Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling is one of the most important intracellular pathways, which can be considered as a master regulator for cancer. Enormous efforts have been dedicated to the development of drugs targeting PI3K signaling, many of which are currently employed in clinical trials evaluation, and it is becoming increasingly clear that PI3K inhibitors are effective in inhibiting tumor progression. PI3K inhibitors are subdivided into dual PI3K/mTOR inhibitors, pan-PI3K inhibitors and isoform-specific inhibitors. In this review, we performed a critical review to summarize the role of the PI3K pathway in tumor development, recent PI3K inhibitors development based on clinical trials, and the mechanisms of resistance to PI3K inhibition.

Amino acids are known regulators of cellular signaling and physiology, but how they are sensed intracellularly is not fully understood. Herein, we report that each aminoacyl-tRNA synthetase (ARS) senses its cognate amino acid sufficiency through catalyzing the formation of lysine aminoacylation (K-AA) on its specific substrate proteins. At physiologic levels, amino acids promote ARSs bound to their substrates and form K-AAs on the ɛ-amine of lysines in their substrates by producing reactive aminoacyl adenylates. The K-AA marks can be removed by deacetylases, such as SIRT1 and SIRT3, employing the same mechanism as that involved in deacetylation. These dynamically regulated K-AAs transduce signals of their respective amino acids. Reversible leucylation on ras-related GTP-binding protein A/B regulates activity of the mammalian target of rapamycin complex 1. Glutaminylation on apoptosis signal-regulating kinase 1 suppresses apoptosis. We discovered non-canonical functions of ARSs and revealed systematic and functional amino acid sensing and signal transduction networks.

Head and neck cancer is difficult to diagnose early. We aimed to estimate the diagnosis value of narrow band imaging(NBI) in head and neck cancers. We identified relevant studies through a search of PubMed, Embase and the Cochrane Library. We used a random effect model. Subgroup analysis and meta-regression analysis were performed to estimate the factors which may influence the sensitivity and specificity of the NBI. We included 25 studies with total 6187 lesions. The pooled sensitivity, specificity, positive likelihood rate, negative likelihood rate and diagnostic odds ratios of NBI were 88.5%, 95.6%, 12.33, 0.11 and 121.26, respectively. The overall area under the curve of SROC was 96.94%. The location, type of assessment, type of endoscope system and high definition were not significant sources of heterogeneity (P > 0.05). However, magnification may be related to the source of heterogeneity (P = 0.0065). Therefore, NBI may be a promising endoscopic tool in the diagnosis of head and neck cancer.

Hyperhomocysteinemia is a common metabolic disorder that imposes major adverse health consequences. Reducing homocysteine levels, however, is not always effective against hyperhomocysteinemia‐associated pathologies. Herein, we report the potential roles of methionyl‐tRNA synthetase (MARS)‐generated homocysteine signals in neural tube defects (NTDs) and congenital heart defects (CHDs). Increased copy numbers of MARS and/or MARS2 were detected in NTD and CHD patients. MARSs sense homocysteine and transmit its signal by inducing protein lysine (N)‐homocysteinylation. Here, we identified hundreds of novel N‐homocysteinylated proteins. N‐homocysteinylation of superoxide dismutases (SOD1/2) provided new mechanistic insights for homocysteine‐induced oxidative stress, apoptosis and Wnt signalling deregulation. Elevated MARS expression in developing and proliferating cells sensitizes them to the effects of homocysteine. Targeting MARSs using the homocysteine analogue acetyl homocysteine thioether (AHT) reversed MARS efficacy. AHT lowered NTD and CHD onsets in retinoic acid‐induced and hyperhomocysteinemia‐induced animal models without affecting homocysteine levels. We provide genetic and biochemical evidence to show that MARSs are previously overlooked genetic determinants and key pathological factors of hyperhomocysteinemia, and suggest that MARS inhibition represents an important medicinal approach for controlling hyperhomocysteinemia‐associated diseases.

Background Positron emission tomography (PET) and PET/computed tomography (PET/CT) imaging with 3,4-dihydroxy-6-[ 18 F] fluoro-L-phenylalanine ( 18 F-FDOPA) has been used in the evaluation of gliomas. We performed a meta-analysis to obtain the diagnostic and grading accuracy of 18 F-FDOPA PET and PET/CT in patients with gliomas. Methods PubMed, Embase, Cochrane Library and Web of Science were searched through 13 May 2019. We included studies reporting the diagnostic performance of 18 F-FDOPA PET or PET/CT in glioma patients. Pooled sensitivity, specificity, and area under the summary receiver operating characteristic (SROC) curve were calculated from eligible studies on a per-lesion basis. Results Eventually, 19 studies were included. Across 13 studies (370 patients) for glioma diagnosis, the pooled sensitivity and specificity of 18 F-FDOPA PET and PET/CT were 0.90 (95%CI: 0.86–0.93) and 0.75 (95%CI: 0.65–0.83). Across 7 studies (219 patients) for glioma grading, 18 F-FDOPA PET and PET/CT showed a pooled sensitivity of 0.88 (95%CI: 0.81–0.93) and a pooled specificity of 0.73 (95%CI: 0.64–0.81). Conclusions 18 F-FDOPA PET and PET/CT demonstrated good performance for diagnosing gliomas and differentiating high-grade gliomas (HGGs) from low-grade gliomas (LGGs). Further studies implementing standardized PET protocols and investigating the grading parameters are needed.

Objective: The aim of the study was to evaluate the diagnostic value of contrast-enhanced ultrasound (CEUS) in distinguishing between benign and malignant cervical lymph nodes in patients with nasopharyngeal carcinoma (NPC). Material and Methods: A total of 144 NPC patients with enlarged superficial cervical lymph nodes underwent CEUS examination. The comparison of CEUS image characteristics between malignant and benign cervical lymph nodes was performed in this study as well. We analyzed parameters of the time–intensity curve (TIC), which includes time to peak (TP), area under the gamma curve (AUC), and peak intensity (PI). Furthermore, receiver operating characteristic (ROC) curve analysis was also investigated to evaluate the diagnostic value of CEUS. Result: We conducted 144 lymph node examinations in total, where 64 cases were biopsy-proven benign nodules and 80 cases were biopsy-proven metastatic nodules. The vast majority of the benign nodes displayed centrifugal perfusion (96.88%, 62/64) and homogeneous enhancement (93.75%, 60/64), while most of the malignant nodes showed centripetal perfusion (92.50%, 74/80) and inhomogeneous 80.00% (64/80). In addition, quantitative analysis showed that CEUS parameters including PI, TP, and AUC in benign lymph nodes (12.51 ± 2.15, 23.79 ± 11.80, and 1110.33 ± 286.17, respectively) were significantly higher than that in the malignant nodes (10.51 ± 2.98, 16.52 ± 6.95, and 784.09 ± 340.24, respectively). The assistance of the three aforementioned parameters and CEUS image characteristics would result in an acceptable diagnostic value. Conclusion: Our results suggest that imaging perfusion patterns as well as quantitative parameters obtained from CEUS provide valuable information for the evaluation of cervical lymph nodes in NPC patients.

The purpose of this study was to assess the ability of contrast-enhanced ultrasonography (CEUS) in the differential diagnosis of cancerous lymph nodes. Methods: Contrast-enhanced ultrasonography was performed in the cervical nodules of included patients, and the diagnoses were confirmed by pathological examination. Contrast-enhanced ultrasonography images and parameters of head and neck lymphomas were compared with those of cancerous lymph nodes. Besides, receiver operating characteristic curve was operated to access the diagnostic value of CEUS. Results: Finally, a total of 63 head and neck lymphomas and 80 cervical cancerous lymph nodes were enrolled in this study. Results showed that the CEUS images of lymphoma were mainly characterized by homogeneous enhancement (71.43%), and approximately half of them were centripetal perfusion (58.73%), whereas most CEUS images of cancerous lymph nodes were inhomogeneous enhancement (82.50%) and centripetal perfusion (92.50%). Quantitative analysis of CEUS parameters indicated that PI (derived peak intensity) and AUC (area under the curve) of lymphomas were both lower than those of cancerous lymph nodes (PI: 8.78 vs. 10.51, AUC: 652.62 vs. 784.09, respectively) (P < 0.05). Receiver operating characteristic analysis showed that the sensitivity of CEUS parameters in the differential diagnosis was significant (80.00%), although the specificity was not high (47.62%). When parameters were combined with the image features, the accuracy of diagnosis was greatly improved (from 0.655 to 0.899). Conclusion: Contrast-enhanced ultrasonography could be a promising tool for the differential diagnosis of head and neck lymphomas and cancerous lymph nodes.

Similar to estrogens, bone morphogenetic protein 4 (BMP4) promotes the accumulation of more metabolically active subcutaneous fat and reduction of visceral fat. However, whether there is a cross-talk between BMP4 and estrogen signaling remained unknown. Herein, we found that BMP4 deficiency in white adipose tissue (WAT) increased the estrogen receptor α (ERα) level and its signaling, which prevented adult female mice from developing high fat diet (HFD)-induced obesity and insulin resistance; estrogens depletion up regulated BMP4 expression to overcome overt adiposity and impaired insulin sensitivity with aging, and failure of BMP4 regulation due to genetic knockout led to more fat gain in aged female mice. This mutual regulation between BMP4 and estrogen/ERα signaling may also happen in adipose tissue of women, since the BMP4 level significantly increased after menopause, and was inversely correlated with body mass index (BMI). These findings suggest a counterbalance between BMP4 and estrogen/ERα signaling in the regulation of adiposity and relative metabolism in females.