Cancer-associated mutations in the p85α N-terminal SH2 domain activate a spectrum of receptor tyrosine kinases.

The phosphoinositide 3-kinase regulatory subunit p85α is a key regulator of kinase signaling and is frequently mutated in cancers. In the present study, we showed that in addition to weakening the inhibitory interaction between p85α and p110α, a group of driver mutations in the p85α N-terminal SH2 domain activated EGFR, HER2, HER3, c-Met, and IGF-1R in a p110α-independent manner. Cancer cells expressing these mutations exhibited the activation of p110α and the AKT pathway. Interestingly, the activation of EGFR, HER2, and c-Met was attributed to the ability of driver mutations to inhibit HER3 ubiquitination and degradation. The resulting increase in HER3 protein levels promoted its heterodimerization with EGFR, HER2, and c-Met, as well as the allosteric activation of these dimerized partners; however, HER3 silencing abolished this transactivation. Accordingly, inhibitors of either AKT or the HER family reduced the oncogenicity of driver mutations. The combination of these inhibitors resulted in marked synergy. Taken together, our findings provide mechanistic insights and suggest therapeutic strategies targeting a class of recurrent p85α mutations.

PRMT1 inhibition perturbs RNA metabolism and induces DNA damage in clear cell renal cell carcinoma.

In addition to the ubiquitous loss of the VHL gene in clear cell renal cell carcinoma (ccRCC), co-deletions of chromatin-regulating genes are common drivers of tumorigenesis, suggesting potential vulnerability to epigenetic manipulation. A library of chemical probes targeting a spectrum of epigenetic regulators is screened using a panel of ccRCC models. MS023, a type I protein arginine methyltransferase (PRMT) inhibitor, is identified as an antitumorigenic agent. Individual knockdowns indicate PRMT1 as the specific critical dependency for cancer growth. Further analyses demonstrate impairments to cell cycle and DNA damage repair pathways upon MS023 treatment or PRMT1 knockdown. PRMT1-specific proteomics reveals an interactome rich in RNA binding proteins and further investigation indicates significant widespread disruptions in mRNA metabolism with both MS023 treatment and PRMT1 knockdown, resulting in R-loop accumulation and DNA damage over time. Our data supports PRMT1 as a target in ccRCC and informs a mechanism-based strategy for translational development.

AKTIP loss is enriched in ERα-positive breast cancer for tumorigenesis and confers endocrine resistance.

Recurrent deletion of 16q12.2 is observed in luminal breast cancer, yet the causal genomic alterations in this region are largely unknown. In this study, we identify that loss of AKTIP, which is located on 16q12.2, drives tumorigenesis of estrogen receptor alpha (ERα)-positive, but not ERα-negative, breast cancer cells and is associated with poor prognosis of patients with ERα-positive breast cancer. Intriguingly, AKTIP-depleted tumors have increased ERα protein level and activity. Cullin-associated and neddylation-dissociated protein 1 (CAND1), which regulates the cullin-RING E3 ubiquitin ligases, protects ERα from cullin 2-dependent proteasomal degradation. Apart from ERα signaling, AKTIP loss triggers JAK2-STAT3 activation, which provides an alternative survival signal when ERα is inhibited. AKTIP-depleted MCF7 cells and ERα-positive patient-derived organoids are more resistant to ERα antagonists. Importantly, the resistance can be overcome by co-inhibition of JAK2/STAT3. Together, our results highlight the subtype-specific functional consequences of AKTIP loss and provide a mechanistic explanation for the enriched AKTIP copy-number loss in ERα-positive breast cancer.

High serum neurofilament levels among Chinese patients with aquaporin-4-IgG-seropositive neuromyelitis optica spectrum disorders.

BACKGROUND: Serum neurofilament light chain (sNfL) is a promising biomarker for neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS), but there is limited validation data in specific ethnic and disease groups. OBJECTIVE: To investigate the levels of sNfL in a cohort of Chinese patients with NMOSD and compare sNfL levels in patients with different disease courses and treatments. METHODS: We analysed sNfL levels in 153 Chinese patients with NMOSD (n = 51) and MS (n = 102) using single-molecule array (Simoa) technology. The sNfL levels were compared with those of 71 healthy controls from two centres in southern China. For each disease, we assessed correlations between sNfL and disease phases and treatments. RESULTS: Higher levels of sNfL were found in the patients with NMOSD [17.97 (10.55-27.94) pg/mL] and MS [15.83 (8.92-25.67) pg/mL] compared to healthy controls [10.09 (7.19-13.29) pg/mL, p < 0.001]. No significant differences were found between the AQP4-IgG-positive NMOSD group and OCB-positive MS group. CONCLUSIONS: sNfL measured by Simoa technology is a potential candidate blood biomarker for the diagnosis and disease monitoring of NMOSD in Chinese patients, warranting further prospective and multicentre studies.

Impaired cognition is related to microstructural integrity in relapsing remitting multiple sclerosis.

BACKGROUND: Cognitive impairment is common in multiple sclerosis (MS). However, the relationship between cognitive deficits and microstructural abnormalities in Chinese MS patients remains unclear. We aimed to investigate the importance of microstructural abnormalities and the associations with cognitive impairment in Chinese MS patients. METHODS: Three-dimensional T1-weighted magnetic resonance imaging (MRI) scans were obtained from 36 relapsing remitting MS patients. Diffusion tensor imaging (DTI) scans were acquired for 29 (81%) patients. Cognitive impairment was assessed using a comprehensive neuropsychological battery. Patients were classified into cognitively impaired (CI) group and cognitively preserved (CP) group. Using volBrain and FSL software, we assessed white matter lesion burden, white matter (WM) and gray matter (GM) volumetric as well as microstructural diffusivity. MRI variables explaining cognitive impairment were analyzed. RESULTS: Fifteen (42%) patients were classified as CI. Verbal learning and memory was the most commonly impaired domain (n = 16, 44%). CI patients had lower mean skeleton fractional anisotropy (FA) value than CP patients (275.45 vs. 283.61 × 10-3 , P = 0.023). The final predicting model including demographic variables and global skeleton mean diffusivity (MD) explained 43.6% of variance of the presence of cognitive impairment (ß = 0.131, P = 0.041). CI patients showed a widespread change of microstructural integrity comparing to CP patients, which was rarely overlapping with lesion probability map. Microstructural abnormalities in corpus callosum were associated with performance in verbal learning and memory, processing speed and selective attention (P < 0.05). CONCLUSION: Loss of microstructural integrity demonstrated by DTI helps explain cognitive dysfunction in Chinese MS patients.

Strategic Combination Therapies for Ovarian Cancer.

Ovarian cancer remains the leading cause of gynecologic cancer-related deaths among women worldwide. The dismal survival rate is partially due to recurrence after standardized debulking surgery and first-line chemotherapy. In recent years, targeted therapies, including antiangiogenic agents or poly (ADP-ribose) polymerase inhibitors, represent breakthroughs in the treatment of ovarian cancer. As more therapeutic agents become available supplemented by a deeper understanding of ovarian cancer biology, a range of combination treatment approaches are being actively investigated to further improve the clinical outcomes of the disease. These combinations, which involve DNA-damaging agents, targeted therapies of signaling pathways and immunotherapies, simultaneously target multiple cancer pathways or hallmarks to induce additive or synergistic antitumor activities. Here we review the preclinical data and ongoing clinical trials for developing effective combination therapies in treating ovarian cancer. These emerging therapeutic modalities may reshape the treatment landscape of the disease.

Advanced MRI features in relapsing multiple sclerosis patients with and without CSF oligoclonal IgG bands.

Oligoclonal IgG bands (OCB) in cerebrospinal fluid (CSF) are important in diagnosis of multiple sclerosis (MS). We evaluated the MRI features of clinically definite MS subjects with and without CSF-OCB. Relapsing MS subjects were recruited from a prospective registry in a university center. CSF-OCB were detected using isoelectric focusing and lgG-specific immunofixation. MRI metrics including brain volumes, lesion volumes and microstructural measures, were analyzed by FMRIB Software Library (FSL) and Statistical Parametric Mapping (SPM). Seventy-five subjects with relapsing MS were analyzed. Forty-four (59%) subjects had an interval MRI at around 1 year. CSF-OCB were detected in 46 (61%) subjects. The OCB-positive group had a higher proportion of cerebellar lesions than the OCB-negative group (23.9% vs. 3.4%, p = 0.057). Except for amygdala volumes which were lower in the OCB-positive group (p = 0.034), other regional brain volumes including the subcortical deep gray matter and corpus callosum were similar. The two groups also showed comparable brain atrophy rate. For DTI, the OCB-positive group showed significantly higher mean diffusivity (MD) value in perilesional normal-appearing white matter (p = 0.043). Relapsing MS patients with and without CSF-OCB shared similar MRI features regarding volumetric analyses and DTI microstructural integrity.

Erodibility of synthetic water repellent granular materials: Adapting the ground to weather extremes.

Granular materials with synthetic water repellent coatings have great potential to be used in ground interfaces (ground-atmosphere-vegetation and ground-structure) as infiltration barriers, due to their altered hydrological properties (suppressed infiltration and decreased sorptivity). However, very few studies have evaluated the impact of synthetic soil water repellency on soil erosion. This paper investigates the effect of water repellency on soil erosional behavior, including splash erosion and rill processes. Twenty-four flume tests were carried out on model slopes under artificial rainfall; soils with three wettability levels were tested, including wettable (contact angle, CA < 90°), subcritical water repellent (CA ~ 90°) and water repellent (CA > 90°). Various rainfall intensities (230 mm/h, 170 mm/h, 100 mm/h and 40 mm/h) and grain sizes (Fujian sand and sand/silt mixture) were adopted. Erosional variables, including splash erosion rate, average sediment concentration, peak sediment concentration and time to peak sediment were measured to quantitatively analyze the behavior. This study confirms the impact of water repellency on soil erosion and unveils the possibility to reduce infiltration at ground-atmosphere interface with controlled soil erosion. The results revealed that: (1) synthetic water repellency does not necessarily lead to increased soil erosion yield; its impact is dependent on grain size with the soil erosion loss increasing for Fujian sand, but decreasing for sand/silt mixtures; (2) splash erosion is positively correlated to soil water repellency and high rainfall intensity, regardless of grain size; (3) the erosion processes for sand/silt mixtures are particle size selective and not affected by soil water repellency, whereas this phenomenon is not observed with Fujian sand.

High prevalence and indexes of anti-John Cunningham virus antibodies in a cohort of Chinese patients with multiple sclerosis.

We performed a cross-sectional study in 123 Chinese multiple sclerosis patients residing in Hong Kong to evaluate their anti-John Cunningham virus status using STRATIFY JCV DxSelect assays. Anti-John Cunningham virus antibody was present in 98/123 (80%) subjects, among which 75/98 (77%) had an anti-John Cunningham virus index ≥1.5. Anti-John Cunningham virus antibody seropositivity was not correlated with age, disease duration, Expanded Disability Status Scale scores, types of multiple sclerosis (relapsing vs progressive), or disease-modifying treatments used. We found a very high seroprevalence and index of anti-John Cunningham virus antibodies in Chinese multiple sclerosis patients, which may impact the risk assessment and recommendation of disease-modifying treatments in this population.