bluuebunny/crossref_metadata_2025 huggingface dataset:
Draft genome of the aardaker (Lathyrus tuberosus L.), a tuberous legume
Authors: Flood Pádraic J. , Nowrousian Minou , Huettel Bruno , Woehle Christian , Becker Kerstin , Wollenweber Tassilo Erik , Begerow Dominik , Grefen Christopher
Published: September 2022

Objectives

Lathyrus tuberosus is a nitrogen-fixing member of the Fabaceae which forms protein-rich tubers. To aid future domestication programs for this legume plant and facilitate evolutionary studies of tuber formation, we have generated a draft genome assembly based on Pacific Biosciences sequence reads.

Data description

Genomic DNA from L. tuberosus was sequenced with PacBio’s HiFi sequencing chemistry generating 12.8 million sequence reads with an average read length of 14 kb (approximately 180 Gb of sequence data). The reads were assembled to give a draft genome of 6.8 Gb in 1353 contigs with an N50 contig length of 11.1 Mb. The GC content of the genome assembly was 38.3%. BUSCO analysis of the genome assembly indicated a genome completeness of at least 96%. The genome sequence will be a valuable resource, for example, in assessing genomic consequences of domestication efforts and developing marker sets for breeding programs. The L. tuberosus genome will also aid in the analysis of the evolutionary history of plants within the nitrogen-fixing Fabaceae family and in understanding the molecular basis of tuber evolution.
Minimally invasive apical cannulation and cannula design for short-term mechanical circulatory support devices
Authors: Székely Marcell , Ruttkay Tamás , Suhai Ferenc Imre , Bóna Áron , Merkely Béla , Székely László
Published: September 2022

Background

Refractory cardiogenic shock is still a major clinical challenge with high mortality rates, although several devices can be used to conquer this event. These devices have different advantages and disadvantages originating from their insertion or cannulation method, therefore many complications can occur during their use. The aim of our study was to develop and create prototypes of a novel minimal invasively insertable, transapical cannula for surgical ventricular assist devices, which uniquely incorporates the inflow and outflow routes for the blood of the patient in itself, therefore it enables the use for only one cannula for patients in cardiogenic shock.

Methods

To define the available space for the planned cannula in the left ventricle and ascending aorta, we analyzed computed tomography scans of 24 heart failure patients, who were indicated to left ventricular assist device therapy. Parallel to these measurements, hydrodynamical calculations were performed to determine the sizes of the cannulas, which were necessary to provide effective cardiac output.

Results

After the designing steps, we produced prototypes of double-lumened, tube-in-tube apically insertable devices for three different patient groups, which included a separated venous and an arterial part using 3D modelling and printing technology. All the created cannulas are able to provide 5 l/min circulatory support.

Conclusion

As a result of our research we created a sizing method based on the specific analysis of computed tomography pictures of end stage heart failure patients and a cannula concept, which can provide effective antegrade flow for patients in cardiogenic shock. We believe the improved version of our tool could have a significant therapeutic role in the future after further development based on animal and in vivo tests.
Gastric lymphangioma: a case report and review of literature
Authors: Bai Kunhao , Dai Yujun , Jiang Chen , Lin Shiyong , Wang Guobao
Published: September 2022

Background

Gastric lymphangioma is one of the highly rare benign tumors characterized by multilocular or unilocular lymphatic spaces. Herein, we report a case of lymphangioma in the gastric antrum.

Case presentation

A 77-year-old male patient who had been experiencing epigastric discomfort for a year was presented to our hospital. A gastric subepithelial lesion was diagnosed by upper endoscopy and was entirely excised via diatal subtotal gastrectomy. Endoscopic ultrasonography revealed an echoless homogenous echo pattern in the third wall layer. A lymphangioma was diagnosed by pathologic investigation of the resected specimen. The PubMed, Embase and Web of Science databases were reviewed for literature in English while using the keywords of “gastric lymphangioma” or “lymphangioma of stomach” or “gastric lymphatic cyst” or “lymphatic cyst of stomach” and the results were discussed.

Conclusion

Gastric lymphangioma is a rarely occurring submucosal tumor that should be considered when diagnosing subepithelial lesions in the stomach.
Are we forgetting to carry out serum protein electrophoresis as part of diagnosis workup?
Authors: Marcondes Mariana Barros , Susuki Cíntia Mitsue Pereira , Hokama Newton Key , Hokama Paula de Oliveira Montandon , Oliver Felipe Aguera , Chaib Paulo Sergio , Qi Xingshun , Romeiro Fernando Gomes
Published: September 2022

Background

Common variable immunodeficiency (CVID) is a rare disease that affects children and adults and is often difficult to diagnose. Despite being one of the most frequent causes of immunodeficiency, involving gastrointestinal (GI), respiratory, and hematological systems, the disease onset can have heterogeneous and intermittent symptoms, frequently leading to diagnostic delay. GI symptoms are common and can include diarrhea, but the asymptomatic periods lead to overlooking the recurrent pattern. The same can occur with respiratory infections, thus delaying CVID suspicion. The starting point for CVID diagnosis is the decreased gamma globulin levels in serum protein electrophoresis (SPE), also observed through direct immunoglobulin’s dosage.

Case presentation

The patient is a 38 years-old man who had intermittent diarrhea and recurrent airway infections for 19 years, but the CVID diagnosis was achieved only after SPE was carried out. At that time, he was already malnourished, and developed other complications related to CVID in a short period.

Conclusions

SPE is readily available and inexpensive, but is not part of the laboratory approach in diarrhea. According to the case presented herein, it can be useful for patients with recurrent infections or other clues of the disease.
A predictive model for first-trimester pregnancy inception after IVF-ET based on multimodal ultrasound evaluation of endometrial receptivity
Authors: Liao Jianmei , Yang Shuping , Chen Keyue , Chen Huijun , Jiang Fan , Zhang Weina , Wu Xuebin
Published: September 2022

Background

In-vitro fertilization-embryo transfer (IVF-ET) is a commonly used assisted reproductive technology. Its success depends on many factors, including endometrial receptivity. Endometrial receptivity can be evaluated by ultrasound, endometrial biopsy, and magnetic resonance imaging. Compared with the latter two methods, ultrasound has the advantages of wide availability, non-invasiveness, and low cost. Three-dimensional (3D) ultrasound imaging examines endometrial thickness, morphology, and blood vessels, which are associated with the success of embryo implantation. However, there are no reports of endometrial receptivity assessment by 3D ultrasound. Therefore, we aimed to evaluate endometrial receptivity using 3D ultrasound and construct a predictive model for first-trimester pregnancy inception following IVF-ET.

Methods

We performed a prospective observational study on infertile women who underwent IVF-ET between December 2019 and February 2021. These women had 3D ultrasound evaluations, measuring endometrial thickness, volume, pattern, morphology, peristalsis, uterine artery blood flow index, sub-endometrial blood flow index, and distribution pattern. We recorded the occurrence of first-trimester pregnancies in these women. Using Akaike information criterion (AIC) and backward stepwise regression, a first-trimester pregnancy prediction model was constructed based on the minimum AIC value and validated internally and externally.

Results

111 women were enrolled, with 103 included in the analysis. Univariate and multiple logistic regression analyses showed that endometrial thickness and vascularization flow index (VFI) were independent factors associated with the occurrence of a pregnancy. The final prediction model corresponding to the minimum AIC value (65.166) was Y = − 6.131–0.182endometrial thickness + 0.542endometrial volume + 4.374VFI + 0.132age. In the test set, modeling cohort, and external validation cohort, the model showed satisfactory differentiation, with C index of 0.841 (95%CI 0.699–0.817), 0.727 (95%CI 0.619–0.815), and 0.745 (95%CI 0.671–0.840), respectively. The Hosmer–Lemeshow goodness of fit tests reported P = 0.865, 0.139, and 0.070, respectively, indicating a high agreement with the actual IVF-ET outcome. This model reached the highest diagnostic efficiency (sensitivity 88.9%, specificity 75%, Youden index 0.639) at a diagnostic cut-off value of ≥ 0.360.

Conclusions

The predictive model based on endometrial receptivity evaluations by 3D ultrasound had high diagnostic efficiency and could be a simple and effective tool to predict first-trimester pregnancy inception after IVF-ET.
Rolling stones: an instructive case of neonatal cholestasis
Authors: Killelea Paige , Sakhuja Shruti , Hernandez Jose , Hicks M. John , Harpavat Sanjiv
Published: September 2022

Background

Jaundice within the first 1–2 weeks of a neonate’s life will generally self-resolve; however, if it lasts longer than this time frame it warrants further work up. Direct or conjugated hyperbilirubinemia can suggest neonatal cholestasis, which in turn reflects marked reduction in bile secretion and flow. The differential diagnosis for neonatal cholestasis is broad. Neonatal choledocholithiasis is a rare cause of neonatal cholestasis, but should be considered on the differential diagnosis for patients presenting with elevated conjugated bilirubin.

Case presentation

We describe an infant who presented with neonatal cholestasis. He subsequently underwent work up for biliary atresia, as this is one of the more time-sensitive diagnoses that must be made in neonates with conjugated hyperbilirubinemia. He was ultimately found to have choledocholithiasis on magnetic resonance cholangiopancreatography. He was managed conservatively with optimizing nutrition and ursodeoxycholic acid therapy.

Conclusions

We found that conservative management, specifically optimizing nutrition and treating with ursodeoxycholic acid, can be a sufficient approach to facilitating resolution of the choledocholithiasis and conjugated hyperbilirubinemia.
Evaluation of a civic engagement approach to catalyze built environment change and promote healthy eating and physical activity among rural residents: a cluster (community) randomized controlled trial
Authors: Seguin-Fowler Rebecca A. , Hanson Karla L. , Villarreal Deyaun , Rethorst Chad D. , Ayine Priscilla , Folta Sara C. , Maddock Jay E. , Patterson Megan S. , Marshall Grace A. , Volpe Leah C. , Eldridge Galen D. , Kershaw Meghan , Luong Vi , Wang Hua , Kenkel Don
Published: September 2022

Background

Prior studies demonstrate associations between risk factors for obesity and related chronic diseases (e.g., cardiovascular disease) and features of the built environment. This is particularly true for rural populations, who have higher rates of obesity, cancer, and other chronic diseases than urban residents. There is also evidence linking health behaviors and outcomes to social factors such as social support, opposition, and norms. Thus, overlapping social networks that have a high degree of social capital and community cohesion, such as those found in rural communities, may be effective targets for introducing and maintaining healthy behaviors.

Methods

This study will evaluate the effectiveness of the Change Club (CC) intervention, a civic engagement intervention for built environment change to improve health behaviors and outcomes for residents of rural communities. The CC intervention provides small groups of community residents (approximately 10–14 people) with nutrition and physical activity lessons and stepwise built environment change planning workshops delivered by trained extension educators via in-person, virtual, or hybrid methods. We will conduct process, multilevel outcome, and cost evaluations of implementation of the CC intervention in a cluster randomized controlled trial in 10 communities across two states using a two-arm parallel design. Change in the primary outcome, American Heart Association’s Life’s Simple 7 composite cardiovascular health score, will be evaluated among CC members, their friends and family members, and other community residents and compared to comparable samples in control communities. We will also evaluate changes at the social/collective level (e.g., social cohesion, social trust) and examine costs as well as barriers and facilitators to implementation.

Discussion

Our central hypothesis is the CC intervention will improve health behaviors and outcomes among engaged citizens and their family and friends within 24 months. Furthermore, we hypothesize that positive changes will catalyze critical steps in the pathway to improving longer-term health among community residents through improved healthy eating and physical activity opportunities. This study also represents a unique opportunity to evaluate process and cost-related data, which will provide key insights into the viability of this approach for widespread dissemination.

Trial registration

ClinicalTrials.gov:NCT05002660, Registered 12 August 2021.
Somewhere to go: assessing the impact of public restroom interventions on reports of open defecation in San Francisco, California from 2014 to 2020
Authors: Amato Heather K. , Martin Douglas , Hoover Christopher M. , Graham Jay P.
Published: September 2022

Background

Open defecation due to a lack of access to sanitation facilities remains a public health issue in the United States. People experiencing homelessness face barriers to accessing sanitation facilities, and are often forced to practice open defecation on streets and sidewalks. Exposed feces may contain harmful pathogens posing a significant threat to public health, especially among unhoused persons living near open defecation sites. The City of San Francisco’s Department of Public Works implemented the Pit Stop Program to provide the unhoused and the general public with improved access to sanitation with the goal of reducing fecal contamination on streets and sidewalks. The objective of this study was to assess the impact of these public restroom interventions on reports of exposed feces in San Francisco, California.

Methods

We evaluated the impact of various public restroom interventions implemented from January 1, 2014 to January 1, 2020 on reports of exposed feces, captured through a 311 municipal service. Publicly available 311 reports of exposed feces were spatially and temporally matched to 31 Pit Stop restroom interventions at 27 locations across 10 San Francisco neighborhoods. We conducted an interrupted time-series analysis to compare pre- versus post-intervention rates of feces reports near the restrooms.

Results

Feces reports declined by 12.47 reports per week after the installation of 13 Pit Stop restrooms (p-value = 0.0002). In the same restrooms, the rate of reports per week declined from the six-month pre-intervention period to the post-intervention period (slope change = -0.024 [95% CI = -0.033, -0.014]). In a subset of restrooms, where new installations were made (Mission and Golden Gate Park), and in another subset of restrooms where restroom attendants were provided (Mission, Castro/Upper Market, and Financial District/South Beach), feces reports also declined.

Conclusions

Increased access to public toilets reduced feces reports in San Francisco, especially in neighborhoods with people experiencing homelessness. The addition of restroom attendants also appeared to have reduced feces reports in some neighborhoods with PEH. These interventions should be audited for implementation quality, observed utilization data, and user experience at the neighborhood level in order to tailor sanitation interventions to neighborhood-specific needs.
Study protocol for the description and evaluation of the “Habit Coach” - a longitudinal multicenter mHealth intervention for healthy habit formation in health care professionals
Authors: Vogelsang Anna , Hinrichs Clara , Fleig Lena , Pfeffer Ines
Published: September 2022

Background

The adoption of a healthy lifestyle plays a crucial role for the health and well-being of health care professionals. Previous e- and mHealth interventions relied on deliberative psychological processes (e.g., intention, planning) to target lifestyle changes, while revealing mixed efficacy. The additional potential of non-deliberative, automatic processes (i.e., habits) for behavior change has been understudied in interventions so far. The Habit Coach mHealth intervention combines deliberative and non-deliberative processes to support health care professionals in forming healthy physical activity, nutrition and mindfulness habits in daily life. The aim of this paper is to outline the study protocol including a detailed description of the mHealth intervention, evaluation plan, and study design. The purpose of this trial is to understand healthy habit formation in health care professionals over time.

Methods

A one-arm, multicenter mHealth intervention study will be conducted. Behavioral and psychosocial predictors will be collected via within-app questionnaires across a 100-day period at baseline, post, as well as at weekly assessments. To understand habit formation across time, linear mixed models will be used.

Discussion

This trial aims to unravel the role of motivational and volitional determinants for healthy habit formation across multiple health behaviors in health care professionals embedded in a mHealth intervention.

Trial registration

This trial is registered in the German Clinical Trials Register, DRKS-ID DRKS00027156. Date of registration 17 November 2021.
Bariatric surgery: to bleed or not to bleed? This is the question
Authors: Pavone Giovanna , Gerundo Alberto , Pacilli Mario , Fersini Alberto , Ambrosi Antonio , Tartaglia Nicola
Published: September 2022

Background

Bariatric surgery procedures are the most successful and durable treatment for morbid obesity. Hemorrhage represents a life-threatening complication, occurring in 1.3–1.7% of bariatric surgeries.

Materials and methods

We examined patients undergoing Bariatric Surgery from July 2017 to June 2020 (Group A) and those operated from July 2020 to June 2022 (Group B) in our Department. Starting from July 2020 we have implemented intraoperative measures to prevent postoperative bleeding, increasing mean arterial pressure (MAP) by 30% compared to preoperative and reducing the pneumoperitoneal pressure of CO2 to 8 mmHg in the last 15 min of the operation.

Results

The study gathered 200 patients divided into the two described groups. The mean age of Group A is 44 ± 8.49 and 43.73 ± 9.28. The mean preoperative BMI is 45.6 kg/m2 ± 6.71 for Group A and 48.9 ± 7.15 kg/m2 for Group B. Group A recorded a mean MAP of 83.06 ± 18.58 mmHg and group B a value of 111.88 ± 12.46 mmHg (p value < 0.05 and z-score is 4.15226 and the value of U is 13,900). We observed 9 cases of bleeding in group A, most of them being treated with medical therapy and transfusions; only 1 hemodynamically unstable patient underwent re-laparoscopy. We reported only 2 cases of bleeding in group B, one of which required blood transfusions.

Conclusion

From our study we can conclude that increasing mean arterial pressure (MAP) by 30% compared to preoperative and reducing the pneumoperitoneum pressure of CO2 to 8 mmHg in the last 15 min of the operation led to a decrease in bleeding cases in group B and, most importantly, all the bleedings were easily controllable with medical therapy and/or transfusions. These measures allowed us to reduce postoperative bleeding.
Preoperative factors analysis on root development after regenerative endodontic procedures: a retrospective study
Authors: Zeng Qian , Zhang Jianying , Guo Jiang , Liu Shuya , Yang Maobin , Lin Jiacheng
Published: September 2022

Background

Regenerative endodontic procedures (REPs) have achieved clinical success on the immature permanent teeth with pulp necrosis, and can promote root development. However, preoperative factors and their effects on root development of REPs have not been definitely concluded. The aim of this study was to investigate the preoperative factors that may influence the root development of REPs.

Methods

A total of 116 teeth in 110 patients treated with REPs in the Paediatric Dentistry Department and Endodontics Department from 2013 to 2017 were included in this study. Preoperative factors including aetiology, age, diagnosis and initial root morphology were collected retrospectively, and the associations between these factors and root development after REPs were analysed by Fisher's exact test and multivariate logistic regression model.

Results

The overall rate of root development after REPs was 89.7%. The dens evaginatus group showed a higher rate (98.8%) in root development than the trauma group (67.6%) (P < 0.01). There was no significant difference among the different age groups (7–13 years old) or among different diagnoses groups (P > 0.05). And it showed in the trauma group that the teeth with apical foramen sizes larger than 3 mm significantly promoted root development than those smaller than 3 mm (P < 0.01). Multivariate logistic regression indicated that aetiology was significantly correlated with root development of REPs (OR: 0.07, 95% CI 0.007, 0.627, P < 0.05).

Conclusions

The REPs promoted more root developments in the dens evaginatus group than the trauma group, indicating that aetiology may be correlated with the root development of REPs.
Protein O-GlcNAcylation and the regulation of energy homeostasis: lessons from knock-out mouse models
Authors: Issad Tarik , Al-Mukh Hasanain , Bouaboud Abdelouhab , Pagesy Patrick
Published: September 2022

O-GlcNAcylation corresponds to the addition of N-Acetylglucosamine (GlcNAc) on serine or threonine residues of cytosolic, nuclear and mitochondrial proteins. This reversible modification is catalysed by a unique couple of enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). OGT uses UDP-GlcNAc produced in the hexosamine biosynthesis pathway, to modify proteins. UDP-GlcNAc is at the cross-roads of several cellular metabolisms, including glucose, amino acids and fatty acids. Therefore, OGT is considered as a metabolic sensor that post-translationally modifies proteins according to nutrient availability. O-GlcNAcylation can modulate protein–protein interactions and regulate protein enzymatic activities, stability or subcellular localization. In addition, it can compete with phosphorylation on the same serine or threonine residues, or regulate positively or negatively the phosphorylation of adjacent residues. As such, O-GlcNAcylation is a major actor in the regulation of cell signaling and has been implicated in numerous physiological and pathological processes. A large body of evidence have indicated that increased O-GlcNAcylation participates in the deleterious effects of glucose (glucotoxicity) in metabolic diseases. However, recent studies using mice models with OGT or OGA knock-out in different tissues have shown that O-GlcNAcylation protects against various cellular stresses, and indicate that both increase and decrease in O-GlcNAcylation have deleterious effects on the regulation of energy homeostasis.
The association between small airway dysfunction and aging: a cross-sectional analysis from the ECOPD cohort
Authors: Dai Cuiqiong , Wu Fan , Wang Zihui , Peng Jieqi , Yang Huajing , Zheng Youlan , Lu Lifei , Zhao Ningning , Deng Zhishan , Xiao Shan , Wen Xiang , Xu Jianwu , Huang Peiyu , Zhou Kunning , Wu Xiaohui , Zhou Yumin , Ran Pixin
Published: September 2022

Background

Aging has been evidenced to bring about some structural and functional lung changes, especially in COPD. However, whether aging affects SAD, a possible precursor of COPD, has not been well characterized.

Objective

We aimed to comprehensively assess the relationship between aging and SAD from computed tomography, impulse oscillometry, and spirometry perspectives in Chinese.

Methods

We included 1859 participants from ECOPD, and used a linear-by-linear association test for evaluating the prevalence of SAD across various age subgroups, and multivariate regression models for determining the impact of age on the risk and severity of SAD. We then repeated the analyses in these subjects stratified by airflow limitation.

Results

The prevalence of SAD increases over aging regardless of definitional methods. After adjustment for other confounding factors, per 10-yrs increase in age was significantly associated with the risk of CT-defined SAD (OR 2.57, 95% CI 2.13 to 3.10) and the increase in the severity of air trapping (β 2.09, 95% CI − 0.06 to 4.25 for LAA-856), airway reactance (β − 0.02, 95% CI − 0.04 to − 0.01 for X5; β 0.30, 95% CI 0.13 to 0.47 for AX; β 1.75, 95% CI 0.85 to 2.66 for Fres), as well as the decrease in expiratory flow rates (β − 3.95, 95% CI − 6.19 to − 1.71 for MMEF%predicted; β − 5.42, 95% CI − 7.88 to − 2.95 for FEF50%predicted) for SAD. All these associations were generally maintained in SAD defined by IOS or spirometry. After stratification of airflow limitation, we further found that the effect of age on LAA-856 was the most significant among almost all subgroups.

Conclusions

Aging is significantly associated with the prevalence, increased risk, as well as worse severity of SAD. CT may be a more optimal measure to assess aging-related SAD. The molecular mechanisms for the role of aging in SAD need to be explored in the future.

Trialregistration Chinese Clinical Trial Registry ChiCTR1900024643. Registered on 19 July 2019
Age-related differences in gait symmetry obtained from kinematic synergies and muscle synergies of lower limbs during childhood
Authors: Xiong Qiliang , Wan Jinliang , Jiang Shaofeng , Liu Yuan
Published: September 2022

The age-related changes of gait symmetry in healthy children concerning individual joint and muscle activation data have previously been widely studied. Extending beyond individual joints or muscles, identifying age-related changes in the coordination of multiple joints or muscles (i.e., muscle synergies and kinematic synergies) could capture more closely the underlying mechanisms responsible for gait symmetry development. To evaluate the effect of age on the symmetry of the coordination of multiple joints or muscles during childhood, we measured gait symmetry by kinematic and EMG data in 39 healthy children from 2 years old to 14 years old, divided into three equal age groups: preschool children (G1; 2.0–5.9 years), children (G2; 6.0–9.9 years), pubertal children (G3; 10.0–13.9 years). Participants walked barefoot at a self-selected walking speed during three-dimensional gait analysis (3DGA). Kinematic synergies and muscle synergies were extracted with principal component analysis (PCA) and non-negative matrix factorization (NNMF), respectively. The synergies extracted from the left and right sides were compared with each other to obtain a symmetry value. Statistical analysis was performed to examine intergroup differences. The results showed that the effect of age was significant on the symmetry values extracted by kinematic synergies, while older children exhibited higher kinematic synergy symmetry values compared to the younger group. However, no significant age-related changes in symmetry values of muscle synergy were observed. It is suggested that kinematic synergy of lower joints can be asymmetric at the onset of independent walking and showed improving symmetry with increasing age, whereas the age-related effect on the symmetry of muscle synergies was not demonstrated. These data provide an age-related framework and normative dataset to distinguish age-related differences from pathology in children with neuromotor disorders.
Elevation of effective p53 expression sensitizes wild-type p53 breast cancer cells to CDK7 inhibitor THZ1
Authors: Wang Yueyuan , Zhang Zhihao , Mi Xuguang , Li Mingxi , Huang Dan , Song Tingting , Qi Xiaoyan , Yang Ming
Published: September 2022

Background

The cyclin-dependent kinase 7 (CDK7) inhibitor THZ1 represses multiple cancer cells. However, its tumor-repressive efficiency in wild-type p53 breast cancer cells remains controversial.

Methods

We conducted various assays, including CCK8, colony formation, flow cytometry, western blotting, and lactate dehydrogenase release detection, to clarify whether p53 elevation sensitizes breast cancer cells to THZ1.

Results

We found that upregulating functional p53 contributes to the increased sensitivity of breast cancer cells to THZ1. Increased THZ1 sensitivity requires active p53 and an intact p53 pathway, which was confirmed by introducing exogenous wild-type p53 and the subsequent elevation of THZ1-mediated tumor suppression in breast cancer cells carrying mutant p53. We confirmed that p53 accumulates in the nucleus and mitochondria during cell death. Furthermore, we identified extensive transcriptional disruption, rather than solely CDK7 inhibition, as the mechanism underlying the nutlin-3 and THZ1-induced death of breast cancer cells. Finally, we observed the combined nutlin-3 and THZ1 treatment amplified gasdermin E cleavage.

Conclusion

Enhanced sensitivity of breast cancer cells to THZ1 can be achieved by increasing effective p53 expression. Our approach may serve as a potential treatment for patients with breast cancer resistant to regular therapies.
circCRKL, a circRNA derived from CRKL, regulates BCR-ABL via sponging miR-877-5p to promote chronic myeloid leukemia cell proliferation
Authors: Wang Jianming , Liang Yang , Qin Yuefeng , Jiang Guoyun , Peng Yuhang , Feng Wenli
Published: September 2022

Background

The BCR-ABL fusion protein is the key factor that results in the occurrence of chronic myeloid leukemia (CML). Imatinib (IM) is a targeted inhibitor of BCR-ABL to achieve complete remission. However, remission failure occurs due to acquired resistance caused by secondary BCR-ABL mutations, underlining the need for novel BCR-ABL-targeting strategies. Circular RNAs (circRNAs) derived from tumor-related genes have been revealed as possible therapeutic targets for relevant cancers in recent investigations. In CML, the roles of this kind of circRNA are yet obscure.

Methods

Firstly, RT-qPCR was used for determining circCRKL expression level in cell lines and clinical samples, RNase R and Actinomycin D were employed to verify the stability of circCRKL. Then shRNAs were designed to specifically knockdown circCRKL. The function of circCRKL in vitro was investigated using CCK-8, colony formation assay, and flow cytometry, while a CML mouse model was constructed to explore the function in vivo. Finally, a dual-luciferase reporter assay, RNA pull-down, RNA immunoprecipitation, and rescue experiments were conducted to investigate the mechanism of circCRKL functioning.

Results

Here, we determined circCRKL, which derives from CML-relevant gene CRKL, is over-expressed in BCR-ABL+ cells. Then we noticed knocking down circCRKL using shRNA lentivirus dampens the proliferation of BCR-ABL+ cells both in vitro and in vivo, and augments susceptibility of resistant cells to IM. Intriguingly, we observed that circCRKL has a considerable impact on the expression level of BCR-ABL. Mechanistically, circCRKL could behave like a decoy for miR-877-5p to enhance the BCR-ABL level, allowing BCR-ABL+ cells to maintain viability.

Conclusions

Overall, the current study uncovers that circCRKL is specifically expressed and regulates BCR-ABL expression level via decoying miR-877-5p in BCR-ABL+ cells, highlighting that targeting circCRKL along with imatinib treatment could be utilized as a potential therapeutic strategy for CML patients.
Heme oxygenase 1 overexpression induces immune evasion of acute myeloid leukemia against natural killer cells by inhibiting CD48
Authors: Zhang Tianzhuo , Fang Qin , Liu Ping , Wang Ping , Feng Cheng , Wang Jishi
Published: September 2022

Background

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Given the high relapse rate, more effective treatments are needed to improve clinical outcomes. We previously demonstrated that heme oxygenase 1 (HO1) is overexpressed in AML, while the functional roles of HO1 remain unclear.

Methods

Bioinformatics analysis and flow cytometry were conducted to assess the association between HO1 levels and immune cells or immune checkpoint/ligand molecules in AML patients. Primary natural killer (NK) cells were purified and subsequently co-cultured in vitro with transduced AML cells to determine the effects of HO1 expression on NK cell functions. AML mice models were established to investigate the effects of HO1 expression on cytotoxic effects of NK cells in vivo. The molecular mechanism was studied by flow cytometry, quantitative real-time PCR (qRT-PCR), western blotting, and immunoprecipitation.

Results

Bioinformatics analysis indicated a correlation between HO1 expression and the AML immune microenvironment. The present study findings indicated that HO1 specifically downregulates the expression of CD48, a ligand of the NK cell-activating receptor 2B4, thus decreasing the cytotoxic effect of NK cells. HO1 overexpression promoted tumor growth and inhibited the cytotoxic effect of NK cells in the AML mice model. Mechanistic investigations found that HO1 directly interacted with Sirt1 and increased its expression and deacetylase activity. With the overexpression of HO1, increased Sirt1 in AML cells enabled histone H3K27 deacetylation to suppress CD48 transcription and expression. Administration of Sirt1 inhibitor restored the expression of CD48.

Conclusions

Collectively, HO1 promotes NK cell dysfunction in AML. Therefore, restoring NK cell function by inhibiting HO1 activity is a potential immunotherapeutic approach against AML.
In silico designing of a novel epitope-based candidate vaccine against Streptococcus pneumoniae with introduction of a new domain of PepO as adjuvant
Authors: Bahadori Zohreh , Shafaghi Mona , Madanchi Hamid , Ranjbar Mohammad Mehdi , Shabani Ali Akbar , Mousavi Seyed Fazlollah
Published: September 2022

Background

Streptococcus pneumoniae is the leading reason for invasive diseases including pneumonia and meningitis, and also secondary infections following viral respiratory diseases such as flu and COVID-19. Currently, serotype-dependent vaccines, which have several insufficiency and limitations, are the only way to prevent pneumococcal infections. Hence, it is plain to need an alternative effective strategy for prevention of this organism. Protein-based vaccine involving conserved pneumococcal protein antigens with different roles in virulence could provide an eligible alternative to existing vaccines.

Methods

In this study, PspC, PhtD and PsaA antigens from pneumococcus were taken to account to predict B-cell and helper T-cell epitopes, and epitope-rich regions were chosen to build the construct. To enhance the immunogenicity of the epitope-based vaccine, a truncated N-terminal fragment of pneumococcal endopeptidase O (PepO) was used as a potential TLR2/4 agonist which was identified by molecular docking studies. The ultimate construct was consisted of the chosen epitope-rich regions, along with the adjuvant role (truncated N-PepO) and suitable linkers.

Results

The epitope-based vaccine was assessed as regards physicochemical properties, allergenicity, antigenicity, and toxicity. The 3D structure of the engineered construct was modeled, refined, and validated. Molecular docking and simulation of molecular dynamics (MD) indicated the proper and stable interactions between the vaccine and TLR2/4 throughout the simulation periods.

Conclusions

For the first time this work presents a novel vaccine consisting of epitopes of PspC, PhtD, and PsaA antigens which is adjuvanted with a new truncated domain of PepO. The computational outcomes revealed that the suggested vaccine could be deemed an efficient therapeutic vaccine for S. pneumoniae; nevertheless, in vitro and in vivo examinations should be performed to prove the potency of the candidate vaccine.
Effects of a 4400 km ultra-cycling non-competitive race and related training on body composition and circulating progenitors differentiation
Authors: Valenti Maria Teresa , Braggio Michele , Minoia Arianna , Dorelli Gianluigi , Bertacco Jessica , Bertoldo Francesco , Cominacini Mattia , De Simone Tonia , Romanelli Maria Grazia , Bhandary Lekhana , Mottes Monica , Dalle Carbonare Luca
Published: September 2022

Background

NorthCape4000 (NC4000) is the most participated ultra-endurance cycling race. Eight healthy male Caucasian amateur cyclists were evaluated: (a) before starting the preparation period; (b) in the week preceding NC4000 (after the training period); (c) after NC4000 race, with the aim to identify the effects of ultra-cycling on body composition, aerobic capacity and biochemical parameters as well as on the differentiation of progenitor cells.

Methods

Bioelectrical impedance analysis (BIA) and dual energy x-ray absorptiometry (DEXA) assessed body composition; cardiopulmonary exercise test (CPET) evaluated aerobic capacity. Differentiation of circulating progenitor cells was evaluated by analyzing the modulation in the expression of relevant transcription factors. In addition, in vitro experiments were performed to investigate the effects of sera of NC4000 participants on adipogenesis and myogenesis. The effects of NC4000 sera on Sestrins and Sirtuin modulation and the promotion of brown adipogenesis in progenitor cells was investigated as well. Two-tailed Student’s paired-test was used to perform statistical analyses.

Results

We observed fat mass decrease after training as well as after NC4000 performance; we also recorded that vitamin D and lipid profiles were affected by ultra-cycling. In addition, our findings demonstrated that post-NC4000 participant’s pooled sera exerted a positive effect in stimulating myogenesis and in inducing brown adipogenesis in progenitor cells.

Conclusions

The training program and Ultra-cycling lead to beneficial effects on body composition and biochemical lipid parameters, as well as changes in differentiation of progenitor cells, with significant increases in brown adipogenesis and in MYOD levels.
Perspectives in Melanoma: meeting report from the Melanoma Bridge (December 2nd – 4th, 2021, Italy)
Authors: Ascierto Paolo A. , Agarwala Sanjiv S. , Blank Christian , Caracò Corrado , Carvajal Richard D. , Ernstoff Marc S. , Ferrone Soldano , Fox Bernard A. , Gajewski Thomas F. , Garbe Claus , Grob Jean-Jacques , Hamid Omid , Krogsgaard Michelle , Lo Roger S. , Lund Amanda W. , Madonna Gabriele , Michielin Olivier , Neyns Bart , Osman Iman , Peters Solange , Poulikakos Poulikos I. , Quezada Sergio A. , Reinfeld Bradley , Zitvogel Laurence , Puzanov Igor , Thurin Magdalena
Published: September 2022

Advances in immune checkpoint and combination therapy have led to improvement in overall survival for patients with advanced melanoma. Improved understanding of the tumor, tumor microenvironment and tumor immune-evasion mechanisms has resulted in new approaches to targeting and harnessing the host immune response. Combination modalities with other immunotherapy agents, chemotherapy, radiotherapy, electrochemotherapy are also being explored to overcome resistance and to potentiate the immune response. In addition, novel approaches such as adoptive cell therapy, oncogenic viruses, vaccines and different strategies of drug administration including sequential, or combination treatment are being tested. Despite the progress in diagnosis of melanocytic lesions, correct classification of patients, selection of appropriate adjuvant and systemic theràapies, and prediction of response to therapy remain real challenges in melanoma. Improved understanding of the tumor microenvironment, tumor immunity and response to therapy has prompted extensive translational and clinical research in melanoma. There is a growing evidence that genomic and immune features of pre-treatment tumor biopsies may correlate with response in patients with melanoma and other cancers, but they have yet to be fully characterized and implemented clinically. Development of novel biomarker platforms may help to improve diagnostics and predictive accuracy for selection of patients for specific treatment. Overall, the future research efforts in melanoma therapeutics and translational research should focus on several aspects including: (a) developing robust biomarkers to predict efficacy of therapeutic modalities to guide clinical decision-making and optimize treatment regimens, (b) identifying mechanisms of therapeutic resistance to immune checkpoint inhibitors that are potentially actionable, (c) identifying biomarkers to predict therapy-induced adverse events, and (d) studying mechanism of actions of therapeutic agents and developing algorithms to optimize combination treatments. During the Melanoma Bridge meeting (December 2nd-4th, 2021, Naples, Italy) discussions focused on the currently approved systemic and local therapies for advanced melanoma and discussed novel biomarker strategies and advances in precision medicine as well as the impact of COVID-19 pandemic on management of melanoma patients.
RET fusions as primary oncogenic drivers and secondary acquired resistance to EGFR tyrosine kinase inhibitors in patients with non-small-cell lung cancer
Authors: Wang Chunyue , Zhang Zhenlong , Sun Yulan , Wang Song , Wu Mengmeng , Ou Qiuxiang , Xu Yang , Chen Zhiming , Shao Yang , Liu Hong , Hou Peifeng
Published: September 2022

Background

RET fusions are rare oncogenic drivers in non-small cell lung cancer (NSCLC). While activating RET rearrangements are found in NSCLC patients harboring epidermal growth factor receptor (EGFR) genetic alterations at resistance to EGFR inhibitors, the extent to which co-occurring genomic alterations exist and how they might affect prognosis or therapy response is poorly understood.

Methods

Targeted next-generation sequencing (NGS) was used to assess 380 baseline patients with primary RET fusions and 71 EGFR-mutated NSCLC patients who acquired RET fusions after developing resistance to EGFR-tyrosine kinase inhibitors (EGFR-TKIs).

Results

Primary RET fusions were more likely associated with females and younger age, with KIF5B being the predominant fusion partner. In baseline patients, both SMAD4 (5.3% vs. 0.0%, P = 0.044) and MYC copy-number gain variants (6.9% vs. 0.0%, P = 0.009) were more frequently co-mutated with KIF5B-RET than CCDC6-RET. By contrast, CDKN2A (11.3% vs. 2.4%, P = 0.003) mutations were significantly enriched in CCDC6-RET-rearranged baseline patients. A significant increase in the proportion of CCDC6-RET was observed in acquired RET-rearranged patients (47.3% vs. 22.5%, P < 0.001). The median progression-free survival (PFS) of patients harboring RB1 and TP53 double-mutations (5.5 vs. 10.0 months, P = 0.020) or ERBB2 amplification (5.6 vs. 10.0 months, P = 0.041) was significantly shorter than the wild-type counterparts. Moreover, we identified that RET fusions were more likely associated with acquired resistance (AR) to third-generation EGFR-TKIs than previous generations of EGFR-TKIs.

Conclusions

In conclusion, we depicted the mutational profiles of NSCLC patients who harbor RET fusions at baseline or after resistance to EGFR-TKIs. Furthermore, our results suggest that RET fusions mediate secondary resistance to third-generation EGFR-TKIs and might be associated with poor prognosis in patients with NSCLC.
The potential of mecciRNA in hepatic stellate cell to regulate progression of nonalcoholic hepatitis
Authors: Liu Boqiang , Tian Yuanshi , He Jing , Gu Qiuxia , Jin Binghan , Shen Hao , Li Weiqi , Shi Liang , Yu Hong , Shan Ge , Cai Xiujun
Published: September 2022

Background

Nonalcoholic steatohepatitis (NASH) occupies a substantial proportion of chronic liver disease worldwide, of which pathogenesis needs further research. Recent studies have demonstrated the significant roles of circular RNAs (circRNAs) in NASH, while the function of a novel type of circRNAs, namely mitochondria-encoded circRNAs (mecciRNAs), remains elusive. Therefore, we aimed to investigate their potential to regulate the progression of NASH in this study.

Methods

GSE134146 was used to screen for differentially expressed mecciRNAs in NASH, while GSE46300 was used to identify NASH-related genes. To establish the mecciRNA-miRNA-mRNA networks, circMINE and miRNet databases were used for predicting downstream targets. Then, consensus clustering analysis was used to determine immune subtypes of NASH. Finally, we successfully validated our findings in vitro (LPS-treated hepatic stellate cells [HSCs]) and in vivo (MCD-diet mice) NASH models.

Results

We confirmed that circRNomics balance is disrupted in HSCs of NASH, while two mecciRNAs (hsa_circ_0089761 and hsa_circ_0089763) could function as competing for endogenous RNAs (ceRNAs) to regulate fibrosis-related signals. Furthermore, we constructed two ceRNA networks based on mecciRNAs for the first time. Cell and animal NASH models validated our findings that c-MYC and SMAD2/3 were upregulated in HSCs, while THBS1 and p-STAT3 were upregulated in hepatocytes. Moreover, we identified 21 core genes by overlapping the differentially expressed genes (NASH vs. Normal) with mecciRNA-targeted genes. According to their expression profiles, NASH patients could be divided in 2 different clusters, in which proinflammatory signals (TNF and IL-17 pathways) are significantly activated in Cluster 1.

Conclusion

We successfully established two novel mecciRNA-miRNA-mRNA networks in HSCs and hepatocytes, which were further confirmed by in vitro and in vivo models. Meanwhile, the novel immunotyping model revealed the heterogeneity of NASH, thereby might guiding treatment options. Altogether, our study brought a distinct perspective on the relationship between mecciRNAs and NASH.