bluuebunny/crossref_metadata_2025 huggingface dataset:
Advanced iron oxide nanotheranostics for multimodal and precision treatment of pancreatic ductal adenocarcinoma
Authors: Zhu Lei , Mao Hui , Yang Lily
Published: April 2022

Despite current advances in new approaches for cancer detection and treatment, pancreatic cancer remains one of the most lethal cancer types. Difficult to detect early, aggressive tumor biology, and resistance to chemotherapy, radiotherapy, and immunotherapy result in a poor prognosis of pancreatic cancer patients with a 5‐year survival of 10%. With advances in cancer nanotechnology, new imaging and drug delivery approaches that allow the development of multifunctional nanotheranostic agents offer opportunities for improving pancreatic cancer treatment using precision oncology. In this review, we will introduce potential applications of innovative theranostic strategies to address major challenges in the treatment of pancreatic cancer at different disease stages. Several important issues concerning targeted delivery of theranostic nanoparticles and tumor stromal barriers are discussed. We then focus on the development of a magnetic iron oxide nanoparticle platform for multimodal therapy of pancreatic cancer, including MRI monitoring targeted nanoparticle/drug delivery, therapeutic response, and tumor re‐staging, activation of tumor immune response by immunoactivating nanoparticle and magnetic hyperthermia therapy, and intraoperative interventions for improving the outcome of targeted therapy.

This article is categorized under:

Nanotechnology Approaches to Biology > Nanoscale Systems in Biology

Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

Diagnostic Tools > In Vivo Nanodiagnostics and Imaging
One-loop matching of the type-II seesaw model onto the Standard Model effective field theory
Authors: Li Xu , Zhang Di , Zhou Shun
Published: April 2022

Abstract

In this paper, we continue to construct the low-energy effective field theories (EFTs) of the canonical seesaw models, which are natural extensions of the Standard Model (SM) to accommodate tiny but nonzero neutrino masses. Different from three right-handed neutrino singlets in the type-I seesaw model, the Higgs triplet in the type-II seesaw model participates directly in the electroweak gauge interactions, rendering the EFT construction more challenging. By integrating out the heavy Higgs triplet in the functional-integral formalism, we carry out a complete one-loop matching of the type-II seesaw model onto the so-called Standard Model Effective Field Theory (SMEFT). It turns out that 41 dimension-six operators (barring flavor structures and Hermitian conjugates) in the Warsaw basis of the SMEFT can be obtained, covering all those 31 dimension-six operators in the case of type-I seesaw model. The Wilson coefficients for 41 dimension-six operators are computed up to $$ \mathcal{O}\left({M}_{\Delta }^{-2}\right) $$
O

M
∆

−
2

with M∆ being the mass scale of the Higgs triplet. Moreover, the branching ratios of rare radiative decays of charged leptons $$ {l}_{\alpha}^{-}\to {l}_{\beta}^{-}+\gamma $$

l
α
−

→

l
β
−

+
γ
are calculated in the EFT and compared with that in the full theory in order to demonstrate the practical application and the correctness of our EFT construction.
Non-planar elliptic vertex
Authors: Bezuglov M. A. , Onishchenko A. I.
Published: April 2022

Abstract

We consider the problem of obtaining higher order in regularization parameter ε analytical results for master integrals with elliptics. The two commonly employed methods are provided by the use of differential equations and direct integration of parametric representations in terms of iterated integrals. Taking non-planar elliptic vertex as an example we show that in addition to two mentioned methods one can use analytical solution of differential equations in terms of power series. Moreover, in the last case it is possible to obtain the exact in ε results.
One-loop matching for quark dipole operators in a gradient-flow scheme
Authors: Mereghetti Emanuele , Monahan Christopher J. , Rizik Matthew D. , Shindler Andrea , Stoffer Peter
Published: April 2022

Abstract

The quark chromoelectric dipole (qCEDM) operator is a CP-violating operator describing, at hadronic energies, beyond-the-standard-model contributions to the electric dipole moment of particles with nonzero spin. In this paper we define renormalized dipole operators in a regularization-independent scheme using the gradient flow, and we perform the matching at one loop in perturbation theory to renormalized operators of the same and lower dimension in the more familiar MS scheme. We also determine the matching coefficients for the quark chromo-magnetic dipole operator (qCMDM), which contributes for example to matrix elements relevant to CP-violating and CP-conserving kaon decays. The calculation provides a basis for future lattice QCD computations of hadronic matrix elements of the qCEDM and qCMDM operators.
$$ \mathrm{T}\overline{\mathrm{T}} $$ + Λ2 deformed CFT on the stretched dS3 horizon
Authors: Shyam Vasudev
Published: April 2022

Abstract

The $$ T\overline{T} $$
T

T
¯

+ Λ2 deformation of a Holographic CFT on a cylinder (or torus in Euclidean signature) inhabits the stretched cosmological horizon in dS3 when the deformation parameter is tuned to a particular value. I will describe how this insight allows us to compute the entropy of the stretched cosmic horizon including the logarithmic correction.
Homogeneous Yang-Baxter deformations as undeformed yet twisted models
Authors: Borsato Riccardo , Driezen Sibylle , Miramontes J. Luis
Published: April 2022

Abstract

The homogeneous Yang-Baxter deformation is part of a larger web of integrable deformations and dualities that recently have been studied with motivations in integrable σ-models, solution-generating techniques in supergravity and Double Field Theory, and possible generalisations of the AdS/CFT correspondence. The σ-models obtained by the homogeneous Yang-Baxter deformation with periodic boundary conditions on the worldsheet are on-shell equivalent to undeformed models, yet with twisted boundary conditions. While this has been known for some time, the expression provided so far for the twist features non-localities (in terms of the degrees of freedom of the deformed model) that prevent practical calculations, and in particular the construction of the classical spectral curve. We solve this problem by rewriting the equation defining the twist in terms of the degrees of freedom of the undeformed yet twisted model, and we show that we are able to solve it in full generality. Remarkably, this solution is a local expression. We discuss the consequences of the twist at the level of the monodromy matrix and of the classical spectral curve, analysing in particular the concrete examples of abelian, almost abelian and Jordanian deformations of the Yang-Baxter class.
On the stability of string theory vacua
Authors: Giri Suvendu , Martucci Luca , Tomasiello Alessandro
Published: April 2022

Abstract

Vacuum compactifications may suffer from instabilities under small perturbations or tunnel effects; both are difficult to analyze. In this paper we consider the issue from a higher-dimensional perspective. We first look at how stability works for supersymmetric vacua, where it is widely expected to hold. We first show that the nucleation of brane bubbles in type II AdS compactifications is forbidden in the probe approximation by a simple argument involving pure spinors and calibrations. We then adapt familiar positive-energy theorems directly to M-theory and type II supergravity, rather than to their effective lower-dimensional reductions, also showing how to consistently include localized sources. We finally initiate an analysis of how these arguments might be extended to non-supersymmetric vacua. In M-theory, at the lower-derivative level, we find that the most natural modifications fail to stabilize the skew-whiffed and Englert vacua.
On massive higher spins in d = 3
Authors: Khabarov M. V. , Zinoviev Y. M.
Published: April 2022

Abstract

In this paper we consider a frame-like gauge invariant description of massive higher spin bosons and fermions in d = 3 and provide for the first time a proof that such formulation does describe just one massive physical degree of freedom with the appropriate helicity. For this purpose we completely fix all the gauge symmetries and show that all other auxiliary components vanish on-shell, while the only remaining highest component satisfies the correct equations. As a bonus, we show that the Lagrangians for the so-called self-dual massive spin-3 and spin-4 fields proposed by Aragone and Khoudeir (as well as their generalization to arbitrary integer and half-integer spins) can be obtained from the gauge invariant ones by the appropriate gauge fixing.
Precision tests of quantum mechanics and $$ \mathcal{CPT} $$ symmetry with entangled neutral kaons at KLOE
Authors:   The KLOE-2 collaboration, Babusci D. , Berlowski M. , Bloise C. , Bossi F. , Branchini P. , Budano A. , Cao B. , Ceradini F. , Ciambrone P. , Curciarello F. , Czerwiński E. , D’Agostini G. , D’Amico R. , Danè E. , De Leo V. , De Lucia E. , De Santis A. , De Simone P. , Di Cicco A. , Di Domenico A. , Diociaiuti E. , Domenici D. , D’Uffizi A. , Fantini A. , Fantini G. , Fermani P. , Fiore S. , Gajos A. , Gauzzi P. , Giovannella S. , Graziani E. , Ivanov V. L. , Johansson T. , Kang X. , Kisielewska-Kamińska D. , Kozyrev E. A. , Krzemien W. , Kupsc A. , Lukin P. A. , Mandaglio G. , Martini M. , Messi R. , Miscetti S. , Moricciani D. , Moskal P. , Passeri A. , Patera V. , Perez del Rio E. , Santangelo P. , Schioppa M. , Selce A. , Silarski M. , Sirghi F. , Solodov E. P. , Tortora L. , Venanzoni G. , Wiślicki W. , Wolke M.
Published: April 2022

Abstract

The quantum interference between the decays of entangled neutral kaons is studied in the process ϕ → KSKL → π+π−π+π−, which exhibits the characteristic Einstein-Podolsky-Rosen correlations that prevent both kaons to decay into π+π− at the same time. This constitutes a very powerful tool for testing at the utmost precision the quantum coherence of the entangled kaon pair state, and to search for tiny decoherence and $$ \mathcal{CPT} $$
CPT
violation effects, which may be justified in a quantum gravity framework.

The analysed data sample was collected with the KLOE detector at DAΦNE, the Frascati ϕ-factory, and corresponds to an integrated luminosity of about 1.7 fb−1, i.e. to about 1.7 × 109ϕ → KSKL decays produced. From the fit of the observed ∆t distribution, being ∆t the difference of the kaon decay times, the decoherence and $$ \mathcal{CPT} $$
CPT
violation parameters of various phenomenological models are measured with a largely improved accuracy with respect to previous analyses.

The results are consistent with no deviation from quantum mechanics and $$ \mathcal{CPT} $$
CPT
symmetry, while for some parameters the precision reaches the interesting level at which — in the most optimistic scenarios — quantum gravity effects might show up. They provide the most stringent limits up to date on the considered models.
Novel integrated workflow allows production and in-depth quality assessment of multifactorial reprogrammed skeletal muscle cells from human stem cells
Authors: Faustino Dinis , Brinkmeier Heinrich , Logotheti Stella , Jonitz-Heincke Anika , Yilmaz Hande , Takan Isil , Peters Kirsten , Bader Rainer , Lang Hermann , Pavlopoulou Athanasia , Pützer Brigitte M. , Spitschak Alf
Published: April 2022

Skeletal muscle tissue engineering aims at generating biological substitutes that restore, maintain or improve normal muscle function; however, the quality of cells produced by current protocols remains insufficient. Here, we developed a multifactor-based protocol that combines adenovector (AdV)-mediated MYOD expression, small molecule inhibitor and growth factor treatment, and electrical pulse stimulation (EPS) to efficiently reprogram different types of human-derived multipotent stem cells into physiologically functional skeletal muscle cells (SMCs). The protocol was complemented through a novel in silico workflow that allows for in-depth estimation and potentially optimization of the quality of generated muscle tissue, based on the transcriptomes of transdifferentiated cells. We additionally patch-clamped phenotypic SMCs to associate their bioelectrical characteristics with their transcriptome reprogramming. Overall, we set up a comprehensive and dynamic approach at the nexus of viral vector-based technology, bioinformatics, and electrophysiology that facilitates production of high-quality skeletal muscle cells and can guide iterative cycles to improve myo-differentiation protocols.
S-acylation-dependent membrane microdomain localization of the regulatory Kvβ2.1 subunit
Authors: Roig Sara R. , Cassinelli Silvia , Navarro-Pérez María , Pérez-Verdaguer Mireia , Estadella Irene , Capera Jesusa , Felipe Antonio
Published: April 2022

The voltage-dependent potassium (Kv) channel Kvβ family was the first identified group of modulators of Kv channels. Kvβ regulation of the α-subunits, in addition to their aldoketoreductase activity, has been under extensive study. However, scarce information about their specific α-subunit-independent biology is available. The expression of Kvβs is ubiquitous and, similar to Kv channels, is tightly regulated in leukocytes. Although Kvβ subunits exhibit cytosolic distribution, spatial localization, in close contact with plasma membrane Kv channels, is crucial for a proper immune response. Therefore, Kvβ2.1 is located near cell surface Kv1.3 channels within the immunological synapse during lymphocyte activation. The objective of this study was to analyze the structural elements that participate in the cellular distribution of Kvβs. It was demonstrated that Kvβ peptides, in addition to the cytoplasmic pattern, targeted the cell surface in the absence of Kv channels. Furthermore, Kvβ2.1, but not Kvβ1.1, targeted lipid raft microdomains in an S-acylation-dependent manner, which was concomitant with peptide localization within the immunological synapse. A pair of C-terminal cysteines (C301/C311) was mostly responsible for the specific palmitoylation of Kvβ2.1. Several insults altered Kvβ2.1 membrane localization. Therefore, growth factor-dependent proliferation enhanced surface targeting, whereas PKC activation impaired lipid raft expression. However, PSD95 stabilized Kvβ2.1 in these domains. This data shed light on the molecular mechanism by which Kvβ2.1 clusters into immunological synapses during leukocyte activation.
Joints of Varieties
Authors: Tidor Jonathan , Yu Hung-Hsun Hans , Zhao Yufei
Published: April 2022

We generalize the Guth–Katz joints theorem from lines to varieties. A special case says that N planes (2-flats) in 6 dimensions (over any field) have $$O(N^{3/2})$$

O
(

N

3
/
2

)

joints, where a joint is a point contained in a triple of these planes not all lying in some hyperplane. More generally, we prove the same bound when the set of N planes is replaced by a set of 2-dimensional algebraic varieties of total degree N, and a joint is a point that is regular for three varieties whose tangent planes at that point are not all contained in some hyperplane. Our most general result gives upper bounds, tight up to constant factors, for joints with multiplicities for several sets of varieties of arbitrary dimensions (known as Carbery’s conjecture). Our main innovation is a new way to extend the polynomial method to higher dimensional objects, relating the degree of a polynomial and its orders of vanishing on a given set of points on a variety.
Dismantling AI capitalism: the commons as an alternative to the power concentration of Big Tech
Authors: Verdegem Pieter
Published: April 2022

This article discusses the political economy of AI capitalism. It considers AI as a General Purpose Technology (GPT) and argues we need to investigate the power concentration of Big Tech. AI capitalism is characterised by the commodification of data, data extraction and a concentration in hiring of AI talent and compute capacity. This is behind Big Tech’s unstoppable drive for growth, which leads to monopolisation and enclosure under the winner takes all principle. If we consider AI as a GPT—technologies that alter society’s economic and social structures—we need to come up with alternatives in terms of ownership and governance. The commons is proposed as an alternative for thinking about how to organise AI development and how to distribute the value that can be derived from it. Using the commons framework is also a way of giving society a more prominent role in the debate about what we expect from AI and how we should approach it.
Should criminal law protect love relation with robots?
Authors: Mamak Kamil
Published: April 2022

Whether or not we call a love-like relationship with robots true love, some people may feel and claim that, for them, it is a sufficient substitute for love relationship. The love relationship between humans has a special place in our social life. On the grounds of both morality and law, our significant other can expect special treatment. It is understandable that, precisely because of this kind of relationship, we save our significant other instead of others or will not testify against her/him. How as a society should we treat love-like relationships humans with robots? Based on the assumption that robots do not have an inner life and are not moral patients, I defend the thesis that this kind of relationship should be protected by criminal law.
Parameterizing animal sounds and motion with animal-attached tags to study acoustic communication
Authors: Casoli Marco , Johnson Mark , McHugh Katherine A. , Wells Randall S. , Tyack Peter L.
Published: April 2022

Stemming from the traditional use of field observers to score states and events, the study of animal behaviour often relies on analyses of discrete behavioural categories. Many studies of acoustic communication record sequences of animal sounds, classify vocalizations, and then examine how call categories are used relative to behavioural states and events. However, acoustic parameters can also convey information independent of call type, offering complementary study approaches to call classifications. Animal-attached tags can continuously sample high-resolution behavioural data on sounds and movements, which enables testing how acoustic parameters of signals relate to parameters of animal motion. Here, we present this approach through case studies on wild common bottlenose dolphins (Tursiops truncatus). Using data from sound-and-movement recording tags deployed in Sarasota (FL), we parameterized dolphin vocalizations and motion to investigate how senders and receivers modified movement parameters (including vectorial dynamic body acceleration, “VeDBA”, a proxy for activity intensity) as a function of signal parameters. We show that (1) VeDBA of one female during consortships had a negative relationship with centroid frequency of male calls, matching predictions about agonistic interactions based on motivation-structural rules; (2) VeDBA of four males had a positive relationship with modulation rate of their pulsed vocalizations, confirming predictions that click-repetition rate of these calls increases with agonism intensity. Tags offer opportunities to study animal behaviour through analyses of continuously sampled quantitative parameters, which can complement traditional methods and facilitate research replication. Our case studies illustrate the value of this approach to investigate communicative roles of acoustic parameter changes.

Significance statement

Studies of animal behaviour have traditionally relied on classification of behavioural patterns and analyses of discrete behavioural categories. Today, technologies such as animal-attached tags enable novel approaches, facilitating the use of quantitative metrics to characterize behaviour. In the field of acoustic communication, researchers typically classify vocalizations and examine usage of call categories. Through case studies of bottlenose dolphin social interactions, we present here a novel tag-based complementary approach. We used high-resolution tag data to parameterize dolphin sounds and motion, and we applied continuously sampled parameters to examine how individual dolphins responded to conspecifics’ signals and moved while producing sounds. Activity intensity of senders and receivers changed with specific call parameters, matching our predictions and illustrating the value of our approach to test communicative roles of acoustic parameter changes. Parametric approaches can complement traditional methods for animal behaviour and facilitate research replication.
Surgeons, Hernia Surgery and Informed Consent in the Seventeenth Century Ottoman Istanbul
Authors: Degerli Mahmut Said
Published: April 2022

Background

In the seventeenth century Ottoman Istanbul, especially Greek surgeons specialized in hernia surgery. Both Muslim and non‐Muslim patients had signed contracts with surgeons in sharia courts before undergoing a surgery. In this study, we analyze these documents, which serve as informed consent in the Ottoman period, in detail.

Methods

We used Istanbul Sharia Court Registers (Istanbul Sicils) as the primary information source. We scanned a total of twenty nine registers dating back to the seventeenth century. In six of these registers, we determined a total of twenty one informed consents (known as rıza senedi in Turkish literature) regarding hernia surgery and surgeons. Based on these data, we examined the surgeons and hernia surgeries, the fees received by surgeons, and the informed consent documents of the seventeenth‐century Istanbul.

Results

In the scanned informed consents, we identified five male surgeons and twenty one patients. While four of the surgeons were Greek, one of them was Muslim. The contracts show that the patients were informed about possible complications before operations, and their permissions were obtained accordingly. The contracts also clearly state that a blood‐money from the surgeons would not be requested if a patient dies during or after an operation. The cost of operations ranged between 500 and 2100 aḳče.

Conclusions

The patient‐physician relationship in Ottomans was seen as a business relationship. Medical processes were recorded in courts before treatment fees were paid. These court records had been a practice that protected the patients and the physicians in terms of criminal liability.
Immune reconstitution and survival of patients with parvovirus B19 related pure red cell aplasia after haplo-PBSCT
Authors: Zhou Xiao , Jiang Peiyao , Gao Lu , Yang Jun , Cai Yu , Tong Yin , Qiu Huiying , Huang Chongmei , Zhou Kun , Xu Xiaowei , Niu Jiahua , Xia Xinxin , Zhang Ying , Shen Chang , Wei Yu , Shao Jie , Song Xianmin , Wan Liping
Published: April 2022

Parvovirus B19 (PvB19) infection and PvB19 related pure red cell aplasia (PRCA) in recipients with allogeneic hematopoietic stem cell transplantation have been reported sporadically. However, clinical studies with large sample sizes are lacking, especially in patients undergoing HLA-haploidentical peripheral blood stem cell transplantation (haplo-PBSCT). In addition, clinical features, immune reconstitution, and outcomes of these patients are not clear. We conducted a retrospective analysis of 164 patients who received haplo-PBSCT with low-dose anti-thymocyte globulin (ATG) plus low-dose posttransplant cyclophosphamide (PTCy)-based regimen as graft-versus-host disease (GVHD) prophylaxis. We analyzed the incidence of PvB19 related PRCA and compared the clinical characteristics, immune reconstitution, incidence of GVHD, relapse rate, and survival between patients with and without PvB19 related PRCA. A total of 14 (8.5%) recipients developed PvB19 related PRCA after a median of 5.3 months after haplo-PBSCT. These patients with PvB19 related PRCA had slower immune reconstitution, but similar incidences of GVHD, relapse rate, and overall survival compared with recipients without PvB19 related PRCA. PvB19 related PRCA indicated relative delayed and poor immune reconstitution of the recipients early after haplo-PBSCT. PvB19 related PRCA had no effects on GVHD, relapse, and survival.
Influence of Boron and Drought Simulation on Germinability and Hardseededness of Black Medick Seeds (Medicago lupulina L.)
Authors: Kintl Antonín , Huňady Igor , Ondrisková Vladěna , Hammerschmiedt Tereza , Brtnický Martin , Vejražka Karel , Kubíková Zuzana , Elbl Jakub
Published: April 2022

This study deals with the determination of germinability of black medick (Medicago lupulina L.) seeds in conditions of different drought intensity induced by different concentrations of PEG 8000 solutions (0.2; 0.4; 0.6 mol). Four batches of seed were tested (Ekola 2–5). At the same time, the influence of boron, some other elements (N, P, K, Ca, Mg, Zn, Cu, Mn) and compounds (starch, lipids and sugars) contents in black medick seeds on their germinability (percentages of germinated, dead and hard seeds) was evaluated. The effect of drought was manifested by germination which was reduced max. by 8% as compared with the control variant and was only partially significant. Statistically significant (P < 0.01) negative correlations (R = − 0.64) were recorded between germinability and the boron content in the seeds, and positive correlations were found between the percentages of hard seeds and the boron content in the seeds. The results show that the higher content of boron in the seeds of black medick increases the proportion of hard seeds at the expense of the germinated seeds percentages.
Intensive exercise therapy for restenosis after superficial femoral artery stenting: the REASON randomized clinical trial
Authors: Kato Tamon , Miura Takashi , Yamamoto Shuhei , Miyashita Yusuke , Hashizume Naoto , Shoin Kyoko , Sasaki Shinya , Kanzaki Yusuke , Yui Hisanori , Maruyama Shusaku , Nagae Ayumu , Sakai Takahiro , Saigusa Tatsuya , Ebisawa Soichiro , Okada Ayako , Motoki Hirohiko , Ikeda Uichi , Kuwahara Koichiro ,   The REASON Investigators, Kato Tamon , Miura Takashi , Yamamoto Shuhei , Miyashita Yusuke , Hashizume Naoto , Shoin Kyoko , Sasaki Shinya , Kanzaki Yusuke , Ikeda Uichi
Published: April 2022

Endovascular treatment (EVT) is the main treatment for peripheral artery disease (PAD). Despite advances in device development, the restenosis rate remains high in patients with femoropopliteal lesions (FP). This study aimed to evaluate the effectiveness of exercise training in reducing the 1-year in-stent restenosis rate of bare metal nitinol stents for FPs. This prospective, randomized, open-label, multicenter study was conducted from January 2017 to March 2019. We randomized 44 patients who had claudication with de novo stenosis or occlusion of the FP into an intensive exercise group (n = 22) and non-intensive exercise group (n = 22). Non-intensive exercise was defined as walking for less than 30 min per session, fewer than three times a week. We assessed exercise tolerance using an activity meter at 1, 3, 6, and 12 months, and physiotherapists ensured maintenance of exercise quality every month. The primary endpoint was instant restenosis defined as a peak systolic velocity ratio > 2.5 on duplex ultrasound imaging. Kaplan–Meier analysis was used to evaluate the data. There were no significant differences in background characteristics between the groups. Six patients dropped out of the study within 1 year. In terms of the primary endpoint, intensive exercise significantly improved the patency rate of bare nitinol stents at 12 months. The 1-year freedom from in-stent restenosis rates were 81.3% in the intensive exercise group and 47.6% in the non-intensive exercise group (p = 0.043). No cases of stent fracture were observed in the intensive exercise group. Intensive exercise is safe and reduces in-stent restenosis in FP lesions after endovascular therapy for PAD. Clinical trial registration: University Hospital Medical Information Network Clinical Trials Registry (No. UMIN 000025259).
Second fertility-sparing surgery and fertility-outcomes in patients with recurrent borderline ovarian tumors
Authors: Wang Lifei , Zhong Qian , Tang Qin , Wang Hongjing
Published: April 2022

Background

At the time of recurrence, many borderline ovarian tumor (BOT) patients are still young with fertility needs. The purpose of this study is to evaluate the reproductive outcomes and recurrence rate of second fertility-sparing surgery (FSS) in women with recurrent BOTs.

Methods

Seventy-eight women of childbearing age diagnosed with recurrent BOTs from November 2009 to 2020 whose primary treatment was FSS were included.

Results

The FIGO stage I disease accounted for 46.2% and serous BOT accounted for 87.2% in the study group. Forty-seven patients underwent second FSS, and the remaining 31 underwent radical surgery (RS). Seventeen patients relapsed again after second surgery, but no malignant transformation and tumor-associated deaths were reported. Compared to FIGO stage I, the FIGO stage III tumors were more likely to relapse, but there was no statistical difference in pregnancy rate among patients with different stages. In the second FSS group, recurrence rate was higher in patients who underwent oophorocystectomy compared to patients with unilateral salpingo-oophorectomy (USO), but the pregnancy rate was similar. There was no significant difference in postoperative recurrence risk between USO and RS. The recurrence rate was not associated with operative route (laparoscopy or laparotomy), or lymphadenectomy, or postoperative chemotherapy. Among the 32 patients who tried to conceive, the pregnancy rate was 46.9% and live birth rate was 81.3%.

Conclusion

Unilateral salpingo-oophorectomy is a safe procedure for FIGO stage I recurrent BOT patients with fertility needs, and can achieve a high postoperative pregnancy rate and live birth rate.
Radiation and chemotherapy variable response induced by tumor cell hypoxia: impact of radiation dose, anticancer drug, and type of cancer
Authors: Ibrahim Ayman M. , Nady Soad , Shafaa Medhat W. , Khalil Magdy M.
Published: April 2022

Hypoxia is a condition in which proliferating tumor cells are deprived of oxygen due to limited blood supply from abnormal tumor microvasculature. This study aimed to investigate the molecular changes that occur in tumor cell hypoxia with special emphasis placed on the efficacy of chemotherapeutic and radiation-related effects. Four commercially available chemotherapeutic agents: cisplatin, cyclophosphamide, doxorubicin, and 5-fluorouracil, were tested for their cytotoxic activity on the cancer cell lines PC3 (prostate), HepG2 (liver), and MCF-7 (breast). Tumor cell lines under hypoxia were treated with both IC50 concentrations of the different chemotherapeutic agents and irradiated with 5 and 10 Gy using a 137Cs gamma source. Hypoxia-inducible factor-1α (HIF-1α) protein levels were examined using an ELISA assay. Hypoxic cells showed a significant change in cell viability to all chemotherapeutic agents in comparison to normoxic controls. HepG2 cells were more resistant to the cytotoxic drug doxorubicin compared to other cancer cell lines. The flow cytometric analysis showed that hypoxic cells have lower levels of total apoptotic cell populations (early and late apoptosis) compared to normoxic cells suggesting decreased hypoxia-induced apoptosis in cancer cells. The highest reduction in HIF-1α level was observed in the MCF-7 cell line (95.5%) in response to the doxorubicin treatment combined with 10 Gy irradiation of cells. Chemoradiotherapy could result in minimal as well as a high reduction of HIF-1α based on cell type, type of chemotherapy, and amount of ionizing radiation. This study highlights future research work to optimize a combined chemoradiotherapeutic regime in individual cancer cell hypoxia.
Early stage breast cancer follow-up in real-world clinical practice: the added value of cell free circulating tumor DNA
Authors: La Rocca E. , De Santis M. C. , Silvestri M. , Ortolan E. , Valenti M. , Folli S. , de Braud F. G. , Bianchi G. V. , Scaperrotta G. P. , Apolone G. , Daidone M. G. , Cappelletti V. , Pruneri G. , Di Cosimo S.
Published: April 2022

Purpose

Physical examinations and annual mammography (minimal follow-up) are as effective as laboratory/imaging tests (intensive follow-up) in detecting breast cancer (BC) recurrence. This statement is now challenged by the availability of new diagnostic tools for asymptomatic cases. Herein, we analyzed current practices and circulating tumor DNA (ctDNA) in monitoring high-risk BC patients treated with curative intent in a comprehensive cancer center.

Patients and methods

Forty-two consecutive triple negative BC patients undergoing neoadjuvant therapy and surgery were prospectively enrolled. Data from plasma samples and surveillance procedures were analyzed to report the diagnostic pattern of relapsed cases, i.e., by symptoms, follow-up procedures and ctDNA.

Results

Besides minimal follow-up, 97% and 79% of patients had at least 1 non-recommended imaging and laboratory tests for surveillance purposes. During a median follow-up of 5.1(IQR, 4.1–5.9) years, 13 events occurred (1 contralateral BC, 1 loco-regional recurrence, 10 metastases, and 1 death). Five recurrent cases were diagnosed by intensive follow-up, 5 by symptoms, and 2 incidentally. ctDNA antedated disseminated disease in all evaluable cases excepted two with bone-only and single liver metastases. The mean time from ctDNA detection to suspicious findings at follow-up imaging was 3.81(SD, 2.68), and to definitive recurrence diagnosis 8(SD, 2.98) months. ctDNA was undetectable in the absence of disease and in two suspected cases not subsequently confirmed.

Conclusions

Some relapses are still symptomatic despite the extensive use of intensive follow-up. ctDNA is a specific test, sensitive enough to detect recurrence before other methods, suitable for clarifying equivocal imaging, and exploitable for salvage therapy in asymptomatic BC survivors.
Voronoi-Based Discrete Element Analyses to Assess the Influence of the Grain Size and Its Uniformity on the Apparent Fracture Toughness of Notched Rock Specimens
Authors: Justo J. , Konietzky H. , Castro J.
Published: April 2022

The fracture toughness reflects the rock resistance to crack propagation, and therefore represents an important parameter for rock fracture assessments. From a strict point of view, the real fracture toughness ($$\it {K}_{\mathrm{\it IC}}$$

K
IC

) corresponds to a cracked situation in which the notch radius is theoretically equal to zero. However, most of the defects in rocks have a finite radius and, therefore, should be studied as notch-type defects. Here, the notch effect is numerically studied together with the influence of the grain size and the sorting coefficient (grain size uniformity) on the apparent fracture toughness ($$\it {K}_{\mathrm{\it IN}}$$

K
IN

). To this end, several four-point bending tests with different U-shaped notch radii, mean grain sizes and degrees of uniformity in grain size and shape have been simulated using the Discrete Element Method. In order to represent the grains of the rocks, the Voronoi tessellation is used to create randomly sized and distributed polygonal blocks. These Voronoi polygons have been defined, on the one hand, by an average edge length of 1, 2 and 3 mm, and, on the other hand, by a different number of iterations ($$n$$
n
) in the relaxation process during the generation of the polygons, which defines the grain size uniformity. The numerical analyses performed and the interpretation of the results show a clear notch effect in all the studied cases, as the apparent fracture toughness ($$\it {K}_{\mathrm{\it IN}}$$

K
IN

) increases with notch radius. Finally, the obtained stress fields at the notch tip have been compared to those obtained from the traditional finite element method.
Botulinum toxin therapy: past, present and future developments
Authors: Dressler Dirk , Johnson Eric A.
Published: April 2022

Although botulinum toxin (BT) is now being used in a large number of different indications in numerous medical specialties, there is still dynamic and rapid development. Treatment algorithms were improved by the introduction of BT short-interval therapy, BT high-dose therapy and improved dosing guidelines. Ultrasound guidance may be helpful in special situations. New indication areas including depression and inflammatory processes are being explored. Drug development projects are mainly focusing on onabotulinumtoxinA analogues, some are addressing liquid preparations and modifications of BT's duration of action. Recombinant BT may simplify production processes. Cell-based assays for potency measurement will soon be required by registration authorities. Treatment algorithms will be further refined and indications will be expanded. New indication areas are still uncertain. BT type A will remain the drug substance of choice. Removal of complexing proteins seems logical. Whether there is a need for BT drugs with modified duration of action and for liquid preparations, is unclear. Bringing BT therapy to those who need it, is the biggest challenge. Current high-price business models need to be changed, either by employing a biosimilar registration approach or by referring to companies from countries where business models are based on different cost structures.
Simultaneous Determination of Carvedilol, Enalaprilat, and Perindoprilat in Human Plasma Using LC–MS/MS and Its Application to a Pharmacokinetic Pilot Study
Authors: Joubert Andre , Kellermann Tracy , Joubert Anton , van der Merwe Marthinus , Norman Jennifer , Castel Sandra , Sliwa Karen , Maartens Gary , Sinxadi Phumla , Wiesner Lubbe
Published: April 2022

A method for the extraction and quantification of carvedilol, enalaprilat, and perindoprilat in 50 µL human plasma, using high-performance liquid chromatography with tandem mass spectrometry (LC–MS/MS) detection was developed and validated. Samples were prepared via protein precipitation with chromatographic separation on a Restek Ultra II Biphenyl column using gradient elution at a corresponding flowrate of 300 µL/min. Electrospray ionisation with mass detection at unit resolution in the multiple reaction monitoring (MRM) mode on an AB Sciex API 5500 mass spectrometer was used. Accuracy, precision, selectivity, sensitivity, matrix effects, recovery, process efficiency, and stability were assessed over the validation period. The assay was validated over the calibration range 0.2–200 ng/mL for all three analytes. The inter- and intra-day precision expressed as the coefficient of variation (CV) and accuracy (%Nom) all fell within acceptable limits. The overall recovery was calculated as 72.9%, 77.1%, and 77.0% for carvedilol, enalaprilat, and perindoprilat respectively, with the recovery being shown to be reproducible at the low, medium and high end of the calibration range for all three analytes. The method proved to be specific for all three analytes with no significant matrix effects observed. The validated method facilitated the analysis of carvedilol, enalaprilat, and perindoprilat in human plasma collected from adults as part of a pilot pharmacokinetic study. This validated analytical method lays the foundation for determining adherence in heart failure patients prescribed with carvedilol, enalapril and perindopril.
Model-based reasoning using answer set programming
Authors: Wotawa Franz , Kaufmann David
Published: April 2022

Diagnosis, i.e., the detection and identification of faults, provides the basis for bringing systems back to normal operation in case of a fault. Diagnosis is a very important task of our daily live, assuring safe and reliable behavior of systems. The automation of diagnosis has been a successful research topic for several decades. However, there are limitations due to complexity issues and lack of expressiveness of the underlying reasoning mechanisms. More recently logic reasoning like answer set programming has gained a lot of attention and practical use. In this paper, we tackle the question whether answer set programming can be used for automating diagnosis, focusing on industrial applications. We discuss a formalization of the diagnosis problem based on answer set programming, introduce a general framework for modeling systems, and present experimental results of an answer set programming based diagnosis algorithm. Past limitations like not being able to deal with numerical operations for modeling can be solved to some extent. The experimental results indicate that answer set programming is efficient enough for being used in diagnosis applications, providing that the underlying system is of moderate size. For digital circuits having less than 500 components, diagnosis time has been less than one second even for computing triple fault diagnoses.
Usage of Tyre Derived Aggregates as backfill around buried pipelines crossing strike-slip faults; model tests
Authors: Karaman Mustafa , Demirci Hasan Emre , Ecemis Nurhan , Bhattacharya Subhamoy
Published: April 2022

Buried pipelines crossing active faults are exposed to excessive soil forces under fault movements due to large relative movement between pipes and the soil surrounding them. As a result, extreme longitudinal strains develop within pipelines under large fault movements and this leads to pipeline failures. Several seismic mitigation techniques were proposed to improve the performance of buried pipelines crossing active faults. In this study, the potential of using Tyre Derived Aggregates (TDA) as a backfill material for mitigating the effects of strike-slip faulting are investigated through physical model tests. First, the details of the physical model test setup and model configuration are presented. Then a comparative study is carried out to study the effect of TDA content in the backfill and trench configurations on TDA mitigation. Model tests revealed that using a sloped trench with 100% TDA content in the backfill can decrease peak axial pipe strains up to 62% and peak bending strains up to 19%. It is observed that enlarging the trench and using an inclined trench improve the performance of the TDA mitigation technique.
Circulating tumor cell detection: A prospective comparison between CellSearch® and RareCyte® platforms in patients with progressive metastatic breast cancer
Authors: Dirix Luc , Buys Andy , Oeyen Steffy , Peeters Dieter , Liègeois Vincent , Prové Annemie , Rondas Dieter , Vervoort Liesbet , Mariën Véronique , Laere Steven Van , Vermeulen Peter
Published: April 2022

Purpose

Circulating tumor cells (CTCs) are prognostic in patients with breast cancer. Several technical platforms exist for their enumeration and characterization. Comparative studies between these platforms are scarce. The RareCyte CTC detection is theoretically more sensitive than the established CellSearch platform, which identifies only CTCs that express EpCAM and cytokeratin.

This study prospectively compares CTC enumeration in patients with breast cancer in a paired analysis using these two platforms. It investigates survival outcomes in groups defined by a CTC count threshold.

Design

CTC enumeration was performed on 100 samples obtained from 86 patients with progressive metastatic breast cancer (MBC) in two independent laboratories each blinded to the clinical data and the results from the other platform.

Results

One hundred paired samples were collected and CTC counts were determined using the CellSearch and RareCyte CTC platforms. In total, 65% and 75% of samples had at least one detectable CTC in 7.5 mL blood with the CellSearch and the RareCyte systems, respectively. CTC counts with the CellSearch system ranged from 0 to 2289 with a median of 3 CTCs, the RareCyte CTC counts ranged from 0 to 1676 with a median of 3 CTCs. The number of samples with 5 or more CTCs in 7.5 mL of blood (the poor prognosis cut-off validated with the CellSearch system) blood was 45% with the CellSearch test and 48% with the RareCyte test. CTC counts quantified with the CellSearch and the RareCyte systems were strongly correlated (Spearman’s r = 0.8235 (0.7450–0.8795) p < 0.001).

86 patients were included for Kaplan–Meier survival analysis. An increased mortality risk in patients with CellSearch of 5 CTCs or more per 7.5 mL blood, with a log-rank hazard ratio of 5.164 (2.579–10.34) (p < 0.001) was confirmed. The survival analysis with RareCyte CTC counts with the identical cut-off showed a significantly impaired survival with a hazard ratio of 4.213 (2.153–8.244) (p < 0.001).

Conclusion

Our data demonstrate the analytical and prognostic equivalence of CellSearch and RareCyte CTC enumeration platforms in patients with MBC using the CellSearch cut-off. This is the first demonstration of prognostic significance using the RareCyte platform.
Overlong simulations of the solar system dynamics with two alternating step-lengths
Authors: Mikkola Seppo , Lehto Harry J.
Published: April 2022

We compare the performance of four symplectic integration methods with leading order symplectic corrector in simulations of the Solar System. These simulations cover 10 Gyr. They are longer than the astrophysical predicted future of the present-day Solar System, thus this work is mainly a study of the integration methods. For the outer Solar System simulation, where the used stepsize was 100 days, the energy errors do not show any secular evolution. The maximum errors show a dependence on the method. The simulations of the full Solar System from Mercury, and including Pluto as a test particle, were calculated with a stepsize of 7 days. The energy errors behave somewhat differently having a small secular behavior. This may due to the short timestep and the short period of the planet Mercury or some small round off error produced by the code. Comparison of the eccentricity evolution’s within simulations show that some planets are dynamically strongly coupled. Venus and Earth form a dynamical pair, also Jupiter and Saturn form a dynamical pair. The FFT of the analysis of the simulations suggests that all the giant planets form a single dynamical quadruple system. The orbit of Mercury is possibly unstable. Each simulation is stopped when Mercury is expelled. All the methods show similar results for times less than $$30\, $$

30

Myr in the way that the results for orbital elements are same within plotting precision. Inclusion of Mercury in simulations shortens the Solar System e-folding time to $$3.3\, $$

3.3

Myr. It is clear that chaos has a strong effect in the evolution of orbital elements, especially eccentricities. This is easily seen in Mercury’s orbit when the simulation time exceeds at least $$30\, $$

30

Myr. Our low-order simulations seem to match high-order methods over long timescales.
Second order semi-smooth Proximal Newton methods in Hilbert spaces
Authors: Pötzl Bastian , Schiela Anton , Jaap Patrick
Published: April 2022

We develop a globalized Proximal Newton method for composite and possibly non-convex minimization problems in Hilbert spaces. Additionally, we impose less restrictive assumptions on the composite objective functional considering differentiability and convexity than in existing theory. As far as differentiability of the smooth part of the objective function is concerned, we introduce the notion of second order semi-smoothness and discuss why it constitutes an adequate framework for our Proximal Newton method. However, both global convergence as well as local acceleration still pertain to hold in our scenario. Eventually, the convergence properties of our algorithm are displayed by solving a toy model problem in function space.