Real-World Experience in Treatment of Patients with Non-Small-Cell Lung Cancer with BRAF or cMET Exon 14 Skipping Mutations.

BRAF and cMET exon 14 skipping are rare mutations of NSCLC. The treatment sequence in these cases for the first and second line is not clear. An international registry was created for patients with advanced NSCLC harboring BRAF or cMET exon 14 skipping mutations, diagnosed from January 2017 to June 2022. Clinicopathological and molecular data and treatment patterns were recorded. Data on 58 patients, from eight centers across five countries, were included in the final analysis. We found that 40 patients had the cMET exon 14 skipping mutation and 18 had the BRAF V600E mutation. In total, 53 and 28 patients received first- and second-line treatments, respectively, among which 52.8% received targeted therapy (TT) in the first line and 53.5% in the second line. The overall response rate (ORR) and disease control rate (DCR) for first-line treatment with TT vs. other treatment such as immune checkpoint inhibitors ± chemotherapy (IO ± CT) were 55.6% vs. 21.7% (p = 0.0084) and 66.7% vs. 39.1% (p = 0.04), respectively. The type of treatment in first-line TT vs. other affected time to treatment discontinuation (TTD) was 11.6 m vs. 4.6 m (p= 0.006). The overall survival for the whole group was 15.4 m and was not statistically affected by the type of treatment (19.2 m vs. 13.5 m; p = 0.83).

Midazolam and hydroxymidazolam plasma concentrations can be monitored with selected biochemical and physiological parameters of palliative care patients.

RATIONALE & OBJECTIVE: Midazolam is one of top three drugs used in palliative care. Its use increases in the last days of hospice patients' lives while safe dosage can be challenging. Equations currently used to estimate glomerular filtration rate, e.g: the Cockroft-Gault (eGFRCR) and the Modification of Diet in Renal Disease (eGFRMDRD) ones, do not generate precise calculations, especially in palliative patients exhibiting variations in body parameters. Our aim was to seek new relationships between mean midazolam (Mavg) and alfahydroxymidazolam (OH-Mavg) concentrations in plasma, and selected biochemical and physiological parameters of palliative patients, to enable optimal midazolam pharmacotherapy. STUDY DESIGN, PARTICIPANTS AND INTERVENTIONS: The pilot study included 11 Caucasians, aged 42-95, with advanced cancer disease, receiving midazolam in a hospice in-patient unit. We tested correlations among Mavg, BMI, eGFRMDRD, midazolam clearance (CL), OH-Mavg, bilirubin (Bil) and blood creatinine concentration (Cr). F test and leave-one out (LOO) validation was applied to verify the correlations' significance and predictive ability. RESULTS: We found ten statistically significant (p < 0.05) correlations related to midazolam pharmacokinetics and physiological factors. We formulated two equations with high degree of predictive ability, based on the eGFRMDRD→CL and the (Bil + BMI × Ln(Cr))→Mavg-(OH-Mavg) correlations. The limitations of the study mainly revolve around its pilot nature and the need to continue testing the results on a bigger population. No funding to disclose. CONCLUSIONS: The significance of correlations corresponding to the arithmetic expressions confirms that Bil, BMI, Ln(Cr) analyzed simultaneously report a series of processes on which midazolam metabolism depends. Two of ten correlations proposed came close to meet all LOO validation criteria. Current findings can help optimize midazolam treatment in palliative therapy.

Haloperidol in palliative care: Indications and risks.

Individual response to medication depends on several factors (age, gender, body weight, general clinical condition, genetics, diet, hydration status, comorbidities, co-administered drugs and their mode of administration, smoking, alcohol overuse, environmental factors, e.g. sunlight) that may contribute to adverse drug reactions even at therapeutic doses. Patients in palliative care are at increased risk of these reactions. Unwanted drug effects diminish the quality of life and may lead to a suboptimal dying process. Haloperidol is one of the three most commonly used drugs in palliative care and the most commonly employed typical antipsychotic. It has also been recommended for inclusion into the palliative care emergency kit of home care teams. As such, it is important to be fully conversant with the indications, benefits, and risks of haloperidol, especially in the context of palliative care.

How effective is freezing at killing Anisakis simplex, Pseudoterranova krabbei, and P. decipiens larvae? An experimental evaluation of time-temperature conditions.

The consumption of raw or inadequately cooked marine fish can lead to several disorders caused by the ingestion of viable anisakid nematodes. Although anisakid larvae can be killed by subzero temperatures, making freezing an important control measure for this potential health hazard, these parasites can survive freezing under some conditions. Therefore, the aim of the present study was to experimentally evaluate the time-temperature conditions needed to kill Anisakis simplex and Pseudoterranova spp. The effectiveness of freezing was tested on two species of fish: cod, Gadus morhua from the North Atlantic, and herring, Clupea harengus membras from the southern Baltic Sea. Samples, which comprised skinless fillets of cod (n = 40) with visible parasites and whole herring (n = 240), were separately frozen at - 15, - 18, or - 20 °C for 24 h, or at - 20 °C for 48 h in the single-compressor freezer and at - 20, - 25, or - 35 °C for 24 h in the double-compressor freezer. After thawing, parasites were stained with malachite green and examined under the microscope for viability. All A. simplex and Pseudoterranova spp. larvae in cod fillets died at a temperature of - 15 °C or lower. However, freezing did not kill all the A. simplex larvae in whole herring: spontaneous movement of these parasites was observed in samples stored in the single-compressor freezer at - 15, - 18, and - 20 °C over 24 h. Our results demonstrate that the freezing procedure must consider both the capability of the freezing device and the nature of the fish product to ensure consumer safety.

Midazolam: Safety of use in palliative care: A systematic critical review.

PURPOSE: The undesired effects of midazolam can be life-threatening. This paper delineates the findings related to the pharmacokinetics, adverse effects and drug-drug interactions as well as associated therapeutic implications for safe midazolam use. METHODS: A systematic review of literature was conducted. RESULTS: The pharmacokinetics of midazolam depends on hepatic and renal functions, fat tissue mass, route and duration of administration, as well as potential drug-drug interactions. Palliative care patients constitute a high-risk group prone to side effects of drugs, due to polytherapy and multi-organ failure. CONCLUSION: Midazolam is one of three most frequently administered drugs in palliative care. The indications for its use include anxiety, dyspnea, seizures, vomiting refractory to treatment, agitation, myoclonus, status epilepticus, restlessness, delirium, pruritus, hiccups, insomnia, analgosedation, palliative sedation and preventing or counteracting undesired effects of ketamine.

Comparison of anthropometrical parameters and dietary habits of young women with and without menstrual disorders.

AIM: The aim of this study was to assess the nutritional status and dietary habits of young women, in order to explore their relationship with the menstrual cycle and to determine the proportion of women with menstrual cycle irregularities. METHODS: A total of 348 young women aged 15-25 years (19.7 ± 3.7 years) participated in the study and were assigned to a younger group (15-18 years; YG) or an older group (19-25 years; OG). Two subgroups were also distinguished: women with menstrual disorders (MD) and women with regular cycles (RC). Body mass, waist circumference, fat mass (FM), energy and nutrient intakes, and eating behaviour of the subjects were evaluated. RESULTS: In both age groups, women with menstrual cycle disorders were more likely to have higher body weight, higher body mass index, larger waist circumference and higher body FM. The daily diets of these women contained larger quantities of animal protein and fat, including saturated fat (in OG), but were poorer in vitamins B1 and B6 (in YG) and in iron. Disinhibition was significantly more common in the MD group. CONCLUSIONS: The results of this study suggest that nutritional habits and status can interfere with the course of the menstrual cycle in young women.

Evaluation of an amino acid residue critical for the specificity and activity of human Gb3/CD77 synthase.

Human Gb3/CD77 synthase (α1,4-galactosyltransferase) is the only known glycosyltransferase that changes acceptor specificity because of a point mutation. The enzyme, encoded by A4GALT locus, is responsible for biosynthesis of Gal(α1-4)Gal moiety in Gb3 (CD77, Pk antigen) and P1 glycosphingolipids. We showed before that a single nucleotide substitution c.631C > G in the open reading frame of A4GALT, resulting in replacement of glutamine with glutamic acid at position 211 (substitution p. Q211E), broadens the enzyme acceptor specificity, so it can not only attach galactose to another galactose but also to N-acetylgalactosamine. The latter reaction leads to synthesis of NOR antigens, which are glycosphingolipids with terminal Gal(α1-4)GalNAc sequence, never before described in mammals. Because of the apparent importance of position 211 for enzyme activity, we stably transfected the 2102Ep cells with vectors encoding Gb3/CD77 synthase with glutamine substituted by aspartic acid or asparagine, and evaluated the cells by quantitative flow cytometry, high-performance thin-layer chromatography and real-time PCR. We found that cells transfected with vectors encoding Gb3/CD77 synthase with substitutions p. Q211D or p. Q211N did not express Pk, P1 and NOR antigens, suggesting complete loss of enzymatic activity. Thus, amino acid residue at position 211 of Gb3/CD77 synthase is critical for specificity and activity of the enzyme involved in formation of Pk, P1 and NOR antigens. Altogether, this approach affords a new insight into the mechanism of action of the human Gb3/CD77 synthase.

Human Gb3/CD77 synthase reveals specificity toward two or four different acceptors depending on amino acid at position 211, creating P(k), P1 and NOR blood group antigens.

Human Gb3/CD77 synthase (α1,4-galactosyltransferase, P(k) synthase), encoded by A4GALT gene, is known for synthesis of Gal(α1-4)Gal moiety in globotriaosylceramide (Gb3Cer, CD77, P(k) blood group antigen), a glycosphingolipid of the globo series. Recently, it was shown that c.631C > G mutation in A4GALT, which causes p.Q211E substitution in the open reading frame of the enzyme, broadens the enzyme specificity, making it able also to synthesize Gal(α1-4)GalNAc moiety, which constitutes the defining terminal disaccharide of the NOR antigen (carried by two glycosphingolipids: NOR1 and NOR2). Terminal Gal(α1-4)Gal disaccharide is also present in another glycosphingolipid blood group antigen, called P1, which together with P(k) and NOR comprises the P1PK blood group system. Despite several attempts, it was never clearly shown that P1 antigen is synthesized by Gb3/CD77 synthase, leaving open an alternative hypothesis that there are two homologous α1,4-galactosyltransferases in humans. In this study, using recombinant Gb3/CD77 synthase produced in insect cells, we show that the consensus enzyme synthesizes both the P(k) and P1 antigens, while its p.Q211E variant additionally synthesizes the NOR antigen. This is the first direct biochemical evidence that Gb3/CD77 synthase is able to synthesize two different glycosphingolipid antigens: P(k) and P1, and when p.Q211E substitution is present, the NOR antigen is also synthesized.

Comparison of common persistent organic pollutants (POPs) in flounder (Platichthys flesus) from the Vistula (Poland) and Douro (Portugal) River estuaries.

Groups of flounder (Platichthys flesus) females were collected in 2011 from the Vistula River and the Duoro River estuaries and corresponding reference sites in the southern Baltic Sea and Portuguese coast of the Atlantic Ocean to measure and compare the levels and profiles of polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), and polybrominated diphenyl ethers (PBDEs). The estuaries' sediments were also investigated. Several differences were found in the POPs between the estuaries and between the two marine regions, which were highlighted by PCA. The Vistula River estuary POPs, significantly higher than in the Douro River estuary, were dominated by DDTs followed by PCBs. PBDEs levels, indifferent between the estuaries, were relatively low. The POP levels in flounder and sediment evaluated against environmental assessment criteria (EACs) indicated that none of the measured contaminants for which EAC had been established exceeded the criterion, except for CB-118 in flounder from the Vistula River estuary.

Solid-state DFT-assisted Raman study of titaniate nanostructures.

The first principle solid-state computations in frame of Density Functional Theory have been employed to analyze the Raman spectra of typical titaniate nanostructures. The Raman scattering studies of the nanotitaniates synthesised hydrothermally at different temperature conditions are reported. Local Density Approximation in combination with linear-response computations have delivered detailed analysis of Raman spectra based on the reference Na2Ti3O7 and NaHTi3O7 structures. The interpretation of the most prominent spectral features commonly reported in the literature have been postulated.

Poly[bis-(µ(6)-benzene-1,3,5-tricarboxyl-ato-κ(7)O(1),O(1'):O(1'):O(3):O(3'):O(5):O(5'))tetra-kis-(dimethyl-formamide-κO)trimagnesium(II)].

The asymmetric unit of the polymeric title compound, [Mg(3)(C(9)H(3)O(6))(2)(C(3)H(7)NO)(4)](n), contains three Mg(II) ions bridged by carboxyl-ate O atoms from two fully deprotonated benzene-1,3,5-tricarboxyl-ate (BTC) trianions and four metal-coordinated dimethyl-formamide (DMF) mol-ecules. One Mg(II) ion is octa-hedrally coordinated by six carboxyl-ate O atoms. The other two cations are each octa-hedrally coordinated by four carboxyl-ate O atoms and two O atoms donated by two DMF mol-ecules: in one, the DMF mol-ecules are cis and in the other they are trans. The three Mg(II) octa-hedra form clusters, which are bridged by the BTC trianions, generating a three-dimensional structure.

trans-Diaqua-bis-(1H imidazolium-4,5-di-carboxyl-ato-κ(2)O(4),O(5))magnesium.

The title compound, [Mg(C(5)H(3)N(2)O(4))(2)(H(2)O)(2)], consists of centrosymmetric neutral monomers in which two O,O'-bidentate imidazolinium-4,5-dicarboxyl-ate ligands are bonded to the Mg(II) ion. One of the carboxyl protons is transferred to the N atom of the imidazole ring. The octa-hedral metal-ion coordination is completed by two trans water O atoms. In the crystal, mol-ecules are linked by N-H⋯(O,O) and O-H⋯O hydrogen bonds.