bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of pegfilgrastim approval on relative dose intensity and outcomes of R-CHOP for diffuse large B-cell lymphoma
Authors: Morita Yuka , Kanemasa Yusuke , Sasaki Yuki , Ohigashi An , Tamura Taichi , Nakamura Shohei , Yagi Yu , Kageyama Akihiko , Omuro Yasushi , Shimoyama Tatsu
Published: April 2022

Maintaining relative dose intensity (RDI) of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) improves the prognosis of patients with diffuse large B-cell lymphoma (DLBCL). Pegfilgrastim was approved in Japan in November 2014 to prevent febrile neutropenia (FN) and maintain RDI.

In this retrospective study, we reviewed 334 patients with DLBCL who received 6 or more courses of R-CHOP and analyzed the differences in the RDI, overall survival (OS), and progression-free survival between patients whose treatment started after November 2014 (postapproval group) and those whose treatment started before October 2014 (pre-approval group).

The incidence of FN was lower (20% vs 38.3%, P < .001) and the RDI of R-CHOP was higher (86.8% vs 67.8%, P < .001) in the postapproval group. Pegfilgrastim was administered to many of these patients (76.8%) and was thought to have contributed to the high RDI maintenance in the postapproval group. Interrupted time-series analysis showed a significant rise of the RDI at the timing of pegfilgrastim approval in patients aged <70 years (estimated change: 18.1%, P < .001). The 5-year OS (85.7% vs 69.9%, P = .009) and progression-free survival (81.4% vs 64.4%, P = .011) were superior in the postapproval group. However, the differences were not significant in matched-pair analysis matching National Comprehensive Cancer Network-International Prognostic Index scores. Improved survival outcomes in this group were observed only among patients with Ann Arbor stage 3/4 (5-year OS: 83.7% vs 61.3%, P = .019) and high-risk on the National Comprehensive Cancer Network-International Prognostic Index (5-year OS: 80.7% vs 32.4%, P = .014). Multivariate analysis showed that a high RDI and low lactate dehydrogenase were associated with superior OS (RDI ≥ 85%, hazard ratio: 0.48, P = .016; lactate dehydrogenase > institutional upper limit of normal, hazard ratio: 2.38, P = .005).

The RDI of R-CHOP was able to be maintained at higher levels, the incidence of FN was lower, and significantly better clinical outcomes were achieved in clinically high-risk groups after pegfilgrastim approval. Maintaining a high RDI in R-CHOP by administering pegfilgrastim to those who are likely to have low RDI without it is important for achieving favorable outcomes in patients with DLBCL.
Clinical study on Yanghe decoction in improving neo-adjuvant chemotherapy efficacy and immune function of breast cancer patients
Authors: Zhang Xinyue , Hu Minhao , Li Siyu , Sha Shanyan , Mao Ruoyu , Liu Yu , Li Qiong , Lu Qing , Chen Weili , Zhang Ying , Wang Rong , Xu Huaijin , Wang Jieqiong , Qiao Yu , Chen Ziyi , Wu Huangan , Pan Yuncui , Wang Qian , Zhang Shuhui , Yang Fan , Li Jianwei , Liu Guangyu , Xue Xiaohong , Ji Yajie
Published: April 2022

Introduction:

Neoadjuvant chemotherapy (NAC) plays an important role in downgrading preoperative tumor size, providing information on regimen activity, and increases treatment efficacy in breast cancer patients. An increasing number of patients have sought Traditional Chinese Medicine (TCM) during NAC to relieve discomfort, regulate immune function, and improve survival. However, limited evidence is available on how concurrent TCM treatment combined with NAC affects tumor response. This study aims to assess the efficacy of Yanghe decoction, a classical warming Yang formula, on pathological complete response (pCR) and explore its mechanism via the phosphatidylinositol-3-kinase/ protein kinase B/nuclear factor kappa-B (PI3K/Akt/NF-κB) pathway-mediated immune-inflammation microenvironment.

Methods:

A single-center, randomized, placebo-controlled, double-blinded randomized control trial (RCT) was designed. This trial aims to recruit 128 participants with breast cancer scheduled to receive NAC in China. All participants will be randomly assigned (1:1) to the Neo-Yanghe group (Yanghe decoction plus NAC) or the control group (placebo plus NAC). The primary outcome will be evaluated by the proportion of participants achieving pCR. The secondary outcomes include the expression level of PI3K/Akt/NF-κB pathway-related proteins, the objective response rate, the time to response, serum level of immune-inflammatory indicators, quality of life, disease-free survival, and overall survival.

Discussion:

This study will be the first RCT to evaluate the efficacy of Yanghe decoction combined with NAC in treating breast cancer patients, and elucidate the antitumor mechanism via the PI3K/Akt/NF-κB pathway-mediated immune-inflammation microenvironment. If possible, Neo-Yanghe treatment pattern will be a better pharmacological intervention to manage breast cancer than chemotherapy alone. The results of the trial will provide research-based evidence for the development of integrated Chinese and Western medicine guidelines and expert consensus.

Trial registration: Chinese Clinical Trial Registry ChiCTR-INR-2000036943. Registered on September 28, 2020 (https://www.chictr.org.cn/hvshowproject.aspx?id=57141).
External treatment of herbal medicine with tuina in congenital muscular torticollis
Authors: Kim Eunjin , Choi Jungyoon , Min Sang Yeon
Published: April 2022

Background:

This study is the protocol to evaluate the clinical evidence for external treatments using herbal medicine (ETHM) with tuina as a congenital muscular treatment (CMT) in pediatrics.

Methods:

Eleven databases will be searched until June 2022, without any language restrictions: four English databases (MEDLINE, Pubmed, EMBASE, and The Cochrane Central Register of Database of Controlled Trials), three Chinese databases (China National Knowledge Infrastructure, Chinese Scientific Journal Database, and Wan Fang Database), and four Korean electronic databases (Oriental Medicine Advanced Searching Integrated System, Korean Studies Information Service System, National Digital Science Links, and Research Information Sharing Service). This review will include randomized clinical trials (RCTs) of ETHM with tuina as an intervention versus the same tuina. All published RCTs for any ETHM for CMT will be included. Non-RCTs, RCT protocol, animal studies, case reports, reviews, and surveys will be excluded. The methodological quality assessment will be performed using the Cochrane risk of bias (ROBs). Review Manager version 5.4. will be used for the data synthesis and quantitative analysis.

Results and discussions:

The systematic review and meta-analysis will provide evidence for ETHM as a treatment of CMT. The evidence can help clinicians and patients recognize more effective therapeutic and safe inventions.

INPLASY registration number:

INPLASY202210017.
Hybrid surgery techniques for the treatment of in-stent restenosis after 5 years of femoral artery self-expanding bare-metal stent implantation
Authors: Zhou Jianguo , Zha Guosong , Qian Guosheng
Published: April 2022

Rationale:

Lower extremity arteriosclerosis obliterans (ASO) disease is caused by the formation of atherosclerotic plaque in the femoral artery, which causes the stenosis and occlusion of lower legs, and then leads to chronic limb ischemia. Stent intervention is the most common treatment for ASO in the lower extremities, although there is a risk of overstretching or fracturing the stent, resulting in stent rupture. We provide a unique method for treating stent rupture.

Patient concerns:

A 79-year-old male presented with intermittent claudication of the left lower limb for 6 months. Five years ago, a stent was placed in the lower extremity femoral artery. According to the examination, the stent suffered a modest torsional fracture.

Diagnosis:

The case was diagnosed with lower extremity ASO.

Interventions:

We performed a combination of femoral endarterectomy and interventional surgery.

Outcomes:

Blood flow was restored after the hybrid operation has been used to treat arterial stenosis in the lower limbs.

Conclusion:

Integrating vascular interventional surgeries can shorten surgical procedures time and increase success rates.
PIM1 is a Poor Prognostic Factor for and Potential Therapeutic Target in Serous Carcinoma of the Endometrium
Authors: Takeuchi Hodaka , Miyamoto Tsutomu , Fuseya Chiho , Asaka Ryoichi , Ida Koichi , Ono Motoki , Tanaka Yasuhiro , Shinagawa Manaka , Ando Hirofumi , Asaka Shiho , Shiozawa Tanri
Published: April 2022

Serous carcinoma (SC) is an aggressive histologic type of endometrial carcinoma (EMC) with a poor prognosis. The development of novel therapeutics for SC is an important issue. PIM1 is a serine/threonine kinase involved in various cellular functions, such as cell cycle progression, apoptosis, and transcriptional activation via the phosphorylation of many target proteins, including MYC. PIM1 is overexpressed in several cancers and has been associated with treatment-resistance. We investigated the expression and function of PIM1 in EMC, particularly SC. Immunohistochemical analysis in 133 EMC cases [103 endometrioid carcinomas (EC) and 30 SC] revealed the significantly stronger expression of PIM1 in SC than in EC and significantly shorter survival of patients with overexpression of PIM1 in all EMC cases, as well as in only SC cases. A multivariate analysis identified overexpression of PIM1 as an independent prognostic factor. The knockdown of PIM1 by siRNA in the SC cell line, ARK1, decreased the expression of phosphorylated MYC and reduced proliferation, migration, and invasion. The PIM1 inhibitor, SGI-1776, reduced cell viability in SC cell lines (ARK1, ARK2, and SPAC1L) with IC50 between 1 and 5 µM. SGI-1776 also reduced the migration and invasion of ARK1 cells. Moreover, the oral administration of SGI-1776 significantly suppressed subcutaneous ARK1 xenograft tumor growth in nude mice without impairing health. These results indicate that PIM1 is involved in the acquisition of aggressiveness and suggest the potential of PIM1 as a novel therapeutic target and SGI-1776 as a therapeutic agent for SC.
FDG PET/CT Features of Polysaccharide-Based Hemostatic Agent
Authors: Bozkurtlar Emine , Oksuzoglu Kevser , Bostanci Korkut , Aslan Sezer , Kissa Tugba Nergiz , Kocakaya Derya , Ones Tunc
Published: April 2022

Purpose

To prevent hemorrhagic complications, hemostatic agents (HAs) have been widely used in recent years. The use of HAs can lead to false-positive results on postoperative imaging. There exists only 1 study in the literature evaluating these applications during surgical procedures. Therefore, we aimed to evaluate the postoperative imaging features of polysaccharide-based HAs in thoracic surgery patients who have had 18F-FDG PET/CT scans.

Patients and Methods

Two hundred nine consecutive patients who underwent thoracic surgery were enrolled in this study. A topical polysaccharide-based HA was applied to the surgical bed for all of the patients. The patients diagnosed with cancer were followed up with subsequent thoracic CT scans, and 42 of these patients were also imaged with 18F-FDG PET/CT, which then comprised the main study group. Due to suspicion of metastasis, 19/42 patients were reoperated or rebiopsied. The latest histopathological findings were accepted as criterion standard, and previous FDG PET/CT images were retrospectively reevaluated.

Results

Polysaccharide-based HAs that appear as amorphous basophilic material were identified in histopathological samples of 11/19 patients. Lymphocytes, plasma cells, and histiocytes, which formed foreign body reaction and/or foreign body granuloma, indicating the presence of chronic inflammation, were seen in all of the samples. 18F-FDG PET/CT showed increased FDG uptake in all of these lesions.

Conclusions

Despite the inconsistency of the literature, polysaccharide-based HAs can be demonstrated in human surgical specimens as amorphous basophilic materials even after a long time from the initial surgical procedure. These agents almost always cause chronic inflammatory changes. In addition, these agents may mimic “false-positive” findings on postoperative FDG PET/CT scans.
FDG PET/CT Imaging Findings of Renal Infarction in a Patient With Gastric Adenocarcinoma
Authors: Tatci Ebru , Ozmen Ozlem , Gökçek Atila
Published: April 2022

We report the FDG PET/CT findings of renal infarction in a 75-year-old woman patient who received chemotherapy for gastric adenocarcinoma. The patient was referred to our hospital for the evaluation of her response to chemotherapy. PET/CT detected circumferential increased FDG uptake in the outer part of the left renal cortex. The remaining of the renal cortex was photopenic. Abdominal CT angiography showed no contrast enhancement within the renal parenchyma. There was no contrast enhancement in the lumen of the left renal artery. These findings were thought to be consistent with the left renal infarct due to the occlusion of the left renal artery.
Speed and safety of mass spectrometry for identification of Burkholderia pseudomallei directly from spiked blood cultures
Authors: Gassiep Ian , Bauer Michelle J. , Harris Patrick N. A. , Norton Robert
Published: April 2022

Burkholderia pseudomallei

is a bipolar Gram-negative bacillus and the causative agent of melioidosis; an infectious disease which commonly presents with bacteraemia.

Data regarding direct from blood culture identification of

B. pseudomallei

using the Vitek mass spectrometer (MS) are limited.

The authors aim to assess the safety and sensitivity of the Vitek MS for identification of

B. pseudomallei

from spiked positive blood culture samples.

Safety was assessed by determining the ability of the standard MS α-cyano-4-hydroxycinnamic acid (CHCA) matrix solution to inactivate

B. pseudomallei

. Organism identification using the manufacturer’s blood culture extraction method was compared to an in-house technique. Additionally, identification following abbreviated agar incubation of blood culture broth was performed.

All 70 MS target spots were inactivated by the matrix solution. The manufacturer’s blood culture extraction method identified 0/26 (0%)

B. pseudomallei

samples. An in-house method using the spun deposit from blood culture broth samples identified 38/38 (100%)

B. pseudomallei

samples. MS analysis of a blood culture broth drop on Chocolate agar following a 6 h incubation identified 30/32 (94%) samples.

Decreased time to diagnosis of melioidosis bacteraemia is likely to improve patient outcomes. This study adds to the literature with regards to the utility of MALDI-TOF MS identification of

B. pseudomallei

both directly from positive blood culture broth and a subsequent 6 h plate incubation. The use of a standard matrix solution inactivates the organism, and use of the spun deposit from a positive blood culture broth is most effective for early identification of

B. pseudomallei

.
More efficient and inclusive time-to-event trials with covariate adjustment: a simulation study
Authors: Momal Raphaëlle , Trichelair Paul , Blum Michael G.B. , Balazard Félix
Published: April 2022

Adjustment for prognostic covariates increases the statistical power of randomized trials. The factors influencing increase of power are well-known for trials with continuous outcomes. Here, we study which factors influence power and sample size requirements in time-to-event trials. We consider both parametric simulations and simulations derived from the TCGA cohort of hepatocellular carcinoma (HCC) patients to assess how sample size requirements are reduced with covariate adjustment. Simulations demonstrate that the benefit of covariate adjustment increases with the prognostic performance of the adjustment covariate (C-index) and with the cumulative incidence of the event in the trial. For a covariate that has an intermediate prognostic performance (C-index=0.65), the reduction of sample size varies from 1.7% when cumulative incidence is of 10% to 26.5% when cumulative incidence is of 90%. Broadening eligibility criteria usually reduces statistical power while our simulations show that it can be maintained with adequate covariate adjustment. In a simulation of HCC trials, we find that the number of patients screened for eligibility can be divided by 2.7 when broadening eligibility criteria. Last, we find that the Cox-Snell is a good approximation of the reduction in sample size requirements provided by covariate adjustment. This metric can be used in the design of time-to-event trials to determine sample size. Overall, more systematic adjustment for prognostic covariates leads to more efficient and inclusive clinical trials especially when cumulative incidence is large as in metastatic and advanced cancers.

Key messages

Covariate adjustment is a statistical technique that leverages prognostic scores within the statistical analysis of a trial. We study its benefits for time-to-event trials.

Power gain achieved with covariate adjustment is determined by the prognostic performance of the covariate and by the cumulative incidence of events at the end of the follow-up period.

Trials in indications with large cumulative incidence such as metastatic cancers can benefit from covariate adjustment to improve their statistical power.

Covariate adjustment maintains statistical power in trials when eligibility criteria are broadened.
Modeling the initial phase of COVID-19 epidemic: The role of age and disease severity in the Basque Country, Spain
Authors: Srivasrav Akhil Kumar , Stollenwerk Nico , Van-Dierdonck Joseba Bidaurrazaga , Mar Javier , Ibarrondo Oliver , Aguiar Maíra
Published: April 2022

Declared a pandemic by the World Health Organization (WHO), COVID-19 has spread rapidly around the globe. With eventually substantial global underestimation of infection, by the end of March 2022, more than 470 million cases were confirmed, counting more than 6.1 million deaths worldwide.

COVID-19 symptoms range from mild (or no) symptoms to severe illness, with disease severity and death occurring according to a hierarchy of risks, with age and pre-existing health conditions enhancing risks of disease severity. In order to understand the dynamics of disease severity during the initial phase of the pandemic, we propose a modeling framework stratifying the studied population into two groups, older and younger, assuming different risks for severe disease manifestation.

The deterministic and the stochastic models are parametrized using epidemiological data for the Basque Country population referring to confirmed cases, hospitalizations and deaths, from February to the end of March 2020. Using similar parameter values, both models were able to describe well the existing data. A detailed sensitivity analysis was performed to identify the key parameters influencing the transmission dynamics of COVID-19 in the population. We observed that the population younger than 60 years old of age would contribute more to the overall force of infection than the older population, as opposed to the already existing age-structured models, opening new ways to understand the effect of population age on disease severity during the COVID-19 pandemic.

With mild/asymptomatic cases significantly influencing the disease spreading and control, our findings support the vaccination strategy prioritising the most vulnerable individuals to reduce hospitalization and deaths, as well as the non-pharmaceutical intervention measures to reduce disease transmission.
Implementation strategies to increase human papillomavirus vaccination uptake for adolescent girls in sub-Saharan Africa: A scoping review protocol
Authors: Lubeya Mwansa Ketty , Mwanahamuntu Mulindi , Chibwesha Carla , Mukosha Moses , Wamunyima Mercy Monde , Kawonga Mary
Published: April 2022

Introduction

The human papillomavirus (HPV) is sexually transmitted and infects approximately 75% of sexually active people early in their sexual life. Persistent infection with oncogenic HPVtypes can lead to malignant conditions such as cervical cancer. In 2006, the World Health Organisation approved the use of efficacious HPV vaccine for girls aged 9 to 14 years to prevent HPV related conditions. Despite the HPV vaccine having been available for about 15 years, dose completion remains at 53% in sub-Saharan Africa for countries implementing the vaccination program. A fraught of barriers to implementation exist which prevent adequate coverage. Achieving success for HPV vaccination in real-world settings requires enacted implementation strategies to overcome implementation bottlenecks. Therefore, a better understanding and mapping of the implementation strategies used in sub-Saharan Africa to increase HPV vaccination uptake is critical. This review aims to identify implementation strategies to increase HPV vaccination uptake for adolescent girls in sub-Saharan Africa and provide a basis for policy and future research including systematic reviews to evaluate effective strategies as we accelerate the elimination of cervical cancer.

Materials and Methods

This review will consider studies that pertain to implementation strategies used to increase HPV vaccination uptake for adolescent girls in sub-Saharan Africa. Studies targeted at different stakeholders to increase adolescent vaccine uptake will be included. Studies using interventions not fitting the definition of implementation strategies as defined by the refined compilation of implementation strategies from the Expert Recommendations for Implementing Change project will be excluded. MEDLINE (via PubMed), Embase, CINAHL (via EBSCO), Scopus and Google scholar will be searched. Two independent reviewers will screen titles and abstracts for studies that meet the review’s inclusion criteria, and the full text of eligible studies will be reviewed. Data will be extracted from eligible studies using data charting table developed by this team for inclusion by two independent reviewers and presented in table and graphical form with a narrative summary.
Similar viral loads in Omicron infections regardless of vaccination status
Authors: Hirotsu Yosuke , Maejima Makoto , Shibusawa Masahiro , Natori Yume , Nagakubo Yuki , Hosaka Kazuhiro , Sueki Hitomi , Mochizuki Hitoshi , Tsutsui Toshiharu , Kakizaki Yumiko , Miyashita Yoshihiro , Omata Masao
Published: April 2022

Background

Although SARS-CoV-2 booster vaccinations are underway, breakthrough infections with Omicron variants are occurring. This study analyzed associations between Omicron sublineage (BA.1.1 and BA.2) viral load and vaccination history.

Methods

Viral loads in nasopharyngeal swabs were evaluated by quantitative real-time PCR, and the virus strain was evaluated by whole-genome analysis or TaqMan assay.

Results

A total of 611 patients positive for an Omicron SARS-CoV-2 variant were included; 199 were unvaccinated, 370 had received two vaccine doses, and 42 had received three doses. Similar viral loads and Ct values of BA.1.1 and BA.2 were detected regardless of vaccination history. No correlations between age and BA.1.1 and BA.2 viral load were observed.

Conclusion

Omicron-infected patients who had received a third vaccine dose had viral loads similar to patients with two doses or who were unvaccinated.
Identification and implication of tissue-enriched ligands in epithelial-endothelial crosstalk during pancreas development
Authors: Moulis Manon , Runser Steve Vincent Maurice , Glorieux Laura , Dauguet Nicolas , Vanderaa Christophe , Gatto Laurent , Tyteca Donatienne , Henriet Patrick , Spagnoli Francesca M. , Iber Dagmar , Pierreux Christophe E.
Published: April 2022

Development of the pancreas is driven by an intrinsic program coordinated with signals from other cell types in the epithelial environment. These intercellular communications have been so far challenging to study because of the low concentration, localized production and diversity of the signals released. Here, we combined scRNAseq data with a computational interactomic approach to identify signals involved in the reciprocal interactions between the various cell types of the developing pancreas. This in silico approach yielded 40,607 potential ligand-target interactions between the different main pancreatic cell types. Among this vast network of interactions, we focused on three ligands potentially involved in communications between epithelial and endothelial cells. Bmp7 and Wnt7b, expressed by pancreatic epithelial cells and predicted to target endothelial cells, and Sema6d, involved in the reverse interaction. In situ hybridization confirmed the localized expression of Bmp7 in the pancreatic epithelial tip cells and of Wnt7b in the trunk cells. On the contrary, Sema6d was enriched in endothelial cells. Functional experiments on ex vivo cultured pancreatic explants indicated that tip cell-produced Bmp7 restrained development of endothelial cells. This work identified ligands with a restricted tissular and cellular distribution and highlighted the role of Bmp7 in the intercellular communications shaping vessel development during pancreas organogenesis.
Serotonin, Etonogestrel and breathing activity in murine Congenital Central Hypoventilation Syndrome
Authors: Casciato Alexis , Bianchi Lola , Joubert Fanny , Delucenay-Clarke Roman , Parrot Sandrine , Ramanantsoa Nélina , Sizun Eléonore , Matrot Boris , Straus Christian , Similowski Thomas , Cayetanot Florence , Bodineau Laurence
Published: April 2022

Congenital Central Hypoventilation Syndrome, a rare disease caused by PHOX2B mutation, is associated with absent or blunted CO2/H+ chemosensitivity due to the dysfunction of PHOX2B neurons of the retrotrapezoid nucleus. No pharmacological treatment is available. Clinical observations have reported non-systematic CO2/H+ chemosensitivity recovery under desogestrel. Here, we used a preclinical model of Congenital Central Hypoventilation Syndrome, the retrotrapezoid nucleus conditional Phox2b mutant mouse, to investigate whether etonogestrel, the active metabolite of desogestrel, led to a restoration of chemosensitivity by acting on serotonin neurons known to be sensitive to etonogestrel, or retrotrapezoid nucleus PHOX2B residual cells that persist despite the mutation. The effect of etonogestrel, alone or combined with serotonin drugs, on the respiratory rhythm of medullary-spinal cord preparations from Phox2b mutants and wildtype mice was analyzed under metabolic acidosis. c-FOS, serotonin and PHOX2B were immunodetected. Serotonin metabolic pathways were characterized by ultra-high-performance liquid chromatography. We observed etonogestrel restored chemosensitivity in Phox2b mutants in a non-systematic way. Histological differences between Phox2b mutants with restored chemosensitivity and others indicated greater activation of serotonin neurons of the raphe obscurus nucleus but no effect on retrotrapezoid nucleus PHOX2B residual cells. Pharmacology of serotonin systems modulated the respiratory effect of etonogestrel differently according to serotonin metabolic pathways. Etonogestrel induced a restoration of chemosensitivity in Phox2b mutants by acting on serotonin neurons. Our work thus highlights that the state of serotonin systems was critically important for the occurrence of an etonogestrel-restoration, an element to consider in potential therapeutic intervention in Congenital Central Hypoventilation Syndrome patients.
Analog of Kynurenic Acid Decreases Tau Pathology by Modulating Astrogliosis in Rat Model for Tauopathy
Authors: Majerova Petra , Olesova Dominika , Golisova Greta , Buralova Martina , Michalicova Alena , Vegh Jozef , Piestansky Juraj , Bhide Mangesh , Hanes Jozef , Kovac Andrej
Published: April 2022

Background and purpose

Kynurenines have immunomodulatory and neuroactive properties and can influence the central nervous system. Previous studies showed the involvement of the kynurenines in the pathogenesis and progression of neurodegenerative disease. In neurodegenerative disorders, including tauopathies, the tryptophan metabolism is shifted toward neurotoxic agents and the reduction of neuroprotectant products. Astrocyte-derived kynurenic acid serves as a neuroprotectant. However, systemic administration of kynurenic acid is not effective because of low permeability across the blood-brain barrier (BBB).

Experimental Approach

We used a kynurenic acid analog with similar biological activity but higher brain permeability to overcome BBB limitations. In the present study, we used amide derivate of kynurenic acid N-(2-N, N-dimethylaminoethyl)-4-oxo-1H-quinoline-2-carboxamid (KYNA-1). We administered KYNA-1 for three months to tau transgenic rats SHR-24 and analyzed the effect on tau pathology and activation of glial cells. Primary glial cell cultures were applied to identify the mechanism of the KYNA-1 effect.

Key results

KYNA-1 was not toxic to rats after chronic three-month administration. When chronically administered, KYNA-1 reduced hyperphosphorylation of insoluble tau in the brain of transgenic rats. Noteworthily, the plasma total tau was also reduced. We determined that the effect of KYNA-1 on tau pathology was induced through the modulation of glial activation. KYNA-1 inhibited LPS induced activation of astrocytes and induced transformation of microglia to M2 phenotype.

Conclusion and Implications

We identified that the administration of KYNA-1 reduced tau hyperphosphorylation and neuroinflammation. KYNA-1 may serve as a promising treatment for tauopathies.

What is already known?

Studies showed tryptophan-kynurenine pathway changes in neurodegenerative disorders including tauopathies

Kynurenines exert immunomodulatory and neuroactive properties and have influence on the central nervous system

What does this study add?

Chronic administration of synthetic analog of kynurenic acid (KYNA-1) reduces tau phosphorylation and astrogliosis in a transgenic rat model for tauopathies

The analog reversed LPS-induced inflammatory changes in glial cell cultures

What is the clinical significance?

Administration of KYNA-1 analog shifted the tryptophan metabolism in the neuroprotectant direction

Neuroprotective analogs KYNA-1 can serve as a new and effective potential therapeutic approach for tauopathies
MALE-MALE SOCIAL BONDING, COALITIONARY SUPPORT AND REPRODUCTIVE SUCCESS IN WILD GUINEA BABOONS
Authors: Dal Pesco Federica , Trede Franziska , Zinner Dietmar , Fischer Julia
Published: April 2022

Male-male bonds may confer substantial fitness benefits. The adaptive value of these relationships is often attributed to coalitionary support, which aids in rank ascension and female defence, ultimately resulting in greater reproductive success. We investigated the link between male-male sociality and both coalitionary support and reproductive success in wild Guinea baboons. This species lives in a tolerant multi-level society with reproductive units comprising a male and 1-6 females at the core. Males are philopatric, form differentiated, stable, and equitable affiliative relationships (‘strong bonds’) with other males, and lack a clear rank hierarchy. Here, we analysed behavioural and paternity data for 30 males and 50 infants collected over four years in the Niokolo-Koba National Park, Senegal. Strongly bonded males supported each other more frequently during conflicts, but strong bonds did not promote reproductive success. Instead, males that spent less time socializing with other males were associated with a higher number of females and sired more offspring. Notably, reproductively active males still maintained bonds with other males, but adjusted their social investment in relation to life-history stage. Long-term data will be needed to test if the adaptive value of male bonding lies in longer male tenure and/or in promoting group cohesion.
Sex-dependent transcriptional control of cardiac electrophysiology by histone acetylation modifiers based on the GTEx database
Authors: Pressler Michael P. , Horvath Anelia , Entcheva Emilia
Published: April 2022

Development of safer drugs based on epigenetic modifiers, e.g. histone deacetylase inhibitors (HDACi), requires better understanding of their effects on cardiac electrophysiology. Using RNAseq data from the genotype-tissue-expression database (GTEx), we created models that link the abundance of chromatin modifiers, such as histone acetylation enzymes (HDAC/SIRT/HATs), and the gene expression of ion channels (IC) via select cardiac transcription factors (TFs) in male and female adult human hearts (left ventricle, LV). Gene expression data (transcripts per million, TPM) from GTEx donors (21 to 70 y.o.) were filtered, normalized and transformed to Euclidian space to allow quantitative comparisons in 84 female and 158 male LVs. Sex-specific partial least-square (PLS) regression models, linking gene expression data for HDAC/SIRT/HATs to TFs and to ICs gene expression, revealed tight co-regulation of cardiac ion channels by HDAC/SIRT/HATs, with stronger clustering in the male LV. Co-regulation of genes encoding excitatory and inhibitory processes in cardiac tissue by the histone modifiers may help their predominantly net-neutral effects on cardiac electrophysiology.ATP1A1, encoding for the Na/K pump, represented an outlier - with orthogonal regulation by the histone modifiers to most of the ICs. The HDAC/SIRT/HAT effects were mediated by strong (+) TF regulators of ICs, e.g.MEF2AandTBX5, in both sexes. Furthermore, for male hearts, PLS models revealed a stronger (+)/(-) mediatory role on ICs forNKX25andTGF1B/KLF4, respectively, whileRUNX1exhibited larger (-) TF effects on ICs in females. Male-trained PLS models of HDAC/SIRT/HAT effects on ICs underestimated the effects on some ICs in females. Insights from the GTEx dataset about the co-expression and transcriptional co-regulation of histone-modifying enzymes, transcription factors and key cardiac ion channels in a sex-specific manner can help inform safer drug design.
Engineering and characterization of a long half-life relaxin receptor RXFP1 agonist
Authors: Erlandson Sarah C. , Wang Jialu , Jiang Haoran , Rockman Howard A. , Kruse Andrew C.
Published: April 2022

Relaxin-2 is a peptide hormone with important roles in human cardiovascular and reproductive biology. Its ability to activate cellular responses such as vasodilation, angiogenesis, and anti-inflammatory and anti-fibrotic effects have led to significant interest in using relaxin-2 as a therapeutic for heart failure and several fibrotic conditions. However, recombinant relaxin-2 has a very short serum half-life, limiting its clinical applications. Here we present protein engineering efforts targeting the relaxin-2 hormone in order to increase its serum half-life, while maintaining its ability to activate the G protein-coupled receptor RXFP1. To achieve this, we optimized a fusion between relaxin-2 and an antibody Fc fragment, generating a version of the hormone with a circulating half-life of up to five days in mice while retaining potent agonist activity at the RXFP1 receptor both in vitro and in vivo.
Prolonged dexamethasone exposure enhances zebrafish lateral-line regeneration but disrupts mitochondrial homeostasis and hair cell function
Authors: Saettele Allison L. , Wong Hiu-tung C , Kindt Katie S , Warchol Mark E , Sheets Lavinia
Published: April 2022

The synthetic glucocorticoid dexamethasone is commonly used to treat inner ear disorders. Previous work in larval zebrafish has shown that dexamethasone treatment enhances hair cell regeneration, yet dexamethasone has also been shown to inhibit regeneration of peripheral nerves after lesion. We therefore used the zebrafish model to determine the impact of dexamethasone treatment on lateral-line hair cells and primary afferents. To explore dexamethasone in the context of regeneration, we used copper sulfate (CuSO4) to induce hair cell loss and retraction of nerve terminals, and then allowed animals to recover in dexamethasone for 48 hours. Consistent with previously work, we observed significantly more regenerated hair cells in dexamethasone-treated larvae. Importantly, we found that the afferent processes beneath neuromasts also regenerated in the presence of dexamethasone and formed an appropriate number of synapses, indicating that innervation of hair cells was not inhibited by dexamethasone. In addition to regeneration, we also explored the effects of prolonged dexamethasone exposure on lateral-line homeostasis and function. Following dexamethasone treatment, we observed hyperpolarized mitochondrial membrane potentials (ΔΨm) in neuromast hair cells and supporting cells. Hair cells exposed to dexamethasone were also more vulnerable to neomycin-induced cell death. In response to a fluid-jet delivered saturating stimulus, calcium influx through hair cell mechanotransduction channels was significantly reduced, yet presynaptic calcium influx was unchanged. Cumulatively, these observations indicate that dexamethasone enhances hair cell regeneration in lateral-line neuromasts, yet also disrupts mitochondrial homeostasis, making hair cells more vulnerable to ototoxic insults and possibly impacting hair cell function.
First detection of Leptospira santarosai in the reproductive track of a boar: a potential threat to swine production and public health
Authors: Diaz Eduardo A. , Luna Ligia , Burgos-Mayorga Ana , Donoso Gustavo , Guzman Diego A. , Baquero María Ines , Pearson Talima , Barragan Veronica
Published: April 2022

Background

Leptospirosis causes significant economic losses and is an occupational risk in the swine industry, especially in developing tropical regions where social and geoclimatic conditions are favorable for the transmission of this disease. Although vaccination can reduce infection risk, efficacy is diminished if local genetic and antigenic variants of the pathogen are not accounted for in the vaccine. Identifying and characterizing strains that circulate in different populations is therefore critical for public health mitigation practices.

Methodology/Principal findings

Our study was conducted on a rural breeding farm in Ecuador, where we identified, for the first time, Leptospira santarosai in the kidneys, testicles, and ejaculate of a vaccinated boar. L. santarosai was detected with a PCR assay that targets lipL32, and identified by target MLST gene sequencing using an Oxford Nanopore MinION sequencer.

Conclusions/Significance

As L. santarosai is pathogenic in other livestock species and humans, our finding highlights the need to evaluate the prevalence and epidemiological significance of this pathogen in pigs. In addition, further studies are needed to identify and characterize local serovars that may impact diagnosis and vaccination programs to better control leptospirosis in pigs and spillover into the human population.

Author summary

Leptospirosis poses a significant threat to human and animal health. In tropical countries, leptospirosis is very common, and responsible of economic losses in the livestock industry. In peridomestic and rural farms, the spillover of leptospira to humans is particularly likely as humans live and work in close proximity to animals. Although animal vaccination can reduce risk of infection, efficacy is diminished when local variants are not included in the vaccine. This report describes, for the first time, the presence of Leptospira santarosai in the reproductive tract of a vaccinated domestic boar from a rural farm in Ecuador. We detected the pathogen in its semen and urine, and despite no tissue damage, was observed in the kidneys, testes or epididymis. The farm veterinarian reported reproductive problems in sows inseminated with the semen from this boar. Our results highlight the importance of recognizing locally circulating serovars and species so that they can be included in vaccines to prevent infection and disease. Effective control of leptospirosis in livestock not only reduces economic losses for breeders, but also reduces the risk of infection and disease in humans.
Speciation without gene-flow in hybridising deer
Authors: Kessler Camille , Wootton Eric , Shafer Aaron B.A.
Published: April 2022

Under the ecological speciation model, divergent selection acts on ecological differences between populations, gradually creating barriers to gene flow and ultimately leading to reproductive isolation. Hybridisation is part of this continuum and can both promote and inhibit the speciation process. Here, we used white-tailed (Odocoileus virginianus) and mule deer (O. hemionus) to investigate patterns of speciation in hybridising sister species. We quantified genome-wide historical introgression and performed genome scans to look for signatures of four different selection scenarios. Despite ample modern evidence of hybridisation, we found negligible patterns of ancestral introgression and no signatures of divergence with gene flow, rather localised patterns of allopatric and balancing selection were detected across the genome. Genes under balancing selection were related to immunity, MHC and sensory perception of smell, the latter of which is consistent with deer biology. The deficiency of historical gene-flow suggests that white-tailed and mule deer were spatially separated during the glaciation cycles of the Pleistocene and genome wide differentiation accrued via genetic drift. Dobzhansky-Muller incompatibilities and selection against hybrids are hypothesised to be acting, and diversity correlations to recombination rates suggests these sister species are far along the speciation continuum.
Crystal structure of the kringle domain of human receptor tyrosine kinase-like orphan receptor 1 (hROR1)
Authors: Guarino Salvatore R. , Di Bello Antonella , Palamini Martina , Capillo Maria Chiara , Forneris Federico
Published: April 2022

Receptor tyrosine kinase-like orphan receptors (RORs) are monotopic membrane proteins belonging to the receptor tyrosine kinase (RTK) family. RTKs play a role in the control of most basic cellular processes, including cell proliferation, differentiation, migration and metabolism. New emerging roles for RORs in cancer progression have recently been proposed: RORs have been shown to be overexpressed in various malignancies but not in normal tissues, and moreover an abnormal expression level of RORs on the cellular surface is correlated with high levels of cytotoxicity in primary cancer cells. Monoclonal antibodies against the extracellular part of RTKs might be of importance to prevent tumor cell growth: targeting extracellular kringle domain molecules induces the internalization of RORs and decreases cell toxicity. Here, the recombinant production and crystallization of the isolated KRD of ROR1 and its high-resolution X-ray crystal structure in a P3121 crystal form at 1.4 Å resolution are reported. The crystal structure is compared with previously solved three-dimensional structures of kringle domains of human ROR1 and ROR2, their complexes with antibody fragments and structures of other kringle domains from homologous proteins.
Nitrato(5,10,15,20-tetraphenylporphinato)manganese(III)–benzene–n-hexane (2/1/1)
Authors: Cao Hongli , Wang Junwen , Li Jianfeng
Published: April 2022

The crystal structure of solvated [Mn(TPP)(NO3)] (TPP = 5,10,15,20-tetraphenylporphyrinato, C44H28N4), [Mn(C44H28N4O3)(NO3)]·0.5C6H14·0.5C6H6, has been determined in the space group Pccn. The MnIII atom has a distorted square-pyramidal environment, being coordinated by four pyrrole N atoms of the porphyrin ligand in the basal plane and an O atom of the nitrato ligand in the apical site. The MnIII atom is displaced out of the porphyrin plane by 0.22 (4) Å with the average Mn—Np distance being 2.011 (6) Å (where Np is a porphyrin N atom). The Mn—O bond length is 2.1246 (18) Å. Two kinds of intermolecular C—H...O hydrogen bonds exist in the crystal structure, with the apical nitrato ligands interacting with solvent molecules and adjacent molecules, respectively.
Business process conceptualizations and the flexibility-support tradeoff
Authors: Antunes Pedro , Tate Mary
Published: April 2022

Purpose

Many organizations struggle to achieve their desired levels of business process flexibility and support. However, these two capabilities conflict with each other and different tradeoffs have to be made. In this paper, the authors analyze different process conceptualizations and discuss their implications. The authors argue that the conceptualizations people adopt to think (conceptualize) about business processes affect the way they model them, which in turn result in different flexibility-support tradeoffs.

Design/methodology/approach

A set of properties is proposed to compare process conceptualizations: dominant concept, contract, and existential and representational properties. Using these properties, several process conceptualizations are analyzed and integrated in a comparison chart, which highlights different flexibility-support tradeoffs. The storytelling method is adopted to support the analytic process.

Findings

The authors show how different process conceptualizations result in different flexibility-support tradeoffs. The authors suggest that we need to intervene on a set of properties of process conceptualizations to achieve different flexibility-support tradeoffs.

Research limitations/implications

This research contributes to understanding the relationships between process conceptualizations, process modeling, and the flexibility-support tradeoff. A comparison chart helps organizations analyze their desired levels of flexibility and support using a set of properties.

Originality/value

The extent of covered viewpoints makes this study unique in the process management field. Such effort provides a contribution towards a more multidisciplinary discussion of process models, which integrates different process conceptualizations.
Nonlinear impact of market segmentation on the upgrading of Chinese manufacturing enterprises
Authors: Yuan Sai , Pan Xiongfeng
Published: April 2022

Purpose

Prior studies have confirmed market segmentation as an important shackle to China's macroeconomy upgrade, but the systematic analysis of microenterprise upgrade remains inadequate. This paper aims to investigate the nonlinear impact of market segmentation on microenterprise upgrade.

Design/methodology/approach

The price method was applied to calculate China's provincial market segmentation, including commodity, capital, labor and energy. The generalized method of moments was employed to examine the nonlinear impact of market segmentation on the upgrading of manufacturing enterprises based on microenterprise data from 2003 to 2019.

Findings

First, China’s heterogeneous market segmentations have been significantly reduced. Macroeconomics and policies are critical factors in market integration. Second, there is an inverted U-shaped relationship between China’s total market segmentation and the upgrading of manufacturing enterprises. Third, the relationship between the commodity market segmentation, labor market segmentation, energy market segmentation and manufacturing enterprises' upgrade is shown as an inverted U-shaped. Nevertheless, the relationship between the capital market segmentation and upgrading of manufacturing enterprises exhibits a U-shape.

Originality/value

The impact of market segmentation on the upgrading of manufacturing enterprises in China performs nonlinearly. An inverted U-shaped relationship exists between market segmentation in commodity, labor and energy and the upgrading of manufacturing enterprises, while a U-shaped relationship prevails between capital market segmentation and the upgrading of manufacturing enterprises.