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Scanning probe microscopy (SPM) since its invention in the 80’s became very popular in examination of many different sample parameters, both in university and industry. This was the effect of bringing this technology closer to the operator. Although the ease of use opened a possibility for measurements without high labour requirement, a quantitative analysis is still a limitation in Scanning ProbeMicroscopes available on the market. Based on experience of Nano-metrology Group, SPM still can be considered as a tool for quantitative examination of thermal, electrical and mechanical surface parameters. In this work we present an ARMScope platform as a versatile SPM controller that is proved to be useful in a variety of applications: fromatomic-resolution STM (Scanning TunnellingMicroscopy) toMulti-resonance KPFM (Kelvin Probe force microscopy) to commercial SEMs (Scanning electron microscopes).

Background:We completed a phase I clinical trial to test the safety and toxicity of combined treatment with cixutumumab (anti-IGF-1R antibody) and selumetinib (MEK 1/2 inhibitor).Methods:Patients with advanced solid tumours, refractory to standard therapy received selumetinib hydrogen sulphate capsules orally twice daily, and cixutumumab intravenously on days 1 and 15 of each 28-day cycle. The study used a 3+3 design, with a dose-finding cohort followed by an expansion cohort at the maximally tolerated dose that included pharmacokinetic and pharmacodynamic correlative studies.Results:Thirty patients were enrolled, with 16 in the dose-finding cohort and 14 in the expansion cohort. Grade 3 or greater toxicities included nausea and vomiting, anaemia, CVA, hypertension, hyperglycaemia, and ophthalmic symptoms. The maximally tolerated combination dose was 50 mg twice daily of selumetinib and 12 mg kg−1 every 2 weeks of cixutumumab. Two patients achieved a partial response (one unconfirmed), including a patient with BRAF wild-type thyroid carcinoma, and a patient with squamous cell carcinoma of the tongue, and six patients achieved time to progression of >6 months, including patients with thyroid carcinoma, colorectal carcinoma, and basal cell carcinoma. Comparison of pre- and on-treatment biopsies showed significant suppression of pERK and pS6 activity with treatment.Conclusions:Our study of anti-IGF-1R antibody cixutumumab and MEK 1/2 inhibitor selumetinib showed that the combination is safe and well-tolerated at these doses, with preliminary evidence of clinical benefit and pharmacodynamic evidence of target inhibition. [ABSTRACT FROM AUTHOR]

Background:Preclinical studies suggest that histone deacetylase (HDAC) inhibitors may restore tumour sensitivity to retinoids. The objective of this study was to determine the safety, tolerability, and the pharmacokinetic (PK)/pharmacodynamic (PD) profiles of the HDAC inhibitor entinostat in combination with 13-cis retinoic acid (CRA) in patients with solid tumours.Methods:Patients with advanced solid tumours were treated with entinostat orally once weekly and with CRA orally twice daily × 3 weeks every 4 weeks. The starting dose for entinostat was 4 mg m−2 with a fixed dose of CRA at 1 mg kg−1 per day. Entinostat dose was escalated by 1 mg m−2 increments. Pharmacokinetic concentrations of entinostat and CRA were determined by LC/MS/MS. Western blot analysis of peripheral blood mononuclear cells and tumour samples were performed to evaluate target inhibition.Results:A total of 19 patients were enroled. The maximum tolerated dose (MTD) was exceeded at the entinostat 5 mg m−2 dose level (G3 hyponatremia, neutropenia, and anaemia). Fatigue (G1 or G2) was a common side effect. Entinostat exhibited substantial variability in clearance (147%) and exposure. CRA trough concentrations were consistent with prior reports. No objective responses were observed, however, prolonged stable disease occurred in patients with prostate, pancreatic, and kidney cancer. Data further showed increased tumour histone acetylation and decreased phosphorylated ERK protein expression.Conclusion:The combination of entinostat with CRA was reasonably well tolerated. The recommended phase II doses are entinostat 4 mg m−2 once weekly and CRA 1 mg kg−1 per day. Although no tumour responses were seen, further evaluation of this combination is warranted. [ABSTRACT FROM AUTHOR]

Background: The purpose of this work was to determine the efficacy of inhibiting mammalian target of rapamycin (mTOR) in pancreatic cancer preclinical models and translate preclinical observations to the clinic.Methods: Temsirolimus (20 mg Kg(-1) daily) was administered to freshly generated pancreatic cancer xenografts. Tumour growth inhibition was determined after 28 days. Xenografts were characterised at baseline by gene expression and comparative genomic hybridisation. Patients with advanced, gemcitabine-resistant pancreatic cancer were treated with sirolimus (5 mg daily). The primary end point was 6-month survival rate (6mSR). Correlative studies included immunohistochemistry assessment of pathway expression in baseline tumours, drug pharmacokinetics (PKs), response assessment by FDG-PET and pharmacodynamic effects in peripheral-blood mononuclear cells (PBMCs).Results: In all, 4 of 17 xenografts (23%) responded to treatment. Sensitive tumours were characterised by gene copy number variations and overexpression of genes leading to activation of the PI3K/Akt/mTOR pathway. Activation of p70S6K correlated with drug activity in the preclinical studies. Sirolimus was well tolerated in the clinic, showed predictable PKs, exerted pathway inhibition in post-treatment PBMCs and resulted in a 6mSR of 26%. No correlation, however, was found between activated p70S6K in tumour tissues and anti-tumour effects.Conclusion: Sirolimus activity in pancreatic cancer was marginal and not predicted by the selected biomarker. [ABSTRACT FROM AUTHOR]

The first experimental study of the spectral dependence of the nucleation of cesium vapor caused by light absorption is carried out in a diffusion cloud chamber. The spectral dependence of the nucleation rate is compared with the absorption and ionization spectra of cesium vapor. The results evidence that the observed structure in the nucleation spectrum at photon energies above the ionization threshold is correlated to the light-induced ionization of cesium dimers Cs[sub 2][sup +]. At lower photon energies light-induced nucleation can be either due to generation of ions by direct ionization of cesium clusters, to various two-step ionization processes, or to optical excitation of cesium atoms. The spectral dependence of the nucleation rate provides a new and powerful tool to study ionization spectra of metal vapors. In addition to results obtained by conventional methods a more consolidated insight into energy levels of atoms and clusters under equilibrium conditions is possible. © 2000 American Institute of Physics. [ABSTRACT FROM AUTHOR]

Abstract Background Glutamate excitotoxicity is thought to be involved in the pathogenesis of neurodegenerative disease. One potential source of glutamate is N-acetyl-aspartyl-glutamate (NAAG) which is hydrolyzed to glutamate and N-acetyl-aspartate (NAA) in a reaction catalyzed by glutamate carboxypeptidase (GCP). As a result, GCP inhibition is thought to be beneficial for the treatment of neurodegenerative diseases where excess glutamate is presumed pathogenic. Both pharmacological and genetic inhibition of GCP has shown therapeutic utility in preclinical models and this has led to GCP inhibitors being pursued for the treatment of nervous system disorders in human clinical trials. Specifically, GCP inhibitors are currently being developed for peripheral neuropathy and neuropathic pain. The purpose of this study was to develop a pharmacodynamic (PD) marker assay to use in clinical development. The PD marker will determine the effect of GCP inhibitors on GCP enzymatic activity in human skin as measure of inhibition in peripheral nerve and help predict drug doses required to elicit pharmacologic responses. Methods GCP activity was first characterized in both human skin and rat paw pads. GCP activity was then monitored in both rodent paw pads and sciatic nerve from the same animals following peripheral administration of various doses of GCP inhibitor. Significant differences among measurements were determined using two-tailed distribution, equal variance student's t test. Results We describe for the first time, a direct and quantifiable assay to evaluate GCP enzymatic activity in human skin biopsy samples. In addition, we show that GCP activity in skin is responsive to pharmacological manipulation; GCP activity in rodent paws was inhibited in a dose response manner following peripheral administration of a potent and selective GCP inhibitor. Inhibition of GCP activity in rat paw pads was shown to correlate to inhibition of GCP activity in peripheral nerve. Conclusion Monitoring GCP activity in human skin after administration of GCP inhibitors could be readily used as PD marker in the clinical development of GCP inhibitors. Enzymatic activity provides a simple and direct measurement of GCP activity from tissue samples easily assessable in human subjects.

An abstract to the research paper titled "A phase I study assessing the feasibility and safety of intraductal pegylated liposomal doxorubicin (PLD) in women awaiting mastectomy," by V. Stearns, L. Jacobs, N. Khouri, S. Jeter, P. Powers, K. Shahverdi, R. Brown, M. Rudek, E. Gabrielson, Z. Zhang, T. Tsangaris and S. Sukumar is presented.

Purpose: COL-3, a matrix metalloproteinase inhibitor, has been evaluated in phase I/II clinical trials for the treatment of cancer. The objective was to establish a population pharmacokinetic (PK) model of COL-3 in cancer patients.Methods: 740 COL-3 plasma concentration data were obtained from 34 cancer patients in a single-dose, dose-escalation (from 36 to 98 mg/m2/day) phase I study. Intense PK sampling was obtained after the first dose and trough concentrations were obtained throughout the treatment. A population PK model of COL-3 was developed with first-order conditional estimation using NONMEM.Results: A one-compartment model with sequential zero-order input, mimicking dissolution, and first-order absorption and elimination described plasma concentration-time profiles well. Estimated population means (RSE%) for apparent clearance and mean absorption time were 0.78 (6%) L/h and 1.8 (7%) h, with interindividual variability of 57% (40%) and 41% (27%), respectively. Covariate screening indicated that V/F was dose-dependent, while body weight, body surface area, sex, age, and creatinine clearance did not exhibit any significant impact on COL-3 PK.Conclusions: A linear one-compartment model with sequential zero- and first-order absorption adequately describes COL-3 PK in cancer patients. This population PK model supports fixed-dosing of COL-3. The dose-dependence of Vd/F is likely the result of reduction in bioavailability (F) with increasing dose due to poor dissolution.Clinical Pharmacology & Therapeutics (2005) 79, P20–P20; doi: 10.1016/j.clpt.2005.12.072 [ABSTRACT FROM AUTHOR]

An isotope-dilution bioanalytical assay for abemaciclib and its metabolites in combination with olaparib was developed and validated in human plasma K2 EDTA. For the quantitative assay, human plasma samples (or human plasma QC samples) were spiked with internal standard solution before a simple protein precipitation with methanol. The extract was injected onto a liquid chromatography-tandem mass spectrometry (LC-MS/MS) instrument where it was chromatographically separated by a polar end-capped reversed phase column and guard using gradient elution with water and methanol both modified with 0.2 % formic acid (v/v) as the mobile phases. The analytes and internal standards were measured by heated electrospray ionization (HESI) in positive polarity using selected reaction monitoring (SRM) on a triple quadrupole mass spectrometer. The assay was validated for linear ranges as follows: 0.4 - 1000 nM abemaciclib, 0.35 - 1000 nM M2 and M18, 0.5 - 1000 nM M20, and 0.75 - 1000 nM olaparib. The inter-day or between day precision for the quality controls (n = 18) was < 13 % and the accuracy was ± 12 %, for all analytes, including the lower limit of quantification (LLOQ). The intra-day or within day precision for the quality controls (n = 6) was ≤ 11 % and the accuracy was ± 12 % for low, mid, and high and < 19 % at LLOQ. The recovery in human plasma was determined to be between 92 % and 102 % for all analytes spanning the linear range. The validated, bioanalytical quantitative assay was designed to measure abemaciclib, its metabolites, and olaparib for pharmacokinetic evaluation of patients in clinical trials for breast, brain, and ovarian cancers., Competing Interests: Declaration of Competing Interest Kathleen Moore: Consultation or advisory fees from Astra Zeneca, Aravive, Aadi, Blueprint, Clovis, Caris, Duality, Eisai, GSK, Genentech/Roche, Immunogen, Mersana, Merck, Myriad, Novartis, Janssen, Regeneron, VBL Theraeputics, Verastem, and Zentalis. Other activities that could influence the work include GOG Foundation BOD, and ASCO BOD., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Recurrent high-grade gliomas (rHGGs) have a dismal prognosis, where the maximum tolerated dose (MTD) of IV terameprocol (5 days/month), a transcriptional inhibitor of specificity protein 1 (Sp1)-regulated proteins, is 1,700 mg/day with median area under the plasma concentration-time curve (AUC) of 31.3 μg∗h/mL. Given potentially increased efficacy with sustained systemic exposure and challenging logistics of daily IV therapy, here we investigate oral terameprocol for rHGGs in a multicenter, phase 1 trial (GATOR). Using a 3 + 3 dose-escalation design, we enroll 20 patients, with median age 60 years (range 31-80), 70% male, and median one relapse (range 1-3). Fasting patients tolerate 1,200 mg/day (n = 3), 2,400 mg/day (n = 6), 3,600 mg/day (n = 3), and 6,000 mg/day (n = 2) oral doses without major toxicities. However, increased dosage does not lead to increased systemic exposure, including in fed state (6,000 mg/day, n = 4), with maximal AUC <5 μg∗h/mL. These findings warrant trials investigating approaches that provide sustained systemic levels of transcription inhibitors to exploit their therapeutic potential. This study was registered at ClinicalTrials.gov (NCT02575794)., Competing Interests: Declaration of interests M.S.A. – grants: Seagen, AstraZeneca, BMS, Bayer, Incyte, Pharmacyclics, Novocure, MimiVax, and Merck. Consultation fees: Bayer, Novocure, Kiyatec, Insightec, GSK, Xoft, Nuvation, Celularity, SDP Oncology, Apollomics, Prelude Therapeutics, Janssen, Tocagen, Voyager Therapeutics, ViewRay, Caris Life Sciences, Pyramid Biosciences, Varian Medical Systems, Cairn Therapeutics, AnHeart Therapeutics, Menarini Ricerche, Sumitomo Pharma Oncology, Autem therapeutics, GT Medical Technologies, Allovir, Equillium Bio., QV Bioelectronics, and Theraguix. Scientific Advisory Board memberships: Cairn Therapeutics, Pyramid Biosciences, Bugworks, and Modifi Biosciences. Data Safety and Monitoring Committee membership: VBI Vaccines. Stock shareholder: MimiVax, CytoDyn, Trisalus Lifesciences, and MedInnovate Advisors, LLC. D.M.P. – consulting or advisory role: Orbus Therapeutics, Sumitomo Dainippon Pharma Oncology, Inc., Stemline Therapeutics, and Novocure. Research funding: Pfizer (Inst), Novartis (Inst), NeOnc Technologies (Inst), Orbus Therapeutics (Inst), Bristol Myers Squibb (Inst), Genentech/Roche (Inst), Pharmacyclics (Inst), Bayer (Inst), Karyopharm Therapeutics (Inst), Apollomics (Inst), Vigeo Therapeutics (Inst), Global Coalition for Adaptive Research (Inst), MimiVax (Inst), Ono Pharmaceutical (Inst), and Mylan (Inst). Equity ownership/stock options: Pfizer (Pharmaceuticals) and Gilead (Pharmaceuticals). M.H. – Data Safety Monitoring Board member: Parexel and Advarra. Institutional research funding: Novartis and Vanquish. P.Y.W. – research support: AstraZeneca, Black Diamond, Bristol Meyers Squibb, Celgene, Chimerix, Eli Lily, Erasca, Genentech/Roche, Kazia, MediciNova, Merck, Novartis, Nuvation Bio, Servier, Vascular Biogenics, and VBI Vaccines. Advisory board/consultant: AstraZeneca, Black Diamond, Celularity, Chimerix, Day One Bio, Genenta, Glaxo Smith Kline, Merck, Mundipharma, Novartis, Novocure, Nuvation Bio, Prelude Therapeutics, Sapience, Servier, Sagimet, Vascular Biogenics, and VBI Vaccines. R.C.H. has patents related to the drug terameprocol and is affiliated with Erimos Pharmaceuticals, which holds rights to the drug. S.G. is an independent contractor/consultant to Erimos Pharmaceuticals, LLC with no ownership or other financial interest in Erimos Pharmaceuticals or its products., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Nowadays, there is an increasing emphasis on the need to alleviate the chronic inflammatory response to effectively treat hypertension. However, there are still gaps in our understanding on how to achieve this. Therefore, research on interaction of antihypertensive drugs with the immune system is extremely interesting, since their therapeutic effect could partly result from amelioration of hypertension-related inflammation, in which macrophages seem to play a pivotal role. Thus, current comprehensive studies have investigated the impact of repeatedly administered hypotensive drugs (captopril, olmesartan, propranolol, carvedilol, amlodipine, verapamil) on macrophage functions in the innate and adaptive immunity, as well as if drug-induced effects are affected by a high-sodium diet (HSD), one of the key environmental risk factors of hypertension. Although the assayed medications increased the generation of reactive oxygen and nitrogen intermediates by macrophages from standard fed donors, they reversed HSD-induced enhancing effects on macrophage oxidative burst and secretion of pro-inflammatory cytokines. On the other hand, some drugs increased macrophage phagocytic activity and the expression of surface markers involved in antigen presentation, which translated into enhanced macrophage ability to activate B cells for antibody production. Moreover, the assayed medications augmented macrophage function and the effector phase of contact hypersensitivity reaction, but suppressed the sensitization phase of cell-mediated hypersensitivity under HSD conditions. Our current findings contribute to the recognition of mechanisms, by which excessive sodium intake affects macrophage immune activity in hypertensive individuals, and provide evidence that the assayed medications mitigate most of the HSD-induced adverse effects, suggesting their additional protective therapeutic activity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction and Objective: Dermacentor reticulatus is one of the tick species of the greatest epidemiological importance in Europe. To date, the Eastern European and Western European populations of this tick species have been separated by an area located in Poland where the species has never been found. In this study, newly discovered D. reticulatus localities in areas transformed by human activities in central-southern Poland are described., Material and Methods: The specimens of the ornate dog tick were identified among ticks collected from companion animals in 2010, 2012, 2013, and 2014. They were examined using PCR methods to detect Borrelia burgdorferi s.l., Rickettsia spp., Anaplasma phagocytophilum , Bartonella spp., Babesia spp., and Toxoplasma gondii . In the case of the positive results, the amplicons were sequenced and examined by a BLAST search., Results: In total, 6 specimens of D. reticulatus were collected (3 females and 3 males). As declared by the owners, animal hosts stayed in the same area throughout the study period and had never travelled outside their place of residence. As many as 3/6 (50%) of D. reticulatus adults removed from dogs were infected with Rickettsia raoultii ., Conclusions: The results expand the available data on the spread of the ornate dog tick and indicate that, since 2010, this tick species and Rickettsia raoultii transmitted by this tick species have probably been present in this area, which has a strongly transformed agricultural structure and and had previously been regarded as a D. reticulatus -free zone. The presence of the ornate dog tick in urban and suburban habitats in central-southern Poland poses new threats to the health of companion animals and humans associated with the transmission of pathogens by this species.

Following kidney transplantation, lifelong immunosuppressive therapy is essential to prevent graft rejection. On the downside, immunosuppression increases the risk of severe infections, a major cause of death among kidney transplant recipients (KTRs). To improve post-transplant outcomes, adequate immunosuppressive therapy is therefore a challenging but vital aspect of clinical practice. Torque teno virus load (TTVL) was shown to reflect immune competence in KTRs, with low TTVL linked to an elevated risk for rejections and high TTVL associated with infections in the first year post-transplantation. Yet, little is known about the dynamics of TTVL after the first year following transplantation and how TTVL changes with respect to short-term modifications in immunosuppressive therapy. Therefore, we quantified TTVL in 106 KTRs with 108 clinically indicated biopsies, including 65 biopsies performed >12 months post-transplantation, and correlated TTVL to histopathology. In addition, TTVL was quantified at 7, 30, and 90 days post-biopsy to evaluate how TTVL was affected by changes in immunosuppression resulting from interventions based on histopathological reporting. TTVL was highest in patients biopsied between 1 and 12 months post-transplantation (N = 23, median 2.98 × 10 7 c/mL) compared with those biopsied within 30 days (N = 20, median 7.35 × 10 3 c/mL) and > 1 year post-transplantation (N = 65, median 1.41 × 10 4 c/mL; p  < 0.001 for both). Patients with BK virus-associated nephropathy (BKVAN) had significantly higher TTVL than patients with rejection ( p  < 0.01) or other pathologies ( p  < 0.001). When converted from mycophenolic acid to a mTOR inhibitor following the diagnosis of BKVAN, TTVL decreased significantly between biopsy and 30 and 90 days post-biopsy ( p  < 0.01 for both). In KTR with high-dose corticosteroid pulse therapy for rejection, TTVL increased significantly between biopsy and 30 and 90 days post-biopsy ( p  < 0.05 and p  < 0.01, respectively). Of note, no significant changes were seen in TTVL within 7 days of changes in immunosuppressive therapy. Additionally, TTVL varied considerably with time since transplantation and among individuals, with a significant influence of age and BMI on TTVL ( p  < 0.05 for all). In conclusion, our findings indicate that TTVL reflects changes in immunosuppressive therapy, even in the later stages of post-transplantation. To guide immunosuppressive therapy based on TTVL, one should consider inter- and intraindividual variations, as well as potential confounding factors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Reineke, Morath, Speer, Rudek, Bundschuh, Klein, Mahler, Kälble, Nusshag, Beimler, Zeier, Bartenschlager, Schnitzler and Benning.)

Background: Prostate cancer remains the most prevalent malignancy and the second-leading cause of cancer-related death in men in the USA. Radiation therapy, typically with androgen suppression, remains a mainstay in the treatment of intermediate- and high-risk, potentially lethal prostate cancers. However, local recurrence and treatment failure remain common. Basic and translational research has determined the potential for using androgen receptor (AR) ligands (e.g., dihydrotestosterone and flutamide) in the context of androgen-deprived prostate cancer to induce AR- and TOP2B-mediated DNA double-strand breaks (DSBs) and thereby synergistically enhance the effect of radiation therapy (RT). The primary aim of this study is to carry out pharmacodynamic translation of these findings to humans., Methods: Patients with newly diagnosed, biopsy-confirmed localized prostatic adenocarcinoma will be recruited. Flutamide, an oral non-steroidal androgen receptor ligand, will be administered orally 6-12 h prior to prostate biopsy (performed under anesthesia prior to brachytherapy seed implantation). Key study parameters will include the assessment of DNA double-strand breaks by γH2A.x foci and AR localization to the nucleus. The initial 6 patients will be treated in a single-arm run-in phase to assess futility by establishing whether at least 2 subjects from this group develop γH2A.x foci in prostate cancer cells. If this criterion is met, the study will advance to a two-arm, randomized controlled phase in which 24 participants will be randomized 2:1 to either flutamide intervention or placebo standard-of-care (with all patients receiving definitive brachytherapy). The key pharmacodynamic endpoint will be to assess whether the extent of γH2A.x foci (proportion of cancer cells positive and number of foci per cancer cell) is greater in patients receiving flutamide versus placebo. Secondary outcomes of this study include an optional, exploratory analysis that will (a) describe cancer-specific methylation patterns of cell-free DNA in plasma and urine and (b) assess the utility of serum and urine samples as a DNA-based biomarker for tracking therapeutic response., Discussion: This study will confirm in humans the pharmacodynamic effect of AR ligands to induce transient double-strand breaks when administered in the context of androgen deprivation as a novel therapy for prostate cancer. The findings of this study will permit the development of a larger trial evaluating flutamide pulsed-dose sequencing in association with fractionated external beam RT (+/- brachytherapy). The study is ongoing, and preliminary data collection and recruitment are underway; analysis has yet to be performed., Trial Registration: ClinicalTrials.gov NCT03507608. Prospectively registered on 25 April 2018., (© 2023. The Author(s).)

Donor-derived cell-free DNA (dd-cfDNA) identifies allograft injury and discriminates active rejection from no rejection. In this prospective study, 106 kidney transplant recipients with 108 clinically indicated biopsies were enrolled at Heidelberg University Hospital between November 2020 and December 2022 to validate the clinical value of dd-cfDNA in a cohort of German patients. dd-cfDNA was quantified at biopsy and correlated to histopathology. Additionally, dd-cfDNA was determined on days 7, 30, and 90 post-biopsy and analyzed for potential use to monitor response to anti-rejection treatment. dd-cfDNA levels were with a median (IQR) % of 2.00 (0.48-3.20) highest in patients with ABMR, followed by 0.92 (0.19-11.25) in patients with TCMR, 0.44 (0.20-1.10) in patients with borderline changes and 0.20 (0.11-0.53) in patients with no signs of rejection. The AUC for dd-cfDNA to discriminate any type of rejection including borderline changes from no rejection was at 0.72 (95% CI 0.62-0.83). In patients receiving anti-rejection treatment, dd-cfDNA levels significantly decreased during the 7, 30, and 90 days follow-up compared to levels at the time of biopsy ( p = 0.006, p = 0.002, and p < 0.001, respectively). In conclusion, dd-cfDNA significantly discriminates active rejection from no rejection. Decreasing dd-cfDNA following anti-rejection treatment may indicate response to therapy. Clinical Trial Registration : https://drks.de/search/de/trial/DRKS00023604, identifier DRKS00023604., Competing Interests: This study received funding from CareDx Inc. (Brisbane, CA). The funder had the following involvement with the study: funding for kits and supplies for dd-cfDNA testing., (Copyright © 2023 Benning, Morath, Fink, Rudek, Speer, Kälble, Nusshag, Beimler, Schwab, Waldherr, Zeier, Süsal and Tran.)

Background: Persons living with human immunodeficiency virus are an underserved population for evidence-based cancer treatment. Paclitaxel and carboplatin (PCb) is an active regimen against a variety of solid tumors, including several seen in excess in patients with HIV infection. We performed a pilot trial to evaluate the safety of full-dose PCb in people living with human immunodeficiency virus and cancer., Methods: Eligible patients, stratified by concurrent antiretroviral therapy (ART) that included CYP3A4 inhibitors or not, received paclitaxel (175 mg/m2) in combination with carboplatin (target AUC 6) intravenously every 3 weeks for up to 6 cycles., Results: Sixteen evaluable patients received 64 cycles of PCb, including 6 patients treated with CYP3A4 inhibiting ART (ritonavir). The adverse event profile was consistent with the known toxicity profile of PCb, with no differences between the 2 strata. There were 4 partial responses (25%, 95% CI: 7%-52%), and overall, CD4+ lymphocyte count was similar after completion of therapy (median: 310/μL) compared with baseline values (median: 389/μL). Pharmacokinetic studies in 6 patients revealed no significant differences in Cmax or AUCinf for paclitaxel between the 2 cohorts., Conclusion: Full doses of PCb chemotherapy are tolerable when given concurrently with ART in people living with human immunodeficiency virus with cancer, including patients receiving CYP3A4 inhibitors., Clinicaltrials.gov Identifier: NCT01249443., (© The Author(s) 2022. Published by Oxford University Press.)

Intravesical chemotherapy is a key approach for treating refractory non-muscle-invasive bladder cancer (NMIBC). However, the effectiveness of intravesical chemotherapy is limited by bladder tissue penetration and retention. Here, we describe the development of a docetaxel nanosuspension that, when paired with a low osmolality (hypotonic) vehicle, demonstrates increased uptake by the bladder urothelium with minimal systemic exposure. We compare the bladder residence time and efficacy in an immune-competent rat model of NMIBC to the clinical comparator, solubilized docetaxel (generic Taxotere) diluted for intravesical administration. We found that only the intravesical docetaxel nanosuspension significantly decreased cell proliferation compared to untreated tumor tissues. The results presented here suggest that the combination of nanoparticle-based chemotherapy and a hypotonic vehicle can provide more efficacious local drug delivery to bladder tissue for improved treatment of refractory NMIBC., (© 2020. Controlled Release Society.)

Background: Innovative strategies to fully exploit the antitumor activity of multitargeted tyrosine kinase inhibitors (TKIs) are urgently needed. Higher concentrations of TKIs at their target site, i.e. intratumorally, may lead to broader kinase inhibition, which might be essential for the optimal suppression of tumor growth and induction of apoptosis. To reach these higher intratumoral concentrations, without encountering dose limiting toxicity, alternative TKI dosing strategies employing higher daily and high intermittent doses have been studied. In this systematic review, we evaluated the current clinical evidence to support (intermittent) high TKI dosing regimens., Methods: A systematic review was conducted in the following databases: PubMed®, EMBASE® and Cochrane Library©, to evaluate efficacy of alternatively scheduled high-dosed regimen (a higher dose in a regular daily schedule than registered or a higher dose in an alternative intermittent schedule) of TKIs in (haemato-)oncology. Data were extracted independently by two authors according to predefined criteria. Extracted data were tabulated to summarize key findings., Results: Out of twenty studies that met the inclusion criteria, thirteen investigated higher daily dose schedules of either afatinib, axitinib, erlotinib, gefitinib, imatinib, sorafenib, and sunitinib. Five of these studies included pharmacokinetic analyses, reporting marginal higher maximum drug concentrations (C max ) in plasma (1.3-4-fold higher) compared to the standard dose schedules. Seven clinical trials investigated intermittent high-dose schedules requiring treatment breaks, with the following TKIs: afatinib, erlotinib, gefitinib, lapatinib, sorafenib, and sunitinib. Six of these included pharmacokinetic results, all reporting higher (2-21-fold) C max in plasma compared to the standard daily dose schedule, with manageable toxicity. No data on tumor concentrations were presented. Data on the efficacy outcomes were limited due to small sample size, study designs, phase 1 population and heterogeneous tumor types., Conclusions: Early phase clinical studies show that high-dose intermittent TKI-treatment schedules can lead to an increased C max compared to standard (low-dose) daily administration with manageable toxicity. These higher concentrations are assumed to reflect higher intratumoral concentrations. Further investigation of the potential improvement in clinical benefit of a high-dose intermittent strategy with multitargeting TKIs is warranted., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The cognitive and affective design aims to attract consumers with products and new products that provide innovative experiences with the intense functional and "cognitive" impact such as ease of use, in addition to "affective" impact as the pleasure of consuming. However, it is difficult to anticipate the consumer's preferences and intentionality, because what happens inside his mind, brain, or subjective experience (wishes, needs, and preferences) is not accessible. This study's objective was to propose an ontological and multidisciplinary approach to the cognitive and affective product experience through an explanation framework and a conceptual model. The model was tested, and the preliminary results indicate that the proposal contributes positively to the advance of the explanation, evaluation and translation of the product experience., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tavares, Canciglieri Junior, Guimarães and Rudek.)

In this paper we describe the design, technology and application of a test and reference sample for calibration and characterization of scanning thermal microscopy (SThM) probes and systems. In our solution temperature field in thin film structure, which is being contacted with the thermal tip is controlled in the traceable manner. The developed technology, integrating plasma etching of Pt and chemical-mechanical planarization (CMP) processing, enabled manufacturing a nanosize 100 nm thick Pt resistor on SiO 2 with topography profile below 10 nm. Four-point setup makes it possible to generate and measure (in other words control) a defined temperature field of such a structure. The size of the thermally active structure is big enough to enable reliable SThM measurements and small enough to reduce the parasitic heat transport between the surface and the cantilever platform. The proposed solution enables measurement of the output signal of the scanning thermal microscope measurement system when the temperature of the reference sample is varied in the quantitative way. Furthermore, basing on the determined sensitivity the assessment of the resolution capabilities is possible., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In this paper we present design and application of novel piezoresistive scanning thermal microscopy (SThM) probes. The proposed probe integrates a piezoresistive deflection sensor and thermally active, resistive nanosize tip. Manufacturing technology includes standard silicon MEMS/CMOS processing and sophisticated postprocessing using Focus Ion Beam milling. Authors also describe dedicated measurement technique in order to perform quantitative nanoscale thermal probing. Performance of the developed thermal probes is validated by test scans (topography and temperature distribution) of silicon nanoresistors supplied with current., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Although definitions of rare disease vary, most acknowledge that there are small numbers of affected patients compared with other conditions. Small numbers of patients, overlapping involvement of investigators as researchers and caregivers, as well as close relationships between researchers and manufacturers require a different pattern of drug development. Regulatory guidances for rare diseases are available, as well as ones for specific rare diseases. Maintaining drug supply for rare diseases also demands innovative approaches., (© 2016 The American Society for Clinical Pharmacology and Therapeutics.)

The fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation is associated with a high relapse rate for patients with acute myeloid leukemia (AML) even after allogeneic hematopoietic stem cell transplantation (HSCT). Sorafenib is a tyrosine kinase inhibitor, which inhibits the FLT3 tyrosine kinase and has shown encouraging activity in FLT3-ITD AML. We conducted a phase I trial of maintenance sorafenib after HSCT in patients with FLT3-ITD AML (ClinicalTrials.govNCT01398501). Patients received a variety of conditioning regimens and graft sources. A dose escalation 3 + 3 cohort design was used to define the maximum tolerated dose (MTD), with an additional 10 patients treated at the MTD. Sorafenib was initiated between days 45 and 120 after HSCT and continued for 12 28-day cycles. Twenty-two patients were enrolled (status at HSCT: first complete remission [CR1], n = 16; second complete remission [CR2], n = 3; refractory, n = 3). The MTD was established at 400 mg twice daily with 1 dose-limiting toxicity (DLT) observed (pericardial effusion). Two patients died of transplantation-related causes, both unrelated to sorafenib. Two patients stopped sorafenib after relapse and 5 stopped because of attributable toxicities after the DLT period. Median follow-up for surviving patients is 16.7 months after HSCT (range, 8.1 to 35.0). There was 1 case of grade II acute graft-versus-host disease (GVHD) after starting sorafenib and the 12-month cumulative incidence of chronic GVHD was 38% (90% confidence interval [CI], 21% to 56%). For all patients, 1-year progression-free survival (PFS) was 85% (90% CI, 66% to 94%) and 1-year overall survival (OS) was 95% (90% CI, 79% to 99%) after HSCT. For patients in CR1/CR2 before HSCT (n = 19), 1-year PFS was 95% (90% CI, 76% to 99%) and 1-year OS was 100%, with only 1 patient who relapsed. Sorafenib is safe after HSCT for FLT3-ITD AML and merits further investigation for the prevention of relapse., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

More than 35% of acute myeloid leukemia (AML) patients harbor a constitutively activating mutation in FMS-like tyrosine kinase-3 (FLT3). The most common type, internal tandem duplication (ITD), confers poor prognosis. We report for the first time on TTT-3002, a tyrosine kinase inhibitor (TKI) that is one of the most potent FLT3 inhibitors discovered to date. Studies using human FLT3/ITD mutant leukemia cell lines revealed the half maximal inhibitory concentration (IC50) for inhibiting FLT3 autophosphorylation is from 100 to 250 pM. The proliferation IC50 for TTT-3002 in these same cells was from 490 to 920 pM. TTT-3002 also showed potent activity when tested against the most frequently occurring FLT3-activating point mutation, FLT3/D835Y, against which many current TKIs are ineffective. These findings were validated in vivo by using mouse models of FLT3-associated AML. Survival and tumor burden of mice in several FLT3/ITD transplantation models is significantly improved by administration of TTT-3002 via oral dosing. Finally, we demonstrated that TTT-3002 is cytotoxic to leukemic blasts isolated from FLT3/ITD-expressing AML patients, while displaying minimal toxicity to normal hematopoietic stem/progenitor cells from healthy blood and bone marrow donors. Therefore, TTT-3002 has demonstrated preclinical potential as a promising new FLT3 TKI in the treatment of FLT3-mutant AML.

Tyrosine kinase inhibitors (TKI) targeting angiogenesis via inhibition of the vascular endothelial growth factor pathway have changed the medical management of metastatic renal cell carcinoma. Although treatment with TKIs has shown clinical benefit, these drugs will eventually fail patients. The potential mechanisms of resistance to TKIs are poorly understood. To address this question, we obtained an excisional biopsy of a skin metastasis from a patient with clear cell renal carcinoma who initially had a response to sunitinib and eventually progressed with therapy. Tumor pieces were grafted s.c. in athymic nude mice. Established xenografts were treated with sunitinib. Tumor size, microvascular density, and pericyte coverage were determined. Plasma as well as tissue levels for sunitinib were assessed. A tumor-derived cell line was established and assessed in vitro for potential direct antitumor effects of sunitinib. To our surprise, xenografts from the patient who progressed on sunitinib regained sensitivity to the drug. At a dose of 40 mg/kg, sunitinib caused regression of the subcutaneous tumors. Histology showed a marked reduction in microvascular density and pericyte dysfunction. More interestingly, histologic examination of the original skin metastasis revealed evidence of epithelial to mesenchymal transition, whereas the xenografts showed reversion to the clear cell phenotype. In vitro studies showed no inhibitory effect on tumor cell growth at pharmacologically relevant concentrations. In conclusion, the histologic examination in this xenograft study suggests that reversible epithelial to mesenchymal transition may be associated with acquired tumor resistance to TKIs in patients with clear cell renal carcinoma.

Purpose: To determine the maximum tolerated dose (MTD), characterize the principal toxicities, and assess the pharmacokinetics of EKB-569, an oral selective irreversible inhibitor of the epidermal growth factor receptor tyrosine kinase, in combination with capecitabine in patients with advanced colorectal cancer., Experimental Design: Patients were treated with EKB-569 daily for 21 days and capecitabine twice daily for 14 days of a 21-day cycle. The dose levels of EKB-569 (mg/day) and capecitabine (mg/m(2) twice daily) assessed were 25/750, 50/750, 50/1,000 and 75/1,000. An expanded cohort was enrolled at the MTD to better study toxicity and efficacy. Samples of plasma were collected to characterize the pharmacokinetics of the agents. Treatment efficacy was assessed every other cycle., Results: A total of 37 patients, the majority of whom had prior chemotherapy, received a total of 163 cycles of treatment. Twenty patients were treated at the MTD, 50 mg EKB-569, daily and 1,000 mg/m(2) capecitabine twice daily. Dose-limiting toxicities were diarrhea and rash. No patients had complete or partial responses but 48% had stable disease. The conversion of capecitabine to 5-fluorouracil was higher for the combination of EKB-569 and capecitabine (321+/-151 ng*h/mL) than for capecitabine alone (176+/-62 ng*hours/mL; P=0.0037)., Conclusion: In advanced colorectal cancer, 50 mg EKB-569 daily can be safely combined with 1,000 mg/m(2) capecitabine twice a day. A statistically significant increase in plasma levels of 5-fluorouracil for the combination of EKB-569 and capecitabine may be due to the single-dose versus multiple-dose exposure difference, variability in exposure or a potential drug interaction.

This paper proposes a procedure to determine the position and volumetric information of a 3-D object, based on two previously calibrated camera images. The positioning and volumetric information is achieved by inscribing the object in a virtual bounding box, created from known vertices and vanishing points. The images of a starting virtual box are adjusted to fit a region of interest around each projection of the solid object. The volumes and positions defined by the adjusted boxes are approximations for the dimensions and location of the solid. The work displays the application of such a technique in an automated manufacturing process.