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Background: Abnormal mitochondrial pyruvate carrier 1 (MPC1) expression plays a key role in tumor metabolic reprogramming and progression. Understanding its significance in non-small cell lung cancer (NSCLC) is crucial for identifying therapeutic targets. Methods: TIMER 2.0 was utilized to assess the expression of MPC1 in both normal and cancer tissues in pan-cancer. Overall survival (OS) differences between high and low MPC1 expression were analyzed in NSCLC using the Cancer Genome Atlas (TCGA) datasets. We also examined the expression of MPC1 in NSCLC cell lines using western blotting and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). In addition, the tissue samples and clinical information of 80 patients with NSCLC from our hospital were collected. Immunohistochemistry (IHC) was used to assess MPC1 expression, and OS was evaluated using Kaplan-Meier curves and the log-rank test. Univariate and multivariate Cox regression analyses were conducted to evaluate the prognostic values of the clinical characteristics and MPC1expression. Results: Analysis of public databases suggested that MPC1 was downregulated in NSCLC compared to that in normal lung tissue and predicted poor prognosis. In addition, the expression of MPC1 in NSCLC cell lines was lower than that in human bronchial epithelial (HBE) cells at both protein and mRNA levels. Further clinical analysis suggested that MPC1 expression was correlated with age, tumor T stage, and TNM stage. Kaplan-Meier analysis revealed that NSCLC patients with high MPC1 expression had a better prognosis, particularly in lung adenocarcinoma (LUAD), whereas no survival benefit was observed in lung squamous cell carcinoma (LUSC). Univariate and multivariate analyses suggested that MPC1 was an independent prognostic factor for patients with NSCLC. Conclusions: MPC1 is poorly expressed in NSCLC, particularly in LUAD, which predicts a poor prognosis and may serve as an independent prognostic factor. Further studies on MPC1 may reveal new targets for the treatment of NSCLC. [ABSTRACT FROM AUTHOR]

DOX/TPOR4@CB[7]4 was synthesized via self-assembly, and its physicochemical properties and ability to generate reactive oxygen species (ROS) were evaluated. The impact of photodynamic therapy on SH-SY5Y cells was assessed using the MTT assay, while flow cytometry analysis was employed to detect cell apoptosis. Confocal laser scanning microscopy was utilized to observe the intracellular distribution of DOX/TPOR4@CB[7]4 in SH-SY5Y cells. Additionally, fluorescence imaging of DOX/TPOR4@CB[7]4 in nude mice bearing SH-SY5Y tumors and examination of the combined effects of photodynamic and chemical therapies were conducted. The incorporation of CB[7] significantly enhanced the optical properties of DOX/TPOR4@CB[7]4, resulting in increased ROS production and pronounced toxicity towards SH-SY5Y cells. Moreover, both the apoptotic and mortality rates exhibited significant elevation. In vivo experiments demonstrated that tumor growth inhibition was most prominent in the DOX/TPOR4@CB[7]4 group. π–π interactions facilitated the binding between DOX and photosensitizer TPOR, with TPOR's naphthalene hydrophilic groups encapsulated within CB[7]'s cavity through host–guest interactions with CB[7]. Therefore, CB[7] can serve as a nanocarrier to enhance the combined application of chemical therapy and photodynamic therapy, thereby significantly improving treatment efficacy against neuroblastoma tumors. [ABSTRACT FROM AUTHOR]

Accurate chromosome segregation requires timely dissolution of chromosome cohesion after chromosomes are properly attached to the mitotic spindle. Separase is absolutely essential for cohesion dissolution in organisms from yeast to [...]

Simultaneous disruption of two different protein-protein interactions within the (APC/C-Cdc20)-substrate complex can synergistically inhibit APC/C-dependent proteolysis and mitotic exit. APC/C activation blocks cell proliferation The anaphase-promoting complex/cyclosome (APC/C) is a thirteen-subunit ubiquitin ligase enzyme that mediates progression through mitotic cell division by targeting substrate proteins for degradation by the ubiquitin-proteasome system. During mitosis, the protein Cdc20 binds to APC/C to activate it, and the two proteins together recognize target substrates. Blocking mitotic exit by blocking APC/C activity could induce tumour-cell death and therefore might be of potential therapeutic value. This study shows that simultaneous disruption of two different protein-protein interactions within the (APC/C-Cdc20)-substrate complex can synergistically inhibit APC/C-dependent proteolysis and mitotic exit. Protein machines are multi-subunit protein complexes that orchestrate highly regulated biochemical tasks. An example is the anaphase-promoting complex/cyclosome (APC/C), a 13-subunit ubiquitin ligase that initiates the metaphase-anaphase transition and mitotic exit by targeting proteins such as securin and cyclin B1 for ubiquitin-dependent destruction by the proteasome.sup.1,2. Because blocking mitotic exit is an effective approach for inducing tumour cell death.sup.3,4, the APC/C represents a potential novel target for cancer therapy. APC/C activation in mitosis requires binding of Cdc20 (ref. 5), which forms a co-receptor with the APC/C to recognize substrates containing a destruction box (D-box).sup.6,7,8,9,10,11,12,13,14. Here we demonstrate that we can synergistically inhibit APC/C-dependent proteolysis and mitotic exit by simultaneously disrupting two protein-protein interactions within the APC/C-Cdc20-substrate ternary complex. We identify a small molecule, called apcin (APC inhibitor), which binds to Cdc20 and competitively inhibits the ubiquitylation of D-box-containing substrates. Analysis of the crystal structure of the apcin-Cdc20 complex suggests that apcin occupies the D-box-binding pocket on the side face of the WD40-domain. The ability of apcin to block mitotic exit is synergistically amplified by co-addition of tosyl-l-arginine methyl ester, a small molecule that blocks the APC/C-Cdc20 interaction.sup.15,16. This work suggests that simultaneous disruption of multiple, weak protein-protein interactions is an effective approach for inactivating a protein machine., Author(s): Katharine L. Sackton [sup.1] , Nevena Dimova [sup.1] , Xing Zeng [sup.1] , Wei Tian [sup.2] [sup.6] , Mengmeng Zhang [sup.1] , Timothy B. Sackton [sup.3] , Johnathan Meaders [...]

Abstract Background In HBV-infected patients, different genotypes of the hepatitis B virus influence liver disease progression and response to antiviral therapy. Moreover, long-term antiviral therapy will eventually select for drug-resistant mutants. Detection of mutations associated to antiviral therapy and HBV genotyping are essential for monitoring treatment of chronic hepatitis B patients. Results In this study, a simple method of partial-S gene sequencing using a common PCR amplification was established for genotyping clinical HBV isolates sensitively, which could detect the drug-resistant mutations successfully at the same time. Conclusions The partial S gene sequencing assay developed in this study has potential for application in HBV genotyping and drug resistant mutation detection. It is simpler and more convenient than traditional S gene sequencing, but has nearly the same sensitivity and specificity when compared to S gene sequencing.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2007.08.048 Byline: Maojun Yang (1), Bing Li (1), Diana R. Tomchick (2), Mischa Machius (2), Josep Rizo (1)(2), Hongtao Yu (1), Xuelian Luo (1) Keywords: CELLCYCLE Abstract: The status of spindle checkpoint signaling depends on the balance of two opposing dynamic processes that regulate the highly unusual two-state behavior of Mad2. In mitosis, a Mad1-Mad2 core complex recruits cytosolic Mad2 to kinetochores through Mad2 dimerization and converts Mad2 to a conformer amenable to Cdc20 binding, thereby facilitating checkpoint activation. p31.sup.comet inactivates the checkpoint through binding to Mad1- or Cdc20-bound Mad2, thereby preventing Mad2 activation and promoting the dissociation of the Mad2-Cdc20 complex. Here, we report the crystal structure of the Mad2-p31.sup.comet complex. The C-terminal region of Mad2 that undergoes rearrangement in different Mad2 conformers is a major structural determinant for p31.sup.comet binding, explaining the specificity of p31.sup.comet toward Mad1- or Cdc20-bound Mad2. p31.sup.comet adopts a fold strikingly similar to that of Mad2 and binds at the dimerization interface of Mad2. Thus, p31.sup.comet exploits the two-state behavior of Mad2 to block its activation by acting as an 'anti-Mad2.' Author Affiliation: (1) Department of Pharmacology, The University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA (2) Department of Biochemistry, The University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA Article History: Received 4 April 2007; Revised 28 June 2007; Accepted 30 August 2007 Article Note: (miscellaneous) Published: November 15, 2007