Structure-Based Survey of the Human Proteome for Opportunities in Proximity Pharmacology

Proximity pharmacology (ProxPharm) is a novel paradigm in drug discovery where a small molecule brings two proteins in close proximity to elicit a signal, generally from one protein onto another. The potential of ProxPharm compounds as a new therapeutic modality is firmly established by proteolysis targeting chimeras (PROTACs) that bring an E3 ubiquitin ligase in proximity to a target protein to induce ubiquitination and subsequent degradation of the target protein. The concept can be expanded to induce other post-translational modifications via the recruitment of different types of protein-modifying enzymes. To survey the human proteome for opportunities in proximity pharmacology, we systematically mapped non-catalytic drug binding pockets on the structure of protein-modifying enzymes available from the Protein Databank. In addition to binding sites exploited by previously reported ProxPharm compounds, we identified putative ligandable non-catalytic pockets in 188 kinases, 42 phosphatases, 26 deubiquitinases, 9 methyltransferases, 7 acetyltransferases, 7 glycosyltransferases, 4 deacetylases, 3 demethylases and 2 glycosidases, including cavities occupied by chemical matter that may serve as starting points for future ProxPharm compounds. This systematic survey confirms that proximity pharmacology is a versatile modality with largely unexplored and promising potential, and reveals novel opportunities to pharmacologically rewire molecular circuitries.

Exercise Cardio-Oncology: Exercise as a Potential Therapeutic Modality in the Management of Anthracycline-Induced Cardiotoxicity

Anthracyclines are one of the most effective chemotherapy agents and have revolutionized cancer therapy. However, anthracyclines can induce cardiac injuries through ‘multiple-hits', a series of cardiovascular insults coupled with lifestyle risk factors, which increase the risk of developing short- and long-term cardiac dysfunction and cardiovascular disease that potentially lead to premature mortality following cancer remission. Therefore, the management of anthracycline-induced cardiotoxicity is a serious unmet clinical need. Exercise therapy, as a non-pharmacological intervention, stimulates numerous biochemical and physiologic adaptations, including cardioprotective effects, through the cardiovascular system and cardiac muscles, where exercise has been proposed to be an effective clinical approach that can protect or reverse the cardiotoxicity from anthracyclines. Many preclinical and clinical trials demonstrate the potential impacts of exercise on cardiotoxicity; however, the underlying mechanisms as well as how to implement exercise in clinical settings to improve or protect against long-term cardiovascular disease outcomes are not clearly defined. In this review, we summarize the current evidence in the field of “exercise cardio-oncology” and emphasize the utilization of exercise to prevent and manage anthracycline-induced cardiotoxicities across high-risk and vulnerable populations diagnosed with cancer.

Antisense oligonucleotide-based therapeutic strategy for progranulin-deficient frontotemporal dementia

Loss-of-function GRN mutations result in progranulin haploinsufficiency and are a common cause of frontotemporal dementia (FTD). Antisense oligonucleotides (ASOs) are emerging as a promising therapeutic modality for neurological diseases, but ASO-based strategies for increasing target protein levels are still relatively limited. Here, we report the use of ASOs to increase progranulin protein levels by targeting the miR-29b binding site in the 3′ UTR of the GRN mRNA, resulting in increased translation.

Superdominant Right Coronary Artery with Absent Left Coronary Artery and Left Circumflex Artery with Anomalous Left Anterior Descending Artery

The occurrence of super-dominant “single coronary artery” is an extremely rare and seldom reported phenomenon. The heart is dependent on a single vessel which makes its occlusion, if present, catastrophic. Here, the authors present an extremely rare combination of superdominant right coronary artery coexisting with absent left coronary artery and left circumflex artery with abnormal origin of left anterior descending artery from right coronary sinus. Precise morphological and physiological knowledge and evaluation of these anomalies is a must for opting the best available therapeutic modality and better prognosis.

Blood Pressure Regulation by the Carotid Sinus Nerve: Clinical Implications for Carotid Body Neuromodulation

Chronic carotid sinus nerve (CSN) electrical modulation through kilohertz frequency alternating current improves metabolic control in rat models of type 2 diabetes, underpinning the potential of bioelectronic modulation of the CSN as a therapeutic modality for metabolic diseases in humans. The CSN carries sensory information from the carotid bodies, peripheral chemoreceptor organs that respond to changes in blood biochemical modifications such as hypoxia, hypercapnia, acidosis, and hyperinsulinemia. In addition, the CSN also delivers information from carotid sinus baroreceptors—mechanoreceptor sensory neurons directly involved in the control of blood pressure—to the central nervous system. The interaction between these powerful reflex systems—chemoreflex and baroreflex—whose sensory receptors are in anatomical proximity, may be regarded as a drawback to the development of selective bioelectronic tools to modulate the CSN. Herein we aimed to disclose CSN influence on cardiovascular regulation, particularly under hypoxic conditions, and we tested the hypothesis that neuromodulation of the CSN, either by electrical stimuli or surgical means, does not significantly impact blood pressure. Experiments were performed in Wistar rats aged 10–12 weeks. No significant effects of acute hypoxia were observed in systolic or diastolic blood pressure or heart rate although there was a significant activation of the cardiac sympathetic nervous system. We conclude that chemoreceptor activation by hypoxia leads to an expected increase in sympathetic activity accompanied by compensatory regional mechanisms that assure blood flow to regional beds and maintenance of hemodynamic homeostasis. Upon surgical denervation or electrical block of the CSN, the increase in cardiac sympathetic nervous system activity in response to hypoxia was lost, and there were no significant changes in blood pressure in comparison to control animals. We conclude that the responses to hypoxia and vasomotor control short-term regulation of blood pressure are dissociated in terms of hypoxic response but integrated to generate an effector response to a given change in arterial pressure.

Hyperthermia: A Potential Game-Changer in the Management of Cancers in Low-Middle-Income Group Countries

Loco-regional hyperthermia at 40–44 °C is a multifaceted therapeutic modality with the distinct triple advantage of being a potent radiosensitizer, a chemosensitizer and an immunomodulator. Risk difference estimates from pairwise meta-analysis have shown that the local tumour control could be improved by 22.3% (p < 0.001), 22.1% (p < 0.001) and 25.5% (p < 0.001) in recurrent breast cancers, locally advanced cervix cancer (LACC) and locally advanced head and neck cancers, respectively by adding hyperthermia to radiotherapy over radiotherapy alone. Furthermore, thermochemoradiotherapy in LACC have shown to reduce the local failure rates by 10.1% (p = 0.03) and decrease deaths by 5.6% (95% CI: 0.6–11.8%) over chemoradiotherapy alone. As around one-third of the cancer cases in low-middle-income group countries belong to breast, cervix and head and neck regions, hyperthermia could be a potential game-changer and expected to augment the clinical outcomes of these patients in conjunction with radiotherapy and/or chemotherapy. Further, hyperthermia could also be a cost-effective therapeutic modality as the capital costs for setting up a hyperthermia facility is relatively low. Thus, the positive outcomes evident from various phase III randomized trials and meta-analysis with thermoradiotherapy or thermochemoradiotherapy justifies the integration of hyperthermia in the therapeutic armamentarium of clinical management of cancer, especially in low-middle-income group countries.

Innate immune responses in patients treated with SBRT irradiation enhances prostate cancer remissions

Stereotactic body radiation therapy (SBRT) is a curative therapeutic modality employing large fractional doses of highly conformal radiation therapy for cancer treatment. To understand the mechanisms underlying clinical responses to radiation therapy, SBRT offers a unique window for high-throughput analysis of post-radiation molecular events to inform predictive biomarker discovery and strategies for multi-disciplinary therapeutics. We performed a longitudinal analysis of plasma proteins and metabolites from patients treated with prostate SBRT, comparing cohorts of patients in clinical remission to cohorts experiencing PSA-determined cancer progression. We observed the onset of post-SBRT DNA Damage Response (DDR), cell cycle arrest, and immune response signaling in patients within one hour of treatment and innate immune response signaling that persisted for up to three months following treatment. Furthermore, patients in remission experienced more robust immune responses and metabolite elevations consistent with a pro-inflammatory, M1-mediated innate immune activation in the short-term following SBRT, whereas patients with disease progression had less robust immune responses and M2-mediated metabolite elevations. We interpret these data to support a critical role for innate immune activation in the clinical outcomes of patients receiving radiation therapy for prostate cancer potentially improving future multidisciplinary therapeutic strategies.

O cão como coterapeuta e os cuidados para a sua atuação em ambiente hospitalar

Este estudo teve por objetivo abordar a cinoterapia como modalidade terapêutica capaz de promover uma maior humanização do atendimento ao doente, atuando como ferramenta efetiva no tratamento do assistido, dando ênfase aos cuidados necessários para o emprego do cão no ambiente hospitalar. A humanização da saúde, hoje já bem discutida, apoia iniciativas que visem à transformação do ambiente hospitalar. Acredita-se que, através de pequenas ações, podemos amenizar a dor de muitos, contribuir para o sucesso dos tratamentos e para a diminuição do tempo de hospitalização. A Cinoterapia, apoiada por uma equipe multidisciplinar, tem assistido crianças e adultos hospitalizados por diferentes patologias, pacientes cardíacos, psiquiátricos, portadores de Alzheimer, Parkinson, AIDS, paralisia cerebral, acidente vascular cerebral, câncer entre outras. Mesmo diante da tendência mundial e do reconhecimento da importância da terapia, a implantação de projetos ainda tem sido dificultada pela carência de estudos que demonstrem o impacto do cão no ambiente hospitalar. O desconhecimento dos riscos inerentes à terapia, principalmente no que diz respeito à transmissão de doenças, assim como a falta de protocolos com normas específicas para a sua implantação, são alguns dos entraves para uma maior disseminação da técnica. The aim of this study was to approach Pet therapy as a therapeutic modality capable of promoting a greater humanization of patient care, acting as an effective tool in the treatment of the assisted, emphasizing the necessary care for the use of the dog in the hospital environment. The humanization of health, now well discussed, supports initiatives aimed at transforming the hospital environment. It is believed that, through small actions, we can ease the pain of many, contribute to the success of the treatments and decrease the length of hospitalization. Pet therapy, supported by a multidisciplinary team, has assisted children and adults hospitalized for different pathologies, cardiac patients, psychiatric patients with Alzheimer's, Parkinson's, AIDS, cerebral palsy, stroke, cancer, among others. Even in the face of the worldwide trend and recognition of the importance of therapy, the implementation of projects has still been hampered by the lack of studies that demonstrate the impact of the dog in the hospital environment. The lack of knowledge about the risks inherent to the therapy, especially regarding the transmission of diseases, as well as the lack of protocols with specific norms for its implantation, are some of the obstacles for a greater dissemination of the technique.

Reliability of Alkaline Phosphatase for Differentiating Flare Phenomenon from Disease Progression with Bone Scintigraphy

The flare phenomenon (FP) on bone scintigraphy after the initiation of systemic treatment seriously complicates evaluations of therapeutic response in patients with bone metastases. The aim of this study was to evaluate whether serum alkaline phosphatase (ALP) can differentiate FP from disease progression on bone scintigraphy in these patients. Breast or prostate cancer patients with bone metastases who newly underwent systemic therapy were reviewed. Pretreatment baseline and follow-up data, including age, pathologic factors, type of systemic therapy, radiologic and bone scintigraphy findings, and ALP levels, were obtained. Univariate and multivariate analyses of these factors were performed to predict FP. An increased extent and/or new lesions were found in 160 patients on follow-up bone scintigraphy after therapy. Among the 160 patients, 80 (50%) had an improvement on subsequent bone scintigraphy (BS), while subsequent scintigraphy also showed an increased uptake in 80 (50%, progression). Multiple regression analysis revealed that stable or decreased ALP was an independent predictor for FP (p < 0.0001). ALP was an independent predictor for FP on subgroup analysis for breast and prostate cancer (p = 0.001 and p = 0.0223, respectively). Results of the study suggest that ALP is a useful serologic marker to differentiate FP from disease progression on bone scintigraphy in patients with bone metastasis. Clinical interpretation for scintigraphic aggravation can be further improved by the ALP data and it may prevent fruitless changes of therapeutic modality by misdiagnosis of disease progression in cases of FP.

Nanomedicine-enabled chemotherapy-based synergetic cancer treatments

Chemotherapy remains one of the most prevailing regimens hitherto in the fight against cancer, but its development has been being suffering from various fatal side effects associated with the non-specific toxicity of common chemical drugs. Advances in biomedical application of nanomedicine have been providing alternative but promising approaches for cancer therapy, by leveraging its excellent intrinsic physicochemical properties to address these critical concerns. In particular, nanomedicine-enabled chemotherapy has been established as a safer and promising therapeutic modality, especially the recently proposed nanocatalytic medicine featuring the capabilities to generate toxic substances by initiating diverse catalytic reactions within the tumor without directly relying on highly toxic but non-selective chemotherapeutic agents. Of special note, under exogenous/endogenous stimulations, nanomedicine can serve as a versatile platform that allows additional therapeutic modalities (photothermal therapy (PTT), photodynamic therapy (PDT), chemodynamic therapy (CDT), etc.) to be seamlessly integrated with chemotherapy for efficacious synergistic treatments of tumors. Here, we comprehensively review and summarize the representative studies of multimodal synergistic cancer treatments derived from nanomedicine and nanocatalytic medicine-enabled chemotherapy in recent years, and their underlying mechanisms are also presented in detail. A number of existing challenges and further perspectives for nanomedicine-synergized chemotherapy for malignant solid tumor treatments are also highlighted for understanding this booming research area as comprehensively as possible. Graphical Abstract