Significant Side Effects Research Articles

Systemic hypertension with VEGFR inhibitor (axitinib) therapy in cancer patients: A meta-analysis and systematic review of randomized controlled trials

Vascular endothelial growth factor receptor inhibitors (VEGFRi), namely axitinib, are commonly used chemotherapeutic agents in patients with cancer; however, this medication has a significant cardiovascular side effect profile, such as high-grade hypertension. We performed this updated meta-analysis of RCTs to compile cardiovascular adverse events, such as all-grade and high-grade (>3) hypertension, the risk for thrombosis (DVT and PE), and peripheral edema. A systematic search was performed on PubMed, Cochrane, and Embase from inception until October 2023 for studies using axitinib to treat various cancers. Trials with patients randomly allocated for VEGFRi drug therapy with axitinib and reported all-grade hypertension as an outcome were included. Statistical analysis was performed using Cochrane Review Manager to calculate pooled proportions of odds ratios (OR) with a 95 % confidence interval (CI) using the random-effects model, Mantel−Haenszel method. A total of 8 RCTs and 2502 patients were included in the review. Compared with the placebo group, the VEGFRi (Axitinib) therapy group was associated with a higher risk of all-grade and high-grade hypertension, hand–foot syndrome, and fatigue. Furthermore, there was no increased risk of thromboembolism (DVT/PE) or hypothyroidism. However, a lower risk of peripheral edema was noted between the two groups. Screening for patients with preexisting hypertension, identifying risk factors for cardiovascular diseases before the initiation of VEGFRi therapy, and careful monitoring of high-risk patients during VEGFRi therapy, as well as prompt treatment with antihypertensive drugs, will help mitigate the adverse effects. Further evaluation using prospective designs is required to study the clinical significance and develop mitigation strategies.

Comparative Proteomics Identified EXOSC1 as a Target Protein of Anticancer Peptide LVTX-8 in Nasopharyngeal Carcinoma Cells.

Nasopharyngeal carcinoma (NPC) is a prevalent malignancy that usually occurs among the nose and throat. Due to mild initial symptoms, most patients are diagnosed in the late stage, and the recurrence rate of tumors is high, resulting in many deaths every year. Traditional radiotherapy and chemotherapy are prone to causing drug resistance and significant side effects. Therefore, searching for new bioactive drugs including anticancer peptides is necessary and urgent. LVTX-8 is a peptide toxin synthesized from the cDNA library of the spider Lycosa vittata, which is consisting of 25 amino acids. In this study, a series of in vitro cell experiments such as cell toxicity, colony formation, and cell migration assays were performed to exam the anticancer activity of LVTX-8 in NPC cells (5-8F and CNE-2). The results suggested that LVTX-8 significantly inhibited cell proliferation and migration of NPC cells. To find the potential molecular targets for the anticancer capability of LVTX-8, high-throughput proteomic and bioinformatics analysis were conducted on NPC cells. The results identified EXOSC1 as a potential target protein with significantly differential expression levels under LVTX-8+/LVTX-8- conditions. The results in this research indicate that spider peptide toxin LVTX-8 exhibits significant anticancer activity in NPC, and EXOSC1 may serve as a target protein for its anticancer activity. These findings provide a reference for the development of new therapeutic drugs for NPC and offer new ideas for the discovery of biomarkers related to NPC diagnosis. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (https://proteomecentral.proteomexchange.org) via the iProX partner repository with the data set identifier PXD050542.

Comparative analysis of immunological changes following realgar and arsenic trioxide treatments in a murine model of myelodysplastic syndrome

Background Myelodysplastic syndrome (MDS) is a prevalent hematological neoplastic disorder in clinics and its immunopathogenesis has garnered growing interest. Oral and intravenous arsenic agents have long been used to treat hematological malignancies. The main component of oral arsenic is realgar (arsenic disulfide), while arsenic trioxide is the main component of intravenous arsenic. Methods This study aimed to assess the effects of ATO and Realgar on the enhancement of peripheral blood, drug safety, and T cell immune status in the NUP98-HOXD13 (NHD13) mice model of MDS, specifically in the peripheral blood, spleen, and liver. Results The study findings indicate that realgar and arsenic trioxide (ATO) can improve peripheral hemogram in mice, whereas realgar promotes higher peripheral blood cell production than ATO. Furthermore, the clinical administration method and dose did not cause significant toxicity or side effects and thus can be considered safe. Coexistence and interconversion of hyperimmune function and immunosuppression in mice were also observed in this study. In addition, there were interactions between immune cells in the peripheral blood, spleen, and liver to regulate the immune balance of the body and activate immunity via T-cell activation. Conclusion In summary, oral and intravenous arsenic agents are beneficial in improving peripheral hemogram and immunity in mice.

A Biodegradable Nano-Drug Delivery Platform for Co-Delivery of Minocycline and Chitosan to Achieve Efficient and Safe Non-Surgical Periodontitis Therapy.

Mesoporous silica nanoparticles (MSN) are widely used as ideal nanovehicles for the delivery of chemotherapeutic drugs. However, the balance between high anti-periodontitis activity and low biotoxicity has been challenging to maintain in most relevant studies owing to the slow degradation of silica in living organisms. In this study, -responsive hydroxyapatite (HAP) was doped into the MSN skeleton, and the chemotherapeutic drug minocycline hydrochloride (MH) was loaded into the pores of MSN, forming a negatively charged drug delivery system. Cationic chitosan (COS) is a biodegradable material with high antibacterial performance and good biosafety. In this study, COS was immobilized on the surface of the drug-loaded particles through stable charge interaction to construct a composite drug delivery system (MH@MSNion@COS). In vitro and cellular experiments demonstrated effective degradation of the nanocarrier system and synchronized controlled release of the drug. Notably, compared with single MH administration, this system, in which MH and COS jointly regulated the expression levels of periodontitis- associated inflammatory factors (TNF-α, IL-6, IL-1β, and iNOS), better inhibited the progress of periodontitis and induced tissue regeneration without showing significant toxic side effects in cells. This system provides a promising strategy for the design of intelligent, efficient, and safe anti-periodontitis drug delivery systems.

Experience of dinoprostone vaginal insert using for cervical ripening and induction of labor

Introduction. Presently, preinduction and induction of labour is one of the approaches to improve maternal and perinatal outcomes. In this regard, the rate of labour induction is steadily increasing.Aim. To determine the efficacy and safety of dinoprostone vaginal insert for cervical ripening and labor induction.Materials and methods. The study included 81 women with a singleton pregnancy of 37 weeks. and more, cephalic presentation of the fetus, with the birth canal not ready and the presence of indications for induction of labor. Dinoprostone vaginal insert was placed for 24 hours or till onset of labor. After removal of the dinoprostone vaginal insert patient was undergoing cervical assessment by digital Bishop Score immediately. If labor didn’t start spontaneously, additional cervical ripening procedures may be considered or labor induction.Result. The Bishop score increased on average by 2 points after cervical ripening with dinoprostone vaginal insert. 77.78% of patients went into labor before dinoprostone vaginal insert removing. 71.6% of the women had the vaginal birth. The cesarean section rate was 29.6%. Failed labor induction was observed in 2.47% cases. All the children were born alive. The average weight of newborns corresponded to the general population. No infectious complications or significant side effects were recorded in the study.Conclusion. The use of dinoprostone vaginal insert is an effective method for cervical ripening (increase in Bishop score by an average of 2 points, p < 0.05) and labor induction (onset of labor before removal of SVT in 78% of cases) with a good safety profile (there were no serious adverse or side effects).

Abstract ED01-01: Optimizing endocrine therapy in premenopausal women

Abstract Premenopausal women with early-stage hormone receptor (HR)-positive breast cancer are candidates for adjuvant endocrine therapy and have several treatment options. The clinical team should assess an individual woman’s risk of recurrence, estimate benefits from specific endocrine manipulations, and consider co-morbidities, adverse event profile and host factors. Risk stratification strategies including clinic-pathologic features, genomic assays and composite scores can guide recommendations regarding type and duration of endocrine therapy, in particular in node-negative disease. Adjuvant tamoxifen for 5 to 10 years significantly reduces breast cancer recurrence and death. Premenopausal women who are at high risk of recurrence benefit from ovarian function suppression (OFS) with tamoxifen or an aromatase inhibitor for 5 years. Those include women with high-risk clinico-pathological features and younger age, and for whom chemotherapy is commonly recommended. There are currently no available data regarding the use of extended OFS beyond 5 years. Newer data support the addition of CDK 4/6 inhibitors to endocrine therapy in women with high-risk disease. Endocrine therpay is associated with frequent bothersome and few significant side effects that can negatively impact quality of life and adherence to treatment. Clinicians must carefully weigh the benefits associated with specific endocrine therapies, and possible short- and long-term side effects to individualize therapy, and to consider interventions to enhance adherence. Citation Format: V. Stearns. Optimizing endocrine therapy in premenopausal women [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr ED01-01.

Oxygen-Evolving Radiotherapy-Radiodynamic Therapy Synergized with NO Gas Therapy by Cerium-Based Rare-Earth Metal-Porphyrin Framework.

The efficacy of traditional radiotherapy (RT) has been severely limited by its significant side effects, as well as tumor hypoxia. Here, the nanoscale cerium (Ce)-based metaloxo clusters (Ce(IV)6)-porphyrin (meso-tetra (4-carboxyphenyl) porphyrin, TCPP) framework loaded with L-arginine (LA) (denoted as LA@Ce(IV)6-TCPP) is developed to serve as a multifarious radio enhancer to heighten X-ray absorption and energy transfer accompanied by O2/NO generation for hypoxia-improved RT-radiodynamic therapy (RDT) and gas therapy. Within tumor cells, LA@Ce(IV)6-TCPP will first react with endogenous H2O2 and inducible NO synthase (iNOS) to produce O2 and NO to respectively increase the oxygen supply and reduce oxygen consumption, thus alleviating tumor hypoxia. Then upon X-ray irradiation, LA@Ce(IV)6-TCPP can significantly enhance hydroxyl radical (•OH) generation from Ce(IV)6 metaloxo clusters for RT and synchronously facilitate singlet oxygen (1O2) generation from adjacently-coordinated TCPP for RDT. Moreover, both the •OH and 1O2 can further react with NO to generate more toxic peroxynitrite anions (ONOO-) to inhibit tumor growth for gas therapy. Benefitting from the alleviation of tumor hypoxia and intensified RT-RDT synergized with gas therapy, LA@Ce(IV)6-TCPP elicited superior anticancer outcomes. This work provides an effective RT strategy by using low doses of X-rays to intensify tumor suppression yet reduce systemic toxicity.

Abstract PO1-01-06: Patterns in use and tolerance of adjuvant neratinib in patients with hormone receptor (HR)-positive, HER2-positive early-stage breast cancer

Abstract Background: In the ExteNET study, 1 year of neratinib therapy was shown to derive a significant invasive disease-free survival (iDFS) benefit in HR+, HER2+, node-positive disease after trastuzumab-based adjuvant therapy. Currently, the NCCN guidelines recommend extended adjuvant neratinib following trastuzumab-based therapy for patients (pts) with high-risk HR+ HER2+ disease. Limitations to use of neratinib include significant gastrointestinal side effects which often result in pts discontinuing treatment. In this study, we aimed to identify high-risk clinical features and characteristics of pts who were offered adjuvant neratinib therapy and factors that impacted treatment completion versus discontinuation. Methods: We performed a retrospective review of all pts with early-stage HR+ HER2+ breast cancer who were prescribed neratinib from 2017-2023 at our institution. We used the electronic medical record to extract information on patient characteristics, clinical and high-risk features. High-risk was defined as any of the following: at least 4 lymph nodes positive for disease, 1-3 lymph nodes positive for disease and a grade 3 (poorly differentiated) tumor, tumor > 5 cm, or Ki67 > 20%. Length of time on treatment, treatment holds, dose reductions and up-titrations were documented. Statistical analysis was performed using two-sided T-tests and chi-square tests. Results: We identified 62 eligible pts of whom 34 (55%) completed 1 year of neratinib and 28 (45%) did not. Median age at diagnosis was 51.5 years. 49% of pts were pre-menopausal at diagnosis, 43% were post-menopausal, 5% were peri-menopausal and 3% had undocumented menopausal status at diagnosis. Clinical features of the pts are documented in Table 1. Sixty percent of patients offered neratinib were considered high-risk at diagnosis, based on definitions described above. 73% of pts received neoadjuvant treatment with pertuzumab in addition to trastuzumab. 24 pts (39%) had residual disease and 22 pts (35%) received adjuvant T-DM1. The most common reason for neratinib discontinuation was inability to tolerate side effects (54%) followed by pill burden (18%). The most common side effect experienced by pts was diarrhea despite anti-diarrheal prophylaxis (56%), followed by rash (8%). Pts who received an up-titration of neratinib were more likely to complete the full course of neratinib when compared to those who did not (76% vs. 40.5% p = 0.013). The median starting dose of those who completed neratinib treatment was 140 mg vs. 240 mg in those who did not (p = 0.016). The median length of time on neratinib for those that did not complete the 1-year treatment course was 30 days. Neither group experienced a statistically significant greater likelihood of treatment holds or dose reductions. In terms of outcomes, 10 pts had progression of disease of whom 7 did not complete neratinib treatment (p = 0.169). Interestingly, those 7 pts developed metastatic disease and 57% had central nervous system metastases. Conclusions: Pts are more likely to complete 1 year of adjuvant neratinib with dose up-titration. Dose reductions and interruptions did not affect neratinib adherence in our patient population. Seven pts in our study developed metastatic disease, all of whom did not complete adjuvant neratinib treatment. Future prospective studies are needed to further determine the impact of adjuvant neratinib treatment on iDFS in pts who have received pertuzumab and/or T-DM1. Table 1: Clinical Features of Patients Prescribed Neratinib Citation Format: Julia Blanter, Elena Baldwin, Rima Patel, Tianxiang Sheng, Amy Tiersten. Patterns in use and tolerance of adjuvant neratinib in patients with hormone receptor (HR)-positive, HER2-positive early-stage breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-01-06.

Abstract PO2-20-06: Using the Australian Cardio-Oncology Registry to study long-term cancer therapy related cardiac dysfunction in adult oncology patients – The Chris O’Brien Lifehouse experience

Abstract Background Cancer therapy related cardiac dysfunction (CTRCD) is a significant side effect of several chemotherapies, targeted agents, and immunotherapies integral to treatment. Anthracyclines are an example of a commonly used chemotherapy drug class that can cause irreversible early and late onset heart failure. CTRCD often leads to dose reductions and treatment delays or cessation, limiting treatment success and contributing to increased mortality and life-long morbidity in oncology survivors. In Australia, there are currently no multi-centre, longitudinal studies examining CTRCD in adult oncology patients. Trial design The Australian Cardiology-Oncology Registry (ACOR) is a prospective observational non-interventional study involving 14 sites across Australia. Patient information is obtained from hospital medical records and de-identified upon entry into the registry. Patient demographics, medical history, cancer diagnosis, treatment, cardiac evaluations, and the management of demonstrated CTRCD are recorded. Data is collected at baseline (prior to treatment), and then at six-monthly intervals thereafter. Additionally, patients who develop anthracycline-induced cardiotoxicity (ACT) will be asked to participate in the biobanking study, which will involve a one-off 12mL peripheral blood draw that will be processed at an external site for whole genome exome sequencing and the development of pluripotent derived stem cell cardiomyocytes. Eligibility criteria Inclusion Criteria • Adult oncology patients (>18+ years of age) treated with cardiotoxic therapies within the last 5-years Exclusion Criteria • Diagnosis of Trisomy 21 • Patients being treated with palliative intent Specific aims Chris O’Brien Lifehouse aims to use the ACOR to explore the epidemiology, clinical presentation, and management of CTRCD amongst adult oncology patients receiving cardiotoxic therapies. In addition, a biobanking sub-study will attempt to identify gene polymorphisms predisposing individuals to developing ACT. It is hoped that such longitudinal data collection can lead to the introduction of an ACT susceptibility genetic screening test allowing for the inclusion of patient risk stratification prior to anthracycline exposure in routine cancer treatment. Statistical methods Descriptive statistics will be used for variables for quantitative analysis. Kaplan Meier analyses will be used for survival curves, freedom from cardiac failure since enrolment and freedom from arrhythmia since enrolment. An annual report will be produced. Present accrual and target accrual At the time of submission, 224 adult oncology patients have been recruited to the ACOR via Chris O’Brien Lifehouse with the opening of the biobanking sub-study currently in progress. The ACOR anticipates with full registered site capacity to capture 600 patients annually. Citation Format: Jocelyn Finney, Ben Felmingham, Sanjeev Kumar, Alina Mahmood, Lisa Horvath, David Celermajer, Rachel Conyers. Using the Australian Cardio-Oncology Registry to study long-term cancer therapy related cardiac dysfunction in adult oncology patients – The Chris O’Brien Lifehouse experience [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-20-06.

Abstract PO3-28-11: Potassium channel activity unveils breast cancer vulnerability

Abstract Decades of studies on ion channels have vastly demonstrated the critical functions of these proteins in many physiological and pathological conditions and have provided for an extraordinary pharmacopeia of useful compounds, often with selective actions and minimal side effects. Nevertheless, the function of ion channels in controlling cancer biology is still unknown and underexplored. Our research demonstrates that breast cancer downregulates expression of specific potassium channels (e.g., Kv11.1, KCa3.1) independently of their molecular characterization (ER+, HERB2+ and TNBC). Furthermore, breast cancer patients expressing high protein level of each of these channels presents a better overall survival when compared with patients with low expression. These data indicate that potassium channels can be prognostic factors and that high activity of these protein affects tumor growth. Therefor we wanted to understand the therapeutic benefits of pharmacological targeting specific potassium channels in breast cancer. We discovered that stimulation of the Kv11.1 with specific and selective activator molecules produced a significant growth arrest in a variety of experimental systems including in vitro, in vivo and ex vivo (e.g. Patient-derived organoids) systems. Studying the biochemical pathways that underline these events we discovered that Kv11.1 agonists affects different hallmarks of cancer including metabolism, growth and metastasis signaling without producing significant side effects. For example, use of Kv11.1 agonists produced a strong suppression of oncogene protein function including c-Myc while increasing oncosuppressors such as p21 and p16. These events associated with activation of a senescent phenotype. Furthermore, stimulation of Kv11.1 channel reversed the epithelial-to-mesenchymal transition by inhibiting the WNT signaling and reduced spreading of a TNBC by arresting the metastatic process.. Furthermore, Kv11.1 activation produced a Ca2+-dependent mitochondria damage where the antioxidant transcription factor NRF2 played a fundamental role in determining resistance to death. Therefore, we conclude that targeting the Kv11.1 potassium channel in breasts cancer can be considered a new, effective and safe targeting strategy for breast cancer. Citation Format: Saverio Gentile. Potassium channel activity unveils breast cancer vulnerability [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-28-11.

On the side effects of fiscal policy: Fiscal rules and income inequality

Contributing to an important literature on the side effects of fiscal policy, this paper employs a treatment effect analysis to show that fiscal rules (FR) have significant side effects on income inequality (IQ). Economically meaningful, this favorable causal direct effect is robust to many alternative specifications. Nevertheless, not all FR are alike: balanced budget and debt rules decrease IQ, contrary to expenditure rules that increase it. Finally, the effect of FR on IQ is found to be subject to heterogeneity related to various factors. Given the current upward global IQ trends, our results provide insightful evidence for governments of countries aiming at reducing IQ.

Short Synthetic Peptides as COX-2 Inhibitor with Antiproliferative Activity: A Probable Future Class of Drugs

Abstract: Cancer remains a leading cause of death worldwide, with traditional chemotherapy treatments causing significant side effects. Short synthetic peptides have emerged as a potential alternative due to their unique properties, including selectivity, stability and biocompatibility. Recent research has shown that short peptides can act as effective anticancer agents through their ability to inhibit the COX-2 (Cyclooxegenase-2) enzyme, a key enzyme involved in tumor growth and progression. In particular, short peptides have demonstrated promising results in targeting the tumor microenvironment, disrupting angiogenesis, and inducing apoptosis in cancer cells. This review summarizes the current literature on short peptides as anticancer agents, including their mechanisms of action and future directions for research and development. The results suggest that short peptides hold significant potential as a new class of anticancer agents and warrant further investigation.

Peanut oral immunotherapy using an extensively heated and baked novel composition of peanuts.

Oral immunotherapy (OIT) is an increasingly acceptable therapeutic option for peanut-allergic (PA) children, despite significant side effects. Major peanut allergenic proteins are heat-resistant and are not rendered hypoallergenic after baking or cooking. Lyophilized peanut protein-MH (LPP-MH) is a novel composition from developing peanuts, enabling cooking-induced reduction in allergenicity. We aimed to explore the safety and efficacy of OIT, with extensively heated and baked (EHEB) LPP-MH in PA children. In a single-arm, single-center, pilot study, PA children with a single highest tolerated dose of <100 mg peanut protein were placed on a 40-week OIT protocol with 300 mg daily of heat-treated LPP-MH. A repeat open peanut food challenge was performed after 40 weeks of treatment and at a 6-12 months of follow-up visit. Thirty-three children with PA were enrolled, with a mean cumulative tolerated dose (MCTD) of 71.2 mg PP (95% CI 45-100 mg). After 40 weeks, 32/33 patients were able to consume more than 300 mg of natural PP, with MCTD of 1709 mg (CI 365-3675 mg). There were no severe allergic reactions requiring epinephrine, during any of the observed LPP-MH challenges or any treatment related doses at home. After 6-12 months on daily maintenance, the MCTD was 8821 mg (95% CI 1930-13,500 mg). This enabled most children age-appropriate dietary inclusion of peanuts. An OIT protocol with heat-treated LPP-MH, a novel composition from developing peanuts, seems a potentially safe and efficacious OIT modality for PA children, enabling the introduction of dietary levels of peanut proteins in highly allergic PA children. Validation in randomized controlled studies is mandated.

Docking study of ferulic acid derivates on FGFR1, ADME prediction, and QSPR analysis

Background: FGFR-1 is an angiogenic receptor that plays a huge role in the cancer growth pathway. Angiogenesis inhibitory drugs released have significant side effects. Therefore, research into discovering anti-angiogenic agents to achieve good health and well-being is still necessary. Objective: To design the novel anti-angiogenic candidates from ferulic acid (FA) by docking study on FGFR1, to predict the ADME profile, and to find out the structural relationship of their pharmacokinetic properties as QSPR analysis. Method: Autodock Tools performed a docking study. ADME prediction was conducted using SwissADME. The MLR approach determined the QSPR model. Result: The docking results showed that FA-8 and FA-18 had the lowest free energy binding, inhibition constant, and GI absorption. The QSPR analysis obtained the equation model: Log HIA = 0,018 Log P2 + 0,069 Log P + 0,020 CMR + 0,001 Etotal + 1,771 with n = 24, correlation coefficient (r)= 0.621, p-value= 0.046 and F-value= 2.975. Conclusion: Modifying FA on the phenolic moiety replaced by an ester increased the activity and ADME profile. The predicted bioavailability was supported by high Log P, molar refractivity (CMR), and electronic factor (Etotal). It is recommended that lipophilicity be increased to achieve better pharmacokinetic properties.

Advancements in bioscavenger mediated detoxification of organophosphorus poisoning.

Organophosphorus compounds, widely used in agriculture and industry, pose a serious threat to human health due to their acute neurotoxicity. Although traditional interventions for organophosphate poisoning are effective, they often come with significant side effects. This paper aims to evaluate the potential of enzymes within biological organisms as organophosphorus bioclearing agents. It analyses the technical challenges in current enzyme research, such as substrate specificity, stereoselectivity, and immunogenicity, while exploring recent advancements in the field. A comprehensive review of literature related to detoxifying enzymes or proteins was conducted. Existing studies on organophosphorus bioclearing agents were summarised, elucidating the biological detoxification mechanisms, with a particular focus on advancements in protein engineering and novel delivery methods. Current bioclearing agents can be categorised into stoichiometric and catalytic bioclearing agents, both of which have shown some success in preventing organophosphate poisoning. Technological advancements have significantly improved various properties of bioclearing agents, yet challenges remain, particularly in substrate specificity, stereoselectivity, and immunogenicity. Future research will focus on expanding the substrate spectrum, enhancing catalytic efficiency, prolonging in vivo half-life, and developing convenient administration methods. With the progression of clinical trials, bioclearing agents are expected to become widely used as a new generation of therapeutic organophosphate detoxifiers.

A Prospective Randomized Clinical Study to Assess and Compare the Efficacy of Ultrasound Guided Quadratus Lumborum Block versus Transversus Abdominis Plane Block for Postoperative Analgesia in Patients Undergoing Abdominal Hysterectomy Under General Anaesthesia

Abstract Background and Aims: Multimodal analgesia regimens for optimizing the postoperative pain following abdominal surgeries are a crucial component of enhanced recovery after surgery (ERAS), as it reduces postoperative opioid consumption along with their adverse effects. We compared the analgesic efficacy of ultrasound-guided transmuscular quadratus lumborum block (QLB) versus posterior transversus abdominis plane block (TAPB) with respect to duration of analgesia, modified Defense and Veterans Pain Rating Scale (DVPRS) scores for pain, activity, sleep, stress, and mood, respectively, the total amount of rescue analgesic consumption, hemodynamics parameters and side effects, in patients undergoing total abdominal hysterectomy under general anesthesia. Materials and Methods: In this study, which was prospective, randomized, and double-blind, 60 patients of the American Society of Anesthesiologists Physical Status I and II, aged 18–65 years, undergoing abdominal hysterectomy, were randomized into two groups. Group QLB (n = 30) and Group TAPB (n = 30) received bilateral QLB and TAPB with 40 ml of 0.375% ropivacaine, respectively. The data were compared using standard qualitative and quantitative tests. Results: The duration of pain relief was longer in Group QLB compared to Group TAPB (981.83 ± 138.62 min vs. 637 ± 127.02 min, P &lt; 0.0001). The DVPRS score for pain, activity, sleep, stress, and mood, respectively, were significantly lower in Group QLB (P &lt; 0.05). The total rescue analgesic consumption was significantly lesser in Group QLB (103.33 ± 18.26 mg) compared to Group TAPB (150.00 ± 50.85 mg) (P &lt; 0.0001). No significant hemodynamic changes or side effects were observed (P &gt; 0.05). Conclusion: Bilateral QLB significantly prolonged the duration of analgesia with reduced rescue analgesic requirement compared with bilateral TAPB in patients undergoing total abdominal hysterectomy.

Role of prophylactic tranexamic acid in reducing blood loss during cesarean section: A double-blind placebo-controlled randomized controlled trial.

Postpartum hemorrhage (PPH) is defined by the World Health Organization as blood loss of ≥500 mL within 24 h of delivery. Globally, hemorrhage accounts for 27.1% of maternal deaths, making it the leading direct cause of maternal death. PPH has been identified in more than two-thirds of reported hemorrhage-related deaths, causing 38% of maternal deaths in India. Tranexamic acid, an antifibrinolytic, has been used to control bleeding after PPH is identified. Antenatal women admitted for elective cesarean section were randomized into two arms: the case group (received one gram of tranexamic acid 20 min prior to skin incision) and the control group (received a placebo), each group consisting of 36 participants. Clinical Trials Registry - India (CTRI) registration number - CTRI/2021/02/031579. The mean (±standard deviation [SD]) intraoperative blood loss in the case group was 241.25 (±67.83) mL, and in the control group, it was 344.92 (±146.67) mL (P = 0.001), while postoperative blood loss did not differ significantly between the groups (P = 0.1470). In terms of the difference in hemoglobin, there was a significant difference between the two groups (P = 0.001). No significant maternal or neonatal side effects were found. Preoperative tranexamic acid, when given in elective cesarean section, significantly reduces intraoperative blood loss.

Understanding the Mechanisms of the Gβ5/R7-RGS Complex in Pain Transmission through Single Cell mRNA Profiling

The dorsal root ganglion (DRG) and trigeminal ganglion (TG) contain cell bodies of the peripheral sensory neurons that transmit pain signals from different parts of body to the central nervous system. Peripheral neuropathy and trigeminal neuralgia are common painful conditions that can be caused by pathologies affecting these nerves. Current clinical treatment of these conditions often relies on anticonvulsant drugs with significant neurological side effects. Lack of effective treatments of these conditions highlights the need for better therapeutic approaches. GNB5 encodes the protein Gβ5, a divergent member of the G protein β family, that binds with members (RGS6, 7, 9 and 11) of the R7 subfamily of the regulators of G signaling (R7-RGS) to form obligate Gβ5/R7-RGS complexes. The Gβ5/R7-RGS complex proteins are expressed primarily in neurons including those in the DRG and TG. They function as GTPase-Activating Proteins (GAP) to dampen signaling downstream of Gi/o-coupled receptors. Studies in our lab demonstrated that Adv-Cre+/−; Gnb5fl/fl mice lacking Gnb5 in sensory neurons have significantly reduced mechanical, thermal and chemical nociception. However, RGS7-Cre+/−; Gnb5fl/fl mice lacking Gnb5 in Rgs7 expressing neurons exhibited only diminished mechanical nociception. Additionally, treatment with GABA-B receptor antagonist 2- hydroxysaclofen abolished the inhibition of mechanical nociception in both Advillin- Cre+/-; Gnb5fl/fl and Rgs7-Cre+/-; Gnb5fl/fl mice, implicating the involvement of GABA-B receptor signaling in Gβ5/Rgs7-associated mechanical nociception. To further understand the cellular and molecular mechanisms of Gβ5/R7-RGS complex-mediated nociception, we analyzed and compared the expression profiles of the Gβ5/R7-RGS genes in DRG and TG through bioinformatic analysis of publicly available scRNAseq datasets and in situ hybridization of selected genes using RNAscope technology. We found high levels of Gnb5 expression across all sensory neuron cell types while the expressions of members of R7-RGS subfamily showed distinctive patterns among these neuron cell types. Single cell clustering analysis using known neuronal markers revealed that Rgs7 and Rgs11 were highly expressed in majority of neuron types, while Rgs6 and Rgs9 were represented in smaller, more distinct clusters. These results suggest that particular members of R7-RGS gene family might play distinct roles in different types of nociception, a finding that warrants further investigation into the individual mechanisms of each member of this gene family in pain transmission. NIDDK Intramural Research Program ZIA DK043304-29. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Current State and Future Perspective of Diabetic Wound Healing Treatment: Present Evidence from Clinical Trials.

Diabetes is a chronic metabolic condition that is becoming more common and is characterised by sustained hyperglycaemia and long-term health effects. Diabetes-related wounds often heal slowly and are more susceptible to infection because of hyperglycaemia in the wound beds. The diabetic lesion becomes harder to heal after planktonic bacterial cells form biofilms. A potential approach is the creation of hydrogels with many functions. High priority is given to a variety of processes, such as antimicrobial, pro-angiogenesis, and general pro-healing. Diabetes problems include diabetic amputations or chronic wounds (DM). Chronic diabetes wounds that do not heal are often caused by low oxygen levels, increased reactive oxygen species, and impaired vascularization. Several types of hydrogels have been developed to get rid of contamination by pathogens; these hydrogels help to clean up the infection, reduce wound inflammation, and avoid necrosis. This review paper will focus on the most recent improvements and breakthroughs in antibacterial hydrogels for treating chronic wounds in people with diabetes. Prominent and significant side effects of diabetes mellitus include foot ulcers. Antioxidants, along with oxidative stress, are essential to promote the healing of diabetic wounds. Some of the problems that can come from a foot ulcer are neuropathic diabetes, ischemia, infection, inadequate glucose control, poor nutrition, also very high morbidity. Given the worrying rise in diabetes and, by extension, diabetic wounds, future treatments must focus on the rapid healing of diabetic wounds.

The Application of 2d Mxene Nanosheet -Based Thermosensitive Gel Delivery System Loaded with Cisplatin and Imiquimod for Lung Cancer.

Lung cancer's high incidence and dismal prognosis with traditional treatments like surgery and radiotherapy necessitate innovative approaches. Despite advancements in nanotherapy, the limitations of single-treatment modalities and significant side effects persist. To tackle lung cancer effectively, we devised a temperature-sensitive hydrogel-based local injection system with near-infrared triggered drug release. Utilizing 2D MXene nanosheets as carriers loaded with R837 and cisplatin (DDP), encapsulated within a temperature-sensitive hydrogel-forming PEG-MXene@DDP@R837@SHDS (MDR@SHDS), we administered in situ injections of MDR@SHDS into tumor tissues combined with photothermal therapy (PTT). The immune adjuvant R837 enhances dendritic cell (DC) maturation and tumor cell phagocytosis, while PTT induces tumor cell apoptosis and necrosis by converting light energy into heat energy. Material characterization employed transmission electron microscopy, X-ray photoelectron spectroscopy, phase transition temperature, and near-infrared thermography. In vitro experiments assessed Lewis cell proliferation and apoptosis using CCK-8, Edu, and TUNEL assays. In vivo experiments on C57 mouse Lewis transplant tumors evaluated the photothermal effect via near-infrared thermography and assessed DC maturation and CD4+/CD8+ T cell ratios using flow cytometry. The in vivo anti-tumor efficacy of MDR@SHDS was confirmed by tumor growth curve recording and HE and TUNEL staining of tumor sections. The hydrogel exhibited excellent temperature sensitivity, controlled release properties, and high biocompatibility. In vitro experiments revealed that MDR@SHDS combined with PTT had a greater inhibitory effect on tumor cell proliferation compared to MDR@SHD alone. Combining local immunotherapy, chemotherapy, and PTT yielded superior anti-tumor effects than individual treatments. MDR@SHDS, with its simplicity, biocompatibility, and enhanced anti-tumor effects in combination with PTT, presents a promising therapeutic approach for lung cancer treatment, offering potential clinical utility.