Endocrine-resistance remains a major challenge in estrogen receptor α positive (ERα⁺) breast cancer (BC) treatment and constitutively active somatic mutations in ERα are a common mechanism. There is an urgent need to develop novel drugs with new mode of mechanism to fight endocrine-resistance. Given aberrant ERα activity, we herein report the identification of novel covalent selective estrogen receptor degraders (cSERDs) possessing the advantages of both covalent and degradation strategies. A highly potent cSERD 29c was identified with superior anti-proliferative activity than fulvestrant against a panel of ERα⁺ breast cancer cell lines including mutant ERα. Crystal structure of ERα‒ 29c complex alongside intact mass spectrometry revealed that 29c disrupted ERα protein homeostasis through covalent targeting C530 and strong hydrophobic interaction collied on H11, thus enforcing a unique antagonist conformation and driving the ERα degradation. These significant effects of the cSERD on ERα homeostasis, unlike typical ERα degraders that occur directly via long side chains perturbing the morphology of H12, demonstrating a distinct mechanism of action (MoA). In vivo, 29c showed potent antitumor activity in MCF-7 tumor xenograft models and low toxicity. This proof-of-principle study verifies that novel cSERDs offering new opportunities for the development of innovative therapies for endocrine-resistant BC.

Objective:To investigate the value of peripheral blood eosinophils (EOS) in predicting the therapeutic effect of sublingual specific immunotherapy (SLIT) in patients with allergic rhinitis (AR).Methods:From January 2018 to June 2020, 200 patients with AR who received SLIT in Dongguan Kanghua Hospital were evaluated for their symptoms before treatment and 6 months after treatment. The curative effect was evaluated according to the improvement of the total symptom score. The number of eosinophils, percentage of eosinophils in peripheral blood were measured before treatment. The correlation between curative effect and EOS count and EOS percentage was analyzed and the value of these two indicators in predicting the efficacy of SLIT was evaluated.Results:Of the 200 AR patients, 178 patients were confirmed to have completed the treatment course of 6months. 126 effective and 52 ineffective, the effective rates were 70.8%. There was a weak correlation between the number of EOS in peripheral blood and the percentage of EOS in peripheral blood before treatment and the efficacy of SLIT ( r=0.168, P=0.048; r=0.250, P=0.001). The area under the curve of peripheral blood EOS count was 0.380, and the percentage of peripheral blood EOS was 0.355, which were all less than 0.5. Conclusions:There was no significant correlation between the number of peripheral blood EOS count and peripheral blood EOS percentage and the efficacy of SLIT , therefore, both of blood EOS count and blood EOS percentage have no value in predicting the efficacy of SLIT.

Objective To investigate the value of P-selectin,thrombomodulin (TM) and von Willebrand factor (vWF) in identifying severe acute pancreatitis (SAP) at an early stage of the disease.Methods 80 patients with acute pancreatitis (25 mild,30 moderate and 25 severe) were selected in this study when they were admitted within 24 hours of the onset of symptoms.20 healthy volunteers were collected as the healthy control.Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of vascular endothelial cell damage markers (P-selectin,TM and vWF) in SAP patients and the control group.Results The levels of 3 markers were significantly higher in SAP patients than in the mild and moderate acute pancreatitis patients and healthy volunteers (P＜0.05).P-selectin,TM and vWF were independent markers for the development of SAP and had higher discriminative powers than conventional marker tumor necrosis factor(TNF-α)(P＜0.05).They were similar to the APACHE-Ⅱ scoring system in distinguishing SAP at an early stage.Conclusions P-selectin,TM and vWF are independent markers to identify the development of SAP at an early stage.They are obviously superior to TNF-α and similar to the APACHE-Ⅱ scoring system.

Objective To investigate the effect of early continuous veno-venous hemofiltration (CVVH) on intra-abdominal pressure (IAP) and serum interleukin-6 (IL-6) in severe acute pancreatitis (SAP) patients with abdominal compartment syndrome (ACS).Methods 41 SAP patients with ACS were selected as treatment group and treated with CVVH as well as conventional methods in ICU.The other 12 patients with the same disease were selected as the control group and were only treated with conventional methods because of economic reasons.IAP and blood level of IL-6 in the two groups were measured daily in order to investigate their changes and the correlation between the two parameters.Results The serum IL-6 level and IAP in the two groups were higher on admission day.IAP and serum IL-6 level in the treatment group were significantly decreased on the first day after treatment,and thereafter decreased rapidly.In the control group,IAP and serum IL-6 level were significantly decreased on the 3rd day after treatment.IAP and serum IL-6 level from the 1st day to the 6th day after treatment in the treatment group were significantly lower than those of the control group at the same time point (P＜0.05).There was a significant positive correlation between blood IL-6 level and IAP in SAP patients with ACS(r=0.48,P＜0.01).IL-6 difference before and after treatment was also positively correlated with the difference of IAP(R=0.39,P＜0.05).Conclusions VVH significantly decreased the IAP and the blood level of IL-6 in ACS patients of SAP.The blood level of IL-6 is significantly correlated with IAP,suggesting that IL-6 may play an important role in the pathogenesis of ACS.Therefore early CVVH may clear the cytokines such as IL-6 and lower IAP,thus to prevent multiple organ dysfunction syndrome (MODS),which should be applied in the early stage of ACS.

Objective To evaluate the efficacy of intratympanic steroid therapy compared with systemic ster‐oid therapy on the treatment of idiopathic sudden sensorineural hearing loss (ISSNHL) patients with damaged glu‐cose tolerance .Methods Fifty first -diagnosed unilateral ISSNHL patients with damaged glucose tolerance were randomized devided equally to the intervention group (intratympanic steroid therapy) or the control group (systemic steroid therapy) ,all patients received conventional drug therapy simultaneously .Pure-tone hearing threshold tests were performed in all patients every 3 days after the first time ,and repeated measures anova was used to assess effects of hearing recovery accompanied with time .Results The mean hearing threshold in the control group de‐creased from 85 .4 ± 5 .6 dB to 48 .2 ± 4 .9 dB ,while in the intervention group it decreased from 84 .8 ± 5 .6 dB to 31 .7 ± 4 .6 dB .Total effective rate in the intervention group (84 .00% ,21/95) was higher than that in the control group (68 .00% ,17/25)(P<0 .05) .Conclusion The intratympanic steroid therapy is more effective than systemic steroid therapy in the treatment of ISSNHL patients with damaged glucose tolerance .

Objective To investigate a reliable and easy assessment method for swallowing function by evaluating objectively the recovery process of swallowing function in patients six months after supracricoid partial laryngectomy.Methods The swallowing function of patients who underwent supracricoid partial laryngectomy was evaluated six months after operation in Nanfang Hospital of Southern Medical University between January 2013 and February 2014 with two methods,the modified barium swallow (MBS) and fiberoptic endoscopic evaluation of swallowing (FEES),combined with modified penetration aspiration scale (MPAS).Furthermore,the feasibility,reliability and accuracy of these two methods were compared.Results Eleven patients were enrolled.MPAS equals score 1 for solid food,semiliquid food,and liquid food was defined as a criteria of normal swallowing function.By MBS evaluation,the numbers of patients with normal swallowing function were two cases at day 16-30 postoperation,two cases at day 31-45 postoperation,five cases at day 46-90 postoperation,and six cases at day 91-180 postoperation,respectively.By FEES evaluation,the above numbers were three cases,four cases,six cases and eight cases,respectively.When the aspiration was minimal and ejected completely and MPAS was less than or equal to score 4 for solid food,semiliquid food,and liquid food,the gastric tube could be removed.According to this standard,the gastric tube was removed in all cases,and the mean time was (21.7 ± 9.8) days.A good correlation was obtained between these two methods when evaluating solid and semiliquid food,and the Kappa values were 0.802 and 0.844,respectively.However,a little agreement was obtained between these two methods when evaluating liquid food,and the Kappa value was 0.529.Conclusions Patients who underwent supracricoid partial laryngectomy could restore good swallowing function in six months after the operation.Both the MBS and FEES are valuable procedures for evaluating objectively the swallowing function in patients after supracricoid partial laryngectomy.The FEES is much better than MBS,because FEES is a simple operation performed alone by otolaryngologists with no radiation.

OBJECTIVE: To study the curative effect and prognosis of salvage surgery performed for recurrent laryngocarcinoma. METHOD: The clinical data of 43 patients with salvage surgery for recurrent laryngocarcinoma hospitalized in Nanfang Hospital between 2003 and 2011 were analyzed retrospectively. Survival analysis was performed by using Kaplan-Meier method and prognosis factors were analyzed by Log-rank test. RESULT: After salvage surgery, 10 (23.3%) patients developed postoperative complications. Pharyngocutaneous fistula and infection occurred in 8 (18.6%) patients. Kaplan-Meier analysis showed that patients survived for 3-year (n = 32) and 5-year 25) after salvage surgery were 56.3% and 32.0% respectively. Univariate analysis indicated that clinical stage in the first diagnosis was significantly correlated with 3 year overall survival (P < 10.05). Local recurrence of laryngeal cavity group and preservation of laryngeal function group had a good prognosis respectively, but no sig nificant difference between them. CONCLUSION Salvage surgery is a good choice for recurrent laryngeal carcinoma. Outcomes of these patients were correlated with clinical stages. Laryngeal function preserving surgery for local recurrent laryngeal carcinoma can achieve a expected curative effect and prognosis.
Adult ; Aged ; Aged, 80 and over ; Female ; Follow-Up Studies ; Humans ; Laryngeal Neoplasms ; surgery ; Male ; Middle Aged ; Neoplasm Recurrence, Local ; surgery ; Prognosis ; Retrospective Studies ; Salvage Therapy ; Treatment Outcome

OBJECTIVE: To evaluate the clinical value of heterogeneous acellular dermalmatrix with autologous bone meal in open tympanoplasty. METHOD: Twenty-eight cases (30 ears) with middle ear cholesteatoma were trea- ted by open tympanoplasty and repaired by heterogeneous acellular dermalmatrix autologous bone meal on study team. Twenty-two cases (22 ears) with middle ear cholesteatoma were treated by open tympanoplasty on control team. All patients were followed up for 12 to 18 months and assessed the fuction postoperatively. RESULT: The re- construction of external auditory canal structure is close to normal, and no narrow happens on study team. The rate of dry ear was about 90%. All cases had no recurrence of cholesteatoma. CONCLUSION Application of decellu- larized dermal matrix with autologous bone meal can rise early to cover the wound, promote wound healing and to reduce the external auditory canal, reduce the effect of granulation and scar formation. It is a kind of method of repair to be promoted.
Acellular Dermis ; Biological Products ; Cholesteatoma, Middle Ear ; surgery ; Cicatrix ; Ear Canal ; surgery ; Humans ; Minerals ; Postoperative Period ; Recurrence ; Tympanoplasty ; methods ; Wound Healing

OBJECTIVETo screen tumor biomarkers in the plasma close related with hypopharyngeal carcinoma.

METHODSPooled plasma from 6 patients with hypopharyngeal carcinoma and 6 healthy individuals were collected. After removal of high-abundance plasma proteins, two-dimensional gel electrophoresis (2-DE) was performed to isolate the total proteins, and the protein spots with more than 2-fold differential expressions were detected by 2D analysis software followed by identification by MALDI-TOF/TOF mass spectrometer. Western blotting was performed to validate the expression level of α2-HS-glycoprotein.

RESULTSA total of 11 differentially expressed protein spots were selected, including 5 upregulated proteins and 6 downregulated proteins. MALDI-TOF/TOF identified the upregulated proteins in hypopharyngeal carcinoma patients as alpha-2-HS-glycoprotein and haptoglobin and downregulated ones as Ig kappa chain C region and apolipoprotein A-I. Western blotting demonstrated that α-2-HS- glycoprotein expression level was consistent with that detected by 2-DE.

CONCLUSIONPatients with hypopharyngeal carcinoma show different plasma protein profiles from healthy individuals. These differentially expressed proteins may serve as potential specific tumor biomarkers for hypopharyngeal carcinoma.

Biomarkers, Tumor ; blood ; Blood Proteins ; metabolism ; Humans ; Hypopharyngeal Neoplasms ; blood ; Male ; Middle Aged ; Proteomics ; methods

OBJECTIVE: To compare and analyze the expression difference of proteins between laryngocarcinoma and healthy individuals to search for protein biomarkers that may be detected in plasm of laryngocarcinoma patients. METHOD: Pooled plasm from 6 laryngocarcinoma patients and 6 healthy individuals as controls were collected. Two-dimensional gel electrophoresis (2-DE) was used to isolate the total proteins, and the differential protein spots were identified by MALDI-TOF/TOF mass spectrometer, and then the biological information of the proteins was analyzed. RESULT: Twenty differential expressed protein spots with more than 1.5-fold between the laryngocarcinoma and healthy individuals were selected, and there were 8 proteins upregulated and 12 proteins downregulated among these proteins. After identifying by MALDI-TOF/TOF, compared with healthy controls, the spots that were L1, C-reactive protein, haptoglobin, ceruloplasmin; the spots that were downregulated were: Serotransferrin, alpha-2-HS-glycoprotein, fibrinogen gamma chain, haptoglobin related protein, Ig lambda-1 chain C regions, Ig kappa chain C region, apolipoprotein A-I, transthyretin, apolipoprotein C-III. CONCLUSION Compared with laryngocarcinoma and healthy individuals, the plasm proteins profile showed differently. The proteins of differential expressed are expected to be the specific plasm biomarkers for laryngocarcinoma patients.
Biomarkers, Tumor ; blood ; Case-Control Studies ; Humans ; Laryngeal Neoplasms ; blood ; Male ; Mass Spectrometry ; Middle Aged ; Proteome ; metabolism ; Proteomics ; methods