The formyl peptide receptors FPR1 and FPR2 as targets for inflammatory disorders: recent advances in the development of small-molecule agonists.

Formyl peptide receptors (FPRs) comprise a class of chemoattractant pattern recognition receptors, for which several physiological functions like host-defences, as well as the regulation of inflammatory responses, have been ascribed. With accumulating evidence that agonism of FPR1/FPR2 can confer pro-resolution of inflammation, increased attention from academia and industry has led to the discovery of new and interesting small-molecule FPR1/FPR2 agonists. Focused attention on the development of appropriate physicochemical and pharmacokinetic profiles is yielding synthesis of new compounds with promising in vivo readouts. This review presents an overview of small-molecule FPR1/FPR2 agonist medicinal chemistry developed over the past 20 years, with a particular emphasis on interrogation in the increasingly sophisticated bioassays which have been developed.

Multidisciplinary care improves outcomes for patients with carotid body paragangliomas-The UCLA experience.

Objective: To evaluate the effects and outcomes of multidisciplinary surgical approaches in the management of carotid body tumors (CBT). Methods: A single-center retrospective study at the University of California-Los Angeles Medical Center was conducted on patients who presented with CBTs and underwent surgical resections from 1998 to 2020. Statistical analysis was performed using IBM SPSS v27 and Excel. Results: A total of 75 patients with 79 CBT resections were included. Operating surgical subspecialties included: 41.8% vascular surgery, 24.1% otolaryngology head and neck surgeons (OHNS), and 31.6% combined OHNS and vascular. 68.4% of tumors underwent preoperative embolization. EBL was directly correlated with tumor size. CBT size was similar for OHNS (30 mm) and vascular (31 mm) but was significantly larger for combined OHNS and vascular cases (38 mm). EBL was higher in combined cases (301 mL) compared to OHNS (124 mL) or vascular (203 mL) alone. Incidence of postoperative cranial nerve deficits was 7.8%, with combined OHNS and vascular cases having an incidence of 4.0% when compared to OHNS (5.3%) versus vascular surgery alone (12.1%). Conclusion: CBTs can be managed effectively by single surgical specialties with similar outcomes between vascular surgery and OHNS. In larger, higher grade tumors, however, a combined vascular and OHNS approach had lower incidence of postoperative cranial nerve injuries when compared to single specialty resections, despite a larger EBL. Thus, a multidisciplinary surgical approach suggests favorable outcomes with fewer incidence of cranial nerve deficits for larger, more complex CBT resections. Level of Evidence: 2b-Individual retrospective cohort study.

A small molecule inhibitor of PTP1B and PTPN2 enhances T cell anti-tumor immunity.

The inhibition of protein tyrosine phosphatases (PTPs), such as PTP1B and PTPN2 that function as intracellular checkpoints, has emerged as an exciting new approach for bolstering T cell anti-tumor immunity to combat cancer. ABBV-CLS-484 is a dual PTP1B and PTPN2 inhibitor currently in clinical trials for solid tumors. Here we have explored the therapeutic potential of targeting PTP1B and PTPN2 with a related small molecule inhibitor, Compound 182. We demonstrate that Compound 182 is a highly potent and selective active site competitive inhibitor of PTP1B and PTPN2 that enhances antigen-induced T cell activation and expansion ex vivo and represses the growth of syngeneic tumors in C57BL/6 mice without promoting overt immune-related toxicities. Compound 182 repressed the growth of immunogenic MC38 colorectal and AT3-OVA mammary tumors as well as immunologically cold AT3 mammary tumors that are largely devoid of T cells. Treatment with Compound 182 increased both the infiltration and activation of T cells, as well as the recruitment of NK cells and B cells that promote anti-tumor immunity. The enhanced anti-tumor immunity in immunogenic AT3-OVA tumors could be ascribed largely to the inhibition of PTP1B/PTPN2 in T cells, whereas in cold AT3 tumors, Compound 182 elicited both direct effects on tumor cells and T cells to facilitate T cell recruitment and thereon activation. Importantly, treatment with Compound 182 rendered otherwise resistant AT3 tumors sensitive to anti-PD1 therapy. Our findings establish the potential for small molecule active site inhibitors of PTP1B and PTPN2 to enhance anti-tumor immunity and combat cancer.

A small molecule inhibitor of PTP1B and PTPN2 enhances T cell anti-tumor immunity.

The inhibition of protein tyrosine phosphatases 1B (PTP1B) and N2 (PTPN2) has emerged as an exciting approach for bolstering T cell anti-tumor immunity. ABBV-CLS-484 is a PTP1B/PTPN2 inhibitor in clinical trials for solid tumors. Here we have explored the therapeutic potential of a related small-molecule-inhibitor, Compound-182. We demonstrate that Compound-182 is a highly potent and selective active site competitive inhibitor of PTP1B and PTPN2 that enhances T cell recruitment and activation and represses the growth of tumors in mice, without promoting overt immune-related toxicities. The enhanced anti-tumor immunity in immunogenic tumors can be ascribed to the inhibition of PTP1B/PTPN2 in T cells, whereas in cold tumors, Compound-182 elicited direct effects on both tumor cells and T cells. Importantly, treatment with Compound-182 rendered otherwise resistant tumors sensitive to α-PD-1 therapy. Our findings establish the potential for small molecule inhibitors of PTP1B and PTPN2 to enhance anti-tumor immunity and combat cancer.

Population-based Long-term Outcomes for Squamous Cell Carcinoma of the Nasal Cavity.

BACKGROUND: This study evaluates population-based outcomes of patients with squamous cell carcinoma (SCC) of the nasal cavity treated in British Columbia. METHODS: A retrospective review of nasal cavity SCC treated from 1984 to 2014 was performed (n = 159). Locoregional recurrence (LRR) and overall survival (OS) were evaluated. RESULTS: The 3-year OS was 74.2% for radiation alone, 75.8% for surgery alone, and 78.4% for surgery and radiation ( P = 0.16). The 3-year LRR was 28.4% for radiation alone, 28.2% for surgery alone, and 22.6% for surgery and radiation ( P = 0.21). On multivariable analysis, surgery and postoperative radiation relative to surgery alone was associated with a lower risk of LRR (hazard ratio: 0.36, P = 0.03). Poor Eastern Cooperative Oncology Group status, node-positive, orbital invasion, smoking, and advanced age were associated with worse OS (all P <0.05). CONCLUSION: In this population-based analysis, multimodality treatment with surgery and adjuvant radiation were associated with improved locoregional control for SCC of the nasal cavity.

Novel Diarylthioether Compounds as Agents for the Treatment of Chagas Disease.

Herein, we describe the hit optimization of a novel diarylthioether chemical class found to be active against Trypanosoma cruzi; the parasite responsible for Chagas disease. The hit compound was discovered through a whole-cell phenotypic screen and as such, the mechanism of action for this chemical class is unknown. Our investigations led to clear structure-activity relationships and the discovery of several analogues with high in vitro potency. Furthermore, we observed excellent activity during acute in vivo efficacy studies in mice infected with transgenic T. cruzi. These diarylthioether compounds represent a promising new chemotype for Chagas disease drug discovery and merit further development to increase oral exposure without increasing toxicity.

Patient-Reported Outcomes in Adolescent and Young Adult Head and Neck Cancer Survivors Treated with Radiotherapy.

Purpose: There are few studies of adolescent and young adult (AYA) head and neck (H&N) cancer survivors treated with radiotherapy. A recall of AYA H&N survivors was performed and this article evaluates their cross-sectional patient-reported outcomes. Methods: AYA H&N cancer survivors who had received radiotherapy in British Columbia between 1970 and 2010 participated in this study. Participants completed the Psychosocial Screen for Cancer-Revised (PSSCAN-R), Research and Development (RAND)-36 health-related quality of life, and the Vanderbilt Head and Neck Symptom Survey, version 2.0 (VHNSS 2.0), to evaluate late effects from treatment. Results: There were 36 participants in the study. Severe symptoms (greater than or equal to 4/10) were reported on the VHNSS 2.0 by 51% of participants for xerostomia, 35% for dysphagia, and 37% for dental/mucosal sensitivity. On the PSSCAN-R, 35% had moderate/high anxiety scores and 48% had moderate/high depression scores. The mean RAND-36 participant scores were as follows: physical functioning, 86.1; physical role functioning, 71.4; emotional role functioning, 75.1; energy/fatigue, 56.6; emotional well-being, 74.6; social functioning, 76.3; bodily pain, 71.7; and general health, 65.6. Conclusions: AYA survivors in our study reported significant late effects from H&N radiotherapy and high depression and anxiety scores, but generally high health-related quality of life. Prospective evaluation of psychosocial needs and H&N-related complications is warranted in this subgroup at high risk of late effects from treatment.

Expressing antigen binding fragments with high titers in a targeted integration CHO host by optimizing expression vector gene copy numbers and position: A case study.

Antigen binding fragments (Fab) are a promising class of therapeutics as they maintain high potency while having significantly smaller size relative to full-length antibodies. Because Fab molecules are aglycosylated, many expression platforms, including prokaryotic, yeast, and mammalian cells, have been developed for their expression, with Escherichia coli being the most commonly used Fab expression system. In this study, we have examined production of a difficult to express Fab molecule in a targeted integration (TI) Chinese Hamster Ovary (CHO) host. Without a need for extensive host or process optimization, as is usually required for E. coli, by simply using different vector configurations, clones with very high Fab expression titers were obtained. In this case, by increasing heavy chain (HC) gene copy numbers, clones with titers of up to 7.4 g/L in the standard fed-batch production culture were obtained. Our findings suggest that having a predetermined transgene integration site, as well as the option to optimize gene copy number/dosage, makes CHO TI hosts an effective system for expression of Fab molecules, allowing Fab expression using platform process and without significant process development efforts.

A xenograft study of human adipose stromal cell-based vocal fold mucosal replacement in rabbits.

Objectives: Vocal fold (VF) scarring, manifested by increased collagen, decreased glycosaminoglycans (GAGs), and disrupted elastic fibers, remains a negative consequence of VF injury or resection. The objective of this study is to compare four reconstructive options after Vf mucosal resection in rabbits. A Cell-Based Outer Vocal fold Replacement (COVR) using human adipose-derived mesenchymal stromal cells (hASCs) in fibrin scaffold is directly compared with a decellularized scaffold implant, hASC injection, and resection alone without reconstruction. The primary hypothesis is that the cells-in-scaffold construct better reconstitutes the VF structure than either cells or scaffold alone, or than healing by secondary intention. Methods: A total of49 rabbits received bilateral VF cordectomy, followed by either COVR implant, decellularized scaffold implant, hASC injection, or no reconstruction (injured control group). Larynges were harvested after 6 weeks. Results: Histology demonstrated greater lamina propria thickness, less collagen deposition, and more GAGs in COVR animals versus all other treatment groups. Evidence of persistent human cells was found in about half of the cell-treated animals. RNA levels of fibrosis pathway and macrophage phenotype markers were statistically unchanged among treatment groups at 6 weeks. Conclusion: These data support the efficacy of COVR implantation in restoring VF microstructure in rabbits. The intact COVR was required; isolated components of decellularized scaffold or injected hASC still produced histologic scarring. We propose that the unique bilayered cell structure within fibrin enables controlled matrix remodeling to minimize wound contraction and fibrosis, and to promote GAG deposition. Level of Evidence: Basic science study.

A rapid and universal liquid chromatograph-mass spectrometry-based platform, refmAb-Q nSMOL, for monitoring monoclonal antibody therapeutics.

Accurate quantitation of antibodies is critical for development of monoclonal antibody therapeutics (mAbs). Therapeutic drug monitoring has been applied to measure levels of mAbs in clinics for dose adjustment for autoimmune disease. Trough levels of mAbs can be a biomarker for cancer immunotherapy. Thus, the deployment of a rapid and universal platform for mAb monitoring may benefit processes ranging from drug development to clinical practice for a wide spectrum of diseases. However, mAb monitoring often requires development and conduct of an individual ligand binding assay such as ELISA, which is impractical to scale. We streamlined quantitation of antibody therapeutics by a nano-surface and molecular-orientation limited (nSMOL) proteolysis assay using LC-MS with a universal reference antibody (refmAb-Q), for accurate multiplexed quantitation of unique signature peptides derived from mAbs. This innovative refmAb-Q nSMOL platform may provide a practical solution for quantitating an ever-increasing number of mAbs from developmental to clinical use settings.

Cluster analysis unveils a severe persistent respiratory impairment phenotype 3-months after severe COVID-19.

BACKGROUND: The mid-term respiratory sequelae in survivors of severe COVID-19 appear highly heterogeneous. In addition, factors associated with respiratory sequelae are not known. In this monocentric prospective study, we performed a multidisciplinary assessment for respiratory and muscular impairment and psychological distress 3 months after severe COVID-19. We analysed factors associated with severe persistent respiratory impairment, amongst demographic, COVID-19 severity, and 3-month assessment. METHODS: Patients with severe SARS-CoV-2 pneumonia requiring ≥ 4L/min were included for a systematic 3-month visit, including respiratory assessment (symptoms, lung function, CT scan), muscular evaluation (body composition, physical function and activity, disability), psychopathological evaluation (anxiety, depression, post-traumatic stress disorder-PTSD) and quality of life. A cluster analysis was performed to identify subgroups of patients based on objective functional measurements: DLCO, total lung capacity and 6-min walking distance (6MWD). RESULTS: Sixty-two patients were analysed, 39% had dyspnea on exercise (mMRC ≥ 2), 72% had DLCO < 80%, 90% had CT-scan abnormalities; 40% had sarcopenia/pre-sarcopenia and 31% had symptoms of PTSD. Cluster analysis identified a group of patients (n = 18, 30.5%) with a severe persistent (SP) respiratory impairment (DLCO 48 ± 12%, 6MWD 299 ± 141 m). This SP cluster was characterized by older age, severe respiratory symptoms, but also sarcopenia/pre-sarcopenia, symptoms of PTSD and markedly impaired quality of life. It was not associated with initial COVID-19 severity or management. CONCLUSIONS AND CLINICAL IMPLICATION: We identified a phenotype of patients with severe persistent respiratory and muscular impairment and psychological distress 3 months after severe COVID-19. Our results highlight the need for multidisciplinary assessment and management after severe SARS-CoV-2 pneumonia. Trial registration The study was registered on ClinicalTrials.gov (May 6, 2020): NCT04376840.

Neoantigen-Specific T Cells in Adoptive Cell Therapy.

ABSTRACT: The holy grail of cancer therapeutics is the destruction of cancer cells while avoiding harm to normal cells. Cancer is unique from normal tissues because of the presence of somatic mutations that accumulate during tumorigenesis. Some nonsynonymous mutations can give rise to mutated peptide antigens (hereafter referred to as neoantigens) that can be specifically recognized by T cells. Thus, the immunological targeting of neoantigens represents a safe and promising strategy to treat patients with cancer. This article reviews the clinical application of adoptive cell therapy targeting neoantigens in patients with epithelial cancers.

Simplified Lung Ultrasound Examination and Telehealth Feasibility in Early SARS-CoV-2 Infection.

BACKGROUND: In COVID-19, inpatient studies have demonstrated that lung ultrasound B-lines relate to disease severity and mortality and can occur in apical regions that can be imaged by patients themselves. However, as illness begins in an ambulatory setting, the aim of this study was to determine the prevalence of apical B-lines in early outpatient infection and then test the accuracy of their detection using telehealth and automated methods. METHODS: Consecutive adult patients (N = 201) with positive results for SARS-CoV-2, at least one clinical risk factor, and mild to moderate disease were prospectively enrolled at a monoclonal antibody infusion clinic. Physician imaging of the lung apices for three B-lines (ultrasound lung comet [ULC]) using 3-MHz ultrasound was performed on all patients for prevalence data and served as the standard for a nested subset (n = 50) to test the accuracy of telehealth methods, including patient self-imaging and automated B-line detection. Patient characteristics, vaccination data, and hospitalizations were analyzed for associations with the presence of ULC. RESULTS: Patients' mean age was 54 ± 15 years, and all lacked hypoxemia or fever. ULC was present in 55 of 201 patients (27%) at a median of 7 symptomatic days (interquartile range, 5-8 days) and in four of five patients who were later hospitalized (P = .03). Presence of ULC was associated with unvaccinated status (odds ratio [OR], 4.11; 95% CI, 1.85-9.33; P = .001), diabetes (OR, 2.56; 95% CI, 1.08-6.05; P = .03), male sex (OR, 2.14; 95% CI, 1.07-4.37; P = .03), and hypertension or cardiovascular disease (OR, 2.06; 95% CI, 1.02-4.23; P = .04), while adjusting for body mass index > 25 kg/m2. Telehealth and automated B-line detection had 84% and 82% accuracy, respectively. CONCLUSIONS: In high-risk outpatients, B-lines in the upper lungs were common in early SARS-CoV-2 infection, were related to subsequent hospitalization, and could be detected by telehealth and automated methods.

Neoantigen T-Cell Receptor Gene Therapy in Pancreatic Cancer.

A patient with progressive metastatic pancreatic cancer was treated with a single infusion of 16.2×109 autologous T cells that had been genetically engineered to clonally express two allogeneic HLA-C*08:02-restricted T-cell receptors (TCRs) targeting mutant KRAS G12D expressed by the tumors. The patient had regression of visceral metastases (overall partial response of 72% according to the Response Evaluation Criteria in Solid Tumors, version 1.1); the response was ongoing at 6 months. The engineered T cells constituted more than 2% of all the circulating peripheral-blood T cells 6 months after the cell transfer. In this patient, TCR gene therapy targeting the KRAS G12D driver mutation mediated the objective regression of metastatic pancreatic cancer. (Funded by the Providence Portland Medical Foundation.).

[Management of suicidal crisis in general practice: evaluation of care practices according to patient age]. / Crise suicidaire, évaluation des pratiques en médecine générale selon l'âge du patient.

Nearly 800,000 people die by suicide each year worldwide. Up to 75% of suicidal patients consulted their general practitioner in the months preceding their attempt. A study, conducted among 167 practitioners in Champagne-Ardenne in 2016-2017, aims to evaluate the practices of general practitioners in the management of suicidal crisis, particularly according to the age of the patient. It provides elements for reflection on their role in suicide prevention.

T Cells Engineered to Express Immunoreceptors Targeting the Frequently Expressed Medullary Thyroid Cancer Antigens Calcitonin, CEA, and RET M918T.

Background: Medullary thyroid cancer (MTC) is a rare malignancy originating from the calcitonin-producing C cells of the thyroid. Despite recent therapeutic advances, metastatic MTC remains incurable. Adoptive cell therapy (ACT) using genetically engineered T cells targeting either tissue-restricted tumor-associated antigens or mutated neoantigens has led to durable remissions in other metastatic solid tumors. The majority of MTC express the tumor-associated antigens calcitonin and carcinoembryonic antigen (CEA), and ∼40% of MTC harbor the RET M918T oncogenic driver mutation. Methods: We developed and characterized three immunoreceptors that recognize extracellular CEA, a calcitonin epitope presented by HLA-A*24:02, or an RET M918T neoepitope restricted by HLA-DPB1*04:01/02. The chimeric antigen receptor (CAR) targeting CEA was synthetically designed, while the T cell receptors (TCRs) targeting calcitonin and RET M918T were isolated from a transgenic mouse and patient with MTC, respectively. These immunoreceptors were genetically engineered into peripheral blood T cells and tested for antigen specificity and antitumor activity. Results: T cells expressing the anti-CEA CAR or the calcitonin-reactive TCR produced effector cytokines and displayed cytotoxicity against cell lines expressing their cognate antigen in vitro. In immunodeficient mice harboring a human MTC cell line, the adoptive transfer of T cells engineered to express the anti-CEA CAR or calcitonin-reactive TCR led to complete tumor regression. T cells expressing the HLA-DPB1*04:01/02-restricted TCR targeting RET M918T, which was cloned from peripheral blood CD4+ T cells of a patient with MTC, demonstrated specific reactivity against cells pulsed with the mutated peptide and MTC tumor cells that expressed HLA-DPB1*04:01 and RET M918T. Conclusion: The preclinical data presented herein demonstrate the potential of using genetically engineered T cells targeting CEA, calcitonin, and/or RET M918T to treat metastatic MTC.

Transcriptomic profiles of neoantigen-reactive T cells in human gastrointestinal cancers.

Tumor-infiltrating neoantigen-reactive T cells can mediate regression of metastatic gastrointestinal cancers yet remain poorly characterized. We performed immunological screening against personalized neoantigens in combination with single-cell RNA sequencing on tumor-infiltrating lymphocytes from bile duct and pancreatic cancer patients to characterize the transcriptomic landscape of neoantigen-reactive T cells. We found that most neoantigen-reactive CD8+ T cells displayed an exhausted state with significant CXCL13 and GZMA co-expression compared with non-neoantigen-reactive bystander cells. Most neoantigen-reactive CD4+ T cells from a patient with bile duct cancer also exhibited an exhausted phenotype but with overexpression of HOPX or ADGRG1 while lacking IL7R expression. Thus, neoantigen-reactive T cells infiltrating gastrointestinal cancers harbor distinct transcriptomic signatures, which may provide new opportunities for harnessing these cells for therapy.

PD-1 and ICOS coexpression identifies tumor-reactive CD4+ T cells in human solid tumors.

CD4+ Th cells play a key role in orchestrating immune responses, but the identity of the CD4+ Th cells involved in the antitumor immune response remains to be defined. We analyzed the immune cell infiltrates of head and neck squamous cell carcinoma and colorectal cancers and identified a subset of CD4+ Th cells distinct from FOXP3+ Tregs that coexpressed programmed cell death 1 (PD-1) and ICOS. These tumor-infiltrating lymphocyte CD4+ Th cells (CD4+ Th TILs) had a tissue-resident memory phenotype, were present in MHC class II-rich areas, and proliferated in the tumor, suggesting local antigen recognition. The T cell receptor repertoire of the PD-1+ICOS+ CD4+ Th TILs was oligoclonal, with T cell clones expanded in the tumor, but present at low frequencies in the periphery. Finally, these PD-1+ICOS+ CD4+ Th TILs were shown to recognize both tumor-associated antigens and tumor-specific neoantigens. Our findings provide an approach for isolating tumor-reactive CD4+ Th TILs directly ex vivo that will help define their role in the antitumor immune response and potentially improve future adoptive T cell therapy approaches.