cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.12601195.v7
title: Mechanistic and biological characterisation of novel <i>N</i> <sup>5</sup>-substituted paullones targeting the biosynthesis of trypanothione in <i>Leishmania</i>

description: Trypanothione synthetase (TryS) produces <i>N</i> <sup>1</sup> <i>,N<sup>8</sup> </i>-bis(glutathionyl)spermidine (or trypanothione) at the expense of ATP. Trypanothione is a metabolite unique and essential for survival and drug-resistance of trypanosomatid parasites. In this study, we report the mechanistic and biological characterisation of optimised <i>N</i> <sup>5</sup>-substituted paullone analogues with anti-TryS activity. Several of the new derivatives retained submicromolar IC<sub>50</sub> against leishmanial TryS. The binding mode to TryS of the most potent paullones has been revealed by means of kinetic, biophysical and molecular modelling approaches. A subset of analogues showed an improved potency (EC<sub>50</sub> 0.5–10 µM) and selectivity (20–35) against the clinically relevant stage of <i>Leishmania braziliensis</i> (mucocutaneous leishmaniasis) and <i>L. infantum</i> (visceral leishmaniasis). For a selected derivative, the mode of action involved intracellular depletion of trypanothione. Our findings shed light on the molecular interaction of TryS with rationally designed inhibitors and disclose a new set of compounds with on-target activity against different <i>Leishmania</i> species.
DOI: 10.6084/m9.figshare.12850343.v2
title: Design, synthesis and biological evaluation of a new thieno[2,3-<i>d</i>]pyrimidine-based urea derivative with potential antitumor activity against tamoxifen sensitive and resistant breast cancer cell lines

description: Breast cancer (BC) and endocrine resistance to chemotherapy are challenging problems where angiogenesis plays fundamental roles. Thus, targeting of VEGFR-2 signalling pathway has been an attractive approach. In this study, we synthesised a new sorafenib analogue, thieno[2,3-<i>d</i>]pyrimidine based urea derivative, <b>KM6</b>. It showed 65% inhibition of VEGF2 tyrosine kinase activity and demonstrated a potential antitumor activity in TAM-resistant, LCC2, and its parental MCF7 BC cells. <b>KM6</b> retained the sensitivity of LCC2 through upregulation of key enzymes of apoptosis and proteins of cell death including caspases 3, 8, 9, P53, BAX/BCL-2 ratio and LDH in media. It downregulated mRNA expression of Ki-67, survivin, Akt, and reduced levels of ROS and glucose uptake. Moreover, <b>KM6</b> reduced the levels of inflammation markers PGE2, COX2, IL-1β and IL6 and metastasis markers MMP-2 and MMP-9. In conclusion, <b>KM6</b> is a promising compound for ER + and TAM-resistant BC with many potential antitumor and polypharmacological mechanisms.
DOI: 10.6084/m9.figshare.12601195.v6
title: Mechanistic and biological characterisation of novel <i>N</i><sup>5</sup>-substituted paullones targeting the biosynthesis of trypanothione in <i>Leishmania</i>

description: Trypanothione synthetase (TryS) produces <i>N</i><sup>1</sup><i>,N<sup>8</sup></i>-bis(glutathionyl)spermidine (or trypanothione) at the expense of ATP. Trypanothione is a metabolite unique and essential for survival and drug-resistance of trypanosomatid parasites. In this study, we report the mechanistic and biological characterisation of optimised <i>N</i><sup>5</sup>-substituted paullone analogues with anti-TryS activity. Several of the new derivatives retained submicromolar IC<sub>50</sub> against leishmanial TryS. The binding mode to TryS of the most potent paullones has been revealed by means of kinetic, biophysical and molecular modelling approaches. A subset of analogues showed an improved potency (EC<sub>50</sub> 0.5–10 µM) and selectivity (20–35) against the clinically relevant stage of <i>Leishmania braziliensis</i> (mucocutaneous leishmaniasis) and <i>L. infantum</i> (visceral leishmaniasis). For a selected derivative, the mode of action involved intracellular depletion of trypanothione. Our findings shed light on the molecular interaction of TryS with rationally designed inhibitors and disclose a new set of compounds with on-target activity against different <i>Leishmania</i> species.
DOI: 10.6084/m9.figshare.12143595
title: Inhibition of African swine fever virus protease by myricetin and myricitrin

description: African swine fever (ASF) caused by the ASF virus (ASFV) is the most hazardous swine disease. Since a huge number of pigs have been slaughtered to avoid a pandemic spread, intense studies on the disease should be followed quickly. Recent studies reported that flavonoids have various antiviral activity including ASFV. In this report, ASFV protease was selected as an antiviral target protein to cope with ASF. With a FRET (Fluorescence resonance energy transfer) method, ASFV protease was assayed with a flavonoid library which was composed of sixty-five derivatives classified based on ten different scaffolds. Of these, the flavonols scaffold contains a potential anti-ASFV protease activity. The most prominent flavonol was myricetin with IC<sub>50</sub> of 8.4 <i>μ</i>M. Its derivative, myricitrin, with the rhamnoside moiety was also showed the profound inhibitory effect on ASFV protease. These two flavonols apparently provide a way to develop anti-ASFV agents based on their scaffold.
DOI: 10.6084/m9.figshare.12143595.v2
title: Inhibition of African swine fever virus protease by myricetin and myricitrin

description: African swine fever (ASF) caused by the ASF virus (ASFV) is the most hazardous swine disease. Since a huge number of pigs have been slaughtered to avoid a pandemic spread, intense studies on the disease should be followed quickly. Recent studies reported that flavonoids have various antiviral activity including ASFV. In this report, ASFV protease was selected as an antiviral target protein to cope with ASF. With a FRET (Fluorescence resonance energy transfer) method, ASFV protease was assayed with a flavonoid library which was composed of sixty-five derivatives classified based on ten different scaffolds. Of these, the flavonols scaffold contains a potential anti-ASFV protease activity. The most prominent flavonol was myricetin with IC<sub>50</sub> of 8.4 <i>μ</i>M. Its derivative, myricitrin, with the rhamnoside moiety was also showed the profound inhibitory effect on ASFV protease. These two flavonols apparently provide a way to develop anti-ASFV agents based on their scaffold.
DOI: 10.6084/m9.figshare.12143595.v1
title: Inhibition of African swine fever virus protease by myricetin and myricitrin

description: African swine fever (ASF) caused by the ASF virus (ASFV) is the most hazardous swine disease. Since a huge number of pigs have been slaughtered to avoid a pandemic spread, intense studies on the disease should be followed quickly. Recent studies reported that flavonoids have various antiviral activity including ASFV. In this report, ASFV protease was selected as an antiviral target protein to cope with ASF. With a FRET (Fluorescence resonance energy transfer) method, ASFV protease was assayed with a flavonoid library which was composed of sixty-five derivatives classified based on ten different scaffolds. Of these, the flavonols scaffold contains a potential anti-ASFV protease activity. The most prominent flavonol was myricetin with IC<sub>50</sub> of 8.4 <i>μ</i>M. Its derivative, myricitrin, with the rhamnoside moiety was also showed the profound inhibitory effect on ASFV protease. These two flavonols apparently provide a way to develop anti-ASFV agents based on their scaffold.
DOI: 10.6084/m9.figshare.12850541
title: Exploring the potential of the dynamic hysteresis loops via high field, high frequency and temperature adjustable AC magnetometer for magnetic hyperthermia characterization

description: The Specific Absorption Rate (SAR) is the key parameter to optimize the effectiveness of magnetic nanoparticles in magnetic hyperthermia. AC magnetometry arises as a powerful technique to quantify the SAR by computing the hysteresis loops' area. However, currently available devices produce quite limited magnetic field intensities, below 45mT, which are often insufficient to obtain major hysteresis loops and so a more complete and understandable magneticcharacterization. This limitation leads to a lack of information concerning some basic properties, like the maximum attainable (SAR) as a function of particles' size and excitation frequencies, or the role of the mechanical rotation in liquid samples. To fill this gap, we have developed a versatile high field AC magnetometer, capable of working at a wide range of magnetic hyperthermia frequencies (100 kHz – 1MHz) and up to field intensities of 90mT. Additionally, our device incorporates a variable temperature system for continuous measurements between 220 and 380 K. We have optimized the geometrical properties of the induction coil that maximize the generated magnetic field intensity. To illustrate the potency of our device, we present and model a series of measurements performed in liquid and frozen solutions of magnetic particles with sizes ranging from 16 to 29 nm. We show that AC magnetometry becomes a very reliable technique to determine the effective anisotropy constant of single domains, to study the impact of the mechanical orientation in the SAR and to choose the optimal excitation parameters to maximize heating production under human safety limits.
DOI: 10.6084/m9.figshare.12850541.v1
title: Exploring the potential of the dynamic hysteresis loops via high field, high frequency and temperature adjustable AC magnetometer for magnetic hyperthermia characterization

description: The Specific Absorption Rate (SAR) is the key parameter to optimize the effectiveness of magnetic nanoparticles in magnetic hyperthermia. AC magnetometry arises as a powerful technique to quantify the SAR by computing the hysteresis loops' area. However, currently available devices produce quite limited magnetic field intensities, below 45mT, which are often insufficient to obtain major hysteresis loops and so a more complete and understandable magneticcharacterization. This limitation leads to a lack of information concerning some basic properties, like the maximum attainable (SAR) as a function of particles' size and excitation frequencies, or the role of the mechanical rotation in liquid samples. To fill this gap, we have developed a versatile high field AC magnetometer, capable of working at a wide range of magnetic hyperthermia frequencies (100 kHz – 1MHz) and up to field intensities of 90mT. Additionally, our device incorporates a variable temperature system for continuous measurements between 220 and 380 K. We have optimized the geometrical properties of the induction coil that maximize the generated magnetic field intensity. To illustrate the potency of our device, we present and model a series of measurements performed in liquid and frozen solutions of magnetic particles with sizes ranging from 16 to 29 nm. We show that AC magnetometry becomes a very reliable technique to determine the effective anisotropy constant of single domains, to study the impact of the mechanical orientation in the SAR and to choose the optimal excitation parameters to maximize heating production under human safety limits.
DOI: 10.6084/m9.figshare.12409574.v1
title: Radiofrequency applicator concepts for thermal magnetic resonance of brain tumors at 297 MHz (7.0 Tesla)

description: Thermal intervention is a potent sensitizer of cells to chemo- and radiotherapy in cancer treatment. Glioblastoma multiforme (GBM) is a potential clinical target, given the cancer’s aggressive nature and resistance to current treatment options. The annular phased array (APA) technique employing electromagnetic waves in the radiofrequency (RF) range allows for localized temperature increase in deep seated target volumes (TVs). Reports on clinical applications of the APA technique in the brain are still missing. Ultrahigh field magnetic resonance (MR) employs higher frequencies than conventional MR and has potential to provide focal temperature manipulation, high resolution imaging and noninvasive temperature monitoring using an integrated RF applicator (ThermalMR). This work examines the applicability of RF applicator concepts for ThermalMR of brain tumors at 297 MHz (7.0 Tesla). Electromagnetic field (EMF) simulations are performed for clinically realistic data based on GBM patients. Two algorithms are used for specific RF energy absorption rate based thermal intervention planning for small and large TVs in the brain, aiming at maximum RF power deposition or RF power uniformity in the TV for 10 RF applicator designs. For both TVs , the power optimization outperformed the uniformity optimization. The best results for the small TV are obtained for the 16 element interleaved RF applicator using an elliptical antenna arrangement with water bolus. The two row elliptical RF applicator yielded the best result for the large TV. This work investigates the capacity of ThermalMR to achieve targeted thermal interventions in model systems resembling human brain tissue and brain tumors.
DOI: 10.6084/m9.figshare.12465986.v1
title: Comparison of transcatheter arterial chemoembolization combined with radiofrequency ablation or microwave ablation for the treatment of unresectable hepatocellular carcinoma: a systemic review and meta-analysis

description: Transcatheter arterial chemoembolization (TACE), radiofrequency ablation (RFA), and microwave ablation (MWA) are regarded as effective therapies for treating unresectable hepatocellular carcinoma (HCC). We conducted this study to compare the efficiency and safety of TACE combined with RFA (TR group) or MWA (TM group). PubMed, the Cochrane Library, Ovid Medline, Web of Science, Scopus, Embase, ScienceDirect, and Google Scholar were searched. The primary endpoints were overall survival (OS), progression-free survival (PFS), response rates, and complications. Eight cohort studies and one randomized controlled trial were included. The TM group had better OS (Hazard ratio [HR]: 1.55; 95% confidence interval [CI]: 1.09–2.21, <i>p</i> = 0.01) and a better 2- and 3-year OS rate, 24-month PFS rate (Risk ratio [RR]: 0.67; 95% CI: 0.46–0.96, <i>p</i> = 0.03), and complete response rate (RR: 0.87; 95% CI: 0.79–0.96, <i>p</i> = 0.003) than the TR group. Furthermore, the TM and TR groups did not show significant differences in PFS, the disease control rate or complications. The advantage of TM was mainly reflected in younger patients (50–60 years old) compared with patients aged 60–70 years, as well as in patients with larger tumors (≥3 cm) compared with patients with tumors &lt;3 cm. Moreover, patients treated with conventional TACE (cTACE) in the TM group showed longer OS, while patients treated with drug-eluting bead transarterial chemoembolization (DEB-TACE) in the TR group showed a higher overall response rate. TM seems to be a more effective therapy than TR for unresectable HCC, with better survival and similar safety.
DOI: 10.6084/m9.figshare.12409574
title: Radiofrequency applicator concepts for thermal magnetic resonance of brain tumors at 297 MHz (7.0 Tesla)

description: Thermal intervention is a potent sensitizer of cells to chemo- and radiotherapy in cancer treatment. Glioblastoma multiforme (GBM) is a potential clinical target, given the cancer’s aggressive nature and resistance to current treatment options. The annular phased array (APA) technique employing electromagnetic waves in the radiofrequency (RF) range allows for localized temperature increase in deep seated target volumes (TVs). Reports on clinical applications of the APA technique in the brain are still missing. Ultrahigh field magnetic resonance (MR) employs higher frequencies than conventional MR and has potential to provide focal temperature manipulation, high resolution imaging and noninvasive temperature monitoring using an integrated RF applicator (ThermalMR). This work examines the applicability of RF applicator concepts for ThermalMR of brain tumors at 297 MHz (7.0 Tesla). Electromagnetic field (EMF) simulations are performed for clinically realistic data based on GBM patients. Two algorithms are used for specific RF energy absorption rate based thermal intervention planning for small and large TVs in the brain, aiming at maximum RF power deposition or RF power uniformity in the TV for 10 RF applicator designs. For both TVs , the power optimization outperformed the uniformity optimization. The best results for the small TV are obtained for the 16 element interleaved RF applicator using an elliptical antenna arrangement with water bolus. The two row elliptical RF applicator yielded the best result for the large TV. This work investigates the capacity of ThermalMR to achieve targeted thermal interventions in model systems resembling human brain tissue and brain tumors.
DOI: 10.6084/m9.figshare.12326126.v1
title: Mathematical modeling of the thermal effects of irreversible electroporation for <i>in vitro</i>, <i>in vivo</i>, and clinical use: a systematic review

description: Irreversible electroporation (IRE) is a relatively new ablation method for the treatment of unresectable cancers. Although the main mechanism of IRE is electric permeabilization of cell membranes, the question is to what extent thermal effects of IRE contribute to tissue ablation. This systematic review reviews the mathematical models used to numerically simulate the heat-generating effects of IRE, and uses the obtained data to assess the degree of mild-hyperthermic (temperatures between 40 °C and 50 °C) and thermally ablative (TA) effects (temperatures exceeding 50 °C) caused by IRE within the IRE-treated region (IRE-TR). A systematic search was performed in medical and technical databases for original studies reporting on numerical simulations of IRE. Data on used equations, study design, tissue models, maximum temperature increase, and surface areas of IRE-TR, mild-hyperthermic, and ablative temperatures were extracted. Several identified models, including Laplace equation for calculation of electric field distribution, Pennes Bioheat Equation for heat transfer, and Arrhenius model for thermal damage, were applied on various electrode and tissue models. Median duration of combined mild-hyperthermic and TA effects is 20% of the treatment time. Based on the included studies, mild-hyperthermic temperatures occurred in 30% and temperatures ≥50 °C in 5% of the IRE-TR. Simulation results in this review show that significant mild-hyperthermic effects occur in a large part of the IRE-TR, and direct thermal ablation in comparatively small regions. Future studies should aim to optimize clinical IRE protocols, maintaining a maximum irreversible permeabilized region with minimal TA effects.
DOI: 10.6084/m9.figshare.12465986
title: Comparison of transcatheter arterial chemoembolization combined with radiofrequency ablation or microwave ablation for the treatment of unresectable hepatocellular carcinoma: a systemic review and meta-analysis

description: Transcatheter arterial chemoembolization (TACE), radiofrequency ablation (RFA), and microwave ablation (MWA) are regarded as effective therapies for treating unresectable hepatocellular carcinoma (HCC). We conducted this study to compare the efficiency and safety of TACE combined with RFA (TR group) or MWA (TM group). PubMed, the Cochrane Library, Ovid Medline, Web of Science, Scopus, Embase, ScienceDirect, and Google Scholar were searched. The primary endpoints were overall survival (OS), progression-free survival (PFS), response rates, and complications. Eight cohort studies and one randomized controlled trial were included. The TM group had better OS (Hazard ratio [HR]: 1.55; 95% confidence interval [CI]: 1.09–2.21, <i>p</i> = 0.01) and a better 2- and 3-year OS rate, 24-month PFS rate (Risk ratio [RR]: 0.67; 95% CI: 0.46–0.96, <i>p</i> = 0.03), and complete response rate (RR: 0.87; 95% CI: 0.79–0.96, <i>p</i> = 0.003) than the TR group. Furthermore, the TM and TR groups did not show significant differences in PFS, the disease control rate or complications. The advantage of TM was mainly reflected in younger patients (50–60 years old) compared with patients aged 60–70 years, as well as in patients with larger tumors (≥3 cm) compared with patients with tumors &lt;3 cm. Moreover, patients treated with conventional TACE (cTACE) in the TM group showed longer OS, while patients treated with drug-eluting bead transarterial chemoembolization (DEB-TACE) in the TR group showed a higher overall response rate. TM seems to be a more effective therapy than TR for unresectable HCC, with better survival and similar safety.
DOI: 10.6084/m9.figshare.12326126
title: Mathematical modeling of the thermal effects of irreversible electroporation for <i>in vitro</i>, <i>in vivo</i>, and clinical use: a systematic review

description: Irreversible electroporation (IRE) is a relatively new ablation method for the treatment of unresectable cancers. Although the main mechanism of IRE is electric permeabilization of cell membranes, the question is to what extent thermal effects of IRE contribute to tissue ablation. This systematic review reviews the mathematical models used to numerically simulate the heat-generating effects of IRE, and uses the obtained data to assess the degree of mild-hyperthermic (temperatures between 40 °C and 50 °C) and thermally ablative (TA) effects (temperatures exceeding 50 °C) caused by IRE within the IRE-treated region (IRE-TR). A systematic search was performed in medical and technical databases for original studies reporting on numerical simulations of IRE. Data on used equations, study design, tissue models, maximum temperature increase, and surface areas of IRE-TR, mild-hyperthermic, and ablative temperatures were extracted. Several identified models, including Laplace equation for calculation of electric field distribution, Pennes Bioheat Equation for heat transfer, and Arrhenius model for thermal damage, were applied on various electrode and tissue models. Median duration of combined mild-hyperthermic and TA effects is 20% of the treatment time. Based on the included studies, mild-hyperthermic temperatures occurred in 30% and temperatures ≥50 °C in 5% of the IRE-TR. Simulation results in this review show that significant mild-hyperthermic effects occur in a large part of the IRE-TR, and direct thermal ablation in comparatively small regions. Future studies should aim to optimize clinical IRE protocols, maintaining a maximum irreversible permeabilized region with minimal TA effects.
DOI: 10.6084/m9.figshare.13078613
title: The impact of HIPEC <i>vs.</i> EPIC for the treatment of mucinous appendiceal carcinoma: a study from the US HIPEC collaborative

description: Mucinous appendiceal carcinoma is a rare malignancy that commonly spreads to the peritoneum leading to peritoneal metastases. Complete cytoreduction with perioperative intraperitoneal chemotherapy (PIC) is the mainstay of treatment, administered as either hyperthermic intra peritoneal chemotherapy (HIPEC) or early post-operative intraperitoneal chemotherapy (EPIC). Our goal was to assess the perioperative and long term survival outcomes associated with these two PIC methods. Patients with mucinous appendiceal carcinoma were identified in the US HIPEC Collaborative database from 12 academic institutions. Patient demographics, clinical characteristics, and survival outcomes were compared among patients who underwent HIPEC <i>vs.</i> EPIC with inverse probability weighting (IPW) used for adjustment. Among 921 patients with mucinous appendiceal carcinoma, 9% underwent EPIC while 91% underwent HIPEC. There was no difference in Grade III–V complications between the two groups (18.5% for HIPEC <i>vs.</i> 15.0% for EPIC, <i>p</i>=.43) though patients who underwent HIPEC had higher rates of readmissions (21.2% <i>vs.</i> 8.8%, <i>p</i> Among patients with mucinous appendiceal carcinoma, both EPIC and HIPEC appear to be associated with similar perioperative and long-term outcomes.