New Frontiers in the Medical Therapy of Hepatocellular Carcinoma

Background: Hepatocellular carcinoma (HCC) is the most common primary liver tumor, and it rates fourth as a cause of cancer-related death. The presence of underlying liver disease and poor chemosensitivity pose major treatment challenges in the management of HCC. However, in the last few years the therapeutic scenario has substantially changed, and immunotherapy in the form of immune checkpoint inhibitors (ICPIs) has become an essential therapeutic strategy in this field. Summary: After controversial results of monotherapy, ICPIs have been mainly investigated in association with anti-angiogenic agents or as dual checkpoint inhibition. The combination of atezolizumab plus bevacizumab has become the new therapeutic standard for unresectable HCC. Currently, a number of ICPIs-based combinations are being studied in phase III clinical trials as front-line therapy for advanced HCC, with growing interest in integration of early-stage disease management in the form of adjuvant or neoadjuvant therapies. With most of the trials investigating ICPIs as first line treatment, the second line scenario relies mainly on tyrosine kinase inhibitors, which however, have not been formally trialed after ICPIs. Key messages: In this review we summarize the main therapeutic advances in the systemic management of HCC focusing on the most relevant ongoing trials. We also discuss the main issues arising from a such rapidly evolving field including therapeutic sequencing and patient stratification.

Depression And HIV/TB In Southern Africa: A Mixed Method Evaluation of An Integrated Primary Care Mental Health Programme In Eswatini

Background: Depression and comorbidity with chronic illnesses is common in Southern Africa, yet there are major treatment gaps. This study evaluates the intervention ‘Healthy Activity Program’ to bridge this gap, which involves training non-specialist nurses in depression: including identification, counselling based on behavioural activation theory and structured referral. This intervention aims to be integrated into routine primary healthcare services for HIV/TB. The patient cohort were people living with HIV and/or tuberculosis (TB) (PLHIV/TB) in rural Eswatini. Aims: To assess the feasibility and acceptability of this intervention and concepts of depression in this setting.Methods: This is a pragmatic mixed methods evaluation of a pilot integrated service.Results: 324 PLHIV/TB were screened for depression, with 19% (62/324) screening positive. Attendance to counselling declined over time, with 16/62 attending the minimum 5 sessions. Qualitative results indicated acceptability, yet concerns around feasibility. Conclusions: The ‘Healthy Activity Program’ represents a promising option to manage the treatment gap for depression in PLHIV/TB. However, task-shifting onto non-specialist healthcare professionals with the aim to integrate care for these conditions in primary care, without increasing staff capacity, is a barrier to implementation. Realistic and pragmatic assessments of capacity and workforce are essential.

The midwife of truth: The nature of irony and a rationale for its prevalence in the Gospel of John

<p>The Gospel of John is renowned for its pervasive use of irony. While this phenomenon is widely recognized by scholars, there have been only a few attempts to explain the “how” of Johannine irony and no meaningful attempt to explain its “why.” The last major treatment of the topic was by Paul Duke in his 1985 work, Irony in the Fourth Gospel, which provides an account of how Johannine irony works through an analysis of local and extended ironies. Other examinations, such as Gail O’Day’s Revelation in the Fourth Gospel in 1986, explore irony as a corollary of some other thematic concern. The reticence of scholars to delve deeper into the nature of Johannine irony is understandable given that as Duke puts it, irony laughs at all pretensions, especially the pretension of claiming to have grasped irony. This study undertakes the demanding but necessary task of describing irony to a level that allows meaningful engagement with ironic texts, while accepting that it remains ultimately indefinable. Particular attention is paid to historical shifts of understanding of the nature of irony and the implications this has for appreciating irony at a conceptual level. From a survey of the Johannine scholarship, a comprehensive but non-exhaustive overview of the Fourth Gospel’s use of irony is derived. No previous work has attempted to approach the subject in this way. The main advantage of doing so is that it allows for the identification of broad patterns of irony and the way it functions in the narrative. This in turn provides a framework for proceeding to an examination of particular texts and the identification of a possible rationale. The present study assesses several hypotheses to explain why the author of the Fourth Gospel makes such sustained use of irony. The preferred hypothesis is that it is intrinsically linked to a predominant Johannine theme of alētheia (truth). Drawing on the conceptual link between irony and truth, it argues that the truth theme is a deliberate literary strategy employed by the author to entice the reader to seek certain propositional truths within the narrative. This ultimately serves the author’s desire to evoke revelation and response in line with the Gospel’s purpose statement in 20:31. The argument that irony serves the Johannine truth theme is tested with particular reference to the Prologue (1:1-18) and the Passion Narrative (chapters 18-19). The study establishes that irony serves as the link between appearance and reality in the narrative. Its subtle and engaging qualities make irony the most suitable vehicle to testify to the Gospel’s propositional statements in a manner that fulfils the author’s stated Christological (a revelation of Jesus’ true identity) and soteriological (a response that leads to salvation) purposes.</p>

The midwife of truth: The nature of irony and a rationale for its prevalence in the Gospel of John

<p>The Gospel of John is renowned for its pervasive use of irony. While this phenomenon is widely recognized by scholars, there have been only a few attempts to explain the “how” of Johannine irony and no meaningful attempt to explain its “why.” The last major treatment of the topic was by Paul Duke in his 1985 work, Irony in the Fourth Gospel, which provides an account of how Johannine irony works through an analysis of local and extended ironies. Other examinations, such as Gail O’Day’s Revelation in the Fourth Gospel in 1986, explore irony as a corollary of some other thematic concern. The reticence of scholars to delve deeper into the nature of Johannine irony is understandable given that as Duke puts it, irony laughs at all pretensions, especially the pretension of claiming to have grasped irony. This study undertakes the demanding but necessary task of describing irony to a level that allows meaningful engagement with ironic texts, while accepting that it remains ultimately indefinable. Particular attention is paid to historical shifts of understanding of the nature of irony and the implications this has for appreciating irony at a conceptual level. From a survey of the Johannine scholarship, a comprehensive but non-exhaustive overview of the Fourth Gospel’s use of irony is derived. No previous work has attempted to approach the subject in this way. The main advantage of doing so is that it allows for the identification of broad patterns of irony and the way it functions in the narrative. This in turn provides a framework for proceeding to an examination of particular texts and the identification of a possible rationale. The present study assesses several hypotheses to explain why the author of the Fourth Gospel makes such sustained use of irony. The preferred hypothesis is that it is intrinsically linked to a predominant Johannine theme of alētheia (truth). Drawing on the conceptual link between irony and truth, it argues that the truth theme is a deliberate literary strategy employed by the author to entice the reader to seek certain propositional truths within the narrative. This ultimately serves the author’s desire to evoke revelation and response in line with the Gospel’s purpose statement in 20:31. The argument that irony serves the Johannine truth theme is tested with particular reference to the Prologue (1:1-18) and the Passion Narrative (chapters 18-19). The study establishes that irony serves as the link between appearance and reality in the narrative. Its subtle and engaging qualities make irony the most suitable vehicle to testify to the Gospel’s propositional statements in a manner that fulfils the author’s stated Christological (a revelation of Jesus’ true identity) and soteriological (a response that leads to salvation) purposes.</p>

Lipid changes during the perioperative period in patients with early breast cancer: a real-world retrospective analysis

Background Surgery remains the major treatment for early breast cancer (BC), but surgery itself is also a trauma which might induce alterations in lipid metabolism. The aim of this study was to investigate the changes in lipid profiles and to explore factors associated with lipid changes pre- and postoperation. Methods We retrospectively analyzed the pre- and postoperative serum lipid profiles of 1934 BC patients. Results The levels of triglycerides (TG) (p < 0.001) and low-density lipoprotein cholesterol (LDL) (p < 0.001) were significantly elevated after surgery, while the levels of high-density lipoprotein cholesterol (HDL) (p < 0.001) were significantly decreased. After surgery, 27.76% of patients with preoperative ortholiposis developed dyslipidemia. Postmenopausal BC patients had a higher incidence of dyslipidemia (32.31%) after surgery than premenopausal BC patients (26.07%; p = 0.041). Additionally, patients with BMI > 24 (34.92%) had a higher incidence of dyslipidemia than patients with BMI ≤ 24 (24.84%; p = 0.001). Moreover, the magnitudes of the TG increase (p < 0.001), cholesterol (TC) increase (p = 0.013) and LDL increase (p = 0.015) in the premenopausal group were all greater than those in the postmenopausal group. After adjusting for multiple baseline covariates, preoperative hyperlipidemia and progesterone receptor (PR)-positive status were significantly associated with elevated TG, TC and LDL levels after surgery. Conclusions Serum lipid profiles of BC patients may increase after surgery, especially premenopausal patients. Additionally, postmenopausal and overweight patients may have a higher risk of being diagnosed with dyslipidemia after surgery. Therefore, lipid monitoring, dyslipidemia prevention and corresponding interventions should be taken into consideration during the perioperative period.

Long-Term Release of Dexamethasone With a Polycaprolactone-Coated Electrode Alleviates Fibrosis in Cochlear Implantation

Cochlear implantation (CI) is the major treatment for severe sensorineural hearing loss. However, the fibrotic tissue forming around the electrodes reduces the treatment effectiveness of CI. Dexamethasone (DEX) is usually applied routinely in perioperative treatment of cochlear implantation (CI), but its diffusion in the inner ear after systemic administration is limited. In the present study, an electrode coated with polycaprolactone (PCL) loaded with dexamethasone was developed with a simple preparation process to maintain the stability of the electrode itself. The DEX-loaded PCL coating has good biocompatibility and does not change the smoothness, flexibility, or compliance of the implant electrode. Stable and effective DEX concentrations were maintained for more than 9 months. Compared with the pristine electrode, decreasing intracochlear fibrosis, protection of hair cells and spiral ganglion cells, and better residual hearing were observed 5 weeks after PCL-DEX electrode implantation. The PCL-DEX electrode has great potential in preventing hearing loss and fibrosis by regulating macrophages and inhibiting the expression of the fibrosis-related factors IL-1β, TNF-α, IL-4, and TGF-β1. In conclusion, the PCL-DEX electrode coating shows promising application in CI surgery.

Design and Characterization of Maltose-Conjugated Polycaprolactone Nanofibrous Scaffolds for Uterine Tissue Engineering

Purpose Uterine anomalies are prevalent in women, and the major treatment assisted to them is hysterectomy as donor availability is extremely low. To overcome this, engineering uterine myometrium smooth muscle tissue has become very important. Several studies have shown that polycaprolactone (PCL) nanofibers are very effective in engineering smooth muscles, as this type of scaffold has structural similarities to the extracellular matrices of the cells. Here, we hypothesize that by electrospinning PCL nanofibers, they form a suitable scaffold for uterine tissue engineering. Methods Polycaprolactone nanofibrous scaffolds were fabricated, and surface modification was performed following two step wet chemistry method. First step is aminolysis which introduces the primary amine groups on the PCL scaffolds following which maltose is conjugated on the scaffolds. This was confirmed by the ninhydrin assay for the presence of amine groups. This was followed by ELLA assay where the presence of maltose on the scaffold was quantified. Modified scaffolds were further characterized by scanning electron microscope (SEM), contact angle analysis and Fourier transform infrared spectroscopy (FTIR). MTT assay, live-dead assay and actin staining were performed on the maltose immobilization to study the improvement of the cell attachment and proliferation rates on the modified scaffolds. Results Human uterine fibroblast (HUF) cells displayed significant proliferation on the maltose-modified PCL scaffolds, and they also exhibited appropriate morphology indicating that these modified fibers are highly suitable for uterine cell growth. Conclusion Our results indicate that the fabricated maltose PCL (MPCL) scaffolds would be a potential biomaterial to treat uterine injuries and promote regeneration. Lay Summary and Future Work Uterine anomalies are prevalent in women, and the major treatment is hysterectomy as donor availability is extremely low. Over the past few years, considerable efforts have been directed towards uterine tissue regeneration. This study is to design a tissue engineered scaffold that could act as a human uterine myometrial patch. We propose to create uterine fibroblast-based synthetic scaffolds that act in a condition similar to the intrauterine microenvironment where the embryos are embedded in the uterine wall. For understanding of the efficiency of the myometrial patch, functional characterization will be performed to study the effects of estrogen and prostaglandins on myometrial activity of the designed patch. Results from these experiments will assist a deeper understanding of how to construct a total bioengineered uterus which can substitute the uterus transplantation procedure, which nonetheless is in its initial stages of development. Graphical Abstract

Incidence of central serous chorioretinopathy (2011–2018): a nationwide population-based cohort study of Japan

AimsThe aim of this study was to elucidate the epidemiological background of central serous chorioretinopathy (CSC), including its incidence and treatment pattern.MethodsThis was a population-based longitudinal cohort study using a nationwide health insurance claims database of the Japan Ministry of Health, Labour and Welfare (MHLW). As Japan employs universal health coverage, the database covers more than 95% of claims issued in Japan. We accessed all data stored in the database with permission from the MHLW. We traced all individuals aged 30 years or older and identified individuals with new onset of CSC between January 2011 and December 2018. CSC cases were categorised by age and sex for each year, and incidence rate was calculated. We also identified major treatments for CSC to elucidate the initial treatment pattern.ResultsDuring the 8-year period, 247 930 incidences of CSC were identified, among which 75.9% were men. The crude incidence rate (per 100 000 person-years) in the general population aged 30 years or older was 34.0 (95% CI 33.9 to 34.2), in men was 54.2 (95% CI 53.9 to 54.4) and in women was 15.7 (95% CI 15.5 to 15.8). The mean age of onset was lower in men than in women (50.5±12.5 years vs 54.7±13.5 years). Most of the patients with newly diagnosed CSC (86.8%) did not receive major treatment.ConclusionsThe current study provides the nationwide population-based evidence to clarify the detailed epidemiology of CSC. These results could help to understand the pathogenesis and mechanisms of CSC in the future.

The newly identified MEK1 tyrosine phosphorylation target MACC1 is druggable by approved MEK1 inhibitors to restrict colorectal cancer metastasis

Cancer metastasis causes >90% of cancer deaths and remains a major treatment challenge. Here we deciphered the impact of tyrosine phosphorylation of MACC1, a causative driver for cancer metastasis, for cancer cell signaling and novel interventions to restrict cancer metastasis. We identified MACC1 as new MEK1 substrate. MEK1 directly phosphorylates MACC1, leading to accelerated and increased ERK1 activation. Mutating in silico predicted hierarchical MACC1 tyrosine phosphorylation sites abrogates MACC1-induced migration, invasion, and MET expression, a transcriptional MACC1 target. Targeting MEK1 by RNAi or clinically applicable MEK1 inhibitors AZD6244 and GSK1120212 reduces MACC1 tyrosine phosphorylation and restricts MACC1-induced metastasis formation in mice. Although MEK1 levels, contrary to MACC1, are not of prognostic relevance for CRC patients, MEK1 expression was found indispensable for MACC1-induced metastasis. This study identifies MACC1 as new MEK1 substrate for tyrosine phosphorylation decisively impacting cell motility, tumor growth, and metastasis. Thus, MAP kinase signaling is not linear leading to ERK activation, but branches at the level of MEK1. This fundamental finding opens new therapeutic options for targeting the MEK1/MACC1 axis as novel vulnerability in patients at high risk for metastasis. This might be extended from CRC to further solid tumor entities.

Up-regulation of ACE2, the SARS-CoV-2 receptor, in asthmatics on maintenance inhaled corticosteroids

Background The first step in SARS-CoV-2 infection is binding of the virus to angiotensin converting enzyme 2 (ACE2) on the airway epithelium. Asthma affects over 300 million people world-wide, many of whom may encounter SARS-CoV-2. Epidemiologic data suggests that asthmatics who get infected may be at increased risk of more severe disease. Our objective was to assess whether maintenance inhaled corticosteroids (ICS), a major treatment for asthma, is associated with airway ACE2 expression in asthmatics. Methods Large airway epithelium (LAE) of asthmatics treated with maintenance ICS (ICS+), asthmatics not treated with ICS (ICS−), and healthy controls (controls) was analyzed for expression of ACE2 and other coronavirus infection-related genes using microarrays. Results As a group, there was no difference in LAE ACE2 expression in all asthmatics vs controls. In contrast, subgroup analysis demonstrated that LAE ACE2 expression was higher in asthmatics ICS+ compared to ICS‾ and ACE2 expression was higher in male ICS+ compared to female ICS+ and ICS‾ of either sex. ACE2 expression did not correlate with serum IgE, absolute eosinophil level, or change in FEV1 in response to bronchodilators in either ICS− or ICS+. Conclusion Airway ACE2 expression is increased in asthmatics on long-term treatment with ICS, an observation that should be taken into consideration when assessing the use of inhaled corticosteroids during the pandemic.