Undesirable Effects Research Articles

SSRI Induced Sleep Bruxism and Jaw Muscle Dystonia- Management with Low Dose Quetiapine Along with Occlusal Guards (D9944, D9945)- Two Case Reports

Background: Long term use of SSRIs (selective serotonin re uptake inhibitors) sometimes induces a problem called nocturnal or sleep bruxism which is nothing but uncoordinated jaw muscle movements which leads to grinding and clenching of teeth. The undesired effect of SSRIs produces a muscle stiffness, jaw and neck muscle tenderness, continuous toothache, hypersensitivity, tooth fracture and TMJ pain. Different treatment modalities are there to manage this kind of problem without hampering the psychiatric prognosis of the patient. Here two cases of SSRI induced sleep bruxism along with successful managements are discussed which will throw some light to the potential treatment approaches of such rare disorders.

Curcumin in Cancer Prevention: Insights from Clinical Trials and Strategies to Enhance Bioavailability.

Cancer remains a leading cause of death worldwide, and current cancer drugs often have high costs and undesirable side effects. Additionally, the development of drug resistance can reduce their effectiveness over time. Natural products have gained attention as potential sources for the treatment and prevention of various diseases. Curcumin, an extract from turmeric (Curcuma longa), is a natural phenolic compound with diverse pharmacological properties, including antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal, antiprotozoal, antidiabetic, antivenom, antiulcer, anticarcinogenic, antimutagenic, anticoagulant, and antifertility activities. Given the increasing interest in curcumin for cancer prevention, this review aims to comprehensively examine clinical trials investigating the use of curcumin in different types of cancer. Additionally, effective techniques and approaches to enhance the bioavailability of curcumin are discussed and summarized. This review article provides insights into the properties of curcumin and its potential as a future anticancer drug.

Chronic Intestinal Failure and Short Bowel Syndrome in Adults: The State of the Art

<b><i>Background:</i></b> Short bowel syndrome (SBS) is a devastating malabsorptive condition and the most common cause of chronic intestinal failure (CIF). During the intestinal rehabilitation process, patients may need parenteral support for months or years, parenteral nutrition (PN), or hydration/electrolyte supplementation, as a bridge for the desired enteral autonomy. <b><i>Summary:</i></b> Several classification criteria have been highlighted to reflect different perspectives in CIF. The management of CIF-SBS in adults is a multidisciplinary process that aims to reduce gastrointestinal secretions, slow transit, correct/prevent malnutrition, dehydration, and specific nutrient deficiencies, and prevent refeeding syndrome. The nutritional support team should have the expertise to take care of these complex patients: fluid support; oral, enteral, and PN; disease/PN-related complications; pharmacologic treatment; and surgical prevention/treatment. <b><i>Key Messages:</i></b> CIF-SBS is a complex disease with undesired consequences, if not adequately identified and managed. A comprehensive approach performed by a multidisciplinary team is essential to reduce PN dependence, promote enteral independence, and improve quality of life.

Water scarcity in the fast‐growing megacity of Lagos, Nigeria and opportunities for managed aquifer recharge

AbstractIn the last three decades, the world has experienced a rapid emergence of megacities. The increasing demographics, urbanization, and water demand brought severe and undesired effects on the quantity and quality of their water resources. A prime example is Lagos (Nigeria, West Africa), which is projected to become the world's largest city by 2100, and faces water scarcity challenges common to other megacities of developing countries. A literature review reveals the vast gap between water demand and regulated supply, inadequate knowledge and information on the current state of water (re)sources, and major, yet unregulated, use of groundwater. It further highlights the impacts of uncontrolled wastewater discharge into surface waters and aquifers, the role of increasing paved surfaces and blocked drainages on flooding, the inadequate supply of potable water, and the unsustainable abstraction of groundwater. Here, we examine the potential of managed aquifer recharge (MAR) to address these recurrent challenges across the megacity. The analysis reveals the opportunities and potential risks associated with the capture of wastewater, storm water, and brackish surface water for MAR. These waters, after appropriate treatment and subsurface storage may bridge the growing water supply–demand gap and mitigate the effects of groundwater (over)exploitation, including aquifer depletion, saltwater intrusion and land subsidence. Immediate efforts should focus on improving the conceptual and quantitative knowledge of Lagos' hydrogeology and groundwater resources through comprehensive spatial–temporal groundwater monitoring and socio‐economic studies of groundwater access and use. The insights provided may inform other fast‐growing coastal megacities in Africa and the wider developing world.This article is categorized under: Science of Water > Water and Environmental Change Engineering Water > Water, Health, and Sanitation Human Water > Value of Water Science of Water > Hydrological Processes

#67 Is Sodium bicarbonate a better alternative in kidney transplantation for better early renal function? A systematic review and meta-analysis

Abstract Background and Aims Kidney transplantation is a choice treatment for end-stage renal disease. It is the most cost-effective treatment and significantly improves the quality of life. However, metabolic acidosis increased following the transplantation. It can lead to several undesirable effects, such as disturbing the protein balance, resulting in a negative nitrogen equilibrium, increased protein degradation and essential amino acid oxidation, reduced physical functioning, and consequently decreased quality of life. The intraoperative crystalloid used may have significant effects on early function and acid-base balance. Also, sodium bicarbonate may enhance early graft function. This study aims to compare the effect of sodium bicarbonate in enhancing early graft function post-renal transplantation. Method We conducted a comprehensive search on multiple databases, including PubMed, MEDLINE, Embase, Scopus, WOS, and the Central Cochrane Registry. We included randomized controlled trials (RCTs) that compared sodium bicarbonate to normal saline during intraoperative kidney transplantation. Results Our search retrieved three RCTs, with 246 patients eligible for our criteria. We used either fixed- or random-effects models in the quantitative synthesis of the eligible studies accounting for clinical heterogeneity. Pooled data revealed that the sodium bicarbonate group was associated with a significantly improve in PH level (MD = 0.1; 95% CI: 0.06, 0.13; P < 0.01), Base Excess level (MD = 4.60 mEq/L; 95% CI: 3.43, 5.77; P = 0.003), and urine volume (MD = 2.59 L; 95% CI: 0.88, 4.29; P < 0.01). However, there was no significant difference between two groups in decreasing creatinine level after first day (MD = −0.46 mg/dl; 95% CI: −1.68, 0.76; P = 0.46), but the creatinine level significantly decreases after 2nd day (MD = −1.11 mg/dl; 95% CI: −1.96, −0.26; P = 0.01), and 3rd day (MD = −1 mg/dl; 95% CI: −1.17, −0.72; P < 0.01). Conclusion Our study suggests a potential advantage of sodium bicarbonate over the normal saline solution as an intraoperative fluid in improving metabolic acidosis during kidney transplantation.

Aniquinazoline B, a fungal natural product, activates the µ-opioid receptor.

The development of new µ-opioid receptor (MOR) agonists without the undesirable side effects, such as addiction or respiratory depression, has been a difficult challenge over the years. In the search for new compounds, we screened our chemical database of over 40.000 substances and further assessed the best 100 through molecular docking. We selected the top 10 compounds and evaluated them for their biological activity and potential to influence cyclic adenosine monophosphate (cAMP) levels. From the tested compounds, compound 7, called aniquinazoline B, belonging to the quinazolinone alkaloids class and isolated from the marine fungus Aspergillus nidulans, showed promising results, by inhibiting cAMP levels and in vitro binding to MOR, verified through microscale thermophoresis. Transcriptomic data investigation profiled the genes affected by compound 7 and discovered activation of different pathways compared to opioids. The western blot analysis revealed compound 7 as a balanced ligand, activating both p-ERK1/2 and β-arrestin1/2 pathways, showing this is a favorable candidate to be further tested.

#2457 Effect of belimumab in renal function and proteinuria in patients with lupus nephritis (LN): our experience

Abstract Background and Aims Belimumab was approved for systemic lupus erythematosus (SLE) after demonstrating its security and effectiveness in patients without renal activity. Recently it has been approved to treat LN [1, 2]. In this study, we analyse the experience of our centre with patients treated with Belimumab with any of the indications and renal SLE affectation. Method We retrospectively reviewed the clinical and analytical presentations and outcomes in patients diagnosed with SLE and treated with belimumab in our centre no matter the indication of the latest. We collected clinical, analytical, therapeutic and histological data of patients diagnosed with biopsy-proven LN and at least 6 months of follow-up and analyzed the evolution after belimumab was initiated. We excluded hemodialysis patients when analyzed renal function. We also reviewed clinical histories seeking potential complications related to belimumab. Results Our cohort includes 14 patients, 71% women, 71% Caucasian, 64% presented HTA and 14% were diabetic. Belimumab was initiated because of extrarenal manifestations in 43% of patients. The mean age at SLE and LN diagnosis was 31 and 36 years respectively, with a mean treatment length of 2.3 years; 71% of patients had class III or IV LN, 14% had V LN and 14% had III+V LN. Before its initiation, our cohort presented a mean SCr 0.8 mg/dL, 2g/g proteinuria, anti-DNA 172 UI/mL, C3 91 mg/dL, C4 21 mg/dL, mean SLEDAI 28.3. Of patients, 71% were under chloroquine, 93% under oral steroids (mean dose 10 mg/day), 93% under MPA (mean dose 1004 mg/day) and 43% under calcineurin inhibitors (CNI). After 6 months mean creatinine was 0.7 mg/dL, proteinuria diminished to 1.5 g/g (p < 0.025), anti-dsDNA were 87UI/mL, C3 was 88.5 and C4 32.7 mg/dL respectively; and after 12 months, creatinine was 0.87 mg/dL, proteinuria was 1.44g/g, anti-dsDNA were 148UI/mL, C3 was 99 and C4 24.7 mg/dL respectively and mean SLEDAI score was 7.1. After one year 66.67% of patients were under chloroquine, 88.89% under corticosteroids (mean dose 6 mg/day), 77.8% under MPA and 33.3% under CNI. After follow up we had 1 death with no secondary effects related to belimumab and reduction in proteinuria kept a trend but was no longer significative (p = 0.052). Belimumab was stopped in 5 patients, 2 of them before their inclusion in a CAR-T programme, 2 of them temporally when diagnosed with endocarditis and 1 of them after the finish of the protocol. Conclusion Our study has several limitations, mostly its reduced sample size. In our cohort, belimumab initiation is related only to a reduction of proteinuria after 6 months, but the most important aspect of this analysis may be that it proved to be safe and allowed clinicians to withdraw or reduce other immunosuppressive drugs to avoid their chronic toxicity with no undesirable side effects.

Challenges to Inflation in the Post-Planck Era

Space-based missions studying the cosmic microwave background (CMB) have progressively refined the parameter space in conventional models of inflation shortly (∼10−37 s) after the Big Bang. While most inflationary scenarios proposed thus far in the context of general relativity have since been ruled out, the basic idea of inflation may still be tenable, albeit with several unresolved conundrums, such as conflicting initial conditions and inconsistencies with the measured CMB power spectrum. In the new slow-roll inflationary picture, inflation arising in plateau-like potentials requires an initiation beyond the Planck time. This delay may be consistent with the cutoff, kmin , measured recently in the primordial power spectrum. However, the actual value of kmin would imply an initiation time too far beyond the Big Bang for inflation to solve the horizon problem. In this paper, we also describe several other undesirable consequences of this delay, including an absence of well-motivated initial conditions and a significant difficulty in providing a viable mechanism for properly quantizing the primordial fluctuations. Nevertheless, many of these inconsistencies may still be avoided if one introduces nonconventional modifications to inflation, such as a brief departure from slow-roll dynamics, possibly due to a dramatic change in the inflationary potential, inflation driven by multiple fields, or a nonminimal coupling to gravity. In addition, some of these difficulties could be mitigated via the use of alternative cosmologies based, e.g., on loop quantum gravity, which replaces the initial Big Bang singularity with finite conditions at a bounce-like beginning.

ETFC-01: a dual-labeled chelate-bridged tracer for SSTR2-positive tumors.

Integrating radioactive and optical imaging techniques can facilitate the prognosis and surgical guidance for cancer patients. Using a single dual-labeled tracer ensures consistency in both imaging modalities. However, developing such molecule is challenging due to the need to preserve the biochemical properties of the tracer while introducing bulky labeling moieties. In our study, we designed a trifunctional chelate that facilitates the coupling of the targeting vector and fluorescent dye at opposite sites to avoid undesired steric hindrance effects. The synthesis of the trifunctional chelate N3-Py-DOTAGA-(tBu)3 (7) involved a five-step synthetic route, followed by conjugation to the linear peptidyl-resin 8 through solid-phase synthesis. After deprotection and cyclization, the near-infrared fluorescent dye sulfo-Cy.5 was introduced using copper free click chemistry, resulting in eTFC-01. Subsequently, eTFC-01 was labeled with [111In]InCl3. In vitro assessments of eTFC-01 binding, uptake, and internalization were conducted in SSTR2-transfected U2OS cells. Ex-vivo biodistribution and fluorescence imaging were performed in H69-tumor bearing mice. eTFC-01 demonstrated a two-fold higher IC50 value for SSTR2 compared to the gold standard DOTA-TATE. Labeling of eTFC-01 with [111In]InCl3 gave a high radiochemical yield and purity. The uptake of [111In]In-eTFC-01 in U2OS.SSTR2 cells was two-fold lower than the uptake of [111In]In-DOTA-TATE, consistent with the binding affinity. Tumor uptake in H69-xenografted mice was lower for [111In]In-eTFC-01 at all-time points compared to [111In]In-DOTA-TATE. Prolonged blood circulation led to increased accumulation of [111In]In-eTFC-01 in highly vascularized tissues, such as lungs, skin, and heart. Fluorescence measurements in different organs correlated with the radioactive signal distribution. The successful synthesis and coupling of the trifunctional chelate to the peptide and fluorescent dye support the potential of this synthetic approach to generate dual labeled tracers. While promising in vitro, the in vivo results obtained with [111In]In-eTFC-01 suggest the need for adjustments to enhance tracer distribution.

Controlled phase distribution of quasi-2D perovskite enables improved electroluminescence

Quasi-two-dimensional (quasi-2D) perovskites are increasingly explored for integration into light-emitting diodes (LEDs) as light-emissive layers. However, the quasi-2D perovskite films likely exhibit non-uniform dimensional phase distribution and irregular internal crystal structures. These characteristics are known to contribute to undesirable effects, including non-radiative recombination losses and radiative recombination in perovskites of various dimensions, impeding the realization of efficient electroluminescence and high color purity in LEDs. In this study, we present an investigation on the correlation between the dimensional distribution of quasi-2D perovskites and charge carrier behavior by modulating anti-solvent dripping during the film fabrication processes. We provide a comprehensive analysis of the impact of controlled dimensional distribution on charge injection and recombination processes associated with the performance of quasi-2D perovskite LEDs. Our work emphasizes the crucial role played by controlled dimensionality in quasi-2D perovskites in realizing efficient and stable perovskite-based LEDs.

Investigation of negative differential resistance on negative capacitance Germanium source vertical TFET

In this article, a systematic investigation of negative differential resistance (NDR) on a negative capacitance Germanium source vertical TFET (NC-Ge-vTFET) is presented. The implementation and increased ferroelectric (FE) film thickness (t FE) offers a significantly high current ratio, improved subthreshold slope, high transconductance with a very low hysteresis voltage. However, NDR is exhibited and is increasingly prominent at lower gate voltage and higher t FE due to the coupling of the internal gate and drain voltages. NDR is an undesired effect in analog circuits that has to be mitigated. To suppress the impacts of NDR on the device, different approaches are carried out: varying the overlap channel thickness, gate length, drain doping and gate-drain underlap. Circuit analysis is carried out with the implementation of NC-Ge-vTFET as digital inverter. When the gate-drain underlap length is increased from 0 nm to 15 nm, the propagation delay is significantly reduced by 30.98%. Benchmarking of the proposed device has also been carried out. This renders the gate-drain underlapped NC-Ge-vTFET to be a viable candidate for high performance, nanoscale, low power digital applications.

Wrench Estimation and Friction Compensation Using Multiple Shooting Method for Tether Units Augmented to Remote Tendon-Driven Continuum Robots

Abstract Remote-actuated mechanisms that employ tendon sheaths or tether units can transmit mechanical force without directly connecting the actuators to the mechanism, but suffer from undesirable side effects like mechanical friction and induced external wrench disturbances on the distal side of the mechanism. In this work, a multiple shooting method is proposed as a superior method to the single shooting method to solve the Cosserat rod boundary value problems, to obtain the states of the system. With that, numerical experiments are provided to demonstrate the difficulty of solving these boundary value problems, simultaneously showing the validity of the proposed approach. 2D reconstruction experiments were conducted to show shape reconstruction capabilities. In addition, friction loss and 6-degree-of-freedom wrench estimations were also experimentally validated with the proposed mathematical model with 0.1679N and 0.0401Nm for root-mean-squared error (RMSE) force estimation and torque estimation error, respectively, while achieving a 3% mean absolute percentage steady-state friction estimation error. Finally, a modified resolved rate controller was applied to steer a remote tendon-driven continuum robot to compensate for friction loss for 3.1-m long tether units.

Performance and Image Enhancing Drug Use Among Australian Women: The Role of Interpersonal Relationships in Facilitating Use

Background: Women comprise a minority of performance and image-enhancing drug (PIED) consumers, with use linked to undesirable side effects. Preliminary work suggests that many women have little knowledge of what substances they are using, with males close to them involved in their use. This study aimed to explore women's motivations for PIED use; to examine the negative health experiences related to use; and to understand how interpersonal relationships facilitate their use. Method: Women who had used PIEDs were invited to participate in an online survey ( N = 28) and/or interview ( N = 10). Open-text survey and interview data were analyzed using content and thematic analyses, respectively. Results: There were three key areas (motivations, health experience, role of third parties) within which 12 theme categories were developed from the survey data. There were three overarching themes developed from interviews that expanded on these data: socializing women's use, facilitating women's use, and PIEDs exacerbating existing issues. Conclusion: The findings substantiate the nuanced gender dynamics of women's PIED use, challenging stereotypes and revealing the complexity of their motivations and experiences. While women's reasons for PIED use may share some semblance with men's, there is a less comprehensive understanding of the physical and psychosocial impacts of these drugs. To empower women and destigmatize PIED use, interventions focusing on substance literacy and stigma management are crucial. Future research should explore these interventions’ effectiveness in promoting women's well-being and autonomy.

In Vivo and In Silico Molecular Modeling Studies of Newly Synthesized Pyrazoles for Their Anti-Inflammatory and Analgesic Properties

Background: Pyrazole derivatives have gained attention as potential leads for developing anti-inflammatory and analgesic drugs. Chemical modifications of pyrazole structures offer a strategy to enhance their therapeutic properties, while minimizing undesirable effects. Objective: This study aimed to synthesize novel pyrazole derivatives through chemical modifications and assess their anti-inflammatory and analgesic activities. Methods: A series of pyrazole variants were synthesized by reacting various acetophenone derivatives and diethyl oxalate in basic conditions, followed by treatment with glacial acetic acid and hydrazine hydrate. The resulting compounds were further methylated and acetylated. The synthesized compounds were characterized using elemental analysis, 1H NMR, IR, and MASS spectroscopy. The anti-inflammatory activity was evaluated using the rat paw edema technique induced by carrageenan, while the analgesic activity was assessed using the writhing reflux method. Results: Among the newly synthesized pyrazole derivatives, compounds 3b, 3e and 3g′ demonstrated significant anti-inflammatory activity with reduced ulcerogenic potential. Compounds 3d, 3b′ and 3d′ exhibited notable analgesic activity compared to the standard drug. The chemical modifications introduced in these derivatives were confirmed through spectroscopic analyses. Conclusion: The findings of this study highlight the potential of pyrazole derivatives as promising candidates for anti-inflammatory and analgesic drug development. The structural modifications performed in this research improved the therapeutic activities of the compounds, while addressing safety concerns. Further investigations are warranted to elucidate the underlying mechanisms of action and optimize the pharmacological profiles of these novel pyrazole derivatives.

National Environmental Taxes and Industrial Waste in Countries across Europe

The use of economic instruments within environmental policy has become a challenging topic for policymakers, governments and scholars. Environmental taxes have emerged as a prevailing preference in developed countries to promote sustainability. Recently, a particular focus has been given to waste generation and disposal, shifting the attention from greenhouse gases to another important source of environmental pollution. This paper investigates the effect of national environmental taxes and policies on industrial waste. A fixed effects model is used for 34 countries across Europe from 2004 to 2022. The results suggest that environmental taxes and energy policies reduce industrial (hazardous and non-hazardous) waste. However, environmental tax reforms should take into consideration the deterioration in environmental quality, the increase in economic costs and undesirable social consequences.

Postsurgical Analgesic Effectiveness of Ultrasound-Guided Parasternal Block After Auricular Reconstruction Using Autologous Costal Cartilage in Pediatric Patients: A Randomized Controlled Trial.

To study the efficacy of ultrasound-guided parasternal block (US-PSI) in pediatric patients undergoing auricular reconstruction surgery. For this study, the authors recruited 60 children between the ages of 5 and 12 years who underwent auricular reconstruction with autologous costal cartilage (ACC) to correct microtia. They were randomized to receive either ultrasound-guided modified parasternal block or periprostatic local infiltration anesthesia (PLIA), with 30 cases in each group. Ultrasound-guided parasternal block was administered following anesthesia induction, whereas PLIA was administered after ACC harvest. Lastly, following surgery, all children were provided with patient-controlled intravenous analgesia with sufentanil, and the numeric pain rating scale (NRS) was used to assess the intensity of pain. Our primary outcomes were the resting NRS pain scores and the NRS scores upon coughing at 1, 6, 12, 24, and 48 hours postsurgery. Sufentanil consumption within the first 24 hours of surgery, the mean duration to first ambulation, and the usage of rescue analgesics were our secondary outcomes. The authors also recorded the occurrence of undesirable side effects as well as more serious side effects like pneumothorax. Pediatric patients who were administered US-PSI showed significantly reduced NRS chest pain scores at 6 and 12 hours postsurgery compared to those who received PLIA (P<0.05). In addition, sufentanil consumption within the first 24 hours postsurgery, duration to first ambulation, and use of rescue analgesics were significantly lower among patients in the US-PSI group when compared to those in the PLIA group (P<0.05). This study found that US-PSI was a highly efficacious and safe technique for postsurgical analgesia following auricular reconstruction with ACC in pediatric patients. Level II, therapeutic study.

The Effectiveness of Herbal Poultice in Relieving Pain and Flexibility in Osteoarthritis Patients

Knee osteoarthritis (OA) is a chronic condition that causes joint degradation and primarily affects the elderly, reducing their quality of life and physical movements. The objective of this study was to determine the efficacy of Thai herbal poultice in relieving pain in OA patients. A single-blind, randomized controlled trial was conducted amongst OA patients at Integrative medicine clinic, Chulabhorn International College of Medicine, Thammasat University, Thailand. Participants were randomly allocated to the Thai herbal poultice or the diclofenac gel group (N=30). The main outcomes were evaluated using visual analog scale (VAS), isokinetic testing, goniometer, and knee injury and osteoarthritis outcome scores (KOOS) at different time assessment. Data were analyzed by the paired t-test and analysis of variance (ANOVA). Thai herbal poultice and diclofenac group showed a significant difference in both the VAS pain scores, extension and flexion as well as KOOS scores (P &lt; 0.01 in both groups). In addition, when compared to diclofenac group, Thai herbal poultice group were significantly improve pain score at the sixth time point following the intervention (P &lt; 0.01). Furthermore, no patients have experienced allergic reactions to therapies. In conclusion, Thai herbal poultice showed more efficiency in reducing pain scores than diclofenac gel without causing undesirable side effects.

Structural investigations on the mitochondrial uncouplers niclosamide and FCCP.

There has been renewed interest in using mitochondrial uncoupler compounds such as niclosamide and carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP) for the treatment of obesity, hepatosteatosis and diseases where oxidative stress plays a role. However, both FCCP and niclosamide have undesirable effects that are not due to mitochondrial uncoupling, such as inhibition of mitochondrial oxygen consumption by FCCP and induction of DNA damage by niclosamide. Through structure-activity analysis, we identified FCCP analogues that do not inhibit mitochondrial oxygen consumption but still provided good, although less potent, uncoupling activity. We also characterized the functional role of the niclosamide 4'-nitro group, the phenolic hydroxy group and the anilide amino group in mediating uncoupling activity. Our structural investigations provide important information that will aid further drug development.

Striking the Balance with a PD-L1×4-1BB Bispecific Antibody.

Antibody-based immune checkpoint blockade therapy has revolutionized the field of cancer immunotherapy, yet its efficacy remains limited in immunologically cold tumors. Combining checkpoint inhibitors with costimulatory agonists improves tumoricidal activity of T cells but also can lead to off-target hepatotoxicity. Although bispecific antibodies confer tumor selectivity to alleviate undesirable adverse effects, toxicity concerns persist with increased dosing. In this issue of Cancer Research, Yuwen and colleagues introduce ATG-101, a tetravalent PD-L1×4-1BB bispecific antibody with high programmed death ligand 1 (PD-L1) affinity and low 4-1BB affinity, aiming to mitigate hepatotoxicity. ATG-101 demonstrates PD-L1-dependent 4-1BB activation, leading to selective T-cell activation within the tumor microenvironment. ATG-101 exhibits potent antitumor activity, even in large, immunologically cold, and monotherapy-resistant tumor models. Single-cell RNA sequencing reveals significant shifts of immune cell populations in the tumor microenvironment from protumor to antitumor phenotypes following ATG-101 treatment. In cynomolgus monkeys, no serious cytokine storm and hepatotoxicity are observed after ATG-101 treatment, indicating a broad therapeutic window for ATG-101 in cancer treatment. This study highlights the potential of tetravalent bispecific antibodies in cancer immunotherapy, with implications for various antibody-based treatment modalities across different fields. See related article by Yuwen et al., p. 1680.

Effect of folA gene in human breast milk-derived Limosilactobacillus reuteri on its folate biosynthesis

IntroductionFolate supplementation is crucial for the human body, and the chemically synthesized folic acid might have undesirable side effects. The use of molecular breeding methods to modify the genes related to the biosynthesis of folate by probiotics to increase folate production is currently a focus of research.MethodsIn this study, the folate-producing strain of Limosilactobacillus reuteri B1-28 was isolated from human breast milk, and the difference between B1-28 and folA gene deletion strain ΔFolA was investigated by phenotyping, in vitro probiotic evaluation, metabolism and transcriptome analysis.ResultsThe results showed that the folate producted by the ΔFolA was 2–3 folds that of the B1-28. Scanning electron microscope showed that ΔFolA had rougher surface, and the acid-producing capacity (p = 0.0008) and adhesion properties (p = 0.0096) were significantly enhanced than B1-28. Transcriptomic analysis revealed that differentially expressed genes were mainly involved in three pathways, among which the biosynthesis of ribosome and aminoacyl-tRNA occurred in the key metabolic pathways. Metabolomics analysis showed that folA affected 5 metabolic pathways, involving 89 different metabolites.DiscussionIn conclusion, the editing of a key gene of folA in folate biosynthesis pathway provides a feasible pathway to improve folate biosynthesis in breast milk-derived probiotics.