Synthesis and Evaluation of the First 68Ga-Labeled C-Terminal Hydroxamate-Derived Gastrin-Releasing Peptide Receptor-Targeted Tracers for Cancer Imaging with Positron Emission Tomography.

Gastrin-releasing peptide receptor (GRPR), overexpressed in many solid tumors, is a promising imaging marker and therapeutic target. Most reported GRPR-targeted radioligands contain a C-terminal amide. Based on the reported potent antagonist D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHOH, we synthesized C-terminal hydroxamate-derived [68Ga]Ga-LW02075 ([68Ga]Ga-DOTA-pABzA-DIG-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHOH) and [68Ga]Ga-LW02050 ([68Ga]Ga-DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHOH), and compared them with the closely related and clinically validated [68Ga]Ga-SB3 ([68Ga]Ga-DOTA-pABzA-DIG-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt). Binding affinities (Ki) of Ga-SB3, Ga-LW02075, and Ga-LW02050 were 1.20 ± 0.31, 1.39 ± 0.54, and 8.53 ± 1.52 nM, respectively. Both Ga-LW02075 and Ga-LW02050 were confirmed to be GRPR antagonists by calcium release assay. Imaging studies showed that PC-3 prostate cancer tumor xenografts were clearly visualized at 1 h post injection by [68Ga]Ga-SB3 and [68Ga]Ga-LW02050 in PET images, but not by [68Ga]Ga-LW02075. Ex vivo biodistribution studies conducted at 1 h post injection showed that the tumor uptake of [68Ga]Ga-LW02050 was comparable to that of [68Ga]Ga-SB3 (5.38 ± 1.00 vs. 6.98 ± 1.36 %ID/g), followed by [68Ga]Ga-LW02075 (3.97 ± 1.71 %ID/g). [68Ga]Ga-SB3 had the highest pancreas uptake (37.3 ± 6.90 %ID/g) followed by [68Ga]Ga-LW02075 (17.8 ± 5.24 %ID/g), while the pancreas uptake of [68Ga]Ga-LW02050 was only 0.53 ± 0.11 %ID/g. Our data suggest that [68Ga]Ga-LW02050 is a promising PET tracer for detecting GRPR-expressing cancer lesions.

A comprehensive meta-analysis of tissue resident memory T cells and their roles in shaping immune microenvironment and patient prognosis in non-small cell lung cancer.

Tissue-resident memory T cells (TRM) are a specialized subset of long-lived memory T cells that reside in peripheral tissues. However, the impact of TRM-related immunosurveillance on the tumor-immune microenvironment (TIME) and tumor progression across various non-small-cell lung cancer (NSCLC) patient populations is yet to be elucidated. Our comprehensive analysis of multiple independent single-cell and bulk RNA-seq datasets of patient NSCLC samples generated reliable, unique TRM signatures, through which we inferred the abundance of TRM in NSCLC. We discovered that TRM abundance is consistently positively correlated with CD4+ T helper 1 cells, M1 macrophages, and resting dendritic cells in the TIME. In addition, TRM signatures are strongly associated with immune checkpoint and stimulatory genes and the prognosis of NSCLC patients. A TRM-based machine learning model to predict patient survival was validated and an 18-gene risk score was further developed to effectively stratify patients into low-risk and high-risk categories, wherein patients with high-risk scores had significantly lower overall survival than patients with low-risk. The prognostic value of the risk score was independently validated by the Cancer Genome Atlas Program (TCGA) dataset and multiple independent NSCLC patient datasets. Notably, low-risk NSCLC patients with higher TRM infiltration exhibited enhanced T-cell immunity, nature killer cell activation, and other TIME immune responses related pathways, indicating a more active immune profile benefitting from immunotherapy. However, the TRM signature revealed low TRM abundance and a lack of prognostic association among lung squamous cell carcinoma patients in contrast to adenocarcinoma, indicating that the two NSCLC subtypes are driven by distinct TIMEs. Altogether, this study provides valuable insights into the complex interactions between TRM and TIME and their impact on NSCLC patient prognosis. The development of a simplified 18-gene risk score provides a practical prognostic marker for risk stratification.

An integrated database of experimentally validated major histocompatibility complex epitopes for antigen-specific cancer therapy.

Cancer immunotherapy represents a paradigm shift in oncology, offering a superior anti-tumor efficacy and the potential for durable remission. The success of personalized vaccines and cell therapies hinges on the identification of immunogenic epitopes capable of eliciting an effective immune response. Current limitations in the availability of immunogenic epitopes restrict the broader application of such therapies. A critical criterion for serving as potential cancer antigens is their ability to stably bind to the major histocompatibility complex (MHC) for presentation on the surface of tumor cells. To address this, we have developed a comprehensive database of MHC epitopes, experimentally validated for their MHC binding and cell surface presentation. Our database catalogs 451 065 MHC peptide epitopes, each with experimental evidence for MHC binding, along with detailed information on human leukocyte antigen allele specificity, source peptides, and references to original studies. We also provide the grand average of hydropathy scores and predicted immunogenicity for the epitopes. The database (MHCepitopes) has been made available on the web and can be accessed at https://github.com/jcm1201/MHCepitopes.git. By consolidating empirical data from various sources coupled with calculated immunogenicity and hydropathy values, our database offers a robust resource for selecting actionable tumor antigens and advancing the design of antigen-specific cancer immunotherapies. It streamlines the process of identifying promising immunotherapeutic targets, potentially expediting the development of effective antigen-based cancer immunotherapies.

Neural circuit-selective, multiplexed pharmacological targeting of prefrontal cortex-projecting locus coeruleus neurons drives antinociception.

Selective manipulation of neural circuits using optogenetics and chemogenetics holds great translational potential but requires genetic access to neurons. Here, we demonstrate a general framework for identifying genetic tool-independent, pharmacological strategies for neural circuit-selective modulation. We developed an economically accessible calcium imaging-based approach for large-scale pharmacological scans of endogenous receptor-mediated neural activity. As a testbed for this approach, we used the mouse locus coeruleus due to the combination of its widespread, modular efferent neural circuitry and its wide variety of endogenously expressed GPCRs. Using machine learning-based action potential deconvolution and retrograde tracing, we identified an agonist cocktail that selectively inhibits medial prefrontal cortex-projecting locus coeruleus neurons. In vivo, this cocktail produces synergistic antinociception, consistent with selective pharmacological blunting of this neural circuit. This framework has broad utility for selective targeting of other neural circuits under different physiological and pathological states, facilitating non-genetic translational applications arising from cell type-selective discoveries.

Elevated risk of sexually transmitted infections among adolescents and young adults with borderline personality disorder: a retrospective longitudinal nationwide population-based study.

In this study, we examined the risk of sexually transmitted infections (STIs) among adolescents and young adults (AYAs) with borderline personality disorder (BPD). A total of 4649 AYAs with BPD and 46,490 age-, sex-, and socioeconomic-matched controls without BPD were enrolled from the National Health Insurance Research Database of Taiwan from 2001 to 2009 and were followed up until the end of 2011. Participants who contracted any STI during the follow-up period were identified. Cox regression analysis was conducted to examine the risk of contracting any STI among both patients and controls. A total of 4649 AYAs with BPD and 46,490 age-, sex-, and socioeconomic-matched controls without BPD were enrolled from the National Health Insurance Research Database of Taiwan from 2001 to 2009 and were followed up until the end of 2011. Participants who contracted any STI (ICD-9-CM code 042, 091-097, 087.11, 078.8, 078.88, 131, and 054.1) during the follow-up period were identified. Cox regression and sub-analyses stratified by sex, age, psychiatric comorbidity subgroups, and psychotropic medication usage were conducted to assess STI risk. AYAs with BPD were at a higher risk of contracting any STI (hazard ratio [HR] = 50.79, 95% confidence interval [CI] = 33.45-77.11) in comparison with controls, including HIV, syphilis, genital warts, gonorrhea, chlamydia, trichomoniasis, and genital herpes. The association of BPD with an increased risk of any STI was prevalent in both sexes, adolescents, and young adult patients. BPD with or without psychiatric comorbid subgroup were all associated with an elevated risk of contracting any STI relative to the control group. AYAs with BPD are highly susceptible to contracting STIs. Future studies should examine the role of the core symptoms of BPD, sexual orientation, risky sex behaviors, depressive and anxiety symptoms, and substance use before sex in the risk of STIs among AYAs with BPD.

Synthesis and Evaluation of Novel 68Ga-Labeled [D-Phe6,Leu13ψThz14]bombesin(6-14) Analogs for Cancer Imaging with Positron Emission Tomography.

Gastrin-releasing peptide receptor (GRPR) is overexpressed in various cancers and is a promising target for cancer diagnosis and therapy. However, the high pancreas uptake and/or metabolic instability observed for most reported GRPR-targeted radioligands might limit their clinical applications. Our group recently reported a GRPR-targeted antagonist tracer, [68Ga]Ga-TacsBOMB2 ([68Ga]Ga-DOTA-Pip-D-Phe6-Gln7-Trp8-Ala9-Val10-Gly11-His12-Leu13ψThz14-NH2), which showed a minimal pancreas uptake in a preclinical mouse model. In this study, we synthesized four derivatives with unnatural amino acid substitutions (Tle10-derived Ga-LW01158, NMe-His12-derived Ga-LW01160, α-Me-Trp8- and Tle10-derived Ga-LW01186, and Tle10- and N-Me-Gly11-derived Ga-LW02002) and evaluated their potential for detecting GRPR-expressing tumors with positron emission tomography (PET). The binding affinities (Ki(GRPR)) of Ga-LW01158, Ga-LW01160, Ga-LW01186, and Ga-LW02002 were 5.11 ± 0.47, 187 ± 17.8, 6.94 ± 0.95, and 11.0 ± 0.39 nM, respectively. [68Ga]Ga-LW01158, [68Ga]Ga-LW01186, and [68Ga]Ga-LW02002 enabled clear visualization of subcutaneously implanted human prostate cancer PC-3 tumor xenografts in mice in PET images. Ex vivo biodistribution studies showed that [68Ga]Ga-LW01158 had the highest tumor uptake (11.2 ± 0.65 %ID/g) and good tumor-to-background uptake ratios at 1 h post-injection. Comparable in vivo stabilities were observed for [68Ga]Ga-LW01158, [68Ga]Ga-LW01186, and [68Ga]Ga-LW02002 (76.5-80.7% remaining intact in mouse plasma at 15 min post-injection). In summary, the Tle10 substitution, either alone or combined with α-Me-Trp8 or NMe-Gly11 substitution, in Ga-TacsBOMB2 generates derivatives that retained good GRPR binding affinity and in vivo stability. With good tumor uptake and tumor-to-background imaging contrast, [68Ga]Ga-LW01158 is promising for detecting GRPR-expressing lesions with PET.

Arginine-linked HPV-associated E7 displaying bacteria-derived outer membrane vesicles as a potent antigen-specific cancer vaccine.

BACKGROUND: Bacteria-based cancer therapy have demonstrated innovative strategies to combat tumors. Recent studies have focused on gram-negative bacterial outer membrane vesicles (OMVs) as a novel cancer immunotherapy strategy due to its intrinsic properties as a versatile carrier. METHOD: Here, we developed an Human Papillomavirus (HPV)-associated E7 antigen displaying Salmonella-derived OMV vaccine, utilizing a Poly(L-arginine) cell penetrating peptide (CPP) to enhance HPV16 E7 (aa49-67) H-2 Db and OMV affinity, termed SOMV-9RE7. RESULTS: Due to OMV's intrinsic immunogenic properties, SOMV-9RE7 effectively activates adaptive immunity through antigen-presenting cell uptake and antigen cross-presentation. Vaccination of engineered OMVs shows immediate tumor suppression and recruitment of infiltrating tumor-reactive immune cells. CONCLUSION: The simplicity of the arginine coating strategy boasts the versatility of immuno-stimulating OMVs that can be broadly implemented to personalized bacterial immunotherapeutic applications.

Tissue-resident memory T cell signatures from single-cell analysis associated with better melanoma prognosis.

Tissue-resident memory T cells (TRM) are a specialized T cell population residing in peripheral tissues. The presence and potential impact of TRM in the tumor immune microenvironment (TIME) remain to be elucidated. Here, we systematically investigated the relationship between TRM and melanoma TIME based on multiple clinical single-cell RNA-seq datasets and developed signatures indicative of TRM infiltration. TRM infiltration is associated with longer overall survival and abundance of T cells, NK cells, M1 macrophages, and memory B cells in the TIME. A 22-gene TRM-derived risk score was further developed to effectively classify patients into low- and high-risk categories, distinguishing overall survival and immune activation, particularly in T cell-mediated responses. Altogether, our analysis suggests that TRM abundance is associated with melanoma TIME activation and patient survival, and the TRM-based machine learning model can potentially predict prognosis in melanoma patients.

A locus coeruleus to dorsal hippocampus pathway mediates cue-induced reinstatement of opioid self-administration in male and female rats.

Opioid use disorder is a chronic relapsing disorder encompassing misuse, dependence, and addiction to opioid drugs. Long term maintenance of associations between the reinforcing effects of the drug and the cues associated with its intake are a leading cause of relapse. Indeed, exposure to the salient drug-associated cues can lead to drug cravings and drug seeking behavior. The dorsal hippocampus (dHPC) and locus coeruleus (LC) have emerged as important structures for linking the subjective rewarding effects of opioids with environmental cues. However, their role in cue-induced reinstatement of opioid use remains to be further elucidated. In this study, we showed that chemogenetic inhibition of excitatory dHPC neurons during re-exposure to drug-associated cues significantly attenuates cue-induced reinstatement of morphine-seeking behavior. In addition, the same manipulation reduced reinstatement of sucrose-seeking behavior but failed to alter memory recall in the object location task. Finally, intact activity of tyrosine hydroxylase (TH) LC-dHPCTh afferents is necessary to drive cue induced reinstatement of morphine-seeking as inhibition of this pathway blunts cue-induced drug-seeking behavior. Altogether, these studies show an important role of the dHPC and LC-dHPCTh pathway in mediating cue-induced reinstatement of opioid seeking.

Development, preclinical evaluation and preliminary dosimetry profiling of SB03178, a first-of-its-kind benzo[h]quinoline-based fibroblast activation protein-α-targeted radiotheranostic for cancer imaging and therapy.

Fibroblast activation protein-α (FAP) is a marker of cancer-associated fibroblasts (CAFs) that constitute a significant portion of most carcinomas. Since it plays a critical role in tumor growth and metastasis, its timely detection to identify tumor lesions in early developmental stages using targeted radiopharmaceuticals has gained significant impetus. In the present work, two novel FAP-targeted precursors SB03178 and SB04033 comprising of an atypical benzo[h]quinoline construct were synthesized and either chelated to diagnostic radionuclide gallium-68 or therapeutic radionuclide lutetium-177, with ≥90% radiochemical purities and 22-76% decay-corrected radiochemical yields. natGa-labeled complexes displayed dose-dependent FAP inhibition, with binding potency of natGa-SB03178 being ∼17 times higher than natGa-SB04033. To evaluate their pharmacokinetic profiles, PET imaging and ex vivo biodistribution analyses were executed in FAP-overexpressing HEK293T:hFAP tumor-bearing mice. While both tracers displayed clear tumor visualization that was primarily FAP-arbitrated, with negligible uptake in most peripheral tissues, [68Ga]Ga-SB03178 demonstrated higher tumor uptake and superior tumor-to-background contrast ratios than [68Ga]Ga-SB04033. 177Lu-labeled SB03178 was subjected to tumor retention studies, mouse dosimetry profiling and mouse-to-human dose extrapolations also using the HEK293T:hFAP tumor model. [177Lu]Lu-SB03178 exhibited a combination of high and sustained tumor uptake, with excellent tumor-to-critical organ uptake ratios resulting in a high radiation absorbed dose to the tumor and a low estimated whole-body dose to humans. Our preliminary findings are considerably encouraging to support clinical development of [68Ga]Ga-/[177Lu]Lu-SB03178 theranostic pair for use in a vast majority of FAP-overexpressing neoplasms, particularly carcinomas.

Unnatural amino acid substitutions to improve in vivo stability and tumor uptake of 68Ga-labeled GRPR-targeted TacBOMB2 derivatives for cancer imaging with positron emission tomography.

BACKGROUND: Overexpressed in various solid tumors, gastrin-releasing peptide receptor (GRPR) is a promising cancer imaging marker and therapeutic target. Although antagonists are preferable for the development of GRPR-targeted radiopharmaceuticals due to potentially fewer side effects, internalization of agonists may lead to longer tumor retention and better treatment efficacy. In this study, we systematically investigated unnatural amino acid substitutions to improve in vivo stability and tumor uptake of a previously reported GRPR-targeted agonist tracer, [68Ga]Ga-TacBOMB2 (68Ga-DOTA-Pip-D-Phe6-Gln7-Trp8-Ala9-Val10-Gly11-His12-Leu13-Thz14-NH2). RESULTS: Unnatural amino acid substitutions were conducted for Gln7, Trp8, Ala9, Val10, Gly11 and His12, either alone or in combination. Out of 25 unnatural amino acid substitutions, tert-Leu10 (Tle10) and NMe-His12 substitutions were identified to be preferable modifications especially in combination. Compared with the previously reported [68Ga]Ga-TacBOMB2, the Tle10 and NMe-His12 derived [68Ga]Ga-LW01110 showed retained agonist characteristics and improved GRPR binding affinity (Ki = 7.62 vs 1.39 nM), in vivo stability (12.7 vs 89.0% intact tracer in mouse plasma at 15 min post-injection) and tumor uptake (5.95 vs 16.6 %ID/g at 1 h post-injection). CONCLUSIONS: Unnatural amino acid substitution is an effective strategy to improve in vivo stability and tumor uptake of peptide-based radiopharmaceuticals. With excellent tumor uptake and tumor-to-background contrast, [68Ga]Ga-LW01110 is promising for detecting GRPR-expressing cancer lesions with PET. Since agonists can lead to internalization upon binding to receptors and foreseeable long tumor retention, our optimized GRPR-targeted sequence, [Tle10,NMe-His12,Thz14]Bombesin(7-14), is a promising template for use for the design of GRPR-targeted radiotherapeutic agents.

Synthesis and Preclinical Evaluation of Two Novel 68Ga-Labeled Bispecific PSMA/FAP-Targeted Tracers with 2-Nal-Containing PSMA-Targeted Pharmacophore and Pyridine-Based FAP-Targeted Pharmacophore.

Some bispecific radiotracers have been developed to overcome the limitations of monospecific tracers and improve detection sensitivity for heterogeneous tumor lesions. Here, we aim to synthesize two bispecific tracers targeting prostate-specific membrane antigen (PSMA) and fibroblast activation protein (FAP), which are key markers expressed in prostate cancer. A pyridine-based FAP-targeted ligand was synthesized through multi-step organic synthesis and then connected to the 2-Nal-containing PSMA-targeted motif. The Ki(PSMA) values of Ga-complexed bispecific ligands, Ga-AV01084 and Ga-AV01088, were 11.6 ± 3.25 and 28.7 ± 6.05 nM, respectively, and the IC50(FAP) values of Ga-AV01084 and Ga-AV01088 were 10.9 ± 0.67 and 16.7 ± 1.53 nM, respectively. Both [68Ga]Ga-AV01084 and [68Ga]Ga-AV01088 enabled the visualization of PSMA-expressing LNCaP tumor xenografts and FAP-expressing HEK293T:hFAP tumor xenografts in PET images acquired at 1 h post-injection. However, the tumor uptake values from the bispecific tracers were still lower than those obtained from the monospecific tracers, PSMA-targeted [68Ga]Ga-PSMA-617 and FAP-targeted [68Ga]Ga-AV02070. Further investigations are needed to optimize the selection of linkers and targeted pharmacophores to improve the tumor uptake of bispecific PSMA/FAP tracers for prostate cancer imaging.

Salmonella immunotherapy engineered with highly efficient tumor antigen coating establishes antigen-specific CD8+ T cell immunity and increases in antitumor efficacy with type I interferon combination therapy.

Bacteria-based cancer therapy employs various strategies to combat tumors, one of which is delivering tumor-associated antigen (TAA) to generate specific immunity. Here, we utilized a poly-arginine extended HPV E7 antigen (9RE7) for attachment on Salmonella SL7207 outer membrane to synthesize the bacterial vaccine Salmonella-9RE7 (Sal-9RE7), which yielded a significant improvement in the amount of antigen presentation compared to the previous lysine-extended antigen coating strategy. In TC-1 tumor mouse models, Sal-9RE7 monotherapy decreased tumor growth by inducing E7 antigen-specific immunity. In addition, pairing Sal-9RE7 with adjuvant Albumin-IFNß (Alb-IFNß), a protein cytokine fusion, the combination significantly increased the antitumor efficacy and enhanced immunogenicity in the tumor microenvironment (TME). Our study made a significant contribution to personalized bacterial immunotherapy via TAA delivery and demonstrated the advantage of combination therapy.

Endogenous opioids gate the locus coeruleus pain generator.

The locus coeruleus (LC) plays a paradoxical role in chronic pain. Although largely known as a potent source of endogenous analgesia, increasing evidence suggests injury can transform the LC into a chronic pain generator. We sought to clarify the role of this system in pain. Here, we show optogenetic inhibition of LC activity is acutely antinociceptive. Following long-term spared nerve injury, the same LC inhibition is analgesic - further supporting its pain generator function. To identify inhibitory substrates that may naturally serve this function, we turned to endogenous LC mu opioid receptors (LC-MOR). These receptors provide powerful LC inhibition and exogenous activation of LC-MOR is antinociceptive. We therefore hypothesized that endogenous LC-MOR-mediated inhibition is critical to how the LC modulates pain. Using cell type-selective conditional knockout and rescue of LC-MOR receptor signaling, we show these receptors bidirectionally regulate thermal and mechanical hyperalgesia - providing a functional gate on the LC pain generator.

Impact of Genomic Alterations on the Clinical Outcome of Patients With Hepatitis B-related Hepatocellular Carcinoma Receiving Curative Surgery: A Retrospective Cohort Study.

BACKGROUND/AIM: The aim of the current study was to obtain comprehensive genomic information on viral hepatitis B (HBV)-related hepatocellular carcinoma (HCC) and identify potential biomarkers of early recurrence in patients receiving curative surgery. PATIENTS AND METHODS: A total of 104 patients with HBV-related HCC receiving curative surgery at Kaohsiung Chang Gung Memorial Hospital between January 2017 and December 2020 were identified, including 52 patients each with and without recurrence. Next-generation sequencing was performed to investigate genomic alterations caused by surgical resection of specimens. The Kaplan-Meier method was used to estimate disease-free survival and overall survival. RESULTS: The landscape of gene mutations in HCC patients of our cohort showed a median number of single nucleotide variants of 250, a median number of insertions and deletions of 22, and a median number of protein-coding mutations of 185. The 10 most frequently mutated genes were TP53 (43%), TTN (39%), MUC16 (28%), PCLO (25%), OBSCN (22%), ADGRV1 (19%), ALB (18%), SYNE1 (18%), DNAH17 (17%), and RYR1 (17%). The tumour mutation burden was 4.8 mutations per megabase, and high microsatellite instability was reported in only three patients. In addition, the mutational signatures showed that aristolochic acid exposure was highly implicated in our HCC cohort. Five mutant genes, TBC1D4, ITGA4, RPS6KA3, VWA8, and FMN2, were more frequent in the recurrence group than that in the non-recurrence group. CONCLUSION: Our results present an in-depth genomic analysis of HBV-related HCC. The study findings provide an improved understanding of the related molecular mechanisms and identify potential biomarkers associated with early tumour recurrence after curative resection.

Targeting Ras signaling excitability in cancer cells through combined inhibition of FAK and PI3K.

The Ras/PI3K/ERK signaling network is frequently mutated in various human cancers including cervical cancer and pancreatic cancer. Previous studies showed that the Ras/PI3K/ERK signaling network displays features of excitable systems including propagation of activity waves, all-or-none responses, and refractoriness. Oncogenic mutations lead to enhanced excitability of the network. A positive feedback loop between Ras, PI3K, the cytoskeleton, and FAK was identified as a driver of excitability. In this study, we investigated the effectiveness of targeting signaling excitability by inhibiting both FAK and PI3K in cervical and pancreatic cancer cells. We found that the combination of FAK and PI3K inhibitors synergistically suppressed the growth of select cervical and pancreatic cancer cell lines through increased apoptosis and decreased mitosis. In particular, FAK inhibition caused downregulation of PI3K and ERK signaling in cervical cancer but not pancreatic cancer cells. Interestingly, PI3K inhibitors activated multiple receptor tyrosine kinases (RTKs), including insulin receptor and IGF-1R in cervical cancer cells, as well as EGFR, Her2, Her3, Axl, and EphA2 in pancreatic cancer cells. Our results highlight the potential of combining FAK and PI3K inhibition for treating cervical and pancreatic cancer, although appropriate biomarkers for drug sensitivity are needed, and concurrent targeting of RTKs may be required for resistant cells.

Highly Active NiO-Ni(OH)2 -Cr2 O3 /Ni Hydrogen Evolution Electrocatalyst through Synergistic Reaction Kinetics.

High activity catalysts for hydrogen evolution reaction (HER) play a key role in converting renewable electricity to storable hydrogen fuel. Great effort has been devoted to the search for noble metal free catalysts to make electrolysis viable for practical applications. Here, a non-precious metal oxide/metal catalyst with high intrinsic activity comparable to Pt/C was reported. The electrocatalyst consisting of NiO, Ni(OH)2 , Cr2 O3 , and Ni metal exhibits a low overpotential of 27, 103, and 153 mV at current densities of 10, 100, and 200 mA cm-2 , respectively, in a 1.0 m NaOH electrolyte. The activity is much higher than that of NiOx /Ni or Cr2 O3 alone, showing the synergistic effect of NiOx /Ni and Cr2 O3 on catalyzing HER. Density functional theory calculations shows that NiO and Cr2 O3 on Ni surface lower the disassociation energy barrier for breaking H-OH bond, while Ni(OH)2 and Cr2 O3 create preferred sites on Ni surface with near-zero H* adsorption free energy to promote H* to gaseous H2 evolution. These synergistic effects of multiple-oxides/metal composition enhance the disassociation of H-OH and the evolution of H* to gaseous H2 , thus achieving high activity and demonstrating a promising composition design for noble metal free catalyst.

Comparing ChatGPT's ability to rate the degree of stereotypes and the consistency of stereotype attribution with those of medical students in New Zealand in developing a similarity rating test: a methodological study.

Learning about one's implicit bias is crucial for improving one's cultural competency and thereby reducing health inequity. To evaluate bias among medical students following a previously developed cultural training program targeting New Zealand Maori, we developed a text-based, self-evaluation tool called the Similarity Rating Test (SRT). The development process of the SRT was resource-intensive, limiting its generalizability and applicability. Here, we explored the potential of ChatGPT, an automated chatbot, to assist in the development process of the SRT by comparing ChatGPT's and students' evaluations of the SRT. Despite results showing non-significant equivalence and difference between ChatGPT's and students' ratings, ChatGPT's ratings were more consistent than students' ratings. The consistency rate was higher for non-stereotypical than for stereotypical statements, regardless of rater type. Further studies are warranted to validate ChatGPT's potential for assisting in SRT development for implementation in medical education and evaluation of ethnic stereotypes and related topics.

Case Report: Morbihan disease treated with tofacitinib successfully.

Introduction: To date, there is no standard treatment for Morbihan disease. Several studies have reported that Morbihan disease responds well to systemic corticosteroids (prednisone and prednisolone), systemic antibiotics (tetracyclines), antihistamines (ketotifen) and surgical therapy (Lymphaticovenous anastomosis). To our knowledge, Tofacitinib, as a Janus-activated kinase (JAK) inhibitor, plays a vital role in the treatment of inflammatory and autoimmune disorders. Therefore, Tofacitinib may be a promising medical option for patients with Morbihan disease. Case Presentation: The first case involves a 43-year-old Chinese man who presented a 12-month history of progressive painless swelling of the left upper eyelid. According to the skin biopsy, perivascular dermal edema with dilatation of lymphatic vessels and telangiectasia was observed, accompanied by mixed lymphocyte infiltrate, including histiocytes, plasma cells, and a few eosinophils. The second case involves a Chinese female patient who presented a 2-year history of progressive left-sided facial edema, which was eventually diagnosed as Morbihan disease. The skin biopsy revealed lymphocyte infiltration in the superficial vessels of dermis and some accessories. Based on patients' clinical presentation, skin biopsy results, and exclusion of differential diagnoses such as systemic lupus erythematosus (SLE), they were diagnosed with Morbihan disease. They were both treated with Tofacitinib (5mg, po twice daily). Outcomes: Patient 1 underwent a trial of Tofacitinib at a dosage of 5 mg twice daily for one month, with notable improvement. His edema and erythema present on the left face were alleviated. Patient 1 reduced the dosage of Tofacitinib by half (5mg, once daily) and continued using it for 5 months. During the 6-month follow-up, the facial erythema in the patient subsided, and there was a noticeable improvement in the swelling of the left eyelid compared to before. Patient 2, her lesions gradually improved after one-week treatment. She received a one-month treatment of Tofacitinib, and during the subsequent six-month follow-up, there was no evidence of eruption recurrence. Conclusion: We present the first cases of two patients receiving short-term Tofacitinib as therapy for Morbihan disease and retrieving huge succession. Tofacitinib may be a promising oral alternative for patients with Morbihan disease. However, its safety and efficacy require further assessment through clinical trials.