Disentangling and quantifying the relative cognitive impact of concurrent mixed neurodegenerative pathologies.

Neurodegenerative pathologies such as Alzheimer disease neuropathologic change (ADNC), Lewy body disease (LBD), limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and cerebrovascular disease (CVD) frequently coexist, but little is known about the exact contribution of each pathology to cognitive decline and dementia in subjects with mixed pathologies. We explored the relative cognitive impact of concurrent common and rare neurodegenerative pathologies employing multivariate logistic regression analysis adjusted for age, gender, and level of education. We analyzed a cohort of 6,262 subjects from the National Alzheimer's Coordinating Center database, ranging from 0 to 6 comorbid neuropathologic findings per individual, where 95.7% of individuals had at least 1 neurodegenerative finding at autopsy and 75.5% had at least 2 neurodegenerative findings. We identified which neuropathologic entities correlate most frequently with one another and demonstrated that the total number of pathologies per individual was directly correlated with cognitive performance as assessed by Clinical Dementia Rating (CDR®) and Mini-Mental State Examination (MMSE). We show that ADNC, LBD, LATE-NC, CVD, hippocampal sclerosis, Pick disease, and FTLD-TDP significantly impact overall cognition as independent variables. More specifically, ADNC significantly affected all assessed cognitive domains, LBD affected attention, processing speed, and language, LATE-NC primarily affected tests related to logical memory and language, while CVD and other less common pathologies (including Pick disease, progressive supranuclear palsy, and corticobasal degeneration) had more variable neurocognitive effects. Additionally, ADNC, LBD, and higher numbers of comorbid neuropathologies were associated with the presence of at least one APOE ε4 allele, and ADNC and higher numbers of neuropathologies were inversely correlated with APOE ε2 alleles. Understanding the mechanisms by which individual and concomitant neuropathologies affect cognition and the degree to which each contributes is an imperative step in the development of biomarkers and disease-modifying therapeutics, particularly as these medical interventions become more targeted and personalized.

Clinicopathologic Characteristics of PANDAS in a Young Adult: A Case Report.

Pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) is an acute onset or exacerbation of neuropsychiatric symptoms following a group A streptococcus infection. It is believed to be a result of autoimmune response to streptococcal infection, but there is insufficient evidence to fully support this theory. Although this disease is primarily thought to be a disease of childhood, it is reported to occur also in adults. PANDAS is a well-defined clinical entity, but the neuropathology of this condition has not been established yet. We describe the clinical course of a 26-year-old female diagnosed with PANDAS. She committed suicide and her brain was biobanked for further studies. We examined the banked tissue and performed special stains, immunohistochemical, and immunofluorescence analyses to characterize the neuropathology of this condition. Histology of the temporal lobes, hippocampus, and basal ganglia shows mild gliosis and Alzheimer's type II astrocytes. Acute hypoxic ischemic changes were noted in hippocampus CA1 and CA2 areas. Immunostaining shows increased parenchymal/perivascular GFAP staining and many vessels with mild increases in CD3-, CD4-, and CD25-stained lymphocytes in the basal ganglia. The findings suggest that CD4- and CD25-positive T cells might have an important role in understanding the neuroinflammation and pathogenesis of this condition. The case represents the first neuropathological evaluation report for PANDAS.

Abdominal wall intramuscular desmoid fibromatosis: a case report.

Desmoid tumors are rare benign myofibroblastic neoplasms that do not have metastatic potential. In this study, we report a case of a desmoid tumor in the left rectus abdominis muscle of a female patient. Computed tomography, abdominal ultrasound and magnetic resonance imaging were obtained preoperatively. We performed a complete resection with negative margins. Microscopic evaluation revealed a desmoid tumor. To definitively diagnose abdominal wall masses, imaging modalities must be used in conjunction with clinical history and histologic findings. For these masses, surgical resection is the preferred line of treatment.

Subcutaneous panniculitis-like T cell lymphoma arising in association with chronic lymphocytic leukaemia.

Subcutaneous panniculitis-like T cell lymphoma (SPTCL) is a rare cutaneous T cell malignancy of cytotoxic T cell origin. It is frequently associated with autoimmune diseases. It is known to preferentially involve subcutaneous adipose tissue and histologically resembles lupus panniculitis. The aetiology and risk factors of SPTCL are unclear and there are limited studies available since this entity was initially described in 2001. There are even fewer case reports describing the association between SPTCL and chronic lymphocytic leukemia (CLL). In this article, we present a case of SPTCL arising during treatment for CLL. We conducted an extensive review of literature to delve into the possible risk factors for SPTCL development in association with CLL, including pre-existing haematological malignancies, autoimmune conditions, immunomodulation and immunosuppressive chemotherapy.

Enhancing Colorectal Cancer Radiation Therapy Efficacy using Silver Nanoprisms Decorated with Graphene as Radiosensitizers.

Metal nanoparticles have significant interaction cross-sections with electromagnetic waves due to their large surface area-to-volume ratio, which can be exploited in cancer radiotherapy to locally enhance the radiation dose deposition in tumors. We developed a new type of silver nanoparticle composite, PEGylated graphene quantum dot (GQD)-decorated Silver Nanoprisms (pGAgNPs), that show excellent in vitro intracellular uptake and radiosensitization in radiation-sensitive HCT116 and relatively radiation-resistant HT29 colorectal cancer cells. Furthermore, following biodistribution analysis of intravenously injected nanoparticles in nude mice bearing HCT116 tumors radiosensitization was evaluated. Treatment with nanoparticles and a single radiation dose of 10 Gy significantly reduces the growth of colorectal tumors and increases the survival time as compared to treatment with radiation only. Our findings suggest that these novel nanoparticles offer a promising paradigm for enhancing colorectal cancer radiation therapy efficacy.

Whole Genome Sequencing and Comparative Genomic Analysis Reveal Allelic Variations Unique to a Purple Colored Rice Landrace (Oryza sativa ssp. indica cv. Purpleputtu).

Purpleputtu (Oryza sativa ssp. indica cv. Purpleputtu) is a unique rice landrace from southern India that exhibits predominantly purple color. This study reports the underlying genetic complexity of the trait, associated domestication and de-domestication processes during its coevolution with present day cultivars. Along-with genome level allelic variations in the entire gene repertoire associated with the purple, red coloration of grain and other plant parts. Comparative genomic analysis using 'a panel of 108 rice lines' revealed a total of 3,200,951 variants including 67,774 unique variations in Purpleputtu (PP) genome. Multiple sequence alignment uncovered a 14 bp deletion in Rc (Red colored, a transcription factor of bHLH class) locus of PP, a key regulatory gene of anthocyanin biosynthetic pathway. Interestingly, this deletion in Rc gene is a characteristic feature of the present-day white pericarped rice cultivars. Phylogenetic analysis of Rc locus revealed a distinct clade showing proximity to the progenitor species Oryza rufipogon and O. nivara. In addition, PP genome exhibits a well conserved 4.5 Mbp region on chromosome 5 that harbors several loci associated with domestication of rice. Further, PP showed 1,387 unique when SNPs compared to 3,023 lines of rice (SNP-Seek database). The results indicate that PP genome is rich in allelic diversity and can serve as an excellent resource for rice breeding for a variety of agronomically important traits such as disease resistance, enhanced nutritional values, stress tolerance, and protection from harmful UV-B rays.

Proton beam therapy outcomes for localized unresectable hepatocellular carcinoma.

BACKGROUND AND PURPOSE: This study documents the utilization and efficacy of proton beam therapy (PBT) in western patients with localized unresectable hepatocellular carcinoma (HCC). METHODS AND METHODS: Forty-six patients with HCC, Child-Pugh class of A or B, no prior radiotherapy history, and ECOG performance status 0-2 received PBT at our institution from 2007 to 2016. Radiographic control within the PBT field (local control, LC) and overall survival (OS) were calculated from the start of PBT. RESULTS: Most (83%) patients had Child-Pugh class A. Median tumor size was 6 cm (range, 1.5-21.0 cm); 22% of patients had multiple tumors and 28% had tumor vascular thrombosis. Twenty-five (54%) patients received prior treatment. Median biologically effective dose (BED) was 97.7 GyE (range, 33.6-144 GyE) administered in 15 fractions. Actuarial 2-year LC and OS rates were 81% and 62% respectively; median OS was 30.7 months. Out-of-field intrahepatic failure was the most common site of disease progression. Patients receiving BED ≥90 GyE had a significantly better OS than those receiving BED <90 GyE (49.9 vs. 15.8 months, p = 0.037). A trend toward 2-year LC improvement was observed in patients receiving BED ≥90 GyE compared with those receiving BED <90 GyE (92% vs. 63%, p = 0.096). On multivariate analysis, higher BED (p = 0.023; hazard ratio = 0.308) significantly predicted improved OS. Six (13%) patients experienced acute grade 3 toxicity. CONCLUSIONS: High-dose PBT is associated with high rates of LC and OS for unresectable HCC. Dose escalation may further improve outcomes.

Radiation-Induced Endothelial Vascular Injury: A Review of Possible Mechanisms.

In radiation therapy for cancer, the therapeutic ratio represents an optimal balance between tumor control and normal tissue complications. As improvements in the therapeutic arsenal against cancer extend longevity, the importance of late effects of radiation increases, particularly those caused by vascular endothelial injury. Radiation both initiates and accelerates atherosclerosis, leading to vascular events like stroke, coronary artery disease, and peripheral artery disease. Increased levels of proinflammatory cytokines in the blood of long-term survivors of the atomic bomb suggest that radiation evokes a systemic inflammatory state responsible for chronic vascular side effects. In this review, the authors offer an overview of potential mechanisms implicated in radiation-induced vascular injury.

A neoepitope derived from a novel human germline APC gene mutation in familial adenomatous polyposis shows selective immunogenicity.

Familial adenomatous polyposis (FAP) is an inherited condition arising from genetic defects in the Adenomatous polyposis coli (APC) gene. Carriers with mutations in the APC gene develop polyps in the colon and rectum which if not managed, transition into colon cancer. In this study, we identified a novel germline mutation in the APC gene in members of an FAP-affected (Familial adenomatous polyposis) family. This unique heterozygous variant (c.735_736insT; p.Ser246PhefsTer6) was identified in ten out of twenty six family members, ranging in age from 6 to 60 years. Polyps were detected in six of the ten individuals (35-60 years) carrying this mutation. The remaining four members (6-23 years) remain polyp free. A significant fraction of FAP affected individuals eventually develop colon cancer and therapeutic interventions to prevent cancer progression remain elusive. To address this issue, we sought to determine if peptides derived from the novel APC mutation could induce a cytotoxic T cell response, thereby qualifying them as vaccine candidates. Peptides harboring the variant amino acids were first interrogated in silico for their immunogenicity using a proprietary neoepitope prioritization pipeline, OncoPeptVAC. A single 9-mer peptide was predicted to be immunogenic. Remarkably, CD8+ T cells isolated from either an FAP+/ APCmut individual, or from a FAP-/ APCmut individual, failed to respond to the peptide, whereas those from either an unaffected family member (FAP-/ APCwt) or from healthy unrelated donors, showed a robust response, suggesting that CD8+ T cells from individuals carrying this germline APC mutation have been tolerized to the mutation. Furthermore, experimental testing of six additional reported APC gene mutation-derived peptides revealed one of the six to be immunogenic. While not all APC mutant peptides are inmmunogenic, a few qualify as vaccine candidates offering novel treatment opportunities to patients with somatic APC gene mutations to delay/treat colorectal cancer.

A cancer vaccine approach for personalized treatment of Lynch Syndrome.

Lynch syndrome (LS) is a cancer predisposition disorder wherein patients have a 70-80% lifetime risk of developing colorectal cancers (CRC). Finding germline mutations in predisposing genes allows for risk assessment of CRC development. Here we report a germline heterozygous frame-shift mutation in the mismatch repair MLH1 gene which was identified in members of two unrelated LS families. Since defects in DNA mismatch repair genes generate frame-shift mutations giving rise to highly immunogenic neoepitopes, we postulated that vaccination with these mutant peptide antigens could offer promising treatment options to LS patients. To this end we performed whole-exome and RNA seq analysis on the blood and tumour samples from an LS-CRC patient, and used our proprietary neoepitope prioritization pipeline OncoPeptVAC to select peptides, and confirm their immunogenicity in an ex vivo CD8+ T cell activation assay. Three neoepitopes derived from the tumour of this patient elicited a potent CD8+ T cell response. Furthermore, analysis of the tumour-associated immune infiltrate revealed CD8+ T cells expressing low levels of activation markers, suggesting mechanisms of immune suppression at play in this relapsed tumour. Taken together, our study paves the way towards development of a cancer vaccine to treat or delay the onset/relapse of LS-CRC.

Imaging predictors of treatment outcomes in rectal cancer: An overview.

The treatment protocols for rectal cancer continue to evolve, with increasing acceptance of a watch-and-wait policy for clinical complete responders to neoadjuvant chemoradiation therapy. It still, however, remains unclear who is likely to achieve a pathological complete response, which unequivocally portends a very favorable overall prognosis. Evolution of modern imaging techniques has paved the way for potential prediction of treatment response based on baseline, on-treatment, early post-treatment and subsequent follow-up imaging alone. Independent of tumor grade and stage, tumor marker levels, tumor size, radiation dose and fractionation, chemotherapy regimen, and extent/type of surgery, imaging biomarkers like circumferential resection margin (CRM), extramural venous space invasion (EMVI), imaging-based tumor regression grade, perfusion/diffusion-based functional imaging parameters, and imaging-based metabolic response have the ability to predict the likelihood of local recurrence and/or distant metastases. Textural features of images can add a further dimension to the predictive power of imaging. Finally, integration of genomic data with imaging biomarkers can potentially discern molecular mechanisms associated with distinct radiographic attributes of tumors. In this review, we evaluate and summarize the evidence to date of each imaging modality as a biomarker and its contribution to personalized decision making in rectal cancer.

Identification of deletion-duplication in HEXA gene in five children with Tay-Sachs disease from India.

BACKGROUND: Tay-Sachs disease (TSD) is a sphingolipid storage disorder caused by mutations in the HEXA gene. To date, nearly 170 mutations of HEXA have been described, including only one 7.6 kb large deletion. METHODS: Multiplex Ligation-dependent Probe Amplification (MLPA) study was carried out in 5 unrelated patients for copy number changes where heterozygous and/or homozygous disease causing mutation/s could not be identified in the coding region by sequencing of HEXA gene. RESULTS: The study has identified the presence of a homozygous deletion of exon-2 and exon-3 in two patients, two patient showed compound heterozygosity with exon 1 deletion combined with missense mutation p.E462V and one patient was identified with duplication of exon-1 with novel variants c.1527-2A > T as a second allele. CONCLUSION: This is the first report of deletion/duplication in HEXA gene providing a new insight into the molecular basis of TSD and use of MLPA assay for detecting large copy number changes in the HEXA gene.

Gold-Small Interfering RNA as Optically Responsive Nanostructures for Cancer Theranostics.

Small interfering RNA (siRNA), with its highly sequence-specific ability to modulate target gene expression, is seen as a promising therapeutic approach in cancer therapy. However, the major impediments to widespread clinical utilization are the optimal and durable targeting of target genes and safe and effective delivery of siRNA to the site of interest in the tumor niche. In this review, we will discuss gold nanocarriers with varied geometries and architecture as siRNA delivery vehicles for targeted cancer treatment. In addition, the gold nanostructures provide optical imaging functionalities as well as the ability to optically track delivery of siRNA to the cancer site, thus enabling true theranostics.

Radiation therapy and immunotherapy: what is the optimal timing or sequencing?

Radiotherapy is a component of the standard of care for many patients with locally advanced nonmetastatic tumors and increasingly those with oligometastatic tumors. Despite encouraging advances in local control and progression-free and overall survival outcomes, continued manifestation of tumor progression or recurrence leaves room for improvement in therapeutic efficacy. Novel combinations of radiation with immunotherapy have shown promise in improving outcomes and reducing recurrences by overcoming tumor immune tolerance and evasion mechanisms via boosting the immune system's ability to recognize and eradicate tumor cells. In this review, we discuss preclinical and early clinical evidence that radiotherapy and immunotherapy can improve treatment outcomes for locally advanced and metastatic tumors, elucidate underlying molecular mechanisms and address strategies to optimize timing and sequencing of combination therapy for maximal synergy.

Radiation-Induced Cardiovascular Disease: A Clinical Perspective.

Cancer survival has improved dramatically, and this has led to the manifestation of late side effects of multimodality therapy. Radiation (RT) to the thoracic malignancies results in unintentional irradiation of the cardiac chambers. RT-induced microvascular ischemia leads to disruption of capillary endothelial framework, and injury to differentiated myocytes results in deposition of collagen and fibrosis. Coexistence of risk factors of metabolic syndrome and preexisting atherosclerosis in addition to RT exposure results in accelerated occurrence of major coronary events. Hence, it becomes pertinent to understand the underlying pathophysiology and clinical manifestations of RT-induced cardiovascular disease to devise optimal preventive and surveillance strategies.

Prevalence of genetic variants associated with cardiovascular disease risk and drug response in the Southern Indian population of Kerala.

BACKGROUND AND AIM: This study reports the prevalence of five clinically significant variants associated with increased risk of cardiovascular disorders, and variable responses of individuals to commonly prescribed cardiovascular drugs in a South Indian population from the state of Kerala. MATERIALS AND METHODS: Genomic DNA isolated from 100 out-patient samples from Kerala were sequenced to examine the frequency of clinically relevant polymorphisms in the genes MYBPC3 (cardiomyopathy), SLCO1B1 (statin-induced myopathy), CYP2C9, VKORC1 (response to warfarin) and CYP2C19 (response to clopidogrel). RESULTS: Our analyses revealed the frequency of a 25 bp deletion variant of MYBPC3 associated with risk of cardiomyopathy was 7%, and the SLCO1B1 "C" allele associated with risk for statin-induced myopathy was 15% in this sample group. Among the other variants associated with dose-induced toxicity of warfarin, VKORC1 (c.1639G>A), was detected at 22%, while CYP2C9*3 and CYP2C9*2 alleles were present at a frequency of 15% and 3% respectively. Significantly, the tested sample population showed high prevalence (66%) of CYP2C19*2 variant, which determines response to clopidogrel therapy. CONCLUSIONS: We have identified that certain variants associated with cardiovascular disease and related drug response in the five genes, especially those in VKORC1, CYP2C19 and MYBPC3, are highly prevalent in the Kerala population, with almost 2 times higher prevalence of CYP2C19*2 variant compared with other regions in the country. Since the variants chosen in this study have relevance in disease phenotype and/or drug response, and are detected at a higher frequency, this study is likely to encourage clinicians to perform genetic testing before prescribing therapy.

Haplotype structures and functional polymorphic variants of the drug target enzyme aromatase (CYP19A1) in South Indian population.

CYP19A1 gene product aromatase (CYP19A1) is a 58-kDa protein and belongs to the member of the cytochrome P450 superfamily, which facilitates the bioconversion of estrogens from androgens. Single-nucleotide polymorphisms (SNPs) of CYP19A1 affect the activity of the enzyme and have been implicated in the association of estrogen-dependent disease, prognosis, therapeutic efficacy, and toxicity of third-generation aromatase inhibitors (AIs). Based on ethnicity, the frequency distribution of CYP19A1 alleles will differ, and until now, no data are available for Indians. Using qRT-PCR with TaqMan assays, the frequencies of functionally important polymorphic variants of CYP19A1 gene were determined in 163 healthy subjects of South Indian origin. The observed frequencies of the CYP19A1 minor alleles for the SNPs rs4646 (T), rs10046 (T), rs700519 (T), rs700518 (G), rs727479 (G), rs4775936 (T), rs10459592 (G), rs749292 (A), rs6493497 (T), and rs7176005 (A) are 41.1 (35.8-46.4), 20.0 (15.6-24.3), 33.7 (28.6-38.9), 17.8 (13.6-21.9), 25.8 (21.0-30.5), 19.9 (15.6-24.3), 33.7 (28.6-38.9), 24.9 (20.2-29.5), 35.9 (30.7-41.1), and 35.9 (30.7-41.1), respectively. Strong linkage disequilibrium existed between CYP19A1 SNPs, and sixteen different haplotype structures with a frequency >1% were derived from all the 10 SNPs tested. The most common being the haplotype (H1) GCTATCTGTG with a frequency of about 17.8%. Gender-specific assessment showed significant difference in the allele frequency for rs749292 (p < 0.04), and greater inter-ethnic variation was detected in the distribution of CYP19A1 variants except for rs727479. Our results could provide preliminary insight for further pharmacogenetic investigations of AIs as well as for subsequent molecular epidemiological studies on the contribution of these variants to the occurrence and development of estrogen-dependent disease in South Indians.

The relationship between visual analysis and five statistical analyses in a simple AB single-case research design.

This study explored some practical issues for single-case researchers who rely on visual analysis of graphed data, but who also may consider supplemental use of promising statistical analysis techniques. The study sought to answer three major questions: (a) What is a typical range of effect sizes from these analytic techniques for data from "effective interventions"? (b) How closely do results from these same analytic techniques concur with visual-analysis-based judgments of effective interventions? and (c) What role does autocorrelation play in interpretation of these analytic results? To answer these questions, five analytic techniques were compared with the judgments of 45 doctoral students and faculty, who rated intervention effectiveness from visual analysis of 35 fabricated AB design graphs. Implications for researchers and practitioners using single-case designs are discussed.