Technological advancements in cancer diagnostics: Improvements and limitations.

BACKGROUND: Cancer is characterized by the rampant proliferation, growth, and infiltration of malignantly transformed cancer cells past their normal boundaries into adjacent tissues. It is the leading cause of death worldwide, responsible for approximately 19.3 million new diagnoses and 10 million deaths globally in 2020. In the United States alone, the estimated number of new diagnoses and deaths is 1.9 million and 609 360, respectively. Implementation of currently existing cancer diagnostic techniques such as positron emission tomography (PET), X-ray computed tomography (CT), and magnetic resonance spectroscopy (MRS), and molecular diagnostic techniques, have enabled early detection rates and are instrumental not only for the therapeutic management of cancer patients, but also for early detection of the cancer itself. The effectiveness of these cancer screening programs are heavily dependent on the rate of accurate precursor lesion identification; an increased rate of identification allows for earlier onset treatment, thus decreasing the incidence of invasive cancer in the long-term, and improving the overall prognosis. Although these diagnostic techniques are advantageous due to lack of invasiveness and easier accessibility within the clinical setting, several limitations such as optimal target definition, high signal to background ratio and associated artifacts hinder the accurate diagnosis of specific types of deep-seated tumors, besides associated high cost. In this review we discuss various imaging, molecular, and low-cost diagnostic tools and related technological advancements, to provide a better understanding of cancer diagnostics, unraveling new opportunities for effective management of cancer, particularly in low- and middle-income countries (LMICs). RECENT FINDINGS: Herein we discuss various technological advancements that are being utilized to construct an assortment of new diagnostic techniques that incorporate hardware, image reconstruction software, imaging devices, biomarkers, and even artificial intelligence algorithms, thereby providing a reliable diagnosis and analysis of the tumor. Also, we provide a brief account of alternative low cost-effective cancer therapy devices (CryoPop®, LumaGEM®, MarginProbe®) and picture archiving and communication systems (PACS), emphasizing the need for multi-disciplinary collaboration among radiologists, pathologists, and other involved specialties for improving cancer diagnostics. CONCLUSION: Revolutionary technological advancements in cancer imaging and molecular biology techniques are indispensable for the accurate diagnosis and prognosis of cancer.

2-deoxy-D-glucose mitigates Citrobacter rodentium and dibenzazepine-induced gastrointestinal damage and colitis: novel implications of 2-DG polypharmacopea.

PURPOSE: Citrobacter rodentium (CR) infection coupled with blocking Notch/Wnt signaling via γ-secretase inhibitor dibenzazepine (DBZ) disrupts the gastro-intestinal (GI) barrier and induces colitis, akin to ionizing radiation (IR)-induced GI-injury. We investigated the effects of 2-deoxy-D-glucose (2-DG) to ameliorate the CR-DBZ-induced GI damage. MATERIALS AND METHODS: NIH:Swiss outbred mice were inoculated with 109CFUs of CR orally. DBZ was administered intraperitoneally (10 µM/kg b.wt; for 10 days 2 days post-CR infection). Mice were fed with 0.4% 2-DG (w/v) daily in drinking water. For microbiota depletion, antibiotics (Abx), 1 g/l metronidazole, and 0.2 g/l ciprofloxacin were administered for 10 days in drinking water. Oxidative stress, survival assay, colonic crypt hyperplasia, Notch/Wnt downstream signaling, immunomodulation, and bacterial dysbiosis were measured. RESULTS: We show that real-time visualization of reactive oxygen species (ROS) is similar during CR-induced colonic infection and IR-induced GI-damage. The histology revealed that dietary 2-DG mitigates CR + DBZ-induced colitis and improves survival compared with CR + DBZ alone. These changes were phenocopied in Abx-treated mice. Both 2-DG and Abx reduced dysbiosis, increased proliferation, inhibited pro-inflammatory response, and restored Hes-1 and ß-catenin protein levels, in the crypts. CONCLUSION: The energy disruptor 2-DG mitigates bacterial infection and its responsive hyperplasia/colitis, indicating its utility as a mitigator of infection/IR-induced GI-damage.

Intracranial Hemorrhage in Term and Late-Preterm Neonates: An Institutional Perspective.

BACKGROUND AND PURPOSE: Distribution of intracranial hemorrhage in term and late-preterm neonates is relatively unexplored. This descriptive study examines the MR imaging-detectable spectrum of intracranial hemorrhage in this population and potential risk factors. MATERIALS AND METHODS: Prevalence and distribution of intracranial hemorrhage in consecutive term/late-preterm neonates who underwent brain MR imaging between January 2011 to August 2018 were assessed. MRIs were analyzed to determine intracranial hemorrhage distribution (intraventricular, subarachnoid, subdural, intraparenchymal, and subpial/leptomeningeal), and chart review was performed for potential clinical risk factors. RESULTS: Of 725 term/late-preterm neonates who underwent brain MR imaging, intracranial hemorrhage occurred in 63 (9%). Fifty-two (83%) had multicompartment intracranial hemorrhage. Intraventricular and subdural were the most common hemorrhage locations, found in 41 (65%) and 39 (62%) neonates, respectively. Intraparenchymal hemorrhage occurred in 33 (52%); subpial, in 19 (30%); subarachnoid, in 12 (19%); and epidural, in 2 (3%) neonates. Twenty infants (32%) were delivered via cesarean delivery, and 5 (8%), via instrumented delivery. Cortical vein thromboses were present in 34 (54%); periventricular or medullary vein thromboses, in 37 (59%); and cerebral venous sinus thrombosis, in 5 (8%). Thirty-seven (59%) had elevated markers of coagulopathy (international normalized ratio > 1.2, fibrinogen level < 234), 9 (14%) had a clinically meaningful elevation in the international normalized ratio (>1.4), and 3 (5%) had a clinically meaningful decrease in the fibrinogen level (<150). Three (5%) neonates had thrombocytopenia (platelet count < 100 × 103/µL). CONCLUSIONS: While relatively infrequent, there was a wide distribution of intracranial hemorrhage in term and late-preterm infants; intraventricular and subdural hemorrhages were the most common types. We report a high prevalence of venous congestion or thromboses accompanying neonatal intracranial hemorrhage.

Technological Advancements in External Beam Radiation Therapy (EBRT): An Indispensable Tool for Cancer Treatment.

Recent technological advancements have increased the efficacy of radiotherapy, leading to effective management of cancer patients with enhanced patient survival and improved quality of life. Several important developments like multileaf collimator, integration of imaging techniques like positron emission tomography (PET) and computed tomography (CT), involvement of advanced dose calculation algorithms, and delivery techniques have increased tumor dose distribution and decreased normal tissue toxicity. Three-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), stereotactic radiotherapy, image-guided radiotherapy (IGT), and particle therapy have facilitated the planning procedures, accurate tumor delineation, and dose estimation for effective personalized treatment. In this review, we present the technological advancements in various types of EBRT methods and discuss their clinical utility and associated limitations. We also reveal novel approaches of using biocompatible yttrium oxide scintillator-photosensitizer complex (YSM) that can generate X-ray induced cytotoxic reactive oxygen species, facilitating X-ray activated photodynamic therapy (XPDT (external beam) and/or iXPDT (internal X-ray source)) and azido-derivatives of 2-deoxy-D-glucose (2-DG) as agents for site-specific radiation-induced DNA damage.

A combinatorial approach of a polypharmacological adjuvant 2-deoxy-D-glucose with low dose radiation therapy to quell the cytokine storm in COVID-19 management.

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a pandemic disease and is the major cause of deaths worldwide. The clinical complexities (inflammation, cytokine storm, and multi-organ dysfunction) associated with COVID-19 poses constraints to effective management of critically ill COVID-19 patients. Low dose radiation therapy (LDRT) has been evaluated as a potential therapeutic modality for COVID-19 pneumonia. However, due to heterogeneity in disease manifestation and inter-individual variations, effective planning for LDRT is limited for this large-scale event. 2-deoxy-D-glucose (2-DG) has emerged as a polypharmacological agent for COVID-19 treatment due to its effects on the glycolytic pathway, anti-inflammatory action, and interaction with viral proteins. We suggest that 2-DG will be a potential adjuvant to enhance the efficacy of LDRT in the treatment of COVID-19 pneumonia. Withal, azido analog of 2-DG, 2-azido-2-DG can produce rapid catastrophic oxidative stress and quell the cytokine storm in critically ill COVID-19 patients.

The tubercular badger and the uncertain curve:- The need for a multiple stressor approach in environmental radiation protection.

This article presents the results of a workshop held in Stirling, Scotland in June 2018, called to examine critically the effects of low-dose ionising radiation on the ecosphere. The meeting brought together participants from the fields of low- and high-dose radiobiology and those working in radioecology to discuss the effects that low doses of radiation have on non-human biota. In particular, the shape of the low-dose response relationship and the extent to which the effects of low-dose and chronic exposure may be predicted from high dose rate exposures were discussed. It was concluded that high dose effects were not predictive of low dose effects. It followed that the tools presently available were deemed insufficient to reliably predict risk of low dose exposures in ecosystems. The workshop participants agreed on three major recommendations for a path forward. First, as treating radiation as a single or unique stressor was considered insufficient, the development of a multidisciplinary approach is suggested to address key concerns about multiple stressors in the ecosphere. Second, agreed definitions are needed to deal with the multiplicity of factors determining outcome to low dose exposures as a term can have different meanings in different disciplines. Third, appropriate tools need to be developed to deal with the different time, space and organisation level scales. These recommendations permit a more accurate picture of prospective risks.

Vedolizumab in patients with concurrent primary sclerosing cholangitis and inflammatory bowel disease does not improve liver biochemistry but is safe and effective for the bowel disease.

BACKGROUND: Blocking of lymphocyte trafficking to bile ducts is a potential mechanism to alter the disease course of patients with primary sclerosing cholangitis (PSC). AIM: To describe the effect of the α4 ß7 integrin antibody, vedolizumab, on liver biochemistry and disease activity in patients with PSC and inflammatory bowel disease (IBD). METHODS: This is a retrospective multi-centre study of adult patients with a diagnosis of both IBD and PSC. The primary outcome was change in serum alkaline phosphatase level at weeks 14 and 30. Secondary outcomes included changes in other liver biochemistries and in clinical outcomes for the bowel disease. A safety analysis for adverse events was performed. RESULTS: Thirty-four patients (16 Crohn's disease, 18 ulcerative colitis) were included. Nine (26%) had a history of liver transplant. Median follow-up on vedolizumab was 9 months (IQR: 7-16). There was no overall change in serum alkaline phosphatase level with vedolizumab therapy (median 268 [IQR: 105-551] IU/L at baseline versus 249 [IQR: 183-634] IU/L, P = 0.99 at week 30). No significant changes in other liver biochemistries or the Mayo PSC Risk Score were demonstrated at week 30. Clinical remission was achieved at week 30 in 55% of Crohn's disease and 29% of ulcerative colitis patients. Seven (21%) patients ceased vedolizumab; six patients stopped therapy due to persistent IBD activity and one for worsening of liver biochemistries. CONCLUSION: Vedolizumab treatment in patients with PSC and IBD did not improve liver biochemistry but was associated with improvement in bowel disease and a favourable safety profile.

Ipsilateral Hemichorea-hemiballism in a Case of Postoperative Stroke.

BACKGROUND: Ipsilateral hemiballismus refers to the rare occurrence of hemiballism developing on the same side of a brain lesion. CASE REPORT: We describe a rare case of postoperative ipsilateral hemiballism in a patient who underwent pituitary adenoma resection and experienced a right internal cerebral artery territory infarct. We review the literature on hemichorea hemiballismus (HCHB) and explore various mechanisms for its occurrence. DISCUSSION: Only three cases of ipsilateral hemiballism have been described, and the exact pathophysiology remains unknown. A dominant left hemisphere with corpus callosal connections to the right basal ganglia is the most probable explanation for this unusual event.

Chemoprevention in gastrointestinal physiology and disease. Natural products and microbiome.

The human intestinal tract harbors a complex ecosystem of commensal bacteria that play a fundamental role in the well-being of their host. There is a general consensus that diet rich in plant-based foods has many advantages in relation to the health and well-being of an individual. In adults, diets that have a high proportion of fruit and vegetables and a low consumption of meat are associated with a highly diverse microbiota and are defined by a greater abundance of Prevotella compared with Bacteroides, whereas the reverse is associated with a diet that contains a low proportion of plant-based foods. In a philosophical term, our consumption of processed foods, widespread use of antibiotics and disinfectants, and our modern lifestyle may have forever altered our ancient gut microbiome. We may never be able to identify or restore our microbiomes to their ancestral state, but dietary modulation to manipulate specific gut microbial species or groups of species may offer new therapeutic approaches to conditions that are prevalent in modern society, such as functional gastrointestinal disorders, obesity, and age-related nutritional deficiency. We believe that this will become an increasingly important area of health research.

A realistic utilization of nanotechnology in molecular imaging and targeted radiotherapy of solid tumors.

Precise dose delivery to malignant tissue in radiotherapy is of paramount importance for treatment efficacy while minimizing morbidity of surrounding normal tissues. Current conventional imaging techniques, such as magnetic resonance imaging (MRI) and computerized tomography (CT), are used to define the three-dimensional shape and volume of the tumor for radiation therapy. In many cases, these radiographic imaging (RI) techniques are ambiguous or provide limited information with regard to tumor margins and histopathology. Molecular imaging (MI) modalities, such as positron emission tomography (PET) and single photon-emission computed-tomography (SPECT) that can characterize tumor tissue, are rapidly becoming routine in radiation therapy. However, their inherent low spatial resolution impedes tumor delineation for the purposes of radiation treatment planning. This review will focus on applications of nanotechnology to synergize imaging modalities in order to accurately highlight, as well as subsequently target, tumor cells. Furthermore, using such nano-agents for imaging, simultaneous coupling of novel therapeutics including radiosensitizers can be delivered specifically to the tumor to maximize tumor cell killing while sparing normal tissue.

Effect of a single hemodialysis session on endothelial dysfunction.

BACKGROUND: The mechanisms of endothelial dysfunction induced by hemodialysis are unclear. To gain a mechanistic view we have evaluated some of the biochemical markers which directly or indirectly lead to endothelial dysfunction during a single dialysis session. METHODS: Time course changes in plasma nitrate levels, arginine (ARG), citrulline, asymmetric dimethylarginine (ADMA), homocysteine (Hcy), malondialdehyde (MDA) and lipoprotein-associated phospholipase A2 (LpPLA2) were evaluated in 27 patients with end-stage renal disease on maintenance hemodialysis. Statistical evaluation of changes was done using analysis of variance for repeated measures and linear regression using generalized estimating equations for repeated measures. RESULTS: Nitrate levels significantly increased as a result of dialysis (p<0.001). Hcy (p<0.05) and ADMA (p<0.001) levels were found to be significantly decreased. ARG/ADMA ratio showed an increase (p<0.001). Presence of oxidative stress (OS) was observed in the form of increased plasma MDA levels. Nitrate levels were negatively associated with Hcy, ADMA and LpPLA2 activity. CONCLUSION: Our results show an increased production of nitric oxide (NO) during dialysis, which however is affected by increased OS ultimately favoring endothelial dysfunction. Measures to reduce the OS during hemodialysis are needed to get the complete benefit of clearance of circulating inhibitors of NO synthase during dialysis.

Analytical radiography for planar radiographic images implemented with a multi-modal system.

A radiographic system is optimized for the contrast inherent to small animals and is developed for a multi-modal imaging system devised for in-vivo studies. The range of X-ray energies utilized (generally considered "soft X-rays") enables enhanced spatial resolution and superior contrast for detailed study of the mouse anatomy and smaller specimens. Despite the difficulties presented by the complicated energy spectrum of soft X-rays, relevant system calibrations for bone measures are described in detail and applied to the mouse. Further, long-bone symmetry modeling using a cylindrical projection is applied to the planar density image, providing convenient bone density estimates that are consistent with other methodologies.

Increased sensitivity in antigen detection with fluorescent latex nanosphere-IgG antibody conjugates.

IgG antibodies were conjugated to Kodak X-Sight nanospheres to develop fluorescent-labeled antibodies using two different synthetic routes: one involving the DTT reduction method, and the other involving Traut's Reagent modification method. These two methods result in different conjugation efficiencies and different performances in antigen detection. Western blotting shows that the nanosphere-IgG antibody conjugates synthesized using the DTT reduction method are more immunospecific than the conjugates synthesized using Traut's Reagent modification method. In addition, the conjugates synthesized using DTT reduction also show higher antigen detection sensitivity than other commercially available fluorescent-IgG antibody conjugates, including Alexa Fluor, Qdot, and CyDye conjugates.

Osteopontin infusion into normal adult rat brain fails to increase cell proliferation in dentate gyrus and subventricular zone.

In the first week after focal ischemia in adult brain, the basal level of neurogenesis increases dramatically in two distinct areas: The dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ) of the lateral ventricles. It is possible that this remotely induced neurogenesis is the result of a proliferation inducing factor, or factors, diffusing from the infarction to the neurogenic regions. The secreted protein osteopontin (OPN) is a possible factor. In this study, OPN mRNA levels were measured in the cerebral infarction of adult rats that underwent I hour of middle cerebral artery occlusion (MCAO). OPN mRNA levels increased 36.0, 55.0 and 46.7 fold at 6, 24 and 72 hours reperfusion respectively. We also determined whether OPN alone could be responsible for this ischemia-induced neurogenesis. OPN (2.4 microg/day) was infused into the lateral ventricles of the brain in non-ischemic adult male rats, continuously over three days. Bromodeoxyuridine (BrdU) immunohistochemistry was performed and the total BrdU positive (BrdU+) cells were counted. OPN, compared to aCSF infusion, decreased BrdU+ cells in DG and had no significant effect on cell proliferation in the SVZ. This study indicates that osteopontin alone does not increase cell proliferation in the normal adult brain.

Suramin interacts with the calmodulin binding site on the ryanodine receptor, RYR1.

Apocalmodulin and Ca(2+) calmodulin bind to overlapping sites on the ryanodine receptor skeletal form, RYR1, but have opposite functional effects on channel activity. Suramin, a polysulfonated napthylurea, displaces both forms of calmodulin, leading to an inhibition of activity at low Ca(2+) and an enhancement of activity at high Ca(2+). Calmodulin binding motifs on RYR1 are also able to directly interact with the carboxy-terminal tail of the transverse tubule dihydropyridine receptor (DHPR) (Sencer, S., Papineni, R. V., Halling, D. B., Pate, P., Krol, J., Zhang, J. Z., and Hamilton, S. L. (2001) J. Biol. Chem. 276, 38237-38241). Suramin binds directly to a peptide that corresponds to the calmodulin binding site of RYR1 (amino acids 3609-3643) and blocks the interaction of this peptide with both calmodulin and the carboxyl-terminal tail of the DHPR alpha(1)-subunit. Suramin, added to the internal solution of voltage-clamped skeletal myotubes, produces a concentration-dependent increase in the maximal magnitude of voltage-gated Ca(2+) transients without significantly altering L-channel Ca(2+) channel conducting activity. Together, these results suggest that an interaction between the carboxyl-terminal tail of the DHPR alpha(1)-subunit with the calmodulin binding region of RYR1 serves to limit sarcoplasmic reticulum Ca(2+) release during excitation-contraction coupling and that suramin-induced potentiation of voltage-gated Ca(2+) release involves a relief of this inhibitory interaction.

GeneChip analysis after acute spinal cord injury in rat.

Spinal cord injury (SCI) leads to induction and/or suppression of several genes, the interplay of which governs the neuronal death and subsequent loss of motor function. Using GeneChip, the present study analyzed changes in the mRNA abundance at 3 and 24 h after SCI in adult rats. SCI was induced at T9 level by the New York University impactor by dropping a 10-g weight from a height of 25 mm. Several transcription factors, immediate early genes, heat-shock proteins, pro-inflammatory genes were up-regulated by 3 h, and persisted at 24 h, after SCI. On the other hand, some neurotransmitter receptors and transporters, ion channels, kinases and structural proteins were down-regulated by 3 h, and persisted at 24 h, after SCI. Several genes that play a role in growth/differentiation, survival and neuroprotection were up-regulated at 24 h after SCI. Using real-time quantitative PCR, the changes observed by GeneChip were confirmed for seven up-regulated (interleukin-6, heat-shock protein-70, heme oxygenase-1, suppressor of cytokine signaling 2, suppressor of cytokine signaling 3, interferon regulatory factor-1, neuropeptide Y), two down-regulated (vesicular GABA transporter and cholecystokinin precursor) and two unchanged (Cu/Zn-superoxide dismutase and phosphatidyl inositol-3-kinase) genes. The present study shows that inflammation, neurotransmitter dysfunction, increased transcription, ionic imbalance and cytoskeletal damage starts as early as 3 h after SCI. In addition to these effects, 24 h after SCI the repair and regeneration process begins in an attempt to stabilize the injured spinal cord.

Protective effects of glial cell line-derived neurotrophic factor on hippocampal neurons after traumatic brain injury in rats.

OBJECT: The purpose of this study was to evaluate whether glial cell line-derived neurotrophic factor (GDNF) can protect against hippocampal neuronal death after traumatic brain injury (TBI). METHODS: Male Sprague-Dawley rats were subjected to moderate TBI with a controlled cortical impact device while in a state of halothane-induced anesthesia. Then, GDNF or artificial cerebrospinal fluid ([aCSF]; vehicle) was infused into the frontal horn of the left lateral ventricle. In eight brain-injured and eight sham-operated rats, GDNF was infused continuously for 7 days (200 ng/day intracerebroventricularly at a rate of 8.35 ng/0.5 microl/hour). An equal volume of vehicle was infused at the same rate into the remaining eight brain-injured and eight sham-operated rats. Seven days post-injury, all rats were killed. Their brains were sectioned and stained with cresyl violet, and the hippocampal neuronal loss was evaluated in the CA2 and CA3 regions with the aid of microscopy. A parallel set of sections from each brain was subjected to immunoreaction with antibodies against glial fibrillary acidic protein (GFAP; astroglia marker). In the aCSF-treated group, TBI resulted in a significant neuronal loss in the CA2 (60%, p < 0.05) and CA3 regions (68%, p < 0.05) compared with the sham-operated control animals. Compared with control rats infused with aCSF, GDNF infusion significantly decreased the TBI-induced neuronal loss in both the CA2 (58%, p < 0.05) and CA3 regions (51%, p < 0.05). There was no difference in the number of GFAP-positive astroglial cells in the GDNF-infused rats in the TBI and sham-operated groups compared with the respective vehicle-treated groups. CONCLUSIONS: The authors found that GDNF treatment following TBI is neuroprotective.

Rhizophorin A, a novel secolabdane diterpenoid from the Indian mangrove plant Rhizophora mucronata.

The ethyl acetate extract of Rhizophora mucronata furnished rhizophorin A, a novel secolabdane diterpenoid, (6R,11S,13S)-6,11,13-trihydroxy-2,3-seco-14-labden-2,8-olide-3-oic acid (1).

Transient focal cerebral ischemia down-regulates glutamate transporters GLT-1 and EAAC1 expression in rat brain.

Transient focal cerebral ischemia leads to extensive excitotoxic neuronal damage in rat cerebral cortex. Efficient reuptake of the released glutamate is essential for preventing glutamate receptor over-stimulation and neuronal death. Present study evaluated the expression of the glial (GLT-1 and GLAST) and neuronal (EAAC1) subtypes of glutamate transporters after transient middle cerebral artery occlusion (MCAO) induced focal cerebral ischemia in rats. Between 24h to 72h of reperfusion after transient MCAO, GLT-1 and EAAC1 protein levels decreased significantly (by 36% to 56%, p < 0.05) in the ipsilateral cortex compared with the contralateral cortex or sham control. GLT-1 and EAAC1 mRNA expression also decreased in the ipsilateral cortex of ischemic rats at both 24h and 72h of reperfusion, compared with the contralateral cortex or sham control. Glutamate transporter down-regulation may disrupt the normal clearance of the synaptically-released glutamate and may contribute to the ischemic neuronal death.