Inhibitor Treatment Research Articles

Real-world analysis of the incidence and risk factors of pneumonitis in non-small cell lung cancer patients treated with combined thoracic radiotherapy and immunotherapy

Abstract Objectives Combining radiotherapy with immune checkpoint inhibitor (ICI) treatment has emerged as an important therapeutic regimen. However, this combined treatment may increase the risk of pneumonitis. The aim of this study is to analyze the incidence and risk factors for pneumonitis in non-small cell lung cancer (NSCLC) patients receiving combined thoracic radiotherapy and ICI (RT + ICI) treatment in the real-world clinical setting, offering a reference and guidance for clinical physicians. Methods This study identified 447 patients with pathologically confirmed NSCLC at West China Hospital of Sichuan University from 2016 to 2021. Clinical characteristics, treatment regimens, immune-related adverse events (irAEs), and hematological data were collected and analyzed. Results Patients receiving combined RT + ICI treatment had a higher risk of developing pneumonitis than those receiving ICI treatment alone (26.9 vs. 6.7 %, p<0.001). The multivariate logistic analysis identified the following independent risk factors for pneumonitis in patients undergoing combined RT + ICI treatment: history of lung disease (p=0.032), first-line ICI treatment (p=0.001), anti-PD-L1 instead of anti-PD-1 treatment (p=0.035), and the development of immunotherapy-related thyroid dysfunction (p=0.019). The independent risk factors were incorporated into a nomogram to predict the incidence of pneumonitis. The area under the receiver operating characteristic curve is 0.727, suggesting an acceptable predictive efficacy. Conclusions Compared to ICI monotherapy, NSCLC patients receiving the combination of thoracic radiotherapy and ICI treatment are at higher risk of developing pneumonitis. The nomogram holds promise for facilitating the risk assessment and early identification of pneumonitis in NSCLC patients receiving combined RT + ICI treatment.

EXTH-30. GENETIC ALTERATIONS THAT DEREGULATE RB AND PDGFRA SIGNALING PATHWAYS DRIVE TUMOR PROGRESSION IN IDH2-MUTANT ASTROCYTOMA

Abstract In IDH-mutant astrocytoma, IDH2 mutation is quite rare and biological mechanisms underlying tumor progression in IDH2-mutant astrocytoma remain unclear. In this presentation, we report a unique case of IDH2 mutant astrocytoma, CNS WHO grade 3 that developed tumor progression. We performed a comprehensive genomic and epigenomic analysis for primary and recurrent tumors and found that both tumors harbored recurrent IDH2R172K and TP53R248W mutation with CDKN2A/B hemizygous deletion. We also found amplifications of CDK4 and MDM2 with PDGFRA gain in the recur- rent tumor and upregulated protein expressions of these genes. We further developed, for the first time, a xenograft mouse model of IDH2R172K and TP53R248W mutant astrocytoma from the recurrent tumor, but not from the primary tumor. Consistent with parent recurrent tumor cells, amplifications of CDK4 and MDM2 and PDGFRA gain were found, while CDKN2A/B was identified as homozygous deletion in the xenografts, qualifying for integrated diagnosis of astro- cytoma, IDH2-mutant, CNS WHO grade 4. Cell viability assay found that CDK4/6 inhibitor and PDGFR inhibitor potently decreased cell viability in recurrent tumor cells, as compared to primary tumor cells. On the other hand, in accord with our previous study that IDH1 inhibitor was not sufficient to induce anti-tumor effects in IDH1-mutant high-grade gliomas (Tateishi K et al. Cancer Cell. 2015), we did not find decreased cell viability nor histone methylation status changes after mutation specific IDH2 inhibitor treatment of recurrent cells. These findings underlie that gene alterations that activate retinoblastoma (RB) signaling pathways and PDGFR may drive tumor progression and xenograft formation in IDH2-mutant astrocytoma, which is equivalent to progressive IDH1-mutant astrocytoma. Also, our findings suggest that these genomic alterations may represent therapeutic targets in IDH2-mutant astrocytoma.

Aurora B inhibitors promote RB hypophosphorylation and senescence independent of p53-dependent CDK2/4 inhibition

Aurora B kinase (AURKB) inhibitors have been trialled in a range of different tumour types but are not approved for any indication. Expression of the human papilloma virus (HPV) oncogenes and loss of retinoblastoma (RB) protein function has been reported to increase sensitivity to AURKB inhibitors but the mechanism of their contribution to sensitivity is poorly understood. Two commonly reported outcomes of AURKB inhibition are polyploidy and senescence, although their relationship is unclear. Here we have investigated the major cellular targets of the HPV E6 and E7, p53 and RB, to determine their contribution to AURKB inhibitor induced polyploidy and senescence. We demonstrate that polyploidy is a universal feature of AURKB inhibitor treatment in all cell types including normal primary cells, but the subsequent outcomes are controlled by RB and p53. We demonstrate that p53 by regulating p21 expression is required for an initial cell cycle arrest by inhibiting both CDK2 and CDK4 activity, but this arrest is only triggered after cells have undergone two failed mitosis and cytokinesis. However, cells can enter senescence in the absence of p53. RB is essential for AURKB inhibitor-induced senescence. AURKB inhibitor induces rapid hypophosphorylation of RB independent of inhibition of CDK2 or CDK4 kinases and p53. This work demonstrates that p53 activation determines the timing of senescence onset, but RB is indispensable for senescence.

Nephroprotective effect of SGLT2 inhibitors in elderly patients with type 2 diabetes mellitus and hypertension: a real-world population-based cohort study

ABSTRACT Objectives This study aimed to investigate the nephroprotective effect of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in elderly patients with type 2 diabetes mellitus (T2DM) and hypertension based on real-world clinical data. The study aimed to provide a theoretical basis for evidence-based pharmacological treatment of chronic kidney disease in this population. Methods The ‘Health Cloud’ platform of the Shanghai Municipal Health Commission was employed to identify and screen elderly patients with T2DM and hypertension. The propensity score matching cohort was further constructed to estimate the effect of SGLT2i on the risk of rapid decline in renal function (∆eGFR≤-5 ml/min/1.73 m2 or ∆eGFR%≤-5%). Multiple sensitivity analyses were conducted to assess the robustness of the results. Results After propensity score matching, no significant differences of covariates were identified between the SGLT2i and non-SGLT2i groups. The results of multivariate logistic models demonstrated a consistent and inverse correlation between SGLT2i use and the risk of rapid eGFR decline, whether defined as ∆eGFR≤-5 ml/min/1.73 m2 (OR = 0.60, 95% CI:0.38-0.96) or ∆eGFR%≤-5%（OR = 0.57, 95% CI:0.37-0.89). In the stratification of renin-angiotensin system inhibitor (RASi) treatment, SGLT2i was associated with a lower risk of rapid eGFR decline in the RASi group (all ORs < 1, p < 0.05), with no interaction between SGLT2i and RASi (all P for interaction > 0.05) detected. Conclusions SGLT2i significantly reduced the risk of rapid eGFR decline in elderly patients with T2DM and hypertension, but the synergistic effect with RASi remains unclear.

The Use of Phosphonates to Inhibit Salt Crystallization: A Laboratory Study for the Sustainable Conservation of Mural Paintings in the Hypogea Context

This research is focused on the laboratory study of salt crystallization inhibitor products as new materials for conservation treatments which can be applied to mortars and painted plasters; as is well known, salt crystallization is one of the most frequent causes of decay processes on decorated architectural surfaces in a wide range of environments. Specifically, the study targets the field of the preventive conservation of mural paintings within rupestrian heritage sites. For the first time, systematic investigations were performed on mock-ups made of plaster painted with two different pigments: yellow ochre and carbon black. Two types of phosphonate inhibitors, PBTC (2-phosphonobutane-1,2,4-tricarboxylic acid) and ATMP (aminotris (methylene phosphonic acid)), were chosen and applied at two different concentrations. Given the limited literature available, and the presence of pigments potentially sensitive to treatment with salt inhibitors, preliminary tests were required. Their effects on the chromatic features of the pigments were evaluated visually and using colorimetry. The changes in the behaviour of water circulation in the mortar resulting from the treatments were evaluated through water vapour permeability and absorption tests. Accelerated crystallization experiments were carried out to assess how inhibitors could influence the growth of salts and the resulting material damage. The latter was carried out by employing sodium sulphate and calcium sulphate solutions, quantifying the damage to the specimens through material loss in weight and the percentage of painted surface loss. Based on the overall results, the product with the best performance was identified was ATMP 0.1% (by volume) in deionized water. The obtained results show that salt inhibitor treatments are promising for in situ application and could represent an innovative approach to promote the sustainable conservation of mural painting, particularly those located in hypogeal contexts, where the salt supply cannot be removed and slowing the growth of salts and/or changing their crystalline habitus may be effective in limiting their damage.

The peri-operative implications of sodium-glucose co-transporter 2 inhibitors: a narrative review.

Sodium-glucose co-transporter 2 inhibitors are a novel class of antihyperglycaemic drugs used in the management of type 2 diabetes, that improve glycaemic control, cardiovascular outcomes and promote weight loss. They are also approved for the treatment of heart failure and chronic kidney disease in patients with or without diabetes. This narrative review discusses the peri-operative effects and implications of sodium-glucose co-transporter 2 inhibitors and gives an overview of current evidence and existing peri-operative guidelines. We conducted a literature review to identify peer-reviewed English language articles published since 2000, with further articles identified by reviewing the references of key papers. Peri-operative sodium-glucose cotransporter 2 inhibitor use carries a risk of euglycaemic ketoacidosis. Although clinically significant diabetic ketoacidosis remains a rare event, sodium-glucose co-transporter 2 inhibitors inhibitor-associated diabetic ketoacidosis has been observed across almost all surgical specialities. Ketoacidosis may present with any blood glucose level. Existing guidelines are inconsistent and may be a source of clinical confusion. Based on the half-life of sodium-glucose cotransporter 2 inhibitors, we recommend withholding treatment for 72 h before elective surgery (5 half-lives), with additional multidisciplinary input for specific procedures with dietary alterations and in patients with poorly controlled diabetes of cardiac/renal disease. In the event of emergency surgery or any surgery within 72 h of sodium-glucose cotransporter 2 inhibitor administration, we recommend pre-, intra- and postoperative blood ketone monitoring (6 hourly for 24 h post-surgery and until full oral diet is resumed). Sodium-glucose cotransporter 2 inhibitor treatment should only be resumed after resumption of full oral diet in the absence of ketosis.

Danicopan (Voydeya)

Canada’s Drug Agency (CDA-AMC) recommends that Voydeya be reimbursed by public drug plans as an add-on to ravulizumab or eculizumab for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH) who have residual hemolytic anemia due to extravascular hemolysis (EVH) if certain conditions are met. Voydeya should only be covered to treat adult patients with a diagnosis of PNH, who have met the public drug plan reimbursement criteria for initiating complement 5 inhibitor (C5i) treatments (ravulizumab or eculizumab) before receiving C5i treatment, and who have been on a stable dose of C5i treatment for 6 months or more, in addition, patients should also have persistent anemia caused by EVH, and an absolute reticulocyte count of 120 × 109/L or greater. Voydeya should only be reimbursed if prescribed by a hematologist with experience managing PNH. The cost of Voydeya should be negotiated so that Voydeya plus a C5i as a regimen does not exceed the drug program cost of treatment with pegcetacoplan for the treatment of adult patients with PNH who have residual hemolytic anemia due to EVH.

Busulfan and cyclophosphamide for autologous stem cell transplantation in patients with multiple myeloma after proteasome inhibitor and/or immunomodulatory drug treatment.

High-dose melphalan at 200mg/m2 (MEL-200) is the standard conditioning regimen before autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM). Busulfan (BU) and cyclophosphamide (CY) can be used as alternatives when MEL is unavailable. However, most studies on BU/CY conditioning regimens were conducted before proteasome inhibitors (PIs) and immunomodulatory drugs (IMIDs) were available. This non-interventional comparative cohort study compared progression-free survival (PFS) between the MEL-200 and BU/CY in patients with MM treated with PIs and/or IMIDs. A total of 137 patients were analyzed (MEL-200,113 patients; BU/CY, 24 patients). The BU/CY group had a higher rate of PI and/or IMID use and very good partial response (VGPR) or complete remission (CR) at ASCT and post-ASCT maintenance. Median PFS was 29.7 and 46.8months in the MEL-200 and BU/CY groups, respectively. In the multivariate analysis, PFS was significantly better in the BU/CY group. International Staging System Stage I and VGPR or CR at ASCT were significantly associated with longer PFS. No treatment-related mortality was observed in either group by day 100. The BU/CY conditioning regimen may be a viable alternative to the MEL-200 regimen in patients with MM who undergo ASCT after treatment with PIs and/or IMIDs.

Surgical resection following chemoradiotherapy for thoracic SMARCA4-deficient undifferentiated tumor: a report of two cases

BackgroundThoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a high-grade malignant neoplasm with a poor prognosis. Most cases of SMARCA4-UT have extensive chest wall and mediastinum involvement. The efficacy of surgical resection has not been clearly established. Here, we report two surgical cases of SMARCA4-UT with chest wall invasion after chemoradiotherapy.Case presentationThe first patient was a 40-year-old man with back pain. Computed tomography revealed a 6.8 cm mass in contact with the thoracic vertebrae near the intervertebral foramen, which was suspected to involve the third to fifth ribs. The patient was diagnosed with SMARCA4-UT with clinical T3N0M0 stage IIB. The tumor shrank after chemoradiotherapy, and conversion surgery combined with partial vertebrectomy was performed. Histopathological findings revealed 30% residual tumor in the tumor bed. Thirty-six days after surgery, the patient developed multiple liver metastases and peritoneal dissemination. Chemotherapy combined with immune checkpoint inhibitor treatment was performed, resulting in tumor shrinkage. However, peritoneal dissemination recurred within a short interval. The patient died 5 months postoperatively. The second patient was a 74-year-old man with chest pain. Computed tomography revealed a 7.4-cm mass in the left upper lobe with invasion of the third and fourth ribs. The patient was initially diagnosed with non-small cell lung cancer with clinical T4N1M0 stage IIIA. The tumor shrank after induction chemoradiotherapy, and a left upper lobectomy combined with the chest wall resection was performed. Based on histopathological findings, the patient was diagnosed with SMARCA4-UT. The residual tumor percentage was 3%. The patient was followed up for 12 months postoperatively without recurrence.ConclusionsWe performed the complete resection of SMARCA4-UT following chemoradiotherapy. The two surgical cases had different postoperative courses. Radical surgery after chemoradiotherapy is effective for local control. However, its long-term prognostic efficacy remains unclear. Multidisciplinary approaches and further investigations of novel therapeutic options are required.

MGST1 facilitates novel KRASG12D inhibitor resistance in KRASG12D-mutated pancreatic ductal adenocarcinoma by inhibiting ferroptosis

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with a low 5-year survival rate. Treatment options for PDAC patients are limited. Recent studies have shown promising results with MRTX1133, a KRASG12D inhibitor that demonstrated potent antitumor activity in various types of tumors with KRASG12D mutation. Resistance to KRAS inhibitors is frequently occurred and one of the main reasons for treatment failure. Understanding resistance mechanisms to novel KRAS inhibitors is crucial to ensure sustained and durable remissions.MethodsTwo KRASG12D inhibitor MRTX1133-resistant PDAC cell lines were established in vitro. The resistance mechanisms to KRASG12D inhibitor MRTX1133 against PDAC in vitro and in vivo were characterized by RNA sequencing, reverse transcript polymerase chain reaction, cytotoxicity test, plasmid transfection, lentivirus transfection, lipid peroxidation detection, malondialdehyde levels detection, glutathione levels detection, western blot, immunofluorescence, nude mice tumorigenesis experiment and immunohistochemistry.ResultsThe bioinformatics analysis and transcriptome sequencing showed that ferroptosis was involved in the resistant effect of the KRASG12D inhibitor treatment, and MGST1 was the key molecule against MRTX1133-induced ferroptosis. Increased expression of MGST1 weakened the cytotoxicity of MRTX1133 by inhibiting lipid peroxidation-induced ferroptosis in KRASG12D inhibitor-resistant PDAC cells. Knockdown or overexpression of MGST1 conferred sensitivity or resistance to KRASG12D inhibitor MRTX1133, respectively. Mechanismly, increased nuclear localization and higher levels of active β-catenin were observed in MRTX1133-resistant PDAC cells, which contributed to higher MGST1 expression. Knockdown of CTNNB1 or TCF4 can decreased MGST1 expression. Additionally, we found that PKF-118-310, an antagonist of β-catenin/Tcf4 complex, repressed MGST1 expression. In both in vitro and in vivo models, a synergistic effect was observed when combining MRTX1133 and PKF-118-310 in KRASG12D inhibitor MRTX1133-resistant PDAC cells and tumors.ConclusionOur data showed that KRASG12D inhibitor MRTX1133 combined with PKF-118-310 could enhance the effectiveness of MRTX1133 treatment response through induction of ferroptosis via inhibiting MGST1 expression in MRTX1133-resistant PDAC cells and tumors. This evidence may provide a promising strategy to overcome KRASG12D inhibitor MRTX1133 resistance in PDAC patients with KRASG12D mutations.Graphical

Total baseline tumor size predicts survival among patients with advanced small-cell lung cancer receiving chemotherapy plus programmed death-ligand 1 inhibitor as first-line therapy: a multicenter retrospective observational study

IntroductionTotal baseline tumor size (BTS) is a prognostic factor for programmed death 1 and programmed death-ligand 1 (PD-L1) inhibitor treatments. However, the prognostic value of total BTS for patients with small-cell lung cancer (SCLC) who receive chemotherapy plus PD-L1 inhibitor remains unknown. Thus, in this study, we aimed to determine whether total BTS is associated with prognosis in patients with SCLC who receive chemotherapy plus PD-L1 inhibitor as first-line therapy.MethodsThis study included patients with extensive-stage SCLC or post-chemoradiotherapy recurrence of limited-stage SCLC who received chemotherapy plus PD-L1 inhibitor as first-line therapy from August 2019 to December 2022. The two lesions with the largest diameter among the measurable lesions in each organ were selected from up to five organs (maximum of 10 lesions), and the sum of all diameters was defined as total BTS. The patients were divided into two groups, large or small, with total BTS using X-tile software. Median survival was analyzed using the Kaplan–Meier method, and the groups were compared using the log-rank test. Univariate and multivariate analyses examined the association between total BTS and prognosis.ResultsFifty patients were included; 14% had large total BTS (&amp;gt;183.2 mm) and 86% had small total BTS (≤183.2 mm). The median observation period was 10.5 months. The large total BTS group showed significantly worse overall survival than the small total BTS group (median: 26.8 months vs. 5.7 months, P = 0.0003). The multivariate analysis indicated that large total BTS was an independent negative predictor of overall survival (hazard ratio: 7.14, 95% confidence interval: 1.89–26.96).DiscussionTotal BTS is a potentially useful prognostic factor for patients with advanced SCLC who receive chemotherapy plus PD-L1 inhibitor as first-line therapy.

The HIF2α-dependent Upregulation of SETDB1 Facilitates Hypoxia-induced Functional and Phenotypical Changes of Pulmonary Microvascular Endothelial Cells.

Background: Emerging studies have reported the vital role of histone modification in the dysfunction of pulmonary vascular endothelial cells, which acts as the key reason to drive the hypoxia-induced pulmonary vascular remodeling and pulmonary hypertension (PH). This study aims to investigate the role of a histone 3 lysine 9 (H3K9) methyltransferase, SET domain bifurcated 1 (SETDB1), in hypoxia-induced functional and phenotypical changes of pulmonary vascular endothelial cells. Methods: Primarily cultured rat pulmonary microvascular endothelial cells (PMVECs) were used as cell model. Specific knockdown and overexpression strategies were used to systematically determine the molecular regulation and function of SETDB1 in PMVECs. Results: SETDB1 is highly expressed and significantly upregulated in the pulmonary vascular endothelium of lung tissue isolated from SU5416/hypoxia-induced PH (SuHx-PH) rats, and also in pulmonary arterial endothelial cells (PAECs) from idiopathic pulmonary arterial hypertension (IPAH) patients, comparing to their respective controls. In primarily cultured rat PMVECs, treatment of hypoxia or CoCl2 induces significant upregulation of HIF2α, SETDB1 and H3K9me3. Specific knockdown and overexpression strategies indicate the hypoxia- or CoCl2-induced upregulation of SETDB1 is mediated through a HIF2α-dependent mechanism. Knockdown of SETDB1 significantly inhibits the hypoxia- or CoCl2-induced apoptosis, senescence and endothelial to mesenchymal transition (EndoMT) in rat PMVECs. Moreover, treatment of the specific inhibitor of histone methyltransferase, Chaetocin, effectively attenuates the disease pathogenesis of SuHx-PH in rat. Conclusions: Our results suggest that the HIF2α-dependent upregulation of SETDB1 facilitates hypoxia-induced functional and phenotypical changes of PMVECs, potentially contributing to the hypoxia-induced pulmonary vascular remodeling and PH.

Hypertension Induced by Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors in Treating Anemia in Patients With Chronic Kidney Disease: A Mini-Review.

Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors are a new class of agents for the treatment of anemia in chronic kidney disease (CKD). Unlike traditional treatments such as erythropoiesis-stimulating agents (ESAs), HIF-PH inhibitors are orally administered drugs and may increase endogenous erythropoietin and improve iron homeostasis. However, a significant concern is their possible side effect on blood pressure. The current mini-review summarizes the data of 26 randomized controlled (placebo or ESAs) trials on six different HIF-PH inhibitors with regard to their potential influence on blood pressure and hypertension in the management of anemia in CKD. Overall, the use of HIF-PH inhibitors was associated with a higher risk of hypertension than placebo (pooled risk ratio 1.36, 95% confidence interval [CI] 1.16-1.59), but a lower risk of hypertension than ESA treatment (pooled risk ratio 0.92, 95% CI 0.86-0.98), especially in CKD patients not undergoing dialysis (pooled risk ratio 0.85, 95% CI 0.73-0.98). This review highlights the importance of blood pressure monitoring during the treatment of HIF-PH inhibitors, especially out-of-office blood pressure measurement.

Prefrontal cortex engagement during an fMRI task of emotion regulation as a potential predictor of treatment response in borderline personality disorder.

Borderline personality disorder (BPD) is a severe mental illness, with high rates of co-morbid depression and suicidality. Despite the importance of optimizing treatment in BPD, little is known about how neural processes relate to individual treatment response. This study examines how baseline regional brain blood oxygen level dependent (BOLD) activation during a functional magnetic resonance imaging (fMRI) task of emotion regulation is related to treatment response following a six-month randomized clinical trial of Dialectical Behavior Therapy (DBT) or Selective Serotonin Reuptake Inhibitor (SSRI) treatment. Unmedicated females with BPD (N = 37), with recent suicidal behavior or self-injury, underwent an fMRI task in which negative personal memories were presented and they were asked to distance (i.e., downregulate their emotional response) or immerse (i.e., experience emotions freely). Patients were then randomized to DBT (N = 16) or SSRI (N = 21) treatment, with baseline and post-treatment depression and BPD severity assessed. BOLD activity in prefrontal cortex, anterior cingulate, and insula was associated with distancing. Baseline BOLD during distancing in dorsolateral, ventrolateral, and orbital prefrontal cortex (dlPFC, vlPFC, OFC) differentially predicted depression response across treatment groups, with higher activity predicting better response in the SSRI group, and lower activity predicting better response in the DBT group. All female samples. Findings indicate that greater prefrontal engagement during emotion regulation may predict more antidepressant benefit from SSRIs, whereas lower engagement may predict better response to DBT. These results suggest different mechanisms of action for SSRI and DBT treatment, and this may allow fMRI to guide individualized treatment selection.

Identification of PSMD2 as a promising biomarker for pancreatic cancer patients based on comprehensive bioinformatics and in vitro studies

BackgroundPancreatic cancer patients have limited treatment options and extremely poor prognosis. Dysregulations of proteasome 26S subunit, non-ATPases (PSMDs) contribute to the development of various cancers, whereas the significance of PSMDs in pancreatic cancer is poorly understood. In the present study, we intended to explore the therapeutic potential of PSMDs in pancreatic cancer. MethodsBased on TCGA database, the expression of PSMDs was analyzed in pancreatic cancer patients. Multivariate Cox regression and Kaplan–Meier survival analyses were conducted to investigate the prognostic value of PSMDs. The correlations between the expression of PSMD2/14 and immune cell infiltration, immune checkpoint genes’ expression, enrichment of signaling pathways, and the sensitivity of chemotherapies were also evaluated. Knockdown and overexpression experiments were performed to explore the biological function of PSMD2/14. Immunoblotting was conducted to detect the downstream signaling pathway of PSMD2. ResultsMost of the PSMDs, except for PSMD5 and PSMD6, were significantly upregulated in pancreatic cancer tissues. Patients with higher grade tumor had increased mRNA levels of PSMD1/2/5/7/8/11/12/14. Survival and multivariate Cox regression analyses indicated that PSMD2 and PSMD14 were biomarkers of worse prognosis. High expression of PSMD2 and PSMD14 was positively correlated with the levels immune checkpoint genes but not with the infiltration of specific immune cell types. In vitro knockdown of PSMD2, but not PSMD14, increased the apoptosis, gemcitabine’s toxicity and inhibited the growth capacity of MIA cells. Conversely, decreased apoptosis and gemcitabine sensitivity along with accelerated cell proliferation ability were observed in PSMD2-overexpressing PANC-1 cells. Mechanistically, PSMD2 activated the AKT/mTOR signaling pathway, consistent with the findings from KEGG and GSEA analysis. The AKT specific inhibitor MK-2206 exhibited higher cytotoxicity in MIA and PANC-1 cells with high PSMD2 expression. Importantly, MK-2206 largely reversed the oncogenic functions of PSMD2 on the growth and proliferation of PANC-1 cells. ConclusionIn summary, our study provided a comprehensive bioinformatics analysis of PSMDs in pancreatic cancer. We identified that PSMD2 acted as a tumor-promoting protein in pancreatic cancer through the activation of the AKT/mTOR pathway. The overexpression of PSMD2 may be a potential biomarker that predicts the response of pancreatic cancer patients to AKT inhibitor treatments.

IL-23 inhibitor treatment of immune checkpoint inhibitor-associated psoriasis: case series and review of literature

IL-23 inhibitor treatment of immune checkpoint inhibitor-associated psoriasis: case series and review of literature

Transcriptomic alterations in APP/PS1 mice astrocytes lead to early postnatal axon initial segment structural changes

Alzheimer´s disease (AD) is characterized by neuronal function loss and degeneration. The integrity of the axon initial segment (AIS) is essential to maintain neuronal function and output. AIS alterations are detected in human post-mortem AD brains and mice models, as well as, neurodevelopmental and mental disorders. However, the mechanisms leading to AIS deregulation in AD and the extrinsic glial origin are elusive. We studied early postnatal differences in AIS cellular/molecular mechanisms in wild-type or APP/PS1 mice and combined neuron-astrocyte co-cultures. We observed AIS integrity alterations, reduced ankyrinG expression and shortening, in APP/PS1 mice from P21 and loss of AIS integrity at 21 DIV in wild-type and APP/PS1 neurons in the presence of APP/PS1 astrocytes. AnkyrinG decrease is due to mRNAs and protein reduction of retinoic acid synthesis enzymes Rdh1 and Aldh1b1, as well as ADNP (Activity-dependent neuroprotective protein) in APP/PS1 astrocytes. This effect was mimicked by wild-type astrocytes expressing ADNP shRNA. In the presence of APP/PS1 astrocytes, wild-type neurons AIS is recovered by inhibition of retinoic acid degradation, and Adnp-derived NAP peptide (NAPVSIPQ) addition or P2X7 receptor inhibition, both regulated by retinoic acid levels. Moreover, P2X7 inhibitor treatment for 2 months impaired AIS disruption in APP/PS1 mice. Our findings extend current knowledge on AIS regulation, providing data to support the role of astrocytes in early postnatal AIS modulation. In conclusion, AD onset may be related to very early glial cell alterations that induce AIS and neuronal function changes, opening new therapeutic approaches to detect and avoid neuronal function loss.

Activation of STAT3-mediated ciliated cell survival protects against severe infection by respiratory syncytial virus.

Respiratory syncytial virus (RSV) selectively targets ciliated cells in human bronchial epithelium and can cause bronchiolitis and pneumonia, mostly in infants. To identify molecular targets of intervention during RSV infection in infants, we investigated how age regulates RSV interaction with the bronchial epithelium barrier. Employing precision-cut lung slices and air-liquid interface cultures generated from infant and adult human donors, we found robust RSV virus spread and extensive apoptotic cell death only in infant bronchial epithelium. In contrast, adult bronchial epithelium showed no barrier damage and limited RSV infection. Single nuclear RNA-Seq revealed age-related insufficiency of an antiapoptotic STAT3 activation response to RSV infection in infant ciliated cells, which was exploited to facilitate virus spread via the extruded apoptotic ciliated cells carrying RSV. Activation of STAT3 and blockade of apoptosis rendered protection against severe RSV infection in infant bronchial epithelium. Lastly, apoptotic inhibitor treatment of a neonatal mouse model of RSV infection mitigated infection and inflammation in the lung. Taken together, our findings identify a STAT3-mediated antiapoptosis pathway as a target to battle severe RSV disease in infants.

Ischaemic cardiotoxicity of aromatase inhibitors in postmenopausal patients with early breast cancer in Denmark: a cohort study of real-world data

For aromatase inhibitor treatment (AIT) in breast cancer, there is an unresolved concern about ischaemic cardiotoxicity. We investigated the association between AIT and ischaemic cardiotoxicity in a prospective cohort of female patients with early breast cancer who received contemporary treatment in Denmark. In this prospective cohort study in Denmark, we identified postmenopausal patients of any age diagnosed with breast cancer as recorded in the nationwide Danish Breast Cancer Cooperative Group (DBCG) clinical database between Jan 1, 2009, and Dec 31, 2020, and linked them to other nationwide registries. Exclusion criteria included having a history of other primary cancer, less than 2 years of residency in Denmark, and no inclusion in a treatment protocol according to the DBCG database, including for metastatic or locally advanced breast cancer. Information on demography, hospital diagnoses, filled prescriptions, laboratory testing, and socioeconomic status were recorded. We stratified the patient cohort according to history (yes vs no) of selected cardiovascular disease defined as ischaemic heart disease, ischaemic stroke, and heart failure, and defined the primary outcome as two-point major adverse cardiovascular events (MACE; acute myocardial infarction or ischaemic stroke). We estimated cause-specific hazard ratios (HRs) according to allocation to AIT versus not in an intention-to-treat analysis using a Cox proportional hazards regression model with age as the underlying time scale, adjusting for demographic characteristics, tumour characteristics, and other anti-cancer treatments. 43 440 postmenopausal patients diagnosed with breast cancer were identified, of whom 32 635 were followed up and included in analyses. Of 29 118 postmenopausal patients with no history of selected cardiovascular disease, we observed 510 two-point MACEs among 22 135 patients allocated to AIT (incidence rate 4·3/1000 person-years of follow-up) and 170 two-point MACEs among 6983 patients not allocated to AIT (4·1/1000 person-years). The adjusted HR was 0·91 (95% CI 0·73-1·14) for patients allocated to AIT versus patients not allocated to AIT. Among 3517 patients with a history of selected cardiovascular disease, we observed 158 two-point MACEs among 2661 patients allocated to AIT (incidence rate 12·4/1000 person-years) and 50 two-point MACEs (12·1/1000 person-years) among 856 patients not allocated to AIT (adjusted HR 0·81 [95% CI 0·58-1·15]). Our findings do not support a clinically relevant ischaemic cardiotoxic potential of AIT in patients with early breast cancer and do not support avoiding AIT prescription in patients with early breast cancer. Bispebjerg and Frederiksberg Hospital, Kræftens Bekæmpelse, Fonden til Lægevidenskabens Fremme, Aase og Ejnar Danielsens Fond, Helsefonden, and Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis' Legat.

A comparative evaluation of the effect of matrix metalloproteinase inhibitor on the fracture resistance of endodontically treated teeth restored with Everstick-reinforced composite resin: An in vitro study

Aim: To evaluate the effect of applying a matrix metalloproteinase (MMP) inhibitor on the fracture resistance of root-filled teeth restored with Everstick fiber-reinforced composite resin. Subjects and Methods: After the selection of 60 freshly extracted human mandibular first molar, root canal access and standard uniformly sized mesio-occluso-distal (MOD) cavities were made and the teeth were randomly assigned into three groups (n = 20 each): Group I, the MOD cavity was first lined with flowable composite resin and then restored with composite resin. In Group II, Everstick fiber was placed into the bed of flowable composite in buccal–pulpal–lingual direction before the composite restoration was placed. In Group III, after etching of the cavity, a 2% chlorhexidine MMP inhibitor was applied. Then, the MOD cavity was restored same as group II. A universal testing machine was employed to compressively load the teeth at a cross-head speed of 0.5 mm/min till fracture. The maximum fracture loads were recorded in Newtons (N) and data were analyzed with one-way ANOVA and post-hoc Tukey tests. Results: Group III exhibited significantly higher fracture resistance compared to all other groups (P &lt; 0.001), whereas Group I demonstrated the lowest fracture resistance. Conclusion: The utilization of Everstick glass fiber, combined with MMP inhibitor treatment, yielded the greatest fracture resistance. Hence, this method may be prioritized over conventional restoration techniques for strengthening root canal-treated teeth with structurally compromised crowns.