Pan-PI3K inhibition with copanlisib overcomes Treg- and M2-TAM-mediated immune suppression and promotes anti-tumor immune responses.

The PI3K pathway is one of the most frequently altered signaling pathways in human cancer. In addition to its function in cancer cells, PI3K plays a complex role in modulating anti-tumor immune responses upon immune checkpoint inhibition (ICI). Here, we evaluated the effects of the pan-Class I PI3K inhibitor copanlisib on different immune cell types in vitro and on tumor growth and immune cell infiltration in syngeneic murine cancer models. Intermittent treatment with copanlisib resulted in a strong in vivo anti-tumor efficacy, increased tumor infiltration of activated T cells and macrophages, and increased CD8+ T cell/regulatory T cell and M1/M2 macrophage ratios. The strong in vivo efficacy was at least partially due to immunomodulatory activity of copanlisib, as in vitro these murine cancer cells were resistant to PI3K inhibition. Furthermore, the combination of copanlisib with the ICI antibody anti-PD-1 demonstrated enhanced anti-tumor efficacy in both ICI-sensitive and insensitive syngeneic mouse tumor models. Importantly, in an ICI-sensitive model, combination therapy resulted in complete remission and prevention of tumor recurrence. Thus, the combination of ICIs with PI3K inhibition by intermittently dosed copanlisib represents a promising new strategy to increase sensitivity to ICI therapies and to treat human solid cancers.

Leg Movement Activity During Sleep in Adults With Attention-Deficit/Hyperactivity Disorder.

Objectives: To conduct a first detailed analysis of the pattern of leg movement (LM) activity during sleep in adult subjects with Attention-Deficit/Hyperactivity Disorder (ADHD) compared to healthy controls. Methods: Fifteen ADHD patients and 18 control subjects underwent an in-lab polysomnographic sleep study. The periodic character of LMs was evaluated with established markers of "periodicity," i.e., the periodicity index, intermovement intervals, and time distribution of LM during sleep, in addition to standard parameters such as the periodic leg movement during sleep index (PLMSI) and the periodic leg movement during sleep arousal index (PLMSAI). Subjective sleep and psychiatric symptoms were assessed using several, self-administered, screening questionnaires. Results: Objective sleep parameters from the baseline night did not significantly differ between ADHD and control subjects, except for a longer sleep latency (SL), a longer duration of the periodic leg movements during sleep (PLMS) in REM sleep and a higher PLMSI also in REM sleep. Data from the sleep questionnaires showed perception of poor sleep quality in ADHD patients. Conclusions: Leg movements during sleep in ADHD adults are not significantly more frequent than in healthy controls and the nocturnal motor events do not show an increased periodicity in these patients. The non-periodic character of LMs in ADHD has already been shown in children and seems to differentiate ADHD from other pathophysiological related conditions like restless legs syndrome (RLS) or periodic limb movement disorder (PLMD). The reduced subjective sleep quality reported by ADHD adults contrasted with the normal objective polysomnographic parameters, which could suggest a sleep-state misperception in these individuals or more subtle sleep abnormalities not picked up by the traditional sleep staging.

Simultaneous Inhibition of PI3Kδ and PI3Kα Induces ABC-DLBCL Regression by Blocking BCR-Dependent and -Independent Activation of NF-κB and AKT.

Compared with follicular lymphoma, high PI3Kα expression was more prevalent in diffuse large B cell lymphoma (DLBCL), although both tumor types expressed substantial PI3Kδ. Simultaneous inhibition of PI3Kα and PI3Kδ dramatically enhanced the anti-tumor profile in ABC-DLBCL models compared with selective inhibition of PI3Kδ, PI3Kα, or BTK. The anti-tumor activity was associated with suppression of p-AKT and a mechanism of blocking nuclear factor-κB activation driven by CD79mut, CARD11mut, TNFAIP3mut, or MYD88mut. Inhibition of PI3Kα/δ resulted in tumor regression in an ibrutinib-resistant CD79BWT/MYD88mut patient-derived ABC-DLBCL model. Furthermore, rebound activation of BTK and AKT was identified as a mechanism limiting CD79Bmut-ABC-DLBCL to show a robust response to PI3K and BTK inhibitor monotherapies. A combination of ibrutinib with the PI3Kα/δ inhibitor copanlisib produced a sustained complete response in vivo in CD79Bmut/MYD88mut ABC-DLBCL models.

Acetyl-CoA carboxylase inhibitors attenuate WNT and Hedgehog signaling and suppress pancreatic tumor growth.

Acetyl-CoA carboxylase (ACC) is the rate-limiting enzyme in de novo fatty acid synthesis, and its ACC1 isoform is overexpressed in pancreatic and various other cancers. The activity of many oncogenic signaling molecules, including WNT and Hedgehog (HH), is post-translationally modified by lipidation. Here, we report that inhibition of ACC by a small molecule inhibitor, BAY ACC002, blocked WNT3A lipidation, secretion, and signaling. In pancreatic cancer cells, where WNT and HH are key oncogenic drivers, ACC inhibition simultaneously suppressed WNT and HH signaling, and led to anti-proliferative effects. Treatment with ACC inhibitors blocked tumor growth and converted the poorly differentiated histological phenotype to epithelial phenotype in multiple cell line-based and patient-derived pancreatic cancer xenograft models. Together, our data highlight the potential utility of ACC inhibitors for pancreatic cancer treatment, and provide novel insight into the link between upregulated de novo fatty acid synthesis in cancer cells, protein lipidation, and oncogenic signaling.

[Treatment of patients with coronary heart disease and depressive disorders in rehabilitation]. / Behandlung von Patienten mit koronarer Herzkrankheit und komorbider Depression in der Rehabilitation.

Depressive disorders in patients with coronary heart disease (CHD) are connected with negative effects on the course of the cardiac disease. Until today there has been no clear etiological model to explain the interaction of depressive disorders and cardiac risk parameters. Both, somatic and behavioural aspects seem to be important. Depressive symptoms are a serious risk factor for CHD-patients demanding for a broad bio-psychosocial treatment conception in cardiac rehabilitation. Most intervention studies have mainly focussed on the reduction of depressive and anxious symptoms in CHD-patients without co-morbid mental disorders. However, for CHD-patients with a co-morbid depressive disorder specific psychotherapeutic and psychopharmacological treatments have proved a reduction in depressive symptoms. This reduction in depression was -- unexpectedly -- not associated with an improved cardiac prognosis. Based on these previous studies the present paper introduces the concept of a combined psychotherapeutic and psychopharmacological intervention for depressed patients in cardiac rehabilitation. Specific characteristics of the patients and of the health care system are taken into consideration. Anticipated difficulties in the psychotherapeutic treatment of depressive CHD-patients are addressed and possible solutions are indicated.

Inpatient psychotherapeutic treatment for cardiac patients with depression in Germany - short term results.

UNLABELLED: The purpose of the PROTeCD(Psychotherapeutic Resource-Orientated Treatment for Cardiac Patients with Depression)-study was to develop and to evaluate a brief psychotherapeutic intervention for rehabilitation in-patients with coronary heart disease (CHD) and depressive disorders. In three cardiac rehabilitation hospitals all patients were screened for mental distress at admission. Patients generally stay for 3 to 4 weeks before being referred to outpatient care. METHOD: Those patients with elevated distress were interviewed for mental disorders and took part in the baseline-assessment. Patients diagnosed with a depressive disorder at baseline were randomised into the intervention or the usual care group. Efficacy was assessed at discharge from hospital (short-term). 59 subjects with CHD and co-morbid depressive disorder were randomised into the trial - 27 into the intervention group (IG) and 32 into the usual care group (UC). Patients in the intervention group received 4 to 6 individual psychotherapeutic sessions of 50 minutes each, including patient education and cognitive-behavioural treatment of depression. Outcome measures were depressive and anxiety symptoms in self report and interview. RESULTS: There was no significant difference between intervention and usual care group in this short-term reduction of depressive symptoms, mental distress and anxiety. However, at discharge the patients still suffer from an increased level of distress compared to the recommended cut off scores of the assessment scales. CONCLUSION: Multimodal inpatient rehabilitation reduces depressive and anxiety symptoms in depressed CHD patients in short term independently of an additional psychotherapeutic intervention.