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1.
J Pharm Bioallied Sci ; 16(Suppl 2): S1012-S1016, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38882842

ABSTRACT

May-Thurner syndrome (MTS) is an anatomical condition of external luminal compression of common iliac vein due to a partial obstruction of the common iliac vein between common iliac artery and lumbar vertebra causes deep-vein thrombosis, venous hypertension, and chronic venous insufficiencies. In this article, we review present evidence of the clinical diagnosis and management of MTS. Here, we conducted a literature review of studies on MTS. We also reviewed different clinical features, presentation, diagnostic methods, and therapeutic procedure for this condition. Most studies mentioned the diagnosis of this condition is performed by color Doppler, computed tomographic angiography, venography, and problem-solving cases by intravascular ultrasound technique. Nonsurgical methods of management are first line, and vascular surgery is reserved for refractory cases. Multiple modalities are required to reach the diagnosis of MTS, and noninvasive intervention radiology methods are the first line of management. This review highlights the presentations of MTS and outlines diagnostic procedure and management.

2.
J Pharm Bioallied Sci ; 16(Suppl 2): S1494-S1497, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38882885

ABSTRACT

Background: In contrast to the standard shoulder arthroscopy, current radio-diagnostic techniques like magnetic resonance arthrography (MRA), and magnetic resonance imaging (MRI) provide less invasive intricate structural detail of shoulder anatomy. Objectives: Comparison of efficacy of MRA and MRI for diagnosing suspected rotator cuff injury. Materials and Methods: Over the course of 4 years (from June 2017 to June 2021), a comparative study, including 100 individuals with suspected rotator cuff pathology, was conducted. For the evaluation of shoulder injuries, the assessment and comparison of MRA and MRI were done in terms of sensitivity (Sn), positive predictive value (PPV), and diagnostic accuracy (DA). Results: MRI and MRA were positive in 76 (76%) and 98 (98%) patients, respectively. The Sn and PPV of MRI for diagnosing the shoulder injury were 76% and 100%, respectively, whereas the Sn and PPV of MRA were 98% and 100%, respectively. MRA was better than MRI in terms of diagnostic accuracy (98% vs. 76%, P = 0.03). Conclusion: MRA is a nonsurgical effective method in evaluating and diagnosing rotator cuff injuries in comparison to MRI.

4.
J Anaesthesiol Clin Pharmacol ; 40(2): 344-350, 2024.
Article in English | MEDLINE | ID: mdl-38919425

ABSTRACT

Background and Aims: Modified radical mastectomy (MRM) is associated with moderate severity of postoperative pain. Besides intravenous (IV) analgesics, various nerve blocks are being described for pain relief of MRM patients. We compared erector spinae plane (ESP) block with midpoint transverse process to pleura (MTP) block in these patients for postoperative analgesia. Material and Methods: After receiving ethical committee approval from the institutional ethics committee (AIIMS, Jodhpur) and written informed consent from study participants, 66 patients who were assigned American Society of Anesthesiologists (ASA) physical status I and II, aged 18-75 years, and were scheduled to undergo MRM were enrolled and randomly allocated into two groups. Unilateral block was given before surgery at T3 or T4 level and with 15 ml of 0.5% ropivacaine in both the groups. Infusion of 0.5% ropivacaine (Neon laboratories limited, Mumbai, India) and 0.2% ropivacaine at a rate of 5 ml/h was maintained intraoperatively and postoperatively, respectively. Pain was assessed using the Visual Analogue Scale (VAS) for the next 24 hours. The total number of patients needing rescue analgesia, the total amount of rescue analgesics consumed in the next 24 hours, and patient satisfaction score were also compared between groups. Results: Demographics and baseline vitals were comparable in the groups. On comparing VAS scores in both the groups during rest and movement at different time intervals, there was no difference in pain scores during the initial two hours. From the third hour, there was a statistically significant difference (P < 0.001) in pain VAS scores in both groups. The ESP group had lower VAS scores compared to the MTP group when followed for the next 24 hours. There was a statistically significant difference in patient satisfaction. Conclusion: ESP block is more efficacious when compared to MTP block for postoperative analgesia in MRM patients.

5.
AAPS PharmSciTech ; 25(5): 131, 2024 Jun 07.
Article in English | MEDLINE | ID: mdl-38849687

ABSTRACT

Lipid-based vectors are becoming promising alternatives to traditional therapies over the last 2 decades specially for managing life-threatening diseases like cancer. Cationic lipids are the most prevalent non-viral vectors utilized in gene delivery. The increasing number of clinical trials about lipoplex-based gene therapy demonstrates their potential as well-established technology that can provide robust gene transfection. In this regard, this review will summarize this important point. These vectors however have a modest transfection efficiency. This limitation can be partly addressed by using functional lipids that provide a plethora of options for investigating nucleic acid-lipid interactions as well as in vitro and in vivo nucleic acid delivery for biomedical applications. Despite their lower gene transfer efficiency, lipid-based vectors such as lipoplexes have several advantages over viral ones: they are less toxic and immunogenic, can be targeted, and are simple to produce on a large scale. Researchers are actively investigating the parameters that are essential for an effective lipoplex delivery method. These include factors that influence the structure, stability, internalization, and transfection of the lipoplex. Thorough understanding of the design principles will enable synthesis of customized lipoplex formulations for life-saving therapy.


Subject(s)
Gene Transfer Techniques , Genetic Therapy , Lipids , Liposomes , Humans , Lipids/chemistry , Genetic Therapy/methods , Liposomes/chemistry , Animals , Transfection/methods , Genetic Vectors/chemistry , Nucleic Acids/chemistry , Nucleic Acids/administration & dosage
6.
Anaesthesiol Intensive Ther ; 56(1): 17-27, 2024.
Article in English | MEDLINE | ID: mdl-38741440

ABSTRACT

The physiological transformations accompanying pregnancy, compounded by the implications of obesity, pose intricate challenges for anaesthesiologists attending to obese parturients. Obesity makes it harder to successfully provide epidural analgesia to a parturient. This narrative review explains the most recent data on the safety and complications of providing labour epidural analgesia in obese expectant mothers. We have emphasised the evidence-based approaches that are the most effective for obese pregnant mothers receiving labour epidural analgesia.


Subject(s)
Analgesia, Epidural , Analgesia, Obstetrical , Obesity , Humans , Pregnancy , Female , Analgesia, Epidural/methods , Analgesia, Epidural/adverse effects , Analgesia, Obstetrical/methods , Obesity/complications , Labor, Obstetric , Pregnancy Complications
7.
Case Rep Radiol ; 2024: 3543906, 2024.
Article in English | MEDLINE | ID: mdl-38756334

ABSTRACT

Tetralogy of Fallot (TOF) is a significant cause of cyanotic congenital heart disease (CHD) encountered in childhood with few cases manifesting in adulthood. It has four classical features (ventricular septal defect, overriding of aorta, hypertrophy of right ventricular hypertrophy, and right ventricular outflow tract obstruction), but the clinical presentation and course can be variable. Due to various anatomical variations and complex anatomy, presurgical planning and postoperative follow-up by pulmonary computed tomographic angiography (CTA) have a very important role. With continued technological advances and the availability of 128-slice computed tomographic (CT) scans, they now play an important role in TOF preoperative evaluation and workup, assisting by minimizing routine invasive digital subtraction catheter angiography. The fast scan of a 128-slice CTA with very sensitive detectors is a very useful modality for studying the complex anatomy and variations as well as its utilization for postoperative management. In this article, we report four cases of TOF where we used a 128-slice scan for performing pulmonary angiography (Optima 660, GE 128, 2180 Premier Row, Orlando, FL 32809, U.S.A.) for preoperative diagnosis and management of three cases and work up for revision surgery for an already operated case with a nonfunctional modified Blalock-Taussig shunt with additional lung parenchymal findings simultaneously. This study will explain the advantageous role of the 128-slice CT scanner over the lesser-slice CT scanners with the ability of pulmonary CTA to facilitate accurate diagnosis and postoperative management.

8.
Indian J Anaesth ; 68(4): 366-373, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38586260

ABSTRACT

Background and Aims: We compared classical (medial) and modified (lateral) thoracolumbar interfascial plane block (TLIP) with only general anaesthesia (GA) using multimodal analgesia in patients undergoing lumbar disc surgeries. Methods: In this study, 100 patients aged 18-70 years were randomised to Group cTLIP (conventional TLIP block with 20 mL of 0.25% ropivacaine with GA), Group mTLIP (modified TLIP block with 20 mL of 0.25% ropivacaine with GA), and Group C (only GA using multimodal analgesia). The primary outcome was to assess the total peri-operative opioid consumption in the first 24 h. The secondary outcomes were to assess pain score upon arriving in the post-anaesthesia care unit, time to first analgesic need after surgery, post-operative opioid consumption in 24 h, and incidence of nausea and vomiting. Results: The total peri-operative opioid consumption in Group cTLIP (507.58 (258.55) µg) and Group mTLIP (491.67 (165.39) µg) was significantly lower than that in Group C (1225.4 (237.03) µg); (P < 0.001). However, it was comparable between groups cTLIP and mTLIP (P = 0.767). Pain score was comparable in groups cTLIP and mTLIP. It was significantly lower than Group C (P = 0.001). Rescue analgesia was needed in all (100%) patients of Group C but in only 15.2% of patients of the cTLIP and mTLIP groups. No patient in groups cTLIP and mTLIP complained of nausea and vomiting in the first 24 h, whereas it was significantly higher (61.8%) in Group C (P = 0.001). Conclusion: The analgesic effect of the modified TLIP block was not superior to the conventional TLIP block. Both techniques provided the same intra-operative and post-operative analgesia for lumbar disc surgeries.

9.
Saudi J Anaesth ; 18(2): 283-285, 2024.
Article in English | MEDLINE | ID: mdl-38654846

ABSTRACT

Frontoethmoidal encephalocele represents protrusion of meninges and brain in a sac through a defect in the anterior skull base, mostly as swelling over the nose. Rarely it is associated with facial dysmorphism and palatal cleft. There are various perioperative concerns like airway difficulties, leaking from the swelling causing fluid and electrolyte disturbances, risk of infection, compression of the swelling causing a rise in intracranial pressure, bleeding, hypothermia, etc., In neonates, these challenges rise exponentially because of the inherent difficulties in dealing with this group of patients. Frontoethmoidal encephaloceles are common in low socioeconomic strata and are often missed in the antenatal period. We are reporting a rare case of frontoethmoidal encephalocele, with a huge swelling protruding through the cleft palate and occupying more than 50% of the face and oral cavity, making mask ventilation impossible.

10.
Lung India ; 41(3): 200-208, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38687231

ABSTRACT

BACKGROUND: In recent years, a significant understanding of delivering optimal aerosol therapy and the availability of various drugs and devices have led to an increase in its use in clinical practice. There are only a few studies available regarding their use in critically ill patients from a few parts of the world. We aimed to study the practice pattern of aerosol therapy in critically ill patients from Indian intensive care units (ICUs). METHODS: After ethical approval, this multi-centric prospective observational study was performed over a study period of four weeks. Newly admitted adult patients considered who had an artificial airway and/or ventilation (including non-invasive). Patients were followed up for the next 14 days or until ICU discharge/death (whichever came first) for details of each aerosol therapy, including ongoing respiratory support, drug type, and aerosol-generating device. RESULTS: From the nine participating centers across India, 218 patients were enrolled. Of 218 enrolled patients, 72.48% received 4884 aerosols with 30.91 ± 27.15 (95%CI: 26.6-35.1) aerosols per patient over 1108 patient days. Approximately 62.7% during IMV, 30.2% during NIV, 2.3% in spontaneously breathing patients with an artificial airway during weaning, and 4.7% were given without an artificial airway after weaning or decannulation. In 59%, a single drug was used, and bronchodilators were the most frequent. The jet nebulizer was the most common, followed by the ultrasonic and vibrating mesh aerosol generator. The ventilator setting was changed in only 6.6% of the aerosol sessions with IMV and none with NIV. CONCLUSION: Aerosol therapy is frequently used with a wide variation in practices; bronchodilators are the most commonly used drugs, and jet nebulizers are the most widely used.

11.
Indian J Crit Care Med ; 28(3): 294-298, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38477006

ABSTRACT

Background: Acute hypoxemic respiratory failure is among the more commonly occurring complications in postoperative patients. Supplemental oxygen and addressing the primary etiology form the basis of its treatment. Materials and methods: We conducted an open-labeled randomized control trial with 90 adult patients and compared three oxygen delivery vehicles (ODV), i.e., noninvasive ventilation (NIV), high-flow nasal cannula (HFNC), and venturi mask (VM) in postoperative hypoxemic patients. The primary outcome variable was a change in the P/F ratio after 2 hours of use of ODV. Results: It was observed that the change in P/F ratio after 2 hours was similar in all three ODV groups (p = 0.274). The mean values of the post-ODV P/F ratio were comparable with the pre-ODV P/F ratio in all three modalities. The P/F ratio after HFNC was 358.08 ± 117.95; after NIV was 357.60 ± 220.67; and after VM was 355.47 ± 101.90 (p = 0.997). Conclusion: Among HFNC, NIV, and VM, none of the devices proved superior to the other for use in postoperative hypoxemia. How to cite this article: Mishra S, Kothari N, Sharma A, Goyal S, Rathod D, Meshram T, et al. Comparison of Oxygen Delivery Devices in Postoperative Patients with Hypoxemia: An Open-labeled Randomized Controlled Study. Indian J Crit Care Med 2024;28(3):294-298.

12.
Environ Monit Assess ; 196(3): 257, 2024 Feb 13.
Article in English | MEDLINE | ID: mdl-38349601

ABSTRACT

Landslide susceptibility zonation (LSZ) mapping is used to delineate areas prone to landslides and is critical for effective landslide hazard management. The existing methodologies for generating such maps tend to neglect the influence of dynamic environmental variables on landslide occurrences, which may lead to obsolete and erroneous estimates of landslide susceptibility (LS) for a concerned area. Although recent studies have started to report the effects of Land Use/ Land Cover (LULC) variation on LSZ mapping, variations in other dynamic variables like rainfall, soil moisture, and evapotranspiration apart from LULC may also influence slope stability in mountainous regions. The present study investigates the impact of variations in these four variables on the LS distribution, of a selected Indian Himalayan region between 2017 and 2021. Random Forest (RF) susceptibility models are utilized for evaluating the LS for the selected years and geospatial technologies are employed for LS change detection. The results indicate up to 19% variations in the spatial extent for some of the zones of the generated LSZ maps. The research findings of this study are crucial since they reveal the impact of dynamic behavior on LS, which has not been previously documented in the literature.


Subject(s)
Landslides , Environmental Monitoring , Safety Management , Soil
14.
J Biomol Struct Dyn ; : 1-15, 2024 Feb 14.
Article in English | MEDLINE | ID: mdl-38356140

ABSTRACT

Cancer is an aberrant differentiation of normal cells, characterized by uncontrolled growth and the potential to acquire invasive and aggressive properties that ultimately lead to metastasis. In the realm of scientific exploration, a multitude of pathways has been investigated and targeted by researchers, among which one specific pathway is recognized as WDR5-MYC. Continuous investigations and research show that WDR5-MYC is a therapeutic target protein. Hence, the discovery of naturally occurring compounds with anticancer properties has been suggested as a rapid and efficient alternative for the development of anticancerous therapeutics. A virtual screening approach was used to identify the most potent compounds from the NP-lib database at the MTiOpenScreen webserver against WDR5-MYC. This process yielded a total of 304 identified compounds. Subsequently, after screening, four potent compounds, namely Estrone (ZINC000003869899), Ethyl-1,2-benzanthracene (ZINC000003157052), Strychnine (ZINC000000119434) and 7H-DIBENZO [C, G] CARBAZOLE (ZINC000001562130), along with a cocrystallized 5-[4-(trifluoromethyl) phenyl]-1H-tetrazole inhibitor (QBP) as a reference ligand, were considered for stringent molecular docking. Thus, each compound exhibited significant docking energy between -8.2 and -7.7 kcal/mol and molecular contacts with essential residue Asn225, Lys250, Ser267 and Lys272 in the active pocket of WDR5-MYC against the QBP inhibitor (the native ligand QBP serves as a reference in the comparative analysis of docked complexes). The results support the potent compounds for drug-likeness and strong binding affinity with WDR5-MYC protein. Further, the stability of the selected compounds was predicted by molecular dynamics simulation (100 ns) contributed by intermolecular hydrogen bonds and hydrophobic interactions. This demonstrates the potential of the selected compounds to be used against breast cancer treatment.Communicated by Ramaswamy H. Sarma.

15.
Vet Res Commun ; 48(3): 1423-1433, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38305958

ABSTRACT

Uncarboxylated osteocalcin (UcOCN), a bone derived circulating protein, has been demonstrated to influence steroidogenesis in testicular Leydig cells of murine and human species. However, the role of UcOCN in testosterone biosynthesis remains unexplored in domestic animals. The present study aimed to investigate the impact of UcOCN on the expressions of steroidogenic genes (HSD3ß1, HSD3ß6, CYP17A1, CYP11A1), testosterone production and GPRC6A receptor localization in buffalo Leydig cells. Leydig cells from the testes of adult Murrah buffalo were isolated, with an average cell count and viability after digestion and Percoll enrichment of 1.43 × 106 cells/g of testes and 78.5%, respectively. Immunophenotyping of Percoll-enriched cell suspension by flow cytometry showed populations of Leydig cells ranging between 69 and 73.9%. Immunostaining confirmed the presence of GPRC6A receptors and CYP11A1 positive Leydig cells. When these cells were cultured and incubated with varying levels of UcOCN (6, 12, 24, and 48 ng/ml) and LH, there was a significant (P < 0.01) increase in testosterone production and up-regulation (P < 0.05) of CYP11A1, CYP17A1, HSD3ß1 and HSD3ß6 gene expression. In summary, the present study underscored the effects of UcOCN on testosterone biosynthesis, expression of crucial steroidogenic genes and interaction with GPRC6A receptors in buffalo Leydig cells, emphasizing its potential implications in andrology.


Subject(s)
Buffaloes , Leydig Cells , Osteocalcin , Testosterone , Animals , Male , Leydig Cells/metabolism , Leydig Cells/drug effects , Testosterone/biosynthesis , Osteocalcin/genetics , Osteocalcin/metabolism
16.
Nat Cancer ; 5(1): 167-186, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38168935

ABSTRACT

Onco-fetal reprogramming of the tumor ecosystem induces fetal developmental signatures in the tumor microenvironment, leading to immunosuppressive features. Here, we employed single-cell RNA sequencing, spatial transcriptomics and bulk RNA sequencing to delineate specific cell subsets involved in hepatocellular carcinoma (HCC) relapse and response to immunotherapy. We identified POSTN+ extracellular matrix cancer-associated fibroblasts (EM CAFs) as a prominent onco-fetal interacting hub, promoting tumor progression. Cell-cell communication and spatial transcriptomics analysis revealed crosstalk and co-localization of onco-fetal cells, including POSTN+ CAFs, FOLR2+ macrophages and PLVAP+ endothelial cells. Further analyses suggest an association between onco-fetal reprogramming and epithelial-mesenchymal transition (EMT), tumor cell proliferation and recruitment of Treg cells, ultimately influencing early relapse and response to immunotherapy. In summary, our study identifies POSTN+ CAFs as part of the HCC onco-fetal niche and highlights its potential influence in EMT, relapse and immunotherapy response, paving the way for the use of onco-fetal signatures for therapeutic stratification.


Subject(s)
Carcinoma, Hepatocellular , Folate Receptor 2 , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/therapy , Carcinoma, Hepatocellular/genetics , Liver Neoplasms/therapy , Liver Neoplasms/genetics , Ecosystem , Endothelial Cells , Cell Movement/genetics , Chronic Disease , Recurrence , Immunotherapy , Tumor Microenvironment/genetics
17.
Science ; 383(6679): eadf6493, 2024 01 12.
Article in English | MEDLINE | ID: mdl-38207030

ABSTRACT

Neutrophils are increasingly recognized as key players in the tumor immune response and are associated with poor clinical outcomes. Despite recent advances characterizing the diversity of neutrophil states in cancer, common trajectories and mechanisms governing the ontogeny and relationship between these neutrophil states remain undefined. Here, we demonstrate that immature and mature neutrophils that enter tumors undergo irreversible epigenetic, transcriptional, and proteomic modifications to converge into a distinct, terminally differentiated dcTRAIL-R1+ state. Reprogrammed dcTRAIL-R1+ neutrophils predominantly localize to a glycolytic and hypoxic niche at the tumor core and exert pro-angiogenic function that favors tumor growth. We found similar trajectories in neutrophils across multiple tumor types and in humans, suggesting that targeting this program may provide a means of enhancing certain cancer immunotherapies.


Subject(s)
Cellular Reprogramming , Neoplasms , Neovascularization, Pathologic , Neutrophils , Humans , Neoplasms/blood supply , Neoplasms/immunology , Neutrophils/immunology , Proteomics , Cellular Reprogramming/genetics , Cellular Reprogramming/immunology , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/immunology , Receptors, TNF-Related Apoptosis-Inducing Ligand/immunology , Epigenesis, Genetic , Hypoxia , Transcription, Genetic
18.
J Vasc Access ; : 11297298231219431, 2024 Jan 10.
Article in English | MEDLINE | ID: mdl-38197213

ABSTRACT

BACKGROUND: In adult patients, there has never been an evaluation of short-axis out-of-plane versus long-axis in-plane approaches of ultrasound-guided dorsalis pedis artery cannulation. This research was conducted to compare these two techniques to cannulate the dorsal pedis artery. METHODS: In this trial, 128 adult patients undergoing surgery and necessitating arterial cannulation were examined. Dorsalis pedis artery cannulation was performed utilizing an ultrasound by long-axis in-plane approach (group L) or short-axis out-of-plane (group S) techniques. RESULTS: Group S had a higher first attempt success rate than group L (46.9% vs 28.6%, p = 0.039). The S group had a lower assessment time than the L group (11.48 ± 3.07 vs 19.68 ± 2.79 s; p = 0.000). Cannulation time was higher in the S group (18.91 ± 1.92 s) compared to the L group (12.48 ± 1.61 s; p = 0.000). Nevertheless, the total procedure time was comparable between the L group and the S group (32.16 ± 2.95 vs 30.42 ± 4.07 s; p = 0.107). CONCLUSIONS: In adults, both views of ultrasonography can be used to guide DPA cannulation. The cannulation time for the DPA in L group was less than the S group, whereas the assessment time was less in S group. The total procedure time, however, was similar between both the groups.

19.
Am J Physiol Cell Physiol ; 326(1): C10-C26, 2024 01 01.
Article in English | MEDLINE | ID: mdl-37955119

ABSTRACT

Sarcoidosis embodies a complex inflammatory disorder spanning multiple systems, with its origin remaining elusive. It manifests as the infiltration of inflammatory cells that coalesce into distinctive noncaseous granulomas within afflicted organs. Unraveling this disease necessitates the utilization of cellular or tissue-based imaging methods to both visualize and characterize the biochemistry of these sarcoid granulomas. Although hematoxylin and eosin stain, standard in routine use alongside cytological stains have found utility in diagnosis within clinical contexts, special stains such as Masson's trichrome, reticulin, methenamine silver, and Ziehl-Neelsen provide additional varied perspectives of sarcoid granuloma imaging. Immunohistochemistry aids in pinpointing specific proteins and gene expressions further characterizing these granulomas. Finally, recent advances in spatial transcriptomics promise to divulge profound insights into their spatial orientation and three-dimensional (3-D) molecular mapping. This review focuses on a range of preexisting imaging methods employed for visualizing sarcoid granulomas at the cellular level while also exploring the potential of the latest cutting-edge approaches like spatial transcriptomics and matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI), with the overarching goal of shedding light on the trajectory of sarcoidosis research.


Subject(s)
Granuloma , Sarcoidosis , Humans , Granuloma/diagnostic imaging , Sarcoidosis/diagnostic imaging
20.
AAPS J ; 26(1): 5, 2023 Dec 12.
Article in English | MEDLINE | ID: mdl-38087107

ABSTRACT

SHetA2 is a promising, orally active small molecule with anticancer properties that target heat shock proteins. In this study, we aimed to investigate the pharmacodynamic (PD) effects of SHetA2 using preclinical in vitro and in vivo models of ovarian cancer and establish a physiologically based pharmacokinetic (PBPK)/PD model to describe their relationships with SHetA2 concentrations in mice. We found that daily oral administration of 60 mg/kg SHetA2 for 7 days resulted in consistent plasma PK and tissue distribution, achieving tumor drug concentrations required for growth inhibition in ovarian cancer cell lines. SHetA2 effectively induced cyclin D1 degradation in cancer cells in a dose-dependent manner, with up to 70% reduction observed and an IC50 of 4~5 µM. We identified cyclin D1 as a potential PD marker for SHetA2, based on a well-correlated time profile with SHetA2 PK. Additionally, we examined circulating levels of ccK18 as a non-invasive PD marker for SHetA2-induced apoptotic activity and found it unsuitable due to high variability. Using a PBPK/PD model, we depicted SHetA2 levels and their promoting effects on cyclin D1 degradation in tumors following multiple oral doses. The model suggested that twice-daily dosing regimens would be effective for sustained reduction in cyclin D1 protein. Our study provides valuable insights into the PK/PD of SHetA2, facilitating future clinical trial designs and dosing schedules.


Subject(s)
Cyclin D1 , Ovarian Neoplasms , Humans , Mice , Animals , Female , Heterografts , Cyclin D1/metabolism , Chromans , Ovarian Neoplasms/drug therapy
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