Gynecological cancer tumor Microenvironment: Unveiling cellular complexity and therapeutic potential.

Gynecological cancers, including ovarian, cervical, endometrial, and vulvar cancers, present significant challenges in diagnosis and treatment globally. The tumor microenvironment (TME) plays a pivotal role in cancer progression and therapy response, necessitating a deeper understanding of its composition and dynamics. This review offers a comprehensive overview of the gynecological cancer tumor microenvironment, emphasizing its cellular complexity and therapeutic potential. The diverse cellular components of the TME, including cancer cells, immune cells, stromal cells, and extracellular matrix elements, are explored, elucidating their interplay in shaping tumor behavior and treatment outcomes. Across various stages of cancer progression, the TME exerts profound effects on tumor heterogeneity, immune modulation, angiogenesis, and metabolic reprogramming. The urgency for novel therapeutic strategies is underscored by understanding immune evasion mechanisms within the TME. Emerging approaches such as immunotherapy, stromal-targeting therapies, anti-angiogenic agents, and metabolic inhibitors are discussed, offering promising avenues for improving patient outcomes. Interdisciplinary collaborations and translational research are emphasized, aiming to advance precision oncology and enhance therapeutic efficacy in gynecological cancers.

Enhancing carboplatin sensitivity in ovarian cancer cells by blocking the mercapturic acid pathway transporter.

Ral-binding/interacting protein (RLIP) acts as a transporter that responds to stress and provides protection, specifically against glutathione-electrophile conjugates and xenobiotic toxins. Its increased presence in malignant cells, especially in cancer, emphasizes its crucial antiapoptotic function. This is achieved by selectively regulating the cellular levels of proapoptotic oxidized lipid byproducts. Suppressing the progression of tumors in human xenografts can be achieved by effectively inhibiting RLIP, a transporter in the mercapturic acid pathway, without involving chemotherapy. Utilizing ovarian cancer (OC) cell lines (MDAH2774, OVCAR4, and OVCAR8), we observed that agents targeting RLIP, such as RLIP antisense and RLIP antibodies, not only substantially impeded the viability of OC cells but also remarkably increased their sensitivity to carboplatin. To delve further into the cytotoxic synergy between RLIP antisense, RLIP antibodies, and carboplatin, we conducted investigations in both cell culture and xenografts of OC cells. The outcomes revealed that RLIP depletion via phosphorothioate antisense led to rapid and sustained remissions in established subcutaneous human ovary xenografts. Furthermore, RLIP inhibition by RLIP antibodies exhibited comparable efficacy to antisense and enhanced the effectiveness of carboplatin in MDAH2774 OC xenografts. These investigations underscore RLIP as a central carrier crucial for supporting the survival of cancer cells, positioning it as a suitable focus for cancer treatment.

Design and Analysis of MEMS Pressure Sensor based on various principles of Microcantilever beam.

In this paper, we have used COMSOL Multiphysics for the design and simulation of three different micro cantilever configurations. These micro cantilevers are analyzed using finite element analysis (FEM) to understand their mechanical behavior, sensitivity, and non-linear characteristics. The goal of the research is to identify the most suitable micro cantilever design for integration with an electro-osmotic pressure sensor. This integrated system is intended to measure variations in glucose concentration levels with accuracy and efficiency, with potential applications in glucose monitoring and biomedical fields. The sensitivity of the microcantilever is reported as 0.10e-7. The stress value is given as 1.64. A change in resistance of 0.00011 Ω·µm is mentioned. The reported output voltage is 0.15 µV. This voltage is likely generated by the microcantilever in response to the changes in resistance, which are in turn caused by variations in glucose concentration. The gauge factor is given as 0.04. The gauge factor is a measure of the sensitivity of a strain gauge (in this case, the microcantilever) and is often used to relate the mechanical strain (stress) to the electrical resistance change. These parameters provide insights into the performance of the microcantilever-based glucose sensor and its ability to detect glucose concentration variations. The small output voltage indicates the need for sensitive detection and measurement equipment to utilize the sensor effectively.

Survival of Trial-Like and Non-Trial-Like Patients With Immunotherapy in Advanced Hepatocellular Carcinoma in Real World: A Collaborative Multicenter Indian Study (IMHEP).

PURPOSE: Immune checkpoint inhibitors (ICIs) is the initial line of management in advanced hepatocellular carcinoma (HCC), but survivals in the real world are not known. MATERIALS AND METHODS: A retrospective study of patients with advanced HCC receiving ICIs (as first-line therapy or as later lines of therapy) across 11 Indian institutions was conducted. Patients were divided into either cohort 1 (trial-like receiving ICI as first-line therapy), with a Child Pugh score (CTP) of ≤6, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0/1, and no VP4 (main portal vein thrombosis [MPVT]) or cohort 2 (trial unlike) who did not satisfy at least one of the above criteria. The primary end point was 12-month overall survival (OS). RESULTS: Between January 2017 and January 2022, 133 patient data were analyzed. The presence of MPVT was seen in 33 patients (25%). The ICIs used were atezolizumab-bevacizumab, nivolumab, and pembrolizumab in 89 (66%), 44 (33%), and one (1%) patients, respectively. With a median follow-up of 13.8 months, the 12-month OS for the entire cohort was 33.4% (95% CI, 23.6 to 43.2). Patients in cohort 1 (n = 31) had a significantly improved OS compared with patients in cohort 2 (n = 102; 12-month OS, 57.9% [95% CI, 38.5 to 77.3] v 24% [95% CI, 13.4 to 34.6]; P = .005). Patients with CTP A as compared with CTP B (9.7 v 4.3 months; P < .001) and an ECOG PS of 0/1 as compared with a PS of ≥2 (8.7 v 7.2 months; P = .04) and without MPVT (9.4 v 4.0; P < .001) had superior survivals. CONCLUSION: Patients with advanced HCC in the real world, trial-like have survivals in consonance with trial data, whereas patients with features excluding them from trials, such as main portal vein thrombosis, poor ECOG PS, and child Pugh B status, have markedly inferior survivals, despite good tolerance to immunotherapy.

Regression of ovarian cancer xenografts by depleting or inhibiting RLIP.

Ovarian cancer (OC) is the most prevalent and deadly cancer of the female reproductive system. Women will continue to be impacted by OC-related morbidity and mortality. Despite the fact that chemotherapy with cisplatin is the main component as the first-line anticancer treatment for OC, chemoresistance and unfavorable side effects are important obstacles to effective treatment. Targets for effective cancer therapy are required for cancer cells but not for non-malignant cells because they are expressed differently in cancer cells compared to normal cells. Targets for cancer therapy should preferably be components that already exist in biochemical and signalling frameworks and that significantly contribute to the development of cancer or regulate the response to therapy. RLIP is an important mercapturic acid pathway transporter that is crucial for survival and therapy resistance in cancers, therefore, we examined the role of RLIP in regulating essential signalling proteins involved in relaying the inputs from upstream survival pathways and mechanisms contributing to chemo-radiotherapy resistance in OC. The findings of our research offer insight into a novel anticancer effect of RLIP depletion/inhibition on OC and might open up new therapeutic avenues for OC therapy.

Design and Analysis of Bio-Inspired Micro-Needle for Drug Delivery Applications.

Years of research show that the Trans-dermal drug delivery (TDD) route showed promising results due to good immunogenic responses. In this paper, we have proposed a bio-inspired micro-needle suggested by a snake belonging to the family of Elapids, since they inject venom with high pressures during the bite. The proposed micro-needle is strong enough to puncture the skin and withstand different kinds of loads during the insertion. The proposed micro-needle is of [Formula: see text] length, and the maximum compressive, buckling, bending, load it can handle are 0.27N, 0.16N, 0.024N respectively. The proposed micro-needle (MN) has an inner channel diameter of 44 [Formula: see text] and it gives a flow rate of [Formula: see text]/s. In our work, we have modeled a substrate of epidermis and dermis as a porous medium with porosity and permeability as 0.74, [Formula: see text] respectively. The porosity and permeability are calculated using an SEM image of the human dermis consisting of only collagen fibers and empty pores. We have applied Darcy's law to the modeled substrate and obtained the velocity field of the drug administrated. The diffusion study of Doxorubicin ( 87 µ mol/l) is carried out using Darcy velocity field and concentration gradient.

Comparison of Postoperative Pain and Analgesia Requirement among Diabetic and Nondiabetic Patients undergoing Lower Limb Fracture Surgery - A Prospective Observational Study.

Background: Diabetic patients usually experience neuropathic pain and have a decreased response to opioids. Fractures are acute conditions and as such, they are very painful. No data is available related to fracture and postoperative pain in diabetics. Aim: This study was conducted to evaluate postoperative pain and analgesics requirement among diabetic and nondiabetic patients undergoing lower limb fracture surgery and the effect of glycosylated hemoglobin (HbA1c) on the postoperative pain. Setting and Design: This was a prospective observational study, conducted on 80 patients comprising of nondiabetic and diabetic, scheduled for elective lower limb fracture surgery under spinal anesthesia. Materials and Methods: HbA1c was done in all the patients who were included in the study. Postoperative Visual Analog Scale (VAS) and analgesic consumption were assessed by an anesthesiologist blinded to the diabetic or nondiabetic status of the patients. VAS was assessed every 2nd hourly, for 24 h and rescue analgesia was given if the VAS was ≥4 and record was maintained. Sedation scores and adverse effects were also recorded postoperatively. Statistical Analysis: The Chi-square test was used for the analysis of categorical variables and Student's t-test was used for continuous variables. Results: Diabetic group of patients had a significantly high VAS score with P ≤ 0.05. Rescue analgesics requirement was significantly different in two groups with diabetic patients requiring more supplementation of analgesia with a P = 0.025. The overall patient satisfaction was lesser in diabetic group (P = 0.004). There was statistically significant correlation between glycosylated hemoglobin and VAS at 2nd, 16th, 18th, 20th, 22nd, and 24th h. Conclusion: Postoperative pain and analgesic requirement was significantly higher in diabetic patients with lower limb fracture. Glycosylated hemoglobin had good correlation with higher VAS.

In vitro studies of DNA condensation by bridging protein in a crowding environment.

The macromolecules of the bacterial cell occupy 20-40% of the total cytosol volume, and crowded environments have long been known to compact and stabilize DNA. Nevertheless, investigations on DNA-protein binding are generally performed in the absence of crowding, which may yield an incomplete understanding of how nucleoid-assembling proteins work. A family of such proteins, abundant in Gram-negative bacteria, is the histone-like nucleoid structuring proteins (H-NS). Herein, the synergistic role of macromolecular crowding (mimicked using polyethylene glycol, PEG) and H-NS was investigated using fluorescence correlation spectroscopy (FCS) and enzyme protection assays. We show that crowding enhances the binding of H-NS to the AT-rich tracks of the DNA, where it preferentially binds to, protecting these tracks towards enzyme digestion, inducing some DNA condensation, and inhibiting the biological function of DNA. We further suggest that the looping of DNA chains, induced by H-NS, contributes to the synergistic effect of DNA-binding protein and crowding agents, on DNA condensation.

Integrative functional genomic analysis identifies epigenetically regulated fibromodulin as an essential gene for glioma cell migration.

An integrative functional genomics study of multiple forms of data are vital for discovering molecular drivers of cancer development and progression. Here, we present an integrated genomic strategy utilizing DNA methylation and transcriptome profile data to discover epigenetically regulated genes implicated in cancer development and invasive progression. More specifically, this analysis identified fibromodulin (FMOD) as a glioblastoma (GBM) upregulated gene because of the loss of promoter methylation. Secreted FMOD promotes glioma cell migration through its ability to induce filamentous actin stress fiber formation. Treatment with cytochalasin D, an actin polymerization inhibitor, significantly reduced the FMOD-induced glioma cell migration. Small interfering RNA and small molecule inhibitor-based studies identified that FMOD-induced glioma cell migration is dependent on integrin-FAK-Src-Rho-ROCK signaling pathway. FMOD lacking C-terminus LRR11 domain (ΔFMOD), which does not bind collagen type I, failed to induce integrin and promote glioma cell migration. Further, FMOD-induced integrin activation and migration was abrogated by a 9-mer wild-type peptide from the FMOD C-terminus. However, the same peptide with mutation in two residues essential for FMOD interaction with collagen type I failed to compete with FMOD, thus signifying the importance of collagen type I-FMOD interaction in integrin activation. Chromatin immunoprecipitation-PCR experiments revealed that transforming growth factor beta-1 (TGF-ß1) regulates FMOD expression through epigenetic remodeling of FMOD promoter that involved demethylation and gain of active histone marks with a simultaneous loss of DNMT3A and EZH2 occupancy, but enrichment of Sma- and Mad-related protein-2 (SMAD2) and CBP. FMOD silencing inhibited the TGF-ß1-mediated glioma cell migration significantly. In univariate and multivariate Cox regression analysis, both FMOD promoter methylation and transcript levels predicted prognosis in GBM. Thus, this study identified several epigenetically regulated alterations responsible for cancer development and progression. Specifically, we found that secreted FMOD as an important regulator of glioma cell migration downstream of TGF-ß1 pathway and forms a potential basis for therapeutic intervention in GBM.

Implications of MGMT methylation status in pituitary adenoma.

BACKGROUND: Very little literature exists on frequency of MGMT methylation status in pituitary adenoma. We assessed the frequency of MGMT methylation and protein expression in pituitary adenoma and correlated with patients' age group and prognosis. METHODS: Tumor tissues from 30 patients with pituitary adenoma were evaluated for MGMT promoter methylation status by methylation specific PCR method. All tumors were also immunostained with MIB-1, anti-p53 and anti-MGMT antibodies. RESULTS: MGMT methylation status was noted in 40% of cases (7/20 non-functioning adenomas and 5/10 functioning adenomas). MGMT protein expression on IHC was noted in 72.2% of unmethylated tumors, while only 41.6% of methylated tumors demonstrated protein expression. The mean labeling index of MGMT protein was higher in unmethylated tumors as compared to the methylated group, though the difference was not statistically significant (18.6% vs 8.8%; p=0.131). Tumor regrowth occurred in four unmethylated tumors as compared to none in methylated group. Even though there was no correlation between patient age and MGMT methylation status (p=0.823), we noted that the frequency of methylation in middle age patients (between 30 and 59 yrs) was 64.7%, which was higher compared to other age groups. CONCLUSION: This is the first study from India showing MGMT promoter methylation status with protein expression in pituitary adenoma. We noted that tumor regrowth was higher in unmethylated tumors.