Phosphatase and Tensin Homolog deleted on Chromosome 10 (PTEN) is a dual phosphatase with both protein and lipid phosphatase activities. PTEN was first discovered as a tumor suppressor with growth and survival regulatory functions. In recent years, the function of PTEN as a metabolic regulator has attracted significant attention. As the lipid phosphatase that dephosphorylates phosphatidylinositol-3, 4, 5-phosphate (PIP3), PTEN reduces the level of PIP3, a critical 2nd messenger mediating the signal of not only growth factors but also insulin. In this review, we introduced the discovery of PTEN, the PTEN-regulated canonical and nuclear signals, and PTEN regulation. We then focused on the role of PTEN and PTEN-regulated signals in metabolic regulation. This included the role of PTEN in glycolysis, gluconeogenesis, glycogen synthesis, lipid metabolism as well as mitochondrial metabolism. We also included how PTEN and PTEN regulated metabolic functions may act paradoxically toward insulin sensitivity and tumor metabolism and growth. Further understanding of how PTEN regulates metabolism and how such regulations lead to different biological outcomes is necessary for interventions targeting at the PTEN-regulated signals in either cancer or diabetes treatment.

Highlights d Impaired alveolar regeneration results in sustained elevated tension on alveoli d Elevated mechanical tension activates a TGF-b signaling loop in AT2 cells d The impacts of mechanical tension on alveoli are not uniformly distributed d Mechanical tension-activated TGF-b signaling is essential for fibrosis progression

Background Critical patients with the coronavirus disease 2019 (COVID-19), even those whose nucleic acid test results had turned negative and those receiving maximal medical support, have been noted to progress to irreversible fatal respiratory failure. Lung transplantation (LT) as the sole therapy for end-stage pulmonary fibrosis related to acute respiratory distress syndrome has been considered as the ultimate rescue therapy for these patients. Methods From February 10 to March 10, 2020, three male patients were urgently assessed and listed for transplantation. After conducting a full ethical review and after obtaining assent from the family of the patients, we performed three LT procedures for COVID-19 patients with illness durations of more than one month and extremely high sequential organ failure assessment scores. Results Two of the three recipients survived post-LT and started participating in a rehabilitation program. Pearls of the LT team collaboration and perioperative logistics were summarized and continually improved. The pathological results of the explanted lungs were concordant with the critical clinical manifestation, and provided insight towards better understanding of the disease. Government health affair systems, virology detection tools, and modern communication technology all play key roles towards the survival of the patients and their rehabilitation. Conclusions LT can be performed in end-stage patients with respiratory failure due to COVID-19-related pulmonary fibrosis. If confirmed positive-turned-negative virology status without organ dysfunction that could contraindicate LT, LT provided the final option for these patients to avoid certain death, with proper protection of transplant surgeons and medical staffs. By ensuring instant seamless care for both patients and medical teams, the goal of reducing the mortality rate and salvaging the lives of patients with COVID-19 can be attained.

To identify microRNAs (miRNAs, miRs) with potential roles in lung fibrogenesis, we performed genome-wide profiling of miRNA expression in lung tissues from a silica-induced mouse model of pulmonary fibrosis using microarrays. Seventeen miRNAs were selected for validation via qRT-PCR based on the fold changes between the silica and the control group. The dysregulation of five miRNAs, including miR-21, miR-455, miR-151-3p, miR-486-5p and miR-3107, were confirmed by qRT-PCRs in silica-induced mouse model of pulmonary fibrosis and were also confirmed in a bleomycin (BLM)-induced mouse lung fibrosis. Notably, miR-486-5p levels were decreased in the serum samples of patients with silicosis, as well as in the lung tissues of patients with silicosis and idiopathic pulmonary fibrosis (IPF). In addition, as determined by luciferase assays and Western blotting, SMAD2, a crucial mediator of pulmonary fibrosis, was identified to be one of target genes of miR-486-5p. To test the potential therapeutic significance of this miRNA, we overexpressed miR-486-5p in animal models. At day 28, miR-486-5p expression significantly decreased both the distribution and severity of lung lesions compared with the silica group (P < 0.01). In addition, miR-486-5p had a similar effect in the BLM group (P < 0.001). These results indicate that miR-486-5p may inhibit fibrosis.

Automated methods for prostate cancer (PCa) diagnosis in multi-parametric magnetic resonance imaging (MP-MRIs) are critical for alleviating requirements for interpretation of radiographs while helping to improve diagnostic accuracy (Artan et al 2010 IEEE Trans. Image Process. 19 2444-55, Litjens et al 2014 IEEE Trans. Med. Imaging 33 1083-92, Liu et al 2013 SPIE Medical Imaging (International Society for Optics and Photonics) p 86701G, Moradi et al 2012 J. Magn. Reson. Imaging 35 1403-13, Niaf et al 2014 IEEE Trans. Image Process. 23 979-91, Niaf et al 2012 Phys. Med. Biol. 57 3833, Peng et al 2013a SPIE Medical Imaging (International Society for Optics and Photonics) p 86701H, Peng et al 2013b Radiology 267 787-96, Wang et al 2014 BioMed. Res. Int. 2014). This paper presents an automated method based on multimodal convolutional neural networks (CNNs) for two PCa diagnostic tasks: (1) distinguishing between cancerous and noncancerous tissues and (2) distinguishing between clinically significant (CS) and indolent PCa. Specifically, our multimodal CNNs effectively fuse apparent diffusion coefficients (ADCs) and T2-weighted MP-MRI images (T2WIs). To effectively fuse ADCs and T2WIs we design a new similarity loss function to enforce consistent features being extracted from both ADCs and T2WIs. The similarity loss is combined with the conventional classification loss functions and integrated into the back-propagation procedure of CNN training. The similarity loss enables better fusion results than existing methods as the feature learning processes of both modalities are mutually guided, jointly facilitating CNN to 'see' the true visual patterns of PCa. The classification results of multimodal CNNs are further combined with the results based on handcrafted features using a support vector machine classifier. To achieve a satisfactory accuracy for clinical use, we comprehensively investigate three critical factors which could greatly affect the performance of our multimodal CNNs but have not been carefully studied previously. (1) Given limited training data, how can these be augmented in sufficient numbers and variety for fine-tuning deep CNN networks for PCa diagnosis? (2) How can multimodal MP-MRI information be effectively combined in CNNs? (3) What is the impact of different CNN architectures on the accuracy of PCa diagnosis? Experimental results on extensive clinical data from 364 patients with a total of 463 PCa lesions and 450 identified noncancerous image patches demonstrate that our system can achieve a sensitivity of 89.85% and a specificity of 95.83% for distinguishing cancer from noncancerous tissues and a sensitivity of 100% and a specificity of 76.92% for distinguishing indolent PCa from CS PCa. This result is significantly superior to the state-of-the-art method relying on handcrafted features.

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The mammalian target of rapamycin (mTOR) signaling pathway in pulmonary fibrosis was investigated in cell and animal models. mTOR overactivation in alveolar epithelial cells (AECs) was achieved in the conditional and inducible Tsc1 knock-down mice SPC-rtTA/TetO-Cre/Tsc1 fx/+ (STT). Doxycycline caused Tsc1 knock-down and consequently mTOR activation in AECs for the STT mice. Mice treated with bleomycin exhibited increased mortality and pulmonary fibrosis compared with control mice. In wild-type C57BL/6J mice, pretreatment with rapamycin attenuated the bleomycin-mediated mortality and fibrosis. Rapamycin-mediated mouse survival benefit was inhibited by chloroquine, an autophagy inhibitor. Autophagosomes were decreased in the lungs after bleomycin exposure. Rapamycin induced the production of autophagosomes and diminished p62. We concluded that mTOR overactivation in AECs and compromised autophagy in the lungs are involved in the pathogenesis of pulmonary fibrosis. The suppression of mTOR and enhancement of autophagy may be used for treatment of pulmonary fibrosis.