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Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®.

Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®.

Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix (R). Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix (R).

Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®. Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®.

The phase 3 KEYNOTE-177 study evaluated pembrolizumab versus chemotherapy with or without bevacizumab or cetuximab in patients with newly diagnosed, microsatellite-instability-high (MSI-H)/mismatch-repair-deficient (dMMR) metastatic colorectal cancer (mCRC). Primary endpoints were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints were overall response rate (ORR) per RECIST v1.1 by BICR and safety. Here, we report results from the post hoc analysis of patients who were enrolled in Asia from the final analysis (FA) of KEYNOTE-177. A total of 48 patients from Japan, Korea, Singapore, and Taiwan (pembrolizumab, n =?22; chemotherapy, n =?26) were included. At FA, median time from randomization to data cutoff (February 19, 2021) was 45.3 (range 38.1?57.8) months with pembrolizumab and 43.9 (range 36.6?55.1) months with chemotherapy. Median PFS was not reached (NR; 95% confidence interval [CI] 1.9 months?NR) with pembrolizumab versus 10.4 (95% CI 6.3?22.0) months with chemotherapy (hazard ratio [HR] 0.56, 95% CI 0.26?1.20). Median OS was NR (range 13.8 months?NR) versus 30.0 (14.7?NR) months (HR 0.65, 95% CI 0.27?1.55) and ORR was 50% (95% CI 28?72) versus 46% (95% CI 27?67). Grade 3/4 treatment-related adverse events (TRAEs) were reported by two patients (9%) in the pembrolizumab arm and 20 (80%) in the chemotherapy arm. Immune-mediated adverse events or infusion reactions were reported by six patients (27%) and 10 patients (40%), respectively. No deaths due to TRAEs occurred. These data support first-line pembrolizumab as a standard of care for patients from Asia with MSI-H/dMMR mCRC. ClinicalTrials.gov identifier: NCT02563002. FUNDING INFORMATION: The study was designed under the responsibility of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, in conjunction with the steering committee. The study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Pembrolizumab was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. All authors had full access to all of the data in the study and had final responsibility for the decision to submit for publication. ACKNOWLEDGMENTS: This work was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. We thank the patients and their families and caregivers for participating in this trial, and all investigators and site personnel. Medical writing and editorial assistance were provided by Jemimah Walker, PhD, Mehak Aggarwal, PharmD, and Doyel Mitra, PhD, CMPP, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Osteoporosis is a disease characterized by a decrease in bone mineral density, thereby increasing the risk of sustaining a fragility fracture. Most medical therapies are systemic and do not restore bone in areas of need, leading to undesirable side effects. Injectable hydrogels can locally deliver therapeutics with spatial precision, and this study reports the development of an injectable hydrogel containing a peptide mimic of bone morphogenetic protein-2 (BMP-2). To create injectable hydrogels, hyaluronic acid was modified with norbornene (HANor) or tetrazine (HATet) which upon mixing click into covalently crosslinked Nor-Tet hydrogels. By modifying HANor macromers with methacrylates (Me), thiolated BMP-2 mimetic peptides were immobilized to HANor via a Michael addition reaction, and coupling was confirmed with 1H NMR spectroscopy. BMP-2 peptides presented in soluble and immobilized form increased alkaline phosphatase (ALP) expression in MSCs cultured on 2D and encapsulated in 3D Nor-Tet hydrogels. Injection of bioactive Nor-Tet hydrogels into hollow intramedullary canals of Lewis rat femurs showed a local increase in trabecular bone density as determined by micro-CT imaging. The presented work shows that injectable hydrogels with immobilized BMP-2 peptides are a promising biomaterial for the local regeneration of bone tissue and for the potential local treatment of osteoporosis.

We aimed to investigate the dynamic changes of gene expression profiles and immune microenvironment linked to resistance to cetuximab-based treatments in patients with metastatic colorectal cancer (mCRC). A total of 106 patients with RAS-wild type mCRC who were treated with cetuximab-based treatments were included as the study population. RNA-sequencing and multiplexed immunohistochemistry were performed using paired or unpaired pre-treatment and post-treatment tumor tissues. Differentially expressed gene analysis of paired pre-treatment and post-treatment tumor tissues that develop acquired resistance (AR) identified the AR signature. Gene ontology analysis of the AR signature indicated enrichment of immune-related pathway genes. Among the immune subsets whose abundance was estimated by CIBERSORT, M2 macrophages showed the most prominent positive correlation with the expression of the AR signature. Among the post-treatment samples, progressive disease (PD) tumors showed a significantly higher abundance of M2 macrophages compared to non-PD tumors. These findings were validated by multiplexed immunohistochemistry analysis: the density of CD68+CD206+ M2 macrophages significantly increased at the time of PD following cetuximab-based treatment, whereas it did not consistently change in the tumor pairs of non-PD. In conclusion, a dynamic increase of M2 macrophages is associated with disease progression during cetuximab-based treatment of mCRCs. Targeting M2 macrophages is a promising immunotherapeutic strategy in this clinical context.

Supplemetary Material for Clinicogenomic Characteristics and Treatment of Young-Onset Colorectal Cancer Patients Treated With Palliative Therapy in Real-World Practice by Hyehyun Jeong, Eunjung Lee, Deokhoon Kim, Jihun Kim, Sun Young Kim, Yong Sang Hong, Tae Won Kim1, and Jeong Eun Kim in Cancer Control

Additional file 1. Supplementary Table 1. Characteristics of patients.

Additional file 15 Supplementary Fig. 14. (A) Screening of synthetic lethality target of FBXW7 mutation using the DepMap dataset. (B, C) Sensitivity of the FH535 molecule in colorectal cancer cell lines with FBXW7 mutation (Wilcoxon rank sum test).

Additional file 3 Supplementary Fig. 2. (A) Spearman’s correlation of variant allele fractions (VAFs) between organoid RNA and organoid DNA. (B) Characteristics of variants detected in organoid DNA and not in tissue RNA; the variants detected in organoids only were associated with low read depth in primary tissue sequences or subclonal events based on organoid sequencing (Wilcoxon rank-sum test). (C) Spearman’s correlation of VAFs between organoid DNA and tissue RNA. (D) Spearman’s correlation of VAF in each gene between organoid DNA and tissue RNA.

Additional file 10 Supplementary Fig. 9. (A) Classification of the TIM using primary cancer tissue. (B) Immune cell types from CIBERSORT based on the TIM class (Wilcoxon rank-sum test). (C) Immune cell types using MCP score based on the TIM class (Kruskal Wallis test). (D) Validation of the exhausted TIM class based on CD8+ T cell exhaustion score using GSVA analysis (Wilcoxon rank-sum test). (E) Significant correlation of HLA-I expression in CCOs versus primary tumor tissues (Spearman correlation test). (F) Fraction of copy number variation (CNV) based on the TIM class (Kruskal Wallis test). (G) Fusion number based on the TIM class (Kruskal Wallis test). TIM, tumor immune microenvironment; CCO, colorectal cancer organoid.

Additional file 13 Supplementary Fig. 12. (A) Enrichment of KRAS (biallelic) mutations in tumors with decreased CD8+ T cells (10,000 randomly permutated p values and one-sided Wilcoxon rank sum test). (B) Increased frequency of KRAS biallelic mutation in non-immunogenic (immuno-desert TIM) tumors (Fisher’s exact test). (C, D) KRAS mutation status and TIM. (E) Characteristics of gene expression and infiltrating immune cell types based on the KRAS mutation status (Spearman’s correlation test). TIM, tumor immune microenvironment.

Additional file 6 Supplementary Fig. 5. (A) Ki-67 immunohistochemistry in the primary tumor tissues and its interpretation by a pathologist and by image analysis. (B) Significant correlation of the Ki-67 proliferation index between the pathologist’s result and image analysis. (C) No correlations in Ki-67 mRNA expression between bulk primary tissues including tumor microenvironment and cancer cells and CCOs. (D) Comparison of our molecular subgrouping and CMS classification in CCOs (Chi-squared test). CCO, colorectal cancer organoid.

Additional file 11 Supplementary Fig. 10. No significant differential gene expression in organoids based on the tumor immune microenvironment (TIM) class of primary tissues (FDR q > 0.25 by one-way ANOVA test).

Additional file 12 Supplementary Fig. 11. (A) Pathway analysis using tissue RNA sequence data based on the tumor immune microenvironment (TIM) class. (B, C) Significance of Wnt/β-catenin signaling pathway in the non-immunogenic group using GSVA analysis (Wilcoxon rank-sum test). (D) APC mutation status based on the TIM class. (E) Significance of biallelic APC mutation and TIM class (Fisher’s exact test). (F) Expression of target genes belonging to the Wnt/beta-catenin pathway (Wilcoxon rank-sum test).

As a part of the American healthcare system's response to the Coronavirus Disease 2019 (COVID-19) global pandemic, the Association of American Medical Colleges recommended that medical schools temporarily remove students from clinical settings and transition to an entirely online learning environment. This posed an unprecedented challenge to students in the clinical years of their medical education. To address this unexpected shift, we modified an in-person workshop to teach orthopaedic trauma basics to 5-week virtual course for third year medical students from several schools in New Jersey and Pennsylvania. We focused on moving students toward the Level-1 milestones for basic fracture care with a combination of weekly lectures and virtual interactive small group sessions, all conducted via WebEx and proctored by an orthopaedic attending or resident. The course was well received by students. Participation in the course was completely voluntary and did not count for credit at any institution. The course was valuable to students because the students who registered chose to fully complete the 5-week course and no student missed more than one small group session. On a postcourse survey, 100% of students said they would be highly likely to recommend the course to a future student, and the average rating for educational value of the course was 4.98 of 5. Given the current limitations in clinical education because of the COVID-19 pandemic, our course provides a reasonable alternative to clinical experience and prepares students with the knowledge and many of the skills that are required to succeed as orthopaedic interns. Furthermore, the success of our course this year suggests that similar programing may be a useful adjunct to clinical experiences even when it is safe to return to more traditional medical school scheduling.

Additional file 2 Supplementary Fig. 1. (A) Histology and immunohistochemistry of the established CCOs and the corresponding primary tumors. (B) Distribution of variant allele fraction (VAF) of detected variants in the MSI-high group and the MSI-low/MSS group. CCO, colorectal cancer organoid; MSI, microsatellite instability; MSS, microsatellite stable; H&E, hematoxylin and eosin.

Additional file 16 Supplementary Fig. 15. (A) FH535 induced cell death and destroyed the organoid structure in the two CCOs with FBXW7 mutation (AMC-17CT-019 and AMC-17CT-048). (B) Sensitivity of the FH535 molecule in CCOs with FBXW7 mutation (Wilcoxon-rank sum test). (C) Sensitivities of various WNT signaling drugs targets showing non-significant responses to drugs targeting WNT pathways in colorectal cancer cells with FBXW7 mutation. (D) CCOs with FBXW7 mutation also showed non-significant responses to ICG-001, which also targets the WNT/β-catenin pathway, suggesting that FH535 has a different mechanism action in colorectal cancers harboring the FBXW7 mutation. CCO, colorectal cancer organoid.

Additional file 5 Supplementary Fig. 4. (A) Spearman’s correlation coefficient matrix of CCOs versus primary tumor tissues. (B) Total immune score and stromal score of CCOs versus primary tumor tissues. (C) Genes that are differentially expressed between CCOs and primary tumor tissues. (D) Spearman correlation of the expression of differentiation or stem cell markers in CCOs versus primary tumor tissues. CCO, colorectal cancer organoid; TIM, tumor immune microenvironment.

Additional file 4 Supplementary Fig. 3. (A) Profiles of copy number variations with microsatellite instability (MSI) information in the 87 CCOs. (B) Circos plot of the detected fusions in the 87 CCOs. (C) HLA class I molecular typing and its frequency in 87 CCOs. (D) Frequency of the HLA supertype in 87 CCOs. CCO, colorectal cancer organoid.

Additional file 14 Supplementary Fig. 13. (A) Frequency of TP53 gain-of-function (GOF) mutation based on the tumor immune microenvironment (TIM) class, showing a high frequency of TP53 GOF mutations in the Desert group (p = 0.033, Fisher’s exact test). (B) Association between TP53 GOF mutations and decreased CD8+ T cell (10,000 random permutation test and Spearman’s correlation test). (C) Tendency for the exclusive occurrence of TP53 and KRAS mutation. (D) Enriched unfolded protein response pathway (GSVA score) in the immune-exhausted group (Wilcoxon rank-sum test).

Additional file 8 Supplementary Fig. 7. (A) Prognostic impact of gene expression in HLA class II in CCOs. (B) Patient survival based on HLA class II expression level using immunohistochemistry (IHC) in cancer cells from primary tissue (log-rank test).

BackgroundNo therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C.MethodsWe conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.ResultsA total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma.ConclusionsSotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).

Dendrobium genus was reported to contain alkaloid, bibenzyl, fluorenone, phenanthrene, sesquiterpenoid, and phenolic acid, which have biological properties. Our aim was to investigate the protective effect of an aqueous extract of Dendrobium nobile Lindl (DNE) against cisplatin-induced acute kidney injury (AKI). Quantification of four phenolic acids (4-hydroxybenzoic, vanillic, syringic, and ferulic acid) in DNE was determined using the HPLC-photodiode array method. Possible protective effects against cisplatin-induced nephrotoxicity were investigated using in-vitro (porcine kidney cells; PK15) and in-vivo (Sprague Dawley rat) studies. Among the four phenolic acids, 4-hydroxybenzoic acid was the most abundant. In the in-vitro study, DNE pretreatment partially prevented decrement of viability after cisplatin (15 μg/mL) treatment in the both the MTT and crystal violet assays. Moreover, relative to cells treated with cisplatin alone, the DNE (50 μg/mL)-pretreated cells showed a ~30% increase in glutathione levels and a ~15% decrease in reactive oxygen species. The expression of p53 was also decreased in DNE-pretreated cells (p < 0.05). In the in-vivo study, the renal function index decreased to normal levels in groups pretreated with DNE (300 and 500 mg/kg); histopathological alterations and apoptotic cells were also attenuated. Moreover, DNE pretreatment ameliorated oxidative stress in the kidney, as evidenced by recovered antioxidant enzyme levels and decreased lipid peroxidation. DNE, by decreasing oxidative stress, was found to have a protective effect against cisplatin-induced nephrotoxicity. Based on these findings, DNE might be beneficial when treating cisplatin-induced AKI.

We present a case of the giant-cell tumor of bone in the scaphoid of a 17-year-old female. Imaging revealed an expansile lytic lesion of her scaphoid, and the diagnosis was confirmed with open biopsy. She was treated with curettage and iliac crest bone graft, in an effort to spare reconstruction of her wrist. After one year, she developed increasing tightness and pain. Local recurrence was apparent on radiographs, and CT revealed increased lucency with bony destruction in the area of prior excision. She was successfully treated, without recurrence to date, with complete scaphoid excision and a four-corner wrist fusion. Local recurrence of the giant-cell tumor of bone is high, especially in carpal bones. When treating patients with advanced lesions, more aggressive initial options should be considered.

Supplemental Material, DS11_TPX_10.11770192623318813143 for Comparison of the Class Effects of Antisense Oligonucleotides in CByB6F1-Tg(HRAS)2Jic and CD-1 Mice by Tae-Won Kim, Chris N. Papagiannis, Laura S. Zwick, Jeffery A. Engelhardt, Christine M. Hoffmaster, Noah M. Post, John E. Matson, Jill A. Hsiao, Sebastien A. Burel, and Scott P. Henry in Toxicologic Pathology

Supplemental Material, DS13_TPX_10.11770192623318813143 for Comparison of the Class Effects of Antisense Oligonucleotides in CByB6F1-Tg(HRAS)2Jic and CD-1 Mice by Tae-Won Kim, Chris N. Papagiannis, Laura S. Zwick, Jeffery A. Engelhardt, Christine M. Hoffmaster, Noah M. Post, John E. Matson, Jill A. Hsiao, Sebastien A. Burel, and Scott P. Henry in Toxicologic Pathology

Supplemental Material, DS9_TPX_10.11770192623318813143 for Comparison of the Class Effects of Antisense Oligonucleotides in CByB6F1-Tg(HRAS)2Jic and CD-1 Mice by Tae-Won Kim, Chris N. Papagiannis, Laura S. Zwick, Jeffery A. Engelhardt, Christine M. Hoffmaster, Noah M. Post, John E. Matson, Jill A. Hsiao, Sebastien A. Burel, and Scott P. Henry in Toxicologic Pathology

Supplemental Material, DS14_TPX_10.11770192623318813143 for Comparison of the Class Effects of Antisense Oligonucleotides in CByB6F1-Tg(HRAS)2Jic and CD-1 Mice by Tae-Won Kim, Chris N. Papagiannis, Laura S. Zwick, Jeffery A. Engelhardt, Christine M. Hoffmaster, Noah M. Post, John E. Matson, Jill A. Hsiao, Sebastien A. Burel, and Scott P. Henry in Toxicologic Pathology

Supplemental Material, DS8_TPX_10.11770192623318813143 for Comparison of the Class Effects of Antisense Oligonucleotides in CByB6F1-Tg(HRAS)2Jic and CD-1 Mice by Tae-Won Kim, Chris N. Papagiannis, Laura S. Zwick, Jeffery A. Engelhardt, Christine M. Hoffmaster, Noah M. Post, John E. Matson, Jill A. Hsiao, Sebastien A. Burel, and Scott P. Henry in Toxicologic Pathology

Supplemental Material, DS7_TPX_10.11770192623318813143 for Comparison of the Class Effects of Antisense Oligonucleotides in CByB6F1-Tg(HRAS)2Jic and CD-1 Mice by Tae-Won Kim, Chris N. Papagiannis, Laura S. Zwick, Jeffery A. Engelhardt, Christine M. Hoffmaster, Noah M. Post, John E. Matson, Jill A. Hsiao, Sebastien A. Burel, and Scott P. Henry in Toxicologic Pathology

Supplemental Material, DS12_TPX_10.11770192623318813143 for Comparison of the Class Effects of Antisense Oligonucleotides in CByB6F1-Tg(HRAS)2Jic and CD-1 Mice by Tae-Won Kim, Chris N. Papagiannis, Laura S. Zwick, Jeffery A. Engelhardt, Christine M. Hoffmaster, Noah M. Post, John E. Matson, Jill A. Hsiao, Sebastien A. Burel, and Scott P. Henry in Toxicologic Pathology

Analysis of sleep for the diagnosis of sleep disorders such as Type-1 Narcolepsy (T1N) currently requires visual inspection of polysomnography records by trained scoring technicians. Here, we used neural networks in approximately 3,000 normal and abnormal sleep recordings to automate sleep stage scoring, producing a hypnodensity graph - a probability distribution conveying more information than classical hypnograms. Accuracy of sleep stage scoring was validated in 70 subjects assessed by six scorers. The best model performed better than any individual scorer (87% versus consensus). It also reliably scores sleep down to 5 instead of 30 second scoring epochs. A T1N marker based on unusual sleep-stage overlaps achieved a specificity of 96% and a sensitivity of 91%, validated in independent datasets. Addition of HLA-DQB1*06:02 typing increased specificity to 99%. Our method can reduce time spent in sleep clinics and automates T1N diagnosis. It also opens the possibility of diagnosing T1N using home sleep studies., 21 pages (not including title or references), 6 figures (1a - 6c), 6 tables, 5 supplementary figures, 9 supplementary tables

Supplemental Digital Content is available in the text, Good oncologic outcomes, demonstrated by a complete pathologic response after preoperative chemoradiotherapy (PCRT), have led to local excision (LE) in selected patients with rectal cancer. We evaluated the oncologic safety of LE compared with total mesorectal excision (TME) in patients with ypT0-T1 rectal cancer. A retrospective review of 304 patients who underwent PCRT, followed by LE or TME, for ypT0-T1 rectal cancer was performed. Propensity scores were computed and used to match groups (LE:TME = 1:1), and analysis of disease-free survival (DFS) and overall survival (OS) was made by comparing patients who underwent LE or TME. Prognostic factors of relapse were analyzed for all patients. Tumor categories were ypT0 in 25 (61.9%) cases, ypTis in 6 (14.3%) cases, and ypT1 in 11 (26.2%) cases for the LE group, and ypT0 in 28 (66.7%) cases, ypTis in 4 (9.5%) cases, and ypT1 in 10 (23.8%) cases for the matched TME patients. There was no significant difference between the matched LE and TME groups in relapse (4.8% and 7.14%, respectively; P = 0.646), 5-year DFS (95.2% vs 91.6%; P = 0.33) and 5-year OS (96.6% vs 88.0%; P = 0.238). In the multivariate Cox regression analysis, tumor distance from the anal verge (hazard ratio [HR] = 0.78; 95% confidence interval (CI) = 0.616–0.992) and the tumor grade (HR = 4.29; 95% CI = 1.430–12.886) were significantly associated with the recurrence risk. LE results in oncologic outcomes that are comparable to those achieved by TME in selected patients with ypT0-T1 rectal cancer after PCRT.

The levels of several hormones fluctuate according to the light and dark cycle and are also affected by sleep, feeding, and general behavior. The regulation and metabolism of several hormones are influenced by interactions between the effects of sleep and the intrinsic circadian system; growth hormone, melatonin, cortisol, leptin, and ghrelin levels are highly correlated with sleep and circadian rhythmicity. There are also endogenous circadian mechanisms that serve to regulate glucose metabolism and similar rhythms pertaining to lipid metabolism, regulated through the actions of various clock genes. Sleep disturbance, which negatively impacts hormonal rhythms and metabolism, is also associated with obesity, insulin insensitivity, diabetes, hormonal imbalance, and appetite dysregulation. Circadian disruption, typically induced by shift work, may negatively impact health due to impaired glucose and lipid homeostasis, reversed melatonin and cortisol rhythms, and loss of clock gene rhythmicity.

The aim of this study was to explore the protective effects of Trichosanthes kirilowii ethanol extract (TKE) against cisplatin-induced acute renal failure (ARF). In the in vitro study, TKE-pretreated porcine kidney cells (PK15) exhibited enhanced cell viability after cisplatin (15 μg mL− 1) treatment in both MTT and crystal violet assays. PK15 cells pretreated with TKE (50 μg mL− 1) exhibited increased glutathione content, decreased reactive oxygen species production and ameliorated p53 expression. In vivo study, rats were administered with TKE for 4 weeks before cisplatin (5 mg kg− 1) injection. TKE (100 mg kg− 1) decreased blood urea nitrogen and creatinine levels by 24% and 47%, respectively, in comparison with cisplatin-alone group. In addition, TKE pretreatment ameliorated cisplatin-induced oxidative stress, as evidenced by increased antioxidative enzyme levels and decreased lipid peroxidation levels. Moreover, TKE pretreatment reduced histopathological alterations in the kidney with decreased apoptotic cells. Taken together, TKE might be beneficial in treating cisplatin-induced ARF.

As international trade has been increased, the competition of major ports is getting hard. The objective of this competition is that to get more cargoes, so port managements and operators are struggling to obtain cargoes. In addition the competition structure has classified several forms bemuse of specialization, integration and subdivision of port players. In this paper, therefore, we analyze the change of competition structure by port players` development characteristics. In the result of this study, competition structure is divided into five groups as among nations, among ports, among container terminal operation companies, among global container terminal operation companies and among container terminal operation companies operated by shipping companies. And they have showed not only competition but also co-operation partly in order to get strategic position

To correspond actively to international economy, shipping and port environment change, world main ports have converged in competitiveness raising. However, existing researches have been intensively analyzed port competitiveness on among ports. So, this study analyzes the relations between the main factors of port selection and port competition players: central government, port authority, terminal operators, shipping companies, etc. This paper has a purpose that each port competition player makes a competitive strategy in accordance with this study. First, this study reviewed shipping and port market`s environment change and port selection decision factors to correspond to these environment changes and on the basis of this review analyzed relativity between component port competition players and port competition factors. However, port authorities and terminal operators appeared high relevance about in side of expense, service, facilities etc. Because port authorities offered incentive to pull many shipping companies to their ports and terminal operators managed port authorities` ports. But we could deduce high relevance according to other market players` properties without port authorities and terminal operators. Port marketing strategy establishment among port competition players is available on the basis of these factors.

As North-east Chinese parts including Shanghai port grow rapidly, competition among the Far-East parts to be a hub port is getting higher, somebody has even raised a crisis of Busan port. However there are same constraints an the North-east parts such as weather aggravation and long distance from main truck routes. When we consider the competitiveness of port, weather aggravation should be considered as one of the significant factors. But previous studies have rarely examined these kinds of external factors of port operation Therefore, this study analyze constraints an the North-east Chinese parts through a survey of same national flag shipping companies and agencies of foreign shipping companies. The result shows that the mast significant constraint in the North-east ports is weather aggravation which causes problems for regular schedules of shipping, operation cast and customer service qualities etc.

Recently, 8,000TEU class containerships has started operating the shipping service and the mega-containership of over 10,000TEU is on planning. A unit cost in relation to shipping service is decreased by the bigger ship based on the economy of scale. Most of the previous studies have been performed and focused on the total operation cost from mega port to mega port. However, the purpose of this paper is to estimate economic efficiency of selected hub ports from point of view of total cost such as service cost(or operation cost), port charge and feeder cost, etc. First, the service-network of mega containerships is based on data of a domestic shipping company operated main line and economic analysis of individual scenarios on the cost and traffic when 10,000TEU mega containerships offer the services. The three scenarios presented in this paper set up the hub ports which are the port of Busan, Shanghai and Yokohama The results show that port of Busan is economically the most efficient one among others.

Traditionally, determination of the optimal containership size is the most important factor for competitiveness of shipping companies in the shipping market. Under this environment, many shipping companies and researchers have studied about it. The objective of this research is to determine the optimal containership size using a total shipping cost in the main trunk lines. Total shipping cost is calculated at the ground of capital costs, vessel operation costs, voyage costs, port charges and miscellaneous costs for `Europe-Far East`, `Far East-North America` and `Europe-Far East-North America` services. Analysis results showed that the 6,500TEU containership is an optimal size on the `Europe-Far East` and `Europe-Far East-North America` services. And the 8,200TEU containership is an optimal size on the `Far East-North America` service. Moreover, if the larger containerships over 8,200TEU class start operation afterward, it would be less competitive in the analyzed 3services.

Source: ICHE Conference Archive - https://mdi-de.baw.de/icheArchive

A 52 year-old woman presented with an incidentally detected retroperitoneal angiosarcoma and multiple hepatic metastases. After chemotherapy with weekly paclitaxel and doxorubicin, angiosarcoma had progressed rapidly. Because few chemotherapeutic options were available for her, sunitinib (37.5 mg/day, daily) as a salvage regimen was administered. Although sunitinib was interrupted after two weeks due to hematologic abnormalities, some metastatic nodules were regressed. Therefore, sunitinib was recommenced at a reduced dose (25 mg/day, daily). Serial computed tomography scans showed variable response in each tumor, however, sunitinib at least delayed tumor progression, compared to previous chemotherapy. With this case report, we suggest sunitinib may be effective against angiosarcomas. When sunitinib is administered to patients with angiosarcomas, hematologic abnormalities should be monitored frequently as severe hematologic toxicity may be caused either by sunitinib per se or angiosarcoma.