Enzyme Abnormalities Research Articles

RNA Editing in Cancer Progression.

Coding and noncoding RNA molecules play their roles in ensuring cell function and tissue homeostasis in an ordered and systematic fashion. RNA chemical modifications can occur both at bases and ribose sugar, and, similarly to DNA and histone modifications, can be written, erased, and recognized by the corresponding enzymes, thus modulating RNA activities and fine-tuning gene expression programs. RNA editing is one of the most prevalent and abundant forms of post-transcriptional RNA modification in normal physiological processes. By altering the sequences of mRNAs, it makes them different from the corresponding genomic template. Hence, edited mRNAs can produce protein isoforms that are functionally different from the corresponding genome-encoded variants. Abnormalities in regulatory enzymes and changes in RNA-modification patterns are closely associated with the occurrence and development of various human diseases, including cancer. To date, the roles played by RNA modifications in cancer are gathering increasing interest. In this review, we focus on the role of RNA editing in cancer transformation and provide a new perspective on its impact on tumorigenesis, by regulating cell proliferation, differentiation, invasion, migration, stemness, metabolism, and drug resistance.

A case of Brugada phenocopy alteration induced by immune checkpoint inhibitors

Immunotherapy has shown remarkable efficacy in various cancer treatments. However, enhanced T-cell immune surveillance can lead to aberrant immune responses, resulting in severe immune checkpoint inhibitor-related adverse events. This is a case report of a patient previously treated with immune checkpoint inhibitors who presented with ST-segment elevation without abnormal troponin and cardiac enzyme spectrum test results. Cardiac toxicity of immune checkpoint inhibitors mainly manifests as acute immune-mediated myocarditis. While Brugada phenocopy is commonly caused by fever, electrolyte abnormalities, tricyclic/tetracyclic antidepressants, and marijuana use, we suspect that it was induced by immune checkpoint inhibitors in the current case.

FRI146 Stereotactic Ablative Radiotherapy As A Local Valuable Therapeutic Procedure To Control Aldosterone-Secreting Adrenocortical Carcinoma

Abstract Disclosure: L.M. Mermejo: None. R.H. Zanella: None. L. Cocicov: None. C.A. Molina: None. S. Tucci Jr: None. J. Elias Jr: None. V.F. Muglia: None. G. Viani: None. P.C. Elias: None. A.C. Moreira: None. M. De Castro: None. Aldosterone-secreting adrenocortical carcinomas (ACC) are rare and usually described as large tumors. We report the case of a 44-year-old man referred to our University Hospital presenting back pain, muscular weakness and hypokalemia. A year earlier, hypertension had been diagnosed triggered by the investigation of daily headaches. Throughout this period, hypertension had been refractory to antihypertensives and patient also showed progressive weight loss of 10 kg. At the time of presentation, the patient had no signs of cortisol or androgen excess, his blood pressure was 180x120 mmHg, and there was no peripheral edema or abdominal mass detected. Due to abdominal pain and liver enzymes abnormalities, an abdominal CT was performed and revealed a heterogeneously 10 x 8 x 6 cm (volume: 256 cm³) left adrenal mass compressing the left renal vein with invasion through the inferior cava vein and extending to the liver caudate lobe. He also had a sodium of 143 mmol/L, potassium of 1.2 mmol/L and metabolic alkalosis. The serum aldosterone level of 75 ng/dL and plasma direct renin concentration < 2 mIU/L whereas urinary fractionated metanephrines were within normal limits, suggesting a probable aldosterone-secreting ACC. His family history was negative for hypertension or adrenal diseases. The patient was initially treated with spironolactone and potassium replacement with clinical improvement and an open adrenalectomy was proposed. However, patient professed to be Jehovah's Witnesses and refused the surgery due to the risk of blood transfusions. Therefore, the patient received mitotane but owing to hepatotoxity, the drug was withdrawn after two months of follow-up. A follow up abdominal MRI after 10 months of diagnosis revealed an increase in the mass (12 x 8 x 9 cm; volume: 460 cm³) and, now, extending to the left kidney. A CT-guided percutaneous biopsy showed an ACC with a Weiss score of three and the immunohistochemistry was positive for vimentin, inhibin and MART-1/ Melan A. After a multidisciplinary discussion, it was proposed to use stereotactic ablative radiotherapy (SABR) as an alternative option. The patient accepted SABR, being treated with 35Gy/5 fractions. During the follow-up, the patients had a progressive improvement of pain complaints, reduction of tumor burden after eighteen months on control abdomen CT (9.1 x 4.9 x 8.7 cm; volume of 202 cm³), improvement of blood pressure and hypokalemia levels, reduction of antihypertensive drugs defined daily dose and potassium replacement as well as reduction of a serum aldosterone to 13 ng/dL and increased of paired renin to 25 mU/L. This is the first published report of a pure aldosterone-producing ACC patient receiving SABR. The response was significant, indicating that the use of SABR should be considered as an alternative for local treatment of aldosterone-secreting ACC when the surgery cannot be indicated. Presentation: Friday, June 16, 2023

A chemical catalyst enabling histone acylation with endogenous acyl-CoA

Life emerges from a network of biomolecules and chemical reactions catalyzed by enzymes. As enzyme abnormalities are often connected to various diseases, a chemical catalyst promoting physiologically important intracellular reactions in place of malfunctional endogenous enzymes would have great utility in understanding and treating diseases. However, research into such small-molecule chemical enzyme surrogates remains limited, due to difficulties in developing a reactive catalyst capable of activating inert cellular metabolites present at low concentrations. Herein, we report a small-molecule catalyst, mBnA, as a surrogate for a histone acetyltransferase. A hydroxamic acid moiety of suitable electronic characteristics at the catalytic site, paired with a thiol-thioester exchange process, enables mBnA to activate endogenous acyl-CoAs present in low concentrations and promote histone lysine acylations in living cells without the addition of exogenous acyl donors. An enzyme surrogate utilizing cellular metabolites will be a unique tool for elucidation of and synthetic intervention in the chemistry of life and disease.

Retrospective Analysis of Liver Enzyme Abnormalities in Patients Prescribed Terbinafine and Itraconazole for Onychomycosis.

Introduction Onychomycosis (OM) is defined as a nail fungal infection. Its prevalence increases with advancing age. Human-to-human transmission makes it a serious public health risk. Although OM is not a life-threatening disease, it has a detrimental effect on patients' quality of life. Due to the long therapy duration and potential side effects of systemic antifungal medicines, physicians may be reluctant to treat OM orally. In this study, we aimed to evaluate the effect of terbinafine and itraconazole on liver transaminases, the side effects of these treatments, and patients' adherence to systemic treatment of OM. Methods This is a retrospective study conducted in our dermatology department (Ordu University, Ordu) between June 2020 and October 2021. Hospital records were analyzed, and patients with the diagnosis of tinea unguium (ICD code B35.1) were investigated. Patients who were prescribed terbinafine or itraconazole were included in the study. Following a clinical diagnosis of OM, the researchers first tried to confirm it through direct microscopic examination with potassium hydroxide (KOH). If the direct microscopic examination was negative but the suspicion about OM continued, confirmation was done through a fungal culture. Results This study included 735 patients, of whom 409 (55.6%) were female and 326 (44.4%) were male. The research covered all of the patients who were given one of these two medications. To find patients who could apply to other hospitals, the Turkish National Healthcare System was checked in addition to hospital information. To identify patients who could apply to other healthcare institutions, all hospitals share their data with this national healthcare system. Terbinafine was used by 433 patients (76.4%), 75 patients (13.2%), and 37 patients (6.5%), respectively, for one, two, and three months. A total of 119 patients (70.8%) took itraconazole for a month, 32 patients (19%) took it for two months, and four patients (2.33%) took it for three months. At the end of the first month, the proportion of the patients with elevated aspartate transaminase (AST) levels was 5.2% for terbinafine and 0% for itraconazole. Eighteen (8.4%) patients with terbinafine had elevated alanine aminotransferase (ALT) levels, and four patients (7.5%) who were on itraconazole treatment had high ALT levels. None of the patients reported cutaneous adverse drug reactions, gastrointestinal disturbances, or headaches due to OM treatment. Also, no patients discontinued treatment because of hepatotoxicity. Conclusion In this study, none of the patients discontinued the treatment because of hepatotoxicity. According to the results of this study, oral terbinafine and itraconazole can be used with close follow-up. Baseline and regular laboratory monitoring for AST and ALT should be done to monitor liver toxicity with terbinafine and itraconazole. Besides, we did not observe other side effects like cutaneous or cardiac side effects or drug-drug interactions.

Cystic fibrosis liver disease in the post-modulator era.

Highly effective modulators of cystic fibrosis transmembrane conductance regulator (CFTR) function have had dramatic impact on pulmonary and nutritional outcomes in persons with cystic fibrosis (pwCF). The impact on liver disease in pwCF was not the focus of the registration trials. The purpose of this review is to assess the current literature on the impact of HEMT on liver disease, progression, regression, and safety. Short-term studies of HEMT in pwCF have shown that there is no significant impact on the frequency of liver enzyme abnormalities. There is no evidence for significant improvement in liver enzymes over time on HEMT therapy. There is conflicting data on improvement in liver fibrosis determined by fibrosis indices (APRI and GPR) or elastography. One study showed improvement, and another showed worsening in younger (<20 years old) pwCF. There are reports of resolution or improvement in hepatic steatosis. There are rare reports of severe acute hepatitis and one report of hepatic decompensation leading to liver transplantation due to drug-induced liver disease. HEMT have not been shown to have a significant impact on improving liver disease or preventing fibrosis with short-term therapy. Longer studies are needed to assess the impact of HEMT on liver disease in pwCF.

Acrochordons as a cutaneous sign of impaired carbohydrate metabolism, hyperlipidemia, liver enzyme abnormalities and hypertension: A case-control study.

Acrochordons are common and benign skin tumours. A few studies with contradictory results have been reported regarding the abnormalities of carbohydrate and/or lipid metabolisms in patients with acrochordons. We aimed to determine if the presence of acrochordons could be a marker of diabetes, hyperlipidemia, liver enzyme abnormalities and hypertension by comparing with a control group. A total of 110 patients having two or more acrochordons and age- and gender-matched 110 controls were included in the study. Localization, size and the total number of acrochordons were recorded in the patient group. Fasting plasma glucose (FPG), serum lipids and liver enzyme levels were tested in patient and controls. All participants underwent a standard 2-h oral glucose tolerance test with 75 g glucose. Diabetes mellitus and impaired glucose intolerance were diagnosed according to the American Diabetes Association criteria. Arterial blood pressures were measured in two groups. A total of 56 patients and 10 controls were diagnosed with overt DM. Thirteen per cent of the patients and 9% of controls had an impaired glucose tolerance test. The difference was statistically significant for the diagnosis of DM and not significant for the impaired glucose tolerance. The mean levels of FPG, total cholesterol, LDL cholesterol, triglyceride, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase and alkaline phosphatase were significantly higher in patients than those in controls. Furthermore, serum levels of HDL were less in patients. Patients with acrochordons had higher systolic and diastolic blood pressures than controls. The results of our study suggest that acrochordons may represent a cutaneous sign for impaired carbohydrate or lipid metabolism, liver enzyme abnormalities and hypertension.

A descriptive study of treatment-seeking adults with avoidant/restrictive food intake disorder at residential and inpatient levels of care

ABSTRACT Most research on avoidant/restrictive food intake disorder (ARFID) has been with children and adolescents, while the limited research on adults with ARFID has been in the domain of outpatient treatment. This descriptive study sought to explore psychological characteristics (N = 45; measured with self-report questionnaires) and physiological characteristics (N = 66; e.g. vital signs, bloodwork) at admission for 66 adults with ARFID seeking residential and inpatient levels of care. While adults with ARFID presented with significant food restriction as well as mild depressive symptoms, high anxiety symptoms, and impaired quality of life, patients presented with mostly normal physiology, except for low bone density, and trivial abnormalities in serum creatinine and hepatic enzymes. Patients in this sample were most likely to endorse fear of aversive consequences, especially those for whom ARFID symptoms had first arisen in adulthood. These results note the psychological impairment and relative physiological normalcy of treatment-seeking adults with ARFID at the outset of residential and inpatient treatment, identifying future treatment and outcome research priorities in this understudied population.

Mechanisms of Action of Heavy Metals, Related with Abnormal Protein and Enzyme Activity in Male Infertility Aspect

Mechanisms of Action of Heavy Metals, Related with Abnormal Protein and Enzyme Activity in Male Infertility Aspect

Approach to Rickets: Is It Calciopenic or Phosphopenic?

Rickets is a childhood disorder of decreased mineralization of bone tissue. It is either calciopenic or phosphopenic, according to the deficient mineral. Calcium, phosphate, and vitamin D metabolism should be known to understand the pathophysiology of rickets. A deficiency of calcium or vitamin D can be caused by several conditions. These conditions lead to defective osteoid mineralization, impaired chondrocyte differentiation, and apoptosis in the growth plate, resulting in clinical and radiological findings of rickets. Rickets developing as a result of vitamin D deficiency is the most frequently encountered form. Vitamin D-dependent rickets classification is made according to genetic abnormalities of enzymes that are involved in vitamin D metabolism. Phosphopenic rickets is divided mainly into 2 categories that are FGF23 related or not. A systemic approach that includes a detailed history, physical examination, and laboratory evaluation is required when performing a diagnostic evaluation. Vitamin D and calcium supplementation should be used to treat nutritional rickets. To prevent rickets and its morbidities, vitamin D prophylaxis in the newborn period is suggested. High dose of vitamin D3, 1.25(OH)2D, and calcium are treatment choices in vitamin D-dependent rickets according to its subgroup. If conventional treatment consisting of phosphate and calcitriol is ineffective in the treatment of phosphopenic rickets, Burosumab is the new treatment option.

Associations between Liver Enzymes, Lifestyle Risk Factors and Pre-Existing Medical Conditions in a Population-Based Cross-Sectional Sample.

While alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) enzymes are commonly used indicators of liver dysfunction recent studies have suggested that these may also serve as predictive biomarkers in the assessment of extrahepatic morbidity. In order to shed further light on the interactions between serum liver enzyme abnormalities, factors of lifestyle and health status we examined ALT and GGT activities in a population-based sample of 8743 adult individuals (4048 men, 4695 women from the National FINRISK 2002 Study, mean age 48.1 ± 13.1 years) with different levels of alcohol drinking, smoking, physical activity, body weight and the presence or absence of various pre-existing medical conditions. The assessments also included laboratory tests for inflammation, lipid status and fatty liver index (FLI), a proxy for fatty liver. The prevalence of ALT and GGT abnormalities were significantly influenced by alcohol use (ALT: p < 0.0005 for men; GGT: p <0.0005 for both genders), smoking (GGT: p <0.0005 for men, p =0.002 for women), adiposity (p < 0.0005 for all comparisons), physical inactivity (GGT: p <0.0005; ALT: p <0.0005 for men, p <0.05 for women) and coffee consumption (p <0.0005 for GGT in both genders; p <0.001 for ALT in men). The total sum of lifestyle risk factor scores (LRFS) influenced the occurrence of liver enzyme abnormalities in a rather linear manner. Significantly higher LRFS were observed in the subgroups of individuals with pre-existing medical conditions when compared with those having no morbidities (p <0.0005). In logistic regression analyses adjusted for the lifestyle factors, both ALT and GGT associated significantly with fatty liver, diabetes and hypertension. GGT levels also associated with coronary heart disease, angina pectoris, cardiac insufficiency, cerebrovascular disease, asthma and depression. Combinations of abnormal ALT and GGT activities significantly increased the odds for hypertension coinciding with abnormalities in biomarkers of inflammation, lipid status and FLI. The data indicates that ALT and GGT activities readily respond to unfavorable factors of lifestyle associating also with a wide array of pre-existing medical conditions. The data supports close links between both hepatic and extrahepatic morbidities and lifestyle risk factors and may open new insights on a more comprehensive use of liver enzymes in predictive algorithms for assessing mechanistically anchored disease conditions.

An effect assessment of microplastics and nanoplastics interacting with androstenedione on mosquitofish (Gambusia affinis)

An increasing number of microplastics have been detected in aquatic environments, causing various damage to organisms. The size of microplastics affects the toxicity once they enter the organisms. Meanwhile, there is an increasing variety of Endocrine-disrupting chemicals (EDCs) present in aquatic environments. Androstenedione (AED) is a typical EDC. In this study, we used polystyrene microspheres of 80 nm (NPs) and 8 μm (MPs) as materials to simulate environmental contaminants in the aquatic environment with AED. We used female mosquitofish (Gambusia affinis) as the research object to investigate the effects of microplastics on fish in waters containing AED. We compared different sizes of particles accumulation in some tissues of fish and variation of enzyme activities (SOD, LDH, CAT), and the content of MDA in the gut. MPs, NPs, and AED combined exposure test investigated mRNA profiles of immune-related genes (IL-1β, IL-6, IL-8, IL-10) and hormone receptor genes (ARα, ARβ, ERα, ERβ) in the liver of fish. Our results indicated that MPs emerged in various tissues (gill, gut, and liver) of mosquitofish. Besides, NPs and MPs caused enteric abnormal enzyme activity after 48 h of exposure, which was particularly pronounced in the MPs-AED group. MPs induced significant upregulation of inflammatory factors and gonadal factor genes after 96 h of exposure, which was more pronounced when co-exposed with AED. In conclusion, NPs and MPs caused mechanisms of immune damage and inflammatory response. MPs were found to be more likely to cause adverse reactions than NPs, and these responses were enhanced by the combined effects of AED. This study demonstrated that AED can exacerbate the negative effects of MPs and NPs on mosquitofish. It provided an important basis for the effective assessment of MPs and NPs on bioaccumulation and biochemical status of mosquitofish. Additionally, it serves as a foundation to investigate the interactive effects of microplastics and EDCs in living organisms.

EVALUATION OF LIPID PROFILE AND LIVER FUNCTION PARAMETERS IN OBESE AND NON-OBESE HYPERTENSIVE INDIVIDUALS ATTENDED TERTIARY CARE TEACHING HOSPITAL

Objective: In this study, lipid profile parameters and liver function parameters were measured and correlated in hypertensive obese and non-obese patients who were attended a tertiary care teaching hospital.&#x0D; Methods: This study is a retrospective observational, cross-sectional study over the course of a year in a tertiary care hospital. All adult patients with hypertension, both obese and non-obese, are included in the study population. The study involved 150 participants in total, including obese and non-obese people (71 men and 79 women). Standard techniques were used to assess the serum levels of TG, TC, LDL, HDL, and liver enzymes such SGOT, SGPT, bilirubin, and ALP. Moreover, BMI was calculated for both study groups. The association between elevated lipid profile markers and liver enzyme abnormalities was assessed by correlation analysis.&#x0D; Results: Out of 150 samples size comprises 75 obese and 75 non-obese individuals, 71 males and 79 females were reported in the current study. Our study gives very good association between lipid profiles to almost all LFT and the highest is shown between HDL, LDL and VLDL to all LFT. There was a high significant difference was noticed between the obese and non-obese individuals in relation to bilirubin (D) concentration, SGOT and SGPT between the two groups P&lt;0.0001. The levels of albumin were lowered and the significant variations were noticed between the two groups. The mean values of cholesterol, LDL and triglycerides were very high in obese individuals than non-obese individuals and the HDL was lower in obese individuals.&#x0D; Conclusion: The study found that liver function variables and abnormal lipid profiles were highly prevalent in obese hypertension patients. In participants with dyslipidemia, increased liver enzymes were seen more frequently.

Topical Isotretinoin (TMB-001) Treatment for 12Weeks Did Not Result in Clinically Relevant Laboratory Abnormalities in Participants with Congenital Ichthyosis in the Phase 2b CONTROL Study.

Treatment with oral retinoids can be effective in patients with congenital ichthyosis (CI) but may be associated with clinically significant laboratory changes. In this Phase 2b CONTROL study analysis, we characterize the effects of TMB-001, a novel topical isotretinoin formulation, on laboratory values in participants with X-linked recessive (XLRI) and autosomal recessive lamellar (ARCI-LI) ichthyosis at 12weeks. A randomized, double-blind, vehicle-controlled, Phase 2b study was conducted with participants ≥ 9years of age with confirmed XLRI and ARCI-LI. Participants were randomized 1:1:1 and stratified by CI subtype to receive TMB-001 0.05%:TMB-001 0.1%:vehicle twice daily for 12weeks. Laboratory analyses were performed at screening and Week12. Among 33 enrolled participants (TMB-001 0.05% n = 11, TMB-001 0.1% n = 10, and vehicle n = 12), 52% had ARCI-LI and 48% had XLRI. At 12weeks, there were single reports of anemia, neutropenia, leukopenia, lymphocytosis, and leukocytosis after vehicle treatment; neutropenia was reported in one participant receiving TMB-001 0.1%. There were single reports of abnormal biochemistry values-liver enzymes, creatinine, urea nitrogen, hyperkalemia, and hyperproteinemia-across treatment cohorts. Non-fasting hyperglycemia was observed in three participants receiving TMB-001 0.1% and one participant receiving vehicle. Urinalysis abnormalities reported in > 1 participant included urobilinogen (TMB-001 0.1% n = 2, vehicle n = 2), protein (TMB-001 0.1% n = 3, vehicle n = 2), and leukocyte esterase (TMB-001 0.1% n = 2). Laboratory parameter changes were asymptomatic and did not require study discontinuation or drug withdrawal. There were no clinically significant laboratory changes in participants receiving TMB-001 isotretinoin ointment through 12weeks of treatment, which differs from reported results for systemic isotretinoin. NCT04154293.

Current Situation and Problems in Diagnosis of Early Chronic Pancreatitis.

The Japan Pancreas Society introduced the concept of early chronic pancreatitis (ECP) in 2009, but its epidemiology remains unclear. This study investigated challenges in ECP diagnosis. Early chronic pancreatitis was diagnosed in 4 cohorts between April 2019 and November 2021 using the Clinical Diagnostic Criteria for Chronic Pancreatitis 2019. These cohorts included patients with abdominal/back pain, abnormal pancreatic enzyme levels, ECP suspected due to other reasons, and those who underwent endoscopic ultrasonography for other diseases. A total of 2502 cases were analyzed and 150 (40 alcoholic and 110 nonalcoholic) cases with ECP findings on endoscopic ultrasonography were included. Early chronic pancreatitis was confirmed in 14 cases (9%), including 9 (22.5%) alcoholic and 5 (4.5%) nonalcoholic cases. Early chronic pancreatitis was confirmed in 15%, 0%, 2.2%, and 0.13% cases in the 4 cohorts, respectively. Early chronic pancreatitis was confirmed in 10 (48%) of the 21 (14%) cases with pancreatic pain. Early chronic pancreatitis diagnostic rate was low, particularly in nonalcoholic cases, but was slightly higher in cases with pancreatic pain. The diagnostic rate was highest in the abdominal/back pain group. Further studies are required to establish appropriate diagnostic criteria for ECP.

Complement C4 gene copy number variations and polymorphisms, autoantibodies, and clinical manifestations of juvenile dermatomyositis– a multi-center study

Abstract Juvenile dermatomyositis (JDM) is an autoimmune myopathy characterized by rash and muscle weakness. Complement C4 gene copy number (GCN) variation is a known risk factor for JDM. JDM patients often develop autoantibodies. We investigated the relationship between C4 GCN, clinical features, and antibody development. METHODS: Subjects were recruited (n=255) from the US, Sweden, and the Czech Republic. C4 GCN was determined by real time PCR. Comparative analyses were performed via student’s t test or Mann Whitney U test. Correlation was assessed via linear regression or Fisher’s exact test. All studies were IRB approved, and informed consent was obtained. RESULTS: C4 GCN correlated with muscle pathology and extra-muscular disease at diagnosis. Lower C4A and C4L GCN were associated with a higher number of abnormal muscle enzymes (p=0.0062 and p=0.0029), while the opposite was true for C4S (p=0.024). Higher C4S GCN correlated with lower muscle strength scores (p=0.039). Lower C4L correlated with abnormal MRI (p= 0.042). C4B GCN correlated with dysphagia (p=0.035). Higher GCN of C4S was a risk factor for arthritis (p=0.032), systemic symptoms (p=0.020), and dysphagia (p=0.0078). C4 GCN was associated with myositis-specific (MSA) and myositis-associated (MAA) antibodies. Patients with homozygous C4A deficiency were more likely to test positive for anti-NXP2 (OR 20.0, p=0.011), and C4A GCN was lower in anti-NXP2 positive subjects (p=0.030). A higher C4B GCN correlated with positive MAA (p=0.043). DISCUSSION: Here, we show that low C4A/C4L GCN and high C4B/C4S GCN correlate with worse muscle disease, extra-muscular pathology, and autoantibodies. Our data suggest that complement C4 may play a key role in the ongoing pathogenesis of JDM. Supported by grants from NIH (R21 AR070509) and the CureJM Foundation

Postoperative liver dysfunction is associated with poor long-term outcomes in patients with colorectal cancer: a retrospective cohort study

BackgroundPostoperative hepatobiliary enzyme abnormalities often present as postoperative liver dysfunction in patients with colorectal cancer. This study aimed to clarify the risk factors of postoperative liver dysfunction and its prognostic impact following colorectal cancer surgery.MethodsWe retrospectively analyzed data from 360 consecutive patients who underwent radical resection for Stage I–IV colorectal cancer between 2015 and 2019. A subset of 249 patients with Stage III colorectal cancer were examined to assess the prognostic impact of liver dysfunction.ResultsForty-eight (13.3%) colorectal cancer patients (Stages I–IV) developed postoperative liver dysfunction (Common Terminology Criteria for Adverse Events version 5.0 CTCAE v5.0 ≥ Grade 2). Univariate and multivariate analyses identified the liver-to-spleen ratio on preoperative plain computed tomography (L/S ratio; P = 0.002, Odds ratio 2.66) as an independent risk factor for liver dysfunction. Patients with postoperative liver dysfunction showed significantly poorer disease-free survival than patients without liver dysfunction (P < 0.001). Univariate and multivariate analyses using Cox’s proportional hazards model revealed that postoperative liver dysfunction independently was a poor prognostic factor (P = 0.001, Hazard ratio 2.75, 95% CI: 1.54–4.73).ConclusionsPostoperative liver dysfunction was associated with poor long-term outcomes in patients with Stage III colorectal cancer. A low liver-to-spleen ratio on preoperative plain computed tomography images was an independent risk factor of postoperative liver dysfunction.

Abstract 886: Fine-tuned CAIX targeted CAR-T cells exhibit superior efficacy and mitigate on-target off-tumor side effects

Abstract Chimeric Antigen Receptor (CAR) T cell therapy is a new type of “living drug” that has proven to be a powerful immunotherapy for hematologic malignancies. To date, there are six CAR-T products approved by the FDA for hematologic malignancies, four targeting CD19, and two targeting B-cell maturation antigen (BCMA). However, this success has not yet been transferred to solid tumors. A major hurdle is the on-target off-tumor toxicities due to the shared expression of target antigen on normal tissues. Carbonic anhydrase IX (CAIX) is highly expressed in clear cell renal cell carcinoma (ccRCC); however, it is also expressed on bile duct at a lower physiological level leading to off-tumor toxicity of CAIX targeted therapies. The first anti-CAIX CAR-T studies, using the 1st generation G250 CAR-T cells plus IL-2 to treat patients with metastatic ccRCC, caused severe liver enzyme abnormalities in the treated patients after CAR-T cell infusions. To understand CAIX expression on tumor and normal tissues, we quantified CAIX expression on ccRCC patient samples and healthy bile duct tissues using direct stochastic optical reconstruction microscopy (dSTORM) which provides single-molecule resolution. Tet-On inducible CAIX expressing cell lines were established to mimic various CAIX densities on normal tissue and tumor samples. Using biolayer interferometry (BLI) and avidity analyzer, we identified a low-affinity, high-avidity anti-CAIX CAR G9. G9 CAR-T cells only kill CAIX high ccRCC tumor cells but not CAIX low normal cholangiocytes, and exhibited a CAIX density dependent response to Tet-On inducible CAIX expressing cell lines. Compared to high-affinity G250 CAR-T cells, G9 showed a better safety profile and a wider therapeutic window. G9 demonstrated a superior ex vivo efficacy on ccRCC patient derived organotypic tumor spheroids (PDOTS) 3D cultures which recapitulate ccRCC patient tumor microenvironment (TME), as well as low toxicity on cholangiocyte derived organotypic spheroids (CDOS). In summary, affinity/avidity fine-tuned CAIX targeted CAR-T cell therapy holds promise to achieve cures of ccRCC by efficaciously killing tumor cells and mitigating on-target off-tumor toxicity on normal tissues. Citation Format: Yufei Wang, Alicia Buck, Gabriella Kastrunes, Rabia Abbas, Michael Lynch, Zhou Zhong, Song-My Hoang, Andras Miklosi, Kun Huang, Jae-Won Cho, Marion Grimaud, Cecile Razimbaud, Matthew Chang, Atef Fayed, Audrey Apollon, Nithyassree Murugan, Ze-Hua Li, Tran Thai, Luann Zerefa, Brandon Piel, Elena Ivanova, Amy Cameron, Quang-De Nguyen, Zhu Zhu, Kevin Wei, Yasmin Nabil Laimon, Aseman Bagheri Sheshdeh, Sabina Signoretti, David A. Braun, Catherine J. Wu, Toni K. Choueiri, Jon Wee, Cloud P. Paweletz, Martin Hemberg, Aedin C. Culhane, David A. Barbie, Gordon J. Freeman, Wayne A. Marasco. Fine-tuned CAIX targeted CAR-T cells exhibit superior efficacy and mitigate on-target off-tumor side effects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 886.

UPS: Opportunities and challenges for gastric cancer treatment.

Gastric cancer remains the fourth most frequently diagnosed malignancy and the fifth leading cause of cancer-related mortality worldwide owning to the lack of efficient drugs and targets for therapy. Accumulating evidence indicates that UPS, which consists of E1, E2, and E3 enzymes and proteasome, plays an important role in the GC tumorigenesis. The imbalance of UPS impairs the protein homeostasis network during development of GC. Therefore, modulating these enzymes and proteasome may be a promising strategy for GC target therapy. Besides, PROTAC, a strategy using UPS to degrade the target protein, is an emerging tool for drug development. Thus far, more and more PROTAC drugs enter clinical trials for cancer therapy. Here, we will analyze the abnormal expression enzymes in UPS and summarize the E3 enzymes which can be developed in PROTAC so that it can contribute to the development of UPS modulator and PROTAC technology for GC therapy.

Treatment recalcitrant cases of tinea corporis/cruris causedby T. mentagrophytes - interdigitale complex with mutations in ERG11 ERG 3, ERG4, MDR1 MFS genes & SQLE and their potential implications.

Recalcitrant dermatophyte infections are being reported from various parts of the world due to varied causes including strain variation, steroid misuse, SQLE mutations, and variable quality of itraconazole pellet formulations. The oral drug preferred in endemic areas is itraconazole, to which MIC levels remain low, and clinical failures to itraconazole reported defy a sound scientific explanation. The objective of the study was to conduct a proteomic and genomic analysis on isolates from therapeutically recalcitrant case with isolation of gene mutations and enzymatic abnormalities to explain azole failures. Trichophyton mentagrophyte interdigitale complex strains were isolated from seven clinically non-responding tinea corporis/cruris patients, who had failed a sequential course of 6 weeks of terbinafine 250 mg QD and itraconazole 100 mg BID. After AFST 1 strain, KA01 with high MIC to most drugs was characterized using whole genome sequencing, comparative proteomic profiling, and total sterol quantification. Sterol quantification showed that the standard strain of Trichophyton mentagrophytes (MTCC-7687) had half the ergosterol content than the resistant KA01 strain. Genomic analysis revealed mutations in SQLE, ERG4, ERG11, MDR1, MFS genes, and a novel ERG3 mutation. Proteomic analysis established the aberrant expression of acetyl Co-A transferase in the resistant strain and upregulation of thioredoxin reductase and peroxiredoxin. Our findings demonstrate possible reasons for multidrug resistance in the prevalent strain with mutations in genes that predict terbinafine (SQLE) and azole actions (ERG4, ERG11, ERG3) apart from efflux pumps (MDR1, MFS) that can explain multidrug clinical failures.