Miracle-dz/UniFAR-FTUs huggingface dataset:
A prospective trial of adjuvant therapy for high-risk uveal melanoma: assessing 5-year survival outcomes

Background/aims Survival after diagnosis of metastasis from uveal melanoma is poor. Identifying individuals at high risk for metastasis and developing adjuvant therapy to prevent clinically apparent metastasis could improve survival. We conducted an adjuvant trial of sequential, low-dose dacarbazine (DTIC) and interferon-alpha-2b (IFN-α−2b) in patients with cytogenetic high-risk uveal melanoma. Methods Patients diagnosed with iris, ciliary body or choroidal melanoma with high-risk tumour cytogenetics (monosomy 3) were offered adjuvant treatment with low-dose DTIC and IFN-α−2b following primary therapy. Eligible but not enrolled patients were observed for comparison. DTIC was administered at 850 mg/m2 intravenously on days 1 and 28. IFN-α−2b was administered at 3 million units three times a week subcutaneously for 24 weeks beginning at week 9. Hepatic imaging was performed prior to adjuvant therapy and then at least every 6 months. Survival data were collected for 5 years after enrolment. Results 33 patients (22%) were enrolled (treatment group), 29 (19%) were eligible but did not enrol (observation group) and 88 (59%) were not eligible. The 5-year metastasis-free survival (MFS) was 64%±9% for treated and 33%±10% for observed patients (p=0.05). The 5-year overall survival (OS) rate was 66%±9% for treated and 37%±10% for observed patients (p=0.02). Conclusions When adjusted for differences in age, tumour size and initial treatment, survival between treated and observed patients was no longer significant (p=0.56 MFS and p=0.92 OS). Differences in baseline tumour characteristics between treated and observed patients can influence interpretation of results. Trial registration number NCT01100528.
Dynamic MAPK signaling activity underlies a transition from growth arrest to proliferation in Drosophila scribble mutant tumors

ABSTRACT Human tumors exhibit plasticity and evolving capacity over time. It is difficult to study the mechanisms of how tumors change over time in human patients, in particular during the early stages when a few oncogenic cells are barely detectable. Here, we used a Drosophila tumor model caused by loss of scribble (scrib), a highly conserved apicobasal cell polarity gene, to investigate the spatial-temporal dynamics of early tumorigenesis events. The fly scrib mutant tumors have been successfully used to model many aspects of tumorigenesis processes. However, it is still unknown whether Drosophila scrib mutant tumors exhibit plasticity and evolvability along the temporal axis. We found that scrib mutant tumors displayed different growth rates and cell cycle profiles over time, indicative of a growth arrest-to-proliferation transition as the scrib mutant tumors progress. Longitudinal bulk and single-cell transcriptomic analysis of scrib mutant tumors revealed that the MAPK pathway, including JNK and ERK signaling activities, showed quantitative changes over time. We found that high JNK signaling activity caused G2/M cell cycle arrest in early scrib mutant tumors. In addition, JNK signaling activity displayed a radial polarity with the JNKhigh cells located at the periphery of scrib mutant tumors, providing an inherent mechanism that leads to an overall decrease in JNK signaling activity over time. We also found that ERK signaling activity, in contrast to JNK activity, increased over time and promoted growth in late-stage scrib mutant tumors. Furthermore, high JNK signaling activity repressed ERK signaling activity in early scrib mutant tumors. Together, these data demonstrate that dynamic MAPK signaling activity, fueled by intratumor heterogeneity derived from tissue topological differences, drives a growth arrest-to-proliferation transition in scrib mutant tumors. This article has an associated First Person interview with the joint first authors of the paper. Summary: The authors provide evidence to show that a well-established Drosophila tumor model, caused by loss of apicobasal cell polarity, harbors a surprising degree of plasticity and evolvability along the temporal axis.
Single-molecule visualization reveals the damage search mechanism for the human NER protein XPC-RAD23B

Abstract DNA repair is critical for maintaining genomic integrity. Finding DNA lesions initiates the entire repair process. In human nucleotide excision repair (NER), XPC-RAD23B recognizes DNA lesions and recruits downstream factors. Although previous studies revealed the molecular features of damage identification by the yeast orthologs Rad4-Rad23, the dynamic mechanisms by which human XPC-RAD23B recognizes DNA defects have remained elusive. Here, we directly visualized the motion of XPC-RAD23B on undamaged and lesion-containing DNA using high-throughput single-molecule imaging. We observed three types of one-dimensional motion of XPC-RAD23B along DNA: diffusive, immobile and constrained. We found that consecutive AT-tracks led to increase in proteins with constrained motion. The diffusion coefficient dramatically increased according to ionic strength, suggesting that XPC-RAD23B diffuses along DNA via hopping, allowing XPC-RAD23B to bypass protein obstacles during the search for DNA damage. We also examined how XPC-RAD23B identifies cyclobutane pyrimidine dimers (CPDs) during diffusion. XPC-RAD23B makes futile attempts to bind to CPDs, consistent with low CPD recognition efficiency. Moreover, XPC-RAD23B binds CPDs in biphasic states, stable for lesion recognition and transient for lesion interrogation. Taken together, our results provide new insight into how XPC-RAD23B searches for DNA lesions in billions of base pairs in human genome.
COP9 signalosome complex subunit 5, an IFT20 binding partner, is essential to maintain male germ cell survival and acrosome biogenesis†

Abstract Intraflagellar transport protein 20 (IFT20) is essential for spermatogenesis in mice. We discovered that COPS5 was a major binding partner of IFT20. COPS5 is the fifth component of the constitutive photomorphogenic-9 signalosome (COP9), which is involved in protein ubiquitination and degradation. COPS5 is highly abundant in mouse testis. Mice deficiency in COPS5 specifically in male germ cells showed dramatically reduced sperm numbers and were infertile. Testis weight was about one third compared to control adult mice, and germ cells underwent significant apoptosis at a premeiotic stage. Testicular poly (ADP-ribose) polymerase-1, a protein that helps cells to maintain viability, was dramatically decreased, and Caspase-3, a critical executioner of apoptosis, was increased in the mutant mice. Expression level of FANK1, a known COPS5 binding partner, and a key germ cell apoptosis regulator was also reduced. An acrosome marker, lectin PNA, was nearly absent in the few surviving spermatids, and expression level of sperm acrosome associated 1, another acrosomal component was significantly reduced. IFT20 expression level was significantly reduced in the Cops5 knockout mice, and it was no longer present in the acrosome, but remained in the Golgi apparatus of spermatocytes. In the conditional Ift20 mutant mice, COPS5 localization and testicular expression levels were not changed. COP9 has been shown to be involved in multiple signal pathways, particularly functioning as a co-factor for protein ubiquitination. COPS5 is believed to maintain normal spermatogenesis through multiple mechanisms, including maintaining male germ cell survival and acrosome biogenesis, possibly by modulating protein ubiquitination. Summary sentence COPS5 is essential for mouse spermatogenesis and particularly in maintaining male germ cell survival and acrosome biogenesis.
Utility of Percentage Signal Recovery and Baseline Signal in DSC-MRI Optimized for Relative CBV Measurement for Differentiating Glioblastoma, Lymphoma, Metastasis, and Meningioma

BACKGROUND AND PURPOSE: The percentage signal recovery in non-leakage-corrected (no preload, high flip angle, intermediate TE) DSC-MR imaging is known to differ significantly for glioblastoma, metastasis, and primary CNS lymphoma. Because the percentage signal recovery is influenced by preload and pulse sequence parameters, we investigated whether the percentage signal recovery can still differentiate these common contrast-enhancing neoplasms using a DSC-MR imaging protocol designed for relative CBV accuracy (preload, intermediate flip angle, low TE). MATERIALS AND METHODS: We retrospectively analyzed DSC-MR imaging of treatment-naïve, pathology-proved glioblastomas (n = 14), primary central nervous system lymphomas (n = 7), metastases (n = 20), and meningiomas (n = 13) using a protocol designed for relative CBV accuracy (a one-quarter-dose preload and single-dose bolus of gadobutrol, TR/TE = 1290/40 ms, flip angle = 60° at 1.5T). Mean percentage signal recovery, relative CBV, and normalized baseline signal intensity were compared within contrast-enhancing lesion volumes. Classification accuracy was determined by receiver operating characteristic analysis. RESULTS: Relative CBV best differentiated meningioma from glioblastoma and from metastasis with areas under the curve of 0.84 and 0.82, respectively. The percentage signal recovery best differentiated primary central nervous system lymphoma from metastasis with an area under the curve of 0.81. Relative CBV and percentage signal recovery were similar in differentiating primary central nervous system lymphoma from glioblastoma and from meningioma. Although neither relative CBV nor percentage signal recovery differentiated glioblastoma from metastasis, mean normalized baseline signal intensity achieved 86% sensitivity and 50% specificity. CONCLUSIONS: Similar to results for non-preload-based DSC-MR imaging, percentage signal recovery for one-quarter-dose preload-based, intermediate flip angle DSC-MR imaging differentiates most pair-wise comparisons of glioblastoma, metastasis, primary central nervous system lymphoma, and meningioma, except for glioblastoma versus metastasis. Differences in normalized post-preload baseline signal for glioblastoma and metastasis, reflecting a snapshot of dynamic contrast enhancement, may motivate the use of single-dose multiecho protocols permitting simultaneous quantification of DSC-MR imaging and dynamic contrast-enhanced MR imaging parameters.
Marine Toxins and Nociception: Potential Therapeutic Use in the Treatment of Visceral Pain Associated with Gastrointestinal Disorders

Visceral pain, of which the pathogenic basis is currently largely unknown, is a hallmark symptom of both functional disorders, such as irritable bowel syndrome, and inflammatory bowel disease. Intrinsic sensory neurons in the enteric nervous system and afferent sensory neurons of the dorsal root ganglia, connecting with the central nervous system, represent the primary neuronal pathways transducing gut visceral pain. Current pharmacological therapies have several limitations, owing to their partial efficacy and the generation of severe adverse effects. Numerous cellular targets of visceral nociception have been recognized, including, among others, channels (i.e., voltage-gated sodium channels, VGSCs, voltage-gated calcium channels, VGCCs, Transient Receptor Potential, TRP, and Acid-sensing ion channels, ASICs) and neurotransmitter pathways (i.e., GABAergic pathways), which represent attractive targets for the discovery of novel drugs. Natural biologically active compounds, such as marine toxins, able to bind with high affinity and selectivity to different visceral pain molecular mediators, may represent a useful tool (1) to improve our knowledge of the physiological and pathological relevance of each nociceptive target, and (2) to discover therapeutically valuable molecules. In this review we report the most recent literature describing the effects of marine toxin on gastrointestinal visceral pain pathways and the possible clinical implications in the treatment of chronic pain associated with gut diseases.
Intravenous infusion of iPSC-derived neural precursor cells increases acid β-glucosidase function in the brain and lessens the neuronopathic phenotype in a mouse model of Gaucher disease.

Gaucher disease is caused by GBA1 mutations leading to functional deficiency of acid-β-glucosidase (GCase). No effective treatment is available for neuronopathic Gaucher disease (nGD). A subclass of neural stem and precursor cells (NPCs) expresses VLA4 (Integrin α4β1, Very Late Antigen-4) that facilitates NPC entry into the brain following intravenous infusion (IV). Here, the therapeutic potential of IV VLA4+NPCs was assessed for nGD using wild-type mouse GFP positive multipotent iPSC-derived VLA4+NPCs. VLA4+NPCs successfully engrafted in the nGD (4L;C*) mouse brain. GFP positive cells differentiated into neurons, astrocytes and oligodendrocytes in brainstem, midbrain, and thalamus of the transplanted mice and significantly improved sensorimotor function and prolonged life span compared to vehicle-treated 4L;C* mice. VLA4+NPC transplantation significantly decreased levels of CD68 and GFAP, as wells as TNFα mRNA levels in the brain, indicating reduced neuroinflammation. Furthermore, decreased Fluoro-Jade C and NeuroSilver staining suggested inhibition of neurodegeneration. VLA4+NPC-engrafted 4L;C* midbrains showed 35% increased GCase activity, reduced substrate [glucosylceramide (-34%) and glucosylsphingosine (-11%)] levels, and improved mitochondrial oxygen consumption rates in comparison to vehicle-4L;C* mice. VLA4+NPC engraftment in 4L;C* brain also led to enhanced expression of neurotrophic factors that have roles in neuronal survival and the promotion of neurogenesis. This study provides evidence that iPSC-derived NPC transplantation has efficacy in a nGD mouse model and provides proof of concept for autologous NPC therapy in nGD.
Impact of transitional care for discharged elderly stroke patients in China: an application of the Integrated Behavioral Model

ABSTRACT Background: Transitional care (TC) has been shown to improve stroke rehabilitation in discharged stroke patients. Previous TC interventions did not report satisfactory stroke rehabilitation outcomes or risk management. Incorporating a health behavior theory in interventions can effectively improve health behaviors and metabolic indicators. Objectives: This study was a clinical controlled trial to investigate the impact of the Integrated Behavioral Model (IBM)-based 3-month TC on health behaviors, clinical outcomes, and stroke knowledge in discharged elderly stroke patients. Methods: Sixty elderly patients were recruited from two wards of a public teaching hospital in China. To prevent potential treatment contamination, patients were allocated into either a control or intervention group depending on which wards they were admitted to. The TC intervention considered all the IBM constructs to provide patients assistance in implementing health behaviors as recommended by the Chinese stroke guidelines. The TC intervention commenced one day before discharge and lasted three months after discharge. A linear mixed model was used to measure the impact of the intervention. Results: The TC intervention improved the discharged elderly stroke patients’ health behaviors, activities of daily living, quality of life, and stroke knowledge. The intervention also controlled the patients’ systolic blood pressure, body mass index, total cholesterol, triglycerides, and low-density lipoprotein cholesterol. Conclusions: This study provided evidence of concurrent self-reported and objective clinical indicators in discharged elderly stroke patients for the impact of the IBM-based 3-month TC intervention, which can be recommended for clinical practice.
Effect of First-line S-1 Plus Oxaliplatin With or Without Ramucirumab Followed by Paclitaxel Plus Ramucirumab on Advanced Gastric Cancer in East Asia

Key Points Question Does the addition of ramucirumab to S-1 and oxaliplatin improve progression-free survival in patients with metastatic gastric or gastroesophageal junction adenocarcinoma in the first-line setting? Findings In this phase 2 randomized clinical trial of 189 East Asian patients with metastatic gastric or gastroesophageal junction adenocarcinoma, median progression-free survival was not prolonged in the ramucirumab plus S-1 and oxaliplatin arm compared with the placebo plus S-1 and oxaliplatin arm (6.34 vs 6.74 months). Meaning Addition of ramucirumab to first-line S-1 and oxaliplatin treatment did not improve progression-free survival, suggesting that the efficacy of ramucirumab in the second-line setting may not be applicable to the first-line setting when combined with fluoropyrimidine and platinum chemotherapy.
Empirically derived food-based dietary inflammatory index is associated with increased risk of psychological disorders in women

ABSTRACT Purpose/introduction: There is no study on the association of empirically derived food-based dietary inflammatory index (FDII) and risk of psychological disorders. We investigated the association between FDII and odds of psychological disorders in Iranian adults. Methods and materials: In this cross-sectional study, data on dietary intakes of 3363 Iranian adult participants were collected using a validated dish-based 106-item semi-quantitative food frequency questionnaire. FDII score was constructed based on participants’ dietary intakes of 28 pre-defined food groups. The Iranian validated version of Hospital Anxiety and Depression Scale (HADS) and General Health Questionnaire (GHQ) was used to assess psychological disorders. Depression, anxiety and psychological distress were defined based on standard criteria. Results: After controlling for potential confounders, participants in the top quintile of FDII score had a greater odds of depression (OR: 1.49; 95% CI: 1.08–2.06), anxiety (OR: 1.92; 95% CI: 1.24–2.96), and psychological distress (OR: 1.55; 95% CI: 1.10–2.19) compared with those in the bottom quintile. When we did the analyses stratified by gender, we found a significant positive association between FDII score and depression (OR: 1.57; 95% CI: 1.04–2.35), anxiety (OR: 1.99; 95% CI: 1.19–3.34), and psychological distress (OR: 1.68; 95% CI: 1.10–2.56) among women comparing the highest and the lowest quintiles. We found no significant association between FDII score and psychological disorders in men. Conclusion: We found that greater FDII score was positively associated with psychological disorders. In the gender-stratified analysis, this was seen in women but not in men.
Radiofrequency ablation using injectable cooled electrode: the effects of lidocaine injection in ex vivo study

Background Pain control is needed during radiofrequency ablation in musculoskeletal tumor. The effect of radiofrequency ablation can be modulated by lidocaine injection. Purpose To evaluate the effects of injectable electrodes with intralesional lidocaine injection and compare its ablation performance with that of non-injectable electrodes in ex vivo pork sirloin. Material and Methods Five specimen groups were used to investigate the effects of fluid injection before radiofrequency ablation using injectable and non-injectable electrodes: three injectable electrode comparison groups with 2% lidocaine (group A); 1% lidocaine (group B); 0.9% sodium chloride (group C); injectable electrode reference group without fluid (group D); and non-injectable electrode control group (group E). The injectable and non-injectable electrodes were 17-gauge electrodes each having a 1-cm active tip. Technical parameters, ablation size, and volumes were compared between the five groups. Results Mean energies and currents during radiofrequency ablation were significantly lower for the four injectable electrode groups compared to group E (all P < 0.005). Two transverse diameters, vertical diameter, and volumes in the four injectable electrode groups were significantly smaller than those in group E (all P < 0.05). Among the injectable electrode groups, volumes and two transverse diameters were significantly smaller in group A than in group D (all P < 0.05). Conclusions A slightly smaller ablation zone is obtained when lidocaine injection is performed before radiofrequency ablation using an injectable electrode compared to a non-injectable electrode.
Preparation, characterization and in vitro evaluation of PEGylated nanoliposomal containing etoposide on lung cancer

Abstract Introduction and objective Lung cancer is the most common one in terms of outbreak and mortality. Since most modern treatments have many side effects, finding an effective and alternative therapy seems necessary. The present study aimed to determine the effect of PEGylated liposomal etoposide nanoparticles on the lung cancer (A-549 and Calu6 cell lines). Materials and methods The PEGylated liposomal etoposide nanoparticles were prepared by reverse-phase evaporation method. The particle size and zeta potential of the nanoparticles were measured by Zetasizer. The nanoparticle cytotoxicity was examined by MTT method. The vesicular drug release pattern was examined by dialysis method. The amount of loaded drug and the encapsulation efficiency (EE) was also measured and calculated. Apoptosis test was performed using flow cytometry with Annexin V kit. Results The mean particle size, size distribution, and zeta potential of PEGylated liposomal etoposide nanoparticles were 122.5 ± 4.8 nm, 0.252 ± 0.12 and −13.7 ± 0.51 mv, respectively. The etoposide release in prepared formulations was detected to be about 15.64% after 50 hr. The cytotoxic effect of etoposide nanoparticles on lung cancer A-549 and Calu6 cell lines showed more anti-tumour activity compared to the free drug used. Conclusion The results showed that the PEGylated liposomal nanoparticles were used as a suitable nanocarrier for etoposide injection. It was also found that the drug effect on the nanodrug formulations was higher than that of the free drug.
Linear Accelerator-Based Radiotherapy Simulation Using On-Board Kilovoltage Cone-Beam Computed Tomography for 3-Dimensional Volumetric Planning and Rapid Treatment in the Palliative Setting

Background: Palliation of advanced disease using radiotherapy can create difficult clinical situations where standard computed tomography simulation and immobilization techniques are not feasible. We developed a linear accelerator-based radiotherapy simulation technique using nonstandard patient positioning for head and neck palliation using on-board kilovoltage cone-beam computed tomography for 3-D volumetric planning and rapid treatment. Material and Methods: We proved cone-beam computed tomography simulation feasibility for semi-upright patient positioning using an anthropomorphic phantom on a clinical Elekta-Synergy linear accelerator. Cone-beam computed tomography imaging parameters were optimized for high-resolution image reconstruction and to ensure mechanical clearance. The patient was simulated using a cone-beam computed tomography–based approach and the cone-beam computed tomography digital imaging and communications in medicine file was imported to the treatment planning software to generate radiotherapy target volumes. Rapid planning was achieved by using a 3-level bulk density correction for air, soft tissue, and bone set at 0, 1.0, and 1.4 g/cm3, respectively. Results: Patient volumetric imaging was obtained through cone-beam computed tomography simulation and treatment was delivered as planned without incident. Bulk density corrections were verified against conventionally simulated patients where differences were less than 1%. Conclusion: We successfully developed and employed a semi-upright kilovoltage cone-beam computed tomography–based head and neck simulation and treatment planning method for 3-D conformal radiotherapy delivery. This approach provides 3-D documentation of the radiotherapy plan and allows tabulation of quantitative spatial dose information which is valuable if additional palliative treatments are needed in the future. This is a potentially valuable technique that has broad clinical applicability for benign and palliative treatments across multiple disease sites—particularly where standard supine simulation and immobilization techniques are not possible.