The phosphatase inhibitor LB-100 creates neoantigens in colon cancer cells through perturbation of mRNA splicing.

Perturbation of protein phosphorylation represents an attractive approach to cancer treatment. Besides kinase inhibitors, protein phosphatase inhibitors have been shown to have anti-cancer activity. A prime example is the small molecule LB-100, an inhibitor of protein phosphatases 2A/5 (PP2A/PP5), enzymes that affect cellular physiology. LB-100 has proven effective in pre-clinical models in combination with immunotherapy, but the molecular underpinnings of this synergy remain understood poorly. We report here a sensitivity of the mRNA splicing machinery to phosphorylation changes in response to LB-100 in colorectal adenocarcinoma. We observe enrichment for differentially phosphorylated sites within cancer-critical splicing nodes of U2 snRNP, SRSF and hnRNP proteins. Altered phosphorylation endows LB-100-treated colorectal adenocarcinoma cells with differential splicing patterns. In PP2A-inhibited cells, over 1000 events of exon skipping and intron retention affect regulators of genomic integrity. Finally, we show that LB-100-evoked alternative splicing leads to neoantigens that are presented by MHC class 1 at the cell surface. Our findings provide a potential explanation for the pre-clinical and clinical observations that LB-100 sensitizes cancer cells to immune checkpoint blockade.

Diagnostic and therapeutic use of oral micronized progesterone in endocrinology.

Progesterone is a natural steroid hormone, while progestins are synthetic molecules. In the female reproductive system, progesterone contributes to the control of luteinizing hormone and follicle-stimulating hormone secretion and their pulsatility, via its receptors on the kisspeptin, neurokinin B, and dynorphin neurons in the hypothalamus. Progesterone together with estradiol controls the cyclic changes of proliferation and decidualization of the endometrium; exerts anti-mitogenic actions on endometrial epithelial cells; regulates normal menstrual bleeding; contributes to fertilization and pregnancy maintenance; participates in the onset of labor. In addition, it exerts numerous effects on other endocrine systems. Micronized progesterone (MP) is natural progesterone with increased bioavailability, due to its pharmacotechnical micronized structure, which makes it an attractive diagnostic and therapeutic tool. This critical literature review aims to summarize and put forward the potential diagnostic and therapeutic uses of MP in the field of endocrinology. During reproductive life, MP is used for diagnostic purposes in the evaluation of primary or secondary amenorrhea as a challenge test. Moreover, it can be prescribed to women presenting with amenorrhea or oligomenorrhea for induction of withdrawal bleeding, in order to time blood-sampling for diagnostic purposes in early follicular phase. Therapeutically, MP, alone or combined with estrogens, is a useful tool in various endocrine disorders including primary amenorrhea, abnormal uterine bleeding due to disordered ovulation, luteal phase deficiency, premenstrual syndrome, polycystic ovary syndrome, secondary amenorrhea [functional hypothalamic amenorrhea, premature ovarian insufficiency], perimenopause and menopause. When administrated per os, acting as a neurosteroid directly or through its metabolites, it exerts beneficial effects on brain function such as alleviation of symptoms of anxiety and depression, asw well as of sleep problems, while it improves working memory in peri- and menopausal women. Micronized progesterone preserves full potential of progesterone activity, without presenting many of the side-effects of progestins. Although it has been associated with more frequent drowsiness and dizziness, it can be well tolerated with nocturnal administration. Because of its better safety profile, especially with regard to metabolic ailments, breast cancer risk and veno-thromboembolism risk, MP is the preferred option for individuals with an increased risk of cardiovascular and metabolic diseases and of all-cause mortality.

Low dialysate sodium and 48-h ambulatory blood pressure in patients with intradialytic hypertension: a randomized crossover study.

BACKGROUND AND HYPOTHESIS: Intradialytic-hypertension (IDH) is associated with increased risk for cardiovascular events and mortality. Patients with IDH exhibit higher 48-h blood pressure (BP) levels than patients without this condition. Volume and sodium excess are considered a major factor contributing in the development of this phenomenon. This study evaluated the effect of low (137mEq/L) compared to standard (140mEq/L) dialysate sodium concentration on 48-h BP in patients with IDH. METHODS: In this randomized, single-blind, crossover study, 29 patients with IDH underwent 4 hemodialysis sessions with low (137mEq/L) followed by 4 sessions with standard (140mEq/L) dialysate sodium or vice-versa. Mean 48-h BP, pre-/post-dialysis and intradialytic BP, pre-dialysis weight, interdialytic weight gain (IDWG) and lung ultrasound B-lines were assessed. RESULTS: Mean 48-h SBP/DBP were significantly lower with low compared to standard dialysate sodium concentration (137.6±17.0/81.4±13.7mmHg with low vs 142.9±14.5/84.0±13.9mmHg with standard dialysate sodium, p=0.005/p=0.007 respectively); SBP/DBP levels were also significantly lower during the 44-h and different 24-h periods. Low dialysate sodium significantly reduced post-dialysis (SBP/DBP: 150.3±22.3/91.2±15.1mmHg with low vs 166.6±17.3/94.5±14.9mmHg with standard dialysate sodium, p<0.001/p=0.134 respectively) and intradialytic (141.4±18.0/85.0±13.4mmHg with low vs 147.5±13.6/88.1±12.5mmHg with standard dialysate sodium, p=0.034/p=0.013, respectively) BP compared with standard dialysate sodium. Pre-dialysis weight, IDWG and pre-dialysis B-lines were also significantly decreased with low dialysate sodium. CONCLUSIONS: Low dialysate sodium concentration significantly reduced 48-h ambulatory BP compared with standard dialysate sodium in patients with IDH. These findings support low dialysate sodium as a major non-pharmacologic approach for BP management in patients with IDH.Registered at ClinicalTrials.gov with study number NCT05430438.

Studying serum neurofilament light chain levels as a potential new biomarker for small fiber neuropathy.

BACKGROUND AND PURPOSE: Diagnosing small fiber neuropathies can be challenging. To address this issue, whether serum neurofilament light chain (sNfL) could serve as a potential biomarker of damage to epidermal Aδ- and C-fibers was tested. METHODS: Serum NfL levels were assessed in 30 patients diagnosed with small fiber neuropathy and were compared to a control group of 19 healthy individuals. Electrophysiological studies, quantitative sensory testing and quantification of intraepidermal nerve fiber density after skin biopsy were performed in both the proximal and distal leg. RESULTS: Serum NfL levels were not increased in patients with small fiber neuropathy compared to healthy controls (9.1 ± 3.9 and 9.4 ± 3.8, p = 0.83) and did not correlate with intraepidermal nerve fiber density at the lateral calf or lateral thigh or with other parameters of small fiber impairment. CONCLUSION: Serum NfL levels cannot serve as a biomarker for small fiber damage.

Rib index is a strong surrogate of scoliometric reading in idiopathic scoliosis.

INTRODUCTION AND AIM: Scoliometry is not always included in the examination protocol of IS patients. The aim of this report is to examine the degree of correlation of Segmental Rib Index (SRI) to scoliometry, in order for SRI to be used as a surrogate of scoliometric angle of trunk rotation (ATR). MATERIAL AND METHOD: 66 Idiopathic Scoliosis (IS) subjects were studied, with a mean age 12.2 ± 2.9 years, 18 boys and 48 girls: 20 thoracic, 22 thoracolumbar and 24 lumbar curves. The standing lateral spine radiographs (LSR) were obtained and the Segmental Rib Index (SRI) from T1 to T12 were assessed. The ATR was documented. RESULTS: In all 66 cases with IS the scoliometer readings (ATR) were significantly correlated to the SRI at the T6, T7 and T8 levels. In the thoracic curves SRI and ATR correlations were significant for the levels T6-T12. DISCUSSION: It was suggested that as long as the patients doesn't have scoliometer measurements, the SRI, could be used as a surrogate for scoliometry. It was also found that in thoracic, thoracolumbar and lumbar level, in both genders, changing from the flexed position to the standing position, the mean trunk asymmetry (TA) decreases. Therefore, if these patients had their TA measured using a scoliometer during the Adams test, their body asymmetry would have been greater than that measured using the SRI method on standing LSR. Consequently, it is evident that the significantly correlated SRI used as a surrogate for the scoliometric assessment of TA is reasonably a strong surrogate.

[The EAN-NeuPSIG guideline on the diagnosis of neuropathic pain-a summary]. / Die EAN-NeuPSIG-Leitlinie zur Diagnostik bei neuropathischen Schmerzen ­ eine Kurzfassung.

In this joint guideline of the scientific societies and working groups mentioned in the title, evidence-based recommendations for the use of screening questionnaires and diagnostic tests in patients with neuropathic pain were developed. The systematic literature search and meta-analysis yielded the following results: Of the screening questionnaires, Douleur Neuropathique en 4 Questions (DN4), I­DN4 (self-administered DN4), and Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) received a strong recommendation, while S­LANSS (self-administered LANSS) and PainDETECT received weak recommendations for their use in the diagnostic workup of patients with possible neuropathic pain. There was a strong recommendation for the use of skin biopsy and a weak recommendation for quantitative sensory testing and nociceptive evoked potentials. The role of confocal corneal microscopy is still unclear. Functional imaging and peripheral nerve blocks are helpful in elucidating the pathophysiology, but current literature does not support their use in diagnosing neuropathic pain. In selected cases, genetic testing in specialized centers may be considered.

Muscle Oxygenation and Microvascular Reactivity Across Different Stages of CKD: A Near-Infrared Spectroscopy Study.

RATIONALE & OBJECTIVE: Previous studies in chronic kidney disease (CKD) showed that vascular dysfunction in different circulatory beds progressively deteriorates with worsening CKD severity. This study evaluated muscle oxygenation and microvascular reactivity at rest, during an occlusion-reperfusion maneuver, and during exercise in patients with different stages of CKD versus controls. STUDY DESIGN: Observational controlled study. SETTING & PARTICIPANTS: 90 participants (18 per CKD stage 2, 3a, 3b, and 4, as well as 18 controls). PREDICTOR: CKD stage. OUTCOME: The primary outcome was muscle oxygenation at rest. Secondary outcomes were muscle oxygenation during occlusion-reperfusion and exercise, and muscle microvascular reactivity (hyperemic response). ANALYTICAL APPROACH: Continuous measurement of muscle oxygenation [tissue saturation index (TSI)] using near-infrared spectroscopy at rest, during occlusion-reperfusion, and during a 3-minute handgrip exercise (at 35% of maximal voluntary contraction). Aortic pulse wave velocity and carotid intima-media thickness were also recorded. RESULTS: Resting muscle oxygenation did not differ across the study groups (controls: 64.3% ± 2.9%; CKD stage 2: 63.8% ± 4.2%; CKD stage 3a: 64.1% ± 4.1%; CKD stage 3b: 62.3% ± 3.3%; CKD stage 4: 62.7% ± 4.3%; P=0.6). During occlusion, no significant differences among groups were detected in the TSI occlusion magnitude and TSI occlusion slope. However, during reperfusion the maximum TSI value was significantly lower in groups of patients with more advanced CKD stages compared with controls, as was the hyperemic response (controls: 11.2%±3.7%; CKD stage 2: 8.3%±4.6%; CKD stage 3: 7.8%±5.5%; CKD stage 3b: 7.3%±4.4%; CKD stage 4: 7.2%±3.3%; P=0.04). During the handgrip exercise, the average decline in TSI was marginally lower in patients with CKD than controls, but no significant differences were detected across CKD stages. LIMITATIONS: Moderate sample size, cross-sectional evaluation. CONCLUSIONS: Although no differences were observed in muscle oxygenation at rest or during occlusion, the microvascular hyperemic response during reperfusion was significantly impaired in CKD and was most prominent in more advanced CKD stages. This impaired ability of microvasculature to respond to stimuli may be a crucial component of the adverse vascular profile of patients with CKD and may contribute to exercise intolerance. PLAIN-LANGUAGE SUMMARY: Previous studies in chronic kidney disease (CKD) have shown that vascular dysfunction in different circulatory beds progressively deteriorates with CKD severity. This study evaluated muscle oxygenation and microvascular reactivity at rest, during an occlusion-reperfusion maneuver, and during exercise in patients with nondialysis CKD versus controls, as well as across different CKD stages. It showed that the microvascular hyperemic response after an arterial occlusion was significantly impaired in CKD and was worst in patients with more advanced CKD. No significant differences were detected in skeletal muscle oxygenation or muscle oxidative capacity at rest or during the handgrip exercise when comparing patients with CKD with controls or comparing across CKD stages. The impaired ability of microvasculature to respond to stimuli may be a component of the adverse vascular profile of patients with CKD and may contribute to exercise intolerance.

Cardiorespiratory fitness assessed with cardiopulmonary exercise testing in patients with juvenile idiopathic arthritis: a systematic review and meta-analysis.

OBJECTIVES: JIA is the most common type of arthritis in children and adolescents, causing joint damage, chronic pain and disability. Deconditioning is also prevalent in patients with JIA due to both inactivity and the disease progression, resulting in reduced cardiorespiratory fitness (CRF). We aimed to evaluate CRF of patients with JIA compared with healthy controls. METHODS: This is a systematic review and meta-analysis of studies using cardiopulmonary exercise testing (CPET) to examine differences in determinants of CRF between patients with JIA vs healthy controls. The primary outcome was peak oxygen uptake (VO2peak). Literature search involved PubMed, Web of Science and Scopus databases, manual search of article references and grey literature. Quality assessment was undertaken with Newcastle-Ottawa Scale. RESULTS: From 480 literature records initially retrieved, eight studies (538 participants) were included in final meta-analysis. VO2peak was significantly lower in patients with JIA compared with controls [weighted mean difference (WMD): -5.95 ml/kg/min (95% CI -9.26, -2.65)]. Exercise duration and VO2peak (% predicted) were found to be significantly impaired in patients with JIA compared with controls [standardized mean difference: -0.67 (95% CI -1.04, -0.29) and WMD: -11.31% (95% CI -20.09, -2.53), respectively], while no significant differences were found in maximum heart rate. CONCLUSION: VO2peak and other CPET variables were lower in patients with JIA compared with controls, indicating reduced CRF in the former. Overall, exercise programs for patients with JIA should be promoted as part of their treatment to improve physical fitness and reduce muscle atrophy. PROSPERO REGISTRATION: CRD42022380833.

The anti-inflammatory effects of aerobic exercise training in patients with type 2 diabetes: A systematic review and meta-analysis.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a low-grade, chronic inflammatory disease, associated with increased cardiovascular risk. The purpose of this systematic review/ meta-analysis was to evaluate the effects of aerobic exercise training (AET) on inflammatory markers in T2DM patients. METHODS: The literature search was conducted utilizing PubMed, Web of Science, Embase, and the Cochrane Library from their inception up to April 2022. We screened only for randomized controlled trials (RCTs) investigating the effects of AET on C-reactive protein (CRP) and adipokines: adiponectin, resistin, interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-a), along with changes in anthropometric indices and glycemic control in adult T2DM patients. Pooled post-exercise weighted mean differences (WMDs) with 95% Confidence Intervals (CIs) were calculated for all outcomes of interest between exercise-treated patients and controls. RESULTS: Twenty-six RCTs involving 1239 T2DM patients were retrieved from the databases for meta-analysis. The cumulative results showed that post-AET inflammatory markers were lower in exercise-treated patients compared to controls regarding CRP (mg/L): WMD: -0.91; 95%CIs: -1.43, -0.40; p < 0.001 resistin (mg/ml): (WMD: -2.08; 95%CIs: -3.32, -0.84; p < 0.001); TNF-a (pg/ml): (WMD: -2.70; 95%CIs: -4.26, -1.14; p < 0.001), and IL-6 (pg/ml): (WMD: -1.05; 95%CIs: -1.68, -0.43; p < 0.001). Those effects were accompanied by significant amelioration of fasting glucose (mg/dl) (WMD: -13.02; 95%CIs: -25.39, -0.66; p = 0.04), HbA1c (%) (WMD: -0.51; 95%CIs: -0.73, -0.28, p < 0.001), and fat mass (%) (WMD: -3.14; 95%CI: -4.71, -1.58; p < 0.001). Our meta-analysis demonstrated less-consistent results for adiponectin (µg/ml), (WMD: 1.00; 95%CI: -0.12, 2.12; p = 0.08) and body-mass index (kg/m2) (WMD: -1.34; 95%CI: -2.76, 0.08; p = 0.06) tending to differ between AET and control group. CONCLUSIONS: AET can significantly reduce the inflammatory burden in T2DM patients. by ameliorating the circulating levels of CRP, resistin, TNF-a and IL-6, even without accompanied significant weight-loss. The clinical impact of those anti-inflammatory effects of AET needs to be determined.

Association of Intradialytic Hypertension with Future Cardiovascular Events and Mortality in Hemodialysis Patients: Effects of Ambulatory Blood Pressure.

INTRODUCTION: Intradialytic hypertension (IDHTN) is associated with increased risk of adverse outcomes. Patients with IDHTN have higher 44-h blood pressure (BP) than patients without this condition. Whether the excess risk in these patients is due to the BP rise during dialysis per se or on elevated 44-h BP or other comorbid conditions is uncertain. This study evaluated the association of IDHTN with cardiovascular events and mortality and the influence of ambulatory BP and other cardiovascular risk factors on these associations. METHODS: 242 hemodialysis patients with valid 48-h ABPM (Mobil-O-Graph-NG) were followed for a median of 45.7 months. IDHTN was defined as: systolic BP (SBP) rise ≥10 mm Hg from pre- to post-dialysis and post-dialysis SBP ≥150 mm Hg. The primary endpoint was all-cause mortality; the secondary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, resuscitation after cardiac arrest, heart failure hospitalization, coronary or peripheral revascularization. RESULTS: Cumulative freedom from both the primary and secondary endpoint was significantly lower for IDHTN patients (logrank-p = 0.048 and 0.022, respectively), corresponding to higher risks for all-cause mortality (hazard ratio (HR) = 1.566; 95% confidence interval (CI) [1.001, 2.450]) and the composite cardiovascular outcome (HR = 1.675; 95% CI [1.071, 2.620]) in these individuals. However, the observed associations lost statistical significance after adjustment for 44-h SBP (HR = 1.529; 95% CI [0.952, 2.457] and HR = 1.388; 95% CI [0.866, 2.225], respectively). In the final model after additional adjustment for 44-h SBP, interdialytic weight gain, age, history of coronary artery disease, heart failure, diabetes, and 44-h pulse wave velocity, the association of IDHTN with the outcomes was also not significant and the respective HRs were 1.377 (95% CI [0.836, 2.268]) and 1.451 (95% CI [0.891, 2.364]). CONCLUSIONS: IDHTN patients had higher risk for mortality and cardiovascular outcomes but this risk is at least partly confounded by the elevated BP levels during the interdialytic period.