bluuebunny/crossref_metadata_2025 huggingface dataset:
Past Climate Variability in the Last Millennium
Authors: Zorita Eduardo , Hünicke Birgit , Tim Nele , Rouault Matthieu
Published: January 2024

We review our knowledge of the climate variability in southern Africa over the past millennium, based on information provided by proxy data and by climate simulations. Since proxy data almost exclusively record past temperature and/or precipitation, the review is focused on those two variables. Proxy data identify three thermal phases in the region: a medieval warm period around year 1000 CE (common era), a Little Ice Age until about the eighteenth century, and a clear warming phase since that temperature minimum until the present period. Variations of precipitation are different in the summer-rainfall and winter-rainfall regions. In the former, precipitation tends to accompany the temperature, with warm/humid and cold/dry phases. In the winter-rainfall zone, the variations are opposite to temperature. Thus, past precipitation variations display a see-saw pattern between the summer- and winter-rainfall zones. However, climate simulations do not display these three different hydroclimatic periods. Instead, the simulations show a clearly warm twentieth century and punctuated cooling due to volcanic eruptions, with otherwise little variations during the pre-industrial period. Also, the simulations do not indicate an anticorrelation between precipitation in the summer- and winter-rainfall zones. Possible reasons for these discrepancies are discussed.
Cardiotoxicity of Targeted Therapies: Imaging of Heart Does Matter
Authors: Calabretta Raffaella , Hacker Marcus
Published: January 2024

Molecular targeted therapies are characterized by blocking essential biochemical pathways or mutant proteins that are required for cancer cell growth and survival. Targeted cancer therapeutics are amongst the major treatment options for cancer today. These treatments are more selective for cancer cells and improve the quality of life for cancer patients undergoing therapy. Nevertheless, cardiotoxicity is a frequent side effect in targeted therapies, frequently described as myocardial dysfunction and heart failure. Cardiotoxicity includes also any subsequent functional or structural heart injury, with a possible accelerated development of cardiovascular diseases. Early identification of patients at risk for cardiotoxicity from cancer target therapies and the early diagnosis of CV complications related to cancer treatments are crucial. Anamnesis and risk stratification are the first steps of the diagnostic process to detect myocardial toxicity. Electrocardiography, cardiac biomarkers, and cardiac imaging modalities (echocardiography, CMR, PET, conventional imaging, and cardiac CT) are essential for a cardiotoxicity screening.
Precision Oncology with PSMA-Targeted α-Particle Therapy of mCRPC
Authors: Jadvar Hossein
Published: January 2024

Prostate-specific membrane antigen (PSMA) has been firmly established as a clinically relevant biomarker in imaging and targeted radionuclide therapy (theranostics) of prostate cancer, particularly in the metastatic castrate-resistant state. Numerous investigations from around the world in both academic and pharma settings are focused on research and development of safe and effective PSMA-based theranostic agents. Encouraging results from retrospective studies using the β-particle emitting 177Lu-PSMA-617 radioligand therapy prompted prospective phase II and phase III randomized clinical trials with recently published favorable results of the VISION trial. While these pivotal investigations continue, there has also been major growing interest in the potential clinical utility of α-particle PSMA-targeted therapeutic agents. After a brief review of PSMA biology, imaging with positron emission tomography, and current experience with targeted β-particle (177Lu) therapy, this article summarizes the preclinical and early clinical studies that have evaluated the PSMA-targeted agents conjugated properly to α-particle radiolabels including 225Ac, 213Bi, 227Th, 212Pb, and 149Tb.
From Radioimmunodetection to Radiomolecular Precision Oncology Via Radionanotargeting by Intelligent Multidisciplinary Radiotheragnostic Nanoparticles
Authors: Kairemo Kalevi
Published: January 2024

This chapter describes briefly some scientific activities common to Richard P. Baum and Kalevi Kairemo. Both started with radioimmunodetection in late 1980s and ended up with radiomolecular precision oncology in 2020s. The author also had own interests which Richard Baum did not touch. The author worked some time with oligonucleotide radionuclide therapy (radionanotargeting) in the 1990s learning that it will be impossible in clinical practice. On the contrary, in spite of his own scepticism, intelligent multidisciplinary targeted nanoparticles could be constructed although being cumbersome. Here radiotheragnostic compounds will play major role. Additionally, some personal aspects are presented in order to honour Richard Baum’s achievements.
PSMA Radioligand Therapy: A Revolution in the Precision Radiomolecular Oncology of Prostate Cancer
Authors: Kulkarni Harshad R.
Published: January 2024

The incidence of prostate cancer is ever increasing. After various time intervals, the disease almost always becomes resistant to the standard hormone treatment (castration-resistant prostate cancer, CRPC). Most patients with CRPC either already have metastases at diagnosis or develop them during the early months of follow-up, which is associated with a relatively poor prognosis. The taxane-based chemotherapy for metastatic CRPC (mCRPC), first line with docetaxel and second line using cabazitaxel, are associated with a high incidence of adverse effects. The novel androgen-axis drugs (NAAD) used after chemotherapy are androgen biosynthesis inhibitor abiraterone acetate (combined with prednisolone), the androgen receptor blockers enzalutamide as well as the newer generation apalutamide and darolutamide. However, these treatment regimens only provide a meager survival benefit in mCRPC. Radium-223 targets only the osteoblastic metastases and does not treat nodal or visceral metastases. Therefore, there has been an unmet need for targeted therapy.
Theranostics in Australia: The Importance of Vision and Training, and the Power of Collaboration
Authors: Lenzo Nat
Published: January 2024

The Australian nuclear medicine landscape is a vibrant mix of public and private sector facilities providing not only high-quality routine care to patients, but also cutting-edge research in diagnostic and therapeutic nuclear medicine. Australia’s unique regulatory framework, its relatively well-funded health system and its long-established rigorous training of physicians and supporting staff, has stimulated more rapid growth and earlier adoption of theranostics and therapeutic nuclear oncology when compared to many other countries around the world. More recently, interest and successful deployment of clinical trials networks across the country is helping obtain the data required to propel these new agents into clinical practice. The evolution of therapeutic nuclear oncology from the early days of I-131 use to the development of the Australasian Radiopharmaceutical Trials Network (ARTNET) and some of the factors for the Australian competitive advantage in this space will be discussed in this chapter.
Theranostic Radiopeptides in Nuclear Oncology: Design, Preclinical Screening, and Clinical Translation
Authors: Nock Berthold A. , Maina Theodosia
Published: January 2024

Cancer theranostics is an emerging and exciting field in nuclear medicine, whereby suitably designed radionuclide carriers, after injection to patients, seek and specifically interact with biomolecular targets overexpressed on cancer cells. When a diagnostic radionuclide is applied, molecular imaging with SPECT (gamma emitter) or PET (positron emitter) will reveal tumor lesions, allowing for initial diagnosis and assessment of disease spread and progression. Hence, molecular imaging represents a reliable tool for patient stratification, dosimetry and planning of therapy that follows next with the respective therapeutic radionuclide (beta, Auger electron, or alpha emitter) carrier in an integrated patient-tailored approach. In this way, patients are spared from ineffective and toxic therapies that only impair quality of life without any tangible benefit. Several recent examples have demonstrated the feasibility and efficacy of this strategy. Thus, the advent of radiolabeled somatostatin analogs in the management of neuroendocrine tumors on one hand, and the successful application of prostate-specific membrane antigen inhibitors to diagnose and combat prostate cancer on the other, are two elegant paradigms of this approach.

In this chapter, we shall discuss important issues pertaining to the design and preclinical evaluation of peptide-based radioligands, focusing on compound examples developed in our center. The steps to be followed for clinical translation of selected analogs will be also briefly described. Emphasis will be given on the significance of pilot proof-of-principle studies in a small number of patients to guide further efforts toward drug development and registration.
High-Performance Radiopharmacy: The Base for Precision Oncology
Authors: Müller Dirk , Fuchs Alexander , Leshch Yevgeniy , Schulze Peter , Pröhl Michael
Published: January 2024

The Zentralklinik Bad Berka is a privately financed hospital, and it is not a university hospital. Since it is not located in the immediate vicinity of a large city, one could assume that it is rather an unspectacular clinic on the edge of a forest. Nevertheless, for many years, this hospital has been generating high-quality scientific publications [1–7].
Therapy of Castration-Resistant Prostate Cancer: Where Is the Place of 225Ac-PSMA?
Authors: Lawal Ismaheel O. , Morgenstern Alfred , Knoesen Otto , Vorster Mariza , Bruchertseifer Frank , Sathekge Mike M.
Published: January 2024

Since the first report in 2004 confirming the survival advantage conferred by docetaxel in the treatment of men with metastatic castration-resistant prostate cancer (mCRPC), many more agents have also been found to prolong life and are now in routine use in clinical practice. Despite the multitude of these effective agents, mCRPC remains a fatal disease with a poor prognosis. Efforts to develop more effective therapies are, therefore, ongoing. Targeting prostate-specific membrane antigen (PSMA) overexpressed on prostate cancer cells has become an attractive option for mCRPC treatment. Ligands that bind to PSMA expressed on prostate cancer cells have been labeled to radionuclides for imaging and therapy in a theranostic approach to prostate cancer management. Actinium-225 (225Ac) is an alpha-emitting radionuclide that has been successfully labeled to PSMA ligands as 225Ac-PSMA for targeted alpha therapy (TAT) of mCRPC. The short path length of the highly energetic alpha particles causes deposition of massive energy in the tumor, leading to irreparable double-strand DNA damage, and consequently, tumor cell death while sparing surrounding normal tissues. When applied as a last-line therapy agent, 225Ac-PSMA therapy effectiveness is comparable or better than agents applied earlier in the treatment sequence of mCRPC. 225Ac-PSMA produces the most remarkable response in the chemotherapy-naïve setting, causing a high and sustained response in men with mCRPC. Xerostomia, a result of 225Ac-PSMA irradiation of the salivary gland parenchyma resulting from its intense accumulation in the glands, is the most worrisome complication of therapy. Different interventions, including dynamic dose de-escalation, combination therapy, and reduced administered activity, are being explored to ameliorate this adverse effect of treatment.
A (188)Rejuvenating Journey with Hercules
Authors: Shinto Ajit S.
Published: January 2024

Prof Richard Baum has been closely associated with the WARMTH Rhenium Task force which was established with a vision to expand the knowledge, research, and clinical base of Re 188, considering its cost-effectiveness and versatile utility.
Evaluation of Real-World Efficiency of 177Lu-PSMA Radioligand Therapy of Metastatic Prostate Cancer
Authors: Turner J. Harvey
Published: January 2024

Throughout the world, hundreds of patients with advanced metastatic prostate cancer are currently being treated with 177Lu-PSMA radioligands on compassionate usage protocols in accord with published guidelines of the European Association of Nuclear Medicine (EANM). However, 7 years after the introduction of 68Ga/177Lu-PSMA theranostic management of metastatic castration-resistant prostate cancer (mCRPC), it remained unapproved by any national regulatory authority, and has yet to achieve oncologist/urologist acceptance into mainstream clinical practice. The reasons for the nonacceptance of 177Lu-PSMA-radioligand therapy (RLT) are explored in this review, which charts the evolution of this very promising treatment modality, pioneered in German, Austrian, and Australian academic hospitals, from which many retrospective reports of efficacy have been published. This efficacy has subsequently been demonstrated by completion of the Pharma randomized controlled trial, the VISION Study which led to formal regulatory approval. However, in order to promote worldwide availability, and to evaluate efficiency in respect of improved survival and quality of life, the proposed WARMTH NIGHTCAP (World Association for Radiopharmaceutical and Molecular Therapy National Investigators Global Harmonised Theranostics of Cancer of Prostate) Study was designed to prospectively audit 68Ga/177Lu-PSMA RLT in a large real-world population of mCRPC patients, in up to 50 countries, now being treated on compassionate access programs. The NIGHTCAP Study did not come to fruition due to the COVID pandemic but the design principles remain valid.
Is It Possible to Target HER2 Using Affibody Receptor Radionuclide Therapy?
Authors: Zhu Hua , Guo Xiaoyi , Meng Xiangxi , Yang Zhi
Published: January 2024

Human epidermal receptor type 2 (HER2; also known as ErbB2) is an idea target for target therapy. HER2-targeted treatments with trastuzumab and its derivates or analogues can improve the overall survival of patients with HER2-overexpression tumors. This chapter describes the construction and clinical translational study of 64Cu-NOTA-Trastuzumab, 124I-Trastuzumab, and 68Ga-HER2 affibody tracer. Inspired by recently most popular peptide receptor radionuclide therapy with lutetium-177 dotatate (177Lu-DOTATATE) for advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and 177Lu-PSMA-617 for metastatic castration resistant prostate cancer therapy (mCRPC), the establishment of affibody receptor radionuclide therapy (ARRT) has the potential to provide an alternative treatment option for future HER2 positive resistant patients.
From Radiochemistry of the Lanthanides to 225Ac and the Interference with Richard Baum
Authors: Beyer Gerd Juergen
Published: January 2024

In 1990, Heinz Schelbert, one of the pioneers of PET, has been asked during an invited lecture at the ZfK Rossendorf, why it happens that few newly created PET centers have significant success and others do not have at all. His answer was simple and clear: institutions where physicians accept scientists, for instance radio-chemists and physicists as equal partners and where they collaborate truly together, there the progress is programmed. In my scientific carrier, I have been privileged to have those fruitful collaborations, for instance with Prof. W. G. Franke, Clinic of Nuclear Medicine of the Medical Academy Dresden in the late 70-th–end 80-th and further at the end of my carrier with Richard Baum. He is one of those distinguished nuclear medical physicians, he is not only just collaborating with experts in different scientific disciplines (biochemistry, radiochemistry, physics, and others), he is promoting those close collaboration and has created a network around the world independent on political and economic situation in countries like Cuba, China, South Africa, and others. His strong engagement is motivating us in developing new techniques making new radionuclides available toward personalized nuclear medicine. In this contribution, I try to give a historical overview over the related research work that has been performed in Dresden, Dubna, and Geneva starting from the methodical developments for nuclear physics basic research in the late 60-th until the recent input especially with the Tb-isotopes to the Bad Berka activities guided by Richard Baum.
A Tree Can Be Recognized by Its Fruit
Authors: de Jong Marion
Published: January 2024

This book’s contribution deals with the delicious fruits of the exciting and hard work performed by Prof. Richard Baum and his team in the Zentralklinik Bad Berka, Germany. Herein the fruits from his work as a scientist in the field of theranostics, as a physician in the clinic, and the fruits from a dear friendship are dealt with.
Notes on gauge fields and discrete series representations in de Sitter spacetimes
Authors: Fukelman Alan Rios , Sempé Matías , Silva Guillermo A.
Published: January 2024

Abstract

In this note we discuss features of the simplest spinning Discrete Series Unitary Irreducible Representations (UIR) of SO(1,4). These representations are known to be realised in the single particle Hilbert space of a free gauge field propagating in a four dimensional fixed de Sitter background. They showcase distinct features as compared to the more common Principal Series realised by heavy fields. Upon computing the 1 loop Sphere path integral we show that the edge modes of the theory can be understood in terms of a Discrete Series of SO(1, 2). We then canonically quantise the theory and show how group theory constrains the mode decomposition. We further clarify the role played by the second SO(4) Casimir in the single particle Hilbert space of the theory.
Test of new physics effects in $$ \overline{B}\to \left({D}^{\left(\ast \right)},\pi \right){\ell}^{-}{\overline{\nu}}_{\ell } $$ decays with heavy and light leptons
Authors: Ray Ipsita , Nandi Soumitra
Published: January 2024

Abstract

We study the $$ \overline{B}\to D\left({D}^{\ast}\right){\ell}^{-}{\overline{\nu}}_{\ell } $$

B
¯

→
D

D
∗

ℓ
−

ν
¯

ℓ

decays based on the up-to-date available inputs from experiments and the lattice. First, we review the standard model (SM) predictions of the different observables associated with these decay channels. In the analyses, we consider new physics (NP) effects in the channels with the heavy (τ), as well as the light leptons (μ, e). We have extracted |Vcb| along with the new physics Wilson coefficients (WCs) from the available data on light leptons; the extracted value of |Vcb| is (40.3 ± 0.5) × 10−3. The extracted WCs are consistent with zero, but some could be of order 10−2. Also, we have done the simultaneous analysis of the data in $$ \overline{B}\to {D}^{\left(\ast \right)}\left({\mu}^{-},{e}^{-}\right)\overline{\nu} $$

B
¯

→

D

∗

μ
−

e
−

ν
¯

alongside the inputs on $$ R\left({D}^{\left(\ast \right)}\right)=\frac{\Gamma \left(\overline{B}\to {D}^{\left(\ast \right)}{\tau}^{-}{\overline{\nu}}_{\tau}\right)}{\Gamma \left(\overline{B}\to {D}^{\left(\ast \right)}{\ell}^{-}{\overline{\nu}}_{\ell}\right)} $$
R

D

∗

=

Γ

B
¯

→

D

∗

τ
−

ν
¯

τ

Γ

B
¯

→

D

∗

ℓ
−

ν
¯

ℓ

and the D∗ longitudinal polarisation fraction $$ {F}_L^{D^{\ast }} $$

F
L

D
∗

in different NP scenarios and extracted |Vcb| which is consistent with the number mentioned above. Also, the simultaneous explanation of R(D(∗)) and $$ {F}_L^{D^{\ast }} $$

F
L

D
∗

is not possible in the one-operator scenarios. However, the two operator scenarios with $$ {\mathcal{O}}_{S_2}^{\tau }=\left({\overline{q}}_R{b}_L\right)\left({\overline{\tau}}_R{\nu}_{\tau L}\right) $$

O

S
2

τ

=

q
¯

R

b
L

τ
¯

R

ν
τL

as one of the operators could explain all these three measurements. Finally, we have given predictions of all the related observables in $$ \overline{B}\to {D}^{\left(\ast \right)}\left({\tau}^{-},{\mu}^{-},{e}^{-}\right)\overline{\nu} $$

B
¯

→

D

∗

τ
−

μ
−

e
−

ν
¯

decays in the NP scenarios, which could be tested in future experiments. We have repeated this exercise for $$ \overline{B}\to \pi {\ell}^{-}{\overline{\nu}}_{\ell } $$

B
¯

→
π

ℓ
−

ν
¯

ℓ

decays with the light lepton and extracted |Vub| and the new physics WCs. Finally, using all these available data for the light and heavy leptons, we have given bounds on the couplings of the relevant SM effective field theory (SMEFT) operators and the probable NP scale Λ.
Non-Lorentzian expansions of the Lorentz force and kinematical algebras
Authors: Cerdeira José Luis V. , Gomis Joaquim , Kleinschmidt Axel
Published: January 2024

Abstract

We consider non-Lorentzian expansions, Galilean and Carrollian, of the Lorentz force equation in which both the particle position and the electro-magnetic field are expanded. There are two well-known limits in the case of a constant field, called electric and magnetic, that are studied separately. We show that the resulting equations of motion follow equivalently from considering a non-linear realisation of a certain infinite-dimensional algebras.
The basis invariant flavor puzzle
Authors: Bento Miguel P. , Silva João P. , Trautner Andreas
Published: January 2024

Abstract

The flavor puzzle of the Standard Model quark sector is formulated in a non-perturbative way, using basis invariants that are independent of the choice of quark field basis. To achieve this, we first derive the algebraic ring of 10 CP even (primary) and 1 CP odd (secondary) basis invariants, using the Hilbert series and plethystic logarithm. An orthogonal basis in the ring of basis invariants is explicitly constructed, using hermitian projection operators derived via birdtrack diagrams. The thereby constructed invariants have well defined CP transformation behavior and give the most direct access to the flavor symmetric alignments of basis covariants. We firstly “measure” the orthogonal basis invariants from experimental data and characterize their location in the available parameter space. The experimentally observed orthogonal basis invariants take very close to maximal values and are highly correlated. Explaining the location of the invariants at close to maximal points, including the associated miniscule and highly correlated deviations, corresponds to solving the flavor puzzle in the invariant language. Once properly normalized, the orthogonal basis invariants are close to scale (RGE) invariant, hence, provide exquisite targets for fits of both, low- and high-scale (bottom-up and top-down) flavor models. Our result provides an entirely new angle on the flavor puzzle, and opens up ample opportunities for its ultimate exploration.
Mapping Large N Slightly Broken Higher Spin (SBHS) theory correlators to free theory correlators
Authors: Jain Prabhav , Jain Sachin , Sahoo Bibhut , K.S. Dhruva , Zade Aashna
Published: January 2024

Abstract

We develop a systematic method to constrain any n-point correlation function of spinning operators in Large N Slightly Broken Higher Spin (SBHS) theories. As an illustration of the methodology, we work out the three point functions which reproduce the previously known results. We then work out the four point functions of spinning operators. We show that the correlation functions of spinning operators in the interacting SBHS theory take a remarkably simple form and that they can be written just in terms of the free fermionic and critical bosonic theory correlators. They also interpolate nicely between the results in these two theories. When expressed in spinor-helicity variables we obtain an anyonic phase which nicely interpolates between the free fermionic and critical bosonic results which makes 3D bosonization manifest. Further, we also obtain a form for five and higher point functions as well by performing a similar analysis.
QCD-collapsed domain walls: QCD phase transition and gravitational wave spectroscopy
Authors: Bai Yang , Chen Ting-Kuo , Korwar Mrunal
Published: January 2024

Abstract

For a discrete symmetry that is anomalous under QCD, the domain walls produced in the early universe from its spontaneous breaking can naturally annihilate due to QCD instanton effects. The gravitational waves generated from wall annihilation have their amplitude and frequency determined by both the discrete symmetry breaking scale and the QCD scale. The evidence of stochastic gravitational waves at nanohertz observed by pulsar timing array experiments suggests that the discrete-symmetry-breaking scale is around 100 TeV, assuming the domain-wall explanation. The annihilation temperature is about 100 MeV, which could naturally be below the QCD phase transition temperature. We point out that the QCD phase transition within some domains with an effective large QCDθangle could be a first-order one. To derive the phase diagram inθand temperature, we adopt a phenomenological linear sigma model with three quark flavors. The domain-wall explanation for the NANOGrav, EPTA, PPTA and CPTA results hints at a first-order QCD phase transition, which predicts additional gravitational waves at higher frequencies. If the initial formation of domain walls is also a first-order process, this class of domain-wall models predicts an interesting gravitational wave spectroscopy with frequencies spanning more than ten orders of magnitude, from nanohertz to 100 Hz.
Repetitio est mater studiorum – Implementierung von HNO-Fällen in fallbasiertes E-Learning
Authors: Engert Jonas , Backhaus Joy , Henig Linda , Spahn Bjoern , Voelker Johannes , Ickrath Pascal , Scherzad Agmal , Rak Kristen , Hagen Rudolf , König Sarah , Hackenberg Stephan , Kaulitz Stefan
Published: January 2024

Hintergrund

Die deutsche universitäre HNO-Heilkunde hat Bedarf an digitalen Lehrinhalten. Fallbasiertes E‑Learning stellt eine digitale Lehrmethodik dar. Die Datenlage zur studentischen Nutzung von fallbasiertem E‑Learning in der Hochschullehre der HNO-Heilkunde ist limitiert.

Fragestellung

Ziel dieser Arbeit war es festzustellen, in welchem Umfang freiwilliges fallbasiertes E‑Learning von Studierenden der HNO-Heilkunde genutzt wird und welchen Einfluss die Qualität des E‑Learnings auf die Motivation zur E‑Learning-Nutzung und auf das Interesse für die HNO-Heilkunde hat.

Material und Methoden

Es wurden 15 freiwillige E‑Learning-Fälle erstellt, welche auf den Inhalten der HNO-Vorlesung im Wintersemester 2022/2023 basierten. Im Anschluss erfolgte eine deskriptive Auswertung der Nutzungsstatistiken der Fälle von 157 Studierenden. Ebenso wurde eine Evaluation der Qualität des E‑Learnings sowie der Motivation zur Durchführung und des Interesses für die HNO-Heilkunde mittels eines freiwilligen Fragebogens durchgeführt.

Ergebnisse

Freiwilliges fallbasiertes E‑Learning wurde von 66 % der Studierenden in unterschiedlichem Ausmaß genutzt. Die Qualität des E‑Learnings korrelierte signifikant mit der Motivation zur Durchführung und dem Interesse für die HNO-Heilkunde.

Schlussfolgerung

Lehrinhalte der HNO-Heilkunde lassen sich suffizient in fallbasiertes E‑Learning implementieren und zeichnen sich durch eine zufriedenstellende studentische Akzeptanz aus. Die Eingliederung sollte auf eine qualitativ hochwertige Art und Weise erfolgen, um die Motivation zur Durchführung und das Interesse an der HNO-Heilkunde zur erhöhen.
Microplastic Abundance and Sources in Surface Water Samples of the Vaal River, South Africa
Authors: Saad Dalia , Ramaremisa Gibbon , Ndlovu Michelle , Chauke Patricia , Nikiema Josiane , Chimuka Luke
Published: January 2024

Microplastics (MPs) have emerged as a global environmental concern due to their persistent nature. In South Africa, microplastic research has primarily focused on marine systems. However, recent years have seen a shift in focus to studying MPs in South African freshwaters. In this study, MPs with a minimum size of 0.055 mm in surface water of the Vaal River, South Africa, were reported. MPs were 100% prevalent, with a mean numerical abundance of 0.68 ± 0.64 particles/m3. Small-sized MPs of < 1 mm accounted for the largest proportion. MPs were chemically identified as high-density polyethylene, low-density polyethylene, and polypropylene according to their Raman spectra. The prevalence of fragments (41.6%) and fibers (38.5%) over pellets (8.1%) indicates that microplastics are from secondary sources. The prevalence of polyethylene and polypropylene is consistent with microplastics being from secondary sources. These polymers are commonly used in single-use plastics, packing bags, textiles, and containers. These characteristics are of great concern due to their implications on the bioavailability and toxicological impacts of MPs. Consequently, these properties may pose more hazards to aquatic biota inhabiting the Vaal River.
Metabolic effects of nuclear receptor activation in vivo after 28-day oral exposure to three endocrine-disrupting chemicals
Authors: Attema Brecht , Kummu Outi , Pitkänen Sini , Weisell Jonna , Vuorio Taina , Pennanen Erika , Vorimo Maria , Rysä Jaana , Kersten Sander , Levonen Anna-Liisa , Hakkola Jukka
Published: January 2024

Environmental exposure to endocrine-disrupting chemicals (EDCs) can lead to metabolic disruption, resulting in metabolic complications including adiposity, dyslipidemia, hepatic lipid accumulation, and glucose intolerance. Hepatic nuclear receptor activation is one of the mechanisms mediating metabolic effects of EDCs. Here, we investigated the potential to use a repeated dose 28-day oral toxicity test for identification of EDCs with metabolic endpoints. Bisphenol A (BPA), pregnenolone-16α-carbonitrile (PCN), and perfluorooctanoic acid (PFOA) were used as reference compounds. Male and female wild-type C57BL/6 mice were orally exposed to 5, 50, and 500 μg/kg of BPA, 1000, 10 000, and 100 000 µg/kg of PCN and 50 and 300 μg/kg of PFOA for 28 days next to normal chow diet. Primary endpoints were glucose tolerance, hepatic lipid accumulation, and plasma lipids. After 28-day exposure, no changes in body weight and glucose tolerance were observed in BPA-, PCN-, or PFOA-treated males or females. PCN and PFOA at the highest dose in both sexes and BPA at the middle and high dose in males increased relative liver weight. PFOA reduced plasma triglycerides in males and females, and increased hepatic triglyceride content in males. PCN and PFOA induced hepatic expression of typical pregnane X receptor (PXR) and peroxisome proliferator-activated receptor (PPAR)α target genes, respectively. Exposure to BPA resulted in limited gene expression changes. In conclusion, the observed changes on metabolic health parameters were modest, suggesting that a standard repeated dose 28-day oral toxicity test is not a sensitive method for the detection of the metabolic effect of EDCs.
Stable Singularity Formation for the Keller–Segel System in Three Dimensions
Authors: Glogić Irfan , Schörkhuber Birgit
Published: January 2024

We consider the parabolic–elliptic Keller–Segel system in dimensions $$d \geqq 3$$

d
≧
3

, which is the mass supercritical case. This system is known to exhibit rich dynamical behavior including singularity formation via self-similar solutions. An explicit example was found more than two decades ago by Brenner et al. (Nonlinearity 12(4):1071–1098, 1999), and is conjectured to be nonlinearly radially stable. We prove this conjecture for $$d=3$$

d
=
3

. Our approach consists of reformulating the problem in similarity variables and studying the Cauchy evolution in intersection Sobolev spaces via semigroup theory methods. To solve the underlying spectral problem, we use a technique we recently established in Glogić and Schörkhuber (Comm Part Differ Equ 45(8):887–912, 2020). To the best of our knowledge, this provides the first result on stable self-similar blowup for the Keller–Segel system. Furthermore, the extension of our result to any higher dimension is straightforward. We point out that our approach is general and robust, and can therefore be applied to a wide class of parabolic models.
Comparison of LC-MS-based methods for the determination of carboxylic acids in animal matrices
Authors: Schwartz-Zimmermann Heidi E. , Hündler Manuel , Reiterer Nicole , Ricci Sara , Rivera-Chacon Raul , Castillo-Lopez Ezequias , Zebeli Qendrim , Berthiller Franz
Published: January 2024

Carboxylic acids (CAs) are key players in human and animal metabolism. As they are hardly retained under reversed-phase liquid chromatography (RP-LC) conditions in their native form, derivatization is an option to make them accessible to RP-LC and simultaneously increase their response for mass spectrometric detection. In this work, two RP-LC tandem mass spectrometry-based methods using aniline or 3-nitrophenylhydrazine (3-NPH) as derivatization agents were compared with respect to several factors including completeness of derivatization, apparent recoveries (RAs) in both cow feces and ruminal fluid, and concentrations obtained in feces and ruminal fluid of cows. Anion exchange chromatography coupled to high-resolution mass spectrometry (AIC-HR-MS) served as reference method. Derivatization efficiencies were close to 100% for 3-NPH derivatization but variable (20–100%) and different in solvent solutions and matrix extracts for aniline derivatization. Likewise, average RAs of 13C-labeled short-chain fatty acids as internal standards were around 100% for 3-NPH derivatization but only 45% for aniline derivatization. Quantification of CAs in feces and ruminal fluid of cows initially fed a forage-only diet and then transitioned to a 65% high-grain diet which yielded similar concentrations for 3-NPH derivatization and AIC-HR-MS, but concentrations determined by aniline derivatization were on average five times lower. For these reasons, derivatization with aniline is not recommended for the quantitative analysis of CAs in animal samples.

Graphical abstract
Oncolytic adenovirus coding for shedding-resistant MICA enhances immune responses against tumors
Authors: Costa-Garcia M , Rojas JJ , Ramos MD , Barlabé P , Calvo P , Navas J , Alemany R , Moreno R
Published: January 2024

Cancer immunotherapies strive to overcome tumor-induced immune suppression and activate antitumor immune responses. Although cytotoxic T lymphocytes (CTLs) play a pivotal role in this process, natural killer (NK) cells have also demonstrated remarkable tumor-killing abilities, given their ability to discriminate tumor cells from normal cells and mediate specific antitumoral cytotoxicity. NK cells activation depends on a balance between activation and inhibition signals from several ligands/receptors. Among them, MICA/NKG2D axis is a master regulator of NK activation. MHC class I chain-related polypeptide A (MICA) expression is upregulated by many tumor cell lines and primary tumors and serves as a ligand for the activating NK group 2D (NKG2D) receptor on NK cells and subpopulations of T cells. However, cancer cells can cleave MICA, making it soluble and de-targeting tumor cells from NK cells, leading to tumor immune escape.

In this study, we present ICOVIR15KK-MICAMut, an oncolytic adenovirus (OAdv) armed with a transgene encoding a non-cleavable MICA to promote NK-mediated cell-killing capacity and activate the immune response against cancer cells. We first demonstrated the correct MICA overexpression from infected cells. Moreover, our MICA-expressing OAdv promotes higher NK activation and killing capacity than the non-armed virus in vitro. In addition, the armed virus also demonstrated significant antitumor activity in immunodeficient mice in the presence of human PBMCs, indicating the activation of human NK cells. Finally, OAdv-MICA overexpression in immunocompetent tumor-bearing mice elicits tumor-specific immune response resulting in a greater tumor growth control.

In summary, this study highlights the significance of NK cells in cancer immunotherapy and presents an innovative approach using a modified oncolytic virus to enhance NK cell activation and antitumor immune response. These findings suggest promising potential for future research and clinical applications.
Trends in health care of patients with vasculitides, including giant cell arteritis, Takayasu arteritis, ANCA-associated vasculitis and Behçet’s disease: cross-sectional data of the German National Database 2007–2021
Authors: Henes Jörg , Richter Jutta G. , Thiele Katja , Kiltz Uta , Callhoff Johanna , Albrecht Katinka
Published: January 2024

The aim of this study is to present the current care situation of patients with giant cell arteritis (GCA), Takayasu arteritis (TAK), ANCA-associated vasculitis (AAV) and Behçet’s disease (BD). Trends over the last 15 years will reflect improvements and remaining deficits in the management of vasculitides. Consecutive cross-sectional data from patients with vasculitides from the German National Database (NDB) of the Collaborative Arthritis Centres between 2007 and 2021 were included. Medication, physician- and patient-reported outcomes on disease activity and disease burden, inpatient stays and occupational participation are compared for different vasculitis entities and over time. Employment rates were compared to German population rates. Between 502 and 854 vasculitis patients were annually documented. GCA and AAV were the most common vasculitides. Median disease duration ranged from 2 to 16 years. Over the years, glucocorticoids decreased in proportion and dose, most markedly in GCA and TAK, while biologic therapies increased up to 27%. Physicians rated disease activity as low for the vast majority of patients, while patients-reported moderate outcomes in many dimensions. PROs remained largely unchanged. The proportion of employed patients (< 65 years) increased from 47 to 57%. In recent years, biologics are increasingly used in patients with vasculitides, while glucocorticoids decreased significantly. PRO’s have not improved. Work participation increased but remains lower than that in the German population.
Data-driven nonlinear parametric model order reduction framework using deep hierarchical variational autoencoder
Authors: Lee SiHun , Lee Sangmin , Jang Kijoo , Cho Haeseong , Shin SangJoon
Published: January 2024

A data-driven parametric model order reduction (MOR) method using a deep artificial neural network is proposed. The present network, a least-squares hierarchical variational autoencoder (LSH-VAE), is capable of performing nonlinear MOR for the parametric interpolation of a nonlinear dynamic system with a significant number of degrees of freedom. LSH-VAE differs from existing networks in two major respects: a deep hierarchical structure and a hybrid weighted, probabilistic loss function. The enhancements result in significantly improved accuracy and stability compared with conventional nonlinear MOR methods, autoencoders, and variational autoencoders. In LSH-VAE, the parametric MOR framework is based on the spherically linear interpolation of the latent manifold. The present framework is validated and evaluated on three nonlinear and multiphysics dynamic systems. First, the present framework is evaluated on the fluid–structure interaction benchmark problem to assess its efficiency and accuracy. Then, a highly nonlinear aeroelastic phenomenon, limit cycle oscillation, is analyzed. Finally, the framework is applied to three-dimensional fluid flow to demonstrate its capability to efficiently analyze a significantly large number of degrees of freedom. The superior performance of LSH-VAE is emphasized by comparing its results against those of widely used nonlinear MOR methods, a convolutional autoencoder, and $$\beta $$
β
-VAE. The proposed framework exhibits significantly enhanced accuracy compared with that of conventional methods, while the computational efficiency continues to remain significantly higher.
A new, deep learning–based method for the analysis of autopsy kidney samples used to study sex differences in glomerular density and size in a forensic population
Authors: Vilmont Valérie , Ngatchou Nadine , Lioux Ghislaine , Kalucki Sabrina , Brito Wendy , Burnier Michel , Rotman Samuel , Lardi Christelle , Pruijm Menno
Published: January 2024

Artificial intelligence (AI) is increasingly used in forensic anthropology and genetics to identify the victim and the cause of death. The large autopsy samples from persons with traumatic causes of death but without comorbidities also offer possibilities to analyze normal histology with AI. We propose a new deep learning–based method to rapidly count glomerular number and measure glomerular density (GD) and volume in post-mortem kidney samples obtained in a forensic population. We assessed whether this new method detects glomerular differences between men and women without known kidney disease. Autopsies performed between 2009 and 2015 were analyzed if subjects were aged ≥ 18 years and had no known kidney disease, diabetes mellitus, or hypertension. A large biopsy was taken from each kidney, stained with hematoxylin and eosin, and scanned. An in-house developed deep learning–based algorithm counted the glomerular density (GD), number, and size. Out of 1165 forensic autopsies, 86 met all inclusion criteria (54 men). Mean (± SD) age was 43.5 ± 14.6; 786 ± 277 glomeruli were analyzed per individual. There was no significant difference in GD between men and women (2.18 ± 0.49 vs. 2.30 ± 0.57 glomeruli/mm2, p = 0.71); glomerular diameter, area, and volume also did not differ. GD correlated inversely with age, kidney weight, and glomerular area. Glomerular area and volume increased significantly with age. In this study, there were no sex differences in glomerular density or size. Considering the size of the kidney samples, the use of the presented deep learning method can help to analyze large renal autopsy biopsies and opens perspectives for the histological study of other organs.
Influence of selected operating conditions on starting spot width of test substance dissolved in solvent of high elution strength
Authors: Gwarda Radosław Ł. , Kwarciany Mateusz , Artykiewicz Klaudia , Chomicki Adam , Dzido Tadeusz H.
Published: January 2024

The operational conditions for applying solutions of a dye (Oil Red) dissolved in acetone and methanol to a chromatographic plate are described. These solvents are characterized by high elution power, but they are very good solvents of various substances, so they are often used for this purpose in laboratory practice. However, their unfavorable feature, due to their use as solvents of samples placed on a chromatographic plate, is their high elution strength, which contributes to an increase of the diameter of the starting spot. To eliminate or reduce this unfavorable effect, this research used operational factors such as reduced speed of applying the test solution to the chromatographic plate, increased temperature (40 and 55 °C), and reduced pressure by 0.15 bar relative to atmospheric pressure. All this accelerated the evaporation of the solvents and led to smaller application spots. Studies have shown that the above-mentioned operational factors performed using equipment available in a regular laboratory contribute to a significant reduction of the starting spot despite the use of sample solvents with high elution strength.
Understanding the interplay between particle shape, grading and sample density on the behaviour of granular assemblies: A DEM approach
Authors: Adesina Peter , O’Sullivan Catherine , Wang Teng
Published: January 2024

This study investigates the interplay between particle shape, grading and initial sample density, three of the most important factors influencing the mechanical behaviour of sheared granular assemblies. Using the discrete element method (DEM), two-dimensional assemblies of varying initial sample density, particle aspect ratio, $$AR$$

AR

, and coefficients of uniformity, $${C}_{u}$$

C
u

, were prepared and subjected to drained biaxial shearing until the critical state was reached. We assessed the interplay between each of these parameters by evaluating whether the effect of any given parameter on a mechanical quantity is influenced by any other parameter. Our analyses show that the effect of some of these key parameters on mechanical response, can indeed be influenced by other key parameters. The effect of the particle $$AR$$

AR

on the peak shear strength for the initially dense assemblies differs when compared with the medium-dense assemblies. The mechanical coordination number of the assemblies at the initial state correlates with the peak strength thereby explaining the interplay between particle $$AR$$

AR

and initial sample density on the peak shear strength. The linear relationship established between strength and dilatancy for a combination of all assemblies studied suggests that the strength-dilatancy relationship is a unique characteristic of granular assemblies. The dilatancy of the assemblies correlates strongly with the amount of contacts lost during shearing. The interplays found between particle shape, grading and initial sample density in this study show that to develop robust constitutive models for the prediction of granular material behaviour, the effects of multiple factors must be considered.

Graphic abstract
Short-term outcomes of preoperative chemotherapy with docetaxel, oxaliplatin, and S-1 for gastric cancer with extensive lymph node metastasis (JCOG1704)
Authors: Kurokawa Yukinori , Doki Yuichiro , Kitabayashi Ryo , Yoshikawa Takaki , Nomura Takashi , Tsuji Kunihiro , Goto Masahiro , Cho Haruhiko , Hihara Jun , Hiki Naoki , Nunobe Souya , Mizusawa Junki , Boku Narikazu , Terashima Masanori
Published: January 2024

Background

The prognosis for marginally resectable gastric cancer with extensive lymph node metastasis (ELM) remains unfavorable, even after R0 resection. To assess the safety and efficacy of preoperative docetaxel, oxaliplatin, and S-1 (DOS), we conducted a multicenter phase II trial.

Methods

Eligibility criteria included histologically proven HER2-negative gastric adenocarcinoma with bulky nodal (bulky N) involvement around major branched arteries or para-aortic node (PAN) metastases. Patients received three cycles of docetaxel (40 mg/m2, day 1), oxaliplatin (100 mg/m2, day 1), and S-1 (80–120 mg/body, days 1–14), followed by gastrectomy with D2 plus PAN dissection. Subsequently, patients underwent postoperative chemotherapy with S-1 for 1 year. The primary endpoint was major (grade ≥ 2a) pathological response rate (pRR) according to the Japanese Classification of Gastric Carcinoma criteria.

Results

Between October 2018 and March 2022, 47 patients (bulky N, 20; PAN, 17; both, 10) were enrolled in the trial. One patient was ineligible. Another declined any protocol treatments before initiation. Among the 45 eligible patients who initiated DOS chemotherapy, 44 (98%) completed 3 cycles and 42 (93%) underwent R0 resection. Major pRR and pathological complete response rates among the 46 eligible patients, including the patient who declined treatment, were 57% (26/46) and 24% (11/46), respectively. Common grade 3 or 4 toxicities were neutropenia (24%), anorexia (16%), febrile neutropenia (9%), and diarrhea (9%). No treatment-related deaths occurred.

Conclusions

Preoperative chemotherapy with DOS yielded favorable pathological responses with an acceptable toxicity profile. This multimodal approach is highly promising for treating gastric cancer with ELM.