Radiotherapy driven immunomodulation of the tumor microenvironment and its impact on clinical outcomes: a promising new treatment paradigm

Abstract Parkinson's disease is a common neurodegenerative disease in which gastrointestinal symptoms may appear prior to motor symptoms. The gut microbiota of patients with Parkinson's disease shows unique changes, which may be used as early biomarkers of disease. Alteration in gut microbiota composition may be related to the cause or effect of motor or non-motor symptoms, but the specific pathogenic mechanisms are unclear. The gut microbiota and its metabolites have been suggested to be involved in the pathogenesis of Parkinson's disease by regulating neuroinflammation, barrier function and neurotransmitter activity. There is bidirectional communication between the enteric nervous system and the central nervous system, and the microbiota-gut-brain axis may provide a pathway for the transmission of α-synuclein. We highlight recent discoveries and alterations of the gut microbiota in Parkinson's disease, and highlight current mechanistic insights on the microbiota-gut-brain axis in disease pathophysiology. We discuss the interactions between production and transmission of α-synuclein and gut inflammation and neuroinflammation. In addition, we also draw attention to diet modification, use of probiotics and prebiotics and fecal microbiota transplantation as potential therapeutic approaches that may lead to a new treatment paradigm for Parkinson's disease.

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STEM-12. THE SMALL MOLECULE DRUG CBL0137 INCREASES THE LEVEL OF DNA DAMAGE AND THE EFFICACY OF RADIOTHERAPY FOR GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noab196.087 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi23-vi23

Author(s):

Miranda Tallman ◽

Abby Zalenski ◽

Amanda Deighen ◽

Treg Grubb ◽

Morgan Schrock ◽

...

Keyword(s):

Dna Damage ◽

Small Molecule ◽

Small Population ◽

Orthotopic Model ◽

Average Life Expectancy ◽

Small Molecule Drug ◽

Specific Cytotoxicity ◽

Treatment Paradigm ◽

New Treatment

Abstract Glioblastoma (GBM) is a fatal and incurable brain tumor, with an average life expectancy after diagnosis of only 12-15 months. A main reason for the lethality of GBM is inevitable recurrence, caused by a small population of the tumor cells, called cancer stem cells (CSCs). These cells are aggressive, infiltrative, and resistant to current GBM treatments of chemotherapy and radiotherapy. We use a small molecule drug, CBL0137, which inhibits the FACT (facilitates chromatin transcription) complex leading to cancer cell specific cytotoxicity. Here, we show that CBL0137 sensitized GBM CSCs to radiotherapy and hence lead to increased CSC death and prolonged survival in preclinical models. Clonogenic assays were used to show that CSCs were radiosensitized after CBL0137 treatment. We saw increased DNA damage when GBM CSCs were treated with CBL0137, as well as a decrease in foci resolution over time, when CBL0137 was combined with irradiation. In order to elucidate if the increase in DNA damage was directly due to the inhibition of the FACT complex, we depleted the level of FACT in our GBM CSCs. FACT depletion also led to increased DNA damage, and even more so when combined with irradiation. To validate whether combination therapy sensitized CSCs to radiotherapy in vivo, we used a subcutaneous mouse model and showed combination treatment decreased CSCs frequency in these tumors as well as decreased tumor volume. With an orthotopic model of GBM, we showed that CBL0137 treatment followed by radiotherapy significantly increased survival of mice bearing tumors over either treatment alone. Together, this work establishes a new treatment paradigm for GBM, which sensitizes radio-resistant GBM CSCs to irradiation, a critical component of patient care. Radio-sensitizing agents, including CBL0137, pose an exciting new therapeutic capable of increasing the efficacy of irradiation, by inclusively targeting CSCs.

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Hemophilia gene therapy: ushering in a new treatment paradigm?

Hematology ◽

10.1182/hematology.2021000254 ◽

2021 ◽

Vol 2021 (1) ◽

pp. 226-233

Author(s):

Lindsey A. George

Keyword(s):

Clinical Trial ◽

Gene Therapy ◽

Clinical Trials ◽

Hemophilia A ◽

Full Potential ◽

Proof Of Concept ◽

Aav Vector ◽

Treatment Paradigm ◽

Clinical Trial Enrollment ◽

New Treatment

Abstract After 3 decades of clinical trials, repeated proof-of-concept success has now been demonstrated in hemophilia A and B gene therapy. Current clinical hemophilia gene therapy efforts are largely focused on the use of systemically administered recombinant adeno-associated viral (rAAV) vectors for F8 or F9 gene addition. With multiple ongoing trials, including licensing studies in hemophilia A and B, many are cautiously optimistic that the first AAV vectors will obtain regulatory approval within approximately 1 year. While supported optimism suggests that the goal of gene therapy to alter the paradigm of hemophilia care may soon be realized, a number of outstanding questions have emerged from clinical trial that are in need of answers to harness the full potential of gene therapy for hemophilia patients. This article reviews the use of AAV vector gene addition approaches for hemophilia A and B, focusing specifically on information to review in the process of obtaining informed consent for hemophilia patients prior to clinical trial enrollment or administering a licensed AAV vector.

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Adaptive Magnetic Resonance-Guided Stereotactic Body Radiotherapy: The Next Step in the Treatment of Renal Cell Carcinoma

Frontiers in Oncology ◽

10.3389/fonc.2021.634830 ◽

2021 ◽

Vol 11 ◽

Author(s):

Brian Keller ◽

Anna M. E. Bruynzeel ◽

Chad Tang ◽

Anand Swaminath ◽

Linda Kerkmeijer ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Oncologic Outcomes ◽

Invasive Treatment ◽

Non Invasive ◽

Treatment Paradigm ◽

Plan Adaptation ◽

New Treatment ◽

Tissue Sparing

Adaptive MR-guided radiotherapy (MRgRT) is a new treatment paradigm and its role as a non-invasive treatment option for renal cell carcinoma is evolving. The early clinical experience to date shows that real-time plan adaptation based on the daily MRI anatomy can lead to improved target coverage and normal tissue sparing. Continued technological innovations will further mitigate the challenges of organ motion and enable more advanced treatment adaptation, and potentially lead to enhanced oncologic outcomes and preservation of renal function. Future applications look promising to make a positive clinical impact and further the personalization of radiotherapy in the management of renal cell carcinoma.

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Exosome-transmitted miR-769-5p confers cisplatin resistance and tumorigenesis in gastric cancer by targeting CASP9 and promoting the ubiquitination degradation of p53

10.1101/2021.09.19.461013 ◽

2021 ◽

Author(s):

Xinming Jing ◽

Mengyan Xie ◽

Kun Ding ◽

Tingting Xu ◽

Yuan Fang ◽

...

Keyword(s):

Gastric Cancer ◽

Tumor Microenvironment ◽

Cisplatin Resistance ◽

Biologically Active ◽

Clinical Prognosis ◽

Anti Cancer ◽

Ubiquitin Proteasome ◽

Proteasome Pathway ◽

New Treatment ◽

Apoptosis Related Protein

AbstractCisplatin resistance is the main cause of poor clinical prognosis in patients with gastric cancer (GC). Yet, the exact mechanism of cisplatin resistance remains unclear. Recent studies have suggested that exocrine miRNAs found in the tumor microenvironment participates in tumor metastasis and drug resistance. In this study, we discovered that cisplatin-resistant GC cells communicate with the tumor microenvironment by secreting microvesicles. The biologically active miR-769-5p can be integrated into exosomes and delivered to sensitive cells, thereby spreading cisplatin resistance. Mi769-5p was upregulated in GC tissues and enriched in the serum exosomes of cisplatin-resistant patients. Mechanistically, miR-769-5p promotes cisplatin resistance by targeting CASP9 so as to inhibit the downstream caspase pathway and promote the degradation of the apoptosis-related protein p53 through the ubiquitin-proteasome pathway. Targeting miR-769 with its antagonist to treat cisplatin-resistant GC cells can restore the cisplatin response, confirming that exosomal miR-769-5p can be a key regulator of cisplatin resistance in GC. Therefore, exosomal miR-769-5p derived from drug-resistant cells can be used as a potential therapeutic predictor of anti-tumor chemotherapy to enhance the effect of anti-cancer chemotherapy, which provides a new treatment option for GC.

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The Potential Role of Psychedelic Drugs in Mental Health Care of the Future

Pharmacopsychiatry ◽

10.1055/a-1486-7386 ◽

2021 ◽

Author(s):

Gerhard Gründer ◽

Henrik Jungaberle

Keyword(s):

Mental Health ◽

Health Care ◽

Mental Health Care ◽

Treatment Practices ◽

Psychedelic Drugs ◽

Treatment Paradigm ◽

New Treatment ◽

Definition Of ◽

The Right ◽

Psychological Integration

AbstractSerotonergic psychedelics such as psilocybin, lysergic acid diethylamide (LSD), or dimethyltryptamine (DMT), as well as psychoactive drugs that trigger phenomenologically- related experiences like 3,4-methylenedioxymethamphetamine (MDMA) and ketamine, belong to the most promising treatment approaches in contemporary psychiatry. Psychedelic-assisted psychotherapy is not only a new treatment paradigm in psychopharmacology, but it also requires a redefinition of psychotherapeutic processes and the contextualization of psychopharmacological interventions within a new treatment infrastructure. Crucial for future practice and research in the field are (1) informed patient referral and co-treatment practices, (2) screening (e. g., choosing the right patients for these therapies), (3) the dosing preparation sessions, (4) the assisted dosing sessions as well as after-care procedures such as (5) psychological integration and (6) supporting the development of structured patient communities. Definition of future treatment delivery infrastructures and requirements for therapist training are further challenges for research and practice. Finally, the implementation of psychedelic-assisted psychotherapy in routine mental health care must be embedded into public communication about the potential and risks of these innovative therapeutic approaches. This paper provides a synopsis of challenges for practitioners, researchers, and regulators to be addressed in the approval processes of psychedelics.

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Sepsis-Induced Immunosuppression

Annual Review of Physiology ◽

10.1146/annurev-physiol-061121-040214 ◽

2021 ◽

Vol 84 (1) ◽

Author(s):

Lisa K. Torres ◽

Peter Pickkers ◽

Tom van der Poll

Keyword(s):

Organ Transplant ◽

Annual Review ◽

Publication Date ◽

Predisposing Factor ◽

Substantial Impact ◽

Immunomodulatory Agents ◽

Secondary Infections ◽

Future Challenges ◽

Treatment Paradigm ◽

New Treatment

Sepsis is expected to have a substantial impact on public health and cost as its prevalence increases. Factors contributing to increased prevalence include a progressively aging population, advances in the use of immunomodulatory agents to treat a rising number of diseases, and immune-suppressing therapies in organ transplant recipients and cancer patients. It is now recognized that sepsis is associated with profound and sustained immunosuppression, which has been implicated as a predisposing factor in the increased susceptibility of patients to secondary infections and mortality. In this review, we discuss mechanisms of sepsis-induced immunosuppression and biomarkers that identify a state of impaired immunity. We also highlight immune-enhancing strategies that have been evaluated in patients with sepsis, as well as therapeutics under current investigation. Finally, we describe future challenges and the need for a new treatment paradigm, integrating predictive enrichment with patient factors that may guide the future selection of tailored immunotherapy. Expected final online publication date for the Annual Review of Physiology, Volume 84 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Cochlear Implantation for Single-Sided Deafness: A New Treatment Paradigm

Journal of Neurological Surgery Part B Skull Base ◽

10.1055/s-0038-1677482 ◽

2019 ◽

Vol 80 (02) ◽

pp. 178-186 ◽

Cited By ~ 8

Author(s):

Daniel Zeitler ◽

Michael Dorman

Keyword(s):

Quality Of Life ◽

Cochlear Implantation ◽

Pediatric Population ◽

Binaural Hearing ◽

Music Appreciation ◽

Speech Understanding In Noise ◽

Treatment Paradigm ◽

New Treatment ◽

Single Sided Deafness

AbstractUnilateral severe-to-profound sensorineural hearing loss (SNHL), also known as single sided deafness (SSD), is a problem that affects both children and adults, and can have severe and detrimental effects on multiple aspects of life including music appreciation, speech understanding in noise, speech and language acquisition, performance in the classroom and/or the workplace, and quality of life. Additionally, the loss of binaural hearing in SSD patients affects those processes that rely on two functional ears including sound localization, binaural squelch and summation, and the head shadow effect. Over the last decade, there has been increasing interest in cochlear implantation for SSD to restore binaural hearing. Early data are promising that cochlear implantation for SSD can help to restore binaural functionality, improve quality of life, and may faciliate reversal of neuroplasticity related to auditory deprivation in the pediatric population. Additionally, this new patient population has allowed researchers the opportunity to investigate the age-old question “what does a cochlear implant (CI) sound like?.”

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