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OBJECTIVES: We hypothesized that combined treatment with extracorporeal shock wave and bone marrow-derived endothelial progenitor cells might exert enhanced protection against critical limb ischemia in rats. METHODS: Male Sprague-Dawley rats (n = 9 for laser Doppler study and n = 6 for laboratory examinations in each group) were divided into group 1 (sham control), group 2 (critical limb ischemia treated with culture medium), group 3 (critical limb ischemia treated with intramuscular bone marrow-derived endothelial progenitor cells [2.0 x 10 cells]), group 4 (critical limb ischemia treated with extracorporeal shock wave [280 impulses at 0.1 mJ/mm]), and group 5 (combined bone marrow-derived endothelial progenitor cell-extracorporeal shock wave) after critical limb ischemia induction. RESULTS: By day 21, laser Doppler showed substantially lower ratios of ischemic/normal blood flow in group 2 compared with other groups (p < .001). The protein expressions of mitochondrial cytochrome c, stromal cell-derived factor-1, C-X-C chemokine receptor type 4, vascular endothelial growth factor, and endothelial nitric oxide synthase were remarkably higher in group 5 than in groups 2 to 4, and notably higher in groups 3 and 4 than in group 2 (all p < .01). The messenger RNA expressions of proinflammatory and apoptotic biomarkers and oxidative stress were reduced in group 5 compared with groups 2 to 4, and notably lower in groups 3 and 4 than in group 2 (all p < .01). The messenger RNA expressions of anti-inflammatory and antiapoptotic biomarkers were lower in group 2 than in other groups (all p < .01). Immunofluorescent staining showed higher numbers of CD31+ stromal cell-derived factor-1+, chemokine receptor type 4+, and von Willebrand factor+ cells, and vessels in the ischemic area in group 5 than in groups 2 to 4, and in groups 3 and 4 than in group 2 (all p < .04). CONCLUSION: Combined treatment with bone marrow-derived endothelial progenitor cells and extracorporeal shock wave is superior to either bone marrow-derived endothelial progenitor cells or extracorporeal shock wave alone in improving ischemia in rodent critical limb ischemia. [ABSTRACT FROM AUTHOR]

The Openness factor was missing from the original Chinese Personality Assessment Inventory (CPAI). We used a combined emic--etic approach to generate six culturally relevant Openness scales. In Study 1, the Openness scales were added to the revised CPAI and standardized using a representative sample of 1,911 adults in China and Hong Kong. Factor analysis showed that the Openness scales merged with the original factors of the CPAI. In Study 2, 1,094 Chinese college students took the CPAI-2 and NEO-FFI. Joint factor analyses showed that four of the CPAI-2 Openness scales loaded with the Openness factor of the NEO-FFI. Implications on the meaning of Openness as a personality factor in Chinese culture were discussed. [ABSTRACT FROM AUTHOR]

Background: Although studies have compared on-treatment effectiveness of infliximab and vedolizumab in patients with ulcerative colitis (UC), there has been limited comparison of treatment sequencing and long-term patient-centred outcomes., Aim: To compare infliximab-first and vedolizumab-first strategy in biologic-naïve patients with UC., Methods: We conducted a retrospective cohort study in biologic-naïve patients with UC who were treated first with either infliximab or vedolizumab between 2015 and 2021 and followed over 30 months following initiation. Primary outcomes were the number of hospitalisations, corticosteroid courses and serious infections with either strategy (regardless of switch to alternative therapies) within 30 months. We matched the groups 1:1 through cardinality matching, and fit logistic and zero-inflated negative binomial models to compare outcomes., Results: We included 181 patients (94 vedolizumab-first and 87 infliximab-first treatment strategy). Of these, 144 were matched 1:1. There was no significant difference in the incidence of IBD-related hospitalisations (incidence rate ratio [IRR], 1.98 [95% CI, 0.64-6.10]), corticosteroid courses (0.66 [0.38-1.15]) and serious infections (5.26 [0.62-45.45]), with comparable incidence of medication switches to alternative advanced therapies (1.08 [0.42-2.81]). At 30 months, there was no difference in proportion of patients in clinical remission (69.4% vs. 76.4%; p = 0.45) and endoscopic remission (55.6% vs. 65.3%; p = 0.36)., Conclusion: In patients with UC, long-term effectiveness and safety outcomes are comparable with infliximab-first and vedolizumab-first treatment strategies at 30 months. This can help to guide selection of treatment strategies in patients with UC., (© 2024 John Wiley & Sons Ltd.)

Background: This study aimed to explore whether cytotoxin-associated gene A (CagA) can inhibit cell cycle progression by activating nuclear factor of activated T cells (NFAT) in lymphoma B cells and contribute to Helicobacter pylori eradication (HPE) responsiveness (complete remission [CR] after HPE) in gastric mucosa-associated lymphoid tissue (MALT) lymphoma., Materials and Methods: We co-cultured three B-lymphoma cell lines (MA-1, OCI-Ly3, and OCI-Ly7) with HP strains (derived from HPE-responsive gastric MALT lymphoma) and evaluated the expression patterns of CagA, phosphorylated (p)-CagA (CagA P-Tyr ), and CagA-signaling molecules, cell-cycle inhibitors, p-NFATc1 (Ser 172 ), and NFATc1 using western blotting. Furthermore, we evaluated the association between nuclear NFATc1 expression in the tumor cells of 91 patients who received first-line HPE (59 patients with HPE responsiveness and 32 without HPE responsiveness) and HPE responsiveness and CagA expression in tumor cells., Results: In HP strains co-cultured with B cell lymphoma cell lines, CagA was translocated to the nucleus through tyrosine phosphorylation (CagA P-Tyr ) and simultaneously dephosphorylated NFATc1, subsequently causing nuclear NFATc1 translocation and stimulating the expression of p-SHP-2/p-ERK/Bcl-xL. Activated NFATc1 causes G1 cell cycle retardation in both MA-1 and OCI-Ly3 cells by triggering p21 and p27 production. Nuclear NFATc1 localization was significantly associated with the presence of CagA in gastric MALT lymphomas (80% [41/51] vs. 33% [13/40]; p < 0.001) and with HPE responsiveness (73% [43/59] vs. 25% [8/32]; p < 0.001). Patients exhibiting both the presence of CagA and nuclear NFATc1 localization responded more rapidly to HPE than those without (median interval to CR, 4.00 vs. 6.00 months, p = 0.003)., Conclusions: Our findings indicated that CagA and NFATc1 cooperatively participate in the lymphomagenesis of HPE-responsive gastric MALT lymphoma., Competing Interests: Declarations Ethics approval and consent to participate The Institutional Review Board of the Research Ethics Committee of National Taiwan University Hospital (approval number: 201801030RINC) approved the study protocol, which included clinical data collection, pathological review, and molecular studies. Consent for publication All listed authors discussed results and commented on the submitted manuscript. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

There is growing evidence of the connection between variations in kinship intensity and cross-cultural differences in psychological traits. Contributing to this literature on kinship intensity, we put forward a mental model to explain the enduring connection between ancestral niche and psychological traits. Our model posits that two primary orientations or dispositions-strong-ties and weak-ties rationalities-have co-evolved with our ancestral niches to perpetuate-by internalizing and reproducing-the social structure (such as preferences for certain attitudes, values, and beliefs) of the ancestral niche. The findings from 1,291 participants across four societies-China, India, Taiwan, and the United States-support our hypothesis that strong-ties (weak-ties) rationalities, when activated, will endorse strong-tie (weak-ties) values and beliefs. This proposed model contributes to the toolbox of cultural and cross-cultural psychology in a twofold sense: First, in addition to the index of kinship intensity, it offers a measure of kin-based rationality as another predictor of psychological traits; second, it renders intelligible the niche and rationality disconnect prevalent in the globalizing era., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yeh, Terpstra Tong, Ting, Bond, Khosla, Yadav, Shukla, Liu and Sundararajan.)

The interim analysis of the CIRCULATE-Japan GALAXY observational study demonstrated the association of circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) detection with recurrence risk and benefit from adjuvant chemotherapy (ACT) in resectable colorectal cancer (CRC). This updated analysis with a 23-month median follow-up, including 2,240 patients with stage II-III colon cancer or stage IV CRC, reinforces the prognostic value of ctDNA positivity during the MRD window with significantly inferior disease-free survival (DFS; hazard ratio (HR): 11.99, P < 0.0001) and overall survival (OS; HR: 9.68, P < 0.0001). In patients who experienced recurrence, ctDNA positivity correlated with shorter OS (HR: 2.71, P < 0.0001). The significantly shorter DFS in MRD-positive patients was consistent across actionable biomarker subsets. Sustained ctDNA clearance in response to ACT was an indicator of favorable DFS and OS compared to transient clearance (24-month DFS: 89.0% versus 3.3%; 24-month OS: 100.0% versus 82.3%). True spontaneous clearance rate with no clinical recurrence was 1.9% (2/105). Overall, our findings provide evidence for the utility of ctDNA monitoring for post-resection recurrence and mortality risk stratification that could be used for guiding adjuvant therapy., Competing Interests: Competing interests Y.N. reports advisory roles with Guardant Health Pte Ltd., Natera, Inc., Roche Ltd., Seagen, Inc., Premo Partners, Inc., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., Exact Sciences Corporation and Gilead Sciences, Inc.; speakers’ bureau from Guardant Health Pte Ltd., MSD K.K., Eisai Co., Ltd., Zeria Pharmaceutical Co., Ltd., Miyarisan Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., CareNet, Inc., Hisamitsu Pharmaceutical Co., Inc., Taiho Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Becton, Dickinson and Company and Guardant Health Japan Corp.; research funding from Seagen, Inc., Genomedia, Inc., Guardant Health AMEA, Inc., Guardant Health, Inc., Tempus Labs, Inc., Roche Diagnostics K.K., Daiichi Sankyo Co., Ltd. and Chugai Pharmaceutical Co., Ltd. J.W. reports receiving honoraria for lectures from Johnson & Johnson, Medtronic, Eli Lilly and Takeda Pharmaceuticals and receiving research funding from Medtronic, AMCO, TERUMO and Stryker Japan, all outside the submitted work. N.A. reports nothing to declare. K.H. reports nothing to declare. K. Kataoka reports speakers’ bureau from Merck Biopharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Eli Lilly Japan Co., Ltd. and Guardant Health Japan Corp. and research funding from Sysmex. M.Y. reports receipt of personal fees and honoraria for lectures from Medtronic, Johnson & Johnson, INTUITIVE, Eli Lilly, Taiho, Merck KGaA, Takeda and Daiichi Sankyo. K. Kato reports nothing to declare. M.K. reports speakers’ bureau from Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Eli Lilly and Yakult Honsha. Y.K. reports speakers’ bureau from Guardant Health Pte Ltd., MSD K.K., Merck Biopharma Co., Ltd., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. and Ono Pharmaceutical Co., Ltd. K.H.Y. reports payment or honoraria for lectures, presentations and speakers’ bureaus from Takeda Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd, TTY Biopharm Co. Ltd., OEP Group Co., Ltd., Bristol Myers Squibb, Amgen, Inc., Bayer Co., Ltd., Daiichi Sankyo Co., Ltd., Merck Biopharma Co., Ltd., Novartis Co., Ltd. and CStone Pharmaceuticals Co., Ltd. and advisory roles with Merck & Co., Inc, Pfizer Inc., Pierre Fabre, Ltd. and AstraZeneca. S.M. reports honoraria from Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd. and Eli Lilly. H.Y. reports nothing to declare. K.A. reports nothing to declare. M. Miyo reports nothing to declare. T.M. reports advisory role with Anaut, Inc. and Fujifilm Corporation and speakers’ bureau from AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd. and Miyarisan Pharmaceutical Co., Ltd. K.Y. reports speakers’ bureau from Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Yakult Honsha Co., Ltd., Takeda Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Taiho Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Ono Pharmaceutical Co., Ltd., MSD Co., Ltd. and Bristol Myers Squibb and research funding from Taiho Pharmaceutical Co., Ltd. H.E. reports honoraria from Amgen, Chugai Pharmaceutical Co., Ltd., Guardant Health Japan Corp., Incyte Japan Co., Ltd., Merck Serono Co., Ltd., Ono Pharmaceutical Co., Ltd. and Konica Minolta Co, Ltd. and research funding from Astellas Pharmaceutical Co., Ltd. K.O. reports speakers’ bureau from Taiho Pharmaceutical Co., Ltd. A.H. reports receiving honoraria for lectures from Medtronic, Johnson & Johnson, Merck Biopharma Co., Ltd., Eli Lilly and Fujifilm Corporation. H.S. reports nothing to declare. S.K. is a full-time employee of EPS Corporation. G.L., V.N.A., S.S. and A.J. are employees of Natera, Inc., with stock or options to own stock. M.C.L. is an employee of Natera, Inc., with stock or options to own stock, and further reports grants/contracts (funding to institution: Mayo Clinic) from Eisai, Exact Sciences Corporation, Genentech, Genomic Health, GRAIL, Menarini Silicon Biosystems, Merck, Novartis, Seattle Genetics and Tesaro; travel support reimbursement from AstraZeneca, Genomic Health and Ionis; and ad hoc advisory board meetings (all funds to Mayo Clinic; no personal compensation) from AstraZeneca, Celgene, Roche/Genentech, Genomic Health, GRAIL, Ionis, Merck, Pfizer, Seattle Genetics and Syndax. A.A. is an employee of Natera, Inc., with a leadership position and stock or options to own stock. M.R. reports employment, leadership position, stock and other ownership interests and consulting and advisory role at Natera, Inc., MyOme and Marble Therapeutics and research funding, patents/royalties/other intellectual property and travel/accommodations/expenses from Natera, Inc. and MyOme. H.B. reports research funding from Ono Pharmaceutical and honoraria from Ono Pharmaceutical, Eli Lilly Japan and Taiho Pharmaceutical. H.T. reports speakers’ bureau from MSD K.K, Merck Biopharma Co., Ltd., Takeda, Taiho, Eli Lilly Japan, Bristol Myers Squibb Japan, Chugai Pharmaceutical, Ono Yakuhin and Amgen and research funding from Takeda and Daiichi Sankyo. I.T. reports speakers’ bureau from Medtronic, Johnson & Johnson, Intuitive, Medicaroid and Eli Lilly and research funding from Medtronic and Sysmex. T.K. reports nothing to declare. D.K. reports honoraria from Takeda, Chugai, Eli Lilly, MSD, Ono Pharmaceutical, Seagen, Guardant Health, Eisai, Taiho, Bristol Myers Squibb, Daiichi Sankyo, Pfizer, Merck Biopharma Co., Ltd. and Sysmex and research funding from Ono Pharmaceutical, MSD, Novartis, Servier, Janssen, IQVIA, Syneoshealth, CIMIC and Cimicshiftzero. M. Mori reports nothing to declare. T.Y. reports honoraria from Chugai Pharmaceutical, Takeda Pharmaceutical, Merck Biopharma Co., Ltd., Bayer Yakuhin, Ono Pharmaceutical and MSD K.K; consulting fee from Sumitomo Corp.; and research funding from Amgen, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, FALCO Biosystems, Genomedia, Medical & Biological Laboratories, Merus N.V., Molecular Health GmbH, MSD, Nippon Boehringer Ingelheim, Ono Pharmaceutical, Pfizer Japan, Roche Diagnostics, Sanofi, Sysmex, Taiho Pharmaceutical and Takeda Pharmaceutical. E.O. reports speakers’ bureau from Chugai Pharmaceutical Co., Ltd., Bristol Meyers Squibb, Ono Pharmaceutical Co., Ltd., Eli Lilly and Takeda Pharmaceutical Co., Ltd.; research funding from Guardant Health, Inc.; and an advisory role with GlaxoSmithKline., (© 2024. The Author(s).)

Background: Immune checkpoint inhibitors (ICIs) are rarely used to treat advanced pancreatic ductal adenocarcinoma (PDAC) due to marginal efficacy., Patients and Methods: This study included 92 consecutive patients diagnosed with advanced or recurrent PDAC who received nivolumab-based treatment. Univariate and multivariate analyses were used to identify prognostic factors. A control group of 301 patients with PDAC who achieved disease control with palliative chemotherapy but without ICIs was selected for comparison using propensity score matching (PSM)., Results: The median overall survival (OS) since nivolumab treatment was 15.8 (95% confidence interval [CI], 12.5-19.0), 2.4 (95% CI 1.2-3.6), and 1.1 (95% CI 1.0-1.2) months in patients who received add-on nivolumab after achieving disease control with chemotherapy, in those who received concomitant nivolumab and chemotherapy without prerequisite confirmation of disease control, and in those who received nivolumab without concomitant chemotherapy, respectively (P < 0.001). After PSM, the median overall survival (OS) since initiation of the concomitant chemotherapy that achieved disease control was significantly longer (P = 0.026) in patients who received add-on nivolumab (19.8 months; 95% CI 14.5-25.1) than in those who received chemotherapy alone (13.8 months; 95% CI 10.8-16.9). The immune profiling of the tumors in resected patients revealed higher scores of CD8 + T cells to Tregs in patients with add-on nivolumab comparing to those who received chemotherapy alone., Conclusion: Adding-on nivolumab was associated with improved OS in patients with advanced PDAC who achieved disease control following chemotherapy., (© 2024. The Author(s).)

Protein complexes are fundamental to all cellular processes, so understanding their evolutionary history and assembly processes is important. Gene duplication followed by divergence is considered a primary mechanism for diversifying protein complexes. Nonetheless, to what extent assembly of present-day paralogous complexes has been constrained by their long evolutionary pathways and how cross-complex interference is avoided remain unanswered questions. Subunits of protein complexes are often stabilized upon complex formation, whereas unincorporated subunits are degraded. How such cooperative stability influences protein complex assembly also remains unclear. Here, we demonstrate that subcomplexes determined by cooperative stabilization interactions serve as building blocks for protein complex assembly. We further develop a protein stability-guided method to compare the assembly processes of paralogous complexes in cellulo. Our findings support that oligomeric state and the structural organization of paralogous complexes can be maintained even if their assembly processes are rearranged. Our results indicate that divergent assembly processes by paralogous complexes not only enable the complexes to evolve new functions, but also reinforce their segregation by establishing incompatibility against deleterious hybrid assemblies., (© 2024. The Author(s).)

A causal relationship exists among the aging process, organ decay and disfunction, and the occurrence of various diseases including cancer. A genetically engineered mouse model, termed Klf1 K74R/K74R or Klf1 (K74R), carrying mutation on the well-conserved sumoylation site of the hematopoietic transcription factor KLF1/EKLF has been generated that possesses extended lifespan and healthy characteristics, including cancer resistance. We show that the healthy longevity characteristics of the Klf1 (K74R) mice, as exemplified by their higher anti-cancer capability, are likely gender-, age-, and genetic background-independent. Significantly, the anti-cancer capability, in particular that against melanoma as well as hepatocellular carcinoma, and lifespan-extending property of Klf1 (K74R) mice, could be transferred to wild-type mice via transplantation of their bone marrow mononuclear cells at a young age of the latter. Furthermore, NK(K74R) cells carry higher in vitro cancer cell-killing ability than wild-type NK cells. Targeted/global gene expression profiling analysis has identified changes in the expression of specific proteins, including the immune checkpoint factors PDCD and CD274, and cellular pathways in the leukocytes of the Klf1 (K74R) that are in the directions of anti-cancer and/or anti-aging. This study demonstrates the feasibility of developing a transferable hematopoietic/blood system for long-term anti-cancer and, potentially, for anti-aging., Competing Interests: JW, CH, YL, CL, KY, KW, ZL, BC, TH, YS, PH, LC, TC, CY, NL, CS No competing interests declared, TL is an employee of Pro-Clintech Co. Ltd, (© 2023, Wang, Hung et al.)

Aims: Pre-emptive prediction to avoid myelosuppression and harmful sequelae is difficult given the complex interplay among patients, drugs and treatment protocols. This study aimed to model plasma and bone marrow concentrations and the likelihood of myelotoxicity following administration of 5-fluorouracil (5-FU) by diverse intravenous (IV) bolus or continuous infusion (cIF) regimens., Methods: Using physicochemical, in vitro and clinical data obtained from the literature consisting of various regimens and patient cohorts, a 5-FU physiologically based pharmacokinetic (PBPK) model was developed. The predicted and observed PK values were compared to assess model performance prior to examining myelotoxicity potential of IV bolus vs. cIF and DPYD wild type vs. genetic variant., Results: The established model was verified by utilizing 5-FU concentration-time profiles of adequate heterogeneity contributed by 36 regimens from 15 studies. The study provided corroborative evidence to explain why cIF (vs. IV bolus) had lower myelotoxicity risk despite much higher total doses. The PBPK model was used to estimate the optimal dosage in patients heterozygous for the DPYD c.1905 + 1G > A allele and suggested that a dose reduction of at least 25% was needed (compared to the dose in wild-type subjects)., Conclusion: A verified PBPK model was used to explain the lower myelotoxicity risk of cIF vs. IV bolus administration of 5-FU and to estimate the dose reduction needed in carriers of a DPYD variant. With appropriate data, expertise and resources, PBPK models have many potential uses in precision medicine application of oncology drugs., (© 2024 British Pharmacological Society.)

Background: KRAS G12C is a mutation that occurs in approximately 3 to 4% of patients with metastatic colorectal cancer. Monotherapy with KRAS G12C inhibitors has yielded only modest efficacy. Combining the KRAS G12C inhibitor sotorasib with panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, may be an effective strategy., Methods: In this phase 3, multicenter, open-label, randomized trial, we assigned patients with chemorefractory metastatic colorectal cancer with mutated KRAS G12C who had not received previous treatment with a KRAS G12C inhibitor to receive sotorasib at a dose of 960 mg once daily plus panitumumab (53 patients), sotorasib at a dose of 240 mg once daily plus panitumumab (53 patients), or the investigator's choice of trifluridine-tipiracil or regorafenib (standard care; 54 patients). The primary end point was progression-free survival as assessed by blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Key secondary end points were overall survival and objective response., Results: After a median follow-up of 7.8 months (range, 0.1 to 13.9), the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 6.3) and 3.9 months (95% CI, 3.7 to 5.8) in the 960-mg sotorasib-panitumumab and 240-mg sotorasib-panitumumab groups, respectively, as compared with 2.2 months (95% CI, 1.9 to 3.9) in the standard-care group. The hazard ratio for disease progression or death in the 960-mg sotorasib-panitumumab group as compared with the standard-care group was 0.49 (95% CI, 0.30 to 0.80; P = 0.006), and the hazard ratio in the 240-mg sotorasib-panitumumab group was 0.58 (95% CI, 0.36 to 0.93; P = 0.03). Overall survival data are maturing. The objective response was 26.4% (95% CI, 15.3 to 40.3), 5.7% (95% CI, 1.2 to 15.7), and 0% (95% CI, 0.0 to 6.6) in the 960-mg sotorasib-panitumumab, 240-mg sotorasib-panitumumab, and standard-care groups, respectively. Treatment-related adverse events of grade 3 or higher occurred in 35.8%, 30.2%, and 43.1% of patients, respectively. Skin-related toxic effects and hypomagnesemia were the most common adverse events observed with sotorasib-panitumumab., Conclusions: In this phase 3 trial of a KRAS G12C inhibitor plus an EGFR inhibitor in patients with chemorefractory metastatic colorectal cancer, both doses of sotorasib in combination with panitumumab resulted in longer progression-free survival than standard treatment. Toxic effects were as expected for either agent alone and resulted in few discontinuations of treatment. (Funded by Amgen; CodeBreaK 300 ClinicalTrials.gov number, NCT05198934.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: Chronic obstructive pulmonary disease (COPD) often causes cardiopulmonary dysfunction, which deteriorates exercise capacity. Cardiopulmonary exercise testing (CPET) and echocardiography are common tools for evaluating cardiovascular function. No studies have analyzed the correlation between echocardiography-derived parameters and cardiopulmonary response during exercise., Objectives: We analyzed the correlation between echocardiographic parameters such as tricuspid regurgitation peak gradient (TRPG), tricuspid annular plane systolic excursion (TAPSE), TRPG/TAPSE and CPET-derived parameters., Methods: Seventy-seven patients with COPD were evaluated. We analyzed the correlation between parameters derived from echocardiography, exercise capacity, cardiovascular and ventilatory parameters derived from CPET., Results: The correlation between TRPG/TAPSE and work rate (WR) was moderate and negative (-0.4423, p = 0.0003), while TRPG had a weak negative correlation with WR (r= -0.3099, p = 0.0127). Oxygen uptake at peak exercise was weakly negatively correlated with TRPG/TAPSE (-0.3404, p = 0.0059), TRPG (r= -0.3123, p = 0.0120), and the ratio of early mitral inflow velocity to early mitral annular diastolic velocity (E/E'). The correlation between TRPG/TAPSE and exercise capacity was higher than that of TPRG, TAPSE, and E/E'. TRPG/TAPSE exhibited a moderate negative correlation with cardiac index, whereas TRPG and TAPSE showed a weak correlation. The correlation between TRPG/TAPSE and cardiac function during exercise was higher than that of TPRG, TAPSE, and E/E'. TRPG/TAPSE, TRPG, TAPSE, and E/E' were weakly negatively correlated with lung function., Conclusions: In assessing exercise capacity, cardiac function, and gas exchange, TRPG/TAPSE proves to be superior to other cardiac parameters. Higher TRPG/TAPSE levels corresponded to lower exercise capacity, cardiovascular and ventilatory function., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest, (Copyright © 2023. Published by Elsevier Inc.)

Blockchain has become a well-known, secured, decentralized datastore in many domains, including medical, industrial, and especially the financial field. However, to meet the requirements of different fields, platforms that are built on blockchain technology must provide functions and characteristics with a wide variety of options. Although they may share similar technology at the fundamental level, the differences among them make data or transaction exchange challenging. Cross-chain transactions have become a commonly utilized function, while at the same time, some have pointed out its security loopholes. It is evident that a secure transaction scheme is desperately needed. However, what about those nodes that do not behave? It is clear that not only a secure transaction scheme is necessary, but also a system that can gradually eliminate malicious players is of dire need. At the same time, integrating different blockchain systems can be difficult due to their independent architectures, and cross-chain transactions can be at risk if malicious attackers try to control the nodes in the cross-chain system. In this paper, we propose a dynamic reputation management scheme based on the past transaction behaviors of nodes. These behaviors serve as the basis for evaluating a node's reputation to support the decision on malicious behavior and enable the system to intercept it in a timely manner. Furthermore, to establish a reputation index with high precision and flexibility, we integrate Particle Swarm Optimization (PSO) into our proposed scheme. This allows our system to meet the needs of a wide variety of blockchain platforms. Overall, the article highlights the importance of securing cross-chain transactions and proposes a method to prevent misbehavior by evaluating and managing node reputation.

The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with metastatic colorectal cancer (mCRC), published in late 2022, were adapted in December 2022, according to previously established standard methodology, to produce the Pan-Asian adapted (PAGA) ESMO consensus guidelines for the management of Asian patients with mCRC. The adapted guidelines presented in this manuscript represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with mCRC representing the oncological societies of China (CSCO), Indonesia (ISHMO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO), co-ordinated by ESMO and the Japanese Society of Medical Oncology (JSMO). The voting was based on scientific evidence and was independent of the current treatment practices, drug access restrictions and reimbursement decisions in the different Asian countries. The latter are discussed separately in the manuscript. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with mCRC across the different countries of Asia, drawing on the evidence provided by both Western and Asian trials, whilst respecting the differences in screening practices, molecular profiling and age and stage at presentation, coupled with a disparity in the drug approvals and reimbursement strategies, between the different countries., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Population-based studies have reported the association between prolonged corrected QT (QTc) intervals and an increased risk of adverse cardiovascular events. Data regarding the association between longer QTc intervals and incident cardiovascular outcomes in patients with lower extremity arterial disease (LEAD) are scarce., Objective: To examine the impact of QTc interval on long-term cardiovascular outcomes in elderly patients with symptomatic LEAD., Methods: This cohort study extracted data from the Tzu-chi Registry of ENDovascular Intervention for Peripheral Artery Disease (TRENDPAD) and enrolled 504 patients aged ≥ 70 treated with endovascular therapy for atherosclerotic LEAD from July 1, 2005, to December 31, 2019. The main outcomes of interest were all-cause mortality and major adverse cardiovascular events (MACE). Multivariate analysis was conducted using the Cox proportional hazard model to determine independent variables. We performed interaction analysis between corrected QT and other covariates and Kaplan-Meier analysis to compare the outcome of interest among the groups stratified by the tercile of QTc intervals., Results: A total of 504 patients [235 men (46.6%); mean age, 79.9 ± 6.2 years; mean QTc interval, 459 ± 33 msec] entered the final data analysis. We categorized the baseline patient characteristics according to terciles of QTc intervals. During the median follow-up time of 3.15 (interquartile ranges, 1.65-5.42) years, we noted 264 deaths and 145 MACEs. The 5-year rates of freedom from all-cause mortality (71% vs. 57% vs. 31%, P  < 0.001) and MACEs (83% vs. 67% vs. 46%, P  < 0.001) were significantly different among the tercile groups. Multivariate analysis showed that a 1-SD increase in the QTc interval increased the risk of all-cause mortality [hazard ratio (HR) 1.49, P  < 0.001] and MACEs (HR 1.59, P  < 0.001) after adjusting for other covariates. The interaction analysis showed that QTc interval and C-reactive protein levels were most strongly associated with death (HR = 4.88, 95% CI 3.09-7.73, interaction P  < 0.001) and MACEs (HR = 7.83, 95% CI 4.14-14.79, interaction P  < 0.001)., Conclusions: In elderly patients with symptomatic atherosclerotic LEAD, a prolonged QTc interval is associated with advanced limb ischemia, multiple medical comorbidities, increased risk of MACEs, and all-cause mortality., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Chang, Tzeng, Jang, Liu, Hsieh, Chou, Yeh, Huang and TRENDPAD Study Group.)

Background: In this randomized phase II study, we evaluated the efficacy and safety of sorafenib in combination with capecitabine and cisplatin (XP) as first-line chemotherapy in advanced gastric cancer., Patients and Methods: Patients with metastatic gastric or gastroesophageal junction adenocarcinoma were randomized (1:1) to receive either sorafenib plus XP (S + XP) or XP alone. In cases of disease progression in the XP arm, crossover to sorafenib alone was allowed. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), response rates, safety profiles, and biomarkers, and the response rates and PFS with secondline sorafenib alone after progression in the XP arm., Results: Between Jan 2011 and Feb 2013, a total of 195 patients were accrued (97 in the S + XP arm and 98 in the XP alone arm). The overall response rate was 54% with S + XP, and 52% with XP alone (p = 0.83). With a median follow-up of 12.6 months (range, 0.1-29.2), the median PFS assessed by independent review was 5.6 months in the S + XP arm and 5.3 months in the XP arm (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.67-1.27, p = 0.61). Overall survival was not different between the two arms (median 11.7 vs. 10.8 months; HR 0.93, 95% CI 0.65-1.31, p = 0.66). Frequencies of grade 3/4 toxicities were similar between the S + XP and XP alone arms, except for neutropenia (21% vs. 37%), anorexia (0% vs. 5%), and hand-foot skin reaction (7% vs. 1%). Among 51 patients who crossed over to sorafenib alone after disease progression in the XP arm, there was no objective response and their median PFS was 1.3 months (95% CI, 1.2-1.7)., Conclusion: The addition of sorafenib to XP chemotherapy was safe but not more effective than XP alone for first-line treatment of metastatic gastric cancer., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

ABCG5 and ABCG8 are two key adenosine triphosphate-binding cassette (ABC) proteins that regulate whole-body sterol trafficking. This study aimed to elucidate the association between ABCG5/G8 gene region variants and lipid profile, cardiometabolic traits, and gallstone disease history in Taiwan. A total of 1494 Taiwan Biobank participants with whole-genome sequencing data and 117,679 participants with Axiom Genome-Wide CHB Array data were enrolled for analysis. Using genotype-phenotype and stepwise linear regression analyses, we found independent associations of four Asian-specific ABCG5 variants, rs119480069, rs199984328, rs560839317, and rs748096191, with total, low-density lipoprotein (LDL), and non-high-density lipoprotein (HDL) cholesterol levels (all p ≤ 0.0002). Four other variants, which were in nearly complete linkage disequilibrium, exhibited genome-wide significant associations with gallstone disease history, and the ABCG8 rs11887534 variant showed a trend of superiority for gallstone disease history in a nested logistic regression model ( p = 0.074). Through regional association analysis of various other cardiometabolic traits, two variants of the PLEKHH2 , approximately 50 kb from the ABCG5/G8 region, exhibited significant associations with blood pressure status ( p < 10 -6 ). In conclusion, differential effects of ABCG5/G8 region variants were noted for lipid profile, blood pressure status, and gallstone disease history in Taiwan. These results indicate the crucial role of individualized assessment of ABCG5/G8 variants for different cardiometabolic phenotypes.

Although fluoride-containing compounds are widely used to inhibit bacterial growth, the reprogramming of gene expression underlying cellular responses to fluoride, especially under anaerobic conditions, is still poorly understood. Here, we compare the genome-wide transcriptomic profiles of E. coli grown in the absence (control) or presence (20 and 70 mM) of sodium fluoride (NaF) under anaerobic conditions and assess the impact of fluoride-dependent ATP depletion on RNA turnover. Tiling array analysis revealed transcripts displaying altered abundance in response to NaF treatments. Quantile-based K-means clustering uncovered a subset of genes that were highly upregulated and then downregulated in response to increased and subsequently decreased fluoride concentrations, many of which (~40%) contained repetitive extragenic palindromic (REP) sequences. Northern blot analysis of some of these highly upregulated REP-containing transcripts (i.e., osmC , proP , efeO and yghA ) confirmed their considerably enhanced abundance in response to NaF treatment. An mRNA stability analysis of osmC and yghA transcripts demonstrated that fluoride treatment slows down RNA degradation, thereby enhancing RNA stability and steady-state mRNA levels. Moreover, we demonstrate that turnover of these transcripts depends on RNase E activity and RNA degradosome. Thus, we show that NaF exerts significant effects at the whole-transcriptome level under hypoxic growth (i.e., mimicking the host environment), and fluoride can impact gene expression posttranscriptionally by slowing down ATP-dependent degradation of structured RNAs. IMPORTANCE Gram-negative Escherichia coli is a rod-shaped facultative anaerobic bacterium commonly found in microaerobic/anaerobic environments, including the dental plaques of warm-blooded organisms. These latter can be treated efficiently with fluoride-rich compounds that act as anticaries agents to prevent tooth decay. Although fluoride inhibits microbial growth by affecting metabolic pathways, the molecular mechanisms underlying its activity under anaerobic conditions remain poorly defined. Here, using genome-wide transcriptomics, we explore the impact of fluoride treatments on E. coli gene expression under anaerobic conditions. We reveal key gene clusters associated with cellular responses to fluoride and define its ATP-dependent stabilizing effects on transcripts containing repetitive extragenic palindromic sequences. We demonstrate the mechanisms controlling the RNA stability of these REP-containing mRNAs. Thus, fluoride can affect gene expression posttranscriptionally by stabilizing structured RNAs.

Objective: First-line pembrolizumab with/without chemotherapy versus chemotherapy was evaluated in programmed death ligand 1 combined positive score ≥1, locally advanced/unresectable or metastatic gastric cancer/gastrooesophageal junction cancer in the KEYNOTE-062 study. We present results for patients enrolled in Asia., Methods: Eligible patients were randomly assigned 1:1:1 to pembrolizumab 200 mg, pembrolizumab plus chemotherapy (cisplatin + 5-fluorouracil or capecitabine) or placebo plus chemotherapy Q3W. End points included overall survival (primary) in combined positive score ≥1 and combined positive score ≥10 populations and safety and tolerability (secondary)., Results: A total of 187 patients were enrolled in Asia (pembrolizumab, n = 62; pembrolizumab plus chemotherapy, n = 64; chemotherapy, n = 61). Compared with the global population, higher proportions of patients had Eastern Cooperative Oncology Group performance status 0 and a diagnosis of stomach cancer. In the programmed death ligand 1 combined positive score ≥1 population, median overall survival was numerically longer with pembrolizumab versus chemotherapy (22.7 vs 13.8 months; hazard ratio, 0.54; 95% confidence interval, 0.35-0.82) and pembrolizumab plus chemotherapy versus chemotherapy (16.5 vs 13.8 months; hazard ratio, 0.78; 95% confidence interval, 0.53-1.16). In the programmed death ligand 1 combined positive score ≥10 population, median overall survival was also numerically longer with pembrolizumab versus chemotherapy (28.5 vs 14.8 months; hazard ratio, 0.43; 95% confidence interval, 0.21-0.89) and pembrolizumab plus chemotherapy versus chemotherapy (17.5 vs 14.8 months; hazard ratio, 0.86; 95% confidence interval, 0.45-1.64). The grade 3-5 treatment-related adverse event rate was 19.4%, 75.8% and 64.9% for patients receiving pembrolizumab, pembrolizumab plus chemotherapy and chemotherapy, respectively., Conclusions: This post hoc analysis showed pembrolizumab monotherapy was associated with numerically improved overall survival and a favourable tolerability profile versus chemotherapy in Asians with programmed death ligand 1-positive advanced gastric cancer/gastrooesophageal junction cancer.This study is registered with ClinicalTrials.gov, NCT02494583., (© The Author(s) 2022. Published by Oxford University Press.)

FAM21 (family with sequence similarity 21) is a component of the Wiskott-Aldrich syndrome protein and SCAR homologue (WASH) protein complex that mediates actin polymerization at endosomal membranes to facilitate sorting of cargo-containing vesicles out of endosomes. To study the function of FAM21 in vivo, we generated conditional knockout (cKO) mice in the C57BL/6 background in which FAM21 was specifically knocked out of CD11c-positive dendritic cells. BMDCs from those mice displayed enlarged early endosomes, and altered cell migration and morphology relative to WT cells. FAM21-cKO cells were less competent in phagocytosis and protein antigen presentation in vitro, though peptide antigen presentation was not affected. More importantly, we identified the TLR2/CLEC4E signaling pathway as being down-regulated in FAM21-cKO BMDCs when challenged with its specific ligand Candida albicans Moreover, FAM21-cKO mice were more susceptible to C. albicans infection than WT mice. Reconstitution of WT BMDCs in FAM21-cKO mice rescued them from lethal C. albicans infection. Thus, our study highlights the importance of FAM21 in a host immune response against a significant pathogen., (© 2023 Kulkarni et al.)

Background: Prognosis of metastatic BRAF V600E mutant colorectal cancer (CRC) is poor, and the prognostic implications of immune contextures in the tumour microenvironment (TME) for CRC remain elusive., Methods: We collected the primary tumour specimens and clinicopathological characteristics of patients with de novo metastatic microsatellite-stable BRAF V600E mutant CRC from two medical centres. Gene expression analysis was performed using the nCounterⓇ PanCancer Immune Profiling Panel. The Cox proportional hazards regression model was used for analysing survival outcomes in association with immune gene expression and immune cells. Our complement score was defined on the basis of the average gene expression in the selected co-expression module., Results: High expression of classical and regulatory complement genes was significantly associated with poor prognosis (N = 54). A high complement score (defined as a score above the median value) indicated significantly shorter survival. The overall survival (OS) impact of the high score remained significant in multivariate analyses. Additionally, our complement score was strongly correlated with C4d expression in immunohistochemical staining and tumour-associated macrophage (TAM) M2 signatures., Conclusions: Complement activation in the TME was significantly associated with poor OS and was correlated with TAM M2 in patients with de novo metastatic BRAF V600E mutant CRC., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

In recent years, artificial intelligence (AI) has been developed vigorously, and a great number of AI autonomous applications have been proposed. However, how to decrease computations and shorten training time with high accuracy under the limited hardware resource is a vital issue. In this paper, on the basis of MobileNet architecture, the dense squeeze with depthwise separable convolutions model is proposed, viz. MiniNet. MiniNet utilizes depthwise and pointwise convolutions, and is composed of the dense connection technique and the Squeeze-and-Excitation operations. The proposed MiniNet model is implemented and experimented with Keras. In experimental results, MiniNet is compared with three existing models, i.e., DenseNet, MobileNet, and SE-Inception-Resnet-v1. To validate that the proposed MiniNet model is provided with less computation and shorter training time, two types as well as large and small datasets are used. The experimental results showed that the proposed MiniNet model significantly reduces the number of parameters and shortens training time efficiently. MiniNet is superior to other models in terms of the lowest parameters, shortest training time, and highest accuracy when the dataset is small, especially., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 ISA. Published by Elsevier Ltd. All rights reserved.)

Purpose: Takotsubo syndrome (TTS) is characterized angiographically by transient left ventricular systolic dysfunction sparing the basal segments of the left ventricle and absence of obstructive coronary artery disease. Epileptic seizures as triggering events for TTS are uncommon, having only been described in approximately 100 previous cases Case report: A 64-year-old woman with a history of recent stroke-related seizures was admitted for an acute onset of right hemiparesis with dull response. Neurological examination revealed a forced deviation of the eyeballs to the left side and quadriplegia. No large intracranial artery occlusion was disclosed through computed tomography angiography, but an acute infarction at the right corona radiata was identified through magnetic resonance imaging. Electroencephalography showed frequent spike-and-wave complexes over the right cerebral hemisphere indicating subtle status epilepticus. Her consciousness deteriorated to a stuporous state, and her eyeballs were forced deviated to the right side with persistent twitching of the right limbs 10 hours later. The convulsive status epilepticus (CSE) subsided after intravenous infusion of midazolam. However, atrial flutter with inverted T-wave and elevated high-sensitivity troponin I were observed 12 hours after CSE. Arrhythmia was soon alleviated through appropriate treatment. A further coronary angiography did not show significant coronary artery stenosis but indicated that the midsection and the apex of the left ventricle ballooned out during systole as the base contracted normally, indicating a Takotsubo syndrome., Conclusion: Physicians need to monitor unusual arrhythmias, particularly atrial and ventricular arrhythmias, for the possibility of TTS in patients with epileptic seizure.

Background: Ramucirumab is indicated for salvage treatment after failure of first-line treatment for metastatic colorectal cancer (mCRC). However, the application of ramucirumab at later-line treatment in real-world practice has not received much discussion., Methods: In this retrospective study, we enrolled 70 patients with mCRC who received ramucirumab plus chemotherapy at National Taiwan University Hospital between 2018 and 2019., Results: Compared with those who received third- or later-line ramucirumab treatment, patients who received second-line ramucirumab treatment had significantly longer median time to treatment discontinuation (mTTD; 6.7 vs 3.6 months, P = .004) and median overall survival (mOS; not reached vs 7.6 months, P = .009). Multivariate analyses revealed that second-line ramucirumab and triplet chemotherapy backbone were the only independent predictive factors for long mTTD and mOS. Patients who received ramucirumab with triplet chemotherapy had a significantly longer mOS than did patients who received ramucirumab with doublet chemotherapy (not reached vs 5.6 months, P = .002). Among those receiving second-line ramucirumab treatment, combination with triplet chemotherapy led to a longer mTTD than did combination with doublet chemotherapy, but the difference was non-significant (not reached vs 4.4 months, P = .108). By contrast, in patients receiving fourth- or later-line ramucirumab, combination with triplet chemotherapy led to significantly longer mTTD than did combination with doublet chemotherapy (8.0 vs 2.9 months, P = .032)., Conclusion: Ramucirumab plus triplet chemotherapy may be an alternative regimen in patients with mCRC, particularly as a later-line treatment modality., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2022 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Several apolipoprotein genes are located at the APOE locus on chromosome 19q13.32. This study explored the genetic determinants of cardiometabolic traits and metabolic syndrome at the APOE locus in a Taiwanese population. A total of 81,387 Taiwan Biobank (TWB) participants were enrolled to undergo genotype−phenotype analysis using data from the Axiom Genome-Wide CHB arrays. Regional association analysis with conditional analysis revealed lead single-nucleotide variations (SNVs) at the APOE locus: APOE rs7412 and rs429358 for total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol levels; CLPTM1 rs3786505 and rs11672748 for LDL and HDL cholesterol levels; and APOC1 rs438811 and APOE-APOC1 rs439401 for serum triglyceride levels. Genotype−phenotype association analysis revealed a significant association of rs429358 and rs438811 with metabolic syndrome and of rs7412, rs438811, and rs439401 with serum albumin levels (p < 0.0015). Stepwise regression analysis indicated that CLPTM1 variants were independently associated with LDL and HDL cholesterol levels (p = 3.10 × 10−15 for rs3786505 and p = 1.48 × 10−15 for rs11672748, respectively). APOE rs429358 and APOC1 rs438811 were also independently associated with metabolic syndrome (p = 2.29 × 10−14) and serum albumin levels (p = 3.80 × 10−6), respectively. In conclusion, in addition to APOE variants, CLPTM1 is a novel candidate locus for LDL and HDL cholesterol levels at the APOE gene region in Taiwan. Our data also indicated that APOE and APOC1 variants were independently associated with metabolic syndrome and serum albumin levels, respectively. These results revealed the crucial role of genetic variants at the APOE locus in predicting cardiometabolic traits and metabolic syndrome.

Strong Ties and Weak Ties Rationality Scale (STWTRS) is a theory-driven questionnaire designed to capture cultural differences in reasoning about the world. It is intended to demonstrate empirically the heuristic value of the ontological turn that shifts the focus of cultural analysis from the down-stream values, beliefs, and behaviors to the upstream process of thinking and reasoning that is rooted in the local ways of being. This paper will present theory development, preliminary results, and potential contributions of this scale toward better understanding of the culturally different other., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The blockchain-enabled internet of medical things (IoMT) is an emerging paradigm that could provide strong trust establishment and ensure the traceability of data sharing in the IoMT networks. One of the fundamental building blocks for Blockchain is Elliptic Curve Digital Signature Algorithm (ECDSA). Nevertheless, when processing a large number of transactions, the verification of multiple signatures will incur cumbersome overhead to the nodes in Blockchain. Although batch verification is able to provide a promising approach that verifies multiple signatures simultaneously and efficiently, the upper bound of batch size is limited to small-scale and the efficiency will drop rapidly as the batch size grows in the state-of-the-art ECDSA batch schemes. Meanwhile, most of the existing researches only focus on improving the efficiency of batch verification algorithms in various cryptosystem while ignoring the identification of invalid signatures, which could cause severe performance degradation when the batch verification fails. Motivated by these observations, this paper proposes an efficient and large-scale batch verification scheme with group testing technology based on ECDSA. The application of the presented protocols in Bitcoin and Hyperledger Fabric has been analyzed as supportive and effective. When the batch verification returns a false result, we utilize group testing technology to improve the efficiency of identifying invalid signatures. Comprehensive simulation results demonstrate that our protocol outperforms the related ECDSA batch verification schemes.

Background: The common non-synonymous mutation of the glucokinase regulator ( GCKR ) gene, namely rs1260326, is widely reported to have pleiotropic effects on cardio-metabolic traits and hematological parameters., Objective: This study aimed to identify whether other GCKR variants may have pleiotropic effects independent of the rs1260326 genotypes., Methods: In total, 81,097 Taiwan Biobank participants were enrolled for the regional plot association studies and candidate variant analysis of the region around the GCKR gene., Results: The initial candidate variant approach showed the significant association of the rs1260326 genotypes with multiple phenotypes. Regional plot association analysis of the GCKR gene region further revealed genome-wide significant associations between GCKR variants and serum total and low-density lipoprotein cholesterol; triglyceride, uric acid, creatinine, aspartate aminotransferase, γ-Glutamyl transferase, albumin, and fasting plasma glucose levels; estimated glomerular filtration rate; leukocyte and platelet counts; microalbuminuria, and metabolic syndrome, with rs1260326 being the most common lead polymorphism. Serial conditional analysis identified genome-wide significant associations of two low-frequency exonic mutations, rs143881585 and rs8179206, with high serum triglyceride and albumin levels. In five rare GCKR exonic non-synonymous or nonsense mutations available for analysis, GCKR rs146175795 showed an independent association with serum triglyceride and albumin levels and rs150673460 showed an independent association with serum triglyceride levels. Weighted genetic risk scores from the combination of GCKR rs143881585 and rs146175795 revealed a significant association with metabolic syndrome., Conclusion: In addition to the rs1260326 variant, low-frequency and rare GCKR exonic mutations exhibit pleiotropic effects on serum triglyceride and albumin levels and the risk of metabolic syndrome. These results provide evidence that both common and rare GCKR variants may play a critical role in predicting the risk of cardiometabolic disorders.

Helicobacter pylori (HP)-unrelated mucosa-associated lymphoid tissue (MALT) lymphoma includes the majority of extragastric MALT lymphomas and a small proportion of gastric MALT lymphomas. Although the role of first-line antibiotics in treating HP-negative gastric MALT lymphomas remains controversial, HP eradication therapy (HPE)-like regimens may result in approximately 20-30% complete remission (CR) for patients with localized HP-negative gastric MALT lymphoma. In these patients, H . heilmannii ,&nbsp; H. bizzozeronii , and H. suis were detected in sporadic gastric biopsy specimens. Extragastric MALT lymphoma is conventionally treated with radiotherapy for localized disease and systemic chemotherapy for advanced and metastatic diseases. However, a proportion of extragastric MALT lymphomas, such as ocular adnexal lesions and small intestinal lesions, were reported to be controlled by antibiotics for Chlamydophila psittaci and Campylobacter jejuni , respectively. Some extragastric MALT lymphomas may even respond to first-line HPE. These findings suggest that some antibiotic-responsive tumors may exist in the family of HP-negative MALT lymphomas. Two mechanisms underlying the antibiotic responsiveness of HP-negative MALT lymphoma have been proposed. First, an HPE-like regimen may eradicate the antigens of unknown bacteria. Second, clarithromycin (the main component of HPE) may have direct or indirect antineoplastic effects, thus contributing to the CR of these tumors. For antibiotic-unresponsive HP-negative MALT lymphoma, high-dose macrolides and immunomodulatory drugs, such as thalidomide and lenalidomide, have reported sporadic success. Further investigation of new treatment regimens is warranted.

Purpose: The aim of this pilot study was to evaluate for differences in metabolomic profiles between fatigued and non-fatigued patients with colorectal cancer (CRC) during chemotherapy (CTX)., Method: Patients were recruited from the department of surgery in a large medical center in Taiwan. In this longitudinal pilot study, the Fatigue Symptom Inventory and fasting blood samples were collected at three assessments (i.e., prior to surgery (T0), three months (T1) and six months (T2) after surgery). Metabolomic profile analysis was used. Multilevel regression and pathway analyses were performed to identify differences in metabolomic profiles between the fatigued and non-fatigued groups., Results: Of the 49 patients, 55.1% (n = 27) were in the fatigue group. All of the 15 metabolites that had statistically significant group × time interactions in the differential metabolite analysis were entered into the pathway analysis. Two pathways were enriched for these metabolites, namely galactose metabolism and phenylalanine, tyrosine, and tryptophan biosynthesis., Conclusions: The results from this pilot study suggest that pathways involved in galactose metabolism and phenylalanine, tyrosine, and tryptophan biosynthesis are associated with cancer-related fatigue (CRF) in patients with CRC during CTX. These findings are consistent with the hypotheses that alterations in energy metabolism and increases in inflammation are associated with the development and maintenance of CRF., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: Colon cancer is the third most incident and life-threatening cancer in Taiwan. A comprehensive survival prediction system would greatly benefit clinical practice in this area. This study was designed to develop an accurate prognostic model for colon cancer patients by using clinicopathological variables obtained from the Taiwan Cancer Registry database., Methods: We analyzed 20,218 colon cancer patients from the Taiwan Cancer Registry database, who were diagnosed between 2007 and 2015, were followed up until December 31, 2017, and had undergone curative surgery. We proposed two prognostic models, with different combinations of predictors. The first model used only traditional clinical features. The second model included several colon cancer site-specific factors (circumferential resection margin, perineural invasion, obstruction, and perforation), in addition to the traditional features. Both prediction models were developed by using a Cox proportional hazards model. Furthermore, we investigated whether race is a significant predictor of survival in colon cancer patients by using Model 1 on the Surveillance, Epidemiology, and End Results (SEER) cancer registry dataset., Results: The proposed models displayed a robust prediction performance (all Harrell's c-index >0.8). For both the calibration and validation steps, the differences between the predicted and observed mortality were mostly less than 5%., Conclusions: The prediction model (Model 1) is an effective predictor of survival regardless of the ethnic background of patients and can potentially help to provide better prediction of colon cancer-specific survival outcomes, thus allowing physicians to improve treatment plans., (© 2021. Society of Surgical Oncology.)

Objectives: Circulating serum amyloid A (SAA) levels are strongly associated with atherosclerotic cardiovascular disease risk and severity. The association between SAA1 genetic variants, SAA levels, inflammatory marker levels, and coronary artery disease (CAD) prognosis has not been fully understood., Materials and Methods: In total, 2199 Taiwan Biobank (TWB) participants were enrolled for a genome-wide association study (GWAS), and the long-term outcomes in 481 patients with CAD were analyzed. The primary endpoint was all-cause mortality, and the secondary endpoint was the combination of all-cause death, myocardial infarction, stroke, and hospitalization for heart failure., Results: Through GWAS, SAA1 rs11024600 and rs7112278 were independently associated with SAA levels ( P = 3.84 × 10 -145 and P = 1.05 × 10 -29 , respectively). SAA levels were positively associated with leukocyte counts and multiple inflammatory marker levels in CAD patients and with body mass index, hemoglobin, high-density lipoprotein cholesterol, and alanine aminotransferase levels in TWB participants. By stepwise linear regression analysis, SAA1 gene variants contributed to 27.53% and 8.07% of the variation of the SAA levels in TWB and CAD populations, respectively, revealing a stronger influence of these two variants in TWB participants compared to CAD patients. Kaplan-Meier survival analysis revealed that SAA levels, but not SAA1 gene variants, were associated with long-term outcomes in patients with CAD. Cox regression analysis also indicated that high circulating SAA levels were an independent predictor of both the primary and secondary endpoints., Conclusion: SAA1 genotypes contributed significantly to SAA levels in the general population and in patients with CAD. Circulating SAA levels but not SAA1 genetic variants could predict long-term outcomes in patients with angiographically confirmed CAD., Competing Interests: Dr. Yu-Lin Ko, an editorial board members at Tzu Chi Medical Journal, had no role in the peer review process of or decision to publish this article. The other authors declared no conflicts of interest in writing this paper., (Copyright: © 2022 Tzu Chi Medical Journal.)

In this study, we employed a dual strategy for parathion organophosphate pesticide (parathion) detection; first, we used a localized surface plasmon resonance (LSPR)-based colorimetric sensor featuring thiol-capped Au NPs, namely cysteine (Cys)@Au NPs, 11-mercaptoundecanoic acid (11-MUA)@Au NPs, and glutathione (GSH)@Au NPs, via acetylcholinesterase (ACHE) and acetylthiocholine (ATCH) enzyme-mediated hydrolysis reactions; second, we developed a color analysis toxicity-sensing app (Toxin APP). Positively charged thiocholine (TCH) molecules, which were continuously generated via hydrolysis, subsequently conjugated with thiol-capped Au NPs, causing Au NP aggregation through electrostatic attractions. The degree of aggregation of the thiol-capped Au NPs was influenced by parathion concentrations in the range 0 to 10 8 ppt, because parathion acted as an ACHE inhibitor by controlling the amount of TCH generated. Based on the values of LSPR absorbance ratio, the limits of detection (LODs) of three types thiol-capped Au NPs were determined to be 100 ppt using ultraviolet-visible spectroscopy measurements. However, the aggregation efficiency of GSH@Au NPs was lower than that of the others regarding gradual changes in their color and LSPR absorbance band. Furthermore, we designed Toxin APP for color analysis which consists of three modules: processing, database collection, and communication. Toxin APP could on-site and precisely detect the color changes of GSH@Au NPs at parathion concentrations in the ranges of 100 ppt to 1, 10, and 100 ppm and could distinguish between OP and non-OP pesticides (e.g., fipronil) in tap water samples with high sensitivity and selectivity. Moreover, the concentration of residual parathion in real samples (tomato and strawberry) was quantified based on the color changes of GSH@Au NPs detected using Toxin APP. Therefore, the combination of an LSPR-based colorimetric assay and Toxin APP can be a reliable method for the facile and rapid detection of parathion in food and water samples.

Background: The phase 3 ATTRACTION-2 study demonstrated that nivolumab monotherapy was superior to placebo for patients with pretreated advanced gastric or gastroesophageal junction cancer, but early progression of tumors in some patients was of concern., Methods: This post hoc analysis statistically explored the baseline characteristics of the ATTRACTION-2 patients and extracted a single-factor and double-factor combinations associated with early disease progression or early death. In the extracted patient subgroups, the 3-year restricted mean survival times of progression-free survival and overall survival were compared between the nivolumab and placebo arms., Results: Two single factors (age and peritoneal metastasis) were extracted as independent predictors of early progression, but none of them, as a single factor, stratified patients into two subgroups with significant differences in restricted mean survival time. In contrast, two double-factor combinations (serum sodium level and white blood cell count; serum sodium level and neutrophil-lymphocyte ratio) stratifying patients into two subgroups with significant differences in the restricted mean survival time were extracted. Additional exploratory analysis of a triple-factor combination showed that patients aged < 60 years with peritoneal metastasis and low serum sodium levels (approximately 7% of all patients) might receive less benefit from nivolumab, and patients aged ≥ 60 years with no peritoneal metastasis and normal serum sodium levels might receive higher benefit., Conclusions: A combination of age, peritoneal metastasis, and serum sodium level might predict benefit from nivolumab as salvage therapy in advanced gastric or gastroesophageal junction cancer patients, especially less benefit for patients having all three risk factors., (© 2021. The Author(s).)

Background: The frontier of onco-nephrology, particularly renal complications of cancer and treatment, remains unexplored. We revisit the fundamental tool of diagnosing kidney disease, renal biopsy, in cancer patients with renal manifestation., Methods: Patients who received renal biopsy from July 2015 to July 2019 were analyzed. Primary outcomes included end-stage renal disease (ESRD), mortality, and catastrophic outcome defined as either ESRD or mortality. A Cox proportional hazards model and Kaplan-Meier technique were used to assess the association with outcome measurements and survival analyses. Immunosuppression after renal biopsy and response to the treatment were evaluated., Results: Among the 77 patients, the median age was 66 years (interquartile range [IQR] 59-73 years) and 46 (59.7%) were male. At the time of renal biopsy, 57 patients (74%) had various degrees of renal insufficiency. Tubulointerstitial damage score, quantified by renal pathology, were associated with higher hazards of ESRD (hazard ratio [HR], 1.77; 95% confidence interval [95% CI], 1.20 to 2.61; P = 0.004) and catastrophic outcome (HR, 1.30; 95% CI, 0.99 to 1.70; P = 0.058). The response rate to immunosuppression was lower in those diagnosed with tubulointerstitial nephritis (1 of 4 patients, 25%) than those with glomerulopathy (10 of 20 patients, 50%)., Conclusion: Renal biopsy may improve diagnostic accuracy and assist in treatment guidance of cancer patients with renal manifestation. Renal biopsy should be encouraged with clinical indication. Collaboration between oncologists and nephrologists is of paramount importance to provide more comprehensive care for caner patients., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2021 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of localised colon cancer was published in 2020. It was decided by both the ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special virtual guidelines meeting in March 2021 to adapt the ESMO 2020 guidelines to take into account the ethnic differences associated with the treatment of localised colon cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with localised colon cancer representing the oncological societies of Japan (JSMO), China (CSCO), India (ISMPO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug availability and reimbursement situations in the different Asian countries., Competing Interests: Disclosure TY has reported research funding from Taiho Pharmaceuticals, Sumitomo Dainippon Pharma Co., Ltd, Chugai Pharmaceutical Co., Ltd, Sanofi KK, Daiichi Sankyo Co., Ltd, Parexel International Inc. and ONO Pharmaceutical Co., Ltd. GA has reported that he has acted as a consultant or speaker for Amgen, Roche, Merck, Sanofi, Servier, Merck Sharp & Dohme and Bayer. EO has declared fees for consultancy, speaking and advisory roles from Eli Lilly, Taiho Pharmaceuticals, Chugai Pharmaceutical Co., Ltd., Takeda, Pharmaceuticals, ONO Pharmaceutical Co., Ltd., Bayer and Bristol-Myers Squibb. EM has received honoraria for lecture and advisory boards from Roche, Amgen, Servier, AstraZeneca, Bayer, Merck Serono, Pierre Fabre, Incyte and Sanofi and speaker support from ESMO. HT declares research funding from RDKK, Sysmex, Daiichi Sankyo, Taiho and Takeda. DA has acted as a consultant or speaker for ACE Oncology, Amgen, Aptitude Health, art tempi media, AstraZeneca, Bayer, Boston Scientific, Bristol-Myers Squibb, CCO, CRA International, Eli Lilly, From Research to Practice, Hexal, Imedex, Ipsen, IQIVIA, Ketchum, MedAhead (Austria), Merck Serono, Merck Sharp and Dohme, Oncolytics, PharmaCept, Pierre Fabre, PRIMA Consulting, Roche, Samsung Bioepsis, Sanofi (Genyme), Terumo and Servier; received fees from Elsevier, WebHealth and Oxford University Press; and institutional funding from Bristol-Myers Squibb, OncoLytics and Pierre Fabre. BKS declares fees for consultancy and advisory roles from Eli Lilly, Novartis, Pfizer, AstraZeneca and Boehringer Ingelheim. IF declares fees for consultancy and advisory roles from Roche, AstraZeneca, Pfizer Merck and Novartis and research funding from Genetech, Samsung and Boehringer Ingelheim. K-HY declares fees for consultancy and advisory roles from Amgen, Boehringer Ingelheim, Bayer, Bristol-Myers Squibb, Merck Serono, Eli Lilly, ONO Pharmaceuticals, Takeda, Merck Sharp and Dohme, Daiichi Sankyo and AstraZeneca. GC declares fees for consultancy and advisory roles from AstraZeneca, Daichii Sankyo, Bristol-Myers Squibb, Lilly, Pfizer, Novartis, Ellipsis, Merck and Seagen. HB declares fees for consultancy and advisory roles from Eli Lilly, Taiho Pharmaceuticals and ONO Pharmaceutical Co., Ltd. FL declares fees for consultancy, speaking and advisory roles from Amgen, Astellas, AstraZeneca, Bayer, Beigene, Bristol-Myers Squibb, Eli Lilly, Imedex, MedUpdate, Merck Serono, Merck Sharp and Dohme, Promedicis, Roche, Servier, StreamedUp and Zymeworks; writing fees from Deutscher Arzteverleg, Imedico and Springer-Nature; expert testimony fees from Biontech and Elsevier; and research funding from Bristol-Myers Squibb. TY declares research funding from Chugai, Bayer and Taiho. JT reports personal financial interest in the form of scientific consultancy roles for Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, Merck Sharp and Dohme, Mirati, Neophore, Novartis, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics and TheraMyc; and educational collaborations with Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER). EB declares research funding from Bristol-Myers Squibb, Merck Sharp & Dohme, Eisai, Taiho, Bayer, Eli Lilly and Daichi-Sankyo. AC has reported fees for consultancy and advisory roles from Merck Serono, Amgen, BeiGene and Bristol-Myers Squibb; and research funding from AbbVie, Actuate Therapeutics, Alkermes Inc, Amgen, Astellas Pharma, Beigene, Bioncotech Therapeutics, Boehringer Ingelheim, Debiopharm International, F. Hoffmann-La Roche, FibroGen, Genmab, Janssen Research & Development, MedImmune, Meranini Ricerche, Novartis, Puma Biotechnology, Symphogen, Tahio, Transgene and WNT Research. AO has received research funding from Bristol-Myers Squibb. SP has reported fees for consultancy/advisory roles from AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, Foundation Medicine, Illumina, Imedex, Incyte, Janssen, Medscape, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, Pharma Mar, Phosplatin Therapeutics, PER, Pfizer, PRIME, Regeneron, Roche/Genentech, RTP, Sanofi, Seattle Genetics and Takeda; speaker roles for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, ecancer, Eli Lilly, Illumina, Imedex, Medscape, Merck Sharp and Dohme, Novartis, PER, Pfizer, Prime, Roche/Genentech, RTP, Sanofi and Takeda; and the receipt of grants/research support: (sub)investigator in trials (institutional financial support for trials) sponsored by Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, GSK, Illumina, Lilly, Merck Sharp and Dohme, Merck Serono, Mirati, Novartis, Pfizer, Phosplatin Therapeutics and Roche/Genentech. CI has received research funding from Chugai, Taiho, Daiichi-Sankyo, Takeda, Shionogi, Novartis, Eisai, Sanofi, Yakult, Merck Serono, Ono, Kyowa-Kirin, Nippon-Kayaku and Eli Lilly. GP reports fees for consultancy/advisory roles from Amgen, AstraZeneca, Bristol-Myers Squibb, Lilly, Merck, Merck Sharp and Dohme and Roche; and institutional funding from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Debiopharm, Enorasis, Genekor, Ipsen, Janssen, Lilly, Merck, Merck Sharp and Dohme, Pfizer, Roche, Sanofi and Servier. The remaining authors have declared no conflicts of interest, (Copyright © 2021. Published by Elsevier Ltd.)

Background: A new strategy, particularly a novel combination, for immunotherapy in microsatellite stable metastatic colorectal cancer (mCRC) treatment needs to be formulated. Studies on the interferon-γ (IFN-γ)/ Janus kinase (JAK)/ signal transducer and activator of transcription (STAT)1 pathway provide new directions in this regard., Methods: Our study applies three colon cancer cell lines, including microsatellite stable (MSS) cell lines, which are SW480 and SW620, and microsatellite instability-high (MSI-H) cell line, which is DLD-1. We compared the expressions of immune surface markers on colon cancer cells in response to IFN-γ. We elucidated these mechanisms, which involved the upregulation of immune surface markers. Furthermore, we examined real-world clinical samples using the PerkinElmer Opal multiplex system and NanoString analysis., Results: We established that the baseline expression of major histocompatibility complex (MHC) class I alleles and programmed death-ligand 1 (PD-L1) were generally low in cell line models. The immune surface markers were significantly increased after IFN-γ stimulation on SW480 but were notably unresponsive on the SW620 cell line. We discovered that STAT1 and phosphorylated STAT1 (pSTAT1) were downregulated in the SW620 cell line. We verified that the STAT1/pSTAT1 could be restored through the application of proteasome inhibitors, especially bortezomib. The expression of MHC class I as downstream signals of STAT1 was also up-regulated by proteasome inhibitors. The similar results were reproduced in DLD-1 cell line, which was also initially unresponsive to IFN-γ. In real-world samples of patients with mCRC, we found that higher STAT1 expression in tumor cells was strongly indicative of a highly immunogenic microenvironment, with significantly higher expression levels of MHC class I and PD-L1, not only on tumor cells but also on non-tumor cells. Furthermore, tumor infiltrating lymphocytes (TILs) were increased in the positive-STAT1 group. Through NanoString analysis, we confirmed that the mRNA expressions of IFN-γ, human leukocyte antigen (HLA)-A, HLA-E, and HLA-G were also significantly higher in the positive-STAT1 group than those in the negative-STAT1 group., Conclusion: Our study provides a novel rationale for the addition of bortezomib, a proteasome inhibitor, into new immunotherapy combinations., (© 2021. The Author(s).)

Background/purpose: This analysis reports safety and effectiveness data from the Taiwanese cohort of the CORRELATE study., Methods: CORRELATE was a prospective, observational study to assess the safety and effectiveness of regorafenib for the treatment of metastatic colorectal cancer (CRC) in real-world clinical practice that was conducted in 13 different countries in Asia, Europe and Latin America. The primary endpoint of the study was incidence of all treatment-emergent AEs (TEAEs), and secondary endpoints included overall survival (OS), progression-free survival (PFS), and disease control rate (DCR)., Results: The global study population (N = 1037) included 128 Taiwanese patients with a median age of 64 years, median weight of 62.02 kg and 66.41% were male. Reduced initiating doses of regorafenib and dose interruptions were common in Taiwanese patients (71.87% and 50.00%, respectively). The safety profile of regorafenib was consistent with that seen in Asian patients in the clinical development trials, including the CORRECT and CONCUR studies, with hand-foot-skin reactions (HFSR) of any grade occurring in 33.59% of patients. Median OS was 11.64 months in the Taiwanese patients (95% confidence interval [CI], 8.36-13.82) and median PFS was 2.17 months (95% CI, 1.97-2.89)., Conclusion: The safety and effectiveness of regorafenib in this real-world study was generally consistent with the known efficacy and safety profile in Asian patients in clinical trials., Trial Registration: NCT02042144., Competing Interests: Declaration of competing interest K-HY has received honoraria from Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly, Merck Serono, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, and Takeda. C-WD and Y-SL are full-time employees of Bayer. SF-B is a full-time employee of Bayer and owns stock in Bayer; MD has received grants/research support from Merck Serono and Roche; has participated on advisory boards for Amgen, Bayer, Celgene, Ipsen, Merck Serono, Roche and Servier; has received honoraria from Amgen, Bayer, Ipsen, Lilly, Merck Serono, Novartis, Roche and Servier; and has received travel/accommodations/expenses from Amgen, Ipsen, Lilly, Merck Serono, Merck Sharp & Dohme, and Roche. T-SY, T-CH, WT-LC, H-HC, H-WT, B-WL, F-CK, F-FC and J-YW have no conflicts of interest to report., (Copyright © 2020 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Immune checkpoint inhibitors have limited efficacy in the treatment of pancreatic ductal adenocarcinoma (PDAC). We investigated prognostic markers for nivolumab-based therapy in advanced or recurrent PDAC. Consecutive patients receiving nivolumab-based therapy at our institution between 2015 and 2020 were evaluated. Overall survival (OS) was analyzed through univariate and multivariate analyses. Spleen volume was estimated from the width, thickness, and length of the spleen. A total of 45 patients were identified. Biweekly nivolumab was administered as monotherapy ( n = 5) or in combination with chemotherapy or targeted therapy ( n = 40). Among 31 evaluable patients, the response and disease control rates were 7% and 36%, respectively. The baseline median spleen volume was 267 (110-674) mL. Patients with spleens ≥267 mL had significantly shorter median OS (1.9 months, 95% confidence interval [CI], 1.0-2.7) than did those with smaller spleens (8.2 months, 95% CI, 5.6-10.8; P = .003). In the multivariate analysis, spleen volume of <267 mL, ≤2 lines of prior chemotherapy, ECOG performance status of 0-2, add-on nivolumab with stable disease after prior therapy, concomitant or sequential cell therapy, high lymphocyte count, and total bilirubin <1 mg/dL were independent favorable prognostic factors for OS. In the control groups of patients receiving gemcitabine-based chemotherapy ( n = 142) or FOLFIRINOX regimen ( n = 24), spleen volume exhibited no prognostic significance. In heavily pretreated PDAC, a large spleen may predict poor OS following nivolumab-based immunotherapy. Studies with larger cohorts should confirm the prognostic value of spleen volume., Competing Interests: Ono Pharmaceutical Co., Ltd supported nivolumab for an ongoing investigator-initiated clinical trial in pancreatic cancer at National Taiwan University Hospital., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Background: We previously demonstrated that nuclear BCL10 translocation participates in the instigation of NF-κB in breast cancer and lymphoma cell lines. In this study, we assessed whether nuclear BCL10 translocation is clinically significant in advanced and metastatic pancreatic ductal adenocarcinoma (PDAC)., Method and Materials: We analyzed the expression of BCL10-, cell cycle-, and NF-κB- related signaling molecules, and the DNA-binding activity of NF-κB in three PDAC cell lines (mutant KRAS lines: PANC-1 and AsPC-1; wild-type KRAS line: BxPC-3) using BCL10 short hairpin RNA (shBCL10). To assess the anti-tumor effect of BCL10 knockdown in PDAC xenograft model, PANC-1 cells treated with or without shBCL10 transfection were inoculated into the flanks of mice. We assessed the expression patterns of BCL10 and NF-κB in tumor cells in 136 patients with recurrent, advanced, and metastatic PDAC using immunohistochemical staining., Results: We revealed that shBCL10 transfection caused cytoplasmic translocation of BCL10 from the nuclei, inhibited cell viability, and enhanced the cytotoxicities of gemcitabine and oxaliplatin in three PDAC cell lines. Inhibition of BCL10 differentially blocked cell cycle progression in PDAC cell lines. Arrest at G1 phase was noted in wild-type KRAS cell lines; and arrest at G2/M phase was noted in mutant KRAS cell lines. Furthermore, shBCL10 transfection downregulated the expression of phospho-CDC2, phospho-CDC25C, Cyclin B1 (PANC-1), Cyclins A, D1, and E, CDK2, and CDK4 (BxPC-3), p-IκBα, nuclear expression of BCL10, BCL3, and NF-κB (p65), and attenuated the NF-κB pathway activation and its downstream molecule, c-Myc, while inhibition of BCL10 upregulated expression of p21, and p27 in both PANC-1 and BxPC-3 cells. In a PANC-1-xenograft mouse model, inhibition of BCL10 expression also attenuated the tumor growth of PDAC. In clinical samples, nuclear BCL10 expression was closely associated with nuclear NF-κB expression (p < 0.001), and patients with nuclear BCL10 expression had the worse median overall survival than those without nuclear BCL10 expression (6.90 months versus 9.53 months, p = 0.019)., Conclusion: Nuclear BCL10 translocation activates NF-κB signaling and contributes to tumor progression and poor prognosis of advanced/metastatic PDAC., (© 2021. The Author(s).)

Background: ATTRACTION-2 demonstrated that nivolumab improved overall survival (OS) vs placebo in patients with advanced gastric cancer treated with ≥ 2 chemotherapy regimens. However, its long-term efficacy and outcome of treatment beyond progression (TBP) with nivolumab have not been clarified., Methods: The 3-year follow-up data were collected. A subset analysis was performed to explore the efficacy of TBP by assessing postprogression survival (PPS) after the first event of disease progression., Results: Overall, 493 patients were randomized (2:1) to receive nivolumab (n = 330) or placebo (n = 163). With a median follow-up of 38.5 (range 36.1-47.5) months, OS of the nivolumab group was significantly longer compared to the placebo group (median 5.3 vs 4.1 months; 3-year survival rate, 5.6% vs 1.9%; hazard ratio [HR], 0.62 [95% confidence interval (CI) 0.50-0.75], P < 0.0001). The median OS of responders (n = 32) who achieved complete response or partial response was 26.7 months and the 3-year survival rate was 35.5% in the nivolumab group. Overall, 109 patients in the nivolumab group and 37 patients in the placebo group received TBP. PPS tended to be longer in the nivolumab group vs placebo group (median 5.8 vs 4.5 months; HR [95% CI], 0.69 [0.47-1.01], P = 0.057). In contrast, PPS was similar between both treatment groups in non-TBP patients (median 2.3 vs 2.2 months; HR 0.90, P = 0.42)., Conclusions: Long-term efficacy of nivolumab was confirmed at the 3-year follow-up, and a survival benefit of TBP with nivolumab was suggested. Biomarkers for selecting patients suitable for TBP with nivolumab should be identified in the future.

Background: The corrected QT interval (QTc) predicts prognosis for the general population and patients with coronary artery disease (CAD). Growth differentiation factor-15 (GDF-15) is a biomarker of myocardial fibrosis and left ventricular (LV) remodelling. The interaction between these two parameters is unknown., Subjects and Methods: This study included 487 patients with angiographically confirmed CAD. QTc was calculated using the Bazett formula. Multiple biochemistries and GDF-15 levels were measured. The primary endpoint was total mortality, and the secondary endpoints comprised the combination of total mortality, myocardial infarction and hospitalisation for heart failure and stroke., Results: The mean follow-up period was 1029 ± 343 days (5-1692 days), during which 21 patients died and 47 had secondary endpoints. ROC curve analysis for the optimal cut-off value of primary endpoint is 1.12 ng/mL for GDF-15 (AUC = 0.787, P = 9.0 × 10 -6 ) and 438.5 msec for QTc (AUC = 0.698, P = .002). Utilising linear regression, QTc has a positive correlation with Log-GDF-15 (r = .216, P = 1.0 × 10 -6 ). Utilising Kaplan-Meier analysis, both QTc interval and GDF-15 level are significant predictors for primary end point (P = .000194, P = 2.0 × 10 -6 , respectively) and secondary endpoint (P = .00028, P = 6.15 × 10 -8 , respectively). When combined these two parameters together, a significant synergistic predictive power was noted for primary and secondary endpoint (P = 2.31 × 10 -7 , P = 1.26 × 10 -8 , respectively). This combined strategy also showed significant correlation with the severity of CAD (P < .001)., Conclusion: In Chinese patient with angiographically confirmed CAD, a combined strategy utilising an ECG parameter (QTc) and a circulating biomarker (GDF-15) has good correlation with the severity of CAD, and improves the predictive power for total mortality., (© 2021 John Wiley & Sons Ltd.)