scholarly journals Targeting Adaptation to Cancer Treatment by Drug Combinations

2021 ◽  
Author(s):  
Heping Wang ◽  
Augustin Luna ◽  
Gonghong Yan ◽  
Xubin Li ◽  
Ozgun Babur ◽  
...  
Keyword(s):  
Mathematical Formulation ◽  
Acquired Resistance ◽  
Drug Combinations ◽  
Therapeutic Interventions ◽  
Precision Oncology ◽  
Adaptive Responses ◽  
Drug Induced ◽  
Targeted Interventions ◽  
Activate Cell

ABSTRACTAdaptation of tumors to therapeutic interventions contributes to dismal long-term patient outcomes. Adaptation to therapy involves co-action of functionally related proteins that together activate cell survival programs and compensate for the therapeutic impact. Oncogenic dependencies to such adaptive events, however, can generate new therapeutic vulnerabilities that can be targeted with drug combinations. The precision medicine approaches in which targeted drugs are matched to pre-existing genomic aberrations fail to address the adaptive responses and resulting vulnerabilities. Here, we provide the mathematical formulation, implementation and validation of the TargetScore method. The TargetScore identifies collective adaptive responses to targeted interventions as concurrent changes of phospho-proteins that are connected within a signaling network. Based on the adaptive responses, the method predicts drug-induced vulnerabilities. Using TargetScore, we inferred the adaptive responses with short-term (i.e., days) stress and long-term (i.e., months) acquired resistance to inhibitors of anti-apoptotic mediators, MCL1 and BCL2. With experiments guided by the predictions, we identified synergistic interactions between inhibitors of PARP, SHP2, and MCL1 in breast cancer cells. TargetScore is readily applicable to existing precision oncology efforts by matching targeted drug combinations to emerging molecular signatures under therapeutic stress.

Rationale and Technique for Single and Multiple Drug Combinations in Long-term Intrathecal Infusions

Pain Practice ◽  
2001 ◽  
Vol 1 (1) ◽  
pp. 68-80 ◽  
Author(s):  
Leland Lou ◽  
Mauricio Orbegozo ◽  
Casey L. King
Keyword(s):  
Drug Combinations ◽  
Multiple Drug

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 Advancement in long-distance bird migration through individual plasticity in departure

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jesse R. Conklin ◽  
Simeon Lisovski ◽  
Phil F. Battley
Keyword(s):  
Bird Migration ◽  
Population Level ◽  
Breeding Site ◽  
Environmental Constraints ◽  
Adaptive Responses ◽  
Long Distance ◽  
Direct Observations ◽  
Breeding Resources ◽  
Plastic Responses

AbstractGlobally, bird migration is occurring earlier in the year, consistent with climate-related changes in breeding resources. Although often attributed to phenotypic plasticity, there is no clear demonstration of long-term population advancement in avian migration through individual plasticity. Using direct observations of bar-tailed godwits (Limosa lapponica) departing New Zealand on a 16,000-km journey to Alaska, we show that migration advanced by six days during 2008–2020, and that within-individual advancement was sufficient to explain this population-level change. However, in individuals tracked for the entire migration (50 total tracks of 36 individuals), earlier departure did not lead to earlier arrival or breeding in Alaska, due to prolonged stopovers in Asia. Moreover, changes in breeding-site phenology varied across Alaska, but were not reflected in within-population differences in advancement of migratory departure. We demonstrate that plastic responses can drive population-level changes in timing of long-distance migration, but also that behavioral and environmental constraints en route may yet limit adaptive responses to global change.

scholarly journals Cancer-Associated Fibroblasts as Players in Cancer Development and Progression and Their Role in Targeted Radionuclide Imaging and Therapy

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1100
Author(s):  
Sofia Koustoulidou ◽  
Mark W. H. Hoorens ◽  
Simone U. Dalm ◽  
Shweta Mahajan ◽  
Reno Debets ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Tumour Microenvironment ◽  
Therapeutic Interventions ◽  
Great Promise ◽  
Cancer Associated Fibroblasts ◽  
Functional Heterogeneity ◽  
Radioligand Therapy ◽  
Targeted Interventions ◽  
Theranostic Applications ◽  
Complex Origin

Cancer Associated Fibroblasts (CAFs) form a major component of the tumour microenvironment, they have a complex origin and execute diverse functions in tumour development and progression. As such, CAFs constitute an attractive target for novel therapeutic interventions that will aid both diagnosis and treatment of various cancers. There are, however, a few limitations in reaching successful translation of CAF targeted interventions from bench to bedside. Several approaches targeting CAFs have been investigated so far and a few CAF-targeting tracers have successfully been developed and applied. This includes tracers targeting Fibroblast Activation Protein (FAP) on CAFs. A number of FAP-targeting tracers have shown great promise in the clinic. In this review, we summarize our current knowledge of the functional heterogeneity and biology of CAFs in cancer. Moreover, we highlight the latest developments towards theranostic applications that will help tumour characterization, radioligand therapy and staging in cancers with a distinct CAF population.

scholarly journals Mitochondrial Dynamics in Drug-Induced Liver Injury

Livers ◽  
2021 ◽  
Vol 1 (3) ◽  
pp. 102-115
Author(s):  
Anup Ramachandran ◽  
David S. Umbaugh ◽  
Hartmut Jaeschke
Keyword(s):  
Liver Injury ◽  
Molecular Mechanisms ◽  
Membrane Lipids ◽  
Mitochondrial Dynamics ◽  
Adaptive Responses ◽  
Drug Induced ◽  
Biologically Relevant ◽  
Drug Induced Liver Injury ◽  
Relevant Role ◽  
Atp Generation

Mitochondria have been studied for decades from the standpoint of metabolism and ATP generation. However, in recent years mitochondrial dynamics and its influence on bioenergetics and cellular homeostasis is also being appreciated. Mitochondria undergo regular cycles of fusion and fission regulated by various cues including cellular energy requirements and pathophysiological stimuli, and the network of critical proteins and membrane lipids involved in mitochondrial dynamics is being revealed. Hepatocytes are highly metabolic cells which have abundant mitochondria suggesting a biologically relevant role for mitochondrial dynamics in hepatocyte injury and recovery. Here we review information on molecular mediators of mitochondrial dynamics and their alteration in drug-induced liver injury. Based on current information, it is evident that changes in mitochondrial fusion and fission are hallmarks of liver pathophysiology ranging from acetaminophen-induced or cholestatic liver injury to chronic liver diseases. These alterations in mitochondrial dynamics influence multiple related mitochondrial responses such as mitophagy and mitochondrial biogenesis, which are important adaptive responses facilitating liver recovery in several contexts, including drug-induced liver injury. The current focus on characterization of molecular mechanisms of mitochondrial dynamics is of immense relevance to liver pathophysiology and have the potential to provide significant insight into mechanisms of liver recovery and regeneration after injury.

scholarly journals Long-Lasting Hyperexcitability Induced by Depolarization in the Absence of Detectable Ca2+ Signals

2009 ◽  
Vol 101 (3) ◽  
pp. 1351-1360 ◽  
Author(s):  
Kumud K. Kunjilwar ◽  
Harvey M. Fishman ◽  
Dario J. Englot ◽  
Roger G. O'Neil ◽  
Edgar T. Walters
Keyword(s):  
Protein Synthesis ◽  
Neuronal Injury ◽  
Adaptive Responses ◽  
Neuronal Responses ◽  
Local Protein Synthesis ◽  
Neuronal Viability ◽  
Nerve Ganglion ◽  
Dissociated Cell Culture ◽  
Activity Dependent

Learning and memory depend on neuronal alterations induced by electrical activity. Most examples of activity-dependent plasticity, as well as adaptive responses to neuronal injury, have been linked explicitly or implicitly to induction by Ca2+ signals produced by depolarization. Indeed, transient Ca2+ signals are commonly assumed to be the only effective transducers of depolarization into adaptive neuronal responses. Nevertheless, Ca2+-independent depolarization-induced signals might also trigger plastic changes. Establishing the existence of such signals is a challenge because procedures that eliminate Ca2+ transients also impair neuronal viability and tolerance to cellular stress. We have taken advantage of nociceptive sensory neurons in the marine snail Aplysia, which exhibit unusual tolerance to extreme reduction of extracellular and intracellular free Ca2+ levels. The axons of these neurons exhibit a depolarization-induced memory-like hyperexcitability that lasts a day or longer and depends on local protein synthesis for induction. Here we show that transient localized depolarization of these axons in an excised nerve–ganglion preparation or in dissociated cell culture can induce short- and intermediate-term axonal hyperexcitability as well as long-term protein synthesis–dependent hyperexcitability under conditions in which Ca2+ entry is prevented (by bathing in nominally Ca2+ -free solutions containing EGTA) and detectable Ca2+ transients are eliminated (by adding BAPTA-AM). Disruption of Ca2+ release from intracellular stores by pretreatment with thapsigargin also failed to affect induction of axonal hyperexcitability. These findings suggest that unrecognized Ca2+-independent signals exist that can transduce intense depolarization into adaptive cellular responses during neuronal injury, prolonged high-frequency activity, or other sustained depolarizing events.

Habituation Theory and Environment-Aging Research: Ennui to Joie De Vivre?

1989 ◽  
Vol 29 (4) ◽  
pp. 241-257 ◽  
Author(s):  
Carolyn Norris-Baker ◽  
Rick J. Scheidt
Keyword(s):  
Older People ◽  
Psychological Control ◽  
Long Term Care ◽  
Aging Research ◽  
Term Care ◽  
Targeted Interventions ◽  
Situational Characteristics ◽  
The Social ◽  
The Impact

Robert Kastenbaum posits that functional aging results in the overadaptation to our own routines and expectations, producing “hyperhabituation,” mental stagnation, and novaphobic response orientations. This article examines the promise and implications of this notion for two areas of environment-aging research: psychological control and environmental comprehension. Possible causal and mediating links between control and habituation are considered, as well as the impact of habituation on environmental perception, cognition, and appraisal. Personal and situational characteristics of older people likely to be at risk for habituated responses are suggested. The article also speculates about individually- and environmentally-targeted interventions which might prevent and/or ameliorate tendencies toward hyperhabituated responses among older people who reside in highly ritualized and constant environments such as long-term care institutions. Interventions subject to future evaluations include modifications for the social, physical, and policy milieux and desensitization of novaphobic responses.

α-Oxoaldehyde metabolism and diabetic complications

2003 ◽  
Vol 31 (6) ◽  
pp. 1358-1363 ◽  
Author(s):  
P.J. Beisswenger ◽  
S.K. Howell ◽  
R.G. Nelson ◽  
M. Mauer ◽  
B.S. Szwergold
Keyword(s):  
Diabetic Complications ◽  
Complex Mixture ◽  
Therapeutic Interventions ◽  
Diabetic Patients ◽  
Human Populations ◽  
Control Mechanisms ◽  
Protective Mechanisms ◽  
Glycation End Products ◽  
End Products

The factors responsible for variable susceptibility to diabetic nephropathy are not clear. According to the non-enzymatic glycation hypothesis, diabetes-related tissue damage occurs due to a complex mixture of toxic products, including α-oxoaldehydes, which are inherently toxic as well as serving as presursors for advanced glycation end-products. Protective mechanisms exist to control this unavoidable glycation, and these are determined by genetic or environmental factors that can regulate the concentrations of the reactive sugars or end-products. In diabetes these protective mechanisms become more important, since glycation stress increases, and less efficient defence systems against this stress could lead to diabetic complications. Some of these enzymatic control mechanisms, including those that regulate α-oxoaldehydes, have been identified. We have observed significant increases in production of the α-oxoaldehydes methylglyoxal and 3-deoxyglucosone in three human populations with biopsy-proven progression of nephropathy. The increase in methylglyoxal could be secondary to defects in downstream glycolytic enzymes (such as glyceraldehyde-3-phosphate dehydrogenase) that regulate its production, or in detoxification mechanisms such as glyoxalase. Other mechanisms, however, appear to be responsible for the observed increase in 3-deoxyglucosone levels. We present results of our studies on the mechanisms responsible for variable production of α-oxoaldehydes by measuring the activity and characteristics of these enzymes in cells from complication-prone and -resistant diabetic patients. New therapeutic interventions designed to control these endogenous mechanisms could potentially enhance protection against excessive glycation and prevent or reverse complications of long-term diabetes.

Sign in / Sign up

Export Citation Format

Share Document