, and 113 were female, and the average age was 50±16 years. The etiology of AP was biliary in 43.7% (n=135), hyperlipidemia in 22.0% (n=68), alcoholic in 7.4% (n=23), trauma in 0.6% (n=2), and postoperative status in 1.6% (n=5) cases; 24.6% (n=76) of patients did not have specified etiologies. The prevalence of pleural effusion and pulmonary consolidation was noted. The pleural effusion volume was quantitatively derived from a CT volume evaluation software tool. The pulmonary consolidation score was based on the number of lobes involved in AP. Each patient's CT severity index (CTSI), acute physiology and chronic health evaluation II (APACHE II) scoring system, and bedside index for severity in acute pancreatitis (BISAP) scores were obtained. The semi-quantitative pleural effusion and pulmonary consolidation were compared to these scores and clinical outcomes by receiver operator characteristic (ROC) curve and area under the curve (AUC) analysis.Results: In the 309 patients, 39.8% had pleural effusion, and 47.9% had pulmonary consolidation. The mean pleural effusion volume was 41.7±38.0 mL. The mean pulmonary consolidation score was 1.0±1.2 points. The mean CTSI was 3.7±1.8 points, the mean APACHE II score was 5.8±5.1 points, and the mean BISAP score was 1.3±1.0 points; 5.5% of patients developed severe AP, and 13.9% of patients developed organ failure. Pleural effusion volume and pulmonary consolidation scores correlated to the scores for the severity of AP. In predicting severe AP, the accuracy (AUC 0.839) of pleural effusion volume was similar to that of the CTSI score (P=0.961), APACHE II score (P=0.757), and BISAP score (P=0.906). The accuracy (AUC 0.805) of the pulmonary consolidation score was also similar to that of the CTSI score (P=0.503), APACHE II score (P=0.343), and BISAP score (P=0.669). In predicting organ failure, the accuracy (AUC 0.783) of pleural effusion volume was similar to that of the CTSI score (P=0.473), APACHE II score (P=0.119), and BISAP score (P=0.980), and the accuracy (AUC 0.808) of the pulmonary consolidation score was also similar to that of the CTSI score (P=0.236), APACHE II score (P=0.293), and BISAP score (P=0.612).Conclusions: Pleural effusion and pulmonary consolidation are common in AP and correlated to the severity of AP. Furthermore, the pleural effusion volume and pulmonary consolidation lobes can provide early prediction of severe AP and organ failure.

Despite advances in chemotherapeutic agents, the prognosis for some cancers remains extremely poor, suggesting the need for other treatment modalities. Immunotherapy appears an ideal approach because the mechanisms of tumor cell killing induced by tumor vaccines are different from those from chemotherapy. Various investigations are ongoing to identify suitable targets for this purpose. Sperm protein 17 (Sp17) was originally identified by our group as a novel cancer-testis antigen in various malignancies, including multiple myeloma. Sp17 is a highly immunogenic protein and the observation that more than 90% of vasectomized males develop immunity against Sp17 suggests the opportunity and safety of Sp17 for tumor vaccines. Recent works by other workers suggest a low level of expression of Sp17 in some normal tissues, and investigators have questioned whether Sp17 is in fact a suitable target for immunotherapy. In this paper, we review the general principles of immunotherapy and provide evidence supporting the highly immunogenic nature of Sp17. We also address the discrepancies between the objectives of oncologists involved in treating cancer patients and their familiarity with acceptable levels of toxicity of any effective therapy and those of pure laboratory-based investigators. Finally, we present some early clinical data supporting the rationale for further investigations of Sp17 for tumor vaccines. Am.

SummaryImmunotherapy is an attractive therapeutic option for patients with haematological malignancies. Until recently, the progress in the development of tumour vaccines for haematological malignancies had been slow due to the lack of suitable targets. Cancer-testis (CT) antigens are potentially suitable molecules for tumour vaccines of haematological malignancies because of their high immunogenicity in vivo and their relatively restricted normal tissue distribution. This review evaluates the properties and potential functions of CT antigens. We discuss the expression of CT antigens in patient with haematological malignancies and provide evidence in support of their immunogenicity in vivo in these patients. We also address the role of 'epigenetic' regulation of CT antigens in haematological malignancies and how hypomethylating agents could induce the expression of some of these antigens in tumour cells to overcome the problem of heterogeneity of expression of the antigen within individual tumour specimens. Data implicating the interaction of the promoter genes of some of these CT antigens with the MeCP2 protein also suggest the potential role of the histone deacetylase inhibitors in inducing antigen expression in tumour cells. Finally, we discuss the direction of future research in advancing the development of tumour vaccines for haematological malignancies.

Engineering efficient biosynthesis of natural products in microorganisms requires optimizing gene expression levels to balance metabolite flux distributions and to minimize accumulation of toxic intermediates. Such metabolic optimization is challenged with identifying the right gene targets, and then determining and achieving appropriate gene expression levels. After decades of having a relatively limited set of gene regulation tools available, metabolic engineers are recently enjoying an ever-growing repertoire of more precise and tunable gene expression platforms. Here we review recent applications of natural and designed transcriptional and translational regulatory machinery for engineering biosynthesis of natural products in microorganisms. Customized trans-acting RNAs (sgRNA, asRNA and sRNA), along with appropriate accessory proteins, are allowing for unparalleled tuning of gene expression. Meanwhile metabolite-responsive transcription factors and riboswitches have been implemented in strain screening and evolution, and in dynamic gene regulation. Further refinements and expansions on these platform technologies will circumvent many long-term obstacles in natural products biosynthesis.