HDAC7, a member of class IIa HDACs, plays a pivotal regulatory role in tumor, immune, fibrosis, and angiogenesis, rendering it a potential therapeutic target. Nevertheless, due to the high similarity in the enzyme active sites of class IIa HDACs, inhibitors encounter challenges in discerning differences among them. Furthermore, the substitution of key residue in the active pocket of class IIa HDACs renders them pseudo-enzymes, leading to a limited impact of enzymatic inhibitors on their function. In this study, proteolysis targeting chimera (PROTAC) technology was employed to develop HDAC7 drugs. We developed an exceedingly selective HDAC7 PROTAC degrader B14 which showcased superior inhibitory effects on cell proliferation compared to TMP269 in various diffuse large B cell lymphoma (DLBCL) and acute myeloid leukemia (AML) cells. Subsequent investigations unveiled that B14 disrupts BCL6 forming a transcriptional inhibition complex by degrading HDAC7, thereby exerting proliferative inhibition in DLBCL. Our study broadened the understanding of the non-enzymatic functions of HDAC7 and underscored the importance of HDAC7 in the treatment of hematologic malignancies, particularly in DLBCL and AML.

Objective: To understand the pathogen spectrum composition of non-bacterial respiratory infections in Pinghu City, Zhejiang Province, so as to provide insights for the prevention and control of respiratory infectious diseases. Methods: A total of 592 throat or nasopharynx swab samples were collected from fever patients in Pinghu First People's Hospital from Jamuary 2021 to November 2022. Multiple real-time fluorescence quantitative polymerase chain reaction was used to detect the nucleic acids of rhinovirus (RhV), respiratory syncytial virus (RSV), parainfluenza virus (PIV), adenovirus (ADV), metapneumovirus (MPV), coronavirus (CoV), Boca virus (Boca), enterovirus (EV), influenza virus (Flu), chlamydia pneumoniae (CP) and mycoplasma pneumoniae (MP). The detection rates of pathogens and mixed infections in different age groups and seasons were analyzed. Results: A total of 212 samples were tested positive for at least one pathogen's nucleic acid from 592 samples, with a total detection rate of 35.81%. The detection rates of RhV (9.80%), PIV (7.26%), Flu (6.76%), RSV (4.39%) and CoV (3.72%) were relatively high. The detection rates were higher among patients at ages of 0 to 2 years and 3 to 17 years than among patients at ages of 18 to 59 years, and in autumn than in spring and winter (all P<0.05). Twenty-three samples were infected by mixed pathogens, accounting for 3.89%. The mixed infections were all detected two pathogens, with PIV, CoV, RhV, and ADV predominant. Conclusions From 2021 to November 2022, the main pathogens of non-bacterial respiratory infections in Pinghu City were RhV, PIV, FLu, RSV and CoV, and there were mixed infections. It is necessary to strengthen the prevention and control of respiratory infection in infants and children.

Objective:To further improve the understanding of paroxysmal nocturnal hemoglobinuria (PNH), we retrospectively analyzed and summarized the clinical characteristics, treatment status, and survival status of patients with PNH in Zhejiang Province.Methods:This study included 289 patients with PNH who visited 20 hospitals in Zhejiang Province. Their clinical characteristics, comorbidity, laboratory test results, and medications were analyzed and summarized.Results:Among the 289 patients with PNH, 148 males and 141 females, with a median onset age of 45 (16-87) years and a peak onset age of 20-49 years (57.8% ). The median lactic dehydrogenase (LDH) level was 1 142 (604-1 925) U/L. Classified by type, 70.9% (166/234) were classical, 24.4% (57/234) were PNH/bone marrow failure (BMF), and 4.7% (11/234) were subclinical. The main clinical manifestations included fatigue or weakness (80.8%, 235/289), dizziness (73.4%, 212/289), darkened urine color (66.2%, 179/272), and jaundice (46.2%, 126/270). Common comorbidities were hemoglobinuria (58.7% ), renal dysfunction (17.6% ), and thrombosis (15.0% ). Moreover, 82.3% of the patients received glucocorticoid therapy, 70.9% required blood transfusion, 30.7% used immunosuppressive agents, 13.8% received anticoagulant therapy, and 6.3% received allogeneic hematopoietic stem cell transplantation. The 10-year overall survival (OS) rate was 84.4% (95% CI 78.0% -91.3% ) . Conclusion:Patients with PNH are more common in young and middle-aged people, with a similar incidence rate between men and women. Common clinical manifestations include fatigue, hemoglobinuria, jaundice, renal dysfunction, and recurrent thrombosis. The 10-year OS of this group is similar to reports from other centers in China.

Objective To study the influence of long term simulated weightlessness on occurrence of laryngopharyngeal reflux(LPR)in healthy volunteers by detection of pepsin in saliva.Methods During a 90-day head-down tilt bed rest(HDTBR)experiment,11 volunteers(4 from the control group and 7 from the countermeasure group)were recruited in the study in the following seven sessions:before bed rest session(Pre),during bed rest sessions for 3 days(BR3),31 days(BR31),61 days(BR61),85 days(BR85)and post bed rest sessions for 7 days(R7)and 25 days(R25).During each testing session,saliva samples were collected for two consecutive days both in the morning and at night before sleeping.Then pepsin in the saliva was measured by enzyme-linked immunosorbent assay.Scale of otorhinolaryngological symptoms for the duration of"Pre-,During-and Post-"were retrospectively performed.Results Among 288 saliva samples of 11 volunteers,17 saliva samples of 8 volunteers were positive for pepsin.The incidence of LPR was 9.1%(1/11)in the Pre session,and it increased to 36.4%in the BR31 session which was higher than the following consequential sessions(0%in BR31,27.3%in BR61 and 27.3%in BR85).Intriguingly,it rose again to 45.5%in R7 session and decreased to 9.1%until in R25 session.There was no significant difference between the control group and the countermeasure group.Total scores for the scale of otorhinolaryngological symptoms showed that a slight elevation tendency emerged during HDTBR session,compared with the pre-HDTBR session.It recovered during the post bed rest sessions.Conclusion The laryngopharyngeal reflux was found in the Pre,During and Post HDTBR experiment.The incidence was significantly increased both in the BR3 and R7 sessions,which indicates that the change of the posture with the stimulation of gastrointestinal dynamic conditions,despite the changes from vertical to horizontal or from horizontal to vertical,might be the major impact factor contributing to the elevation tendency of the incidence of laryngopharyngeal reflux.

Objective: To perform an epidemiological survey of the first case with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Pinghu City of Jiaxing City, Zhejiang Province on March 13, 2022, so as to provide insights into the management of coronavirus disease (COVID-19) epidemics. Methods: According to the requirements of the Protocol on Prevention and Control of COVID-19 (8th Edition), epidemiological investigations were performed among 39 cases with SARS-CoV-2 infections in Pinghu City from March 13 to 20, 2022. Cases' demographics, clinical symptoms, history of immunization and exposure were collected, and close contacts were identified. Pharyngeal swabs were sampled from infected cases for detection of SARS-CoV-2 nucleic acid and whole-genome sequencing, and the source of infection and transmission route were investigated. Results: The index case for this COVID-19 epidemic was an imported case from Shanghai Municipality, who infected 6 persons via aerosol transmission when playing in the badminton venue of Pinghu National Fitness Center on March 9; subsequently, one of these infected cases infected another 18 persons when playing in the badminton venue of Jiadian Village Resident's Fitness Center in Zhapu Township on March 12. Sixteen confirmed cases were reported, and all cases were mild; another 23 asymptomatic cases were diagnosed, with no death reported. This epidemic occurred from March 11 to 20, with 3 generations of spread and a median incubation period of 3 days. The SARS-CoV-2 infected cases had a median age of 33.5 (interquartile range, 12.0) years and included 36 cases with a history of COVID-19 vaccination. There were 16 cases with fever, cough, runny nose and sore throat, and 13 cases with imaging features of pneumonia. The effective reproductive number (Rt) of the COVID-19 epidemic was 7.73 at early stage, and was less than 1 since March 21. Whole-genome sequencing identified Omicron BA.2 variant among 33 cases, which had high homology with the index cases. Conclusion This epidemic was a cluster of COVID-19 caused by imported Omicron BA.2 variant infection from Shanghai Municipality, and the COVID-19 transmission was mainly caused by indoor aerosols.

Objective:Cushing′s disease(CD) is caused by the pituitary adrenocorticotroph hormone(ACTH) secreting adenomas, leading to increased serum cortisol levels and various abnormal metabolic processes. Untreated CD is linked to high mortality, thus it is critical to elucidate its pathogenesis. This study aims to explore the pathogenesis of pituitary ACTH adenomas using whole-genome sequencing analysis.Methods:Fresh tumor tissues and peripheral blood samples were collected in 9 confirmed cases of pituitary ACTH adenomas who underwent surgery. Whole genome sequencing was then performed, followed by analysis and verification of single nucleotide mutations, copy number variation(CNV) and chromosome structure variations.Results:Somatic USP8 mutations(p.Ser718del, p. Ser718Pro, p. Pro720Arg, p. Pro720Gln) were found in 5 patients, with a rate of 55.6%; CNV of USP8 was detected in 1 patient; TP53(p.Cys135Tyr), NF1(p.Val1049Glufs*11) and KMT2C(c.3323+ 1G>A) mutations were identified in 1 patient harboring wild-type USP8. CNV analysis showed a loss of heterozygosity in multiple chromosomes in a wild-type USP8 patient. Structural variations were found in 2 with unknown significance. No germline gene mutations were detected in this study.Conclusion:Somatic USP8 mutations, increased copy number of USP8, variations of tumor-related genes such as TP53 and extensive somatic CNV all contribute to pathogenesis of CD. Chromosomal structure variations may suggest high-risk pituitary ACTH adenomas, and call for frequent follow-up and aggressive treatment.

A 22-year-old female has complained of hirsutism, acanthosis nigricans, enlarged clitoris, and menstrual disorders since puberty. Laboratory examinations revealed hyperandrogenemia. Severe insulin resistance and diabetes were found during hospitalization in our hospital. She was diagnosed with type A insulin resistance syndrome finally. After treatment with metformin, the acanthosis nigricans was significantly relieved, blood glucose was controlled satisfactorily, and the menstrual cycle was restored.

Objective:To investigate the clinical characteristics of four McCune-Albright syndrome (MAS) patients associated with growth hormone(GH)-prolactin(PRL) pituitary adenoma, and explore more effective clinical treatment and management methods.Methods:The clinical data of four patients with MAS and GH-PRL pituitary adenoma diagnosed by Peking Union Medical College Hospital were retrospectively analyzed, including clinical manifestations, biochemical parameters, radiographic characteristics, as well as treatment and prognosis. Literature review was also conducted to analyze the efficacy of surgical operations and drug intervention.Results:Clinical characteristics: 3 females and 1 male, all of whom had onset before the age of 7 years. The types of fibrous dysplasia of bone were all polyosseous and involved craniofacial region. There were obvious gigantism/acromegaly manifestations in all cases, 3 cases had evident visual impairment and 1 case with optic chiasm compression. There was no spontaneous or triggered lactation in all 4 patients. Laboratory examination: GH and insulin-like growth factor-Ⅰ(IGF-Ⅰ) levels were significantly increased in 4 patients, GH levels were not inhibited by oral glucose tolerance test (OGTT), PRL levels were over 100 ng/ml, ALP levels were significantly increased in 4 patients, while serum calcium and phosphorus levels were remained normal. Imaging features: All pituitary adenomas in 4 patients were macroadenomas, with unilateral cavernous sinus enclosure in cases 2 and 3, and recurrence of macroadenoma with bilateral cavernous sinus enclosure in case 4 after the first operation. Four cases of skull CT showed multiple FD in craniofacial bone and skull base. Treatment and outcome: All 4 patients underwent pituitary adenoma resection and bisphosphonate therapy, and somatostatin analogues, dopamine receptor agonists and other treatments were selected according to the situation. Two patients with early diagnosis and initial treatment achieved partial remission after treatment, while the other two patients did not.Conclusions:Patients with MAS and GH-PRL pituitary adenoma had earlier onset age and were more likely to suffer from optic nerve damage. Early diagnosis and reasonable surgical treatment may help to improve biochemical indicators (GH, IGF-Ⅰ, and PRL, etc.) rapidly, and combined drug therapy (somatostatin analogues and dopamine receptor agonists) can better maintain or close to normal biochemical indicators, and ultimately improve the prognosis of patients.

Objective　To dissect the clinical and imaging differences between atypical multiple sclerosis and cerebral small vessels diseases.Methods　We presented one case of a hereditary cerebral small vessel disease-autosomal dominant genetic disease combined with subcortical infarction and white matter encephalopathy (CADASIL),which was initially misdiagnosed as multiple sclerosis.Afterwards.We reviewed literature regarding typical images and clinical aspects in multiple sclerosis and cerebral small vessels diseases and discussed the differential diagnosis points.Results　Multiple sclerosis often starts in young adults,with IgG index greater than 0.7,positive oligoclonal band,central venous signs,few microbleeding and asymmetric periventricular white matter lesions on MRI scan.On the contrary,cerebral small vessel diseases often start in old patients with vascular risk factors.MRI scan often shows the lacunar cerebral infarction,microbleeding,brain atrophy and symmetric periventricular white matter hyperintensity.Conclusion　Understanding the differential points between the two diseases may help avoid misdiagnosis and initiate reasonable treatment immediately.

Objective: To explore the correlation between menopausal hormone therapy（MHT）and breast lesions in perimenopausal women,and to provide evidence for safe use of MHT. Methods: The 40-60 year-old women who visited Hangzhou Women's Hospital and met the diagnostic criteria for perimenopausal syndrome were recruited. The intervention group received MHT and was divided into three subgroups according to the MHT regimen：estrogen-progesterone cycle therapy（A）,estrogen-progesterone continuous therapy（B）,estrogen therapy（C）. The control group did not receive MHT. All the patients received regular mammography to quantify and evaluate breast lesions. The generalized estimating equation was used to analyze the changes of breast lesions between different groups. Results: There were 80 cases in the intervention group,with 49 in group A,26 in group B,5 in group C,and 80 cases in the control group. After two years of follow-up,there was no statistically significant differences of time,group and interaction in breast density,volume of breast fibrous tissue and the volume of breast between three intervention groups and the control group（P>0.05）; there was no statistically significant differences of group and interaction in positive rate of calcification and breast mass between the intervention group and the control group（P>0.05）. Conclusion Receiving MHT intervention for two years did not increase the risk of breast lesions.