Current therapy of KRAS-mutant lung cancer

KRAS mutations are the most frequent gain-of-function alterations in patients with lung adenocarcinoma (LADC) in the Western world. Although they have been identified decades ago, prior efforts to target KRAS signaling with single-agent therapeutic approaches such as farnesyl transferase inhibitors, prenylation inhibition, impairment of KRAS downstream signaling, and synthetic lethality screens have been unsuccessful. Moreover, the role of KRAS oncogene in LADC is still not fully understood, and its prognostic and predictive impact with regards to the standard of care therapy remains controversial. Of note, KRAS-related studies that included general non-small cell lung cancer (NSCLC) population instead of LADC patients should be very carefully evaluated. Recently, however, comprehensive genomic profiling and wide-spectrum analysis of other co-occurring genetic alterations have identified unique therapeutic vulnerabilities. Novel targeted agents such as the covalent KRAS G12C inhibitors or the recently proposed combinatory approaches are some examples which may allow a tailored treatment for LADC patients harboring KRAS mutations. This review summarizes the current knowledge about the therapeutic approaches of KRAS-mutated LADC and provides an update on the most recent advances in KRAS-targeted anti-cancer strategies, with a focus on potential clinical implications

Comparative effectiveness of depot and oral second generation antipsychotic drugs in schizophrenia: A nationwide study in Hungary.

We conducted a nationwide, full-population based investigation to evaluate the comparative effectiveness of all marketed second generation antipsychotic drugs (SGA) prescribed for outpatients with the diagnosis of schizophrenia in Hungary. Using the national central register, our observational follow-up study included all patients with schizophrenia or related disorder between 01/01/2006 and 30/06/2008. The study cohort comprised 9567 patients who started new SGA during the inclusion period (01/07/2007-30/06/2008). All-cause medication discontinuation of 8 SGAs (1 depot and 7 oral formulations) marketed during the inclusion period, and the time to all-cause discontinuation were the main outcomes. Statistical models included the Kaplan-Meier and the Cox proportional hazards models with propensity score adjustment. Patients treated with a depot formulation risperidone had the longest time to discontinuation with a median of 215 days (95%CI:181-242 days), which was statistically significantly different compared to patients treated with the rest of the medications: olanzapine (136 days, 95%CI:121-153 days), aripiprazole (102 days, 95%CI:81-126 days), ziprasidone (93 days, 95%CI:82-119 days), quetiapine (89 days, 95%CI:81-100 days), clozapine (76 days, 95%CI:54-92 days), amisulpride (73 days, 95%CI:62-85 days), and risperidone (55 days, 95%CI: 41-63 days). Our results in Hungary are partly similar to those of a recent register-based study in Finland with patients who were discharged from their first hospitalization for schizophrenia (Tiihonen et al., 2006, 2011); namely the median times to all-cause medication discontinuation were <120 days for the majority of the oral SGA. In terms of medication differences, our data support the superior effectiveness of the depot formulation regarding all-cause discontinuation, followed by olanzapine at the efficacy rank order

Légzőszervi környezet-epidemiológiai vizsgálat Nyergesújfalun és Komáromban : Összehasonlító tanulmány = Envitonmental epidemiological study on respiratory diseases in two Hungarian towns

A szerzők korábban beszámoltak egyrészt a Nyergesújfalun, az azbesztcementgyár környezetében, másrészt az iparral jóval kevésbé terhelt Komáromban élő felnőtt lakosság körében végzett, alapvetően légzőszervi, standardizált kérdőíves keresztmetszeti epidemiológiai vizsgálat eredményeiről. Nyergesújfalun (a továbbiakban is: az azbeszttel foglalkozásilag nem exponáltak között) a légzőszervi tünetek, egyéb betegségek és daganatok nem voltak szignifikánsan gyakoribbak az azbesztcementgyár sem 500 m-es, sem 1 km-es körzetén belül az azon kívül élőkhöz viszonyítva, nyers összehasonlítás és logisztikus regressziós modellek szerint. A két várost összehasonlítva megállapítható, hogy krónikus aspecifikus (obstruktív) légzőszervi betegségre (KALB) jellemző tünetek Nyergesújfalun körülbelül másfélszer-két és félszer nagyobb eséllyel fordultak elő (p < 0,001), mint Komáromban. Az ezekkel összefüggő kockázati tényezők közül is több szignifikánsan gyakoribb volt Nyergesújfalun, mint Komáromban. A szerzők ezután a két város logisztikus regressziós modelljeiben alkalmazott korrekciós tényezőket csoportonként összevonták, és az összehasonlítást az összevont korrekciós tényezők alkalmazásával is elvégezték. A legtöbb KALB-tünet esélye ez esetben is szignifikánsan nagyobb volt Nyergesújfalun, mint Komáromban. Mindezekből következik, hogy a környezeti azbesztexpozíció szerepe továbbra sem zárható ki a foglalkozásilag azbeszttel nem exponáltak KALB-tüneteinek kialakulásában. (Megjegyzendő, hogy ez a tanulmány is támogatja a nem, kor, dohányzás, alkoholfogyasztás, elhízás, foglalkozási expozícó, a penészes lakás és az öröklődés etiológiai szerepét a vizsgált végpontok esetében.) Analitikus vizsgálatok igénye felvethető annak tisztázására, hogy mekkora és különbözik-e a két város levegőjében az aktuális azbesztrost-koncentráció (ez utalhat a korábbi koncentrációk alakulására), illetve hogy mekkora és különbözik-e a két városban vett autopsziás tüdőmintákban az akkumulálódott azbesztrost-koncentráció. Főként e kérdések tisztázása esetén átgondolandó, hogy javasolt-e döntéshozói szinten, akár most is, megfelelő intervenció. Ezenfelül, az azonosított egyéb kockázati tényezők eliminálása egészségnevelési lépéseket sürget. | Authors performed standardized, respiratory and risk factor questionnaire surveys among the adult population of two towns of Hungary: the first in Nyergesújfalu, according to the distance of the flat from asbestos cement factory, and the second in Komárom, a settlement of a smaller burden of industry. They excluded the data of former asbestos industry workers from the calculations. By the analysis of the Nyergesújfalu data they concluded that odds of chronic obstructive pulmonary disease (COPD) symptoms, other illnesses and tumors were not significantly higher among the inhabitants living in the vicinity of the asbestos factory than those living farther from there, based on raw and adjusted comparisons. However, the odds of these health endpoints were significantly and approximately one and a half to two and a half times greater in Nyergesújfalu than in Komárom. Indeed, more of the odds of the investigated risk factors were also greater in Nyergesújfalu than in Komárom. So the aim of this analysis was to compare the odds of COPD and other illnesses’ burdens in the two towns adjusted to the checked lifestyle, household and workplace factors. Logistic regression models were used. The adjusted odds of the most COPD symptoms were also significantly greater in Nyergesújfalu than in Komárom. The conclusion is that the role of the environmental asbestos exposure should furthermore not be excluded, influencing the odds of the COPD symptoms of adults who were not exposed to asbestos occupationally. (However, even this study confirms the significant associations between the health endpoints and gender, age, smoking, alcohol consumption, obesity, occupational exposure, indoor mould and heredity.) The need for performing analytic studies, e.g. by transmission electron microscopy, can be put, for how great are, and, how different are the asbestos concentrations in the air of the two towns (this can allude to the former asbestos concentrations in the air), moreover, how great are, and, how different are the asbestos concentrations in autopsy lung samples in the two towns. Mainly after seeing clearly in these questions, it is to consider suggesting the right intervention steps. Moreover, the elimination of the identified risk factors claims for effective health education activity

Dynamics of ocular surface topography in healthy subjects

Our topography system is an enhancement of a standard TMS-1 corneal topograph instrument (Computed Anatomy Inc., New York, NY, USA). Topographic images are captured at a rate of 4 s^-1, allowing the recording of a series of 120 images in 30 s after a complete blink. In this prospective preliminary study 15 healthy volunteers were examined. The main outcome measures were the time profile of changes in surface regularity index (SRI), surface asymmetry index (SAI) and simulated keratometry values (K1, K2). After a blink there was a tendency for improvement in ocular surface regularity. Later trends were less clear. Our topography system makes possible the detailed evaluation of tear-film dynamics in the post-blink period. The new technique may play an important role in the diagnosis of various tear-film abnormalities; the results may also have significant implications in the planning of refractive surgeries

Mate‐guarding success depends on male investment in a butterfly

Abstract Males of many insects, including butterflies, produce mate‐guarding devices, such as mating plugs, to prolong guarding and prevent future female matings in the male's absence. In a few butterflies, large external mate‐guarding devices, that is, sphragides, occur. Gór et al. (Behaviour, 160, 2023 and 515−557) found conspicuously large size and morphological variation of mate‐guarding devices within a single population of the potentially polyandrous Clouded Apollo (Parnassius mnemosyne, L.) butterfly. They termed the externally visible male‐produced devices as Copulatory opening APpendices (CAP) consisting of small devices, termed small CAPs and the much larger shield (i.e. sphragis). Our aim was to reveal CAP replacement dynamics within females during their lifetime and to understand how male investment into small CAPs or shields was (i) related to CAP persistence on the female, that is securing paternity, (ii) associated with female quality, measured as size and (iii) with actual adult sex ratio. We investigated a univoltine Clouded Apollo population to estimate CAP replacement risks, using multistate survival models, in an extensive observational study through 6 years based on mark‐recapture. Shields were the most frequent mate‐guarding devices and were more persistent than small CAPs, often lasting for life, excluding future matings. Thus, most females bearing a shield were deprived of postcopulatory female choice, and the genetic variance in their offspring could be reduced compared to those bearing small CAPs, thus mating more often. The ratio of shields to all CAPs gradually decreased towards the end of the flight period. Males were more prone to produce a shield when mating females with wider thoraces and when the ratio of males (i.e. competition) was higher in the population. To our best knowledge, this is the first quantitative study to investigate potential factors on which male investment in mate‐guarding devices may depend, and how the variation in these devices impacts CAP persistence on females