A Probabilistic Digital Twin for Leak Localization in Water Distribution Networks Using Generative Deep Learning.

Localizing leakages in large water distribution systems is an important and ever-present problem. Due to the complexity originating from water pipeline networks, too few sensors, and noisy measurements, this is a highly challenging problem to solve. In this work, we present a methodology based on generative deep learning and Bayesian inference for leak localization with uncertainty quantification. A generative model, utilizing deep neural networks, serves as a probabilistic surrogate model that replaces the full equations, while at the same time also incorporating the uncertainty inherent in such models. By embedding this surrogate model into a Bayesian inference scheme, leaks are located by combining sensor observations with a model output approximating the true posterior distribution for possible leak locations. We show that our methodology enables producing fast, accurate, and trustworthy results. It showed a convincing performance on three problems with increasing complexity. For a simple test case, the Hanoi network, the average topological distance (ATD) between the predicted and true leak location ranged from 0.3 to 3 with a varying number of sensors and level of measurement noise. For two more complex test cases, the ATD ranged from 0.75 to 4 and from 1.5 to 10, respectively. Furthermore, accuracies upwards of 83%, 72%, and 42% were achieved for the three test cases, respectively. The computation times ranged from 0.1 to 13 s, depending on the size of the neural network employed. This work serves as an example of a digital twin for a sophisticated application of advanced mathematical and deep learning techniques in the area of leak detection.

Dual targeting of mitochondrial Lon peptidase 1 and chymotrypsin-like protease by small molecule BT317, as potential therapeutics in malignant astrocytoma.

Malignant astrocytomas are aggressive glioma tumors characterized by extensive hypoxia-induced, mito-chondria-dependent changes such as altered respiration, increased chymotrypsin-like (CT-L) proteasome activity, decreased apoptosis, drug resistance, stemness and increased invasiveness. Mitochondrial Lon Peptidase I (LonP1) overexpression and increased CT-L proteasome inhibitors activity are the biomarkers of aggressive high grade glioma phenotype, poor prognosis and found to be associated with recurrence and poor patient survival, and drugs targeting either LonP1 or the CT-L activity have anti-glioma activity in pre-clinical models. We here for the first time introduced and evaluated a novel small molecule, BT317, derived from coumarinic compound 4 (CC4) using structure-activity modeling which we found to inhibit both LonP1 and CT-L proteasome activity. Using gain-of-function and loss-of-function genetic models, we dis-covered that BT317 is more effective than the individual LonP1 or CT-L inhibition in increasing reactive oxy-gen species (ROS) generation and inducing apoptosis in high-grade astrocytoma lines. In vitro, BT317 had activity as a single agent but, more importantly, enhanced synergy with the standard of care commonly used chemotherapeutic temozolomide (TMZ). In orthotopic xenograft, patient derived glioma models, BT317 was able to cross the blood-brain barrier, to show selective activity at the tumor site and to demonstrate therapeutic efficacy both as a single agent and in combination with TMZ. BT317 defines an emerging class of dual LonP1, and CT-L proteasome inhibitors exhibited promising anti-tumor activity and could be a promising candidate for clinical translation in the space of malignant astrocytoma therapeutics.

Integrin αvß3 Upregulation in Response to Nutrient Stress Promotes Lung Cancer Cell Metabolic Plasticity.

Cancer stem/tumor-initiating cells display stress tolerance and metabolic flexibility to survive in a harsh environment with limited nutrient and oxygen availability. The molecular mechanisms underlying this phenomenon could provide targets to prevent metabolic adaptation and halt cancer progression. Here, we showed in cultured cells and live human surgical biopsies of non-small cell lung cancer that nutrient stress drives the expression of the epithelial cancer stem cell marker integrin αvß3 via upregulation of the ß3 subunit, resulting in a metabolic reprogramming cascade that allows tumor cells to thrive despite a nutrient-limiting environment. Although nutrient deprivation is known to promote acute, yet transient, activation of the stress sensor AMP-activated protein kinase (AMPK), stress-induced αvß3 expression via Src activation unexpectedly led to secondary and sustained AMPK activation. This resulted in the nuclear localization of peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC1α) and upregulation of glutamine metabolism, the tricarboxylic acid cycle, and oxidative phosphorylation. Pharmacological or genetic targeting of this axis prevented lung cancer cells from evading the effects of nutrient stress, thereby blocking tumor initiation in mice following orthotopic implantation of lung cancer cells. These findings reveal a molecular pathway driven by nutrient stress that results in cancer stem cell reprogramming to promote metabolic flexibility and tumor initiation. SIGNIFICANCE: Upregulation of integrin αvß3, a cancer stem cell marker, in response to nutrient stress activates sustained AMPK/PGC1α signaling that induces metabolic reprogramming in lung cancer cells to support their survival. See related commentary by Rainero, p. 1543.

Pancreatic cancer cells upregulate LPAR4 in response to isolation stress to promote an ECM-enriched niche and support tumour initiation.

Defining drivers of tumour initiation can provide opportunities to control cancer progression. Here we report that lysophosphatidic acid receptor 4 (LPAR4) becomes transiently upregulated on pancreatic cancer cells exposed to environmental stress or chemotherapy where it promotes stress tolerance, drug resistance, self-renewal and tumour initiation. Pancreatic cancer cells gain LPAR4 expression in response to stress by downregulating a tumour suppressor, miR-139-5p. Even in the absence of exogenous lysophosphatidic acid, LPAR4-expressing tumour cells display an enrichment of extracellular matrix genes that are established drivers of cancer stemness. Mechanistically, upregulation of fibronectin via an LPAR4/AKT/CREB axis is indispensable for LPAR4-induced tumour initiation and stress tolerance. Moreover, ligation of this fibronectin-containing matrix via integrins α5ß1 or αVß3 can transfer stress tolerance to LPAR4-negative cells. Therefore, stress- or drug-induced LPAR4 enhances cell-autonomous production of a fibronectin-rich extracellular matrix, allowing cells to survive 'isolation stress' and compensate for the absence of stromal-derived factors by creating their own tumour-initiating niche.

Metabolic targeting of cancer by a ubiquinone uncompetitive inhibitor of mitochondrial complex I.

SMIP004-7 is a small molecule inhibitor of mitochondrial respiration with selective in vivo anti-cancer activity through an as-yet unknown molecular target. We demonstrate here that SMIP004-7 targets drug-resistant cancer cells with stem-like features by inhibiting mitochondrial respiration complex I (NADH:ubiquinone oxidoreductase, complex I [CI]). Instead of affecting the quinone-binding site targeted by most CI inhibitors, SMIP004-7 and its cytochrome P450-dependent activated metabolite(s) have an uncompetitive mechanism of inhibition involving a distinct N-terminal region of catalytic subunit NDUFS2 that leads to rapid disassembly of CI. SMIP004-7 and an improved chemical analog selectively engage NDUFS2 in vivo to inhibit the growth of triple-negative breast cancer transplants, a response mediated at least in part by boosting CD4+ and CD8+ T cell-mediated immune surveillance. Thus, SMIP004-7 defines an emerging class of ubiquinone uncompetitive CI inhibitors for cell autonomous and microenvironmental metabolic targeting of mitochondrial respiration in cancer.

Peripheral Inflammatory Blood Markers in Diagnosis of Glioma and IDH Status.

Objective Gliomas are the most common intracranial tumors. Histopathology and neuroimaging are the main modalities used for diagnosis and treatment response monitoring. However, both are expensive and insensitive methods and can cause neurological deterioration. This study aimed to develop a minimally invasive peripheral inflammatory biomarker for diagnosis of glioma, its grade, and isocitrate dehydrogenase (IDH) status. Materials and Methods Patients undergoing surgery for glioma, acoustic neuroma, and meningioma between January 2019 and December 2019 were included. Preoperative neutrophil/lymphocyte ratio (NLR), derived NLR (dNLR), platelet/lymphocyte ratio (PLR), lymphocyte/monocyte ratio (LMR), eosinophil/lymphocyte ratio (ELR), and prognostic nutritional index (PNI) were calculated. Histopathology and immunohistochemistry (IHC) staining were done postoperatively. Results A total of 154 patients of glioma, 36 patients of acoustic neuroma, 58 patients of meningioma, and 107 healthy controls were included. dNLR showed the maximum area under the curve (AUC) (0.656639) for diagnosis of glioma from other tumors and among combinations. dNLR +NLR showed the maximum AUC (0.647865). Maximum AUC for glioblastoma multiforme (GBM) versus other grades and among combinations was shown by NLR (0.83926). NLR + dNLR had the maximum AUC (0.764794). NLR showed significant p value in differentiating IDH wild from IDH mutant GBM. Conclusion dNLR has the maximum diagnostic value in diagnosing glioma from other tumors. NLR (AUC = 0.83926) showed the highest accuracy for GBM diagnosis and may be a parameter in predicting the grade of glioma; also, it has maximum diagnostic value in differentiating IDH wild GBM from IDH mutant GBM. These peripheral inflammatory parameters may prove to be sensitive and cost-effective markers for glioma diagnosis, predicting grade of glioma, monitoring of treatment response, and in predicting recurrence.

Tannic acid inhibits lipid metabolism and induce ROS in prostate cancer cells.

Prostate cancer (PCa) cells exploit the aberrant lipid signaling and metabolism as their survival advantage. Also, intracellular storage lipids act as fuel for the PCa proliferation. However, few studies were available that addressed the topic of targeting lipid metabolism in PCa. Here, we assessed the tannic acid (TA) lipid-targeting ability and its capability to induce endoplasmic reticulum (ER) stress by reactive oxygen species (ROS) in PCa cells. TA exhibited dual effects by inhibiting lipogenic signaling and suppression of lipid metabolic pathways. The expression of proteins responsible for lipogenesis was down regulated. The membrane permeability and functionality of PCa were severely affected and caused nuclear disorganization during drug exposure. Finally, these consolidated events shifted the cell's survival balance towards apoptosis. These results suggest that TA distinctly interferes with the lipid signaling and metabolism of PCa cells.

Prevalence, risk factors and pattern of severe retinopathy of prematurity in eastern Madhya Pradesh.

Purpose: To describe the prevalence, characteristics including risk factors, and pattern of severe ROP from eastern Madhya Pradesh region of India. Methods: In this 5-year retrospective study, Baseline characteristics, systemic risk factors, and findings of ROP screening were noted. Factors associated with severe ROP including aggressive posterior ROP (APROP), stage IV and V ROP were analyzed. Statistical analysis was done using SPSS version 20. Results: Of 763 babies screened, 30% were diagnosed to have ROP. Prevalence of severe ROP was 14.2% (109) of which 60 (55.5%) were classic and 30 (27.7%) were APROP. Eighteen (16.6%) were diagnosed as advanced ROP (stage IV and V). Mean gestational age (GA) and birth weight (BW) for severe ROP were 31.05 weeks and 1.34 kg, respectively which were inversely associated with severe ROP. But a significant 10% of severe ROP were seen in late preterm babies, >34 weeks. Low GA and respiratory distress syndrome (RDS) were significant risk factors for APROP. Most important factor for stage IV and V ROP was late presentation for screening. Conclusion: The study found a high prevalence of severe ROP including APROP. Almost 7% severe ROP cases were outside screening guidelines of NNF. Late presentation for screening is the most important factor associated with ROP related blindness.

Preoperative Diffusion Tensor Imaging: A Landmark Modality for Predicting the Outcome and Characterization of Supratentorial Intra-Axial Brain Tumors.

BACKGROUND AND OBJECTIVE: In view of the few large prospective studies available on the role of preoperative diffusion tensor imaging (DTI), and the potential of DTI in showing the relationship between tumor and white matter tracts, we studied the role of preoperative DTI in planning a safe surgical corridor, predicting the neurologic and surgical outcome and tumor characterization in supratentorial intra-axial brain tumors. METHODS: We included 128 cases. Preoperative neurologic status and tumor volume were assessed. A magnetic resonance imaging (MRI)-based surgical plan was decided and reviewed for changes after DTI (site of corticotomy or limit of resection) by senior faculty of neurosurgery and neuroradiologist. Tracts were classified as displaced, infiltrated, or disrupted. Postoperative neurologic and surgical outcome was assessed along with evaluation of association of DTI with tumor type. RESULTS: DTI-based change in surgical corridor was seen in 60 patients (47%). Sixty-six patients harbored low-grade gliomas, 48 had high-grade gliomas, and 14 had metastastic lesions. Resectability (maximum safe resection) was higher in patients with displaced fibers and lower in those with disrupted/infiltrated fibers, which was statistically significant. Fewer patients had neurologic deterioration in the displaced category (7.1%) compared with the disrupted/infiltrated category (13.9%). Although no significant association could be established between neurologic outcome and fiber type, displaced fibers were associated mainly with low-grade glioma (71%), whereas disrupted/infiltrated fibers were associated mainly with high-grade glioma (66%); this correlation was significant. CONCLUSIONS: Preoperative DTI is a landmark tool for planning a safe surgical corridor and predicting the tumor type along with neurologic and surgical outcome of patients.

Endoscopic versus Microscopic Pituitary Adenoma Surgery: An Institutional Experience.

AIM: The aim of this study was to compare the efficacy of endoscopic versus microscopic excision of pituitary adenoma, and to evaluate the merits and demerits of each approach. MATERIALS AND METHODS: Prospective data were collected and patients were surgically treated for pituitary adenoma at SMS Hospital, Jaipur, Rajasthan, India. Patients consent was obtained. Age, sex, presenting symptoms, length of hospital stay, pre- and post-operative hormone status, extent of resections of tumors, and intra- and post-operative complication were noted. RESULTS: A total of thirty patients with pituitary adenoma were operated transsphenoidally. Seventeen patients were operated by endonasal endoscopic transsphenoidal surgery and 13 patients were operated by microscopic transsphenoidal surgery. In an endoscopic group, complete tumor excision was achieved in 11 (64.71%) patients, and in microscopic group, it was achieved in 6 (46.15%) patients. In endoscopic group, mean operative time was 111.29 ± 21.95 min (ranged 80-135 min), and in microscopic group, it was 134.38 ± 8.33 min (ranged 120-145 min). In endoscopic group, mean blood loss was 124.41 ± 39.64 ml (60-190 ml), and in microscopic group, it was 174.62 ± 37.99 (100-220 ml). Postoperative sinusitis was present in 1 (5.88%) patient in endoscopic group and in 2 (15.38%) patients in microscopic group. CONCLUSION: Endoscopic approach provides a wide surgical field and broad lateral vision making easier distinction of tumor tissues. Thus, there is less blood loss, greater extent of tumor removal and it had less operative time, less postoperative complication, and early discharge from the hospital.

Use of Preoperative Ependymal Enhancement on Magnetic Resonance Imaging Brain as a Marker of Grade of Glioma.

OBJECTIVES: Neural stem cells within the subventricular zone (SVZ) are thought to be responsible for the origin and the heterogeneous nature of the gliomas. The relationship of the gliomas to the SVZ can be appreciated as ependymal enhancement on contrast magnetic resonance imaging (MRI). This study evaluates the rate of ependymal enhancement and its association with the histopathological grade of gliomas. PATIENTS AND METHODS: Seventy-five patients with radiological features of glioma were recruited. Preoperative MRI was evaluated for the presence of ependymal enhancement and fluid-attenuated inversion recovery (FLAIR) signal proximity of tumor to ependyma, and the association to grade was investigated. RESULTS: Seventy-five patients studied showed a male predominance (62.66%) with a mean age of 44.91 ± 13.64 years. Evidence of ependymal enhancement was positive in 24% (n = 18), 46.67% (n = 35) showed no evidence, and in 29.33% (n = 22), assessment was inconclusive. According to WHO grading, 76% (n = 57) were high-grade gliomas (HGGs) including Grade III (n = 17) and Grade IV (n = 40) and 24% (n = 18) were low-grade gliomas (LGGs) Grade II. HGGs were significantly associated with ependymal enhancement (P < 0.01) and FLAIR signal proximity to the ependyma (P < 0.001). Among HGGs, rate of ependymal enhancement and FLAIR signal proximity was more in Grade IV than Grade III but was not statistically significant (P > 0.05). CONCLUSION: SVZ is associated with HGGs. These MRI features can be helpful in predicting the tumor grade preoperatively and by including LGGs, the role of SVZ in the heterogeneous disease process of glioma can be studied as a whole, not only in the glioblastoma (GBM).

Gliosarcoma: A rare variant of glioblastoma multiforme in paediatric patient: Case report and review of literature.

Gliosarcoma is rare central nervous system tumour and a variant of glioblastoma multiforme with bimorphic histological pattern of glial and sarcomatous differentiation. It occurs in elderly between 5(th) and 6(th) decades of life and extremely rare in children. It is highly aggressive tumour and managed like glioblastoma multiforme. A 12-year-old female child presented with complaints of headache and vomiting from 15 d and blurring of vision from 3 d. Magnetic resonance imaging of brain shows heterogeneous mass in right parieto-occipital cortex. A right parieto-occipito-temporal craniotomy with complete excision of mass revealed a primary glioblastoma on histopathological investigation. Treatment consists of maximum surgical excision followed by adjuvant radiotherapy. The etiopathogenesis, treatment modalities and prognosis is discussed. The available literature is also reviewed.

Metabolomic analysis of molecular species of phospholipids from normotensive and preeclamptic human placenta electrospray ionization mass spectrometry.

Electrospray ionization mass spectrometry (ESI/MS) is a highly sensitive, fast and powerful technique for the metabolite and metabolomic analysis of mixtures of lipids in a biological extract. We have exploited this technique to identify and characterize various phospholipids present in the placenta of preeclamptic and normal pregnant women. Multiple major molecular species can be detected in each phospholipid class have arachidonic acid as major fatty acid constituent. There is no remarkable difference in the molecular composition in each of these phospholipids in both the extracts. However, there seems to be lower amounts of the plasmenyl phosphatidylethanolamine and greater amounts of free fatty acids in preeclamptic placenta.

Maxillary zoster with corneal involvement.

A case, of maxillary zoster with corneal involvement in a young patient is described. Corneal involvement in maxillary zoster (Medline search) is rare.

Huge malignant melanoma of caruncle with extensive involvement of conjunctiva.

The caruncle is nodular structure lying at internal canthus medial to plica semilunaris. It is composed of elements of conjunctiva, cutaneous and lacrimal tissue. In spite of its diverse histopathology, lesions of caruncle are rare and malignant melanoma is further rarer. This tumour is potentially lethal, even after prompt and proper treatment, especially after delayed onset of therapy. Clinical metastases usually occur first to the lymph nodes in approximately 45% to 60% of patients with regional metastases. Eventually systemic dissemination may occur to lung, brain, liver, skin, bone and the gastrointestinal tract, although this often arises without prior clinical evidence of regional lymph node involvement. Here a rare case of huge malignant melanoma of caruncle with extensive involvement of plica semilunaris, fornix and palpebral conjuctiva in a 58-years old male is reported who was treated with local excision combined with cryotherapy and topical 0.02% mitomycin-C eye drops.

Diabetic retinopathy: a preventable scourge.

In recent years, the India has witnessed a rapidly exploding epidemic of diabetes mellitus. It would not be hyperbolic to state that diabetes mellitus is the mother of morbidity of all vital organs. Diabetic retinopathy and its complications cause considerable ocular morbidity as well. With effective management strategies visual loss due to the disease can be controlled and further dissemination of the disease could be prevented. The key to proper management of diabetic retinopathy includes prophylaxis by controlling blood sugar, periodical screening of retina for early detection, prompt referral for prevention of progression by appropriate laser photocoagulation, surgical correction of various anatomical abnormalities, low vision aids and rehabilitative measures in patients with severe visual loss. Howerver, the awareness level of visual consequences of this widely prevalent disease even amongst diabetics is lacking.

Clonal divergence and genetic heterogeneity in clear cell renal cell carcinomas with sarcomatoid transformation.

BACKGROUND: Approximately 5% of clear cell renal cell carcinomas contain components with sarcomatoid differentiation. It has been suggested that the sarcomatoid elements arise from the clear cell tumors as a consequence of clonal expansions of neoplastic cells with progressively more genetic alterations. Analysis of the pattern of allelic loss and X-chromosome inactivation in both the clear cell and sarcomatoid components of the same tumor allows assessment of the genetic relationship of these tumor elements. METHODS: The authors of the current study examined the pattern of allelic loss in clear cell and sarcomatoid components of renal cell carcinomas from 22 patients who had tumors with both components. DNA samples were prepared from formalin-fixed, paraffin-embedded renal tissue sections using laser-capture microdissection. Five microsatellite polymorphic markers for putative tumor suppressor genes on 5 different chromosomes were analyzed. These included D3S1300 (3p14), D7S522 (7q31), D8S261 (8p21), D9S171 (9p21), and TP53 (17p13). In addition, X-chromosome inactivation analysis was performed in 14 tumors from female patients. RESULTS: The clear cell components showed loss of heterozygosity (LOH) at the D3S1300, D7S522, D8S261, D9S171, and TP53 loci in 18% (4/22), 18% (4/22), 50% (10/20), 15% (3/20), and 20% (4/20) of informative cases, respectively. LOH in the sarcomatoid components was seen at the D3S1300, D7S522, D8S261, D9S171, and TP53 loci in 18% (4/22), 41% (9/22), 70% (14/20), 35% (7/20), and 20% (4/20) of informative cases, respectively. Six cases demonstrated an LOH pattern in the clear cell component that was not seen in the sarcomatoid component. Different patterns of allelic loss were seen in the clear cell and sarcomatoid components in 15 cases. Clonality analysis showed the same pattern of nonrandom X-chromosome inactivation in both clear cell and sarcomatoid components in 13 of the 14 cases studied. One case showed a random pattern of X-chromosome inactivation. CONCLUSION: X-chromosome inactivation analysis data suggest that both clear cell and sarcomatoid components of renal cell carcinomas are derived from the same progenitor cell. Different patterns of allelic loss in multiple chromosomal regions were observed in clear cell and sarcomatoid components from the same patient. This genetic heterogeneity indicates genetic divergence during the clonal evolution of renal cell carcinoma.

Vitamin C enrichment of fruit juice based ready-to-serve beverages through blending of Indian gooseberry (Emblica officinalis Gaertn.) juice.

Physiconutritional qualities of fruits viz. apple, lime, pomegranate, Perlette grape, and Pusa Navrang grape were analyzed and compared with those of Indian gooseberry (Emblica officinalis Gaertn.). Indian gooseberry juice contained the highest vitamin C (478.56 mg/100 ml). Hence, when gooseberry juice was blended with other fruits' juice for the preparation of ready-to-serve (RTS) beverages, it boosted their nutritional quality in terms of vitamin C content. On the basis of overall sensory quality and vitamin C content, RTS beverage prepared by blending gooseberry and Pusa Navrang grape juice in 20:80 ratio was found to be the best.