Deficiency of mevalonate kinase (MVK) causes systemic inflammation. However, the molecular mechanisms linking the mevalonate pathway to inflammation remain obscure. Geranylgeranyl pyrophosphate (GGPP), a non-sterol intermediate of the mevalonate pathway, is the substrate for protein geranylgeranylation, protein post-translational modification catalyzed by protein geranylgeranyl transferase I (GGTase I). Pyrin is an innate immune sensor that forms an active inflammasome in response to bacterial toxins. Mutations in MEFV (encoding human PYRIN) cause autoinflammatory Familial Mediterranean Fever (FMF) syndrome. Here, we show that protein geranylgeranylation enables Toll-like receptor (TLR)-induced phosphatidylinositol-3-OH kinase PI(3)K) activation by promoting the interaction between the small GTPase Kras and the PI(3)K catalytic subunit p110δ. Macrophages deficient for GGTase I or p110δ exhibited constitutive interleukin-1β release that was MEFV-dependent, but NLRP3-, AIM2- and NLRC4- inflammasome independent. In the absence of protein geranylgeranylation, compromised PI(3)K activity allows for an unchecked TLR-induced inflammatory responses and constitutive activation of the Pyrin inflammasome.

The aim of this study was to determine the clinical features, treatment factors, and prognosis of patients with multiple primary malignant tumors (MPMTs). In total, 161 patients with MPMTs at our hospital (The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China) were analyzed in this study. We found that among 161 patients with MPMTs, 78 (48.4%) patients had synchronous tumors and 83 (51.6%) patients had metachronous tumors. Most clinical and pathological features were similar in both groups. Most patients with MPMTs were men and older patients (>50 years old), and adenocarcinoma was the most frequent pathology type. The most frequent location of all MPMTs was the digestive system. The leading tumor association was between digestive–digestive tumors, also. However, patients with synchronous tumors and MPMTs of the digestive system showed a shorter survival time. In the metachronous cancer group, the median interval time was 60 months, and a short interval time (≤60 months) was associated with a shorter survival time. In addition, survival time was increased in the younger age group (≤50 years old) and in patients who accepted surgery-based comprehensive therapy. However, only interval time (≤60 months) was an independent prognostic factor associated with survival for the metachronous cancer group. Therefore, careful surveillance and follow-up are especially important in these patients.

Bacteria are an enormous and largely untapped reservoir of biosensing proteins. We describe an approach to identify and isolate bacterial allosteric transcription factors (aTFs) that recognize a target analyte and to develop these TFs into biosensor devices. Our approach utilizes a combination of genomic screens and functional assays to identify and isolate biosensing TFs, and a quantum-dot Förster Resonance Energy Transfer (FRET) strategy for transducing analyte recognition into real-time quantitative measurements. We use this approach to identify a progesterone-sensing bacterial aTF and to develop this TF into an optical sensor for progesterone. The sensor detects progesterone in artificial urine with sufficient sensitivity and specificity for clinical use, while being compatible with an inexpensive and portable electronic reader for point-of-care applications. Our results provide proof-of-concept for a paradigm of microbially-derived biosensors adaptable to inexpensive, real-time sensor devices.

Abstract. Multiphoton microscopy was employed for monitoring the structure changes of mouse dermis collagen in the intrinsic-or the extrinsic-age-related processes in vivo. The characteristics of textures in different aging skins were uncovered by fast Fourier transform in which the orientation index and bundle packing of collagen were quantitatively analyzed. Some significant differences in collagen-related changes are found in different aging skins, which can be good indicators for the statuses of aging skins. The results are valuable to the study of aging skin and also of interest to biomedical photonics. C 2011 Society of Photo-Optical Instrumentation Engineers (SPIE).

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The mammalian STE20-like protein kinase 1 (MST1)-MOB kinase activator 1 (MOB1) complex has been shown to suppress the oncogenic activity of Yes-associated protein (YAP) in the mammalian Hippo pathway, which is involved in the development of multiple tumors, including pancreatic cancer (PC). However, it remains unclear whether other MST-MOB complexes are also involved in regulating Hippo-YAP signaling and have potential roles in PC. Here, we report that mammalian STE20-like kinase 4 (MST4), a distantly related ortholog of the MST1 kinase, forms a complex with MOB4 in a phosphorylation-dependent manner. We found that the overall structure of the MST4-MOB4 complex resembles that of the MST1-MOB1 complex, even though the two complexes exhibited opposite biological functions in PC. In contrast to the tumor-suppressor effect of the MST1-MOB1 complex, the MST4-MOB4 complex promoted growth and migration of PANC-1 cells. Moreover, expression levels of MST4 and MOB4 were elevated in PC and were positively correlated with each other, whereas MST1 expression was down-regulated. Because of divergent evolution of key interface residues, MST4 and MOB4 could disrupt assembly of the MST1-MOB1 complex through alternative pairing and thereby increased YAP activity. Collectively, these findings identify the MST4-MOB4 complex as a noncanonical regulator of the Hippo-YAP pathway with an oncogenic role in PC. Our findings highlight that although MST-MOB complexes display some structural conservation, they functionally diverged during their evolution.

Since 1997, the hydrophilic polyacrylamide gel (PAAG), an injectable alloplastic biomaterial, imported from the Ukraine has been used for augmentation mammaplasty in China. There were twelve patients with various complications visiting our hospitals after breast augmentation with injected hydrophilic polyacrylamide gel by other clinics, even though such procedures are not performed in our clinical practices. The complications included four cases of PAAG-induced multiple induration and lumps, and one with lactation, three cases of hematoma, two cases of inflammation (infection), and persistent mastodymia, unsatisfactory contour results and abnormal skin sensations in each case. All patients have been treated by removing the injected gel and giving antibiotics. Other procedures included replacement by silicon breast prostheses, mammotomy, and segmental mastectomy. We suggest that the injectable hydrophilic polyacrylamide gel be contraindications for breast augmentation in any young female who is not married, or without a child, with a tendency to hemorrhage, and with little mammary tissue. Some considerations to prevent and manage these complications are discussed.

Upconversion nanoparticles (UCNPs) have been extensively explored for photodynamic therapy (PDT) and imaging due to their representative large anti-Stokes shifts, deep penetration into biological tissues, narrow emission bands, and high spatial-temporal resolution. Conventional UCNP-based PDT system, however, utilizes exitation at 980 nm, at which water has significant absorption, leading to a huge concern that the cell killing effect is from the irradiation due to overheating effect. Here we report an efficient nanoplatform using 808-nm excited NaYbF4:Nd@NaGdF4:Yb/Er@NaGdF4 core−shell−shell nanoparticles loaded with Chlorin e6 and folic acid for simultaneous imaging and PDT. At this wavelength, the absorption of water is minimized. High energy transfer efficiency is achieved to generate cytotoxic singlet oxygen. Our nanoplatform effectively kills cancer cells in concentration-, time-, and receptor-dependent manners. More importantly, our nanoplatform is still able to efficiently generate singlet oxygen beneath 15-mm thickness of muscle tissue but 980 nm excitation cannot, showing that a higher penetration depth is achieved by our system. These results imply that our nanoplatform has the ability to effectively kill intrinsic tumor or the center of large tumors through PDT, which significantly improves the anticancer efficacy using UCNP-based PDT system and broadens the types of tumors that could be cured.