The Heterogeneity Metabolism of Renal Cell Carcinomas.

According to data from the American Cancer Society, cancer is one of the deadliest health problems globally. Annually, renal cell carcinoma (RCC) causes more than 100,000 deaths worldwide [1-4], posing an urgent need to develop effective treatments to increase patient survival outcomes. New therapies are expected to address a major factor contributing to cancer's resistance to standard therapies: oncogenic heterogeneity. Gene expression can vary tremendously among different types of cancers, different patients of the same tumor type, and even within individual tumors; various metabolic phenotypes can emerge, making singletherapy approaches insufficient. Novel strategies targeting the diverse metabolism of cancers aim to overcome this obstacle. Though some have yielded positive results, it remains a challenge to uncover all of the distinct metabolic profiles of RCC. In the quest to overcome this obstacle, the metabolic oriented research focusing on these cancers has offered freshly new perspectives, which are expected to contribute heavily to the development of new treatments.

Long wavelength light exposure reduces systemic inflammation coagulopathy, and acute organ injury following polytrauma in mice.

BACKGROUND: Evidence suggests that variation in light exposure strongly influences the dynamic of inflammation, coagulation, and the immune system. Polytrauma induces systemic inflammation that can lead to end-organ injury. Here, we hypothesize that alterations in light exposure influence post-trauma inflammation, coagulopathy, and end-organ injury. METHODS: Study Type: Original Research Article. Level of Evidence: Basic Science (Level IV).C57BL/6 mice underwent a validated polytrauma and hemorrhage model performed following 72 hours of exposure to red (617 nm, 1,700lux), blue (321 nm, 1,700lux), and fluorescent white light (300lux) (n = 6-8/group). The animals were sacrificed at 6 h post-trauma. Plasma samples were evaluated and compared for pro-inflammatory cytokine expression levels, coagulation parameters, markers of liver and renal injury, and histological changes (Carstairs staining). One-way ANOVA statistical tests were applied to compare study groups. RESULTS: Pre-exposure to long-wavelength red light significantly reduced the inflammatory response at 6 hours post-polytrauma compared to blue and ambient light, as evidenced by decreased levels of IL-6, MCP-1 (both p < 0.001), liver injury markers (ALT, p < 0.05), and kidney injury markers (cystatin C, p < 0.01). Additionally, Carstairs staining of organ tissues revealed milder histological changes in the red light-exposed group, indicating reduced end-organ damage. Furthermore, PT was significantly lower (p < 0.001) and fibrinogen levels were better maintained (p < 0.01) in the red light-exposed mice compared to those exposed to blue and ambient light. CONCLUSION: Prophylactic light exposure can be optimized to reduce systemic inflammation, coagulopathy and minimize acute organ injury following polytrauma. Understanding the mechanisms by which light exposure attenuates inflammation may provide a novel strategy to reducing trauma related morbidity.

Evaluation of the pharmacokinetics, dosimetry, and therapeutic efficacy for the α-particle-emitting transarterial radioembolization (αTARE) agent [225Ac]Ac-DOTA-TDA-Lipiodol® against hepatic tumors.

BACKGROUND: The liver is a common site for metastatic disease for a variety of cancers, including colorectal cancer. Both primary and secondary liver tumors are supplied through the hepatic artery while the healthy liver is supplied by the portal vein. Transarterial radioembolization (TARE) using yttrium-90 glass or resin microspheres have shown promising results with reduced side-effects but have similar survival benefits as chemoembolization in patients with hepatocellular carcinoma (HCC). This highlights the need for new novel agents against HCC. Targeted alpha therapy (TAT) is highly potent treatment due to the short range (sparing adjacent normal tissue), and densely ionizing track (high linear energy transfer) of the emitted α-particles. The incorporation of α-particle-emitting radioisotopes into treatment of HCC has been extremely limited, with our recent publication pioneering the field of α-particle-emitting TARE (αTARE). This study focuses on an in-depth evaluation of the αTARE-agent [225Ac]Ac-DOTA-TDA-Lipiodol® as an effective therapeutic agent against HCC regarding pharmacokinetics, dosimetry, stability, and therapeutic efficacy. RESULTS: [225Ac]Ac-DOTA-TDA was shown to be a highly stable with bench-top stability at ≥ 95% radiochemical purity (RCP) over a 3-day period and serum stability was ≥ 90% RCP over 5-days. The pharmacokinetic data showed retention in the tumor of [225Ac]Ac-DOTA-TDA-Lipiodol® and clearance through the normal organs. In addition, the tumor and liver acted as suppliers of the free daughters, which accumulated in the kidneys supplied via the blood. The dose limiting organ was the liver, and the estimated maximum tolerable activity based on the rodents whole-body weight: 728-3641 Bq/g (male rat), 396-1982 Bq/g (male mouse), and 453-2263 Bq/g (female mouse), depending on an RBE-value (range 1-5). Furthermore, [225Ac]Ac-DOTA-TDA-Lipiodol® showed significant improvement in survival for both the male and female mice (median survival 47-days) compared with controls (26-days untreated, and 33-35-days Lipiodol® alone). CONCLUSIONS: This study shows that [225Ac]Ac-DOTA-TDA-Lipiodol® is a stable compound allowing for centralized manufacturing and distribution world-wide. Furthermore, the result of this study support the continue development of evaluation of the αTARE-agent [225Ac]Ac-DOTA-TDA-Lipiodol® as a potential treatment option for treating hepatic tumors.

Double right coronary artery diagnosed by computed tomographic angiography: A case report and systematic review of the literature.

Double right coronary artery (RCA) is an extremely uncommon anomaly that is mostly detected incidentally in patients undergoing coronary angiography. It can be a benign and isolated anomaly or associated with other congenital abnormalities, mostly other coronary anomalies. Although atherosclerosis and myocardial ischemia have been frequently reported in patients with double RCA, this likely reflects that the patients were evaluated for chest pain rather than the predisposition to atherosclerosis in double RCA. Paralleling the increased awareness of this entity and the availability of non-invasive and cost-effective imaging of the coronary arteries, the diagnosis of double RCA has increased recently. Here, we present a case of double RCA diagnosed by coronary computed tomographic angiography, and provide a mini-review on the demography, anatomic variants, and clinical significance of double RCA.

Systematic Review and Pharmacokinetic Meta-analysis of Doxorubicin Exposure in Transcatheter Arterial Chemoembolization and Doxorubicin-Eluted Beads Chemoembolization for Treatment of Unresectable Hepatocellular Carcinoma.

BACKGROUND: Almost 15 years after the introduction of transarterial chemoembolization (TACE) with drug-eluting beads (DEB-TACE) for hepatocellular carcinoma (HCC) therapy, the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) for doxorubicin have still not been systematically reviewed or meta-analyzed. OBJECTIVE: To conduct a systematic review and meta-analysis of available data and establish a reference range for Cmax and AUC of doxorubicin DEB-TACE and TACE, as well as explore the potential influence of microspheres' size and type on these parameters. METHODS: PubMed, EMBASE, and Web of Science were searched from August 1992 through December 2021. Studies measuring exposure parameters among HCC patients treated with doxorubicin DEB-TACE without restriction on language were included. Two independent reviewers extracted and unified data sets for pooled estimate analysis. The quality of the evidence was assessed via the Grading of Recommendations Assessment, Development and Evaluation framework. The ClinPK Statement checklist and Newcastle-Ottawa Scale (NOS) were used to determine the quality of studies. RESULTS: Out of 666 studies, 246 full-text were reviewed, and 8 studies entered the meta-analysis (120 patients). Cmax and AUC of doxorubicin were 7.52-fold (95% CI 7.65 to 7.42-fold; P < 0.0001) and 1.91-fold (95% CI 1.95 to 1.88-fold; P = 0.0001) lower with DEB-TACE compared to TACE. Significant reduction in pooled standardized mean difference (SMD) of Cmax and AUC was observed with DEB-TACE versus TACE in direct comparison analysis (- 2.93; 95% CI - 3.60 to - 2.26, P < 0.00001, and - 1.73 95% CI - 2.55 to - 0.91, P < 0.0001, respectively). Moreover, in DEB-TACE stratification analysis, small microspheres revealed higher Cmax, AUC and tumor response rate as well as lower complication rate. LIMITATION: The heterogeneity could not be completely addressed through sensitivity and stratification analysis. CONCLUSION: This meta-analysis provides exposure parameters of doxorubicin and justifies the advantage of DEB-TACE over TACE in terms of safety for patients with unresectable HCC. This study showed a marked association between the size of microsphere and exposure parameters of doxorubicin supporting the preference for small microspheres in DEB-TACE. The moderate and low quality of evidence is assigned to the Cmax and AUC, respectively.

Preliminary evaluation of alpha-emitting radioembolization in animal models of hepatocellular carcinoma.

Hepatocellular carcinoma is the most common primary liver cancer and the fifth most frequently diagnosed cancer worldwide. Most patients with advanced disease are offered non-surgical palliative treatment options. This work explores the first alpha-particle emitting radioembolization for the treatment and monitoring of hepatic tumors. Furthermore, this works demonstrates the first in vivo simultaneous multiple-radionuclide SPECT-images of the complex decay chain of an [225Ac]Ac-labeled agent using a clinical SPECT system to monitor the temporal distribution. A DOTA chelator was modified with a lipophilic moiety and radiolabeled with the α-particle emitter Actinium-225. The resulting agent, [225Ac]Ac-DOTA-TDA, was emulsified in ethiodized oil and evaluated in vivo in mouse model and the VX2 rabbit technical model of liver cancer. SPECT imaging was performed to monitor distribution of the TAT agent and the free daughters. The [225Ac]Ac-DOTA-TDA emulsion was shown to retain within the HEP2G tumors and VX2 tumor, with minimal uptake within normal tissue. In the mouse model, significant improvements in overall survival were observed. SPECT-imaging was able to distinguish between the Actinium-225 agent (Francium-221) and the loss of the longer lived daughter, Bismuth-213. An α-particle emitting TARE agent is capable of targeting liver tumors with minimal accumulation in normal tissue, providing a potential therapeutic agent for the treatment of hepatocellular carcinoma as well as a variety of hepatic tumors. In addition, SPECT-imaging presented here supports the further development of imaging methodology and protocols that can be incorporated into the clinic to monitor Actinium-225-labeled agents.

Whole body hypothermia extends tissue plasminogen activator treatment window in the rat model of embolic stroke.

Late treatment with tissue plasminogen activator (tPA) leads to reperfusion injury and poor outcome in ischemic stroke. We have recently shown the beneficial effects of local brain hypothermia after late thrombolysis. Herein, we investigated whether transient whole-body hypothermia was neuroprotective and could prevent the side effects of late tPA therapy at 5.5 h after embolic stroke. After induction of stroke, male rats were randomly assigned into four groups: Control, Hypothermia, tPA and Hypothermia+tPA. Hypothermia started at 5 h after embolic stroke and continued for 1 h. Thirty min after hypothermia, tPA was administrated. Infarct volume, brain edema, blood-brain barrier (BBB) and matrix metalloproteinase-9 (MMP-9) were assessed 48 h and neurological functions were assessed 24 and 48 hour post-stroke. Compared with the control or tPA groups, whole-body hypothermia decreased infarct volume (P < 0.01), BBB disruption (P < 0.05) and MMP-9 level (P < 0.05). However, compared with hypothermia alone a combination of hypothermia and tPA was more effective in reducing infarct volume. While hypothermia alone did not show any effect, its combination with tPA reduced brain edema (P < 0.05). Hypothermia alone or when combined with tPA decreased MMP-9 compared with control or tPA groups (P < 0.01). Although delayed tPA therapy exacerbated BBB integrity, general cooling hampered its leakage after late thrombolysis (P < 0.05). Moreover, only combination therapy significantly improved sensorimotor function as well as forelimb muscle strength at 24 or 48 h after stroke (P < 0.01). Transient whole-body hypothermia in combination with delayed thrombolysis therapy shows more neuroprotection and extends therapeutic time window of tPA up to 5.5 h.

Transient brain hypothermia reduces the reperfusion injury of delayed tissue plasminogen activator and extends its therapeutic time window in a focal embolic stroke model.

It has been reported that restriction of reperfusion after thrombolytic therapy in ischemic stroke may reduce tissue plasminogen activator (tPA) adverse effects and extend its time window. We examined whether shortIt has been reported that restriction of reperfusion after thrombolytic therapy in ischemic stroke may reduce tissue plasminogen activator (tPA) adverse effects and extend its time window. We examined whether short-term and mild local brain cooling can prevent hyperemia and/or adverse effects of delayed tPA in rat embolic stroke model. Male animals were subjected to embolic stroke and then randomly classified into control (saline), tPA (1mg/kg; i.v.), local hypothermia (LH), and tPA+LH. The drug was injected at 6 h after ischemia. LH was conducted by direct ipsilateral (injured) hemisphere cooling at 6.5h after stroke and maintained for approximately 30min. Cerebral blood flow was monitored in duration of 60 minute after tPA administration and hyperemic response was measured. Infarct volume, blood-brain barrier (BBB) disruption, edema formation, neurological deficits, and matrix metalloproteinase-9 (MMP-9) level were measured 48 h later. A combination of tPA+LH significantly diminished infarct volume in comparison with the tPA (P< 0.001) and control (P<0.05) groups. Combination therapy also decreased BBB leakage (P<0.001), MMP-9 level or edema (P<0.05) and improved neurological functions at 24 and 48h after stroke. LH caused a gradual decrease in hyperemic response after thrombolysis compared to the control (P<0.05) or tPA (P<0.001) groups. LH alone also reduced infarct volume, BBB leakage or edema (P<0.05). The short-term local brain hypothermia may mitigate reperfusion injury following delayed tPA therapy and extend its time window up to 6h.

Regulatory effects of chronic low-dose morphine on nitric oxide level along with baroreflex sensitivity in two-kidney one-clip hypertensive rats.

INTRODUCTION: Opiates are traditionally used for treatment of some acute heart disorders. There are only few reports on the effects of long-term treatment of cardiovascular diseases with morphine. This study aimed to investigate the effects of chronic low-dose morphine use on the cardiovascular system in two-kidney one-clip (2K1C) hypertensive rats. MATERIALS AND METHODS: Male Wistar rats were divided into two groups as the sham and 2K1C groups and each group was further subdivided into saline and morphine treatment subgroups. Blood pressure, heart rate, plasma rennin activity, serum nitric oxide concentration, and baroreflex sensitivity were measured. RESULTS: Morphine significantly attenuated systolic blood pressure, diastolic blood pressure, and mean arterial pressure in the 2K1C animals. In addition, morphine decreased plasma rennin activity in the 2K1C group. Serum concentrations of nitric oxide were also decreased, and morphine prevented the reduction of nitric oxide. The baroreflex sensitivity was also improved following morphine administration in the 2K1C group. CONCLUSIONS: According to the results presented in this study, chronic administration of low-dose morphine reduces regulated hypertension in the 2K1C rats, probably via a nitric oxide-dependent pathway.

Delayed combination therapy of local brain hypothermia and decompressive craniectomy on acute stroke outcome in rat.

OBJECTIVES: Hypothermia and decompressive craniectomy (DC) have been shown to be neuroprotective. This study was designed to evaluate neuroprotective effects of delayed singular or combination of DC and local hypothermia on stroke. MATERIALS AND METHODS: Cerebral ischemia was induced in 48 Wistar rats assigned to 4 groups: control, decompressive craniectomy (DC), local hypothermia (LH), combination of hypothermia and craniectomy (HC). Infarct size and BBB disruption were measured 48 hr after ischemia insult. Neurological deficits were assessed at 24 and 48 hr after stroke by using sticky tape test, hanging-wire test and Bederson's scoring system. BBB disruption was measured by Evans blue dye leakage. RESULTS: Although infarct size was significantly reduced in LH, DC and HC groups (P<0.001), combination therapy was more neuroprotective compared to craniectomy alone (P<0.01). BBB disruption was significantly reduced in DC (P< 0.05) and LH and HC (P< 0.01).While sticky tape test (P<0.05 at 24 hr; P<0.001 at 48 hr) and hanging-wire test (P<0.05) showed better behavioral performance only in HC, Bederson test showed improved behavioral functions of both LH (P<0.05 at 24 hr and P<0.01 at 48 hr) and HC animals (P<0.01). Neurological deficits were also decreased in LH (P<0.05) or HC (P<0.05 at 24 hr; P<0.01 at 48 hr) groups compared to the DC group at the same time. CONCLUSION: Based on our data, although both delayed local hypothermia and craniectomy are protective after stoke, combination therapy of them is more neuroprotective than given alone.