Few-Shot Medical Image Segmentation via Generating Multiple Representative Descriptors.

Automatic medical image segmentation has witnessed significant development with the success of large models on massive datasets. However, acquiring and annotating vast medical image datasets often proves to be impractical due to the time consumption, specialized expertise requirements, and compliance with patient privacy standards, etc. As a result, Few-shot Medical Image Segmentation (FSMIS) has become an increasingly compelling research direction. Conventional FSMIS methods usually learn prototypes from support images and apply nearest-neighbor searching to segment the query images. However, only a single prototype cannot well represent the distribution of each class, thus leading to restricted performance. To address this problem, we propose to Generate Multiple Representative Descriptors (GMRD), which can comprehensively represent the commonality within the corresponding class distribution. In addition, we design a Multiple Affinity Maps based Prediction (MAMP) module to fuse the multiple affinity maps generated by the aforementioned descriptors. Furthermore, to address intra-class variation and enhance the representativeness of descriptors, we introduce two novel losses. Notably, our model is structured as a dual-path design to achieve a balance between foreground and background differences in medical images. Extensive experiments on four publicly available medical image datasets demonstrate that our method outperforms the state-of-the-art methods, and the detailed analysis also verifies the effectiveness of our designed module.

TMEM127 suppresses tumor development by promoting RET ubiquitination, positioning, and degradation.

The TMEM127 gene encodes a transmembrane protein of poorly known function that is mutated in pheochromocytomas, neural crest-derived tumors of adrenomedullary cells. Here, we report that, at single-nucleus resolution, TMEM127-mutant tumors share precursor cells and transcription regulatory elements with pheochromocytomas carrying mutations of the tyrosine kinase receptor RET. Additionally, TMEM127-mutant pheochromocytomas, human cells, and mouse knockout models of TMEM127 accumulate RET and increase its signaling. TMEM127 contributes to RET cellular positioning, trafficking, and lysosome-mediated degradation. Mechanistically, TMEM127 binds to RET and recruits the NEDD4 E3 ubiquitin ligase for RET ubiquitination and degradation via TMEM127 C-terminal PxxY motifs. Lastly, increased cell proliferation and tumor burden after TMEM127 loss can be reversed by selective RET inhibitors in vitro and in vivo. Our results define TMEM127 as a component of the ubiquitin system and identify aberrant RET stabilization as a likely mechanism through which TMEM127 loss-of-function mutations cause pheochromocytoma.

"Warm in Winter and Cool in Summer": Scalable Biochameleon Inspired Temperature-Adaptive Coating with Easy Preparation and Construction.

The highly reflective solar radiation of passive daytime radiative cooling (PDRC) increases heating energy consumption in the cold winter. Inspired by the temperature-adaptive skin color of chameleon, we efficiently combine temperature-adaptive solar absorption and PDRC technology to achieve "warm in winter and cool in summer". The temperature-adaptive radiative cooling coating (TARCC) with color variability is designed and fabricated, achieving 41% visible light regulation capability. Comprehensive seasonal outdoor tests confirm the reliability of the TARCC: in summer, the TARCC exhibits high solar reflectance (∼93%) and atmospheric transmission window emittance (∼94%), resulting in a 6.5 K subambient temperature. In the winter, the TARCC's dark color strongly absorbs solar radiation, resulting in a 4.3 K temperature rise. Compared with PDRC coatings, the TARCC can save up to 20% of annual energy in midlatitude regions and increase suitable human hours by 55%. With its low cost, easy preparation, and simple construction, the TARCC shows promise for achieving sustainable and comfortable indoor environments.

A RET::GRB2 fusion in pheochromocytoma defies the classic paradigm of RET oncogenic fusions.

The RET kinase receptor is a target of mutations in neural crest tumors, including pheochromocytomas, and of oncogenic fusions in epithelial cancers. We report a RET::GRB2 fusion in a pheochromocytoma in which RET, functioning as the upstream partner, retains its kinase domain but loses critical C-terminal motifs and is fused to GRB2, a physiological RET interacting protein. RET::GRB2 is an oncogenic driver that leads to constitutive, ligand-independent RET signaling; has transforming capability dependent on RET catalytic function; and is sensitive to RET inhibitors. These observations highlight a new driver event in pheochromocytomas potentially amenable for RET-driven therapy.

Wrinkled surface microstructure for enhancing the infrared spectral performance of radiative cooling.

Radiative cooling is a passive cooling method that does not consume additional energy and has broad application prospects. In recent studies, the surface microstructure was found to have a significant influence on improving the emissivity in infrared spectra for radiative cooling. Accordingly, in this paper, an innovative wrinkled surface microstructure without any periodicity is proposed for enhancing the infrared spectral performance of radiative cooling. The effects of the height and number of wrinkles as well as the radius and volume fraction of particles on the infrared spectral performance of radiative cooling are investigated. The radiative cooling performances of the plane, pyramid, moth-eye, and wrinkled microstructures are comparatively investigated using the finite-difference time-domain (FDTD) method. The results show that the mean emissivity of innovative radiative cooling films with the wrinkled surface microstructure reaches 99.58% in the "atmospheric window" wavelength range. The mean emissivity of the wrinkled microstructure is improved by 19%, 22.16%, and 8.41% over those of the plane, pyramid, and moth-eye microstructures, respectively. This indicates that the wrinkled microstructure exhibits a better performance for radiative cooling than single periodic surface microstructures. Furthermore, the wrinkled microstructure has no periodicity so it has low production cost, which makes it possible to replace other periodic surface microstructures.

Genotype-Phenotype Features of Germline Variants of the TMEM127 Pheochromocytoma Susceptibility Gene: A 10-Year Update.

PURPOSE: This work aimed to evaluate genotype-phenotype associations in individuals carrying germline variants of transmembrane protein 127 gene (TMEM127), a poorly known gene that confers susceptibility to pheochromocytoma (PHEO) and paraganglioma (PGL). DESIGN: Data were collected from a registry of probands with TMEM127 variants, published reports, and public databases. MAIN OUTCOME ANALYSIS: Clinical, genetic, and functional associations were determined. RESULTS: The cohort comprised 110 index patients (111 variants) with a mean age of 45 years (range, 21-84 years). Females were predominant (76 vs 34, P < .001). Most patients had PHEO (n = 94; 85.5%), although PGL (n = 10; 9%) and renal cell carcinoma (RCC, n = 6; 5.4%) were also detected, either alone or in combination with PHEO. One-third of the cases had multiple tumors, and known family history was reported in 15.4%. Metastatic PHEO/PGL was rare (2.8%). Epinephrine alone, or combined with norepinephrine, accounted for 82% of the catecholamine profiles of PHEO/PGLs. Most variants (n = 63) occurred only once and 13 were recurrent (2-12 times). Although nontruncating variants were less frequent than truncating changes overall, they were predominant in non-PHEO clinical presentations (36% PHEO-only vs 69% other, P < .001) and clustered disproportionately within transmembrane regions (P < .01), underscoring the relevance of these domains for TMEM127 function. Integration of clinical and previous experimental data supported classification of variants into 4 groups based on mutation type, localization, and predicted disruption. CONCLUSIONS: Patients with TMEM127 variants often resemble sporadic nonmetastatic PHEOs. PGL and RCC may also co-occur, although their causal link requires further evaluation. We propose a new classification to predict variant pathogenicity and assist with carrier surveillance.

Functional Characterization of TMEM127 Variants Reveals Novel Insights into Its Membrane Topology and Trafficking.

CONTEXT: TMEM127 is a poorly known tumor suppressor gene associated with pheochromocytomas, paragangliomas, and renal carcinomas. Our incomplete understanding of TMEM127 function has limited our ability to predict variant pathogenicity. PURPOSE: To better understand the function of the transmembrane protein TMEM127 we undertook cellular and molecular evaluation of patient-derived germline variants. DESIGN: Subcellular localization and steady-state levels of tumor-associated, transiently expressed TMEM127 variants were compared to the wild-type protein using immunofluorescence and immunoblot analysis, respectively, in cells genetically modified to lack endogenous TMEM127. Membrane topology and endocytic mechanisms were also assessed. RESULTS: We identified 3 subgroups of mutations and determined that 71% of the variants studied are pathogenic or likely pathogenic through loss of membrane-binding ability, stability, and/or internalization capability. Investigation into an N-terminal cluster of missense variants uncovered a previously unrecognized transmembrane domain, indicating that TMEM127 is a 4- transmembrane, not a 3-transmembrane domain-containing protein. Additionally, a C-terminal variant with predominant plasma membrane localization revealed an atypical, extended acidic, dileucine-based motif required for TMEM127 internalization through clathrin-mediated endocytosis. CONCLUSION: We characterized the functional deficits of several germline TMEM127 variants and identified novel structure-function features of TMEM127. These findings will assist in determining pathogenicity of TMEM127 variants and will help guide future studies investigating the cellular role of TMEM127.

K-Ras-ERK1/2 accelerates lung cancer cell development via mediating H3K18ac through the MDM2-GCN5-SIRT7 axis.

Context: H3K18ac is linked to gene expression and DNA damage. Nevertheless, whether H3K18ac participates in regulating Ras-ERK1/2-affected lung cancer cell phenotypes remains unclear. Objective: We explored the effects of H3K18ac on Ras-ERK1/2-affected lung cancer cell phenotypes. Material and methods: NCI-H2126 cells were transfected with, pEGFP-K-RasWT and pEGFP-K-RasG12V/T35S plasmids for 48 h, and transfection with pEGFP-N1 served as a blank control. Then H3K18ac and AKT and ERK1/2 pathways-associated factors were examined. Different amounts of the H3K18Q (0.5, 1, and 2 µg) plasmids and RasG12V/T35S were co-transfected into NCI-H2126 cells, cell viability, cell colonies and migration were analyzed for exploring the biological functions of H3K18ac in NCI-H2126 cells. The ERK1/2 pathway downstream factors were detected by RT-PCR and ChIP assays. The regulatory functions of SIRT7, GCN5 and MDM2 in Ras-ERK1/2-regulated H3K18ac expression were finally uncovered. Results: RasG12V/T35S transfection decreased the expression of H3K18ac about 2.5 times compared with the pEGFP-N1 transfection group, and activated ERK1/2 and AKT pathways. Moreover, H3K18ac reduced cell viability, colonies, migration, and altered ERK1/2 downstream transcription in NCI-H2126 cells. Additionally, SIRT7 knockdown increased H3K18ac expression and repressed cell viability, migration and the percentage of cells in S phase by about 50% compared to the control group, as well as changed ERK1/2 downstream factor expression. Besides, Ras-ERK1/2 decreased H3K18ac was linked to MDM2-regulated GCN5 degradation. Conclusion: These observations disclosed that Ras-ERK1/2 promoted the development of lung cancer via decreasing H3K18ac through MDM2-mediated GCN5 degradation. These findings might provide a new therapeutic strategy for lung cancer.

The tumor suppressor TMEM127 regulates insulin sensitivity in a tissue-specific manner.

Understanding the molecular components of insulin signaling is relevant to effectively manage insulin resistance. We investigated the phenotype of the TMEM127 tumor suppressor gene deficiency in vivo. Whole-body Tmem127 knockout mice have decreased adiposity and maintain insulin sensitivity, low hepatic fat deposition and peripheral glucose clearance after a high-fat diet. Liver-specific and adipose-specific Tmem127 deletion partially overlap global Tmem127 loss: liver Tmem127 promotes hepatic gluconeogenesis and inhibits peripheral glucose uptake, while adipose Tmem127 downregulates adipogenesis and hepatic glucose production. mTORC2 is activated in TMEM127-deficient hepatocytes suggesting that it interacts with TMEM127 to control insulin sensitivity. Murine hepatic Tmem127 expression is increased in insulin-resistant states and is reversed by diet or the insulin sensitizer pioglitazone. Importantly, human liver TMEM127 expression correlates with steatohepatitis and insulin resistance. Our results suggest that besides tumor suppression activities, TMEM127 is a nutrient-sensing component of glucose/lipid homeostasis and may be a target in insulin resistance.

LINC01419 promotes cell proliferation and metastasis in lung adenocarcinoma via sponging miR-519b-3p to up-regulate RCCD1.

Lung adenocarcinoma (LUAD) is one of the most common type of lung cancer notorious for the high incidence and mortality around the world. Long non-coding RNAs (LncRNAs) are defined as a class of RNAs with length more than 200 nucleotides. Mounting studies have proved that lncRNAs are related closely to incidence of diseases and play crucial roles in cancer progression. Although LINC01419 has been studied in several cancers, the function and mechanism of LINC01419 in LUAD remains a mystery. Our findings showed that LINC01419 level was high in LUAD cells, and LINC01419 knockdown inhibited carcinogenesis via suppressing cell proliferation, migration as well as invasion. Moreover, bioinformatics prediction, luciferase reporter experiments and RIP assay were used to confirm miR-519-3p was sequestered and negatively regulated by LINC01419. Subsequently, RCCD1 was identified as a miR-519b-3p target and had inverse relationship with miR-519b-3p. LINC01419 was positively related to RCCD1. Furthermore, rescue assays confirmed that miR-519b-3p inhibitor or RCCD1 overexpression could neutralize the effect of LINC01419 silenced in cell proliferation, migration and invasion. Taken together, all the results indicated that LINC01419 exhibited oncogenic behaviors LUAD via binding to miR-519b-3p to enhance the expression of RCCD1, manifesting the underlying therapy values of LINC01419 in LUAD.

Synonymous but Not Silent: A Synonymous VHL Variant in Exon 2 Confers Susceptibility to Familial Pheochromocytoma and von Hippel-Lindau Disease.

CONTEXT: von Hippel-Lindau (VHL) disease, comprising renal cancer, hemangioblastoma, and/or pheochromocytoma (PHEO), is caused by missense or truncating variants of the VHL tumor-suppressor gene, which is involved in degradation of hypoxia-inducible factors (HIFs). However, the role of synonymous VHL variants in the disease is unclear. OBJECTIVE: We evaluated a synonymous VHL variant in patients with familial PHEO or VHL disease without a detectable pathogenic VHL mutation. DESIGN: We performed genetic and transcriptional analyses of leukocytes and/or tumors from affected and unaffected individuals and evaluated VHL splicing in existing cancer databases. RESULTS: We identified a synonymous VHL variant (c.414A>G, p.Pro138Pro) as the driver event in five independent individuals/families with PHEOs or VHL syndrome. This variant promotes exon 2 skipping and hence, abolishes expression of the full-length VHL transcript. Exon 2 spans the HIF-binding domain required for HIF degradation by VHL. Accordingly, PHEOs carrying this variant display HIF hyperactivation typical of VHL loss. Moreover, other exon 2 VHL variants from the The Cancer Genome Atlas pan-cancer datasets are biased toward expression of a VHL transcript that excludes this exon, supporting a broader impact of this spliced variant. CONCLUSION: A recurrent synonymous VHL variant (c.414A>G, p.Pro138Pro) confers susceptibility to PHEO and VHL disease through splice disruption, leading to VHL dysfunction. This finding indicates that certain synonymous VHL variants may be clinically relevant and should be considered in genetic testing and surveillance settings. The observation that other coding VHL variants can exclude exon 2 suggests that dysregulated splicing may be an underappreciated mechanism in VHL-mediated tumorigenesis.

Ailanthone exerts an antitumor function on the development of human lung cancer by upregulating microRNA-195.

BACKGROUND: Lung cancer is a common leading cause of cancer-related death worldwide. Ailanthone, a natural compound isolated from Chinese herb Ailanthus altissima, has been reported to exert antiproliferative effects on various cancer cells. METHODS: The present study aimed to investigate the role of ailanthone in the lung cancer cells and the correlation between the ailanthone and microRNA (miR)-195. The cell viability, proliferation, and apoptosis were determined by cell counting kit-8 assay, bromodeoxyuridine incorporation method, annexin V-fluorescein isothiocyanate/propidium iodide assay, respectively. Apoptosis- and autophagy-related proteins, as well as regulatory factors in the signaling pathways, were analyzed by Western blot method. The expression of miR-195 was quantified by quantitative reverse transcription-polymerase chain reaction. RESULTS: The results confirmed that ailanthone was involved in the lung cancer cell progress by inhibiting cell viability and proliferation, but promoted cell apoptosis and autophagy. We also found that ailanthone upregulated the expression of miR-195. Further, the downregulated miR-195 inhibited the apoptosis and autophagy induced by ailanthone. Moreover, our studies revealed that miR-195 inhibitor promoted the phosphorylation of PI3K, AKT, JAK, and STAT3, which was inhibited by ailanthone. CONCLUSION: All these findings suggest that ailanthone plays key roles in lung cancer progress and is closely correlated with miR-195 expression.

The TMEM127 human tumor suppressor is a component of the mTORC1 lysosomal nutrient-sensing complex.

The TMEM127 tumor suppressor gene encodes a transmembrane protein of unknown function mutated in pheochromocytomas and, rarely, in renal cancers. Tumors with inactivating TMEM127 mutations have increased mTORC1 signaling by undefined mechanisms. Here we report that TMEM127 interacts with the lysosome-anchored complex comprised of Rag GTPases, the LAMTOR pentamer (or 'ragulator') and vATPase, which controls amino acid-mediated mTORC1 activation. We found that under nutrient-rich conditions TMEM127 expression reduces mTORC1 recruitment to Rags. In addition, TMEM127 interacts with LAMTOR in an amino acid-dependent manner and decreases the LAMTOR1-vATPase association, while TMEM127-vATPase binding requires intact lysosomal acidification but is amino acid independent. Conversely, both murine and human cells lacking TMEM127 accumulate LAMTOR proteins in the lysosome. Consistent with these findings, pheochromocytomas with TMEM127 mutations have increased levels of LAMTOR proteins. These results suggest that TMEM127 interactions with ragulator and vATPase at the lysosome contribute to restrain mTORC1 signaling in response to amino acids, thus explaining the increased mTORC1 activation seen in TMEM127-deficient tumors.

Incidence and risk of hepatic toxicities associated with anaplastic lymphoma kinase inhibitors in the treatment of non-small-cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: Two anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors (-TKIs) have been approved for the treatment of patients with ALK-rearranged (ALK-positive) advanced non-small cell lung cancer (NSCLC). Severe hepatotoxicity has been observed in several clinical studies. We aim to assess the incidence and risk of liver toxicity with these drugs by a systematic review and meta-analysis of clinical trials. MATERIALS AND METHODS: The databases of PubMed, Web of Science and abstracts presented at oncology conferences' proceedings were searched for relevant studies from January 2000 to January 2017. Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated by using either random effects or fixed effect models. RESULTS: A total of 1,908 patients from 10 clinical trials were included. The incidences of all-grade aspartate aminotransferase (AST) and alanine transaminase (ALT) elevation were 25.2% (95% CI 17.7-34.7%), and 26.0% (95% CI 17.8-36.3%), respectively. The incidences of high-grade (grade 3 and 4) AST and ALT elevation were 7.0% (95% CI: 5.4-9.0%), and 9.9% (95%CI: 5.6-16.7%), respectively. Sub-group analysis according to ALK-TKIs showed that the incidence of liver toxicities associated with ceritinib was higher than that of crizotinib and alectinib. In comparison with chemotherapy, ALK-TKIs significantly increased the risk of developing all-grade and high-grade AST elevation (RR, 2.30, 95%CI: 1.87-2.83, p < 0.001; RR 10.14, 95% CI: 3.9-26.39, p < 0.001) and ALT elevation (RR 2.37, 95%CI: 1.97-2.86, p < 0.001; RR 7.34, 95% CI: 3.95-13.63, p < 0.001), respectively. CONCLUSIONS: The use of ALK-TKIs significantly increases the risk of developing all-grade and high-grade liver toxicities in lung cancer patients.

Non-small cell lung cancer: miR-30d suppresses tumor invasion and migration by directly targeting NFIB.

OBJECTIVE: To evaluate the role and the molecular mechanism of miR-30d in non-small cell lung cancer (NSCLC). RESULTS: qRT-PCR was used to detect miR-30d expression in NSCLC tissues and cell lines. miR-30d was frequently down-regulated in NSCLC and its expression was associated with clinicopathological features of NSCLCC patients. Over-expression of miR-30d notably inhibited cell migration and invasion in NSCLC cell lines. miR-30d could negatively regulate Nuclear factor I B (NFIB) by directly targeting its 3'-UTR, which was confirmed by luciferase assay. NFIB also reversed miR-30d-mediated suppression on the migration and invasion in NSCLC cell lines. CONCLUSION: miR-30d suppressed cell migration and invasion by directly targeting NFIB in NSCLC, and NFIB could partially abrogated the inhibition of biological functions by miR-30d.

Evaluation of short-term and long-term efficacy of surgical and non-surgical treatment in patients with early-stage small cell lung cancer: A comparative study.

OBJECTIVE: The aim of this study is to compare surgery with adjuvant chemoradiotherapy versus non-surgical treatments for patients with early-stage small cell lung cancer (SCLC) based on the short-term and long-term efficacy. METHODS: SCLC patients who underwent a pulmonary lobectomy with post-surgical radiotherapy or chemotherapy were assigned to the surgical group. SCLC patients who received radiotherapy or chemotherapy alone were classified into the non-surgical group. The clinical efficacy was evaluated as complete remission (CR), partial remission (PR), stable disease (SD), or progressive disease (PD). The total effectiveness rate was calculated as CR + PR. The 1-, 3-, and 5-year survival rates of the two groups were compared. RESULTS: Compared with the non-surgical group, the CR rate and the total effectiveness rate were higher in the surgical group, and the total effectiveness rate for male patients and patients without a smoking history were also higher in the surgical group. Distant metastasis and local recurrence concurrent with distant metastasis in the surgical group were both lower in the surgical group than in the non-surgical group. Compared with the non-surgical group, the local recurrence in male patients was lower in the surgical group, and patients in the surgical group had lower distant metastasis at TNM stage IIb. The 1-, 3-, and 5-year survival rates were higher in the surgical group than in the non-surgical group. CONCLUSIONS: These findings indicate that for patients with early-stage SCLC, better scores in effectiveness rate, disease progression, and 1-, 3-, and 5-year survival rates were observed in patients who underwent surgery followed by adjuvant chemoradiotherapy when compared with patients without surgical treatment.

Context Matters: Distinct Disease Outcomes as a Result of Crebbp Hemizygosity in Different Mouse Bone Marrow Compartments.

Perturbations in CREB binding protein (CREBBP) are associated with hematopoietic malignancies, including myelodysplastic syndrome (MDS). Mice hemizygous for Crebbp develop myelodysplasia with proliferative features, reminiscent of human MDS/myeloproliferative neoplasm-unclassifiable (MDS/MPN-U), and a proportion goes on to develop acute myeloid leukemia (AML). We have also shown that the Crebbp+/- non-hematopoietic bone marrow microenvironment induces excessive myeloproliferation of wild-type cells. We now report that transplantation of unfractionated Crebbp+/- bone marrow into wild-type recipients resulted in either early-onset AML or late-onset MDS and MDS/MPN-U. In contrast, purified Lin-Sca-1+c-Kit++ cells primarily gave rise to MDS with occasional transformation to AML. Furthermore, Crebbp+/- common myeloid progenitors and granulocyte/macrophage progenitors could trigger skewed myelopoiesis, myelodysplasia and late-onset AML. Surprisingly, the phenotypically abnormal cells were all of wild-type origin. MDS, MPN and AML can thus all be transferred from Crebbp+/- BM to wild-type hosts but fractionated bone marrow does not recapitulate the full disease spectrum of whole bone marrow, indicating that not only mutational status but also cellular context contribute to disease outcome. This has important consequences for structuring and interpreting future investigations into the underlying mechanisms of myeloid malignancies as well as for their treatment.