Autologous human preclinical modeling of melanoma interpatient clinical responses to immunotherapeutics.

BACKGROUND: Despite recent advances in immunotherapy, a substantial population of late-stage melanoma patients still fail to achieve sustained clinical benefit. Lack of translational preclinical models continues to be a major challenge in the field of immunotherapy; thus, more optimized translational models could strongly influence clinical trial development. To address this unmet need, we designed a preclinical model reflecting the heterogeneity in melanoma patients' clinical responses that can be used to evaluate novel immunotherapies and synergistic combinatorial treatment strategies. Using our all-autologous humanized melanoma mouse model, we examined the efficacy of a novel engineered interleukin 2 (IL-2)-based cytokine variant immunotherapy. METHODS: To study immune responses and antitumor efficacy for human melanoma tumors, we developed an all-autologous humanized melanoma mouse model using clinically annotated, matched patient tumor cells and peripheral blood mononuclear cells (PBMCs). After inoculating immunodeficient NSG mice with patient tumors and an adoptive cell transfer of autologous PBMCs, mice were treated with anti-PD-1, a novel investigational engineered IL-2-based cytokine (nemvaleukin), or recombinant human IL-2 (rhIL-2). The pharmacodynamic effects and antitumor efficacy of these treatments were then evaluated. We used tumor cells and autologous PBMCs from patients with varying immunotherapy responses to both model the diversity of immunotherapy efficacy observed in the clinical setting and to recapitulate the heterogeneous nature of melanoma. RESULTS: Our model exhibited long-term survival of engrafted human PBMCs without developing graft-versus-host disease. Administration of an anti-PD-1 or nemvaleukin elicited antitumor responses in our model that were patient-specific and were found to parallel clinical responsiveness to checkpoint inhibitors. An evaluation of nemvaleukin-treated mice demonstrated increased tumor-infiltrating CD4+ and CD8+ T cells, preferential expansion of non-regulatory T cell subsets in the spleen, and significant delays in tumor growth compared with vehicle-treated controls or mice treated with rhIL-2. CONCLUSIONS: Our model reproduces differential effects of immunotherapy in melanoma patients, capturing the inherent heterogeneity in clinical responses. Taken together, these data demonstrate our model's translatability for novel immunotherapies in melanoma patients. The data are also supportive for the continued clinical investigation of nemvaleukin as a novel immunotherapeutic for the treatment of melanoma.

Determining Surface Areas and Pore Volumes of Metal-Organic Frameworks.

The surface area and pore volume of a metal-organic framework (MOF) can provide insight into its structure and potential applications. Both parameters are commonly determined using the data from nitrogen sorption experiments; commercial instruments to perform these measurements are also widely available. These instruments will calculate structural parameters, but it is essential to understand how to select input data and when calculation methods apply to the sample MOF. This article outlines the use of the Brunauer-Emmett-Teller (BET) method and Barrett-Joyner-Halenda (BJH) method for the calculation of surface area and pore volume, respectively. Example calculations are performed on the representative MOF UiO-66. Although widely applicable to MOFs, sample materials and adsorption data must meet certain criteria for the calculated results to be considered accurate, in addition to proper sample preparation. The assumptions and limitations of these methods are also discussed, along with alternative and complementary techniques for the MOF pore space characterization.

Multi-modal cryo-EM reveals trimers of protein A10 to form the palisade layer in poxvirus cores.

Poxviruses are among the largest double-stranded DNA viruses, with members such as variola virus, monkeypox virus and the vaccination strain vaccinia virus (VACV). Knowledge about the structural proteins that form the viral core has remained sparse. While major core proteins have been annotated via indirect experimental evidence, their structures have remained elusive and they could not be assigned to individual core features. Hence, which proteins constitute which layers of the core, such as the palisade layer and the inner core wall, has remained enigmatic. Here we show, using a multi-modal cryo-electron microscopy (cryo-EM) approach in combination with AlphaFold molecular modeling, that trimers formed by the cleavage product of VACV protein A10 are the key component of the palisade layer. This allows us to place previously obtained descriptions of protein interactions within the core wall into perspective and to provide a detailed model of poxvirus core architecture. Importantly, we show that interactions within A10 trimers are likely generalizable over members of orthopox- and parapoxviruses.

Mid-infrared supermirrors with finesse exceeding 400 000.

For trace gas sensing and precision spectroscopy, optical cavities incorporating low-loss mirrors are indispensable for path length and optical intensity enhancement. Optical interference coatings in the visible and near-infrared (NIR) spectral regions have achieved total optical losses below 2 parts per million (ppm), enabling a cavity finesse in excess of 1 million. However, such advancements have been lacking in the mid-infrared (MIR), despite substantial scientific interest. Here, we demonstrate a significant breakthrough in high-performance MIR mirrors, reporting substrate-transferred single-crystal interference coatings capable of cavity finesse values from 200 000 to 400 000 near 4.5 µm, with excess optical losses (scatter and absorption) below 5 ppm. In a first proof-of-concept demonstration, we achieve the lowest noise-equivalent absorption in a linear cavity ring-down spectrometer normalized by cavity length. This substantial improvement in performance will unlock a rich variety of MIR applications for atmospheric transport and environmental sciences, detection of fugitive emissions, process gas monitoring, breath-gas analysis, and verification of biogenic fuels and plastics.

Does Mixed Linker-Induced Surface Heterogeneity Impact the Accuracy of IAST Predictions in UiO-66-NH2?

To move toward more energy-efficient adsorption-based processes, there is a need for accurate multicomponent data under realistic conditions. While the Ideal Adsorbed Solution Theory (IAST) has been established as the preferred prediction method due to its simplicity, limitations and inaccuracies for less ideal adsorption systems have been reported. Here, we use amine-functionalized derivatives of the UiO-66 structure to change the extent of homogeneity of the internal surface toward the adsorption of the two probe molecules carbon dioxide and ethylene. Although it might seem plausible that more functional groups lead to more heterogeneity and, thus, less accurate predictions by IAST, we find a mixed-linker system with increased heterogeneity in terms of added adsorption sites where IAST predictions and experimental loadings agree exceptionally well. We show that incorporating uncertainty analysis into predictions with IAST is important for assessing the accuracy of these predictions. Energetic investigations combined with Grand Canonical Monte Carlo simulations reveal almost homogeneous carbon dioxide but heterogeneous ethylene adsorption in the mixed-linker material, resulting in local, almost pure phases of the individual components.

The predictive value of comorbidities on postoperative complication rates and overall survival in left-sided oncological colorectal resections: a multicentre cohort study.

INTRODUCTION: Surgical- and nonsurgical complications significantly worsen postoperative outcomes, and identification of patients at risk is crucial to improve care. This study investigated whether comorbidities, graded by the Charlson Comorbidity Index (CCI), impact complication rates and impair long-term outcome in a cohort of left-sided colorectal resections. METHODS: Retrospective analysis of patients undergoing oncological left-sided colorectal resections due to colorectal cancer between 01/2015 and 12/2020 in two referral centers in Austria using electronic medical records and national statistical bureau survival data. Patients with recurrent disease, peritoneal carcinomatosis, and emergency surgeries were excluded. Comorbidities were assessed using the CCI, and complication severity was defined by the Clavien-Dindo classification (CDC). Logistic regression analysis was performed to identify factors influencing the risk for postoperative complications, and overall survival was assessed using data from the national statistics bureau. RESULTS: A total of 471 patients were analyzed. Multinominal logistic regression analysis identified a CCI greater than or equal to 6 ( P =0.049; OR 1.59, 95% CI: 1.10-2.54) and male sex ( P =0.022; OR 1.47, 95% CI: 1.21-2.98) as independent risk factors for major complications. While patients with a high CCI had the worst postoperative survival rates, perioperative complications only impacted on overall survival in patients with low CCIs, but not in patients with high CCIs. CONCLUSION: Although a high CCI is a risk factor for major postoperative complications, the presence of comorbidities should not result in withholding surgery.

Adaptive Pore Opening to Form Tailored Adsorption Sites in a Cooperatively Flexible Framework Enables Record Inverse Propane/Propylene Separation.

A proposed low-energy alternative to the separation of alkanes from alkenes by energy-intensive cryogenic distillation is separation by porous adsorbents. Unfortunately, most adsorbents preferentially take up the desired, high-value major component alkene, requiring frequent regeneration. Adsorbents with inverse selectivity for the minor component alkane would enable the direct production of purified, reagent-grade alkene, greatly reducing global energy consumption. However, such materials are exceedingly rare, especially for propane/propylene separation. Here, we report that through adaptive and spontaneous pore size and shape adaptation to optimize an ensemble of weak noncovalent interactions, the structurally responsive metal-organic framework CdIF-13 (sod-Cd(benzimidazolate)2) exhibits inverse selectivity for propane over propylene with record-setting separation performance under industrially relevant temperature, pressure, and mixture conditions. Powder synchrotron X-ray diffraction measurements combined with first-principles calculations yield atomic-scale insight and reveal the induced fit mechanism of adsorbate-specific pore adaptation and ensemble interactions between ligands and adsorbates. Dynamic column breakthrough measurements confirm that CdIF-13 displays selectivity under mixed-component conditions of varying ratios, with a record measured selectivity factor of α ≈ 3 at 95:5 propylene:propane at 298 K and 1 bar. When sequenced with a low-cost rigid adsorbent, we demonstrated the direct purification of propylene under ambient conditions. This combined atomic-level structural characterization and performance testing firmly establishes how cooperatively flexible materials can be capable of unprecedented separation factors.

GLP-2 Improves Hepatic Inflammation and Fibrosis in Mdr2-/- Mice Via Activation of NR4a1/Nur77 in Hepatic Stellate Cells and Intestinal FXR Signaling.

BACKGROUND & AIMS: Glucagon-like peptide (GLP)-2 may exert antifibrotic effects on hepatic stellate cells (HSCs). Thus, we aimed to test whether application of the GLP-2 analogue teduglutide has hepatoprotective and antifibrotic effects in the Mdr2/Abcb4-/- mouse model of sclerosing cholangitis displaying hepatic inflammation and fibrosis. METHODS: Mdr2-/- mice were injected daily for 4 weeks with teduglutide followed by gene expression profiling (bulk liver; isolated HSCs) and immunohistochemistry. Activated HSCs (LX2 cells) and immortalized human hepatocytes and human intestinal organoids were treated with GLP-2. mRNA profiling by reverse transcription polymerase chain reaction and electrophoretic mobility shift assay using cytosolic and nuclear protein extracts was performed. RESULTS: Hepatic inflammation, fibrosis, and reactive cholangiocyte phenotype were improved in GLP-2-treated Mdr2-/- mice. Primary HSCs isolated from Mdr2-/- mice and LX2 cells exposed to GLP-2 in vitro displayed significantly increased mRNA expression levels of NR4a1/Nur77 (P < .05). Electrophoretic mobility shift assay revealed an increased nuclear NR4a1 binding after GLP-2 treatment in LX2 cells. Moreover, GLP-2 alleviated the Tgfß-mediated reduction of NR4a1 nuclear binding activity. In vivo, GLP-2 treatment of Mdr2-/- mice resulted in increased intrahepatic levels of muricholic acids (accordingly Cyp2c70 mRNA expression was significantly increased), and in reduced mRNA levels of Cyp7a1 and FXR. Serum Fgf15 levels were increased in Mdr2-/- mice treated with GLP-2. Accordingly, GLP-2 treatment of human intestinal organoids activated their FXR-FGF19 signaling axis. CONCLUSIONS: GLP-2 treatment increased NR4a1/Nur77 activation in HSCs, subsequently attenuating their activation. GLP-2 promoted intestinal Fxr-Fgf15/19 signaling resulting in reduced Cyp7a1 and increased Cyp2c70 expression in the liver, contributing to hepatoprotective and antifibrotic effects of GLP-2 in the Mdr2-/- mouse model.

Retrospective Evaluation of a Single Surgeon's Learning Curve of Robot-Assisted Radical Cystectomy with Intracorporeal Urinary Diversion via Ileal Conduit.

Robot-assisted radical cystectomy with intracorporeal urinary diversion (iRARC) is increasingly being performed instead of open surgery. A criticism of this technique is the long learning curve, but limited data are available on this topic. At our center, the transition from open radical cystectomy (ORC) to iRARC began in May 2017. A retrospective analysis was conducted on the initial 53 cases of robot-assisted cystectomy with intracorporeal urinary diversion via ileal conduit, which were performed by one single surgeon. The patients were divided into four consecutive groups according to the surgeon's increasing experience, and perioperative parameters were analyzed as a surrogate for the learning curve. Over the course of the learning curve, a decline in median operation time from 415 to 361 min (p = 0.02), blood loss from 400 to 200 mL (p = 0.01), and minor complications from 71% to 15% (p = 0.02) was observed. No significant difference in overall and major complications, length of hospital stay, and total lymph node yield was shown. During the initial period of the learning curve, only the less complex cases were operated on using robotic surgery, while the more challenging ones were handled through open surgery. After experience with 28 cases, no more cystectomies were performed through open surgery. This led to an increase in operation time and length of hospital stay, as well as a higher incidence of both minor and overall complications among cases 28-40. After 40 cases, a significant decrease in these parameters was observed again. Our analysis demonstrated that operation time, blood loss, and minor complications decrease with increasing surgical experience in iRARC, while suggesting that technically challenging cases should be operated on after experience with 40 robotic cystectomies.

Surprising Use of the Business Innovation Bass Diffusion Model To Accurately Describe Adsorption Isotherm Types I, III, and V.

Using adsorption isotherm data to determine heats of adsorption or predict mixture adsorption using the ideal adsorbed solution theory (IAST) relies on accurate fits of the data with continuous, mathematical models. Here, we derive an empirical two-parameter model to fit isotherm data of IUPAC types I, III, and V in a descriptive way based on the Bass model for innovation diffusion. We report 31 isotherm fits to existing literature data covering all six types of isotherms, various adsorbents, such as carbons, zeolites, and metal-organic frameworks (MOFs), as well as different adsorbing gases (water, carbon dioxide, methane, and nitrogen). We find several cases, especially for flexible MOFs, where previously reported isotherm models reached their limits and either failed to fit the data or could not sufficiently be fitted due to stepped type V isotherms. Moreover, in two instances, models specifically developed for distinct systems are fitted with a higher R2 value compared to the models in the original reports. Using these fits, it is demonstrated how the new Bingel-Walton isotherm can be used to qualitatively assess the hydrophilic or hydrophobic behavior of porous materials from the relative magnitude of the two fitting parameters. The model can also be employed to find matching heats of adsorption values for systems with isotherm steps using one, continuous fit instead of partial, stepwise fits or interpolation. Additionally, using our single, continuous fit to model stepped isotherms in IAST mixture adsorption predictions leads to good agreement with the results from the osmotic framework adsorbed solution theory that was specifically developed for these systems using a stepwise, approximate fitting, which is yet far more complex. Our new isotherm equation accomplishes all of these tasks with only two fitted parameters, providing a simple, accurate method for modeling a variety of adsorption behavior.

Endoplasmic reticulum stress in the intestinal epithelium initiates purine metabolite synthesis and promotes Th17 cell differentiation in the gut.

Intestinal IL-17-producing T helper (Th17) cells are dependent on adherent microbes in the gut for their development. However, how microbial adherence to intestinal epithelial cells (IECs) promotes Th17 cell differentiation remains enigmatic. Here, we found that Th17 cell-inducing gut bacteria generated an unfolded protein response (UPR) in IECs. Furthermore, subtilase cytotoxin expression or genetic removal of X-box binding protein 1 (Xbp1) in IECs caused a UPR and increased Th17 cells, even in antibiotic-treated or germ-free conditions. Mechanistically, UPR activation in IECs enhanced their production of both reactive oxygen species (ROS) and purine metabolites. Treating mice with N-acetyl-cysteine or allopurinol to reduce ROS production and xanthine, respectively, decreased Th17 cells that were associated with an elevated UPR. Th17-related genes also correlated with ER stress and the UPR in humans with inflammatory bowel disease. Overall, we identify a mechanism of intestinal Th17 cell differentiation that emerges from an IEC-associated UPR.

Evaluation of Intestinal Fibrosis with 68Ga-FAPI PET/MR Enterography in Crohn Disease.

Background In Crohn disease, differentiation between active intestinal inflammation and fibrosis has implications for treatment, but current imaging modalities are not reliably accurate. Purpose To evaluate the predictive value of gallium 68 (68Ga)-labeled fibroblast activation protein inhibitor (FAPI) PET/MR enterography for the assessment of bowel wall fibrosis in Crohn disease. Materials and Methods In this prospective single-center study, consecutive participants with Crohn disease and obstructive symptoms underwent preoperative 68Ga-FAPI PET/MR enterography from May 2021 to January 2022. Histopathologic analysis of resected bowel segments was performed to grade active inflammation (A0-A2) and fibrosis (F0-F2), which served as the reference standard. The fibroblast activation protein (FAP) expression in bowel wall layers was analyzed immunohistochemically for each layer. 68Ga-FAPI-derived maximum standardized uptake value (SUVmax) was compared with histopathologic results by using mixed-model analysis of variance and Bonferroni-corrected post hoc tests. Results In 14 participants (mean age, 45 years ± 9 [SD]; 10 men), fibrosis was diagnosed histopathologically in 28 of 51 bowel segments (grade F1, n = 14; grade F2, n = 14). Mean SUVmax was higher in segments with fibrosis than without (7.6 vs 2.0; P < .001). In severe fibrosis, mean SUVmax was higher than in mild to moderate fibrosis (8.9 ± 0.9 vs 6.2 ± 0.9; P = .045). Bowel segments with isolated active inflammation had lower mean 68Ga-FAPI uptake than segments with combined active inflammation and fibrosis (SUVmax, 3.2 ± 0.4 vs 8.1 ± 0.1; P = .005). With an SUVmax cutoff value of 3.5, the area under the receiver operating characteristic curve for the prediction of fibrosis was 0.94 (95% CI: 0.9, 1.0), with sensitivity of 26 of 28 segments (93%) and specificity of five of six segments (83%). 68Ga-FAPI-derived SUVmax correlated with FAP expression across all bowel layers (R2 = 0.50, P < .001). Conclusion Higher gallium 68 fibroblast activation protein inhibitor uptake at PET/MR enterography was associated with histopathologically assessed bowel wall fibrosis in participants with Crohn disease, suggesting diagnostic potential for treatment decisions. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by O'Shea in this issue.

Circulating caspase-cleaved cytokeratin 18 correlates with tumour burden and response to therapy in patients with colorectal cancer liver metastasis.

BACKGROUND AND AIMS: Systemic chemotherapy followed by hepatic resection is the treatment of choice for patients with colorectal cancer liver metastasis (CRCLM) but reliable biomarkers predicting response to therapy are needed. Spontaneous apoptosis of single tumour cells is common in CRCLM. We explored the potential of circulating apoptosis markers to predict treatment response. MATERIALS AND METHODS: Fifty-eight patients with CRCLM or hepatocellular carcinoma (HCC) were included in this study. Tumour tissue and blood samples were obtained before and after initiation of chemotherapy. Immunohistochemistry and ELISA assays were utilized to quantify the apoptosis marker caspase-cleaved cytokeratin 18 (M30) in tissue and circulation. RESULTS: CRCLM tissues showed more apoptotic tumour cells than HCC, or healthy liver. This was associated with elevated levels of circulating M30 (median = 244 U/l vs. 37 U/l in healthy controls, p = 0.009) which correlated with tumour volume (r2 = 0.92). Patients with progressive disease during chemotherapy showed higher M30 levels before therapy than responders (745 U/l vs. 136 U/l, p = 0.016). The predictive potential of M30 was higher than that of the tumour markers CA19-9 or CEA (AUC: 0.93, 0.63, and 0.78, respectively). CONCLUSIONS: Apoptotic tumour cells release cellular debris into the circulation, which provides information about tumour size and vitality.

Chronic CD40L blockade is required for long-term cardiac allograft survival with a clinically relevant CTLA4-Ig dosing regimen.

Introduction: In de-novo kidney transplantation, the CTLA4-Ig fusion protein belatacept is associated with improved graft function but also an increased risk of acute rejection compared to calcineurin inhibitor therapy. The combination with a second costimulation blocker could potentially improve outcome while avoiding calcineurin inhibitor toxicity. The aim of this study was to define the conditions under which the combination of CTLA4-Ig and CD40L blockade leads to rejection-free permanent graft survival in a stringent murine heart transplantation model. Methods: Naïve wild-type or CD40L (CD154) knock-out mice received a fully mismatched BALB/c cardiac allograft. Selected induction and maintenance protocols for CTLA4-Ig and blocking αCD40L monoclonal antibodies (mAB) were investigated. Graft survival, rejection severity and donor-specific antibody (DSA) formation were assessed during a 100-day follow-up period. Results and Discussion: Administering αCD40L mAb as monotherapy at the time of transplantation significantly prolonged heart allograft survival but did not further improve the outcome when given in addition to chronic CTLA4-Ig therapy (which prolongs graft survival to a median of 22 days). Likewise, chronic αCD40L mAb therapy (0.5mg) combined with perioperative CTLA4-Ig led to rejection in a proportion of mice and extensive histological damage, despite abrogating DSA formation. Only the permanent interruption of CD40-CD40L signaling by using CD40L-/- recipient mice or by chronic αCD40L administration synergized with chronic CTLA4-Ig to achieve long-term allograft survival with preserved histological graft integrity in all recipients without DSA formation. The combination of α-CD40L and CTLA4-Ig works most effectively when both therapeutics are administered chronically.

A purine metabolic checkpoint that prevents autoimmunity and autoinflammation.

Still's disease, the paradigm of autoinflammation-cum-autoimmunity, predisposes for a cytokine storm with excessive T lymphocyte activation upon viral infection. Loss of function of the purine nucleoside enzyme FAMIN is the sole known cause for monogenic Still's disease. Here we discovered that a FAMIN-enabled purine metabolon in dendritic cells (DCs) restrains CD4+ and CD8+ T cell priming. DCs with absent FAMIN activity prime for enhanced antigen-specific cytotoxicity, IFNγ secretion, and T cell expansion, resulting in excessive influenza A virus-specific responses. Enhanced priming is already manifest with hypomorphic FAMIN-I254V, for which ∼6% of mankind is homozygous. FAMIN controls membrane trafficking and restrains antigen presentation in an NADH/NAD+-dependent manner by balancing flux through adenine-guanine nucleotide interconversion cycles. FAMIN additionally converts hypoxanthine into inosine, which DCs release to dampen T cell activation. Compromised FAMIN consequently enhances immunosurveillance of syngeneic tumors. FAMIN is a biochemical checkpoint that protects against excessive antiviral T cell responses, autoimmunity, and autoinflammation.

Clinical algorithms for the prevention of variceal bleeding and rebleeding in patients with liver cirrhosis.

Portal hypertension (PH), a common complication of liver cirrhosis, results in development of esophageal varices. When esophageal varices rupture, they cause significant upper gastrointestinal bleeding with mortality rates up to 20% despite state-of-the-art treatment. Thus, prophylactic measures are of utmost importance to improve outcomes of patients with PH. Several high-quality studies have demonstrated that non-selective beta blockers (NSBBs) or endoscopic band ligation (EBL) are effective for primary prophylaxis of variceal bleeding. In secondary prophylaxis, a combination of NSBB + EBL should be routinely used. Once esophageal varices develop and variceal bleeding occurs, standardized treatment algorithms should be followed to minimize bleeding-associated mortality. Special attention should be paid to avoidance of overtransfusion, early initiation of vasoconstrictive therapy, prophylactic antibiotics and early endoscopic therapy. Pre-emptive transjugular intrahepatic portosystemic shunt should be used in all Child C10-C13 patients experiencing variceal bleeding, and potentially in Child B patients with active bleeding at endoscopy. The use of carvedilol, safety of NSBBs in advanced cirrhosis (i.e. with refractory ascites) and assessment of hepatic venous pressure gradient response to NSBB is discussed. In the present review, we give an overview on the rationale behind the latest guidelines and summarize key papers that have led to significant advances in the field.

Simple approach for extending the ambiguity-free range of dual-comb ranging.

Dual-comb (DC) ranging is an established method for high-precision and high-accuracy distance measurements. It is, however, restricted by an inherent length ambiguity and the requirement for complex control loops for comb stabilization. Here, we present a simple approach for expanding the ambiguity-free measurement length of DC ranging by exploiting the intrinsic intensity modulation of a single-cavity dual-color DC for simultaneous time-of-flight and DC distance measurements. This measurement approach enables the measurement of distances up to several hundred kilometers with the precision and accuracy of a DC interferometric setup while providing a high data acquisition rate (≈2kHz) and requiring only the repetition rate of one of the combs to be stabilized.

Individualized treatment options for patients with non-cirrhotic and cirrhotic liver disease.

The obesity pandemic has led to a significant increase in patients with metabolic dysfunction-associated fatty liver disease (MAFLD). While dyslipidemia, type 2 diabetes mellitus and cardiovascular diseases guide treatment in patients without signs of liver fibrosis, liver related morbidity and mortality becomes relevant for MAFLD's progressive form, non-alcoholic steatohepatitis (NASH), and upon development of liver fibrosis. Statins should be prescribed in patients without significant fibrosis despite concomitant liver diseases but are underutilized in the real-world setting. Bariatric surgery, especially Y-Roux bypass, has been proven to be superior to conservative and/or medical treatment for weight loss and resolution of obesity-associated diseases, but comes at a low but existent risk of surgical complications, reoperations and very rarely, paradoxical progression of NASH. Once end-stage liver disease develops, obese patients benefit from liver transplantation (LT), but may be at increased risk of perioperative infectious complications. After LT, metabolic comorbidities are commonly observed, irrespective of the underlying liver disease, but MAFLD/NASH patients are at even higher risk of disease recurrence. Few studies with low patient numbers evaluated if, and when, bariatric surgery may be an option to avoid disease recurrence but more high-quality studies are needed to establish clear recommendations. In this review, we summarize the most recent literature on treatment options for MAFLD and NASH and highlight important considerations to tailor therapy to individual patient's needs in light of their risk profile.