bluuebunny/crossref_metadata_2025 huggingface dataset:
Soluble antigen arrays provide increased efficacy and safety over free peptides for tolerogenic immunotherapy
Authors: Firdessa-Fite Rebuma , Johnson Stephanie N. , Bechi Genzano Camillo , Leon Martin A. , Ku Amy , Ocampo Gonzalez Fernando A. , Milner Joshua D. , Sestak Joshua O. , Berkland Cory , Creusot Remi J.
Published: June 2024

Autoantigen-specific immunotherapy using peptides offers a more targeted approach to treat autoimmune diseases, but clinical implementation has been challenging. We previously showed that multivalent delivery of peptides as soluble antigen arrays (SAgAs) efficiently protects against spontaneous autoimmune diabetes in the non-obese diabetic (NOD) mouse model. Here, we compared the efficacy, safety, and mechanisms of action of SAgAs versus free peptides. SAgAs, but not their corresponding free peptides at equivalent doses, efficiently prevented the development of diabetes. SAgAs increased the frequency of regulatory T cells among peptide-specific T cells or induce their anergy/exhaustion or deletion, depending on the type of SAgA used (hydrolysable (hSAgA) and non-hydrolysable ‘click’ SAgA (cSAgA)) and duration of treatment, whereas their corresponding free peptides induced a more effector phenotype following delayed clonal expansion. Over time, the peptides induced an IgE-independent anaphylactic reaction, the incidence of which was significantly delayed when peptides were in SAgA form rather than in free form. Moreover, the N-terminal modification of peptides with aminooxy or alkyne linkers, which was needed for grafting onto hyaluronic acid to make hSAgA or cSAgA variants, respectively, influenced their stimulatory potency and safety, with alkyne-functionalized peptides being more potent and less anaphylactogenic than aminooxy-functionalized peptides. Immunologic anaphylaxis occurred in NOD mice in a dose-dependent manner but not in C57BL/6 or BALB/c mice; however, its incidence did not correlate with the level of anti-peptide antibodies. We provide evidence that SAgAs significantly improve the efficacy of peptides to induce tolerance and prevent autoimmune diabetes while at the same time reducing their anaphylactogenic potential.
Acid ceramidase expression reduces IFNγ secretion by mouse CD4+ T cells and is crucial for maintaining B-cell numbers in mice
Authors: Mandasari Putri , Hollmann Claudia , Zaidi Rehan-Haider , Löw Samira , Schrama Jann , Wigger Dominik , Schumacher Fabian , Kleuser Burkhard , Beyersdorf Niklas
Published: June 2024

Acid ceramidase (Ac) is a lysosomal enzyme catalyzing the generation of sphingosine from ceramide, and Ac inhibitors are currently being investigated as potential cancer therapeutics. Yet, the role of the Ac in immune responses, particularly anti-viral immunity, is not fully understood. To investigate the impact of Ac expression on various leukocyte populations, we generated a tamoxifen-inducible global knockout mouse model for the Ac (iAc-KO). Following tamoxifen administration to healthy mice, we extracted primary and secondary lymphoid organs from iAc-KO and wild-type (wt) littermates and subsequently performed extensive flow cytometric marker analysis. In addition, we isolated CD4+ T cells from the spleen and lymph nodes for sphingolipid profiling and restimulated them in vitro with Dynabeads™ Mouse T-activator CD3/CD28. Intracellular cytokine expression (FACS staining) was analyzed and secreted cytokines detected in supernatants. To study cell-intrinsic effects, we established an in vitro model for iAc-KO in isolated CD4+ T and B cells. For CD4+ T cells of iAc-KO versus wt mice, we observed reduced Ac activity, an increased ceramide level, and enhanced secretion of IFNγ upon CD3/CD28 costimulation. Moreover, there was a marked reduction in B cell and plasma cell and blast numbers in iAc-KO compared to wt mice. To study cell-intrinsic effects and in line with the 3R principles, we established in vitro cell culture systems for iAc-KO in isolated B and CD4+ T cells. Our findings pinpoint to a key role of the Ac in mature B and antibody-secreting cells and in IFNγ secretion by CD4+ T cells.
Single-cell transcriptomic analysis reveals heterogeneous features of myeloid-derived suppressor cells in newborns
Authors: Yao Meng , Cao Yingjiao , He Juan , Dong Rui , Liu Gaoyu , Chen Yingying , Wang Jun , Zhou Jie
Published: June 2024

The transitory emergence of myeloid-derived suppressor cells (MDSCs) in infants is important for the homeostasis of the immune system in early life. The composition and functional heterogeneity of MDSCs in newborns remain elusive, hampering the understanding of the importance of MDSCs in neonates. In this study, we unraveled the maturation trajectory of polymorphonuclear (PMN)-MDSCs from the peripheral blood of human newborns by performing single-cell RNA sequencing. Results indicated that neonatal PMN-MDSCs differentiated from self-renewal progenitors, antimicrobial PMN-MDSCs, and immunosuppressive PMN-MDSCs to late PMN-MDSCs with reduced antimicrobial capacity. We also established a simple framework to distinguish these distinct stages by CD177 and CXCR2. Importantly, preterm newborns displayed a reduced abundance of classical PMN-MDSCs but increased late PMN-MDSCs, consistent with their higher susceptibility to infections and inflammation. Furthermore, newborn PMN-MDSCs were distinct from those from cancer patients, which displayed minimum expression of genes about antimicrobial capacity. This study indicates that the heterogeneity of PMN-MDSCs is associated with the maturity of human newborns.
Single cell transcriptomic analysis of the canine duodenum in chronic inflammatory enteropathy and health
Authors: Manchester Alison C. , Ammons Dylan T. , Lappin Michael R. , Dow Steven
Published: June 2024

Chronic inflammatory enteropathy (CIE) is a common condition in dogs causing recurrent or persistent gastrointestinal clinical signs. Pathogenesis is thought to involve intestinal mucosal inflammatory infiltrates, but histopathological evaluation of intestinal biopsies from dogs with CIE fails to guide treatment, inform prognosis, or correlate with clinical remission. We employed single-cell RNA sequencing to catalog and compare the diversity of cells present in duodenal mucosal endoscopic biopsies from 3 healthy dogs and 4 dogs with CIE. Through characterization of 35,668 cells, we identified 31 transcriptomically distinct cell populations, including T cells, epithelial cells, and myeloid cells. Both healthy and CIE samples contributed to each cell population. T cells were broadly subdivided into GZMAhigh (putatively annotated as tissue resident) and IL7Rhigh (putatively annotated as non-resident) T cell categories, with evidence of a skewed proportion favoring an increase in the relative proportion of IL7Rhigh T cells in CIE dogs. Among the myeloid cells, neutrophils from CIE samples exhibited inflammatory (SOD2 and IL1A) gene expression signatures. Numerous differentially expressed genes were identified in epithelial cells, with gene set enrichment analysis suggesting enterocytes from CIE dogs may be undergoing stress responses and have altered metabolic properties. Overall, this work reveals the previously unappreciated cellular heterogeneity in canine duodenal mucosa and provides new insights into molecular mechanisms which may contribute to intestinal dysfunction in CIE. The cell type gene signatures developed through this study may also be used to better understand the subtleties of canine intestinal physiology in health and disease.
Cellular succinate metabolism and signaling in inflammation: implications for therapeutic intervention
Authors: Huang Hong , Li Gejing , He Yini , Chen Jing , Yan Jianye , Zhang Qin , Li Liqing , Cai Xiong
Published: June 2024

Succinate, traditionally viewed as a mere intermediate of the tricarboxylic acid (TCA) cycle, has emerged as a critical mediator in inflammation. Disruptions within the TCA cycle lead to an accumulation of succinate in the mitochondrial matrix. This excess succinate subsequently diffuses into the cytosol and is released into the extracellular space. Elevated cytosolic succinate levels stabilize hypoxia-inducible factor-1α by inhibiting prolyl hydroxylases, which enhances inflammatory responses. Notably, succinate also acts extracellularly as a signaling molecule by engaging succinate receptor 1 on immune cells, thus modulating their pro-inflammatory or anti-inflammatory activities. Alterations in succinate levels have been associated with various inflammatory disorders, including rheumatoid arthritis, inflammatory bowel disease, obesity, and atherosclerosis. These associations are primarily due to exaggerated immune cell responses. Given its central role in inflammation, targeting succinate pathways offers promising therapeutic avenues for these diseases. This paper provides an extensive review of succinate’s involvement in inflammatory processes and highlights potential targets for future research and therapeutic possibilities development.
PHE1-based IgG-like antibody platform provides a novel strategy for enhanced T-cell immunotherapy
Authors: Wang Lingbin , Jiang Haojie , Yin Xuying , Liang Tingting , Li Guoming , Ding Chen , Yang Mina , Zhang Lin , Liu Junling , Xu Yanyan
Published: June 2024

Introduction

Bispecific antibodies (BsAbs) can simultaneously target two epitopes of different antigenic targets, bringing possibilities for diversity in antibody drug design and are promising tools for the treatment of cancers and other diseases. T-cell engaging bsAb is an important application of the bispecific antibody, which could promote T cell-mediated tumor cell killing by targeting tumor-associated antigen (TAA) and CD3 at the same time.

Methods

This study comprised antibodies purification, Elisa assay for antigen binding, cytotoxicity assays, T cell activation by flow cytometry in vitro and xenogenic tumor model in vivo.

Results

We present a novel bsAb platform named PHE-Ig technique to promote cognate heavy chain (HC)-light chain (LC) pairing by replacing the CH1/CL regions of different monoclonal antibodies (mAbs) with the natural A and B chains of PHE1 fragment of Integrin β2 based on the knob-in-hole (KIH) technology. We had also verified that PHE-Ig technology can be effectively used as a platform to synthesize different desired bsAbs for T-cell immunotherapy. Especially, BCMA×CD3 PHE-Ig bsAbs exhibited robust anti-multiple myeloma (MM) activity in vitro and in vivo.

Discussion

Moreover, PHE1 domain was further shortened with D14G and R41S mutations, named PHE-S, and the PHE-S-based BCMA×CD3 bsAbs also showed anti BCMA+ tumor effect in vitro and in vivo, bringing more possibilities for the development and optimization of different bsAbs. To sum up, PHE1-based IgG-like antibody platform for bsAb construction provides a novel strategy for enhanced T-cell immunotherapy.
Spring circulation characteristics and formation mechanism in the Beibu Gulf
Authors: Gao Jingsong , Mo Lingqing , Lu Hanfang , Meng Xiaoni , Wu Guidan , Wang Dapeng , Nguyen Kim-Cuong , Hu Baoqing , Tran Anh Tu
Published: June 2024

Spring circulation in the Beibu Gulf remains an underinvestigated research topic. Model results validated by observations reveal that the northern and southern parts of the Beibu Gulf are controlled by an enclosed cyclonic gyre and a cyclonic gyre, respectively, while in the vertical, the circulation at the surface differs from those in the middle and deep layers. Contrary to that of the classical view, the modeled Qiongzhou Strait (QS) current flows eastward during some days in spring. This eastward current has an occurrence proportion of 29.3–55.4%, and its longest duration period is 7~18 d. The average current in the QS in spring is approximately westward except in some typical years. In spring, the northern Beibu Gulf is affected by the cold water mass (CWM), which is depicted by the 12°C and 10°C isolines in strong and weak years, respectively. Sensitivity experiments show that the heat flux is dominant in the northern Beibu Gulf via the effect of the CWM, and the monsoon wind favors the formation of the cyclonic gyre. Conversely, the cyclonic gyre in the southern Beibu Gulf is jointly driven by the monsoon wind and heat flux, with the effect of the monsoon wind being more significant. The current off the northern coast of Vietnam (VNC) can be either northeastward or southwestward in spring in different years. The VNC is mainly controlled by the elevation gradient along the northern coast of Vietnam, and the Coriolis force, horizontal advection, and vertical diffusion also play significant roles. Additionally, the CWM is mainly controlled by the heat flux whereas the monsoon wind plays a secondary role. And the VNC, current in the QS, CWM, and cyclonic gyre jointly affect nutrient distributions in the northern Beibu Gulf.
New clinical insight in amyotrophic lateral sclerosis and innovative clinical development from the non-profit repurposing trial of the old drug guanabenz
Authors: Ambrosini Anna , Dalla Bella Eleonora , Ravasi Maddalena , Melazzini Mario , Lauria Giuseppe
Published: June 2024

Drug repurposing is considered a valid approach to accelerate therapeutic solutions for rare diseases. However, it is not as widely applied as it could be, due to several barriers that discourage both industry and academic institutions from pursuing this path. Herein we present the case of an academic multicentre study that considered the repurposing of the old drug guanabenz as a therapeutic strategy in amyotrophic lateral sclerosis. The difficulties encountered are discussed as an example of the barriers that academics involved in this type of study may face. Although further development of the drug for this target population was hampered for several reasons, the study was successful in many ways. Firstly, because the hypothesis tested was confirmed in a sub-population, leading to alternative innovative solutions that are now under clinical investigation. In addition, the study was informative and provided new insights into the disease, which are now giving new impetus to laboratory research. The message from this example is that even a repurposing study with an old product has the potential to generate innovation and interest from industry partners, provided it is based on a sound rationale, the study design is adequate to ensure meaningful results, and the investigators keep the full clinical development picture in mind.
The trade-off of Vibrio parahaemolyticus between bacteriophage resistance and growth competitiveness
Authors: Zeng Xiuxiu , Liang Shanyan , Dong Jiayi , Gao Guosheng , Hu Yaoren , Sun Yuechao
Published: June 2024

Vibrio parahaemolyticus is a food-borne pathogen, which is often isolated from various seafood products. In this study, two kinds of bacteriophages was isolated from the offshore sediments samples. The anti-phage mutant strain were obtained after seventeen rounds of co-culture of Vibrio parahaemolyticus and mixed bacteriophage, multigroup sequencing was carried out on spontaneous the anti-phage mutant strain and the wild-type strain. We used the Sanger sequencing to verify the accuracy of the mutation sites. Biolog GEN III MicroPlates were used to evaluate the metabolic capacity of wild-type strains and the anti-phage mutant strain. In this study, we found that with flaG gene (slight homology to N terminus of multiple flagellins) mutated, making the bacteriophage unable to absorb to the cell surface of the host. And, the growth competitiveness of the anti-phage mutant strain is lower than the wild-type strain. These results indicated that the fitness cost, including loss of the growth competitiveness, constitutes a barrier to the prevalence of these defense mechanisms. And the selection pressure on different anti-phage strategies depends on the trade-off between mortality imposed by bacteriophages and fitness cost of the defense strategy under the given environmental conditions. In conclusion, this study provides valuable insights into the phage-host interaction and phage resistance in Vibrio parahaemolyticus. Our study provided knowledge for the evolutionary adaption of bacteria against the bacteriophage, which could add more information to understand the phage resistance mechanism before applying in the industry.
Biocontrol of Fusarium head blight in rice using Bacillus velezensis JCK-7158
Authors: Yeo Yu Jeong , Park Ae Ran , Vuong Bien Sy , Kim Jin-Cheol
Published: June 2024

Fusarium head blight (FHB) is a destructive disease caused by several species of Fusarium, such as Fusarium graminearum and F. asiaticum. FHB affects cereal crops, including wheat, barley, and rice, worldwide. Fusarium-infected kernels not only cause reduced yields but also cause quality loss by producing mycotoxins, such as trichothecenes and zearalenone, which are toxic to animals and humans. For decades, chemical fungicides have been used to control FHB because of their convenience and high control efficacy. However, the prolonged use of chemical fungicides has caused adverse effects, including the emergence of drug resistance to pathogens and environmental pollution. Biological control is considered one of the most promising alternatives to chemicals and can be used for integrated management of FHB due to the rare possibility of environment pollution and reduced health risks. In this study, Bacillus velezensis JCK-7158 isolated from rice was selected as an ecofriendly alternative to chemical fungicides for the management of FHB. JCK-7158 produced the extracellular enzymes protease, chitinase, gelatinase, and cellulase; the plant growth hormone indole-3-acetic acid; and the 2,3-butanediol precursor acetoin. Moreover, JCK-7158 exhibited broad antagonistic activity against various phytopathogenic fungi and produced iturin A, surfactin, and volatile substances as active antifungal compounds. It also enhanced the expression of PR1, a known induced resistance marker gene, in transgenic Arabidopsis plants expressing β-glucuronidase (GUS) fused with the PR1 promoter. Under greenhouse conditions, treatments with the culture broth and suspension concentrate formulation of JCK-7158 at a 1,000-fold dilution inhibited the development of FHB by 50 and 66%, respectively. In a field experiment, treatment with the suspension concentrate formulation of JCK-7158 at a 1,000-fold dilution effectively controlled the development of FHB with a control value of 55% and reduced the production of the mycotoxin nivalenol by 40%. Interestingly, treatment with JCK-7158 enhanced the expression of plant defense-related genes in salicylic acid, jasmonic acid, ethylene, and reactive oxygen species (ROS) signaling pathways before and after FHB pathogen inoculation. Taken together, our findings support that JCK-7158 has the potential to serve as a new biocontrol agent for the management of FHB.
Biosynthesis, classification, properties, and applications of Weissella bacteriocins
Authors: Singh Jahnavi Kumari , Devi Palanisamy Bruntha , Reddy G. Bhanuprakash , Jaiswal Amit K. , Kavitake Digambar , Shetty Prathapkumar Halady
Published: June 2024

This review aims to comprehensively chronicle the biosynthesis, classification, properties, and applications of bacteriocins produced by Weissella genus strains, particularly emphasizing their potential benefits in food preservation, human health, and animal productivity. Lactic Acid Bacteria (LAB) are a class of microorganisms well-known for their beneficial role in food fermentation, probiotics, and human health. A notable property of LAB is that they can synthesize antimicrobial peptides known as bacteriocins that exhibit antimicrobial action against both closely related and other bacteria as well. Bacteriocins produced by Weissella spp. are known to exhibit antimicrobial activity against several pathogenic bacteria including food spoilage species, making them highly invaluable for potential application in food preservation and food safety. Importantly, they provide significant health benefits to humans, including combating infections, reducing inflammation, and modulating the gut microbiota. In addition to their applications in food fermentation and probiotics, Weissella bacteriocins show promising prospects in poultry production, processing, and improving animal productivity. Future research should explore the utilization of Weissella bacteriocins in innovative food safety measures and medical applications, emphasizing their potential to combat antibiotic-resistant pathogens, enhance gut microbiota composition and function, and synergize with existing antimicrobial therapies.
Case report: Misdiagnosed orolingual dyskinesia as a consequence of seizures in a chorea-acanthocytosis patient with a novel VPS13A variation from a family with consanguineous marriage
Authors: Wang Mengying , Li Huimin , Zhou Qing , Zhao Qin , Wang Man , Geng Yumei , Kang Huicong
Published: June 2024

Chorea-acanthocytosis (ChAc) is a rare autosomal recessive inherited syndrome with heterogeneous symptoms, which makes it a challenge for early diagnosis. The mutation of VPS13A is considered intimately related to the pathogenesis of ChAc. To date, diverse mutation patterns of VPS13A, consisting of missense, nonsense, and frameshift mutations, have been reported. In this study, we first report a clinical case that was misdiagnosed as epilepsy due to recurrent seizures accompanied by tongue bite for 9 months, which was not rectified until seizures were controlled and involuntary orolingual movements with awareness became prominent and were confirmed to be orolingual dyskinesia. The patient was eventually diagnosed as ChAc based on whole-exome sequencing revealing novel homozygous c.2061dup (frameshift mutation) and c.6796A > T dual mutations in VPS13A. The patient from a family with consanguineous marriage manifested epileptic seizures at onset, including both generalized tonic–clonic seizures and absence but normal long-term electroencephalography, and gradually developed orofacial dyskinesia, including involuntary tongue protrusion, tongue biting and ulcers, involuntary open jaws, occasionally frequent eye blinks, and head swings. The first test of the peripheral blood smear was negative, and repeated checks confirmed an elevated percentage of acanthocytes by 15–21.3%. Structural brain MRI indicated a mildly swollen left hippocampus and parahippocampal gyrus and a progressively decreased volume of the bilateral hippocampus 1 year later, along with atrophy of the head of the caudate nucleus but no progression in 1 year. We deeply analyzed the reasons for long-term misdiagnosis in an effort to achieve a more comprehensive understanding of ChAc, thus facilitating early diagnosis and treatment in future clinical practice.
The efficacy of repetitive transcranial magnetic stimulation in postherpetic neuralgia: a meta-analysis of randomized controlled trials
Authors: Dai Qi , Xu Aihua , Wang Kunpeng , Yang Yang , Shao Yang , Sun Yongxin
Published: June 2024

Purpose

This systematic review and meta-analysis aimed to evaluate the efficacy of repetitive transcranial magnetic stimulation (rTMS) in postherpetic neuralgia (PHN).

Methods

Through an extensive search in four databases until October 2023, we selected five randomized controlled trials adhering to our specific criteria, involving 257 patients in total. For continuous outcomes, the standardized mean difference (SMD) was calculated. Heterogeneity among the studies was assessed using Cochran’s I2 and Q statistics, adopting a random-effects model for I2 values over 50%. For assessing potential publication bias, we utilized both funnel plot and Egger’s test.

Results

Our analysis found that rTMS reduced the overall visual analogue scale (VAS) (SMD: −1.52, 95% CI: −2.81 to −0.23, p = 0.02), VAS at 1 month post-treatment (SMD: −2.21, 95% CI: −4.31 to −0.10, p = 0.04), VAS at 3 months post-treatment (SMD: −1.51, 95% CI: −2.81 to −0.22, p = 0.02), as well as patients’ global impression of change scale (PGIC) (SMD: −1.48, 95% CI: −2.87 to −0.09, p = 0.04) and short-form McGill pain questionnaire (SF-MPQ) (SMD: −1.25, 95% CI: −2.41 to −0.09, p = 0.03) compared to the sham-rTMS group.

Conclusion

Our study suggests that rTMS might have a potential alleviating effect on PHN symptoms. However, due to the limited number of studies and variations in rTMS parameters, larger sample studies involving more diverse populations, as well as further clarification of the most appropriate stimulation protocol, are still needed.

Systematic review registration

https://www.crd.york.ac.uk/prospero/, Identifier ID: CRD42023488420.
Personal risk factors and types of sport associated with drive for thinness and drive for muscularity in NextGen athletes
Authors: Maurin Juliette , Labossière Sophie , Pomerleau-Fontaine Lara , Boudreault Véronique , Brassard Sophie , Dion Jacinthe , Durand-Bush Natalie , Parent Sylvie , Soulard Amélie
Published: June 2024

Introduction

Professional and student-athletes are at risk of developing symptoms of eating disorders (ED), including drive for thinness and muscularity due to personal risk factors (e.g., low self-esteem) and sport-specific characteristics (e.g., sport requirements). However, limited studies have focused on ED symptoms among NextGen athletes (identified in Canada as élite or relève) who compete at the provincial, national, and international levels but are not yet part of national teams. As such, they have access to fewer financial resources and support from their sport federations, which can create additional stress for these athletes. The present study aimed to identify personal risk factors and types of sports associated with (a) drive for thinness and (b) drive for muscularity in NextGen athletes.

Methods

These athletes (n = 254) aged between 14 and 25 years old completed an online questionnaire. Perfectionism, self-esteem in sport, drive for thinness, and drive for muscularity were, respectively, assessed by the Multidimensional Inventory of Perfectionism in Sport, the Sport State Self-Esteem Scale, the Eating Attitude Test-26, and the Drive for Muscularity Scale. Other personal risk factor (e.g., athletic status) were measured using in-house questions. Each personal risk factor was included in two multiple linear regressions, respectively, to determine which factors were most associated with drive for thinness and drive for muscularity.

Results

Analyses revealed that perfectionist aspirations during training were linked to a stronger desire for thinness. In addition, not being in school or not having a job were also linked to a stronger desire for thinness. Several variables were found to be associated with a greater desire for muscularity: being a male athlete, playing team sport, weight category sport or endurance sport (as opposed to esthetic sport), having elite status, being less satisfied with one’s current sporting performance and having higher perfectionist aspirations during training.

Discussion

This study offers initial insights into the factors influencing EDs among NextGen athletes, which provides a foundation for deeper exploration and the creation or modification of targeted interventions. These findings can guide sport organizations in creating guidelines and programs to better support the next generation of national athletes (e.g., create programs to help athletes maintain investments outside).
Enfortumab vedotin–related cutaneous toxicity correlates with overall survival in patients with urothelial cancer: a retrospective experience
Authors: Vlachou Evangelia , Johnson Burles Avner , McConkey David , Jing Yuezhou , Matoso Andres , Hahn Noah M. , Hoffman-Censits Jean
Published: June 2024

Introduction

Enfortumab vedotin (EV) is an antibody drug conjugate approved for advanced urothelial cancer, consisting of a monomethyl auristatin E payload linked to a human monoclonal antibody targeting nectin-4. No validated biomarker predictive of or correlated with response exists for EV. Cutaneous toxicity is among the most common EV-related toxicities and typically emerges in early cycles. This retrospective experience of patients with urothelial cancer treated with EV monotherapy evaluated whether EV-related cutaneous toxicity correlated with improved outcomes including progression-free (PFS) and overall (OS) survival and overall response rate (ORR).

Patients and methods

Patients treated with EV monotherapy at Johns Hopkins were identified, and baseline characteristics, treatment, and toxicity details were extracted through chart review. Univariable Cox hazard ratios (HRs) were calculated for assessing the effect of baseline patient characteristics and cutaneous toxicity in PFS and OS. Based on the univariable analysis and known risk factors, all subsequent analyses were adjusted for: Eastern Cooperative Oncology Group performance status, visceral metastases at baseline, gender as well as EV dose, and weight to account for dosing differences. Multivariable Cox proportional HRs were used for comparing PFS and OS between patients with and without cutaneous toxicity, assessing toxicity and EV dose as a time-dependent variables. Adjusted p-values were calculated to compare ORR and disease control rate (DCR) between groups using the Poisson regression model.

Results

Of the 78 patients analyzed, 42 (53.8%) experienced EV-related cutaneous toxicity that appeared early during treatment (median time to occurrence 0.5 months from EV initiation). Cutaneous toxicity correlated with significantly improved OS [HR, 0.48; 95% confidence interval (CI), 0.25, 0.9; P = 0.0235], ORR (68.3% vs. 20.7%, P = 0.0033) and DCR (82.9% vs. 48.3%, P = 0.0122). Median PFS was numerically longer in the cutaneous toxicity group (6.3 vs. 1.7 months), although no significance was achieved in the multivariable analysis (HR, 0.62; 95% CI: 0.35, 0.108; P = 0.0925).

Conclusion

In this retrospective study, EV-related cutaneous toxicity was associated with improved patient outcomes. Confirming this observation and understanding its mechanism could lead to discovery of a new clinical biomarker of EV response that can emerge in the first cycle.
Challenges and innovations in CAR-T cell therapy: a comprehensive analysis
Authors: Luo Jingming , Zhang Xianwen
Published: June 2024

Recent years have seen a marked increase in research on chimeric antigen receptor T (CAR-T) cells, with specific relevance to the treatment of hematological malignancies. Here, the structural principles, iterative processes, and target selection of CAR-T cells for therapeutic applications are described in detail, as well as the challenges faced in the treatment of solid tumors and hematological malignancies. These challenges include insufficient infiltration of cells, off-target effects, cytokine release syndrome, and tumor lysis syndrome. In addition, directions in the iterative development of CAR-T cell therapy are discussed, including modifications of CAR-T cell structures, improvements in specificity using multi-targets and novel targets, the use of Boolean logic gates to minimize off-target effects and control toxicity, and the adoption of additional protection mechanisms to improve the durability of CAR-T cell treatment. This review provides ideas and strategies for the development of CAR-T cell therapy through an in-depth exploration of the underlying mechanisms of action of CAR-T cells and their potential for innovative modification.
Evaluation of the synergistic effects of curcumin-resveratrol co-loaded biogenic silica on colorectal cancer cells
Authors: Ochoa-Sanchez Adriana , Sahare Padmavati , Pathak Surajit , Banerjee Antara , Estevez Miriam , Duttaroy Asim K. , Luna-Bárcenas Gabriel , Paul Sujay
Published: June 2024

Colorectal cancer (CRC) remains a significant global health concern, being the third most diagnosed cancer in men and the second most diagnosed cancer in women, with alarming mortality rates. Natural phytochemicals have gained prominence among various therapeutic avenues explored due to their diverse biological properties. Curcumin, extracted from turmeric, and resveratrol, a polyphenol found in several plants, have exhibited remarkable anticancer activities. However, their limited solubility and bioavailability hinder their therapeutic efficacy. To enhance the bioavailability of these compounds, nanomaterials work as effective carriers with biogenic silica (BS) attracting major attention owing to their exceptional biocompatibility and high specific surface area. In this study, we developed Curcumin-resveratrol-loaded BS (Cur-Res-BS) and investigated their effects on colorectal cancer cell lines (HCT-116 and Caco-2). Our results demonstrated significant concentration-dependent inhibition of cell viability in HCT-116 cells and revealed a complex interplay of crucial proto-onco or tumor suppressor genes, such as TP53, Bax, Wnt-1, and CTNNB1, which are commonly dysregulated in colorectal cancer. Notably, Cur-Res-BS exhibited a synergistic impact on key signaling pathways related to colorectal carcinogenesis. While these findings are promising, further investigations are essential to comprehensively understand the mechanisms and optimize the therapeutic strategy. Moreover, rigorous safety assessments and in vitro studies mimicking the in vivo environment are imperative before advancing to in vivo experiments, ensuring the potential of Cur-Res-BS as an efficient treatment for CRC.
A phase I, randomized study to evaluate the safety, tolerability, and pharmacokinetics of mefunidone in healthy subjects
Authors: Han Mai , Huo Bishan , Hu Gaoyun , Zhang Xin , Cui Gang , Wu Wei , Mi Na , Zhang Shixi , Jin Jiangli , Lu Xing , Wu Bidong , Xiao Chunyan , Wang Jing , Bian Zheng , Li Jintong
Published: June 2024

Background

Mefunidone is a novel synthetic compound and is better when compared to pirfenidone for the anti-fibrotic treatment of renal fibrosis in end-stage renal disease. We conducted this first-in-human, phase I clinical trial to determine the safety, tolerability, and pharmacokinetic (PK) (including food effect) profiles of mefunidone administered orally as single and multiple ascending doses in healthy subjects.

Methods

Part A assessed single ascending doses of mefunidone from 25 mg to 800 mg or placebo once daily in the fasting state. Part A also assessed the effect of food on tolerability and PK in the 100 mg cohort. Part B consisted of three treatment groups who received 100 mg, 200 mg, or 400 mg of mefunidone or placebo twice daily (BID, bis in die) on days 1–6 and once in the morning on day 7.

Results

Single oral doses of mefunidone up to 800 mg and multiple doses of mefunidone up to 400 mg BID were all well-tolerated. Mefunidone behaved with ideal dose proportionality within the single-dose range of 50 mg–600 mg and the multiple-dose range of 100 mg BID to 400 mg BID by day 7. High-fat fed conditions led to a delay in Tmax by approximately 1 h and a slight reduction of approximately 20% in Cmax compared to that in fasting conditions, but it did not significantly affect systemic exposure.

Conclusion

Mefunidone exhibited favorable pharmacokinetics and safety profiles. The present study informed and supported further developmental clinical studies of mefunidone.

Clinical Trial Registration

clinicaltrials.gov, identifier CXHL1900206
Prompt gamma energy integration: a new method for online-range verification in proton therapy with pulsed-beams
Authors: Everaere Pierre , Dauvergne Denis , Gallin-Martel Marie-Laure , Hérault Joël , Koudia Ayoub , Koumeir Charbel , Létang Jean Michel , Testa Étienne
Published: June 2024

Introduction: We propose a method for prompt-gamma verification of proton range during particle therapy, called Prompt-Gamma Energy Integration (PGEI).

Method: This method is based on the measurement of the total energy deposited in a set of detectors located around a patient. It is particularly suited in the case of high-instantaneous beam intensities, like for pulsed beams extracted from a synchro-cyclotron. GATE simuations were used to evaluate the sensitivity, and dedicated scintillators were tested as a function of beam intensity.

Results and discussion: Simulations show that millimetric range shifts can be measured at a beam-spot scale. The sensitivity is slightly degraded as compared to the Prompt-Gamma Peak Integration Method, for which Time-of-Flight can be employed to reduce the background in single-photon detection conditions at cyclotron accelerators. Experimentally, lead tungstate scintillators have shown to cope with the high instantaneous gamma count rates for PGEI at synchro-cyclotrons.
Gestational intermittent hypoxia reduces mandibular growth with decreased Sox9 expression and increased Hif1a expression in male offspring rats
Authors: Suzuki Takumi , Hosomichi Jun , Maeda Hideyuki , Ishida Yuji , Usumi-Fujita Risa , Moro Manaka , Jariyatheerawong Korkuan , Ono Takashi
Published: June 2024

Introduction

Maternal obstructive sleep apnea (OSA) during pregnancy is the risk factor for impaired fetal growth with low birth weight in the offspring. However, it is unclear whether gestational intermittent hypoxia (IH, a hallmark of maternal OSA) has long-term detrimental consequences on the skeletal development of offspring. This study aimed to investigate postnatal maxillofacial bone growth and cartilage metabolism in male and female offspring that were exposed to gestational IH.

Methods

Mother rats underwent IH at 20 cycles/h (nadir, 4% O2; peak, 21% O2; 0% CO2) for 8 h per day during gestational days (GD) 7–20, and their male and female offspring were analyzed postnatally at 5 and 10 weeks of age. All male and female offspring were born and raised under normoxic conditions.

Results

There was no significant difference in whole-body weight and tibial length between the IH male/female offspring and their control counterparts. In contrast, the mandibular condylar length was significantly shorter in the IH male offspring than in the control male offspring at 5 and 10 weeks of age, while there was no significant difference in the female offspring. Real-time polymerase chain reaction (PCR) showed that gestational IH significantly downregulated the mRNA level of SOX9 (a chondrogenesis marker) and upregulated the mRNA level of HIF-1α (a hypoxia-inducible factor marker) in the mandibular condylar cartilage of male offspring, but not in female offspring.

Conclusion

Gestational IH induced underdeveloped mandibular ramus/condyles and reduced mRNA expression of SOX9, while enhancing mRNA expression of HIF-1α in a sex-dependent manner.
Automatic classification of fetal heart rate based on a multi-scale LSTM network
Authors: Rao Lin , Lu Jia , Wu Hai-Rong , Zhao Shu , Lu Bang-Chun , Li Hong
Published: June 2024

Introduction

Fetal heart rate monitoring during labor can aid healthcare professionals in identifying alterations in the heart rate pattern. However, discrepancies in guidelines and obstetrician expertise present challenges in interpreting fetal heart rate, including failure to acknowledge findings or misinterpretation. Artificial intelligence has the potential to support obstetricians in diagnosing abnormal fetal heart rates.

Methods

Employ preprocessing techniques to mitigate the effects of missing signals and artifacts on the model, utilize data augmentation methods to address data imbalance. Introduce a multi-scale long short-term memory neural network trained with a variety of time-scale data for automatically classifying fetal heart rate. Carried out experimental on both single and multi-scale models.

Results

The results indicate that multi-scale LSTM models outperform regular LSTM models in various performance metrics. Specifically, in the single models tested, the model with a sampling rate of 10 exhibited the highest classification accuracy. The model achieves an accuracy of 85.73%, a specificity of 85.32%, and a precision of 85.53% on CTU-UHB dataset. Furthermore, the area under the receiver operating curve of 0.918 suggests that our model demonstrates a high level of credibility.

Discussion

Compared to previous research, our methodology exhibits superior performance across various evaluation metrics. By incorporating alternative sampling rates into the model, we observed improvements in all performance indicators, including ACC (85.73% vs. 83.28%), SP (85.32% vs. 82.47%), PR (85.53% vs. 82.84%), recall (86.13% vs. 84.09%), F1-score (85.79% vs. 83.42%), and AUC(0.9180 vs. 0.8667). The limitations of this research include the limited consideration of pregnant women’s clinical characteristics and disregard the potential impact of varying gestational weeks.
The role of O-GlcNAcylation in bone metabolic diseases
Authors: Yang Yajing , Zhou Xuchang , Deng HuiLi , Chen Li , Zhang Xiaolin , Wu Song , Song Aiqun , Liang Fengxia
Published: June 2024

O-GlcNAcylation, as a post-translational modification, can modulate cellular activities such as kinase activity, transcription-translation, protein degradation, and insulin signaling by affecting the function of the protein substrate, including cellular localization of proteins, protein stability, and protein/protein interactions. Accumulating evidence suggests that dysregulation of O-GlcNAcylation is associated with disease progression such as cancer, neurodegeneration, and diabetes. Recent studies suggest that O-GlcNAcylation is also involved in the regulation of osteoblast, osteoclast and chondrocyte differentiation, which is closely related to the initiation and development of bone metabolic diseases such as osteoporosis, arthritis and osteosarcoma. However, the potential mechanisms by which O-GlcNAcylation regulates bone metabolism are not fully understood. In this paper, the literature related to the regulation of bone metabolism by O-GlcNAcylation was summarized to provide new potential therapeutic strategies for the treatment of orthopedic diseases such as arthritis and osteoporosis.
Exploring regulatory network of icariin synthesis in Herba Epimedii through integrated omics analysis
Authors: Zhu Xuedong , Wen Shiqi , Gul Hameed , Xu Pan , Yang Yang , Liao Ximei , Ye Yunling , Xu Zijian , Zhang Xiaofang , Wu Lin
Published: June 2024

Herba Epimedii’s leaves are highly valued in traditional Chinese medicine for their substantial concentration of flavonoids, which play a crucial role in manifesting the plant’s therapeutic properties. This study investigated the metabolomic, transcriptomic and proteomic profiles of leaves from two Herba Epimedii cultivars, Epipremnum sagittatum (J) and Epipremnum pubescens (R), at three different developmental stages. Metabolite identification and analysis revealed a total of 1,412 and 1,421 metabolites with known structures were found. Flavonoids made up of 33%, including 10 significant accumulated icariin analogues. Transcriptomic analysis unveiled totally 41,644 differentially expressed genes (DEGs) containing five encoded genes participated in icariin biosynthesis pathways. Totally, 9,745 differentially expressed proteins (DEPs) were found, including Cluster-47248.2.p1 (UDP-glucuronosy/UDP-glucosyltransferase), Cluster-30441.2.p1 (O-glucosyltransferase), and Cluster-28344.9.p1 (anthocyanidin 3-O-glucoside 2 “-O-glucosyltransferase-like) through proteomics analysis which are involved to icariin biosynthesis. Protein-protein interaction (PPI) assay exhibited, totally 12 proteins showing a strong relationship of false discovery rate (FDR) <0.05 with these three proteins containing 2 leucine-rich repeat receptor kinase-like protein SRF7, and 5 methyl jasmonate esterase 1. Multi-omics connection networks uncovered 237 DEGs and 72 DEPs exhibited significant associations with the 10 icariin analogues. Overall, our integrated omics approach provides comprehensive insights into the regulatory network underlying icariin synthesis in Herba Epimedii, offering valuable resources for further research and development in medicinal plant cultivation and pharmaceutical applications.
Effects of gold and copper mining on the structure and diversity of the surrounding plant communities in Northeast Tiger and Leopard National Park
Authors: Wang Xue , Li Yue , Bai Xueyuan , Sheng Lianxi , Zhang Houling , Chen Faping , Xiao Yujun , Liu Wenze , Zhai Yuquan
Published: June 2024

Introduction

Northeast China Tiger and Leopard National Park is home to the largest and only breeding family of wild tigers and leopards in China. The mining of open-pit gold and copper mines in the core zone might affect the surrounding forest ecosystem and the survival activities of wild tigers and leopards.

Methods

In order to understand the impacts of gold and copper mining on the structure and diversities of the surrounding plant communities, the vegetation of the forest layer, shrub layer and herb layer of the forest community in the original forest area, mining area, tailings area and restoration area of the Northeast China Tiger and Leopard National Park were investigated, and the influence of plant community structure on species diversity was also evaluated.

Results

This study concluded that there are 25 species belonging to 11 families, 16 genera of trees, 43 species belonging to 22 families, 35 genera of shrubs, and 57 species belonging to 23 families, 46 genera of herb in the sampling sites. There were no significant differences in the community structure characteristics and species diversities of the tree layer and the shrub layer in different operational areas. However, in herb layer, the heights, the coverage and the species diversity index were higher in the restoration area. Additionally, the community structure was one of the major factors that influence the diversity indices, which might be an important way for mining to impact plant diversity.

Discussion

Therefore, mining had some impacts on the structure and diversity of the surrounding plant communities, but the impacts did not reach a significant level. These results could provide scientific support for the management of the forest ecosystems around the mining area of Northeast Tiger and Leopard Park.
Unraveling the mechanism of flower color variation in Brassica napus by integrated metabolome and transcriptome analyses
Authors: Cui Cheng , Zhang Ka , Chai Liang , Zheng Benchuan , Zhang Jinfang , Jiang Jun , Tan Chen , Li Haojie , Chen Daozong , Jiang Liangcai
Published: June 2024

Brassica napus is one of the most important oil crops in the world. Breeding oilseed rape with colorful flowers can greatly enhance the ornamental value of B. napus and thus improve the economic benefits of planting. As water-soluble flavonoid secondary metabolites, anthocyanins are very important for the synthesis and accumulation of pigments in the petals of plants, giving them a wide range of bright colors. Despite the documentation of over 60 distinct flower shades in B. napus, the intricacies underlying flower color variation remain elusive. Particularly, the mechanisms driving color development across varying flower color backgrounds necessitate further comprehensive investigation. This research undertook a comprehensive exploration through the integration of transcriptome and metabolome analyses to pinpoint pivotal genes and metabolites underpinning an array of flower colors, including beige, beige-red, yellow, orange-red, deep orange-red, white, light-purple, and purple. First, we used a two-way BLAST search to find 275 genes in the reference genome of B. napus Darmor v10 that were involved in making anthocyanins. The subsequent scrutiny of RNA-seq outcomes underscored notable upregulation in the structural genes F3H and UGT, alongside the MYB75, GL3, and TTG1 transcriptional regulators within petals, showing anthocyanin accumulation. By synergizing this data with a weighted gene co-expression network analysis, we identified CHS, F3H, MYB75, MYB12, and MYB111 as the key players driving anthocyanin synthesis in beige-red, orange-red, deep orange-red, light-purple, and purple petals. By integrating transcriptome and weighted gene co-expression network analysis findings with anthocyanin metabolism data, it is hypothesized that the upregulation of MYB75, which, in turn, enhances F3H expression, plays a pivotal role in the development of pigmented oilseed rape flowers. These findings help to understand the transcriptional regulation of anthocyanin biosynthesis in B. napus and provide valuable genetic resources for breeding B. napus varieties with novel flower colors.