Cancer stem cell markers interplay with chemoresistance in triple negative breast cancer: A therapeutic perspective.

Triple-negative breast cancer (TNBC) is one of the most fatal and aggressive type of cancer in younger population. TNBC is poorly diagnosed, detected only at later stages with low survival rate and high chemoresistance. The expression of the cancer stem cell (CSC) markers has critical role in chemoresistance and recurrence. In this review, focus is on potential CSC targets and treatment strategies for TNBC. Inhibition of proliferative genes involved in TNBC can reduce its spread and tumor invasiveness. Also, inhibiting proteins that are involved in signaling pathways that help in the expression of CSC markers can improve chemosensitivity. Thus, combining inhibition of critical genes and proteins can be a potential therapy strategy. Therefore, functioning of γ-secretase inhibitors (GSI-IX, Presenilin1/2, Pen-2, Nicastrin, APH-1), BEZ235, GANT61 inhibitor, NVP-LDE225, GSK3ß inhibitor, AMPK activator (Aza- podophyllotoxin, demethoxycurcumin, N, N-diarylurea FND-4b) and MYC inhibitors (Triptolide, Quinoxalines) in TNBC are reviewed extensively.

Author Response to the Manuscript "Inflammation and Hemorrhagic Stroke Outcomes: Other Players in the Nexus".

How to cite this article: Babu S, Pulicken M, Thazhathuveedu AK. Author Response to the Manuscript "Inflammation and Hemorrhagic Stroke Outcomes: Other Players in the Nexus". Indian J Crit Care Med 2022;26(5):652.

Erratum to 'Indian National Association for the Study of Liver Consensus Statement on Acute Liver Failure (Part-2): Management of Acute Liver Failure' [J Clin Exp Hepatol 10 (2020) 477-517].

[This corrects the article DOI: 10.1016/j.jceh.2020.04.011.].

Peripheral Blood Neutrophil-to-lymphocyte Ratio as a Predictor of Functional Outcomes in Patients with Hemorrhagic Stroke.

BACKGROUND: Peripheral blood neutrophil-to-lymphocyte ratio (NLR) has recently emerged as a prognostic biomarker in many disease states. The aim of this study was to evaluate the diagnostic utility of NLR to predict poor functional outcomes in patients with hemorrhagic stroke and to compare it with the intracranial hemorrhage (ICH) score. MATERIALS AND METHODS: Patients who presented to the emergency department with clinical features suggestive of stroke were evaluated with computed tomography (CT) brain to identify ICH. The ICH scores and NLR were estimated at the time of admission. Modified Rankin Scale (mRS) score equal to or greater than 3 at 90 days was used to define poor functional outcomes (major disability or death). Receiver operating characteristic (ROC) curve was plotted with NLR and the ICH score to analyze and compare their discriminative ability to predict poor functional outcomes. RESULTS: A total of 158 patients were recruited for the study. One hundred and seven patients were found to have poor functional outcomes as per their mRS score at 90 days. The mean NLR and the ICH scores at presentation were significantly higher for the poor outcome group (6.57 and 2.83) compared to the good outcome group (2.75 and 1.49). The ROC analysis revealed that both NLR and the ICH scores were good predictors of functional outcomes at 90 days with area under the curve (AUC) of 0.814 and 0.819, respectively. The sensitivity and specificity of NLR were 84 and 66.3% and those of the ICH score were 66.7 and 78.3% to predict poor functional outcomes. CONCLUSION: In patients with hemorrhagic stroke, NLR at admission is a good predictor of functional outcomes at 90 days. When compared to the ICH score, NLR is more sensitive but less specific in predicting poor functional outcomes. HOW TO CITE THIS ARTICLE: Babu S, Pulicken M, Thazhathuveedu AK. Peripheral Blood Neutrophil-to-lymphocyte Ratio as a Predictor of Functional Outcomes in Patients with Hemorrhagic Stroke. Indian J Crit Care Med 2022;26(1):18-22.

Indian National Association for the Study of Liver Consensus Statement on Acute Liver Failure (Part-2): Management of Acute Liver Failure.

Acute liver failure (ALF) is not an uncommon complication of a common disease such as acute hepatitis. Viral hepatitis followed by antituberculosis drug-induced hepatotoxicity are the commonest causes of ALF in India. Clinically, such patients present with appearance of jaundice, encephalopathy, and coagulopathy. Hepatic encephalopathy (HE) and cerebral edema are central and most important clinical event in the course of ALF, followed by superadded infections, and determine the outcome in these patients. The pathogenesis of encephalopathy and cerebral edema in ALF is unique and multifactorial. Ammonia plays a crucial role in the pathogenesis, and several therapies aim to correct this abnormality. The role of newer ammonia-lowering agents is still evolving. These patients are best managed at a tertiary care hospital with facility for liver transplantation (LT). Aggressive intensive medical management has been documented to salvage a substantial proportion of patients. In those with poor prognostic factors, LT is the only effective therapy that has been shown to improve survival. However, recognizing suitable patients with poor prognosis has remained a challenge. Close monitoring, early identification and treatment of complications, and couseling for transplant form the first-line approach to manage such patients. Recent research shows that use of dynamic prognostic models is better for selecting patients undergoing liver transplantation and timely transplant can save life of patients with ALF with poor prognostic factors.

Indian National Association for the Study of the Liver Consensus Statement on Acute Liver Failure (Part 1): Epidemiology, Pathogenesis, Presentation and Prognosis.

Acute liver failure (ALF) is an infrequent, unpredictable, potentially fatal complication of acute liver injury (ALI) consequent to varied etiologies. Etiologies of ALF as reported in the literature have regional differences, which affects the clinical presentation and natural course. In this part of the consensus article designed to reflect the clinical practices in India, disease burden, epidemiology, clinical presentation, monitoring, and prognostication have been discussed. In India, viral hepatitis is the most frequent cause of ALF, with drug-induced hepatitis due to antituberculosis drugs being the second most frequent cause. The clinical presentation of ALF is characterized by jaundice, coagulopathy, and encephalopathy. It is important to differentiate ALF from other causes of liver failure, including acute on chronic liver failure, subacute liver failure, as well as certain tropical infections which can mimic this presentation. The disease often has a fulminant clinical course with high short-term mortality. Death is usually attributable to cerebral complications, infections, and resultant multiorgan failure. Timely liver transplantation (LT) can change the outcome, and hence, it is vital to provide intensive care to patients until LT can be arranged. It is equally important to assess prognosis to select patients who are suitable for LT. Several prognostic scores have been proposed, and their comparisons show that indigenously developed dynamic scores have an edge over scores described from the Western world. Management of ALF will be described in part 2 of this document.

Cardiopulmonary Exercise Testing in the Assessment of Dysfunctional Breathing.

Dysfunctional breathing (DB) is a disabling condition which affects the biomechanical breathing pattern and is challenging to diagnose. It affects individuals in many circumstances, including those without underlying disease who may even be athletic in nature. DB can also aggravate the symptoms of those with established heart or lung conditions. However, it is treatable and individuals have much to gain if it is recognized appropriately. Here we consider the role of cardiopulmonary exercise testing (CPET) in the identification and management of DB. Specifically, we have described the diagnostic criteria and presenting symptoms. We explored the physiology and pathophysiology of DB and physiological consequences in the context of exercise. We have provided examples of its interplay with co-morbidity in other chronic diseases such as asthma, pulmonary hypertension and left heart disease. We have discussed the problems with the current methods of diagnosis and proposed how CPET could improve this. We have provided guidance on how CPET can be used for diagnosis, including consideration of pattern recognition and use of specific data panels. We have considered categorization, e.g., predominant breathing pattern disorder or acute or chronic hyperventilation. We have explored the distinction from gas exchange or ventilation/perfusion abnormalities and described other potential pitfalls, such as false positives and periodic breathing. We have also illustrated an example of a clinical pathway utilizing CPET in the diagnosis and treatment of individuals with suspected DB.

An Expert Review and Recommendations on the Rational Use of Proton Pump Inhibitors: Indian Perspective.

BACKGROUND: Proton pump inhibitors (PPIs) are the mainstay of treatment for acid peptic diseases (APDs), but are often irrationally prescribed in clinical practice. Appropriate prescription of PPIs is needed to optimize outcomes, and minimize risks and cost burden on the healthcare system. OBJECTIVE: To review available literature on efficacy and safety of proton pump inhibitors (PPIs) and give recommendations for rational use of PPIs from an Indian perspective. METHODS: Twelve healthcare professionals (9 gastroenterologists, 1 cardiologist, 1 orthopedist, 1 clinical pharmacologist) comprised the expert group; members disclosed conflicts of interest. The creation of the expert review was through a process that included meetings (in-person, online, telephone) where each professional contributed their experiences with regards to efficacy and safety of PPIs. Articles published between the years 2000 and 2017 were reviewed for evaluation of safety and efficacy of PPIs in treatment of various APDs. CONCLUSION: This expert review provides key recommendations for decision making in order to minimize the irrational use of PPIs. Some significant recommendations include: patients with GERD and acid-related complications should take a PPI for minimum 12 weeks for healing of esophagitis, and for maximum up to 48 weeks for symptom control. Patients with Barrett's esophagus should take long-term PPI. Patients at high risk for ulcer-related bleeding from NSAIDs including aspirin should take a PPI if they continue to take NSAIDs. Best practice recommendations are meant to merely assist with decision making in conjunction with patients' clinical history, and are not intended to dictate mandatory rules.

The effectiveness of extracorporeal shock wave therapy in lower limb tendinopathy: a systematic review.

BACKGROUND: There is accumulating evidence for the effectiveness of extracorporeal shock wave therapy (ESWT) when treating lower limb tendinopathies including greater trochanteric pain syndrome (GTPS), patellar tendinopathy (PT), and Achilles tendinopathy (AT). PURPOSE: To evaluate the effectiveness of ESWT for lower limb tendinopathies. STUDY DESIGN: Systematic review and meta-analysis. METHODS: PubMed (Medline), Embase, Web of Knowledge, Cochrane, and CINAHL were searched from inception to February 2013 for studies of any design investigating the effectiveness of ESWT in GTPS, PT, and AT. Citation tracking was performed using PubMed and Google Scholar. Animal and non-English language studies were excluded. A quality assessment was performed by 2 independent reviewers, and effect size calculations were computed when sufficient data were provided. RESULTS: A total of 20 studies were identified, with 13 providing sufficient data to compute effect size calculations. The energy level, number of impulses, number of sessions, and use of a local anesthetic varied between studies. Additionally, current evidence is limited by low participant numbers and a number of methodological weaknesses including inadequate randomization. Moderate evidence indicates that ESWT is more effective than home training and corticosteroid injection in the short (<12 months) and long (>12 months) term for GTPS. Limited evidence indicates that ESWT is more effective than alternative nonoperative treatments including nonsteroidal anti-inflammatory drugs, physical therapy, and an exercise program and equal to patellar tenotomy surgery in the long term for PT. Moderate evidence indicates that ESWT is more effective than eccentric loading for insertional AT and equal to eccentric loading for midportion AT in the short term. Additionally, there is moderate evidence that combining ESWT and eccentric loading in midportion AT may produce superior outcomes to eccentric loading alone. CONCLUSION: Extracorporeal shock wave therapy is an effective intervention and should be considered for GTPS, PT, and AT particularly when other nonoperative treatments have failed.

Tissue is issue: Not all masses are tumors.

BACKGROUND: Tuberculosis can disguise itself in any form. Endobronchial tuberculosis usually presents in young adults. Endobronchial tumor-like presentation of tuberculosis (EBTB) is very rare and often mistaken as a malignancy. Diagnosis is usually delayed, as clinical and radiological features are non-specific. Direct implantation of tubercle bacilli into the bronchus, or an contiguous spread, leads to EBTB. Bronchoscopic biopsy and culture are the best modality for diagnosis. CARE REPORTS: Clinical and radiological presentations of all cases were similar and one of them had rib erosion on bone scan. All cases were proven to be tuberculosis by histopathology and culturing mycobacterium tuberculosis. All of them are diagnosed as endobronchial tuberculosis, either histopathology or by culture that grew mycobacterium tuberculosis, and were successfully treated with anti-tuberculous treatment alone, without residual scarring. CONCLUSIONS: Tuberculosis should be considered in the differential diagnosis of endobronchial mass lesions in the appropriate clinical setting since this is an uncommon presentation for which invasive procedures are needed to establish the diagnosis. Initially, it was mistaken as a malignancy and there was delay in diagnosis and initiation of treatment. Prompt treatment is crucial to avert residual bronchostenosis.

Impact of topological and electronic descriptors in the QSAR of pyrazine containing thiazolines and thiazolidinones as antitubercular and antibacterial agents.

Quantitative structure activity relationships (QSAR) were developed relating the 14th and 21st day antituberculosis activity against H(37)Rv strain of Mycobacterium tuberculi and antibacterial activity against Staphylococcus aureus ATCC3750, Bacillus subtilis 6633, Escherichia coli ATCC3750, and Salmonella typhi NCTC786 of 55 pyrazine containing thiazolines and thiazolidinones, with the molecular descriptors. The developed models were able to fit the data well (r(2) = 0.69-0.87) and had reasonable predictive capability (q(2) > 0.62). The data were also divided into a training set and a test set, the former was used to develop the QSAR and the latter was used to evaluate the predictive capability of these developed models. In all the cases, the models were able to predict the test data set reasonably well. Predominantly, pyrazine ring is well-known for its antimycobacterial activity and hence these equation could be used to design newer analogues with higher activity. These compounds also possess both antitubercular and antibacterial activity. Descriptors pertaining to electronic, topology, and hydrophobicity of the molecules appear in the model equations.

QSAR studies on chalcones and flavonoids as anti-tuberculosis agents using genetic function approximation (GFA) method.

Design of compounds having good anti-tubercular activity is gaining much importance in the field of tuberculosis research due to reemergence of antibiotic resistance strains. In this paper quantitative structure activity relationships (QSAR) were developed on chalcones, chalcone-like compounds, flavones and flavanones to understand the relationship between biological activity and structural features. Genetic function approximation (GFA) method was used to identify the descriptors that would lead to good regression equations. The best molecular descriptors identified were Jurs descriptors (Jurs charged partial surface area), hydrogen bond donor, principal moment of inertia, molecular energy, dipole magnetic, molecular area, absorption, distribution, metabolism and excretion (ADME) properties and Chi indices (Kier & Hall chi connectivity indices). Excellent statistically significant models were developed by this approach (r(2)=0.8-0.97) for the four groups of compounds. The cross validated r(2) (XV r(2)) which is an indication of the predictive capability of the model for all the cases was also very good (=0.79-0.94).

Safety and efficacy of an indigenous human recombinant interferon alpha 2b (Shanferon) in patients with chronic hepatitis B.

Interferon treatment is the established option for the treatment of patients with chronic hepatitis B without decompensated liver disease. However, such treatment is expensive. We report here our data of a multi-center, open-label trial of the use of an indigenously produced interferon in the treatment of chronic HBeAg-positive chronic hepatitis B. Adult patients with chronic HBeAg-positive hepatitis B with elevated serum transaminase activity and positive serum HBV DNA test were treated with 5 MU/day of an indigenously produced interferon (Shanferon; Shantha Biotechnics, Hyderabad, India) for 4 months, and were then followed up for 6 months. Of the 39 patients enrolled, 36 completed the treatment and 33 completed the post-treatment follow-up. Of the 33 patients who completed the study, end-of-treatment biochemical and virological responses were observed in 10 (30%) and 5 (15%) respectively. Sustained biochemical and virological responses were observed in 15 (45%) and 7 (21%), patients respectively. Adverse effects led to the discontinuation of treatment in only one patient. Our data suggest that safety and efficacy of the indigenously produced interferon were similar to those previously reported results with interferon from other sources.