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Treatments with two-small molecule tropomyosin receptor kinase B (trkB) ligands, 7,8 dihydroxyflavone (7,8 DHF) and deoxygedunin, were evaluated for their ability to promote the regeneration of cut axons in injured peripheral nerves in mice in which sensory and motor axons are marked by YFP. Peripheral nerves were cut and repaired with grafts from strain-matched, nonfluorescent donors and secured in place with fibrin glue. Lengths of profiles of regenerating YFP ⁺ axons were measured 2 wk later from confocal images. Axon regeneration was enhanced when the fibrin glue contained dilutions of 500-nM solution of either small-molecule trkB agonist. In mice in which the neurotrophin receptor trkB is knocked out selectively in neurons, axon regeneration is very weak, and topical treatment with 7,8 DHF had no effect on axon regeneration. Similar treatments with deoxygedunin had only a modest effect. In conditional BDNF knockout mice, topical treatments with either 7,8 DHF or deoxygedunin resulted in a reversal of the poor regeneration found in controls and produced significant enhancement of regeneration. In WT mice treated with 2 wk of daily i.p. injections of either 7,8 DHF or deoxygedunin (5 mg/kg), regenerating axon profiles were nearly twice as long as in controls. Restoration of direct muscle responses evoked by sciatic nerve stimulation to pretransection levels over an 8-wk survival period was found only in the treated mice. Treatments with either small-molecule trkB agonist enhanced axon regeneration and muscle reinnervation after peripheral nerve injuries.

Background: Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85% of the administered dose of fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients’ risk of fluoropyrimidine-related severe toxicity. Methods: The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 3 fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg’s False Discovery Rate (FDR) procedure was used. Results: FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR<0.0001), *2A rs3918290 A allele carriers (FDR<0.0001), and rs2297595 GG genotype carriers (FDR=0.0014). Neutropenia was the most common FAEs (28.5%). *6 rs1801160 (FDR<0.0001), and *2A rs3918290 (FDR=0.0004) variant alleles were significantly associated with time to neutropenia. Conclusions: This study adds evidence on the role of DPYD pharmacogenetics for safety of patients undergoing fluoropyrimidine-based chemotherapy.

Nowadays, treatment of metastatic breast cancer (MBC) has been enriched with novel therapeutical strategies. Metronomic chemotherapy (mCHT) is a continuous and frequent administration of chemotherapy at a lower dose and so whit less toxicity. Thus, this strategy could be attractive for elderly MBC patients. Aim of this analysis is to provide insights into mCHT’s activity in a real-life setting of elderly MBC patients. Data of patients ≥ 75 years old included in VICTOR-6 study were analyzed. VICTOR-6 is a multicentre, Italian, retrospective study, which collected data on mCHT in MBC patients treated between 2011 and 2016. A total of 112 patients were included. At the beginning of mCHT, median age was 81 years (75–98) and in 33% of the patients mCHT was the first line choice. Overall Response Rate (ORR) and Disease Control Rate (DCR) were 27.9% and 79.3%, respectively. Median PFS ranged between 7.6 and 9.1 months, OS between 14.1 and 18.5 months. The most relevant toxicity was the hematological one (24.1%); severe toxicity (grade 3–4) ranged from 0.9% for skin toxicity up to 8% for hematologic one. This is a large study about mCHT in elderly MBC patients, providing insights to be further investigated in this subgroup of frail patients.

The mismatch hypothesis suggests that students admitted through affirmative action have higher graduation rates at less selective institutions than at more selective ones (e.g., state universities as opposed to Ivy Leagues). This hypothesis has sparked debates in politics and education, prompting numerous empirical studies. However, a definitive conclusion has been elusive due to a lack of systematic, quantitative research. This meta-analysis synthesizes 65 effects (N = 526,679) and finds evidence contradicting the mismatch hypothesis. Results indicate that affirmative action students have higher graduation rates at selective institutions compared to less selective universities. The findings highlight important implications for inclusion and diversity in higher education.

Purpose The VICTOR-1 study demonstrated that the all-oral metronomic combination of vinorelbine and capecitabine is highly active and well tolerated in hormone receptor-positive/HER2-negative patients. The VICTOR-2 study was designed to confirm these results. Methods Patients received mVNR 40 mg three times a week and mCAPE 500 mg three times a day, continuously. The primary endpoint was the clinical benefit rate (CBR); secondary endpoints were toxicity, objective response rate (ORR), and progression-free survival (PFS). Results Eighty patients were evaluable for the primary efficacy analysis. Median age was 65.3 years; most patients had HR-positive tumors (65 %). The CBR was 45.7 % (95 % CI 28.8–63.4) and 51.1 % (95 % CI 35.8–66.3) in first- and ≥ second-line therapy, respectively. The ORR was 35.5 % in first-line (95 % CI 19.2–54.6) and 25.6 % in ≥second-line (95 % CI 13.5–41.2). The median duration of response was 11.3 and 6.4 months and PFS rates at 1 year were 24.3 and 22.2 %, respectively. In triple-negative breast cancer patients ( N  = 28, 35 %) a lower, but clinically relevant CBR (35.7, 95 % CI 18.6–55.9) was observed. The main toxicities per cycle were non-febrile neutropenia (1.1 %), hand-foot syndrome (1.0 %), nausea and vomiting (1.0 %), leucopenia (0.8 %), fatigue (0.7 %), and diarrhea (0.4 %). Conclusion The VICTOR-2 study confirms the clinical activity of mVNR and mCAPE in HER2-negative breast cancer patients, suggesting that the easy schedule of administration, which requires monthly blood tests and limits patients’ dependence on hospitals, and the low cost of the drugs are valuable elements, even for countries with limited access to innovative or expensive drugs.

The research on methods for radiochemical determination of alpha-emitting radioactive elements is constantly evolving, and is essentially focused on reducing sample analysis times and using increasingly less aggressive and polluting chemical reagents. Even the most widely used chromatographic resins can be dangerous for operators and for the environment, and researchers try as much as possible to reduce the quantities used. In particular, an attempt is made to reuse the chromatographic resins at least a second time, also considering the fact that these reagents can also be quite expensive for a test laboratory. The present study presents a radiochemical method for the simultaneous determination of alpha-emitting isotopes of thorium, uranium, plutonium, americium, and curium in agri-food matrices and water, using a single commercially available chromatographic resin that is used twice in the same analytical run. The method, designed for laboratories that need to analyze many matrices for radioactivity monitoring programs, has proven to be precise and accurate, achieving very high values of chemical yield (> 75% in solid matrices, > 90% in water) and z -scores lower than 2 in the context of two important international proficiency tests.

PurposeTriple-negative breast cancer (TNBC) represents a subtype of breast cancer which lacks the expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2): TNBC accounts for approximately 20% of newly diagnosed breast cancers and is associated with younger age at diagnosis, greater recurrence risk and shorter survival time. Therapeutic options are very scarce. Aim of the present analysis is to provide further insights into the clinical activity of metronomic chemotherapy (mCHT), in a real-life setting.MethodsWe used data included in the VICTOR-6 study for the present analysis. VICTOR-6 is an Italian multicentre retrospective cohort study, which collected data of metastatic breast cancer (MBC) patients who have received mCHT between 2011 and 2016. Amongst the 584 patients included in the study, 97 were triple negative. In 40.2% of the TNBC patients, mCHT was the first chemotherapy treatment, whereas 32.9% had received 2 or more lines of treatment for the metastatic disease. 45.4% out of 97 TNBC patients received a vinorelbine (VRL)-based regimen, which resulted in the most used type of mCHT, followed by cyclophosphamide (CTX)-based regimens (30.9%) and capecitabine (CAPE)-based combinations (22.7%).ResultsOverall response rate (ORR) and disease control rate (DCR) were 17.5% and 64.9%, respectively. Median progression free survival (PFS) and overall survival (OS) were 6.0 months (95% CI: 4.9–7.2) and 12.1 months (95% CI: 9.6–16.7). Median PFS was 6.9 months for CAPE-based regimens (95% CI: 5.0–18.4), 6.1 months (95% CI: 4.0–8.9) for CTX-based and 5.3 months (95% CI: 4.1–9.5) for VRL-based ones. Median OS was 18.2 months (95% CI: 9.1-NE) for CAPE-based regimens and 11.8 months for VRL- (95% CI: 9.3–16.7 and CTX-based ones (95%CI: 8.7–52.8). Tumour response, PFS and OS decreased proportionally in later lines.ConclusionThis analysis represents the largest series of TNBC patients treated with mCHT in a real-life setting and provides further insights into the advantages of using this strategy even in this poor prognosis subpopulation.

Moisture is transported in South America westward from the tropical Atlantic Ocean to the Amazon basin, and then southward toward the extratropics. A regional intensification of this circulation to the east of the Andes Mountains is called the South American low-level jet (SALLJ), with the strongest winds found over eastern Bolivia. SALLJ is present all year and channels moisture to the La Plata basin, which is analogous to the better-known Amazon basin in terms of its biological and habitat diversity, and far exceeds the latter in its economic importance to southern and central South America in terms of hydroelectricity and food production. The relatively small SALLJ spatial scale (compared with the density of the available sounding network) has a limited understanding of and modeling capability for any variations in the SALLJ intensity and structure as well as its possible relationship to downstream rainfall. The SALLJ Experiment (SALLJEX), aimed at describing many aspects of SALLJ, was carried out between 15 November 2002 and 15 February 2003 in Bolivia, Paraguay, central and northern Argentina, western Brazil, and Peru. Scientists, collaborators, students, National Meteorological Service personnel, and local volunteers from South American countries and the United States participated in SALLJEX activities in an unprecedented way, because SALLJEX was the most extensive meteorological field activity to date in subtropical South America, and was the first World Climate Research Program/Climate Variability and Prediction Program international campaign in South America. This paper describes the motivation for the field activity in the region, the special SALLJEX observations, and SALLJEX modeling and outreach activities. We also describe some preliminary scientific conclusions and discuss some of the remaining questions.

This study aims to assess the risk of severe forms of COVID-19, based on clinical, laboratory, and imaging markers in patients initially admitted to the ward. This is a retrospective observational study, with data from electronic medical records of inpatients, with laboratory confirmation of COVID-19, between March and September 2020, in a hospital from Juiz de Fora-MG, Brazil. Participants (n = 74) were separated into two groups by clinical evolution: those who remained in the ward and those who progressed to the ICU. Mann–Whitney U test was taken for continuous variables and the chi-square test or Fisher’s exact test for categorical variables. Comparing the proposed groups, lower values of lymphocytes (p = <0.001) and increases in serum creatinine (p = 0.009), LDH (p = 0.057), troponin (p = 0.018), IL-6 (p = 0.053), complement C4 (p = 0.040), and CRP (p = 0.053) showed significant differences or statistical tendency for clinical deterioration. The average age of the groups was 47.9 ± 16.5 and 66.5 ± 7.3 years (p = 0.001). Hypertension (p = 0.064), heart disease (p = 0.048), and COPD (p = 0.039) were more linked to ICU admission, as well as the presence of tachypnea on admission (p = 0.051). Ground-glass involvement >25% of the lung parenchyma or pleural effusion on chest CT showed association with evolution to ICU (p = 0.027), as well as bilateral opacifications (p = 0.030) when compared to unilateral ones. Laboratory, clinical, and imaging markers may have significant relation with worse outcomes and the need for intensive treatment, being helpful as predictive factors.

The cardiac action potential (AP) is vital for understanding healthy and diseased cardiac biology and drug safety testing. However, techniques for high throughput cardiac AP measurements have been limited. Here, we introduce a novel technique for reliably increasing the coupling of cardiomyocyte syncytium to planar multiwell microelectrode arrays, resulting in a stable, label-free local extracellular action potential (LEAP). We characterized the reliability and stability of LEAP, its relationship to the field potential, and its efficacy for quantifying AP morphology of human induced pluripotent stem cell derived and primary rodent cardiomyocytes. Rise time, action potential duration, beat period, and triangulation were used to quantify compound responses and AP morphology changes induced by genetic modification. LEAP is the first high throughput, non-invasive, label-free, stable method to capture AP morphology from an intact cardiomyocyte syncytium. LEAP can accelerate our understanding of stem cell models, while improving the automation and accuracy of drug testing.