68 Ga-Pentixafor PET/CT for In Vivo Imaging of CXCR4 Receptors in Glioma Demonstrating a Potential for Response Assessment to Radiochemotherapy: Preliminary Results.

PURPOSE: The aim of this study was to evaluate the diagnostic potential of 68 Ga-pentixafor PET/CT for in vivo CXCR4 receptors imaging in glioma and its possible role in response assessment to radiochemotherapy (R-CT). METHODS: Nineteen (12 men, 7 women) patients with glioblastoma multiforme (GBM) underwent 68 Ga-pentixafor PET/CT, contrast-enhanced MR, and MR spectroscopy. Patients were divided in to 2 groups, that is, group I was the presurgical (n = 9) group in which the scanning was done before surgery, and PET findings were correlated with CXCR4 receptors' density. The group II was the postsurgical (n = 10) group in which the scanning was done before and after R-CT and used for treatment response evaluation. The quantitative analysis of 68 Ga-pentixafor PET/CT evaluated the mean SUV max , SUV mean , SUV peak , and T/B values. MR spectroscopy data evaluated the ratios of tumor metabolites (choline, NAA, creatine). RESULTS: 68 Ga-Pentixafor uptake was noted in all (n = 19) the patients. In the group I, the mean SUV max , SUV mean , SUV peak , and T/B values were found to be 4.5 ± 1.6, 0.60 ± 0.26, 1.95 ± 0.8, and 6.9 ± 4.6, respectively. A significant correlation ( P < 0.005) was found between SUV mean and choline/NAA ratio. Immunohistochemistry performed in 7/9 showed CXCR4 receptors' positivity (intensity 3 + ; stained cells >50.0%). In the group II, the mean SUV max at baseline was 4.6 ± 2.1 and did not differ (4.4 ± 1.6) significantly from the value noted at post-R-CT follow-up PET/CT imaging. At 6 months' clinical follow-up, 4 patients showed stable disease. SUV max and T/B ratios at follow-up imaging were lower (3.70 ± 0.90, 2.64 ± 1.35) than the corresponding values (4.40 ± 2.8; 2.91 ± 0.93) noted at baseline. Six (6/10) patients showed disease progression, and the mean SUV max , and T/B ratio in these patients were significantly ( P < 0.05) higher than the corresponding values at baseline and also higher than that noted in the stable patients. CONCLUSIONS: 68 Ga-Pentixafor PET/CT can be used for in vivo mapping of CXCR4 receptors in GBM. The technique after validation in a large cohort of patients may have added diagnostic value for the early detection of GBM recurrence and for treatment response evaluation.

Efficacy of Yttrium-90 Transarterial Radioembolisation in Advanced Hepatocellular Carcinoma: An Experience With Hybrid Angio-Computed Tomography and Glass Microspheres.

Background: Hepatocellular carcinoma is one of the most common malignancies worldwide. Transarterial radioembolisation (TARE) involves selective intra-arterial administration of microspheres loaded with a radioactive compound like Yttrium-90 (Y-90). Conventionally, C-arm-based cone-beam computed tomography has been extensively used during TARE. However, angio-computed tomography (CT) is a relatively new modality which combines the advantages of both fluoroscopy and fCT. There is scarce literature detailing the use of angio-CT in Y90 TARE. Methods: This was a retrospective study of primary liver cancer cases in which the TARE procedure was done from November 2017 to December 2021. Glass-based Y-90 microspheres were used in all these cases. All the cases were performed in the hybrid angio-CT suite. A single photon emission computed tomography-computed comography (SPECT-CT) done postplanning session determined the lung shunt fraction and confirmed the accurate targeting of the lesion. Postdrug delivery, positron emission tomography-computed tomography (PET-CT) was obtained to confirm the distribution of the Y-90 particles. The technical success, median follow-up, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were recorded. Results: A total of 56 hepatocellular carcinoma patients underwent TARE during this period, out of which 36 patients (30 males and 6 females) underwent Y90 TARE. The aetiology of cirrhosis included non-alcoholic steatohepatitis (NASH) (11), hepatitis C (HCV) (11), hepatitis B (HBV) (9), metabolic dysfunction and alcohol-associated liver disease (MetALD) (2), alcoholic liver disease (ALD) (1), cryptogenic (1), and autoimmune hepatitis (AIH) (1). The technical success was 100 % and the median follow-up was 7 months (range: 1-32 months). The median OS was 15 months (range 10.73-19.27 months; 95 % CI) and the median local PFS was 4 months (range 3.03-4.97 months; 95 % CI). The ORR (best response, CR + PR) was 58 %. No major complications were seen in this study. Conclusion: TARE is a viable option for liver cancer in all stages, but more so in the advanced stages. The use of angio-CT in TARE aids in the precise delivery of the particles to the tumour and avoids non-target embolisation.

68 Ga-Pentixafor PET/CT for in-vivo mapping of CXCR4 receptors as potential radiotheranostic targets in soft tissue and bone sarcoma: preliminary results.

OBJECTIVE: To evaluate the diagnostic utility of 68 Ga-Pentixafor PET/CT for in vivo imaging of CXCR4 receptors in soft tissue/bone sarcoma. METHODS: Ten (7M: 3F; mean age = 24.7 ± 14.2 years) consecutive patients with clinical and radiological evidence of bone/soft tissue sarcoma were recruited prospectively whole body 68 Ga-Pentixafor PET/CT imaging was performed at 60-min after tracer administration. After performing standard CT, PET acquisition from head to toe was done (3 min/bed position) in a caudocranial direction. PET/CT data was reconstructed and SUV max , SUV mean values, target-to-background ratio (TBR) and active tumor volume (cc) were computed for the tracer avid lesions. Histopathological and IHC analysis was performed on the surgically excised primary tumors. CXCR4 receptors' intensity was evaluated by visual scoring. RESULTS: The mean SUV max and SUV mean values in the primary tumors were 4.80 ±â€…1.0 (3.9-7.7) and 2.40 ±â€…0.60 (0.9-4.0). The mean TBR and tumor volume (cc) were 1.84 ±â€…1.3 and 312.2 ±â€…285. Diagnosis of osteosarcoma in 7, chondrosarcoma, leiomyosarcoma and synovial sarcoma in 1 patient each was confirmed on HP analysis. Distant metastatic lesions were seen in 3/10 patients. Nuclear CXCR4 receptors' positivity was seen in 5, cytoplasmic in 4 and both pattern seen in 1 patient. The mean CXCR4 receptors' intensity was found to be 7.6 ±â€…2. The highest SUV max value of 7.7 was observed in the patient having both cytoplasmic and nuclear CXCR4 expression. SUV max was found to be poorly correlated ( r  = 0.441) with CXCR4 expression. CONCLUSION: 68 Ga-Pentixafor PET/CT detects CXCR4 receptors over-expressed in sarcoma, its radio-theranostics potential needs detailed evaluation.

Discovery, Optimization, and Biological Evaluation of Arylpyridones as Cbl-b Inhibitors.

Casitas B-lymphoma proto-oncogene-b (Cbl-b), a member of the Cbl family of RING finger E3 ubiquitin ligases, has been demonstrated to play a central role in regulating effector T-cell function. Multiple studies using gene-targeting approaches have provided direct evidence that Cbl-b negatively regulates T, B, and NK cell activation via a ubiquitin-mediated protein modulation. Thus, inhibition of Cbl-b ligase activity can lead to immune activation and has therapeutic potential in immuno-oncology. Herein, we describe the discovery and optimization of an arylpyridone series as Cbl-b inhibitors by structure-based drug discovery to afford compound 31. This compound binds to Cbl-b with an IC50 value of 30 nM and induces IL-2 production in T-cells with an EC50 value of 230 nM. Compound 31 also shows robust intracellular target engagement demonstrated through inhibition of Cbl-b autoubiquitination, inhibition of ubiquitin transfer to ZAP70, and the cellular modulation of phosphorylation of a downstream signal within the TCR axis.

Green synthesis and biological evaluation of glaucanic acid and dihydrocompactin acid by endophytic fungus Penicillium polonicum from Zingiber officinale.

Fungal endophytes are valued for biosynthesizing chemically diverse metabolic cascade with interesting biological activities. In the current investigation, two compounds were isolated from Penicillium polonicum, an endophyte of Zingiber officinale. The active moieties, glaucanic acid (1) and dihydrocompactin acid (2) were isolated from the ethyl acetate extract of P. polonicum and characterized by NMR and mass spectroscopy. Further, bioactive potential of the isolated compounds was evaluated by antimicrobial, antioxidant and cytotoxicity assays. Compounds 1 and 2 displayed antifungal activity against phytopathogen Colletotrichum gloeosporioides with more than 50% reduction in its growth. Both the compounds exhibited antioxidant activity against free radicals (DPPH and ABTS) and cytotoxicity activity against cancer cell lines respectively. The compounds, glaucanic acid and dihydrocompactin acid are being reported for the first time from an endophytic fungus. This is the first report on the biological activities of Dihydrocompactin acid produced by endophytic fungal strain.

Light-Responsive Layer-By-Layer Film Containing Gold Nanorods for Sequential Drug Release.

Chemically and physically stable multidrug-loaded layer-by-layer (LbL) films are promising candidates for sequential and on-demand drug release at concentrations suitable for various applications. The synergistic effect of the sequential release of drugs may enhance their therapeutic efficacy in treating skin cancer and other complex medical conditions. In this study, we prepared LbL films by alternating the deposition of cationic linear polyethylenimine, camptothecin (CPT)-loaded gold nanorods (GNRs), anionic poly(styrenesulfonate), and doxorubicin (DOX) based on electrostatic interactions. The film exhibited loading of CPT and DOX, which could be tuned according to the requirements of the application by changing the parameters of the LbL process. Herein, CPT was encapsulated in GNRs and showed good stability and absorption in the near-infrared (NIR) range (650-900 nm). The prepared LbL film showed a pH-dependent DOX release. Subsequently, the functionalized GNRs showed excellent photothermal properties, which assisted the on-demand release of CPT upon NIR irradiation with further release of DOX. Our results suggest that the LbL approach for sequential drug release can be an effective drug delivery platform owing to its cytocompatibility, anticancer effects, and stimuli-responsive properties.

Preclinical and Clinical Use of Indigenously Developed 99mTc-Diethylenetriaminepentaacetic Acid-Bis-Methionine: l-Type Amino Acid Transporter 1-Targeted Single Photon Emission Computed Tomography Radiotracer for Glioma Management.

A new era in tumor classification, diagnosis, and prognostic evaluation has begun as a consequence of recent developments in the molecular and genetic characterization of central nervous system tumors. In this newly emerging era, molecular imaging modalities are essential for preoperative diagnosis, surgical planning, targeted treatment, and post-therapy evaluation of gliomas. The radiotracers are able to identify brain tumors, distinguish between low- and high-grade lesions, confirm a patient's eligibility for theranostics, and assess post-radiation alterations. We previously synthesized and reported the novel l-type amino acid transporter 1 (LAT-1)-targeted amino acid derivative in light of the use of amino acid derivatives in imaging technologies. Further, we have developed a single vial ready to label Tc-lyophilized kit preparations of diethylenetriaminepentaacetic acid-bis-methionine [DTPA-bis(Met)], also referred to as methionine-diethylenetriaminepentaacetic acid-methionine (MDM) and evaluated its imaging potential in numerous clinical studies. This review summarizes our previous publications on 99mTc-DTPA-bis(Met) in different clinical studies such as detection of breast cancer, as a prognostic marker, in detection of recurrent/residual gliomas, for differentiation of recurrent/residual gliomas from radiation necrosis, and for comparison of 99mTc-DTPA-bis(Met) with 11C-L-methionine (11C-MET), with relevant literature on imaging modalities in glioma management.

Delineation of novel genomic loci and putative candidate genes associated with seed iron and zinc content in lentil (Lens culinaris Medik.).

The use of molecular breeding approaches for development of lentil genotypes biofortified with essential micro-nutrients such as iron and zinc, could serve as a promising solution to address the problem of global malnutrition. Thus, genome-wide association study (GWAS) strategy was adopted in this study to identify the genomic regions associated with seed iron and zinc content in lentil. A panel of 95 diverse lentil genotypes, grown across three different geographical locations and evaluated for seed iron and zinc content, exhibited a wide range of variation. Genotyping-by-sequencing (GBS) analysis of the panel identified 33,745 significant single nucleotide polymorphisms (SNPs) that were distributed across all the 7 lentil chromosomes. Association mapping revealed 23 SNPs associated with seed iron content that were distributed across all the chromosomes except chromosome 3. Similarly, 14 SNPs associated with seed zinc content were also identified that were distributed across chromosomes 1, 2, 4, 5 and 6. Further, 80 genes were identified in the proximity of iron associated markers and 36 genes were identified in the proximity of zinc associated markers. Functional annotation of these genes revealed their putative involvement in iron and zinc metabolism. For seed iron content, two highly significant SNPs were found to be located within two putative candidate genes namely iron-sulfur cluster assembly (ISCA) and flavin binding monooxygenase (FMO) respectively. For zinc content, a highly significant SNP was detected in a gene encoding UPF0678 fatty acid-binding protein. Expression analysis of these genes and their putative interacting partners suggests their involvement in iron and zinc metabolism in lentil. Overall, in this study we have identified markers, putative candidate genes and predicted putative interacting protein partners significantly associated with iron and zinc metabolism that could be utilized in future breeding studies of lentil for nutrient biofortification.

Critical review on uranium and arsenic content and their chemical mobilization in groundwater: A case study of the Malwa region Punjab, India.

The presence of pollutants like uranium and arsenic in the groundwater can have a terrible impact on people's health (both radiologically and toxicologically) and their economic conditions. Their infiltration into groundwater can occur through geochemical reactions, natural mineral deposits, mining and ore processing. Governments and scientists are working to address these issues, and significant progress has been achieved, but it's challenging to deal with and mitigate without adequately understanding the different chemical processes and the mobilization mechanism of these hazardous chemicals. Most of the articles and reviews have focused on the particular form of contaminants and specific sources of pollution, such as fertilizers. However, no literature report exists explaining why particular forms appear and the possible basis of their chemical origins. Hence, in this review, we tried to answer the various questions by devising a hypothetical model and chemical schematic flowcharts for the chemical mobilization of arsenic and uranium in groundwater. An effort has been made to explain how chemical seepage and excessive groundwater use resulted in the change in aquifers' chemistry, as evidenced by their physicochemical parameters and heavy metal analysis. Many technological advancements have taken place to mitigate these issues. Still, in low-middle-income countries, especially in the Malwa region of Punjab, also known as Punjab's cancer belt, paying a high amount for installing and maintaining these technologies is an unviable option. In addition to working to improve people's access to sanitary facilities and clean water to drink, the policy-level intervention would focus on increasing community awareness and continued research on developing better and more economical technologies. Our designed model/chemical flowcharts will help policymakers and researchers better understand the problems and alleviate their effects. Moreover, these models can be utilized in other parts of the globe where similar questions exist. This article emphasises the value of understanding the intricate issue of groundwater management through a multidisciplinary and interdepartmental approach.

Bedaquiline in Drug-Resistant Tuberculosis: A Mini-Review.

Mycobacterium tuberculosis causes a contagious pulmonary disease with a high mortality rate in developing countries. However, the recommendation of DOTS (approved by WHO) was effective in treating tuberculosis, but nowadays, resistance from the first line (MDR-TB) and the second line (XDR-TB) drugs is highly common. Whereas, the resistance is a result of factors like poor patient constancy due to the long duration of therapy and co-infection with HIV. The approval of bedaquiline under an accelerated program for the treatment of MDR-TB has revealed its effectiveness in clinical trials as a therapeutic novel molecule. BDQ selectively inhibits the ATP synthase of bacterium and reduces ATP production. Additionally, the poor pharmacokinetic properties raised provocations in the MDR therapy, but the use of targeted drug delivery can solve the hurdles. While the preclinical and clinical studies included in this review are strongly suggesting the usefulness of BDQ in MDR-TB and XDR-TB, the repurposing of different drug classes in resistant TB is opening new opportunities to manage the disease conditions. In this review, we have summarized the examples of pipeline drugs and repurposed molecules with preclinical formulation developments.

Simple CaroTID-VasC score to predict one-year risk of stroke in symptomatic carotid stenosis patients.

BACKGROUND: A subset of extracranial symptomatic carotid stenosis (ESCS) patients may fare well on current optimal medical therapy (OMT), and surgery may be avoided in these patients. Therefore, we aimed to develop and validate a stroke risk prediction model to stratify the risk among ESCS patients. METHODS: Adult ESCS patients who denied revascularization procedures were enrolled prospectively and prescribed OMT. Patients were followed-up for twelve months after assessing the clinical, imaging, and hemodynamics-based risk predictors at baseline. Cox regression analysis was performed on predictors which were significant in univariate analysis. Beta coefficients of significant predictors in Cox regression were used to generate a numeric score. The model was internally validated using bootstrapping. RESULTS: A total of 20 (20.2%) out of 99 patients had event recurrence during the follow-up. Transient ischemic attack index event (P = 0.014), diabetes mellitus (P = 0.018), contralateral significant stenosis (P = 0.007), echolucent plaque (P = 0.011), and impaired vasomotor reactivity (P = 0.006) were significant predictors in Cox regression analysis. A points score (0-6) was derived from regression coefficients of the significant predictors. The area under ROC was 0.884 for the developed model and 0.832 for the bootstrapped model. Youden's index divided the score into low-risk (2.2%) and high-risk (35.8%) groups, and the difference in risk was significant (P < 0.001). CONCLUSIONS: Most ESCS patients benefited from OMT, and the CaroTID-VasC score was effective in stratifying patients for risk of endpoint occurrence. The developed model may help identify high-risk subgroups of ESCS patients and assist the decision-making of carotid interventions.

[68Ga]Ga-Pentixafor PET/CT imaging for in vivo CXCR4 receptor mapping in different lung cancer histologic sub-types: correlation with quantitative receptors' density by immunochemistry techniques.

PURPOSE: In vivo CXCR4 receptor quantification in different lung cancer (LC) sub-types using [68Ga]Ga-Pentixafor PET/CT and to study correlation with quantitative CXCR4 receptors' tissue density by immunochemistry analyses. METHODS: [68Ga]Ga-Pentixafor PET/CT imaging was performed prospectively in 94 (77 M: 17F, mean age 60.1 ± 10.1 years) LC patients. CXCR4 receptors' expression on lung mass in all the patients was estimated by immunohistochemistry (IHC) and fluorescence-activated cell sorting (FACS) analyses. SUVmax on PET, intensity score on IHC, and mean fluorescence index (MFI) on FACS analyses were measured. RESULTS: A total of 75/94 (79.8%) cases had non-small cell lung cancer (NSCLC), 14 (14.9%) had small cell lung cancer (SCLC), and 5 (5.3%) had lung neuroendocrine neoplasm (NEN). All LC types showed increased CXCR4 expression on PET (SUVmax) and FACS (MFI). However, both these parameters (mean SUVmax = 10.3 ± 5.0; mean MFI = 349.0 ± 99.0) were significantly (p = 0.005) higher in SCLC as compared to those in NSCLC and lung NEN. The mean SUVmax in adenocarcinoma (n = 16) was 8.0 ± 1.9 which was significantly (p = 0.003) higher than in squamous cell carcinoma (n = 54; 6.2 ± 2.1) and in not-otherwise specified (NOS) sub-types (n = 5; 5.8 ± 1.5) of NSCLC. A significant correlation (r = 0.697; p = 001) was seen between SUVmax and MFI values in squamous cell NSCLC as well as in NSCLC adenocarcinoma (r = 0.538, p = 0.031) which supports the specific in vivo uptake of [68Ga]Ga-Pentixafor by CXCR4 receptors. However, this correlation was not significant in SCLC (r = 0.435, p = 0.121) and NEN (r = 0.747, p = 0.147) which may be due to the small sample size. [68Ga]Ga-Pentixafor PET/CT provided good sensitivity (85.7%) and specificity (78.1%) for differentiating SCLC from NSCLC (ROC cutoff SUVmax = 7.2). This technique presented similar sensitivity (87.5%) and specificity (71.4%) (ROC cutoff SUVmax = 6.7) for differentiating adenocarcinoma and squamous cell variants of NSCLC. CONCLUSION: The high sensitivity and specificity of [68Ga]Ga-Pentixafor PET/CT for in vivo targeting of CXCR4 receptors in lung cancer can thus be used effectively for the response assessment and development of CXCR4-based radioligand therapies in LC.

Evaluation of Reconstruction Algorithms to Validate the NEMA Phantom Results in Clinical Scenario - A Comparative Study Using Time-of-Flight versus Non-Time-of-Flight Positron Emission Tomography Imaging.

Objectives: The objective is to standardize the reconstruction parameters for the time-of-flight (TOF) versus non-TOF positron-emission tomography/computed tomography (PET/CT) imaging data and validation of the same in a clinical setting. Methods: The four spheres (10.0/13.0/17.0/22.0 mm) of the PET phantom (NEMA IQ Nu 2-2001) were filled with four times higher activity of [18F]-NaF than the background (5.3kBq/mL). Imaging (image matrix - 128 × 128 × 47, 2 min, 3D model) was done using two different (TOF/non-TOF) PET scanners. Phantom data were reconstructed in TOF and non-TOF modes for lutetium-yttrium oxyorthosilicate and non-TOF mode for bismuth germanate-based PET scanners. The reconstructed data (by varying iteration and subsets) that provided the best image contrast and signal-to-noise ratio (SNR) were evaluated. The whole-body [18F]-fludeoxyglucose (FDG) PET/CT scans (7-8 frames; 2.0 min/frame) in 16 lymphoma patients were acquired at 60 min after injecting the radioactivity (370.0-444.0 MBq of [18F]-FDG. The clinical PET/CT data were reconstructed using phantom-derived reconstruction parameters and evaluated for image contrast and SNR of the detected lesions. Results: TOF reconstruction at second iteration provided significantly (P ≤ 0.02) higher SNR (20.7) and contrast (contrast recovery coefficient/background variability = 3.21) for the smallest hot lesions (10.0 mm) in the phantom than the non-TOF system. Similarly, in patient data analysis for the selected FDG avid lesions, the SNR values were significantly (P = 0.02) higher (13.3 ± 6.49) in TOF than (11 ± 6.48) in non-TOF system. Further, the small (≤10.0 mm) lesions were seen more distinctly in TOF system. Conclusion: It is thus observed that TOF reconstruction converged faster than the non-TOF, and the applicability of the same may impact the image quality and interpretation in the clinical PET data. The validation of the phantom-based experimental reconstruction parameters to clinical PET imaging data is highly warranted.

Imaging CXCR4 receptors expression for staging multiple myeloma by using 68Ga-Pentixafor PET/CT: comparison with 18F-FDG PET/CT.

OBJECTIVES: 68Ga-Pentixafor positron emission tomography (PET) imaging targets CXCR4 expression which is overexpressed in multiple myeloma (MM). In this study, we evaluated the diagnostic utility of 68Ga-Pentixafor PET/CT for imaging CXCR4 expression in MM and compared results with 18F-fluorodeoxyglucose (18F-FDG) PET/CT. METHODS: 34 (21M; 13F; median age = 57.5 years) treatment naive multiple myeloma patients were recruited. All the patients underwent 18F-FDG PET/CT and 68Ga-Pentixafor PET/CT imaging. Freshly prepared 68Ga-Pentixafor (148-185 MBq) was injected intravenously and whole-body PET/CT (low-dose CT) was acquired at 1 h post-injection. The pattern of uptake (diffuse, focal or mixed) and the mean SUVmax value of all the lesions (when lesions were ≤5) or of the five most tracer avid lesions (when lesions was >5) were evaluated. Tumor to background ratio (TBRmax) was calculated for both the tracers. Durie Salmon plus staging (DSPS) was used for disease staging on PET and the results were compared with International staging system (ISS). RESULTS: 68Ga-Pentixafor PET/CT showed higher disease extent than seen on 18F-FDG PET/CT in 23/34 patients (68.0%), lesser disease extent in 2/34 (6%) and similar disease extent in 9/34 (26%) patients. Significantly (p < 0.001) higher TBRmax values (5.7; IQR 8.8) were observed on 68Ga-Pentixafor PET/CT as compared to 18F-FDG PET/CT values (2.9; IQR = 4.0). Both the techniques detected extramedullary lesions in six patients. On the other hand, 68Ga-Pentixafor detected medullary lesions in five, whereas, 18F-FDG PET in three patients. Further, only 68Ga-Pentixafor TBRmax correlated significantly (ρ = 0.421; 0.013) with bone marrow plasma cell percentage. 68Ga-Pentixafor PET upstaged more number (9/29) of patients as compared to (4/29) 18F-FDG PET imaging. On the other hand, 18F-FDG PET down-staged 9/29, whereas 68Ga-Pentixafor PET downstaged only 3/29 patients. CONCLUSION: 68Ga-Pentixafor PET/CT evaluated the whole-body disease burden of CXCR4 receptors non-invasively which is not possible by tissue sampling methods. This novel PET tracer has also implication for disease staging. Dual 68Ga-Pentixafor/18F-FDG PET/CT imaging may help in determining the tumor heterogeneity in MM. ADVANCES IN KNOWLEDGE: This CXCR4 targeting PET tracer has a promising role in the development of CXCR4 targeting theranostics and also for response assessment to these therapies including the conventional treatment.

68Ga-Pentixafor PET/CT Demonstrating In Vivo CXCR4 Receptor Overexpression in Rare Lung Malignancies: Correlation with Histologic and Histochemical Findings.

68Ga-pentixafor PET/CT imaging allows noninvasive assessment of C-X-C chemokine receptor type 4 (CXCR4) expression in various malignancies, but its use in rare lung cancer variants has not been reported. Methods: 68Ga-pentixafor PET/CT imaging was performed on 6 patients (3 men, 3 women; mean age, 57.0 ± 16.8 y) with suspected lung masses. Whole-body PET/CT images were acquired 1 h after intravenous injection of 148.0-185.0 MBq of the tracer. PET/CT images were reconstructed and analyzed. The image findings were correlated with histopathologic and quantitative (CXCR4) fluorescence-activated cell sorting analysis. Results: Histopathologic diagnosis of hemangioendothelioma, sarcomatoid carcinoma, and hemangiopericytoma was confirmed in 1 patient each. Lung metastasis was diagnosed in the remaining 3 of 6 patients with primary sarcoma (n = 1), renal cell carcinoma (n = 1), and unknown primary (n = 1). Increased uptake in the primary lung mass, with an SUVmax of 3.0, 6.34, and 13.0, was noted in the hemangiopericytoma, sarcomatoid carcinoma and hemangioendothelioma cases, respectively. The mean SUVmax, mean fluorescence intensity, and percentage of stained cells were highest in hemangioendothelioma. Among 3 patients with lung metastases, the highest SUVmax, 9.5, was in the primary sarcoma patient. Conclusion: 68Ga-pentixafor selectively targets the in vivo whole-body disease burden of CXCR4 receptors. This approach thus holds promise for developing suitable radiotheranostics for lung cancers expressing these targets.

Physiologic Targets and Modes of Action for CBL0137, a Lead for Human African Trypanosomiasis Drug Development.

CBL0137 is a lead drug for human African trypanosomiasis, caused by Trypanosoma brucei Herein, we use a four-step strategy to 1) identify physiologic targets and 2) determine modes of molecular action of CBL0137 in the trypanosome. First, we identified fourteen CBL0137-binding proteins using affinity chromatography. Second, we developed hypotheses of molecular modes of action, using predicted functions of CBL0137-binding proteins as guides. Third, we documented effects of CBL0137 on molecular pathways in the trypanosome. Fourth, we identified physiologic targets of the drug by knocking down genes encoding CBL0137-binding proteins and comparing their molecular effects to those obtained when trypanosomes were treated with CBL0137. CBL0137-binding proteins included glycolysis enzymes (aldolase, glyceraldehyde-3-phosphate dehydrogenase, phosphofructokinase, phosphoglycerate kinase) and DNA-binding proteins [universal minicircle sequence binding protein 2, replication protein A1 (RPA1), replication protein A2 (RPA2)]. In chemical biology studies, CBL0137 did not reduce ATP level in the trypanosome, ruling out glycolysis enzymes as crucial targets for the drug. Thus, many CBL0137-binding proteins are not physiologic targets of the drug. CBL0137 inhibited 1) nucleus mitosis, 2) nuclear DNA replication, and 3) polypeptide synthesis as the first carbazole inhibitor of eukaryote translation. RNA interference (RNAi) against RPA1 inhibited both DNA synthesis and mitosis, whereas RPA2 knockdown inhibited mitosis, consistent with both proteins being physiologic targets of CBL0137. Principles used here to distinguish drug-binding proteins from physiologic targets of CBL0137 can be deployed with different drugs in other biologic systems. SIGNIFICANCE STATEMENT: To distinguish drug-binding proteins from physiologic targets in the African trypanosome, we devised and executed a multidisciplinary approach involving biochemical, genetic, cell, and chemical biology experiments. The strategy we employed can be used for drugs in other biological systems.

[99mTc]Tc-DTPA-Bis(cholineethylamine) as an Oncologic Tracer for the Detection of Choline Transporter (ChT) and Choline Kinase (ChK) Expression in Cancer.

OBJECTIVE: The elevated choline transporters (ChT), choline kinase (ChK), choline uptake, and phosphorylation in certain tumor cells have influenced the development of radiolabeled choline derivatives as diagnostic probes for imaging cell membrane proliferation. We, therefore, aimed to develop a choline-based moiety for imaging choline kinase-overexpressed tumors by single-photon emission tomography (SPECT). A novel choline-based diagnostic probe was synthesized and evaluated preclinically in various ChT- and ChK-overexpressed tumor models for SPECT imaging applications. METHODS: The synthesis of diethylenetriaminepentaacetic acid-bis-choline ethylamine [DTPA-bis(ChoEA)] featured the conjugation of dimethylaminoethanol to a bifunctional chelator DTPA anhydride. [99mTc]Tc-DTPA-bis(ChoEA) was prepared, and its in vivo characteristics were evaluated in BALB/c mice and tumor-xenografted PC3, A549, and HCT116 athymic mouse models. The in vitro parameters, including cell binding and cytotoxicity, were assessed in PC3, A549, and HCT116 cell lines. To evaluate the specificity of the radioprobe, competitive binding studies were performed. Small-animal SPECT/CT diagnostic imaging was performed for in vivo evaluation. The mouse biodistribution data was further investigated to estimate the radiation dose in humans. RESULTS: In silico studies suggested high binding with enhanced specificity. A standard radiolabeling procedure using stannous chloride as a reducing agent showed a labeling yield of 99.5 ± 0.5%. The in silico studies suggested high binding with enhanced specificity. [99mTc]Tc-DTPA-bis(ChoEA) showed high in vitro stability and specificity. The pharmacokinetic studies of [99mTc]Tc-DTPA-bis(ChoEA) in mice showed an increased tumor-to-background ratio after few minutes of intravenous administration. The first-in-human trial was also conducted. The effective dose was estimated to be 0.00467 mSv/MBq (4.67 mSv/GBq), resulting in a radiation dose of up to 1.73 mSv for the 370 MBq injection of [99mTc]Tc-DTPA-bis(ChoEA). CONCLUSIONS: The synthesized radioprobe [99mTc]Tc-DTPA-bis(ChoEA) accumulates specifically in choline kinase-overexpressed tumors with a high signal-to-noise ratio. The preclinical and first-in-man data suggested that [99mTc]Tc-DTPA-bis(ChoEA) could potentially be used as a diagnostic SPECT tracer in the monitoring and staging of cancer.

Microbe mediated remediation of dyes, explosive waste and polyaromatic hydrocarbons, pesticides and pharmaceuticals.

Industrialization and human activities have led to serious effects on environment. With the progress taking place in the biodegradation field, it is important to summarize the latest advancement. In this review, we intend to provide insights on the recent progress on the biodegradation of environmental contaminants such as dyes, pesticides, pharmaceuticals, explosive waste and polyaromatic hydrocarbons by microorganisms. Along with the biodegradation of environmental contaminants, toxicity effects have also been discussed.