Severe Side Effects Research Articles

A Real-World Experience of Rituximab: A Panacea in Therapy of Multiple Sclerosis in Low- and Middle-Income Setting.

Anti-CD20 monoclonal antibodies have received increasing attention in the past few years in the treatment of multiple sclerosis (MS). This study describes the (i) efficacy and safety of rituximab in people living with MS and (ii) assesses clinical and imaging outcomes following rituximab in MS. This is a chart review from the MS registry maintained at the institute from a University Hospital in South India. Eighty-three (M:F, 26:57) people living with MS received rituximab as immunomodulation between 2007 and 2022 with a median follow-up duration of 18 months. Fifty-nine (71%) were classified as relapsing-remitting MS, 16 (19%) were secondary progressive MS, and 8 (10%) were primary progressive MS. Seventy-two (87%) MS patients did not experience any relapse after receiving rituximab. In relapsing-remitting MS patients, the mean annualized recurrence rate dropped from 1.24 ± 1.19 to 0.16 ± 0.37. Infusion-related reaction occurred in 5 (6% of adverse events), urinary infections in 7 (8.4%), systemic infections in 3 (3%), Pneumocystis carinii pneumonia occurred in 1 (1%), and herpes zoster infection in 1 (1%) patient. Mortality was observed in 3 (3.5%) patients. While being on rituximab, 18 (22%) patients had mild COVID-19 illness and they all made complete recovery without any sequalae. Rituximab is a safe, well-tolerated, easily accessible, inexpensive, and effective therapeutic option for people with MS. Rituximab showed both clinical and radiological improvement after a median follow-up of 1.5 years. None of our patients showed any severe COVID infection nor side effects after receiving COVID vaccination.

Salbutamol safety in children under 2 years of age with acute wheezing: a meta-analysis of randomised controlled trials

ObjectiveTo evaluate the safety of short-term use of inhaled salbutamol in children under 2 years of age with acute wheezing.Data sourcesElectronic databases (PubMed, Trip, MEDLINE) and the Cochrane Library were...

Mu-Opioid Receptor (MOR) Dependence of Pain in Chemotherapy-Induced Peripheral Neuropathy.

We recently demonstrated that transient attenuation of Toll-like receptor 4 (TLR4) in dorsal root ganglion (DRG) neurons, can both prevent and reverse pain associated with chemotherapy-induced peripheral neuropathy (CIPN), a severe side effect of cancer chemotherapy, for which treatment options are limited. Given the reduced efficacy of opioid analgesics to treat neuropathic, compared with inflammatory pain, the cross talk between nociceptor TLR4 and mu-opioid receptors (MORs), and that MOR and TLR4 agonists induce hyperalgesic priming (priming), which also occurs in CIPN, we determined, using male rats, whether (1) antisense knockdown of nociceptor MOR attenuates CIPN, (2) and attenuates the priming associated with CIPN, and (3) CIPN also produces opioid-induced hyperalgesia (OIH). We found that intrathecal MOR antisense prevents and reverses hyperalgesia induced by oxaliplatin and paclitaxel, two common clinical chemotherapy agents. Oxaliplatin-induced priming was also markedly attenuated by MOR antisense. Additionally, intradermal morphine, at a dose that does not affect nociceptive threshold in controls, exacerbates mechanical hyperalgesia (OIH) in rats with CIPN, suggesting the presence of OIH. This OIH associated with CIPN is inhibited by interventions that reverse Type II priming [the combination of an inhibitor of Src and mitogen-activated protein kinase (MAPK)], an MOR antagonist, as well as a TLR4 antagonist. Our findings support a role of nociceptor MOR in oxaliplatin-induced pain and priming. We propose that priming and OIH are central to the symptom burden in CIPN, contributing to its chronicity and the limited efficacy of opioid analgesics to treat neuropathic pain.

Monitoring Apoptosis and Myeloid Differentiation of Acridine Orange-Mediated Sonodynamic Therapy-Induced Human Promyelocytic Leukemia HL60 Cells.

In the treatment of acute myeloid leukemia (AML), conventional therapies can lead to severe side effects and drug resistance. There is a need for alternative treatments that do not cause treatment resistance and have minimal or no side effects. Sonodynamic therapy (SDT), due to its noninvasive, multiple repeatability, localized treatment feature and do not cause treatment resistance, emerges as an alternative treatment option. However, it has not received sufficient attention in the treatment of AML especially acute promyelocytic leukemia (APL). The aim of the study was to investigate the potential differentiation and antileukemic effects of acridine orange (AO)-mediated SDT on HL60 cells. Cell viability was determined by the 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT)method in the control, ultrasound, AO concentrations, and ultrasound-exposed AO concentrations groups. Transmission electron microscopy (TEM) was used to determine morphology, and flow cytometry was used to determine apoptosis, DNA cycle, cell volume, mitochondria membrane potential (Δψm), reactive oxygen species (ROS) production, and differentiation markers (CD11b and CD15) expressions. Additionally, toluidine blue staining for semithin sections was used to determine differentiation. The cytotoxicity of AO-mediated SDT on HL60 cells was significantly higher than other groups, and TEM images showed that it caused various morphological changes typical for apoptosis. Flow cytometry results showed the presence of early apoptosis, subG1 arrest, loss of Δψm, increase of intracellular ROS production, decreased cell volume, and increased expression of CD11b (1.3-fold) antigen and CD15 (1.2-fold) antigen. Data showed that AO-mediated SDT significantly induced apoptosis in HL60 cells. Increased expression of CD11b and CD15 antigens and morphological findings demonstrated that AO-mediated SDT contributes to granulocytic differentiation in HL60 cells. AO-mediated SDT has potential as an alternative treatment of APL.

Insights into the Pathogenesis and Treatment of Chemotherapy-Induced Neuropathy: A Focus on Oxidative Stress and Neuroinflammation.

Cancer is a high-morbidity disease prevalent worldwide. Chemotherapy is the primarily used regimen for cancer treatment; however, it also brings severe side effects. Chemotherapy-induced Peripheral Neuropathy (CIPN) and Chemotherapy-induced Cognitive Impairment (CICI) are two main complications occurring in chemotherapy. They are both associated with nervous system injury and are therefore collectively referred to as Chemotherapy-induced Neuropathy (CIN). CIPN induces neuralgia and numbness in limbs, while CICI causes amnesia and cognitive dysfunction. Currently, there are no effective therapeutics to prevent or cure CIN, so research into new drugs to alleviate CIN becomes urgent. Oxidative stress and neuroinflammation are the common pathogenic mechanisms of CIPN and CICI. Excessive Reactive Oxygen Species (ROS) and pro-inflammatory cytokines cause peripheral nervous system damage and hence CIPN. Peripheral ROS and cytokines also change the permeability of the blood-brain barrier, thereby increasing oxidative stress and neuroinflammation in the central nervous system, ultimately leading to CICI. Several antidepressants have been used to treat CIN and exhibited good clinical effects. Their potential pharmacological mechanism has been reported to ameliorate oxidative stress and neuroinflammation, guiding a new feasible way for effective therapeutic development against CIN. This mini-review has summarized the latest advances in the research on CIN with respect to clinical status, pathogenesis, and treatment. It has also discussed the potential of repurposing antidepressants for CIN treatment and prospected the strategy of developing therapeutics by targeting oxidative stress and neuroinflammation against CIN.

Structure-Guided Identification of Novel Aromatase Inhibitors Targeting Breast Carcinoma.

Aromatase inhibitors play a critical therapeutic role in treating ER+ breast cancer, especially in postmenopausal women. However, their efficacy is often limited by resistance and severe side effects. Identifying new compounds that can disrupt aromatase enzyme function is essential. In this study, structural anomalies in the aromatase enzyme were corrected through energy minimization, and the structure was validated via Ramachandran plot. We screened 170,269 natural compounds from the ASINEX Biodesign library using high-throughput screening algorithms to target the aromatase enzyme. Molecular docking identified three compounds: BDD30170158, BDE33872639, and BDE30177677, all showing stable binding interactions with the aromatase enzyme. Molecular dynamics simulations over 100 ns confirmed the conformational stability of these compounds. Although all three compounds exhibited the desired pharmacokinetic and drug metabolism properties, only one compound (BDE33872639) was identified as a non-blocker, demonstrating a reduced risk of adverse cardiac effects. This compound exhibits significant potential as a novel aromatase inhibitor, warranting further experimental research to develop it as a therapeutic option for ER+ breast cancer.

In silico analysis reveals α-amylase inhibitory potential of Taraxerol (Coccinia indica) and Epoxywithanolide-1 (Withania coagulans): a possible way to control postprandial hyperglycemia-induced endothelial dysfunction and cardiovascular events.

Postprandial hyperglycemia (PPG) exacerbates endothelial dysfunction and impairs vascular function in diabetes as well in healthy people. Though synthetic drugs are available to regulate PPG, the severe gastrointestinal side effects of those medications have prompted the search for alternative treatments. Recently, some phytochemicals captured the attention because of their inhibitory effects on α-amylase to control diabetes. The aim of this study was to investigate and identify potential alpha-amylase inhibitors in C. indica and W. coagulans. This study also aims to understand one of the possible mechanisms of action of plants for their anti-diabetic activity. A total of 36 phytochemical ligands were subjected for protein-ligand docking analysis. Among the phytochemicals, Taraxerol and Epoxywithanolide-I demonstrated significant binding free energy of -10.2kcal/mol and -11.9kcal/mol respectively, which was higher than the reference acarbose with -8.6kcal/mol. These molecules were subjected for molecular dynamics simulation (MDS) analysis with alpha-amylase protein for a duration of 150ns. Among the three complexes, Taraxerol and Epoxywithanolide-I complexes demonstrates strong potential as inhibitors of the target protein. MDS results were analyzed via root mean square deviation (RMSD), fluctuation of residues, potential energy, radii of gyration and solvent access surface area analysis. Taraxerol demonstrated a significantly low potential energy of -1,924,605.25kJ/mol, and Epoxywithanolide-I demonstrated -1,964,113.3kJ/mol of potential energy. RMSD plot shows that Epoxywithanolide-I has much higher stability than the other MDS complexes. Drugability and toxicity studies show that the test ligands are demonstrating strong potential as drug like molecules. The results of the study conclude that, Taraxerol of C. indica and Epoxywithanolide-I of W. coagulans are strong inhibitors of alpha-amylase enzyme and that, this is one of the possible mechanisms of action of the plants for their reported anti-diabetic activities. Further in-vitro analysis is in demand to prove the observed results.

Study Reveals a New Approach to Treating Tripple Negative Breast Cancer

riple-negative breast cancer (TNBC) makes up about 15% of all breast cancer cases worldwide. It's particularly hard to treat because it lacks the three common receptors that most therapies target. As a result, most TNBC patients undergo high doses of non-targeted chemotherapy, which often leads to severe side effects such as hair loss, nausea, and pain. The spread of TNBC cells to other organs, such as the brain or lungs, is the main cause of death in patients.

Immunoinformatic approach to design an efficient multi-epitope peptide vaccine against melanoma.

Melanoma is known to be the most hazardous and life-threatening type of skin cancer. Although numerous treatments have been authorized in recent years, they often result in severe side effects and may not fully cure the disease. To combat this issue, immunotherapy has emerged as a promising approach for the prevention and treatment of melanoma. Specifically, the use of epitope melanoma vaccine, a subset of immunotherapy, has recently gained attention. The aim of this study was to create a multi-epitope melanoma vaccine using immunoinformatic methods. Two well-known antigens, NYESO-1 and MAGE-C2, were selected due to their strong immunogenicity and high expression in melanoma. To enhance the immunogenicity of the peptide vaccine, Brucella cell-surface protein 31 (BCSP31), the G5 domain of resuscitation-promoting factor B (RpfB) adjuvants, and the helper epitope of pan HLADR-binding epitope (PADRE) were incorporated to vaccine construct. These different segments were connected with suitable linkers and the resulting vaccine structure was evaluated for its physicochemical, structural, and immunological properties using computational tools. The designed vaccine was found to have satisfactory allergenicity, antigenicity, and physicochemical parameters. Additionally, a high-quality tertiary structure of the vaccine was achieved through modeling, refinement, and validation. Docking and molecular dynamics studies showed that the vaccine had a stable and appropriate interaction with the cognate TLR2 and TLR4 receptors during the simulation period. Finally, in silico immune simulation analysis revealed a significant increase in the levels of helper and cytotoxic T cells, as well as the cytokines interferon-gamma and interleukin-2, after repeated exposure to the melanoma vaccine. These results suggest that the designed vaccine has the potential to be an effective therapeutic option for melanoma. However, additional in vitro and in vivo validations are crucial to assess real-world efficacy and safety.

Mechanisms of traditional Chinese medicine in the treatment and prevention of gastric cancer

BackgroundGastric cancer (GC) ranks as the fifth most prevalent malignancy worldwide. Conventional treatments, including radiotherapy and chemotherapy, often induce severe side effects and significant adverse reactions, and they may also result in drug resistance. Consequently, there is a critical need for the development of new therapeutic agents. Traditional Chinese Medicine (TCM) and natural products are being extensively researched due to their low toxicity, multi-targeted approaches, and diverse pathways. Scholars are increasingly focusing on identifying active anticancer components within TCM. PurposeThis review aims to summarise research conducted over the past 14 years on the treatment of GC using TCM. The focus is on therapeutic targets, mechanisms, and efficacy of Chinese medicine and natural products, including monomer compounds, extracts or analogues, and active ingredients. MethodsRelevant articles on TCM and GC were retrieved from PubMed using appropriate keywords. The collected articles were screened and classified according to the types of TCM, with an emphasis on the molecular mechanisms underlying the treatment of GC. ResultsThe research on TCM indicates that TCM and natural products can effectively inhibit the metastasis, proliferation, and invasion of tumour cells. They can also induce apoptosis, autophagy and improve the chemosensitivity of drug-resistant cells. Additionally, injections derived from Chinese herbal medicine, when used as an adjunct to conventional chemotherapy, can significantly improve the prognosis of GC patients by reducing chemotherapy toxicity. ConclusionThis review summarises the progress of TCM treatment of GC over the past 14 years, and discusses its therapeutic application of GC, which proves that TCM is a promising treatment strategy for GC in the future.

Anti-cancer activity of brucine loaded Cu(OH)2/ZnO nanoparticles against chronic myeloid leukemia cell line (K562) via apoptotic signaling pathway

Background and objectiveChronic myeloid leukemia (CML) is marked by abnormal blood cell production and traditional treatments often cause severe side effects and resistance. This study improves cancer therapy by using copper (II) hydroxide (Cu(OH)₂) and zinc oxide (ZnO) nanoparticles combined with brucine (Bru) to enhance targeted drug delivery and efficacy. Materials and methodsBru-Cu(OH)₂-ZnO NPs were synthesized and characterized using various analytical techniques. Their cytotoxicity was evaluated on K562 myeloid leukemia cells through cell viability assays, dichloro-dihydro-fluorescein diacetate (DCFH-DA) staining, and measurement of oxidative stress indicators such as nitric oxide and lipid peroxidation levels. Antioxidant activity was assessed by glutathione (GSH) levels, while apoptosis was investigated via Caspase 3 and 9 activity and gene expression analysis (Bax, p53, and Bcl-2) using real-time polymerase chain reaction (RT-PCR). ResultsThe novel Bru-Cu(OH)₂-ZnO NPs demonstrated significant anti-cancer activity by markedly reducing K562 cell viability and enhancing cytotoxicity in a dose-dependent manner. These nanoparticles effectively scavenged free radicals, increased lipid peroxidation and nitric oxide levels, and improved caspase activity. Notably, gene expression analysis revealed that Bru-Cu(OH)₂-ZnO NPs led to overexpression of pro-apoptotic genes (Bax and p53) and downregulation of the anti-apoptotic gene (Bcl-2), highlighting their potential as effective cancer therapeutics. ConclusionThe synthesized Bru-Cu(OH)2-ZnO NPs shown excellent anti-cancer efficacy against the K562 cell line. This study underscores the potential of combining bioactive compounds with metal oxide nanoparticles to enhance targeted drug delivery and therapeutic effectiveness, offering a promising approach for advancing cancer treatment.

Bacteria-responsive drug release platform for the local treatment of bacterial vaginosis

Bacterial vaginosis (BV) is a common vaginal infection affecting millions of women. Vaginal anaerobic dysbiosis occurs whenLactobacillusspp., the dominant flora in healthy vagina is replaced by certain overgrown anaerobes, resulting in unpleasant symptoms such as vaginal discharge and odor. With a high recurrence rate, BV also severely impacts the overall quality of life of childbearing women by inducing preterm delivery and increasing the risks of pelvic inflammatory disease and sexually transmitted infections. Among various BV-associated bacteria,Gardnerella vaginalis(G. vaginalis) has been identified as a primary pathogen since it has been isolated from almost all women carrying BV and exhibits higher virulence potential over other bacteria. When dealing with BV relapse, intravaginal drug delivery systems are superior to conventional oral antibiotic therapies in improving therapeutic efficacy owing to more effective drug dose, reduced drug resistance and minimized side effects such as stomach irritation. Traditional intravaginal drug administration generally involves solids, semi-solids and delivery devices inserted into the vaginal lumen to achieve sustained drug release. However, they are mostly designed for continuous drug release and are not preventative therapies, resulting in severe side effects caused by excess dosing. Stimuli-responsive systems that can release drug only when needed ('on-demand') can help diminish these negative side effects. Hence, we developed a bacteria-responsive liposomal platform for the prevention and treatment of BV. This platform demonstrated sustained drug release in the presence of vaginolysin, a toxin secreted specifically byG. vaginalis. We prepared four liposome formulations and evaluated their responsiveness toG. vaginalis. The results demonstrated that the liposome formulations could achieve cumulative drug release ranging from 46.7% to 51.8% over a 3-5 d period in response toG. vaginalisand hardly any drug release in the presence ofLactobacillus crispatus(L. crispatus), indicating the high specificity of the system. Overall, the bacteria-responsive drug release platform has great potential, since it will be the first time to realize sustained drug release stimulated by a specific pathogen for BV prevention and treatment. This on-demand therapy can potentially provide relief to the millions of women affected by BV.

Profile of Dermatologic Side Effects of Tyrosine Kinase Inhibitor (EGFR-TKIs) in Lung Cancer Patients

Background: Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKIs) drugs are commonly used target therapies in patients with advanced-stage non-small cell carcinoma lung cancer (NSCLC).Objectives: This study aims to provide an overview of dermatologic side effects and quality of life index of NSCLC patients who received EGFR-TKIs targeted therapy at Dharmais Cancer Hospital.Methods: This study used a cross-sectional design. Inclusion criteria were patients who received EGFR-TKIs targeted therapy, namely gefitinib, erlotinib, and afatinib, in September - October 2023, who were willing to be research subjects, and patients who were not in a medical emergency. In total, 52 patients filled out the dermatology life quality index (DLQI) questionnaire through interviews and medical records. Data evaluation was performed descriptively in the form of percentages.Results: The most common occurrence of dermatologic side effects was skin hypersensitivity reactions with mild severity (grade 1) by 59.6%, moderate severity (grade 2) by 19.2%, and severe severity (grade 3) by 1.9%, and no drug dermatologic side effects by 19.2%. In comparison, the most DLQI was in the category of not affecting patient life. In general, side effects with moderate (grade 2) and severe (grade 3). The severity will decrease to mild severity (grade 1) when already getting topical corticosteroid drugs or combinations with oral antibiotics and antihistamine drugs.Conclusion: The most severe side effect was grade 1, which slightly affected the patient's quality of life. Education and monitoring of side effects and management of symptoms are necessary to reduce the severity and improve patients' quality of life.

Ocular pharmacokinetics of acetazolamide from intravitreal implants by high-performance liquid chromatography coupled to tandem mass spectrometry

Glaucoma, a leading cause of irreversible blindness, affects about 70 million people globally. Its treatment focuses on reducing intraocular pressure. Acetazolamide, a potent anti-glaucoma drug, is currently used only systemically due to low solubility and permeation, which cause severe side effects. Developing topical medications with acetazolamide requires robust analytical methods for its detection in biological samples. In this context, this study aimed to develop a method to quantify acetazolamide in rabbit vitreous humor samples. The method involved a simple, fast, inexpensive, and environmentally friendly protein precipitation step for sample preparation, needing just 50 μL of sample and 200 μL of organic solvent, with adequate recovery. This was combined with high-performance liquid chromatography coupled to tandem mass spectrometry, enabling highly sensitive (LOQ of 5 ng/mL) quantification within only 5 min. The method proved to be selective, precise, and accurate, with well-fitted analytical curves, with no carryover, and no matrix effect impacting reliability. The method was successfully applied to analyze vitreous humor samples from rabbits in pharmacokinetic studies, monitoring drug release from intravitreal implants. Results showed a controlled release profile, with a maximum drug concentration (Cmax) of 426.01 ± 64.57 ng/mL, time to reach Cmax (Tmax) of 28 days, and area under the curve (AUC0–42 and AUC0-∞) of 7722.66 ± 1125.96 ng days/mL and 8998.11 ± 1311.92 ng days/mL, respectively. The device demonstrated significantly slower elimination, ensuring therapeutic levels for an extended period when compared to intravitreal injection.

Network pharmacology, molecular docking and experimental approaches of the anti-proliferative effects of Rhamnus prinoides ethyl-acetate extract in cervical cancer cells

BackgroundCervical cancer, one of the lethal cancers among women, is a challenging disease to treat. The current therapies often come with severe side effects and the risk of resistance development. Traditional herbal medicine, with its potential to offer effective and less toxic options, is a promising avenue. This study was undertaken to investigate the potential of Rhamnus prinoides (R. prinoides) root bark extracts in selectively inhibiting the proliferation of cervical cancer cells, using the HeLa cell line as an in vitro model. MethodsR. prinoides plant extracts were first screened at a fixed concentration of 200 μg/ml to determine the active extract. The selective anti-proliferative activity of the active extract was evaluated in a concentration dilution assay using the (3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide) MTT assay on cancerous (HeLa) cells and non-cancerous (Vero) cells to determine the half-maximal inhibitory (IC50) and half-cytotoxic concentrations (CC50), respectively. Functional assays on cell morphology (by microscopy), cell migration (wound healing assay) and cell cycle (by flow cytometry) were also conducted. The active extract was analyzed using Gas Chromatography/Mass Spectrometry (GC/MS) to determine any compounds it contained. Following identification of possible gene targets by network pharmacology, the genes were validated by molecular docking and Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR). ResultsThe ethyl acetate extract of R. prinoides (EARP), the most active extract, selectively inhibited the growth of cervical cancer cells, their migration and induced cell cycle arrest at the S phase. In silico analysis revealed that squalene, 3,3a,6,6-tetramethyl-4,5,5a,7,8,9-hexahydro-1H-cyclopenta[i]indene and Olean-12-en-3.beta.-ol, acetate showed acceptable drug-like characteristics and may be partly attributed to the bioactivity demonstrated and the deregulation of the mRNA expression of AKT1, NF-κB, p53, Bax, Bcl-2, and Er-b-B2. ConclusionThis study, for the first time, demonstrates the anti-proliferation effects of EARP and forms a firm foundation for further drug development studies.

3-T MR-guided focused ultrasound thalamotomy for tremor in patients with a cardiac pacemaker: case series and review of the literature.

MR-guided focused ultrasound (MRgFUS) has proven its efficacy and safety for the treatment of essential tremor (ET) and/or Parkinson's disease (PD). However, having a cardiac pacemaker has been considered an exclusion criterion for the use of MRgFUS. Only 2 patients with a cardiac pacemaker treated with MRgFUS have been previously reported, both treated using 1.5-T MRI. In this paper, the authors present their experience performing 3-T MRgFUS thalamotomy in 4 patients with an implanted cardiac pacemaker. Treatments were uneventful regarding complications or severe side effects. MRgFUS using 3-T MRI was found to be an efficient and safe treatment for ET and/or PD in patients with an MRI-compatible pacemaker.

Unveiling the antiurolithiatic potentiality of two benzene sulfonamide derivatives against ethylene glycol-induced renal calculi

ObjectiveOxidative stress and inflammation play crucial roles in the onset of kidney injury and crystal formation caused by hyperoxaluria. Indapamide is a potent medication for treating renal calculi, but it has severe side effects such as hypokalemia, hypercalcemia, and hyperuricemia. Therefore, it is advisable to explore alternative treatments that do not have these side effects. The study aimed to reveal the antiurolithiatic potential of two benzene sulfonamide derivatives (SBCl and SBF; A and B, respectively) against ethylene glycol-induced kidney stones. MethodsThe rats were divided into two main groups: the first group consisted of 20 rats with induced kidney stones, and the second group included 15 control rats. This division enabled a comparative analysis between rats with kidney stones and those without, offering insights into the effects of kidney stone induction on various physiological parameters and biochemical markers. The effectiveness of benzene sulfonamide derivatives (compounds A and B) was assessed in rats with induced kidney stones. The treatment was given orally by gavage for 21 days, administered every 48h after inducing kidney stones with 0.12ml of 5% ethylene glycol (EG). ResultsThe influence of compounds A and B on electrolytes, biochemical, antioxidant, and inflammatory reactions in induced kidneys underscores their potential therapeutic advantages in alleviating the advancement of kidney stone disease and related complications. ConclusionBoth compounds were found to possess equal effectiveness in inhibiting the complications of stone formation. However, SBCl-EG showed superior antioxidant and inflammatory parameters effects compared to SBF-EG. Our study's findings underscore the potential benefits of derivatives in treating nephrolithiasis and related oxidative disorders, highlighting their superior effects on antioxidant and inflammatory responses compared to standard treatments.

Doxorubicin-induced Immunogenic Cell Death Impairs Tumor Progression and Distant Metastasis in a 4T1 Breast Cancer Tumor Model.

Cancer is an individual disease and its formation and development are specific to each host. Conventional treatments are ineffective in complex cases, such as metastasis, and have severe adverse side effects. New strategies are needed to address the problem, and the use of immunogenic cell death (ICD) as a trigger or booster of the immune system through the exposure of damage-associated molecular patterns, along with tumor antigens, by cancerous cells is presented as an immunization approach in this work. For this purpose, 4T1 cells were exposed to doxorubicin (DOX) for 24 hours and then, these cells undergoing ICD were subcutaneously administered to mice. The ICD induction by DOX on 4T1 was assessed by flow cytometry and image analysis. This immunization process was performed three times and after the last administration, the immunized mice were challenged with a subcutaneous xenograft of live cancer cells. The results demonstrate that the mice immunized with cells undergoing ICD after exposure to DOX presented no primary tumor or indications of distant metastatic lesion development. In summary, our findings indicate that the immunization process utilizing ICD is indeed efficacious in managing this aggressive form of pre-clinical breast cancer.

Single-cell RNA sequencing of pediatric Hodgkin lymphoma to study the inhibition of T cell subtypes.

Pediatric classic Hodgkin lymphoma (cHL) patients have a high survival rate but suffer from severe long-term side effects induced by chemo- and radiotherapy. cHL tumors are characterized by the low fraction (0.1%-10%) of malignant Hodgkin andReed-Sternberg (HRS) cells in the tumor. The HRS cells depend on the surrounding immune cells for survival and growth. This dependence is leveraged by current treatments that target the PD-1/PD-L1 axis in cHL tumors. The development of more targeted therapies that are specific for the tumor and are therefore less toxic for healthy tissue compared with conventional chemotherapy could improve the quality of life of pediatric cHL survivors. Here, we applied single-cell RNA sequencing (scRNA-seq) on isolated HRS cells and the immune cells from the same cHL tumors. Besides TNFRSF8 (CD30), we identified other genes of cell surface proteins that are consistently overexpressed in HRS cells, such as NRXN3 and LRP8, which can potentially be used as alternative targets for antibody-drug conjugates or CAR T cells. Finally, we identified potential interactions by which HRS cells inhibit T cells, among which are the galectin-1/CD69 and HLA-II/LAG3 interactions. RNAscope was used to validate the enrichment of CD69 and LAG3 expression on T cells near HRS cells and indicated large variability of the interaction strength with the corresponding ligands between patients and between tumor tissue regions. In conclusion, this study identifies new potential therapeutic targets for cHL and highlights the importance of studying heterogeneity when identifying therapy targets, specifically those that target tumor-immune cell interactions.

Real-world experience with long-term albumin in patients with cirrhosis and ascites

Background and AimsLong-term albumin (LTA) is currently standard of care for patients with decompensated cirrhosis in many Italian hepatological centres. This real-life study aimed to describe patient, logistical and treatment-related characteristics in daily clinical practice and to identify predictors of response. MethodsMulticentre, retrospective, observational study in patients with cirrhosis and ascites receiving LTA between 01/2016 and 02/2022 and followed until death, TIPS, transplantation or 02/2023. Results312 patients, the majority with alcohol-related cirrhosis, were included. At baseline, median Child-Pugh was 8, MELD 15, and MELD-Na 18. Ascites was grade 2 in 55% of patients, grade 3 in 35% and refractory in 27%, while 47% had paracentesis in the previous 6 months. Median LTA was 10 months with a median dose of 40 g/week.Ascites resolved to grade 0-1 in 34% of patients within the first 3 months and 56% at the end of treatment. Predictors of ascites resolution were age (p=0.007), baseline grade of ascites (p=0.007), no paracentesis in the previous 6 months (p=0.001), etiological treatment in the past 12 months or during LTA (p=0.005), weekly albumin dose (p=0.014) and serum albumin concentration of 40 g/L after one month of treatment (p=0.017). Of the 83 patients with refractory ascites at inclusion, 26% had grade 0/1 ascites at the last observation. No severe albumin-related side-effects were reported and only 1% discontinued due to logistic reasons. ConclusionsLTA is feasible as an outpatient treatment for the management of ascites. In the current study, more than half of patients receiving LTA on top of diuretics resolved their ascites, including some with refractory ascites. Predictors of response to LTA provide useful information for tailoring treatment. IMPACT AND IMPLICATIONSThe ANSWER randomized clinical trial has shown that long-term albumin treatment (LTA) is an effective approach for the management of patients with cirrhosis and ascites. This observational study provides novel information on target patients, modalities and length of treatment, predictors of ascites resolution, stopping criteria, and clinical trajectories of patients on treatment.LTA is a feasible option in the daily clinical practice for the management of ascites when given on top of diuretics. Rather than an alternative therapy, LTA should be integrated with the other treatments options already available for patients with difficult-to-treat ascites. The predictive factors of response identified in the present study can help physicians to individualize LTA and optimize the decision-making process.