Synthesis and evaluation of 4/5-hydroxy-2,3-diaryl(substituted)-cyclopent-2-en-1-ones as cis-restricted analogues of combretastatin A-4 as novel anticancer agents

A new series of 2,3-diaryl-4/5-hydroxy-cyclopent-2-en-1-one analogues replacing the cis double bond of combretastatin A-4 (CA-4) by 4/5-hydroxy cyclopentenone moieties was designed and synthesized. The analogues displayed potent cytotoxic activity (IC50<1 microg/mL) against a panel of human cancer cell lines and endothelial cells. The most potent analogues 11 and 42 belonging to the 5-hydroxy cyclopentenone class were further evaluated for their mechanism of action. Both of the analogues led to cell cycle arrest at G2/M phase and induced apoptosis in endothelial cells. Antitubulin property of 42 was superior to 11 and comparable to CA-4. The compound 42 had better aqueous solubility, metabolic stability, and pharmacokinetic profile than CA-4 and also demonstrated significant tumor regression in the human colon xenograft model. Our data suggests that cis-restricted analogues of CA-4 are a new class of molecules that have the potential to be developed as novel agents for the treatment of cancer.     

Impact of molecular profiling on clinical trial design for glioblastoma

This review highlights the ways in which molecular and genetic profiling of malignant gliomas has led to intelligent clinical trial design. The review also highlights known resistance mechanisms to conventional therapies in malignant gliomas and potential strategies to overcome these mechanisms with the use of targeted therapy.     

High intensity exercise training programme following cardiac transplant

A 26-year-old male patient who presented with symptoms of end stage cardiac failure as a result of dilated cardiomyopathy, had an orthotopic cardiac transplantation. A comprehensive cardiac rehabilitation programme was provided to him and he was introduced to a sport (tennis). The exercise training programme progressed from low intensity training to high intensity programme over a period of 15 months. A cardio-pulmonary exercise test done 22 months after surgery suggested that he was able to achieve the aerobic capacity comparable to that of a normal South Indian subject. He participated successfully in the World Transplant Games in Sydney and returned safely. This suggests that after a proper cardiac rehabilitation programme, patients undergoing heart transplantation can achieve normal physiological responses to lead a normal active life.     

Carbapenem Resistance in Clonally Distinct Clinical Strains of Vibrio fluvialis Isolated from Diarrheal Samples

Carbapenems have been used for many years to treat severe nosocomial Enterobacteriaceae infections. The spread of resistance to these drugs among other bacterial families is an emerging problem worldwide, mostly caused by New Delhi metallo-β-lactamase (NDM-1). We screened for the prevalence of NDM-1–expressing enteric pathogens from hospitalized patients with acute diarrhea in Kolkata, India, and identified 27 Vibrio fluvialis–harboring bla_NDM-1 (NDM-VF) strains. These isolates were also resistant to all the tested antimicrobial drugs except doxycycline. The large plasmid of V. fluvialis harboring bla_NDM-1 could be easily transferred to other enteric pathogens. Genes flanking the bla_NDM-1 were found to be identical to the reported sequence from an Escherichia coli isolate. Analyses showed that the V. fluvialis possessing the NDM-VF region belonged to different clones. The pathogenicity of V. fluvialis to humans and its ubiquitous presence in the environment call for constant monitoring of this species for emerging antimicrobial drug resistance.     

Malakoplakia presenting as Pleuropulmonary masses: A rare clinical,radiological and histopathological diagnosis

Pleuropulmonary malakoplakia is a rare granulomatous inflammatory condition characterized by the accumulation of histiocytes that contain basophilic inclusions called Michaelis-Gutmann bodies . It is usually reported in patients with acquired immunodeficiency syndrome. We present clinical, radiological, pathological features and management of a rare case of pulmonary malakoplakia in an immunocompetent male patient with a past history of empyema treated with surgical decortication. Clinically, the patient presented with shortness of breath, productive cough and lethargy. On imaging, Computed Tomography of Thorax showed multiple nodular lung masses and nodular pleural thickening with marked Fluorodeoxyglucose Positron Emission Tomography avidity raising suspicion of advanced pulmonary malignancy. Characteristic Michaelis-Gutmann bodies were identified on histopathology, confirming the diagnosis of malakoplakia. The patient was medically managed with a long course of antibiotics. On follow-up, there was a significant clinical and radiological improvement. Pulmonary malakoplakia is a rare entity, with very few cases reported worldwide, and even fewer in immunocompetent individuals.     

A study on the morbid histopathological changes in COVID-19 patients with or without comorbidities using minimally invasive tissue sampling

COVID-19 causes morbid pathological changes in different organs including lungs, kidneys, liver, and so on, especially in those who succumb. Though clinical outcomes in those with comorbidities are known to be different from those without—not much is known about the differences at the histopathological level. To compare the morbid histopathological changes in COVID-19 patients between those who were immunocompromised (Gr 1), had a malignancy (Gr 2), or had cardiometabolic conditions (hypertension, diabetes, or coronary artery disease) (Gr 3), postmortem tissue sampling (minimally invasive tissue sampling [MITS]) was done from the lungs, kidney, heart, and liver using a biopsy gun within 2 hours of death. Routine (hematoxylin and eosin) and special staining (acid fast bacilli, silver methanamine, periodic acid schiff) was done besides immunohistochemistry. A total of 100 patients underwent MITS and data of 92 patients were included (immunocompromised: 27, malignancy: 18, cardiometabolic conditions: 71). In lung histopathology, capillary congestion was more in those with malignancy, while others like diffuse alveolar damage, microthrombi, pneumocyte hyperplasia, and so on, were equally distributed. In liver histopathology, architectural distortion was significantly different in immunocompromised; while steatosis, portal inflammation, Kupffer cell hypertrophy, and confluent necrosis were equally distributed. There was a trend towards higher acute tubular injury in those with cardiometabolic conditions as compared to the other groups. No significant histopathological difference in the heart was discerned. Certain histopathological features were markedly different in different groups (Gr 1, 2, and 3) of COVID-19 patients with fatal outcomes.     

Role of MIF1/MIF2/CD74 interactions in bladder cancer

Macrophage migration inhibitory factor (MIF1) is a pleiotropic cytokine involved in inflammation and cancer. Genetic knockout of Mif1 in the validated N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) model of bladder cancer (BCa) resulted in stage arrest at non-muscle-invasive disease in prior studies. Small-molecule inhibition of MIF1 reduced cancer-associated outcomes, but it did not fully recapitulate genetic models. D-dopachrome tautomerase (gene symbol DDT), commonly referred to as MIF2, is a functional homolog of MIF1, and both MIF1 and MIF2 can bind the cell surface receptor CD74 on multiple cell types to initiate a signaling cascade. It has been proposed that this interaction mediates part of the protumorigenic effects of MIF1 and MIF2 and may explain the discordance in prior studies. We hypothesized that MIF2 functions redundantly with MIF1 in BCa development and progression. The Cancer Genome Atlas (TCGA) analysis indicated MIF and DDT expression were increased in BCa patients compared to control. 4-Iodopyridine (4-IPP), a combined MIF1/MIF2 inhibitor, was more efficacious than ISO-1, a MIF1-only inhibitor, in preventing cellular proliferation in BCa cell lines. To evaluate these findings in vivo, wild-type (WT) and Mif1^−/− animals were exposed to 0.05% BBN in drinking water for 16 weeks to initiate tumorigenesis and then evaluated over the subsequent 4 weeks for tumor formation and progression in the presence or absence of 4-IPP. 4-IPP reduced bladder weights in WT animals and bladder weights/tumor stage in Mif1^−/− animals. To determine whether MIF1/MIF2 functioned through CD74 in BCa, WT or Cd74^−/− animals were used in the same BBN model. Although these animals were partially protected against BBN-induced BCa, 4-IPP did not enhance this effect. In conclusion, our data suggest that MIF2 mechanistically functions in a similar protumorigenic manner to MIF1, and this is at least partially through CD74. Dual inhibition of MIF homologs is more efficacious at reducing tumor burden in this model of BCa. © 2022 The Pathological Society of Great Britain and Ireland.