Iatrogenic Kaposi's sarcoma from induction therapy for myeloma: to transplant or not to transplant?

We present the case of an HIV-negative man in his 50s who developed a generalised nodular rash while having first-line bortezomib-cyclophosphamide-dexamethasone chemotherapy for multiple myeloma. The rash was biopsied and proven to be Kaposi's sarcoma. The patient's treatment was interrupted at the sixth cycle of chemotherapy, by which time the rash had also spread to the oral mucosa and eyelid. The rash regressed spontaneously on stopping treatment. We were reluctant to restart myeloma treatment, but on the other hand, we wished to consolidate the very good partial response achieved. An autologous marrow transplant was done months later without any recurrence of his Kaposi's with the initiation of bortezomib maintenance. Bortezomib has putative activity against Kaposi's. The patient could benefit from imid-based (thalidomide, lenalidomide, pomalidomide) combination chemotherapy once his myeloma progresses or if there is a recurrence of Kaposi's sarcoma.

Neurofibromatosis Type 1: A Rare Predisposition for Gastrinomas and Other Neuroendocrine Tumors.

ABSTRACT: Neurofibromatosis type (NF-1) is an autosomal dominant disorder characterized predominantly by neurocutaneous manifestations. Involvement of the gastrointestinal tract is uncommon but is associated with a significant risk of malignancy. There are a handful of case reports linking NF-1 with pancreatic neuroendocrine tumors; these include gastrin-secreting variants with the attendant Zollinger-Ellison syndrome. We present the case of a 52-year-old lady who presented with recurrent peptic ulceration and diarrhea. Serum gastrin levels were elevated and magnetic resonance imaging demonstrated the presence of a pancreatic lesion with multiple liver metastases. The lesion was moderately fludeoxyglucose avid on positron emission tomography-computed tomography. Endoscopic ultrasonography-guided sampling revealed the presence of synaptophysin positive neuroendocrine cells with positive gastrin immunostaining. A conservative approach was adopted, and the patient's symptoms improved on proton pump inhibitors. Zollinger-Ellison syndrome is an important condition, which should be kept in mind in the patient with NF-1 who presents with recurrent peptic ulceration and diarrhea. The emerging association between these 2 conditions is being examined on a cellular and immunohistochemical level.

Mechanochemical halogenation of unsymmetrically substituted azobenzenes.

The direct and selective mechanochemical halogenation of C-H bonds in unsymmetrically substituted azobenzenes using N-halosuccinimides as the halogen source under neat grinding or liquid-assisted grinding conditions in a ball mill has been described. Depending on the azobenzene substrate used, halogenation of the C-H bonds occurs in the absence or only in the presence of PdII catalysts. Insight into the reaction dynamics and characterization of the products was achieved by in situ Raman and ex situ NMR spectroscopy and PXRD analysis. A strong influence of the different 4,4'-substituents of azobenzene on the halogenation time and mechanism was found.

Impact of Road Marking Retroreflectivity on Machine Vision in Dry Conditions: On-Road Test.

(1) Background: Due to its high safety potential, one of the most common ADAS technologies is the lane support system (LSS). The main purpose of LSS is to prevent road accidents caused by road departure or entrance in the lane of other vehicles. Such accidents are especially common on rural roads during nighttime. In order for LSS to function properly, road markings should be properly maintained and have an adequate level of visibility. During nighttime, the visibility of road markings is determined by their retroreflectivity. The aim of this study is to investigate how road markings' retroreflectivity influences the detection quality and the view range of LSS. (2) Methods: An on-road investigation comprising measurements using Mobileye and a dynamic retroreflectometer was conducted on four rural roads in Croatia. (3) Results: The results show that, with the increase of markings' retroreflection, the detection quality and the range of view of Mobileye increase. Additionally, it was determined that in "ideal" conditions, the minimal value of retroreflection for a minimum level 2 detection should be above 55 mcd/lx/m2 and 88 mcd/lx/m2 for the best detection quality (level 3). The results of this study are valuable to researchers, road authorities and policymakers.

A complex case of a granulosa cell tumour.

This is a case of a 73-year-old woman who first presented in 2020 with a fullness in her abdomen. After several thorough investigations and unforeseen complications, the fullness was diagnosed as a granulosa cell tumour. In 2003, she had been diagnosed with a granulosa cell tumour of the ovary. Complete excision was performed, however she was not given a follow-up appointment after the procedure. This case highlights the importance of frequent follow-up of these tumours, the high recurrence rate, the severe complications which may result and the awareness of possible variations in this tumour's histologic appearance.

Large cell neuroendocrine carcinoma arising from the anterior mediastinum.

Anterior mediastinal large cell neuroendocrine carcinomas (LCNECs) are extremely rare, extremely aggressive malignancies that carry a dismal prognosis. We discuss a woman aged 60 years who presented with a 2-month history of recurrent severe constant epigastric pain. Abdominal examination revealed massive hepatomegaly and a CT scan of the liver confirmed coarse liver lesions. Histology from a liver biopsy was consistent with a large cell (non-small cell) neuroendocrine carcinoma. A CT scan of the chest showed a large anterior mediastinal mass unrelated to the lung, suggesting that the anterior mediastinum was the primary origin of the tumour. The patient was planned to receive platinum/etoposide chemotherapy for a metastatic mediastinal large cell neuroendocrine carcinoma. Unfortunately, her health deteriorated, and she was unfit to undergo any further treatment. She was treated palliatively and died 2 months after the diagnosis.

A ferrocene-based pseudopeptide chiroptical switch.

We present a double-stranded ferrocene pseudopeptide 2b which exhibits stimuli responsive chirality inversion triggered by solvent exchange or acid addition. Compound 2b exists as a mixture of self-assembled fast exchanging oligomers which macroscopically behave as a chiroptical switch with two stable states. The ferrocene group inversion results in a distinct CD signal in the visible part of the spectrum. The inversion is accomplished through a conformational change due to a rearrangement of hydrogen bonding forcing the rotation of ferrocene rings.

A Detailed Kinetico-Mechanistic Investigation on the Palladium C-H Bond Activation in Azobenzenes and Their Monopalladated Derivatives.

Palladium C-H bond activation in azobenzenes with R1 and R2 at para positions of the phenyl rings (R1 = NMe2, R2 = H (L1); R1 = NMe2, R2 = Cl (L2); R1 = NMe2, R2 = I (L3); R1 = NMe2, R2 = NO2 (L4); R1 = H, R2 = H (L5)) and their monopalladated derivatives, using cis-[PdCl2(DMF)2], has been studied in detail by in situ 1H NMR spectroscopy in N,N-dimethylformamide-d7 (DMF-d7) at room temperature; the same processes have been monitored in parallel via time-resolved UV-vis spectroscopy in DMF at different temperatures and pressures. The final goal was to achieve, from a kinetico-mechanistic perspective, a complete insight into previously reported reactivity results. The results suggest the operation of an electrophilic concerted metalation-deprotonation mechanism for both the mono- and dipalladation reactions, occurring from the coordination compound and the monopalladated intermediates, respectively. The process involves deprotonation of the C-H bond assisted by the presence of a coordinated DMF molecule, which acts as a base. For the first time, NMR monitoring provides a direct evidence of all the intermediate stages: that is, (i) coordination of the azo ligand to the PdII center, (ii) formation of the monopalladated species, and (iii) coordination of the monopalladated species to another PdII unit, which finally result in the (iv) formation of the dipalladated product. All of these species have been identified as intermediates in the dipalladation of azobenzenes, evidenced also by UV-vis spectroscopy time-resolved monitoring. The data also confirm that the cyclopalladation of asymmetrically substituted azobenzenes occurs by two concurrent reaction paths. In order to identify the species observed by NMR and by UV-vis spectroscopy, the final products, intermediates, and the PdII precursor have been prepared and characterized by X-ray diffraction and IR and NMR spectroscopy. DFT calculations have also been used in order to explain the isomerism observed for the isolated complexes, as well to assign their NMR and IR spectra.

Driver eye movements in relation to unfamiliar traffic signs: An eye tracking study.

Traffic signs are an integral part of the traffic control plan and they provide road users with necessary information on the upcoming situation. This paper aims to examine the level of understanding of traffic sign imagery used in different countries and to track participants' eye movement when they encounter unfamiliar signs. Tobii eye tracking glasses were used to track gaze differences between familiar and unfamiliar traffic signs. Our findings show that sign characteristics (such as the amount of information on the sign) and the observer's knowledge of the sign meaning have a significant impact on eye behaviour. Signs containing more information (loaded with more content) and unfamiliar to the participant systematically produced the longest overall and average fixations and gazing duration. Given that longer gaze time for unfamiliar traffic signs presents a potential traffic hazard, we evaluated the need for standardization of traffic signs.

Photophysical properties and immobilisation of fluorescent pH responsive aminated benzimidazo[1,2-a]quinoline-6-carbonitriles.

This work presents a systematic evaluation of 2-amino, 5-amino and 2,5-diamino substituted benzimidazo[1,2-a]quinoline-6-carbonitriles as novel pH probes with a potential application in pH sensing materials or as H+ fluoroionophores in bulk optode membranes. The study was carried out by varying the length, type and position of amino substituents in ten fluorescent dyes with the same benzimidazo[1,2-a]quinoline-6-carbonitrile core. The photophysical and acid-base properties of the dyes were investigated by the UV/Vis absorption and fluorescence spectroscopies, and interpreted by the electronic structure DFT calculations. pH sensing mechanisms and structure-property relations affecting the fluorescence response were discussed through a detailed analysis of the piperidine substituted derivatives 1-4. Push-pull donor-acceptor interactions stimulate strong fluorescence in the visible spectral range (up to Φ = 0.65 for 7) and induce significant changes in the photophysical properties associated with the acid-base equilibria (up to a 50-fold increase in the fluorescence intensity). pKa values in aqueous and mixed solutions (v/v H2O:EtOH 99:1, 50:50), appear suitable for monitoring acidic pH in solution. The most promising candidates were immobilised in thin polymer matrices by the spin coating technique to form fluorescent sensing materials - optodes, and examined as novel pH-sensitive fluoroionophores. In the liquid membrane environment, dyes exhibited significant increase of the apparent pKas by almost 4 units. Bright and blue emissive thin films showed pH response and dynamic range around pKa = 5, making them suitable for a wide range of optical sensing applications.

Resolution of protein hydrogen/deuterium exchange by fitting amide exchange probabilities to the peptide isotopic envelopes.

RATIONALE: Mass spectra processing in protein hydrogen/deuterium (H/D) exchange has been remarkably improved by the introduction of fitting of the amide exchange probabilities to peptide isotopic envelope intensities (Kan et al., 2013), in contrast to methods in which only the peptide deuterium uptakes (centroid shifts of isotopic envelopes) are used. However, the known implementations are based on the general fitting routines that use only the objective function values. Besides, applicability of more than one fitting method makes necessary their comparative evaluation. METHODS: Two fitting methods were considered: the common least squares and the fitting of the multinomial distribution representing the number of deuterium atoms exchanged in the individual peptides. Both methods were applied either directly to the isotopic envelope data or to the deuterium distributions obtained by envelope deconvolution (i.e. de-isotoping). RESULTS: An autonomous Matlab script was prepared, based on the exact expressions for the gradient and Hessian of the objective function, with the trust-region algorithm implemented in the compact analytical form recently made available. The least-squares fitting to the envelope data produced the best results, with the greatest precision and good coverage of exact values by the confidence intervals. The deuterium distributions were sensitive to the (simulated) experimental error whose progression by envelope deconvolution caused degradation in accuracy. The multinomial distribution fitting exhibited poor performance due to inadequate representation of the experimental error and missing of the appropriate weight parameters. Some specific peptide arrangement details were discussed as potential sources of ambiguity in the fitting results. CONCLUSIONS: The method of fitting to peptide isotopic envelopes has been improved by using the exact gradient and Hessian of the objective function. The fitting should be repeated with different initial guesses in order to find not only the global minimum, but also the local minima with similar depths which may exist due to eventual ambiguity of the fitting results.

Computational Tale of Two Enzymes: Glycerol Dehydration With or Without B12.

We present a series of QM/MM calculations aimed at understanding the mechanism of the biological dehydration of glycerol. Strikingly and unusually, this process is catalyzed by two different radical enzymes, one of which is a coenzyme-B12-dependent enzyme and the other which is a coenzyme-B12-independent enzyme. We show that glycerol dehydration in the presence of the coenzyme-B12-dependent enzyme proceeds via a 1,2-OH shift, which benefits from a significant catalytic reduction in the barrier. In contrast, the same reaction in the presence of the coenzyme-B12-independent enzyme is unlikely to involve the 1,2-OH shift; instead, a strong preference for direct loss of water from a radical intermediate is indicated. We show that this preference, and ultimately the evolution of such enzymes, is strongly linked with the reactivities of the species responsible for abstracting a hydrogen atom from the substrate. It appears that the hydrogen-reabstraction step involving the product-related radical is fundamental to the mechanistic preference. The unconventional 1,2-OH shift seems to be required to generate a product-related radical of sufficient reactivity to cleave the relatively inactive C-H bond arising from the B12 cofactor. In the absence of B12, it is the relatively weak S-H bond of a cysteine residue that must be homolyzed. Such a transformation is much less demanding, and its inclusion apparently enables a simpler overall dehydration mechanism.

Identifying the safety factors over traffic signs in state roads using a panel quantile regression approach.

OBJECTIVE: This study intended to investigate the interactions between accident rate and traffic signs on state roads located in Croatia and accommodate the heterogeneity attributed to unobserved factors. Data from 130 state roads between 2012 and 2016 were collected from Traffic Accident Database System maintained by the Republic of Croatia's Ministry of the Interior. METHODS: To address the heterogeneity, a panel quantile regression model was proposed, in which a quantile regression model offers a more complete view and a highly comprehensive analysis of the relationship between accident rate and traffic signs, and the panel data model accommodates the heterogeneity attributed to unobserved factors. RESULTS: Results revealed that (1) low visibility of material damage (MD) and death or injury (DI) increased the accident rate; (2) the number of mandatory signs and the number of warning signs were more likely to reduce the accident rate; (3) the average speed limit and the number of invalid traffic signs per kilometer exhibited a high accident rate. CONCLUSIONS: To our knowledge, this study is the first attempt to analyze the interactions between accident consequences and traffic signs by employing a panel quantile regression model; by including visibility, the present study demonstrates that low visibility causes a relatively higher risk of MD and DI. It is noteworthy that average speed limit positively corresponds with accident rate; the number of mandatory signs and the number of warning signs are more likely to reduce the accident rate; and the number of invalid traffic signs per kilometer is significant for the accident rate; thus, regular maintenance should be performed for a safer roadway environment.

Tandem In Situ Monitoring for Quantitative Assessment of Mechanochemical Reactions Involving Structurally Unknown Phases.

We report herein quantitative in situ monitoring by simultaneous PXRD and Raman spectroscopy of the mechanochemical reaction between benzoic acid and nicotinamide, affording a rich polymorphic system with four new cocrystal polymorphs, multiple phase transformations, and a variety of reaction pathways. After observing polymorphs by in situ monitoring, we were able to isolate and characterize three of the four polymorphs, most of which are not accessible from solution. Relative stabilities among the isolated polymorphs at ambient conditions were established by slurry experiments. Using two complementary methods for in situ monitoring enabled quantitative assessment and kinetic analysis of each studied mechanochemical reaction, even when involving unknown crystal structures, and short-lived intermediates. In situ Raman monitoring was introduced here also as a standalone laboratory technique for quantitative assessment of mechanochemical reactions and understanding of mechanochemical reactivity. Our results provide an important step toward a complete and high-throughput quantitative approach to mechanochemical reaction kinetics and mechanisms, necessary for the development of the mechanistic framework of milling reactions.

Spin-coupling in dimers of 2,3-dicyano-5,6-dichlorosemiquinone radical anions in the crystalline state.

A crystal engineering approach is used to stabilize a radical anion in the crystalline state and to modulate the separation distance within π-stacks of anion radicals. Alkali metal salts of 2,3-dicyano-5,6-dichlorosemiquinone (C8Cl2N2O2, DDQ∙- radical anions were prepared and their crystal structures determined: LiDDQ·2H2O·(CH3)2CO, RbDDQ·2H2O and CsDDQ·2H2O. In these structures, stacked dimers of radical anions are formed within π-stacked columns. Within the stacked dimers, interplanar separation distances are significantly shorter than the sum of the van der Waals radii for two C atoms; the shortest is 2.812 Šfor the Li salt and the longest is 2.925 Šfor the Cs salt. Diamagnetic character, observed by electron paramagnetic resonance spectroscopy, indicates spin-coupling of the unpaired electrons within the radical anion dimer. The electron-rich cyano substituents on DDQ∙- influence the electron redistribution within the ring skeleton. The crystalline compounds are also characterized by IR spectroscopy, complemented by quantum-chemical calculations based on both isolated and periodic models.

Lymphoma of the cervix.

Primary non-Hodgkins lymphoma of the uterine cervix is a very rare diagnosis. A 54-year-old woman presented with a 3-month history of postmenopausal bleeding per vaginum. On examination, a friable, fungating lesion was seen on the cervix. Histology revealed a CD 20 positive high-grade non-Hodgkin's diffuse large B cell lymphoma from cervical biopsies and endometrial curettage. She was diagnosed as stage IE after workup and subsequently treated with six cycles of R-CHOP chemotherapy followed by radiotherapy of the involved field.

New insight into solid-state molecular dynamics: mechanochemical synthesis of azobenzene/triphenylphosphine palladacycles.

Solid-state reactions of dicyclopalladated azobenzenes and triphenylphosphine lead to the thermodynamically favorable bridged complexes. It was demonstrated for the first time that very complex molecular dynamics involving a series of structural transformations is also feasible in the solid state.

Unusual azobenzene/bipyridine palladacycles: structural, dynamical, photophysical and theoretical studies.

Two types of Pd(ii) azobenzene/bipyridine complexes with unusual coordination mode of azobenzenes, PdCl{(mu-Cl)(mu-R(1)C(6)H(3)N=NC(6)H(3)R(2))}Pd(bpy) 1a-4a and [(bpy)PdCl(mu-NH(2)C(6)H(3)N=NC(6)H(4))Pd(bpy)]Cl 3b were formed by the reaction of dicyclopalladated azobenzenes (DMF)PdCl(mu-R(1)C(6)H(3)N=NC(6)H(3)R(2))PdCl(DMF) with excess of bpy, where bpy=2,2'-bipyridine; R(2)=H and R(1)=H (1), CH(3) (2), NH(2) (3) or R(1)=N(CH(3))(2) and R(2)=NO(2) (4). Neutral species 1a-4a were obtained in acetone, while in DMSO or MeOH the ionic complex 3b was produced. When dissolved, 3b decomposes to 3a and free bpy; however in DMSO upon addition of bpy 3b crystallizes again. X-ray structures of all complexes confirmed breaking of one Pd-N bond in the initial precursors, thus allowing rotation of one phenyl ring and positioning of both Pd atoms on the same side of the azobenzene ligand. Two Pd atoms are connected by the azobenzene ligand and in neutral complexes additionally by the Cl-bridge. In all complexes in the solid-state azobenzenes act simultaneously as monodentate C- and bidentate C,N-donors while bpy acts as bidentate donor. Variable-temperature (1)H NMR experiments established that structures of 1a-4a in DMF and DMSO at ambient temperature are not consistent with solid-state structures due to the fast exchange of one of the bpy nitrogen atoms bound to the Pd atom with solvent molecules. Theoretical studies confirmed the experimental structures as the most stable isomers. Photoabsorption and photoemission properties of the new complexes have been measured and photoabsorption is rationalized by time dependent DFT calculations. The presence of bpy significantly increases the intensity of fluorescence either in the solution (4a) or in the solid state (3a, 4a, 3b) at ambient temperature.

Composite carcinoma of the stomach associated with sarcoid-like granulomas.

Composite glandular/exocrine-endocrine carcinoma of the gastrointestinal tract is a special tumor type composed of common adenocarcinoma and the neuroendocrine component comprising at least one-third of the whole tumor area. These tumors are rare in the stomach and mostly published as case reports. We describe a further case of a 36-year-old man being unique in that it was associated with extensive formation of sarcoid-like granulomas. Tumor consisted of, predominantly poorly differentiated, intestinal-type adenocarcinoma and poorly differentiated neuroendocrine, small cell carcinoma. The adenocarcinomatous and neuroendocrine areas were separated, but closely juxtaposed with focal areas showing gradual transition from one to another. Perigastric lymph node metastases corresponded either to neuroendocrine or adenocarcinomatous component. On immunohistochemistry, the exocrine part was positive for cytokeratin 7, whereas superficial well-differentiated parts showed positivity with cytokeratin 20 as well. The neuroendocrine component was negative with those two types of cytokeratin. Both adenocarcinomatous and neuroendocrine tumor portions showed carcinoembryonic antigen (CEA) immunoexpression. Neuroendocrine markers (chromogranin A, synaptophysin and neuron-specific enolase) were diffusely positive in the neuroendocrine component, and found only in the scattered cells within the neoplastic glands of the adenocarcinoma. Entire gastric mucosa and all perigastric lymph nodes were extensively affected by noncaseating, sarcoid-like granulomas. The absence of any clinical manifestations combined with the negative results of chest radiograph and laboratory test for the serum angiotensin converting enzyme argued against the possibility of systemic sarcoidosis.