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Background: Few studies have compared the survival outcomes of stages II and IIIA rectal cancer patients who did not receive neoadjuvant treatment. This study aimed to compare oncologic outcomes between 2 groups., Patients and Methods: This study analyzed stage II or IIIA rectal cancer patients who underwent radical operation without neoadjuvant treatment between 1996 and 2013. The 3:1 propensity score analysis was used to adjust for several variables. After propensity score matching, 364 stage II rectal cancer, and 172 stage IIIA rectal cancer patients were analyzed., Results: There were no significant differences in 5-year overall survival or disease-free survival rates between the 2 groups. When stage II rectal cancer was subdivided into stages IIA, IIB, and IIC, the 5-year DFS and OS rates of stage IIIA rectal cancer patients were similar to those of stage IIA cancer patients. Moreover, stage IIIA rectal cancer patients showed a statistically significantly better survival rates than stage IIC rectal cancer patients., Conclusion: Stage IIIA group showed similar survival outcomes compared to stage IIA and IIB group and significantly better outcomes than stage IIC group. Thus, it should be considered to classify stage IIIA as a subgroup of stage II rather than as a subgroup of stage III rectal cancer. It should be also be considered to change to determine whether to do adjuvant treatment according to stage II rectal cancer., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: To improve the quality of surgery for rectal cancer, both transanal total mesorectal excision (taTME) and robotic total mesorectal excision (R-TME) can be performed. However, few studies have compared outcomes of taTME and R-TME, especially for patients with low rectal cancer after undergoing neoadjuvant chemoradiation (nCRT). Thus, the objective of this study was to compare outcomes of taTME and R-TME for patients with low rectal cancer after undergoing nCRT., Methods: A total of 306 consecutive patients with low rectal cancer who underwent taTME or R-TME after nCRT between 2008 and 2018 were analyzed retrospectively. Patients were classified into two groups: 1) taTME surgery group (n = 94); and 2) R-TME surgery group (n = 212)., Results: Clinicopathologic variables were comparable between the two groups. There was no significant difference in circumference margin involvement (1.1% in taTME vs. 2.8% in R-TME, p = 0.680) or distal resection margin (2.3 cm in taTME vs. 2.4 cm in R-TME, p = 0.629). Total operation time (239 min in taTME vs. 243 min in R-TME, p = 0.675) and major complications (including anastomosis site leakage, surgical site infection, and voiding difficulty) showed no significant difference between the two groups either., Conclusions: Transanal and robotic TMEs have similar short-term outcomes for patients with rectal cancer after undergoing nCRT. High quality TME can be equally achieved with both transanal and robotic approaches., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Orbitides are plant-derived small cyclic peptides with a wide range of biological activities. Phytochemical investigation of the whole plants of Dianthus chinensis was performed with the aim to discover new bioactive orbitides. Five undescribed proline-containing orbitides, dianthiamides A-E ( 1 - 5 ), were isolated from a methanolic extract of Dianthus chinensis . Their structures were elucidated by extensive analysis of 1D and 2D NMR and HRESI-TOF-MS as well as ESI-MS/MS fragmentation data. The absolute configuration of the amino acid residues of compounds 1 - 5 was determined by Marfey's method. All compounds were tested for their cytotoxic activity, and dianthiamide A ( 1 ) exhibited weak activity against A549 cell line with IC 50 value of 47.9 μM.

Background: Young patients with colorectal cancer (CRC) exhibit poor prognoses compared to older patients due to the difficulty in early diagnosis and treatment. However, the underlying molecular characteristics are still unclear., Methods: We conducted a comprehensive analysis of 49 CRC patients without hereditary CRC using the whole-exome and RNA sequencing with tumor and matched normal samples. A total of 594 TCGA samples and 4 patient-derived cells were utilized for validation., Results: Consensus molecular subtype 4 (CMS4) (53.85%) and CMS2 (38.46%) were enriched in the young (≤ 40 years) and old (> 60 years) age groups, respectively. A CMS4-associated gene, platelet-derived growth factor receptor α (PDGFRA), was significantly upregulated in young patients with CRC (FC = 3.21, p = 0.0001) and was negatively correlated with age (p = 0.0001, R = - 0.526). Moreover, PDGFRA showed a positive co-expression with metastasis-related genes in young CRC patients. In vitro validation confirmed that young patient-derived cells (PDCs) showed an enriched expression of PDGFRA compared to old PDCs and a reduced proliferation rate by knockdown of PDGFRA. Furthermore, young CRC patients were more sensitive to regorafenib, a PDGFRA-targeting drug, than old CRC patients., Conclusions: Our study suggests that CRC in young patients is associated with CMS4 and PDGFRA. In addition, PDGFRA may serve potential of novel therapeutic strategies and represent a predictive biomarker of response to regorafenib for young CRC patients., (© 2021. The Author(s).)

We evaluated the predictive value of semiquantitative volumetric parameters derived from sequential PET/CT and developed a nomogram to predict pathological complete response (pCR) in patients with rectal cancer treated by neoadjuvant chemoradiotherapy (nCRT). From April 2008 to December 2013, among the patients who underwent nCRT, those who were taken sequential PET/CT before and after nCRT were included. MRI-based staging and semiquantitative parameters of PET/CT including standardized uptake value (SUV), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were evaluated before and after nCRT. Multivariable analysis was performed to select significant predictors to construct a nomogram. Sensitivity, specificity, accuracy, and area under the receiver operating characteristics curve (AUC) of the model were evaluated to determine its performance. Among 137 eligible patients, 17 (12.4%) had pCR. All post-PET/CT parameters showed significant differences between pCR and non-pCR groups. Patients were randomly assigned to a training group (91 patients) and a validation group (46 patients). In multivariable analysis with the training group, post-CEA, post-MRI T staging, post-SUV max , and post-MTV were significantly associated with pCR. There was no significant pre-nCRT variable for predicting pCR. Using significant predictors, a nomogram was developed. Sensitivity, specificity, accuracy, and AUC of the nomogram were 0.882, 0.808, 0.848, and 0.884 with the training group and 0.857, 0.781, 0.783, and 0.828 with the validation group, respectively. This model showed the better performance than other predictive models that did not contain PET/CT parameters. A nomogram containing semiquantitative post-PET/CT could effectively select candidates for organ-sparing strategies., 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 © 2021 Pyo, Choi, Lee, Yun, Kim, Huh, Park, Shin and Cho.)

Background/purpose: MTA is used to induce hard tissue regeneration in various procedures. This study evaluated the biocompatibility and mineralization potential of mineral trioxide aggregate (MTA) containing calcium fluoride (CaF 2 ). To verify if the change of components affected physical properties, the setting time, solubility, and surface roughness were measured., Materials and Methods: Human dental pulp cells (HDPCs) were treated with powder and set MTA containing CaF 2 (0, 1, 5, and 10 wt %) . The proliferation of HDPCs was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The mineralization potential of HDPCs was investigated with the relative gene expression of alkaline phosphatase (ALP), collagen type I (ColI), osteocalcin (OCN), and runt-related transcription factor 2 (Runx2) using real-time reverse transcription polymerase chain reaction (RT-PCR). For investigating the physical properties, setting time and solubility were tested. Surface profiles of material were analyzed by a non-contact surface profiler and a scanning electron microscope (SEM)., Results: MTA-5% CaF 2 mixtures increased the proliferation and the mineralization-related gene expression of HDPCs to a greater degree than pure MTA. The addition of CaF 2 to MTA delayed the setting, but the difference was only significant in the MTA-10% CaF 2 . Solubility and surface roughness was not altered., Conclusion: The addition of more than 5% CaF 2 can be considered to increase the regeneration potential of pulp cells without adverse effects on physical property., Competing Interests: The authors declare no conflicts of interest., (© 2021 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Aim: There is controversy about the treatment of para-aortic lymph node (PALN) metastasis and usefulness of surgical removal. We investigated the clinical effects of synchronous isolated PALN dissection in patients with this metastasis., Methods: Patients with colorectal cancer with isolated PALN metastasis were selected between January 2008 and December 2016 at Samsung Medical Center. Patients who were selected for gross-free PALN dissection were set as the dissection group (DG). Patients who did not undergo PALN dissection or underwent biopsy were set as the non-dissection group (NDG). The oncological and operative outcomes were compared., Results: A total of 73 patients were recruited. The most clinical and pathological characteristics were not significantly different. The incidence of postoperative complications was also similar. The 5-year overall survival of DG patients was 33.9%, that of NDG patients was 10.1%, and the survival curves were significantly different (P = 0.044). Multivariate analysis revealed that location of tumour in the left colon rather than in the right colon was a risk factor affecting survival in sub-analysis., Conclusion: PALN dissection did not increase postoperative complications and had a better effect on patient survival. It is suggested that lymphadenectomy be performed more aggressively when PALN metastasis is seen in patients with right colon cancer., (© 2021 The Association of Coloproctology of Great Britain and Ireland.)

Purpose: Coronavirus disease 2019 (COVID-19) has affected many parts of daily life and healthcare, including cancer screening and diagnosis. The purpose of this study was to determine whether there was an upshift in the colorectal cancer stage at diagnosis due to delays related to the COVID-19 outbreak., Methods: From January to June of each year from 2017 to 2020, a total of 3,229 patients who were first diagnosed with colorectal cancer were retrospectively reviewed. Those enrolled from 2017 to 2019 were classified as the 'pre-COVID' group, and those enrolled in 2020 were classified as the 'COVID' group. The primary outcome was the rate of stage IV disease at the time of diagnosis., Results: There was no statistically significant difference in the proportion of stage IV patients between the pre-COVID and COVID groups (P = 0.19). The median preoperative carcinoembryonic antigen level in the COVID group was higher than in the pre-COVID group in all stages (all P < 0.05). In stage I, II patients who underwent radical surgery, the lymphatic invasion was more presented in COVID patients (P = 0.009)., Conclusion: We did not find significant stage upshifting in colorectal cancer during the COVID-19 outbreak. However, there were more initially unresectable stage IV colorectal cancer patients with a low conversion rate to resectable status, and more patients had factors related to poor prognosis. These results may become more apparent over time, so it is vital not to neglect cancer screening to not delay the diagnosis during the COVID-19 epidemic.

Patient-derived cancer models that reconstitute the characteristics of the tumor microenvironment may facilitate efforts in precision immune-oncology and the discovery of effective anticancer therapies. Organoids that have recently emerged as robust preclinical models typically contain tumor epithelial cells and lack the native tumor immune microenvironment. A patient-derived organotypic tumor spheroid (PDOTS) is a novel and innovative ex vivo system that retains key features of the native tumor immune microenvironment. Here, we established and characterized a series of colorectal cancer PDOTS models for use as a preclinical platform for testing effective immunotherapy and its combinations with other drugs. Partially dissociated (> 100 μm in diameter) tumor tissues were embedded in Matrigel-containing organoid media and subsequently formed into organoid structures within 3 to 7 days of culture. The success rate of growing PDOTS from fresh tissues was ~86%. Morphological analysis showed that the PDOTSs varied in size and structure. Immunofluorescence and flow cytometry analysis revealed that the PDOTSs retained autologous tumor-infiltrating lymphoid cells and tumor-infiltrating lymphoid cells were continually decreased through serial passages. Notably, PDOTSs from tumors from a high-level microsatellite instability-harboring patient were sensitive to anti-PD-1 or anti-PD-L1 antibodies. Our results demonstrate that the PDOTS model in which the tumor immune microenvironment is preserved may represent an advantageous ex vivo system to develop effective immune therapeutics., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: The survival benefit of neoadjuvant chemotherapy (NAC) prior to surgical resection in colorectal cancer with liver metastases (CRCLM) patients remains controversial. The aim of this study was to compare overall outcome of CRCLM patients who underwent NAC followed by surgical resection versus surgical treatment first., Methods: We retrospectively analyzed 429 patients with stage IV colorectal cancer with synchronous liver metastases who underwent simultaneous liver resection between January 2008 and December 2016. Using propensity score matching, overall outcome between 60 patients who underwent NAC before surgical treatment and 60 patients who underwent surgical treatment first was compared., Results: Before propensity score matching, metastatic cancer tended to involve a larger number of liver segments and the primary tumor size was bigger in the NAC group than in the primary resection group, so that a larger percentage of patients in the NAC group underwent major hepatectomy (P<0.001). After propensity score matching, demographic features and pathologic outcomes showed no significant differences between the 2 groups. In addition, there was no significant difference in short-term recovery outcomes such as postoperative morbidity (P=0.603) and oncologic outcome, including 3-year overall survival rate (P=0.285) and disease-free survival rate (P=0.730), between the 2 groups., Conclusion: NAC prior to surgical treatment in CRCLM is considered a safe treatment that does not increase postoperative morbidity, and its impact on oncologic outcome was not inferior.

Background: Statins preferentially promote tumor-specific apoptosis by depleting isoprenoid such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate. However, statins have not yet been approved for clinical cancer treatment due, in part, to poor understanding of molecular determinants on statin sensitivity. Here, we investigated the potential of statins to elicit enhanced immunogenicity of KRAS -mutant ( KRAS mut ) tumors., Methods: The immunogenicity of treated cancer cells was determined by western blot, flow cytometry and confocal microscopy. The immunotherapeutic efficacy of mono or combination therapy using statin was assessed in KRAS mut tumor models, including syngeneic colorectal cancer and genetically engineered lung and pancreatic tumors. Using NanoString analysis, we analyzed how statin influenced the gene signatures associated with the antigen presentation of dendritic cells in vivo and evaluated whether statin could induce CD8+ T-cell immunity. Multiplex immunohistochemistry was performed to better understand the complicated tumor-immune microenvironment., Results: Statin-mediated inhibition of KRAS prenylation provoked severe endoplasmic reticulum (ER) stress by attenuating the anti-ER stress effect of KRAS mutation, thereby resulting in the immunogenic cell death (ICD) of KRAS mut cancer cells. Moreover, statin-mediated ICD enhanced the cross-priming ability of dendritic cells, thereby provoking CD8+ T-cell immune responses against KRAS mut tumors. Combination therapy using statin and oxaliplatin, an ICD inducer, significantly enhanced the immunogenicity of KRAS mut tumors and promoted tumor-specific immunity in syngeneic and genetically engineered KRAS mut tumor models. Along with immune-checkpoint inhibitors, the abovementioned combination therapy overcame resistance to PD-1 blockade therapies, improving the survival rate of KRAS mut tumor models., Conclusions: Our findings suggest that KRAS mutation could be a molecular target for statins to elicit potent tumor-specific immunity., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Intersphincteric resection (ISR) is a surgical technique intended to avoid abdominoperineal resection (APR) in patients diagnosed with low-lying rectal cancer. However, the oncologic outcomes of minimally invasive ISR are still controversial. We analyzed the long-term oncologic outcomes of open and minimally invasive ISR. A total of 313 rectal cancer patients who underwent ISR between 2000 and 2014 were analyzed, including 147 in the open surgery group and 166 in the minimally invasive surgery (MIS) group. This study also analyzed 113 patients who received neoadjuvant chemoradiotherapy (nCRT) for advanced lower rectal cancer. Propensity score matching (PSM) was used to correct for differences between the two groups. 5-year disease-free survival (DFS) rate was the primary end point. The length of hospital stay was significantly shorter in the MIS group (9.6 vs. 11.8 days, p < 0.001). Differences in overall postoperative morbidity rates between the groups were not significant; however, the rate of surgical site infection was significantly lower in the MIS group (1.2 vs. 10.9%, p < 0.001). The 5-year DFS associated with all stages combined in the matched patients were not significantly different: 75.2% in the open group vs. 64.2% in the MIS group (p = 0.214). Similar results were found in matched patients treated with nCRT, with 72.0% in the open group and 61.3% in the MIS group (p = 0.078) showing DFS. Both minimally-invasive and open ISR for rectal cancer yielded similar 5-year oncologic outcomes. MIS showed statistically significant advantages in some postoperative outcomes such as reduced surgical site infection and shorter hospital stay, and similar long-term outcomes compared with open ISR. This study also suggests that MIS after nCRT for advanced rectal cancer represents a surgical option with similar oncological results.

Three new guaianolide lactones ( 1 -3 ) and four new 9-oxonerolidol glucosides ( 5 - 8 ) together with 20 known compounds were isolated from the MeOH extract of the flowers of Chrysanthemum indicum . Their structures were elucidated based on the interpretation of NMR, HRESIMS, and electronic circular dichroism (ECD) data along with acid hydrolysis. Of the isolates, sesquiterpenoids 1 - 4 and 15 and flavones 17 and 18 exhibited inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide production in RAW 264.7 cells with IC 50 values in the range 0.2-27.0 μM.

Glucose-regulated protein 94 (GRP94) is an endoplasmic reticulum (ER)-resident member of the heat shock protein 90 (HSP90) family. In physiological conditions, it plays a vital role in regulating biological functions, including chaperoning cellular proteins in the ER lumen, maintaining calcium homeostasis, and modulating immune system function. Recently, several reports have shown the functional role and clinical relevance of GRP94 overexpression in the progression and metastasis of several cancers. Therefore, the current review highlights GRP94's physiological and pathophysiological roles in normal and cancer cells. Additionally, the unmet medical needs of small chemical inhibitors and the current development status of monoclonal antibodies specifically targeting GRP94 will be discussed to emphasize the importance of cell surface GRP94 as an emerging therapeutic target in monoclonal antibody therapy for cancer.

Chios mastic gum (CMG), a resin of the mastic tree ( Pistacia lentiscus var. chia), has been used to treat multiple disorders caused by gastrointestinal malfunctions and bacterial infections for more than 2500 years. However, little is known about CMG's antiviral activity. CMG is known to influence multiple cellular processes such as cell proliferation, differentiation and apoptosis. As virus replication is largely dependent on the host cellular metabolism, it is conceivable that CMG regulates virus infectivity. Therefore, in this study, we evaluated CMG's potential as an antiviral drug to treat influenza A virus (IAV) infection. CMG treatment dramatically reduced the cytopathogenic effect and production of RNAs, proteins and infectious particles of IAV. Interestingly, CMG interfered with the early stage of the virus life cycle after viral attachment. Importantly, the administration of CMG greatly ameliorated morbidity and mortality in IAV-infected mice. The results suggest that CMG displays a potent anti-IAV activity by blocking the early stage of viral replication. Thus, mastic gum could be exploited as a novel therapeutic agent against IAV infection.

Three new ursane-type triterpenes (1-3) and twenty-one known triterpenoids (4-24) were isolated from the methanolic extract of the whole plants of Potentilla chinensis. Their structures were elucidated by extensive spectroscopic analysis of 1D and 2D NMR (HSQC, HMBC, COSY and ROESY) and HRESIMS data. The bioassay screening revealed the inhibitory effects on nitric oxide production of compounds 2, 5, 7, 9, 10, and 13-24 in LPS-induced RAW264.7 macrophages., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Naturally abundant vermiculite clay was expanded by using an aqueous solution of H 2 O 2 and its surface was modified with ultra-thin polydimethylsiloxane (PDMS) using facile thermal vapor deposition to prepare an ecologically friendly, low-cost oil sorbent that plays an important role in oil spillage remediation. The resulting PDMS-coated expanded vermiculite (eVMT@PDMS) particles exhibited adequate hydrophobicity and oleophilicity for oil/water separation, with numerous conical slit pores (a size of 0.1-100 μm) providing a great sorption capacity and an efficient capillarity-driven flow pathway for oil collection. Simply with using a physically-packed eVMT@PDMS tube (or pouch), selective oil removals were demonstrated above and beneath the surface of the water. Furthermore, these sorbents were successfully integrated and then applied to the advanced oil-collecting devices such as a barrel-shaped oil skimmer and a self-primed oil pump.

Epithelial ovarian cancer remains the leading cause of mortality among all gynecologic malignancies owing to recurrence and ultimate development of chemotherapy resistance in the majority of patients. In the chemotherapy-resistant ovarian cancer preclinical model, we investigated whether AZD6738 (an ataxia telangiectasia and Rad3-related (ATR) inhibitor) could synergize with belotecan (a camptothecin analog and topoisomerase I inhibitor). In vitro, both chemotherapy-resistant and chemotherapy-sensitive ovarian cancer cell lines showed synergistic anti-proliferative activity with a combination treatment of belotecan and AZD6738. The combination also demonstrated synergistic tumor inhibition in mice with a chemotherapy-resistant cell line xenograft. Mechanistically, belotecan, a DNA-damaging agent, increased phospho-ATR (pATR) and phospho-Chk1 (pChk1) in consecutive order, indicating the activation of the DNA repair system. This consequently induced G2/M arrest in the cell cycle analysis. However, when AZD6738 was added to belotecan, pATR and pChk1 induced by belotecan alone were suppressed again. A cell cycle analysis in betotecan showed a sub-G1 increase as well as a G2/M decrease, representing the release of G2/M arrest and the induction of apoptosis. In ascites-derived primary cancer cells from both chemotherapy-sensitive and -resistant ovarian cancer patients, this combination was also synergistic, providing further support for our hypothesis. The combined administration of ATR inhibitor and belotecan proved to be synergistic in our preclinical model. This combination warrants further investigation in a clinical trial, with a particular aim of overcoming chemotherapy resistance in ovarian cancer.

Recently, cyclin-dependent kinase (CDK) 4/6 inhibitors have been widely used to treat advanced hormone receptor-positive breast cancer. Despite promising clinical outcomes, almost all patients eventually acquire resistance to CDK4/6 inhibitors. Here, we screened genes associated with palbociclib resistance through genomics and transcriptomics in preclinical breast cancer models. Palbociclib-resistant cells were generated by exposing hormone receptor-positive breast cancer cell lines to palbociclib. Whole-exome sequencing (WES) and a mRNA microarray were performed to compare the genomic and transcriptomic landscape between both palbociclib-sensitive and resistant cells. Microarray analysis revealed 651 differentially expressed genes (DEGs), while WES revealed 107 clinically significant mutated genes. Furthermore, pathway analysis of both DEGs and mutated genes revealed immune pathway deregulation in palbociclib-resistant cells. Notably, DEG annotation revealed activation of type I interferon pathway, activation of immune checkpoint inhibitory pathway, and suppression of immune checkpoint stimulatory pathway in palbociclib-resistant cells. Moreover, mutations in NCOR1, MUC4 , and MUC16 genes found in palbociclib-resistant cells were annotated to be related to the immune pathway. In conclusion, our genomics and transcriptomics analysis using preclinical model, revealed that deregulated immune pathway is an additional mechanism of CDK4/6 inhibitor resistance besides the activation of cyclin E-CDK2 pathway and loss of RB, etc. Further studies are warranted to evaluate whether immune pathways may be a therapeutic target to overcome CDK4/6 inhibitor resistance.

Purpose: To investigate whether there is a volume threshold in target volume of brain metastases below which a small cone size and sharp penumbra in Gamma Knife (GK) may provide improved plan quality when compared to Volumetric Modulated Arc Therapy (VMAT)-based stereotactic radiosurgery (SRS)., Methods: For patients treated on GK SRS for brain metastases in 2018-2019 in our institution, 121 patients with two and three targets were identified. Twenty-six patients with two or three brain metastases (total of 76 lesions) were selected for this study. Two VMAT plans, SmartArc (Pinnacle) and HyperArc (Eclipse), were generated retrospectively for each patient. Plan quality was evaluated based on RTOG conformity index (CI), Paddick gradient index (GI), normal tissue (NT) V12Gy and V4.5Gy. By using the receiver operating characteristic (ROC) curve for both VMAT plans (SmartArc and HyperArc) and metrics of RTOG CI and NT V12Gy, we compared GK plans to SmartArc and HyperArc plans separately to determine the threshold volume., Results: For SmartArc plans, both ROC curve analyses showed a threshold volume of 0.4 cc for both CI and NT V12Gy. For HyperArc plans, the threshold volumes were 0.2 cc for the CI and 0.5 cc for NT V12Gy. GK plans produced improved dose distribution compared to VMAT for targets ≤0.4 cc, but HyperArc was found to have competing results with GK in terms of CI and NT V12Gy. For targets > 0.4 cc, both SmartArc and HyperArc showed better plan quality when compared to the GK plans., Conclusions: Target volumes ≤0.4 cc may require a small cone size and sharp penumbra in GK while for target volumes >0.4 cc, VMAT-based SRS can provide improved overall plan quality and faster treatment delivery., Competing Interests: Authors’ declaration of potential conflicts of interest Dr. Neyman reports personal fees from Elekta AB, outside the submitted work. Dr. Chao reports personal fees from Varian Medical Systems, outside the submitted work. Dr. Suh reports personal fees from Philips, other from Neutron Therapeutics, personal fees from Novocure, outside the submitted work. Dr. Xia reports grants from AVO, during the conduct of the study; grants from Philips, outside the submitted work. Other authors have nothing to disclose., (© 2021 Old City Publishing, Inc.)

Viral infectious diseases are a significant burden on public health and the global economy, and new viral threats emerge continuously. Since CD4 + and CD8 + T cell responses are essential to eliminating viruses, it is important to understand the underlying mechanisms of anti-viral T cell-mediated immunopathogenesis during viral infections. Remarkable progress in transgenic (Tg) techniques has enabled scientists to more readily understand the mechanisms of viral pathogenesis. T cell receptor (TCR) Tg mice are extremely useful in studying T cell-mediated immune responses because the majority of T cells in these mice express specific TCRs for partner antigens. In this review, we discuss the important studies utilizing TCR Tg mice to unveil underlying mechanisms of T cell-mediated immunopathogenesis during viral infections.

Purpose: This study aimed to identify the risk factors for locoregional recurrence (LR) and determine possible candidates for postoperative concurrent chemoradiotherapy (CCRT) in pathologic T3N0 (pT3N0) rectal cancer patients with a negative resection margin after total mesorectal excision (TME)., Method: Data from 365 patients who had pT3N0 rectal cancer between 2003 and 2012 in the Samsung Medical Center were reviewed. All patients underwent upfront surgery without preoperative treatment. Postoperative management involved either no adjuvant therapy (n = 122), chemotherapy alone (n = 100), or CCRT (n = 143)., Results: The median follow-up duration was 71 months. The 5-year overall survival, disease-free survival, and LR-free survival (LRFS) rates were 95.9%, 86.9%, and 96.3%, respectively. When comparing the three groups (surgery alone [n = 122], chemotherapy alone [n = 100], and CCRT [n = 143]), there was no significant difference in LRFS among them (94.0%, 93.4%, and 99.2%, respectively; p = 0.20). However, when patients were stratified by risk factors (distance from anal verge ≤ 5 cm and distal resection margin [DRM] ≤ 2 cm), the 5-year LRFS improved by more than 10% by adding CCRT (98.9% with CCRT vs. 87.4% without CCRT, p = 0.006) in those with more than one risk factor. Postoperative CCRT did not affect the 5-year LRFS (100% with CCRT vs. 99.0% without CCRT, p = 0.66) in patients with no risk factors., Conclusion: Postoperative CCRT significantly decreased LR in patients with pT3N0 rectal cancer with a negative resection margin but having a distance from the anal verge ≤ 5 cm or DRM ≤ 2 cm.

Chronic viral infections are often established by the exploitation of immune-regulatory mechanisms that result in nonfunctional T cell responses. Viruses that establish persistent infections remain a serious threat to human health. Sphingosine kinase 2 (SphK2) generates sphingosine 1-phosphate, which is a molecule known to regulate multiple cellular processes. However, little is known about SphK2's role during the host immune responses to viral infection. Here, we demonstrate that SphK2 functions during lymphocytic choriomeningitis virus Cl 13 (LCMV Cl 13) infection to limit T cell immune pathology, which subsequently aids in the establishment of virus-induced immunosuppression and the resultant viral persistence. The infection of Sphk2-deficient (Sphk2-/-) mice with LCMV Cl 13 led to the development of nephropathy and mortality via T cell-mediated immunopathology. Following LCMV infection, Sphk2-/- CD4+ T cells displayed increased activity and proliferation, and these cells promoted overactive LCMV Cl 13-specific CD8+ T cell responses. Notably, oral instillation of an SphK2-selective inhibitor promoted protective T cell responses and accelerated the termination of LCMV Cl 13 persistence in mice. Thus, SphK2 is indicated as an immunotherapeutic target for the control of persistent viral infections.

Breast cancer represents the number one global cancer burden in women and the hormone receptor (HR)-positive subtype comprises approximately 70% of breast cancers. Unfortunately, acquired resistance ultimately occurs in almost all cases, even though cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are a highly effective therapy for HR-positive/human epidermal growth factor receptor 2-negative subtype. Here, we investigated mechanisms of resistance to CDK4/6 inhibitor and potential therapeutic strategies using our palbociclib-resistant preclinical model. We observed that cyclin E was significantly overexpressed in palbociclib-resistant cells, and similar association was also confirmed in pleural effusion samples collected from HR-positive breast cancer patients. After confirmation of cyclin E-CDK2 interaction by co-immunoprecipitation, we demonstrated CDK2 inhibition combined with palbociclib synergistically suppressed proliferation of palbociclib-resistant cells and growth of palbociclib-resistant xenograft in mice. We also proved that enhancing C-MYC-mediated senescence is a novel mechanism behind the synergism created by targeting both CDK2 and CDK4/6. Furthermore, the clinical relevance of cyclin E as a therapeutic target was supported by significant association between CCNE1 overexpression and poor prognosis based on large-scale public gene expression data sets in HR-positive breast cancer patients. Therefore, we propose cyclin E-CDK2 signaling as a promising therapeutic target for overcoming cyclin E-associated resistance to CDK4/6 inhibitor.

Regorafenib (Stivarga, BAY 73-4506; Bayer Pharma AG, Berlin, Germany) is a novel oral multikinase inhibitor that blocks the activity of several protein kinases. However, few guidelines exist for novel biomarkers to select patients who will likely benefit from regorafenib treatment. Metastatic colorectal cancer (mCRC) patients treated with regorafenib were evaluated in this study. Tumor tissues of these patients were subjected to next-generation sequencing-based cancer panel tests. The relationship between molecular profiling and efficacy of regorafenib was analyzed. Among the 76 mCRC patients, the median age was 58 years (range 22-79 years), and 73.7% received regorafenib as a third-line therapy. The primary tumor locations were the right side ( n  = 15, 19.8%) and the left side ( n  = 61, 80.2%). Most patients (97.4%) had received prior anti-angiogenetic agents, and a prior anti-Epidermal Growth Factor Receptor (EGFR) agent had been administered to 32.9%. Of these 76 patients, 65 were evaluated to determine the efficacy of treatment. We observed zero complete responses, seven confirmed partial responses (PR 9.2%), 26 stable disease states (34.2%), and 32 disease progressions (42.1%). The overall confirmed response rate and the disease control rate were 9.2% and 43.4%, respectively. Genomic analysis revealed that APC mutations were significant in patients who demonstrated a tumor response to regorafenib ( p  < 0.05). Interestingly, FGFR1 amplification was detected in only three of 76 patients (3.9%), and these three patients achieved a PR to regorafenib. The median progression-free survival time was 2.8 months (95% Confidence Interval [CI] 1.6-4.0). Patients with BRAF mutation and/or SMAD4 mutation had significantly worse progression-free survival (PFS) than those without such a mutation. On pathway analysis, Tumor Growth Factor (TGF)-beta pathways were significantly associated with worse PFS. We found that efficacy of regorafenib might be correlated with specific genetic aberrations, such as APC mutation and FGFR1 amplification. In addition, SMAD4 mutation and TGF-beta pathway were associated with worse PFS after regorafenib. We found that efficacy of regorafenib might be correlated with specific genetic aberrations, such as APC mutation and FGFR1 amplification. In addition, SMAD4 mutation and the TGF-beta pathway were associated with worse PFS after regorafenib., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2020.)

Background: Laparoscopic liver resection for metastatic colorectal cancer (CRC) remains controversial. The objective of this study was to compare the short-term and mid-term outcomes of patients with CRC undergoing laparoscopic versus open colorectal resection with simultaneous resection for liver metastases., Methods: A total of 126 patients underwent combined laparoscopic resection of CRC and synchronous colorectal liver metastases between 2008 and 2016. A total of 318 patients were treated by an open approach during the above period. By propensity score matching, 109 patients who underwent laparoscopic resection and 109 patients who had an open approach were compared. Analyzed variables included patient characteristics, tumor features, and short-term and mid-term outcomes., Results: Demographic features and pathologic outcomes were similar in both groups after propensity score matching. Three (2.8%) patients undergoing laparoscopic liver resection experienced conversion to open procedure. There was no difference in hospital stay (p = 0.078), transfusion rate (p = 0.686), or time of bowel function return (p = 0.570) between the two groups. The laparoscopic group and the open approach group also showed similar 3-year overall survival rate (74.4% vs. 79.1%; p = 0.792) and 3-year disease-free survival rate (58.5% vs. 55.2%; p = 0.391). However, postoperative morbidity rate was significantly lower in the laparoscopic group (20.2% vs. 33.0%; p = 0.032)., Conclusions: Laparoscopic colorectal resection with simultaneous resection of liver metastases showed satisfactory oncologic outcomes with some short-term advantages compared to the open approach. Thus, laparoscopic approach could be a good alternative of open approach for simultaneous liver and colon resection in patients with CRC.

Background: Well-characterized preclinical models are essential for immune-oncology research. We investigated the feasibility of our humanized mouse model for evaluating the long-term efficacy of immunotherapy and biomarkers., Methods: Humanized mice were generated by injecting human fetal cord blood-derived CD34+ hematopoietic stem cells to NOD-scid IL2rγnull (NSG) mice myeloablated with irradiation or busulfan. The humanization success was defined as a 25% or higher ratio of human CD45+ cells to mice peripheral blood mononuclear cells., Results: Busulfan was ultimately selected as the appropriate myeloablative method because it provided a higher success rate of humanization (approximately 80%) and longer survival time (45 weeks). We proved the development of functional T cells by demonstrating the anticancer effect of the programmed cell death-1 (PD-1) inhibitor in our humanized mice but not in non-humanized NSG mice. After confirming the long-lasting humanization state (45 weeks), we further investigated the response durability of the PD-1 inhibitor and biomarkers in our humanized mice. Early increase in serum tumor necrosis factor α levels, late increase in serum interleukin 6 levels and increase in tumor-infiltrating CD8+ T lymphocytes correlated more with a durable response over 60 days than with a non-durable response., Conclusions: Our CD34+ humanized mouse model is the first in vivo platform for testing the long-term efficacy of anticancer immunotherapies and biomarkers, given that none of the preclinical models has ever been evaluated for such a long duration., Competing Interests: Competing interests: The corresponding author received research funds from several pharmaceutical companies including the AstraZeneca, Eisai, Dong-A ST, Chong Kun Dang, and Celltrion., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Colorectal cancer (CRC) is prevalent with high mortality, with liver metastasis contributing as a major factor that worsens the survival of patients. The roles of miRNAs in CRC have been elucidated, subsequent to recent studies that suggest the involvement of miRNAs in cancer biology. In this study, we compare the miRNA and gene expression profiles of primary tumors between two groups of patients (with and without liver metastasis) to identify the metastasis-initiating microRNA-target gene regulations. Analysis from 33 patients with metastasis and 14 patients without metastasis revealed that 17 miRNAs and their 198 predicted target genes are differentially expressed, where the target genes showed association with cancer progression and metastasis with statistical significance. In order to evaluate the clinical implications of the findings, we classified CRC patients of independent data into two groups based on the identified miRNA-target regulations, where one group was closer to primary tumors with metastasis than the other group. The comparison of survival showed statistically significant difference, thereby implying the roles of the identified miRNA-target regulations in cancer progression and metastasis. The identification of metastasis-initiating miRNA-target regulations in this study will lead to better understanding of the roles of miRNAs in CRC progression.

Background: Epithelial-mesenchymal transition (EMT) is the most common cause of death in colorectal cancer (CRC). In this study, we investigated the functional roles of miRNA-17-5p in EMT of CRC cells., Methods: In order to determine if miRNA-17-5p regulated EMT, the precursors and inhibitors of miR-17-5p were transduced into four CRC cells. To evaluate the regulatory mechanism, we performed argonaute 2 (Ago2) immunoprecipitation (IP) and luciferase assay. In addition, we used an intra-splenic injection mouse model of BALB/c nude mice to investigate the metastatic potential of miRNA-17-5p in vivo., Results: The miRNA-17-5p expression was lower in primary CRC tissues with metastasis than in primary CRC tissues without metastasis in our RNA sequencing data of patient tissue. Real-time quantitative PCR revealed that miRNA-17-5p was inversely correlated with that of vimentin in five CRC cell lines. Over-expression of miRNA-17-5p decreased vimentin expression and inhibited cell migration and invasion in both LoVo and HT29 cells. However, inhibition of miRNA-17-5p showed the opposite effect. Ago2 IP and luciferase assay revealed that miRNA-17-5p directly bound to the 3'UTR of VIM mRNA. Furthermore, miRNA-17-5p inhibited the metastasis of CRC into liver in vivo., Conclusions: Our results demonstrated that miRNA-17-5p regulates vimentin expression, thereby regulating metastasis of CRC.

Purpose: The impact of postoperative complications on long-term oncologic outcome after radical colorectal cancer surgery is controversial. The aim of this study was to examine the risk factors and oncologic outcomes of surgery-related postoperative complication groups., Methods: From January 2010 to December 2010, 310 patients experienced surgery-related postoperative complications after radical colorectal cancer surgery. These stage I-III patients were classified into 2 subgroups, minor (grades I, II) and major (grades III, IV) complication groups, according to extended Clavien-Dindo classification system criteria. Clinicopathologic differences between the 2 groups were analyzed to identify risk factors for major complications. The disease-free survival rates of surgery-related postoperative complication groups were also compared., Results: Minor and major complication groups were stratified with 194 patients (62.6%) and 116 patients (37.4%), respectively. The risk factors influencing the major complication group were pathologic N category and operative method. The prognostic factors associated with disease-free survival were preoperative perforation, perineural invasion, tumor budding, and receiving neoadjuvant therapy. With a median follow-up period of 72.2 months, the 5-year disease-free survival rates were 84.4% in the minor group and 78.5% in the major group, but there was no statistical significance between the minor and major groups (P = 0.392)., Conclusion: Advanced cancer and open surgery were identified as risk factors for increased surgery-related major complications after radical colorectal cancer surgery. However, severity of postoperative complications did not affect disease-free survival from colorectal cancer.

Background: The aim of the study was to determine factors predicting lymph node metastasis in patients with T1 or T2 colon cancer., Methods: A total of 906 patients with T1 or T2 colon cancer who underwent colon resection with regional lymphadenectomy in a tertiary hospital, from January 2008 to December 2013, were analyzed. The prognostic factors for LN metastasis and the risk factors for survival were analyzed., Results: There were 728 patients (80.4%) without lymph node metastasis (LN-negative group) and 178 patients (19.6%) with lymph node metastasis (LN-positive group). Tumor invasion depth (P < 0.001), lymphatic invasion (P < 0.001), and perineural invasion (P = 0.008) were significantly different between the two groups. During the median follow-up period of 69 months, the 5-year disease-free survival rate was 98.6% for the LN-negative group and 92.8% for the LN-positive group (P ≤ 0.001). In multivariate analysis, influencing factors associated with disease-free survival rate were LN metastasis (P = 0.001) and perineural invasion (P = 0.040). Female, depth of tumor invasion (P = 0.001), and lymphatic invasion (P < 0.001) were significant independent predictive factors for lymph node metastasis in multivariate analysis., Conclusion: Positive LN status predicted poor disease-free survival in patients with early cancer. This suggests that depth of tumor invasion ≥ sm2 and the presence of lymphatic invasion in early colon cancer provide useful information to determine which patients would benefit from radical surgery.

Cyclo(Phe-Pro) (cFP), produced by the Vibrio species, plays the dual roles of being a signaling molecule and a virulence factor. Acting modes of this compound have recently been characterized at the molecular level. Nevertheless, the method by which this compound passes across biological membranes remains obscure. Using radiolabeled cFP, we examined the kinetics of transport for this compound across membranes using V. vulnificus, Escherichia coli, and sheep red blood cells. We observed that cFP was taken up by these cells in a concentration-dependent manner and was not affected by the addition of the proton ionophore carbonyl cyanide m-chlorophenyl hydrazone (CCCP), suggesting that cFP is taken up by passive transport. The kinetics of uptake of cFP by the above three types of cells revealed no significant differences, indicating that no specific protein is involved in this process. When the intracellular accumulation of cFP in the tested cells was measured, the concentrations did not exhibit significant differences between the 1-min and 10-min time points after cFP was added to the culture. In contrast, the intracellular concentration of fumarate, which is well known to be taken up by cells via active transport, was significantly higher at the 10-min than at the 1-min time point after addition. Taken together, this study shows that cFP is a diffusible molecule that does not require energy for transportation across biological membranes, and that cFP does not need membrane machinery in order to cross membranes and consequently act as a virulence factor or signal. KEY POINTS: • Kinetics of cFP uptake into cells of V. vulnificus, E. coli, or RBS was studied. • The uptake was not saturated and required no energy, indicating passive transport. • The lack of cell specificity in cFP uptake means no specific protein is needed. • Therefore, the cFP moves across the biological membrane by simple diffusion.

We investigated microbiota changes following surgical colon cancer resection and evaluate effects of probiotics on microbiota and surgical recovery. This randomized double-blind trial was performed at four medical centers in South Korea. Of 68 patients expected to undergo anterior sigmoid colon cancer resection, 60 were eligible, of whom 29 and 31 received probiotics and placebo, respectively, for four weeks, starting at one week preoperatively. Third- and/or fourth-week information on anterior resection syndrome (ARS), inflammatory markers, and quality of life was obtained. Stool sample analysis was conducted after randomization and bowel preparation and at three and four postoperative weeks. Bacteria were categorized into Set I (with probiotic effects) and II (colon cancer-associated). The probiotic group's ARS score showed an improving trend ( p = 0.063), particularly for flatus control ( p = 0.030). Serum zonulin levels significantly decreased with probiotics. Probiotic ingestion resulted in compositional changes in gut microbiota; greater increases and decreases in Set I and II bacteria, respectively, occurred with probiotics. Compositional increase in Set I bacteria was associated with reduced white blood cells, neutrophils, neutrophil-lymphocyte ratio, and zonulin. Bifidobacterium composition was negatively correlated with zonulin levels in the probiotic group. Probiotics improved postoperative flatus control and modified postoperative changes in microbiota and inflammatory markers.

Metastasis is the primary cause of cancer mortality. The primary tumors of colorectal cancer (CRC) often metastasize to the liver. In this study, we have collected 122 samples from 45 CRC patients. Among them, 32 patients have primary tumors, adjacent normal tissues, and matched liver metastases. Thirteen patients have primary tumors without distant metastasis and matched normal tissues. Characterization of these samples was conducted by whole-exome and RNA sequencing and SNP6.0 analysis. Our results revealed no significant difference in genetic alterations including common oncogenic mutations, whole genome mutations and copy number variations between primary and metastatic tumors. We then assembled gene co-expression networks and identified metastasis-correlated gene networks of immune-suppression, epithelial-mesenchymal transition (EMT) and angiogenesis as the key events and potentially synergistic drivers associated with CRC metastasis. Further independent cohort validation using published datasets has verified that these specific gene networks are up regulated throughout the tumor progression. The gene networks of EMT, angiogenesis, immune-suppression and T cell exhaustion are closely correlated with the poor patient outcome and intrinsic anti-PD-1 resistance. These results offer insights of combinational strategy for the treatment of metastatic CRC.

Purpose: To date, there have been many studies on postoperative complications and oncologic outcomes, but the findings remain controversial. The purpose of the study was to determine the prognostic value of serum inflammatory markers as pretreatment in curatively resected colorectal cancer. The effects of serum inflammatory marker levels on postoperative morbidity were also examined., Methods: Prospectively collected data from 1590 patients with primary sporadic colorectal adenocarcinoma who underwent curative resection between September 2012 and December 2013 at our institution were retrospectively analyzed. White blood cell count (× 10 3 /mcl), neutrophil/lymphocyte ratio, C-reactive protein, erythrocyte sedimentation rate (ESR), and Glasgow prognostic score (GPS) were evaluated. GPS was determined as follows: GPS of 2, elevated CRP level (> 1.0 mg/dl) and hypoalbuminemia (< 3.5 g/dl); GPS of 1, elevated CRP or hypoalbuminemia; and GPS of 0, neither elevated CRP nor hypoalbuminemia., Results: The median follow-up period for the 1590 patients was 59 months. The overall postoperative morbidity rate was 24.8%. In multivariate analysis, female sex (P = 0.006), rectal cancer other than colon cancer (P < 0.001), CEA level > 5 ng/ml (P < 0.001), ESR > 27 mm/h (P = 0.014), and a GPS of 1 or 2 (P < 0.001) were independent risk predictors for morbidity. A GPS of 1 or 2 (P < 0.001) and postoperative morbidity (P < 0.001) significantly affected both overall survival and disease-free survival in multivariate analyses., Conclusions: A GPS of 1 or 2 is a significant risk factor for postoperative morbidity and a prognostic factor for long-term survival.

Epoxy resin-based sealers are currently widely used, and several studies have considered AH Plus to be the gold-standard sealer. However, it still has limitations, including possible mutagenicity, cytotoxicity, inflammatory response, and hydrophobicity. Drawing upon the advantages of mineral trioxide aggregate, calcium silicate-based sealers were introduced with high levels of biocompatibility and hydrophilicity. Because of the hydrophilic environment in root canals, water resorption and solubility of root canal sealers are important factors contributing to their stability. Sealers displaying lower microleakage and stronger push-out bond strength are also needed to endure the dynamic tooth environment. Although the physical properties of calcium silicate-based sealers meet International Organization for Standardization recommendations, and they have consistently reported to be biocompatible, they have not overcome conventional resin-based sealers in actual practice. Therefore, further studies aiming to improve the physical properties of calcium silicate-based sealers are needed., Competing Interests: Conflict of Interest: No potential conflict of interest relevant to this article was reported., (Copyright © 2020. The Korean Academy of Conservative Dentistry.)

Since effective immunotherapeutic agents such as immune checkpoint blockade to treat cancer have emerged, the need for reliable preclinical cancer models that can evaluate and discover such drugs became stronger than ever before. The traditional preclinical cancer model using a cancer cell line has several limitations to recapitulate intra-tumor heterogeneity and in-vivo tumor activity including interactions between tumor-microenvironment. In this review, we will go over various preclinical cancer models recently discovered including patient-derived xenografts, humanized mice, organoids, organotypic-tumor spheroids, and organ-on-a-chip models. Moreover, we will discuss the future directions of preclinical cancer research.

Immunotherapy for metastatic colorectal cancer is effective only for mismatch repair-deficient tumors with high microsatellite instability that demonstrate immune infiltration, suggesting that tumor cells can determine their immune microenvironment. To understand this cross-talk, we analyzed the transcriptome of 91,103 unsorted single cells from 23 Korean and 6 Belgian patients. Cancer cells displayed transcriptional features reminiscent of normal differentiation programs, and genetic alterations that apparently fostered immunosuppressive microenvironments directed by regulatory T cells, myofibroblasts and myeloid cells. Intercellular network reconstruction supported the association between cancer cell signatures and specific stromal or immune cell populations. Our collective view of the cellular landscape and intercellular interactions in colorectal cancer provide mechanistic information for the design of efficient immuno-oncology treatment strategies.

The name of the author of the original published version of this article was presented incorrectly. The author name "JungWook Huh" should have been presented as "Jung Wook Huh".

Acetate is the main by-product from microbial succinate production. In this study, we performed acetate removal by Methanosarcina barkeri 227 for succinate fermentation by Actinobacillus succinogenes 130Z. The acetoclastic methanogen M. barkeri requires similar environmental factors to A. succinogenes, and the conditions required for co-cultivation were optimized in this study: gas used for anaerobicization, strain adaptation, medium composition, pH adjustment, and inoculation time points. M. barkeri 227 was adapted to acetate for 150 days, which accelerated the acetate consumption to 9-fold (from 190 to 1726 mmol gDW -1  day -1 ). In the acetate-adapted strain, there was a noticeable increase in transcription of genes required for acetoclastic pathway-satP (acetate transporter), ackA (acetate kinase), cdhA (carbon monoxide dehydrogenase/acetyl-CoA synthase complex), and mtrH (methyl-H 4 STP:CoM methyltransferase), which was not induced before the adaptation process. The activities of two energy-consuming steps in the pathway-acetate uptake and acetate kinase-increased about 3-fold. This acetate-adapted M. barkeri could be successfully applied to succinate fermentation culture of A. succinogenes, but only after pH adjustment following completion of fermentation. This study suggests the utility of M. barkeri as an acetate scavenger during fermentation for further steps towards genetic and process engineering.

The influenza virus is one of the major public health threats. However, the development of efficient vaccines and therapeutic drugs to combat this virus is greatly limited by its frequent genetic mutations. Because of this, targeting the host factors required for influenza virus replication may be a more effective strategy for inhibiting a broader spectrum of variants. Here, we demonstrated that inhibition of a motor protein kinesin family member 18A (KIF18A) suppresses the replication of the influenza A virus (IAV). The expression of KIF18A in host cells was increased following IAV infection. Intriguingly, treatment with the selective and ATP-competitive mitotic kinesin KIF18A inhibitor BTB-1 substantially decreased the expression of viral RNAs and proteins, and the production of infectious viral particles, while overexpression of KIF18A enhanced the replication of IAV. Importantly, BTB-1 treatment attenuated the activation of AKT, p38 MAPK, SAPK and Ran-binding protein 3 (RanBP3), which led to the prevention of the nuclear export of viral ribonucleoprotein complexes. Notably, administration of BTB-1 greatly improved the viability of IAV-infected mice. Collectively, our results unveiled a beneficial role of KIF18A in IAV replication, and thus, KIF18A could be a potential therapeutic target for the control of IAV infection., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: The diagnostic impact of lymphovascular invasion (LVI), perineural invasion (PNI), and tumor budding in stage I colon cancer is currently unknown. This study was conducted to evaluate the prognostic impact of LVI, PNI, and tumor budding in stage I colon cancer., Methods: From January 2008 to December 2013, 720 patients who underwent curative surgery and were diagnosed with stage I colon cancer were reviewed retrospectively. These patients were categorized into two groups based on LVI, PNI, and tumor budding: the no risk group (n = 566) and risk group (n = 154)., Results: Median follow-up period was 103.5 months, and the 5-year disease-free survival rate of the risk group was significantly lower than that of the no risk group (p = 0.025). In multivariate analysis, only the risk group had prognostic factors for 5-year disease-free survival (p = 0.036). In addition, only differentiation was an independent predictor in the risk group (p = 0.009)., Conclusion: LVI, PNI, and tumor budding are strong prognostic factors for stage I colon cancer. Therefore, patients with positive LVI, PNI, or tumor budding should receive close follow-up and potentially be considered for chemotherapy.

Colorectal cancer is a devastating disease with a low 5-year survival rate. Recently, many researchers have studied the mechanisms of tumor progression related to the tumor microenvironment. Here, we addressed the prognostic value of tumor-associated macrophages (TAMs) using a total of 232 CRC patient tissue samples and investigated the mechanisms underlying TAM-related colon cancer progression with respect to PI3Kγ regulation using in vitro, in vivo, and ex vivo approaches. Patients with M2/M1 < 3 had significantly improved progression-free survival and overall survival compared with patients with M2/M1 > 3. M1 and M2 macrophages elicited opposite effects on colon cancer progression via the FBW7-MCL-1 axis. Blocking macrophage PI3Kγ had cytotoxic effects on colon cancer cells and inhibited epithelial-mesenchymal transition features by regulating the FBW7-MCL-1 axis. The results of this study suggest that macrophage PI3Kγ may be a promising target for immunotherapy in colon cancer.

Purpose: The purpose of this study was to investigate the role of carcinoembryonic antigen (CEA) levels in improving the performance of magnetic resonance imaging (MRI) for the prediction of pathologic response after the neoadjuvant chemoradiation (NCRT) for patients with rectal cancer., Materials and Methods: We retrospectively reviewed the medical records of 524 rectal cancer patients who underwent NCRT and total mesorectal excision between January 2009 and December 2014. The performances of MRI with or without CEA parameters (initial CEA and CEA dynamics) for prediction of pathologic tumor response grade (pTRG) were compared by receiver-operating characteristic analysis with DeLong's method. Cox regression was used to identify the independent factors associated to pTRG and disease-free survival (DFS) after NCRT., Results: The median follow-up was 64.0 months (range, 3.0 to 113.0 months). On multivariate analysis, poor tumor regression grade on MRI (mrTRG; p < 0.001), initial CEA (p < 0.001) and the mesorectal fascia involvement on MRI before NCRT (mrMFI; p=0.054) showed association with poor pTRG. The mrTRG plus CEA parameters showed significantly improved performances in the prediction of pTRG than mrTRG alone. All of mrTRG, mrMFI, and initial CEA were also identified as independent factors associated with DFS. The initial CEA further discriminated DFS in the subgroups with good mrTRG or that without mrMFI., Conclusion: The CEA parameters significantly improved the performance of MRI in the prediction of pTRG after NCRT for patients with rectal cancer. The DFS was further discriminated by initial CEA level in the groups with favorable MRI parameters.

Purpose: The integral quality monitor (IQM) is a real-time radiotherapy beam monitoring system, which consists of a spatially sensitive large-area ion chamber, mounted at the collimator of the linear accelerator (linac), and a calculation algorithm to predict the detector signal for each beam segment. By comparing the measured and predicted signals the system validates the beam delivery. The current commercial version of IQM uses an analytic method to predict the signal, which requires a semi-empirical approach to determine and optimize various calculation parameters. The process of developing the calculation model is complex and time consuming, and moreover, the model cannot be easily generalized across various beam delivery platforms with different combinations of beam energy, beam flattening, beam shaping elements, and Linac models. Therefore, as an alternative solution, we investigated the feasibility of developing a machine learning (ML) method, using an artificial neural network (ANN), to predict the ion chamber signal. In developing an ANN, it is not necessary to explicitly account for each of the elements of beam interactions with various structures in the beam path to the ion chamber., Methods: The ANN was designed with multilayer perceptron (MLP). The input layer consisted of multiple features, derived from the geometrical characteristics of beam segments. Gradient descent error backpropagation technique was used to train the ANN. The combined training dataset included 270 rectangular fields, and 801 clinical IMRT fields delivered using 6 MV beams on Varian TrueBeam TM and Elekta Infinity TM . Each of 12 different ANN configurations (3 different sets of input features × 4 different sets of number of hidden nodes) was simulated 10 times with randomly selected 80% of data for training and the remaining data for validation., Results: Artificial neural networks with one hidden layer, consisting of 10 nodes, and 10 input features provided optimum results. Once the feature sets were extracted, the time required for the network training was on the order of a few minutes, and the time required to perform an output calculation per field was only fraction of a second. More than 95% of clinical intensity-modulated radiation therapy (IMRT) segments were calculated within ± 3.0% modeling error for Varian Truebeam (90% and ±3.3% for Elekta Infinity). A total of 3320 volumetric-modulated arc therapy (VMAT) segments from Truebeam were calculated using the ANN trained with IMRT fields. More than 95% of the cumulative VMAT beam segments were within 3.6% modeling error, similar to the performance for IMRT segments. In general the modeling error was found to be inversely proportional to the size and intensity of the beam segment., Conclusions: A prototype ANN has been developed for predicting the signals of the IQM system, with substantially less efforts compared to the analytic model. The performance of the ANN was found to be at least equivalent to that of the analytic method, in terms of average and maximum error, for 6 MV beams on both Varian TrueBeam and Elekta Infinity platforms., (© 2020 American Association of Physicists in Medicine.)

Purpose: The goal of this study was to evaluate the long-term oncologic outcomes after laparoscopic converted surgery for patients with colon cancer., Methods: Retrospective database of consecutive curative-intent laparoscopic-assisted surgery for primary stage I-III colon cancer was reviewed from 2000 to 2013. The patients were divided into non-conversion and conversion groups. The patient characters, operative features, perioperative parameters, pathologic features, and oncologic outcomes were compared., Results: A total of 4010 patients were included in the study: 3929 in the non-conversion group and 81 (2%) in the conversion group. The median follow-up period was 63.9 months. There were significant differences in age, preoperative clinical T-stage, and tumor size between the groups. In operative details between the two groups, there were also significant differences in access to surgery, tumor location, cancer obstruction, cancer perforation, and estimated blood loss (P < 0.001). The two most common reasons for conversion were adhesion (n = 37, 46%) and bleeding (n = 21, 26%). Multivariate analysis showed that conversion was an independent predictor of both overall survival (OS) (P < 0.001) and disease-free survival (P = 0.003). The 5-year OS rate of the conversion group was 79.6%, and that of the non-conversion group was 96.2% (P < 0.001). The multivariate predictors of conversion were age, type of surgery, cancer obstruction, cancer perforation, and clinical T-stage., Conclusion: Conversion to open surgery may affect patient survival and recurrence after laparoscopic-assisted surgery for colon cancer. Our data suggest that conversion is associated with poor outcomes, but we should not hesitate to convert it to patients who have difficulty in laparoscopic surgery.

Colorectal cancer (CRC) is one of the leading causes of world cancer deaths. To improve the survival rate of CRC, diagnosis and post-operative monitoring is necessary. Currently, biomarkers are used for CRC diagnosis and prognosis. However, these biomarkers have limitations of specificity and sensitivity. Levels of plasma lysyl-tRNA synthetase (KARS1), which was reported to be secreted from colon cancer cells by stimuli, along with other secreted aminoacyl-tRNA synthetases (ARSs), were analyzed in CRC and compared with the currently used biomarkers. The KARS1 levels of CRC patients (n = 164) plasma were shown to be higher than those of healthy volunteers (n = 32). The diagnostic values of plasma KARS1 were also evaluated by receiving operating characteristic (ROC) curve. Compared with other biomarkers and ARSs, KARS1 showed the best diagnostic value for CRC. The cancer specificity and burden correlation of plasma KARS1 level were validated using azoxymethane (AOM)/dextran sodium sulfate (DSS) model, and paired pre- and post-surgery CRC patient plasma. In the AOM/DSS model, the plasma level of KARS1 showed high correlation with number of polyps, but not for inflammation. Using paired pre- and post-surgery CRC plasma samples (n = 60), the plasma level of KARS1 was significantly decreased in post-surgery samples. Based on these evidence, KARS1, a surrogate biomarker reflecting CRC burden, can be used as a novel diagnostic and post-operative monitoring biomarker for CRC., Competing Interests: All authors declare no conflicts of interest.