Sintilimab combined with anlotinib as first-line treatment for advanced sarcomatoid carcinoma of head and neck: a case report and literature review.

Sarcomatoid carcinoma (SC) is a rare, complex, aggressive tumor that spreads rapidly, is highly malignant, and has metastasized. Surgical resection is the primary treatment, and it usually occurs in the lungs and kidneys but rarely in the neck. Patients with advanced sarcomatoid carcinoma (SC) of the head and neck (HN) have a poor progonsis. In recent years, immune checkpoint inhibitors (ICIs) have been established as treatments for many solid tumors; however, the effectiveness of ICIs in treating SC of HN is still little recognized. We report a case study of a middle-aged woman with primary sarcomatoid carcinoma of the neck. She developed sarcomatoid carcinoma of the contralateral neck 7 months after the first surgical treatment. Subsequently, disease recurrence and metastasis occurred 8 months after the second surgery. The patient did not receive any treatment after both surgeries. The tumor showed high programmed death-ligand 1 (PD-L1) expression, with a combined positive score (CPS): 95. The patient's response to treatment was assessed as partial remission (PR) after 2 cycles of anlotinib combined with sintilimab. The patient has survived for over 2 years and remains in PR status, despite experiencing grade 2 hypothyroidism as an adverse event during treatment. The case highlights the efficacy and safety of anlotinib and sintilimab as a first-line treatment.

Sustaining attention in visuomotor timing is associated with location-based binding.

Maintaining focus of attention over prolonged periods can be challenging, especially when the target stimulus is absent from the temporal sequence. Prior research has shown that a temporal attentional cue filling in the temporal blank can improve sustained attention: in a sustained visual attention task requiring synchronizing finger tapping with a temporally regular sequence composed of brief flash disks interleaved with blank periods, task performance was improved when a continuous fixation point that served as a temporal attentional cue was presented superimposed on the disk stimulus. To test the hypothesis that binding the temporal attentional cue with the target temporal sequence by spatial overlapping is crucial for enhancing sustained attention, the present study conducted a series of three experiments that deconstructed the bound connection between the cue and the sequence stimulus. In Experiment 1, the cue was placed above or below a flash disk. In Experiment 2, the cue was between two vertically arranged flash disks. In Experiment 3, the cue was in a flash ring. No significant effect of sustained attention improvement was found in any of the three experiments. Experiment 4 further replicated these null results and the previously observed effect of sustained attention improvement when the temporal cue was superimposed on the sequence stimulus. Our finding demonstrates that binding by spatial overlapping during the temporal blank when the sequence stimulus is absent is critical for enhancing sustained attention, which should be beneficial for improving performance across a broader range of tasks that require prolonged maintenance of attention.

Physiological principles underlying the kidney targeting of renal nanomedicines.

Kidney disease affects more than 10% of the global population and is associated with considerable morbidity and mortality, highlighting a need for new therapeutic options. Engineered nanoparticles for the treatment of kidney diseases (renal nanomedicines) represent one such option, enabling the delivery of targeted therapeutics to specific regions of the kidney. Although they are underdeveloped compared with nanomedicines for diseases such as cancer, findings from preclinical studies suggest that renal nanomedicines may hold promise. However, the physiological principles that govern the in vivo transport and interactions of renal nanomedicines differ from those of cancer nanomedicines, and thus a comprehensive understanding of these principles is needed to design nanomedicines that effectively and specifically target the kidney while ensuring biosafety in their future clinical translation. Herein, we summarize the current understanding of factors that influence the glomerular filtration, tubular uptake, tubular secretion and extrusion of nanoparticles, including size and charge dependency, and the role of specific transporters and processes such as endocytosis. We also describe how the transport and uptake of nanoparticles is altered by kidney disease and discuss strategic approaches by which nanoparticles may be harnessed for the detection and treatment of a variety of kidney diseases.

Fried food consumption, genetic risk, and incident obesity: a prospective study.

Background and aims: Genetic and dietary factors contribute to adiposity risk, but little evidence supports genetic personalization of fried food intake recommendations for the management of obesity. This study aimed to assess the associations between fried food consumption and adiposity incidence and whether the associations were modified by an individual's genotype. Methods: We included 27 427 participants who had dietary data assessed by a validated 24 h dietary recall and available anthropometric information from the UK Biobank study. The genetic risk score (GRS) was calculated using 940 BMI associated variants. Results: With an average of 8.1 years of follow-up, 1472 and 2893 participants were defined as having overall obesity and abdominal obesity, respectively. Individuals in the highest categories of fried food consumption were positively associated with the risk of obesity (HR = 1.31; 95% CI 1.10-1.56) and abdominal obesity (HR = 1.27; 95% CI 1.12-1.45) compared with the lowest categories. Moreover, fried food consumption had a significant interatction with obesity GRS for abdominal obesity risk (P interaction = 0.016). Fried food intake was associated with a higher abdominal obesity risk (HR = 1.59, 95% CI: 1.25-2.00) among participants with a lower genetic risk. Conclusions: Our findings indicated that fried food consumption had a higher abdominal obesity risk among individuals with a lower genetic risk, suggesting the restriction of fried food intake for this group of people.

Crosstalk between Hepatic Glutathione Efflux and Tumor Targeting Efficiency of Indocyanine Green-Conjugated Gold Nanoparticles.

The elevated glutathione (GSH) level in solid tumors has been used as a major hallmark for GSH-responsive nanoparticles to enhance targeting efficiency and specificity. Meanwhile, GSH is mainly synthesized inside the hepatocytes of the liver in the body and constantly released into the blood through hepatic GSH efflux to regulate redox potential of the entire body. However, it remains largely unknown how this hepatic GSH efflux affects the tumor targeting of GSH-responsive nanoparticles. Herein, we report that depletion of hepatic GSH enhanced the tumor targeting of GSH-responsive indocyanine green-conjugated Au25 nanoclusters coated with 18 GSH ligand (ICG-Au25 SG18 ). The dissociation of ICG from Au25 SG18 by the hepatic GSH through thiol-exchange reaction and the subsequent hepatobiliary clearance of the detached ICG were slowed down by GSH depletion, which in turn prolonged the blood circulation of intact ICG-Au25 SG18 and enhanced its tumor targeting. Our work highlights glutathione-mediated crosstalk between the liver and tumor, in addition to well-known Kupffer cell-mediated uptake, in the tumor targeting of engineered nanoparticles, which could be modulated to enhance targeting efficiency and specificity of cancer nanomedicines while reducing their nonspecific accumulation.

Proximal tubules eliminate endocytosed gold nanoparticles through an organelle-extrusion-mediated self-renewal mechanism.

Proximal tubules energetically internalize and metabolize solutes filtered through glomeruli but are constantly challenged by foreign substances during the lifespan. Thus, it is critical to understand how proximal tubules stay healthy. Here we report a previously unrecognized mechanism of mitotically quiescent proximal tubular epithelial cells for eliminating gold nanoparticles that were endocytosed and even partially transformed into large nanoassemblies inside lysosomes/endosomes. By squeezing ~5 µm balloon-like extrusions through dense microvilli, transporting intact gold-containing endocytic vesicles into the extrusions along with mitochondria or other organelles and pinching the extrusions off the membranes into the lumen, proximal tubular epithelial cells re-eliminated >95% of endocytosed gold nanoparticles from the kidneys into the urine within a month. While this organelle-extrusion mechanism represents a new nanoparticle-elimination route, it is not activated by the gold nanoparticles but is an intrinsic 'housekeeping' function of normal proximal tubular epithelial cells, used to remove unwanted cytoplasmic contents and self-renew intracellular organelles without cell division to maintain homoeostasis.

High fried food consumption impacts anxiety and depression due to lipid metabolism disturbance and neuroinflammation.

Western dietary patterns have been unfavorably linked with mental health. However, the long-term effects of habitual fried food consumption on anxiety and depression and underlying mechanisms remain unclear. Our population-based study with 140,728 people revealed that frequent fried food consumption, especially fried potato consumption, is strongly associated with 12% and 7% higher risk of anxiety and depression, respectively. The associations were more pronounced among male and younger consumers. Consistently, long-term exposure to acrylamide, a representative food processing contaminant in fried products, exacerbates scototaxis and thigmotaxis, and further impairs exploration ability and sociality of adult zebrafish, showing anxiety- and depressive-like behaviors. Moreover, treatment with acrylamide significantly down-regulates the gene expression of tjp2a related to the permeability of blood-brain barrier. Multiomics analysis showed that chronic exposure to acrylamide induces cerebral lipid metabolism disturbance and neuroinflammation. PPAR signaling pathway mediates acrylamide-induced lipid metabolism disorder in the brain of zebrafish. Especially, chronic exposure to acrylamide dysregulates sphingolipid and phospholipid metabolism, which plays important roles in the development of anxiety and depression symptoms. In addition, acrylamide promotes lipid peroxidation and oxidation stress, which participate in cerebral neuroinflammation. Acrylamide dramatically increases the markers of lipid peroxidation, including (±)5-HETE, 11(S)-HETE, 5-oxoETE, and up-regulates the expression of proinflammatory lipid mediators such as (±)12-HETE and 14(S)-HDHA, indicating elevated cerebral inflammatory status after chronic exposure to acrylamide. Together, these results both epidemiologically and mechanistically provide strong evidence to unravel the mechanism of acrylamide-triggered anxiety and depression, and highlight the significance of reducing fried food consumption for mental health.

Visual over auditory superiority in sensorimotor timing under optimized condition.

Auditory over visual advantage in temporal processing is generally appreciated, such as the well-established auditory superiority in sensorimotor timing. To test for a possible visual superiority in temporal processing, here, we present a data set composed of a large 60 subjects sample and a data set including eight smaller samples of approximately 15 subjects, showing that synchronization to a temporally regular sequence was more stable for a visual bouncing ball (VB) than for auditory tones (ATs). The results demonstrate that vision can be superior over audition in sensorimotor timing under optimized conditions, challenging the generally believed auditory superiority in temporal processing. In contrast to the auditory-specific biological substrates of timing in sensorimotor interaction, the present finding points to tight visual-motor cortical coupling in sensorimotor timing.

Sustained visual attention improves visuomotor timing.

Relative to audition, vision is considered much less trustworthy in sensorimotor timing such as synchronizing finger movements with a temporally regular sequence. Visuomotor timing requires maintaining attention over time, whereas the sustained visual attention may not be well held in conventional visuomotor timing task settings where flashing visual stimuli consisted of a briefly presented flash and a long blank period. In the present study, the potential attentional lapses in time due to the disappearance of the flash were carefully controlled in Experiment 1 by changing the color of the flash instead of its disappearance, or in Experiment 2 by adding an additional continuously presented fixation point serving as an external attentional cue when the flash disappeared. Improvement of visuomotor timing performance was found in both experiments. The finding suggests a role of enhanced sustained visual attention in improving visuomotor timing, by which vision could also be a trustworthy modality for processing temporal information in sensorimotor interactions.

Drug-Drug Interactions With Cyclosporine in the Anti-Hepatitis C Viral PrOD Combination Regimen of Paritaprevir/Ritonavir-Ombitasvir and Dasabuvir in Organ Transplant Recipients With Severe Hepatic Fibrosis or Cirrhosis.

BACKGROUND: The clinical guidelines suggest that the dosing of cyclosporine (CsA), during combination therapy with paritaprevir/ritonavir-ombitasvir and dasabuvir (PrOD), would be only one-fifth of the pre-PrOD total daily dose to be administered once daily. However, this dosing may not be applicable to all patients depending on their clinical condition. This study focuses on the pharmacokinetic dynamics of PrOD with CsA in Asian organ transplant recipients with severe liver fibrosis or cirrhosis who undergo concurrent treatment with PrOD treatment and CsA. The efficacy and safety of PrOD treatment was also evaluated. METHODS: Data from 7 patients obtained between January 2017 and September 2017 were retrospectively analyzed. Determinations of the blood concentrations of CsA were made, whether used as a single treatment or in combination therapy with PrOD. RESULTS: The combination regimen compared with CsA administered alone resulted in a 4.53-fold and 5.52-fold increase in the area under the concentration-time curve from time 0-12 hours (AUC0-12 h) of CsA on days 1 and 15, respectively. In addition, the maximal concentration, time to maximum concentration, and terminal phase elimination half-life (t1/2) of CsA were increased during the combined treatment of PrOD and CsA. The authors proposed reducing the CsA dosage during PrOD treatment to one-seventh of that of the pre-PrOD treatment of the total daily dose to maintain target CsA levels. All patients achieved sustained virologic responses at week 12. There were no episodes of serious adverse events or graft rejections observed. CONCLUSIONS: Although the combination with PrOD significantly affects the pharmacokinetics of CsA, it is effective and safe with regular monitoring of the CsA blood concentrations and appropriate CsA dose adjustment.

Corynoxine Protects Dopaminergic Neurons Through Inducing Autophagy and Diminishing Neuroinflammation in Rotenone-Induced Animal Models of Parkinson's Disease.

Recent studies have shown that impairment of autophagy is related to the pathogenesis of Parkinson's disease (PD), and small molecular autophagy enhancers are suggested to be potential drug candidates against PD. Previous studies identified corynoxine (Cory), an oxindole alkaloid isolated from the Chinese herbal medicine Uncaria rhynchophylla (Miq.) Jacks, as a new autophagy enhancer that promoted the degradation of α-synuclein in a PD cell model. In this study, two different rotenone-induced animal models of PD, one involving the systemic administration of rotenone at a low dosage in mice and the other involving the infusion of rotenone stereotaxically into the substantia nigra pars compacta (SNpc) of rats, were employed to evaluate the neuroprotective effects of Cory. Cory was shown to exhibit neuroprotective effects in the two rotenone-induced models of PD by improving motor dysfunction, preventing tyrosine hydroxylase (TH)-positive neuronal loss, decreasing α-synuclein aggregates through the mechanistic target of the rapamycin (mTOR) pathway, and diminishing neuroinflammation. These results provide preclinical experimental evidence supporting the development of Cory into a potential delivery system for the treatment of PD.

Noninvasive monitoring of hepatic glutathione depletion through fluorescence imaging and blood testing.

Hepatic glutathione plays a key role in regulating redox potential of the entire body, and its depletion is known to increase susceptibility to oxidative stress involved in many diseases. However, this crucial pathophysiological event can only be detected noninvasively with high-end instrumentation or invasively with surgical biopsy, limiting both preclinical research and clinical prevention of oxidative stress-related diseases. Here, we report that both in vivo fluorescence imaging and blood testing (the first-line detection in the clinics) can be used for noninvasive and consecutive monitoring of hepatic glutathione depletion at high specificity and accuracy with assistance of a body-clearable nanoprobe, of which emission and surface chemistries are selectively activated and transformed by hepatic glutathione in the liver sinusoids. These findings open a new avenue to designing exogenous blood markers that can carry information of local disease through specific nanobiochemical interactions back to the bloodstream for facile and rapid disease detection.

Temporal recalibration in vision requires location-based binding.

Occupying the same location and occurring at the same time are the essential spatial and temporal factors for different features of a natural event or object to be integrated. Audio-visual temporal recalibration, as a temporal integration mechanism, refers to the brain's capacity to perceive simultaneity by adjusting for differential delays in the transmission of auditory and visual signals. Co-localization of auditory and visual information, however, is found not to be necessary for audio-visual temporal recalibration to occur. Here, we show that after exposure to a time lag between a visual flash and a visual collision, simultaneity responses were shifted toward an adapt lag in a bound condition where the flash and collision belonged to the same object but not in a separate condition where the flash and collision belonged to spatially separated objects. The results demonstrate that location-based binding is a requisite for temporal recalibration within the visual modality. Our finding suggests that the brain takes the modality difference in object localization into consideration when integrating temporally asynchronous signals.

Salivary Excretion of Renal-Clearable Silver Nanoparticles.

Salivary elimination is an important pathway for the body to excrete small molecules with digestive enzymes. However, very few engineered nanoparticles can be excreted through salivary glands, which often host bacteria or viruses during infection and involve in disease transmission. Herein, we report that renal clearable glutathione coated AgNPs (GS-AgNPs) can selectively accumulate in the submandibular salivary gland, followed by being excreted in its excretory duct. By conducting head-to-head comparison on in vivo transport and interactions of both GS-AgNPs and glutathione coated gold nanoparticles (GS-AuNPs) with the same sizes, we found that low-density GS-AgNPs showed much higher vascular permeability than GS-AuNPs and can rapidly penetrate into submandibular salivary glands, be efficiently taken up by striated and excretory duct cells, and eventually secreted into saliva.

Cancer Photothermal Therapy with ICG-Conjugated Gold Nanoclusters.

The coming era of precision nanomedicine demands engineered nanoparticles that can be readily translated into the clinic, like that of molecular agents, without being hindered by intrinsic size heterogeneity and long-term body retention. Herein we report that conjugation of indocyanine green (ICG), an FDA-approved near-infrared (NIR) dye, onto an atomically precise glutathione-coated Au25 (GS-Au25) nanocluster led to a molecular-like photothermal nanoparticle (ICG4-GS-Au25) with significantly enhanced ICG photostability and tumor targeting. Under weak NIR light irradiation conditions, free ICG failed to suppress tumor growth but the original tumors were completely eradicated with ICG4-GS-Au25. In the meantime, "off-target" ICG4-GS-Au25 was effectively cleared out from the body like small-molecule drugs after glutathione-mediated biotransformation in the liver. These findings highlight the merits of molecular-like nanomedicines, offering a new pathway to meet FDA's criteria for the clinical translation of nanomedicines.

Enhancing ZnO nanowire gas sensors using Au/Fe2O3 hybrid nanoparticle decoration.

Heterojunctions are an important strategy for designing high performance electrical sensor materials and related devices. Herein, a new type of metal-semiconductor hybrid nanoparticle has been successfully used to remarkably sensitize the surface of ZnO nanowires for detecting NO2 with high responses over a broad temperature window ranging from room temperature to 600 °C. These hybrid nanoparticles are comprised of iron oxide nanowires with well dispersed single crystalline Au nanoparticles. The hybrid nanoparticle decorated ZnO nanowires have achieved a giant response, as high as 74 500 toward NO2 gas, about 42 times that of Au decorated ZnO nanowire sensors. This dramatic enhancement may be attributed to the efficient charge transfer across the Au-Fe2O3 Schottky and Fe2O3-ZnO semiconductor heterojunction interfaces. Due to the incorporation of thermally-stable Fe2O3 nanoparticles as the support of Au nanoparticles, the working temperature of nanowire sensors was successfully extended to higher temperatures, with an increase of 200 °C, from 400 °C to 600 °C. Such a combination of semiconductor heterojunction and semiconductor-metal Schottky contact presents a new strategy for designing high performance electrical sensors with high sensitivity, stability, selectivity, and wide operation temperature window, which are potentially suitable for advanced energy systems such as automotive engines and power plants.

Renal clearable nanocarriers: Overcoming the physiological barriers for precise drug delivery and clearance.

Physiological barriers encountered in the clinical translation of cancer nanomedicines inspire the community to more deeply understand nano-bio interactions in not only tumor microenvironment but also entire body and develop new nanocarriers to tackle these barriers. Renal clearable nanocarriers are one kind of these newly emerged drug delivery systems (DDSs), which enable drugs to rapidly penetrate into the tumor cores with no need of long blood retention and escape macrophage uptake in the meantime they can also enhance body elimination of non-targeted anticancer drugs. As a result, they can improve therapeutic efficacies and reduce side effects of anticancer drugs. Not limited to anticancer drugs, diagnostic agents can also be achieved with these renal clearable DDSs, which might also be applied to improve the precision in the gene editing and immunotherapy in the future.

Tapping ahead of time: its association with timing variability.

Researchers have puzzled over the phenomenon in sensorimotor timing that people tend to tap ahead of time. When synchronizing movements (e.g., finger taps) with an external sequence (e.g., a metronome), humans typically tap tens of milliseconds before event onsets, producing the elusive negative asynchrony. Here, we present 24 metronome-tapping data sets from 8 experiments with different experimental settings, showing that less negative asynchrony is associated with lower tapping variability. Further analyses reveal that this negative mean-SD correlation of asynchrony is likely to be observed for sequence types appropriate for synchronization, as indicated by the statistically negative lag 1 autocorrelation of inter-response intervals. The reported findings indicate an association between negative asynchrony and timing variability.

Tailoring Kidney Transport of Organic Dyes with Low-Molecular-Weight PEGylation.

Subtle changes in size can induce distinct responses of the body to hard nanomaterials; however, it is largely unknown whether just a few ethylene oxide unit differences in soft poly(ethylene glycol) (PEG) molecules could significantly alter the renal clearance of small molecules. By systematically investigating in vivo transport of the representative renal clearable organic dyes, IRDye800CW after being conjugated with a series of PEG molecules with molecular weight (MW) below 10 kDa, we found a MW-dependent scaling law: PEG45 (MW = 2100 Da) is an optimized MW to generate the most efficient renal clearance for IRDye800CW by expediting the glomerular filtration of organic dyes and reducing their nonspecific interactions with background tissue. Moreover, the uniqueness of PEG45 can be generalized to other organic dyes such as ZW800-1 and fluorescein. This finding highlights the importance of low-MW PEGylation in tailoring in vivo transport of organic fluorophores, which would broaden their biomedical applications.

Advantage of audition over vision in a perceptual timing task but not in a sensorimotor timing task.

Timing is essential for various behaviors and relative to vision, audition is considered to be specialized for temporal processing. The present study conducted a sensorimotor timing task that required tapping in synchrony with a temporally regular sequence and a perceptual timing task that required detecting a timing deviation among a temporally regular sequence. The sequence was composed of auditory tones, visual flashes, or a visual bouncing ball. In the sensorimotor task, sensorimotor timing performance (synchronization stability) of the bouncing ball was much greater than that of flashes and was comparable to that of tones. In the perceptual task, where perceptual timing performance of the bouncing ball was greater than that of flashes, it was poorer than that of tones. These results suggest the facilitation of both perceptual and sensorimotor processing of temporal information by the bouncing ball. Given such facilitation of temporal processing, however, audition is still superior over vision in perceptual detection of timing.