bluuebunny/crossref_metadata_2025 huggingface dataset:
Species comparison: human and minipig PBMC reactivity under the influence of immunomodulating compounds in vitro
Authors: Pernold Clara P. S. , Lagumdzic Emil , Stadler Maria , Dolezal Marlies , Jäckel Sven , Schmitt Michael W. , Mair Kerstin H. , Saalmüller Armin
Published: January 2024

Considering the similarities between swine and humans, it is a logical consequence to use swine as a translational model in research and drug development, including non-clinical safety. Here, we compared the reactivity of peripheral blood mononuclear cells (PBMCs) from humans and minipigs under the influence of different compounds in vitro. We conducted a flow cytometry-based proliferation assay that focused on the T-cell response to three different stimuli: concanavalin A (ConA), phytohemagglutinin-L (PHA-L), and staphylococcal Enterotoxin B (SEB). Furthermore, four approved immunosuppressive drugs—abatacept, belatacept, rapamycin, and tofacitinib—which are used for the treatment of rheumatoid arthritis or rejection in transplant recipients, were combined with the different stimuli. This allowed us to study the effect of suppressive drugs in comparison with the different stimuli in both species. We examined proliferating T cells (CD3+) and investigated the presence of TCR-αβ+ and TCR-γδ+ T cells. Differences in the response of T cells of the two species under these various conditions were evident. CD4+ T cells were more activated within humans, whereas CD8+ T cells were generally more abundant in swine. The effectiveness of the used humanized antibodies is most likely related to the conserved structure of CTLA-4 as abatacept induced a much stronger reduction in swine compared with belatacept. The reduction of proliferation of rapamycin and tofacitinib was highly dependent on the used stimuli. We further investigated the effect of the immunosuppressive compounds on antigen-specific restimulation of pigs immunized against porcine circovirus 2 (PCV2). Treatment with all four compounds resulted in a clear reduction of the proliferative response, with rapamycin showing the strongest effect. In conclusion, our findings indicate that the effectiveness of suppressive compounds is highly dependent on the stimuli used and must be carefully selected to ensure accurate results. The results highlight the importance of considering the response of T cells in different species when evaluating the potential of an immunomodulatory drug.
Impact of sea level rise on tidal energy budget in a macro-tidal coastal bay with archipelago
Authors: Lu Chengzhi , Zhang Fan , Jia Jianjun , Wang Ya Ping
Published: January 2024

With sea level rise (SLR), tidal nuisance flooding has become a growing threat, especially around estuaries with large tidal amplitudes. This study investigated how sea level change affects tides in Hangzhou Bay, a macro-tidal estuary with high SLR rate. By downscaling climate projections to a regional hydrodynamic model, the amplitude of primary tidal constituent (M2) was predicted to increase by 0.25 m in the upper bay, where the amplitude of major diurnal tide (K1) was also predicted to increase by 15%. In addition, the sensitivity of tidal amplitude to mean sea level was examined by a set of numerical simulations with different SLR. It was found that the increase of tidal amplitude is nonlinear to SLR, and the tidal amplitudes almost cease to increase when SLR is over 1.5 m. Although predictions show less amplitude changes in the lower bay, Zhoushan Archipelago around the bay mouth strongly modulates the incoming tidal energy, thus affecting the tidal amplitude in the upper bay. Energy budget analysis revealed that the complex topography, such as narrow channels, in the archipelago area leads to strong horizontal shear, which dissipates approximately 25% of total tidal energy in the bay. On the other hand, around 60% of the energy is dissipated in the bottom boundary layer. However, the bottom dissipation decreases by 4% due to reduced friction, while horizontal dissipation increases by 10% due to enhanced horizontal shear with SLR. This suggests that the strong horizontal shear in the Zhoushan archipelago region can play a more important role in the tidal energy budget in the future.
Gestational age at birth in pregnancies with antenatal corticosteroid administration in relation to risk factors: a retrospective cohort study
Authors: Graf Joachim , Abele Harald , Pauluschke-Fröhlich Jan
Published: January 2024

Background

The aim was to investigate gestational age at birth of women after induction of fetal lung maturation (antenatal corticosteroids = ACS) because of imminent preterm birth (PTB), and to quantify incidence of late PTB (gestational age < 260 days) and extreme immaturity (gestational age < 196 days) in relation to several diagnoses (PPROM, placental bleeding, premature labor, preeclampsia, oligohydramnios, amniotic infection syndrome (AIS), cervical insufficiency) and risk factors (age > 35, history of preterm delivery, multifetal gestation, gestational diabetes, hypertension, nicotine abuse).

Methods

The study was designed as a retrospective cohort trial, in which the data of all births taking place in 2016 in the German federal state Rhineland-Palatinate were evaluated. Frequency analyses, subgroup analysis (Chi-square tests and Friedman’s tests), as well as multinomial logistic regressions and linear regressions were used to determine odds ratios (OR).

Results

In total, N = 1,544 patients were included who had been hospitalized due to an imminent PTB and had received ACS, of whom 52% had a late PTB and 8% a PTB with extreme immaturity. Regarding the gestational age at birth, there were only minor differences between the individual risk factors and diagnoses, only AIS patients showed a significantly lower gestational age (mean: 207 days). A significantly increased risk of PTB with extreme immaturity was found in patients with AIS (OR = 5.57) or placental bleeding (OR = 2.10).

Conclusion

There is a need for further research in order to be able to apply therapeutic measures more accurately in relation to risk factors and diagnoses.
Prediction model for elevated intraocular pressure risk after silicone oil filling based on clinical features
Authors: Fan Wen , Zhang Chaohe , Ge Lexin , Su Na , Chen Jiaqin , Song Siyao , Wang Yasha , Yuan Songtao
Published: January 2024

Background

To evaluate risk factors and further develop prediction models for intraocular pressure elevation (IOP) after vitreoretinal surgery with silicone oil tamponade to support clinical management.

Methods

A retrospective study analyzed 1,061 eyes of 1,061 consecutive patients that presented to the Jiangsu Province Hospital between December 2015 and December 2020, the IOP was measured from the preoperative visit and at the 1-week, 1-month, 3-month, and 6-month visits, and the final postoperative visit before silicone oil removal. Four machine learning methods were used to carried out the prediction of IOP elevation: Decision Tree, Logistic Regression, Random Forest, and Gradient-Boosted Decision Trees (GBDT) based on features including demographic and clinical characteristics, preoperative factors and surgical factors. Predictors were selected based on the p-value of the univariate analysis.

Results

Elevated intraocular pressure developed in 26.01% of the eyes postoperatively. Elevated intraocular pressure primarily occurred within 1–2 weeks after surgery. Additionally, the majority of IOP values were distributed around 25–40 mmHg. GBDT utilizing features with p-values less than 0.5 from the hypothesis testing demonstrated the best predictive performance for 0.7944 in accuracy. The analysis revealed that age, sex, hypertension, diabetes, myopia, retinal detachment, lens status and biological parameters have predictive value.

Conclusion

Age, sex, hypertension, diabetes, myopia, retinal detachment, lens status and biological parameters have influence on postoperative intraocular pressure elevation for patients with silicone oil tamponade after pars plana vitrectomy. The prediction model showed promising accuracy for the occurrence of IOP elevation. This may have some reference significance for reducing the incidence of high intraocular pressure after pars plana vitrectomy combined with silicone oil filling.
The dysfunction in intestinal microorganisms and enzyme activity as significant contributors to diarrhea with kidney-yang deficiency syndrome
Authors: Zhou Mengsi , Li Xiaoya , Wang Xuehong , Deng Na , Cai Ying , Tan Zhoujin
Published: January 2024

Object

To investigate the pathogenesis of diarrhea with kidney-yang deficiency syndrome by examining characteristic changes in intestinal microorganisms, enzyme activities, oxidative stress, and metabolism indices.

Methods

Twenty mice were randomly and equally divided into control group (NC) and model group (NM). Mice in NM group received adenine suspension at a dosage of 50 mg/(kg⋅day) by gavage, 0.4 mL/time, once a day for 14 days, and Folium sennae decoction at a dosage of 10 g/(kg⋅day) by gavage, 0.4 mL/time, once a day for 7 days, starting on 8th day. Mice in NC group were administered an equivalent amount of sterile water by gavage once a day for 7 days, and twice a day from the 8th day. After modeling, assessments encompassed microbial culture, organ index calculation, microbial and enzyme activity detection, malondialdehyde (MDA) content determination, superoxide dismutase (SOD) activity, blood biochemical tests, and observation of kidney tissue pathological changes.

Results

The results showed that in NM group, a reduction in the number of Lactobacillus and Bifidobacteria was noted, accompanied by an increase in the number of bacteria and E. coli. Xylanase activity in the intestinal contents and mucosa, protease activity in the intestinal mucosa, and intestinal mucosa microbial activity were diminished. Conversely, the activities of amylase, sucrase, and lactase increased in intestinal mucosa. Additionally, there was an elevation in the level of MDA. Renal tubular dilatation and inflammatory cell infiltration were observed in the renal interstitium.

Conclusion

These dysfunctions in intestinal microorganisms and enzyme activities suggest potential involvement in diarrhea with kidney-yang deficiency syndrome.
Effect of additive cellulase on fermentation quality of whole-plant corn silage ensiling by a Bacillus inoculant and dynamic microbial community analysis
Authors: Liu Xudong , Wang Aifang , Zhu Liqi , Guo Wei , Guo Xiaojun , Zhu Baocheng , Yang Ming
Published: January 2024

Whole-plant corn silage (WPCS) has been widely used as the main roughage for ruminant, which promoted the utilization of corn stover for animal feed production. However, rigid cell wall structure of corn stover limits the fiber digestion and nutrients adsorption of WPCS. This study investigated the effect of adding cellulase on improving the fermentation quality of WPCS ensiling with a Bacillus complex inoculant. With the Bacillus (BA), the lactic acid accumulation in the WPCS was significantly higher than that in control (CK). The additive cellulase (BC) increased the lactic acid content to the highest of 8.2% DW at 60 days, which was significantly higher than that in the CK and BA groups, and it reduced the neutral detergent fiber (NDF) and acid detergent fiber (ADF) contents from 42.5 to 31.7% DW and 28.4 to 20.3% DW, respectively, which were significantly lower than that in the CK and BA groups. The crude protein and starch were not obviously lost. Dynamic microbial community analysis showed that the Bacillus inoculant promoted the lactic acid bacteria (LAB) fermentation, because higher abundance of Lactobacillus as the dominant bacteria was observed in BA group. Although the addition of cellulase slowed the Lactobacillus fermentation, it increased the bacterial community, where potential lignocellulolytic microorganisms and more functional enzymes were observed, thus leading to the significant degradation of NDF and ADF. The results revealed the mechanism behind the degradation of NDF and ADF in corn stover, and also suggested the potential of cellulase for improving the nutritional quality of WPCS.
The addition of discrimination inhibitors stimulations discrimination potential and N2O emissions were linked to predation among microorganisms in long term nitrogen application and straw returning systems
Authors: Jia Chunhua , Zhou Guixiang , Ma Ling , Qiu Xiuwen , Zhang Jiabao , Wang Jingkuan , Zhang Congzhi , Chen Lin , Ma Donghao , Zhao Zhanhui , Xue Zaiqi
Published: January 2024

Introduction

Ammonia oxidizing archaea (AOA) and ammonia oxidizing bacteria (AOB) have been proven to be key microorganisms driving the ammonia oxidation process. However, under different fertilization practices, there is a lack of research on the impact of interaction between predators and AOA or AOB on nitrogen cycling at the multi-trophic level.

Methods

In this study, a network-oriented microscopic culture experiment was established based on four different long-term fertilization practices soils. We used the nitrification inhibitors 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxide-3-oxyl (PTIO) and 3, 4-Dimethylpyrazole phosphate (DMPP) inhibited AOA and AOB, respectively, to explore the impact of interaction between protists and AOA or AOB on nitrogen transformation.

Results

The results showed that long-term nitrogen application promoted the potential nitrification rate (PNR) and nitrous oxide (N2O) emission, and significantly increased the gene abundance of AOB, but had no obvious effect on AOA gene abundance. DMPP significantly reduced N2O emission and PNR, while PTIO had no obvious effect on them. Accordingly, in the multi-trophic microbial network, Cercozoa and Proteobacteria were identified as keystone taxa of protists and AOB, respectively, and were significantly positively correlated with N2O, PNR and nitrate nitrogen. However, Nitrososphaerota archaeon as the keystone species of AOA, had an obvious negative linkage to these indicators. The structural equation model (SEM) showed that AOA and AOB may be competitors to each other. Protists may promote AOB diversity through direct trophic interaction with AOA.

Conclusion

The interaction pattern between protists and ammonia-oxidizing microorganisms significantly affects potential nitrification rate and N2O emission, which has important implications for soil nitrogen cycle.
The role of non-coding RNAs in muscle aging: regulatory mechanisms and therapeutic potential
Authors: Shin Yeo Jin , Kwon Ki-Sun , Suh Yousin , Lee Kwang-Pyo
Published: January 2024

Muscle aging is a complex physiological process that leads to the progressive decline in muscle mass and function, contributing to debilitating conditions in the elderly such as sarcopenia. In recent years, non-coding RNAs (ncRNAs) have been increasingly recognized as major regulators of muscle aging and related cellular processes. Here, we comprehensively review the emerging role of ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), in the regulation of muscle aging. We also discuss how targeting these ncRNAs can be explored for the development of novel interventions to combat age-related muscle decline. The insights provided in this review offer a promising avenue for future research and therapeutic strategies aimed at improving muscle health during aging.
Analysis of muscle synergy and gait kinematics during regain of gait function through rehabilitation in a monoplegic patient
Authors: Ebihara Akira , Hirota Mitsuki , Kumakura Yasuhiro , Nagaoka Masanori
Published: January 2024

Purpose

We conducted muscle synergy and gait analyses in a monoplegic patient whose gait function improved through training, to explore the possibility of using these parameters as indicators of training.

Case presentation

A 49-year-old male had monoplegia of the right lower limb caused by infarction of the left paracentral lobule. After 2 months of training, he was able to walk and returned to work.

Methods

Consecutive analyses were done after admission. Muscle synergy analysis: during walking, surface electromyograms of gluteus maximus, quadriceps femoris, adductor femoris, hamstrings, tibialis anterior, medial/lateral gastrocnemius, and soleus on both sides were recorded and processed for non-negative matrix factorization (NNMF) analysis. Gait analysis: markers were placed at foot, and walking movements were video recorded as changes in position of the markers.

Results

Compared with three muscle synergies detected on the non-paretic side, two muscle synergies were extracted on the paretic side at admission, and the number increased to three and then four with progress in rehabilitation training. Changes in weighting and activity of the muscle synergies were greater on the non-paretic side than on the paretic side. With training, the knee joint flexor and the ankle dorsiflexor activities on the paretic side and the gluteus maximus activity on the non-paretic side increased during swing phase as shown by weight changes of muscle synergies, and gait analysis showed increased knee joint flexion and ankle joint dorsiflexion during swing phase in the paretic limb. On the non-paretic side, however, variability of muscle activity was observed, and three or four muscle synergies were extracted depending on the number of strides analyzed.

Conclusion

The number of muscle synergies is considered to contribute to motor control. Rehabilitation training improves gait by increasing the number of muscle synergies on the paretic side and changing the weights of the muscles constituting the muscle synergies. From the changes on the non-paretic side, we propose the existence of compensatory mechanisms also on the non-paretic side. In muscle synergy analysis, in addition to the filters, the number of strides used in each analysis set has to be examined. This report highlights the issues of NNMF as analytical methods in gait training for stroke patients.
3.0 T multi-parametric MRI reveals metabolic and microstructural abnormalities in the posterior visual pathways in patients with thyroid eye disease
Authors: Luo Lan , Zhang Liling , Huang Huaidong , Guan Jitian , Zhang Xiaolei , Lin Yan , Wu Renhua
Published: January 2024

Introduction

We aim to explore the microstructural and metabolic changes in visual pathways in patients with thyroid eye disease (TED) using 3T multi-parametric MRI.

Methods

Thirty-four TED patients (inactive group = 20; active group = 14; acute group = 18; chronic group = 16) and 12 healthy controls (HC) were recruited from November 2020 to July 2021. Proton magnetic resonance spectroscopy (1H-MRS), glutamate chemical exchange saturation transfer (GluCEST) and diffusion kurtosis imaging (DKI) were performed on 3.0T MR scanner. Data analysis and group comparisons were performed after MR data processing.

Results

As compare to HC group, the levels of total choline (tCh) in optic radiation (OR) in active group ([1.404 ± 0.560] vs. [1.022 ± 0.260]; p < 0.05), together with tCh ([1.415 ± 0.507] vs. [1.022 ± 0.260]; p < 0.05) in OR in acute group were significantly increased. Glutamine (Gln) levels were higher in OR in the chronic group than those in HCs and were positively correlated with the levels of thyroglobulin antibody (TgAb), thyroid peroxidase antibody (TPOAb), free triiodothyronine (FT3) and FT4 in chronic group. Glutamate (Glu) levels by 1H-MRS did not show significant differences between any two groups. Interestingly, MTRasym (3.0 ppm) was higher in OL in inactive group, active group, acute group and chronic group than those in HCs, and was positively correlated with Glu levels in OL in 1H-MRS. Fractional anisotropy (FA) values from DKI in OR in acute group were significantly lower than those in HCs.

Discussion

Our initial study demonstrate that GluCEST performs better than 1H-MRS to monitor Glu alterations in visual pathway in TED patients. Changes of brain glutamine levels in TED patients are closely related to their associated hormones alterations, indicating that disease injury status could be reflected through non-invasive metabolites detection by brain 1H-MRS. FA is the most sensitive DKI index to reveal the visual pathway impairment in TED patients. Altogether, our study revealed that 3T multiparametric MR techniques are useful to demonstrate metabolic and microstructural alterations in visual pathways in TED patients. We found that damage to visual pathways occurs in mild TED cases, which not only offers a new approach to the diagnosis of dysthyroid optic neuropathy, but also demonstrates neuropathy in TED is a gradual and continuous spatio-emporal progression.
Memory consolidation in honey bees is enhanced by down-regulation of Down syndrome cell adhesion molecule and changes its alternative splicing
Authors: Ustaoglu Pinar , McQuarrie David W. J. , Rochet Anthony , Dix Thomas C. , Haussmann Irmgard U. , Arnold Roland , Devaud Jean-Marc , Soller Matthias
Published: January 2024

Down syndrome cell adhesion molecule (Dscam) gene encodes a cell adhesion molecule required for neuronal wiring. A remarkable feature of arthropod Dscam is massive alternative splicing generating thousands of different isoforms from three variable clusters of alternative exons. Dscam expression and diversity arising from alternative splicing have been studied during development, but whether they exert functions in adult brains has not been determined. Here, using honey bees, we find that Dscam expression is critically linked to memory retention as reducing expression by RNAi enhances memory after reward learning in adult worker honey bees. Moreover, alternative splicing of Dscam is altered in all three variable clusters after learning. Since identical Dscam isoforms engage in homophilic interactions, these results suggest a mechanism to alter inclusion of variable exons during memory consolidation to modify neuronal connections for memory retention.
Breakthrough pain among cancer patients at oncology units in Northern Ethiopia; a multi-center study
Authors: Tekie Yohanes , Nigatu Yonas Addisu , Mekonnen Wudie , Berhe Yophtahe Woldegerima
Published: January 2024

Background

Breakthrough cancer pain (BTCP) is a transient exacerbation of pain that affects the length of hospitalization and quality of life of patients. The objective of this study was to determine the prevalence and factors associated with BTCP among cancer patients at oncology units in Northern Ethiopia in 2022.

Methods

A multi-center cross-sectional study was conducted from April to June 2022. After obtaining ethical approval, data were collected prospectively from 424 adult cancer patients admitted to oncology units. Breakthrough cancer pain was assessed by the numeric rating scale. Descriptive and binary logistic regression analyses were performed to determine the factors associated with BTCP. The strength of association was described in adjusted odds ratio (AOR) with 95% confidence intervals and variables with a P-value < 0.05 were considered to have a statistically significant association with BTCP.

Result

The prevalence of BTCP among cancer patients was 41.5%. The factors that were found to be associated with BTCP were colorectal cancer (AOR: 7.7, 95% CI: 1.8, 32.3), lung cancer (AOR: 6.9, 95% CI: 1.9, 26.0), metastasis (AOR: 9.3, 95% CI: 3.0, 29.1), mild background pain (AOR: 7.5, 95% CI: 2.5, 22.6), moderate background pain (AOR: 7.0, 95% CI: 2.2, 23.1), severe background pain (AOR: 7.1, 95% CI: 2.2, 22.8), no analgesics taken for background pain (AOR: 5.1, 95% CI: 2.8, 9.3) and uncontrolled background pain (AOR: 3.3, 95% CI: 1.8, 6.1).

Conclusion

The prevalence of BTCP was high. Colorectal cancer, lung cancer, the presence of metastasis, the presence of background pain, not taking analgesics for background pain, and uncontrolled background pain were significantly associated with BTCP.
Ropeginterferon alfa-2b treatment in a young patient with multi-refractory polycythemia vera and double JAK2 gene mutation: a case report
Authors: Ligia Silvio , Scalzulli Emilia , Carmosino Ida , Palumbo Giovanna , Molinari Maria Chiara , Poggiali Rebecca , Costa Alessandro , Bisegna Maria Laura , Martelli Maurizio , Breccia Massimo
Published: January 2024

This case report presents a 3-year-old female patient initially diagnosed with polycythemia vera (PV) in 2001. The patient exhibited elevated red blood cell (RBC) counts, high hemoglobin (Hb) levels, hyperleukocytosis, and moderate thrombocytosis, with sporadic abdominal pain and significant splenomegaly. Despite various treatments, including phlebotomies, hydroxyurea, and alpha-interferon, the patient struggled to maintain optimal hematocrit levels and experienced persistent symptoms. Subsequent genomic analysis revealed a rare JAK2 G301R mutation alongside the canonical JAK2 V617F mutation, potentially contributing to disease severity. In 2023, the patient started Ropeginterferon alfa-2b, leading to improved hematological parameters and symptom relief. The case underscores the challenges in managing PV, particularly in young patients, and highlights the potential clinical significance of additional JAK2 mutations/variants and the potential benefits of Ropeginterferon alfa-2b in achieving better disease control.
Addition of bevacizumab to EGFR tyrosine kinase inhibitors in advanced NSCLC: an updated systematic review and meta-analysis
Authors: Zheng Haosheng , Qin Xianyu , Zheng Yuzhen , Yang Xingping , Tan Jian , Cai Weijie , He Shiyun , Liao Hongying
Published: January 2024

Background: The synergistic effects of antiangiogenic inhibitor bevacizumab and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) therapy were encouraging in patients with EGFR-mutant advanced NSCLC, though some controversy remains. The specific subgroup of patients who might benefit most from the EGFR-TKI and bevacizumab combination therapy is yet to be determined.

Methods: Randomized clinical trials (RCTs) that had compared the clinical efficacy of EGFR-TKI and bevacizumab combination therapy with EGFR-TKI monotherapy in treating EGFR-mutant advanced NSCLC patients published before 23 December 2022 were searched in the Cochrane, PubMed and Embase. We performed a meta-analysis for the overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events with a grade equal or more than 3 (grade≥3 TRAEs). Subgroup analyses of PFS and OS stratified by clinical characteristics and treatment were conducted.

Results: We included 10 RCTs involving 1520 patients. Compared with EGFR-TKI monotherapy, addition of bevacizumab to EGFR-TKI resulted in a significantly higher PFS (hazard ratio (HR) = 0.74, 95% confidence interval (95% CI): 0.62–0.87)) and ORR (risk ratio (RR) = 1.07, 95% CI: 1.01–1.13). However, no significant difference in OS (HR = 0.96, 95% CI: 0.83–1.12) was noticed. Patients with EGFR-mutant advanced NSCLC receiving combination therapy showed PFS improvement regardless of gender (male or female), Eastern Cooperative Oncology Group performance status (0 or 1), baseline central nervous system (CNS) metastasis (presence or absence) and EGFR mutation type (19del or 21L858R). Subgroup analyses showed that, with the treatment of bevacizumab and EGFR-TKI, patients who ever smoked achieved significantly better OS and PFS benefits (HR = 0.68, 95% CI: 0.48–0.95; HR = 0.59, 95% CI: 0.46–0.74, respectively), and those aged <75 years and the Asian population had significantly prolonged PFS (HR = 0.69, 95% CI: 0.52–0.91; HR = 0.71, 95% CI: 0.58–0.87; respectively). The superiority of EGFR-TKI and bevacizumab combination therapy against EGFR-TKI monotherapy in improving PFS was more significant in the erlotinib regimen subgroup. The risk of grade≥3 TRAEs was remarkably higher in the combination therapy group (HR = 1.73, 95% CI: 1.39–2.16).

Conclusion: Addition of bevacizumab to EGFR-TKI therapy provided significantly better PFS and ORR for EGFR-mutant advanced NSCLC patients, though with higher risk of grade≥3 TRAEs. Patients who ever smoked, aged <75 years, and Asian population might benefit more from the combination regimen.

Systematic Review Registration: This systematic review and meta-analysis was registered in the PROSPERO database (CRD42023401926)
Destabilizing the genome as a therapeutic strategy to enhance response to immune checkpoint blockade: a systematic review of clinical trials evidence from solid and hematological tumors
Authors: Alotaibi Faizah , Alshammari Kanaan , Alotaibi Badi A. , Alsaab Hashem
Published: January 2024

Background: Genomic instability is increased alterations in the genome during cell division and is common among most cancer cells. Genome instability enhances the risk of initial carcinogenic transformation, generating new clones of tumor cells, and increases tumor heterogeneity. Although genome instability contributes to malignancy, it is also an “Achilles’ heel” that constitutes a therapeutically-exploitable weakness—when sufficiently advanced, it can intrinsically reduce tumor cell survival by creating DNA damage and mutation events that overwhelm the capacity of cancer cells to repair those lesions. Furthermore, it can contribute to extrinsic survival-reducing events by generating mutations that encode new immunogenic antigens capable of being recognized by the immune system, particularly when anti-tumor immunity is boosted by immunotherapy drugs. Here, we describe how genome-destabilization can induce immune activation in cancer patients and systematically review the induction of genome instability exploited clinically, in combination with immune checkpoint blockade.

Methods: We performed a systematic review of clinical trials that exploited the combination approach to successfully treat cancers patients. We systematically searched PubMed, Cochrane Central Register of Controlled Trials, Clinicaltrials.gov, and publication from the reference list of related articles. The most relevant inclusion criteria were peer-reviewed clinical trials published in English.

Results: We identified 1,490 studies, among those 164 were clinical trials. A total of 37 clinical trials satisfied the inclusion criteria and were included in the study. The main outcome measurements were overall survival and progression-free survival. The majority of the clinical trials (30 out of 37) showed a significant improvement in patient outcome.

Conclusion: The majority of the included clinical trials reported the efficacy of the concept of targeting DNA repair pathway, in combination with immune checkpoint inhibitors, to create a “ring of synergy” to treat cancer with rational combinations.
Repurposing beta-blockers for combinatory cancer treatment: effects on conventional and immune therapies
Authors: Massalee Rachel , Cao Xuefang
Published: January 2024

Beta-adrenergic receptor signaling regulates cellular processes associated with facilitating tumor cell proliferation and dampening anti-tumor immune response. These cellular processes may lead to compromised tumor control and cancer progression. Based on this ramification, Beta-blockers (BBs) have emerged as a potential treatment by inhibiting beta-adrenergic receptor signaling. This review aimed to investigate the relationship between the use of BBs and tumor progression and treatment response. Therefore, the authors explored several aspects: the potential synergistic relationship of BBs with chemotherapy and immunotherapy in enhancing the effectiveness of chemotherapeutic and immunotherapeutic treatments and their role in boosting endogenous immunity. Further, this review explores the distinctions between the major types of BBs: Non-selective Beta Blockers (NSBBs) and Selective Beta Blockers (SBBs), and their contributions to combinatory cancer treatment. In this review, we presented a perspective interpretation of research findings and future directions. Overall, this review discusses the potential and challenge that BBs present in improving the effectiveness and outcome of cancer treatment.
Contribution of membrane-associated oscillators to biological timing at different timescales
Authors: Stengl Monika , Schneider Anna C.
Published: January 2024

Environmental rhythms such as the daily light-dark cycle selected for endogenous clocks. These clocks predict regular environmental changes and provide the basis for well-timed adaptive homeostasis in physiology and behavior of organisms. Endogenous clocks are oscillators that are based on positive feedforward and negative feedback loops. They generate stable rhythms even under constant conditions. Since even weak interactions between oscillators allow for autonomous synchronization, coupling/synchronization of oscillators provides the basis of self-organized physiological timing. Amongst the most thoroughly researched clocks are the endogenous circadian clock neurons in mammals and insects. They comprise nuclear clockworks of transcriptional/translational feedback loops (TTFL) that generate ∼24 h rhythms in clock gene expression entrained to the environmental day-night cycle. It is generally assumed that this TTFL clockwork drives all circadian oscillations within and between clock cells, being the basis of any circadian rhythm in physiology and behavior of organisms. Instead of the current gene-based hierarchical clock model we provide here a systems view of timing. We suggest that a coupled system of autonomous TTFL and posttranslational feedback loop (PTFL) oscillators/clocks that run at multiple timescales governs adaptive, dynamic homeostasis of physiology and behavior. We focus on mammalian and insect neurons as endogenous oscillators at multiple timescales. We suggest that neuronal plasma membrane-associated signalosomes constitute specific autonomous PTFL clocks that generate localized but interlinked oscillations of membrane potential and intracellular messengers with specific endogenous frequencies. In each clock neuron multiscale interactions of TTFL and PTFL oscillators/clocks form a temporally structured oscillatory network with a common complex frequency-band comprising superimposed multiscale oscillations. Coupling between oscillator/clock neurons provides the next level of complexity of an oscillatory network. This systemic dynamic network of molecular and cellular oscillators/clocks is suggested to form the basis of any physiological homeostasis that cycles through dynamic homeostatic setpoints with a characteristic frequency-band as hallmark. We propose that mechanisms of homeostatic plasticity maintain the stability of these dynamic setpoints, whereas Hebbian plasticity enables switching between setpoints via coupling factors, like biogenic amines and/or neuropeptides. They reprogram the network to a new common frequency, a new dynamic setpoint. Our novel hypothesis is up for experimental challenge.
Elevated tropospheric ozone and crop production: potential negative effects and plant defense mechanisms
Authors: Nowroz Farzana , Hasanuzzaman Mirza , Siddika Ayesha , Parvin Khursheda , Caparros Pedro Garcia , Nahar Kamrun , Prasad P.V. Vara
Published: January 2024

Ozone (O3) levels on Earth are increasing because of anthropogenic activities and natural processes. Ozone enters plants through the leaves, leading to the overgeneration of reactive oxygen species (ROS) in the mesophyll and guard cell walls. ROS can damage chloroplast ultrastructure and block photosynthetic electron transport. Ozone can lead to stomatal closure and alter stomatal conductance, thereby hindering carbon dioxide (CO2) fixation. Ozone-induced leaf chlorosis is common. All of these factors lead to a reduction in photosynthesis under O3 stress. Long-term exposure to high concentrations of O3 disrupts plant physiological processes, including water and nutrient uptake, respiration, and translocation of assimilates and metabolites. As a result, plant growth and reproductive performance are negatively affected. Thus, reduction in crop yield and deterioration of crop quality are the greatest effects of O3 stress on plants. Increased rates of hydrogen peroxide accumulation, lipid peroxidation, and ion leakage are the common indicators of oxidative damage in plants exposed to O3 stress. Ozone disrupts the antioxidant defense system of plants by disturbing enzymatic activity and non-enzymatic antioxidant content. Improving photosynthetic pathways, various physiological processes, antioxidant defense, and phytohormone regulation, which can be achieved through various approaches, have been reported as vital strategies for improving O3 stress tolerance in plants. In plants, O3 stress can be mitigated in several ways. However, improvements in crop management practices, CO2 fertilization, using chemical elicitors, nutrient management, and the selection of tolerant crop varieties have been documented to mitigate O3 stress in different plant species. In this review, the responses of O3-exposed plants are summarized, and different mitigation strategies to decrease O3 stress-induced damage and crop losses are discussed. Further research should be conducted to determine methods to mitigate crop loss, enhance plant antioxidant defenses, modify physiological characteristics, and apply protectants.
CeO2NP priming enhances the seed vigor of alfalfa (Medicago sativa) under salt stress
Authors: Gao Jinzhu , Liu Yanzhi , Zhao Donghao , Ding Yanzhi , Gao Le , Su Xihao , Song Kexiao , He Xueqing
Published: January 2024

Soil salinization is a common environmental problem that seriously threatens crop yield and food security, especially through its impact on seed germination. Nanoparticle priming, an emerging seed treatment method, is receiving increasing attention in improving crop yield and stress resistance. This study used alfalfa seeds as materials to explore the potential benefits of cerium oxide nanoparticle (CeO2NP) priming to promote seed germination and improve salt tolerance. CeO2NPs at concentrations up to 500 mg/L were able to significantly alleviate salt stress in alfalfa seeds (200 mM), with 50 mg/L of CeO2NP having the best effect, significantly (P< 0.05) increasing germination potential (from 4.0% to 51.3%), germination rate (from 10.0% to 62.7%), root length (from 8.3 cm to 23.1 cm), and seedling length (from 9.8 cm to 13.7 cm). Priming treatment significantly (P< 0.05) increased seed water absorption by removing seed hardness and also reducing abscisic acid and jasmonic acid contents to relieve seed dormancy. CeO2NP priming increased α-amylase activity and osmoregulatory substance level, decreased reactive oxygen species and malonaldehyde contents and relative conductivity, and increased catalase enzyme activity. Seed priming regulated carotenoid, zeatin, and plant hormone signal transduction pathways, among other metabolic pathways, while CeO2NP priming additionally promoted the enrichment of α-linolenic acid and diterpenoid hormone metabolic pathways under salt stress. In addition, CeO2NPs enhanced α-amylase activity (by 6.55%) in vitro. The optimal tested concentration (50 mg/L) of CeO2NPs was able to improve the seed vigor, enhance the activity of α-amylase, regulate the osmotic level and endogenous hormone levels, and improve the salt tolerance of alfalfa seeds. This study demonstrates the efficacy of a simple seed treatment strategy that can improve crop stress resistance, which is of great importance for reducing agricultural costs and promoting sustainable agricultural development.
Understanding salinity stress responses in sorghum: exploring genotype variability and salt tolerance mechanisms
Authors: Rajabi Dehnavi Ahmad , Zahedi Morteza , Piernik Agnieszka
Published: January 2024

Salinity, a significant abiotic stressor, adversely affects global plant growth. To address this, monitoring genetic diversity within a plant species germplasm for salt tolerance traits is vital. This study investigates the responses of ten sorghum genotypes to varying salt stress levels (control, 60 mM NaCl, and 120 mM NaCl), aiming to assess genetic diversity. Using a randomized complete block design with three replications and a split-plot arrangement, salt treatments were assigned to main plots, and genotypes were placed in sub-plots. Physiological attributes, including photosynthetic rate, stomatal conductance, CO2 concentration, leaf area index, chlorophyll concentrations, and antioxidant enzyme activity, were measured during the 50% flowering stage. Fresh forage yield was evaluated at the early dough stage, while dry forage yield and sodium/potassium concentrations were determined post-drying. Salinity induced 10–23% and 21–47% reductions in forage fresh yield at 60 mM and 120 mM NaCl, respectively, across sorghum genotypes. Forage dry yield also declined by 11–33% at 60 mM NaCl and 30–58% at 120 mM NaCl. Increased oxidative stress markers, proline, soluble carbohydrates, and antioxidant enzyme activity accompanied salinity. Genotypes exhibited diverse responses, with Payam showing significant chlorophyll and yield reductions at 60 mM NaCl and notable stress indicators at 120 mM NaCl. Pegah and GS4 demonstrated robust osmoregulation. In stress tolerance indices, Sepideh excelled at 60 mM NaCl, while GS4 outperformed at 120 mM NaCl. Pegah demonstrated high tolerance at 120 mM NaCl. Our findings highlight the importance of combating oxidative stress, managing water-related stress, and maintaining ionic homeostasis for sorghum’s salt stress resilience. Key indicators like K/Na ratio, MDA, MSI, SOD, and proline effectively differentiate between tolerant and sensitive genotypes, offering valuable insights for sorghum breeding. Salt-tolerant sorghum genotypes exhibit stable photosynthesis, improved stomatal function, and membrane integrity through efficient osmotic regulation and robust antioxidant enzyme activity. This capability enables them to sustain performance, minimizing final product loss. The results suggest cultivating salt-tolerant sorghum in saline areas for increased sustainable production, with Pegah and GS4 emerging as promising candidates for further testing in salt-affected environments to obtain reliable yield data.
Safety, feasibility, tolerability, and clinical effects of repeated psilocybin dosing combined with non-directive support in the treatment of obsessive-compulsive disorder: protocol for a randomized, waitlist-controlled trial with blinded ratings
Authors: Ching Terence H. W. , Amoroso Lucia , Bohner Calvin , D’Amico Elizabeth , Eilbott Jeffrey , Entezar Tara , Fitzpatrick Madison , Fram Geena , Grazioplene Rachael , Hokanson Jamila , Jankovsky Anastasia , Kichuk Stephen A. , Martins Bradford , Patel Prerana , Schaer Henry , Shnayder Sarah , Witherow Chelsea , Pittenger Christopher , Kelmendi Benjamin
Published: January 2024

Background

To date, few randomized controlled trials of psilocybin with non-directive support exist for obsessive-compulsive disorder (OCD). Results and participant feedback from an interim analysis of an ongoing single-dose trial (NCT03356483) converged on the possibility of administering a higher fixed dose and/or more doses of psilocybin in future trials for presumably greater benefits.

Objectives

This trial aims to evaluate the safety, feasibility, tolerability, and clinical effects of two doses of psilocybin paired with non-directive support in the treatment of OCD. This trial also seeks to examine whether two doses of psilocybin lead to greater OCD symptom reduction than a single dose, and to elucidate psychological mechanisms underlying the effects of psilocybin on OCD.

Design

A randomized (1:1), waitlist-controlled design with blinded ratings will be used to examine the effects of two doses of oral psilocybin paired with non-directive support vs. waitlist control on OCD symptoms. An adaptive dose selection strategy will be implemented (i.e., first dose: 25 mg; second dose: 25 or 30 mg).

Methods and analysis

This single-site trial will enroll 30 adult participants with treatment-refractory OCD. Aside from safety, feasibility, and tolerability metrics, primary outcomes include OCD symptoms assessed on the Yale-Brown Obsessive-Compulsive Scale – Second Edition (Y-BOCS-II). A blinded independent rater will assess primary outcomes at baseline and the primary endpoint at the end of the second dosing week. Participants will be followed up to 12 months post-second dosing. Participants randomized to waitlist will be rescreened after 7 weeks post-randomization, and begin their delayed treatment phase thereafter if still eligible.

Ethics

Written informed consent will be obtained from participants. The institutional review board has approved this trial (protocol v. 1.7; HIC #2000032623).

Discussion

This study seeks to advance our ability to treat refractory OCD, and catalyze future research seeking to optimize the process of psilocybin treatment for OCD through understanding relevant psychological mechanisms.

Clinical trial registration: ClinicalTrials.gov, identifier NCT05370911.
Association between plain water intake and risk of hypertension: longitudinal analyses from the China Health and Nutrition Survey
Authors: Li Shizhen , Xiao Xun , Zhang Xiangyu
Published: January 2024

Objective

This study aimed to investigate the prospective association between plain water intake and the risk of hypertension based on a longitudinal cohort study in China.

Methods

Logistic regression analyses were performed to investigate the association between plain water intake and hypertension. Restricted cubic spline model was use to evaluate non-linear relationship between plain water intake and hypertension. Subgroup analyses and interaction tests were conducted based on age, gender, residence site, educational level and tea consumption.

Results

A total of 3,823 participants (46.5% male) with a mean age of 46.8 years from the China Health and Nutrition Survey (CHNS) were assessed and divided into 4 groups based on plain water intake. There was a decreasing trend of hypertension risk as plain water intake increased. Logistic regression analyses indicated that participants consuming plain water ≥6 cups/day (1 cup ≈ 240 mL) had significantly lower risk of hypertension compared to those consuming ≤1 cup/day, even after adjustments for covariates. Restricted cubic spline curve revealed that participants consuming about 6–8 cups/day were at lower risk for developing hypertension. In subgroup analyses, the results were generally consistent with the main findings in participants who aged less than 60 years, who were male, who attained higher education and who were low tea consumers.

Conclusion

Our findings suggested that there might be a favorable effect of plain water intake on preventing hypertension in a large cohort of Chinese adults from the general population. Drinking adequate amounts of plain water (about 6–8 cups/day) may reduce the risk of hypertension, particularly in the selected population. Further interventional studies are required to investigate the potential effect of increasing plain water intake on blood pressure regulation.