bluuebunny/crossref_metadata_2025 huggingface dataset:
Different color regulation mechanism in willow barks determined using integrated metabolomics and transcriptomics analyses
Authors: Zhou Jie , Guo Jiahui , Chen Qingsheng , Wang Baosong , He Xudong , Zhuge Qiang , Wang Pu
Published: November 2022

Background

The rich yellow-orange to vividly deep red bark of willow (Salix spp.) branches have high ornamental and economic value. However, the mechanism underlying the regulation of willow branch color remains unknown. Therefore, we performed metabolomics and transcriptomics analyses of purple, green, and red willow barks to elucidating the mechanisms regulating color development.

Results

Seven anthocyanins were isolated; pelargonidin, petunidin 3-O-rutinoside, and cyanin chloride were the most abundant in red bark, whereas pelargonin chloride was most abundant in purple bark. The green bark contained the highest level of malvidin; however, the malvidin level was not significantly higher than in the red bark. The purple bark contained the largest amount of canthaxanthin, a carotenoid pigment. The integrated pathways of flavonoid biosynthesis, carotenoid biosynthesis, and porphyrin and chlorophyll metabolism were constructed for the willow barks. Among the three barks, the expression of the structural genes ANS, ANR, and BZ1, which are involved in anthocyanin synthesis, was the highest in red bark, likely causing anthocyanin accumulation. The expression of CrtZ, which participates in the carotenoid pathway, was the highest in purple bark, likely leading to canthaxanthin accumulation. The high expression of DVR, POR, and CRD1 may be associated with green pigment synthesis in the chlorophyll biosynthesis pathway.

Conclusions

Purple bark color is co-regulated by anthocyanins and carotenoids, whereas red bark is characterized by anthocyanin accumulation and chlorophyll degradation. The green pigment is regulated by maintaining chlorophyll synthesis. BZ1 and CrtZ are candidate genes regulating anthocyanin and canthaxanthin accumulation in red and purple barks respectively. Collectively, our results may facilitate the genetic breeding and cultivation of colorful willows with improved color and luster.
Barriers to mutational testing in patients with gastrointestinal stromal tumors (GIST) – a survey of life raft group members
Authors: Montoya Denisse , Call Jerry W. , Eshak Jennily , Knox Pete , Luedke Maeven , Kaur Sahibjeet , Rothschild Sara , Garland Mary , Scherzer Norman J.
Published: November 2022

Background

Due to the low mutational testing rate in patients with Gastrointestinal Stromal Tumors (GIST), The Life Raft Group (LRG), a non-profit organization that provides support, advocacy and conducts research for patients with GIST, analyzed various factors that may have an impact on patients’ ability to receive mutational testing.

Methods

A survey about mutational testing for patients with GIST or their caregivers, was conducted in June 2020. The survey, sent to 1004 GIST patients and caregivers through email, was promoted through social media with instructions to contact the LRG to participate. The survey was designed by the LRG Patient Registry Department. Members of the LRG, regardless of Patient Registry status, were eligible to participate.

Results

A total of 295 patients/caregivers participated in this study (response rate: 29.4%). The percentage of patients who indicated they had received mutational testing was much higher in this survey (80%) than in the general GIST community (26.7%).

Several reasons were cited for having a test, including: “My doctor ordered/suggested that I have it done” (54%); “The Life Raft Group advised/suggested I have it done” (25%); “I asked my doctor to have it done” (22%); “I had it done as part of a clinical trial” (5%); “I am not sure” (3%) and “Other” (14%). Mutational testing resulted in a treatment change in 25% of cases. Patients were able to select more than one option when completing this question resulting in a percentage greater than 100.

Conclusions

The LRG membership is voluntary and proactive; patients who join are more likely to participate in surveys and mutational testing, as well as more likely to have a GIST specialist. Mutational testing can influence understanding of a patient’s GIST and the treatment best suited to each case. These are extremely important findings, as it helps ensure that patients are on the proper treatment, which should lead to better outcomes.
Serum CTRP9 and high-molecular weight adiponectin are associated with ischemic stroke
Authors: Zhang Yan-Qing , Zhang Yan-Wei , Dai Jian-Li , Li Chen , Wang Wen-Qing , Zhang Hai-Feng , Lau Wayne Bond , Wang Xiao-Ming , Liu Xiao-Gang , Li Rong
Published: November 2022

Background

C1q/TNF-related protein 9 (CTRP9) and adiponectin (APN) have beneficial metabolic regulatory and vasoprotective effects. This study explored alteration of CTRP9 and APN multimers during onset of ischemic stroke and development, to provide novel clinical and experimental basis for recognition and prevention of ischemic stroke.

Methods

There were 269 patients with ischemic stroke and 182 control subjects included in this study. Serum levels of CTRP9 and APN multimers in different disease stages were measured.

Results

Serum CTRP9, total APN (tAPN), and high-molecular weight (HMW) APN decreased gradually in stage I (acute stage, within 72 h of onset) of ischemic stroke and increased during stage III (11th day to one month) and stage IV (1 month after), compared to control. In the non-hyperlipidemia group, serum CTRP9, tAPN, and HMW were decreased in ischemic stroke patients compared to control (P < 0.05). Serum CTRP9 is closely related to serum tAPN and HMW (r = 0.992, 0.991). Serum CTRP9 are protective against ischemic stroke (OR = 0.400, 95% CI 0.197–0.810, P < 0.05).

Conclusions

Lower serum CTRP9, tAPN, LMW, and HMW are significantly associated with increased ischemic stroke risk in non-hyperlipidemia subjects. CTRP9, tAPN, and HMW isoforms may be valuable clinical indicators for patients with ischemic stroke.
Combination of orthokeratology lens with 0.01% atropine in slowing axial elongation in children with myopia: a randomized double-blinded clinical trial
Authors: Yu Shiao , Du Liping , Ji Na , Li Binbin , Pang Xuena , li Xiuhong , Ma Nana , Huang Congcong , Fu Aicun
Published: November 2022

Background:

To evaluate the additive effects of orthokeratology (OK) lenses and 0.01% atropine on slowing axial elongation in myopic children.

Methods:

A prospective, randomized, double-blinded, placebo-controlled trial was conducted over a 12-month period. Sixty children aged 8 to 12 years with spherical equivalent refraction from − 1.00 to -4.00 D who had been wearing OK lenses successfully for 2 months (as baseline) were randomly assigned in a 1:1 ratio to combination group (combination of OK lens and 0.01% atropine eye drops) and control group (combination of OK lens and placebo). The primary outcome was change in axial length, along with secondary outcomes including change in pupil diameter (PD) and accommodative amplitude (AMP) at 12 months (measured at 4-month intervals).

Results:

After 12 months, the overall axial elongation was 0.10 ± 0.14 mm and 0.20 ± 0.15 mm (p = 0.01) in the combination and control groups, respectively. The change in axial length in the two groups showed significant differences only in the first four months (median [Q1, Q3] (95% CI), -0.01 mm [-0.07, 0.05] (-0.06, 0.04) vs. 0.04 mm [0.00, 0.10] (0.02, 0.09); p = 0.04), but no difference thereafter. Multivariate linear regression analysis showed that the axial elongation was significantly slower in the combination group than in the control group (standard β = -0.10, p = 0.02). PD significantly increased by 0.45 mm [0.20, 0.68] at the 4th month visit (p < 0.001) and then remained stable in the combination group. The PD in the control group and AMP in the two groups remained stable from baseline to 12 months (all p > 0.05).

Conclusion:

The combination therapy was more effective than the OK lens alone in slowing axial elongation after 12 months of treatment, and mainly in the first 4 months.

Trial registration:

The First Affiliated Hospital of Zhengzhou University, ChiCTR2000033904. Registered 16/06/2020, http://www.chictr.org.cn/login.aspx?referurl=%2flistbycreater.aspx
Age-specific prevalence, subtypes and risk factors of metabolic diseases in Chinese adults and the different patterns from other racial/ethnic populations
Authors: Cao Qiuyu , Zheng Ruizhi , He Ruixin , Wang Tiange , Xu Min , Lu Jieli , Dai Meng , Zhang Di , Chen Yuhong , Zhao Zhiyun , Wang Shuangyuan , Lin Hong , Wang Weiqing , Ning Guang , Bi Yufang , Xu Yu , Li Mian
Published: November 2022

Background

Age has substantial influence on metabolic diseases patterns. Ethnic disparities of metabolic characteristics between Chinese and other populations also exist. Large-scale investigations of age-specific prevalence, subtypes and modifiable risk factors of metabolic disorders are essential to promote individualized strategies for the control and prevention of metabolic diseases in multi-ethnic populations. The study aims to address the age-specific prevalence, subtype characteristics and risk factor profiles of metabolic diseases among different races/ethnicities.

Methods

We analyzed data from the China Noncommunicable Disease Surveillance 2010 and the National Health and Nutrition Evaluation Survey (NHANES). We examined the prevalence and subtypes of hypertension, diabetes and hyperlipidemia across age groups in four ethnic populations. We also investigated the odds ratios (ORs) of metabolic diseases associated with 11 classical risk factors in the young and the elder Mainland Chinese.

Results

The sex and BMI standardized prevalence of hypertension in Chinese aged 18–40 years was 18.5% and was the highest among the four populations. The main pathophysiologic subtype of diabetes was characterized by insulin resistance, instead of β-cell dysfunction in Mainland Chinese, and this pattern was more evident in obese subjects. The major subtype of hyperlipidemia in Mainland Chinese was hypertriglyceridemia, while Non-Hispanic Whites and Blacks were more prone to high low-density lipoprotein cholesterol. For risk of hypertension, diabetes and hyperlipidemia, young Chinese adults were more prone to general and central obesity than older ones. The other factors showed similar effects on the young and the old.

Conclusions

The age-specific prevalence, subtypes and risk factors of metabolic diseases were substantially different in Chinese and other ethnic/racial populations.
Anonymous view on transgender soldiers: content analysis of online news headlines and comments in South Korea
Authors: Lee Jeehye , Ryu Dong-Hee , Lee Su-Jin
Published: November 2022

Background

The inclusion of transgender soldiers in the military service raises a fundamental question about the dichotomous categorization of human sexes based on anatomy and gender role within a specialized organization where the most masculine is commonly accepted. In March 2021, Hee-Soo Byun, the first transgender soldier in Korea to come out in public, and who was forcefully discharged after gender affirming surgery, died by suicide. With no anti-discrimination laws, the cultural background of the Korean society hardly creates an LGBT (Lesbian, Gay, Bisexual, and Transgender) — friendly environment and shows a negative attitude towards gender minorities.

Methods

A total of 193 online news article headlines were analyzed, and 1046 comments were categorized inductively based on the presented rationales.

Results: Before Byun’s public appearance, the frequent use of provocative expressions, which could evoke prejudice and discrimination, was found in published article headlines. Of the 724 comments that presented opinions on transgender soldiers, approximately 75% opposed Byun serving in the military in any form, including as a female soldier.

Conclusions

This study aimed to investigate online news articles and the comments regarding Byun’s case to estimate the acceptability of transgender people serving in the military. The results of this study are expected to serve as a basis for the formulation of policies that protect the human rights of transgender people.
Thromboprophylaxis with unilateral pneumatic device led to less edema and blood loss compared to enoxaparin after knee arthroplasty: randomized trial
Authors: Maradei-Pereira João Alberto Ramos , Sauma Marcel Lobato , Demange Marco Kawamura
Published: November 2022

Background

Pharmacological and mechanical thromboprophylaxis are frequently used together after total knee arthroplasty (TKA). Most studies in this context compare anticoagulants versus a combination of these drugs with an intermittent pneumatic compression device (IPCD). However, there is uncertainty about the need for the combination of both and whether a unilateral IPCD would alone affect other important clinical outcomes: edema and blood loss. We compared the effects of enoxaparin versus unilateral portable IPCD after TKA on edema and blood loss. We hypothesised that unilateral IPCD would cause the same level of edema and the same blood loss as enoxaparin.

Methods

In this open, randomized trial (1:1), adults with no history of coagulation disorders, anticoagulant use, venous thromboembolism, liver or malignant diseases underwent TKA. For 10 days, participants received the IPCD, used 24 h/day on the operated leg from the end of surgery, or 40 mg of enoxaparin, starting 12 h after surgery. All underwent the same rehabilitation and were encouraged to walk on the same day of surgery. We measured edema (thigh, leg and ankle circumference) before and on the third postoperative day. Blood loss (volume accumulated in the suction drain and drop of hemoglobin and hematocrit in 48 h) was a secondary outcome.

Results

We randomized 150 patients and lost 3 to follow-up with enoxaparin and 2 with IPCD. There was no case of symptomatic venous thromboembolism. Four patients needed transfusions (three receiving enoxaparin), one had infection and one hemarthrosis (both in the enoxaparin group). Leg circumference increased by approximately 2 cm for enoxaparin group and 1.5 cm in IPCD (p <  0.001). The increase in ankle circumference was about 1.5 cm in the enoxaparin group (p <  0.001), and almost zero in IPCD (p = 0.447). Enoxaparin group lost 566.1 ml (standard deviation, SD, 174.5) of blood in the first 48 h, versus 420.8 ml (SD 142.5) in the IPCD.

Conclusions

Exclusively mechanical prophylaxis after TKA with portable IPCD only on the operated leg reduces leg and ankle swelling and post-operative blood loss compared to exclusively pharmacological prophylaxis with enoxaparin. Portable devices that can prevent deep vein thrombosis and pulmonary embolism without increasing blood loss or other risks should be further investigated.

Trial registration

REBEC RBR-8k2vpx. Registration date: 06/04/2019.
Comparison of outcomes between flexible ureteroscopy and mini-percutaneous nephrolithotomy in the management of upper calyceal calculi larger than 2 cm
Authors: Xuan Hanqing , Du Zhebin , Xia Lei , Cao Yang , Chen Qi , Xue Wei
Published: November 2022

Objective

To compare the outcomes of FURSL and m-PNL in the management of upper calyceal calculi larger than 2 cm.

Methods

A total of 75 patients with upper calyceal calculi larger than 2 cm that were treated by FURSL (n = 37) or mini-PNL (n = 38) were retrospectively analysed. The mean age, sex, stone burden, operative time, complications, length of hospitalization, and stone-free rate (SFR) were compared between the groups. The success of the procedure was defined by the absence of residual stones or residual fragments smaller than 4 mm on computed tomography at 4 weeks postoperatively.

Results

The two groups had comparable preoperative parameters. The mean operative time was significantly longer in the mini-PNL group than in the FURSL group (87.8 vs. 69.8 min, p < 0.001). The length of hospitalization was greater in the mini-PNL group than in the FURSL group (2.5 vs. 1.3 days, p < 0.001). Although the perioperative complication rate was higher in the mini-PNL group (23.7%) than in the FURSL group (13.5%), this difference was not statistically significant (p = 0.258). The SFR for the mini-PNL group was 89.5%, and that of the FURSL group was 81.1%; the difference was not significantly different (p = 0.304).

Conclusions

Both FURSL and mini-PNL are effective and safe for the management of upper calyceal calculi larger than 2 cm. Of these two procedures, mini-PNL is less time consuming, FURSL is associated with faster recovery. FURSL can be considered a good alternative treatment in selected patients.
Reconstruction of vertical alveolar ridge deficiencies utilizing a high-density polytetrafluoroethylene membrane /clinical impact of flap dehiscence on treatment outcomes: case series/
Authors: Palkovics Daniel , Bolya-Orosz Fanni , Pinter Csaba , Molnar Balint , Windisch Peter
Published: November 2022

Objectives

The aim of this study was to evaluate the effects of membrane exposure during vertical ridge augmentation (VRA) utilizing guided bone regeneration with a dense polytetrafluoroethylene (d-PTFE) membrane and a tent-pole space maintaining approach by registering radiographic volumetric, linear and morphological changes.

Methods

In 8 cases alveolar ridge defects were accessed utilizing a split-thickness flap design. Following flap elevation VRA was performed with tent-pole space maintaining approach utilizing the combination of a non-reinforced d-PTFE membrane and a composite graft (1:1 ratio of autogenous bone chips and bovine derived xenografts). Three-dimensional radiographic evaluation of hard tissue changes was carried out with the sequence of cone-beam computed tomography (CBCT) image segmentation, spatial registration and 3D subtraction analysis.

Results

Class I or class II membrane exposure was observed in four cases. Average hard tissue gain was found to be 0.70 cm3 ± 0.31 cm3 and 0.82 cm3 ± 0.40 cm3 with and without membrane exposure resulting in a 17% difference. Vertical hard tissue gain averaged 4.06 mm ± 0.56 mm and 3.55 mm ± 0.43 mm in case of submerged and open healing, respectively. Difference in this regard was 14% between the two groups. Horizontal ridge width at 9-month follow-up was 5.89 mm ± 0.51 mm and 5.61 mm ± 1.21 mm with and without a membrane exposure respectively, resulting in a 5% difference.

Conclusions

With the help of the currently reported 3D radiographic evaluation method, it can be concluded that exposure of the new-generation d-PTFE membrane had less negative impact on clinical results compared to literature data reporting on expanded polytetrafluoroethylene membranes.
Effect of sintering time on the marginal and internal fit of monolithic zirconia crowns containing 3–4 mol% Y2O3
Authors: Ozden Yunus Emre , Guncu Mustafa Baris , Aktas Guliz , Canay Senay
Published: November 2022

Background

Short-term sintering may offer advantages including saving time and energy but there is limited evidence on the effect that altering sintering time has on the accuracy of monolithic zirconia crowns. The purpose of this in vitro study was to investigate the effect of shortened sintering time on the marginal and internal fit of 3Y-TZP and 4Y-TZP monolithic crowns.

Methods

Sixty monolithic zirconia crowns were fabricated for the maxillary first molar tooth on the prefabricated implant abutment. Groups were created according to the material composition: 3Y-TZP Generation 1, 3Y-TZP Generation 2 and 4Y-TZP. Two different sintering protocols were performed: same final sintering temperature (1500 °C) and various rates of heating (10 °C/min and 40 °C/min), cooling down speed (− 10 °C/min and − 40 °C/min), holding time (45 and 120 minutes), and total sintering time (approximately 2 and 7 hours, respectively). The marginal and internal fit of the crowns were determined using the silicone replica technique. Comparisons between groups were analyzed using two-way ANOVA. Pairwise multiple comparisons were performed using t-test (p < 0.05).

Results

The mean marginal gap values of 4Y-TZP zirconia revealed statistically significant increase for the short-term sintering protocol (p < 0.0001), while no difference was observed between the sintering protocols for the mean marginal gap values of 3Y-TZP groups. Although all groups showed clinically acceptable gap values, altering the sintering time had an effect on marginal fit of the crowns manufactured from 4Y-TZP zirconia.

Conclusions

Shortening the sintering time may lead to differences within clinically acceptable limits. The manufacturer’s recommendations according to material composition should be implemented with care.
Evolution of a chronic pain management program in a Northwestern Ontario community: from structural elements to practical application
Authors: Shojaei Hadi , Lakha Shehnaz Fatima , Lyon Ashley , Halabecki Mark , Donaghy Mary , Mailis Angela
Published: November 2022

Background

Chronic pain is a highly prevalent health problem especially in rural regions. There is a dearth of comprehensive pain management programs particularly in rural areas.

Aim

The objectives of this paper are to describe the evolution of an interprofessional chronic pain team employing a patient-centered model of care with a biopsychosocial approach, and health services metrics.

Method

This descriptive case study approach includes an overview of the Chronic Pain Management Program (CPMP) services at St. Joseph Care Group in Thunder Bay, NW Ontario; the process involved in the development of an interprofessional chronic pain team employing a patient-centered model of care with a biopsychosocial approach; and metrics of the program’s operations.

Results

Established in 1998, CPMP has evolved to become inter-professional, providing consultations and management, with partial funding by the Ontario Ministry of Health and Long term Care that has allowed expansion of services. The CPMP currently provides three distinct program streams as follows: a) Intensive 6-week, four half-days/week, outpatient program that offers an interdisciplinary team approach in groups and individual format; b) PACE-IT (Pain Assessment Collaborative Education Inter-professional Therapy), 8-week long, half-day/ week, interprofessional treatment program, in person; and c) Individual format for one-on-one services for patients not fitting in either the 6-Week or PACE-IT programs. In addition, Additional services provide virtual consultations and didactic videoteleconference sessions on opioid stewardship and pain management to health providers. Health services outcomes, research, and educational opportunities across the Northwestern Ontario Region, challenges and future needs are discussed.

Conclusion

The CPMP’s model of care can serve as a foundation for expert chronic pain care delivery across rural Canada, and as template for similar institutionally-based and publicly funded pain clinics.
Association between the triglyceride-glucose index and carotid plaque incidence: a longitudinal study
Authors: Zhang Yichi , Wu Zhuchao , Li Xiaona , Wei Jingkai , Zhang Qun , Wang Jianming
Published: November 2022

Background

Carotid plaque and triglyceride-glucose (TyG) index are associated with insulin resistance. However, a highly debated question is whether there is an association between the TyG index and carotid plaque incidence. Thus we performed an in-depth longitudinal study to investigate the relationship between carotid plaque occurrence and the TyG index among Chinese individuals.

Methods

Two thousand and three hundred seventy subjects (1381 males and 989 females) were enrolled and followed up for three years. The subjects were stratified into four groups based on the quartile of the TyG index at baseline. Univariate and multivariate Cox proportional hazard models were conducted to examine the role of TyG played in the carotid plaque. The strength of association was expressed as hazard ratio (HR) and 95% confidence interval (CI).

Results

After three years of follow-up, 444 subjects were detected with newly formed carotid plaque. The overall 3-year cumulative carotid plaque incidence was 18.7%, and the risk of carotid plaque increased with elevated TyG index (p < 0.001). The Cox regression analysis showed that males (HR: 1.33, 95% CI: 1.10–1.61), and people with higher systolic blood pressure (HR:1.01, 95% CI: 1.01–1.02), lower high-density lipoprotein cholesterol (HR: 0.68, 95% CI: 0.50–0.93), diabetes (HR: 2.21, 95% CI: 1.64–2.97), and hypertension (HR:1.49, 95% CI: 1.23–1.81) had a significantly increased risk for the carotid plaque formation. Similar results remained in the sensitivity analysis.

Conclusions

The TyG index can be used as a dose-responsive indicator of carotid plaque in the Chinese population. Elderly males with dyslipidemia, diabetes, or hypertension should be more vigilant about their TyG index since they are susceptible to developing carotid plaque. Physicians are encouraged to monitor the TyG index to help identify and treat patients with carotid plaque at an early stage.
Lactobacilli extracellular vesicles: potential postbiotics to support the vaginal microbiota homeostasis
Authors: Croatti Vanessa , Parolin Carola , Giordani Barbara , Foschi Claudio , Fedi Stefano , Vitali Beatrice
Published: November 2022

Background

Lactobacillus species dominate the vaginal microflora performing a first-line defense against vaginal infections. Extracellular vesicles (EVs) released by lactobacilli are considered mediators of their beneficial effects affecting cellular communication, homeostasis, microbial balance, and host immune system pathways. Up to now, very little is known about the role played by Lactobacillus EVs in the vaginal microenvironment, and mechanisms of action remain poorly understood.

Results

Here, we hypothesized that EVs can mediate lactobacilli beneficial effects to the host by modulating the vaginal microbiota colonization. We recovered and characterized EVs produced by two vaginal strains, namely Lactobacillus crispatus BC5 and Lactobacillus gasseri BC12. EVs were isolated by ultracentrifugation and physically characterized by Nanoparticle Tracking Analysis (NTA) and Dynamic Light Scattering (DLS). EVs protein and nucleic acids (DNA and RNA) content was also evaluated. We explored the role of EVs on bacterial adhesion and colonization, using a cervical cell line (HeLa) as an in vitro model. Specifically, we evaluated the effect of EVs on the adhesion of both vaginal beneficial lactobacilli and opportunistic pathogens (i.e., Escherichia coli, Staphylococcus aureus, Streptococcus agalactiae, and Enterococcus faecalis). We demonstrated that EVs from L. crispatus BC5 and L. gasseri BC12 significantly enhanced the cellular adhesion of all tested lactobacilli, reaching the maximum stimulation effect on strains belonging to L. crispatus species (335% and 269% of average adhesion, respectively). At the same time, EVs reduced the adhesion of all tested pathogens, being EVs from L. gasseri BC12 the most efficient.

Conclusions

Our observations suggest for the first time that EVs released by symbiotic Lactobacillus strains favor healthy vaginal homeostasis by supporting the colonization of beneficial species and preventing pathogens attachment. This study reinforces the concept of EVs as valid postbiotics and opens the perspective of developing postbiotics from vaginal strains to maintain microbiota homeostasis and promote women’s health.
Tumor cell-derived asymmetric dimethylarginine regulates macrophage functions and polarization
Authors: Chen Yi-Ling , Lowery AKaychia T. , Lin Samuel , Walker Ameae M. , Chen Kuan-Hui E.
Published: November 2022

Background

Asymmetric dimethylarginine (ADMA), which is significantly elevated in the plasma of cancer patients, is formed via intracellular recycling of methylated proteins and serves as a precursor for resynthesis of arginine. However, the cause of ADMA elevation in cancers and its impact on the regulation of tumor immunity is not known.

Methods

Three mouse breast cell lines (normal breast epithelial HC11, breast cancer EMT6 and triple negative breast cancer 4T1) and their equivalent 3D stem cell culture were used to analyze the secretion of ADMA using ELISA and their responses to ADMA. Bone marrow-derived macrophages and/or RAW264.7 cells were used to determine the impact of increased extracellular ADMA on macrophage-tumor interactions. Gene/protein expression was analyzed through RNAseq, qPCR and flow cytometry. Protein functional analyses were conducted via fluorescent imaging (arginine uptake, tumor phagocytosis) and enzymatic assay (arginase activity). Cell viability was measured via MTS assay and/or direct cell counting using Countess III FL system.

Results

For macrophages, ADMA impaired proliferation and phagocytosis of tumor cells, and even caused death in cultures incubated without arginine. ADMA also led to an unusual macrophage phenotype, with increased expression of arginase, cd163 and cd206 but decreased expression of il10 and dectin-1. In contrast to the severely negative impacts on macrophages, ADMA had relatively minor effects on proliferation and survival of mouse normal epithelial HC11 cells, mouse breast cancer EMT6 and 4T1 cells, but there was increased expression of the mesenchymal markers, vimentin and snail2, and decreased expression of the epithelial marker, mucin-1 in EMT6 cells. When tumor cells were co-cultured ex vivo with tumor antigen in vivo-primed splenocytes, the tumor cells secreted more ADMA and there were alterations in the tumor cell arginine metabolic landscape, including increased expression of genes involved in arginine uptake, metabolism and methylation, and decreased expression of a gene that is responsible for arginine demethylation. Additionally, interferon-gamma, a cytokine involved in immune challenge, increased secretion of ADMA in tumor cells, a process attenuated by an autophagy inhibitor.

Conclusion

Our results suggest initial immune attack promotes autophagy in tumor cells, which then secrete ADMA to manipulate macrophage polarization favoring tumor tolerance.
The RNA demethylase ALKBH5 promotes the progression and angiogenesis of lung cancer by regulating the stability of the LncRNA PVT1
Authors: Shen Wenyi , Pu Juan , Zuo Zhi , Gu Shanye , Sun Jing , Tan Bing , Wang Lili , Cheng Jianmeng , Zuo Yangsong
Published: November 2022

Background

N6-methyladenosine (m6A) is the most common posttranscriptional modification of RNA and plays critical roles in human cancer progression. However, the biological function of m6A methylation requires further studied in cancer, especially in tumor angiogenesis.

Methods

A public database was used to analyze the expression and overall survival of ALKBH5 and PVT1 in lung cancer patients. CCK-8 and colony formation assays were performed to detect cell proliferation, a transwell assay was used to assess cell migration, and a tube formation assay was performed to assess angiogenic potential in vitro. A zebrafish lung cancer xenograft model was used to verify the function of ALKBH5 and PVT1 in vivo. Western blot assays were used to measure the relative protein expression in lung cancer cells. SRAMP predictor analysis and RNA stability experiments were used to examine the potential m6A modification.

Results

Bioinformatics analysis showed that the expression levels of m6A-related genes were changed significantly in lung cancer tissues compared with normal lung tissues. We then identified that ALKBH5 was upregulated in lung cancer tissues and associated with poor prognosis of lung cancer patients by analyzing a public database. Knockdown of ALKBH5 inhibited the proliferation and migration of cultured lung cancer cell lines. Zebrafish lung cancer xenografts showed that ALKBH5 silencing also suppressed the growth and metastasis of lung cancer cells. Moreover, knockdown of ALKBH5 inhibited the angiogenesis of lung cancer in vitro and in vivo. Mechanistic studies showed that knockdown of ALKBH5 decreased the expression and stability of PVT1 in lung cancer cells. We next observed that PVT1 promoted the progression of lung cancer cells in vitro and in vivo and regulated the expression of VEGFA and angiogenesis in lung cancer. Finally, rescue experiments revealed that ALKBH5 regulated the proliferation, migration and angiogenesis of lung cancer cells, partially through PVT1.

Conclusion

Our results demonstrate that ALKBH5 promotes the progression and angiogenesis of lung cancer by regulating the expression and stability of PVT1, which provides a potential prognostic and therapeutic target for lung cancer patients.
The prognostic value of IPI in patients with primary breast lymphoma, a multicenter retrospective study
Authors: Feng Kexin , Zhao Shuangtao , Shang Qingyao , Qiao Guangdong , Liu Jiaxiang , Yang Chenxuan , Wei Ya , Li Yalun , Ren Fei , Xuan Lixue , Wang Xiang , Wang Xin
Published: November 2022

Background

Due to the rarity of PBL and the lack of large-scale studies, the prognostic value of IPI in PBL was controversial. Especially in the rituximab era, the ability of IPI to stratify prognosis in patients receiving immunochemotherapy was severely reduced. Then revised IPI (R-IPI) and National Comprehensive Cancer Network IPI (NCCN-IPI) were introduced. The present study aimed to evaluate the prognostic value of IPI and the other IPIs in patients with PBL in a Chinese population.

Methods

We performed a multicenter retrospective study of 71 patients with PBL from 3 institutions in China. The Kaplan–Meier method and log-rank tests were used for the survival analysis. Cox regression analysis was performed to evaluate the prognostic factors. Subgroup analysis was performed to assess the prognostic significance of IPI scores, R-IPI scores, and NCCN-IPI scores.

Results

The median follow-up was 4.7 years (0.7–21.8 years). The 5-year progression-free survival (PFS) and overall survival (OS) rates were 90.2% and 96.3%. In the multivariate analysis, only IPI scores and radiotherapy were significantly associated with OS and PFS (P < 0.05). Applying the R-IPI in our patient cohort indicates a significant difference in PFS between the two groups of R-IPI (P = 0.034) but not for OS (P = 0.072). And the NCCN-IPI was prognostic for OS (P = 0.025) but not for PFS (P = 0.066). Subgroup analyses of IPI showed that survival analysis of IPI scores for the PFS and OS of patients using rituximab were not significantly different (P > 0.05).

Conclusions

Our study confirms the prognostic value of IPI in patients with PBL, but the predictive value of IPI proved to be relatively low with the addition of the rituximab. The R-IPI and NCCN-IPI can accurately assess the high and low-risk groups of PBL patients but were insufficient to evaluate the intermediate risk group.
A literature review exploring how health systems respond to acute shocks in fragile and conflict-affected countries
Authors: Thu Kyaw Myat , Bernays Sarah , Abimbola Seye
Published: November 2022

Understanding how health systems respond to shocks has become a pressing need to strengthen response efforts. With already fragmented and disrupted health services, fragile and conflict affected [FCA] countries are more vulnerable to shocks. Previous studies have focused more on conceptualizing health system resilience rather than how health systems [especially in FCA countries] respond to or are resilient to acute shocks. To understand how health systems in FCA countries respond to the shocks and what influence their responses, we conducted a review of the literature published between January 2011 and September 2021 on health system responses to acute shocks in FCA countries. We searched Medline, Embase, Scopus, Jester and Google Scholar – 60 empirical studies in FCA countries on response to sudden, extreme, and unanticipated shocks were included in the review. We found that health systems in FCA countries responded to acute shock using absorptive, adaptive, or transformative capacities. These capacities were mediated by four dimensions of context; knowledge, uncertainties, interdependence, and legitimacy. In addition, we identified the cross-cutting role of community involvement [and its self-evolving nature], frontline workers, and leadership capacity. To our knowledge, this is among the first reviews that focus on FCA country health systems responses to acute shock. By highlighting enabling and constraining factors to each type of capacity, this study provides important lessons and practical strategies from FCA countries on how to absorb, adapt and transform in response to acute shocks – thus promoting health system resilience globally.
Preclinical evaluation of combination nemtabrutinib and venetoclax in chronic lymphocytic leukemia
Authors: Muhowski Elizabeth M. , Ravikrishnan Janani , Gordon Britten , Yu Lianbo , Misra Shrilekha , Walker Brandi , Eathiraj Sudharshan , Sampath Deepa , Rogers Kerry A. , Byrd John C. , Woyach Jennifer A.
Published: November 2022

Inhibitors of B cell receptor (BCR) signaling such as the Bruton’s tyrosine kinase (BTK) inhibitors are effective therapeutics for chronic lymphocytic leukemia (CLL). The first-in-class covalent BTK inhibitor, ibrutinib, produces durable responses in most CLL patients; however, complete responses are only observed in a minority of patients. B cell lymphoma 2 (BCL2), an anti-apoptotic protein that contributes to CLL cell survival, has also been investigated as a therapeutic target. The BCL2 inhibitor venetoclax is effective in patients with CLL and can produce undetectable minimal residual disease, allowing discontinuation of therapy. In combination, ibrutinib and venetoclax have shown preclinical synergy and clinical efficacy. Nemtabrutinib is a next generation, reversible inhibitor of BTK that potently inhibits BCR signaling in treatment-naïve and ibrutinib-refractory CLL cells ex vivo. The clinical efficacy of combining BTK inhibitors with BCL2 inhibitors motivated us to evaluate the novel combination of nemtabrutinib and venetoclax. In vitro studies show that nemtabrutinib and venetoclax are not antagonistic to each other. In an adoptive transfer CLL mouse model, mice treated with nemtabrutinib and venetoclax had prolonged survival compared to mice treated with ibrutinib and venetoclax. Our preclinical studies further validate the combination of BTK inhibitors with venetoclax and justify further investigation of combining nemtabrutinib with venetoclax in CLL.
Nitrogen and sulfur-doped carbon quantum dots as fluorescent nanoprobes for spectrofluorimetric determination of olanzapine and diazepam in biological fluids and dosage forms: application to content uniformity testing
Authors: Magdy Galal , Said Noura , El-Domany Ramadan A. , Belal Fathalla
Published: November 2022

A validated, sensitive, and simple spectrofluorimetric method was developed for the analysis of two important CNS-acting drugs, olanzapine and diazepam, in their commercial tablets without the need for any pretreatment steps. The developed method relied on the quantitative quenching effect of each of olanzapine and diazepam on the native fluorescence of nitrogen and sulfur-doped carbon quantum dots (NS@CQDs). NS@CQDs were prepared from thiosemicarbazide and citric acid by a facile one-pot hydrothermal technique. The synthesized NS@CQDs were characterized by different spectroscopic and microscopic techniques. NS@CQDs produced a maximum emission peak at 430 nm using 360 nm as an excitation wavelength. Calibration curves showed a good linear regression over the range of 5.0–200.0 and 1.0–100.0 μM with detection limits of 0.68 and 0.29 μM for olanzapine and diazepam, respectively. The adopted method was used for the determination of the investigated drugs in their tablets with high % recoveries (98.84–101.70%) and low % RSD values (< 2%). As diazepam is one of the most commonly abused benzodiazepines, the developed method was successfully applied for its determination in spiked human plasma with high % recoveries and low % RSD values, providing further insights for monitoring its potential abuse. The quenching mechanism was also studied and confirmed to be through dynamic and static quenching for olanzapine and diazepam, respectively. Due to the high selectivity and sensitivity, content uniformity testing of low-dose tablets was successfully performed by applying the United States Pharmacopoeia guidelines. The method's validation was performed in compliance with ICHQ2 (R1) recommendations.
Cryopreservation does not change the performance and characteristics of allogenic mesenchymal stem cells highly over-expressing a cytoplasmic therapeutic transgene for cancer treatment
Authors: Ho Yoon Khei , Loke Kin Man , Woo Jun Yung , Lee Yee Lin , Too Heng-Phon
Published: November 2022

Background

Mesenchymal stem cells (MSCs) driven gene directed enzyme prodrug therapy is a promising approach to deliver therapeutic agents to target heterogenous solid tumours. To democratize such a therapy, cryopreservation along with cold chain transportation is an essential part of the logistical process and supply chain. Previously, we have successfully engineered MSCs by a non-viral DNA transfection approach for prolonged and exceptionally high expression of the fused transgene cytosine deaminase, uracil phosphoribosyl transferase and green fluorescent protein (CD::UPRT::GFP). The aim of this study was to determine the effects of cryopreservation of MSCs engineered to highly overexpress this cytoplasmic therapeutic transgene.

Methods

Modified MSCs were preserved in a commercially available, GMP-grade cryopreservative—CryoStor10 (CS10) for up to 11 months. Performance of frozen-modified MSCs was compared to freshly modified equivalents in vitro. Cancer killing potency was evaluated using four different cancer cell lines. Migratory potential was assessed using matrigel invasion assay and flow cytometric analysis for CXCR4 expression. Frozen-modified MSC was used to treat canine patients via intra-tumoral injections, or by intravenous infusion followed by a daily dose of 5-flucytosine (5FC).

Results

We found that cryopreservation did not affect the transgene expression, cell viability, adhesion, phenotypic profile, and migration of gene modified canine adipose tissue derived MSCs. In the presence of 5FC, the thawed and freshly modified MSCs showed comparable cytotoxicity towards one canine and three human cancer cell lines in vitro. These cryopreserved cells were stored for about a year and then used to treat no-option-left canine patients with two different types of cancers and notably, the patients showed progression-free interval of more than 20 months, evidence of the effectiveness in treating spontaneously occurring cancers.

Conclusion

This study supports the use of cryopreserved, off-the-shelf transiently transfected MSCs for cancer treatment.
MDDI-SCL: predicting multi-type drug-drug interactions via supervised contrastive learning
Authors: Lin Shenggeng , Chen Weizhi , Chen Gengwang , Zhou Songchi , Wei Dong-Qing , Xiong Yi
Published: November 2022

The joint use of multiple drugs may cause unintended drug-drug interactions (DDIs) and result in adverse consequence to the patients. Accurate identification of DDI types can not only provide hints to avoid these accidental events, but also elaborate the underlying mechanisms by how DDIs occur. Several computational methods have been proposed for multi-type DDI prediction, but room remains for improvement in prediction performance. In this study, we propose a supervised contrastive learning based method, MDDI-SCL, implemented by three-level loss functions, to predict multi-type DDIs. MDDI-SCL is mainly composed of three modules: drug feature encoder and mean squared error loss module, drug latent feature fusion and supervised contrastive loss module, multi-type DDI prediction and classification loss module. The drug feature encoder and mean squared error loss module uses self-attention mechanism and autoencoder to learn drug-level latent features. The drug latent feature fusion and supervised contrastive loss module uses multi-scale feature fusion to learn drug pair-level latent features. The prediction and classification loss module predicts DDI types of each drug pair. We evaluate MDDI-SCL on three different tasks of two datasets. Experimental results demonstrate that MDDI-SCL achieves better or comparable performance as the state-of-the-art methods. Furthermore, the effectiveness of supervised contrastive learning is validated by ablation experiment, and the feasibility of MDDI-SCL is supported by case studies. The source codes are available athttps://github.com/ShenggengLin/MDDI-SCL.
Multi-locus sequence analysis reveals great genetic diversity among Mycoplasma capricolum subsp. capripneumoniae strains in Asia
Authors: Akhtar Arooba , Boissière Anne , Hao Huafang , Saeed Muhammad , Dupuy Virginie , Exbrayat Antoni , Khan Farhan Anwar , Chu Yuefeng , Manso-Silván Lucía
Published: November 2022

Multi-Locus Sequence Analysis (MLSA) of Mycoplasma capricolum subsp. capripneumoniae (Mccp) strains from Asia revealed unforeseen diversity and a central position for genotyping groups representing strains from Central/East Asia, suggesting a possible origin of contagious caprine pleuropneumonia in this continent. A better assessment of the emergence, diversity and distribution of Mccp in Asia and Africa calls for renewed efforts to dramatically enlarge the sample of strains. Availability and affordability in the field, added to superior typeability (directly from poor samples) and high stability, discriminatory power and concordance with epidemiological and phylogenetic analyses, make MLSA an excellent tool for such investigations.
Deep reinforcement learning-based beam training with energy and spectral efficiency maximisation for millimetre-wave channels
Authors: Narengerile  , Thompson John , Patras Paul , Ratnarajah Tharmalingam
Published: November 2022

The millimetre-wave (mmWave) spectrum has been investigated for the fifth generation wireless system to provide greater bandwidths and faster data rates. The use of mmWave signals allows large-scale antenna arrays to concentrate the radiated power into narrow beams for directional transmission. The beam alignment at mmWave frequency bands requires periodic training because mmWave channels are sensitive to user mobility and environmental changes. To benefit from machine learning technologies that will be used to build the sixth generation (6G) communication systems, we propose a new beam training algorithm via deep reinforcement learning. The proposed algorithm can switch between different beam training techniques according to the changes in the wireless channel such that the overall beam training overhead is minimised while achieving good performance of energy efficiency or spectral efficiency. Further, we develop a beam training strategy which can maximise either energy efficiency or spectral efficiency by controlling the number of activated radio frequency chains based on the current channel conditions. Simulation results show that compared to baseline algorithms, the proposed approach can achieve higher energy efficiency or spectral efficiency with lower training overhead.