Search

Background: In the postacute phase of coronavirus disease-2019 (COVID-19), survivors may have persistent symptoms, lung function abnormalities, and sequelae lesions on thoracic computed tomography (CT). This new entity has been defined as post-COVID interstitial lung disease (ILD) or residual disease., Aims: To evaluate the characteristics, risk factors and clinical significance of post-COVID ILD., Study Design: Multicenter cross-sectional analysis of data from a randomized clinical study., Methods: In this study, patients with persistent respiratory symptoms 3 months after recovery from COVID-19 were evaluated by two pulmonologists and a radiologist. post-COVID ILD was defined as the presence of respiratory symptoms, hypoxemia, restrictive defect on lung function tests, and interstitial changes on follow-up high-resolution computed tomography (HRCT)., Results: At the three-month follow-up, 375 patients with post-COVID-19 syndrome were evaluated, and 262 patients were found to have post-COVID ILD. The most prevalent complaints were dyspnea (n = 238, 90.8%), exercise intolerance (n = 166, 63.4%), fatigue (n = 142, 54.2%), and cough (n = 136, 52%). The mean Medical Research Council dyspnea score was 2.1 ± 0.9, oxygen saturation was 92.2 ± 5.9%, and 6-minute walking distance was 360 ± 140 meters. The mean diffusing capacity of the lung for carbon monoxide was 58 ± 21, and the forced vital capacity was 70% ± 19%. Ground glass opacities and fibrotic bands were the most common findings on thoracic HRCT. Fibrosis-like lesions such as interlobular septal thickening and traction bronchiectasis were observed in 38.3% and 27.9% of the patients, respectively. No honeycomb cysts were observed. Active smoking [odds ratio (OR), 1.96; 95% confidence interval (CI), 1.44-2.67), intensive care unit admission during the acute phase (OR, 1.46; 95% CI, 1.1-1.95), need for high-flow nasal oxygen (OR, 1.55; 95% CI, 1.42-1.9) or non-invasive ventilation (OR, 1.31; 95% CI, 0.8-2.07), and elevated serum lactate dehydrogenase levels (OR, 1.23; 95% CI 1.18-1.28) were associated with the development of post-COVID ILD. At the 6-month follow-up, the respiratory symptoms and pulmonary functions had improved spontaneously without any specific treatment in 35 patients (13.4%). The radiological interstitial lesions had spontaneously regressed in 54 patients (20.6%)., Conclusion: The co-existence of respiratory symptoms, radiological parenchymal lesions, and pulmonary functional abnormalities which suggest a restrictive ventilatory defect should be defined as post-COVID-19 ILD. However, the term “fibrosis” should be used carefully. Active smoking, severe COVID-19, and elevated lactate dehydrogenase level are the main risk factors of this condition. These post-COVID functional and radiological changes could disappear over time in 20% of the patients., Competing Interests: Conflict of Interest: The authors declare that they have no conflict of interest.

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) have transformed the ovarian cancer (OC) treatment landscape. This narrative review provides a comprehensive overview of data for the PARPis olaparib, niraparib, and rucaparib in patients with OC and discusses their role in disease management, with a focus on the use of PARPis as maintenance therapy in the United States (US). Olaparib was the first PARPi to be approved as first-line maintenance monotherapy in the US, with maintenance niraparib subsequently approved in the first-line setting. Data also support the efficacy of rucaparib as first-line maintenance monotherapy. PARPi maintenance combination therapy (olaparib plus bevacizumab) also provides benefit in patients with newly diagnosed advanced OC whose tumors tested positive for homologous recombination deficiency (HRD). Biomarker testing is critical in the newly diagnosed setting to identify patients most likely to benefit from PARPi maintenance therapy and guide treatment decisions. Clinical trial data support the use of PARPis (olaparib, niraparib, rucaparib) as second-line or later maintenance therapy in patients with platinum-sensitive relapsed OC. Although distinct differences in tolerability profile were observed between PARPis, they were generally well tolerated, with the majority of adverse events managed by dose modification. PARPis had no detrimental effect on patients' health-related quality of life. Real-world data support the use of PARPis in OC, although some differences between PARPis are apparent. Data from trials investigating novel combination strategies, such as PARPis plus immune checkpoint inhibitors, are awaited with interest; the optimal sequencing of novel therapies in OC remains to be established., (© 2023. The Author(s).)

Objective: The choice of steroids and antibiotics is optional for the management of acute exacerbation of chronic obstructive pul- monary diseases according to international guidelines. The study hypothesized that the steroid and antibiotic choice can be decided by using the neutrophil-lymphocyte ratio and peripheral blood eosinophilia in patients with acute exacerbation of chronic obstructive pulmonary diseases. This would reduce the rate of re-hospitalization in 28 days., Material and Methods: Patients were hospitalized due to acute exacerbation of chronic obstructive pulmonary diseases from February 1, 2018, to January 31, 2019. Patients were divided into 2 groups: Sureyyapasa protocol group and conventional group. In the Sureyyapasa protocol group, patients were divided into 4 subgroups according to peripheral blood eosinophilia and neutrophil-lympho- cyte ratio values. Treatment success was defined as 5-7 days acute exacerbation of chronic obstructive pulmonary diseases treatment was enough to discharge and no re-hospitalization within 28 days. Treatment failure was defined that the hospital stay was longer than 7 days or transport to intensive care and death or readmission to the hospital due to acute exacerbation of chronic obstructive pulmonary diseases within 28 days after discharge., Results: The Sureyyapasa protocol group (n = 96) and the conventional group (n = 95) were randomly selected. The conventional group and Sureyyapasa protocol group had similar hospital stay (P = .22), and antibiotic and steroid uses were significantly higher in the conventional group than the Sureyyapasa protocol group (antibiotic use 100% vs. 83%, P < .001 and steroid use 84% vs. 29%, P < .001, respectively). Treatment failure in the conventional Group (n = 23, 24%) is higher than the Sureyyapasa protocol group (n = 17, 18%)., Conclusions: Initiating treatment by evaluating eosinophilia and neutrophil-lymphocyte ratio in patients with acute exacerbation of chronic obstructive pulmonary diseases in the ward reduces unnecessary antibiotic and steroid use and cost rates in hospitalizations.

Aim: Rotary instrumentation in pediatric dentistry is an emerging concept, thus this study was performed to evaluate the remaining dentine thickness (RDT), canal transportation, centering ability, quality of obturation using cone-beam computed tomography (CBCT), and the time efficiency of rotary versus manual instrumentation in mandibular second primary molars., Materials and Methods: Forty mandibular primary second molars (160 canals) were randomly and equally allocated to four groups. Instrumentation was done using K files in groups I and II; in each group, the obturation was done by two different obturation techniques; incremental technique and disposable syringe technique, respectively. MM rotary files (Innovative Material and Devices, Inc. [IMD], Shanghai, China) were used in groups III and IV; in each group, the obturation was done by incremental technique and disposable syringe technique. Preoperative and postoperative CBCT scans were performed and evaluated for the RDT, centering ability, canal transportation, and the canal filling quality, which was assessed as (underfill, optimal fill, and overfill). Instrumentation time was recorded for groups I and II collectively (manual instrumentation), and groups II and III collectively (rotary instrumentation). Statistical analysis was done using Chi-square, ANOVA, and post hoc Tukey tests, at p < 0.05)., Results: The MM rotary file removed a significantly less amount of dentine at all levels specifically at the middle section ( p = 0.003). The canal transportation was significantly higher in the manual group at the cervical level ( p = 0.022). In all sections, the rotary group had significantly higher values of centering ratio than the manual group ( p < 0.05), which means a lower deviation of rotary instruments. For both types of files, there was no significant difference between different obturation techniques ( p > 0.05). Instrumentation time was significantly lower in the rotary group ( p < 0.001)., Conclusion: Regarding the dentine removal and the shaping ability of MM files acceptable results were obtained; however, no significant difference between the different obturation techniques. Notable time efficiency was reported in the rotary files as well., Clinical Significance: The use of rotary files resulted in better conservation of tooth structure, better canal centering, and obturation quality as well as less canal transportation and less instrumentation time compared to manual K files.

Objective: Olaparib treatment resulted in significant improvement in objective response rates (ORRs) and progression-free survival (PFS) over non‑platinum chemotherapy in patients with BRCA1/BRCA2-mutated (BRCAm) platinum-sensitive relapsed ovarian cancer (PSROC) and ≥2 prior lines of platinum-based chemotherapy in the phase III SOLO3 study. LIGHT (NCT02983799) prospectively evaluated olaparib treatment for patients with PSROC and known BRCAm and homologous recombination deficiency (HRD) status., Methods: In this phase II open-label multicenter study, patients with PSROC and ≥1 prior line of platinum-based chemotherapy were assigned to cohorts by presence of germline BRCAm (gBRCAm), somatic BRCAm (sBRCAm), HRD-positive tumors without BRCAm, or HRD-negative tumors. The primary endpoint was investigator-assessed ORR. Secondary endpoints included disease control rate (DCR) and PFS. Tumors were analyzed using Myriad BRACAnalysis CDx and myChoice HRD assays; HRD-positive tumors were defined using a genomic instability score of ≥42., Results: Of 272 enrolled patients, 271 received olaparib and 270 were included in efficacy analyses. At data cut-off, ORRs in the gBRCAm, sBRCAm, HRD-positive, and HRD-negative cohorts were 69.3%, 64.0%, 29.4%, and 10.1%, respectively. DCRs were 96.0%, 100.0%, 79.4%, and 75.3% in each cohort, respectively. Median PFS was 11.0, 10.8, 7.2, and 5.4 months, respectively. The most common (≥ 20%) treatment-emergent adverse events included nausea, fatigue/asthenia, vomiting, anemia, constipation, diarrhea, and decreased appetite., Conclusions: Olaparib treatment demonstrated activity across all cohorts. The greatest efficacy was observed in the BRCAm cohorts, regardless of gBRCAm/sBRCAm. For patients without a BRCAm, greater efficacy was observed in the HRD-positive than the HRD-negative cohorts. The safety profile was consistent with that established in previous olaparib studies., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate self-assembling peptides (SAP) for caries prevention and arrest in primary tooth enamel in vitro ., Materials and Methods: Overall, 180 extracted primary teeth were used. In the prevention experiment ( n = 20 samples per group), self-assembling peptide for prevention (SAPP), fluoride varnish/mouthwash (FV/FMW), casein-phosphopeptide amorphous-calcium phosphate (CPP-ACP), and nanohydroxyapatite (nHA) were applied. Samples were subjected to a demineralizing pH cycling for 14 days. In the arrest experiment ( n = 15/group), 60 samples were pre-demineralized; induced lesions were treated using self-assembling peptide for repair (SAPR), FV, CPP-ACP plus fluoride, and resin infiltration (RI) and submitted to pH cycling. Mineral loss and its differences as well as lesion depth were determined using transversal microradiography. Numerical data were tested for normality using Shapiro-Wilk's test and were compared using Kruskal-Wallis test followed by pairwise comparisons utilizing multiple Mann-Whitney U tests with Bonferroni correction. The significance level was set at P < 0.05 within all tests., Results: FV (median: -46.3 [interquartile range: 175.52] vol% × µm) and FMW (-33.35 [124.65] vol% × µm) prevented caries significantly more effectively than all other groups ( P < 0.001), which did not show significant preventive effects. RI (median: 4949.70 [1637.20] vol% × µm) and FV (median = 6076.05 [5190.08] vol% × µm) arrested lesions, whereas SAPR and CPP-ACPF did not show such arrest., Conclusions: FV and FMW showed the largest caries-preventive effect, whereas RI and FV arrested lesion progression in primary tooth enamel in vitro ., Competing Interests: The authors declare no conflict of interest, and the study has received no funding., (Copyright: © 2022 Journal of International Society of Preventive and Community Dentistry.)

Purpose: On the basis of strong preclinical rationale, we sought to confirm recommended phase II dose (RP2D) for olaparib, a PARP inhibitor, combined with the AKT inhibitor capivasertib and assess molecular markers of response and resistance., Patients and Methods: We performed a safety lead-in followed by expansion in endometrial, triple-negative breast, ovarian, fallopian tube, or peritoneal cancer. Olaparib 300 mg orally twice daily and capivasertib orally twice daily on a 4-day on 3-day off schedule was evaluated. Two dose levels (DL) of capivasertib were planned: 400 mg (DL1) and 320 mg (DL-1). Patients underwent biopsies at baseline and 28 days., Results: A total of 38 patients were enrolled. Seven (18%) had germline BRCA1/2 mutations. The first 2 patients on DL1 experienced dose-limiting toxicities (DLT) of diarrhea and vomiting. No DLTs were observed on DL-1 ( n = 6); therefore, DL1 was reexplored ( n = 6) with no DLTs, confirming DL1 as RP2D. Most common treatment-related grade 3/4 adverse events were anemia (23.7%) and leukopenia (10.5%). Of 32 evaluable subjects, 6 (19%) had partial response (PR); PR rate was 44.4% in endometrial cancer. Seven (22%) additional patients had stable disease greater than 4 months. Tumor analysis demonstrated strong correlations between response and immune activity, cell-cycle alterations, and DNA damage response. Therapy resistance was associated with receptor tyrosine kinase and RAS-MAPK pathway activity, metabolism, and epigenetics., Conclusions: The combination of olaparib and capivasertib is associated to no serious adverse events and demonstrates durable activity in ovarian, endometrial, and breast cancers, with promising responses in endometrial cancer. Importantly, tumor samples acquired pre- and on-therapy can help predict patient benefit., (©2021 American Association for Cancer Research.)

High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic cancer. Emerging evidence suggests that tumor-associated macrophages (TAMs) play an immunosuppressive role in the tumor microenvironment and promote tumor growth, angiogenesis, and metastasis in ovarian cancer. Therefore, targeting TAMs in patients with ovarian cancer is an appealing strategy; however, all trials to date have failed. To improve the efficacy of this approach, we sought to elucidate the underlying mechanisms of the role of TAMs in ovarian cancer. We found that the developmental transcription factor GATA3 was highly expressed in HGSOC cell lines but not in the fallopian tube, which is the main origin of HGSOC. GATA3 expression was associated with poor prognosis in HGSOC patients (P < .05) and was found to promote proliferation and migration in HGSOC cell lines. GATA3 was released abundantly from TAM cells via exosomes and contributed to tumor growth in the tumor microenvironment. Moreover, GATA3 acted as a regulator for macrophage polarization and interactions between TAMs and HGSOC to support proliferation, motility, and cisplatin chemoresistance in mutant TP53 HGSOC cell lines. Furthermore, GATA3 played a critical role in the interactions between TAMs and mutant TP53 HGSOC to promote angiogenesis and epithelial-mesenchymal transition with epigenetic regulation. Targeting GATA3 using GATA3siRNA in TAMs impeded GATA3-driven proliferation, migration, cisplatin chemoresistance, and angiogenesis in mutant TP53 HGSOC cell lines. Our findings indicate that GATA3 plays a novel role in immunoediting of HGSOC and demonstrate that GATA3 may serve as a prognostic marker for HGSOC and a promising target in the treatment of HGSOC., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose., (Published by Elsevier Inc.)

Genistein, the major isoflavone in soybean, has been reported to exert anticancer effects on various types of cancer including ovarian cancer; however, its chemopreventive effects and mechanisms of action in ovarian cancer have not been fully elucidated in spontaneously developing ovarian cancer models. In this study, we demonstrated the preventive effects and mechanisms of genistein in the laying hen model that develops spontaneous ovarian cancer at high incidence rates. Laying hens were randomized to three groups: control (3.01 mg/hen, n = 100), low (52.48 mg/hen n = 100), and high genistein supplementation (106.26 mg/hen/day; per group). At the end of 78 weeks, hens were euthanized and ovarian tumors were collected and analyzed. We observed that genistein supplementation significantly reduced the ovarian tumor incidence ( P = 0.002), as well as the number and size of the tumors ( P = 0.0001). Molecular analysis of the ovarian tumors revealed that genistein downregulated serum malondialdehyde, a marker for oxidative stress and the expression of NFκB and Bcl-2, whereas it upregulated Nrf2, HO-1, and Bax expression at protein level in ovarian tissues. Moreover, genistein intake decreased the activity of mTOR pathway as evidenced by reduced phosphorylation of mTOR, p70S6K1, and 4E-BP1. Taken together, our findings strongly support the potential of genistein in the chemoprevention of ovarian cancer and highlight the effects of the genistein on the molecular pathways involved in ovarian tumorigenesis., (©2019 American Association for Cancer Research.)

Objectives: Lung cancer is the leading cause of cancer related deaths in worldwide. Despite recent advances in treatment options, patient survival has not improved substantially due to lack of commonly expressed molecular targets and effective targeted therapeutics. Thus, better understanding of the biology of lung cancer and identification of novel therapeutic targets are urgently needed for development of highly effective molecularly targeted therapies., Materials and Methods: Viability, proliferation and metastatic ability of lung cancer cells were evaluated using methylthiazoltetrazolium (MTT), colony formation and matrigel invasion assays, respectively. Western blotting, RT-PCR, and gene knockdown by siRNA transfections were carried out to investigate the effects of eEF-2K on lung cancer cells. Athymic Nu/Nu mice were treated with liposomal eEF-2KeEF-2K or control siRNA and tumor growth was evaluated in tumor xenograft models of lung cancer., Results and Discussion: Here, we report that Eukaryotic Elongation Factor-2 kinase (eEF-2K), a member of an atypical alpha kinases family, is significantly upregulated in lung cancer cell lines and its expression is associated with shorter overall patient survival in lung cancer. Inhibition eEF-2K expression by siRNA or a chemical inhibitorsignificantly suppressed lung cancer cell proliferation, colony formation, survival, migration/invasion and tumorigenesis by inhibiting cyclin D1, Src and Mitogen-Activated Protein Kinases/Extracellular Signal-Regulated Kinase (MAPK/ERK) signaling. In vivo targeting of eEF-2K by systemically injected nanoliposomal eEF-2K siRNA resulted in a significant inhibition of lung cancer tumor xenografts in nude mice. Our results suggest, for the first time, that expression of eEF-2K is associated with poor patient prognosis and involved in regulation of critical pathways, including Src and MAPK/ERK and cyclin D1, promoting tumor growth and progression, and thus may be a novel potential therapeutic target in lung cancer., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background/purpose: Triple-negative breast cancer (TNBC) is the most aggressive and chemoresistant subtype of breast cancer. Therefore, new molecular targets and treatments need to be developed to improve poor patient prognosis and survival. We have previously shown that eukaryotic elongation factor 2 kinase (eEF-2K) is highly expressed in TNBC cells, is associated with poor patient survival and prognosis, and promotes cell proliferation, migration, and invasion. In vivo targeting of eEF-2K significantly reduces the tumor growth of orthotopic TNBC xenograft mouse models, suggesting that eEF-2K may serve as a potential novel therapeutic target., Methods/results: In the current study, we identified thymoquinone (TQ), an active ingredient of Nigella sativa, as a potential safe and effective eEF-2K inhibitor in TNBC. We demonstrated for the first time that TQ inhibits the protein and mRNA expression of eEF-2K, as well as the clinically relevant downstream targets, including Src/FAK and Akt, and induces the tumor suppressor miR-603, in response to NF-kB inhibition. This effect was associated with a significant decrease in the proliferation, colony formation, migration, and invasion of TNBC cells. Furthermore, systemic in vivo injection of TQ (20 and 100 mg/kg) significantly reduced the growth of MDA-MB-231 tumors and inhibited the eEF-2K expression in an orthotopic tumor model in mice., Conclusion: Our study provides first evidence that TQ treatment inhibits cell proliferation, migration/invasion, and tumor growth, in part through the inhibition of eEF-2K signaling in TNBC. Thus, our findings suggest that systemic TQ treatment may be used as a targeted therapeutic strategy for the inhibition of eEF-2K in TNBC tumor growth and progression.