Calcium carbonate precipitation by heterotrophic bacteria isolated from biofilms formed on deteriorated ignimbrite stones: influence of calcium on EPS production and biofilm formation by these isolates.

Heterotrophic CaCO3-precipitating bacteria were isolated from biofilms on deteriorated ignimbrites, siliceous acidic rocks, from Morelia Cathedral (Mexico) and identified as Enterobacter cancerogenus (22e), Bacillus sp. (32a) and Bacillus subtilis (52g). In solid medium, 22e and 32a precipitated calcite and vaterite while 52g produced calcite. Urease activity was detected in these isolates and CaCO3 precipitation increased in the presence of urea in the liquid medium. In the presence of calcium, EPS production decreased in 22e and 32a and increased in 52g. Under laboratory conditions, ignimbrite colonization by these isolates only occurred in the presence of calcium and no CaCO3 was precipitated. Calcium may therefore be important for biofilm formation on stones. The importance of the type of stone, here a siliceous stone, on biological colonization is emphasized. This calcium effect has not been reported on calcareous materials. The importance of the effect of calcium on EPS production and biofilm formation is discussed in relation to other applications of CaCO3 precipitation by bacteria.

ConcreteXAI: A multivariate dataset for concrete strength prediction via deep-learning-based methods.

Concrete is a prominent construction material globally, owing to its reputed attributes such as robustness, endurance, optimal functionality, and adaptability. Formulating concrete mixtures poses a formidable challenge, mainly when introducing novel materials and additives and evaluating diverse design resistances. Recent methodologies for projecting concrete performance in fundamental aspects, including compressive strength, flexural strength, tensile strength, and durability (encompassing homogeneity, porosity, and internal structure), exist. However, actual approaches need more diversity in the materials and properties considered in their analyses. This dataset outlines the outcomes of an extensive 10-year laboratory investigation into concrete materials involving mechanical tests and non-destructive assessments within a comprehensive dataset denoted as ConcreteXAI. This dataset encompasses evaluations of mechanical performances and non-destructive tests. ConcreteXAI integrates a spectrum of analyzed mixtures comprising twelve distinct concrete formulations incorporating diverse additives and aggregate types. The dataset encompasses 18,480 data points, establishing itself as a cutting-edge resource for concrete analysis. ConcreteXAI acknowledges the influence of artificial intelligence techniques in various science fields. Emphatically, deep learning emerges as a precise methodology for analyzing and constructing predictive models. ConcreteXAI is designed to seamlessly integrate with deep learning models, enabling direct application of these models to predict or estimate desired attributes. Consequently, this dataset offers a resourceful avenue for researchers to develop high-quality prediction models for both mechanical and non-destructive tests on concrete elements, employing advanced deep learning techniques.

Pralsetinib in Patients with Advanced/Metastatic Rearranged During Transfection (RET)-Altered Thyroid Cancer: Updated Efficacy and Safety Data from the ARROW Study.

Background: Rearranged during transfection (RET) alterations are targetable oncogenic drivers in thyroid cancer. Primary data from the open-label, phase 1/2 ARROW study demonstrated clinical activity and manageable safety with pralsetinib, a selective RET inhibitor, in patients with advanced/metastatic RET-altered thyroid cancer. We present an updated analysis with more patients and longer follow-up. Methods: Adult patients with advanced/metastatic RET-mutant medullary thyroid cancer (MTC) or RET fusion-positive thyroid cancer who initiated oral pralsetinib at 400 mg once daily were included. Primary endpoints were overall response rate (ORR) by blinded independent central review (per RECIST v1.1) and safety. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival. Responses were assessed in three cohorts of patients with baseline measurable disease: patients with RET-mutant MTC who had received prior cabozantinib and/or vandetanib (C/V), treatment-naïve patients with RET-mutant MTC, and patients with previously treated RET fusion-positive thyroid cancer. Patient-reported outcomes (PROs) were an exploratory endpoint. Results: As of October 18, 2021, the measurable disease population comprised of 61 patients with RET-mutant MTC and prior C/V, 62 treatment-naïve patients with RET-mutant MTC, and 22 patients with RET fusion-positive thyroid cancer who had received prior systemic therapy, including radioactive iodine. The ORR was 55.7% [confidence interval; 95% CI: 42.4-68.5] in patients with RET-mutant MTC and prior C/V, 77.4% [95% CI: 65.0-87.1] in treatment-naïve patients with RET-mutant MTC, and 90.9% [95% CI: 70.8-98.9] in patients with previously treated RET fusion-positive thyroid cancer. Median DoR and median PFS were both 25.8 months in patients with RET-mutant MTC and prior C/V, not reached in treatment-naïve patients with RET-mutant MTC, and 23.6 and 25.4 months, respectively, in patients with previously treated RET fusion-positive thyroid cancer. In the RET-altered thyroid cancer safety population (N = 175), 97.1% of patients reported a treatment-related adverse event (TRAE); these led to discontinuation in 5.7% and dose reduction in 52.6% of patients. There was one death (0.6%) due to a TRAE. PROs improved or remained stable after pralsetinib treatment. Conclusions: In this updated analysis of the ARROW study, pralsetinib continued to show deep and durable clinical activity and a manageable safety profile in patients with advanced/metastatic RET-altered thyroid cancer. Clinical Trial Registration: NCT03037385.

MYC targeting by OMO-103 in solid tumors: a phase 1 trial.

Among the 'most wanted' targets in cancer therapy is the oncogene MYC, which coordinates key transcriptional programs in tumor development and maintenance. It has, however, long been considered undruggable. OMO-103 is a MYC inhibitor consisting of a 91-amino acid miniprotein. Here we present results from a phase 1 study of OMO-103 in advanced solid tumors, established to examine safety and tolerability as primary outcomes and pharmacokinetics, recommended phase 2 dose and preliminary signs of activity as secondary ones. A classical 3 + 3 design was used for dose escalation of weekly intravenous, single-agent OMO-103 administration in 21-day cycles, encompassing six dose levels (DLs). A total of 22 patients were enrolled, with treatment maintained until disease progression. The most common adverse events were grade 1 infusion-related reactions, occurring in ten patients. One dose-limiting toxicity occurred at DL5. Pharmacokinetics showed nonlinearity, with tissue saturation signs at DL5 and a terminal half-life in serum of 40 h. Of the 19 patients evaluable for response, 12 reached the predefined 9-week time point for assessment of drug antitumor activity, eight of those showing stable disease by computed tomography. One patient defined as stable disease by response evaluation criteria in solid tumors showed a 49% reduction in total tumor volume at best response. Transcriptomic analysis supported target engagement in tumor biopsies. In addition, we identified soluble factors that are potential pharmacodynamic and predictive response markers. Based on all these data, the recommended phase 2 dose was determined as DL5 (6.48 mg kg-1).ClinicalTrials.gov identifier: NCT04808362 .

Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial.

KRAS G12C mutation is prevalent in ~4% of colorectal cancer (CRC) and is associated with poor prognosis. Divarasib, a KRAS G12C inhibitor, has shown modest activity as a single agent in KRAS G12C-positive CRC at 400 mg. Epidermal growth factor receptor has been recognized as a major upstream activator of RAS-MAPK signaling, a proposed key mechanism of resistance to KRAS G12C inhibition in CRC. Here, we report on divarasib plus cetuximab (epidermal growth factor receptor inhibitor) in patients with KRAS G12C-positive CRC (n = 29) from arm C of an ongoing phase 1b trial. The primary objective was to evaluate safety. Secondary objectives included preliminary antitumor activity. The safety profile of this combination was consistent with those of single-agent divarasib and cetuximab. Treatment-related adverse events led to divarasib dose reductions in four patients (13.8%); there were no treatment withdrawals. The objective response rate was 62.5% (95% confidence interval: 40.6%, 81.2%) in KRAS G12C inhibitor-naive patients (n = 24). The median duration of response was 6.9 months. The median progression-free survival was 8.1 months (95% confidence interval: 5.5, 12.3). As an exploratory objective, we observed a decline in KRAS G12C variant allele frequency associated with response and identified acquired genomic alterations at disease progression that may be associated with resistance. The manageable safety profile and encouraging antitumor activity of divarasib plus cetuximab support the further investigation of this combination in KRAS G12C-positive CRC.ClinicalTrials.gov identifier: NCT04449874.

Phase 1 first-in-human dose-escalation study of ANV419 in patients with relapsed/refractory advanced solid tumors.

BACKGROUND: ANV419 is a stable antibody-cytokine fusion protein consisting of interleukin-2 (IL-2) fused to an anti-IL-2 monoclonal antibody that sterically hinders binding of IL-2 to the α subunit of its receptor but has selective affinity for the receptor ßγ subunits. Thus, ANV419 preferentially stimulates CD8+ effector T cells and natural killer cells which are associated with tumor killing, while minimizing the activation of immunosuppressive regulatory T cells. METHODS: ANV419-001 is an open-label, multicenter, phase 1 study to evaluate the safety, tolerability, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ANV419. Secondary objectives were to characterize the pharmacokinetics, pharmacodynamics and tumor response. Adult patients with advanced solid tumors and disease progression after ≥1 previous line of systemic therapy were enrolled. ANV419 was administered by intravenous infusion once every 2 weeks, with a planned treatment duration of 12 months. The dose escalation part of the study explored doses 3, 6 and 12 µg/kg as single patient cohorts followed by 24-364 µg/kg in a 3+3 design. Interim results are reported here (data cut-off: March 22, 2023). RESULTS: Forty patients were enrolled and received at least one dose of ANV419. The MTD and RP2D were determined to be 243 µg/kg. The most common ANV419-related treatment-emergent adverse events were Grade 1 and 2 fever (31 (77.5%)), chills (23 (57.5%), vomiting (14 (35.0%)), cytokine release syndrome and nausea (12 (30.0%) each). Transient and self-limiting lymphopenia due to lymphocyte redistribution was observed in all patients. In the RP2D cohort, Grade ≥3 thrombocytopenia and fever were reported by one patient (12.5%) each. All events were manageable with standard supportive care. At doses of 243 µg/kg (RP2D/MTD), the estimated T1/2 was approximately 12 hours. At ANV419 doses ≥108 µg/kg, 64% of patients had a best response of at least SD (15 SD and 1 confirmed PR). CONCLUSIONS: ANV419 at doses up to 243 µg/kg (the RP2D) was well tolerated and showed signs of antitumor activity in a heavily pretreated patient population with advanced solid tumors. TRIAL REGISTRATION NUMBER: NCT04855929.

Selpercatinib in Patients With RET Fusion-Positive Non-Small-Cell Lung Cancer: Updated Safety and Efficacy From the Registrational LIBRETTO-001 Phase I/II Trial.

PURPOSE: Selpercatinib, a first-in-class, highly selective, and potent CNS-active RET kinase inhibitor, is currently approved for the treatment of patients with RET fusion-positive non-small-cell lung cancer (NSCLC). We provide a registrational data set update in more than double (n = 316) of the original reported population (n = 144) and better characterization of long-term efficacy and safety. METHODS: Patients were enrolled to LIBRETTO-001, a phase I/II, single-arm, open-label study of selpercatinib in patients with RET-altered cancers. An analysis of patients with RET fusion-positive NSCLC, including 69 treatment-naive and 247 with prior platinum-based chemotherapy, was performed. The primary end point was objective response rate (ORR; RECIST v1.1, independent review committee). Secondary end points included duration of response (DoR), progression-free survival (PFS), overall survival, and safety. RESULTS: In treatment-naive patients, the ORR was 84% (95% CI, 73 to 92); 6% achieved complete responses (CRs). The median DoR was 20.2 months (95% CI, 13.0 to could not be evaluated); 40% of responses were ongoing at the data cutoff (median follow-up of 20.3 months). The median PFS was 22.0 months; 35% of patients were alive and progression-free at the data cutoff (median follow-up of 21.9 months). In platinum-based chemotherapy pretreated patients, the ORR was 61% (95% CI, 55 to 67); 7% achieved CRs. The median DoR was 28.6 months (95% CI, 20.4 to could not be evaluated); 49% of responses were ongoing (median follow-up of 21.2 months). The median PFS was 24.9 months; 38% of patients were alive and progression-free (median follow-up of 24.7 months). Of 26 patients with measurable baseline CNS metastasis by the independent review committee, the intracranial ORR was 85% (95% CI, 65 to 96); 27% were CRs. In the full safety population (n = 796), the median treatment duration was 36.1 months. The safety profile of selpercatinib was consistent with previous reports. CONCLUSION: In a large cohort with extended follow-up, selpercatinib continued to demonstrate durable and robust responses, including intracranial activity, in previously treated and treatment-naive patients with RET fusion-positive NSCLC.

Ongoing and evolving clinical trials enhancing future colorectal cancer treatment strategies.

INTRODUCTION: Molecular profiling has led to significantly longer survival in metastatic colorectal cancer (CRC) patients. Clinical guidelines recommend testing for KRAS/NRAS, BRAF, and MSI status, and over the last few years, several promising new biomarkers have also been identified. Circulating tumor DNA has reshaped the prognosis of localized CRC. These genomic findings can guide treatment management to improve clinical outcomes. AREAS COVERED: Preclinical and clinical data over the last decade were reviewed for known and novel biomarkers with clinical implications in refractory and metastatic CRC. In the localized stage, all clinical trials involving new approaches such as liquid biopsy or neoadjuvant immunotherapy are also discussed. Molecular alterations and targeted agents are described, and data from completed and ongoing studies with targeted therapy and immunotherapies are presented. EXPERT OPINION: The implementation of liquid biopsies in the localized CRC setting has reshaped management of this disease. The expanded use of biomarkers to guide CRC patients' treatment has revealed a level of complexity arising from interactions between different biomarkers. Prevalence of most established targetable biomarkers is low; however, the number of identified biomarkers in CRC is increasing. Thus, metastatic CRC may ultimately be considered an umbrella diagnosis encompassing numerous rare disease subtypes.

Adherence to the Mediterranean Diet Is Inversely Associated with the Prevalence of Metabolic Syndrome in Older People from the North of Spain.

Background: The aim of this study was to relate adherence to the Mediterranean diet (MedDiet) to the prevalence of metabolic syndrome (MetS) in an elderly population from the north of Spain. Methods: We carried out an observational, descriptive, cross-sectional, and correlational study involving 556 non-institutionalised individuals aged 65 to 79 years. The MEDAS-14 questionnaire score was used to define the degree of adherence to the Mediterranean diet. The diagnosis of MetS was conducted using the International Diabetes Federation (IDF) criteria. Results: In 264 subjects with an average age of 71.9 (SD: ±4.2), 39% of whom were men, 36.4% had good adherence (score ≥ 9 in MEDAS-14), with no differences by gender or age. The prevalence of MetS was 40.2%, with 47.6% in men and 35.4% in women (p < 0.05). The prevalence of MetS was 2.4 times more frequent among individuals who consumed less than two servings (200 g) of vegetables daily compared with those who consumed two or more servings of vegetables daily (OR: 2.368, 95%CI: 1.141−4.916, p = 0.021). Low adherence to the MedDiet (MEDAS-14 score ≤ 8) was associated with an 82% higher prevalence of MetS (OR: 1.817, 95%CI: 1.072−3.081, p = 0.027). Conclusion: An inverse relationship was established between adherence to the MedDiet and the prevalence of MetS.

Preclinical Characterization and Phase I Trial Results of a Bispecific Antibody Targeting PD-L1 and 4-1BB (GEN1046) in Patients with Advanced Refractory Solid Tumors.

Checkpoint inhibitors (CPI) have revolutionized the treatment paradigm for advanced solid tumors; however, there remains an opportunity to improve response rates and outcomes. In preclinical models, 4-1BB costimulation synergizes with CPIs targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis by activating cytotoxic T-cell-mediated antitumor immunity. DuoBody-PD-L1×4-1BB (GEN1046) is an investigational, first-in-class bispecific immunotherapy agent designed to act on both pathways by combining simultaneous and complementary PD-L1 blockade and conditional 4-1BB stimulation in one molecule. GEN1046 induced T-cell proliferation, cytokine production, and antigen-specific T-cell-mediated cytotoxicity superior to clinically approved PD-(L)1 antibodies in human T-cell cultures and exerted potent antitumor activity in transplantable mouse tumor models. In dose escalation of the ongoing first-in-human study in heavily pretreated patients with advanced refractory solid tumors (NCT03917381), GEN1046 demonstrated pharmacodynamic immune effects in peripheral blood consistent with its mechanism of action, manageable safety, and early clinical activity [disease control rate: 65.6% (40/61)], including patients resistant to prior PD-(L)1 immunotherapy. SIGNIFICANCE: DuoBody-PD-L1×4-1BB (GEN1046) is a first-in-class bispecific immunotherapy with a manageable safety profile and encouraging preclinical and early clinical activity. With its ability to confer clinical benefit in tumors typically less sensitive to CPIs, GEN1046 may fill a clinical gap in CPI-relapsed or refractory disease or as a combination therapy with CPIs. See related commentary by Li et al., p. 1184. This article is highlighted in the In This Issue feature, p. 1171.

Estimation of the main conditions in (SARS-CoV-2) Covid-19 patients that increase the risk of death using Machine learning, the case of Mexico.

Nowadays, society faces a catastrophic problem related to respiratory syndrome due to the coronavirus SARS-CoV-2: the Covid-19 disease. This virus has changed our coexistence rules and, in consequence, has reshaped the daily activities in modern societies. Thus, there are many efforts to understand the virus behaviour in order to reduce its negative impact, and these efforts produce an incredible amount of information and data sources every week. Data scientists, which use techniques such as Machine learning, are focusing their abilities to develop mathematical models for analysing this critical situation. This paper uses Machine Learning techniques as tools to help understand some specific new patterns in Covid patients that arise from unknown complex interactions in the transmission-dynamic models of the SARS-CoV-2 virus, and their relation with the corresponding social contact patterns which are often known or can be inferred from populations variables. One of the main motivations of this research is to find the diseases that cause an increase in the risk of death in infected people with the Covid-19 virus. Mexico is the case of study in this research. The general conditions of health that cause death are well known generally in the world. However, these conditions in each country can differ depending on different factors such as the general health status of people. The results show that the principal causes of death in Mexico are related to age, bad eating habits, chronic diseases, and contact with infected people having not proper care. Results from the analysis show a remarkable accuracy of 87%, which is considered satisfactory.

Reinforced Concrete Structure Performance in Marine Structures: Analyzing Durability Indexes to Obtain More Accurate Corrosion Initiation Time Predictions.

This paper presents a comparison of six index properties collected during durability inspections of five Mexican seaports. Typical durability indicators such as compressive strength, saturated electrical resistivity, ultrasonic pulse velocity, percent total void content, capillary porosity, and chloride concentration profiles were analyzed to obtain empirical correlations with the non-steady-state chloride diffusion coefficient. These indices were compared to determine correlation coefficients that are the most important for obtaining better corrosion initiation forecasting. Two models of corrosion initiation time (ti) were used: Fick's second law of diffusion and the reported UNE-83994-2 (Spanish Association for Standardization, UNE) in which electrical resistivity was used to calculate concrete service life. The data from both models were cleaned using correlated variables, and the initial variables were compared with ti. The main result achieved was the verification of the feasibility of using correlations of variables to clean unnecessary data in order to calculate ti. Additionally, electrical resistivity was identified as one of the main durability indexes for in-service concrete structures exposed to marine environments. This is important because electrical resistivity is a non-destructive and reliable test that can be measured both in the laboratory and in the field very easily.

Phase I prognostic online (PIPO): A web tool to improve patient selection for oncology early phase clinical trials.

PURPOSE: Patient selection in phase 1 clinical trials (Ph1t) continues to be a challenge. The aim of this study was to develop a user-friendly prognostic calculator for predicting overall survival (OS) outcomes in patients to be included in Ph1t with immune checkpoint inhibitors (ICIs) or targeted agents (TAs) based on clinical parameters assessed at baseline. METHODS: Using a training cohort with consecutive patients from the VHIO phase 1 unit, we constructed a prognostic model to predict median OS (mOS) as a primary endpoint and 3-month (3m) OS rate as a secondary endpoint. The model was validated in an internal cohort after temporal data splitting and represented as a web application. RESULTS: We recruited 799 patients (training and validation sets, 558 and 241, respectively). Median follow-up was 21.2 months (m), mOS was 10.2 m (95% CI, 9.3-12.7) for ICIs cohort and 7.7 m (95% CI, 6.6-8.6) for TAs cohort. In the multivariable analysis, six prognostic variables were independently associated with OS - ECOG, number of metastatic sites, presence of liver metastases, derived neutrophils/(leukocytes minus neutrophils) ratio [dNLR], albumin and lactate dehydrogenase (LDH) levels. The phase 1 prognostic online (PIPO) calculator showed adequate discrimination and calibration performance for OS, with C-statistics of 0.71 (95% CI 0.64-0.78) in the validation set. The overall accuracy of the model for 3m OS prediction was 87.2% (95% CI 85%-90%). CONCLUSIONS: PIPO is a user-friendly objective and interactive tool to calculate specific survival probabilities for each patient before enrolment in a Ph1t. The tool is available at https://pipo.vhio.net/.

Asphalt Mixes Processed with Recycled Concrete Aggregate (RCA) as Partial Replacement of the Natural Aggregate.

Materials play a fundamental role in any branch of civil engineering. From ancient times to the present day, society has required enormous amounts of construction materials, which implies an excessive exploitation of the natural environment. The present research work consisted in the design and development of asphalt mixes with a partial substitution of the natural aggregate (NA) by means of recycled concrete aggregate (RCA). The mix was designed with the Marshall methodology, considering the next percentages of substitution and addition by mass: 90% NA and 10% RCA; 80% NA and 20% RCA; 70% NA and 30% RCA. The mixtures were elaborated and analysed under the international standards and the Mexican regulation of the Communications and Transport Ministry, to determine the best option regarding their performance. The materials were characterized according to the current regulations and later employed in the mixes design. A total of 38 specimens were elaborated for each mixture, determining the optimum asphalt content; after that, mechanical tests were performed to analyse and determine the best results. In the aftermath of the examination of all mixtures, we concluded that the 70%AN/30%RCA is the best alternative option according to its performance and numeric results, complying with the cited regulations, and allowing a lower content of asphalt during the process.

Effect of the Addition of Agribusiness and Industrial Wastes as a Partial Substitution of Portland Cement for the Carbonation of Mortars.

The present research work shows the effect on the carbonation of Portland cement-based mortars (PC) with the addition of green materials, specifically residues from two groups: agricultural and industrial wastes, and minerals and fibres. These materials have the purpose of helping with the waste disposal, recycling, and improving the durability of concrete structures. The specimens used for the research were elaborated with CPC 30R RS, according to the Mexican standard NMX-C-414, which is equivalent to the international ASTM C150. The aggregates were taken from the rivers Lerma and Huajumbaro, in the State of Michoacan, Mexico, and the water/cement relation was 1:1 in weight. The carbonation analyses were performed with cylinder specimens in an accelerated carbonation test chamber with conditions of 65 +/- 5% of humidity and 25 +/- 2 °C temperature. The results showed that depending on the PC substitutions, the carbonation front advance of the specimens can increase or decrease. It is highlighted that the charcoal ashes, blast-furnace slags, and natural perlite helped to reduce the carbonation advance compared to the control samples, consequently, they contributed to the durability of concrete structures. Conversely, the sugarcane bagasse ash, brick manufacturing ash, bottom ash, coal, expanded perlite, metakaolin, and opuntia ficus-indica dehydrated fibres additions increased the velocity of carbonation front, helping with the sequestration of greenhouse gases, such as CO2, and reducing environmental pollution.