Synergistic Effects of Magnesium Oxide and SBR Latex Additives on Cement Sheath Stability in Oil Well Operations.

Leaks through cement sheaths remain a complex and challenging issue in the oil industry, representing a persistent obstacle that has endured for decades. The drying shrinkage, an inherent characteristic of Portland cement, substantially exacerbates this problem, driving the formation of microcracks and heightened permeability under variable stress conditions. In this context, additives emerge as significant elements in addressing this issue, offering a pathway to mitigate the adverse effects of leaks. Among these additives, magnesium oxide (MgO) stands out for its ability to reduce drying shrinkage through structural modifications in the cement matrix. Simultaneously, SBR Latex, another important additive, acts to minimize gas migration due to its polymeric microstructure while also strengthening acid resistance and enhancing microstructural cohesion. This study aims to deepen the understanding of the interaction between MgO and SBR Latex additives in cement slurries, employing an experimental design to substantiate and expand upon the analyses conducted. The results reveal a synergistic integration of these additives, with MgO acting as an effective agent in reducing drying shrinkage and gel formation, thereby contributing to the strengthening of shear strength. Conversely, SBR Latex provides elasticity to the slurry, although with a slight compromise in compressive strength, with a relatively limited effect on shear strength. The strategic combination of these additives results in improvements in the mechanical integrity of cement slurries, a positive advancement in the context of petroleum well cementing operations. Thus, this study not only highlights the individual properties of MgO and SBR Latex but also offers valuable perspectives for the careful formulation of cements, with potential applications in challenging operational environments in the oil industry.

Unveiling contrasts in microbiota response: A1c control improves dysbiosis in low-A1c T2DM, but fails in high-A1c cases-a key to metabolic memory?

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is associated with dysbiosis in the gut microbiota (MB). Individually, each medication appears to partially correct this. However, there are no studies on the response of the MB to changes in A1c. Therefore, we investigated the MB's response to intensive glycemic control. RESEARCH DESIGN AND METHODS: We studied two groups of patients with uncontrolled T2DM, one group with an A1c <9% (18 patients-G1) and another group with an A1c >9% (13 patients-G2), aiming for at least a 1% reduction in A1c. We collected A1c and fecal samples at baseline, 6, and 12 months. G1 achieved an average A1c reduction of 1.1%, while G2 a reduction of 3.13%. RESULTS: G1's microbiota saw a decrease in Erysipelotrichaceae_UCG_003 and in Mollicutes order (both linked to metabolic syndrome and associated comorbidities). G2, despite having a more significant reduction in A1c, experienced an increase in the proinflammatory bacteria Megasphaera and Acidaminococcus, and only one beneficial genus, Phascolarctobacterium, increased, producer of butyrate. CONCLUSION: Despite a notable A1c outcome, G2 could not restore its MB. This seeming resistance to change, leading to a persistent inflammation component found in G2, might be part of the "metabolic memory" in T2DM.

The potential role of artificial intelligence-assisted chest X-ray imaging in detecting early-stage lung cancer in the community-a proposed algorithm for lung cancer screening in Malaysia.

INTRODUCTION: The poor prognosis of lung cancer has been largely attributed to the fact that most patients present with advanced stage disease. Although low dose computed tomography (LDCT) is presently considered the optimal imaging modality for lung cancer screening, its use has been hampered by cost and accessibility. One possible approach to facilitate lung cancer screening is to implement a risk-stratification step with chest radiography, given its ease of access and affordability. Furthermore, implementation of artificial-intelligence (AI) in chest radiography is expected to improve the detection of indeterminate pulmonary nodules, which may represent early lung cancer. MATERIALS AND METHODS: This consensus statement was formulated by a panel of five experts of primary care and specialist doctors. A lung cancer screening algorithm was proposed for implementation locally. RESULTS: In an earlier pilot project collaboration, AI-assisted chest radiography had been incorporated into lung cancer screening in the community. Preliminary experience in the pilot project suggests that the system is easy to use, affordable and scalable. Drawing from experience with the pilot project, a standardised lung cancer screening algorithm using AI in Malaysia was proposed. Requirements for such a screening programme, expected outcomes and limitations of AI-assisted chest radiography were also discussed. CONCLUSION: The combined strategy of AI-assisted chest radiography and complementary LDCT imaging has great potential in detecting early-stage lung cancer in a timely manner, and irrespective of risk status. The proposed screening algorithm provides a guide for clinicians in Malaysia to participate in screening efforts.

Establishment of oral microbiome in very low birth weight infants during the first weeks of life and the impact of oral diet implementation.

Very low birth weight (VLBW) infants, mostly preterm, have many barriers to feeding directly from the mother's breast, and need to be fed alternatively. Feeding is a major influencer in oral microbial colonization, and this colonization in early life is crucial for the promotion of human health. Therefore, this research aimed to observe the establishment of oral microbiome in VLBW infants during their first month of life through hospitalization, and to verify the impact caused by the implementation of oral diet on the colonization of these newborns. We included 23 newborns followed during hospitalization and analyzed saliva samples collected weekly, using 16S rRNA gene sequencing. We observed a significant decrease in richness and diversity and an increase in dominance over time (q-value < 0.05). The oral microbiome is highly dynamic during the first weeks of life, and beta diversity suggests a microbial succession in early life. The introduction of oral diet does not change the community structure, but affects the abundance, especially of Streptococcus. Our results indicate that although time is related to significant changes in the oral microbial profile, oral feeding benefits genera that will remain colonizers throughout the host's life.

Clinicogenomic factors and treatment patterns among patients with advanced non-small cell lung cancer with or without brain metastases in the United States.

BACKGROUND: This retrospective, real-world study evaluated the prevalence of brain metastases, clinicodemographic characteristics, systemic treatments, and factors associated with overall survival among patients with advanced non-small cell lung cancer (aNSCLC) in the US. We also described the genomic characterization of 180 brain metastatic specimens and frequency of clinically actionable genes. MATERIALS AND METHODS: De-identified electronic health records-derived data of adult patients diagnosed with aNSCLC between 2011 and 2017 were analyzed from a US-nationwide clinicogenomic database. RESULTS: Of 3257 adult patients with aNSCLC included in the study, approximately 31% (n = 1018) had brain metastases. Of these 1018 patients, 71% (n = 726) were diagnosed with brain metastases at initial NSCLC diagnosis; 57% (n = 583) of patients with brain metastases received systemic treatment. Platinum-based chemotherapy combinations were the most common first-line therapy; single-agent chemotherapies, epidermal growth factor receptor tyrosine kinase inhibitors, and platinum-based chemotherapy combinations were used in second line. Patients with brain metastases had a 1.56 times greater risk of death versus those with no brain metastases. In the brain metastatic specimens (n = 180), a high frequency of genomic alterations in the p53, MAPK, PI3K, mTOR, and cell-cycle associated pathways was observed. CONCLUSION: The frequency of brain metastases at initial clinical presentation and associated poor prognosis for patients in this cohort underscores the importance of early screening for brain metastasis in NSCLC. Genomic alterations frequently identified in this study emphasize the continued need for genomic research and investigation of targeted therapies in patients with brain metastases.

C-Terminal p53 Palindromic Tetrapeptide Restores Full Apoptotic Function to Mutant p53 Cancer Cells In Vitro and In Vivo.

We previously demonstrated that a synthetic monomer peptide derived from the C-terminus of p53 (aa 361−382) induced preferential apoptosis in mutant p53 malignant cells, but not normal cells. The major problem with the peptide was its short half-life (half-life < 10 min.) due to a random coil topology found in 3D proton NMR spectroscopy studies. To induce secondary/tertiary structures to produce more stability, we developed a peptide modelled after the tetrameric structure of p53 essential for activation of target genes. Starting with the above monomer peptide (aa 361−382), we added the nuclear localization sequence of p53 (aa 353−360) and the end of the C-terminal sequence (aa 383−393), resulting in a monomer spanning aa 353−393. Four monomers were linked by glycine to maximize flexibility and in a palindromic order that mimics p53 tetramer formation with four orthogonal alpha helices, which is required for p53 transactivation of target genes. This is now known as the 4 repeat-palindromic-p53 peptide or (4R-Pal-p53p). We explored two methods for testing the activity of the palindromic tetrapeptide: (1) exogenous peptide with a truncated antennapedia carrier (Ant) and (2) a doxycycline (Dox) inducer for endogenous expression. The exogenous peptide, 4R-Pal-p53p-Ant, contained a His tag at the N-terminal and a truncated 17aa Ant at the C-terminal. Exposure of human breast cancer MB-468 cells and human skin squamous cell cancer cells (both with mutant p53, 273 Arg->His) with purified peptide at 7 µM and 15 µM produced 52% and 75%, cell death, respectively. Comparatively, the monomeric p53 C-terminal peptide-Ant (aa 361−382, termed p53p-Ant), at 15 µM and 30 µM induced 15% and 24% cell death, respectively. Compared to the p53p-Ant, the exogenous 4R-pal-p53p-Ant was over five-fold more potent for inducing apoptosis at an equimolar concentration (15 µM). Endogenous 4R-Pal-p53p expression (without Ant), induced by Dox, resulted in 43% cell death in an engineered MB468 breast cancer stable cell line, while endogenous p53 C-terminal monomeric peptide expression produced no cell death due to rapid peptide degradation. The mechanism of apoptosis from 4R-Pal-p53p involved the extrinsic and intrinsic pathways (FAS, caspase-8, Bax, PUMA) for apoptosis, as well as increasing reactive oxygen species (ROS). All three death pathways were induced from transcriptional/translational activation of pro-apoptotic genes. Additionally, mRNA of p53 target genes (Bax and Fas) increased 14-fold and 18-fold, respectively, implying that the 4R-Pal-p53p restored full apoptotic potential to mutant p53. Monomeric p53p only increased Fas expression without a transcriptional or translational increase in Fas, and other genes and human marrow stem cell studies revealed no toxicity to normal stem cells for granulocytes, erythrocytes, monocytes, and macrophages (CFU-GEMM). Additionally, the peptide specifically targeted pre-malignant and malignant cells with mutant p53 and was not toxic to normal cells with basal levels of WT p53.

Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed FLT3mut+ AML ineligible for intensive chemotherapy.

Treatment results for patients with newly diagnosed FMS-like tyrosine kinase 3 (FLT3)-mutated (FLT3mut+) acute myeloid leukemia (AML) ineligible for intensive chemotherapy are disappointing. This multicenter, open-label, phase 3 trial randomized (2:1) untreated adults with FLT3mut+ AML ineligible for intensive induction chemotherapy to receive gilteritinib (120 mg/d orally) and azacitidine (GIL + AZA) or azacitidine (AZA) alone. The primary end point was overall survival (OS). At the interim analysis (August 26, 2020), a total of 123 patients were randomized to treatment (GIL + AZA, n = 74; AZA, n = 49). Subsequent AML therapy, including FLT3 inhibitors, was received by 20.3% (GIL + AZA) and 44.9% (AZA) of patients. Median OS was 9.82 (GIL + AZA) and 8.87 (AZA) months (hazard ratio, 0.916; 95% CI, 0.529-1.585; P = .753). The study was closed based on the protocol-specified boundary for futility. Median event-free survival was 0.03 month in both arms. Event-free survival defined by using composite complete remission (CRc) was 4.53 months for GIL + AZA and 0.03 month for AZA (hazard ratio, 0.686; 95% CI, 0.433-1.087; P = .156). CRc rates were 58.1% (GIL + AZA) and 26.5% (AZA) (difference, 31.4%; 95% CI, 13.1-49.7; P < .001). Adverse event (AE) rates were similar for GIL + AZA (100%) and AZA (95.7%); grade ≥3 AEs were 95.9% and 89.4%, respectively. Common AEs with GIL + AZA included pyrexia (47.9%) and diarrhea (38.4%). Gilteritinib steady-state trough concentrations did not differ between GIL + AZA and gilteritinib. GIL + AZA resulted in significantly higher CRc rates, although similar OS compared with AZA. Results support the safety/tolerability and clinical activity of upfront therapy with GIL + AZA in older/unfit patients with FLT3mut+ AML. This trial was registered at www.clinicaltrials.gov as #NCT02752035.

Venetoclax Plus Gilteritinib for FLT3-Mutated Relapsed/Refractory Acute Myeloid Leukemia.

PURPOSE: The FMS-related tyrosine kinase 3 (FLT3) inhibitor gilteritinib is standard therapy for relapsed/refractory FLT3-mutated (FLT3mut) acute myeloid leukemia (AML) but seldom reduces FLT3mut burden or induces sustained efficacy. Gilteritinib combines synergistically with the BCL-2 inhibitor venetoclax in preclinical models of FLT3mut AML. METHODS: This phase Ib open-label, dose-escalation/dose-expansion study (ClinicalTrials.gov identifier: NCT03625505) enrolled patients with FLT3 wild-type and FLT3mut (escalation) or FLT3mut (expansion) relapsed/refractory AML. Patients received 400 mg oral venetoclax once daily and 80 mg or 120 mg oral gilteritinib once daily. The primary objectives were safety, identification of the recommended phase II dose, and the modified composite complete response (mCRc) rate (complete response [CR] + CR with incomplete blood count recovery + CR with incomplete platelet recovery + morphologic leukemia-free state) using ADMIRAL phase III-defined response criteria. RESULTS: Sixty-one patients were enrolled (n = 56 FLT3mut); 64% (n = 36 of 56) of FLT3mut patients had received prior FLT3 inhibitor therapy. The recommended phase II dose was 400 mg venetoclax once daily and 120 mg gilteritinib once daily. The most common grade 3/4 adverse events were cytopenias (n = 49; 80%). Adverse events prompted venetoclax and gilteritinib dose interruptions in 51% and 48%, respectively. The mCRc rate for FLT3mut patients was 75% (CR, 18%; CR with incomplete blood count recovery, 4%; CR with incomplete platelet recovery, 18%; and morphologic leukemia-free state, 36%) and was similar among patients with or without prior FLT3 inhibitor therapy (80% v 67%, respectively). The median follow-up was 17.5 months. The median time to response was 0.9 months, and the median remission duration was 4.9 months (95% CI, 3.4 to 6.6). FLT3 molecular response (< 10-2) was achieved in 60% of evaluable mCRc patients (n = 15 of 25). The median overall survival for FLT3mut patients was 10.0 months. CONCLUSION: The combination of venetoclax and gilteritinib was associated with high mCRc and FLT3 molecular response rates regardless of prior FLT3 inhibitor exposure. Dose interruptions were needed to mitigate myelosuppression.

Clinical outcomes in patients with relapsed/refractory FLT3-mutated acute myeloid leukemia treated with gilteritinib who received prior midostaurin or sorafenib.

The fms-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib is indicated for relapsed or refractory (R/R) FLT3-mutated acute myeloid leukemia (AML), based on its observed superior response and survival outcomes compared with salvage chemotherapy (SC). Frontline use of FLT3 tyrosine kinase inhibitors (TKIs) midostaurin and sorafenib may contribute to cross-resistance to single-agent gilteritinib in the R/R AML setting but has not been well characterized. To clarify the potential clinical impact of prior TKI use, we retrospectively compared clinical outcomes in patients with R/R FLT3-mutated AML in the CHRYSALIS and ADMIRAL trials who received prior midostaurin or sorafenib against those without prior FLT3 TKI exposure. Similarly high rates of composite complete remission (CRc) were observed in patients who received a FLT3 TKI before gilteritinib (CHRYSALIS, 42%; ADMIRAL, 52%) and those without prior FLT3 TKI therapy (CHRYSALIS, 43%; ADMIRAL, 55%). Among patients who received a prior FLT3 TKI in ADMIRAL, a higher CRc rate (52%) and trend toward longer median overall survival was observed in the gilteritinib arm versus the SC arm (CRc = 20%; overall survival, 5.1 months; HR = 0.602; 95% CI: 0.299, 1.210). Remission duration was shorter with prior FLT3 TKI exposure. These findings support gilteritinib for FLT3-mutated R/R AML after prior sorafenib or midostaurin.

Impact of Oropharyngeal Administration of Colostrum in Preterm Newborns' Oral Microbiome.

The initial colonization of the human microbiota is of paramount importance. In this context, the oropharyngeal administration of colostrum is a safe, viable, and well-tolerated practice even by the smallest preterm infants. Therefore, this study evaluated the effects of oropharyngeal administration of colostrum on the establishment of preterm infants' oral microbiota. A longitudinal observational study was carried out with 20 premature neonates, divided into two groups: one receiving the protocol (Oropharyngeal Administration of Colostrum; OAC) and the other one receiving Standard Caare (SC). Saliva samples were collected from the newborns weekly during the study period (from the day of birth until the 21st day of life) for analysis of oral microbiota through 16S rRNA gene sequencing. We observed that the colonization of the oral microbiota of preterm newborns preseanted a higher relative abundance of Staphylococcus on the 7th day of life, mainly in the OAC group. Additionally, an increased abundance of Bifidobacterium and Bacteroides was observed in the OAC group at the first week of life. Regarding alpha and beta diversity, time was a key factor in the oral modulation of both groups, showing how dynamic this environment is in early life.

ERK Inhibitor LY3214996-Based Treatment Strategies for RAS-Driven Lung Cancer.

RAS gene mutations are the most frequent oncogenic event in lung cancer. They activate multiple RAS-centric signaling networks among them the MAPK, PI3K, and RB pathways. Within the MAPK pathway, ERK1/2 proteins exert a bottleneck function for transmitting mitogenic signals and activating cytoplasmic and nuclear targets. In view of disappointing antitumor activity and toxicity of continuously applied MEK inhibitors in patients with KRAS-mutant lung cancer, research has recently focused on ERK1/2 proteins as therapeutic targets and on ERK inhibitors for their ability to prevent bypass and feedback pathway activation. Here, we show that intermittent application of the novel and selective ATP-competitive ERK1/2 inhibitor LY3214996 exerts single-agent activity in patient-derived xenograft (PDX) models of RAS-mutant lung cancer. Combination treatments were well tolerated and resulted in synergistic (ERKi plus PI3K/mTORi LY3023414) and additive (ERKi plus CDK4/6i abemaciclib) tumor growth inhibition in PDX models. Future clinical trials are required to investigate if intermittent ERK inhibitor-based treatment schedules can overcome toxicities observed with continuous MEK inhibition and-equally important-to identify biomarkers for patient stratification.

Low-Dose Vertical Inhibition of the RAF-MEK-ERK Cascade Causes Apoptotic Death of KRAS Mutant Cancers.

We address whether combinations with a pan-RAF inhibitor (RAFi) would be effective in KRAS mutant pancreatic ductal adenocarcinoma (PDAC). Chemical library and CRISPR genetic screens identify combinations causing apoptotic anti-tumor activity. The most potent combination, concurrent inhibition of RAF (RAFi) and ERK (ERKi), is highly synergistic at low doses in cell line, organoid, and rat models of PDAC, whereas each inhibitor alone is only cytostatic. Comprehensive mechanistic signaling studies using reverse phase protein array (RPPA) pathway mapping and RNA sequencing (RNA-seq) show that RAFi/ERKi induced insensitivity to loss of negative feedback and system failures including loss of ERK signaling, FOSL1, and MYC; shutdown of the MYC transcriptome; and induction of mesenchymal-to-epithelial transition. We conclude that low-dose vertical inhibition of the RAF-MEK-ERK cascade is an effective therapeutic strategy for KRAS mutant PDAC.

Women's multisite microbial modulation during pregnancy.

The composition of female microbiome varies with age, physiological and socio-behavior conditions. Also, changes in microbiome composition are observed as pregnancy progresses, especially in the vaginal site. Together with the physiological adaptations of gestation, changes in microbiome composition seem to be fundamental for proper fetal development. This study aimed at simultaneously evaluating the vaginal, gut, and oral microbiome of healthy pregnant women, and comparing it with those observed in healthy non-pregnant women of reproductive age. In a cross-sectional study, vaginal, oral and gut samples were collected from 42 pregnant and 18 non-pregnant women, and the microbiome composition was evaluated by 16S rRNA sequencing, using Illumina platform. In the pregnant group, we observed a positive correlation between Eubacterium and Akkermansia in the gut samples; between Eubacterium and Ruminococcus in the vaginal samples; and between Streptococcus and Gemella in the oral samples. Notwithstanding, we observed a negative correlation between Lactobacillus and Atopobium and between Lactobacillus and Gardnerella in vaginal microbiome. Prevotella was the only genus found in all three sites studied; however, there was no signal of bacterial influence between sites during pregnancy. These results suggest that in addition to hormonal and immunological variations during healthy pregnancy, the female body also undergoes microbiome modulation in multiple sites in order to maintain an eubiotic status.

Diffusion maps of Bacillus subtilis biofilms via magnetic resonance imaging highlight a complex network of channels.

Bacillus subtilis microorganism when cultivated under chemically-defined conditions developed a biofilm with an unusual pattern of wrinkles on the surface. Some questions were raised about whether there was a special function of these wrinkles for the biofilm itself, since they resembled microchannels that could be involved in the transport of nutrients within the biofilm. Since the diffusion is the main mechanism for nutrient transport to biofilm from the medium, the role of these wrinkled structures in the whole diffusion within the biofilm was investigated using diffusion-weighted magnetic resonance imaging (DW-MRI). Data from these diffusion images was used to generate 2D diffusion maps which highlighted the striking channel features of the biofilm surface. The diffusion maps revealed a network of interconnected channels, with self-diffusion coefficients higher in the microchannels than in other regions of the biofilms. Polar plots made from 2D diffusion maps obtained from the plane of the biofilm show an anisotropy of the diffusion inside the microchannels, with the diffusion higher when along the principal direction of the microchannels. These results agree with the model, that the buckling of the biofilm surface from the B. subtilis creates microchannels that can enhance diffusion throughout the biofilm.

Correction: Evaluation of ERK as a therapeutic target in acute myelogenous leukemia.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A Phase I Study of LY3009120, a Pan-RAF Inhibitor, in Patients with Advanced or Metastatic Cancer.

Mutations in ERK signaling drive a significant percentage of malignancies. LY3009120, a pan-RAF and dimer inhibitor, has preclinical activity in RAS- and BRAF-mutated cell lines including BRAF-mutant melanoma resistant to BRAF inhibitors. This multicenter, open-label, phase I clinical trial (NCT02014116) consisted of part A (dose escalation) and part B (dose confirmation) in patients with advanced/metastatic cancer. In part A, oral LY3009120 was dose escalated from 50 to 700 mg twice a day on a 28-day cycle. In part B, 300 mg LY3009120 was given twice a day. The primary objective was to identify a recommended phase II dose (RP2D). Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary efficacy. Identification of pharmacodynamic biomarkers was exploratory. In parts A and B, 35 and 16 patients were treated, respectively (N = 51). In part A, 6 patients experienced eight dose-limiting toxicities. The RP2D was 300 mg twice a day. Common (>10%) any-grade drug-related treatment-emergent adverse events were fatigue (n = 15), nausea (n = 12), dermatitis acneiform (n = 10), decreased appetite (n = 7), and maculopapular rash (n = 7). The median duration of treatment was 4 weeks; 84% of patients completed one or two cycles of treatment. Exposures observed at 300 mg twice a day were above the preclinical concentration associated with tumor regression. Eight patients had a best overall response of stable disease; there were no complete or partial clinical responses. Despite adequate plasma exposure levels, predicted pharmacodynamic effects were not observed.

ERK Inhibitor LY3214996 Targets ERK Pathway-Driven Cancers: A Therapeutic Approach Toward Precision Medicine.

The ERK pathway is critical in oncogenesis; aberrations in components of this pathway are common in approximately 30% of human cancers. ERK1/2 (ERK) regulates cell proliferation, differentiation, and survival and is the terminal node of the pathway. BRAF- and MEK-targeted therapies are effective in BRAF V600E/K metastatic melanoma and lung cancers; however, responses are short-lived due to emergence of resistance. Reactivation of ERK signaling is central to the mechanisms of acquired resistance. Therefore, ERK inhibition provides an opportunity to overcome resistance and leads to improved efficacy. In addition, KRAS-mutant cancers remain an unmet medical need in which ERK inhibitors may provide treatment options alone or in combination with other agents. Here, we report identification and activity of LY3214996, a potent, selective, ATP-competitive ERK inhibitor. LY3214996 treatment inhibited the pharmacodynamic biomarker, phospho-p90RSK1, in cells and tumors, and correlated with LY3214996 exposures and antitumor activities. In in vitro cell proliferation assays, sensitivity to LY3214996 correlated with ERK pathway aberrations. LY3214996 showed dose-dependent tumor growth inhibition and regression in xenograft models harboring ERK pathway alterations. Importantly, more than 50% target inhibition for up to 8 to 16 hours was sufficient for significant tumor growth inhibition as single agent in BRAF- and KRAS-mutant models. LY3214996 also exhibited synergistic combination benefit with a pan-RAF inhibitor in a KRAS-mutant colorectal cancer xenograft model. Furthermore, LY3214996 demonstrated antitumor activity in BRAF-mutant models with acquired resistance in vitro and in vivo. Based on these preclinical data, LY3214996 has advanced to an ongoing phase I clinical trial (NCT02857270).

Gut Microbiome of Children and Adolescents With Primary Sclerosing Cholangitis in Association With Ulcerative Colitis.

Few studies reported the relation of intestinal microbiome composition and diversity in pediatric patients with primary sclerosing cholangitis (PSC) and ulcerative colitis (UC). In this cross-sectional study, we selected patients younger than 19 years old from the pediatric gastroenterology and hepatology outpatient clinic of a tertiary hospital to describe the intestinal microbiome of pediatric patients with PSC associated or not to UC. Patients were divided in PSC, PSC+UC, and UC diagnosis. A stool sample was collected from each patient (n=30) and from a healthy relative/neighbor (n=23). The microbiome composition was assessed using MiSeq (Illumina) platform. Differences in microbial composition were found between PSC and PSC+UC groups. The relative abundance of Veillonella and Megasphaera genera were increased depending on patients' age at diagnosis. Veillonella was also increased in patients who were in an active status of the disease. Both genera were positively correlated to total bilirubin and gamma-glutamyl transferase. As a conclusion, the disease, the age and the disease activity status seem to influence the intestinal microbiome, highlighting the difference of intestinal microbiome profile for patients depending on age at diagnosis. We also showed an increase of Veillonella in patients with PSC and PSC+UC, and a positive correlation of dysbiosis and higher gamma-glutamyl transferase and total bilirubin in PSC+UC patients. Our findings are promising in the diagnosis, prognosis, and future therapeutic perspectives for PSC patients.

Microbiome and its relation to gestational diabetes.

PURPOSE: Gestational diabetes mellitus (GDM), the major endocrine pathology in pregnancy, has been associated with the development of an intense inflammatory process and increased insulin resistance. The maternal microbiota is involved in several metabolic functions; however, its role in GDM physiopathology remains unclear. The aim of this study was to assess the composition of the microbiota at different sites and evaluate its relationship with the occurrence of GDM. METHODS: This cross-sectional study recruited women in the third trimester of gestation with and without GDM. Oral, vaginal, and stool samples were evaluated using next-generation sequencing. We included 68 participants: 26 with and 42 without GDM. RESULTS: The analysis of the oral microbiome did not show significant differences in phyla and genus among the studied groups. In contrast, GDM patients presented a specific vaginal and intestinal microbiome composition, which was less diverse than those found in the control group, showing genera related to dysbiosis. CONCLUSIONS: Our findings suggest that changes in the composition of the vaginal and intestinal microbiome might be involved in the development of GDM. The follow-up of these patients in order to evaluate vaginal and intestinal samples after delivery may contribute to understanding the development of metabolic disease in women with previous GDM.