bluuebunny/crossref_metadata_2025 huggingface dataset:
Bone Metastasis From Gastric Adenocarcinoma—What Are the Risk Factors and Associated Survival? A Large Comprehensive Population-Based Cohort Study
Authors: Huang Lei , Zhao Yajie , Shi Yan , Hu Weiguo , Zhang Jun
Published: March 2022

Background

While bone metastasis is not common in gastric adenocarcinoma (GaC), it can have important impacts on prognosis. This large cohort study aimed at exploring factors associated with bone metastasis in GaC and investigating the time-dependent cumulative mortalities and prognostic factors in GaC patients with bone metastasis at the population level.

Methods

Data on patients with GaC diagnosed in 2010–2016 were retrieved from a large population-based database. We explored factors associated with bone metastasis using the multivariable-adjusted logistic model. We then calculated the time-dependent cancer-specific mortalities in GaC patients with bone metastasis using the cumulative incidence function and compared mortalities across subgroups using Gray’s test. We further assessed factors associated with mortality using the multivariable-adjusted Fine–Gray subdistribution hazard model.

Results

Together 11,072 eligible patients with metastatic GaC were enrolled, which comprised 1,511 (14%) people with bone metastasis and 9,561 (86%) with other metastasis, encompassing 6,999 person-years of follow-up. Bone metastasis was more frequently detected in 2014 or later, in younger patients, in patients with gastric cardia cancers, in people with signet-ring cell carcinoma, and in those with poorly differentiated/undifferentiated cancers; it was less commonly observed in black patients. Bone metastasis was associated with more frequent brain and lung metastases. The median survival of patients with bone metastasis was 4 months; the 6-month and 3-year cancer-specific cumulative mortalities were 56% and 85%, respectively. In patients receiving chemotherapy, American Indians/Alaskan Natives, patients with gastric antrum/pylorus cancers, and those with positive lymph nodes had higher mortality risks, while those undergoing resection had lower mortality hazards.

Conclusion

In GaC patients, bone metastasis was associated with various clinicopathologic factors including age, ethnicity, tumor location, histology, differentiation, and metastasis to other sites. Patients with bone metastasis had poor prognosis which was associated with ethnicity, tumor location, lymph node involvement, and treatment. Our findings provide important hints for tailed patient management and for further mechanistic investigations.
Novel Therapeutic Savior for Osteosarcoma: The Endorsement of Ferroptosis
Authors: Qiu Cheng , Liu Tianyi , Luo Dan , Luan Dongyang , Cheng Lin , Wang Songgang
Published: March 2022

Ferroptosis has recently been discovered as an iron-dependent and non-apoptotic regulated mechanism of cell death. The induction of ferroptosis in tumor cells improves tumor treatment, making it a current research hotspot. Mechanistically, it starts by lipid peroxidation, iron accumulation, reactive oxygen species (ROS) production, and glutathione deprivation, highlighting novel treatment opportunities for many tumors and neurodegenerative disorders. Several tumor cell lines are resistant to ferroptosis inducers, even when the ferroptosis key enzyme glutathione peroxidase 4 (GPX4) is blocked, indicating that other important elements are also involved in this process. Ferroptosis-suppressor-protein 1 (FSP1) was discovered to be one of these elements in addition to a few others such as ferroptotic gatekeepers like GTP cyclohydrolase 1 (GCH1) and dihydroorotate dehydrogenase (DHODH). Osteosarcoma is the most common primary malignant bone tumor observed most frequently in children and adolescents. Several studies demonstrated that ferroptosis plays a critical role in the treatment of osteosarcoma, in particular drug-resistant osteosarcoma cells. We outlined four primary regulators involved in ferroptosis in this article, reviewed previously published studies of ferroptosis in osteosarcoma to provide covert insights about osteosarcoma treatment, and highlighted several critical issues to point out future research possibilities.
Development and Validation of a Preoperative Nomogram for Predicting Benign and Malignant Gallbladder Polypoid Lesions
Authors: Han Shuai , Liu Yu , Li Xiaohang , Jiang Xiao , Li Baifeng , Zhang Chengshuo , Zhang Jialin
Published: March 2022

Purpose

The purpose of this study was to develop and validate a preoperative nomogram of differentiating benign and malignant gallbladder polypoid lesions (GPs) combining clinical and radiomics features.

Methods

The clinical and imaging data of 195 GPs patients which were confirmed by pathology from April 2014 to May 2021 were reviewed. All patients were randomly divided into the training and testing cohorts. Radiomics features based on 3 sequences of contrast-enhanced computed tomography were extracted by the Pyradiomics package in python, and the nomogram further combined with clinical parameters was established by multiple logistic regression. The performance of the nomogram was evaluated by discrimination and calibration.

Results

Among 195 GPs patients, 132 patients were pathologically benign, and 63 patients were malignant. To differentiate benign and malignant GPs, the combined model achieved an area under the curve (AUC) of 0.950 as compared to the radiomics model and clinical model with AUC of 0.929 and 0.925 in the training cohort, respectively. Further validation showed that the combined model contributes to better sensitivity and specificity in the training and testing cohorts by the same cutoff value, although the clinical model had an AUC of 0.943, which was higher than 0.942 of the combined model in the testing cohort.

Conclusion

This study develops a nomogram based on the clinical and radiomics features for the highly effective differentiation and prediction of benign and malignant GPs before surgery.
Confocal Laser Endomicroscopy Can Improve the Diagnosis Rate and Range Assessment of Patients With Conflicting Chronic Atrophic Gastritis Results of White Light Endoscopic and Pathological Diagnosis
Authors: Pang Suya , Yao Hailing , Jiang Chen , Zhang Qin , Lin Rong
Published: March 2022

Background and Aims

Chronic atrophic gastritis (CAG) is closely related to the development of gastric cancer. However, the diagnostic accuracy of white light endoscopy (WLE) biopsy for CAG is poor. The diagnostic role and efficacy of confocal laser endomicroscopy (CLE) in CAG missed under WLE biopsy remain unclear.

Methods

This study is a single-center prospective study that included 21 patients from 1,349 patients who underwent WLE and biopsy and whose WLE results confirmed CAG, but pathological results did not. Then, all these patients received CLE examination and underwent targeted biopsies and five-point standard biopsies. The sensitivity, specificity, and accuracy of CLE diagnosis and targeted biopsy were analyzed.

Results

The pathological results of five-point standard biopsies in 21 patients confirmed CAG, and 17 patients (81.0%) were confirmed to have intestinal metaplasia (IM). According to the image diagnosis of CLE, there were 19 cases (90.5%) of CAG and 14 cases (66.7%) of IM among these 21 patients. According to the targeted biopsy of CLE, 17 cases (81.0%) of CAG and 14 cases (66.7%) of IM were diagnosed. There was no significant difference between CLE image diagnosis and five-point standard biopsies in terms of atrophy severity score (p = 0.927), IM severity score (p = 0.250), atrophy scope score (p = 0.781), and IM scope score (p = 0.195). For CAG, the sensitivity and accuracy of CLE image diagnosis were higher than those of CLE targeted biopsies (90.5% vs. 81.0%, p = 0.331), but for IM, the diagnosis was the same.

Conclusions

CLE can improve the diagnosis rate of CAG and can increase the comprehensive assessment of the scope and severity of CAG.
The Therapeutic Effects of DDP/CD44-shRNA Nanoliposomes in AMF on Ovarian Cancer
Authors: Guo Ting , Zhu Yinxing , Yue Miao , Wang Fujin , Li Zhifeng , Lin Mei
Published: March 2022

Background

Globally, ovarian cancer is one of the most common gynecological malignant tumors, and the overall curative effect has been unsatisfactory for years. Exploring and investigating novel therapeutic strategy for ovarian cancer are an imperative need.

Methods

Using manganese zinc ferrite nanoparticles (PEG-MZF-NPs) as gene transferring vector and drug delivery carrier, a new combinatorial regimen for the target treatment of ovarian cancer by integrating CD44-shRNA, DDP (cisplatin) and magnetic fluid hyperthermia (MFH) together was designed and investigated in vivo and in vitro in this study.

Results

PEG-MZF-NPs/DDP/CD44-shRNA nanoliposomes were successfully prepared, and TEM detection indicated that they were 15–20 nm in diameter, with good magnetothermal effect in AMF, similar to the previously prepared PEG-MZF-NPs. Under the action of AMF, PEG-MZF-NPs/shRNA/DDP nanoliposomes effectively inhibited ovarian tumors’ growth, restrained the cancer cells’ proliferation and invasion, and promoted cell apoptosis. VEGF, survivin, BCL-2, and BCL-xl proteins significantly decreased, while caspase-3 and caspase-9 proteins markedly increased both in vitro and in vivo, far better than any of the individual therapies did. Moreover, no significant effects were found on bone marrow hematopoiesis and liver and kidney function of nude mice intervened by the combinatorial therapeutic regimen.

Conclusion

In the present study, we developed PEG-MZF-NPs/DDP/CD44-shRNA magnetic nanoliposomes and inaugurated an integrated therapy through the synergistic effect of MFH, gene therapy, and chemotherapy, and it shows a satisfactory therapeutic effect on ovarian cancer in vitro and in vivo, much better than any single treatment regimen did, with no significant side effects. This study provides a new promising method for ovarian cancer treatment.
Experimental Comparison of Fiducial Markers Used in Proton Therapy: Study of Different Imaging Modalities and Proton Fluence Perturbations Measured With CMOS Pixel Sensors
Authors: Reidel Claire-Anne , Horst Felix , Schuy Christoph , Jäkel Oliver , Ecker Swantje , Henkner Katrin , Brons Stephan , Durante Marco , Weber Uli
Published: March 2022

Fiducial markers are used for image guidance to verify the correct positioning of the target for the case of tumors that can suffer interfractional motion during proton therapy. The markers should be visible on daily imaging, but at the same time, they should produce minimal streak artifacts in the CT scans for treatment planning and induce only slight dose perturbations during particle therapy. In this work, these three criteria were experimentally investigated at the Heidelberg Ion Beam Therapy Center. Several small fiducial markers with different geometries and materials (gold, platinum, and carbon-coated ZrO2) were evaluated. The streak artifacts on treatment planning CT were measured with and without iMAR correction, showing significantly smaller artifacts from markers lighter than 6 mg and a clear improvement with iMAR correction. Daily imaging as X-ray projections and in-room mobile CT were also performed. Markers heavier than 6 mg showed a better contrast in the X-ray projections, whereas on the images from the in-room mobile CT, all markers were clearly visible. In the other part of this work, fluence perturbations of proton beams were measured for the same markers by using a tracker system of several high spatial resolution CMOS pixel sensors. The measurements were performed for single-energy beams, as well as for a spread-out Bragg peak. Three-dimensional fluence distributions were computed after reconstructing all particle trajectories. These measurements clearly showed that the ZrO2 markers and the low-mass gold/platinum markers (0.35mm diameter) induce perturbations being 2–3 times lower than the heavier gold or platinum markers of 0.5mm diameter. Monte Carlo simulations, using the FLUKA code, were used to compute dose distributions and showed good agreement with the experimental data after adjusting the phase space of the simulated proton beam compared to the experimental beam.
Clinicopathologic and Genomic Features in Triple-Negative Breast Cancer Between Special and No-Special Morphologic Pattern
Authors: Li Ying-Zi , Chen Bo , Lin Xiao-Yi , Zhang Guo-Chun , Lai Jian-Guo , Li Cheukfai , Lin Jia-Li , Guo Li-Ping , Xiao Wei-Kai , Mok Hsiaopei , Ren Chong-Yang , Wen Ling-Zhu , Cao Fang-Rong , Lin Xin , Qi Xiao-Fang , Liu Yang , Liao Ning
Published: March 2022

Background

Triple-negative breast cancer (TNBC) is refractory and heterogeneous, comprising various entities with divergent phenotype, biology, and clinical presentation. As an aggressive subtype, Chinese TNBC patients with special morphologic patterns (STs) were restricted to its incidence of 10-15% in total TNBC population.

Methods

We recruited 89 patients with TNBC at Guangdong Provincial People’s Hospital (GDPH) from October 2014 to May 2021, comprising 72 cases of invasive ductal carcinoma of no-special type (NSTs) and 17 cases of STs. The clinical data of these patients was collected and statistically analyzed. Formalin-fixed, paraffin-embedded (FFPE) tumor tissues and matched blood samples were collected for targeted next-generation sequencing (NGS) with cancer-related, 520- or 33-gene assay. Immunohistochemical analysis of FFPE tissue sections was performed using anti-programmed cell death-ligand 1(PD-L1) and anti-androgen receptor antibodies.

Results

Cases with NSTs presented with higher histologic grade and Ki-67 index rate than ST patients (NSTs to STs: grade I/II/III 1.4%, 16.7%,81.9% vs 0%, 29.4%, 58.8%; p<0.05; Ki-67 ≥30%: 83.3% vs. 58.8%, p<0.05), while androgen receptor (AR) and PD-L1 positive (combined positive score≥10) rates were lower than of STs cases (AR: 11.1% vs. 47.1%; PD-L1: 9.6% vs. 33.3%, p<0.05). The most commonly altered genes were TP53 (88.7%), PIK3CA (26.8%), MYC (18.3%) in NSTs, and TP53 (68.8%), PIK3CA (50%), JAK3 (18.8%), KMT2C (18.8%) in STs respectively. Compared with NSTs, PIK3CA and TP53 mutation frequency showed difference in STs (47.1% vs 19.4%, p=0.039; 64.7% vs 87.5%, p=0.035).

Conclusions

In TNBC patients with STs, decrease in histologic grade and ki-67 index, as well as increase in PD-L1 and AR expression were observed when compared to those with NSTs, suggesting that TNBC patients with STs may better benefit from immune checkpoint inhibitors and/or AR inhibitors. Additionally, lower TP53 and higher PIK3CA mutation rates were also found in STs patients, providing genetic evidence for deciphering at least partly potential mechanism of action.
Detection of Host Cell Gene/HPV DNA Methylation Markers: A Promising Triage Approach for Cervical Cancer
Authors: Zhang Lingyi , Tan Wenxi , Yang Hongmei , Zhang Songling , Dai Yun
Published: March 2022

Cervical cancer is the most prevalent gynecologic malignancy, especially in women of low- and middle-income countries (LMICs). With a better understanding of the etiology and pathogenesis of cervical cancer, it has been well accepted that this type of cancer can be prevented and treated via early screening. Due to its higher sensitivity than cytology to identify precursor lesions of cervical cancer, detection of high-risk human papillomavirus (HR-HPV) DNA has been implemented as the primary screening approach. However, a high referral rate for colposcopy after HR-HPV DNA detection due to its low specificity in HR-HPV screening often leads to overtreatment and thus increases the healthcare burden. Emerging evidence has demonstrated that detection of host cell gene and/or HPV DNA methylation represents a promising approach for the early triage of cervical cancer in HR-HPV-positive women owing to its convenience and comparable performance to cytology, particularly in LMICs with limited healthcare resources. While numerous potential markers involving DNA methylation of host cell genes and the HPV genome have been identified thus far, it is crucial to define which genes or panels involving host and/or HPV are feasible and appropriate for large-scale screening and triage. An ideal approach for screening and triage of CIN/ICC requires high sensitivity and adequate specificity and is suitable for self-sampling and inexpensive to allow population-based screening, particularly in LMICs. In this review, we summarize the markers of host cell gene/HR-HPV DNA methylation and discuss their triage performance and feasibility for high-grade precancerous cervical intraepithelial neoplasia or worse (CIN2+ and CIN3+) in HR-HPV-positive women.
Machine-Learning-Based Bibliometric Analysis of Pancreatic Cancer Research Over the Past 25 Years
Authors: Wang Kangtao , Herr Ingrid
Published: March 2022

Machine learning and semantic analysis are computer-based methods to evaluate complex relationships and predict future perspectives. We used these technologies to define recent, current and future topics in pancreatic cancer research. Publications indexed under the Medical Subject Headings (MeSH) term ‘Pancreatic Neoplasms’ from January 1996 to October 2021 were downloaded from PubMed. Using the statistical computing language R and the interpreted, high-level, general-purpose programming language Python, we extracted publication dates, geographic information, and abstracts from each publication’s metadata for bibliometric analyses. The generative statistical algorithm “latent Dirichlet allocation” (LDA) was applied to identify specific research topics and trends. The unsupervised “Louvain algorithm” was used to establish a network to identify relationships between single topics. A total of 60,296 publications were identified and analyzed. The publications were derived from 133 countries, mostly from the Northern Hemisphere. For the term “pancreatic cancer research”, 12,058 MeSH terms appeared 1,395,060 times. Among them, we identified the four main topics “Clinical Manifestation and Diagnosis”, “Review and Management”, “Treatment Studies”, and “Basic Research”. The number of publications has increased rapidly during the past 25 years. Based on the number of publications, the algorithm predicted that “Immunotherapy”, Prognostic research”, “Protein expression”, “Case reports”, “Gemcitabine and mechanism”, “Clinical study of gemcitabine”, “Operation and postoperation”, “Chemotherapy and resection”, and “Review and management” as current research topics. To our knowledge, this is the first study on this subject of pancreatic cancer research, which has become possible due to the improvement of algorithms and hardware.
Sex, Gender and Age Differences in Treatment Allocation and Survival of Patients With Metastatic Pancreatic Cancer: A Nationwide Study
Authors: Pijnappel Esther N. , Schuurman Melinda , Wagner Anna D. , de Vos-Geelen Judith , Geest Lydia G. M. van der , de Groot Jan-Willem B. , Koerkamp Bas Groot , de Hingh Ignace H. J. T. , Homs Marjolein Y. V. , Creemers Geert-Jan , Cirkel Geert A. , van Santvoort Hjalmar C. , Busch Olivier R. , Besselink Marc G. , van Eijck Casper H.J. , Wilmink Johanna W. , van Laarhoven Hanneke W. M.
Published: March 2022

Background

Biological sex, gender and age have an impact on the incidence and outcome in patients with metastatic pancreatic cancer. The aim of this study is to investigate whether biological sex, gender and age are associated with treatment allocation and overall survival (OS) of patients with metastatic pancreatic cancer in a nationwide cohort.

Methods

Patients with synchronous metastatic pancreatic cancer diagnosed between 2015 and 2019 were selected from the Netherlands Cancer Registry (NCR). The association between biological sex and the probability of receiving systemic treatment were examined with multivariable logistic regression analyses. Kaplan Meier analyses with log-rank test were used to describe OS.

Results

A total of 7470 patients with metastatic pancreatic cancer were included in this study. Fourty-eight percent of patients were women. Women received less often systemic treatment (26% vs. 28%, P=0.03), as compared to men. Multivariable logistic regression analyses with adjustment for confounders showed that women ≤55 years of age, received more often systemic treatment (OR 1.82, 95% CI 1.24-2.68) compared to men of the same age group. In contrast, women at >55 years of age had a comparable probability to receive systemic treatment compared to men of the same age groups. After adjustment for confounders, women had longer OS compared to men (HR 0.89, 95% CI 0.84-0.93).

Conclusion

This study found that women in general had a lower probability of receiving systemic treatment compared to men, but this can mainly be explained by age differences. Women had better OS compared to men after adjustment for confounders.
Cytokine Release Syndrome and Associated Acute Toxicities in Pediatric Patients Undergoing Immune Effector Cell Therapy or Hematopoietic Cell Transplantation
Authors: Baumeister Susanne H. C. , Mohan Gopi S. , Elhaddad Alaa , Lehmann Leslie
Published: March 2022

Immune effector cells (IEC) are a powerful and increasingly targeted tool, particularly for the control and eradication of malignant diseases. However, the infusion, expansion, and persistence of autologous or allogeneic IEC or engagement of endogenous immune cells can be associated with significant systemic multi-organ toxicities. Here we review the signs and symptoms, grading and pathophysiology of immune-related toxicities arising in the context of pediatric immunotherapies and haploidentical T cell replete Hematopoietic Cell Transplantation (HCT). Principles of management are discussed with particular focus on the intersection of these toxicities with the requirement for pediatric critical care level support.
Targeting Epigenetic Regulatory Enzymes for Cancer Therapeutics: Novel Small-Molecule Epidrug Development
Authors: Jin Ye , Liu Tianjia , Luo Haoming , Liu Yangyang , Liu Da
Published: March 2022

Dysregulation of the epigenetic enzyme-mediated transcription of oncogenes or tumor suppressor genes is closely associated with the occurrence, progression, and prognosis of tumors. Based on the reversibility of epigenetic mechanisms, small-molecule compounds that target epigenetic regulation have become promising therapeutics. These compounds target epigenetic regulatory enzymes, including DNA methylases, histone modifiers (methylation and acetylation), enzymes that specifically recognize post-translational modifications, chromatin-remodeling enzymes, and post-transcriptional regulators. Few compounds have been used in clinical trials and exhibit certain therapeutic effects. Herein, we summarize the classification and therapeutic roles of compounds that target epigenetic regulatory enzymes in cancer treatment. Finally, we highlight how the natural compounds berberine and ginsenosides can target epigenetic regulatory enzymes to treat cancer.
Patient-Reported Financial Burden Following Stereotactic Body Radiation Therapy for Localized Prostate Cancer
Authors: Sholklapper Tamir N. , Creswell Michael L. , Payne Alexandra T. , Markel Michael , Pepin Abigail , Carrasquilla Michael , Zwart Alan , Danner Malika , Ayoob Marilyn , Yung Thomas , Collins Brian , Kumar Deepak , Aghdam Nima , Suy Simeng , Hankins Ryan A. , Kowalczyk Keith , Collins Sean P.
Published: March 2022

Introduction and Objectives

In patients with localized prostate cancer, 5-fraction, stereotactic body radiation therapy (SBRT) has been found to offer comparable oncologic outcomes and potential for improved treatment compliance compared to conventional, 40-plus fraction radiation therapy (RT). Recent studies of oncologic patient experiences have highlighted both the impact of therapy-associated financial toxicity (FT) on treatment adherence and health-related quality of life (HRQOL).

Methods

A cross-sectional assessment of FT after SBRT was performed using the 12-item COST questionnaire. The total questionnaire score (range 0–44) was used to evaluate the FT grade (0–3), with a higher COST value representing lower grade. The patient zip code was used to approximate the distance from the index hospital. Univariate and multivariate analyses of the average COST score (0–4) are performed.

Results

The response rate was 57.5% (332 of 575 consented patients) with 90.7%, 8.2%, and 1.1% experiencing grade 0, 1, and 2 FT, respectively, with no grade 3. Unemployment or disability, non-white race, low income, and concurrent hormonal therapy were associated with a statistically significant worse FT (lower COST value) on univariate and multivariate analyses (p < 0.05). Education level and insurance status significant were evaluated on univariate analysis only. There was a non-statistically significant difference in age, marital status, time since treatment, and distance from the index hospital.

Conclusions

SBRT was associated with low FT. However, statistically significant socioeconomic disparities in FT remain despite ultra-hypofractionated treatment.
Chronic Stress Does Not Influence the Survival of Mouse Models of Glioblastoma
Authors: Lopes Marta , Vieira de Castro Joana , Pojo Marta , Gonçalves Céline S. , Martins Eduarda P. , Coimbra Bárbara , Sotiropoulos Ioannis , Sousa Nuno , Rodrigues Ana João , Costa Bruno M.
Published: March 2022

The existence of a clear association between stress and cancer is still a matter of debate. Recent studies suggest that chronic stress is associated with some cancer types and may influence tumor initiation and patient prognosis, but its role in brain tumors is not known. Glioblastoma (GBM) is a highly malignant primary brain cancer, for which effective treatments do not exist. Understanding how chronic stress, or its effector hormones glucocorticoids (GCs), may modulate GBM aggressiveness is of great importance. To address this, we used both syngeneic and xenograftin vivoorthotopic mouse models of GBM, in immunocompetent C57BL/6J or immunodeficient NSG mice, respectively, to evaluate how different paradigms of stress exposure could influence GBM aggressiveness and animals’ overall survival (OS). Our results demonstrated that a previous exposure to exogenous corticosterone administration, chronic restraint stress, or chronic unpredictable stress do not impact the OS of these mice models of GBM. Concordantly,ex vivoanalyses of various GBM-relevant genes showed similar intra-tumor expression levels across all experimental groups. These findings suggest that corticosterone and chronic stress do not significantly affect GBM aggressiveness in murine models.
The Mitochondrial Routing of the Kv1.3 Channel
Authors: Capera Jesusa , Navarro-Pérez María , Moen Anne Stine , Szabó Ildiko , Felipe Antonio
Published: March 2022

Voltage-gated potassium channels control neuronal excitability and cardiac action potentials. In addition, these proteins are involved in a myriad of cellular processes. The potassium channel Kv1.3 plays an essential role in the immune response mediated by leukocytes. Kv1.3 is functional both at the plasma membrane and the inner mitochondrial membrane. Plasma membrane Kv1.3 mediates cellular activation and proliferation, whereas mitochondrial Kv1.3 participates in cell survival and apoptosis. Therefore, this protein emerges as an important target in cancer therapies. Several forward-traffic motifs target the channel to the plasma membrane in a COPII-dependent manner. However, the mitochondrial import pathway for Kv1.3 is largely unknown. Here, we deciphered the mitochondrial routing of the mitoKv1.3 channel. Kv1.3 uses the TIM23 complex to translocate to the inner mitochondrial membrane. This mechanism is unconventional because the channel is a multimembrane spanning protein without a defined N-terminal presequence. We found that transmembrane domains cooperatively mediate Kv1.3 mitochondrial targeting and identified the cytosolic HSP70/HSP90 chaperone complex as a key regulator of the process. Our results provide insights into the mechanisms mediating the localization of Kv1.3 to mitochondrial membranes, further extending the knowledge of ion channel biogenesis and turnover in mitochondria.
Sensitive Skin Syndrome: A Low-Noise Small-Fiber Neuropathy Related to Environmental Factors?
Authors: Misery Laurent , Bataille Adeline , Talagas Matthieu , Le Gall-Ianotto Christelle , Fouchard Maxime , Huet Flavien , Ficheux Anne-Sophie , Roudot Alain-Claude , Fluhr Joachim W. , Brenaut Emilie
Published: March 2022

Background and Objectives

Patients frequently complain of mild, transient, unpleasant skin sensations that cannot be diagnosed as common neuropathies. Dermatologists have termed these symptoms “sensitive skin syndrome.” This narrative review was performed for a better knowledge by other specialists.

Databases and Data Treatment

Publications on pain in sensitive skin syndrome were obtained from PubMed.

Results

There is a growing body of data supporting the concept that sensitive skin is a type of small-fiber neuropathy. The arguments are based on clinical data, a decrease in intra-epidermal nerve fiber density, quantitative sensory testing abnormalities and an association with irritable bowel syndrome and sensitive eyes. Sensitive skin is triggered by environmental factors. Sensitive skin is a frequent condition, with a lifetime prevalence of ~50% according to self-reports.

Conclusions

Mild levels of skin pain or itch are frequently experienced by patients, who rarely report them. There is a need for a better knowledge of sensitive skin because it can be the first level of small-fiber neuropathies.
Determinants of Postnatal Care and Timing of the First Postnatal Care for Newborns in Ethiopia: Further Analysis of 2019 Ethiopian Demographic and Health Survey
Authors: Kebede Sewnet Adem , Weldesenbet Adisu Birhanu , Tusa Biruk Shalmeno
Published: March 2022

Background

Neonatal mortality remains a persisting public health challenge in Ethiopia. Most of the factors that lead to neonatal deaths could be prevented through postnatal checkups. However, in Ethiopia, the provision of postnatal care (PNC) continues to be low. This study aims to assess the socioeconomic and demographic factors associated with PNC visits and the timing of PNC among newborns in Ethiopia.

Methods

Using the Ethiopia Mini Demographic and Health Survey (EMDHS) 2019, a total weighted sample of 2,105 women aged 15–49 giving birth in the 2 years preceding the survey were included in the study. The generalized linear mixed models were separately fitted to identify factors associated with any PNC for newborns delivered at home and health facilities. Multinomial logistic regression was used to assess the timing of PNC with their associated factors.

Results

Overall, only 13% (95% CI: 11.2, 14.0) of the newborns received PNC in Ethiopia. Among newborns delivered at home, utilization of any PNC was determined by region, maternal educational status, and birth order. On the other hand, among newborns delivered in a health facility, region, number of antenatal care (ANC) visits, and religion were determinants of any PNC. Furthermore, utilization of the first PNC within 48 h after the delivery was determined by region and religion. On the other hand, utilization of the first PNC after 48 h after the delivery was determined by region number of ANC visits, maternal educational status, and religion.

Conclusion

The finding of the current study revealed low coverage of PNC among newborns regardless of the place of delivery in Ethiopia. The study makes the following recommendation: increase community health education on PNC, encourage delivery at health facilities, and link community home birth with PNC. It will be more valuable if there is sharing good practice.
Anti-Inflammatory Effects of Ginsenoside Rb3 in LPS-Induced Macrophages Through Direct Inhibition of TLR4 Signaling Pathway
Authors: Xu Honglin , Liu Min , Chen Guanghong , Wu Yuting , Xie Lingpeng , Han Xin , Zhang Guoyong , Tan Zhangbin , Ding Wenjun , Fan Huijie , Chen Hongmei , Liu Bin , Zhou Yingchun
Published: March 2022

Panax ginseng has therapeutic effects on various inflammation-related diseases. Ginsenoside Rb3 (GRb3), a natural compound with anti-inflammatory and immunomodulatory properties, is one of the main active panaxadiol extracted from Panax ginseng. We explored whether GRb3 inhibited LPS-mediated inflammation through TLR4/NF-κB/MAPK signaling in macrophages. GRb3 attenuated NO and PGE2 production by attenuating iNOS and COX2 expression. GRb3 also suppressed pro-inflammatory cytokines levels, including IL-1β, IL-6, and TNF-α. Moreover, GRb3 administration significantly suppressed NF-κB (p65) nuclear translocation and the phosphorylation levels of p65, IκBα, JNK, p38, and ERK dose-dependently. Molecular docking demonstrated that GRb3 could dock onto the hydrophobic binding site of TLR4/MD2 complex, with a binding energy of −8.79 kcal/mol. Molecular dynamics (MD) displayed stable TLR4-MD2-GRb3 modeling. GRb3 dose-dependently inhibited LPS binding to cell membranes and blocked TLR4 expression. Surface plasmon resonance imaging (SPRi) revealed that GRb3 had an excellent binding affinity to TLR4/MD2 complex. Notably, resatorvid (TAK242), a selective TLR4 inhibitor, did not increase the repressive influence of GRb3 in RAW264.7 macrophages. Moreover, TLR4 overexpression partially reversed the repressive roles of GRb3 on the NF-κB/MAPK pathway and inflammatory mediators. Collectively, our study strongly indicated that GRb3 attenuated LPS-mediated inflammation through direct inhibition of TLR4 signaling. A novel insight into the underlying mechanism of anti-inflammatory effects of GRb3 in macrophages was confirmed.
Defining Molecular Treatment Targets for Bladder Pain Syndrome/Interstitial Cystitis: Uncovering Adhesion Molecules
Authors: Inal-Gultekin Guldal , Gormez Zeliha , Mangir Naside
Published: March 2022

Bladder pain syndrome/interstitial cystitis (BPS/IC) is a debilitating pain syndrome of unknown etiology that predominantly affects females. Clinically, BPS/IC presents in a wide spectrum where all patients report severe bladder pain together with one or more urinary tract symptoms. On bladder examination, some have normal-appearing bladders on cystoscopy, whereas others may have severely inflamed bladder walls with easily bleeding areas (glomerulations) and ulcerations (Hunner’s lesion). Thus, the reported prevalence of BPS/IC is also highly variable, between 0.06% and 30%. Nevertheless, it is rightly defined as a rare disease (ORPHA:37202). The aetiopathogenesis of BPS/IC remains largely unknown. Current treatment is mainly symptomatic and palliative, which certainly adds to the suffering of patients. BPS/IC is known to have a genetic component. However, the genes responsible are not defined yet. In addition to traditional genetic approaches, novel research methodologies involving bioinformatics are evaluated to elucidate the genetic basis of BPS/IC. This article aims to review the current evidence on the genetic basis of BPS/IC to determine the most promising targets for possible novel treatments.
Incremental Concentrations of Tacrolimus Eye Drops as a Strategy for the Management of Severe Vernal Keratoconjunctivitis
Authors: Albarry Maan Abdullah , Parekh Mohit , Ferrari Stefano , Eltahir Heba Mahmoud , Shehata Ahmed M , Shaker Mohamed A , Elbadawy Hossein Mostafa
Published: March 2022

Purpose: To assess the effect of different concentrations of tacrolimus eye suspension on the epithelium and stromal keratocytes of human corneas and investigate whether it can be safely used for severe cases of vernal keratoconjunctivitis (VKC).

Methods: Tacrolimus eye suspension was prepared in a range of concentrations of 0.005%, 0.01%, 0.05%, 0.1%, and 0.2%. Molecular analysis was performed ex vivo on human corneas (n = 18), obtained from the eye bank. Transparency and thickness of each cornea were measured while live/dead staining was performed using a triple labeling assay. An incremental concentration approach was then tested on three severe cases of VKC.

Results: All tested tacrolimus concentrations showed no significant changes in corneal thickness or transparency. In corneas treated with 0.1%, rare scattered dead cells were observed, while the folds of corneal surfaces were mostly viable, unlike concentrations higher than 0.1% and lower than 0.05%. Stromal cell densities were highest in the 0.1% tacrolimus treatment condition. Incremental concentrations of tacrolimus suspension were shown to significantly improve VKC cases, where the concentration used for each case depended on the severity of the case.

Conclusions: Topical administration of tacrolimus was not toxic to human corneal cells at all tested concentrations, and the 0.1% concentration has shown the best viability of the corneal tissue. Tacrolimus eye suspension was shown to be safe and effective for use in severe VKC and is proposed as a topical ocular immunosuppressant drug enabling clinicians to incrementally increase the drug concentration according to the clinical severity of the disease to achieve the optimal therapeutic response.
JAK/STAT Signaling: Molecular Targets, Therapeutic Opportunities, and Limitations of Targeted Inhibitions in Solid Malignancies
Authors: Rah Bilal , Rather Rafiq A , Bhat Gh Rasool , Baba Abdul Basit , Mushtaq Ifra , Farooq Muzamil , Yousuf Tahira , Dar Sadaf B , Parveen Sabra , Hassan Rukhsana , Mohammad Fozia , Qassim Iqbal , Bhat Abida , Ali Shazia , Zargar Mahrukh Hamid , Afroze Dil
Published: March 2022

JAK/STAT signaling pathway is one of the important regulatory signaling cascades for the myriad of cellular processes initiated by various types of ligands such as growth factors, hormones, and cytokines. The physiological processes regulated by JAK/STAT signaling are immune regulation, cell proliferation, cell survival, apoptosis and hematopoiesis of myeloid and non-myeloid cells. Dysregulation of JAK/STAT signaling is reported in various immunological disorders, hematological and other solid malignancies through various oncogenic activation mutations in receptors, downstream mediators, and associated transcriptional factors such as STATs. STATs typically have a dual role when explored in the context of cancer. While several members of the STAT family are involved in malignancies, however, a few members which include STAT3 and STAT5 are linked to tumor initiation and progression. Other STAT members such as STAT1 and STAT2 are pivotal for antitumor defense and maintenance of an effective and long-term immune response through evolutionarily conserved programs. The effects of JAK/STAT signaling and the persistent activation of STATs in tumor cell survival; proliferation and invasion have made the JAK/STAT pathway an ideal target for drug development and cancer therapy. Therefore, understanding the intricate JAK/STAT signaling in the pathogenesis of solid malignancies needs extensive research. A better understanding of the functionally redundant roles of JAKs and STATs may provide a rationale for improving existing cancer therapies which have deleterious effects on normal cells and to identifying novel targets for therapeutic intervention in solid malignancies.
Association Between Aspirin Usage and Age-Related Macular Degeneration: An Updated Systematic Review and Meta-analysis
Authors: Yan Ruijia , Zhao Jing , Zhang Xinai , Wang Wei , Jiang Zhengyao
Published: March 2022

Purpose: To investigate the association between long-term use of aspirin and age-related macular degeneration (AMD).

Methods: An updated systematic literature search was conducted in PubMed, Medline, Cochrane Library, and embase from conception to February 26, 2021, without any language restriction. All studies that evaluated the relationship between long-term aspirin use and AMD were included.

Results: In the current study, 16 articles were pooled. Overall, no significant association was observed (estimate ratio = 1.108, 95% confidence interval (CI): 0.886–1.385). When the subgroups were evaluated according to various standards, aspirin use was significantly correlated with AMD in studies with volunteer participants (estimate ratio = 0.899, 95% CI: 0.830–0.974, p < 0.01), studies followed up for >10 years (estimate ratio = 2.206, 95% CI: 2.124–2.292, p < 0.01), duration of aspirin use >10 years (estimate ratio = 2.323, 95% CI: 2.234–2.416, p < 0.01), and cohort studies (estimate ratio = 1.961, 95% CI: 1.893–2.032, p < 0.01).

Conclusion: Therefore, the association of aspirin and AMD can be demonstrated with a long-term follow-up or aspirin use, appropriate study design and participant source. The findings in our study might provide practical information on intervention strategies.
Isorhamnetin Alleviates Airway Inflammation by Regulating the Nrf2/Keap1 Pathway in a Mouse Model of COPD
Authors: Xu Yifan , Li Jing , Lin Zhiwei , Liang Weiquan , Qin Lijie , Ding Jiabin , Chen Shuqi , Zhou Luqian
Published: March 2022

Chronic obstructive pulmonary disease (COPD) is a severely disabling chronic lung disease characterized by persistent airway inflammation, which leads to limited expiratory airflow that deteriorates over time. Isorhamnetin (Iso) is one of the most important active components in the fruit ofHippophae rhamnoides L.and leaves ofGinkgo biloba L, which is widely used in many pulmonary disease studies because of its anti-inflammatory effects. Here, we investigated the pharmacological action of Iso in CS-induced airway inflammation and dissected the anti-inflammation mechanisms of Iso in COPD mice. A mouse model of COPD was established by exposure to cigarette smoke (CS) and intratracheal inhalation of lipopolysaccharide (LPS). Our results illustrated that Iso treatment significantly reduced leukocyte recruitment and excessive secretion of interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and regulated upon activation, normal T-cell expressed and secreted (RANTES) in BALF of CS-induced COPD mice in a dose-dependent manner. This improved airway collagen deposition and emphysema, and further alleviated the decline in lung functions and systemic symptoms of hypoxia and weight loss. Additionally, Iso treatment obviously improves the T lymphocyte dysregualtion in peripheral blood of COPD mice. Mechanistically, Iso may degrade Keap1 through ubiquitination of p62, thereby activating the nuclear factor erythroid 2-related factor (Nrf2) pathway to increase the expression of protective factors, such as heme oxygenase-1 (HO-1), superoxide dismutase (SOD) 1, and SOD2, in lungs of CS-exposed mice, which plays an anti-inflammatory role in COPD. In conclusion, our study indicates that Iso significantly alleviates the inflammatory response in CS-induced COPD mice mainly by affecting the Nrf2/Keap1 pathway. More importantly, Iso exhibited anti-inflammatory effects comparable with Dex in COPD and we did not observe discernible side effects of Iso. The high safety profile of Iso may make it a potential drug candidate for COPD.
Perftoran® Inhibits Hypoxia-Associated Resistance in Lung Cancer Cells to Carboplatin
Authors: Gamal-Eldeen Amira M. , Alrehaili Amani A. , Alharthi Afaf , Raafat Bassem M.
Published: March 2022

Perftoran® (perfluorodecalin) is an oxygen carrier, and carboplatin is a common chemotherapy drug used worldwide for lung cancer treatment. Hypoxia is one of the factors that induce resistance of lung cancer cells to carboplatin. This study explored the role of Perftoran®, as an oxygen carrier, in lowering the resistance of lung cancer cells to carboplatin through suppression of hypoxia pathway mediators. The effect of Perftoran® on the resistance of human lung cancer A549 cells to carboplatin was investigated through the evaluation of cytotoxicity by MTT, cell death mode by dual DNA staining, DNA damage by comet assay, DNA platination (DNA/carboplatin adducts) by atomic absorption spectroscopy, hypoxia degree by pimonidazole, HIF-1α/HIF-2α concentrations by ELISA, expression of miRNAs (hypoxamiRs miR-210, miR-21, and miR-181a) by qRT-PCR, and the content of drug resistance transporter MRP-2 by immunocytochemical staining. Results indicated that compared to carboplatin, Perftoran®/carboplatin decreased cell resistance to carboplatin by potentiating its cytotoxicity using only 45% of carboplatin IC50 and inducing apoptosis. Perftoran® induced DNA platination and DNA damage index in cells compared to carboplatin alone. Moreover, compared to treatment with carboplatin alone, co-treatment of cells with Perftoran® and carboplatin inhibited cellular pimonidazole hypoxia adducts, diminished HIF-1α/HIF-2α concentrations, suppressed hypoxamiR expression, and decreased MRP-2. In conclusion, Perftoran® inhibited resistance of lung cancer cells to carboplatin through the inhibition of both hypoxia pathway mediators and the drug resistance transporter MRP-2 and through the induction of DNA/carboplatin adduct formation.
Integrating Pharmacy and Registry Data Strengthens Clinical Assessments of Patient Adherence
Authors: Serhal Sarah , Armour Carol , Billot Laurent , Krass Ines , Emmerton Lynne , Saini Bandana , Bosnic-Anticevich Sinthia , Bereznicki Bonnie , Bereznicki Luke , Shan Sana , Campain Anna
Published: March 2022

Background: Accurate clinical assessment of patient adherence using reliable and valid measures is essential in establishing the presence of adherence issues and support practices for pharmacists.

Objective: This investigation aims to conduct a novel assessment of patient adherence to asthma controller therapy by combining 1) patient-specific dosage data found in pharmacy dispensing data with 2) centrally collected administrative claims records, to determine the added value of using both sources of data.

Methods: A total of 381 clinically uncontrolled asthma patients, from 95 community pharmacies across three Australian States were recruited and provided consent for the retrieval of their claims records and pharmacy dispensing data. Patients were stratified as multiple or single pharmacy users and adherence scores were calculated via the proportion of days covered (PDC) method using 1) patient claims records, 2) patient pharmacy dispensing data, and 3) combined claims records and pharmacy dispensing data. Cohort and subgroup adherence estimates were then compared.

Results: Low levels of adherence were evident amongst the cohort irrespective of the data source used. PDC estimates based on claims records alone or combined claims records and pharmacy dispensing data were significantly higher than estimates based on pharmacy dispensing data for the total cohort (56%, 52%, 42% respectively, p < 0.001) and more noticeably for multiple pharmacy users (67%, 64%, 35% respectively, p < 0.001). PDC estimates based on combined claims records and pharmacy dispensing data were significantly lower than estimates based on claims records alone, indicating that perhaps standard daily dose is not a robust proxy for prescribed dosage to inhaled respiratory devices in adherence approximations. Poorer adherence was found amongst single pharmacy users than multiple pharmacy users when combined claims records and pharmacy dispensing data (46% compared to 64% respectively, p < 0.001) or claims records alone (51% compared to 67% respectively, p < 0.001) were compared.

Conclusion: Access to routine collected data increases clinical acuity over patient adherence to asthma controller medications and is a valuable resource for health care professionals. A policy of secure accessibility of such data at the patient-pharmacist or patient-GP interface may allow real-time intervention and assist in decision making across numerous therapeutic areas.