In-vitro and in-silico investigations of SLC-0111 hydrazinyl analogs as human carbonic anhydrase I, II, IX, and XII inhibitors.

Two novel series of hydrazinyl-based benzenesulfonamides 9a-j and 10a-j were designed and synthesized using SLC-0111 as the lead molecule. The newly synthesized compounds were evaluated for their inhibitory activity against four different human carbonic anhydrase (hCA) isoforms I, II, IX, and XII. Both the series reported here were practically inactive against the off-target isozyme hCA I. Notably, derivative 10a exhibited superior potency (Ki of 10.2 nM) than acetazolamide (AAZ) against the cytosolic isoform hCA II. The hCA IX and XII isoforms implicated in tumor progression were effectively inhibited with Kis in the low nanomolar range of 20.5-176.6 nM and 6.0-127.5 nM, respectively. Compound 9g emerged as the most potent and selective hCA IX and XII inhibitor with Ki of 20.5 nM and SI of 200.1, and Ki of 6.0 nM and SI of 683.7, respectively, over hCA I. Furthermore, six compounds (9a, 9h, 10a, 10g, 10i, and 10j) exhibited significant inhibition toward hCA IX (Kis = 27.0, 41.1, 27.4, 25.9, 40.7, and 30.8 nM) relative to AAZ and SLC-0111 (Kis = 25.0 and 45.0 nM, respectively). These findings underscore the potential of these derivatives as potent and selective inhibitors of hCA IX and XII over the off-target hCA I and II.

Ultrafast symmetry-breaking charge separation in Perylenemonoimide-embedded multichromophores: impact of regioisomerism.

Symmetry-breaking charge separation (SB-CS) has recently evolved as an emerging concept offering its potential to the latest generation of organic photovoltaics. However there are several concerns that need to be addressed to reach the state-of-the-art in SB-CS chemistry, for instance, the desirable molecular geometry, interchromophoric distance and extent of electronic coupling. To shed light on those features, it is reported herein, that ortho-functionalized perylene monoimide (PMI) constituted regioisomeric dimer and trimer derivatives with varied molecular twisting and electronic conjugation have been synthesized. In steady-state photophysical studies, all the dimers and trimer derivatives exhibit a larger bathochromic shift in the emission spectra and a significant reduction of fluorescence quantum yield in polar DMF. Among the series of multichromophores, ortho- and self-coupled dimers display the strikingly different optical feature of SB-CS with a very fast charge separation rate (τCS = 80.2 ps) upon photoexcitation in DMF, which is unveiled by femtosecond transient absorption (fs-TA) studies. The SB-CS for two dimers is well-supported by the formation of PMI˙+ and PMI˙- bands in the fs-TA spectra. Further analysis of fs-TA data revealed that, among the other multichromophores the trimer also exhibits a clear charge separation, whereas SB-CS signatures are less prominent, but can not be completely disregarded, for the meta- and para-dimers. Additionally, the charge separation dynamics of those above-mentioned PMI derivatives are devoid of a kinetically favorable excimer or triplet formation. The evidence of a profound charge transfer phenomenon in the ortho-dimer is characterized by density functional theory (DFT) calculations on excited state electronic structures. The excitonic communications in the excited state electronic arrangements unravel the key role of dihedral twisting in SB-CS. The thermodynamic feasibility of CS (ΔGCS) and activation barrier (ΔG≠) of the derivatives in DMF are established from the Rehm-Weller equation and Marcus's theory, respectively. This work is an in-depth study of the effect of mutual orientation of PMIs and regioisomerism in determining sustainable guidelines for using SB-CS.

A Spectrum of Chemoport-Associated Complications and Their Management in Cancer Patients.

INTRODUCTION: Chemotherapy is part and parcel of the multimodality approach to cancer treatment. Chemoports are frequently used to administer chemotherapy, preventing complications associated with the use of peripheral lines. However, chemoports have their own set of complications and can be very debilitating at times. Accurate knowledge and correct technique can help prevent and manage these complications properly. METHODS: We retrospectively analyzed all patients who underwent chemoport insertion for chemotherapy infusion over three years between July 2020 and June 2023. The patient's profile, type of cancer, the technique of chemoport insertion, complications related to chemoport, and its management were recorded retrospectively from patient records. RESULTS: The total number of patients in our study was 119. The age group of patients ranged from 13 years to 76 years. Of the 119 patients, 55 had breast cancer, 23 had ovarian cancers, 29 had GI cancers including gastroesophageal junction (GEJ)/ stomach/periampullary/colorectal, and 12 had leukemias. The most common intraoperative complication was catheter tip malposition (9.2%). The most common postoperative complications were infection (7.5%), followed by drug extravasation (5.0%), thrombosis (3.3%), wound dehiscence (2.5%), and skin necrosis (0.8%) in decreasing order of frequency. Serious complications such as hemothorax, pneumothorax, air emboli, brachial plexus injury, and pericardial tamponade, commonly reported in the literature, were not seen in any of our cases. CONCLUSION:  Totally implanted venous access devices (TIVAD)/chemoports are indispensable in the management of cancer patients, especially in patients requiring long duration of infusion and prolonged treatment. Although chemoports are associated with a spectrum of complications, proper technique of implantation and use makes it a safe and reliable tool.

Innovative Technique of Chest Wall Reconstruction After Extensive Tumour Ablation Surgery.

Chest wall reconstruction is among one of the most challenging surgeries because the defect comprises multiple components and each needs to be reconstructed separately with like tissues. Chest wall reconstruction ranges from simple skin cover to complex bony and or mediastinal/precordial reconstruction. Various methods of reconstruction include autologous as well alloplastic techniques. Autologous techniques include regional or distant flaps with or without bone. Whereas alloplastic techniques include the placement of a variety of implant materials like titanium plate/mesh, stainless steel mesh, medpore and biocompatible 3D-printed models. we present this article where extensive resection was performed, aiming to complete removal of recurrent chest wall chondrosarcoma and defect included all components of chest wall including precordial lining. The reconstruction was performed by using combined autologous as well as alloplastic techniques using acrylic implant.

Toward microfluidic continuous-flow and intelligent downstream processing of biopharmaceuticals.

Biopharmaceuticals have emerged as powerful therapeutic agents, revolutionizing the treatment landscape for various diseases, including cancer, infectious diseases, autoimmune and genetic disorders. These biotherapeutics pave the way for precision medicine with their unique and targeted capabilities. The production of high-quality biologics entails intricate manufacturing processes, including cell culture, fermentation, purification, and formulation, necessitating specialized facilities and expertise. These complex processes are subject to rigorous regulatory oversight to evaluate the safety, efficacy, and quality of biotherapeutics prior to clinical approval. Consequently, these drugs undergo extensive purification unit operations to achieve high purity by effectively removing impurities and contaminants. The field of personalized precision medicine necessitates the development of novel and highly efficient technologies. Microfluidic technology addresses unmet needs by enabling precise and compact separation, allowing rapid, integrated and continuous purification modules. Moreover, the integration of intelligent biomanufacturing systems with miniaturized devices presents an opportunity to significantly enhance the robustness of complex downstream processing of biopharmaceuticals, with the benefits of automation and advanced control. This allows seamless data exchange, real-time monitoring, and synchronization of purification steps, leading to improved process efficiency, data management, and decision-making. Integrating autonomous systems into biopharmaceutical purification ensures adherence to regulatory standards, such as good manufacturing practice (GMP), positioning the industry to effectively address emerging market demands for personalized precision nano-medicines. This perspective review will emphasize on the significance, challenges, and prospects associated with the adoption of continuous, integrated, and intelligent methodologies in small-scale downstream processing for various types of biologics. By utilizing microfluidic technology and intelligent systems, purification processes can be enhanced for increased efficiency, cost-effectiveness, and regulatory compliance, shaping the future of biopharmaceutical production and enabling the development of personalized and targeted therapies.

Pilot Evaluation of Perioperative High Dose Rate Brachytherapy in Head Neck Cancers.

Perioperative high dose rate brachytherapy involves insertion of brachytherapy catheter over the tumor bed during surgical removal of disease followed by radiation in the postoperative period. It has applications in radiotherapy dose escalation or reirradiation and for extending the surgical margins. We report here initial results of treatment in five cases of locally advanced head and neck cancers.

Peri-alkylated terrylenes and ternaphthalenes building-blocks towards multi-edge nanographenes.

Since its first synthesis by Clar in 1948, terrylene - a fully connected ternaphthalene oligomer via naphthalene's peri-positions - has gained special focus within the rylene family, drawing interest for its unique chemical, structural, optoelectronic and single photon emission properties. In this study, we introduce a novel synthetic pathway that enhances the solubility of terrylene derivatives through complete peri-alkylation, while also facilitating extensions at the bay-positions. This approach not only broadens the scope of terrylene's chemical versatility but also opens new avenues for developing solution processable novel multi-edge nanographenes and tailoring electronic energy levels through topological edge structures. Our findings include a comprehensive structural and spectroscopic characterization which include transient absorption spectroscopy and photophysics of both the synthesized peri-alkylated terrylene and its phenylene-fused derivative.

Safety, Tolerability, and Pharmacokinetics of Oral BI 1358894 in Healthy Japanese Male Volunteers.

BACKGROUND AND OBJECTIVES: BI 1358894, a novel small-molecule inhibitor of transient receptor potential canonical ion channels, is under development for treatment of major depressive disorder. Phase I trials assessing the safety and pharmacokinetics of BI 1358894 in Caucasian male healthy volunteers (HVs) have been performed. This Phase I, double-blind, placebo-controlled, parallel-group trial assessed the safety, tolerability and pharmacokinetics of BI 1358894 in Japanese male HVs. METHODS: Male HVs were randomized to receive oral BI 1358894 (n = 18) or placebo (n = 6) after a high-fat, high-calorie meal within three dose groups (50 mg, 100 mg, 200 mg), administered sequentially in dose-ascending order. The primary endpoint was number of HVs with drug-related adverse events (DRAEs). Secondary endpoints were the pharmacokinetic parameters of BI 1358894. RESULTS: Overall, 24 male HVs entered the trial [mean (standard deviation) age: 30.0 (7.6) years]. DRAEs occurred in 3/18 HVs (BI 1358894 100 mg group: one HV experienced dizziness and headache; BI 1358894 200 mg group: one HV experienced headache, another reported sleep disorder). BI 1358894 exposure increased dose dependently and proportionally, peaking 4-6 h after administration before declining in a multiphasic manner with a terminal elimination half-life of ~70 h in the 50 mg and 100 mg dose groups, and 203 h in the 200 mg dose group. CONCLUSION: BI 1358894 was well tolerated with a favorable pharmacokinetic profile in Japanese male HVs, similar to findings from a previous study in Caucasian male HVs. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03875001; 08-Mar-2019).

Efficacy and Safety of Cryoablation Compared with Cooled Radiofrequency Ablation of Genicular Nerves in Advanced Osteoarthritis of the Knee: A Study Protocol of Single-Centric, Assessor-Blinded, Randomized, Parallel-Group, Non-inferiority Study.

PURPOSE: In patients with symptomatic osteoarthritis knee (OAK), cryoneurolysis (CRYO) and cooled radiofrequency ablation (C-RFA) are reported to be effective and safe; however, they have not been compared directly. The objective of this study is to compare CRYO and C-RFA of the genicular nerve (GN) in terms of efficacy and safety profile in patients with Kellgren and Lawrence (KL) grade ≥ 3 OAK. METHODS: This single-centric, assessor-blinded, randomized, parallel-group, non-inferiority study will include 80 patients with KL grade ≥ 3 OAK. The patients with ≥ 50% pain relief on diagnostic block of three GNs will be randomized to one of the two groups, i.e., CRYO (n = 40) or C-RFA (n = 40). The three target GNs for the interventions will include: superior medial, superior lateral, and inferior medial. The primary outcome will be efficacy of CRYO or C-RFA at 2, 12, and 24 weeks post-procedure based on the 11-point Numerical Pain Rating Scale. The secondary outcomes will be functional improvement based on 12-item Oxford Knee Score and safety of both the procedures. The study is registered in the Clinical Trials Registry-India. CONCLUSION: CRYO and C-RFA provide pain relief and improve functional outcome by preventing transmission of pain signals, though by distinct mechanisms. While C-RFA is an established treatment modality, recent evidence supports CRYO in patients with OAK. This study intends to demonstrate non-inferiority of CRYO against C-RFA, thereby supporting the use of CRYO as an additional treatment modality in patients with KL grade ≥ 3 OAK.

Comparison of diagnostic capability of macular ganglion cell complex vs retinal fiber layer thickness in primary open angle glaucoma patients of Indian origin.

PURPOSE: Comparison of diagnostic capability of macular ganglion cell complex thickness vs. retinal nerve fiber layer (RNFL) thickness in patients of primary open-angle glaucoma (POAG). SETTINGS AND DESIGN: This cross-sectional observational study was carried out between June 2021 and October 2022 at a tertiary care hospital in North India. METHODS: A total of 118 eyes were included in the study with 30 control and the rest 88 eyes with POAG were divided into three groups based on visual field loss Group 1 (30 eyes): early field loss with mean deviation (MD) < -6 dB; Group 2 (30 eyes): moderate field loss with MD -6 to -12 dB; and Group 3 (28 eyes): severe field loss with MD > -12 dB. Optical coherence tomography (OCT) scans to measure RNFL loss and ganglion cell inferior plexiform layer (GCIPL) loss were taken for each patient. STATISTICAL ANALYSIS USED: Categorical variables were analyzed using either the Chi-square test or Fisher's exact test. A receiver operating characteristics analysis was calculated to determine optimal cut-off values of superior, inferior, and average GCIPL and RNFL for determining the severity of field loss as compared to controls (30 normal eyes). RESULTS: In the mild field loss group the sensitivity of superior, inferior, and average GCIPL was 86.7, 96.7, and 96.7%, respectively. Similarly, the specificity was 96.7, 93.3, and 100%, respectively. In the same group, the sensitivity of superior, inferior, and average RNFL was 70, 93, and 66%, respectively. Similarly, the specificity was 46.7, 83.3, and 70%, respectively. In the moderate and severe groups, the results were comparable. CONCLUSION: The sensitivity and specificity of GCIPL loss are significantly better than that of RNFL parameters in the mild field loss group.

Modulation of gut-microbiota through probiotics and dietary interventions to improve host health.

Dietary patterns play an important role in regards to the modulation and control of the gut microbiome composition and function. The interaction between diet and microbiota plays an important role in order to maintain intestinal homeostasis, which ultimately affect the host's health. Diet directly impacts the microbes that inhabit the gastrointestinal tract (GIT), which then contributes to the production of secondary metabolites, such as short-chain fatty acids, neurotransmitters, and antimicrobial peptides. Dietary consumption with genetically modified probiotics can be the best vaccine delivery vector and protect cells from various illnesses. A holistic approach to disease prevention, treatment, and management takes these intrinsically linked diet-microbes, microbe-microbe interactions, and microbe-host interactions into account. Dietary components, such as fiber can modulate beneficial gut microbiota, and they have resulting ameliorative effects against metabolic disorders. Medical interventions, such as antibiotic drugs can conversely have detrimental effects on gut microbiota by disputing the balance between Bacteroides and firmicute, which contribute to continuing disease states. We summarize the known effects of various dietary components, such as fibers, carbohydrates, fatty acids, vitamins, minerals, proteins, phenolic acids, and antibiotics on the composition of the gut microbiota in this article in addition to the beneficial effect of genetically modified probiotics and consequentially their role in regards to shaping human health. © 2024 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Eco-friendly approaches to phytochemical production: elicitation and beyond.

Highly ameliorated phytochemicals from plants are recognized to have numerous beneficial effects on human health. However, obtaining secondary metabolites directly from wild plants is posing a great threat to endangered plant species due to their over exploitation. Moreover, due to complicated structure and stereospecificity chemical synthesis of these compounds is a troublesome procedure. As a result, sustainable and ecofriendly in vitro strategy has been adopted for phytochemicals production. But, lack of fully differentiated cells lowers down cultured cells productivity. Consequently, for enhancing yield of metabolites produced by cultured plant cells a variety of methodologies has been followed one such approach includes elicitation of culture medium that provoke stress responses in plants enhancing synthesis and storage of bioactive compounds. Nevertheless, for conclusive breakthrough in synthesizing bioactive compounds at commercial level in-depth knowledge regarding metabolic responses to elicitation in plant cell cultures is needed. However, technological advancement has led to development of molecular based approaches like metabolic engineering and synthetic biology which can serve as promising path for phytochemicals synthesis. This review article deals with classification, stimulating effect of elicitors on cultured cells, parameters of elicitors and action mechanism in plants, modern approaches like metabolic engineering for future advances.

Clinical Profile and Renal Survival of Anti-Glomerular Basement Membrane Disease Patients: A Retrospective Case Series from Northern India.

Introduction: Anti-glomerular basement membrane (anti-GBM) disease is a rare organ-specific autoimmune disease. The overall and renal outcomes of patients have mostly been reported in small-sized cohorts. We aimed to study the clinical profile, overall survival, and renal survival of anti-glomerular basement membrane disease patients at our center. Methods: We conducted a retrospective analysis of the data regarding the clinical profile and renal survival of patients diagnosed with anti-GBM disease from October 2019 to March 2022, having a minimum follow-up of 12 months. Results: There were 15 patients in the study, with the mean age of presentation being 51.6 ± 13.7 years. The median duration of symptoms onset to the nephrologist opinion was 15 (10-23) days. The extrarenal manifestations were seen in the respiratory, otorhinolaryngological, and neurological systems. The mean serum anti-GBM titers were 154.5 (14.9-263.5) U/mL. Serum anti-GBM titers were present in 13/15 (86.6%) patients, and 12/13 (92.3%) patients had above the reference range. Anti-neutrophil cytoplasm antibody (ANCA) levels were assessed in 12/15 (80%) patients, and 9/12 (75%) had higher levels. Renal biopsy was available in 14 patients with more than 50% crescents. Along with crescents, necrotizing lesions, rupture of the Bowman's capsule, and granulomatous lesions were also seen. Among the initial therapies, the steroid pulse was given to 13 (86.6%) patients, whereas membrane plasmapheresis was given to 8 (53.3%) patients. Inj. cyclophosphamide and inj. rituximab were given to 8 (53.3%) and 4 (26.6%) patients, respectively. No difference was seen in clinical characteristics, renal biopsy features, treatment received, and outcomes with ANCA positivity except for age, where patients who were ANCA positive were older compared to patients who were ANCA negative. One-year renal and patient survival was seen in 4 (26.6%) and 6 (40%) patients, respectively. Conclusion: Most patients of anti-GBM disease have active sediments, raised creatinine, and non-specific symptomatology. There is poor renal and patient outcome as most patients present with advanced renal failure.

Microbial cell-free DNA detection: Minimally invasive diagnosis of infectious diseases.

BACKGROUND: Detection of infectious diseases, especially among immunocompromised and patients on prolonged anti-microbial treatment, remains challenging, limited by conventional techniques with low sensitivity and long-turnaround time. Molecular detection by polymerase chain reaction (PCR) also has limited utility as it requires a targeted approach with prior suspicion of the infecting organism. Advancements in sequencing methodologies, specifically next-generation sequencing (NGS), have presented a promising opportunity to identify pathogens in cases where conventional techniques may be inadequate. However, the direct application of these techniques for diagnosing invasive infections is still limited by the need for invasive sampling, highlighting the pressing need to develop and implement non-invasive or minimally invasive approaches to improve the diagnosis of invasive infections. OBJECTIVES: The objectives of this article are to explore the notable features, clinical utility, and constraints associated with the detection of microbial circulating cell-free DNA (mcfDNA) as a minimally invasive diagnostic tool for infectious diseases. CONTENT: The mcfDNA detection provides an opportunity to identify micro-organisms in the blood of a patient. It is especially beneficial in immunocompromised patients where invasive sampling is not possible or where repeated cultures are negative. This review will discuss the applications and constraints of detecting mcfDNA for diagnosing infections and the various platforms available for its detection.

Effects of Single and Multiple Ascending Doses of BI 1358894 in Healthy Male Volunteers on Safety, Tolerability and Pharmacokinetics: Two Phase I Partially Randomised Studies.

INTRODUCTION: The transient receptor potential canonical (TRPC) ion channels have been implicated in the pathophysiology of major depressive disorder (MDD), and TRPC inhibition has been shown to reduce depressive-like behaviour in rodent models of depression. BI 1358894, a small-molecule inhibitor of TRPC ion channels, is currently being developed for the treatment of MDD. OBJECTIVE: Two phase I studies assessed the safety, tolerability, and pharmacokinetics (PK) of oral BI 1358894 in fed and fasted states following a single ascending dose (SAD) [NCT03210272/1402-0001] and multiple ascending doses (MAD) [NCT03754959/1402-0002] in healthy male volunteers. In addition, any potential food effect was evaluated after a single dose. METHODS: In both studies, eligible healthy male volunteers (aged 18-45 years; body mass index of 18.5-29.9 kg/m2) were allocated to receive BI 1358894 or placebo. In the SAD study (1402-0001), volunteers were randomised 3:1 to receive BI 1358894 or placebo in fasted (3, 6, 10, 25, 50, 100, or 200 mg) and fed states (200 mg). The food effect part was conducted as an open-label, randomised, two-way crossover study at doses of 50 and 100 mg in fasted and fed states (high-calorie, high-fat breakfast). For the MAD study (1402-0002), volunteers were randomised 4:1 to receive BI 1358894 (10, 25, 50, 100, or 200 mg) or placebo once daily for 14 days under fed conditions. Primary endpoint (both studies): number of volunteers with drug-related adverse events (DRAEs). Secondary PK endpoints for study 1402-0001: area under the concentration-time curve (AUC) from time zero extrapolated to infinity (AUC∞), maximum plasma concentration (Cmax), and AUC from time zero to the last quantifiable data time point (AUC0-tz). Secondary PK endpoints for study 1402-0002: AUC over 0-24 h (AUC0-24), Cmax after the first dose, and steady-state AUC and Cmax over a uniform dosing interval (AUCτ,ss and Cmax,ss, respectively) after the last dose. RESULTS: BI 1358894 was well tolerated at doses ≤ 200 mg under all tested conditions and no dose dependency was observed in DRAE frequency for either study. In the SAD study, BI 1358894 exposure increased dose proportionally across 3-50 mg in the fasted state and across 50-200 mg in the fed state. A positive food effect was observed at the tested doses. In the MAD study, BI 1358894 exposure increased less than dose proportionally across 10-200 mg. CONCLUSIONS: These studies demonstrate that BI 1358894 is well tolerated in healthy male volunteers following single and multiple doses, with no dose dependency observed in DRAE frequency. BI 1358894 exposure increased dose dependently in both the SAD and MAD studies, with higher exposure of BI 1358894 observed in the fed state. CLINICALTRIALS REGISTRATION: These trials have been registered on ClinicalTrials.gov: NCT03210272/1402-0001 (registered on 6 July 2017) and NCT03754959/1402-0002 (registered on 27 November 2018).

Effect of BI 1358894 on Cholecystokinin-Tetrapeptide (CCK-4)-Induced Anxiety, Panic Symptoms, and Stress Biomarkers: A Phase I Randomized Trial in Healthy Males.

INTRODUCTION: Depression, anxiety, and/or panic disorder are often comorbid and have a complex etiology mediated through the same neuronal network. Cholecystokinin-tetrapeptide (CCK-4), a synthetic analog of the endogenous neuropeptide cholecystokinin (CCK), is thought to be implicated in this network. The CCK-4 challenge model is an accepted method of investigating the pathophysiology of panic and has been shown to mediate neuronal activation via the transient receptor potential canonical (TRPC) ion channels. OBJECTIVES: This study aimed to assess the pharmacodynamic effects of BI 1358894, a small-molecule inhibitor of TRPC ion channel members 4 and 5 (TRPC4/5), on CCK-4-induced anxiety/panic-like symptoms and evaluate circuit engagement. METHODS: Twenty healthy male CCK-4-sensitive volunteers entered a Phase I, double blind, randomized, two-way cross-over, single dose, placebo-controlled trial. Randomization was to oral BI 1358894 100 mg in the fed state followed by oral placebo in the fed state, or vice versa. Treatments were administered 5 h prior to intravenous CCK-4 50 µg. The primary endpoint was maximum change from baseline of the Panic Symptom Scale (PSS) sum intensity score after CCK-4 injection. Further endpoints included the emotional faces visual analog score (EVAS), the Spielberger State-Trait Anxiety Inventory (STAI), plasma adrenocorticotropic hormone (ACTH), and serum cortisol values. The safety and tolerability of BI 1358894 was assessed based on a number of parameters including occurrence of adverse events (AEs). All pharmacodynamic, pharmacokinetic, and safety endpoints were analyzed using descriptive statistics. RESULTS: Single oral doses of BI 1358894 were generally well tolerated by the healthy male volunteers included in this study. Adjusted mean maximum change from baseline in PSS sum intensity score was 24.4 % lower in volunteers treated with BI 1358894 versus placebo, while adjusted mean maximum change from baseline of EVAS was reduced by 19.2 % (BI 1358894 vs placebo). The STAI total score before CCK-4 injection was similar in both groups (placebo: 25.1; BI 1358894: 24.3). Relative to placebo, BI 1358894 reduced CCK-4-induced mean maximum plasma ACTH and serum cortisol values by 58.6 % and 27.3 %, respectively. Investigator-assessed drug-related AEs were reported for 13/20 participants (65.0 %). There were no serious or severe AEs, AEs of special interest, AEs leading to discontinuation of trial medication, or deaths. CONCLUSIONS: Overall, BI 1358894 reduced psychological and physiological responses to CCK-4 compared with placebo, as measured by PSS, subjective EVAS and objectively measured stress biomarkers. BI 1358894 had a positive safety profile, and single oral doses were well tolerated by the healthy volunteers. This trial (NCT03904576/1402-0005) was registered on Clinicaltrials.gov on 05.04.19.

Toxicities and clinical outcome of adjuvant dysphagia optimized versus standard intensity-modulated radiotherapy for post-operative oral cavity cancers: A prospective comparative study.

BACKGROUND: We prospectively assessed acute and late toxicity in post-operative oral cavity squamous cell carcinoma (PO-OCSCC) treated with adjuvant dysphagia optimized intensity-modulated radiotherapy (Do-IMRT) versus standard IMRT (S-IMRT). MATERIAL AND METHODS: Fifty-six patients of PO-SCC without indications of concurrent chemotherapy were alternatively allocated to adjuvant Do-IMRT (n = 28) versus S-IMRT (n = 28) arms. High- and low-risk planning target volume received 60 and 54 Gy, respectively, in 30 fractions over 6 weeks. Dysphagia aspiration-related structures (DARS) were contoured in both arms. While dosimetric constraints were given in Do-IMRT arm, doses to DARS were only observed without dose constraints in S-IMRT arm. Acute and late toxicity were assessed by common terminology criteria for adverse events (CTCAE) v5.0 and RTOG criteria, respectively. RESULTS: The primary site of disease was buccal mucosa (64% vs. 53%) and oral tongue (21% vs. 32%), in Do-IMRT and S-IMRT, respectively. The mean doses to DARS was significantly less with Do-IMRT (all p < 0.001) as compared to S-IMRT. Median follow-up was 24.2 months. Grade ≥2 oral pain was less in the Do-IMRT arm (50% vs. 78.6%, p = 0.05). Grade ≥2 late dysphagia at 2 years were significantly less in Do-IMRT arm (0% vs. 17.9%, p = 0.016). Two-year locoregional control was 89.2% in Do-IMRT and 78.5% in S-IMRT (p = 0.261). CONCLUSION: DARS can be spared in PO-OCSCC patients treated with Do-IMRT without compromising coverage of the target volumes. Limiting doses to DARS leads to lesser acute and late toxicity without compromising locoregional control.

Brassinosteroids as promoters of seedling growth and antioxidant activity under heavy metal zinc stress in mung bean (Vigna radiata L.).

The escalation of harmful pollutants, including heavy metals, due to industrialization and urbanization has become a global concern. To mitigate the negative impacts of heavy metal stress on germination and early plant development, growth regulators have been employed. This study aimed to evaluate the response of mung bean (Vigna radiata L.) to zinc stress in the presence of brassinosteroids, focusing on seedling growth and antioxidant potential. Mung bean seedlings were treated with three concentrations of 24-epibrassinolide (EBL) (0.1, 0.2, and 0.4 PPM) with or without zinc. Results demonstrated that the application of brassinosteroids, combined with zinc stress, significantly enhanced germination percentage (about 47.06, 63.64, and 120%), speed of germination (about 39.13, 50, and 100%), seedling growth (about 38% in case of treatment combined 0.4 PPM 24-EBL and 1.5 mM ZnSO4) and seedling vigor index (204% in case of treatment combined 0.4 PPM 24-EBL and 1.5 mM ZnSO4) compared to zinc-treated seedlings alone after 24 h. The activities of antioxidative enzymes (catalase, ascorbate peroxidase, polyphenol oxidase, and peroxidase) and total soluble protein content decreased, while lipid peroxidation and proline content exhibited a significant increase (p ≤ 0.05) when compared to the control. However, the negative effects induced by heavy metal stress on these parameters were significantly mitigated by EBL application. Notably, the most effective concentration of EBL in overcoming zinc stress was found to be 0.4 PPM. These findings underscore the potential of exogenously applied brassinosteroids as a valuable tool in phytoremediation projects by ameliorating heavy metal stress.

A Comprehensive Review Uncovering the Challenges and Advancements in the In Vitro Propagation of Eucalyptus Plantations.

The genus Eucalyptus is a globally captivated source of hardwood and is well known for its medicinal uses. The hybrid and wild species of Eucalyptus are widely used as exotic plantations due to their renowned potential of adapting to various systems and sites, and rapid large-scale propagation of genetically similar plantlets, which further leads to the extensive propagation of this species. Tissue culture plays a crucial role in the preservation, propagation, and genetic improvement of Eucalyptus species. Despite unquestionable progression in biotechnological and tissue culture approaches, the productivity of plantations is still limited, often due to the low efficiency of clonal propagation from cuttings. The obtained F1 hybrids yield high biomass and high-quality low-cost raw material for large-scale production; however, the development of hybrid, clonal multiplication, proliferation, and post-developmental studies are still major concerns. This riveting review describes the problems concerning the in vitro and clonal propagation of Eucalyptus plantation and recent advances in biotechnological and tissue culture practices for massive and rapid micropropagation of Eucalyptus, and it highlights the Eucalyptus germplasm preservation techniques.

Potent inhibitors of tumor associated carbonic anhydrases endowed with cathepsin B inhibition.

Twenty-one novel extended analogs of acetazolamide were synthesized and screened in vitro for their inhibition efficacy against human carbonic anhydrase (hCA) isoforms I, II, IX, XII, and cathepsin B. The majority of the compounds were found to be effective inhibitors of tumor-associated hCA IX and XII, and poor inhibitors of cytosolic hCA I. Despite the strong to moderate inhibition potential possessed by these compounds toward another cytosolic isoform hCA II, some of them demonstrated better potency against hCA IX and/or XII isoforms as compared to hCA II. Four compounds (11f, 11g, 12c, and 12g) effectively inhibited hCA IX and/or XII isoforms with considerable selectivity over the off-targets hCA I and II. Interestingly, five compounds, including 11f, 11g, 12c, 12d, and 12g, inhibited hCA IX even better than the clinically used acetazolamide. Some of the novel synthesized compounds exhibited higher anti-cathepsin B potential than acetazolamide, with % inhibition of around 50%, at a concentration of 10-7 M. Further, two compounds (12g and 12c) that showed effective and selective inhibition activity profiles against hCA IX and XII were additionally found to be effective inhibitors of cathepsin B.