Inhibitory effects of the nucleoside analogue gemcitabine on prostatic carcinoma cells

Gemcitabine (2≺,2≺difluoro-2≺deoxycytidine, dFdC) is a synthetic antimetabolite of the cellular pyrimidine nucleotide metabolism. In a first series of in vitro experiments, the drug showed a strong effect on the proliferation and colony formation of the human androgen-sensitive tumor cell line LNCaP and the androgen-insensitive cell lines PC-3 and DU-145. Maximal inhibition occurred at a dFdC concentration as low as 30 nM. In contrast to the cell lines which were derived from metastatic lesions of prostate cancer patients, no inhibitory effects were found in normal primary prostatic epithelial cells at concentrations up to 100 nM. The effect of gemcitabine was reversed by co-administration of 10–100 μM of its natural analogue deoxycytidine. In view of a future clinical application of this anti-tumor drug in advanced prostatic carcinoma, we have compared the effect of gemcitabine on prostatic tumor cells with that on bone marrow granulopoietic-macrophagic progenitor cells, because neutropenia is a common side effect of gemcitabine treatment. The time course of action on the two kinds of cells was markedly different. Colony formation of tumor cells was inhibited by two thirds at a gemcitabine concentration of about 3.5 nM. The same effect on granulopoietic-macrophagic progenitor cells required a concentration of 9 nM. Co-administration of deoxycytidine to gemcitabine-treated tumor cell cultures completely antagonized the effect of gemcitabine whereas addition of deoxycytidine after 48 hr of gemcitabine treatment could not prevent gemcitabine action on the tumor cells. In contrast, more than half of the granulopoietic-macrophagic progenitor cells could still be rescued by deoxycytidine administration after 48 hr. These findings and the marked difference in the susceptibility of neoplastic and normal prostatic cells suggest that gemcitabine is a promising substance which should be further evaluated as to its efficacy in the treatment of advanced prostatic carcinoma. © 1996 Wiley-Liss, Inc.     

Metabolic Syndrome,Cognitive Impairment and the Role of Diet: A Narrative Review

Background: This narrative review presents the association between metabolic syndrome (MetS), along with its components, and cognition-related disorders, as well as the potential reversal role of diet against cognitive impairment by modulating MetS. Methods: An electronic research in Medline (Pubmed) and Scopus was conducted. Results: MetS and cognitive decline share common cardiometabolic pathways as MetS components can trigger cognitive impairment. On the other side, the risk factors for both MetS and cognitive impairment can be reduced by optimizing the nutritional intake. Clinical manifestations such as dyslipidemia, hypertension, diabetes and increased central body adiposity are nutrition-related risk factors present during the prodromal period before cognitive impairment. The Mediterranean dietary pattern stands among the most discussed predominantly plant-based diets in relation to cardiometabolic disorders that may prevent dementia, Alzheimer’s disease and other cognition-related disorders. In addition, accumulating evidence suggests that the consumption of specific dietary food groups as a part of the overall diet can improve cognitive outcomes, maybe due to their involvement in cardiometabolic paths. Conclusions: Early MetS detection may be helpful to prevent or delay cognitive decline. Moreover, this review highlights the importance of healthy nutritional habits to reverse such conditions and the urgency of early lifestyle interventions.     

All near-infrared multiparametric luminescence thermometry using Er3+, Yb3+-doped YAG nanoparticles

This paper presents four new temperature readout approaches to luminescence nanothermometry in spectral regions of biological transparency demonstrated on Yb³⁺/Er³⁺-doped yttrium aluminum garnet nanoparticles. Under the 10 638 cm⁻¹ excitation, down-shifting near infrared emissions (>10 000 cm⁻¹) are identified as those originating from Yb³⁺ ions'' ²F_5/2 → ²F_7/2 (∼9709 cm⁻¹) and Er³⁺ ions'' ⁴I_13/2 → ⁴I_15/2 (∼6494 cm⁻¹) electronic transitions and used for 4 conceptually different luminescence thermometry approaches. Observed variations in luminescence parameters with temperature offered an exceptional base for studying multiparametric temperature readouts. These include the temperature-dependence of: (i) intensity ratio between emissions from Stark components of Er^{3+ 4}I_13/2 level; (ii) intensity ratio between emissions of Yb³⁺ (²F_5/2 → ²F_7/2 transition) and Er³⁺ (⁴I_13/2 → ⁴I_15/2 transition); (iii) band shift and bandwidth and (iv) lifetime of the Yb³⁺ emission (²F_5/2 → ²F_7/2 transition) with maximal sensitivities of 1% K⁻¹, 0.8% K⁻¹, 0.09 cm⁻¹ K⁻¹, 0.46% K⁻¹ and 0.86% K⁻¹, respectively. The multimodal temperature readout provided by this material enables its application in different luminescence thermometry setups as well as improved the reliability of the temperature sensing by the cross-validation between measurements.

Four completely new NIR luminescence temperature readouts in the second and third biological windows are demonstrated with YAG:Er³⁺, Yb³⁺ nanoparticles.     

In reply to Swain et al.: Re-evaluation of updated meta-analysis including trials RTOG 1016 and De-ESCALaTE

European Archives of Oto-Rhino-Laryngology -     

Incorporating genetics services into adult kidney disease care

Studies have shown that as many as 1 in 10 adults with chronic kidney disease has a monogenic form of disease. However, genetic services in adult nephrology are limited. An adult Kidney Genetics Clinic was established within the nephrology division at a large urban academic medical center to increase access to genetic services and testing in adults with kidney disease. Between June 2019 and December 2021, a total of 363 patients were referred to the adult Kidney Genetics Clinic. Of those who completed genetic testing, a positive diagnostic finding was identified in 27.1%, a candidate diagnostic finding was identified in 6.7% of patients, and a nondiagnostic positive finding was identified in an additional 8.6% of patients, resulting in an overall yield of 42.4% for clinically relevant genetic findings in tested patients. A genetic diagnosis had implications for medical management, family member testing, and eligibility for clinical trials. With the utilization of telemedicine, genetic services reached a diverse geographic and patient population. Genetic education efforts were integral to the clinic's success, as they increased visibility and helped providers identify appropriate referrals. Ongoing access to genomic services will remain a fundamental component of patient care in adults with kidney disease.     

Evaluation of ventricular synchrony using novel Doppler echocardiographic indices in patients with heart failure receiving cardiac resynchronization therapy.

Cardiac resynchronization therapy improves hemodynamics in selected patients with heart failure. Mechanic asynchrony parameters that may guide patient selection or therapy optimization are still being investigated. A biventricular (BiV) pacemaker was implanted in 34 patients with dilated ischemic, idiopathic, or valvular cardiomyopathy, and a QRS duration of > or =130 milliseconds. Two-dimensional standard and Doppler tissue echocardiography was performed during right ventricular (RV), left ventricular (LV), BiV, and no pacing in a random and blinded manner. LV and BiV pacing increased stroke volume (P <.02 for both) and ejection fraction (P <.001 for both). Regional contractility assessed by displacement, strain rate, and peak systolic strain was improved in some segments (P <.05) during LV and BiV pacing. A homogenization of segmental contractions was observed during LV and BiV pacing as evaluated by net systolic displacement and segmental myocardial performance index. LV and BiV pacing provides benefits that can be quantified by echocardiography.     

Cytotoxicity of dimethyl sulfoxide and antineoplastic combinations against human tumors

Five human tumor reference cell lines were tested in vitro against 0 percent, 5 percent, and 10 percent DMSO; four antineoplastic agents; and combinations of 5 percent or 10 percent DMSO plus each antineoplastic agent. Synergistic cytotoxicity between DMSO and antineoplastic agents against each cell line were demonstrated. We have concluded that delivery of standard doses of antineoplastic agents in 5 percent or 10 percent DMSO may be useful in the treatment of some tumors because of the marked increase in tumoricidal effect seen with some DMSO and drug combinations. Alternatively, lower doses of antineoplastic agents might be delivered in DMSO, producing the same cytotoxic effect as a full dose of drug without DMSO but with less systemic toxicity.     

Histopathologic comparison between human oral squamous cell carcinomas and their xenografts in nude mice

Tumor portions were obtained from 11 oral squamous cell carcinomas and used to produce tumors in a xenogeneic gnotobiotic nude mouse model system. The tumors that developed were examined histologically. The cellular features and tumor growth patterns were compared between the original oral squamous cell carcinoma (T0) and the tumor that developed in the xenogeneic host (T1). The T1 tumors were more highly differentiated in comparison with the T0 tumors. The T1 tumors exhibited less cellular pleomorphism and a more uniform pattern of stratification. The cells in the T1 tumors exhibited an increased mitotic index but did not contain abnormal mitoses. The T1 tumors usually exhibited nodular growth patterns rather than the infiltrating pattern exhibited by the parenchyma of the T0 tumors. The desmoplastic reaction was markedly reduced in the T1 tumors. The results indicated that the gnotobiotic nude mouse model system either selects for or induces a more differentiated pattern of tumor growth than that found in the original human oral squamous cell carcinomas.