NK1 Receptor Research Articles

Possibilities of prevention of nausea during cytostatic therapy: literature review and clinical cases

Chemotherapy-induced nausea and vomiting (CINV) is a side effect of cancer treatment, affecting up to 40% of patients. Nausea and vomiting are the most dangerous and also the most common side effects among patients undergoing chemotherapy. CINV remains one of the most worrisome syndromes associated with cancer therapy and can lead to dehydration, electrolyte imbalances, malnutrition, and metabolic disorders. Risk factors for developing CINV include the patient’s gender and age, a history of CINV, and the emetogenicity and timing of chemotherapy. Options for preventing CINV are 5-HT3 receptor antagonists (i.e., ondansetron, granisetron, palonosetron) in combination with corticosteroids (i.e., dexamethasone) or additionally in combination with NK1 receptor antagonists (i.e., aprepitant, fosaprepitant, netupitant, rolapitant). Palonosetron is a selective 5-hydroxytryptamine 3 (5-HT3) receptor antagonist. The effectiveness of palonosetron for delayed nausea and vomiting is also supported by the results of three randomized trials that demonstrated no side effects of the simplified regimen with palonosetron and single dose dexamethasone for the control of CINV associated with moderately emetogenic chemotherapy or AC regimen. A clinical observation of the treatment of a young patient with breast cancer is given. After the first course of chemotherapy, the patient developed a rather serious complication in the form of vomiting, which required hospitalization for infusion therapy. The above clinical observation demonstrates the effectiveness of palonosetron in neo-adjuvant chemotherapy in a young patient, which made it possible to complete the entire course of treatment. After completion of neo-adjuvant chemotherapy, a radical operation was performed and a complete morphological response was noted.

Effect of GR205171 on autonomic dysreflexia induced by colorectal distension in spinal cord injured rats.

Preclinical pharmacology. To determine whether blocking substance P signaling attenuates the hypertension and bradycardia evoked by colorectal distension (CRD) in spinal cord injured (SCI) rats. University laboratory in Pennsylvania, U.S.A. Tachykinin NK1 receptor antagonists were administered 30 min prior to CRD three weeks after complete spinal cord transection at the 4th thoracic (T4) level. The dose range, route of administration, and pretreatment time was based on published data demonstrating occupancy of brain NK1 receptors in rodents. Subcutaneous (SC) administration of 10-30 mg/kg GR205171 ((2S,3S)-N-[[2-methoxy-5-[5-(trifluoromethyl)tetrazol-1-yl]phenyl]methyl]-2-phenylpiperidin-3-amine dihydrochloride) reduced CRD-induced hypertension and bradycardia by 55 and 49%, respectively, compared with pretreatment values. There was no effect of GR205171 on resting blood pressure or heart rate. In contrast, the same dose range of CP-99,994 ((2S,3S)-N-[(2-methoxyphenyl)methyl]-2-phenyl-3-piperidinamine dihydrochloride) had no effect on CRD-induced cardiovascular responses. The effective dose range of GR205171 to alleviate autonomic dysreflexia is consistent with the blockade of NK1 receptors on pelvic sensory afferents in the lumbosacral spinal cord, which may in turn prevent the over-excitation of sympathetic preganglionic neurons (SPNs) that regulate blood pressure and heart rate. The findings provide preclinical support for the utility of NK1 receptor antagonists to treat autonomic dysreflexia in people with SCI. The difference in the effects of the two NK1 receptor antagonists may reflect the ~200-fold lower affinity of CP-99,994 than GR205171 for the rat NK1 receptor.

Efficacy and safety of pharmacotherapy for refractory or unexplained chronic cough: a systematic review and network meta-analysis

Refractory chronic cough (RCC) has a significant impact on patient's health-related quality of life and represents a challenge in clinical management. However, the optimal treatment for RCC remains controversial. This study aimed to investigate and compare the efficacy and safety of the current pharmacological therapeutic options for RCC. A systematic review was performed by searching PubMed, Web of Science, Embase, and Ovid databases from January 1, 2008 to March 1, 2023. All randomised control trials (RCTs) reporting outcomes of efficacy or/and safety were included in the Bayesian network meta-analysis. Here, we compared the effects on Leicester Cough Questionnaire (LCQ), Visual Analogue Scale (VAS), and objective cough frequency of patients with RCC. Besides, we also compared the incidence of adverse events (AEs) for analysis of safety. PROSPERO registration: CRD42022345940. 19 eligible RCTs included 3326 patients and 7 medication categories: P2X3 antagonist, GABA modulator, Transient Receptor Potential (TRP) modulator, NK-1 agonist, opioid analgesic, macrolide, and sodium cromoglicate. Compared with placebo, mean difference (MD) of LCQ and 24 h cough frequency for P2X3 antagonist relief were 1.637 (95% CI: 0.887-2.387) and-11.042 (P=0.035). Compared with placebo, effect sizes (MD for LCQ and cough severity VAS) for GABA modulator were 1.347 (P=0.003) and-7.843 (P=0.003). In the network meta-analysis, gefapixant is the most effective treatment for patients with RCC (The Surface Under the Cumulative Ranking Curves (SUCRA) is 0.711 in LCQ, 0.983 in 24 h cough frequency, and 0.786 in cough severity VAS). Lesogaberan had better efficacy than placebo (SUCRA: 0.632 vs. 0.472) in 24 h cough frequency. Eliapixant and lesogaberan had better efficacy than placebo in cough severity VAS. However, TRP modulator had worse efficacy than placebo. In the meta-analysis of AEs, the present study found P2X3 antagonist had a significant correlation to AEs (RR: 1.129, 95% CI: 1.012-1.259), especially taste-related AEs (RR: 6.216, P<0.05). In this network meta-analysis, P2X3 antagonist showing advantages in terms of efficacy is currently the most promising medication for treatment of RCC. GABA modulator also showed potential efficacy for RCC but with AEs of the central system. Nevertheless, the role of TRP modulator needed to be revisited. Further research is needed to determine the potential beneficiary population for optimizing the pharmacological management of chronic cough. National Natural Science Foundation of China (81870079), Guangdong Science and Technology Project (2021A050520012), Incubation Program of National Science Foundation for Distinguished Young Scholars (GMU2020-207).

Association of killer cell immunoglobulin-like receptors and their cognate HLA class I ligands with susceptibility to acute myeloid leukemia in Iranian patients

Acute myeloid leukemia (AML) is one of the most prevalent leukemia in adults. Among the various NK receptors, killer immunoglobulin-like receptors (KIRs) carry out indispensable roles in NK cell development and function through engaging with class I human leukocyte antigens (HLA-I) as their ligands. Besides divergent KIR and HLA loci, KIR/HLA-I combinations have a significant effect on NK cell response. In this case–control study, we aimed to verify the association of KIR/HLA-I combinations with susceptibility to AML in the Southwestern Iranian population. KIR and HLA genotyping was performed with PCR-SSP by some novel primers for 181 patients with AML and 181 healthy controls. According to our results, the frequencies of KIR3DS1 (p = 0.0001, OR = 2.32, 95% CI 1.51–3.58), KIR2DS4fl (p = 0.02, OR = 1.53, 95% CI 1.05–2.21), CxT4 genotypes (p = 0.03, OR = 2.0, 95% CI 1.05–3.82), and T4 gene cluster (p = 0.01, OR = 1.99, 95% CI 1.17–3.41) were significantly higher in patients than controls, while C1/C2 genotype (p = 0.00002, OR = 0.39, 95% CI 0.25–0.61), HLA-A Bw4 (p = 0.02, OR = 0.6, 95% CI 0.38–0.94), and HLA-A*11 (p = 0.03, OR = 0.57, 95% CI 0.34–0.95) alleles were more frequent in controls. In addition, inhibitory (i)KIR/HLA-I combinations analysis revealed higher frequencies of KIR2DL1( +)/HLA-C2( +), KIR2DL2/3( +)/HLA-C1( +), KIR3DL1( +)/HLA-A Bw4( +), and KIR3DL2( +)/HLA-A*03/11( +) in the control group (p = 0.002, OR = 0.49, 95% CI 0.3–0.78; p = 0.04, OR = 0.62, 95% CI 0.39–0.99; p = 0.04, OR = 0.63, 95% CI 0.4–0.99; and p = 0.03, OR = 0.62, 95% CI 0.4–0.95, respectively). Overall, the number of iKIR/HLA-I combinations was more in the control group. Moreover, KIR3DS1( +)/HLA-B Bw4Ile80( +) and the sum of HLA-B Bw4/A Bw4 combined with KIR3DS1 as activating KIR/HLA-I combinations were more frequent among patients than controls (p = 0.01, OR = 1.99, 95% CI 1.14–3.49 and p = 0.005, OR = 1.97, 95% CI 1.22–3.19, respectively). In conclusion, our results postulate that inhibitory combinations play a protective role against AML by developing potent NK cells during education. It is noteworthy that KIR/HLA-I combination studies can be applicable in donor selection for allogeneic NK cell therapy in hematological malignancies.

Prolonged usage of fosaprepitant for prevention of delayed chemotherapy-induced nausea and vomiting(CINV) in patients receiving highly emetogenic chemotherapy

BackgroundEven though chemotherapy-induced nausea and vomiting (CINV) can be well controlled in the acute phase, the incidence of delayed CINV remains high. In this study, we intend to investigate whether prolonged use of NK-1 receptor antagonist (RA) in addition to 5-HT3 RA and dexamethasone (DEX) was more effective in preventing delayed CINV.MethodsThis randomised, open-label, controlled study was designed to compare the efficacy and safety of fosaprepitant 150 mg given on days 1,3 (prolonged group) versus on day 1 (regular group) in patients receiving highly emetogenic chemotherapy (HEC). All patients also treated with palonosetron on day 1 and DEX on days 1–3. The primary endpoint was the incidence of delayed nausea and vomiting. The second endpoint was AEs. All the above endpoints were defined according to CTCAE 5.0.ResultsSeventy-seven patients were randomly assigned to prolonged group and seventy-nine to regular group. Prolonged group demonstrated superiority in controlling delayed CINV to regular group, with statistically significant lower incidence of nausea (6.17% vs 12.66%, P = 0.0056), and slightly lower incidence of grade 1 vomiting (1.62% vs 3.80%, P = 0.0953) in the delayed phase. In addition, prolonged use of fosaprepitant was safe. No significant difference was found between the two groups regarding constipation, diarrhea, hiccough, fatigue, palpitation and headache in delayed phase.ConclusionsProlonged use of fosaprepitant can effectively and safely prevent delayed CINV in patients receiving HEC.

Systematized review of the literature on postoperative nausea and vomiting

Introduction: Postoperative nausea and vomiting (PONV) is the most common adverse effect, after postoperative pain, with an incidence of 31.1% to 80%, which increases pain, favors broncho aspiration, wound dehiscence, and hematoma formation. Methodology: Systematized search keywords, postoperative nausea and vomiting, Incidence, therapeutics, Apfel score and risk score for postoperative nausea and vomiting, in PubMed database, the Cochrane central register of controlled trials and in http://www.clinicaltrials.gov. Results: A total of 2750 articles were obtained, and 62 articles were chosen for inclusion. Discussion: The drugs used as monotherapy to mitigate PONV such as palonosetron, fosaprepitant and aprepitant, show better results than the rest of the drugs. Conclusion: Currently, NK1 receptor antagonist drugs and 5-HT3 antagonists have been shown to have the best results in preventing PONV, however, the management of PONV should be multimodal and individualized.

AATF/Che-1 RNA polymerase II binding protein overexpression reduces the anti-tumor NK-cell cytotoxicity through activating receptors modulation.

AATF/Che-1 over-expression in different tumors is well known and its effect on tumorigenicity is mainly due to its central role demonstrated in the oncogenic pathways of solid tumors, where it controls proliferation and viability. The effect exerted by tumors overexpressing Che-1 on the immune response has not yet been investigated. Starting from ChIP-sequencing data we confirmed Che-1 enrichment on Nectin-1 promoter. Several co-cultures experiments between NK-cells and tumor cells transduced by lentiviral vectors carrying Che-1-interfering sequence, analyzed by flow-cytometry have allowed a detailed characterization of NK receptors and tumor ligands expression. Here, we show that Che-1 is able to modulate the expression of Nectin-1 ligand at the transcriptional level, leading to the impairment of killing activity of NK-cells. Nectin-1 down-modulation induces a modification in NK-cell ligands expression able to interact with activating receptors and to stimulate NK-cell function. In addition, NK-cells from Che-1 transgenic mice, confirming a reduced expression of activating receptors, exhibit impaired activation and a preferential immature status. The critical equilibrium between NK-cell ligand expression on tumor cells and the interaction with NK cell receptors is affected by Che-1 over-expression and partially restored by Che-1 interference. The evidence of a new role for Che-1 as regulator of anti-tumor immunity supports the necessity to develop approaches able to target this molecule which shows a dual tumorigenic function as cancer promoter and immune response modulator.

Brain nanotargeted [131I] I-Rolapitant as a model for brain imaging: Intranasal formulation, radiolabelling, biodistribution, and comparative study

The goal of this study was to create a novel single-photon emission computed tomography (SPECT) probe that would enable the visualization of neurokinin-1 NK1 receptor systems in the brain for the precise diagnosis and follow-up of many brain-related disorders. Rolapitant (RT), a selective, high-affinity NK1 receptor antagonist, was successfully radiolabelled with the radioactive Iodine 131I with high radiolabelling efficiency after refining several parameters impacting the radiolabelling process' efficiency. To improve the radiopharmaceutical's bioavailability, and brain delivery and boost the diagnostic yield of the novel radiopharmaceutical formulation, [131I] I-Rolapitant was successfully fabricated in a spanlastic nanovesicle (SNV) formulation with a convenient hydrodynamic size, a reasonable biocompatibility profile, and feasible in vitro stability. The selected formula was evaluated comparatively in a parallel biodistribution study in contrast to RT intravenous and intranasal solutions comparing brain targeting efficiency. The in vivo study revealed a high brain uptake (6.740 ± 0.09% ID/g) 2 h post-administration which was 3fold greater than the brain uptake of [131I] I-Rolapitant intravenous solution. Regarding the Brain/Blood Ratio, [131I] I-Rolapitant SNV outperformed RT intravenous and intranasal solutions, with a maximum ratio of 2.03 reached 24 h after administration. These results suggest that the proposed spanlastic nanoform could be regarded as a promising drug vector for the transnasal delivery of radiopharmaceuticals to the brain.

Antiemetic activity of trans-ferulic acid possibly through muscarinic receptors interaction pathway: In vivo and in silico study

Current study was conducted to assess the effectiveness of the polyphenol trans-ferulic acid (TFA) as an antiemetic agent using in vivo and in silico methods. To evaluate this, we induced emesis in 3-day-old chicks through the oral administration of copper sulfate (CuSO4·5H2O) at a dose of 50 mg/kg. To ascertain the potential antiemetic mechanism of TFA, we employed various reference drugs such as domperidone (6 mg/kg), ondansetron (5 mg/kg), and hyoscine (21 mg/kg) as positive control groups, while the vehicle acted as a negative control group. TFA was administered orally at the doses of 25, 50 and 100 mg/kg body weight. Both the TFA and reference drug provided alone or in combined groups to assess their synergistic or antagonistic activity on the chicks. Molecular docking of TFA and the selected reference drugs was conducted against 5HT3, D2, H1, NK1,and mAChRs (M1-M5) receptors for determining binding affinity to the receptors. Active binding sites and drug-receptor interactions were predicted with the aid of various computational tools. Various pharmacokinetic features and drug-likeness of all the selected ligands were determined through the SwissADME online server. The results suggest that TFA diminishes the mean number of retches and enhances latency in the chicks at lower doses. In the combined drug therapy, TFA exhibited better antiemetic effects with ondansetron and hyoscine. In silico ADME proposed that TFA retains preferable drug-likeness and better pharmacokinetic properties to be a reliable lead. Additionally, TFA revealed the elevated binding affinity against mAChRs and the ligand (TFA) expressed the highest binding affinity (−7 kcal/mol) with the M5 receptor (6OL9). In conclusion, TFA demonstrated mild antiemetic effects in chicks, possibly through the mAChRs interaction pathway.

Nausea and vomiting induced by pharmacotherapy: have all issues of maintenance therapy been resolved?

Many patients with various localizations of malignant neoplasms require therapy aimed at preventing or reducing the manifestations of nausea and vomiting induced by anticancer pharmacotherapy. New drugs to prevent the development of complications of chemotherapy are critical to improve the quality of life of patients and their adherence to therapy. Palonosetron, a new generation 5-HT3 receptor antagonist, has a long half-life (up to 40 hours) and a 30-fold higher affinity for 5-HT3 receptors compared to previous generations of 5-HT3 receptor antagonists. Clinical studies have shown the ability of palonosetron in combination with dexamethasone and, if indicated, neurokinin antagonists to effectively prevent the development of nausea and vomiting during single- and multi-day cycles of chemotherapy for both solid tumors and hematological diseases, including high-dose chemotherapy, in preparation for transplantation of auto- and allogeneic stem cells. The innovative oral drug Akynzeo is currently available for use in clinical practice, which includes 2 highly selective NK1 and 5-HT3 receptor antagonists in fixed doses. The drug prevents induced nausea and vomiting during moderate and highly emetogenic chemotherapy in more than 90 % of cases, both in the acute and delayed phases.

AphaFold2 models of tachykinin receptors NK1 and NK2 in complex with natural ligands substance P and NKA

AphaFold2 models of tachykinin receptors NK1 and NK2 in complex with natural ligands substance P and NKA

Current Management of CINV

Chemotherapy-induced nausea and vomiting (CINV) prevention is important to reduce overall morbidity and financial burden in patients receiving chemotherapy. Severe symptoms reduce the patient's quality of life and can interfere with further treatment. The five major forms of CINV (ie, acute, delayed, predicted, breakthrough, and refractory) often include 5-HT3 receptor antagonists, NK1 receptor antagonists, and various treatments that often include corticosteroids. Despite significant research and development efforts on antiemetics, treatment of CINV remains a major challenge, waiting for many needs to be adequately addressed, including those that are vulnerable to CINV despite adequately treated. This review hope to raise awareness and discuss current current CINV management.

Vasomotor symptoms: modulation of the neurokinin 3 receptors

Vasomotor symptoms (VMS) are highly prevalent, up to 80%, among peri- and postmenopausal women. Their frequency and intensity may impose a considerable effect on the quality of life (QoL) of many subjects. There is strong evidence in favor of hormone therapy as the most appropriate option to control VMS. Research on the pathophysiology of VMS has shown that the mechanism consists of an increased sensitivity of the thermo-regulatory centre at the hypothalamus. The system is regulated by estrogens, and new data have shown the implication of the group of kisspeptin-neurokinin-dynorphin (KNDY) neurons. The decline in estrogens liberates the release of neurokinin-3 that, through increased interaction with NK3 receptors (NK3R) at the median preoptic nucleus, resets the thermal threshold to favor the heat dissipation mechanism. Research in the latter years has come to synthesize specific antagonists of the NK3R receptors, which have confirmed efficacy in experimental models and early stages of clinical research, and finally have arrived at the level of clinical trials. The interest of current research mainly concentrates on the efficacy on VMS and on safety. The good balance at this level has opened new areas that have experienced indirect improvement. Among them, QoL, severely affected when VMS are frequent and severe, something that affects around 25% of the women. Several QoL dimensions, like the quality of sleep, sexual function, or performance in daily living are being investigated. Interest has also arisen in the use by patients who cannot, or do not accept hormone therapy. Survivors of endocrine related tumors, like breast cancer, are one of the several groups potentially affected.

Chemotherapy-induced nausea and vomiting

Chemotherapy-induced nausea and the subsequent vomiting (CINV) are adverse effects of cancer treatment associated with considerable burden for the patient. CINV has asignificant negative impact on quality of life. The consequent loss of fluids and electrolytes can lead to impaired renal function or weight loss, which may lead to hospitalization. If CINV later results in anticipatory vomiting, this complicates both CINV prophylaxis and further chemotherapy, which can endanger the continuation of cancer treatment. The introduction of high-dose dexamethasone as well as 5‑HT3 and NK1 receptor antagonists has led to asignificant improvement of CINV prophylaxis since the 1990s. Recommendations on CINV prophylaxis are in available in guidelines. Adherence to these guidelines results in better outcomes.

Impact of Emend on Perioperative Bariatric Surgery Antiemetic Utilization, Patient Satisfaction, and Costs.

Postoperative nausea and vomiting (PONV) is one of the most common adverse effects of anesthesia and surgery, resulting in patient discomfort and dissatisfaction. Latest research has demonstrated the efficacy of NK-1 receptor antagonists in PONV management and its use in chemotherapy nausea prophylaxis. The authors of this article would like to provide evidence to support the use fosaprepitant, as monotherapy, in postoperative care, replacing a polypharmacological standard of care regimen. This was a retrospective chart review of 400 patients who received standard of care antiemetic regimen or received fosaprepitant (No-Fosaprepitant vs. Fosaprepitant groups, respectively). The primary outcome of this study is to evaluate the impact of fosaprepitant (administered intravenously) on perioperative antiemetic use, treatment cost, and patient satisfaction. Total PONV medication cost decreased with the replacement of standard of care regimen for fosaprepitant, from 46.47±20.54 United States Dollars in the no-Fosaprepitant group to 25.69±14.84 United States Dollars in the Fosaprepitant group. There was a significant reduction in antiemetic doses between groups; 0.37±0.745 versus 7.61±5.202 for ondansetron (P=0.001), 92±1.279 versus 2.21±2.399 for promethazine (P=0.001), 0.25±0.685 versus 1.41±0.577 for scopolamine patch (P=0.001), and 0.05±0.218 versus 1.14±0.398 for dexamethasone (P=0.001). Patient satisfaction, measured by a questionnaire, was a 11.6% higher in the Fosaprepitant group. Fosaprepitant is a relevant alternative in preventing and treating PONV in patients who underwent bariatric/metabolic surgical procedures.

The ELiPSE-1 study: A phase 1, multicenter, open-label study of CNTY-101 in subjects with relapsed or refractory CD19-positive B-cell malignancies.

TPS7580 Background: Century Therapeutics’ foundational technology is built on induced pluripotent stem cells, differentiated from allogeneic approaches that utilize non-renewable donor-derived cells. This approach allows production of a clonal cell bank of precisely edited cells that can be expanded and differentiated to supply large amounts of homogeneous allogeneic therapeutic products for off-the-shelf use. CNTY-101 is an allogeneic Chimeric Antigen Receptor NK (CAR-NK) cell product with genetic modifications designed to specifically target CD19-expressing B-cell malignancies, reduce allorejection in the recipient allowing for repeat dosing, increase persistence, and enable cell elimination in the event of unexpected adverse events. CNTY-101, as a CAR-NK product, has the potential for improved safety over T-cell based cellular therapies. Methods: This first-in-human study will determine the MTD and recommended Phase 2 regimen (RP2R) of CNTY-101 in combination with subcutaneous (SC) IL-2 in patients with R/R aggressive and indolent CD19-positive B-cell Non-Hodgkin lymphomas including diffuse large B-cell lymphoma, mantle cell lymphoma, primary mediastinal large B-cell lymphoma, follicular lymphoma and marginal zone lymphoma, who are without other treatment options. Part 1 of the study (dose escalation using the BOIN design) will start with a dose of CNTY-101 cells without IL-2 (1 to 3 subjects), followed by dose escalation up to four dose cohorts administering a single dose of CNTY-101 cells in combination with IL-2 daily for 8 days (Sched A). After the single-dose MTD (or the maximal single dose) has been reached, a fractionated schedule of 3 doses per 28-day cycle, administered on Days 1, 8, and 15 (Sched B), will also be explored, starting with approximately one-third the maximum single dose level of CNTY-101, followed by escalation/de-escalation. Subjects in whom CNTY-101 shows signs of clinical benefit (i.e. stable disease or better per Lugano 2014 criteria) may receive additional cycles of CNTY-101 if the Investigator, Sponsor, and appropriate regulatory authorities, as required, concur that the benefit-risk is positive. One overall CNTY-101 RP2R will be declared in Part 1. Part 2, expansion, will further evaluate the safety, pharmacokinetics (PK), and efficacy of the CNTY-101 regimen, treating up to an additional 12 subjects to reach a total of approximately 20 subjects treated at the RP2R. In addition to safety and efficacy endpoints, the trial will evaluate exploratory PK, immunogenicity and pharmacodynamic endpoints including evaluations of tumor cfDNA, iNK tumor trafficking and serum cytokines. Clinical trial information: NCT05336409 .

Novel trajectories of the NK1R antagonist aprepitant in rotenone-induced Parkinsonism-like symptoms in rats: Involvement of ERK5/KLF4/p62/Nrf2 signaling axis

Regulation of the interplay between autophagy and oxidative stress is vital in maintaining neuronal homeostasis during neurotoxicity. The interesting involvement of NK1 receptor (NK1R) in neurodegeneration has highlighted the value of investigating the neuroprotective effect of aprepitant (Aprep), an NK1R antagonist in Parkinson's disease (PD). This study was conducted to disclose Aprep's ability to modulate extracellular signal-regulated kinase 5/Krüppel-like factor 4 (ERK5/KLF4) cue as molecular signaling implicated in regulating autophagy and redox signaling in response to rotenone neurotoxicity. Rotenone (1.5 mg/kg) was administered on alternate days, and rats were given Aprep simultaneously with or without PD98059, an ERK inhibitor, for 21 days. Aprep ameliorated motor deficits as verified by restored histological features, and intact neurons count in SN and striata along with tyrosine hydroxylase immunoreactivity in SN. The molecular signaling of Aprep was illustrated by the expression of KLF4 following the phosphorylation of its upstream target, ERK5. Nuclear factor erythroid 2-related factor 2 (Nrf2) was up-regulated, shifting the oxidant/antioxidant balance towards the antioxidant side, as evidenced by elevated GSH and suppressed MDA levels. In parallel, Aprep noticeably reduced phosphorylated α-synuclein aggregates due to autophagy induction as emphasized by marked LC3II/LC3I elevation and p62 level reduction. These effects were diminished upon PD98059 pre-administration. In conclusion, Aprep showed neuroprotective effects against rotenone-induced PD, which may be partially attributed to the activation of the ERK5/KLF4 signaling pathway. It modulated p62-mediated autophagy and Nrf2 axis which act cooperatively to counter rotenone-associated neurotoxicity pointing to Aprep's prospect as a curious candidate in PD research.

A Novel Semi-Solid Self-Emulsifying Formulation of Aprepitant for Oral Delivery: An In Vitro Evaluation.

Aprepitant is the first member of a relatively new antiemetic drug class called NK1 receptor antagonists. It is commonly prescribed to prevent chemotherapy-induced nausea and vomiting. Although it is included in many treatment guidelines, its poor solubility causes bioavailability issues. A particle size reduction technique was used in the commercial formulation to overcome low bioavailability. Production with this method consists of many successive steps that cause the cost of the drug to increase. This study aims to develop an alternative, cost-effective formulation to the existing nanocrystal form. We designed a self-emulsifying formulation that can be filled into capsules in a melted state and then solidified at room temperature. Solidification was achieved by using surfactants with a melting temperature above room temperature. Various polymers have also been tested to maintain the supersaturated state of the drug. The optimized formulation consists of CapryolTM 90, Kolliphor® CS20, Transcutol® P, and Soluplus®; it was characterized by DLS, FTIR, DSC, and XRPD techniques. A lipolysis test was conducted to predict the digestion performance of formulations in the gastrointestinal system. Dissolution studies showed an increased dissolution rate of the drug. Finally, the cytotoxicity of the formulation was tested in the Caco-2 cell line. According to the results, a formulation with improved solubility and low toxicity was obtained.

HLA-F transcriptional and protein differential expression according to its genetic polymorphisms.

Many specificities single out HLA-F: its structure, expression regulation at cell membrane and function. HLA-F mRNA is detected in the most cell types and the protein is localized in the ER and Golgi apparatus. When expressed at cell surface, HLA-F may be associated to β2-microglobulin and peptide or expressed as an open-conformer molecule. HLA-F reaches the membrane upon activation of different primary cell types and cell-lines. HLA-F has its highest affinity for the KIR3DS1-activating NK receptor, but also binds inhibitory immune receptors. Some studies reported that HLA-F expression is associated with its genotype. Higher HLA-F mRNA expression associated with F*01:01:02, and 3 noncoding SNPs, rs1362126, rs2523405, and rs2523393, located in HLA-F-AS1 or upstream the HLA-F sequence were associated with HLA-F mRNA expression. Given the implication of HLA-F in many clinical setting, and the undisclosed process of its expression regulation, we aim to confirm the effect of the aforementioned SNPs with HLA-F transcriptional and protein expression. We analyzed the distribution, frequency and linkage disequilibrium of these SNPs at worldwide scale in the 1000 Genomes Project samples. Influence on the genotype of each SNP on HLA-F expression was explored using RNAseq data from the 1000 Genomes Project, and using Q-PCR and intracellular cytometry in PBMC from healthy individuals. Our results show that the SNPs under studied displayed remarkably different allelic proportion according to geography and confirm that rs1362126, rs2523405, and rs2523393 displayed the most concordant results, with the highest effect size and a double-dose effect.

Issue highlights-May 2023.

In the era of personalized medicine, the list of targeted therapeutic drugs has been greatly expanded, many of which are employed to treat hematolymphoid neoplasms. These include drugs specifically targeting immune checkpoint signaling epitopes such as programmed cell death 1 (PD1) and its ligand PDL1 to inhibit T-cell activation. Alternatively, these drugs might target the surface antigens expressed by tumor cells such as CD19 and CD22 in B-cell neoplasms. Of the latter, targeted immunotherapies include monoclonal antibodies with or without drug conjugates, bispecific T-cell engagers, or chimeric antigen receptor (CAR) T-cell therapy. The binding sites of these therapeutic antibodies are often identical or in proximity with the binding sites of the diagnostic antibodies. Therefore, use of these therapies pose great challenges for clinical cytometry labs in the assessment of post-treatment samples, especially in the detection of measurable/minimal residual disease (MRD). In this issue, Chen, Gao, et al. (2023) provided an overview of MRD detection in B-lymphoblastic leukemia/lymphoma in the era of immunotherapy, and Gao et al. (2023) focused their review on the impact of targeted therapy on mature B- and plasma cell neoplasms utilizing flow cytometry assessments. In both reviews, the authors illustrated the challenges, identified the problems, and provided a list of available options and solutions. For each of the above-mentioned disease categories, optimal gating and analysis strategies were illustrated with literature review and inputs from the authors' experience and insights. The utility and interpretation of additional B-cell markers other than CD19 and CD20 for mature or immature B-cell neoplasms such as CD22, CD24, and cCD79a (Mikhailova et al., 2022) were studied as well as VS38, CD229, and CD319 (Pojero et al., 2016; Soh et al., 2021) for plasma cell neoplasms. The authors recommended that the flow cytometry assays in the era of targeted therapies must contain significant redundancy in the antibody panels allowing the detection of the cells of interest and additionally should be ready to utilize several gating strategies for accurate and consistent population identification. Neoplastic mature B-cells often show restricted kappa or lambda light chain expression; however, light chain expression may be absent in around 5%–10% of mature B-cell lymphoma (Li et al., 2002). It is suggested that mature B-cells lacking surface light chain expression can be used as a surrogate marker to diagnose mature B-cell lymphomas. Huang et al. (2023) reported a series of 89 cases of surface light chain negative B-cell lymphoma which consisted primarily of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Interestingly, the authors also reported no detectable light chain expression in normal/reactive mature B cells collected from body fluids and cystic fluids from 14 patients with no clinical and pathological evidence of lymphoma/leukemia. Body fluids are often proteaceous; thus additional washing prior to kappa/lambda staining is often required to obtain adequate light chain staining and caution is needed in the interpretation of light chain expression in B-cells collected from body fluids. It is known that out of the context of chronic myeloid leukemia (CML) (Soma et al., 2016), lymphoblastic crisis is extremely rare in other chronic myeloid neoplasms, such as myelodysplastic syndrome (MDS) (Xie et al., 2019) and Philadelphia negative myeloproliferative neoplasms (MPN). Chan et al. (2023) reported the detection of a low level of abnormal B-lymphoblasts ranging from 0.012% to 3.6% in 9 out of 1262 MDS or Ph-negative MPN. Cell sorting coupled with next-generational sequencing showed that the abnormal B- lymphoblasts in myeloid neoplasms were often, but not always, clonally related to the myeloid compartment, and the molecular genetic findings suggested a mutant multipotent progenitor cell with different lineage output that might be determined by the specific mutations and the particular cell stage where the mutations occurred. Importantly, unlike CML, the presence of abnormal B-lymphoblasts in MDS and Ph-neg MPNs did not necessarily indicate blast crisis, and therapy for the underlying myeloid neoplasms with close monitoring is suggested to be a reasonable approach. The last article in this issue (Chen, Zhang, et al., 2023) studied mucosal-associated invariant T cells (MAIT) (Godfrey et al., 2019) in aplastic anemia (AA), a type of bone marrow failure directly linked to abnormal immune responses. MAIT cells exhibit an effector-memory phenotype and express several NK receptors such as NKG2D and CD161 and play an important role in the development of autoimmune diseases. The authors showed an increased frequency of MAIT cells with an activation and effector function-related cell surface marker profile in patients with aplastic anemia. The specific property of NKG2D expression on MAIT cells suggests that these cells may have a distinct mechanism involved in AA immune pathogenesis.