Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers. We performed exome sequencing on 113 tumor-normal pairs, yielding a mean of 82 non-silent mutations per tumor, and 8 cell lines. The mutational profile of ESCC closely resembles those of squamous cell carcinomas of other tissues but differs from that of esophageal adenocarcinoma. Genes involved in cell cycle and apoptosis regulation were mutated in 99% of cases by somatic alterations of TP53 (93%), CCND1 (33%), CDKN2A (20%), NFE2L2 (10%) and RB1 (9%). Histone modifier genes were frequently mutated, including KMT2D (also called MLL2; 19%), KMT2C (MLL3; 6%), KDM6A (7%), EP300 (10%) and CREBBP (6%). EP300 mutations were associated with poor survival. The Hippo and Notch pathways were dysregulated by mutations in FAT1, FAT2, FAT3 or FAT4 (27%) or AJUBA (JUB; 7%) and NOTCH1, NOTCH2 or NOTCH3 (22%) or FBXW7 (5%), respectively. These results define the mutational landscape of ESCC and highlight mutations in epigenetic modulators with prognostic and potentially therapeutic implications.

Spectrometers with ever-smaller footprints are sought after for a wide range of applications in which minimized size and weight are paramount, including emerging in situ characterization techniques. We report on an ultracompact microspectrometer design based on a single compositionally engineered nanowire. This platform is independent of the complex optical components or cavities that tend to constrain further miniaturization of current systems. We show that incident spectra can be computationally reconstructed from the different spectral response functions and measured photocurrents along the length of the nanowire. Our devices are capable of accurate, visible-range monochromatic and broadband light reconstruction, as well as spectral imaging from centimeter-scale focal planes down to lensless, single-cell–scale in situ mapping.

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Summary PTEN is one of the most frequently mutated genes in human cancer. It is known that PTEN has a wide range of biological functions beyond tumor suppression. Here we report that PTENα, an N-terminally extended form of PTEN, functions in metabolism. Translation of PTENα is initiated from a CUG codon upstream of and in-frame with the coding region of canonical PTEN. Eukaryotic translation initiation factor 2A (eIF2A) controls PTENα translation and a CUG-centered palindromic motif is required in this process. PTENα induces cytochrome c oxidase activity and ATP production in mitochondria. TALEN-mediated somatic deletion of PTENα impairs mitochondrial respiratory chain function. We show that PTENα interacts with canonical PTEN to increase PINK1 and promote energy production. These data provide insights into the mechanism by which the PTEN family is involved in multiple cellular processes. Our studies suggest that mammalian cells can use alternate translation initiation mechanisms to generate protein isoforms.

IMPORTANCE Appropriate antibiotic use is a key strategy to control antibacterial resistance. The first step in achieving this is to identify the major problems in antibiotic prescription in health care facilities, especially in primary health care settings, which is where most patients receive medical care. OBJECTIVE To identify current patterns of antibiotic use and explore the reasons for inappropriate prescription in primary health care settings in China. DESIGN, SETTING, AND PARTICIPANTS A total of 48 primary health care facilities in China were randomly selected from 6 provinces at various levels of economic development. Data for the years 2009 through 2011 from 39 qualifying facilities (23 city and 16 rural primary health care centers) were analyzed retrospectively. The study sample consisted of prescription records for 7311 outpatient visits and 2888 inpatient hospitalizations. MAIN OUTCOMES AND MEASURES General health center information, drug usage, disease diagnoses, and antibiotic use by outpatients and inpatients were surveyed. Cases of inappropriate antibiotic prescription were identified. RESULTS Most staff in the primary health care facilities had less than a college degree, and the medical staff consisted primarily of physician assistants, assistant pharmacists, nurses, and nursing assistants. The median (range) governmental contribution to each facility was 34.0% (3.6%-92.5%) of total revenue. The facilities prescribed a median (range) of 28 (8-111) types of antibiotics, including 34 (10-115) individual agents. Antibiotics were included in 52.9% of the outpatient visit prescription records: of these, only 39.4% were prescribed properly. Of the inpatients, 77.5% received antibiotic therapy: of these, only 24.6% were prescribed properly. Antibiotics were prescribed for 78.0% of colds and 93.5% of cases of acute bronchitis. Of the antibiotic prescriptions, 28.0% contained cephalosporins and 15.7% fluoroquinolones. A total of 55.0% of the antibiotic prescriptions were for antibiotic combination therapy with 2 or more agents. In nonsurgical inpatients in cities, the mean (SD) duration of antibiotic therapy was 10.1 (7.8) days. Of the surgical patients, 98.0% received antibiotics, with 63.8% of these prescriptions for prophylaxis. CONCLUSIONS AND RELEVANCE Antibiotics are frequently prescribed in Chinese primary health care facilities, and a large proportion of these prescriptions are inappropriate. Frequent and inappropriate use of antibiotics in primary health care settings in China is a serious problem that likely contributes to antimicrobial resistance worldwide.

Pyruvate kinase M2 isoform (PKM2) catalyzes the last step of glycolysis and plays an important role in tumor cell proliferation. Recent studies have reported that PKM2 also regulates apoptosis. However, the mechanisms underlying such a role of PKM2 remain elusive. Here we show that PKM2 translocates to mitochondria under oxidative stress. In the mitochondria, PKM2 interacts with and phosphorylates Bcl2 at threonine (T) 69. This phosphorylation prevents the binding of Cul3-based E3 ligase to Bcl2 and subsequent degradation of Bcl2. A chaperone protein, HSP90α1, is required for this function of PKM2. HSP90α1's ATPase activity launches a conformational change of PKM2 and facilitates interaction between PKM2 and Bcl2. Replacement of wild-type Bcl2 with phosphorylation-deficient Bcl2 T69A mutant sensitizes glioma cells to oxidative stress-induced apoptosis and impairs brain tumor formation in an orthotopic xenograft model. Notably, a peptide that is composed of the amino acid residues from 389 to 405 of PKM2, through which PKM2 binds to Bcl2, disrupts PKM2-Bcl2 interaction, promotes Bcl2 degradation and impairs brain tumor growth. In addition, levels of Bcl2 T69 phosphorylation, conformation-altered PKM2 and Bcl2 protein correlate with one another in specimens of human glioblastoma patients. Moreover, levels of Bcl2 T69 phosphorylation and conformation-altered PKM2 correlate with both grades and prognosis of glioma malignancy. Our findings uncover a novel mechanism through which mitochondrial PKM2 phosphorylates Bcl2 and inhibits apoptosis directly, highlight the essential role of PKM2 in ROS adaptation of cancer cells, and implicate HSP90-PKM2-Bcl2 axis as a potential target for therapeutic intervention in glioblastoma.

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We demonstrate single-mode laser emission in single nanowires. By folding a 200 nm diameter CdSe nanowire to form loop mirrors, single-mode laser emission around 738 nm wavelength is obtained with line width of 0.12 nm and low threshold. The mode selection is realized by the vernier effect of coupled cavities in the folded nanowire. In addition, the loop structure makes it possible to tune the nanowire cavity, opening an opportunity to realize a tunable single-mode nanowire laser.