Natural products reverse cancer multidrug resistance.

Cancer stands as a prominent global cause of death. One of the key reasons why clinical tumor chemotherapy fails is multidrug resistance (MDR). In recent decades, accumulated studies have shown how Natural Product-Derived Compounds can reverse tumor MDR. Discovering novel potential modulators to reduce tumor MDR by Natural Product-Derived Compounds has become a popular research area across the globe. Numerous studies mainly focus on natural products including flavonoids, alkaloids, terpenoids, polyphenols and coumarins for their MDR modulatory activity. Natural products reverse MDR by regulating signaling pathways or the relevant expressed protein or gene. Here we perform a deep review of the previous achievements, recent advances in the development of natural products as a treatment for MDR. This review aims to provide some insights for the study of multidrug resistance of natural products.

Clinical efficacy of tumor organoid-guided cancer therapy for locally advanced unresectable or metastatic breast cancer.

Patient-derived organoids (PDOs) may facilitate treatment selection. This retrospective cohort study evaluated the feasibility and clinical benefit of using PDOs to guide personalized treatment in metastatic breast cancer (MBC). Patients diagnosed with MBC were recruited between January 2019 and August 2022. PDOs were established and the efficacy of customized drug panels was determined by measuring cell mortality after drug exposure. Patients receiving organoid-guided treatment (OGT) were matched 1:2 by nearest neighbor propensity scores with patients receiving treatment of physician's choice (TPC). The primary outcome was progression-free survival. Secondary outcomes included objective response rate and disease control rate. Targeted gene sequencing and pathway enrichment analysis were performed. Forty-six PDOs (46 of 51, 90.2%) were generated from 45 MBC patients. PDO drug screening showed an accuracy of 78.4% (95% CI 64.9%-91.9%) in predicting clinical responses. Thirty-six OGT patients were matched to 69 TPC patients. OGT was associated with prolonged median progression-free survival (11.0 months vs. 5.0 months; hazard ratio 0.53 [95% CI 0.33-0.85]; p = .01) and improved disease control (88.9% vs. 63.8%; odd ratio 4.26 [1.44-18.62]) compared with TPC. The objective response rate of both groups was similar. Pathway enrichment analysis in hormone receptor-positive, human epidermal growth factor receptor 2-negative patients demonstrated differentially modulated pathways implicated in DNA repair and transcriptional regulation in those with reduced response to capecitabine/gemcitabine, and pathways associated with cell cycle regulation in those with reduced response to palbociclib. Our study shows that PDO-based functional precision medicine is a feasible and effective strategy for MBC treatment optimization and customization.

A multiple cancer cell optical biosensing metastructure realized by CPA.

A one-dimensional optical biosensing metastructure (OBM) with graphene layers is presented in this paper. It is realized by coherent perfect absorption (CPA) and operates in the transverse electric mode. It shows a strong linear fitting relationship between the refractive index (RI) of the analysis layer and the frequency corresponding to the absorption peak, and the R-square is up to 1. Additionally, based on the principle of CPA, the OBM can realize the function of multiple cancer cell detection by adjusting the detection range by controlling the phase difference of coherent electromagnetic waves. Its detection ranges are 1.34-1.355 and 1.658-1.662. Thanks to its high-quality factor, great figure of merit, and low detection limit, whose best values are, respectively, 6.9 × 104, 1.2 × 104 RIU-1, and 3.6 × 10-6 RIU, the detection of weak changes in the RI of a cancer cell is possible. Additionally, its sensitivity can reach 26.57 THz RIU-1. This OBM based on CPA has major implications for advancing the study and investigation into the application of CPA. It also provides a simple and efficient approach to distinguish cancer cells and may be widely used in the biomedical field.

Undescribed matrine-type alkaloids from Sophora alopecuroides with anti-inflammatory activity.

A phytochemical investigation on the alkaloid fractions of Sophora alopecuroides L. led to the production of 11 undescribed matrine-type alkaloids, sophaloseedlines I-S (1-11), 12 known analogs (12-23), and an unexpected artificial matrine-derived Al(III) complex (24). The corresponding structures were elucidated by the interpretation of spectroscopic analyses, quantum chemical calculation, and six instances (1-4, 18, and 24), verified by X-ray crystallography. The biological activities screening demonstrated that none of the isolates exhibited cytotoxicity against four human cancer cell lines (HepG2, A549, THP-1, and MCF-7) and respiratory syncytial virus (RSV) at 50 µM, while moderate anti-inflammatory activity with IC50 value from 15.6 to 47.8 µM was observed. The key structure-activity relationships of those matrine-type alkaloids for anti-inflammatory effects have been summarized. In addition, the most potent 7-epi-sophoramine (19) and aluminum sophaloseedline T (24) could effectively inhibit the release of pro-inflammatory factors (TNF-α, IL-6, and IL-1ß), as well as the expression of iNOS and COX-2 proteins.

IL-2Rα-biased agonist enhances antitumor immunity by invigorating tumor-infiltrating CD25+CD8+ T cells.

To avoid regulatory T cell promotion and vascular toxicity, the interleukin-2 receptor-ß/interleukin-2 receptor-γ (IL-2Rßγ)-biased approach is used by most IL-2 analogs in immuno-oncology. However, recent clinical disappointments in these IL-2 agonists have questioned this strategy. Here we show that both wild-type (IL-2wt) and IL-2Rßγ-attenuated (IL-2α-bias) agonists that preserve IL-2Rα (CD25) activities can effectively expand tumor-specific CD8+ T cells (TSTs) and exhibit better antitumor efficacy and safety than the 'non-α' counterpart (IL-2nα). Mechanistically, TSTs coexpress elevated CD25 and PD-1 and are more susceptible to stimulation by IL-2Rα-proficient agonists. Moreover, the antitumor efficacy of anti-PD-1 depends on activation of PD-1+CD25+ TSTs through autocrine IL-2-CD25 signaling. In individuals with cancer, a low IL-2 signature correlates with non-responsiveness to anti-PD-1 treatment. In mouse models, IL-2α-bias, but not IL-2nα, restores the IL-2 signature and synergizes with anti-PD-1 to eradicate large established tumors. These findings underscore the indispensable function of CD25 in IL-2-based immunotherapy and provide rationales for evaluating IL-2Rα-biased agonists in individuals with cancer.

Intrathecal rapamycin attenuates the mechanical hyperalgesia of paclitaxel-induced peripheral neuropathy in mice.

Paclitaxel is an extensively used chemotherapy antitumor drug and paclitaxel-induced peripheral neuropathy (PIPN) is one of the most common side effect. Rapamycin, originally used as an adjuvant drug for chemotherapy, has recently been found to possess potential neuroprotective activities. Our purposes of this study are to verify the effect of rapamycin on PIPN, which contributes to a new target for PIPN treatment. Mice were given paclitaxel or rapamycin with different injection methods. Paw withdrawal threshold was tested at different time points for mechanical sensitivity assessment. Administration of paclitaxel, both 2 mg/kg and 5 mg/kg, could induce mechanical hypersensitivity. 0.01 mg intrathecal injection of rapamycin showed the best effect on attenuate the mechanical hyperalgesia of PIPN. Intrathecal injection of only rapamycin would not induce the mechanical hyperalgesia while when rapamycin and paclitaxel were used together the mechanical hyperalgesia induced by paclitaxel could be attenuated. Paclitaxel could induce mechanical hyperalgesia in mice and rapamycin could attenuate such mechanical hyperalgesia of PIPN.

Isolation of Projection-Specific and Behavior-Relevant Amygdala Circuit for RNA Sequencing.

One of the most sought-after topics in neuroscience is to understand how the environment regulates the activity and function of neural circuitry and subsequently influences relevant behaviors. In response to alterations in the environment, the neural circuits undergo adaptive changes ranging from gene expression changes to altered cellular function. Performing sequencing of the transcriptome involved in these behavior-related circuits will provide clues to accurately dissect the detailed mechanisms of related behavior. Here, we describe methods for marking and collecting the ventral hippocampus-projecting basolateral amygdala neurons, which have been repeatedly implicated in regulation of anxiety-like behavior, and subsequently constructing a library ready for sequencing. Specifically, the reported approaches include adeno-associated virus injection, acute brain slice isolation, cell suspension preparation, cell extraction, and cDNA library construction. By utilizing the techniques described here, researchers can comprehensively investigate the transcriptional levels of neural clusters embedded in particular circuits and discover potential pathogenic and therapeutic targets for behavior-relevant disorders. © 2023 Wiley Periodicals LLC. Basic Protocol 1: Tagging of behavior-related neural circuits Basic Protocol 2: Isolation and capture of fluorescent-positive cells Basic Protocol 3: Foundation of sequencing library.

Hypobaric Hypoxia Aggravates Renal Injury by Inducing the Formation of Neutrophil Extracellular Traps through the NF-κB Signaling Pathway.

OBJECTIVE: The hypersensitivity of the kidney makes it susceptible to hypoxia injury. The involvement of neutrophil extracellular traps (NETs) in renal injury resulting from hypobaric hypoxia (HH) has not been reported. In this study, we aimed to investigate the expression of NETs in renal injury induced by HH and the possible underlying mechanism. METHODS: A total of 24 SD male rats were divided into three groups (n=8 each): normal control group, hypoxia group and hypoxia+pyrrolidine dithiocarbamate (PDTC) group. Rats in hypoxia group and hypoxia+PDTC group were placed in animal chambers with HH which was caused by simulating the altitude at 7000 meters (oxygen partial pressure about 6.9 kPa) for 7 days. PDTC was administered at a dose of 100 mg/kg intraperitoneally once daily for 7 days. Pathological changes of the rat renal tissues were observed under a light microscope; the levels of serum creatinine (SCr), blood urea nitrogen (BUN), cell-free DNA (cf-DNA) and reactive oxygen species (ROS) were measured; the expression levels of myeloperoxidase (MPO), citrullinated histone H3 (cit-H3), B-cell lymphoma 2 (Bcl-2), Bax, nuclear factor kappa B (NF-κB) p65 and phospho-NF-κB p65 (p-NF-κB p65) in rat renal tissues were detected by qRT-qPCR and Western blotting; the localization of NF-κB p65 expression in rat renal tissues was observed by immunofluorescence staining and the expression changes of NETs in rat renal tissues were detected by multiplex fluorescence immunohistochemical staining. RESULTS: After hypoxia, the expression of NF-κB protein in renal tissues was significantly increased, the levels of SCr, BUN, cf-DNA and ROS in serum were significantly increased, the formation of NETs in renal tissues was significantly increased, and a large number of tubular dilatation and lymphocyte infiltration were observed in renal tissues. When PDTC was used to inhibit NF-κB activation, NETs formation in renal tissue was significantly decreased, the expression level of Bcl-2 in renal tissues was significantly increased, the expression level of Bax was significantly decreased, and renal injury was significantly alleviated. CONCLUSION: HH induces the formation of NETs through the NF-κB signaling pathway, and it promotes apoptosis and aggravates renal injury by decreasing Bcl-2 and increasing Bax expression.

Risk factors of pancreatitis after endoscopic retrograde cholangiopancreatography in patients with biliary tract diseases.

BACKGROUND: To investigate the risk factors of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) in patients with biliary tract diseases. METHODS: We retrospectively analyzed the clinical data of 480 patients who underwent ERCP for biliary tract diseases at the Affiliated Zhongshan Hospital of Dalian University from October 2011 to October 2016. The patients were divided into a study group (n = 75, with PEP) and a control group (n = 405, without PEP) based on whether they developed post-ERCP pancreatitis (PEP), and their clinical baseline data and intraoperative conditions were retrieved and compared. Then, factors associated with PEP were analyzed using logistic regression model, based on which a nomogram prediction model was constructed. The receiver operating characteristic (ROC) curve and calibration curve were used to evaluate the performance of the prediction model. RESULTS: Significant differences in age, sex, history of pancreatitis, history of choledocholithiasis, pancreatic duct imaging, pancreatic sphincterotomy, difficult cannulation, multiple cannulation attempts and juxtapapillary duodenal diverticula were observed between the two groups. Multivariate logistic regression analysis showed that age less than 60 years (OR, 0.477; 95% CI, 0.26-0.855), female sex (OR, 2.162; 95% CI, 1.220-3.831), history of pancreatitis (OR, 2.567; 95% CI, 1.218-5.410), history of choledocholithiasis (OR, 2.062; 95% CI, 1.162-3.658), pancreatic sphincterotomy (OR, 2.387; 95% CI, 1.298-4.390), pancreatic duct imaging (OR, 4.429; 95% CI, 1.481-13.242), multiple cannulation attempts (OR, 2.327; 95% CI, 1.205-4.493), difficult cannulation (OR, 2.421; 95% CI, 1.143-5.128), and JPD (OR, 2.002; 95% CI, 1.125-3.564) were independent risk factors for PEP. The nomogram for predicting the occurrence of PEP demonstrated an area under the ROC curve (AUC) of 0.787, and the calibration curves of the model showed good consistency between the predicted and actual probability of PEP. CONCLUSION: Our results showed that age less than 60 years, female sex, history of pancreatitis, history of choledocholithiasis, pancreatic sphincterotomy, pancreatic duct imaging, multiple cannulation attempts, difficult cannulation and juxtapapillary duodenal diverticula were independent risk factors for PEP. In addition, the established nomogram demonstrated promising clinical efficacy in predicting PEP risk in patients who underwent ERCP for biliary tract diseases.

Subcutaneous phaeohyphomycosis caused by plant pathogenic Corynespora cassiicola: A case report.

Corynespora cassiicola is a common plant pathogen responsible for leaf-spotting diseases in the tropical and subtropical areas. C. cassiicola seldom causes human infections. Here we describe a case of subcutaneous phaeohyphomycosis caused by C. cassiicola in a 76-year-old Chinese man, who presented to our hospital with a purulent discharge and painful sensation on his right leg. Skin biopsy revealed an abscess, and culture confirmed C. cassiicola to be the causative agent. The result was further identified by sequence analysis of the internal transcribed spacer region. The patient was successfully treated with systemic voriconazole and wound debridement: the lesion disappeared after 20 days.

Glycolytic and fatty acid oxidation genes affect the treatment and prognosis of liver cancer.

BACKGROUND: Metabolic reprogramming is a feature of tumour cells and is essential to support their rapid proliferation. The glycolytic activity of liver cancer cells is significantly higher than that of normal liver cells, and the rapidly proliferating tumour cells are powered by aerobic glycolysis. Lipid metabolism reprogramming enables tumour cells to meet their needs for highly proliferative growth and is an important driving force for the development of hepatocellular carcinoma (HCC). AIM: To explore the influence of different metabolic subtypes of HCC and analyse their significance in guiding prognosis and treatment based on the molecular mechanism of glycolysis and fatty acid oxidation (FAO). METHODS: By downloading related data from public databases including the Cancer Genome Atlas (TCGA), the Molecular Signatures Database, and International Cancer Genome Consortium, we utilised unsupervised consensus clustering to divide TCGA Liver Hepatocellular Carcinoma samples into four metabolic subgroups and compared single nucleotide polymorphism, copy number variation, tumour microenvironment, and Genomics of Drug Sensitivity in Cancer and Tumour Immune Dysfunction and Exclusion between different metabolites. The differences and causes of survival and the clinical characteristics between them were analysed, and a prognostic model was established based on glycolysis and FAO genes. Combined with the clinical features, a Norman diagram was created to compare the pros and cons of each model. RESULTS: In the four metabolic subgroups, with the increase in glycolytic expression, the median survival of patients showed the worst results, while FAO showed the best. When comparing the follow-up analysis of each group, we considered that the differences between them might be related to reactive oxygen species, somatic copy number variation of key genes, and immune microenvironment. It was also found that the FAO group and the low-risk group had better efficacy and response to immune checkpoint blockade treatment and anti-tumour drugs. CONCLUSION: There are obvious differences in genes, chromosomes, and clinical characteristics between metabolic subgroups. The establishment of a prognostic model could predict patient prognosis and guide clinical treatment.

Superkine IL-2 and IL-33 Armored CAR T Cells Reshape the Tumor Microenvironment and Reduce Growth of Multiple Solid Tumors.

Chimeric-antigen receptor (CAR) T-cell therapy has shown remarkable efficacy against hematologic tumors. Yet, CAR T-cell therapy has had little success against solid tumors due to obstacles presented by the tumor microenvironment (TME) of these cancers. Here, we show that CAR T cells armored with the engineered IL-2 superkine Super2 and IL-33 were able to promote tumor control as a single-agent therapy. IFNγ and perforin were dispensable for the effects of Super2- and IL-33-armored CAR T cells. Super2 and IL-33 synergized to shift leukocyte proportions in the TME and to recruit and activate a broad repertoire of endogenous innate and adaptive immune cells including tumor-specific T cells. However, depletion of CD8+ T cells or NK cells did not disrupt tumor control, suggesting that broad immune activation compensated for loss of individual cell subsets. Thus, we have shown that Super2 and IL-33 CAR T cells can promote antitumor immunity in multiple solid tumor models and can potentially overcome antigen loss, highlighting the potential of this universal CAR T-cell platform for the treatment of solid tumors.

Mettl14-Mediated m6A Modification Is Essential for Germinal Center B Cell Response.

The germinal center (GC) response is essential for generating memory B and long-lived Ab-secreting plasma cells during the T cell-dependent immune response. In the GC, signals via the BCR and CD40 collaboratively promote the proliferation and positive selection of GC B cells expressing BCRs with high affinities for specific Ags. Although a complex gene transcriptional regulatory network is known to control the GC response, it remains elusive how the positive selection of GC B cells is modulated posttranscriptionally. In this study, we show that methyltransferase like 14 (Mettl14)-mediated methylation of adenosines at the position N 6 of mRNA (N 6-methyladenosine [m6A]) is essential for the GC B cell response in mice. Ablation of Mettl14 in B cells leads to compromised GC B cell proliferation and a defective Ab response. Interestingly, we unravel that Mettl14-mediated m6A regulates the expression of genes critical for positive selection and cell cycle regulation of GC B cells in a Ythdf2-dependent but Myc-independent manner. Furthermore, our study reveals that Mettl14-mediated m6A modification promotes mRNA decay of negative immune regulators, such as Lax1 and Tipe2, to upregulate genes requisite for GC B cell positive selection and proliferation. Thus, our findings suggest that Mettl14-mediated m6A modification plays an essential role in the GC B cell response.

IκB kinase promotes Nrf2 ubiquitination and degradation by phosphorylating cylindromatosis, aggravating oxidative stress injury in obesity-related nephropathy.

BACKGROUND: Obesity-related nephropathy (ORN) has become one of the leading causes of end-stage renal disease and has tripled over the past decade. Previous studies have demonstrated that decreased reactive oxygen species production may contribute to improving ORN by ameliorating oxidative stress injury. Here, IκB kinase (IKK) was hypothesized to inactivate the deubiquitination activity of cylindromatosis (CYLD) by activating the phosphorylation of CYLD, thus promoting the ubiquitination of NF-E2-related factor 2 (Nrf2) and further aggravating oxidative stress injury of the kidney in ORN. This study was aimed to confirm this hypothesis. METHODS: Haematoxylin and eosin (HE), periodic acid-Schiff (PAS) and Oil Red O staining were performed to assess histopathology. Dihydroethidium (DHE) staining and MDA, SOD, CAT, and GSH-PX assessments were performed to measure reactive oxygen species (ROS) production. Immunohistochemical (IHC) staining, qRT-PCR and/or western blotting were performed to assess the expression of related genes. JC-1 assays were used to measure the mitochondrial membrane potential (ΔΨm) of treated HK-2 cells. Co-immunoprecipitation experiments (Co-IP) were used to analyse the interaction between CYLD and Nrf2 in ORN. RESULTS: ORN in vivo and in vitro models were successfully constructed, and oxidative stress injury was detected in the model tissues and cells. Compared with the control groups, the phosphorylation level of CYLD increased while Nrf2 levels decreased in ORN model cells. An IKK inhibitor reduced lipid deposition, ROS production, CYLD phosphorylation levels and ΔΨm in vitro, which were reversed by knockdown of CYLD. Nrf2 directly bound to CYLD and was ubiquitinated in ORN cells. The proteasome inhibitor MG132 activated the Nrf2/ARE signalling pathway, thereby reversing the promoting effect of CYLD knockdown on oxidative stress. CONCLUSION: IKK inactivates the deubiquitination activity of CYLD by activating the phosphorylation of CYLD, thus promoting the ubiquitination of Nrf2 and further aggravating oxidative stress injury of the kidney in ORN. This observation provided a feasible basis for the treatment of kidney damage caused by ORN.

A Novel 5-HT1B Receptor Agonist of Herbal Compounds and One of the Therapeutic Uses for Alzheimer's Disease.

The serotonin receptor 5-HT1B is widely expressed in the central nervous system and has been considered a drug target in a variety of cognitive and psychiatric disorders. The anti-inflammatory effects of 5-HT1B agonists may present a promising approach for Alzheimer's disease (AD) treatment. Herbal antidepressants used in the treatment of AD have shown functional overlap between the active compounds and 5-HT1B receptor stimulation. Therefore, compounds in these medicinal plants that target and stimulate 5-HT1B deserve careful study. Molecular docking, drug affinity responsive target stability, cellular thermal shift assay, fluorescence resonance energy transfer (FRET), and extracellular regulated protein kinases (ERK) 1/2 phosphorylation tests were used to identify emodin-8-O-ß-d-glucopyranoside (EG), a compound from Chinese medicinal plants with cognitive deficit attenuating and antidepressant effects, as an agonist of 5-HT1B. EG selectively targeted 5-HT1B and activated the 5-HT1B-induced signaling pathway. The activated 5-HT1B pathway suppressed tumor necrosis factor (TNF)-α levels, thereby protecting neural cells against beta-amyloid (Aß)-induced death. Moreover, the agonist activity of EG towards 5-HT1B receptor, in FRET and ERK1/2 phosphorylation, was antagonized by SB 224289, a 5-HT1B antagonist. In addition, EG relieved AD symptoms in transgenic worm models. These results suggested that 5-HT1B receptor activation by EG positively affected Aß-related inflammatory process regulation and neural death resistance, which were reversed by antagonist SB 224289. The active compounds such as EG might act as potential therapeutic agents through targeting and stimulating 5-HT1B receptor for AD and other serotonin-related disorders. This study describes methods for identification of 5-HT1B agonists from herbal compounds and for evaluating agonists with biological functions, providing preliminary information on medicinal herbal pharmacology.

Fruquintinib beneficial in elderly patient with neoplastic pericardial effusion from rectal cancer: A case report.

BACKGROUND: Neoplastic pericardial effusion (NPE) is a rare consequence of rectal cancer and carries a poor prognosis. Optimal management has yet to be determined. Fruquintinib is an oral anti-vascular endothelial growth factor receptor tyrosine kinase inhibitor approved by the China Food and Drug Administration in September 2018 as third-line treatment of metastatic colorectal cancer. CASE SUMMARY: Herein, we report an elderly patient with NPE from rectal cancer who responded to the use of fruquintinib. In March 2015, a 65-year-old Chinese woman diagnosed with KRAS-mutated adenocarcinoma of the rectum was subjected to proctectomy, adjuvant concurrent chemoradiotherapy, and adjuvant chemotherapy. By October 2018, a mediastinal mass was detected via computed tomography. The growth had invaded parietal pericardium and left hilum, displaying features of rectal adenocarcinoma in a bronchial biopsy. FOLFIRI and FOLFOX chemotherapeutic regimens were administered as first- and second-line treatments. After two cycles of second-line agents, a sizeable pericardial effusion resulting in tamponade was drained by pericardial puncture. Fluid cytology showed cells consistent with rectal adenocarcinoma. Single-agent fruquintinib was initiated on January 3, 2019, as a third-line therapeutic. Ten cycles were delivered before the NPE recurred and other lesions progressed. The recurrence-free interval for NPE was 9.2 mo, attesting to the efficacy of fruquintinib. Ultimately, the patient entered a palliative care unit for best supportive care. CONCLUSION: Fruquintinib may confer good survival benefit in elderly patients with NPEs due to rectal cancer.

Identification of dihydrotanshinone I as an ERp57 inhibitor with anti-breast cancer properties via the UPR pathway.

Salvia miltiorrhiza (Danshen) is a well-known traditional Chinese medicine for treating various diseases, such as breast cancer. However, knowledge regarding its mechanisms is scant. Herein, the active ingredient dihydrotanshinone I (DHT) in Salvia miltiorrhiza extract (SME), which binds ERp57 was identified and verified by an enzymatic solid-phase method combined with LC-MS/MS. DHT potentially inhibited ERp57 activity and suppressed ERp57 expression at both the RNA and protein levels. Molecular docking simulation indicated that DHT could form a hydrogen bond with catalytic site of ERp57. Moreover, ERp57 overexpression decreased DHT-induced cytotoxicity in MDA-MB-231 cells. Thereafter, the signaling pathway downstream of ERp57 was investigated by Western blot analysis. The mechanistic study revealed that DHT treatment resulted in activation of endoplasmic reticulum (ER) stress, the unfolded protein response (UPR), and cellular apoptosis. In conclusion, our data implied that DHT targeted ERp57 for inhibition and induced ER stress and UPR activation, which in turn triggered breast cancer cell apoptosis.

Hybrid endoscopic submucosal dissection: An alternative resection modality for large laterally spreading tumors in the cecum?

BACKGROUND: Endoscopic resection for large, laterally spreading tumors (LSTs) in the cecum is challenging. Here we report on the clinical outcomes of hybrid endoscopic submucosal dissection (ESD) in large cecal LSTs. METHODS: We retrospectively reviewed data from patients with cecal LSTs ≥ 2 cm who underwent ESD or hybrid ESD procedures between January of 2008 and June of 2019. We compared the baseline characteristics and clinical outcomes, including procedure time, the en bloc and complete resection rates, and adverse events. RESULTS: A total of 62 patients were enrolled in the study. There were 27 patients in the ESD group and 35 patients in the hybrid ESD group, respectively. Hybrid ESD was more used for lesions with submucosal fibrosis. No other significant differences were found in patient characteristics between the two groups. The hybrid ESD group had a significantly shorter procedure time compared with the ESD group (27.60 ± 17.21 vs. 52.63 ± 44.202 min, P = 0.001). The en bloc resection rate (77.1% vs. 81.5%, P = 0.677) and complete resection rate (71.4% vs. 81.5%, P = 0.359) of hybrid ESD were relatively lower than that of the ESD group in despite of no significant difference was found. The perforation and post-procedure bleeding rate (2.9% vs. 3.7%, P = 0.684) were similar between the two groups. One patient perforated during the ESD procedure, which was surgically treated. One patient in the hybrid ESD group experienced post-procedure bleeding, which was successfully treated with endoscopic hemostasis. Post-procedural fever and abdominal pain occurred in six patients in the ESD group and five patients in the hybrid ESD group. One patient in the ESD group experienced recurrence, which was endoscopically resected. CONCLUSION: The results of this study indicate that hybrid ESD may be an alternative resection strategy for large cecal LSTs with submucosal fibrosis.

The characteristics and evolution of pulmonary fibrosis in COVID-19 patients as assessed by AI-assisted chest HRCT.

The characteristics and evolution of pulmonary fibrosis in patients with coronavirus disease 2019 (COVID-19) have not been adequately studied. AI-assisted chest high-resolution computed tomography (HRCT) was used to investigate the proportion of COVID-19 patients with pulmonary fibrosis, the relationship between the degree of fibrosis and the clinical classification of COVID-19, the characteristics of and risk factors for pulmonary fibrosis, and the evolution of pulmonary fibrosis after discharge. The incidence of pulmonary fibrosis in patients with severe or critical COVID-19 was significantly higher than that in patients with moderate COVID-19. There were significant differences in the degree of pulmonary inflammation and the extent of the affected area among patients with mild, moderate and severe pulmonary fibrosis. The IL-6 level in the acute stage and albumin level were independent risk factors for pulmonary fibrosis. Ground-glass opacities, linear opacities, interlobular septal thickening, reticulation, honeycombing, bronchiectasis and the extent of the affected area were significantly improved 30, 60 and 90 days after discharge compared with at discharge. The more severe the clinical classification of COVID-19, the more severe the residual pulmonary fibrosis was; however, in most patients, pulmonary fibrosis was improved or even resolved within 90 days after discharge.

A Rare Giant Midesophageal Diverticulum: Fever is the Only Symptom.

A 55-year-old man was treated at the village hospital with six months medical history of recurrent chills and fever. Due to the lack of imaging examination, antipyretic and anti-infective medications were given. Although symptomatic treatment can relieve fever symptoms, symptoms easily flare up again two to three days after taking the drug. Later, the patient suffered from fever again during the COVID-19 epidemic and was sent to our hospital for isolation and treatment. During this hospitalization, chest CT examination is mandatory for all patients in order to meet the requirements of epidemic prevention and control. This led to the inadvertent discovery of a large cystic solid mass in the right thoracic cavity communicating with the esophageal lumen. The patient was preliminarily diagnosed as giant midesophageal diverticulum after three-dimensional CT image reconstruction of the chest was reviewed. Considering the patient's persistent fever with poor nutritional status, we decided to temporarily place two gastric tubes (diverticulum decompression and gastrointestinal nutrition), and antibiotics were used at the same time as another main treatment. However, after the symptoms eased and nutritional status improved, he refused all further treatment. We believe that this patient's diverticulum is very classic, and the treatment plan is highly integrated with the needs of epidemic prevention and control and achieves a satisfactory therapeutic effect, so we hope to provide colleagues with new diagnosis and treatment enlightenment through this case.