Neighborhoods and functionality in metals.

The fundamental construct of organic chemistry involves understanding molecular behavior through functional groups. Much of computational chemistry focuses on this very principle, but metallic materials are rarely analyzed using these techniques owing to the assumption that they are delocalized and do not possess inherent functionality. In this paper, we propose a methodology that recovers functional groups in metallic materials from an energy perspective. We characterize neighborhoods associated with functional groups in metals by observing the evolution of Bader energy of the central cluster as a function of cluster size. This approach can be used to conceptually decompose metallic structure into meaningful chemical neighborhoods allowing for localization of energy-dependent properties. The generalizability of this approach is assessed by determining neighborhoods for crystalline materials of different structure types, and significant structural defects such as grain boundaries and dislocations. In all cases, we observe that the neighborhood size may be universal-around 2-3 atomic diameters. In its practical sense, this approach opens the door to the application of chemical concepts, e.g., orbital methods, to investigate a broad range of metallurgical phenomena, one neighborhood at a time.

Phase III randomized study of taselisib or placebo with fulvestrant in estrogen receptor-positive, PIK3CA-mutant, HER2-negative, advanced breast cancer: the SANDPIPER trial.

BACKGROUND: The phase III SANDPIPER study assessed taselisib (GDC-0032), a potent, selective PI3K inhibitor, plus fulvestrant in estrogen receptor-positive, HER2-negative, PIK3CA-mutant locally advanced or metastatic breast cancer. PATIENTS AND METHODS: Postmenopausal women with disease recurrence/progression during/after an aromatase inhibitor were randomized 2 : 1 to receive taselisib (4 mg; taselisib arm) or placebo (placebo arm) plus fulvestrant (500 mg). Stratification factors were visceral disease, endocrine sensitivity, and geographic region. Patients with PIK3CA-mutant tumors (central cobas® PIK3CA Mutation Test) were randomized separately from those without detectable mutations. The primary endpoint was investigator-assessed progression-free survival (INV-PFS) in patients with PIK3CA-mutant tumors. Secondary endpoints included objective response rate, overall survival, clinical benefit rate, duration of objective response, PFS by blinded independent central review (BICR-PFS), safety, and time to deterioration in health-related quality of life. RESULTS: The PIK3CA-mutant intention-to-treat population comprised 516 patients (placebo arm: n = 176; taselisib arm: n = 340). INV-PFS was significantly improved in the taselisib {7.4 months [95% confidence interval (CI), 7.26-9.07]} versus placebo arm (5.4 months [95% CI, 3.68-7.29]) (stratified hazard ratio [HR] 0.70; 95% CI, 0.56-0.89; P = 0.0037) and confirmed by BICR-PFS (HR 0.66). Secondary endpoints, including objective response rate, clinical benefit rate, and duration of objective response, showed consistent improvements in the taselisib arm. Safety was assessed in all randomized patients who received at least one dose of taselisib/placebo or fulvestrant regardless of PIK3CA-mutation status (n = 629). Serious adverse events were lower in the placebo versus taselisib arm (8.9% versus 32.0%). There were more discontinuations (placebo arm: 2.3%; taselisib arm: 16.8%) and dose reductions (placebo arm: 2.3%; taselisib arm: 36.5%) in the taselisib arm. CONCLUSION: SANDPIPER met its primary endpoint; however, the combination of taselisib plus fulvestrant has no clinical utility given its safety profile and modest clinical benefit.

Current management of small bowel obstruction in the UK: results from the National Audit of Small Bowel Obstruction clinical practice survey.

AIM: Small bowel obstruction (SBO) is associated with high rates of morbidity and mortality. The National Audit of Small Bowel Obstruction (NASBO) is a collaboration between trainees and specialty associations to improve the care of patients with SBO through national clinical audit. The aim of this study was to define current consultant practice preferences in the management of SBO in the UK. METHOD: A survey was designed to assess practice preferences of consultant surgeons. The anonymous survey captured demographics, indications for surgery or conservative management, use of investigations including water-soluble contrast agents (WSCA), use of laparoscopy and nutritional support strategies. The questionnaire underwent two pilot rounds prior to dissemination via the NASBO network. RESULTS: A total of 384 responses were received from 131 NASBO participating units (overall response rate 29.2%). Abdominal CT and serum urea and electrolytes were considered essential initial investigations by more than 80% of consultants. Consensus was demonstrated on indications for early surgery and conservative management. Three hundred and thirty-eight (88%) respondents would consider use of WSCA; of these, 328 (97.1%) would use it in adhesive SBO. Two hundred (52.1%) consultants considered a laparoscopic approach when operating for SBO. Oral nutritional supplements were favoured in operatively managed patients by 259 (67.4%) respondents compared with conservatively managed patients (186 respondents, 48.4%). CONCLUSION: This survey demonstrates consensus on imaging requirements and indications for early surgery in the management of SBO. Significant variation exists around awareness of the need for nutritional support in patients with SBO, and on strategies to achieve this support.

Somatic mutation, copy number and transcriptomic profiles of primary and matched metastatic estrogen receptor-positive breast cancers.

BACKGROUND: Estrogen receptor-positive (ER+) breast cancers (BCs) constitute the most frequent BC subtype. The molecular landscape of ER+ relapsed disease is not well characterized. In this study, we aimed to describe the genomic evolution between primary (P) and matched metastatic (M) ER+ BCs after failure of adjuvant therapy. MATERIALS AND METHODS: A total of 182 ER+ metastatic BC patients with long-term follow-up were identified from a single institution. P tumor tissue was available for all patients, with 88 having matched M material. According to the availability of tumor material, samples were characterized using a 120 mutational hotspot qPCR, a 29 gene copy number aberrations (CNA) and a 400 gene expression panels. ESR1 mutations were assayed by droplet digital PCR. Molecular alterations were correlated with overall survival (OS) using the Cox proportional hazards regression models. RESULTS: The median follow-up was 6.4 years (range 0.5-26.6 years). Genomic analysis of P tumors revealed somatic mutations in PIK3CA, KRAS, AKT1, FGFR3, HRAS and BRAF at frequencies of 41%, 6%, 5%, 2%, 1% and 2%, respectively, and CN amplification of CCND1, ZNF703, FGFR1, RSF1 and PAK1 at 23%, 19%, 17%, 12% and 11%, respectively. Mutations and CN amplifications were largely concordant between P and matched M (>84%). ESR1 mutations were found in 10.8% of the M but none of the P. Thirteen genes, among which ESR1, FOXA1, and HIF1A, showed significant differential expression between P and M. In P, the differential expression of 18 genes, among which IDO1, was significantly associated with OS (FDR < 0.1). CONCLUSIONS: Despite the large concordance between P and matched M for the evaluated molecular alterations, potential actionable targets such as ESR1 mutations were found only in M. This supports the importance of characterizing the M disease. Other targets we identified, such as HIF1A and IDO1, warrant further investigation in this patient population.

Randomized, phase II, placebo-controlled trial of onartuzumab and/or bevacizumab in combination with weekly paclitaxel in patients with metastatic triple-negative breast cancer.

BACKGROUND: Increased hepatocyte growth factor/MET signaling is associated with an aggressive phenotype and poor prognosis in triple-negative breast cancer (TNBC). We evaluated the benefit of adding onartuzumab, a monoclonal anti-MET antibody, to paclitaxel with/without bevacizumab in patients with TNBC. PATIENTS AND METHODS: Women with metastatic TNBC were randomized to receive onartuzumab plus placebo plus weekly paclitaxel (OP; n = 60) or onartuzumab plus bevacizumab plus paclitaxel (OBP; n = 63) or placebo plus bevacizumab plus paclitaxel (BP; n = 62). The primary end point was progression-free survival (PFS); additional end points included overall survival (OS), objective response rate (ORR), and safety. This trial was hypothesis generating and did not have power to detect minimum clinically meaningful differences between treatment arms. RESULTS: There was no improvement in PFS with the addition of onartuzumab to BP [hazard ratio (HR), 1.08; 95% confidence interval (CI) 0.69-1.70]; the risk of a PFS event was higher with OP than with BP (HR, 1.74; 95% CI 1.13-2.68). Most patients had MET-negative tumors (88%); PAM50 subtype analysis showed basal-like tumors in 68% of samples. ORR was higher in the bevacizumab arms (OBP: 42.2%; 95% CI 28.6-57.1; BP: 54.7%; 95% CI 41.0-68.4) compared with OP (27.5%; 95% CI 15.9-40.6). Median OS was shorter with OBP (HR, 1.36; 95% CI 0.75-2.46) and OP (HR, 1.92; 95% CI 1.03-3.59), than with BP. Peripheral edema was more frequent in the onartuzumab arms (OBP, 51.8%; OP, 58.6%) versus BP (17.7%). CONCLUSION: This study did not show a clinical benefit of the addition of onartuzumab to paclitaxel with/without bevacizumab in patients with predominantly MET-negative TNBC. CLINICALTRIALSGOV: NCT01186991.

Utility of contrast enema to assess anastomotic integrity and the natural history of radiological leaks after low rectal surgery: systematic review and meta-analysis.

PURPOSE: There is no clear consensus on how to assess low rectal anastomotic integrity and patency prior to reversal of de-functioning stoma. The aim of this systematic review was to assess the utility of contrast enema (CE) in this context and to clarify the natural history of radiological leaks. METHODS: Keyword search of electronic databases (Embase, MEDLINE, Cochrane Library, Google Scholar) and bibliographic cross-referencing were performed to identify appropriate studies. Data extraction and synthesis was performed with the primary outcomes being the sensitivity and specificity of CE for detecting clinically significant abnormalities. Statistical analysis was performed using Open Meta-Analyst software. Narrative review of outcomes including those of clinical and radiological leaks was also undertaken. RESULTS: A total of 1,142 CE from 11 articles were included in the final meta-analysis. CE had high specificity (95.4; 95 % confidence interval = 92.0-97.4) and negative predictive value (98.4; 97.4-99.1) and moderate sensitivity (79.9; 63.9-89.9) and positive predictive value (64.6; 55.5-72.9) for the detection of clinically significant anastomotic problems. There was a high degree of correlation between CE and clinical examination findings (96.7 %). Occult radiological leaks were seen in 5.7 % of CE, and all but one (97 %) eventually underwent successful reversal. Only three quarters of patients with clinical leak underwent successful reversal. CONCLUSION: CE is effective at excluding clinically significant anastomotic problems, especially after clinical anastomotic leaks. However, false positive results can be observed in asymptomatic patients, and it is unclear how much additional information CE provides over clinical assessment in the low uncomplicated anastomosis.

Changes in PIK3CA mutation status are not associated with recurrence, metastatic disease or progression in endocrine-treated breast cancer.

The phosphatidylinositol-3-kinase pathway plays an important role in proliferation, migration and survival in breast cancer and may play a role in resistance to endocrine therapy. Pathway activation occurs as a result of mutations in PIK3CA or loss of functional PTEN. Matched primary and recurrent samples from 120 breast cancer patients treated with endocrine therapy were profiled with a qPCR-based mutation assay covering eight mutational hotspots in PIK3CA. PTEN was assayed by immunohistochemistry. Samples were well characterized with respect to anatomic location of recurrence (metastatic nodal or local recurrence as opposed to contralateral or ipsilateral new primary cancers). In total, 43 % of patients had at least one PIK3CA mutation at diagnosis, and 41 % had a mutation at the time of recurrence. Only 8 % of patients with local recurrence, metastatic disease or progression on primary endocrine treatment changed their PIK3CA mutation status (four gains, two losses, total 76). The most common changes in PIK3CA mutation status were seen in patients who developed a new cancer either in the treated or contralateral breast (64 %, three gains, four losses, total 11). PIK3CA mutation status does not change in the majority of patients with breast cancer and the acquisition of mutations in PIK3CA is not responsible for the development of endocrine resistance. PTEN loss at diagnosis is associated with a significantly shorter time to progression compared with tumours in which PTEN was retained. These are the most comprehensive data currently available correlating PIK3CA status, site of recurrence and endocrine resistance.

The success of rectus and gracilis muscle flaps in the treatment of chronic pelvic sepsis and persistent perineal sinus: a systematic review.

AIM: Chronic pelvic sepsis is a challenging problem, which may require muscle flaps to fill the pelvic cavity. The aim of this systematic review was to determine the relative success of rectus and gracilis flaps used for this purpose. METHOD: A systematic review was conducted to identify papers that reported the outcome of rectus or gracilis myocutaneous flaps in the treatment of persistent perineal sinuses or chronic pelvic sepsis. Reports of muscle flaps used for reconstruction or treatment of fistula in the absence of chronic sepsis were excluded. A successful outcome was defined as complete perineal healing within 12 months of surgery. RESULTS: The review identified 19 studies reporting the outcome of 73 rectus and 87 gracilis flaps. Their respective success was 84% and 64%. Heterogeneity of the underlying cases did not allow for direct comparison of the flaps. Full healing of the flaps was generally achieved within 3 months. Donor site morbidity was minimal. CONCLUSION: The surgical treatment of chronic pelvic sepsis should be tailored to the individual, but the rectus flap has a reasonable success rate with little morbidity.

Influence of enhanced recovery after surgery pathways and laparoscopic surgery on health-related quality of life.

AIM: This study set out to compare the postoperative health related quality of life (HQoL) of patients undergoing elective open colorectal surgery using a well-established enhanced recovery after surgery (ERAS) pathway with those undergoing laparoscopic surgery without an established an ERAS pathway. METHOD: Using a power calculation, it was estimated that 40 patients would be required in each group. HQoL of the two groups was prospectively assessed using SF-12 (Short Form 12) and EORTC QLQ 30 (European Organisation of Research and Treatment of Cancer, Quality of Life Questionnaire) preoperatively, and at 2 and 6 weeks after discharge. RESULTS: Data were collected from 83 patients, 41 in the laparoscopic group and 42 in the open-ERAS group. There was a significant difference between the median length of stay of the open-ERAS (5 days) and laparoscopic (7 days, P = 0.028) groups. There were no significant differences between the HQoL score of the two groups at any stage. In both groups, the majority of HQoL scores had improved considerably by 6 weeks. CONCLUSION: Laparoscopic and open-ERAS surgery have a similar impact on postoperative HQoL. HQoL tends to improve by the 6-week stage.

Screening for malnutrition in emergency laparotomy patients: a comparison of three tools.

INTRODUCTION: Malnourished patients undergoing emergency laparotomy are at risk of significant morbidity. The optimum screening tool to identify such patients in practice and research is yet to be determined. This study aims to compare the performance of three nutrition risk tools in predicting time without enteral nutrition in this population. METHODS: A prospective cohort study (NCT04696367) was conducted across two sites, recruiting patients undergoing National Emergency Laparotomy Audit eligible procedures. Data collected included demographics, diagnosis, procedure and outcomes. Nutrition risk was assessed using three tools: Malnutrition Universal Screening Tool (MUST) score, Nutritional Risk Index (NRI) and Nutritional Risk Score 2002 (NRS-2002). Complications were assessed with the Comprehensive Complication Index. Quality of life was measured at baseline and 5 days postsurgery using EQ-5D-5L. RESULTS: A total of 59 patients were recruited. Median age was 69 years. Of the 59 participants, 23 were judged high risk using MUST score, 13 using NRS and 8 using NRI. Median time to restart enteral intake was 7 days (interquartile range 7-14). Time without intake was correlated with increasing score using MUST (r=0.463, p<0.001) and NRS-2002 (r=0.296, p=0.03) but not NRI (r=-0.121, p=0.38). High-risk nutritional groups also had increased length of hospital stay, but not complication scores. CONCLUSIONS: Patients undergoing emergency laparotomy spend a prolonged time without enteral nutrition. Although all nutritional tools demonstrated some propensity to identify patients at higher risk of needing nutritional support, their performance was variable. Nevertheless, some may be useful in future clinical studies.

Raised intraocular pressure (IOP) and perioperative visual loss in laparoscopic colorectal surgery: a catastrophe waiting to happen? A systematic review of evidence from other surgical specialities.

BACKGROUND: Case reports of healthy patients experiencing total perioperative visual loss (POVL) after elective laparoscopic surgery, including colorectal resection, are appearing increasingly frequently in the literature. We reviewed the literature exploring the relationship between patient positioning and intraocular pressure (IOP) across all surgical specialties. This was then applied to the potential risk of developing POVL in patients undergoing laparoscopic colorectal surgery. METHODS: A systematic review of the relevant literature was performed to identify all studies exploring the relationship between intraocular pressure and patient positioning. RESULTS: Eight relevant studies on both elective patients and healthy non-anaesthetised volunteers in the spinal, neurosurgical and urological fields were identified which explore the changes in IOP according to patient positioning. These all reported significant rises in IOP in both head-down positioning and prone positioning, and the strongest effects were seen in those patients placed in combined head-down and prone position (such as prone jackknife). Rises in IOP were time-dependent in all studies. CONCLUSIONS: Patients undergoing laparoscopic colorectal surgery in a prolonged head-down position are likely to experience raised IOP and thus are at risk of POVL. Those having a laparoscopic abdominoperineal excision with prone positioning for the perineal component are probably those in the greatest danger. Surgeons need to be aware of this under-recognised but potentially catastrophic complication.

Genomic context of NTRK1/2/3 fusion-positive tumours from a large real-world population.

Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are rare oncogenic drivers in solid tumours. This study aimed to interrogate a large real-world database of comprehensive genomic profiling data to describe the genomic landscape and prevalence of NTRK gene fusions. NTRK fusion-positive tumours were identified from the FoundationCORE® database of >295,000 cancer patients. We investigated the prevalence and concomitant genomic landscape of NTRK fusions, predicted patient ancestry and compared the FoundationCORE cohort with entrectinib clinical trial cohorts (ALKA-372-001 [EudraCT 2012-000148-88]; STARTRK-1 [NCT02097810]; STARTRK-2 [NCT02568267]). Overall NTRK fusion-positive tumour prevalence was 0.30% among 45 cancers with 88 unique fusion partner pairs, of which 66% were previously unreported. Across all cases, prevalence was 0.28% and 1.34% in patients aged ≥18 and <18 years, respectively; prevalence was highest in patients <5 years (2.28%). The highest prevalence of NTRK fusions was observed in salivary gland tumours (2.62%). Presence of NTRK gene fusions did not correlate with other clinically actionable biomarkers; there was no co-occurrence with known oncogenic drivers in breast, or colorectal cancer (CRC). However, in CRC, NTRK fusion-positivity was associated with spontaneous microsatellite instability (MSI); in this MSI CRC subset, mutual exclusivity with BRAF mutations was observed. NTRK fusion-positive tumour types had similar frequencies in FoundationCORE and entrectinib clinical trials. NTRK gene fusion prevalence varied greatly by age, cancer type and histology. Interrogating large datasets drives better understanding of the characteristics of very rare molecular subgroups of cancer and allows identification of genomic patterns and previously unreported fusion partners not evident in smaller datasets.

A qualitative study of patient perspectives of health-related quality of life in colorectal cancer: comparison with disease-specific evaluation tools.

AIM: Little is known about the factors that patients with colorectal cancer (CRC) consider as important in shaping their health-related quality of life (HrQoL) and whether these are adequately represented by currently used HrQoL instruments. The aim of this study was to determine which areas of HrQoL are important to patients with CRC and to establish whether these areas are represented by validated questionnaires. METHOD: Semi-structured interviews were conducted with 20 patients who were undergoing treatment or follow up for potentially curable CRC. The areas of HrQoL that were important to the patients were identified from the interview data using a qualitative thematic framework analysis. These themes were then compared with the item content of two CRC-specific HrQoL questionnaires, FACT-C and QLQ-C30/CR38. RESULTS: The interviews identified 10 themes considered by patients to be important determinants of their HrQoL. These comprised control, normality, fatigue, uncertainty, information, emotional support, self-image, coping, symptoms and emotionally challenging events. Both HrQoL instruments contained questions that concerned some of the themes identified, but none of the FACT-C scales and only three from QLQ-C30/CR38 produced scores from which clinicians could identify problems in these areas. CONCLUSION: Identifying and addressing areas of concern for patients may assist clinicians in improving HrQoL outcomes. However, validated instruments currently used in CRC provide little information with regard to these areas.

Prehabilitation in elective abdominal cancer surgery in older patients: systematic review and meta-analysis.

BACKGROUND: Prehabilitation has emerged as a strategy to prepare patients for elective abdominal cancer surgery with documented improvements in postoperative outcomes. The aim of this study was to assess the evidence for prehabilitation interventions of relevance to the older adult. METHODS: Systematic searches were conducted using MEDLINE, Web of Science, Scopus, CINAHL and PsychINFO. Studies of preoperative intervention (prehabilitation) in patients undergoing abdominal cancer surgery reporting postoperative outcomes were included. Age limits were not set as preliminary searches revealed this would be too restrictive. Articles were screened and selected based on PRISMA guidelines, and assessment of bias was performed. Qualitative, quantitative and meta-analyses of data were conducted as appropriate. RESULTS: Thirty-three studies (3962 patients) were included. Interventions included exercise, nutrition, psychological input, comprehensive geriatric assessment and optimization, smoking cessation and multimodal (two or more interventions). Nine studies purposely selected high-risk, frail or older patients. Thirty studies were at moderate or high risk of bias. Ten studies individually reported benefits in complication rates, with meta-analyses for overall complications demonstrating significant benefit: multimodal (risk difference -0·1 (95 per cent c.i. -0·18 to -0·02); P = 0·01, I2  = 18 per cent) and nutrition (risk difference -0·18 (-0·26 to -0·10); P < 0·001, I2  = 0 per cent). Seven studies reported reductions in length of hospital stay, with no differences on meta-analysis. CONCLUSION: The conclusions of this review are limited by the quality of the included studies, and the heterogeneity of interventions and outcome measures reported. Exercise, nutritional and multimodal prehabilitation may reduce morbidity after abdominal surgery, but data specific to older patients are sparse.

ANTECEDENTES: La pre-habilitación ha surgido como una estrategia para preparar a los pacientes para la cirugía electiva del cáncer abdominal con mejoras documentadas en los resultados postoperatorios. El objetivo de este estudio fue evaluar la evidencia sobre las intervenciones de pre-habilitación relevantes en adultos de edad avanzada. MÉTODOS: Se realizaron búsquedas sistemáticas utilizando MEDLINE, Web of Science, Scopus, CINAHL y PsychINFO. Registro PROSPERO: CRD42019120381. Se incluyeron estudios de intervención preoperatoria (pre-habilitación) en pacientes sometidos a cirugía oncológica abdominal que describiesen resultados postoperatorios. No se fijaron límites en la edad dado que las búsquedas preliminares revelaron que ello sería demasiado restrictivo. Los artículos fueron examinados y seleccionados en base a las guías PRISMA y se realizó una evaluación del sesgo. Se llevó a cabo un análisis cualitativo, cuantitativo y metaanálisis de los datos según fuese apropiado. RESULTADOS: Se incluyeron 33 estudios (3.962 patients). Las intervenciones incluyeron ejercicio, nutrición, intervención psicológica, evaluación geriátrica global y optimización, abandono del tabaquismo y multimodal (dos o más intervenciones). Nueve estudios seleccionaron expresamente una población de pacientes de elevado riesgo, frágiles o de edad avanzada. Treinta estudios presentaban un riesgo moderado/alto de sesgo. Diez estudios describieron de forma individual beneficios en las tasas de complicaciones con metaanálisis para las complicaciones globales demostrando un beneficio significativo: multimodal (diferencia de riesgo -0,1 (i.c. del 95% −0,18 a −0,02); P = 0,01, I2 = 18%) e intervención nutricional (diferencia de riesgo −0,18 (i.c. del 95% −0,26 a −0,10); P < 0,001, I2 = 0%). Siete estudios describieron reducciones en la duración de la estancia hospitalaria, sin diferencias en el metaanálisis. CONCLUSIÓN: Las conclusiones de esta revisión están limitadas por la calidad de los estudios incluidos, heterogeneidad de las intervenciones y descripción de las medidas de resultados. Las intervenciones de pre-habilitación de ejercicio, nutricionales y multimodales puede reducir la morbilidad tras cirugía abdominal, pero los datos concretos en pacientes de edad avanzada son escasos.

Potassium enrichments in interstitial waters of recent marine sediments.

Potassium enrichments in marine sediments have been reported which would imply a rate of diffusion of potassium into the oceans much larger than any of the know rates of addition or removal by other mechanisms. Experiments with mixtures of seawater and clay suggest that spurious enrichments can be produced if sediment samples are allowed to warm up before the pore water is expressed.

Oxidation fronts in pelagic sediments: diagenetic formation of metal-rich layers.

The periodic deposition of distal turbidites at a site on the Madeira Abyssal Plain causes the development of a nonsteady-state diagenetic system in which an oxidation front migrates downward into the sediment. Data presented here show that iron, manganese, and particulate organic carbon are oxidized at this front by oxidants (molecular oxygen and nitrate) diffusing from above. A numerical model of systems of this type predicts the formation of iron-rich layers under certain nonsteady-state conditions. The layers predicted by the model are closely comparable in thickness and general morphology to iron-rich layers found in certain ocean sediments, the origin of which has been until now unexplained.

In situ Sampler for Marine Sedimentary Pore Waters: Evidence for Potassium Depletion and Calcium Enrichment.

A device for sampling the interstitial waters of deep-sea sediments in situ has been developed and tested. The sampler collects a series of samples over a depth of 1.5 meters in the sediment and thus makes possible the accurate delineation of chemical gradients existing in the pore waters. Samples collected in the North Atlantic indicate that significant gradients of K(+) and Ca(2+) exist in the sediments sampled. Interstitial solutions sampled between Ireland and Cape Cod, Massachusetts, are characterized by the depletion of K(+) and the enrichment of Ca(2+).

Clinical and non-clinical factors influencing postoperative health-related quality of life in patients with colorectal cancer.

BACKGROUND: The aim was prospectively to evaluate health-related quality of life (HRQoL) after treatment of potentially curable colorectal cancer. METHODS: HRQoL measurements were acquired by postal questionnaire sent to 210 patients with colorectal cancer for whom there was at least of 1 year of follow-up. Data were collected at seven time points using two validated questionnaires, QLQ-C30/CR38 and Short Form 12. Scores from salient HRQoL domains were compared with population norms. The independent associations between HRQoL and 13 treatment and non-treatment variables were evaluated using linear regression. Recurrences were excluded. RESULTS: A total of 186 patients (88.6 per cent) were followed up for 1 year, with 136 (64.8 per cent) and 84 (40.0 per cent) reaching the 18-month and 2-year follow-up points respectively. HRQoL improved rapidly after surgery, with most scores equating to population norms by 3-6 months. In addition to baseline performance status, three factors were associated with significantly poorer HRQoL scores: age less than 65 years, low rectal anastomoses and presence of a stoma. The areas predominantly affected were normal daily routines, work and social activities. CONCLUSION: HRQoL largely recovered by 6 months in disease-free patients, but some subgroups had poorer scores than others.

c-FLIP inhibits chemotherapy-induced colorectal cancer cell death.

c-FLIP inhibits caspase 8 activation and apoptosis mediated by death receptors such as Fas and DR5. We studied the effect of c-FLIP on the apoptotic response to chemotherapies used in colorectal cancer (CRC) (5-fluorouracil, oxaliplatin and irinotecan). Simultaneous downregulation of both c-FLIP splice forms c-FLIP(L) and c-FLIP(S) with siRNA synergistically enhanced chemotherapy-induced apoptosis in p53 wild-type (HCT116p53(+/+), RKO), null (HCT116p53(-/-)) and mutant (H630) CRC cell lines. Furthermore, overexpression of c-FLIP(L), but not c-FLIP(S), potently inhibited apoptosis induced by chemotherapy in HCT116p53(+/+) cells, suggesting that c-FLIP(L) was the more important splice form in mediating chemoresistance. In support of this, siRNA specifically targeted against c-FLIP(L) synergistically enhanced chemotherapy-induced apoptosis in a manner similar to the siRNA targeted against both splice forms. Inhibition of caspase 8 blocked the enhanced apoptosis induced by c-FLIP-targeted (FT) siRNA and chemotherapy. Furthermore, we found that downregulating cell surface DR5, but not Fas, also inhibited apoptosis induced by FT siRNA and chemotherapy. Interestingly, these effects were not dependent on activation of DR5 by its ligand TRAIL. These results indicate that c-FLIP inhibits TRAIL-independent, DR5- and caspase 8-dependent apoptosis in response to chemotherapy in CRC cells. Moreover, targeting c-FLIP in combination with existing chemotherapies may have therapeutic potential for the treatment of CRC.