Exploiting the intrinsic misfolding propensity of the KRAS oncoprotein.

Mutant KRAS is a major driver of oncogenesis in a multitude of cancers but remains a challenging target for classical small molecule drugs, motivating the exploration of alternative approaches. Here, we show that aggregation-prone regions (APRs) in the primary sequence of the oncoprotein constitute intrinsic vulnerabilities that can be exploited to misfold KRAS into protein aggregates. Conveniently, this propensity that is present in wild-type KRAS is increased in the common oncogenic mutations at positions 12 and 13. We show that synthetic peptides (Pept-ins™) derived from two distinct KRAS APRs could induce the misfolding and subsequent loss of function of oncogenic KRAS, both of recombinantly produced protein in solution, during cell-free translation and in cancer cells. The Pept-ins exerted antiproliferative activity against a range of mutant KRAS cell lines and abrogated tumor growth in a syngeneic lung adenocarcinoma mouse model driven by mutant KRAS G12V. These findings provide proof-of-concept that the intrinsic misfolding propensity of the KRAS oncoprotein can be exploited to cause its functional inactivation.

A gain-of-function HCN4 mutant in the HCN domain is responsible for inappropriate sinus tachycardia in a Spanish family.

In a family with inappropriate sinus tachycardia (IST), we identified a mutation (p.V240M) of the hyperpolarization-activated cyclic nucleotide-gated type 4 (HCN4) channel, which contributes to the pacemaker current (If) in human sinoatrial node cells. Here, we clinically study fifteen family members and functionally analyze the p.V240M variant. Macroscopic (IHCN4) and single-channel currents were recorded using patch-clamp in cells expressing human native (WT) and/or p.V240M HCN4 channels. All p.V240M mutation carriers exhibited IST that was accompanied by cardiomyopathy in adults. IHCN4 generated by p.V240M channels either alone or in combination with WT was significantly greater than that generated by WT channels alone. The variant, which lies in the N-terminal HCN domain, increased the single-channel conductance and opening frequency and probability of HCN4 channels. Conversely, it did not modify the channel sensitivity for cAMP and ivabradine or the level of expression at the membrane. Treatment with ivabradine based on functional data reversed the IST and the cardiomyopathy of the carriers. In computer simulations, the p.V240M gain-of-function variant increases If and beating rate and thus explains the IST of the carriers. The results demonstrate the importance of the unique HCN domain in HCN4, which stabilizes the channels in the closed state.

Continuous Positive Airway Pressure Effect on Albuminuria Progression in Patients with Obstructive Sleep Apnea and Diabetic Kidney Disease: A Randomized Clinical Trial.

Rationale: Obstructive sleep apnea (OSA) is associated with impaired glycemic control and a higher risk of vascular complications, such as diabetic kidney disease (DKD). However, the effect of apnea-hypopnea suppression on DKD progression is unclear. Objectives: To assess the effect of continuous positive airway pressure (CPAP) on the urinary albumin-to-creatinine ratio (UACR) in patients with DKD and OSA. Methods: In a 52-week, multicentric, open-label, parallel, and randomized clinical trial, 185 patients with OSA and DKD were randomized to CPAP and usual care (n = 93) or usual care alone (n = 92). Measurements and Main Results: UACR, estimated glomerular filtration rate, serum concentrations of creatinine and glycated hemoglobin, insulin resistance, lipid concentrations, sleepiness, and quality of life. A 52-week change in UACR from baseline did not differ significantly between the CPAP group and the usual-care group. However, in per-protocol analyses that included 125 participants who met prespecified criteria for adherence, CPAP treatment was associated with a great reduction in UACR (mean difference, -10.56% [95% confidence interval, -19.06 to -2.06]; P = 0.015). CPAP effect on UACR was higher in nonsleepy patients with more severe OSA, worse renal function, and a more recent diagnosis of DKD. CPAP treatment also improved glycemic control and insulin resistance, as well as sleepiness and health-related quality of life. Conclusions: In patients with OSA and DKD, the prescription of CPAP did not result in a statistically significant reduction in albuminuria. However, good adherence to CPAP treatment in addition to usual care may result in long-term albuminuria reduction compared with usual care alone. Clinical trial registered with www.clinicaltrials.gov (NCT02816762).

Role of Leptin in Obesity, Cardiovascular Disease, and Type 2 Diabetes.

Diabetes mellitus (DM) is a highly prevalent disease worldwide, estimated to affect 1 in every 11 adults; among them, 90-95% of cases are type 2 diabetes mellitus. This is partly attributed to the surge in the prevalence of obesity, which has reached epidemic proportions since 2008. In these patients, cardiovascular (CV) risk stands as the primary cause of morbidity and mortality, placing a substantial burden on healthcare systems due to the potential for macrovascular and microvascular complications. In this context, leptin, an adipocyte-derived hormone, plays a fundamental role. This hormone is essential for regulating the cellular metabolism and energy balance, controlling inflammatory responses, and maintaining CV system homeostasis. Thus, leptin resistance not only contributes to weight gain but may also lead to increased cardiac inflammation, greater fibrosis, hypertension, and impairment of the cardiac metabolism. Understanding the relationship between leptin resistance and CV risk in obese individuals with type 2 DM (T2DM) could improve the management and prevention of this complication. Therefore, in this narrative review, we will discuss the evidence linking leptin with the presence, severity, and/or prognosis of obesity and T2DM regarding CV disease, aiming to shed light on the potential implications for better management and preventive strategies.

Can Oncologists Prompt Patient Prognostic Awareness to Enhance Decision-Making? Data From the NEOetic Study.

INTRODUCTION: Anti-neoplastic therapy improves the prognosis for advanced cancer, albeit it is not curative. An ethical dilemma that often arises during patients' first appointment with the oncologist is to give them only the prognostic information they can tolerate, even at the cost of compromising preference-based decision-making, versus giving them full information to force prompt prognostic awareness, at the risk of causing psychological harm. METHODS: We recruited 550 participants with advanced cancer. After the appointment, patients and clinicians completed several questionnaires about preferences, expectations, prognostic awareness, hope, psychological symptoms, and other treatment-related aspects. The aim was to characterize the prevalence, explanatory factors, and consequences of inaccurate prognostic awareness and interest in therapy. RESULTS: Inaccurate prognostic awareness affected 74%, conditioned by the administration of vague information without alluding to death (odds ratio [OR] 2.54; 95% CI, 1.47-4.37, adjusted P = .006). A full 68% agreed to low-efficacy therapies. Ethical and psychological factors oriented first-line decision-making, in a trade-off in which some lose quality of life and mood, for others to gain autonomy. Imprecise prognostic awareness was associated with greater interest in low-efficacy treatments (OR 2.27; 95% CI, 1.31-3.84; adjusted P = .017), whereas realistic understanding increased anxiety (OR 1.63; 95% CI, 1.01-2.65; adjusted P = 0.038), depression (OR 1.96; 95% CI, 1.23-3.11; adjusted P = .020), and diminished quality of life (OR 0.47; 95% CI, 0.29-0.75; adjusted P = .011). CONCLUSION: In the age of immunotherapy and targeted therapies, many appear not to understand that antineoplastic therapy is not curative. Within the mix of inputs that comprise inaccurate prognostic awareness, many psychosocial factors are as relevant as the physicians' disclosure of information. Thus, the desire for better decision-making can actually harm the patient.

Transglenoidal Approach in Pigmented Villonodular Synovitis of the Temporomandibular Joint.

Pigmented villonodular synovitis is a benign pathology with locally aggressive behavior caused by an uncontrolled proliferation of the articular synovial membranes. Here the authors present a case of pigmented villonodular synovitis of the temporomandibular joint with middle cranial fossa extension and review the different management options including surgery, which have been proposed to target this condition in the recent literature.

Asbestos exposure and small cell lung cancer: Systematic review and meta-analysis.

Asbestos is a mineral that is carcinogenic to humans. Its use has been banned in many occidental countries yet it is still produced in the United States, and materials that contain asbestos remain in many occupational settings and indoor environments. Even though asbestos carcinogenicity is well known, there is scant literature on its specific effects regarding small cell lung cancer (SCLC). We therefore conducted a systematic review and meta-analysis to determine SCLC risk among workers exposed to asbestos. A systematic search of the literature was conducted to identify studies which reported occupational exposure to asbestos and SCLC-related deaths and/or incidence. We identified seven case-control studies that included 3,231 SCLC cases; four studies reported smoking-adjusted risks. A significantly increased risk of SCLC (pooled OR 1.89; 95% CI, 1.25-2.86) was observed on pooling studies on men (six studies) that displayed moderate heterogeneity (I2 = 46.0%). Overall, our synthesis suggests that occupational exposure to asbestos significantly increases the risk of SCLC on men.

Non-tuberculous mycobacteria: clinical and laboratory characterisation (2009 and 2019).

A cross-sectional and retrospective study of patients with Mycobacterium spp. in a Portuguese tertiary hospital, in 2009 and 2019, was performed to understand better the rise in isolations of nontuberculous mycobacteria (NTM). The number of patients with positive samples for Mycobacterium spp. grew from 56 in 2009 to 83 in 2019. The proportion of NTM rose from 39.3% to 49.4% (P = 0.240), with Mycobacterium avium complex being more frequent in 2009 and Mycobacterium gordonae in 2019, and Mycobacterium tuberculosis complex decreased from 60.7% to 50.6%. Higher age was associated with NTM in both years, and pulmonary disease and immunosuppression were associated with NTM in 2019 (P < 0.05), with weak to moderate correlation (V = 0.231-0.343). The overall rise of NTM, allied to their known capacity to resist antimicrobial therapy, alerts clinicians to the importance of recognising potential risk factors for infection and improving future prevention strategies.

Early Experiences in Switching between Monoclonal Antibodies in Patients with Nonresponsive Migraine in Spain: A Case Series.

Monoclonal antibodies targeting the calcitonin gene-related peptide have been introduced into the therapeutic arsenal of migraine prophylaxis. Clinical trials report similar efficacy between them, and there is no evidence of switching to another one after failure. We aim to describe our experience in switching from erenumab to galcanezumab after therapeutic failure. We retrospectively reviewed 30 migraine patients who received monoclonal antibodies, with 15 of them switched after failure to achieve reduction in migraine days per month ≥30%. A ≥30% reduction in migraine days per month compared to baseline was observed in 8/15 (4/15 ≥ 50%) patients after switch. Some nonresponsive patients may benefit from switching between monoclonal antibodies with different therapeutic targets.

Dignity and psychosocial related variables in elderly advanced cancer patients.

INTRODUCTION: Most cancers occur in older individuals, who are more vulnerable due to functional impairment, multiple comorbidities, cognitive impairment, and lack of socio-familial support. These can undermine patients' sense of dignity. This study seeks to compare dignity scores in older patients with advanced cancer on sociodemographic and clinical variables and analyze the predictive value of anxiety, depression, functional limitations, and social support on dignity scores. METHODS: A prospective, multicenter, observational study conducted with participation of 15 hospitals in Spain from February 2020 to October 2021. Patients with newly-diagnosed, advanced cancer completed the dignity (PPDS), anxiety and depression (BSI), Social Support (Duke-UNC-11), and functional limitations (EORTC-C30) scales. Lineal regression analyses explored the effects of anxiety, depression, functional status, and social support on dignity, adjusting for sociodemographic and clinical variables. RESULTS: A total of 180 subjects participated in this study. The results of the correlation analysis revealed that dignity correlated negatively with anxiety, depression, and sex, and positively with social support, functional status, and longer estimated survival. Thus, women, and more anxious and depressed individuals scored lower on the dignity scale, whereas patients with more social support, fewer functional limitations, and longer estimated survival scored higher. CONCLUSION: In conclusion, being female, having a lower educational level, lower estimated survival, depression, anxiety, less social support, and limited functionality are correlated with less dignity in the elderly with advanced cancer. It is a priority to manage both physical and psychological symptoms in patients with unresectable advanced cancer to mitigate psychological distress and increase their sense of dignity.