Upregulation of LHPP by saRNA inhibited hepatocellular cancer cell proliferation and xenograft tumor growth.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer worldwide and no pharmacological treatment is available that can achieve complete remission of HCC. Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) is a recently identified HCC tumor suppressor gene which plays an important role in the development of HCC and its inactivation and reactivation has been shown to result in respectively HCC tumorigenesis and suppression. Small activating RNAs (saRNAs) have been used to achieve targeted activation of therapeutic genes for the restoration of their encoded protein through the RNAa mechanism. Here we designed and validated saRNAs that could activate LHPP expression at both the mRNA and protein levels in HCC cells. Activation of LHPP by its saRNAs led to the suppression of HCC proliferation, migration and the inhibition of Akt phosphorylation. When combined with targeted anticancer drugs (e.g., regorafenib), LHPP saRNA exhibited synergistic effect in inhibiting in vitro HCC proliferation and in vivo antitumor growth in a xenograft HCC model. Findings from this study provides further evidence for a tumor suppressor role of LHPP and potential therapeutic value of restoring the expression of LHPP by saRNA for the treatment of HCC.

Endoscopic-ultrasound-guided biliary drainage with placement of electrocautery-enhanced lumen-apposing metal stent for palliation of malignant biliary obstruction: Updated meta-analysis.

BACKGROUND: Endoscopic ultrasound-guided biliary drainage using electrocautery-enhanced (ECE) delivery of lumen-apposing metal stent (LAMS) is gradually being recognized as a viable palliative technique for malignant biliary obstruction after endoscopic retrograde cholangiopancreatography (ERCP) failure. However, most of the studies that have assessed its efficacy and safety were small and heterogeneous. Prior meta-analyses of six or fewer studies that were published 2 years ago were therefore underpowered to yield convincing evidence. AIM: To update the efficacy and safety of ECE-LAMS for treatment of biliary obstruction after ERCP failure. METHODS: We searched PubMed, EMBASE, and Scopus databases from the inception of the ECE technique to May 13, 2022. Primary outcome measure was pooled technical success rate, and secondary outcomes were pooled rates of clinical success, reintervention, and adverse events. Meta-analysis was performed using a random-effects model following Freeman-Tukey double-arcsine transformation in R software (version 4.1.3). RESULTS: Fourteen eligible studies involving 620 participants were ultimately included. The pooled rate of technical success was 96.7%, and clinical success was 91.0%. Adverse events were reported in 17.5% of patients. Overall reintervention rate was 7.3%. Subgroup analyses showed results were generally consistent. CONCLUSION: ECE-LAMS has favorable success with acceptable adverse events in relieving biliary obstruction when ERCP is impossible. The consistency of results across most subgroups suggested that this is a generalizable approach.

Efficacy of Intravenous Administration of Esketamine in Preventing and Treating Rebound Pain After Thoracic Paravertebral Nerve Block: A Prospective Randomized, Double-Blind, Placebo-Controlled Trial.

Purpose: Investigating the efficacy of intraoperative fractionated intravenous esketamine in the prevention of rebound pain after cessation of thoracic paravertebral nerve blockade. Methods: One hundred and twenty patients who underwent elective thoracoscopic lobectomy were selected for the study and were randomly divided into two groups, the esketamine group was given 0.5 mg/kg and 0.3 mg/kg of esketamine at the induction of anaesthesia and 30 minutes before the end of the operation, respectively, and the control group was given an equal amount of saline. The incidence of rebound pain (RP) 7 days after surgery and postoperative recovery were compared between the two groups. Results: The NRS pain scores at 24 and 48 hours postoperatively in the esketamine group were significantly lower than those in the control group (P < 0.05). The incidence of postoperative rebound pain was significantly lower in the esketamine group than in the control group (P < 0.05). The consumption of sufentanil was less in the esketamine group in the postoperative 48 hours (P < 0.05). Postoperative recovery was compared between the two groups and the difference was not statistically significant. Conclusion: Intravenous esketamine reduces postoperative pain scores, decreases the incidence of rebound pain after cessation of thoracic paravertebral block, and reduces opioid consumption.

The role of olfactory ensheathing cells in the repair of nerve injury.

Cell transplantation has brought about a breakthrough in the treatment of nerve injuries, and the efficacy of cell transplantation compared to drug and surgical therapies is very exciting. In terms of transplantation targets, the classic cells include neural stem cells (NSCs) and Schwann cells, while a class of cells that can exist and renew throughout the life of the nervous system - olfactory ensheathing cells (OECs) - has recently been discovered in the olfactory system. OECs not only encircle the olfactory nerves but also act as macrophages and play an innate immune role. OECs can also undergo reprogramming to transform into neurons and survive and mature after transplantation. Currently, many studies have confirmed the repairing effect of OECs after transplantation into injured nerves, and safe and effective results have been obtained in clinical trials. However, the specific repair mechanism of OECs among them is not quite clear. For this purpose, we focus here on the repair mechanisms of OECs, which are summarized as follows: neuroprotection, secretion of bioactive factors, limitation of inflammation and immune regulation, promotion of myelin and axonal regeneration, and promotion of vascular proliferation. In addition, integrating the aspects of harvesting, purification, and prognosis, we found that OECs may be more suitable for transplantation than NSCs and Schwann cells, but this does not completely discard the value of these classical cells. Overall, OECs are considered to be one of the most promising transplantation targets for the treatment of nerve injury disorders.

Effect of magnesium sulfate perioperative infusion on postoperative catheter-related bladder discomfort in male patients undergoing laparoscopic radical resection of gastrointestinal cancer: a prospective, randomized and controlled study.

BACKGROUND: Laparoscopic radical resection of gastrointestinal cancer is associated with a high incidence of postoperative catheter-related bladder discomfort (CRBD). Studies on the benefits of magnesium sulfate intravenous infusion during the perioperative period post-laparoscopic surgery are yet lacking. METHODS: A total of 88 gastrointestinal cancer male patients scheduled for laparoscopic radical resection were randomly divided into two groups: normal saline (control) and magnesium. In the magnesium group, a 40 mg/kg loading dose of intravenous magnesium sulfate was administered for 10 min just after the induction of anesthesia, followed by continuous intravenous infusion of 15 mg/kg/h magnesium sulfate until the end of the surgery; the control group was administered the same dose of normal saline. Subsequently, 2 µg/kg sufentanil was continuously infused intravenously by a postoperative patient-controlled intravenous analgesia (PCIA) device. The primary outcome was the incidence of CRBD at 0 h after the surgery. The secondary outcomes included incidence of CRBD at 1, 2, and 6 h postsurgery, the severity of CRBD at 0, 1, 2, and 6 h postsurgery. Remifentanil requirement during surgery, sufentanil requirement within 24 h postsurgery, the postoperative numerical rating scale (NRS) score at 48 h after the surgery, magnesium-related side effects and rescue medication (morphine) requirement were also assessed. RESULTS: The incidence of CRBD at 0, 1, 2, and 6 h postoperatively was lower in the magnesium group than the control group (0 h: P = 0.01; 1 h: P = 0.003; 2 h: P = 0.001; 6 h: P = 0.006). The incidence of moderate to severe CRBD was higher in the control group at postoperative 0 and 1 h (0 h: P = 0.002; 1 h: P = 0.028), remifentanil requirement during surgery were significantly lower in the magnesium group than the control group. Sufentanil requirements during the 24 h postoperative period were significantly lower in the magnesium group than the control group. The NRS score was reduced in the magnesium group compared to the control group in the early postoperative period. Magnesium-related side effects and rescue medication (morphine) did not differ significantly between the two groups. CONCLUSIONS: Intravenous magnesium sulfate administration reduces the incidence and severity of CRBD and remifentanil requirement in male patients undergoing radical resection of gastrointestinal cancer. Also, no significant side effects were observed. TRIAL REGISTRATION: Chictr.org.cn ChiCTR2100053073. The study was registered on 10/11/2021.

Global metabolic profile and multiple phytometabolites in the different varieties of Gastrodia elata Blume.

Gastrodia elata Blume (Tianma in Chinese), a myco-heterotrophic orchid, is widely distributed in China. Tubers derived from this orchid are traditionally used as both medicinal and edible materials. At present, five primary varieties of G. elata are recorded in the "Flora of China." Among them, the three main varieties currently in artificial cultivation are G. elata f. elata (GR, red stem), G. elata f. glauca (GB, black stem), and G. elata f. viridis (GG, green stem). In our study, the metabolic profiles and chemical composition of these three varieties were determined via UPLC-MS/MS and HPLC-UV. In total, 11,132 metabolites were detected, from which multiple phytometabolites were identified as aromatic compounds, heteroatomic compounds, furans, carbohydrates, organic acids, and their derivatives. A number of differentially expressed metabolites (DEMs) were annotated as bioactive ingredients. Overall, parishins, vanilloloside, and gastrodin A/B in the GB group were markedly higher, whereas gastrodin, gastrol, and syringic acid were more enriched in the GG or GR groups. Moreover, HPLC fingerprint analysis also found six metabolites used as markers for the identification of Gastrodiae Rhizoma in the Chinese Pharmacopoeia, which were also typical DEMs in metabolomics. Of these, gastrodin, 4-hydroxybenzyl alcohol, citric acid, and adenosine were quantitatively detected, showing a similar result with the metabolomic data. In summary, our findings provide novel insights into the phytochemical ingredients of different G. elata varieties, highlighting diverse biological activities and healthcare value.

Efficacy and Interpretability Analysis of Noninvasive Imaging Based on Computed Tomography in Patients with Hepatocellular Carcinoma After Initial Transarterial Chemoembolization.

RATIONALE AND OBJECTIVES: The objective of this study is to accurately and timely assess the efficacy of patients with hepatocellular carcinoma (HCC) after the initial transarterial chemoembolization (TACE). MATERIALS AND METHODS: This retrospective study consisted of 279 patients with HCC in Center 1, who were split into training and validation cohorts in the ratio of 4:1, and 72 patients in Center 2 as an external testing cohort. Radiomics signatures both in the arterial phase and venous phase of contrast-enhanced computed tomography images were selected by univariate analysis, correlation analysis, and least absolute shrinkage and selection operator regression to build the predicting models. The clinical model and combined model were constructed by independent risk factors after univariate and multivariate logistic regression analysis. The biological interpretability of radiomics signatures correlating transcriptome sequencing data was explored using publicly available data sets. RESULTS: A total of 31 radiomics signatures in the arterial phase and 13 radiomics signatures in the venous phase were selected to construct Radscore_arterial and Radscore_venous, respectively, which were independent risk factors. After constructing the combined model, the area under the receiver operating characteristic curve in three cohorts was 0.865, 0.800, and 0.745, respectively. Through correlation analysis, 11 radiomics signatures in the arterial phase and 4 radiomics signatures in the venous phase were associated with 8 and 5 gene modules, respectively (All P < .05), which enriched some pathways closely related to tumor development and proliferation. CONCLUSION: Noninvasive imaging has considerable value in predicting the efficacy of patients with HCC after initial TACE. The biological interpretability of the radiological signatures can be mapped at the micro level.

Hydrogen sulfide protects Sertoli cells against toxicant Acrolein-induced cell injury.

Acrolein (ACR), a highly toxic α,ß-unsaturated aldehyde, is considered to be a common mediator behind the reproductive injury induced by various factors. However, the understanding of its reproductive toxicity and prevention in reproductive system is limited. Given that Sertoli cells provide the first-line defense against various toxicants and that dysfunction of Sertoli cell causes impaired spermatogenesis, we, therefore, examined ACR cytotoxicity in Sertoli cells and tested whether hydrogen sulfide (H2S), a gaseous mediator with potent antioxidative actions, could have a protective effect. Exposure of Sertoli cells to ACR led to cell injury, as indicated by reactive oxygen species (ROS) generation, protein oxidation, P38 activation and ultimately cell death that was prevented by antioxidant N-acetylcysteine (NAC). Further studies revealed that ACR cytotoxicity on Sertoli cells was significantly exacerbated by the inhibition of H2S-synthesizing enzyme cystathionine γ-lyase (CSE), while significantly suppressed by H2S donor Sodium hydrosulfide (NaHS). It was also attenuated by Tanshinone IIA (Tan IIA), an active ingredient of Danshen that stimulated H2S production in Sertoli cells. Apart from Sertoli cells, H2S also protected the cultured germ cells from ACR-initiated cell death. Collectively, our study characterized H2S as endogenous defensive mechanism against ACR in Sertoli cells and germ cells. This property of H2S could be used to prevent and treat ACR-related reproductive injury.

Synthetic cannabinoid-associated acute interstitial nephritis: An emerging cause of pediatric acute kidney injury?

Synthetic cannabinoid (SCB) usage among children is a rapidly emerging public health concern in the United States. Acute kidney injury (AKI) is an uncommon manifestation of SCB usage, with acute tubular necrosis (ATN) as the predominant histology. Here we describe a 16-year-old adolescent who sustained severe non-oliguric AKI in association with SCB usage. Emesis, right flank pain, and hypertension were the presenting clinical features. There was no uveitis, skin rash, joint pains, or eosinophilia. Urinalysis showed absence of proteinuria or hematuria. Urine toxicology was negative. Renal sonogram showed bilateral echogenic kidneys. Renal biopsy demonstrated severe acute interstitial nephritis (AIN), mild tubulitis, and absence of ATN. AIN responded with pulse steroid followed by oral steroid. Renal replacement therapy was not required. Although the exact pathophysiology of SCB-associated AIN is not known, immune response elicited by the renal tubulointerstitial cells against the antigens present in the SCB is the most likely mechanism. A high index of suspicion for SCB-induced AKI is necessary in adolescents who present with AKI of unclear etiology.

Deep learning-based diagnosis of osteoblastic bone metastases and bone islands in computed tomograph images: a multicenter diagnostic study.

OBJECTIVE: To develop and validate a deep learning (DL) model based on CT for differentiating bone islands and osteoblastic bone metastases. MATERIALS AND METHODS: The patients with sclerosing bone lesions (SBLs) were retrospectively included in three hospitals. The images from site 1 were randomly assigned to the training (70%) and intrinsic verification (10%) datasets for developing the two-dimensional (2D) DL model (single-slice input) and "2.5-dimensional" (2.5D) DL model (three-slice input) and to the internal validation dataset (20%) for evaluating the performance of both models. The diagnostic performance was evaluated using the internal validation set from site 1 and additional external validation datasets from site 2 and site 3. And statistically analyze the performance of 2D and 2.5D DL models. RESULTS: In total, 1918 SBLs in 728 patients in site 1, 122 SBLs in 71 patients in site 2, and 71 SBLs in 47 patients in site 3 were used to develop and test the 2D and 2.5D DL models. The best performance was obtained using the 2.5D DL model, which achieved an AUC of 0.996 (95% confidence interval [CI], 0.995-0.996), 0.958 (95% CI, 0.958-0.960), and 0.952 (95% CI, 0.951-0.953) and accuracies of 0.950, 0.902, and 0.863 for the internal validation set, the external validation set from site 2 and site 3, respectively. CONCLUSION: A DL model based on a three-slice CT image input (2.5D DL model) can improve the prediction of osteoblastic bone metastases, which can facilitate clinical decision-making. KEY POINTS: • This study investigated the value of deep learning models in identifying bone islands and osteoblastic bone metastases. • Three-slice CT image input (2.5D DL model) outweighed the 2D model in the classification of sclerosing bone lesions. • The 2.5D deep learning model showed excellent performance using the internal (AUC, 0.996) and two external (AUC, 0.958; AUC, 0.952) validation sets.

Puerarin extends the lifespan of Drosophila melanogaster by activating autophagy.

Lifespan longevity has attracted increasing attention with societal development. To counter the effects of aging on longevity, we focused on the natural chemicals of plants. In this study, we investigated the effects of puerarin supplementation on the lifespan of Drosophila melanogaster. Puerarin supplementation significantly extended the lifespan of D. melanogaster at 60 µM and 120 µM by upregulating proteasome subunit beta 5 (prosbeta5) and sirtuin-1 (Sirt1). However, puerarin-induced longevity of male flies (F0 generation) may not be passed on to descendants. Additionally, a puerarin diet for 10 and 25 days did not influence the body weight and food intake of male Canton-S flies. Puerarin significantly improved the climbing ability, starvation resistance, and oxidation resistance of male flies by upregulating the expression of Shaker, catalase (CAT), superoxide dismutase 1 (SOD1), and Methuselah, and downregulating poly [ADP-ribose] polymerase (PARP-1) and major heat shock 70 kDa protein Aa (HSP70). Moreover, 120 µM puerarin supplementation for 25 days significantly increased adenosine 5' triphosphate (ATP) content by increasing adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) levels. Additionally, the puerarin diet for 25 days suppressed male fecundity in male flies by decreasing the levels of Bam and Punt. Mechanistically, puerarin enhanced lysosome-involved autophagy by promoting the expression of lysosome markers [ß-galactosidase and lysosomal associated membrane protein 1 (LAMP1)], and elevating the levels of autophagy-related genes, including autophagy-associated gene 1 (ATG1), ATG5, and ATG8b. However, puerarin decreased the phosphorylation of the target of rapamycin (TOR) protein. In conclusion, puerarin is a promising compound for improving the longevity of D. melanogaster by activating autophagy.

Does kidney biopsy in pediatric lupus patients "complement" the management and outcomes of silent lupus nephritis? Lessons learned from a pediatric cohort.

BACKGROUND: Silent lupus nephritis (SLN) is systemic lupus erythematosus (SLE) without clinical and laboratory features of kidney involvement but with biopsy-proven nephritis. This study aims to describe and compare the baseline characteristics and outcomes of pediatric SLN with overt LN (OLN) and to identify associated risk factors and biochemical markers. METHODS: In this retrospective, observational study, multivariate logistic regression and receiver operating characteristic (ROC) analyses studied age, sex, race, serum complements, anti-double-stranded-DNA antibody, anti-Smith antibody, eGFR, and proliferative nephritis. RESULTS: In our cohort of 69 patients, 47 were OLN, and 22 were SLN. OLN (OR = 4.9, p = 0.03) and non-African Americans (AA) (OR = 13.0, p < 0.01) had higher odds, and increasing C3 and C4 were associated with lower odds of proliferative nephritis (OR 0.95 and 0.65 per one unit increase in C3 and C4, respectively, p < 0.01). They demonstrated a good discriminative ability to detect proliferative nephritis as assessed by the area under the ROC curve (C3 = 0.78, C4 = 0.78). C3 and C4 in proliferative SLN and OLN were comparable and significantly lower than their non-proliferative counterparts. No association was observed between age, sex, anti-double-stranded-DNA antibody, anti-Smith antibody, eGFR, and proliferative nephritis. Proliferative SLN and OLN patients received similar treatments. Adverse events were identified in the proliferative OLN only. CONCLUSIONS: Lower complement levels are associated with proliferative lesions in pediatric LN-both SLN and OLN. The non-AA population had higher odds of having proliferative nephritis than the AA. Prospective, randomized, long-term follow-up of proliferative SLN patients is needed to ascertain the beneficial effect of early diagnosis and treatment. A higher resolution version of the Graphical abstract is available as Supplementary information.

The therapeutic effect of an autologous and allogenic mixed glioma cell lysate vaccine in a rat model.

PURPOSE: Tumor immunotherapy has the advantages of high specificity, minimal damage to the patient's body, and a long-lasting anti-tumor effect. However, due to the existence of immune escape phenomenon, the effect of anti-tumor immunotherapy is still poor. Therefore, a cancer vaccine that reverses tumor-associated immunosuppression is a very promising approach for research and treatment. METHODS: Vaccines were prepared using autologous and allogeneic tumor cells and their lysates to syngeneic tumor cell lysates as immunogens. The glioma cell proliferation, apoptosis and the secretion level of MCP-2, IFN-γ were detected to evaluate the efficacy of this treatment against glioma in vitro. In addition, a rat glioma model was established to investigate the anti-tumor effect in vivo, and evaluated its efficacy by observing the changes of CD4 + T cells, CD8 + T cells, NK cells, and the level of IL-2 and IL-10 in peripheral blood before and after treatment. RESULTS: The C6 + 9L glioma cell lysate vaccine (C6 + 9L-CL) not only inhibited the proliferation of glioma cells and promoted their apoptosis in vitro, but also significantly inhibited the tumor growth in vivo and improved the survival time of rats. In addition, the C6 + 9L-CL vaccine enhanced the anti-tumor immune response by promoting the secretion of T cell chemokines MCP-2, IFN-γ and IL-2, and by stimulating the proliferation of T cells and NK cells in peripheral blood and glioma tissues. CONCLUSION: Our findings demonstrate the inhibitory effect of molecular mimic vaccines on glioma and provided a theoretical basis for molecular mimic hybrid vaccines as a potential therapeutic approach.

New Insight into CO2 Reduction to Formate by In Situ Hydrogen Produced from Hydrothermal Reactions with Iron.

To reveal the nature of CO2 reduction to formate with high efficiency by in situ hydrogen produced from hydrothermal reactions with iron, DFT calculations were used. A reaction pathway was proposed in which the formate was produced through the key intermediate species, namely iron hydride, produced in situ in the process of hydrogen gas production. In the in situ hydrogenation of CO2, the charge of H in the iron hydride was -0.135, and the Fe-H bond distance was approximately 1.537 Å. A C-H bond was formed as a transition state during the attack of Hδ- on Cδ+. Finally, a HCOO species was formed. The distance of the C-H bond was 1.107 Å. The calculated free energy barrier was 16.43 kcal/mol. This study may provide new insight into CO2 reduction to formate in hydrothermal reactions with metal.

Single-Cell Transcriptomics Reveals Longevity Immune Remodeling Features Shared by Centenarians and Their Offspring.

Centenarians, who show mild infections and low incidence of tumors, are the optimal model to investigate healthy aging. However, longevity related immune characteristics has not been fully revealed largely due to lack of appropriate controls. In this study, single-cell transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) derived from seven centenarians (CEN), six centenarians' offspring (CO), and nine offspring spouses or neighbors (Control, age-matched to CO) are performed to investigate the shared immune features between CEN and CO. The results indicate that among all 12 T cell clusters, the cytotoxic-phenotype-clusters (CPC) and the naïve-phenotype-clusters (NPC) significantly change between CEN and ontrol. Compared to Control, both CEN and CO are characterized by depleted NPC and increased CPC, which is dominated by CD8+ T cells. Furthermore, CPC from CEN and CO share enhanced signaling pathways and transcriptional factors associated with immune response, and possesse similar T-cell-receptor features, such as high clonal expansion. Interestingly, rather than a significant increase in GZMK+ CD8 cells during aging, centenarians show accumulation of GZMB+ and CMC1+ CD8 T cells. Collectively, this study unveils an immune remodeling pattern reflected by both quantitative increase and functional reinforcement of cytotoxic T cells which are essential for healthy aging.

Polyethylene Glycol 3350 Crystal Nephropathy in Association With Glomerular Mesangial Immunoglobin A Deposition.

Polyethylene glycol (PEG) 3350, an active ingredient of over-the-counter MiraLAX, is a commonly used laxative in children and is produced by polymerization of ethylene glycol (EG). Masked EG toxicity secondary to contamination of PEG 3350 could occur. We present a 7-year-old child with developmental delay who presented with altered mental status and acute kidney injury (AKI) following intake of generic PEG 3350 for few days prior to presentation. There was high anion gap metabolic acidosis, hypernatremia, elevated osmolar gap, lactic acidosis, and AKI. Urinalysis showed tubular proteinuria, microscopic hematuria, and calcium oxalate crystals. Prior urinalyses were normal without hematuria or proteinuria. Renal biopsy revealed evidence of mesangial dominant immunoglobulin A (IgA) and complement 3 (C3) deposits along with dense tubular deposition of calcium oxalate crystals. He subsequently developed worsening oliguric AKI and required hemodialysis (HD) for several sessions. The AKI resolved within 2 weeks and further HD was not required. Mental status improved in few days. Follow-up urinalyses showed resolution of microscopic hematuria and crystalluria. We hypothesized that the generic PEG 3350 most likely was contaminated with EG leading to the presentation. A high index of suspicion of contamination of PEG 3350 with EG is required in patients presenting with unexplained high anion gap metabolic acidosis, elevated osmolar gap, lactic acidosis, AKI, calcium oxalate crystalluria, and oxalate crystals on renal biopsy. Further studies are needed to determine whether there is an association between transient glomerular mesangial IgA deposition and crystal nephropathy.

CC chemokine receptor 7 promotes macrophage recruitment and induces M2-polarization through CC chemokine ligand 19&21 in oral squamous cell carcinoma.

PURPOSE: This study aimed to investigate the impact of CC chemokine receptor 7 (CCR7) on the recruitment and polarization of tumor-associated macrophages (TAMs) in oral squamous cell carcinoma (OSCC). METHODS: We analyzed CCR7 expression pattern, clinicopathological significance, and its association with M2 macrophage infiltration in OSCC by bioinformatic methods. Small interfering RNA (siRNA) was utilized to silence CCR7 in OSCC cells. Conditioned media (CM) was harvested from transfected OSCC cells to establish a co-culture model of THP-1 derived macrophages and OSCC cells. Transwell assay and cell adhesion assay were performed to examine the effect of CCR7 on macrophages recruitment and adhesion. Cytoskeleton was labelled by phalloidin to observe macrophage morphological changes. Moreover, phenotypic alteration of macrophages was measured using quantitative real-time PCR (qRT-PCR), flow cytometry, and immunofluorescence (IF) staining. Ultimately, recombinant human CCL19 and CCL21 were added into the medium of THP-1 derived macrophages to explore their effects on polarization in vitro. RESULTS: In OSCC patients, the overexpression of CCR7 positively correlated with lymph node metastasis and M2 macrophage infiltration. Macrophage not only exhibited enhanced migration, invasion and adhesion abilities, but also appeared more spindle and branched in vitro when treated with CM from OSCC cells. However, these phenomena were abrogated with knockdown of CCR7. We also discovered that inhibition of CCR7 in OSCC cells suppressed TAMs polarization to an M2 phenotype. In addition, recombinant human CCL19 and CCL21 promoted macrophage M2-polarization in vitro. CONCLUSION: CCR7 in OSCC cells promoted recruitment and M2-polarization of THP-1 derived macrophages in vitro by regulating production of CCL19 and CCL21.

Drug-Induced Lupus Secondary to Ethosuximide in Association with Acute Tubulointerstitial Nephritis and Nephrotic Syndrome.

Background. Drug-induced lupus (DIL) is an autoimmune phenomenon where the patient develops lupus-like symptoms after exposure to a long-term medication. Case Summary. Here we describe a 10-year-old female with absence seizures who developed a lupus-like syndrome after being on ethosuximide for three months. She presented with nephrotic syndrome (NS) and acute kidney injury. Four weeks prior to presentation, she had been prescribed a seven-day course of oral amoxicillin for submental swelling after dental extraction. Investigations showed high titer of antinuclear antibody (ANA) and anti-double stranded DNA, elevated serum IgE level, and positive Coombs' test, along with positive anti-histone antibodies. Renal biopsy showed features of acute tubulointerstitial nephritis (TIN) and partial podocyte foot process effacement without evidence of lupus nephritis. The patient had an excellent response to the steroid therapy with remission within two weeks. The patient remained in remission for two months as evaluated during the most recent follow-up; the autoimmune antibodies and immunoglobulin E trended down. Ethosuximide has been reported to cause DIL, however its possible association with TIN has not been reported. Although amoxicillin could have caused the TIN and NS in this patient, a possible novel association of ethosuximide with this nephrotic-nephritic presentation (NNP) cannot be ruled out. Conclusions. A renal histology is important to determine the accurate etiology of NNP in patients with DIL. Further studies are necessary to determine any possible causal effect of ethosuximide with NNP.

Discovery and preclinical profile of LX-039, a novel indole-based oral selective estrogen receptor degrader (SERD).

We previously described the discovery of a novel indole series compounds as oral SERD for ER positive breast cancer treatment. Further SAR exploration focusing on substitutions on indole moiety of compound 12 led to the discovery of a clinical candidate LX-039. We report herein its profound anti-tumor activity, desirable ER antagonistic characteristics combined with favorable pharmacokinetic and preliminary safety properties. LX-039 is currently in clinical trial (NCT04097756).