Interpreting a Diagnosis of Atypical Squamous Cells of Undetermined Significance in Cervical Cytology and its Association with Human Papillomavirus: A retrospective analysis of 180 cases in Kuwait

Objectives: Atypical squamous cells of undetermined significance (ASC-US) represent a diagnostic challenge during cervical cytology. This study aimed to review and identify high-risk human papillomavirus (HR-HPV) genotypes among previously diagnosed ASC-US cases in Kuwait. Methods: This retrospective study analysed 180 cases diagnosed as ASC-US between June 2017 and May 2018 at the Mubarak Al-Kabeer Hospital, Kuwait. Cervical specimens were assayed to determine the presence of HR-HPV DNA; subsequently, positive cases underwent genotyping and were categorised into three groups (HPV 16, HPV 18/45 and other HR-HPV types). Results: In total, ASC-US was confirmed in only 105 cases (58.3%), with the remaining cases reclassified as negative for intraepithelial lesions or malignancy (NILM; 32.2%) and epithelial cell abnormalities (ECA; 9.4%). Of these, HRHPV DNA was present in 20 ASC-US (19%), one NILM (1.7%) and six ECA (35.3%) cases. There were 62 Kuwaiti and 43 non-Kuwaiti women with confirmed ASC-US; of these, three (4.8%), six (9.7%) and four (6.5%) Kuwaitis and one (2.3%), one (2.3%) and five (11.6%) non-Kuwaitis had HPV 16, both HPV 16 and 18/45 and other HRHPV genotypes, respectively. Of those with HR-HPV DNA, the NILM case had the HPV 18/45 genotype, while the six ECA cases had the HPV 16 (n = 1), both HPV 16 and 18/45 (n = 1) and other HR-HPV (n = 4) genotypes. Conclusion: Overall, HR-HPV DNA was present in 19% of ASC-US cases compared to 1.7% of NILM cases initially misdiagnosed as ASC-US. Re-review of cervical cytology diagnoses may reduce unnecessary costs associated with HR-HPV genotyping. Keywords: Cervical Smears; Atypical Squamous Cells of Undetermined Significance; Human Papilloma Virus; Cytological Techniques; Papanicolaou Test; Kuwait

Ziziphus nummularia attenuates the malignant phenotype of human pancreatic cancer cells: Role of ros

Pancreatic cancer (PC) is the fourth leading cause of all cancer-related deaths. Despite major improvements in treating PC, low survival rate remains a major challenge, indicating the need for alternative approaches, including herbal medicine. Among medicinal plants is Ziziphus nummu-laria (family Rhamnaceae), which is a thorny shrub rich in bioactive molecules. Leaves of Ziziphus nummularia have been used to treat many pathological conditions, including cancer. However, their effects on human PC are still unknown. Here, we show that the treatment of human pancreatic ductal adenocarcinoma cells (Capan-2) with Ziziphus nummularia ethanolic extract (ZNE) (100–300 µg/mL) attenuated cell proliferation in a time-and concentration-dependent manner. Pretreatment with N-acetylcysteine, an ROS scavenger, attenuated the anti-proliferative effect of ZNE. In addition, ZNE significantly decreased the migratory and invasive capacity of Capan-2 with a concomitant downregulation of integrin α2 and increased cell–cell aggregation. In addition, ZNE inhibited in ovo angiogenesis as well as reduced VEGF and nitric oxide levels. Furthermore, ZNE downregulated the ERK1/2 and NF-κB signaling pathways, which are known to drive tumorigenic and metastatic events. Taken together, our results suggest that ZNE can attenuate the malignant phenotype of Capan-2 by inhibiting hallmarks of PC. Our data also provide evidence for the potential anticancer effect of Ziziphus nummularia, which may represent a new resource of novel anticancer compounds, especially ones that can be utilized for the management of PC

Origanum syriacum L. Attenuates the Malignant Phenotype of MDA-MB231 Breast Cancer Cells

Breast cancer is the leading cause of cancer-related deaths among women. Among breast cancer types, triple negative breast cancer (TNBC) is the most aggressive, and is resistant to hormonal and chemotherapeutic treatments. As such, alternative approaches that may provide some benefit in fighting this debilitating pathology are critically needed; hence the utilization of herbal medicine. Origanum syriacum L., one of the most regularly consumed plants in the Mediterranean region, exhibits antiproliferative effect on several cancer cell lines. However, whether this herb modulates the malignant phenotype of TNBC remains poorly investigated. Here, we show that in MDA-MB-231, a TNBC cell line, Origanum syriacum L. aqueous extract (OSE) inhibited cellular viability, induced autophagy determined by the accumulation of lipidized LC3 II, and triggered apoptosis. We also show that OSE significantly promoted homotypic cell-cell adhesion while it decreased cellular migration, adhesion to fibronectin, and invasion of MDA-MB-231 cells. This was supported by decreased activity of focal adhesion kinase (FAK), reduced α2 integrin expression, and downregulation of secreted PgE2, MMP2 and MMP-9, in OSE-treated cells. Finally, we also show that OSE significantly inhibited angiogenesis and downregulated the level of nitric oxide (NO) production. Our findings demonstrate the ability of OSE to attenuate the malignant phenotype of the MDA-MB-231 cells, thus presenting Origanum syriacum L. as a promising potential source for therapeutic compounds for TNBC

Leukotriene biosynthesis inhibition ameliorates acute lung injury following hemorrhagic shock in rats

<p>Abstract</p> <p>Background</p> <p>Hemorrhagic shock followed by resuscitation is conceived as an insult frequently induces a systemic inflammatory response syndrome and oxidative stress that results in multiple-organ dysfunction syndrome including acute lung injury. MK-886 is a leukotriene biosynthesis inhibitor exerts an anti inflammatory and antioxidant activity.</p> <p>Objectives</p> <p>The objective of present study was to assess the possible protective effect of MK-886 against hemorrhagic shock-induced acute lung injury via interfering with inflammatory and oxidative pathways.</p> <p>Materials and methods</p> <p>Eighteen adult Albino rats were assigned to three groups each containing six rats: group I, sham group, rats underwent all surgical instrumentation but neither hemorrhagic shock nor resuscitation was done; group II, Rats underwent hemorrhagic shock (HS) for 1 hr then resuscitated with Ringer's lactate (1 hr) (induced untreated group, HS); group III, HS + MK-886 (0.6 mg/kg i.p. injection 30 min before the induction of HS, and the same dose was repeated just before reperfusion period). At the end of experiment (2 hr after completion of resuscitation), blood samples were collected for measurement of serum tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). The trachea was then isolated and bronchoalveolar lavage fluid (BALF) was carried out for measurement of leukotriene B₄(LTB₄), leukotriene C₄(LTC₄) and total protein. The lungs were harvested, excised and the left lung was homogenized for measurement of malondialdehyde (MDA) and reduced glutathione (GSH) and the right lung was fixed in 10% formalin for histological examination.</p> <p>Results</p> <p>MK-886 treatment significantly reduced the total lung injury score compared with the HS group (<it>P </it>< 0.05). MK-886 also significantly decreased serum TNF-α & IL-6; lung MDA; BALF LTB₄, LTC₄& total protein compared with the HS group (<it>P </it>< 0.05). MK-886 treatment significantly prevented the decrease in the lung GSH levels compared with the HS group (<it>P </it>< 0.05).</p> <p>Conclusions</p> <p>The results of the present study reveal that MK-886 may ameliorate lung injury in shocked rats via interfering with inflammatory and oxidative pathways implicating the role of leukotrienes in the pathogenesis of hemorrhagic shock-induced lung inflammation.</p

Expertise in surgical neuro-oncology. Results of a survey by the EANS neuro-oncology section

Introduction: Technical advances and the increasing role of interdisciplinary decision-making may warrant formal definitions of expertise in surgical neuro-oncology. Research question: The EANS Neuro-oncology Section felt that a survey detailing the European neurosurgical perspective on the concept of expertise in surgical neuro-oncology might be helpful. Material and methods: The EANS Neuro-oncology Section panel developed an online survey asking questions regarding criteria for expertise in neuro-oncological surgery and sent it to all individual EANS members. Results: Our questionnaire was completed by 251 respondents (consultants: 80.1%) from 42 countries. 67.7% would accept a lifetime caseload of &gt;200 cases and 86.7% an annual caseload of &gt;50 as evidence of neuro-oncological surgical expertise. A majority felt that surgeons who do not treat children (56.2%), do not have experience with spinal fusion (78.1%) or peripheral nerve tumors (71.7%) may still be considered experts. Majorities believed that expertise requires the use of skull-base approaches (85.8%), intraoperative monitoring (83.4%), awake craniotomies (77.3%), and neuro-endoscopy (75.5%) as well as continuing education of at least 1/year (100.0%), a research background (80.0%) and teaching activities (78.7%), and formal interdisciplinary collaborations (e.g., tumor board: 93.0%). Academic vs. non-academic affiliation, career position, years of neurosurgical experience, country of practice, and primary clinical interest had a minor influence on the respondents’ opinions. Discussion and conclusion: Opinions among neurosurgeons regarding the characteristics and features of expertise in neuro-oncology vary surprisingly little. Large majorities favoring certain thresholds and qualitative criteria suggest a consensus definition might be possible

Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection

BACKGROUND Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively. METHODS We conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population. RESULTS In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, −10.1 percentage points; 95% confidence interval [CI], −15.9 to −4.3; P<0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference, −9.9 percentage points; 95% CI, −15.5 to −4.3; P<0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs. 28% [109 of 395]; adjusted difference, −11.6 percentage points; 95% CI, −17.4 to −5.9; P<0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, −10.7 percentage points; 95% CI, −16.4 to −5.1; P<0.001). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea. CONCLUSIONS Among participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. (Funded by Merck; MODIFY I and MODIFY II ClinicalTrials.gov numbers, NCT01241552 and NCT01513239.

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

2-Nucleobase-substituted 4,6-Diaminotriazine Analogs: Synthesis and Anti-cancer Activity in 5-Fluorouracil-Sensitive and Resistant Colorectal Cancer Cells.

Cancer continues to be the second leading cause of death worldwide with colorectal cancer (CRC) being the third most common type. Despite significant advances in cancer therapies, current treatment of CRC remains suboptimal. In addition, the effectiveness of available chemotherapeutic drugs such as 5-Fluorouracil (5-FU) is limited by CRC-acquired resistance. In this study, we provide innovative approaches employed in synthesizing four novel nucleobase analogs. Equally, we describe the effects of these compounds on proliferation, migration, aggregation, adhesion of 5-FU-sensitive (HCT116) and -resistant (5-FU-R-HCT116) human CRC cells. In either cell type, our synthesized novel analogs significantly inhibited cell viability in a concentration- and time-dependent manner. This highlights the higher potency of these novel analogs. In addition, these compounds attenuated migration and adhesion of both cell types, while they promoted homotypic cell-cell interaction. These changes were reflected by the downregulation matrix metalloproteases (MMP-2 and MMP-9). Furthermore, our analogs exhibited a potent anti-angiogenic activity in vivo. In addition, these compounds reduced the level of secreted vascular endothelial growth factor (VEGF) and nitric oxide (NO) production in both 5-FU-sensitive and -resistant cells. Taken together, our data highlight the potential chemotherapeutic properties of our novel analogs against CRC, including the 5-FU-resistant form