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Laryngeal granuloma, vocal process granuloma, or post-intubation granuloma are benign, inflammatory lesions of the arytenoid cartilage vocal process. The etiology of laryngeal granulomas is multifactorial, such as chronic irritation due to endotracheal intubation, vocal cord injury or trauma, and gastroesophageal reflux disease. They can arise postoperatively after mucosal injury due to orotracheal intubation. Clinical manifestations include voice change and dyspnea, which may start one to four months after extubation and may rarely lead to asphyxia. We presented a case of death due to glottic granuloma occurring after a surgical procedure to remove a laryngeal polyp attributed to previous laryngeal injuries by multiple intubations.
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Gemcitabine (GEM) is an important chemotherapeutic agent used alone or in combination with other anticancer agents for the treatment of various solid tumors. In this study, the potential of a dietary supplement, α-tocopherol succinate (TOS) was investigated in combination with GEM by utilizing human serum albumin-based nanoparticles (HSA NPs). The developed nanoparticles were characterized using DLS, SEM and FTIR and evaluated in a panel of cell lines to inspect cytotoxic efficacy. The ratio metric selected combination of the NPs was further investigated in human pancreatic cancer cell line (MIA PaCa-2 cells) to assess the cellular death mechanism via a myriad of biochemical and bio-analytical assays including nuclear morphometric analysis by DAPI staining, ROS generation, MMP loss, intracellular calcium release, in vitro clonogenic assay, cell migration assay, cell cycle analysis, immunocytochemical staining followed by western blotting, Annexin V-FITC and cellular uptake studies. The desolvation-crosslinking method was used to prepare the NPs. The average size of TOS-HSA NPs and GEM-HSA NPs was found to be 189.47 ± 5 nm and 143.42 ± 7.4 nm, respectively. In combination, the developed nanoparticles exhibited synergism by enhancing cytotoxicity in a fixed molar ratio. The selected combination also significantly triggered ROS generation and mitochondrial destabilization, alleviated cell migration potential and clonogenic cell survival in MIA PaCa-2 cells. Further, cell cycle analysis, Annexin-V FITC assay and caspase-3 activation, up regulation of Bax and down regulation of Bcl-2 protein confirmed the occurrence of apoptotic event coupled with the G0/G1 phase arrest. Nanocarriers based this combination also offered approximately 14-folds dose reduction of GEM. Overall, the combined administration of TOS-HSA NPs and GEM-HSA NPs showed synergistic cytotoxicity accompanied with dose reduction of the gemcitabine. These encouraging findings could have implication in designing micronutrient based-combination therapy with gemcitabine and demands further investigation.
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Antineoplásicos , Neoplasias Pancreáticas , Humanos , Gencitabina , alfa-Tocoferol/farmacologia , Desoxicitidina/química , Espécies Reativas de Oxigênio , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , ApoptoseRESUMO
ABSTRACT Laryngeal granuloma, vocal process granuloma, or post-intubation granuloma are benign, inflammatory lesions of the arytenoid cartilage vocal process. The etiology of laryngeal granulomas is multifactorial, such as chronic irritation due to endotracheal intubation, vocal cord injury or trauma, and gastroesophageal reflux disease. They can arise postoperatively after mucosal injury due to orotracheal intubation. Clinical manifestations include voice change and dyspnea, which may start one to four months after extubation and may rarely lead to asphyxia. We presented a case of death due to glottic granuloma occurring after a surgical procedure to remove a laryngeal polyp attributed to previous laryngeal injuries by multiple intubations.
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OBJECTIVE: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. METHODS: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses. RESULTS: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors. CONCLUSIONS: This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.
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Transtorno Depressivo Maior , Estudo de Associação Genômica Ampla , Humanos , Tentativa de Suicídio , Transtorno Depressivo Maior/genética , Fatores de Risco , Ideação Suicida , Polimorfismo de Nucleotídeo Único/genética , Predisposição Genética para Doença/genética , Loci Gênicos/genéticaRESUMO
The unique physiology of tumors limits the efficacy of chemotherapeutics. In efforts to improve the effectiveness of the existing chemotherapy drugs, nanomedicine emerged as a new hope but proved inadequate due to the transport barriers present within the tumor tissues, which limits the potential of nanomedicine. Dense collagen networks in fibrotic tissues contribute to hindering the penetration of molecular- or nano-scale medicine through tumor interstitium. In the present study, human serum albumin (HSA)-based nanoparticles (NPs) were developed for gemcitabine (GEM) and losartan (LST), which could offer secreted protein acids rich in cysteine (SPARC) and enhanced permeability and retention effect (EPR)-mediated drug accumulation in tumors. Also, the tumor microenvironment (TME) modulation approach using LST was coupled to investigate the impact on antitumor efficacy. GEM-HSA NPs and LST-HSA NPs were prepared by the desolvation-cross-linking method and characterized for size, potential, morphology, drug loading, drug-polymer interactions, and hemocompatibility. For investigating the efficacy of prepared NPs, cytotoxicity and mechanisms of cell death were elucidated in vitro by using various assays. Intracellular uptake studies of prepared HSA NPs indicated their uptake and cytoplasmic localization. Furthermore, in vivo studies demonstrated significantly improved anticancer efficacy of GEM-HSA NPs in combination with LST pretreatment. Extended LST treatment further improved the anticancer potential. It was shown that the improved efficacy of the nanomedicine was correlated with the reduced thrombospondin-1 (TSP-1) and collagen level in tumor tissue upon LST pretreatment. Moreover, this approach exhibited augmented nanomedicine accumulation in the tumor, and hematological, biochemical, and tissue histology indicated the safety profile of this combination regimen. Concisely, the undertaken study demonstrated the potential of the triple targeting (SPARC, EPR, TME modulation) approach for augmented efficacy of chemotherapeutics.
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Nanomedicina , Nanopartículas , Humanos , Nanomedicina/métodos , Microambiente Tumoral , Linhagem Celular Tumoral , Gencitabina , Albumina Sérica Humana , Nanopartículas/químicaRESUMO
Background: Suicide is a preventable but escalating global health crisis. Genome-wide association studies (GWAS) studies to date have been limited, and some are underpowered. In this study, we aimed to perform the PsychArray-based GWAS study to identify single nucleotide variations associated with suicide in the Indian population. Methods: We recruited unrelated subjects who died by suicide as cases (N = 313) and the non-suicidal deaths as controls (N = 294). The 607 samples were genotyped, including cases and controls using the Illumina Infinium PsychArray-24 BeadChip v1.3 Results: In our study, four single nucleotide polymorphisms (SNPs) crossed the threshold of significance level <1 × 10−5. One of them is intronic at Chromosome2:rs1901851 and three are intergenic at Chromosome12:rs3847911, Chromosome8:rs2941489, Chromosome8:rs1464092. At a significance level of 5 × 10−5, we found a few more SNPs, with the majority of them being intergenic variants. The associated genes were associated with various important functions ranging from cell signaling, GTP binding, GPCR binding, and transcription factor binding. Conclusions: The SNPs identified in our study were not reported earlier. To our best knowledge, this study is one of the first GWAS for suicide in the Indian population. The results indicate few novel SNPs that may be associated with suicide and require further investigation. Their clinical significance is to be studied in the future.
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A redox-responsive macromolecular prodrug of tacrolimus, HA-ss-Tac, was constructed by conjugation of tacrolimus (TAC, FK506) through its succinate ester to cystamine-modified hyaluronic acid (HA-Cys), and its physicochemical properties and immunosuppressive activity were studied. The synthesized HA-ss-TAC was determined to contain 8% of chemically loaded TAC with significantly enhanced water solubility. The release study showed a sustained release of drug through slow degradation of linker-drug bonds. In vitro inhibition of proliferation of T- and B-lymphocytes was almost comparable to that of TAC, implying that the biologically active compound could be released from the conjugate. The polymeric prodrug lacks obvious cytotoxicity on Raw 264.7 macrophages and significantly suppressed the production of inflammatory cytokines IL-2 and IL-1ß by LPS-activated cells. Additionally, the cellular uptake study of the FITC-labeled conjugate confirmed the HA receptor-mediated internalization of the conjugate into targeted cells, thus avoiding systemic side effects. Taken together, the HA-ss-TAC prodrug could be an optimal prodrug for intravenous administration based on this preliminary data and can be expected to have improved therapeutic efficacy.
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Pró-Fármacos , Tacrolimo , Tacrolimo/farmacologia , Pró-Fármacos/farmacologia , Ácido Hialurônico/farmacologia , Ácido Hialurônico/química , Oxirredução , SolubilidadeRESUMO
Background: Investigating the underlying psychosocial factors is a cornerstone of planning need-based intervention for adult males accused of rape. Unresolved debates on its etiology, mediation, or interaction among causal psychosocial variables fuel curiosity to scrutinize it further. Hence, we studied potential influence of and relation between adverse childhood experiences, aggression, empathy, and psychopathology in adult males accused of rape in India and investigated the risk factors for the same. Methods: With a correlational research design, 40 literate and consenting adult males medically confirmed for rape were recruited using convenient sampling. The assessment was done on Adverse Childhood Experiences, Aggression Questionnaire, Symptom Checklist-90, and Interpersonal Reactivity Index. Descriptive statistics, Pearson's product-moment correlation, and stepwise linear regression analysis were calculated. Results: Approximately 75% of the participants experienced at least one category of Adverse Childhood Experiences. Scores above cut-off points were obtained on anger, hostility, fantasy, and personal distress. Significant correlations were obtained between adverse childhood experiences and psychopathology; between hostility and psychopathology, perspective taking, and personal distress; and in case of indirect aggression, with perspective taking and empathetic concerns. Regression analysis revealed that an increase in Symptom Checklist-90 global scores increases hostility and that lower personal distress predicts higher scores on hostility on Aggression Questionnaire. Conclusions: Adverse childhood experiences, aggression, and psychopathology play a critical role and, therefore, should be included as core components of the prevention of rape or relapse prevention programs at the community level.
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Cabazitaxel (CZT) loaded chitosan-alginate based (CSA) nanoparticles were developed with dual targeting functions of both folate receptor and epidermal growth factor receptor (EGFR) using ionic gelation technique. The chitosan-folate conjugate was synthesized, and characterized by using FTIR, NMR and Mass spectroscopy. The physicochemical parameters and morphology of all CSA nanoparticles were examined. The degree of conjugation of folic acid and cetuximab (CTXmab) was determined by UV-Visible spectroscopy and Bradford assay, respectively. Moreover, XPS analysis also supported the presence of the ligands on nanoparticles. The cellular-uptake study performed on A-549 cells demonstrated a significant enhancement in the uptake of dual-receptor targeted CSA nanoparticles than non-targeted and single-receptor targeted CSA nanoparticles. Further, CZT-loaded dual receptors targeted CSA nanoparticles also showed significantly lower IC50 values (~38 folds) than the CZT control against A-549 cells. Further, in-vivo histopathological evaluations of dual receptor-targeted CSA nanoparticles have demonstrated better safety in Wistar rats. Moreover, its treatment on the Benzo(a)pyrene (B(a)P) induced lung cancer mice model has showed the enhanced anticancer efficacy of CZT with a prolonged survival rate.
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Quitosana , Neoplasias Pulmonares , Nanopartículas , Ratos , Camundongos , Animais , Quitosana/química , Alginatos , Linhagem Celular Tumoral , Ratos Wistar , Nanopartículas/química , Neoplasias Pulmonares/tratamento farmacológico , Ácido Fólico/químicaRESUMO
Background: Predicted increases in suicide were not generally observed in the early months of the COVID-19 pandemic. However, the picture may be changing and patterns might vary across demographic groups. We aimed to provide a timely, granular picture of the pandemic's impact on suicides globally. Methods: We identified suicide data from official public-sector sources for countries/areas-within-countries, searching websites and academic literature and contacting data custodians and authors as necessary. We sent our first data request on 22nd June 2021 and stopped collecting data on 31st October 2021. We used interrupted time series (ITS) analyses to model the association between the pandemic's emergence and total suicides and suicides by sex-, age- and sex-by-age in each country/area-within-country. We compared the observed and expected numbers of suicides in the pandemic's first nine and first 10-15 months and used meta-regression to explore sources of variation. Findings: We sourced data from 33 countries (24 high-income, six upper-middle-income, three lower-middle-income; 25 with whole-country data, 12 with data for area(s)-within-the-country, four with both). There was no evidence of greater-than-expected numbers of suicides in the majority of countries/areas-within-countries in any analysis; more commonly, there was evidence of lower-than-expected numbers. Certain sex, age and sex-by-age groups stood out as potentially concerning, but these were not consistent across countries/areas-within-countries. In the meta-regression, different patterns were not explained by countries' COVID-19 mortality rate, stringency of public health response, economic support level, or presence of a national suicide prevention strategy. Nor were they explained by countries' income level, although the meta-regression only included data from high-income and upper-middle-income countries, and there were suggestions from the ITS analyses that lower-middle-income countries fared less well. Interpretation: Although there are some countries/areas-within-countries where overall suicide numbers and numbers for certain sex- and age-based groups are greater-than-expected, these countries/areas-within-countries are in the minority. Any upward movement in suicide numbers in any place or group is concerning, and we need to remain alert to and respond to changes as the pandemic and its mental health and economic consequences continue. Funding: None.
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OBJECTIVE: Nisin is an antibacterial peptide with anticancer properties, but the main drawback is its rapid enzymatic degradation and limited permeation across the cell membrane. This research aims to overcome these drawbacks by developing nisin-loaded nanoparticles (NPN) with improved cytotoxic effects. SIGNIFICANCE: PLGA nanoparticles are one of the most effective biodegradable and biocompatible drug delivery carriers. In the present study, nisin-loaded nanoparticles showed enhanced anticancer effects. METHODS: NPN was prepared by a double emulsion solvent evaporation method and characterized for different parameters. The cytotoxic investigation of NPN was carried out on various cell lines, including A549, SW-620, HT-29, PC-3, MDA-MB-231, MCF-7, MiaPaca-2, and fR2 by sulforhodamine B (SRB) assay. Mechanistic investigation of cellular cytotoxicity was performed by using bright-field microscopy, DAPI staining, intracellular reactive oxygen species (ROS), changes in mitochondrial membrane potential (ΔΨm), Western blotting and cellular uptake study. A comparative cytotoxicity study of nisin and NPN was performed on normal breast epithelial cells (fR2). RESULTS: NPN showed spherical shape, 289.09 ± 3.63 nm particle size, and 63.37 ± 3.12% entrapment efficiency. NPN was more cytotoxic to the MDA-MB-231 cell line, showing higher nuclear fragmentation, ROS generation, depletion of ΔΨm, and enhanced intracellular uptake with apoptosis signs compared with nisin and with no cytotoxicity on normal cells. CONCLUSIONS: The findings suggest that nisin delivery via PLGA nanoparticles can be used to treat cancer without significant effects on healthy cells.
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Antineoplásicos , Nanopartículas , Nisina , Antibacterianos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Portadores de Fármacos/química , Emulsões , Humanos , Nanopartículas/química , Nisina/química , Nisina/farmacologia , Tamanho da Partícula , Espécies Reativas de Oxigênio , SolventesRESUMO
The limitations associated with cancer monotherapy including dose dependent toxicity and drug resistance can be addressed by combination chemotherapy. The combination of antineoplastic agents improves the cytotoxic activity in comparison to the single-agent based therapy in a synergistic or an additive mode by reducing tumor growth as well as metastatic ability. In the present investigation, we explored the potential of methylselenocysteine (MSC) in combination chemotherapy with gemcitabine (GEM). The cytotoxic activity of GEM and MSC was determined in various cell lines and based on the activity, A549 cells were explored for the mechanistic studies including DAPI staining, measurement of oxidative stress, mitochondrial membrane potential loss, nitric oxide level, western blotting, cell migration and colony formation assays. A549 cells in combination treatment with MSC and GEM demonstrated enhanced cytotoxicity with more irregular cellular morphology as well as chromatin condensation and nuclear blebbing. The selected combination also significantly triggered ROS generation and mitochondrial destabilization, and alleviated cell migration potential and clonogenic propensity of A549 cells. Also, caspase-3 and PARP mediated apoptosis was observed in the combination treated cells. MSC based drug combination could offer the attributes of improved drug delivery and there was a 6-folds dose reduction of GEM in combination. Further, antitumor study in Ehrlich solid tumor model showed the efficacy of MSC combination with GEM for the enhanced antitumor activity. The proposed combination demonstrated the potential for further translational studies.
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Antineoplásicos , Desoxicitidina , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose , Linhagem Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Selenocisteína/análogos & derivados , GencitabinaRESUMO
Ovarian Hyperstimulation Syndrome (OHSS) is uncommon among oocyte donors during in vitro fertilization (IVF) procedure and is rarely associated with death. We report a case of a 23-year-old oocyte donor who suddenly died on the operation table during oocyte retrieval. She had no risk factors in her menstrual history, laboratory, or clinical parameters. The antagonist cycle, triggered with the GnRH agonist protocol, was carried out. The cause of death at autopsy was attributed to respiratory failure due to acute massive pulmonary edema, which developed due to the complication of OHSS. Only a few autopsy cases associated with OHSS have been published, but, as far as we know, no clinical or autopsy cases of sudden death caused by OHSS have been reported.
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In breast cancer therapy, Gemcitabine (Gem) is an antineoplastic antimetabolite with greater anticancer efficacy and tolerability. However, effectiveness of Gem is limited by its off-target effects. The synergistic potential of MUC1 (mucin 1) inhibitors and Gem-loaded polymeric nanoparticles (NPs) was discussed in this work in order to reduce dose-related toxicities and enhance the therapeutic efficacy. The double emulsion solvent evaporation method was used to prepare poly(ethylene glycol) methyl ether-block-poly-caprolactone (PEG-PCL)-loaded Gem and MUC 1 inhibitor NPs. The average size of Gem and MUC 1 inhibitor-loaded NPs was 128 nm, with a spherical shape. Twin-loaded NPs containing Gem and the MUC1 inhibitor decreased IC50 and behaved synergistically. Furthermore, in vitro mechanistic studies, that is, loss of MMP, clonogenic assay, Annexin V FITC assay, and Western blotting to confirm apoptosis with simultaneous induction of autophagy using acridine orange (AO) staining were performed in this study. Furthermore, the investigated NPs upon combination exhibited greater loss of MMP and decreased clonogenic potential with simultaneous induction of autophagy in MCF-7 cells. Annexin V FITC clearly showed the percentage of apoptosis while Western blotting protein expression analysis revealed an increase in caspase-3 activity with simultaneous decrease in Bcl-2 protein expression, a hallmark of apoptosis. The effectiveness of the Ehrlich ascites solid (EAT) mice treated with Gem-MUC1 inhibitor NPs was higher than that of the animals treated alone. Overall, the combined administration of Gem and MUC1 inhibitor-loaded NPs was found to be more efficacious than Gem and MUC1 inhibitor delivered separately.
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Neoplasias da Mama , Nanopartículas , Animais , Anexina A5/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Desoxicitidina/análogos & derivados , Feminino , Fluoresceína-5-Isotiocianato , Humanos , Camundongos , Mucina-1 , Poliésteres , Polietilenoglicóis , GencitabinaRESUMO
Identifying missing persons and unidentified dead bodies is a well-documented global problem in recent years. To curb this issue, countries such as the USA, UK, and Australia already have well-established DNA databases. Considering the alarming number of unidentified/unclaimed dead bodies reported in India every year, it is evident that the current practices are not sufficient to establish their identities. Forensic medicine professionals are ethically, morally, and dutybound to collect information about missing and unidentified persons and work with the government agencies to determine their identity. Concerning the social and public interest, we have developed the first-ever identification portal and DNA database of unidentified dead bodies autopsied at the Department of Forensic Medicine and Toxicology, AIIMS, New Delhi, India. After the investigation officer's informed consent, biological samples from unidentified dead bodies and a detailed phenotypic description, anthropological data and other visual characteristics of the deceased are recorded at the time of autopsy. This information is uploaded on our database which is available for public access, and the genotypic information generated through STR analysis is only available for internal usage.Claimants (biological relatives) may browse through the URL (https://umid-aiims.icmr.org.in/), and if they wish to claim an unidentified dead body, they may approach as per the given guidelines. The DNA profiles generated include a total of 16 STRs (15 autosomal tetranucleotide microsatellite STRs and 1 Sex Chromosome Specific STR). The claimant's STR profile is run through the questioned database to look for a potential match. If positive, the investigating officer of that particular case is informed for further necessary action. Until December 2020, our database consisted the information of 255 individuals and two unidentified cadavers were identified. This project's success can also lead to a pioneering National DNA database of unidentified and missing persons in India.
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Bases de Dados de Ácidos Nucleicos , Medicina Legal , Autopsia , DNA/análise , Impressões Digitais de DNA , Humanos , Repetições de MicrossatélitesRESUMO
OBJECTIVE: Suicidal behavior in pregnancy is a known fact worldwide. However, the published literature is still debating whether pregnancy is associated with an increase in the risk of suicide. Nonetheless, this is an important phenomenon that should not be ignored as the life of an unborn fetus is involved. The present study is a retrospective analysis of suicide death in pregnancy for the years 2011-2020 to study the different parameters. METHODS: The cases were collected from the archives of the department with due permission from the authority. Data were analyzed according to the age of the victim, duration of pregnancy, and time and cause of death. RESULT: The commonest age group was 21-25 years, the time of death was mostly during the daytime, and most of the deaths were due to hanging. These findings are not unusual in comparison to the general population. The pregnancy duration of most of the cases was first and second trimester, and third-trimester pregnancy accounted for far less number. In contrast, some studies showed that suicidal ideation and depression were more common during the first trimester and third trimester. Most of the pregnant women were pregnant with male fetuses. CONCLUSION: Though suicidal ideation is more during the first and third trimester, suicide occurs mostly in the first and second trimester, with third-trimester suicide deaths being far less. Being pregnant with a male fetus might be a risk factor in comparison to having female fetuses. These are two aspects that need to be explored further.
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Ideação Suicida , Suicídio , Adulto , Autopsia , Feminino , Humanos , Índia/epidemiologia , Masculino , Gravidez , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
OBJECTIVES: Cancer monotherapy is associated with various limitations; therefore, combination chemotherapy is widely explored for optimum drug efficacy. In this study, 4-(N-Phenyl-N'-substituted benzenesulfonyl)-6-(4-hydroxyphenyl) quinoline-based mammalian target of rapamycin (mTOR) inhibitor (IIIM-4Q) was investigated in combination with tocopherol succinate (TOS), and the mechanism of cytotoxicity was elucidated. METHODS: The cytotoxic potential of IIIM-4Q and TOS was evaluated in five cell lines. Further, to understand the mechanism of cytotoxicity of IIIM-4Q, TOS and their combination, various studies including morphological analysis using scanning electron microscopy and 6-diamidino-2-phenylindole (DAPI) staining, estimation of reactive oxygen species (ROS) level, measurement of mitochondrial membrane potential (MMP), in-vitro cell migration assay, Western blotting and staining with acridine orange (AO) for autophagy detection were performed. KEY FINDINGS: Investigated combination was synergistic in nature and exhibited greater oxidative stress and mitochondrial dysfunction in pancreatic cancer cells. The migration potential of MIA PaCa-2 cells was significantly mitigated under the influence of this combination, and morphological changes such as chromatin condensation and nuclear blebbing were observed. Also, poly (adenosine diphosphate-ribose) polymerase cleavage and caspase-3 activation were observed in IIIM-4Q and TOS combination-treated cells. CONCLUSIONS: The investigated combination synergistically inhibited proliferation of MIA PaCa-2 cells through simultaneous induction of autophagy followed by apoptosis, and this combination demonstrated potential for further translational studies.
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Sirolimo , alfa-Tocoferol , Apoptose , Autofagia , Linhagem Celular Tumoral , Poli(ADP-Ribose) Polimerases/metabolismo , Quinolinas , Serina-Treonina Quinases TOR/metabolismoRESUMO
ABSTRACT Ovarian Hyperstimulation Syndrome (OHSS) is uncommon among oocyte donors during in vitro fertilization (IVF) procedure and is rarely associated with death. We report a case of a 23-year-old oocyte donor who suddenly died on the operation table during oocyte retrieval. She had no risk factors in her menstrual history, laboratory, or clinical parameters. The antagonist cycle, triggered with the GnRH agonist protocol, was carried out. The cause of death at autopsy was attributed to respiratory failure due to acute massive pulmonary edema, which developed due to the complication of OHSS. Only a few autopsy cases associated with OHSS have been published, but, as far as we know, no clinical or autopsy cases of sudden death caused by OHSS have been reported.
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A 42-year-old woman who fell through a glass tabletop had her lower back pierced by a long shard of glass. She rapidly exsanguinated. At autopsy, a single penetrating wound was present in her left lower back, with complete transection of her left kidney and a 3.5 L haematoperitoneum. Death was due to exsanguination following accidental transection of the left kidney by a penetrating glass injury of the lower back. Glass-topped tables are a well-recognised source of injury in a domestic setting There are far more non-lethal than lethal injuries, many of which involve children. Quite long shards may remain undetected in wounds for considerable amounts of time. Non-tempered glass is a particular risk for breakage. Glass-topped tables should not be used as substitutes for chairs, particularly in overweight or obese individuals.