Effect of Ibuprofen as an Albumin Binder on Melanoma-Targeting Properties of Lu-Labeled Ibuprofen-Conjugated Alpha-Melanocyte-Stimulating Hormone Peptides.

The purpose of this study was to examine how the introduction of ibuprofen (IBU) affected tumor-targeting and biodistribution properties of Lu-labeled IBU-conjugated alpha-melanocyte-stimulating hormone peptides. The IBU was used as an albumin binder and conjugated to the DOTA-Lys moiety without or with a linker to yield DOTA-Lys(IBU)-GG-Nle-CycMSH {1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-Lys(IBU)-Gly-Gly-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH}, DOTA-Lys(Asp-IBU)-GGNle-CycMSH, DOTA-Lys(Asn-IBU)-GGNle-CycMSH, and DOTA-Lys(Dab-IBU)-GGNle-CycMSH peptides. Their melanocortin-receptor 1 (MC1R) binding affinities were determined on B16/F10 melanoma cells first.

A phase 1 study of triple-targeted therapy with BRAF, MEK, and AKT inhibitors for patients with BRAF-mutated cancers.

Background: Aberrant PI3K/AKT signaling in BRAF-mutant cancers contributes to resistance to BRAF inhibitors. The authors examined dual MAPK and PI3K pathway inhibition in patients who had BRAF-mutated solid tumors (ClinicalTrials.gov identifier NCT01902173).

Health-Related Quality of Life with Pembrolizumab in Patients with Locally Advanced or Recurrent or Metastatic Cutaneous Squamous Cell Carcinoma: KEYNOTE-629.

Introduction: At first interim analysis of KEYNOTE-629, health-related quality of life (HRQoL) with pembrolizumab was stable or improved over 48 weeks in recurrent or metastatic (R/M) cutaneous squamous cell carcinoma (cSCC). HRQoL results from the second interim analysis in R/M or locally advanced (LA) cSCC are presented.

Methods: Patients received pembrolizumab 200 mg every 3 weeks for ≤ 2 years.

Introduction of a Polyethylene Glycol Linker Improves Uptake of Cu-NOTA-Conjugated Lactam-Cyclized Alpha-Melanocyte-Stimulating Hormone Peptide in Melanoma.

The aim of this study was to evaluate the effect of linker on tumor targeting and biodistribution of Cu-NOTA-PEGNle-CycMSH {Cu-1,4,7-triazacyclononane-1,4,7-triyl-triacetic acid-polyethylene glycol-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH} and Cu-NOTA-GGNle-CycMSH {Cu-NOTA-GlyGlyNle-CycMSH} on melanoma-bearing mice. NOTA-PEGNle-CycMSH and NOTA-GGNle-CycMSH were synthesized and purified by HPLC. The biodistribution of Cu-NOTA-PEGNle-CycMSH and Cu-NOTA-GGNle-CycMSH was determined in B16/F10 melanoma-bearing C57 mice.

Effects of Polyethylene Glycol and 8-Aminooctanoic Acid Linkers on Melanoma Uptake of [Tc]Tc-Tricarbonyl-NOTA-Conjugated Lactam-Cyclized α-MSH Peptides.

The purpose of this study was to evaluate the effect of linkers on tumor targeting and biodistribution of [Tc]Tc(CO)-NOTA-PEGNle-CycMSH {[Tc]Tc(CO)-1,4,7-triazacyclononane-1,4,7-triyl-triacetic acid-polyethylene glycol-Nle-c[Asp-His-d-Phe-Arg-Trp-Lys]-CONH} and [Tc]Tc(CO)-NOTA-AocNle-CycMSH {[Tc]Tc(CO)-NOTA-8-aminooctanoic acid-Nle-CycMSH} on B16/F10 melanoma-bearing mice. NOTA-PEGNle-CycMSH and NOTA-AocNle-CycMSH were synthesized and radiolabeled with [Tc]Tc via the {[Tc]Tc(CO)(OH)} intermediate. The biodistribution of [Tc]Tc(CO)-NOTA-PEGNle-CycMSH and [Tc]Tc(CO)-NOTA-AocNle-CycMSH was determined on B16/F10 melanoma-bearing C57 mice.

The interaction of the oxytocin receptor gene and child abuse subtypes on social cognition in euthymic patients with bipolar disorder type I.

Background: Most studies on cognitive impairment in bipolar disorder have neglected the role of early stress, despite the high frequency of childhood maltreatment in this clinical group. The aim of this study was to establish a connection between a history of emotional, physical, and sexual abuse in childhood and social cognition (SC) in patients with bipolar disorder type I (BD-I) in euthymia, and to test a possible moderating effect of the single nucleotide polymorphism in the oxytocin receptor gene ().

Methods: One hundred and one participants were included in this study.

Targeting MDSC Differentiation Using ATRA: A Phase I/II Clinical Trial Combining Pembrolizumab and All-Trans Retinoic Acid for Metastatic Melanoma.

Purpose: A phase Ib/II clinical trial was conducted to evaluate the safety and efficacy of the combination of all-trans retinoic acid (ATRA) with pembrolizumab in patients with stage IV melanoma.

Patients And Methods: Anti-PD-1 naïve patients with stage IV melanoma were treated with pembrolizumab plus supplemental ATRA for three days surrounding each of the first four pembrolizumab infusions. The primary objective was to establish the MTD and recommended phase II dose (RP2D) of the combination.

Novel Cu-Labeled NOTA-Conjugated Lactam-Cyclized Alpha-Melanocyte-Stimulating Hormone Peptides with Enhanced Tumor to Kidney Uptake Ratios.

The aim of this study was to evaluate the effect of linker on tumor targeting and biodistribution of Cu-NOTA-PEGNle-CycMSH {Cu-1,4,7-triazacyclononane-1,4,7-triyl-triacetic acid-polyethylene glycol-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH} and Cu-NOTA-AocNle-CycMSH {Cu-NOTA-8-aminooctanoic acid-Nle-CycMSH} on melanoma-bearing mice. NOTA-PEGNle-CycMSH and NOTA-AocNle-CycMSH were synthesized and purified by HPLC. The melanocortin-1 (MC1) receptor binding affinities of the peptides were examined on B16/F10 melanoma cells.

Novel AlF-NOTA-Conjugated Lactam-Cyclized α-Melanocyte-Stimulating Hormone Peptides with Enhanced Melanoma Uptake.

The purpose of this study was to evaluate the effect of linker on tumor targeting and biodistribution of AlF-NOTA-PEGNle-CycMSH {AlF-1,4,7-triazacyclononane-1,4,7-triyl-triacetic acid-poly(ethylene glycol)-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH} and AlF-NOTA-AocNle-CycMSH {AlF-NOTA-8-aminooctanoic acid-Nle-CycMSH} on melanoma-bearing mice. NOTA-PEGNle-CycMSH and NOTA-AocNle-CycMSH were synthesized using fluorenylmethoxycarbonyl (Fmoc) chemistry. The melanocortin-1 (MC1) receptor binding affinities of the peptides were determined on B16/F10 melanoma cells.

Polymorphisms in Schizophrenia-Related Genes Are Potential Predictors of Antipsychotic Treatment Resistance and Refractoriness.

Background: Approximately 30% of individuals with schizophrenia (SZ) are resistant to conventional antipsychotic drug therapy (AP). Of these, one-third are also resistant to the second-line treatment, clozapine. Treatment resistance and refractoriness are associated with increased morbidity and disability, making timely detection of these issues critical.

Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma.

Purpose: In the phase III CheckMate 067 trial, durable clinical benefit was demonstrated previously with nivolumab plus ipilimumab and nivolumab alone versus ipilimumab. Here, we report 6.5-year efficacy and safety outcomes.

The Effect of Albumin-Binding Moiety on Tumor Targeting and Biodistribution Properties of Ga-Labeled Albumin Binder-Conjugated Alpha-Melanocyte-Stimulating Hormone Peptides.

The purpose of this study was to examine the effect of 4--(tolyl)butyric acid as an albumin-binding (ALB) moiety on tumor targeting and biodistribution properties of Ga-labeled albumin binder-conjugated alpha-melanocyte-stimulating hormone peptides. DOTA-Lys(ALB)-G/GG/GGG-Nle-CycMSH {1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-Lys(ALB)-Gly/GlyGly/GlyGlyGly-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH} were synthesized with 4--(tolyl)butyric acid serving as an ALB moiety. The melanocortin-1 receptor (MC1R)-binding affinities of the peptides were determined on B16/F10 melanoma cells.

Adjuvant Therapy for Stage III Melanoma Without Immediate Completion Lymph Node Dissection.

Introduction: For patients with stage III melanoma with occult lymph node metastasis, the use of adjuvant therapy is increasing, and completion lymph node dissection (CLND) is decreasing. We sought to evaluate the use of modern adjuvant therapy and outcomes for patients with stage III melanoma who did not undergo CLND.

Methods: Patients with a positive SLNB from 2015 to 2020 who did not undergo CLND were evaluated retrospectively.

Overcoming PD-1 Blockade Resistance with CpG-A Toll-Like Receptor 9 Agonist Vidutolimod in Patients with Metastatic Melanoma.

Unlabelled: Patients with advanced melanoma that is resistant to PD-1 blockade therapy have limited treatment options. Vidutolimod (formerly CMP-001), a virus-like particle containing a CpG-A Toll-like receptor 9 (TLR9) agonist, may reverse PD-1 blockade resistance by triggering a strong IFN response to induce and attract antitumor T cells. In the dose-escalation part of this phase Ib study, vidutolimod was administered intratumorally at escalating doses with intravenous pembrolizumab to 44 patients with advanced melanoma who had progressive disease or stable disease on prior anti-PD-1 therapy.

Myeloid arginase-1 controls excessive inflammation and modulates T cell responses in Pseudomonas aeruginosa pneumonia.

Regulatory properties of macrophages associated with alternative activation serve to limit the exaggerated inflammatory response during pneumonia caused by Pseudomonas aeruginosa infection. Arginase-1 is an important effector of these macrophages believed to play an essential role in decreasing injury and promoting repair. We investigated the role of arginase-1 in the control of inflammatory immune responses to P.

Safety and efficacy of combination nivolumab plus ipilimumab in patients with advanced melanoma: results from a North American expanded access program (CheckMate 218).

CheckMate 218, a North American expanded access program (EAP), investigated nivolumab plus ipilimumab in patients with advanced melanoma. Safety and efficacy, including 2-year survival in clinically relevant patient subgroups, are reported. Eligible patients were aged ≥18 years with unresectable stage III/IV melanoma, an Eastern Cooperative Oncology Group performance status of 0/1, and no prior checkpoint inhibitors.

Facile preparation of a novel Ga-67-labeled NODAGA-conjugated lactam-cyclized alpha-MSH peptide at room temperature for melanoma targeting.

In this study, the melanoma targeting property of Ga-NODAGA-GGNle-CycMSH {1,4,7-triazacyclononane,1-gluteric acid-4,7-acetic acid-GlyGlyNle-c[Asp-His-D-Phe-Arg-Trp-Lys]-CONH} was determined on B16/F10 melanoma-bearing C57 mice to demonstrate the feasibility of NODAGA as a radiometal chelator for facile room temperature radiolabeling of NODAGA-GGNle-CycMSH. The IC value of NODAGA-GGNle-CycMSH was 0.87 ± 0.

Studying Immunotherapy Resistance in a Melanoma Autologous Humanized Mouse Xenograft.

Resistance to immunotherapy is a significant challenge, and the scarcity of human models hinders the identification of the underlying mechanisms. To address this limitation, we constructed an autologous humanized mouse (aHM) model with hematopoietic stem and progenitor cells (HSPC) and tumors from 2 melanoma patients progressing to immunotherapy. Unlike mismatched humanized mouse (mHM) models, generated from cord blood-derived HSPCs and tumors from different donors, the aHM recapitulates a patient-specific tumor microenvironment (TME).

Whole-genome sequencing of acral melanoma reveals genomic complexity and diversity.

To increase understanding of the genomic landscape of acral melanoma, a rare form of melanoma occurring on palms, soles or nail beds, whole genome sequencing of 87 tumors with matching transcriptome sequencing for 63 tumors was performed. Here we report that mutational signature analysis reveals a subset of tumors, mostly subungual, with an ultraviolet radiation signature. Significantly mutated genes are BRAF, NRAS, NF1, NOTCH2, PTEN and TYRP1.

[History of child abuse among patients with bipolar disorders].

Background: A history of child abuse is common and has a significant impact in the clinical course of patients diagnosed with bipolar disorders (BD).

Aims: To assess the frequency of child abuse experiences in patients BD type I and to evaluate its association with clinical course and cognitive functioning variables.

Material And Methods: 117 patients with BD aged 45 ± 14 years (66% women) answered the Childhood Trauma Questionnaire (CTQ).

A Portable Fuzzy Driver Drowsiness Estimation System.

The adequate automatic detection of driver fatigue is a very valuable approach for the prevention of traffic accidents. Devices that can determine drowsiness conditions accurately must inherently be portable, adaptable to different vehicles and drivers, and robust to conditions such as illumination changes or visual occlusion. With the advent of a new generation of computationally powerful embedded systems such as the Raspberry Pi, a new category of real-time and low-cost portable drowsiness detection systems could become standard tools.

Pre-Treatment Mutational and Transcriptomic Landscape of Responding Metastatic Melanoma Patients to Anti-PD1 Immunotherapy.

Immunotherapy, such as anti-PD1, has improved the survival of patients with metastatic melanoma. However, predicting which patients will respond to immunotherapy remains a significant knowledge gap. In this study we analyzed pre-immunotherapy treated tumors from 52 patients with metastatic melanoma and monitored their response based on RECIST 1.