Frailty, Sarcopenia and Osteoporosis. / Fragilidad, sarcopenia y osteoporosis.

Frailty, sarcopenia and osteoporosis are entities specific to the elderly, who share some risk factors. For this reason, their relationship has been studied in different works, which have provided disparate results, probably because these studies have not always focused on the same aspects. This article reviews the relationship of frailty and sarcopenia with osteoporosis.

iMS-Bmal1-/- mice show evident signs of sarcopenia that are counteracted by exercise and melatonin therapies.

Sarcopenia is an age-related disease characterized by a reduction in muscle mass, strength, and function and, therefore, a deterioration in skeletal muscle health and frailty. Although the cause of sarcopenia is still unknown and, thus, there is no treatment, increasing evidence suggests that chronodisruption, particularly alterations in Bmal1 clock gene, can lead to those deficits culminating in sarcopenia. To gain insight into the cause and mechanism of sarcopenia and the protective effect of a therapeutic intervention with exercise and/or melatonin, the gastrocnemius muscles of male and female skeletal muscle-specific and inducible Bmal1 knockout mice (iMS-Bmal1-/- ) were examined by phenotypic tests and light and electron microscopy. Our results revealed a disruption of the normal activity/rest rhythm, a drop in skeletal muscle function and mass, and increased frailty in male and female iMS-Bmal1-/- animals compared to controls. A reduction in muscle fiber size and increased collagenous tissue were also detected, accompanied by reduced mitochondrial oxidative capacity and a compensatory shift towards a more oxidative fiber type. Electron microscopy further supports mitochondrial impairment in mutant mice. Melatonin and exercise ameliorated the damage caused by loss of Bmal1 in mutant mice, except for mitochondrial damage, which was worsened by the latter. Thus, iMS-Bmal1-/- mice let us to identify Bmal1 deficiency as the responsible for the appearance of sarcopenia in the gastrocnemius muscle. Moreover, the results support the exercise and melatonin as therapeutic tools to counteract sarcopenia, by a mechanism that does not require the presence of Bmal1.

Sexual dysfunction in patients with cancer, a challenge in oncology practice: results of the CLARIFY project.

BACKGROUND: Sexual dysfunction (SD) associated with oncological treatment is a common and understudied disorder. Our aim was to characterize SD in a cohort of Spanish patients. METHODS: Analytic observational study in patients included in the CLARIFY H2020 project at the Hospital Universitario Puerta de Hierro. Clinical variables and validated measures of sexual function were collected from October 2020 to May 2022. Frequency and quality of sexual activity were assessed. Descriptive, trend associations, and logistic regression analyses were performed. RESULTS: A total of 383 patients were included: breast cancer 68.14% (261), lung cancer 26.37% (101), and lymphoma 5.50% (21). Mean age was 56.5 years (range 33-88). 19.58% (75) were men and 80.42% (308) were women. 69% and 31% of men and women, respectively, reported being sexually active. The absolute frequency of overall sexual dissatisfaction was 76% in women and 24% in men. Women with breast cancer were most likely to have severe sexual dysfunction. Those with early disease had resolved complaints after 5 years. In multinomial logistic regression, significant associations were found in women with metastatic breast cancer and severe disorders of arousal (p 0.000), lubrication (p 0.002), orgasm (p 0.000), as well as dissatisfaction with sexual performance (p 0.000) and global sexual dissatisfaction (p 0.000). Women with lung cancer have severe arousal dysfunction (p 0.016) and global sexual dissatisfaction (p 0.044). CONCLUSIONS: Our population has a high prevalence of SD, which supports the need to increase awareness of this disorder among the medical oncology team and the importance of including sexual health assessment in oncological patient follow-up.

Nivel de comunicación familiar y autoeficacia en pacientes con Diabetes Mellitus tipo 2 en atención primaria de salud / Level of family communication and self-efficacy in patients with type 2 Diabetes Mellitus in primary health care primary health care

Objetivo principal: establecer la relación entre el nivel de comunicación familiar y autoeficacia en pacientes con Diabetes Mellitus Tipo 2 que asisten a un centro de salud primaria. Metodología: Estudio analítico de corte transversal, con una muestra de 238 pacientes con DM2 a los que se les aplicó la Escala de Comunicación Familiar de FACES IV y la Escala de Autoeficacia en Diabetes. Resultados principales: El 75,6% identificó un nivel de comunicación familiar “muy alto” relacionado significativamente con el “apoyo de parientes” (p=0,001). La autoeficacia percibida presentó un puntaje general de 8,2 con correlación altamente significativa entre nivel de comunicación y los ítems de autoeficacia (p < 0,05). Los mayores puntajes de autoeficacia se concentraron en niveles “muy alto” de comunicación familiar. Conclusión principal: Una alta comunicación familiar puede impactar positivamente en la autopercepción y el empoderamiento del paciente en el manejo de su DM2.(AU)

Objective: to establish the relationship between the level of family communication and self-efficacy in patients with Type 2 Diabetes Mellitus attending a primary health center. Methodology: Cross-sectional analytical study. A sample of 238 patients with T2DM was obtained and administered the FACES IV Family Communication Scale and the Diabetes Self-Efficacy Scale. Results: 75.6% identified a "very high" level of family communication significantly related to "support from relatives" (p=0.001). Perceived self-efficacy had an overall score of 8.2 with a highly significant correlation between level of communication and self-efficacy items (p-value < 0.05). The highest self-efficacy scores were concentrated in "very high" levels of family communication. Conclusion: High family communication can positively impact the patient’s self-perception and empowerment in the management of their T2DM.(AU)

From Chronodisruption to Sarcopenia: The Therapeutic Potential of Melatonin.

Sarcopenia is an age-related condition that involves a progressive decline in muscle mass and function, leading to increased risk of falls, frailty, and mortality. Although the exact mechanisms are not fully understood, aging-related processes like inflammation, oxidative stress, reduced mitochondrial capacity, and cell apoptosis contribute to this decline. Disruption of the circadian system with age may initiate these pathways in skeletal muscle, preceding the onset of sarcopenia. At present, there is no pharmacological treatment for sarcopenia, only resistance exercise and proper nutrition may delay its onset. Melatonin, derived from tryptophan, emerges as an exceptional candidate for treating sarcopenia due to its chronobiotic, antioxidant, and anti-inflammatory properties. Its impact on mitochondria and organelle, where it is synthesized and crucial in aging skeletal muscle, further highlights its potential. In this review, we discuss the influence of clock genes in muscular aging, with special reference to peripheral clock genes in the skeletal muscle, as well as their relationship with melatonin, which is proposed as a potential therapy against sarcopenia.

NLRP3 inflammasome activation and symptom burden in KRAS-mutated CMML patients is reverted by IL-1 blocking therapy.

Chronic myelomonocytic leukemia (CMML) is frequently associated with mutations in the rat sarcoma gene (RAS), leading to worse prognosis. RAS mutations result in active RAS-GTP proteins, favoring myeloid cell proliferation and survival and inducing the NLRP3 inflammasome together with the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which promote caspase-1 activation and interleukin (IL)-1ß release. Here, we report, in a cohort of CMML patients with mutations in KRAS, a constitutive activation of the NLRP3 inflammasome in monocytes, evidenced by ASC oligomerization and IL-1ß release, as well as a specific inflammatory cytokine signature. Treatment of a CMML patient with a KRASG12D mutation using the IL-1 receptor blocker anakinra inhibits NLRP3 inflammasome activation, reduces monocyte count, and improves the patient's clinical status, enabling a stem cell transplant. This reveals a basal inflammasome activation in RAS-mutated CMML patients and suggests potential therapeutic applications of NLRP3 and IL-1 blockers.

Effects of an organic diet intervention on the levels of organophosphorus metabolites in an adult cohort.

Pesticides are a group of organic compounds used to control weeds or insect infestations in agriculture. Diet is the major route of human exposure to these compounds, which can cause serious health problems, even when the intake occurs at low concentrations. Hence, the consumption of organic food is an appropriate strategy to minimize the exposure to pesticides. A prospective, randomized study was conducted to assess the impact of an organic dietary intervention on the levels of urinary dialkyl phosphates (DAP). A screening of 204 pesticides was also carried out in order to confirm the absence of these compounds in organic food. The analytical results showed that only 20 of the 204 pesticides (9.8 %) had concentrations above the limit of quantification in one or more samples of the organic food consumed by the participants. It is substantially lower than the levels of pesticides found in other studies analysing conventional food, confirming the diet as suitable for the organic dietary intervention. A general reduction of most DAP metabolites in urine was found, being significant (p < 0.05) the decrease of dimethyl phosphate (DMP) (0.49 µg/g creatinine in Day 1 vs. 0.062 µg/g creatinine in Day 6), dimethyl thiophosphate (DMTP) (0.49 µg/g creatinine in Day 1 vs. 0.093 µg/g creatinine in Day 6) and diethyl phosphate (DEP) (0.28 µg/g creatinine in Day 1 vs. 0.12 µg/g creatinine in Day 6). In addition, the molar score for the total dimethyl DAP (ΣMP) and total dialkyl phosphate (ΣDAP) also showed significant differences after changing a conventional diet by an organic diet, being reduced from 0.008 µmol/g to 0.002 µmol/g for ΣMP and from 0.012 µmol/g to 0.003 µmol/g for ΣDAP. To the best of our knowledge, this is the first study that evaluates both the impact of an organic diet in the exposure to DAP and the levels of 204 pesticides in the organic food provided to the participants. In summary, the consumption of organic products decreases the dietary intake of pesticides, thus reducing also the potential adverse effects on human health.

ACOD frente a AVK en pacientes con fibrilación auricular y bioprótesis: revisión sistemática y metanálisis / DOAC versus VKA in patients with atrial fibrillation and bioprosthetic valves: a systematic review and meta-analysis

Introducción y objetivos: Los anticoagulantes orales directos (ACOD) se han mostrado eficaces y seguros en pacientes con fibrilación auricular; sin embargo, los pacientes con FA y bioprótesis están infrarrepresentados en los ensayos clínicos, por lo que la evidencia en este grupo es menor. Nuestro objetivo fue analizar la seguridad y eficacia de los ACODs en esta población revisando la información existente en la literatura. Métodos: Se realizó una búsqueda y revisión sistemática con los ensayos clínicos aleatorizados y estudios observacionales comparativos desde 2017 a enero de 2022, que comparasen ACODs y antagonistas de vitamina K (AVK) en pacientes con FA y bioprótesis. Se utilizó la hazard ratio al 95% del intervalo de confianza para comparar ambos grupos en términos de mortalidad total y cardiovascular, ictus/embolia sistémica y hemorragia mayor. Se realizó un metanálisis combinando los resultados de los estudios incluidos. Resultados: Se incluyeron 12 estudios (un total de 30.283 pacientes). Los ACODs se asociaron a una reducción significativa del 9% de la mortalidad total (HR=0,91; IC95%, 0,85-0,97; p=0,0068; I2=8%), sin diferencias significativas en el riesgo de ictus/embolismo sistémico (HR=0,87; IC95%, 0,67-1,14; p=0,29; I2=45%) o hemorragia mayor (HR=0,82; IC95%, 0,67-1,00; p=0,054; I2=48.7%). Conclusiones: En pacientes con FA portadores de bioprótesis, los ACODs podrían asociarse a una reducción de la mortalidad total sin reducción de eficacia en la prevención de ictus/embolia sistémica o aumento del riesgo de hemorragia mayor.(AU)

Introduction and objectives: Direct oral anticoagulant (DOAC) therapy has been shown to be safe and effective in patients with atrial fibrillation (AF). However, outcomes in AF patients with bioprosthetic valves are unclear, as this population has been underrepresented in clinical trials. The aim of this study was to assess the safety and efficacy of DOACs in this population based on the existing published literature. Methods: A systematic search and review were conducted to identify randomized clinical trials and comparative observational studies published from 2017 to January 2022 that compared DOACs and vitamin K antagonists (VKAs) in AF patients with bioprosthetic valves. Hazard ratios (HR) were collected to compare the 2 treatments in terms of cardiovascular and all-cause mortality, stroke/systemic embolism, and major bleeding. A meta-analysis combining the results was performed. Results: We included 12 studies (30 283 patients). DOACs and VKAs were compared based on HRs at the 95% confidence interval. DOAC therapy was associated with a significant 9% reduction in all-cause mortality (HR, 0.91; 95%CI, 0.85-0.97; P=.0068; I2=8%), with no significant differences in the risk of stroke/systemic embolism (HR, 0.87; 95%CI, 0.67-1.14; P=.29; I2=45%) or major bleeding (HR, 0.82; 95%CI, 0.67-1.00; P=.054; I2=48.7%). Conclusions: DOAC therapy in AF patients with bioprosthetic valves may be associated with a significant reduction in all-cause mortality, with no reduction in the efficacy of stroke/systemic embolism prevention or increase in major bleeding risk.(AU)

Etiologia e fisiopatologia da fibromialgia / Etiology and pathophysiology of fibromyalgia

A fibromialgia é uma condição crônica de etiologia desconhecida e desvinculada de marcadores laboratoriais específicos para diagnóstico, devido à pobre caracterização da etiopatogenia. Em geral, as alterações comuns à fibromialgia também são observadas em outras condições de dor crônica, tornando a patogênese controversa entre diferentes condições patológicas. A etiologia desconhecida dificulta o diagnóstico e, consequentemente, repercute em um tratamento não tão eficaz de pacientes com fibromialgia. A restauração de desordens sistêmicas confere amplo espectro de possibilidades terapêuticas com potencial de orientar profissionais a estabelecer metas e métodos de avaliação. Diante disso, essa revisão narrativa se volta para debater hipóteses etiológicas e fisiopatológicas no desenvolvimento da fibromialgia.

Fibromyalgia is a chronic condition of unknown etiology unrelated to specific laboratory markers for diagnosis because of poor etiopathogenesis. In general, the changes common to fibromyalgia are also seen in other chronic pain conditions, making the pathogenesis controversial among different pathological conditions. The unknown etiology makes the diagnosis difficult and consequently has repercussions on a not so effective treatment of patients with fibromyalgia. The restoration of systemic disorders provides a wide spectrum of therapeutic possibilities with the potential to guide professionals in establishing goals and evaluation methods. Therefore, this narrative review discusses the etiological and pathophysiological hypotheses involved in the development of fibromyalgia.

Perceptions of the Role of Living Alone in Providing Services to Patients With Cognitive Impairment.

Importance: The potential role of living alone in either facilitating or hampering access to and use of services for older adults with cognitive impairment is largely unknown. Specifically, it is critical to understand directly from health care and social services professionals how living alone creates barriers to the access and use of supportive health care and social services for racially and ethnically diverse patients with cognitive impairment. Objective: To identify the potential role of living alone in the access and use of health care and social services for diverse patients with cognitive impairment by investigating professionals' perceptions of caring for such patients who live alone in comparison with counterparts living with others. Design, Setting, and Participants: This qualitative study of 76 clinicians, social workers, and other professionals used semistructured interviews conducted between February 8, 2021, and June 8, 2022, with purposively sampled professionals providing services to diverse patients with cognitive impairment in Michigan, California, and Texas. Main Outcomes and Measures: Clinicians, social workers, and other professionals compared serving patients with cognitive impairment and living alone vs counterparts living with others. An inductive content analysis was used to analyze the interview transcripts. Results: A total of 76 professionals were interviewed (mean [SD] age, 49.3 [12.7] years); 59 were female (77.6%), 8 were Black or African American (11%), and 35 were White (46%). Participants included physicians, nurses, social workers, and home-care aides, for a total of 20 professions. Participants elucidated specific factors that made serving older adults living alone with cognitive impairment more challenging than serving counterparts living with others (eg, lacking an advocate, incomplete medical history, requiring difficult interventions), as well as factors associated with increased concerns when caring for older adults living alone with cognitive impairment, such as isolation and a crisis-dominated health care system. Participants also identified reasons for systematic unmet needs of older adults living alone with cognitive impairment for essential health care and social services, including policies limiting access and use to public home-care aides. Conclusions and Relevance: In this qualitative study of professionals' perspectives, findings suggest that living alone is a social determinant of health among patients with cognitive impairment owing to substantial barriers in access to services. Results raised considerable concerns about safety because the US health care system is not well equipped to address the unique needs of older adults living alone with cognitive impairment.

Austrian Syndrome: Community-Acquired Pneumonia in an Unusual Triad.

Austrian syndrome corresponds to the triad of meningitis, pneumonia, and endocarditis caused by Streptococcus pneumoniae, there is no global or local incidence given the infrequency of entity. Scarce cases are published in Latin America, with none of them in Colombia. A case of Austrian syndrome by penicillin-resistant S. pneumoniae in an immunocompetent patient is presented. Aortic valve is the most frequent site involved in Austrian syndrome; this patient had an unusual localization of the vegetation on the right coronary artery ostium. The prognosis is poor with a mortality rate of 30% or higher, this patient survived despite systemic complications. Vaccination status impacts in prevention and severity of cases because responsible serotypes are often included in available vaccines. The patient had a serotype covered by available vaccines; however, her vaccination status was unknown. Thus, we present the first case reported in Colombia of Austrian syndrome by a penicillin-resistant S. pneumoniae, in a patient with no identified comorbidities or toxicological history, with a successful evolution.

Effects of Creatine Supplementation on the Myostatin Pathway and Myosin Heavy Chain Isoforms in Different Skeletal Muscles of Resistance-Trained Rats.

Creatine has been used to maximize resistance training effects on skeletal muscles, including muscle hypertrophy and fiber type changes. This study aimed to evaluate the impact of creatine supplementation on the myostatin pathway and myosin heavy chain (MyHC) isoforms in the slow- and fast-twitch muscles of resistance-trained rats. Twenty-eight male Wistar rats were divided into four groups: a sedentary control (Cc), sedentary creatine supplementation (Cr), resistance training (Tc), and resistance training combined with creatine supplementation (Tcr). Cc and Tc received standard commercial chow; Cr and Tcr received a 2% creatine-supplemented diet. Tc and Tcr performed a resistance training protocol on a ladder for 12 weeks. Morphology, MyHC isoforms, myostatin, follistatin, and ActRIIB protein expressions were analyzed in soleus and white gastrocnemius portion samples. The results were analyzed using two-way ANOVA and Tukey's test. Tc and Tcr exhibited higher performance than their control counterparts. Resistance training increased the ratio between muscle and body weight, the cross-sectional area, as well as the interstitial collagen fraction. Resistance training alone increased MyHC IIx and follistatin while reducing myostatin (p < 0.001) and ActRIIB (p = 0.040) expressions in the gastrocnemius. Resistance training induced skeletal muscle hypertrophy and interstitial remodeling, which are more evident in the gastrocnemius muscle. The effects were not impacted by creatine supplementation.

Pleiotrophin and the Expression of Its Receptors during Development of the Human Cerebellar Cortex.

During embryonic and fetal development, the cerebellum undergoes several histological changes that require a specific microenvironment. Pleiotrophin (PTN) has been related to cerebral and cerebellar cortex ontogenesis in different species. PTN signaling includes PTPRZ1, ALK, and NRP-1 receptors, which are implicated in cell differentiation, migration, and proliferation. However, its involvement in human cerebellar development has not been described so far. Therefore, we investigated whether PTN and its receptors were expressed in the human cerebellar cortex during fetal and early neonatal development. The expression profile of PTN and its receptors was analyzed using an immunohistochemical method. PTN, PTPRZ1, and NRP-1 were expressed from week 17 to the postnatal stage, with variable expression among granule cell precursors, glial cells, and Purkinje cells. ALK was only expressed during week 31. These results suggest that, in the fetal and neonatal human cerebellum, PTN is involved in cell communication through granule cell precursors, Bergmann glia, and Purkinje cells via PTPRZ1, NRP-1, and ALK signaling. This communication could be involved in cell proliferation and cellular migration. Overall, the present study represents the first characterization of PTN, PTPRZ1, ALK, and NRP-1 expression in human tissues, suggesting their involvement in cerebellar cortex development.

Telomerase Upregulation Induces Progression of Mouse BrafV600E-Driven Thyroid Cancers and Triggers Nontelomeric Effects.

Mutations in the promoter of the telomerase reverse transcriptase (TERT) gene are the paradigm of a cross-cancer alteration in a noncoding region. TERT promoter mutations (TPM) are biomarkers of poor prognosis in cancer, including thyroid tumors. TPMs enhance TERT transcription, which is otherwise silenced in adult tissues, thus reactivating a bona fide oncoprotein. To study TERT deregulation and its downstream consequences, we generated a Tert mutant promoter mouse model via CRISPR/Cas9 engineering of the murine equivalent locus (Tert-123C>T) and crossed it with thyroid-specific BrafV600E-mutant mice. We also employed an alternative model of Tert overexpression (K5-Tert). Whereas all BrafV600E animals developed well-differentiated papillary thyroid tumors, 29% and 36% of BrafV600E+Tert-123C>T and BrafV600E+K5-Tert mice progressed to poorly differentiated cancers at week 20, respectively. Tert-upregulated tumors showed increased mitosis and necrosis in areas of solid growth, and older animals displayed anaplastic-like features, that is, spindle cells and macrophage infiltration. Murine TPM increased Tert transcription in vitro and in vivo, but temporal and intratumoral heterogeneity was observed. RNA-sequencing of thyroid tumor cells showed that processes other than the canonical Tert-mediated telomere maintenance role operate in these specimens. Pathway analysis showed that MAPK and PI3K/AKT signaling, as well as processes not previously associated with this tumor etiology, involving cytokine, and chemokine signaling, were overactivated. These models constitute useful preclinical tools to understand the cell-autonomous and microenvironment-related consequences of Tert-mediated progression in advanced thyroid cancers and other aggressive tumors carrying TPMs. IMPLICATIONS: Telomerase-driven cancer progression activates pathways that can be dissected and perhaps therapeutically exploited.

Short telomeres in alveolar type II cells associate with lung fibrosis in post COVID-19 patients with cancer.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) pandemic. The severity of COVID-19 increases with each decade of life, a phenomenon that suggest that organismal aging contributes to the fatality of the disease. In this regard, we and others have previously shown that COVID-19 severity correlates with shorter telomeres, a molecular determinant of aging, in patient's leukocytes. Lung injury is a predominant feature of acute SARS-CoV-2 infection that can further progress to lung fibrosis in post-COVID-19 patients. Short or dysfunctional telomeres in Alveolar type II (ATII) cells are sufficient to induce pulmonary fibrosis in mouse and humans. Here, we analyze telomere length and the histopathology of lung biopsies from a cohort of alive post-COVID-19 patients and a cohort of age-matched controls with lung cancer. We found loss of ATII cellularity and shorter telomeres in ATII cells concomitant with a marked increase in fibrotic lung parenchyma remodeling in post- COVID-19 patients compared to controls. These findings reveal a link between presence of short telomeres in ATII cells and long-term lung fibrosis sequel in Post-COVID-19 patients.

Associations between psychotropic and anti-dementia medication use and falls in community-dwelling older adults with cognitive impairment.

OBJECTIVES: Evidence for effective fall prevention strategies is limited for people with cognitive impairment. Understanding what factors contribute to fall risk identifies potential intervention strategies. We aimed to determine if psychotropic and anti-dementia medication use are associated with falls in community-dwelling older people with mild-moderate cognitive impairment and dementia. DESIGN: Secondary analysis of an RCT (i-FOCIS). PARTICIPANTS AND SETTING: 309 community-dwelling people with mild to moderate cognitive impairment or dementia from Sydney, Australia. METHODS: Demographic information, medical history, and medication use were collected at baseline and participants were followed up for 1-year for falls using monthly calendars and ancillary telephone falls. RESULTS: Psychotropic medication use was associated with an increased rate of falls (IRR 1.41, 95%CI 1.03, 1.93) and slower gait speed, poor balance and reduced lower limb function when adjusting for age, sex, education and cognition, as well as RCT group allocation when examining prospective falls. Antidepressants use increased the rate of falls in a similarly adjusted model (IRR 1.54, 95%CI 1.10, 2.15), but when additionally adjusting for depressive symptoms, antidepressant use was no longer significantly associated with falls while depressive symptoms was. Anti-dementia medication use was not associated with rate of falls. CONCLUSIONS: Psychotropic medication use increases fall risk, and anti-dementia medication does not reduce fall risk in older adults with cognitive impairment. Effective management of depressive symptoms, potentially with non-pharmacological approaches, is needed to prevent falls in this population. Research is also required to ascertain the risks/benefits of withdrawing psychotropic medications, particularly in relation to depressive symptoms.

Pre- and Post-Neoadjuvant Clinicopathological Parameters Can Help in the Prognosis and the Prediction of Response in HER2+ and Triple Negative Breast Cancer.

Neoadjuvant treatment (NAT) is one of the most widely used options for HER2+ and triple negative (TN) early breast cancer (BC). Since around half of the patients treated with NAT do not achieve a pathologically complete response (pCR), biomarkers to predict resistance are urgently needed. The correlation of clinicopathological factors with pCR was studied in 150 patients (HER2 = 81; TN = 69) and pre- and post-NAT differences in tumour biomarkers were compared. Low estrogen receptor (ER) expression, high tumour-infiltrating lymphocytes (TILs) and low cT-stage were associated with pCR in HER2+ tumours (p = 0.022; p = 0.032 and p = 0.005, respectively). Furthermore, ER expression was also associated with residual cancer burden (RCB; p = 0.046) in the HER2+ subtype. Similarly, pre-NAT, low progesterone receptor expression (PR; 1-10%) was associated with higher RCB (p < 0.001) in TN tumours. Only clinical and pathological T-stage (cpT-stage) had prognostic capacity in HER2+ tumours, whereas pre-NAT cpT-stage and post-NAT TILs had this capacity for the prognosis of TN tumours. We conclude that ER and PR expression may help predict response to NAT in HER2 and TN BC and should be taken into account in residual tumours. Also, changes observed in the phenotype after NAT suggest the need to reevaluate biomarkers in surviving residual tumour cells.

Dy4, Dy5, and Ho2 Complexes of an N3O2 Aminophenol Donor: A Dy5-µ3-Peroxide Single Molecule Magnet.

The reactivity of the new flexible potentially pentadentate N3O2 aminophenol ligand H4Lr (2,2'-((pyridine-2,6-diylbis(methylene))bis(azanediyl))diphenol) towards different dysprosium salts and holmium(III) nitrate was investigated. Accordingly, this reactivity seems to greatly depend on the metal ion and salt employed. In this way, the reaction of H4Lr with dysprosium(III) chloride in air leads to the oxo-bridged tetranuclear complex [Dy4(H2Lr)3(Cl)4(µ3-O)(EtOH)2(H2O)2]·2EtOH·H2O (1·2EtOH·H2O), while the same reaction just changing the chloride salt by the nitrate one renders the peroxo-bridged pentanuclear compound [Dy5(H2Lr)2(H2.5Lr)2(NO3)4(µ3-O2)2]·2H2O (2·2H2O), where both peroxo ligands seem to come from the fixation and reduction of atmospheric oxygen. However, if holmium(III) nitrate is used instead of dysprosium(III) nitrate, no evidence of a peroxide ligand is observed, and the dinuclear complex {[Ho2(H2Lr)(H3Lr)(NO3)2(H2O)2](NO3)} 2.5H2O (3·2.5H2O) is isolated. The three complexes were unequivocally characterized by X-ray diffraction techniques, and their magnetic properties were analyzed. Thus, while the Dy4 and Ho2 complexes do not show magnet-like behavior even in the presence of an external magnetic field, 2·2H2O is a single molecule magnet, with an Ueff barrier of 61.2 K (43.2 cm-1). This is the first homonuclear lanthanoid peroxide SMM, which also shows the highest barrier among the reported 4f/3d peroxide zero field SMMs to date.

Chronodisruption and Loss of Melatonin Rhythm, Associated with Alterations in Daily Motor Activity and Mitochondrial Dynamics in Parkinsonian Zebrafish, Are Corrected by Melatonin Treatment.

Beyond sleep/wake, clock genes regulate the daily rhythms of melatonin production, motor activity, innate immunity, and mitochondrial dynamics, among others. All these rhythms are affected in Parkinson's disease (PD), suggesting that chronodisruption may be an early stage of the disease. The aim of this study was to evaluate the connection between clock genes and these rhythms in PD, and whether melatonin administration reestablished the normal clock function. Parkinsonism was induced with 600 µM MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in 24-120 h post fertilization (hpf) zebrafish embryos and melatonin was administered at a dose of 1 µM. Day-night melatonin rhythm disappeared in MPTP-treated embryos, which showed an advance in the activity phase in parallel with changes in the rhythm of clock genes. An alteration in the fission-to-fusion mitochondrial dynamics was also detected in parkinsonian embryos, increasing the former and leading to apoptosis. Melatonin administration to MPTP-treated embryos fully restored the circadian system, including the rhythms of clock genes, motor activity, melatonin rhythm, and mitochondrial dynamics, and decreasing apoptosis. Because clock-controlled rhythms such as sleep/wake alterations are early events in PD, the data here reported may point to chronodisruption as one initial pathophysiological event of the disease.

Telomerase deficiency and dysfunctional telomeres in the lung tumor microenvironment impair tumor progression in NSCLC mouse models and patient-derived xenografts.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer death. Tumor progression depends on interactions of cancer cells with the tumor microenvironment. Here, we find increased copy number and mRNA expression of the catalytic subunit of telomerase, TERT, in tumors from NSCLC patients, contributing to a lower survival. Moreover, TERT expression in NSCLC patients from the TCGA cohort is mainly associated to the reduced infiltration of CD8+ T lymphocytes, as well as to increased infiltration of myeloid-derived suppressor cells (MDSCs). We also show that TERT deficiency and dysfunctional telomeres induced by 6-thio-dG treatment in mice reduced lung tumor implantation and vascularization, increased DNA damage response, cell cycle arrest and apoptosis, as well as reduced proliferation, inflammation, lung tumor immunosupression and invasion upon induction of a Lewis lung carcinoma (LLC). Furthermore, 6-thio-dG-treated human NSCLC xenografts exhibited increased telomere damage, cell cycle arrest and apoptosis, as well as reduced proliferation, resulting in a reduced tumor growth. Our results show that targeting telomeres might be an effective therapeutic strategy in NSCLC.