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Abstract We sought to evaluate the genomic and transcriptomic landscapes in primary and metastatic germ cell tumors (GCTs; N = 138) to uncover factors that drive cisplatin resistance. Prevalence was calculated for platinum-resistant alterations (PRAs; KRAS, TP53, and KIT mutations, and MDM2 amplification) and high copy number amplifications (CNA ≥ 6 copies). Tumors were designated as chemo-naïve (PreC, N = 66) or post-chemotherapy (PostC, N = 17). A transcriptomic signature associated with platinum sensitivity (PSS, high suggests increased sensitivity) was applied. KIT mutations were observed in 14.5% of primary versus 1.8% of met and 0% of lymph. TP53 mutations were identified in 10% of primary GCTs versus 17% of met and 16.7% of lymph. MDM2 CNAs were similar between sites. PRA-positive PreC GCTs had significantly lower average PSS scores compared to PRA-negative tumors. Lower PSS scores in chemo-naïve tumors were associated with PRAs, suggesting a potential mechanism for platinum resistance.

Abstract In this study, a novel approach for the environmentally conscious extraction of titanium dioxide from ilmenite ore while limiting the environmental impact and enhancing the advantage from an economic process. Leaching conditions were tested with different acids for effective separation of the TiO2 and were optimized concerning different experimental parameters. TiO2 and TiO2NPs were characterized using with different tools. Catechol polyurethane foam immobilized with TiO2NPs was prepared and its antimicrobial action was tested against Gram-negative bacterium E. coli, Gram-positive bacterium B. cereus, and fungus A. niger. CAT-PUF /TiO2NPs showed antimicrobial effect against E. coli, B. cereus, and A. niger with inhibition zones of 27 ± 0.14, 12 ± 0.14, and 22 ± 0.06 mm, respectively. Incorporating bioinformatics, this research contributes to the burgeoning field of nanotechnology-enabled antimicrobial materials, offering insights into the potential applications of CAT-PUF/TiO2NPs in combating microbial threats. Through bio-informatics tools, the potential toxicity of the synthesized nanoparticles was assessed, providing valuable insights into their safety profile and environmental impact. Furthermore, simulating the binding affinity between the nanoparticles and target biomolecules, such as cell membrane proteins or enzyme receptors, this aspect of the research sheds light on the mechanistic underpinnings of their antimicrobial efficacy.

PURPOSEThe Brazilian Public Health System (BPHS) serves approximately 71,730 patients with prostate cancer (PC) every year for which androgen deprivation therapy (ADT) is the primary treatment for patients with advanced hormone-sensitive prostate cancer (aHSPC). Androgen receptor pathway inhibitors (ARPIs) are not accessible through the BPHS. Using the BPHS as a model, this study assesses the long-term economic effect of surgical versus medical castration in aHSPC treatment to strategize cost reduction and the incorporation of ARPI in developing countries.PATIENTS AND METHODSData of patients with aHSPC (ie, TxN1M0 ineligible for local treatment or TxNxM1) from the BPHS database were analyzed from January 1, 2011, to December 31, 2021, using the TECHTRIALS artificial intelligence platform. The main outcomes were quantitative and descriptive analyses as well as a cost analysis of surgical versus chemical castration.RESULTSOf the 274,519 patients with aHSPC who received active treatment during the 11-year study period, 90% (n = 246,683) underwent chemical castration and 10% (n = 27,836) underwent bilateral subcapsular orchiectomy (BSO). The median duration of chemical castration was 28 months. The BPHS spent an estimated total of $665,552,091.40 US dollars (USD) on chemical castration and $5,939,348.47 USD on BSO, respectively. The cost per patient was $2,698 USD and $213.37 USD for chemical castration and BSO, respectively. Hypothetically, if all patients with aHSPC had undergone BSO, the total direct cost for the BPHS would have been $42,774,832.20 USD, saving $622,777,259.20 USD over 11 years, making it possible to offer low-dose abiraterone to 65% of aHSPC patients.CONCLUSIONOn the basis of this extensive financial analysis from the world's largest public health system database, BSO appears to be a valuable alternative to chemical castration for treating aHSPC. In resource-limited environments, the cost savings from using BSO may allow access to drugs that will improve survival such as ARPIs.

Desulfurization is the process of removing the organic sulfur component from fuel oils. In this work, model fuel containing the sulfur compounds benzothiophene and dibenzothiophene was oxidized using plasma technique and plasma technique assisted by 30% hydrogen peroxide. Acetonitrile was used as a polar solvent in a liquid-liquid extraction stage that followed the oxidation reaction to remove the produced sulfones from the model fuel. The oxidation process was performed at operating conditions including the molar ratio of hydrogen peroxide to sulfur (5:1), temperature 50 ºC, air flow rate 75 ml/min, and voltage 11000 volts. The oxidation reaction was done using a dielectric barrier discharge process for generating non-thermal plasma. The plasma technique and a combination of plasma with hydrogen peroxide together to oxidize BT and DBT. The results showed that both methods follow the pseudo-first-order reaction and that the removal efficiency is 93.78% per cent for plasma compared to the combination of plasma and hydrogen peroxide together, which reached 95.12%. Hydrogen peroxide (H2O2) in an aqueous solution is the most commonly used oxidant in oxidative desulfurization. However, the use of hydrogen peroxide creates organ wastewater, which must be collected and disposed of after the reaction, whereas ozone is a highly promising oxidant for oxidative desulfurization(ODS) since it does not produce wastewater and has a greater oxidation potential (2.8V) than hydrogen peroxide (1.7V). To put oxidative desulfurization with ozone into practice, establishing a more efficient desulfurization process with ozone is extremely desirable.

Background: The structural, physical, and mechanical properties of denture-based acrylic resin are still compromised by water sorption, water solubility, and porosity. These issues have long called for improved techniques, and the use of nanoparticles is one of them. The main objective of the current investigation was to evaluate and contrast some physical parameters (water sorption, water solubility, and porosity) after the incorporation of ZrO2 nanoparticles (0%, 3% and 5%) into heat-cured acrylic denture base materials (Ivoclare, Major) and microwave-cured acrylic (Acron MC). Materials and methods: A total of 60 resin specimens were manufactured, including 5 specimens for each concentration of ZrO2 NP (30 for porosity and 30 for water sorption and solubility). Followed the manufacturer's directions for preparing the sample of each material. Results: The results were analysed with descriptive statistics, Analysis of Variance(ANOVA) test, Duncan multiple range test, and independent T test demonstrated that the addition of nanoparticles (3% and 5%) decreased water sorption, water solubility, and porosity of PMMA(polymethyl methacrylate) for both types(microwave-cured and heat-cured acrylic denture base materials). Where, at 3%, the ZrO2 nanoparticles showed the best values for all tests compared to the control group. Conclusions: ZrO2 (3% and 5%) nanoparticle reinforcement of acrylic resin can be a useful tactic for lowering water sorption, solubility and porosity, thereby enhancing the performance of the material in various applications for microwave-cured and heat-cured acrylic denture base materials.

Aims: The study seeks to investigate the hardness and chemical structure of the MWCNTs-Nanonystatin-modified hard chairside denture reliner after nanosizing nystatin macromolecules to be conjugated with MWCNTs for loading into chairside hard denture reliners. Materials and Methods: The examined material was chairside hard denture reliner (CHDR) (Rebase II). Tokuyama®. Japan. The nano additives applied were Nystatin (Nys). SDI (Samirraa’ Drugs, Iraq) and Multiwalled carbon nanotubes (MWCNT, 95%, VCN materials). Chairside relining material was manufactured following the manufacturers' specifications. Surface hardness was tested using a shore D durometer tester, while FTIR Spectroscopy was conducted using an IRAFFINITY-1S-FTIR spectrophotometer (SHIMADZU, Japan). The chairside hard denture reliner specimens were divided into (a control group,5 specimens) and a modified chairside hard denture reliner (MWCNTs-Nys- CHDR at 0.025%, 0.05%, and 0.1% by weight, 5 specimens for each group). The CHDR specimens have dimensions of 10×10×3.3 ±0.2mm. Total number of samples in this study was 40 samples. Results: The bioactive modification of CHDR resulted in increased hardness without changing the chemical structure of the materials in comparison to the control group. Conclusions: The bioactive modification of CHDR led to improved hardness, without any chemical modifications.

This work presents an investigation into the ultra-desulfurization of heavy naphtha fuel (model using BT and DBT) using oxidation and solvent extraction techniques. Ozone produced by the DBD (Dielectric barrier discharge) plasma generator was employed in the oxidation process as an oxidant, and acetonitrile was used as a solvent extraction. Box-Behnken experimental design was adopted in the current study to examine oxidation desulfurization by non-thermal plasma for the various operation conditions including time, flow rate, and temperature on sulfur removal efficiency. Acetonitrile with an oxidized oil/solvent ratio of 1:1(v/v ratio) was utilized as the extraction solvent. The results showed that the maximum sulfur removal of about 91% was obtained with a temperature of 50°C, flow rate of 75 ml/min, and time of 4 hours.

Abstract Nanocomposites incorporating titanium dioxide (TiO2) have a significant potential for various industrial and medical applications. These nanocomposites exhibit selectivity as antimicrobial and anticancer agents. Antimicrobial activity is crucial for medical uses, including applications in food processing, packaging, and surgical instruments. Additionally, these nanocomposites exhibit selectivity as anticancer agents. A stable nanocomposite as a new anticancer and antibacterial chemical was prepared by coupling titanium dioxide nanoparticles with a polyurethane foam matrix through the thiourea group. The titanium dioxide/thiopolyurethane nanocomposite (TPU/TiO2) was synthesized from low-cost Ilmenite ore and commercial polyurethane foam. EDX analysis was used to determine the elemental composition of the titanium dioxide (TiO2) matrix. TiO2NPs were synthesized and were characterized using TEM, XRD, IR, and UV–Vis spectra. TiO2NPs and TPU foam formed a novel composite. The MTT assay assessed Cisplatin and HepG-2 and MCF-7 cytotoxicity in vitro. Its IC50 values for HepG-2 and MCF-7 were 122.99 ± 4.07 and 201.86 ± 6.82 µg/mL, respectively. The TPU/TiO2 exhibits concentration-dependent cytotoxicity against MCF-7 and HepG-2 cells in vitro. The selective index was measured against both cell lines; it showed its safety against healthy cells. Agar well-diffusion exhibited good inhibition zones against Escherichia coli (12 mm), Bacillus cereus (10 mm), and Aspergillus niger (19 mm). TEM of TPU/TiO2-treated bacteria showed ultrastructure changes, including plasma membrane detachment from the cell wall, which caused lysis and bacterial death. TPU/TiO2 can treat cancer and inhibit microbes in dentures and other items. Also, TPU/TiO2 inhibits E. coli, B. cereus, and A. niger microbial strains.

Background and aims: Combination therapy is a promising new strategy that has been proposed to increase the efficacy of cancer treatment. We aimed to investigate the anti-cancer activity of rifampicin monotherapy and its combination with doxorubicin against hepatocellular carcinoma (HCC). Materials and methods: The in vitro half maximal inhibitory concentration (IC50) and selectivity index (SI) of the drugs under investigation against HepG2 and human lung fibroblast (WI38) cell lines were determined. For the in vivo experiment, male Sprague-Dawley albino rats were injected with thioacetamide at 200 mg/kg twice a week for 90 days; HCC development was confirmed histopathologically. Following HCC induction, the rats were treated with intraperitoneal doxorubicin, rifampicin, or their combination for 45 or 90 days. After sacrifice, the livers were examined histopathologically. The levels of aminotransferases, albumin, bilirubin, malondialdehyde, superoxide dismutase (SOD), catalase (CAT), total antioxidant capacity (TAC), and nitric oxide were measured by spectrophotometry. Alpha-fetoprotein, cancer antigen 19-9, tumor necrosis factor-alpha, interleukin-6, Bcl-2-associated X protein, caspase 3, caspase 8, and p53 were estimated using ELISA. Results: In vitro, the combination of doxorubicin and rifampicin showed the highest SI of 3.43. In vivo, among the measured markers, the levels of TAC, CAT, SOD, and p53 decreased (P

Abstract Background Non‐canonical WNT family (WNT5A pathway) signaling via WNT5A through ROR1 and its partner, ROR2, or Frizzled2 (FZD2) is linked to processes driving tumorigenesis and therapy resistance. We utilized a large dataset of urothelial carcinoma (UC) tumors to characterize non‐canonical WNT signaling through WNT5A, ROR1, ROR2, or FZD2 expression. Methods NextGen Sequencing of DNA (592 genes or WES)/RNA (WTS) was performed for 4125 UC tumors submitted to Caris Life Sciences. High and low expression of WNT5A, ROR1, ROR2, and FZD2 was defined as ≥ top and

Background Patients with paraneoplastic syndromes (PNS) are excluded from clinical trials involving immune checkpoint inhibitors (ICIs) due to safety concerns. Moreover, real-world data on efficacy and safety is scarce.Methods In this retrospective study, data were collected on patients with PNS and solid tumors receiving ICI between 2015 and 2022 at nine institutions. Patients were classified into: Cohort 1 (pre-existing PNS before ICI initiation), cohort 2 (PNS during ICI treatment), and cohort 3 (PNS after ICI discontinuation). Patients with metastatic non-small cell lung cancer (NSCLC) (mNSCLC) from cohort 1 were matched to patients who were PNS-free at each institution up to a 1:3 ratio for age, sex, type of ICI, use of concurrent chemotherapy, and number of lines of systemic therapy prior to ICI initiation. Kaplan-Meier method was used to assess overall survival (OS) and time-to-next treatment (TTNT).Results Among 109 patients with PNS treated with ICIs, median age at ICI initiation was 67 years (IQR: 58–74). The most represented cancer type was NSCLC (n=39, 36%). In cohort 1 (n=55), PNS exacerbations occurred in 16 (29%) patients with median time to exacerbation after ICI of 1.1 months (IQR: 0.7–3.3). Exacerbation or de novo PNS prompted temporary/permanent interruption of ICIs in 14 (13%) patients. For cohort 2 (n=16), median time between ICI initiation and de novo PNS was 1.2 months (IQR: 0.4–3.5). Treatment-related adverse events (trAEs) occurred in 43 (39%) patients. Grade ≥3 trAEs occurred in 18 (17%) patients. PNS-directed immunosuppressive therapy was required in 55 (50%) patients. We matched 18 patients with mNSCLC and PNS (cohort 1) to 40 without PNS, treated with ICIs. There was no significant difference in OS or TTNT between patients with mNSCLC with and without PNS, although a trend was seen towards worse outcomes in patients with PNS. TrAEs occurred in 6/18 (33%) and 14/40 (35%), respectively. Grade ≥3 trAEs occurred in 4 (22%) patients with PNS and 7 (18%) patients without PNS.Conclusions Exacerbations of pre-existing PNS occurred in 29% of patients treated with ICIs and both exacerbations and de novo PNS occur early in the ICI course. TrAE from ICIs were similar between patients with and without PNS. Our data suggest that pre-existing PNS should not preclude consideration of ICI therapy although patients may not derive the same clinical benefit compared with patients without PNS.

Water quality indexes (WQI) were applied in the Tigris River using thirteen water quality parameters (pH, chlorides, sulfate, nitrate, salts, BOD5, iron, boron, zinc, lead, cadmium, copper, and chromium) in this study. They were calculated for the six years from 2008 to 2013, then compared with sets of standard values of rivers maintaining system. The results indicated that the water quality of the Tigris River for CCME-WQI was generally "Fair" to "Good" in 2008, 2009, and 2010 (CCME WQI range: 69.67 - 88.46) for all sites. CCME WQI values fell from "Marginal" to "Fair" in all sites over the last two years (2012 and 2013). WPI was " pure" to " Moderately polluted " from 2008-2011 (WPI range: 0.6-1.08) for all sites. Whereas, WPI values dropped to ranging from " Moderately polluted " to "polluted" (WPI range: 1.1-2.3) in all sites at 2012 and 2013. The effect of various human activities and dryness were evident on some parameters such as the heavy metals, Sulfate, Chlorides, Salts and Nitrate. Where their concentrations exceeded the permissible limits of the rivers maintaining system in most of the sites, and thus were the reason for the decline in the values of the indices. So, the monitoring of the Tigris River is important for proper management and for preserving this important water source.

Renal cell carcinoma (RCC) is the most common type of kidney cancer and is divided into two distinct subtypes, clear cell renal cell carcinoma (ccRCC) and non-clear cell renal cell carcinoma (nccRCC). Although many treatments exist for RCC, these are largely based on clinical trials performed in ccRCC and there are limited studies on the management of nccRCC. Non-clear cell RCC consists of multiple histological subtypes: papillary, chromophobe, translocation, medullary, collecting duct, unclassified, and other rare histologies. Due to variations in pathogenesis and therapeutic response, therapy should be tailored to specific variant histologies. For patients with localized nccRCC, surgical resection remains the gold standard. In the metastatic setting, the standard of care has yet to be clearly defined, and most guidelines recommend clinical trial participation. General therapeutic options include immunotherapy, either as monotherapy or in combination, targeted therapies such as vascular endothelial growth factor tyrosine kinase inhibitors and MET inhibitors, and chemotherapy in certain subtypes. Here we present a review of the incidence and pathogenesis of the various subtypes, as well as available clinical data to support therapeutic recommendations for these subtypes. We also highlight currently available clinical trials in nccRCC and future directions in investigating novel treatment modalities tailored to patients with variant histology.

Abstract Herein, we present the utilization of Ni2+-doped, amine-functionalized, UiO-66-NH2 metal–organic framework (MOF) nanoparticles deposited onto multi-walled carbon nanotubes (MWCNTs) as a precursor to generate electrocatalytically active catalyst towards methanol (MeOH) oxidation. The electrode material displayed an onset potential of 0.42 V (vs Hg/HgO) with maximum activity at 1 M MeOH concentration (143 mA/cm2 current density at 0.6 V vs Hg/HgO). The catalyst also demonstrated high stability, retaining 93.5% of its initial activity under continuous electrolysis for 1 h, and 84.1% after 10 h.

Background: Guidelines suggest that active surveillance (AS) may be considered for select patients with favorable intermediate-risk (fIR) prostate cancer. Objective: To compare the outcomes between fIR prostate cancer patients included by Gleason score (GS) or prostate-specific antigen (PSA). Most patients are classified with fIR disease due to either a 3 + 4 = 7 GS (fIR-GS) or a PSA level of 10–20 ng/ml (fIR-PSA). Previous research suggests that inclusion by GS 7 may be associated with worse outcomes. Design, setting, and participants: We conducted a retrospective cohort study of US veterans diagnosed with fIR prostate cancer from 2001 to 2015. Outcome measurements and statistical analysis: We compared the incidence of metastatic disease, prostate cancer–specific mortality (PCSM), all-cause mortality (ACM), and receipt of definitive treatment between fIR-PSA and fIR-GS patients managed with AS. Outcomes were compared with those of a previously published cohort of patients with unfavorable intermediate-risk disease using cumulative incidence function and Gray’s test for statistical significance. Results and limitations: The cohort included 663 men; 404 had fIR-GS (61%) and 249 fIR-PSA (39%). There was no evidence of difference in the incidence of metastatic disease (8.6% vs 5.8%, p = 0.77), receipt of definitive treatment (77.6% vs 81.5%, p = 0.43), PCSM (5.7% vs 2.5%, p = 0.274), and ACM (16.8% vs 19.1%, p = 0.14) between the fIR-PSA and fIR-GS groups at 10 yr. On multivariate regression, unfavorable intermediate-risk disease was associated with higher rates of metastatic disease, PCSM, and ACM. Limitations included varying surveillance protocols. Conclusions: There is no evidence of difference in oncological and survival outcomes between men with fIR-PSA and fIR-GS prostate cancer undergoing AS. Thus, presence of GS 7 disease alone should not exclude patients from consideration of AS. Shared decision-making should be utilized to optimize management for each patient. Patient summary: In this report, we compared the outcomes of men with favorable intermediate-risk prostate cancer in the Veterans Health Administration. We found no significant difference between survival and oncological outcomes.

One of the possible candidates for the treatment of diabetic cardiomyopathy is liraglutide, a glucagon-like peptide-1 receptor (GLP1R) agonist. In this study, the impacts of liraglutide on the integrin-linked kinase (ILK)-related PI3K/AKT axis in rats with type 2 diabetes induced via streptozotocin were examined. Twenty-four Wistar albino rats were distributed in four different groups, and a high-fat diet and streptozotocin were used to induce type 2 in two groups. Rats in the untreated control groups were administered 0.9% NaCl solution over a 6-week period, and those in the treatment groups were administered 0.9% NaCl for 3 weeks, followed by subcutaneous injection of liraglutide (150 μg/kg) for an additional 3 weeks. In the liraglutide-treated diabetic group, the heart-to-body weight ratio was significantly reduced, levels of cardiac biomarkers, troponin I and creatine-kinase-MB, were improved; activities of antioxidant enzymes, glutathione peroxidase and superoxide dismutase, were increased; and levels of malondialdehyde were decreased. Western blotting and immunohistochemical studies revealed increased levels of ILK, P-PI3K, P-AKT, and BCL2, as well as those of caspase 3, BAX, and P-PTEN, indicating mitigation of cardiomyocyte apoptosis. Our results show that liraglutide, by targeting GLP1Rs, enhances the expression of proteins in the ILK/PI3K/AKT/PTEN pathway and thereby exerts its cardioprotective effects in rats with DCM.

Background: Limited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations. Methods: This is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity. Results: 1383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32–1.67]); Black patients (aOR 1.74; 95 CI 1.24–2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70–6.79) and Other (aOR 2.97; 95 CI 1.71–5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83–12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63–3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20–2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66–3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89–22.6]). Hispanic ethnicity, timing, and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status. Conclusions: Using one of the largest registries on cancer and COVID-19, we identified patient and BC-related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to non-Hispanic White patients. Funding: This study was partly supported by National Cancer Institute grant number P30 CA068485 to Tianyi Sun, Sanjay Mishra, Benjamin French, Jeremy L Warner; P30-CA046592 to Christopher R Friese; P30 CA023100 for Rana R McKay; P30-CA054174 for Pankil K Shah and Dimpy P Shah; KL2 TR002646 for Pankil Shah and the American Cancer Society and Hope Foundation for Cancer Research (MRSG-16-152-01-CCE) and P30-CA054174 for Dimpy P Shah. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH). The funding sources had no role in the writing of the manuscript or the decision to submit it for publication. Clinical trial number: CCC19 registry is registered on ClinicalTrials.gov, NCT04354701.

Abstract Background Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death, so we should be concerned and look for effective/less-harmful treatments than chemotherapeutics already clinically in application. Aspirin works well ''in conjunction'' with other therapies for HCC since aspirin can boost the sensitivity of anti-cancer activity. Vitamin C also was shown to have antitumor effects. In this study, we examined the anti-HCC activities of synergistic combination (aspirin and vitamin C) vs. doxorubicin on HCC-bearing rats and hepatocellular carcinoma (HepG-2) cells. Methods In vitro, we evaluated IC50 and selectivity index (SI) using HepG-2 and human lung fibroblast (WI-38) cell lines. In vivo, four rat groups were used: Normal, HCC (intraperitoneally (i.p.) administered 200 mg thioacetamide/kg/twice a week), HCC + DOXO (HCC-bearing rats i.p. administered 0.72 mg doxorubicin (DOXO)/rat/once a week), and HCC + Aspirin + Vit. C (i.p. administered vitamin C (Vit. C) 4 g/kg/day after day concomitant with aspirin 60 mg/kg/orally day after day). We evaluated biochemical factors [aminotransferases (ALT and AST), albumin, and bilirubin (TBIL) spectrophotometrically, caspase 8 (CASP8), p53, Bcl2 associated X protein (BAX), caspase 3 (CASP3), alpha-fetoprotein (AFP), cancer antigen 19.9 (CA19.9), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) using ELISA], and liver histopathologically. Results HCC induction was accompanied by significant time-dependent elevations in all measured biochemical parameters except the p53 level significantly declined. Liver tissue architecture organization appeared disturbed with cellular infiltration, trabeculae, fibrosis, and neovascularization. Following drug medication, all biochemical levels significantly reversed toward normal, with fewer signs of carcinogenicity in liver tissues. Compared to doxorubicin, aspirin & vitamin C therapy ameliorations were more appreciated. In vitro, combination therapy (aspirin & vitamin C) exhibited potent cytotoxicity (HepG-2 IC50 of 17.41 ± 1.4 µg/mL) and more excellent safety with a SI of 3.663. Conclusions Based on our results, aspirin plus vitamin C can be considered reliable, accessible, and efficient synergistic anti-HCC medication.

Abstract In recent decades, variability in the incidence and mortality of kidney cancer (KC) has been reported. This study aimed to compare trends in incidence, mortality, and disability-adjusted life years (DALY) of KC between the European Union (EU) 15 + countries and 6 World Health Organization (WHO) regions. The data of KC Age-standardized incidence rates (ASIRs), age-standardized mortality rates (ASMRs), and age-standardized DALYs were extracted from the Global Burden of Disease database. Joinpoint regression was employed to examine trends. From 1990 to 2019, the ASIR increased in most countries except for Luxembourg (males), the USA (females) and Austria and Sweden (both sexes). ASIR increased across all 6 WHO regions for both sexes except for females in Americas. The ASMR increased in 10/19 countries for males and 9/19 for females as well across most WHO regions. The mortality-to-incidence ratio (MIR) decreased in all countries and WHO regions. Trends in DALYs were variable across countries and WHO regions. While the incidence and mortality from KC rose in most EU15 + countries and WHO regions from 1990 to 2019, the universal drop in MIR suggests an overall improvement in KC outcomes. This is likely multifactorial, including earlier detection of KC and improved treatments.

As the therapeutic landscape for metastatic clear cell renal cell carcinoma (mccRCC) expands to include vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) and immunotherapies, new challenges are in place for evaluating and treating refractory disease. Assessing and managing refractory disease has several elements: (1) the mechanism(s) of front-line treatment, (2) timing of progressive disease, (3) rapidity and sites of progressing disease, (4) use of adjuvant therapy, and (5) incorporation of surgical and radiation techniques. These variables all have distinct impact on the biology of refractory or resistant mccRCC. A better understanding of the essential mechanisms of both primary and secondary immunotherapy resistance will inform biomarker development and therapeutic strategies in the refractory setting. This paper addresses the current understanding of treatment sequencing in refractory mccRCC, focusing on treatment options with prospective clinical trial data, considers refractory mccRCC after adjuvant immunotherapy, and incorporates radiation or surgical resection for oligoprogressive disease.

Background: Data regarding outcomes among patients with cancer and co-morbid cardiovascular disease (CVD)/cardiovascular risk factors (CVRF) after SARS-CoV-2 infection are limited. Objectives: To compare Coronavirus disease 2019 (COVID-19) related complications among cancer patients with and without co-morbid CVD/CVRF. Methods: Retrospective cohort study of patients with cancer and laboratory-confirmed SARS-CoV-2, reported to the COVID-19 and Cancer Consortium (CCC19) registry from 03/17/2020 to 12/31/2021. CVD/CVRF was defined as established CVD or no established CVD, male ≥ 55 or female ≥ 60 years, and one additional CVRF. The primary endpoint was an ordinal COVID-19 severity outcome including need for hospitalization, supplemental oxygen, intensive care unit (ICU), mechanical ventilation, ICU or mechanical ventilation plus vasopressors, and death. Secondary endpoints included incident adverse CV events. Ordinal logistic regression models estimated associations of CVD/CVRF with COVID-19 severity. Effect modification by recent cancer therapy was evaluated. Results: Among 10,876 SARS-CoV-2 infected patients with cancer (median age 65 [IQR 54–74] years, 53% female, 52% White), 6253 patients (57%) had co-morbid CVD/CVRF. Co-morbid CVD/CVRF was associated with higher COVID-19 severity (adjusted OR: 1.25 [95% CI 1.11–1.40]). Adverse CV events were significantly higher in patients with CVD/CVRF (all p

By the reaction of Benzoin with melamine and Benzoin with 5-aminosalysilc acid a new Schiff base is obtained the reaction of the legends with Mn++, Zn++, and Ag + salts leads to the complexes [M (L)2 ] X at PH=7-6, and [M (L)2 ] at PH=9-10, L= BMA, BMS M= Mn++ Zn++ and Ag +, Several chemical and physical measurements, such as melting point, molar conductivity, and magnetic properties, as well as FT-IR spectroscopy, UV-VIS spectroscopy element analysis (C.H.N.), and (1 H-NMR)spectroscopy, and GC-MASS. was used to identify the produced ligands and complex structures, the complexes of Mn++, and Znand ++ give hexacoordinated complexes having the shape octane al but Ag+ gives tetracoordinate complexes. having shape tetrahedral. then they were screened for biological activity using agar plate diffusion technique against Gram(+) (Staphylococcus aureus bacteria, pseudomonas aeruginosa bacteria) and Gram(−) (Escherichia coli bacteria, Klebsiella pneumonia bacteria) When compared to streptomycin and trimethoprim drug, all these ligands and their complexes show good antimicrobial effectualness.

Summary: Background: Metastatic renal cell carcinoma (mRCC) is a heterogenous disease with poor 5-year overall survival (OS) at 14%. Patients with mRCC to endocrine organs historically have prolonged OS. Pancreatic metastases are uncommon overall, with mRCC being the most common etiology of pancreatic metastases. In this study, we report the long-term outcomes of patients with mRCC to the pancreas in two separate cohorts. Methods: We performed a multicenter, international retrospective cohort study of patients with mRCC to the pancreas at 15 academic centers. Cohort 1 included 91 patients with oligometastatic disease to the pancreas. Cohort 2 included 229 patients with multiples organ sites of metastases including the pancreas. The primary endpoint for Cohorts 1 and 2 was median OS from time of metastatic disease in the pancreas until death or last follow up. Findings: In Cohort 1, the median OS (mOS) was 121 months with a median follow up time of 42 months. Patients who underwent surgical resection of oligometastatic disease had mOS of 100 months with a median follow-up time of 52.5 months. The mOS for patients treated with systemic therapy was not reached. In Cohort 2, the mOS was 90.77 months. Patients treated with first-line (1L) VEGFR therapy had mOS of 90.77 months; patients treated with IL immunotherapy (IO) had mOS of 92 months; patients on 1L combination VEGFR/IO had mOS of 74.9 months. Interpretations: This is the largest retrospective cohort of mRCC involving the pancreas. We confirmed the previously reported long-term outcomes in patients with oligometastatic pancreas disease and demonstrated prolonged survival in patients with multiple RCC metastases that included the pancreas. In this retrospective study with heterogeneous population treated over 2 decades, mOS was similar when stratified by first-line therapy. Future research will be needed to determine whether mRCC patients with pancreatic metastases require a different initial treatment strategy. Funding: Statistical analyses for this study were supported in part by the University of Colorado Cancer Center Support Grant from the NIH/NCI, P30CA046934-30.

PurposeWe hypothesized that two-tier re-classification of the “M” (metastasis) domain of the Tumor-Node-Metastasis (TNM) staging of Renal Cell Carcinoma (RCC) may improve staging accuracy than the current monolithic classification, as advancements in the understanding of tumor biology have led to increased recognition of the heterogeneous potential of metastatic RCC (mRCC).MethodsMulticenter retrospective analysis of patients from the REMARCC (REgistry of MetAstatic RCC) database. Patients were stratified by number of metastases into two groups, M1 (≤3, “Oligometastatic”) and M2 (>3, “Polymetastatic”). Primary outcome was overall survival (OS). Secondary outcomes were cancer-specific survival (CSS). Cox-regression and Kaplan-Meier (KMA) analysis were utilized for outcomes, and receiver operating characteristic analysis (ROC) was utilized to assess diagnostic accuracy compared to current “M” staging.Results429 patients were stratified into proposed M1 and M2 groups (M1 = 286/M2 = 143; median follow-up 19.2 months). Cox-regression revealed M2 classification as an independent risk factor for worsened all-cause mortality (HR=1.67, p=0.001) and cancer-specific mortality (HR=1.74, p

Patients with cancer represent a particularly vulnerable population at risk of adverse outcomes related to COVID-19. Collectively, the initial studies, including patients with and without cancer, confirmed that patients with cancer had a higher risk of complications and death related to COVID-19. Subsequent studies on patients with COVID-19 and cancer investigated patient and disease-related factors associated with COVID-19 severity and morality. Multiple interconnected factors include demographics, comorbidities, cancer-associated variables, treatment side effects, and other parameters. However, there is a lack of clarity on the contributions of any one factor. In this commentary, we deconvolute the data of specific risk factors associated with worse outcomes due to COVID-19 in cancer patients and focus on understanding the recommended guidelines to mitigate COVID-19 risk in this vulnerable population. In the first section, we highlight the key parameters, including age and race, cancer status, type of malignancy, cancer therapy, smoking status and comorbidities that impact outcomes for cancer patients with COVID-19. Next, we discuss efforts made at the patient, health system, and population levels to mitigate the effects of the ongoing outbreak for patients with cancer, including (1) screening, barrier and isolation strategies (2), Masking/PPE (3), vaccination, and (4) systemic therapies (e.g., evusheld) to prevent disease onset in patients. In the last section, we discuss optimal treatment strategies for COVID-19, including additional therapies for patients with COVID-19 and cancer. Overall, this commentary focuses on articles with high yield and impact on understanding the evolving evidence of risk factors and management guidelines in detail. We also emphasize the ongoing collaboration between clinicians, researchers, health system administrators and policymakers and how its role will be important in optimizing care delivery strategies for patients with cancer. Creative patient-centered solutions will be critical in the coming years, post the pandemic.

Summary: Background: Breakthrough SARS-CoV-2 infections following vaccination against COVID-19 are of international concern. Patients with cancer have been observed to have worse outcomes associated with COVID-19 during the pandemic. We sought to evaluate the clinical characteristics and outcomes of patients with cancer who developed breakthrough SARS-CoV-2 infections after 2 or 3 doses of mRNA vaccines. Methods: We evaluated the clinical characteristics of patients with cancer who developed breakthrough infections using data from the multi-institutional COVID-19 and Cancer Consortium (CCC19; NCT04354701). Analysis was restricted to patients with laboratory-confirmed SARS-CoV-2 diagnosed in 2021 or 2022, to allow for a contemporary unvaccinated control population; potential differences were evaluated using a multivariable logistic regression model after inverse probability of treatment weighting to adjust for potential baseline confounding variables. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) are reported. The primary endpoint was 30-day mortality, with key secondary endpoints of hospitalization and ICU and/or mechanical ventilation (ICU/MV). Findings: The analysis included 2486 patients, of which 564 and 385 had received 2 or 3 doses of an mRNA vaccine prior to infection, respectively. Hematologic malignancies and recent receipt of systemic anti-neoplastic therapy were more frequent among vaccinated patients. Vaccination was associated with improved outcomes: in the primary analysis, 2 doses (aOR: 0.62, 95% CI: 0.44–0.88) and 3 doses (aOR: 0.20, 95% CI: 0.11–0.36) were associated with decreased 30-day mortality. There were similar findings for the key secondary endpoints of ICU/MV (aOR: 0.60, 95% CI: 0.45–0.82 and 0.37, 95% CI: 0.24–0.58) and hospitalization (aOR: 0.60, 95% CI: 0.48–0.75 and 0.35, 95% CI: 0.26–0.46) for 2 and 3 doses, respectively. Importantly, Black patients had higher rates of hospitalization (aOR: 1.47, 95% CI: 1.12–1.92), and Hispanic patients presented with higher rates of ICU/MV (aOR: 1.61, 95% CI: 1.06–2.44). Interpretation: Vaccination against COVID-19, especially with additional doses, is a fundamental strategy in the prevention of adverse outcomes including death, among patients with cancer. Funding: This study was partly supported by grants from the National Cancer Institute grant number P30 CA068485 to C-YH, YS, SM, JLW; T32-CA236621 and P30-CA046592 to C.R.F; CTSA 2UL1TR001425-05A1 to TMW-D; ACS/FHI Real-World Data Impact Award, P50 MD017341-01, R21 CA242044-01A1, Susan G. Komen Leadership Grant Hunt to MKA. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH).

Abstract Objective To analyse the effect of age at diagnosis on clinical outcomes of localized prostate cancer (PCa) treated with radiation therapy. Subjects and methods We identified 12 784 patients with intermediate‐ or high‐risk localized PCa treated with radiation therapy (RT) and neoadjuvant androgen deprivation therapy (ADT) between 2000 and 2015 from nationwide Veterans Affairs data. Patients were grouped into three age categories (≤59, 60–69, and ≥70 years old). Outcomes included immediate PSA response (3‐month post‐RT PSA and 2‐year PSA nadir, grouped into

Herbal products are increasingly used against lipid to attenuate its negative impact on vasculature system. However, there are uncertainty regarding the best administration approaches and preparation of herbal product to be used due to variation in absorption rate and extent with subsequent impaction on the lipid levels. The aim of the present study was comparing the pharmacological and analytical aspects of soaked versus powder form of Hypericum perforatum; a well-known anti-hyperlipidemic herbal product, using atorvastatin drug as a reference drug for comparison in addition to controlling groups (on/off lipid diet) handled as an additional control group. To conduct this research, the hyperlipidemia mice models were created by exposing the mice to a fatty diet and using H. perforatum and atorvastatin for evaluation. The plant extracts were also analyzed for active constituents. The results indicate that the plant analysis detected the presence of different antihyperlipidemic agents and the plant has effectively reduced plasma lipid parameters in exposed mice compared to control group; especially when taken forms of the plant was used. The study concluded that; soaked H. perforatum extract shown an effective reduction of lipid parameters and analysis of which revealed the presence of herbal active constituent which might be utilized in industrial pharmacy for new drug innovation.

A comprehensive evaluation of the clear cell renal cell carcinoma (ccRCC) immune landscape was found using 584 RNA-sequencing datasets from The Cancer Genome Atlas (TCGA), we identified 17 key dysregulated immune-associated genes in ccRCC based on association with clinical variables and important immune pathways. Of the numerous findings from our analyses, we found that several of the 17 key dysregulated genes are heavily involved in interleukin and NF-kB signaling and that somatic copy number alteration (SCNA) hotspots may be causally associated with gene dysregulation. More importantly, we also found that key immune-associated genes and pathways are strongly upregulated in ccRCC. Our study may lend novel insights into the clinical implications of immune dysregulation in ccRCC and suggests potential immunotherapeutic targets for further evaluation.

Abstract Background CDK12 inactivation leading to increased neoantigen burden has been hypothesized to sensitize tumors to immune checkpoint inhibition. Pan‐cancer data regarding the frequency of CDK12 alterations are limited. We aimed to characterize CDK12 alterations across all cancer types through real‐world clinical‐grade sequencing. Methods This was a single‐center retrospective analysis of 4994 cancer patients who underwent tissue or blood genomic profiling, including CDK12 assessment, conducted as part of routine care from December 2012 to January 2020. Prevalence, clinical characteristics, and treatment outcomes of patients with tumors with pathogenic CDK12 alterations were described. Results In all, 39 (0.78%, n = 39/4994) patients had pathogenic CDK12 alterations. Among CDK12‐altered tumors, the most common organ site was prostate (n = 9, 23.1%) followed by colorectal (n = 5, 12.8%). Adenocarcinoma was the most common histology (n = 26, 66.7%). Median follow‐up from time of diagnosis was 4.02 years. Median overall survival from time of metastasis was 4.43 years (95% CI: 3.11–5.74). Ten patients with CDK12‐altered tumors received at least one immune checkpoint inhibitor‐containing regimen. The majority of patients (n = 6/10, 60%) experienced an objective response. Progression‐free survival for patients who had metastatic disease and received a checkpoint inhibitor‐containing regimen was 1.16 years (95% CI: 0.32–2.00). Conclusion CDK12 alterations are rare events across hematologic and solid tumor malignancies. They represent a clinically distinct molecular cancer subtype which may have increased responsiveness to checkpoint inhibition. Prospective studies are warranted to investigate checkpoint inhibition in CDK12‐altered tumors.

Objectives To describe the feeding profile of low birthweight (LBW) infants in the first half of infancy; and to examine growth patterns and early risk factors of poor 6-month growth outcomes.Design Prospective observational cohort study.Setting and participants Stable, moderately LBW (1.50 to

Globally, increasing rates of facility-based childbirth enable early intervention for small vulnerable newborns. We describe health system-level inputs, current feeding, and discharge practices for moderately low birthweight (MLBW) infants (1500-10% less than their birthweight; 18.8% of infants were discharged with weights below facility-specific policy [1800g in India, 1500g in Malawi, and 2000g in Tanzania]. Based on descriptive analysis, we found constraints in health system inputs which have the potential to hinder high quality care for MLBW infants. Targeted LBW-specific lactation support, discharge at appropriate weight, and access to feeding alternatives would position MLBW for successful feeding and growth post-discharge.

Abstract Background Little is known regarding the rate and clinical outcomes of asymptomatic carriers of SARS‐CoV‐2 among patients with cancer. Detection of asymptomatic carriers is important in this population given the use of myelosuppressive and immunomodulating therapies. Understanding the asymptomatic carrier rate will help to develop mitigation strategies in this high‐risk cohort. Methods Retrospective cohort analysis of an asymptomatic screening protocol which required patients receiving infusional anti‐cancer therapy to undergo a symptom/exposure screen and SARS‐CoV‐2 PCR testing 24–96 h prior to their infusion. The primary outcome of this analysis was the rate of asymptomatic SARS‐CoV‐2 infection. Secondary outcomes included the rate of COVID‐19‐related hospitalization and mortality and delays in oncologic therapy. Results Among a cohort of 2691 cancer patients who underwent asymptomatic screening, 1.6% (N = 43/2691) of patients were found to be SARS‐CoV‐2 positive on asymptomatic screening. 11.6% (N = 5/43) of the cohort ultimately developed COVID‐19‐related symptoms. Four patients required hospitalization for complications of COVID‐19 infection. No patient died from COVID‐related complications. 97.7% (N = 42/43) had their anti‐cancer therapy delayed or deferred with a median delay of 21 days (range: 7–77 days). Conclusions Overall, among a cohort of active cancer patients receiving anti‐cancer therapy, an asymptomatic SARS‐CoV2 PCR‐based screening protocol detected a small cohort of asymptomatic carriers. The majority of these patients remained asymptomatic on long‐term follow‐up and outcomes were much more favorable compared to previously described outcomes of cancer patients with symptomatic COVID‐19 infection.

Prostate cancer disproportionately affects racial and ethnic minority populations. Reasons for disparate outcomes among minority patients are multifaceted and complex, involving factors at the patient, provider, and system levels. Although advancements in our understanding of disease biology have led to novel therapeutics for men with advanced prostate cancer, including the introduction of biomarker-driven therapeutics, pivotal translational studies and clinical trials are underrepresented by minority populations. Despite attempts to bridge the disparities gap, there remains an unmet need to expand minority engagement and participation in clinical trials to better define the impact of therapy on efficacy outcomes, quality of life, and role of biomarkers in diverse patient populations. The IRONMAN registry (ClinicalTrials.gov identifier: NCT03151629), a global, prospective, population-based study, was borne from this unmet medical need to address persistent gaps in our knowledge of advanced prostate cancer. Through integrated collection of clinical outcomes, patient-reported outcomes, epidemiologic data, and biospecimens, IRONMAN has the goal of expanding our understanding of how and why prostate cancer outcomes differ by race and ethnicity. To this end, the Diversity Working Group of the IRONMAN registry has developed informed strategies for site selection, recruitment, engagement and retention, and trial design and eligibility criteria to ensure broad inclusion and needs awareness of minority participants. In concert with systematic strategies to tackle the complex levels of disparate care, our ultimate goal is to expand minority engagement in clinical research and bridge the disparities gap in prostate cancer care.

ObjectiveThe majority of pediatric severe acute respiratory syndrome coronavirus 2 (COVID-19) cases demonstrate asymptomatic, mild or moderate disease. The main symptoms in children with COVID-19 are respiratory symptoms but some patients develop gastrointestinal symptoms and liver injury. We aim to review gastrointestinal symptoms and liver injury in children with confirmed COVID-19 infection.MethodThis is a retrospective case note review of children with positive COVID-19 nasal Polymerase Chain Reaction aged 0–18 years admitted to a tertiary pediatric hospital from March 1st till June 1st 2020.Results180 children were identified. Mean age was 5 years (Range: 0.01–17), the majority of patients were school aged (30%). Patients were mainly from East Asia 81 (45%) and Arabs 67 (37%). Gastrointestinal symptoms were encountered in 48 (27%) patients and 8 (4%) patients had only Gastrointestinal symptoms with no associated fever or respiratory symptoms. Liver injury was seen in 57 (32%) patients. Patients with fever and cough were more likely to have gastrointestinal symptoms (P =

Radium-223 dichloride (223Ra) is an α-emitter approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC) with bone metastases, but without visceral involvement. Despite being a life-prolonging therapy (LPT), 223Ra remains underutilized. A large body of real-world evidence (RWE) for 223Ra has been published in the decade since the pivotal phase 3 ALSYMPCA study, a period during which the treatment landscape has continued to evolve. How to optimize 223Ra use, including how to integrate it into the mCRPC management pathway amongst other current LPTs (i.e., with respect to timing and concurrent, layered, or sequential use), is therefore of considerable interest. RWE studies lack the conventional restraints of clinical trials and can therefore help to build an understanding of how treatments may be best used in routine practice. Here we review RWE studies investigating the efficacy and safety of 223Ra in mCRPC [including in sequence with the recently approved 177-Lutetium conjugated to the ligand prostate-specific membrane antigen (177Lu-PSMA)], as well as response marker development, imaging techniques, and current clinical practice recommendations.

Abstract Background Malignancies are molecularly complex and become more resistant with each line of therapy. We hypothesized that offering matched, individualized combination therapies to patients with treatment-naïve, advanced cancers would be feasible and efficacious. Patients with newly diagnosed unresectable/metastatic, poor-prognosis cancers were enrolled in a cross-institutional prospective study. Methods A total of 145 patients were included in the study. Genomic profiling (tissue and/or circulating tumor DNA) was performed in all patients, and PD-L1 immunohistochemistry, tumor mutational burden, and microsatellite status assessment were performed in a subset of patients. We evaluated safety and outcomes: disease-control rate (stable disease for ≥ 6 months or partial or complete response), progression-free survival (PFS), and overall survival (OS). Results Seventy-six of 145 patients (52%) were treated, most commonly for non-colorectal gastrointestinal cancers, carcinomas of unknown primary, and hepatobiliary malignancies (53% women; median age, 63 years). The median number of deleterious genomic alterations per patient was 5 (range, 0–15). Fifty-four treated patients (71%) received ≥ 1 molecularly matched therapy, demonstrating the feasibility of administering molecularly matched therapy. The Matching Score, which reflects the percentage of targeted alterations, correlated linearly with progression-free survival (R 2 = 0.92; P = 0.01), and high (≥ 60%) Matching Score was an independent predictor of improved disease control rate [OR 3.31 (95% CI 1.01–10.83), P = 0.048], PFS [HR 0.55 (0.28–1.07), P = 0.08], and OS [HR 0.42 (0.21–0.85), P = 0.02]. Serious adverse event rates were similar in the unmatched and matched groups. Conclusions Personalized combination therapies targeting a majority of a patient’s molecular alterations have antitumor activity as first-line treatment. These findings underscore the feasibility and importance of using tailored N-of-1 combination therapies early in the course of lethal malignancies. Trial registration I-PREDICT ( NCT02534675 ) was registered on August 25, 2015.

Although therapeutic options for patients with advanced renal cell carcinoma (RCC) have increased in the past decade, no biomarkers are yet available for patient stratification or evaluation of therapy resistance. Given the dynamic and heterogeneous nature of clear cell RCC (ccRCC), tumor biopsies provide limited clinical utility, but liquid biopsies could overcome these limitations. Prior liquid biopsy approaches have lacked clinically relevant detection rates for patients with ccRCC. This study employed ccRCC‐specific markers, CAIX and CAXII, to identify circulating tumor cells (CTC) from patients with metastatic ccRCC. Distinct subtypes of ccRCC CTCs were evaluated for PD‐L1 and HLA‐I expression and correlated with patient response to therapy. CTC enumeration and expression of PD‐L1 and HLA‐I correlated with disease progression and treatment response, respectively. Longitudinal evaluation of a subset of patients demonstrated potential for CTC enumeration to serve as a pharmacodynamic biomarker. Further evaluation of phenotypic heterogeneity among CTCs is needed to better understand the clinical utility of this new biomarker.

Background Neuroendocrine prostate cancer (NEPC) is an aggressive subtype, the presence of which changes the prognosis and management of metastatic prostate cancer.Methods We performed analytical validation of a Circulating Tumor Cell (CTC) multiplex RNA qPCR assay to identify the limit of quantification (LOQ) in cell lines, synthetic cDNA, and patient samples. We next profiled 116 longitudinal samples from a prospectively collected institutional cohort of 17 patients with metastatic prostate cancer (7 NEPC, 10 adenocarcinoma) as well as 265 samples from 139 patients enrolled in 3 adenocarcinoma phase II trials of androgen receptor signaling inhibitors (ARSIs). We assessed a NEPC liquid biomarker via the presence of neuroendocrine markers and the absence of androgen receptor (AR) target genes.Results Using the analytical validation LOQ, liquid biomarker NEPC detection in the longitudinal cohort had a per-sample sensitivity of 51.35% and a specificity of 91.14%. However, when we incorporated the serial information from multiple liquid biopsies per patient, a unique aspect of this study, the per-patient predictions were 100% accurate, with a receiver-operating-curve (ROC) AUC of 1. In the adenocarcinoma ARSI trials, the presence of neuroendocrine markers, even while AR target gene expression was retained, was a strong negative prognostic factor.Conclusion Our analytically validated CTC biomarker can detect NEPC with high diagnostic accuracy when leveraging serial samples that are only feasible using liquid biopsies. Patients with expression of NE genes while retaining AR-target gene expression may indicate the transition to neuroendocrine differentiation, with clinical characteristics consistent with this phenotype.Funding NIH (DP2 OD030734, 1UH2CA260389, R01CA247479, and P30 CA014520), Department of Defense (PC190039 and PC200334), and Prostate Cancer Foundation (Movember Foundation — PCF Challenge Award).

Background: Muscle-invasive bladder cancer (MIBC) remains undertreated despite multiple potentially curative options. Both radical cystectomy (RC) with or without neoadjuvant chemotherapy and trimodal therapy (TMT), including transurethral resection of bladder tumor followed by chemoradiotherapy, are standard treatments. Objective: To evaluate real-world clinical outcomes of RC with neoadjuvant chemotherapy (RC-NAC), RC without NAC, TMT with National Comprehensive Cancer Network guideline–preferred radiosensitizing chemotherapy including cisplatin or mitomycin-C and 5-fluorouracil (pTMT), and TMT with nonpreferred chemotherapy (npTMT). Design, setting, and participants: US veterans with nonmetastatic MIBC (T2-4aN0-3M0) were studied. Outcome measurements and statistical analysis: Overall mortality (OM) was evaluated with multivariable Cox proportional hazard model. Bladder cancer-specific mortality (BCSM) was evaluated with multivariable Fine-Gray regression. Salvage cystectomy rates were obtained by chart review. Results and limitations: Overall 2306 patients were included: 1472 (64%) with RC without NAC, 506 (22%) with RC-NAC, 163 (7%) with pTMT, and 165 (7%) with npTMT. On multivariable analysis, pTMT was associated with similar OM (hazard ratio [HR] 1.19; 95% confidence interval [CI] 0.94–1.50; p = 0.15) and BCSM (HR 1.34; 95% CI 0.99–1.83; p = 0.06) to RC-NAC; npTMT was associated with worse OM (HR 1.30; 95% CI 1.04–1.61; p = 0.02) and BCSM (HR 1.45; 95% CI 1.09–1.94; p = 0.01). RC without NAC was associated with similar OM (HR 1.08; 95% CI 0.95–1.24; p = 0.24) and BCSM (HR 1.02; 95% CI 0.86–1.21; p = 0.79). When stratified by age, among patients ≥65 yr of age, treatment with pTMT was associated with similar OM (HR 1.14; 95% CI 0.87–1.50; p = 0.35) and BCSM (HR 1.11; 95% CI 0.76–1.62; p = 0.60). Among patients

We evaluated the effects of behavioral skills training on improving participant implementation of functional communication training with multiple schedules when working with a confederate. Behavioral skills training produced mastery-level responding for all six participants who required training, providing the first empirically supported training for this functional communication training approach. Next, we assessed durability during training challenges with (a) procedural changes to the original protocol, (b) a novel confederate with different discriminative stimuli and reinforcers, and (c) relapsed confederate destructive behavior. Training effects degraded at least once for all participants and in 62% of training challenges, although continuing to expose the participant to the challenging situations or providing postsession booster training resolved the degradation in most cases. We discuss these findings in relation to their clinical implications and directions for future research.

Astaxanthin is a xanthophyll carotenoid possessing impressive nutraceutical, antioxidant, and bioactive merits. Traditionally, astaxanthin is extracted from crustacean wastes via solvent extraction methods. However, the rigid structure of shells that comprise complex proteins and chitin challenges the extraction process. This investigation addressed an efficient microbial-assisted method to facilitate astaxanthin recovery from crab exoskeleton waste utilizing chitinolytic and proteolytic microorganisms. Herein, we evaluated the effect of pretreatment of the exoskeleton waste with a newly isolated probiotic strain, Bacillus amyloliquefaciens CPFD8, showing remarkable protease and chitinase activity and a proteolytic Saccharomyces cerevisiae 006-001 before solvent extraction, using acetone/hexane, on astaxanthin recovery. Furthermore, the antioxidant and anti-inflammatory activities of the recovered astaxanthin were inspected. Results revealed that both strains boosted the astaxanthin yield from the crab (Callinectes sapidus) exoskeleton compared with solvent extraction using acetone/hexane. Under optimum conditions, astaxanthin yield was 217 and 91 µg/g crab exoskeleton in samples treated with B. amyloliquefaciens CPFD8 and S. cerevisiae 006-001, respectively. Interestingly, pretreatment of crab exoskeleton waste with B. amyloliquefaciens CPFD8 yielded more than 6-fold astaxanthin compared with the solvent extraction method that yielded just 35 µg/g. This increase could be attributed to the proteolytic activity of B. amyloliquefaciens CPFD8 that rendered deproteinized shell chitin accessible to chitinase, facilitating the penetration of solvents and the recovery of astaxanthin. The recovered astaxanthin exhibited excellent antioxidant activity in scavenging DPPH or ABTS free radicals with IC50 values of 50.93 and 17.56 µg/mL, respectively. In addition, the recovered astaxanthin showed a remarkable anti-inflammatory impact on LPS-induced murine macrophage RAW264.7 cells and significantly inhibited the production of nitric oxide, TNF-α, and IL-6 compared with the untreated control. These findings suggest the potential use of the developed microbial-assisted method utilizing chitinolytic and proteolytic B. amyloliquefaciens CPFD8 to maximize the recovery of bioactive astaxanthin from crab (C. sapidus) exoskeleton waste.

Nosocomial infections caused by microbial biofilm formation on biomaterial surfaces such as urinary catheters are complicated by antibiotic resistance, representing a common problem in hospitalized patients. Therefore, we aimed to modify silicone catheters to resist microbial adherence and biofilm formation by the tested microorganisms. This study used a simple direct method to graft poly-acrylic acid onto silicone rubber films using gamma irradiation to endow the silicone surface with hydrophilic carboxylic acid functional groups. This modification allowed the silicone to immobilize ZnO nanoparticles (ZnO NPs) as an anti-biofilm. The modified silicone films were characterized by FT-IR, SEM, and TGA. The anti-adherence ability of the modified silicone films was evidenced by the inhibition of biofilm formation by otherwise strong biofilm-producing Gram-positive, Gram-negative, and yeast clinical isolates. The modified ZnO NPs grafted silicone showed good cytocompatibility with the human epithelial cell line. Moreover, studying the molecular basis of the inhibitory effect of the modified silicone surface on biofilm-associated genes in a selected Pseudomonas aeruginosa isolate showed that anti-adherence activity might be due to the significant downregulation of the expression of lasR, lasI, and lecB genes by 2, 2, and 3.3-fold, respectively. In conclusion, the modified silicone catheters were low-cost, offering broad-spectrum anti-biofilm activity with possible future applications in hospital settings.

Diabetic nephropathy (DN) is a microvascular complication of diabetes mellitus. This study examined the therapeutic effects of sitagliptin, a dipeptidyl peptidase inhibitor, on DN and explored the underlying mechanism. Male Wistar albino rats (n = 12) were intraperitoneally administered a single dose of streptozotocin (30 mg/kg) to induce diabetes. Streptozotocin-treated and untreated rats (n = 12) were further divided into normal control, normal sitagliptin-treated control, diabetic control, and sitagliptin-treated diabetic groups (n = 6 in each). The normal and diabetic control groups received normal saline, whereas the sitagliptin-treated control and diabetic groups received sitagliptin (100 mg/kg, p.o.). We assessed the serum levels of DN and inflammatory biomarkers. Protein tyrosine phosphatase 1 B (PTP1B), phosphorylated Janus kinase 2 (P-JAK2), and phosphorylated signal transducer activator of transcription (P-STAT3) levels in kidney tissues were assessed using Western blotting, and kidney sections were examined histologically. Sitagliptin reduced DN and inflammatory biomarkers and the expression of PTP1B, p-JAK2, and p-STAT3 (p < 0.001) and improved streptozotocin-induced histological changes in the kidney. These results demonstrate that sitagliptin ameliorates inflammation by inhibiting DPP-4 and consequently modulating the PTP1B-related JAK/STAT axis, leading to the alleviation of DN.

PURPOSETo investigate whether black race is an independent predictor of overall survival (OS) in metastatic renal cell carcinoma (mRCC).METHODSWe performed a retrospective 2-cohort (International Metastatic Renal Cell Carcinoma Database Consortium [IMDC] and trial-database) study of patients with mRCC treated with first-line tyrosine kinase inhibitors (TKIs). Unmatched (UM) and matched (M) analyses accounting for imbalances in region, year of treatment, age, and sex between races were performed. Cox models adjusting for histology, number of metastatic sites, nephrectomy, and IMDC risk compared time to treatment failure (TTF; IMDC cohort), progression-free survival (PFS; trial-database cohort), and OS.RESULTSThe IMDC cohort included 73 black versus 3,381 (UM) and 1,236 (M) white patients. The trial-database cohort included 21 black versus 1,040 (UM) and 431 (M) white patients. Median OS for black versus white patients was 18.5 versus 25.8 months in the IMDC group and 21.0 versus 25.6 months in the trial-database group. Differences in OS were not significant in multivariable analysis in the IMDC group (hazard ratio [HR]M, 1.0; 95% CI, 0.7 to 1.5; HRUM, 1.1; 95% CI, 0.8 to 1.4) and trial-database (HRM, 1.5; 95% CI, 0.8 to 2.7; HRUM, 1.4; 95% CI, 0.8 to 2.6) cohorts. TTF for black patients was shorter in the UM IMDC cohort (HRUM, 1.4; 95% CI, 1.1 to 1.8; P = .003), but not in the M analysis. PFS was shorter for black patients in both analyses in the trial-database cohort (HRM, 2.3; 95% CI, 1.4 to 3.9; P = .002; HRUM, 2.3; 95% CI, 1.4 to 3.9; P = .002).CONCLUSIONBlack patients had more IMDC risk factors and worse outcomes with TKIs versus white patients. Race was not an independent predictor of OS. Strategies to understand biologic determinants of outcomes for minority patients are needed to optimize care.

PURPOSE To understand readiness measures taken by oncologists to protect patients and health care workers from the novel coronavirus (COVID-19) and how their clinical decision making was influenced by the pandemic. METHODS An online survey was conducted between March 24 and April 29, 2020. RESULTS A total of 343 oncologists from 28 countries participated. The median age was 43 years (range, 29-68 years), and the majority were male (62%). At the time of the survey, nearly all participants self-reported an outbreak in their country (99.7%). Personal protective equipment was available to all participants, of which surgical mask was the most common (n = 308; 90%). Telemedicine, in the form of phone or video encounters, was common and implemented by 80% (n = 273). Testing patients with cancer for COVID-19 via reverse transcriptase polymerase chain reaction before systemic treatment was not routinely implemented: 58% reported no routine testing, 39% performed testing in selected patients, and 3% performed systematic testing in all patients. The most significant factors influencing an oncologist’s decision making regarding choice of systemic therapy included patient age and comorbidities (81% and 92%, respectively). Although hormonal treatments and tyrosine kinase inhibitors were considered to be relatively safe, cytotoxic chemotherapy and immune therapies were perceived as being less safe or unsafe by participants. The vast majority of participants stated that during the pandemic they would use less chemotherapy, immune checkpoint inhibitors, and steroids. Although treatment in neoadjuvant, adjuvant, and first-line metastatic disease was less affected, most of the participants stated that they would be more hesitant to recommend second- or third-line therapies in metastatic disease. CONCLUSION Decision making by oncologists has been significantly influenced by the ongoing COVID-19 pandemic.

BackgroundCOVID-19 caused by SARS-CoV-2 has infected 219 million individuals at the time of writing of this paper. A large volume of research findings from observational studies about disease interactions with COVID-19 is being produced almost daily, making it difficult for physicians to keep track of the latest information on COVID-19’s effect on patients with certain pre-existing conditions. ObjectiveIn this paper, we describe the creation of a clinical decision support tool, the SMART COVID Navigator, a web application to assist clinicians in treating patients with COVID-19. Our application allows clinicians to access a patient’s electronic health records and identify disease interactions from a large set of observational research studies that affect the severity and fatality due to COVID-19. MethodsThe SMART COVID Navigator takes a 2-pronged approach to clinical decision support. The first part is a connection to electronic health record servers, allowing the application to access a patient’s medical conditions. The second is accessing data sets with information from various observational studies to determine the latest research findings about COVID-19 outcomes for patients with certain medical conditions. By connecting these 2 data sources, users can see how a patient’s medical history will affect their COVID-19 outcomes. ResultsThe SMART COVID Navigator aggregates patient health information from multiple Fast Healthcare Interoperability Resources–enabled electronic health record systems. This allows physicians to see a comprehensive view of patient health records. The application accesses 2 data sets of over 1100 research studies to provide information on the fatality and severity of COVID-19 for several pre-existing conditions. We also analyzed the results of the collected studies to determine which medical conditions result in an increased chance of severity and fatality of COVID-19 progression. We found that certain conditions result in a higher likelihood of severity and fatality probabilities. We also analyze various cancer tissues and find that the probabilities for fatality vary greatly depending on the tissue being examined. ConclusionsThe SMART COVID Navigator allows physicians to predict the fatality and severity of COVID-19 progression given a particular patient’s medical conditions. This can allow physicians to determine how aggressively to treat patients infected with COVID-19 and to prioritize different patients for treatment considering their prior medical conditions.

BackgroundTreatment options for many cancers include immune checkpoint inhibitor (ICI) monotherapy and combination therapy with impressive clinical benefit across cancers. We sought to define the comparative cardiac risks of ICI combination and monotherapy.MethodsWe used VigiBase, the World Health Organization pharmacovigilance database, to identify cardiac ADRs (cADRs), such as carditis, heart failure, arrhythmia, myocardial infarction, and valvular dysfunction, related to ICI therapy. To explore possible relationships, we used the reporting odds ratio (ROR) as a proxy of relative risk. A lower bound of a 95% confidence interval of ROR > 1 reflects a disproportionality signal that more ADRs are observed than expected due to chance.ResultsWe found 2278 cADR for ICI monotherapy and 353 for ICI combination therapy. Combination therapy was associated with significantly higher odds of carditis (ROR 6.9, 95% CI: 5.6-8.3) versus ICI monotherapy (ROR 5.0, 95% CI: 4.6-5.4). Carditis in ICI combination therapy was fatal in 23.4% of reported ADRs, compared to 15.8% for ICI monotherapy (P = 0.058).ConclusionsUsing validated pharmacovigilance methodology, we found increased odds of carditis for all ICI therapies, with the highest odds for combination therapy. Given the substantial risk of severe ADR and death, clinicians should consider these findings when prescribing checkpoint inhibitors.

Purpose: Chemoradiation (CRT) is a definitive treatment option for muscle-invasive bladder cancer (MIBC). Despite its effectiveness, CRT is underused, in part owing to concerns of tolerability and the need for integrated multidisciplinary care. We investigated factors associated with and the impact of treatment discontinuation in patients with MIBC treated with CRT. Methods and Materials: In the US Veterans Affairs’ national database, we identified patients with urothelial histology, MIBC (T2-4a/N0-3/M0) diagnosed between 2000 and 2018 and treated with definitive-intent CRT. The primary endpoint of discontinued radiation was evaluated in a multivariable logistic regression. Secondary endpoints of 30-day and 90-day mortality, overall mortality, and nonbladder cancer mortality were evaluated in multivariable models. Results: Of 369 veterans with MIBC who underwent CRT, 30 patients (8.1%) did not complete radiation. The most common reasons for treatment discontinuation included comorbidities or infections necessitating hospital admission (63.3%) and treatment intolerance or declining performance status (26.7%). In multivariable logistic regression, variables associated with radiation discontinuation were creatinine clearance ≤ 50 (odds ratio [OR], 3.93; 95% CI, 1.63-9.50; P = .002), incomplete transurethral resection of bladder tumor (TURBT) (OR, 3.16; 95% CI, 1.15-8.63; P = .02), and nonpreferred chemotherapy (OR, 3.31; 95% CI, 1.31-8.36; P = .01). In the cohort that discontinued radiation, 30-day mortality was 33.3% and 90-day mortality was 50.0%, with the majority of deaths attributed to nonbladder cancer causes. No patient or tumor variables were associated with either endpoint. In the cohort that completed radiation, 30-day mortality was 2.7% and 90-day mortality was 6.8%. In multivariable analysis, radiation discontinuation was associated with worse overall mortality (hazard ratio [HR], 2.48; 95% CI, 1.36-4.50; P = .003) and worse nonbladder cancer mortality (HR, 2.32; 95% CI, 1.24-4.34; P = .008). Conclusions: With a low rate of treatment discontinuation, CRT is an effective and feasible treatment option for the typically elderly and comorbid population of patients with MIBC. In addition to identified predictors of treatment discontinuation (poor renal function, incomplete TURBT, etc.), further research is required to develop evidence-based guidelines for optimal patient selection.