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Mitochondrial proteostasis, regulated by the mitochondrial unfolded protein response ([UPR.sup.mt]), is crucial for maintenance of cellular functions and survival. Elevated oxidative and proteotoxic stress in mitochondria must be attenuated by the activation of a ubiquitous [UPR.sup.mt] to promote prostate cancer (PCa) growth. Here we show that the 2 key components of the [UPR.sup.mt], heat shock protein 60 (HSP60, a mitochondrial chaperonin) and caseinolytic protease P (ClpP, a mitochondrial protease), were required for the development of advanced PCa. HSP60 regulated ClpP expression via c-Myc and physically interacted with ClpP to restore mitochondrial functions that promote cancer cell survival. HSP60 maintained the ATPproducing functions of mitochondria, which activated the [beta]-catenin pathway and led to the upregulation of c-Myc. We identified a [UPR.sup.mt] inhibitor that blocked HSP60's interaction with ClpP and abrogated survival signaling without altering HSP60's chaperonin function. Disruption of HSP60-ClpP interaction with the [UPR.sup.mt] inhibitor triggered metabolic stress and impeded PCa-promoting signaling. Treatment with the [UPR.sup.mt] inhibitor or genetic ablation of Hsp60 inhibited PCa growth and progression. Together, our findings demonstrate that the HSP60-ClpP-mediated [UPR.sup.mt] is essential for prostate tumorigenesis and the HSP60-ClpP interaction represents a therapeutic vulnerability in PCa., Introduction Maintaining protein homeostasis (proteostasis) is essential for normal cellular functions and dysregulated proteostasis has been implicated in many types of cancer (1-3). Proteostasis is regulated by the unfolded protein [...]

Abstract Background Matrix metalloproteinases (MMPs) are enzymes that degrade all the components of extra cellular matrix and collagen. Various types of MMPs are known to be expressed and activated in patients with oral submucous fibrosis (OSMF) as well as head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to asses the association of the single nucleotide polymorphism (SNP) adenosine insertion/deletion polymorphism (-1171 5A->6A) in the MMP-3 promoter region in these lesions. Methods MMP-3 SNP was genotyped by polymerase chain reaction-restriction fragment polymorphism (PCR-RFLP) analysis in a case control study consisting of 362 participants; 101 cases of OSMF, 135 of HNSCC and 126 controls, compared for age, sex and habits. ROC distribution was plotted to assess the contributions of genetic variation in MMP-3 genotypes with relation to age. Results Analysis of MMP 3 (-1171 5A->6A) polymorphism revealed the frequency of 5A allele in OSMF, HNSCC and controls to be 0.15, 0.13 and 0.07, respectively. A significant difference was found in 5A genotype frequency between OSMF (5A genotype frequency = 0.15, p = 0.01, OR = 2.26, 95% CI = 1.22-4.20) and in controls (5A genotype frequency 0.07) as well as HNSCC (5A genotype frequency 0.13, p = 0.03,95%CI = 1.06-3.51) and controls (5A genotype frequency = 0.07) In this study, 5A genotype had greater than two fold risk for developing OSMF (OR = 2.26) and nearly the same in case of HNSCC (OR = 1.94) as compared to controls. In patients with OSMF as well as HNSCC, the ROC analysis between the MMP-3 genotype and age, 6A/6A allele was found to be significant in patients both over and under 45 years of age; while the 5A/5A carrier alleles showed an association only in patients less than 45 years of age. Conclusions This study concluded that the expression of MMP-3 genotype associated with the 5A alleles, it may have an important role in the susceptibility of the patients to develop OSMF and HNSCC.

Aims and Context: The objective of the present study was to evaluate the analgesic and adverse effects of intrathecal clonidine with hyperbaric bupivacaine in spinal anesthesia. Settings and Design: Randomized single blind trial. Methods: 210 ASA I-II pregnant females undergoing emergency cesarean section were randomized in a single-blind fashion to one of the three groups. In group I (n=70) patients received 12.5 mg of 0.5% hyperbaric bupivacaine intrathecally. In group II (n=70) patients received intrathecal mixture of 0.5% hyperbaric bupivacaine (8 mg) and clonidine 50 μg. In group III (n=70), patients received 0.5% hyperbaric bupivacaine (10 mg) intrathecally along with 50 μg of clonidine. Statistical Analysis Used: Groups were compared using one-way ANOVA with the Bonferroni multiple comparison post hoc test. The proportion of adverse events was compared using the chi-square test (χ2=57.2410). Results: On adding 50 μg clonidine, we were able to reduce intrathecal dose of bupivacaine for cesarean section to 8 mg. Patients receiving intrathecal clonidine along with bupivacaine had significantly long lasting analgesia with lower bupivacaine dose [246.21±5.15 min. (group II) vs 146.0±4.55 min (group I), P=0.021; 95% confidence interval: 238.01- 257.40, group II and 134.99-157.0 group I]. Conclusions: Addition of intrathecal clonidine causes some sedation in the postoperative period, but it provides adequate analgesia and motor paralysis at lower dose of bupivacaine. It also significantly prolongs postoperative pain relief. [ABSTRACT FROM AUTHOR]

Background: Matrix metalloproteinases (MMPs) are enzymes that degrade all the components of extra cellular matrix and collagen. Various types of MMPs are known to be expressed and activated in patients with oral submucous fibrosis (OSMF) as well as head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to asses the association of the single nucleotide polymorphism (SNP) adenosine insertion/deletion polymorphism (-1171 5A->6A) in the MMP-3 promoter region in these lesions. Methods: MMP-3 SNP was genotyped by polymerase chain reaction-restriction fragment polymorphism (PCR-RFLP) analysis in a case control study consisting of 362 participants; 101 cases of OSMF, 135 of HNSCC and 126 controls, compared for age, sex and habits. ROC distribution was plotted to assess the contributions of genetic variation in MMP-3 genotypes with relation to age. Results: Analysis of MMP 3 (-1171 5A->6A) polymorphism revealed the frequency of 5A allele in OSMF, HNSCC and controls to be 0.15, 0.13 and 0.07, respectively. A significant difference was found in 5A genotype frequency between OSMF (5A genotype frequency = 0.15, p = 0.01, OR = 2.26, 95% CI = 1.22-4.20) and in controls (5A genotype frequency 0.07) as well as HNSCC (5A genotype frequency 0.13, p = 0.03,95%CI = 1.06-3.51) and controls (5A genotype frequency = 0.07) In this study, 5A genotype had greater than two fold risk for developing OSMF (OR = 2.26) and nearly the same in case of HNSCC (OR = 1.94) as compared to controls. In patients with OSMF as well as HNSCC, the ROC analysis between the MMP-3 genotype and age, 6A/6A allele was found to be significant in patients both over and under 45 years of age; while the 5A/5A carrier alleles showed an association only in patients less than 45 years of age. Conclusions: This study concluded that the expression of MMP-3 genotype associated with the 5A alleles, it may have an important role in the susceptibility of the patients to develop OSMF and HNSCC. [ABSTRACT FROM AUTHOR]

Background: General anesthesia remains the most popular technique for ambulatory surgeries with patients, surgeons, and anesthesia providers. The supraglottic airway (SGA) devices result in fewer incidences of sore throat, laryngospasm, coughing, and hoarseness as compared to inserting a tracheal tube. This study was conducted to compare two second-generation SGA devices, LMA ProSeal and I-gel airway, in anesthetized patients on spontaneous ventilation during daycare procedures to establish the superior SGA device., Methodology: This prospective randomized study was done on 90 patients of either sex aged 15-60 years, ASA grade I-II, Mallampatti grade I and II, and BMI between 20 and 30 kg/m 2 scheduled for elective surgeries of duration less than 90 min. Patients were randomly allocated into two groups-group A (I-gel) and group B (LMA ProSeal). Insertion parameters, hemodynamic responses, oxygenation, ventilation, peak airway pressure (PAP), and postoperative complications were recorded. Statistical analysis was done using SPSS version 21.0 statistical analysis software., Results: Mean insertion time of LMA ProSeal was found to be significantly higher as compared to I-gel (33.27 ± 3.88 vs 18.49 ± 3.18 s; P < 0.001). No significant difference was found between the groups in the number of attempts and of operators attempted for insertion, as well as in hemodynamic response, oxygenation, and ventilation. Postoperative complications were lesser in group A., Conclusion: I-gel is an easy-to-insert cuffless SGA device requiring lesser time for insertion, provides adequate ventilation with lesser postoperative complications and thus appears to be better than LMA ProSeal., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 National Journal of Maxillofacial Surgery.)

Background and Aims: Pre-anesthesia checkup (PAC) gives unique opportunity for providing necessary information, patient education and allaying anxiety. Our objective was to measure the effect of preoperative multimedia video information (self made short video of 12 minutes) on patient's anxiety and hemodynamic parameters during surgery under spinal anesthesia., Methods: This prospective randomized study was conducted in 80 patients of either sex with ASA physical status I and II posted for lower limb surgery under spinal anesthesia. Patents were randomized to control or test group. At the end of preoperative visit, patients in test group watched the film and patient in control group did not watch any video. Verbal briefing by the attending anesthesiologist on the day of surgery was given to all patients of both the groups. Anxiety using Amsterdam Preoperative Anxiety and Information Scale (APAIS) and hemodynamic parameters (SBP, DBP and HR) at various time intervals (A1: Baseline, A2: post intervention, A3: just before surgery, A4: after surgery) were measured., Results: Baseline anxiety (A1) scores were severe in both the groups and showed no statistical significance ( P = 0.436). Patients in test group (video) showed better/lower anxiety levels than the control group (non video) at A2 ( P = 0.020) and A3 ( P = 0.005) respectively, similarly hemodynamic parameters were better controlled and showed lesser deviation from baseline values in test group as compared to control group and showed statistical significant difference ( P < 0.001) just before surgery., Conclusion: Combination of multimedia based video information at the time of PAC and short verbal briefing on the day of surgery by the attending anesthesiologist provides effective management of perioperative anxiety. It can be cost effective way of enhancing patient care and providing adequate information to people with reading and comprehension difficulties., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Journal of Family Medicine and Primary Care.)

The gap between prostate cancer disparities among American men is narrowing, which is mostly due to increased screening of African American (AA) men. However, the biological reasons for prostate cancer disparities among American men still remain undefined. Mitochondrion, an organelle within cells, regulates both cell survival and cell death mechanisms. These cellular signaling pathways require various proteins localized to mitochondria, which are encoded by both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). Interestingly, prostate tissues from AA men harbor reduced mtDNA content compared to Caucasian American (CA) men. Therefore, changes in mitochondrial genes may have detrimental consequences in terms of cellular signaling regulated by mitochondria in AA men. This review describes the plausible underlying mechanism of mtDNA depletion and its impact in driving resistance to therapy leading to faster progression and poor prognosis in African American men with prostate cancer. Since defective cellular signaling is critical for prostate cancer cell survival, restoring mitochondrial function may provide strategies to alleviate prostate cancer disparities among American men.

Background: Matrix metalloproteinase -2 (gelatinase-A, Mr 72,000 type IV collagenase, MMP-2) and -9 (gelatinase-B, Mr 92,000 type IV collagenase, MMP-9) are key molecules that play roles in tumor growth, invasion, tissue remodeling, metastasis and stem-cell regulation by digesting extracellular matrix barriers. MMP-2 and -9 are well known to impact on solid cancer susceptibility, whereas, in hematological malignancies, a paucity of data is available to resolve the function of these regulatory molecules in bone marrow mononuclear cells (BM-MNCs) and stromal cells of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML)., Objectives: The present study aimed to investigate mRNA expression and gelatinase A and B secretion from BM-MNCs in vitro and genotypic associations of MMP-2 (-1306 C/T; rs243865), MMP-9 (-1562 C/T; rs3918242), tissue inhibitor of metalloproteinase -1 (TIMP-1) (372T/C; rs4898, Exon 5) and TIMP-2 (-418G/C; rs8179090) in MDS and AML., Results: The study covered cases of confirmed MDS (n=50), AML (n=32) and healthy controls (n=110). MMP- 9 mRNA expression revealed 2 fold increased expression in MDS-RAEB II and 2.5 fold in AML M-4 (60-70% blasts). Secretion of gelatinase- B also revealed the MMP-9 mRNA expression and ELISA data also supported these data. We noted that those patients having more blast crises presented with more secretion of MMP-9 and its mRNA expression. In contrast MMP-9 (-1562 C/T) showed significant polymorphic associations in MDS (p<0.02) and AML (p<0.02). MMP-9 mRNA expression of C/T and T/T genotypes were 1.5 and 2.5 fold increased in MDS and AML respectively. In AML, MMP-2 C/T and T/T genotypes showed 2.0 fold mRNA expression. Only MMP-9 (-1306 C/T) showed significant 4 fold (p<0.001) increased risk with chemical and x-ray exposed MDS, while tobacco and cigarette smokers have 3 fold (p<0.04) risk in AML., Conclusions: In view of our results, MMP-9 revealed synergistic secretion and expression in blast crises of MDS and AML with 'gene' polymorphic effects and is significantly associated with increased risk with tobacco, cigarette and environmental exposure. Release and secretion of these enzymes may influence hematopoietic cell behavior and may be important in the clinical point of view. It may offer valuable tools for diagnosis and prognosis, as well as possible targets for the treatments.

Controlled remodeling of the extracellular matrix (ECM) is essential for cell growth, invasion and metastasis. Matrix metalloproteinases (MMPs) are a family of secreted, zincdependent endopeptidases capable of degradation of ECM components. The expression and activity of MMPs in a variety of human cancers have been intensively studied. They play important roles at different steps of malignant tumor formation and have central significance in embryogenesis, tissue remodeling, inflammation, angiogenesis and metastasis. However, increasing evidence demonstrates that MMPs are involved earlier in tumorigenesis. Recent studies also suggest that MMPs play complex roles in tumor progression. MMPs and membrane type (MT)MMPs are potentially significant therapeutic targets in many cancers, so that designing of specific MMP inhibitors would be helpful for clinical trials. Here, we review the pleiotropic roles of the MMP system in hematological malignancies invitro and invivo models.