Discovery of Selective Proteolysis-Targeting Chimera Degraders Targeting PTP1B as Long-Term Hypoglycemic Agents.

PTP1B, a promising target for insulin sensitizers in type 2 diabetes treatment, can be effectively degraded using proteolysis-targeting chimera (PROTAC). This approach offers potential for long-acting antidiabetic agents. We report potent bifunctional PROTACs targeting PTP1B through the E3 ubiquitin ligase cereblon. Western blot analysis showed significant PTP1B degradation by PROTACs at concentrations from 5 nM to 5 µM after 48 h. Evaluation of five highly potent PROTACs revealed compound 75 with a longer PEG linker (23 atoms), displaying remarkable degradation activity after 48 and 72 h, with DC50 values of 250 nM and 50 nM, respectively. Compound 75 induced selective degradation of PTP1B, requiring engagement with both the target protein and CRBN E3 ligase, in a ubiquitination and proteasome-dependent manner. It significantly reduced blood glucose AUC0-2h to 29% in an oral glucose tolerance test and activated the IRS-1/PI3K/Akt signaling pathway in HepG2 cells, showing promise for long-term antidiabetic therapy.

Research progress of PROTACs for neurodegenerative diseases therapy.

Neurodegenerative diseases (NDD) are characterized by the gradual deterioration of neuronal function and integrity, resulting in an overall decline in brain function. The existing therapeutic options for NDD, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, fall short of meeting the clinical demand. A prominent pathological hallmark observed in numerous neurodegenerative disorders is the aggregation and misfolding of proteins both within and outside neurons. These abnormal proteins play a pivotal role in the pathogenesis of neurodegenerative diseases. Targeted degradation of irregular proteins offers a promising avenue for NDD treatment. Proteolysis-targeting chimeras (PROTACs) function via the ubiquitin-proteasome system and have emerged as a novel and efficacious approach in drug discovery. PROTACs can catalytically degrade "undruggable" proteins even at exceptionally low concentrations, allowing for precise quantitative control of aberrant protein levels. In this review, we present a compilation of reported PROTAC structures and their corresponding biological activities aimed at addressing NDD. Spanning from 2016 to present, this review provides an up-to-date overview of PROTAC-based therapeutic interventions. Currently, most protein degraders intended for NDD treatment remain in the preclinical research phase. Overcoming several challenges is imperative, including enhancing oral bioavailability and permeability across the blood-brain barrier, before these compounds can progress to clinical research or eventually reach the market. However, armed with an enhanced comprehension of the underlying pathological mechanisms and the emergence of innovative scaffolds for protein degraders, along with further structural optimization, we are confident that PROTAC possesses the potential to make substantial breakthroughs in the field of neurodegenerative diseases.

Synthesis and Neuroprotective Evaluation of Substituted Indanone/Benzofuranone and Piperidine Hybrids.

Based on the neuroprotection of butylphthalide and donepezil, a series of indanone/benzofuranone and piperidine hybrids were designed and synthesized for assessment of their neuroprotective activities, aiming to enhance the bioavailability and therapeutic efficacy of natural phthalide analogues. Within this study, it was observed that most indanone derivatives bearing 1-methylpiperidine in the tail segment demonstrated superior neuroprotective effects on the oxygen glucose deprivation/reperfusion (OGD/R)-induced rat primary neuronal cell injury model in vitro compared to benzofuranone compounds. Among the synthesized compounds, 11 (4, 14, 15, 22, 26, 35, 36, 37, 48, 49, and 52) displayed robust cell viabilities in the OGD/R model, along with favorable blood-brain barrier permeability as confirmed by the parallel artificial membrane permeability assay. Notably, compound 4 showed significant neuronal cell viabilities within the concentration range of 3.125 to 100 µM, without inducing cytotoxicity. Further results from in vivo middle cerebral artery occlusion/R experiments revealed that 4 effectively ameliorated ischemia-reperfusion injury, reducing the infarct volume to 18.45% at a dose of 40 mg/kg. This outcome suggested a superior neuroprotective effect compared to edaravone at 20 mg/kg, further highlighting the potential therapeutic efficacy of compound 4 in addressing neurological disorders.

Diagnosis of Acute Q Fever in a Patient by Using Metagenomic Next-Generation Sequencing: A Case Report.

Background: Q fever is a zoonotic disease caused by Coxiella burnetii infection, with domestic ruminants as the main source of infection and tick bites as one of the transmission vectors. The clinical manifestations of Q fever are varied and atypical. For the reason that C. burnetii is a strictly intracellular pathogen, it is difficult to be diagnosed by traditional culture methods. Additionally, serological and molecular diagnostic methods to assist in the diagnosis of Q fever are not routinely performed in most clinical laboratories. Therefore, early and rapid diagnosis of Q fever is a challenge. Case Presentation: In the present study, a 34-year-old male patient presented with an acute onset and symptoms such as high fever, lethargy, pulmonary infection, and liver damage. In addition, he had a history of tick bites. Despite conducting relevant laboratory and radiological examinations, the etiology remained unknown. Subsequently, we detected the sequence reads of C. burnetii in a venous blood sample using metagenomic next-generation sequencing (mNGS), and the symptoms of patients were significantly improved after timely treatment with the special drug tetracycline. To our knowledge, this is the first report of Q fever associated with C. burnetii detected directly from venous blood sample in Wuhan, China. Conclusion: Metagenomic next-generation sequencing is a new diagnostic technology that provides rapid and accurate detection of unexplained infections, including Q fever. Its application plays a crucial role in clinical diagnosis for identifying elusive pathogens.

Effectiveness and tolerability of camrelizumab combined with molecular targeted therapy for patients with unresectable or advanced HCC.

There is a lack of effective programmed cell death protein 1 (PD-1)-targeted immunotherapy with good tolerability in patients with advanced hepatocellular carcinoma (HCC) and severely compromised liver function. We assessed patient outcomes after combined camrelizumab and molecular targeted therapy in a multicenter cohort study in China. The study included 99 patients with advanced HCC (58 Child-Pugh A and 41 Child-Pugh B), 84 of them received camrelizumab combined with molecular targeted therapy from January 10, 2019, to March 31, 2021. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were assessed. The median follow-up was 12.1 months. For patients with Child-Pugh B, the OS probability at 12-months, ORR and DCR were 49.7%, 31.7% and 65.9%, respectively, and the median PFS was 5.1 months [95% confidence interval (CI) 3.0-7.1], which were comparable with Child-Pugh A patients, although median OS was shorter in Child-Pugh B patients (20.5 vs.13.4 months, P = 0.12). In multivariate analysis, macrovascular infiltration (MVI), but not sex, age, hepatitis B virus etiology, extrahepatic metastasis, Child-Pugh B, or AFP > 400 ng/ml, was associated with 12-months OS [hazard ratio (HR) 2.970, 95% CI 1.276-6.917, P = 0.012] and ORR (HR 2.906, 95% CI 1.18-7.16, P = 0.020). Grade 3/4 immune-related AEs occurred in 26.8% of Child-Pugh B patients, including one potentially treatment-related death. In both groups, the most common AEs were immune thrombocytopenia and hepatotoxicity. Camrelizumab combined with targeted therapy showed favorable effectiveness and tolerability with manageable toxicities in Chinese HCC patients, regardless of Child-Pugh A/B liver function. MVI was associated with suboptimal immunotherapy response and poor prognosis.

Multidisciplinary collaboration for the successful treatment of a giant hepatic solitary fibrous tumor protruding into the thorax: A case report.

Solitary fibrous tumors (SFTs) are composed of spindle cells and collagen fibers, and these form rare mesenchymal tumors. SFTs are most frequently observed in intrathoracic sites; however, they may also occur in extrathoracic sites, such as the liver. Unlike the hepatic SFTs (HSFTs) reported in the literature, the SFT detailed in the present case report was a large tumor that originated from the liver, with a dumbbell-shaped growth through the diaphragm into the right thoracic cavity. This posed substantial challenges in both diagnosis and treatment. Thus, the present report outlines the findings of a multidisciplinary team meeting that was used to discuss and develop an optimal and personalized treatment strategy for the patient. Transhepatic arterial embolization was performed to block the major arterial blood supply to the tumor in order to reduce its size. Subsequently, the tumor was fully resected, following the collaboration of the experienced hepatobiliary and thoracic surgeons. Following surgery, the abdominal distension experienced by the patient ceased, and no tumor recurrence was detected at the 1-year follow-up. In conclusion, due to limited previous reports of HSFT treatment using multidisciplinary collaboration, the present study outlined the treatment used for this specific tumor type, and the corresponding literature was reviewed.

Stability issues of RT-PCR testing of SARS-CoV-2 for hospitalized patients clinically diagnosed with COVID-19.

In this study, we collected a total of 610 hospitalized patients from Wuhan between February 2, 2020, and February 17, 2020. We reported a potentially high false negative rate of real-time reverse-transcriptase polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 in the 610 hospitalized patients clinically diagnosed with COVID-19 during the 2019 outbreak. We also found that the RT-PCR results from several tests at different points were variable from the same patients during the course of diagnosis and treatment of these patients. Our results indicate that in addition to the emphasis on RT-PCR testing, clinical indicators such as computed tomography images should also be used not only for diagnosis and treatment but also for isolation, recovery/discharge, and transferring for hospitalized patients clinically diagnosed with COVID-19 during the current epidemic. These results suggested the urgent needs for the standard of procedures of sampling from different anatomic sites, sample transportation, optimization of RT-PCR, serology diagnosis/screening for SARS-CoV-2 infection, and distinct diagnosis from other respiratory diseases such as fluenza infections as well.

Effectiveness of modified complex decongestive physiotherapy for preventing lower extremity lymphedema after radical surgery for cervical cancer: a randomized controlled trial.

BACKGROUND: There is a lack of evidence in support of any prophylactic measure to prevent secondary lower extremity lymphedema after radical hysterectomy among patients with cervical cancer. This study aimed to determine the effectiveness of modified complex decongestive physiotherapy in reducing the risk of secondary lower extremity lymphedema after radical surgery. METHODS: A randomized single-blind clinical trial was conducted in 120 patients with cervical cancer who underwent laparoscopic radical hysterectomy with pelvic lymphadenectomy between January 2016 and April 2017 in the Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China. Participants were randomly assigned to a modified complex decongestive physiotherapy intervention group (n=60) or control group (n=60). The intervention group received a modified complex decongestive physiotherapy program, which included manual lymph drainage, compression hosiery, regular exercise, and health education. The control group only received a health education program. The main outcome was the incidence of secondary lower extremity lymphedema. RESULTS: A total of 117 patients with cervical cancer completed a 1-year follow-up. Twenty-eight (23.9%) patients developed secondary lower extremity lymphedema (20 (34.5%) patients in the control group and 8 (13.6%) in the intervention group). The incidence of secondary lower extremity lymphedema was significantly higher in the control group than in the intervention group (p=0.008; OR 0.30 (95% CI 0.12 to 0.75). The median percentage of excess volume was significantly less in the intervention group (2.1%, IQR 0.5-3.4%) than in the control group (2.96%, IQR 1.1-4.98%); (p=0.042). The mean (SD) onset time of lymphedema was 8 (2.00) months vs 4.6 (2.82) months in the intervention and control groups, respectively (p=0.004). CONCLUSIONS: This randomized trial showed that modified complex decongestive physiotherapy is effective for preventing lower extremity lymphedema in patients with cervical cancer after laparoscopic radical hysterectomy with pelvic lymphadenectomy.

High Post-treatment α-Fetoprotein Levels and Aspartate Aminotransferase-to-Platelet Ratio Index Predict Hepatocellular Carcinoma in Hepatitis C Virus Decompensated Cirrhotic Patients with Sustained Virological Response After Antiviral Therapy.

Although eradication of hepatitis C virus (HCV) decreases the risk of hepatocellular carcinoma (HCC) development, a considerable level of risk remains in cirrhotic patients with advanced liver disease. Yet, data for the effect of serum markers on HCC development in this population after viral eradication are still lacking. Seventy-eight consecutive patients with HCV infection and decompensated cirrhosis were administered interferon-based regimens at our hospital between August 2008 and December 2013. Thirty-four achieved sustained virological response and were enrolled in the study. Occurrence of HCC was evaluated every 3-6 months post-treatment. The mean age of the 34 patients was 55.7 ± 8.3 years (range: 39-70) old. Compared with baseline, at 24 weeks post-treatment the serum levels were significantly decreased for α-fetoprotein (AFP) (12.20 ± 4.12 versus 8.37 ± 2.75 ng/mL, P < 0.001), aspartate aminotransferase (AST) (58.44 ± 15.12 versus 36.59 ± 11.22 IU/L, P < 0.001), and AST-to-platelet ratio index (APRI) (2.21 ± 0.74 versus 1.35 ± 0.61, P < 0.001) but significantly increased for platelet count (69.65 ± 17.46 versus 73.65 ± 18.0 × 103/µL, P = 0.022). Median follow-up time was 41.4 ± 16.8 (range: 9-71) months, and 5 patients (14.7%) developed HCC. Post-treatment APRI ≥1.5 and AFP ≥10 ng/mL were associated with HCC development (both P < 0.01). Post-treatment AFP and APRI maybe are useful markers to further classify HCC risk in HCV-decompensated cirrhotic patients after viral eradication.

[Antiviral treatment and long-term clinical outcome of decompensated cirrhotic patients with hepatitis C virus infection].

OBJECTIVE: To investigate the efficacy and safety of antiviral treatment in patients with hepatitis C virus (HCV) infection and decompensated cirrhosis and determine the effects of virological response on long-term prognosis. METHODS: Sixty-six consecutive,interferon (IFN)-na(i)ve patients with HCV infection and decompensated cirrhosis were enrolled in this prospective study. All patients were given a 48-to 72-week course of IFN plus ribavirin (RBV) combined therapy,with a low accelerating dosage regimen using either:pegylated (PEG)-IFNa-2b at 1.0-1.5 mug/kg/week,PEG-IFNa-2a at 90-180 mug,or standard IFN-a-2b at 3MU,every other day.RBV was given at 800 to 1000 mg/day. All patients were routinely monitored for adverse drug reactions and virological response.Effects of treatments on patient survival were assessed by Kaplan-Meier analysis. RESULTS: At the end of treatment,74.2% of patients were HCV RNA-negative,with 45.5% having achieved sustained virological response and 28.8% having relapsed;the remaining 25.7% of patients showed non-virological response (NVR). Among the patients with HCV genotype 1, 65.9% achieved end-of-treatment virological response (ETVR) and 34.1% achieved SVR;among the patients with HCV genotype 2,90.9% achieved ETVR and 68.2% achieved SVR. The positive and negative predictive values of early virological response (EVR) for ETVR were 95.7% and 75.0% respectively, and for SVR were 65.2% and 100% respectively. Compared with baseline,patients who achieved ETVR had better liver function,as evidenced by changes in levels of total bilirubin,alanine aminotransferase and albumin,as well as prothrombin activity and Child-Pugh score (t =4.564,11.486,2.303,2.699,3.694 respectively, all P less than 0.05).Compared with the NVR patients, the ETVR patients had lower risk of hepatic decompensation and hepatocellular carcinoma, and had improved survival (x2=18.756,6.992,7.580, respectively, all P less than 0.05).Twelve (18.2%) patients experienced serious adverse events,with 10 requiring premature treatment withdrawal and 2 dying. CONCLUSION: Antiviral treatment for patients with HCV infection and decompensated cirrhosis using interferon in a low accelerating dosage regimen in combination with ribavirin is feasible.Patients who achieved ETVR had significantly improved long-term prognosis.

The Decrease of Peripheral Blood CD4+ T Cells Indicates Abdominal Compartment Syndrome in Severe Acute Pancreatitis.

OBJECTIVE: Few data are available on the role of T lymphocytes and inflammatory cytokines in abdominal compartment syndrome (ACS) in severe acute pancreatitis (SAP). We conducted a retrospective study to assess the risk factors associated with ACS in SAP. METHODS: A total of 76 SAP patients who were admitted within 24 hours after symptom onset in our study. There were 36 patients suffering from ACS and 40 from intra-abdominal hypertension (IAH). On the 1st, 3rd and 7th days after hospital admission, the following variables were assessed: serum value of C-reactive protein (CRP), and the proportions of peripheral CD4+ and CD8+ T lymphocytes. Acute Physiology and Chronic Health Evaluation II (APACHE II) score, and computed tomography severity index (CTSI) score were assessed on days 1 and 7 after hospitalization. RESULTS: Compared with the patients with IAH, ACS patients showed statistically higher CRP value on 7th day after hospital admission, proportions of CD4+ T cells on days 1, 3, 7 and CD4+/CD8+ ratio on day 1 were significantly lower (P < 0.05, respectively). A CD4+ T cell proportion of 30.3% on the 1st day indicated ACS with an area under the curve (AUC) of 0.774, a sensitivity with 82.5% and specificity with 72.0%, respectively. Sensitivity/specificity for predicting ACS in SAP patients on day 1 was 70.0%/68.0% for CD4+/CD8+ ratio, 72.2%/65.0% for APACHE II score. CONCLUSIONS: The reduction of peripheral blood CD4+ T lymphocytes is associated with ACS in SAP, and may act as a potential predictor of ACS in SAP.

Dendritic-cell-based technology landscape: Insights from patents and citation networks.

As the most potent antigen-presenting cells, dendritic cells (DCs) are pivotal players in regulating immune responses. DC-based technologies have generated a series of typical and promising therapeutic options, especially after the first DC-based cancer vaccine was approved by US. Food and Drug Administration (US. FDA). In this context, this paper employs patents and citation networks to conduct a fundamental analysis in order to show overall landscape of DC-based technologies. The results in this research can be used as references for decision-making in developing efficacious DC therapeutic products.

Hairpin oligonucleotides anchored terbium ion: a fluorescent probe to specifically detect lead(II) at sub-nM levels.

A terbium based fluorescent probe was synthesized by coordinating terbium ions with a designed oligonucleotides (5'-ATATGGGGGATAT-3', termed GH5). GH5 improved the fluorescence of terbium ions by four orders of magnitude. The fluorescence enhancement of terbium ions by different oligonucleotides sequences indicated that the polyguanine loop of the hairpin GH5 is key to enhance terbium ion emission. The quantum yield of Tb-GH5 probe was 10.5% and the probe was photo-stable. The result of conductivity titration indicated that the stoichiometry of the probe is 3.5 Tb: 1 GH5, which is confirmed by fluorescence titration. This probe had high sensitivity and specificity for the detection of lead ions. The fluorescence intensity of this probe was linear with respect to lead concentration over a range 0.3-2.1 nM (R(2) = 0.99). The limit of detection for lead ions was 0.1 nM at a signal-to-noise ratio of 3.

Luminescent silver nanoclusters anchored by oligonucleotides detect human telomerase ribonucleic acid template.

Luminescent silver nanoclusters were anchored by designed oligonucleotides. After hybridizing with human telomerase RNA template, the luminescence of the cluster decreased linearly with respect to the concentration of the complementary strand (25-250 nM). The cluster is therefore a potential candidate for human telomerase detection.

[Effects of qingyi II recipe on the intestinal barrier function of severe acute pancreatitis rats].

OBJECTIVE: To observe the effects of Qingyi II Recipe (QR) on the intestinal barrier function (IBF) of severe acute pancreatitis (SAP) rats. METHODS: Forty-eight SD rats were selected to prepare SAP model. After modeling, they were randomly divided into the model group and the QR treatment group, 24 in each group. Another 8 rats were selected as the sham-operation group. The intervention was started just when they came to resuscitation from anesthesia. Rats in the QR treatment group was administered with QR (1 mL/100 g) by gastrogavage, while an equal volume of normal saline was given to rats in the sham-operation group and the model group by gastrogavage. The gastrogavage was performed once every 6 h. Eight rats were selected from each group 6, 12, and 24 h after intervention. The ascites amount was measured after opening abdomens. The concentrations of serum diamine oxidase (DAO) and D-lactate were measured. Pathological changes of pancreas and ileum were observed. The pathological scoring of the pancreas was performed. The ileum were scanned by electron microscope. RESULTS: There was no ascites in the sham-operation group. There was no obviously pathological abnormality in the pancreas or ileum. Compared with the sham-operation group, the ascites amount, serum DAO, D-lactate, and pathological scoring all increased at 6 h in the model group, showing statistical difference (P<0.05). In the model group, the serum DAO, D-lactate, and pathological scoring increased gradually at 6 -24 h with statistical difference (P<0.05). Results under microscope showed disarranged structure, interstitial edema, hemorrhage, a large amount of neutrophil infiltration, local foci or lamellar intestinal necrosis. The 24-h ascites amount increased more at 24 h than at 12 h in the model group with statistical difference (P<0.05). The serum D-lactate and patho- logical scoring increased gradually at 6 -24 h in the QR treatment group with statistical difference (P<0.05). The 24-h ascites amount and DAO increased more at 24 h than at 12 h in the model group with statistical difference (P<0.05). Compared with the model group at the same time point, each index decreased at 6 -24 h in the QR treatment group with statistical difference (P<0.05). Results under microscope showed edema and congestion of the intestinal mucosa tissue, little amount of neutrophil infiltration. But the degrees were milder when compared with those of the model group. CONCLUSION: QR protected IBF of SAP rats.

[Three-dimensional analysis of pharyngeal airway in skeletal Class III patients after sagittal split ramus osteotomy].

OBJECTIVE: To analyze the three-dimensional changes of pharyngeal airway in patients with skeletal Class III malocclusion after the combined orthodontic and orthognathic treatment. METHODS: Twenty patients (9 males, 11 females) and 40 subjects with normal occlusion were involved in the study. Cone-beam computed tomography (CBCT) were performed on patients one week and six months after treatment. Raw data were reconstructed into three-dimensional model and sagittal and transversal measurements, cross sectional areas, partial and total volumes were computed. RESULTS: After treatment, the sagittal diameters of each section were significantly reduced by (2.7 ± 3.5), (3.0 ± 3.8), (2.7 ± 3.3) mm, respectively (P < 0.05). The transversal diameter of laryngopharyngeal airway constricted significantly by (4.8 ± 4.1) mm (P < 0.05). Cross sectional areas and volumes of each part in patients after surgery were significantly narrower compared with those of the controls. CONCLUSIONS: After combined therapy the pharyngeal airway space decreased.

[Detection to changes in hyoid and tongue positions, and pharyngeal airway following mandibular setback surgery by cone beam CT].

OBJECTIVE: To observe changes in tongue and hyoid position, and pharyngeal airway in patients with skeletal class III malocclusion after the combined orthodontic and orthognathic treatment. METHODS: Twenty patients were involved in this study. Cone beam CT (CBCT) was performed on patients one week before and six months after treatment. Raw data were reconstructed into three-dimensional model. To set up a three-dimensional reference frame, which was based by point "S", the sagittal and transversal measurements, cross sectional areas, partial and total volumes were computed. The three-dimensional position changes of chin, hyoid bone and tongue were measured in order to analyze the amount of mandibular setback relationship with the changes of pharyngeal airway, hyoid bone and tongue positions. RESULTS: After treatment, the pharyngeal airway was constricted significantly. The hyoid significantly moved inferoposteriorly by 5.72 mm (backward) and 2.76 mm (downward) and the tongue moved posteriorly by 4.04 mm after surgery (P < 0.05). Among the 19 correlated indexes between the amount of mandibular setback and other measurements, 14 of which were significantly correlated (P < 0.05). The strongest correlation was found between the amount of mandibular setback and total volumes of pharyngeal airway (r = 0.834, P < 0.01). CONCLUSION: Following combination therapy, the pharyngeal airway space decreased, the hyoid moved inferoposteriorly and tongue moved posteriorly. There were great correlations between the amount of mandibular setback and the changes.