bluuebunny/crossref_metadata_2025 huggingface dataset:
RPS3 Promotes the Metastasis and Cisplatin Resistance of Adenoid Cystic Carcinoma
Authors: Rui Xi , Huang Zixian , Chen Rui , Chen Yongju , Wang Yan , Huang Zhiquan
Published: June 2022

Background

Adenoid cystic carcinoma (ACC) is a malignant tumor in salivary gland tissue, that is characterized by strong invasiveness and lung metastasis, leading to poor survival rates. RPS3 is been reported to be associated with the biological functions of tumor cells. This study explored the regulatory effect of RPS3 in ACC to provide new therapeutic targets for ACC therapy.

Methods

We reviewed the clinical and pathologic data of 73 ACC patients. The expression of RPS3 was examined in ACC by immunohistochemistry. Transwell, wound healing, half-maximal inhibitory concentration (IC50) and other experiments were used to determine the regulatory effect of RPS3 on ACC functions. Coimmunoprecipitation and mass spectrometry analysis were used to detect the binding proteins of RPS3, mechanisms by which RPS3/STAT1/NF-kB signaling regulates ACC behavior were assessed using western blotting (WB), qPCR, etc. To explore the regulatory effect of RPS3 on ACC in vivo, we constructed nude mouse sciatic nerve infiltration model and a lung metastasis model for studies.

Results

High RPS3 expression was associated with metastasis and a poor prognosis in ACC patients. Inhibition of RPS3 expression reduced ACC migration, invasion and cisplatin resistance, and overexpression of RPS3 promoted ACC migration, invasion and cisplatin resistance. Further experiments revealed that RPS3 can activate the STAT1/NF-kB signaling pathway and regulate ACC behavior through binding to STAT1. The incidence of sciatic nerve infiltration and lung metastasis in nude mice after RPS3 knockdown was lower than that of the control group in vivo.

Conclusion

RPS3 is highly expressed and associated with the prognosis and survival of ACC patients. The RPS3/STAT1/NF-kB pathway may play an important regulatory role in ACC migration, invasion and chemoresistance. As a new therapeutic target of ACC, its clinical application value is worthy of attention and further exploration.
Based on the Development and Verification of a Risk Stratification Nomogram: Predicting the Risk of Lung Cancer-Specific Mortality in Stage IIIA-N2 Unresectable Large Cell Lung Neuroendocrine Cancer Compared With Lung Squamous Cell Cancer and Lung Adenocarcinoma
Authors: Yang Ying , Shen Cheng , Shao Jingjing , Wang Yilang , Wang Gaoren , Shen Aiguo
Published: June 2022

Background

The purpose of this study is to predict overall survival (OS) and lung cancer-specific survival (LCSS) in patients with stage IIIA-N2 unresectable lung squamous cell cancer (LUSC), lung adenocarcinoma (LUAD), and large cell neuroendocrine cancer (LCNEC) by constructing nomograms and to compare risk and prognostic factors affecting survival outcomes in different histological subtypes.

Methods

We included 11,505 unresectable NSCLC patients at stage IIIA-N2 between 2010 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database. Moreover, competition models and nomograms were developed to predict prognostic factors for OS and LCSS.

Results

Analysis of the SEER database identified 11,505 NSCLC patients, of whom 5,559 (48.3%) have LUAD, 5,842 (50.8%) have LUSC, and 104 (0.9%) have LCNEC. Overall, both OS and LCSS were significantly better in stage IIIA-N2 unresectable LUAD than in LCNEC, while there was no statistically significant difference between LUSC and LCNEC. Age, gender, T stage, chemotherapy, and radiotherapy were significantly associated with OS rates in LUAD and LUSC. However, chemotherapy was the only independent factor for LCNEC (p < 0.01).From competitive risk models, we found that older age, larger tumors, non-chemotherapy and non-radiotherapy were associated with a increased risk of death from LUAD and LUSC. Unlike prognostic factors for OS, our study showed that both chemotherapy and radiotherapy were all LCNEC-specific survival factors for both LCSS and non-LCSS LCNEC.

Conclusion

Our study reports that unresectable patients with stage IIIA-N2 LCNEC and LUSC have worse LCSS than LUAD. The study’s first prognostic nomogram constructed for patients with unresectable stage IIIA-N2 NSCLC can accurately predict the survival of different histological types, which may provide a practical tool to help clinicians assess prognosis and stratify these prognostic risks to determine which patients should be given an optimized individual treatment strategy based on histology.
Novel Pyroptosis-Related Gene Signatures Identified as the Prognostic Biomarkers for Bladder Carcinoma
Authors: You Jia , Li Huawei , Wei Yuanfeng , Fan Peng , Zhao Yaqin , Yi Cheng , Guo Qing , Yang Xi
Published: June 2022

Background

Bladder carcinoma (BLCA) is a common malignant tumor with high morbidity and mortality in the urinary system. Pyroptosis is a pattern of programmed cell death that is closely associated with progression of tumors. Therefore, it is significant to probe the expression of pyroptosis-related genes (PRGs) in BLCA.

Methods

The differentially expressed genes in normal and BLCA tissues were first obtained from the Cancer Genome Atlas (TCGA) database analysis, as well as PRGs from the National Center for Biotechnology Information (NCBI) database, intersecting to obtain differentially expressed pyroptosis-related genes (DEPRGs) in BLCA. With the construction of a prognostic model of pyroptosis by regression analysis, we derived and validated key genes, which were ascertained as a separate prognostic marker by individual prognostic and clinical relevance analysis. In addition, we gained six immune cells from the Tumor Immune Evaluation Resource (TIMER) website and analyzed the relationship between pyroptosis prognostic genes and immune infiltration.

Result

Our results revealed that 31 DEPRGs were available by comparing normal and BLCA tissues with |log2 (fold change, FC)| > 0.5 and FDR <0.05. Four key genes (CRTAC1, GSDMB, AIM2, and FOXO3) derived from the pyroptosis prognostic model were experimentally validated for consistent expression in BLCA patients. Following risk scoring, the low-risk group of BLCA patients had noticeably higher overall survival (OS) than the high-risk group (p < 0.001). Risk score was still an independent prognostic factor (HR = 1.728, 95% CI =1.289–2.315, p < 0.001). In addition, we found remarkable correlations among the expression of pyroptosis-related prognostic genes and the immune infiltration of CD4+ T cells, CD8+ T cells, B cells, dendritic cells, macrophages, and neutrophils.

Conclusion

Genes (CRTAC1, GSDMB, AIM2, and FOXO3) associated with pyroptosis are potential BLCA prognostic biomarkers that act as an essential part in the predictive prognosis of survival and immunotherapy of BLCA.
Inflammatory Breast Cancer: The Secretome of HCMV+ Tumor-Associated Macrophages Enhances Proliferation, Invasion, Colony Formation, and Expression of Cancer Stem Cell Markers
Authors: Mohamed Hossam Taha , El-Sharkawy Aya Ali , El-Shinawi Mohamed , Schneider Robert J. , Mohamed Mona Mostafa
Published: June 2022

Inflammatory breast cancer (IBC) is a highly aggressive phenotype of breast cancer that is characterized by a high incidence early metastasis. We previously reported a significant association of human cytomegalovirus (HCMV) DNA in the carcinoma tissues of IBC patients but not in the adjacent normal tissues. HCMV-infected macrophages serve as “mobile vectors” for spreading and disseminating virus to different organs, and IBC cancer tissues are highly infiltrated by tumor-associated macrophages (TAMs) that enhance IBC progression and promote breast cancer stem cell (BCSC)-like properties. Therefore, there is a need to understand the role of HCMV-infected TAMs in IBC progression. The present study aimed to test the effect of the secretome (cytokines and secreted factors) of TAMs derived from HCMV+ monocytes isolated from IBC specimens on the proliferation, invasion, and BCSC abundance when tested on the IBC cell line SUM149. HCMV+ monocytes were isolated from IBC patients during modified radical mastectomy surgery and tested in vitro for polarization into TAMs using the secretome of SUM149 cells. MTT, clonogenic, invasion, real-time PCR arrays, PathScan Intracellular Signaling array, and cytokine arrays were used to characterize the secretome of HCMV+ TAMs for their effect on the progression of SUM149 cells. The results showed that the secretome of HCMV+ TAMs expressed high levels of IL-6, IL-8, and MCP-1 cytokines compared to HCMV- TAMs. In addition, the secretome of HCMV+ TAMs induced the proliferation, invasion, colony formation, and expression of BCSC-related genes in SUM149 cells compared to mock untreated cells. In addition, the secretome of HCMV+ TAMs activated the phosphorylation of intracellular signaling molecules p-STAT3, p-AMPKα, p-PRAS40, and p-SAPK/JNK in SUM149 cells. In conclusion, this study shows that the secretome of HCMV+ TAMs enhances the proliferation, invasion, colony formation, and BCSC properties by activating the phosphorylation of p-STAT3, p-AMPKα, p-PRAS40, and p-SAPK/JNK intracellular signaling molecules in IBC cells.
Geriatric Nutritional Risk Index and Survival of Patients With Colorectal Cancer: A Meta-Analysis
Authors: Zhao Haiming , Xu Li , Tang Peng , Guo Rui
Published: June 2022

Background

Geriatric nutritional risk index (GNRI) is an indicator of nutritional status derived by serum albumin level and ideal body weight, which has been proposed as a predictor of prognosis for elderly population with various clinical conditions. The objective of the meta-analysis was to comprehensively evaluate the association between baseline GNRI and survival of patients with colorectal cancer (CRC).

Methods

Cohort studies were identified by search of PubMed, Embase, and Web of Science databases from inception to January 05, 2022 according to the aim of the meta-analysis. A random-effect model incorporating the potential between-study heterogeneity was adopted to pool the results.

Results

Nine studies including 3658 patients with CRC contributed to the meta-analysis. Results showed that CRC patients with lower GNRI at baseline had worse overall survival (OS, hazard ratio [HR] 2.39, 95% confidence interval [CI] 1.78-3.23, p<0.001; I2 = 60%) and progression-free survival (PFS, HR 1.77, 95% CI 1.38-2.26, p<0.001; I2 = 33%). The results were consistent in sensitivity analyses limited to elderly patients (HR for OS 2.25, p<0.001; HR for PFS 1.65, p=0.003). Subgroup analyses showed consistent results in patents with different cancer stages, and in studies with median follow-up < and ≥ 5 years (p for subgroup effects all < 0.05).

Conclusion

A lower GNRI at baseline may be independent associated with poor survival outcomes of patients with CRC. Evaluating the nutritional status using GNRI may be important for risk stratification of patients with CRC.
Differential Diagnosis Value of Shear-Wave Elastography for Superficial Enlarged Lymph Nodes
Authors: Sun Yanjuan , Wang Wen , Mi Chengrong , Zhang Qian , Zhang Kun
Published: June 2022

Objectives

To evaluate the diagnostic efficiency and diagnostic threshold of conventional US and shear-wave elastography (SWE) in superficial enlarged lymph nodes (LNs).

Methods

A total of 204 patients with superficial enlarged LNs were enrolled in this retrospective study aged 46.0 ± 15.2 years from March 2020 to March 2021. LNs with a long axis larger than 0.7 cm were considered as superficial enlarged. Before the histological biopsy, LNs that were considered suspicious according to both conventional US and SWE were included, while LNs with no or unclear pathological results, or with no satisfactory SWE images, were excluded. The conventional and 2-D SWE examinations were performed with Aplio i800 and Acuson sequoia equipped with i18LX5 linear-array transducer (5-18 MHz) and 10L4 linear-array transducer (4-10 MHz), respectively. Both E Median and Vs Median parameters were investigated by two senior ultrasound physicians. The pathological results were performed as the gold standard.

Results

Variables including transverse axis size, lymphatic hilum, L/T ratio, echogenicity, and color Doppler pattern were considered significant. The mean E Median value in benign, metastatic LNs, and lymphoma were 28.26 ± 8.87 kPa, 77.46 ± 22.85 kPa, and 50.37 ± 5.41 kPa (p <0.001), while Vs Median values were 3.02 ± 0.50 m/s, 4.87 ± 0.90 m/s, and 4.09 ± 0.22 m/s, respectively (p < 0.001). The diagnostic performance indicated the high sensitivity, specificity, PPV, NPV, and overall accuracy of conventional US combined with SWE. The optimal cutoff values of E Median and Vs Median for predicting malignant LNs were 42.90 kPa and 3.73 m/s, respectively. As AUC value, sensitivity, specificity, accuracy, PPV, and NPV revealed, the indexes of E Median were 0.976, 0.927, 0.975, 0.946, 0.983, and 0.897, respectively, while Vs Median were 0.970, 0.927, 0.963, 0.941, 0.975, and 0.895, respectively (p <0.001). The ROC curves of both E Median (AUC=0.976) Vs Median (AUC=0.970) suggested the remarkable diagnostic efficiency in distinguishing benignity between suspected malignant LNs.

Conclusions

Above results indicated that conventional US together with 2-D SWE could elevate the diagnostic performance. Meanwhile, the parameters of 2-D SWE including E Median and Vs Median could effectively assess malignant LNs, which provide valuable differentiating information in superficial enlarged LNs.
Outer Membrane Vesicles From The Gut Microbiome Contribute to Tumor Immunity by Eliciting Cross-Reactive T Cells
Authors: Tomasi Michele , Caproni Elena , Benedet Mattia , Zanella Ilaria , Giorgetta Sebastiano , Dalsass Mattia , König Enrico , Gagliardi Assunta , Fantappiè Laura , Berti Alvise , Tamburini Silvia , Croia Lorenzo , Di Lascio Gabriele , Bellini Erika , Valensin Silvia , Licata Giada , Sebastiani Guido , Dotta Francesco , Armanini Federica , Cumbo Fabio , Asnicar Francesco , Blanco-Míguez Aitor , Ruggiero Eliana , Segata Nicola , Grandi Guido , Grandi Alberto
Published: June 2022

A growing body of evidence supports the notion that the gut microbiome plays an important role in cancer immunity. However, the underpinning mechanisms remain to be fully elucidated. One attractive hypothesis envisages that among the T cells elicited by the plethora of microbiome proteins a few exist that incidentally recognize neo-epitopes arising from cancer mutations (“molecular mimicry (MM)” hypothesis). To support MM, the human probiotic Escherichia coli Nissle was engineered with the SIINFEKL epitope (OVA-E.coli Nissle) and orally administered to C57BL/6 mice. The treatment with OVA-E.coli Nissle, but not with wild type E. coli Nissle, induced OVA-specific CD8+ T cells and inhibited the growth of tumors in mice challenged with B16F10 melanoma cells expressing OVA. The microbiome shotgun sequencing and the sequencing of TCRs from T cells recovered from both lamina propria and tumors provide evidence that the main mechanism of tumor inhibition is mediated by the elicitation at the intestinal site of cross-reacting T cells, which subsequently reach the tumor environment. Importantly, the administration of Outer Membrane Vesicles (OMVs) from engineered E. coli Nissle, as well as from E. coli BL21(DE3)ΔompA, carrying cancer-specific T cell epitopes also elicited epitope-specific T cells in the intestine and inhibited tumor growth. Overall, our data strengthen the important role of MM in tumor immunity and assign a novel function of OMVs in host-pathogen interaction. Moreover, our results pave the way to the exploitation of probiotics and OMVs engineered with tumor specific-antigens as personalized mucosal cancer vaccines.
Cu-Hemin Nanosheets and Indocyanine Green Co-Loaded Hydrogel for Photothermal Therapy and Amplified Photodynamic Therapy
Authors: Zhu Shu , Wang Shuntao , Liu Chunping , Lyu Meng , Huang Qinqin
Published: June 2022

Near-infrared (NIR) organic small molecule indocyanine green (ICG) could respond well to 808 nm laser to promote local high temperature and ROS generation for realizing photothermal therapy (PTT)/photodynamic therapy (PDT). However, the high content of GSH in the tumor microenvironment (TME) limited the further therapeutic performance of ICG. Herein, injectable agarose in situ forming NIR-responsive hydrogels (CIH) incorporating Cu-Hemin and ICG were prepared for the first time. When CIH system was located to the tumor tissue through local injection, the ICG in the hydrogel could efficiently convert the light energy emitted by the 808 nm laser into thermal energy, resulting in the heating and softening of the hydrogel matrix, which releases the Cu-Hemin. Then, the over-expressed GSH in the TME could also down-regulated by Cu-Hemin, which amplified ICG-mediated PDT. In vivo experiments validated that ICG-based PDT/PTT and Cu-Hemin-mediated glutathione depletion could eliminate cancer tissues with admirable safety. This hydrogel-based GSH-depletion strategy is instructive to improve the objective response rate of PDT.
Glutor, a Glucose Transporter Inhibitor, Exerts Antineoplastic Action on Tumor Cells of Thymic Origin: Implication of Modulated Metabolism, Survival, Oxidative Stress, Mitochondrial Membrane Potential, pH Homeostasis, and Chemosensitivity
Authors: Temre Mithlesh Kumar , Yadav Saveg , Goel Yugal , Pandey Shrish Kumar , Kumar Ajay , Singh Sukh Mahendra
Published: June 2022

Neoplastic cells overexpress glucose transporters (GLUT), particularly GLUT1 and GLUT3, to support altered metabolism. Hence, novel strategies are being explored to effectively inhibit GLUTs for a daunting interference of glucose uptake. Glutor, a piperazine-2-one derivative, is a newly reported pan-GLUT inhibitor with a promising antineoplastic potential. However, several aspects of the underlying mechanisms remain obscure. To understand this better, tumor cells of thymic origin designated as Dalton’s lymphoma (DL) were treated with glutor and analyzed for survival and metabolism regulatory molecular events. Treatment of tumor cells with glutor caused a decrease in cell survival with augmented induction of apoptosis. It also caused a decrease in glucose uptake associated with altered expression of GLUT1 and GLUT3. HIF-1α, HK-2, LDH-A, and MCT1 also decreased with diminished lactate production and deregulated pH homeostasis. Moreover, glutor treatment modulated the expression of cell survival regulatory molecules p53, Hsp70, IL-2 receptor CD25, and C-myc along with mitochondrial membrane depolarization, increased intracellular ROS expression, and altered Bcl-2/BAX ratio. Glutor also enhanced the chemosensitivity of tumor cells to cisplatin, accompanied by decreased MDR1 expression. Adding fructose to the culture medium containing glutor reversed the latter’s inhibitory action on tumor cell survival. These results demonstrate that in addition to inhibited glucose uptake, modulated tumor growth regulatory molecular pathways are also implicated in the manifestation of the antineoplastic action of glutor. Thus, the novel findings of this study will have a long-lasting clinical significance in evaluating and optimizing the use of glutor in anticancer therapeutic strategies.
Reconstruction of Tumor-Induced Pelvic Defects With Customized, Three-Dimensional Printed Prostheses
Authors: Xu Shenglin , Guo Zehao , Shen Qiling , Peng Yongjun , Li Jian , Li Sheng , He Peng , Jiang Zheng , Que Yukang , Cao Kun , Hu Bo , Hu Yong
Published: June 2022

Background

Reconstruction of pelvis girdle stability after tumor-induced hemipelvectomy remains challenging. We surgically treated 13 patients with custom-made, three-dimensional printed hemipelvic prostheses. We aim to identify the preliminary outcomes for patients who have been managed with more mixed regions of prosthetic pelvic reconstruction and the feasibility of two reconstructive systems.

Methods

Seven male patients and 6 female patients treated at our center between January 2019 and May 2021 were included. There were 11 primary sarcomas and 2 solitary bone metastases. After en bloc tumor resection, two types of personalized, three-dimensional printed prostheses were fixed to restore the stability and rebuild the load transfer. The position of the reconstructed hemipelvis was evaluated on an anteroposterior plain radiograph. The complications and outcomes were traced. One amputation specimen was discovered through histological analysis of the porous structure.

Results

The operative duration was 467 ± 144 min, and the blood loss was 3,119 ± 662 ml. During a follow-up of 22.4 ± 8.5 months, two patients had delayed wound healing and one had a second-stage flap transfer. One patient with osteosarcoma died of pulmonary metastasis 27 months after surgery. Two patients with marginal resection suffered from local recurrence and had extra surgeries. One patient had traumatic hip dislocation 2 months after surgery and manipulative reduction was performed. The acetabular inclination of the affected side was 42.2 ± 4.3°, compared with 42.1 ± 3.9° on the contralateral side. The horizontal distance between the center of the femoral head and the middle vertical line was 10.4 ± 0.6 cm, while the reconstructed side was 9.8 ± 0.8 cm. No significant difference in acetabular position after surgery was found (p > 0.05). The amputation specimen harvested from one patient with local recurrence demonstrated bone and soft tissue ingrowth within the three-dimensional printed trabecular structure. Walking ability was preserved in all patients who are still alive and no prosthesis-related complications occurred. The MSTS score was 22.0 ± 3.7.

Conclusions

Both types of custom-made, three-dimensional printed prostheses manifested excellent precision, mechanical stability, and promising functional rehabilitation. The porous structure exhibited favorable histocompatibility to facilitate the ingrowth of bone and soft tissue.
Improved Ophthalmic Outcomes Following Venous Sinus Stenting in Idiopathic Intracranial Hypertension
Authors: Oyemade Kafayat A. , Xu Timothy T. , Brinjikji Waleed , Cutsforth-Gregory Jeremy K. , Lanzino Giuseppe , Kallmes David F. , Moss Heather E. , Dodd Robert , Bhatti M. Tariq , Chen John J.
Published: June 2022

Background

Ophthalmic outcomes following venous sinus stenting (VSS) in patients with idiopathic intracranial hypertension (IIH) are not well characterized.

Materials and Methods

A retrospective chart review was conducted on 86 consecutive patients with IIH who underwent venous sinus stenting at Mayo Clinic, Rochester, Minnesota and Stanford Medical Center, Palo Alto, California between May 2015 and October 2021. Patients with raised intracranial pressure from a non-IIH etiology were excluded. Clinical symptoms and neuro-ophthalmological data, including best corrected visual acuity (BCVA), visual field mean deviation, papilledema, and optical coherence tomography (OCT) peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell inner plexiform layer (GC-IPL), were analyzed. Baseline measurements before VSS and 3 months or more postoperatively were compared.

Results

Eighty-six subjects (82 female) were included in this study, with a median age of 33 (16–68) years and a median body mass index of 36.69 (22.30–62.00) kg/m2. 85/86 (98.8%) had attempted prior management with medication, and 12/86 (14%) had prior surgical management with optic nerve sheath fenestration, ventriculoperitoneal shunt, or bariatric surgery. Prior to VSS, 67/86 (77.9%) had papilledema, 85/86 (98.8%) had headaches, and 68/86 (79.1%) had pulsatile tinnitus. For patients with both pre- and post-VSS data available, the average papilledema grade was 1.76 (0–5) (n = 74) and the average OCT pRNFL was 186.34 (52.00–588.00) µm (n = 70), prior to VSS. A median of 4.0 (interquartile range 3.3–5.4) months after VSS, the average papilledema grade improved to 0.39 (0–2), p <0.001, and OCT pRNFL improved to 96.86 (47.00–168.00) µm, p <0.001. 28/86 (32.6%) patients no longer required medication for high intracranial pressure. 14/85 (16.5%) patients reported complete resolution of their headache and 55/71 (77.5%) reported improvement in headache quality. 40/68 (66.7%) reported complete resolution of pulsatile tinnitus. OCT GC-IPL, BCVA, and visual field mean deviation did not significantly change pre- vs post-VSS.

Conclusions

Our large consecutive case series corroborates smaller prior studies in demonstrating the overall efficacy of VSS for patients with IIH. We found both ophthalmic improvements, as demonstrated by the significantly reduced papilledema and pRNFL, and overall clinical symptom improvement.
Educational Review: The Impact of Perinatal Oxidative Stress on the Developing Kidney
Authors: DeFreitas Marissa J. , Katsoufis Chryso P. , Benny Merline , Young Karen , Kulandavelu Shathiyah , Ahn Hyunyoung , Sfakianaki Anna , Abitbol Carolyn L.
Published: June 2022

Oxidative stress occurs when there is an imbalance between reactive oxygen species/reactive nitrogen species and antioxidant systems. The interplay between these complex processes is crucial for normal pregnancy and fetal development; however, when oxidative stress predominates, pregnancy related complications and adverse fetal programming such as preterm birth ensues. Understanding how oxidative stress negatively impacts outcomes for the maternal-fetal dyad has allowed for the exploration of antioxidant therapies to prevent and/or mitigate disease progression. In the developing kidney, the negative impact of oxidative stress has also been noted as it relates to the development of hypertension and kidney injury mostly in animal models. Clinical research addressing the implications of oxidative stress in the developing kidney is less developed than that of the neurodevelopmental and respiratory conditions of preterm infants and other vulnerable neonatal groups. Efforts to study the oxidative stress pathway along the continuum of the perinatal period using a team science approach can help to understand the multi-organ dysfunction that the maternal-fetal dyad sustains and guide the investigation of antioxidant therapies to ameliorate the global toxicity. This educational review will provide a comprehensive and multidisciplinary perspective on the impact of oxidative stress during the perinatal period in the development of maternal and fetal/neonatal complications, and implications on developmental programming of accelerated aging and cardiovascular and renal disease for a lifetime.
The Outcome of Allogeneic Hematopoietic Stem Cell Transplantation From Different Donors in Recipients With Mucopolysaccharidosis
Authors: Qu Yuhua , Liu Hao , Wei Likun , Nie Shushan , Ding Wenjiao , Liu Sha , Liu Haiyan , Jiang Hua
Published: June 2022

There is limited information regarding hematopoietic stem cell transplantation (HSCT) for mucopolysaccharidosis (MPS) IV and VI. This study examined the full donor chimerism, specific lysosomal enzyme levels, and the survival of different MPS children after HSCT from various donor sources and compared the prognosis. A total of 42 children with MPS underwent HSCT, 9 cases were type I, 14 were type II, 15 were type IV, and 4 were type VI. A total of 24 patients received peripheral blood stem cells (PBSC) and 18 patients received umbilical cord blood (UCB). Patients who received PBSC were conditioned with intravenous (IV) busulfan every 6 h for a total of 16 doses, IV cyclophosphamide (CY, 200 mg/kg), and antihuman thymocyte globulin (ATG, 10 mg/kg). While conditioning regimen of patients who received UCB was adjusted to ATG (preposed, pre-) + busulfan + fludarabine + Cy, which includes IV ATG (pre-, 6 mg/kg), IV busulfan every 6 h for a total of 16 doses, IV fludarabine (200 mg/m2) and CY (200 mg/kg). Also, 95.2% (40 of 42) of patients achieved full donor chimerism, and all patients’ specific lysosomal enzyme levels reached normal. The estimated overall survival (OS) at 1 year was 92.9%. There was no significant difference in 1-year OS between patients who received PBSC transplantation and those who received UCB grafts (87.5% vs. 100%, p = 0.0247). The incidence of acute and chronic GVHD did not differ between them. The incidences of pneumonia in PBSC recipients and UCB recipients were 45.8 and 33.3%, respectively, but there few patients suffering from respiratory failure (4.2 and 5.6%, respectively) due to pneumonia. The incidence of cytomegaloviremia was also high in both groups, 58.3 and 44.4% respectively, However, no patient developed CMV disease. All deaths (3 of 42) occurred in patients receiving PBSC grafts, and there was no death in patients receiving UCB grafts. There was no death after transplantation in patients with MPS IV and VI. In addition, respiratory and nervous system functions were improved, whereas valvular heart disease was improved in some patients but progressed in more patients after transplantation. In summary, HSCT is a good therapeutic option for MPS, not only for patients with MPS I or II but also for those with MPS IV or VI. The specific lysosomal enzyme levels can be completely restored to normal, which is the basis for patients to resolve a broad range of clinical outcomes. Moreover, UCB with suitable HLA (HLA-match above 7/10 and 4/6) is a suitable donor source for MPS. Patients who underwent UCB transplantation using the conditioning regimen ATG (pre-) + busulfan + fludarabine + Cy can achieve a higher proportion of full donor chimerism and survival with less severe complications. HSCT can improve organs function in patients with MPS, but it is still worth exploring.
Comparison of Respiratory Pathogens in Children With Lower Respiratory Tract Infections Before and During the COVID-19 Pandemic in Shanghai, China
Authors: Xu Menghua , Liu Pengcheng , Su Liyun , Cao Lingfeng , Zhong Huaqing , Lu Lijuan , Jia Ran , Xu Jin
Published: June 2022

Objectives

This study aimed to assess the impact of COVID-19 on the prevalence of respiratory pathogens among hospitalized children with lower respiratory tract infections (LRTIs) in Shanghai.

Methods

Respiratory specimens were collected from children with LRTIs in Children’s Hospital of Fudan University from February 2019 to January 2021 and common respiratory pathogens were detected using multiplex PCR. The data of 13 respiratory pathogens were analyzed and compared between the year of 2020 (from February 2020 to January 2021) and 2019 (from February 2019 to January 2020).

Results

A total of 1,049 patients were enrolled, including 417 patients in 2019 and 632 patients in 2020. In 2020, 27.53% of patients were tested positive for at least one pathogen, which was significantly lower than that in 2019 (78.66%). The top three pathogens were Mycoplasma pneumoniae (Mp), human adenovirus (ADV) and human rhinovirus (RV) in 2019, whereas RV, human respiratory syncytial virus (RSV) and human parainfluenza virus (PIV) were the predominant ones in 2020. The positive rates of Mp, ADV, RV, PIV, Influenza virus B (InfB), H3N2, and H1N1 were significantly decreased in 2020. RV was the most detectable respiratory pathogen in 2020, and become the most frequent pathogen in all five age groups. PIV had a high prevalence from October to December 2020 which was even higher than that in 2019. Influenza virus A (InfA) was not detected in 2020. Co-infection was significantly less frequent in 2020.

Conclusion

The public health interventions aiming to eliminate COVID-19 have great impact on the prevalence of common respiratory pathogens. The prevalence of RV and PIV reminds us a possible resurgence of some pathogens.
Therapeutic Endoscopic Retrograde Cholangiopancreatography for Pediatric Hepato-Pancreato-Biliary Diseases: A Systematic Review and Meta-Analysis
Authors: Sun Rongjuan , Xu Xiaodan , Zheng Qipeng , Zhan Jianghua
Published: June 2022

Background

Hepato-pancreato-biliary (HPB) disease has different causes and types between children and adults, which has been increasingly diagnosed in the pediatric group. Endoscopic retrograde cholangiopancreatography (ERCP) has been gradually considered as a therapeutic method in adults, while in pediatric patients, there are not many reports of its usage. This systematic review and meta-analysis aims to assess the use condition of therapeutic ERCP in the management of pediatric HPB diseases.

Methods

This systematic literature search was conducted in the PubMed, Embase, Web of Science, and Cochrane library databases to identify all relevant articles published from inception to February 2022 that evaluated therapeutic ERCP in pediatric patients with HPB diseases. The researchers included studies in which patients were less than 18 years old and underwent therapeutic ERCP procedures. A random-effects model was used to analyze the usage rate of therapeutic ERCP procedures, procedural success rates, adverse event rates, and the rate of different therapeutic procedures. Subgroup analysis, sensitivity analysis, and meta-regression were conducted to analyze the source of heterogeneity.

Results

A total of 33 articles were included. After homogenization, the overall use of therapeutic interventions accounts for 77% [95% confidence interval (CI) 74–81%] of all ERCP procedures. After excluding outlier studies, the estimation success rate of the therapeutic procedure is 74% (95% CI 69–79%), and adverse event rate is 8% (95% CI 6–10%). In our study, stent placement is the most common procedure, which makes up 75% (95% CI 65–86%) of all therapeutic procedures. In addition, the usage proportion of sphincterotomy (ST), stone extraction/removal, bougienage/balloon dilation is, respectively, 46% (95% CI 39–53%), 34% (95% CI 31–38%), and 26% (95% CI 22–29%).

Conclusion

The ERCP procedure is gradually considered a therapeutic technique in pediatric patients, the proportion of therapeutic ERCP is 77% of total usage, which is increasing every year. Meanwhile, its success rate is relatively high. It reflects that this operation modality is promising in the treatment of HPB disorders and is gradually expanded as more branch technologies are being used. A variety of operations can be achieved through ERCP procedures, and more functions should be developed in the future.

Systematic Review Registration

[https://www.crd.york.ac.uk/prospero/], identifier [CRD42022302911].
The Anti-Histamine Azelastine, Identified by Computational Drug Repurposing, Inhibits Infection by Major Variants of SARS-CoV-2 in Cell Cultures and Reconstituted Human Nasal Tissue
Authors: Konrat Robert , Papp Henrietta , Kimpel Janine , Rössler Annika , Szijártó Valéria , Nagy Gábor , Madai Mónika , Zeghbib Safia , Kuczmog Anett , Lanszki Zsófia , Gesell Tanja , Helyes Zsuzsanna , Kemenesi Gábor , Jakab Ferenc , Nagy Eszter
Published: June 2022

Background and purpose: The COVID-19 pandemic continues to pose challenges, especially with the emergence of new SARS-CoV-2 variants that are associated with higher infectivity and/or compromised protection afforded by the current vaccines. There is a high demand for additional preventive and therapeutic strategies effective against this changing virus. Repurposing of approved or clinically tested drugs can provide an immediate solution.

Experimental Approach: We applied a novel computational approach to search among approved and commercially available drugs. Antiviral activity of a predicted drug, azelastine, was tested in vitro in SARS-CoV-2 infection assays with Vero E6 cells, Vero cells stably overexpressing the human TMPRSS2 and ACE2 proteins as well as on reconstituted human nasal tissue using the predominant variant circulating in Europe in summer 2020, B.1.177 (D614G variant), and its emerging variants of concern; B.1.1.7 (alpha), B.1.351 (beta) and B.1.617.2 (delta) variants. The effect of azelastine on viral replication was assessed by quantification of viral genomes by droplet digital PCR or qPCR.

Key results: The computational approach identified major drug families, such as anti-infective, anti-inflammatory, anti-hypertensive, antihistamine, and neuroactive drugs. Based on its attractive safety profile and availability in nasal formulation, azelastine, a histamine 1 receptor-blocker was selected for experimental testing. Azelastine reduced the virus-induced cytopathic effect and SARS-CoV-2 copy numbers both in preventive and treatment settings upon infection of Vero cells with an EC50 of 2.2–6.5 µM. Comparable potency was observed with the alpha, beta and delta variants. Furthermore, five-fold dilution (containing 0.02% azelastine) of the commercially available nasal spray formulation was highly potent in inhibiting viral propagation in reconstituted human nasal tissue.

Conclusion and Implications: Azelastine, an antihistamine available as nasal sprays developed against allergic rhinitis may be considered as a topical prevention or treatment of nasal colonization by SARS-CoV-2. A Phase 2 efficacy indicator study with azelastine-containing nasal spray that was designed based on the findings reported here has been concluded recently, confirming accelerated viral clearance in SARS-CoV-2 positive subjects.
Herb and Spices in Colorectal Cancer Prevention and Treatment: A Narrative Review
Authors: Hossain Md. Sanower , Kader Md. Abdul , Goh Khang Wen , Islam Maidul , Khan Md. Sharif , Harun-Ar Rashid Md. , Ooi Der Jiun , Melo Coutinho Henrique Douglas , Al-Worafi Yaser Mohammed , Moshawih Said , Lim Ya Chee , Kibria K. M. Kaderi , Ming Long Chiau
Published: June 2022

Colorectal cancer (CRC) is the second most deadly cancer worldwide. CRC management is challenging due to late detection, high recurrence rate, and multi-drug resistance. Herbs and spices used in cooking, practised for generations, have been shown to contain CRC protective effect or even be useful as an anti-CRC adjuvant therapy when used in high doses. Herbs and spices contain many bioactive compounds and possess many beneficial health effects. The chemopreventive properties of these herbs and spices are mainly mediated by the BCL-2, K-ras, and MMP pathways, caspase activation, the extrinsic apoptotic pathway, and the regulation of ER-stress-induced apoptosis. As a safer natural alternative, these herbs and spices could be good candidates for chemopreventive or chemotherapeutic agents for CRC management because of their antiproliferative action on colorectal carcinoma cells and inhibitory activity on angiogenesis. Therefore, in this narrative review, six different spices and herbs: ginger (Zingiber officinale Roscoe), turmeric (Curcuma longa L.), garlic (Allium sativum L.), fenugreek (Trigonella foenum-graecum L.), sesame (Sesamum indicum L.), and flaxseed (Linum usitatissimum L.) used in daily cuisine were selected for this study and analyzed for their chemoprotective or chemotherapeutic roles in CRC management with underlying molecular mechanisms of actions. Initially, this study comprehensively discussed the molecular basis of CRC development, followed by culinary and traditional uses, current scientific research, and publications of selected herbs and spices on cancers. Lead compounds have been discussed comprehensively for each herb and spice, including anti-CRC phytoconstituents, antioxidant activities, anti-inflammatory properties, and finally, anti-CRC effects with treatment mechanisms. Future possible works have been suggested where applicable.
Associations Between Asthma Diagnosis/Asthma Exacerbation and Previous Proton-Pump Inhibitor use: A Nested Case-Control Study Using a National Health Screening Cohort
Authors: Choi Hyo Geun , Min Chanyang , Yoo Dae Myoung , Tan Bruce K. , Kim Joo-Hee , Kim Hwan Il , Park Ji-Young , Park Sunghoon , Hwang Yong Il , Jang Seung Hun , Jung Ki-Suck
Published: June 2022

Background: Proton-pump inhibitors (PPIs) block acid secretion from gastric parietal cells; however, recent studies have reported that PPIs have antioxidant and anti-inflammatory properties in various cells. Newer PPIs are stronger inhibitors of acid secretion; however, the anti-inflammatory effects of these drugs have not been assessed. We evaluated anti-inflammatory effect of PPIs on the development of asthma/asthma exacerbation (AE) in a national health screening cohort.

Methods: This case-control study comprised 64,809 participants with asthma who were 1:1 matched with controls from the Korean National Health Insurance Service-Health Screening Cohort. Conditional logistic regression analysis was used to evaluate the effect of previous PPI use on an asthma diagnosis in all participants. Unconditional logistic regression was used to assess the effect of PPI use on AE in participants with asthma. These relationships were estimated in a subgroup analysis according to PPI generation.

Results: Overall, PPI use increased the risk of asthma diagnosis [adjusted odds ratio (aOR) = 1.29, 95% confidence interval (CI) = 1.23–1.35, p < 0.001]. Use of the first-generation PPIs was associated with asthma (aOR = 1.34, 95% CI = 1.18–1.52, p < 0.001), while use of second-generation PPIs was not (aOR = 0.97, 95% CI = 0.82–1.15, p = 0.748). In contrast, overall PPI use decreased the risk of AE in participants with asthma (aOR = 0.79, 95% CI = 0.75–0.84, p < 0.001), although this effect was observed only for second-generation PPIs (aOR = 0.76, 95% CI = 0.65–0.89, p = 0.001).

Conclusion: PPI use increased the risk for subsequent asthma diagnosis. However, this effect was confined to first-generation PPIs. Second-generation PPIs decreased the risk of AE.
Evaluation of the Acute and Sub-Acute Oral Toxicity of Jaranol in Kunming Mice
Authors: Liu Tianlong , Zhang Yao , Liu Jing , Peng Junwen , Jia Xin , Xiao Yunfeng , Zheng Lanbing , Dong Yu
Published: June 2022

Background: Jaranol has shown a wide range of pharmacological activities; however, no study has yet examined in vivo toxicity. The study aimed to investigate the oral acute and sub-acute toxicity of jaranol in mice.

Methods: The acute toxicity was determined by a single oral dose of jaranol (2000 mg/kg). Therein animal behaviour and mortality rate were observed for 14 days. The jaranol (50, 100 and 200 mg/kg BW·d−1) was given by gavage for 28 days daily in the sub-acute study. The mouse body weight (BW), organ weight, food, water intake, biochemical, haematological parameters, and histopathology were studied in acute and sub-acute toxicity.

Results: During the acute toxicity test, a single oral dose (2000 mg/kg) jaranol did not cause significant alteration in majority of the hematological indices. However, jaranol decreased the level of serum alanine aminotransferase and aspartate aminotransferase. Those results showed that the oral lethal dose 50 (LD50) of jaranol was higher than 2000 mg/kg BW, regardless of sex. In repeated daily oral doses (50, 100 and 200 mg/kg BW·d−1), no mortality was recorded in the various experimental groups. The jaranol reduced body weight gain (200 mg/kg BW·d−1), the relative spleen weight (all doses) and serum alanine aminotransferase activity (200 mg/kg BW·d−1). On the other hand, jaranol significantly elevated red blood cell count (100 and 200 mg/kg BW·d−1) and serum creatinine levels (200 mg/kg BW·d−1). Histological study revealed that spleen bleeding was identified in 200 mg/kg jaranol-treated mice.

Conclusion: Jaranol was relatively safe in Kunming Mice when repetitively administered orally in small doses for a prolonged period of time. We recommend more chronic toxicity studies and clinical trials on jaranol to ensure that its use is free of potential toxicity to humans.
Targeting Ferroptosis Pathway to Combat Therapy Resistance and Metastasis of Cancer
Authors: Liu Xuan , Zhang Yiqian , Wu Xuyi , Xu Fuyan , Ma Hongbo , Wu Mengling , Xia Yong
Published: June 2022

Ferroptosis is an iron-dependent regulated form of cell death caused by excessive lipid peroxidation. This form of cell death differed from known forms of cell death in morphological and biochemical features such as apoptosis, necrosis, and autophagy. Cancer cells require higher levels of iron to survive, which makes them highly susceptible to ferroptosis. Therefore, it was found to be closely related to the progression, treatment response, and metastasis of various cancer types. Numerous studies have found that the ferroptosis pathway is closely related to drug resistance and metastasis of cancer. Some cancer cells reduce their susceptibility to ferroptosis by downregulating the ferroptosis pathway, resulting in resistance to anticancer therapy. Induction of ferroptosis restores the sensitivity of drug-resistant cancer cells to standard treatments. Cancer cells that are resistant to conventional therapies or have a high propensity to metastasize might be particularly susceptible to ferroptosis. Some biological processes and cellular components, such as epithelial–mesenchymal transition (EMT) and noncoding RNAs, can influence cancer metastasis by regulating ferroptosis. Therefore, targeting ferroptosis may help suppress cancer metastasis. Those progresses revealed the importance of ferroptosis in cancer, In order to provide the detailed molecular mechanisms of ferroptosis in regulating therapy resistance and metastasis and strategies to overcome these barriers are not fully understood, we described the key molecular mechanisms of ferroptosis and its interaction with signaling pathways related to therapy resistance and metastasis. Furthermore, we summarized strategies for reversing resistance to targeted therapy, chemotherapy, radiotherapy, and immunotherapy and inhibiting cancer metastasis by modulating ferroptosis. Understanding the comprehensive regulatory mechanisms and signaling pathways of ferroptosis in cancer can provide new insights to enhance the efficacy of anticancer drugs, overcome drug resistance, and inhibit cancer metastasis.
Formulation Development and Characterization of pH Responsive Polymeric Nano-Pharmaceuticals for Targeted Delivery of Anti-Cancer Drug (Methotrexate)
Authors: Ullah Farhad , Iqbal Zafar , Khan Amjad , Khan Saeed Ahmad , Ahmad Lateef , Alotaibi Amal , Ullah Riaz , Shafique Muhammad
Published: June 2022

Oral administration of pH sensitive/stimuli responsive nanoparticles are gaining importance because of the limited side effects, minimum dose and controlled drug release. The objective of this study was to develop and evaluate pH sensitive polymeric nanoparticles for methotrexate with the aim to maximize the drug release at target site. In the presented study, pH sensitive polymeric nanoparticles of methotrexate were developed through modified solvent evaporation technique using polymer Eudragit S100. Different process parameters like drug to polymer ratio, speed of sonication, concentration of surfactant and time of sonication were optimized by evaluating their effects on particle size, PDI, zeta potential, entrapment/encapsulation efficiency. The developed formulations were evaluated for their size, polydispersity (PDI), zeta potential, encapsulation efficiency, XRD, scanning electron microscopy, in-vitro drug release and stability studies. Best results were obtained with poloxamer-407 and PVA and were selected as surfactants. Physicochemical characterization of the developed formulations showed that the particle size lies in the range 165.7 ± 1.85–330.4 ± 4.19, PDI 0.119 ± 0.02–0.235 ± 0.008, zeta potential −0.163 ± 0.11–−5.64 ± 0.36 mV, and encapsulation efficiency more than 61%. The results of scanning electron microscopy revealed that nanoparticles have regular geometry with spherical shape. Initially the drug release occur through diffusion followed by erosion. The present studies showed that MTX-ES100 nanoparticles prepared during this study have the desired physicochemical properties, surface morphology and release characteristics used to target the desired organs.