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In an industrial process exists several variables to be monitored, in particular, temperature is a main variable for many systems as a hydraulic circuit. Due to friction effects and recirculation of the fluid, a temperature increasing is noted causing some variations on physical properties of the oil. In this work, the design and implementation of a low-cost system is covered for data acquisition of the oil temperature and advance time of the final actuator. This system is composed by a minicomputer Raspberry Pi, a submersible digital sensor and programming code in Python; the hydraulic circuit is built with a hydraulic source equipment, a solenoid valve, a double-acting cylinder and two limit switches. The proposed approach is experimentally proved in a continuous process with 200 iterations for the cylinder to advance and retract, which results in a rising temperature. Furthermore, with available data from the advance time, the effect caused by the temperature on the advance velocity is observed by means of plots of temperature and velocity from the low-cost monitoring system.

Background Advanced gastro-oesophageal cancer (GEA) treatment has been improved by the introduction of immune checkpoint inhibitors (CPIs), yet identifying predictive biomarkers remains a priority, particularly in patients with a combined positive score (CPS) Design Through integrative transcriptomic and clinicopathological analyses, we studied in both a retrospective and a prospective cohort, the immune tumour microenvironment features. We analysed the cell types composing the immune infiltrate highlighting their functional activity. Results This integrative study allowed the identification of four different groups across our patients. Among them, we identified a cluster whose tumours expressed the most gene signatures related to immunomodulatory pathways and immunotherapy response. These tumours presented an enriched immune infiltrate showing high immune function activity that could potentially achieve the best benefit from CPIs. Finally, our findings were proven in an external CPI-exposed population, where the use of our transcriptomic results combined with CPS helped better identify those patients who could benefit from immunotherapy than using CPS alone (p = 0.043). Conclusions This transcriptomic classification could improve precision immunotherapy for GEA.

Hemicrania continua is an uncommon headache disorder that requires complete response to indomethacin for its diagnosis, that becomes on most of the cases chronic pain resilient to treatment. On the other hand, temporomandibular pain is very common on the general population and happens to be undiagnosed most of the time when headache or migraines are happening at the same time. In this case we aim to highlight the importance of treating all concomitant diagnosis for a better long-term prognosis. In this paper, a case of a 51-year-old male with chronic resilient facial pain is presented. The patient described right sided facial pain with six years of evolution that started with no triggers. The pain was described as constant bilateral pressure being worse on the right side, located on the temples, masseteric and preauricular areas; with an intensity of 6 on a scale of 0 to 10. It is accompanied by episodes of paroxysmal pulsating hemifacial pain with autonomic symptoms (rhinorrhea, conjunctival injections and lacrimation). The pain during exacerbations was located on the right periorbital and hemifacial area and with an intensity of 10 on a scale of 0 to 10, lasting a few minutes to more than 2 hours. After the clinical examination and pain history, the patient was given the diagnosis of hemicrania continua and masticatory myofascial pain. He was started on Indomethacin 25mg twice a day and started on temporomandibular therapy (self-care, jaw exercises, motivation and advice for stress management). Three months after the first evaluation the patient reported total resolution of his symptoms. The main goal of this article is to highlight that the presence of temporomandibular disorders is common in patients with headaches, for which it is necessary to carry out a comprehensive approach for both entities, which include the therapies for treating axis I diagnosis and behavioral management for axis II, this including most of the time a multidisciplinary human centered approach. La hemicránea continua es un trastorno de cefalea poco común que requiere una respuesta completa a la indometacina para su diagnóstico, lo cual deja como resultado la mayoría de los casos en un dolor crónico resistente al tratamiento. Por otro lado, el dolor temporomandibular es muy común en la población general y no se diagnostica la mayor parte del tiempo cuando el dolor de cabeza o las migrañas ocurren al mismo tiempo. En este caso pretendemos resaltar la importancia de tratar todos los diagnósticos concomitantes para un mejor pronóstico a largo plazo. En este artículo se presenta el caso de un hombre de 51 años con dolor facial crónico resistente. El paciente refirió dolor facial en lado derecho de seis años de evolución que comenzó sin desencadenantes. El dolor se describió como presión constante bilateral, siendo peor en el lado derecho, localizado en temporales, zona maseterina y preauricular; con una intensidad de 6 en una escala de 0 a 10. Se acompaña de episodios de dolor hemifacial pulsátil paroxístico con síntomas autonómicos (rinorrea, inyecciones conjuntivales y lagrimeo). El dolor exacerbado, se localizaba en la zona periorbitaria y hemifacial derecha y con una intensidad de 10 en una escala de 0 a 10, con una duración de unos minutos a más de 2 horas. Tras el examen clínico y la historia del dolor, se le dio al paciente el diagnóstico de hemicránea continua y dolor miofascial masticatorio. El paciente inició tratamiento con Indometacina 25mg dos veces al día y comenzó con terapia temporomandibular (autocuidado, ejercicios de mandíbula, motivación y consejos para el manejo del estrés). Tres meses después de la primera evaluación el paciente reportó resolución total de sus síntomas. El objetivo principal de este artículo es resaltar que la presencia de trastornos temporomandibulares es frecuente en pacientes con cefalea, por lo que es necesario realizar un abordaje integral de ambas entidades, que incluya las terapias para el tratamiento diagnóstico del Eje I y manejo conductual para el Eje II, lo anterior incluye la mayoría de las veces un abordaje multidisciplinario centrado en el ser humano.

Figure legend to Supplementary Figure S1.

Supplementary Table S1. IC50 values of ipatasertib on cell viability in cell lines with or without alterations in PTEN or PIK3CA. Supplementary Table S2. Percent tumor growth inhibition (%TGI) in xenograft models with or without alterations in PTEN or PIK3CA. Supplementary Table S3. PI3K/Akt pathway status in archival tumors. Supplementary Table S4. Reasons for discontinuation of study. Supplementary Table S5. Common adverse events for ipatasertib in {greater than or equal to} 10% of patients in any presented group. Supplementary Table S6. All Grade {greater than or equal to} 3 adverse events related to ipatasertib. Supplementary Table S7. Hemoglobin A1C (HgbA1C) values for patients who had both pre-treatment and post-treatment values in Stages 1 and 2. Supplementary Table S8. Summary data for patients with best radiographic stable disease (SD) by RECIST version 1.0 criteria. Supplementary Figure S1. Exposure plots confirm that exposures achieved in patients in the dose-escalation stage (right side) correlated with exposures in preclinical models at TGI90 (left side). Supplementary Figure S2. Relationship between exposure of ipatasertib to the most common ipatasertib-related AEs of fatigue, diarrhea, nausea, and rash. Supplementary Figure S3. Suppression of pGSK3β in platelet-rich plasma versus ipatasertib concentrations. Supplementary Figure S4. Pharmacodynamic (PD) dose-dependent elevations in glucose and insulin following treatment with ipatasertib.

Overall sequencing CONSORT diagram. Flow diagram of study patients and analyzed biospecimens processed through and selected for central sequencing using MSK-IMPACT and Guardant360. cfDNA, cell-free DNA; FFPE, formalin-fixed paraffin-embedded; MSK-IMPACT, Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets; QC, quality control.

Supplementary Table S2. Sym004 pharmacokinetic derived measures - dose-escalation and dose-expansion cohorts.

Supplementary Figure S1. Pharmacokinetic profile of Sym004.

Tumor growth in the context of EGFR inhibitor resistance may remain EGFR-dependent and is mediated by mechanisms including compensatory ligand upregulation and de novo gene alterations. Sym004 is a two-antibody mixture targeting nonoverlapping EGFR epitopes. In preclinical models, Sym004 causes significant EGFR internalization and degradation, which translates into superior growth inhibition in the presence of ligands. In this phase I trial, we observed grade 3 skin toxicity and hypomagnesemia as mechanism-based dose-limiting events during dose escalation. In dose-expansion cohorts of 9 and 12 mg/kg of Sym004 weekly, patients with metastatic colorectal cancer and acquired EGFR inhibitor resistance were enrolled; 17 of 39 patients (44%) had tumor shrinkage, with 5 patients (13%) achieving partial response. Pharmacodynamic studies confirmed marked Sym004-induced EGFR downmodulation. MET gene amplification emerged in 1 patient during Sym004 treatment, and a partial response was seen in a patient with EGFRS492R mutation that is predictive of cetuximab resistance.Significance: Potent EGFR downmodulation with Sym004 in patients with metastatic colorectal cancer and acquired resistance to cetuximab/panitumumab translates into significant antitumor activity and validates the preclinical hypothesis that a proportion of tumors remains dependent on EGFR signaling. Further clinical development and expanded correlative analyses of response patterns with secondary RAS/EGFR mutations are warranted. Cancer Discov; 5(6);598–609. ©2015 AACR.See related commentary by Stintzing and Heinemann, p. 578This article is highlighted in the In This Issue feature, p. 565

HER2 mutations define a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversible pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with HER2-mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER+ patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating HER2 or HER3 alterations were associated with poor treatment outcome. Similarly, acquisition of multiple HER2-activating events, as well as gatekeeper alterations, were observed at disease progression in a high proportion of patients deriving clinical benefit from neratinib. Collectively, these data define HER2 mutations as a therapeutic target in breast cancer and suggest that coexistence of additional HER signaling alterations may promote both de novo and acquired resistance to neratinib.Significance:HER2 mutations define a targetable breast cancer subset, although sensitivity to irreversible HER kinase inhibition appears to be modified by the presence of concurrent activating genomic events in the pathway. These findings have implications for potential future combinatorial approaches and broader therapeutic development for this genomically defined subset of breast cancer.This article is highlighted in the In This Issue feature, p. 161

Supplementary data

Purpose: We evaluated the influence of RAS mutation status on the treatment effect of panitumumab in a prospective–retrospective analysis of a randomized, multicenter phase III study of panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) versus FOLFIRI alone as second-line therapy in patients with metastatic colorectal cancer (mCRC; ClinicalTrials.gov, NCT0039183).Experimental Design: Outcomes were from the study's primary analysis. RAS mutations beyond KRAS exon 2 (KRAS exons 3, 4; NRAS exons 2, 3, 4; BRAF exon 15) were detected by bidirectional Sanger sequencing in wild-type KRAS exon 2 tumor specimens. Progression-free survival (PFS) and overall survival (OS) were coprimary endpoints.Results: The RAS ascertainment rate was 85%; 18% of wild-type KRAS exon 2 tumors harbored other RAS mutations. For PFS and OS, the hazard ratio (HR) for panitumumab plus FOLFIRI versus FOLFIRI alone more strongly favored panitumumab in the wild-type RAS population than in the wild-type KRAS exon 2 population [PFS HR, 0.70 (95% confidence interval [CI], 0.54–0.91); P = 0.007 vs. 0.73 (95% CI, 0.59–0.90); P = 0.004; OS HR, 0.81 (95% CI, 0.63–1.03); P = 0.08 vs. 0.85 (95% CI, 0.70–1.04); P = 0.12]. Patients with RAS mutations were unlikely to benefit from panitumumab. Among RAS wild-type patients, the objective response rate was 41% in the panitumumab–FOLFIRI group versus 10% in the FOLFIRI group.Conclusions: Patients with RAS mutations were unlikely to benefit from panitumumab–FOLFIRI and the benefit–risk of panitumumab–FOLFIRI was improved in the wild-type RAS population compared with the wild-type KRAS exon 2 population. These findings support RAS testing for patients with mCRC. Clin Cancer Res; 21(24); 5469–79. ©2015 AACR.See related commentary by Salazar and Ciardiello, p. 5415

Supplementary Table 1. Hits from the dalotuzumab enhancer screen. Supplementary Table 2. Patient and disease characteristics. Supplementary Table 3. Summary of dose-limiting toxicities. Supplementary Table 4. Summary of clinical efficacy in breast cancer patients.

PDF file 155K, Principal component analysis (PCA) of the ten biomarkers provides a biomarker profile for each cell line

Study disposition

PDF file 285K, Biomarker validation by Western blot

PDF file 252K, In vivo pharmacodynamic IHC-based biomarker dose-response quantifications

PDF file 64K, Unsupervised clustering of the core biomarker modulation in cell lines, xenograft tumors, and in tumors from three patients in the 100mg cohort

Participant PIK3CA-mutation central testing results

Supplementary Figure 1. Treatment and pharmacodynamic assessment schedules.

Purpose: Mammalian target of rapamycin (mTOR) inhibition activates compensatory insulin–like growth factor receptor (IGFR) signaling. We evaluated the ridaforolimus (mTOR inhibitor) and dalotuzumab (anti-IGF1R antibody) combination.Experimental Design:In vitro and in vivo models, and a phase I study in which patients with advanced cancer received ridaforolimus (10–40 mg/day every day × 5/week) and dalotuzumab (10 mg/kg/week or 7.5 mg/kg/every other week) were explored.Results: Preclinical studies demonstrated enhanced pathway inhibition with ridaforolimus and dalotuzumab. With 87 patients treated in the phase I study, main dose-limiting toxicities (DLT) of the combination were primarily mTOR-related stomatitis and asthenia at doses of ridaforolimus lower than expected, suggesting blockade of compensatory pathways in normal tissues. Six confirmed partial responses were reported (3 patients with breast cancer); 10 of 23 patients with breast cancer and 6 of 11 patients with ER+/high-proliferative breast cancer showed antitumor activity.Conclusions: Our study provides proof-of-concept that inhibiting the IGF1R compensatory response to mTOR inhibition is feasible with promising clinical activity in heavily pretreated advanced cancer, particularly in ER+/high-proliferative breast cancer (ClinicalTrials.gov identifier: NCT00730379). Clin Cancer Res; 21(1); 49–59. ©2014 AACR.

Primers obtained from PrimerBank database.

PDF file 168K, Pearson and Spearman correlation with survival fraction for all cell lines together or individual cell lines

XLS file 37K, RPPA quantification of laser captured microscopy needle biopsies in patients from the 100mg cohort

Purpose: The oncogenic PI3K/Akt/mTOR pathway is an attractive therapeutic target in cancer. However, it is unknown whether the pathway blockade required for tumor growth inhibition is clinically achievable. Therefore, we conducted pharmacodynamic studies with GDC-0068, an ATP competitive, selective Akt1/2/3 inhibitor, in preclinical models and in patients treated with this compound.Experimental Design: We used a reverse phase protein array (RPPA) platform to identify a biomarker set indicative of Akt inhibition in cell lines and human-tumor xenografts, and correlated the degree of pathway inhibition with antitumor activity. Akt pathway activity was measured using this biomarker set in pre- and post-dose tumor biopsies from patients treated with GDC-0068 in the dose escalation clinical trial.Results: The set of biomarkers of Akt inhibition is composed of 10 phosphoproteins, including Akt and PRAS40, and is modulated in a dose-dependent fashion, both in vitro and in vivo. In human-tumor xenografts, this dose dependency significantly correlated with tumor growth inhibition. Tumor biopsies from patients treated with GDC-0068 at clinically achievable doses attained a degree of biomarker inhibition that correlated with tumor growth inhibition in preclinical models. In these clinical samples, compensatory feedback activation of ERK and HER3 was observed, consistent with preclinical observations.Conclusion: This study identified a set of biomarkers of Akt inhibition that can be used in the clinical setting to assess target engagement. Here, it was used to show that robust Akt inhibition in tumors from patients treated with GDC-0068 is achievable, supporting the clinical development of this compound in defined patient populations. Clin Cancer Res; 19(24); 6976–86. ©2013 AACR.

Purpose: Insulin-like growth factor-1 receptor (IGF-1R) mediates cellular processes in cancer and has been proposed as a therapeutic target. Dalotuzumab (MK-0646) is a humanized IgG1 monoclonal antibody that binds to IGF-1R preventing receptor activation. This study was designed to evaluate the safety and tolerability of dalotuzumab, determine the pharmacokinetic (PK) and pharmacodynamic (PD) profiles, and identify a recommended phase II dose.Experimental Design: Patients with tumors expressing IGF-1R protein were allocated to dose-escalating cohorts of three or more patients each and received intravenous dalotuzumab weekly, every 2 or 3 weeks. Plasma was collected for PK analysis. Paired baseline and on-treatment skin and tumor biopsy samples were collected for PD analyses.Results: Eighty patients with chemotherapy-refractory solid tumors were enrolled. One dose-limiting toxicity was noted, but a maximum-tolerated dose was not identified. Grade 1 to 3 hyperglycemia, responsive to metformin, occurred in 15 (19%) patients. At dose levels or more than 5 mg/kg, dalotuzumab mean terminal half-life was 95 hours or more, mean Cmin was more than 25 μg/mL, clearance was constant, and serum exposures were approximately dose proportional. Decreases in tumor IGF-1R, downstream receptor signaling, and Ki67 expression were observed. 18F-Fluorodeoxy-glucose positron emission tomography metabolic responses occurred in three patients. One patient with Ewing's sarcoma showed a mixed radiologic response. The recommended phase II doses were 10, 20, and 30 mg/kg for the weekly, every other week, and every third week schedules, respectively.Conclusions: Dalotuzumab was generally well-tolerated, exhibited dose-proportional PK, inhibited IGF-1R pathway signaling and cell proliferation in treated tumors, and showed clinical activity. The low clearance rate and long terminal half-life support more extended dosing intervals. Clin Cancer Res; 17(19); 6304–12. ©2011 AACR.