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Abstract Leaf scald, caused by Xanthomonas albilineans, is a severe disease affecting sugarcane worldwide. One of the most practical ways to control it is by developing resistant sugarcane cultivars. It is essential to identify genes associated with the response to leaf scald. A panel of 170 sugarcane genotypes was evaluated for resistance to leaf scald in field conditions for 2 years, followed by a 1-year greenhouse experiment. The phenotypic evaluation data showed a wide continuous distribution, with heritability values ranging from 0.58 to 0.84. Thirteen single nucleotide polymorphisms (SNPs) were identified, significantly associated with leaf scald resistance. Among these, eight were stable across multiple environments and association models. The candidate genes identified and validated based on RNA-seq and qRT-PCR included two genes that encode NB-ARC leucine-rich repeat (LRR)-containing domain disease-resistance protein. These findings provide a basis for developing marker-assisted selection strategies in sugarcane breeding programs.

BackgroundBeinaglutide, whose active ingredient is rhGLP-1, has been widely used as a pharmacological therapy for T2DM. We explored the safety and pharmacokinetics of beinaglutide in Chinese overweight/obese volunteers to lay a foundation for clinical applications of beinaglutide as an anti-obesity drug.MethodsAn open-label, single center, multiple ascending dose phase I clinical trial was conducted in 16 overweight/obese Chinese volunteers. The plasma concentrations of beinaglutide were determined by a validated ELISA method and the pharmacokinetic parameters were estimated via non-compartmental analysis methods. Adverse events were also recorded.ResultsBeinaglutide sequentially multiple dosing (three times daily) at different doses were generally well tolerated, without serious AEs leading to discontinuation of the trial. After multiple subcutaneous injections of different doses (0.1, 0.14 and 0.2 mg), the average blood concentration of beinaglutide with or without baseline correction showed a similar trend among different dose groups on different study days. After reaching the peak concentration around 15 min, it began to decrease, and the median of Tmax and Tmax,adj was 10–15 min. The exposure in vivo increased in proportion to the dosage increment, demonstrating linear pharmacokinetic characteristics. There were no statistically significant differences in the main PK parameters and no accumulation of beinaglutide after multiple dosing. After multiple subcutaneous injections, a gender difference was observed, while no differences in BMI were found under the grouping conditions.ConclusionThe safety profile and pharmacokinetic properties support further development and clinical applications of beinaglutide as an anti-obesity drug.Systematic Review Registration[https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S000BPEI&selectaction=Edit&uid=U00050YQ&ts=2&cx=wy0ioj].

Abstract Background Saccharum spontaneum L. is a closely related species of sugarcane and has become an important genetic component of modern sugarcane cultivars. Stem development is one of the important factors for affecting the yield, while the molecular mechanism of stem development remains poorly understanding in S. spontaneum. Phenylalanine ammonia-lyase (PAL) is a vital component of both primary and secondary metabolism, contributing significantly to plant growth, development and stress defense. However, the current knowledge about PAL genes in S. spontaneum is still limited. Thus, identification and characterization of the PAL genes by transcriptome analysis will provide a theoretical basis for further investigation of the function of PAL gene in sugarcane. Results In this study, 42 of PAL genes were identified, including 26 SsPAL genes from S. spontaneum, 8 ShPAL genes from sugarcane cultivar R570, and 8 SbPAL genes from sorghum. Phylogenetic analysis showed that SsPAL genes were divided into three groups, potentially influenced by long-term natural selection. Notably, 20 SsPAL genes were existed on chromosomes 4 and 5, indicating that they are highly conserved in S. spontaneum. This conservation is likely a result of the prevalence of whole-genome replications within this gene family. The upstream sequence of PAL genes were found to contain conserved cis-acting elements such as G-box and SP1, GT1-motif and CAT-box, which collectively regulate the growth and development of S. spontaneum. Furthermore, quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis showed that SsPAL genes of stem had a significantly upregulated than that of leaves, suggesting that they may promote the stem growth and development, particularly in the + 6 stem (The sixth cane stalk from the top to down) during the growth stage. Conclusions The results of this study revealed the molecular characteristics of SsPAL genes and indicated that they may play a vital role in stem growth and development of S. spontaneum. Altogether, our findings will promote the understanding of the molecular mechanism of S. spontaneum stem development, and also contribute to the sugarcane genetic improving.

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Aim: VDJ001 is a novel recombinant humanized monoclonal antibody against the anti-interleukin-6 receptor. As an analog of tocilizumab, it exhibited improved affinity and in vitro activity. Based on preclinical studies, a first-in-human clinical study was conducted to evaluate the safety, tolerability, and pharmacokinetics of VDJ001.Methods: This is a single-center, randomized, double-blinded, placebo-controlled phase I dose-escalation study conducted in healthy Chinese volunteers. Four cohorts were designed with dosages ranging from 1 to 8 mg/kg. There were equal numbers of female and male volunteers in each cohort. Enrolled subjects randomly received a single intravenous administration of VDJ001 or placebo (VDJ001: placebo = 4:1 in both female and male volunteers). Three sentinel volunteers in the 1 mg/kg cohort were first administered, and the treatment of the other seven volunteers was carried out after a safety assessment on D15. The following cohort was conducted only when the safety profile was evaluated as acceptable on D29 of the previous cohort. Samples for pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity were collected at specified time points and analyzed through validated methods. Adverse events and the results of the examination and laboratory were analyzed to assess the safety profile.Results: All cohorts were carried out according to the protocol. With the escalation of dosage, Cmax increased linearly, and AUC0-t and AUC0-∞ increased in a non-linear manner, while clearance decreased and t1/2 prolonged. Six volunteers who received VDJ001 tested ADA-positive, among whom one participant tested Nab-positive on D57. One volunteer in the placebo group tested ADA-positive but Nab-negative. CRP concentrations were not found to be correlated with the dosage. Both IL-6 and sIL-6R concentrations increased after the administration of VDJ001. All adverse events were mild to moderate in severity. No serious adverse events were reported in this study. No unexpected or clinically significant safety issues were found.Conclusion: The safety and tolerability of VDJ001 are acceptable with a single intravenous dosage of 1∼8 mg/kg. Further clinical trials are warranted.

Abstract Background Gonadotropin-releasing hormone (GnRH) antagonists are a promising therapeutic approach for treating hormone-dependent prostate cancer. Currently, the mainstream GnRH antagonists are polypeptide agents administered through subcutaneous injection. In this study, we evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of SHR7280, an oral small molecule GnRH antagonist, in healthy men. Methods This phase 1 trial was a randomized, double-blind, placebo-controlled, and dose-ascending study. Eligible healthy men were randomized in a 4:1 ratio to receive either oral SHR7280 tablets or placebo twice daily (BID) for 14 consecutive days. The SHR7280 dose was initiated at 100 mg BID and then sequentially increased to 200, 350, 500, 600, 800, and 1000 mg BID. Safety, PK, and PD parameters were assessed. Results A total of 70 subjects were enrolled and received the assigned drug, including 56 with SHR7280 and 14 with placebo. SHR7280 was well-tolerated. The incidence of adverse events (AEs, 76.8% vs 85.7%) and treatment-related AEs (75.0% vs 85.7%), as well as the severity of AEs (moderate AEs, 1.8% vs 7.1%) were similar between the SHR7280 group and placebo group. SHR7280 was rapidly absorbed in a dose-dependent manner, with a median T max of each dose group ranging from 0.8 to 1.0 h on day 14 and a mean t 1/2 ranging from 2.8 to 3.4 h. The PD results demonstrated that SHR7280 exhibited a rapid and dose-proportional suppression of hormones, including LH, FSH, and testosterone, with maximum suppression achieved at doses of 800 and 1000 mg BID. Conclusions SHR7280 showed an acceptable safety profile, as well as favorable PK and PD profiles within a dose range of 100 to 1000 mg BID. This study proposes a rationale for further investigation of SHR7280 as a potential androgen deprivation therapy. Trial registration Clinical trials.gov NCT04554043; registered September 18, 2020.

Abstract Background Voriconazole is a second-generation triazole that is used to prevent and treat invasive fungal infections. The purpose of this study was to evaluate the pharmacokinetic equivalency of a test formulation and reference formulation (Vfend®) of Voriconazole. Materials and methods This was a randomized, open-label, single-dose, two-treatment, two-sequence, two-cycle, crossover phase I trial. The 48 subjects were equally divided into 4 mg/kg and 6 mg/kg groups. Within each group, the subjects were randomized 1:1 to the test or reference formulation.. After a 7-day washout period, crossover formulations were administered. The blood samples were collected at 0.5, 1.0, 1.33,1.42,1.5, 1.75, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 12.0, 24.0, 36.0, 48.0 h later in the 4 mg/kg group, while at 0.5, 1.0, 1.5, 1.75, 2.0, 2.08, 2.17, 2.33, 2.5, 3.0, 4.0, 6.0, 8.0, 12.0, 24.0, 36.0, 48.0 h later in the 6 mg/kg group. The plasma concentrations of Voriconazole were determined by Liquid chromatography-tandem mass spectrometry (LC–MS/MS). The safety of the drug was evaluated. Results The 90% confidence intervals (CIs) of the ratio of geometric means (GMRs) of Cmax, AUC0-t, and AUC0-∞ in both 4 mg/kg and 6 mg/kg groups were within the prespecified bioequivalence limits between 80 ~ 125%. In the 4 mg/kg groups, 24 subjects were enrolled and completed the study. The mean Cmax was (2.552 ± 0.448) μg/mL, AUC0-t was (11.875 ± 7.157) h*μg/mL and AUC0-∞ was (12.835 ± 9.813) h*μg/mL after a single dose of 4 mg/kg test formulation. The mean Cmax was (2.615 ± 0.464) μg/mL, AUC0-t was (12.500 ± 7.257) h*μg/mL and AUC0-∞ was (13.416 ± 9.485) h*μg/mL after a single dose of 4 mg/kg reference formulation. In the 6 mg/kg groups, 24 subjects were enrolled and completed the study. The mean Cmax was (3.538 ± 0.691) μg/mL, AUC0-t was (24.976 ± 12.364) h*μg/mL and AUC0-∞ was (26.212 ± 14.057) h*μg/mL after a single dose of 6 mg/kg test formulation. The mean Cmax was (3.504 ± 0.667) μg/mL AUC0-t was (24.990 ± 12.455) h*μg/mL and AUC0-∞ was (26.160 ± 13.996) h*μg/mL after a single dose of 6 mg/kg reference formulation. Serious adverse event (SAE) was not observed. Conclusion In both 4 mg/kg group and 6 mg/kg group, equivalent pharmacokinetic characteristics that satisfied the criteria of bioequivalence for both test and reference formulations of Voriconazole. Trial registration NCT05330000 (15/04/2022).

Abstract Background Ezetimibe is a new class of antihyperlipidemic agent indicated for the prevention of atherosclerosis disease and for the treatment of hypercholesterolemia. Information on the pharmacokinetic profiles of ezetimibe tablet in healthy Chinese volunteers are lacking, and regulatory requirements necessitate a bioequivalence study of ezetimibe tablet versus Ezetrol® in China. Methods A single-dose randomized, open-label, two-group, two-period crossover study was conducted in 59 healthy Chinese volunteers under fasting or fed conditions to assess the bioequivalence between two preparations. Eligible participants were randomly divided into fasted and fed groups. Blood samples were collected at specified time intervals, and the plasma concentrations of ezetimibe and ezetimibe glucuronide were determined by a validated liquid chromatography-tandem mass spectrometry (LC–MS/MS) method. PK and bioavailability parameters were estimated via non-compartmental methods. Adverse events were also recorded. Results Fifty-nine healthy volunteers were enrolled in the study. The main pharmacokinetic parameters of total ezetimibe in the plasma of the ezetimibe tablet (10 mg) and the Ezetrol® (10 mg) after a single fasting administration: Cmax were (65.73 ± 47.14), (71.32 ± 51.98) ng·mL− 1; Tmax were 1.75, 1.25 h; T½ were (17.09 ± 13.22), (17.35 ± 12.14) h; AUC0-t were (643.34 ± 400.77), (668.49 ± 439.57) h·ng·mL− 1; AUC0-∞ were (706.36 ± 410.92), (734.23 ± 468.26) h·ng·mL− 1. The main pharmacokinetic parameters of total ezetimibe in plasma of ezetimibe tablet (10 mg) and Ezetrol® (10 mg) after a fed administration: Cmax were (83.38 ± 38.95), (84.74 ± 34.62) ng·mL− 1; Tmax were 2.50, 2.50 h; T½ were (22.56 ± 12.68), (19.80 ± 15.59) h; AUC0-t were (494.21 ± 208.65), (536.69 ± 209.11) h·ng·mL− 1; AUC0-∞ were (573.74 ± 252.74), (604.75 ± 247.13) h·ng·mL− 1. The main pharmacokinetic parameters Cmax, AUC0-t, and AUC0-∞ of the two drugs were analyzed by variance analysis after logarithmic transformation. The total ezetimibe under fasting state with 90% confidence intervals (CIs) were 85.29 ~ 97.19, 90.41% ~ 104.38%, and 90.81 ~ 106.05%; total ezetimibe in fed state were 86.36% ~ 109.17, 84.96% ~ 96.40, and 85.32% ~ 101.0%. The 90% CIs of the ratio of geometric means (GMRs) of Cmax, AUC0-t, and AUC0-∞ of Ezetrol® and ezetimibe tablet both fasting and fed conditions fell within the conventional bioequivalence criteria of 0.80–1.25. Both Cmax and AUC met the predetermined criteria for assuming bioequivalence. No severe adverse events were observed. Conclusions The test ezetimibe tablet and Ezetrol® were determined to be bioequivalent under both fasting and fed conditions in Chinese people. Trial registration Clinicaltrials, NCT05681247 (retrospectively registered in 11/01/ 2023).

Naoqingzhiming, whose active ingredient is echinacoside, is the first new Class I natural medicine approved for clinical trials for the therapeutic potential of vascular dementia in China. We report randomized, double-blind, placebo-controlled trials to evaluate the safety, tolerability and pharmacokinetics of single ascending doses of Naoqingzhiming tablet after oral administration in healthy Chinese subjects. The single ascending dose of Naoqingzhiming tablet (180–2160 mg) were well tolerated in all enrolled subjects, without serious adverse events and adverse events leading to withdrawal from the study. The most common drug-related treatment-emergent adverse events were elevated blood bilirubin and serum uric acid. No clinically significant findings were found in the physical examinations, vital signs or electrocardiograms. After single-dose administration of Naoqingzhiming tablet, echinacoside was absorbed with a Tmax at 1.25–1.75 h and declined with a t1/2 of 2.42–3.33 h. However, the proportionality coefficients for Cmax, AUC0−t and AUC0-∞ of echinacoside were not fully contained in the pre-defined 90 % CI criterion (0.91–1.09). As a result, the dose proportionality could not be concluded statistically within the dosage range of this study. Overall, the safety profile and PK properties support further development and use of Naoqingzhiming in vascular dementia.

Abstract Background APETALA2/ETHYLENE RESPONSIVE FACTOR (AP2/ERF) transcription factors play essential roles in plant growth, development, metabolism, and responses to biotic and abiotic stresses. However, few studies concerning AP2/ERF genes in sugarcane which are the most critical sugar and energy crops worldwide. Results A total of 218 AP2/ERF genes were identified in the Saccharum spontaneum genome. Phylogenetic analysis showed that these genes could be divided into four groups, including 43 AP2s, 160 ERFs and Dehydration-responsive element-binding (DREB) factors, 11 ABI3/VPs (RAV), and four Soloist genes. These genes were unevenly distributed on 32 chromosomes. The structural analysis of SsAP2/ERF genes showed that 91 SsAP2/ERFs lacked introns. Sugarcane and sorghum had a collinear relationship between 168 SsAP2/ERF genes and sorghum AP2/ERF genes that reflected their similarity. Multiple cis-regulatory elements (CREs) present in the SsAP2/ERF promoter were related to abiotic stresses, suggesting that SsAP2/ERF activity could contribute to sugarcane adaptation to environmental changes. The tissue-specific analysis showed spatiotemporal expression of SsAP2/ERF in the stems and leaves of sugarcane at different development stages. In ten sugarcane samples, 39 SsAP2/ERFs were not expressed, whereas 58 SsAP2/ERFs were expressed in all samples. Quantitative PCR experiments showed that SsERF52 expression was up-regulated under salt stress, but suppressed under dehydration stress. SsSoloist4 had the most considerable upregulation in response to treatment with the exogenous hormones ABA and GA. Within 3 h of ABA or PEG6000 treatment, SsSoloist4 expression was up-regulated, indicating that this gene could play a role in the responses to ABA and GA-associated dehydration stress. Analysis of AP2/ERF gene expression patterns under different treatments indicated that SsAP2/ERF genes played an essential role in dehydration and salt stress responses of S. spontaneum. Conclusions In this study, a total of 218 members of the AP2 / ERF superfamily were identified in sugarcane, and their genetic structure, evolution characteristics, and expression patterns were studied and analyzed. The results of this study provide a foundation for future analyses to elucidate the importance of AP2/ERF transcription factors in the function and molecular breeding of sugarcane.

Sugarcane is a major crop for sugar production around the world. The complexity of the sugarcane genome creates challenges for the use of both conventional and molecular breeding methods to improve sugarcane at a genetic level. DNA sequencing is an important tool to assess how the genus Saccharum and the genera of the Saccharum complex are interrelated. Here, we identify the kinship of Nepal2013-6 (Saccharum spontaneum, x = 10) using a tetra-primer amplification refractory mutation system (ARMS) PCR. Based on rDNA-ITS sequence analysis, the accession Nepal2013-6 falls within a single cluster with S. spontaneum (Yunnan82-114 and SES208), which is consistent with the previous results. Moreover, fluorescence in situ hybridization (FISH) results indicate that the 5S rDNA spots are consistent with the chromosomal ploidy in the analytical Saccharum materials, whereas 35S rDNA has similar or fewer sites than the ploidy. Therefore, 5S rDNA FISH patterns would be more suitable than 35S rDNA for chromosomal ploidy analysis in S. spontaneum with varied basic chromosome number x = 8, 9, 10. Altogether, these results indicate that the rDNA sequences will be a useful marker for further rapidly identifying the relationship and ploidy of S. spontaneum in sugarcane breeding.

A genetic diversity analysis and identification of plant germplasms and varieties are important and necessary for plant breeding. Deoxyribonucleotide (DNA) fingerprints based on genomic molecular markers play an important role in accurate germplasm identification. In this study, Specific-Locus Amplified Fragment Sequencing (SLAF-seq) was conducted for a sugarcane population with 103 cultivated and wild accessions. In total, 105,325 genomic single nucleotide polymorphisms (SNPs) were called successfully to analyze population components and genetic diversity. The genetic diversity of the population was complex and clustered into two major subpopulations. A principal component analysis (PCA) showed that these accessions could not be completely classified based on geographical origin. After filtration, screening, and comparison, 192 uniformly-distributed SNP loci were selected for the 32 chromosomes of sugarcane. An SNP complex genotyping detection system was established using the SNaPshot typing method and used for the precise genotyping and identification of 180 sugarcane germplasm samples. According to the stability and polymorphism of the SNPs, 32 high-quality SNP markers were obtained and successfully used to construct the first SNP fingerprinting and quick response codes (QR codes) for sugarcane. The results provide new insights for genotyping, classifying, and identifying germplasm and resources for sugarcane breeding

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with minimally effective treatments, highlighting the importance of developing novel biomarkers and therapeutic targets. Here, we disclosed the mechanisms that leukocyte cell-derived chemotaxin-2 (LECT2) modulates PDAC development using in vitro and in vivo models. LECT2 is downregulated in metastatic PDACs compared with the primary tumor, and its expression is correlated with multiple clinical pathologic features and prognosis. The absence promotes multiple malignant behaviors, including cell proliferation, epithelial-mesenchymal transition, migration, and invasion. In vivo studies showed that LECT2 overexpression inhibits tumor growth and lung metastasis. Mechanistically, LECT2 inhibits FOXM1 signaling by targeting HGF/MET to retard PDAC progression, revealing LECT2 as a promising biomarker and therapeutic target for PDAC in the future.

Drought is the main abiotic stress that constrains sugarcane growth and production. To understand the molecular mechanisms that govern drought stress, we performed a comprehensive comparative analysis of physiological changes and transcriptome dynamics related to drought stress of highly drought-resistant (ROC22, cultivated genotype) and weakly drought-resistant (Badila, wild genotype) sugarcane, in a time-course experiment (0 h, 4 h, 8 h, 16 h and 32 h). Physiological examination reviewed that ROC22, which shows superior drought tolerance relative to Badila, has high performance photosynthesis and better anti-oxidation defenses under drought conditions. The time series dataset enabled the identification of important hubs and connections of gene expression networks. We identified 36,956 differentially expressed genes (DEGs) in response to drought stress. Of these, 15,871 DEGs were shared by the two genotypes, and 16,662 and 4423 DEGs were unique to ROC22 and Badila, respectively. Abscisic acid (ABA)-activated signaling pathway, response to water deprivation, response to salt stress and photosynthesis-related processes showed significant enrichment in the two genotypes under drought stress. At 4 h of drought stress, ROC22 had earlier stress signal transduction and specific up-regulation of the processes response to ABA, L-proline biosynthesis and MAPK signaling pathway–plant than Badila. WGCNA analysis used to compile a gene regulatory network for ROC22 and Badila leaves exposed to drought stress revealed important candidate genes, including several classical transcription factors: NAC87, JAMYB, bHLH84, NAC21/22, HOX24 and MYB102, which are related to some antioxidants and trehalose, and other genes. These results provide new insights and resources for future research and cultivation of drought-tolerant sugarcane varieties.

Viola philippica, as a traditional Chinese medicine, has great value in treating various diseases. Here, we report the chloroplast genome of V. philippica and its phylogenetic feature. The complete chloroplast genome is 156,744 bp in length, assembled from 22,346,570 reads, and its GC contents ratio is 36.26%. Its long single-copy (LSC) region is 85,892 bp. The small single-copy (SSC) region covers 18,006 bp and inverted repeat (IR) is 26,423 bp. It encodes 77 genes, including 43 protein genes, 4 rRNA genes, and 30 tRNA genes. Moreover, according to the phylogenetic analysis for a total of 12 chloroplast sequences, V. philippica demonstrated close relationship within genus Viola.

The binding interaction between tetra-(p-sulfoazophenyl-4-aminosulfonyl)-substituted aluminum (III) phthalocyanine (AlPc), and two-serum albumins (bovine serum albumin (BSA) and human serum albumin (HSA)) has been investigated. AlPc could quench the intrinsic fluorescence of BSA and HSA through a static quenching process. The primary and secondary binding sites of AlPc on BSA were domain I and III of BSA. The primary binding site of AlPc on HSA was domain I, and the secondary binding sites of AlPc on HSA were found at domains I and II. Our results suggest that AlPc readily interact with BSA and HSA implying that the amphiphilic substituents AlPc may contribute to their transportation in the blood.

The epidermal growth factor receptor (EGFR), a ubiquitously expressed receptor tyrosine kinase, is recognized as a key mediator of tumorigenesis in many human epithelial tumors. Erlotinib is tyrosine kinase inhibitor approved by FDA for use in oncology. It inhibits the intracellular phosphorylation of tyrosine kinase associated with the EGFR to restrain the development of the tumor. To investigate the antitumor effect of erlotinib at different dosing times and the underlying molecular mechanism via the PI3K/AKT pathway, we established a mouse model of Lewis lung cancer xenografts. The tumor-bearing mice were housed four or five per cage under standardized light-dark cycle conditions (light on at 7:00 AM, 500 Lux, off at 7:00 PM, 0 Lux) with food and water provided ad libitum. The mice were observed for quality of life, their body weight and tumor volume measured, and the tumor growth curves drawn. After being bled, the mice were sacrificed by cervical dislocation. The tumor masses were removed at different time points and weighed. The mRNA expression of EGFR, AKT, Cyclin D1 and CDK-4 were assayed by quantitative real-time PCR (qRT-PCR). Protein expression levels of AKT, P-AKT and Cyclin D1 were determined by Western blot analysis. The results suggest that erlotinib has a significant antitumor effect on xenografts of non-small cell lung cancer in mice, and its efficacy and toxicity is dependent on the time of day of administration. Its molecular mechanism of action might be related to the EGFR-AKT-Cyclin D1-CDK-4 pathway which plays a crucial role in the development of pathology. Therefore, our findings suggest that the time of day of administration of Erlotinib may be a clinically important variable.