bluuebunny/crossref_metadata_2025 huggingface dataset:
Successful treatment of rituximab-unresponsive elderly-onset neuromyelitis optica spectrum disorder and hypogammaglobulinemia with ofatumumab plus intravenous immunoglobulin therapy in a patient with mutant FCGR3A genotype: A case report
Authors: Zhang Weihe , Jiao Yujuan , Jiao Jinsong , Jin Ming , Peng Dantao
Published: December 2022

Background

Elderly-onset neuromyelitis optica spectrum disorder (NMOSD) is a rare entity that poses a therapeutic challenge. We report a case of elderly-onset NMOSD with mutant FCGR3A genotype who was successfully treated with ofatumumab after multiple episodes of relapse.

Case Report

The patient was a 67-year-old woman who was diagnosed with NMOSD with high disease activity. She experienced six episodes of relapse over a period of 2 years despite immunosuppressant therapy with intravenous rituximab (RTX), oral steroids, mycophenolate mofetil, and tacrolimus. At the last relapse, she was unable to walk and developed immunosuppressant-induced hypogammaglobulinemia. Based on the insufficient B cell depletion and FCGR3A-FF genotype carrier, the patient was diagnosed as RTX non-responder. After subcutaneous ofatumumab plus intravenous immunoglobulin replacement therapy, she was able to walk independently, and experienced no further relapse. Ofatumumab was well-tolerated, and sufficiently depleted the circulating B cells.

Conclusion

Ofatumumab might be an effective alternative in RTX-unresponsive NMOSD, and seems to be safe in elderly patients.
Patients with positive HER-2 amplification advanced gastroesophageal junction cancer achieved complete response with combined chemotherapy of AK104/cadonilimab (PD-1/CTLA-4 bispecific): A case report
Authors: Peng Jieqiong , Zhu Qiang , Peng Ziru , Chen Zhen , Liu Yuantao , Liu Bo
Published: December 2022

Background

Human epidermal growth factor receptor 2 (HER2) is the most prominent therapeutic target for advanced gastric (G)/GEJ cancer. However, targeted therapy did not significantly improve survival. Currently, there are no regimens for the treatment of HER-2 amplification that exclude targeted agents.

Case presentation

A 42-year-old man was diagnosed with adenocarcinoma of GEJ (stage IV) with liver metastasis and lung metastasis. The patient was enrolled in a trial that excluded patients with known HER2-positivity: AK104, a PD-1/CTLA-4 bispecific antibody, combined with chemotherapy (mXELOX) as first-line therapy for advanced gastric G/GEJ cancer (NCT03852251). After six cycles of AK104 combined with chemotherapy therapy, immune-related pulmonary toxicity was observed. We rechallenged AK104 after hormone therapy, and no further pulmonary toxicity was observed. Immune-related hepatitis occurred in the patient during immunotherapy combined with single-drug capecitabine therapy. After combining steroid therapy with mycophenolate mofetil, the patient’s immune hepatitis improved. Nevertheless, the patient was excluded from the clinical study due to the long-term absence of medication. Antitumor therapy was also discontinued in view of the patient’s adverse immune response. The patient did not receive subsequent immune antitumor therapy, and immune-related hepatitis still occurred intermittently, but the disease evaluation was maintained at PR. A complete response was confirmed by PET/CT and the biopsy specimen from gastroscopy on 2020-06-10. Next generation sequencing of biopsy tissue was used to guide subsequent therapy at a recent follow-up visit. The results indicated that ERBB2 mutations occurred at copy number 58.4934 (HER-2), TMB = 3.1, MSS. IHC: EBV (−), PD-L1 CPS = 3, HER-2 (3+).

Conclusion

Patients with HER-2-positive advanced GEJ cancer received PD-1/CTLA-4 bispecific immunotherapy combined with chemotherapy and achieved complete remission. It offers a novel, highly specific, and highly potent therapeutic option for HER-2-positive patients. Its use should be considered as a new treatment when trastuzumab is not viable. Currently, we are working to overcome this resistance.
Prognosis of hyperviscosity syndrome in newly diagnosed multiple myeloma in modern-era therapy: A real-life study
Authors: Debureaux Pierre-Edouard , Harel Stéphanie , Parquet Nathalie , Lemiale Virginie , Siguret Virginie , Goubeau Laurie , Morin Florence , Royer Bruno , Cuccuini Wendy , Elessa Dikelele , Theves Floriane , Brignier Anne C. , Azoulay Elie , Arnulf Bertrand , Talbot Alexis
Published: December 2022

Hyperviscosity syndrome (HVS) is a rare complication of newly diagnosed multiple myeloma (NDMM) related to high tumour burden. Studies about the prognosis of HVS in modern-era therapy for NDMM are missing. We investigated a retrospective cohort study of NDMM with HVS between 2011-2021. Thirty-nine NDMM patients with HVS were included. HVS presentation was heterogeneous, with asymptomatic, mild, and neurological forms in 23%, 59%, and 18% of cases, respectively. No thrombosis or major bleeding was observed. Therapeutic plasma exchanges were used in 92% of patients, which were effective and well tolerated. No rebound effect was observed. All patients except one had at least one CRAB criterion. Most of the patients received bortezomib and high-dose steroids (95%) associated with an immunomodulatory drug (43%) or alkylating agents (42%). HVS in NDMM patients had dismal overall survival matched to multiple myeloma patient controls (without HVS) in our center (median: 3.6 vs. 7.7 years, p=0.01), as confirmed by multivariate analysis. Early deaths (in the first two months) occurred in 21% of older patients (>65 years). HVS in NDMM patients is a rare but life-threatening complication associated with high lethality in older patients and be a potential dismal prognosis factor in the modern treatment era.
Sintilimab plus autologous NK cells as second-line treatment for advanced non-small-cell lung cancer previous treated with platinum-containing chemotherapy
Authors: Jia Lin , Chen Naifei , Chen Xiao , Niu Chao , Liu Ziling , Ma Kewei , Wang Nanya , Yang Lei , Zhao Yuguang , Song Wei , Lu Jin , Chen Chen , Cong Xiaofeng , Wang Xu , Xu Yinghui , Cui Guozhen , Liu Zengguang , Chen Rongrong , Li Wei , Cui Jiuwei
Published: December 2022

This pilot study (NCT03958097; https://www.clinicaltrials.gov/ct2/show/NCT03958097) was aimed to evaluate the efficacy and safety of PD-1 antibody combined autologous NK cells in the treatment of patients with stage IIIB/IIIC or IV non-small-cell lung cancer (NSCLC) who failed the first-line platinum-based chemotherapy. All patients received both sintilimab 200mg and 3×109 NK cells every 3 weeks. 20 patients were enrolled, median follow up time was 22.6 months. The median PFS was 11.6 months, ORR was 45%. Median OS was 17.7 months, 6-month OS rate and 12-month OS rate was 95.0% and 80.0%. Unexpected adverse events were not observed. 2 patients reported grade 3 adverse events (hypertriglyceridemia, neutropenia and increased creatine kinase). The autologous NK cells did not add extra adverse events to the ICI treatment. Autologous NK plus sintilimab showed promising antitumor activity and an acceptable safety profile in advanced driven-mutation negative NSCLC who failed on the first line treatment.
An Updated Review on MSMD Research Globally and A Literature Review on the Molecular Findings, Clinical Manifestations, and Treatment Approaches in China
Authors: Xia Lu , Liu Xu-Hui , Yuan Yuan , Lowrie Douglas B. , Fan Xiao-Yong , Li Tao , Hu Zhi-Dong , Lu Shui-Hua
Published: December 2022

Mendelian susceptibility to mycobacterial disease (MSMD) arises from a group of rare inherited errors of immunity that result in selective susceptibility of otherwise healthy people to clinical disease caused by low virulence strains of mycobacteria, such as Mycobacterium bovis Bacille Calmette-Guérin (BCG) and environmental mycobacteria. Patients have normal resistance to other pathogens and no overt abnormalities in routine immunological and hematological evaluations for primary immunodeficiencies. At least 19 genes and 34 clinical phenotypes have been identified in MSMD. However, there have been no systematic reports on the clinical characteristics and genetic backgrounds of MSMD in China. In this review, on the one hand, we summarize an update findings on molecular defects and immunological mechanisms in the field of MSMD research globally. On the other hand, we undertook a systematic review of PubMed (MEDLINE), the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, EMBASE, CNKI, and Wanfang to identify articles published before Jan 23, 2022, to summarize the clinical characteristics, diagnosis, treatment, and prognosis of MSMD in China. All the English and Chinese publications were searched without any restriction on article types.
The importance of relational values in gaining people’s support and promoting their involvement in social-ecological system management: A comparative analysis
Authors: Uehara Takuro , Sakurai Ryo , Hidaka Takeshi
Published: December 2022

People’s support and involvement are critical to the sustainable use and conservation of social-ecological systems (SESs). Integrating people’s values into management decisions is pivotal. Without proper integration, the resulting SES may not align with their desires and may not be supported by people. Furthermore, values can be a deep leverage point within a system that is difficult to change, as people may be more willing to be involved in activities that support what they value. Recent studies have illustrated the importance of relational values as the third value class (in addition to instrumental and intrinsic). Relational values are preferences, principles, and virtues associated with human-nature relationships. Although studies on relational values are available, empirical studies, particularly studies about the usefulness of relational values in promoting pro-SES behavior, are rare. Consequently, our study administered questionnaires to residents in three SESs in Japan (N = 864, 1136, and 1000, respectively) to understand how relational values impact people’s support and involvement in SES management as measured by pro-SES behavior scales. In addition, due to the lack of pro-SES behavior measurements, we developed measurement items and a development guideline. Our findings support previous theoretical discussions positing that relational values are critical as a single value class or as part of the plural values and need to be integrated into SES management decisions to gain people’s support. Furthermore, our study demonstrated that cultivating relational values could promote pro-SES behavior to realize a desirable state of SES. Although from the viewpoint of residents, relational values overlapped with instrumental and intrinsic values; however, as per theoretical discussions, the results indicated that relational values were important in their own right as they were well associated with pro-SES behavior scales. The findings were similar across the three SESs, with different social-ecological characteristics. In summary, managers must integrate relational values into management decisions to gain people’s support and should cultivate relational values to promote pro-SES behavior, in order to realize a desirable state of SES.
Application of interpolation methodology with dynamical constraint to the suspended particulate matter in the Liaodong Bay
Authors: Geng Haoyi , Peng Haohong , Shi Jie , Mao Xinyan , Lv Xianqing
Published: December 2022

Introduction

Suspended Particulate Matter (SPM) influences the primary production and the distributions of pollutants in the ocean. Besides, the regulation mechanisms of SPM in the Liaodong Bay were complicated.

Method

To analyze the distributions and influencing factors of SPM, based on the adjoint assimilation method, an interpolation method with dynamical constraint was established in the Liaodong Bay.

Result

In two ideal experiments, the cost function, Mean Absolute Error (MAE) and Normalized Mean Error (NME) all had reduced by more than 90%, which proved the accuracy of the interpolation method. Based on conventional observations of SPM, the distributions of dynamically constrained, Kriging and radial basis function (RBF) interpolations in March, May, August and October of 2015 were obtained.

Discussion

The cross-validation was carried out to compare the dynamically constrained interpolation and the unconstrained interpolations. Among seven unconstrained interpolation methods, the averaged MAE of RBF interpolation was the lowest, which was 10.976 mg/L. The averaged MAE of dynamically constrained interpolation was 7.703 mg/L, reduced by 29.8% compared with the RBF interpolation. It was indicated that RBF interpolation was the most accurate among the seven unconstrained interpolations and dynamically constrained interpolation was more accurate than unconstrained interpolations at the observation stations. The distributions of dynamically constrained and RBF interpolations were compared with Korean Geostationary Ocean Color Imager (GOCI) satellite-derived distributions of SPM concentrations in the Liaodong Bay. Fully considering the influences of the hydrodynamic processes, the dynamically constrained interpolation provided distributions more consistent with the satellite-derived distributions. However, due to the lack of observations in some areas and ignoring the influences of currents, some high values of SPM concentration were not captured by the distributions of RBF interpolation. Moreover, in accordance with the results of dynamically constrained interpolation, it was found that the SPM concentrations in the bay were affected by the SPM discharge from the Liao River Basin.
Estimation of sound speed profiles based on remote sensing parameters using a scalable end-to-end tree boosting model
Authors: Ou Zhenyi , Qu Ke , Shi Min , Wang Yafen , Zhou Jianbo
Published: December 2022

Introduction

In underwater acoustic applications, the three-dimensional sound speed distribution has a significant impact on signal propagation. However, the traditional sound speed profile (SSP) measurement method requires a lot of manpower and time, and it is difficult to popularize. Satellite remote sensing can collect information on a large ocean surface area, from which the underwater information can be derived.

Method

In this paper, we propose a method for reconstructing the SSP based on an extensible end-to-end tree boosting (XGBoost) model. Combined with satellite remote sensing data and Argo profile data, it extracts the characteristic matrix of the SSP and analyzes the contribution rate of each order matrix to reduce the introduction of noise. The model inverts the SSP above 1000 m in the South China Sea by using the root mean square error (RMSE) as the precision evaluation index.

Result

The results showed that the XGBoost model could better reconstruct the SSP above 1000 m, with a RMSE of 1.75 m/s. Compared with the single empirical orthogonal function regression (sEOF-r) model of the linear regression method, the RMSE of the XGBoost model was reduced by 0.59 m/s.

Discussion

For this model, the RMSE of the inversion results was smaller, the robustness was better, and the regression performance was superior to that of the sEOF-r model at different depths. This study provided an efficient tree boosting model for SSP reconstruction, which could reliably and instantaneously monitor the 3D sound speed distribution.
Numerical studies on wake and turbulence characteristics of aquaculture nets
Authors: Xu Lingyun , Li Peng , Qin Hongde , Xu Zhijing
Published: December 2022

This paper aims to understand the drag coefficient discrepancy between the equivalent-twine and twisted-twine nets based on their wake and turbulence characteristics. To that end, we conduct unsteady Reynolds-averaged Navier-Stokes (URANS) and the second-moment (Reynolds stress, RSM) simulations at a Reynolds number,Re=4.5×103, based on the effective diameter of the net twine, which corresponds to the subcritical flow regime. Then, the vortex structures and the turbulence statistics are assessed at AOA=90°. The results highlight that the wake interactions for the twisted-twine net are relatively strong compared to the equivalent-twine net, due to the disturbance of the helixes on the twisted twines. In comparison to the classical Karman vortex, the overall vortex shedding of these two nets is well organized. Symmetric vortices form behind the equivalent-twine net, while single vortices form behind the twisted-twine net. Moreover, the Reynolds normal and shear stresses show symmetric and anti-symmetric profiles. The addition of helixes to smooth circular cylinders changes the flow development, leading to a decrease of turbulence kinetic energy. With this understanding, engineers need to be carefully select the net type for preliminary design of marine aquaculture cages to avoid over- or underestimation of the drag forces.
Wave diffraction of a hybrid wind turbine foundation with a double-layer aquaculture cage
Authors: Zhu Xiaokang , Dong Guohai , Bi Chunwei , Zhao Yunpeng
Published: December 2022

A hybrid wind turbine foundation combined with a double-layer offshore net cage for marine aquaculture is proposed in this paper. To study the diffraction and hydrodynamic loads on the structure for waves with small steepness, a numerical model was established using linear potential theory and solved using the eigenfunction expansion method. A porosity parameter was introduced to describe the hydrodynamic characteristics of the net panels. The model was validated based on existing numerical results and experimental data. An empirical formula was derived to calculate the porosity parameter based on the opening ratios of the nets. The wavefield and wave force were calculated and analyzed by setting different porosity parameters, spacings between the exterior net and interior net, radius ratios of the exterior net to the wind turbine tower and thicknesses of the friction wheel. Noticeable differences in the wave elevation were observed between the upstream and downstream sides of the nets. At downstream sites, the wavefield exhibits different profiles, particularly for structures with low porosities. Sloshing modes were observed that impacted the force and wave elevation at certain frequencies. For the common fishing nets with large porosities, the spacing between the nets does not have a significant impact on the wavefield and wave force acting on the structure. Moreover, the radius and thickness of the friction wheel have a non-negligible influence on the force acting on the structure, which also narrows the intervals between adjacent sloshing frequencies. In summary, this study provides a perspective for the engineering design and hydrodynamic analysis of a hybrid wind turbine foundation with a double-layer aquaculture cage.
Immunometabolic involvement of hepcidin genes in iron homeostasis, storage, and regulation in gilthead seabream (Sparus aurata)
Authors: Serna-Duque Jhon A. , Espinosa Ruiz Cristóbal , Martínez Lopez Salvadora , Sánchez-Ferrer Álvaro , Esteban Maria Ángeles
Published: December 2022

Iron is essential for all living things, especially marine organisms, due to its low availability in the marine environment. Iron regulation is key in all vertebrates and is controlled by hepcidin–ferroportin. To improve the knowledge of iron homeostasis in fish, an iron overload was induced in gilthead seabream (Sparus aurata), which was chosen as a study species because of its high interest in Mediterranean aquaculture. The amount of iron in different tissues was measured to determine its biodistribution and/or bioaccumulation. Since the liver is directly involved in iron metabolism, the morphological changes induced in this organ as a consequence of the iron increase were studied. The bactericidal activity of fish skin mucus was also determined, observing that it decreased in fish with high iron levels compared to control fish. In addition, to better understand iron regulation, the gene expression of hepcidin, ferroportin, transferrin, and ferritin was evaluated in the head kidney (the main hematopoietic organ in this species) and in the liver. Special interest was taken in the study of the multiple copies of the hamp2 gene present in the gilthead seabream genome. Bioinformatic analysis of the protein sequences derived from these hepcidin genes allowed us to determine the presence of one type I hepcidin and 12 type II hepcidins, all of them with antimicrobial potential. This number of mature hepcidin sequences found in gilthead seabream is the highest within Eupercaria described to date. All the results obtained indicate that the modulation of iron in seabream seems to be much more complicated than in other vertebrates, probably due to the possible involvement of the different hepcidins as mediators between iron metabolism and host immune response.
The distribution of North Atlantic right whales in Canadian waters from 2015-2017 revealed by passive acoustic monitoring
Authors: Durette-Morin Delphine , Evers Clair , Johnson Hansen D. , Kowarski Katie , Delarue Julien , Moors-Murphy Hilary , Maxner Emily , Lawson Jack W. , Davies Kimberley T. A.
Published: December 2022

Northward range shifts are increasingly being identified in mobile animals that are responding to climate change. Range shifts are consequential to animal ecology, ecosystem function, and conservation goals, yet for many species these cannot be characterised without means of synoptically measuring their distribution. The distribution of critically endangered North Atlantic right whale (Eubalaena glacialis;NARW) north of 45°N has been largely unknown due to a lack of systematic monitoring. The objectives of this study were to characterize the spatial and temporal variation in NARW acoustic occurrence in the northern portion of their foraging range. In addition, we sought to identify relevant NARW migratory corridors and explore potential previously unidentified high-use habitats beyond the highly surveyed Gulf of St. Lawrence (GSL). To achieve this, passive acoustic monitoring data were collected and analyzed from 67 moorings and 13 gliders deployed (across 38 recording stations) throughout the Atlantic Canadian continental shelf, between 42°N and 58°N during 2015 through 2017. The results support that while a portion of the population has moved northward into the GSL, this shift was constrained to temperate latitudinal ranges < 52°N during the study period. NARWs were not detected in the Labrador Sea and Newfoundland Shelf, despite their preferred prey occurring in those areas. NARWs were present on the Scotian Shelf (45°N) nearly year-round, but only from May through December in the Cabot Strait (50°N). These results indicate that the northern range of the population is probably influenced by energetic requirements to minimize the distance between suitable foraging habitat and low latitude calving grounds, rather than an absence of suitable foraging conditions in high latitude waters, or other environmental or physiological factors. This work provides critical information to conserve the species and mitigate human-induced risks.
Insoluble chitosan complex as a potential adsorbent for aflatoxin B1 in poultry feed
Authors: Delgado-Cedeño Armando , Hernández-Martínez Sara Paola , Ramos-Zayas Yareellys , Marroquín-Cardona Alicia Guadalupe , Méndez-Zamora Gerardo , Franco-Molina Moisés Armides , Kawas Jorge R.
Published: December 2022

As a class of secondary metabolites or toxins produced by fungi, aflatoxins can poison humans and animals; among them, aflatoxin B1 (AFB1) is the most dangerous one owing to its carcinogenic and mutagenic properties that increase risks for hepatocellular carcinoma in humans; hence, adsorbents such as smectites are commonly included in poultry feed to mitigate their effects. In this study, chitosan was crosslinked with sodium dodecyl sulfate (SDS) to form an insoluble polymer complex that is stable at the relevant physiological pH levels. The characterization via Fourier transforms infrared spectroscopy revealed the interaction between the sulfate groups of the SDS and the amine group of chitosan (1,016 and 819 cm−1); this result was further confirmed by the X-ray diffraction patterns with a change in the crystalline structure of the chitosan-insoluble complex (2θ = 4.76°, 7°, and 22°). The morphology of the chitosan-insoluble complex obtained using a field emission scanning electron microscope (FE-SEM) revealed that particles were slightly porous. After characterization, the performance of the chemically modified polymer complex was evaluated as an adsorbent for AFB1 and compared with those of the unmodified chitosan, soluble chitosan complex, and commercial montmorillonite clay binder. In addition, the polymer complex was investigated as an adsorbent in an in vitro model for the poultry gastrointestinal system. Sequestration of AFB1 by a chemically modified polymer complex was 93.4%, equivalent to that of commercial montmorillonite clay (99.5%). However, these treatments also sequestered microminerals, particularly selenium and iron. This pH-stable, high-capacity adsorbent could be used in poultry feed to reduce the uptake of AFB1.
Aluminum electron energy loss spectra. A comparison between Monte Carlo and experimental data
Authors: Dapor Maurizio
Published: December 2022

One of the most interesting applications of the Monte Carlo method consists in the simulation of the energy loss spectrum of backscattered electrons when a solid target is bombarded with an electron beam of given kinetic energy. Knowing the elastic and inelastic scattering cross-sections of the electrons in their interaction with the atoms of the target, it is possible to calculate the probabilities of angular diffusion and the loss of kinetic energy for each collision between the electrons of the incident beam and the atoms of the target. In this way, it is possible to model the history of each electron following its trajectory and calculating its energy losses, its final energy, and the exit point from the target surface whether and where it exists. By averaging over a large number of trajectories, it is possible to obtain a spectrum representing the energy distribution of the backscattered electrons from any given solid target. This paper compares experimental and Monte Carlo data concerning reflection electron energy loss spectra. In particular, the paper is aimed at understanding the interplay between surface and bulk features for incident electrons in Al.
AAV8-mediated sVEGFR2 and sVEGFR3 gene therapy combined with chemotherapy reduces the growth and microvasculature of human ovarian cancer and prolongs the survival in mice
Authors: Kujala Anni , Valkonen Elina , Sallinen Hanna , Tuppurainen Laura , Laakso Hanne , Ylä-Herttuala Elias , Liimatainen Timo , Kujala Jouni , Jokelainen Otto , Sironen Reijo , Anttila Maarit , Ylä-Herttuala Seppo
Published: December 2022

Background

Vascular endothelial growth factors (VEGFs) are major regulators of intratumoral angiogenesis in ovarian cancer (OVCA). Overexpression of VEGFs is associated with increased tumor growth and metastatic tendency and VEGF-targeting therapies are thus considered as potential treatments for OVCA. Here, we examined the antiangiogenic and antitumoral effects on OVCA of adeno-associated virus 8 (AAV8)-mediated expression of soluble VEGF receptors (sVEGFRs) sVEGFR2 and sVEGFR3 together with paclitaxel and carboplatin chemotherapy.

Materials and methods

Immunodeficient mice were inoculated with human OVCA cell line SKOV-3m. Development of tumors was confirmed with magnetic resonance imaging (MRI) and mice were treated with gene therapy and paclitaxel and carboplatin chemotherapy. The study groups included (I) non-treated control group, (II) blank control vector AAV8-CMV, (III) AAV8-CMV with chemotherapy, (IV) AAV8-sVEGFR2, (V) AAV8-sVEGFR3, (VI) AAV8-sVEGFR2 and AAV8-sVEGFR3, and (VII) AAV8-sVEGFR2 and AAV8-sVEGFR3 with chemotherapy. Antiangiogenic and antitumoral effects were evaluated with immunohistochemical stainings and serial MRI.

Results

Reduced intratumoral angiogenesis was observed in all antiangiogenic gene therapy groups. The combined use of AAV8-sVEGFR2 and AAV8-sVEGFR3 with chemotherapy suppressed ascites fluid formation and tumor growth, thus improving the overall survival of mice. Antitumoral effect was mainly caused by AAV8-sVEGFR2 while the benefits of AAV8-sVEGFR3 and chemotherapy were less prominent.

Conclusion

Combined use of the AAV8-sVEGFR2 and AAV8-sVEGFR3 with chemotherapy reduces intratumoral angiogenesis and tumor growth in OVCA mouse model. Results provide preclinical proof-of-concept for the use of soluble decoy VEGFRs and especially the AAV8-sVEGFR2 in the treatment of OVCA.
Reduced blood-brain barrier penetration of acne vulgaris antibiotic sarecycline compared to minocycline corresponds with lower lipophilicity
Authors: Grada Ayman , Del Rosso James Q. , Moore Angela Y. , Stein Gold Linda , Harper Julie , Damiani Giovanni , Shaw Katharina , Obagi Sabine , Salem Raidah J. , Tanaka S. Ken , Bunick Christopher G.
Published: December 2022

Background

Vestibular side effects such as dizziness and vertigo can be a limitation for some antibiotics commonly used to treat acne, rosacea, and other dermatology indications.

Objective

Unlike minocycline, which is a second-generation tetracycline, sarecycline, a narrow-spectrum third-generation tetracycline-class agent approved to treat acne vulgaris, has demonstrated low rates of vestibular-related adverse events in clinical trials. In this work, we evaluate the brain-penetrative and lipophilic attributes of sarecycline in 2 non-clinical studies and discuss potential associations with vestibular adverse events.

Methods

Rats received either intravenous sarecycline or minocycline (1.0 mg/kg). Blood-brain penetrance was measured at 1, 3, and 6 h postdosing. In another analysis, the lipophilicity of sarecycline, minocycline, and doxycycline was measured via octanol/water and chloroform/water distribution coefficients (logD) at pH 3.5, 5.5, and 7.4.

Results

Unlike minocycline, sarecycline was not detected in brain samples postdosing. In the octanol/water solvent system, sarecycline had a numerically lower lipophilicity profile than minocycline and doxycycline at pH 5.5 and 7.4.

Conclusion

The reduced blood-brain penetrance and lipophilicity of sarecycline compared with other tetracyclines may explain low rates of vestibular-related adverse events seen in clinical trials.
Recent estimates and predictions of 5-year survival rate in patients with pancreatic cancer: A model-based period analysis
Authors: Li Jing , Li Yunmei , Chen Chong , Guo Jiayu , Qiao Mengmeng , Lyu Jun
Published: December 2022

Background

The 5-year survival rate for pancreatic cancer (PC) is incredibly low, resulting in this often being a fatal disease. Timely and accurate assessment of the survival rate and prognosis of patients with PC is of great significance for the development of new programs for prevention, monitoring, and treatment.

Methods

Period analysis and further stratified analysis were used to determine the 5-year relative survival rate (RSR) of patients with PC from 2002 to 2016 using the Surveillance, Epidemiology, and End Results (SEER) project database of the National Cancer Institute. Based on this, a generalized linear model was created to predict the survival rate of patients from 2017 to 2021.

Result

During 2002–2016, the 5-year RSR of patients with PC increased from 7.9 to 23.7%. The generalized linear model predicted that the survival rate had increased to 33.9% during 2017–2021, and hence, it was still unacceptably low. The survival rate of patients aged ≥75 years at diagnosis was the lowest among all age groups and was predicted to be only 21.4% during 2017–2021. Notably, the survival rate of patients with differentiation grade III at diagnosis remains particularly low at 7.6%.

Conclusion

The survival rates of patients with PC, although slightly improved, remain extremely low. Timely assessment of the trend of survival rate changes in patients with PC further improves the prognosis of tumor patients and provides data support for relevant medical works to formulate effective tumor prevention and control policies.
Case report: Successful treatment of acute generalized pustular psoriasis of puerperium with secukinumab
Authors: Xue Gao , Lili Ma , Yimiao Fang , Miao Wu , Xiaohong Yang , Dongmei Wang
Published: December 2022

Generalized pustular psoriasis (GPP) is a rare and severe form of psoriasis presenting with erythematous, aseptic pustules. Common systemic symptoms include fever and myalgias. The presentation of GPP resembles acute generalized exanthematous pustulosis (AGEP). However, the treatment of these two pathologies differs. While AGEP is self-limiting and treated with topical corticosteroids and constrain of systemic steroids. GPP treatment avoids corticosteroid, choosing acitretin, methotrexate, and cyclosporine as first-line agents. In this case report, a 27-year-old female with a medical history of AGEP presented to the hospital with extensive erythema and pustules. Complete blood count acute phase reactant analysis revealed an elevated white blood cell count and C-reactive protein (CRP). Two histopathological examinations revealed psoriatic hyperplasia of the epidermis with keratosis, along with Kogoj and Munro micro abscesses above the spina layer. Lymphocytic and neutrophilic infiltrate was present in the superficial derma layer along with vasodilation. The patient was diagnosed with GPP according to pathological and clinical criteria. Treatment was initiated with secukinumab because of the patient’s failure to respond to systemic treatment with Acitretin, methotrexate, and cyclosporin. Following 2 weeks of therapy with 300 mg of secukinumab, the pustular lesions had resolved. This study indicates the potential efficacy of secukinumab as an effective therapy that can rapidly improve the clinical symptoms of GPP.
Comparison of lens refractive parameters in myopic and hyperopic eyes of 6–12-year-old children
Authors: Shang Jianming , Hua Yanjun , Wang Yuliang , He Ji C. , Zhou Xingtao , Qu Xiaomei
Published: December 2022

Background/aims

To evaluate the influence of cycloplegia on lens refractive parameters in 6–12-year-old children with myopia and hyperopia for exploring the pathogenesis of myopia.

Methods

One hundred eyes of 100 patients (50 boys) were included. In the myopic group, 50 subjects (25 boys and 25 right eyes) were enrolled with a mean age of 9.20 ± 1.69 years. IOLMaster 700 measurements were performed pre- and post-cycloplegia. The pictures were marked using semi-automatic software. The lens curvature and power were obtained using MATLAB image processing software. Paired and independent samplet-tests were used for data analysis. Statistical significance was set atP< 0.05.

Results

Anterior and posterior lens curvature radius in myopic eyes were larger than those in hyperopic eyes, both pre- and post-cycloplegia (bothP< 0.001). The refractive power in myopic eyes was lower than that in hyperopic eyes without cycloplegia, both pre- and post-cycloplegia (bothP< 0.001). The changes in anterior lens curvature and refractive power between pre- and post-cycloplegia in hyperopic eyes were larger than those in myopic eyes (bothP< 0.05). No significant difference was found in the change in posterior lens curvature and refractive power after cycloplegia in hyperopic and myopic eyes (P> 0.05).

Conclusion

Anterior and posterior surfaces of the lens were flatter, and the refractive power was lower in the myopia group than in the hyperopia group. Myopic and hyperopic patients showed a tendency for lens flattening and refractive power decrease after cycloplegia. Hyperopic patients had more changes in anterior lens curvature and refractive power after cycloplegia.
Crystal structure of the feruloyl esterase from Lentilactobacillus buchneri reveals a novel homodimeric state
Authors: Kasmaei Kamyar Mogodiniyai , Kalyani Dayanand C. , Reichenbach Tom , Jiménez-Quero Amparo , Vilaplana Francisco , Divne Christina
Published: December 2022

Ferulic acid is a common constituent of the plant cell-wall matrix where it decorates and can crosslink mainly arabinoxylans to provide structural reinforcement. Microbial feruloyl esterases (FAEs) specialize in catalyzing hydrolysis of the ester bonds between phenolic acids and sugar residues in plant cell-wall polysaccharides such as arabinoxylan to release cinnamoyl compounds. Feruloyl esterases from lactic acid bacteria (LAB) have been highlighted as interesting enzymes for their potential applications in the food and pharmaceutical industries; however, there are few studies on the activity and structure of FAEs of LAB origin. Here, we report the crystal structure and biochemical characterization of a feruloyl esterase (LbFAE) from Lentilactobacillus buchneri, a LAB strain that has been used as a silage additive. The LbFAE structure was determined in the absence and presence of product (FA) and reveals a new type of homodimer association not previously observed for fungal or bacterial FAEs. The two subunits associate to restrict access to the active site such that only single FA chains attached to arabinoxylan can be accommodated, an arrangement that excludes access to FA cross-links between arabinoxylan chains. This narrow specificity is further corroborated by the observation that no FA dimers are produced, only FA, when feruloylated arabinoxylan is used as substrate. Docking of arabinofuranosyl-ferulate in the LbFAE structure highlights the restricted active site and lends further support to our hypothesis that LbFAE is specific for single FA side chains in arabinoxylan.
Diversity and effects of competitive Trichoderma species in Ganoderma lucidum–cultivated soils
Authors: Wang Yongjun , Zeng Linzhou , Wu Jiayi , Jiang Hong , Mei Li
Published: December 2022

Ganoderma lucidum (GL) is a well-known medicinal mushroom that has been extensively cultivated. Our previous study has shown that abundant Trichoderma colonies grow on the casing soil surface, posing cultivation obstacles for GL. However, an understanding of species-level characteristics of Trichoderma strains and their adverse effects on GL growth is limited. This study aimed to investigate the diversity and potential effects of Trichoderma from GL-cultivated soils. Over 700 Trichoderma isolates were collected from two trails in Longquan Country, southeast China. Eight Trichoderma species, including T. atrioviride, T. guizhouense, T. hamatum, T. harzianum, T. koningiopsis, T. pleuroticola, T. sp. irale, and T. virens, were identified based on the combination alignment of tef-1α and rpb2 sequences. The number of Trichoderma colonies increased dramatically during GL cultivation, with an increase of 9.2-fold in the Lanju trail. T. virens accounted for the most colonies (33.33 and 32.50% in Lanju and Chengbei, respectively) at the end of GL cultivation. The Trichoderma species growth varied but was satisfactory under different temperature or pH conditions. Moreover, Trichoderma species showed different adverse effects on GL growth. The non-volatile metabolites from T. virens and volatile metabolites from T. atroviride displayed the strongest antagonistic activity. Furthermore, the volatile 6-pentyl-2H-pyran-2-one (6-PP) showed a significant inhibitory effect on GL growth with an 8.79 μl mL−1 headspace of 50% effective concentration. The different Trichoderma spp. produced different amounts of 6-PP. The most efficient 6-PP producer was T. atroviride. To the best of our knowledge, this study is the first to demonstrate the abundance of competitive Trichoderma species associated with GL cultivation. Our results would contribute to.
Iron restriction induces the small-colony variant phenotype in Staphylococcus aureus
Authors: Islam Shariful , Callender Anna C. , Ho Quynh N. , Wakeman Catherine A.
Published: December 2022

Pathogens such as Staphylococcus aureus must overcome host-induced selective pressures, including limited iron availability. To cope with the harsh conditions of the host environment, S. aureus can adapt its physiology in multiple ways. One of these adaptations is the fermenting small-colony variant (SCV) phenotype, which is known to be inherently tolerant to certain classes of antibiotics and heme toxicity. We hypothesized that SCVs might also behave uniquely in response to iron starvation since one of the major cellular uses of iron is the respiration machinery. In this study, a respiring strain of S. aureus and fermenting SCV strains were treated with different concentrations of the iron chelator, 2,2′ dipyridyl (DIP). Our data demonstrate that a major impact of iron starvation in S. aureus is the repression of respiration and the induction of the SCV phenotype. We demonstrate that the SCV phenotype transiently induced by iron starvation mimics the aminoglycoside recalcitrance exhibited by genetic SCVs. Furthermore, prolonged growth in iron starvation promotes increased emergence of stable aminoglycoside-resistant SCVs relative to the naturally occurring subpopulation of SCVs within an S. aureus community. These findings may have relevance to physiological and evolutionary processes occurring within bacterial populations infecting iron-limited host environments.
Regulatory roles of RpoS in the biosynthesis of antibiotics 2,4-diacetyphloroglucinol and pyoluteorin of Pseudomonas protegens FD6
Authors: Zhang Qing Xia , Xiong Zheng Wen , Li Shen Yu , Yin Yue , Xing Cheng Lin , Wen De Yu , Xu Jian , Liu Qin
Published: December 2022

The rhizosphere microbe Pseudomonas protegens FD6 possesses beneficial traits such as the production of antibiotics like pyoluteorin (Plt) and 2,4-diacetylphloroglucinol (2,4-DAPG). The alternative RpoS (σ38 factor), as a master regulator, activates or inhibits the transcription of stationary phase genes in several biocontrol organisms. Here, we investigated the complicated function and regulatory mechanism of RpoS in the biosynthesis of 2,4-DAPG and Plt in strain FD6. Phenotypic assays suggested that ΔrpoS was impaired in biofilm formation, swimming motility, swarming motility, and resistance to stress, such as heat, H2O2 and 12% ethanol. The RpoS mutation significantly increased both 2,4-DAPG and Plt production and altered the transcription and translation of the biosynthetic genes phlA and pltL, indicating that RpoS inhibited antibiotic production by FD6 at both the transcriptional and translational levels. RpoS negatively controlled 2,4-DAPG biosynthesis and transcription of the 2,4-DAPG operon phlACBD by directly interacting with the promoter sequences of phlG and phlA. In addition, RpoS significantly inhibited Plt production and the expression of its operon pltLABCDEFG by directly binding to the promoter regions of pltR, pltL and pltF. Further analyzes demonstrated that a putative R147 mutation in the RpoS binding domain abolished its inhibitory activity on the expression of pltL and phlA. Overall, our results reveal the pleiotropic regulatory function of RpoS in P. protegens FD6 and provide the basis for improving antibiotic biosynthesis by genetic engineering in biocontrol organisms.
ADMET profiling and molecular docking of potential antimicrobial peptides previously isolated from African catfish, Clarias gariepinus
Authors: Okella Hedmon , Okello Emmanuel , Mtewa Andrew Glory , Ikiriza Hilda , Kaggwa Bruhan , Aber Jacqueline , Ndekezi Christian , Nkamwesiga Joseph , Ajayi Clement Olusoji , Mugeni Ivan Mulongo , Ssentamu Geofrey , Ochwo Sylvester , Odongo Steven , Tolo Casim Umba , Kato Charles Drago , Engeu Patrick Ogwang
Published: December 2022

Amidst rising cases of antimicrobial resistance, antimicrobial peptides (AMPs) are regarded as a promising alternative to traditional antibiotics. Even so, poor pharmacokinetic profiles of certain AMPs impede their utility necessitating, a careful assessment of potential AMPs’ absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties during novel lead exploration. Accordingly, the present study utilized ADMET scores to profile seven previously isolated African catfish antimicrobial peptides (ACAPs). After profiling, the peptides were docked against approved bacterial protein targets to gain insight into their possible mode of action. Promising ACAPs were then chemically synthesized, and their antibacterial activity was validated in vitro utilizing the broth dilution method. All seven examined antimicrobial peptides passed the ADMET screening, with two (ACAP-IV and ACAP-V) exhibiting the best ADMET profile scores. The ACAP-V had a higher average binding energy (−8.47 kcal/mol) and average global energy (−70.78 kcal/mol) compared to ACAP-IV (−7.60 kcal/mol and −57.53 kcal/mol), with the potential to penetrate and disrupt bacterial cell membrane (PDB Id: 2w6d). Conversely, ACAP-IV peptide had higher antibacterial activity against E. coli and S. aureus (Minimum Inhibitory Concentration, 520.7 ± 104.3 μg/ml and 1666.7 ± 416.7 μg/ml, respectively) compared to ACAP-V. Collectively, the two antimicrobial peptides (ACAP-IV and ACAP-V) are potential novel leads for the food, cosmetic and pharmaceutical industries. Future research is recommended to optimize the expression of such peptides in biological systems for extended evaluation.
The malaria parasite chaperonin containing TCP-1 (CCT) complex: Data integration with other CCT proteomes
Authors: Wilkinson Mark D. , Ferreira Josie L. , Beeby Morgan , Baum Jake , Willison Keith R.
Published: December 2022

The multi-subunit chaperonin containing TCP-1 (CCT) is an essential molecular chaperone that functions in the folding of key cellular proteins. This paper reviews the interactome of the eukaryotic chaperonin CCT and its primary clients, the ubiquitous cytoskeletal proteins, actin and tubulin. CCT interacts with other nascent proteins, especially the WD40 propeller proteins, and also assists in the assembly of several protein complexes. A new proteomic dataset is presented for CCT purified from the human malarial parasite, P. falciparum (PfCCT). The CCT8 subunit gene was C-terminally FLAG-tagged using Selection Linked Integration (SLI) and CCT complexes were extracted from infected human erythrocyte cultures synchronized for maximum expression levels of CCT at the trophozoite stage of the parasite’s asexual life cycle. We analyze the new PfCCT proteome and incorporate it into our existing model of the CCT system, supported by accumulated data from biochemical and cell biological experiments in many eukaryotic species. Together with measurements of CCT mRNA, CCT protein subunit copy number and the post-translational and chemical modifications of the CCT subunits themselves, a cumulative picture is emerging of an essential molecular chaperone system sitting at the heart of eukaryotic cell growth control and cell cycle regulation.
Controlled CO labilization of tungsten carbonyl precursors for the low-temperature synthesis of tungsten diselenide nanocrystals
Authors: Geisenhoff Jessica Q. , Yin Hang , Oget Natacha , Chang Haeun , Chen Linfeng , Schimpf Alina M.
Published: December 2022

We report a low-temperature colloidal synthesis of WSe2 nanocrystals from tungsten hexacarbonyl and diphenyl diselenide in trioctylphosphine oxide (TOPO). We identify TOPO-substituted intermediates, W(CO)5TOPO and cis-W(CO)4(TOPO)2 by infrared spectroscopy. To confirm these assignments, we synthesize aryl analogues of phosphine-oxide-substituted intermediates, W(CO)5TPPO (synthesized previously, TPPO = triphenylphosphine oxide) and cis-W(CO)4(TPPO)2 and fac-W(CO)3(TPPO)3 (new structures reported herein). Ligation of the tungsten carbonyl by either the alkyl or aryl phosphine oxides results in facile labilization of the remaining CO, enabling low-temperature decomposition to nucleate WSe2 nanocrystals. The reactivity in phosphine oxides is contrasted with syntheses containing phosphine ligands, where substitution results in decreased CO labilization and higher temperatures are required to induce nanocrystal nucleation.