Differences in the proteome within extracellular vesicles between premalignant and malignant plasma cell disorders.

BACKGROUND: Precursor plasma cell disorders such as monoclonal gammopathy of undetermined significance (MGUS) always precede the development of active malignancies such as multiple myeloma (MM). There is a need for novel biomarkers to identify those patients with such precursor plasma cell disorders who rapidly progress to MM. Plasma-derived extracellular vesicles (EVs) may serve as a reservoir of potential biomarkers that can shed light on the pathogenesis and disease biology of MM. METHODS: This study isolated small EVs (SEVs) and large EVs (LEVs) from the platelet-poor peripheral blood plasma of MGUS (n = 9) and MM (n = 12) patients using the size exclusion chromatography-based method and evaluated their proteome using a label-free proteomics workflow. RESULTS: In total, 2055 proteins were identified in SEVs, while 2794 proteins were identified in LEVs. The transferrin receptor (or CD71) protein was upregulated in both populations of EVs derived from MM patients compared to MGUS patients and was of prognostic significance. Similarly, three isoforms of serum amyloid A (SAA) protein, SAA1, SAA2, and SAA4, were also highly upregulated in SEVs within MM patients relative to MGUS patients. Finally, CD40 expression was also higher in the LEVs derived from MM patients than in MGUS patients. CONCLUSIONS: This study demonstrates the feasibility of successfully isolating both SEVs and LEVs from the peripheral blood of patients with plasma cell disorders and quantifying protein biomarkers within these EVs that could be of prognostic and diagnostic interest.

Lifestyle intervention for metabolic dysfunction-associated fatty liver disease: a 24-h integrated behavior perspective.

INTRODUCTION: The prevalence, health and socioeconomic burden of metabolic dysfunction-associated fatty liver disease (MAFLD) is growing, increasing the need for novel evidence-based lifestyle approaches. Lifestyle is the cornerstone for MAFLD management and co-existing cardiometabolic dysfunction. The aim of this review was to evaluate the evidence for lifestyle management of MAFLD, with a specific lens on 24-hour integrated behaviour and provide practical recommendations for implementation of the evidence. RESULTS: Weight loss ≥ 7-10% is central to lifestyle management; however, liver and cardiometabolic benefits are attainable with improved diet quality and exercise even without weight loss. Lifestyle intervention for MAFLD should consider an integrated '24-h' approach that is cognisant of diet, physical activity/exercise, sedentary behavior, smoking, alcohol intake and sleep. Dietary management emphasises energy deficit and improved diet quality, especially the Mediterranean diet, although sociocultural adaptations to meet preferences should be considered. Increasing physical activity and reducing sedentary behavior can prevent MAFLD, with strongest evidence in MAFLD supporting regular structured moderate-vigorous aerobic exercise for 150-240 min/week. Resistance training in addition to aerobic exercise should be considered and prioritised for those who are losing body mass via diet and/or pharmacological approaches and those with sarcopenia, to minimise bone and lean mass loss. Limited evidence suggests that sleep is important for MAFLD prevention. Emerging novel approaches to diet and exercise may address some of the key barriers to behaviour change (e.g. lack of time, access to resources and social support). FUTURE DIRECTIONS: Large-scale multidisciplinary trials in people with MAFLD with long-term follow-up, that can be scaled up into mainstream healthcare, are required. Future management guidelines should consider the heterogeneity of MAFLD and specialised models of care that coordinate the health workforce to manage the increased and growing MAFLD population.

A Study of Impact of Fixed-Dose Albumin Infusion on Outcome in Patients With Cirrhosis and Infection: A Randomized Open-label Clinical Trial.

Background and aim: Antibiotics and albumin infusion constitute the standard of treatment in patients with decompensated cirrhosis who have spontaneous bacterial peritonitis (SBP). Recent studies have also shown that the use of albumin in patients with advanced liver disease who have infections other than SBP leads to the resolution of acute and chronic liver failure and prevents the development of nosocomial infections. The recommended dose of albumin for these patients is out of reach for many in resource-limited settings like India. The evidence for this recommendation is also scarce. This study aimed to assess the efficacy of a lower dose of albumin infusion in addition to antibiotics on short-term mortality and morbidity in patients with cirrhosis and infections. Patients and methods: A prospective, open-label, randomized control study was performed. Consecutive patients with cirrhosis and infections were randomized in a 2:1 ratio into two groups: group A (116) and group B (58) patients. In addition to antibiotics and standard medical therapy, group A was given albumin in a dose of 20 g/day for five days, and group B was given the recommended dose (1.5 g/kg/body weight and 1 g/kg body weight on days one and three, respectively). The primary outcome was in-hospital mortality. Secondary outcomes were improvements in clinical and laboratory parameters. Results: Except for etiology, all the baseline clinical and laboratory variables in both groups were comparable. The in-hospital mortality in groups A and B was (11 [10.67%] vs. 6 [10.09%], (P = 0.965). The duration of hospitalization, 30-day mortality, improvement in shock and sensorium, and absolute improvements in serum creatinine, international normalized ratio (INR), and serum bilirubin were also comparable in both groups. Conclusion: Low-dose albumin infusion in patients with cirrhosis and infections can have the same results as standard-dose albumin and can be used in resource-limited situations. Clinical trial registration number: CTRI/2020/03/023794.

Role of Computed Tomography Perfusion in Patients with Liver Cirrhosis and Hepatocellular Carcinoma.

Background: There is a lack of data on computed tomography (CT) perfusion parameters in patients with cirrhosis and the vascular changes that occur with increasing severity of cirrhosis, as well as changes that can occur in the remote/background liver parenchyma when hepatocellular carcinoma (HCC) develops. This study aimed to evaluate the association between CT perfusion parameters in the background liver parenchyma in cirrhotic patients with and without HCC. Methods: This prospective study comprised consecutive patients with cirrhosis with or without HCC. A CT perfusion scan of the whole liver was done on a 128-detector row CT scanner in the four-dimensional spiral mode. Arterial liver perfusion (ALP), portal venous perfusion (PVP), hepatic perfusion index (HPI), blood flow (BF), blood volume (BV), and time to peak (TTP) were assessed. The perfusion parameters of the background liver parenchyma (bALP, bPVP, bHPI, bBF, bBV, and bTTP) were compared between the patients with cirrhosis (group I) and cirrhosis with HCC (group II). Perfusion parameters were also compared between the background liver parenchyma and the HCC in group II. Results: Of the 93 patients evaluated during the study period, 60 patients (30 in group I and 30 in group II, mean age, 54.5 years, 53 men) were included in the analysis. Among the perfusion parameters in the background parenchyma, bPVP was lower and bHPI was higher in group II, suggesting increased hepatic arterial perfusion of even the remote background liver parenchyma in patients with HCC (P = 0.001 and P = 0.01, respectively). Perfusion parameters were significantly altered with increasing severity of cirrhosis (based on Child-Pugh class) both within and between groups. Additionally, there were significant differences in all the perfusion parameters between HCC and the background cirrhotic liver. Conclusion: HPI and PVP of background liver parenchyma were significantly different in cirrhosis with and without HCC and also showed a worsening trend with increasing grades of cirrhosis.

TBK1 and IKKε protect target cells from IFNγ-mediated T cell killing via an inflammatory apoptotic mechanism.

Cytotoxic T cells produce interferon gamma (IFNγ), which plays a critical role in anti-microbial and anti-tumor responses. However, it is not clear whether T cell-derived IFNγ directly kills infected and tumor target cells, and how this may be regulated. Here, we report that target cell expression of the kinases TBK1 and IKKε regulate IFNγ cytotoxicity by suppressing the ability of T cell-derived IFNγ to kill target cells. In tumor targets lacking TBK1 and IKKε, IFNγ induces expression of TNFR1 and the Z-nucleic acid sensor, ZBP1, to trigger RIPK1-dependent apoptosis, largely in a target cell-autonomous manner. Unexpectedly, IFNγ, which is not known to signal to NFκB, induces hyperactivation of NFκB in TBK1 and IKKε double-deficient cells. TBK1 and IKKε suppress IKKα/ß activity and in their absence, IFNγ induces elevated NFκB-dependent expression of inflammatory chemokines and cytokines. Apoptosis is thought to be non-inflammatory, but our observations demonstrate that IFNγ can induce an inflammatory form of apoptosis, and this is suppressed by TBK1 and IKKε. The two kinases provide a critical connection between innate and adaptive immunological responses by regulating three key responses: (1) phosphorylation of IRF3/7 to induce type I IFN; (2) inhibition of RIPK1-dependent death; and (3) inhibition of NFκB-dependent inflammation. We propose that these kinases evolved these functions such that their inhibition by pathogens attempting to block type I IFN expression would enable IFNγ to trigger apoptosis accompanied by an alternative inflammatory response. Our findings show that loss of TBK1 and IKKε in target cells sensitizes them to inflammatory apoptosis induced by T cell-derived IFNγ. Short Summary: In the absence of TBK1 and IKKε, target cells are killed by T cells in an IFNγ-dependent manner. In TBK1 and IKKε-deficient cells, IFNγ induces RIPK1-dependent death, as well as hyper-induction of NFκB-dependent inflammatory genes. This suggests that any inhibition of TBK1/IKKε to block type I IFN expression will result in the demise of the cell accompanied by an alternate inflammatory program.

Expert consensus on the diagnosis and treatment of end-stage liver disease complicated by infections.

End-stage liver disease (ESLD) is a life-threatening clinical syndrome and when complicated with infection the mortality is markedly increased. In patients with ESLD, bacterial or fungal infection can induce or aggravate the occurrence or progression of liver decompensation. Consequently, infections are among the most common complications of disease deterioration. There is an overwhelming need for standardized protocols for early diagnosis and appropriate management for patients with ESLD complicated by infections. Asia Pacific region has the largest number of ESLD patients, due to hepatitis B and the growing population of alcohol and NAFLD. Concomitant infections not only add to organ failure and high mortality but also to financial and healthcare burdens. This consensus document assembled up-to-date knowledge and experience from colleagues across the Asia-Pacific region, providing data on the principles as well as evidence-based current working protocols and practices for the diagnosis and treatment of patients with ESLD complicated by infections.

2023 Update of Indian National Association for Study of the Liver Consensus on Management of Intermediate and Advanced Hepatocellular Carcinoma: The Puri III Recommendations.

Hepatocellular carcinoma (HCC) presents significant treatment challenges despite considerable advancements in its management. The Indian National Association for the Study of the Liver (INASL) first published its guidelines to aid healthcare professionals in the diagnosis and treatment of HCC in 2014. These guidelines were subsequently updated in 2019. However, INASL has recognized the need to revise its guidelines in 2023 due to recent rapid advancements in the diagnosis and management of HCC, particularly for intermediate and advanced stages. The aim is to provide healthcare professionals with evidence-based recommendations tailored to the Indian context. To accomplish this, a task force was formed, and a two-day round table discussion was held in Puri, Odisha. During this event, experts in their respective fields deliberated and finalized consensus statements to develop these updated guidelines. The 2023 INASL guidelines offer a comprehensive framework for the diagnosis, staging, and management of intermediate and advanced HCC in India. They represent a significant step forward in standardizing clinical practices nationwide, with the primary objective of ensuring that patients with HCC receive the best possible care based on the latest evidence. The guidelines cover various topics related to intermediate and advanced HCC, including biomarkers of aggressive behavior, staging, treatment options, and follow-up care.