scholarly journals Upregulation of the ErbB family by EZH2 in hepatocellular carcinoma confers resistance to FGFR inhibitor

2021 ◽  
Author(s):  
Aldo Prawira ◽  
Thi Bich Uyen Le ◽  
Rebecca Zhi Wen Ho ◽  
Hung Huynh
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Investigation ◽  
Treatment Options ◽  
Acquired Resistance ◽  
Feedback Mechanism ◽  
Term Treatment ◽  
Gene Overexpression ◽  
Antitumour Effect ◽  
Erbb Family ◽  
Long Term Treatment

Abstract Purpose Hepatocellular carcinoma (HCC), the most common manifestation of liver cancer, is one of the leading causes of cancer-related mortality worldwide with limited treatment options. Infigratinib, a pan-FGFR inhibitor, has shown a potent antitumour effect in HCC. However, drug resistance is often observed in long-term treatment. In this study, we examined the potential feedback mechanism(s) leading to infigratinib and explored a combination therapy to overcome resistance in HCC. Methods Patient-derived xenograft (PDX) tumours were subcutaneously implanted into SCID mice and were subsequently treated with infigratinib. Tumour growth was monitored over time, and tumour samples were subjected to immunohistochemistry and Western blotting. For drug combination studies, mice were treated with infigratinib and/or varlitinib. Gene overexpression and knockdown studies were conducted to investigate the relationship between EZH2 and ErbB activity in infigratinib resistance. Results Infigratinib-resistant tumours exhibited higher levels of p-ErbB2 and p-ErbB3, concomitant with an increase in EZH2 expression. Gene overexpression and knockdown studies revealed that EZH2 directly regulates the levels of p-ErbB2 and p-ErbB3 in acquired resistance to infigratinib. The addition of varlitinib effectively overcame infigratinib resistance and prolonged the antitumour response, with minimal toxicity. Conclusion The upregulation of the ErbB family by EZH2 appears to contribute to infigratinib resistance. The combination of infigratinib and varlitinib showed a potent antitumour effect and did not result in additional toxicity, warranting further clinical investigation.

scholarly journals Upregulation of the ErbB family by EZH2 in hepatocellular carcinoma confers resistance to FGFR inhibitor

2021 ◽  
Author(s):  
Aldo Prawira ◽  
Thi Bich Uyen Le ◽  
Rebecca Zhi Wen Ho ◽  
Hung Huynh
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Investigation ◽  
Treatment Options ◽  
Acquired Resistance ◽  
Feedback Mechanism ◽  
Term Treatment ◽  
Gene Overexpression ◽  
Antitumour Effect ◽  
Erbb Family ◽  
Long Term Treatment

Abstract Purpose Hepatocellular carcinoma (HCC), the most common manifestation of liver cancer, is one of the leading causes of cancer-related mortality worldwide with limited treatment options. Infigratinib, a pan-FGFR inhibitor, has shown a potent antitumour effect in HCC. However, drug resistance is often observed in long term treatment. In this study, we examined the potential feedback mechanism(s) leading to infigratinib and explored a combination therapy to overcome resistance in HCC. Methods Patient-derived xenograft (PDX) tumours were subcutaneously implanted into SCID mice and were subsequently treated with infigratinib. Tumour growth was monitored over time, and tumour samples were subjected to immunohistochemistry and Western blotting. For drug combination studies, mice were treated with infigratinib and/or varlitinib. Gene overexpression and knockdown studies were conducted to investigate the relationship between EZH2 and ErbB activity in infigratinib resistance. Results Infigratinib-resistant tumours exhibited higher levels of p-ErbB2 and p-ErbB3, concomitant with an increase in EZH2 expression. Gene overexpression and knockdown studies revealed that EZH2 directly regulates the levels of p-ErbB2 and p-ErbB3 in acquired resistance to infigratinib. The addition of varlitinib effectively overcame infigratinib resistance and prolonged the antitumour response, with minimal toxicity. Conclusion The upregulation of the ErbB family by EZH2 appears to contribute to infigratinib resistance. The combination of infigratinib and varlitinib showed a potent antitumour effect and did not result in additional toxicity, warranting further clinical investigation.

scholarly journals Sunitinib treatment promotes metastasis of drug-resistant renal cell carcinoma via TFE3 signaling pathway

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Luchao Li ◽  
Shuo Zhao ◽  
Zhengfang Liu ◽  
Nianzhao Zhang ◽  
Shuo Pang ◽  
...  
Keyword(s):  
Renal Cell ◽  
Cell Cancer ◽  
Acquired Resistance ◽  
Resistant Cell ◽  
Term Treatment ◽  
Acquired Drug Resistance ◽  
Sunitinib Treatment ◽  
Long Term Treatment

AbstractReceptor tyrosine kinase (RTK) inhibitors, such as sunitinib and sorafenib, remain the first-line drugs for the treatment of mRCC. Acquired drug resistance and metastasis are the main causes of treatment failure. However, in the case of metastasis Renal Cell Cancer (mRCC), which showed a good response to sunitinib, we found that long-term treatment with sunitinib could promote lysosome biosynthesis and exocytosis, thereby triggering the metastasis of RCC. By constructing sunitinib-resistant cell lines in vivo, we confirmed that TFE3 plays a key role in the acquired resistance to sunitinib in RCC. Under the stimulation of sunitinib, TFE3 continued to enter the nucleus, promoting the expression of endoplasmic reticulum (ER) protein E-Syt1. E-Syt1 and the lysosomal membrane protein Syt7 form a heterodimer, which induces ER fragmentation, Ca2+ release, and lysosomal exocytosis. Lysosomal exocytosis has two functions: pumping sunitinib out from the cytoplasm, which promotes resistance to sunitinib in RCC, releasing cathepsin B (CTSB) into the extracellular matrix (ECM), which can degrade the ECM to enhance the invasion and metastasis ability of RCC. Our study found that although sunitinib is an effective drug for the treatment of mRCC, once RCC has acquired resistance to sunitinib, sunitinib treatment will promote metastasis.

scholarly journals Adjunct pharmacotherapy for psychotherapy

BJPsych Open ◽  
2021 ◽  
Vol 7 (S1) ◽  
pp. S166-S167
Author(s):  
Jessica Lochtenberg ◽  
Ari Kirshenbaum ◽  
Matthew Johnson
Keyword(s):  
Posttraumatic Stress Disorder ◽  
Therapeutic Alliance ◽  
Posttraumatic Stress ◽  
Substance Dependence ◽  
Stress Disorder ◽  
Psychiatric Symptoms ◽  
Treatment Options ◽  
Term Treatment ◽  
Compulsive Disorder ◽  
Long Term Treatment

AimsA variety of pharmacotherapies have been used to assist the psychotherapy process as “adjunctive therapies.” These drugs are used in an acute, targeted fashion, such that they are explicitly delivered in the context of psychotherapy for anxiety, mood and substance-dependence disorders (SUDs). Our narrative review highlights the potential of medically-assisted psychotherapy by outlining the current state of research on few of these medications and describing the basic science that supports their use.MethodFirstly, we researched an assortment of medications that have been used off-label to enhance psychotherapy, and selected a few that have received the most empirical attention in preclinical and clinical-trial settings. Our review of clinical trials focused on three of the most common psychiatric ailments. For all studies reviewed, we identify the strengths and weaknesses of the data supporting the use of the medications for the three aforementioned disorders.ResultD-cycloserine: accelerates the process of associative emotional learning, enhancing exposure therapy in the treatment of various anxiety disorders, including obsessive-compulsive disorder and posttraumatic stress disorder. Limited studies are available on efficacy in treating SUDs.Intranasal oxytocin: accelerates memory retrieval-extinction procedures used in posttraumatic stress disorder, and promotes prosocial cognition and behaviour, facilitating a therapeutic alliance. Sufficiently powered studies and safety studies are required before strong conclusions can be made.Propranolol: interrupts the reconsolidation of memories (leading to maladaptive learned responses) involved in posttraumatic stress disorder during memory-reactivation therapy sessions, but there is little evidence that this drug can be used for depression or SUDs.Psychedelics: may effect the brain's default mode network, engendering a transformative experience that is often followed by a reduction in psychiatric symptoms. 3,4-methylenedioxymethamphetamine may additionally modulate the amygdala response in a way that allows for reprocessing of traumatic memories, and improves the therapeutic alliance. Anxiety, mood, and SUDs appear to be positively influence by traditional and non-traditional (ketamine) psychedelics.ConclusionAlthough the efficacy of the medically-assisted psychotherapies reviewed is still under investigation, we propose that these novel treatment approaches may be preferred over traditional psychopharmacological treatments due to the presence of fewer chronic side effects, as well less toxicity and abuse potential. Furthermore, these adjunctive pharmacotherapies may help to reinforce the psychotherapeutic alliance and may ultimately yield better long-term treatment outcomes. If at least some of the adjunctive pharmacotherapies outlined in this review are found to be clinically efficacious and safe, patients will benefit from having more treatment options available to them in the future.

Progress in Hodgkin lymphoma: a population-based study on patients diagnosed in Sweden from 1973-2009

Blood ◽  
2012 ◽  
Vol 119 (4) ◽  
pp. 990-996 ◽  
Author(s):  
Jan Sjöberg ◽  
Cat Halthur ◽  
Sigurdur Y. Kristinsson ◽  
Ola Landgren ◽  
Ulla Axdorph Nygell ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Treatment Options ◽  
Age Groups ◽  
Relative Survival ◽  
Population Based ◽  
Term Treatment ◽  
Cure Rate ◽  
Population Based Study ◽  
Long Term Treatment

Abstract In recent decades, attention has focused on reducing long-term, treatment-related morbidity and mortality in Hodgkin lymphoma (HL). In the present study, we looked for trends in relative survival for all patients diagnosed with HL in Sweden from 1973-2009 (N = 6949; 3985 men and 2964 women; median age, 45 years) and followed up for death until the end of 2010. Patients were categorized into 6 age groups and 5 calendar periods (1973-1979, 1980-1986, 1987-1994, 1994-2000, and 2001-2009). Relative survival improved in all age groups, with the greatest improvement in patients 51-65 years of age (P < .0005). A plateau in relative survival was observed in patients below 65 years of age during the last calendar period, suggesting a reduced long-term, treatment-related mortality. The 10-year relative survival for patients diagnosed in 2000-2009 was 0.95, 0.96, 0.93, 0.80, and 0.44 for the age groups 0-18, 19-35, 36-50, 51-65, and 66-80, respectively. Therefore, despite progress, age at diagnosis remains an important prognostic factor (P < .0005). Advances in therapy for patients with limited and advanced-stage HL have contributed to an increasing cure rate. In addition, our findings support that long-term mortality of HL therapy has decreased. Elderly HL patients still do poorly, and targeted treatment options associated with fewer side effects will advance the clinical HL field.

Long term treatment with lamivudine and incidence of hepatocellular carcinoma (HCC) in HBV-related cirrhosis

2001 ◽  
Vol 34 ◽  
pp. 171
Author(s):  
V. Di Marco ◽  
D. Ferraro ◽  
C. Bonura ◽  
P. Parisi ◽  
L. Sandonato ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Term Treatment ◽  
Long Term Treatment

scholarly journals Pediatric Atopic Dermatitis: Update on the Treatment Options

2020 ◽  
Vol 25 (4) ◽  
pp. 60-62
Author(s):  
Corina Adelina Zah ◽  
Andreea Emiliana Toporău ◽  
Paul Grama
Keyword(s):  
Atopic Dermatitis ◽  
Chronic Treatment ◽  
Pediatric Patients ◽  
Treatment Options ◽  
Chronic Inflammatory Disease ◽  
Term Treatment ◽  
Phosphodiesterase 4 ◽  
Systemic Corticosteroids ◽  
Long Term Treatment

Abstract Atopic dermatitis (AD) is a chronic inflammatory disease characterized by skin dryness, pruritus and eczematous lesions with various periods of relapse. Symptomatology can appear in childhood and can persist in adulthood. Chronic treatment is required with corticosteroids being the standard options. The side effects of this type of long-term treatment represent a major concern for the pediatric patients. This review aims to give an update of the options used for treatment, apart from the systemic corticosteroids. Mild-to-moderate AD had a good response to creams containing fig and oatmeal extracts and inhibitors of phosphodiesterase-4 (crisaborole). In cases of severe AD, future treatment options could include monoclonal antibodies such as omalizumab and dupilumab

scholarly journals New Therapeutic Approaches for Allergy: A Review of Cell Therapy and Bio- or Nano-Material-Based Strategies

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2149
Author(s):  
Juan L. Paris ◽  
Paz de la Torre ◽  
Ana I. Flores
Keyword(s):  
Cell Therapy ◽  
Treatment Options ◽  
Allergic Diseases ◽  
Immunological Tolerance ◽  
Term Treatment ◽  
Therapeutic Approaches ◽  
New Therapeutic Approaches ◽  
Long Term Treatment ◽  
Nano Material

Allergy constitutes a major health issue due to its large prevalence. The established therapeutic approaches (allergen avoidance, antihistamines, and corticosteroids) do not address the underlying causes of the pathology, highlighting the need for other long-term treatment options. Antigen-specific immunotherapy enables the long-term control of allergic diseases by promoting immunological tolerance to the allergen. However, efficacious immunotherapies are not available for all possible allergens, and the risk of undesired reactions during therapy remains a concern, especially in patients with severe allergic reactions. In this context, two types of therapeutic strategies appear especially promising for the future in the context of allergy: cell therapy and bio- or nano-material-based therapy. In this review, the main strategies developed this far in these two types of strategies are discussed, with several examples illustrating the different approaches.

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