Rare diseases still lack effective treatments, and the development of drugs for rare diseases (known as orphan drugs) is an urgent medical problem. As natural active ingredients in living organisms, some biomacromolecule drugs have good biocompatibility, low immunogenicity, and high targeting. They have become one of the most promising fields in drug research and development in the 21st century. However, there are still many obstacles in terms of in vivo delivery. In view of the unique advantages of nanocarriers prepared from polymers, lipids, organic biomimetic and inorganic materials in drug delivery, researchers are committed to building an efficient delivery system with versatility and synergy to solve the bottleneck issues in treating rare diseases with biomacromolecule drugs. Therefore, this article reviews the research progress of nanocarrier delivering proteins, peptides and nucleic acids in the field of rare disease treatment in the past ten years, which provides ideas for researches on biomacromolecule drug nanosystems in the field of treatment of rare diseases.

With the increasing proportion of human papilloma virus(HPV)infection in the pathogenic factors of oro-pharyngeal cancer,a series of changes have occurred in the surgical treatment.While the treatment mode has been im-proved,there are still many problems,including the inconsistency between diagnosis and treatment modes,the lack of popularization of reconstruction technology,the imperfect post-treatment rehabilitation system,and the lack of effective preventive measures.Especially in terms of treatment mode for early oropharyngeal cancer,there is no unified conclu-sion whether it is surgery alone or radiotherapy alone,and whether robotic minimally invasive surgery has better func-tional protection than radiotherapy.For advanced oropharyngeal cancer,there is greater controversy over the treatment mode.It is still unclear whether to adopt a non-surgical treatment mode of synchronous chemoradiotherapy or induction chemotherapy combined with synchronous chemoradiotherapy,or a treatment mode of surgery combined with postopera-tive chemoradiotherapy.In order to standardize the surgical treatment of oropharyngeal cancer in China and clarify the indications for surgical treatment of oropharyngeal cancer,this expert consensus,based on the characteristics and treat-ment status of oropharyngeal cancer in China and combined with the international latest theories and practices,forms consensus opinions in multiple aspects of preoperative evaluation,surgical indication determination,primary tumor re-section,neck lymph node dissection,postoperative defect repair,postoperative complication management prognosis and follow-up of oropharyngeal cancer patients.The key points include:① Before the treatment of oropharyngeal cancer,the expression of P16 protein should be detected to clarify HPV status;② Perform enhanced magnetic resonance imaging of the maxillofacial region before surgery to evaluate the invasion of oropharyngeal cancer and guide precise surgical resec-tion of oropharyngeal cancer.Evaluating mouth opening and airway status is crucial for surgical approach decisions and postoperative risk prediction;③ For oropharyngeal cancer patients who have to undergo major surgery and cannot eat for one to two months,it is recommended to undergo percutaneous endoscopic gastrostomy before surgery to effectively improve their nutritional intake during treatment;④ Early-stage oropharyngeal cancer patients may opt for either sur-gery alone or radiation therapy alone.For intermediate and advanced stages,HPV-related oropharyngeal cancer general-ly prioritizes radiation therapy,with concurrent chemotherapy considered based on tumor staging.Surgical treatment is recommended as the first choice for HPV unrelated oropharyngeal squamous cell carcinoma(including primary and re-current)and recurrent HPV related oropharyngeal squamous cell carcinoma after radiotherapy and chemotherapy;⑤ For primary exogenous T1-2 oropharyngeal cancer,direct surgery through the oral approach or da Vinci robotic sur-gery is preferred.For T3-4 patients with advanced oropharyngeal cancer,it is recommended to use temporary mandibu-lectomy approach and lateral pharyngotomy approach for surgery as appropriate;⑥ For cT1-2N0 oropharyngeal cancer patients with tumor invasion depth＞3 mm and cT3-4N0 HPV unrelated oropharyngeal cancer patients,selective neck dissection of levels ⅠB to Ⅳ is recommended.For cN+HPV unrelated oropharyngeal cancer patients,therapeutic neck dissection in regions Ⅰ-Ⅴ is advised;⑦ If PET-CT scan at 12 or more weeks after completion of radiation shows intense FDG uptake in any node,or imaging suggests continuous enlargement of lymph nodes,the patient should undergo neck dissection;⑧ For patients with suspected extracapsular invasion preoperatively,lymph node dissection should include removal of surrounding muscle and adipose connective tissue;⑨ The reconstruction of oropharyngeal cancer defects should follow the principle of reconstruction steps,with priority given to adjacent flaps,followed by distal pedicled flaps,and finally free flaps.The anterolateral thigh flap with abundant tissue can be used as the preferred flap for large-scale postoperative defects.

Objective:To explore changes in the serum TBNK lymphocyte subset levels in patients with lung cancer undergoing chemother-apy and analyze their correlation with prognosis.Methods:Ninety-two patients undergoing standard regimen lung cancer chemotherapy who attended Beijing Jingmei Group General Hospital from January 2020 to June 2023 were selected.The level of TBNK lymphocyte subpop-ulations was detected before the first chemotherapy and after one and three cycles of chemotherapy.Their prognosis was evaluated 3 months after the end of chemotherapy and assigned into the remission group(63 cases)and the non-remission group(29 cases).The correl-ation between the levels of TBNK lymphocyte subsets and prognosis was analyzed.Results:The CD3+,CD3+CD4+,and CD3-CD19+levels in the stage Ⅲ group were lower than those in the stage Ⅳ group after one and three cycles of chemotherapy,while the CD3+CD8+and CD3-CD16+CD56+levels were higher than those in the stage Ⅳ group(P<0.05).The CD3+,CD3+CD4+,and CD3-CD19+levels in the remission group were lower than those in the non-remission group after one and three cycles of chemotherapy,while the CD3+CD8+and CD3-CD16+CD56+levels were higher than those in the non-remission group(P<0.05).The staging and prognosis of lung cancer patients un-dergoing chemotherapy positively correlated with CD3+,CD3+CD4+,and CD3-CD19+,and negatively correlated with CD3+CD8+and CD3-CD16+CD56+(P<0.05).The area under the curve(AUC)of the TBNK lymphocyte subsets combined to predict the prognosis of lung can-cer patients after three cycles of chemotherapy was the highest,reaching 0.907(P<0.05).The TBNK lymphocyte subsets have a good risk warning effect on the prognosis of patients with lung cancer undergoing chemotherapy.Conclusions:Changes in peripheral blood TBNK lymphocyte subsets in patients with lung cancer undergoing chemotherapy were associated with immune function status and prognosis.Monitoring the levels of the relevant indicators can predict the prognosis of patients with lung cancer undergoing chemotherapy.

AIM:To explore the correlation between trimethylamine-N-oxide(TMAO)and type 2 diabetic kidney disease(DKD),and to provide new ideas for the early clinical diagnosis of DKD.METHODS:A total 246 patients with type 2 diabetes mellitus(T2DM)ad-mitted to the Department of Endocrinology of the First Hospital of Lanzhou University from January 1,2020 to May 31,2020 were divided into diabetic kidney disease group(DKD group)and simple diabetes mellitus group(NDKD group).According to urinary albumin/creatinine ratio(UACR),the patients were divided into A1,A2 and A3 subgroups.According to the estimated glomerular filtration rate(eGFR),the patients were divided into G1,G2,G3 and G4-5 sub-groups.According to the Kidney Disease:Improving Global Outcomes(KDIGO)guidelines,the risk of progression of DKD was assessed(low,medium,high or very high risk).General clinical data and laboratory indicators were collected.TMAO level was measured by euzymelinked immunosorbent assay.SPSS 25.0 software was used for statistical analysis.RESULTS:In T2DM patients,TMAO level was positively correlated with UACR(r=0.515,P<0.01)and negatively correlated with eGFR(r=-0.409,P<0.01).TMAO is an indepen-dent risk factor for the onset and progression of DKD.In diagnostic model,the AUROC was 0.745 with op-timal cut-off value was 5.37μmol/L.CONCLUSION:TMAO is closely related to the occurrence and de-velopment of DKD,and it has certain clinical predictive value for DKD.Therefore,TMAO may become a po-tential target for the early diagnosis and treatment of DKD.

Objective     To explore the causes of conversion to thoracotomy in patients with minimally invasive esophagectomy (MIE) in a surgical team, and to obtain a deeper understanding of the timing of conversion in MIE. Methods     The clinical data of patients who underwent MIE between September 9, 2011 and February 12, 2022 by a single surgical team in the Department of Thoracic Surgery of the Fourth Hospital of Hebei Medical University were retrospectively analyzed. The main influencing factors and perioperative mortality of patients who converted to thoracotomy in this group were analyzed. Results     In the cohort of 791 consecutive patients with MIE, there were 520 males and 271 females, including 29 patients of multiple esophageal cancer, 156 patients of upper thoracic cancer, 524 patients of middle thoracic cancer, and 82 patients of lower thoracic cancer. And 46 patients were converted to thoracotomy for different causes. The main causes for thoracotomy were advanced stage tumor (26 patients), anesthesia-related factors (5 patients), extensive thoracic adhesions (6 patients), and accidental injury of important structures (8 patients). There was a statistical difference in the distribution of tumor locations between patients who converted to thoracotomy and the MIE patients (P<0.05). The proportion of multiple and upper thoracic cancer in patients who converted to thoracotomy was higher than that in the MIE patients, while the proportion of lower thoracic cancer was lower than that in the MIE patients. The perioperative mortality of the thoracotomy patients was not significantly different from that of the MIE patients (P=1.000). Conclusion     In MIE, advanced-stage tumor, anesthesia-related factors,extensive thoracic adhesions, and accidental injury of important structures are the main causes of conversion to thoracotomy. The rate varies at different tumor locations. Intraoperative conversion to thoracotomy does not affect the perioperative mortality of MIE.

Variations in the dynein axonemal heavy chain gene, dynein axonemal heavy chain 6 (DNAH6), lead to multiple morphological abnormalities of the flagella. Recent studies have reported that these deficiencies may result in sperm head deformation. However, whether DNAH6 is also involved in human acrosome biogenesis remains unknown. The purpose of this study was to investigate DNAH6 gene variants and their potential functions in the formation of defective sperm heads and flagella. Whole-exome sequencing was performed on a cohort of 375 patients with asthenoteratozoospermia from the First Affiliated Hospital of Anhui Medical University (Hefei, China). Hematoxylin and eosin staining, scanning electron microscopy, and transmission electron microscopy were performed to analyze the sperm morphology and ultrastructure. Immunofluorescence staining and Western blot analysis were conducted to examine the effects of genetic variants. We identified three novel deleterious variants in DNAH6 among three unrelated families. The absence of inner dynein arms and radial spokes was observed in the sperm of patients with DNAH6 variants. Additionally, deficiencies in the acrosome, abnormal chromatin compaction, and vacuole-containing sperm heads were observed in these patients with DNAH6 variants. The decreased levels of the component proteins in these defective structures were further confirmed in sperm from patients with DNAH6 variants using Western blot. After intracytoplasmic sperm injection (ICSI) treatment, the partner of one patient with a DNAH6 variant achieved successful pregnancy. Overall, novel variants in DNAH6 genes that contribute to defects in the sperm head and flagella were identified, and the findings indicated ICSI as an effective clinical treatment for such patients.

Laryngeal cyst is a cystic lesion occurring in the laryngeal cavity. Large laryngeal cyst in infants and young children can cause laryngeal wheezing and other upper airway obstruction symptoms. In severe cases, it can be even life-threatening and requires timely surgical treatment. Currently, there is a lack of unified clinical treatment strategy for this disease.This article summarizes the surgical methods, the advantages and disadvantages of various surgical methods for laryngeal cysts in recent years. It is recommended that needle aspiration, partial cyst wall resection, radical cyst dissection, transoral robotic surgery or external approach cyst resection should be selected through full communication and evaluation to clarify the extent of the lesion scope and the advantages and disadvantages of surgery.
Infant ; Child ; Humans ; Child, Preschool ; Cysts/diagnosis* ; Laryngeal Diseases/diagnosis* ; Larynx/surgery* ; Robotic Surgical Procedures ; Biopsy, Needle

It is a challenge to determine the cause of death in cases caused by both injury and disease in forensic pathology examinations.Here,we retrospectively analyzed 140 such cases enrolled in the Sun Yat-sen University Forensic Identification Center from 2013 to 2021.It was found that the cases caused by both injury and disease accounted for 2.89%of the total number of cases during the same period.The male-to-female ratio was 5.09.Cardiovascular disease accounted for 71.43%of the death-leading diseases,and coronary heart disease accounted for 49.29%.Among the three types of injury and disease relationship,the proportion of disease-based and injury-assisted cases accounted for more than half(65.86%),and the proportion of injury and disease with the same effect cases was the least(12.14%).Medical treatment was involved in as more as 82.86%of the cases.Re-identification were carried out in 10.71%of the cases,53.33%of which were with a≤24-hour-survival time,higher than the proportion(20.80%)of this survival time in initial identification cases(x2 = 13.84,P = 0.000 2).This study revealed the epidemiological characteristics of cases caused by both injury and disease,and supplied useful data for improving the level of forensic identification in such cases.

Objective:To summarize the existing problems in the follow-up management of the clinical research project on cerebrovascular diseases at the National Clinical Research Center for Neurological Diseases, Affiliated Beijing Tiantan Hospital, Capital Medical University, and propose solutions and strategies to improve the level of follow-up management in clinical research, this study provided a reference basis.Methods:A comprehensive quality control system was established based on the follow-up management platform, data collection platform, quality control platform, and project management platform.Results:Strategies were proposed for key points in each stage of clinical research follow-up, quality control of the follow-up process, and follow-up progress. Furthermore, a follow-up assistant software management system was established.Conclusions:The follow-up management platform established by this study can timely address the issues encountered during follow-up, help standardize the follow-up management of clinical research, improve the follow-up rate, and ensure the quality of follow-up data.

Objective: This study aimed to investigate the impact of molecular classification and PTEN, KRAS and PIK3CA gene mutation on the outcome of fertility-preserving treatment in the patients with endometrioid endometrial cancer (EEC) and endometrial atypical hyperplasia (EAH). Methods: This is a single-center retrospective study. A total of 135 patients with EEC and EAH receiving fertility-preserving treatment and molecular classification were reviewed. The distribution of the four types of molecular classification was described. The impact of non-specific molecular profile (NSMP), mismatch repair-deficiency (MMRd), and PTEN, KRAS and PIK3CA gene mutation on the outcome of fertility-preserving treatment was analyzed. Results: Of the patients analyzed, 86.7% (117/136) were classified as having NSMP; 14 (10.4%), MMRd; 1 (0.7%), POLEmut EAH; and 3 (2.2%), p53abn EEC. The patients having NSMP and MMRd achieved similar 16-, 32-, and 48-week complete response rates. The patients harboring tier I and tier II PTEN mutations (PTENmut-Clin) achieved lower cumulative 32-week CR rates than those with PTEN-others (without PTENmut-Clin) (22/47, 46.8% vs. 50/74, 67.6%; p=0.023; odds ratio=0.422; 95% confidence interval [CI]=0.199–0.896). Insulin-resistance (hazard ratio [HR]=0.435; 95% CI=0.269–0.702; p=0.001) and PTENmut-Clin (HR=0.535; 95% CI=0.324–0.885; p=0.015) were independent negative predictors for lower 32-week CR rates. Conclusion PTENmut-Clin is an independent risk factor for unfavorable fertility-preserving treatment outcomes in the patients with EEC and EAH. The patients with MMRd receiving fertility-preserving treatment achieved outcomes similar to those of the patients with NSMP. The molecular profiles might guide fertility-preserving treatment in the prognosis and clinical decisions.