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HER2-positive breast cancers are among the most heterogeneous breast cancer subtypes. The early amplification of HER2 and its known oncogenic isoforms provide a plausible mechanism in which distinct programs of tumor heterogeneity could be traced to the initial oncogenic event. Here a Cancer rainbow mouse simultaneously expressing fluorescently barcoded wildtype (WTHER2), exon-16 null (d16HER2), and N-terminally truncated (p95HER2) HER2 isoforms is used to trace tumorigenesis from initiation to invasion. Tumorigenesis was visualized using whole-gland fluorescent lineage tracing and single-cell molecular pathology. We demonstrate that within weeks of expression, morphologic aberrations were already present and unique to each HER2 isoform. Although WTHER2 cells were abundant throughout the mammary ducts, detectable lesions were exceptionally rare. In contrast, d16HER2 and p95HER2 induced rapid tumor development. d16HER2 incited homogenous and proliferative luminal-like lesions which infrequently progressed to invasive phenotypes whereas p95HER2 lesions were heterogenous and invasive at the smallest detectable stage. Distinct cancer trajectories were observed for d16HER2 and p95HER2 tumors as evidenced by oncogene-dependent changes in epithelial specification and the tumor microenvironment. These data provide direct experimental evidence that intratumor heterogeneity programs begin very early and well in advance of screen or clinically detectable breast cancer. IMPLICATIONS: Although all HER2 breast cancers are treated equally, we show a mechanism by which clinically undetected HER2 isoforms program heterogenous cancer phenotypes through biased epithelial specification and adaptations within the tumor microenvironment.

Approximately 30% of breast cancer survivors deemed free of disease will experience locoregional or metastatic recurrence even up to 30 years after initial diagnosis, yet how residual/dormant tumor cells escape immunity elicited by the primary tumor remains unclear. We demonstrate that intrinsically dormant tumor cells are indeed recognized and lysed by antigen-specific T cells in vitro and elicit robust immune responses in vivo. However, despite close proximity to CD8+ killer T cells, dormant tumor cells themselves support early accumulation of protective FoxP3+ T regulatory cells (Tregs), which can be targeted to reduce tumor burden. These intrinsically dormant tumor cells maintain a hybrid epithelial/mesenchymal state that is associated with immune dysfunction, and we find that the tumor-derived, stem cell/basal cell protein Dickkopf WNT signaling pathway inhibitor 3 (DKK3) is critical for Treg inhibition of CD8+ T cells. We also demonstrate that DKK3 promotes immune-mediated progression of proliferative tumors and is significantly associated with poor survival and immunosuppression in human breast cancers. Together, these findings reveal that latent tumors can use fundamental mechanisms of tolerance to alter the T cell microenvironment and subvert immune detection. Thus, targeting these pathways, such as DKK3, may help render dormant tumors susceptible to immunotherapies.

The development of effective therapies against brain metastasis is currently hindered by limitations in our understanding of the molecular mechanisms driving it. Here we define the contributions of tumour-secreted exosomes to brain metastatic colonization and demonstrate that pre-conditioning the brain microenvironment with exosomes from brain metastatic cells enhances cancer cell outgrowth. Proteomic analysis identified cell migration-inducing and hyaluronan-binding protein (CEMIP) as elevated in exosomes from brain metastatic but not lung or bone metastatic cells. CEMIP depletion in tumour cells impaired brain metastasis, disrupting invasion and tumour cell association with the brain vasculature, phenotypes rescued by pre-conditioning the brain microenvironment with CEMIP+ exosomes. Moreover, uptake of CEMIP+ exosomes by brain endothelial and microglial cells induced endothelial cell branching and inflammation in the perivascular niche by upregulating the pro-inflammatory cytokines encoded by Ptgs2, Tnf and Ccl/Cxcl, known to promote brain vascular remodelling and metastasis. CEMIP was elevated in tumour tissues and exosomes from patients with brain metastasis and predicted brain metastasis progression and patient survival. Collectively, our findings suggest that targeting exosomal CEMIP could constitute a future avenue for the prevention and treatment of brain metastasis.

Introduction: Coronavirus Disease-2019 (COVID-19) Reporting and Data System (CO-RADS) score in Computed Tomography (CT) scan of the chest is a priority investigation in early identification of the disease. Although, a CT scan gives a clear parenchymal picture of the condition, it has its disadvantages of the cost and specificity in the prognosis of COVID-19. In addition, clinical studies have revealed its decreased utility in assessing the severity of the disease. Aim: To understand the correlation of the CO-RADS score with various inflammatory markers and explore the changes in CORADS score with the severity of COVID-19 infection. Materials and Methods: The present study is a retrospective observational study in a designated COVID-19 centre in Kolhapur, India. The radiological and pathological records of 64 cases for two months (September to October 2020) were reviewed and charted. The present study included all the cases over 18 years. The authors excluded pregnant women, patients with tuberculosis, interstitial lung disease, and pulmonary malignancy with a view of interference with the radiological presentation of COVID19. Along with demographics, biomarkers like Total Leucocyte Count (TLC), C-Reactive Protein (CRP), Lactate Dehydrogenase (LDH), D-Dimer, Interleukin-6 (IL-6), Procalcitonin (PCT), and serum ferritin were retrospectively reviewed and documented. The CO-RADS score, as reported by an expert radiologist, was noted down. Pearson’s correlation coefficient was used to correlate the CO-RADS score with various inflammatory markers. Results: The authors found significant high positive correlation of CT score with LDH (r=0.754; p-value

Although the majority of papillary thyroid cancer (PTC) is indolent, a subset of PTC behaves aggressively despite the best available treatment. A major clinical challenge is to reliably distinguish early on between those patients who need aggressive treatment from those who do not. Using a large cohort of PTC samples obtained from The Cancer Genome Atlas (TCGA), we analyzed the association between disease progression and multiple forms of genomic data, such as transcriptome, somatic mutations, and somatic copy number alterations, and found that genes related to FOXM1 signaling pathway were significantly associated with PTC progression. Integrative genomic modeling was performed, controlling for demographic and clinical characteristics, which included patient age, gender, TNM stages, histological subtypes, and history of other malignancy, using a leave-one-out elastic net model and 10-fold cross validation. For each subject, the model from the remaining subjects was used to determine the risk index, defined as a linear combination of the clinical and genomic variables from the elastic net model, and the stability of the risk index distribution was assessed through 2,000 bootstrap resampling. We developed a novel approach to combine genomic alterations and patient-related clinical factors that delineates the subset of patients who have more aggressive disease from those whose tumors are indolent and likely will require less aggressive treatment and surveillance (p = 4.62 × 10-10, log-rank test). Our results suggest that risk index modeling that combines genomic alterations with current staging systems provides an opportunity for more effective anticipation of disease prognosis and therefore enhanced precision management of PTC.

Background We previously demonstrated potent antitumor activity against human breast cancer xenografts using photodynamic therapy (PDT) targeting a novel tumor-specific photosensitizer (HS201), which binds heat shock protein 90 (HS201-PDT). However, induction of systemic antitumor immunity by HS201-PDT alone or by the combination strategy with immune checkpoint blockade has yet to be determined.Methods Using unilateral and bilateral implantation models of syngeneic breast tumors (E0771, MM3MG-HER2, and JC-HER3) in mice, we assessed whether HS201-PDT could induce local and systemic antitumor immunity. In an attempt to achieve a stronger abscopal effect for distant tumors, the combination strategy with anti-PD-L1 antibody was tested. Tumor-infiltrating leukocytes were analyzed by single cell RNA-sequencing and receptor-ligand interactome analysis to characterize in more detailed the mechanisms of action of the treatment and key signaling pathways involved.Results HS201-PDT demonstrated greater tumor control and survival in immune competent mice than in immunocompromised mice, suggesting the role of induced antitumor immunity; however, survival was modest and an abscopal effect on distant implanted tumor was weak. A combination of HS201-PDT with anti-PD-L1 antibody demonstrated the greatest antigen-specific immune response, tumor growth suppression, prolonged mouse survival time and abscopal effect. The most significant increase of intratumoral, activated CD8+T cells and decrease of exhausted CD8+T cells occurred following combination treatment compared with HS201-PDT monotherapy. Receptor-ligand interactome analysis showed marked enhancement of several pathways, such as CXCL, GALECTIN, GITRL, PECAM1 and NOTCH, associated with CD8+T cell activation in the combination group. Notably, the expression of the CXCR3 gene signature was the highest in the combination group, possibly explaining the enhanced tumor infiltration by T cells.Conclusions The increased antitumor activity and upregulated CXCR3 gene signature induced by the combination of anti-PD-L1 antibody with HS201-PDT warrants the clinical testing of HS201-PDT combined with PD-1/PD-L1 blockade in patients with breast cancer, and the use of the CXCR3 gene signature as a biomarker.

Background The majority of colorectal carcinomas (CRCs) are insensitive to programmed death protein-1/programmed death-ligand 1 (anti-PD-1/PD-L1) immune checkpoint inhibitor (ICI) antibodies. While there are many causes for ICI insensitivity, recent studies suggest that suppression of innate immune gene expression in tumor cells could be a root cause of this insensitivity and an important factor in the evolution of tumor immunosuppression.Methods We first assessed the reduction of mitochondrial antiviral signaling gene (MAVS) and related RIG-I pathway gene expression in several patient RNA expression datasets. We then engineered MAVS expressing tumor cells and tested their ability to elicit innate and adaptive anti-tumor immunity using both in vitro and in vivo approaches, which we then confirmed using MAVS expressing viral vectors. Finally, we observed that MAVS stimulated PD-L1 expression in multiple cell types and then assessed the combination of PD-L1 ICI antibodies with MAVS tumor expression in vivo.Results MAVS was significantly downregulated in CRCs, but its re-expression could stimulate broad cellular interferon-related responses, in both murine and patient-derived CRCs. In vivo, local MAVS expression elicited significant anti-tumor responses in both immune-sensitive and insensitive CRC models, through the stimulation of an interferon responsive axis that provoked tumor antigen-specific adaptive immunity. Critically, we found that tumor-intrinsic MAVS expression triggered systemic adaptive immune responses that enabled abscopal CD8 +T cell cytotoxicity against distant CRCs. As MAVS also induced PD-L1 expression, we further found synergistic anti-tumor responses in combination with anti-PD-L1 ICIs.Conclusion These data demonstrate that intratumoral MAVS expression results in local and systemic tumor antigen-specific T cell responses, which could be combined with PD-L1 ICI to permit effective anti-tumor immunotherapy in ICI resistant cancers.

Context: Chronic diseases such as diabetes, hypertension, and respiratory diseases are affecting the younger age groups occurring across the world. Raised blood pressure in children is increasing at an alarming rate. Aims: The aim was to study the prevalence of hypertension and prehypertension among children of schools in rural health training center area of a tertiary care hospital in Nagpur, Maharashtra, and to find any association between generalized obesity and central obesity with hypertension/prehypertension. Settings and Design: A cross-sectional study was conducted in the schools under the administrative cover of Indira Gandhi Government Medical College, Nagpur. Materials and Methods: Schoolchildren who had completed 10 years and not more than 13 years, whose parents gave consent, who gave assent, and apparently healthy were included in the study. The demographic particulars such as age and gender were collected using the case record form. Anthropometric measurements and blood pressure were measured using the standard guidelines. Statistical Analysis Used: Qualitative variables expressed in terms of percentages and quantitative in terms of mean and standard deviation. Chi-square test for trend and Student's t-test were used. Results: The prevalence of hypertension and prehypertension was 3.57% and 6.25%, respectively. We found a significant association between hypertension/prehypertension with waist-to-hip ratio of the children (P < 0.05). Conclusions: We found a higher prevalence of hypertension and prehypertension among the schoolchildren in rural areas, and we found a significant association between central obesity and hypertension/prehypertension.

Abstract Background To evaluate the association of patient and IVF cycle characteristics with blastulation rate and formation of high-quality blastocysts Results We analyzed autologous blastocyst cycles from 2013 to 2017. Cycles were subdivided into low ( 66%) blastulation rates. Embryo quality was assigned by embryologists using Gardner Criteria. R statistical package was used, and the blastulation groups were compared using analysis of variance (ANOVA) for continuous variables and chi-squared tests for categorical variables. The Bonferroni correction was used to adjust for multiple comparisons. One hundred seventeen IVF cycles met our inclusion criteria. Of these, 20 (17.1%) had low, 74 (63.2%) had intermediate, and 23 (19.7%) had high blastulation rates. Low blastulation rate was associated with a lower number of blastocysts, including fewer high-quality blastocysts. The mean number of oocytes retrieved was highest (18.1) in the group with the lowest blastulation rate, and lowest (13.4) in those with the highest blastulation rate, although this did not reach statistical significance. There were no significant differences between blastulation rates and age, gravidity, prior live birth, anti-mullerian hormone, estradiol and progesterone levels on the day of ovulation trigger, follicle-stimulating hormone dose, or fertility diagnosis. Conclusions High blastulation rate is associated with a greater number of blastocysts, including a greater number of high-quality blastocysts. Higher oocyte yield, however, is not associated with improved blastulation rates. Blastulation rates, blastocyst number, and quality remain difficult to predict based on cycle characteristics alone, and oocyte yield may not be an accurate predictor of either outcome.

Despite effective antiretroviral therapy (ART), mild forms of HIV-associated neurocognitive disorders (HAND) continue to afflict approximately half of all people living with HIV (PLWH). As PLWH age, HIV-associated inflammation perturbs the balance between brain matrix metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs), likely contributing to neuropathogenesis. The MMP/TIMP balance is associated with cognition, learning, and memory, with TIMPs eliciting neuroprotective effects. Dysregulation of the MMP/TIMP balance was evident in the brains of PLWH where levels of TIMP-1, the inducible family member, were significantly lower than non-infected controls, and MMPs were elevated. Here, we evaluated the MMP/TIMP levels in the doxycycline (DOX)-induced glial fibrillary acidic protein promoter-driven HIV-1 transactivator of transcription (Tat) transgenic mouse model. The HIV-1 protein Tat is constitutively expressed by most infected cells, even during ART suppression of viral replication. Many studies have demonstrated indirect and direct mechanisms of short-term Tat-associated neurodegeneration, including gliosis, blood-brain barrier disruption, elevated inflammatory mediators and neurotoxicity. However, the effects of acute vs. prolonged exposure on Tat-induced dysregulation remain to be seen. This is especially relevant for TIMP-1 as expression was previously shown to be differentially regulated in human astrocytes during acute vs. chronic inflammation. In this context, acute Tat expression was induced with DOX intraperitoneal injections over 3 weeks, while DOX-containing diet was used to achieve long-term Tat expression over 6 months. First, a series of behavior tests evaluating arousal, ambulation, anxiety, and cognition was performed to examine impairments analogous to those observed in HAND. Next, gene expression of components of the MMP/TIMP axis and known HAND-relevant inflammatory mediators were assessed. Altered anxiety-like, motor and/or cognitive behaviors were observed in Tat-induced (iTat) mice. Gene expression of MMPs and TIMPs was altered depending on the duration of Tat expression, which was independent of the HIV-associated neuroinflammation typically implicated in MMP/TIMP regulation. Collectively, we infer that HIV-1 Tat-mediated dysregulation of MMP/TIMP axis and behavioral changes are dependent on duration of exposure. Further, prolonged Tat expression demonstrates a phenotype comparable to asymptomatic to mild HAND manifestation in patients.

Paralysis of hypoglossal nerve is rare and often underreported. The paralysis leads to the deviation of tongue, dysarthria, dysphagia, and airway dysfunction, affecting the quality of life. We report a case of a middle-aged woman with malignancy of unknown origin with bone and brain metastasis who presented with unilateral deviation of the tongue. Detailed workup inferred with metastasis to the clivus bone which is related to the hypoglossal canal at the base of the skull and the primary origin could not be established. Intravenous steroids, radiotherapy, and systemic chemotherapy were helpful in improvement of the nerve palsy in our patient. Hypoglossal nerve palsy is often an underrated and underreported lesion; however, it can be a starting point for a major underlying problem.

Introduction: India is facing a dual burden of overweight/obesity and under nutrition among children less than 5 years of age. Neck circumference is recently studied marker for malnutrition among adults and older children. Objective: To correlate neck circumference with body mass index and to associate it with wasting and underweight status. Material & Methods: A cross sectional study was conducted among children less than 5 years of age attending the outpatient setup of a tertiary care setup in Nagpur, Maharashtra. Demographic details and anthropometric measurements were done for the children with necessary permission before the start of the study. Anthropometry was done using standard guidelines and WHO charts were used for classification of wasting and underweight Results: We included 260 study subjects in our study. The mean age of the children was 21.55 ± 17.31 months and majority of them were females, belonged to Hindu religion (58.07%), belonged to Class 4 (33.08%) and the mothers were educated up to senior secondary (34.62%). Neck circumference had significant positive correlation with birth weight (r=0.138) and body mass index (r=0.211). The average neck circumference was significantly lower in case of wasted (p< 0.05) and underweight children (p< 0.05). Conclusion: Neck circumference correlated significantly with body mass index and was significantly lower in wasted and underweight in children less than 5 years of age.