Disproportionality Analysis of Lenvatinib-Caused Gastrointestinal Perforation in Cancer Patients: A Pharmacovigilance Analysis Based on the US Food and Drug Administration Adverse Event Reporting System.

Lenvatinib is a medication that targets multiple tyrosine kinases and is commonly used to treat various types of cancer. With its frequent usage, monitoring and assessing its potential adverse effects has become crucial. This study utilizes the US Food and Drug Administration Adverse Event Reporting System (FAERS) database to analyze the possible link between lenvatinib and gastrointestinal perforation. FAERS was used to analyze adverse drug reactions (ADRs) linked with lenvatinib from the first quarter of 2015 to the last quarter of 2022. The association between lenvatinib and gastrointestinal perforation was evaluated using disproportionality analyses. This study included 464 patients who developed gastrointestinal perforation after using lenvatinib. Perforation involved the entire digestive tract, with the colon among the most commonly affected perforation sites, and previously undetected esophageal perforation was frequently observed. Patients with uterine and liver cancer were at a higher risk of developing gastrointestinal perforation; patients with liver cancer experienced a shorter onset time, whereas patients with endometrial cancer had a slower onset time. Middle-aged and elderly patients exhibited a higher propensity for developing gastrointestinal perforation than younger adults. Patients with gastrointestinal perforation were found to have a significantly higher mortality rate than patients without gastrointestinal perforation. This study has identified several gastrointestinal perforation events not included in the drug instructions. It has also described the perforation site and clinical characteristics based on various types of cancer. These results could provide valuable insights for developing safer and more effective regulatory strategies concerning the use of lenvatinib.

TMEM232 promotes the inflammatory response in atopic dermatitis via the nuclear factor-κB and signal transducer and activator of transcription 3 signalling pathways.

BACKGROUND: Our group previously found that the transmembrane protein 232 (TMEM232) gene was associated with atopic dermatitis (AD) by genome-wide association study and fine mapping study. However, its function is unclear so far. OBJECTIVES: To investigate the roles and mechanisms of TMEM232 in AD. METHODS: The expression of TMEM232 was investigated in skin lesions of patients with AD, the MC903-induced AD mouse model, human primary keratinocytes and immortalized human keratinocyte cell line (HaCaT) cells stimulated with different inflammatory factors. The role of TMEM232 in AD was analysed in HaCaT cells and Tmem232 knockout (Tmem232-/-) mice. Tmem232-specific small interfering RNA (siRNA) was used to evaluate its therapeutic potential in the AD mouse model. RESULTS: The expression of TMEM232 was significantly increased in skin lesions of patients with AD, the MC903-induced AD mouse model and human primary keratinocytes and HaCaT cells stimulated with different inflammatory factors compared with controls. In the presence of MC903, Tmem232-/- mice exhibited significantly reduced dermatitis severity, mast-cell infiltration in the back, and expression of T-helper (Th)1 and Th2-related inflammatory factors in skin tissue compared with wild-type mice. In vitro and in vivo experiments further showed that upregulation of TMEM232 in AD exacerbated the inflammation response through activating the pathway of nuclear factor-κB and signal transducer and activator of transcription (STAT) 3, and was regulated by the interleukin-4/STAT6 axis, which formed a self-amplifying loop. Finally, topical application of Tmem232 siRNA markedly ameliorated AD-like lesions in the AD model. CONCLUSIONS: This study is the first to outline the function of TMEM232. It is involved in regulating inflammation in AD and may be a potential target for AD treatment.

Neuronal Response to Reward and Luminance in Macaque LIP During Saccadic Choice.

Recent work in decision neuroscience suggests that visual saliency can interact with reward-based choice, and the lateral intraparietal cortex (LIP) is implicated in this process. In this study, we recorded from LIP neurons while monkeys performed a two alternative choice task in which the reward and luminance associated with each offer were varied independently. We discovered that the animal's choice was dictated by the reward amount while the luminance had a marginal effect. In the LIP, neuronal activity corresponded well with the animal's choice pattern, in that a majority of reward-modulated neurons encoded the reward amount in the neuron's preferred hemifield with a positive slope. In contrast, compared to their responses to low luminance, an approximately equal proportion of luminance-sensitive neurons responded to high luminance with increased or decreased activity, leading to a much weaker population-level response. Meanwhile, in the non-preferred hemifield, the strength of encoding for reward amount and luminance was positively correlated, suggesting the integration of these two factors in the LIP. Moreover, neurons encoding reward and luminance were homogeneously distributed along the anterior-posterior axis of the LIP. Overall, our study provides further evidence supporting the neural instantiation of a priority map in the LIP in reward-based decisions.

One-Pot and Unsymmetrical Bis-Allylation of Malononitrile with Conjugated Dienes and Allylic Alcohols.

A Pd/Ca catalytic system to promote the unsymmetrical bis-allylation of malononitrile was developed by selecting conjugated dienes and allylic alcohols as allylic reagents. This catalytic system suppressed the competitive symmetrical bis-allylation process and guaranteed the desired unsymmetrical bis-allylation with high chemoselectivity. A wide range of conjugated dienes and allylic alcohols were tolerated well in this transformation, and diverse 1,6-dienes were obtained with high efficiency.

Development and Application of Global Health Events-Mental Stress Scale for Assessment of Medical Staff's Acute Mental Stress Responses.

Background: Medical workers have been increasingly involved in emergent public health events, which can lead to severe stress. However, no standardized, officially recognized, unified tool exists for mental distress measurement in medical workers who experienced the public health events. Purpose: In the present study, we propose the Global Health Events-Mental Stress Scale (GHE-MSS), as a revised version of the Impact of Event Scale-Revision (IES-R), for assessment of medical workers' acute mental stress responses within one month and their chronic mental stress responses within six months after major health events. Patients and methods: The IES-R was slightly modified, developed, and its reliability and validity were tested using the Delphi survey, primary survey with 115 participants, formal survey with 300 participants, and clinical evaluation with 566 participants. Results: Exploratory factor analysis and confirmatory factor analysis confirmed a promising validity of the scale. The values of Cronbach's alpha coefficient, the Spearman-Brown coefficient, and the retested Cronbach's alpha coefficient of the scale applied for the clinical evaluation were 0.88, 0.87, and 0.98, respectively, which confirmed a good internal consistency and stability. The results of the goodness-of-fit test indicated a good adaptation of the model. A correlation analysis was conducted to assess the correlation between the GHE-MSS and the PCL-C, which had a correlation coefficient of 0.68 (P<0.01). Conclusion: GHE-MSS can be applied with a promising reliability and validity for the assessment of the acute mental stress response of medical workers experiencing public health events. This method can also be used for the screening of mental stress-associated disorders.

Confirming the TMEM232 gene associated with atopic dermatitis through targeted capture sequencing.

Atopic dermatitis (AD) is a common and complex skin disorder, and the 5q22.1 region had been reported to be associated with AD. To confirm the susceptibility gene for AD in the 5q22.1 region by haplotype and targeted capture sequencing. The haplotypes were reconstructed with the genotyping data of four SNPs and six deletions from 3624 Chinese Hans AD patients and 5076 controls. The targeted capture sequencing spanning 5q22.1 region was performed in the selected samples. The gene level enrichment analysis was done using loss of function variants. A total of 62 haplotypes were found, and the H15 haplotype had the strongest association with AD (P = 3.92 × 10-10, OR 0.17, 95% CI 0.09-0.32). However, no co-segregation mutation sites were found in the sequencing analysis within the 16 selected samples, while the enrichment analysis indicated that TMEM232 was significantly associated with AD (P = 7.33 × 10-5, OR 0.33, 95% CI 0.19-0.58). This study confirms previous findings that the TMEM232 gene is associated with AD by haplotype analysis and targeted capture sequencing.

Neuronal activity in dorsal anterior cingulate cortex during economic choices under variable action costs.

The role of the dorsal anterior cingulate cortex (ACCd) in decision making has often been discussed but remains somewhat unclear. On the one hand, numerous studies implicated this area in decisions driven by effort or action cost. On the other hand, work on economic choices between goods (under fixed action costs) found that neurons in ACCd encoded only post-decision variables. To advance our understanding of the role played by this area in decision making, we trained monkeys to choose between different goods (juice types) offered in variable amounts and with different action costs. Importantly, the task design dissociated computation of the action cost from planning of any particular action. Neurons in ACCd encoded the chosen value and the binary choice outcome in several reference frames (chosen juice, chosen cost, chosen action). Thus, this area provided a rich representation of post-decision variables. In contrast to the OFC, neurons in ACCd did not represent pre-decision variables such as individual offer values in any reference frame. Hence, ongoing decisions are unlikely guided by ACCd. Conversely, neuronal activity in this area might inform subsequent actions.

Chronic Progression of Lung Cancer Recurrence After Surgery: Warning Role of Postoperative Pneumonia.

PURPOSE: The association between the process of postoperative pneumonia and lung cancer recurrence remains elusive in lung cancer surgery. Herein, the association between postoperative pneumonia and lung cancer recurrence was investigated, emphasizing the warning role of postoperative specific pneumonia in primary lung cancer resection patients. METHODS: The occurrence of postoperative pneumonia was assessed in 4-6 months (PPFS), 7-12 months (PPST), and lung cancer recurrence within 1 year (LRO) in 332 patients. The primary outcome was the development of PPST and LRO according to PPFS occurrence. The relevant risk factors of PPFS, PPST, and LRO were identified through multivariable regression analysis. RESULTS: During follow-up, 151 (45.48%) participants experienced PPFS. Irrespective of the existing postoperative pneumonia in 1-3 months (PPOT), PPFS significantly increased the risk of PPST (P < 0.01) and LRO (P < 0.01), and persistent PPST further increased the risk of LRO (P < 0.001). The generalized estimating equation identified chemotherapy as an independent risk factor for PPFS and PPST. CONCLUSION: PPFS was associated with the increased risk of PPST and LRO. Postoperative pulmonary inflammation assessed 4 months post-surgery also significantly influenced LRO development, indicating a need for close follow-up of lung inflammatory conditions to improve patient outcomes.

The Neural Instantiation of an Abstract Cognitive Map for Economic Choice.

Since the discovery of cognitive maps in rodent hippocampus (HC), the cognitive map has evolved from originally referring to spatial representations encoding locations and objects in Euclidean spaces to a general low-dimensional organization of information along selected feature dimensions. A cognitive map includes hypothetical constructs that bridge between environmental stimuli and the final overt behavior. To neuroeconomists, utility and utility functions are such constructs with neurobiological basis that drive choice behavior. Emergence of distinct functional neuron groups in the primate orbitofrontal cortex (OFC) during simple economic choice indicates the formation of an abstract cognitive map for organizing information of goods for value computation. Experimental evidence suggests that organization of neuronal activity in such cognitive map reflects the abstraction of core task features. Thus, such map can be adapted to accommodate economic choices under various task contexts.

Establishing Performance Evaluation for Quality Inspection of Specialty Nurses.

PURPOSE: The present study aimed to establish an index system for the performance evaluation of specialty nurses (SNs) in tertiary hospitals. BACKGROUND: An objective index system for performance evaluation of SN has not yet been established in China. DESIGN: A 2-round Delphi survey sought opinions from experts about the index system for SNs' performance evaluation in tertiary hospitals in China. METHODS: Delphi survey was used to inquire approximately 20 experts from the fields of nursing management, nursing education, and clinical nursing. We determined the weight coefficient of each index of performance evaluation based on the opinion. Finally, the index of the quality evaluation was established for SN. RESULTS: A total of 20 experts from 10 provinces in China reached a consensus on the tertiary indexes of the assessment model. The indexes contained first-level (4), second-level (16), and third-level (24) indicators. The 4 aspects of the performance evaluation, including clinical specialist practice assessment, nursing research, education assessment, medical cooperation recognition, and personal comprehensive ability assessment, reached consensus. CONCLUSION: Establishing the performance evaluation for SNs aided the SNs in achieving the best clinical practice after training. The performance evaluation still needed to be continuously improved.

Dehydrative Allylation of Alkenyl sp2 C-H Bonds.

We designed a cooperative catalytic system by combining commercially available Ca(NTf2)PF6 and Pd(PPh3)4 to address the dehydrative allylation of alkenyl sp2 C-H bonds in an environmentally benign manner. A novel C-OH bond cleavage method was found to be crucial for this practical protocol. A variety of alkenes and allylic alcohols equipped with wide-spectrum functional groups can be successfully incorporated into the desired cross-coupling, affording 1,4-dienes with moderate to excellent yields and high stereo- and regioselectivity.

Robust and distributed neural representation of action values.

Studies in rats, monkeys, and humans have found action-value signals in multiple regions of the brain. These findings suggest that action-value signals encoded in these brain structures bias choices toward higher expected rewards. However, previous estimates of action-value signals might have been inflated by serial correlations in neural activity and also by activity related to other decision variables. Here, we applied several statistical tests based on permutation and surrogate data to analyze neural activity recorded from the striatum, frontal cortex, and hippocampus. The results show that previously identified action-value signals in these brain areas cannot be entirely accounted for by concurrent serial correlations in neural activity and action value. We also found that neural activity related to action value is intermixed with signals related to other decision variables. Our findings provide strong evidence for broadly distributed neural signals related to action value throughout the brain.

Molecular Diagnosis of Neurofibromatosis by Multigene Panel Testing.

Neurofibromatosis (NF) is an autosomal genetic disorder for which early and definite clinical diagnoses are difficult. To identify the diagnosis, five affected probands with suspected NF from unrelated families were included in this study. Molecular analysis was performed using multigene panel testing and Sanger sequencing. Ultradeep sequencing was used to analyze the mutation rate in the tissues from the proband with mosaic mutations. Three different pathogenic variants of the NF1 gene were found in three probands who mainly complained of café-au-lait macules (CALMs), including one frameshift variant c.5072_5073insTATAACTGTAACTCCTGGGTCAGGGAGTACACCAA:p.Tyr1692Ilefs in exon 37, one missense variant c.3826C > T:p.Arg1276Ter in exon 28, and one splicing variant c.4110 + 1G > T at the first base downstream of the 3'-end of exon 30. One NF1 gene mosaic variant was found in a proband who complained of cutaneous neurofibroma with the frameshift variant c.495_498del:p.Thr165fs in exon 5, and ultradeep sequencing showed the highest mutation rate of 10.81% in cutaneous neurofibromas. A frameshift variant, c.36_39del:p.Ser12fs in exon 1 of the NF2 gene, was found in a proband who presented with skin plaques and intracranial neurogenic tumors. All of these pathogenic variants were heterozygous, one was not reported, and one not in Chinese before. This study expands the pathogenic variant spectrum of NF and demonstrates the clinical diagnosis.

Validation of Susceptibility Loci for Vitiligo Identified by GWAS in the Chinese Han Population.

Forty-nine susceptible loci have been reported to be significantly associated with vitiligo by genome-wide association studies (GWASs) in European-derived whites. To date, some of these reported susceptibility loci have not yet been validated in the Chinese Han population. The purpose of this study was to examine whether the 16 reported susceptible loci in European-derived whites were associated with vitiligo in the Chinese Han population. Imputation was performed using our previous GWAS dataset by IMPUTE v2.2.2. The 16 imputed top single-nucleotide polymorphisms (SNPs) with suggestive signals, together with the reported SNPs, were genotyped in a total of 2581 patients and 2579 controls by the Sequenom MassARRAY system. PLINK 2.0 software was used to perform association analysis. The dbSNP database, HaploReg, and eQTL data were adopted to annotate the biological function of the SNPs. Finally, four SNPs from three loci were significantly associated with vitiligo, including rs3747517 (P = 1.29 × 10-3, OR = 0.87) in 2q24.2, rs4807000 (P = 7.78 × 10-24, OR = 0.66) and rs6510827 (P = 3.65 × 10-5, OR = 1.19) in 19p13.3, and rs4822024 (P = 6.37 × 10-10, OR = 0.67) in 22q13.2. According to the dbSNP database, rs3747517 is a missense variant of IFIH1, rs4807000 and rs6510827 are located in TICAM1, and rs4822024 is located 6 kb upstream of TEF. Further bioinformatics analysis by HaploReg and eQTL found that rs4807000, rs6510827, and rs4822024 are involved in regulating gene expression. Our study revealed the strong association of 2q24.2 (rs3747517), 19p13.3 (rs4807000, rs6510827), and 22q13.2 (rs4822024) with the risk of vitiligo in the Chinese Han population, which implicates common factors for vitiligo across different ethnicities, and helps expand the understanding of the genetic basis of this disease.

Comparison of a Novel Muscle Training Device with Conventional Rehabilitation Training in Motor Dysfunction of Lower Limb Patients: A Pilot Study.

BACKGROUND: Postoperative functional training for fracture or osteoarthritis is mainly focused on functional self-exercise, which aims to recover the function of the lower limbs. PURPOSE: To compare the function and life quality recovery in patients with fracture or arthritis treated with novel muscle training device (NMT) or conventional rehabilitation training (CRT) following surgery. PATIENTS AND METHODS: A total of 32 fracture patients were randomly divided into the NMT or the CRT groups. The evaluation was performed on the first and 7th day after surgery. The outcome measurements included the incidence of foot drop, Deep Vein Thrombosis and pressure ulcers, Hospital for Special Surgery knee score (HSS scores), pain scores for the Visual Analogue Scale (Pain scores for VAS), Zung self-rating anxiety scale (SAS), Pittsburgh sleep quality index (PSQI) and the Barthel Index score. RESULTS: The comparison of the change scores between the two groups indicated significant differences on day 7 following surgery in the Barthel Index score (P<0.01). The Pain scores for VAS between the two groups indicated a significant difference (P<0.05, U=20.0). The HSS scores between the two groups indicated a significant difference (P<0.05, U=19.0). The HSS scores exhibited a highly significant difference in the NMT group (P<0.01). The Mann-Whitney test was used to analyze the various components of the HSS scores. The comparison of the change scores on the function between the two groups indicated a significant difference (P<0.05). The Range of Motion difference between groups exhibited highly significant differences (P<0.01). CONCLUSION: The novel muscle training device positively influenced the decrease in pain score, which resulted in a range increase of knee joint movement and a significant overall improvement in motion.

A PD-1 peptide antagonist exhibits potent anti-tumor and immune regulatory activity.

Antibodies blocking the PD-1/PD-L1 pathway have achieved great success. However, some disadvantages of antibodies have been found, which limit their clinical applications. Peptide antagonists are alternatives to antibodies in PD-1/PD-L1 blockage, but successful studies in this area are limited. A PD-1 targeting peptide, P-F4, was identified using phage display. P-F4 bound PD-1 with an affinity of 0.119 µM, inhibited PD-1/PD-L1 interaction at the cellular level and modulated T cell activity in vitro. We have overcome the poor solubility and rapid degradation problems of this peptide by packaging P-F4 in nanoparticles. In vivo experiments demonstrated that P-F4 nanoparticles could strongly inhibit tumor growth in a CT26 mouse model. Further research revealed that treatment of P-F4 nanoparticles increased CD8+T cells and reduced Tregs in the tumor microenvironment and tumor-draining lymph nodes. It was shown that treatment of P-F4 nanoparticles also increased lymphocytic activities, including proliferation, cytokine secretion and cytolytic activity. Moreover, computer modeling suggested that the P-F4 binding site to PD-1 overlaps with the PD-L1 binding surface. In this study, a peptide candidate for cancer immunotherapy was provided, and its working mechanisms were studied.

Reciprocal-Activation Strategy for Allylic Sulfination with Unactivated Allylic Alcohols.

A reciprocal-activation strategy for allylic sulfination with unactivated allylic alcohols was developed. In this reaction, the hydrogen bond interaction between allylic alcohols and sulfinic acids allowed for reciprocal activation, which enabled a dehydrative cross-coupling process to occur under mild reaction conditions. This reaction worked in an environmentally friendly manner, yielding water as the only byproduct. A variety of allylic sulfones could be obtained in good to excellent yields with wide functional group tolerance. In gram scale reactions, allylic sulfones could be conveniently isolated in high yield by filtration.

Dehydrative Cross-Coupling of Allylic Alcohols with Alkynes.

A highly efficient Pd/Ca catalytic system for the directly dehydrative cross-coupling of allylic alcohols with terminal alkynes was developed. This calcium salt cocatalyst facilitates the oxidative addition of the palladium catalyst (1 mol %) to the C-OH bond. Then, the in situ-generated hydroxide ion deprotonates the terminal alkynes to promote the formation of the allylalkynylpalladium intermediate, liberating water as the only byproduct. This proposed mechanism is also supported by density functional theory calculations. An anticancer agent was prepared from inexpensive starting materials on a 10 g scale.

Alkaline-Earth Metal Catalyzed Dehydrative Allylic Alkylation.

An alkaline-earth metal catalytic system for environmentally benign allylic alkylation was developed. Allylic alcohols can be utilized directly at room temperature in this transition-metal-free process, producing water as the only byproduct. A variety of allylic compounds, including the ones containing all-carbonyl quaternary centers, can be obtained with high yields.

Optimal concentration of necrostatin-1 for protecting against hippocampal neuronal damage in mice with status epilepticus.

Hippocampal neurons undergo various forms of cell death after status epilepticus. Necrostatin-1 specifically inhibits necroptosis mediated by receptor interacting protein kinase 1 (RIP1) and RIP3 receptors. However, there are no reports of necroptosis in mouse models of status epilepticus. Therefore, in this study, we investigated the effects of necrostatin-1 on hippocampal neurons in mice with status epilepticus, and, furthermore, we tested different amounts of the compound to identify the optimal concentration for inhibiting necroptosis and apoptosis. A mouse model of status epilepticus was produced by intraperitoneal injection of kainic acid, 12 mg/kg. Different concentrations of necrostatin-1 (10, 20, 40, and 80 µM) were administered into the lateral ventricle 15 minutes before kainic acid injection. Hippocampal damage was assessed by hematoxylin-eosin staining 24 hours after the model was successfully produced. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining, western blot assay and immunohistochemistry were used to evaluate the expression of apoptosis-related and necroptosis-related proteins. Necrostatin-1 alleviated damage to hippocampal tissue in the mouse model of epilepsy. The 40 µM concentration of necrostatin-1 significantly decreased the number of apoptotic cells in the hippocampal CA1 region. Furthermore, necrostatin-1 significantly downregulated necroptosis-related proteins (MLKL, RIP1, and RIP3) and apoptosis-related proteins (cleaved-Caspase-3, Bax), and it upregulated the expression of anti-apoptotic protein Bcl-2. Taken together, our findings show that necrostatin-1 effectively inhibits necroptosis and apoptosis in mice with status epilepticus, with the 40 µM concentration of the compound having an optimal effect. The experiments were approved by the Animal Ethics Committee of Fujian Medical University, China (approval No. 2016-032) on November 9, 2016.