Inhibiting the Leidenfrost effect above 1,000 °C for sustained thermal cooling.

The Leidenfrost effect, namely the levitation of drops on hot solids1, is known to deteriorate heat transfer at high temperature2. The Leidenfrost point can be elevated by texturing materials to favour the solid-liquid contact2-10 and by arranging channels at the surface to decouple the wetting phenomena from the vapour dynamics3. However, maximizing both the Leidenfrost point and thermal cooling across a wide range of temperatures can be mutually exclusive3,7,8. Here we report a rational design of structured thermal armours that inhibit the Leidenfrost effect up to 1,150 °C, that is, 600 °C more than previously attained, yet preserving heat transfer. Our design consists of steel pillars serving as thermal bridges, an embedded insulating membrane that wicks and spreads the liquid and U-shaped channels for vapour evacuation. The coexistence of materials with contrasting thermal and geometrical properties cooperatively transforms normally uniform temperatures into non-uniform ones, generates lateral wicking at all temperatures and enhances thermal cooling. Structured thermal armours are limited only by their melting point, rather than by a failure in the design. The material can be made flexible, and thus attached to substrates otherwise challenging to structure. Our strategy holds the potential to enable the implementation of efficient water cooling at ultra-high solid temperatures, which is, to date, an uncharted property.

Molecular Characterization of Juxtaglomerular Cell Tumors: Evidence of Alterations in MAPK-RAS Pathway.

Juxtaglomerular cell tumor (JGCT) is a rare neoplasm, part of the family of mesenchymal tumors of the kidney. Although the pathophysiological and clinical correlates of JGCT are well known, as these tumors are an important cause of early-onset arterial hypertension refractory to medical treatment, their molecular background is unknown, with only few small studies investigating their karyotype. Herein we describe a multi-institutional cohort of JGCTs diagnosed by experienced genitourinary pathologists, evaluating clinical presentation and outcome, morphologic diversity, and, importantly, the molecular features. Ten JGCTs were collected from 9 institutions, studied by immunohistochemistry, and submitted to whole exome sequencing. Our findings highlight the morphologic heterogeneity of JGCT, which can mimic several kidney tumor entities. Three cases showed concerning histologic features, but the patient course was unremarkable, which suggests that morphologic evaluation alone cannot reliably predict the clinical behavior. Gain-of-function variants in RAS GTPases were detected in JGCTs, with no evidence of additional recurrent genomic alterations. In conclusion, we present the largest series of JGCT characterized by whole exome sequencing, highlighting the putative role of the MAPK-RAS pathway.

Constant p.L424H Mutation in GTF2I in Micronodular Thymomas With Lymphoid Stroma: Evidence Supporting Close Relationship With Type A and AB Thymomas.

Micronodular thymoma with lymphoid stroma is a rare thymic neoplasm characterized by discrete nodules of epithelial tumor cells separated by abundant lymphoid stroma. The genetic features of micronodular thymoma with lymphoid stroma remain largely unexplored. Owing to the interference of abundant intratumoral, nonneoplastic lymphoid cells, a highly sensitive approach is necessary to study genetic changes in these tumors. In this study, we used a highly sensitive next-generation sequencing assay using the molecular barcoding Ion AmpliSeq HD technology to study the most commonly mutated genes in thymomas, including GTF2I, HRAS, NRAS, KRAS, and TP53. A total of 12 cases of micronodular thymomas with lymphoid stroma were tested, and 2 cases also had areas of type A thymoma in their tumor bed. Two micronodular thymic carcinomas with lymphoid stroma, a histological mimic of micronodular thymoma, were also included for comparison. Recurrent p.L424H mutations in GTF2I were found in all the cases of micronodular thymoma with lymphoid stroma but not in the cases of micronodular thymic carcinomas. In addition, 3 cases of micronodular thymoma with lymphoid stroma also had concomitant HRAS and/or KRAS mutations. Our study showed that p.L424H mutations in GTF2I is a constant genetic feature of micronodular thymoma with lymphoid stroma. This finding strongly suggests that micronodular thymoma with lymphoid stroma is closely related to type A and AB thymomas because they all share p.L424H mutations in GTF2I.

Klotho Overexpression Is Frequently Associated With Upstream Rearrangements in Fusion-Negative Phosphaturic Mesenchymal Tumors of Bone and Sinonasal Tract.

Phosphaturic mesenchymal tumors (PMT) are uncommon neoplasms that cause hypophosphatemia/osteomalacia mainly by secreting fibroblast growth factor 23. We previously identified FN1::FGFR1/FGF1 fusions in nearly half of the PMTs and frequent KL (Klotho or α-Klotho) overexpression in only those with no known fusion. Here, we studied a larger cohort of PMTs for KL expression and alterations. By FN1 break-apart fluorescence in situ hybridization (FISH) and reappraisal of previous RNA sequencing data, 6 tumors previously considered "fusion-negative" (defined by negative results of FISH for FN1::FGFR1 fusion and FGF1 break-apart and/or of RNA sequencing) were reclassified as fusion-positive PMTs, including 1 containing a novel FN1::ZACN fusion. The final cohort of fusion-negative PMTs included 33 tumors from 32 patients, which occurred in the bone (n = 18), soft tissue (n = 10), sinonasal tract (n = 4), and brain (n = 1). In combination with previous work, RNA sequencing, RNA in situ hybridization, and immunohistochemistry showed largely concordant results and demonstrated KL/α-Klotho overexpression in 17 of the 28 fusion-negative and none of the 10 fusion-positive PMTs studied. Prompted by a patient in this cohort harboring germline KL upstream translocation with systemic α-Klotho overexpression and multifocal PMTs, FISH was performed and revealed KL rearrangement in 16 of the 33 fusion-negative PMTs (one also with amplification), including 14 of the 17 cases with KL/α-Klotho overexpression and none of the 11 KL/α-Klotho-low fusion-negative and 11 fusion-positive cases studied. Whole genomic sequencing confirmed translocation and inversion in 2 FISH-positive cases involving the KL upstream region, warranting further investigation into the mechanism whereby these rearrangements may lead to KL upregulation. Methylated DNA immunoprecipitation and sequencing suggested no major role of promoter methylation in KL regulation in PMT. Interestingly, KL-high/-rearranged cases seemed to form a clinicopathologically homogeneous group, showing a predilection for skeletal/sinonasal locations and typically matrix-poor, cellular solitary fibrous tumor-like morphology. Importantly, FGFR1 signaling pathways were upregulated in fusion-negative PMTs regardless of the KL status compared with non-PMT mesenchymal tumors by gene set enrichment analysis, perhaps justifying FGFR1 inhibition in treating this subset of PMTs.

Interobserver reproducibility of cribriform cancer in prostate needle biopsies and validation of International Society of Urological Pathology criteria.

AIMS: There is strong evidence that cribriform morphology indicates a worse prognosis of prostatic adenocarcinoma. Our aim was to investigate its interobserver reproducibility in prostate needle biopsies. METHODS AND RESULTS: A panel of nine prostate pathology experts from five continents independently reviewed 304 digitised biopsies for cribriform cancer according to recent International Society of Urological Pathology criteria. The biopsies were collected from a series of 702 biopsies that were reviewed by one of the panellists for enrichment of high-grade cancer and potentially cribriform structures. A 2/3 consensus diagnosis of cribriform and noncribriform cancer was reached in 90% (272/304) of the biopsies with a mean kappa value of 0.56 (95% confidence interval 0.52-0.61). The prevalence of consensus cribriform cancers was estimated to 4%, 12%, 21%, and 20% of Gleason scores 7 (3 + 4), 7 (4 + 3), 8, and 9-10, respectively. More than two cribriform structures per level or a largest cribriform mass with ≥9 lumina or a diameter of ≥0.5 mm predicted a consensus diagnosis of cribriform cancer in 88% (70/80), 84% (87/103), and 90% (56/62), respectively, and noncribriform cancer in 3% (2/80), 5% (5/103), and 2% (1/62), respectively (all P < 0.01). CONCLUSION: Cribriform prostate cancer was seen in a minority of needle biopsies with high-grade cancer. Stringent diagnostic criteria enabled the identification of cribriform patterns and the generation of a large set of consensus cases for standardisation.

Touch print smear of testicular tissue with thionine stain for intraoperative diagnosis in azoospermic men.

PURPOSE: To compare the diagnostic value of testicular tissue touch print smear (TPS) conducted on azoospermic patients with results obtained from histopathology and in vitro fertility (IVF) lab findings. METHODS: Microdissection testicular sperm extraction was performed on a group of 148 azoospermic patients and testicular samples obtained intraoperatively. Using TPS, the samples were smeared onto a sterile slide, followed with staining using thionine. The testis tissue bulk samples were also transferred to the IVF lab, and determinations of sperm presence or absence obtained from IVF lab tests were compared with the TPS sample results. Needle testis biopsy was separately performed on a group of 360 azoospermic patients, and results of pathohistology review on the biopsies were further compared with determinations of spermatogenesis stage obtained from TPS for those patients. RESULTS: When compared with IVF lab results, TPS was found to have 100% (126/126) positive predictive value and 95.5% (25/26) negative predictive value for predicting sperm presence or absence, respectively. Furthermore, TPS was further found to have a 93.6% correlation (337 of 360 biopsies) with results of histological diagnoses performed by needle biopsy. Results from histology and TPS for the detection of sperm presence were concordant in 96.1% (346/360) of biopsies. Diagnosis of SCO by TPS shows the highest correlation with histopathology (98.6%), followed by complete spermatogenesis (97.5%), early maturation arrest (78.9%), and late maturation arrest (27.3%). CONCLUSIONS: The results support the continued use of TPS in testicular tissue analysis for more rapid assessment of spermatogenesis and for detection of spermatozoa in azoospermic subjects.

Blockchained Industry Information Handoff Based on Internet of Things Devices with Intelligent Customized Object Recognition.

To determine the quality and safety of each product used in manufacturing, the exchange of measured data between machines, operators, production lines, and manufacturing companies is crucial. In this study, we developed a system with customized object recognition capability for the secure blockchain-based transfer of industry information through Internet of Things (IoT) devices. In the proposed system, product history data are transferred through blockchains through artificial intelligence (AI)-based object recognition. Individual objects are recognized and represented using a unique number sequence for use as a private key on a blockchain. The data history can be automatically secured, and all the data are traceable and trackable. The reliability and validity of the proposed system were verified using the Jetson Nano Developer Kit. The proposed AI-based system is a low-cost embedded system. Based on the open-source cloud computing platform, the required computing resources for blockchain computing and storage are available. In an experiment, the proposed system achieved >99% accuracy within 1 s. Furthermore, the computational cost of the proposed system was 10% that of traditional AI systems. The proposed device can be rapidly connected to IoT devices that require limited manual operation and can be adopted in manufacturing and production lines.

HIV-1 Tat Interacts with a Kaposi's Sarcoma-Associated Herpesvirus Reactivation-Upregulated Antiangiogenic Long Noncoding RNA, LINC00313, and Antagonizes Its Function.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS), an AIDS-defining cancer with abnormal angiogenesis. The high incidence of KS in human immunodeficiency virus (HIV)-infected AIDS patients has been ascribed to an interaction between HIV type 1 (HIV-1) and KSHV, focusing on secretory proteins. The HIV-1 secreted protein HIV Tat has been found to synergize with KSHV lytic proteins to induce angiogenesis. However, the impact and underlying mechanisms of HIV Tat in KSHV-infected endothelial cells undergoing viral lytic reactivation remain unclear. Here, we identified LINC00313 as a novel KSHV reactivation-activated long noncoding RNA (lncRNA) that interacts with HIV Tat. We found that LINC00313 overexpression inhibits cell migration, invasion, and tube formation, and this suppressive effect was relieved by HIV Tat. In addition, LINC00313 bound to polycomb repressive complex 2 (PRC2) complex components, and this interaction was disrupted by HIV Tat, suggesting that LINC00313 may mediate transcription repression through recruitment of PRC2 and that HIV Tat alleviates repression through disruption of this association. This notion was further supported by bioinformatics analysis of transcriptome profiles in LINC00313 overexpression combined with HIV Tat treatment. Ingenuity Pathway Analysis (IPA) showed that LINC00313 overexpression negatively regulates cell movement and migration pathways, and enrichment of these pathways was absent in the presence of HIV Tat. Collectively, our results illustrate that an angiogenic repressive lncRNA, LINC00313, which is upregulated during KSHV reactivation, interacts with HIV Tat to promote endothelial cell motility. These results demonstrate that an lncRNA serves as a novel connector in HIV-KSHV interactions.IMPORTANCE KS is a prevalent tumor associated with infections with two distinct viruses, KSHV and HIV. Since KSHV and HIV infect distinct cell types, the virus-virus interaction associated with KS formation has focused on secretory factors. HIV Tat is a well-known RNA binding protein secreted by HIV. Here, we revealed LINC00313, an lncRNA upregulated during KSHV lytic reactivation, as a novel HIV Tat-interacting lncRNA that potentially mediates HIV-KSHV interactions. We found that LINC00313 can repress endothelial cell angiogenesis-related properties potentially by interacting with chromatin remodeling complex PRC2 and downregulation of cell migration-regulating genes. An interaction between HIV Tat and LINC00313 contributed to the dissociation of PRC2 from LINC00313 and the disinhibition of LINC00313-induced repression of cell motility. Given that lncRNAs are emerging as key players in tissue physiology and disease progression, including cancer, the mechanism identified in this study may help decipher the mechanisms underlying KS pathogenesis induced by HIV and KSHV coinfection.

Clinicopathological and molecular characterisation of papillary renal neoplasm with reverse polarity and its renal papillary adenoma analogue.

AIMS: Papillary renal neoplasm with reverse polarity (PRNRP) is a newly defined entity with distinct histomorphology and recurrent KRAS mutation. It has been estimated to constitute 4% of previously diagnosed papillary renal cell carcinoma (PRCC). Renal papillary adenoma (PA) is suggested to be the precursor of PRCC. This study aimed to investigate the association between PRNRP and PA, particularly the morphologically similar type D PA. METHODS AND RESULTS: Nephrectomy specimens of PRCC and PA from our 10-year pathology archives were retrieved and reviewed. GATA3 immunohistochemistry and RAS/BRAF testing were performed in all cases reclassified as PRNRP and all PAs with sufficient materials. Overall, PRNRP accounted for 9.1% (10 of 110) of PRCC and there was no recurrence/metastasis with a mean follow-up period of 39 months. Three novel morphological features were described, including clear cell change, mast cell infiltration and metaplastic ossification. Nine of the 10 PRNRPs showed diffuse and strong GATA3 expression and KRAS missense mutations at codon 12. One case exhibited moderate GATA3 staining on 80% of the tumour cells and RAS/BRAF wild-type. In a total of 73 PAs, 11 were classified as type D. GATA3 expression was significantly more frequent in type D versus non-type D PAs (100 versus 35%, P < 0.01). KRAS missense mutations were identified in six of eight (75%) of the type D PAs but none of the 18 non-type D PAs. CONCLUSIONS: Type D PA was different from other types of PA and represented an analogue or a small-sized PRNRP for their identical morphology, immunophenotype and molecular signature.

The Genitourinary Pathology Society Update on Classification and Grading of Flat and Papillary Urothelial Neoplasia With New Reporting Recommendations and Approach to Lesions With Mixed and Early Patterns of Neoplasia.

The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in bladder neoplasia with a focus on issues relevant to the practicing surgical pathologist for the understanding and effective reporting of bladder cancer, emphasizing particularly on the newly accumulated evidence post-2016 World Health Organization (WHO) classification. The work is presented in 2 manuscripts. Here, in the first, we revisit the nomenclature and classification system used for grading flat and papillary urothelial lesions centering on clinical relevance, and on dilemmas related to application in routine reporting. As patients of noninvasive bladder cancer frequently undergo cystoscopy and biopsy in their typically prolonged clinical course and for surveillance of disease, we discuss morphologies presented in these scenarios which may not have readily applicable diagnostic terms in the WHO classification. The topic of inverted patterns in urothelial neoplasia, particularly when prominent or exclusive, and beyond inverted papilloma has not been addressed formally in the WHO classification. Herein we provide a through review and suggest guidelines for when and how to report such lesions. In promulgating these GUPS recommendations, we aim to provide clarity on the clinical application of these not so uncommon diagnostically challenging situations encountered in routine practice, while also importantly advocating consistent terminology which would inform future work.

The Genitourinary Pathology Society Update on Classification of Variant Histologies, T1 Substaging, Molecular Taxonomy, and Immunotherapy and PD-L1 Testing Implications of Urothelial Cancers.

The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in bladder cancer focusing on important topics of high interest for the practicing surgical pathologist and urologist. This review represents the second of 2 manuscripts ensuing from this effort. Herein, we address the effective reporting of bladder cancer, focusing particularly on newly published data since the last 2016 World Health Organization (WHO) classification. In addition, this review focuses on the importance of reporting bladder cancer with divergent differentiation and variant (subtypes of urothelial carcinoma) histologies and the potential impact on patient care. We provide new recommendations for reporting pT1 staging in diagnostic pathology. Furthermore, we explore molecular evolution and classification, emphasizing aspects that impact the understanding of important concepts relevant to reporting and management of patients.

Artificial intelligence for diagnosis and grading of prostate cancer in biopsies: a population-based, diagnostic study.

BACKGROUND: An increasing volume of prostate biopsies and a worldwide shortage of urological pathologists puts a strain on pathology departments. Additionally, the high intra-observer and inter-observer variability in grading can result in overtreatment and undertreatment of prostate cancer. To alleviate these problems, we aimed to develop an artificial intelligence (AI) system with clinically acceptable accuracy for prostate cancer detection, localisation, and Gleason grading. METHODS: We digitised 6682 slides from needle core biopsies from 976 randomly selected participants aged 50-69 in the Swedish prospective and population-based STHLM3 diagnostic study done between May 28, 2012, and Dec 30, 2014 (ISRCTN84445406), and another 271 from 93 men from outside the study. The resulting images were used to train deep neural networks for assessment of prostate biopsies. The networks were evaluated by predicting the presence, extent, and Gleason grade of malignant tissue for an independent test dataset comprising 1631 biopsies from 246 men from STHLM3 and an external validation dataset of 330 biopsies from 73 men. We also evaluated grading performance on 87 biopsies individually graded by 23 experienced urological pathologists from the International Society of Urological Pathology. We assessed discriminatory performance by receiver operating characteristics and tumour extent predictions by correlating predicted cancer length against measurements by the reporting pathologist. We quantified the concordance between grades assigned by the AI system and the expert urological pathologists using Cohen's kappa. FINDINGS: The AI achieved an area under the receiver operating characteristics curve of 0·997 (95% CI 0·994-0·999) for distinguishing between benign (n=910) and malignant (n=721) biopsy cores on the independent test dataset and 0·986 (0·972-0·996) on the external validation dataset (benign n=108, malignant n=222). The correlation between cancer length predicted by the AI and assigned by the reporting pathologist was 0·96 (95% CI 0·95-0·97) for the independent test dataset and 0·87 (0·84-0·90) for the external validation dataset. For assigning Gleason grades, the AI achieved a mean pairwise kappa of 0·62, which was within the range of the corresponding values for the expert pathologists (0·60-0·73). INTERPRETATION: An AI system can be trained to detect and grade cancer in prostate needle biopsy samples at a ranking comparable to that of international experts in prostate pathology. Clinical application could reduce pathology workload by reducing the assessment of benign biopsies and by automating the task of measuring cancer length in positive biopsy cores. An AI system with expert-level grading performance might contribute a second opinion, aid in standardising grading, and provide pathology expertise in parts of the world where it does not exist. FUNDING: Swedish Research Council, Swedish Cancer Society, Swedish eScience Research Center, EIT Health.

AKT1 internal tandem duplications and point mutations are the genetic hallmarks of sclerosing pneumocytoma.

Sclerosing pneumocytoma is a unique benign neoplasm of the lungs. The molecular alterations in sclerosing pneumocytoma are not well understood. In a previous whole-exome sequencing study, recurrent AKT1 point mutation was observed in about half of the cases of sclerosing pneumocytoma. However, in the remaining half, cancer-related mutations have still not been identified. In this study, we first analyzed the raw sequence data from the previous whole-exome sequencing study (PRJNA297066 cohort). Using Genomon-ITDetector, a special software for detection of internal tandem duplications, we identified recurrent internal tandem duplications in the AKT1 gene in 22 of the 44 tumor samples (50%). All the cases positive for AKT1 internal tandem duplications lacked AKT1 point mutations. Next, we performed targeted next-generation sequencing in an independent cohort of sclerosing pneumocytoma from our hospital (VGH-TPE cohort), and again identified recurrent AKT1 internal tandem duplications in 20 of the 40 (50%) tumor samples analyzed. The internal tandem duplications resulted in duplications of 7 to 16 amino acids in a narrow region of the Pleckstrin homology domain of the AKT1 protein. This region contains the interaction interface between the Pleckstrin homology and kinase domains, which is known to play a critical role in the activation of the AKT1 protein. Moreover, we found that AKT1 internal tandem duplications were mutually exclusive of other forms of AKT1 mutations, including point mutations and short indels. Taking all forms of AKT1 mutations together, we detected AKT1 mutations in almost all the sclerosing pneumocytomas in our study (PRJNA297066 cohort: 41 out of 44 cases, 93%; VGH-TPE cohort: 40 out of 40 cases, 100%). Our results suggest that AKT1 mutation is the genetic hallmark of sclerosing pneumocytoma. These results would help in better understanding of the pathogenesis of sclerosing pneumocytoma.

ALK rearranged renal cell carcinoma (ALK-RCC): a multi-institutional study of twelve cases with identification of novel partner genes CLIP1, KIF5B and KIAA1217.

ALK rearranged renal cell carcinoma (ALK-RCC) has recently been included in 2016 WHO classification as a provisional entity. In this study, we describe 12 ALK-RCCs from 8 institutions, with detailed clinical, pathological, immunohistochemical (IHC), fluorescence in situ hybridization (FISH), and next generation sequencing (NGS) analyses. Patients' age ranged from 25 to 68 years (mean, 46.3 years). Seven patients were females and five were males (M:F = 1:1.4). Tumor size ranged from 17 to 70 mm (mean 31.5, median 25 mm). The pTNM stage included: pT1a (n = 7), pT1b (n = 1), and pT3a (n = 4). Follow-up was available for 9/12 patients (range: 2 to 153 months; mean 37.6 months); 8 patients were alive without disease and one was alive with distant metastases. The tumors demonstrated heterogeneous, 'difficult to classify' morphology in 10/12 cases, typically showing diverse architectural and cellular morphologies, including papillary, tubular, tubulocystic, solid, sarcomatoid (spindle cell), rhabdoid, signet-ring cell, and intracytoplasmic vacuoles, often set in a mucinous background. Of the remaining two tumors, one showed morphology resembling mucinous tubular and spindle cell renal cell carcinoma (MTSC RCC-like) and one was indistinguishable from metanephric adenoma. One additional case also showed a focal metanephric adenoma-like area, in an otherwise heterogeneous tumor. By IHC, all tumors were diffusely positive for ALK and PAX8. In both cases with metanephric adenoma-like features, WT1 and ALK were coexpressed. ALK rearrangement was identified in 9/11 tumors by FISH. ALK fusion partners were identified by NGS in all 12 cases, including the previously reported: STRN (n = 3), TPM3 (n = 3), EML4 (n = 2), and PLEKHA7 (n = 1), and also three novel fusion partners: CLIP1 (n = 1), KIF5B (n = 1), and KIAA1217 (n = 1). ALK-RCC represents a genetically distinct entity showing a heterogeneous histomorphology, expanded herein to include unreported metanephric adenoma-like and MTSC RCC-like variants. We advocate a routine ALK IHC screening for "unclassifiable RCCs" with heterogeneous features.

Synthesis and Biological Evaluation of a Carbamate-Containing Tubulysin Antibody-Drug Conjugate.

Antibody-drug conjugates (ADCs) use antibodies to deliver cytotoxic payloads directly into tumor cells via specifically binding to the target cell surface antigens. ADCs can enhance the anti-tumor effects of antibodies, and increase the delivery of cytotoxic payloads to cancer cells with a better therapeutic index. An ADC was prepared with a potent carbamate-containing tubulysin analogue attached to an anti-mesothelin antibody via a Cit-Val dipeptide linker. An aniline functionality in the tubulysin analogue was created to provide a site of linker attachment via an amide bond that would be stable in systemic circulation. Upon ADC internalization into antigen-positive cancer cells, the Cit-Val dipeptide linker was cleaved by lysosomal proteases, and the drug was released inside the tumor cells. The naturally occurring acetate of tubulysin was modified to a carbamate to reduce acetate hydrolysis of the ADC in circulation and to increase the hydrophilicity of the drug. The ADC bearing the monoclonal anti-mesothelin antibody and the carbamate-containing tubulysin was highly potent and immunologically specific to H226 human lung carcinoma cells in vitro, and efficacious at well-tolerated doses in a mesothelin-positive OVCAR3 ovarian cancer xenograft mouse model.

Differential expression analysis of clear cell renal cell carcinomas in The Cancer Genome Atlas distinguishes an aggressive subset enriched with chromosomes 7 and 12 gains.

AIMS: The Cancer Genome Atlas (TCGA) provides an integrated resource for investigating the genetic, phenotypical and clinical characteristics of cancer. In this study, we aimed to define distinct subsets of clear cell renal cell carcinoma (ccRCC) through differential expression and principal component analyses. METHODS AND RESULTS: We used DESeq2 to examine the expression profiles of 472 cases in TCGA. After a process of segregation and regrouping, we compared the mutation and copy number variation landscapes to discern two major clusters: cluster 1, composed mainly of classic ccRCC, and cluster 2, which was associated with gains at chromosomes 7 and 12. Gene set enrichment analysis disclosed that cluster 2 tumours were enriched in genes involving epithelial-mesenchymal transition. Histologically, cluster 2 tumours frequently exhibited cell elongation or spindling. Patients with cluster 2 tumours or tumours harbouring chromosomes 7 or 12 gains had a significantly greater cumulative incidence of mortality. We then employed fluorescence in-situ hybridisation with probes against chromosomes 7 and 12 in a cohort of 119 cases of ccRCC from our institute for validation. Chromosomes 7 and 12 gains were associated with lower survival rates in both univariate and multivariate analyses. CONCLUSIONS: Our study demonstrates that genetic data obtained through appropriate molecular methodologies can be a useful adjunct to help predict prognosis. It also provides an example of exploring TCGA to extract meaningful information that can eventually contribute to precision medicine.

Design, synthesis and biological evaluation of phenol-linked uncialamycin antibody-drug conjugates.

Uncialamycin is one of the structurally simpler and newer members of enediyne family of natural products. It exhibits highly potent activity against several types of bacteria and cancer cells. Described herein is a strategy for the targeted delivery of this cytotoxic agent to tumors using an antibody-drug conjugate (ADC) approach. Central to the design of ADC were the generation of potent and chemically stable uncialamycin analogues and attachment of protease cleavable linkers to newly realized phenolic handles to prepare linker-payloads. Conjugation of the linker-payloads to tumor targeting antibody, in vitro activity and in vivo evaluation are presented.

Cone beam computed tomographic analysis of the spatial limitation during mandibular arch distalization.

BACKGROUND: In the literature, attempts are seldom made to quantify spatial limitation during mandibular arch distalization. This study aimed to investigate the spatial limitations associated with cortical contact with the mandibular second molar during mandibular arch distalization. METHODS: The study population included 67 individuals who had undergone cone beam computed tomography (CBCT) (34 male and 33 female; mean age: 23.9 ± 2.72 years). The total ridge width, alveolar housing width, and root width were measured to evaluate the buccolingual limit. The space distal to the molar root represented the mesiodistal limit. The influence of sex, right versus left side, root-contact condition, malocclusion category, and presence of wisdom teeth were evaluated. RESULTS: The rate of cortical contact was 49.3% before any orthodontic movement. No significant differences were observed in the alveolar width according to sex (male vs female), side assessed (right vs left), wisdom teeth (present vs absent), or malocclusion category. The ridge width and the alveolar width were smaller in the contact group than in the non-contact group (P < 0.01). The group with wisdom teeth showed a larger available distalization distance, but a significant difference was observed only near the alveolar crest. CONCLUSIONS: Both ridge width and available distalization distance were limiting factors for mandibular teeth distalization. For cases in which whole-arch distalization is planned, CBCT is recommended before treatment, especially for non-extraction treatment. This approach ensures safe and predictable tooth movement.

A novel semi-mechanistic tumor growth fraction model for translation of preclinical efficacy of anti-glypican 3 antibody drug conjugate to human.

The growing fraction (GF) of tumor has been reported as one of the predictive markers of the efficacy of chemotherapeutics. Therefore, a semi-mechanistic model has been developed that describes tumor growth on the basis of cell cycle, allowing the incorporation of the GF of a tumor in pharmacokinetic/pharmacodynamic (PK/PD) modeling. Efficacy data of anti-glypican 3 (GPC3) antibody drug conjugate (ADC) in a hepatocellular carcinoma (HCC) patient derived xenograft (PDX) model was used for evaluation of this proposed model. Our model was able to describe the kinetics of growth inhibition of HCC PDX models following treatment with anti-GPC3 ADC remarkably well. The estimated tumurostatic concentrations were used in tandem with human PKs translated from cynomolgus monkey for prediction of the efficacious dose. The projected efficacious human dose of anti-GPC3 ADC was in the range 0.20-0.63 mg/kg for the Q3W dosing regimen, with a median dose of 0.50 mg/kg. This publication is the first step in evaluating the applicability of GF in PK/PD modeling of ADCs. The authors are hopeful that incorporation of GF will result in an improved translation of the preclinical efficacy of ADCs to clinical settings and thereby better prediction of the efficacious human dose.

Recognizing the peak bone mass (age 30) as a cutoff point to achieve the success of orthodontic implants.

The aim of present study was to investigate the critical risk factor (age 30: peak bone mass) to evaluate the success of orthodontic implants. A total of 426 orthodontic implants were placed in 270 patients as orthodontic anchorages. Data were analyzed according to patient's characteristics, location of placement, implant categories, and orthodontic force. The young patients were the age ≤ 30 years and the older patients were the age > 30 years. Statistical analysis was performed and a p value < 0.05 was considered to indicate statistical significance. The Chi-square or Fisher exact test was used depending on sample sizes. The null hypothesis was no statistically significant correlation between age ≤ 30 years and age > 30 years. The overall success rate (with and without predrill) was 89.2%. The success rate of orthodontic implants was significantly larger in younger patients (89.9%) than in older patients (76.1%). Recognizing age-related factor in the success rates, older patient (> 30 years) were significant lower than young patients (≤ 30 years) in the gender (female and male), malocclusion (Class II), facial pattern (ortho and hyperdivergent), location (infrazygomatic crest), jaw (maxilla), side (right), material (titanium and stainless), length (9 mm and 10 mm), diameter (2 mm), load (< 3 weeks), and force (intrusion). Therefore, the null hypothesis was rejected. Age 30 is a cutoff point to achieve the success of orthodontic implants. The success rates of older patients (age > 30 years) were significant lower than young patients (age ≤ 30 years), especially in female.