Germline findings in cancer predisposing genes from a small cohort of chordoma patients.

INTRODUCTION: Chordoma is a rare slow-growing tumor that occurs along the length of the spinal axis and arises from primitive notochordal remnants (Stepanek et al., Am J Med Genet 75:335-336, 1998). Most chordomas are sporadic, but a small percentage of cases are due to hereditary cancer syndromes (HCS) such as tuberous sclerosis 1 and 2 (TSC1/2), or constitutional variants in the gene encoding brachyury T (TBXT) (Pillay et al., Nat Genet 44:1185-1187, 2012; Yang et al., Nat Genet 41:1176-1178, 2009). PURPOSE: The genetic susceptibility of these tumors is not well understood; there are only a small number of studies that have performed germline genetic testing in this population. METHODS: We performed germline genetic in chordoma patients using genomic DNA extracted by blood or saliva. CONCLUSION: We report here a chordoma cohort of 24 families with newly found germline genetic mutations in cancer predisposing genes. We discuss implications for genetic counseling, clinical management, and universal germline genetic testing for cancer patients with solid tumors.

Longitudinal Natural History Study of Children and Adults with Rare Solid Tumors: Initial Results for First 200 Participants.

Understanding of tumor biology and identification of effective therapies is lacking for many rare tumors. My Pediatric and Adult Rare Tumor (MyPART) network was established to engage patients, advocates, and researchers and conduct a comprehensive longitudinal Natural History Study of Rare Solid Tumors. Through remote or in-person enrollment at the NIH Clinical Center, participants with rare solid tumors ≥4 weeks old complete standardized medical and family history forms, patient reported outcomes, and provide tumor, blood and/or saliva samples. Medical records are extracted for clinical status and treatment history, and tumors undergo genomic analysis. A total of 200 participants (65% female, 35% male, median age at diagnosis 43 years, range = 2-77) enrolled from 46 U.S. states and nine other countries (46% remote, 55% in-person). Frequent diagnoses were neuroendocrine neoplasms (NEN), adrenocortical carcinomas (ACC), medullary thyroid carcinomas (MTC), succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (sdGIST), and chordomas. At enrollment, median years since diagnosis was 3.5 (range = 0-36.6), 63% participants had metastatic disease and 20% had no evidence of disease. Pathogenic germline and tumor mutations included SDHA/B/C (sdGIST), RET (MTC), TP53 and CTNNB1 (ACC), MEN1 (NEN), and SMARCB1 (poorly-differentiated chordoma). Clinically significant anxiety was observed in 20%-35% of adults. Enrollment of participants and comprehensive data collection were feasible. Remote enrollment was critical during the COVID-19 pandemic. Over 30 patients were enrolled with ACC, NEN, and sdGIST, allowing for clinical/genomic analyses across tumors. Longitudinal follow-up and expansion of cohorts are ongoing to advance understanding of disease course and establish external controls for interventional trials. SIGNIFICANCE: This study demonstrates that comprehensive, tumor-agnostic data and biospecimen collection is feasible to characterize different rare tumors, and speed progress in research. The findings will be foundational to developing external controls groups for single-arm interventional trials, where randomized control trials cannot be conducted because of small patient populations.

Targeting Replication Stress and Chemotherapy Resistance with a Combination of Sacituzumab Govitecan and Berzosertib: A Phase I Clinical Trial.

PURPOSE: Despite promising preclinical studies, toxicities have precluded combinations of chemotherapy and DNA damage response (DDR) inhibitors. We hypothesized that tumor-targeted chemotherapy delivery might enable clinical translation of such combinations. PATIENTS AND METHODS: In a phase I trial, we combined sacituzumab govitecan, antibody-drug conjugate (ADC) that delivers topoisomerase-1 inhibitor SN-38 to tumors expressing Trop-2, with ataxia telangiectasia and Rad3-related (ATR) inhibitor berzosertib. Twelve patients were enrolled across three dose levels. RESULTS: Treatment was well tolerated, with improved safety over conventional chemotherapy-based combinations, allowing escalation to the highest dose. No dose-limiting toxicities or clinically relevant ≥grade 4 adverse events occurred. Tumor regressions were observed in 2 patients with neuroendocrine prostate cancer, and a patient with small cell lung cancer transformed from EGFR-mutant non-small cell lung cancer. CONCLUSIONS: ADC-based delivery of cytotoxic payloads represents a new paradigm to increase efficacy of DDR inhibitors. See related commentary by Berg and Choudhury, p. 3557.

Follicle Center Lymphoma (FCL) of the Lower Female Genital Tract (LFGT): A Novel Variant of Primary Cutaneous Follicle Center Lymphoma (PCFCL).

Primary cutaneous follicle center lymphoma has been distinguished from nodal follicular lymphoma (FL) based on genomic and clinical features. The nature of other extranodal FLs is not well defined. We report 15 cases of follicle center lymphoma involving the lower female genital tract. Cases were evaluated using an immunohistochemical panel for B-cell lymphoma, B-cell clonality, fluorescence in situ hybridization for BCL2 gene rearrangement, and next-generation sequencing. All patients had localized disease with no evidence of bone marrow involvement. Most cases (12/15, 80%) had a follicular pattern, at least focally. Large centrocytes were a prominent feature leading to concern for diffuse large B-cell lymphoma by referring pathologists. Neoplastic cells were positive for CD20 and BCL-6, while BCL-2 was positive in 2/15 (13%) cases. Fluorescence in situ hybridization for BCL2 gene rearrangement was negative in 10/11 (91%) cases. Next-generation sequencing performed in 10 cases revealed TNFRSF14 as the most frequently mutated gene in 6/10 (60%) cases. No case had CREBBP or KMT2D mutations as seen in nodal FL. None of the patients had progressive disease with durable complete remission achieved in 10/12 (83%) cases. The median follow-up period was 7.8 years (range: 0.2 to 20.5 y) with a 5-year overall survival of 100%. We conclude that follicle center lymphoma of the lower female genital tract is a novel variant of primary cutaneous follicle center lymphoma. Despite a frequent component of large cells, it is characterized by localized disease and low risk for dissemination. Awareness and recognition are important to distinguish these lesions from aggressive B-cell lymphomas.

Case report: Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, associated with a germline mutation in PMS2.

Most tumors, including brain tumors, are sporadic. However, a small subset of CNS tumors are associated with hereditary cancer conditions like Lynch Syndrome (LS). Here, we present a case of an oligodendroglioma, IDH-mutant and 1p/19q-codeleted, and LS with a germline pathogenic PMS2 mutation. To our knowledge, this has only been reported in a few cases in the literature. While the family history is less typical of LS, previous studies have indicated the absence of a significant family history in patient cohorts with PMS2 mutations due to its low penetrance. Notably, only a handful of studies have worked on characterizing PMS2 mutations in LS, and even fewer have looked at these mutations in the context of brain tumor development. This report aims to add to the limited literature on germline PMS2 mutations and oligodendrogliomas. It highlights the importance of genetic testing in neuro-oncology.

Clinicopathologic and Molecular Characterization of Epstein-Barr Virus-positive Plasmacytoma.

Epstein-Barr virus (EBV)-positive plasmacytoma is a rare plasma cell neoplasm. It remains unclear whether EBV-positive plasmacytoma represents a distinct entity or a variant of plasmacytoma. It shares morphologic features with plasmablastic lymphoma (PBL) and may cause diagnostic uncertainty. To better understand EBV-positive plasmacytoma and explore diagnostic criteria, this study describes 19 cases of EBV-positive plasmacytoma, compared with 27 cases of EBV-negative plasmacytoma and 48 cases of EBV-positive PBL. We reviewed the clinicopathologic findings and performed immunohistochemistry, in situ hybridization for EBV, fluorescence in situ hybridization for MYC , and next-generation sequencing. We found that 63.2% of patients with EBV-positive plasmacytoma were immunocompromised. Anaplastic features were observed in 7/19 cases. MYC rearrangement was found in 25.0% of them, and extra copies of MYC in 81.3%. EBV-positive and EBV-negative plasmacytomas possessed similar clinicopathologic features, except more frequent cytologic atypia, bone involvement and MYC aberrations in the former group. The survival rate of patients with EBV-positive plasmacytoma was comparable to that of patients with EBV-negative plasmacytoma. In comparison to PBL, EBV-positive plasmacytoma is less commonly associated with a "starry-sky" appearance, necrosis, absence of light chain expression, and a high Ki67 index (>75%). The most recurrently mutated genes/signaling pathways in EBV-positive plasmacytoma are epigenetic regulators, MAPK pathway, and DNA damage response, while the most frequently reported mutations in PBL are not observed. Collectively, EBV-positive plasmacytoma should be regarded as a biological variant of plasmacytoma. Thorough morphologic examination remains the cornerstone for distinguishing EBV-positive plasmacytoma and PBL, and molecular studies can be a valuable complementary tool.

Impact of the methylation classifier and ancillary methods on CNS tumor diagnostics.

BACKGROUND: Accurate CNS tumor diagnosis can be challenging, and methylation profiling can serve as an adjunct to classify diagnostically difficult cases. METHODS: An integrated diagnostic approach was employed for a consecutive series of 1258 surgical neuropathology samples obtained primarily in a consultation practice over 2-year period. DNA methylation profiling and classification using the DKFZ/Heidelberg CNS tumor classifier was performed, as well as unsupervised analyses of methylation data. Ancillary testing, where relevant, was performed. RESULTS: Among the received cases in consultation, a high-confidence methylation classifier score (>0.84) was reached in 66.4% of cases. The classifier impacted the diagnosis in 46.7% of these high-confidence classifier score cases, including a substantially new diagnosis in 26.9% cases. Among the 289 cases received with only a descriptive diagnosis, methylation was able to resolve approximately half (144, 49.8%) with high-confidence scores. Additional methods were able to resolve diagnostic uncertainty in 41.6% of the low-score cases. Tumor purity was significantly associated with classifier score (P = 1.15e-11). Deconvolution demonstrated that suspected glioblastomas (GBMs) matching as control/inflammatory brain tissue could be resolved into GBM methylation profiles, which provided a proof-of-concept approach to resolve tumor classification in the setting of low tumor purity. CONCLUSIONS: This work assesses the impact of a methylation classifier and additional methods in a consultative practice by defining the proportions with concordant vs change in diagnosis in a set of diagnostically challenging CNS tumors. We address approaches to low-confidence scores and confounding issues of low tumor purity.

Immuno-transcriptomic profiling of extracranial pediatric solid malignancies.

We perform an immunogenomics analysis utilizing whole-transcriptome sequencing of 657 pediatric extracranial solid cancer samples representing 14 diagnoses, and additionally utilize transcriptomes of 131 pediatric cancer cell lines and 147 normal tissue samples for comparison. We describe patterns of infiltrating immune cells, T cell receptor (TCR) clonal expansion, and translationally relevant immune checkpoints. We find that tumor-infiltrating lymphocytes and TCR counts vary widely across cancer types and within each diagnosis, and notably are significantly predictive of survival in osteosarcoma patients. We identify potential cancer-specific immunotherapeutic targets for adoptive cell therapies including cell-surface proteins, tumor germline antigens, and lineage-specific transcription factors. Using an orthogonal immunopeptidomics approach, we find several potential immunotherapeutic targets in osteosarcoma and Ewing sarcoma and validated PRAME as a bona fide multi-pediatric cancer target. Importantly, this work provides a critical framework for immune targeting of extracranial solid tumors using parallel immuno-transcriptomic and -peptidomic approaches.

Whole-exome sequencing reveals germline-mutated small cell lung cancer subtype with favorable response to DNA repair-targeted therapies.

Because tobacco is a potent carcinogen, secondary causes of lung cancer are often diminished in perceived importance. To assess the extent of inherited susceptibility to small cell lung cancer (SCLC), the most lethal type of lung cancer, we sequenced germline exomes of 87 patients (77 SCLC and 10 extrapulmonary small cell) and considered 607 genes, discovering 42 deleterious variants in 35 cancer-predisposition genes among 43.7% of patients. These findings were validated in an independent cohort of 79 patients with SCLC. Loss of heterozygosity was observed in 3 of 14 (21.4%) tumors. Identification of variants influenced medical management and family member testing in nine (10.3%) patients. Unselected patients with SCLC were more likely to carry germline RAD51 paralog D (RAD51D), checkpoint kinase 1 (CHEK1), breast cancer 2 (BRCA2), and mutY DNA glycosylase (MUTYH) pathogenic variants than healthy controls. Germline genotype was significantly associated with the likelihood of a first-degree relative with cancer or lung cancer (odds ratio: 1.82, P = 0.008; and 2.60, P = 0.028), and longer recurrence-free survival after platinum-based chemotherapy (P = 0.002), independent of known prognostic factors. Treatment of a patient with relapsed SCLC and germline pathogenic mutation of BRCA1 interacting protein C-terminal helicase 1 (BRIP1), a homologous recombination-related gene, using agents synthetically lethal with homologous recombination deficiency, resulted in a notable disease response. This work demonstrates that SCLC, currently thought to result almost exclusively from tobacco exposure, may have an inherited predisposition and lays the groundwork for targeted therapies based on the genes involved.

Tremelimumab in Combination With Microwave Ablation in Patients With Refractory Biliary Tract Cancer.

Treatment options for patients with advanced biliary tract cancer are limited. Dysregulation of the immune system plays an important role in the pathogenesis of biliary tract cancer (BTC). This study aimed to investigate whether tremelimumab, an anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor, could be combined safely with microwave ablation to enhance the effect of anti-CTLA4 treatment in patients with advanced BTC. Patients were enrolled to receive monthly tremelimumab (10 mg/kg, intravenously) for six doses, followed by infusions every 3 months until off-treatment criteria were met. Thirty-six days after the first tremelimumab dose, patients underwent subtotal microwave ablation. Interval imaging studies were performed every 8 weeks. Adverse events (AEs) were noted and managed. Tumor and peripheral blood samples were collected to perform immune monitoring and whole-exome sequencing (WES). Twenty patients with refractory BTC were enrolled (median age, 56.5 years). No dose-limiting toxicities were encountered. The common treatment-related AEs included lymphopenia, diarrhea, and elevated transaminases. Among 16 patients evaluable for efficacy analysis, 2 (12.5%) patients achieved a confirmed partial response (lasting for 8.0 and 18.1 months, respectively) and 5 patients (31.3%) achieved stable disease. Median progression free survival (PFS) and overall survival (OS) were 3.4 months (95% confidence interval [CI], 2.5-5.2) and 6.0 months (95% CI, 3.8-8.8), respectively. Peripheral blood immune cell subset profiling showed increased circulating activated human leukocyte antigen, DR isotype ([HLA-DR] positive) CD8+ T cells. T-cell receptor (TCR)ß screening showed tremelimumab expanded TCR repertoire, but not reaching statistical significance (P = 0.057). Conclusion: Tremelimumab in combination with tumor ablation is a potential treatment strategy for patients with advanced BTC. Increased circulating activated CD8+ T cells and TCR repertoire expansion induced by tremelimumab may contribute to treatment benefit.

Keratomycosis due to Purpureocillium lilacinum: A case report from Sub-Himalayan region of Uttarakhand.

The fungus Purpureocillium lilacinum previously known as Paceliomyces lilacinus is an emerging pathogen that can cause severe human infections including devastating oculomycosis. Treatment with traditional antifungals often fails, and the organism shows variable susceptibility to novel triazoles. We hereby report a case of keratomycosis caused by Pur. lilacinum in an immunocompetent male patient following trauma. The patient was successfully treated with voriconazole. The drug shows good activity against Pur. lilacinum and could be a promising therapeutic alternative to treat infections caused by this fungus, which generally shows resistance to conventional antifungal agents including novel triazoles.

Inhibition of Spontaneous Contractility of Isolated Caprine Ureter by Flupirtine.

CONTEXT: Kv7 potassium channels are expressed in several types of smooth muscles and could mediate physiological responses in the tissues expressed. Flupirtine is an analgesic that acts by opening Kv7 potassium channels. It has been shown to inhibit the contractility of several types of isolated smooth muscle. AIMS: This study investigated the ability of flupirtine to inhibit the spontaneous contractility of isolated distal caprine (goat) ureter. SETTINGS AND DESIGN: Spontaneous contractility of the isolated goat ureter was recorded using a physiograph. MATERIALS AND METHODS: The ability of 1, 3, 10, 30, and 90 µM concentrations of flupirtine maleate to inhibit the spontaneous contractility of isolated distal goat ureter was investigated. The ability of the nonspecific potassium channel blocker 4-aminopyridine (4-AP; 1 mM) and the specific Kv7 channel blocker XE-991 (100 µM) to reverse the inhibitory effect of flupirtine on ureteric contractility was also investigated. STATISTICAL ANALYSIS USED: Both parametric and nonparametric statistical tests were used. RESULTS: At 10, 30, and 90 µM concentrations, flupirtine significantly inhibited the spontaneous contractility of the isolated goat ureter. The EC50 of flupirtine for a contact period of 10 min was 17.7 µM. The inhibitory effect of flupirtine on ureteric contractility was significantly reversed by 4-AP and XE-991. CONCLUSIONS: Flupirtine inhibits the spontaneous contractility of the isolated goat ureter by opening Kv7 channels.

An activating mutation of interferon regulatory factor 4 (IRF4) in adult T-cell leukemia.

The human T-cell leukemia virus-1 (HTLV-1) oncoprotein Tax drives cell proliferation and resistance to apoptosis early in the pathogenesis of adult T-cell leukemia (ATL). Subsequently, probably as a result of specific immunoediting, Tax expression is down-regulated and functionally replaced by somatic driver mutations of the host genome. Both amplification and point mutations of interferon regulatory factor 4 (IRF4) have been previously detected in ATL., K59R is the most common single-nucleotide variation of IRF4 and is found exclusively in ATL. High-throughput whole-exome sequencing revealed recurrent activating genetic alterations in the T-cell receptor, CD28, and NF-κB pathways. We found that IRF4, which is transcriptionally activated downstream of these pathways, is frequently mutated in ATL. IRF4 RNA, protein, and IRF4 transcriptional targets are uniformly elevated in HTLV-1-transformed cells and ATL cell lines, and IRF4 was bound to genomic regulatory DNA of many of these transcriptional targets in HTLV-1-transformed cell lines. We further noted that the K59R IRF4 mutant is expressed at higher levels in the nucleus than WT IRF4 and is transcriptionally more active. Expression of both WT and the K59R mutant of IRF4 from a constitutive promoter in retrovirally transduced murine bone marrow cells increased the abundance of T lymphocytes but not myeloid cells or B lymphocytes in mice. IRF4 may represent a therapeutic target in ATL because ATL cells select for a mutant of IRF4 with higher nuclear expression and transcriptional activity, and overexpression of IRF4 induces the expansion of T lymphocytes in vivo.

Knowledge-based prediction of protein backbone conformation using a structural alphabet.

Libraries of structural prototypes that abstract protein local structures are known as structural alphabets and have proven to be very useful in various aspects of protein structure analyses and predictions. One such library, Protein Blocks, is composed of 16 standard 5-residues long structural prototypes. This form of analyzing proteins involves drafting its structure as a string of Protein Blocks. Predicting the local structure of a protein in terms of protein blocks is the general objective of this work. A new approach, PB-kPRED is proposed towards this aim. It involves (i) organizing the structural knowledge in the form of a database of pentapeptide fragments extracted from all protein structures in the PDB and (ii) applying a knowledge-based algorithm that does not rely on any secondary structure predictions and/or sequence alignment profiles, to scan this database and predict most probable backbone conformations for the protein local structures. Though PB-kPRED uses the structural information from homologues in preference, if available. The predictions were evaluated rigorously on 15,544 query proteins representing a non-redundant subset of the PDB filtered at 30% sequence identity cut-off. We have shown that the kPRED method was able to achieve mean accuracies ranging from 40.8% to 66.3% depending on the availability of homologues. The impact of the different strategies for scanning the database on the prediction was evaluated and is discussed. Our results highlight the usefulness of the method in the context of proteins without any known structural homologues. A scoring function that gives a good estimate of the accuracy of prediction was further developed. This score estimates very well the accuracy of the algorithm (R2 of 0.82). An online version of the tool is provided freely for non-commercial usage at http://www.bo-protscience.fr/kpred/.

Somatic Variants in the Human Lens Epithelium: A Preliminary Assessment.

PURPOSE: We hypothesize that somatic mutations accumulate in cells of the human lens and may contribute to the development of cortical or posterior sub-capsular cataracts. Here, we used a Next-generation sequencing (NGS) strategy to screen for low-allelic frequency variants in DNA extracted from human lens epithelial samples. METHODS: Next-Generation sequencing of 151 cancer-related genes (WUCaMP2 panel) was performed on DNA extracted from post-mortem or surgical specimens obtained from 24 individuals. Usually, pairwise comparisons were made between two or more ocular samples from the same individual, allowing putative somatic variants detected in lens samples to be differentiated from germline variants. RESULTS: Use of a targeted hybridization approach enabled high sequence coverage (>1000-fold) of the WUCaMP2 genes. In addition to high-frequency variants (corresponding to homozygous or heterozygous SNPs and Indels), somatic variants with allelic frequencies of 1-4% were detected in the lens epithelial samples. The presence of one such variant, a T > C point substitution at position 32907082 in BRCA2, was verified subsequently using droplet digital PCR. CONCLUSIONS: Low-allelic fraction variants are present in the human lens epithelium, at frequencies consistent with the presence of millimeter-sized clones.

Proteinase activated receptor-2-mediated dual oxidase-2 up-regulation is involved in enhanced airway reactivity and inflammation in a mouse model of allergic asthma.

Airway epithelial cells (AECs) express a variety of receptors, which sense danger signals from various aeroallergens/pathogens being inhaled constantly. Proteinase-activated receptor 2 (PAR-2) is one such receptor and is activated by cockroach allergens, which have intrinsic serine proteinase activity. Recently, dual oxidases (DUOX), especially DUOX-2, have been shown to be involved in airway inflammation in response to Toll-like receptor activation. However, the association between PAR-2 and DUOX-2 has not been explored in airways of allergic mice. Therefore, this study investigated the contribution of DUOX-2/reactive oxygen species (ROS) signalling in airway reactivity and inflammation after PAR-2 activation. Mice were sensitized intraperitoneally with intact cockroach allergen extract (CE) in the presence of aluminium hydroxide followed by intranasal challenge with CE. Mice were then assessed for airway reactivity, inflammation, oxidative stress (DUOX-2, ROS, inducible nitric oxide synthase, nitrite, nitrotyrosine and protein carbonyls) and apoptosis (Bax, Bcl-2, caspase-3). Challenge with CE led to up-regulation of DUOX-2 and ROS in AECs with concomitant increases in airway reactivity/inflammation and parameters of oxidative stress, and apoptosis. All of these changes were significantly inhibited by intranasal administration of ENMD-1068, a small molecule antagonist of PAR-2 in allergic mice. Administration of diphenyliodonium to allergic mice also led to improvement of allergic airway responses via inhibition of the DUOX-2/ROS pathway; however, these effects were less pronounced than PAR-2 antagonism. The current study suggests that PAR-2 activation leads to up-regulation of the DUOX-2/ROS pathway in AECs, which is involved in regulation of airway reactivity and inflammation via oxidative stress and apoptosis.

Performance of common analysis methods for detecting low-frequency single nucleotide variants in targeted next-generation sequence data.

Next-generation sequencing (NGS) is becoming a common approach for clinical testing of oncology specimens for mutations in cancer genes. Unlike inherited variants, cancer mutations may occur at low frequencies because of contamination from normal cells or tumor heterogeneity and can therefore be challenging to detect using common NGS analysis tools, which are often designed for constitutional genomic studies. We generated high-coverage (>1000×) NGS data from synthetic DNA mixtures with variant allele fractions (VAFs) of 25% to 2.5% to assess the performance of four variant callers, SAMtools, Genome Analysis Toolkit, VarScan2, and SPLINTER, in detecting low-frequency variants. SAMtools had the lowest sensitivity and detected only 49% of variants with VAFs of approximately 25%; whereas the Genome Analysis Toolkit, VarScan2, and SPLINTER detected at least 94% of variants with VAFs of approximately 10%. VarScan2 and SPLINTER achieved sensitivities of 97% and 89%, respectively, for variants with observed VAFs of 1% to 8%, with >98% sensitivity and >99% positive predictive value in coding regions. Coverage analysis demonstrated that >500× coverage was required for optimal performance. The specificity of SPLINTER improved with higher coverage, whereas VarScan2 yielded more false positive results at high coverage levels, although this effect was abrogated by removing low-quality reads before variant identification. Finally, we demonstrate the utility of high-sensitivity variant callers with data from 15 clinical lung cancers.

Ocular chemical injuries and their management.

Chemical burns represent potentially blinding ocular injuries and constitute a true ocular emergency requiring immediate assessment and initiation of treatment. The majority of victims are young and exposure occurs at home, work place and in association with criminal assaults. Alkali injuries occur more frequently than acid injuries. Chemical injuries of the eye produce extensive damage to the ocular surface epithelium, cornea, anterior segment and limbal stem cells resulting in permanent unilateral or bilateral visual impairment. Emergency management if appropriate may be single most important factor in determining visual outcome. This article reviews the emergency management and newer techniques to improve the prognosis of patients with chemical injuries.

Cancer missense mutations alter binding properties of proteins and their interaction networks.

Many studies have shown that missense mutations might play an important role in carcinogenesis. However, the extent to which cancer mutations might affect biomolecular interactions remains unclear. Here, we map glioblastoma missense mutations on the human protein interactome, model the structures of affected protein complexes and decipher the effect of mutations on protein-protein, protein-nucleic acid and protein-ion binding interfaces. Although some missense mutations over-stabilize protein complexes, we found that the overall effect of mutations is destabilizing, mostly affecting the electrostatic component of binding energy. We also showed that mutations on interfaces resulted in more drastic changes of amino acid physico-chemical properties than mutations occurring outside the interfaces. Analysis of glioblastoma mutations on interfaces allowed us to stratify cancer-related interactions, identify potential driver genes, and propose two dozen additional cancer biomarkers, including those specific to functions of the nervous system. Such an analysis also offered insight into the molecular mechanism of the phenotypic outcomes of mutations, including effects on complex stability, activity, binding and turnover rate. As a result of mutated protein and gene network analysis, we observed that interactions of proteins with mutations mapped on interfaces had higher bottleneck properties compared to interactions with mutations elsewhere on the protein or unaffected interactions. Such observations suggest that genes with mutations directly affecting protein binding properties are preferably located in central network positions and may influence critical nodes and edges in signal transduction networks.