Ali Raza

Hepatocellular carcinoma review: Current treatment, and evidence-based medicine

Hepatocellular carcinoma (HCC) is the fifth most common tumor worldwide. Multiple treatment options are available for HCC including curative resection, liver transplantation, radiofrequency ablation, trans-arterial chemoembolization, radioembolization and systemic targeted agent like sorafenib. The treatment of HCC depends on the tumor stage, patient performance status and liver function reserve and requires a multidisciplinary approach. In the past few years with significant advances in surgical treatments and locoregional therapies, the short-term survival of HCC has improved but the recurrent disease remains a big problem. The pathogenesis of HCC is a multistep and complex process, wherein angiogenesis plays an important role. For patients with advanced disease, sorafenib is the only approved therapy, but novel systemic molecular targeted agents and their combinations are emerging. This article provides an overview of treatment of early and advanced stage HCC based on our extensive review of relevant literature.

Cancer cachexia, mechanism and treatment

It is estimated that half of all patients with cancer eventually develop a syndrome of cachexia, with anorexia and a progressive loss of adipose tissue and skeletal muscle mass. Cancer cachexia is characterized by systemic inflammation, negative protein and energy balance, and an involuntary loss of lean body mass. It is an insidious syndrome that not only has a dramatic impact on patient quality of life, but also is associated with poor responses to chemotherapy and decreased survival. Cachexia is still largely an underestimated and untreated condition, despite the fact that multiple mechanisms are reported to be involved in its development, with a number of cytokines postulated to play a role in the etiology of the persistent catabolic state. Existing therapies for cachexia, including orexigenic appetite stimulants, focus on palliation of symptoms and reduction of the distress of patients and families rather than prolongation of life. Recent therapies for the cachectic syndrome involve a multidisciplinary approach. Combination therapy with diet modification and/or exercise has been added to novel pharmaceutical agents, such as Megestrol acetate, medroxyprogesterone, ghrelin, omega-3-fatty acid among others. These agents are reported to have improved survival rates as well as quality of life. In this review, we will discuss the emerging understanding of the mechanisms of cancer cachexia, the current treatment options including multidisciplinary combination therapies, as well an update on new and ongoing clinical trials.

Effect of Thermal Treatment on Meat Proteins with Special Reference to Heterocyclic Aromatic Amines (HAAs)

Meat is one of the most imperative protein sources available with respect to its production and consumption. It is the richest source of some valuable nutrients like proteins, essential amino acids, polyunsaturated fatty acids, vitamins, and minerals like iron, zinc, and selenium. Thermal treatment produces conformational changes in protein structure as well as flavor, texture, and appearance, and chemical properties of the ingredients are also changed. Heterocyclic aromatic amines (HAAs), potent mutagens/carcinogens, are formed during the cooking of meat at high temperature. The review paper highlights the effects of various cooking methods, i.e., pan-frying, deep-frying, charcoal grilling, and roasting, on the formation of HAAs. The levels of HAAs produced in cooked meats vary depending upon the cooking method, time of cooking, and the type of meat being cooked. Metabolic behavior of HAAs is very unique, they interfere in the activity of many enzymes, modify the metabolic pathways, and lead to the adduct formation of DNA. The application of black pepper and several other spices during processing may reduce the formation of these (HAAs) mutagenic compounds.

Garlic (Allium sativum): Diet based therapy of 21st century-a review

Functional and nutraceutical foods provide an opportunity to improve ones health by reducing health care costs and to support economic development in rural communities. For this reason, various phyto-based functional foods are becoming popular worldwide owing to number of evidences for their safer therapeutic applications. Garlic (Allium sativum L.,) is an essential vegetable that has been widely utilized as seasoning, flavoring, culinary and in herbal remedies. The consumption of traditional plants especially garlic has progressively increased worldwide because of their great effectiveness, fewer side effects and relatively low cost. Garlic is well known to contain an array of phytochemicals. These bioactive molecules are playing pivotal role in maintaining human health and having potential to reduce various ailments. It has distinct nutritional profile with special reference to its various bioactive components that can be used in different diet based therapies to cure various life-style related disorders. The present review is an attempt to explore the functional/nutraceutical role of garlic against various threats including dyslipidemia and hyperglycemia, cardiovascular disorders, antioxidant capacity and carcinogenic perspectives.

Current treatment options for colon cancer peritoneal carcinomatosis

Peritoneal carcinomatosis (PC), the dissemination of cancer cells throughout the lining of the abdominal cavity, is the second most common presentation of colon cancer distant metastasis. Despite remarkable advances in cytotoxic chemotherapy and targeted therapy for colon cancer over the last 15 years, it has been repeatedly shown that these therapies remain ineffective for colon cancer PC. Recently, there has been a rapid accumulation of reports that cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) prolongs the life of colon cancer PC patients. Here, we will review the clinical presentation, the mechanisms of disease progression, and current treatment options for colon cancer PC, with a focus on the benefits and limitations of CRS-HIPEC.

Stress-induced dynamic regulation of mitochondrial STAT3 and its association with cyclophilin D reduce mitochondrial ROS production

Stress depletes STAT3 in the mitochondria, and restoration of this STAT3 pool suppresses stress-induced ROS production. Dynamic regulation of mitochondrial STAT3 In cytokine-stimulated cells, the transcription factor STAT3 translocates from the cytoplasm to the nucleus to transcriptionally activate genes involved in stress responses. STAT3 also functions in the mitochondria to regulate cellular respiration. Meier et al. found that oxidative stress and cytokines depleted the mitochondrial pool of STAT3, and restoration of this pool required the chaperone protein cyclophilin D. Moreover, the restored STAT3 suppressed the stress-induced generation of reactive oxygen species in the mitochondria. These results suggest that the mitochondrial pool is dynamically regulated similar to the cytoplasmic and nuclear pools of STAT3 and that the mitochondrial pool is responsive to external stimuli. Signal transducer and activator of transcription 3 (STAT3) is associated with various physiological and pathological functions, mainly as a transcription factor that translocates to the nucleus upon tyrosine phosphorylation induced by cytokine stimulation. In addition, a small pool of STAT3 resides in the mitochondria, where it serves as a sensor for various metabolic stressors including reactive oxygen species (ROS). Mitochondrially localized STAT3 largely exerts its effects through direct or indirect regulation of the activity of the electron transport chain (ETC). It has been assumed that the amounts of STAT3 in the mitochondria are static. We showed that various stimuli, including oxidative stress and cytokines, triggered a signaling cascade that resulted in a rapid loss of mitochondrially localized STAT3. Recovery of the mitochondrial pool of STAT3 over time depended on phosphorylation of Ser727 in STAT3 and new protein synthesis. Under these conditions, mitochondrially localized STAT3 also became competent to bind to cyclophilin D (CypD). Binding of STAT3 to CypD was mediated by the amino terminus of STAT3, which was also important for reducing mitochondrial ROS production after oxidative stress. These results outline a role for mitochondrially localized STAT3 in sensing and responding to external stimuli.

Larval development assays reveal the presence of sub-populations showing high- and low-level resistance in a monepantel (Zolvix®)-resistant isolate of Haemonchus contortus

Resistance to the amino-acetonitrile derivative monepantel has been reported in several species of gastrointestinal nematodes over recent years. We were interested in the use of in vitro assays with free-living worm life-stages to detect resistance to this drug. We therefore used larval development and larval migration assays to examine dose response relationships for the drug against two susceptible and one resistant isolate of Haemonchus contortus. The resistant isolate was established by laboratory propagation of the survivors of a field treatment with Zolvix(®) that had originally resulted in a drug efficacy of over 99%. Drug efficacy against this field-derived laboratory-propagated resistant isolate in vivo was approximately 15%. The larval development assay proved able to discriminate between the susceptible and resistant isolates, with larvae of the resistant isolate showing an ability to develop at higher drug concentrations than the two susceptible isolates. The resistant isolate showed the presence of two distinct subpopulations, separated by a plateau in the dose-response curve. Sub-population 1 (approximately 40% of the total population) showed a low level of resistance with an IC50 increased approximately 7-fold compared to the baseline susceptible isolate, while sub-population 2 (the remaining 60% of the total population) showed an IC50 increased over 1000-fold compared to the baseline susceptible isolate. This level of resistance is unusually high for any gastrointestinal nematode species in drug dose-response in vitro assays. In contrast, the migration assay could not discriminate between the three isolates, with migration not reduced to zero at any of the drug concentrations tested. This study demonstrates that a larval development assay is able to detect resistance to monepantel in H. contortus, and that resistance can exist in two distinct forms. This suggests that at least two separate monepantel resistance mechanisms are acting within the worm isolate studied here, with one or more mechanisms conferring a much higher level of resistance than the other(s).

Effects of in vitro exposure to ivermectin and levamisole on the expression patterns of ABC transporters in Haemonchus contortus larvae.

This study investigated the interaction of ATP binding cassette (ABC) transport proteins with ivermectin (IVM) and levamisole (LEV) in larvae of susceptible and resistant isolates of Haemonchus contortus in vitro by measuring transcription patterns following exposure to these anthelmintics. Furthermore, we studied the consequences of drug exposure by measuring the sensitivity of L3 to subsequent exposure to higher drug concentrations using larval migration assays. The most highly transcribed transporter genes in both susceptible and resistant L3 were pgp-9.3, abcf-1, mrp-5, abcf-2, pgp-3, and pgp-10. The resistant isolate showed significantly higher transcription of pgp-1, pgp-9.1 and pgp-9.2 compared to the susceptible isolate. Five P-gp genes and the haf-6 gene showed significantly higher transcription (up to 12.6-fold) after 3 h exposure to IVM in the resistant isolate. Similarly, five P-gp genes, haf-6 and abcf-1 were transcribed at significantly higher levels (up to 10.3-fold) following 3 h exposure to LEV in this isolate. On the other hand, there were no significant changes in transcriptional patterns of all transporter genes in the susceptible isolate following 3 and 6 h exposure to IVM or LEV. In contrast to these isolate-specific transcription changes, both isolates showed an increase in R-123 efflux following exposure to the drugs, suggesting that the drugs stimulated activity of existing transporter proteins in both isolates. Exposure of resistant larvae to IVM or LEV resulted, in some instances, in an increase in the proportion of the population able to migrate at the highest IVM concentrations in subsequent migration assays. The significant increase in transcription of some ABC transporter genes following 3 h exposure to both IVM and LEV in the resistant isolate only, suggests that an ability to rapidly upregulate protective pathways in response to drugs may be a component of the resistance displayed by this isolate.

Advances in the management of peritoneal mesothelioma

Malignant peritoneal mesothelioma (PM) is an infrequent disease which has historically been associated with a poor prognosis. Given its long latency period and non-specific symptomatology, a diagnosis of PM can be suggested by occupational exposure history, but ultimately relies heavily on imaging and diagnostic biopsy. Early treatment options including palliative operative debulking, intraperitoneal chemotherapy, and systemic chemotherapy have marginally improved the natural course of the disease with median survival being approximately one year. The advent of cytoreduction (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has dramatically improved survival outcomes with wide median survival estimates between 2.5 to 9 years; these studies however remain largely heterogeneous, with differing study populations, tumor biology, and specific treatment regimens. More recent investigations have explored extent of cytoreduction, repeated operative intervention, and choice of chemotherapy but have been unable to offer definitive conclusions. CRS and HIPEC remain morbid procedures with complication rates ranging between 30% to 46% in larger series. Accordingly, an increasing interest in identifying molecular targets and developing targeted therapies is emerging. Among such novel targets is sphingosine kinase 1 (SphK1) which regulates the production of sphingosine-1-phosphate, a biologically active lipid implicated in various cancers including malignant mesothelioma. The known action of specific SphK inhibitors may warrant further exploration in peritoneal disease.

The potential of antioxidant rich essential oils against avian coccidiosis

The poultry industry is currently facing a serious problem of controlling coccidiosis, owing to the development of drug resistance against commonly available anticoccidials. Furthermore, an increasing demand in the consumers for drug residue free poultry and poultry products has led to the development of alternative strategies for the treatment and control of avian coccidiosis. In response to the invasion of Eimeria species in coccidiosis, oxidative stress is created by host cellular response which imparts pathology to the host tissue besides damaging the parasite. Hence, in order to alleviate the damage caused by oxidative stress during coccidiosis, the use of essential oils (EOs) rich in antioxidant compounds is being considered as an appealing approach. However, results are very divergent and often not as satisfactory as expected. Essential oils, as natural products, obtained from aromatic plants have the potential to serve as an alternate to anticoccidials. The present work aims to review the current state of knowledge, informative collection of results obtained over the years and to attain a critical decision in aspects of the use of EOs as anticoccidials.