bluuebunny/crossref_metadata_2025 huggingface dataset:
Potential 18F-RGD PET/CT and DCE-MRI Imaging-Based Biomarkers for Postoperative Survival Prediction Among Patients With Newly Diagnosed Glioblastoma Treated With Bevacizumab and Chemoradiotherapy
Authors: Li Li , Liu Ning , Zhang Hui , Tao Rongjie , Zhao Shuqiang , Chen Zhaoqiu , Fu Zheng , Li Wanhu , Xu Liang , Liu Yuhui , Yu Jinming , Yuan Shuanghu
Published: August 2022

Purpose

To investigate the ability of potential imaging biomarkers based on 18F-AlF-NOTA-PRGD2 positron emission tomography/computed tomography (18F-RGD PET/CT) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) imaging to predict the response to bevacizumab combined with conventional therapy in postoperative newly diagnosed glioblastoma.

Methods

Twenty patients with newly diagnosed with glioblastoma after surgery were prospectively enrolled to receive bevacizumab plus conventional concurrent radiotherapy and temozolomide (CCRT). 18F-RGD PET/CT and DCE-MRI were performed at baseline, week 3, and week 10 for each patient. Statistical methods included the analysis of variance (ANOVA), Kaplan–Meier method and Cox proportional hazard analysis.

Results

All patients completed CCRT plus bevacizumab therapy without interruption. The median follow-up time was 33.9 months (95% confidence interval [CI], 28.3-39.5 months). The median progression-free survival (PFS) and overall survival (OS) was 9.66 months (95% CI, 6.20-13.12 months) and 15.89 months (95% CI, 13.89-17.78), respectively. Treatment was generally well tolerated, and there were no Treatment emergent adverse events (TEAEs) with a toxicity grade equal to or exceeding 3 or that led to termination of treatment or patient death.Over the treatment interval of bevacizumab therapy from week 3 to week 10, patients with a large decrease of SUVmean was associated with a better PFS with a hazard ratio (HR) of 6.562, 95% CI (1.318-32.667), p=0.022. According to Kaplan-Meier analysis, patients with a decrease in the SUVmean of more than 0.115 on 18F-RGD PET/CT had a longer PFS than those with a decrease in the SUVmean of 0.115 or less (12.25 months vs.7.46 months, p=0.009). For OS, only a small decrease of Ktrans was also found to have certain prognostic value (HR=0.986, 95% CI (0.975-0.998), p=0.023). Patients with a decrease in Ktrans larger than 37.03 (min-1) on DCE-MRI had worse OS than those with a decrease in Ktrans of 37.03 (min-1) or less (15.93 months vs. 26.42 months, p=0.044).

Conclusion

18F-RGD PET/CT and DCE-MRI may be valuable in evaluating the response of glioblastoma to treatment with the combination of bevacizumab and CCRT, with a greater decrease in SUVmean predicting better PFS as well as a small decrease in Ktrans predicting improved OS.
DNA methylation regulators-related molecular patterns and tumor immune landscape in hepatocellular carcinoma
Authors: Song Dingli , Zhou Zhenyu , Wu Jie , Wei Tao , Zhao Guang , Ren Hong , Zhang Boxiang
Published: August 2022

Increasing evidence showed that the dysregulation of DNA methylation regulators is a decisive feature of almost all cancer types and affects tumor progressions. However, few studies focused on the underlying influences of DNA methylation regulators-related genes (DMRegs) in immune cell-infiltration characteristics, tumor microenvironment (TME) and immunotherapy in HCC patients. In our study, the alterations of DNA methylation regulators modification patterns (DMRPs) were clustered from hepatocellular carcinoma (HCC) samples based on the expression of DNA methylation regulators as well as genetic and transcriptional features. In addition, based on molecular identification of three distinct molecular subtypes, we found that different DMRPs alterations were related to different clinicopathological characteristics, prognosis, and immune cells infiltration features. Moreover, we constructed and validated a DNA methylation regulators-related genes score (DMRegs_score) to predict the survival of HCC patients. A high DMRegs _score, which was characterized by more TP53 wild mutation, high expression of PD-1, CTLA-4, and remarkable immunity activation, was indicative of poor prognosis. Furthermore, we validated the expression of eight genes which were used for the prognostic signature in this risk score by RT-qPCR using tissues from our center. More importantly, DMRegs_score was highly correlated with targeted drug sensitivity. Additionally, we developed a highly accurate scoring system that could be used to improve the clinical applicability of DMRegs _score. In conclusion, these findings may contribute to a better understanding of DNA methylation regulators and provide new strategies for evaluating prognosis and developing more effective combination therapy for HCC patients.
Different functional lung-sparing strategies and radiotherapy techniques for patients with esophageal cancer
Authors: Zhou Pi-Xiao , Wang Rui-Hao , Yu Hui , Zhang Ying , Zhang Guo-Qian , Zhang Shu-Xu
Published: August 2022

Background

Integration of 4D-CT ventilation function images into esophageal cancer radiation treatment planning aimed to assess dosimetric differences between different functional lung (FL) protection strategies and radiotherapy techniques.

Methods

A total of 15 patients with esophageal cancer who had 4D-CT scans were included. Lung ventilation function images based on Jacobian values were obtained by deformation image registration and ventilation imaging algorithm. Several different plans were designed for each patient: clinical treatment planning (non-sparing planning), the same beam distribution to FL-sparing planning, three fixed-beams FL-sparing intensity-modulated radiation therapy (IMRT) planning (5F-IMRT, 7F-IMRT, 9F-IMRT), and two FL-sparing volumetric modulated arc therapy (VMAT) planning [1F-VMAT (1-Arc), 2F-VMAT (2-Arc)]. The dosimetric parameters of the planning target volume (PTV) and organs at risk (OARs) were compared and focused on dosimetric differences in FL.

Results

The FL-sparing planning compared with the non-sparing planning significantly decreased the FL-Dmean, V5-30 and Lungs-Dmean, V10-30 (Vx: volume of receiving ≥X Gy), although it slightly compromised PTV conformability and increased Heart-V40 (P< 0.05). The 5F-IMRT had the lowest PTV-conformability index (CI) but had a lower Lungs and Heart irradiation dose compared with those of the 7F-IMRT and 9F-IMRT (P< 0.05). The 2F-VMAT had higher PTV-homogeneity index (HI) and reduced irradiation dose to FL, Lungs, and Heart compared to those of the 1F-VMAT planning (P< 0.05). The 2F-VMAT had higher PTV conformability and homogeneity and decreased FL-Dmean, V5-20 and Lungs-Dmean, V5-10 but correspondingly increased spinal cord-Dmean compared with those of the 5F-IMRT planning (P< 0.05).

Conclusion

In this study, 4D-CT ventilation function image-based FL-sparing planning for esophageal cancer can effectively reduce the dose of the FL. The 2F-VMAT planning is better than the 5F-IMRT planning in reducing the dose of FL.
Patient-reported outcomes for patients with breast cancer undergoing radiotherapy: A single-center registry experience
Authors: Laughlin Brady S. , Bhangoo Ronik S. , Thorpe Cameron S. , Golafshar Michael A. , DeWees Todd A. , Anderson Justin D. , Vern-Gross Tamara Z. , McGee Lisa A. , Wong William W. , Halyard Michele Y. , Keole Sameer R. , Vargas Carlos E.
Published: August 2022

Background

We present Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) for patients undergoing adjuvant radiotherapy for breast cancer with curative intent. We describe the frequency and severity of PRO-CTCAE and analyze them with respect to dose fractionation.

Methods

Patients were included in this study if they were treated with curative intent for breast cancer and enrolled on a prospective registry. Patients must have completed at least one baseline and one post-radiation survey that addressed PRO-CTCAE. For univariate and multivariate analysis, categorical variables were analyzed by Fisher’s exact test and continuous variables by Wilcoxon rank sum test. PRO-CTCAE items graded ≥2 and ≥3 were analyzed between patients who received hypofractionation (HF) versus standard conventional fractionation (CF) therapy by the Chi-square test.

Results

Three hundred thirty-one patients met inclusion criteria. Pathologic tumor stage was T1–T2 in 309 (94%) patients. Eighty-seven (29%) patients were node positive. Two hundred forty-seven patients (75%) experienced any PRO-CTCAE grade ≥2, and 92 (28%) patients experienced any PRO-CTCAE grade ≥3. CF was found to be associated with an increased risk of grade ≥3 skin toxicity, swallowing, and nausea (all p < 0.01). HF (OR 0.48, p < 0.01) was significant in the multivariate model for decreased risk of any occurrence of PRO-CTCAE ≥3.

Conclusions

Our study reports one of the first clinical experiences utilizing multiple PRO-CTCAE items for patients with breast cancer undergoing radiation therapy with curative intent. Compared with CF, HF was associated with a significant decrease in any PRO-CTCAE ≥3 after multivariate analysis.
The 18F-PSMA-1007 PET/CT performance on metastasis status and therapy assessment in oligo-metastasis prostate cancer
Authors: Wang Zhuonan , Zheng Anqi , Li Yunxuan , Gao Jungang , Dong Weixuan , Li Yan , Duan Xiaoyi
Published: August 2022

Objective

The prostate-specific membrane antigen (PSMA) PET/CT is potentially identifying patients with oligo-metastasis who would be deemed to only have localized disease in the traditional approaches. However, the best selected oligo-metastasis prostate cancer (PCa) patients most likely to benefit from system androgen deprivation therapy (ADT) are still unknown. The aim of this study was to explore the potential 18F-PSMA-1007 PET/CT parameters and clinicopathologic characteristics for oligo-metastasis PCa discrimination and follow-up evaluation.

Materials and methods

A total of 180 retrospective patients with different metastasis burdens (PCa of none-metastases, oligo-metastases, and poly-metastases), different metastasis status (untreated and recurrent oligo-metastases), and follow-up ADT were included respectively. A one-way analysis of variance was used to evaluate whether PET/CT parameters and clinicopathologic characteristics were different and univariate/multivariate logistic regression models were applied to assess independent predictors in the metastasis burdens group (89/180). Selected predictors were further compared between different metastasis statuses to test the diagnostic accuracy (69/180). The predictor efficiency was evaluated by the ROC and the cut-off value was used to test the ADT response-to-treatment with a longitudinal cohort (22/180) from untreated baseline to 3-15 months.

Results

The significant group differences were observed on SUVmax (P = 0.012), International Society of Urologic Pathologists (ISUP, P<0.001) and Gleason Score (P<0.001). Poly-Metastases patients had higher SUVmax, ISUP and Gleason Score compared to Non-Metastases and Oligo-Metastases patients, respectively (P<0.05, all), and no difference between Non-Metastases and Oligo-Metastases. The SUVmax, ISUP and Gleason Score were independent predictors for metastasis burdens discrimination. The untreated and recurrent oligo-metastases lesions SUVmax were also different (P = 0.036). The AUC of ROC for oligo-metastasis prediction was 0.658 (P = 0.039) when the primary prostatic carcinoma focus SUVmax was higher than 28.22, ADT response-to-treatment patients (5/5 in 22) were all progress in a follow-up test.

Conclusion

The SUVmax can discriminate PCa metastasis degree and oligo-metastasis status. The ADT-treated oligo-metastasis patient may still have disease progression when the primary prostatic carcinoma focus SUVmax is greater than 28.22.
A happy cell stays home: When metabolic stress creates epigenetic advantages in the tumor microenvironment
Authors: Hanse Eric A. , Kong Mei
Published: August 2022

A paradox of fast-proliferating tumor cells is that they deplete extracellular nutrients that often results in a nutrient poor microenvironment in vivo. Having a better understanding of the adaptation mechanisms cells exhibit in response to metabolic stress will open new therapeutic windows targeting the tumor’s extreme nutrient microenvironment. Glutamine is one of the most depleted amino acids in the tumor core and here, we provide insight into how important glutamine and its downstream by-product, α-ketoglutarate (αKG), are to communicating information about the nutrient environment. This communication is key in the cell’s ability to foster adaptation. We highlight the epigenetic changes brought on when αKG concentrations are altered in cancer and discuss how depriving cells of glutamine may lead to cancer cell de-differentiation and the ability to grow and thrive in foreign environments. When we starve cells, they adapt to survive. Those survival “skills” allow them to go out looking for other places to live and metastasize. We further examine current challenges to modelling the metabolic tumor microenvironment in the laboratory and discuss strategies that consider current findings to target the tumor’s poor nutrient microenvironment.
Acidic urine is associated with poor prognosis in patients with bladder cancer undergoing radical cystectomy
Authors: Han Jang Hee , Jeong Seung-hwan , Yuk Hyeong Dong , Jeong Chang Wook , Kwak Cheol , Ku Ja Hyeon
Published: August 2022

Purpose

To assess the prognostic value of acidic urine (low urine pH) in patients with bladder cancer undergoing radical cystectomy.

Materials and methods

We reviewed patients enrolled in the Seoul National University Prospectively Enrolled Registry for Urothelial Cancer-Cystectomy (SUPER-UC-Cx) who underwent radical cystectomy for bladder cancer between March 2016 and December 2020 at the Seoul National University Hospital. During this period, 368 patients were registered in our database. To eliminate confounding factors, we excluded patients diagnosed with non-urothelial cancer and end-stage renal disease.

Results

A total of 351 patients with a mean age of 69.8 ± 10.5 years and median follow-up of 16.0 months were eligible for the analysis. The mean preoperative urine pH was 6.0. The patients were divided into low (pH ≤ 5.5) and high (pH≥6.0) urine pH groups for comparison. All clinicopathological features, including the tumor size, grade, and stage were comparable between the low and high urine pH groups. A Cox regression analysis was performed to assess the independent effect of acidic urine on patient survival. A multivariate analysis showed that high T stage (T3-4) (hazard ratio (HR) 5.18, P<0.001), decreased renal function (estimated glomerular filtration rate <60 mL/min/1.73 m2) (HR 2.29, P=0.003), and low urine pH (≤5.5) (HR 1.69, P=0.05) were associated with shortened recurrence-free survival (RFS). Regarding the overall survival (OS), high T stage (T3-4) (HR 7.15, P<0.001) and low urine pH (≤5.5) (HR 2.66, P=0.029) were significantly associated with shortened survival. A Kaplan–Meier analysis demonstrated that the acidic urine group showed shorter RFS (P=0.04) and OS (P=0.028) than the other groups.

Conclusions

Acidic urine was independently associated with reduced RFS and OS in patients with bladder cancer undergoing radical cystectomy. Acidic urine contributing to an acidic tumor environment may promote aggressive behavior in bladder cancer.
MRI-guided focal or integrated boost high dose rate brachytherapy for recurrent prostate cancer
Authors: Ménard Cynthia , Navarro-Domenech Inmaculada , Liu Zhihu (Amy) , Joseph Lisa , Barkati Maroie , Berlin Alejandro , Delouya Guila , Taussky Daniel , Beauchemin Marie-Claude , Nicolas Benedicte , Kadoury Samuel , Rink Alexandra , Raman Srinivas , Sundaramurthy Aravindhan , Weersink Robert , Beliveau-Nadeau Dominic , Helou Joelle , Chung Peter
Published: August 2022

Background and purpose

Locally recurrent prostate cancer after radiotherapy merits an effective salvage strategy that mitigates the risk of adverse events. We report outcomes of a cohort enrolled across two institutions investigating MRI-guided tumor-targeted salvage high dose rate brachytherapy (HDR-BT).

Materials and methods

Analysis of a prospective cohort of 88 patients treated across two institutions with MRI-guided salvage HDR-BT to visible local recurrence after radiotherapy (RT). Tumor target dose ranged from 22-26 Gy, using either an integrated boost (ibBT) or focal technique (fBT), delivered in two implants over a median of 7 days. Outcome metrics included cancer control and toxicity (CTCAE). Quality of life (QoL-EPIC) was analyzed in a subset.

Results

At a median follow-up of 35 months (6 -134), 3 and 5-year failure-free survival (FFS) outcomes were 67% and 49%, respectively. At 5 years, fBT was associated with a 17% cumulative incidence of local failure (LF) outside the GTV (vs. 7.8% ibBT, p=0.14), while LF within the GTV occurred in 13% (vs. 16% ibBT, p=0.81). Predictors of LF outside fBT volumes included pre-salvage PSA>7 ng/mL (p=0.03) and interval since RT less than 5 years (p=0.04). No attributable grade 3 events occurred, and ibBT was associated with a higher rate of grade 2 toxicity (p<0.001), and trend towards a larger reduction in QoL sexual domain score (p=0.07), compared to fBT.

Conclusion

A tumor-targeted HDR-BT salvage approach achieved favorable cancer control outcomes. While a fBT was associated with less toxicity, it may be best suited to a subgroup with lower PSA at later recurrence. Tumor targeted dose escalation may be warranted.
Active surveillance of highly suspicious thyroid nodules cohort in China shows a worse psychological status in younger patients
Authors: Liu Chunhao , Zhao Hao , Xia Yu , Cao Yue , Zhang Liyang , Zhao Ya , Gao Luying , Liu Ruifeng , Liu Yuewu , Liu Hongfeng , Meng Zhilan , Liu Shuzhou , Li Xiaoyi
Published: August 2022

Background

Active surveillance has been considered a safe alternative to surgery for low-risk papillary thyroid microcarcinoma. This study aimed to assess the oncological outcomes and psychological status of active surveillance of highly suspicious thyroid nodules ≤10 mm in China.

Methods

This prospective single-center cohort study enrolled 336 patients with highly suspicious thyroid nodules for active surveillance to assess oncological outcomes and psychological status. The psychological status of patients was assessed by two different questionnaires and compared among different patient groups.

Results

During a median follow-up period of 28.5 months, eight patients underwent delayed surgery for tumor enlargement and one for lymph node metastases. The cumulative incidence of disease progression at 5 and 10 years was 6.0% and 12.8%, respectively. Patients who underwent delayed surgery had no permanent complications, and no patient had distant metastasis or death. Patients ≤30 years old had a higher baseline anxiety score (4.9 vs. 3.8, p=0.024), a higher proportion of baseline anxiety score, i.e., ≥8 points (24.0% vs. 12.6%, p=0.033), and a worse baseline emotional function (62.7 vs. 70.7, p=0.013) than patients >30. During AS, patients ≤30 years of age had higher overall anxiety levels (p=0.005) and a worse overall emotional function (p=0.001).

Conclusions

Active surveillance in Chinese patients with highly suspicious subcentimetre thyroid nodules has good oncological outcomes and can be used as a safe alternative to surgery. Younger patients (≤30) show a worse psychological status; therefore, more attention should be paid to younger patients.
The contribution of pain and disability on the transition from acute to chronic pain-related TMD: A 3-month prospective cohort study
Authors: Velly Ana Miriam , Elsaraj Sherif M. , Botros Jack , Samim Firoozeh , der Khatchadourian Zovinar , Gornitsky Mervyn
Published: August 2022

Although most cases of pain-related temporomandibular disorders (TMD) are mild and self-limiting, about 10% of TMD patients develop severe disorders associated with chronic pain and disability. It has been suggested that pain intensity contributes to the transition from acute to chronic pain-related TMD. Therefore, the aims of this current prospective cohort study were to assess if pain intensity, pain always being present, pain or stiffness on awakening, jaw activities, and interference, were associated with the transition from acute to chronic pain-related TMD at 3 months of follow-up. One hundred and nine participants, recruited from four clinics in Montreal and Ottawa, received examinations and completed the required instruments at baseline and at the 3rd month of follow-up. In a multivariable analysis including sex, age, characteristic pain index (CPI) (OR = 1.03, 95%CI = 1.01–1.06, P = 0.005), moderate to severe average pain intensity (OR = 3.51, 95%CI = 1.24–9.93, P = 0.02), disability points score (OR = 1.29, 95%CI = 1.06–1.57, P = 0.01), interferences (ORs = 1.30–1.32, P = 0.003–0.005), screening score (OR = 1.37, 95%CI = 1.08–1.76, P = 0.01), and pain always present (OR = 2.55, 95%CI = 1.08–6.00, P = 0.03) assessed at first-visit were related to the transition outcome at the 3rd month of follow-up. Further, we found that if 4 patients with acute pain-related TMD on average were exposed to these risk factors at baseline, 1 would have the transition from acute to chronic pain at 3 months of follow-up. Results indicate that these factors are associated with the transition from acute to chronic pain-related TMD, and therefore should be considered as important factors when evaluating and developing treatment plans for patients with pain-related TMD.
Senolytics in the treatment of diabetic retinopathy
Authors: Hassan Jannah Waled , Bhatwadekar Ashay D.
Published: August 2022

Diabetic retinopathy (DR) is the most common complication of diabetes. DR is characterized by damage to retinal vasculature resulting in vision impairment and, if untreated, could eventually lead to blindness. The pathogenic mechanism of DR is complex; emerging studies suggest that premature senescence of retinal cells and subsequent secretion of inflammatory cytokines exacerbate DR disease state by stimulating paracrine senescence, pathological angiogenesis, and reparative vascular regeneration. Senolytics are a new class of drugs that can selectively clear out senescent cells from the retina, thus holding a significant promise in DR treatment and prevention. In this review, we discuss the critical role of cellular senescence in DR’s pathogenesis; A literature review was conducted in September of 2021 to explore the therapeutic potential of senolytics in the treatment of DR. Studies that were relevant to the research topic were selected through multiple keyword searches in the search engine, PubMed and thoroughly reviewed using abstracts and full-text articles. We present evidence from animal models for studying cellular senescence in DR and discuss multiple pathogenic mechanisms in cellular senescence and its involvement in DR. We also discuss the current state of pharmaceutical development at preclinical and clinical stages focusing on the senolytic drugs navitoclax, 17-DMAG, piperlongumine, UBX-1325, dasatinib quercetin, and fisetin. In particular, UBX-1325 holds a promising prospect for DR treatment based on the positive outcome of early clinical studies in individuals with diabetic macular edema (DME) and wet age-related macular degeneration.
Factors related to irritable bowel syndrome and differences among subtypes: A cross-sectional study in the UK Biobank
Authors: Wang Kexin , Liu Huan , Liu Jingjing , Han Liyuan , Kang Zheng , Liang Libo , Jiang Shengchao , Meng Nan , Chen Peiwen , Xu Qiao , Wu Qunhong , Hao Yanhua
Published: August 2022

Background: Irritable bowel syndrome (IBS) reduces patients’ quality of life and causes great burdens due to its unclear pathogenesis and criteria for diagnosis. This study aimed to explore the differences in prevalence and the influencing factors for IBS and its subtypes.

Methods: The UK Biobank surveyed 174,771 adult participants who completed the Digestive Health Questionnaire (DHQ) through emails and websites. DHQ included the Rome III criteria, IBS symptom severity score, and Patient Health Questionnaire 12 Somatic Symptom score. The UK Biobank also asked regarding previous IBS diagnosis, diagnosis for post-infectious IBS (PI-IBS), and environmental exposures and associated conditions (including anxiety or depression, based on treatment sought or offered). Pearson’s Chi-squared test or Wilcoxon’s rank-sum test was used for potential associations. Binary logic regression based on sex stratification was used to examine associations between selected factors and IBS and its subtypes.

Results: This study included 31,918 participants who met the Rome III criteria for IBS. The pooled prevalence of IBS in the UK Biobank was 18.3%, with mixed IBS as the predominant subtype (59.0%), followed by diarrhea-predominant IBS (25.1%), constipation-predominant IBS (14.7%), and untyped IBS (1.1%). IBS was significantly associated with somatization (male: OR = 5.326, 95% CI = 4.863–5.832; female: OR = 4.738, 95% CI = 4.498–4.992) and coeliac disease (male: OR = 4.107, 95% CI = 3.132–5.385; female: OR = 3.783, 95% CI = 3.310–4.323). Differences in antibiotics and mental status were presented among subtypes and sex. Furthermore, 1,787 individuals were diagnosed with PI-IBS in the group of patients with IBS. The prevalence of PI-IBS in IBS was 16.6% in the UK Biobank, and it was characterized by diarrhea, fever, bloody diarrhea, and vomiting.

Conclusion: Somatization and coeliac disease are primary risk factors for IBS. Distinguishing differential risk factors is critical for the precise diagnosis and treatment of IBS subtypes, particularly sex-specific differences in mental health status. General practitioners should focus on the treatment according to IBS subtypes.
Myricetin activates the Caspase-3/GSDME pathway via ER stress induction of pyroptosis in lung cancer cells
Authors: Han Jicheng , Cheng Cheng , Zhang Jinxin , Fang Jinbo , Yao Wei , Zhu Yilong , Xiu Zhiru , Jin Ningyi , Lu Huijun , Li Xiao , Li Yiquan
Published: August 2022

Pyroptosis is related to the occurrence, development, and therapeutic response of tumors, mediated by the proteins of the Gasdermin family. These proteins have become potential biomarkers for cancer treatment, and their agonists are likely to become a new direction in research and development of antitumor drugs. In this study, we found that myricetin has an inhibitory effect on lung cancer cells of the activation of pyroptosis. Analysis of the expression of Gasdermin family proteins revealed that this phenomenon was caused by the cleavage of GSDME. Subsequently, specific inhibitors, we found that caspase-3 was its upstream activation factor. In addition, mitochondrial and endoplasmic reticulum (ER) analysis showed that myricetin can cause endoplasmic reticulum stress and increase reactive oxygen species (ROS) levels. Subsequent inhibition of caspase-12 revealed that the expression levels of cleaved-caspase-3 and cleaved-GSDME were significantly reduced, resulting in the inhibition of pyroptosis. Using in vivo experiments, we also found that the treatment with myricetin can reduce tumor volume and significantly increase the level of pyroptosis-related proteins in tumor tissues. Overall, our findings show that myricetin induces cell death of lung cancer cells primarily through an ER stress pathway-induced pyroptosis. Therefore, myricetin has the potential to be used as a pyroptosis agonist in research and development of antitumor drugs.
The interaction between cellular senescence and chronic kidney disease as a therapeutic opportunity
Authors: Zhao Jing-Li , Qiao Xiao-Hui , Mao Jian-Hua , Liu Fei , Fu Hai-Dong
Published: August 2022

Chronic kidney disease (CKD) is an increasingly serious public health problem in the world, but the effective therapeutic approach is quite limited at present. Cellular senescence is characterized by the irreversible cell cycle arrest, senescence-associated secretory phenotype (SASP) and senescent cell anti-apoptotic pathways (SCAPs). Renal senescence shares many similarities with CKD, including etiology, mechanism, pathological change, phenotype and outcome, however, it is difficult to judge whether renal senescence is a trigger or a consequence of CKD, since there is a complex correlation between them. A variety of cellular signaling mechanisms are involved in their interactive association, which provides new potential targets for the intervention of CKD, and then extends the researches on senotherapy. Our review summarizes the common features of renal senescence and CKD, the interaction between them, the strategies of senotherapy, and the open questions for future research.
Iron supplementation inhibits hypoxia-induced mitochondrial damage and protects zebrafish liver cells from death
Authors: Hu Ruiqin , Li Genfang , Xu Qianghua , Chen Liangbiao
Published: August 2022

Acute hypoxia in water has always been a thorny problem in aquaculture. Oxygen and iron play important roles and are interdependent in fish. Iron is essential for oxygen transport and its concentration tightly controlled to maintain the cellular redox homeostasis. However, it is still unclear the role and mechanism of iron in hypoxic stress of fish. In this study, we investigated the role of iron in hypoxic responses of two zebrafish-derived cell lines. We found hypoxia exposed zebrafish liver cells (ZFL) demonstrated reduced expression of Ferritin and the gene fth31 for mitochondrial iron storage, corresponding to reduction of both intracellular and mitochondrial free iron and significant decrease of ROS levels in multiple cellular components, including mitochondrial ROS and lipid peroxidation level. In parallel, the mitochondrial integrity was severely damaged. Addition of exogenous iron restored the iron and ROS levels in cellular and mitochondria, reduced mitochondrial damage through enhancing mitophagy leading to higher cell viability, while treated the cells with iron chelator (DFO) or ferroptosis inhibitor (Fer-1) showed no improvements of the cellular conditions. In contrast, in hypoxia insensitive zebrafish embryonic fibroblasts cells (ZF4), the expression of genes related to iron metabolism showed opposite trends of change and higher mitochondrial ROS level compared with the ZFL cells. These results suggest that iron homeostasis is important for zebrafish cells to maintain mitochondrial integrity in hypoxic stress, which is cell type dependent. Our study enriched the hypoxia regulation mechanism of fish, which helped to reduce the hypoxia loss in fish farming.
Resting state electroretinography: An innovative approach to intrinsic retinal function monitoring
Authors: Gauthier Mercedes , Simard Antoine Brassard , Polosa Anna , Dorfman Allison L. , Qian Cynthia X. , Lina Jean-Marc , Lachapelle Pierre
Published: August 2022

The electroretinogram (ERG) represents the biopotential evoked by the retina in response to a light stimulus. The flash evoked ERG (fERG) is the ERG modality most frequently used clinically to diagnose and monitor retinal disorders. We hereby present a new method to record spontaneous retinal activity, without the use of a flash stimulus, that we named the resting-state ERG (rsERG). The recordings were done in normal subjects under light- and dark-adaptation and with different background light conditions (i.e., variations of wavelength and intensity). Additionally, rsERG recordings were obtained in five patients with retinopathies. The signals were subsequently analyzed in the frequency domain, extracting both periodic (i.e., frequency peaks) and aperiodic (i.e., background trend) components of the signal. The later was further assessed through a multifractal analysis using Wavelet Leaders. Results show that, irrespective of the recording conditions used, the rsERG always includes the same 90 Hz component; a frequency component also present in the fERG response, suggesting a retinally-intrinsic origin. However, in addition, the fERGs also includes a low-frequency component which is absent in the rsERGs, a finding supporting a retinally-induced origin. Comparing rsERGs with fERGs in selected patients with various retinal disorders indicates that the two retinal signals are not always similarly affected (either as a result of underlying retinal pathology or otherwise), suggesting an added value in the assessment of retinal function. Thus, the rsERG could have a similar role in clinical visual electrophysiology as that of the resting-state EEG in neurology namely, to quantify changes in spontaneous activity that result from a given disease processes.
Analysis of exosome-derived microRNAs as early biomarkers of lipopolysaccharide-induced acute kidney injury in rats
Authors: Da-Silva Carolina Carvalho Serres , Anauate Ana Carolina , Guirao Tatiana Pinotti , Novaes Antônio da Silva , Maquigussa Edgar , Boim Mirian Aparecida
Published: August 2022

Sepsis contributes to the high prevalence of acute kidney injury (AKI), which mainly occurs in hospitalized patients. The delay in AKI detection is a risk factor for death and chronicity; thus, early diagnosis is essential for initiating proper treatment strategies. Although serum creatinine is used as biomarker, it is increased in plasma serum creatinine only at late stages of AKI. MicroRNAs (miRNAs), a class of noncoding RNAs responsible for gene regulation, can be found in biological fluids within vesicles such as exosomes and may be promising tools for the early detection of AKI. We aimed to identify potential blood miRNAs that can be used as early biomarkers of sepsis-induced AKI in rats. Adult male Wistar rats received a single dose of lipopolysaccharide (LPS). The earliest significant increase in serum creatinine was detected 4 h after LPS administration. To evaluate whether miRNAs could act as early biomarkers, blood samples were collected before and 2 h after LPS infusion. Serum NGAL levels were used as a comparative marker. Serum miRNAs were derived from exosomes, and their expression were evaluated by the PCR array. miR-181a-5p and miR-23b-3p showed higher expression in LPS-treated rats than in the control animals (p < 0.05). Bioinformatics analysis showed that both miRNAs target molecules associated with transcription factors that regulate genes related to proinflammatory cytokines. Considering that LPS activates transcription factors that lead to the production of proinflammatory cytokines, possible premature changes in the serum levels of miR-181a-5p and miR-23b-3p may be used to identify sepsis-induced AKI earlier.
The regulatory roles of the E3 ubiquitin ligase NEDD4 family in DNA damage response
Authors: Lu Xinxin , Xu Haiqi , Xu Jiaqi , Lu Saien , You Shilong , Huang Xinyue , Zhang Naijin , Zhang Lijun
Published: August 2022

E3 ubiquitin ligases, an important part of ubiquitin proteasome system, catalyze the covalent binding of ubiquitin to target substrates, which plays a role in protein ubiquitination and regulates different biological process. DNA damage response (DDR) is induced in response to DNA damage to maintain genome integrity and stability, and this process has crucial significance to a series of cell activities such as differentiation, apoptosis, cell cycle. The NEDD4 family, belonging to HECT E3 ubiquitin ligases, is reported as regulators that participate in the DDR process by recognizing different substrates. In this review, we summarize recent researches on NEDD4 family members in the DDR and discuss the roles of NEDD4 family members in the cascade reactions induced by DNA damage. This review may contribute to the further study of pathophysiology for certain diseases and pharmacology for targeted drugs.
Quantitative proteomic analytic approaches to identify metabolic changes in the medial prefrontal cortex of rats exposed to space radiation
Authors: Laiakis Evagelia C. , Pinheiro Maisa , Nguyen Tin , Nguyen Hung , Beheshti Afshin , Dutta Sucharita M. , Russell William K. , Emmett Mark R. , Britten Richard A.
Published: August 2022

NASA’s planned mission to Mars will result in astronauts being exposed to ∼350 mSv/yr of Galactic Cosmic Radiation (GCR). A growing body of data from ground-based experiments indicates that exposure to space radiation doses (approximating those that astronauts will be exposed to on a mission to Mars) impairs a variety of cognitive processes, including cognitive flexibility tasks. Some studies report that 33% of individuals may experience severe cognitive impairment. Translating the results from ground-based rodent studies into tangible risk estimates for astronauts is an enormous challenge, but it would be germane for NASA to use the vast body of data from the rodent studies to start developing appropriate countermeasures, in the expectation that some level of space radiation (SR) -induced cognitive impairment could occur in astronauts. While some targeted studies have reported radiation-induced changes in the neurotransmission properties and/or increased neuroinflammation within space radiation exposed brains, there remains little information that can be used to start the development of a mechanism-based countermeasure strategy. In this study, we have employed a robust label-free mass spectrometry (MS) -based untargeted quantitative proteomic profiling approach to characterize the composition of the medial prefrontal cortex (mPFC) proteome in rats that have been exposed to 15 cGy of 600 MeV/n28Si ions. A variety of analytical techniques were used to mine the generated expression data, which in such studies is typically hampered by low and variable sample size. We have identified several pathways and proteins whose expression alters as a result of space radiation exposure, including decreased mitochondrial function, and a further subset of proteins differs in rats that have a high level of cognitive performance after SR exposure in comparison with those that have low performance levels. While this study has provided further insight into how SR impacts upon neurophysiology, and what adaptive responses can be invoked to prevent the emergence of SR-induced cognitive impairment, the main objective of this paper is to outline strategies that can be used by others to analyze sub-optimal data sets and to identify new information.
Abscopal effects of thoracic X-ray radiation on spermatogenesis in mice
Authors: Lai Pan-Pan , Jing Yun-Tao , Guo Ling , Qin Tong-Zhou , Xue Yi-Zhe , Zhang Zhao-Wen , Wang Xing , Miao Xia , Zhang Wei , Ding Gui-Rong
Published: August 2022

The study aimed to elucidate abscopal effects of thoracic X-ray irradiation on spermatogenesis in mice. Male C57BL/6 mice were randomly divided into sham group and radiation group, and subjected to thorax fractionated X-ray irradiation or sham irradiation with the total dose of 5 Gy/day for each animal for four consecutive days. After irradiation, sperm morphology was observed, and sperm number was counted under microscope, and sperm apoptosis was detected by flow cytometry. Meanwhile, testis index was calculated, testicular morphology was observed using haematoxylin-eosin (HE) staining, and testicular ultrastructure was observed under transmission electron microscopy. The permeability of blood-testis barrier (BTB) was detected by Evans Blue fluorescence colorimetry. The protein levels of Bcl-2 associated X protein (Bax), B-cell leukemia-lymphoma-2 (Bcl-2) and Cleaved caspase 3, promyelocytic leukaemia zinc finger (PLZF) and c-kit proto-oncogene (c-kit) in testes were determined by western blotting (WB). The location of apoptotic cells was confirmed by terminal deoxynucleotidyl transferase (TdT) enzymaticated dUTP nick end labelling (TUNEL) assay. The levels of tumor necrosis factor alpha (TNF-α), transforming growth factor-β1 (TGF-β1), interleukin 10 (IL-10) were measured by enzyme-linked immunosorbent assay (ELISA). The levels of Total superoxide dismutase (T-SOD) and malondialdehyde (MDA) were measured by the biochemical assay kit. Compared with sham group, the sperm quality of mice in radiation group showed decreased number and survival rate, along with increased abnormality and total apoptosis rate. The testis index of irradiated mice was lower, the testicular apoptosis was increased, and their testicular histology and ultrastructure was severely damaged. The permeability of BTB was increased, the level of PLZF in testis was decreased, and the level of c-kit was increased by irradiation. After irradiation, the levels of TNF-α, TGF-β1, IL-10, T-SOD and MDA in testes were significantly changed. Taken together, abscopal effects of thoracic X-ray irradiation on spermatogenesis were obvious, which could decrease sperm quality and damage testicular morphology and increase the permeability of BTB, and a series of inflammation and oxidative stress factors were involved in the process. These findings provide novel insights into prevention and treatment for male reproductive damage induced by clinical thoracic irradiation.
The elite judo female athlete’s heart
Authors: Milovančev Aleksandra , Petrović Milovan , Miljković Tatjana , Ilić Aleksandra , Mudrinić Tatjana Redžek , Miljković Aleksandar , Ivanov Olivera , Tripunović Jelena , Anđelic Bogdan , Bianco Antonino , Drid Patrik
Published: August 2022

Purpose: There is a paucity of data on physiological heart adaptation in elite-level judo female athletes. This study aimed to assess left ventricular morphology and function in highly trained elite female judokas.

Methods: The study prospectively included 18 females aged 23.5 ± 2.25 years, nine elite level judokas, and nine healthy non-athlete volunteers. All participants underwent a medical examination, electrocardiogram, and transthoracic 2D echocardiogram. Left ventricular diastolic and systolic diameters and volumes were determined, and parameters of left heart geometry and function (systolic and diastolic) were measured, calculated, and compared between groups.

Results: When groups were compared, judokas had significantly increased left ventricular cavity dimensions p < 0.01, left ventricular wall thickness p < 0.01, and volumes p < 0.01. Elite female judokas exhibited left ventricular dilatation demonstrated as high prevalence increased end-diastolic volume/index, and increased end-systolic volume/index in 88.9% of judokas vs. 0% in controls, p < 0.01. Left ventricle mass/index was significantly increased in judokas, p < 0.01), with a 43.3% difference between groups. The majority (77.7%) of judokas had normal left ventricular geometry, although eccentric hypertrophy was revealed in 2 (22.2%) of judokas.

Conclusion: Elite, highly trained female judokas exhibit significant changes in left heart morphology as a result of vigorous training compared to non-athletes. These findings suggest that female judokas athletes’ heart follows a pattern toward chamber dilatation rather than left ventricular wall hypertrophy.
Ion channel molecular complexes in vascular smooth muscle
Authors: Pereira da Silva Eric A. , Martín-Aragón Baudel Miguel , Navedo Manuel F. , Nieves-Cintrón Madeline
Published: August 2022

Ion channels that influence membrane potential and intracellular calcium concentration control vascular smooth muscle excitability. Voltage-gated calcium channels (VGCC), transient receptor potential (TRP) channels, voltage (KV), and Ca2+-activated K+ (BK) channels are key regulators of vascular smooth muscle excitability and contractility. These channels are regulated by various signaling cues, including protein kinases and phosphatases. The effects of these ubiquitous signaling molecules often depend on the formation of macromolecular complexes that provide a platform for targeting and compartmentalizing signaling events to specific substrates. This manuscript summarizes our current understanding of specific molecular complexes involving VGCC, TRP, and KV and BK channels and their contribution to regulating vascular physiology.
Spatial range, temporal span, and promiscuity of CLE-RLK signaling
Authors: Narasimhan Madhumitha , Simon Rüdiger
Published: August 2022

CLAVATA3/EMBRYO SURROUNDING REGION-RELATED (CLE) signaling through receptor-like kinases (RLKs) regulates developmental transitions and responses to biotic and abiotic inputs by communicating the physiological state of cells and tissues. CLE peptides have varying signaling ranges, which can be defined as the distance between the source, i.e., the cells or tissue that secrete the peptide, and their destination, i.e., cells or tissue where the RLKs that bind the peptide and/or respond are expressed. Case-by-case analysis substantiates that CLE signaling is predominantly autocrine or paracrine, and rarely endocrine. Furthermore, upon CLE reception, the ensuing signaling responses extend from cellular to tissue, organ and whole organism level as the downstream signal gets amplified. CLE-RLK-mediated effects on tissue proliferation and differentiation, or on subsequent primordia and organ development have been widely studied. However, studying how CLE-RLK regulates different stages of proliferation and differentiation at cellular level can offer additional insights into these processes. Notably, CLE-RLK signaling also mediates diverse non-developmental effects, which are less often observed; however, this could be due to biased experimental approaches. In general, CLEs and RLKs, owing to the sequence or structural similarity, are prone to promiscuous interactions at least under experimental conditions in which they are studied. Importantly, there are regulatory mechanisms that suppress CLE-RLK cross-talk in vivo, thereby eliminating the pressure for co-evolving binding specificity. Alternatively, promiscuity in signaling may also offer evolutionary advantages and enable different CLEs to work in combination to activate or switch off different RLK signaling pathways.
The road to molecular identification and detection of fungal grapevine trunk diseases
Authors: Azevedo-Nogueira Filipe , Rego Cecília , Gonçalves Helena Maria Rodrigues , Fortes Ana Margarida , Gramaje David , Martins-Lopes Paula
Published: August 2022

Grapevine is regarded as a highly profitable culture, being well spread worldwide and mostly directed to the wine-producing industry. Practices to maintain the vineyard in healthy conditions are tenuous and are exacerbated due to abiotic and biotic stresses, where fungal grapevine trunk diseases (GTDs) play a major role. The abolishment of chemical treatments and the intensification of several management practices led to an uprise in GTD outbreaks. Symptomatology of GTDs is very similar among diseases, leading to underdevelopment of the vines and death in extreme scenarios. Disease progression is widely affected by biotic and abiotic factors, and the prevalence of the pathogens varies with country and region. In this review, the state-of-the-art regarding identification and detection of GTDs is vastly analyzed. Methods and protocols used for the identification of GTDs, which are currently rather limited, are highlighted. The main conclusion is the utter need for the development of new technologies to easily and precisely detect the presence of the pathogens related to GTDs, allowing to readily take phytosanitary measures and/or proceed to plant removal in order to establish better vineyard management practices. Moreover, new practices and methods of detection, identification, and quantification of infectious material would allow imposing greater control on nurseries and plant exportation, limiting the movement of infected vines and thus avoiding the propagation of fungal inoculum throughout wine regions.