A multicenter, randomized phase 2 study to establish combinations of CBP501, cisplatin and nivolumab for ≥3rd-line treatment of patients with advanced pancreatic adenocarcinoma.

BACKGROUND: There is no standard of care for ≥ 3rd-line treatment of metastatic pancreatic adenocarcinoma (PDAC). CBP501 is a novel calmodulin-binding peptide that has been shown to enhance the influx of platinum agents into tumor cells and tumor immunogenicity. This study aimed to (1) confirm efficacy of CBP501/cisplatin/nivolumab for metastatic PDAC observed in a previous phase 1 study, (2) identify combinations that yield 35% 3-month progression-free survival rate (3MPFS) and (3) define the contribution of CBP501 to the effects of combination therapy. METHODS: CBP501 16 or 25 mg/m2 (CBP(16) or CBP(25)) was combined with 60 mg/m2 cisplatin (CDDP) and 240 mg nivolumab (nivo), administered at 3-week intervals. Patients were randomized 1:1:1:1 to (1) CBP(25)/CDDP/nivo, (2) CBP(16)/CDDP/nivo, (3) CBP(25)/CDDP and (4) CDDP/nivo, with randomization stratified by ECOG PS and liver metastases. A Fleming two-stage design was used, yielding a one-sided type I error rate of 2.5% and 80% power when the true 3MPFS is 35%. RESULTS: Among 36 patients, 3MPFS was 44.4% in arms 1 and 2, 11.1% in arm 3% and 33.3% in arm 4. Two patients achieved a partial response in arm 1 (ORR 22.2%; none in other arms). Median PFS and OS were 2.4, 2.1, 1.5 and 1.5 months and 6.3, 5.3, 3.7 and 4.9 months, respectively. Overall, all treatment combinations were well tolerated. Most treatment-related adverse events were grade 1-2. CONCLUSIONS: The combination CBP(25)/(16)/CDDP/nivo demonstrated promising signs of efficacy and a manageable safety profile for the treatment of advanced PDAC. CLINICAL TRIAL REGISTRATION: NCT04953962.

Reactive Amine Functionalized Microelectrode Arrays Provide Short-Term Benefit but Long-Term Detriment to In Vivo Recording Performance.

Intracortical microelectrode arrays (MEAs) are used for recording neural signals. However, indwelling devices result in chronic neuroinflammation, which leads to decreased recording performance through degradation of the device and surrounding tissue. Coating the MEAs with bioactive molecules is being explored to mitigate neuroinflammation. Such approaches often require an intermediate functionalization step such as (3-aminopropyl)triethoxysilane (APTES), which serves as a linker. However, the standalone effect of this intermediate step has not been previously characterized. Here, we investigated the effect of coating MEAs with APTES by comparing APTES-coated to uncoated controls in vivo and ex vivo. First, we measured water contact angles between silicon uncoated and APTES-coated substrates to verify the hydrophilic characteristics of the APTES coating. Next, we implanted MEAs in the motor cortex (M1) of Sprague-Dawley rats with uncoated or APTES-coated devices. We assessed changes in the electrochemical impedance and neural recording performance over a chronic implantation period of 16 weeks. Additionally, histology and bulk gene expression were analyzed to understand further the reactive tissue changes arising from the coating. Results showed that APTES increased the hydrophilicity of the devices and decreased electrochemical impedance at 1 kHz. APTES coatings proved detrimental to the recording performance, as shown by a constant decay up to 16 weeks postimplantation. Bulk gene analysis showed differential changes in gene expression between groups that were inconclusive with regard to the long-term effect on neuronal tissue. Together, these results suggest that APTES coatings are ultimately detrimental to chronic neural recordings. Furthermore, interpretations of studies using APTES as a functionalization step should consider the potential consequences if the final functionalization step is incomplete.

Surveillance for lumpy skin disease and foot and mouth disease in the Kimberley, Western Australia.

We quantified the sensitivity of surveillance for lumpy skin disease (LSD) and foot and mouth disease (FMD) in cattle in the Kimberley region of Western Australia. We monitored producer and veterinary activity with cattle for 3 years commencing January 2020. Each year, ~274,000 cattle of 685,540 present on 92 pastoral leases (stations) were consigned to other stations, live export or slaughter. Veterinarians examined 103,000 cattle on the stations, 177,000 prior to live export, and 10,000 prior to slaughter. Detection probabilities for the disease prior to transport or during veterinary procedures and inspections were elicited by survey of 17 veterinarians working in Northern Australia. The veterinarians estimated the probabilities that they would notice, recognise, and submit samples from clinical cases of LSD and FMD, given a 5% prevalence of clinical signs in the herd. We used scenario tree methodology to estimate monthly surveillance sensitivity of observations made by producers and by veterinarians during herd management visits, pre-export inspections, and ante-mortem inspections. Average monthly combined sensitivities were 0.49 for FMD and 0.37 for LSD. Sensitivity was high for both diseases during the dry season and low in the wet season. We estimated the confidence in freedom from the estimated surveillance sensitivity given one hypothetically infected herd, estimated probability of introduction, and prior confidence in freedom. This study provided assurance that the Kimberley is free of these diseases and that routine producer and veterinary interactions with cattle are adequate for the timely detection of the disease should they be introduced.

Aerobic Exercise Improves Cortical Inhibitory Function After Stroke: A Preliminary Investigation.

BACKGROUND AND PURPOSE: Aerobic exercise can elicit positive effects on neuroplasticity and cognitive executive function but is poorly understood after stroke. We tested the effect of 4 weeks of aerobic exercise training on inhibitory and facilitatory elements of cognitive executive function and electroencephalography markers of cortical inhibition and facilitation. We investigated relationships between stimulus-evoked cortical responses, blood lactate levels during training, and aerobic fitness postintervention. METHODS: Twelve individuals with chronic (>6 months) stroke completed an aerobic exercise intervention (40 minutes, 3×/wk). Electroencephalography and motor response times were assessed during congruent (response facilitation) and incongruent (response inhibition) stimuli of a Flanker task. Aerobic fitness capacity was assessed as o2peak during a treadmill test pre- and postintervention. Blood lactate was assessed acutely (<1 minute) after exercise each week. Cortical inhibition (N2) and facilitation (frontal P3) were quantified as peak amplitudes and latencies of stimulus-evoked electroencephalographic activity over the frontal cortical region. RESULTS: Following exercise training, the response inhibition speed increased while response facilitation remained unchanged. A relationship between earlier cortical N2 response and faster response inhibition emerged postintervention. Individuals who produced higher lactate during exercise training achieved faster response inhibition and tended to show earlier cortical N2 responses postintervention. There were no associations between o2peak and metrics of behavioral or neurophysiologic function. DISCUSSION AND CONCLUSIONS: These preliminary findings provide novel evidence for selective benefits of aerobic exercise on inhibitory control during the initial 4-week period after initiation of exercise training and implicate a potential therapeutic effect of lactate on poststroke inhibitory control.

Impact of baricitinib in combination with topical steroids on atopic dermatitis symptoms, quality of life and functioning in adult patients with moderate-to-severe atopic dermatitis from the BREEZE-AD7 Phase 3 randomized trial.

BACKGROUND: Baricitinib is an oral, selective, reversible Janus kinase 1/2 inhibitor approved in the European Union and Japan and under investigation in the United States for treatment of atopic dermatitis (AD). OBJECTIVES: To evaluate the impact of baricitinib plus background topical corticosteroids (TCS) on health-related quality of life (HRQoL), how AD symptoms impact work productivity and life functioning, and treatment benefit using patient-reported outcome (PRO) assessments in patients with moderate-to-severe AD previously experiencing inadequate response to TCS. METHODS: Adult patients with AD in BREEZE-AD7, a Phase 3, multicentre, double-blind trial, were randomised 1 : 1 : 1 to daily oral placebo (control) or baricitinib 4- or 2-mg plus TCS. PROs reported Week 1 through Week 16: Dermatology Life Quality Index (DLQI), Work Productivity and Activity Impairment-AD (WPAI-AD); Patient-Reported Outcomes Measurement Information System (PROMIS) Itch and Sleep measures, and Patient Benefit Index (PBI). Data were analysed using logistic regression (categorical) and mixed model repeated measures (continuous). PBI scores were analysed using analysis of variance. RESULTS: A total of 329 patients were randomised. Treatment with baricitinib 4-mg (N = 111) or 2 mg (N = 109) plus TCS led to rapid, statistically significant improvements [vs. TCS plus placebo (N = 109)] in DLQI ≥4-point improvement starting at Week 2 (4-mg plus TCS, P ≤ 0.001; 2-mg plus TCS P ≤ 0.05), change from baseline in WPAI-AD presenteeism at Week 1 (4-mg plus TCS, P ≤ 0.01; 2-mg plus TCS P ≤ 0.05) and PROMIS itch interference at Week 2 (4-mg plus TCS P ≤ 0.01). Improvements were sustained through Week 16 for baricitinib 4-mg. Statistically significant improvements were observed at Week 16 for PBI global score (4-mg plus TCS, P ≤ 0.001; 2-mg plus TCS P ≤ 0.05). CONCLUSIONS: Baricitinib plus TCS vs. placebo plus TCS showed significant improvements in treatment benefit at Week 16 and rapid significant improvements in HRQoL and impact of AD symptoms on work productivity and functioning through 16 weeks.

Prevention of childhood obesity and food policies in Latin America: from research to practice.

BACKGROUND: Addressing childhood obesity in Latin America requires a package of multisectoral, evidence-based policies that enable environments conducive to healthy lifestyles. OBJECTIVE: Identify and examine key elements to translating research into effective obesity policies in Latin America. METHODS: We examined obesity prevention policies through case studies developed with an expert in the specific policy. Policies were selected based on their level of implementation, visibility and potential impact to reduce childhood obesity. They include: (i) excise taxes on sugar sweetened beverages and energy-dense foods; (ii) front-of-package food label legislation; (iii) trans fatty acids removal from processed foods; and (iv) Ciclovías recreativas or 'open streets'. Case studies were coded to identify components that explained successful implementation and sustainability using the Complex Adaptive Health Systems framework. RESULTS: The analysis identified key elements for effective and sustainable policy, including evidence justifying policy; evidence-based advocacy by civil society; political will; and legislation and skillful negotiations across government, academia, the private sector and civil society. Scientific evidence and evaluation played an important role in achieving tipping points for policies' launch and sustain effective implementation. CONCLUSIONS: Well-coordinated, intersectoral partnerships are needed to successfully implement evidence-based anti-obesity policies. Prospective policy research may be useful for advancing knowledge translation.

Motion-induced interruptions and postural equilibrium in linear lateral accelerations.

This study assesses lateral tipping motion-induced interruptions (MIIs) in a simulated motion environment. The objective is to revisit MII occurrence and sway motion relationship by focusing on the frequency and acceleration of the lateral motion stimulus. Results verify that MIIs increase with increasing peak sway acceleration, but the effect of sway frequency is not as clear as that of acceleration. Complex multidirectional motions create more tipping MIIs than unidirectional motion. Research should incorporate acceleration, frequency and motion complexity as factors influencing MII occurrence. To describe a temporary loss of balance without tipping, the term 'probable' MII is introduced. This term fills the gap between the theoretical definition and a human-centred perception of an MII where loss of balance is not a binary phenomenon. The 'probable' MIIs were 16-67% more common than the 'definite' MIIs. The developed mathematical model of MII occurrence versus sway acceleration (amplitude, frequency) approximated the observed MIIs with less than 9% difference.

Surgical treatment of osteochondral lesions of the talus.

When conservative treatment is unsuccessful, there are many surgical options to treat patients with symptomatic chronic osteochondral lesions of the talus. The chosen treatment depends on the patient's symptoms, clinical examination findings, preoperative imaging results, and whether prior surgery was unsuccessful. It is important to be aware of treatment alternatives such as marrow stimulation, osteochondral autograft or allograft plugs, autologous chondrocyte implantation, and newer techniques currently being investigated outside the United States.

The genetic code--more than just a table.

The standard codon table is a primary tool for basic understanding of molecular biology. In the minds of many, the table's orderly arrangement of bases and amino acids is synonymous with the true genetic code, i.e., the biological coding principle itself. However, developments in the field reveal a much more complex and interesting picture. In this article, we review the traditional codon table and its limitations in light of the true complexity of the genetic code. We suggest the codon table be brought up to date and, as a step, we present a novel superposition of the BLOSUM62 matrix and an allowed point mutation matrix. This superposition depicts an important aspect of the true genetic code-its ability to tolerate mutations and mistranslations.

General methodology for evaluating the adhesion force of drops and bubbles on solid surfaces.

The shortcomings of the current formulation for calculating the adhesion force for drops and bubbles with noncircular contact lines are discussed. A general formulation to evaluate the adhesion force due to surface forces is presented. Also, a novel methodology, that is, IBAFA, image based adhesion force analysis, was developed to allow implementation of the general formulation. IBAFA is based on the use of multiple profile images of a drop. The images are analyzed (1) to accurately reconstruct the contact line shape, which is analytically represented by a Fourier cosine series, and (2) to measure contact angles at multiple locations along the contact line and determine the contact angle distribution based on a linear piecewise interpolation routine. The contact line shape reconstruction procedure was validated with both actual experiments and simulated experiments. The procedure for the evaluation of the adhesion force was tested using simulated experiments with synthetic drops of known shapes. A comparison with current methods showed that simplifying assumptions (e.g., elliptical contact line or linear contact angle distribution) used in these methods result in errors up to 76% in the estimated adhesion force. However, the drop adhesion force evaluated using IBAFA results in small errors on the order of 1%.

Arthrodesis of the first metatarsocuneiform joint: a comparative study of fixation methods.

BACKGROUND: The Lapidus bunionectomy is a popular procedure for severe bunion deformity where metatarsus primus varus is equal to or exceeds 15 degrees. We evaluated a new locking compression plate which may improve outcomes with the Lapidus procedure. METHODS: Ten matched pairs of cadaver feet were used to compare the standard crossed 4.0-mm compression screw method of fixation to the LPS Lapidus plate. After performing the matched operations the cadaver constructs were stressed to failure using the INSTRON and Wavemaker software. RESULTS: The LPS Lapidus plate load to failure was 108 Nm with a bending moment of 6.0 Nm. The crossed screw technique was inferior at 78 Nm with a bending moment of 4.4 Nm (p = 0.02) CONCLUSION: Unlike other H-plates or locking plates, load to failure was higher with the Lapidus plate constructs. CLINICAL RELEVANCE: The increased rigidity provided by these plates may help to minimize the risk of nonunion or malunion.

Site-specific gene modification by oligodeoxynucleotides in mouse bone marrow-derived mesenchymal stem cells.

Synthetic oligodeoxynucleotides (ODNs) had been employed in gene modification and represent an alternative approach to 'cure' genetic disorders caused by mutations. To test the ability of ODN-mediated gene repair in bone marrow-derived mesenchymal stem cells (MSCs), we established MSCs cell lines with stably integrated mutant neomycin resistance and enhanced green fluorescent protein reporter genes. The established cultures showed morphologically homogenous population with phenotypic and functional features of mesenchymal progenitors. Transfection with gene-specific ODNs successfully repaired targeted cells resulting in the expression of functional proteins at relatively high frequency approaching 0.2%. Direct DNA sequencing confirmed that phenotype change resulted from the designated nucleotide correction at the target site. The position of the mismatch-forming nucleotide was shown to be important structural feature for ODN repair activity. The genetically corrected MSCs were healthy and maintained an undifferentiated state. Furthermore, the genetically modified MSCs were able to engraft into many tissues of unconditioned transgenic mice making them an attractive therapeutic tool in a wide range of clinical applications.

Idiopathic pulmonary fibrosis fibroblasts migrate and proliferate to CC chemokine ligand 21.

Idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP) is the severest form of idiopathic interstitial pneumonia for which therapeutic targets are needed. Surgical lung biopsy specimens from IPF/UIP patients exhibit focal expression of CC chemokine receptor (CCR) 7, but the identity of these CCR7-positive cells is unknown. The purpose of the present study was to examine the functional and signalling significance of CCR7 expression of primary fibroblasts grown from IPF/UIP and normal surgical lung biopsy specimens. Primary fibroblasts were cultured from surgical lung biopsy specimens from IPF/UIP and normal patients. Fibroblasts treated with or without CC chemokine ligand (CCL) 21 were analysed for functional, transcriptional and proteomic differences using immunocytochemical analysis, gene arrays, Taqman real-time PCR, and migration, proliferation and Western blot assays. CCR7 was expressed by IPF/UIP fibroblasts, but not normal fibroblasts. IPF/UIP fibroblasts, but not normal fibroblasts, showed significant migratory and proliferative responses when exposed to CCL21, which were inhibited by pertussis toxin or neutralising antibodies to CCR7. Exposure of IPF/UIP fibroblasts to CCL21 altered the phosphorylation status of mitogen-activated protein kinase kinase 1/2, extracellular signal-regulated kinase 1/2 and ribosomal S6 kinase (90 kDa) in these cells; this was abrogated by pertussis toxin or CCR7-specific small interfering RNA. Together, these data demonstrate that CC chemokine ligand 21 modulates the functional properties of idiopathic pulmonary fibrosis/usual interstitial pneumonia fibroblasts, but not normal fibroblasts.

Delivery and mechanistic considerations for the production of knock-in mice by single-stranded oligonucleotide gene targeting.

Single-stranded oligodeoxynucleotide (ssODN) gene targeting may facilitate animal model creation and gene repair therapy. Lipofection of ssODN can introduce point mutations into target genes. However, typical efficiencies in mouse embryonic stem cells (ESC) are <10(-4), leaving corrections too rare to effectively identify. We developed ESC lines with an integrated mutant neomycin resistance gene (Tyr22Ter). After targeting with ssODN, repaired cells survive selection in G418. Correction efficiencies varied with different lipofection procedures, clonal lines, and ssODN designs, ranging from 1 to 100 corrections per million cells plated. Uptake studies using cell sorting of Cy5-labelled ssODN showed 40% of the corrections concentrated in the best transfected 22% of cells. Four different basepair mismatches were tested and results show that the base-specificity of the mismatch is critical. Dual mismatch ssODN also showed mismatch preferences. These ESC lines may facilitate development of improved ssODN targeting technologies for either animal production or ex vivo gene therapy.