Structural and signaling mechanisms of TAAR1 enabled preferential agonist design.

Trace amine-associated receptor 1 (TAAR1) senses a spectrum of endogenous amine-containing metabolites (EAMs) to mediate diverse psychological functions and is useful for schizophrenia treatment without the side effects of catalepsy. Here, we systematically profiled the signaling properties of TAAR1 activation and present nine structures of TAAR1-Gs/Gq in complex with EAMs, clinical drugs, and synthetic compounds. These structures not only revealed the primary amine recognition pocket (PARP) harboring the conserved acidic D3.32 for conserved amine recognition and "twin" toggle switch for receptor activation but also elucidated that targeting specific residues in the second binding pocket (SBP) allowed modulation of signaling preference. In addition to traditional drug-induced Gs signaling, Gq activation by EAM or synthetic compounds is beneficial to schizophrenia treatment. Our results provided a structural and signaling framework for molecular recognition by TAAR1, which afforded structural templates and signal clues for TAAR1-targeted candidate compounds design.

Characterizing the distribution pattern of traffic-related air pollutants in near-road neighborhoods.

In near-road neighborhoods, residents are more frequently exposed to traffic-related air pollution (TRAP), and they are increasingly aware of pollution levels. Given this consideration, this study adopted portable air pollutant sensors to conduct a mobile monitoring campaign in two near-road neighborhoods, one in an urban area and one in a suburban area of Shanghai, China. The campaign characterized spatiotemporal distributions of fine particulate matter (PM2.5) and black carbon (BC) to help identify appropriate mitigation measures in these near-road micro-environments. The study identified higher mean TRAP concentrations (up to 4.7-fold and 1.7-fold higher for PM2.5 and BC, respectively), lower spatial variability, and a stronger inter-pollutant correlation in winter compared to summer. The temporal variations of TRAP between peak hour and off-peak hour were also investigated. It was identified that district-level PM2.5 increments occurred from off-peak to peak hours, with BC concentrations attributed more to traffic emissions. In addition, the spatiotemporal distribution of TRAP inside neighborhoods revealed that PM2.5 concentrations presented great temporal variability but almost remained invariant in space, while the BC concentrations showed notable spatiotemporal variability. These findings provide valuable insights into the unique spatiotemporal distributions of TRAP in different near-road neighborhoods, highlighting the important role of hyperlocal monitoring in urban micro-environments to support tailored designing and implementing appropriate mitigation measures.

Luteolin Attenuates Diabetic Myocardial Hypertrophy by Inhibiting Proteasome Activity.

INTRODUCTION: Luteolin is a flavonoid polyphenolic compound exerting broad pharmacological and medicinal properties. Diabetes-related obesity increases the total blood volume and cardiac output and may increase the myocardial hypertrophy progression. However, the mechanism of luteolin in diabetic myocardial hypertrophy remains uncertain. Therefore, this study aimed to evaluate whether luteolin improved diabetic cardiomyopathy (DCM) by inhibiting the proteasome activity. METHODS: Cardiomyopathy was induced in streptozotocin-treated diabetes mellitus (DM) and db/db mice. Luteolin (20 mg kg-1·day-1) was administrated via gavage for 12 weeks. In vitro, high glucose and high insulin (HGI, glucose at 25.5 mM and insulin at 0.1 µM) inducing primary neonatal rat cardiomyocytes (NRCMs) were treated with or without luteolin for 48 h. Echocardiography, reverse transcription quantitative polymerase chain reaction, histology, immunofluorescence, and Western blotting were conducted. Proteasome activities were also detected using a fluorescent peptide substrate. RESULTS: Luteolin administration significantly prevented the onset of cardiac hypertrophy, fibrosis, and dysfunction in type 1 DM (T1DM) and type 2 DM (T2DM). Compared with DCM mice, luteolin groups showed lower serum triglyceride and total cholesterol levels. Furthermore, luteolin attenuated HGI-induced myocardial hypertrophy and reduced atrial natriuretic factor mRNA level in NRCMs. Proteasome activities were inhibited by luteolin in vitro. Luteolin also reduces the proteasome subunit levels (PSMB) 1, PSMB2, and PSMB5 of the 20S proteasome, as well as proteasome-regulated particles (Rpt) 1 and Rpt4 levels of 19S proteasome. Furthermore, luteolin treatment increased protein kinase B (AKT) and GSK-3α/ß (inactivation of GSK-3) phosphorylation. The phosphorylation level of AMPK activity was also reversed after the treatment with luteolin in comparison with the HGI-treated group. CONCLUSION: This study indicates that luteolin protected against DCM in mice, including T1DM and T2DM, by upregulating phosphorylated protein AMPK and AKT/GSK-3 pathways while decreasing the proteasome activity. These findings suggest that luteolin may be a potential therapeutic agent for DCM.

[Screen and Function Study of the Key Regulative Odontogenic Genes in Mice].

OBJECTIVE: To screen the key odontogenic genes in mice and verify the odontogenic inducing effect on amniotic epithelial cells (WISH). METHODS: The spatially and temporally different expression of bone morphogenetic proteins 4 (BMP4), fibroblast growth factor 8 (FGF8), sonic hedgehog (SHH), lymphoid enhancer factor 1 (LEF1) proteins and their genes expression in the early odontogenesis stage (embryo day 10.5 (E10.5)、E11.5、E14.5) in fetal mice were detected by immunohistochemistry staining and quantitative real-time PCR (RT-qPCR). According to the results, we screened the probable key odontogenic genes. Then adding osteogenic inducing solution to induce non-odontogenic epithelium cells, WISH. After 3 weeks culture of non-odontogenic epithelial WISH for osteogenic induction, the epithelial-mesenchymal transformation cap ability was evaluated by using Alizarin (ALZ) red staining and RT-qPCR on the alkaline phosphatase ( ALP) mRNA expression level. Using germ layer recombination experiment to observe and verify whether the screened genes can induce non-odontogenic epithelium cells acquire odontogenesis ability. The recombined tissue grafts containing key genes were transplanted beneath the renal capsule of mice. RESULTS: The results of immunohistochemistry staining and RT-qPCR showed that on E10.5 BMP4 protein and gene were differently expressed in the first and second branchial arch epithelium, which synchronized the odontogenic capability transferring from epithelium to mesenchyme from E10.5-E14.5. Though the expression of FGF8 protein and gene existed such difference in the first and second branchial arch epithelium, there was no synchronization in transfer. The expression of LEF1 and SHH proteins and genes had neither difference nor synchronization. So far, we considered the BMP4 was the probable key odontogenic gene. Through 3 weeks' osteogenic induction, ALZ red stained positively and calcium nodules were observed in WISH, and the expression level of ALP mRNA increased. In the germ layer recombination experiment, exogenous BMP4 protein enabled the second branchial arch mesenchyme forming tooth-like structures after recombined with the second branchial arch epithelium or WISH. CONCLUSIONS: The proteins and genes of BMP4, FGF8, SHH and LEF1 are spatially and temporally differently expressed in the early tooth development stage in mice. The protein and gene of BMP4 are differently expressed between the first and second branchial arch epithelium and enables the non-odontogenic epithelium acquiring odontogenic ability. BMP4 is the possible key odontogenic gene.

Ultrasonographic findings in cows with left displacement of abomasum, before and after reposition surgery.

BACKGROUND: The natural incidence of left displacement of abomasum (LDA) in dairy cows was high. The diagnosis of LDA usually relies on characteristic physical exam findings but that transabdominal ultrasound is a useful technique that has been applied to the diagnosis of gastrointestinal diseases of dairy cows in equivocal cases. METHODS: Forty dairy cows with LDA were clinically and ultrasonographically examined to determine the position and the echogenic property of the abomasum. The cows were examined ultrasonographically on the left side, from the 9th intercostal space (ICS) to the 12th ICS as well as the ventral left abdomen before and after reposition surgery. RESULTS: The vital signs were within normal range in most of the cows and the 'pinging' were clearly heard in 37 cows. The abomasal gas cap was visualized from the 9th to 12th ICS in 37 cows and characterized by reverberation artifacts. The abomasal ingesta appeared as homogeneous hypoechoic fluid with scattered hyperechoic foci and were mainly visible in the median region and ventral region of the 9th to 11th ICS in 35 cows. The pyloric canal was detected from the ventral left abdomen wall in 30 cows and appeared as a loop with hypoechogenic wall and echogenic luminal contents in cross section. CONCLUSION: These typical ultrasonograms, including reverberation artifacts, homogenous hypoechoic structures, are important diagnostic feature in ultrasonography of LDA. Furthermore, the circular acoustic image structure of the pyloric canal is an important characteristic of LDA, so it can be used as an important diagnostic basis of LDA.

Berberine Protects against NEFA-Induced Impairment of Mitochondrial Respiratory Chain Function and Insulin Signaling in Bovine Hepatocytes.

Fatty liver is a major lipid metabolic disease in perinatal dairy cows and is characterized by high blood levels of non-esterified fatty acid (NEFA) and insulin resistance. Berberine (BBR) has been reported to improve insulin sensitivity in mice with hepatic steatosis. Mitochondrial dysfunction is considered a causal factor that induces insulin resistance. This study investigates the underlying mechanism and the beneficial effects of BBR on mitochondrial and insulin signaling in bovine hepatocytes. Revised quantitative insulin sensitivity check index (RQUICKI) of cows with fatty liver was significantly lower than that of healthy cows. Importantly, the Akt and GSK3ß phosphorylation levels, protein levels of PGC-1α and four of the five representative subunits of oxidative phosphorylation (OXPHOS) were significantly decreased in cows with fatty liver using Western Blot analysis. In bovine hepatocytes, 1.2 mmol/L NEFA reduced insulin signaling and mitochondrial respiratory chain function, and 10 and 20 umol/L BBR restored these changes. Furthermore, activation of PGC-1α played the same beneficial effects of BBR on hepatocytes treated with NEFA. BBR treatment improves NEFA-impaired mitochondrial respiratory chain function and insulin signaling by increasing PGC-1α expression in hepatocytes, which provides a potential new strategy for the prevention and treatment of fatty liver in dairy cows.

Waveguide-coupled hybrid plasmonic modulator based on graphene.

In this paper, we propose a low-transmission-loss, high-speed, graphene-based electro-absorption modulator with a hybrid plasmonic waveguide at 1.55 µm. In the proposed device, double-layer graphene is placed on top of the horizontal hybrid plasmonic waveguide to enhance the light-graphene interaction. The adjustment of the in-plane permittivity of the anisotropy graphene causes a significant modulation of the absorption at the operating bandwidth of 0.4 THz, with modulation length of 8.5 µm and modulator footprint of 1.6 µm2. A taper silicon coupler is used for waveguide coupling, and 80% coupling efficiency is achieved. In addition, the modulation potential on a smaller footprint is further shown.

[An HPLC-MS/MS method for the determination of trans-ferulic acid in human plasma].

In this study, we developed a sensitive and rapid HPLC-MS/MS method for the determination of trans-ferulic acid(trans-FA) in plasma samples, and investigated the pharmacokinetics characteristics in healthy volunteers. The plasma samples were extracted with acetic ether, and then separated on a Hedera ODS-2 column with a mobile phase of methanol and 5 mmol·L(-1) ammonium acetate buffer solution containing 0.05% acetic acid(34∶66) at a flow rate of 0.4 m L·min(-1). Electrospray ionization source was applied and operated in the positive ion mode using MRM. The method exhibited a good linearity over the concentration range of 0.1-5 ng·m L(-1)(r ≥ 0.999 2). The values on both the occasions(intra- and inter-day) were all within 9.2%, and the accuracy was 95.4%-111.4%. No matrix effect and carry-over effect were observed. Trans-FA was stable in human plasma under different storage conditions. The developed HPLC-MS/MS method is rapid, sensitive, accurate, and reproducible, and suitable for the pharmacokinetic study of trans-FA in healthy Chinese volunteers.

[An LC-MS/MS method for the simultaneous determination of amygdalin and paeoniflorin in human urine and application to urinary excretion study].

ABSTRACT: The study aims to develop an LC-MS/MS method for the simultaneous determination of amygdalin and paeoniflorin in urine samples, and to investigate their urinary excretion characteristics in healthy volunteers after intravenous infusion administration of Huoxue-Tongluo lyophilized powder for injection (HTLPI). The urine samples were extracted by methanol, and then separated on a Hedera ODS-2 column with a mobile phase of acetonitrile and 5 mmol · L(-1) ammonium acetate buffer solution containing 0.05% formic acid (20:80). Electrospray ionization source was applied and operated in the positive ion mode using MRM. The method exhibited good linearity over the concentration range of 0.03 -40 µg · mL(-1). The values on both the occasions (intra- and inter-day) were all within 15% at three concentration levels. No matrix effect and carry-over effect were observed. Amygdalin and paeoniflorin were stable in human urine under different storage conditions. Approximately 79.6% of the administered amount of amygdalin was excreted unchanged in urine within 24 h and which was 48.4% for paeoniflorin. The developed LC-MS/MS method can be applied to evaluate the urinary excretion of amygdalin and paeoniflorin.

Syntheses of diacyltanshinol derivatives and their suppressive effects on macrophage foam cell formation by reducing oxidized LDL uptake.

A series of diacyltanshinol derivatives were synthesized by esterifying the corresponding o-hydroquinones of tanshinones. The suppressive effects of the synthesized compounds on oxidized low-density lipoprotein (oxLDL) uptake and oxLDL-induced macrophage-derived foam cell formation were evaluated. Our results indicated that the nicotinate derivatives 1a and 2a, modified from tanshinone IIA and cryptotanshinone, showed stronger suppressive activity on oxLDL uptake and the resultant foam cell formation relative to tanshinone IIA. Western Blot analysis indicated that derivatives 1a and 2a could dose-dependently inhibit the expression of oxLDL-induced LOX-1, implying that the suppressive effects of 1a and 2a on oxLDL uptake and foam cell formation could be at least partially attributed to the inhibition of LOX-1 expression in macrophages.

Syntheses of tanshinone anhydrides and their suppression on oxidized LDL uptake in macrophages and foam cell formation.

We synthesized eight tanshinone anhydrides and the alcoholytic derivatives through a mild oxygen-insertion under Pd/C catalytic hydrogenation conditions. The suppressive effects of the anhydrides on the oxidized low-density lipoprotein (oxLDL) uptake and the oxLDL-induced macrophage-derived foam cell formation were studied. Our results revealed that both anhydrides 1a and 2a could significantly suppress the oxLDL uptake in macrophages and the foam cell formation at micromolar level, which might be partially attributed to their inhibition of oxLDL-induced LOX-1 expression in macrophages.

[Research progress on mitochondrial genome structure in the phylum apicomplexa].

Mitochondria are ubiquitous organelles in all eukaryotic cells which are essential for a series of cellular processes and signal transduction. The phylum Apicomplexa includes series of unicellular eukaryotes and some of them are clinically or economically important parasites. Recent studies have demonstrated that apicomplexan parasites' mitochondrial genomes exhibit remarkably diverse structures and they are ideal biological models to comprehend the evolution of mitochondrial genomes. This paper summarizes the mitochondrial genome structure of some representative apicomplexan, highlights their structure characteristics along with evolution process, and briefly describes their nuclear mitochondrial DNA and nuclear plastid DNA.

A severe case of iatrogenic botulism associated with COVID-19 infection.

Background: The botulinum toxin is an extremely potent substance that impacts the nervous system. There has been a rise in cases of medical poisoning associated with it, particularly in the field of plastic and aesthetic procedures, in recent years. Case description: A 51-year-old woman underwent a facial wrinkle reduction procedure with an unauthorized injection of 100 U of botulinum toxin at an unlicensed medical facility six days prior to hospitalization. Over time, her toxicity symptoms intensified, impacting her respiratory muscles, and she did not receive antitoxin treatment. She was concurrently diagnosed with a COVID-19 infection during this period. Nonetheless, she experienced a full recovery 86 days after the injection. Conclusion: Currently, there is no effective antidote for botulism. Nevertheless, the timely administration of antitoxin can contribute to reducing the duration of the illness, alleviating symptoms, and preventing its recurrence. It is essential to recognize that individual responses may vary, and in this instance, the absence of antitoxin treatment did not significantly prolong the course of the disease. Accurate diagnosis of medical poisoning can be based on injection history and clinical symptoms. Early indications like fatigue and dry mouth warrant particular attention, emphasizing the importance of immediate medical intervention. To address emergencies, the Center for Disease Control (CDC) should maintain an accessible supply of antitoxin. Patients with severe poisoning should be hospitalized until their respiratory muscle strength is fully restored.

[Analysis of the factors affecting pathologic complete response to neoadjuvant chemotherapy in breast cancer patients].

OBJECTIVE: To analyze the factors affecting pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) in breast cancer patients. METHODS: A retrospective cohort study was carried out to analyze the clinical data of 141 breast cancer patients treated with neoadjuvant chemotherapy. The factors affecting pCR and the changes of tumor receptor status before and after treatment were analyzed. RESULTS: Among all the 141 patients, 21 patients (14.9%) achieved pCR. The rate of pCR achieved by regimens of anthracycline combined with taxane was higher (16.8%, 19/113) than that by anthracycline-containing regimens (7.1%, 1/14). The dose intensity of anthracycline had a significant correlation with pCR rate (P < 0.05). The pCR rate in the relative dose intensity of taxane ≥ 0.85 arm was higher than that of < 0.85 arm (P = 0.02). Eighty patients (56.7%) had completed more than 4 cycles of chemotherapy and the median time to achieve pCR was 6 (3 to 10) cycles. The pCR rate had a significant difference between patients < 6 and ≥ 6 cycles (7.1% vs. 22.5%,P = 0.01). Multivariate analysis showed that tumor size measured by palpation ≤ 5 cm and ≥ 6 chemotherapy cycles were significantly related with pCR rate (P < 0.05). In all the 21 pCR patients, the pre-treatment ER(-), PR(-), HER-2(-) statuses were in 14, 14 and 17 patients, respectively. The status of ER, PR, HER-2 of most patients (74.2%, 69.7% and 87.7%, respectively) was not changed after treatment. Among the patients with changes in receptor status, ER changed from negative to positive was in the majority (37.1%, 13/35 vs. 12.9%, 4/31, P < 0.05), and the percentage of changes in PR and HER-2 status had no significant differences. CONCLUSIONS: The regimens of anthracycline combined with taxane can achieve a higher pCR rate. The lymph node and receptor status before therapy have no significant correlation with pCR. Patients who have primary tumor size ≤ 5 cm, ≥ 6 chemotherapy cycles and enough dose intensity are easier to achieve pCR. The receptor status before and after therapy should be determined, and according to any positive results, physicians can chose HER-2 targeted therapy and/or endocrine therapy after surgery to benefit the patients.

Bis[2,4-di-bromo-6-(N-{4-[(E)-1-(benzyl-oxy-imino)-eth-yl]phen-yl}carboximido-yl)phenolato]copper(II).

In the title complex, [Cu(C22H17Br2N2O2)2], the Cu(II) ion is four-coordinated in a trans-CuN2O2 square-planar geometry by two phenolate O and two imino N atoms from two deprotonated N,O-bidentate ligands. In the crystal, the packing of the mol-ecules is controlled by C-H⋯π and π-π inter-actions [centroid-centroid distances = 3.568 (3), 3.678 (2), 3.717 (3) and 3.799 (2) Å] and weak Br⋯Br halogen bonds [3.508 (4) Å], linking the mol-ecules into an infinite three-dimensional supra-molecular network.

[A case of two-stage orthodontic treatment of skeletal Classâ ¡malocclusion with mandibular retrusion and maxillary dental arch stenosis].

This article reviewed two-stage orthodontic treatment of a patient with skeletal ClassⅡmalocclusion with mandibular retrusion and maxillary dental arch stenosis. The patient was also accompanied by premature loss of bilateral mandibular deciduous canines and mesialization of mandibular posterior teeth. The first-stage treatment mainly corrected the maxillary dental arch stenosis, maxillary anterior teeth protrusion, mandibular retrusion and skeletal ClassⅡmalocclusion, while the second-stage treatment mainly corrected the mesialization of mandibular posterior teeth and alignment of maxillary and mandibular dentition. The two-stage orthodontic treatment finally enabled the patient to achieve good dental arch shape, tooth alignment, skeletal face pattern and soft tissue profile.

A Case of Comorbid Weber Syndrome Following Mechanical Thrombectomy for Middle Cerebral Artery Occlusion.

Background: In Weber syndrome, one side of the cerebral peduncle of the midbrain is infarcted due to the occlusion of the interpeduncular branch of the posterior cerebral artery and the posterior choroidal artery, resulting in ipsilateral oculomotor nerve palsy and contralateral hemiparesis. However, Weber syndrome induced by simple anterior choroidal artery lesions has rarely been reported. Case Description: Computed tomographic angiography revealed occlusion of the left internal carotid artery in a 57-year-old male patient who was admitted to the Beijing Haidian Hospital with cerebral infarction. Thrombectomy to clear the occlusion of the left internal carotid artery and the middle cerebral artery was successfully performed in the emergency department. However, postoperative digital subtraction angiography indicated occlusion of the middle and distal segments of the left anterior choroidal artery. After recovery from anesthesia, the patient had left blepharoptosis, inability to abduct the left eye, limitation of the upward and downward gaze, left mydriasis, absence of response to light, and right hemiplegia. Complete head magnetic resonance imaging suggested left cerebral peduncle and basal ganglia infarction. Therefore, the diagnosis was that the patient had left Weber syndrome caused by a left anterior choroidal arterial embolism. Conclusion: When the anterior choroidal artery is the dominant supplier of blood to the medial region of the ipsilateral cerebral peduncle, the occlusion of this artery may lead to ipsilateral Weber syndrome.

[Efficacy of early maxillary slow expansion in mixed dentition on maxillary teeth and alveolar crest in the central segment].

PURPOSE: To study the effect of slow maxillary expansion(SME) appliance on the development of premolar tooth germ, primary molar and alveolar crest in the central segment of maxilla in the mixed dentition. METHODS: According to the inclusion and exclusion criteria, 17 children (average age 7.41±0.80 years old ) with maxillary transverse deficiency were selected for SME. Before and after treatment, based on cone-beam CT(CBCT) and Dolphin Imaging software, the position of maxillary premolar tooth germ, the position of maxillary primary molar, the shape of maxillary alveolar crest in the central segment were analyzed. SPSS 21.0 software package was used for data analysis. RESULTS: There was no significant change in the buccal-lingual movement and inclination of the tooth germs of the maxillary first and second premolars relative to the maxillary alveolar bone cortex after expansion(P＞0.05).After expansion, the maxillary alveolar crest in the central segment had an obvious expansion effect(P＜0.05). There was an arch expansion effect in the alveolar crest bottom of the maxillary second primary molar(P＜0.05), but there was no significant difference in the alveolar crest bottom of the maxillary first primary molar before and after treatment. Buccal cusp width of maxillary first and second primary molars increased after arch expansion (P＜0.05) without inclination of alveolar crest(P＞0.05). CONCLUSIONS: SME in the mixed dentition did not affect the position of premolar tooth germ in alveolar bone. SME can expand and buccally tilt central alveolar crest and dental arch, and buccal inclination is greater than that of skeletal expansion and buccal inclination. The closer tooth site is to the first molar, the greater the skeletal effect of arch expansion is at this site. SME is an effective treatment for early maxillary expansion in the clinic.

[Experimental study on the stimulation effect of temperature and capsaicin on oral mucosa of rats].

PURPOSE: This study investigated the effects of different temperatures and capsaicin solution on changes of morphology and inflammatory factor expressions in the oral mucosa. METHODS: The oral mucosa of rats was stimulated with normal saline (NS) and capsaicin solution at 25, 45, and 55 ℃ respectively for 4 weeks, and then the rats were sacrificed with chloral hydrate. H-E staining and immunohistochemical staining of the oral mucosa were prepared. The morphological changes of oral mucosa epithelium were observed and the expressions of TNF-α, IL-6 and IL-8 were detected. SPSS 22.0 software package was used for statistical analysis, and Graphpad Prism 8.0 software was used for statistical graphing. RESULTS: When stimulated with NS and capsaicin solution at different temperatures, the results of H-E staining showed that there was no distinct injury in the mucosal epithelium at 25 ℃ and 45 ℃. Histopathological changes were observed in the oral mucosa at 55 ℃. The expressions of IL-6 and IL-8 in the epithelium were significantly increased (P＜0.05). CONCLUSIONS: 55 ℃ NS solution and 55 ℃ capsaicin solution stimulated oral mucosa of the rats and caused infiltration of inflammatory cells in the lamina propria of the oral mucosa. They also stimulated the oral mucosa of rats, resulting in a significant increase in the expression of IL-6 and IL-8 in the oral mucosal epithelium. The effect of capsaicin on IL-8 expression was enhanced with increasing temperature.

Efficiency and toxicity of nab-paclitaxel and camrelizumab in the second or above line treatment of advanced non-small cell lung cancer: a retrospective cohort study.

Background: Paclitaxel-based chemotherapy represented by nanoparticle albumin-bound paclitaxel (nab-ptx) combined with programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors has become the standard model for the 1st treatment of advanced non-small cell lung cancer (NSCLC) with negative driver genes (such as EGFR, ALK, etc.), indicating that nab-ptx and PD-1/PD-L1 inhibitors are synergistic. Considering PD-1/PD-L1 inhibitors alone or chemotherapy single has limited efficiency in the 2nd line or above of NSCLC, so it is of great significance to explore the combination of PD-1/PD-L1 inhibitors and nab-ptx to further improve the therapeutic efficiency in such field. Methods: We retrospectively collected the date of these advanced NSCLC patients who accept the combination treatment of PD-1/PD-L1 inhibitor and nab-ptx in the 2nd or above line. We further analysed baseline clinical characteristics, therapeutic efficacy, treatment-related adverse events (AEs) and followed up survival. The main parameters of the study were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and AEs. Results: A total of 53 patients were enrolled in this study. The preliminary results indicated that the ORR of the combination of camrelizumab and nab-ptx was about 36% in the 2nd or above line of NSCLC, with 19 cases of partial response (PR), 16 of stable disease (SD), and 18 cases of progressive disease (PD); the mean PFS and OS were 5 months and 10 months, respectively. Further subgroup analysis demonstrated that the expression of PD-L1 level and the decrease of regulatory T cell (Treg) correlated with the efficiency. the main adverse reactions were neuropathy, bone marrow suppression, fatigue, and hypothyroidism, most of which were mild and tolerable, indicating such regimen was higher efficiency and lower cytotoxicity for NSCLC. Conclusions: The combination of nab-ptx and camrelizumab shows promising efficiency and lower toxicities for advanced NSCLC in the 2nd or above line treatment. The mechanism of action may be related to depleting Treg ratio; such a regimen may have the potential to become an effective treatment approach for NSCLC. However, due to the limitation of sample size, the real value of this regimen needs to be further confirmed in the future.