bluuebunny/crossref_metadata_2025 huggingface dataset:
An improved method in fabrication of smart dual-responsive nanogels for controlled release of doxorubicin and curcumin in HT-29 colon cancer cells
Authors: Abedi Fatemeh , Davaran Soodabeh , Hekmati Malak , Akbarzadeh Abolfazl , Baradaran Behzad , Moghaddam Sevil Vaghefi
Published: January 2021

The combination therapy which has been proposed as the strategy for the cancer treatment could achieve a synergistic effect for cancer therapies and reduce the dosage of the applied drugs. On account of the the unique properties as the high absorbed water content, biocompatibility, and flexibility, the targeting nanogels have been considred as a suitable platform. Herein, a non-toxic pH/thermo-responsive hydrogel P(NIPAAm-co-DMAEMA) was synthesized and characterized through the free-radical polymerization and expanded upon an easy process for the preparation of the smart responsive nanogels; that is, the nanogels were used for the efficient and controlled delivery of the anti-cancer drug doxorubicin (DOX) and chemosensitizer curcumin (CUR) simultaneously like a promising strategy for the cancer treatment. The size of the nanogels, which were made, was about 70 nm which is relatively optimal for the enhanced permeability and retention (EPR) effects. The DOX and CUR co-loaded nanocarriers were prepared by the high encapsulation efficiency (EE). It is important to mention that the controlled drug release behavior of the nanocarriers was also investigated. An enhanced ability of DOX and CUR-loaded nanoformulation to induce the cell apoptosis in the HT-29 colon cancer cells which represented the greater antitumor efficacy than the single-drug formulations or free drugs was resulted through the In vitro cytotoxicity. Overall, according to the data, the simultaneous delivery of the dual drugs through the fabricated nanogels could synergistically potentiate the antitumor effects on the colon cancer (CC).
Engagement of TREM2 by a novel monoclonal antibody induces activation of microglia and improves cognitive function in Alzheimer’s disease models
Authors: Fassler Michael , Rappaport Maya Saban , Cuño Clara Benaim , George Jacob
Published: January 2021

Background

Genetic variants and mutations in triggering receptor expressed in myeloid cells (TREM2) are associated with premature and late onset Alzheimer’s disease (AD).

Methods

We developed a panel of monoclonal antibodies, the selected lead of which was avidly shown to bind the extracellular domain of human and murine TREM2.

Results

By engaging membrane-bound TREM2, the selected antibody was shown to promote their cellular proliferation, uptake of oligomeric beta amyloid/apoptotic neurons, and activation in a Syk and Akt dependent manner. The antibody was shown to avidly bind soluble TREM2 in the CSF from AD patients and blunted the proinflammatory program driven by its intracerebral injection. Upon in vivo treatment, the antibody was shown to improve cognitive function in experimental amyloidopathy models and to facilitate plaque-associated microglial coverage and activation.

Conclusion

Thus, we describe a novel monoclonal antibody targeting membrane bound and soluble TREM2, that improves cognitive function by inducing microglial activation and attenuating chronic neuroinflammation.
The impact of dextran sodium sulphate and probiotic pre-treatment in a murine model of Parkinson’s disease
Authors: Dwyer Zach , Chaiquin Melany , Landrigan Jeffrey , Ayoub Kiara , Shail Pragya , Rocha Julianna , Childers Christie L. , Storey Kenneth B. , Philpott Dana J. , Sun Hongyu , Hayley Shawn
Published: January 2021

Background

Recent work has established that Parkinson’s disease (PD) patients have an altered gut microbiome, along with signs of intestinal inflammation. This could help explain the high degree of gastric disturbances in PD patients, as well as potentially be linked to the migration of peripheral inflammatory factors into the brain. To our knowledge, this is the first study to examine microbiome alteration prior to the induction of a PD murine model.

Methods

We presently assessed whether pre-treatment with the probiotic, VSL #3, or the inflammatory inducer, dextran sodium sulphate (DSS), would influence the PD-like pathology provoked by a dual hit toxin model using lipopolysaccharide (LPS) and paraquat exposure.

Results

While VSL #3 has been reported to have anti-inflammatory effects, DSS is often used as a model of colitis because of the gut inflammation and the breach of the intestinal barrier that it induces. We found that VSL#3 did not have any significant effects (beyond a blunting of LPS paraquat-induced weight loss). However, the DSS treatment caused marked changes in the gut microbiome and was also associated with augmented behavioral and inflammatory outcomes. In fact, DSS markedly increased taxa belonging to the Bacteroidaceae and Porphyromonadaceae families but reduced those from Rikencellaceae and S24-7, as well as provoking colonic pro-inflammatory cytokine expression, consistent with an inflamed gut. The DSS also increased the impact of LPS plus paraquat upon microglial morphology, along with circulating lipocalin-2 (neutrophil marker) and IL-6. Yet, neither DSS nor VSL#3 influenced the loss of substantia nigra dopamine neurons or the astrocytic and cytoskeleton remodeling protein changes that were provoked by the LPS followed by paraquat treatment.

Conclusions

These data suggest that disruption of the intestinal integrity and the associated microbiome can interact with systemic inflammatory events to promote widespread brain-gut changes that could be relevant for PD and at the very least, suggestive of novel neuro-immune communication.
Required concentration index quantifies effective drug combinations against hepatitis C virus infection
Authors: Kakizoe Yusuke , Koizumi Yoshiki , Ikoma Yukino , Ohashi Hirofumi , Wakita Takaji , Iwami Shingo , Watashi Koichi
Published: January 2021

Successful clinical drug development requires rational design of combination treatments based on preclinical data. Anti-hepatitis C virus (HCV) drugs exhibit significant diversity in antiviral effect. Dose-response assessments can be used to determine parameters profiling the diverse antiviral effect during combination treatment. In the current study, a combined experimental and mathematical approaches were used to compare and score different combinations of anti-HCV treatments. A “required concentration index” was generated and used to rank the antiviral profile of possible double- and triple-drug combinations against HCV genotype 1b and 2a. Rankings varied based on target HCV genotype. Interestingly, multidrug (double and triple) treatment not only augmented antiviral activity, but also reduced genotype-specific efficacy, suggesting another advantage of multidrug treatment. The current study provides a quantitative method for profiling drug combinations against viral genotypes, to better inform clinical drug development.
Integrated TB and HIV care for Mozambican children: temporal trends, site-level determinants of performance, and recommendations for improved TB preventive treatment
Authors: Buck W. Chris , Nguyen Hanh , Siapka Mariana , Basu Lopa , Greenberg Cowan Jessica , De Deus Maria Inês , Gleason Megan , Ferreira Ferreira , Xavier Carla , Jose Benedita , Muthemba Criménia , Simione Beatriz , Kerndt Peter
Published: January 2021

Background

Pediatric tuberculosis (TB), human immunodeficiency virus (HIV), and TB-HIV co-infection are health problems with evidence-based diagnostic and treatment algorithms that can reduce morbidity and mortality. Implementation and operational barriers affect adherence to guidelines in many resource-constrained settings, negatively affecting patient outcomes. This study aimed to assess performance in the pediatric HIV and TB care cascades in Mozambique.

Methods

A retrospective analysis of routine PEPFAR site-level HIV and TB data from 2012 to 2016 was performed. Patients 0–14 years of age were included. Descriptive statistics were used to report trends in TB and HIV indicators. Linear regression was done to assess associations of site-level variables with performance in the pediatric TB and HIV care cascades using 2016 data.

Results

Routine HIV testing and cotrimoxazole initiation for co-infected children in the TB program were nearly optimal at 99% and 96% in 2016, respectively. Antiretroviral therapy (ART) initiation was lower at 87%, but steadily improved from 2012 to 2016. From the HIV program, TB screening at the last consultation rose steadily over the study period, reaching 82% in 2016. The percentage of newly enrolled children who received either TB treatment or isoniazid preventive treatment (IPT) also steadily improved in all provinces, but in 2016 was only at 42% nationally. Larger volume sites were significantly more likely to complete the pediatric HIV and TB care cascades in 2016 (p value range 0.05 to < 0.001).

Conclusions

Mozambique has made significant strides in improving the pediatric care cascades for children with TB and HIV, but there were missed opportunities for TB diagnosis and prevention, with IPT utilization being particularly problematic. Strengthened TB/HIV programming that continues to focus on pediatric ART scale-up while improving delivery of TB preventive therapy, either with IPT or newer rifapentine-based regimens for age-eligible children, is needed.
False negative rate of COVID-19 PCR testing: a discordant testing analysis
Authors: Kanji Jamil N. , Zelyas Nathan , MacDonald Clayton , Pabbaraju Kanti , Khan Muhammad Naeem , Prasad Abhaya , Hu Jia , Diggle Mathew , Berenger Byron M. , Tipples Graham
Published: January 2021

Background

COVID-19 is diagnosed via detection of SARS-CoV-2 RNA using real time reverse-transcriptase polymerase chain reaction (rtRT-PCR). Performance of many SARS-CoV-2 rtRT-PCR assays is not entirely known due to the lack of a gold standard. We sought to evaluate the false negative rate (FNR) and sensitivity of our laboratory-developed SARS-CoV-2 rtRT-PCR targeting the envelope (E) and RNA-dependent RNA-polymerase (RdRp) genes.

Methods

SARS-CoV-2 rtRT-PCR results at the Public Health Laboratory (Alberta, Canada) from January 21 to April 18, 2020 were reviewed to identify patients with an initial negative rtRT-PCR followed by a positive result on repeat testing within 14 days (defined as discordant results). Negative samples from these discordant specimens were re-tested using three alternate rtRT-PCR assays (targeting the E gene and N1/N2 regions of the nucleocapsid genes) to assess for false negative (FN) results.

Results

During the time period specified, 95,919 patients (100,001 samples) were tested for SARS-CoV-2. Of these, 49 patients were found to have discordant results including 49 positive and 52 negative swabs. Repeat testing of 52 negative swabs found five FNs (from five separate patients). Assuming 100% specificity of the diagnostic assay, the FNR and sensitivity in this group of patients with discordant testing was 9.3% (95% CI 1.5–17.0%) and 90.7% (95% CI 82.6–98.9%) respectively.

Conclusions

Studies to understand the FNR of routinely used assays are important to confirm adequate clinical performance. In this study, most FN results were due to low amounts of SARS-CoV-2 virus concentrations in patients with multiple specimens collected during different stages of infection. Post-test clinical evaluation of each patient is advised to ensure that rtRT-PCR results are not the only factor in excluding COVID-19.
Post-traumatic stress disorder and its associated factors among people who experienced traumatic events in east African countries, 2020: a protocol for systematic review and meta-analysis
Authors: Biresaw Mengesha Srahbzu , Gebeyehu Enguday Tirfeneh
Published: January 2021

Background

Post-traumatic stress disorder (PTSD) is the most commonly reported mental health consequence following disasters and traumatic events, either natural or man-made. Nothing is written regarding its pooled prevalence and pooled estimate of factors. Therefore, this study aimed to determine the pooled prevalence of PTSD and estimate the pooled effect of associated factors.

Methods

An English version of published articles will be retrieved using the following; PubMed/Medline, Africa-wides, Science Direct, Cochrane Library, Global Health, Google Scholar, EMBASE, and psycINFO. Research reports will be searched from October 10/2020 to November 10/2020. The research reports quality will be assessed using the Newcastle–Ottawa Scale. Relevant information from the searched research reports will be extracted in a Microsoft Excel format. After extraction, the data will be imported to STATA version 14.0 for analysis. An appropriate guideline for a systematic review and meta-analysis report will be used, i.e. the Preferred Reporting Items for Systematic reviews and Meta-Analyses. A random-effects meta-analysis model will be used to estimate the Der Simonian and Laird’s pooled prevalence of PTSD and its associated factors.

Discussion

This study aims to determine the pooled prevalence of PTSD and estimate the pooled effect of associated factors. Several kinds of research have reported the increasing magnitude of PTSD and its determinants in a different population. This might be due to reasons, such as little attention being given to the issue. Therefore, this study will try to fill this gap by giving new evidence-based results to attract policymakers’ attention.
Split-root systems: detailed methodology, alternative applications, and implications at leaf proteome level
Authors: Saiz-Fernández Iñigo , Černý Martin , Skalák Jan , Brzobohatý Břetislav
Published: January 2021

Background

Split-root systems (SRS) have many applications in plant sciences, but their implementation, depending on the experimental design, can be difficult and time-consuming. Additionally, the system is not exempt from limitations, since the time required for the establishment of the SRS imposes a limit to how early in plant development experiments can be performed. Here, we optimized and explained in detail a method for establishing a SRS in youngArabidopsis thalianaseedlings, both in vitro and in soil.

Results

We found that the partial de-rooting minimized the recovery time compared to total de-rooting, thus allowing the establishment of the split-root system in younger plants. Analysis of changes in the Arabidopsis leaf proteome following the de-rooting procedure highlighted the distinct metabolic alterations that totally and partially de-rooted plants undergo during the healing process. This system was also validated for its use in drought experiments, as it offers a way to apply water-soluble compounds to plants subjected to drought stress. By growing plants in a split-root system with both halves being water-deprived, it is possible to apply the required compound to one half of the root system, which can be cut from the main plant once the compound has been absorbed, thus minimizing rehydration and maintaining drought conditions.

Conclusions

Partial de-rooting is the suggested method for obtaining split-root systems in small plants likeArabidopsis thaliana, as growth parameters, survival rate, and proteomic analysis suggest that is a less stressful procedure than total de-rooting, leading to a final rosette area much closer to that of uncut plants. Additionally, we provide evidence that split root-systems can be used in drought experiments where water-soluble compounds are applied with minimal effects of rehydration.
Reliability of circulating fibrinogen in the diagnosis of prosthesis-related infections: a systematic review and meta-analysis
Authors: Zhu Xingyang , Zhang Haitao , Sun Xiaobo , Li Yijin , Li Jiahao , Zeng Yuqing , Deng Peng , Qi Xinyu , Chen Jinlun , Ye Pengcheng , Feng Wenjun , Li Jie , Zeng Jianchun , Zeng Yirong
Published: January 2021

Background

Fibrinogen (FIB) has recently been used as a biomarker to diagnose periprosthetic joint infection (PJI), but its reliability is still questionable. The aim of this study was to investigate the accuracy of FIB in the diagnosis of PJI after joint replacement.

Methods

We searched for literatures published in PubMed, EMBASE, and the Cochrane Library from the time of database inception to September 2020 and screened the studies according to the inclusion criteria. Then, we calculated the diagnostic parameters of FIB, including the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), area under the curve (AUC), and diagnostic odds ratio (DOR). In addition, we implemented subgroup analyses to identify the sources of heterogeneity.

Results

Seven studies including 1341 patients were selected in our meta-analysis. The pooled sensitivity, specificity, PLR, NLR, and DOR of FIB for PJI diagnosis were 0.78 (95% confidence interval [CI], 0.73–0.82), 0.83 (95% CI, 0.81–0.86), 4.60 (95% CI, 3.30–6.42), 0.24 (95% CI, 0.18–0.34), and 20.13 (95% CI, 14.80–27.36), respectively, while the AUC was 0.896.

Conclusion

The present study indicated that FIB was a reliable detection method and might be introduced into the diagnostic criteria for PJI. However, more robust studies are still needed to confirm the current findings, because most of the included studies were retrospective and had small sample sizes.
Determining the stability of minimally displaced lateral humeral condyle fractures in children: ultrasound is better than arthrography
Authors: Wu Xing , Li Xiongtao , Yang Shaowei , Wang Si , Xia Jingdong , Chen Xiaoliang , Shen Xiantao
Published: January 2021

Background

Evaluating of the articular cartilage status of the distal humeral epiphysis is difficult. Ultrasound imaging of the elbow is increasingly being used to confirm the integrity of the articular cartilage of minimally displaced lateral humeral condyle fractures in children with minimally displaced fractures. The aims of this study were to assess the correlations between ultrasound and arthrography findings for predicting the integrity of the cartilage hinge and to describe the utility of ultrasound in determining the need for pre-treatment.

Methods

Thirty-nine patients with minimally displaced lateral humeral condyle fractures who underwent ultrasound and arthrography examinations before surgery from May 2018 to December 2019 were included in this study. Ultrasound and arthrography predictors of the cartilage hinge status were independently measured. The ultrasound and arthrography results were compared.

Results

The mean displacement of the fractures was 3.1 mm (range, 2.0~5.0 mm). Arthrography showed incomplete fractures in 24 patients (61.5%) and complete fractures in 15 patients (38.5%). Ultrasound showed incomplete fractures in 25 patients (64.1%) and complete fractures in 14 patients (35.9%). The ultrasound and arthrography results of the integrity of the articular surface were consistent in 92.3% of the cases, including 23 that were predicted to have an intact articular surface and 13 that were predicted to have an incongruity articular surface. There was no correlation between the displacement and the fracture appearing complete on the ultrasound scan. The Pearson coefficient between ultrasound and arthrography for assessing the integrity of the articular surface was 0.837.

Conclusions

Ultrasound and arthrography assessments of the integrity of the cartilage hinge status appear to be highly consistent. Ultrasound can be used as a complementary tool with arthrography to predict the integrity of the cartilage hinge status in children with minimally displaced lateral humeral condyle fractures.

Level of evidence

Prospective study; level II.
Mid-term outcomes of the R3™ delta ceramic acetabular system in total hip arthroplasty
Authors: Davis Edward T. , Remes Ville , Virolainen Petri , Gebuhr Peter , Van Backlé Bart , Revell Matthew P. , Kopjar Branko
Published: January 2021

Background

Whilst bony fixation of hip replacement has stable solutions, there remains controversy over which bearing best optimizes longevity and function. Ceramic-on-ceramic (CoC) bearing combinations are associated with lower risk of revision due to aseptic loosening and dislocation. Evidence for long-term functional outcomes of modern, 4th generation CoC bearings is limited. The aim of this study was to analyze outcomes and complications of the R3™ Acetabular System (Smith & Nephew, Inc., Cordova, TN, USA) in combination with BIOLOX® Delta ceramic femoral head in patients undergoing primary total hip arthroplasty (THA).

Methods

Between June 2009 and May 2011, 175 patients (178 hips) were enrolled into a prospective, study at 6 sites in Europe and prospectively followed-up at 3 months and 1, 3, 5, and 7 years postoperative.

Results

Total WOMAC score improved from 63 (range, 22–91) preoperative to 8 (range, 0–8) at 1-year follow-up and remained unchanged at 7-year follow-up. Modified Harris hip score improved from 45 (range, 10–87) preoperative to 83 (range, 25–100) at 3 months, 91 (range, 42–100) at 1 year, and 92 (range, 46, 100) at 7 years. UCLA Activity Rating Scale score improved from 3.3 (range, 1–8) preoperative to 6.2 (range, 2–8) at 1 year; it marginally declined to 5.8 (range, 3–8) at 7-year follow-up. There were 4 trochanteric fractures and 5 patients died of unrelated reasons. Three hips were revised (2 periprosthetic fractures and 1 subluxation). The 7-year cumulative survival rate was 98.3%.

Conclusion

Clinical and functional improvements of THA with CoC bearing are maintained at 7 years postoperative.

Trial registration

ClinicalTrials.Gov, NCT03566082, Registered 10 January 2018—retrospectively registered,
Wrist tuberculosis-experience from eighteen cases: a retrospective study
Authors: Zou Longfei , Guo Xing , Xue Hao , Huang Denghua , Lv Hui , Tan Meiyun
Published: January 2021

Background

Wrist tuberculosis is a rare disease, which is easy to be misdiagnosed, leading to delayed treatment and poor prognosis. In this study, the clinical manifestations, diagnosis, treatment, and prognosis of 18 cases of wrist tuberculosis were analyzed retrospectively.

Methods

A retrospective study was conducted, investigating tuberculosis of the wrist, diagnosed in 18 patients from August 2013 to November 2018. Puncture biopsy confirmed the diagnosis. The study includes 11 males and 7 females, and 8 left and 10 right wrists. The average age was 53.5 ± 18.3 years and ranged from 15 to 81 years. The disease course was 1 to 42 months, with an average of 15.1 ± 11.3 months. Eighteen patients were underwent surgery and chemotherapy, 3 patients with severe bone defects were treated with wrist fusion, and 15 patients were underwent focus removal. The Gartland and Werley score, DASH score, the range of motion (ROM), grip strength, and imaging examinations were used to evaluate the postoperative recovery of the patients.

Results

Eighteen patients were followed up for 15 to 77 months, with an average follow up of 39.7 ± 15.3 months. The ESR and CRP levels were normal for all patients after chemotherapy. No recurrence of tuberculosis was observed in any of the patients. Among the 15 focus removals, the Gartland and Werley scores at admission, two weeks of chemotherapy, 1 month after surgery, and the last follow-up were 21.73 ± 4.33, 18.60 ± 3.16,11.27 ± 2.79, and 5.07 ± 2.28, respectively; and the DASH scores were 45.87 ± 5.58, 39.47 ± 4.72, 22.67 ± 6.54, and 6.73 ± 2.94, respectively. The range of motion (ROM) of the wrist and grip strength improved significantly when compared to those at admission. Among the three cases of wrist fusion, 2 were fixed with a steel plate and the fixation position of wrist joint was good. One case was fixed with Kirschner wire and resulted in a slightly deformed wrist joint.

Conclusion

For patients with wrist tuberculosis, early diagnosis, preoperative and postoperative chemotherapy, thorough focus removal, and appropriate fixation of the affected limb can help restore the function of the affected wrist, reduce the recurrence rate, and improve the quality of life.
Can a shift to regional and organic diets reduce greenhouse gas emissions from the food system? A case study from Qatar
Authors: Vicente-Vicente José Luis , Piorr Annette
Published: January 2021

Background

Qatar is one of the countries with the highest carbon (C) footprints per capita in the world with an increasing population and food demand. Furthermore, the international blockade by some countries that is affecting Qatar—which has been traditionally a highly-dependent country on food imports—since 2017 has led the authorities to take the decision of increasing food self-sufficiency. In this study we have assessed the effect on greenhouse gas (GHG) emissions of shifting diets from conventional to organic products and from import-based diets to more regionalized diets for the first time in a Gulf country.

Results

We found that considering the production system, the majority of the emissions come from the animal products, but the differences between conventional and organic diets are very small (738 and 722 kg CO2-eq capita−1 year−1, of total emissions, respectively). Conversely, total emissions from plant-based products consumption might be around one order of magnitude smaller, but the differences in the emissions between the organic and conventional systems were higher than those estimated for animal products, leading to a decrease in 44 kg CO2-eq capita−1 year−1when changing from 100% conventional to 50% of organic consumption of plant-based products. Regarding the shift to regionalized diets, we found that packaging has a small influence on the total amount of GHG emissions, whereas emissions from transportation would be reduced in around 450 kg CO2capita−1 year−1when reducing imports from 100 to 50%.

Conclusions

However, these results must be read carefully. Due to the extreme adverse pedoclimatic conditions of the country, commercial organic regional livestock would not be possible without emitting very high GHG emissions and just only some traditional livestock species may be farmed in a climate-friendly way. On the other hand, organic and regional low-CO2emission systems of plant-based products would be possible by implementing innovations in irrigation or other innovations whose GHG emissions must be further studied in the future. Therefore, we conclude that shifting towards more plant-based organic regional consumption by using climate-friendly irrigation is a suitable solution to both increasing self-sufficiency and reducing C footprint. We encourage national authorities to including these outcomes into their environmental and food security policies.
Psychological processes in the experience of hereditary angioedema in adult patients: an observational study
Authors: Savarese Livia , Bova Maria , Maiello Assunta , Petraroli Angelica , Mormile Ilaria , Cancian Mauro , Senter Riccardo , Zanichelli Andrea , Spadaro Giuseppe , Freda Maria Francesca
Published: January 2021

Background

Hereditary angioedema associated to C1 inhibitor deficiency (C1-INH-HAE) is a pathological condition characterized by episodes of subcutaneous swelling and it is frequently associated with discomfort and social impairment of the patients, due to the anxiety experienced for an unpreventable manifestation of an attack during daily life. In children increased level of stress and alexithymia have been associated to C1-INH-HAE, and the latter correlated also with the severity of the disease. We hypothesized that the involvement of psychological issues may impact on the severity of C1-INH-HAE in adult patients as well, interfering with their ability to engage with the management of the disease.

Methods

28 adult patients with C1-INH-HAE were evaluated for clinical (C1-INH-HAE Severity Score) and psychological factors (alexithymia, emotion regulation, stress, patient health engagement, general severity index) by means of validated questionnaires.

Results

Mean age (standard deviation [SD]) was 45 (11) years and time from diagnosis was 20 (12) years. The mean C1-INH-HAE severity score was 6.4. Alexithymia was absent in 22 (78%) patients. Moderate and high stress levels were present in 17 (61%) and 4 (14%) patients, respectively. Moderate-high discomfort was experienced by 9 (36%) patients and a discomfort beyond the clinical attention threshold was shown by 3 (12%) patients. Stress correlated with patient health engagement and with psychological discomfort.

Conclusions

In C1-INH-HAE, patients health engagement and moderate-high psychological discomfort are linked with stress but not with the severity of the disease or alexithymia. A better patient health engagement may be a target for psychological intervention in clinics to ameliorate the stress perceived by C1-INH-HAE patients.
Effect of a peer‐led intervention combining mental health promotion with coping‐strategy‐based workshops on mental health awareness, help‐seeking behavior, and wellbeing among university students in Hong Kong
Authors: Ahorsu Daniel Kwasi , Sánchez Vidaña Dalinda Isabel , Lipardo Donald , Shah Parth Bharat , Cruz González Pablo , Shende Sachin , Gurung Shilpa , Venkatesan Harun , Duongthipthewa Anchalee , Ansari Talha Qasim , Schoeb Veronika
Published: January 2021

Background

The psychological well-being of university students is an important factor in successfully coping with the demands of academic life. This study aimed to assess the impact of a peer-led intervention of mental health promotion combined with coping-strategy-based group workshops on mental health awareness and help-seeking behavior among university students in Hong Kong.

Method

A mixed-method concurrent design was used for this study. Quantitative data, based on one-group pretest-posttest design, were collected using Mental Health Knowledge Schedule Questionnaire to assess mental health awareness, and Attitude Towards Seeking Professional Help Questionnaire-Short Form to examine help-seeking behavior of university students from The Hong Kong Polytechnic University. Qualitative data were collected from written post-activity reflections and focus group discussions which were thematically analyzed.

Results

A total of 62 university students (mean age: 23.2 ± 5.1 years) were included in this study. Mental health awareness was significantly improved (p = 0.015, 95% Confidence Interval of − 2.670, − 0.297) after program implementation. Help-seeking behavior mean score increased from pretest to posttest, however, no significant difference was observed (p = 0.188, 95% CI = − 1.775, 0.355). Qualitative analysis revealed that the program helped participants learn about coping strategies to help themselves and others with mental health challenges.

Conclusions

The peer-led intervention provided a positive impact through increased mental health awareness and knowledge of coping strategies on self-help and helping others among university students. Further study could focus on the impact of the program when applied regularly throughout the entire academic year.
Patient-friendly integrated first trimester screening by NIPT and fetal anomaly scan
Authors: Srebniak Malgorzata Ilona , Knapen Maarten F. C. M. , Joosten Marieke , Diderich Karin E. M. , Galjaard Sander , Van Opstal Diane
Published: January 2021

Many major structural fetal anomalies can be diagnosed by first trimester fetal anomaly scan. NIPT can accurately detect aneuploidies and large chromosomal aberrations in cfDNA in maternal blood plasma. This study shows how a patient-friendly first trimester screening for both chromosomal and structural fetal anomalies in only two outpatient visits can be provided. Genotype-first approach assures not only the earliest diagnosis of trisomy 21 (the most prevalent chromosome aberration), but also completion of the screening at 12–14 weeks. To ensure proper management and avoid unnecessary anxiety abnormal NIPT different from trisomy 21, 18 and 13 should be referred for genetic counseling.
Increased O-GlcNAcylation of Drp1 by amyloid-beta promotes mitochondrial fission and dysfunction in neuronal cells
Authors: Park So Jung , Bae Ji-Eun , Jo Doo Sin , Kim Joon Bum , Park Na Yeon , Fang Jianguo , Jung Yong-Keun , Jo Dong Gyu , Cho Dong-Hyung
Published: January 2021

As a dynamic organelle, mitochondria continuously fuse and divide with adjacent mitochondria. Imbalance in mitochondria dynamics leads to their dysfunction, which implicated in neurodegenerative diseases. However, how mitochondria alteration and glucose defect contribute to pathogenesis of Alzheimer’s disease (AD) is still largely unknown. Dynamin‐related protein 1 (Drp1) is an essential regulator for mitochondria fission. Among various posttranslational modifications, O-GlcNAcylation plays a role as a sensor for nutrient and oxidative stress. In this study, we identified that Drp1 is regulated by O-GlcNAcylation in AD models. Treatment of Aβ as well as PugNAc resulted in mitochondrial fragmentation in neuronal cells. Moreover, we found that AD mice brain exhibits an upregulated Drp1 O-GlcNAcylation. However, depletion of OGT inhibited Drp1 O-GlcNAcylation in Aβ-treated cells. In addition, overexpression of O-GlcNAc defective Drp1 mutant (T585A and T586A) decreased Drp1 O-GlcNAcylation and Aβ-induced mitochondria fragmentation. Taken together, these finding suggest that Aβ regulates mitochondrial fission by increasing O-GlcNAcylation of Drp1.
Targeting hypoxia in the tumor microenvironment: a potential strategy to improve cancer immunotherapy
Authors: Wang Bin , Zhao Qin , Zhang Yuyu , Liu Zijing , Zheng Zhuangzhuang , Liu Shiyu , Meng Lingbin , Xin Ying , Jiang Xin
Published: January 2021

With the success of immune checkpoint inhibitors (ICIs), significant progress has been made in the field of cancer immunotherapy. Despite the long-lasting outcomes in responders, the majority of patients with cancer still do not benefit from this revolutionary therapy. Increasing evidence suggests that one of the major barriers limiting the efficacy of immunotherapy seems to coalesce with the hypoxic tumor microenvironment (TME), which is an intrinsic property of all solid tumors. In addition to its impact on shaping tumor invasion and metastasis, the hypoxic TME plays an essential role in inducing immune suppression and resistance though fostering diverse changes in stromal cell biology. Therefore, targeting hypoxia may provide a means to enhance the efficacy of immunotherapy. In this review, the potential impact of hypoxia within the TME, in terms of key immune cell populations, and the contribution to immune suppression are discussed. In addition, we outline how hypoxia can be manipulated to tailor the immune response and provide a promising combinational therapeutic strategy to improve immunotherapy.
The EGFR-HSF1 axis accelerates the tumorigenesis of pancreatic cancer
Authors: Qian Weikun , Chen Ke , Qin Tao , Xiao Ying , Li Jie , Yue Yangyang , Zhou Cancan , Ma Jiguang , Duan Wanxing , Lei Jianjun , Han Liang , Li Li , Shen Xin , Wu Zheng , Ma Qingyong , Wang Zheng
Published: January 2021

Background

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant diseases because of its non-symptomatic tumorigenesis. We previous found heat shock factor 1 (HSF1) was critical for PDAC progression and the aim of this study was to clarified the mechanisms on early activation of HSF1 and its role in the pancreatic cancer tumorigenesis.

Methods

The expression and location of HSF1 on human or mice pancreatic tissues were examined by immunohistochemically staining. We mainly used pancreatic acinar cell 3-dimensional (3D) culture and a spontaneous pancreatic precancerous lesion mouse model called LSL-KrasG12D/+; Pdx1-Cre (KC) (and pancreatitis models derived from KC mice) to explore the pro-tumorigenesis mechanisms of the HSF1 in vitro and in vivo. Bioinformatics and molecular experiments were used to explore the underlying mechanisms between HSF1 and epidermal growth factor receptor (EGFR).

Results

In this study, we found that pharmacological inhibition of HSF1 slowed pancreatic cancer initiation and suppressed the pancreatitis-induced formation of pancreatic precancerous lesion. Next, bioinformatics analysis revealed the closely linked between HSF1 and EGFR pathway and we also confirmed their parallel activation in pancreatic precancerous lesions. Besides, the pharmacological inhibition of EGFR suppressed the initiation of pancreatic cancer and the activation of HSF1 in vivo. Indeed, we demonstrated that the EGFR activation that mediated pancreatic cancer tumorigenesis was partly HSF1-dependent in vitro.

Conclusion

Hence, we concluded that the EGFR-HSF1 axis promoted the initiation of pancreatic cancer.
YAP and endothelin-1 signaling: an emerging alliance in cancer
Authors: Tocci Piera , Blandino Giovanni , Bagnato Anna
Published: January 2021

The rational making the G protein-coupled receptors (GPCR) the centerpiece of targeted therapies is fueled by the awareness that GPCR-initiated signaling acts as pivotal driver of the early stages of progression in a broad landscape of human malignancies. The endothelin-1 (ET-1) receptors (ET-1R), known as ETA receptor (ETAR) and ETB receptor (ETBR) that belong to the GPCR superfamily, affect both cancer initiation and progression in a variety of cancer types. By the cross-talking with multiple signaling pathways mainly through the scaffold protein β-arrestin1 (β-arr1), ET-1R axis cooperates with an array of molecular determinants, including transcription factors and co-factors, strongly affecting tumor cell fate and behavior. In this scenario, recent findings shed light on the interplay between ET-1 and the Hippo pathway. In ETAR highly expressing tumors ET-1 axis induces the de-phosphorylation and nuclear accumulation of the Hippo pathway downstream effectors, the paralogous transcriptional cofactors Yes-associated protein (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ). Recent evidence have discovered that ET-1R/β-arr1 axis instigates a transcriptional interplay involving YAP and mutant p53 proteins, which share a common gene signature and cooperate in a oncogenic signaling network. Mechanistically, YAP and mutp53 are enrolled in nuclear complexes that turn on a highly selective YAP/mutp53-dependent transcriptional response. Notably, ET-1R blockade by the FDA approved dual ET-1 receptor antagonist macitentan interferes with ET-1R/YAP/mutp53 signaling interplay, through the simultaneous suppression of YAP and mutp53 functions, hampering metastasis and therapy resistance. Based on these evidences, we aim to review the recent findings linking the GPCR signaling, as for ET-1R, to YAP/TAZ signaling, underlining the clinical relevance of the blockade of such signaling network in the tumor and microenvironmental contexts. In particular, we debate the clinical implications regarding the use of dual ET-1R antagonists to blunt gain of function activity of mutant p53 proteins and thereby considering them as a potential therapeutic option for mutant p53 cancers. The identification of ET-1R/β-arr1-intertwined and bi-directional signaling pathways as targetable vulnerabilities, may open new therapeutic approaches able to disable the ET-1R-orchestrated YAP/mutp53 signaling network in both tumor and stromal cells and concurrently sensitizes to high-efficacy combined therapeutics.
Heterogeneous constitutional mismatch repair deficiency with MSH6 missense mutation clinically benefits from pembrolizumab and regorafenib combination therapy: a case report and literature review
Authors: Xie Tong , Feng Qin , Li Zhongwu , Lu Ming , Li Jian , Lizaso Analyn , Xiang Jianxing , Zhang Lu , Shen Lin , Peng Zhi
Published: January 2021

Background

Germline DNA mismatch repair (MMR) gene aberrations are associated with colorectal cancer (CRC) predisposition and high tumor mutation burden (TMB-H), with increased likelihood of favorable response to immune checkpoint inhibitors (ICIs).

Case presentation

We present a 32-year old male patient diagnosed with constitutional MMR deficiency (CMMRD) CRC whose MMR immunohistochemistry (IHC) revealed inconsistent results from two tumor blocks. Targeted sequencing of two tumor specimens used in MMR-IHC and plasma-derived circulating tumor DNA consistently revealed the detection of bi-allelic germline MSH6 c.3226C > T (p.R1076C) mutation, TMB-H as well as the genetic heterogeneity of the tumor samples. Unexpectedly, both blocks were microsatellite stable (MSS) after PCR confirmation. Interestingly, the patient failed to show response to ICI monotherapy or dual therapy, but clinically benefitted from combined therapy of ICI pembrolizumab plus multi-kinase inhibitor regorafenib.

Conclusion

Our case reported a CMMRD patient with heterogeneous MMR results who showed complicated response to ICIs, highlighting the importance of accurate diagnosis using targeted sequencing with multiple specimens to reveal the possible mechanism of response to ICI in patients with CMMRD.
Integration of human cell lines gene expression and chemical properties of drugs for Drug Induced Liver Injury prediction
Authors: Lesiński Wojciech , Mnich Krzysztof , Golińska Agnieszka Kitlas , Rudnicki Witold R.
Published: January 2021

Motivation

Drug-induced liver injury (DILI) is one of the primary problems in drug development. Early prediction of DILI can bring a significant reduction in the cost of clinical trials. In this work we examined whether occurrence of DILI can be predicted using gene expression profile in cancer cell lines and chemical properties of drugs.

Methods

We used gene expression profiles from 13 human cell lines, as well as molecular properties of drugs to build Machine Learning models of DILI. To this end, we have used a robust cross-validated protocol based on feature selection and Random Forest algorithm. In this protocol we first identify the most informative variables and then use them to build predictive models. The models are first built using data from single cell lines, and chemical properties. Then they are integrated using Super Learner method with several underlying methods for integration. The entire modelling process is performed using nested cross-validation.

Results

We have obtained weakly predictive ML models when using either molecular descriptors, or some individual cell lines (AUC ∈(0.55−0.61)). Models obtained with the Super Learner approach have a significantly improved accuracy (AUC=0.73), which allows to divide substances in two categories: low-risk and high-risk.
Why call it developmental bias when it is just development?
Authors: Salazar-Ciudad Isaac
Published: January 2021

The concept of developmental constraints has been central to understand the role of development in morphological evolution. Developmental constraints are classically defined as biases imposed by development on the distribution of morphological variation.

This opinion article argues that the concepts of developmental constraints and developmental biases do not accurately represent the role of development in evolution. The concept of developmental constraints was coined to oppose the view that natural selection is all-capable and to highlight the importance of development for understanding evolution. In the modern synthesis, natural selection was seen as the main factor determining the direction of morphological evolution. For that to be the case, morphological variation needs to be isotropic (i.e. equally possible in all directions). The proponents of the developmental constraint concept argued that development makes that some morphological variation is more likely than other (i.e. variation is not isotropic), and that, thus, development constraints evolution by precluding natural selection from being all-capable.

This article adds to the idea that development is not compatible with the isotropic expectation by arguing that, in fact, it could not be otherwise: there is no actual reason to expect that development could lead to isotropic morphological variation. It is then argued that, since the isotropic expectation is untenable, the role of development in evolution should not be understood as a departure from such an expectation. The role of development in evolution should be described in an exclusively positive way, as the process determining which directions of morphological variation are possible, instead of negatively, as a process precluding the existence of morphological variation we have no actual reason to expect.

This article discusses that this change of perspective is not a mere question of semantics: it leads to a different interpretation of the studies on developmental constraints and to a different research program in evolution and development. This program does not ask whether development constrains evolution. Instead it asks questions such as, for example, how different types of development lead to different types of morphological variation and, together with natural selection, determine the directions in which different lineages evolve.
Geographical distribution of Gyrodactylus salaris Malmberg, 1957 (Monogenea, Gyrodactylidae)
Authors: Paladini Giuseppe , Shinn Andrew P. , Taylor Nicholas G. H. , Bron James E. , Hansen Haakon
Published: January 2021

Background

Gyrodactylus salaris Malmberg, 1957 is an OIE (Office International des Epizooties)-listed parasitic pathogen and had until the current study been reported from 19 countries across Europe, although many of these records require confirmation. The last comprehensive evaluation regarding the distribution of G. salaris, however, was made in 2007, although some of the states identified as being G. salaris-positive were ascribed this status based on misidentifications, on partial data resulting from either morphological or molecular tests, or from records that have not been revisited since their early reporting. It is thus important to go through the reports on G. salaris to obtain a status for each country.

Methods

To provide a revised update of the G. salaris distribution, a literature review was necessary. This literature, however, was not always readily accessible and, in certain cases, the article only made superficial reference to the parasite without providing details or data to support the identification. In most cases, the original specimens were not deposited in a national collection. Additional Gyrodactylus material for the current study was obtained from selected salmonid populations with the aim to contribute to current understanding regarding the distribution of G. salaris. Additional parasite material collected for this study was processed following standard procedures for species identification in Gyrodactylus [1].

Results

From the work conducted in the current study, G. salaris is reported from a further three regions in Italy, alongside three other species, and appears to occur extensively throughout central Italy without causing significant mortalities to its rainbow trout, Oncorhynchus mykiss (Walbaum), host. The analysis of archive material from G. salaris-positive farms would suggest that G. salaris has been in this country since at least 2000. Material obtained from rainbow trout from Finland and Germany are confirmed as G. salaris, supporting existing data for these countries. No specimens of G. salaris, however, were found in the additional Gyrodactylus material obtained from rainbow trout reared in Portugal and Spain. A morphologically similar species, Gyrodactylus teuchis Lautraite, Blanc, Thiery, Daniel et Vigneulle, 1999, however, was found.

Conclusions

Following the present review, Gyrodactylus salaris is reported from 23 out of 50 recognised states throughout Europe; only records from 14 of these states have been confirmed by either morphology and/or by an appropriate molecular test and are considered valid, while only nine of these records have been confirmed by a combination of both methods.

Graphical Abstract