Preoperative factors associated with lateral lymph node metastasis in lower rectal cancer and the evaluation of the middle rectal artery.

PURPOSE: This study aimed to identify cases in which lateral lymph node (LLN) dissection (LLND) can be excluded by clarifying preoperative factors, including an evaluation of the middle rectal artery (MRA), associated with LLN metastasis. METHODS: Fifty-five consecutive patients who underwent preoperative positron emission tomography-computed tomography (PET/CT) and total mesorectal excision with LLND for rectal cancer were included. We retrospectively investigated the preoperative clinical factors associated with pathological LLN (pLLN) metastasis. We analyzed the regions of pLLN metastasis using MRA. RESULTS: pLLN metastasis occurred in 13 (23.6%) patients. According to a multivariate analysis, clinical LLN (cLLN) metastasis based on short-axis size and LLN status based on PET/CT were independent preoperative factors of pLLN metastasis. The negative predictive value (NPV) was high (97.1%) in patients evaluated as negative based on PET/CT and cLLN short-axis size. MRA was detected in 24 patients (43.6%) using contrast-enhanced CT, and there was a significant relationship between pLLN metastasis and the presence of MRA. pLLN metastasis in the internal iliac region but not in the obturator region was significantly correlated with the presence of MRA. CONCLUSION: Combined cLLN metastasis based on short-axis size and PET/CT showed a higher NPV, suggesting this to be a useful method for identifying cases in which LLND can be excluded.

Development of Orally Bioavailable Peptides Targeting an Intracellular Protein: From a Hit to a Clinical KRAS Inhibitor.

Cyclic peptides as a therapeutic modality are attracting a lot of attention due to their potential for oral absorption and accessibility to intracellular tough targets. Here, starting with a drug-like hit discovered using an mRNA display library, we describe a chemical optimization that led to the orally available clinical compound known as LUNA18, an 11-mer cyclic peptide inhibitor for the intracellular tough target RAS. The key findings are as follows: (i) two peptide side chains were identified that each increase RAS affinity over 10-fold; (ii) physico-chemical properties (PCP) including Clog P can be adjusted by side-chain modification to increase membrane permeability; (iii) restriction of cyclic peptide conformation works effectively to adjust PCP and improve bio-activity; (iv) cellular efficacy was observed in peptides with a permeability of around 0.4 × 10-6 cm/s or more in a Caco-2 permeability assay; and (v) while keeping the cyclic peptide's main-chain conformation, we found one example where the RAS protein structure was changed dramatically through induced-fit to our peptide side chain. This study demonstrates how the chemical optimization of bio-active peptides can be achieved without scaffold hopping, much like the processes for small molecule drug discovery that are guided by Lipinski's rule of five. Our approach provides a versatile new strategy for generating peptide drugs starting from drug-like hits.

Validation of a New Methodology to Create Oral Drugs beyond the Rule of 5 for Intracellular Tough Targets.

Establishing a technological platform for creating clinical compounds inhibiting intracellular protein-protein interactions (PPIs) can open the door to many valuable drugs. Although small molecules and antibodies are mainstream modalities, they are not suitable for a target protein that lacks a deep cavity for a small molecule to bind or a protein found in intracellular space out of an antibody's reach. One possible approach to access these targets is to utilize so-called middle-size cyclic peptides (defined here as those with a molecular weight of 1000-2000 g/mol). In this study, we validated a new methodology to create oral drugs beyond the rule of 5 for intracellular tough targets by elucidating structural features and physicochemical properties for drug-like cyclic peptides and developing library technologies to afford highly N-alkylated cyclic peptide hits. We discovered a KRAS inhibitory clinical compound (LUNA18) as the first example of our platform technology.

Comparison between preoperative chemoradiotherapy and lateral pelvic lymph node dissection in clinical T3 low rectal cancer without enlarged lateral lymph nodes.

AIM: The standard strategy for clinical T3 rectal cancer without enlarged lateral lymph nodes is preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME) in Western countries and TME with bilateral lateral pelvic lymph node dissection (LPLND) in Japan. This study compared surgical, pathological and oncological results of these two strategies. METHOD: Patients who underwent preoperative CRT followed by TME in France (CRT + TME group) and those who underwent TME with LPLND in Japan (TME + LPLND group) for clinical T3 rectal adenocarcinoma without enlarged lateral lymph nodes from 2010 to 2016 were retrospectively analysed. RESULTS: In total, 439 patients were included in this study. The estimated local recurrence rate (LRR), disease-free survival and overall survival at 5 years post-surgery was 4.9%, 71% and 82% in the CRT + TME group, and 8.6%, 75% and 90% in the TME + LPLND group, respectively. Lateral LRR versus non-lateral LRR was 0.5% versus 4.2% in the CRT + TME group and 1.8% versus 6.2% in the TME + LPLND group. Obturator nerve injury and isolated pelvic abscess were shown only in the TME + LPLND group. Urinary complications were more frequent in the TME + LPLND group than in the CRT + TME group. CONCLUSION: Disease-free survival was not significantly different after TME with LPLND and after CRT followed by TME. LRR was not significantly different after both strategies; however, there was a trend for higher LRR after TME with LPLND than after CRT followed by TME. Obturator nerve injury, isolated lateral pelvic abscess and urinary complications should be noted when TME with LPLND is applied.

Retroperitoneal urothelial carcinoma arising after bladder diverticulectomy: a case report.

BACKGROUND: Urothelial carcinoma arises from the inner urothelial membrane of the renal pelvis, ureter, and bladder and often causes macrohematuria. Here, we report a rare case in which the patient developed non-symptomatic urothelial carcinoma anatomically outside the bladder wall 17 years after bladder diverticulectomy. CASE PRESENTATION: An 82-year-old male patient previously underwent gastrectomy for stomach cancer and partial hepatectomy for intrahepatic cholangiocarcinoma. Follow-up computed tomography revealed a tumor in the retroperitoneal space, where a bladder diverticulum was removed 17 years earlier. Multiparametric magnetic resonance imaging suggested that the tumor was malignant with rectal invasion. Subsequent computed tomography-guided percutaneous biopsy revealed that the tumor was urothelial carcinoma. The patient underwent two courses of neoadjuvant chemotherapy followed by pelvic exenteration with pelvic lymph node dissection. He is currently receiving adjuvant therapy with an immune checkpoint inhibitor and has had no recurrence for 3 months. CONCLUSIONS: Multiparametric magnetic resonance imaging is a helpful tool for predicting both tumor malignancy and invasion before a pathologically confirmed diagnosis. Although this case is rare, urologists should be aware of the occurrence of urothelial carcinoma after bladder diverticulectomy in cases of incomplete resection of the diverticulum.

Association of High LAT1 Expression with Poor Prognosis and Recurrence in Colorectal Cancer Patients Treated with Oxaliplatin-Based Adjuvant Chemotherapy.

The mammalian target of rapamycin (mTOR) is often activated in several cancers. We focused on two mTOR regulatory mechanisms: oxaliplatin-induced mTOR signaling and L-type amino acid transporter 1 (LAT1)-induced mTOR activation. High LAT1 expression in several cancers is associated with mTOR activation and resistance to chemotherapy. However, the significance of LAT1 has not yet been elucidated in colorectal cancer (CRC) patients treated with post-operative adjuvant chemotherapy. Immunohistochemistry was conducted to examine the significance of membrane LAT1 expression in 98 CRC patients who received adjuvant chemotherapy, including oxaliplatin. In vitro analysis was performed using CRC cell lines to determine the effects of LAT1 suppression on proliferation, oxaliplatin sensitivity, and mTOR signaling. LAT1 expression was associated with cancer aggressiveness and poor prognosis in 98 CRC patients treated with adjuvant chemotherapy. We found that positive LAT1 expression correlated with shorter survival in 43 patients treated with the capecitabine-plus-oxaliplatin (CAPOX) regimen. LAT1 suppression in CRC cells inhibited the proliferation potency and oxaliplatin-induced activation of mTOR signaling, and improved oxaliplatin sensitivity. LAT1 evaluation before adjuvant treatment may therefore be a sensitive marker for oxaliplatin-based regimens. Moreover, LAT1 may be a promising target for patients with refractory CRC.

HLA Class I Expression Is Associated with DNA Damage and Immune Cell Infiltration into Dysplastic and Neoplastic Lesions in Ulcerative Colitis.

Human leukocyte antigen class I (HLA-I) is considered a genetic pathogen for ulcerative colitis (UC). This study aimed to investigate the significance of DNA damage and HLA-I expression in infiltrating immune cells and immune checkpoint protein PD-L1 expression in dysplasia/colitic cancer (CC) and sporadic colorectal cancer (SCRC). We performed immunohistochemical staining for HLA-I, PD-L1, γH2AX (DNA damage marker), and immune cell markers such as CD8, FOXP3, CD68, and CD163 (in surgically resected specimens from 17 SCRC patients with 12 adjacent normal mucosa (NM) and 9 UC patients with 18 dysplasia/CC tumors. The ratio of membrane HLA-I-positive epithelial cells in UC and dysplasia/CC tissues was significantly higher than that in NM and SCRC. High HLA-I expression in dysplasia/CC was associated with high positivity of γH2AX and PD-L1 expression compared to SCRC. The infiltration of CD8-positive T cells and CD68-positive macrophages in HLA-I-high dysplasia/CC was significantly higher than in UC and SCRC. Dysplasia/CC specimens with DNA damage exhibited high levels of HLA-I-positive epithelial cells with high CD8- and CD68-positive immune cell infiltration compared to UC and SCRC specimens. Targeting DNA damage in UC may regulate immune cell infiltration, immune checkpoint proteins, and carcinogenesis by modulating DNA damage-induced HLA-I antigen presentation.

Retrospective study of online ligation student practice incorporating flipped learning into e-learning.

PURPOSE: Flipped learning has been applied in various fields, including medical professional education. E-learning is compatible with flipped learning; however, it is considered to be unsuitable for providing training on surgical techniques. In this study, we retrospectively examined the ligation performance of online students who underwent training with flipped learning incorporated into e-learning. METHODS: We conducted a retrospective study of the ligation practices of online students at the Department of General Surgery from March 2020 to June 2021. The subjects included 134 fourth- and fifth-year medical students from Gunma University School of Medicine. We conducted mid-term checks on the 8th day of practice and an examination on the 19th day. Two instructors independently evaluated and calculated scores using the original Global Rating Scale of Gunma University. We also conducted a questionnaire survey on the ligation practice of online students. RESULTS: The total average score of the three tasks was 12.4 for Instructor 1 and 12.0 for Instructor 2. All students had a passing score. The questionnaire survey showed that 70% of the students were trained in ligation at the time of the first evaluation. CONCLUSIONS: Our online training materials and training methods enabled the acquisition of ligation skills by students who had not previously received ligation training.

High expression of TMEM180, a novel tumour marker, is associated with poor survival in stage III colorectal cancer.

BACKGROUND: Transmembrane protein 180 (TMEM180) is a newly identified colorectal cancer (CRC)-specific molecule that is expressed very rarely in normal tissue and up-regulated under hypoxic conditions. We developed a monoclonal antibody (mAb) against TMEM180 and decided to examine the medical significance using the mAb. METHODS: A total of 157 patients (86 men and 71 women; median age 63.0 years) with stage III CRC who underwent curative surgery were analyzed for TMEM180 expression as a retrospective cohort design. Immunohistochemistry with anti-TMEM180 mAb was conducted on frozen sections, and the data were evaluated for any correlation with clinicopathological indices or prognosis. SW480 CRC cells were examined to investigate the relationship between the expression of TMEM180 and tumourigenesis of xenografts. RESULTS: In total, 92 cases had low TMEM expression and 65 had high TMEM180 expression. For disease-free survival, hazard ratio in high-TMEM180 cases was 1.449 (95% confidential interval = 0.802-2.619) higher than in low-TMEM180 cases, but the difference was not significant (p = 0.219). For cancer specific survival, hazard ratio in high-TMEM180 cases was 3.302 (95% confidential interval = 1.088-10.020), significantly higher than in low-TMEM180 cases (p = 0.035). In an assay examining in vitro colony-forming activity in soft agar, SW480-WT cells clearly formed colonies, but neither KD1 nor KD2 cells did. The in vivo tumour-initiating activity of SW480 cell lines was positively correlated with the level of TMEM180 expression. CONCLUSION: These results indicate that TMEM180 is a useful marker for clinical prognosis in patients with CRC. We believe that these fundamental data warrant further basic and translational studies of TMEM180, and its mAb, for development of therapeutics against CRC.

Radiologic Factors and Areas of Local Recurrence in Locally Advanced Lower Rectal Cancer After Lateral Pelvic Lymph Node Dissection.

BACKGROUND: Identifying preoperative risk factors of local recurrence and patterns of treatment failure resulting after rectal cancer management is important for planning treatment strategies and improving the results of multidisciplinary care. OBJECTIVE: The purpose of this study was to analyze the associations between the preoperative factors and local recurrence and to investigate the local recurrence areas in patients with locally advanced lower rectal cancer who underwent lateral pelvic lymph node dissection. DESIGN: The study used a retrospective cohort design. SETTINGS: It was conducted at a single institution. PATIENTS: Overall 469 patients with locally advanced lower rectal adenocarcinoma located below the peritoneal reflex who received curative resection with lateral pelvic lymph node dissection during 2010 to 2018 were included. MAIN OUTCOME MEASURES: Independent risk factors for local recurrence were assessed using multivariate Cox regression. Local recurrence was classified into 3 areas using follow-up images. RESULTS: A total of 286 patients underwent upfront surgery, 132 patients received neoadjuvant chemotherapy followed by surgery, and 51 patients received preoperative chemoradiotherapy followed by surgery. Eighty-six patients (18.3%) were extramural venous invasion positive, and 113 patients (24.1%) were circumferential resection margin positive. The median follow-up period was 46 months. Local recurrence showed significant association with extramural venous invasion positive (HR = 2.596 (95% CI, 1.321-5.102); p = 0.006) or circumferential resection margin positive (HR = 2.298 (95% CI, 1.158-4.560); p = 0.017). The incidence of local recurrence was observed in 51 patients (10.8%), with the pelvic plexus and internal iliac area being the most frequent (6.6%), followed by the central pelvis area (3.8%), and was markedly low in the obturator area (0.4%). LIMITATIONS: This was a retrospective, single-institution design. CONCLUSIONS: Extramural venous invasion status and circumferential resection margin status were associated with a high local recurrence rate in patients who underwent lateral pelvic lymph node dissection. In addition, local recurrence in the obturator area was low compared with that in other areas. See Video Abstract at http://links.lww.com/DCR/B683. FACTORES RADIOLGICOS Y REAS DE RECURRENCIA LOCAL EN EL CNCER DE RECTO INFERIOR LOCALMENTE AVANZADO DESPUS DE LA DISECCIN GANGLIONAR PLVICA LATERAL: ANTECEDENTES:El identificar los factores de riesgo preoperatorios para recurrencia local y los patrones de fracaso del tratamiento que resultan del manejo del cáncer de recto es importante para planificar las estrategias de tratamiento y mejorar los resultados de la atención multidisciplinaria.OBJETIVO:Analizar las asociaciones entre los factores preoperatorios y la recidiva local, e investigar las áreas de recidiva local en pacientes con cáncer de recto inferior localmente avanzado que se sometieron a disección de ganglios linfáticos pélvicos laterales.DISEÑO:Un diseño de cohorte retrospectivo.ENTORNO CLÍNICO:Una sola institución.PACIENTES:Un total de 469 pacientes con adenocarcinoma rectal inferior localmente avanzado ubicado debajo del reflejo peritoneal que recibieron resección curativa con disección de ganglios linfáticos pélvicos laterales durante 2010-2018.PRINCIPALES MEDIDAS DE RESULTADO:Los factores de riesgo independientes de recurrencia local se evaluaron mediante regresión de Cox multivariante. La recurrencia local se clasificó en 3 áreas utilizando imágenes de seguimiento.RESULTADOS:Doscientos ochenta y seis pacientes se sometieron a cirugía inicial, 132 pacientes recibieron quimioterapia neoadyuvante seguida de cirugía y 51 pacientes recibieron quimiorradioterapia preoperatoria seguida de cirugía. Ochenta y seis pacientes (18,3%) fueron positivos para invasión venosa extramural y 113 pacientes (24,1%) fueron positivos para el margen de resección circunferencial. La mediana del período de seguimiento fue de 46 meses. La recidiva local mostró una asociación significativa con la invasión venosa extramural positiva (cociente de riesgo: 2,596; intervalo de confianza del 95%: 1,321-5,102; p = 0,006) o el margen de resección circunferencial positivo (cociente de riesgo: 2,298; intervalo de confianza del 95%: 1,158-4,560; p = 0,017). La incidencia de recidiva local se observó en 51 pacientes (10,8%), siendo el plexo pélvico y el área ilíaca interna los más frecuentes (6,6%), seguidos del área pélvica central (3,8%), y fue marcadamente baja en el área del obtudador (0.4%).LIMITACIONES:Un diseño retrospectivo de una sola institución.CONCLUSIONES:El estado de invasión venosa extramural o el estado del margen de resección circunferencial se asociaron con una alta tasa de recurrencia local en pacientes que se sometieron a disección de ganglios linfáticos pélvicos laterales. Además, la recurrencia local en el área del obturador fue baja en comparación con la de otras áreas. Consulte Video Resumen en http://links.lww.com/DCR/B683.

6-Arylcoumarin as a Scaffold of Photofunctional Molecules with OFF-ON-OFF Type Regulation.

Coumarin has been utilized as a core structure of photofunctional molecules, such as fluorescent sensors and photoremovable protecting groups. Here, we show that the 6-arylcoumarin moiety can provide OFF-ON-OFF type regulatory functionality for such compounds. To illustrate its utility, we synthesized a coumarin derivative bearing two phenolic hydroxy groups at 7-position and on 6-aryl group as a fluorescent sensor showing an OFF-ON-OFF change in fluorescence intensity in response to an increase in pH from a strongly acidic condition. Further, we show that the efficiency of photoreaction of other derivatives with the same hydroxyl groups is switched from "OFF" at pH 3 and 6 to "ON" at pH 9 and then to OFF at pH 12, enabling their application as switchable photoremovable protective groups. These features arise from sequential deprotonation of two hydroxyl groups: the monoanionic form is responsible for the photoinduced fluorescence and photoreaction.

Association between urinary function and resected pattern of the autonomic nerve system after transanal total mesorectal excision for rectal cancer.

AIM: Transanal total mesorectal excision (TaTME) is expected to improve the quality of total mesorectal excision as well as preserve urinary function. We aimed to study the frequency and risk factors of urinary dysfunction in rectal cancer patients after TaTME. Moreover, we analysed the association between urinary function and resected pattern of the autonomic nerve system (ANS) in TaTME. METHOD: We retrospectively analysed 231 patients who underwent TaTME at our hospital from 2013 to 2018. Independent risk factors for urinary dysfunction were assessed by multivariate analysis. Urinary dysfunction was defined as a condition that requires urethral catheterisation. We intraoperatively judged and classified the preserved or resected pattern of ANS into four categories. RESULTS: The rate of urinary dysfunction after TaTME was 12.1% at discharge. Multivariate analysis revealed that beyond TME and ANS resection were the two major independent risk factors for urinary dysfunction. Total ANS preservation had reduced rates of urinary dysfunction, and all patients were free from catheterisation 6 months post-surgery. There was a higher rate of urinary dysfunction in total ANS resection than in partial ANS resection at 6 months post-surgery. CONCLUSION: This study showed that urinary function after TaTME was associated with resection of the ANS. Furthermore, the rate of urinary dysfunction and recovery time were closely related to the pattern of ANS resection.

The Plant Noncanonical Antiviral Resistance Protein JAX1 Inhibits Potexviral Replication by Targeting the Viral RNA-Dependent RNA Polymerase.

Understanding the innate immune mechanisms of plants is necessary for the breeding of disease-resistant lines. Previously, we identified the antiviral resistance gene JAX1 from Arabidopsis thaliana, which inhibits infection by potexviruses. JAX1 encodes a unique jacalin-type lectin protein. In this study, we analyzed the molecular mechanisms of JAX1-mediated resistance. JAX1 restricted the multiplication of a potexviral replicon lacking movement-associated proteins, suggesting inhibition of viral replication. Therefore, we developed an in vitro potato virus X (PVX) translation/replication system using vacuole- and nucleus-free lysates from tobacco protoplasts, and we revealed that JAX1 inhibits viral RNA synthesis but not the translation of the viral RNA-dependent RNA polymerase (RdRp). JAX1 did not affect the replication of a resistance-breaking mutant of PVX. Blue native polyacrylamide gel electrophoresis of fractions separated by sucrose gradient sedimentation showed that PVX RdRp constituted the high-molecular-weight complex that seems to be crucial for viral replication. JAX1 was detected in this complex of the wild-type PVX replicon but not in that of the resistance-breaking mutant. In addition, JAX1 interacted with the RdRp of the wild-type virus but not with that of a virus with a point mutation at the resistance-breaking residue. These results suggest that JAX1 targets RdRp to inhibit potexviral replication.IMPORTANCE Resistance genes play a crucial role in plant antiviral innate immunity. The roles of conventional nucleotide-binding leucine-rich repeat (NLR) proteins and the associated defense pathways have long been studied. In contrast, recently discovered resistance genes that do not encode NLR proteins (non-NLR resistance genes) have not been investigated extensively. Here we report that the non-NLR resistance factor JAX1, a unique jacalin-type lectin protein, inhibits de novo potexviral RNA synthesis by targeting the huge complex of viral replicase. This is unlike other known antiviral resistance mechanisms. Molecular elucidation of the target in lectin-type protein-mediated antiviral immunity will enhance our understanding of the non-NLR-mediated plant resistance system.

Risk factors for the incidence and severity of peristomal skin disorders defined using two scoring systems.

PURPOSE: Peristomal skin disorders (PSDs) are common stoma-related complications. However, there is no standard method for the evaluation of PSDs, and the true incidence is unclear. There are also no reports on risk factors for severe PSDs. Therefore, this study was performed to analyze the incidence of PSD in temporary loop stoma based on the DET score and ABCD-stoma score and to determine the risk factors for all and severe PSDs. METHODS: A retrospective analysis of patient and surgical characteristics was carried out in 333 consecutive cases of stoma creation with loop ileostomy or colostomy performed at our hospital from January 2014 to December 2016. RESULTS: PSDs were diagnosed in 262 patients (78.7%), including 79 (23.7%) and 71 (21.3%) that were defined as severe based on DET and ABCD-stoma scores, respectively. Multivariate analyses showed that parastomal hernia was an independent risk factor for severe PSD defined by DET score and that adjuvant chemotherapy was an independent risk factor for severe PSD defined by the ABCD-stoma score. CONCLUSIONS: Severe PSDs are associated with parastomal hernia when diagnosed by the DET score and with adjuvant chemotherapy when diagnosed by the ABCD-stoma score.

Risk factors for parastomal hernia of loop stoma and relationships with other stoma complications in laparoscopic surgery era.

BACKGROUND: Laparoscopic approach is now a widespread technique used worldwide, but there are few recent studies on risk factors for parastomal hernia. Therefore, this study was performed to analyze the incidence of parastomal hernia in laparoscopic and open surgery in which a loop stoma was created and was intended to be temporary, and to determine risk factors for parastomal hernia formation. Associations between parastomal hernia and other stoma-related complications were also analyzed. METHODS: A retrospective analysis of patient and surgical characteristics was performed in 153 consecutive patients who underwent a temporary diverting loop ileostomy or colostomy after surgery related to malignant diseases at our hospital from January to December 2016. RESULTS: Parastomal hernia developed in 77 cases (50.3%), including 39 (25.5%) diagnosed by physical examination and 38 (24.8%) detected by CT alone. On multivariate analysis, a stoma not passing through the middle of the rectus abdominis muscle was the only independent risk factor for parastomal hernia formation (p = 0.005) during the median follow-up of 245.0 days. When we analyzed the factors that were associated with a stoma not passing through the middle of the rectus abdominis muscle, the only independent factor associated with this misplacement of the stoma was a laparoscopic approach (p = 0.012). An analysis of stoma-related complications showed that peristomal skin disorders were significantly associated with parastomal hernia (p = 0.049). CONCLUSIONS: This study showed that a stoma that is not formed through the middle of the rectus abdominis muscle is a risk factor for parastomal hernia formation, and that a laparoscopic approach is associated with this risk factor. Moreover, parastomal hernia is significantly associated with peristomal skin disorders.

Predicting prognosis according to preoperative chemotherapy response in patients with locally advanced lower rectal cancer.

BACKGROUND: Neoadjuvant chemoradiotherapy is regarded as the standard of treatment for locally advanced lower rectal cancer, although some of these cases are systemic, and distant control may be inadequate. Neoadjuvant chemotherapy could compensate for such shortcomings, potentially yielding better survival outcomes. We aimed to stratify patients into prognostic groups on the basis of preoperative factors, including response to neoadjuvant chemotherapy. METHODS: We retrospectively analyzed patients with locally advanced lower rectal adenocarcinoma (clinical stage II/III with high-risk features of distant metastasis) who were treated with neoadjuvant chemotherapy (without radiotherapy) followed by curative resection between 2010 and 2017. Reduction in tumor volume (before vs. after neoadjuvant chemotherapy) was measured using magnetic resonance imaging, and a reduction above 60% was defined as a good response. Recurrence and overall survival were evaluated. RESULTS: The cohort comprised 102 patients. Good response to neoadjuvant chemotherapy was associated with better 5-year recurrence-free survival (good responders: 81.1%, poor responders: 49.0%; p = 0.001) and 5-year overall survival (good responders: 94.9%, poor responders: 80.6%; p = 0.06). In a multivariate analysis, extramural venous invasion on magnetic resonance imaging after neoadjuvant chemotherapy and a tumor volume reduction rate < 60 were found to be significantly and independently associated with worse recurrence-free survival (hazard ratio: 2.74, 95% confidence interval: 1.36-5.50, p = 0.005 and hazard ratio: 3.48, 95% confidence interval: 1.57-7.72, p = 0.002, respectively). Good responders without extramural venous invasion had the best 5-year recurrence-free and overall survival (89.0 and 93.8%, respectively). Poor responders with extramural venous invasion had the worst 5-year recurrence-free and overall survival (21.4 and 50.0%, respectively). CONCLUSIONS: Reductions in tumor volume after neoadjuvant chemotherapy were associated with a better prognosis in patients with locally advanced lower rectal cancer. Extramural venous invasion was a preoperative prognostic factor.

Factor VII and incidence of myocardial infarction in a Japanese population: The Jichi Medical School Cohort Study.

BACKGROUND: The role of factor VII (FVII) as a risk factor in myocardial infarction (MI) has been the subject of numerous studies. However, it remains uncertain whether the FVII levels are associated with development of MI. METHODS: The subjects were 4142 men and women whose activated FVII (FVIIa) and FVII coagulant (FVIIc) levels were measured in the Jichi Medical School Cohort Study. Subjects were divided into tertiles by FVIIa and FVIIc levels, and Cox's proportional hazard model was used to calculate hazard ratios (HRs) for MI. RESULTS: The multivariate-adjusted HRs (95% confidential interval [CI]) for FVIIa in men were 0.67 (0.67-1.78) in tertile 2 (T2), and 0.52 (0.17-1.60) in T3. In women, the multivariate-adjusted HRs (95% CI) were 0.18 (0.02-1.60) in T2, and 0.39 (0.07-2.20) in T3. The multivariate-adjusted HRs (95% CI) for FVIIc in men were 0.54 (0.21-1.36) in T2, and 0.20 (0.04-0.91) in T3. In women, the multivariate-adjusted HRs (95% CI) were 0.44 (0.07-2.85) in T2, and 0.35 (0.06-2.22) in T3. We used T1 as a reference for all measures. CONCLUSION: Our findings revealed a significant association between low FVIIc level and incidence of MI in men. The FVIIa and FVIIc levels were inversely related to increased MI risk, but did not reach statistical significance. Future studies are needed to confirm this association.

Cell Death Triggered by a Putative Amphipathic Helix of Radish mosaic virus Helicase Protein Is Tightly Correlated With Host Membrane Modification.

Systemic necrosis is one of the most severe symptoms caused by plant RNA viruses. Recently, systemic necrosis has been suggested to have similar features to a defense response referred to as the hypersensitive response (HR), a form of programmed cell death. In virus-infected plant cells, host intracellular membrane structures are changed dramatically for more efficient viral replication. However, little is known about whether this replication-associated membrane modification is the cause of the symptoms. In this study, we identified an amino-terminal amphipathic helix of the helicase encoded by Radish mosaic virus (RaMV) (genus Comovirus) as an elicitor of cell death in RaMV-infected plants. Cell death caused by the amphipathic helix had features similar to HR, such as SGT1-dependence. Mutational analyses and inhibitor assays using cerulenin demonstrated that the amphipathic helix-induced cell death was tightly correlated with dramatic alterations in endoplasmic reticulum (ER) membrane structures. Furthermore, the cell death-inducing activity of the amphipathic helix was conserved in Cowpea mosaic virus (genus Comovirus) and Tobacco ringspot virus (genus Nepovirus), both of which are classified in the family Secoviridae. Together, these results indicate that ER membrane modification associated with viral intracellular replication may be recognized to prime defense responses against plant viruses.

A Potent and Site-Selective Agonist of TRPA1.

TRPA1 is a member of the transient receptor potential (TRP) cation channel family that is expressed primarily on sensory neurons. This chemosensor is activated through covalent modification of multiple cysteine residues with a wide range of reactive compounds including allyl isothiocyanate (AITC), a spicy component of wasabi. The present study reports on potent and selective agonists of TRPA1, discovered through screening 1657 electrophilic molecules. In an effort to validate the mode of action of hit molecules, we noted a new TRPA1-selective agonist, JT010 (molecule 1), which opens the TRPA1 channel by covalently and site-selectively binding to Cys621 (EC50 = 0.65 nM). The results suggest that a single modification of Cys621 is sufficient to open the TRPA1 channel. The TRPA1-selective probe described herein might be useful for further mechanistic studies of TRPA1 activation.

Lectin-mediated resistance impairs plant virus infection at the cellular level.

Plants possess a multilayered defense response, known as plant innate immunity, to infection by a wide variety of pathogens. Lectins, sugar binding proteins, play essential roles in the innate immunity of animal cells, but the role of lectins in plant defense is not clear. This study analyzed the resistance of certain Arabidopsis thaliana ecotypes to a potexvirus, plantago asiatica mosaic virus (PlAMV). Map-based positional cloning revealed that the lectin gene JACALIN-TYPE LECTIN REQUIRED FOR POTEXVIRUS RESISTANCE1 (JAX1) is responsible for the resistance. JAX1-mediated resistance did not show the properties of conventional resistance (R) protein-mediated resistance and was independent of plant defense hormone signaling. Heterologous expression of JAX1 in Nicotiana benthamiana showed that JAX1 interferes with infection by other tested potexviruses but not with plant viruses from different genera, indicating the broad but specific resistance to potexviruses conferred by JAX1. In contrast with the lectin gene RESTRICTED TEV MOVEMENT1, which inhibits the systemic movement of potyviruses, which are distantly related to potexviruses, JAX1 impairs the accumulation of PlAMV RNA at the cellular level. The existence of lectin genes that show a variety of levels of virus resistance, their targets, and their properties, which are distinct from those of known R genes, suggests the generality of lectin-mediated resistance in plant innate immunity.