bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemotherapy-induced peripheral neuropathy in children and adolescent cancer patients
Authors: Tay Nicolette , Laakso E-Liisa , Schweitzer Daniel , Endersby Raelene , Vetter Irina , Starobova Hana
Published: October 2022

Brain cancer and leukemia are the most common cancers diagnosed in the pediatric population and are often treated with lifesaving chemotherapy. However, chemotherapy causes severe adverse effects and chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting and debilitating side effect. CIPN can greatly impair quality of life and increases morbidity of pediatric patients with cancer, with the accompanying symptoms frequently remaining underdiagnosed. Little is known about the incidence of CIPN, its impact on the pediatric population, and the underlying pathophysiological mechanisms, as most existing information stems from studies in animal models or adult cancer patients. Herein, we aim to provide an understanding of CIPN in the pediatric population and focus on the 6 main substance groups that frequently cause CIPN, namely the vinca alkaloids (vincristine), platinum-based antineoplastics (cisplatin, carboplatin and oxaliplatin), taxanes (paclitaxel and docetaxel), epothilones (ixabepilone), proteasome inhibitors (bortezomib) and immunomodulatory drugs (thalidomide). We discuss the clinical manifestations, assessments and diagnostic tools, as well as risk factors, pathophysiological processes and current pharmacological and non-pharmacological approaches for the prevention and treatment of CIPN.
Long noncoding RNA maternally expressed gene 3 improves trophoblast dysfunction and inflammation in preeclampsia through the Wnt/β-Catenin/nod-like receptor pyrin domain-containing 3 axis
Authors: Liang Yue , Wang Ping , Shi Yueyang , Cui Bihong , Meng Jinlai
Published: October 2022

Inadequate trophoblastic infiltration and resulting placental hypoxia and inflammation comprise the core pathological basis of preeclampsia (PE). Maternally expressed gene 3 (MEG3) is known to be involved in the pathogenesis of preeclampsia by inhibiting the migration and invasion of trophoblasts and promoting their apoptosis. Nevertheless, the specific underlying downstream molecular mechanism of MEG3 is less well characterized. In this study, we detected lower expression levels of MEG3 and β-Catenin and higher expression of nod-like receptor pyrin domain-containing 3 (NLRP3) in placental tissues of pregnant women with severe preeclampsia (sPE) than in normal pregnancies. Elevated serum levels of IL-1β and TNF-α were also observed in the sPE group. Then, we established a hypoxia/reoxygenation (H/R) model to mimic preeclampsia. Similar results with sPE group were found in the H/R group compared with the control group. In addition, suppressive trophoblast proliferation, migration and invasion and increases in the apoptotic rate and inflammation were also detected in the H/R group. Notably, overexpressing MEG3 markedly improved trophoblast dysfunction and inflammation caused by H/R. However, the effects of MEG3 on trophoblasts, whether upregulated or downregulated, can be reversed by DKK-1 (Wnt/β-Catenin inhibitor) and MCC950 (NLRP3 inhibitor). The current study revealed that MEG3 regulates trophoblast function and inflammation through the Wnt/β-Catenin/NLRP3 axis and provided new insights into the pathogenesis of preeclampsia.
Glutamatergic and GABAergic neurons in the preoptic area of the hypothalamus play key roles in menopausal hot flashes
Authors: Sun Yanrong , Wang Hanfei , Wang Wenjuan , Lu Jiali , Zhang Jinglin , Luo Xiaofeng , Luan Liju , Wang Ke , Jia Jing , Yan Junhao , Qin Lihua
Published: October 2022

During menopause, when estrogen levels are low, abnormalities in the hypothalamic preoptic area (POA) of the thermoregulatory center can cause hot flashes. However, the involved neural population has not been identified. Proteomics showed that under low estrogen, differentially expressed proteins in the hypothalamus were associated with glutamatergic and GABAergic synapses. RNAscope, Western blotting and qRT-PCR indicated that the number of glutamatergic neurons in the POA was decreased, while the number of GABAergic neurons was increased. Chemogenetics showed that the rat body temperature decreased slowly after glutamatergic neurons were activated and increased quickly after glutamatergic neurons were inhibited, while it increased quickly after GABAergic neurons were activated and decreased slowly after GABAergic neurons were inhibited. RNAscope, immunofluorescence, Western blotting and qRT-PCR further showed that glutamate decarboxylase (GAD) 1 expression in the POA was increased, while GAD2 expression in the POA was decreased; that thermosensitive transient receptor potential protein (ThermoTRP) M (TRPM) 2 expression in glutamatergic neurons was decreased, while TRPM8 expression in GABAergic neurons was increased; and that estrogen receptor (ER) α and β expression in the POA was decreased, and ERα and ERβ expressed in both glutamatergic and GABAergic neurons. Estrogen therapy corrected these abnormalities. In addition, CUT&Tag and Western blot after injection of agonists and inhibitors of ERs showed that ERα and ERβ were both transcription factors in glutamatergic and GABAergic synapses. Mechanistically, during menopause, estrogen may regulate the transcription and expression of GADs and ThermoTRPs through ERs, impacting the number and function of glutamatergic and GABAergic neurons, resulting in unbalanced heat dissipation and production in the POA and ultimately triggering hot flashes.
Neuroprotective effect of naringin against cerebellar changes in Alzheimer’s disease through modulation of autophagy, oxidative stress and tau expression: An experimental study
Authors: Hassan Hend M. , Elnagar Mohamed R. , Abdelrazik Eman , Mahdi Mohamed R. , Hamza Eman , Elattar Eman M. , ElNashar Eman Mohamed , Alghamdi Mansour Abdullah , Al-Qahtani Zainah , Al-Khater Khulood Mohammed , Aldahhan Rashid A. , ELdesoqui Mamdouh
Published: October 2022

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by gradual cognitive decline. Strong antioxidants that inhibit free radicals, such as polyphenols, reduce the likelihood of developing oxidative stress-related degenerative diseases such as AD. Naringin, a flavonoid found in citrus fruit shown to be neuroprotective, reduce oxidative damage and minimize histopathological changes caused by ischemic reperfusion, enhance the long-term memory in AD animal models. This work aimed to comprehend the role of naringin in the defense of the cerebellum against aluminum chloride (AlCl3)-induced AD in rats by investigating the behavioral, neurochemical, immunohistochemical, and molecular mechanisms that underpin its possible neuroprotective effects. Twenty-four adult albino rats were divided into four groups (n = 6/group): (i) Control (C) received saline per oral (p.o.), (ii) Naringin(N)-received naringin (100 mg/kg/d) p.o, (iii) AlCl3-recived AlCl3 (100 mg/kg/d) p.o and (iv) AlCl3 + Naringin (AlCl3 + N) received both AlCl3 and naringin p.o for 21 days. Behavioral tests showed an increase in the time to reach the platform in Morris water maze, indicating memory impairment in the AlCl3-treated group, but co-administration of naringin showed significant improvement. The Rotarod test demonstrated a decrease in muscle coordination in the AlCl3-treated group, while it was improved in the AlCl3 + N group. Neurochemical analysis of the hippocampus and cerebellum revealed that AlCl3 significantly increased lipid peroxidation and oxidative stress and decreased levels of reduced glutathione. Administration of naringin ameliorated these neurochemical changes via its antioxidant properties. Cerebellar immunohistochemical expression for microtubule assembly (tau protein) and oxidative stress (iNOS) increased in A1C13-treated group. On the other hand, the expression of the autophagic marker (LC3) in the cerebellum showed a marked decline in AlCl3-treated group. Western blot analysis confirmed the cerebellar immunohistochemical findings. Collectively, these findings suggested that naringin could contribute to the combat of oxidative and autophagic stress in the cerebellum of AlCl3-induced AD.
The role of non-coding RNAs in the formation of long-term associative memory after single-trial learning in Lymnaea
Authors: Kemenes György , Benjamin Paul R. , Kemenes Ildikó
Published: October 2022

Investigations of the molecular mechanisms of long-term associative memory have revealed key roles for a number of highly evolutionarily conserved molecular pathways in a variety of different vertebrate and invertebrate model systems. One such system is the pond snail Lymnaea stagnalis, in which, like in other systems, the transcription factors CREB1 and CREB2 and the enzyme NOS play essential roles in the consolidation of long-term associative memory. More recently, epigenetic control mechanisms, such as DNA methylation, histone modifications, and control of gene expression by non-coding RNAs also have been found to play important roles in all model systems. In this minireview, we will focus on how, in Lymnaea, even a single episode of associative learning can activate CREB and NO dependent cascades due to the training-induced up- or downregulation of the expression levels of recently identified short and long non-coding RNAs.
How common is a common error term? The rules that govern associative learning in sensory preconditioning and second-order conditioning
Authors: Todd Travis P. , Holmes Nathan M.
Published: October 2022

In standard (first-order) Pavlovian conditioning protocols, pairings of an initially neutral conditioned stimulus (CS) and a biologically significant unconditioned stimulus (US) result in the formation of a CS-US association. The strength of this association is theoretically regulated by prediction error: specifically, the difference between the total level of conditioning supported by the US and the degree to which it is predicted by all stimuli present (i.e., a common error term). In higher-order conditioning protocols (e.g., sensory preconditioning and second-order conditioning), a Pavlovian CS is used to condition responses to other stimuli with which it is paired. At present, it is unknown whether error-correction processes regulate associative learning in higher-order conditioning and, if so, whether these processes are the same as those that regulate formation of a CS-US association in first-order conditioning. Here we review studies that have provided findings relevant to this question: specifically, studies that have examined blocking and/or inhibitory learning in sensory preconditioning and second-order conditioning. These studies show that: (1) animals can form inhibitory associations between relatively neutral sensory stimuli; (2) the learning that occurs in sensory preconditioning and second-order conditioning can be blocked; and, finally, (3) a first-order CS can block conditioning to a second-order CS, and vice versa. The findings are taken to imply that a common error term regulates associative learning in higher-order conditioning, just as it regulates associative learning in first-order conditioning. They are discussed with respect to the nature of the error signal that underlies conditioning and future work that is needed to advance our understanding of the rules that govern different types of learning.
A Natural Human-Drone Embodied Interface: Empirical Comparison With a Traditional Interface
Authors: Di Vincenzo Marina , Palini Francesco , De Marsico Maria , Borghi Anna M. , Baldassarre Gianluca
Published: October 2022

Despite the importance of usability in human-machine interaction (HMI), most commonly used devices are not usable by all potential users. In particular, users with low or null technological experience, or with special needs, require carefully designed systems and easy-to-use interfaces supporting recognition over recall. To this purpose, Natural User Interfaces (NUIs) represent an effective strategy as the user's learning is facilitated by features of the interface that mimic the human “natural” sensorimotor embodied interactions with the environment. This paper compares the usability of a new NUI (based on an eye-tracker and hand gesture recognition) with a traditional interface (keyboard) for the distal control of a simulated drone flying in a virtual environment. The whole interface relies on “dAIsy”, a new software allowing the flexible use of different input devices and the control of different robotic platforms. The 59 users involved in the study were required to complete two tasks with each interface, while their performance was recorded: (a) exploration: detecting trees embedded in an urban environment; (b) accuracy: guiding the drone as accurately and fast as possible along a predefined track. Then they were administered questionnaires regarding the user's background, the perceived embodiment of the device, and the perceived quality of the virtual experience while either using the NUI or the traditional interface. The results appear controversial and call for further investigation: (a) contrary to our hypothesis, the specific NUI used led to lower performance than the traditional interface; (b) however, the NUI was evaluated as more natural and embodied. The final part of the paper discusses the possible causes underlying these results that suggest possible future improvements of the NUI.
Artificial sleep-like up/down-states induce synaptic plasticity in cortical neurons from mouse brain slices
Authors: Besing Gai-Linn Kay , St. John Emily Kate , Potesta Cobie Victoria , Gallagher Martin J. , Zhou Chengwen
Published: October 2022

During non-rapid eye movement (NREM) sleep, cortical neuron activity alternates between a depolarized (firing, up-state) and a hyperpolarized state (down-state) coinciding with delta electroencephalogram (EEG) slow-wave oscillation (SWO, 0. 5–4 Hz) in vivo. Recently, we have found that artificial sleep-like up/down-states can potentiate synaptic strength in layer V cortical neurons ex vivo. Using mouse coronal brain slices, whole cell voltage-clamp recordings were made from layer V cortical pyramidal neurons to record spontaneous excitatory synaptic currents (sEPSCs) and inhibitory synaptic currents (sIPSCs). Artificial sleep-like up/down-states (as SWOs, 0.5 Hz, 10 min, current clamp mode) were induced by injecting sinusoidal currents into layer V cortical neurons. Baseline pre-SWO recordings were recorded for 5 min and post-SWO recordings for at least 25–30 min. Compared to pre-SWO sEPSCs or sIPSCs, post-SWO sEPSCs or sIPSCs in layer V cortical neurons exhibited significantly larger amplitudes and a higher frequency for 30 min. This finding suggests that both sEPSCs and sIPSCs could be potentiated in layer V cortical neurons by the low-level activity of SWOs, and sEPSCs and sIPSCs maintained a balance in layer V cortical neurons during pre- and post-SWO periods. Overall, this study presents an ex vivo method to show SWO's ability to induce synaptic plasticity in layer V cortical neurons, which may underlie sleep-related synaptic potentiation for sleep-related memory consolidation in vivo.
Electrophysiological evidence of subclinical trigeminal dysfunction in patients with COVID-19 and smell impairment: A pilot study
Authors: Cosentino Giuseppe , Maiorano Eugenia , Todisco Massimiliano , Prunetti Paolo , Antoniazzi Elisa , Tammam Giulia , Quartesan Ilaria , Lettieri Sara , De Icco Roberto , Corsico Angelo Guido , Benazzo Marco , Pisani Antonio , Tassorelli Cristina , Alfonsi Enrico
Published: October 2022

Background

Smell and taste disturbances are among the most frequent neurological symptoms in patients with COVID-19. A concomitant impairment of the trigeminal nerve has been suggested in subjects with olfactory dysfunction, although it has not been confirmed with objective measurement techniques. In this study, we explored the trigeminal function and its correlations with clinical features in COVID-19 patients with impaired smell perception using electrophysiological testing.

Methods

We enrolled 16 consecutive patients with mild COVID-19 and smell impairment and 14 healthy controls (HCs). Olfactory and gustatory symptoms were assessed with self-reported questionnaires. Electrophysiological evaluation of the masseter inhibitory reflex (MIR) and blink reflex (BR) was carried out to test the trigeminal function and its connections within the brainstem.

Results

Masseter inhibitory reflex (MIR) analysis revealed higher latency of ipsilateral and contralateral early silent period in patients when compared with HCs. No significant differences between groups were detected as regards the duration of the early and late silent period. However, several patients showed a prolonged duration of the early silent period. BR evaluation disclosed only an increased amplitude of early components in patients.

Conclusions

Patients with COVID-19 and smell impairment show a subclinical trigeminal nerve impairment. Trigeminal alterations mainly involve the oligosynaptic pathway, as a result of either direct viral damage or secondary neuroinflammation of the peripheral trigeminal fibers, whereas the polysynaptic ponto-medullary circuits seem to be spared. The prolonged duration of the early silent period and the increased amplitude of early BR response might reflect a compensatory upregulation of the trigeminal function as a consequence of the olfactory dysfunction.
Tau PET following acute TBI: Off-target binding to blood products, tauopathy, or both?
Authors: Butler Tracy , Chiang Gloria C. , Niogi Sumit Narayan , Wang Xiuyuan Hugh , Skudin Carly , Tanzi Emily , Wickramasuriya Nimmi , Spiegel Jonathan , Maloney Thomas , Pahlajani Silky , Zhou Liangdong , Morim Simon , Rusinek Henry , Normandin Marc , Dyke Jonathan P. , Fung Edward K. , Li Yi , Glodzik Lidia , Razlighi Qolamreza Ray , Shah Sudhin A. , Leon Mony de
Published: October 2022

Repeated mild Traumatic Brain Injury (TBI) is a risk factor for Chronic Traumatic Encephalopathy (CTE), characterized pathologically by neurofibrillary tau deposition in the depths of brain sulci and surrounding blood vessels. The mechanism by which TBI leads to CTE remains unknown but has been posited to relate to axonal shear injury leading to release and possibly deposition of tau at the time of injury. As part of an IRB-approved study designed to learn how processes occurring acutely after TBI may predict later proteinopathy and neurodegeneration, we performed tau PET using 18F-MK6240 and MRI within 14 days of complicated mild TBI in three subjects. PET radiotracer accumulation was apparent in regions of traumatic hemorrhage in all subjects, with prominent intraparenchymal PET signal in one young subject with a history of repeated sports-related concussions. These results are consistent with off-target tracer binding to blood products as well as possible on-target binding to chronically and/or acutely-deposited neurofibrillary tau. Both explanations are highly relevant to applying tau PET to understanding TBI and CTE. Additional study is needed to assess the potential utility of tau PET in understanding how processes occurring acutely after TBI, such as release and deposition of tau and blood from damaged axons and blood vessels, may relate to development CTE years later.
A biologically oriented algorithm for spatial sound segregation
Authors: Chou Kenny F. , Boyd Alexander D. , Best Virginia , Colburn H. Steven , Sen Kamal
Published: October 2022

Listening in an acoustically cluttered scene remains a difficult task for both machines and hearing-impaired listeners. Normal-hearing listeners accomplish this task with relative ease by segregating the scene into its constituent sound sources, then selecting and attending to a target source. An assistive listening device that mimics the biological mechanisms underlying this behavior may provide an effective solution for those with difficulty listening in acoustically cluttered environments (e.g., a cocktail party). Here, we present a binaural sound segregation algorithm based on a hierarchical network model of the auditory system. In the algorithm, binaural sound inputs first drive populations of neurons tuned to specific spatial locations and frequencies. The spiking response of neurons in the output layer are then reconstructed into audible waveforms via a novel reconstruction method. We evaluate the performance of the algorithm with a speech-on-speech intelligibility task in normal-hearing listeners. This two-microphone-input algorithm is shown to provide listeners with perceptual benefit similar to that of a 16-microphone acoustic beamformer. These results demonstrate the promise of this biologically inspired algorithm for enhancing selective listening in challenging multi-talker scenes.
Ultra-processed food consumption is associated with increase in fat mass and decrease in lean mass in Brazilian women: A cohort study
Authors: Rudakoff Lívia Carolina Sobrinho , Magalhães Elma Izze da Silva , Viola Poliana Cristina de Almeida Fonseca , de Oliveira Bianca Rodrigues , da Silva Coelho Carla Cristine Nascimento , Bragança Maylla Luanna Barbosa Martins , Arruda Soraia Pinheiro Machado , Cardoso Viviane Cunha , Bettiol Heloisa , Barbieri Marco Antonio , Levy Renata Bertazzi , da Silva Antônio Augusto Moura
Published: October 2022

Objective

To investigate the association between ultra-processed food consumption at 23–25 years of age and measurements of body composition–fat mass, fat mass distribution and lean mass at 37–39 years of age in Brazilian adults.

Methods

1978/1979 birth cohort study conducted with healthy adults from Ribeirão Preto, São Paulo, Brazil. A total of 1,021 individuals participated in the fat mass analysis (measured by air displacement plethysmography) and 815 in the lean mass analysis and fat mass distribution (assessed by dual energy X-ray absorptiometry). Food consumption was evaluated by a food frequency questionnaire. Food items were grouped according to the level of processing as per the NOVA classification. Ultra-processed food consumption was expressed as a percentage of total daily intake (g/day). Linear regression models were used to estimate the effect of ultra-processed food consumption (g/day) on body mass index, body fat percentage, fat mass index, android fat, gynoid fat, android-gynoid fat ratio, lean mass percentage, lean mass index and appendicular lean mass index. Marginal plots were produced to visualize interactions.

Results

The mean daily ultra-processed food consumption in grams was 35.8% (813.3 g). There was an association between ultra-processed food consumption and increase in body mass index, body fat percentage, fat mass index, android fat and gynoid fat and decrease in lean mass percentage, only in women.

Conclusion

A high ultra-processed food consumption is associated with a long-term increase in fat mass and a decrease in lean mass in adult women.
Gut microbiota and obesity: New insights
Authors: Sarmiento-Andrade Yoredy , Suárez Rosario , Quintero Beatriz , Garrochamba Kleber , Chapela Sebastián Pablo
Published: October 2022

Obesity is a pathology whose incidence is increasing throughout the world. There are many pathologies associated with obesity. In recent years, the influence of the microbiota on both health and pathological states has been known. There is growing information related to changes in the microbiome and obesity, as well as its associated pathologies. Changes associated with age, exercise, and weight changes have been described. In addition, metabolic changes associated with the microbiota, bariatric surgery, and fecal matter transplantation are described. In this review, we summarize the biology and physiology of microbiota in obese patients, its role in the pathophysiology of several disorders associated, and the emerging therapeutic applications of prebiotics, probiotics, and fecal microbiota transplantation.
Associations of folate intake with all-cause and cause-specific mortality among individuals with diabetes
Authors: Su Hexin , Bo Yacong , Zhang Xiaoan , Zhang Junxi , Gao Zhan , Yu Zengli
Published: October 2022

Background and aims

The evidence regarding folate intake and mortality risk among patients with type 2 diabetes (T2D) remains unclear. This study aimed to investigate the association of folate intake with the risk of mortality among individuals with T2D.

Methods

A total of 9,196 participants with T2D from the Third National Health and Nutrition Examination Survey (NHANES III) and NHANES 1999–2014 were included. The data of survival were obtained by the cohort database linked with the national death index up to 31 December 2015. The Cox proportional hazard model was used to evaluate the relationship between dietary folate with all-cause and cause-specific mortality.

Results

Among patients with T2D, dietary folate intake was negatively correlated with all-cause mortality, cardiovascular mortality, and cancer mortality in men, and for women with all-cause mortality and cardiovascular mortality. The multivariate adjustment hazard ratio (HR) (95% CIs) for men of highest vs. lowest quartile was 0.77 (0.66–0.90), 0.61 (0.45–0.83), and 0.70 (0.49–0.99) for all-cause, cardiovascular, and cancer mortality, respectively. Among women, the multivariate adjustment HR (95% CIs) of highest vs. lowest quartile was 0.77 (0.64–0.92), 0.52 (0.33–0.83), and 0.78 (0.50–1.22) for all-cause, cardiovascular, and cancer mortality, respectively.

Conclusion

Higher dietary intake of folate was significantly associated with lower all-cause and cardiovascular mortality. This cohort study suggested that increasing the dietary folate intake may reduce mortality risk among U.S. adults with T2D.
Melanoma lymph node metastases – moving beyond quantity in clinical trial design and contemporary practice
Authors: Rhodin Kristen E. , Fimbres Denisse Porras , Burner Danielle N. , Hollander Shayna , O’Connor Margaret H. , Beasley Georgia M.
Published: October 2022

The presence of lymph node metastases is a well-studied prognostic factor for cutaneous melanoma. Characterization of melanoma lymph node metastases and their association with survival in multiple, large observational studies has led to recognition of the following high-risk features: quantity of lymph node metastases (number of nodes), size of the nodal tumor deposit (in mm), and extracapsular extension. Despite increasing utilization of these features in the design of randomized clinical trials, in addition to their role in contemporary clinical decision-making, current staging systems lag behind, only accounting for the quantity of lymph nodes with metastases. Herein, we review the prognostic role of melanoma lymph node metastases and their high-risk features, current reporting standards, how such features have been utilized in practice-changing trials, and best practices for future clinical trial design and clinical decision-making.
PD-1/PD-L1 inhibitors for advanced or metastatic cervical cancer: From bench to bed
Authors: Huang Weijia , Liu Jiewei , Xu Kai , Chen Huilin , Bian Ce
Published: October 2022

Advanced or metastatic cervical cancer has a poor prognosis, and the 5-year overall survival is <5% with conventional radiotherapy and chemotherapy. Immunotherapy, particularly immune checkpoint inhibitors (ICIs), achieved initial success in advanced solid tumors, while their efficacy and safety in advanced or metastatic cervical cancer remains to be explored. Previous studies found high-risk HPV infection and elevated PD-L1 expression in cervical precancerous lesions and squamous cell carcinoma. Meanwhile, elevated PD-L1 expression, high cytotoxic T lymphocyte infiltration, and abnormal cytotoxic T lymphocyte function might benefit inflammation infiltration for ICIs in the tumor microenvironment. Patients with HPV infection, squamous cell carcinoma, advanced stage, large tumor size, poor differentiation, metastatic disease, history of multiple childbirth and abortion, or a previous history of receiving chemotherapy might be associated with positive PD-L1 expression. Although there is no correlation between PD-L1 expression and prognosis using conventional radiotherapy, patients with high PD-L1 expression have a poorer prognosis. Several clinical studies demonstrate preliminary safety and efficacy for PD-1/PD-L1 inhibitors, and the exploration of combination strategies such as immunotherapy combined with chemotherapy, radiotherapy, anti-angiogenesis therapy, or dual ICIs is ongoing. This paper systematically reviews PD-L1 expression patterns and their relationship with prognosis, along with reported and ongoing clinical trials of PD-1/PD-L1 inhibitors in cervical cancer to clarify the prospect of ICIs for cervical cancer from bench to bed.
The predictive value of patient-reported outcomes on the impact of breast cancer treatment-related quality of life
Authors: Zhou Ke , Bellanger Martine , Le Lann Sophie , Robert Marie , Frenel Jean-Sebastien , Campone Mario
Published: October 2022

Purpose

Patient-reported outcomes (PROs) have been widely used to measure breast cancer (BC) treatment outcomes. However, evidence is still limited on using routinely PROs to personalize treatment decision-making, including or not chemotherapy, targeted therapy, and radiotherapy. Using patient baseline PRO scores, we aimed to use PROs before treatment initiation to predict improvement or decline in health-related quality of life (HRQoL) due to treatment that they receive.

Methods

In two French cancer sites, women with non-metastatic BC completed the EORTC QLQ-C30 and QLQ-BR23 and BREAST-Q questionnaires to assess their PROs at baseline and again at 6 months. The outcome measured was post-operative change in PROs with minimal important difference for QLQ-C30 domains. We performed multivariate ordinal logistic regression to estimate the incremental probability of post-operative PRO improvements and deteriorations depending upon treatment options and baseline HRQoL.

Results

One hundred twenty-seven women completed questionnaires. Chemotherapy had significant negative impacts on Global health status (GHS) and on physical and social functioning. Chemotherapy and radiotherapy increased patient fatigue scores after adjusting for clinical factors (p< 0.01 and p< 0.05, respectively). The incremental probability of GHS deteriorations for chemotherapy was +0.3, +0.5, and +0.34 for patients with baseline GHS scores of 40, 70, and 100, respectively. This showed that different pre-treatment PROs might predict differential effects of chemotherapy on women change in HRQoL.

Conclusion

Patients with different baseline PRO scores may experience dissimilar impacts from BC treatments on post-operative PROs in terms of improvements and deteriorations. Oncologists might decide to adapt the treatment option based on a given level of the negative impact. Future studies should concentrate on incorporating this information into routine clinical decision-making strategies to optimize the treatment benefit for patients.
Cellular milieu in clear cell renal cell carcinoma
Authors: Raghubar Arti M. , Roberts Matthew J. , Wood Simon , Healy Helen G. , Kassianos Andrew J. , Mallett Andrew J.
Published: October 2022

Clear cell renal cell carcinoma (ccRCC) is globally the most prevalent renal cancer. The cells of origin in ccRCC have been identified as proximal tubular epithelial cells (PTEC); however, the transcriptomic pathways resulting in the transition from normal to malignant PTEC state have remained unclear. Immunotherapy targeting checkpoints have revolutionized the management of ccRCC, but a sustained clinical response is achieved in only a minority of ccRCC patients. This indicates that our understanding of the mechanisms involved in the malignant transition and resistance to immune checkpoint therapy in ccRCC is unclear. This review examines recent single-cell transcriptomics studies of ccRCC to clarify the transition of PTEC in ccRCC development, and the immune cell types, states, and interactions that may limit the response to targeted immune therapy, and finally suggests stromal cells as key drivers in recurrent and locally invasive ccRCC. These and future single-cell transcriptomics studies will continue to clarify the cellular milieu in the ccRCC microenvironment, thus defining actional clinical, therapeutic, and prognostic characteristics of ccRCC.
Impact of skeletal muscle loss during conversion therapy on clinical outcomes in lavage cytology positive patients with gastric cancer
Authors: Ding Ping’an , Yang Peigang , Yang Li , Sun Chenyu , Chen Shuya , Li Min , Lowe Scott , Guo Honghai , Tian Yuan , Liu Yang , Zhao Qun
Published: October 2022

Background

The relationship between sarcopenia and clinical outcomes during conversion therapy in patients with lavage cytology positive gastric cancer (GC-CY1) remains unclear. This study aimed to investigate the impact of sarcopenia and skeletal muscle loss on the efficacy of conversion therapy, tumour response and survival in GC-CY1 patients.

Methods

Retrospective analysis of data from a prospective trial of conversion therapy conducted between April 2018 and August 2019 in patients with GC-CY1 (NCT03718624). Skeletal muscle index (SMI) was measured at the level of the third lumbar (L3) vertebra and the sarcopenia was defined using published cut-off points in all patients. We defined ΔSMI (%)/50 days above 9.53% for men and ΔSMI (%)/50 days above 8.81% for women as significant muscle loss (SML) and analysed the changes in skeletal muscle during conversion therapy in relation to treatment efficacy, survival and tumour response.

Results

Of the 36 patients, 7 patients (19.44%) developed sarcopenia before conversion therapy, 6 (16.67%) developed new sarcopenia after conversion therapy, and 8 (22.22%) developed SML during treatment. Multivariate analysis showed that sarcopenia before treatment [Odds Ratio (OR) =8.923, 95%CI: 1.341-25.321, p=0.002] and SML during treatment (OR=7.803, 95%CI: 1.106-16.189, p=0.001) had a negative impact on the success rate of conversion therapy. Cox multifactorial analysis found that pre-treatment sarcopenia [overall survival (OS): Hazard Ratio (HR) =6.341, 95%CI: 1.269-18.943, p=0.001; progression-free survival (PFS): HR=8.212, 95%CI: 1.569-36.582, p=0.001], newly developed sarcopenia after conversion therapy (OS: HR=3.189, 95%CI: 1.023-9.811, p=0.012; PFS: HR=3.084, 95%CI: 1.042-14.236, p=0.013) and the presence of SML during treatment (OS: HR=10.234, 95%CI: 2.532-54.231, p=0.002; PFS: HR=9.562, 95%CI: 2.341-38.092, p=0.002) were independent risk factor for OS and PFS in GC-CY1 patients.

Conclusion

Pre-treatment sarcopenia and the presence of SML during treatment are strongly correlated with the immediate and long-term outcomes of GC-CY1 patients and can be used as imaging markers to predict the treatment efficacy and prognosis of patients in clinical practice.
Improving radiomic model reliability using robust features from perturbations for head-and-neck carcinoma
Authors: Teng Xinzhi , Zhang Jiang , Ma Zongrui , Zhang Yuanpeng , Lam Saikit , Li Wen , Xiao Haonan , Li Tian , Li Bing , Zhou Ta , Ren Ge , Lee Francis Kar-ho , Au Kwok-hung , Lee Victor Ho-fun , Chang Amy Tien Yee , Cai Jing
Published: October 2022

Background

Using high robust radiomic features in modeling is recommended, yet its impact on radiomic model is unclear. This study evaluated the radiomic model’s robustness and generalizability after screening out low-robust features before radiomic modeling. The results were validated with four datasets and two clinically relevant tasks.

Materials and methods

A total of 1,419 head-and-neck cancer patients’ computed tomography images, gross tumor volume segmentation, and clinically relevant outcomes (distant metastasis and local-regional recurrence) were collected from four publicly available datasets. The perturbation method was implemented to simulate images, and the radiomic feature robustness was quantified using intra-class correlation of coefficient (ICC). Three radiomic models were built using all features (ICC > 0), good-robust features (ICC > 0.75), and excellent-robust features (ICC > 0.95), respectively. A filter-based feature selection and Ridge classification method were used to construct the radiomic models. Model performance was assessed with both robustness and generalizability. The robustness of the model was evaluated by the ICC, and the generalizability of the model was quantified by the train-test difference of Area Under the Receiver Operating Characteristic Curve (AUC).

Results

The average model robustness ICC improved significantly from 0.65 to 0.78 (P< 0.0001) using good-robust features and to 0.91 (P< 0.0001) using excellent-robust features. Model generalizability also showed a substantial increase, as a closer gap between training and testing AUC was observed where the mean train-test AUC difference was reduced from 0.21 to 0.18 (P< 0.001) in good-robust features and to 0.12 (P< 0.0001) in excellent-robust features. Furthermore, good-robust features yielded the best average AUC in the unseen datasets of 0.58 (P< 0.001) over four datasets and clinical outcomes.

Conclusions

Including robust only features in radiomic modeling significantly improves model robustness and generalizability in unseen datasets. Yet, the robustness of radiomic model has to be verified despite building with robust radiomic features, and tightly restricted feature robustness may prevent the optimal model performance in the unseen dataset as it may lower the discrimination power of the model.
Serum exosomal and serum glypican-1 are associated with early recurrence of pancreatic ductal adenocarcinoma
Authors: Zhao Juan , Guo Madi , Song Yushuai , Liu Shan , Liao Ran , Zhang Yu , Zhang Yumin , Yang Qi , Gu Yuanlong , Huang Xiaoyi
Published: October 2022

Background

The diagnostic performance and prognostic value of serum exosomal glypican 1 (GPC-1) in pancreatic ductal adenocarcinoma (PDAC) remain controversial. In this study, we detected serum exosomal GPC-1 using enzyme-linked immunosorbent assay (ELISA) and determined whether it serves as a predictor of diagnosis and recurrence for early-stage PDAC.

Methods

Serum samples were obtained from patients with 50 PDAC, 6 benign pancreatic tumor (BPT), or 9 chronic pancreatitis (CP) and 50 healthy controls (HCs). Serum exosomes were isolated using an exosome isolation kit. Exosomal and serum GPC-1 levels were measured using ELISA. The freeze–thaw process was carried out to analyze the stability of GPC-1. Receiver operating characteristic (ROC) analysis was employed to assess the diagnostic value of GPC-1. Kaplan–Meier and multivariate Cox analyses were used to evaluate the prognostic value of GPC-1.

Results

The average concentrations of serum exosomal and serum GPC-1 were 1.5 and 0.8 ng/ml, respectively. GPC-1 expression levels were stable under repeated freezing and thawing (d1-5 freeze–thaw cycles vs. d0 P > 0.05). Serum exosomal and serum GPC-1 were significantly elevated in patients with PDAC compared with HCs (P < 0.0001) but were slightly higher compared with that in patients with CP and BPT (P > 0.05). The expression levels of exosomal and serum GPC-1 were elevated 5 days after surgery in patients with PDAC, CP, and BPT (P < 0.05). Patients with high levels of exosomal and serum GPC-1 had a shorter relapse-free survival (RFS) (P = 0.006, and P = 0.010). Multivariate analyses showed that serum exosomal and serum GPC-1 were independent prognostic indicators for early RFS (P = 0.008, and P = 0.041).

Conclusion

ELISA is an effective and sensitive method to detect exosomal and serum GPC-1. The detection of GPC-1 was stable under repeated freezing and thawing cycles and could distinguish early-stage PDAC from HCs but not CP and BPT. Exosomal and serum GPC-1 may be good independent predictors of early recurrence in early-stage PDAC.
Temporal radiographic and histological study of necrosis development in a mouse glioblastoma model
Authors: Yee Patricia P. , Wang Jianli , Chih Stephen Y. , Aregawi Dawit G. , Glantz Michael J. , Zacharia Brad E. , Thamburaj Krishnamoorthy , Li Wei
Published: October 2022

Tumor necrosis is a poor prognostic marker in glioblastoma (GBM) and a variety of other solid cancers. Accumulating evidence supports that necrosis could facilitate tumor progression and resistance to therapeutics. GBM necrosis is typically first detected by magnetic resonance imaging (MRI), after prominent necrosis has already formed. Therefore, radiological appearances of early necrosis formation and the temporal-spatial development of necrosis alongside tumor progression remain poorly understood. This knowledge gap leads to a lack of reliable radiographic diagnostic/prognostic markers in early GBM progression to detect necrosis. Recently, we reported an orthotopic xenograft GBM murine model driven by hyperactivation of the Hippo pathway transcriptional coactivator with PDZ-binding motif (TAZ) which recapitulates the extent of GBM necrosis seen among patients. In this study, we utilized this model to perform a temporal radiographic and histological study of necrosis development. We observed tumor tissue actively undergoing necrosis first appears more brightly enhancing in the early stages of progression in comparison to the rest of the tumor tissue. Later stages of tumor progression lead to loss of enhancement and unenhancing signals in the necrotic central portion of tumors on T1-weighted post-contrast MRI. This central unenhancing portion coincides with the radiographic and clinical definition of necrosis among GBM patients. Moreover, as necrosis evolves, two relatively more contrast-enhancing rims are observed in relationship to the solid enhancing tumor surrounding the central necrosis in the later stages. The outer more prominently enhancing rim at the tumor border probably represents the infiltrating tumor edge, and the inner enhancing rim at the peri-necrotic region may represent locally infiltrating immune cells. The associated inflammation at the peri-necrotic region was further confirmed by immunohistochemical study of the temporal development of tumor necrosis. Neutrophils appear to be the predominant immune cell population in this region as necrosis evolves. This study shows central, brightly enhancing areas associated with inflammation in the tumor microenvironment may represent an early indication of necrosis development in GBM.
Prevalence and predictors of medication-related emergency department visit in older adults: A multicenter study linking national claim database and hospital medical records
Authors: Park Soyoung , Kim A Jeong , Ah Young-Mi , Lee Mee Yeon , Lee Yu Jeong , Chae Jungmi , Rho Ju Hyun , Kim Dong-Sook , Lee Ju-Yeun
Published: October 2022

Objectives: Older adults are more likely to experience drug-related problems (DRP), which could lead to medication-related emergency department visits (MRED). To properly evaluate MRED, the entire history of drug use should be evaluated in a structured manner. However, limited studies have identified MRED with complete prescription records. We aimed to evaluate the prevalence and risk factors of MRED among community-dwelling older patients by linking national claims data and electronic medical records using a standardized medication related admission identification method.

Methods: We included older patients who visited the emergency departments of four participating hospitals in 2019. Among the 54,034 emergency department (ED) visitors, we randomly selected 6,000 patients and structurally reviewed their medical records using a standardized MRED identification method after linking national claims data and electronic medical records. We defined and categorized MRED as ED visits associated with adverse drug events and those caused by the underuse of medication, including treatment omission and noncompliance and assessed as having probable or higher causality. We assessed preventability using Schumock and Thornton criteria.

Results: MRED was observed in 14.3% of ED visits, of which 76% were preventable. In addition, 32.5% of MRED cases were related to underuse or noncompliance, and the rest were related to adverse drug events. Use of antipsychotics, benzodiazepines, anticoagulants, traditional nonsteroidal anti-inflammatory drugs without the use of proton pump inhibitors, P2Y12 inhibitors, insulin, diuretics, and multiple strong anticholinergic drugs were identified as predictors of MRED.

Conclusion: One in seven cases of ED visits by older adults were medication related and over three-quarters of them were preventable. These findings suggest that DRPs need to be systemically screened and intervened in older adults who visit ED.
Atovaquone attenuates experimental colitis by reducing neutrophil infiltration of colonic mucosa
Authors: Manzanares Laura D. , David Joseph , Ren Xingsheng , Yalom Lenore K. , Piccolo Enzo B. , Dehghan Yalda , David Aidan J. , Hanauer Stephen B. , Sumagin Ronen
Published: October 2022

Ulcerative colitis (UC) is a chronic relapsing disease featuring aberrant accumulation of neutrophils in colonic mucosa and the luminal space. Although significant advances in UC therapy have been made with the development of novel biologics and small molecules targeting immune responses, success of most current therapies is still limited, with significant safety concerns. Thus, there is a need to develop additional safe and effective therapies for the treatment of UC. Antimalarial drugs have been safely used for many years to resolve tissue inflammation and the associated pathologies. Atovaquone is a recent FDA-approved antimalarial drug that has shown anti-viral and tumor-suppressive properties in vitro however, its role in mucosal inflammation has not been evaluated. Using pre-clinical murine DSS-induced colitis model combined with complementary in vivo peritonitis and ex vivo human neutrophil activation and chemotaxis assays we investigated functional and mechanistic impacts of atovaquone on disease resolution and neutrophil trafficking. We demonstrate that atovaquone promotes resolution of DSS-induced murine colitis by reducing neutrophil accumulation in the inflamed colonic mucosa. Mechanistically, we show that atovaquone suppressed induction of CD11b expression in neutrophils, reducing their polarization and migratory ability. Thus, our findings identify a new role of atovaquone in promoting resolution of mucosal inflammation, supporting the idea of potential repurposing of this FDA-approved drug as UC therapeutic.
Novel ultrashort-acting benzodiazepine remimazolam lowers shivering threshold in rabbits
Authors: Muroya Kenji , Ueda Kenta , Wada Keiichi , Kotoda Masakazu , Matsukawa Takashi
Published: October 2022

Shivering after surgery or during therapeutic hypothermia can lead to serious complications, such as myocardial infarction and respiratory failure. Although several anesthetics and opioids are shown to have anti-shivering effects, their sedative and respiratory side effects dampen the usefulness of these drugs for the prevention of shivering. In the present study, we explored the potential of a novel ultrashort-acting benzodiazepine, remimazolam, in the prevention of shivering using a rabbit model of hypothermia. Adult male Japanese white rabbits were anesthetized with isoflurane. The rabbits received saline (control), remimazolam (either 0.1 or 1 mg/kg/h), or remimazolam + flumazenil, a selective γ-aminobutyric acid (GABA) type A receptor antagonist (n = 6 each). Thirty minutes after discontinuation of the drugs, cooling was initiated by perfusing 10°C water via a plastic tube positioned in the colon until the animal shivered. Core body temperature and hemodynamic and physiological parameters were recorded. Remimazolam at 1 mg/kg/h significantly lowered the core temperature change during shivering (−2.50 ± 0.20°C vs. control: −1.00 ± 0.12°C, p = 0.0009). The effect of 1 mg/kg/h remimazolam on the core temperature change was abolished by flumazenil administration (−0.94 ± 0.16°C vs. control: −1.00 ± 0.12°C, p = 0.996). Most of the hemodynamic and physiological parameters did not differ significantly among groups during cooling. Remimazolam at a clinically relevant dose successfully suppressed shivering in rabbits via the GABA pathway even after its anesthetic effects likely disappeared. Remimazolam may have the potential to prevent shivering in patients undergoing surgery or therapeutic hypothermia.