P2Y2 purinergic receptor gene deletion protects mice from bacterial endotoxin and sepsis-associated liver injury and mortality.

The liver plays a significant role in regulating a wide range of metabolic, homeostatic, and host-defense functions. However, the impact of liver injury on the host's ability to control bacteremia and morbidity in sepsis is not well understood. Leukocyte recruitment and activation lead to cytokine and chemokine release, which, in turn, trigger hepatocellular injury and elevate nucleotide levels in the extracellular milieu. P2Y2 purinergic receptors, G protein-coupled and activated by extracellular ATP/UTP, are expressed at the cell surface of hepatocytes and nonparenchymal cells. We sought to determine whether P2Y2 purinergic receptor function is necessary for the maladaptive host response to bacterial infection and endotoxin-mediated inflammatory liver injury and mortality in mice. We report that P2Y2 purinergic receptor knockout mice (P2Y2-/-) had attenuated inflammation and liver injury, with improved survival in response to LPS/galactosamine (LPS/GalN; inflammatory liver injury) and cecal ligation and puncture (CLP; polymicrobial sepsis). P2Y2-/- livers had attenuated c-Jun NH2-terminal kinase activation, matrix metallopeptidase-9 expression, and hepatocyte apoptosis in response to LPS/GalN and attenuated inducible nitric oxide synthase and nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 protein expression in response to CLP. Implicating liver injury in the disruption of amino acid homeostasis, CLP led to lower serum arginine and higher bacterial load and morbidity in the WT mice, whereas serum arginine levels were comparable to sham-operated controls in P2Y2-/- mice, which had attenuated bacteremia and improved survival. Collectively, our studies highlight the pathophysiological relevance of P2Y2 purinergic receptor function in inflammatory liver injury and dysregulation of systemic amino acid homeostasis with implications for sepsis-associated immune dysfunction and morbidity in mice.NEW & NOTEWORTHY Our studies provide experimental evidence for P2Y2 purinergic receptor-mediated potentiation of inflammatory liver injury, morbidity, and mortality, in two well-established animal models of inflammatory liver injury. Our findings highlight the potential to target P2Y2 purinergic signaling to attenuate the induction of "cytokine storm" and prevent its deleterious consequences on liver function, systemic amino acid homeostasis, host response to bacterial infection, and sepsis-associated morbidity and mortality.

Histone Deacetylase Sirtuin 1 Promotes Loss of Primary Cilia in Cholangiocarcinoma.

BACKGROUND AND AIMS: Sirtuin 1 (SIRT1) is a complex NAD+ -dependent protein deacetylase known to act as a tumor promoter or suppressor in different cancers. Here, we describe a mechanism of SIRT1-induced destabilization of primary cilia in cholangiocarcinoma (CCA). APPROACH AND RESULTS: A significant overexpression of SIRT1 was detected in human CCA specimens and CCA cells including HuCCT1, KMCH, and WITT1 as compared with normal cholangiocytes (H69 and NHC). Small interfering RNA (siRNA)-mediated knockdown of SIRT1 in HuCCT1 cells induced cilia formation, whereas overexpression of SIRT1 in normal cholangiocytes suppressed ciliary expression. Activity of SIRT1 was regulated by presence of NAD+ in CCA cells. Inhibition of NAD -producing enzyme nicotinamide phosphoribosyl transferase increased ciliary length and frequency in CCA cells and in SIRT1-overexpressed H69 cells. Furthermore, we also noted that SIRT1 induces the proteasomal mediated degradation of ciliary proteins, including α-tubulin, ARL13B, and KIF3A. Moreover, overexpression of SIRT1 in H69 and NHC cells significantly induced cell proliferation and, conversely, SIRT1 inhibition in HuCCT1 and KMCH cells using siRNA or sirtinol reduced cell proliferation. In an orthotopic transplantation rat CCA model, the SIRT1 inhibitor sirtinol reduced tumor size and tumorigenic proteins (glioma-associated oncogene 1, phosphorylated extracellular signal-regulated kinase, and IL-6) expression. CONCLUSIONS: In conclusion, these results reveal the tumorigenic role of SIRT1 through modulation of primary cilia formation and provide the rationale for developing therapeutic approaches for CCA using SIRT1 as a target.

COVID-19: The Impact in Oncology Care.

The COVID-19 pandemic has imposed a critical challenge to the current oncology care and practices including late diagnoses, delayed anti-cancer treatment, and static clinical trials. With the increasing risk of cancer patients acquiring infection during receiving the essential care, the debate ensues on how to balance the risk factors and benefits out of the oncologic emergencies in cancer patients. In this review article, we have focused on the current global re-organization of the integrity and effectiveness of the treatment modalities depending on the patient and cancer-specific urgencies while minimizing exposure to the infection. In this review, we addressed how the worldwide oncology community is united to share therapy schemes and the best possible guidelines to help cancer patients, and to strategize and execute therapy/trial protocols. This review provides collective knowledge on the current re-structuring of the general framework that prioritizes cancer care with the available exploitation of the reduced resources and most importantly the unparalleled levels of companionship as a large health care community towards the need to offer the best possible care to the patients.

Knock-down of the TIM/TIPIN complex promotes apoptosis in melanoma cells.

The Timeless (TIM) and it's interacting partner TIPIN protein complex is well known for its role in replication checkpoints and normal DNA replication processes. Recent studies revealed the involvement of TIM and TIPIN in human malignancies; however, no evidence is available regarding the expression of the TIM/TIPIN protein complex or its potential role in melanoma. Therefore, we investigated the role of this complex in melanoma. To assess the role of the TIM/TIPIN complex in melanoma, we analyzed TIM/TIPIN expression data from the publicly accessible TCGA online database, Western blot analysis, and RT-qPCR in a panel of melanoma cell lines. Lentivirus-mediated TIM/TIPIN knockdown in A375 melanoma cells was used to examine proliferation, colony formation, and apoptosis. A xenograft tumor formation assay was also performed. The TIM/TIPIN complex is frequently overexpressed in melanoma cells compared to normal melanocytes. We also discovered that the overexpression of TIM and TIPIN was significantly associated with poorer prognosis of melanoma patients. Furthermore, we observed that shRNA-mediated knockdown of TIM and TIPIN reduced cell viability and proliferation due to the induction of apoptosis and increased levels of γH2AX, a marker of DNA damage. In a xenograft tumor nude mouse model, shRNA-knockdown of TIM/TIPIN significantly reduced tumor growth. Our results suggest that the TIM/TIPIN complex plays an important role in tumorigenesis of melanoma, which might reveal novel approaches for the development of new melanoma therapies. Our studies also provide a beginning structural basis for understanding the assembly of the TIM/TIPIN complex. Further mechanistic investigations are needed to determine the complex's potential as a biomarker of melanoma susceptibility. Targeting TIM/TIPIN might be a potential therapeutic strategy against melanoma.

HDAC6-dependent ciliophagy is involved in ciliary loss and cholangiocarcinoma growth in human cells and murine models.

Reduced ciliary expression is reported in several tumors, including cholangiocarcinoma (CCA). We previously showed primary cilia have tumor suppressor characteristics, and HDAC6 is involved in ciliary loss. However, mechanisms of ciliary disassembly are unknown. Herein, we tested the hypothesis that HDAC6-dependent autophagy of primary cilia, i.e., ciliophagy, is the main mechanism driving ciliary disassembly in CCA. Using the cancer genome atlas database, human CCA cells, and a rat orthotopic CCA model, we assessed basal and HDAC6-regulated autophagy levels. The effects of RNA-silencing or pharmacological manipulations of ciliophagy on ciliary expression were assessed. Interactions of ciliary proteins with autophagy machinery was assessed by immunoprecipitations. Cell proliferation was assessed by MTS and IncuCyte. A CCA rat model was used to assess the effects of pharmacological inhibition of ciliophagy in vivo. Autophagy is increased in human CCA, as well as in a rat orthotopic CCA model and human CCA cell lines. Autophagic flux was decreased via inhibition of HDAC6, while it was increased by its overexpression. Inhibition of autophagy and HDAC6 restores cilia and decreases cell proliferation. LC3 interacts with HDAC6 and ciliary proteins, and the autophagy cargo receptor involved in targeting ciliary components to the autophagy machinery is primarily NBR1. Treatment with chloroquine, Ricolinostat (ACY-1215), or their combination decreased tumor growth in vivo. Mice that overexpress the autophagy transcription factor TFEB show a decrease of ciliary number. These results suggest that ciliary disassembly is mediated by HDAC6-regulated autophagy, i.e., ciliophagy. Inhibition of ciliophagy may decrease cholangiocarcinoma growth and warrant further investigations as a potential therapeutic approach.NEW & NOTEWORTHY This work identifies novel targets against primary ciliary disassembly that can lead to new cholangiocarcinoma therapeutic strategies. Furthermore, ciliary loss has been described in different tumors, increasing the significance of our research.

The primary cilium: Its role as a tumor suppressor organelle.

The primary cilium is an organelle that nearly all cells within the body contain. Its function is to sense the extracellular environment through its abundance of receptors and linked signaling pathways, working as an antenna. Ciliary defects lead to different pathologies. In particular, many tumors lose primary cilia, and this is linked with negative implications for the cell such as an increase in malignancy. In this work we will go through the knowledge of the role of primary cilia in normal conditions, how it is involved in diverse signaling pathways, and in disease, particularly in cancer, highlighting its tumor suppressor properties.

Impact of Cancer Awareness Drive on Generating Awareness of and Improving Screening for Cervical Cancer: A Study Among Schoolteachers in India.

PURPOSE: Cervical cancer is the second most common cancer in India. Our study assessed the level and impact of awareness programs in the adoption of safe practices in prevention and early detection. METHODS: This assessment was part of a Pink Chain Campaign, the mission of which is to fight cancer. During cancer awareness events from 2013 to 2015 at various women's colleges in different parts in India, a pretest related to cervical cancer was followed by an awareness program. A post-test was conducted 6 months and 1 year later. RESULTS: A total of 872 of 985 teachers participated in the study, for a response rate of 88.5%. Mean age of the population was 42.4 years. There was a significant increase in the level of knowledge regarding cervical cancer at 6 months, which was sustained at 1 year. Regarding cervical cancer screening, knowledge and practice of the Papanicolaou (Pap) test as a screening test for cervical cancer among teachers were changed significantly at 6 months and 1 year. More than 75% of teachers were educated by physicians about the Pap test. At the time of the post-test, there was a significant change in alcohol and smoking habits. The main reasons for not undergoing a screening test were ignorance (50%), lethargic attitude (44.8%), and lack of time (34.6%). CONCLUSION: The level of knowledge of cervical cancer was poor. A significant increase in the level of knowledge of cervical cancer among the population was found after this study. To inculcate safe lifestyle practices, awareness programs should be conducted more widely and frequently.

Current Trends in Management of Oral Mucositis in Cancer Treatment

Oral Mucositis (OM) is among the most common and dreaded toxicities of cancer therapy. It occurs in almost all patients who receive radiation therapy in which areas of oral and oropharyngeal mucosa are included in the treatment field. With the advent of chemotherapy in 1940 and its extended clinical legacy, it is only within the past two decade or so that mucositis' complex pathobiology has become fully appreciated. There are still many unanswered questions about the risk factors for developing OM, but historically, risk factors have been attributed to both therapy and patient m characteristics. One thing that has been consistent from the initial descriptions of its clinical manifestations has been the frustration on the part of clinicians and patients with the scarcity of therapeutic options to prevent or treat the condition, or effectively ameliorate the symptoms. Clinicians, researchers and those involved in oral and periodontal medicine should join hand in hand in persuit of understanding and developing treatment strategies for treatment of inflammatory conditions like OM in oncology. This will lead to development of effective treatments and reducing the burden of OM and other inflammatory conditions in oncology.

Impact of Cancer Awareness Drive on Generating Understanding and Improving Screening Practices for Breast Cancer: a Study on College Teachers in India

Background: Breast cancer is the most common cancer among women in India and most present at advanced stage. Although early detection is the only way to reduce morbidity and mortality, people have a very low awareness about breast cancer signs and symptoms and screening practices. The purpose of this study was to assess the level of awareness and impact of awareness programs in adoption of safe practices in prevention and early detection. Methods: This assessment was part of a pink chain campaign on cancer awareness. During events from 2011 to 2015 at various women colleges in different parts in India, a pre-test of knowledge related to breast cancer was followed by an awareness program. Post-tests using the same questionnaire were conducted at the end of the interactive sessions, at 6 months and after1 year. Results: A total of 872 out of 985 teachers participated in the study (overall response rate of 88.5 %). Mean age of the study population was 41.6 years (range 28-59 yrs). There was a significant increase in level of knowledge regarding breast cancer at 6 months and this was sustained at 1 year. Adoption of breast self-examination (BSE) was significantly more frequent in comparison to CBE and mammography. Magazines and newspapers were sources for knowledge regarding screening tests for breast cancer for more than 60% of teachers. Regarding post-awareness at 6 months and 1 year, there was a significant change in alcohol and smoking habits. Major reasons came out to be ignorance (83%) at the start of the campaign which was changed to lack of time (37.7%), lethargic attitude (32.2 %) and lack of time (31.5 %) at 6 months and same at 1 year also. Conclusions: With our awareness program there was a significant increase in level of knowledge regarding breast cancer at 6 months and this was sustained at 1 year. Adoption of BSE was significantly greater in comparison to CBE, mammography. To inculcate safe lifestyle practices in people, awareness programmes such as pink chain campaigns should be conducted more widely and frequently.

Sexual Dysfunction in Females after Cancer Treatment: an Unresolved Issue

Cancer besides being a leading cause of mortality also creates a myriad of morbidities in survivors whether treated or untreated. Among women surviving after gynecological malignancies sexual dysfunction is a morbidity unexplored in Indian context because of cultural barriers. With the increasing proportion of women surviving carcinoma of the cervix, quality of life has become an important clinical issue. Despite the immense distress it causes in patients, sexual dysfunction is neither screened nor treated in Indian scenario. Despite this recognition, the area is not well researched and there is a paucity of information on the impact of cancer treatment on sexual health in Indian Context. Research has shown that up to 50% of women treated for cervix cancers have sexual dysfunction as they recover and become cancer survivors. This article aims to review the phases of sexual response and how each may be affected by the physical and emotional stress of cancer diagnosis and treatment. We will then discuss existing tools for assessment of sexual function and approaches to their treatment. Finally, we will conclude with advice to health care professionals based on current research and suggest questions for future study.