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Background: Pamiparib is a potent, selective, poly (ADP‐ribose) polymerase 1/2 inhibitor that demonstrates synthetic lethality in cells with breast cancer susceptibility gene mutations or other homologous recombination deficiency. This two‐stage phase 1b study (NCT03150810) assessed pamiparib in combination with temozolomide (TMZ) in adult patients with histologically confirmed locally advanced and metastatic solid tumors. Methods: Oral pamiparib 60 mg was administered twice daily. During the dose‐escalation stage, increasing doses of TMZ (40–120 mg once daily pulsed or 20–40 mg once daily continuous) were administered to determine the recommended dose to be administered in the dose‐expansion stage. The primary objectives were to determine safety and tolerability, maximum tolerated/administered dose, recommended phase 2 dose and schedule, and antitumor activity of pamiparib in combination with TMZ. Pharmacokinetics of pamiparib and TMZ and biomarkers were also assessed. Results: Across stages, 139 patients were treated (dose escalation, n = 66; dose expansion, n = 73). The maximum tolerated dose of TMZ, which was administered during dose expansion, was 7‐day pulsed 60 mg once daily. The most common treatment‐emergent adverse events (TEAEs) were anemia (dose escalation, 56.1%; dose expansion, 63.0%), nausea (dose escalation, 54.5%; dose expansion, 49.3%), and fatigue (dose escalation, 48.5%; dose expansion, 47.9%). In the dose‐escalation stage, four patients experienced dose‐limiting toxicities (three neutropenia and one neutrophil count decreased). No TEAEs considered to be related to study drug treatment resulted in death. Antitumor activity was modest, indicated by confirmed overall response rate (dose escalation, 13.8%; dose expansion, 11.6%), median progression‐free survival (3.7 and 2.8 months), and median overall survival (10.5 and 9.2 months). Administration of combination therapy did not notably impact pamiparib or TMZ pharmacokinetics. Conclusions: Pamiparib in combination with TMZ had a manageable safety profile. Further investigation of the efficacy of this combination in tumor types with specific DNA damage repair deficiencies is warranted. [ABSTRACT FROM AUTHOR]

Background: An international multidisciplinary panel of experts aimed to provide consensus guidelines describing the optimal intratumoral and intranodal injection of NBTXR3 hafnium oxide nanoparticles in head and neck squamous cell carcinoma (HNSCC) of the oral cavity, oropharynx, and cervical lymph nodes and to review data concerning safety, feasibility, and procedural aspects of administration. Methods: The Delphi method was used to determine consensus. A 4‐member steering committee and a 10‐member monitoring committee wrote and revised the guidelines, divided into eight sections. An independent 3‐member reading committee reviewed the recommendations. Results: After two rounds of voting, strong consensus was obtained on all recommendations. Intratumoral and intranodal injection was deemed feasible. NBTXR3 volume calculation, choice of patients, preparation and injection procedure, potential side effects, post injection, and post treatment follow‐up were described in detail. Conclusions: Best practices for the injection of NBTXR3 were defined, thus enabling international standardization of intratumoral nanoparticle injection. [ABSTRACT FROM AUTHOR]

Observational studies have suggested a protective role for eosinophils in colorectal cancer (CRC) development and implicated neutrophils, but the causal relationships remain unclear. Here, we aimed to estimate the causal effect of circulating white blood cell (WBC) counts (N = ~550 000) for basophils, eosinophils, monocytes, lymphocytes and neutrophils on CRC risk (N = 52 775 cases and 45 940 controls) using Mendelian randomisation (MR). For comparison, we also examined this relationship using individual‐level data from UK Biobank (4043 incident CRC cases and 332 773 controls) in a longitudinal cohort analysis. The inverse‐variance weighted (IVW) MR analysis suggested a protective effect of increased basophil count and eosinophil count on CRC risk [OR per 1‐SD increase: 0.88, 95% CI: 0.78‐0.99, P =.04; OR: 0.93, 95% CI: 0.88‐0.98, P =.01]. The protective effect of eosinophils remained [OR per 1‐SD increase: 0.88, 95% CI: 0.80‐0.97, P =.01] following adjustments for all other WBC subtypes, to account for genetic correlation between the traits, using multivariable MR. A protective effect of increased lymphocyte count on CRC risk was also found [OR: 0.84, 95% CI: 0.76‐0.93, P = 6.70e‐4] following adjustment. Consistent with MR results, a protective effect for eosinophils in the cohort analysis in the fully adjusted model [RR per 1‐SD increase: 0.96, 95% CI: 0.93‐0.99, P =.02] and following adjustment for the other WBC subtypes [RR: 0.96, 95% CI: 0.93‐0.99, P =.001] was observed. Our study implicates peripheral blood immune cells, in particular eosinophils and lymphocytes, in CRC development, highlighting a need for mechanistic studies to interrogate these relationships. [ABSTRACT FROM AUTHOR]

Background: Larotrectinib, a first‐in‐class, highly selective tropomyosin receptor kinase (TRK) inhibitor, has demonstrated efficacy in adult and pediatric patients with various solid tumors harboring NTRK gene fusions. This subset analysis focuses on the efficacy and safety of larotrectinib in an expanded cohort of adult patients with TRK fusion sarcomas. Methods: Patients (≥18 years old) with sarcomas harboring NTRK gene fusions were identified from three clinical trials. Patients received larotrectinib 100 mg orally twice daily. Response was investigator‐assessed per RECIST v1.1. Data cutoff was July 20, 2021. Results: At the data cutoff, 36 adult patients with TRK fusion sarcomas had initiated larotrectinib therapy: two (6%) patients had bone sarcomas, four (11%) had gastrointestinal stromal tumors, and 30 (83%) had soft tissue sarcomas. All patients were evaluable for response and demonstrated an objective response rate of 58% (95% confidence interval, 41–74). Patients responded well to larotrectinib regardless of number of prior lines of therapy. Adverse events (AEs) were mostly grade 1/2. Grade 3 treatment‐emergent AEs (TEAEs) occurred in 15 (42%) patients. There were no grade 4 TEAEs. Two grade 5 TEAEs were reported, neither of which were considered related to larotrectinib. Four (11%) patients permanently discontinued treatment due to TEAEs. Conclusions: Larotrectinib demonstrated robust and durable responses, extended survival benefit, and a favorable safety profile in adult patients with TRK fusion sarcomas with longer follow‐up. These results continue to demonstrate that testing for NTRK gene fusions should be incorporated into the clinical management of adult patients with various types of sarcomas. Plain Language Summary: Tropomyosin receptor kinase (TRK) fusion proteins result from translocations involving the NTRK gene and cause cancer in a range of tumor types.Larotrectinib is an agent that specifically targets TRK fusion proteins and is approved for the treatment of patients with TRK fusion cancer.This study looked at how well larotrectinib worked in adult patients with sarcomas caused by TRK fusion proteins.Over half of patients had a durable response to larotrectinib, with no unexpected side effects.These results show that larotrectinib is safe and effective in adult patients with TRK fusion sarcomas. Larotrectinib, a first‐in‐class tropomyosin receptor kinase (TRK) inhibitor, demonstrated robust and durable responses, extended survival benefit, and a favorable safety profile in adult patients with TRK fusion sarcomas. Testing for NTRK gene fusions should be incorporated into the clinical management of adult patients with various types of sarcomas to identify those suitable for targeted therapy. [ABSTRACT FROM AUTHOR]

Use of artificial sweeteners (AS) such as aspartame, cyclamate, saccharin and sucralose is widespread. We evaluated the association of use of aspartame and other AS with cancer. In total 1881 colorectal, 1510 breast, 972 prostate and 351 stomach cancer and 109 chronic lymphocytic leukaemia (CLL) cases and 3629 population controls from the Spanish Multicase‐Control (MCC‐Spain) study were recruited (2008‐2013). The consumption of AS, from table‐top sweeteners and artificially sweetened beverages, was assessed through a self‐administered and validated food frequency questionnaire (FFQ). Sex‐specific quartiles among controls were determined to compare moderate consumers (

Deucravacitinib, a novel, selective inhibitor of TYK2 is currently under review at the FDA and EMA for treatment of moderate‐to‐severe plaque psoriasis. It is unclear whether recent safety concerns (ie, elevated rates of lung cancer and lymphoma) related to similar medications (ie, other JAK inhibitors) are shared with this novel TYK2 inhibitor. We used a partial loss‐of‐function variant in TYK2 (rs34536443), previously shown to protect against psoriasis and other autoimmune diseases, to evaluate the potential effect of therapeutic TYK2 inhibition on risk of lung cancer and non‐Hodgkin lymphoma. Summary genetic association data on lung cancer risk were obtained from a GWAS meta‐analysis of 29 266 cases and 56 450 controls in the Integrative Analysis of Lung Cancer Risk and Aetiology (INTEGRAL) consortium. Summary genetic association data on non‐Hodgkin lymphoma risk were obtained from a GWAS meta‐analysis of 8489 cases and 374 506 controls in the UK Biobank and InterLymph consortium. In the primary analysis, each copy of the minor allele of rs34536443, representing partial TYK2 inhibition, was associated with an increased risk of lung cancer (OR 1.15, 95% CI 1.09‐1.23, P = 2.29 × 10−6) and non‐Hodgkin lymphoma (OR 1.18, 95% CI 1.05‐1.33, P = 5.25 × 10−3). Our analyses using an established partial loss‐of‐function mutation to mimic TYK2 inhibition provide genetic evidence that therapeutic TYK2 inhibition may increase risk of lung cancer and non‐Hodgkin lymphoma. These findings, consistent with recent reports from postmarketing trials of similar JAK inhibitors, could have important implications for future safety assessment of deucravacitinib and other TYK2 inhibitors in development. What's new? Increased rates of lymphoma and lung cancer associated with Janus kinase (JAK) inhibitors used in the treatment of chronic inflammatory conditions have raised significant concern. A promising alternative, particularly for the treatment of plaque psoriasis, is deucravacitinib, a selective inhibitor of JAK family member TYK2. Here, the authors explored possible carcinogenic effects of TYK2 inhibition by genetic proxy based on a partial loss‐of‐function variant in TYK2 that provides protection against psoriasis. Analyses show that genetically proxied TYK2 inhibition increases lung cancer and non‐Hodgkin lymphoma risk. The findings could impact safety assessments of deucravacitinib and future novel TYK2 inhibitors. [ABSTRACT FROM AUTHOR]

Background: CC‐90011 is an oral, potent, selective, reversible inhibitor of lysine‐specific demethylase 1 (LSD1) that was well tolerated, with encouraging activity in patients who had advanced solid tumors or relapsed/refractory marginal zone lymphoma. The authors present long‐term safety and efficacy and novel pharmacodynamic and pharmacokinetic data from the first‐in‐human study of CC‐90011. Methods: CC‐90011‐ST‐001 (ClincalTrials.gov identifier NCT02875223; Eudract number 2015–005243‐13) is a phase 1, multicenter study in which patients received CC‐90011 once per week in 28‐day cycles. The objectives were to determine the safety, maximum tolerated dose, and/or recommended phase 2 dose (primary) and to evaluate preliminary efficacy and pharmacokinetics (secondary). Results: Sixty‐nine patients were enrolled, including 50 in the dose‐escalation arm and 19 in the dose‐expansion arm. Thrombocytopenia was the most common treatment‐related adverse event and was successfully managed with dose modifications. Clinical activity with prolonged, durable responses were observed, particularly in patients who had neuroendocrine neoplasms. In the dose‐escalation arm, one patient with relapsed/refractory marginal zone lymphoma achieved a complete response (ongoing in cycle 58). In the dose‐expansion arm, three patients with neuroendocrine neoplasms had stable disease after nine or more cycles, including one patient who was in cycle 46 of ongoing treatment. CC‐90011 decreased levels of secreted neuroendocrine peptides chromogranin A, progastrin‐releasing peptide, and RNA expression of the blood pharmacodynamic marker monocyte‐to‐macrophage differentiation–associated. Conclusions: The safety profile of CC‐90011 suggested that its reversible mechanism of action may provide an advantage over other irreversible LSD1 inhibitors. The favorable tolerability profile, clinical activity, durable responses, and once‐per‐week dosing support further exploration of CC‐90011 as monotherapy and in combination with other treatments for patients with advanced solid tumors and other malignancies. This first‐in‐human study evaluated CC‐90011, a highly potent, selective, and reversible oral lysine‐specific demethylase 1 inhibitor, in patients with advanced solid tumors and relapsed/refractory lymphoma. The tolerability, clinical activity, and once‐weekly dosing support further exploration of CC‐90011 in patients with advanced malignancies. [ABSTRACT FROM AUTHOR]

Molibresib is an orally bioavailable, selective, small molecule BET protein inhibitor. Results from a first time in human study in solid tumors resulted in the selection of a 75 mg once daily dose of the besylate formulation of molibresib as the recommended Phase 2 dose (RP2D). Here we present the results of Part 2 of our study, investigating safety, pharmacokinetics, pharmacodynamics and clinical activity of molibresib at the RP2D for nuclear protein in testis carcinoma (NC), small cell lung cancer, castration‐resistant prostate cancer (CRPC), triple‐negative breast cancer, estrogen receptor‐positive breast cancer and gastrointestinal stromal tumor. The primary safety endpoints were incidence of adverse events (AEs) and serious AEs; the primary efficacy endpoint was overall response rate. Secondary endpoints included plasma concentrations and gene set enrichment analysis (GSEA). Molibresib 75 mg once daily demonstrated no unexpected toxicities. The most common treatment‐related AEs (any grade) were thrombocytopenia (64%), nausea (43%) and decreased appetite (37%); 83% of patients required dose interruptions and 29% required dose reductions due to AEs. Antitumor activity was observed in NC and CRPC (one confirmed partial response each, with observed reductions in tumor size), although predefined clinically meaningful response rates were not met for any tumor type. Total active moiety median plasma concentrations after single and repeated administration were similar across tumor cohorts. GSEA revealed that gene expression changes with molibresib varied by patient, response status and tumor type. Investigations into combinatorial approaches that use BET inhibition to eliminate resistance to other targeted therapies are warranted. What's new? Molibresib is a BET inhibitor currently being tested against various solid tumors. Part 1 of this study, published previously, established a recommended dosage in patients with nuclear protein in testis carcinoma. Here, the authors present part 2, reporting on the safety and efficacy of molibresib in a wider array of tumor types. While they found no unexpected toxicities, adverse events caused 83% of patients to pause treatment, and 29% to lower their dosage. Molibresib showed some anti‐tumor activity, although clinically meaningful response rates were not observed by the end of the trial. [ABSTRACT FROM AUTHOR]

Dabrafenib is an oral BRAF kinase inhibitor approved for the treatment of various BRAF V600 mutation–positive solid tumors. In vitro observations suggesting cytochrome P450 (CYP) 3A induction and organic anion transporting polypeptide (OATP) inhibition prompted us to evaluate the effect of dabrafenib 150 mg twice daily on the pharmacokinetics of midazolam 3 mg (CYP3A substrate) and rosuvastatin 10 mg (OATP1B1/1B3 substrate) in a clinical phase 1, open‐label, fixed‐sequence study in patients with BRAF V600 mutation–positive tumors. Repeat dabrafenib dosing resulted in a 2.56‐fold increase in rosuvastatin maximum observed concentration (Cmax), an earlier time to Cmax, but only a 7% increase in area under the concentration‐time curve from time 0 (predose) extrapolated to infinite time. Midazolam Cmax and AUC extrapolated to infinite time decreased by 47% and 65%, respectively, with little effect on time to Cmax. No new safety findings were reported. Exposure of drugs that are CYP3A4 substrates is likely to decrease when coadministered with dabrafenib. Concentrations of medicinal products that are sensitive OATP1B1/1B3 substrates may increase during the absorption phase. [ABSTRACT FROM AUTHOR]

We evaluated the association between germline genetic variants located within the 3′‐untranlsated region (polymorphic 3′UTR, ie, p3UTR) of candidate genes involved in multiple myeloma (MM). We performed a case‐control study within the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 3056 MM patients and 1960 controls recruited from eight countries. We selected p3UTR of six genes known to act in different pathways relevant in MM pathogenesis, namely KRAS (rs12587 and rs7973623), VEGFA (rs10434), SPP1 (rs1126772), IRF4 (rs12211228) and IL10 (rs3024496). We found that IL10‐rs3024496 was associated with increased risk of developing MM and with a worse overall survival of MM patients. The variant allele was assayed in a vector expressing eGFP chimerized with the IL10 3′‐UTR and it was found functionally active following transfection in human myeloma cells. In this experiment, the A‐allele caused a lower expression of the reporter gene and this was also in agreement with the in vivo expression of mRNA measured in whole blood as reported in the GTEx portal. Overall, these data are suggestive of an effect of the IL10‐rs3024496 SNP on the regulation of IL10 mRNA expression and it could have clinical implications for better characterization of MM patients in terms of prognosis. What's new? The polymorphic 3′‐untranslated region (p3UTR) has been shown to affect gene expression and lead to differential predisposition or prolonged survival in a variety of cancer types. Here, the authors evaluate the association between germline genetic variants within the p3UTR of candidate genes involved in multiple myeloma. The results show that IL10‐rs3024496 might affect immune homeostasis through the modulation of IL10 mRNA expression. Overall, the findings suggest that the inclusion of personal genetic background information into the clinical evaluation criteria could help to improve the stratification of patients with multiple myeloma in terms of risk progression and prognosis. [ABSTRACT FROM AUTHOR]

Obesity is considered a chronic inflammatory state characterized by continued secretion of adipokines and cytokines. Experimental and epidemiological evidence indicates that circulating adipokines may be associated with the development of obesity‐related cancers, but it is unclear if these associations are causal or confounded. We examined potential causal associations of specific adipokines (adiponectin, leptin, soluble leptin receptor [sOB‐R] and plasminogen activator inhibitor‐1 [PAI‐1]) with five obesity‐related cancers (colorectal, pancreatic, renal cell carcinoma [RCC], ovarian and endometrial) using Mendelian randomization (MR) methods. We used summary‐level data from large genetic consortia for 114 530 cancer cases and 245 284 controls. We constructed genetic instruments using 18 genetic variants for adiponectin, 2 for leptin and 4 for both sOB‐R and PAI‐1 (P value for inclusion<5 × 10−8). Causal estimates were obtained using two‐sample MR methods. In the inverse‐variance weighted models, we found an inverse association between adiponectin and risk of colorectal cancer (odds ratio per 1 μg/mL increment in adiponectin concentration: 0.90 [95% confidence interval = 0.84‐0.97]; P =.01); but, evidence of horizontal pleiotropy was detected and the association was not present when this was taken into consideration. No association was found for adiponectin and risks of pancreatic cancer, RCC, ovarian cancer and endometrial cancer. Leptin, sOB‐R and PAI‐1 were also similarly unrelated to risk of obesity‐related cancers. Despite the large sample size, our MR analyses do not support causal effects of circulating adiponectin, leptin, sOB‐R and PAI‐1 concentrations on the development of five obesity‐related cancers. What's new? Chronic inflammation attributed to obesity may influence cancer development. However, little is known about the relationship between oncogenesis and changes in adipokine secretion stemming from immune cell infiltration in adipose tissue. Here, large‐scale Mendelian randomization analysis was used to assess possible causal associations of adipokine concentrations influenced by genetic variation and risk of five obesity‐related cancers, including renal cell carcinoma and colorectal, pancreatic, ovarian and endometrial cancer. In general, no association was detected between adipokines and the five malignancies, suggesting that adipokine levels have no causal influence on these cancers. [ABSTRACT FROM AUTHOR]

Experimental evidence indicates that exercise performed at different times of the day may affect circadian rhythms and circadian disruption has been linked to breast and prostate cancer. We examined in a population‐based case‐control study (MCC‐Spain) if the time‐of‐day when physical activity is done affects prostate and breast cancer risk. Lifetime recreational and household physical activity was assessed by in‐person interviews. Information on time‐of‐day of activity (assessed approximately 3 years after the assessment of lifetime physical activity and confounders) was available for 781 breast cancer cases, 865 population female controls, 504 prostate cases and 645 population male controls from 10 Spanish regions, 2008‐2013. We estimated odds ratios (ORs) and 95% confidence intervals (95% CI) for different activity timings compared to inactive subjects using unconditional logistic regression adjusting for confounders. Early morning (8‐10 am) activity was associated with a protective effect compared to no physical activity for both breast (OR = 0.74, 95% CI = 0.48‐1.15) and prostate cancer (OR = 0.73, 95% CI = 0.44‐1.20); meta‐OR for the two cancers combined 0.74 (95%CI = 0.53‐1.02). There was no effect observed for breast or prostate cancer for late morning to afternoon activity while a protective effect was also observed for evening activity only for prostate cancer (OR = 0.75, 95% CI = 0.45‐1.24). Protective effects of early morning activity were more pronounced for intermediate/evening chronotypes for both cancers. This is the first population‐based investigation identifying a differential effect of timing of physical activity on cancer risk with more pronounced effects for morning hour activity. Our results, if confirmed, may improve current physical activity recommendations for cancer prevention. What's new?: Exercise protects against a variety of cancers, but does time of day matter? Disrupting the body's circadian rhythm can boost cancer risk. Here, the authors compared breast and prostate cancer risk among people who exercised in the early morning, late morning, afternoon, and evening. They conducted a population‐based case‐control study, in which participants filled out a questionnaire about their patterns of sleeping, eating, and exercising. Exercising in the early morning appeared to be more strongly protective against breast and prostate cancer than exercising later in the day. Evening exercise appeared to have a moderate protective effect on prostate cancer. [ABSTRACT FROM AUTHOR]

Lay Summary: Currently, the complexity of clinical trial development in oncology is being further complicated by the coronavirus disease 2019 (COVID-19) pandemic, which is reducing the resources needed to comply with protocol-specific procedures while putting patients in units, who are already vulnerable, at increased general risk not only for COVID-19 infection but also with respect to their baseline disease. Individualizing the management of patients while ensuring their safety and adherence to the study protocol, establishing specific staff contingency plans, and maintaining sponsor and contract research organization (CRO) alignment are some of the key issues for maintaining the continuity of cancer patients' investigational treatment and minimizing their infection risk as well as the risk to staff members of the unit, sponsors, and CROs while maintaining the integrity of data quality and compliance with good clinical practice. [ABSTRACT FROM AUTHOR]

Classification and regression trees (CARTs) for data analysis, an hourly weather dataset, and a 3 year field incidence and severity dataset of winter wheat rust were integrated to forecast pathogens' presence/absence. The field dataset of incidence and severity was collected for three production cycles. Measured records of 88 Automatic Meteorological Stations and the indirect weather dataset generated in the Weather Research and Forecasting environment interpolated to each Automatic Meteorological Station location were analysed in the Python ecosystem. The focal point of the analysis was the severity of the disease. The analysis of direct weather data revealed the association of leaf rust severity with a night temperature of <14.25°C and global radiation of <521.67 W•m-2, while the estimated dataset showed that its severity is better explained by the dew point temperature of <13.7°C and a mean temperature of <19.06°C. The direct dataset also indicated that stripe rust severity was associated with relative humidity of <88.73%, global radiation of <597.39 W•m-2 and dew point temperature of <16.09°C, whereas the estimated data revealed that pathogen severity is better explained by a model composed of a dew point temperature of <14.6°C, night temperature of <20.4°C and a maximum temperature of <27.9°C. The severity and intensity analysis indicated the pathogen's preference for non-dry ambient conditions and the preference of stripe rust pathogen for humid and warmer temperatures than leaf rust. The weather thresholds of both pathogens, and CART analysis, unveiled that winter wheat rust can be forecasted. This constitutes the foundation of a more efficient extension programme based on the internet of things. [ABSTRACT FROM AUTHOR]

Osimertinib is a potent, third‐generation, irreversible, central nervous system active epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) that selectively inhibits EGFR‐TKI sensitizing and EGFR T790M resistance mutations. It is approved for first‐line treatment of patients with advanced non–small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, and for patients with T790M‐positive advanced NSCLC whose disease has progressed on or after EGFR‐TKI therapy. This study investigated the pharmacokinetics (PK) of fexofenadine (P‐glycoprotein substrate) following single‐ and multiple‐dose osimertinib in patients with advanced NSCLC who have progressed on prior EGFR‐TKI therapy. This open‐label, phase 1 study (NCT02908750) comprised the PK phase and continued access phase. The former comprised 2 distinct periods with a 3‐ to 7‐day washout: treatment period 1 (n = 24, fexofenadine 120 mg, day 1) and treatment period 2 (fexofenadine 120 mg + osimertinib 80 mg single dose on days 1 and 39 and osimertinib 80 mg once daily from days 4 to 41). Patients could continue osimertinib 80 mg once daily based on investigator's discretion in the continued access phase. Fexofenadine area under the plasma concentration–time curve and maximum concentration increased by 56% (90% confidence interval [CI], 35.4–78.6) and 76% (90%CI, 49.3–108.3) following coadministration with osimertinib single dose, and by 27% (90%CI, 11.2–45.8) and 25% (90%CI, 5.6–48.1) when given with osimertinib at steady state, respectively. Following osimertinib coadministration, median fexofenadine time to maximum concentration increased by approximately 30 minutes compared with time to maximum concentration following fexofenadine alone. No new osimertinib safety findings were observed. The increase in fexofenadine exposure following osimertinib coadministration shows osimertinib as a weak P‐glycoprotein inhibitor. [ABSTRACT FROM AUTHOR]

Modern life involves mistimed sleeping and eating patterns that in experimental studies are associated with adverse health effects. We assessed whether timing of meals is associated with breast and prostate cancer risk taking into account lifestyle and chronotype, a characteristic correlating with preference for morning or evening activity. We conducted a population‐based case‐control study in Spain, 2008–2013. In this analysis we included 621 cases of prostate and 1,205 of breast cancer and 872 male and 1,321 female population controls who had never worked night shift. Subjects were interviewed on timing of meals, sleep and chronotype and completed a Food Frequency Questionaire. Adherence to the World Cancer Research Fund/American Institute of Cancer Research recommendations for cancer prevention was examined. Compared with subjects sleeping immediately after supper, those sleeping two or more hours after supper had a 20% reduction in cancer risk for breast and prostate cancer combined (adjusted Odds Ratio [OR] = 0.80, 95%CI 0.67–0.96) and in each cancer individually (prostate cancer OR = 0.74, 0.55–0.99; breast cancer OR = 0.84, 0.67–1.06). A similar protection was observed in subjects having supper before 9 pm compared with supper after 10 pm. The effect of longer supper‐sleep interval was more pronounced among subjects adhering to cancer prevention recommendations (OR both cancers= 0.65, 0.44–0.97) and in morning types (OR both cancers = 0.66, 0.49–0.90). Adherence to diurnal eating patterns and specifically a long interval between last meal and sleep are associated with a lower cancer risk, stressing the importance of evaluating timing in studies on diet and cancer. What's new? Evidence shows that long‐term disruption of endogenous circadian rhythms may be associated with cancer. The effects of mistimed sleeping and eating patterns that come with modern life are however less clear. This large Spanish population‐based study examined whether meal timing and sleep patterns are associated with the two most common nightshift‐related cancers. Adherence to a more diurnal eating pattern, and specifically an early supper and a long interval between last meal and sleep were associated with a lower breast and prostate cancer risk, stressing the importance of evaluating circadian rhythms in diet and cancer studies and revisiting recommendations for prevention. [ABSTRACT FROM AUTHOR]

Abstract: The causal association of NUDT1 (=MTH1) and OGG1 with hereditary colorectal cancer (CRC) remains unclear. Here, we sought to provide additional evidence for or against the causal contribution of NUDT1 and OGG1 mutations to hereditary CRC and/or polyposis. Mutational screening was performed using pooled DNA amplification and targeted next‐generation sequencing in 529 families (441 uncharacterized MMR‐proficient familial nonpolyposis CRC and 88 polyposis cases). Cosegregation, in silico analyses, in vitro functional assays, and case–control associations were carried out to characterize the identified variants. Five heterozygous carriers of novel (n = 1) or rare (n = 4) NUDT1 variants were identified. In vitro deleterious effects were demonstrated for c.143G>A p.G48E (catalytic activity and protein stability) and c.403G>T p.G135W (protein stability), although cosegregation data in the carrier families were inconclusive or nonsupportive. The frequency of missense, loss‐of‐function, and splice‐site NUDT1 variants in our familial CRC cohort was similar to the one observed in cancer‐free individuals, suggesting lack of association with CRC predisposition. No OGG1 pathogenic mutations were identified. Our results suggest that the contribution of NUDT1 and OGG1 germline mutations to hereditary CRC and to polyposis is inexistent or, at most, negligible. The inclusion of these genes in routine genetic testing is not recommended. [ABSTRACT FROM AUTHOR]

Abstract: Two phase 1, open‐label studies assessed the impact of food or gastric pH modification (omeprazole) on the exposure and safety/tolerability of osimertinib and its metabolites. The food effect study was an open‐label, 2‐period crossover study in patients with advanced non‐small‐cell lung cancer, randomized into 2 treatment sequences: single‐dose osimertinib 80 mg in a fed then fasted state or fasted then fed. The gastric pH study was an open‐label, 2‐period fixed sequence study assessing the effect of omeprazole on osimertinib exposure in healthy male volunteers. In period 1, volunteers received omeprazole 40 mg (days 1‐4), then omeprazole 40 mg plus osimertinib 80 mg (day 5). In period 2, volunteers received osimertinib 80 mg alone (single dose). Blood samples were collected at prespecified time points for pharmacokinetic analyses. Safety/tolerability was also assessed. In the food effect study 38 patients were randomized to fed/fasted (n = 18) or fasted/fed (n = 20) sequences with all patients completing treatment. Coadministration with food did not affect osimertinib exposure (geometric least‐squares mean ratios [90% confidence intervals]: 106.05% [94.82%, 118.60%] [area under the plasma concentration time curve from zero to 72 hours] and 92.75% [81.40%, 105.68%] [maximum plasma concentration]). In the gastric pH study (n = 68 received treatment, n = 47 completed the study), coadministration with omeprazole did not affect osimertinib exposure (geometric least‐squares mean ratios 106.66% [100.26%, 113.46%] [area under the concentration‐time curve], 101.65% [94.65%, 109.16%] [peak concentration]). Osimertinib was well tolerated in both studies. Osimertinib may be administered without regard to food. Dose restriction is not required in patients whose gastric pH may be altered by concomitant agents or medical conditions. ClinicalTrials.gov: NCT02224053, NCT02163733. [ABSTRACT FROM AUTHOR]

Background Differences in Helicobacter pylori protein expression have been related to the risk of severe gastric diseases. In Spain, a marked geographic pattern in gastric cancer mortality has long been reported. Objective: To characterize antibody reactivity patterns against 16 H. pylori proteins, by age, sex, and region of birth, in a large sample of the Spanish adult population. Materials and Methods Antibody reactivity was quantified by H. pylori multiplex serology in a sample from the control group of the multicase-control study MCC-Spain. For this analysis, 2555 population-based controls were included. Each participant was classified as seropositive or seronegative for each protein according to specific cutoffs. Overall H. pylori seroprevalence was defined as positivity against ≥4 proteins. Descriptive analyses by age, sex, and region of birth were performed for both seroprevalence and seroreactivity (continuous measure). Differences among groups were tested by logistic and linear regression models. Results Overall H. pylori seroprevalence increased with age in both sexes. For ages 55-74, seroprevalence was lower in women than in men (84% vs 92%, P<.001). Region of birth explained 7% of the variability in seroprevalence. Among H. pylori seropositive subjects, proteins with the highest seroprevalence were Gro EL, NapA, HP231, and Omp. Seropositivity for most of the proteins increased or remained stable with age, rising mainly for CagA, Gro EL, and HyuA in women. A clear cohort effect was not observed. Conclusions This is the first study to describe the antibody patterns against 16 H. pylori proteins in the Spanish population. We found variability in the H. pylori antibody profiles according to both individual factors such as age and sex, and environmental factors such as the region of birth. The slightness of the reduction in seropositivity with decreasing age highlights the ongoing importance of this infection. [ABSTRACT FROM AUTHOR]

Prostate, breast and colorectal cancer are the most common tumours in Spain. The aim of the present study was to evaluate the association between adherence to nutrition-based guidelines for cancer prevention and prostate, breast and colorectal cancer, in the MCC-Spain case-control study. A total of 1,718 colorectal, 1,343 breast and 864 prostate cancer cases and 3,431 population-based controls recruited between 2007 and 2012, were included in the present study. The World Cancer Research Fund/American Institute for Cancer Research (WCRC/AICR) score based on six recommendations for cancer prevention (on body fatness, physical activity, foods and drinks that promote weight gain, plant foods, animal foods and alcoholic drinks; score range 0-6) was constructed. We used unconditional logistic regression analysis adjusting for potential confounders. One-point increment in the WCRF/AICR score was associated with 25% (95% CI 19-30%) lower risk of colorectal, and 15% (95% CI 7-22%) lower risk of breast cancer; no association with prostate cancer was detected, except for cases with a Gleason score ≥7 (poorly differentiated/undifferentiated tumours) (OR 0.87, 95% CI 0.76-0.99). These results add to the wealth of evidence indicating that a great proportion of common cancer cases could be avoided by adopting healthy lifestyle habits. [ABSTRACT FROM AUTHOR]

The aim of this study was to characterize the physicochemical, functional, and digestion properties of bagasses derived from broad beans, chickpeas, lentils, and white beans, and to isolate the starch and a fiber-rich fraction that can be used as a food ingredient. The bagasses showed different chemical compositions that were related to their botanical origin. The further processing that involved mechanical separation of starch yielded up to 69.65% with ≥80.12% recovery and high purity (≥94.42%), and a fiber-rich fraction (total dietary fiber content ≥72.75%) in which the majority was insoluble fiber. The starch digestion fractions of the isolated lentil starch showed the highest amount of slowly digestible starch (30.76%), whereas the white bean contained the highest resistant starch content (15.65%). All starches showed predicted glycemic indexes ≤ 66.90, which classify them as medium glycemic foods. In vitro protein digestion was higher for the bagasse fraction (up to 89.78%), followed by the fiber-rich fraction (84.36%). This research demonstrates that it is possible to revalorize the use of pulses bagasse, which could contribute to enhance the technological and economic output of the protein isolation process, rendering two potentially functional fractions. [ABSTRACT FROM AUTHOR]

The colonic opportunist Streptococcus gallolyticus subspecies gallolyticus (SGG) is potentially associated with colorectal cancer (CRC). Large-scale seroepidemiological data for SGG antibodies and their possible association with CRC is currently missing. Associations between CRC and antibody responses to SGG were examined in 576 CRC cases and 576 controls matched by sex, age and province from a population-based multicase-control project (MCC-Spain). MCC-Spain was conducted between 2008 and 2013 in 12 Spanish provinces. Antibody responses to recombinant affinity-purified SGG pilus proteins Gallo1569, 2039, 2178 and 2179 were analysed by multiplex serology. Polyomavirus (PyV) JC VP1 and PyV 6 VP1 proteins served as disease-specificity controls. In the control population, antibody responses to pilus proteins were mostly weak. Antibody responses to individual pilus proteins Gallo2039 (OR: 1.58, 95% CI: 1.09-2.28), Gallo2178 (OR: 1.58, 95% CI: 1.09-2.30) and Gallo2179 (OR: 1.45, 95% CI: 1.00-2.11) were significantly associated with CRC risk. The association was stronger for positivity to two or more pilus proteins of Gallo1569, Gallo2178 and Gallo2179 (OR:1.93, 95% CI: 1.04-3.56) and for double-positivity to Gallo2178 and Gallo2179 (OR: 3.54, 95% CI: 1.49-8.44). The association between SGG infection and CRC risk was stronger among individuals younger than 65 years. For the first time we demonstrated a statistically significant association of exposure to SGG antigens and CRC in a large seroepidemiological study. These results should stimulate further studies on the role of SGG in CRC pathogenesis. [ABSTRACT FROM AUTHOR]

Open ecosystems in Mexico are under increasing pressure, due particularly to the expansion of cities and agricultural activities. These developments occur without integrating biodiversity concerns in land use planning and result in extensive fragmentation and transformation of the landscapes. The semiarid region of Mesa Central was characterized using ten precipitation-based indices. Using multivariate statistical and geostatistical spatial analysis techniques, the influence of those indices on five land use strata was explored. Land use analysis indicated that the maximum values of the five significant precipitation-based indices were found in Grasslands, Agricultural Use, and Shrubs; minimum values were characteristic of substrates Secondary Desert Vegetation and Other Use. Our results suggest that the greatest number of extreme precipitation events is likely to occur in open ecosystems and consequently will have a strong influence on landscaping and land use. The semivariogram analysis and geostatistical layers demand attention from research institutions, policy makers, researchers, and food producers to take the appropriate and coordinated actions to propose scenarios to deal with climate change. Perhaps this study can stimulate thought concerning research endeavours aimed at promoting initiatives for biodiversity conservation and planning programs for climate change mitigation. [ABSTRACT FROM AUTHOR]

ABSTRACT In northwestern Mexico in an annual cycle comprised months 2008-2009, we estimated the effects of cumulative rainfall and previous vegetation status on current vegetative greenness adjusted for soil reflectance [via the Transformed Soil Adjusted Vegetation Index ( TSAVI)] and canopy water content [via the Normalized Difference Infrared Index ( NDII)]. Sample kernels (540 of <0.4 ha) were stratified in nine areas by latitude, distance to the Pacific Ocean and slope across a 15 000 km2 area on the Baja California peninsula. Rainfall data were accumulated over 2-, 4- and 6-week periods from daily satellite estimates [via the Tropical Rainfall Measuring Mission ( TRMM)]. TSAVI and NDII were calculated from Landsat 5 TM images. When restricted by season, multiple regressions results were 0.59 < [ABSTRACT FROM AUTHOR]

Little is known about the difference in gene expression between carcinoma-associated fibroblasts (CAFs) and paired normal colonic fibroblasts (NCFs) in colorectal cancer. Paired CAFs and NCFs were isolated from eight primary human colorectal carcinoma specimens. In culture conditions, soluble factors secreted by CAFs in the conditioned media increased clonogenicity and migration of epithelial cancer cells lines to a greater extent than did NCF. In vivo , CAFs were more competent as tumour growth enhancers than paired NCFs when co-inoculated with colorectal cell lines. Gene expression analysis of microarrays of CAF and paired NCF populations enabled us to identify 108 deregulated genes (38 upregulated and 70 downregulated genes). Most of those genes are fibroblast-specific. This has been validated in silico in dataset GSE39396 and by qPCR in selected genes. GSEA analysis revealed a differential transcriptomic profile of CAFs, mainly involving the Wnt signallingsignalling pathway, focal adhesion and cell cycle. Both deregulated genes and biological processes involved depicted a considerable degree of overlap with deregulated genes reported in breast, lung, oesophagus and prostate CAFs. These observations suggest that similar transcriptomic programs may be active in the transition from normal fibroblast in adjacent tissues to CAFs, independently of their anatomic demarcation. Additionally NCF already depicted an activated pattern associated with inflammation. The deregulated genes signature score seemed to correlate with CAF tumour promoter abilities in vitro , suggesting a high degree of heterogeneity between CAFs, and it has also prognostic value in two independent datasets. Further characterization of the roles these biomarkers play in cancer will reveal how CAFs provide cancer cells with a suitable microenvironment and may help in the development of new therapeutic targets for cancer treatment. [ABSTRACT FROM AUTHOR]

SUMMARY As an attempt to make network managers' life easier, we present M3Omon, a system architecture that helps to develop monitoring applications and perform network diagnosis. M3Omon behaves as an intermediate layer between the traffic and monitoring applications that provides advanced features, high performance and low cost. Such advanced features leverage a multi-granular and multi-purpose approach to the monitoring problem. Multi-granular monitoring provides answers to tasks that use traffic aggregates to identify an event, and requires either flow records or packet data or even both to understand it and, eventually, take convenient countermeasures. M3Omon provides a simple API to access traffic simultaneously at several different granularities, i.e. packet-level, flow-level and aggregate statistics. The multi-purposed design of M3Omon allows not only performing tasks in parallel that are specifically targeted to different traffic-related purposes (e.g. traffic classification and intrusion detection) but also sharing granularities between applications, e.g. several concurrent applications fed from flow records that are provided by M3Omon. Finally, the low-cost characteristic is brought by off-the-shelf systems (the combination of open-source software and commodity hardware) and the high performance is achieved thanks to modifications in the standard NIC driver, low-level hardware interaction, efficient memory management and programming optimization. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

SUMMARY Voice over IP (VoIP) is increasingly replacing the old public switched telephone network (PSTN) technology. In this new scenario, there are several challenges for VoIP providers. First, VoIP requires a detailed monitoring of both users' quality of service (QoS) and experience (QoE) to a greater extent than in traditional PSTNs. Second, such a monitoring process must be able to track VoIP traffic in high-speed networks, nowadays typically of multi-Gb/s rates. Third, recent government directives require that providers retain information from their users' calls. Similarly, the convergence of data and voice services allows operators to provide new services such as full-data retention, in which users' calls can be recorded for either quality assessment (call centers, QoE) or security purposes (lawful interception). This implies a significant investment in infrastructure, especially in large-scale networks which require multiple points of measurement and redundancy. This paper proposes a novel methodology, architecture and system to fulfill such challenges, called VoIPCallMon, as well as the data structures and necessary hardware-tuning knowledge for its development. As distinguishing features, VoIPCallMon provides very high performance, being able to process VoIP traffic on-the-fly at high bitrates, novel services and significant cost reduction by using commodity hardware with minimal interference with operational VoIP networks. The performance evaluation shows that the system copes with the VoIP load of real-world operators. We further evaluated the system performance at a fully saturated 10 Gb/s link and no packet loss was reported, therefore demonstrating the potential of commodity hardware solutions. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACT Next-generation sequencing ( NGS) has revolutionized genomic research and is set to have a major impact on genetic diagnostics thanks to the advent of benchtop sequencers and flexible kits for targeted libraries. Among the main hurdles in NGS are the difficulty of performing bioinformatic analysis of the huge volume of data generated and the high number of false positive calls that could be obtained, depending on the NGS technology and the analysis pipeline. Here, we present the development of a free and user-friendly Web data analysis tool that detects and filters sequence variants, provides coverage information, and allows the user to customize some basic parameters. The tool has been developed to provide accurate genetic analysis of targeted sequencing of common high-risk hereditary cancer genes using amplicon libraries run in a GS Junior System. The Web resource is linked to our own mutation database, to assist in the clinical classification of identified variants. We believe that this tool will greatly facilitate the use of the NGS approach in routine laboratories. [ABSTRACT FROM AUTHOR]

In most colorectal cancer (CRC) patients, outcome cannot be predicted because tumors with similar clinicopathological features can have differences in disease progression and treatment response. Therefore, a better understanding of the CRC biology is required to identify those patients who will benefit from chemotherapy and to find a more tailored therapy plan for other patients. Based on unsupervised classification of whole genome data from 188 stages I-IV CRC patients, a molecular classification was developed that consist of at least three major intrinsic subtypes (A-, B- and C-type). The subtypes were validated in 543 stages II and III patients and were associated with prognosis and benefit from chemotherapy. The heterogeneity of the intrinsic subtypes is largely based on three biological hallmarks of the tumor: epithelial-to-mesenchymal transition, deficiency in mismatch repair genes that result in high mutation frequency associated with microsatellite instability and cellular proliferation. A-type tumors, observed in 22% of the patients, have the best prognosis, have frequent BRAF mutations and a deficient DNA mismatch repair system. C-type patients (16%) have the worst outcome, a mesenchymal gene expression phenotype and show no benefit from adjuvant chemotherapy treatment. Both A-type and B-type tumors have a more proliferative and epithelial phenotype and B-types benefit from adjuvant chemotherapy. B-type tumors (62%) show a low overall mutation frequency consistent with the absence of DNA mismatch repair deficiency. Classification based on molecular subtypes made it possible to expand and improve CRC classification beyond standard molecular and immunohistochemical assessment and might help in the future to guide treatment in CRC patients. [ABSTRACT FROM AUTHOR]

PARP inhibitors ( PARPi) for the treatment of BRCA1 or BRCA2 deficient tumours are currently the focus of seminal clinical trials exploiting the concept of synthetic lethality. Although clinical resistance to PARPi has been described, the mechanism underlying this has not been elucidated. Here, we investigate tumour material from patients who had developed resistance to the PARPi olaparib, subsequent to showing an initial clinical response. Massively parallel DNA sequencing of treatment-naive and post-olaparib treatment biopsies identified tumour-specific BRCA2 secondary mutations in olaparib-resistant metastases. These secondary mutations restored full-length BRCA2 protein, and most likely cause olaparib resistance by re-establishing BRCA2 function in the tumour cells. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The article presents information on the main effects of the genetic polymorphisms on multiple myeloma (MM). MM is characterized by the proliferation of a single clone of plasma cells located in the bone marrow that can migrate to extra-medullary districts. The genotype frequencies for each of the three single nucleotide polymorphisms indicated a relationship with MM risk consistent with previous observations.

Genome-wide association studies ( GWAS) have shown that the 8q24 region harbours multiple independent cancer susceptibility loci, even though it is devoid of genes. Given that no GWAS data are currently available for multiple myeloma ( MM), we tested the hypothesis that genetic variants in this region could play a role in MM risk. We genotyped 20 single nucleotide polymorphisms of 8q24 in 1188 MM cases and 2465 controls and found a statistically significant ( P = 0·0022) association between and MM risk. These data provide further evidence that the genetic variability in the 8q24 region is associated with cancer risk, particularly haematological malignancies. [ABSTRACT FROM AUTHOR]

We consider the inference problem of estimating covariate and genetic effects in a family-based case-control study where families are ascertained on the basis of the number of cases within the family. However, our interest lies not only in estimating the fixed covariate effects but also in estimating the random effects parameters that account for varying correlations among family members. These random effects parameters, though weakly identifiable in a strict theoretical sense, are often hard to estimate due to the small number of observations per family. A hierarchical Bayesian paradigm is a very natural route in this context with multiple advantages compared with a classical mixed effects estimation strategy based on the integrated likelihood. We propose a fully flexible Bayesian approach allowing nonparametric modeling of the random effects distribution using a Dirichlet process prior and provide estimation of both fixed effect and random effects parameters using a Markov chain Monte Carlo numerical integration scheme. The nonparametric Bayesian approach not only provides inference that is less sensitive to parametric specification of the random effects distribution but also allows possible uncertainty around a specific genetic correlation structure. The Bayesian approach has certain computational advantages over its mixed-model counterparts. Data from the Prostate Cancer Genetics Project, a family-based study at the University of Michigan Comprehensive Cancer Center including families having one or more members with prostate cancer, are used to illustrate the proposed methods. A small-scale simulation study is carried out to compare the proposed nonparametric Bayes methodology with a parametric Bayesian alternative. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

We consider analysis of data from an unmatched case-control study design with a binary genetic factor and a binary environmental exposure when both genetic and environmental exposures could be potentially misclassified. We devise an estimation strategy that corrects for misclassification errors and also exploits the gene-environment independence assumption. The proposed corrected point estimates and confidence intervals for misclassified data reduce back to standard analytical forms as the misclassification error rates go to zero. We illustrate the methods by simulating unmatched case-control data sets under varying levels of disease-exposure association and with different degrees of misclassification. A real data set on a case-control study of colorectal cancer where a validation subsample is available for assessing genotyping error is used to illustrate our methods. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Monitoring of organochlorine pesticides (OCPs) was carried out to identify and quantify the contribution of point and nonpoint sources to the total OCP flux in a southeastern region of Argentina. Natural, recreational, and agricultural soils located in the surrounding of a lagoon were analyzed by gas chromatography with electron-capture detector. Physical and chemical characteristics (texture, humidity, and organic matter content) were determined at different depths (0-15 cm, 15-30 cm, and 45-55 cm). The pattern of OCP distribution was similar in all soil sampled, with DDT and metabolites > hexachlorocyclohexanes (HCHs) > heptachlor > chlordanes. The highest values of OCPs (656.1 ng/g dry wt) were found in the surface natural soil despite its never having received direct OCP application. This would be mainly due to the high organic matter content of the surface natural soils as well as its topographic position (highland hills), with main winds arriving from agricultural areas. Microorganism abundance and edaphic biota in the upper layer would justify the high levels of metabolites found. The agricultural soil (intensive tillage) also showed the highest OCP values (30.19 ng/g dry wt) in the surface horizon. Because of management practices, volatilization could have been one of the major causes of pesticide loss from this target area. Recreational soil showed the lowest OCP levels in the surface layer because of weathering that occurs when the nearby lagoon floods this zone. Our results show that, although most of these pesticides are banned, they are present in these soils and the atmospheric transport and deposition would be the major processes for distributing OCPs from target to natural areas. [ABSTRACT FROM AUTHOR]

Summary Background Objectives Methods Results Conclusions Varying obesogenic inherited predisposition in early to later life may differentially impact colorectal cancer (CRC) development. Previous Mendelian randomization (MR) studies, conducted in populations of European genetic similarity, have not observed any significant associations between early life body weight with CRC risk. However, it remains unclear whether body mass index (BMI) at different early lifetime points is causally related with CRC risk in both Europeans and East Asian populations.We conducted a two‐sample MR study to investigate potential causal relationships between genetically predicted BMI during early life (birth to 8 years old) and at specific periods (birth, transient, early rise and late rise) and CRC risk.Summary data were obtained from genome‐wide association study (GWAS) of BMI in 28 681 children from the Norwegian Mother, Father and Child Cohort Study (MoBa) study and applied to CRC GWAS data from European and East Asian descent populations (102 893 cases and 485 083 non‐cases).There were no significant associations observed between early life BMI and CRC risk in European or East Asian populations. The effect estimates were similar in European studies (odds ratio [OR] per a 1‐standard deviation [SD] increase: 1.01, 95% confidence interval [CI]: 0.95, 1.07) and in East Asians (OR per a 1‐SD increase: 1.02, 95% CI: 0.91, 1.14). Similar nonsignificant associations were found between time of BMI measurement during childhood and cancer‐site‐specific analyses.We found little evidence of any associations between early life adiposity on later life CRC risk. [ABSTRACT FROM AUTHOR]

The de novo biosynthesis of fatty acids in the wild, calanoid copepod Paracalanus parvus was studied. The incubation of labeled acetate proved the de novo biosynthesis of saturated and monounsaturated even fatty acids from 14 to 20 carbons and the 22∶1 acid. Saturated and monounsaturated uneven fatty acids from 15 to 21 carbons were also synthesized. The copepod could not synthesize linoleic and α-linolenic acids. By administration of [1-C]palmitate, [1-C] stearate and [1-C]oleate, it was possible to elucidate the general pattern of the de novo biosynthesis of fatty acids in the wild P. parvus. [ABSTRACT FROM AUTHOR]

The metabolic fate of radioactive linoleate and α-linolenate administered to the South Atlantic copepod Paracalanus parvus was studied. The wild copepod was able to incorporate the labeled acids dissolved in seawater. The radioactive linoleate was elongated to 20∶2ω6 and 22∶2ω6 and desaturated by a Δ6 desaturase to 18∶3ω6. α-Linolenate was also desaturated by a Δ6 desaturase to 18∶4ω3 and elongated to 20∶3ω3. The copepod was able to convert α-18∶3 to 20∶5ω3 and 22∶6ω3. [ABSTRACT FROM AUTHOR]

The biosynthesis of fatty acids in the diatom Phaeodactylum tricornutum was studied. The diatom was incubated with sodium [1C] acetate and the acids [1-C] palmitic, [1-C] stearic, [1-C] linoleic and [1-C] α-linolenic. The distribution of radioactivity in the products was determined by gas liquid radiochromatography. The diatom synthesized 'de novo' not only saturated and monounsaturated fatty acids, but also linoleic, α-linolenic and other fatty acids including the highly polyunsaturated 20∶5ω3 and 22∶6ω3. When labeled acetate, stearic, α-linolenic or even linoleic acid were incubated with the diatom, the polyunsaturated C fatty acids synthesized belonged predominantly to the ω 3 family. The existence of Δ9, Δ6, Δ5, Δ4, ω6 and possibly ω3 desaturases in P. tricornutum is suggested. [ABSTRACT FROM AUTHOR]

The fate of labeled palmitate, stearate, and acetate administered to the yellow clam, Mesodesma mactroides, was investigated. 1-C palmitic and 1-C stearic acids were oxidized to CO to a limited extent. They were mainly incorporated in diacylglycerols and triacylglycerols and were converted to higher homologs. After administration, palmitic acid was converted to stearic and oleic acids, whereas administered stearic acid was converted to 18∶1, 18∶2, 20∶1, and 20∶2 acids. Labeled acetate was readily included by the clam in 12∶0, 14∶0, 14∶1, 15∶0, 16∶1, 16∶1, 16∶2, 18∶2, 18∶1, 18∶2, 20∶1, 20∶2, and 20∶3 acids. [ABSTRACT FROM AUTHOR]