Rumen microbiota and its relation to fermentation in lactose-fed calves.

In our previous studies, we revealed the effect of lactose inclusion in calf starters on the growth performance and gut development of calves. We conducted the present study as a follow-up study to identify the shift in rumen microbiota and its relation to rumen fermentation when calves are fed a lactose-containing starter. Thirty Holstein bull calves were divided into 2 calf starter treatment groups: texturized calf starter (i.e., control; n = 15) or calf starter in which starch was replaced with lactose at 10% (i.e., LAC10; n = 15) on a dry matter basis. All calves were fed their respective treatment calf starter ad libitum from d 7, and kleingrass hay from d 35. Rumen digesta were collected on d 80 (i.e., 3 wk after weaning) and used to analyze rumen microbiota and fermentation products. There was no apparent effect of lactose feeding on the α-diversity and overall composition of rumen microbiota. Amplicon sequencing and real-time PCR quantification of the 16S rRNA gene confirmed that the abundance of butyrate-producing bacteria (i.e., Butyrivibrio group and Megasphaera elsdenii) did not differ between the control and LAC10 groups. Conversely, the relative abundance of Mitsuokella spp., which produce lactate, succinate, and acetate, was significantly higher in the rumen of calves that were fed lactose, whereas the lactate concentration did not differ between the control and LAC10 groups. These findings suggest that the lactate production can be elevated by an increase of Mitsuokella spp. and then converted into butyrate, not propionate, since the proportion of propionate was lower in lactose-fed calves. In addition, we observed a higher abundance of Coriobacteriaceae and Pseudoramibacter-Eubacterium in the LAC10 group. Both these bacterial taxa include acetate-producing bacteria, and a positive correlation between the acetate-to-propionate ratio and the abundance of Pseudoramibacter-Eubacterium was observed. Therefore, the higher abundance of Coriobacteriaceae, Mitsuokella spp., and Pseudoramibacter-Eubacterium in the rumen of lactose-fed calves partially explains the increase in the proportion of rumen acetate that was observed in our previous study.

Transverse Single-Spin Asymmetry for Very Forward Neutral Pion Production in Polarized p+p Collisions at sqrt[s]=510 GeV.

Transverse single-spin asymmetries of very forward neutral pions generated in polarized p+p collisions allow us to understand the production mechanism in terms of perturbative and nonperturbative strong interactions. During 2017, the RHICf Collaboration installed an electromagnetic calorimeter in the zero-degree region of the STAR detector at the Relativistic Heavy Ion Collider (RHIC) and measured neutral pions produced at pseudorapidity larger than 6 in polarized p+p collisions at sqrt[s]=510 GeV. The large nonzero asymmetries increasing both in longitudinal momentum fraction x_{F} and transverse momentum p_{T} have been observed at low transverse momentum p_{T}<1 GeV/c for the first time, at this collision energy. The asymmetries show an approximate x_{F} scaling in the p_{T} region where nonperturbative processes are expected to dominate. A non-negligible contribution from soft processes may be necessary to explain the nonzero neutral pion asymmetries.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with intermediate and advanced/relapsed hepatocellular carcinoma: a TOS-ESMO initiative endorsed by CSCO, ISMPO, JSMO, KSMO, MOS and SSO.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of hepatocellular carcinoma (HCC) was published in 2018, and covered the diagnosis, management, treatment and follow-up of early, intermediate and advanced disease. At the ESMO Asia Meeting in November 2018 it was decided by both the ESMO and the Taiwan Oncology Society (TOS) to convene a special guidelines meeting immediately after the Taiwan Joint Cancer Conference (TJCC) in May 2019 in Taipei. The aim was to adapt the ESMO 2018 guidelines to take into account both the ethnic and the geographic differences in practice associated with the treatment of HCC in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with intermediate and advanced/relapsed HCC representing the oncology societies of Taiwan (TOS), China (CSCO), India (ISMPO) Japan (JSMO), Korea (KSMO), Malaysia (MOS) and Singapore (SSO). The voting was based on scientific evidence, and was independent of the current treatment practices, the drug availability and reimbursement situations in the individual participating Asian countries.

Prognostic impact of residual lateral lymph node metastasis after neoadjuvant (chemo)radiotherapy in patients with advanced low rectal cancer.

Background: There is a lack of large studies focusing on the prognostic significance of lateral lymph node (LLN) metastasis following LLN dissection (LLND) in rectal cancer. The aim of this study was to evaluate the prognostic impact of LLN metastases on survival of patients with advanced low rectal cancer. Methods: Consecutive patients with locally advanced, but not metastatic, extraperitoneal rectal cancer treated with neoadjuvant (chemo)radiotherapy plus total mesorectal excision between 2004 and 2015 were included in the study. LLND was performed when pretreatment imaging documented enlarged LLNs (7 mm or greater in size). Localization of nodal metastases and long-term outcomes were analysed. Kaplan-Meier analysis was used to compare the survival of patients with ypN0 disease with that of patients with mesorectal ypN+/LLN- status and patients with positive LLNs. The Cox proportional hazards model was used to evaluate predictors of disease-free survival (DFS) and local recurrence. Results: A total of 613 patients were included in the study; LLND was performed in 212 patients (34·6 per cent) and 57 (9·3 per cent) had LLN metastasis. Patients with LLN metastasis had improved DFS and local recurrence cumulative incidence rates compared with patients with mesorectal ypN2+/LLN- disease (DFS: P = 0·014; local recurrence: P = 0·006). Although the DFS rate of patients with LLN metastasis was worse than that of patients with ypN0 disease (P < 0·001), the cumulative incidence of local recurrence was similar (P = 0·491). In multivariable analysis, residual LLN metastasis was not an independent predictor of worse DFS or local recurrence. Conclusion: LLN metastasis is not an independent predictor of local recurrence or survival. Survival of patients presenting with LLN metastasis after (chemo)radiotherapy was intermediate between that of patients with ypN0 status and those with mesorectal ypN2 positivity.

Antecedentes: No existen en la literatura grandes estudios dirigidos a investigar la importancia pronóstica de las metástasis en los ganglios linfáticos laterales (lateral lymph nodes, LLN) después de la disección de los mismos (LLN dissection, LLND) en pacientes con cáncer de recto. El objetivo de este estudio fue evaluar el impacto pronóstico de las metástasis en los LLN sobre la supervivencia de los pacientes con cáncer de recto. Métodos: Se analizaron 613 pacientes consecutivos con cáncer de recto localmente avanzado extraperitoneal y no metastásico tratados con (quimio)radioterapia neoadyuvante seguida de resección total del mesorrecto (total mesorectal excision, TME) entre 2004 y 2015. Se realizó una LLND cuando el estudio mediante pruebas de imagen previo el tratamiento mostró LLN aumentados de tamaño ≥ 7 mm. Se analizó la localización de las metástasis ganglionares y los resultados a largo plazo. El análisis de supervivencia se realizó mediante el método de Kaplan­Meier para comparar las supervivencias de los pacientes ypN0 frente a los pacientes ypN con positividad mesorrectal/LLN negativos y frente a los pacientes LLN positivos. Se utilizó el modelo de riesgo proporcional de Cox para evaluar los factores predictivos de supervivencia libre de enfermedad y de recidiva local. Resultados: Se realizó una LLND en 212 (34,6%) pacientes, y 57 (9,3%) pacientes presentaban metástasis en los LLN. Los pacientes con metástasis en los LLN presentaron mejores curvas de incidencia acumulada de recidiva local y de supervivencia libre de enfermedad en comparación con los pacientes con ganglios mesorrectales ypN2 positivos/LLN negativos (respectivamente, P = 0,0135 y P = 0,0060). Aunque la curva de la supervivencia libre de enfermedad de los pacientes con metástasis en los LLN fue peor que la de los pacientes ypN0 (P < 0,0001), la incidencia acumulada de recidiva local fue similar (P = 0,4905). En el análisis multivariable, la metástasis residual en los LLN no fue un factor predictivo independiente de peor supervivencia libre de enfermedad ni de recidiva local. Conclusión: Las metástasis en los LLN no es un factor predictivo independiente de recidiva local o supervivencia. Los pacientes que presentaron metástasis en los LLN después de (quimio)radioterapia mostraron características de supervivencia intermedias entre ypN0 y pacientes con ganglios mesorrectales ypN2 positivos.

Combination gemcitabine plus S-1 versus gemcitabine plus cisplatin for advanced/recurrent biliary tract cancer: the FUGA-BT (JCOG1113) randomized phase III clinical trial.

BACKGROUND: Gemcitabine plus cisplatin (GC) is the standard treatment of advanced biliary tract cancer (BTC); however, it causes nausea, vomiting, and anorexia, and requires hydration. Gemcitabine plus S-1 (GS) reportedly has equal to, or better, efficacy and an acceptable toxicity profile. We aimed to confirm the non-inferiority of GS to GC for patients with advanced/recurrent BTC in terms of overall survival (OS). PATIENTS AND METHODS: We undertook a phase III randomized trial in 33 institutions in Japan. Eligibility criteria included chemotherapy-naïve patients with recurrent or unresectable BTC, an Eastern Cooperative Oncology Group Performance Status of 0 - 1, and adequate organ function. The calculated sample size was 350 with a one-sided α of 5%, a power of 80%, and non-inferiority margin hazard ratio (HR) of 1.155. The primary end point was OS, while the secondary end points included progression-free survival (PFS), response rate (RR), adverse events (AEs), and clinically significant AEs defined as grade ≥2 fatigue, anorexia, nausea, vomiting, oral mucositis, or diarrhea. RESULTS: Between May 2013 and March 2016, 354 patients were enrolled. GS was found to be non-inferior to GC [median OS: 13.4 months with GC and 15.1 months with GS, HR, 0.945; 90% confidence interval (CI), 0.78-1.15; P = 0.046 for non-inferiority]. The median PFS was 5.8 months with GC and 6.8 months with GS (HR 0.86; 95% CI 0.70-1.07). The RR was 32.4% with GC and 29.8% with GS. Both treatments were generally well-tolerated. Clinically significant AEs were observed in 35.1% of patients in the GC arm and 29.9% in the GS arm. CONCLUSIONS: GS, which does not require hydration, should be considered a new, convenient standard of care option for patients with advanced/recurrent BTC. CLINICAL TRIAL NUMBER: This trial has been registered with the UMIN Clinical Trials Registry (http://www.umin.ac.jp/ctr/index.htm), number UMIN000010667.

Visualization and quantification of anastomotic perfusion in colorectal surgery using near-infrared fluorescence.

BACKGROUND: Anastomotic leakage (AL) is one of the most troublesome complications in colorectal surgery. Recently, near-infrared fluorescence (NIRF) imaging has been used intraoperatively to detect sentinel lymph nodes and visualize the blood supply at the region of interest (ROI). The aim of this study was to evaluate the role of visualization and quantification of bowel perfusion around the anastomosis using NIRF system in predicting AL. METHODS: A prospective study was conducted on patients who had laparoscopic surgery for colorectal cancer at our institution. Perfusion of the anastomosis was evaluated with NIRF imaging after intravenous injection of indocyanine green (ICG). The time course of fluorescence intensity was recorded by an imaging analyzer We measured the time from ICG injection to the beginning of fluorescence (T0), maximum intensity (Imax), time to reach Imax (Tmax), time to reach Imax 50% ([Formula: see text]) and slope (S) after the anastomosis. RESULTS: Tumor locations were as follows; cecum: 2, ascending colon: 2, transverse colon: 7, descending colon: 1, sigmoid colon: 2, rectosigmoid colon: 3 and rectum: 6 (one case with synchronous cancer). All operations were performed laparoscopically. Four patients were diagnosed with or suspected to have AL (2 patients with grade B anastomotic leakage after low anterior resection, 1 patient with minor leakage in transverse colon resection and 1 patient needing re-anastomosis intraoperatively in transverse colon resection). T0 was significantly longer in the AL group than in patients without AL (64.3 ± 27.6 and 18.2 ± 6.6 s, p = 2.2 × 10-3). CONCLUSIONS: Perfusion of the anastomosis could be successfully visualized and quantified using NIRF imaging with ICG. T0 might be a useful parameter for prediction of AL.

Immunogenomic profiles associated with response to neoadjuvant chemoradiotherapy in patients with rectal cancer.

BACKGROUND: Accumulating evidence suggests that radiotherapy success has an immune-associated component. The immunogenomic profiles associated with responses to chemoradiotherapy (CRT) were assessed in patients with locally advanced rectal cancer in this study. METHODS: CD8+ tumour-infiltrating lymphocyte (TIL) and stromal lymphocyte densities were assessed by immunohistochemistry using pretreatment biopsies from patients with advanced rectal cancer who had preoperative CRT. Whole-exome sequencing and gene expression microarray analysis were conducted to investigate the genomic properties associated with the response to CRT and CD8+ TIL density. Response to CRT was determined based on Dworak tumour regression grade (TRG); tumours with complete (TRG 4) or near-complete (TRG 3) regression were grouped as good responders, and those with TRG 1 as non-responders. RESULTS: Immunohistochemical examinations (275 patients) showed that pre-CRT CD8+ TIL density was associated with better response to CRT and improved recurrence-free survival, whereas pre-CRT stromal CD8+ cell density was not associated with either response to CRT or recurrence-free survival. Whole-exome sequencing (74 patients) showed that the numbers of single-nucleotide variations (SNVs) and neoantigens predicted from SNVs were higher in good responders than in non-responders, and these correlated positively with CD8+ TIL density (rS = 0·315 and rS = 0·334 respectively). Gene expression microarray (90 patients) showed that CD8A expression correlated positively with the expression of programmed cell death 1 (PDCD1) (rS = 0·264) and lymphocyte-activation gene 3 (LAG3) (rS = 0·507). CONCLUSION: Pre-CRT neoantigen-specific CD8+ T cell priming may be a key event in CRT responses where immune checkpoint molecules could be useful targets to enhance tumour regression.

ANTECEDENTES: Las evidencias existentes sugieren que el éxito de la radioterapia tiene un componente asociado con el sistema inmunitario. En este estudio se evaluaron los perfiles inmunogenómicos asociados con la respuesta a la quimiorradioterapia (chemoradiotherapy, CRT) en pacientes con cáncer de recto localmente avanzado. MÉTODOS: Las densidades de los linfocitos infiltrantes de tumor CD8+ (tumour-infiltrating lymphocyte, TIL) y de los linfocitos del estroma se evaluaron por inmunohistoquímicas en las biopsias antes del tratamiento de pacientes con cáncer de recto localmente avanzado que recibieron CRT preoperatoria. Se realizó secuenciación de todo el exoma, así como microarrays de expresión génica, para investigar las propiedades genómicas asociadas con la respuesta a la CRT y a la densidad de los TIL CD8+. La respuesta a la CRT se determinó según el grado de regresión del tumor de Dworak (tumour regression grade, TRG), agrupándose como buenos respondedores los casos de regresión tumoral completa (TRG4) o casi completa (TRG3) y como no respondedores, los casos de grado TRG1. RESULTADOS: Los exámenes inmunohistoquímicos (n = 275) mostraron que la densidad pre-CRT de TIL CD8+ se asoció con una mejor respuesta a la CRT y una mejor supervivencia libre de recidiva, aunque la densidad de células CD8+ del estroma previa a la CRT no se asoció con la respuesta a la CRT ni con la supervivencia libre de recidiva. La secuenciación de todo el exoma (n = 74) mostró que el número de variaciones de nucleótidos únicos (single nucleotide variations, SNVs) y los neoantígenos predichos a partir de los SNVs fueron mayores en los que respondieron bien que en los que no respondieron, y éstos se correlacionaron positivamente con la densidad de los TIL CD8+ (Spearman r = 0,315 y r = 0,334 respectivamente). Los microarrays de expresión génica (n = 90) mostraron que la expresión CD8A se correlacionó positivamente con la expresión del ligando de muerte programada-1 (r = 0,264) y con el antígeno linfocitario del gen 3 (r = 0,507). CONCLUSIÓN: La activación de células T CD8+ específicas para neoantígenos previa a la CRT puede ser un evento clave en la respuesta a la misma donde las moléculas del punto de control inmunitario podrían ser dianas útiles para intensificar la regresión del tumor.

Randomized controlled trial on efficacy of oligomeric formula (HINE E-GEL®) versus polymeric formula (MEIN®) enteral nutrition after esophagectomy for esophageal cancer with gastric tube reconstruction.

The efficacy of early enteral nutrition after esophageal cancer surgery has been reported. However, the choice of formula and management of diarrhea are important to achieve the goal of enhanced recovery after surgery. The aim of this study is to assess the frequency of diarrhea/completion rate of enteral nutrition regimen as primary endpoints and the postoperative nutritional status/body composition analysis/operative morbidity as secondary endpoints was compared between the two nutrition groups. Among the 122 patients who underwent esophagectomy for esophageal cancer between December 2015 and September 2017, 67 patients who met the eligibility criteria were randomly assigned to receive enteral nutrition with either HINE E-GEL® (HINE group; n = 33) or MEIN® (MEIN group; n = 34). The incidence of diarrhea was significantly lower in the HINE group (18.2 % vs. 64.7 %, P < 0.001). The score of Bristol scale of POD 6/7 was significantly lower in the HINE group (P = 0.019/P = 0.006, respectively). The completion rate of enteral nutrition regimen was significantly higher in the HINE group (97.4 % vs. 86.6 %, P = 0.002). The Controlling Nutritional Status scores and total protein levels at 6 months after surgery were significantly better in the HINE group (P = 0.030 and P = 0.023, respectively), indicating improved tendency in nutritional status in the HINE group. However, there were no significant differences in Prognostic Nutritional Index values, blood test results, rapid turnover proteins, body mass index, or body composition between the two groups. HINE E-GEL compared with MEIN may reduce the frequency of diarrhea, enabling patients to adhere to the scheduled enteral nutrition plan. Also, maintenance of nutritional status with HINE E-GEL was comparable or potentially better in some nutrition components to that with MEIN, indicating that HINE E-GEL can be an option for enteral nutrition following esophageal surgery to achieve the goal of successful completion of scheduled enteral nutrition and smooth transition to the normal diet.

Validity of self-reported tooth counts and masticatory status study of a Japanese adult population.

Self-reported measures of oral health are often used to assess oral health in populations or groups, but their validity or reliability needs repeated confirmation. The objective of this cross-sectional study was to evaluate the validity of self-reported tooth counts and masticatory status, using data obtained from a sample of Japanese adults. A total of 2356 adults aged 40 to 75 years participated in a questionnaire survey and a clinical oral examination from 2013 through 2016. Self-reported measures were compared with clinically measured values. For tooth counts, mean clinical and self-reported tooth counts in all participants were 23.68 and 23.78 teeth, and no significant difference was detected. Spearman's, Pearson's and intra-class correlation coefficients between clinical and self-reported tooth counts were 0.771, 0.845 and 0.843, respectively. According to the Bland-Altman analysis, the mean difference between clinical and self-reported tooth counts was -0.098 (95% CI: -0.242, 0.047). The upper limit of agreement was 6.919 (95% CI: 6.669, 7.169), and the lower limit of agreement was -7.115 (95% CI: -7.365, -6.865). No significant fixed or proportional bias was observed. For masticatory status, the crude or age- and gender-adjusted mean numbers of total teeth, posterior teeth and 3 kinds of functional tooth units significantly decreased with the deterioration of masticatory status. This study indicated that self-reports were within an acceptable range of clinical measures. Therefore, self-reports were considered valid alternatives to clinical measures to estimate tooth counts and masticatory status in a current Japanese adult population.

Relationship between self-assessment and clinical evaluation of dental plaque and gingival condition in Japanese adolescents.

OBJECTIVES: To apply a self-administered assessment form about dental plaque level and gingival condition to Japanese adolescents and to examine the extent to which they can evaluate their own dental plaque and gingivae by comparing with dentists' clinical evaluation. METHODS: Participants were 151 senior high school students (adolescents) who observed their own mouths and recorded dental plaque seen on their 12 anterior teeth, and gingival inflammation condition of 10 anterior interdental papillae, on a self-assessment form. Dentists clinically evaluated dental plaque using the, modified Debris Index (modified DI) and gingival condition, modified PMA index (P-index). "Recognition score" of dental plaque and gingival condition was the total number of agreement between the adolescents' self-assessment and dentists' evaluation. RESULTS: Proportion of agreement on dental plaque between the adolescents' self-assessment and dentists' evaluation with modified DI was 37.4%, and agreement on modified DI score 1, 2 or 3 was significantly lower than that on score 0 (P<.01). Agreement on gingivae was 47.3% in total, and agreement was significantly lower on gingival condition with inflammation than gingivae without inflammation (P<.01). Recognition scores of dental plaque or gingival condition were significantly lower in adolescents with fair or poor modified DI or P-index than in those with good condition (P<.01). CONCLUSION: Most adolescents could not recognize their dental plaque and gingival condition. Adolescents with poorer dental plaque level or gingival condition had lower recognition scores compared to those with better oral health. Improving oral health self-assessment skills could help adolescents achieve better oral health.

Photoexcitation dynamics of p-nitroaniline and N,N-dimethyl-p-nitroaniline in 1-alkyl-3-methylimidazolium-cation based ionic liquids with different alkyl-chain lengths.

Photoexcitation dynamics of p-nitroaniline (pNA) and N,N-dimethyl-p-nitroaniline (DMpNA) in 1-alkyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide ([Cnmim][NTf2]) with different alkyl chain lengths (from C2 to C12) was investigated using transient absorption spectroscopy. The internal conversion rate from the excited state to the ground state was estimated from bleach recovery around the ground state absorption centre, and the successive vibrational cooling rate in the ground state was estimated from the decay of the hot band observed at the red-edge of ground state absorption. The internal conversion rate slightly decreased with an increase in the alkyl-chain length of the cation, while the dependence of DMpNA was more significant than that of pNA. The extent of change was correlated with the change of the reaction free energy and solvent reorganization energy estimated from the absorption spectrum assuming that the internal conversion process is modelled by a back-electron-transfer process. The vibrational cooling rate estimated from the decay of hot-band absorption slightly decreased with an increase in the alkyl-chain length of the cation for both solutes. The hot-band decay of pNA was about 1.5-times faster than that of DMpNA, irrespective of the alkyl-chain length.

Effects of partial replacement of corn grain with lactose in calf starters on ruminal fermentation and growth performance.

The objective of this study was to evaluate effects of partial replacement of dry ground corn with lactose in calf starters on dry matter intake, growth rate, ruminal pH, and volatile fatty acid profile. Sixty Holstein bull calves were raised on a high plane of nutrition program until 55 d of age. Calves were fed texturized calf starters containing 30.1% steam-flaked grains and lactose at 0 (control), 5, or 10% (n = 20 for each treatment) on a dry matter basis. All calves were fed treatment calf starters ad libitum from d 7 and kleingrass hay from d 35. Ruminal pH was measured continuously immediately after weaning (d 55-62) for 15 calves (n = 5 per treatment), and 3 wk after weaning (d 77 to 80) for the other 45 calves (n = 15 per treatment). Dry matter intake, growth performance, and ruminal pH variables were not affected by treatment. However, according to Spearman's correlation coefficient (rs) analyses, lactose intake was positively correlated with dairy minimum ruminal pH (rs = 0.306) for the data collected from d 77 to 80. Similarly, hay intake was not affected by treatment, but positively correlated with daily mean (rs = 0.338) and maximum ruminal pH (rs = 0.408) and negatively correlated with duration pH <5.8 (rs = -0.329) and area pH <5.8 (rs = -0.325), indicating that the variation in hay intake among animals might have masked treatment effects on ruminal pH. Ruminal molar ratio of acetate was higher (45.2 vs. 40.6%), and that of propionate was lower in 10% lactose than control (35.3 vs. 40.2%) for ruminal fluid collected on d 80; however, molar ratio of butyrate was not affected by treatment. These results indicate that lactose inclusion in calf starters up to 10% of dry matter might not affect dry matter intake and growth performance of calves, but that greater lactose and hay intake might be associated with higher ruminal pH.

CXCR4 polymorphism predicts progression-free survival in metastatic colorectal cancer patients treated with first-line bevacizumab-based chemotherapy.

We analyzed associations between CXCR4/CXCL12 single-nucleotide polymorphisms and outcomes in metastatic colorectal cancer (mCRC) patients who underwent first-line bevacizumab-based chemotherapy. A total of 874 patients were included in this study: 144 treated with bevacizumab and FOLFOX or XELOX (training cohort), 653 treated with bevacizumab and FOLFIRI or FOLFOXIRI (validation cohort A or B) and 77 treated with cetuximab- and oxaliplatin-based regimens (control cohort). One CXCR4 polymorphism (rs2228014) and two CXCL12 polymorphisms (rs1801157 and rs3740085) were analyzed by PCR-based direct sequencing. Patients with a C/C genotype had a prolonged progression-free survival (PFS) compared with those with any T allele (P=0.030) in the training cohort. Similarly, patients with the C/C genotype had a superior PFS in the validation cohorts, but not in the control cohort. Our findings suggest that a common genetic variant, CXCR4 rs2228014, could predict PFS and may guide therapeutic decisions in mCRC patients receiving first-line bevacizumab-based chemotherapy.

Randomized clinical trial of oral and intravenous versus intravenous antibiotic prophylaxis for laparoscopic colorectal resection.

BACKGROUND: The use of oral prophylactic antibiotics for the prevention of surgical-site infection (SSI) in patients undergoing laparoscopic surgery for colorectal cancer is controversial. The aim of this RCT was to evaluate whether intravenous perioperative antibiotics are inferior to combined preoperative oral and perioperative intravenous antibiotics in this setting. METHODS: Patients undergoing elective laparoscopic colorectal resection in a single cancer centre were assigned randomly to combined preoperative oral antibiotics (metronidazole and kanamycin) and perioperative intravenous antibiotics (cefmetazole) (oral/IV group) or to perioperative intravenous antibiotics (cefmetazole) alone (IV-only group). Patients were stratified for the analyses based on type of operation (colonic surgery, anterior resection or abdominoperineal resection), preoperative use of mechanical bowel preparation, preoperative chemoradiotherapy and the presence of diabetes mellitus. The primary endpoint was the overall rate of SSI. Secondary endpoints were the rates of incisional site infection, organ/space infection, anastomotic leakage, intra-abdominal abscess, adverse events and postoperative complications. RESULTS: Of 540 patients offered participation in the trial in 2013-2014, 515 agreed to take part and were randomized. Some 256 patients in the IV-only group and 255 in the oral/IV group completed the treatment per protocol. The overall rate of SSI was 7·8 per cent (20 of 256) in the IV-only group and 7·8 per cent (20 of 255) in the oral/IV group, confirming that perioperative administration of intravenous antibiotics alone was not inferior to the combined regimen (P = 0·017). There were no differences in rates of incisional site infection (5·5 versus 5·9 per cent respectively), organ/space infection (2·3 versus 2·0 per cent) or other secondary endpoints between the two groups. CONCLUSION: Intravenous perioperative antimicrobial prophylaxis alone is not inferior to combined preoperative oral and intravenous perioperative prophylaxis with regard to SSI in patients with colorectal cancer undergoing elective laparoscopic resection. Registration number: UMIN000019339 ( http://www.umin.ac.jp/ctr/).

A diffusion model for the coordination of DNA replication in Schizosaccharomyces pombe.

The locations of proteins and epigenetic marks on the chromosomal DNA sequence are believed to demarcate the eukaryotic genome into distinct structural and functional domains that contribute to gene regulation and genome organization. However, how these proteins and epigenetic marks are organized in three dimensions remains unknown. Recent advances in proximity-ligation methodologies and high resolution microscopy have begun to expand our understanding of these spatial relationships. Here we use polymer models to examine the spatial organization of epigenetic marks, euchromatin and heterochromatin, and origins of replication within the Schizosaccharomyces pombe genome. These models incorporate data from microscopy and proximity-ligation experiments that inform on the positions of certain elements and contacts within and between chromosomes. Our results show a striking degree of compartmentalization of epigenetic and genomic features and lead to the proposal of a diffusion based mechanism, centred on the spindle pole body, for the coordination of DNA replication in S. pombe.

Germline polymorphisms in genes involved in the Hippo pathway as recurrence biomarkers in stages II/III colon cancer.

The Hippo pathway regulates tissue growth and cell fate. In colon cancer, Hippo pathway deregulation promotes cellular quiescence and resistance to 5-Fluorouracil (5-Fu). In this study, 14 polymorphisms in 8 genes involved in the Hippo pathway (MST1, MST2, LATS1, LATS2, YAP, TAZ, FAT4 and RASSF1A) were evaluated as recurrence predictors in 194 patients with stages II/III colon cancer treated with 5-Fu-based adjuvant chemotherapy. Patients with a RASSF1A rs2236947 AA genotype had higher 3-year recurrence rate than patients with CA/CC genotypes (56 vs 33%, hazard ratio (HR): 1.87; P=0.017). Patients with TAZ rs3811715 CT or TT genotypes had lower 3-year recurrence rate than patients with a CC genotype (28 vs 40%; HR: 0.66; P=0.07). In left-sided tumors, this association was stronger (HR: 0.29; P=0.011) and a similar trend was found in an independent Japanese cohort. These promising results reveal polymorphisms in the Hippo pathway as biomarkers for stages II and III colon cancer.The Pharmacogenomics Journal advance online publication, 15 September 2015; doi:10.1038/tpj.2015.64.