Tata Memorial Hospital

About: Tata Memorial Hospital is a healthcare organization based out in Mumbai, India. It is known for research contribution in the topics: Cancer & Breast cancer. The organization has 3187 authors who have published 4636 publications receiving 109143 citations.

Tracheal intubation in the ICU: Life saving or life threatening?

Abstract: Tracheal intubation (TI) is a routine procedure in the intensive care unit (ICU), and is often life saving. However, life-threatening complications occur in a significant proportion of procedures, making TI perhaps one the most common but underappreciated airway emergencies in the ICU. In contrast to the controlled conditions in the operating room (OR), the unstable physiologic state of critically ill patients along with underevaluation of the airways and suboptimal response to pre-oxygenation are the major factors for the high incidence of life-threatening complications like severe hypoxaemia and cardiovascular collapse in the ICU. Studies have shown that strategies planned for TI in the OR can be adapted and extrapolated for use in the ICU. Non-invasive positive-pressure ventilation for pre-oxygenation provides adequate oxygen stores during TI for patients with precarious respiratory pathology. The intubation procedure should include not only airway management but also haemodynamic, gas exchange and neurologic care, which are often crucial in critically ill patients. Hence, there is a necessity for the implementation of an Intubation Bundle during routine airway management in the ICU. Adherence to a plan for difficult airway management incorporating the use of intubation aids and airway rescue devices and strategies is useful.

Cell-free chromatin from dying cancer cells integrate into genomes of bystander healthy cells to induce DNA damage and inflammation

Abstract: Bystander cells of the tumor microenvironment show evidence of DNA damage and inflammation that can lead to their oncogenic transformation. Mediator(s) of cell–cell communication that brings about these pro-oncogenic pathologies has not been identified. We show here that cell-free chromatin (cfCh) released from dying cancer cells are the key mediators that trigger both DNA damage and inflammation in the surrounding healthy cells. When dying human cancer cells were cultured along with NIH3T3 mouse fibroblast cells, numerous cfCh emerged from them and rapidly entered into nuclei of bystander NIH3T3 cells to integrate into their genomes. This led to activation of H2AX and inflammatory cytokines NFκB, IL-6, TNFα and IFNγ. Genomic integration of cfCh triggered global deregulation of transcription and upregulation of pathways related to phagocytosis, DNA damage and inflammation. None of these activities were observed when living cancer cells were co-cultivated with NIH3T3 cells. However, upon intravenous injection into mice, both dead and live cells were found to be active. Living cancer cells are known to undergo extensive cell death when injected intravenously, and we observed that cfCh emerging from both types of cells integrated into genomes of cells of distant organs and induced DNA damage and inflammation. γH2AX and NFκB were frequently co-expressed in the same cells suggesting that DNA damage and inflammation are closely linked pathologies. As concurrent DNA damage and inflammation is a potent stimulus for oncogenic transformation, our results suggest that cfCh from dying cancer cells can transform cells of the microenvironment both locally and in distant organs providing a novel mechanism of tumor invasion and metastasis. The afore-described pro-oncogenic pathologies could be abrogated by concurrent treatment with chromatin neutralizing/degrading agents suggesting therapeutic possibilities.

Progesterone Receptor as an Indicator of Sperm Function

Abstract: Expression of progesterone receptor (PR) localization on spermatozoa was determined in men with normal and abnormal spermiograms. Studies were also carried out to evaluate the potential of PR as a marker of sperm function. Progesterone receptor expression on spermatozoa from men with normozoospermia (n = 8), oligozoospermia (n = 7), asthenozoospermia (n = 8), oligoasthenozoospermia (n = 7), and teratozoospermia (n = 11) was analyzed using an immunocytochemical method with monoclonal antibodies against PR, and flow cytometry using a cell-impermeable fluorescein-tagged progesterone coupled to BSA complex (P-FITC-BSA). Both methods revealed significantly fewer (P < 0.05) PR-positive spermatozoa in men with oligozoospermia, asthenozoospermia, oligoasthenozoospermia, and teratozoospermia compared with men with normozoospermia, thereby suggesting that down-regulation of PR expression in spermatozoa may be one of the causes of male infertility. Spermatozoa from men with normozoospermia (n = 12), oligozoospermia (n = 12), asthenozoospermia (n = 12), oligoasthenozoospermia (n = 9), and teratozoospermia (n = 10) were exposed to low osmotic conditions in the hypoosmotic swelling (HOS) test and then analyzed for PR expression using P-FITC-BSA complex. A significantly higher percentage (P < 0.05) of spermatozoa with physiologically active plasma membrane (HOS+) lacked PR expression (HOS+PR-) in all categories of men with infertility, thereby suggesting that compared to the HOS test, PR expression is a better indicator of sperm function. Furthermore, PR expression in spermatozoa showed a strong (P < 0.05) positive correlation with their ability to undergo an in vitro acrosome reaction. This was observed in all study groups (i.e., normozoospermia, r = 0.8545; oligozoospermia, r = 0.8711; asthenozoospermia, r = 0.7645; oligoasthenozoospermia, r = 0.9003; and teratozoospermia, r = 0.8676). This suggests a potential role for PR in the events leading to the acrosome reaction in sperm.

Lactoferrin-Endothelin-1 Axis Contributes to the Development and Invasiveness of Triple Negative Breast Cancer Phenotypes

Abstract: Triple-negative breast cancer (TNBC) is characterized by the lack of expression of estrogen receptor-α (ER-α), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER-2). However, pathways responsible for downregulation of therapeutic receptors, as well as subsequent aggressiveness, remain unknown. In this study, we discovered that lactoferrin (Lf) efficiently downregulates levels of ER-α, PR, and HER-2 in a proteasome-dependent manner in breast cancer cells, and it accounts for the loss of responsiveness to ER- or HER-2-targeted therapies. Furthermore, we found that lactoferrin increases migration and invasiveness of both non-TNBC and TNBC cell lines. We discovered that lactoferrin directly stimulates the transcription of endothelin-1 (ET-1), a secreted proinvasive polypeptide that acts through a specific receptor, ET(A)R, leading to secretion of the bioactive ET-1 peptide. Interestingly, a therapeutic ET-1 receptor-antagonist blocked lactoferrin-dependent motility and invasiveness of breast cancer cells. The physiologic significance of this newly discovered Lf-ET-1 axis in the manifestation of TNBC phenotypes is revealed by elevated plasma and tissue lactoferrin and ET-1 levels in patients with TNBC compared with those in ER(+) cases. These findings describe the first physiologically relevant polypeptide as a functional determinant in downregulating all three therapeutic receptors in breast cancer, which uses another secreted ET-1 system to confer invasiveness. Results presented in this article provide proof-of-principle evidence in support of the therapeutic effectiveness of ET-1 receptor antagonist to completely block the lactoferrin-induced motility and invasiveness of the TNBC as well as non-TNBC cells, and thus, open a remarkable opportunity to treat TNBC by targeting the Lf-ET-1 axis using an approved developmental drug.

REctus Sheath block for postoperative analgesia in gynecological ONcology Surgery (RESONS): a randomized-controlled trial

Abstract: Opioid-sparing pain management is important for Enhanced Recovery After Surgery. Rectus sheath (RS) blocks are emerging as a promising modality for pain relief following midline laparotomy; however, there are limited prospective clinical trials testing their efficacy. The purpose of this randomized-controlled trial is to assess the morphine-sparing effect of local anesthetic (LA) boluses through RS catheters following elective gynecological oncology surgery. After patients’ informed consent, bilateral RS catheters were placed intraoperatively in 74 females (American Society of Anesthesiologists physical status I-II) undergoing elective midline laparotomy under general anesthesia. The patients were randomized to receive 20-mL injections of either LA (0.25% bupivacaine) or normal saline (NS) postoperatively every six hours for 48 hr. Groups were compared for the co-primary outcomes of 24- and 48-hr morphine requirements. The secondary outcomes were numeric rating scale (NRS) scores for pain recorded at rest and with movement. The mean (SD) morphine consumption was significantly reduced in the LA group compared with the NS group at 24 hr [8.8 (8.3) mg vs 27.3 (10.0) mg, respectively; mean difference, 18.5 mg; 95% confidence interval (CI), 14.3 to 22.8; P < 0.001] and at 48 hr [14.8 (11.0) mg vs 42.4 (16.8) mg, respectively; mean difference, 27.7 mg; 95% CI, 20.9 to 34.3; P < 0.001]. At 48 hr postoperatively, there was also a significant decrease in the median [interquartile range] NRS scores for pain in the LA group compared with the NS group, both at rest (3 [2-3] vs 5 [5-6], respectively; P < 0.001) and with movement (4 [4-5] vs 7 [6-8], respectively; P < 0.001). The use of intermittent LA boluses through RS catheters is an effective morphine-sparing pain management strategy for females undergoing midline laparotomy for gynecological cancer surgery. This study was registered with the Clinical Trial Registry of India (CTRI/2013/10/004075).