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Sichuan Da Xue Xue Bao. Yi Xue Ban =... May 2024The patient 1, a 13-year-old boy, was admitted due to "recurrent oral ulcers for 3 years, abdominal pain for 8 months, and perianal ulcers for 10 days"; The patient 2, a...
The patient 1, a 13-year-old boy, was admitted due to "recurrent oral ulcers for 3 years, abdominal pain for 8 months, and perianal ulcers for 10 days"; The patient 2, a 3-year-old boy, was admitted due to "recurrent abdominal pain, diarrhea, and fever for over 3 months". Genetic testing of both patients revealed "deficiency in , X-linked" (DEX), and the patients were diagnosed with Behcet's disease-like syndrome due to deficiency in , accordingly. The patient 1 was successively given intravenous methylprednisolone pulses and oral prednisone and mesalazine for symptomatic treatment. The patient 2 was successively treated with corticosteroids combined with enteral nutrition, as well as oral mercaptopurine. Subsequently, both patients showed improvements in symptoms and were discharged.
PubMed: 38948265
DOI: 10.12182/20240560606 -
Human Reproduction Update Jun 2024Chemotherapy-associated ovarian damage (CAOD) is one of the most feared short- and long-term side effects of anticancer treatment in premenopausal women. Accumulating...
BACKGROUND
Chemotherapy-associated ovarian damage (CAOD) is one of the most feared short- and long-term side effects of anticancer treatment in premenopausal women. Accumulating detailed data show that different chemotherapy regimens can lead to disturbance of ovarian hormone levels, reduced or lost fertility, and an increased risk of early menopause. Previous studies have often focused on the direct effects of chemotherapeutic drugs on ovarian follicles, such as direct DNA damage-mediated apoptotic death and primordial follicle burnout. Emerging evidence has revealed an imbalance in the ovarian microenvironment during chemotherapy. The ovarian microenvironment provides nutritional support and transportation of signals that stimulate the growth and development of follicles, ovulation, and corpus luteum formation. The close interaction between the ovarian microenvironment and follicles can determine ovarian function. Therefore, designing novel and precise strategies to manipulate the ovarian microenvironment may be a new strategy to protect ovarian function during chemotherapy.
OBJECTIVE AND RATIONALE
This review details the changes that occur in the ovarian microenvironment during chemotherapy and emphasizes the importance of developing new therapeutics that protect ovarian function by targeting the ovarian microenvironment during chemotherapy.
SEARCH METHODS
A comprehensive review of the literature was performed by searching PubMed up to April 2024. Search terms included 'ovarian microenvironment' (ovarian extracellular matrix, ovarian stromal cells, ovarian interstitial, ovarian blood vessels, ovarian lymphatic vessels, ovarian macrophages, ovarian lymphocytes, ovarian immune cytokines, ovarian oxidative stress, ovarian reactive oxygen species, ovarian senescence cells, ovarian senescence-associated secretory phenotypes, ovarian oogonial stem cells, ovarian stem cells), terms related to ovarian function (reproductive health, fertility, infertility, fecundity, ovarian reserve, ovarian function, menopause, decreased ovarian reserve, premature ovarian insufficiency/failure), and terms related to chemotherapy (cyclophosphamide, lfosfamide, chlormethine, chlorambucil, busulfan, melphalan, procarbazine, cisplatin, doxorubicin, carboplatin, taxane, paclitaxel, docetaxel, 5-fluorouraci, vincristine, methotrexate, dactinomycin, bleomycin, mercaptopurine).
OUTCOMES
The ovarian microenvironment shows great changes during chemotherapy, inducing extracellular matrix deposition and stromal fibrosis, angiogenesis disorders, immune microenvironment disturbance, oxidative stress imbalances, ovarian stem cell exhaustion, and cell senescence, thereby lowering the quantity and quality of ovarian follicles. Several methods targeting the ovarian microenvironment have been adopted to prevent and treat CAOD, such as stem cell therapy and the use of free radical scavengers, senolytherapies, immunomodulators, and proangiogenic factors.
WIDER IMPLICATIONS
Ovarian function is determined by its 'seeds' (follicles) and 'soil' (ovarian microenvironment). The ovarian microenvironment has been reported to play a vital role in CAOD and targeting the ovarian microenvironment may present potential therapeutic approaches for CAOD. However, the relation between the ovarian microenvironment, its regulatory networks, and CAOD needs to be further studied. A better understanding of these issues could be helpful in explaining the pathogenesis of CAOD and creating innovative strategies for counteracting the effects exerted on ovarian function. Our aim is that this narrative review of CAOD will stimulate more research in this important field.
REGISTRATION NUMBER
Not applicable.
PubMed: 38942605
DOI: 10.1093/humupd/dmae020 -
Cureus May 2024Crohn's disease is a type of inflammatory bowel disease (IBD) that typically presents in the second or third decade of life. There are various pharmaceutical therapies...
Crohn's disease is a type of inflammatory bowel disease (IBD) that typically presents in the second or third decade of life. There are various pharmaceutical therapies that have been developed to treat the disease's symptoms. However, some patients still do not find relief with these medications and turn to other therapies such as diet modification. The underlying cause of Crohn's disease involves multiple factors such as uncontrolled inflammation and several genetic variants. While most current medication therapies control the symptoms that occur due to this uncontrolled level of inflammation, an anti-inflammatory diet (AID) may actually lower the level of inflammation in the gut and therefore reduce the amount of disease symptoms in Crohn's disease. Some such diets include the IBD-AID, Crohn's disease exclusion diet, and the Groningen AID (GrAID). This report describes a case of treatment-resistant Crohn's disease in a patient who was given all categories of pharmaceutical therapies including prednisone, budesonide, sulfasalazine, olsalazine, 6-mercaptopurine, methotrexate, mesalamine, and adalimumab. These only gave temporary relief of symptoms and eventually failed for various reasons including allergic reaction, insufficient symptom control, and antibody formation against the medication. This prompted the patient to independently research AIDs instead. In conclusion, for patients whose disease is refractory to different treatments, or who develop antibodies to the medication, AIDs may offer a solution to reduce disease symptoms and progression. Education of healthcare professionals and patients alike is vital in order for Crohn's patients to gain the benefits from dietary therapy.
PubMed: 38939280
DOI: 10.7759/cureus.61262 -
BMJ Case Reports Jun 2024In this paper, we report the case of a boy in early childhood who presented with iron-deficiency anaemia, initially thought to be nutritional, who had a subsequent...
In this paper, we report the case of a boy in early childhood who presented with iron-deficiency anaemia, initially thought to be nutritional, who had a subsequent diagnosis of idiopathic pulmonary haemosiderosis (IPH). This is a slowly progressive and life-threatening disorder and is of paramount importance that this is identified early and treated appropriately. His first chest CT was not typical for IPH, and this appearance should be highlighted (small cystic changes alone initially). He also had focal disease, which allowed us to make the diagnosis using CT-guided biopsy. During his treatment, he experienced an uncommon side effect to a commonly prescribed medication (bradycardia with methylprednisolone). Since starting azathioprine as a steroid-sparing agent, he has been doing well.
Topics: Humans; Hemosiderosis; Male; Hemosiderosis, Pulmonary; Lung Diseases; Tomography, X-Ray Computed; Anemia, Iron-Deficiency; Azathioprine; Diagnosis, Differential; Methylprednisolone
PubMed: 38937263
DOI: 10.1136/bcr-2024-261171 -
In Vivo (Athens, Greece) 2024Hematotoxicity is a life-threatening condition that has become the major cause of drug discontinuation in patients with acute lymphoblastic leukemia (ALL). The nudix...
BACKGROUND/AIM
Hematotoxicity is a life-threatening condition that has become the major cause of drug discontinuation in patients with acute lymphoblastic leukemia (ALL). The nudix hydrolase 15 (NUDT15) gene polymorphism (c.415C>T) is reported to have an association with the hematotoxicity of 6-mercaptopurine (6-MP) as maintenance therapy in patients with ALL. However, the prevalence of this genetic polymorphism in the Indonesian population is unknown. This study aimed to assess the frequency of NUDT15 polymorphism among Indonesian pediatric patients with ALL and its association with the hematotoxicity of 6-MP.
PATIENTS AND METHODS
A total of 101 stored DNA samples from pediatric patients with ALL receiving 6-MP treatment were used for genetic testing. Direct sequencing was conducted to determine the NUDT15 c.415C>T genotype. Chi-square or Fisher's exact test were employed to examine the association between the NUDT15 c.415C>T genotype and hematotoxicity.
RESULTS
All (100%) of the DNA samples from patients with ALL treated with 6-MP exhibited a homozygous variant of the NUDT15 c.415C>T genotype, 70.3% of which showed hematotoxicity to some extent. We found no significant differences in NUDT15 gene polymorphism among patients with ALL with different states of hematotoxicity.
CONCLUSION
The observed high frequency of NUDT15 c.415C>T in our study population might explain the elevated prevalence of 6-MP-associated hematotoxicity in pediatric patients with ALL within the Indonesian population. Our study provides new insight regarding the NUDT15 gene polymorphism and its relation to hematotoxicity. Further studies are required to determine the necessity of adjusting the initial dose of 6-MP for Indonesian pediatric patients with ALL.
Topics: Humans; Child; Mercaptopurine; Female; Male; Pyrophosphatases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Child, Preschool; Indonesia; Adolescent; Genotype; Infant; Polymorphism, Single Nucleotide; Alleles; Gene Frequency; Genetic Predisposition to Disease; Antimetabolites, Antineoplastic; Polymorphism, Genetic; Nudix Hydrolases
PubMed: 38936894
DOI: 10.21873/invivo.13662 -
Biomedicine & Pharmacotherapy =... Jun 2024The interaction between the gut microbiota and mercaptopurine (6-MP), a crucial drug used in pediatric acute lymphoblastic leukemia (ALL) treatment, has not been...
The interaction between the gut microbiota and mercaptopurine (6-MP), a crucial drug used in pediatric acute lymphoblastic leukemia (ALL) treatment, has not been extensively studied. Here we reveal the significant perturbation of gut microbiota after 2-week 6-MP treatment in beagles and mice followed by the functional prediction that showed impairment of SCFAs production and altered amino acid synthesis. And the targeted metabolomics in plasma also showed changes in amino acids. Additionally, targeted metabolomics analysis of feces showed changes in amino acids and SCFAs. Furthermore, ablating the intestinal microbiota by broad-spectrum antibiotics exacerbated the imbalance of amino acids, particularly leading to a significant decrease in the concentration of S-adenosylmethionine (SAM). Importantly, the depletion of gut microbiota worsened the damage of small intestine caused by 6-MP, resulting in increased intestinal permeability. Considering the relationship between toxicity and 6-MP metabolites, we conducted a pharmacokinetic study in pseudo germ-free rats to confirm that gut microbiota depletion altered the methylation metabolites of 6-MP. Specifically, the concentration of MeTINs, a secondary methylation metabolite, showed a negative correlation with SAM, the pivotal methyl donor. Additionally, we observed a strong correlation between Alistipes and SAM levels in both feces and plasma. In conclusion, our study demonstrates that 6-MP disrupts the gut microbiota, and depleting the gut microbiota exacerbates 6-MP-induced intestinal toxicity. Moreover, SAM derived from microbiota plays a crucial role in influencing plasma SAM and the methylation of 6-MP. These findings underscore the importance of comprehending the role of the gut microbiota in 6-MP metabolism and toxicity.
PubMed: 38925017
DOI: 10.1016/j.biopha.2024.116975 -
Chemistry (Weinheim An Der Bergstrasse,... Jun 2024We present herein a novel photo-mediated homolytic C-S bond formation for the preparation of alkylthiopurines and alkylthiopurine nucleosides. Despite the presence of...
We present herein a novel photo-mediated homolytic C-S bond formation for the preparation of alkylthiopurines and alkylthiopurine nucleosides. Despite the presence of reactive sites for the Minisci reaction, chemoselective S-alkylation remained the predominant pathway. This method allows for the late-stage introduction of a broad spectrum of alkyl groups onto the sulfur atom of unprotective mercaptopurine derivatives, encompassing 2-, 6-, and 8-mercaptopurine rings. Organoborons serve as efficient and eco-friendly alkylating reagents, providing advantages in terms of readily availability, stability, and reduced toxicity. Further derivatization of the thioetherified nucleosides, together with anti-tumor assays, led to the discovery of potent anti-tumor agents with an IC50 value reaching 6.1 µM (Comp. 31 for Jurkat).
PubMed: 38923704
DOI: 10.1002/chem.202401774 -
The Pharmacogenomics Journal Jun 2024Thiopurines, an effective therapy for Crohn's disease (CD), often lead to adverse events (AEs). Gene polymorphisms affecting thiopurine metabolism may predict AEs. This...
Thiopurines, an effective therapy for Crohn's disease (CD), often lead to adverse events (AEs). Gene polymorphisms affecting thiopurine metabolism may predict AEs. This retrospective study in CD patients (n = 114) with TPMT activity > 5 Units/Red Blood Cells analyzed TPMT (c.238 G > C, c.460 G > A, c.719 A > G), ITPA (c.94 C > A, IVS2 + 21 A > C), and NUDT15 (c.415 C > T) polymorphisms. All patients received azathioprine (median dose 2.2 mg/kg) with 41.2% experiencing AEs, mainly myelotoxicity (28.1%). No NUDT15 polymorphisms were found, 7% had TPMT, and 31.6% had ITPA polymorphisms. AEs led to therapy modifications in 41.2% of patients. Multivariate analysis identified advanced age (OR 1.046, p = 0.007) and ITPA IVS2 + 21 A > C (OR 3.622, p = 0.015) as independent predictors of AEs. IVS2 + 21 A > C was also associated with myelotoxicity (OR 2.863, p = 0.021). These findings suggest that ITPA IVS2 + 21 A > C polymorphism and advanced age predict AEs during thiopurine therapy for CD with intermediate-normal TPMT activity.
Topics: Humans; Crohn Disease; Pyrophosphatases; Female; Male; Adult; Retrospective Studies; Azathioprine; Methyltransferases; Middle Aged; Young Adult; Immunosuppressive Agents; Adolescent; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Polymorphism, Genetic; Mercaptopurine; Multivariate Analysis; Aged; Risk Factors; Nudix Hydrolases; Inosine Triphosphatase
PubMed: 38906864
DOI: 10.1038/s41397-024-00341-2 -
Advances in Rheumatology (London,... Jun 2024To develop the second evidence-based Brazilian Society of Rheumatology consensus for diagnosis and treatment of lupus nephritis (LN).
OBJECTIVE
To develop the second evidence-based Brazilian Society of Rheumatology consensus for diagnosis and treatment of lupus nephritis (LN).
METHODS
Two methodologists and 20 rheumatologists from Lupus Comittee of Brazilian Society of Rheumatology participate in the development of this guideline. Fourteen PICO questions were defined and a systematic review was performed. Eligible randomized controlled trials were analyzed regarding complete renal remission, partial renal remission, serum creatinine, proteinuria, serum creatinine doubling, progression to end-stage renal disease, renal relapse, and severe adverse events (infections and mortality). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to develop these recommendations. Recommendations required ≥82% of agreement among the voting members and were classified as strongly in favor, weakly in favor, conditional, weakly against or strongly against a particular intervention. Other aspects of LN management (diagnosis, general principles of treatment, treatment of comorbidities and refractory cases) were evaluated through literature review and expert opinion.
RESULTS
All SLE patients should undergo creatinine and urinalysis tests to assess renal involvement. Kidney biopsy is considered the gold standard for diagnosing LN but, if it is not available or there is a contraindication to the procedure, therapeutic decisions should be based on clinical and laboratory parameters. Fourteen recommendations were developed. Target Renal response (TRR) was defined as improvement or maintenance of renal function (±10% at baseline of treatment) combined with a decrease in 24-h proteinuria or 24-h UPCR of 25% at 3 months, a decrease of 50% at 6 months, and proteinuria < 0.8 g/24 h at 12 months. Hydroxychloroquine should be prescribed to all SLE patients, except in cases of contraindication. Glucocorticoids should be used at the lowest dose and for the minimal necessary period. In class III or IV (±V), mycophenolate (MMF), cyclophosphamide, MMF plus tacrolimus (TAC), MMF plus belimumab or TAC can be used as induction therapy. For maintenance therapy, MMF or azathioprine (AZA) are the first choice and TAC or cyclosporin or leflunomide can be used in patients who cannot use MMF or AZA. Rituximab can be prescribed in cases of refractory disease. In cases of failure in achieving TRR, it is important to assess adherence, immunosuppressant dosage, adjuvant therapy, comorbidities, and consider biopsy/rebiopsy.
CONCLUSION
This consensus provides evidence-based data to guide LN diagnosis and treatment, supporting the development of public and supplementary health policies in Brazil.
Topics: Lupus Nephritis; Humans; Immunosuppressive Agents; Brazil; Societies, Medical; Creatinine; Proteinuria; Mycophenolic Acid; Antibodies, Monoclonal, Humanized; Rheumatology; Rituximab; Biopsy; Cyclophosphamide; Leflunomide; Glucocorticoids; Hydroxychloroquine; Azathioprine; Remission Induction; Cyclosporine; Evidence-Based Medicine; Consensus; Disease Progression; Kidney Failure, Chronic; Randomized Controlled Trials as Topic
PubMed: 38890752
DOI: 10.1186/s42358-024-00386-8 -
Digestive Diseases and Sciences Jun 2024Patients with inflammatory bowel disease (IBD) receiving infliximab (IFX) commonly experience immunogenic loss of response (LOR) by formation of anti-drug antibodies...
BACKGROUND AND AIMS
Patients with inflammatory bowel disease (IBD) receiving infliximab (IFX) commonly experience immunogenic loss of response (LOR) by formation of anti-drug antibodies (ADAs). An immunomodulator (IMM) used in combination with initial IFX induction is known to reduce ADA development and improve clinical outcomes. We aimed to assess the impact of reactively adding an IMM to patients on IFX monotherapy.
METHODS
We conducted a retrospective cohort study and systematic review with meta-analysis of patients with IBD demonstrating immunologic LOR, with or without clinical LOR, that had an IMM (azathioprine, 6-mercaptopurine, or methotrexate) reactively added (reactive combination therapy; rCT) to combat elevated ADAs and raise IFX level. Data were extracted for pooled effect size estimation using random-effects models, and ADA and IFX trough levels were compared pre- and post-IMM initiation.
RESULTS
We identified 6 patients who received rCT due to rising ADA titers and low IFX levels. Median ADA titer decreased from 506 ng/mL (interquartile range (IQR) [416-750]) to 76.5 ng/mL (IQR [25.8-232]), an 85% decrease (p = 0.031). Median IFX trough increased from 0.4 µg/mL (IQR [0.4-0.48]) to 8.25 µg/mL (IQR [3.7-9.6]), a 20.6-fold increase (p = 0.038). Meta-analysis pooled effect size of 7 studies with 89 patients showed an 87% ADA titer reduction [95% confidence interval (CI) = 72-94%], 6.7-fold increased IFX trough (95% CI = 2.4-18.7), and 76% clinical remission rescue rate (95% CI = 59-93%).
CONCLUSIONS
These results suggest rCT is a valid rescue strategy in patients with immunogenic LOR to IFX to reduce ADA titers, restore therapeutic IFX levels, and recapture clinical remission of IBD.
PubMed: 38877332
DOI: 10.1007/s10620-024-08515-5