bluuebunny/crossref_metadata_2025 huggingface dataset:
Low-Dose Everolimus Maintenance Therapy for Renal Angiomyolipoma Associated With Tuberous Sclerosis Complex
Authors: Luo Cong , Ye Wen-Rui , Zu Xiong-Bin , Chen Min-Feng , Qi Lin , Li Yang-Le , Cai Yi
Published: November 2021

Objective: To assess the safety and efficacy of low-dose everolimus maintenance therapy for tuberous sclerosis complex-related renal angiomyolipoma (TSC-RAML) patients that had previously undergone standard-dose treatment for a minimum of 6 months.

Materials and Methods: In total, 24 patients with a definitive TSC diagnosis were enrolled from April 2018 – April 2019 at Xiangya Hospital, Central South University. All patients underwent low-dose everolimus maintenance therapy following standard-dose everolimus induction therapy for a minimum of 6 months. Patients additionally underwent TSC1/TSC2 genetic testing, And they were followed-up at 3, 6, 12, 18, and 24 months. The Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) criteria were used to monitor patient RAML responses, while adverse events (AEs) were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4.0). P < 0.05 was the significance level for all analyses, which were performed using SPSS 19.0.

Results: TSC1/TSC2 gene mutations were present in all 24 patients, all of whom achieved a significant reduction in TSC-RAML volume within the initial 6-month induction therapy period, and exhibited volume stabilization during the low-dose maintenance therapy treatment period without any instances of TSC-RAML regrowth. Adverse events (AEs) were significantly less severe and less frequent over the course of maintenance therapy relative to standard therapy.

Conclusions: Low-dose everolimus maintenance therapy represents an effective approach to achieving TSC-RAML control following a minimum of 6 months of full-dose induction therapy, and may be associated with decreases in everolimus-related AE frequency and severity.
Clinical Features of Early Stage COVID-19 in a Primary Care Setting
Authors: Kawatani Yohei , Nakayama Kei , Sawamura Atsushi , Fujikawa Koichi , Nagai Motoki , Hori Takaki
Published: November 2021

Background: The coronavirus disease 2019 (COVID-19) pandemic remains a global healthcare crisis. Nevertheless, the majority of COVID-19 cases involve mild to moderate symptoms in the early stages. The lack of information relating to these cases necessitates further investigation.

Methods: Patients visiting the outpatient clinic at the Kamagaya General Hospital were screened by interview and body temperature check. After initial screening, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was suspected in 481 patients who then underwent blood tests and the loop-mediated isothermal amplification (LAMP) test for SARS-CoV-2. Clinical characteristics between positive and negative SARS-CoV-2 groups were compared. Further, the novel predictive value of routine blood test results for SARS-CoV-2 infection was evaluated using ROC analysis.

Results: A total of 15,560 patients visited our hospital during the study period. After exclusion and initial screening by interview, 481 patients underwent the LAMP test and routine blood tests. Of these patients, 69 (14.3%) were positive for SARS-CoV-2 and diagnosed with COVID-19 (positive group), and 412 (85.7%) were negative (negative group). The median period between the first onset of symptoms and visit to our hospital was 3.4 and 2.9 days in the negative and positive groups, respectively. Cough (p = 0.014), rhinorrhea (p = 0.039), and taste disorders (p < 0.001) were significantly more common in the positive group, while gastrointestinal symptoms in the negative group (p = 0.043). The white blood cell count (p < 0.001), neutrophil count (p < 0.001), and percentage of neutrophils (p < 0.001) were higher in the negative group. The percentage of monocytes (p < 0.001) and the levels of ferritin (p < 0.001) were higher in the positive group. As per the predictive values for COVID-19 using blood tests, the values for the area under the curve for the neutrophil-to-monocyte ratio (NMR), white blood cell-to-hemoglobin ratio (WHR), and the product of the two (NMWH) were 0.857, 0.837, and 0.887, respectively.

Conclusion: Symptoms in early stage COVID-19 patients were similar to those in previous reports. Some blood test results were not consistent with previous reports. NMR, WHR, and NMWH are novel diagnostic scores in early-stage mild-symptom COVID-19 patients in primary care settings.
Probing Isoform Switching Events in Various Cancer Types: Lessons From Pan-Cancer Studies
Authors: Karakulak Tülay , Moch Holger , von Mering Christian , Kahraman Abdullah
Published: November 2021

Alternative splicing is an essential regulatory mechanism for gene expression in mammalian cells contributing to protein, cellular, and species diversity. In cancer, alternative splicing is frequently disturbed, leading to changes in the expression of alternatively spliced protein isoforms. Advances in sequencing technologies and analysis methods led to new insights into the extent and functional impact of disturbed alternative splicing events. In this review, we give a brief overview of the molecular mechanisms driving alternative splicing, highlight the function of alternative splicing in healthy tissues and describe how alternative splicing is disrupted in cancer. We summarize current available computational tools for analyzing differential transcript usage, isoform switching events, and the pathogenic impact of cancer-specific splicing events. Finally, the strategies of three recent pan-cancer studies on isoform switching events are compared. Their methodological similarities and discrepancies are highlighted and lessons learned from the comparison are listed. We hope that our assessment will lead to new and more robust methods for cancer-specific transcript detection and help to produce more accurate functional impact predictions of isoform switching events.
TNF-ɑ Induces Methylglyoxal Accumulation in Lumbar Herniated Disc of Patients With Radicular Pain
Authors: Zhang Xinsheng , Wang Xiaogang , Gao Liang , Yang Bin , Wang Yahan , Niu Kerun , Lai Jiahui , Wan Shun , Luo Jianping
Published: November 2021

Lumbar disc herniation (LDH) with radicular pain is a common and complicated musculoskeletal disorder. Our previous study showed that LDH-induced methylglyoxal (MG) accumulation contributed to radicular pain. The underlying mechanisms through which MG accumulates are poorly understood. In the present study, we found that both MG and tumor necrosis factor-alpha (TNF-ɑ) levels in the herniated disc of patients with radicular pain were significantly increased, and the activity of Glyoxalase 1 (GLO1), the rate-limiting enzyme that metabolizes MG, was decreased. In rats, the LDH model was mimicked by implantation of autologous nucleus pulposus (NP) to the left lumbar five spinal nerve root. The mechanical allodynia was observed in LDH rats. Besides, MG and TNF-ɑ levels were increased, and GLO1 activity was significantly decreased in the implanted NP. In cultured rat NP cells, stimulation with the inflammatory mediator TNF-ɑ reduced GLO1 activity and expression. These results suggested that TNF-ɑ-induced GLO1 activity decrease contributed to MG accumulation in the herniated disc of patients with radicular pain.
Molecular Investigation of Chicken Acid-Sensing Ion Channel 1 β11-12 Linker Isomerization and Channel Kinetics
Authors: Rook Matthew L. , Ananchenko Anna , Musgaard Maria , MacLean David M.
Published: November 2021

Structures of the trimeric acid-sensing ion channel have been solved in the resting, toxin-bound open and desensitized states. Within the extracellular domain, there is little difference between the toxin-bound open state and the desensitized state. The main exception is that a loop connecting the 11th and 12th β-strand, just two amino acid residues long, undergoes a significant and functionally critical re-orientation or flipping between the open and desensitized conformations. Here we investigate how specific interactions within the surrounding area influence linker stability in the “flipped” desensitized state using all-atom molecular dynamics simulations. An inherent challenge is bringing the relatively slow channel desensitization and recovery processes (in the milliseconds to seconds) within the time window of all-atom simulations (hundreds of nanoseconds). To accelerate channel behavior, we first identified the channel mutations at either the Leu414 or Asn415 position with the fastest recovery kinetics followed by molecular dynamics simulations of these mutants in a deprotonated state, accelerating recovery. By mutating one residue in the loop and examining the evolution of interactions in the neighbor, we identified a novel electrostatic interaction and validated prior important interactions. Subsequent functional analysis corroborates these findings, shedding light on the molecular factors controlling proton-mediated transitions between functional states of the channel. Together, these data suggest that the flipped loop in the desensitized state is stabilized by interactions from surrounding regions keeping both L414 and N415 in place. Interestingly, very few mutations in the loop allow for equivalent channel kinetics and desensitized state stability. The high degree of sequence conservation in this region therefore indicates that the stability of the ASIC desensitized state is under strong selective pressure and underlines the physiological importance of desensitization.
Endothelial Dysfunction and Hyperhomocysteinemia-Linked Cerebral Small Vessel Disease: Underlying Mechanisms and Treatment Timing
Authors: Li Shuang , Li Guangjian , Luo Xia , Huang Yan , Wen Lan , Li Jinglun
Published: November 2021

Cerebral small vessel disease (cSVD)—a common cause of stroke and vascular dementia—is a group of clinical syndromes that affects the brain's small vessels, including arterioles, capillaries, and venules. Its pathogenesis is not fully understood, and effective treatments are limited. Increasing evidence indicates that an elevated total serum homocysteine level is directly and indirectly associated with cSVD, and endothelial dysfunction plays an active role in this association. Hyperhomocysteinemia affects endothelial function through oxidative stress, inflammatory pathways, and epigenetic alterations at an early stage, even before the onset of small vessel injuries and the disease. Therefore, hyperhomocysteinemia is potentially an important therapeutic target for cSVD. However, decreasing the homocysteine level is not sufficiently effective, possibly due to delayed treatment, which underlying reason remains unclear. In this review, we examined endothelial dysfunction to understand the close relationship between hyperhomocysteinemia and cSVD and identify the optimal timing for the therapy.
Functional Neural Networks in Writer's Cramp as Determined by Graph-Theoretical Analysis
Authors: Schill Jana , Zeuner Kirsten E. , Knutzen Arne , Tödt Inken , Simonyan Kristina , Witt Karsten
Published: November 2021

Dystonia, a debilitating neurological movement disorder, is characterized by involuntary muscle contractions and develops from a complex pathophysiology. Graph theoretical analysis approaches have been employed to investigate functional network changes in patients with different forms of dystonia. In this study, we aimed to characterize the abnormal brain connectivity underlying writer's cramp, a focal hand dystonia. To this end, we examined functional magnetic resonance scans of 20 writer's cramp patients (11 females/nine males) and 26 healthy controls (10 females/16 males) performing a sequential finger tapping task with their non-dominant (and for patients non-dystonic) hand. Functional connectivity matrices were used to determine group averaged brain networks. Our data suggest that in their neuronal network writer's cramp patients recruited fewer regions that were functionally more segregated. However, this did not impair the network's efficiency for information transfer. A hub analysis revealed alterations in communication patterns of the primary motor cortex, the thalamus and the cerebellum. As we did not observe any differences in motor outcome between groups, we assume that these network changes constitute compensatory rerouting within the patient network. In a secondary analysis, we compared patients with simple writer's cramp (only affecting the hand while writing) and those with complex writer's cramp (affecting the hand also during other fine motor tasks). We found abnormal cerebellar connectivity in the simple writer's cramp group, which was less prominent in complex writer's cramp. Our preliminary findings suggest that longitudinal research concerning cerebellar connectivity during WC progression could provide insight on early compensatory mechanisms in WC.
Interactions Between Kidney Function and Cerebrovascular Disease: Vessel Pathology That Fires Together Wires Together
Authors: Marini Sandro , Georgakis Marios K. , Anderson Christopher D.
Published: November 2021

The kidney and the brain, as high-flow end organs relying on autoregulatory mechanisms, have unique anatomic and physiological hemodynamic properties. Similarly, the two organs share a common pattern of microvascular dysfunction as a result of aging and exposure to vascular risk factors (e.g., hypertension, diabetes and smoking) and therefore progress in parallel into a systemic condition known as small vessel disease (SVD). Many epidemiological studies have shown that even mild renal dysfunction is robustly associated with acute and chronic forms of cerebrovascular disease. Beyond ischemic SVD, kidney impairment increases the risk of acute cerebrovascular events related to different underlying pathologies, notably large artery stroke and intracerebral hemorrhage. Other chronic cerebral manifestations of SVD are variably associated with kidney disease. Observational data have suggested the hypothesis that kidney function influences cerebrovascular disease independently and adjunctively to the effect of known vascular risk factors, which affect both renal and cerebral microvasculature. In addition to confirming this independent association, recent large-scale human genetic studies have contributed to disentangling potentially causal associations from shared genetic predisposition and resolving the uncertainty around the direction of causality between kidney and cerebrovascular disease. Accelerated atherosclerosis, impaired cerebral autoregulation, remodeling of the cerebral vasculature, chronic inflammation and endothelial dysfunction can be proposed to explain the additive mechanisms through which renal dysfunction leads to cerebral SVD and other cerebrovascular events. Genetic epidemiology also can help identify new pathological pathways which wire kidney dysfunction and cerebral vascular pathology together. The need for identifying additional pathological mechanisms underlying kidney and cerebrovascular disease is attested to by the limited effect of current therapeutic options in preventing cerebrovascular disease in patients with kidney impairment.
Pre-processing Cooling of Harvested Grapes Induces Changes in Berry Composition and Metabolism, and Affects Quality and Aroma Traits of the Resulting Wine
Authors: Modesti Margherita , Shmuleviz Ron , Macaluso Monica , Bianchi Alessandro , Venturi Francesca , Brizzolara Stefano , Zinnai Angela , Tonutti Pietro
Published: November 2021

Due to the greenhouse gas increase, grapes are often exposed to high temperatures in several growing areas especially during the final developmental stages, and this is particularly true when early ripening cultivars are harvested. This may cause undesirable effects on berry metabolism and composition and wine quality, particularly concerning the aroma profile. Harvesting at night or keeping the harvested grapes in cold rooms before vinification are empirical protocols applied in specific viticultural areas. To study the effects of decreasing berry temperature after harvest, white-skinned berries (cv Vermentino) were maintained at 4 or 10°C for 24 or 48 h before processing (pre-cooling). Control grapes were kept at 22°C. Grapes cooled at 10°C for 24 and 48 h resulted richer in polyphenols and showed a significant up-regulation of genes involved in polyphenols biosynthesis (i.e.,VvPAL, VvSTS2, andVvFLS1). Similar behavior was observed in samples kept at 4°C for 48 h. Pre-cooling induced specific changes in the volatile organic compound (VOC) profiles. In particular, higher amounts of a specific subcategory of terpenes, namely sesquiterpenes, were detected in cooled samples. The induction of the expression of key genes involved in terpenoids biosynthesis (VvHDR, VvDX3, VvTER, VvGT14) was detected in cooled grapes, with variable effects depending on temperature and treatment duration. In both cooled samples, the evolution of alcoholic fermentation followed a regular trend but ended earlier. Higher phenolic content was detected in wines obtained from the 10°C-treated grapes. Higher residual concentration of malic acid at the end of fermentation was detected in wine samples from grapes pre-cooled at 4°C. Sesquiterpenes also showed a general increase in wines from cooled grapes, especially after pre-cooling at 10°C for 48 h. Different sensory profiles characterized the wine samples, with the best scores in terms of general pleasantness obtained by the wine produced from grapes pre-cooled at 4°C for 24 h. These results demonstrate that pre-cooling harvested grapes induces specific effect on the VOC profile and other quality parameters of Vermentino wine, and this appears to be the result of specific metabolic and compositional changes occurring in the berries.
Artemisinin Mediates Its Tumor-Suppressive Activity in Hepatocellular Carcinoma Through Targeted Inhibition of FoxM1
Authors: Nandi Deeptashree , Cheema Pradeep Singh , Singal Aakriti , Bharti Hina , Nag Alo
Published: November 2021

The aberrant up-regulation of the oncogenic transcription factor Forkhead box M1 (FoxM1) is associated with tumor development, progression and metastasis in a myriad of carcinomas, thus establishing it as an attractive target for anticancer drug development. FoxM1 overexpression in hepatocellular carcinoma is reflective of tumor aggressiveness and recurrence, poor prognosis and low survival in patients. In our study, we have identified the antimalarial natural product, Artemisinin, to efficiently curb FoxM1 expression and activity in hepatic cancer cells, thereby exhibiting potential anticancer efficacy. Here, we demonstrated that Artemisinin considerably mitigates FoxM1 transcriptional activity by disrupting its interaction with the promoter region of its downstream targets, thereby suppressing the expression of numerous oncogenic drivers. Augmented level of FoxM1 is implicated in drug resistance of cancer cells, including hepatic tumor cells. Notably, FoxM1 overexpression rendered HCC cells poorly responsive to Artemisinin-mediated cytotoxicity while FoxM1 depletion in resistant liver cancer cells sensitized them to Artemisinin treatment, manifested in lower proliferative and growth index, drop in invasive potential and repressed expression of EMT markers with a concomitantly increased apoptosis. Moreover, Artemisinin, when used in combination with Thiostrepton, an established FoxM1 inhibitor, markedly reduced anchorage-independent growth and displayed more pronounced death in liver cancer cells. We found this effect to be evident even in the resistant HCC cells, thereby putting forth a novel combination therapy for resistant cancer patients. Altogether, our findings provide insight into the pivotal involvement of FoxM1 in the tumor suppressive activities of Artemisinin and shed light on the potential application of Artemisinin for improved therapeutic response, especially in resistant hepatic malignancies. Considering that Artemisinin compounds are in current clinical use with favorable safety profiles, the results from our study will potentiate its utility in juxtaposition with established FoxM1 inhibitors, promoting maximal therapeutic efficacy with minimal adverse effects in liver cancer patients.
A Prospective Phase II Study of Simultaneous Modulated Accelerated Radiotherapy Concurrently With CDDP/S1 for Esophageal Squamous Cell Carcinoma in the Elderly
Authors: Guo SuPing , Liu FangJie , Liu Hui , Wu YingJia , Zhang XuHui , Ye WenFeng , Luo GuangYu , Li QiWen , Chen NaiBin , Hu Nan , Wang Bin , Zhang Jun , Lin MaoSheng , Feng HuiXia , Qiu Bo
Published: November 2021

Background

To explore the efficacy and toxicity of simultaneous modulated accelerated radiotherapy (SMART) concurrently with cisplatin (CDDP) and S1 (tegafur/gimeracil/oteracil) in elderly patients with esophageal squamous cell carcinoma (ESCC).

Methods

This single-arm, phase II study enrolled pathologically confirmed, stage II–IVa ESCC of 70–80 years old and Eastern Cooperative Oncology Group performance status (ECOG PS) 0–2. Patients received SMART (64 Gy to gross tumor volume and 48 Gy to clinical target volume in 30 fractions) with concurrent CDDP (day 1 of each week) and S1 (days 1–14, 22–35). The primary endpoint was objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), overall survival (OS) and toxicities.

Results

Thirty-seven eligible patients were analyzed with median follow-up of 25.7 months for all and 46.1 months for survivors. The ORR was 88.9%. Patients with baseline weight loss <5% (p=0.050) and nutritional risk index (NRI) ≥105.2 (p=0.023) had better tumor response. Median PFS was 13.8 months with 2-year PFS of 37.5%. Median OS was 27.7 months with 2-year OS of 57.5%. OS was significantly associated with ECOG PS (p=0.005), stage (p=0.014), gross tumor volume (p=0.004), baseline NRI (p=0.036), baseline C-reactive protein (CRP) level (p=0.003) and tumor response (p=0.000). CRP level (p=0.016) and tumor response (p=0.021) were independently prognostic of OS. ≥grade 3 anemia, neutropenia and thrombocytopenia occurred in 2.7%, 10.8% and 13.5% of patients; ≥grade 3 esophagitis and pneumonitis occurred in 18.9% and 2.7% of patient, respectively.

Conclusion

SMART concurrently with CDDP/S1 yielded satisfactory response rate, survival outcome and tolerable treatment-related toxicities in elderly patients with ESCC. Further studies are warranted to validate the results.
LncRNA CASC11 Promotes Hepatocellular Carcinoma Progression via Upregulation of UBE2T in a m6A-Dependent Manner
Authors: Chen Fei , Li Meijun , Wang Liang
Published: November 2021

Hepatocellular carcinoma (HCC) is one of the most frequent malignancies and the third leading cause of cancer-related deaths worldwide. Besides, it has been revealed that long non-coding RNA (LncRNA) cancer susceptibility candidate 11 (CASC11) is involved in cancer progression. However, the functional role and underlying mechanism of CASC11 in HCC remains largely unknown. In this context, here, it was found that CASC11 was upregulated in HCC tissues and associated with tumor grades, metastasis, and prognosis of HCC patients. Functionally, CASC11 facilitated HCC cell proliferation, migration, and invasion in vitro, and enhanced tumor growth and metastasis in vivo. Mechanistically, CASC11 associated with and stabilized Ubiquitin-conjugating enzyme E2T (UBE2T) mRNA. To be specific, it decreased UBE2T N6-methyladenosine (m6A) level via recruiting ALKBH5. Moreover, CASC11 inhibited the association between UBE2T mRNA and m6A reader protein YTHDF2. Taken together, our findings demonstrate the epigenetic mechanism of CASC11 in the regulation of UBE2T expression and possibly provide a novel therapeutic target for HCC treatment.
Multiple Survival Outcome Prediction of Glioblastoma Patients Based on Multiparametric MRI
Authors: Wang Bin , Zhang Shan , Wu Xubin , Li Ying , Yan Yueming , Liu Lili , Xiang Jie , Li Dandan , Yan Ting
Published: November 2021

Purpose

Construction of radiomics models for the individualized estimation of multiple survival stratification in glioblastoma (GBM) patients using the multiregional information extracted from multiparametric MRI that could facilitate clinical decision-making for GBM patients.

Materials and Methods

A total of 134 eligible GBM patients were selected from The Cancer Genome Atlas. These patients were separated into the long-term and short-term survival groups according to the median of individual survival indicators: overall survival (OS), progression-free survival (PFS), and disease-specific survival (DSS). Then, the patients were divided into a training set and a validation set in a ratio of 2:1. Radiomics features (n = 5,152) were extracted from multiple regions of the GBM using multiparametric MRI. Then, radiomics signatures that are related to the three survival indicators were respectively constructed using the analysis of variance (ANOVA) and the least absolute shrinkage and selection operator (LASSO) regression for each patient in the training set. Based on a Cox proportional hazards model, the radiomics model was further constructed by combining the signature and clinical risk factors.

Results

The constructed radiomics model showed a promising discrimination ability to differentiate in the training set and validation set of GBM patients with survival indicators of OS, PFS, and DSS. Both the four MRI modalities and five tumor subregions have different effects on the three survival indicators of GBM. The favorable calibration and decision curve analysis indicated the clinical decision value of the radiomics model. The performance of models of the three survival indicators was different but excellent; the best model achieved C indexes of 0.725, 0.677, and 0.724, respectively, in the validation set.

Conclusion

Our results show that the proposed radiomics models have favorable predictive accuracy on three survival indicators and can provide individualized probabilities of survival stratification for GBM patients by using multiparametric and multiregional MRI features.
Hypoxia Regulates Endogenous Double-Stranded RNA Production via Reduced Mitochondrial DNA Transcription
Authors: Arnaiz Esther , Miar Ana , Dias Junior Antonio Gregorio , Prasad Naveen , Schulze Ulrike , Waithe Dominic , Nathan James A. , Rehwinkel Jan , Harris Adrian L.
Published: November 2021

Hypoxia is a common phenomenon in solid tumours strongly linked to the hallmarks of cancer. Hypoxia promotes local immunosuppression and downregulates type I interferon (IFN) expression and signalling, which contribute to the success of many cancer therapies. Double-stranded RNA (dsRNA), transiently generated during mitochondrial transcription, endogenously activates the type I IFN pathway. We report the effects of hypoxia on the generation of mitochondrial dsRNA (mtdsRNA) in breast cancer. We found a significant decrease in dsRNA production in different cell lines under hypoxia. This effect was HIF1α/2α-independent. mtdsRNA was responsible for induction of type I IFN and significantly decreased after hypoxia. Mitochondrially encoded gene expression was downregulated and mtdsRNA bound by the dsRNA-specific J2 antibody was decreased during hypoxia. These findings reveal a new mechanism of hypoxia-induced immunosuppression that could be targeted by hypoxia-activated therapies.
Anti-PD-1 Immunotherapy Combined With Stereotactic Body Radiation Therapy and GM-CSF as Salvage Therapy in a PD-L1-Positive Patient With Refractory Metastatic Thyroid Hürthle Cell Carcinoma: A Case Report and Literature Review
Authors: He Haihua , Xu Tangpeng , Li Ping , Jia Guohua , Li Xiangpan , Song Qibin
Published: November 2021

Thyroid Hürthle cell carcinoma, known as thyroid eosinophilic carcinoma, is a rare pathological type of differentiated thyroid cancer (DTC), representing 3-4% of all thyroid cancers. However, given the high risk of invasion and metastasis, thyroid Hürthle cell carcinoma has a relatively poor prognosis. Traditional treatment methods have limited effects on patients with metastatic thyroid cancers. Developing a valuable therapy for advanced thyroid carcinomas is an unfilled need, and immunotherapy could represent another choice for these tumors. We herein reported the case of a patient with recurrent advanced thyroid Hürthle cell cancer and positive programmed death-ligand 1 (PD-L1) expression, who suffered tumor progression after re-surgery, radiotherapy, and targeted therapy. It is encouraging that PD-1 inhibitors in combination with GM-CSF and stereotactic body irradiation (SBRT) on metastatic disease have a significant anti-tumor effect.
Targeting Mitochondrial Protein Expression as a Future Approach for Cancer Therapy
Authors: Criscuolo Daniela , Avolio Rosario , Matassa Danilo Swann , Esposito Franca
Published: November 2021

Extensive metabolic remodeling is a fundamental feature of cancer cells. Although early reports attributed such remodeling to a loss of mitochondrial functions, it is now clear that mitochondria play central roles in cancer development and progression, from energy production to synthesis of macromolecules, from redox modulation to regulation of cell death. Biosynthetic pathways are also heavily affected by the metabolic rewiring, with protein synthesis dysregulation at the hearth of cellular transformation. Accumulating evidence in multiple organisms shows that the metabolic functions of mitochondria are tightly connected to protein synthesis, being assembly and activity of respiratory complexes highly dependent on de novo synthesis of their components. In turn, protein synthesis within the organelle is tightly connected with the cytosolic process. This implies an entire network of interactions and fine-tuned regulations that build up a completely under-estimated level of complexity. We are now only preliminarily beginning to reconstitute such regulatory level in human cells, and to perceive its role in diseases. Indeed, disruption or alterations of these connections trigger conditions of proteotoxic and energetic stress that could be potentially exploited for therapeutic purposes. In this review, we summarize the available literature on the coordinated regulation of mitochondrial and cytosolic mRNA translation, and their effects on the integrity of the mitochondrial proteome and functions. Finally, we highlight the potential held by this topic for future research directions and for the development of innovative therapeutic approaches.
Central Multifocal Choroiditis: Platelet Granularity as a Potential Marker for Treatment With Steroid-Sparing Immunomodulatory Therapy
Authors: de Groot Evianne L. , Ossewaarde-van Norel Jeannette , Hoefer Imo E. , Haitjema Saskia , de Boer Joke H. , Kuiper Jonas J. W.
Published: November 2021

Purpose

We aimed to evaluate the blood cell composition in patients with central multifocal choroiditis (cMFC), a rare form of posterior uveitis predominantly affecting young myopic women.

Methods

In this retrospective observational case-control study, a 104-parameter automated hematocytometry was conducted by the Cell-Dyn Sapphire hematology analyzer for 122 cases and 364 age- and sex-matched controls. Cox proportional regression analysis was used to assess the relation between the blood cell composition and the time between disease onset (first visit) and the start of systemic corticosteroid-sparing immunomodulatory therapy (IMT).

Results

At a false discovery rate of 5% (Padj), we identified a decrease of blood monocytes in cases with cMFC, which could be attributed to disease activity. Cox proportional hazard analysis including age and sex revealed that increased platelet granularity (measured by mean intermediate angle scatter) was an independent risk factor for treatment with IMT (hazard ratio = 2.3 [95% confidence interval = 1.28 - 4.14], Padj = 0.049). The time between the first presentation and the start of IMT was 0.3 years in the group with an increased platelet granularity and 3.4 years in the group without increased platelet granularity.

Conclusions

Patients with cMFC demonstrated a decrease in blood monocytes. Moreover, platelet granularity could potentially be used as a marker for treatment with IMT.
PPARγ2 Pro12Ala Polymorphism is Associated in Children With Traits Related to Susceptibility to Type 2 Diabetes
Authors: Vales-Villamarín Claudia , de Dios Olaya , Pérez-Nadador Iris , Gavela-Pérez Teresa , Soriano-Guillén Leandro , Garcés Carmen
Published: November 2021

Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated nuclear receptor that regulates glucose and lipid metabolism. Pharmacological activators of PPARγ are being used as a treatment of obesity related disorders such as dyslipidaemia and type 2 diabetes, but questions remain open regarding the effects of PPARγ on traits related to the development of type 2 diabetes. In our study, we have analyzed the relationship of the common variant Pro12Ala in the human PPARγ2 gene with the presence of obesity and with insulin, HOMA and lipid profile in a representative sample of 6-to 8-year-old children free from the confounding factors associated with adults. We found that Ala12Ala genotype was significantly more frequent in females with obesity than in those without obesity, with Ala12Ala carriers having significantly higher weight and body mass index (BMI), however the association disappeared when adjusting by leptin concentrations. The Ala12Ala genotype was associated with significantly higher HDL-cholesterol and apoA-I levels in males but not in females, independently of BMI. In a recessive model, in females, leptin levels appeared higher in Ala12Ala carriers. Although no apparent differences were observed in any sex when analyzing insulin levels and HOMA among genotypes without adjusting, lower insulin levels and lower HOMA appeared associated with Ala12Ala carriers when adjusting for BMI and leptin levels. In summary, our data showed that leptin seems to be having an effect on the association between the PPARγ2 Pro12Ala and BMI. Besides, after controlling for BMI and leptin, a protective effect of the Ala12Ala variant of the PPARγ2 Pro12Ala polymorphism on insulin sensitivity is evident already in prepubertal children.
An Integrated Deep Learning and Molecular Dynamics Simulation-Based Screening Pipeline Identifies Inhibitors of a New Cancer Drug Target TIPE2
Authors: Zhang Haiping , Li Junxin , Saravanan Konda Mani , Wu Hao , Wang Zhichao , Wu Du , Wei Yanjie , Lu Zhen , Chen Youhai H. , Wan Xiaochun , Pan Yi
Published: November 2021

The TIPE2 (tumor necrosis factor-alpha-induced protein 8-like 2) protein is a major regulator of cancer and inflammatory diseases. The availability of its sequence and structure, as well as the critical amino acids involved in its ligand binding, provides insights into its function and helps greatly identify novel drug candidates against TIPE2 protein. With the current advances in deep learning and molecular dynamics simulation-based drug screening, large-scale exploration of inhibitory candidates for TIPE2 becomes possible. In this work, we apply deep learning-based methods to perform a preliminary screening against TIPE2 over several commercially available compound datasets. Then, we carried a fine screening by molecular dynamics simulations, followed by metadynamics simulations. Finally, four compounds were selected for experimental validation from 64 candidates obtained from the screening. With surprising accuracy, three compounds out of four can bind to TIPE2. Among them, UM-164 exhibited the strongest binding affinity of 4.97 µM and was able to interfere with the binding of TIPE2 and PIP2 according to competitive bio-layer interferometry (BLI), which indicates that UM-164 is a potential inhibitor against TIPE2 function. The work demonstrates the feasibility of incorporating deep learning and MD simulation in virtual drug screening and provides high potential inhibitors against TIPE2 for drug development.
Geniposide Ameliorates Liver Fibrosis Through Reducing Oxidative Stress and Inflammatory Respose, Inhibiting Apoptosis and Modulating Overall Metabolism
Authors: Yang Lu , Bi Liping , Jin Lulu , Wang Yuming , Li Yuting , Li Zixuan , He Wenju , Cui Huantian , Miao Jing , Wang Li
Published: November 2021

Liver fibrosis is a progressive liver damage condition caused by various factors and may progress toward liver cirrhosis, and even hepatocellular carcinoma. Many studies have found that the disfunction in metabolism could contribute to the development of liver fibrosis. Geniposide, derived from Gardenia jasminoides J. Ellis, has been demonstrated with therapeutic effects on liver fibrosis. However, the exact molecular mechanisms of such liver-protection remain largely unknown. The aim of this study was to explored the effect of geniposide on metabolic regulations in liver fibrosis. We used carbon tetrachloride (CCl4) to construct a mouse model of liver fibrosis and subsequently administered geniposide treatment. Therapeutic effects of geniposide on liver fibrosis were accessed through measuring the levels of hepatic enzymes in serum and the pathological changes in liver. We also investigated the effects of geniposide on inflammatory response, oxidative stress and apoptosis in liver. Furthermore, serum untargeted metabolomics were used to explore the metabolic regulatory mechanisms behind geniposide on liver fibrosis. Our results demonstrated that geniposide could reduce the levels of hepatic enzymes in serum and ameliorate the pathological changes in liver fibrosis mice. Geniposide enhanced the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and decreased methane dicarboxylic aldehyde (MDA) levels in liver. Geniposide treatment also decreased the levels of interleukin (IL)-6, IL-1β, and tumor necrosis factor-alpha (TNF-a) in liver tissue homogenate. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL) staining demonstrated that geniposide could reduce the apoptosis of hepatocytes. Geniposide increased the protein expression of B-cell lymphoma-2 (Bcl-2) and downregulated the protein expression of Bcl-2 Associated X (Bax), cleaved-Caspase 3, and cleaved-Caspase 9. Serum untargeted metabolomics analysis demonstrated that geniposide treatment improved the metabolic disorders including glycerophospholipid metabolism, arginine and proline metabolism, and arachidonic acid (AA) metabolism. In conclusion, our study demonstrated the protective effects of geniposide on liver fibrosis. We found that geniposide could treat liver fibrosis by inhibiting oxidative stress, reducing inflammatory response and apoptosis in the liver, and modulating glycerophospholipid, and arginine, proline, and AA metabolism processes.
Research Advances in Pharmacology, Safety, and Clinical Applications of Yunnan Baiyao, a Traditional Chinese Medicine Formula
Authors: Yao Qi , Chang Bo-tao , Chen Rong , Wei Yi-jing , Gong Qiu-ju , Yu Dan , Zhang Yang , Han Xu , Yang Hong-bo , Tang Song-jiang , Gao Ying
Published: November 2021

Ethnopharmacology relevance: Yunnan Baiyao (YNBY), a traditional Chinese medicine formulae, has some significant properties including activating blood circulation to dissipate blood stasis (Huo-Xue-Hua-Yu), eliminating swelling and alleviating pain (Xiao-Zhong-Zhi-Tong), and eliminating necrotic tissues and promoting granulation (Qu-Fu-Sheng-Ji).

Aim of this study: This paper intends to provide a comprehensive and critical analysis of studies on YNBY, proposing new possible therapeutic directions of this formula.

Materials and methods: Relevant data on YNBY were retrieved from available databases and a hand-search by searching the keywords such as “Yunnan Baiyao,” “pharmacology,” “toxicity,” and “clinical applications.”

Results: Traditionally, YNBY has been used to cure hemorrhage, bruises, swelling, and pain caused by injuries in the Chinese folk. Modern pharmacological studies show that YNBY possesses pharmacological activities including hemostasis, invigorating the circulation of blood, wound healing, anti-inflammation, analgesia, antibiosis, infection prevention, and other effects. Toxicological studies demonstrate that YNBY has a certain toxicology, which is mainly caused by Aconitum alkaloids from Cao-wu (CW, Aconiti Kusnezoffii Radix). The developmental non-toxic reaction dose (NOAEL) of YNBY for embryos and fetuses is 0.5 g/kg in rats. In addition, the NOAEL for fertility and early embryo development toxicity is 4.0 g/kg in rats. Clinical trials have confirmed the safety of YNBY in a large number of patients, and adverse drug reactions (ADRs) such as abdominal pain, diarrhea, allergy, and others in very few people. YNBY is routinely used in clinic to cure bleeding, pain, swelling, upper digestive tract ulcer, postoperative wound, arthritis, mouth ulcers, ulcerative colitis, etc.

Conclusions: Hemostasis is a conspicuous effect of YNBY. Except for this effect, analgesia and anti-infection may be new research directions of this formula. In addition, the in vitro and in vivo pharmacology and mechanisms of action of YNBY are encouraged as well as the pharmacokinetics of this formulae. Furthermore, the material basis of the pharmacological effects of YNBY also needs clear identification.
Low Temperature Effect on the Endocrine and Circadian Systems of Adult Danio rerio
Authors: Sua-Cespedes Cristhian D. , David Daniela Dantas , Souto-Neto José A. , Lima Otoniel Gonçalves , Moraes Maria Nathália , de Assis Leonardo V. Monteiro , Castrucci Ana Maria de Lauro
Published: November 2021

The control of the biological rhythms begins with the activation of photo- and thermosensitive cells located in various organs of the fish such as brain, eye, and skin, but a central clock is still to be identified in teleosts. Thermal changes are stressors which increase cortisol and affect the rhythm of other hormones such as melatonin and growth hormone (GH), in both endo- and ectothermic organisms. Our aim was to investigate how temperature (23°C for 6 days) lower than the optimal (28°C) modulates expression of several gene pathways including growth hormone (gh1) and its receptors (ghra, ghrb), insulin-like growth factor1 (igf1a, igf1b) and its receptors (igf1ra, igf1rb), cortisol and its receptor (gr), the limiting enzyme of melatonin synthesis (arylalkylamine N-acetyltransferase, aanat) and melatonin receptors (mtnr1aa, mtnr1bb), as well as their relationship with clock genes in Danio rerio in early light and early dark phases of the day. Lower temperature reduced the expression of the hormone gene gh1, and of the related receptors ghra, ghrb, igf1ra, and igf1rb. Cortisol levels were higher at the lower temperature, with a decrease of its receptor (gr) transcripts in the liver. Interestingly, we found higher levels of aanat transcripts in the brain at 23°C. Overall, lower temperature downregulated the transcription of hormone related genes and clock genes. The results suggest a strong correlation of temperature challenge with the clock molecular mechanism and the endocrine systems analyzed, especially the growth hormone and melatonin axes, in D. rerio tissues.
Cardiac and Autonomic Dysfunctions Assessed Through Recurrence Quantitative Analysis of Electrocardiogram Signals and an Application to the 6-Hydroxydopamine Parkinson’s Disease Animal Model
Authors: Shinoda Lucas , Damasceno Laís , Freitas Leandro , Campos Ruy , Cravo Sergio , Scorza Carla A. , Scorza Fúlvio A. , Faber Jean
Published: November 2021

A classic method to evaluate autonomic dysfunction is through the evaluation of heart rate variability (HRV). HRV provides a series of coefficients, such as Standard Deviation of n-n intervals (SDNN) and Root Mean Square of Successive Differences (RMSSD), which have well-established physiological associations. However, using only electrocardiogram (ECG) signals, it is difficult to identify proper autonomic activity, and the standard techniques are not sensitive and robust enough to distinguish pure autonomic modulation in heart dynamics from cardiac dysfunctions. In this proof-of-concept study we propose the use of Poincaré mapping and Recurrence Quantification Analysis (RQA) to identify and characterize stochasticity and chaoticity dynamics in ECG recordings. By applying these non-linear techniques in the ECG signals recorded from a set of Parkinson’s disease (PD) animal model 6-hydroxydopamine (6-OHDA), we showed that they present less variability in long time epochs and more stochasticity in short-time epochs, in their autonomic dynamics, when compared with those of the sham group. These results suggest that PD animal models present more “rigid heart rate” associated with “trembling ECG” and bradycardia, which are direct expressions of Parkinsonian symptoms. We also compared the RQA factors calculated from the ECG of animal models using four computational ECG signals under different noise and autonomic modulatory conditions, emulating the main ECG features of atrial fibrillation and QT-long syndrome.
Thoracic Outlet Syndrome: Fingertip Cannot Replace Forearm Photoplethysmography in the Evaluation of Positional Venous Outflow Impairments
Authors: Hersant Jeanne , Ramondou Pierre , Durand Sylvain , Feuilloy Mathieu , Daligault Mickael , Abraham Pierre , Henni Samir
Published: November 2021

Objective: Fingertip photoplethysmography (PPG) resulting from high-pass filtered raw PPG signal is often used to record arterial pulse changes in patients with suspected thoracic outlet syndrome (TOS). Results from venous (low-pass filtered raw signal) forearm PPG (V-PPG) during the Candlestick-Prayer (Ca + Pra) maneuver were recently classified into four different patterns in patients with suspected TOS, two of which are suggestive of the presence of outflow impairment. We aimed to test the effect of probe position (fingertip vs. forearm) and of red (R) vs. infrared (IR) light wavelength on V-PPG classification and compared pattern classifications with the results of ultrasound (US).

Methods: In patients with suspected TOS, we routinely performed US imaging (US + being the presence of a positional compression) and Ca + Pra tests with forearm V-PPGIR. We recruited patients for a Ca + Pra maneuver with the simultaneous fingertip and forearm V-PPGR. The correlation of each V-PPG recording to each of the published pattern profiles was calculated. Each record was classified according to the patterns for which the coefficient of correlation was the highest. Cohen’s kappa test was used to determine the reliability of classification among forearm V-PPGIR, fingertip V-PPGR, and forearm V-PPGR.

Results: We obtained 40 measurements from 20 patients (40.2 ± 11.3 years old, 11 males). We found 13 limbs with US + results, while V-PPG suggested the presence of venous outflow impairment in 27 and 20 limbs with forearm V-PPGIR and forearm V-PPGR, respectively. Fingertip V-PPGR provided no patterns suggesting outflow impairment.

Conclusion: We found more V-PPG patterns suggesting venous outflow impairment than US + results. Probe position is essential if aiming to perform upper-limb V-PPG during the Ca + Pra maneuver in patients with suspected TOS. V-PPG during the Ca + Pra maneuver is of low cost and easy and provides reliable, recordable, and objective evidence of forearm swelling. It should be performed on the forearm (close to the elbow) with either PPGR or PPGIR but not at the fingertip level.