Targeting triple-negative breast cancer: A clinical perspective.

Triple-negative breast cancer (TNBC) is a disease with often an aggressive course and a poor prognosis compared to other subtypes of breast cancer. TNBC accounts for approximately 10%-15% of all diagnosed breast cancer cases and represents a high unmet need in the field. Up to just a few years ago, chemotherapy was the only systemic treatment option for this subtype (1). To date, TNBC is considered a heterogeneous disease. One of the existing classifications is based on the analysis of mRNA expression in 587 TNBC cases, in which Lehman et al. proposed six subtypes of TNBC as follows: two basal-like (BL1 and BL2) subtypes, a mesenchymal (M) subtype, a mesenchymal stem-like (MSL) subtype, an immunomodulatory (IM) subtype, and a luminal androgen receptor (LAR) subtype (2). Later studies have demonstrated that the IM and MSL subtypes do not correlate with independent subtypes but reflect background expression by dense infiltration of tumor-infiltrating lymphocytes (TILs) or stromal cells. According to this finding, the classification of TNBC has been revised into the following four subtypes: basal 1, basal 2, LAR, and mesenchymal subtypes (3). Over the last years, several new strategies have been investigated for the treatment of patients with TNBC. Among them, immunotherapy, antibody drug conjugates, new chemotherapy agents, and targeted therapy have been and are currently being developed. The present article aims to provide an updated overview on the different treatment options that are now available or are still under investigation for patients with TNBC.

Immunotherapy: A new standard in the treatment of metastatic clear cell renal cell carcinoma.

Renal cell cancer (RCC) represents 2%-3% of all adulthood cancers and is the most common malignant neoplasm of the kidney (90%). In the mid-nineties of the last century, the standard of treatment for patients with metastatic RCC was cytokines. Sunititib and pazopanib were registered in 2007 and 2009, respectively, and have since been the standard first-line treatment for metastatic clear cell RCC (mccRCC). Renal cell cancer is a highly immunogenic tumor with tumor infiltrating cells, including CD8+ T lymphocytes, dendritic cells, natural killer cells (NK) and macrophages. This observation led to the design of new clinical trials in which patients were treated with immunotherapy. With the growing evidence that proangiogenic factors can have immunomodulatory effects on the host's immune system, the idea of combining angiogenic drugs with immunotherapy has emerged, and new clinical trials have been designed. In the last few years, several therapeutic options have been approved [immunotherapy and immunotherapy/tyrosine kinase inhibitors (TKI)] for the first-line treatment of mccRCC. Nivolumab/ipilimumab is approved for the treatment of patients with intermediate and poor prognoses. Several checkpoint inhibitors (pembrolizumab, nivolumab, avelumab) in combination with TKI (axitinib, lenvatinib, cabozantinib) are approved for the treatment of patients regardless of their International mRCC Database Consortium prognostic group and PD-L1 expression. There is no specific and ideal biomarker that could help in selecting the ideal patient for the appropriate first-line treatment.

Immunotherapy in the treatment of lymphoma.

Relapsed or refractory non-Hodgkin's lymphomas, especially diffuse large B-cell lymphoma as well as relapsed or refractory Hodgkin lymphomas are hard-to-treat diseases. Patients who do not respond to initial therapy or experience relapse are treated with salvage regimens, and if eligible for aggressive therapy, treatment is continued with high-dose chemotherapy and autologous stem cell transplantation. Current therapy options can cure substantial numbers of patients, however for some it is still an uncurable disease. Numerous new drugs and cell therapies are being investigated for the treatment of relapsed or refractory lymphomas. Different types of immunotherapy options have shown promising results, and some have already become the standard of care. Here, we review immunotherapy options for the treatment of lymphoma and discuss the results, positions, practical aspects, and future directions of different drugs and cellular therapies for the treatment of this disease.

Calcium Fluxes in Work-Related Muscle Disorder: Implications from a Rat Model.

INTRODUCTION: Ca2+ regulatory excitation-contraction coupling properties are key topics of interest in the development of work-related muscle myalgia and may constitute an underlying cause of muscle pain and loss of force generating capacity. METHOD: A well-established rat model of high repetition high force (HRHF) work was used to investigate if such exposure leads to an increase in cytosolic Ca2+ concentration ([Ca2+]i) and changes in sarcoplasmic reticulum (SR) vesicle Ca2+ uptake and release rates. RESULT: Six weeks exposure of rats to HRHF increased indicators of fatigue, pain behaviors, and [Ca2+]i, the latter implied by around 50-100% increases in pCam, as well as in the Ca2+ handling proteins RyR1 and Casq1 accompanied by an ∼10% increased SR Ca2+ uptake rate in extensor and flexor muscles compared to those of control rats. This demonstrated a work-related altered myocellular Ca2+ regulation, SR Ca2+ handling, and SR protein expression. DISCUSSION: These disturbances may mirror intracellular changes in early stages of human work-related myalgic muscle. Increased uptake of Ca2+ into the SR may reflect an early adaptation to avoid a sustained detrimental increase in [Ca2+]i similar to the previous findings of deteriorated Ca2+ regulation and impaired function in fatigued human muscle.

A Comparative Quantitative Analysis of the Postnatal Changes in the Myocardium of the Left and Right Ventricles in Rats.

BACKGROUND: The growth of the heart during the foetal and early postnatal development takes places mainly due to hyperplasia. The late postnatal development is characterised by cardiomyocytic hypertrophy in response to normal physiological mechanisms and increased load. To study the cell size most authors measure the diameter either directly or indirectly. AIM: The aim of the present study was to make a comparative quantitative analysis of the postnatal changes observed in the left and right ventricles in rat by evaluating the changes in three morphometric parameters - thickness of the free wall, transverse section of the cardiomyocytes and cardiomyocytic density in the left ventricle and right ventricle. MATERIALS AND METHODS: In the present study, we used histological material from the hearts of 15 male Wistar rats, distributed in five groups aged 2 weeks, 1 month, 3 months, 6 months and 12 months, respectively. RESULTS: In both ventricles, the wall thickness and the transverse section of the cardiomyocytes increased with age, while the cardiomyocytic density decreased. Changes were identical in both ventricles; however, they were more dynamic and pronounced in the left ventricle. CONCLUSIONS: The studied morphometric parameters reveal that age-related hypertrophy and the gradual loss of cardiac muscle cells take place in both ventricles but have a more dynamic pattern of progression in the left ventricle as compared with the right ventricle.

Checkpoint inhibitors in the treatment of urological malignancies.

Checkpoint inhibitors are monoclonal antibodies attach to several different receptors on T-cells or tumour cells expressing receptors for cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death-1 (PD-1) and their ligand (PD-L1). Since 2010, numerous trials on different tumour types have been conducted, which was resulted in these drugs being approved for the treatment of melanoma, lung cancer, Hodgkin's lymphoma and head and neck cancers. Urological cancers, especially urothelial and renal-cell carcinomas, are immunogenic tumours. Since the late 70s, the bacillus Calmette-Gurin (BCG) vaccine has been used for intravesical instillation in non-muscle invasive bladder cancer from the mid-90s up until the discovery of tyrosine kinase inhibitors (TKIs) in 2007, interleukin-2 (IL-2) and interferon alpha (IFNα), which were the standard of care for metastatic renal-cell cancer. Two checkpoint inhibitors are already approved by the Food and Drug Administration: atezolizumab for metastatic urothelial cancer and nivolumab for metastatic renal-cell carcinoma. There are many drugs are in different phases of clinical development. Here we review the current status of checkpoint inhibitors in the treatment of urological tumours.

Determining oxygen relaxations at an interface: A comparative study between transmission electron microscopy techniques.

Nowadays, aberration corrected transmission electron microscopy (TEM) is a popular method to characterise nanomaterials at the atomic scale. Here, atomically resolved images of nanomaterials are acquired, where the contrast depends on the illumination, imaging and detector conditions of the microscope. Visualization of light elements is possible when using low angle annular dark field (LAADF) STEM, annular bright field (ABF) STEM, integrated differential phase contrast (iDPC) STEM, negative spherical aberration imaging (NCSI) and imaging STEM (ISTEM). In this work, images of a NdGaO3-La0.67Sr0.33MnO3 (NGO-LSMO) interface are quantitatively evaluated by using statistical parameter estimation theory. For imaging light elements, all techniques are providing reliable results, while the techniques based on interference contrast, NCSI and ISTEM, are less robust in terms of accuracy for extracting heavy column locations. In term of precision, sample drift and scan distortions mainly limits the STEM based techniques as compared to NCSI. Post processing techniques can, however, partially compensate for this. In order to provide an outlook to the future, simulated images of NGO, in which the unavoidable presence of Poisson noise is taken into account, are used to determine the ultimate precision. In this future counting noise limited scenario, NCSI and ISTEM imaging will provide more precise values as compared to the other techniques, which can be related to the mechanisms behind the image recording.

Alcohol metabolism is not affected by sleeve gastrectomy.

INTRODUCTION: It has been published that patients who underwent gastric bypass surgery have impaired alcohol metabolism, predisposing them to higher rates of intoxication and DUI arrests. Yet the impact of laparoscopic sleeve gastrectomy (LSG) on alcohol metabolism and in particular the long-term effects are still unclear. We hypothesized that LSG does not alter alcohol metabolism. METHODS: A prospective cohort study of patients undergoing LSG was evaluated. Blood alcohol concentration (BAC) was extrapolated using a Breathalyzer(®). Alcohol metabolism was evaluated by determining BAC every 5 min after a single dose of alcohol (5 oz. glass of 14% v/v Malbec wine), until BAC was equal to zero. Subjects were queried about alcohol intoxication symptoms. All parameters were obtained and analyzed preoperatively and at 3 and 12 months postoperatively. RESULTS: Our study consisted of 10 patients (9 female) with a mean age of 46.6 ± 2.2 years and BMI of 43.5 ± 2.2 kg/m(2). The mean percentage excess weight loss was 39.5 ± 3.3 at 3 months and 55.6 ± 4.4 at 12 months. Peak BAC at 20 min was not different at 3 months (0.068 ± 0.007, p = 0.77) or at 12 months (0.047 ± 0.008, p = 0.19) when compared to the preoperative assessment (0.059 ± 0.014). In addition, the time to BAC equal to zero was not significantly different between baseline and the follow-up values (preoperative: 70 ± 9 min, 3 months: 95 ± 18 min, and 12 months: 57 ± 8 min, (p > 0.05). Symptoms of intoxication were not significantly different in patients before and after surgery. CONCLUSIONS: Our study suggests that LSG does not alter alcohol metabolism. Patients who undergo LSG do not have higher levels of intoxication following alcohol consumption and are therefore not prone to higher rates of DUI charges than the general public, in contrast to that previously reported following in patients who undergo gastric bypass surgery.

Image formation in the scanning transmission electron microscope using object-conjugate detectors.

This work presents a theoretical analysis of image formation in a scanning transmission electron microscope equipped with electron detectors in a plane conjugate to the specimen. This optical geometry encompasses both the three-dimensional imaging technique of scanning confocal electron microscopy (SCEM) and a recently developed atomic resolution imaging technique coined real-space scanning transmission electron microscopy (R-STEM). Image formation in this geometry is considered from the viewpoints of both wave optics and geometric optics, and the validity of the latter is analysed by means of Wigner distributions. Relevant conditions for the validity of a geometric interpretation of image formation are provided. For R-STEM, where a large detector is used, it is demonstrated that a geometric optics description of image formation provides an accurate approximation to wave optics, and that this description offers distinct advantages for interpretation and numerical implementation. The resulting description of R-STEM is also demonstrated to be in good agreement with experiment. For SCEM, it is emphasized that a geometric optics description of image formation is valid provided that higher-order aberrations can be ignored and the detector size is large enough to average out diffraction from the angle-limiting aperture.

Delocalized radiation damage in polymers.

We present and discuss measurements of electron-irradiation damage in polystyrene and other polymers, based on fading of the 7-eV energy-loss peak. These measurements suggest a large increase in characteristic dose as the electron-beam diameter is reduced from 1 µm to below 1 nm. This finding is discussed in terms of secondary-electron production and delocalization of the inelastic scattering, both as it affects the volume of specimen in which the energy is deposited and the volume giving rise to the inelastic signal used to assess the damage.

Quantitative statistical analysis, optimization and noise reduction of atomic resolved electron energy loss spectrum images.

In this work we investigate methods of statistical processing and background fitting of atomic resolution electron energy loss spectrum image (SI) data. Application of principal component analysis to SI data has been analyzed in terms of the spectral signal-to-noise ratio (SNR) and was found to improve both the spectral SNR and its standard deviation over the SI, though only the latter was found to improve significantly and consistently across all data sets analyzed. The influence of the number of principal components used in the reconstructed data set on the SNR and resultant elemental maps has been analyzed and the experimental results are compared to theoretical calculations.

[The role of computer tomography in differential diagnostic of incidentalomas adrenal glands].

The possibilities of computer tomography (CT) for differential diagnosis of adrenal incidentalomas (AI) were investigated. CT was done for 157 patients with AT: 17--with malignant adrenal tumors (MAT) and 70--with benign adrenal tumors (BAT) (61--adrenocortical adenoma, 5--cyst, 3--hematoma, 1--myelolipoma). CT--main method of topic diagnostic for AI, which allow to make assumption about potential malignancy AI in 76.5% patients. Incidentalomas size more than 10,1sm, irregular contours, density more +51HU, signs of invasion, lymphadenopathy, regional or remote metastasis are the diagnostic criteria for MAT. In 23.5% cases with CT impossible to differentiate the malignant nature of AI. 10.0% patients with BAT had a false positive results, which slightly limits the diagnostic value of CT.

Detection of single atoms and buried defects in three dimensions by aberration-corrected electron microscope with 0.5-A information limit.

The ability of electron microscopes to analyze all the atoms in individual nanostructures is limited by lens aberrations. However, recent advances in aberration-correcting electron optics have led to greatly enhanced instrument performance and new techniques of electron microscopy. The development of an ultrastable electron microscope with aberration-correcting optics and a monochromated high-brightness source has significantly improved instrument resolution and contrast. In the present work, we report information transfer beyond 50 pm and show images of single gold atoms with a signal-to-noise ratio as large as 10. The instrument's new capabilities were exploited to detect a buried Sigma3 {112} grain boundary and observe the dynamic arrangements of single atoms and atom pairs with sub-angstrom resolution. These results mark an important step toward meeting the challenge of determining the three-dimensional atomic-scale structure of nanomaterials.

Angular and local spectroscopic analysis to probe the vertical alignment of N-doped well-separated carbon nanotubes.

Vertically aligned well-separated N-doped multiwalled carbon nanotubes (CNTs) were grown on a silicon substrate by plasma enhanced chemical vapor deposition (PECVD). Angular near-edge X-ray absorption fine structure (NEXAFS) was used to investigate the vertical alignment of as-grown CNTs. In addition, both individual tubes and tube bundles were characterized by high-resolution electron energy loss spectroscopy (HREELS). Simultaneous analysis of both spectroscopic techniques provides information on chemical environment, orbital orientation between carbon and heteroatoms, and local curvature effects. We demonstrate the utility of NEXAFS as an in situ probe of CNTs.

Enhancement of resolution in core-loss and low-loss spectroscopy in a monochromated microscope.

The significant enhancement of the energy resolution in the new generation of commercially available monochromated transmission electron microscopes presents new challenges in term of selecting the correct experimental conditions and understanding the various effects that can potentially influence the quality of the EELS data. In this respect we investigated the effect of point spread function of the detector and spectrum-diffraction mixing on the energy resolution and the intensity of the zero loss peak tails. Alternative approaches to improve the energy resolution by mathematical methods have been tested. By using a simple and commonly available test case (Si L(2,3) edges) we assessed the efficiency of the deconvolution algorithms to improve the resolution. The results show that the deconvolution is not always successful in improving the resolution of the core loss EELS data and the results may not always be reliable. Contrary to this, the application of the Richardson-Lucy deconvolution algorithm on some bandgap measurements data appears to be very effective. The procedure proved successful in removing the contribution of the zero-loss peak tails and allows an easier access to spectroscopic information starting at energy losses as low as of 0.5 eV with monochromated spectra and 1 eV with the non-monochromated spectra.

Cerenkov losses: a limit for bandgap determination and Kramers-Kronig analysis.

Measuring low energy losses in semiconductors and insulators with high spatial resolution becomes attractive with the increasing availability of modern transmission electron microscopes (TEMs) equipped with monochromators, C(s) correctors and energy filters. In this paper, we demonstrate that Cerenkov losses pose a limit for the interpretation of low energy loss spectra (EELS) in terms of interband transistions and bandgap determination for many materials. If the velocity of a charged particle in a medium exceeds the velocity of light, photons are emitted leading to a corresponding energy loss of a few electronvolt. Since these losses are strong for energies below the onset of interband transitions, they change the apparent loss function of semiconductors and insulators, with the risk of erroneous interpretation of spectra. We measured low energy losses of Si and GaAs with a monochromated TEM demonstrating the effect of sample thickness on Cerenkov losses. Angle resolved EELS and energy filtered diffraction patterns (taken without a monochromator) show the extremely narrow angular distribution of Cerenkov losses. The latter experiment provides a method that allows to decide whether Cerenkov radiation masks the very low loss signal in EELS.

[The role of computer tomography in differential diagnosis of benign and malignant tumors of the adrenals cortex].

Possibilities of computer tomography (CT) application for differential diagnosis of tumors of the adrenal cortex (TAC) were studied. CT was conducted in 157 patients with TAC, including 75--with malignant (MTAC), 82--with benign (BTAC), permitting to revealed MTAC in 76% patients. In 17.1% patients with BTAC false-positive results were noted, reducing, thus, the method diagnostic value. While the trustworthy signs of malignancy are absent, it is necessary to conduct morphological verification of the adrenal tumors nature using puncture biopsy and/or intraoperative express-cytological investigation.

Enantioselective synthesis of 2- and 3-substituted 2,3-dihydro[1,4]dioxino[2,3-b]pyridine derivatives and enantiomeric purity control by capillary electrophoresis.

A rapid and simple procedure for enantioselective preparation of 2- and 3-substituted 2,3-dihydro[1,4]dioxino[2,3-b]pyridine derivatives (A and B, respectively) is described. The enantiomeric purity of each isomer was determined by capillary electrophoresis using a dual-cyclodextrin system (S-beta-CD/beta-CD) dissolved in formic acid-ammonia buffer (pH 4, ionic strength 50 mM).

[Using magnetic-resonance tomography in differential diagnosis of the adrenal glands malignant tumors].

Possibilities of application of magnet-resonance tomography (MRT) for differential diagnosis of the adrenal glands tumors were studied up. MRT was conducted to 39 patients with adrenal glands tumors, including 22 - with malignant adrenal gland tumor, 17 - with benign tumor of adrenal gland. MRT constitutes the most effective method of topic diagnosis of the adrenal glands tumor, owes multipurpose possibilities, do not deliver radiation load, permits to visualize the vessels without the contrast media usage. The tumor diameter more than 10,1 cm, irregular form, illegible edges, uneven contours, presence of lymphadenopathy, regional or remote metastases constitutes diagnostic criterions of the adrenal glands malignant tumors. The intensity of MRT signal could not be used for differential diagnosis of malignant and benign tumors of adrenal glands.