bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of characteristics and outcomes on ETP-ALL/LBL and non-ETP ALL patients receiving allogeneic hematopoietic stem cell transplantation
Authors: Chen Juan , Liu Li , Ma Runzhi , Pang Aiming , Yang Donglin , Chen Xin , Wei Jialin , He Yi , Zhang Rongli , Zhai Weihua , Ma Qiaoling , Jiang Erlie , Han Mingzhe , Feng Sizhou
Published: January 2023

Objective

This study aims to compare the characteristics of early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) and non-ETP ALL patients and the outcomes of these patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Method

A total of 57 patients with T-cell acute lymphoblastic leukemia/lymphoma receiving allo-HSCT at our center between January 2016 and March 2022 were enrolled in the study. Twenty-eight patients were diagnosed as ETP-ALL/LBL (28/57, 49.12%) in the cohort.

Results

The baseline characteristic was not significantly different between the two groups. The median time for myeloid engraftment was 14 days (ranged from 11 to 21) versus 14 days (ranged from 10 to 20) (P = 0.067) and 18 days (ranged from 12 to 27) versus 15.5 days (ranged from 12 to 72) (P = 0.183) for platelet engraftment in the ETP-ALL/LBL and non-ETP ALL groups, respectively. There was no significant difference in 5-year overall survival (54.74% ± 10.33% vs. 64.20% ± 10.30%, P = 0.786), relapse-free survival (56.22% ± 10.11% vs. 57.17% ± 12.71%, P = 0.841), cumulative incidence of relapse (30.14% ± 9.85% vs. 22.79% ± 8.24%, P = 0.774), and non-relapse mortality (19.52% ± 8.99% vs. 25.95% ± 14.44%, P = 0.967) between the two groups. The incidence of acute graft versus host disease (aGVHD) (P = 0.922), II–IV aGVHD (P = 0.940), III–IV aGVHD (P = 0.664), cytomegalovirus infection (P = 0.862), Epstein–Barr virus infection (P = 0.610), and severe bacterial infection (P = 0.145) was also similar.

Conclusion

The prognosis of patients with ETP-ALL/LBL was similar to non-ETP ALL patients when they received allo-HSCT.
Superior survival for breast-conserving therapy over mastectomy in patients with breast cancer: A population-based SEER database analysis across 30 years
Authors: Ke Shanbao , Wang Wei , Li Baiyu , Feng Xiao , Yan Danfang , Liu Jianbo
Published: January 2023

Introduction

It has been believed that breast-conserving therapy (lumpectomy plus adjuvant radiation, Lum + RT) and mastectomy without radiation (Mast + NoRT) have equivalent survival outcomes. However, there is a need to re-evaluate the role of lumpectomy plus adjuvant radiation due to changed breast cancer management over time. This study aimed to conduct a population-based study that compare long-term oncologic survival outcomes after Lum + RT vs Mast + NoRT.

Methods

The Surveillance, Epidemiology and End Results database was used to identify female breast cancer patients with a primary localized breast cancer diagnosis from 1988 to 2018. The standardized incidence/mortality ratio (SIR/SMR) for breast cancer recurrence (BCR) and breast cancer-specific death (BSD) was estimated by the SEER*Stat program. Cumulative incidences of BCR and BSD were assessed using Gray’s method. We evaluated the effects of Lum + RT vs. Mast + NoRT on breast cancer recurrence-free survival (BRFS) and breast cancer-specific survival (BCSS). Fine-Gray competing risk model analyses, propensity score-adjusted Kaplan-Meier analyses and Cox proportional hazards model analyses were applied.

Results

A total of 205,788 women were included in the study. Patients who underwent Lum + RT had higher SIR of BCR (4.14 [95% confidence interval, CI: 3.94-4.34] vs. 1.11 [95% CI: 1.07-1.14]) and lower SMR (9.89 [95% CI: 9.71-10.08] vs. 17.07 [95% CI: 16.82-17.33]) than patients who underwent Mast + NoRT. Lum + RT was associated with higher competing risk of BCR (adjusted hazard ratio [HR]: 1.996, 95% CI: 1.925-2.069, p < 0.001) and lower competing risk of BSD when compared to Mast + RT (adjusted HR: 0.584, 95% CI: 0.572-0.597, p < 0.001). Multivariate Cox regression analysis revealed similar results (adjusted HR after PSW for BRFS: 1.792, 95% CI 1.716-1.871, p < 0.001; adjusted HR after PSW for BCSS: 0.706, 95% CI 0.688-0.725, p < 0.001). These findings persisted in the sensitivity and subgroup analyses.

Discussion

The present study further confirmed superior long-term survival with lumpectomy plus adjuvant radiation over mastectomy independent of patient characteristics including age, race, time period, historic subtype, tumor size, historic grade and stage, indicating that this benefit may result from the treatment itself.
The function of natural compounds in important anticancer mechanisms
Authors: Nan Yang , Su Hongchan , Zhou Bo , Liu Shumin
Published: January 2023

The existence of malignant tumors has been a threat to human life, health, and safety. Although the rapid development of radiotherapy, drug therapy, surgery, and local therapy has improved the quality of life of tumor patients, there are still some risks. Natural compounds are widely used in cancer because they are easy to obtain, have a good curative effects and have no obvious side effects, and play a vital role in the prevention and treatment of various cancers. Phenolic, flavonoids, terpenoids, alkaloids, and other natural components of traditional Chinese medicine have certain anti-tumor activities, which can promote apoptosis, anti-proliferation, anti-metastasis, inhibit angiogenesis, change the morphology of cancer cells and regulate immune function, etc., and have positive effects on breast cancer, liver cancer, lung cancer, gastric cancer, rectal cancer and so on. To better understand the effects of natural compounds on cancer, this paper screened out four important pathways closely related to cancer, including cell death and immunogenic cell death, immune cells in the tumor microenvironment, inflammation and related pathways and tumor metastasis, and systematically elaborated the effects of natural compounds on cancer.
Tissue distribution of ethanol after intraprostatic injection using a porous needle
Authors: Eubank Megan N. , Švihra Ján , DiBona Kevin C. , Sommers Matthew , Oe Tyler , Strnádel Ján , Miklušica Juraj , Szépe Peter , Marcinek Juraj , King Benjamin J. , Plante Mark K. , Ľupták Ján , Poulsen Mads Hvid Aaberg , Kida Masatoshi , Baco Eduard , Švihra Ján , Zvara Peter
Published: January 2023

Purpose

To develop a safe and precise method for intraprostatic injection, and to establish correlation between the volume of ethanol injectate and the volume of subsequent infiltrated prostate tissue.

Materials and methods

We performed intraprostatic injection of 96% ethanol using a needle which has a segment of its wall made of capillary membrane with hundreds of pores in an acute and chronic canine experiment, in heart-beating cadaveric organ donors, and in a xenograft model of human prostate cancer. Whole mount tissue sections were used for three-dimensional reconstruction of the necrotic lesions and calculation of their volumes.

Results

The ethanol injection resulted in oval shaped lesions of well-delineated coagulative necrosis. In both healthy human and canine prostates, the prostatic pseudocapsule and neurovascular bundle remained intact without evidence of disruption. There was a linear correlation between administered volume of ethanol and the volume of necrotic lesion. Regression analysis showed strong correlation in the acute canine experiments and in experiments performed on xenografts of human prostate cancer. A formula was calculated for each experiment to estimate the relationship between the injected volume and the volume of infiltrated prostate tissue area.

Conclusions

Intraprostatic injection using a porous needle allows for effective and predictable tissue distribution of the injectate in the prostate. Through varying the volume of the agent injected and use of needles with a different length of the porous segment, the volume of infiltrated tissue could be adjusted allowing for targeted focal treatment.
Role of Notch2 pathway in mature B cell malignancies
Authors: Mesini Nicolò , Fiorcari Stefania , Atene Claudio Giacinto , Maffei Rossana , Potenza Leonardo , Luppi Mario , Marasca Roberto
Published: January 2023

In recent decades, the Notch pathway has been characterized as a key regulatory signaling of cell-fate decisions evolutionarily conserved in many organisms and different tissues during lifespan. At the same time, many studies suggest a link between alterations of this signaling and tumor genesis or progression. In lymphopoiesis, the Notch pathway plays a fundamental role in the correct differentiation of T and B cells, but its deregulated activity leads to leukemic onset and evolution. Notch and its ligands Delta/Jagged exhibit a pivotal role in the crosstalk between leukemic cells and their environment. This review is focused in particular on Notch2 receptor activity. Members of Notch2 pathway have been reported to be mutated in Chronic Lymphocytic Leukemia (CLL), Splenic Marginal Zone Lymphoma (SMZL) and Nodal Marginal Zone Lymphoma (NMZL). CLL is a B cell malignancy in which leukemic clones establish supportive crosstalk with non-malignant cells of the tumor microenvironment to grow, survive, and resist even the new generation of drugs. SMZL and NMZL are indolent B cell neoplasms distinguished by a distinct pattern of dissemination. In SMZL leukemic cells affect mainly the spleen, bone marrow, and peripheral blood, while NMZL has a leading nodal distribution. Since Notch2 is involved in the commitment of leukemic cells to the marginal zone as a major regulator of B cell physiological differentiation, it is predominantly affected by the molecular lesions found in both SMZL and NMZL. In light of these findings, a better understanding of the Notch receptor family pathogenic role, in particular Notch2, is desirable because it is still incomplete, not only in the physiological development of B lymphocytes but also in leukemia progression and resistance. Several therapeutic strategies capable of interfering with Notch signaling, such as monoclonal antibodies, enzyme or complex inhibitors, are being analyzed. To avoid the unwanted multiple “on target” toxicity encountered during the systemic inhibition of Notch signaling, the study of an appropriate pharmaceutical formulation is a pressing need. This is why, to date, there are still no Notch-targeted therapies approved. An accurate analysis of the Notch pathway could be useful to drive the discovery of new therapeutic targets and the development of more effective therapies.
Lysine specific demethylase 1 is a molecular driver and therapeutic target in sarcoma
Authors: Dreher Rachel D. , Theisen Emily R.
Published: January 2023

Sarcomas are a diverse group of tumors with numerous oncogenic drivers, and display varied clinical behaviors and prognoses. This complexity makes diagnosis and the development of new and effective treatments challenging. An incomplete understanding of both cell of origin and the biological drivers of sarcomas complicates efforts to develop clinically relevant model systems and find new molecular targets. Notably, the histone lysine specific demethylase 1 (LSD1) is overexpressed in a number of different sarcomas and is a potential therapeutic target in these malignancies. With the ability to modify histone marks, LSD1 is a key player in many protein complexes that epigenetically regulate gene expression. It is a largely context dependent enzyme, having vastly different and often opposing roles depending on the cellular environment and which interaction partners are involved. LSD1 has been implicated in the development of many different types of cancer, but its role in bone and soft tissue sarcomas remains poorly understood. In this review, we compiled what is known about the LSD1 function in various sarcomas, to determine where knowledge is lacking and to find what theme emerge to characterize how LSD1 is a key molecular driver in bone and soft tissue sarcoma. We further discuss the current clinical landscape for the development of LSD1 inhibitors and where sarcomas have been included in early clinical trials.
Contribution of natural killer cells in innate immunity against colorectal cancer
Authors: Ghazvinian Zeinab , Abdolahi Shahrokh , Tokhanbigli Samaneh , Tarzemani Shadi , Piccin Andrea , Reza Zali Mohammad , Verdi Javad , Baghaei Kaveh
Published: January 2023

Natural killer cells are members of the innate immune system and promote cytotoxic activity against tumor or infected cells independently from MHC recognition. NK cells are modulated by the expression of activator/inhibitory receptors. The ratio of this activator/inhibitory receptors is responsible for the cytotoxic activity of NK cells toward the target cells. Owing to the potent anti-tumor properties of NK cells, they are considered as interesting approach in tumor treatment. Colorectal cancer (CRC) is the second most common cause of death in the world and the incidence is about 2 million new cases per year. Metastatic CRC is accompanied by a poor prognosis with less than three years of overall survival. Chemotherapy and surgery are the most adopted treatments. Besides, targeted therapy and immune checkpoint blockade are novel approach to CRC treatment. In these patients, circulating NK cells are a prognostic marker. The main target of CRC immune cell therapy is to improve the tumor cell’s recognition and elimination by immune cells. Adaptive NK cell therapy is the milestone to achieve the purpose. Allogeneic NK cell therapy has been widely investigated within clinical trials. In this review, we focus on the NK related approaches including CAR NK cells, cell-based vaccines, monoclonal antibodies and immunomodulatory drugs against CRC tumoral cells.
Multiple primary malignant neoplasm: Case report and comprehensive literature review
Authors: Ma Xue-Yan , Tian Kun , Sun Peng-Fei
Published: January 2023

Multiple primary tumors, especially quadruple primary tumors, are extremely rare clinically, and there is no standard protocol for clinical management. We described a case in which a bone tumor, a malignant bladder tumor, a malignant melanoma, and an intrahepatic cholangiocarcinoma were all original malignancies. The patient is a 79-year-old woman who underwent surgery for a left middle finger bone tumor 45 years ago, as well as surgery for bladder malignancy and postoperative adjuvant chemotherapy 15 years ago, and the precise pathological results and treatment are unclear. One year ago, she underwent amputation of the toe due to a black mass of the right toe and was diagnosed pathologically as a freckled malignant melanoma of the extremity. Prior to postoperative adjuvant systemic medication, PET/CT revealed malignancy in the lateral segment of the left lobe of the liver, and multiple lymphadenopathies in the left parotid gland, hilar hepatic, and retroperitoneal region. Intrahepatic cholangiocarcinoma was found in the liver puncture biopsy’s pathology report. The serum sample’s next-generation sequencing (NGS) revealed a missense mutation, designated P.G12V, in exon 2 of the KRAS gene. Based on patients with malignant melanoma and intrahepatic cholangiocarcinoma, she received 6 cycles of GP (gemcitabine/cisplatin) combined with Camrelizumab systemic therapy, and followed by 3 cycles of Camrelizumab maintenance therapy, the efficacy was evaluated as stable disease (SD) during treatment. When the 4th cycle of Camrelizumab was suggested for maintenance therapy, the efficacy evaluation revealed that the tumor had greatly advanced. The patient refused to continue anti-tumor therapy and passed away from septic shock and multiple organ failure 3 months later. The patient had satisfactory efficacy and lived for a year after being diagnosed with two primary cancers. Despite the rarity of quadruple primary tumors and the lack of a conventional clinical management strategy, we postulate that germline mutations in the KRAS gene may be closely associated with the formation and development of multiple primary tumors. NGS testing is necessary for clinical management, and systemic treatment based on concurrent multiple main tumors is the key to improving prognosis.
Reverse translation of artificial intelligence in glaucoma: Connecting basic science with clinical applications
Authors: Ma Da , Pasquale Louis R. , Girard Michaël J. A. , Leung Christopher K. S. , Jia Yali , Sarunic Marinko V. , Sappington Rebecca M. , Chan Kevin C.
Published: January 2023

Artificial intelligence (AI) has been approved for biomedical research in diverse areas from bedside clinical studies to benchtop basic scientific research. For ophthalmic research, in particular glaucoma, AI applications are rapidly growing for potential clinical translation given the vast data available and the introduction of federated learning. Conversely, AI for basic science remains limited despite its useful power in providing mechanistic insight. In this perspective, we discuss recent progress, opportunities, and challenges in the application of AI in glaucoma for scientific discoveries. Specifically, we focus on the research paradigm of reverse translation, in which clinical data are first used for patient-centered hypothesis generation followed by transitioning into basic science studies for hypothesis validation. We elaborate on several distinctive areas of research opportunities for reverse translation of AI in glaucoma including disease risk and progression prediction, pathology characterization, and sub-phenotype identification. We conclude with current challenges and future opportunities for AI research in basic science for glaucoma such as inter-species diversity, AI model generalizability and explainability, as well as AI applications using advanced ocular imaging and genomic data.
Clinical and laboratory features of childhood-onset primary Sjögren's syndrome: A retrospective study from China
Authors: Liu Chenxi , Jin Yingying , Huang Hua , Ding Fei , Xu Xuemei , Bao Shengfang , Yang Zhen , Jin Yanliang
Published: January 2023

Introduction

The initial presentations of childhood-onset primary Sjögren’s syndrome (C-pSS) vary, making diagnosis challenging. We aimed to improve the diagnosis and evaluation of C-pSS by summarizing its clinical and laboratory features.

Methods

A total of 49 patients with C-pSS between July 2015 and August 2022 in the Department of Rheumatology and Immunology of Shanghai Children's Medical Centre were enrolled in this study. Their clinical manifestations and laboratory examinations of these patients were compared based on the presence or absence of thrombocytopenia and parotitis and whether the immunological markers, including anti-nuclear antibodies (ANA), rheumatoid factor (RF), anti-Ro52/SSA antibodies (anti-SSA/Ro52), anti-Ro60/SSA antibodies (anti-SSA/Ro60), and anti-Ro/SSB antibodies (anti-SSB), were positive.

Results

The mean age at C-pSS diagnosis was 10.34 ± 3.45 years, and the ratio of boys to girls was 1:6. In the thrombocytopenia group, parotitis (P = 0.044), organ involvement except for hematology (P = 0.002), positive anti-SSB (P = 0.004), and positive RF (P = 0.001) were less frequently observed. Complement C4 (P = 0.038) and white blood cells (P = 0.002) levels decreased and increased significantly, respectively. Anti-SSB (P = 0.010) and RF (P = 0.004) positivity were independent potential protective factors against thrombocytopenia in patients with C-pSS. In the parotitis group, higher ANA titers (P = 0.027), higher focus scores on labial gland biopsy (P = 0.024), and positive RF (P = 0.001), anti-SSA/Ro60 (P = 0.003), and anti-SSB (P = 0.001) were observed more frequently. Furthermore, positive anti-SSB (P = 0.012) and positive RF (P = 0.028) were independent risk factors for parotitis in patients with C-pSS. The hemoglobin level was significantly lower in patients with positive anti-SSA/Ro52 and positive anti-SSA/Ro60 results (P = 0.022 and P = 0.029, respectively), while immunoglobulin G level was significantly higher in patients in the same group (P = 0.048 and P = 0.007, respectively).

Conclusions

Positive anti-SSB and positive RF values may be independent potential protective factors of thrombocytopenia in patients with C-pSS. In contrast, positive anti-SSB and positive RF were independent risk factors of parotitis in patients with C-pSS. More studies are needed to reveal the diagnostic role and pathogenic mechanism of immunological markers in C-pSS.
Risk factors for anesthesia-associated postoperative capillary leakage after thoracoscopic surgery in neonates: A single-center observational study
Authors: Liu Heqi , Wang Fang , Zhang Jianmin , Gao Zhengzheng
Published: January 2023

Background

Thoracoscopy is considered the surgical method of choice for addressing a wide range of conditions in neonates. However, there is a lack of experience in anesthesia management for this procedure. On reviewing the newborns who had undergone thoracoscopic surgery at our medical center, some had developed edema after surgery. After excluding other etiologies, these neonates were diagnosed with capillary leakage secondary to thoracoscopy.

Aims

This study aimed to identify the potential risk factors for capillary leakage secondary to thoracoscopy in neonates and to provide reference information for optimal anesthesia management.

Methods

This single-center, retrospective, observational study examined neonates who had undergone thoracoscopic surgery between January 1, 2018, and September 31, 2021. Their electronic medical records were analyzed for demographic and clinical characteristics associated with anesthesia, and postoperative capillary leakage occurring within 24 and 48 h of surgery was assessed based on medical records.

Results

A total of 56 neonates that underwent thoracoscopic surgery were included in this study. Postoperative capillary leakage within 24 h was diagnosed in 14 neonates (25%). The partial pressure of carbon dioxide was an independent factor influencing the occurrence of postoperative edema within 24 h (P = 0.021). Overall, 21 cases (37.5%) were diagnosed as postoperative capillary leakage within 48 h, and age was an independent factor influencing the occurrence of postoperative edema within 48 h (P = 0.027).

Conclusions

According to our findings, we concluded that preventing the elevation of the partial pressure of carbon dioxide may reduce the occurrence of secondary capillary leakage within 24 h after thoracoscopic surgery, and that older newborns are less likely to have secondary capillary leakage within 48 h after thoracoscopic surgery. Our findings provide evidence that directly informs anesthesia management for thoracoscopic surgery in neonates.

Clinical trial registration

The study was registered in the Chinese Clinical Trial Registry (ChiCTR2100054117).
Effects of bronchoalveolar lavage on Mycoplasma Pneumoniae pneumonia: A propensity score matched-cohort study
Authors: Lu Jinmiao , Zhang Junqi , Wang Guangfei , Zhang Xiaobo , Li Zhiping
Published: January 2023

Background

The purpose of this study was to evaluate the efficacy and safety of BAL in treating MPP.

Methods

From January 2013 to January 2019, 1,689 pediatric patients with MPP were analyzed retrospectively. Patients were subdivided into BAL group and non-BAL group according to whether they received BAL treatment within seven days after admission. The propensity score matching method matched patients' baseline characteristics (1:1). The primary outcomes were hospital stays and the cure rate. Secondary outcomes included mortality, co-infection, repeat hospitalization within 30 days, and total cost of treatment.

Results

After matching, 524 patients (BAL: 262; control: 262) were recorded. The BAL group had significantly shorter hospital stays (OR: 0.5, 95% CI: 0.4–0.7). Meanwhile, BAL did not significantly modify the cost, co-infection rate, and mortality. In subgroup analyses, the group with BAL intervention within three days had a significantly shorter hospital stay (OR: 0.4, 95% CI: 0.3–0.5) compared with the group with BAL intervention three days after admission.

Conclusions

Early BAL intervention is a better treatment than conventional drug therapy alone, and no significant complications were seen in this study. BAL intervention has an excellent clinical benefit. The earlier the intervention, the better the effect.
Bibliometric and visualized analysis of sodium–Glucose cotransporter 2 inhibitors
Authors: Sun He , Wang Zhongqing , Wang Yuxi , Rong Haichuan , Wang Danyang , Liu Xiangnian , Jin Ke , Sun Zhicheng , Fan Qiuling
Published: January 2023

Background: Sodium—glucose cotransporter 2 inhibitors have proved to be extremely effective and reliable in reducing hyperglycemia, and have also been used for the treatment of cardiovascular and renal disease in patients with or without type 2 diabetes. Thousands of research articles on SGLT2 inhibitors have been published in the past, but few bibliometric analyses have systematically been studied this field. We aimed to visualize the global research hotspots and trends of SGLT2 inhibitors using a bibliometric analysis to provide new evidence and ideas for researchers and clinicians in this field.

Methods: We retrieved publications from Science Citation Index Expanded of Web of Science Core Collection in 2004–2022 on 1 July 2022. Microsoft Excel, CiteSpace and VOSviewer were employed to collect publication data, analyze publication trends, and visualize relevant results.

Results: We identified 4,419 original research articles on SGLT2 inhibitors published between 2004 and the first half of 2022. Global SGLT2 inhibitors-related research increased rapidly from 2004 to 2022, especially recently. United States made the greatest contribution to the topic, with (1,629, 36.86%) publications and citations (88,892). AstraZeneca was the most prolific institutions (272, 6.16%). Heerspink HJL published the most related articles (98), whereas Zinman B was cited the most frequently (1,784 citations). Diabetes Obesity and Metabolism was the journal with the most studies (406, 9.19%), and The New England Journal of Medicine was the most commonly cited journal (11,617 citations), with nine of the top 10 co-cited references published in this journal. The emerging keywords “heart failure,” “diabetic cardiomyopathy,” “ejection fraction,” “mortality,” “biomarker,” “fibrosis,” “ampk,” and “guideline” appeared the most recently as research frontiers.

Conclusion: United States is the leader in SGLT2 inhibitor research. Recently, the research on SGLT2 inhibitors has focused on clinical trials, related mechanisms, and therapy. In the future, the research on SGLT2 inhibitors will delve into molecular mechanisms, especially those related to fibrosis and AMPK, revealing the link between SGLT2 inhibitors and heart failure and diabetic cardiomyopathy will be the next research hotspot.
Identification of kinases activated by multiple pro-angiogenic growth factors
Authors: Gruver Scott , Rata Scott , Peshkin Leonid , Kirschner Marc W.
Published: January 2023

Antiangiogenic therapy began as an effort to inhibit VEGF signaling, which was thought to be the sole factor driving tumor angiogenesis. It has become clear that there are more pro-angiogenic growth factors that can substitute for VEGF during tumor vascularization. This has led to the development of multi-kinase inhibitors which simultaneously target multiple growth factor receptors. These inhibitors perform better than monotherapies yet to date no multi-kinase inhibitor targets all receptors known to be involved in pro-angiogenic signaling and resistance inevitably occurs. Given the large number of pro-angiogenic growth factors identified, it may be impossible to simultaneously target all pro-angiogenic growth factor receptors. Here we search for kinase targets, some which may be intracellularly localized, that are critical in endothelial cell proliferation irrespective of the growth factor used. We develop a quantitative endothelial cell proliferation assay and combine it with “kinome regression” or KIR, a recently developed method capable of identifying kinases that influence a quantitative phenotype. We report the kinases implicated by KIR and provide orthogonal evidence of their importance in endothelial cell proliferation. Our approach may point to a new strategy to develop a more complete anti-angiogenic blockade.
Comparative differences in the risk of major gastrointestinal bleeding among different direct oral anticoagulants: An updated traditional and Bayesian network meta-analysis
Authors: Chen Xiuehui , Wang Lili , Li Huijun , Huang Weichao , Zhao Lingyue , Guo Wenqin
Published: January 2023

Background: The most favorable gastrointestinal (GI) bleeding safety profile among different types of direct oral anticoagulants (DOACs) remains controversial. This meta-analysis includes the latest studies and aims to compare GI bleeding risk associated with the use of various DOACs.

Methods: PubMed, Cochrane library, and clinicaltrial.gov were searched. Randomized control trials (RCTs) evaluating the safety of DOACs were identified. The primary endpoint assessed was major GI bleeding.

Results: A total of 37 RCTs were included in the analyses. Based on the traditional meta-analysis, the major GI bleeding risk was different among various DOACs (interactive p-value <.10). Network meta-analysis findings showed that no DOACs increased the risk of major GI bleeding compared with conventional therapy. Furthermore, a 10 mg daily administration of apixaban reduced the major GI bleeding risk more than daily doses of 60 mg edoxaban, ≥15 mg rivaroxaban, and 300 mg dabigatran etexilate. No difference was observed between daily doses of 300 mg dabigatran etexilate, 60 mg edoxaban, and ≥15 mg rivaroxaban. The major GI bleeding risk associated with 30 mg daily dose of edoxaban was lower than with 10 mg daily rivaroxaban, and no differences between daily 5 mg apixaban, 30 mg edoxaban, and 220 mg dabigatran etexilate were observed.

Conclusion: Differences in the major GI bleeding risk were observed when various DOACs were compared. Among standard-dose DOACs, apixaban was associated with the lowest degree of major GI risk. Among low-dose DOACs, edoxaban was associated with a lower major GI bleeding risk than rivaroxaban.
Necroptotic kinases are involved in the reduction of depression-induced astrocytes and fluoxetine’s inhibitory effects on necroptotic kinases
Authors: Zeb Salman , Ye Huan , Liu Yuan , Du Hua-Ping , Guo Yi , Zhu Yong-Ming , Ni Yong , Zhang Hui-Ling , Xu Yuan
Published: January 2023

The role of astrocytes in major depressive disorder has received great attention. Increasing evidence indicates that decreased astrocyte numbers in the hippocampus may be associated with depression, but the role of necroptosis in depression is unknown. Here, in a chronic unpredictable mild stress (CUMS) mouse model and a corticosterone (Cort)-induced human astrocyte injury model in vitro, we found that mice treated with chronic unpredictable mild stress for 3–5 weeks presented depressive-like behaviors and reduced body weight gain, accompanied by a reduction in astrocytes and a decrease in astrocytic brain-derived neurotropic factors (BDNF), by activation of necroptotic kinases, including RIPK1 (receptor-interacting protein kinase 1)/p-RIPK1, RIPK3 (receptor-interacting protein kinase 3)/p-RIPK3 and MLKL (mixed lineage kinase domain-like protein)/p-MLKL, and by upregulation of inflammatory cytokines in astrocytes of the mouse hippocampus. In contrast, necroptotic kinase inhibitors suppressed Cort-induced necroptotic kinase activation, reduced astrocytes, astrocytic necroptosis and dysfunction, and decreased Cort-mediated inflammatory cytokines in astrocytes. Treatment with fluoxetine (FLX) for 5 weeks improved chronic unpredictable mild stress-induced mouse depressive-like behaviors; simultaneously, fluoxetine inhibited depression-induced necroptotic kinase activation, reversed the reduction in astrocytes and astrocytic necroptosis and dysfunction, decreased inflammatory cytokines and upregulated brain-derived neurotropic factors and 5-HT1A levels. Furthermore, fluoxetine had no direct inhibitory effect on receptor-interacting protein kinase 1 phosphorylation. The combined administration of fluoxetine and necroptotic kinase inhibitors further reduced corticosterone-induced astrocyte injury. In conclusion, the reduction in astrocytes caused by depressive-like models in vivo and in vitro may be associated with the activation of necroptotic kinases and astrocytic necroptosis, and fluoxetine exerts an antidepressive effect by indirectly inhibiting receptor-interacting protein kinase 1-mediated astrocytic necroptosis.
Combination therapy of cisplatin and resveratrol to induce cellular aging in gastric cancer cells: Focusing on oxidative stress, and cell cycle arrest
Authors: Rahimifard Mahban , Baeeri Maryam , Mousavi Taraneh , Azarnezhad Asaad , Haghi-Aminjan Hamed , Abdollahi Mohammad
Published: January 2023

Background: As a medical dilemma, gastric cancer will have 7.3 million new cases in 2040. Despite the disease’s high economic and global burden, conventional chemotherapy regimens containing cisplatin have insufficient effectiveness and act non-specifically, leading to several adverse drug reactions To address these issues, the biological efficacy of the cisplatin-resveratrol combination was tested.

Methods: To find IC50, gastric adenocarcinoma cells (AGS) were exposed to different concentrations of resveratrol and cisplatin. Anti-cancer and anti-metastatic effects of 100 M resveratrol with concentrations of cisplatin (25, 50, and 100 g/ml) were studied by assessing ß-galactosidase and telomerase activities, senescence and migration gene expression, reactive oxygen species (ROS) level, and cell cycle arrest.

Results: Co-administration of cisplatin and resveratrol increased ß-galactosidase activity, ROS level as a key marker of oxidative stress, p53, p38, p16, p21, and MMP-2 gene expression, and induced G0/G1 cell cycle arrest. Additionally, telomerase activity, pro-inflammatory gene expression, and cell invasion were suppressed. The best results were achieved with 100 g/ml cisplatin co-administered with resveratrol.

Conclusion: The current study proved the synergistic effect of the cisplatin-resveratrol combination on suppressing metastasis and inducing apoptosis and cell senescence through targeting P38/P53 and P16/P21 pathways. Such promising results warrant translation to animal models and the clinic. This may lead to cost-effective, available, and accessible treatment regimens with targeted action and the fewest ADRs.
Amelioration of cognitive impairment using epigallocatechin-3-gallate in ovariectomized mice fed a high-fat diet involves remodeling with Prevotella and Bifidobacteriales
Authors: Qu Yang , Wu Yan , Cheng Wei , Wang Dongyang , Zeng Lu , Wang Yanru , Li Tingting , Zhang Liye , Yang Jinan , Sun Liyang , Ai Jing
Published: January 2023

Background: Estrogen deficiency and a high-fat diet (HFD) are both risk factors for Alzheimer’s disease (AD). HFD can accelerate cognitive impairment in estrogen-deficient patients, but there is currently no effective treatment. Epigallocatechin-3-galate (EGCG) is widely studied for its anti-inflammatory, anti-cancer, and anti-neurodegeneration effects. Nevertheless, whether EGCG can ameliorate cognitive impairment in HFD-fed estrogen-deficient mice has not been studied.

Methods and Results: Ovariectomized (OVX) mice fed an HFD (HFOVX) for 8 weeks experienced impaired object recognition and spatial memory, but this damage was significantly attenuated by the administration of EGCG at a dose of 45 mg/kg. Through 16S rRNA gene sequencing, we found that HFOVX changed the diversity and structure of the gut microbiota in mice, which could be restored with EGCG. Further analysis showed that HFOVX exposure not only resulted in a decrease of Alloprevotella in Bacteroidetes, Lactobacillaceae in Firmicutes, and Prevotella in Bacteroidetes but also in an increase of Bifidobacteriales in Actinobacteria. EGCG effectively reversed the decrease of Prevotella and inhibited the increase of Bifidobacteriales but had no effect on the decrease of Alloprevotella or Lactobacillaceae or on the increase of Enterorhabdus in HFOVX mice. Additionally, using Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, we found that EGCG significantly reversed the five functional gut microbiota genes elevated by HFOVX, including iron complex transport system substrate-binding protein, iron complex transport system permease protein, 3-oxoacyl- [acyl-carrier protein] reductase, transketolase, and 8-oxo-dGTP diphosphatase.

Conclusions: We concluded that EGCG improved cognitive impairment in mice with estrogen deficiency exacerbated by an HFD involved a rebuilding of the disrupted gut microbiota composition.
Targeted ferroptotic potency of ferrous oxide nanoparticles-diethyldithiocarbamate nanocomplex on the metastatic liver cancer
Authors: Abu-Serie Marwa M.
Published: January 2023

Existing treatments are frequently ineffective in combating liver cancer (LC) due to its rapid growth, high metastatic potential, and chemoresistance. Thus, inducing ferroptosis, a new non-apoptotic regulated cell death-dependent massive iron overload-mediated lipid peroxidation, is an alternative effective approach for treating LC. The efficient trigger of ferroptosis requires blocking cellular antioxidant (anti-ferroptosis) response and selectivity to avoid harming other healthy tissues. In this study, green chemically synthesized ferrous oxide nanoparticles (F(II) NPs) were used for enhancing selective iron accumulation in tumor tissue, while diethyldithiocarbamate (DE) was for inhibiting the antioxidant system (glutathione and aldehyde dehydrogenase (ALDH) 2) which protects the tumor from damage-dependent lipid peroxides. Thus, F(II) NPs were used with DE as a nanocomplex (DF(II) NPs), whose anti-LC activity was compared to that of the typical complex, DF(II). In HepG2 cells and a chemically induced metastatic LC animal model, DF(II) NPs outperformed DF(II) in eradicating metastatic LC cells, as evidenced by flow cytometry, histological and immunohistochemical analyses, and α-fetoprotein depletion. The superior therapeutic potency-dependent ferroptotic activity of DF(II) NPs, attributed to their higher selective accumulation (∼77%) than DF(II) in tumor tissues (liver and lung), resulted in a strong elevation of cellular lipid peroxidation with extreme suppression of nuclear related factor 2 (Nrf2) transcriptional activity, glutathione (GSH), glutathione peroxidase 4, and ALDH2. Subsequently, a severe inhibition in the expression of oncogenes and metastatic cancer stem cell genes was recorded in DF(II) NPs-treated LC animal group. In contrast to DF(II), DF(II) NPs were able to normalize liver functions and did not show any variations in hematological and histological parameters in the blood and tissues of DF(II) NPs-treated normal mouse group. These findings validate the potency and safety of DF(II) nanocomplex as a promising nanodrug for combating metastatic LC.
The anti-inflammatory and analgesic activities of 2Br-Crebanine and Stephanine from Stephania yunnanenses H. S.Lo
Authors: Cui Lili , Peng Chaorui , Li Jun , Cheng Xin , Fan Xiao , Li Jingyu , Yang Zixian , Zhao Yuancui , Ma Yunshu
Published: January 2023

Ethnopharmacological relevance: Crebanine (Cre) and Stephanine (Step) are isoquinoline aporphine-type alkaloids that are extracted from Stephania yunnanenses H. S. Lo. Plants of the Stephania genus are often used for treatment of stomach pain, abdominal pain, and rheumatoid arthritis. Both Cre and Step exhibit strong activities but are also associated with a certain level of toxicity, 10,11-dibrominecrebanine (2Br-Cre) is a bromine-modified derivative of Cre that we prepared and tested in order to reduce toxicity and enhance efficacy.

Aim of this study: To investigate the anti-inflammatory and analgesic effects of 2Br-Cre and Step based on previous research findings and explore the specific biological mechanisms involved.

Materials and methods: The anti-inflammatory and analgesic effects of 2Br-Cre and Step were investigated using a range of experimental models, including xylene-induced ear edema, carrageenan-induced pleurisy, carrageenan-induced paw edema, the hot-plate test, the naloxone antagonism test and the acetic acid writhing test. A model of chronic constriction injury (CCI) of the sciatic nerve was also established to investigate therapeutic effects. A RAW264.7 cell model was established using lipopolysaccharide (LPS) to estimate the effects of these compounds on cytokines levels.

Results: 2Br-Cre and step significantly inhibited ear edema, paw edema and presented anti-inflammatory activity in the pleurisy model by inhibiting leukocyte migration and nitric oxide (NO) production, and by reducing the levels of PGE2. 2Br-Cre and Step significantly increased the pain threshold of mice subjected to heat stimulation; the effect was blocked by naloxone, thus suggesting that the analgesic effects of 2Br-Cre and Step were mediated by opioid receptors. 2Br-Cre and Step inhibited the frequency of writhing and prolonged the latency of writhing, and reduced the abnormal increase in the levels of BDNF in the serum and brain, thus alleviating the pain caused by CCI. In addition, 2Br-Cre and Step significantly inhibited the production of several inflammatory cytokines (IL-6, IL-1β and TNF-α) by LPS-induced RAW264.7 macrophages (p < .01).

Conclusion: 2Br-Cre and Step exerted remarkable anti-inflammatory and analgesic effects. As a structural modification of Cre, 2Br-Cre retains the anti-inflammatory and analgesic activity of Cre but with better efficacy. Consequently, 2Br-Cre should be investigated further as a lead compound for analgesia.
Research progress of nano selenium in the treatment of oxidative stress injury during hepatic ischemia-reperfusion injury
Authors: Deng Xin , Ouyang Peng , Xu Wei , Yang Erhua , Bao Zhen , Wu Yijing , Gong Jin , Pan Jinghua
Published: January 2023

Hepatic ischemia-reperfusion injury (HIRI) is an additional injury to ischemic tissue after hepatic revascularization, and its pathological mechanism is complex. HIRI is not only involved in the molecular targets that mediate cell death, such as ion channel activation, abnormal protease activation and mitochondrial dysfunction, but also related to the down-regulation of endogenous protective signals. As a by-product of normal aerobic metabolism, reactive oxygen species (ROS) act as a multi effect physiological signal factor at low concentration. However, liver ischemia-reperfusion will lead to excessive ROS accumulation, destroy redox homeostasis, lead to oxidative stress, cause cell death through a variety of mechanisms, and drive the further damage of ischemic liver. Recent studies have found that the antioxidant treatment of nano selenium can reduce the excessive production of ROS and play a potential protective role in reducing HIRI. This paper reviews the molecular mechanism of the antioxidant effect of nano selenium for the prevention and treatment of HIRI, in order to provide further experimental basis for the clinical prevention and treatment of HIRI.
Mechanism of ferroptosis in traditional chinese medicine for clinical treatment: A review
Authors: Liu Jiajiao , Jiang Guanyin , He Pengfei , Du Xing , Hu Zhenming , Li Fuxiang
Published: January 2023

Ferroptosis is an iron-dependent regulation of cell death driven by lipid peroxidation, which is intracellularly dependent on iron and independent of other metals, and morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. Ferroptosis is closely related to physiological and pathological processes, such as development, aging, and immunity, and it plays an important role in a variety of diseases. In many departments, traditional Chinese medicine plays an increasingly important role in their clinical treatment. In recent years, an increasing number of studies have been conducted on the mechanism of ferroptosis in traditional Chinese medicine. However, the role of ferroptosis in the clinical treatment of traditional Chinese medicine requires further exploration. This article mainly introduces the application of ferroptosis in studies of the mechanism of traditional Chinese medicine to help clinicians understand the current status of traditional Chinese medicine therapy for the treatment of ferroptosis-related diseases.
Therapeutic effect and rebound evaluation of dapagliflozin on glycated hemoglobin (HbA1c) in type 1 diabetes mellitus patients
Authors: Wang Dong-Dong , Zhang Cun , Hu Ke , He Su-Mei , Zhu Ping , Chen Xiao
Published: January 2023

Dapagliflozin has been used to treat patients with type 1 diabetes mellitus; however, the actual drug efficacy of dapagliflozin on glycated hemoglobin (HbA1c) and whether there is a rebound from dapagliflozin efficacy on HbA1c remain unknown. The present study aimed to explore the actual therapeutic effect and rebound situation of dapagliflozin on HbA1c in type 1 diabetes mellitus patients. A total of 1,594 type 1 diabetes mellitus patients were enrolled for analysis using a non-linear mixed effect model from randomized controlled trials from published literature works including two 5 mg/day dapagliflozin dosage groups and three 10 mg/day dapagliflozin dosage groups. The change rate of HbA1c from a baseline value was chosen as a dapagliflozin pharmacodynamic evaluation index. After deducting control group effects, the therapeutic effect of 5 and 10 mg/day dapagliflozin on HbA1c in type 1 diabetes mellitus patients had no significant difference. In addition, the actual maximal efficacy (AEmax) of dapagliflozin on HbA1c was -6.24% at week 9. When it reached the AEmax, the dapagliflozin pharmacodynamic rebound on HbA1c occurred, and when the treatment was continued for 0.5 and 1 year, the actual efficacies were -4.70% (75% AEmax) and -3.27% (52% AEmax), respectively. This was the first time to clarify the actual therapeutic effect and rebound situation of dapagliflozin on HbA1c in type 1 diabetes mellitus patients, providing a reference value for clinical practices.
Evaluation of Mollugo oppositifolia Linn. as cholinesterase and β-secretase enzymes inhibitor
Authors: Das Bhaskar , Bhardwaj Pardeep K. , Sharma Nanaocha , Sarkar Arnab , Haldar Pallab Kanti , Mukherjee Pulok K.
Published: January 2023

Mollugo oppositifolia Linn. is traditionally used in neurological complications. The study aimed to investigate in-vitro neuroprotective effect of the plant extracts through testing against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-secretase linked to Alzheimer’s disease (AD). To understand the safety aspects, the extracts were tested for CYP450 isozymes and human hepatocellular carcinoma cell (HepG2) inhibitory potential. The heavy metal contents were estimated using atomic absorption spectroscopy (AAS). Further, the antioxidant capacities as well as total phenolic content and total flavonoid content (TFC) were measured spectrophotometrically. UPLC-QTOF-MS/MS analysis was employed to identify phytometabolites present in the extract. The interactions of the ligands with the target proteins (AChE, BChE, and BACE-1) were studied using AutoDockTools 1.5.6. The results showed that M. oppositifolia extract has more selectivity towards BChE (IC50 = 278.23 ± 1.89 μg/ml) as compared to AChE (IC50 = 322.87 ± 2.05 μg/ml). The IC50 value against β-secretase was 173.93 μg/ml. The extract showed a CC50 value of 965.45 ± 3.07 μg/ml against HepG2 cells and the AAS analysis showed traces of lead 0.02 ± 0.001 which was found to be within the WHO prescribed limits. Moreover, the IC50 values against CYP3A4 (477.03 ± 2.01 μg/ml) and CYP2D6 (249.65 ± 2.46 μg/ml) isozymes justify the safety aspects of the extract. The in silico molecular docking analysis of the target enzymes showed that the compound menthoside was found to be the most stable and showed a good docking score among all the identified metabolites. Keeping in mind the multi-targeted drug approach, the present findings suggested that M. oppositifolia extract have anti-Alzheimer’s potential.