CD133-Dependent Activation of Phosphoinositide 3-Kinase /AKT/Mammalian Target of Rapamycin Signaling in Melanoma Progression and Drug Resistance.

Melanoma frequently harbors genetic alterations in key molecules leading to the aberrant activation of PI3K and its downstream pathways. Although the role of PI3K/AKT/mTOR in melanoma progression and drug resistance is well documented, targeting the PI3K/AKT/mTOR pathway showed less efficiency in clinical trials than might have been expected, since the suppression of the PI3K/mTOR signaling pathway-induced feedback loops is mostly associated with the activation of compensatory pathways such as MAPK/MEK/ERK. Consequently, the development of intrinsic and acquired resistance can occur. As a solid tumor, melanoma is notorious for its heterogeneity. This can be expressed in the form of genetically divergent subpopulations including a small fraction of cancer stem-like cells (CSCs) and non-cancer stem cells (non-CSCs) that make the most of the tumor mass. Like other CSCs, melanoma stem-like cells (MSCs) are characterized by their unique cell surface proteins/stemness markers and aberrant signaling pathways. In addition to its function as a robust marker for stemness properties, CD133 is crucial for the maintenance of stemness properties and drug resistance. Herein, the role of CD133-dependent activation of PI3K/mTOR in the regulation of melanoma progression, drug resistance, and recurrence is reviewed.

Mechanisms of Melanoma Progression and Treatment Resistance: Role of Cancer Stem-like Cells.

Melanoma is the third most common type of skin cancer, characterized by its heterogeneity and propensity to metastasize to distant organs. Melanoma is a heterogeneous tumor, composed of genetically divergent subpopulations, including a small fraction of melanoma-initiating cancer stem-like cells (CSCs) and many non-cancer stem cells (non-CSCs). CSCs are characterized by their unique surface proteins associated with aberrant signaling pathways with a causal or consequential relationship with tumor progression, drug resistance, and recurrence. Melanomas also harbor significant alterations in functional genes (BRAF, CDKN2A, NRAS, TP53, and NF1). Of these, the most common are the BRAF and NRAS oncogenes, with 50% of melanomas demonstrating the BRAF mutation (BRAFV600E). While the successful targeting of BRAFV600E does improve overall survival, the long-term efficacy of available therapeutic options is limited due to adverse side effects and reduced clinical efficacy. Additionally, drug resistance develops rapidly via mechanisms involving fast feedback re-activation of MAPK signaling pathways. This article updates information relevant to the mechanisms of melanoma progression and resistance and particularly the mechanistic role of CSCs in melanoma progression, drug resistance, and recurrence.

Reactive oxygen species (ROS) in cancer pathogenesis and therapy: An update on the role of ROS in anticancer action of benzophenanthridine alkaloids.

Reactive oxygen species play crucial role in biological homeostasis and pathogenesis of human diseases including cancer. In this line, now it has become evident that ROS level/concentration is a major factor in the growth, progression and stemness of cancer cells. Moreover, cancer cells maintain a delicate balance between ROS and antioxidants to promote pathogenesis and clinical challenges via targeting a battery of signaling pathways converging to cancer hallmarks. Recent findings also entail the therapeutic importance of ROS for the better clinical outcomes in cancer patients as they induce apoptosis and autophagy. Moreover, poor clinical outcomes associated with cancer therapies are the major challenge and use of natural products have been vital in attenuation of these challenges due to their multitargeting potential with less adverse effects. In fact, most available drugs are derived from natural resources, either directly or indirectly and available evidence show the clinical importance of natural products in the management of various diseases, including cancer. ROS play a critical role in the anticancer actions of natural products, particularly phytochemicals. Benzophenanthridine alkaloids of the benzyl isoquinoline family of alkaloids, such as sanguinarine, possess several pharmacological properties and are thus being studied for the treatment of different human diseases, including cancer. In this article, we review recent findings, on how benzophenanthridine alkaloid-induced ROS play a critical role in the attenuation of pathological changes and stemness features associated with human cancers. In addition, we highlight the role of ROS in benzophenanthridine alkaloid-mediated activation of the signaling pathway associated with cancer cell apoptosis and autophagy.

Case study-based systematic review of literature on lymphoma-associated cardiac tamponade.

This study aimed to compile all the relevant studies of patients presenting with pericardial tamponade before or after diagnosis of lymphoma, describe the clinical presentations of patients with lymphoma and cardiac tamponade, and assess the difference in overall survival based on the timing of cardiac tamponade diagnosis. A comprehensive search strategy was conducted in the following databases: PubMed and Cochrane Library, using the following keywords: Lymphoma AND Cardiac Tamponade. The criteria for eligibility included cases with a confirmed diagnosis of lymphoma and cardiac tamponade, human studies, and publications in English language. The statistical analysis was performed using IBM Statistical Package for Social Sciences (SPSS) version 20. We included 48 research articles (n = 52 cases) with adequate reporting of measured outcomes. The median age of the patients was 52 (9-94) years. Only 6 patients were noted to have primary cardiac lymphoma, while the majority of cases were considered to have secondary cardiac lymphoma (88.5%). According to the data on the type of lymphoma reported through cytology and immunohistochemistry, 49 patients were diagnosed with non-Hodgkin lymphoma, and of these cases the most common subtype was large B-cell lymphoma (42.9%). Overall, the average duration of illness was 14 ± 23 days. A total of 13 patients had distant heart sounds, 12 cases were noted to be hypotensive, and 13 subjects were found to have increased jugular venous pressure. Our retrospective study demonstrated that most patients presented with pericardial tamponade after lymphoma diagnosis, and those were mostly secondary cardiac lymphoma of the non-Hodgkin type with large B-cell as the most common subtype. Dyspnoea, oedema, and constitutional symptoms were the most common presenting signs. The median overall survival of patients with lymphoma and cardiac tamponade is 4 months, with no significant difference in mortality in the presentation timing before and after the diagnosis of lymphoma.

Medical therapy options for endometriosis related pain, which is better? A systematic review and network meta-analysis of randomized controlled trials.

Our objective was to assess and rank different pharmacological interventions for relieving endometriosis-related pain. We conducted an online bibliographic search in different databases from their inception until March 2019. We included randomized controlled trials (RCTs) that assessed different medical therapies in the management of endometriosis-related pain. We applied this network meta-analysis (NMA) based on the frequentist approach using statistical package "netmeta" (version 1.0-1) in R software. Our main outcomes were the change in severity of pelvic pain, dysmenorrhea score, non-menstrual pelvic pain score, and dyspareunia score. Overall, 36 RCTs were included in this study (patients no. = 7942). Dienogest (0.94), combined hormonal contraceptives (CHCs) (0.782), and elagolix (0.38) were the highest-ranked interventions for reducing the severity of pelvic pain at three months, while at six months, gonadotropin-releasing hormone (GnRH) analogues (0.75), levonorgestrel-releasing intrauterine system (LNG-IUS) (0.73), and dienogest (0.65) were linked to more reduction in pelvic pain. The ranking p-score showed that GnRH analogues was the highest-ranked treatment for reducing dysmenorrhea at 3 months (1.00), while CHCs were the highest-ranked treatment at 6 months (0.97), followed by GnRH analogues (0.89). GnRH analogues (0.63) and elagolix (0.54) at three months while desogestrel (0.94) and CHCs (0.91) at six months were the highest-ranked treatment to reduce non-menstrual pelvic pain. GnRH analogues and elagolix were the highest-ranked pharmacologic therapies for reducing dyspareunia. In conclusion, CHCs, GnRH analogues, progesterone, and elagolix were the best approaches in reducing the pain of endometriosis.

Recent developments in unraveling signaling mechanisms underlying drug resistance due to cancer stem-like cells.

Resistance in cancer cells to therapeutic measures is challenging and requires a rigorous delineation of the underlying mechanisms. Emerging findings reflect the characteristics of tumor cells to do the reprogramming of signaling machinery in order to overturn the therapeutic responses. Recent evidence shows that the tumor acquires drug resistance due to the presence of cancer stem cells (CSCs). Hence the understanding that how tumor cells reprogram their signaling mechanisms converging towards the stemness of CSCs is imperative for novel and effective therapy. This review outlines the current updates on how CSC-associated signaling pathways and its enhanced stemness trigger the development of drug resistance. Furthermore, we also discussed the strategies with a combinational approach that can simultaneously target both CSC-induced stemness and the resistance-related signaling pathways, which may provide an optimal outcome to overcome the problem of drug resistance in cancer therapy.

Melanoma stem cell maintenance and chemo-resistance are mediated by CD133 signal to PI3K-dependent pathways.

Melanoma stem cells (MSCs) are characterized by their unique cell surface proteins and aberrant signaling pathways. These stemness properties are either in a causal or consequential relationship to melanoma progression, treatment resistance and recurrence. The functional analysis of CD133+ and CD133- cells in vitro and in vivo revealed that melanoma progression and treatment resistance are the consequences of CD133 signal to PI3K pathway. CD133 signal to PI3K pathway drives two downstream pathways, the PI3K/Akt/MDM2 and the PI3K/Akt/MKP-1 pathways. Activation of PI3K/Akt/MDM2 pathway results in the destabilization of p53 protein, while the activation of PI3K/Akt/MKP-1 pathway results in the inhibition of mitogen-activated protein kinases (MAPKs) JNK and p38. Activation of both pathways leads to the inhibition of fotemustine-induced apoptosis. Thus, the disruption of CD133 signal to PI3K pathway is essential to overcome Melanoma resistance to fotemustine. The pre-clinical verification of in vitro data using xenograft mouse model of MSCs confirmed the clinical relevance of CD133 signal as a therapeutic target for melanoma treatment. In conclusion, our study provides an insight into the mechanisms regulating MSCs growth and chemo-resistance and suggested a clinically relevant approach for melanoma treatment.

Pulmonary Hypertension and Polycythemia Secondary to Pulmonary Alveolar Microlithiasis Treated with Sequential Bilateral Lung Transplant: A Case Study and Literature Review.

BACKGROUND Pulmonary alveolar microlithiasis is an autosomal recessive disease in which a mutation in the SLC34A2 gene that codes for a sodium phosphate type IIb transporter protein (expressed in human epithelial tissues and functions in the clearance of phosphate ions) leads to the formation of extensive pulmonary intra-alveolar microliths. The subsequent characteristic clinical features of dyspnea and hypoxia are a manifestation of these microliths. There have been fewer than 1000 cases of pulmonary alveolar microlithiasis reported worldwide, and there have been 19 reported lung-transplanted patients. CASE REPORT A 49-year-old Saudi male patient presented with longstanding history of easy fatigability and tiredness on exertion since he was 16 years old. Throughout his follow-up in different hospitals (1986-1989), tuberculosis and pulmonary fibrosis were suspected. The patient was lost to follow-up between 1989 and 2001. In 2002, he presented to the emergency room with coughing, shortness of breath on exertion, abdominal swelling, and pedal edema. An investigation with chest x-rays, CT scan, electrocardiogram, and an echocardiogram was conducted. After referral to a tertiary care center, the patient was diagnosed with pulmonary alveolar microlithiasis. He subsequently developed pulmonary hypertension and polycythemia and therefore received a bilateral lung transplant in 2016. Following the lung transplant, he developed a mild reperfusion injury and tonic-clonic seizures, requiring ICU admission. After a successful extubatation with stable vitals and good recovery, he was discharged home in stable condition with planned follow-up. CONCLUSIONS We report a case of pulmonary alveolar microlithiasis successfully treated with a bilateral lung transplant. Although pulmonary alveolar microlithiasis is a rare entity, healthcare providers should consider it in the differential diagnoses of parenchymal lung diseases and differentiate it from tuberculosis and pulmonary fibrosis.

A Case Report of Intrapulmonary Teratoma in the Right Upper Lung Zone in a 35-year-old Female Patient.

Teratomas are rare germ cell tumors usually found in the gonads. Extra-gonadal teratomas are especially rare, mostly occurring in the thorax. Only a few cases of intrathoracic teratomas have been reported in medical literature and most reported were located in the mediastinum. An additional intrathoracic location for teratoma occurrence is in the pulmonary system, most commonly in the upper lobe of the left lung. In this report, we describe a case of a 35-year-old woman diagnosed with an intrapulmonary mature teratoma found in the right upper lobe. A 35-year-old Saudi female presented with a chief complaint of a three-week history of dry cough. Chest X-ray revealed a right-sided para-pericardial mass in the anterior mediastinum and a significant decrease in the size of the right middle lobe opacity. Subsequently, a chest computed tomography (CT) was performed and revealed a cystic mass in the right lung, which required removal by surgical intervention. The surgery was performed via a thoracoscopic approach and the tumor was excised with no complications. Intrapulmonary teratomas (IPT) usually present with vague and non-specific symptoms such as cough, hemoptysis, and chest pain. It is a rare condition without diagnostic features detected preoperatively, save for trichoptysis which is reported in approximately 13% of the cases. We report a rare appearance of mature IPT in the right upper lung zone which is an unusual location.

Sterile Bronchopleural Fistula Following Surgical Removal of Primary Lung Leiomyoma Inducing Secondary Hypertrophic Osteoarthropathy.

BACKGROUND Leiomyomas are benign neoplasms of the smooth muscle. When found in the pulmonary system, a rare occurrence, leiomyomas can result in hypertrophic osteoarthropathy, or significant clubbing, associated with proliferation of long bone periosteum. Bronchopulmonary fistulas, or communications between the bronchial tree and pleural space, are an uncommon postoperative complication of pneumonectomies. Even more infrequent is the presence of a bronchopulmonary fistula that is determined to be sterile. CASE REPORT The patient presented in the current case report is a 40-year-old previously healthy woman who presented with a 5-year history of chronic cough, right-sided chest discomfort, and dyspnea associated with back pain, and lower leg pain. The CT scan performed on the patient revealed a mass originating from the right lower lobe. Activity at the site of the lesion, in the long bones of the upper and lower limbs, rib cage, and vertebral bones was demonstrated by a bone scan. A CT-guided biopsy was performed, and the pathology report confirmed the presence of a leiomyoma. Following a right-sided lobectomy, the resected tumor was sent for histopathology, with the results confirming the biopsy. The patient subsequently presented with a history of persistent cough associated with increased watery secretions. The CT scan revealed the presence of a bronchopleural fistula, after which the patient underwent surgical correction. All symptoms resolved, and the patient was discharged in stable condition. CONCLUSIONS Here, we report on a patient who presented with 3 rare clinical findings: pulmonary leiomyoma, hypertrophic osteoarthropathy, and sterile bronchopulmonary fistula.

Benign Pericardial Schwannoma: Case Report and Summary of Previously Reported Cases.

BACKGROUND Primary pericardial tumors have a prevalence of between 6.7% and 12.8% of all tumors arising in the cardiac region. Pericardial schwannoma is a rare entity. It arises from the cardiac plexus and vagus nerve innervating the heart. Most of the reported cases, have presented with benign behavior, however, in rare situations, they can undergo transformation to malignant behavior When comparing the prevalence of cardiac tumors to that of pericardial tumors, the latter is much lower in occurrence. A review of English literature identified six pericardial schwannoma cases. CASE REPORT We present a case of a 30-year-old male patient who presented to our center with the chief complaint of six months of gradually progressive left chest pain. His past medical history (PMH) was positive for panic attacks (for which he was taking beta-blockers), paroxysmal tachycardia, sweating, and irritability. A computed tomography chest scan was done; a differential diagnosis of paraganglioma was suggested. However, histopathological examination confirmed the pericardial mass was a schwannoma. The patient was surgically treated by thoracotomy to resect the lesion. CONCLUSIONS This case adds to the existing limited literature on pericardial schwannoma as the seventh reported case. Neurogenic cardiac tumors; our case marks the second case reported to occur in the subcarinal area near the left atrium.

Interferon gamma-induced apoptosis of head and neck squamous cell carcinoma is connected to indoleamine-2,3-dioxygenase via mitochondrial and ER stress-associated pathways.

BACKGROUND: Tumor response to immunotherapy is the consequence of a concerted crosstalk between cytokines and effector cells. Interferon gamma (IFNγ) is one of the common cytokines coordinating tumor immune response and the associated biological consequences. Although the role of IFNγ in the modulation of tumor immunity has been widely documented, the mechanisms regulating IFNγ-induced cell death, during the course of immune therapy, is not described in detail. RESULTS: IFNγ triggered apoptosis of CLS-354 and RPMI 2650 cells, enhanced the protein expression and activation of indoleamine 2,3-dioxygenase (IDO), and suppressed the basal expression of heme oxygenase-1(HO-1). Interestingly, IFNγ induced the loss of mitochondrial membrane potential (Δψm) and increased accumulation of reactive oxygen species (ROS). The cytokine also induced the activation of Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT)1, apoptosis signal-regulating kinase 1 (ASK1), p38, c-jun-N-terminal kinase (JNK) and NF-κB pathways and the transcription factors STAT1, interferon regulatory factor 1 (IRF1), AP-1, ATF-2, NF-κB and p53, and expression of Noxa protein. Furthermore, IFNγ was found to trigger endoplasmic reticulum (ER) stress as evidenced by the cleavage of caspase-4 and activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and inositol-requiring-1α (IRE1α) pathways. Using specific inhibitors, we identified a potential role for IDO as apoptotic mediator in the regulation of IFNγ-induced apoptosis of head and neck squamous cell carcinoma (HNSCC) cells via Noxa-mediated mitochondrial dysregulation and ER stress. CONCLUSION: In addition to the elucidation of the role of IDO in the modulation of apoptosis, our study provides new insights into the molecular mechanisms of IFNγ-induced apoptosis of HNSCC cells during the course of immune therapy.

Cancer stem cell as therapeutic target for melanoma treatment.

Human malignant melanoma is a highly aggressive skin tumor that is characterized by its extraordinary heterogeneity, propensity for dissemination to distant organs and resistance to cytotoxic agents. Although chemo- and immune-based therapies have been evaluated in clinical trials, most of these therapeutics do not show significant benefit for patients with advanced disease. Treatment failure in melanoma patients is attributed mainly to the development of tumor heterogeneity resulting from the formation of genetically divergent subpopulations. These subpopulations are composed of cancer stem-like cells (CSCs) as a small fraction and non-cancer stem cells that form the majority of the tumor mass. In recent years, CSCs gained more attention and suggested as valuable experimental model system for tumor study. In melanoma, intratumoral heterogeneity, progression and drug resistance result from the unique characteristics of melanoma stem cells (MSCs). These MSCs are characterized by their distinct protein signature and tumor growth-driving pathways, whose activation is mediated by driver mutation-dependent signal. The molecular features of MSCs are either in a causal or consequential relationship to melanoma progression, drug resistance and relapse. Here, we review the current scientific evidence that supports CSC hypothesis and the validity of MSCs-dependent pathways and their key molecules as potential therapeutic target for melanoma treatment.