Molecular Signatures for Microbe-Associated Colorectal Cancers.

Background: Genetic factors and microbial imbalances play crucial roles in colorectal cancers (CRCs), yet the impact of infections on cancer initiation remains poorly understood. While bioinformatic approaches offer valuable insights, the rising incidence of CRCs creates a pressing need to precisely identify early CRC events. We constructed a network model to identify continuum states during CRC initiation spanning normal colonic tissue to pre-cancer lesions (adenomatous polyps) and examined the influence of microbes and host genetics. Methods: A Boolean network was built using a publicly available transcriptomic dataset from healthy and adenoma affected patients to identify an invariant Microbe-Associated Colorectal Cancer Signature (MACS). We focused on Fusobacterium nucleatum ( Fn ), a CRC-associated microbe, as a model bacterium. MACS-associated genes and proteins were validated by RT-qPCR, RNA seq, ELISA, IF and IHCs in tissues and colon-derived organoids from genetically predisposed mice ( CPC-APC Min+/- ) and patients (FAP, Lynch Syndrome, PJS, and JPS). Results: The MACS that is upregulated in adenomas consists of four core genes/proteins: CLDN2/Claudin-2 (leakiness), LGR5/leucine-rich repeat-containing receptor (stemness), CEMIP/cell migration-inducing and hyaluronan-binding protein (epithelial-mesenchymal transition) and IL8/Interleukin-8 (inflammation). MACS was induced upon Fn infection, but not in response to infection with other enteric bacteria or probiotics. MACS induction upon Fn infection was higher in CPC-APC Min+/- organoids compared to WT controls. The degree of MACS expression in the patient-derived organoids (PDOs) generally corresponded with the known lifetime risk of CRCs. Conclusions: Computational prediction followed by validation in the organoid-based disease model identified the early events in CRC initiation. MACS reveals that the CRC-associated microbes induce a greater risk in the genetically predisposed hosts, suggesting its potential use for risk prediction and targeted cancer prevention.

The effects of moderate concentrations of Karenia brevis on stone crab reproduction.

The stone crab, Menippe mercenaria, supports a commercial fishery along Florida's Gulf coast where harmful algae blooms, known as red tides (Karenia brevis) develop. Red tides occur nearly annually and can overlap with the stone crab reproductive season. We determined the impact of moderate red tide (K. brevis) concentrations (∼105 cells L-1) on stone crab embryo development, hatching success, female stress, hatch duration, and larval survival. Crabs and larvae were exposed to a control (no K. brevis) or moderate concentrations of K. brevis. No difference in embryo development or hatching success was observed. Stress was elevated in the K. brevis treatment, resulting in prolonged hatching relative to the control. Larval survival was reduced in K. brevis relative to the control. Moderate concentrations of K. brevis results in sublethal effects on stone crabs and reduces larval survival, suggesting that mitigation that reduces bloom concentrations could provide relief to stone crab populations.

[Signs of diabetic cardiomyopathy in patients with controlled arterial hypertension and early postprandial hyperglycemia].

AIM: To study signs of diabetic cardiomyopathy (DCM) in nondiabetic patients with controlled arterial hypertension (AH) and glycemic response during first hour of glucose tolerance test (GTT). MATERIAL AND METHODS: Patients (n = 47) with controlled AH were divided into 2 groups according to results of GTT with 75 g of glucose: patients of group 1 (n = 22) had glucose level ≤ 200 mg/dl during 1-st hour of GTT; other patients (n = 25) composed group 2. Examination of all patients included transthoracic echocardiography, ultrasound Dopplerography, tissue Doppler (TD) and 24-hour Holter ECG monitoring. Using data of these methods we calculated left ventricular (LV) mass and the following characteristics of mitral ring: E/A, TD e', TD a', TD s', TD e'/a'/. The following characteristics of heart rate variability were obtained: standard deviation of normal RR intervals (SDNN), low and high frequency (LF, HF) power, LF/HF ratio. RESULTS: Patients of group 2 had higher LV mass (229.5 ± 58.2 vs. 192.1 ± 50.6 g; p = 0.036), more pronounced changes of TD e'/a' (0.71 ± 0.25 vs. 1.06 ± 0.58; p = 0.011), lower SDNN both during day (85.4 ± 14.1 vs. 112.5 ± 31.3 ms, p = 0.007) and night (82.2 ± 22.1 vs. 105.9 ± 28.5 ms, p = 0,004) time, higher nocturnal LF/HF ratio (3.75 ± 4.02 vs. 1.72 ± 0.81, p = 0,029). CONCLUSION: In patients with controlled arterial hypertension (AH) and glycemic response during first hour of GCT we revealed various pronounced manifestations of DCM. These data constitute a basis for further studies.

LRRK2 G2019S mutations are associated with an increased cancer risk in Parkinson disease.

Leucine rich repeat kinase (LRRK2) G2019S mutations are presumed to cause PD through a toxic gain of function of the protein kinase. Small molecule kinase inhibitors have been developed for the treatment of certain cancers, and some antioncogenic agents such as sunitinib, may nonspecifically inhibit LRRK2. Few studies, however, have assessed cancer risk in LRRK2 mutation carriers. To explore this risk, we evaluated records of Ashkenazi Jewish (AJ) PD patients participating in genetic research. Charts were reviewed for 163 unrelated AJ PD patients, 31 of whom harbored the G2019S mutation. History of cancer was queried at baseline intake using a form reviewing medical conditions, and charts were reviewed for all follow-up visits. 9/31 LRRK2 G2019S mutation carriers had nonskin cancers, whereas 15/132 without mutations had nonskin cancers, representing an almost threefold increased risk in this group (HR 2.9, 95% CI 1.3-6.6). Age at first nonskin cancer was younger in the LRRK2 carriers (56.0 years) than the noncarriers (62.0 years), but was not significant. 67% of the LRRK2 carriers had their cancer before the onset of PD, whereas only 40% of noncarriers developed their first nonskin cancer before onset of PD. While further evaluation is warranted, our findings indicate an increased risk of nonskin cancers in LRRK2 G2019S mutation carriers, which may be related to toxic gain of function of mutated LRRK2.