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Despite remarkable initial responses of anaplastic lymphoma kinase (ALK) inhibitors in ALK-positive non-small cell lung cancer (NSCLC) patients, cancers eventually develop resistance within one to two years. This study aimed to compare the properties of iruplinalkib (WX‑0593) with other ALK inhibitors and report the comprehensive characterization of iruplinalkib against the crizotinib resistance. The inhibitory effect of iruplinalkib on kinase activity was detected. A kinase screen was performed to evaluate the selectivity of iruplinalkib. The effect of iruplinalkib on related signal transduction pathways of ALK and c-ros oncogene 1 (ROS1) kinases was examined. The cellular and in vivo activities of ALK inhibitors were compared in engineered cancer-derived cell lines and in mice xenograft models, respectively. Human hepatocytes derived from three donors were used for evaluating hepatic enzyme inducing activity. HEK293 cell lines expressing transportors were used to invesigated the drug interaction potential mediated by several transporters. The results showed iruplinalkib potently inhibited the tyrosine autophosphorylation of wild-type ALK, ALKL1196M, ALKC1156Y and epidermal growth factor receptor (EGFR)L858R/T790M. The inhibitory effects of iruplinalkib in patient-derived xenograft and cell line-derived xenograft models were observed. Moreover, iruplinalkib showed robust antitumor effects in BALB/c nude mice xenograft models with ALK-/ROS1-positive tumors implanted subcutaneously, and the tumor suppressive effects in crizotinib-resistant model was significantly better than that of brigatinib. Iruplinalkib did not induce CYP1A2, CYP2B6 and CYP3A4 at therapeutic concentration, and was also a strong inhibitor of MATE1 and MATE2K transporters, as well as P-gp and BCRP. In conclusion, iruplinalkib, a highly active and selective ALK/ROS1 inhibitor, exhibited strong antitumor effects in vitro and in crizotinib-resistant models.

Leiomyoma with bizarre nuclei (LBN), also known as symplastic leiomyoma, is a histological subtype of benign leiomyoma with bizarre cells and nuclear atypia. Differentiating LBN from other benign leiomyoma subtypes, uterine smooth muscle tumors of uncertain malignant potential (STUMP), or leiomyosarcoma (LMS) can be diagnostically challenging owing to overlapping features in clinical presentation and pathologic morphological analysis. The difficulty of distinguishing LBN from other lesions, especially from LMS, and the potential of LBN for subsequent malignant transformation make LBN an important topic of research. Herein, we review the definition, diagnosis, treatment, and prognosis of LBN. Histopathological examination is essential for distinguishing LBN from other diseases. Pathology sampling and morphological examination remain the key to diagnosis. The newly established ancillary immunohistochemical (IHC) and molecular genetic analysis can be useful tools for differential diagnosis. Furthermore, serum biomarkers and imaging examination may also be useful diagnostic tools. Attention should be paid to the differentiation between LBN and LMS because morphological diagnosis may still be challenging in some cases. Some IHC markers of LBN have been identified, which may be helpful for differential diagnosis. Furthermore, the use of IHC panels as diagnostic markers may be advocated. Molecular genetic studies suggest that some genes can aid with the differential diagnosis between LBN and LMS. However, increasing evidence support the idea that LBN and LMS are molecularly related, indicating that LBN may represent a potentially malignant stage of precancerous progression. At present, conservative treatment is recommended for primary LBN, especially for patients desiring to retain fertility, but close follow-up with imaging examinations is required.

A classification system for endocervical adenocarcinoma (ECA) based on high-risk human papillomavirus (HPV) status has been established; however, the immunohistochemical markers distinguishing HPV-independent and HPV-associated ECAs have not been fully described. Here, we aimed to characterize ECA immunopathological features.We evaluated the immunohistochemical profile of CLDN18, CDX2, PAX8, p16, p53, and CEA in 60 ECAs comprising 10 HPV-independent ECAs and 50 HPV-associated ECAs. Both the membranous and nuclear expression levels of CLDN18 were analyzed.Membranous CLDN18 (CLDN18 [M]) was found to be expressed in the mucinous epithelium of all HPV-independent ECAs, including eight gastric-type ECAs (G-ECAs), one endometrioid ECA, and one clear cell ECA, but no nuclear CLDN18 (CLDN18 [N]) expression was detected in HPV-independent ECAs. Among HPV-associated ECAs, CLDN18 (M) expression levels in intestinal-type (I-ECAs) and usual-type ECAs (U-ECAs) were significantly different from those in invasive stratified mucin-producing (iSMILE) carcinomas (p = 0.036). Positive CLDN18 (M) staining was present in 55.6% (5/9) of intestinal-type and 39.4% (13/33) of usual-type ECAs and was not present in iSMILE ECAs. Silva pattern C cancers expressed higher levels of CLDN18 (M) than Silva pattern A and B cancers (p = 0.004), whereas the CLDN18 (N) expression levels in cancers showing Silva pattern A were significantly higher than those in cancers exhibiting Silva patterns B and C (p 0.001).Membranous CLDN18 is expressed in ECAs and is particularly frequently expressed in HPV-independent ECAs, and membranous CLDN18 expression has potential as a therapeutic target. Nuclear staining of CLDN18 is a new immunohistochemical marker for diagnosing Silva pattern A HPV-associated ECAs and is associated with a good prognosis. Further studies should investigate the therapeutic and prognostic significance of membranous and nuclear CLDN18 expression and develop a related test that can be implemented in the clinical evaluation of ECAs.

BACKGROUND: To evaluate the safety and therapeutic efficacy of WX-0593, a newly developed potent anaplastic lymphoma kinase (ALK) inhibitor, in combination with an epithelial growth factor receptor (EGFR) monoclonal antibody (QL1203 or Vectibix) for the treatment of xenograft tumors carrying mutant EGFR and osimertinib-resistant mutations (EGFR/T790M/C797S). METHODS: The inhibition of tumor cell proliferation by WX-0593 and Vectibix alone or combined was evaluated in four EGFR triple-mutant cell lines: PC9 (EGFR Del19/T790M/C797S), NCI-H1975 (EGFR L858R/T790M/C797S), Ba/F3 (EGFR L858R/T790M/C797S and EGFR Del19/T790M/C797S). The in vivo antitumor efficacy of WX-0593 alone or combined with QL1203 or Vectibix was evaluated in xenograft tumor models of BALB/c nude mice developed from H1975 (EGFR-Del19/T790M/C797S) and Ba/F3 (EGFR-L858R/T790M/C797S) cell lines. Mice were randomized into groups and treated with or without WX-0593, QL1203, Vectibix, or their combination. The tumor volume, mouse body weight, and therapeutic side effects were monitored routinely. Blood samples were obtained from all mice at different time points after the last dosage of treatment to evaluate the pharmacokinetic parameters of the drugs. RESULTS: WX-0593 and Vectibix showed a strong synergistic inhibitory effect on the proliferation of two EGFR triple-mutant Ba/F3 cell lines (EGFR L858R/T790M/C797S and Del19/T790M/C797S), but little synergistic inhibitory effect on the proliferation of NCI-H1975 (EGFR L858R/T790M/C797S) and PC9 (EGFR Del19/T790M/C797S). In vivo, WX-0593 (25 mg/kg) showed a modest therapeutic effect when combined with QL1203 or Vectibix, but had no effect on tumor growth as a monotherapy at this dosage. WX-0593 (75 mg/kg) exhibited modest antitumor efficacy that was further enhanced in combination with QL1203 or Vectibix in both tumor models (H1975 and Ba/F3). No significant body weight alteration, any other side effect, or deaths were observed during treatment. Pharmacokinetic analysis showed that the serum level of QL1203 or Vectibix was significantly increased and lasted longer when combined with WX-0593. CONCLUSIONS: WX-0593 exhibited a synergetic effect with an EGFR monoclonal antibody on osimertinib-resistant EGFR-mutant non-small cell lung cancer (NSCLC) both in vitro and in vivo. Their combination showed potent antitumor efficacy and an acceptable safety profile, which may be a promising strategy for the treatment of patients with EGFR triple-mutant NSCLC resistant to osimertinib.

Background With increasing cases of iatrogenic premature ovarian insufficiency (POI), more clinicians are required to counsel patients regarding the gonadotoxic effects of iatrogenic treatments. This survey aimed to explore obstetricians and gynaecologists’ knowledge regarding iatrogenic POI. A national online questionnaire survey was conducted across China. Respondents were asked to select the iatrogenic condition(s) that can cause POI based on their experience and knowledge. Results Of the 5523 returned questionnaires, 4995 were analysed. Among tumour therapies causing POI, most respondents agreed that radiotherapy (73.5% of respondents) and chemotherapy (64.1%) are risk factors for POI. While only 6.5 and 7.8% of the gynaecological oncologists believed that tumour immunotherapy and tumour-targeting therapy, respectively, may cause ovarian impairment, 31.8 and 22.2% of the non-gynaecologic oncologists believed that these therapies could affect ovarian health. Most respondents believed that ovarian cystectomy (54.4%) was a risk factor for POI. In contrast, only a few respondents believed that hysterectomy with bilateral salpingectomy (39.6%) and uterine artery embolisation (33.5%) could cause ovarian impairment. Only 30.5% of respondents believed that immunosuppressants (ISs) increased the risk of POI. Views differed with experience and hospital setting. Conclusions The knowledge of gonadal toxicity due to traditional tumour treatments is generally high among Chinese obstetricians and gynaecologists. A misunderstanding may exist in primary care hospitals and general gynaecologists regarding a link between novel tumour treatments and POI, owing to the lack of convincing evidence. Knowledge of POI caused by hysterectomy and ISs should be improved.

Association of single-nucleotide polymorphisms (SNPs) of the ghrelin gene with polycystic ovary syndrome (PCOS)is unclear. However, their correlation with PCOS-related obesity has been observed. The objective of this study was to evaluate the effects of ghrelin gene SNPs on PCOS-related obesity in Chinese women. The full-length sequence of the ghrelin gene was determined to explore the relationship of the SNPs with PCOS-related obesity in Chinese women. The gene was sequenced, including all exons, introns and exon-intron boundaries in 230 Han Chinese women with PCOS and 162 normal women. Significant genotypic and allelic differences were observed between the obese PCOS group and obese control group at rs35681 locus (

Background. PCOS is a prevalent endocrine and metabolic disorder in women characterized by abnormal blood glucose, dyslipidemia, and abnormal mental health. To improve patient care, the goal of our study is to find out if there are differences in how PCOS patients are treated at different hospital levels within the hierarchical medical system. Methods. Obstetricians and gynecologists from primary, secondary, and tertiary hospitals were the participants in the survey. The responses provided and collected were analyzed using various statistical techniques like the chi-square test, Fisher exact test, and logistic regression with multiple variables. Results. The investigation examined 2298 survey replies (13.1% primary hospitals, 52.4% secondary hospitals, and 34.5% tertiary hospitals). As hospital grade increases, more participants inquire about a patient’s history of unfavorable pregnancies concerning hormone evaluation; the better the hospital’s grade, the greater the number of participants who would undergo AMH and androgen-related tests. The higher the hospital level, the more participants would pick the oral glucose tolerance test (OGTT) to determine insulin resistance, the BMI Asian criteria for defining obesity, and blood lipids. Participants in primary (odds ratio OR = 0.383 , 95% confidence interval (CI) 0.282-0.520) and secondary ( OR = 0.607 , 95% confidence interval (CI) 0.481-0.765) hospitals were significantly less likely to select OGTT than those in tertiary hospitals. Comparatively, fewer primary hospitals chose to do lipid profiling than tertiary hospitals (OR 0.689, 95% CI 0.523-0.909). With the increase in hospital level, participants were more knowledgeable about the multiple efficacies and dose alternatives of metformin and selected letrozole and assisted reproduction more frequently. Conclusion. Our study uncovered differences in the endocrine evaluation, metabolic screening, and management of PCOS patients across obstetrics and gynecology at various hospital levels. Simultaneously, it underlines the need to improve the hierarchical medical system and close the knowledge gap across hospitals.

Cationic amino acid transporters (SLC7A1/CAT1) are highly expressed in human ovarian cancer (OC) tissues. However, the specific biological functions and mechanisms involved remain unclear. We used bioinformatics analysis to explore SLC7A1 expression level, prognostic value, and tumor mutation burden (TMB) in ovarian cancer (OC) tissues. We performed in vitro experiments to identify the expression and biological function of SLC7A1 in epithelial ovarian cancer (EOC) tissues and cells. An amino acid autoanalyzer was used to detect the effect of SLC7A1 on amino acid metabolism in EOC cells. Finally, SLC7A1 in OC was evaluated for cell-to-cell signalling and immune infiltration using online databases. We found that increased SLC7A1 expression in EOC cells and tissues was associated with poorer survival outcomes ( P < 0.05 ) but not with tumor stage or grade of OC ( P > 0.05 ). SLC7A1 is involved in the transport of phenylalanine and arginine in EOC cells, and its knockdown reduced the proliferation and migration of EOC cells and the resistance of cells to cisplatin. Furthermore, the TIMER database indicated that SLC7A1 overexpression was significantly positively correlated with levels of CD4+ memory resting cells, CD8+ effector memory cells, M0 macrophages, and cancer-associated fibroblasts (CAFs) in OC ( P < 0.05 ) and significantly negatively correlated with CD4+ memory-activated cells ( P < 0.05 ). Cell immunofluorescence indicated that SLC7A1 overexpression may affect the distribution of immune-infiltrating lymphocytes in tumors by inhibiting the expression of CCL4. Therefore, we concluded that SLC7A1 is involved in the metabolic remodelling of amino acids in EOC to promote tumor development and cisplatin resistance and is related to the tumor-infiltrating immune microenvironment of OC. SLC7A1 is a biomarker for predicting EOC progression and cisplatin resistance and represents a promising target for EOC treatment.

Background Obesity is associated with the development of polycystic ovary syndrome (PCOS) and contributes substantially to metabolic abnormalities in women with PCOS. The study aimed to describe and compare the practices of physicians in the diagnosis, evaluation, and treatment of obesity in patients with PCOS. Methods Reproductive endocrinologists (Repro-Endo) and obstetrician-gynecologists (non-reproductive medicine specialty, OB-Gyn) in China participated in a survey, and their responses were analyzed using χ2 tests, Fisher exact tests, and multivariable logistic regression analysis. Results The study analyzed 1318 survey responses (85.8% OB-Gyn; 97.3% women). Body mass index was the most common diagnostic criterion for obesity; only 1.3% of participants measured waist circumference to identify abdominal obesity. More Repro-Endo participants (25% of all participants) enquired about the psychological problems of patients with obesity than OB-Gyn participants, and 42.5% of participants reported ordering both a lipid profile and oral glucose tolerance test (OGTT) for patients with obesity and PCOS. Multivariable analysis, that included physician’s specialty, age, hospital grade, and number of patients with PCOS seen annually, revealed that OB-Gyn participants were less likely to order OGTT (OR, 0.3; 95% CI, 0.2–0.4) and lipid profile (OR, 0.2; 95% CI, 0.1–0.3) than Repro-Endo participants. The most common treatments for patients with PCOS were lifestyle modification (> 95%) and metformin (> 80%). More Repro-Endo participants prescribed metformin at a dose of 1.5 g/day compared with OB-Gyn (47.6% vs. 26.3%), and more OB-Gyn participants reported being unclear about the appropriate dosage of metformin for patients with obesity and PCOS (8.9% vs. 1.6%). Conclusion Our survey identified knowledge gaps in metabolic screening for patients with obesity and PCOS and a disparity in the evaluation and treatment of obesity in PCOS among different specialties. Similarly, it highlights the need to improve obesity management education for physicians caring for women with PCOS.

Objective: To evaluate the antitumor activity of WX-0593 (anaplastic lymphoma kinase/ROS proto-oncogene 1 receptor tyrosine kinase [ALK/ROS1] tyrosine kinase inhibitor) combined with bevacizumab biosimilar in vivo. Methods: Cell line-derived xenograft (CDX) model: NCI-H3122 cell suspension was subcutaneously inoculated into the right axilla of BALB/c-nu mice. When the average tumor volume reached 100-300 mm3, the mice were randomly divided into six groups (eight mice/group) and administered with solvent, WX-0593 1.5 or 5 mg/kg, bevacizumab biosimilar 1 mg/kg, or WX-0593 1.5 or 5 mg/kg + bevacizumab biosimilar 1 mg/kg, respectively. Patient-derived xenografts (PDX) model: LU-01-1443 tumor tissue blocks of 20-30 mm3 were subcutaneously inoculated into the right axilla of BALB/c-nu mice. When the average tumor volume reached 115 mm3, the mice were randomly divided into four groups (eight mice/group) and administered with solvent, WX-0593 2.5 mg/kg, bevacizumab biosimilar 1.5 mg/kg or their combination. Tumor diameter was measured twice a week. The tolerability was also assessed. Results: CDX tumor model: There were significant differences between each group and the control group (all P Conclusions: The combination of WX-0593 and bevacizumab biosimilar had obvious synergistic effect and showed potent tumor suppressive activity, which was significantly better than WX-0593 or bevacizumab biosimilar alone at the same dose. There was no drug-related toxicity in all groups, and no increase in toxicity after combined administration. Citation Format: Shansong Zheng, Qingmei Zheng, Xin Dong, Xinmei Wang, Dongmei Chen, Huicheng Duan, Cuicui Ma, Chenwei Zhang. Pharmacodynamics of WX-0593 combined with bevacizumab biosimilar on human lung cancer xenograft mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5458.

4-1BB (CD137, TNFRSF9) is a potent co-stimulatory receptor found on T and NK cells. Activation of 4-1BB requires receptor clustering, which is naturally mediated by the endogenous trimeric 4-1BB ligand. Cross-linking via agnostic monoclonal antibodies can also activate 4-1BB but has generally resulted in unwanted side effects, mainly liver toxicity. To address the shortcomings of 4-1BB agonists, we have developed QL301, a PD-L1 x 4-1BB bispecific antibody that conditionally activates 4-1BB only when concurrently engaged to PD-L1, an immune checkpoint mediator elevated in the immuno-suppressive tumor microenvironment. The IgG1 backbone of QL301 was mutated to eliminate Fc gamma receptor-dependent functions such as antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), thereby preventing depletion of effector immune cells and non-specific activation of 4-1BB through Fc gamma receptor binding. In addition, QL301 blocks the suppressive interaction of PD-1 with PD-L1. Therefore, through a combination of 4-1BB agonism and PD-L1 blockade, QL301 provides both a co-stimulatory signal and the release of a suppressive signal to reinvigorate anti-tumor immune response. In vitro, QL301 induced robust cytokine release and expansion of CD8+ T cells conditional on the presence of tumor or antigen presenting cells expressing PD-L1. In xenograft and transgenic mice models, QL301 had potent anti-tumor effect that was superior to PD-L1 monoclonal antibodies. Tumor regression correlated with the expansion of CD8+ T cells. In addition, QL301 potentiated tumor cell killing mediated by an EGFR targeted CD3 bispecific antibody, providing a basis for combination therapy. In non-human primates, QL301 was well tolerated up to 30 mg/kg. There was no chronic elevation of serum AST and ALT levels, and histopathology analysis showed minimal inflammation of liver tissue. A phase 1 clinical trial to evaluate the safety, tolerability, and early efficacy of QL301 is currently ongoing. Citation Format: Shenda Gu, Irene Tang, Shirley Mihardja, Wei Wei Prior, Hieu V. Tran, Allan Chan, Anna McClain, Aaron Kurtzman, Shihao Chen, Youguang Luo, Xiaoyan Kang, Xiaoran Wu, Qingmei Zheng, Guodong Jia. QL301, a PD-L1 dependent 4-1BB agonist with enhanced preclinical anti-tumor efficacy and minimal liver toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4245.

Objective: To preliminarily demonstrate the synergistic effect of WX-0593 (anaplastic lymphoma kinase/ROS proto-oncogene 1 receptor tyrosine kinase [ALK/ROS1] tyrosine kinase inhibitor) in combination with panitumumab on osimertinib-resistant cis EGFR triple-mutant non-small cell lung cancer (NSCLC) both in vitro and in vivo. Methods: The tumor cell inhibition rates of WX-0593 and panitumumab alone or combined were assessed in osimertinib-resistant cis EGFR triple-mutant cell lines, including PC9 (EGFR Del19/T790M/C797S), NCI-H1975 (EGFR L858R/T790M/C797S), Ba/F3 (EGFR L858R/T790M/C797S and EGFR Del19/T790M/C797S). The in vivo tumor suppressive efficacy of single-agent WX-0593, panitumumab, and their combination was evaluated in H1975 (EGFR del19/T790M/C797S) and Ba/F3 (EGFR L858R/T790M/C797S) cell line-derived xenograft (CDX) models of BALB/c nude mice. The tolerability was also assessed. Results: In vitro studies showed that the combination of WX-0593 and panitumumab had a potent synergistic effect on proliferation inhibition in all the four cell lines with cis EGFR triple mutations resistant to osimertinib. WX-0593 in combination with panitumumab demonstrated a delaying effect on tumor growth without increasing drug toxicity in the H1975 CDX model. WX-0593 and panitumumab alone had tumor suppressive effects in the Ba/F3 CDX model. And WX-0593 plus panitumumab significantly enhanced the antitumor activity in the Ba/F3 model. Conclusion: The data from the study suggested that WX-0593 and panitumumab had a promising synergistic effect on osimertinib-resistant EGFR-mutant NSCLC both in vitro and in vivo. The combination regimen may have important clinical implications for the future treatment of patients with EGFR triple-mutant NSCLC resistant to osimertinib. Citation Format: Shansong Zheng, Qingmei Zheng, Dongmei Chen, Xinmei Wang, Xin Dong, Xin Zhang, Cuicui Ma, Huicheng Duan, Chenwei Zhang. Synergistic effects of WX-0593 in combination with panitumumab on osimertinib-resistant EGFR-mutantnon-small cell lung cancer in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5459.

Background: The 3rd-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), like osimertinib, provide marked clinical benefit for EGFR-mutant non-small cell lung cancer (NSCLC) patients with extended overall survival vs former EGFR TKIs (e.g., gefitinib). Approximate 10%-24% of NSCLC patients acquired C797S mutation when treated with osimertinib. Unfortunately, limited treatments are available for patients after osimertinib resistance. QLH11811 is a new generation EGFR TKI designed to target the EGFR with ex19del/L858R/T790M/C797S mutations. Here, we disclosed its preclinical data to support its clinical development in EGFR-mutant NSCLC. Methods: The inhibitory activity of QLH11811 on mutated and wild-type EGFR was tested in engineered cell lines and patient-derived organoid (PDO). The in vivo antitumor activity of QLH11811 was evaluated in the patient-derived xenograft (PDX) model with cis EGFR ex19del/T790M/C797S triple mutations, and the H1975 (cis EGFR L858R/T790M/C797S and cis EGFR ex19del/T790M/C797S), PC-9 (EGFR ex19del), and Ba/F3 (EGFR ex19del/C797S) cell line-derived xenograft (CDX) models. The pharmacokinetic (PK) profile was investigated in animals, and the human PK profile was projected using allometric scaling method. Results: QLH11811 displayed potent anti-proliferation activity against Ba/F3 (EGFR ex19del/T790M/C797S, L858R/T790M/C797S, ex19del/C797S, or L858R/C797S), PC-9 (EGFR ex19del/T790M/C797S), H1975 (EGFR L858R/T790M/C797S, L858R/T790M), H3255 (L858R) and HCC827 (ex19del) with IC50 of 2.6, 3.1, 2.4, 4.1, 51, 50, 27, 21, and 11 nM, respectively. QLH11811 also showed excellent selectivity when compared the above values with its IC50 against Ba/F3 (EGFR wild-type, 61 nM) and A431 (EGFR wild-type, 440nM). QLH11811 demonstrated excellent inhibitory activities against seven osimertinib-resistant PDO models. Daily oral QLH11811 significantly inhibited tumor growth at all doses tested (P Conclusion: The in vitro and in vivo preclinical data demonstrated QLH11811 is a highly potent and selective 4th-generation EGFR TKI with activity against the osimertinib-resistant NSCLC with EGFR C797S mutation. The preclinical PK data supported the efficacious dose of QLH11811 in human would be 103 mg. Citation Format: Shansong Zheng, Wei Deng, Qingmei Zheng, Yingying Yang, Na Li, Tan Pang, Xueying Feng, Simon Taylor, Lina Ma, Yaqiong Wu, Ziwei Zhao. QLH11811, a selective 4th-generation EGFR inhibitor for osimertinib-resistant EGFR-mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5457.

The currently used anti-cytokine therapeutic antibodies cannot selectively neutralize pathogenic cytokine signaling that cause collateral damage to protective signaling cascades carrying the potential for unwanted side effects. The variable domains of heavy-chain only antibodies (HCAbs) discovered in Camelidae are stable and display to be fully functional in antigen-binding against variable targets, which seem to be attractive candidates for the next-generation biologic drug study. The purpose of our study was to establish a simple prokaryotic expression system for large-scale expression, purification, and refolding of the recombinant anti-tumor necrosis factor α (TNF-α) fusion protein (FVH1-1) from inclusion bodies. Over 95% purity of the recombinant anti-TNF-α fusion proteins was obtained by just one purification step in our developed prokaryotic expression system, while the results of surface plasmon resonance (SPR) established the high-efficiency potent binding ability of FVH1-1 to human TNF-α. The counteraction of TNF-α cytotoxic effect experiment on the mouse fibroblast fibrosarcoma cell line (L929) confirmed that the expressed FVH1-1 were able to selectively and highly combine with human recombinant TNF-α (hTNF-α) in vitro. Western blot results showed that FVH1-1 can inhibit the activation of caspase-9 and PARP, which are the apoptotic signaling pathway proteins activated by hTNF-α. Meanwhile, lysosome autophagy signaling pathways stimulated by hTNF-α were inhibited by FVH1-1, which down-regulated the expression of LC3II/LC3I and up-regulated the expression of P62, indicating that the autophagy linked with TNF-α-induced apoptosis in response to rheumatoid arthritis. The results of the AIA rat model experiment presented that FVH1-1 can reduce the degree of joint swelling and inflammatory factors to a certain extent in vivo.

Additional file 3 : Supplementary Table 2. Comparison of views on iatrogenic condition(s) to induce POI among respondents from different levels of hospital.

Additional file 2 : Supplementary Table 1. Comparison of views on iatrogenic condition(s) to induce POI among respondents with different length of service (years).

Additional file 1. Questionnaire.

AIM: To evaluate the feasibility of promoting genetic detection for granular corneal dystrophy type 2 (GCD2) by a questionnaire conducted among citizens in five cities in China. METHODS: The data were collected by questionnaire, and analyzed by Chi-square test and one-tailed t test in IBM SPSS statistics. RESULTS: Based on the survey data on the awareness of GCD2 genetic detection in this study and the positive predictive analysis report of the citizens in five cities in China, the vast majority (84.2%) of respondents had never heard of it and did not know that GCD2 patients have been prohibited from performing excimer surgery that can deteriorate GCD2 patients’ condition even leading to blindness. Though 3.4% of patients understood GCD2 very much, they have no idea that GCD2 could not be 100% accuracy diagnosed by the conventional inspection methods. CONCLUSION: It is feasible and necessary to use GCD2 genetic detection as an excimer preoperative examination project. In order to promote the development of detection project, a few improvements should be carried out in terms of the promoting efforts, costs, and research progress.

RATIONALE The gonads of patients with Turner syndrome (TS) were previously thought to be funicular. There was no increase in androgen level. The gonad that is testis should be taken into account when the patient's serum testosterone level was abnormal and hypothalamic-pituitary-adrenal disease was excepted. PATIENT CONCERNS A 16-year-old girl was admitted to our hospital because of chromosomal abnormalities and elevated androgen levels. DIAGNOSIS Turner syndrome could be diagnosed since her chromosome karyotype was 45, XO. INTERVENTIONS The patient was given bilateral gonadectomy and hormone replacement therapies. OUTCOME The level of the patient's serum testosterone was

An 8-week feeding trial was conducted to evaluate the effects of dietary supplementation with green tea waste (GTW) on growth, digestive enzyme and lipid metabolism of juvenile hybrid tilapia, Oreochromis niloticus × O. aureus. The fish (initial mean body weight, 12.63 ± 0.75 g) were fed five experimental diets that included 0 (control), 0.8, 1.6, 3.2 or 6.4 % of GTW in triplicate aquaria, twice daily. Growth performance, plasma metabolites content and liver and intestine digestive enzyme activities were determined. Fish accepted well all experimental diets during the trial, and no mortality was observed. The weight gain increased (P

This study was designed to investigate the effects of dietary lipid levels on growth performance, lipid deposition and activities of lipid metabolic enzymes in hybrid tilapia (Oreochromis niloticus × O. aureus). Four isonitrogenous (300 g/kg crude protein) experimental diets containing graded levels of lipid (25, 55, 85 and 115 g/kg) were randomly assigned to triplicate groups of 180 juvenile fish. Fish were fed twice daily for 8 weeks. At the end of the experiment, the growth performance and proximate composition of fish were determined. The activities and gene expression of lipoprotein lipase (LPL) and hormone-sensitive lipase (HSL) were assessed as well. Fish fed the diets with 55 and 85 g/kg lipid had a significantly (p < 0.05) higher body weight gain than those fed the diets with 25 and 115 g/kg lipid. The whole-body and liver lipid contents were significantly (p < 0.05) elevated with increasing dietary lipid levels. Moreover, the activities and mRNA abundances of LPL and HSL in the liver, dorsal muscle and fat tissues were markedly altered by dietary lipid levels. Our data demonstrate a profound influence of dietary lipid levels on the growth and lipid deposition in hybrid tilapia, which is likely associated with the regulation of lipid metabolic enzymes including LPL and HSL.

Background Most women with polycystic ovary syndrome (PCOS) have insulin resistance, hyperinsulinemia, and elevated serum IL-6 levels. These elevated IL-6 levels may have links with insulin resistance and hyperandrogenism. Metformin may have beneficial effects on the chronic low-grade inflammatory background associated with PCOS. Methods A systematic review was performed via PUBMED, EMBASE, and The Cochrane Library on PCOS studies published through November 30, 2013. Studies were selected that evaluated the effect of metformin on IL-6 levels in PCOS patients. Studies not containing adequate diagnosis information about PCOS or not excluding of other causes of hyperandrogenism were excluded. Results Five studies met the inclusion criteria. Of these, one study reported a significant decrease in IL-6 levels after metformin treatment in women with PCOS. Two studies reported that treatment-related reductions in IL-6 levels were significantly correlated with insulin metabolism. In the remaining two studies, plasma IL-6 levels did not change following metformin treatment. Conclusions Serum IL-6 levels of PCOS patients may be influenced by metformin. Early application of metformin therapy may relieve chronic low-grade inflammation in women with PCOS. However, further investigations with larger samples are needed to better understand the effects of metformin on IL-6 levels and chronic inflammation in PCOS.

A total of 587 individuals from 12 indigenous chicken breeds from South China and two commercial breeds were genotyped for 26 microsatellites to investigate the genetic diversity and population structure. All microsatellites were found to be polymorphic. The number of alleles per locus ranged from 5 to 36, with an average of 12.10 ± 7.00 (SE). All breeds, except White Recessive Rock, had high allelic polymorphism (>0.5). Higher genetic diversity was revealed in the indigenous chicken breeds rather than in the commercial breeds. Potential introgression from the commercial breeds into the indigenous chickens was also detected. The population structure of these indigenous chicken breeds could be explained by their geographical distribution, which suggested the presence of independent history of breed formation. Data generated in this study will provide valuable information to the conservation for indigenous chicken breeds in future.

Catalase (CAT) is a key enzyme in the antioxidant systems of living organisms and plays an important role in avoiding producing oxidative stress by eliminating hydrogen peroxide. In this paper, the full-length cDNA of CAT was cloned from hepatopancreas of grass carp ( Ctenopharyngodon idellus ). The full-lengthcDNA of CAT was 2 263 base-pairs (bp) (GenBank accession No. FJ560431), including a complete open reading frame (ORF) of 1 575 bp, a 5' untranslated region (UTR) of 118 bp and 3' UTR of 570 bp. The ORF encoded 525 amino acid (aa) residues and the molecular mass of the predicted protein was 59.59 kD with an estimated pI of 7.02. Near the termination codon of CAT cDNA of grass carp, the 3' UTR had a long and integrated AC repeat sequences, which had the same characteristic of catalase in zebrafish, silver carp and rodents. Sequence alignment results showed that the nucleotide sequence and the deduced amino acid sequence of grass carp CAT cDNA shared high identity with other selected species, about 93.4%~43.0% and 98.1%~63.3%, respectively. Meanwhile, the deduced amino acid sequence of CAT cDNA of grass carp had several highly conserved motifs compared with other animals, including the heme-ligand signal sequence “RLFSYPDTH”, the enzyme active center sequence “FDRERIPERVVHAKGA” and three catalytic amino acid residues (His 74 , Asn 147 and Tyr 357 ). Besides, the CAT of grass carp also had highly conserved heme binding pocket and NADPH binding site. According the above sequence characteristics, we can presume that the grass carp CAT gene belonged to the subgenotypes group of single-function or typical CAT gene in CAT family. Real-time quantitative PCR (Q-PCR) method was used to analyze the CAT mRNA expression characterization in 11 species of tissues in grass carp. The results showed that the expression of CAT mRNA was found in all the detected tissues, especially, strongly in hepatopancreas, followed by spleen, intestine, kidney, but poorly in muscle and lipid. Therefore, the results of this study would contribute to further investigate the genetic structure and function of fish CAT , and lay the foundation for CAT molecular mechanism of antioxidation.

A 4-week study was conducted to determine the effect of starvation on activities and mRNA expression of lipoprotein lipase (LPL) and hormone-sensitive lipase (HSL) in hybrid tilapia (Oreochromis niloticus × O. areus). The tissue samples were sampled once a week. Results showed that body weight (BW) and hepatosomatic index (HSI) were decreased significantly (P < 0.05) during starvation. The percentages of crude fat and crude protein in the whole body and the fat content in muscle decreased significantly (P < 0.05), while the rate of moisture and crude ash increased significantly (P < 0.05). The response of LPL, HSL activities and mRNA expression in tissues was tissue dependent. The activities of LPL and HSL in muscle at day 7 were elevated by 2.5 times (P < 0.05) and 11.8 times (P < 0.05) of the value at day 0, respectively, and both then decreased to pre-starvation levels at day 14 and finally stabilized at a certain level afterward. LPL and HSL mRNA abundance in muscle remained relatively stable between 0 and 14 day; then, a significant increase was seen after 14 days. In the liver, LPL activity maintained a significantly increasing trend during starvation, while HSL activity rose dramatically at day 7 of starvation by 2.35 times (P < 0.05) and finally stabilized at a certain level. The mRNA abundance of liver LPL increased significantly during the whole process of starvation (P < 0.05), whereas the mRNA abundance of liver HSL decreased significantly at day 7 of starvation, elevating significantly afterward (P < 0.05).

The aim of the study was to determine the association between three single nucleotide polymorphism (SNP) variants (rs35368790, rs35069869 and rs684846) of the MCF2 cell line-derived transforming sequence-like 2 (MCF2L2) gene and polycystic ovary syndrome (PCOS) in PCOS family trios.Genotyping was done by TaqMan assay that incorporates minor groove-binding probe technology for allelic discrimination. One hundred and fifty-two unrelated PCOS probands and their biological parents were recruited. All subjects were of Han Chinese origin and from Shandong Province.The transmission disequilibrium test (TDT) for allelic association demonstrated that a weak association was detected in SNP rs35368790 with p = 0.008. However, we found no significant transmission distortion of the other two SNPs (rs35069869, chi(2) = 3.645, p = 0.056; rs684846, chi(2) = 1.429, p = 0.232, respectively).These results suggest that the genetic polymorphisms within MCF2L2 are likely to confer an increased susceptibility to PCOS in the Chinese population. Our present data may provide a basis for further studies of the role of the MCF2L2 gene in the etiology of PCOS.

An 8-week feeding trial was conducted to evaluate the effect of replacing soybean meal (SBM) with cottonseed meal (CSM) on growth and health of grass carp. Four isonitrogenous diets containing 0, 16.64, 32.73 and 48.94% of CSM, respectively, as replacements of 0, 35, 68 and 100% of SBM were fed to fish (initial body weight 7.14 ± 0.75 g/fish) in triplicate aquaria twice daily. The results indicated that fish fed diet containing 16.64% CSM as a replacement of 35% of SBM was not affected in weight gain (WG), feed efficiency ratio (FER) and feed conversion ratio (FCR) (P > 0.05), while fish fed diets containing higher level of dietary CSM (32.73 and 48.94%) significantly decreased WG and PER and significantly increased FCR (P