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There are increased opportunities in oncology clinics to identify multiple pancreatic ductal adenocarcinomas (PDAC) that co‐occur simultaneously or arise metachronously in the pancreatic parenchyma, yet their pathogenesis remains elusive. We hypothesized that two potential pathways, multicentric carcinogenesis and intrapancreatic metastasis, might contribute to forming multiple PDAC. Among 241 resected cases, we identified 20 cancer nodules from nine patients with multiple PDAC (six with synchronous PDAC, one with metachronous PDAC, and two with both synchronous and metachronous PDAC). Integrated clinical, pathological, and mutational analyses, using TP53 and SMAD4 immunostaining and targeted next‐generation sequencing of 50 cancer‐related genes, were conducted to examine the intertumor relationships. Four of the nine patients were assessed as having undergone multicentric carcinogenesis because of heterogeneity of immunohistochemical and/or mutation characteristics. In contrast, tumors in the other five patients showed intertumor molecular relatedness. Two of these five patients, available for matched sequencing data, showed two or more shared mutations. Moreover, all the smaller nodules in these five patients showed identical TP53 and SMAD4 expression patterns to the corresponding main tumors. Consequently, these five patients were considered to have undergone intrapancreatic metastasis. None of the five smaller nodules arising from intrapancreatic metastasis was accompanied by pancreatic intraepithelial neoplasia, and three of them were tiny (≤1mm). Patients whose tumors resulted from intrapancreatic metastasis appeared to have higher disease stages and worse outcome than those with tumors from multicentric carcinogenesis. Our results provide insight into pancreatic carcinogenesis, showing that the development of multiple PDAC involves distinct evolutionary paths that potentially affect patient prognosis. Integrated clinical, pathological, and mutational analyses on multiple pancreatic cancers identify distinct evolutionary paths: multicentric carcinogenesis and intrapancreatic metastasis.

Objectives Wilson disease (WD) is a rare autosomal recessive genetic disorder associated with various mutations in the ATP7B gene and leads to significant disability or death if untreated. Early diagnosis and proper therapy usually predict a good prognosis, especially in pre‐symptomatic WD. Genetic testing provides an accurate and effective diagnostic method for the early diagnosis of WD. Methods We recruited 18 clinically diagnosed WD patients from 16 unrelated families and two independent individuals. The next‐generation sequencing of the ATP7B gene was performed. The 293T cell lines were divided into wild‐type (WT) ATP7B and mutated ATP7B groups. Cell proliferation was determined by Cell Counting Kit‐8 (CCK‐8) assay and apoptosis was detected by Annexin V/propidium iodide (PI) assays. Results Pedigree analysis showed that compound heterozygous variants (17/18, 94.44%) were present in the majority of WD patients. A total of 33 ATP7B gene variants were identified, including three variants with uncertain significance (VUS) [two splice mutations (c.51+2T>G, c.1543+40G>A) and one frameshift mutation (c.3532_3535del)]. The CCK‐8 and apoptosis assays demonstrated that the VUS of ATP7B could significantly affect the transportation of copper. Conclusions The study revealed genetic defects of 16 Chinese families and two independent individuals with WD, which enriched the mutation spectrum of the ATP7B gene worldwide and provided valuable information for studying the mutation types of ATP7B in the Chinese populations. Genetic testing in WD patients is necessary to shorten the time to initiate therapy, reduce damage to the liver and improve the prognosis. Wilson disease (WD), is a rare autosomal recessive inherited disease involving copper metabolism disturbance due to the mutations of ATP7B gene that encodes the P‐type ATPase. Early diagnosis and intervention of WD are critical to limit disease progression, and the disease is lethal if the patients is not treated early. The detection of ATP7B gene mutation may be powerful tools for WD accurately diagnosis, especially for patients who have mild to moderate disease. Therefore, we recruited 18 WD Chinese patients and their 43 first‐degree relatives from 16 families and 2 independent individuals for DNA sequencing to systematically analyze the genotypes of Chinese WD patients. We also conducted a series of experiments to elucidation of possible functional consequences of these ATP7B mutations. A total of 33 ATP7B gene variants were identified, including three variants with uncertain significance (VUS) [two splice mutations (c.51+2T>G, c.1543+40G>A) and one frameshift mutation (c.3532_3535del)]. The CCK‐8 and apoptosis assays demonstrated that the VUS of ATP7B could significantly affect the transportation of copper. Our study enriches the mutation spectrum of the ATP7B gene worldwide and provides valuable reference data for studying the mutation type and genetic mode of ATP7B in the Chinese population.

Background This study aimed to investigate the validity of pathological diagnosis of early CRC (E‐CRC) from the genetic background by comparing data of E‐CRC to colorectal adenoma (CRA) and The Cancer Genome Atlas (TCGA) on advanced CRC (AD‐CRC). Methods TCGA data on AD‐CRC were studied in silico, whereas by next‐generation sequencer, DNA target sequences were performed for endoscopically obtained CRA and E‐CRC samples. Immunohistochemical staining of mismatch repair genes and methylation of MLH1 was also performed. The presence of oncogenic mutation according to OncoKB for the genes of the Wnt, MAPK, and cell‐cycle–signaling pathways was compared among CRA, E‐CRC, and AD‐CRC. Results The study included 22 CRA and 30 E‐CRC lesions from the Chiba University Hospital and 212 AD‐CRC lesions from TCGA data. Regarding the number of lesions with driver mutations in the Wnt and cell‐cycle–signaling pathways, E‐CRC was comparable to AD‐CRC, but was significantly greater than CRA. CRA had significantly more lesions with a driver mutation for the Wnt signaling pathway only, versus E‐CRC. Conclusions In conclusion, the definition of E‐CRC according to the Japanese criteria had a different genetic profile from CRA and was more similar to AD‐CRC. Based on the main pathway, it seemed reasonable to classify E‐CRC as adenocarcinoma. The pathological diagnosis of E‐CRC according to Japanese definition seemed to be valid from a genetic point of view. Regarding the number of lesions with driver mutations in the Wnt and cells‐cycle–signaling pathways, Early CRC was comparable to Advanced CRC. It seemed reasonable to classify Early CRC as adenocarcinoma.

Chromosomal copy number aberrations (CNAs) are a hallmark of bladder cancer and a useful target for diagnostic explorations. Here we constructed a low-coverage whole-genome sequencing method for the detection of CNAs in urine sediment DNA from patients with bladder cancer. We conducted a prospective study using urine sediment samples from 65 patients with bladder tumors, including 54 patients with bladder cancer and 11 patients with benign bladder tumors. Forty-three healthy individuals were included as normal controls. DNA was extracted from urine sediments and analyzed by low-coverage whole-genome sequencing to compare differences in CNAs among these three groups. CNAs are defined by arbitrary R values (normal range ± 2). When these values exceed ± 0.2 of normal range, gain/duplication or loss/deletion are suspected. With this method, CNAs were detected in 39 of 51 patients with bladder cancer, 2 of 10 patients with benign bladder tumors, and 8 of 39 normal controls. The lengths of DNA deletion and duplication were significantly larger in patients with bladder cancer than in patients with benign tumors or normal controls (P < 0.05). Bladder cancer duplicate CNAs mainly occurred on chromosomes 1q, 5p, 6p, 7p, 8q, and 13q, while deletions mainly occurred on 2q, 8p, 9q, 9p, and 11p. Those regions contained bladder cancer tumor-related genes, such as STK3, COX6C, SPAG1, CDKAL1, C9orf53, CDKN2A, CDKN2B, MIR31, and IFNA1. The number of CNAs detected in urine sediment DNA during the follow-up period was significantly reduced. Our sequencing method is highly sensitive and can detect a minimal chromosome repeat/microdeletion change of 0.15 Mb. The use of 0.1~0.3× low-coverage whole-genome sequencing can be used to detect bladder cancer CNAs in urine sediment DNA. This method provides a promising method for noninvasive diagnosis of bladder cancer, but still needs further verification in a larger sample size.

Background Anaplastic lymphoma kinase (ALK) fusion genes are found in 3%–5% of non‐small cell lung cancers (NSCLCs). ALK inhibitors show a very high response rate to ALK‐positive NSCLCs. However, the emergence of acquired resistance is inevitable. In this study, we investigated the drugs for overcoming resistance especially compound mutations after sequential treatment with crizotinib, alectinib, and lorlatinib. Method Next‐generation sequencing (NGS) and Sanger sequencing were performed on a liver biopsy tissue obtained from a clinical case. Ba/F3 cells in which mutant EML4‐ALK were overexpressed were prepared, and cell viability assay and immunoblotting were performed to check the sensitivity of five independent ALK inhibitors. Results I1171S + G1269A double mutation was identified by NGS and Sanger sequencing on a liver biopsy tissue from a patient who relapsed on lorlatinib treatment. Ceritinib and brigatinib—but not other ALK inhibitors—were active against the compound mutations in the cell line model. Conclusions With the sequential ALK inhibitors treatment, cancer cells accumulate new mutations in addition to mutations acquired previously. The identified compound mutation (I1171S + G1269A) was found to be sensitive to ceritinib and brigatinib, and indeed the patient's tumor partially responded to ceritinib. Key points ALK compound mutation was found in a clinical sample that was resistant to lorlatinib after sequential ALK‐tyrosine kinase inhibitor (TKI) treatment. Ceritinib and brigatinib are potential overcoming drugs against ALK I1171S + G1269A double mutation.

The purpose of the paper is to explore the problem of modeling technological assembly process, particularly generating assembly sequence for parts and machinery sets. A new computer program Msassembly is introduced. The program was invented by the authors on the basis of an algorithm for determining assembly sequence for parts and machinery sets. The algorithm is based on hypergraphs and directed graphs, as well as on assessment of transitions between assembly states. The principles of operation of Msassembly are presented on the example of modelling the assembly sequence of a ball joint. At the end of the paper, research findings are submitted.

Introductions When tumor tissue samples are unavailable to search for actionable driver mutations, archival cytology samples can be useful. We investigate whether archival cytology samples can yield reliable genomic information compared to corresponding formalin‐fixed paraffin‐embedded (FFPE) tumor samples. Patients and Methods Pretreatment class V archival cytology samples with adequate tumor cells were selected from 172 lung cancer patients. The genomic profiles of the primary lung tumors have been analyzed through whole‐exome regions of 53 genes. We compared the genomic profiles based on the oncogenicity and variant allele frequency (VAF) between the archival cytology and the corresponding primary tumors. We also analyzed the genomic profiles of serial cytological samples during the treatment of EGFR‐TKI. Results A total of 43 patients were analyzed with the paired samples for DNA mutations and other three patients were analyzed for their fusion genes. A total of 672 mutations were detected. Of those, 106 mutations (15.8%) were shared with both samples. Sixty of seventy‐seven (77.9%) shared mutations were oncogenic or likely oncogenic mutations with VAF ≧10%. As high as 90% (9/10) actionable driver mutations and ALK and ROS1 fusion genes were successfully detected from archival cytology samples. Sequential analysis revealed the dynamic changes in EGFR‐TKI‐resistant mutation (EGFR p.T790M) during the course of treatment. Conclusion Archival cytology sample with adequate tumor cells can yield genetic information compared to the primary tumors. If tumor tissue samples are unavailable, we can use archival cytology samples to search for actionable driver mutations. Limited quantity of tumor tissue is a matter to obtain full genomic information in lung cancer. Archival cytology samples can yield genetic information of the correspondent primary tumor. 90% targetable driver mutations were successfully detected from archival cytology samples.

We report the case of an 85‐year‐old man who was surgically diagnosed with lung adenocarcinoma (pT2aN1M0 stage IIA). He was administered platinum combination chemotherapy as first‐line treatment for lung cancer recurrence. The patient's pleural fluid sample was obtained and analysed using a next‐generation sequencer, which demonstrated the presence of mesenchymal–epithelial transition gene (MET) exon 14 skipping mutations. As the patient developed progressive disease after receiving first‐line chemotherapy, crizotinib was administered as the second‐line treatment. The treatment was effective, and the patient had a stable disease for 7 months. This case suggests that crizotinib is effective against non‐small cell lung cancer with MET exon 14 alterations. Non‐small cell lung cancer patients with mesenchymal–epithelial transition gene exon 14 skipping mutation were treated with crizotinib. The treatment was effective, and the patient had stable disease for 7 months.

Computational models starting from large ensembles of evolutionarily related protein sequences capture a representation of protein families and learn constraints associated to protein structure and function. They thus open the possibility for generating novel sequences belonging to protein families. Protein language models trained on multiple sequence alignments, such as MSA Transformer, are highly attractive candidates to this end. We propose and test an iterative method that directly employs the masked language modeling objective to generate sequences using MSA Transformer. We demonstrate that the resulting sequences score as well as natural sequences, for homology, coevolution, and structure-based measures. For large protein families, our synthetic sequences have similar or better properties compared to sequences generated by Potts models, including experimentally validated ones. Moreover, for small protein families, our generation method based on MSA Transformer outperforms Potts models. Our method also more accurately reproduces the higher-order statistics and the distribution of sequences in sequence space of natural data than Potts models. MSA Transformer is thus a strong candidate for protein sequence generation and protein design.

Sign languages are multi-channel visual languages, where signers use a continuous 3D space to communicate. Sign language production (SLP), the automatic translation from spoken to sign languages, must embody both the continuous articulation and full morphology of sign to be truly understandable by the Deaf community. Previous deep learning-based SLP works have produced only a concatenation of isolated signs focusing primarily on the manual features, leading to a robotic and non-expressive production. In this work, we propose a novel Progressive Transformer architecture, the first SLP model to translate from spoken language sentences to continuous 3D multi-channel sign pose sequences in an end-to-end manner. Our transformer network architecture introduces a counter decoding that enables variable length continuous sequence generation by tracking the production progress over time and predicting the end of sequence. We present extensive data augmentation techniques to reduce prediction drift, alongside an adversarial training regime and a mixture density network (MDN) formulation to produce realistic and expressive sign pose sequences. We propose a back translation evaluation mechanism for SLP, presenting benchmark quantitative results on the challenging PHOENIX14T dataset and setting baselines for future research. We further provide a user evaluation of our SLP model, to understand the Deaf reception of our sign pose productions.