Empagliflozin and Dapagliflozin Improve Endothelial Function in Mexican Patients with Type 2 Diabetes Mellitus: A Double-Blind Clinical Trial.

AIM: To assess the acute effect of empagliflozin versus dapagliflozin administration on flow-mediated vasodilation in patients with type 2 diabetes mellitus. DESIGN: A double-blind clinical trial, at the Experimental and Clinical Therapeutics Institute, University Health Sciences Center, at the Universidad de Guadalajara, in inpatients with T2D according to the 2023 ADA criteria. METHODS: Thirty patients (15 males and 15 females), aged between 35 and 65 years, were included in this study, according to the 2023 ADA criteria. The eligible patients were randomly assigned to three groups: empagliflozin 25 mg once daily, dapagliflozin 10 mg once daily, or placebo once daily. Anthropometric parameters were taken using validated techniques. FMD was measured using a high-resolution semiautomatic ultrasound UNEX-EF 38G (UNEX Co., Ltd., Nagoya, Japan). Arterial tension was determined with the OMRON electronic digital sphygmomanometer (HEM 907 XL, Kyoto, Japan). RESULTS: The group of patients who received empagliflozin had a significantly lower baseline flow-mediated dilation (FMD) compared to the group receiving dapagliflozin (p = 0.017); at the end of this study, the empagliflozin group achieved a comparable FMD to the dapagliflozin group (p = 0.88). CONCLUSION: After the treatment period, the empagliflozin and dapagliflozin groups achieved similar FMD, suggesting a class effect.

Primary Small-Cell Carcinoma of the Urinary Bladder: A Case Report and Literature Review.

Small-cell carcinoma of the bladder (SCCB) is an uncommon and aggressive malignancy of the urinary tract. Its clinical presentation often mimics that of other bladder neoplasms, posing a diagnostic challenge. This case report presents a rare instance of SCCB in a 65-year-old female, shedding light on the diagnostic journey and emphasizing the need for heightened and prompt clinical suspicion due to its aggressive nature. The patient presented to the urological department with hematuria, dysuria, and hypogastric pain. Initial investigations revealed a bladder mass, prompting biopsies with inconclusive results. A comprehensive histopathological examination, including immunohistochemistry, confirmed a SCCB. A computed tomography (CT) scan was used to evaluate local and distal extention. Following the initial evaluation, a referral to an oncological service was needed. Diagnoses encompassed SCCB, with interventions that comprise chemotherapy without radical cystectomy. Despite the rarity of SCCB, timely and accurate diagnosis facilitated a tailored multidisciplinary approach, leading to prompt clinical oncology management. This case demonstrates the importance of meticulous diagnostic evaluation in rare malignancies, guiding individualized therapeutic strategies for optimal patient outcomes.

X-Ray Visible Protein Scaffolds by Bulk Iodination.

Protein-based biomaterial use is expanding within medicine, together with the demand to visualize their placement and behavior in vivo. However, current medical imaging techniques struggle to differentiate between protein-based implants and surrounding tissue. Here a fast, simple, and translational solution for tracking transplanted protein-based scaffolds is presented using X-ray CT-facilitating long-term, non-invasive, and high-resolution imaging. X-ray visible scaffolds are engineered by selectively iodinating tyrosine residues under mild conditions using readily available reagents. To illustrate translatability, a clinically approved hernia repair mesh (based on decellularized porcine dermis) is labeled, preserving morphological and mechanical properties. In a mouse model of mesh implantation, implants retain marked X-ray contrast up to 3 months, together with an unchanged degradation rate and inflammatory response. The technique's compatibility is demonstrated with a range of therapeutically relevant protein formats including bovine, porcine, and jellyfish collagen, as well as silk sutures, enabling a wide range of surgical and regenerative medicine uses. This solution tackles the challenge of visualizing implanted protein-based biomaterials, which conventional imaging methods fail to differentiate from endogenous tissue. This will address previously unanswered questions regarding the accuracy of implantation, degradation rate, migration, and structural integrity, thereby accelerating optimization and safe translation of therapeutic biomaterials.

YKL-40 serum levels are predicted by inflammatory state, age and diagnosis of idiopathic inflammatory myopathies.

YKL-40 increase according to the aging process, and its functions have been associated with tissue remodeling and systemic inflammation. In Rheumatoid Arthritis (RA) it has been proposed as a possible biomarker of activity and severity, however; in the field of idiopathic inflammatory myopathies (IIM) the role of YKL-40 in IIM is not clear. Thus, we aimed to evaluate if there is an association between the serum levels and muscle tissue expression of YKL-40 with age, IIM phenotype, muscle strength and myositis disease activity. The main finding was that age is the most important variable that affects the YKL-40 serum levels. In muscle biopsy, we observed that YKL-40 is mainly expressed in infiltrating lymphoid cells than in muscle tissue. Using ANCOVA according to the b-coefficients, YKL-40 serum levels are predicted by inflammatory state, age, and IIM diagnosis.

Effect of antiretroviral therapy on decreasing arterial stiffness, metabolic profile, vascular and systemic inflammatory cytokines in treatment-naïve HIV: A one-year prospective study.

INTRODUCTION: Cardiovascular disease is a major cause of death among people living with HIV (PLH). Non-treated PLH show increased levels of inflammation and biomarkers of vascular activation, and arterial stiffness as a prognostic cardiovascular disease risk factor. We investigated the effect of one year of ART on treatment-naïve HIV(+) individuals on arterial stiffness and inflammatory and vascular cytokines. METHODS: We cross-sectionally compared aortic stiffness via tonometry, inflammatory, and vascular serum cytokines on treatment-naïve (n = 20) and HIV (-) (n = 9) matched by age, sex, metabolic profile, and Framingham score. We subsequently followed young, treatment-naïve individuals after 1-year of ART and compared aortic stiffness, metabolic profile, and inflammatory and vascular serum biomarkers to baseline. Inflammatory biomarkers included: hs-CRP, D-Dimer, SAA, sCD163s, MCP-1, IL-8, IL-18, MRP8/14. Vascular cytokines included: myoglobin, NGAL, MPO, Cystatin C, ICAM-1, VCAM-1, and MMP9. RESULTS: Treatment-naïve individuals were 34.8 years old, mostly males (95%), and with high smoking prevalence (70%). Baseline T CD4+ was 512±324 cells/mcL. cfPWV was similar between HIV(-) and treatment-naïve (6.8 vs 7.3 m/s; p = 0.16) but significantly decreased after ART (-0.52 m/s; 95% CI -0.87 to -0.16; p0.006). Almost all the determined cytokines were significantly higher compared to controls, except for MCP-1, myoglobin, NGAL, cystatin C, and MMP-9. At follow-up, only total cholesterol and triglycerides increased and all inflammatory cytokines significantly decreased. Regarding vascular cytokines, MPO, ICAM-1, and VCAM-1 showed a reduction. D-Dimer tended to decrease (p = 0.06) and hs-CRP did not show a significant reduction (p = 0.17). CONCLUSION: One year of ART had a positive effect on reducing inflammatory and vascular cytokines and arterial stiffness.

An Exosome-based Transcriptomic Signature for Noninvasive, Early Detection of Patients With Pancreatic Ductal Adenocarcinoma: A Multicenter Cohort Study.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) incidence is rising worldwide, and most patients present with an unresectable disease at initial diagnosis. Measurement of carbohydrate antigen 19-9 (CA19-9) levels lacks adequate sensitivity and specificity for early detection; hence, there is an unmet need to develop alternate molecular diagnostic biomarkers for PDAC. Emerging evidence suggests that tumor-derived exosomal cargo, particularly micro RNAs (miRNAs), offer an attractive platform for the development of cancer-specific biomarkers. Herein, genomewide profiling in blood specimens was performed to develop an exosome-based transcriptomic signature for noninvasive and early detection of PDAC. METHODS: Small RNA sequencing was undertaken in a cohort of 44 patients with an early-stage PDAC and 57 nondisease controls. Using machine-learning algorithms, a panel of cell-free (cf) and exosomal (exo) miRNAs were prioritized that discriminated patients with PDAC from control subjects. Subsequently, the performance of the biomarkers was trained and validated in independent cohorts (n = 191) using quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. RESULTS: The sequencing analysis initially identified a panel of 30 overexpressed miRNAs in PDAC. Subsequently using qRT-PCR assays, the panel was reduced to 13 markers (5 cf- and 8 exo-miRNAs), which successfully identified patients with all stages of PDAC (area under the curve [AUC] = 0.98 training cohort; AUC = 0.93 validation cohort); but more importantly, was equally robust for the identification of early-stage PDAC (stages I and II; AUC = 0.93). Furthermore, this transcriptomic signature successfully identified CA19-9 negative cases (<37 U/mL; AUC = 0.96), when analyzed in combination with CA19-9 levels, significantly improved the overall diagnostic accuracy (AUC = 0.99 vs AUC = 0.86 for CA19-9 alone). CONCLUSIONS: In this study, an exosome-based liquid biopsy signature for the noninvasive and robust detection of patients with PDAC was developed.

Cognitive Outcomes in Congenital Hypothyroidism: Impact of Socioeconomic Status - A Case-Control Study.

OBJECTIVE: Chile is one of the few high-income countries in Latin America, being a pioneer in implementing a national newborn screening (NBS) program in 1992. Currently, it covers 98% of the population, but no long-term outcomes have been described so far. The aim of this study was to report the neurocognitive outcomes of children with congenital hypothyroidism (CH) diagnosed by the NBS program in Chile between 2005 and 2012 and to identify variables associated with the outcomes. METHODS: We performed a case-control study in children with CH born in the two largest regions of the country. The Leiter-R and TEVI-R tests were administered at home to 69 children with CH and 68 matched control subjects. Other variables affecting cognition were obtained. Multivariate logistic regression analyses were performed for Leiter-R and TEVI-R tests, using a model for cases alone and another model for cases and controls. RESULTS: No differences in Leiter-R and TEVI-R results were observed between children with CH and the control group. Children who performed better, regardless of whether they had CH, had a higher family income and more assets. CONCLUSIONS: These results suggest that the Chilean NBS program strategy results in children with normal language, attention, and memory development. Socioeconomic disadvantage represents a significant detriment in cognitive function.

A phase I, open-label study evaluating the safety and pharmacokinetics of trifluridine/tipiracil in patients with advanced solid tumors and varying degrees of renal impairment.

PURPOSE: Trifluridine/tipiracil (FTD/TPI) is approved for advanced colorectal and gastric/gastroesophageal cancer; however, data in patients with renal impairment (RI) are limited. This phase I study evaluated FTD/TPI in patients with advanced solid tumors and varying degrees of RI to develop dosing guidance. METHODS: Patients were enrolled into normal renal function (CrCl ≥ 90 mL/min), mild RI (CrCl 60-89 mL/min), or moderate RI (CrCl 30-59 mL/min) cohorts and administered the recommended FTD/TPI dose (35 mg/m2 twice daily, days 1-5 and 8-12; 28-day cycle). Based on interim pharmacokinetics/safety data, patients with severe RI (CrCl 15-29 mL/min) were enrolled and received FTD/TPI 20 mg/m2 twice daily. RESULTS: Forty-three patients (normal renal function [n = 12]; mild RI [n = 12]; moderate RI [n = 11]; severe RI [n = 8]) were enrolled and treated. At steady state, compared to values in patients with normal renal function, FTD area under the curve (AUC) was not significantly different in patients with RI, but TPI AUC was significantly higher and increased with RI severity. FTD/TPI safety profile was consistent with prior experience, but grade ≥ 3 adverse events (AEs) were more frequent in the RI cohorts (83.3% [mild], 90.9% [moderate], 75.0% [severe], and normal [50.0%]). Hematologic AEs (anemia and neutropenia) were more frequent with RI. Overall, seven patients discontinued because of unrelated, nonhematologic AEs. CONCLUSION: FTD/TPI is safe and tolerable at the recommended 35 mg/m2 dose in patients with mild/moderate RI and at the reduced 20 mg/m2 dose in patients with severe RI. TRIAL REGISTRATION: NCT02301117, registration date: November 21, 2014.

Analysis of recurrently protected genomic regions in cell-free DNA found in urine.

Cell-free DNA (cfDNA) in urine is a promising analyte for noninvasive diagnostics. However, urine cfDNA is highly fragmented. Whether characteristics of these fragments reflect underlying genomic architecture is unknown. Here, we characterized fragmentation patterns in urine cfDNA using whole-genome sequencing. Size distribution of urine cfDNA fragments showed multiple strong peaks between 40 and 120 base pairs (bp) with a modal size of 81- and sharp 10-bp periodicity, suggesting transient protection from complete degradation. These properties were robust to preanalytical perturbations, such as at-home collection and delay in processing. Genome-wide sequencing coverage of urine cfDNA fragments revealed recurrently protected regions (RPRs) conserved across individuals, with partial overlap with nucleosome positioning maps inferred from plasma cfDNA. The ends of cfDNA fragments clustered upstream and downstream of RPRs, and nucleotide frequencies of fragment ends indicated enzymatic digestion of urine cfDNA. Compared to plasma, fragmentation patterns in urine cfDNA showed greater correlation with gene expression and chromatin accessibility in epithelial cells of the urinary tract. We determined that tumor-derived urine cfDNA exhibits a higher frequency of aberrant fragments that end within RPRs. By comparing the fraction of aberrant fragments and nucleotide frequencies of fragment ends, we identified urine samples from cancer patients with an area under the curve of 0.89. Our results revealed nonrandom genomic positioning of urine cfDNA fragments and suggested that analysis of fragmentation patterns across recurrently protected genomic loci may serve as a cancer diagnostic.

Interleukin-6 as a Biomarker of Early-Onset Neonatal Sepsis.

OBJECTIVE: The aim of this study is to determine the utility of C reactive protein (CRP) and interleukin (IL)-6 in the diagnosis of neonatal sepsis (NS) in a neonatal intensive care unit (NICU) in the south of Colombia. STUDY DESIGN: A nonmatched case-control study was conducted. Convenience sampling was performed. Data were obtained from clinical records. IL-6 levels were determined using enzyme-linked immunosorbent assay. Receiver operator characteristic (ROC) curve analysis and Youden's index were used to determine the optimal cutoffs for CRP and IL-6 levels in diagnosing NS, early-onset NS (EONS), and late-onset NS (LONS). RESULTS: Data from 31 cases and 62 controls were included. History of chorioamnionitis (infinite odds ratio [OR] [3.07-infinity]), and the presence of meconium-stained amniotic fluid during birth (OR: 9.04 [1.35-112]) were identified as risk factors for NS. Differences in CRP (p < 0.0001) and IL-6 (p < 0.0485) levels were also found, more significantly for LONS and EONS patients, respectively. In the diagnosis of LONS using CRP levels, the area under the ROC curve (AUC) was 0.8371 (p < 0.0001). The optimal cutoff was 0.53 mg/dL. For EONS diagnosis using IL-6, the AUC was 0.6869 (p = 0.0315) and the optimal cutoff was 17.75 pg/mL. CONCLUSION: Differences between CRP and IL-6 levels were found between control and NS groups. Furthermore, CRP showed greater potential diagnostic utility in the LONS group, whereas IL-6 showed greater potential utility in the EONS group. KEY POINTS: · NS is a major morbimortality cause worldwide. · CRP and IL-6 levels may be useful NS biomarkers. · No biomarker alone is enough for the diagnosis of NS.

Abemaciclib in Combination With Endocrine Therapy for Patients With Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: A Phase 1b Study.

BACKGROUND: Cyclin-dependent kinases (CDK) 4 and 6 regulate G1 to S cell cycle progression and are often altered in cancers. Abemaciclib is a selective inhibitor of CDK4 and CDK6 approved for administration on a continuous dosing schedule as monotherapy or as combination therapy with an aromatase inhibitor or fulvestrant in patients with advanced or metastatic breast cancer. This Phase 1b study evaluated the safety and tolerability, pharmacokinetics, and antitumor activity of abemaciclib in combination with endocrine therapy for metastatic breast cancer (MBC), including aromatase inhibitors (letrozole, anastrozole, or exemestane) or tamoxifen. PATIENTS AND METHODS: Women ≥18 years old with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) MBC were eligible for enrollment. Eligibility included measurable disease or non-measurable but evaluable bone disease by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, Eastern Cooperative Oncology Group performance status 0-1, and no prior chemotherapy for metastatic disease. Adverse events were graded by the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 and tumor response were assessed by RECIST v1.1. RESULTS: Sixty-seven patients were enrolled and received abemaciclib 200 mg every 12 hours in combination with letrozole (Part A, n=20), anastrozole (Part B, n=16), tamoxifen (Part C, n=16), or exemestane (Part D, n=15). The most common treatment-emergent adverse events (TEAE) were diarrhea, fatigue, nausea, and abdominal pain. Grade 4 TEAEs were reported in five patients (one each with hyperglycemia, hypertension, neutropenia, procedural hemorrhage, and sepsis). There was no effect of abemaciclib or endocrine therapy on the pharmacokinetics of any combination study drug. Across all treated patients, the median progression-free survival was 25.4 months (95% confidence interval: 18.0, 35.8). The objective response rate was 38.9% in 36 patients with measurable disease. CONCLUSIONS: Abemaciclib in combination with multiple endocrine therapy options exhibited manageable safety and promising antitumor activity in patients with HR+, HER2- MBC. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/, identifier NCT02057133.

A Phase Ib multicenter, dose-escalation study of the polyamine analogue PG-11047 in combination with gemcitabine, docetaxel, bevacizumab, erlotinib, cisplatin, 5-fluorouracil, or sunitinib in patients with advanced solid tumors or lymphoma.

PURPOSE: Polyamines are absolutely essential for maintaining tumor cell proliferation. PG-11047, a polyamine analogue, is a nonfunctional competitor of the natural polyamine spermine that has demonstrated anticancer activity in cells and animal models of multiple cancer types. Preclinical investigations into the effects of common chemotherapeutic agents have revealed overlap with components of the polyamine metabolic pathway also affected by PG-11047. This report describes a Phase Ib clinical trial investigating PG-11047 in combination with cytotoxic and anti-angiogenic chemotherapeutic agents in patients with advanced refractory metastatic solid tumors or lymphoma. METHODS: A total of 172 patients were assigned to treatment arms based on cancer type to receive the appropriate standard-of-care therapy (gemcitabine, docetaxel, bevacizumab, erlotinib, cisplatin, 5-fluorouracil (5-FU), or sunitinib as directed) along with once weekly intravenous infusions of PG-11047. PG-11047 dose escalation ranged from 50 to 590 mg. RESULTS: The maximum tolerated dose (MTD) of PG-11047 in combination with bevacizumab, erlotinib, cisplatin, and 5-FU was 590 mg. Dose-limiting toxicities (DLTs) in these groups were rare (5 of 148 patients). Overall partial responses (PR) were observed in 12% of patients treated with PG-11047 and bevacizumab, with stable disease documented in an additional 40%. Stable disease occurred in 71.4% of patients in the 5-FU arm, 54.1% in the cisplatin arm, and 33.3% in the erlotinib arm. Four of the patients receiving cisplatin + PG-11047 (20%) had unconfirmed PRs. MTDs for gemcitabine, docetaxel, and sunitinib could not be determined due to DLTs at low doses of PG-11047 and small sample size. CONCLUSIONS: Results of this Phase Ib trial indicate that PG-11047 can be safely administered to patients in combination with bevacizumab, erlotinib, cisplatin, and 5-FU on the once weekly dosing schedule described and may provide therapeutic benefit. The manageable toxicity profile and high MTD determination provide a safety profile for further clinical studies.

Aortic stiffness and central hemodynamics in treatment-naïve HIV infection: a cross-sectional study.

BACKGROUND: Human immunodeficiency virus (HIV) infection is associated with a greater risk of cardiovascular disease (CVD). HIV infection causes a chronic inflammatory state and increases oxidative stress which can cause endothelial dysfunction and arterial stiffness. Aortic stiffness measured by carotid femoral-pulse wave velocity (cfPWV) and central hemodynamics are independent cardiovascular risk factors and have the prognostic ability for CVD. We assessed cfPWV and central hemodynamics in young individuals with recent HIV infection diagnosis and without antiretroviral therapy. We hypothesized that individuals living with HIV would present greater cfPWV and central hemodynamics (central systolic blood pressure and pulse pressure) compared to uninfected controls. METHODS: We recruited 51 treatment-naïve individuals living with HIV (HIV(+)) without previous CVD and 51 age- and sex-matched controls (HIV negative (-)). We evaluated traditional CVD risk factors including metabolic profile, blood pressure (BP), smoking, HIV viral load, and CD4+ T-cells count. Arterial stiffness and central hemodynamics were evaluated by cfPWV, central systolic BP, and central pulse pressure (cPP) via applanation tonometry. RESULTS: HIV(+) individuals presented a greater prevalence of smoking, reduced high-density lipoprotein cholesterol, and body mass index. 65.9% of HIV(+) individuals exhibited lymphocyte CD4+ T-cells count < 500 cells/µL. There was no difference in brachial or central BP between groups; however, HIV(+) individuals showed significantly lower cPP. We observed a greater cfPWV (mean difference = 0.5 m/s; p < 0.01) in HIV(+) compared to controls, even after adjusting for heart rate, mean arterial pressure and smoking. CONCLUSION: In the early stages of infection, non-treated HIV individuals present a greater prevalence of traditional CVD risk factors, arterial stiffness, and normal or in some cases central hemodynamics.

Phase Ib clinical trial of the anti-frizzled antibody vantictumab (OMP-18R5) plus paclitaxel in patients with locally advanced or metastatic HER2-negative breast cancer.

PURPOSE: Vantictumab is a monoclonal antibody that binds to frizzled (FZD) receptors and inhibits canonical WNT signaling. This phase Ib dose escalation study enrolled patients with locally recurrent or metastatic HER2-negative breast cancer who were treated with weekly paclitaxel in combination with escalating doses of vantictumab. METHODS: Patients were enrolled in dose escalation cohorts treated with weekly paclitaxel 90 mg/m2 on days 1, 8 and 15 in combination with vantictumab 3.5-14 mg/kg days 1 and 15 or 3-8 mg/kg day 1 of every 28-day cycle. Primary endpoints were safety, dose-limiting toxicities (DLTs). Secondary endpoints included pharmacokinetics, efficacy and an exploratory biomarker analysis. RESULTS: Forty-eight female patients with a mean age of 54 were enrolled. The majority (66.6%) received prior chemotherapy for recurrent or metastatic disease; 45.8% were hormone receptor (HR)-positive, HER2-negative and 54.2% triple-negative. The most frequent adverse events related to any study treatment were nausea (54.2%), alopecia (52.1%), fatigue (47.9%), and peripheral neuropathy (43.8%). No DLTs occurred; however, 6 patients experienced fractures outside of the DLT window. The overall response rate was 31.3% and the clinical benefit rate was 68.8%. A 6-gene WNT pathway signature showed significant association with progression-free survival (PFS) and overall survival (OS) for the biomarker high versus biomarker low groups (PFS: p = 0.029 and OS: p = 0.00045, respectively). CONCLUSIONS: The combination of vantictumab and weekly paclitaxel was generally well tolerated with promising efficacy; however, the incidence of fractures limits future clinical development of this particular WNT inhibitor in metastatic breast cancer. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov registration: NCT01973309.

Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours.

BACKGROUND: In this first-in-human, Phase 1 study of a microRNA-based cancer therapy, the recommended Phase 2 dose (RP2D) of MRX34, a liposomal mimic of microRNA-34a (miR-34a), was determined and evaluated in patients with advanced solid tumours. METHODS: Adults with various solid tumours refractory to standard treatments were enrolled in 3 + 3 dose-escalation cohorts and, following RP2D determination, expansion cohorts. MRX34, with oral dexamethasone premedication, was given intravenously daily for 5 days in 3-week cycles. RESULTS: Common all-cause adverse events observed in 85 patients enrolled included fever (% all grade/G3: 72/4), chills (53/14), fatigue (51/9), back/neck pain (36/5), nausea (36/1) and dyspnoea (25/4). The RP2D was 70 mg/m2 for hepatocellular carcinoma (HCC) and 93 mg/m2 for non-HCC cancers. Pharmacodynamic results showed delivery of miR-34a to tumours, and dose-dependent modulation of target gene expression in white blood cells. Three patients had PRs and 16 had SD lasting ≥4 cycles (median, 19 weeks, range, 11-55). CONCLUSION: MRX34 treatment with dexamethasone premedication demonstrated a manageable toxicity profile in most patients and some clinical activity. Although the trial was closed early due to serious immune-mediated AEs that resulted in four patient deaths, dose-dependent modulation of relevant target genes provides proof-of-concept for miRNA-based cancer therapy. CLINICAL TRIAL REGISTRATION: NCT01829971.

Phase I dose-escalation trial of the oral AKT inhibitor uprosertib in combination with the oral MEK1/MEK2 inhibitor trametinib in patients with solid tumors.

PURPOSE: This study aimed to determine the safety, tolerability, and recommended phase II doses of trametinib plus uprosertib (GSK2141795) in patients with solid tumors likely to be sensitive to MEK and/or AKT inhibition. METHODS: This was a phase I, open-label, dose-escalation, and dose-expansion study in patients with triple-negative breast cancer or BRAF-wild type advanced melanoma. The primary outcome of the expansion study was investigator-assessed response. Among 126 enrolled patients, 63 received continuous oral daily dosing of trametinib and uprosertib, 29 received various alternative dosing schedules, and 34 were enrolled into expansion cohorts. Doses tested in the expansion cohort were trametinib 1.5 mg once daily (QD) + uprosertib 50 mg QD. RESULTS: Adverse events (AEs) were consistent with those reported in monotherapy studies but occurred at lower doses and with greater severity. Diarrhea was the most common dose-limiting toxicity; diarrhea and rash were particularly difficult to tolerate. Overall, 59% and 6% of patients reported AEs with a maximum severity of grade 3 and 4, respectively. Poor tolerability prevented adequate delivery of uprosertib with trametinib at a concentration predicted to have clinical activity. The study was terminated early based on futility in the continuous-dosing expansion cohorts and a lack of pharmacological or therapeutic advantage with intermittent dosing. The objective response rate was < 5% (1 complete response, 5 partial responses). CONCLUSIONS: Continuous and intermittent dosing of trametinib in combination with uprosertib was not tolerated, and minimal clinical activity was observed in all schedules tested.

Variable association of 24-h peripheral and central hemodynamics and stiffness with hypertension-mediated organ damage: the VASOTENS Registry.

OBJECTIVE: In this analysis of the telehealth-based Vascular health ASsessment Of The hypertENSive patients Registry, we checked how 24-h central and peripheral hemodynamics compare with hypertension-mediated organ damage (HMOD). METHODS: In 646 hypertensive patients (mean age 52 ±â€Š16 years, 54% males, 65% treated) we obtained ambulatory brachial and central SBP and pulse pressure (PP), SBP, and PP variability, pulse wave velocity and augmentation index with a validated cuff-based technology. HMOD was defined by an increased left ventricular mass index (cardiac damage, evaluated in 482 patients), an increased intima-media thickness (vascular damage, n = 368), or a decreased estimated glomerular filtration rate or increased urine albumin excretion (renal damage, n = 388). RESULTS: Ambulatory SBP and PPs were significantly associated with cardiac damage: the largest odds ratio was observed for 24-h central SBP [1.032 (1.012, 1.051), P = 0.001] and PP [1.042 (1.015, 1.069), P = 0.002], the weakest for brachial estimates. The association was less strong for vascular damage with a trend to the superiority of 24-h central [1.036 (0.997, 1.076), P = 0.070] over brachial PP [1.031 (1.000, 1.062), P = 0.052]. No statistically significant association was observed for renal damage. SBP and PP variabilities, pulse wave velocity and augmentation index were not associated with any form of HMOD. In the multivariate analysis, age was associated with any type of HMOD, whereas central SBP and PP were predictive of an increased risk of cardiac damage. CONCLUSION: In hypertensive patients a variable association exists between peripheral and central hemodynamics and various types of HMOD, with the most predictive power being observed for central SBP and PP for cardiac damage.

Sepsis neonatal: aspectos fisiopatológicos y biomarcadores / Neonatal sepsis: physiopathology and biomarkers

Resumen La sepsis neonatal es una causa importante de morbilidad y mortalidad en recién nacidos a nivel mundial. Su diagnóstico es difícil por sus manifestaciones clínicas inespecíficas y la poca disponibilidad de métodos diagnósticos eficientes. En la fisiopatología de la sepsis se ha descrito una respuesta inmune excesiva o suprimida que puede conducir a desenlaces potencialmente fatales. Se ha estudiado la utilidad pronóstica, diagnóstica y de seguimiento de factores solubles que se alteran en la sepsis neonatal y se han agrupado bajo el término biomarcadores de sepsis neonatal. Aquí se describen los principios fisiopatológicos de la sepsis neonatal y las características de los biomarcadores más usados para su diagnóstico, además, se mencionan detalles de otros marcadores que también han sido estudiados recientemente. Actualmente, se recomienda el uso de un biomarcador temprano en combinación con uno tardío para lograr un mejor rendimiento, sin embargo, aún no se ha identificado un biomarcador ideal para la sepsis neonatal. MÉD.UIS.2019;32(3):35-47

Abstract Neonatal sepsis is a major cause of morbidity and mortality in newborns worldwide. Its diagnosis remains a challenge due to the nonspecific clinical findings and the lack of efficient diagnostic tools. In the physiopathology of neonatal sepsis, an excessive or suppressed immune response has been described, which can lead to potentially fatal conditions. The prognostic, diagnostic, and follow-up value of several soluble factors altered in neonatal sepsis has been studied. These have been grouped under the term neonatal sepsis biomarkers. Here, aspects of the physiopathology in neonatal sepsis and the characteristics of the most studied biomarkers used for neonatal sepsis diagnosis are described, also, details about other recently studied markers are mentioned. Currently, the use of an early-warning biomarker together with a late-warning biomarker is recommended to get higher diagnostic accuracy. However, a single ideal biomarker for neonatal sepsis has not been found yet. MÉD.UIS.2019;32(3):35-47

A phase Ib, open-label, dose-escalation study of the safety and pharmacology of taselisib (GDC-0032) in combination with either docetaxel or paclitaxel in patients with HER2-negative, locally advanced, or metastatic breast cancer.

PURPOSE: This open-label, phase Ib, dose-escalation, and dose-expansion study (NCT01862081) evaluated taselisib with a taxane in locally advanced or metastatic breast cancer (BC) and/or non-small cell lung cancer (NSCLC). METHODS: Patients received taselisib (2-6 mg tablet or 3-6 mg capsule) plus docetaxel or paclitaxel. Primary endpoints were safety, dose-limiting toxicities, maximum tolerated dose, and identification of a recommended phase II dose. Secondary endpoints included pharmacokinetics and antitumor activity assessment. RESULTS: Eighty patients (BC: 72; NSCLC: 7; BC/NSCLC: 1) were enrolled (docetaxel-receiving arms: 21; paclitaxel-receiving arms: 59). Grade ≥ 3 adverse events (AEs), serious AEs, and AEs leading to death were reported in 90.5%, 42.9%, and 14.3% of patients, respectively (docetaxel-receiving arms), and 78.9%, 40.4%, and 3.5% of patients, respectively (paclitaxel-receiving arms). Eight patients experienced dose-limiting toxicities. The maximum tolerated dose was exceeded with 3 mg taselisib (capsule) for 21 consecutive days plus 75 mg/m2 docetaxel and not exceeded with 6 mg taselisib (tablet) for 5 days on/2 days off plus 80 mg/m2 paclitaxel. Objective response rates and clinical benefit rates were 35.0% and 45.0%, respectively (docetaxel-receiving arms), and 20.4% and 27.8%, respectively (paclitaxel-receiving arms). Exposure for paclitaxel or docetaxel plus taselisib was consistent with the single agents. CONCLUSIONS: Taselisib in combination with a taxane has a challenging safety profile. Despite evidence of antitumor activity, the benefit-risk profile was deemed not advantageous. Further development is not planned.