Preliminary results of phase I trial of oral uracil/tegafur (UFT), leucovorin plus irinotecan and radiation therapy for patients with locally recurrent rectal cancer

BACKGROUND: Surgical attempts for locally recurrent rectal cancer often fail due to local re-recurrence and distant metastasis. Preoperative chemoradiation may enhance better local control and survival. The aim of this study was to assess the safety of oral uracil and tegafur (UFT) plus leucovorin (LV), and irinotecan combined with radiation and determine the maximum-tolerated dose (MTD) and dose limiting toxicity (DLT) of the triple drug regimen. PATIENTS AND METHODS: Patients with locally recurrent rectal cancer received escalating doses of irinotecan on days 1, 8, 15, and 22 (starting at 30 mg/m(2), with 10 mg increments between consecutive cohorts) and fixed doses of UFT (300 mg/m(2)) plus LV (75 mg/day) on days 3 to 7, 10 to 14, 17 to 21, and 24 to 28. Radiation was given 5 days per week totaling 40 to 50 Gy (2Gy/day). RESULTS: Six patients were treated at the starting dose, and 2 received the full scheduled chemoradiotherapy. The other 4 patients had grade 3 diarrhea and diarrhea was the DLT. One patient had partial response and he had subsequently radical surgical resection. Median progression free survival for local recurrence was 320 days. CONCLUSION: Irinotecan plus UFT/LV with concomitant radiotherapy in patients with locally recurrent rectal cancer was not feasible due to diarrhea in this setting. Modification of the treatment is needed

Prognostic Significance of C-reactive Protein-to-prealbumin Ratio in Patients with Esophageal Cancer

Background: The prognostic value of combination of C-reactive protein and prealbumin (CRP/PAlb) in esophageal cancer remains unclear. Methods: We enrolled 167 esophageal cancer patients who underwent curative esophagectomy. Univariate and multivariate analyses were performed to determine the prognostic significance of various markers, including CRP-to-albumin (CRP/Alb) ratio, modified Glasgow prognostic score, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and prognostic nutritional index. Results: Receiver operating characteristic analysis revealed the optimal cut-off value of each inflammatory factor, and CRP/PAlb ratio had the greatest discriminative power in predicting recurrence-free survival (RFS) among the examined measures (AUC 0.668). The 5-year overall survival and RFS rates were significantly lower in patients with high CRP/PAlb ratio than in those with low CRP/PAlb ratio (P < 0.001, P = 0.001, respectively). In the univariate analysis, RFS was significantly worse in patients with low BMI, T2 or deeper tumor invasion, positive lymph node metastasis, positive venous invasion, high CRP/PAlb ratio, high CRP/Alb ratio, high NLR, and high LMR. Multivariate analysis revealed that CRP/PAlb, but not CRP/Alb, was an independent prognostic factor along with lymph node metastasis. Conclusion: CRP/PAlb ratio was useful for predicting the prognosis of esophageal cancer patients

The role of AGE-Rage system in the development of diabetic nephropathy in vivo

金沢大学大学院医学部医学系研究科Vascular complications are what eventually threaten the lives of diabetic patients. Here we show direct in vivo evidence that the interaction between advanced glycation end products (AGE), the formation of which is accelerated during prolonged hyperglycemic exposure, and a cell surface receptor for AGE (RAGE) is the major cause of such complications. We created transgenic mice that overexpress human RAGE in vascular cells and crossbred them with another transgenic line which develops insulin-dependent diabetes early after birth. The resultant double transgenic mice exhibited accelerated kidney changes compared with single transgenic littermates, and the nephropathy was ameliorated by an inhibitor of AGE formation. The AGE–RAGE system will thus be a promising target for overcoming diabetic complications

A call for new approaches to quantifying biases in observations of sea-surface temperature

Global surface-temperature changes are a fundamental expression of climate change. Recent, much-debated, variations in the observed rate of surface-temperature change have highlighted the importance of uncertainty in adjustments applied to sea-surface temperature (SST) measurements. These adjustments are applied to compensate for systematic biases and changes in observing protocol. Better quantification of the adjustments and their uncertainties would increase confidence in estimated surface-temperature change and provide higher- quality gridded SST fields for use in many applications. Bias adjustments have been based either on physical models of the observing processes or on the assumption of an unchanging relationship between SST and a reference data set such as night marine air temperature. These approaches produce similar estimates of SST bias on the largest space and timescales, but regional differences can exceed the estimated uncertainty. We describe challenges to improving our understanding of SST biases. Overcoming these will require clarification of past observational methods, improved modeling of biases associated with each observing method, and the development of statistical bias estimates that are less sensitive to the absence of metadata regarding the observing method. New approaches are required that embed bias models, specific to each type of observation, within a robust statistical framework. Mobile platforms and rapid changes in observation type require biases to be assessed for individual historic and present-day platforms (i.e., ships or buoys) or groups of platforms. Lack of observational metadata and of high-quality observations for validation and bias model development are likely to remain major challenges

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

A multicenter prospective observational study of lymph node metastasis patterns and short‐term outcomes of extended lymphadenectomy in right‐sided colon cancer

Abstract Background The lymph node metastasis rate in right‐sided colon cancer is unknown, and the optimal central vascular ligation level remains controversial. We aimed to determine the lymph node metastasis rate and short‐term results of radical surgery with extended lymph node dissection in right‐sided colon cancer. Methods This prospective multicenter observational study included patients with stage II/III right‐sided colon cancer from five cancer hospitals. The metastasis rate of each node station was analyzed according to tumor location and main feeding artery. Results Between April 2018 and August 2021, 208 patients underwent dissection around the superior mesenteric artery (SMA) and vein (SMV). In transverse colon cancer, 7.5% and 2.5% of metastases occurred around the SMV and SMA at the root of the middle colic artery (MCA), respectively; 6.7% and 6.7% at the root of the right colic artery. In caecal cancer, 1.9% of metastases occurred around the SMV and 1.9% around the SMA. In ascending colon cancer, the rate was 1.1% around the SMV. Of the tumors, 17% fed mainly by the ileocolic artery had node metastases along the middle or right colic artery, as did 66.7% fed mainly by the right colic artery and 41.2% fed by the MCA (p = 0.01). Postoperative complications occurred in 42 patients (20.2%). Conclusion Routine prophylactic extended lymphadenectomy around the SMA might not be necessary in caecum and ascending colon cancer. Dissection around the SMA may be necessary in cases of transverse colon cancer or when the feeding artery is the MCA