The emergence of SARS-CoV-2 variants of concern and repeated outbreaks of coronavirus epidemics in the past two decades emphasize the need for next-generation pan-coronaviral therapeutics. Drugging the multi-functional papain-like protease (PLpro) domain of the viral nsp3 holds promise. However, none of the known coronavirus PLpro inhibitors has been shown to be in vivo active. Herein, we screened a structurally diverse library of 50,080 compounds for potential coronavirus PLpro inhibitors and identified a noncovalent lead inhibitor F0213 that has broad-spectrum anti-coronaviral activity, including against the Sarbecoviruses (SARS-CoV-1 and SARS-CoV-2), Merbecovirus (MERS-CoV), as well as the Alphacoronavirus (hCoV-229E and hCoV-OC43). Importantly, F0213 confers protection in both SARS-CoV-2-infected hamsters and MERS-CoV-infected human DPP4-knockin mice. F0213 possesses a dual therapeutic functionality that suppresses coronavirus replication via blocking viral polyprotein cleavage, as well as promoting antiviral immunity by antagonizing the PLpro deubiquitinase activity. Despite the significant difference of substrate recognition, mode of inhibition studies suggest that F0213 is a competitive inhibitor against SARS2-PLpro via binding with the 157K amino acid residue, whereas an allosteric inhibitor of MERS-PLpro interacting with its 271E position. Our proof-of-concept findings demonstrated that PLpro is a valid target for the development of broad-spectrum anti-coronavirus agents. The orally administered F0213 may serve as a promising lead compound for combating the ongoing COVID-19 pandemic and future coronavirus outbreaks.
Animals ; Coronavirus Papain-Like Proteases/antagonists & inhibitors* ; Cricetinae ; Humans ; Mice ; Pandemics ; SARS-CoV-2/enzymology* ; COVID-19 Drug Treatment

Precipitating hydrophobic injectable liquid (PHIL; MicroVention, Aliso Viejo, CA, USA) and Squid (Balt, Irvine, CA, USA) are 2 newer liquid embolic agents used in endovascular embolization of cerebral arteriovenous malformation (AVM). This study aims to investigate and compare the effectiveness and safety profile of the 2 newer liquid embolic agents in the embolization of cerebral AVM. This is a retrospective study on all patients diagnosed with cerebral AVM undergoing endovascular embolization with liquid embolic agents PHIL and Squid admitted to the Division of Neurosurgery, Department of Surgery in Prince of Wales Hospital from January 2014 to June 2021. Twenty-three patients with cerebral AVM were treated with 34 sessions of endovascular embolization with either PHIL or Squid (17 sessions each) liquid embolic agents with a male to female ratio of 2.3:1 (male 16; female 7) and mean age of 44.6 (range, 12 to 67). The mean total nidus obliteration rate per session was 57% (range, 5% to 100%). Twenty-one patients (91.3%) received further embolization, stereotactic radiosurgery, or surgical excision after initial endovascular embolization. There were 2 morbidities (1 neurological and 1 non-neurological, 6%) and no mortalities (0%). All patients had static or improvement in modified Rankin Scale at 3 to 6 months at discharge. PHIL and Squid are effective and safe liquid embolic agents for endovascular embolization of cerebral AVM, achieving satisfactory nidal obliteration rates and patient functional outcomes.

OBJECTIVES: To study the early clinical efficacy of combined therapy of stage 4 neuroblastoma. METHODS: A retrospective analysis was performed on the medical data and follow-up data of 14 children with stage 4 neuroblastoma who were diagnosed in Hong Kong University-Shenzhen Hospital from January 2016 to June 2021. RESULTS: The median age of onset was 3 years and 7.5 months in these 14 children. Among these children, 9 had positive results of bone marrow biopsy, 4 had N-Myc gene amplification, 13 had an increase in neuron-specific enolase, and 7 had an increase in vanilmandelic acid in urine. Based on the results of pathological examination, differentiated type was observed in 6 children, undifferentiated type in one child, mixed type, in one child and poorly differentiated type in 6 children. Of all the children, 10 received chemotherapy with the N7 regimen (including 2 children receiving arsenic trioxide in addition) and 4 received chemotherapy with the Rapid COJEC regimen. Thirteen children underwent surgery, 14 received hematopoietic stem cell transplantation, and 10 received radiotherapy. A total of 8 children received Ch14.18/CHO immunotherapy, among whom 1 child discontinued due to anaphylactic shock during immunotherapy, and the other 7 children completed Ch14.18/CHO treatment without serious adverse events, among whom 1 child was treated with Lu177 Dotatate 3 times after recurrence and is still undergoing chemotherapy at present. The median follow-up time was 45 months for all the 14 children. Four children experienced recurrence within 2 years, and the 2-year overall survival rate was 100%; 4 children experienced recurrence within 3 years, and 7 achieved disease-free survival within 3 years. CONCLUSIONS Multidisciplinary combined therapy is recommended for children with stage 4 neuroblastoma and can help them achieve better survival and prognosis.
Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Child ; Child, Preschool ; Combined Modality Therapy ; Humans ; Infant ; Neuroblastoma/drug therapy* ; Positron-Emission Tomography ; Radionuclide Imaging ; Retrospective Studies ; Treatment Outcome

Objective: To investigate changes in the median nerve, retinaculum, and carpal tunnel on ultrasound after successful endoscopic carpal tunnel release (ECTR). Materials and Methods: This prospective study involved 37 wrists in 35 patients (5 male, 30 female; mean age ± standard deviation [SD], 56.9 ± 6.7 years) with primary carpal tunnel syndrome (CTS). An in-house developed scoring system (0–3) was used to gauge the clinical improvement after ECTR. Ultrasound was performed before ECTR, and at 1, 3, and 12 months post-ECTR. Changes in the median nerve, flexor retinaculum, and carpal tunnel morphology on ultrasound after ECTR were analyzed. Ultrasound parameters for different clinical improvement groups were compared. Results: All patients improved clinically after ECTR. The average clinical improvement score ± SD at 12 months post-ECTR was 2.2 ± 0.7. The median nerve cross-sectional area proximal and distal to the tunnel decreased at all time intervals postECTR but remained swollen compared to normal values. Serial changes in the median nerve caliber and retinacular bowing after ECTR were more pronounced at the tunnel outlet than at the tunnel inlet. The flexor retinaculum had reformed in 25 (68%) of 37 wrists after 12 months. Conclusion Postoperative changes in median nerve and retinaculum parameters were most pronounced at the tunnel outlet.Even in patients with clinical improvement after ECTR, nearly all ultrasound parameters remain abnormal at one year postECTR. These ultrasound parameters should not necessarily be relied upon to diagnose persistent CTS after ECTR.

Objective: To investigate changes in the median nerve, retinaculum, and carpal tunnel on ultrasound after successful endoscopic carpal tunnel release (ECTR). Materials and Methods: This prospective study involved 37 wrists in 35 patients (5 male, 30 female; mean age ± standard deviation [SD], 56.9 ± 6.7 years) with primary carpal tunnel syndrome (CTS). An in-house developed scoring system (0–3) was used to gauge the clinical improvement after ECTR. Ultrasound was performed before ECTR, and at 1, 3, and 12 months post-ECTR. Changes in the median nerve, flexor retinaculum, and carpal tunnel morphology on ultrasound after ECTR were analyzed. Ultrasound parameters for different clinical improvement groups were compared. Results: All patients improved clinically after ECTR. The average clinical improvement score ± SD at 12 months post-ECTR was 2.2 ± 0.7. The median nerve cross-sectional area proximal and distal to the tunnel decreased at all time intervals postECTR but remained swollen compared to normal values. Serial changes in the median nerve caliber and retinacular bowing after ECTR were more pronounced at the tunnel outlet than at the tunnel inlet. The flexor retinaculum had reformed in 25 (68%) of 37 wrists after 12 months. Conclusion Postoperative changes in median nerve and retinaculum parameters were most pronounced at the tunnel outlet.Even in patients with clinical improvement after ECTR, nearly all ultrasound parameters remain abnormal at one year postECTR. These ultrasound parameters should not necessarily be relied upon to diagnose persistent CTS after ECTR.

PURPOSE: The aims of this study were to investigate the prevalence of upper tract involvement in ketamine-associated uropathy, and to determine the predictors of hydronephrosis in patients with a history of ketamine abuse. METHODS: This was a cross-sectional study of a prospective cohort of patients with ketamine-associated uropathy. Data including demographics, pattern of ketamine abuse, pelvic pain and urgency or frequency (PUF) symptom score, uroflowmetry (UFM) parameters, serum renal function, and liver function tests were collected. Upon consultation, ultrasonography was performed to assess the function of the urinary system. RESULTS: From December 2011 to October 2015, we treated 572 patients with ketamine-associated uropathy. Of these patients, 207 (36.2%) had managed to achieve abstinence at the time of their first consultation. Ninety-six patients (16.8%) in the cohort were found to have hydronephrosis on ultrasonography. Univariate analysis identified age, duration of ketamine abuse, PUF symptom score, voided volume on UFM, serum creatinine levels >100 μmol/L, and an abnormal serum liver enzyme profile as factors associated with hydronephrosis. Logistic regression revealed the following parameters to be statistically related to hydronephrosis: age (adjusted odds ratio [OR], 1.090; 95% confidence interval [CI], 1.020–1.166; P=0.012), functional bladder capacity (adjusted OR, 0.997; 95% CI, 0.995–0.999; P=0.029), serum creatinine >100 μmol/L (adjusted OR, 3.107; 95% CI, 1.238–7.794; P=0.016, and an abnormal serum liver enzyme profile (adjusted OR, 1.967; 95% CI, 1.213–3.187; P=0.006). CONCLUSIONS: Ketamine-associated uropathy can involve the upper urinary tract. Patient demographics as well as investigations of UFM, renal function tests, and liver function tests may allow us to identify at-risk patients.
Cohort Studies ; Creatinine ; Cross-Sectional Studies ; Cystitis ; Demography ; Humans ; Hydronephrosis ; Ketamine ; Liver ; Liver Function Tests ; Logistic Models ; Lower Urinary Tract Symptoms ; Odds Ratio ; Pelvic Pain ; Prevalence ; Prospective Studies ; Ultrasonography ; Urinary Bladder ; Urinary Tract* ; Urination Disorders

OBJECTIVETo observe the expression of hypoxia-inducible factor-lalpha subunit (HIF-1alpha), HIF prolyl hydroxylase domain-containing protein(PHDs) and factor inhibiting HIF-1(FIH) in pulmonary arteries of patient with chronic obstructive pulmonary disease (COPD).

METHODSPulmonary specimens were obtained from patients undergoing lobectomy for lung cancer, 12 had concurrent COPD (COPD group) and 14 without COPD (control group). The ratio of vascular wall area to total vascular area (WA%) and pulmonary artery media thickness (PAMT) was observed, and HIF-1alpha and its hydroxylases(PHD1, PHD2, PHD3, FIH) mRNA and protein were detected by in situ hybridization and immunohistochemistry respectively.

RESULTSWA% and PAMT of COPD patients(50 microm +/- 9 microm, 40% +/- 5%, were statistically different from those of the control subjects (39 microm +/- 6 microm, 31% +/- 4%, P < 0.01). Relative quantification of mRNA and protein levels (absorbance, A) showed that HIF-lalpha mRNA and protein levels in COPD group (0.230 +/- 0.036,0.275 +/- 0.039) were statistically higher than those of the control subjects (0.174 +/- 0.029, 0.102 +/- 0.015, P < 0.01 ), and that the protein level increased more markedly. PHD1 mRNA in COPD subjects (0.180 +/- 0.030) was comparable to that in control group (0.191 +/- 0.029, P > 0.05); PHD2 and PHD3 mRNA levels in COPD (0.245 +/- 0.044, 0.252 +/- 0.023) were significantly higher than those in control group(0.182 +/- 0.028, 0.127 +/- 0.017, P < 0.01). On the other hand, in COPD subjects PHD1 protein (0.104 +/- 0.015) was significantly lower(P < 0.01), whereas PHD2 protein (0.274 +/- 0.044) was significantly higher(P < 0.01) than those in control group(0.209 +/- 0.023, 0.219+/- 0.043). As for PHD3 protein, no significant changes were observed between the two groups (0.161+/- 0.023 in COPD, 0.146 +/- 0.021 in control, P > 0.05). FIH mRNA and protein both showed no differences between the two groups. Linear correlation analysis showed that HIF1alpha protein was positively correlated with WA%, PAMT, PHD2 mRNA and protein, PHD3 mRNA, and that HIF1alpha protein was negatively correlated with PHD1 protein.

CONCLUSIONPHDs may be involved in the process of hypoxic pulmonary vascular remodeling in COPD via regulation of HIF-1alpha gene expression

Aged ; Case-Control Studies ; Female ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit ; metabolism ; Lung ; blood supply ; metabolism ; Male ; Middle Aged ; Mixed Function Oxygenases ; metabolism ; Procollagen-Proline Dioxygenase ; metabolism ; Pulmonary Artery ; metabolism ; Pulmonary Disease, Chronic Obstructive ; metabolism ; RNA, Messenger ; genetics ; Repressor Proteins ; metabolism

OBJECTIVETo investigate the feasibility and efficacy of neoadjuvant chemoradiotherapy followed by combined thoracoscopic and laparoscopic esophagectomy (CTLE) in the treatment of advanced esophageal carcinoma.

METHODSFrom June 2011 to February 2012, 11 patients with locally advanced esophageal carcinoma underwent neoadjuvant chemoradiotherapy followed by CTLE (clinical stage IIB-IIIA). NP (vinorelbine pin and cisplatin) or TP (program paclitaxel-pin and cisplatin) were applied as preoperative chemotherapy. During the same period, conventional fractionated radiotherapy was used with the radiation dose of 40 Gy/20 F. At four to six weeks after CRT, 11 patients received three-incision CTLE.

RESULTSDuring chemoradiation, 9 patients developed bone marrow suppression. The interval between completion of chemoradiation and surgery was (49.6±15.4) d. Intraoperative findings revealed local fibrosis in one patient (75 days after chemoradiation) while operative difficulty was not increased in the remaining 10 patients. Compared to 15 patients who received surgery alone, operative time was shorter [(242.3±27.0) min vs.(280.5±27.2) min, P=0.002] and intraoperative blood loss was less [(168.2±95.6) ml vs. (244.5±84.8) ml, P=0.042], the number of removal lymph nodes was similar [(19.5±5.8) vs. (20.5±7.1), P=0.683], postoperative hospital stay was prolonged [(18.9±10.3) d vs. (12.5±4.6) d, P=0.020]. The postoperative complication rate was 36.4% including cervical anastomotic leak with pulmonary infection (n=1), cervical anastomotic fistula and hoarseness (n=1), pulmonary infection with pleural effusion (n=2). Follow up ranged from 1 to 9 months, and no recurrence was found.

CONCLUSIONThe neoadjuvant chemoradiotherapy followed by combined thoracoscopic and laparoscopic esophagectomy in the treatment of locally advanced esophageal carcinoma is safe, feasible, and the short-term outcomes are favorable.

Adult ; Aged ; Esophageal Neoplasms ; surgery ; therapy ; Esophagectomy ; methods ; Female ; Follow-Up Studies ; Humans ; Laparoscopy ; Male ; Middle Aged ; Neoadjuvant Therapy ; Preoperative Care ; Thoracoscopy ; Treatment Outcome

With the evolution of immunochemical staining techniques and better imaging modalities with better image resolution and whole body coverage, gastrointestinal stromal tumor (GIST), the most common mesenchymal tumor of the gastrointestinal tract, is often encountered in clinical practice. Metastasis is common with malignant GIST and can be found in up to 50% of patients at presentation. Liver and peritoneum are the two most common sites of metastasis and accounted for 95% of cases. Lymphatics, bone and lung metastasis are rare. Malignant GIST with intracranial metastasis is even rarer, with only a few cases reported in the literature, and most of these had earlier metastasis elsewhere. Radiological features for GISTs are not specific but it does contribute to confirming early and accurate diagnosis of malignant GISTs by judging the tumor size, enhancement pattern and the invasion of adjacent structures. We report a case of a 26-year-old male with metastatic GIST to the liver and subsequently to the brain and skull vault. This is the first case reported in our locality and he is the youngest patient reported with this disease entity. The clinical progress, radiological features and the role of imaging will be discussed further in this paper. The radiological and clinical features of the primary tumor will specifically be addressed. The purpose of this paper is to enrich the current database of this rare disease entity and to alert both radiologists and clinicians about the imaging features of GIST with intracranial metastasis.
Adult ; Brain Neoplasms ; diagnostic imaging ; secondary ; Gastrointestinal Stromal Tumors ; complications ; diagnostic imaging ; Humans ; Male ; Radiography

OBJECTIVETo explore and evaluate the feasibility, safety, radicality and the short-term outcome of minimally invasive esophagectomy versus open esophagectomy for esophageal cancer.

METHODSFrom July 2007 to October 2009, 67 patients with esophageal cancer received minimally invasive esophagectomy (MIE group), while 38 patients underwent conventional open esophagectomy (OE group: via right thorax, abdomen, left neck). The operative procedures, clinicopathological data and short-term outcome were collected and compared between the two groups.

RESULTSThe clinical data of the two groups were comparable. No significant differences was found in demographics between the two groups. Median blood loss in MIE group was less than that in OE group (chest: 112.3 ml vs. 175.3 ml, P = 0.035, abdominal: 31.4 ml vs. 100.5 ml, P = 0.026). More patients in OE group were transferred to ICU (P = 0.042) and more obvious pain (P = 0.005). The rate of pulmonary infection and intestinal obstruction in OE group were higher than MIE group (P = 0.046 and 0.045). There were no differences in the number of lymph node dissection for two groups, the average was 20.9 and lymph node metastasis rate was 26.9% in MIE group. Mean follow up was (14.0 ± 2.2) months (range, 2 to 29 months). Recurrence rate and survival rate were no differences.

CONCLUSIONThe Minimally invasive esophagectomy for esophageal cancer is feasible, safe, and reliable short-term effect, and can achieve radical tumor resection, which may lead to better future of surgical treatment for esophageal carcinoma.

Aged ; Esophageal Neoplasms ; surgery ; Esophagectomy ; methods ; Female ; Follow-Up Studies ; Humans ; Laparoscopy ; Male ; Middle Aged ; Retrospective Studies ; Thoracoscopy ; Treatment Outcome