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Leukaemia inhibitory factor (LIF) is a pleotropic cytokinc, regulating differentiation, cell growth, cachexia and inflammation. Using the reverse transcription-polymerase chain reaction (RT-PCR) we found that, in culture, normal human keratinoeytcs (KC) expressed mRNA transcripts for both LIF and the LIF receptor. In the conditioned medium (CM), constitutive LIF protein production was barely detectable but stimulation of KC with 10ng/ml of either interleukin (IL)- 1α or IL-8, for 24 h, resulted in small but significant increases (P < 0.05) in LIF protein, as measured by enzyme-linked immunosorbent assay. After culture in media containing 1.5mmol/l calcium, a time-dependent increase in LIF mRNA was seen up to 72h (an 8.5-fold increase), over levels in cells cultured in 0.05mmol/l calcium. A large increase in LIF protein in the CM (from 1.15 ± 0.15 pg/ml to 178.7 ± 75.7 pg/ml) was seen 72h after a switch to media containing 1.5mmol/l calcium (P = 0.05). Twenty-four hours after stimulation of human KC in culture with 10ng/ml recombinant LIF, a twofold increase in both IL-1α and IL-8 protein in the CM (P < 0.05) was observed. In normal human scalp and foreskin, the epidermis was shown to contain LIF protein by immunostaining. LIF staining was found throughout the epidermis, and in the cells of the outer layer of the root sheath. Thus, KC synthesize LIF in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Inverting papilloma of the nose and paranasal sinuses can sometimes be very difficult to distinguish from other nasal tumors, and the confusion ranges from allergic nasal polyposis to carcinoma. They are also certainly characterized by multiple recurrence, particularly after limited operations. The experience with 34 cases seen at UCLA over the past two decades is analyzed and a philosophy of treatment is outlined. We favor wide local excision which generally necessitates a lateral rhinotomy and medial maxillectomy. The operative approach will be described in detail. [ABSTRACT FROM AUTHOR]

The asebia mouse represents a spontaneous mutation in BALB/c mice leading to hyperplasia of the epidermis and chronic inflammatory dermal changes including enhanced cellularity, oedema and elevated mast cell numbers. We demonstrated that asebia mice have constitutively elevated intercellular adhesion molecule-1 (ICAM-1) mRNA expression, which is not detectable in the wild type, and that dermal mast cell numbers were 3.1-fold higher than the wild type (P < 0.001). We utilized this model to explore the anti-inflammatory effects of cyclosporin A (CsA). After 3 weeks subcutaneous injection with 5 or 10mg/kg CsA the expression of ICAM-1 mRNA was determined by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and was found lo be decreased 2.7-fold (P < 0.001) and three-fold (P < 0.001) relative to controls for 5 and 10mg/kg treatments, respectively. Dermal mast cell counts were dose-dependently decreased by CsA. Mast cells, visualized by toluidine blue staining, decreased 4.5-fold with 10mg/kg CsA (P < 0.001) bringing them down to numbers typical of the wild type. CsA also appeared to stabilize mast cell histamine content. Histological examination of haematoxylin-eosin-stained sections revealed that CsA treatment restored the wild-type skin phenotype decreasing epidermal hyperplasia, dermal cellularity and oedema. Thus, CsA exhibits a wide range of anti-inflammatory effects including reduction of ICAM-1 expression and mast cell numbers, and may be useful in the treatment of mast cell-mediated dermatoses. [ABSTRACT FROM AUTHOR]

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is generally divided in two subtypes, classical and basal. Recently, single-cell RNA sequencing has uncovered the coexistence of basal and classical cancer cells, as well as intermediary cancer cells, in individual tumors. The latter remains poorly understood; here, we sought to characterize them using a multimodal approach., Experimental Design: We performed subtyping on a single-cell RNA sequencing dataset containing 18 human PDAC samples to identify multiple intermediary subtypes. We generated patient-derived PDAC organoids for functional studies. We compared single-cell profiling of matched blood and tumor samples to measure changes in the local and systemic immune microenvironment. We then leveraged longitudinally patient-matched blood to follow individual patients over the course of chemotherapy., Results: We identified a cluster of KRT17-high intermediary cancer cells that uniquely express high levels of CXCL8 and other cytokines. The proportion of KRT17high/CXCL8+ cells in patient tumors correlated with intratumoral myeloid abundance, and, interestingly, high protumor peripheral blood granulocytes, implicating local and systemic roles. Patient-derived organoids maintained KRT17high/CXCL8+ cells and induced myeloid cell migration in a CXCL8-dependent manner. In our longitudinal studies, plasma CXCL8 decreased following chemotherapy in responsive patients, while CXCL8 persistence portended worse prognosis., Conclusions: Through single-cell analysis of PDAC samples, we identified KRT17high/CXCL8+ cancer cells as an intermediary subtype, marked by a unique cytokine profile and capable of influencing myeloid cells in the tumor microenvironment and systemically. The abundance of this cell population should be considered for patient stratification in precision immunotherapy. See related commentary by Faraoni and McAllister, p. 2297., (©2023 The Authors; Published by the American Association for Cancer Research.)

Malignant pleural mesothelioma is a rare cancer characterized by a very poor prognosis. Exposure to asbestos is the leading cause of malignant pleural mesothelioma. The preinvasive lesions, the mesothelial hyperplasia and its possible evolution are the focus of the majority of the studies aiming to identify the treatable phase of the disease. The role of BAP-1 and MTAP in the diagnosis of mesothelioma in situ and in the prognosis of malignant pleural mesothelioma is the main topic of recent studies. The management of preinvasive lesions in mesothelioma is still unclear and many aspects are the subject of debate. The diagnosis, the disease staging and the accurate, comprehensive assessment of patients are three key instants for an appropriate management of patients/the disease.

Background: Overprescription of opioids has fueled an epidemic of addiction and overdose deaths. The FDA required manufacturers of extended-release/long-acting (ER/LA) opioids to fund continuing medical education (CME) on opioids as part of a Risk Evaluation and Mitigation Strategy (REMS)., Objectives: We sought to determine whether industry-funded REMS on long-acting opioids were consistent with the FDA's goal to reduce serious, adverse outcomes resulting from inappropriate prescribing, misuse, and abuse., Study Design: In 2018, we analyzed all internet-based REMS CME activities funded by the REMS Program Companies (RPC), a consortium of ER/LA opioid manufacturers., Methods: We utilized systematic narrative thematic analysis, an inductive approach that allows for mapping of concepts and meanings across a body of data by identifying, recording, analyzing, and refining key narrative points, called "themes". Authors viewed all REMS activities multiple times., Results: Ten themes were identified, all of which were at least somewhat incongruent with federal guidelines and their goals: 1. Chronic pain is a common, under-treated problem. 2.Chronic pain is a chronic disease.3.Opioids are an appropriate treatment for chronic pain. 4.LAs are more appropriate than immediate-release (IR) opioids for chronic pain. 5.Tolerance is normal, expected, and beneficial. 6. Opioid rotation" can maximize analgesia and minimize adverse effects.7. There is no population for whom opioids are absolutely contraindicated or inappropriate. 8. Screening and monitoring tools are effective for preventing opioid-related problems. 9. Opioid related adverse effects, such as respiratory depression and addiction, are due only to misuse and abuse. Addiction, overdose, and death are due to street drugs such as heroin and fentanyl, not prescription opioids.Themes and statements repeated in these activities were inconsistent with current medical knowledge, evidence-based federal guidelines, and FDA goals., Limitations: We evaluated only online, not live, CME. We also did not evaluate individual conflicts of interest of faculty., Conclusions: Industry-funded REMS-compliant CME on opioids contain messages that misrepresent scientific evidence and may foster overprescribing of opioids.

Pancreatic ductal adenocarcinoma (PDA) is characterized by an immune-suppressive tumor microenvironment that renders it largely refractory to immunotherapy. We implemented a multimodal analysis approach to elucidate the immune landscape in PDA. Using a combination of CyTOF, single-cell RNA sequencing, and multiplex immunohistochemistry on patient tumors, matched blood, and non-malignant samples, we uncovered a complex network of immune-suppressive cellular interactions. These experiments revealed heterogeneous expression of immune checkpoint receptors in individual patient's T cells and increased markers of CD8 + T cell dysfunction in advanced disease stage. Tumor-infiltrating CD8 + T cells had an increased proportion of cells expressing an exhausted expression profile that included upregulation of the immune checkpoint TIGIT , a finding that we validated at the protein level. Our findings point to a profound alteration of the immune landscape of tumors, and to patient-specific immune changes that should be taken into account as combination immunotherapy becomes available for pancreatic cancer., Competing Interests: Competing interests: The authors have declared that no conflict of interest exists.

Purpose: This study aims to assess the microbiological profile, antimicrobial susceptibility and adequacy of intravenous ceftriaxone and metronidazole as empirical therapy for surgical patients presenting with complicated intra-abdominal infection., Methods: This retrospective audit reviews the microbiological profile and sensitivity of intra-abdominal cultures from adult patients with complicated intra-abdominal infection who presented to the emergency department at Western Health (Melbourne, Australia) between November 2013 and June 2017. Using the hospital's database, an audit was completed using diagnosis related group (DRG) coded data. Ethics approval has been granted by the Western Health Human Research Ethics Committee. Results are stratified according to surgical conditions (appendicitis, cholecystitis, sigmoid diverticulitis and bowel perforation). The antimicrobial coverage of ceftriaxone and metronidazole is evaluated against these microbial profiles., Results: A total of 1,412 patients were identified using DRG codes for intra-abdominal infection. All patients with microscopy and sensitivity results were included in the study. Patients without these results were excluded. 162 patients were evaluable. 180 microbiological cultures were performed through surgical intervention or radiologically guided aspiration of the intra-abdominal infection. Single or multiple pathogens were identified in 137 cultures. The most commonly identified pathogens were mixed anaerobes (12.6%), Escherichia coli ( E. coli ) (12.1%), mixed coliforms (11.6%) and Pseudomonas aeruginosa (7%). Other common pathogens (6% each) included Enterococcus faecalis, Streptococcus anginosus, Vancomycin-resistant Enterococci (VRE) and Extended Spectrum Beta-Lactamases (ESBL) producing E. coli . Organisms isolated in our study are consistent with existing literature. However, a significant proportion of antibiotic resistant organisms was identified in cases of perforated bowel and sigmoid diverticulitis. Broader spectrum antimicrobial therapy should therefore be considered in lieu of ceftriaxone and metronidazole in these cases. Ceftriaxone and metronidazole remain as appropriate empirical therapy for patients who presented with perforated appendicitis and cholecystitis., Discussion: The empirical regime of ceftriaxone and metronidazole remains appropriate for intra-abdominal infection secondary to appendicitis and cholecystitis. In cases involving perforated small and large bowel, including complicated sigmoid diverticulitis, the judicious use of ceftriaxone and metronidazole is recommended., Competing Interests: The authors declare there are no competing interests.

Objective: To determine whether topical hypotensive medications prevent postoperative ocular hypertension (POH) after phacoemulsification., Animals Studied: 52 client-owned dogs (88 eyes)., Procedures: Diabetic and nondiabetic dogs having undergone phacoemulsification were included in this retrospective study. The control group received no ocular hypotensive medications. The treatment groups received latanoprost, dorzolamide, or dorzolamide/timolol, beginning immediately after surgery, for 2-week duration. IOPs were obtained at initial examination followed by 4 h, 24 h, 7 days, and 14 days postoperatively. POH was defined as an IOP above 20 mmHg (POH20) or 25 mmHg (POH25)., Results: POH20 occurred in 33 of 87 eyes (37.93%), including 11 of 21 eyes (52.38%) in the control group, three of 23 eyes (13.04%) in the latanoprost group, eight of 15 eyes (53.33%) in the dorzolamide group, and 11 of 28 eyes (39.29%) in the dorzolamide/timolol group. Active treatment groups were compared to the control group, and the overall group effect was not significant (P = 0.11). POH25 occurred in 22 of 86 eyes (25.58%), including seven of 21 eyes (33.33%) in the control group, two of 23 eyes (8.70%) in the latanoprost group, five of 15 eyes (33.33%) in the dorzolamide group, and eight of 27 eyes (29.63%) in the dorzolamide/timolol group. Active treatment groups were compared to the control group, and the overall group effect was not significant (P = 0.31). Intraoperative use of intracameral tissue plasminogen activator significantly decreased the chances of POH25 (P = 0.0063)., Conclusions and Clinical Relevance: The latanoprost group had a substantially lower percentage of POH 20 and POH25 compared to the control and other active treatment groups, although statistical significance was not achieved. Intraoperative intracameral tissue plasminogen activator decreased the incidence of POH25., (© 2017 American College of Veterinary Ophthalmologists.)